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Metabolic agents in the contemporary treatment of angina

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Vol 38, No. 3, 2016
Medicographia
128
A Ser vier publication

Metabolic agents
in the contemporary
treatment of angina
E DITORIAL
245 Metabolic agents and angina treatment
F. J. Pinto, Portugal

T HEMED ARTICLES
251 Chronic ischemic heart disease: an energy imbalance
G. Guarini, M. Marzilli, Italy

257 Mitochondria as a therapeutic target in ischemia

D. J. Hausenloy, United Kingdom

264 The place of metabolic agents in contemporary coronary

artery disease guidelines
L. H. W. Gowdak, Brazil

271 Revascularization in angina patients: addressing

cardiac metabolism challenges
G. D. Lopaschuk, Canada

277 The endothelium: a therapeutic target in post-PCI patients and the role
of trimetazidine in endothelial function
S. Lim, South Korea

282 Metabolic agents in the protection of patients who undergo

revascularization
Y. Chen, China

288 How effective can trimetazidine be in preventing myocardial and

renal revascularization injury?
Y. Lopatin, Russia

Contents continued on next page

Vol 38, No. 3, 2016
Medicographia
128
A Ser vier publication

C ONTROVERSIAL QUESTION
297 Is targeting only stenosis sufficient to optimally improve angina?
P. S. Farsky, Brazil - L. O. Go, Philippines - H. Hasan-Ali, Egypt -
H. Q. T. Ho, Vietnam - D. Isaza-Restrepo, Colombia - T. Kovarnik,
Czech Republic - O. H. Masoli, Argentina - A. N. Parkhomenko and
O. S. Gurjeva, Ukraine - C. K. Ponde, India - V. Sansoy, Turkey -
D. Vassilev, Bulgaria

VASTAREL MR
309 Trimetazidine: targeting the cardiac cell in stable angina
M. Gliebova, France

I NTERVIEW
317 The ATPCI trial: a new international phase 3 study assessing the clinical
impact of adding a metabolic agent to post-PCI angina treatment
R. Ferrari, Italy

320 F OCUS
Combining hemodynamic and metabolic agents in ischemic
heart disease
G. Fragasso, Italy

U PDATE
328 History and evolution of coronary stenting
M. E. Bertrand, France

EDITORIAL
drugs that act directly by
increasing the energy supply in
cardiac cells are of use, whatever
the causal mechanism involved,
and as such are essential for the
optimal treatment of ischemia. To
Metabolic agents
protect myocardial cells from is-
chemia, energy supply needs to
match energy demand. b-Blockers
and angina treatment
have a positive impact, reducing
energy demand, while metabolic
agents, such as trimetazidine, in-
crease energy supply. That is why
the use of an agent like trimetazi-
dine fully complements b-blocker
therapy.

b y F. J . P i n t o , Po r t u g a l

hronic ischemic heart disease (IHD) and stable angina are a major clinical

C problem worldwide. the prevalence of stable angina is estimated to be

in the region of 20 000 to 50 000 per million in the general population.1,2
According to the rEACH (rEduction of Atherothrombosis for Continued
Health) registry of more than 38 000 patients, 3 in every 20 patients with established
coronary artery disease (CAD) has had a major event or been hospitalized within the
previous year.3

Fausto J. PINTO, MD, PhD,
FESC, FACC
Department of Cardiology
University Hospital Santa
Maria/CHLN, CCUL
University of Lisbon
Lisbon, PortUgAL
Despite great advances in the management of CAD patients in recent times, symp-
toms are still common in many patients, sometimes even after revascularization.
In the Heart and Soul Study, over a third (38%) of outpatients with stable CAD had
angina, ischemia, or both.1 A substantial number of patients with typical angina do
not have significant coronary atherosclerotic obstructions.4 Furthermore, the preva-
lence of coronary atherosclerotic obstruction in patients with or without typical angi-
na is similar and is age-related in both sexes.

the treatment of stable CAD includes several potential strategies, including revas-
cularization procedures (coronary artery bypass graft [CABg] or percutaneous coro-
nary intervention [PCI]) and pharmacotherapy.5 one of the potential strategies for
the treatment of CAD consists in targeting cardiac cells directly and in particular the
energetic origin of ischemia with the use of a metabolic agent, such as trimetazidine,
on top of b-blockers and other vasoactive agents.5

Myocardial ischemia is multifactorial and, above all, a deficiency

Address for correspondence:
Professor Fausto J. Pinto, Servio de
Cardiologia, Hospital de Santa Maria -
Centro Hospitalar de Lisboa Norte,
E.P.E., Av. Professor Egas Moniz,
Piso 08, 1649-035 Lisboa, Portugal
(email:
faustopinto@medicina.ulisboa.pt/
fpinto@icvl.pt)
Medicographia. 2016;38:245-250
www.medicographia.com
in energy
recent data clearly show that above and beyond coronary atherosclerotic obstruc-
tion, IHD is due to a large number of mechanisms, including coronary vasomotor,
microcirculatory, endothelial, and platelet dysfunction and inflammation, among oth-
ers.6 Because myocardial ischemia is multifactorial in nature, it should, above all,
be defined as a deficiency in energy (in the form of AtP, adenosine triphosphate)
at the cardiac cell level.7 Under conditions of energy deficit, drugs that act directly
by increasing the energy supply in cardiac cells are of use, whatever the causal mech-
anism involved, and as such are essential for the optimal treatment of ischemia.
to protect myocardial cells from ischemia, energy supply needs to match energy
demand. b-Blockers have a positive impact, reducing energy demand, while
metabolic agents, such as trimetazidine, increase energy supply. that is why the
use of an agent like trimetazidine fully complements b-blocker therapy.

Metabolic agents and angina treatment Pinto MEDICOGRAPHIA, Vol 38, No. 3, 2016 245
EDITORIAL
Trimetazidine + -blocker: an optimal combination
for reducing angina
the trIMPoL (trIMetazidine in PoLand) II study was one of
the first studies to test the use of a metabolic agent on top
of b-blockers in 426 patients with stable CAD.8 It was a ran-
domized, multicenter, double-blind, placebo-controlled par-
allel group study. Patients with documented CAD and stable,
effort-induced angina uncontrolled by metoprolol received
either placebo or trimetazidine 20 mg three times daily in ad-
dition to metoprolol 50 mg twice daily. In this study, 12 weeks
treatment with trimetazidine plus metoprolol significantly im-
proved treadmill exercise test parameters and significantly re-
duced clinical symptoms compared with placebo plus meto-
prolol. this was achieved without any further hemodynamic
changes in these patients. In addition to its antianginal effica-
cy, trimetazidine was well tolerated.
Michaelides et al performed a randomized, double-blind, con-
trolled trial in angina patients who were symptomatic despite
treatment with propranolol.9 the trial demonstrated that adding
trimetazidine to treatment significantly decreased the mean
number of angina attacks (63%) twice as much as adding
isosorbide dinitrate (31%). this finding might be explained by
the mode of action of trimetazidine, which provides a syner-
gistic and complementary approach to hemodynamic agents,
such as b-blockers. In a recent meta-analysis of almost 20 000
angina patients, trimetazidine was shown to be as effective
as calcium channel blockers or nitrates at reducing ischemia
and angina symptoms.10
Nesukay demonstrated that directly adding trimetazidine to
b-blockers in over 1400 patients with stable angina allowed for
a quick reduction in angina symptoms, regardless of whether
or not these patients who were on b-blockers were also on
nitrates or calcium channel blockers.11
Adding trimetazidine to -blockers: evidence of
improved prognosis in ischemic patients
In a recent heart failure registry, approximately 40% of chron-
ic heart failure patients were found to have heart failure of
ischemic origin.12 In a contemporary meta-analysis in nearly
SELECTED ABBREVIATIONS AND ACRONYMS
CABG coronary artery bypass graft
CAD coronary artery disease
DES drug-eluting stent
IHD ischemic heart disease
MACCE major adverse cerebrovascular or cardiovascular event
PCI percutaneous coronary intervention
REACH rEduction of Atherothrombosis for Continued Health
TRIMPOL trIMetazidine in PoLand
246 MEDICOGRAPHIA, Vol 38, No. 3, 2016
1000 patients with heart failure, of mainly ischemic origin (93%),
gao et al showed that adding trimetazidine significantly re-
duced all-cause mortality as well as cardiovascular events and
hospitalization for heart failure (P<0.01 versus placebo).13 In
postmyocardial infarction patients with stable angina and
heart failure, the use of modified-release trimetazidine was re-
lated to a significant reduction in major adverse cardiac events
(cardiac death, nonfatal myocardial infarction, acute stroke,
need for coronary revascularization, and hospitalization for
unstable angina or heart failure) after 6 years of follow-up.14
Adding trimetazidine to decrease ischemic
reperfusion injury during revascularization and
angina recurrence afterwards
Labrou et al have investigated whether the administration of
trimetazidine before and after PCI minimizes procedure-in-
duced myocardial damage and improves left ventricular func-
tion 1 and 3 months after PCI.15 twenty-four hours after PCI,
troponin I levels were >1 ng/mL in 26% of patients treated
with trimetazidine versus 44% of patients in the control group.
Forty-eight hours after revascularization, troponin levels re-
mained elevated in 15% vs 32% of patients. About a fifth
(22%) of patients in the trimetazidine group had creatine ki-
nase MB (CK-MB) levels >5 ng/mL, 24 hours after PCI, com-
pared with 40% in the control group.
the number of patients with an ejection fraction <50% was
significantly reduced in the trimetazidine-treated group com-
pared with the control group at 1 and 3 months after PCI:
11% versus 16% (P=0.046) after 1 month and 4% versus
16% (P=0.017) after 3 months. A significant improvement in
regional wall motion versus placebo was noted after treat-
ment with trimetazidine. the use of trimetazidine appeared to
minimize myocardial reperfusion injury during PCI and im-
proved global and regional wall motion 1 and 3 months after
PCI, according to the authors.
the incidence of stent restenosis has risen, as increasing
numbers of patients are treated with drug-eluting stents (DES).
Chen et al16 evaluated whether long-term treatment with tri-
metazidine reduced the incidence of stent restenosis in 768
patients who underwent PCI with DES. the group on long-
term trimetazidine treatment had a lower incidence of stent
restenosis compared with the control group (4.2% vs 11.1%;
P=0.001). At the 30-day follow-up, the trimetazidine patients
exhibited a higher left ventricular ejection fraction than con-
trol patients (65.410.7% vs 63.110.4%; P=0.006). the
incidence of major adverse cerebrovascular or cardiovascular
events (MACCEs) was also lower in the trimetazidine group
at 1-year follow-up (6.1% vs 10.8%; P=0.032). treatment
with trimetazidine was found to predict a reduction in stent
restenosis (odds ratio [or], 0.376; 95% CI, 0.196 to 0.721;
P=0.003). the authors concluded that trimetazidine treat-
ment effectively reduced the incidence of stent restenosis and
MACCEs 1 year after DES implantation.
Metabolic agents and angina treatment Pinto

Xu et al17 also appraised the effects of trimetazidine after DES
implantation on recurrent angina pectoris and left ventricular
structure in elderly patients with multivessel CAD and with di-
abetes mellitus and a left ventricular ejection fraction >50%.
After 2 years, patients in the trimetazidine group were shown
to have significant reductions in the incidence and severity
of angina pectoris, compared with the control group, as well
as a reduction in silent myocardial ischemia and increase in
angina pectorisfree survival. Left ventricular function and
structure in trimetazidine-treated patients were relatively sta-
ble after 2 years, but in control patients these parameters de-
teriorated. Adjunctive therapy with trimetazidine after DES
implantation appears to have a beneficial effect in preventing
recurrent angina pectoris as well as in improving left ventric-
ular function and structure in elderly multivessel CAD patients
with diabetes.
References
1. gehi AK, Ali S, Na B, Schiller NB, Whooley MA. Inducible ischemia and the
risk of recurrent cardiovascular events in outpatients with stable coronary heart
disease: the heart and soul study: the Heart and Soul Study. Arch Intern Med.
2008;168:1423-1428.
2. Leal J, Luengo-Fernndez r, gray A, Petersen S, rayner M Economic burden
of cardiovascular diseases in the enlarged European Union. Eur Heart J. 2006;
27:1610-1619.
3. Steg Pg, Bhatt DL, Wilson PW, et al; rEACH registry Investigators. one-year
cardiovascular event rates in outpatients with atherothrombosis. JAMA. 2007;
297:1197-1206.
4. Cheng VY, Berman DS, rozanski A, et al. Performance of the traditional age,
sex, and angina typicality-based approach for estimating pretest probability of
angiographically significant coronary artery disease in patients undergoing coro-
nary computed tomographic angiography: results from the multinational coro-
nary Ct angiography evaluation for clinical outcomes: an international multi-
center registry (CoNFIrM). Circulation. 2011;124:2423-2432.
5. Montalescot g, Sechtem U, Achenbach S, et al; task Force Members. 2013
ESC guidelines on the management of stable coronary artery disease: the task
Force on the management of stable coronary artery disease of the European
Society of Cardiology. Eur Heart J. 2013;34:2949-3003.
6. Crea F, Camici Pg, De Caterina r, Lanza gA. Chronic ischaemic heart disease.
In: Camm AJ, Lscher tF, Serruys PW, eds. The ESC Textbook of Cardiovas-
cular Medicine. 2nd ed. New York, NY: oxford University Press Inc.; 2009.
7. Marzilli M, Merz CN, Boden WE, et al. obstructive coronary atherosclerosis and
ischemic heart disease: an elusive link! J Am Coll Cardiol. 2012;60:951-956.
8. Szwed H, Sadowski Z, Elikowski W, et al. Combination treatment in stable ef-
fort angina using trimetazidine and metoprolol: results of a randomized, double-
blind, multicentre study (trIMPoL II). trIMetazidine in PoLand. Eur Heart J.
2001;22:2267-2274.
9. Michaelides AP, Spiropoulos K, Dimopoulos K, Athanasiades D, toutouzas P.
Antianginal efficacy of the combination of trimetazidine-propranolol compared
Keywords: b-blocker; cardiac metabolism; myocardial ischemia; revascularization; stable angina; trimetazidine
Metabolic agents and angina treatment Pinto
EDITORIAL
Conclusion
Chronic IHD is still a significant clinical burden in daily practice,
and in stable angina b-blockers and revascularization proce-
dures are extensively used treatments. Although the current
pharmacological treatment of angina with vasoactive agents
is effective, the addition to therapy of metabolic antianginal
agents that act directly at the cardiac cell level could provide
further treatment benefits, by targeting alternative mechanisms
of ischemia. Moreover, use of these metabolic agents during
and after revascularization procedures may also offer addition-
al benefits, by decreasing ischemic reperfusion injury and de-
creasing angina recurrence. targeting the cardiac cell directly
and addressing the energetic origin of ischemia with metabol-
ic agentssuch as trimetazidineon top of treatment with va-
soactive agentssuch as b-blockersseems a clinically per-
tinent strategy for managing IHD as effectively as possible.
with isosorbide dinitrate-propranolol in patients with stable angina. Clin Drug
Invest. 1997;13:8-14.
10. Danchin N, Marzilli M, Parkhomenko A, ribeiro JP. Efficacy comparison of tri-
metazidine with therapeutic alternatives in stable angina pectoris: a network
meta-analysis. Cardiology. 2011;120:59-72.
11. Nesukay E. Assessment of the most effective combination of antianginal med-
ications in the treatment of patients with stable angina pectoris. Circulation.
2012;125:e773. doi:10.1161/CIr.0b013e31824fcdb3. Poster P144.
12. Maggioni AP, Dahlstrm U, Filippatos g, et al; Heart Failure Association (HFA) of
the European Society of Cardiology. EUrobservational research Programme:
regional differences and 1-year follow-up results of the Heart Failure Pilot Survey
(ESC-HF Pilot). Eur J Heart Fail. 2013;15:808-817.
13. gao D, Ning N, Niu X, Hao g, Meng Z. trimetazidine: a meta-analysis of ran-
domised controlled trials in heart failure. Heart. 2011;97:278-286.
14. Lopatin YM, Ilyukhin oV, Ilyukhina MV, Kalganova EL, tarasov DL, Ivanenko VV.
Long-term trimetazidine modified release therapy improves prognosis in post-
myocardial infarction patients with angina pectoris and heart failure. Eur Heart
J. 2012;33(suppl abstract):346-347. Abstract 2052.
15. Labrou A, giannoglou g, Zioutas D, Fragakis N, Katsaris g, Louridas g. trimeta-
zidine administration minimizes myocardial damage and improves left ventric-
ular function after percutaneous coronary intervention. Am J Cardiovasc Drugs.
2007;7:143-150.
16. Chen J, Zhou S, Jin J, et al. Chronic treatment with trimetazidine after dis-
charge reduces the incidence of restenosis in patients who received coronary
stent implantation: a 1-year prospective follow-up study. Int J Cardiol. 2014;
174:634-639.
17. Xu X, Zhang W, Zhou Y, et al. Effect of trimetazidine on recurrent angina pec-
toris and left ventricular structure in elderly multivessel coronary heart disease
patients with diabetes mellitus after drug-eluting stent implantation: a single-
centre, prospective, randomized, double-blind study at 2-year follow-up. Clin
Drug Investig. 2014;34:251-258.
MEDICOGRAPHIA, Vol 38, No. 3, 2016 247
 DITORIAL

les mdicaments qui agis-

sent directement en augmentant
lnergie fournie aux cellules car-
diaques sont essentiels pour trai-
ter lischmie de manire optimale.
Afin de protger les cellules myo-
cardiques de lischmie, lapport
Agents mtaboliques
et traitement de langor
en nergie doit rpondre la de-
mande. Les b-bloquants ont un
impact positif, en rduisant la de-
mande nergtique, tandis que les
agents mtaboliques augmentent
lapport en nergie. Un mdica-
ment comme la trimtazidine com-
plte donc parfaitement laction
des b-bloquants.

p a r F. J . P i n t o , Po r t u g a l

L
a cardiopathie ischmique (CI) chronique et langor stable reprsentent un
problme clinique majeur au niveau mondial. La prvalence de langor sta-
ble est estime environ 20 000 50 000 par million dans la population g-
nrale1,2. Selon le registre REACH (rEduction of Atherothrombosis for Conti-
nued Health), qui comprend plus de 38 000 patients, 3 patients sur 20 ayant une
maladie coronaire tablie ont prsent un vnement majeur ou ont t hospitali-
ss au cours de lanne prcdente3.

Malgr dimportantes avances dans la prise en charge des patients atteints de

MC au cours des dernires annes, de nombreux patients sont encore frquem-
ment symptomatiques, parfois mme aprs une revascularisation. Dans ltude
Heart and Soul, plus dun tiers des patients ambulatoires (38 %) prsentant une MC
stable avaient de langor, une ischmie ou les deux1. Un nombre important de pa-
tients prsentant un angor typique nont pas dobstruction athrosclreuse coronaire
significative4. En outre, la prvalence de lobstruction athrosclreuse coronaire chez
les patients prsentant ou non un angor typique est lie lge et similaire et dans
les deux sexes.

Le traitement de la MC stable repose sur plusieurs stratgies, notamment les pro-

cdures de revascularisation (pontage aorto-coronaire [PAC] ou intervention coro-
naire percutane [ICP]) et la pharmacothrapie5. Lune des stratgies pouvant tre
utilise dans le traitement de la MC consiste cibler les cellules cardiaques direc-
tement, et en particulier lorigine nergtique de lischmie, en utilisant un agent
mtabolique, comme la trimtazidine, en complment des b-bloquants et dautres
agents vasoactifs5.

Lischmie myocardique est multifactorielle, mais cest avant tout

un dficit en nergie
Des donnes rcentes montrent clairement quau-del de lobstruction coronaire
par lathrosclrose, la CI est provoque par un grand nombre de mcanismes, no-
tamment un dysfonctionnement vasomoteur coronaire, microcirculatoire, endoth-
lial et plaquettaire et une inflammation6. Lischmie myocardique tant de nature
multifactorielle, elle devrait avant tout tre considre comme un dficit en nergie
(sous forme dATP [adnosine triphosphate]) au niveau des cellules cardiaques7. En
conditions de dficit nergtique, les mdicaments qui agissent directement en aug-
mentant lnergie fournie aux cellules cardiaques sont utiles, quel que soit le m-
canisme causal impliqu, et sont donc essentiels pour traiter lischmie de manire
optimale.

248 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Agents mtaboliques et traitement de langor Pinto

Afin de protger les cellules myocardiques de lischmie, lap-
port en nergie doit rpondre la demande. Les b-bloquants
ont un impact positif, en rduisant la demande nergtique,
tandis que les agents mtaboliques, comme la trimtazidine,
augmentent lapport en nergie. Un mdicament comme la
trimtazidine complte donc parfaitement laction des b-blo-
quants.
Trimtazidine + b -bloquant : une association
optimale pour reduire langor
Ltude TRIMPOL II (trIMetazidine in PoLand) a t lune des
premires tester lutilisation dun agent mtabolique en com-
plment des b-bloquants chez 426 patients atteints de MC
stable8. Dans cette tude randomise, multicentrique, en dou-
ble aveugle, contrle par placebo et en groupes parallles,
les patients atteints de MC documente et dangor stable in-
duit par leffort, non contrls par le mtoprolol, ont reu soit
un placebo, soit 20 mg de trimtazidine trois fois par jour, en
complment de deux doses quotidiennes de 50 mg de m-
toprolol. Un traitement de 12 semaines avec lassociation tri-
mtazidine plus mtoprolol a permis damliorer de manire
significative les paramtres des preuves deffort sur tapis
roulant et a rduit significativement les symptmes cliniques
par rapport lassociation placebo plus mtoprolol. Ces r-
sultats ont t obtenus sans changements hmodynamiques
supplmentaires chez ces patients. Outre son efficacit an-
tiangoreuse, la trimtazidine a t bien tolre.
Michaelides et coll. ont ralis une tude contrle, randomi-
se et en double aveugle chez des patients atteints dangor,
encore symptomatiques malgr un traitement par le propra-
nolol9. Cette tude a dmontr que lajout de trimtazidine
permet de diminuer significativement le nombre moyen de
crises dangor de manire deux fois plus efficace que lajout du
dinitrate disosorbide (63 % vs 31 %). Ce rsultat pourrait
sexpliquer par le mode daction de la trimtazidine, qui est
synergique et complmentaire celui des agents hmodyna-
miques comme les b-bloquants. Dans une rcente mta-ana-
lyse portant sur prs de 20 000 patients angoreux, la trimta-
zidine sest avre aussi efficace que les inhibiteurs calciques
ou les drivs nitrs pour rduire les symptmes dischmie les taux de troponine restaient levs chez 15 % du groupe
et dangor10.
SELECTED ABBREVIATIONS AND ACRONYMS
CI cardiopathie ischmique
ICP intervention coronaire percutane
MACCE major adverse cerebrovascular or cardiovascular
event (vnement indsirable vasculaire crbral
ou cardio-vasculaire majeur)
MC maladie coronaire
REACH REduction of Atherothrombosis for Continued
Health (rduction de lathrothrombose pour
le maintien de la sant)
TRIMPOL TRIMetazidine in POLand (trimtazidine en Pologne)
Agents mtaboliques et traitement de langor Pinto
DITORIAL
Par ailleurs, Nesukay a dmontr que lajout direct de trimta-
zidine des b-bloquants chez plus de 1 400 patients atteints
dangor stable permet une rduction rapide des symptmes
angoreux, que les patients traits par les b-bloquants aient
reu simultanment ou non des drivs nitrs ou des inhi-
biteurs calciques11.
Ajout de la trimtazidine aux b -bloquants :
amlioration du pronostic chez les patients
ischmiques
Lanalyse dun registre rcent de patients souffrant dinsuf-
fisance cardiaque a montr quenviron 40 % des patients in-
suffisants cardiaques chroniques prsentaient une pathologie
dorigine ischmique12. Dans une mta-analyse contempo-
raine mene chez prs de 1 000 patients atteints dinsuffi-
sance cardiaque, principalement dorigine ischmique (93 %),
Gao et coll. ont montr que laddition de trimtazidine rdui-
sait significativement la mortalit de toute cause, ainsi que
les vnements cardio-vasculaires et lhospitalisation pour in-
suffisance cardiaque (p < 0,01 vs placebo)13. Chez les patients
en post-infarctus du myocarde prsentant un angor stable et
une insuffisance cardiaque, un suivi de six ans a montr que
lutilisation de trimtazidine libration modifie tait lie
une rduction significative des vnements cardiaques ma-
jeurs (mortalit cardiaque, infarctus du myocarde non fatal,
accident vasculaire crbral aigu, ncessit dune revascu-
larisation coronaire et hospitalisation pour angor instable ou
insuffisance cardiaque)14.
Ajout de la trimtazidine pour diminuer
les lsions de reperfusion ischmique au cours
de la revascularisation et les rcidives dangor
par la suite
Labrou et coll. ont cherch dterminer si ladministration de
trimtazidine avant et aprs une ICP diminue les lsions myo-
cardiques induites par la procdure et amliore la fonction ven-
triculaire gauche 1 et 3 mois aprs une ICP15. Vingt-quatre
heures aprs lICP, 26 % des patients traits par trimtazidine
avaient un taux de troponine I > 1 ng/ml, contre 44 % dans le
groupe tmoin. Quarante-huit heures aprs la revascularisation,
trimetazidine, contre 32 % dans le groupe tmoin. Environ un
cinquime des patients (22 %) du groupe trimtazidine prsen-
taient des taux de cratine kinase MB (CK-MB) > 5 ng/ml,
24 heures aprs lICP, contre 40 % dans le groupe tmoin. Le
nombre de patients montrant une fraction djection < 50 %
a diminu de manire significative dans le groupe trait par
la trimtazidine, par rapport au groupe tmoin : 11 % vs 16 %
(p = 0,046) 1 mois aprs lICP, et 4 % vs 16 % (p = 0,017) 3
mois aprs lICP. Une amlioration significative de la motilit
paritale locale a t observe aprs le traitement par la tri-
mtazidine par rapport au placebo. Daprs les auteurs, luti-
lisation de la trimtazidine semble minimiser les lsions myo-
cardiques de reperfusion au cours de lICP et amliorer la
motilit paritale globale et rgionale 1 et 3 mois aprs lICP.
MEDICOGRAPHIA, Vol 38, No. 3, 2016 249
DITORIAL
Le nombre de patients traits par stents actifs (endoprothses
libration de principe actif) ayant augment, lincidence des
restnoses intra-stent est en progression. Chen et coll.16 ont
valu dans quelle mesure un traitement long terme par la
trimtazidine pouvait rduire lincidence des restnoses in-
tra-stent chez 768 patients ayant bnfici dune ICP avec un
stent actif. Lincidence des restnoses intra-stent tait inf-
rieure dans le groupe ayant reu un traitement long terme
par la trimtazidine par rapport au groupe tmoin (4,2 % vs
11,1 % ; p = 0,001). Aprs 30 jours de suivi, la fraction djec-
tion ventriculaire gauche des patients sous trimtazidine tait
suprieure celle des patients du groupe tmoin (65,4
10,7 % vs 63,1 10,4 % ; p = 0,006). Lincidence des v-
nements vasculaires crbraux ou cardio-vasculaires majeurs
(major adverse cerebrovascular or cardiovascular events,
MACCE) tait galement infrieure dans le groupe recevant
la trimtazidine lors du suivi un an (6,1 % vs 10,8 % ; p =
0,032). Le traitement par la trimtazidine sest avr tre un
facteur prdictif de la rduction des restnoses intra-stent
(odds ratio, [OR] : 0,376 ; intervalle de confiance [IC] 95 % :
0,196 0,721 ; p = 0,003). Les auteurs ont conclu quun trai-
tement par la trimtazidine rduisait de manire efficace lin-
cidence des restnoses intra-stent et des MACCE un an aprs
la mise en place dun stent actif.
Xu et coll. ont galement valu les effets de la trimtazidine
aprs la mise en place dun stent actif, sur la rcidive de lan-
gor et sur la structure du ventricule gauche chez des patients
gs atteints de MC pluritronculaire et dun diabte, et pr-
sentant une fraction djection ventriculaire gauche > 50 %17.
Aprs deux ans, des rductions significatives de lincidence
et de la svrit de langor, une diminution de lischmie myo- la plus efficace possible.
250 MEDICOGRAPHIA, Vol 38, No. 3, 2016
cardique silencieuse et une augmentation de la survie sans
angor ont t observes chez les patients du groupe trim-
tazidine par rapport au groupe tmoin. La fonction et la struc-
ture du ventricule gauche chez les patients traits par la tri-
mtazidine sont restes relativement stables aprs deux ans,
alors que chez les patients tmoins ces paramtres se sont
dtriors. Un traitement complmentaire par la trimtazidine
aprs la mise en place dun stent actif semble exercer un ef-
fet bnfique sur la prvention des rcidives dangor, et sur
lamlioration de la fonction et de la structure du ventricule
gauche chez des patients gs diabtiques prsentant une
MC pluritronculaire.
Conclusion
La CI chronique reste une charge clinique significative en
pratique courante et, dans langor stable, les b-bloquants et
la revascularisation sont des traitements largement utiliss.
Bien que le traitement pharmacologique actuel de langor par
des agents vasoactifs savre efficace, laddition dagents an-
tiangoreux mtaboliques agissant directement au niveau des
cellules cardiaques pourrait apporter des bnfices thrapeu-
tiques supplmentaires, en ciblant dautres mcanismes de
lischmie. En outre, lutilisation de ces agents mtaboliques
pendant et aprs les procdures de revascularisation aurait
galement lavantage de diminuer les lsions de reperfusion
post-ischmiques et de rduire les rcidives dangor. La stra-
tgie consistant cibler directement les cellules cardiaques
et traiter lorigine nergtique de lischmie par des agents
mtaboliques comme la trimtazidine en complment des
agents vasoactifs comme les b-bloquants semble clinique-
ment pertinente pour prendre en charge la CI de la manire
Agents mtaboliques et traitement de langor Pinto

The unexpected prevalence
of angina despite optimal medical
therapy plus successful revascu-
larization strongly challenges the
current approach to treating is-
chemic heart disease. Up to this
point, cardiologists have focused
on the vascular inability to supply
myocytes with sufficient oxygen
and nutrients. Only recently has the
scientific community considered
additional mechanisms that may
contribute to myocardial ischemia.
Mario MARZILLI, MD
Giacinta GUARINI, MD, PhD
Cardiovascular Medicine Division
Cardio Thoracic and Vascular
Department, University of Pisa
ITALY
D therapy and well-designed educational programs, ischemic heart disease
Address for correspondence:
Professor Mario Marzilli,
Cardiovascular Medicine Division,
Cardio Thoracic and Vascular
Department, University of Pisa, Via
Paradisa n 2, 56100 Pisa, Italy.
(email: mario.marzilli@med.unipi.it)
www.medicographia.com
Chronic ischemic heart disease: an energy imbalance Guarini and Marzilli
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
Chronic ischemic heart
disease: an energy imbalance
by G. Guarini and M. Marzilli, Italy
A
lterations in cardiac metabolism have recently been implicated in the
pathophysiology of ischemic heart disease. In normal conditions, the
heart derives most of its energy from b -oxidation of free fatty acids.
However, the healthy heart can easily switch from one substrate to another
according to substrate availability, nutritional status, and exercise level. Par-
adoxically, during prolonged and severe ischemia, the myocardium continues
to derive most of its energy (up to 90%) from b -oxidation. A greater amount
of oxygen is required to completely oxidize a fatty acid with a carbon-chain
length equivalent to that of glucose. Fatty acid oxidation is thought to be detri-
mental in that, while requiring more oxygen, it produces less adenosine tri-
phosphate (ATP) and more reactive oxygen species, thus further reducing mi-
tochondrial respiratory efficiency. Aside from metabolic alterations, the process
of producing and utilizing energy is very complex and includes multiple steps
from uptake of metabolites by cardiac myocytes, oxidative phosphorylation in
the mitochondria, and transport of ATP to intracellular components. There-
fore, impairment in any one of these steps can have a tremendous impact on
cell homeostasis. In addition to acute and chronic changes in cardiac metab-
olism, mitochondrial dysfunction has been implicated in promoting myocar-
dial ischemia and myocardial damage during the reperfusion phase of an is-
chemic event, thereby further reducing the hearts ability to synthesize and
utilize ATP.
Medicographia. 2016;38:251-256 (see French abstract on page 256)
espite a global reduction in cardiovascular mortality owing to improved
(IHD) remains the most important cause of death in Western countries. In
the United States, in the 10-year period from 2003 to 2013, death rates attribut-
able to cardiovascular disease (CVD) declined by 28.8%, while the actual number
of CVD deaths per year declined by 11.7%. Even so, CVD still accounted for 30.8%
of all deaths (ie, 1 out of every 3 deaths) in the United States in 2013. That same
time period witnessed a decline in the prevalence of angina pectoris: between 2009
and 2012, there was an average of 3.4 million people aged 40 years or over in the
United States with angina each year compared with 4 million between 1988 and
1994.1 In Europe, as in the United States, the prevalence of angina increases with
age, with prevalence ranging from 2%-5% in men aged 45-54 years to 11%-20%
in men aged over 60; in women, from 0.5%-1% to 10%-14%, respectively.2
MEDICOGRAPHIA, Vol 38, No. 3, 2016 251
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
Myocardial ischemia is often due to coronary atherosclerotic
disease, which limits coronary blood flow, causing an imbal-
ance between available blood supply and the hearts meta-
bolic demands. Anti-ischemic therapy is based on this con-
cept and focuses on alleviating the problem by removal of the
coronary obstructions by mechanical means, and/or modu-
lating cardiac work and coronary blood flow through pharma-
cological agents. Although such therapeutic strategies aim
to restore an adequate supply/demand balance, to improve
symptoms, and to prolong survival, available evidence indi-
cates that this goal is not always reached. Indeed, a number
of trials report persistent angina in over 30% of patients de-
spite optimal medical therapy and despite successful coro-
nary revascularization, both in patients treated by percuta-
neous coronary intervention and those treated by coronary
artery bypass graft (CABG) surgery.3-5
The unexpected prevalence of angina despite optimal med-
ical therapy plus successful revascularization strongly chal-
lenges the current approach to treating IHD. Up to this point,
cardiologists have focused on the vascular inability to supply
myocytes with sufficient oxygen and nutrients. Only recently
has the scientific community considered additional mecha-
nisms that may contribute to myocardial ischemia. Just as
there may be multiple paths to a dysfunctional car engine,
there may be multiple paths to myocardial ischemia. In this
analogy, an inadequate blood supply for the heart would be
like a shortage of gasoline for a car; an impaired cellular up-
take of nutrients would be like an altered transmission of gaso-
line to the car engine; mitochondrial dysfunction, like an en-
gines inability to transform chemical energy into mechanical
energy; and an inability to transfer adenosine triphosphate (ATP)
to the cellular contractile machinery, like an inability of the en-
SELECTED ABBREVIATIONS AND ACRONYMS
Ca2+ calcium
CHF congestive heart failure
CoA coenzyme A
CVD cardiovascular disease
DNA deoxyribonucleic acid
FA fatty acid
FFA free fatty acid
HF heart failure
IHD ischemic heart disease
MPTP mitochondrial permeability transition pore
NADH nicotinamide adenine dinucleotide
RAAS renin-angiotensin-aldosterone system
RISK reperfusion injury salvage kinase [pathway]
ROS reactive oxygen species
SAFE survival activating factor enhancement [pathway]
SNS sympathetic nervous system
TACT Trimetazidine in Angina Combination Therapy
TNF tumor necrosis factor
252 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Chronic ischemic heart disease: an energy imbalance Guarini and Marzilli
gines receiving system to generate external work. Indeed,
free fatty acids (FFAs) and glucose that are taken up by the
cells need to be transformed into intermediary components
(acetyl coenzyme A [CoA]) by b-oxidation and glycolysis so
that they can enter the Krebs cycle and produce carbon diox-
ide (CO2) and nicotinamide adenine dinucleotide (NADH), a
key substrate of oxidative phosphorylation. Respiratory-chain
complexes I through IV transfer electrons from NADH to oxy-
gen, creating a proton electrochemical gradient (Dm H+) across
the inner mitochondrial membrane. This gradient is used by
ATP synthase to phosphorylate adenosine diphosphate (ADP),
thereby producing the high-energy phosphate compound ATP,
the direct source of energy for all energy-consuming reac-
tions in the heart. Once generated in the mitochondria, ATP is
transferred by the creatine kinase energy shuttle to myofibrils
and to sarcolemmal and sarcoplasmic reticulum ion pumps.
On the basis of these considerations and an overwhelming
body of evidence, factors other than epicardial stenosis, such
as mitochondrial dysfunction and metabolic derangement,
have been recognized as pathological mechanisms for per-
sistent ischemia.6,7
Due to the complex pathophysiology of IHD, some challeng-
ing questions about treatment arise. How should we deal with
persistent angina in patients that have already been revas-
cularized? Which drugs can be used to treat IHD in patients
free of coronary stenosis? Indeed, most available antianginal
drugs were developed to counteract the effects of a flow-lim-
iting stenosis, and their efficacy has been attributed to their
ability to either increase coronary blood flow or to decrease
myocardial oxygen demand. None of these agents were test-
ed after the removal of the flow-limiting stenosis. The incom-
plete success with current treatment has fostered a large
interest in therapeutic strategies that target the alternative
pathological mechanisms, ie, metabolic modulation. Indeed,
there is evidence that metabolic modulation therapy may play
a key role in the acute phase of ischemic events, where it
would affect results of acute interventions on the subsequent
development of heart failure (HF)stunned and hibernated
myocardiumas well as for those who experience chronic
stable angina.8 Our improved understanding of metabolic
changes that occur during ischemic events and after reper-
fusion is now being translated into new therapeutic oppor-
tunities.
Ischemic heart disease: an energy crisis
Significant progress has been made in recent years in under-
standing the role of cardiac energy metabolism in the patho-
genesis of myocardial ischemia. As a natural consequence, a
better understanding of the metabolic derangements asso-
ciated with IHD is translating into new therapeutic strategies.
Under normal conditions, the healthy heart derives approx-
imately two-thirds of its energy (in the form of ATP) from the
FFA pathway; glucose oxidation and pyruvate are the other

