The The MyogenicMyogenic TheoryTheory ofof MyocardialMyocardial InfarctionInfarction

Fourth International Conference on Advanced Cardiac Sciences

King King ofof OrgansOrgans, 2012, 2012 KingdomKingdom ofof SaudiSaudi ArabiaArabia

Carlos MonteiroCarlos Monteiro

InfarctInfarct CombatCombat ProjectProject http://infarctcombat.orghttp://infarctcombat.org

""The coronary patient The coronary patient does not die from coronary disease, he does not die from coronary disease, he dies from myocardial disease.“* dies from myocardial disease.“*

*Burch GE and col., Ischemic *Burch GE and col., Ischemic cardiomyopathycardiomyopathy, Am Heart J. 1972 Mar;83(3):340, Am Heart J. 1972 Mar;83(3):340--50 50

It is It is importantimportant toto note note thethe coronarycoronary thrombosisthrombosis theorytheory, , introducedintroduced byby

James Bryan James Bryan HerrickHerrick, in 1912, , in 1912, remainsremains sufferingsuffering seriousserious doubtdoubt onon its its cause cause andand effecteffect relationshiprelationship. .

ThisThis hashas ledled FriedbergFriedberg andand Horn Horn toto suggestsuggest in 1939 in 1939 thatthat thethe termterm coronarycoronary thrombosisthrombosis shouldshould bebe abandonedabandoned in favor in favor ofof thethe more more genericgeneric oneone ofof acuteacute myocardialmyocardial infarctioninfarction. In . In theirtheir paperpaper theythey saysay thatthat ““thethe clinicalclinical andand electrocardiographicelectrocardiographic featuresfeatures ofof coronarycoronary thrombosisthrombosis maymay bebe observedobserved in in patientspatients in in whomwhom a a coronarycoronary arteryartery thrombusthrombus isis subsequentlysubsequently notnot foundfound atat necropsynecropsy as as hashas beenbeen notednoted byby LibmanLibman, , ObendorferObendorfer, , BuchnerBuchner, , HamburgerHamburger andand SaphirSaphir, Dietrich, Levy , Dietrich, Levy andand BruennBruenn andand othersothers.”.”

AfterAfter thatthat time time manymany otherother investigatorsinvestigators came came toto thethe samesame conclusionconclusion as as wewe willwill seesee followingfollowing......

* * FriedbergFriedberg CK CK andand Horn H. Horn H. AcuteAcute myocardialmyocardial infarctioninfarction notnot duedue to to coronarycoronary arteryartery occlusionocclusion. J. . J. AmAm MedMed AssocAssoc 1939;112(17):1939;112(17):16751675--16791679

(1941) Hermann (1941) Hermann andand colleaguescolleagues foundfound thethe thromboticthrombotic occlusionocclusion couldcould occuroccur withoutwithout infarctioninfarction whenwhen thethe collateralcollateral circulationcirculation appearedappeared adequateadequate andand ifif anan infarctinfarct hashas happenedhappened, it , it couldcould bebe attributedattributed to to anan occlusiveocclusive thrombusthrombus atat a a criticalcritical locationlocation in in thethe coronarycoronary treetree. .

(Angina (Angina PectorisPectoris, , coronarycoronary failurefailure andand acuteacute myocardialmyocardial infarctioninfarction: The role : The role ofof coronarycoronary occlusionsocclusions andand collateralcollateral circulationcirculation, JAMA 1941;116(2):91, JAMA 1941;116(2):91--97; 97; MultipleMultiple freshfresh coronarycoronary occlusionsocclusions in in patientspatients withwith antecedentantecedent shockshock, , ArchArch InternIntern MedMed 1941;68(2):1811941;68(2):181--198; Experimental 198; Experimental studiesstudies onon thethe effecteffect ofof temporarytemporary occlusionocclusion ofof coronarycoronary arteriesarteries; The ; The productionproduction ofof myocardialmyocardial infarctioninfarction, American Heart , American Heart JournalJournal 1941 V22;I3 1941 V22;I3 --374374--389)389)

(1951) Miller (1951) Miller andand colleaguescolleagues pointedpointed out out thatthat subendocardialsubendocardial infarctsinfarcts werewere rarelyrarely associatedassociated withwith coronarycoronary thrombithrombi. .

((MyocardialMyocardial infarctioninfarction withwith andand withoutwithout acuteacute coronarycoronary occlusionocclusion: A : A pathologicpathologic studystudy. AMA . AMA ArchArch InternIntern MedMed 1951;88(5):5971951;88(5):597--604)604)

(1960) Spain (1960) Spain andand BradessBradess foundfound complete complete coronarycoronary obstructionobstruction ofof atheroscleroticatherosclerotic naturenature, , representingrepresenting aroundaround ofof 75% 75% ofof thethe cases cases andand recentrecent coronarycoronary thrombosisthrombosis in in justjust 25% 25% ofof thethe autopsiedautopsied cases. cases. AlsoAlso, , theythey havehave observedobserved crescentcrescent incidenceincidence ofof coronarycoronary thrombosisthrombosis withwith thethe crescentcrescent durationduration ofof survivalsurvival afterafter thethe myocardialmyocardial infarctioninfarction. . LessLess thanthan a hour a hour withwith 16% 16% ofof thrombosisthrombosis, , betweenbetween 1 1 andand 24 hours 24 hours withwith 37% 37% andand in more in more thanthan 24 hours 24 hours withwith 52% 52% ofof coronarycoronary thrombosisthrombosis*.*.

(Spain, DM (Spain, DM andand BradessBradess VA. The VA. The relationshiprelationship ofof coronarycoronary thrombosisthrombosis toto coronarycoronary

atherosclerosisatherosclerosis andand ischemicischemic heartheart diseasedisease –– a a necropsynecropsy studystudy coveringcovering a a periodperiod ofof 25 25 yearsyears, , AmAm J J MedMed SciSci, 240:7, 240:7--1, 1960; Spain DM 1, 1960; Spain DM andand BradessBradess VA. VA. FrequencyFrequency ofof coronarycoronary thrombosisthrombosis relatedrelated toto durationduration ofof survivalsurvival fromfrom onsetonset ofof acuteacute fatal fatal episodesepisodes ofof myocardialmyocardial ischemiaischemia. . CirculationCirculation, 22:816, 1960), 22:816, 1960)

(1970) (1970) HellstromHellstrom demonstrateddemonstrated experimentallyexperimentally thethe coronarycoronary thrombosisthrombosis secondarysecondary toto acuteacute myocardialmyocardial infarctioninfarction causedcaused byby ligatureligature ofof thethe coronarycoronary arteryartery. .

((HellstromHellstrom, HR. , HR. MyocardialMyocardial infarctioninfarction as a cause as a cause ofof coronarycoronary thrombosisthrombosis. .

CirculationCirculation, 42, , 42, SupplSuppl. III); 165, 1970). III); 165, 1970)

(1972) William Roberts (1972) William Roberts suggestedsuggested thatthat thethe coronarycoronary arterial arterial thrombithrombi are are consequencesconsequences ratherrather thanthan causes causes ofof acuteacute myocardialmyocardial infarctioninfarction. In . In hishis studystudy iinvolvingnvolving 107 107 patientspatients whowho werewere submittedsubmitted toto necropsynecropsy hehe foundfound thatthat onlyonly 54% 54% ofof thosethose withwith a a transmuraltransmural infarctioninfarction, , andand onlyonly 10% 10% ofof thosethose withwith subendocardialsubendocardial necrosisnecrosis, , hadhad a a thrombusthrombus in in thethe infarctinfarct relatedrelated arteryartery..

((Frequency Frequency of coronary thrombosis related to duration of survival of coronary thrombosis related to duration of survival from from onset of onset of acute fatal episodes of myocardial ischemia, Circulation, acute fatal episodes of myocardial ischemia, Circulation, 22:816, 196022:816, 1960; ; RobertsRoberts, , W.CW.C.:; .:; Coronary arteries in fatal acute myocardial infarction, Coronary arteries in fatal acute myocardial infarction, Circulation,42:215Circulation,42:215, , 1972, Roberts W. C1972, Roberts W. C.).)

(1980) (1980) DeWoodDeWood and colleagues demonstrated the prevalence of total and colleagues demonstrated the prevalence of total coronary occlusion during the early hours of coronary occlusion during the early hours of transmuraltransmural infarction by infarction by means of coronary arteriography. Their results were accepted by the means of coronary arteriography. Their results were accepted by the cardiology community as the definitive clinical evidence about the causal cardiology community as the definitive clinical evidence about the causal role of thrombosis in acute myocardial infarction.role of thrombosis in acute myocardial infarction.

