Positive Health Online

The thrombogenic theory, that advocates the myocardial infarction as consequence of coronary thrombosis, was introduced by the American Dr. James Bryan Herrick in 1912,[1] being entrenched worldwide in the medical culture in spite of important clinical, pathological and cardiac images studies showing discrepancies in their findings, basically conflicting with the conceived pathophysiology for this theory.

Myocardial Infarction: Credit to med.utah.edu

It is interesting to notice that Herrick in his classic paper have written about his therapeutic experience praising the use of digitalis and strophanthin for angina and in the event of coronary thrombosis, with the hope for the damaged myocardium in the direction of securing a supply of blood through friendly neighbouring vessels, so as to restore so far as possible its functional integrity. He also said that the timely use of this remedy may occasionally in such cases save live and quick results should also be thought by using it hypodermically or intravenously. Herrick’s thrombogenic theory was adopted, but his therapeutic conduct was forgotten.[2]

The Failure of Anticoagulants

The introduction of anticoagulants - coumadin derivatives and heparin - started in 1944 with the great hope that these specific and logic agents could avoid the myocardial infarction as occurred in the prevention and in the treatment of thrombophlebitis processes. Allen B Weisse, discussing about the controversies over coronary thrombosis in myocardial infarction, said in his paper from 2006:[3]

“Initial efforts to apply anticoagulant therapy early in the treatment of acute myocardial infarction and then long- term did not serve to further the cause of the coronary thrombosis hypothesis. In addition to some flaws in study design (e.g. failure to achieve true randomization in the selection of treatment and control groups), trials of anticoagulation for acute myocardial infarction were not very encouraging; any improvement in survival statistics were more likely due to prevention of thromboembolic complications (e.g. fatal pulmonary embolism) than in the treatment of the offending coronary artery thrombus itself, and the risk of bleeding sometimes life-threatening, was another consideration.

“In retrospect, such findings could have been expected. The early agents used for anticoagulation, coumadin derivatives, and later heparin, while preventing clot formation, have no effect of dissolving thrombi once formed. However, long-term studies using these agents following an initial myocardial infarction were similar disappointing in preventing recurrences”

Studies claiming about the failure of the anticoagulant use for the treatment or prevention of acute myocardial infarction were presented in 1969-1970 through the publication of reports in important medical journals like the British Medical Journal, American Medical Association Journal, Lancet, etc. [4,5,6,7]

However, some groups still using anticoagulants in acute coronary syndromes. An important study published in 2008 found that compared to placebo, patients treated with heparins had similar risk of mortality, revascularization, recurrent angina, major bleeding and thrombocytopenia.[8] 

The Failure of Thrombolysis

David K Cundiff, in a review in 2002, said the proof of efficacy of thrombolysis for acute myocardial infarction depends on 9 randomized placebo-controlled trials totalling 58,511 patients. The meta-analysis of these trials showed an overall survival advantage of 2% (11.5% vs 9.6%) in favour of thrombolysis. Iatrogenic deaths from thrombolysis complications occur in about 1% of AMI patients.[9]

Incidentally, studies also have shown the failure of thrombolytics in restraining unstable angina pectoris. Bar and colleagues expressed about the matter: “Angiographic but no clinical improvement after thrombolytic treatment with anistreplase was found in patients with unstable angina with an excess of bleeding complications. Therefore, thrombolytic treatment cannot be recommended in patients diagnosed as having unstable angina until proven otherwise.”[10 - 15]

Myocardial Reperfusion Injury

On the other hand, in patients with myocardial infarction (MI), the current treatment of choice for reducing acute myocardial ischemic injury and limiting MI size is the use of myocardial reperfusion either with thrombolytic therapy, primary percutaneous coronary intervention or coronary bypass surgery. However, the process of reperfusion can itself induce cardiomyocyte death (minor infarction/infarctlet), known as myocardial reperfusion injury, for which there is still no effective therapy. [16] These myocardial infarctlets may lead to an adverse long-term prognosis, and particularly to an increase in late mortality.[17]

The Dogmatism on Coronary Thrombosis as the Cause of Myocardial Infarction

Allen B Weisse also told in his paper[3] about the low occurrence of coronary occlusion related with the myocardial infarction, found in many studies. He said:

“Although the later studies indicated a higher percentage of thrombosis found, the number of studies performed almost contemporaneously by equally respected and competent researchers and showing much lower percentages of coronary thrombi in acute myocardial infarction was disturbing. Also of important among some of these researchers was the belief that coronary thrombosis might have occurred as the result of the myocardial infarction and not the other way around.”