source for the remainder of the energy produced. The healthy
heart switches easily from one substrate to another as need-
ed, according to substrate availability, nutritional status, and
exercise level. The myocardium responds to mild-to-mod-
erate cardiac ischemia by increasing uptake of glucose so
that it can produce the ATP necessary to maintain ionic gra-
dients and calcium (Ca2+) homeostasis. Paradoxically and to
detrimental effect, the myocardium continues to rely on b-ox-
idation for production of most of its energy (90%) during pro-
longed and severe ischemia, despite the elevated lactate pro-
duction that occurs under these conditions. Furthermore, due
to the Randle phenomenona competitive interaction be-
tween fatty acid (FA) oxidation and glucose oxidationhigh
rates of FA oxidation inhibit glucose oxidation, already low,
even further. Although the complete oxidation of FAs produces
more ATP per molecule of CO2 than that produced from the
complete oxidation of glucose, more oxygen is used to com-
pletely oxidize a FA of equivalent carbon-chain length. There-
fore, glucose oxidation, which produces roughly 15% more
ATP for a given amount of oxygen used, is considered more
oxygen sparing than FA oxidation. During ischemia, FA oxi-
dation can become detrimental, because it uses more oxygen
and produces less ATP and more reactive oxygen species
(ROS), and so further depresses mitochondrial respiratory
efficiency. FFAs promote their own uptake and oxidation and
they antagonize the uptake of glucose, lactate, and pyruvate,
in part through direct inhibition of pyruvate dehydrogenase.
The effects of FFAs on the mitochondria include uncoupling
of cellular respiration, resulting in decreased ATP production
and oxygen wasting. Thus, excessive levels of FFAs in the
blood lead to lactate and proton accumulation, lowered cel-
lular pH, and disrupted cellular function, as well as impaired
Ca2+ handling, oxidative stress, reduced activity of the glucose
transporter GLUT-4, and apoptosis of myocytes.9 Such meta-
bolic changes disrupt cell homeostasis and alter membrane
structure, and they ultimately lead to cell death.
Interestingly, derangements in myocardial energy metabolism
are associated with heart failure (HF) as well10; such altered
metabolism is the final common pathway of several cardiac
disorders, such as IHD, cardiomyopathies, hypertension, and
diabetes-induced HF. Recent data suggest that HF may it-
self promote metabolic changes, such as insulin resistance,
in part through neurohumoral activation, generating a vicious
cycle in which metabolic abnormalities further aggravate and
precipitate HF. The associations between altered energy me-
tabolism, insulin resistance, and HF may be explained by the
following compatible processes: (i) activation of the neuro-
humoral system, including the sympathetic nervous system
(SNS) and the renin-angiotensin-aldosterone system (RAAS);
(ii) inflammation, indicated by increased levels of tumor necro-
sis factor a (TNF-a) and its soluble receptors; (iii) alterations in
skeletal muscle function and mass as a result of reduced phys-
ical activity; (iv) endothelial dysfunction; (v) increased adipocy-
tokines, such as adiponectin and leptin; and (vi) pharmaco-
Chronic ischemic heart disease: an energy imbalance Guarini and Marzilli
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
logical exacerbation of insulin resistance (eg, by diuretics). Of
these, neurohumoral activation has been the most studied
and is probably the strongest contributor to altered metabo-
lism in HF. Neurohumoral homeostasis is activated in response
to a long-term depression in cardiac outputcharacterized by
persistent activation of the SNS and the interlinked RAAS
resulting in increased catecholamine secretion. At the same
time, catecholamine reuptake in the heart is decreased. In-
creased levels of catecholamines are directly detrimental to
the heart, causing substantial enzyme loss as an index of dif-
fuse myocardial damage, and much oxygen wastage even
in the absence of FFAs in the perfusate. Furthermore, the cat-
echolamine norepinephrine promotes both coronary vaso-
constriction and increased plasma FFA levels, further exacer-
bating oxygen wastage. Therefore, addressing the abnormal
cardiac metabolism in IHD patients may also improve patient
prognosis by halting the progression to HF.
Ischemic heart disease: a mitochondrial issue
Aside from their key role in energy production and metabolic
modulation, mitochondria are essential to cardiomyocyte sur-
vival during ischemia and reperfusion. They are implicated
in ATP synthesis, maintenance of Ca2+ homeostasis, cell sur-
vival, and cardioprotection, all of which are regulated by the
proton gradient across the mitochondrial membrane. Under
aerobic physiologic conditions, mitochondria are not involved
in the beat-to-beat regulation of cytosolic Ca2+ levels, though
a small flux of Ca2+ into the mitochondrial matrix has been ob-
served. Small increases in mitochondrial Ca2+ concentration
stimulate the Krebs cycle and the NADH redox potential.
This fine regulation of mitochondrial Ca2+ is important to en-
hance oxidative phosphorylation and ATP synthesis. Howev-
er, under pathological conditions, the mitochondria can take
up too much Ca2+, activating a series of steps that trigger a
vicious cycle that ultimately leads to irreversible cell damage.
During ischemia, intracellular Ca2+ homeostasis is deranged;
however, mitochondria can still buffer cytosolic Ca2+, suggest-
ing that they do not lose their ability to pump Ca2+. Mitochon-
dria isolated after prolonged periods of ischemia are still able
to use oxygen for ATP phosphorylation. Conversely, mitochon-
dria isolated after reperfusion are structurally altered; their mem-
brane pores are open; they contain large amounts of Ca2+;
they produce large amounts of oxygen free radicals, and the
oxidative phosphorylation system is irreversibly damaged. In
addition, ischemia followed by reperfusion induces irreversible
deletions in several parts of the mitochondrial genome, im-
pairing ATP production, which is ultimately responsible for car-
diomyocyte death (ischemia-reperfusion injury).
Notably, strategies that confer cardioprotection from myocar-
dial ischemia-reperfusion injury involve the activation of the
reperfusion injury salvage kinase (RISK) and survival activat-
ing factor enhancement (SAFE) pathways and the inhibition
of mitochondrial permeability transition pore (MPTP) opening.
The MPTP is a nonselective channel located on the inner mi-
MEDICOGRAPHIA, Vol 38, No. 3, 2016 253
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tochondrial membrane. When this channel is open, the mi-
tochondrial membrane potential collapses, uncoupling ox-
idative phosphorylation; this results in the depletion of ATP
and cell death.11 The MPTP remain closed during myocar-
dial ischemia and they open only during the first few min-
utes of myocardial reperfusion in response to mitochondrial
Ca2+ overload, oxidative stress, and restoration of physiologic
pH.12 The RISK pathway13 involves the protein kinases Akt and
Erk 1 and 2; the SAFE pathway involves activation of TNF-a
and the signal transducer and activator of transcription 3
(STAT3). When specifically activated, these pathways confer
powerful cardioprotection against lethal reperfusion injury.14
Thus, from one perspective, the RISK and SAFE pathways
could be considered to mediate a form of programmed cell
survival. There is extensive evidence that pharmacological or
mechanical activation of these two pathways, via ischemic
preconditioning or postconditioning for example, may reduce
myocardial infarct size by up to 50%.15 The cardioprotective
role of these pathways is believed to be due to inhibition of
MPTP opening,16 improved mitochondrial Ca2+ handling,17 and
recruitment of antiapoptotic pathways. Mitochondria offer sev-
eral potential targets for cardioprotective therapies. These in-
clude the following: (i) prevention of Ca2+ overload; (ii) pre-
vention of ROS generation; and (iii) activation of the ATP-
dependent potassium channels (KATP channels) that maintain
the inner mitochondrial membrane integrity, leading to (iv) pre-
vention of the opening of the nonspecific MPTP complex.18
Innovative approaches to manage myocardial
ischemia: mitochondria and cardiac energy
metabolism modulators
On the basis of this biochemical background, the pharma-
cological manipulation of mitochondria to optimize cardiac
energy metabolism makes for an attractive therapeutic option.
Such an approach is largely based on the promotion of car-
diac glucose oxidation along with the suppression of b-ox-
idation, leading to an improvement in cardiac function and
protection against ischemia-reperfusion injury, as well as at-
tenuated progression to congestive HF (CHF). Owing to the
Randle phenomenon, carbohydrate metabolism may be in-
directly increased by a decreasing rate of FA oxidation. Such
a decrease in FA oxidation may be achieved in different ways.
One of these involves decreasing the availability of FAs as
an energy substrate; this can be achieved through treatment
with glucose, insulin, and potassium (GIK therapy), which de-
creases the circulating levels of FFAs and/or their uptake by
cardiac myocytes, or through suppression of carnitine palmi-
toyl transferase (CPT) I or II to inhibit FA uptake by the mito-
chondria. Another way to decrease FA oxidation is by direct
inhibition of the enzymes involved. Of note, drugs that can
manipulate FFA oxidation (eg, trimetazidine) have been shown
not only to provide cardioprotection in the acute phase of an
ischemic event, but also to ameliorate cardiac metabolism
and angina symptoms in patients with IHD with long-term use.
These findings are supported by a link between key glycolytic
254 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Chronic ischemic heart disease: an energy imbalance Guarini and Marzilli
enzymes and the activity of two membrane-bound pumps
considered to be survival promotingthe sodium-potassi-
um ATPase and the Ca2+-uptake pump of the sarcoplasmic
reticulum. Indeed, ischemia-induced derangement of cardiac
metabolism can be minimized through treatment with meta-
bolic modulators that decrease FA oxidation and increase uti-
lization of glucose and lactate as energy substrates. The great-
est progress in the use of metabolic therapy occurred with
the advent of the direct inhibitors of myocardial FA oxidation,
specifically trimetazidine, discussed next in further detail.19
u Trimetazidine
Trimetazidine was the first and, for many years, the only reg-
istered drug in its class. It is available in over 80 countries
worldwide. It has an established antianginal efficacy, known
even before the discovery of how the drug acts, which is via
partial inhibition of myocardial FA oxidation.19,20 Initial preclinical
studies in animal models of myocardial ischemia and reper-
fusion demonstrated a cytoprotective effect for this drug.21
It has been shown by Kantor et al to specifically inhibit the
long-chain activity of the enzyme 3-ketoacyl CoA thiolase
(EC 2.3.1.16) (3-KAT),22 the enzyme that catalyzes the last
step in FA b-oxidation, using long-chain 3-ketoacyl-CoA as a
substrate to generate acetyl-CoA. Trimetazidines inhibition of
3-KAT reduces the NADH/NAD+ and acetyl-CoA/free CoA ra-
tios in the mitochondrial matrix, in effect removing the inhibi-
tion on pyruvate dehydrogenase and thus increasing the rate
of glucose oxidation. Indeed, in the working rat heart, although
only modestly reducing the rate of FA oxidation, trimetazidine
significantly increases the rate of glucose oxidation.22,23 Tri-
metazidines efficacy in refractory angina has been demon-
strated in clinical trials, which also support the superior ben-
efit associated with the addition of this metabolic agent to
classic hemodynamic drug therapy, such as b-blockers or
nitrates. The efficacy and acceptability of trimetazidine in com-
bination with hemodynamic agents was tested in the TACT
study (Trimetazidine in Angina Combination Therapy).24 In that
study, exercise stress test parameters and angina symptoms
were significantly improved with the addition of trimetazidine
to therapy including b-blockers or long-acting nitrates, com-
pared with addition of placebo. Similar results were observed
in the VASCO-Angina study. This randomized, double-blind,
placebo-controlled trial, assessed antianginal efficacy on ex-
ercise test parameters and safety of both a standard dosage
(70 mg/day) and a high dosage (140 mg/day) of modified-re-
lease trimetazidine in symptomatic and asymptomatic patients
with chronic stable angina who were receiving background
b-blocker therapy with atenolol (50 mg/day).25 That study con-
firmed the efficacy and tolerability of both trimetazidine dos-
ages in improving effort-induced myocardial ischemia and
functional capacity in such patients.25 Furthermore, evidence
from other studies suggest trimetazidine may improve clinical
manifestation in patients with stable IHD. Indeed, with long-
term administration of trimetazidine, the following have been
observed: a lower average number of weekly attacks, a low-

er mean weekly consumption of short-acting nitrates, im-
provement in quality of life, lessened severity of main clinical
manifestations of chronic HF, and improved (lowered) func-
tional class.26-29 Moreover, as trimetazidine has been demon-
strated to have similar efficacy in men and women, this met-
abolic myocardial cytoprotector can be recommended for
patients with IHD irrespective of sex.30,31 Trimetazidine has also
been used for cardioprotection in patients undergoing coro-
nary bypass surgery and percutaneous coronary interven-
tion.28,32 Consistent with IHD and HF being considered ener-
getic disorders, trimetazidine was effective in reducing mortality
and event-free survival in patients with chronic HF in an in-
ternational, multicenter, retrospective cohort study. The ad-
dition of trimetazidine to optimal medical therapy improved
long-term survival in these patients.33 That retrospective analy-
sis further confirmed the results of previous small studies in
patients with chronic HF that had shown that trimetazidine
improves left ventricular function, exercise capacity, and New
York Heart Association functional class compared with place-
bo. Furthermore, the addition of trimetazidine to exercise train-
ing resulted in greater improvements in functional capacity,
left ventricular ejection fraction, and endothelium-dependent
dilation in patients with chronic HF.34
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Chronic ischemic heart disease: an energy imbalance Guarini and Marzilli
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C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
Conclusions: ischemic heart disease,
an energetic disorder
Historically, IHD has been considered a vascular disease, where
coronary atherosclerosis causes an imbalance between blood
supply and demand. However, recent evidence suggests that
cardiac metabolic derangement and the inability of mitochon-
dria to efficiently produce energy are able to induce energy
starvation similar to that produced by coronary blood flow
blockage. In other words, it is conceivable that cardiac meta-
bolic derangements and/or mitochondrial dysfunction can di-
rectly put the myocardium under ischemic conditions, inde-
pendently of oxygen and nutrient availability. Accordingly, in an
experimental model (Zucker obese fatty rat), repairing mito-
chondrial DNA damage improved mitochondrial function, re-
stored vascular and myocyte properties, and reduced the
consequences of oxidative stress.35 Similarly, in Zucker lean
rats in which mitochondrial dysfunction was selectively in-
duced through mitochondrial DNA damage, areas of myocar-
dial ischemia, endothelial dysfunction, and depressed con-
tractile function under cardiac stress were observed in the
absence of coronary atherosclerosis.35 These observations
support the hypothesis that myocardial ischemia should be
considered an energetic disorder. n
tor signaling in limiting lethal reperfusion injury? Trends Cardiovasc Med. 1999;
9(8):245-249.
15. Guarini G, Huqi A, Capozza P, Morrone D, Donati F, Marzilli M. Therapy against
ischemic injury. Curr Pharm Des. 2013;19(25):4597-4621.
16. Davidson SM, Hausenloy D, Duchen MR, Yellon DM. Signalling via the reper-
fusion injury signalling kinase (RISK) pathway links closure of the mitochon-
drial permeability transition pore to cardioprotection. Int J Biochem Cell Biol.
2006;38(3):414-419.
17. Abdallah Y, Gkatzoflia A, Gligorievski D, et al. Insulin protects cardiomyocytes
against reoxygenation-induced hypercontracture by a survival pathway tar-
geting SR Ca2+ storage. Cardiovasc Res. 2006;70(2):346-353.
18. Di Lisa F, Canton M, Carpi A, et al. Mitochondrial injury and protection in ischemic
pre- and postconditioning. Antioxid Redox Signal. 2011;14(5):881-891.
19. Stanley WC. Partial fatty acid oxidation inhibitors for stable angina. Expert Opin
Investig Drugs. 2002;11(5):615-629.
20. McClellan KJ, Plosker GL. Trimetazidine. A review of its use in stable angina
pectoris and other coronary conditions. Drugs. 1999;58(1):143-157.
21. Vaillant F, Tsibiribi P, Bricca G, et al. Trimetazidine protective effect against is-
chemia-induced susceptibility to ventricular fibrillation in pigs. Cardiovasc Drugs
Ther. 2008;22(1):29-36.
22. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazi-
dine shifts cardiac energy metabolism from fatty acid oxidation to glucose ox-
idation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.
Circ Res. 2000;86(5):580-588.
23. Lopaschuk GD. Optimizing cardiac energy metabolism: how can fatty acid and
carbohydrate metabolism be manipulated? Coron Artery Dis. 2001;12(suppl
1):S8-S11.
24. Chazov EI, Lepakchin VK, Zharova EA, et al. Trimetazidine in Angina Combina-
tion Therapythe TACT study: trimetazidine versus conventional treatment
in patients with stable angina pectoris in a randomized, placebo-controlled,
multicenter study. Am J Ther. 2005;12(1):35-42.
25. Vitale C, Spoletini I, Malorni W, Perrone-Filardi P, Volterrani M, Rosano GM.
Efficacy of trimetazidine on functional capacity in symptomatic patients with sta-
ble exertional angina The VASCO-angina study. Int J Cardiol. 2013;168(2):
1078-1081.
26. Grabczewska Z, Bialoszynski T, Szymanski P, et al. The effect of trimetazidine
added to maximal anti-ischemic therapy in patients with advanced coronary
artery disease. Cardiol J. 2008;15(4):344-350.
27. Marzilli M. Cardioprotective effects of trimetazidine: a review. Curr Med Res
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Opin. 2003;19(7):661-672.
28. Danchin N, Marzilli M, Parkhomenko A, Ribeiro JP. Efficacy comparison of
trimetazidine with therapeutic alternatives in stable angina pectoris: a network
meta-analysis. Cardiology. 2011;120(2):59-72.
29. Marzilli M. Does trimetazidine prevent myocardial injury after percutaneous coro-
nary intervention? Nat Clin Pract Cardiovasc Med. 2008;5(1):16-17.
30. Danchin N. Clinical benefits of a metabolic approach with trimetazidine in revas-
cularized patients with angina. Am J Cardiol. 2006;98(5A):8J-13J.
31. Vasiuk IuA, Shal'nova SA, Shkol'nik EL, Kulikov KG. The (PRIMA) Study. Com-
parison of clinical effect of trimetazidine MR in men and women [in Russian].
Kardiologiia. 2011;51(6):11-15.
32. Martins GF, Siqueira Filho AG, Santos JB, et al. Trimetazidine on ischemic in-
jury and reperfusion in coronary artery bypass grafting. Arq Bras Cardiol. 2011;
97(3):209-216.
33. Fragasso G, Rosano G, Baek SH, et al. Effect of partial fatty acid oxidation
inhibition with trimetazidine on mortality and morbidity in heart failure: results
from an international multicentre retrospective cohort study. Int J Cardiol. 2013;
163(3):320-325.
34. Belardinelli R, Lacalaprice F, Faccenda E, Volpe L. Trimetazidine potentiates the
effects of exercise training in patients with ischemic cardiomyopathy referred
for cardiac rehabilitation. Eur J Cardiovasc Prev Rehabil. 2008;15(5):533-540.
35. Guarini G, Kiyooka T, Ohanyan V, et al. Impaired coronary metabolic dilatation
in the metabolic syndrome is linked to mitochondrial dysfunction and mito-
chondrial DNA damage. Basic Res Cardiol. 2016;111(3):29.

Keywords: cardiac metabolism; ischemic heart disease; metabolic agent; mitochondrial dysfunction

LA MALADIE CORONAIRE CHRONIQUE : UN DSQUILIBRE NERGTIQUE

Rcemment, des altrations du mtabolisme cardiaque ont t impliques dans la physiopathologie de la maladie
coronaire. En conditions normales, la plus grande partie de lnergie cardiaque provient de la b -oxydation des acides
gras libres. Cependant, le cur sain peut facilement passer dun substrat un autre selon la disponibilit du subs-
trat, ltat nutritionnel et le niveau deffort. Paradoxalement, au cours dune ischmie prolonge et svre, le myocarde
continue de tirer la plupart de son nergie (jusqu 90 %) de la b -oxydation. Il faut une plus grande quantit doxy-
gne pour oxyder compltement un acide gras avec une chane de carbone dont la longueur est quivalente celle
du glucose. Loxydation des acides gras est considre comme prjudiciable car elle produit moins dATP et plus de
drivs ractifs de loxygne, tout en ncessitant plus doxygne, ce qui rduit donc encore lefficacit de la chaine
respiratoire mitochondriale. Hormis les changements mtaboliques, le processus de production et dutilisation de
lnergie est trs complexe et comprend de nombreuses tapes : labsorption des mtabolites par les myocytes car-
diaques, la phosphorylation oxydative dans les mitochondries et le transport de lATP vers les diffrents comparti-
ments intracellulaires. Cest ainsi quune dtrioration de lune de ces tapes peut avoir un impact norme sur lho-
mostasie cellulaire. En plus des changements aigus et chroniques du mtabolisme cardiaque, il a t montr que
la dysfonction mitochondriale favorise lischmie myocardique et les troubles myocardiques pendant la phase de
reperfusion dun vnement ischmique, ce qui rduit alors encore un peu plus laptitude du cur synthtiser et
utiliser lATP.

256 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Chronic ischemic heart disease: an energy imbalance Guarini and Marzilli

Mitochondria lie at the heart
of a number of cardioprotective
signaling pathways underlying is-
chemic conditioning. As such, a
variety of pharmacological treat-
ment strategies aimed at protect-
ing mitochondria against the detri-
mental effects of acute myocardial
ischemia/reperfusion injury have
been investigated in both experi-
mental and clinical studies, with
mixed results. Of these strategies,
the current treatments that are al-
ready in clinical practice include
trimetazidine and ivabradine.
Derek J. HAUSENLOY, MD, PhD
Cardiovascular and Metabolic
Disorders Program, Duke-NUS
Graduate Medical School
SINGAPORE
National Heart Research Institute
Singapore, National Heart Centre
Singapore, SINGAPORE
The Hatter Cardiovascular Institute
Institute of Cardiovascular Science
University College London
London, UNITED KINGDOM
National Institute of Health Research
University College London Hospitals
Biomedical Research Centre
London, UNITED KINGDOM
Address for correspondence:
Professor Derek Hausenloy,
Cardiovascular and Metabolic
Disorders Program, Duke-National
University of Singapore,
8 College Road, Singapore 169857
(email:
derek.hausenloy@duke-nus.edu.sg)
www.medicographia.com
Mitochondria as a therapeutic target in ischemia Hausenloy
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
Mitochondria as a
therapeutic target in ischemia
b y D . J . H a u s e n l oy, U n i t e d K i n g d o m
I
schemic heart disease is the leading cause of death and disability world-
wide. As such, novel therapeutic targets are urgently required to protect the
heart against the detrimental effects of acute ischemia/reperfusion injury
in order to preserve cardiac function and improve clinical outcomes in patients
with ischemic heart disease. In this regard, mitochondria, which are the pow-
erhouses of the cell and which make up one-third of the volume of a cardiomy-
ocyte, are an important target for cardioprotection. Elucidation of the signal-
ing pathways underlying the endogenous cardioprotective phenomenon of
ischemic conditioning, in which the heart can be protected by brief nonlethal
episodes of ischemia and reperfusion, has identified mitochondria to be the
end-effector in many of the signal transduction pathways. In this article, we re-
view the role of mitochondria as targets for protecting the heart against acute
ischemia/reperfusion injury, the therapeutic application of which should help
improve clinical outcomes in patients with ischemic heart disease.
Medicographia. 2016;38:257-263 (see French abstract on page 263)
schemic heart disease remains the leading cause of death and disability both in
I
Europe specifically and worldwide. As such, there remains an urgent need to dis-
cover novel therapies that can protect the heart against the detrimental effects
of acute ischemia/reperfusion injury (IRI) in order to preserve left ventricular (LV) sys-
tolic function and prevent the onset of heart failure. In this article, we review the role
of mitochondria as a therapeutic target for protecting the heart against acute IRI.
In the heart, mitochondria occupy nearly one-third the volume of a cardiomyocyte,
highlighting their importance as the powerhouses of the cell, providing the energy
required for normal cardiac contractile function.
Metabolic and biochemical consequences of acute
ischemia/reperfusion
An acute coronary artery occlusion results in a critical reduction in coronary blood
flow and deprivation of oxygen and nutrients to the affected area of myocardium,
and it impairs the clearance of waste metabolites, subjecting cardiomyocytes to the
abrupt metabolic and biochemical changes associated with acute myocardial is-
chemia. If blood flow is restored to the affected area by the removal of the coronary
artery occlusion, the ischemic myocytes are then exposed to the further metabolic
and biochemical changes associated with the reperfusion process. The combined
injury sustained by the myocardium during these processes is termed acute my-
ocardial IRI, and the sequential metabolic and biochemical perturbations that oc-
MEDICOGRAPHIA, Vol 38, No. 3, 2016 257
M E TA B O L I C AGENTS IN THE
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cur during this process are reviewed below and presented in

Figure 1. Deprivation of oxygen during acute myocardial is-
chemia impairs oxidative phosphorylation by reducing elec-
tron flow through the mitochondrial electron transport chain,
leading to an accumulation of NADH and FADH and cessa-
tion of adenosine triphosphate (ATP) production.1 The mito-
chondrial membrane potential collapses as it is no longer
maintained by the electrochemical gradient across the inner
mitochondrial membrane.2 Intracellular creatine phosphate
is depleted with a concomitant rise in intracellular inorganic
phosphate (Pi), resulting in mitochondria accumulating Pi.3
Residual reserves of ATP are hydrolyzed by F0F1-ATPase in
an attempt to restore the mitochondrial membrane potential,4
resulting in catalytic metabolites such as hypoxanthine, which
are oxidized to release free radicals. The activity of the adenine
nucleotide translocase is reduced, impairing oxidative phos-
Figure 1. The metabolic and biochemical changes that occur
phorylation further still.5
during acute myocardial ischemia and reperfusion.
During acute myocardial ischemia, there is an increase in intracellular calcium
The reduced availability of ATP and oxygen drives anaerobic (Ca2+), inorganic phosphate (Pi), sodium (Na+), reactive oxygen species (ROS),
glycolysis, which results in lactic acid accumulation, leading to NADH, and hydrogen (H+), a fall in adenosine triphosphate (ATP) levels, and
collapse of the mitochondrial membrane potential (Dm). At reperfusion, there
intracellular acidification. The fall in pH activates the sodium is repolarization of the Dm and restoration of mitochondrial ATP production; a
(Na+)/hydrogen (H+) exchanger in an effort to remove cytoso- further increase in Ca2+, Pi, and ROS; oxidation of NADH; and restoration of
neutral pHfactors that mediate cell death by inducing mitochondrial perme-
lic protons, which causes the entry of Na+. The Na+/potassium ability transition pore (MPTP) opening and cardiomyocyte hypercontracture.

(K+)-ATPase, which normally removes excess Na+, is inhibited

SELECTED ABBREVIATIONS AND ACRONYMS
because of the reduced availability of ATP and the increase in
AMI acute myocardial infarction intracellular Pi. This results in a rise in intracellular Na+, which
CABG coronary artery bypass graft triggers the Na+/calcium (Ca2+) exchanger to function in re-
CAD coronary artery disease verse in order to remove cytosolic Na+.6 However, this occurs
CIRCUS does Cyclosporine ImpRove Clinical oUtcome in at the expense of an increase in intracellular Ca2+. The rise in
ST-elevation myocardial infarction patients cytosolic Ca2+ results in the mitochondrial accumulation of
CsA cyclosporin A Ca2+ via the mitochondrial Na+/Ca2+ exchanger.7 The onset of
CYCLE CYCLosporinE A in reperfused acute myocardial rigor contracture coincides with the depletion of ATP,8 and is
infarction [trial] followed by cellular Ca2+ overload.9
EMBRACE Evaluation of Myocardial effects of Bendavia for
STEMI reducing Reperfusion injury in patients with Acute Therefore, after an episode of acute myocardial ischemia, the
Coronary Events [trial] metabolic and biochemical derangements include a low in-
EMIP-FR European Myocardial Infarction Project tracellular pH (<7.0), high intracellular [Ca2+] and [Pi ], and ATP
Free Radicals
depletion (Figure 1), conditions which are exacerbated once
ERK1/2 extracellular signalregulated kinase the acutely ischemic myocardium is reperfused.
IRI ischemia/reperfusion injury
JAK Janus kinase Reperfusion of acutely ischemic myocardium has several im-
LV left ventricular portant consequences: (i) re-energization of the cardiomyo-
MEK1/2 mitogen-activated protein kinase (MAP)/extracellular cyte, causing repolarization of the mitochondrial membrane
signalregulated kinase (ERK) 1/2 potential; (ii) reoxygenation of a reduced mitochondrial res-
MI myocardial infarction piratory chain, resulting in the production of reactive oxygen
MPTP mitochondrial permeability transition pore species (ROS) and oxidation of NADH/FADH; (iii) a drop in in-
PCI percutaneous coronary intervention tracellular Ca2+, but a further influx of Ca2+ into mitochondria
PI3K phosphatidylinositol 3-kinase via the Ca2+-uniporter driven by the restored mitochondrial
PPCI primary percutaneous coronary intervention membrane potential9; and (iv) the wash-out of lactic acid,
RISK reperfusion injury salvage kinase [pathway] which in combination with the reactivation of the Na+/H+ ex-
SAFE survival activating factor enhancement [pathway] change acts to restore a neutral pH. Many of the biochemical
STAT3 signal transducer and activator of transcription 3 and metabolic changes that take place during the first few
STEMI ST-segment elevation myocardial infarction minutes of reperfusion can mediate cardiomyocyte death by
inducing the opening of the mitochondrial permeability tran-

258 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Mitochondria as a therapeutic target in ischemia Hausenloy
 M E TA B O L I C AGENTS IN THE
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sition pore (MPTP), a nonselective channel of the inner mi- Inhibiting MPTP opening to protect the heart
tochondrial membrane whose opening uncouples oxidative against acute IRI
phosphorylation, resulting in ATP depletion and cell death by The MPTP is a nonselective channel of the inner mitochon-
necrosis.10 drial membrane, the opening of which mediates cell death
by uncoupling oxidative phosphorylation and inducing mito-
Therefore, the ultimate aim of any cardioprotective strategy chondrial swelling, resulting in ATP depletion and necrotic cell
designed to protect the cardiomyocyte against acute IRI is death.10 The molecular composition of the MPTP is not clear,
to preserve cellular energetic and ionic homeostasis during although it has been suggested that ATP synthase11-13 and
this insult. In this regard, protecting mitochondrial function mitochondrial cyclophilin D14,15 are important components. In
to preserve energy production in response to acute myocar- the setting of an acute myocardial infarction (AMI), it has been
dial IRI is an important strategy of cardioprotection, which has shown to remain closed during acute myocardial ischemia
been investigated in both experimental and clinical studies and to be open in only the first few minutes of reperfusion.
(see Figure 2). Therefore, preventing its opening at the onset of reperfusion is
an important therapeutic strategy
for reducing myocardial infarct
(MI) size after an AMI.16,17 Prevent-
ing MPTP opening at the onset of
reperfusion can be achieved in
various ways as follows10,18,19: (i)
directly by pharmacological MPTP
inhibition; (ii) indirectly through
the activation of signaling path-
ways that converge on the MPTP;
or (iii) indirectly by modifying fac-
tors such as mitochondrial Ca2+
overload and ROS production,
which are known to induce MPTP
opening (see Figure 2).

u Signaling pathways under-

lying ischemic conditioning
that target the MPTP
The heart can be protected from
the detrimental effects of acute
IRI by subjecting it to brief non-
lethal episodes of ischemia and
reperfusion, a phenomenon that
Figure 2. Mitochondrial targets for cardioprotection. has been termed ischemic con-
The diagram provides a simplified scheme of some of the potential mitochondrial targets for cardioprotection, many of ditioning.20,21 Importantly, the pro-
which have been elucidated from studies investigating the signaling pathways underlying ischemic conditioning. These
signal transduction pathways include the RISK (involving PI3K-Akt and MEK1/2-Erk1/2), SAFE (involving JAK-STAT), tective stimulus can be applied
and NO-cGMP pathways, all of which terminate at the mitochondria and, particularly, the mitochondrial permeability directly to the heart before the in-
transition pore (MPTP). These reperfusion salvage pathways have been shown to activate downstream mediators, such
as eNOS, GSK3b, HKII, PKCe, and KATP , which then mediate the inhibitory effect on MPTP opening. The modulation dex ischemic event (ischemic pre-
of mitochondrial energetics by actions on the electron transport chain and adenosine triphosphate production can conditioning)22 or at the onset of
also indirectly prevent MPTP opening in response to acute ischemia/reperfusion injury (IRI).
Cyclosporin A protects against acute IRI by inhibiting MPTP opening via inhibition of CypD. TRO40303 is believed to
reperfusion (ischemic postcon-
protect the heart by inhibiting MPTP opening via attenuation of reactive oxygen species (ROS) production in response ditioning)23 or it can be applied to
to acute IRI. MTP-131 protects the heart against acute IRI by improving mitochondrial energetics via targeting of car- an organ or tissue remote from
diolipin in the inner mitochondrial membrane. Trimetazidine protects the heart against acute IRI by inhibiting fatty acid
oxidation, thereby promoting glucose oxidation, the result of which is improved mitochondrial energetics. Ivabradine the heart (remote ischemic con-
protects the heart against acute IRI by lowering the heart rate and through pleiotropic effects, which include attenua- ditioning).24 A number of different
tion of ROS production and inhibition of MPTP opening.
Abbreviations: cGMP, cyclic guanosine monophosphate; Cardio, cardiolipin; CypD, cyclophilin D; eNOS, endothelial
signal transduction pathways
nitric oxide synthase; Erk1/2, extracellular signalregulated kinase 1/2; ETC, electron transport chain; GSK3, glyco- have been shown to mediate is-
gen synthase kinase 3b; HKII, Hexokinase II; IRI, ischemia/reperfusion injury; JAK, Janus kinase; KATP, mitochondrial chemic conditioning, including
adenosine-triphosphatedependent potassium channel; MEK1/2, mitogen-activated protein kinase (MAP)/extracellular
signalregulated kinase (ERK)1/2; MPTP, mitochon-drial permeability transition pore; NO, nitric oxide; PI3K, phosphatidyli- the reperfusion injury salvage ki-
nositol 3-kinase; PKC, protein kinase C epsilon; PKG, protein kinase G; ROS, reactive oxygen species; SAFE, sur- nase (RISK) pathway (compris-
vivor activating factor enhancement; STAT, signal transducer and activator of transcription; RISK, reperfusion injury
salvage kinase.
ing the PI3K- Akt and MEK1/2-
Modified from reference 64: Hausenloy et al. Basic Res Cardiol. 2009;104(2):189-202. 2009, Springer-Verlag. Erk1/2),25,26 the survival activat-

Mitochondria as a therapeutic target in ischemia Hausenloy MEDICOGRAPHIA, Vol 38, No. 3, 2016 259
M E TA B O L I C AGENTS IN THE
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ing factor enhancement (SAFE) pathway (comprising tumor
necrosis factor a, JAK-STAT3),27,28 and the nitric oxide [NO]-
cyclic guanosine monophosphate [cGMP] pathway.29 These
signaling cascades mediate the ischemic conditioning stim-
ulus from the cell surface receptor to the mitochondria where
they mediate cardioprotection by inhibiting MPTP opening (see
Figure 2). The elucidation of these signaling pathways under-
lying ischemic conditioning has made it possible to use phar-
macological agents to activate these signal mediators and
recapitulate cardioprotection (Figure 2). Examples of RISK,
SAFE, and NO-cGMP pathway activators that have been
shown to protect the heart against acute IRI include growth
factors and cytokines, such as atrial natriuretic peptide, in-
sulin, erythropoietin, and glucagon-like peptide-1.25-29
u Cyclosporin A: a direct inhibitor of the MPTP
The immunosuppressant drug cyclosporin A (CsA) is a po-
tent inhibitor of MPTP opening that has been demonstrated
to reduce MI size in a number of experimental animal stud-
ies,16,30,31 but not all.32 This therapeutic strategy has been trans-
lated into the clinical setting in several phase 2 clinical trials in
AMI, coronary artery bypass graft (CABG) surgery, and stroke,
but the results have been mixed.33-37 The recently completed
CYCLE trial (CYCLosporinE A in reperfused acute myocardial
infarction [NCT01650662]), which included 410 ST-segment
elevation MI (STEMI) patients, also failed to demonstrate any
benefits with CsA administered before primary percutaneous
coronary intervention (PPCI), in terms of ST-segment reso-
lution and enzymatically estimated MI size.38 Whether MPTP
inhibition can improve clinical outcomes has been recently
tested in the CIRCUS trial (does Cyclosporine ImpRove Clin-
ical oUtcome in ST-elevation myocardial infarction patients),
which involved 970 patients. In that trial, it was shown that
the administration of CsA immediately before PPCI failed to
improve clinical outcomes at one year (all-cause death, heart
failure hospitalization, and adverse LV remodeling) in anterior
STEMI patients.39 Why this large phase 3 trial did not confirm
the positive results reported in previous phase 2 studies re-
mains unclear, but potential reasons include the following40:
(i) a possible type I error observed in small-size clinical stud-
ies; (ii) off-target effects of CsA, as CsA is known to inhibit
cyclophilin A and calcineurin, the results of which may have
counteracted the benefit of inhibiting MPTP opening41; and,
perhaps, (iii) changes in STEMI patients since the initial phase 2
trial, including a greater use of the new P2Y12 platelet inhib-
itors (prasugrel, ticagrelor), which are known to reduce MI
size per se.42
u TRO40303: an indirect inhibitor of the MPTP
TRO40303 binds to the translocator protein TSPO in the out-
er mitochondrial membrane and is believed to inhibit MPTP
opening by attenuating ROS production. It has been report-
ed in small animal experimental studies to reduce MI size,43
but the cardioprotective effect was not replicated in a clini-
cally relevant porcine MI model.44 In the 163STEMI-patient
260 MEDICOGRAPHIA, Vol 38, No. 3, 2016
MITOCARE study (which investigated the efficacy and safety
of TRO40303 for reduction in reperfusion injury in patients un-
dergoing revascularization for STEMI),45 this agent failed to
reduce MI size when administered at the time of PPCI, de-
spite careful patient selection (completely occluded infarct-re-
lated artery, large area at risk [AAR]). The neutral findings of
the MITOCARE study may be due in part to ambiguous car-
dioprotective effects previously revealed in experimental stud-
ies and the fact that the formulation and dosage of TRO40303
used in the clinical study differed from that in experimental
studies. Finally, more adverse events were reported in patients
administered TRO40303 than in the placebo arm,45 thereby
limiting the clinical application of this therapeutic approach.
u MTP-131 and myocardial energetics
MTP-131, a mitochondria-targeting peptide, has been shown
to optimize mitochondrial energetics and attenuate the pro-
duction of ROS by selectively targeting cardiolipin in the in-
ner mitochondrial membrane. It has been reported in both
small and large animal experimental studies to reduce MI
size when administered at the onset of reperfusion and to
prevent adverse LV remodeling after MI.46,47 However, in the
EMBRACE STEMI clinical trial (Evaluation of Myocardial ef-
fects of Bendavia for reducing Reperfusion injury in patients
with Acute Coronary Events),48 intravenous MTP-131 admin-
istered before PPCI failed to reduce enzymatically estimated
MI size in a carefully selected population of anterior STEMI
patients (ischemic time <4 hours, no collateral vessels, and
fully occluded coronary artery). The reasons for the neutral re-
sults of this study are not known, but potential reasons may
include a single-targeted approach to cardioprotection, or
pharmacokinetic or pharmacodynamic difficulties in targeting
mitochondria in STEMI patients.
Metabolic modulation to protect the heart
against acute IRI
Improving myocardial energetics by modulating mitochondrial
metabolism is an important strategy for cardioprotection that
has been extensively investigated over the last 30 to 40 years.
In 1970, Lionel Opie first used insulin to promote glucose ox-
idation to protect the heart against acute myocardial ische-
mia.49 This metabolic approach to protecting the ischemic
heart underlies the cardioprotective effects of trimetazidine.
u Trimetazidine and metabolic modulation
Trimetazidine is known to improve myocardial glucose uti-
lization by inhibiting fatty acid metabolism. It does this by in-
hibiting long-chain 3-ketoacyl-coenzyme A thiolase, there-
by blocking b-oxidation of fatty acids and promoting glucose
oxidation.50 In the ischemic heart, where oxygen is scarce,
glucose oxidation is more beneficial than fatty acid oxidation
as the former requires less oxygen consumption than the lat-
ter. This metabolic effect of trimetazidine is central to its anti-
anginal effects in patients with stable coronary artery disease
(CAD).51
Mitochondria as a therapeutic target in ischemia Hausenloy

A number of experimental studies have shown that trimetazi-
dine can protect the heart against acute IRI, as evidenced by
reductions in MI size when administered as a pretreatment
and when administered at the onset of reperfusion.52 This ther-
apeutic approach has been investigated in patients present-
ing with an AMI in the large EMIP-FR clinical trial (European
Myocardial Infarction Project Free Radicals), and although it
did not improve clinical outcomes in AMI patients reperfused
by thrombolysis, it appeared to have a beneficial effect in non-
reperfused patients, underscoring its anti-ischemic effect.53
Recent meta-analyses have shown that it can decrease pe-
rioperative and periprocedural myocardial injury in patients
undergoing coronary revascularization by CABG surgery54
and PCI,55 respectively, suggesting it has a cardioprotective
effect in these clinical settings. The beneficial effects from
modulating mitochondrial metabolism may also be helpful in
heart failure, another condition in which disturbances in mi-
tochondrial metabolism play an important role.56
u Ivabradine and myocardial energetics
Another effective approach to cardioprotection is to reduce
the myocardial energy requirements of the heart during acute
IRI. This can be achieved with little hemodynamic conse-
quence by the drug ivabradine, which by inhibiting the If cur-
rent in the sinus node can induce a selective lowering of heart
rate.57 This drug has been demonstrated to lower heart rate
and reduce myocardial ischemia in several experimental stud-
ies.58-60 However, whether the anti-ischemic effect of ivabra-
dine is secondary to heart rate lowering is not clear, and recent
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39. Cung TT, Morel O, Cayla G, et al. Cyclosporine before PCI in patients with
acute myocardial infarction. N Engl J Med. 2015;373(11):1021-1031.
40. Hausenloy DJ, Yellon DM. Targeting myocardial reperfusion injurythe search
continues. N Engl J Med. 2015;373(11):1073-1075.
41. Hausenloy DJ, Boston-Griffiths EA, Yellon DM. Cyclosporin A and cardioprotec-
tion: from investigative tool to therapeutic agent. Br J Pharmacol. 2012;165(5):
1235-1245.
42. Yang XM, Liu Y, Cui L, et al. Platelet P2Y12 blockers confer direct postcondi-
tioning-like protection in reperfused rabbit hearts. J Cardiovasc Pharmacol Ther.
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Keywords: cardioprotection; ischemia; ischemic conditioning; mitochondria; therapeutic target; trimetazidine
262 MEDICOGRAPHIA, Vol 38, No. 3, 2016
46. Dai W, Shi J, Gupta RC, Sabbah HN, Hale SL, Kloner RA. Bendavia, a mito-
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61. Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and antiischemic effects
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63. Fox K, Komajda M, Ford I, et al. Effect of ivabradine in patients with left-ven-
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64. Hausenloy DJ, Ong SB, Yellon DM. The mitochondrial permeability transition
pore as a target for preconditioning and postconditioning. Basic Res Cardiol.
2009;104(2):189-202.
Mitochondria as a therapeutic target in ischemia Hausenloy
 M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A

LA MITOCHONDRIE , CIBLE THRAPEUTIQUE DANS L ISCHMIE

La maladie coronaire est la cause principale de dcs et dinvalidit dans le monde. Il est donc urgent de trouver de
nouvelles cibles thrapeutiques pour protger le cur des effets dltres des lsions aigus dischmie/reperfu-
sion afin de prserver la fonction cardiaque et damliorer les rsultats cliniques chez les patients coronariens. cet
gard, les mitochondries, qui sont les centrales nergtiques de la cellule et reprsentent le tiers du volume dun
cardiomyocyte, sont une cible importante pour la cardioprotection. La comprhension des voies de signalisation sous-
tendant le phnomne endogne de cardioprotection du conditionnement ischmique, par lequel le cur peut tre
protg par des pisodes brefs non ltaux dischmie et de reperfusion, a permis dtablir que la mitochondrie est
leffecteur terminal dans beaucoup de voies de transduction des signaux. Dans cet article, nous examinons la mito-
chondrie en tant que cible pour la protection du cur contre les lsions dischmie/reperfusion, une approche dont
lapplication thrapeutique pourrait aider amliorer les rsultats cliniques des patients coronariens.