((DeWoodDeWood MA, Spores J, MA, Spores J, NotskeNotske R et al. Prevalence of total coronary R et al. Prevalence of total coronary oclusionoclusion

during the early hours of during the early hours of transmuraltransmural myocardial infarction. N myocardial infarction. N EnglEngl J Med J Med 1980;303:8971980;303:897--902)902)

(1996) (1996) QuintilianoQuintiliano H. de H. de MesquitaMesquita pointed out that the interpretation pointed out that the interpretation

given by given by DeWoodDeWood about the angiographic image, suggestive of about the angiographic image, suggestive of intracoronary thrombus, do not correspond to the absolute reality intracoronary thrombus, do not correspond to the absolute reality whether it represents a true thrombus or just aggregated platelets that are whether it represents a true thrombus or just aggregated platelets that are precocious, unstable or reversible commonly registered in the first hours precocious, unstable or reversible commonly registered in the first hours of unstable angina and in the course of the acute myocardial infarction.of unstable angina and in the course of the acute myocardial infarction.

(Book: (Book: RemédioRemédio boicotadoboicotado substituisubstitui cirurgiacirurgia de de ponteponte de de safenasafena, , CompsetCompset,,, 1996), 1996)

((2005) Giorgio 2005) Giorgio BaroldiBaroldi and and colleagues, colleagues, discussing the findings from discussing the findings from

DeWoodDeWood, , told that the first main question is how many of the 87% told that the first main question is how many of the 87% cineangiocineangio occlusion are occlusion are pseudopseudo--occlusion occlusion and whether the "layered" and whether the "layered" thrombus recovered at bypass thrombus recovered at bypass surgery surgery was a true thrombus or a was a true thrombus or a coagulum which frequently show a layering of blood elements not seen in coagulum which frequently show a layering of blood elements not seen in thrombus formation. Also saying that "Red" thrombus, namely a thrombus formation. Also saying that "Red" thrombus, namely a coagulum, is frequently and erroneously considered as thrombuscoagulum, is frequently and erroneously considered as thrombus. .

In another paper from the same year they say In another paper from the same year they say that that the the frequency of an frequency of an occlusive thrombus is significantly higher in the occlusive thrombus is significantly higher in the largest infarcts largest infarcts supporting supporting its secondary its secondary formation. formation.

((BaroldiBaroldi G, G, BigiBigi R, R, CortigianiCortigiani L: Ultrasound imaging versus L: Ultrasound imaging versus morphopathologymorphopathology in in cardiovascular diseases: coronary collateral cardiovascular diseases: coronary collateral and myocardial and myocardial ischemia. ischemia. CardiovascCardiovasc Ultrasound 2005, 3:6; Giorgio Ultrasound 2005, 3:6; Giorgio BaroldiBaroldi, Riccardo , Riccardo BigiBigi and and LauroLauro CortigianiCortigiani. . Ultrasound imaging versus Ultrasound imaging versus morphopathologymorphopathology in cardiovascular in cardiovascular diseases. diseases. Myocardial cell damage. Cardiovascular Ultrasound 3:32Myocardial cell damage. Cardiovascular Ultrasound 3:32., 2005)., 2005)

(2001(2001) In a significant number of cases ) In a significant number of cases angioscopicangioscopic examination continues examination continues

to find thrombus on to find thrombus on the presumed the presumed culprit lesion, at 6 months after culprit lesion, at 6 months after myocardial myocardial infarction.infarction.

((YasunoriYasunori Ueda, Masanori Ueda, Masanori AsakuraAsakura, et al. 2001. The healing process of infarct, et al. 2001. The healing process of infarct--

related plaque: Insights from related plaque: Insights from 18 months 18 months of serial of serial angioscopicangioscopic followfollow--up. Am up. Am CollColl CardiolCardiol, 38:1916, 38:1916--19221922.) .)

((1998) Murakami and colleagues from Japan using intracoronary 1998) Murakami and colleagues from Japan using intracoronary catheters to aspirate occlusive tissues, performed during the acute catheters to aspirate occlusive tissues, performed during the acute myocardial myocardial infarction, infarction, have confirmed the pathological findings that have confirmed the pathological findings that intracoronary thrombus is absent in a substantial number of patients intracoronary thrombus is absent in a substantial number of patients indicating it contributes little to the pathogenesis of average indicating it contributes little to the pathogenesis of average acute acute myocardial infarction.myocardial infarction.

(Murakami (Murakami T. Intracoronary aspiration T. Intracoronary aspiration thrombectomythrombectomy for acute myocardial for acute myocardial infarction, Am. J Cardiology 1998 Oct 1;82(7):839infarction, Am. J Cardiology 1998 Oct 1;82(7):839--44)44)

(2005(2005) ) RittersmaRittersma and colleagues and colleagues examined retrieved thrombus material examined retrieved thrombus material aspirated using the percutaneous aspirated using the percutaneous thrombectomythrombectomy catheter in 211 patients catheter in 211 patients undergoing undergoing primary primary ppercutaneous coronary intervention ercutaneous coronary intervention within six hours within six hours of symptom onset. They then established, of symptom onset. They then established, by by histological indicators, the histological indicators, the age of the aspirated thrombi. The age of the aspirated thrombi. The researchers researchers found thrombus in found thrombus in 199 of 199 of the 211 the 211 patients, of whom fresh thrombus was patients, of whom fresh thrombus was identified identified in just under in just under half. By contrast, 51% of patient samples contained half. By contrast, 51% of patient samples contained thrombus thrombus that had that had lytic or organized changes suggesting that it had originated lytic or organized changes suggesting that it had originated days days or or weeks before the occlusive event. weeks before the occlusive event. They said that “StrikinglyThey said that “Strikingly, clinical , clinical characteristics characteristics did not differ between the patients with fresh thrombus did not differ between the patients with fresh thrombus and those and those with ‘older’ with ‘older’ thrombus, although men were more likely to have thrombus, although men were more likely to have fresh fresh thrombus than thrombus than were were women.” women.”

((RittersmaRittersma SZH, van der SZH, van der WalWal AC, Koch KT, et al. Plaque AC, Koch KT, et al. Plaque instability instability frequently frequently occurs days or weeks before occlusive coronary thrombosis. occurs days or weeks before occlusive coronary thrombosis. A A pathological pathological thrombectomythrombectomy study in primary percutaneous study in primary percutaneous coronary interventioncoronary intervention. Circulation . Circulation 2005; 111:11602005; 111:1160--11651165

The PASSION The PASSION trialtrial, , recentlyrecently publishedpublished, , foundfound thatthat thethe use use ofof thrombusthrombus aspirationaspiration in in adjunctadjunct toto primaryprimary percutaneouspercutaneous coronarycoronary interventionintervention (PPCI) (PPCI) diddid notnot affectedaffected rates rates ofof major adverse major adverse cardiaccardiac eventsevents atat 2 2 yearsyears followfollow--up, as up, as comparedcompared withwith convencional PPCI. convencional PPCI. SoSo, , basedbased in in thisthis studystudy, , it is fair to it is fair to saysay thatthat thrombusthrombus aspirationaspiration do do notnot preventprevent thethe occurrenceoccurrence ofof thethe myocardialmyocardial infarctioninfarction..

Martin A Martin A VinkVink, , MauritsMaurits T T DirksenDirksen, et al. , et al. LackLack ofof longlong--termterm clinicalclinical benefitbenefit ofof thrombusthrombus aspirationaspiration duringduring primaryprimary percutaneouspercutaneous coronarycoronary interventionintervention withwith paclitaxelpaclitaxel--elutingeluting stentsstents oror barebare--metal metal stentsstents: Post: Post--hoc hoc analysisanalysis ofof thethe PASSION PASSION trialtrial. . CatheterizationCatheterization andand Cardiovascular Cardiovascular InterventionsInterventions, 1 May 2012;Volume 79: , 1 May 2012;Volume 79: IssueIssue 66,, pagespages 870870--877877

Myocardial Myocardial infarction associated with normal coronary arteries is a infarction associated with normal coronary arteries is a

well known conditionwell known condition. The overall prevalence rate of myocardial . The overall prevalence rate of myocardial infarction with normal infarction with normal coronary arteries coronary arteries is considered to be low, is considered to be low, varying from 1% varying from 1% to 12to 12% depending on the definition of "% depending on the definition of "normal“ normal“ coronary arteries.coronary arteries.

