Heart attacks occur, according to the modern view, primarily when unstable plaques in the lining of coronary arteries rupture. This causes a clot to develop, which in some cases ultimately compromises the flow of blood to the heart. In the scientific literature, these clots are called “thrombi,” the plural of “thrombus,” and the process is called “thrombosis.” When the cells are vulnerable enough and the thrombosis severe enough, the cells die. Widespread death and destruction of these cells produces what we colloquially call a “heart attack.” While this sequence of events involves many different issues that each deserve attention, this article will focus on evidence for the essential role of thrombosis in heart attacks.
Origins of the Thrombosis Theory
Though this is the modern view, it is also nearly a century old. It dates at least to 1926, when R.L. Benson described thrombi forming on top of plaques that had physically broken.1
Other research in the 1930s supported the concept of the rupturing plaque,2 but the issue was hardly settled. Several groups of investigators in the 1930s and 1950s looked for ruptured plaques in the coronary arteries of humans who had died from heart disease, but found them in only a minority of cases.3
In the 1930s, moreover, J.C. Patterson put forth a competing theory: tiny vessels from within the wall of the coronary artery invade the inside of the plaque and hemorrhage there, filling the plaque with blood and causing it to expand until it blocks the flow of blood to the heart.3 In this theory, neither the rupture of plaques nor the consequent thrombosis plays a meaningful role. Patterson’s theory was controversial but influential, and debate about its plausibility captured the minds of many medical scientists4 even as direct evidence supporting it remained scant.3
In the 1960s, Paris Constantinides studied coronary arteries isolated from twenty consecutive cases of fatal heart attacks.3 He found thrombi on the surfaces of ruptured plaques in every single case. Constantinides had examined the entire portion that had undergone thrombosis within each affected artery, whereas most of his predecessors had spot-checked these sections. He thus argued that his predecessors could have easily missed clear evidence of ruptured plaques simply because they were not looking at the entire section, and he concluded that his own results were superior.
Challenges to the Thrombosis Theory
While some experts in that era considered the analysis of Constantinides to be the pivotal work that finally reestablished the importance of plaque rupture, others argued that thrombi did not cause heart attacks at all. Rather, they argued, heart attacks cause thrombosis. If thrombi were a consequence rather than a cause of heart attacks, then whether they always form at the site of ruptured plaques would hardly seem important.
One of the reasons for this controversy was that different postmortem analyses found occlusive coronary thrombi in wildly different proportions of fatal heart attacks.6 For example, Baroldi and colleagues published an analysis of 100 cases where only about 40 percent were associated with thrombotic occlusions, while Davies and colleagues published an analysis of 500 cases where the proportion was 90 percent. Others reported proportions that were higher, lower, or somewhere in between, resulting in data that was all over the map and very difficult to interpret.
Spain and Bradess, moreover, had published a postmortem analysis in 1960 showing that thrombi were more common in people who survived longer after the onset of their heart attacks. One way to interpret this study is that thrombi form during some window of time that exists after the onset of the heart attack but before death. Thus, the longer that window of time, the more likely it is that the investigator will find a thrombus. This study remained influential through the 1980s, with opponents of the thrombosis theory using it to argue that thrombi were the consequence rather than the cause of heart attacks.
Michael Davies from St. George’s Medical School in London and several of his colleagues—all supporters of the thrombosis theory—argued that the contradictions within the evidence were largely driven by investigators lumping together sudden cardiac death, caused by electrical disturbances in the heart, and heart attacks, caused by blockages of blood flow.4,5 They argued that thrombosis does usually occur in sudden death, but the thrombi found are smaller than those found in heart attacks and harder to detect using the techniques that were most common at the time. Studies that included larger proportions of people who died from sudden death, according to the Davies team, were thus likely to report a lower incidence of thrombosis. People who died shortly after the onset of symptoms, moreover, were likely to have died from sudden death rather than a heart attack. Thus, the reason Spain and Bradess found fewer thrombi in the coronary arteries of people who died very soon after the onset of their symptoms is because these people had actually died from sudden cardiac death rather than from heart attacks.
In 1980, coronary angiography allowed researchers to look for the first time for coronary thrombi in live people suffering from heart attacks.7 Coronary thrombi were almost always present in the first six hours after the onset of symptoms, and their incidence gradually declined to 65-70 percent over the course of twenty-four hours. This finding suggested that thrombi begin dissolving over the course of the day after a heart attack. When viewing the work of Spain and Bradess within the light of this study, it would seem likely that they had misclassified cases of sudden death rather than that they showed thrombi to begin forming only in the aftermath of a heart attack.
Competing groups of investigators attacked this chicken-and-egg debate head-on in the 1970s using radiolabeled fibrinogen.4 Fibrinogen is a protein that is broken down into fibrin during the clotting process. Fibrin then clumps together with platelets to form a thrombus. By labeling fibrinogen with a radioactive isotope, medical researchers were able to trace its metabolism to fibrin within live humans—providing that some of the humans died by the end of the experiment.
One group of investigators gave radiolabeled fibrinogen to patients undergoing a heart attack as soon as possible after the onset of pain. In those who died, the radiolabel was found in the thrombi that appeared to be blocking their coronary arteries. The investigators argued that the thrombus must have formed after the heart attack since the heart attack began before they administered the radiolabel.4
The Davies team, however, followed a similar procedure and came to the opposite conclusion by examining the clots more closely. They found no radiolabel in the portion of the thrombus in contact with the blood vessel. They instead found the radiolabel exclusively on the opposite end of the thrombus.4
Thrombosis is a dynamic process, and a thrombus can continue to grow larger or dissolve, depending on whether the body continues to perceive that the thrombus is needed. The conclusion was simple: the thrombus forms before the heart attack occurs, but it continues to grow for some time afterwards before it begins dissolving. If medical researchers give radiolabeled fibrinogen to patients who have just begun having a heart attack, their thrombi will continue to grow and incorporate radiolabeled fibrin in the process, but will accumulate the label only in their outer edges.4
Plaque : Stability or Stenosis ?
