Stress: the triggering factor of cardiovascular

disease
The Myogenic Theory
of Myocardial Infarction
Fourth International Conference on
Advanced Cardiac Sciences
King of Organs, 2012
Kingdom of Saudi Arabia
Carlos Monteiro
Infarct Combat Project
http://infarctcombat.org

"The coronary patient does not die from coronary disease, he

dies from myocardial disease.*

!urch "# and col.$ Ischemic cardiom%opath%$ Am &eart '. ()*+ Mar,-./.0:.12342
Coronary Thrombosis: Cause or Consequence
of Myocardial Infarction?

It is important to note the coronar% thrombosis theor%$ introduced b% 'ames !r%an &erric5$ in ()(+$
remains suffering serious doubt on its cause and effect relationship.

6his has led Friedberg and &orn to suggest in ().) that the term coronar% thrombosis should be
abandoned in favor of the more generic one of acute m%ocardial infarction. In their paper the% sa%
that 7the clinical and electrocardiographic features of coronar% thrombosis ma% be observed in
patients in 8hom a coronar% arter% thrombus is subse9uentl% not found at necrops% as has been noted
b% :ibman$ ;bendorfer$ !uchner$ &amburger and Saphir$ <ietrich$ :ev% and !ruenn and others.=

After that time man% other investigators came to the same conclusion as 8e 8ill see follo8ing...

Friedberg C> and &orn &. Acute m%ocardial infarction not due to coronar% arter% occlusion. '. Am Med Assoc
().),((+/(*0:(?*43(?*)
Coronary Thrombosis: Cause or Consequence
of Myocardial Infarction?

/()1(0 &ermann and colleagues found the thrombotic occlusion could occur 8ithout infarction
8hen the collateral circulation appeared ade9uate and if an infarct has happened$ it could be
attributed to an occlusive thrombus at a critical location in the coronar% tree.

/Angina Pectoris$ coronar% failure and acute m%ocardial infarction: 6he role of coronar% occlusions and
collateral circulation$ 'AMA ()1(,((?/+0:)(3)*, Multiple fresh coronar% occlusions in patients 8ith
antecedent shoc5$ Arch Intern Med ()1(,?-/+0:(-(3()-, #@perimental studies on the effect of temporar%
occlusion of coronar% arteries, 6he production of m%ocardial infarction$ American &eart 'ournal ()1( A++,I.
3.*13.-)0

/()4(0 Miller and colleagues pointed out that subendocardial infarcts 8ere rarel% associated 8ith
coronar% thrombi.

/M%ocardial infarction 8ith and 8ithout acute coronar% occlusion: A pathologic stud%. AMA Arch Intern
Med ()4(,--/40:4)*3?210

Coronary Thrombosis: Cause or Consequence
of Myocardial Infarction?

/()?20 Spain and !radess found complete coronar% obstruction of atherosclerotic

nature$ representing around of *4B of the cases and recent coronar% thrombosis
in just +4B of the autopsied cases. Also$ the% have observed crescent incidence
of coronar% thrombosis 8ith the crescent duration of survival after the
m%ocardial infarction. :ess than a hour 8ith (?B of thrombosis$ bet8een ( and
+1 hours 8ith .*B and in more than +1 hours 8ith 4+B of coronar%
thrombosis.

/Spain$ <M and !radess AA. 6he relationship of coronar% thrombosis to coronar%
atherosclerosis and ischemic heart disease C a necrops% stud% covering a period of +4 %ears$
Am ' Med Sci$ +12:*3($ ()?2, Spain <M and !radess AA. Fre9uenc% of coronar%
thrombosis related to duration of survival from onset of acute fatal episodes of m%ocardial
ischemia. Circulation$ ++:-(?$ ()?20
Coronary Thrombosis: Cause or Consequence
of Myocardial Infarction?

/()*20 &ellstrom demonstrated e@perimentall% the coronar% thrombosis secondar% to

acute m%ocardial infarction caused b% ligature of the coronar% arter%.

/&ellstrom$ &D. M%ocardial infarction as a cause of coronar% thrombosis. Circulation$ 1+$ Suppl.
III0, (?4$ ()*20

/()*+0 Eilliam Doberts suggested that the coronar% arterial thrombi are conse9uences
rather than causes of acute m%ocardial infarction. In his stud% involving (2* patients
8ho 8ere submitted to necrops% he found that onl% 41B of those 8ith a transmural
infarction$ and onl% (2B of those 8ith subendocardial necrosis$ had a thrombus in the
infarct related arter%.

/Fre9uenc% of coronar% thrombosis related to duration of survival from onset of acute fatal
episodes of m%ocardial ischemia$ Circulation$ ++:-(?$ ()?2, Doberts$ E.C.:, Coronar% arteries in
fatal acute m%ocardial infarction$ Circulation$1+:+(4$ ()*+$ Doberts E. C.0
Coronary Thrombosis: Cause or Consequence
of Myocardial Infarction?

/()-20 <eEood and colleagues demonstrated the prevalence of total coronar%

occlusion during the earl% hours of transmural infarction b% means of coronar%
arteriograph%. 6heir results 8ere accepted b% the cardiolog% communit% as the
definitive clinical evidence about the causal role of thrombosis in acute m%ocardial
infarction.