Mitochondria as a therapeutic target in ischemia Hausenloy MEDICOGRAPHIA, Vol 38, No. 3, 2016 263

the less traditional view held
by the Brazilian Society of Cardiol-
ogy recognizes that trimetazidine
may be offered early onbefore
long-acting nitratesin combina-
tion with any hemodynamic agent,
as long as blood pressure and
heart rate are properly controlled.
With this latter position, a different
view emerges of the treatment of
patients with stable IHD, one that
widens the concept of optimal
medical therapy and allows for
the inclusion of trimetazidine be-
fore the commonplace after every-
thing else has failed stance.
Luis Henrique Wolff GOWDAK,
MD, PhD, FESC
Laboratory of Genetics & Molecular
Cardiology and Chronic Coronary
Artery Unit, Heart Institute (InCor)
University of So Paulo Medical
School, So Paulo, BrAzIL
Address for correspondence:
Dr Luis Henrique W. Gowdak,
Laboratory of Genetics & Molecular
Cardiology, Heart Institute (InCor),
Av. Dr. Eneas de Carvalho Aguiar, 44
05403-000 So Paulo, Brazil
(email: luis.gowdak@incor.usp.br)
www.medicographia.com
264 MEDICOGRAPHIA, Vol 38, No. 3, 2016
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
The place of metabolic agents
in contemporary coronary
artery disease guidelines
b y L . H . W. G o w d a k , B ra z i l
I
n the healthy human heart, free fatty acids (FFAs) supply approximately 60%
to 90% of the energy used to synthesize adenosine triphosphate (ATP); 10%
to 40% comes from glucose and lactate. During ischemia, reduced deliv-
ery of oxygen to cardiomyocytes leads to a decrease in ATP formation by ox-
idative phosphorylation, an increase in the rate of glycolysis, and a high rate of
conversion of pyruvate to lactate. This metabolic disturbance yields a disrup-
tion in cell homeostasis (with accumulation of lactate and H + ions), a fall in
intracellular pH, and a reduction in contractile work. A metabolic shift by direct
inhibition of FFA oxidation in the mitochondria with trimetazidine results in
a decrease in the frequency of angina attacks, increased exercise tolerance,
improvement in quality of life, enhanced myocardial contractility in patients
with left ventricular dysfunction, and reduced myocardial damage during my-
ocardial revascularization procedures. The European Society of Cardiology
guidelines on stable angina indicate that trimetazidine may be considered sec-
ond-line for the treatment of angina/relief of ischemia in patients already re-
ceiving a b -blocker and/or calcium channel antagonist to control symptoms.
With a different view, the Brazilian guidelines on stable angina recommend
trimetazidine for symptom relief as an add-on therapy right after b -blockers,
but before long-acting nitrates (unless there is a need for better blood pres-
sure control, in which case calcium channel antagonists are preferable).
Medicographia. 2016;38:264-270 (see French abstract on page 270)
hen William Heberden first named and described angina pectoris in
W 1772, its treatment appeared the stuff of far-off dreams: () With re-
spect to the treatment of this complaint, I have little or nothing to ad-
vance: nor indeed is it to be expected we should have made much progress in
the cure of a disease, which has hitherto hardly had a place or a name in medical
books.1 How times have changed. Since the description more than 250 years ago
of the clinical presentation of an entity of which William Heberden could not recol-
lect any mention among medical authors,1 and for which he had little or nothing
to advance regarding its treatment, the modern cardiologist now faces a complete-
ly different challenge: that of devising an adequate therapeutic strategy for patients
with stable angina using the many options available, which include antianginal drugs
and myocardial revascularization procedures (percutaneous or surgical). But for
physicians of the past the treatment scenario was very different: it took almost a
century after Heberdens description before the Scottish physician Sir Thomas Brun-
ton2 first used amyl nitrite in the treatment of angina pectoris in 1867. In angina
The place of metabolic agents in contemporary coronary artery disease guidelines Gowdak
 M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A

pectoris we wish a drug which will relax spasm

of the vessels very quickly, but as a rule we do
not require the relaxation to be prolonged, said
Brunton of the type of pharmacological effect
he thought would be useful.3 While Brunton
was using amyl nitrite, another British physician,
William Murrell, began using nitroglycerine in
the treatment of angina pectoris.4 After almost
a century during which the use of nitrates had
gained wide popularity as the only medical treat-
ment for angina, there were two important new
arrivals in the twentieth century: b-blockers5
(early-1960s) and calcium channel antagonists6
(late-1960s to mid-1970s). These drugs formed
the new medical management basis for symp-
tom relief in patients with stable angina; they
could either be used alone or in combination,
Figure 1. Temporal sequence of ischemic events during stress-induced myocar-
as tolerated, in the absence of contraindications dial ischemia. Note that after perfusion heterogeneity sets in, metabolic alteration
to their use. appears before any detectable functional abnormality. Chest pain is usually the
latest manifestation of ongoing myocardial ischemia.
Although many patients certainly benefited from Abbreviation: ECG, electrocardiography.
a combination of these so-called hemodynam- Korean Copied from reference 10: Kim and Youn. J Cardiovasc Ultrasound. 2009;17(2):40-53. 2009,
Society of Echocardiography.
ic agents, it later became apparent that others
remained symptomatic despite the use of maximally tolerat- optimal medical therapy with or without PCI was offered to
ed doses of these drugs. Moreover, even after an increase patients with stable angina, about 40% of patients were still
in the use of myocardial revascularization procedures, includ- complaining of angina after only 3 years of follow-up, regard-
ing a boom in the number of percutaneous coronary inter- less of the therapeutic strategy assigned. These observations,
ventions (PCIs), patients would remain free of angina for dif- which are not unique in the literature, raised the question,
ferent lengths of time, only to return a couple of years later When it comes to offering optimal symptom control, what is
complaining of angina again. In the randomized trial MASS true optimal medical therapy in patients with stable angina?
(Medicine, Angioplasty, or Surgery Study) II,7 for example, in This led to an intensive search for drugs with alternative mech-
patients with nonlimiting angina, multivessel disease, and anisms of action to hemodynamic modulation to be added to
preserved left ventricular function at baseline, 45% of those the therapeutic armamentarium for the management of pa-
initially assigned to optimal medical therapy (a combination of tients with ischemic heart disease (IHD).
b-blockers and/or long-acting nitrates and/or calcium chan-
nel antagonists) were still symptomatic after 5 years of follow- Optimizing energy metabolism as a therapeutic
up; however, it should be noted that even for those who were target in patients with angina
assigned to a myocardial revascularization procedure, the Even though angina is regarded as the clinical hallmark of
prevalence of angina was 22% (PCI group) and 25% (surgical coronary artery disease (CAD), as so eloquently described by
group). In the COUrAGE (Clinical Outcomes Utilizing revas- Heberden, myocardial ischemia cannot be considered an
cularization and AGgressive drug Evaluation) trial,8 in which event precisely circumscribed by the onset and resolution of
angina. In fact, the identification of an ischemic cascade of
pathophysiologic events9 broadened not only our understand-
SELECTED ABBREVIATIONS AND ACRONYMS
ing of different clinical presentations of CAD, but also opened
3-KAT 3-ketoacyl coenzyme A thiolase up opportunities for new therapeutic strategies. Figure 1 shows
ATP adenosine triphosphate the temporal sequence of ischemic events during stress-in-
CAD coronary artery disease duced myocardial ischemia.10
COURAGE Clinical Outcomes Utilizing revascularization and
AGgressive drug Evaluation u Basic concepts in heart metabolism
EMA European Medicines Agency Because metabolic disturbances occur early on during my-
FFA free fatty acid ocardial ischemia, the clinician should bear in mind basic
IHD ischemic heart disease concepts related to heart metabolism. In the healthy human
MASS Medicine, Angioplasty, or Surgery Study heart, free fatty acids (FFAs) supply approximately 60% to
PCI percutaneous coronary intervention 90% of the energy used to synthesize adenosine triphos-
phate (ATP), whereas the remaining 10% to 40% of the ener-

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M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A

gy comes from different energetic substrates, ie, glucose and

lactate.11 Once in the mitochondrion, FFAs undergo b-oxida-
tion, a complex multistep enzymatic process, to produce ATP
for contractile work, calcium uptake by the sarcoplasmic retic-
ulum, and ion homeostasis.12 Glucose is taken up by the my-
ocardium and is either stored as glycogen or broken down
by glycolysis to pyruvate in the cytosol of the cell. Pyruvate
is oxidized to acetyl-CoA in the mitochondria by the enzyme
pyruvate dehydrogenase. Oxidation of glucose and lactate is
strongly inhibited by high rates of FFA oxidation in the heart
(Figure 2).11

u Heart metabolism during ischemia

reduced oxygen delivery to cardiomyocytes during ischemia
leads to mitochondrial metabolic dysfunction, resulting in a
decrease in ATP formation by oxidative phosphorylation and
an increase in the rate of glycolysis. Pyruvate produced by gly-
colysis is not so readily oxidized in the mitochondria, which
allows a high rate of conversion of pyruvate to lactate in the
cytosol and a consequent rise in tissue lactate levels.13 This
Figure 2. Cardiac energy metabolism under normal aerobic con-
ditions.
Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; SR,
sarcoplasmic reticulum.
Modified from reference 11: Stanley. Eur Heart J Suppl. 2001;3(suppl O):O2-O7.
2001, The European Society of Cardiology.

metabolic disturbance seen during myocardial ischemia yields

a dramatic disruption in cell homeostasis, with accumulation
of lactate and H+ ions, a fall in intracellular pH, and a reduc-
tion in contractile work (Figure 3).11

u Targeting FFA and carbohydrate oxidation in IHD

Direct inhibition of FFA oxidation in the mitochondria with the
3-ketoacyl coenzyme A thiolase (3-KAT) inhibitor trimetazidine
results in an increase in the rates of glucose and/or lactate
uptake and oxidation.14 The suppression of FFA oxidation and
increased oxidation of pyruvate by pyruvate dehydrogenase
in the mitochondria reduces ischemia-induced disruption of
cardiac metabolism. In other words, inhibiting cardiac FFA
oxidation and increasing the oxidation of pyruvate results in
less lactate production and less of a fall in cell pH, resulting
in clinical benefit for the ischemic patient. This direct meta-
bolic approach is optimally suited to conditions in which there
is sufficient residual oxygen delivery to the myocardium to sup-
port pyruvate oxidation in the mitochondria.15 In other words,
Figure 3. Cardiac energy metabolism during ischemia of moderate
it is important that there be a sufficient rate of acetyl-CoA ox- severity.
idation and oxygen consumption so that increasing the rate Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi,
of pyruvate oxidation has a meaningful effect on the rate of inorganic phosphate.
lactate production. This metabolic shift from FFA oxidation to Modified from reference 11: Stanley. Eur Heart J Suppl. 2001;3(suppl O):O2-O7.
2001, The European Society of Cardiology.
glucose oxidation has proven effective in different scenarios
in patients with IHD and/or heart failure. lar antianginal efficacy was observed between the trimetazi-
dine and propranolol groups. No significant differences were
Clinical benefits of trimetazidine in patients with observed between trimetazidine and propranolol as regards
stable angina weekly number of angina attacks, exercise duration, or time
Back in the late 1960s, the use of trimetazidine in patients with to 1-mm ST-segment depression. Similar results were found
angina pectoris had been proposed and successfully used when trimetazidine was compared to nifedipine.18 Moreover,
in small series of patients, although the exact mechanism of trimetazidine can be effectively and safely combined with dif-
action implicated in pain relief was not clear at that time.15,16 ferent antianginal drugs including calcium channel antago-
Later on, the effects of trimetazidine were compared with those nists,19,20 b-blockers,21,22 and long-acting nitrates.23 The com-
of propranolol in a double-blind parallel group multicenter bination of trimetazidine with a hemodynamic agent yielded
study in 149 men with stable angina.17 After 3 months, simi- subjective (a decrease in the frequency of angina attacks) and

266 MEDICOGRAPHIA, Vol 38, No. 3, 2016 The place of metabolic agents in contemporary coronary artery disease guidelines Gowdak

objective (increase in exercise tolerance assessed during a
treadmill test) evidence for its role in the management of pa-
tients with stable angina not sufficiently controlled with a sin-
gle hemodynamic agent.
Since most clinical trials of trimetazidine involved a limited
number of patients, a recently published study looked at 13
randomized controlled trials comprising 1628 patients to de-
termine the efficacy of trimetazidine combined with other anti-
anginal drugs versus other antianginal drugs in the treatment
of stable angina pectoris.24 Figure 4 (page 268) shows that the
weekly mean number of angina attacks decreased (panel A)
and exercise duration improved (panel B) in patients receiving
trimetazidine on top of conventional antianginal therapy.24
Trimetazidine in patients with stable angina:
what do the guidelines say?
The unequivocal benefits of trimetazidine in patients with sta-
ble IHD include: (i) a decrease in the frequency of angina at-
tacks and in the need for short-acting nitrates for pain relief 24;
(ii) increased exercise tolerance25; (iii) improvement in quality
of life26; (iv) enhanced myocardial contractility in patients with
left ventricular dysfunction27; and (v) a reduction in myocardial
damage during myocardial revascularization procedures, such
as angioplasty28 or bypass surgery.29 In terms of cardiovascu-
lar events, trimetazidine may decrease the risk of hospital-
izations in patients with heart failure30; the use of trimetazi-
dine has been linked to a lower risk of death in patients after
an acute myocardial infarction31 and in patients with heart fail-
ure.30,32 So, how do different medical societies value these ben-
efits and incorporate trimetazidine in their guidelines on sta-
ble angina?
u The European perspective
The most recent guidelines on stable angina issued by the
European Society of Cardiology33 acknowledge trimetazidine
as an anti-ischemic metabolic modulator with similar antiang-
inal efficacy to propranolol and devoid of any discernible he-
modynamic action. In June 2012, the European Medicines
Agency (EMA) reviewed available data regarding its efficacy
in effort-induced myocardial ischemia.34 A thorough analysis
of the safety and effectiveness of trimetazidine carried out by
the EMA concluded that the drug was safe, although move-
ment disorders (including parkinsonism), which were uncom-
mon and reversible after drug discontinuation, could not be
excluded with the use of trimetazidine. Thus, in patients with
angina pectoris, treatment with trimetazidine should be con-
sidered as an add-on to existing treatments in those who are
not adequately controlled by, or who are intolerant to, oth-
er medicines for angina pectoris. Accordingly, the European
guidelines stated that trimetazidine may be considered for
the second-line treatment of angina/relief of ischemia in pa-
tients already receiving a b-blocker and/or calcium channel
antagonist to control symptoms (class of recommendation:
IIb; level of evidence: B).33
The place of metabolic agents in contemporary coronary artery disease guidelines Gowdak
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
u The North American perspective
Although trimetazidine is not marketed in the United States,
its ability to improve cellular tolerance to ischemia, delay the
onset of exercise-induced ischemia, and reduce angina epi-
sodes and nitroglycerin use has been recognized by US ex-
perts in the American College of Cardiology/American Heart
Association guidelines on the management of patients with
stable angina.35
u The Brazilian perspective
Trimetazidine is marketed worldwide and, therefore, included
in different national guidelines for the management of patients
with stable CAD or stable angina. Because a detailed North
American reference to its use is lacking, many countries
around the world where trimetazidine is available follow the
recommendations proposed by the European Society of Car-
diology. The Brazilian Society of Cardiology, however, has tak-
en a slightly different approach in its placement of trimetazi-
dine in the treatment of patients with stable angina.
In the most recent version of the Brazilian guidelines on stable
angina,36 b-blockers have kept their position as the first-line
treatment for the prophylaxis of angina attacks and short-
acting nitrates remain the cornerstone treatment for the im-
mediate relief of chest pain due to CAD. But for patients whose
symptoms are poorly controlled with b-blockers, the Brazilian
guidelines now recommend that physicians consider adding
trimetazidine early on, provided blood pressure and heart rate
have been controlled. However, if one needs better control
of blood pressure calcium channel antagonists may be pre-
ferred.
There are a couple of studies that may support this approach.
In these studies, the effects of early administration of trimeta-
zidine on top of different background antianginal therapies
were assessed. In one study, 53 patients with symptomatic
stable angina receiving propranolol 40 mg tid were random-
ized to long-acting nitrates or trimetazidine as an add-on ther-
apy for 6 weeks.37 Patients on the combination of a b-block-
er + long-acting nitrates had a 30% reduction in the number
of angina episodes per week compared to a 62% reduction
seen in patients on the b-blocker + trimetazidine combina-
tion (P=0.001). A treadmill test revealed that the latter com-
bination yielded a 6-fold increase in total exercise duration
(95 s versus 16 s).
In another study, investigators looked at the benefit of adding
trimetazidine in 1213 highly symptomatic patients with sta-
ble angina being treated with different antianginal strate-
gies, comprising b-blocker alone, b-blocker + long-acting
nitrates, or b-blocker + calcium channel antagonist.38 The ad-
dition of trimetazidine significantly reduced the weekly num-
ber of angina attacks and consumption of short-acting ni-
trates in all patients, regardless of the treatment strategy used.
But, maybe more importantly, the combination of long-acting
MEDICOGRAPHIA, Vol 38, No. 3, 2016 267
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A

A. Weekly number of angina attacks

B. Exercise duration

Figure 4. Forest plot for the aggregate weekly mean number of angina attacks (panel A) and exercise duration at peak exercise (panel B)
in patients received trimetazidine combined with conventional antianginal agents in the treatment of stable angina pectoris, in comparison
with conventional antianginal agents.
Modified from reference 24: Peng et al. Int J Cardiol. 2014;177(3):780-785. 2014, Elsevier Ireland Ltd.

268 MEDICOGRAPHIA, Vol 38, No. 3, 2016 The place of metabolic agents in contemporary coronary artery disease guidelines Gowdak

nitrates or calcium channel antagonists with b-blockers did
not provide any additional reduction in the number of angina
attacks compared with patients receiving b-blocker + trimeta-
zidine.
So, when the time came to review the Brazilian guidelines on
stable angina, the committee decided to give trimetazidine
a class IIa recommendation (level of evidence: B) for symp-
tom relief as a second-line treatment, as an add-on therapy
right after b-blockers (unless, as previously stated, there is a
need for better blood pressure control, in which case calci-
um channel antagonists are preferable).
Another particular aspect of this document is that long-acting
nitrates have been downgraded to a third-line treatment for
angina control. The reason being that at least two studies
have demonstrated that the long-term use of long-acting ni-
trates leads to an increase in the risk of cardiovascular events,
including death, in healed myocardial infarction patients39 and
in diabetes patients who underwent elective PCI.40 Worsening
of endothelial dysfunction is a potential complication of long-
acting nitrates that may be linked to adverse outcomes.41
Conclusion
The benefits of trimetazidine in patients with cardiovascular
disease have been demonstrated in several studies and meta-
analyses, allowing for its incorporation into practice guide-
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Keywords: angina; coronary artery disease; guidelines; treatment; trimetazidine

LA PLACE DES AGENTS MTABOLIQUES

DANS LES RECOMMANDATIONS ACTUELLES SUR LA MALADIE CORONAIRE
Dans le cur humain sain, les acides gras libres (AGL) fournissent environ 60 % 90 % de lnergie utilise pour
synthtiser lATP (adnosine triphosphate) ; 10 % 40 % viennent du glucose et du lactate. Pendant lischmie, la
rduction de lapport en oxygne aux cardiomyocytes conduit une diminution de la formation dATP par phospho-
rylation oxydative, une augmentation du taux de la glycolyse et un taux lev de conversion du pyruvate en lac-
tate. Ce trouble mtabolique provoque une perturbation de lhomostasie cellulaire (avec laccumulation de lactate
et dions H+), une chute du pH intracellulaire et une rduction du travail contractile. Avec la trimtazidine, un trans-
fert mtabolique par inhibition directe de loxydation des AGL dans la mitochondrie diminue la frquence des crises
dangor, majore la tolrance leffort, amliore la qualit de vie, augmente la contractilit myocardique des patients
ayant une dysfonction ventriculaire gauche et diminue les lsions myocardiques pendant les procdures de revas-
cularisation myocardique. Daprs les recommandations de la Socit Europenne de Cardiologie sur langor stable,
la trimtazidine peut tre utilise en seconde ligne pour le traitement de langor ou le soulagement de lischmie chez
les patients recevant dj un b -bloquant et/ou un antagoniste calcique pour contrler les symptmes. Voyant les
choses diffremment, les directives brsiliennes sur langor stable recommandent la trimtazidine pour le soulage-
ment des symptmes comme traitement dappoint juste aprs les b -bloquants (sauf sil faut un meilleur contrle de
la pression artrielle, auquel cas les antagonistes calciques sont prfrables), mais avant les drivs nitrs longue
dure daction.

270 MEDICOGRAPHIA, Vol 38, No. 3, 2016 The place of metabolic agents in contemporary coronary artery disease guidelines Gowdak

While revascularization can
improve cardiac function and de-
crease mortality risk, alterations in
cardiac energetics can persist in
the heart after revascularization.
This includes persistent abnormal-
ities in mitochondrial oxidative me-
tabolism, as well as alterations in
energy substrate preference by the
heart. In particular, a continued in-
creased reliance on fatty acid ox-
idation at the expense of glucose
oxidation can occur after reper-
fusion.
T
Gary D. LOPASCHUK, PhD,
MSc, BSc
Cardiovascular Research Centre
Mazankowski Alberta Heart Institute
University of Alberta, Edmonton
CANADA
Address for correspondence:
Dr Gary Lopaschuk, 423 Heritage
Medical Research Centre, University
of Alberta, Edmonton, Canada,
T6G 2S2
(email: gary.lopaschuk@ualberta.ca)
www.medicographia.com
Revascularization in angina patients: addressing cardiac metabolism challenges Lopaschuk
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
Revascularization in angina
patients: addressing cardiac
metabolism challenges
b y G . D . Lo p a s c h u k , C a n a d a
he onset of an angina pectoris attack is associated with dramatic alter-
ations in cardiac energy metabolism. A mismatch between oxygen (O2 )
demand and O2 supply to the heart muscle results in a decrease in mi-
tochondrial oxidative metabolism, leading to an energy-deficient state in the
heart. In addition, changes in the source of substrates for cardiac mitochon-
drial energy metabolism contribute to contractile dysfunction and to a de-
crease in cardiac efficiency. These changes include an increase in the contri-
bution of cardiac fatty acid (FA) oxidation to residual mitochondrial oxidative
metabolism and an uncoupling of glycolysis from glucose oxidation. Revas-
cularization can lessen angina symptoms predominantly by lessening the mis-
match between O2 demand and O2 supply to the heart muscle. However, while
revascularization can improve O2 supply, some of the switches in cardiac me-
tabolism persist after revascularization. In particular, the muscle becomes over-
ly reliant on FA oxidation as a source of energy, primarily at the expense of
glucose oxidation. This can continue to uncouple glycolysis from glucose ox-
idation, resulting in a continued decrease in cardiac efficiency. As a result, a
challenge in revascularized angina patients is to normalize cardiac energy
metabolism and improve cardiac efficiency. Recent evidence suggests that
therapeutically regulating cardiac energy metabolism by reducing FA oxida-
tionwhich increases glucose oxidationcan improve cardiac efficiency and
cardiac function and lessen the symptoms of angina, even in revascularized
patients. In this article, we review the cardiac mitochondrial energy meta-
bolic changes that occur in the heart in angina patients, and the changes that
occur during revascularization, as well as the potential for targeting FA oxi-
dation to treat angina, both in the presence or absence of revascularization.
Medicographia. 2016;38:271-276 (see French abstract on page 276)
ngina pectoris due to coronary artery disease (CAD) is a major health prob-
A lem in the world. Revascularization of angina patients, either by percutaneous
coronary interventions (PCI) or by coronary artery bypass graft (CABG) sur-
gery, can substantially improve angina symptoms for most patients. However, symp-
toms of angina can persist and may return over time, even when taking optimal
antianginal medications.1 As a result, it is imperative to identify new approaches to
treat angina, even in the revascularized patient. One potentially promising approach
to treating angina is to optimize cardiac energy metabolism.2 This would appear to
be a logical approach, as a decrease in oxygen availability and alterations in car-
diac energy metabolism are prominent changes in the angina patient. However, in
MEDICOGRAPHIA, Vol 38, No. 3, 2016 271
M E TA B O L I C AGENTS IN THE
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order to fully exploit the potential of optimizing cardiac ener-

gy metabolism in angina patients, it is first important to un-
derstand how cardiac energy metabolism is regulated in the
normal patient, in the angina patient, and after revascular-
ization of the angina patient. This paper reviews the cardiac
metabolic changes that occur in the angina patient, and how
optimizing cardiac energy metabolism can be used as an ap-
proach to treat such patients, both those with or without revas-
cularization.

Cardiac energy metabolism in the normal heart

The heart has a very high energy demand, due to the need
to produce large amounts of adenosine triphosphate (ATP)
to support the continuous contractile function of the heart.
There are no significant energy reserves in the heart, and there
is a near complete turnover of the myocardial ATP pool every
5 to 10 seconds.2,3 To meet these high energy demands, the
heart generates ATP by metabolizing a variety of energy sub-
strates, including fatty acids, glucose, lactate, ketone bod-
ies, and amino acids (Figure 1). The contributions of each of
these energy substrates to ATP generation are tightly regu-
lated, and there is a significant degree of plasticity and inter-
dependence in the use of these energy substrates. Under
normal, physiological conditions, fatty acids and carbohy-
drates (ie, glucose and lactate) represent the primary meta-
bolic fuels that sustain cardiac function, and upwards of 95%
of ATP production is attributable to mitochondrial oxidative
phosphorylation.2,3 The remainder of this ATP production pri-
marily originates from glycolysis, which has the benefit of pro-
ducing ATP without the need for oxygen (Figure 1). The trade
off of this anaerobic ATP production is that lactate and pro-
tons (H+s) are two of the metabolic byproducts of glycolysis
if the pyruvate produced from glycolysis is not subsequently
subjected to mitochondrial oxidative metabolism.2
The heart normally displays substantial metabolic flexibility,
with fatty acid and glucose metabolism having a considerable
degree of interdependence, a process referred to as the Ran-
dle Cycle or the glucose/fatty acid cycle.4 Increasing fatty acid
oxidation in the heart decreases glucose oxidation, where-
as increasing glucose oxidation inhibits fatty acid oxidation.
A key site at which fatty acid oxidation decreases glucose
metabolism is at the level of pyruvate dehydrogenase (PDH),
the rate-limiting enzyme for glucose oxidation. High rates of
fatty acid oxidation inhibit PDH, secondary to activating a PDH
kinase that phosphorylates and inhibits PDH.
SELECTED ABBREVIATIONS AND ACRONYMS
CABG coronary artery bypass graft
CAD coronary artery disease
DCA dichloroacetate
PCI percutaneous coronary intervention
PDH pyruvate dehydrogenase
Figure 1. Overview of energy metabolism in the heart.
Abbreviations: I-IV, complexes I to IV in the electron transport chain; ADP,
adenosine diphosphate; ATP, adenosine triphosphate; CoA, coenzyme A; CPT,
carnitine palmitoyl transferase; H +, proton; H2O, water; LDH, lactate dehydro-
genase; MPC, mitochondrial pyruvate carrier; O2 , oxygen; PDH, pyruvate dehy-
drogenase; PDHK, pyruvate dehydrogenase kinase; TCA, tricarboxylic acid.
Cardiac energy metabolism in angina
Various cardiac pathophysiological states cause perturba-
tions of the tightly regulated pathways of myocardial energy
substrate metabolism, and these perturbations contribute to
the progression of myocardial injury. In CAD, repeated oxy-
gen (O2) supply and demand mismatches results in down-
regulation of mitochondrial oxidative metabolism, and an in-
crease in glucose uptake and glycolysis.5 During an angina
attack, where O2 availability is not sufficient to meet the O2
requirements of the heart, impaired mitochondrial oxidative
metabolism results in a rapid decline in ATP production from
fatty acid oxidation and glucose oxidation that is proportional
to the degree of ischemia (Figure 2A). Glycolysis becomes a
very important source of energy during ischemia due to its
ability to generate ATP in the absence of O2. During periods of
mild-to-moderate ischemia, glucose uptake and the mobi-
lization of endogenous glucose from stored glycogen con-
tribute to increased flux through the glycolytic pathway.2
Despite the presence of ischemia, mitochondrial fatty acid ox-
idation remains the predominant source of residual oxidative
metabolism.6 This is due to a number of ischemia-induced
changes, which include the following: (i) an increase in cir-
culating fatty acids to which the heart is exposed; (ii) an in-
crease in myocardial fatty acid uptake; and (iii) an increase in
mitochondrial fatty acid uptake (see Lopaschuk et al2 for re-

272 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Revascularization in angina patients: addressing cardiac metabolism challenges Lopaschuk
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view). The increase in the relative contribution of fatty acid
oxidation to mitochondrial oxidative metabolism results in a
parallel decrease in glucose oxidation during ischemia. Since
glycolysis is accelerated during ischemia, the hydrolysis of gly-
colytically derived ATP uncoupled from subsequent pyruvate
oxidation leads to an increased generation of lactate and H+
(Figure 2A). In severely ischemic hearts, this can result in a de-
crease in pH in the myocardium, which can lead to cell death.
In milder ischemia (such as seen during angina), the produc-
tion of H+ from glycolysis leads to disturbances in ionic home-
ostasis, which leads to a decrease in cardiac efficiency, as
ATP is required to restore these ionic imbalances.
Cardiac energy metabolism after revascularization
Revascularization is an important approach to reducing the
myocardial O2 supply and demand mismatch that can occur
in the CAD patient. However, during revascularization, the
short complete interruptions of blood flow produce a pro-
found ischemia, which are accompanied by dramatic alter-
ations in cardiac energy metabolism. During reperfusion of
the ischemic heart, overall cardiac fatty acid oxidation rates
are elevated, due, at least partially, to elevated levels of circu-
lating fatty acids (Figure 2B).5,7 In addition, the subcellular con-
trol of fatty acid oxidation is altered, such that fatty acid oxida-
tion becomes deregulated. Elevated levels of circulating fatty
acids combined with an increase in mitochondria fatty acid
uptake results in an increase in fatty acid oxidation rates dur-
ing reperfusion, with a concomitant marked decrease in glu-
cose oxidation rates (Figure 2B).2,6-8 This elevation in circulating
fatty acids and cardiac fatty acid oxidation after restoration
of blood flow can impair cardiac function and cardiac efficien-
cy (Figure 2B).6,7 The decrease in glucose oxidation after revas-
cularization can result in increased uncoupling of glycolysis
from glucose oxidation and a subsequent increase in produc-
tion of lactate and H+, which can decrease cardiac efficiency
and impair heart function.2,6,7 As a result, a challenge in the re-
vascularized angina patient is to normalize cardiac energy me-
tabolism, particularly by increasing glucose oxidation rates.
While revascularization can improve cardiac function and de-
crease mortality risk, alterations in cardiac energetics can per-
sist in the heart after revascularization. This includes persist-
ent abnormalities in mitochondrial oxidative metabolism,5 as
well as alterations in energy substrate preference by the heart.
In particular, a continued increased reliance on fatty acid ox-
idation at the expense of glucose oxidation can occur after
reperfusion,6-9 providing a challenge in the revascularized pa-
tient to restore normal cardiac energy metabolism.

A B

Figure 2. Alterations in myocardial energy metabolism during ischemia and reperfusion.

During ischemia (A), glycolysis becomes the main source of energy production in the absence of or a decreased supply of oxygen. Fatty acids dominate as the
substrate for residual oxidative metabolism due to increased plasma levels of fatty acids, as well as alterations in the subcellular control of fatty acid oxidation. During
reperfusion (B), glycolytic rates remain high, while fatty acid oxidation dominates over glucose oxidation as the main source of oxidative metabolism. The dominant
fatty acid oxidation rates during reperfusion inhibit glucose oxidation. The uncoupling of glycolysis from glucose oxidation leads to an increase in proton production,
which ultimately leads to myocardial acidosis and calcium overload.
Abbreviations: I-IV, complexes I to IV in the electron transport chain; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoA, coenzyme A; CPT, carnitine
palmitoyl transferase; H +, proton; H2O, water; LDH, lactate dehydrogenase; MPC, mitochondrial pyruvate carrier; O2 , oxygen; PDH, pyruvate dehydrogenase; PDHK,
pyruvate dehydrogenase kinase; TCA, tricarboxylic acid.

Revascularization in angina patients: addressing cardiac metabolism challenges Lopaschuk MEDICOGRAPHIA, Vol 38, No. 3, 2016 273
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Targeting fatty acid oxidation to treat angina

Classically, the pharmacological treatment of angina patients
has focused on the use of agents that alter systemic and/or
cardiac hemodynamics. With increasing knowledge of the
mechanisms regulating cardiac energy substrate metabolism,
and with the understanding that alterations in such metab-
olism contribute to the severity of angina symptoms, the
modulation and optimization of energy substrate metabolism
represents a novel and promising area for therapeutic inter-
vention in angina patients. In this regard, pharmacological
agents that shift the balance between the oxidative utilization
of fatty acid and glucose toward glucose oxidation have been
an area of intense research activity.2,3 In particular, pharma-
cological agents that either inhibit fatty acid oxidation and/or
stimulate glucose oxidation are promising anti-ischemic in-
terventions (Figure 3).2,3,8-18

Fatty acid oxidation can be inhibited directly by decreasing

fatty acid uptake into the mitochondria or by inhibiting mito-
chondrial fatty acid oxidation. Fatty acid oxidation can also be
inhibited indirectly by increasing glucose oxidation. Pharma-
cological inhibition of fatty acid oxidation with drugs that low-
er fatty acid levels, block mitochondrial fatty acid uptake, or
directly inhibit fatty acid oxidation all have potential benefit
in the setting of angina.
One drug that directly targets mitochondrial fatty acid oxi-
dation is trimetazidine.8-15 Trimetazidine is a partial fatty acid
oxidation inhibitor that competitively inhibits the fatty acid
oxidation enzyme, long chain 3-ketoacyl coenzyme A thio-
lase.8-10 The inhibition of fatty acid oxidation is accompanied
by an increase in glucose oxidation. This is beneficial in both
ischemic myocardium during restoration of blood flow or in
already revascularized myocardium, as the increased glucose
oxidation decreases the production of H+s arising from the
uncoupling of glycolysis from glucose oxidation.
Results from clinical studies have confirmed the effectiveness
of trimetazidine as an anti-ischemic agent. Treatment of angi-
na with trimetazidine increases time to 1-mm ST segment de-
pression as well as weekly nitrate consumption.11,12 Trimetazi-
dine has been shown to have comparable effectiveness to
propranolol in treating stable angina.11-14 Combination thera-
py with standard antianginal therapy reduces the number of
symptomatic episodes of angina and improves time to is-
chemia-related electrocardiogram changes on exercise test-
ing.13 As discussed, many revascularized angina patients still
require antianginal therapy.14,15 The use of metabolic agents
during and after revascularization has been shown to provide
myocardial protection.15,16 Angina patients with previous PCI
or CABG show significant improvement in time to 1-mm ST-
segment depression, exercise test duration, total workload,
time to onset of angina, and weekly angina attacks and ni-
trate consumption.15 Trimetazidine is cardioprotective in pa-
tients undergoing CABG and PCI procedures, evidenced by
Figure 3. Diagrams for pharmacological targets that decrease
fatty acid oxidation and/or increase glucose oxidation in the heart.
Abbreviations: I-IV, complexes I to IV in the electron transport chain; ADP,
adenosine diphosphate; ATP, adenosine triphosphate; CoA, coenzyme A; CPT,
carnitine palmitoyl transferase; DCA, dichloroacetate; H+, proton; H2 O, water;
LDH, lactate dehydrogenase; MPC, mitochondrial pyruvate carrier; O2 , oxygen;
PDH, pyruvate dehydrogenase; PDHK, pyruvate dehydrogenase kinase; TCA,
tricarboxylic acid.
its ability to decrease the release of troponin T and decrease
ST-segment elevation, respectively, during balloon inflation.17,18
A recent meta-analysis of patients undergoing PCI also showed
that the use of trimetazidine during the PCI procedure re-
sulted in a significant reduction in myocardial injury and in
improved cardiac function,18 effects that would be expected
by inhibiting fatty acid oxidation in the myocardium.
Although classified as a late sodium current inhibitor, rano-
lazine is also a partial fatty acid oxidation inhibitor, which has
been shown to inhibit fatty acid oxidation and reciprocally
increase glucose oxidation and PDH activity.19 In experi-
mental studies, ranolazine attenuates myocardial stunning,
reduces infarct size, increases cardiac ejection fraction, in-
creases stroke volume, and increases mechanical efficiency
without increasing oxygen consumption.19,20 Clinically, rano-
lazine, as an anti-ischemic agent, has been shown to increase
exercise capacity and time to 1-mm ST-segment depression,
and reduce the number of weekly angina attacks and nitro-
glycerin consumption as a monotherapy or combined ther-
apy.21 However, a recent study showed that ranolazine had
no incremental benefit in angina or quality of life in patients
with incomplete revascularization after PCI.22 b-Adrenoceptor
antagonists (b-blockers) are classic drugs used in the setting

274 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Revascularization in angina patients: addressing cardiac metabolism challenges Lopaschuk

of angina. This class of drug is believed to exert an oxygen-
sparing effect by a reduction in inotropic and chronotropic
effects, thus reducing cardiac workload. However, blockade
of b-adrenoceptors decreases catecholamine-induced lipol-
ysis and therefore decreases plasma fatty acid availability
and extraction. As a result, part of the benefit of b-blockade
in the setting of angina may occur secondary to decreased
myocardial fatty acid oxidation. Indeed, carvedilol has been
shown to reduce myocardial free fatty acid uptake by 57%
in patients with heart failure.23
In addition to inhibiting fatty acid oxidation, directly increas-
ing myocardial glucose oxidation may be another approach
to optimizing energy metabolism in angina. Dichloroacetate
(DCA) acts via direct stimulation of the mitochondrial PDH
complex via the inhibition of the activity of PDH kinase. The
improved coupling between glycolysis and glucose oxida-
tion is believed to be the mechanism by which DCA exerts
its cardioprotective effects.7,24 Experimental studies show that
DCA is cardioprotective in the setting of ischemia and reper-
fusion (see Lopaschuk et al2 for review). However, clinical data
on the use of DCA is scarce. In a small clinical study, where
DCA was given to patients with CAD via intravenous infusion,
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improvements in left ventricular stroke volume were observed
in the absence of changes in heart rate, left ventricular end
diastolic pressure, or myocardial oxygen consumption.25 The
poor potency and pharmacokinetic profile of DCA make it
unlikely that this drug will ever be used clinically.
Conclusion
Alterations in cardiac energy metabolism are an important
factor in the severity of angina in both the revascularized and
nonrevascularized patient. Significant metabolic changes re-
sult in an increase in the contribution of fatty acid oxidation
compared with glucose oxidation to cardiac energy produc-
tion, that leads to a decrease in cardiac efficiency. A challenge
in the revascularized angina patient is to normalize cardiac
energy metabolism and to improve cardiac efficiency. Thera-
peutic strategies aimed at inhibiting fatty acid oxidation are
one potential approach to optimizing energy metabolism in
the angina patient. One such approach is to directly inhibit
fatty acid oxidation with trimetazidine, which leads to an in-
direct increase in glucose oxidation in the heart. The subse-
quent improvement in cardiac efficiency is associated with
beneficial effects of trimetazidine in decreasing angina symp-
toms, even in the revascularized patient. n
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Circulation. 1996;93:135-142.
20. Clarke B, Spedding M, Patmore L, McCormack JG. Protective effects of ra-
nolazine in guinea-pig hearts during low-flow ischaemia and their association
with increases in active pyruvate dehydrogenase. Br J Pharmacol. 1993;109:
748-750.
21. Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol,
amlodipine, or diltiazem on exercise tolerance and angina frequency in patients
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22. Alexander KP, Weisz G, Prather K, et al. Effects of ranolazine on angina and
quality of life after percutaneous coronary intervention with incomplete revas-
cularization: results from the Ranolazine for Incomplete VEssel Revascular-
ization (RIVER-PCI) Trial. Circulation. 2016;133(1):39-47.
23. Al-Hesayen A, Azevedo ER, Floras JS, Hollingshead S, Lopaschuk GD, Parker
JD. Selective versus nonselective b-adrenergic receptor blockade in chronic
heart failure: differential effects on myocardial energy substrate utilization. Eur
J Heart Fail. 2005;7:618-623.
24. Liu B, Clanachan AS, Schulz R, Lopaschuk GD. Cardiac efficiency is improved
after ischemia by altering both the source and fate of protons. Circ Res. 1996;
79:940-948.
25. Wargovich TJ, MacDonald RG, Hill JA, Feldman RL, Stacpoole PW, Pepine CJ.
Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary
artery disease. Am J Cardiol. 1988;6:65-70.
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Keywords: fatty acid oxidation; glucose oxidation; pyruvate dehydrogenase

LA REVASCULARISATION CHEZ LES PATIENTS ANGOREUX :

TRAITER LES PERTURBATIONS DU MTABOLISME CARDIAQUE
La survenue dune crise dangor sassocie des perturbations considrables du mtabolisme nergtique car-
diaque. Un dsquilibre entre besoins et apports en O2 au niveau du muscle cardiaque entrane une diminution du
mtabolisme oxydatif mitochondrial, aboutissant un tat de dficit nergtique dans le cur. De plus, des modi-
fications de la source des substrats du mtabolisme nergtique mitochondrial cardiaque contribuent une dys-
fonction contractile et une diminution de lefficacit cardiaque. Parmi ces modifications on compte une augmen-
tation de la contribution de loxydation des acides gras au mtabolisme oxydatif mitochondrial rsiduel et un d-
couplage entre la glycolyse et loxydation du glucose. La revascularisation peut rduire les symptmes angoreux,
principalement en diminuant le dsquilibre entre besoins et apports en O2 au niveau du muscle cardiaque. Ce-
pendant, mme si la revascularisation permet daccroitre lapport en O2 , certaines altrations du mtabolisme car-
diaque persistent aprs la revascularisation. Notamment, le muscle devient trop dpendant de loxydation des acides
gras comme source dnergie, principalement aux dpens de loxydation du glucose. Ce mcanisme accroitre le
dcouplage entre la glycolyse et loxydation du glucose, aboutissant une diminution prolonge de lefficacit car-
diaque. Cest ainsi que la difficult chez les patients angoreux vasculariss est de normaliser le mcanisme nerg-
tique cardiaque et damliorer lefficacit cardiaque. Daprs des donnes rcentes, un traitement visant rguler
le mtabolisme nergtique cardiaque en diminuant loxydation des acides gras, ce qui augmente loxydation du glu-
cose, peut permettre damliorer lefficacit et la fonction cardiaques et diminuer les symptmes dangor, mme chez
les patients revasculariss. Dans cet article, nous analysons les modifications mtaboliques nergtiques mitochon-
driales cardiaques qui interviennent au niveau du cur chez les patients angoreux et les changements apparais-
sant au cours de la revascularisation, ainsi que la possibilit de cibler loxydation des acides gras pour traiter langor
chez les patients revasculariss ou non revasculariss.

276 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Revascularization in angina patients: addressing cardiac metabolism challenges Lopaschuk

Although the development of
drug-eluting stents to solve in-stent
restenosis has markedly reduced
the extent of restenosis after an-
gioplasty, there is concern about
delayed reendothelialization and
late in-stent thrombosis. Various
strategies to prevent restenosis by
stimulating endothelialization or by
inhibiting vascular smooth muscle
cell (VSMC) proliferation have thus
been tried. However, few reports
have identified optimal agents with
cell-specific effects on VSMCs and
endothelial cells.
Soo LIM, MD, PHD
Department of Internal Medicine
Seoul National University College
of Medicine, Seoul National
University Bundang Hospital
Seongnam, SOUTH KOREA
Address for correspondence:
Soo Lim, Associate Professor of
Medicine, Department of Internal
Medicine, Seoul National University
College of Medicine, Seoul National
University Bundang Hospital,
300, Gumi-dong, Bundang-gu,
Seongnam-city, South Korea
(Postal code: 463-707)
(email: limsoo@snu.ac.kr)
www.medicographia.com
Trimetazidine and endothelial function Lim
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
T he endothelium: a therapeutic
target in post-PCI patients
and the role of trimetazidine
in endothelial function
b y S . L i m , S o u t h Ko re a
T
he vascular endothelium, the surface monolayer of the vascular wall,
plays an important role in the maintenance of vascular health. It releas-
es various mediatorssuch as angiotensin II, endothelin-1, endothe-
lium-derived hyperpolarizing factor, nitric oxide, prostacyclin, prostaglandin
H2 , and thromboxane A2 that are involved in vasodilation or vasoconstric-
tion under specific conditions. Dysfunction of the endothelium has been im-
plicated in various vascular pathophysiological processes, including abnor-
mal vascular proliferation, excessive thrombus formation, vasoconstriction, and
vasospasm. It is also associated with restenosis after percutaneous coronary
intervention (PCI). However, there are few clinical studies on the use of phar-
macological agents to improve endothelial function and decrease the rate
of restenosis after PCI. Trimetazidinean agent possessing a broad spectrum
of pharmacological activities, including protection against damage to the car-
diovascular systemhas recently been shown to improve vascular endothe-
lial cell function and may reduce the risk of restenosis after PCI. These actions
occur through antioxidative and anti-inflammatory activities, increased adipo-
nectin levels, and decreased insulin resistance. Although there is no direct ev-
idence that trimetazidine can reduce cardiovascular morbidity and mortality,
reductions in these may result indirectly from its effects on endothelial func-
tion. Prospective studies with a cardiovascular end point as a primary objec-
tive are warranted to confirm the cardioprotective effects of trimetazidine.
Medicographia. 2016;38:277-281 (see French abstract on page 281)
orldwide, cardiovascular disease (CVD) and stroke impose huge health
W and economic burdens, with CVD being the number one cause of death
globally.1 Roughly 17.5 million people died from CVD in 2012, repre-
senting 31% of all global deaths. An estimated 7.4 million of these CVD deaths
were due to coronary heart disease and 6.7 million, stroke. In the United States, in
2011, CVD accounted for 31.3% (786 641) of the 2 515 458 deaths overall, with a
CVD death rate of 229.6 per 100 000 Americans2 (275.7 in men, 192.3 in women),
this after a 30.8% decline in CVD death rate and 15.5% decline in actual number
of CVD deaths from 2001 to 2011.2
The prevalence of diabetes mellitus is increasing rapidly worldwide, and this increase
implies an increase in vascular complications. Vascular complications in the heart,
brain, and peripheral arteries are more than twice as prevalent in people with dia-
betes compared with those without diabetes. Nearly 80% of people with diabetes
MEDICOGRAPHIA, Vol 38, No. 3, 2016 277
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C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A

Figure 1. Role of endothelial dysfunction

in the development of restenosis after
percutaneous coronary intervention.
Abbreviations: eNOS, endothelial nitric oxide synthase;
PCI, percutaneous coronary intervention;
ROS, reactive oxygen species.

die from CVDs, such as coronary heart dis-

ease, cerebrovascular disease, and periph-
eral artery occlusive disease. Therefore, the
vascular complications of diabetes are now
an important public health priority world-
wide.