((LegrandLegrand V, V, DeliegeDeliege M, M, HenrardHenrard L, Boland J, L, Boland J, KulbertusKulbertus H: H: PatientsPatients withwith

myocardialmyocardial infarctioninfarction andand normal normal coronarycoronary arteriogramarteriogram. . ChestChest 1982, 1982, 82(6):82(6):678678--685; Raymond 685; Raymond R, Lynch J, R, Lynch J, UnderwoodUnderwood D, D, LeathermanLeatherman J, J, RazaviRazavi M: M: MyocardialMyocardial infarctioninfarction andand normal normal coronarycoronary arteriographyarteriography: a : a 10 10 yearyear clinicalclinical andand riskrisk analysisanalysis ofof 74 74 patientspatients. J . J AmAm Coll Coll CardiolCardiol 19881988, 11(3):471, 11(3):471--477477.).)

(1993) (1993) ArbustiniArbustini and colleagues found in and colleagues found in a series of 132 autopsies of a series of 132 autopsies of hearts from patients hearts from patients who died who died of of noncardiacnoncardiac causes, causes, that coronary that coronary thrombi were shown thrombi were shown to overlay to overlay the intima of a coronary vessel the intima of a coronary vessel independently independently of plaque of plaque type and type and severity.severity.

ArbustiniArbustini E, Grasso M, E, Grasso M, DiegoliDiegoli M, et al. M, et al. CoronaryCoronary thrombosisthrombosis in nonin non--cardiaccardiac deathdeath. .

CoronCoron ArteryArtery DisDis 1993;4:7511993;4:751––9.9.

A A recentrecent ““StateState--ofof--thethe--ArtArt” ” reviewreview andand commentarycommentary publishedpublished atat thethe JournalJournal ofof thethe American American CollegeCollege ofof CardiologyCardiology mademade thethe followingfollowing conclusionconclusion::

“A “A largelarge bodybody ofof evidenceevidence conclusivelyconclusively suggestssuggests thatthat coronarycoronary arteryartery obstructionobstruction isis onlyonly 1 1 elementelement in a in a complexcomplex multifactorialmultifactorial pathophysiologicalpathophysiological processprocess thatthat leads leads toto IschemicIschemic Heart Heart DiseaseDisease (IHD) (IHD) andand thatthat thethe presencepresence ofof obstructiveobstructive lesionslesions in in patientspatients withwith IHD does IHD does notnot necessarilynecessarily implyimply a a causativecausative role. A more role. A more comprehensivecomprehensive approach approach seemsseems necessarynecessary toto refocusrefocus preventivepreventive andand therapeutictherapeutic strategiesstrategies andand toto decreasedecrease morbiditymorbidity andand mortalitymortality. . ToTo thisthis effecteffect, , wewe proposepropose a shift in a shift in approach approach toto include include thethe myocardialmyocardial cellcell as as wellwell as as thethe coronarycoronary vesselvessel””

Mario Mario MarzilliMarzilli, , C. Noel C. Noel BaireyBairey MerzMerz,, William ,, William E. E. BodenBoden, Robert , Robert O. O. BonowBonow,,

Paola G. Paola G. CapozzaCapozza, , William M. William M. ChilianChilian, , Anthony Anthony N. N. DeMariaDeMaria, , GiacintaGiacinta GuariniGuarini, , Alda Alda HuqiHuqi, , DoralisaDoralisa MorroneMorrone, , ManeshManesh R. R. PatelPatel, , William William S. S. WeintraubWeintraub. . ObstructiveObstructive coronarycoronary atherosclerosisatherosclerosis andand ischemicischemic heartheart diseasedisease: : AnAn elusiveelusive link!. JACC link!. JACC VolVol 60, 60, No. 11, 2012; No. 11, 2012; SeptemberSeptember 11: 95111: 951--66

One One of the major of the major developments developments of of Doctor Doctor MesquitaMesquita was the Myogenic Theory of Myocardial Infarction, was the Myogenic Theory of Myocardial Infarction, from from 1972. The 1972. The MyogenicMyogenic Theory supports the use Theory supports the use of cardiac glycosides (of cardiac glycosides (cardiotonicscardiotonics) for the ) for the prevention and clinical treatment of acute coronary prevention and clinical treatment of acute coronary syndromes. Among other developments are the syndromes. Among other developments are the Ventricular Aneurism Surgery of the Heart Ventricular Aneurism Surgery of the Heart performed by Charles Bailey in 1954 and the first performed by Charles Bailey in 1954 and the first diagnosis of Right Ventricular Infarction, in vivo, by diagnosis of Right Ventricular Infarction, in vivo, by ECG, made in 1958. (He did more than 30 pioneer ECG, made in 1958. (He did more than 30 pioneer contributions to medical literaturecontributions to medical literature))

Dr. Dr. MesquitaMesquita deceased in 2000 with 82 years olddeceased in 2000 with 82 years old

His memorial is at the following webpage: His memorial is at the following webpage: http://www.infarctcombat.org/qhm/homepage.htmlhttp://www.infarctcombat.org/qhm/homepage.html

The The coronary atherosclerosis and slow coronary flow in the normal coronary atherosclerosis and slow coronary flow in the normal extramural coronaries develop myocardial ischemic process through the extramural coronaries develop myocardial ischemic process through the imbalance between demand and blood supply to the myocardial imbalance between demand and blood supply to the myocardial segments, dependent on the right and left coronary arteries. Basically, the segments, dependent on the right and left coronary arteries. Basically, the large extramural coronary arteries are responsible for nutrition of the large extramural coronary arteries are responsible for nutrition of the segmental myocardium and mainly by the contractile balance of each segmental myocardium and mainly by the contractile balance of each segment of the ventricular wall.segment of the ventricular wall.

Every Every time when is developed a relative coronary insufficiency through time when is developed a relative coronary insufficiency through physical or psychophysical or psycho--emotional stress results in emotional stress results in an an immediate loss of immediate loss of contractility of the ischemic area and simultaneous exaltation of other contractility of the ischemic area and simultaneous exaltation of other unaffected contractile ventricular segments. unaffected contractile ventricular segments.

The The continuity of such repetitive ischemic manifestations tend to continuity of such repetitive ischemic manifestations tend to contribute to the installation of contribute to the installation of nonsynergicnonsynergic segments, by ischemia + loss segments, by ischemia + loss of contractility and overload imposed by the remaining intact ventricular of contractility and overload imposed by the remaining intact ventricular segments, during the ventricular ejection phase. segments, during the ventricular ejection phase.

Thus, Thus, the the coronariopathycoronariopathy contributes to the deterioration of the contributes to the deterioration of the ventricular segment, constituting areas of ventricular segment, constituting areas of myocardiosclerosismyocardiosclerosis or or segmental myocardial disease, possible future site of the myocardial segmental myocardial disease, possible future site of the myocardial infarction. infarction.

Book “Book “MyogenicMyogenic TheoryTheory ofof MyocardialMyocardial InfarctionInfarction”, 1979. ”, 1979.

CoronaryCoronary AtherosclerosisAtherosclerosis

SlowSlow CCoronaryoronary FFlowlow

↓↓

StableStable Angina Angina PectorisPectoris –– SilentSilent CoronariopathyCoronariopathy

11-- RelativeRelative MyocardialMyocardial IschemiaIschemia

22-- ReciprocalReciprocal ContractileContractile LossLoss

↓↓

PhysicalPhysical andand PsychoPsycho--EmotionalEmotional Stress Stress FactorsFactors

/ / oror

PharmacologicalPharmacological FactorsFactors -- Negative Negative InotropicInotropic AgentsAgents

↓↓

Segmental Segmental MyocardialMyocardial DiseaseDisease

Segmental Segmental MyocardialMyocardial DiseaseDisease ↓↓

UnstableUnstable Angina/ Angina/ IntermediateIntermediate SyndromeSyndrome

InfarctingInfarcting ClinicalClinical PicturePicture

11-- Regional Regional MyocardialMyocardial InsufficiencyInsufficiency 22-- ReciprocalReciprocal MyocardialMyocardial IschemiaIschemia

↓↓ PrimaryPrimary MyocardialMyocardial NecrosisNecrosis

((InfarctionInfarction)) ↓↓

CoronaryCoronary StasisStasis oror FragmentationFragmentation andand DisplacementDisplacement ofof AtheromatousAtheromatous Plaque Plaque byby EdemaEdema

↓↓ SecondarySecondary CoronaryCoronary ThrombosisThrombosis

((NotNot ObligatoryObligatory))

TheThe termterm ““coronarycoronary” ” hashas becomebecome synonymoussynonymous withwith ischemiaischemia andand it is it is usedused to define to define anan atheroscleroticatherosclerotic occlusiveocclusive lesionlesion thatthat is is believedbelieved to to bebe responsibleresponsible for for allall clinicalclinical patternspatterns..