/<eEood MA$ Spores '$ Fots5e D et al. Prevalence of total coronar% oclusion during the earl%
hours of transmural m%ocardial infarction. F #ngl ' Med ()-2,.2.:-)*3)2+0

/())?0 Guintiliano &. de Mes9uita pointed out that the interpretation given b%
<eEood about the angiographic image$ suggestive of intracoronar% thrombus$ do not
correspond to the absolute realit% 8hether it represents a true thrombus or just
aggregated platelets that are precocious$ unstable or reversible commonl% registered
in the first hours of unstable angina and in the course of the acute m%ocardial
infarction.

/!oo5: DemHdio boicotado substitui cirurgia de ponte de safena$ Compset$$ ())?0

Coronary Thrombosis: Cause or Consequence
of Myocardial Infarction?

/+2240 "iorgio !aroldi and colleagues$ discussing the findings from <eEood$ told that the first
main 9uestion is ho8 man% of the -*B cineangio occlusion are pseudo3occlusion and 8hether
the Ila%eredI thrombus recovered at b%pass surger% 8as a true thrombus or a coagulum 8hich
fre9uentl% sho8 a la%ering of blood elements not seen in thrombus formation. Also sa%ing that
IDedI thrombus$ namel% a coagulum$ is fre9uentl% and erroneousl% considered as thrombus.

In another paper from the same %ear the% sa% that the fre9uenc% of an occlusive thrombus is
significantl% higher in the largest infarcts supporting its secondar% formation.

/!aroldi "$ !igi D$ Cortigiani :: Jltrasound imaging versus morphopatholog% in cardiovascular diseases:
coronar% collateral and m%ocardial ischemia. Cardiovasc Jltrasound +224$ .:?, "iorgio !aroldi$ Diccardo
!igi and :auro Cortigiani. Jltrasound imaging versus morphopatholog% in cardiovascular diseases.
M%ocardial cell damage. Cardiovascular Jltrasound .:.+.$ +2240
Coronary Thrombosis: Cause or Consequence
of Myocardial Infarction?

/+22(0 In a significant number of cases angioscopic e@amination continues to find thrombus

on the presumed culprit lesion$ at ? months after m%ocardial infarction.

/Kasunori Jeda$ Masanori Asa5ura$ et al. +22(. 6he healing process of infarct3related pla9ue: Insights
from (- months of serial angioscopic follo83up. Am Coll Cardiol$ .-:()(?3()++.0

/())-0 Mura5ami and colleagues from 'apan using intracoronar% catheters to aspirate
occlusive tissues$ performed during the acute m%ocardial infarction$ have confirmed the
pathological findings that intracoronar% thrombus is absent in a substantial number of patients
indicating it contributes little to the pathogenesis of average acute m%ocardial infarction.

/Mura5ami 6. Intracoronar% aspiration thrombectom% for acute m%ocardial infarction$ Am. ' Cardiolog%
())- ;ct (,-+/*0:-.)3110
Coronary Thrombosis: Cause or Consequence
of Myocardial Infarction?

/+2240 Dittersma and colleagues e@amined retrieved thrombus material aspirated using the
percutaneous thrombectom% catheter in +(( patients undergoing primar% percutaneous
coronar% intervention 8ithin si@ hours of s%mptom onset. 6he% then established$ b%
histological indicators$ the age of the aspirated thrombi. 6he researchers found thrombus in
()) of the +(( patients$ of 8hom fresh thrombus 8as identified in just under half. !% contrast$
4(B of patient samples contained thrombus that had l%tic or organiLed changes suggesting
that it had originated da%s or 8ee5s before the occlusive event. 6he% said that 7Stri5ingl%$
clinical characteristics did not differ bet8een the patients 8ith fresh thrombus and those 8ith
MolderN thrombus$ although men 8ere more li5el% to have fresh thrombus than 8ere 8omen.=

/Dittersma SO&$ van der Eal AC$ >och >6$ et al. Pla9ue instabilit% fre9uentl% occurs da%s or 8ee5s
before occlusive coronar% thrombosis. A pathological thrombectom% stud% in primar% percutaneous
coronar% intervention. Circulation +224, (((:((?23((?4
Coronary Thrombosis: Cause or Consequence
of Myocardial Infarction?

6he PASSI;F trial$ recentl% published$ found that the use of thrombus aspiration in
adjunct to primar% percutaneous coronar% intervention /PPCI0 did not affected rates
of major adverse cardiac events at + %ears follo83up$ as compared 8ith convencional
PPCI. So$ based in this stud%$ it is fair to sa% that thrombus aspiration do not prevent
the occurrence of the m%ocardial infarction.

Martin A Ain5$ Maurits 6 <ir5sen$ et al. :ac5 of long3term clinical benefit of thrombus
aspiration during primar% percutaneous coronar% intervention 8ith paclita@el3eluting stents or
bare3metal stents: Post3hoc anal%sis of the PASSI;F trial. CatheteriLation and Cardiovascular
Interventions$ ( Ma% +2(+,Aolume *): Issue ?$ pages -*23-**
Coronary Thrombosis: Cause or
Consequence of Myocardial Infarction?

M%ocardial infarction associated 8ith normal coronar% arteries is a 8ell 5no8n

condition. 6he overall prevalence rate of m%ocardial infarction 8ith normal
coronar% arteries is considered to be lo8$ var%ing from (B to (+B depending on
the definition of Inormal7 coronar% arteries.

