10/2/2011

Prof.AHMADABDELLATIF
M.D.,F.A.C.C.

STATINSINCHRONICHEART
FAILURE
Oneofthegreatsuccessstoriesincardiologyisthe

abilityofstatins toimproveprognosisinpatientsat
riskofprimaryorsecondarycardiovasculat events.
Thisfacthasbeenchallanged onlyin:

patientsondialysis

patientswithchronicheartfailure

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INOURAGINGPOPULATION
WITHGROWINGNUMBERSOF
CASESOFHEARTFAILURESEVERAL
QUESTIONS HAVE TO BE
QUESTIONSHAVETOBE
ANSWEREDTOIMPROVE
OUTCOMESOFTHESECASES
WHICH UP TO MOMENT REMAINS
WHICHUPTOMOMENTREMAINS
POOR

ISITBENEFICIALTOCONTNUE
STATINTREATMENTINEND
STAGE CAD THAT HAS RESULTED
STAGECADTHATHASRESULTED
INCHRONICHEARTFAILURE
ISITBENEFICIALTOBEGIN
STATIN THERAPY IN END STAGE
STATINTHERAPYINENDSTAGE
CADTHATHASRESULTEDIN
CHRONICHEARTFAILURE

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BACKGROUNDOFTHIS
CHALLENGE
inFraminghamstudy:dyslipidemia
g
y y p
isariskfactorforthe

develoment ofCHF
detailedanalysisofthesameFraminghamdatabase:total
cholesterolassociationwithmortalityhasbeen:
positiveatage40
negligibleatage5070
negativeatage80andup
InischemicCHFhighercholesterollevelsareassociated
withlessmortality
Epidemiologicalstudies:higher riskofadverseeventswith
lowlevelsofLDLincasesofCHF

BACKGROUND(contin.)
lowcholesterollevelcanbeaconsequenceof
lowcholesterollevelcanbeaconsequenceof

advancedCHFwithoutacausalrole
lowchlesterol levelmaybeonlyamarkerofpoor
health
OR
STATINSMAYHAVEPOTENTIALLYHARMFULL
EFFECTSinCHF

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Effect of pravastatin on coronary events in patients with coronary artery disease and a left
ventricular ejection fraction (LVEF) of >0.40 enrolled in the Cholesterol And Recurrent
Events trial (2)

Krum, H. et al. J Am Coll Cardiol 2002;39:1567-1573

Copyright 2002 American College of Cardiology Foundation. Restrictions may apply.

POTENTIALLYHARMFULLEFFECTS
OFSTATINSINCHF
Endotoxin
Endotoxin LipoproteinHypothesis:

serumlipoproteinsactasnaturalnonspecific
buffersofendotoxins

diminishedlipoproteinsleeds toincreased
endotoxins

CHFpatientshavehighlevelofcytokines
p
g
y
whichmaybeduetoincreasedendotoxin

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POTENTIALLYHARMFULLEFFECTS
OFSTATINS(continu.)
UBIQUINONEHYPOTHESIS
statins inhhibit mevalonate synthesis,thisdecreases

productionofUBIQUINONE(COENZYMEQ10)
COENZYMEQ10:lipidsolublequinone ,electron
trasporter,essentialformitochondrialoxidative
phosphorelation andproductionofATP,alsolipophilic
antioaxidant protectingcellmembranesand
lipoproteins.Halfisingested,halfissynthesized
throughmevalonate pathway:inhibited bystatins

COENZYMQ10
COENZYMQ10DEFICIENCYISASSOCIATED
COENZYMQ10DEFICIENCYISASSOCIATED

WITHMYOPATHY,THEREARECONCERNSABOUT
CARDIACMUSCLEDYSFUNTION:MUSCLEENERGY
STARVATION,OXIDATIVEDAMAGETO
MYOCYTES
LOWCHOLESTEROLISASSOCIATEDWITH
WORSEPROGNOSISINCHF
RECENTSTUDY:LOWPLASMACOENZYMEQ10IS
ANINDEPENDENTPREDICTOROFMORTALITYIN
CHF

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The mevalonate-isoprene pathway

Krum, H. et al. J Am Coll Cardiol 2002;39:1567-1573

Copyright 2002 American College of Cardiology Foundation. Restrictions may apply.

The hypothetical effects of statins on Chronic Heart Failure through the intermediates of the
mevalonate pathway.

van der Harst P et al. Cardiovasc Res 2006;71:443-454

Copyright 2006, European Society of Cardiology

10/2/2011

Effect of simvastatin on mortality among patients developing chronic heart failure (CHF)
compared with those without clinical evidence of CHF in the Scandinavian Simvastatin
Survival Study trial(1)

Krum, H. et al. J Am Coll Cardiol 2002;39:1567-1573

Copyright 2002 American College of Cardiology Foundation. Restrictions may apply.