SoSo, , insideinside thethe sensesense ofof thethe myogenicmyogenic theorytheory ofof myocardialmyocardial infarctioninfarction I I willwill taketake thethe libertyliberty to to use some use some termsterms more more adequatedadequated to it to it likelike ““coronarycoronary--cardiomyopathycardiomyopathy” ” oror ““coronarycoronary--myocardialmyocardial diseasedisease” ” ratherrather coronarycoronary heartheart diseasedisease, , coronarycoronary arteryartery diseasedisease andand” ” acuteacute myocardialmyocardial syndromessyndromes” ” ratherrather acuteacute coronarycoronary syndromessyndromes..

Several Several studies have shown studies have shown a a close connection close connection between catecholamine between catecholamine and myocardial and myocardial infarction. infarction. The hyperactivity of the sympathetic nervous The hyperactivity of the sympathetic nervous system, with system, with an intense outflow an intense outflow of of catecholaminescatecholamines (adrenaline/epinephrine and (adrenaline/epinephrine and noradrenalinenoradrenaline//norepinephrinenorepinephrine) also occur ) also occur in unstable angina, alternatively called in unstable angina, alternatively called preinfarctionpreinfarction angina or angina or intermediate syndrome, being smaller and less long than in acute intermediate syndrome, being smaller and less long than in acute myocardial infarctionmyocardial infarction. . TakotsuboTakotsubo cardiomyopathy, also known as broken cardiomyopathy, also known as broken heart heart syndromesyndrome, , a sudden a sudden temporary weakening of the temporary weakening of the myocardium, myocardium, which simulates an evolving myocardial infarction clinical picture, which simulates an evolving myocardial infarction clinical picture, likewise likewise has has am intense am intense outflow of outflow of catecholaminescatecholamines..

((IncreasedIncreased cardiaccardiac sympatheticsympathetic nervousnervous activityactivity in in patientspatients withwith unstableunstable coronarycoronary

heartheart diseasedisease, , McCanceMcCance AJ, Thompson PA, AJ, Thompson PA, ForfarForfar JC. JC. EurEur Heart J 1993 Heart J 1993 Jun;14(6):751Jun;14(6):751--7 ; 7 ; SympatheticSympathetic neural neural hyperactivityhyperactivity andand its its normalizationnormalization followingfollowing unstableunstable angina angina andand acuteacute myocardialmyocardial infarctioninfarction, Graham LN, Smith PA et al. , Graham LN, Smith PA et al. ClinClin SciSci ((LondLond) 2004 Jun;106(6):605) 2004 Jun;106(6):605--11)11)

Acute stress (or stress Acute stress (or stress overload)overload)

Beyond intense physical Beyond intense physical activity, particularly in sports competition, activity, particularly in sports competition, or or unusual unusual efforts, surpassing the limits of his/her heart conditionsefforts, surpassing the limits of his/her heart conditions, or else , or else the heavy use of stimulant drugs, there the heavy use of stimulant drugs, there are many risk factors for acute are many risk factors for acute myocardial myocardial syndromes, based on recent syndromes, based on recent severe stress situations or severe stress situations or sudden sudden emotional emotional stress, like:stress, like:

Marital separation or divorce, loss of work or retirement, loss of revenue Marital separation or divorce, loss of work or retirement, loss of revenue or business failure, important family conflicts, important personal injury or business failure, important family conflicts, important personal injury or illness, death or illness of a close family member, shock of a surprise or illness, death or illness of a close family member, shock of a surprise party, armed robbery or other kind of violence, heated discussion, threats party, armed robbery or other kind of violence, heated discussion, threats or acts of war, earthquakes, to track or acts of war, earthquakes, to track the team of preference in matches live the team of preference in matches live footballfootball, etc…, etc…

The recent discovery of endogenous The recent discovery of endogenous cardiotoniccardiotonic hormones (digitalis, hormones (digitalis, strophanthinstrophanthin, , proscillaridineproscillaridine, etc..), isolated from human tissues and body fluids, , etc..), isolated from human tissues and body fluids, may represent may represent a a strong new strong new argument argument for the myogenic theory of myocardial infarction. for the myogenic theory of myocardial infarction.

An elevated concentration of endogenous An elevated concentration of endogenous cardiotonicscardiotonics have been found under have been found under different conditions such as sodium imbalance, hypertension, cardiac arrhythmias, different conditions such as sodium imbalance, hypertension, cardiac arrhythmias, chronic renal failure, congestive heart failure and acute myocardial infarction. chronic renal failure, congestive heart failure and acute myocardial infarction. Vigorous physical exercises as well physiological stress situations may also elevate Vigorous physical exercises as well physiological stress situations may also elevate the concentration of endogenous the concentration of endogenous cardiotonicscardiotonics in the body.in the body.

We We think the think the cardiotonicscardiotonics found in nature may complement a deficient production found in nature may complement a deficient production of endogenous of endogenous cardiotoniccardiotonic hormones produced by the human body and thus hormones produced by the human body and thus support cardiac metabolism and protect the heart from the infarction, as proposed support cardiac metabolism and protect the heart from the infarction, as proposed in Myogenic Theory. in Myogenic Theory.

TwoTwo quotesquotes relatedrelated to to thesethese findingsfindings::

“The “The diseaseddiseased heartheart isis avidavid for for cardiotonicscardiotonics”” QuintilianoQuintiliano H. de Mesquita, 1997H. de Mesquita, 1997

““CardiotonicsCardiotonics are are thethe insulininsulin for cardiovascular for cardiovascular diseasedisease””

Carlos Monteiro, 2005Carlos Monteiro, 2005

(1912) James Herrick: Proclaimed the myocardial infarction (MI) as (1912) James Herrick: Proclaimed the myocardial infarction (MI) as consequence of coronary thrombosis and consequence of coronary thrombosis and cardiotonicscardiotonics (digitalis and (digitalis and strophanthinstrophanthin) as the best therapy. He declared: "The timely use of this ) as the best therapy. He declared: "The timely use of this remedy may occasionally save live". remedy may occasionally save live".

(1926) Louis (1926) Louis HammanHamman: Shared in same concepts and enthusiasm of : Shared in same concepts and enthusiasm of Herrick regarding the use of Herrick regarding the use of cardiotonicscardiotonics to treat the MI. He said: "The to treat the MI. He said: "The patient should be promptly and fully digitalized... not only is the patient should be promptly and fully digitalized... not only is the digitalized heart better prepared to withstand the added burden of digitalized heart better prepared to withstand the added burden of certain arrhythmias should they come on, but it is also stimulated to put certain arrhythmias should they come on, but it is also stimulated to put forth its better efforts. How desirable the best efforts may be when a large forth its better efforts. How desirable the best efforts may be when a large area of heart muscle is infarcted, needs no further comment"area of heart muscle is infarcted, needs no further comment"

((JAMA,59: 2015, JAMA,59: 2015, 1912 ; 1912 ; Bull Bull Johns Hopkins Hosp.; 38: 273, Johns Hopkins Hosp.; 38: 273, 19261926))

((1934) Ernst 1934) Ernst EdensEdens: After 3 years using : After 3 years using strophanthinstrophanthin by intravenous way by intravenous way in angina pectoris and MI in more than 100 patients he declared: " in angina pectoris and MI in more than 100 patients he declared: " Subsequently to the recognition of the Subsequently to the recognition of the strophanthinstrophanthin as the best and safest as the best and safest medicine for the myocardial infarction we don't have the right to use it in medicine for the myocardial infarction we don't have the right to use it in a patient only for scientific reasons and tests, giving preference to other a patient only for scientific reasons and tests, giving preference to other remedies remedies losing losing precious time for the cure". He also told that will come precious time for the cure". He also told that will come the moment in which the omission of the use of the moment in which the omission of the use of strophanthinstrophanthin would would be be seen as a professional malpracticeseen as a professional malpractice..