/:egrand A$ <eliege M$ &enrard :$ !oland '$ >ulbertus &: Patients 8ith m%ocardial
infarction and normal coronar% arteriogram. Chest ()-+$ -+/?0:?*-3?-4, Da%mond D$ :%nch
'$ Jnder8ood <$ :eatherman '$ DaLavi M: M%ocardial infarction and normal coronar%
arteriograph%: a (2 %ear clinical and ris5 anal%sis of *1 patients. ' Am Coll Cardiol ()--$
((/.0:1*(31**.0
Coronary Thrombosis: Cause or
Consequence of Myocardial Infarction?

/()).0 Arbustini and colleagues found in a series of (.+ autopsies of hearts from
patients 8ho died of noncardiac causes$ that coronar% thrombi 8ere sho8n to
overla% the intima of a coronar% vessel independentl% of pla9ue t%pe and
severit%.

Arbustini #$ "rasso M$ <iegoli M$ et al. Coronar% thrombosis in non3cardiac death. Coron

Arter% <is ()).,1:*4(C).
Coronary Thrombosis: Cause or
Consequence of Myocardial Infarction?

A recent 7State3of3the3Art= revie8 and commentar% published at the 'ournal of

the American College of Cardiolog% made the follo8ing conclusion:

7A large bod% of evidence conclusivel% suggests that coronar% arter% obstruction

is onl% ( element in a comple@ multifactorial pathoph%siological process that
leads to Ischemic &eart <isease /I&<0 and that the presence of obstructive
lesions in patients 8ith I&< does not necessaril% impl% a causative role. A more
comprehensive approach seems necessar% to refocus preventive and therapeutic
strategies and to decrease morbidit% and mortalit%. 6o this effect$ 8e propose a
shift in approach to include the m%ocardial cell as 8ell as the coronar% vessel=

Mario MarLilli$ C. Foel !aire% MerL$$ Eilliam #. !oden$ Dobert ;. !ono8$

Paola ". CapoLLa$ Eilliam M. Chilian$ Anthon% F. <eMaria$ "iacinta "uarini$ Alda &u9i$
<oralisa Morrone$ Manesh D. Patel$ Eilliam S. Eeintraub. ;bstructive coronar%
atherosclerosis and ischemic heart disease: An elusive lin5P. 'ACC Aol ?2$ Fo. (($ +2(+,
September ((: )4(3?
Prof. Dr. uintiliano !. de Mesquita"
#ra$ilian Cardiologist and Scientist
;ne of the major developments of <octor Mes9uita 8as the
M%ogenic 6heor% of M%ocardial Infarction$ from ()*+. 6he
M%ogenic 6heor% supports the use of cardiac gl%cosides
/cardiotonics0 for the prevention and clinical treatment of acute
coronar% s%ndromes. Among other developments are the
Aentricular Aneurism Surger% of the &eart performed b% Charles
!aile% in ()41 and the first diagnosis of Dight Aentricular
Infarction$ in vivo$ b% #C"$ made in ()4-. /&e did more than .2
pioneer contributions to medical literature0
Dr. Mesuita deceased in !""" #ith $! years old
&is memorial is at the follo8ing 8ebpage:
http://888.infarctcombat.org/9hm/homepage.html
Introduction and %undamentals
of the Myogenic Theory

6he coronar% atherosclerosis and slo8 coronar% flo8 in the normal e@tramural coronaries develop
m%ocardial ischemic process through the imbalance bet8een demand and blood suppl% to the
m%ocardial segments$ dependent on the right and left coronar% arteries. !asicall%$ the large e@tramural
coronar% arteries are responsible for nutrition of the segmental m%ocardium and mainl% b% the
contractile balance of each segment of the ventricular 8all.

#ver% time 8hen is developed a relative coronar% insufficienc% through ph%sical or ps%cho3emotional
stress results in an immediate loss of contractilit% of the ischemic area and simultaneous e@altation of
other unaffected contractile ventricular segments.

6he continuit% of such repetitive ischemic manifestations tend to contribute to the installation of
nons%nergic segments$ b% ischemia Q loss of contractilit% and overload imposed b% the remaining
intact ventricular segments$ during the ventricular ejection phase.

6hus$ the coronariopath% contributes to the deterioration of the ventricular segment$ constituting areas
of m%ocardiosclerosis or segmental m%ocardial disease$ possible future site of the m%ocardial
infarction.

!oo5 7M%ogenic 6heor% of M%ocardial Infarction=$ ()*).

Myogenic Theory Mechanism
The sequence of events

Coronary Atherosclerosis

Slo8 Coronar% Flo8

Stable Angina Pectoris C Silent Coronariopath%

(3 Delative M%ocardial Ischemia

+3 Deciprocal Contractile :oss

Ph%sical and Ps%cho3#motional Stress Factors

/ or

Pharmacological Factors 3 Fegative Inotropic Agents

Segmental Myocardial Disease

Myogenic Theory Mechanism
The sequence of events

Segmental Myocardial Disease

Jnstable Angina/ Intermediate S%ndrome

Infarcting Clinical Pictre

(3 Degional M%ocardial Insufficienc%

+3 Deciprocal M%ocardial Ischemia

Primar% M%ocardial Fecrosis

!Infarction"

Coronar% Stasis or Fragmentation and

<isplacement of Atheromatous Pla9ue b% #dema

Secondar% Coronar% 6hrombosis

/Fot ;bligator%0

&''ro'riated terms to the myogenic
theory of myocardial infarction

6he term 7coronar%= has become s%non%mous 8ith ischemia and it is used to
define an atherosclerotic occlusive lesion that is believed to be responsible for
all clinical patterns.