Weisse noticed that in 1973 at the National Heart and Lung Institute of the National Institutes of Health in Bethesda, Maryland, a workshop was convened in which the various investigators who had grappled with the problem discussed their views.[18]

About this meeting he said that “attempts were made to reconcile the discordant findings among different groups of investigators, noting the integral relations between the alterations in the artery wall (i.e. atheroma) and thromboses that had been reported in the past. However, the end result, for the most part, consisted of a restatement of positions previously held. Although the joint conclusion emphasized the importance of coronary thrombosis, it also concluded that the idea that coronary thrombosis was a secondary event, following the infarction, was provocative and deserved serious consideration.”

In Weisse’s point of view the role of coronary thrombosis in acute myocardial infarction was resolved, once for all, through a study from Marcus DeWood and colleagues published in 1980.[19] This study involved 322 patients, all studied by coronary arteriography. The patients studied within 4 hours of the event's onset 87 percent demonstrated an occluding coronary artery thrombus on angiography. Among those studied 12 to 24 hours after the onset of symptoms, there was a decline in the frequency of thrombi, 65 percent, evidence according to Weisse showing that soon after formation coronary thrombi begin to undergo lysis. He stated that this supported the contention that among those post-mortem studies previously performed in patients who died several days after their infarction, thrombi would be reduced in size (non-occluding) or absent.

The prevalence of total coronary occlusion during the early hours in patients presenting with transmural infarction by means of coronary arteriography, found by DeWood and colleagues, was accepted peacefully by the large majority of the cardiological community as the definitive clinical evidence about the causal role of thrombosis in acute myocardial infarction (AMI). It also brought some relief in this area by keeping intact the medical options and directions dictated by the Mainstream and thus passing over necropsy findings and other pathological studies contradicting the coronary thrombosis concept.

Then, the voice of dissenters advocating coronary thrombosis as consequence of myocardial infarction has been mostly lost since the eighties, due to the mainstream discourse in favour of the coronary thrombosis theory as cause of myocardial infarction.

Even thus the acute myocardial infarction occurring in the absence of obstructive coronary artery disease (CAD), still generating questions as occurred in 2016 through a position of a working group from the European Heart Journal. Some of their questions are: “What is the mechanism of the myocardial damage in these patients?” and “Do these patients differ from those with obstructive CAD?”[20]

Coronary Thrombosis: Cause or Consequence of Myocardial Infarction?

Taking in view the controversies already mentioned and the results obtained in the study by Marcus DeWood and colleagues[19] we present here old and new pathological studies aside critical reasoning about coronary thrombosis as the cause of myocardial infarction:

a.    Friedberg and Horn suggested in 1939 that the term coronary thrombosis should be abandoned in favour of the more generic one of acute myocardial infarction. In their paper they say that “the clinical and electrocardiographic features of coronary thrombosis may be observed in patients in whom a coronary artery thrombus is subsequently not found at necropsy as has been noted by Libman, Obendorfer, Buchner, Hamburger and Saphir, Dietrich, Levy and Bruenn and others;”[21]

b.    Hermann and colleagues published in 1941 their findings that the thrombotic occlusion could occur without infarction when the collateral circulation appeared adequate and if an infarct has happened, it could be attributed to an occlusive thrombus at a critical location in the coronary tree;[22-24]

c.    Miller and colleagues in 1951 pointed out that subendocardial infarcts were rarely associated with coronary thrombi;[25]

d.    Spain and Bradess published in 1960 their findings showing complete coronary obstruction of atherosclerotic nature, representing around of 75% of the cases and recent coronary thrombosis in just 25% of the autopsied cases. Also, they have observed crescent incidence of coronary thrombosis with the crescent duration of survival after the myocardial infarction. Less than a hour with 16% of thrombosis, between 1 and 24 hours with 37% and in more than 24 hours with 52% of coronary thrombosis*;[26,27]

e.    Hellstrom in 1970 demonstrated experimentally the coronary thrombosis secondary to acute myocardial infarction caused by ligature of the coronary artery;[28]

f.    William Roberts suggested in 1972 that the coronary arterial thrombi are consequences rather than causes of acute myocardial infarction. In his study involving 107 patients who were submitted to necropsy he found that only 54% of those with a transmural infarction, and only 10% of those with subendocardial necrosis, had a thrombus in the infarct related artery; [29] 

g.    Quintiliano H. de Mesquita pointed out in 1996 that the interpretation given by DeWood in 1980 [19] about the angiographic images, suggestive of intracoronary thrombus, do not correspond to the absolute reality whether it represents a true thrombus or just aggregated platelets that are precocious, unstable or reversible commonly registered in the first hours of unstable angina and in the course of the acute myocardial infarction;[30] 

h.    Giorgio Baroldi and colleagues in a study from 2005, discussing the findings from DeWood,[19] told that the first main question is how many of the 87% cineangio occlusion are pseudo-occlusion and whether the "layered" thrombus recovered at bypass surgery was a true thrombus or a coagulum which frequently show a layering of blood elements not seen in thrombus formation. Also saying that "Red" thrombus, namely a coagulum, is frequently and erroneously considered as thrombus;[31]