A 2015 statistical report on heart disease

and stroke in the United States demonstrat-
ed that the number of percutaneous coro-
nary intervention (PCI) procedures is increas-
ing.2 In patients undergoing PCI, the use
of drug-eluting stents (DESs) has greatly re-
duced the need for reintervention compared
with the use of bare metal stents (BMSs).3,4
However, the incidence of in-stent restenosis in patients af- cated, contribute to restenosis.7 Many people with diabetes
ter PCI, using either DESs or BMSs, remains high.5 Thus, in- have increasingly complex lesion characteristics and disease
stent restenosis continues to be a major problem after coro- comorbidities,6 and the risk for restenosis is high among di-
nary stenting.6 abetics.8

Endothelial dysfunction, a key step in the The vascular endotheliumthe surface monolayer of the vas-
development of restenosis after PCI cular wallplays a critical role in the maintenance of vascu-
Restenosis is the recurrence of narrowing of the coronary ar- lar health. In response to physical and chemical stimuli, it re-
tery in a maladaptive response to damage caused by angio- leases various vasoactive mediators, such as angiotensin II,
plasty. Chronic exposure to cardiovascular risk factors, such endothelin-1, endothelial cell growth factors, endothelium-
as high blood pressure, high blood glucose concentration, dependent hyperpolarizing factor, interleukins, plasminogen
dyslipidemia, smoking, and low physical activity level impair inhibitors, prostacyclin, prostaglandin H2, nitric oxide, and
the defense mechanisms in the vascular endothelium (Fi- thromboxane A2.
gure 1). Chronic inflammation and oxidative stress are well-
known causes of endothelial dysfunction, which along with Although the development of DESs to solve in-stent resteno-
proliferation of vascular cells, production of extracellular ma- sis has markedly reduced the extent of restenosis after angio-
trix, platelet activation, and increased thrombotic activity, plasty,9 there is concern about delayed reendothelialization
processes in which endothelial dysfunction has been impli- and late in-stent thrombosis.10 Various strategies to prevent
restenosis by stimulating endothelialization or by inhibiting vas-
cular smooth muscle cell (VSMC) proliferation have thus been
SELECTED ABBREVIATIONS AND ACRONYMS
tried. However, few reports have identified optimal agents with
CVD cardiovascular disease cell-specific effects on VSMCs and endothelial cells.
DES drug-eluting stent
HUVEC human umbilical vein endothelial cell Role of trimetazidine in preventing the
LysoPC lysophosphatidylcholine
development of endothelial dysfunction and in
reducing the incidence of restenosis after PCI
MCP-1 monocyte chemoattractant protein-1
The piperazine derivative trimetazidine (1-[2,3,4-trimethoxy-
OLETF Otsuka Long-Evans Tokushima Fatty [rat]
benzyl] piperazine dihydrochloride) is an anti-ischemic drug
PCI percutaneous coronary intervention effective in treating patients with angina pectoris (Figure 2).11
ROS reactive oxygen species Protective effects on cardiomyocytes have been shown in pa-
SD Sprague Dawley [rat] tients treated in primary intervention via coronary artery graft
TNF-a tumor necrosis factor a surgery.11 Trimetazidines beneficial effects on heart failure and
VSMC vascular smooth muscle cell ischemic heart disease are related to cardiac energy metab-
olism, which shifts from fatty acid oxidation to glucose oxida-

278 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Trimetazidine and endothelial function Lim
 M E TA B O L I C AGENTS IN THE
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In addition, we found that trimetazidine suppresses caspase-3

activity.14 The effect of trimetazidine on apoptosis in HUVECs
was also assessed by measuring mitochondrial membrane
Figure 2. function.14 Compared with LysoPC-treated HUVECs, the num-
Chemical struc- ber of apoptotic cells was markedly lower in the trimetazidine-
ture of trimetazi- treated groups. After LysoPC treatment, the ratio of active
dine (1-[2,3,4- versus inactive caspase-3 was significantly higher than in
trimethoxybenzyl] controls,14 and trimetazidine lowered the active caspase-3
piperazine dihy-
drochloride). ratio in a dose-dependent manner.

tion through trimetazidines inhibition of mitochondrial long- These findings from in vitro cell studies and in vivo animal
chain 3-ketoacyl coenzyme A thiolase; this may contribute studies indicate that trimetazidine helps to prevent damage
to its antianginal effect (Figure 3).12 In addition to trimetaz- to the coronary vasculature and to reduce neointimal prolif-
dines myocardial anti-ischemic effect, it has a vasodilatory eration after vascular injury by way of targeting both vascular
effect on coronary vessels.13 endothelial cells and VSMCs. Recent studies have shown that
trimetazidine has a protective effect against restenosis after
We have recently shown that trimetazidine has beneficial ef- PCI in humans.17-19 In one study, trimetazidine treatment for
fects on the occurrence of restenosis after vascular balloon 10 weeks lessened endothelial damage in the radial artery af-
injury in diabetes.14 We investigated whether trimetazidine ter transradial coronary artery angiography or transradial PCI.19
treatment can lower the extent of restenosis occurring in the Another study of longer duration showed that trimetazidine
carotid artery after balloon injury in animal models of dia- treatment reduced the incidence of in-stent restenosis after
betes, both type 1 (streptozotocin-injected Sprague Dawley PCI with DES implantation measured at the 1-year follow-up.20
[SD] rats) and type 2 (Otsuka Long-Evans Tokushima Fatty There were also fewer major adverse cardiac events in the
[OLETF] rats). OLETF rats represent an obese model of type 2 trimetazidine-treated group than in the control group.
diabetes, in which 5-week-old rats are al-
lowed to grow to 24 weeks of age, at which
time obesity and insulin resistance devel-
op.15 Rats from both models were treated
with trimetazidine at different concentrations
or were sham treated with normal saline,
and a well-established balloon injury pro-
cedure16 was carried out in the carotid artery.
Two weeks after the procedure, the trimeta-
zidine-treated rats in both models showed
significantly less neointimal formation than
controls; in the type 1 diabetes model, trime-
tazidine-treated rats also had lower mean
intima-media ratios (this was dose depend-
ent) and markedly lower in vivo cell prolifer-
ation (as measured by immunostaining for
proliferating cell nuclear antigen) than con-
trols.14

A series of in vitro experimental studies have

shown that reendothelialization after bal-
loon injury is accelerated by trimetazidine Figure 3. Mechanism of action of trimetazidine in energy metabolism in cardiomyocytes.
treatment.17,18 In one study, trimetazidine had Abbreviations: ATP, adenosine triphosphate; CoA, coenzyme A.
a direct effect on endothelial proliferation in
human umbilical vein endothelial cells (HUVECs).14 Prolifer- Antioxidant effects of trimetazidine
ation of HUVECs incubated in medium containing 20 mM There is a large amount of evidence that oxidative stress
lysophosphatidylcholine (LysoPC) was about 20% lower than plays a role in the pathogenesis of diabetes, as well as in di-
in controls. Trimetazidine treatment restored cell proliferation abetic complications such as atherosclerosis and resteno-
in a concentration-dependent manner. Similarly, HUVEC pro- sis.21 Indeed, in the vascular wall, oxidative stress may be a
liferation was decreased by tumor necrosis factor a (TNF-a) key mechanism in processes leading to endothelial dysfunc-
treatment and recovered with trimetazidine treatment.14 tion22; it promotes VSMC migration and proliferation and is

Trimetazidine and endothelial function Lim MEDICOGRAPHIA, Vol 38, No. 3, 2016 279
M E TA B O L I C AGENTS IN THE
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Figure 4. Cardioprotective effects of trimetazidine.
involved in abnormal VSMC cell growth after balloon injury.7,23
We have shown that trimetazidine treatment lowers, in a dose-
dependent manner, the cellular production of reactive oxy-
gen species (ROS) in HUVECs treated with LysoPC,14 which
is known to generate ROS.8 Repeated administration of tri-
metazidine reduces production of mitochondrial ROS in rats,
and pretreatment with trimetazidineadded to cardioplegic
solutionreduces oxidative damage in human patients.9,10
Also, the ischemia-induced increase in free radical produc-
tion is attenuated by trimetazidine treatment before the onset
of ischemia in rat hearts.24 The antioxidant effects of trimeta-
zidine occur in various cells of the cardiovascular system.11
Effect of trimetazidine on the inflammatory
process and on adipocytokines
Early after endothelial denudation, an infiltration of inflamma-
tory cells occurs in the vascular wall,25 with the presence of
monocytes associated with the neointimal area.26 Neointimal
thickening has been shown to be lessened with the use of
anti-inflammatory agents that block the early recruitment of
monocytes.27 Collectively, these findings suggest a causative
role for inflammation and its associated monocyte infiltration
in the development of restenosis.
Previous studies have reported that specific markersinclud-
ing the adipocytokines adiponectin, monocyte chemoattrac-
tant protein-1 (MCP-1), and TNF-a, and also the inflamma-
tory marker high-sensitivity C-reactive protein (hsCRP)can
affect the development of restenosis and atherosclerosis.28-30
A low adiponectin concentration is a risk factor for the sub-
sequent development of CVDs.28 MCP-1 is involved in mono-
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Here, I have described substantial evidence
to support the concept that trimetazidine
plays a positive role in reducing the extent
of restenosis after PCI and have suggested
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Trimetazidine has a broad spectrum of pharmacological ac-
tivities that provide cardiovascular protection through its an-
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improved endothelial dysfunction (Figure 4). Therefore, using
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7. Griendling KK, Ushio-Fukai M. Redox control of vascular smooth muscle
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9. Guarnieri C, Muscari C. Beneficial effects of trimetazidine on mitochondrial func-
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ed rats. Biochem Pharmacol. 1988;37(24):4685-4688.
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trophil activation induced by reperfusion in the ischaemic human heart. Eur
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Circ Res. 2000;86(5):580-588.
13. Onay-Besikci A, Guner S, Arioglu E, Ozakca I, Ozcelikay AT, Altan VM. The ef-
fects of chronic trimetazidine treatment on mechanical function and fatty acid
oxidation in diabetic rat hearts. Can J Physiol Pharmacol. 2007;85(5):527-535.
14. Yoon JW, Cho BJ, Park HS, et al. Differential effects of trimetazidine on vascu-
lar smooth muscle cell and endothelial cell in response to carotid artery bal-
loon injury in diabetic rats. Int J Cardiol. 2013;167(1):126-133.
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and accumulation of myocardial collagen at insulin-resistant prediabetic stage
of a type II diabetic rat model. Circulation. 2000;101(8):899-907.
16. Clowes AW, Reidy MA, Clowes MM. Kinetics of cellular proliferation after ar-
terial injury. I. Smooth muscle growth in the absence of endothelium. Lab In-
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17. Belardinelli R, Solenghi M, Volpe L, Purcaro A. Trimetazidine improves en-
dothelial dysfunction in chronic heart failure: an antioxidant effect. Eur Heart J.
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18. Park KH, Park WJ, Kim MK, et al. Effects of trimetazidine on endothelial dys-
function after sheath injury of radial artery. Am J Cardiol. 2010;105(12):1723-1727.
19. Park KH, Park DW, Kim MK, et al. Effects of sheath injury and trimetazidine on
endothelial dysfunction of radial artery after transradial catheterization. J In-
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21. Kanellakis P, Nestel P, Bobik A. Angioplasty-induced superoxide anions and
neointimal hyperplasia in the rabbit carotid artery: suppression by the isoflavone
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24. Maupoil V, Rochette L, Tabard A, Clauser P, Harpey C. Evolution of free radi-
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Cardiovasc Drugs Ther. 1990;4(suppl 4):791-795.
25. Moreno PR, Fallon JT, Murcia AM, et al. Tissue characteristics of restenosis af-
ter percutaneous transluminal coronary angioplasty in diabetic patients. J Am
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26. Rogers C, Welt FG, Karnovsky MJ, Edelman ER. Monocyte recruitment and
neointimal hyperplasia in rabbits. Coupled inhibitory effects of heparin. Arte-
rioscler Thromb Vasc Biol. 1996;16(10):1312-1318.
27. Mori E, Komori K, Yamaoka T, et al. Essential role of monocyte chemoattrac-
tant protein-1 in development of restenotic changes (neointimal hyperplasia and
constrictive remodeling) after balloon angioplasty in hypercholesterolemic rab-
bits. Circulation. 2002;105(24):2905-2910.
28. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adipo-
nectin levels and risk of myocardial infarction in men. JAMA. 2004;291(14):
1730-1737.
29. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive pro-
tein on human endothelial cells. Circulation. 2000;102(18):2165-2168.
30. Tousoulis D, Antoniades C, Stefanadis C. Assessing inflammatory status in car-
diovascular disease. Heart. 2007;93(8):1001-1007.
31. Nishida M, Miyagawa JI, Tokunaga K, et al. Early morphologic changes of ath-
erosclerosis induced by ventromedial hypothalamic lesion in the spontaneous-
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32. Tulis DA. Rat carotid artery balloon injury model. Methods Mol Med. 2007;139:
1-30.

Keywords: endothelium; inflammation; oxidative stress; percutaneous coronary intervention; restenosis; trimetazidine

LENDOTHLIUM COMME CIBLE THRAPEUTIQUE CHEZ LES PATIENTS

EN POST-ICP ET RLE DE LA TRIMTAZIDINE DANS LA FONCTION ENDOTHLIALE
Lendothlium vasculaire, la monocouche de surface de la paroi vasculaire, joue un rle important dans le maintien
de la sant vasculaire. Il libre diffrents mdiateurs impliqus dans la vasodilatation ou la vasoconstriction en condi-
tions particulires, comme langiotensine 2, lendothline-1, le facteur hyperpolarisant driv de lendothlium, le
dioxyde dazote, la prostaglandine H2 et le thromboxane A2 . Un dysfonctionnement de lendothlium a t impliqu
dans diffrents processus physiopathologiques vasculaires, y compris une prolifration vasculaire anormale, une for-
mation excessive de thrombus, une vasoconstriction et un vasospasme. Ce dysfonctionnement sassocie aussi une
restnose aprs intervention coronaire percutane (ICP). Pourtant, les tudes cliniques sur lutilisation des agents
pharmacologiques pour amliorer la fonction endothliale et diminuer le taux de restnose aprs ICP sont peu nom-
breuses. La trimtazidine, un agent au spectre dactivit pharmacologique large protgeant contre les atteintes du
systme cardiovasculaire, amliore la fonction cellulaire endothliale vasculaire et rduit le risque de restnose aprs
ICP grce ses proprits antioxydantes et anti-inflammatoires, qui augmentent les taux dadiponectine et dimi-
nuent la rsistance linsuline. Aucune donne directe nindique que la trimtazidine rduit la morbimortalit car-
diovasculaire, mais une diminution de la morbidit et de la mortalit pourrait rsulter indirectement de son effet sur
la fonction endothliale. Des tudes prospectives ayant pour objectif principal dvaluer la morbimortalit cardio-
vasculaire sont ncessaires pour confirmer les effets cardioprotecteurs de la trimtazidine.

Trimetazidine and endothelial function Lim MEDICOGRAPHIA, Vol 38, No. 3, 2016 281

[We have] sufficient reason to
believe that for elective percuta-
neous coronary intervention (PCI)
patients, pre- or perioperative treat-
ment with trimetazidine reduces
PCI-related myocardial and vascu-
lar injury and improves heart func-
tion; and that for acute coronary
syndrome patients, an acute oral
loading dose of trimetazidine or
long-term treatment with trimetazi-
dine after stent implantation would
also benefit these patients.
Yundai CHEN, MD, PhD
Department of Cardiology
Chinese PLA General Hospital
Beijing, CHINA
Address for correspondence:
Professor Yundai Chen, Department
of Cardiology, Chinese PLA General
Hospital, Beijing, China, 100853.
(email: cyundai@vip.163.com)
www.medicographia.com
282 MEDICOGRAPHIA, Vol 38, No. 3, 2016
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
Metabolic agents in the
protection of patients who
undergo revascularization
b y Y. C h e n , C h i n a
I
n clinical practice, metabolic agents, including trimetazidine, ranolazine,
and glucose-insulin-potassium, often play an adjunctive role in the treat-
ment of angina pectoris. With the worldwide use of percutaneous coronary
intervention, especially stent implantation, doctors have come to realize that
some patients still suffer from angina, percutaneous coronary intervention
related complications, or poor quality of life. For such reasons, researchers
have used metabolic agents to treat patients who have undergone percuta-
neous coronary interventions, and some progress has been observed in this
area. In this review article, we mainly discuss the protective role of three wide-
ly used agents: trimetazidine, ranolazine, and glucose-insulin-potassium in pa-
tients with coronary artery disease, with a particular focus on patients who
have undergone percutaneous coronary intervention. Aside from these three,
there are other metabolic agents requiring further investigation to confirm their
benefits for patients undergoing revascularization.
Medicographia. 2016;38:282-287 (see French abstract on page 287)
n recent years, evidence-based medicine has demonstrated that revasculariza-
I tion can save lives in patients with acute coronary syndrome (ACS) and improve
their quality of life. Research has shown that some metabolic agents could further
benefit those patients and reduce ischemia-reperfusion injury or percutaneous coro-
nary intervention (PCI)-related injury. Metabolic agents proven to be useful in pa-
tients who undergo revascularization include trimetazidine, ranolazine, L-carnitine,
glucose-insulin-potassium (GIK), ribose, dichloroacetate, and perhexiline, of which
trimetazidine, ranolazine, and GIK were the most evaluated in recent years.
Metabolic agents as adjunctive therapy in patients undergoing PCI
u Trimetazidine
Trimetazidine, a piperazine derivative, has a long history of research, especially with
regard to cardiac protection. Used worldwide as an adjunctive therapy for stable
angina, trimetazidines protective effect in patients that undergo PCI has become
a research focus.
In a small (n=20), randomized, double-blind, placebo-controlled trial, Kober et al found
that trimetazidine treatment during percutaneous transluminal coronary angioplas-
ty (PTCA) decreases intervention-related myocardial ischemia.1 Polonski et al re-
ported that pretreatment with trimetazidine appears to be cardioprotective, helping
to prevent myocardial ischemia during PTCA.2 In a study by Steg and his colleagues,
Metabolic agents in the protection of patients who undergo revascularization Chen

patients with acute myocardial infarction (AMI) were pre-
scribed intravenous trimetazidine as an adjunctive therapy to
primary angioplasty. The authors demonstrated that trimetazi-
dine was safe and led to earlier resolution of ST-segment ele-
vation.3 Later, in a prospective study, Labrou et al demonstrat-
ed that pretreatment with trimetazidine minimizes myocardial
reperfusion injury during PCI and improves global and region-
al wall motion at 1 and 3 months after PCI.4 This result was fur-
ther supported by a multicenter, randomized, and controlled
study aiming to evaluate the myocardial protection of trimetazi-
dine during PCI; the results suggested that perioperative tri-
metazidine therapy can reduce the frequency of angina at-
tacks and myocardial damage during PCI and improve left
ventricular function during follow-up after PCI.5 A study specif-
ically aimed at the effect of trimetazidine on recurrent angina
and left ventricular structure in elderly multivessel coronary
heart disease patients with diabetes mellitus after drug-elut-
ing stent implantation also found that adjunctive therapy
with trimetazidine had a beneficial effect in these patients.6
For elective PCI patients, pretreatment with trimetazidine is a
reasonable option; but what about acute PCI patients? To an-
swer this question, Bonello et al carried out a study focus-
ing on the protective effect of an acute oral loading dose of
trimetazidine on myocardial injury induced by PCI. The results
suggested that preprocedural acute oral trimetazidine admin-
istration significantly reduces PCI-induced myocardial injury.7
Aside from patients undergoing PCI, researchers also stud-
ied trimetazidines effect on ischemic injury and reperfusion in
patients undergoing coronary artery bypass graft (CABG) sur-
gery, with the same result.8,9
u Cardioprotective mechanism
A number of investigations have looked into the mechanism in-
volved in the cardioprotection afforded by trimetazidine. Tritto
et al showed us that trimetazidine protects the post-ischemic
heart from neutrophil-mediated injury.10 In an ischemia-injury
SELECTED ABBREVIATIONS AND ACRONYMS
ACS acute coronary syndrome
AMI acute myocardial infarction
CABG coronary artery bypass graft
CIN contrast-induced nephropathy
GIK glucose-insulin-potassium
IMMEDIATE Immediate Myocardial Metabolic Enhancement
During Initial Assessment and Treatment in
Emergency care [trial]
MACE major adverse cardiac event
PCI percutaneous coronary intervention
POAF post-revascularization atrial fibrillation
PTCA percutaneous transluminal coronary angioplasty
RIVER-PCI Ranolazine for Incomplete Vessel Revascular-
ization [trial]
Metabolic agents in the protection of patients who undergo revascularization Chen
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
rat model, Khan et al found that trimetazidine administered
at the onset of reperfusion ameliorates myocardial dysfunc-
tion and injury by activation of p38 mitogen-activated pro-
tein kinase and Akt signaling.11 In a recent study, Yang et al
revealed that by upregulating microRNA-21 (miR-21) expres-
sion, trimetazidine counteracts the apoptotic effect of hypox-
ia/reperfusion.12 Consistent with previous studies, Senturk et
al found that combination of N-acetylcysteine and trimetazi-
dine effectively decreases oxidative stress, infarct area, and
apoptotic activity in a rat model of ischemic reperfusion.13 Tri-
metazidine also improves endothelium-dependent relaxation
in patients with ischemic cardiomyopathy, owing to its anti-
oxidant properties.14 A recent experimental study suggested
that trimetazidine ameliorates intracellular calcium (Ca2+) home-
ostasis via a switch from lipid metabolism to glucose metab-
olism, thereby producing its cardioprotective effect and reduc-
ing damage to hypoxic cardiomyocytes.15
On the basis of these findings, Kim et al analyzed data from
the Korean Acute Myocardial Infarction Registry and found
that trimetazidine improves clinical outcomes in AMI patients
by significantly reducing all-cause mortality and major ad-
verse cardiac events (MACEs) over 12 months.16 For specific
patients, such as diabetic patients with renal dysfunction un-
dergoing elective PCI, a study demonstrated that trimetazi-
dine administered before elective PCI decreases the incidence
of contrast-induced nephropathy (CIN).17
Our team also demonstrated that long-term treatment with
trimetazidine after stent implantation reduced in-stent resteno-
sis and MACE in a 1-year follow-up study.18 In this study, 768
patients were enrolled and randomized into a trimetazidine
group (n=384) or a control group. After drug-eluting stent im-
plantation, all patients were treated with regular medication.
In the trimetazidine group, 20 mg trimetazidine was admin-
istered three times a day for at least 30 days. All patients re-
ceived follow-up angiography 9-13 months after discharge.
The final analysis included 635 patients (trimetazidine group,
n=312; control group, n=323). Stent restenosis occurred in
49 (7.7%) patients. The trimetazidine group had a lower in-
cidence of stent restenosis than the control group (4.2% vs
11.1%; P=0.001). At the 30-day follow-up, the trimetazidine
group exhibited a higher left ventricular ejection fraction than
the control group (65.410.7 vs 63.110.4; P=0.006). The in-
cidence of major adverse cardiac and cerebrovascular events
(MACCEs) was also lower in the trimetazidine group at the
1-year follow-up (6.1% vs 10.8%; P=0.032). Further multivari-
ate analysis revealed that trimetazidine treatment was a pre-
dictor for stent restenosis (odds ratio, 0.376; 95% confidence
interval, 0.196-0.721; P=0.003). This result was also support-
ed by a Sprague-Dawley rat model experiment that demon-
strated that trimetazidine inhibits the proliferation and mi-
gration of vascular smooth muscle cells and promotes the
proliferation of human umbilical vein endothelial cells.19
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Aside from these benefits for the heart, trimetazidine also pro-
tects the artery from PCI-related injury. Yoon et al reported
that trimetazidine effectively accelerates re-endothelialization
after carotid balloon injury.20 Recent studies have also demon-
strated that trimetazidine significantly lessens endothelial dys-
function in the radial artery after catheterization.21,22 In a re-
cent meta-analysis, the authors concluded from nine studies
involving a total of 778 patients that adjunctive therapy with
trimetazidine in patients undergoing PCI may reduce myocar-
dial injury during the procedure and improve cardiac func-
tion.23
u Other protective effects
Besides the protective effect on the cardiovascular system,
recent studies suggest that trimetazidine may have poten-
tial for use in prevention of CIN. In one meta-analysis includ-
ing three randomized controlled trials in the final analysis, the
addition of trimetazidine treatment significantly decreased
the incidence of CIN in patients that underwent coronary an-
giography.24 The authors pointed out that care should be tak-
en in the interpretation of this result, taking into account the
small sample size.
u Final comments about trimetazidine
Collectively, these studies provide sufficient reason to believe
that for elective PCI patients, pre- or perioperative treatment
with trimetazidine reduces PCI-related myocardial and vas-
cular injury and improves heart function; and that for ACS
patients, an acute oral loading dose of trimetazidine or long-
term treatment with trimetazidine after stent implantation would
also benefit these patients; however, the use of trimetazidine
for preventing CIN is not recommended as first-line therapy
and still needs to be assessed in more clinical trials.
u Ranolazine
Ranolazine is another drug used as an adjunctive therapy for
angina in symptomatic patients who are inadequately con-
trolled with first-line antianginal therapies.25,26 Among diabet-
ic patients that have chronic angina despite treatment with up
to two agents, ranolazine was found to reduce angina and
sublingual nitroglycerin use and to be well tolerated.27 A sys-
tematic review of randomized controlled trials included sev-
en studies and concluded that ranolazine reduces anginal
symptoms among patients with symptomatic chronic stable
angina pectoris28 and is probably cost effective.29 Recent stud-
ies have shown additional benefits of ranolazine in patients
with coronary heart disease. Some experimental studies have
demonstrated that ranolazine reduces myocardial infarct size
and improves left ventricular function.30,31 It also markedly
reduces ventricular arrhythmias induced by ischemia and
ischemia-reperfusion, indicating a protective role in PCI in pa-
tients with ACS.32 Possible mechanisms involved in these phe-
nomena include reduction in Ca2+ overload and oxidative stress
and improvement in mitochondrial integrity.33-35 On the basis
of these findings, some clinical research focused on the role
284 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Metabolic agents in the protection of patients who undergo revascularization Chen
of ranolazine in post-revascularization atrial fibrillation (POAF).
Tagarakis et al found a protective role for oral ranolazine when
administered preoperatively at a moderate dose in patients
undergoing on-pump CABG surgery. Their findings suggest
that perioperative treatment with ranolazine effectively re-
duces the incidence of POAF,36 a result that has been sup-
ported by further studies.37-39 In patients that underwent PCI,
ranolazine has been found to reduce recurrent ischemic events
and improve quality of life.40,41
However, as presented at the 2015 American Heart Asso-
ciation (AHA) Scientific Sessions, the RIVER-PCI study (Ra-
nolazine for Incomplete Vessel Revascularization) showed
no incremental benefit in angina or quality of life measures from
adding ranolazine treatment in an angiographically-identified
population.42 Furthermore, an overall analysis of this study re-
vealed that ranolazine did not reduce the composite rate of
ischemia-driven revascularization or hospitalization without
revascularization in patients with a history of chronic angina
who had incomplete revascularization after PCI.43
u Final comments about ranolazine
In our opinion, despite a confirmed role for ranolazine in angi-
na frequency and in quality of life, further investigationwell-
designed clinical trials, especiallyare warranted to evaluate
its effect in CAD patients undergoing PCI. The use of ranola-
zine in patients that are to undergo PCI should not be en-
couraged for now.
u Glucose-insulin-potassium
GIK has been used as metabolic therapy in practice for many
years. Earlier studies found that GIK improves hemodynam-
ic performance and is associated with reduced troponin I
release after on-pump CABG surgery.44,45 It also improves
myocardial perfusion after revascularization and lessens the
LV remodeling observed at follow-up.46,47 These results are
supported by other experimental research.48,49 However, a
1-year follow-up study found that GIK therapy offers no clin-
ical benefit in patients with ST-elevated myocardial infarction
(STEMI) without signs of heart failure.50 Further meta-analysis
also suggested that GIK does not reduce mortality in patients
with AMI.51 Despite these negative results, some important
studies were carried out to determine the effect of GIK on pa-
tients with CAD. In the IMMEDIATE randomized controlled
trial (Immediate Myocardial Metabolic Enhancement During
Initial Assessment and Treatment in Emergency care), Selker
et al found that in patients with suspected ACS, out-of-hos-
pital treatment with GIK did not reduce progression to MI and
although it did not improve 30-day survival, it was associat-
ed with lower rates of the composite outcome comprising
cardiac arrest and in-hospital mortality.52 Similar results were
found in a 1-year follow-up of this study, whereas in those
with STEMI, the composite of cardiac arrest or 1-year mortal-
ity, and of cardiac arrest, mortality, or hospitalization for heart
failure within 1 year, were significantly reduced. This benefit

might be limited to AMI patients.53 A further meta-analysis also
revealed that administration of GIK in ACS patients did not
significantly reduce mortality after the onset of symptoms.54
u Final comments about GIK
On the basis of the above, we believe that presently we do
not have enough evidence to support the first-line use of GIK
in patients undergoing PCI. Studies to further investigate the
role of GIK in these patients are needed.
u Other metabolic agents
L-Carnitine is another adjunctive therapy for angina pectoris
and has been shown to attenuate left ventricular dilation dur-
ing the first year after an AMI, resulting in smaller left ventric-
ular volumes at follow-up.55 In the stent era, L-carnitine has
also been used in patients undergoing PCI, with inconsis-
tent results. Xue et al found that L-carnitine as an adjunctive
therapy to PCI was associated with a reduced level of cardiac
markers in patients with non-STEMI.56 A later systematic re-
view and meta-analysis found that, compared with placebo
or control, L-carnitine was associated with a 27% reduction
in all-cause mortality, a 65% reduction in ventricular arrhyth-
mias, and a 40% reduction in anginal symptoms in patients
experiencing an AMI.57 However, these findings were not con-
sistent with results from another meta-analysis in which the
authors concluded that there was no significant marginal ben-
efit in terms of all-cause mortality, heart failure, unstable angina,
or myocardial reinfarction in the setting of AMI for oral L-car-
nitine maintenance doses of 2 g or greater per day.58 A pos-
sible reason behind the differing results of these two studies
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 M E TA B O L I C AGENTS IN THE
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Keywords: adjunctive therapy; coronary artery disease; glucose-insulin-potassium; metabolic agent; percutaneous coro-
nary intervention; ranolazine; trimetazidine

UTILISATION DES AGENTS MTABOLIQUES POUR

LA CARDIOPROTECTION DES PATIENTS APRS UNE REVASCULARIZATION
En pratique clinique, les agents mtaboliques, dont la trimtazidine, la ranolazine et lassociation glucose-insuline-
potassium (GIK), jouent souvent un rle dappoint dans le traitement de langor. Lintervention coronaire percutane
tant trs utilise au niveau mondial, notamment limplantation de stents, les mdecins se sont rendu compte que
certains patients continuaient souffrir dangor et de complications lies lintervention coronaire percutane ou
quils avaient une mauvaise qualit de vie. Cest pourquoi des agents mtaboliques ont t tests pour traiter les
patients ayant subi ce type dinterventions et des progrs ont t observs. Dans cet article, nous analysons prin-
cipalement le rle protecteur de trois agents largement utiliss dans la maladie coronaire : la trimtazidine, la rano-
lazine et le GIK, avec un accent particulier sur les patients ayant subi une intervention coronaire percutane. Outre
ces trois traitements dappoint, il existe dautres agents mtaboliques dont les effets bnfiques sur les patients ayant
subi une revascularisation restent confirmer par des examens plus approfondis.

Metabolic agents in the protection of patients who undergo revascularization Chen MEDICOGRAPHIA, Vol 38, No. 3, 2016 287

Contrast-induced nephropa-
thy (CIN) or contrast-induced acute
kidney injury is a common but un-
derdiagnosed complication of
coronary diagnostic and interven-
tional procedures that is associat-
ed with increased in-hospital mor-
bidity and mortality, prolonged
hospital stay, and raised health care
costs.The search continues for
new pharmacologic and nonphar-
macologic interventions for the
prevention of CIN in patients un-
dergoing [such procedures].
Yury LOPATIN, MD, PhD, FHFA
Volgograd Medical State University
Volgograd Regional Cardiology
Centre, Volgograd
RUSSIA
Address for correspondence:
Yury Lopatin, Professor and Head
of the Cardiology Department,
Volgograd Regional Cardiology
Centre, 106, Universitetsky prospekt,
Volgograd, Russia
(email: yu.lopatin@gmail.com)
www.medicographia.com
288 MEDICOGRAPHIA, Vol 38, No. 3, 2016
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
How effective
can trimetazidine be
in preventing myocardial and
renal revascularization injury?
b y Y. Lo p a t i n , R u s s i a
C
urrently, percutaneous coronary intervention is considered one of the
key treatment strategies for the management of occlusive coronary ar-
tery disease. Even with the technical advances in percutaneous coro-
nary intervention that have made the procedure safe, with a minimal rate of
complications, myocardial revascularization procedures per se still cause my-
ocardial or renal injuries. Lately, particular attention has been paid to such
complications, including periprocedural myocardial injury and contrast-in-
duced nephropathy. These complications can occur frequently and are as-
sociated with a worse prognosis. In this regard, the search for strategies that
prevent the development of these periprocedural injuries seems very impor-
tant. Results of experimental and clinical studies suggest promising poten-
tial for trimetazidine in the prevention of periprocedural myocardial and renal
injuries.
Medicographia. 2016;38:288-295 (see French abstract on page 295)
rimetazidine is an anti-ischemic metabolic modulator that has been approved
T worldwide for symptomatic treatment of chronic stable angina. Moreover, there
is sound evidence to consider appropriate the use of this agent in patients
with heart failure of ischemic etiology.1 In the past few years, several randomized
clinical trials (RCTs) have demonstrated that therapy with trimetazidine after per-
cutaneous coronary intervention (PCI) reduces the incidence of major adverse car-
diac events, recurrent angina pectoris, and stent restenosis, and that it improves
cardiac function.2-4
At the same time, evidence continues to accumulate that myocardial revascular-
ization procedures per se cause myocardial or renal injuries, which can be associ-
ated with worse clinical outcomes.
How effective can the use of trimetazidine be in prevention of myocardial and renal
revascularization injury?
Periprocedural myocardial injury during percutaneous coronary
intervention
In about one-third of patients undergoing coronary revascularization by PCI, the pro-
cedure itself causes myocardial injury (termed periprocedural myocardial injury,
PMI),5,6 which has been associated with an increased rate of major adverse cardiac
events, including death.7,8
Trimetazidine and prevention of myocardial and renal revascularization injury Lopatin

PMI during PCI is often clinically silent; however, it can be de-
tected if the level of serum cardiac enzymes increases above
the 99th percentile upper reference limit (ULR). The Joint Eu-
ropean Society of Cardiology (ESC)/American College of Car-
diology Foundation (ACCF)/American Heart Association (AHA)/
World Heart Federation (WHF) Task Force Universal Defini-
tion of Myocardial Infarction 20129 defined PMI during PCI
as an elevation of cardiac troponin (cTn) level above the 99th
percentile URL after PCI, assuming a normal baseline troponin
value. This document also noted that in patients undergo-
ing PCI with normal (99th percentile URL) baseline cTn con-
centrations, elevations of cTn greater than 5 x 99th percentile
URL occurring within 48 hours of the procedure plus ischemic,
angiographic, or imaging findings are already defined as PCI-
related myocardial infarction (MI) (type 4a). The document
also clarifies that when a cTn value is less than or equal to
5 x 99th percentile URL after PCI and if the cTn value was
normal before PCIor when the cTn value is greater than 5 x
99th percentile URL in the absence of ischemic, angiograph-
ic, or imaging findingsthe term myocardial injury should
be used.
Herrmann5 in his review classified the key factors that might
determine the incidence and magnitude of PMI into three
groups: patient-related, lesion-related, and procedure-relat-
ed. The most frequently reported among these are older age;
multivessel diffuse coronary artery disease (CAD); pre-exist-
ing renal impairment; presence of anemia; plaque burden;
number of lesions; presence of bifurcation lesions; tortuosity
of coronary arteries; suboptimal stenting; and multiple stents.
Of course, the assessment of these factors before the inter-
vention allows risk stratification for PMI. The most common
mechanisms of myocardial injury during PCI are distal em-
bolization and side branch occlusion; others are dissection,
thrombus, no reflow/slow flow, or coronary perforation.6
Several strategies to protect from PMI during PCI have been
applied in clinical practice. Babu et al6 have divided them into
three subgroups: strategies to prevent side branch occlusion,
SELECTED ABBREVIATIONS AND ACRONYMS
CAD coronary artery disease
CIN contrast-induced nephropathy
CKD chronic kidney disease
CK-MB creatine kinase-MB
CM contrast media
cTnI cardiac troponin I
MI myocardial infarction
PCI percutaneous coronary intervention
PMI periprocedural myocardial injury
RCT randomized clinical trial
SCr serum creatinine
ULR upper reference limit
Trimetazidine and prevention of myocardial and renal revascularization injury Lopatin
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
strategies to prevent distal embolization and microvascular
coagulation, and strategies of protecting the myocardium it-
self against PMI (cardioprotection).
Regarding prevention of side branch occlusion, the current
ESC/European Association for Cardiothoracic Surgery (EACTS)
Guidelines on myocardial revascularization10 favor stent im-
plantation in the main vessel only, followed by provisional bal-
loon angioplasty with or without stenting of the side branch
rather than routine stenting of both vessels. Several stents,
designed specifically for treatment of bifurcation lesions, have
undergone extensive evaluation.
Strategies to prevent distal embolization and microvascular
coagulation include administration of antiplatelet and anti-
thrombotic agents, use of distal protection devices, or direct
stenting of the coronary lesion without predilatation.6
Strategies for protecting the myocardium against PMI are
based on pharmacological and nonpharmacological interven-
tions. Among these interventions, the most discussed ones
are a high dose of statins,11,12 intracoronary b-blocker or ade-
nosine administration,13-17 trimetazidine,18 cyclosporine A,19,20
and remote ischemic preconditioning.21,22 However, the abil-
ity of some of these interventions to provide effective car-
dioprotection has not been confirmed in all RCTs.
Trimetazidine for the prevention of periprocedural
myocardial injury in patients undergoing coronary
intervention
The first clinical trial on this issue was the open-label, random-
ized, controlled, two parallel groups study trial performed by
Polonski et al,23 in which 22 patients with one-vessel CAD re-
ceived oral trimetazidine, 60 mg daily, at least 4 days before
percutaneous transluminal coronary angioplasty. It was found
that, compared with the control group (22 patients) pretreat-
ment with trimetazidine reduced not only angina, rhythm distur-
bances, and ischemic ST-T changes on the electrocardiogram
during the procedure, but also demonstrated a nonsignificant
trend to lower levels of cardiac troponin I (cTnI) 6 and 12 hours
after the procedure.
Later, two independent groups from France and Greece re-
ceived more clear evidence of the ability of trimetazidine to
prevent periprocedural myocardial injury in patients undergo-
ing coronary interventions. The single-center, prospective,
randomized evaluation study of Bonello et al24 included 206
stable angina patients with one-vessel CAD. Patients who un-
derwent more than one inflation procedure during PCI were
excluded from the study. Half of the patients received an acute
loading dose of trimetazidine (60 mg) starting 30 min before
recanalization, after which the operator was allowed to pro-
ceed with angioplasty. The main outcome of this study was
the frequency and the increase in the level of cTnI after a suc-
cessful PCI. cTnI levels were measured before and 6, 12, 18,
MEDICOGRAPHIA, Vol 38, No. 3, 2016 289
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
and 24 hours after PCI. It was found that there were no sta-
tistically significant differences in the frequency of cTnI levels
between the trimetazidine group and the control group. How-
ever, postprocedural cTnI levels were significantly reduced
in the trimetazidine group at all time points (mean [standard
deviation] for control vs trimetazidine group, respectively: at
6 hours, 4.2 ng/mL [0.8] vs 1.7 ng/mL [0.2], P<0.001; at 12
hours, 5.5 ng/mL [1.5] vs 2.3 ng/mL [0.4], P<0.001; at 18
hours, 9 ng/mL [2.3] vs 3 ng/mL [0.5], P<0.001; and at 24
hours, 3.2 ng/mL [1.2] vs 1 ng/mL [0.5], P<0.001). Moreover,
the total amount of cTnI released after PCI, as assessed by
the area under the curve of serial measurements, was signifi-
cantly reduced in the trimetazidine group (P<0.05) (Figure 1).
Figure 1. Time course of cardiac troponin I release.
Mean circulating cardiac troponin I concentrations (error bars showing standard
deviation) are indicated for control (open symbols; n=130) and trimetazidine
(closed symbols; n=136) groups. The arrow indicates the time of PCI. ***P<0.001.
Abbreviations: cTnI, cardicac troponin I; PCI, percutaneous coronary intervention.
From reference 24: Bonello et al. Heart. 2007;93:703-707. 2007, BMJ Pub-
lishing Group Ltd.
In the other trial, Labrou et al25 included 52 patients hospital-
ized for acute coronary syndromes. Coronary angiography
was performed in all patients, and more specifically, after 6
days of hospitalization in patients with MI. Patients who had
undergone primary PCI were excluded from this study. All pa-
tients received bare metal stents; drug-eluting stents were
not used in the study. In addition to conventional antianginal
therapy, 27 patients received 20 mg oral trimetazidine every 8
hours, starting 15 days before PCI and continuing for 3 months
after the procedure. The other 25 patients were included in
the placebo group. For each patient, serum cTnI and crea-
tine kinase-MB (CK-MB) levels were measured before PCI,
then at 6, 24, and 48 hours after the procedure. Serum cTnI
and CK-MB measurements were considered negative for my-
ocardial damage when levels were lower than 0.2 ng/mL and
lower than 5 ng/mL, respectively. It was observed that 24 hours
after PCI, cTnI levels were higher than 1 ng/mL in 7 of 27 pa-
tients (26%) in the trimetazidine group and in 11 of 25 pa-
290 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Trimetazidine and prevention of myocardial and renal revascularization injury Lopatin
tients (44%) in the placebo group. Forty-eight hours after the
procedure, cTnI levels remained elevated in 15% of patients
receiving trimetazidine and in 32% of patients in the place-
bo group. Twenty-four hours after PCI, CK-MB levels were
above 5 ng/mL in 22% of patients in the trimetazidine group
and 40% of patients in the placebo group. The authors con-
cluded that trimetazidine can reduce myocardial reperfusion
injury during PCI. They also stressed the need for further stud-
ies with inclusion of more patients.
Xu et al26 in a single-center, prospective, randomized, con-
trolled study again demonstrated that trimetazidine reduced
post-PCI cTnI release in patients with unstable angina pec-
toris. A total of 106 patients who underwent successful elec-
tive PCI and drug-eluting stent implantation were random-
ized to a trimetazidine group (n=51, 60 mg trimetazidine oral
loading dose 0.5-1.0 hour before PCI followed by 20 mg three
times daily after PCI on top of standard therapy) or a control
group (standard therapy without trimetazidine, n=55). cTnI
level was measured before and 16-18 hours after PCI. It was
found that cTnI levels after PCI were higher than before the
procedure in both groups of patients (P<0.01). However, post-
procedural cTnI levels increased from 0.02 mg/L (95% CI,
0.01-0.03)] at baseline to 0.11 mg/L (95% CI, 0.07-0.13)]
(P<0.05) at 16-18 hours in the trimetazidine group, whereas
in the control group, it increased from 0.02 mg/L (95% CI,
0.01-0.03)] to 1.31 mg/L (95% CI, 0.44-2.31)] (P<0.05). The
proportion of patients in the trimetazidine group who showed
a postprocedural cTnI level elevation of greater than 0.10 mg/L
was lower than that in the control group (P<0.01).
Recently Zhang et al18 have published a meta-analysis that
covered data from 9 RCTs with a total of 778 patients hav-
ing undergone PCI. It was shown that additional use of trimeta-
zidine in the periprocedural period of PCI significantly im-
proved left ventricular ejection fraction, reduced elevated cTnI
level (relative risk [RR], 0.69; 95% confidence interval [CI], 0.48-
0.99), angina attacks during PCI (odds ratio [OR], 0.16; 95%
CI, 0.07-0.38), and ischemic ST-T changes on the electro-
cardiogram during PCI (RR, 0.76; 95% CI, 0.59-0.98).
It should be noted that this meta-analysis is in line with anoth-
er meta-analysis27 that also showed a cardioprotective effect
of trimetazidine in patients that underwent coronary artery by-
pass graft surgery. The authors of both meta-analyses have
noted the superiority of trimetazidine over conventional ther-
apy during revascularization procedures. However, the au-
thors also emphasize that new clinical trials with large sam-
ples and rigorous designs are needed.
Several mechanisms are responsible for the prevention of is-
chemic reperfusion injury; one of these is the ability of trimeta-
zidine to inhibit the opening of mitochondrial permeability
transition pores, a crucial event in cardiomyocyte death after
myocardial ischemia-reperfusion.28