So$ inside the sense of the m%ogenic theor% of m%ocardial infarction I 8ill ta5e
the libert% to use some terms more ade9uated to it li5e 7coronar%3
cardiom%opath%= or 7coronar%3m%ocardial disease= rather coronar% heart
disease$ coronar% arter% disease and= acute m%ocardial s%ndromes= rather acute
coronar% s%ndromes.
Stress and acute myocardial syndromes

Several studies have sho8n a close connection bet8een catecholamine and

m%ocardial infarction. 6he h%peractivit% of the s%mpathetic nervous s%stem$ 8ith
an intense outflo8 of catecholamines /adrenaline/epinephrine and
noradrenaline/norepinephrine0 also occur in unstable angina$ alternativel% called
preinfarction angina or intermediate s%ndrome$ being smaller and less long than in
acute m%ocardial infarction. 6a5otsubo cardiom%opath%$ also 5no8n as bro5en
heart s%ndrome$ a sudden temporar% 8ea5ening of the m%ocardium$ 8hich
simulates an evolving m%ocardial infarction clinical picture$ li5e8ise has am
intense outflo8 of catecholamines.

/Increased cardiac s%mpathetic nervous activit% in patients 8ith unstable coronar% heart
disease$ McCance A'$ 6hompson PA$ Forfar 'C. #ur &eart ' ()). 'un,(1/?0:*4(3* ,
S%mpathetic neural h%peractivit% and its normaliLation follo8ing unstable angina and acute
m%ocardial infarction$ "raham :F$ Smith PA et al. Clin Sci /:ond0 +221 'un,(2?/?0:?243((0
Stress: The main ris( factor for &cute
Myocardial Syndromes

Acte stress !or stress o#erload"

!e%ond intense ph%sical activit%$ particularl% in sports competition$ or unusual

efforts$ surpassing the limits of his/her heart conditions$ or else the heav% use of
stimulant drugs$ there are man% ris5 factors for acute m%ocardial s%ndromes$
based on recent severe stress situations or sudden emotional stress$ li5e:

Marital separation or divorce$ loss of 8or5 or retirement$ loss of revenue or

business failure$ important famil% conflicts$ important personal injur% or illness$
death or illness of a close famil% member$ shoc5 of a surprise part%$ armed
robber% or other 5ind of violence$ heated discussion$ threats or acts of 8ar$
earth9ua5es$ to trac5 the team of preference in matches live football$ etcS
Cardiotonic: The com'atible drug )ith
the Myogenic Theory

6he recent discover% of endogenous cardiotonic hormones /digitalis$ strophanthin$ proscillaridine$ etc..0$ isolated from
human tissues and bod% fluids$ ma% represent a strong ne8 argument for the m%ogenic theor% of m%ocardial infarction.

An elevated concentration of endogenous cardiotonics have been found under different conditions such as sodium
imbalance$ h%pertension$ cardiac arrh%thmias$ chronic renal failure$ congestive heart failure and acute m%ocardial infarction.
Aigorous ph%sical e@ercises as 8ell ph%siological stress situations ma% also elevate the concentration of endogenous
cardiotonics in the bod%.

Ee thin5 the cardiotonics found in nature ma% complement a deficient production of endogenous cardiotonic hormones
produced b% the human bod% and thus support cardiac metabolism and protect the heart from the infarction$ as proposed in
M%ogenic 6heor%.

T#o uotes related to these findings%

The diseased heart is avid for cardiotonics

&uintiliano '. de Mesuita, ())*

Cardiotonics are the insulin for cardiovascular disease

+arlos Monteiro, !"",

The use of cardiotonics for coronary
heart disease during the *+th century

/()(+0 'ames &erric5: Proclaimed the m%ocardial infarction /MI0 as conse9uence

of coronar% thrombosis and cardiotonics /digitalis and strophanthin0 as the best
therap%. &e declared: I6he timel% use of this remed% ma% occasionall% save
liveI.

/()+?0 :ouis &amman: Shared in same concepts and enthusiasm of &erric5

regarding the use of cardiotonics to treat the MI. &e said: I6he patient should be
promptl% and full% digitaliLed... not onl% is the digitaliLed heart better prepared
to 8ithstand the added burden of certain arrh%thmias should the% come on$ but it
is also stimulated to put forth its better efforts. &o8 desirable the best efforts
ma% be 8hen a large area of heart muscle is infarcted$ needs no further commentI

/'AMA$4): +2(4$ ()(+ , !ull 'ohns &op5ins &osp., .-: +*.$ ()+?0
The use of cardiotonics for coronary
heart disease during the *+th century

/().10 #rnst #dens: After . %ears using strophanthin b% intravenous 8a% in

angina pectoris and MI in more than (22 patients he declared: I Subse9uentl% to
the recognition of the strophanthin as the best and safest medicine for the
m%ocardial infarction 8e donTt have the right to use it in a patient onl% for
scientific reasons and tests$ giving preference to other remedies losing precious
time for the cureI. &e also told that 8ill come the moment in 8hich the omission
of the use of strophanthin 8ould be seen as a professional malpractice.