(Munchener (Munchener Medizinischen Wochenschrift; 37, 1934)Medizinischen Wochenschrift; 37, 1934)

(1950) Ferdinand (1950) Ferdinand R. R. SchemmSchemm:: Preconized the use free from restraint Preconized the use free from restraint of of digitalis for MI treatment. He used digitalis in 265 patients recording a digitalis for MI treatment. He used digitalis in 265 patients recording a mortality of 10%. In practice he noticed that instead of any myocardial mortality of 10%. In practice he noticed that instead of any myocardial damages, the damages, the cardiotoniccardiotonic presented compatibility with the acute presented compatibility with the acute myocardial infarction, reason of salutary effects and lower mortality.myocardial infarction, reason of salutary effects and lower mortality.

(1951) John (1951) John Martin Martin AskeyAskey: Applied : Applied digitalis in 50 consecutive patients digitalis in 50 consecutive patients with acute MI. Citing the results achieved by with acute MI. Citing the results achieved by SchemmSchemm with digitalis refers with digitalis refers that the medical profession was unable to take full advantage of this that the medical profession was unable to take full advantage of this valuable drug, offering the Henry Thoreau thought: "It is never too late to valuable drug, offering the Henry Thoreau thought: "It is never too late to give up our prejudices. No way of thinking however ancient, can be give up our prejudices. No way of thinking however ancient, can be trusted without proof". This affirmation from trusted without proof". This affirmation from AskeyAskey was stated during was stated during the presentation about his results and to appreciate the clinical and the presentation about his results and to appreciate the clinical and experimental proceedings realized at that time. Likewise he demonstrated experimental proceedings realized at that time. Likewise he demonstrated a healthy apprehension in front of the accommodation and disinterest a healthy apprehension in front of the accommodation and disinterest regarding so exciting theme. regarding so exciting theme.

((PostgradPostgrad Med.; 385, 1950; JAMA; 146: 1008, 1951) Med.; 385, 1950; JAMA; 146: 1008, 1951)

(1955) Norman (1955) Norman H. H. Boyer: Boyer: Mentioned that after an unexpected but Mentioned that after an unexpected but fortunate experience using digitalis by intravenously way ceased his fear fortunate experience using digitalis by intravenously way ceased his fear about the use of digitalis applying it starting from this moment in a about the use of digitalis applying it starting from this moment in a sequence of 50 patients with MIsequence of 50 patients with MI..

(1970) Berthold Kern: Wrote that he used sublingual (1970) Berthold Kern: Wrote that he used sublingual strophanthinstrophanthin in more in more than 15.000 cardiac patients during the period of 1947 till than 15.000 cardiac patients during the period of 1947 till 1968 resulting 1968 resulting in in a very low mortality rate and few myocardial infarctions. a very low mortality rate and few myocardial infarctions.

(New (New EnglandEngland J. J. MedMed; 252: 536, ; 252: 536, 1955; Der 1955; Der MyokardMyokard--InfarktInfarkt. . HaugHaug VerlagVerlag. .

HeidelbergHeidelberg, 1970), 1970)

(1972) (1972) QuintilianoQuintiliano H. de H. de MesquitaMesquita: : Advocated that treatment with Advocated that treatment with cardiotonicscardiotonics should be started the earliest possible in order to correct the should be started the earliest possible in order to correct the regional myocardial collapse in progress. He also regional myocardial collapse in progress. He also stated stated that that cardiotoniccardiotonic administration protects the myocardial fibers in collapse, ischemic, but administration protects the myocardial fibers in collapse, ischemic, but viable to be kept from the necrosis which viable to be kept from the necrosis which would would certainly occur in case of certainly occur in case of nonnon--use of this remedy. Surpassing the acute period, the use of this remedy. Surpassing the acute period, the cardiotoniccardiotonic should be used, according him, as a maintenance treatment, which blends should be used, according him, as a maintenance treatment, which blends with the MI prophylaxis, in order to defend the ischemic myocardium in with the MI prophylaxis, in order to defend the ischemic myocardium in its functional side. During 7 years applied its functional side. During 7 years applied cardiotonicscardiotonics by intravenously by intravenously way (way (digitalis and digitalis and strophanthinstrophanthin) in 1183 patients with acute MI, recording ) in 1183 patients with acute MI, recording a survival of almost 90%. a survival of almost 90%. Professor Professor MesquitaMesquita was awarded in 1975 with was awarded in 1975 with the Ernst the Ernst EdensEdens TraditionspreisTraditionspreis by the International Society Against by the International Society Against Myocardial Infarct Myocardial Infarct located located in Stuttgartin Stuttgart-- GermanyGermany..

(Mesquita(Mesquita, QH De: Angina de esforço e síndrome de enfarte miocárdico iminente: , QH De: Angina de esforço e síndrome de enfarte miocárdico iminente:

aspectos sintomáticos dependentes de insuficiência miocárdica regional. Nota aspectos sintomáticos dependentes de insuficiência miocárdica regional. Nota prévia. Trabalho apresentado ao XXVIII Congresso Brasileiro de Cardiologia, prévia. Trabalho apresentado ao XXVIII Congresso Brasileiro de Cardiologia, Curitiba (PR), Julho de Curitiba (PR), Julho de 1972)1972)

(1974) (1974) PritpalPritpal PuriPuri havehave demonstrateddemonstrated thatthat thethe intermediateintermediate hypocontractilehypocontractile areaarea betweenbetween thethe infarctioninfarction andand normal normal myocardiummyocardium respondedresponded to to thethe cardiotoniccardiotonic StrophanthinStrophanthin maintainingmaintaining normal normal contractilitycontractility starting starting fromfrom thethe thethe myocardialmyocardial ischemiaischemia andand hypocontractilityhypocontractility..

(1975) (1975) BankaBanka andand colcol, , confirmedconfirmed thethe experimentsexperiments fromfrom PuriPuri usingusing DigitalisDigitalis andand recordingrecording thethe samesame resultsresults..

((PritpalPritpal S S PuriPuri. Modification of experimental myocardial infarct size by cardiac . Modification of experimental myocardial infarct size by cardiac drugs, Am J drugs, Am J CardiolCardiol, 33 :52, 1974; Banka, VS, , 33 :52, 1974; Banka, VS, BodenheimerBodenheimer, MM, , MM, HelfantHelfant, RH e , RH e ChaddaChadda, KD: Digitalis in experimental acute myocardial infarction. Differential , KD: Digitalis in experimental acute myocardial infarction. Differential effects on contractile performance of ischemic, border and effects on contractile performance of ischemic, border and nonischemicnonischemic ventricular ventricular zones in the dog, Am J zones in the dog, Am J CardiolCardiol, 35:801, 1975), 35:801, 1975)

(1975) (1975) PizarelloPizarello etet alal andand Morrison Morrison etet alal in 1976 in 1976 havehave shownshown thethe serial serial enzymaticenzymatic reactionsreactions usingusing digitalisdigitalis thethe infarctioninfarction waswas haltedhalted andand, , thusthus, , thethe cardiotoniccardiotonic mightmight bebe consideredconsidered as as ableable to to rescuerescue thethe viableviable myocardialmyocardial fibersfibers..

(1980) Morrison (1980) Morrison etet alal confirmedconfirmed no no changechange in serial in serial creatininecreatinine MB MB isoenzymeisoenzyme in a in a groupgroup ofof patientspatients withwith heartheart failurefailure afterafter myocardialmyocardial infarctioninfarction takingtaking digitalisdigitalis, in , in contrastcontrast withwith pastpast observationsobservations mademade in in animalsanimals followingfollowing coronarycoronary arteryartery ligationligation, , whichwhich havehave shownshown anan extensionextension ofof thethe areaarea ofof infarctioninfarction afterafter digitalisdigitalis administrationadministration. .

((PizarelloPizarello R, R, RedutoReduto L, Geller K, L, Geller K, GullotaGullota S, Morrison J S, Morrison J –– Protection of the ischemic Protection of the ischemic myocardium in man by digitalis. Circulation 1975; 51myocardium in man by digitalis. Circulation 1975; 51--52 (52 (supplsuppl III): 895; Morrison III): 895; Morrison J, J, PizarelloPizarello R, R, RedutoReduto L, L, GullotaGullota S S –– Effect of digitalis on predicted myocardial Effect of digitalis on predicted myocardial infarct size. Circulation 1976; 53infarct size. Circulation 1976; 53--54 (54 (SupplSuppl II): 102II): 102; ; Morrison J, Morrison J, CoromilasCoromilas J, Robbins J, Robbins M et al M et al –– Digitalis and myocardial infarction in man. Circulation 1980; 62: 8Digitalis and myocardial infarction in man. Circulation 1980; 62: 8--16)16)

(1980) Peter (1980) Peter SchmidsbergerSchmidsberger, medical , medical journalistjournalist: : ReportReport thethe resultsresults obtainedobtained byby Professor Mesquita in Professor Mesquita in BrazilBrazil informinginforming thatthat Rolf Rolf DorhmanDorhman fromfrom thethe BerlinerBerliner WaldkrankenhausesWaldkrankenhauses in Berlin in Berlin -- GermanyGermany, , achievedachieved duringduring 5 5 yearsyears similar similar resultsresults ofof thethe BrazilianBrazilian professor professor applyingapplying thethe samesame treatmenttreatment withwith strophanthinstrophanthin duringduring thethe acuteacute myocardialmyocardial infarctioninfarction..