POTENTIALLYHARMFUL
EFFECTS(continu)
Selenoprotein Hypothesis:statins interferewith

mevalonate pathway,andsopreventmaturationof
functionaltRNA molecule:may beharmfull inCHF

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POTENTIALLYBENEFICIALEFFECTS
OFSTATINSINCHF
cholesterolloweringcanimprovecoronarybloodflow
cholesterolloweringcanimprovecoronarybloodflow
statins canmodifyneurohormonal systemsinvolved

inpathophysiology ofheartfailure
LVH:statins caninhibitangiotensin 11induced,and
noradrenalininducedhypertrophy
retardprogressionofatherosclerosis
p g
antiinflammatoryeffect
metalloproteinases

Simplified schematic overview of the known processes involved in atherosclerosis and the
established effects of statin treatment.

van der Harst P et al. Cardiovasc Res 2006;71:443-454

Copyright 2006, European Society of Cardiology

10/2/2011

(A) Adapted with permission from Kureishi et al. [75].

van der Harst P et al. Cardiovasc Res 2006;71:443-454

Copyright 2006, European Society of Cardiology

One-year hazard ratios (HRs) and 95% confidence intervals (CIs) for death or urgent
transplantation, death from any cause, progressive heart failure death, and sudden death
for patients receiving statins compared with those not receiving statins

Horwich, T. B. et al. J Am Coll Cardiol 2004;43:642-648

Copyright 2004 American College of Cardiology Foundation. Restrictions may apply.

10/2/2011

TNF-{alpha} and MMP-2

Zaca, V. et al. J Am Coll Cardiol 2007;50:551-557

Copyright 2007 American College of Cardiology Foundation. Restrictions may apply.

Two-year rates of death or urgent transplantation in statin versus no-statin cohorts

Horwich, T. B. et al. J Am Coll Cardiol 2004;43:642-648

Copyright 2004 American College of Cardiology Foundation. Restrictions may apply.

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Effect of myocardial infarction and unstable angina on risk of death and of hospitalization
for chronic heart failure (CHF) in the Studies Of Left Ventricular Dysfunction (5)

Krum, H. et al. J Am Coll Cardiol 2002;39:1567-1573

Copyright 2002 American College of Cardiology Foundation. Restrictions may apply.

Figure. Age- and Sex-Adjusted Rates of Death From Any Cause and Hospitalization for Heart
Failure by Incident Statin Exposure Rates are during follow-up among cohort members with
dyslipidemia eligible for lipid-lowering treatment as defined by National Cholesterol
Education Panel Adult Treatment Panel III risk-based criteria who had no known prior statin
use, overall, and stratified by the presence or absence of known coronary heart disease
(CHD) at study entry.

Go, A. S. et al. JAMA 2006;296:2105-2111

Copyright restrictions may apply.

11

10/2/2011

Three-dimensional bar graph showing hypothetical relation of decreased coronary blood flow
reserve (vertical axis) in relation to increasing levels of cholesterol (horizontal axis) and
decreasing Left Ventricular Ejection Fraction (LVEF; diagonal axis).

van der Harst P et al. Cardiovasc Res 2006;71:443-454

Copyright 2006, European Society of Cardiology

CLINICALTRIALS
CORONAtrial(controlledrosuvastatin
CORONAtrial(controlledrosuvastatin multinational

inheartfailure):
5011patient,60yearsormore,NYHA class11ormore
ischemicheartfailure
10mgrosuvastatin orplacebo
2.7years
7y
nosignificantbenefit

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CLINICALTRIALS(continu.)
GISSIHF(groppo
GISSI HF(groppo itaiano perlostudiodella

sopravivenza nell insuuficienza cardiaca heartfailure):

4574CHFpatients,for3.9years
samefindingsasCORONA
?ATSOMEPOINTWITHADVANCEDIHD,HEART
FAILURE,ANDOLDAGEPATIENTSREACHA
POINTWHERETHEIRCARDIOVASCULARDISEASE
ISTOOADVANCEDTOMODIFYWITHSTATINS

Figure. Age- and Sex-Adjusted Rates of Death From Any Cause and Hospitalization for Heart
Failure by Incident Statin Exposure Rates are during follow-up among cohort members with
dyslipidemia eligible for lipid-lowering treatment as defined by National Cholesterol
Education Panel Adult Treatment Panel III risk-based criteria who had no known prior statin
use, overall, and stratified by the presence or absence of known coronary heart disease
(CHD) at study entry.

Go, A. S. et al. JAMA 2006;296:2105-2111

Copyright restrictions may apply.

13

10/2/2011

Figure 3. Kaplan-Meier survival and survival without cardiovascular (CV) hospitalization in

propensity-matched patients grouped by statin therapy.

Fukuta H et al. Circulation 2005;112:357-363

Copyright American Heart Association

Cannaturetic peptideshelp
identifyheartfailurepatientsfor
whomstatins arebenficial
CLELANDetalposthocanalysisof3664patients

fromtheCORONAstudy:patients withthelowest
levelofNterminalproBtypenaturetic peptidedid
benefitfromstatin therapy:?lowerriskheartfailure
patientsmaystillbenefitfromstatin therapy

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CONCLUSION
THEORETICALDOWNSIDESTOSTATINTHERAPYIN

CHFINCLUDE:REDUCTIONSINCOENZYMEQ
10,SELENOPROTEINLEVEL,ANDDECREASEDABLLITY
OFLIPOPROREINSTOBINDENDOTOXINS.
SMALLSCALESTUDIESANDPOSTHOCANALYSIS
SUGGESTBENEFICIALEFFECTOFSTATINSINCHF
NATURETICPEPTIDESMAYHELPIDENTIFYCASES
NATURETICPEPTIDESMAYHELPIDENTIFYCASES
OFHFTHATBENEFITFROMSTATINTHERAPY
DEFINITIVEPROSPECTIVELARGESCALETRIALIS
REQUIREDTOANSWERVARIOUSQUESTIONINTHIS
IMPORTANTSUBJECT

THANKYOU

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