/Munchener MediLinischen Eochenschrift, .*$ ().10

The use of cardiotonics for coronary
heart disease during the *+th century

/()420 Ferdinand D. Schemm: PreconiLed the use free from restraint of digitalis for MI treatment.
&e used digitalis in +?4 patients recording a mortalit% of (2B. In practice he noticed that instead
of an% m%ocardial damages$ the cardiotonic presented compatibilit% 8ith the acute m%ocardial
infarction$ reason of salutar% effects and lo8er mortalit%.

/()4(0 'ohn Martin As5e%: Applied digitalis in 42 consecutive patients 8ith acute MI. Citing the
results achieved b% Schemm 8ith digitalis refers that the medical profession 8as unable to ta5e
full advantage of this valuable drug$ offering the &enr% 6horeau thought: IIt is never too late to
give up our prejudices. Fo 8a% of thin5ing ho8ever ancient$ can be trusted 8ithout proofI. 6his
affirmation from As5e% 8as stated during the presentation about his results and to appreciate the
clinical and e@perimental proceedings realiLed at that time. :i5e8ise he demonstrated a health%
apprehension in front of the accommodation and disinterest regarding so e@citing theme.

/Postgrad Med., .-4$ ()42, 'AMA, (1?: (22-$ ()4(0

The use of cardiotonics for coronary
heart disease during the *+th century

/()440 Forman &. !o%er: Mentioned that after an une@pected but fortunate e@perience
using digitalis b% intravenousl% 8a% ceased his fear about the use of digitalis appl%ing it
starting from this moment in a se9uence of 42 patients 8ith MI.

/()*20 !erthold >ern: Erote that he used sublingual strophanthin in more than (4.222
cardiac patients during the period of ()1* till ()?- resulting in a ver% lo8 mortalit% rate
and fe8 m%ocardial infarctions.

/Fe8 #ngland '. Med, +4+: 4.?$ ()44, <er M%o5ard3Infar5t. &aug Aerlag. &eidelberg$ ()*20
The use of cardiotonics for coronary
heart disease during the *+th century

/()*+0 Guintiliano &. de Mes9uita: Advocated that treatment 8ith cardiotonics should
be started the earliest possible in order to correct the regional m%ocardial collapse in
progress. &e also stated that cardiotonic administration protects the m%ocardial fibers
in collapse$ ischemic$ but viable to be 5ept from the necrosis 8hich 8ould certainl%
occur in case of non3use of this remed%. Surpassing the acute period$ the cardiotonic
should be used$ according him$ as a maintenance treatment$ 8hich blends 8ith the MI
proph%la@is$ in order to defend the ischemic m%ocardium in its functional side. <uring
* %ears applied cardiotonics b% intravenousl% 8a% /digitalis and strophanthin0 in ((-.
patients 8ith acute MI$ recording a survival of almost )2B. Professor Mes9uita 8as
a8arded in ()*4 8ith the #rnst #dens 6raditionspreis b% the International Societ%
Against M%ocardial Infarct located in Stuttgart3 "erman%.

/Mes9uita$ G& <e: Angina de esforUo e sVndrome de enfarte miocWrdico iminente: aspectos
sintomWticos dependentes de insuficiXncia miocWrdica regional. Fota prHvia. 6rabalho
apresentado ao YYAIII Congresso !rasileiro de Cardiologia$ Curitiba /PD0$ 'ulho de ()*+0
The use of cardiotonics for coronary
heart disease during the *+th century

/()*10 Pritpal Puri have demonstrated that the intermediate h%pocontractile area
bet8een the infarction and normal m%ocardium responded to the cardiotonic
Strophanthin maintaining normal contractilit% starting from the the m%ocardial
ischemia and h%pocontractilit%.

/()*40 !an5a and col$ confirmed the e@periments from Puri using <igitalis and
recording the same results.

/Pritpal S Puri. Modification of e@perimental m%ocardial infarct siLe b% cardiac drugs$ Am

' Cardiol$ .. :4+$ ()*1, !an5a$ AS$ !odenheimer$ MM$ &elfant$ D& e Chadda$ ><:
<igitalis in e@perimental acute m%ocardial infarction. <ifferential effects on contractile
performance of ischemic$ border and nonischemic ventricular Lones in the dog$ Am '
Cardiol$ .4:-2($ ()*40
The use of cardiotonics for coronary
heart disease during the *+th century

/()*40 PiLarello et al and Morrison et al in ()*? have sho8n the serial enL%matic
reactions using digitalis the infarction 8as halted and$ thus$ the cardiotonic might
be considered as able to rescue the viable m%ocardial fibers.

/()-20 Morrison et al confirmed no change in serial creatinine M! isoenL%me in a

group of patients 8ith heart failure after m%ocardial infarction ta5ing digitalis$ in
contrast 8ith past observations made in animals follo8ing coronar% arter% ligation$
8hich have sho8n an e@tension of the area of infarction after digitalis
administration.

/PiLarello D$ Deduto :$ "eller >$ "ullota S$ Morrison ' C Protection of the ischemic
m%ocardium in man b% digitalis. Circulation ()*4, 4(34+ /suppl III0: -)4, Morrison '$
PiLarello D$ Deduto :$ "ullota S C #ffect of digitalis on predicted m%ocardial infarct siLe.
Circulation ()*?, 4.341 /Suppl II0: (2+, Morrison '$ Coromilas '$ Dobbins M et al C
<igitalis and m%ocardial infarction in man. Circulation ()-2, ?+: -3(?0
The use of cardiotonics for coronary
heart disease during the *+th century

/()-20 Peter Schmidsberger$ medical journalist: Deport the results obtained b% Professor
Mes9uita in !raLil informing that Dolf <orhman from the !erliner Eald5ran5enhauses in
!erlin 3 "erman%$ achieved during 4 %ears similar results of the !raLilian professor
appl%ing the same treatment 8ith strophanthin during the acute m%ocardial infarction.