i.    Giorgio Baroldi and colleagues in a study published in 2005 discussed about the findings that the frequency of an occlusive thrombus is significantly higher in the largest infarcts supporting its secondary formation;[32,33]

j.    In a study from 2001 Yasunori Ueda and colleagues show that in a significant number of cases angioscopic examination continues to find thrombus on the presumed culprit lesion, at 6 months after myocardial infarction;[34] 

k.    Murakami in a study published in 1998 using intracoronary catheters to aspirate occlusive tissues, performed during the acute myocardial infarction, have confirmed the pathological findings that intracoronary thrombus is absent in a substantial number of patients indicating it contributes little to the pathogenesis of average acute myocardial infarction;[35]

l.    Rittersma and colleagues in a study published in 2005 examined retrieved thrombus material aspirated using the percutaneous thrombectomy catheter in 211 patients undergoing primary percutaneous coronary intervention within six hours of symptom onset. They then established, by histological indicators, the age of the aspirated thrombi. The researchers found thrombus in 199 of the 211 patients, of whom fresh thrombus was identified in just under half. By contrast, 51% of patient samples contained thrombus that had lytic or organized changes suggesting that it had originated days or weeks before the occlusive event. They said that “Strikingly, clinical characteristics did not differ between the patients with fresh thrombus and those with ‘older’ thrombus, although men were more likely to have fresh thrombus than were women.”;[36]

m.   The Post-hoc analysis of the PASSION trial, published in 2012, found that the use of thrombus aspiration in adjunct to primary percutaneous coronary intervention (PPCI) did not affected rates of major adverse cardiac events at 2 years follow-up, as compared with conventional PPCI;[37] 

n.    Bo Lagerqvist and colleagues in a study published in 2014 confirm the findings from the Passion Trial that routine aspiration of thrombus before primary percutaneous coronary intervention in patients with ST segment elevation (STEMI) has not been proved to reduce the rate of death and rehospitalization for myocardial infarction at 1 year after the procedure;[38]

o.    Myocardial infarction associated with normal coronary arteries is a well-known condition. The overall prevalence rate of myocardial infarction with normal coronary arteries is considered to be low, varying from 1% to 12% depending on the definition of ‘normal’ coronary arteries;[39,40] 

p.    Arbustini and colleagues in a study published in 1993 found in a series of 132 autopsies of hearts from patients who died of noncardiac causes that coronary thrombi were shown to overlay the intima of a coronary vessel independently of plaque type and severity; [41]

q.    Ambrose and colleagues found in 1988 that the risk of a heart attack or other acute myocardial events is not proportional to the severity of coronary stenosis. Several studies in which more than one angiography was performed in patients who developed acute syndromes showed that most of these syndromes appear to be developed from lesions that on the first angiography caused not significant stenosis. Also saying these less severe stenotic lesions lead to myocardial infarction because they have not developed 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 have an increased risk for a myocardial infarction than an obstruction of 90%;[42-44] 

r.    Recent papers confirm the finds that non-obstructive coronary artery disease is associated with significantly increased risk of myocardial infarctions, consistent with previous studies indicating the majority of myocardial infarctions are caused by non-significant stenoses. Interesting to mention is that one of these found in patients without obstructive CAD had equivalent rates of all-cause and cardiac rehospitalization as those with obstructive CAD, indicating that the downstream effects of the patients’ chest pain, whether truly ischaemic or not, were the same in these two groups;[45-47]

s.    The plaque instability and rupture might start in a considerable time before the AMI, according to some studies.(36, 48) Stretching, tearing and perforation, related to cholesterol crystallization and expansion, may play a role in the process.(49,50) Also, sympathetic overstimulation and hemodynamic forces like left ventricular muscle mass and elevated heart rate may be associated with the future development of plaque disruption;[51]

t.    A recent study by Armin Arbab-Zadeh and Valentin Fuster, says: “Despite major advancements in coronary artery imaging and identification of atherosclerotic lesion morphology associated with rupture, there is no conclusive evidence that individual plaque assessment better predicts acute coronary event risk than established risk factors, such as the extent and severity of coronary artery disease. Pathology and clinical studies consistently demonstrate that atherosclerotic plaques rupture without clinical symptoms much more frequently than is widely acknowledged, challenging the notion of a close association between plaque rupture and clinical events. Conversely, the atherosclerotic disease burden is a consistent, strong predictor of adverse cardiovascular events and deserves greater attention. Current data suggest that rather than focusing on individual coronary arterial lesions, we need a comprehensive, integrative approach for identifying and managing patients at risk of adverse cardiovascular events;[52]