(1993) (1993) QiaoQiao DR told that from the hemodynamic studies the beneficial DR told that from the hemodynamic studies the beneficial effect of effect of cedilanidcedilanid is greater than its adverse effect, concluding that is greater than its adverse effect, concluding that digitalis can be safely and effectively used in the treatment of AMI.digitalis can be safely and effectively used in the treatment of AMI.

(In This Manner a Brazilian Fights Against The Infarction "(In This Manner a Brazilian Fights Against The Infarction "-- BUNTE magazine, BUNTE magazine, Offenburg Offenburg –– Germany; Germany; R.E.DohrmannR.E.Dohrmann; ; H.D.JanischH.D.Janisch & & M.KesselM.Kessel: : KlinischKlinisch--poliklinischepoliklinische StudieStudie überüber die die WirksamkeitWirksamkeit von gvon g--StrophanthinStrophanthin beibei Angina pectoris Angina pectoris und und MyokardinfarktMyokardinfarkt,; ,; CardiolCardiol Bull (Bull (CardiologischesCardiologisches Bulletin) 14/15: 183Bulletin) 14/15: 183--187, 1977; 187, 1977; QiaoQiao DR. A study on the hemodynamic effect of DR. A study on the hemodynamic effect of cedilanidcedilanid in the treatment of acute in the treatment of acute myocardial infarction, myocardial infarction, ZhonghuaZhonghua XinXin XueXue GuanGuan Bing Bing ZaZa ZhiZhi. 1993 . 1993 AprApr;21(2):83;21(2):83--4)4)

(1995) Leor J and colleagues found in patients recovering from (1995) Leor J and colleagues found in patients recovering from myocardial infarction that one year mortality was significantly higher myocardial infarction that one year mortality was significantly higher among patients treated with a full dose [19 of 112 (17%)] than patients among patients treated with a full dose [19 of 112 (17%)] than patients treated with a low dose of treated with a low dose of digoxindigoxin [1 of 41 (2%)][1 of 41 (2%)]

((LeorLeor J, J, GoldbourtGoldbourt U U etet al. al. DigoxinDigoxin andand increasedincreased mortalitymortality amongamong patientspatients

recoveringrecovering fromfrom acuteacute myocardialmyocardial infarctioninfarction: : importanceimportance ofof digoxindigoxin dose, dose, CardiovascCardiovasc DrugsDrugs TherTher 1995 1995 OctOct;9(5):723;9(5):723--9)9)

“I wish it was as easy to write upon the Digitalis “I wish it was as easy to write upon the Digitalis –– I despair of pleasing myself or I despair of pleasing myself or

instructing others in a subject so difficult. It is much easier to write upon a instructing others in a subject so difficult. It is much easier to write upon a disease than upon a remedy. The former is in the hands of nature and a faithful disease than upon a remedy. The former is in the hands of nature and a faithful observer with an eye to tolerable judgment can not fail to delineate a likeness; the observer with an eye to tolerable judgment can not fail to delineate a likeness; the latter will ever be subject to the whims, the inaccuracies and the blunders of latter will ever be subject to the whims, the inaccuracies and the blunders of mankind". William Withering, Letter, Sep 29, 1778mankind". William Withering, Letter, Sep 29, 1778

“Digitalis: A God“Digitalis: A God--given remedy” by Friedrich Ludwig given remedy” by Friedrich Ludwig KreysigKreysig –– Berlin, 1814 Berlin, 1814

“Digitalis: The opium of the heart” by Jean “Digitalis: The opium of the heart” by Jean BaptisteBaptiste BouillaudBouillaud –– Paris, 1841Paris, 1841

The risk of a heart attack or other acute myocardial events is not proportional The risk of a heart attack or other acute myocardial events is not proportional to the severity of coronary to the severity of coronary stenosisstenosis. Several studies in which more than one . Several studies in which more than one angiography was performed in patients who developed acute syndromes angiography was performed in patients who developed acute syndromes showed that most of these syndromes appear to be developed from lesions showed that most of these syndromes appear to be developed from lesions that on the first angiography caused not significant that on the first angiography caused not significant stenosisstenosis. These less severe . These less severe stenoticstenotic lesions lead to myocardial infarction because they have not developed lesions lead to myocardial infarction because they have not developed a sufficient collateral circulation around that would prevent or limit the extent a sufficient collateral circulation around that would prevent or limit the extent of myocardial necrosis. This means that a 30% reduction in arterial caliber may of myocardial necrosis. This means that a 30% reduction in arterial caliber may have an increased risk for a myocardial infarction than an obstruction 90%. have an increased risk for a myocardial infarction than an obstruction 90%.

(Ambrose J A, (Ambrose J A, TannenbaumTannenbaum M A et al, Angiographic progression of coronary artery M A et al, Angiographic progression of coronary artery disease and the development of myocardial infarction, J Am disease and the development of myocardial infarction, J Am CollColl CardiolCardiol 1988; 12:561988; 12:56--62; 62; Little W C et al, Can coronary angiography predict the site of a subsequent myocardial Little W C et al, Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild to moderate coronary artery disease?, Circulation 1988; infarction in patients with mild to moderate coronary artery disease?, Circulation 1988; 78:115778:1157--66; John A Ambrose, 66; John A Ambrose, ValentinValentin FusterFuster, The risk of coronary occlusion is not , The risk of coronary occlusion is not proportional to the prior severity of coronary proportional to the prior severity of coronary stenosesstenoses, Editorial, Heart 1998; 79:3, Editorial, Heart 1998; 79:3--4)4)

Dr. Dr. QuintilianoQuintiliano de de MesquitaMesquita, said in his book ", said in his book "MyogenicMyogenic Theory of Theory of

Myocardial Infarction, 1979: Myocardial Infarction, 1979:

"The collateral coronary circulation is absolutely prevalent in cases of total "The collateral coronary circulation is absolutely prevalent in cases of total obstruction of the obstruction of the coronary artery. coronary artery. He also told: "The net of coronary collateral He also told: "The net of coronary collateral circulation is not always able to prevent myocardial infarction, because it develops circulation is not always able to prevent myocardial infarction, because it develops depending on the anatomical features of the obstructive process, and is not always depending on the anatomical features of the obstructive process, and is not always sufficient to face the demands of the physical activity of the coronary patient. The sufficient to face the demands of the physical activity of the coronary patient. The role of the role of the cardiotoniccardiotonic is to complete the effects of collateral circulation and ensure is to complete the effects of collateral circulation and ensure functional preservation of the ischemic myocardium, thus avoiding the infarction." functional preservation of the ischemic myocardium, thus avoiding the infarction."

A recent metaA recent meta--analysis confirmed that heart disease patients with a wellanalysis confirmed that heart disease patients with a well--developed collateral coronary circulation have an improved survival developed collateral coronary circulation have an improved survival compared with patients with less developed collaterals*.compared with patients with less developed collaterals*.

*Meier P, Hemingway H, Lansky AJ, et al. The impact of the coronary collateral *Meier P, Hemingway H, Lansky AJ, et al. The impact of the coronary collateral

circulation on mortality: a metacirculation on mortality: a meta--analysis. analysis. EurEur Heart J 2011; DOI: Heart J 2011; DOI: 10.1093/10.1093/eurheartjeurheartj/ehr308*/ehr308*

In In mymy viewview, in , in additionaddition ofof positive positive inotropicinotropic effectseffects over over thethe heartheart musclemuscle contractilitycontractility, , cardiotonicscardiotonics maymay alsoalso havehave possiblepossible beneficbenefic effectseffects for for cardiovascular cardiovascular diseasedisease, , includingincluding in in haltinghalting acuteacute myocardialmyocardial syndromessyndromes, , throughthrough thethe reductionreduction ofof heightenedheightened catecholaminecatecholamine levelslevels in in bloodblood andand in in reductionreduction ofof thethe resultingresulting elevatedelevated lactatelactate productionproduction andand accumulationaccumulation byby thethe cardiaccardiac musclemuscle..