/()).0 Giao <D told that from the hemod%namic studies the beneficial effect of cedilanid
is greater than its adverse effect$ concluding that digitalis can be safel% and effectivel%
used in the treatment of AMI.

/In 6his Manner a !raLilian Fights Against 6he Infarction I3 !JF6# magaLine$ ;ffenburg C
"erman%, D.#.<ohrmann, &.<.'anisch Z M.>essel: >linisch3poli5linische Studie [ber die
Eir5sam5eit von g3Strophanthin bei Angina pectoris und M%o5ardinfar5t$, Cardiol !ull
/Cardiologisches !ulletin0 (1/(4: (-.3(-*$ ()**, Giao <D. A stud% on the hemod%namic effect of
cedilanid in the treatment of acute m%ocardial infarction$ Ohonghua Yin Yue "uan !ing Oa Ohi.
()). Apr,+(/+0:-.310
The use of cardiotonics for coronary
heart disease during the *+th century

/())40 :eor ' and colleagues found in patients recovering from m%ocardial
infarction that one %ear mortalit% 8as significantl% higher among patients treated
8ith a full dose \() of ((+ /(*B0] than patients treated 8ith a lo8 dose of
digo@in \( of 1( /+B0]

/:eor '$ "oldbourt J et al. <igo@in and increased mortalit% among patients recovering from
acute m%ocardial infarction: importance of digo@in dose$ Cardiovasc <rugs 6her ())4
;ct,)/40:*+.3)0
,ld citations about the use of digitalis in
heart disease

- #ish it #as as easy to #rite upon the Digitalis . - despair of pleasing myself
or instructing others in a sub/ect so difficult. -t is much easier to #rite upon a
disease than upon a remedy. The former is in the hands of nature and a faithful
obser0er #ith an eye to tolerable /udgment can not fail to delineate a li1eness2
the latter #ill e0er be sub/ect to the #hims, the inaccuracies and the blunders of
man1ind". 3illiam 3ithering, 4etter, Sep !), (**$

Digitalis% A 5od6gi0en remedy7 by 8riedrich 4ud#ig Kreysig . 9erlin, ($(:

Digitalis% The opium of the heart7 by ;ean 9aptiste 9ouillaud . <aris, ($:(
Dissociation bet)een the severity of
stenosis and the ris( of infarction

6he ris5 of a heart attac5 or other acute m%ocardial events is not proportional to the
severit% of coronar% stenosis. Several studies in 8hich more than one angiograph% 8as
performed in patients 8ho developed acute s%ndromes sho8ed that most of these
s%ndromes appear to be developed from lesions that on the first angiograph% caused
not significant stenosis. 6hese less severe stenotic lesions lead to m%ocardial infarction
because the% have not developed a sufficient collateral circulation around that 8ould
prevent or limit the e@tent of m%ocardial necrosis. 6his means that a .2B reduction in
arterial caliber ma% have an increased ris5 for a m%ocardial infarction than an
obstruction )2B.

/Ambrose ' A$ 6annenbaum M A et al$ Angiographic progression of coronar% arter% disease and
the development of m%ocardial infarction$ ' Am Coll Cardiol ()--, (+:4?3?+, :ittle E C et al$
Can coronar% angiograph% predict the site of a subse9uent m%ocardial infarction in patients 8ith
mild to moderate coronar% arter% disease^$ Circulation ()--, *-:((4*3??, 'ohn A Ambrose$
Aalentin Fuster$ 6he ris5 of coronar% occlusion is not proportional to the prior severit% of
coronar% stenoses$ #ditorial$ &eart ())-, *):.310
Collateral circulation and infarction

<r. Guintiliano de Mes9uita$ said in his boo5 IM%ogenic 6heor% of M%ocardial Infarction$ ()*):

"The collateral coronary circulation is absolutely pre0alent in cases of total obstruction of the
coronary artery. 'e also told% "The net of coronary collateral circulation is not al#ays able to
pre0ent myocardial infarction, because it de0elops depending on the anatomical features of the
obstructi0e process, and is not al#ays sufficient to face the demands of the physical acti0ity of the
coronary patient. The role of the cardiotonic is to complete the effects of collateral circulation and
ensure functional preser0ation of the ischemic myocardium, thus a0oiding the infarction."

A recent meta3anal%sis confirmed that heart disease patients 8ith a 8ell3developed collateral
coronar% circulation have an improved survival compared 8ith patients 8ith less developed
collaterals.

Meier P$ &eming8a% &$ :ans5% A'$ et al. 6he impact of the coronar% collateral circulation on mortalit%: a meta3
anal%sis. #ur &eart ' +2((, <;I: (2.(2)./eurheartj/ehr.2-
Cardiotonic -ffects and Stress
In m% vie8$ in addition of positive inotropic effects over the heart muscle contractilit%$
cardiotonics ma% also have possible benefic effects for cardiovascular disease$
including in halting acute m%ocardial s%ndromes$ through the reduction of heightened
catecholamine levels in blood and in reduction of the resulting elevated lactate
production and accumulation b% the cardiac muscle.