u.    A “State-of-the-Art” review and commentary by Mario Marzilli and colleagues, published in 2012, have the following conclusion: “A large body of evidence conclusively suggests that coronary artery obstruction is only 1 element in a complex multifactorial pathophysiological process that leads to Ischemic Heart Disease (IHD) and that the presence of obstructive lesions in patients with IHD does not necessarily imply a causative role. A more comprehensive approach seems necessary to refocus preventive and therapeutic strategies and to decrease morbidity and mortality. To this effect, we propose a shift in approach to include the myocardial cell as well as the coronary vessel”;[53]

v.    Erhardt and colleagues in 1973 published findings that radioactive fibrinogen administered to patients with AMI was incorporated into the entire coronary thrombus in non-survivors, supporting the view that myocardial infarction occurs first and thrombus formation is a secondary event. Another study published in 1976 by the same group confirmed the previous findings;[54,55]

w.   Giorgio Baroldi, emphasizing the inconsistency of the current myths about the behaviour and meaning of components of the human coronary atherosclerotic plaque, told in 2004 that the degree and number of severe coronary plaques do no predict onset, course, complications and death in coronary heart disease (CHD);[56]

x.    Many other studies have advocated coronary thrombosis as consequence of myocardial infarction;[57-62]

y.    A study published at JAMA in 2016 found that temporal increases in levels of cardiac troponin T by high-sensitive essay (hs-cTnT), suggestive of myocardial injury or progressive myocardial damage, was independently associated with later risk of death, coronary heart disease, and especially heart failure in apparently healthy middle-aged people. The study which enrolled 8.838 participants (mean age 56) was followed from January 1990 to December 2011, with an analysis of 6-year change in hs-cTnT. In their conclusion the authors say that their results indicated that 2 measurements of hs-cTnT appeared to be better than 1 for characterizing risk and that large increase in hs-cTnT are particularly deleterious. Also that temporal change in hs-cTnT may help guide the preventive management of asymptomatic persons at risk for coronary artery disease. This study didn’t discuss about the etiology of the progressive myocardial injury found. However one could notice and surmise from it the absence of relationship to the thrombocentric coronary heart disease universe.[63] On the other hand, studies show that mental stress and exercise may induce cardiac troponin T (hs-cTnT) elevation, in apparently healthy individuals;[64-65]

z.    George E Burch and colleagues raised an important point in 1972 when they said: “The patient with coronary artery disease does not die of coronary artery disease; he dies of myocardial disease. It is the heart muscle that is the pumping element. To accept the term “heart muscle disease” as the primary factor in coronary artery disease assists the physician in management of the patient.”.[66]

The studies and reasoning listed above provide very strong evidences that can clarify once and for all any doubts about the matter, pointing out that the occasional coronary thrombosis is a consequence of the process and not the real cause of acute myocardial infarction or death of the patient with coronary-myocardial disease.

On the other hand there are poor or non-existent benefit results (In absolute risk reduction statistics - Scientific and clinical significance is usually set at 5% level), justifying the use of drugs, coronary bypass surgery, angioplasty and stents, current medical treatments based on the coronary thrombosis theory. These are treating symptoms and/or biomarkers not the disease itself, with the possible risk of harms to the patients.[67-76]

The Myogenic Theory of Myocardial Infarction

Our interest on the discussion about this subject is related to our position as advocates of the Myogenic Theory of Myocardial Infarction, developed by my father in law, the Brazilian Cardiologist Quintiliano H. de Mesquita, in 1972. In the myogenic theory point of view coronary thrombosis is a consequence of the myocardial infarction being cardiac glycosides (digitalis, strophanthin, etc..) the fundamental and specific therapeutic.[77-79].

Dr Mesquita (1918 - 2000†) Photo, 1983

Among other developments from Dr Mesquita are the Ventricular Aneurism Surgery of the Heart
performed by Charles Bailey in 1954 and the first diagnosis of Right Ventricular Infarction, in vivo, by ECG,
made in 1958. (He did more than 30 pioneer contributions to medical literature)

Anticoagulant Use by Dr Mesquita

One point I would like to emphasize is that Dr Mesquita received the introduction of the anticoagulants in 1944 with large enthusiasm and the hope that finally reached the solution for the prevention of myocardial infarction. Then, he applied anticoagulants, particularly in unstable angina, during a period of 10 years (1944-1954) with records of absolute failure in restraining unstable angina and in prevention of infarction, leading to his abandonment of this therapeutic. Thenceforth, he started to use only the coronary dilator having published in 1962 a study involving 296 patients with myocardial infarction treated at their home, recording the exceptional mortality of 7.7%, comprising 14 cases of heart failure, 6 cases of sudden death and 3 cases of cardiogenic shock. The low mortality found in his study was later justified due to the habitual conduct from Dr Mesquita to apply intravenous strophanthin in all cases presenting precocious pulmonary stasis in the acute myocardial infarction, ever interpreted as incipient left ventricular insufficiency.[80]