((SchobelSchobel HP et al. 1991HP et al. 1991. . ContrastingContrasting effectseffects ofof digitalisdigitalis andand dobutaminedobutamine onon

baroreflexbaroreflex sympatheticsympathetic controlcontrol in in normal normal humanshumans, , CirculationCirculation V84, V84, 11181118--1129; 1129;

M M GheorgiadeGheorgiade andand D Ferguson, 1991. D Ferguson, 1991. DigoxinDigoxin: A : A neurohormonalneurohormonal modulatormodulator in in heartheart failurefailure? 84: 2181? 84: 2181--2186; 2186; GutmanGutman Y, Y, BoonyavirojBoonyaviroj P. P. NaunynNaunyn SchmiedebergsSchmiedebergs. . 1977. 1977. MechanismMechanism ofof inhibitioninhibition ofof catecholaminecatecholamine release release fromfrom adrenal adrenal medullamedulla byby diphenylhydantoindiphenylhydantoin andand byby lowlow concentrationconcentration ofof ouabainouabain (10 ((10 (--10) M). 10) M). ArchArch PharmacolPharmacol Feb;296(3Feb;296(3):):293293--6);6); SchadeSchade DS. The role of DS. The role of catecholaminescatecholamines in metabolic in metabolic acidosis. Ciba Found acidosis. Ciba Found SympSymp. 1982;87:235. 1982;87:235--53)53)

The myogenic theory recommends the use of the The myogenic theory recommends the use of the cardiotoniccardiotonic + coronary + coronary dilator in stable coronary dilator in stable coronary myocardiopathymyocardiopathy, with or w/out previous , with or w/out previous infarction in the long infarction in the long run, complementing run, complementing the the beneficial beneficial and protective and protective effects of collateral coronary circulation in front of effects of collateral coronary circulation in front of severe coronary severe coronary obstructions.obstructions.

In short, according the myogenic theory, In short, according the myogenic theory, cardiotonicscardiotonics are the are the antianti--infarction infarction drugs.drugs.

Excerpts from the paper from Excerpts from the paper from MesquitaMesquita QHdeQHde et al Effects of the et al Effects of the CardiotonicCardiotonic + +

Coronary Dilator in Chronic Stable CoronaryCoronary Dilator in Chronic Stable Coronary--Myocardial Disease, with and Myocardial Disease, with and without Prior Myocardial Infarction, in the Long Runwithout Prior Myocardial Infarction, in the Long Run”, ”, Ars Cvrandi 2002 Ars Cvrandi 2002 (setembro);(setembro);35:7. Text available at the following webpage: 35:7. Text available at the following webpage: http://www.infarctcombat.org/CMDhttp://www.infarctcombat.org/CMD--CE.pdfCE.pdf

Dr. Dr. MesquitaMesquita and colleagues say that the and colleagues say that the following effects should be following effects should be highlighted highlighted from the from the uninterrupted use of uninterrupted use of cardiotoniccardiotonic + + coronarycoronary dilatordilator in in chronicchronic stablestable coronarycoronary--myocardiopathymyocardiopathy, , withwith oror w/out w/out previousprevious myocardialmyocardial infarctioninfarction::

To counteract To counteract the negative inotropic effects of the negative inotropic effects of ischemia;ischemia; To preserve the ventricular To preserve the ventricular function, leveling over the ischemic segments function, leveling over the ischemic segments --

contractile contractile deficient deficient -- with with nonnon--ischemic ischemic segments, segments, annulling annulling the the deleterious segmental confrontation;deleterious segmental confrontation;

To prevent To prevent Unstable Angina, Myocardial Infarction, Heart Failure and Unstable Angina, Myocardial Infarction, Heart Failure and Sudden Death Sudden Death -- symptomatic symptomatic and myocardial instability, ensuring and myocardial instability, ensuring permanent state of permanent state of stability;stability;

To Increase and to provide peaceful survival, To Increase and to provide peaceful survival, comfortable and long, comfortable and long, predominantly predominantly asymptomatic, in front of the common asymptomatic, in front of the common efforts and according efforts and according to the to the achieved parameters.achieved parameters.

Again, they have said that “the Again, they have said that “the coronary collateral circulation has its role in the fate of coronary collateral circulation has its role in the fate of coronary artery disease and represents coronary artery disease and represents the compensatory reinforcement the compensatory reinforcement of of the "Naturethe "Nature", ", complemented by complemented by the the cardiotoniccardiotonic, , in the preservation in the preservation of myocardial of myocardial contractility.”contractility.”

In a paper published in 2002, In a paper published in 2002, QuintilianoQuintiliano MesquitaMesquita and his assistant, and his assistant, CláudioCláudio BaptistaBaptista, have prospectively analyzed data from a period of 28 , have prospectively analyzed data from a period of 28 years (1972 years (1972 -- 2000) using cardiac 2000) using cardiac glycosides glycosides at low concentration (low at low concentration (low dose) in dose) in patients with stable coronary artery disease patients with stable coronary artery disease with or without with or without previous infarction *. Their results have showed previous infarction *. Their results have showed very low rates in very low rates in mortality and morbiditymortality and morbidity. . The patients were divided in two The patients were divided in two groups...groups...

CardiotonicCardiotonic: Insuperable in preservation of myocardial stability, as preventive of : Insuperable in preservation of myocardial stability, as preventive of acute coronary syndromes and responsible for a acute coronary syndromes and responsible for a prolonguedprolongued survival. Casuistry of survival. Casuistry of 28 years (197228 years (1972--2000)2000)”, ”, QuintilianoQuintiliano H. de Mesquita e Cláudio A S Baptista, H. de Mesquita e Cláudio A S Baptista, ArsArs CvrandiCvrandi 2002 (maio); 35:3 2002 (maio); 35:3 . . Text available at the following webpage: Text available at the following webpage: httphttp://://www.infarctcombat.org/28years/digitalis.html www.infarctcombat.org/28years/digitalis.html

The The first group included 994 patients w/out prior first group included 994 patients w/out prior infarction, infarction, presenting presenting in 28 years the following morbidity and mortalityin 28 years the following morbidity and mortality::

-- Myocardial infarction: 14 cases (1.4Myocardial infarction: 14 cases (1.4%)%)

-- Heart failure: 35 cases (3.5%)Heart failure: 35 cases (3.5%)

-- Heart failure mortality: 32 cases (3.2%)Heart failure mortality: 32 cases (3.2%)

-- Sudden Death: Sudden Death: 72 72 cases (7.2%)cases (7.2%)

-- Stroke mortality: 13 cases (1.3%)Stroke mortality: 13 cases (1.3%)

-- Cancer mortality: 14 cases (1.4Cancer mortality: 14 cases (1.4%)%)

-- Other causes of mortality: 11 cases (1.1%)Other causes of mortality: 11 cases (1.1%)

-- Total Mortality: 142 cases (14.2%) Total Mortality: 142 cases (14.2%) -- (0.5% per (0.5% per year!)year!)

-- Mean Age at Death: 76 yearsMean Age at Death: 76 years

The The second group included 156 patients with prior infarction, second group included 156 patients with prior infarction, presenting in 28 years the following morbidity and mortality:presenting in 28 years the following morbidity and mortality:

-- ReRe--infarction: 8 cases (5.1%)infarction: 8 cases (5.1%)

-- Heart failure: 17 cases (10.8%)Heart failure: 17 cases (10.8%)

-- Heart failure mortality: 17 cases (10.8%)Heart failure mortality: 17 cases (10.8%)

-- Sudden Death: 31 cases (20.5%)Sudden Death: 31 cases (20.5%)

-- Stroke mortality: 7 cases (4.4%)Stroke mortality: 7 cases (4.4%)

-- Cancer mortality: 3 cases (1.9%)Cancer mortality: 3 cases (1.9%)

-- Other causes mortality: 5 cases (3.2%)Other causes mortality: 5 cases (3.2%)

-- Total Mortality: 64 cases (Total Mortality: 64 cases (40.8%) 40.8%) -- (1.45% per (1.45% per year!)year!)