/Schobel &P et al. ())(. Contrasting effects of digitalis and dobutamine on barorefle@
s%mpathetic control in normal humans$ Circulation A-1$ (((-3((+),

M "heorgiade and < Ferguson$ ())(. <igo@in: A neurohormonal modulator in heart failure^
-1: +(-(3+(-?, "utman K$ !oon%aviroj P. Faun%n Schmiedebergs. ()**. Mechanism of
inhibition of catecholamine release from adrenal medulla b% diphen%lh%dantoin and b% lo8
concentration of ouabain /(2 /3(20 M0. Arch Pharmacol Feb,+)?/.0:+).3?0, Schade <S. 6he
role of catecholamines in metabolic acidosis. Ciba Found S%mp. ()-+,-*:+.434.0
The cardiotonic use in stable coronary.
myocardial disease

6he m%ogenic theor% recommends the use of the cardiotonic Q coronar% dilator in
stable coronar% m%ocardiopath%$ 8ith or 8/out previous infarction in the long run$
complementing the beneficial and protective effects of collateral coronar%
circulation in front of severe coronar% obstructions.

In short$ according the m%ogenic theor%$ cardiotonics are the anti3infarction

drugs.

#@cerpts from the paper from Mes9uita G&de et al #ffects of the Cardiotonic Q Coronar%
<ilator in Chronic Stable Coronar%3M%ocardial <isease$ 8ith and 8ithout Prior M%ocardial
Infarction$ in the :ong Dun=$ Ars Cvrandi +22+ /setembro0,.4:*. 6e@t available at the
follo8ing 8ebpage: http://888.infarctcombat.org/CM<3C#.pdf
The cardiotonic use in stable coronary.
myocardial disease
<r. Mes9uita and colleagues sa% that the follo8ing effects should be highlighted from the
uninterrupted use of cardiotonic Q coronar% dilator in chronic stable coronar%3m%ocardiopath%$
8ith or 8/out previous m%ocardial infarction:

6o counteract the negative inotropic effects of ischemia,

6o preserve the ventricular function$ leveling over the ischemic segments 3 contractile deficient 3
8ith non3ischemic segments$ annulling the deleterious segmental confrontation,

6o prevent Jnstable Angina$ M%ocardial Infarction$ &eart Failure and Sudden <eath 3
s%mptomatic and m%ocardial instabilit%$ ensuring permanent state of stabilit%,

6o Increase and to provide peaceful survival$ comfortable and long$ predominantl%

as%mptomatic$ in front of the common efforts and according to the achieved parameters.
Again, they ha0e said that the coronary collateral circulation has its role in the fate of coronary
artery disease and represents the compensatory reinforcement of the "=ature", complemented by
the cardiotonic, in the preser0ation of myocardial contractility.7
The cardiotonic use in stable coronary.
myocardial disease

In a paper published in +22+$ Guintiliano Mes9uita and his assistant$ ClWudio

!aptista$ have prospectivel% anal%Led data from a period of +- %ears /()*+ 3
+2220 using cardiac gl%cosides at lo8 concentration /lo8 dose0 in patients 8ith
stable coronar% arter% disease 8ith or 8ithout previous infarction . 6heir results
have sho8ed ver% lo8 rates in mortalit% and morbidit%. 6he patients 8ere
divided in t8o groups...

Cardiotonic: Insuperable in preservation of m%ocardial stabilit%$ as preventive of acute

coronar% s%ndromes and responsible for a prolongued survival. Casuistr% of +- %ears /()*+3
+2220=$ Guintiliano &. de Mes9uita e ClWudio A S !aptista$ Ars Cvrandi +22+ /maio0, .4:. .
6e@t available at the follo8ing 8ebpage:
http://888.infarctcombat.org/+-%ears/digitalis.html
The cardiotonic use in stable coronary.
myocardial disease
The first gro$ inclded %%& $atients '(ot $rior infarction, $resenting in 2)
years the follo'ing mor*idity and mortality+

3 M%ocardial infarction: (1 cases /(.1B0

3 &eart failure: .4 cases /..4B0

3 &eart failure mortalit%: .+ cases /..+B0

3 Sudden <eath: *+ cases /*.+B0

3 Stro5e mortalit%: (. cases /(..B0

3 Cancer mortalit%: (1 cases /(.1B0

3 ;ther causes of mortalit%: (( cases /(.(B0

3 6otal Mortalit%: (1+ cases /(1.+B0 3 /2.4B per %earP0

3 Mean Age at <eath: *? %ears

The cardiotonic use in the stable
coronary.myocardial disease
The second gro$ inclded 1,- $atients 'ith $rior infarction, $resenting in 2) years
the follo'ing mor*idity and mortality+