Our tributes to Dr Quintiliano H de Mesquita

In November of 2012 I made a presentation about the myogenic theory in a lecture during the Fourth International Conference of Advanced Cardiac Sciences - the King of Organs Conference, held in Saudi Arabia.[81]

(L-R) David Diamond, Malcolm Kendrick, Carlos Monteiro and Paul Rosch, during a break in proceedings at The King of Organs Conference

In 2014 was published our article Stress as Cause of Heart Attacks: The Myogenic Theory telling the history of its development and making a comparison between the thrombogenic theory versus the myogenic theory in its different philosophies, therapeutics and outcomes for the three stages of ischemic heart disease.[82]

Book Myogenic Theory of Myocardial Infarction, 1979[75]

The myogenic theory developed by Dr Mesquita was the template for our acidity theory of atherosclerosis launched in 2006.[83] In our view the acidic environment evoked by chronic stress has an important role in the mechanism generating atherosclerotic lesions. It follows the response to injury concept of atherosclerosis.

 “Science is a Method of Investigation to Search for Evidences, not Beliefs nor Wishes,
Conveniences or Preferences”

References

1.    Herrick JB. Clinical features of sudden obstruction of the coronary arteries. JAMA 1912;59:2015-2020 (Reproduced by JAMA in 1983 at http://jama.jamanetwork.com/article.aspx?articleid=388174 )

2.    Carlos ETB Monteiro, Digitalis and Strophanthin in Stable Ischemic Heart Disease and to Restrain or Reverse Heart Attacks - An Amazing and Shocking Story. Positive Health Online issue 229 - April 2016 at http://goo.gl/l6oxZ8

3.    Weisse AB. The elusive clot: the controversy over coronary thrombosis in myocardial infarction. J Hist Med Allied Sci. 2006 Jan;61(1):66-78 at http://jhmas.oxfordjournals.org/content/61/1/66.abstract

4.    Report of the Working Party on Anticoagulant Therapy in Coronary Thrombosis to the Medical Research Council. Brit Med J 1969;1:335-42 at www.ncbi.nlm.nih.gov/pmc/articles/PMC1982596/ 

5.    Long Term anticoagulation after myocardial infarction. Final Report of the Veterans Adninistration Cooperative Study. J Am Med Assoc 297:2263-67. 1969.

6.    Meuwissen OGAT, Vervoorn Ac, Cohn C, et al. Double blind trial of long term anticoagulant treatment after myocardial infarction. Acta Med Scand 186:361-68. 1969.

7.    Collaborative analysis of long term anticoagulation administration following acute myocardial infarction. An international anticoagulant review group. Lancet 1:203-09. 1970.

8.    Magee K et al. Heparin versus placebo for acute coronary syndromes. Cochrane Database Syst Rev. 2008 Apr 16;(2) at http://www.ncbi.nlm.nih.gov/pubmed/18425889

9.    David K. Cundiff, Thrombolysis for Acute Myocardial Infarction: Drug Review, Medscape General Medicine, January 2, 2002, at www.medscape.com/viewarticle/414942

10.   Rentrop P et al. Selective Intracoronary Thrombolysis in Acute Myocardial Infarction and Unstable Angina Pectoris Circulation, 1981;63:307 at https://circ.ahajournals.org/content/63/2/307.full.pdf+html

11.   Williams DO et al. Intravenous Recombinant Tissue-Type Plasminogen Activator in Patients With Unstable Angina Pectoris Results of a Placebo-Controlled, Randomized Trial. Circulation 1990;82:376 at http://circ.ahajournals.org/content/82/2/376.full.pdf

12.   Leinbach RC. Thrombolysis in unstable angina. Circulation, 1992;85:376 at http://circ.ahajournals.org/content/85/1/376.long

13.   Freeman MR et al. Thrombolysis in Unstable Angina Randomized Double-Blind Trial of t-PA and Placebo. Circulation, 1992:150 at http://circ.ahajournals.org/content/85/1/150.full.pdf

14.   Bar FW, et al. Thrombolysis in Patients With Unstable Angina Improves the Angiographic but Not the Clinical Outcome Results of UNASEM, A Multicenter, Randomized, Placebo-Controlled, Clinical Trial With Anistreplase. Circulation 1992;86:131 at http://circ.ahajournals.org/content/86/1/131.full.pdf

15.   Early effects of tissue-type plasminogen activator added to conventional therapy on the culprit coronary lesion in patients presenting with ischemic cardiac pain at rest. Results of the Thrombolysis in Myocardial Ischemia (TIMI IIIA) Trial. Circulation 1993;87:38 at http://circ.ahajournals.org/content/87/1/38.long

16.   Derek J. Hausenloy and Derek M. Yellon. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest. 2013;123(1):92–100 at https://www.jci.org/articles/view/62874

17.   Abdelmeguid AE and Topol EJ. The Myth of the Myocardial ‘Infarctlet’ During Percutaneous Coronary Revascularization Procedures. Circulation. 1996; 94:3369-3375

http://circ.ahajournals.org/content/94/12/3369.full

18.   Chandler AB, Chapman I, Erhardt LR, Roberts WC, Schwartz CJ, Sinapius D, Spain DM, Sherry S, Ness PM, Simon TL. Coronary thrombosis in myocardial infarction. Report of a workshop on the role of coronary thrombosis in the pathogenesis of acute myocardial infarction. Am J Cardiol 34:823. 1974.