-- Mean Age at Death: 72 yearsMean Age at Death: 72 years

PermanentPermanent TherapeuticTherapeutic MaintenanceMaintenance

CardiotonicsCardiotonics employedemployed:: ProscillaridinProscillaridin--AA 0.750.75--1.50mg/1.50mg/dayday AcetildigoxinAcetildigoxin 0.50mg/0.50mg/dayday LanatosideLanatoside--C 0.50mg/C 0.50mg/dayday DigitoxinDigitoxin 0.1mg/0.1mg/dayday DigoxinDigoxin 0.1250.125--0.25mg/0.25mg/dayday BetamethildigoxinBetamethildigoxin 0.100.10--0.20mg/0.20mg/dayday

CoronaryCoronary dilatorsdilators : : CalciumCalcium antagonistsantagonists:: VerapamilVerapamil 120120--240mg/240mg/dayday PrenilaminePrenilamine 120120--180mg/180mg/dayday NifedipineNifedipine 2020--30mg/30mg/dayday FendilineFendiline 100100--150mg/150mg/dayday DiltiazemDiltiazem 9090--180mg/180mg/dayday

TextText availableavailable atat http://http://www.infarctcombat.org/CMDwww.infarctcombat.org/CMD--CE.pdfCE.pdf

The myogenic theory recommends the The myogenic theory recommends the use use of the of the cardiotoniccardiotonic + coronary + coronary dilator in dilator in the treatment of unstable angina, the treatment of unstable angina, for for correction of correction of regional regional myocardial myocardial insufficiency, presented as the insufficiency, presented as the determinant factor in the determinant factor in the pathophysiological pathophysiological mechanism mechanism of this alarming clinical syndrome, of this alarming clinical syndrome, usually characterizing the preusually characterizing the pre--infarctioninfarction..

ExcerptsExcerpts fromfrom thethe articlearticle ofof Mesquita Mesquita QHdeQHde et et alal ““Effects of the Effects of the CardiotonicCardiotonic + + Coronary Dilator in Unstable AnginaCoronary Dilator in Unstable Angina” ” TextText availableavailable atat thethe followoingfollowoing webpagewebpage: : http://http://www.infarctcombat.org/UAwww.infarctcombat.org/UA--CE.pdfCE.pdf

ResultsResults

Perfect drug tolerancePerfect drug tolerance. .

Immediate Immediate disappearance of disappearance of spontaneous spontaneous anginalanginal episodes episodes since since the first the first injection and injection and in a in a shortshort--term term following the administration of the drug by following the administration of the drug by oral route. oral route.

Interruption Interruption of unstable angina in 199 of unstable angina in 199 ptspts; ;

Only Only 1 case 1 case evolved evolved to myocardial infarction to myocardial infarction in the in the eighth day. eighth day.

No No deaths. deaths.

ECG alterations ECG alterations with rapid disappearance. with rapid disappearance.

Arrhythmic Arrhythmic benign benign transitional manifestations transitional manifestations (20.5%). (20.5%).

Mild Mild enzymatic changes in the first 24 hours.enzymatic changes in the first 24 hours.

TherapeuticTherapeutic attackattack ofof unstableunstable angina angina duringduring 6 6 daysdays

CardiotonicsCardiotonics:: SStrophanthintrophanthin--K K : : 0.250.25--0.34 mg/0.34 mg/dayday, IV, IV StrophanthinStrophanthin--G G : : 0.250.25--0.50 mg/0.50 mg/dayday, IV, IV LanatosideLanatoside--C C : : 0.40 mg/0.40 mg/dayday, IV, IV DigoxinDigoxin : : 0.50 mg/0.50 mg/dayday, IV, IV MethildigoxinMethildigoxin : : 0.200.20--0.30 mg/0.30 mg/dayday, PO, PO ProscillaridinProscillaridin--AA : : 1.501.50--2.0 mg/2.0 mg/dayday, PO, PO

CoronaryCoronary dilatorsdilators:: Dipiridamol : 20 Dipiridamol : 20 mg/mg/dayday, IV, IV VerapamilVerapamil : 240 : 240 mg/mg/dayday, PO, PO PrenilaminePrenilamine : 180 : 180 mg/mg/dayday, PO, PO NifedipineNifedipine : 30 : 30 mg/mg/dayday, PO, PO

* The * The strophanthinstrophanthin K or G (IV) was employed in 150 patients, Digitalis (IV) in 30 K or G (IV) was employed in 150 patients, Digitalis (IV) in 30

patients and, patients and, exceptionally, exceptionally, by oral route, by oral route, MethildigoxinMethildigoxin in 1 patient and in 1 patient and ProscillaridinProscillaridin--A in 18 ptsA in 18 pts..

IVIV: Intravenous route PO: Oral route: Intravenous route PO: Oral route

Why Why infarctinginfarcting clinical picture?clinical picture?

Because with the use of Because with the use of cardiotonicscardiotonics the myocardial infarction can be the myocardial infarction can be halted as halted as occurred occurred in 63.5% in 63.5% of the cases of the cases as shown in the studies by Dr. as shown in the studies by Dr. MesquitaMesquita..

MesquitaMesquita QHdeQHde et al “Effects of the et al “Effects of the CardiotonicCardiotonic + Coronary Dilator in the + Coronary Dilator in the InfarctingInfarcting Clinical Picture“. Text Clinical Picture“. Text available at available at the following webpage the following webpage httphttp://://www.infarctcombat.org/ICPwww.infarctcombat.org/ICP--CE.pdfCE.pdf

ResultsResults

AbsoluteAbsolute tolerancetolerance fromfrom thethe drugdrug

ReductionReduction in in administrationadministration ofof analgesicsanalgesics andand narcoticsnarcotics

LowLow incidenceincidence ofof cardiaccardiac arrhythmiasarrhythmias

LowLow incidenceincidence ofof cardiaccardiac insufficiencyinsufficiency

LowLow incidenceincidence ofof cardiogeniccardiogenic shockshock

RelativeRelative loweringlowering ofof enzymaticenzymatic reactionreaction peakspeaks

LowLow mortalitymortality

ClinicalClinical picturepicture more more calmcalm andand safesafe

TherapeuticTherapeutic attackattack ofof thethe infarctioninginfarctioning clinicalclinical picturepicture duringduring 6 6 daysdays

CardiotonicsCardiotonics:: StrophanthinStrophanthin--K : K : 0.250.25--0.34 0.34 mg/mg/dayday, IV, IV StrophanthinStrophanthin--G : G : 0.250.25--0.50 0.50 mg/mg/dayday, IV, IV LanatosideLanatoside--C : C : 0.40 0.40 mg/mg/dayday, IV, IV DigoxinDigoxin : : 0.50 0.50 mg/mg/dayday, IV, IV

CoronaryCoronary dilatorsdilators:: Dipiridamol : 20 mg/Dipiridamol : 20 mg/dayday, IV, IV VerapamilVerapamil : 240 mg/: 240 mg/dayday, PO, PO PrenilaminePrenilamine : 180 mg/: 180 mg/dayday, PO, PO NifedipineNifedipine : 30 mg/: 30 mg/dayday, PO, PO

* The * The strophanthinstrophanthin K K oror G (IV) G (IV) waswas employedemployed in in 962 962 patientspatients, , andand ddigitalisigitalis (IV) in (IV) in 147 147

patientspatients, , duringduring thethe firstfirst phasephase ofof treatmenttreatment..

IV: IV: IntravenousIntravenous routeroute PO: Oral PO: Oral routeroute

Results (Results (IndicesIndices ofof clinicalclinical complicationscomplications):):

-- Ventricular Ventricular extrasystolesextrasystoles: 24.1%: 24.1% -- PartialPartial AV AV blockblock: 5.8%: 5.8% -- Complete AV Complete AV blockblock: 4.6%: 4.6% -- Atrial Atrial tachycardiatachycardia: 1.7%: 1.7% -- FlutterFlutter -- Atrial Atrial fibrillationfibrillation: 4.4%: 4.4% -- TachycardiaTachycardia + Ventricular + Ventricular FibrilationFibrilation: 2.7%: 2.7% -- AsystoleAsystole: 4.5%: 4.5% -- CardiogenicCardiogenic shockshock: 2%: 2% -- AcuteAcute pulmonarypulmonary edema: 1.3%edema: 1.3% -- HeartHeart failurefailure: 1%: 1% -- Overall Overall mortalitymortality: 12.2%: 12.2% -- MortalityMortality byby age: 9.4% in age: 9.4% in patientspatients underunder 70 70 yearsyears andand 26.6% in 26.6% in patientspatients over 70 over 70 yearsyears

ThisThis book in book in PortuguesePortuguese languagelanguage maymay bebe downloadeddownloaded freefree ofof charge. charge. TheThe summarysummary andand conclusionsconclusions in in EnglishEnglish are are atat http://www.infarctcombat.org/LivroTM/parte8.htmhttp://www.infarctcombat.org/LivroTM/parte8.htm

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