Contrast-induced nephropathy following
percutaneous coronary intervention
Contrast-induced nephropathy (CIN) or contrast-induced acute
kidney injury is a common but underdiagnosed complication
of coronary diagnostic and interventional procedures that is
associated with increased in-hospital morbidity and mortal-
ity, prolonged hospital stay, and raised health care costs.29-33
CIN is the third most common cause of hospital-acquired
acute renal failure.34
It is known that the administration of contrast media (CM) rap-
idly induces intense renal vasoconstriction and subsequent
reduced blood perfusion. This can lead to ischemic and hy-
poxic damage of the renal medulla and the production of oxy-
gen free radicals, inducing tubular epithelial damage.35 Ad-
ditional factors such as hypotension, microembolization of
atheromatous debris, or bleeding complications can also be
responsible for the development of CIN.36
In spite of the growing importance of this complication, there
is a lack of consensus on how to define CIN. According to the
most recognized definition, CIN is an absolute (0.5 mg/dL;
44 mmol/L) or relative (25%) increase in baseline serum
creatinine (SCr) levels 48-72 hours after an exposure to io-
dinated CM.
Generally, the incidence of CIN in individuals with normal re-
nal function who undergo PCI is low (<3%).37 However, it rises
remarkably in patients with chronic kidney disease (CKD) (up
to 40% and even more).29,37 Besides pre-existing CKD, other
predisposing factors for CIN are diabetes, congestive heart
failure, hypotension, hypertension, preprocedure shock, re-
cent MI, anemia, female sex, advanced age, and concomitant
use of nephrotoxic agents.29,38 Procedure-related risk factors
for the development of CIN include high volume of CM, as
well as its high osmolarity, intra-arterial injection, and multi-
Figure 2. Serum creatinine levels in control group and trimetazidine
group.
Abbreviation: TMZ, trimetazidine.
Adapted from reference 43: Onbasili et al. Heart. 2007;93:698-702. 2007,
BMJ Publishing Group Ltd.
Trimetazidine and prevention of myocardial and renal revascularization injury Lopatin
M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A
ple CM exposures within the past 72 hours.38 There is no
specific treatment for CIN after PCIprevention remains the
most effective strategy. The first step in the prevention of CIN
is the identification of patients at high risk. The most com-
monly used scoring system is the Mehran score.39 Preven-
tive strategies for CIN include the limitation of CM volume;
use of preheated (37C) iso-osmolar CM; pre-PCI hydration
with normal saline; use of N-acetylcysteine, sodium bicarbon-
ate, and statins; and stopping nephrotoxic drugs 48 hours
before and after CM exposure.40-42 The search continues for
new pharmacologic and nonpharmacologic interventions for
the prevention of CIN in patients undergoing coronary diag-
nostic and interventional procedures.
Trimetazidine for the prevention of
contrast-induced nephropathy in patients
undergoing coronary interventions
Onbasili et al43 were the first to clinically evaluate the efficacy
of trimetazidine in the prevention of CIN in patients with high
SCr levels undergoing coronary angiography or PCI. A total of
82 patients with basal SCr levels between 1.2 and 2.5 mg/dL
were enrolled in a prospective double-blind, randomized, con-
trolled trial. Indications of the coronary interventions were acute
coronary syndrome, stable angina, dilated cardiomyopathy,
and preoperative assessment. Of all patients, 19 had diabetes
mellitus (all of them type 2). In this study, patients were ran-
domized into a trimetazidine group (20 mg three times daily,
orally, for 72 hours starting 48 hours before the procedure)
or a control group. The standard parenteral hydration pro-
tocol was applied to patients in both groups. SCr levels were
measured before the procedure, 48 hours, and 7 days after
the procedure. An increase in SCr level exceeding 0.5 mg/day
or one-quarter of the baseline value was considered as CIN.
It was found that SCr levels in the control group increased sig-
nificantly 2 days after the procedure (P<0.05) and returned to
the baseline values on the seventh day (Figure 2). On the oth-
er hand, they did not change significantly on the second day,
and they even significantly decreased on the seventh day in
the trimetazidine group (P<0.05). CIN developed in 2.5% (1/
40) of patients in the trimetazidine group and in 16.6% (7/42)
of patients in the control group (P<0.05).
Later, Rahman et al44 in a large prospective randomized,
controlled trial again confirmed the ability of trimetazidine to
prevent CIN after coronary angiogram or PCI. A total of 400
patients were enrolled in this study; in contrast to the study
performed by Onbasili et al,43 patients with diabetes were ex-
cluded. Of the 400 enrolled, 200 patients were treated with
trimetazidine plus hydration with normal saline and 200 pa-
tients (control group) were given hydration with normal saline
only. The dose of trimetazidine was 35 mg twice daily for 96
hours starting 48 hours before the procedure. It was found
that the incidence of CIN was significantly reduced by admin-
istration of trimetazidine with saline in comparison with saline
alone (4% vs 14%; P<0.05).
MEDICOGRAPHIA, Vol 38, No. 3, 2016 291
M E TA B O L I C AGENTS IN THE
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While the two above-mentioned trials43,44 enrolled nondiabetic
or a mixture of diabetic and nondiabetic patients with CKD,
the study performed by Shehata45 evaluated the effect of peri-
procedural administration of trimetazidine on the incidence
of PCI-induced myocardial injury and CIN in high-risk pa-
tients with diabetes and mild-to-moderate renal dysfunction.
The primary end point of the study was the development of
CIN 72 hours after PCI. A total of 100 consecutive diabetic
patients with chronic stable angina and mild-to-moderate CKD
were randomized into a trimetazidine group (35 mg of agent
twice daily for 72 hours starting 48 hours before the proce-
dure) and a control group (without trimetazidine). The stan-
dard parenteral hydration protocol was applied to all included
patients. Additionally, N-acetylcysteine (1200 mg) was given
to patients in both groups 24 hours before and after the pro-
cedure. There was no statistically significant difference be-
tween the two groups in terms of the preliminary angiographic
findings and procedural characteristics. However, postpro-
cedural mean cTnI level was significantly higher in the con-
trol group than in the trimetazidine group (6 hours: 80.3 vs
160.2 pg/mL, P<0.001; 12 hours: 130.9 vs 240.8 pg/mL,
P<0.001; and 24 hours: 70.7 vs 140.3 pg/mL, P<0.001).
The SCr level in the control group significantly increased 3
days after PCI and decreased on the tenth day. On the other
hand, no significant change was observed in the trimetazidine
group. Mean cTnI levels as well as mean SCr levels in both
study groups are graphically presented in Figures 3 and 4.
CIN was noted in 6 patients (12%) of the trimetazidine group,
Figure 3. Graphic presentation showing changes in mean cardiac
troponin I levels in control group and trimetazidine group.
Abbreviation: PCI, percutaneous coronary intervention.
Adapted from reference 45: Shehata. Am J Cardiol. 2014;114:389-394. 2014,
Elsevier Inc. All rights reserved.
292 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Trimetazidine and prevention of myocardial and renal revascularization injury Lopatin
whereas it occurred in 14 patients (28%) of the control group
(P<0.05). Thus, the study performed by Shehata45 was the
first one to evaluate both the anti-CIN and the anti-PMI ef-
fects of trimetazidine in diabetic patients with CKD undergo-
ing elective PCI.
Last year Nadkarni et al46 published a meta-analysis that pooled
data from the three above-mentioned RCTs, which altogeth-
er included 582 patients with CKD and SCr levels ranging
from 1.26 to 2 mg/dL. It was shown that in patients under-
going coronary angiography, administration of trimetazidine in
conjunction with normal saline and/or oral N-acetylcysteine
was associated with a significant reduction in the incidence of
CIN by 11% (risk difference 0.11; 95% CI, 0.16-0.06; P<0.01)
when compared with the control group. The number need-
ed to treat to prevent 1 episode of CIN was 9. The authors
concluded that trimetazidine could be considered a poten-
tial tool for prevention of CIN in patients with renal dysfunc-
tion. On the other hand, Nadkarni et al46 emphasized that
considering the small sample size of these studies and the
level of evidence being 1C, decision making about the use of
trimetazidine should be individualized to each patient and
each clinical context.
Recently Liu et al47 have confirmed once again the renopro-
tective effect of trimetazidine on CIN in patients with mild-to-
moderate renal dysfunction who undergo coronary angiog-
raphy or PCI. In this single-center prospective, randomized
Figure 4. Graphic presentation showing changes in mean serum
creatinine levels in control group and trimetazidine group.
Abbreviation: PCI, percutaneous coronary intervention.
Adapted from reference 45: Shehata. Am J Cardiol. 2014;114:389-394. 2014,
Elsevier Inc. All rights reserved.
 M E TA B O L I C AGENTS IN THE
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controlled clinical trial, 132 patients with re-

nal dysfunction undergoing coronary an-
giography or PCI (more than half of all pa-
tients) were divided into a control group
(n=70) and a trimetazidine group (n=62). Tri-
metazidine was administered orally 48 hours
before and 24 hours after the procedure.
Standard hydration was used in all included
patients.

Postoperative SCr concentration was signif-

icantly lower in the trimetazidine group than
in the control group at 48 hours but not at
24 hours (P=0.026 and P=0.056, respec-
tively), whereas postoperative cystatin C lev-
el was significantly lower in the trimetazidine
group both at 24 and 48 hours than in the
control group (P=0.000 and P=0.025, re-
spectively). Trimetazidine significantly re-
duced the incidence of CIN (8% vs 20% in Figure 5. Kaplan-Meier survival curve of the timing of adverse events during the follow-
control; P=0.034). Moreover, the incidence up period.
of adverse events within 12 months of fol- Abbreviation: TMZ, trimetazidine.
low-up was significantly lower in the trimeta- Adapted from reference 47: Liu et al. Am J Med Sci. 2015;350:398-402. Copyright 2015 Southern
Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.
zidine group than in the control group (9.6%
vs 22.8%; P=0.043). The Kaplan-Meier survival curves of ad- It is important to mention that the potent antioxidant effect of
verse events showed that the incidence of adverse events trimetazidine has been demonstrated not only in myocardial
significantly decreased in the trimetazidine group compared and renal, but also hepatic, pulmonary, intestinal, and testic-
with the control group (log rank P=0.035) (Figure 5). A sig- ular ischemia-reperfusion injuries.49-53 This allows us to con-
nificant correlation between the adverse events and the in- sider trimetazidine a promising agent that can prevent develop-
cidence of CIN was also noted. ment of ischemia-reperfusion injuries during revascularization
procedures. However, several issues are still to be clarified.
Akgll et al48 explain the renoprotective properties of trimeta- First of all, it is necessary to identify the optimal duration of the
zidine against CIN by its antioxidant properties. In an exper- pre- and post-procedural administration of trimetazidine. The
imental study, the authors showed significantly higher levels question regarding the optimal dose of trimetazidine also re-
of malondialdehyde and lower levels of superoxide dismu- mains open. Moreover, new studies are needed to evaluate not
tase activity in a CM alone group than in a CM plus trimetazi- only the efficacy but also the safety of trimetazidine in differ-
dine group. Moreover, histopathological analysis demonstrated ent patient populations having undergone revascularization
a significant expansion of Bowmans capsule, tubule epithe- procedures. For example, this agent is contraindicated when
lium degeneration, tubule epithelium necrosis, and intersti- creatinine clearance is below 30 mL/min. The dose of trimeta-
tial infiltration in the CM group compared with the CM plus zidine that will be most effective in the context of prevention of
trimetazidine group. Interestingly, none of the histopatholog- ischemia-reperfusion injury in patients with creatinine clear-
ical scores differed significantly between the CM plus trimetazi- ance of 30-60 mL/min is still to be defined as well. Large-
dine group and the control group (without CM). scale studies are required to answer these questions. n

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A in Reperfused Myocardial Infarction: the multicenter, controlled, open-label
CYCLE Trial. J Am Coll Cardiol. 2016;67:365-374.
21. Hoole SP, Heck PM, Sharples L, et al. Cardiac Remote Ischemic Precondition-
ing in Coronary Stenting (CRISP Stent) Study: a prospective, randomized con-
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22. Zografos TA, Katritsis GD, Katritsis DG. Remote ischemic preconditioning re-
duces peri-procedural myocardial injury in elective percutaneous coronary in-
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23. Polonski L, Dec I, Wojnar R, et al. Trimetazidine limits the effects of myocar-
dial ischaemia during percutaneous coronary angioplasty. Curr Med Res Opin.
2002;18:389-396.
24. Bonello L, Sbragia P, Amabile N, et al. Protective effect of an acute oral load-
ing dose of trimetazidine on myocardial injury following percutaneous coro-
nary intervention. Heart. 2007;93:703-707.
25. Labrou A, Giannoglou G, Zioutas D, et al. Trimetazidine administration mini-
mizes myocardial damage and improves left ventricular function after percu-
taneous coronary intervention. Am J Cardiovasc Drug. 2007;7:143-150.
26. Xu XH, Zhang WJ, Zhou YJ, et al. Effects of trimetazidine therapy on left ven-
tricular function after percutaneous coronary intervention. Zhonghua Xin Xue
Guan Bing Za Zhi. 2013;41:205-209.
27. Zhang N, Lei JY, Liu Q, et al. The effectiveness of preoperative trimetazidine on
myocardial preservation in coronary artery bypass graft patients: a systematic
review and meta-analysis. Cardiology. 2015;131:86-96.
28. Argaud L, Gomez L, Gateau-Roesch O, et al. Trimetazidine inhibits mitochon-
drial permeability transition pore opening and prevents lethal ischemia-reper-
fusion injury. J Mol Cell Cardiol. 2005;39:893-899.
29. Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients
undergoing primary angioplasty for acute myocardial infarction. J Am Coll
Cardiol. 2004;44:1780-1785.
30. Blackman DJ, Pinto R, Ross JR, et al. Impact of renal insufficiency on out-
Keywords: contrast-induced nephropathy; percutaneous coronary intervention; periprocedural myocardial injury;
trimetazidine
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long-term implications. Semin Nephrol. 2011;31:300-309
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intervention is associated with high mortality. Catheter Cardiovasc Interv. 2005;
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Circulation. 2015;132:1931-1936.
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occlusions. Am J Cardiol. 2015;115:844-851.
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contrast-induced nephropathy after coronary procedures. Heart. 2007;93:698-
702.
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21:292-299.
45. Shehata M. Impact of trimetazidine on incidence of myocardial injury and con-
trast-induced nephropathy in diabetic patients with renal dysfunction under-
going elective percutaneous coronary intervention. Am J Cardiol. 2014;114:
389-394.
46. Nadkarni GN, Konstantinidis I, Patel A, et al. Trimetazidine decreases risk of con-
trast-induced nephropathy in patients with chronic kidney disease: a meta-analy-
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of trimetazidine for the prevention of contrast-induced nephropathy. Ren Fail.
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stress in cardiac surgery. Circ J. 2006;70:1169-1173.
50. Singh D, Chopra K. Effect of trimetazidine on renal ischemia/reperfusion injury
in rats. Pharmacol Res. 2004;50:623-629.
51. Inci I, Dutly A, Rousson V, et al. Trimetazidine protects the energy status after
ischemia and reduces reperfusion injury in a rat single lung transplant model.
J Thorac Cardiovasc Surg. 2001;122:1155-1161.
52. Tetik C, Ozden A, Calli N, et al. Cytoprotective effect of trimetazidine on 60
minutes of intestinal ischemiareperfusion injury in rats. Transpl Int. 1999;12:
108-112.
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ular ischemia-reperfusion injury in rats. Urol Int. 2007;78:356-362.
 M E TA B O L I C AGENTS IN THE
C O N T E M P O R A R Y T R E AT M E N T O F A N G I N A

COMMENT LA TRIMTAZIDINE PEUT-ELLE TRE EFFICACE

DANS LA PRVENTION DES LSIONS DE REVASCULARISATION RNALE ET MYOCARDIQUE ?
Lintervention coronaire percutane est actuellement considre comme lun des traitements cls dans la prise en
charge de la maladie coronaire occlusive. Les nouvelles techniques dintervention coronaire percutane lont rendue
sre, avec un taux minimal de complications, mais la revascularisation myocardique per se provoque encore des l-
sions rnales ou myocardiques. Rcemment, ces complications ont fait lobjet dune attention particulire, notam-
ment les lsions myocardiques priprocdurales et la nphropathie aux produits de contraste. Ces complications
peuvent arriver frquemment et sont associes un pronostic dfavorable. Cest pourquoi la recherche de strat-
gies visant prvenir le dveloppement de ces lsions priprocdurales est trs importante. Les rsultats des tudes
cliniques et exprimentales laissent entrevoir des rsultats prometteurs pour la trimtazidine dans la prvention des
lsions rnales et myocardiques priprocdurales.

Trimetazidine and prevention of myocardial and renal revascularization injury Lopatin MEDICOGRAPHIA, Vol 38, No. 3, 2016 295
 THE QUESTION CONTROVERSIAL QUESTION

oronary revascularization

C procedures are commonly

performed for the sympto-
matic treatment of patients with
myocardial ischemia. Neverthe-
less, current data show that even
Is targeting only stenosis
after successful revascularization
a third of angina patients still suf-
fer from pain. Angina that recurs or
sufficient to optimally
persists after coronary revascular-
ization represents a significant clin-
ical problem and its management
improve angina?
is particularly challenging. There-
fore, this begs the question: are we
doing enough by targeting steno-
sis only?

1. P. S. Farsky, Brazil

2. L. O. Go, Philippines

3. H. Hasan-Ali, Egypt

4. H. Q. T. Ho, Vietnam

5. D. Isaza-Restrepo, Colombia

6. T. Kovarnik, Czech Republic

7. O. H. Masoli, Argentina

8. A. N. Parkhomenko and
O. S. Gurjeva, Ukraine

9. C. K. Ponde, India

10 . V. Sansoy, Turkey

11. D. Vassilev, Bulgaria

Is targeting only stenosis sufficient to optimally improve angina? MEDICOGRAPHIA, Vol 38, No. 3, 2016 297
CONTROVERSIAL QUESTION
1. P. S. Farsky, Brazil
Pedro Silvio FARSKY, MD
Doutor em Cincias pela Fac Medicina USP
Fellow da European Society of Cardiology
Instituto Dante Pazzanese de Cardiologia
Hospital Israelita Albert Einstein
So Paulo, BRAZIL
(email: farskyp@uol.com.br)
M
yocardial revascularization with percutaneous coro-
nary intervention (PCI) or coronary artery bypass
graft surgery (CABG) is indicated when there is sig-
nificant obstruction of coronary blood flow associated with
myocardial ischemia, in order to relieve symptoms or prolong
survival.
Several mechanisms may explain the persistence of angina/
ischemia after a revascularization procedure, including graft or
PCI failure, incomplete revascularization, and disease pro-
gression in native coronary arteries. Microvascular dysfunc-
tion may play a prominent role in the unexpected prevalence
of angina after the removal of obstructions in the major coro-
nary branches.
Graft failure and new atherosclerotic lesions
Angina may recur at any time in the first few months follow-
ing apparently successful CABG surgery, and may present
as stable or unstable angina. In the early postoperative peri-
od, angina is usually caused by graft closure due to a tech-
nical problem. One year after CABG, angina may occur as
a result of the gradual development of graft stenosis or of the
progression of new atherosclerotic lesions, either in nonby-
passed vessels or distal to graft anastomosis.
After 10 years, the rate of saphenous vein graft closure is about
50%, and is associated with anatomical factors (eg, artery
diameter), clinical factors (eg, male sex and aging), and risk
factors for atherosclerotic cardiovascular disease.1 Using the
internal thoracic artery reduces angina recurrence and pro-
longs survival.
Late recurrent angina after CABG can also result from pro-
gressive atherosclerosis in a native vessel. Studies performed
before the widespread use of arterial grafting found that saphe-
nous vein graft (SVG) disease was responsible for 80% of new
angina symptoms, as opposed to new native artery disease,
which was responsible for 54% of the cases.2 Later, an analy-
sis from the BARI trial (Bypass Angioplasty Revascularization
Investigation), which investigated the use of CABG versus
298 MEDICOGRAPHIA, Vol 38, No. 3, 2016
PCI in patients with stable angina, showed that native coro-
nary disease progression exceeded failed revascularization
as the cause of angina after five years.3 Disease progression
occurred in native untreated arteries in two-thirds of cases.
In this study, the myocardial jeopardy score fell following ini-
tial revascularization, from 60% to 17% for PCI-treated pa-
tients compared with a reduction from 60% to 7% for CABG
surgery patients ( P<0.001), but rebounded after five years
to 25% for PCI and 20% for surgery patients ( P=0.01). Myo-
cardial jeopardy increased between study entry and the five-
year follow-up in 42% of PCI-treated patients and 51% of
CABG-treated patients ( P=0.06).
The MASS II trial (Medicine, Angioplasty, or Surgery Study)
randomly assigned 611 patients with multivessel disease, pre-
served left ventricular systolic function, and stable angina to
CABG, PCI, or optimal medical therapy.4 After only one year,
12% of the patients in the CABG group, 21% in the PCI group,
and 54% in the medical therapy group had angina (P<0.0001).
Furthermore, after 10 years, 64% of patients in the CABG
group, 59% of patients in the PCI group, and 43% in the op-
timal medical therapy group ( P<0.001) were angina free.
Incomplete coronary revascularization
In many patients with chronic stable angina, complete revas-
cularization is not achieved at the time of PCI or CABG. Com-
plete revascularization of all significantly obstructed coronary
segments is the goal of CABG, and recent data has shown
that complete revascularization following PCI has a positive
effect on long-term clinical outcomes. However, incomplete
coronary revascularization following CABG or PCI is associat-
ed with increased mortality as well as with an increased inci-
dence of myocardial infarction, repeat revascularization, and
major adverse cardiovascular or cerebrovascular events.5
References
1. Goldman S, Copeland J, Moritz T, et al. Improvement in early saphenous vein
graft patency after coronary artery bypass surgery with antiplatelet therapy: results
of a Veterans Administration Cooperative Study. Circulation. 1988;77:1324-1332.
2. Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton JR. Coronary
bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts
related to survival and reoperation in 1,388 patients during 25 years. J Am Coll
Cardiol. 1996;28:616-626.
3. Alderman EL, Kip KE, Whitlow PL, et al. Native coronary disease progression
exceeds failed revascularization as cause of angina after five years in the Bypass
Angioplasty Revascularization Investigation (BARI). J Am Coll Cardiol. 2004;44:
766-774.
4. Hueb W, Soares PR, Gersh BJ, et al. The medicine, angioplasty, or surgery study
(MASS-II): a randomized, controlled clinical trial of three therapeutic strategies
for multivessel coronary artery disease: one-year results. J Am Coll Cardiol. 2004;
43:1743-1751.
5. Kereiakes DJ. Reassessing the importance of complete versus incomplete coro-
nary revascularization. Rev Cardiovasc Med. 2014;15:24-30.
Is targeting only stenosis sufficient to optimally improve angina?

2. L. O. Go, Philippines
Loewe O. GO, MD, FACC
H. B. Calleja Heart and Vascular Institute
ST. LUKES MEDICAL CENTER
Quezon City
PHILIPPINES
(email: goloewe@yahoo.com.ph)
B
ack in the early 1990s, when I was a cardiology fellow
in Mount Sinai Hospital in New York, coronary angio-
plasty was a very popular treatment for treating angina
in patients with coronary artery disease. However, the direc-
tor of the cardiac catheterization laboratory, Dr John Ambrose,
taught us something radical at the time: patients presenting
with stable and even unstable angina often have nonsignif-
icant or no coronary stenosis during angiography. It turns out
that this was a very prescient observation.
Two lines of evidence strongly suggest that targeting only
coronary stenosis is NOT sufficient to optimally improve angi-
na in patients with ischemic heart disease (IHD). First, angina
actually occurs in patients in the absence of coronary steno-
sis. In one study of 1630 patients with typical angina, the ob-
served prevalence of angiographically confirmed >50% stenot-
ic coronary artery disease ranged from 38%-53% in men and
15%-29% in women over 50 years old1which implies that
the majority of these patients do not have significant coronary
obstruction. And in patients with the most dramatic mani-
festations of IHD, namely those with ST-elevation myocar-
dial infarction (2251 patients) or unstable angina (2406 pa-
tients), up to 7%-14% of men and 10%-30% of women have
normal coronary artery angiograms.2 Second, multiple stud-
ies show that even after successful revascularization a signif-
icant number of patients still suffer from angina. The landmark
COURAGE trial (Clinical Outcomes Utilizing Revasculariza-
tion and Aggressive druG Evaluation) showed that after per-
cutaneous coronary intervention on top of optimal medical
therapy, many patients remain symptomatic41% at three
years and 26% at five years.3 A meta-analysis which includ-
ed studies published from 1992-2007 (RITA-2 [Randomized
Intervention Treatment of Angina 2], SWISSI II [SWiss Inter-
ventional Study on Silent Ischemia 2], MASS II [Medicine, An-
gioplasty, or Surgery Study 2], and COURAGE 2007) showed
that angina persists in 29%-31% of revascularized patients
from one to five years out.4 Despite the current technical ad-
vancements in revascularization procedures, angina is still
present at 12 months of follow-up in 29.4% of percutaneous
Is targeting only stenosis sufficient to optimally improve angina?
CONTROVERSIAL QUESTION
coronary intervention patients and 23.7% of coronary artery
bypass graft surgery patients.5 And in the most aggressively
managed IHD patient group, those with acute coronary syn-
drome, residual angina at one year of follow-up is found in
37% of those patients who received early invasive therapy.6
Taken together, these observations suggest that coronary
stenosis or obstruction is not the only causative factor of
symptomatic IHD, and hence revascularization alone cannot
relieve angina in all patients. Other factors such as vasospasm,
microvascular disease, endothelial dysfunction, thrombosis,
inflammation and even an excessive heart rate can also
provoke angina. And keep in mind that these factors are not
mutually exclusive (ie, several of them can be operating si-
multaneously in the same patient). Thus, guidelines for IHD
management emphasize global risk assessment and recom-
mend optimizing treatment by using renin-angiotensin sys-
teminhibitors, statins, antithrombotic agents, b-blockers,
and/or other heart ratelowering agents. But whatever the
etiology of angina, the end result is a metabolic derangement
in the cardiomyocytes leading to an imbalance between en-
ergy production and consumption. This imbalance produces
increased lactic acid levels, which then stimulate sensory
nerve fibers in the myocardium and manifest as angina. Cor-
recting these derangements requires the use of unique agents,
such as trimetazidine, which shifts mitochondrial energy pro-
duction from fatty acid oxidation (more oxygen consuming) to
glucose oxidation (more oxygen sparing) and thus can help
to restore the balance between energy supply and demand,
decrease lactic acidosis, and ultimately reduce angina.
References
1. Cheng VY, Berman DS, Rozanski A, et al. Performance of the Traditional Age,
Sex, and Angina TypicalityBased Approach for Estimating Pretest Probability
of Angiographically Significant Coronary Artery Disease in Patients Undergo-
ing Coronary Computed Tomographic Angiography. Results From the Multina-
tional Coronary CT Angiography Evaluation for Clinical Outcomes: An Interna-
tional Multicenter Registry (CONFIRM). Circulation. 2011;124:2423-2432.
2. Hochman JS, Tamis, JE, Thompson TD, et al. Sex, clinical presentation, and out-
come in patients with acute coronary syndromes. N Engl J Med. 1999;341:226-
232.
3. Weintraub WS, Spertus JA, Kolm P, et al; COURAGE Trial Research Group. Ef-
fect of PCI on Quality of Life in Patients with Stable Coronary Disease. N Engl
J Med. 2008;359:677-687.
4. Wijeysundera HC, Nallamothu BK, Krumholz HM, Tu JV, Ko DT. Meta-analy-
sis: Effects of Percutaneous Coronary Intervention Versus Medical Therapy on
Angina Relief. Ann Intern Med. 2010;152:370-379.
5. Cohen DJ, Van Hout B, Serruys PW, et al; SYNTAX Investigators. Quality of Life
after PCI with Drug-Eluting Stents or Coronary-Artery Bypass Surgery. N Engl
J Med. 2011;364:1016-1026.
6. Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conserva-
tive treatment for patients with unstable angina or non-ST-elevation myocardial
infarction: the British Heart Foundation RITA 3 randomised trial. Lancet. 2002;
360:743-751.
MEDICOGRAPHIA, Vol 38, No. 3, 2016 299
CONTROVERSIAL QUESTION
3. H. Hasan-Ali, Egypt
Hosam HASAN-ALI, MD, PhD
A Board Member of the Egyptian Society
of Cardiology
Head of Cardiovascular Medicine Department
Assiut University Cardiac Hospital
Assiut University Hospitals
Assiut Governorate, EGYPT
(e-mail: hosam_hasan@hotmail.com)
T
raditionally, ischemic heart disease has been linked to
the presence of obstructive epicardial coronary artery
disease.1 However, extensive data have failed to show
that all patients who have atherosclerotic obstructions have
ischemic heart disease or, conversely, that all patients who
have ischemic heart disease present with obstructive coro-
nary atherosclerosis.2 Obstructive coronary artery disease
has been reported in asymptomatic individuals and this is
referred to as silent ischemia.1,3 In contrast, obstructive coro-
nary artery disease is absent in patients with typical angina1
and in patients with positive non-invasive testing.3 This is more
obvious in women than in men.3 More than half the women
with stable chest pain undergoing coronary angiography do
not have obstructive coronary artery disease, while this is true
for only one-third of men.4
Traditionally, this was considered to be due to false positive
non-invasive tests.3 Patients with stable angina and normal
coronary arteries or diffuse nonobstructive coronary artery
disease were thought to experience little more than a re-
duction in their quality of life and have a benign prognosis;
however, they actually have elevated risks of major adverse
cardiovascular events and all-cause mortality compared with
a reference population without ischemic heart disease.4
In addition, large myocardial infarction registries have showed
an absence of flow-limiting coronary pathology in 5%-25%
of cases.5 This changed our view of this type of patients and
the term cardiac syndrome X emerged to describe patients
who show signs of ischemic heart disease in the absence of
obstructive epicardial coronary artery disease.5 In these pa-
tients the pathophysiological mechanisms underlying ischemic
heart disease are endothelial dysfunction and microvascular
dysfunction, sometimes associated with coronary microvas-
cular spam and epicardial coronary artery spasm.2,5
300 MEDICOGRAPHIA, Vol 38, No. 3, 2016
According to the so-called plaque-centric hypothesis, it was
thought that removing epicardial coronary stenosis by per-
cutaneous coronary intervention could cure ischemic heart
disease, and therefore, angina. However, in the COURAGE tri-
al (Clinical Outcomes Utilizing Revascularization and Aggres-
sive druG Evaluation), only 66% of stable angina patients
treated by percutaneous coronary intervention were free from
angina at one year, and 74% at 5 years.6 The recent reports
of persistent angina occurring after percutaneous coronary
intervention with evidence of ischemia in the absence of resid-
ual stenosis or restenosis have showed that microvascular
ischemia may coexist in patients with epicardial obstructive
coronary artery disease.2,5 These findings shifted the para-
digm of ischemic heart disease pathophysiology from the
traditional plaque-centric hypothesis to a multifactorial hy-
pothesis. This new modelwhich Marzilli et al 2 call the solar
system of ischemic heart diseaseis centered around my-
ocardial ischemia, and the orbiting planets are the six fac-
tors that contribute to ischemia: epicardial coronary artery
obstruction, endothelial dysfunction, microvascular dysfunc-
tion, coronary spasm (microvascular and epicardial), spon-
taneous thrombosis and platelet aggregation, and inflamma-
tion. Since epicardial coronary artery obstruction is only one
of these factors, targeting epicardial coronary stenosiswhen
it is presentis actually only one step in the management of
ischemic heart disease. A more comprehensive approach that
also includes the myocardial cell and microvascular ischemia
is essential to improve patient morbidity and mortality.
References
1. Cheng VY, Berman DS, Rozanski A, et al. Performance of the traditional age,
sex, and angina typicality-based approach for estimating pretest probability of
angiographically significant coronary artery disease in patients undergoing coro-
nary computed tomographic angiography: Results from the multinational coro-
nary CT angiography evaluation for clinical outcomes: An international multicen-
ter registry (confirm). Circulation. 2011;124:2423-2432.
2. Marzilli M, Merz CN, Boden WE, et al. Obstructive coronary atherosclerosis and
ischemic heart disease: An elusive link! J Am Coll Cardiol. 2012;60:951-956.
3. Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary
angiography. New Engl J Med. 2010;362:886-895.
4. Jespersen L, Hvelplund A, Abildstrom SZ, et al. Stable angina pectoris with no
obstructive coronary artery disease is associated with increased risks of major
adverse cardiovascular events. Eur Heart J. 2012;33:734-744.
5. Cocco G, Jerie P. Angina pectoris in patients without flow-limiting coronary ar-
tery disease (cardiac syndrome x). A forest of a variety of trees. Cardiol J. 2015;
22(6):605-612.
6. Boden WE, O'Rourke RA, Teo KK, et al; Group CTR. Optimal medical therapy
with or without PCI for stable coronary disease. New Engl J Med. 2007;356:
1503-1516.
Is targeting only stenosis sufficient to optimally improve angina?

4 . H. Q. T. Ho, Vietnam
Huynh Quang Tri HO, MD, PhD
Head of Intensive Care Unit,
Heart Institute of Hochiminh City
VIETNAM
(email: hohuynhquangtri@yahoo.com)
W
hen treating patients with chronic stable angina,
clinicians should aim at reducing anginal symp-
toms, which will improve their patients exercise
capacity and quality of life. The traditional approach to symp-
tom reduction is the prescription of hemodynamic drugs such
as b-blockers, calcium antagonists, and nitrates. In case of
poor response to medical therapy, coronary revascularization
with percutaneous coronary intervention (PCI) or coronary ar-
tery bypass graft surgery (CABG) is often performed. The ra-
tionale for prescribing hemodynamic drugs and performing
coronary revascularization as the next step in the treatment of
angina is the assumption that the unique cause of angina is
coronary artery stenosis.
However, numerous clinical studies have proven the short-
comings of this traditional approach. In the COURAGE trial
(Clinical Outcomes Utilizing Revascularization and Aggressive
druG Evaluation), 2287 patients with stable coronary artery
disease were randomized to undergo PCI with optimal med-
ical therapy (PCI group) or optimal medical therapy alone.1
Optimal medical therapy included antiplatelet agents, a statin,
and hemodynamic antianginal drugs alone or in combination.
Although antianginal drugs were widely prescribed, 21.1%
of patients in the PCI group needed to undergo additional
revascularization, and at the end of the study, only 74% of
patients were free of angina. The design of the BARI 2D trial
(Bypass Angioplasty Revascularization Investigation 2 dia-
betes), which was carried out in 2364 patients with coronary
artery disease and type 2 diabetes, was similar to that of the
COURAGE trial.2 In the group of patients who underwent
prompt coronary revascularization (PCI or CABG), more than
90% needed antianginal drugs (b-blockers, calcium antago-
Is targeting only stenosis sufficient to optimally improve angina?
CONTROVERSIAL QUESTION
nists, and nitrates) alone or in combination to control their
symptoms. Despite this extensive use of antianginal drugs,
only 66% of patients were free from angina after 3 years of
follow-up. The results of the COURAGE and BARI 2D trials
indicate that targeting coronary artery stenosis only is far from
sufficient to optimally improve angina.
On the other hand, myocardial ischemia in the absence of ob-
structive coronary disease is a marker of poor prognosis. In
the WISE study (Womens Ischemia Syndrome Evaluation),
women with myocardial ischemia (seen on magnetic reso-
nance spectroscopy) who did not have obstructive coronary
disease had a similarly high rate of hospitalization for unsta-
ble angina than women with obstructive coronary disease.3
Trimetazidine, an antianginal drug that controls myocardial is-
chemia through intracellular metabolic changes, represents a
useful alternative and can be used as add-on therapy to he-
modynamic antianginal drugs. A growing body of evidence
supports the antianginal efficacy of trimetazidine, alone or in
combination.
The data described here point to the conclusion that the treat-
ment of angina should focus on myocardial ischemia rather
than solely on coronary artery stenosis. Accordingly, the lat-
est ESC guidelines on the management of stable coronary
artery disease have recognized the important role of meta-
bolic agents like trimetazidine.4
References
1. Boden WE, ORourke RA, Teo KK, et al; COURAGE Trial Research Group. Op-
timal medical therapy with or without PCI for stable coronary disease. N Engl
J Med. 2007;356:1503-1516.
2. Dagenais GR, Lu J, Faxon DP, et al; BARI 2D Study Group. Effects of optimal
medical treatment with or without coronary revascularization on angina and sub-
sequent revascularizations in patients with type 2 diabetes mellitus and stable
ischemic heart disease. Circulation. 2011;123:1492-1500.
3. Johson BD, Shaw LJ, Buchthal SD, et al. Prognosis in women with myocardial
ischemia in the absence of obstructive coronary disease. Results from the Na-
tional Institutes of Health-National Heart, Lung, and Blood Institute-sponsored
Womens Ischemia Syndrome Evaluation (WISE). Circulation. 2004;109:2993-
2999.
4. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the man-
agement of stable coronary artery disease. Eur Heart J. 2013;34:2949-3003.
MEDICOGRAPHIA, Vol 38, No. 3, 2016 301
CONTROVERSIAL QUESTION
5 . D. Isaza-Restrepo, Colombia
Daniel ISAZA-RESTREPO, MD, FACC
Director Coronary Care Unit
Fundacin Cardioinfantil
Director of Cardiology Fellowship program
Universidad del Rosario, and Universidad
del Bosque at Fundacin Cardioinfantil
Bogot, COLOMBIA
(email: disaza@cardioinfantil.org)
C
ardiac energy metabolism alterations are the main
pathophysiological factor involved in many heart con-
ditions, such as ischemic heart disease, where oxy-
gen delivery is impaired by the presence of stenosis.1 Oxygen
is required to produce enough energy to maintain cardiac
function using substrates such as glucose, free fatty acids
(FFAs), and proteins. The lack of oxygen caused by ischemic
heart disease alters the metabolic pathways of individual cells.
Current data show that even after successful revasculariza-
tion a third of angina patients still suffer from pain. Reasons
for this include: mechanical aspects such as neointimal hy-
perplasia/restenosis, incomplete revascularization, athero-
sclerotic plaque progression, microvascular dysfunction, or
coronary vasospasm. However, the diffuse nature of angina
and the fact that ischemia affects the metabolism of every car-
diomyocyte may perpetuate this condition.
Modifying the energy substrate supply has been proposed as
a way to improve the metabolic performance of cardiomyo-
cytes. Initially, studies that used an infusion of glucose-insulin-
potassium to increase the rate of glycolysis and decrease the
bioavailability of FFAs to potentiate cardiac metabolism were
not conclusive in showing clinical benefit.2 Other drugs, such
as fibrates, niacin, and nicotinic acidwhich act as PPAR lig-
andactivated nuclear hormone receptor agonists and de-
crease triglyceride levels, and therefore FFA levels, thereby
reducing the rate of b-oxidationshowed benefits but their
side effects casted doubt about their clinical usefulness.3
Modifying enzyme expression should theoretically be bene-
ficial, but more clinical evidence is needed to support the
use of etomoxir, oxfenicine, and perhexiline. These drugs in-
hibit the action of malonyl-CoA decarboxylase, an enzyme in
the fatty acid synthesis pathway, which degrades malonyl-
CoA. In turn, malonyl-CoA acts as an inhibitor of carnitine
palmitoyltransferase-1 (CPT-1), a key enzyme involved in b-ox-
idation. This prevents the use of FFAs as an energy substrate,
thereby optimizing energy production in cardiomyocytes.4 The
302 MEDICOGRAPHIA, Vol 38, No. 3, 2016
effects of dichloroacetate, a drug that increases glucose ox-
idation by stimulating pyruvate dehydrogenase, have been
studied in patients with ischemic heart disease.5 However,
some pharmacokinetic and pharmacodynamic issues need to
be clarified before its real clinical benefit can be determined.5
As mentioned above, these methods either require further ev-
idence or are not used because of concerns regarding their
safety.
Taking into account these issues, trimetazidine appears to
be the best evidence-based option to optimize metabolism in
ischemic heart disease. It competitively inhibits long-chain
3-ketoacyl CoA thiolase, and therefore inhibits b-oxidation and
stimulates glucose oxidation. Meta-analyses have proven its
clinical benefit in patients suffering from angina pectoris sec-
ondary to ischemic heart disease, and have suggested that
it may be beneficial in patients with heart failure.6,7
As exposed previously, we can be sure that modifying the
cardiomyocytes metabolic machinery in patients with coro-
nary artery disease improves ischemic symptoms further than
mechanical coronary interventions alone. This knowledge
opens up a broad range of possibilities for improving the qual-
ity of life of our patients. The results of the ongoing ATPCI clin-
ical trial (efficAcy and safety of Trimetazidine in Patients with
angina pectoris having been treated by percutaneous Coro-
nary Intervention), which is currently enrolling patients with
angina pectoris undergoing PCI who are then randomized to
trimetazidine or placebo and treated for 2 to 4 years, are ex-
pected to further our knowledge in this area.
References
1. Taegtmeyer H, Young ME, Lopaschuk GD, et al. Assessing Cardiac Metabolism:
A Scientific Statement From the American Heart Association. Circ Res. 2016;
118(10):1659-1701.
2. Selker HP, Beshansky JR, Sheehan PR, et al. Out-of-hospital administration of
intravenous glucose-insulin-potassium in patients with suspected acute coro-
nary syndromes: the IMMEDIATE randomized controlled trial. JAMA. 2012;307:
1925-1933.
3. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug
Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245-
1255.
4. Cole PL, Beamer AD, McGowan N, et al. Efficacy and safety of perhexiline maleate
in refractory angina. A double-blind placebo-controlled clinical trial of a novel
antianginal agent. Circulation. 1990;81:1260-1270.
5. Wargovich TJ, MacDonald RG, Hill JA, Feldman RL, Stacpoole PW, Pepine CJ.
Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary
artery disease. Am J Cardiol. 1988;61:65-70.
6. Ciapponi A, Pizarro R, Harrison J. Trimetazidine for stable angina. Cochrane Da-
tabase Syst Rev. 2005;CD003614.
7. Gao D, Ning N, Niu X, Hao G, Meng Z. Trimetazidine: a meta-analysis of ran-
domised controlled trials in heart failure. Heart. 2011;97:278-286.
Is targeting only stenosis sufficient to optimally improve angina?