19.   DeWood MA, Spores J, Notske R et al. Prevalence of total coronary oclusion during the early hours of transmural myocardial infarction. N Engl J Med 303:897-902. 1980.

20.   Stefan Agewall, John F. Beltrame, Harmony R. Reynolds, Alexander Niessner, Giuseppe Rosano, Alida L. P. Caforio, Raffaele De Caterina, Marco Zimarino, Marco Roffi, Keld Kjeldsen, Dan Atar, Juan C. Kaski, Udo Sechtem, Per Tornval. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. European Heart Journal, First published online: 28 April 2016 http://eurheartj.oxfordjournals.org/content/early/2016/04/28/eurheartj.ehw149

21.   Friedberg CK and Horn H. Acute myocardial infarction not due to coronary artery occlusion. J. Am Med Assoc 112(17):1675-1679. 1939.

22.   Angina Pectoris, coronary failure and acute myocardial infarction: The role of coronary occlusions and collateral circulation, JAMA 116(2):91-97. 1941.

23.   Multiple fresh coronary occlusions in patients with antecedent shock, Arch Intern Med 68(2):181-198. 1941.

24.   Experimental studies on the effect of temporary occlusion of coronary arteries; The production of myocardial infarction, American Heart Journal V22;I3 -374-389). 1941.

25.   Miller RD and col. Myocardial infarction with and without acute coronary occlusion: A pathologic study. AMA Arch Intern Med 88(5):597-604). 1951.

26.   Spain, DM and Bradess VA. The relationship of coronary thrombosis to coronary atherosclerosis and ischemic heart disease – a necropsy study covering a period of 25 years, Am J Med Sci, 240:7-1, 1960.

27.   Spain DM and Bradess VA. Frequency of coronary thrombosis related to duration of survival from onset of acute fatal episodes of myocardial ischemia. Circulation, 22:816, 1960.

28.   Hellstrom, HR. Myocardial infarction as a cause of coronary thrombosis. Circulation, 42, Suppl. III); 165, 1970.

29.   Roberts, W.C.:; Coronary arteries in fatal acute myocardial infarction, Circulation,42:215, 1972 at http://circ.ahajournals.org/content/45/1/215.full.pdf 

30.   Mesquita, QHde. Book: Remédio boicotado substitui cirurgia de ponte de safena, Compset,, 1996.

31.   Baroldi G, Bigi R, Cortigiani L: Ultrasound imaging versus morphopathology in cardiovascular diseases: coronary collateral and myocardial ischemia. Cardiovasc Ultrasound 2005, 3:6 at http://cardiovascularultrasound.biomedcentral.com/articles/10.1186/1476-7120-3-6

32.   Baroldi G, Bigi Ri and Cortigiani L. Ultrasound imaging versus morphopathology in cardiovascular diseases. Myocardial cell damage. Cardiovascular Ultrasound 3:32., 2005 at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1262736/

33.   Roberts W. C. 1974. Coronary Thrombosis and Fatal Myocardial Ischemia. Circulation;49;1-3 Full free paper at http://circ.ahajournals.org/cgi/reprint/49/1/1.pdf

34.   Yasunori Ueda, Masanori Asakura, et al.. The healing process of infarct-related plaque: Insights from 18 months of serial angioscopic follow-up. Am Coll Cardiol 2001, 38:1916-1922.

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

36.   Rittersma SZH, van der Wal AC, Koch KT, et al. Plaque instability frequently occurs days or weeks before occlusive coronary thrombosis. A pathological thrombectomy study in primary percutaneous coronary intervention. Circulation 2005; 111:1160-1165 at http://circ.ahajournals.org/content/111/9/1160.full

37.   Martin A Vink, Maurits T Dirksen, et al. Lack of long-term clinical benefit of thrombus aspiration during primary percutaneous coronary intervention with paclitaxel-eluting stents or bare-metal stents: Post-hoc analysis of the PASSION trial. Catheterization and Cardiovascular Interventions Volume 79: Issue 6, pages 870-877. 1 May 2012.

38.   Bo Lagerqvist, Ole Fröbert et al. Outcomes 1 year after thrombus aspiration for myocardial infarction. N Engl J Med 371: 1111- 1120. 2014.