3 De3infarction: - cases /4.(B0

3 &eart failure: (* cases /(2.-B0

3 &eart failure mortalit%: (* cases /(2.-B0

3 Sudden <eath: .( cases /+2.4B0

3 Stro5e mortalit%: * cases /1.1B0

3 Cancer mortalit%: . cases /(.)B0

3 ;ther causes mortalit%: 4 cases /..+B0

3 6otal Mortalit%: ?1 cases /12.-B0 3 /(.14B per %earP0

3 Mean Age at <eath: *+ %ears

The cardiotonic use in stable coronary.
myocardial disease

Permanent Thera$etic Maintenance

Cardiotonics em$loyed+

Proscillaridin3A 2.*43(.42mg/da%

Acetildigo@in 2.42mg/da%

:anatoside3C 2.42mg/da%

<igito@in 2.(mg/da%

<igo@in 2.(+432.+4mg/da%

!etamethildigo@in 2.(232.+2mg/da%

Coronary dilators + Calcim antagonists+

Aerapamil (+23+12mg/da%

Prenilamine (+23(-2mg/da%

Fifedipine +23.2mg/da%

Fendiline (223(42mg/da%

<iltiaLem )23(-2mg/da%

6e@t available at http://888.infarctcombat.org/CM<3C#.pdf

The cardiotonic use in the
unstable angina

6he m%ogenic theor% recommends the use of the cardiotonic Q coronar% dilator
in the treatment of unstable angina$ for correction of regional m%ocardial
insufficienc%$ presented as the determinant factor in the pathoph%siological
mechanism of this alarming clinical s%ndrome$ usuall% characteriLing the pre3
infarction.

#@cerpts from the article of Mes9uita G&de et al 7#ffects of the Cardiotonic Q Coronar%
<ilator in Jnstable Angina= 6e@t available at the follo8oing 8ebpage:
http://888.infarctcombat.org/JA3C#.pdf
The cardiotonic use in the
unstable angina

.eslts

Perfect drug tolerance.

Immediate disappearance of spontaneous anginal episodes since the first injection

and in a short3term follo8ing the administration of the drug b% oral route.

Interruption of unstable angina in ()) pts,

;nl% ( case evolved to m%ocardial infarction in the eighth da%.

Fo deaths.

#C" alterations 8ith rapid disappearance.

Arrh%thmic benign transitional manifestations /+2.4B0.

Mild enL%matic changes in the first +1 hours.

The cardiotonic in the
unstable angina

Thera$etic attac/ of nsta*le angina dring - days

Cardiotonics+

Strophanthin3> : 2.+432..1 mg/da%$ IA

Strophanthin3" : 2.+432.42 mg/da%$ IA

:anatoside3C : 2.12 mg/da%$ IA

<igo@in : 2.42 mg/da%$ IA

Methildigo@in : 2.+232..2 mg/da%$ P;

Proscillaridin3A : (.423+.2 mg/da%$ P;

Coronary dilators+

<ipiridamol : +2 mg/da%$ IA

Aerapamil : +12 mg/da%$ P;

Prenilamine : (-2 mg/da%$ P;

Fifedipine : .2 mg/da%$ P;

6he strophanthin > or " /IA0 8as emplo%ed in (42 patients$ <igitalis /IA0 in .2 patients and$ e@ceptionall%$
b% oral route$ Methildigo@in in ( patient and Proscillaridin3A in (- pts.

IA: Intravenous route P;: ;ral route

The cardiotonic use in the
infarcting clinical 'icture

0hy infarcting clinical $ictre1

!ecause 8ith the use of cardiotonics the m%ocardial infarction can be halted as
occurred in ?..4B of the cases as sho8n in the studies b% <r. Mes9uita.

Mes9uita G&de et al 7#ffects of the Cardiotonic Q Coronar% <ilator in the Infarcting

Clinical Picture7. 6e@t available at the follo8ing 8ebpage
http://888.infarctcombat.org/ICP3C#.pdf
The cardiotonic use in the
infarcting clinical 'icture
.eslts

Absolute tolerance from the drug

Deduction in administration of analgesics and narcotics

:o8 incidence of cardiac arrh%thmias

:o8 incidence of cardiac insufficienc%

:o8 incidence of cardiogenic shoc5

Delative lo8ering of enL%matic reaction pea5s

:o8 mortalit%

Clinical picture more calm and safe

The cardiotonic use in the
infarcting clinical 'icture

Thera$etic attac/ of the infarctioning clinical $ictre dring - days

Cardiotonics:

Strophanthin3> : 2.+432..1 mg/da%$ IA

Strophanthin3" : 2.+432.42 mg/da%$ IA

:anatoside3C : 2.12 mg/da%$ IA

<igo@in : 2.42 mg/da%$ IA

Coronar% dilators:

<ipiridamol : +2 mg/da%$ IA

Aerapamil : +12 mg/da%$ P;

Prenilamine : (-2 mg/da%$ P;

Fifedipine : .2 mg/da%$ P;

6he strophanthin > or " /IA0 8as emplo%ed in )?+ patients$ and digitalis /IA0 in (1* patients$ during the first phase of treatment.

IA: Intravenous route P;: ;ral route

The cardiotonic use in the
infarcting clinical 'icture

.eslts !Indices of clinical com$lications"+

2 Aentricular e@tras%stoles: +1.(B

3 Partial AA bloc5: 4.-B
3 Complete AA bloc5: 1.?B
3 Atrial tach%cardia: (.*B
3 Flutter 3 Atrial fibrillation: 1.1B
3 6ach%cardia Q Aentricular Fibrilation: +.*B
3 As%stole: 1.4B
3 Cardiogenic shoc5: +B
3 Acute pulmonar% edema: (..B
3 &eart failure: (B
3 ;verall mortalit%: (+.+B
3 Mortalit% b% age: ).1B in patients under *2 %ears and +?.?B in patients over *2
%ears
#oo( Myogenic Theory of Myocardial Infarction
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/ideo and Po)er'oint 'resentations on the
Myogenic Theory of Myocardial Infarction

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