6 . T. Kovarnik, Czech Republic
Tomas KOVARNIK, MD, PhD
Associate Professor of Internal Medicine
Charles University Hospital
Prague, CZECH REPUBLIC
(email: Tomas.Kovarnik@vfn.cz)
A
ngina pectoris (AP) refers to chest pain caused by
myocardial ischemia and is actually only a symptom.
Myocardial ischemia can develop either gradually
and cause clinical manifestations known as stable angina
pectoris (SAP)or suddenlywith the development of acute
coronary syndrome (ACS).
In both clinical scenarios the extent of myocardial ischemia
is the strongest predictor of prognosis. Myocardial ischemia
can be treated by (i) improving blood flow to the myocardi-
um (revascularization), (ii) decreasing myocardial demand on
blood flow (eg, with b-blockers, calcium channel blockers,
and ivabradinea drug that lowers oxygen consumption and
increases blood flow to the myocardium by decreasing the
heart rate), and (iii) increasing myocardial metabolic efficiency
when blood supply is limited (eg, with trimetazidine, a drug
that improves the efficiency of energy production in myocar-
dial cells suffering from ischemia by shifting their metabolism
from free-fatty-acid b-oxidation back to glycolysis). Nitrates
fall somewhere between revascularization and the latter two
conservative strategies, because they can enlarge coronary
arteries and increase blood flow, while at the same time de-
creasing preload (by venous dilatation). This action, in turn,
decreases oxygen consumption.
The greater the extent of myocardial ischemia, the greater
the benefit of revascularization will be. Revascularization not
only limits AP better than conservative therapy, but it also
improves the prognosis in patients with significant stenosis
located in the left main coronary artery; significant stenosis
located in a proximal part of the left anterior descending ar-
tery; significant stenosis located in two or three major vessels
together with systolic dysfunction of the left ventricle (ejec-
tion fraction <45%); myocardial ischemia affecting a large area
(>10%); and significant stenosis located in the last patent coro-
nary artery.1
However, about 30% patients suffer from AP after successful
revascularization, which significantly impairs their quality of
life.2
Is targeting only stenosis sufficient to optimally improve angina?
CONTROVERSIAL QUESTION
Post-revascularization AP occurs when:
(i) Revascularization is inappropriately indicated. The only un-
questionable indication for coronary revascularization in sta-
ble patients is the presence of significant ischemia with (SAP)
or without (silent ischemia) angina pectoris. Revascularization
simply cannot overcome the inherent risk of complications
(in-stent restenosis, periprocedural myocardial necrosis, in-
stent thrombosis, bleeding during antithrombotic treatment,
potential wound infection, and many others) in patients with-
out significant ischemia. Moreover, in patients without evi-
dence of ischemia, chest pain may have other causes, and its
recurrence after revascularization cannot be considered as
treatment failure.
(ii) There is a coronary etiology. In this case, AP recurs after
appropriately indicated and well-performed revascularization.
This relapse can be caused by target lesion failure (in-stent
restenosis, in-stent thrombosis) or the progression of a lesion
that was not significant at the time of revascularization. Revas-
cularization itself does not affect the process of atherosclero-
sis, which can continue unless appropriate medication is pre-
scribed. These conditions must be treated according to the
underlying causes.
(iii) AP persists despite appropriately indicated revasculariza-
tion, which may be due to incomplete revascularization (an-
other significant stenosis that has been left untreated), the
presence of microvessel disease, a technical complication
during PCI (peripheral embolization, untreated dissection), or
stretch pain (probably due to extension of vessel adventitia).
Several smaller studies have suggested that the incidence of
chest pain is lower after implantation of fully biodegradable
stents rather than metallic stents. However, the large ran-
domized controlled trial ABSORB 3 did not confirm this find-
ing.3 In this trial, AP occurred in 18% of patients, both in the
biodegradable and drug-eluting stent groups.
Conclusion
For every patient it is necessary to determine whether chest
pain is caused by ischemia, and if it is, to what extent. Based on
this information, the treatment can be properly tailored to each
patient to avoid unnecessary revascularization, which would
not only without any benefit, but could actually be harmful.
References
1. Windecker S, Kolh P, Alfonso F. 2014 ESC/EACTS Guidelines on myocardial
Revascularization. Eur Heart J. 2014;35:2541-2619.
2. Abbate A, Biondi-Zoccai G, Agostoni P, Lipinski M, Vetrovec G. Recurrent angi-
na after coronary revascularization: a clinical challenge. Eur Heart J. 2007;28:
1057-1065.
3. Kereiakes D. ABSORB 3 trial. Presented at: TCT 2015; October 2015; San Fran-
cisco, CA.
MEDICOGRAPHIA, Vol 38, No. 3, 2016 303
CONTROVERSIAL QUESTION
7. O. H. Masoli, Argentina
Osvaldo H. MASOLI, MD, FACC, FESC
Chief of Cardiac Imaging
Image Department of TCba Salguero
Buenos Aires, ARGENTINA
(email: ohmasoli@fibertel.com.ar)
Determinants of myocardial flow
T
he coronary circulation is composed of the epicardial
coronary arteries, which are of large caliber, and the
resistance vessels, which are less than 300 m in di-
ameter. Whereas the epicardial vessels exert little or no flow
resistance, flow resistance in the resistance vessels increas-
es gradually as the vessel diameter decreases to less than
100 m (eg, in arterioles). Exchange of substances between
blood and tissue occurs at the capillary level.
In the myocardium, blood flow largely depends on the pres-
sure gradient between the aortic root and the left atrium (coro-
nary pressure). Under normal conditions, coronary pressure
is fully maintained in the epicardial vessels, with minimal or no
loss of pressure in the distal epicardial arteries. In contrast,
intracoronary pressure decreases along the microvascula-
ture to a pressure of 20-30 mm Hg (with most of the pres-
sure dissipating in vessels with a diameter of 100-300 m).
As a result of a decrease in microvascular resistance caused
by metabolic changespossibly involving adenosine, a met-
abolite of adenosine monophosphate which induces vascu-
lar muscle relaxationwork-related myocardial flow increases.
The resulting flow increase is augmented by endothelium-de-
pendent factors, and this faster flow exerts more shear stress
on the endothelium, stimulates the enzyme nitric oxide syn-
thase (eNOS), triggering the release of nitric oxide, which
relaxes smooth muscles. In this scenario, endothelial cells and
smooth muscle cells interact closely, which helps the ves-
sels adjust their diameter according to changes in flow rate in
the microvascular and epicardial vessels.
304 MEDICOGRAPHIA, Vol 38, No. 3, 2016
Coronary reserve
A good understanding of the physiology of the coronary cir-
culation is necessary to understand the concept of coronary
reserve. In a nutshell, coronary reserve refers to the ability of
the vascular circuits to adapt to myocardial oxygen consump-
tion by vasodilation. Depending on the level of endothelial health
and on the extent of the mechanical obstruction present in
the epicardial arteries as a result of the atherosclerotic process,
an adaptive process called vascular remodeling may take place.
This process initially leads to an increase in vessel diameter.
When atherosclerosis involves the lumen, the percentage of
obstruction will affect the coronary reserve capacity, ie, the
ability to lower vascular resistance, and thus increase flow, so
that the arterial blood can reach peripheral tissues without
altering cellular metabolism. But this compensation mecha-
nism is limited. Unless we try to stop the progress of ather-
osclerosis or remove the obstruction, with medication and/or
invasive treatments such as myocardial revascularization pro-
cedures, the damage may be irreversible and permanently
alter the affected vessel, and thus tissue function.
Conclusion
The mechanisms involved in the genesis of myocardial ische-
mia and its manifestation as angina are very complex and
go beyond the epicardial arteries. Therefore, efforts aiming to
normalize the lumen of the arteries or bypass the obstruction
only act on part of the problem. Fortunately, we now have
drugs that can improve cell metabolism, such as trimetazidine,
or new drugs that can reduce the heart rate, such as ivabra-
dine, a drug whose pleiotropic effects lead to vasodilatation
and the release of nitric oxide, and thus improve endothelium
function. But we should not forget all the other drugs that
have been shown to have a beneficial effect on the outcome
of patients with coronary heart disease, nor the positive ef-
fects of healthy eating and physical activity.
References
1. Masoli O, Balio NP, Sabat D, et al. Effect of endothelial dysfunction on region-
al dysfunction on regional perfusion in myocardial territories supplied by nor-
mal and diseased vessels in patients with coronary artery disease. J Nucl Cardiol.
2000;7:199-204.
2. Schelbert HR. Anatomy and physiology of coronary blood flow. J Nucl Cardiol.
2010;4:545-554.
Is targeting only stenosis sufficient to optimally improve angina?

8 . A. N. Parkhomenko and O. S. Gurjeva, Ukraine
Alexander N. PARKHOMENKO, MD, PhD
Olga S. GURJEVA, MD, PhD, MH
Ukrainian Institute of Cardiology - Kiev, UKRAINE
(e-mail: aparkhomenko@yahoo.com)
M
icrovascular angina (MVA) is found in about one-
third of patients undergoing coronary angiography
for angina who have no significant obstructive coro-
nary lesions, and is strongly associated with adverse long-
term prognosis.1 In patients with normal, near-normal, or
restored epicardial flow, several factors contributing to an
imbalance between oxygen demand and supply may coexist.
About half the patients with coronary artery disease (CAD)
have concomitant hypertension, and a growing proportion of
elderly patients may present with aortic stenosis (AS). In this
group of patients, increased oxygen demand is the result of
increased left ventricular end-systolic pressure, left ventricular
hypertrophy, impaired diastolic function, increased heart rate,
and increased wall stress. As left ventricular hypertrophy pro-
gresses, coronary flow reserve may be affected by increased
diastolic filling pressure, which compresses the endocardi-
um, impairs perfusion, and reduces capillary distribution.2 In
patients with AS, MVA has been attributed to preexisting ab-
normal resting arteriolar vasodilation in patchily distributed
microvasculature preserving myocardial perfusion and ab-
normally constricted prearteriolar vessels preventing distal
pressure overload.3
MVA may follow an endothelium-dependent or an endothe-
lium-independent pattern. According to the current in-depth
understanding of the pathways underlying angina symptoms,
there is a close correlation between the ratio of oxygen de-
mand to oxygen supply and cardiac energy metabolism (sub-
strate utilization, production of ATP by oxidative phosphory-
lation, and ATP transfer and utilization).4 The cardiac metabolic
system is very flexible, and can switch from one energy source
to another. However, its adaptive capacity decreases in states
associated with increased oxygen demand or steadily de-
creased coronary blood flow, triggering metabolic remodel-
ing. Prolonged energy deficit triggers the expression of fetal
genes and a switch from fat to glucose metabolism, stimu-
lates glycogen accumulation and changes in cell signaling, in-
Is targeting only stenosis sufficient to optimally improve angina?
CONTROVERSIAL QUESTION
creases the number of dysfunctional mitochondria, leads to
collagen deposition, macrophage infiltration, fibrosis, deple-
tion of sarcomeres, and activates apoptosis. More profound
changes occur in stunned myocardium and result from in-
hibition of Na-K-ATPase, increased intracellular Na+ level, Ca2+
overload, stimulation of reactive oxygen species (ROS) pro-
duction, and depression of contractile function in near nor-
mal coronary flow. Revascularization partially attenuates these
changes, but patients may still experience coronary micro-
embolization and microvascular obstruction, which may lead
to abnormal gene expression and apoptosis.5 Apoptosis oc-
curs in low-flow states and may be triggered by reperfusion
injury and severe energy depletion and follows either intrin-
sic mitochondria-mediated or extrinsic membrane-mediated
pathways. The intrinsic pathway involves mechanisms that
impact the functioning of mitochondrial permeability transi-
tion pores (mPTPs). The extrinsic pathway is receptor-mediat-
ed and may be activated by oxidative stress late after reper-
fusion. Reperfusion injury and slow-reflow states contribute
to necrosis, increased mitochondrial membrane permeability,
cell swelling, lysis, fragmentation of cellular structures, activa-
tion of inflammatory pathways, and leukocyte infiltration.
These maladaptive cascades often partially persist after epi-
cardial flow is restored and should be addressed medically.
Metabolic agents such as trimetazidine counteract the effect
of myocardial ischemia on mitochondrial membrane perme-
ability by diminishing oxidative stress and inhibiting mPTP
opening, and also reduce caspase 3 activity and apoptosis.6
The mechanisms that underlie angina are so complex that it
cannot be resolved by relying on revascularization only; other
nonmechanistic approaches are therefore needed to man-
age patients after revascularization.
References
1. Jespersen L, Hvelplund A, Abildstrm S, et al. Stable angina pectoris with no
obstructive coronary artery disease is associated with increased risks of major
adverse cardiovascular events. Eur Heart J. 2012;33(6):734-744.
2. Rajappan K, Rimoldi OE, Camici PG, et al. Functional changes in coronary mi-
crocirculation after valve replacement in patients with aortic stenosis. Circulation.
2003;107:3170-3175.
3. Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Kaski JC, Sechtem U. High
prevalence of a pathological response to acetylcholine testing in patients with sta-
ble angina pectoris and unobstructed coronary arteries. The ACOVA Study (Ab-
normal COronary VAsomotion in patients with stable angina and unobstructed
coronary arteries). J Am Coll Cardiol. 2012;59:655-662.
4. Neubauer S. The failing heartan engine out of fuel. N Engl J Med. 2007;356
(11):1140-1151.
5. Reffelmann T, Kloner RA. The "no-reflow" phenomenon: basic science and clin-
ical correlates. Heart. 2002;87(2):162-168.
6. Hu B, Li W, Xu T, Chen T, Guo J. Evaluation of trimetazidine in angina pectoris
by echocardiography and radionuclide angiography: a meta-analysis of random-
ized, controlled trials. Clin Cardiol. 2011;34(6):395-400.
MEDICOGRAPHIA, Vol 38, No. 3, 2016 305
CONTROVERSIAL QUESTION
9 . C. K. Ponde, India
C. K. PONDE, MD, DM(Card), DNB (Card),
FACC, FSCAI, FCSI, FIAE, FISE, FICC
Consultant cardiologist
Head, Department of Cardiology
P.D. Hinduja National Hospital
Mumbai, INDIA
(email: ckpshekhar@yahoo.co.in)
T
he number of percutaneous coronary angioplasty pro-
cedures (PCI) performed in patients with chronic stable
angina (CSA) has increased tremendously in the last
two decades.1 In a series of 2000 patients with CSA (of whom
39% underwent PCI and 28% CABG) almost a third had mul-
tiple episodes of angina per week after 6 months of follow-up.2
Moreover, the Euro Heart Survey reports that 60% of patients
with persistent angina post-PCI are moderately/severely dis-
abled.
The most common causes of persistent/recurrent angina post-
PCI are either structural (stretch pain, in-stent restenosis,
in-stent thrombosis, incomplete revascularization, or progres-
sion of coronary atherosclerosis) or functional (microvascu-
lar dysfunction or epicardial coronary spasm). A recent meta-
analysis of randomized clinical trials comparing PCI versus
optimal medical therapy (OMT) in patients with CSA has shown
that PCI does not reduce the risk of mortality, cardiovascu-
lar death, nonfatal myocardial infarction, or revascularization
procedures; however, it provides greater relief from angina
compared with OMT, at least in the first year.3 Most interna-
tional guidelines recommend revascularization procedures
in CSA only when symptoms are not controlled by OMT.
In-stent restenosis usually manifests between 4 and 8 months
after PCI and is associated with angina and objective evi-
dence of myocardial ischemia on provocative testing.4 If OMT
fails to control it, repeat revascularization is usually required.
However, the use of drug-eluting stents (DESs) has substan-
tially reduced its occurrence.
Inappropriate vasoconstriction of small vessels in the distal coro-
nary bed of the target vessel is a frequent cause of positive
stress tests after successful angioplasty.5 Stent implantation
also induces distal coronary endothelial dysfunction. Exercise-
induced spasm of a large epicardial coronary artery in the dis-
tal post-stent segment has been documented and reported.
The two most frequent causes of early post-CABG angina are
anastomotic site lesions and rapid venous graft degeneration/
thrombosis. A thorough clinical evaluation is crucial in such
patients. In those with established angina, direct coronary an-
giography should be performed, while non-invasive stress tests
(vs myocardial scintigraphy/stress echocardiography) are ap-
306 MEDICOGRAPHIA, Vol 38, No. 3, 2016
propriate in those whose probability of having angina is inter-
mediate. Estimation of coronary flow reserve is a boon for those
in whom angiography shows borderline stenosis (70%). A
fractional flow reserve (FFR) of 0.75 or less is usually con-
sidered to be a good indication for PCI. The DEFER trial has
shown that performing PCI for lesions with a FFR of 0.75 or
more does not improve symptoms nor prognosis.6
Achieving and maintaining an optimal body weight and fol-
lowing a graded exercise training program are known to im-
prove exercise capacity in patients with CSA. Achieving an
optimal hematocrit and excellent blood pressure control, and
lowering LDL-C levels to below 70 mg/dL are all extremely
important ways to improve the prognosis of these patients.
Post-PCI stretch pain is usually treated with analgesics and is,
thankfully, self-limiting. The functional causes of recurrent angi-
na (microvascular dysfunction/epicardial coronary spasm) re-
spond best to diltiazem and long-acting nitrates. Trimetazidine
(an inhibitor of fatty acid oxidation), which improves angina
by shifting myocardial metabolism toward glucose oxidation
(TRIMPOL II study)7 has also been found to be useful in such
patients. b-Blockers should be prescribed to all post-PCI pa-
tients unless contraindicated. Statins and angiotensin-con-
verting enzyme (ACE) inhibitors should also be part of OMT in
most patients. High compliance rates with OMT, such as those
obtained in the COURAGE trial, (90% at 5 years) are not easy
to obtain in clinical practice unless combinations are used to
reduce the number of pills patients are prescribed. Thankful-
ly in India various combinations are freely available. Recent-
ly, the BEAUTIFUL and ASSOCIATE trials have shown some
promising results for the use of ivabradine as an add-on ther-
apy or in those in whom b-blockers are contraindicated to
reduce the frequency of angina attacks and the number of
cardiac events.
References
1. Ko DT, Tu JV, Samadashvili Z, et al. Temporal trends in the use of percutaneous
coronary intervention and coronary artery bypass surgery in New York State and
Ontario. Circulation. 2010;121:2635-2644.
2. Vetrovec GW, Watson J, Chaitman B, Cody R, Wenger N. Symptoms persist in
patients with chronic angina despite frequent antianginal use and prior revas-
cularization. J Am Coll Cardiol. 2004;43(Suppl. II):A281.
3. Pursnani S, Korley F, Gopaul R, et al. Percutaneous coronary intervention versus
optimal medical therapy in stable coronary artery disease, a systematic review
and meta-analysis of randomized clinical trials. Circ Cardiovasc Interv. 2012;
5:476-490.
4. Holmes DR Jr. In-stent restenosis. Rev Cardiovasc Med. 2001;2:115-119.
5. Ito S, Nakasuka K, Morimoto K, et al. Angiographic and clinical characteristics of
patients with acetylcholine-induced coronary vasospasm on follow-up coronary
angiography following drug-eluting stent implantation. J Invasive Cardiol. 2011;
23:57-64.
6. Pijls NH, Van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary
intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER
Study. J Am Coll Cardiol. 2007;49:2105-2111.
7. Szwed H, Sadowski Z, Elikowski W. Combination treatment in stable effort angi-
na using trimetazidine and metoprolol: results of a randomized, double-blind, mul-
ticentre study (TRIMPOL II). TRIMetazidine in POLand. Eur Heart J. 2001;22:
2267-2274.
Is targeting only stenosis sufficient to optimally improve angina?

10. V. Sansoy, Turkey
Vedat SANSOY, MD, FESC
Professor of Cardiology
Institute of Cardiology
University of Istanbul
Istanbul, TURKEY
(email: vedat.sansoy@gmail.com)
D
espite the progress made by the various therapeutic
methods used in cardiology in the last decades, coro-
nary artery disease remains the leading cause of mor-
tality and morbidity worldwide. Percutaneous coronary inter-
vention is an effective and safe treatment to relieve severe
stenosis in patients with coronary artery disease, but studies
have shown that many patients still suffer from recurrent angi-
na or silent myocardial ischemia after revascularization.1
Traditional antianginal agents for the treatment of stable angi-
na pectoris include nitrates, calcium antagonists, and b-block-
ers, which reduce angina attacks either by reducing ATP con-
sumption via a reduction in the heart rate and blood pressure
or by increasing ATP production through an increase in coro-
nary blood flow.2 Optimizing myocardial metabolism with meta-
bolic agents is a new strategy that can be used in patients
with stenotic coronary artery disease. These drugs represent
a new class in the treatment of ischemic heart disease. Tri-
metazidine is a metabolic agent, and unlike conventional an-
tianginal drugs, it restores the balance between myocardial
oxygen supply and demand by selectively inhibiting the long-
chain 3-ketoacyl coenzyme A thiolase, thus partially suppress-
ing the b-oxidation of fatty acids, stimulating glucose metab-
olism, and increasing myocardial ischemic tolerance.3,4 Xu
et al 5 have showed that adjunctive therapy with trimetazidine
after drug-eluting stent implantation reduces the incidence
and the severity of angina pectoris as well as that of silent is-
Is targeting only stenosis sufficient to optimally improve angina?
CONTROVERSIAL QUESTION
chemia in elderly patients with multivessel coronary artery dis-
ease and diabetes mellitus. In addition, pretreatment or con-
comitant treatment with trimetazidine seems to have a cardio-
protective effect in patients undergoing percutaneous
coronary intervention. These studies have shown that
trimetazidine treatment results in an improvement in several
ischemic parameters, such as a reduction in the frequency of
angina pectoris attacks and of myocardial damage during
percutaneous coronary intervention and coronary artery by-
pass graft surgery. These benefits are achieved because
trimetazidine protects the heart from ischemic damage and
oxidative stress. In addition, trimetazidine has also been
shown to improve left ventricular function in the follow-up pe-
riod after percutaneous angioplasty.6
References
1. Hueb W, Soares PR, Gersh BJ, et al. The Medicine, Angioplasty, or Surgery trial
(MASS-II): a randomized, controlled, clinical trial of three therapeutic strategies
for multivessel coronary artery disease. One-year results. J Am Coll Cardiol.
2004;43:1743-1751.
2. Kolh P, Windecker S, Alfonso F, et al; Task Force on Myocardial Revasculariza-
tion of the European Society of Cardiology and the European Association for
Cardio-Thoracic Surgery; European Association of Percutaneous Cardiovascu-
lar Interventions. 2014 ESC/EACTS Guidelines on myocardial revascularization:
the Task Force on Myocardial Revascularization of the European Society of
Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery
(EACTS). Developed with the special contribution of the European Association
of Percutaneous Cardiovascular Interventions (EAPCI). Eur J Cardiothorac Surg.
2014;46:517-592.
3. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine
shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation
by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res.
2000;86:580-588.
4. Desideri A, Celegon L. Metabolic management of ischemic heart disease: clin-
ical data with trimetazidine. Am J Cardiol. 1998;82:50K-53K.
5. Xu X, Zhang W, Zhou Y, et al. Effect of trimetazidine on recurrent angina pec-
toris and left ventricular structure in elderly multivessel coronary heart disease pa-
tients with diabetes mellitus after drug-eluting stent implantation: a single-centre,
prospective, randomized, double-blind study at 2-year follow-up. Clin Drug In-
vestig. 2014;34:251-258.
6. Bonello L, Sbragia P, Amabile N, et al. Protective effect of an acute oral loading
dose of trimetazidine on myocardial injury following percutaneous coronary in-
tervention. Heart. 2007;93:703-707.
MEDICOGRAPHIA, Vol 38, No. 3, 2016 307
CONTROVERSIAL QUESTION
11. D. Vassilev, Bulgaria
Dobrin VASSILEV, PhD
Head of cardiology department
Medical University of Sofia
Sofia, BULGARIA
(email: dobrinv@gmail.com)
I
schemic heart disease is a diffuse disease encompass-
ing not only the epicardial compartment, but also the mi-
crovascular compartment. This is one of the reasons for
continuing chest pain even after complete mechanical epi-
cardial revascularization: about 40% of all bypassed or stent-
ed patients still have angina one year after the procedure.1 We
present a case in which the patient had residual ischemia de-
spite complete revascularization with the use of last-gener-
ation drug-eluting stents. In cases such as this onein which
further revascularization is impossiblea metabolic drug that
can reduce ischemia may improve symptoms.
A fifty-two year-old male smoker, with a history of hyperten-
sion and dyslipidemia, was admitted to our clinic with stable
angina triggered by low-level physical activity, which he had
started to experience approximately one year earlier (class
III CCS). His ECG at rest was normal, and did not show any
signs of ischemia. Echocardiography did not show any kinet-
ic dysfunction at rest; the ejection fraction was 53%, the left
ventricle was not dilated, and there were no significant valvular
lesions. In addition, the cardiac markers of myocardial necro-
sis were normal.
Coronary angiography, which was performed through right
radial access, showed 80% stenosis in the distal left main (LM)
artery. There was 70% stenosis in the proximal and middle
segments of the left anterior descending (LAD) artery, where
there were two Medina 110 bifurcation stenotic lesions in the
first and second diagonal branches, respectively. The SYN-
TAX score was 28. According to the ESC Guidelines for My-
ocardial Revascularization, the patient had left main artery dis-
ease with a SYNTAX score of 23-32, which corresponds to
class I and level of evidence B for coronary artery bypass
graft surgery (CABG).2 Treatment with percutaneous coronary
intervention is class IIa with a level B of evidence. However,
the Heart Team decided that percutaneous coronary interven-
tion was an option as the patient was reluctant to go through
CABG surgery.
Before the procedure, the patient was preloaded with clopi-
dogrel 600 mg and 500 mg aspirin. The procedure was per-
308 MEDICOGRAPHIA, Vol 38, No. 3, 2016
formed through radial access, and a JL 4, 6F guiding catheter
was used to canulate the LM. Two wires were placed in the
LAD and LCX. First, we predilated the LM-LAD with a balloon,
after which two overlapping stents (Biofreedom 3.0x28 mm
and 3.5x24 mm) were implanted into the LAD. There was no
significant stenosis in the diagonal ostia (grade III TIMI flow).
Another overlapping stent was placed in the LM and ostio-
proximal part of the LAD (Biofreedom 3.5x24 mm). We then
dilated the stented region (LM and LAD) with noncompliant
(NC) balloons. Because there was 70% stenosis in the LCX
ostium we performed a balloon dilation of the LAD and LCX
ostia. The final angiographic result showed no dissection and
no residual stenosis, and normal flow was restored in all treat-
ed vessels. A final intravascular ultrasound (IVUS) was per-
formed in the LAD, LCX and left main artery, and showed no
signs of dissection and stent strut malposition. The circum-
flex artery ostium was not compromised, so there was no need
for additional stenting.
The patient was discharged 2 days after the procedure; he
had no angina symptoms, nor any elevation of the markers
of myocardial necrosis, and there were no adverse events. He
was prescribed rosuvastatin, ramipril, bisoprolol, clopidogrel,
and acetylsalicylic acid.
At 1 month of follow-up, there were no adverse events, but
the patient still had intermittent episodes of chest pain. The
stress test at 11 METs (metabolic equivalents) was ECG neg-
ative, with slight chest discomfort. For this reason we decid-
ed to add trimetazidine to his treatment. At the next visitthe
following monththe patient was completely asymptomatic.
This case clearly illustrates the fact that even after complete
mechanical revascularization microvascular dysfunction can
still cause discomfort. Increasing hemodynamic therapy pro-
vides no additional benefit in this kind of situation and the only
option is to directly alter the ischemic threshold by adding a
metabolic drug (eg, trimetazidine) according to the currently
proposed algorithm for the treatment of angina.3
References
1. Cohen DJ, Van Hout B, Serruys PW, et al. Quality of life after PCI with drug-elut-
ing stents or coronary-artery bypass surgery. N Engl J Med. 2011;17;364(11):
1016-1026.
2. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocar-
dial revascularization: The Task Force on Myocardial Revascularization of the
European Society of Cardiology (ESC) and the European Association for Cardio-
Thoracic Surgery (EACTS)Developed with the special contribution of the Euro-
pean Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur
Heart J. 2014;35(37):2541-2619.
3. Task Force Members; Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC
guidelines on the management of stable coronary artery disease: the Task Force
on the management of stable coronary artery disease of the European Society
of Cardiology. Eur Heart J. 2013;34(38):2949-3003.
Is targeting only stenosis sufficient to optimally improve angina?

This overall improvement in
adenosine triphosphate produc-
tion with trimetazidine protects the
cell against acidosis and ionic im-
balance during ischemia. Notably,
trimetazidine has been shown to
prevent calcium overload, the pro-
duction of free radicals, and apop-
tosis in the cardiac cell during re-
perfusion. By preventing all these
deleterious effects, trimetazidine
maintains the contractile function
of the cardiac cell and reduces
anginal symptoms.
Mariia GLIEBOVA, MD
Servier International
Global Medical Strategy
and Information Department
Cardiovascular
Suresnes, FranCe
S ic disease associated with poor prognosis and impaired quality of life. Patients
Address for correspondence:
Dr Mariia Gliebova,
Servier International, 50 rue Carnot,
92284 Suresnes Cedex, France
(email: mariia.gliebova@servier.com)
www.medicographia.com
Trimetazidine: targeting the cardiac cell in stable angina Gliebova
VA STA R E L M R
Trimetazidine:
targeting the cardiac cell
in stable angina
b y M . G l i e b ova , Fra n c e
A
ngina is now recognized as a multifaceted disease where coronary ar-
tery obstructions are only one among many contributing factors. Be-
cause of its central involvement in a number of ischemic processes,
the cardiac cell is recognized as a major player in cardiac ischemia. At the cell
level, myocardial ischemia is characterized by altered myocardial energy me-
tabolism, which results in an ionic imbalance, misuse of and deficit in energy,
and ultimately functional defects. During ischemia, trimetazidine acts direct-
ly at the cell level by decreasing fatty acid oxidation and increasing glucose
oxidation, which helps restore normal energy metabolism. This leads to an
overall improvement in the general function of the cell and, at the organ level,
provides anti-ischemic activity. By directly targeting the cardiac cell, trimetazi-
dines mechanism of action complements those of hemodynamically active
antianginal therapies, thus maximizing clinical efficacy when used in a com-
bination strategy. Trimetazidine has been shown to provide additional reduc-
tion in symptoms and increase exercise capacity in angina patients whose
symptoms are inadequately controlled by b-blockers and/or calcium chan-
nel blockers. The beneficial effect of trimetazidine has been demonstrated
in various angina patients, including those with a history of myocardial infarc-
tion, previous percutaneous coronary intervention, diabetes, or left ventricu-
lar dysfunction. In addition to its proven antianginal effect, trimetazidine may
also provide extra benefits in terms of cardioprotection and prognosis in many
cardiovascular patients.
Medicographia. 2015;37:309-316 (see French abstract on page 316)
table angina pectoris, a clinical manifestation of myocardial ischemia, is a chron-
with severe angina are at greater risk for cardiovascular events, including my-
ocardial infarction or death, and the rate of hospitalizations is particularly high in this
population.
One therapeutic option for relieving angina symptoms is the use of invasive pro-
cedures, such as myocardial revascularization. However, this type of approach has
unclear effects on survival,1 and its use is restricted to angina patients with obstruc-
tive coronary artery stenosis. Thus, medical therapyby reducing the symptoms
of angina, increasing exercise tolerance, and improving quality of liferemains a
cornerstone in the management of angina patients.2 antianginal drugs exert their
effects by reducing cardiac workload, ie, reducing myocardial oxygen consumption
MEDICOGRAPHIA, Vol 38, No. 3, 2016 309
VA STA R E L M R
and/or increasing oxygen supply to the heart. This is the mode
of action of standard antianginal treatments, such as b-block-
ers or calcium channel blockers. another approach consists
in optimizing oxygen use by directly increasing energy produc-
tion at the cardiac level, such as with the anti-anginal agent
trimetazidine. In view of their complementary mechanisms
of action, antianginal drugs are often used in combination for
additive or synergic effects. Here we review the pharmaco-
logical rationale and clinical efficacy of trimetazidine in patients
with stable angina pectoris, in light of recent experimental and
clinical findings.
Angina: a single clinical entity with
multiple etiologies
angina pectoris is generally recognized as the clinical expres-
sion of underlying coronary artery disease (CaD). In patients
with CaD, myocardial ischemia results from flow-limiting ob-
structions in the epicardial coronary arteries, as documented
by coronary angiography. However, a significant proportion of
patients with typical angina symptoms do not present obstruc-
tive lesions in their angiograms. In a recent report, 83.5% of
angina patients with no previously documented CaD had no
evidence of obstructive CaD.3 These patients often present
with occult coronary abnormalities, which explain their angina
symptoms. These vascular defects often occur concomitantly,
supporting the notion that multiple causative mechanisms in
anginaincluding endothelial dysfunction, microvascular im-
pairment, and myocardial bridgingare common.4 Beyond
coronary mechanisms, additional nonvascular mechanisms
can contribute to myocardial ischemia (Table I). These are
particularly relevant in a significant minority of angina patients
for whom there is no coronary explanation for their symptoms.4
Because of its central involvement in a number of ischemic
processes, including inflammation and impaired myocardial
energy metabolism, the cardiac cell is recognized as a major
nonvascular player in ischemic heart disease (Table I).5,6 Pro-
gression in angina is a complex and multifactorial process, with
both vascular and nonvascular contributing mechanisms.
Coronary obstruction represents only one piece of the puzzle.
SELECTED ABBREVIATIONS AND ACRONYM S
ATP adenosine triphosphate
ATPCI efficacy and safety of Trimetazidine in Patients with
angina pectoris having been treated by percuta-
neous Coronary Intervention
CAD coronary artery disease
DIETRIC estudio prospectivo en pacientes DIabticos de la
efectividad y tolerabilidad de la TrImetazidina en
asociacin al tratamiento previo de su enfermedad
Coronaria
MACCE major adverse cardiac and cerebrovascular event
METRO Management of angina: a reTrospective cOhort
PCI percutaneous coronary intervention
TRIMPOL TrIMetazidine in POLand
310 MEDICOGRAPHIA, Vol 38, No. 3, 2016
Targeting the cardiac cell for increased
clinical efficacy
The recognition of myocardial ischemia as a multifactorial
process implies that antianginal management should not sole-
ly focus on large coronary vessels, but also on the microves-
sels and cardiac cell. One option would be to adjust treat-
ment for each patient according to the underlying causes of
angina. However, this would prove difficult to diagnose in prac-
Origin Possible mechanisms of ischemia
Vascular
Macrovessels Flow-limiting stenosis (atherosclerosis)
endothelial dysfunction
Vasospasm
Muscle bridge
Inflammation
Microvessels Microvascular dysfunction
endothelial dysfunction
Spasm
Inflammation
Microemboli
Nonvascular
Cardiomyocytes Impaired energy metabolism
Defective cellular oxygen transport
Mitochondrial dysfunction
Inflammation/fibrosis
Table I. Multiple causes of stable ischemic heart disease.
These different mechanisms of ischemia are not mutually exclusive and often
occur concomitantly during angina.
Modified from reference 6: Pepine and Douglas. J Am Coll Cardiol. 2012;60(11):
957-959.
tice. a more convenient approach would consist in a glob-
al therapeutic strategy that encompasses all causes of is-
chemia. In the euro Heart Survey, over half of stable angina
patients (59%) were prescribed two or more antianginal drugs.7
Combining different anti-ischemic drugs, each with its own
distinct mechanism of action, may improve clinical efficacy by
additive or even synergistic effects. Moreover, a combination
strategy allows more treatment flexibility, by permitting drug
selection according to a patients comorbidities and/or car-
diac function.
The heart requires a large amount of energy to support its
continuous contractile activity, making energy metabolism a
fundamental process in the cardiac cell. Under normal con-
ditions, the main source of energy in the cardiac cell comes
from the oxidative metabolism of fatty acids in the mitochon-
dria, which provides 70% of total adenosine triphosphate
(aTP). However, the mitochondrial oxidation of glucose re-
mains a more efficient metabolic process, as it requires 12%
less oxygen than fatty acids for an equivalent aTP produc-
tion. During ischemia, where oxygen supply is limited, oxida-
tive metabolism is dramatically reduced, and glycolysis (ie,
conversion of glucose to pyruvate) becomes a preponderant
Trimetazidine: targeting the cardiac cell in stable angina Gliebova