39.   Legrand V, Deliege M, Henrard L, Boland J, Kulbertus H: Patients with myocardial infarction and normal coronary arteriogram. Chest 82(6):678-685. 1982.

40.   Raymond R, Lynch J, Underwood D, Leatherman J, Razavi M: Myocardial infarction and normal coronary arteriography: a 10 year clinical and risk analysis of 74 patients. J Am Coll Cardiol 11(3):471-477.). 1988.

41.   Arbustini E, Grasso M, Diegoli M, et al. Coronary thrombosis in non-cardiac death. Coron Artery Dis 4:751–9. 1993.

42.   Ambrose J A, Tannenbaum M A et al, Angiographic progression of coronary artery disease and the development of myocardial infarction, J Am Coll Cardiol 12:56-62. 1988.

43.   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 78:1157-66. 1988. 

44.   John A Ambrose, Valentin Fuster, The risk of coronary occlusion is not proportional to the prior severity of coronary stenoses, Editorial, Heart 79:3-4). 1998.

45.   Thomas M. Maddox, Maggie A. Stanislawski et al. Nonobstructive coronary artery disease and risk of myocardial infarction, JAMA. 312(17):1754-1763. 2014. doi:10.1001/jama.2014.14681 

46.   Rossini R, Capodanno D, Lettieri C et al . Long-term outcomes of patients with acute coronary syndrome and nonobstructive coronary artery disease. Am J Cardiol 112(2):150-5. 15 Jul 2013.

47.   Anna Grodzinsky, Suzanne V. Arnold, Kensey Gosch et al. Angina Frequency After Acute Myocardial Infarction In Patients Without Obstructive Coronary Artery Disease. European Heart Journal – Quality of Care and Clinical Outcomes, published August 19, 2015, full text at http://ehjqcco.oxfordjournals.org/content/ehjqcco/early/2015/08/05/ehjqcco.qcv014.full.pdf 

48.   Ojio S, Takatsy H, et al. 2000. Considerable time from the onset of plaque rupture and/or thrombi until the onset of acute myocardial infarction in humans coronary angiographic findings within 1 week before the onset of infarction. Circulation;102:2063 at http://www.circ.ahajournals.org/cgi/reprint/102/17/2063

49.   Abela GS, Aziz K. Cholesterol crystals cause mechanical damage to biological membranes: a proposed mechanism of plaque rupture and erosion leading to arterial thrombosis. Clin Cardiol. 28:413. 2005.

50.   Abela GS, Aziz K. Cholesterol crystals rupture biological membranes and human plaques during acute cardiovascular events: a novel insight into plaque rupture by scanning electron microscopy. Scanning. 28:1–10. 2006.

51.   Ulrich E. Heidlan, Bodo E. Strauer. 2001. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption, Circulation 104:1477 at http://circ.ahajournals.org/cgi/content/full/104/13/1477

52.   Armin Arbab-Zadeh, Valentin Fuster. "The Myth of the “Vulnerable Plaque -- Transitioning From a Focus on Individual Lesions to Atherosclerotic Disease Burden for Coronary Artery Disease Risk Assessment", J Am Coll Cardiol. 2015; doi:10.1016/j.jacc.2014.11.041 at http://content.onlinejacc.org/article.aspx?articleID=2091922

53.   Mario Marzilli, C. Noel Bairey Merz,, William E. Boden, Robert O. Bonow, Paola G. Capozza, William M. Chilian, Anthony N. DeMaria, Giacinta Guarini, Alda Huqi, Doralisa Morrone, Manesh R. Patel, William S. Weintraub. Obstructive coronary atherosclerosis and ischemic heart disease: An elusive link!. JACC Vol 60, No. 11, 2012; September 11: 951-6 at http://content.onlinejacc.org/article.aspx?articleid=1356505

54.   Erhardt LR, Lundman T, Mellstedt H. Incorporation of 125 I-labelled fibrinogen into coronary arterial thrombi in acute myocardial infarction in man. Lancet 1(7800):387-90. 1973.

55.   Erhardt, LR, Unge G and Boman,G: Formation of coronary arterial thrombi in relation to onset of necrosis in acute myocardial infarction in man, a clinical and autoradiographic study, Am Heart J, 91:592, 1976.

56.   Giorgio Baroldi, Riccardo Bigi and Lauro Cortigiani. Ultrasound imaging versus morphopathology in cardiovascular diseases. Coronary atherosclerotic plaque. Cardiovascular Ultrasound 2004, 2:29 at http://cardiovascularultrasound.biomedcentral.com/articles/10.1186/1476-7120-3-6

57.   Eliot, RS. Baroldi G and Leone A: Necropsy studies in myocardial infarction with minimal or no coronary luminal reduction due to atherosclerosis, Circulation, 49:1127,1974 at http://circ.ahajournals.org/content/49/6/1127.full.pdf

58.   Bulkley, BH, Klacsmann, PG, Hutchins, GM: Angina pectoris, myocardial infarction and sudden cardiac death with normal arteries: a clinicopathologic study of 9 patients with progressive systemic sclerosis, Am Heart J, 95:563,1978.