source of energy (Figure 1).8 This alteration in myocardial me-
tabolism is accompanied by an uncoupling of glycolysis and
glucose oxidation, an increase in intracellular lactate and pro-
tons, and an ionic imbalance, with serious consequences at
the cellular level. These maladaptive metabolic changes cause
a depletion in the cellular energy store, as evidenced by a de-
crease in aTP production and other high-energy phosphate
levels. In order to maintain ionic homeostasis, aTP-depend-
ent ion transporters are activated to eject protons and sodium
out of the cardiac cell. This consumption of aTP for noncon-
tractile purposes further impairs cardiac function, in a con-
text where energy levels are already dramatically reduced.
This vicious cycle has been summarized by Pepine et al in
the following terms: ischemia begets more ischemia.9
Trimetazidine acts directly at the cell level by inhibiting long-
chain 3-ketoacyl coenzyme a thiolase, a mitochondrial en-
zyme involved in fatty acid oxidation. Inhibition of this enzyme
leads to a decrease in fatty acid oxidation and, as a conse-
quence, stimulates glucose oxidation and inhibits glycolysis
(Figure 1).10 This beneficial effect of trimetazidine on energy
metabolism pathways is accompanied by a restoration of in-
tracellular energy levels. This has been demonstrated in an-
Trimetazidine: targeting the cardiac cell in stable angina Gliebova
VA STA R E L M R
imal studies11-13 and confirmed in a clinical setting,14 where
treatment with trimetazidine for 3 months was shown to in-
crease myocardial levels of high energy phosphates in heart
failure patients by 33%. This overall improvement in aTP pro-
duction with trimetazidine protects the cell against acidosis
and ionic imbalance during ischemia.12,15,16 notably, trimeta-
zidine has been shown to prevent calcium overload,17 the pro-
duction of free radicals,18 and apoptosis19 in the cardiac cell
during reperfusion. By preventing all these deleterious effects,
trimetazidine maintains the contractile function of the cardiac
cell and reduces anginal symptoms.12,20
To summarize, trimetazidine exerts its anti-ischemic effects
directly at the cardiac cell level, by optimizing aTP use and op-
posing deleterious changes that occur during ischemia.
Clinical efficacy of trimetazidine in stable angina
The anti-ischemic and antianginal efficacy of trimetazidine has
been demonstrated in a range of randomized clinical trials in-
volving nearly 4000 patients with chronic stable angina world-
wide.20 This clinical efficacy is associated with a good safety
profile. The positive benefit-risk balance of trimetazidine in sta-
ble angina was recently reaffirmed in an assessment of the
european Medicines agency in 2012 and recog-
nized in the latest european Society of Cardiology
guidelines for the treatment of stable CaD in 2013,22
and for the treatment of heart failure in 2016.23
Efficacy of trimetazidine in comparison
with b-blockers
The antianginal efficacy of trimetazidine (60 mg dai-
ly) was compared with that of propranolol (120 mg
daily) in a randomized, double-blind, multicenter
study in 149 patients with stable angina and doc-
umented CaD.24 results indicated that the antiang-
inal efficacy of trimetazidine was similar to that of
the b-blocker.
The improvement in clinical parameters was com-
parable in both groups of patients after 3 months
of treatment (mean propranolol-trimetazidine dif-
ference in number of weekly angina attacks, 2.0
[P=0.117]; and in weekly use of short-acting ni-
trates, 1.1 [P=0.426]). a similar anti-ischemic ef-
fect for trimetazidine and propranolol was observed
during exercise testing.
Figure 1. The alteration in fatty acid oxidation during
cardiac ischemia is accompanied by an increase in
glycolysis and a decrease in glucose oxidation, with
deleterious consequences for cardiac homeostasis
and efficiency (black arrows). The inhibition of fatty acid
oxidation with trimetazidine restores the coupling of
glycolysis to glucose oxidation, which in turn increases
production of ATP and restores cell function (red arrows).
Modified after reference 8: Fillmore et al. Br J Pharmacol. 2014;
171:2080-2090. 2014, The British Pharmacological Society.
MEDICOGRAPHIA, Vol 38, No. 3, 2016 311
VA STA R E L M R
Figure 2. Mean number of weekly angina attacks in patients
whose symptoms were inadequately controlled with propranolol
before (D0) and after (D60) add-on treatment with isosorbide
dinitrate (beige bar) or trimetazidine (red bar).
This study shows that trimetazidine possesses the clinical ef-
ficacy of a first-line antianginal agent. The comparable effica-
cy of trimetazidine and b-blocker was acknowledged in the
2013 european Society of Cardiology guidelines on the man-
agement of stable CaD.22
Efficacy of trimetazidine in comparison with calcium
channel blockers
The antianginal efficacy of trimetazidine (60 mg daily) was
compared with that of nifedipine (40 mg daily) in a random-
ized, double-blind study with a cross-over design in 39 pa-
tients with stable angina and documented CaD.25 each treat-
ment lasted for 6 weeks, separated by a 1-week washout
period. Both treatments reduced the frequency of angina at-
tacks to a similar degree. The comparable anti-ischemic activ-
ity of the two drugs was also shown by a similar improvement
in exercise test parameters (ie, increase in total workload of
24% and 30% for trimetazidine and nifedipine, respectively;
in duration of exercise of 13% and 17%; and in time to 1-mm
ST-segment depression of 17% and 19% [with no significant
difference between treatments]).
In a separate study using a parallel-arm design, trimetazidine
and the nondihydropyridine calcium channel blocker diltiazem
decreased the number of weekly angina attacks and nitrate
consumption to the same extent. Moreover, both drugs had
a similar effect profile with regards to exercise test parame-
ters.26 These clinical data suggest that trimetazidine could be
an effective alternative to calcium channel blockers in the treat-
ment of stable angina patients.
312 MEDICOGRAPHIA, Vol 38, No. 3, 2016
Efficacy of trimetazidine as a combination therapy
with b-blockers
The antianginal efficacy of trimetazidine as an add-on ther-
apy to b-blockers was evaluated in a series of randomized
clinical studies.27-29 In the TrIMPOL-II (TrIMetazidine in PO-
Land-II) study, a total of 426 stable angina patients with doc-
umented CaD were randomized to trimetazidine (60 mg daily)
or placebo, in addition to receiving a background treatment
of metoprolol (100 mg daily).30 exercise testing, evaluated at
baseline and after 3 months of treatment, revealed a significant
improvement in the trimetazidine-treated group compared
with the placebo group (increase in total exercise duration
of 16% and 10% for trimetazidine and placebo, respectively;
in total workload of 14% and 7%; in time to onset of angina
of 24% and 13%; and in time to 1-mm ST-segment depres-
sion of 29% and 22% [P<0.01 for all]). Clinical symptoms
(number of angina attacks, use of nitrate, and intensity of angi-
nal pain) were also significantly reduced with trimetazidine
plus metoprolol compared with placebo plus metoprolol.
In a separate randomized, double-blind study, the antiangi-
nal efficacy of trimetazidine in combination with propranolol
was evaluated versus isosorbide dinitrate plus propranolol.31
Stable angina patients (n=53) for whom symptoms were not
adequately controlled by propranolol (120 mg daily) received
add-on therapy with trimetazidine (60 mg daily) or isosorbide
dinitrate (30 mg daily) for 2 months. Patients who received
trimetazidine had a greater reduction in the weekly number of
angina attacks (Figure 2) and in consumption of short-act-
ing nitrates compared with the reference group. Moreover,
exercise test results only improved in the group where trimeta-
zidine was used (increase in exercise duration of 14% ver-
sus 2% for trimetazidine versus isosorbide dinitrate, respec-
tively; and in time to 1-mm ST-segment depression of 15%
versus 3%). Overall, trimetazidine appeared to have better an-
tianginal efficacy compared with the long-acting nitrate isosor-
bide dinitrate.
The use of trimetazidine in combination with a b-blocker pro-
vides better clinical efficacy than b-blocker alone or another
combination strategy. This may be related to an additive, or
possibly synergetic, effect of the two drugs, each of which
works via a distinct mechanism of action. The use of trimetazi-
dine, which acts directly at the cardiac level, appears a ra-
tional choice for optimizing the treatment of patients inade-
quately controlled by b-blockers.
Antianginal effectiveness of trimetazidine in
different clinical situations
In everyday practice
The antianginal effectiveness of trimetazidine in clinical prac-
tice was evaluated in a large prospective cohort of 1213 out-
patients with stable angina inadequately controlled by stan-
dard therapy consisting of b-blocker alone or a combination of
b-blocker plus long-acting nitrate or calcium channel block-
Trimetazidine: targeting the cardiac cell in stable angina Gliebova
 VA STA R E L M R

er.32 all patients received trimetazidine (35 mg modified-re-
lease formulation, twice daily) on top of their standard treat-
ment for 2 months. In all patients, trimetazidine significant-
ly reduced the number of weekly angina attacks, regardless
of the background therapy (Figure 3). Moreover, in this
study maximal antianginal efficacy was achieved with a dual
combination of trimetazidine and b-blocker only. These data
suggest that combination therapy with b-blocker and
trimetazidine should be considered for the optimal manage-
ment of stable angina patients in real-life situations.
decreased the number of angina episodes in clinical prac-
tice (from 2.8/week at baseline to 0.9/week after treatment
[P<0.001]). Short-acting nitrate consumption was also re-
duced (from 2.5/week at baseline to 0.7/week after treatment
[P<0.001]). Interestingly, in a separate study in the same pop-
ulation (diabetic patients with CaD), the addition of trimetazi-
dine on top of standard treatment was able to reduce not only
symptomatic episodes of myocardial ischemia, but also silent
ischemia, a feature commonly observed in diabetic patients
and associated with a worse prognosis.35

Trimetazidine has also been demonstrated to have

benefits in challenging clinical situations, such as
in elderly diabetic patients with multivessel coro-
nary heart disease undergoing percutaneous coro-
nary intervention (PCI).36 In this population (n=700),
treatment with trimetazidine (60 mg daily) for two
years on top of conventional treatment significant-
ly reduced the incidence of angina, recurrent angi-
na, and silent ischemia compared with placebo.
Moreover, these beneficial effects of trimetazidine
were associated with a stabilization of cardiac func-
tion and structure.

Overall, these data suggest that the efficacy of tri-

metazidine in angina patients with diabetes goes
beyond the relief of angina symptoms by providing
additional benefits in terms of cardioprotection.
Figure 3. Mean number of weekly angina attacks in outpatients whose symp-
toms were inadequately controlled by standard therapy (b-blocker alone, In angina patients with left ventricular
b-blocker + long-acting nitrate, or b-blocker + calcium channel blocker) before dysfunction
(gray bars) and after (red bars) add-on treatment with trimetazidine for 2 a number of reports tend to indicate that trimetazi-
months. Data are presented in patients who had 7 angina attacks per week
at inclusion. dine could improve the cardiac function of patients
Modified after reference 32: Nesukay. Ukr J Cardiol. 2014;2:43-47. 2014, Ukrcardio.
with ischemic heart disease. In CaD patients with
left ventricular dysfunction, 2 years treatment with
In angina patients with diabetes trimetazidine (60 mg daily) on top of background therapy im-
angina patients often present with associated comorbidities proved both myocardial perfusion and contractile function
that make their therapeutic management particularly challeng- versus placebo, with single photon emission computerized to-
ing. Patients with concomitant diabetes mellitus and CaD mography imaging.37 Trimetazidine was shown to increase left
are considered to be at especially high cardiovascular risk.22 ventricular ejection fraction, reduce left ventricular volumes,
In fact, type 2 diabetes patients without previous myocardial and improve the quality of life of CaD patients with left ven-
infarction have a similar risk of myocardial infarction to that tricular dysfunction in various clinical settings, including in the
of nondiabetic patients with previous myocardial infarction.33 elderly38 and diabetic39 patients.
In diabetic patients, cardiac energy metabolism is significant-
ly altered, and these alterations are further amplified in the Interestingly, the beneficial effects of trimetazidine on cardiac
presence of underlying ischemic heart disease. Trimetazidine function observed in CaD may extend to heart failure, whether
appears an attractive tool for the management of angina pa- of ischemic origin or not. a recent meta-analysis of 17 ran-
tients with diabetes. This hypothesis is supported by findings domized clinical trials in heart failure that included 955 patients
from the DIeTrIC trial (estudio prospectivo en pacientes DIa- treated with trimetazidine or placebo suggests so.40 Treatment
bticos de la efectividad y tolerabilidad de la TrImetazidina with trimetazidine was associated with a significant improve-
en asociacin al tratamiento previo de su enfermedad Coro- ment in left ventricular ejection fraction in patients with is-
naria), a prospective, observational study that investigated chemic heart failure (weighted mean difference with placebo,
the antianginal effect of trimetazidine in 580 outpatients with +7.37%; 95% CI, 6.05 to 8.70; P<0.01) or nonischemic heart
type 2 diabetes and CaD.34 The addition of trimetazidine (60 failure (weighted mean difference, +8.72%; 95% CI, 5.51 to
mg/day) to conventional background therapy for 6 months 11.92; P<0.01). This was accompanied by a reduction in the

Trimetazidine: targeting the cardiac cell in stable angina Gliebova MEDICOGRAPHIA, Vol 38, No. 3, 2016 313
VA STA R E L M R
risks of all-cause mortality (relative risk [rr], 0.29; 95% CI,
0.17 to 0.49; P<0.00001) and of cardiovascular events and
hospitalization (rr, 0.42; 95% CI, 0.30 to 0.58; P<0.00001).
These findings are further supported by a retrospective analy-
sis of a cohort of 669 patients with heart failure, in which the
use of trimetazidine was associated with improved survival
from all-cause death and cardiovascular death.41
The addition of trimetazidine to conventional medical therapy
is likely to improve cardiac function and prognosis in patients
with left ventricular dysfunction and heart failure. Importantly,
trimetazidine has a neutral effect at the hemodynamic level
and can thus be safely used in these types of patient. additon-
ally, trimetazidine has been recognized as an effective anti-angi-
nal treatment that is safe to use in heart failure and has been
granted with class IIb of recommendation and level a of evi-
dence in the latest eSC guidelines for heart failure treatment.23
In angina patients with a history of
myocardial infarction
Trimetazidine may also provide benefits in terms of outcomes
in patients after myocardial infarction. The MeTrO study (Man-
agement of angina: a reTrospective cOhort) included 353
patients with stable angina treated with at least one antiang-
inal drug (nitrates, b-blockers, calcium channels blockers,
trimetazidine, or nicorandil) who had previously been hospi-
talized for myocardial infarction.42 Of all the antianginal strate-
gies, only the one that included trimetazidine was associat-
ed with a significant reduction in all-cause mortality over 6
months following hospital discharge for myocardial infarc-
tion (odds ratio [Or], 0.36; 95% CI, 0.15 to 0.86; P=0.022).
Similarly, a retrospective analysis of a Korean registry that
included 13 733 patients hospitalized for myocardial infarc-
tion showed that treatment with trimetazidine during the in-
hospital period was independently associated with a signif-
icant reduction in all-cause mortality (hazard ratio [Hr], 0.41;
95% CI, 0.18 to 0. 97; P=0.042) and major adverse cardiac
events (Hr, 0.24; 95% CI, 0.10 to 0.56; P=0.001) over 12
months.43
These data suggest that trimetazidine, in addition to its clin-
ical antianginal efficacy, may offer long-term cardioprotection
by improving survival in patients after acute myocardial in-
farction.
In angina patients with percutaneous coronary
intervention
although it is a minimally invasive procedure, PCI leads to my-
ocardial injury in about one third of patients. a rise in troponin
level immediately following PCI, a marker for myocardial in-
jury, is correlated with a worse prognosis in these patients.44
The effect of trimetazidine has been investigated in this spe-
cific setting in a randomized study involving 266 angina pa-
tients undergoing elective PCI.45 Patients were randomized to
314 MEDICOGRAPHIA, Vol 38, No. 3, 2016
trimetazidine (60 mg administered as a single dose 30 minutes
before intervention) or no treatment. Treatment with trimetazi-
dine prior to PCI limited periprocedural myocardial injury, as
shown by the significant reduction in cardiac troponin Ic lev-
el up to 24 hours post-PCI in these patients compared with
patients who received no treatment. Thus, the direct effect of
trimetazidine on the cardiac cell may provide cardioprotection
immediately after PCI.
Figure 4. Incidences of stent restenosis and major adverse car-
diac and cerebrovascular events (MACCEs)including all-cause
mortality, nonfatal myocardial infarction, revascularization, stroke,
and cerebral bleedingin the control (gray bars; n=323) and
trimetazidine (red bars; n=312) groups 12 months after percuta-
neous coronary intervention.
a recent report investigated the effect of trimetazidine on the
incidence of stent restenosis and major adverse cardiac and
cerebrovascular events (MaCCes) in patients undergoing PCI.46
a total of 786 patients were randomized after implantation
of a drug-eluting stent to trimetazidine (60 mg daily) on top
of standard treatment for at least 30 days or standard treat-
ment only, ie, no additional therapy. at 1-year follow-up, pa-
tients in the trimetazidine group had a significantly lower in-
cidence of stent restenosis and MaCCes compared with
those in the control group who received standard treatment
only (Figure 4). Interestingly, in a rat model of diabetes, trimeta-
zidine decreased the proliferation of vascular smooth muscle
cells and promoted re-endothelialization after injury of the
carotid artery.47 Both mechanisms could have contributed
to the lower rate of stent restenosis observed with trimetazi-
dine after PCI.
Overall, these findings suggest that beyond its antianginal
effect, trimetazidine may improve prognosis in patients under-
going revascularization procedures. This hypothesis is cur-
rently being tested in the aTPCI (The efficacy and safety of
Trimetazidine: targeting the cardiac cell in stable angina Gliebova

Trimetazidine in Patients with angina pectoris having been
treated by percutaneous Coronary Intervention) study, a large
morbidity-mortality trial in angina patients with a post-PCI fol-
low-up of 2 to 4 years.
Conclusion
Trimetazidine is an antianginal treatment with well-established
efficacy, whether as monotherapy or part of combination ther-
apy (for patients inadequately controlled by hemodynami-
cally active therapy alone). Based on its mechanism of action
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Keywords: antianginal efficacy; cardiac cell; cardiac energy metabolism; cardioprotection; myocardial ischemia; stable angina
pectoris; trimetazidine

CIBLER LA CELLULE CARDIAQUE DANS LANGOR STABLE GRCE LA TRIMTAZIDINE

Langor est maintenant reconnu comme une maladie multiforme o lobstruction coronaire ne constitue quun fac-
teur de risque parmi dautres. La cellule cardiaque, dont le rle est central dans un grand nombre de processus is-
chmiques, est reconnue comme lun des acteurs principaux de lischmie cardiaque. Au niveau cellulaire, lisch-
mie myocardique se caractrise par un mtabolisme nergtique myocardique modifi, rsultant en un dsquilibre
ionique, un msusage et un dficit en nergie et aboutit finalement un dysfonctionnement. Pendant lischmie,
la trimtazidine agit directement au niveau cellulaire en diminuant loxydation des acides gras et en augmentant loxy-
dation du glucose, ce qui contribue rtablir un mtabolisme nergtique normal. Ce mcanisme conduit une am-
lioration globale du fonctionnement gnral de la cellule et exerce une action anti-ischmique au niveau des organes.
En ciblant directement la cellule cardiaque, le mcanisme daction de la trimtazidine complte celui des traitements
antiangoreux hmodynamiques, optimisant ainsi lefficacit clinique lorsquelle est associe dautres traitements.
La trimtazidine diminue les symptmes et augmente laptitude leffort des patients angoreux dont les symptmes
sont mal contrls par les b-bloquants et/ou les antagonistes calciques. Leffet bnfique de la trimtazidine a t d-
montr chez de nombreux patients angoreux, dont ceux ayant des antcdents dinfarctus du myocarde et ceux
qui ont eu une intervention coronaire percutane, un diabte ou une dysfonction ventriculaire gauche. En plus de
ses effets antiangoreux prouvs, la trimtazidine peut aussi apporter dautres effets bnfiques en termes de car-
dioprotection et de pronostic chez de nombreux patients risque cardiovasculaire.

316 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Trimetazidine: targeting the cardiac cell in stable angina Gliebova

ATPCI (efficAcy and safety of
Trimetazidine in Patients with angi-
na pectoris having been treated
by percutaneous Coronary Inter-
ventions [PCI]) will improve our
knowledge about coronary artery
disease and its treatment by PCI.
It will also identify the role of meta-
bolic therapy in this patient set-
ting. It is the first study to test the
value of increasing the energy sta-
tus of the ischemic myocyte with
trimetazidine in terms of hard end
points such as cardiac death and
hospitalization.
Roberto FERRARI, MD
Department of Cardiology
and LTTA Centre
University Hospital of Ferrara
ITALY
Address for correspondence:
Roberto Ferrari, MD, Chair of
Cardiology, Azienda Ospedaliero-
Universitaria di Ferrara, Ospedale di
Cona, Via Aldo Moro 8, 44124
(Cona) Ferrara, Italy
(email: fri@unife.it)
Medicographia. 2016;38:317-319
www.medicographia.com
Adding a metabolic agent to post-PCI angina treatment: the ATPCI trial Ferrari
INTERVIEW
The ATPCI trial: a new
international phase 3 study
assessing the clinical impact of
adding a metabolic agent to
post-PCI angina treatment
I n t e r v i e w w i t h R . Fe r ra r i , I t a l y
Can you tell us what ATPCI stands for?
TPCI is the short name of an international, multicenter, randomized, double-
A blind, placebo-controlled study in patients treated with trimetazidine for 2
to 4 years. The full title of the trial is efficAcy and safety of Trimetazidine in
Patients with angina pectoris having been treated by percutaneous Coronary Inter-
ventions. The sponsor of the study is the Institut de Recherches Internationales
Servier (I.R.I.S.) and it is registered with the World Health Organization (WHO) under
the universal trial number (UTN) UIIII-1145-1743.
The acronym ATPCI is particularly appropriate for the study as it targets patients
with ischemic heart disease who have received a percutaneous coronary interven-
tion (PCI) and pharmacological treatment by trimetazidinethe active drug under
testing, a piperazine derivative with anti-ischemic properties that are different from
any other anti-ischemic drugsa drug that increases the adenosine triphosphate
(ATP) levels. The standard approach to treat coronary artery disease (CAD) is based
on increasing oxygen supply to the myocardium and/or reducing oxygen consump-
tion by means of hemodynamic effects, acting via the heart rate in the case of iva-
bradine, or via heart rate and myocardial contractility in the case of b-blockers and
verapamil or diltiazem, and via the peripheral arterial coronary and/or venous re-
sistance in the case of dihydropyridine calcium-channel blockers and nitrates. An
alternative approach is to improve the efficiency and the energy of the heart for a
given supply of oxygen, which is reduced during ischemia. In other words, such an
approach aims to increase the level of ATP. This metabolic approach is interesting
considering that trimetazidine does not have hemodynamic effects, but acts as a
modulator of cardiac metabolism.
Under physiological conditions, the energy demand of the heart is met by the me-
tabolism of two main substratesglucose and free fatty acids (FFAs). Glucose
metabolism occurs by means of glycolysis and oxidation. Whereas the oxidative
pathway converts pyruvate into acetyl-coenzyme A (CoA), which is incorporated
in the Krebs cycle and produces 36 molecules of ATP, the conversion of glucose to
pyruvate during glycolysis produces only two molecules of ATP, but this ATP is im-
portant as oxygen is not required in the process.1 The FFAs are the main sources
of ATP, corresponding to about 70% of the myocardial production, but the oxida-
tion of FFAs requires about 10% more oxygen than that of glucose to produce an
equivalent amount of energy.1 During ischemia and/or angina, all oxidative process-
es are depressed, leading to acetyl-coA accumulation in the mitochondria with a
MEDICOGRAPHIA, Vol 38, No. 3, 2016 317
INTERVIEW
block of FFA b-oxidation and of the activity of pyruvate de-
hydrogenase, the enzyme that allows the entry of pyruvate
into the mitochondria. Pyruvate is then converted into lactic
acid, which is released from the myocytes into the extracel-
lular space, thus reducing the pH and causing pain by irrita-
tion of the myocardial nerve fibers. Thus, in ischemia, glycol-
ysis, contrary to oxidation, continues in an anaerobic fashion,
having as final product lactate instead of pyruvate, and be-
comes the only and most important source of anaerobic ATP.1
Trimetazidine further inhibits FFA b-oxidation and, indirectly,
stimulates the activity of pyruvate dehydrogenase, thus di-
recting pyruvate into the mitochondria, avoiding lactic acid
formation, and allowing anaerobic glycolysis to continue. This
has two important consequencesreduction in intra- and
extracellular acidosis, thus preventing pain, and improvement
in anaerobic ATP production through glycolysis, ensuring
maintenance of cellular homeostasis and viability.2 As ancil-
lary properties resulting from the maintenance of ATP, trimetazi-
dine has also been shown to reduce oxygen free radical pro-
duction and oxidative stress and to inhibit the opening of
mitochondrial calcium pores with the consequent release of
cytochrome C, thus reducing apoptosis and attenuating in-
flammation.2
The acronym ATPCI is well-suited to this study, which aims
to test whether treatment with trimetazidine to maintain ATP
levels after PCI is useful to reduce symptoms and improve
outcomes in patients with ischemic heart diseases.
What is the rationale of the study and what is the
main objective of ATPCI?
TPCI aims to assess the long-term efficacy and safe-
A ty of trimetazidine versus placebo, when given in ad-
dition to other evidence-based cardiovascular ther-
apies in patients having had a recent PCI. The rationale for
ATPCI is based on three considerations.
The first is that, despite the wide use of PCI for patients with
chronic or acute angina, it is not clear whether this interven-
tion results in an improvement in outcomes when compared
with medical therapy. In addition, several studies have shown
that, after PCI, not all patients are angina free or stop the an-
tianginal treatment.3
SELECTED ABBREVIATIONS AND ACRONYMS
ATP
ATPCI
adenosine triphosphate
efficAcy and safety of trimetazidine in Patients with
angina pectoris having been treated by percuta-
neous Coronary Interventions
CAD coronary artery disease
FFA free fatty acid
PCI percutaneous coronary intervention
318 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Adding a metabolic agent to post-PCI angina treatment: the ATPCI trial Ferrari
The second consideration relies on the unique anti-ischemic
and antianginal effects of trimetazidine, which could be ide-
al after PCI. The antianginal effect of trimetazidine in stable
angina pectoris is well-known and documented by 25 stud-
ies, including more than 4000 patients, in which trimetazi-
dine was compared with placebo or active comparator. Ef-
ficacy has always been assessed on ergometric criteria and
symptoms.
In addition, a first Cochrane meta-analysis conducted in 2005,
involving a total of 1378 patients, reported a statistically sig-
nificant and clinically relevant efficacy of trimetazidine in the
treatment of angina, either alone or in combination with con-
ventional antianginal treatments.4 In 2012, a second Cochrane
meta-analysis, including 2283 patients and two additional
ergometric criteriatotal exercise duration and time to onset
of anginaconfirmed the conclusion of the first meta-analy-
sis (unpublished data). A third network meta-analysis was
then conducted in 2011, including studies with positive re-
sults as well as studies with inconclusive results, as required
by European guidelines. The conclusion was that trimetazi-
dine is as efficacious as other antianginal agents despite the
different mechanism of action.5
The third consideration is related to the increasing evidence
of microvascular dysfunction as a cause of angina. Trimetazi-
dine, by improving energy metabolism, could be particularly
useful in this setting, where classic agents, which mainly act
on the epicardial coronary artery, are less likely to be active.
A previous proof-of-concept study showed a benefit of tri-
metazidine over placebo in reducing the incidence of recur-
rent angina in CAD patients after drug-eluting stent implan-
tation.6 Another study showed a reduction in major adverse
cardiovascular events after 1-year follow-up in patients who
received trimetazidine for at least 1 month after PCI.7 A recent
meta-analysis evaluates the effects of trimetazidine on pa-
tients undergoing PCI in a total of 778 patients.8 The addition-
al use of trimetazidine, before intervention, reduced angina
attacks and electrocardiographic changes during PCI and
cardiac troponin level. It also improved the left ventricular ejec-
tion fraction.8
What is the study design and who are the target
patients?
TPCI is a phase 3, international, multicenter, double-
A blind, placebo-controlled study randomized in two
parallel and balanced armson top of post-PCI rec-
ommended treatment for CAD, patients receive either trimeta-
zidine 35 mg twice daily or placebofor both secondary
prevention and regular antianginal therapies, as per current
guidelines. Randomization at inclusion is stratified according
to country and nature of PCI procedure, whether elective or
urgent after an acute presentation but without STEMI.

A total of 5800 patients from 27 countries will be included
within 30 days of PCI and followed-up during a 2- to 4-year
treatment period with a maximum of 10 visits. ATPCI includes
patients (women or men 21 years old and <85 years old
of any ethnic origin) presenting with a single or multivessel
CAD and having undergone PCI for at least one stenosis to
either a native coronary artery or a coronary graft where the
PCI fell into any of the following categories: (i) indicated be-
cause of angina pectoris occurring either in the context of
stable angina (elective PCI) or in the context of an acute pres-
entation, such as unstable angina/nonST-segment elevation
myocardial infarction (NSTEMI), but excluding ST-segment
elevation myocardial infarction (STEMI); (ii) achieved by stent
implantation or by other acceptable interventional (nonsur-
gical) means; (iii) successful as planned by the operator and
with no further revascularization (either percutaneous or sur-
gical) planned; or (iv) uncomplicated, such that the patients
discharge was not delayed because of a cardiac or cerebro-
vascular problem.
A measurement of left ventricular ejection fraction (LVEF) needs
to be performed within 3 months before inclusion for patients
having undergone elective PCI and between PCI and inclu-
sion for patients having undergone index PCI performed in
the context of an acute syndrome. Patients can be select-
ed after PCI regardless of whether they are asymptomatic
or symptomatic with regard to angina, and regardless of their
Canadian Cardiovascular Society (CCS) class.
What is the primary end point of the study?
he primary efficacy end point of ATPCI is the time to
T first occurrence of an event in the composite of: (i) car-
diac death; (ii) hospitalization for a cardiac event; (iii)
recurrent or persistent angina leading to adding, switching,
Keywords: angina; cardiac metabolism; percutaneous coronary intervention; trimetazidine
References
1. Ferrari R, Williams AJ. The role of mitochondria in myocardial damage occur-
ring on post-ischaemic reperfusion. J Appl Cardiol. 1986;1:501-519.
2. Cargnoni A, Pasini E, Ceconi C, Curello S, Ferrari R. Insight into cytoprotection
with metabolic agents. Eur Heart J. 1999;1(suppl O):O40-O48.
3. Babu GG, Walker J M, Yellon DM, Hausenloy DJ. Peri-procedural myocardial
injury during percutaneous coronary intervention: an important target for car-
dioprotection. Eur Heart J. 2011;32:23-32.
4. Ciapponi A, Pizzarro R, Harrison J. Trimetazidine for stable angina. Cochrane
Database Syst Rev. 2005;(4):CD003614.
5. Danchin N, Marzilli M, Parkhomenko A, Ribeiro JP. Efficacy comparison of tri-
metazidine with therapeutic alternatives in stable angina pectoris: a network
meta-analysis. Cardiology. 2011;120:59-72.
6. Xiaohan X, Zhang W, Zhou Y, et al. Effect of trimetazidine on recurrent angina
pectoris and left ventricular structure in elderly multivessel coronary heart disease
Adding a metabolic agent to post-PCI angina treatment: the ATPCI trial Ferrari
INTERVIEW
or increasing the dose of one of the evidence-based antiang-
inal therapies; and (iv) recurrent or persistent angina, lead-
ing to performance of a coronary angiography, all of which will
be reviewed by an independent adjudication committee. The
primary safety end point is the incidence of serious emer-
gency adverse events (in all visits) with trimetazidine as com-
pared with placebo.
The secondary end points are the time to first occurrence of
each of the separate four components of the primary end
point, with the addition of evidence of ischemia (documented
by stress imaging and leading to adding, switching, or in-
creasing the dose of one of the evidence-based antianginal
therapies). Other efficacy end points include the following:
CCS class of angina symptoms, number of angina episodes
per week, number of doses of short-acting nitrates taken per
week, number of antianginal drugs taken by the patient, Seat-
tle Angina Questionnaire scores (in countries where a validat-
ed translation is available), EQ-5D-3L Questionnaire scores,
and level of cardiac troponin (before each repeat PCI and be-
tween 6 and 24 hours after).
What might we expect from the study?
TPCI will improve our knowledge of CAD and its treat-
A ment by PCI. It will also identify the role of metabolic
therapy in this setting of patients. It is the first study to
test the value of increasing the energy status of the ischemic
myocyte with trimetazidine in terms of hard end points such
as cardiac death and hospitalization. This is particularly rele-
vant considering that a recent study with ranolazine, another
piperazine derivative, in a similar patient setting failed to show
a benefit.9
Acknowledgments. This work was supported by a grant from Fon-
dazione Anna Maria Sechi per il Cuore (FASC), Italy.
patients with diabetes mellitus after drug-eluting stent implantation: a single-
centre, prospective, randomized, double-blind study at 2-year follow-up. Clin
Drug Investig. 2014;34:251-258.
7. Chen J, Zhou S, Jin J, et al. Chronic treatment with trimetazidine after discharge
reduces the incidence of restenosis in patients who received coronary stent
implantation: a 1-year prospective follow-up study. Int J Cardiol. 2014;174:634-
639.
8. Zhang Y, Xiao-juan M, Da-zhuo S. Effect of trimetazidine in patients undergoing
percutaneous coronary intervention: a meta-analysis. PLoS One. 2015;10(9):
e0137775.
9. Weisz G, Gnreux P, Iiguez A; RIVER-PCI investigators. Ranolazine in patients
with incomplete revascularization after percutaneous coronary intervention
(RIVER-PCI): a multicentre, randomised, double-blind, placebo-controlled trial.
Lancet. 2016;387(10014):136-145.
MEDICOGRAPHIA, Vol 38, No. 3, 2016 319

Given thepathophysiology
of ischemic heart disease and the
difficulties encountered when
trying to control the total ischemic
burden with classic hemodynam-
ically active drugs, an adjunctive
therapeutic option that pharmaco-
logically manipulates cardiac en-
ergy metabolism seems reason-
able. This approach is based on
stimulating myocardial glucose ox-
idation to optimize cardiac energy
metabolism, and is proven to im-
prove cardiac function and protect
myocardial tissue against ische-
mia-reperfusion injury.
Gabriele FRAGASSO, MD
Heart Failure Unit
Istituto Scientifico San Raffaele
Milano, ITALY
Address for correspondence:
Gabriele Fragasso, Heart Failure Unit,
Istituto Scientifico San Raffaele,
Via Olgettina 60, 20132 Milano, Italy
(email: gabriele.fragasso@hsr.it)
www.medicographia.com
320 MEDICOGRAPHIA, Vol 38, No. 3, 2016
FOCUS
Combining hemodynamic
and metabolic agents
in ischemic heart disease
by G. Fragasso, Italy
M
yocardial ischemia can be looked at as a metabolic problem, as it
leads to an imbalance in the pathways the normal heart relies on
for energy production. Use of pharmacological agents to optimize
cardiac energy metabolism by stimulating myocardial glucose oxidation can
be an effective therapeutic option. The metabolic agent trimetazidine does
this indirectly by inhibiting fatty acid b-oxidation, in effect changing the en-
ergy substrate preference, promoting a shift from fatty acid metabolism to-
ward glucose metabolism, which is more efficient for ATP production. The ef-
ficacy of trimetazidine in the treatment of angina pectoris has been evaluated
under various conditions: trimetazidine administered as a monotherapy or in
combination, acutely or over a longer-term period, as initial treatment, and in
patients resistant to b-blockers or calcium-channel antagonists. All published
studies employing trimetazidine in patients with chronic ischemic heart dis-
ease have invariably reported beneficial clinical effects without adverse he-
modynamic events. In fact, in chronic ischemic heart disease patients with left
ventricular dysfunction, trimetazidine has been shown to be a particularly ef-
fective adjunctive treatment in terms of improvement in left ventricular me-
tabolism and function. An ongoing randomized clinical study in patients with
revascularized coronary artery disease should clarify whether the reported
experimental and clinical benefits of trimetazidine also translate into improved
prognosis.
Medicographia. 2016;38:320-327 (see French abstract on page 327)
schemic heart disease is a major cause of morbidity and mortality worldwide. In
I patients with acute coronary syndromes, revascularization interventions have been
shown to reduce myocardial infarction and death1,2; however, this is not the case
in patients with chronic stable angina. In fact, according to the European Society
of Cardiology (ESC) and the European Association for Cardio Thoracic Surgery
(EACTS) 2014 guidelines,3 percutaneous coronary intervention (PCI) or coronary ar-
tery bypass grafting (CABG) should be reserved for patients with refractory angina
and for patients in whom such procedures would be expected to provide a survival
benefit; this would be influenced by a number of factors, such as the number of
diseased vessels, lesion location and severity, and the presence of left ventricular
dysfunction. Thus, all patients with stable ischemic heart disease, whether they are
asymptomatic or experiencing severe symptoms, should first receive optimal med-
ical therapy, which would usually be maintained even after revascularization.
Combining hemodynamic and metabolic agents in ischemic heart disease Fragasso

Current anti-ischemic/antianginal therapy focuses on two ma-
jor actions. The first pertains to vascular protection, in this case
aiming to delay progression of atherosclerosis (by use of sta-
tins, antithrombotic drugs), which would reduce future car-
diovascular events and death and improve quantity of life. The
second pertains to improvement in the imbalance between
myocardial oxygen supply and demand (ischemic imbalance),
which would reduce the severity and frequency of angina
symptoms and also contribute to improvement in quality of
life. However, this therapeutic view does not consider the car-
diac metabolic consequences of myocardial ischemia. In fact,
ischemia can be thought of as a metabolic problem (previ-
ously discussed in Salerno et al4), because it leads to an im-
balance in the pathways the normal heart relies on for energy
production. Under normoxic conditions, the healthy heart gen-
erates approximately two-thirds of its energy (in the form of
adenosine triphosphate, ATP) from the free fatty acid (FFA)
pathway; the remaining energy production is derived from
glucose oxidation and lactate.5-7 Under hypoxic conditions,
such as mild-to-moderate ischemia, myocardial cells turn to
another more oxygen-efficient pathway to generate sufficient
ATP to support calcium homeostasis and maintenance of ion-
ic gradients: their response is to increase glucose uptake, as
glycolysis requires less oxygen per mole of ATP generated
than FFA oxidation. Severe ischemia, however, rapidly induces
an imbalance between cardiac tissue oxygen demand and
the available coronary blood supply. Changes in myocardial
function, metabolism, and morphology ensue, leading to ar-
rhythmias, contractile failure, and electrophysiological abnor-
malities. Myocardial cell uptake of glucose decreases and
conversion to lactate increases; there is a switch from lactate
uptake to lactate production, and most pyruvate is trans-
formed into lactate, increasing cell acidosis. Concurrently, use
of the FFA pathway slows, and overall ATP production de-
creases. The results of such metabolic changes include the
disruption of cell homeostasis, alterations in membrane
structure, and ultimately cell death.
This review discusses the rationale behind a pharmacological
approach to stop this vicious circle in patients with chronic is-
chemic heart disease.
Medical treatment of chronic ischemic heart disease
In addition to lifestyle and hygienic dietary measures, guide-
line-recommended first-line treatment for patients with stable
angina includes aspirin, statins, and b-blockers. This recom-
mendation is consistent across all guidelines for the diagno-
sis and management of this condition. The main probable
mechanism by which b-blockers relieve anginal symptoms is
a reduction in both heart rate and contractility. However, their
indication as a first-line treatment is still under debate. They
are given a class I indication for the treatment of chronic angi-
na, mainly on the basis of a general agreement on the issue,
whereas they are attributed a level of evidence A on the basis
of studies that were carried out in patients after a myocardial
Combining hemodynamic and metabolic agents in ischemic heart disease Fragasso
FOCUS
infarction or heart failure, in which they consistently decreased
morbidity and mortality. However, several reports have dis-
cussed potential pitfalls in their use in patients with stable coro-
nary artery disease (CAD). In the REACH registry (REduction
of Atherothrombosis for Continued Health), b-blockers were
not associated with a lower risk of composite cardiovascular
events, and they were associated with higher rates for the sec-
ondary outcome (comprising primary outcome and hospital-
ization for atherothrombotic events or a revascularization pro-
cedure) in chronic CAD patients.8 A recent post-hoc analysis
of the CHARISMA study (Clopidogrel for High Atherothrom-
botic Risk and Ischemic Stabilization Management and Avoid-
ance) indicated that use of b-blockers in patients that had a
previous myocardial infarction but no heart failure was asso-
ciated with a better cardiovascular prognosisdetermined by
reduced reinfarction ratebut did not reduce overall mortal-
ity. Additionally, in patients without previous myocardial infarc-
tion, b-blockers did not reduce cardiovascular events but were
rather associated with a higher incidence of stroke, confirm-
ing previous meta-analyses of studies performed in hyperten-
sive patients.9 The hypothesized mechanism to explain these
potential deleterious effects of b-blockers is related to an in-
sufficient reduction in central aortic pressure, potentially re-
lated to heart rate reduction, which in certain contexts would
not play a positive role. Therefore, there is still no clear evidence
from randomized clinical trials for the efficacy of b-blockers
used in first-line treatment in patients with chronic stable angi-
na. Yet, we enthusiastically continue to use them.
If a patient continues to complain of symptoms after the first-
line treatment scheme has been implemented, other drugs,
such as calcium-channel blockers or long-acting nitrates,
could be prescribed. Calcium-channel blockers (mostly dihy-
dropyridine derivatives) cause coronary and peripheral vasodi-
lation (but increase heart rate and partially reduce the beneficial
heart ratelowering effect of b-blockers); the phenylalkylamine
derivative verapamil and, to a lesser extent, diltiazem (benzo-
thiazepine calcium-channel blocker) reduce heart rate and
SELECTED ABBREVIATIONS AND ACRONYMS
ATP adenosine triphosphate
ATPCI efficAcy and safety of trimetazidine in Patients
with angina pectoris having been treated by
percutaneous Coronary Interventions
CAD coronary artery disease
CHARISMA Clopidogrel for High Atherothrombotic Risk
and Ischemic Stabilization Management and
Avoidance
FFA free fatty acid
PCI percutaneous coronary intervention
REACH REduction of Atherothrombosis for Continued
Health [registry]
TRIMPOL-I TRIMetazidine in POLand [study]
MEDICOGRAPHIA, Vol 38, No. 3, 2016 321
FOCUS
contractility and are used when b-blockers are contraindicat-
ed. Combining verapamil or diltiazem with b-blockers yields
additive effects in terms of bradycardia, heart block, and neg-
ative inotropic effects. When added to b-blockers or calcium-
channel blockers, long-acting nitrates improve exercise toler-
ance, increase time to onset of angina, and reduce ST-segment
depression during exercise testing; however, their use is limited
by the development of tolerance on long-term administration.
In summary and similarly to b-blockers, there is no clear-cut
evidence of the prognostic utility of these additional antiang-
inal drugs in chronic CAD. Furthermore, conflicting evidence
exists about combining antianginal hemodynamic drugs.
Having said this, pharmacological treatment of chronic is-
chemic heart disease continues to be based mostly on b-
blockers, calcium-channel blockers, and nitrates. In most cas-
es, if symptoms are not brought under control by treatment
with a single traditional antianginal drug, a drug combination
would be used, with the addition of a second or third agent.
However, there are no clinical studies demonstrating a real
additive efficacy of a combination of classic hemodynamical-
ly active drugs as compared with monotherapy. Furthermore,
significant side effects may limit the maximal doses that can
be used for such drugs, especially in an aged population. In
such a context, the use of alternative therapeutic approaches
would be warmly welcomed and, with this in mind, pharma-
cologically addressing the underlying derangements in car-
diac metabolism, discussed next in further detail, could be a
rational solution to this problem.
Pharmacological manipulation of cardiac energy
metabolism
Given the above-described pathophysiology of ischemic heart
disease and the difficulties encountered with many patients
when trying to control the total ischemic burden with classic
hemodynamically active drugs, an adjunctive therapeutic op-
tion that pharmacologically manipulates cardiac energy me-
tabolism seems reasonable (previously discussed in Salerno
et al4). This approach is based on stimulating myocardial glu-
cose oxidation to optimize cardiac energy metabolism, and
is proven to improve cardiac function and protect myocar-
dial tissue against ischemia-reperfusion injury.10 Myocardial
glucose oxidation can be promoted either directly by stimu-
lating glucose metabolism or indirectly by inhibiting fatty acid
b-oxidation, producing a shift of energy substrate utilization
away from fatty acid metabolism and toward glucose metab-
olism, a more oxygen-efficient path to ATP production (more
ATP produced per mole of oxygen used). Indeed, oxygen con-
sumption efficiency in the heart can be improved within the
range of 16% to 26% by the increased use of glucose and
lactatemore efficient fuels for aerobic respiration.10
Additionally, the uptake of glucose in the heart and arm skele-
tal muscle has been shown to be inversely related to serum
FFA levels,11 and an increased flux of FFA from adipose tissue
322 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Combining hemodynamic and metabolic agents in ischemic heart disease Fragasso
to nonadipose tissue exacerbates metabolic abnormalities
characteristic of the insulin resistance syndrome,12 a common
pattern in patients with ischemic heart disease. Furthermore,
there is new evidence that elevated levels of FFA may not only
impair glucose uptake in heart and skeletal muscle but also
alter metabolism in the vascular endothelium, which leads to
premature cardiovascular disease.13 These findings suggest
that metabolic therapy could have a beneficial role in glucose
metabolism homeostasis.
Manipulation of cardiac energy metabolism through a num-
ber of approaches has been investigated. Trimetazidine is the
most extensively studied cardiac metabolic drug and has been
shown to increase glucose oxidation and reduce FFA utiliza-
tion, restoring cardiac coupling between glycolysis and glu-
cose oxidation. The next section will look more closely at the
beneficial effects of cardiac metabolic manipulation by trimeta-
zidine in ischemic heart disease.
Complementary role of trimetazidine in ischemic
heart disease
Trimetazidines use in patients with ischemic heart disease has
consistently provided clinical benefits (previously discussed
in Salerno et al4). Although its mechanism of action is still un-
der debate,14,15 experimental evidence indicates that trimetazi-
dine exerts its effects predominantly through partial inhibition
of mitochondrial long-chain 3-ketoacyl coenzyme A thio-
lase, the last enzyme involved in b-oxidation,16 in effect caus-
ing a switch in energy substrate use away from FFA to glucose
and lactate. As mentioned briefly in the previous section, the
resulting reduction in FFA oxidation and increase in glucose
oxidation restores the myocardial coupling between glycoly-
sis and carbohydrate oxidation, allowing ATP production with
less consumption of oxygen.17 Trimetazidine also promotes
membrane phospholipid turnover during ischemia and reper-
fusion, redirecting FFA toward phospholipids and thus increas-
es the cells tolerance to ischemia-reperfusion damage.17-19
Trimetazidines anti-ischemic actions are independent of he-
modynamic changes and are associated with a greater re-
covery of mechanical function after ischemia.17
Trimetazidines efficacy in the treatment of angina pectoris has
been investigated under various conditions: trimetazidine ad-
ministered as a monotherapy or in combination, acutely or
over a longer-term period, as initial treatment, and in patients
resistant to b-blockers or calcium-channel antagonists.20-30
Initially studied in patients with chronic stable effort angina
during exercise testing, acute administration of trimetazidine
increased effort tolerance and delayed the appearance of is-
chemic symptoms and electrocardiogram changes.20
With long-term treatment, the benefits seen with acute admin-
istration were confirmed. Such treatment was well-tolerat-
ed, with no appreciable side effects, including no significant
 FOCUS

A B

Figure 1. Bar charts showing mean values (+ 1 standard deviation) from dobutamine stress echocardiography in chronic ischemic
heart disease patients taking placebo (grey bars) or trimetazidine (red bars) on top of optimal hemodynamic therapy.
Trimetazidine significantly induced an increase in the administered dobutamine dose (panel A) versus placebo. Despite a higher administered stress, left ventricular
function (assessed by wall motion score index) was significantly less impaired when patients were on trimetazidine (panel B). These findings indicate that metabolic
therapy added to treatment schemes yields a better response to stress.
Based on data from reference 32: Lu et al. Am J Cardiol. 1998;82:898-901.

changes in heart rate and/or aortic pressure.21 In comparison
studies, improvement in ischemic threshold and exercise tol-
erance on trimetazidine treatment is similar to that reported
for propranolol and nifedipine, and there was even a lower
incidence of side effects.22,23
In diabetic patients with chronic stable angina, Marazzi et al
have shown that trimetazidine added to standard medical ther-
apy reduces the number of episodes of ST-segment depres-
sion and silent ischemia and reduces total ischemic burden.28
In patients with stable angina pectoris, the efficacy of trime-

Trimetazidines effects were shown to be additive to those of

hemodynamically active drugs, with direct evidence provided
by a randomized, double-blind study in patients with chronic
effort angina and documented CAD. This study compared the
combination of trimetazidine plus the b-blocker propranolol
with nitrates plus propranolol, and found that the combina-
tion including trimetazidine was not only more effective and
better tolerated than the other combination, but also the only
one that showed improvement. The other combination had no
effect on symptoms and exercise capacity.24 In another ran-
domized, double-blind study in patients with angina uncon-
trolled by diltiazem, the addition of trimetazidine to a full-dose
diltiazem treatment scheme yielded beneficial effects.25 It sig-
nificantly reduced the number of ischemic attacks, prolonged
the time to 1-mm ST-segment depression, increased the time
to onset of exercise-induced angina, and increased the max-
imum work at peak exercise, without adverse hemodynamic
Figure 2. Insulin sensitivity. Bar chart showing mean (+1 standard
events or increased side effects. In yet another study, this time deviation) glucose infusion rate at the hyperinsulinemic/euglycemic
in patients with stable effort angina uncontrolled by metoprolol clamp during short-term (15 days) and long-term (6 months)
alone, 12-week treatment with trimetazidine and metoprolol placebo and trimetazidine administration in patients with chronic
significantly reduced clinical symptoms compared with place- ischemic heart disease, left ventricular dysfunction, and diabetes.
bo and metoprolol.26 A previous study, TRIMPOL-I (TRIMetazi- The infusion rate of glucose necessary to maintain euglycemia after an insulin
bolus was greater when patients were on trimetazidine, both in the short and
dine in POLand), had already shown that in diabetic patients, long term. This indicates that in these high-risk patients, trimetazidine, compared
4 weeks of treatment with trimetazidine was associated with with placebo, was also able to significantly improve insulin sensitivity.
Abbreviations: LT, long term; ST, short term.
a significantly lower number of anginal episodes and an im- Based on data from reference 33: Fragasso G et al. Am Heart J. 2003;146: E1-E8
provement in myocardial ischemia and exercise capacity.27 and reference 36: Monti et al. Am J Physiol Endocrinol Metab. 2006; 290:E54-E59.

Combining hemodynamic and metabolic agents in ischemic heart disease Fragasso MEDICOGRAPHIA, Vol 38, No. 3, 2016 323
FOCUS
tazidine was found to be comparable to that of other drugs
that have no influence on heart rate (ie, other nonheart-rate-
lowering antianginal drugs).29
Trimetazidine has also been confirmed to be effective in dif-
ferent settings of stable coronary disease,30-32 expanding its
use to include patients with heart failure both of ischemic and
nonischemic origin.33,34 In such contexts, trimetazidine im-
proves symptoms, cardiac response to ischemia, left ventric-
ular function (Figure 1, page 323),32 and thus quality of life
as well. The main mechanism of action is probably through
a trimetazidine-induced increase in myocardial cellular ener-
gy reserve.35 However, improved endothelial function36 and
increased insulin sensitivity33,36 (Figure 2, page 323) may also
play a role; it is possible that indirect beneficial electrophys-
Figure 4. Effects of trimetazidine versus conventional therapy alone
(control) on 5-year global and cardiovascular mortality in patients
with ischemic and nonischemic left ventricular dysfunction.
The histogram on the left shows an 11.3% reduction in 5-year global mortality
when trimetazidine (TMZ) is administered in addition to standard medical therapy
(P=0.015). The histogram on the right shows an 8.7% reduction in 5-year cardio-
vascular mortality in the same patients (P=0.05).
Abbreviations: CV, cardiovascular; TMZ, trimetazidine.
Based on data from reference 38: : Fragasso G et al. Int J Cardiol. 2013;163:
320-325.
324 MEDICOGRAPHIA, Vol 38, No. 3, 2016 Combining hemodynamic and metabolic agents in ischemic heart disease Fragasso
Figure 3. Baseline and follow-up
Tpeak-Tend dispersion (mean + 1
standard deviation) in patients with
left ischemic and nonischemic left
ventricular dysfunction and treated
with trimetazidine (red columns) or
conventional therapy alone (controls;
greycolumns).
Tpeak-Tend dispersion index is a noninvasive
marker of dispersion of ventricular repolariza-
tion and is positively related to the risk of
arrhythmias. The evidence of a significant
TMZ-induced Tpeak-Tend dispersion reduc-
tion only in patients with post-ischemic left
ventricular dysfunction supports the hypothe-
sis that the potential antiarrhythmic properties
of TMZ could be directly mediated by the
anti-ischemic action of the drug.
Abbreviations: TMZ, trimetazidine.
Based on data from reference 37: Cera et
al. J Cardiovasc Pharmacol Ther. 2010;15:
24-30.
iological effects37 (Figure 3) may also be involved. Long-term
administration of trimetazidine has also been shown to im-
prove survival and event-free survival in patients with ischemic
and nonischemic left ventricular dysfunction (Figure 4).38
Similarly to other established antianginal drugs, the main lim-
itations on the wide use of trimetazidine in chronic ischemic
heart disease include the paucity of data on mortality and ma-
jor cardiovascular events and on direct comparisons between
trimetazidine and established antianginal therapies. Neverthe-
less, in 2005, a Cochrane review including 23 studies (1378
patients) concluded that trimetazidine is a well-tolerated drug
that provides benefit in patients with stable angina, in terms
of patient-reported intake of glyceryl trinitrate tablets and num-
ber of weekly angina episodes when used as monotherapy
and in combination with conventional antianginal agents.39
A more recent meta-analysis (13 studies, 1628 patients) that
compared trimetazidine with conventional antianginal drugs
confirmed the efficacy of trimetazidine treatment for stable
angina pectoris, regardless of treatment duration.40
At present, the European Society of Cardiology indicates tri-
metazidine as an effective adjunctive treatment in patients with
angina not completely controlled by standard hemodynamic
therapy.41
Combined metabolic action of b-blockers and
trimetazidine
Despite their above-described pitfalls, b-blockers continue to
be the clinical mainstay of ischemic heart disease treatment.
They act principally through reduction in oxygen consumption
by reducing heart rate and inotropism. However, they could
have a direct complementary metabolic effect themselves, by
reducing peripheral lipolysis and reducing FFA availability. In-
deed, there is evidence that b-blockade reduces FFA use in fa-
vor of greater glucose use in cardiac patients.42 Such a change
in cardiac energy metabolism could be a potential mechanism

for the decreased cardiac oxygen consumption and improve-
ment in energy efficiency observed with b-blocker treatment
of ischemic heart disease and heart failure.43 Whether nonse-
lective b-blockers are more efficient than selective ones in shift-
ing whole-body substrate utilization from FFA to glucose oxi-
dation44 is still under debate.45 Nonetheless, the better survival
rates observed with nonselective b-blockers could be explained
by their effect on the metabolism.46 Additionally, inhibition of
activity in the sympathetic nervous system with the central-
acting antihypertensive drug moxonidine has been associ-
ated with increased mortality in patients with chronic heart fail-
ure.47 In fact, despite a significant reduction in catecholamine
spillover from the synapses in the sympathethic nervous sys-
temthus reducing catecholamine levels in the bloodand,
consequently, heart rate, moxonidine increases both FFA use
and myocardial oxygen consumption.48 This could be the rea-
son why central sympathetic inhibition fails to prevent deaths
in long-term studies in patients with chronic heart failure; it also
indicates that the main mechanism of action of b-blockers in
cardiac syndromes probably involves something other than
a simple reduction in heart rate. Thus, it is possible that the de-
gree of heart rate reduction is just a marker of the functional
response after the administration of b-blockers, ie, a conse-
quent effect rather than a mechanism. On this basis, we can
hypothesize that b-blockers and trimetazidine have a comple-
mentary, synergistic metabolic action: whereas the former re-
duces FFA availability, the latter decreases their cardiac utiliza-
tion. Overall, this drug-induced metabolic shift could reduce
FFA oxidation and increase flux through pyruvate dehydro-
genase with a consequent energy-sparing effect.35,49
There is evidence to suggest that trimetazidines metabolic
effect may occur in other organs and tissues as well.50 In fact,
apart from a reduction in whole-body energy demand, a trend
for a reduction in whole-body lipid oxidation and in fasting plas-
ma FFA concentration has also been observed (Figure 5).50
This general metabolic shift could in the end reduce the over-
all metabolic requirements of the body, resulting in a very at-
tractive adaptation strategy in the context of coronary and my-
ocardial insufficiencies. Interestingly, b-blockers have also been
shown to directly affect whole-body metabolism. In trained
athletes, b-blockade abolishes the increase in plasma glu-
cose levels that occur during intense exercise, owing to an in-
creased peripheral glucose uptake and no significant change
in glucose production.51 Such effects from b-blockade on glu-
cose kinetics could be mediated directly; they could also be
indirectly mediated through changes in lipid substrates and/or
counter-regulatory hormones.
Potential role of metabolic therapy in revascularized
chronic ischemic heart disease
Despite no clearly demonstrated prognostic gain, nowadays,
revascularization procedures are often considered first for the
control of angina pectoris. However, recurrent or persistent
angina after initially successful revascularization is not infre-
Combining hemodynamic and metabolic agents in ischemic heart disease Fragasso
FOCUS
quent and is frustrating for patients and doctors. In fact, sub-
sequent repeat coronary angiography and revascularization
procedures introduce both additional risk for the patient and
cost to the health care system. A more effective medical strat-
egy could certainly improve the management of these pa-
tients. In this context, an ongoing international, multicenter,
randomized clinical study would provide the cardiological com-
munity with new solid data in a few years time. The purpose
of the ongoing ATPCI study (efficAcy and safety of Trimetazi-
dine in Patients with angina pectoris having been treated by
percutaneous Coronary Intervention; EudraCT Number: 2010-
022134-89) is to evaluate the long-term efficacy and safety of
trimetazidine, in addition to evidence-based cardiovascular
therapy, in patients having had a recent percutaneous coro-
nary intervention. The primary objectives are to demonstrate
the superiority of trimetazidine over placebo in preventing re-
currence or exacerbation of angina pectoris and in reducing
cardiac events, and also to document its safety by analyzing
the occurrence of serious adverse events. Apart from the eval-
uation of the effects of trimetazidine in this widely encoun-
Figure 5. Bar chart showing mean (+ 1 SD) resting energy expen-
diture (kcal/day) at baseline and after 3 months of follow-up in
patients with ischemic and nonischemic left ventricular dysfunction
treated with conventional therapy plus trimetazidine (red columns)
or conventional therapy alone (grey columns).
Trimetazidine significantly reduces the whole-body energy expenditure, indicating
a potential role of this metabolic drug on overall metabolic requirements of the body.
Based on data from reference 50: Fragasso et al. Heart. 2011;97:1495-1500.
tered patient population, this new study will also provide us
with much useful information about the current epidemiolo-
gy, treatment, and outcome in patients with chronic ischemic
heart disease. It is expected to provide some of the most sol-
id data about the treatment of chronic ischemic heart disease
ever produced.
Conclusions
Optimization of cardiac energy metabolism is attractive as an
approach to protect myocardial cells from ischemia and to
improve performance of dysfunctioning myocardium. To that
effect, trimetazadine, which shifts the energy substrate pref-
erence away from FFA metabolism toward increased glu-
MEDICOGRAPHIA, Vol 38, No. 3, 2016 325
FOCUS
cose oxidation, has been shown by a number of studies to be
an effective adjunctive treatment in patients with chronic is-
chemic heart disease and heart failure, reducing ischemic
burden and improving left ventricular metabolism and func-
tion. Whether the reported experimental and clinical benefits
translate into improved prognosis is currently being ascer-
tained by an ongoing international randomized clinical trial.
This has potential to be a major therapeutic advance in chron-
ic ischemic heart disease patients, who continue to experi-
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Keywords: angina; metabolism; myocardial ischemia; trimetazidine

LASSOCIATION D AGENTS HMODYNAMIQUES ET MTABOLIQUES

DANS LA CARDIOPATHIE ISCHMIQUE
Lischmie myocardique peut tre considre comme un problme mtabolique conduisant un dsquilibre des
voies utilises normalement par le cur pour produire de lnergie. Lutilisation dagents pharmacologiques pour
optimiser le mtabolisme nergtique cardiaque en stimulant loxydation du glucose au niveau du myocarde peut tre
une option thrapeutique efficace. Ainsi, la trimetazidine est un agent mtabolique qui agit indirectement en inhibant
loxydation b des acides gras, ce qui privilgie le mtabolisme du glucose, un substrat nergtique plus efficace pour
la production dATP que les acides gras. Lefficacit de la trimtazidine dans le traitement de langor a t value
dans diffrentes conditions : administration de la trimtazidine en monothrapie ou en association, en priode aigu
ou plus long terme, en traitement initial, et chez les patients rsistants aux b-bloquants ou aux inhibiteurs calciques.
Toutes les tudes publies employant la trimtazidine chez des patients ayant une cardiopathie ischmique chro-
nique ont invariablement rapport des effets cliniques bnfiques sans vnements indsirables hmodynamiques.
En fait, chez les patients ayant une cardiopathie ischmique chronique avec dysfonction ventriculaire gauche, la tri-
mtazidine est un complment particulirement efficace en termes damlioration de la fonction et du mtabolisme
ventriculaires gauches. Une tude clinique randomise en cours chez des patients ayant une maladie coronaire re-
vascularise devrait permettre de dterminer si les bnfices cliniques et exprimentaux de la trimtazidine se tra-
duisent aussi par une amlioration du pronostic.

Combining hemodynamic and metabolic agents in ischemic heart disease Fragasso MEDICOGRAPHIA, Vol 38, No. 3, 2016 327

Bioresorbable stents are very
promising: they offer the vascular
scaffold for a certain amount of
time and then the implanted ma-
terials are progressively resorbed.
This offers a number of advantages,
including the elimination of foreign
bodies inside the wall, restoration
of endothelial coverage, and pos-
sibly restoration of vasomotion.
These biodegradable stents can
be divided into two categories:
metallic stents that are magne-
sium based and those that are
polymeric resorbable.
Michel E. BERTRAND,
MD, FESC, FRCP, FACC
Hpital Universitaire
Cardiologique, Lille
FRANCE
Address for correspondence:
Michel E. Bertrand,
Hpital Universitaire Cardiologique,
Lille, FRANCE
(e-mail: mbertrand2007@gmail.com)
www.medicographia.com
328 MEDICOGRAPHIA, Vol 38, No. 3, 2016
U P DAT E
History and evolution
of coronary stenting
by M. E. Bertrand, France
C
oronary stenting represents a major step in the history of percutaneous
coronary angioplasty. Jacques Puel performed the first stent implanta-
tion in man in 1986, and research in the area took off immediately. The
primary concern about balloon angioplasty procedures was safety, as there is
a risk of abrupt occlusion during the procedure. This risk and the subsequent
need for emergency bypass surgery were dramatically reduced with stent im-
plantation. Nevertheless, investigators then faced another problem: the risk
of stent thrombosis. However, such risk is suppressed by the use of a dual an-
tiplatelet treatment. Coronary stenting has now played a major role in the fight
against restenosis, with drug-eluting stents considerably reducing this risk,
even in high-risk patients (diabetics). With coronary stenting, coronary inter-
ventional procedures have become the primary approach to myocardial revas-
cularization.
Medicographia. 2016;38:328-334 (see French abstract on page 334)
he first coronary angioplasty in man was performed by Andreas Gruentzig
T from Zurich (Switzerland) in September 1977.1 This new, noninvasive approach
for myocardial revascularization would have an immediate and great success.
In the years that followed, significant technical improvements were proposed. The
over-the-wire technique, designed by John Simpson,2 and the monorail system3 were
rapidly adopted by the interventional cardiology community. However, new problems
were observed: the most important pertained to the safety of the procedure. During
or immediately after angioplasty, an abrupt occlusion of the vessel was observed in
3% to 5% of cases. This accident was related to an occlusive dissection or an occlu-
sive thrombosis of the vessel. Thus, when use of coronary angioplasty was beginning,
it was recommended to perform the procedure with a surgical backup, enabling im-
mediate emergency bypass surgery if needed. In most cases, this emergency opera-
tion was followed by limited myocardial necrosis. Aside from this immediate problem,
30% to 45% of cases experienced later restenosis in a process such as the follow-
ing: the mechanism of initial enlargement of the lumen was through dissection of the
vessel; and this dissection was followed by a process of healing, which involved mi-
gration and proliferation of smooth muscle cells into a loose extracellular matrix; thus,
intimal hyperplasia occurred, contributing to the renarrowing of the dilated vessel.
Later, it was discovered that another important phenomenon was occurring nega-
tive remodeling of the vessel, leading to shrinkage of the dilated segment. It is with-
in this context that coronary stenting arose and solved, at least partially, the two ma-
jor problems of coronary angioplasty, namely abrupt occlusion and restenosis.
History and evolution of coronary stenting Bertrand

History of stenting
It has been said that the Egyptians tried to cure the narrow-
ing of urethra by introducing a small reed in the urinary canal
in order to reestablish a more fluid relationship between the
internal and external milieu.
In September 1912, the French surgeon, Alexis Carrel made
a prophetic statement following the publication of his work
on permanent intubation of the thoracic aorta in dogs4:
The permanent intubation of a large vessel is a simple opera-
tion. It may become practical, if the shape and the nature of
the tube be modified as to avoid lacerations (). The question
of the application of this method to human surgery may then,
possibly, be considered.
It took more than 70 years to verify this assumption.
The first stent was conceived from the progress in therapeu-
tic intervention initiated by Charles Dotter5; he was a true in-
ventor and a pioneer in the interventional cardiovascular world.
He opened the way for interventional cardiology, and he start-
ed to design the first vascular stent at the end of the 1980s
with insertion of plastic tubes and collapsible stainless-steel
prostheses into the femoral or popliteal arteries of dogs.
In 1978, a young fellow who had recently arrived from Argenti-
na attended a lecture by Andreas Gruentzig at a meeting of
the Society of Cardiovascular and Interventional Radiology.
His name was Julio Palmaz, and he thought that the prob-
lems that doctor Gruentzig had with his balloon could be avoid-
ed by inserting some sort of a scaffold at the time of dilata-
tion.6 The chairman of the department said that it could be
a nice research project. After writing a report and making draw-
ings, he started to build a prototype in his garage with cop-
per wire and solder materials.
The wire was woven in a crisscross mesh around a pencil with
two rows of pins. Solder was used to fix the cross points to
allow the mesh to retain its shape. Once built, the mesh diam-
eter was decreased by compressing it on progressively small-
er wooden dowels and then was crimped by hand on a fold-
ed balloon. However, the material was excessively rigid, and
the slots and the spaces between were inadequate. Julio Pal-
maz searched for a manufacturer, but several companies re-
fused to consider this device.
In Switzerland, the story of stenting started during a party: two
Swedish persons metone, Hans Wallstn, was the design-
er of a revolutionary machine intended to manufacture paper;
the other, Ake Senning, was a well-known cardiovascular sur-
geon. During the meeting, Senning explained that aortic dis-
section was a very serious acute disease and went on to de-
tail his concept of a mechanical scaffolding of the arterial wall
by a latticed metallic tube. Wallstn, very excited, decided to
take up the problem of metallic endoprostheses. He created
the Wallstent but had some difficulties finding a solution for a
History and evolution of coronary stenting Bertrand
U P DAT E
percutaneous approach; the solution was found by the engi-
neer Christian Imbert. The self-expandable stent, which could
be implanted via a percutaneous femoral approach, was thus
created. Looking for centers to experiment with his device,
Christian Imbert met Ulrich Sigwart in Lausanne and the group
of Jacques Puel in Toulouse.
In cooperation with radiologists from Toulouse, Jacques Puel
conducted experiments in sheep and dogs. These experi-
ments quickly (probably too quickly) met with success and
showed, at least at first glance, that it was easy (possibly too
easy) to implant the endocoronary prosthesis percutaneous-
ly and that rapid endothelialization of the struts occurred. How-
ever, these animal experiments did not reveal the high risk of
subsequent thrombosis. Later, Puel confessed that he had
probably underestimated this risk. Simultaneously in Lau-
sanne, Ulrich Sigwart was conducting experimental implan-
tation in dogs.
The first stent implantation in man was performed on March
28, 1986 by Puel using the Wallstent.7 The medical history of
this first patient is quite simple: the patient was a 63-year-old
male with arterial hypertension and symptomatic restenosis
6 months after treatment of a midleft anterior descending ar-
tery lesion (Figure 1). In 1986, with evidence-based medicine
A
B
C
Figure 1. First stent implantation in man.
Stent implantation in a 63-year-old male with arterial hypertension and sympto-
matic hypertension 6 months after treatment of a midleft anterior descending
artery lesion. The procedure was carried out by Jacques Puel in 1986.
A. Angiogram showing high-grade stenosis of the proximal left anterior descend-
ing artery (yellow arrow) before the procedure. B. The bare metal stent used in
the procedure. C. Angiogram showing the stent in place (yellow arrow).
All rights reserved.
MEDICOGRAPHIA, Vol 38, No. 3, 2016 329
U P DAT E
still in its infancy, the patient received no antiplatelet drugs
or statins in preparation for stent implantation; rather, he re-
ceived only subcutaneous heparin during the procedure and
within the next 6 weeks. By chance, he had no stent throm-
bosis or in-stent restenosis within that time span; however,
he did not escape progression of the atherosclerotic process
and has had recurrent episodes of angina pectoris related to
a new lesion on the ostium of the left anterior descending ar-
tery and another one on the circumflex artery, which was treat-
ed in 2004 by a new stent implantation. In the weeks after
that first implant, seven other patients received a self-expand-
able Wallstent without any complications.
In Lausanne, the results obtained from 9 months of animal ex-
periments were convincing enough to persuade the Institu-
tional Review Board to give approval in April 1986 for the use
of stent implants for three indications: abrupt vessel closure
after balloon angioplasty, restenosis after balloon angioplas-
ty, and stenosis of saphenous vein bypass grafts.8 After a
number of deployments in human femoral and iliac arteries,
the self-expanding mesh stent was first deployed after balloon
dilatation of a tight stenosis in a vein bypass procedure.
Although initial results were promising, they were misleading
the next four patients to undergo the stent procedure expe-
rienced a subacute stent thrombosis. With a single antithrom-
botic treatment using full-dose heparin, the risk of thrombosis
was very high.
Later, Ulrich Sigwart would perform the stent implantation pro-
cedure under full anticoagulation treatment with heparin fol-
lowed by oral anticoagulation with warfarin.8 This medical treat-
ment slightly decreased the risk of stent thrombosis, though
it remained very high (occurring in 5% to 10% of cases).
330 MEDICOGRAPHIA, Vol 38, No. 3, 2016
Figure 2.
Impact of
stenting on
acute occlu-
sion and
emergency
surgical bailout
procedures.
Abbreviation:
Emerg CABG,
emergency
coronary artery
bypass graft
surgery.
All rights
reserved.
These two clinical trials, conducted initially in Toulouse and lat-
er in Lausanne, proved the feasibility of the stent implanta-
tion method. However, they also demonstrated the high po-
tential thrombogenic risk posed by introduction of this foreign
body; nevertheless, stents markedly reduced the risk of acute
or subacute occlusion. As a result, the need for emergency
surgical bailout procedures was drastically reduced (Figure 2).
The evolution of coronary stenting over the years that followed
can be divided into three different partstechnical improve-
ment, safety improvement, and restenosis prevention and treat-
ment. These will be discussed in turn.
u Technical improvements in stenting
A number of variations of the stent have been proposed over
the years. The first stent implanted in the coronary arteries in
man was the Wallstent (Medinvent) (Figure 3A). It was a self-
expanding stent composed of 20 strands of 0.06 to 0.09 mm
diameter arranged into a self-expanding mesh design. It was
flexible; its length ranging from 15 to 30 mm; and its diam-
eter between 3.0 to 6.0 mm. The mesh was compressed and
elongated on the delivery catheter owing to a double wall sleeve
membrane. Retraction of this membrane allowed the progres-
sive release into the vessel. The aforementioned work of Julio
Palmaz led to creation of a tubular slotted stent; together
with Richard Schatz, it was implanted in coronary arteries for
the first time in December 1987 (Figure 3B).9 This was a bal-
loon-expandable stent crimped on the delivery catheter, and
it became very popular. The Gianturco Roubin stent10 (ap-
proved in the United States in 1993) (Figure 3C) had a poor
radial strength, which was responsible for an increased rate of
restenosis and stent thrombosis. Later, Medtronic proposed
a coil stent or Wiktor stent (Figure 3D). Finally, stents covered
by a membrane of polytetrafluoroethylene were proposed
History and evolution of coronary stenting Bertrand
 U P DAT E

Figure 3. Four types of stents: the precursors.

Coronary stents: the precursors A number of variations of the stent have been proposed. Shown
here are the (A) Wallstent, (B) Schatz-Palmaz, (C) Gianturco-
A Wallstent: self-expanding C Gianturco-Roubin Roubin, and (D) Wiktor stents.
All rights reserved.

The first drug-eluting stent of this group was the

Cypher (Cordis Corporation). Almost simultane-
ously proposed was paclitaxel, which inhibits cell
replication and is the drug delivered by the Taxus
B Schatz-Palmaz: tubular stents (Boston Scientific). Cypher and Taxus stents
D Wiktor stent: coil were the first-generation drug-eluting stents. These
were followed by second-generation (followed by
a second generation (Xience, Endeavor stents) and
third-generation drug-eluting stents, the latter be-
ing fully bioresorbable vascular scaffolds (BVS), in-
cluding: (Igaki-Tamai (Igaki Medical Planning), BVS
1.0 (Abbott Vascular), DESolve (Elxir Medical Cor-
poration), REVA (Reva Medical), ART 18AZ (Arterial
Remodeling Technologies), and Amaranth stents.

and used in saphenous vein graft stenoses to avoid the em- u Safety improvements in stenting: the fight against
bolization of the friable materials characteristic of these le- acute or subacute stent thrombosis (first revolution in
sions. It was also used for the emergency treatment of coro- coronary stenting)
nary perforations. It would take nearly 10 years to eliminate the frightening risk
of acute or subacute stent thrombosis. A number of strate-
Drug-eluting stents were introduced in 2000. They are com- gies were proposed; these included use of full-dose unfrac-
posed of two parts: the polymer coating the strut (one or sev- tionated heparin, low-molecular-weight heparin, dextran, sulfin-
eral layers) and the drug delivered into the vessel wall. The pyrazone, aspirin, and antivitamin K. The combination of these
drugs act on the cell cycle (Figure 4) and are able to suppress drugs was ineffective and led to significant bleeding at the
smooth muscle cell proliferation without toxicity and with a puncture site resulting in big hematomas that required vas-
low inflammatory risk. Most drug-eluting stents use an analog cular repair. In this context, although stenting was recognized
of sirolimus (drugs used from the limus group include sirolimus, to be effective for the treatment of abrupt periprocedural oc-
everolimus, zotarolimus, biolimus, the sirolimus metabolite no- clusion and to help avoid emergency bypass operations,
volimus, and myolimus, a macrocyclic lactone close to the many investigators were ready to abandon this technique
rapamycin family). for the treatment of restenosis. However, coronary stenting
would be resuscitated by two new findings by An-
tonio Colombo from Italy and Paul Barragan from
Marseille.
Limus family S phase
DNA
replcation Antonio Colombo, through extensive use of intra-
FKBP120
vascular ultrasound, demonstrated that in many
mTOR
cases, stent implantation was far from perfect, with
Paclitaxel
Low dose malapposition and insufficient deployment. From
these observations, he recommended inflation of
G0 phase G1 phase G2 phase the balloon at a higher level of pressure to improve
Cell works but Cell enlarges Preparation
is not actively and makes for division embedding of the stent inside the wall. With a larg-
replicating new proteins
er lumen and a better flow, stent thrombosis might
be avoided.
Paclitaxel
M phase High dose
Figure 4. Impact of the drugs delivered by
Cell division
drug-eluting stents on the cell cycle.
Abbreviations: G0 phase, resting phase of the cell cycle;
CELL DIVISION G1, G2 phases, interphases of the cell cycle; M phase, mitotic
phase of the cell cycle; mTOR, mammalian target of rapamycin.
All rights reserved.

History and evolution of coronary stenting Bertrand MEDICOGRAPHIA, Vol 38, No. 3, 2016 331
U P DAT E
Figure 5. Rate of stent thrombosis in patients taking a dual an-
tiplatelet treatment (aspirin + ticlopidine) compared with patients
taking aspirin + a vitamin K antagonist.
Abbreviations: ASA, acetylsalicylic acid; FANTASTIC, Full ANTicoagulation versus
ASpirin and TIClopidine (study); ISAR, Intracoronary Stenting and Antithrombotic
Regimen; STARS, STent Anticoagulation Restenosis Study; Vit, vitamin.
Based on data from references 13-15. All rights reserved.
Almost simultaneously, Paul Barragan reported that a dual an-
tiplatelet treatment with aspirin and ticlopidine was success-
ful.11 Barragan participated in a trial launched by Bertrand et
al (The TACT trial [Ticlopidine Angioplasty Coronary Trial]).
The goal of this trial was to verify if an antiplatelet drug (ticlo-
pidine) could prevent restenosis. This study presented at the
American Heart Association meeting in 1992 had negative re-
sults but was able to demonstrate the benefits of ticlopidine
+ aspirin in preventing acute periprocedural complications of
balloon angioplasty. Thus, Barragan continued to use this dual
anti-platelet treatment after completion of the study. In perform-
ing stent implantations, he was the only investigator to have
no (or rare) cases of stent thrombosis. Finally, on the basis of
a French registry collecting data on the usual strategies, it was
observed that the combination of aspirin and ticlopidine was
markedly effective for reductions in stent thrombosis and vas-
cular complications.12 Three randomized studies performed
initially in Europe13,14 and later in the United States15 demon-
strated the benefit of this dual antiplatelet treatment (Figure 5).
Subsequently, Bertrand et al showed that another thienopy-
ridine (clopidogrel) was superior to ticlopidine (the CLASSIC tri-
al [CLopidogrel Aspirin Stent International Cooperative study]).16
The danger of acute/subacute thrombosis having been over-
come, the so-called stentomania began, with an increasing
number of stent implantation procedures taking place.
u The fight against restenosis
u The role of stenting
In 1991, Serruys et al published in the New England Journal
of Medicine the results from the first 105 patients in the world
treated with the Wallstent.17 This report essentially addressed
the problem of subacute thrombosis, but few readers over-
looked the fact that the rate of restenosis after stenting was
only 14%. In this context, Dutch investigators began a multi-
center registry, and several investigators (Serruys, Bertrand,
332 MEDICOGRAPHIA, Vol 38, No. 3, 2016
Rutsch) launched a randomized study assessing the role of
coronary stenting in the treatment of restenosis. Although ini-
tially impossible to find support from industry for such a trial,
the tenacity of Serruys, de Jaegere, Kiemeneij and colleagues
led to the launch of the BENESTENT I trial (BElgian-NEther-
lands STENT) in Belgium and the Netherlands. This pilot study
included only 60 patients and took almost 1 year to complete
in four centers with a total number of almost 4000 interven-
tions, demonstrating the skepticism of the interventional car-
diology community for stenting.18 This landmark study demon-
strated the benefit of coronary stenting for the treatment of
restenosis. The results were confirmed by an American trial
(STRESS [STent REStenosis Study]).19 Later, the results were
complemented by the BENESTENT II study, which was per-
formed with a heparin-coated stent and showed that bleed-
ing complications almost completely disappeared.20
However, over time, it appeared that in-stent restenosis was
a true matter of concern. It was discovered that though the
scaffolding role of stenting prevented negative remodeling
the shrinkage of the arteryas a reaction to the metallic for-
eign body, the vascular wall generated a new, intense hyper-
plasia. Solinas et al21 showed the different aspects of in-stent
restenosis, as follows: in-stent restenosis was focal (margin
or mid-stent) in 42%, diffuse in 22%, proliferative (ie, with ex-
tension beyond the stent) in 30%, and even occlusive in 6%.
Several techniques were used to address this new problem;
these included redilatation by balloon (mainly for focal in-stent
restenosis), by the stent-in-stent technique, by Rotablator ther-
apy, and even by brachytherapy. At first glance, brachythera-
py seemed promising but was subject to numerous regula-
tions due to the rules of radioprotection. This method was
never well accepted, was limited to a small number of centers,
and was finally abandoned with the emergence of drug-elut-
ing stents.
u Drug-eluting stents (the second revolution in coronary
stenting)
Over the years, several investigatorsparticularly Wim van der
Giessenattempted to coat the struts of the metallic stents
with different substances, the goal being to coat the struts
with a polymer as a drug-carrier vehicle; these drugs sought
to inhibit the cell cycle. In July 1999, Cordis Corporation stud-
ied a stent coated with a polymer releasing the drug rapa-
mycin. The company conducted a pilot study in Rotterdam,
the Netherlands with Patrick Serruys and in Sao Paulo, Brazil
with Eduardo Souza, in which 15 patients were studied with
angiographic and intravascular ultrasound follow-up. The two
principal investigators were surprised to discover that at 4
and 12 months follow-up there was no evidence of neointimal
hyperplasia. These results led to a randomized clinical trial
conducted in 237 patients treated by bare-metal stent or the
Cypher, the first drug-eluting stentthe RAVEL study (RAn-
domized study with the sirolimus-eluting VElocity balloon-ex-
pandable stent in the treatment of patients with de novo na-
History and evolution of coronary stenting Bertrand
 U P DAT E

tive coronary artery Lesions).22 This study, presented at the
European Society of Cardiology congress in Vienna (Septem-
ber 2001) by Marie-Claude Morice, was a new turning point
in coronary interventional cardiology, as there was zero re-
stenosis.
Subsequently, two major trials confirmed these excellent re-
sults: the SIRIUS trial (SIRolImus-elUting Stent in coronary
lesions),23 as well as the TAXUS trial (Treatment of de novo
coronAry disease using a single paclitaXel-elUting Stent),24
which used another eluting drug, paclitaxel. Later, the course
of drug-eluting stents was disturbed by a frighten-
ing issueat the 2006 European Society of Car-
Before balloon angioplasty
diology congress in Vienna, results suggesting late
stent thrombosis were presented. Fortunately, these
scary results were not confirmed,25 but they led to
a still ongoing debate about the duration of dual
antiplatelet treatment: 6 months, 12 months, or
more? Nevertheless, the development of drug-elut- After balloon angioplasty
ing stents continued and with the new drug-elut-
ing stents using a different drug-carrier vehicle, all of
them have been shown to offer efficacy and safety.
be divided into two categories: metallic stents that are mag-
nesium based and those that are polymeric resorbable
more than 10 stents of this type have been studied, made of
poly-L-lactic acid (PLLA) and poly-D,L-lactic acid. Absorb
BVS (Abbott Vascular) is a fully resorbable stent which has
obtained the CE mark (Conformit Europenne [European
conformity]); the ABSORB II trial published in the Lancet in
2014 compared Absorb BVS vs the Xience metallic drug-
eluting stent in a cohort of 501 patients.27-29 At follow-up, there
was no significant difference in terms of safety and efficacy
between the two devices. Currently, there is great interest for
Prevention of
Lumen restenosis
with stents
BMS Stent Drug-eluting stent
Prevention of shrinkage Prevention of shrinkage
and hyperplasia

Thus, the challenges were overcome: the cage pre- Restenosis

vents negative remodeling and the eluted drug pre-
vents cell proliferation and migration (Figure 6). A fi-
nal step was the development of stents that used
biodegradable polymers and bioresorbable scaf-
folds: drug-eluting stents with biodegradable poly-
mers provide the benefit of drug-eluting stents in
the early days/months and of the bare-metal stents
later. A number of prostheses were studied: AX-
XESS (Biosensors), Orsiro (Biotronik), DESyne (Elixir),
Infinium (Sahajanand), Biomine (Meril Life).
Hyperplasia and
negative remodeling
Figure 6. Summary of the relationship between restenosis and stenting.
Whereas balloon angioplasty often results in negative remodeling and sometimes in restenosis,
the use of stents prevents negative remodeling. Drug-eluting stents can provide this benefit
and also prevent cell proliferation and migration.
Abbreviation: BMS, bare-metal stent.
All rights reserved.

As the polymer may induce side effects, polymer-free drug-
eluting stents have been proposed. The eluting drug may be
introduced into a microporous surface on metallic stents. Ex-
amples include the Yukon stent (Translumina), BioFreedom
(Biosensors), VESTAsync (MIV Therapeutics), Nano (Xience),
and Bicare (Lepu Medical). In other examples, the Optima
stent (CID Vascular) proposes small reservoirs of tacrolimus
covered with carbofilm, and the Amazonia PAX stent (MIN-
VASYS) is a cobalt-chromium stent coated with paclitaxel.
Bioresorbable stents are very promising: they offer the vascu-
lar scaffold for a certain amount of time and then the implant-
ed materials are progressively resorbed. This offers a number
of advantages, including the elimination of foreign bodies in-
side the wall, restoration of endothelial coverage, and possi-
bly restoration of vasomotion. These biodegradable stents can
these new bioresorbable stents, but it is obvious that a longer
follow-up is needed in order to reach final conclusions. There
are currently a number of studies underway evaluating these
new devices.
Conclusion
Coronary stenting represents one the most important ad-
vances in the field of coronary angioplasty. With this technique,
percutaneous coronary interventions are safe in most cases
and the risk for patients to be sent for surgery for emergency
bailout procedures has become minimal. Additionally, the risk
of reintervention after angioplasty is markedly reduced after
drug-eluting stent implantation. With coronary stenting, coro-
nary interventional procedures, as minimally invasive tech-
niques, have become the primary method of myocardial revas-
cularization in man.

Keywords: coronary stenting; interventional cardiology; myocardial revascularization; percutaneous coronary angioplasty

History and evolution of coronary stenting Bertrand MEDICOGRAPHIA, Vol 38, No. 3, 2016 333
U P DAT E

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HISTOIRE ET VOLUTION DE L IMPLANTATION DES ENDOPROTHSES CORONAIRES

Limplantation des endoprothses coronaires est une tape majeure dans lhistoire de langioplastie coronaire per-
cutane. Jacques Puel a ralis la premire implantation dendoprothse chez lhomme en 1986 et la recherche dans
ce domaine sest dveloppe immdiatement. La premire crainte concernant langioplastie par ballonnet tait la s-
curit, cause du risque docclusion brutale pendant lintervention. Le risque, et donc le besoin dun pontage en ur-
gence, sont considrablement rduits par limplantation dendoprothses. Nanmoins, les mdecins ont t confron-
ts un autre problme : le risque de thrombose de lendoprothse. Ce risque peut, cependant, tre limin grce
un double traitement antiplaquettaire. Limplantation dendoprothses coronaires joue maintenant un rle majeur
dans le combat contre la restnose, les endoprothses libration de principes actifs rduisant considrablement
ce risque, mme chez les patients haut risque (les diabtiques). Avec limplantation dendoprothses, langioplas-
tie coronaire est dsormais la principale mthode de revascularisation myocardique.

334 MEDICOGRAPHIA, Vol 38, No. 3, 2016 History and evolution of coronary stenting Bertrand
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 Medicographia
Vol 38, No. 3, 2016 ISSN 0243-3397

Metabolic agents in the contemporary treatment of angina

C hance
Medicographia
favors only
the prepared mind Metabolic agents
Pa s t e u r in the contemporary
treatment of angina

Vol 38, No. 3

Pages 243-336
16 MP 0128 X Printed in France

Servier - 50, rue Carnot - 92284 SureSneS Cedex (FranCe) Quarterly Thematic Journal

of Clinical and Therapeutic Research

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2016

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