59.   Baroldi, G: Acute coronary occlusion as a cause of myocardial infarct and sudden coronary heart death, Am J Cardiol, 16:899,1965.

60.   Baroldi. G: Editorial. Coronary heart disease: significance of the morphologic lesions, Am Heart J, 85: 1,1973

61.   Baroldi, G: Coronary thrombosis: facts and beliefs, Am Heart J, 91:683,1976.

62.   Baroldi, G: Different types of myocardial necrosis in coronary heart disease. A pathophysiologic review of their functional significance, Am Heart J, 89:742,1975.

63.   McEvoy JW, Chen Y, Ndumele CI. Six-year change in high-sensitivity cardiac troponin T and risk of subsequent coronary heart disease, heart failure, and death. JAMA Cardiol 2016; Full free text at http://cardiology.jamanetwork.com/article.aspx?articleid=2527090

64.   Lazzarino AI, Hamer M, Gaze D, Collinson P, Steptoe A. The association between cortisol response to mental stress and high-sensitivity cardiac Troponin T plasma concentration in healthy adults. J Am Coll Cardiol. 62(18):1694-1701. 2013. Full text at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807660/

65.   Rob Shave, Aaron Baggish et al. Exercise-Induced Cardiac Troponin Elevation: Evidence, Mechanisms, and Implications. J Am Coll Cardiol 56:169–76). 2010. Full text at http://www.sciencedirect.com/science/article/pii/S0735109710017055

66.   Burch GE and col. Ischemic cardiomyopathy. Am Heart J, March, 83(3): 340-50, 1972.

67.   http://www.thennt.com/nnt/aspirin-to-prevent-a-first-heart-attack-or-stroke/

68.   http://www.thennt.com/nnt/coronary-heart-bypass-surgery-for-prevention-of-death/

69.   http://www.thennt.com/nnt/coronary-stenting-for-non-acute-coronary-disease-compared-to-medical-therapy

70.   http://www.thennt.com/nnt/early-invasive-management-for-acute-coronary-syndromes/

71.   http://www.thennt.com/nnt/statins-for-acute-coronary-syndrome/

72.   http://www.thennt.com/nnt/statins-for-heart-disease-prevention-with-known-heart-disease/

73.   http://www.thennt.com/nnt/statins-for-heart-disease-prevention-without-prior-heart-disease/

74.   http://www.thennt.com/nnt/beta-blockers-for-heart-attack/ 

75.   Elmariah, Sammy; Mauri, Laura; Doros, Gheorghe; Galper, Benjamin Z; O'Neill, Kelly E; Steg, Philippe Gabriel; Kereiakes, Dean J; Yeh, Robert W (November 2014). "Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis". The Lancet 385: 792–798. doi:10.1016/S0140-6736(14)62052-3

76.   FDA Drug Safety Communication: FDA review finds long-term treatment with blood-thinning medicine Plavix (clopidogrel) does not change risk of death". FDA. 11-06-2015.at http://www.fda.gov/Drugs/DrugSafety/ucm471286.htm

77.   Memorial to Dr. Quintiliano H. de Mesquita at http://www.infarctcombat.org/qhm/homepage.html

78.   Quintiliano H. de Mesquita. Book Myogenic Theory of Myocardial Infarction, 1979. Summary in English at www.infarctcombat.org/LivroTM/parte8.htm

79.   Myogenic Theory of Myocardial Infarction: News, presentations, articles, books, etc.. at http://www.infarctcombat.org/MyogenicTheory.html

80.   Mesquita, QHde. Anticoagulante e Enfarte Miocárdico, Publicações Médicas, 211:3. 1962.

81.   Carlos ETB Monteiro, Video presentation about the myogenic theory in the Fourth International Conference of Advanced Cardiac Sciences - The King of Organs Conference, 2012, Saudi Arabia at https://www.youtube.com/watch?v=VdheMY2yvjY (Short)

82.   Carlos ETB Monteiro, “Stress as Cause of Heart Attacks - The Myogenic Theory”. Published at the Journal Wise Traditions in Food, Farming, and the Healing Arts, Fall 2014. Reproduced by Positive Health Online, Edition 222 - May 2015. See at http://www.westonaprice.org/modern-diseases/cardiovascular-disease/stress-as-cause-of-heart-attacks/ 

83.   Carlos Monteiro, Acidity Theory of Atherosclerosis -- History, Pathophysiology, Therapeutics and Risk Factors – A Mini Review. Positive Health Online, Edition 226, November 2015 at http://goo.gl/AejGAV