The Davies team made critical strides in defining the characteristics of an unstable plaque: rich in oxidized lipids, poor in collagen.4 More recently, we have also discovered that calcium salts make a plaque much more likely to rupture.8 Thus, the danger a plaque poses has very little to do with how big it is: the danger is rather a result of its instability, which is determined by its composition.
In 1985, the Davies team warned that many medical experts were jumping the gun by assuming that the degree of narrowing produced by a plaque—called “stenosis”—is a good index of how likely it is to rupture.4 While some studies showed that the two correlated, the Davies team argued that these studies were fundamentally flawed. Medical investigators would treat coronary thrombosis with anticoagulants and then use angiography to measure the degree of stenosis and collect the data. These studies therefore told us absolutely nothing about the degree of narrowing before the rupture, and as a result provided no evidence at all to justify using the degree of stenosis as an index of the danger posed by a plaque.
In fact, a pivotal study published just two years later in 1987 showed that plaque rupture is an essential prerequisite to arterial narrowing.9 Until a plaque ruptures, it actually grows outward, not inward. As a result, the wall of the blood vessel expands, and the pathway through which blood flows—called the “lumen”—stays the same. Sometimes the lumen may even increase in size.
If the plaque ruptures, thrombosis will likely occur. Several scenarios could allow the thrombosis to produce an adverse cardiovascular event such as a heart attack: it may itself be severe enough to block the artery; it may get caught in a flap of tissue and the flap of tissue may block the artery; or pieces of the thrombus may break off and block the smaller vessels that extend from the coronary artery to nourish the heart. To cause an adverse cardiovascular event, each of these scenarios would require that the degree to which the blood flow is compromised exceeds the capacity of the heart to withstand the transient lack of nourishment.
Often the body is able to heal the rupture, however, which leads to new plaque growth on the surface of the old plaque rather than from within its center. If this happens repeatedly, new plaque continually deposits on the surface of old plaque. This cycle of successive rupture and healing leads a plaque to grow inward rather than outward, and thus leads the plaque to narrow the arterial lumen.
If rupture is the cause of luminal stenosis, it cannot be the case that only plaques causing a great degree of luminal stenosis will rupture. The first plaques to rupture must be the ones that have produced no narrowing at all.
Scientists, however, often revert to measuring what they can measure because they can measure it. In this sense, scientists sometimes operate like the drunk man who looks for his keys under the streetlamp even though he lost them several blocks away, because under the streetlamp is where he can see most clearly.
Coronary angiography thus became the “gold standard” means of assessing the severity of atherosclerosis. It was a widely available tool that allowed the measurement of severe luminal stenosis in a live human being. It had no ability, however, to shine light on the composition of coronary plaque or to provide an accurate assessment of the likelihood that the plaque would rupture.
In 1995, Peter Libby of Harvard Medical School wrote an editorial in Nature Medicine titled “Lesion versus lumen,” hailing magnetic resonance imaging (MRI) as a new tool with great potential for cardiovascular research.10 In it, he lamented the “gold standard” status of coronary angiography.
“New clinical data,” Libby wrote, “have forced this reassessment of our reliance on angiography.” Among this data, he included the following: thrombi that cause heart attacks often arise from plaques that do not critically narrow the lumen; some tested therapies provide much more clinical benefit than their “disappointingly minimal effects” on luminal stenosis would suggest; and studies focused on disease mechanisms had thus far failed to support using luminal stenosis as the central hallmark of disease progression. Libby and several of his colleauges later added to this list that stents and bypass surgeries had largely “proven disappointing” in preventing heart attacks and prolonging life.11
While most advanced imaging techniques in the post-angiography era still face considerable technical and practical challenges to routine use in a clinical setting, their use in research studies has continued to build support for the concept of the unstable plaque.12
Beyond the Plaque
It would be a huge mistake to suggest that because plaque rupture and thrombosis appear to play a critical role in heart attacks, they must be the only factors that determine whether a heart attack occurs. Even if we assume the existence of a very unstable plaque, we still have a chain of events that must occur in order to produce a heart attack, and we can and should ask scientific questions about how and why each event occurs.
Why does the unstable plaque rupture in one minute, when the minute prior it remained intact? Why does the resulting thrombus sometimes occlude the artery rather than quietly healing the rupture? Why do the body’s own compensatory responses to restore nourishment to the heart sometimes succeed and sometimes fail? What determines the vulnerability of heart cells to transient deprivation of nourishment? While these questions are far from settled, a variety of factors could contribute to these events, including mental stress,13 overstimulation of the sympathetic nervous system,14 and many aspects of metabolic dysfunction.15
A great deal of work thus far has focused on the mechanisms that lead to atherosclerosis and the progression of plaques toward an unstable form prone to thrombosis. Developing a strong holistic theory to account for heart disease will ultimately depend on our ability to integrate these understandings with those focused on the coronary circulation and the metabolism of heart cells, and to develop a deep understanding of how we can harness diet and lifestyle to address all aspects of heart health.
WESTON A. PRICE FOUNDATION RESEARCH PROGRAM ENTERS NEW PHASE
As you may know, member donations to our research program over the last few years have supported research at the Burnsides Laboratory at the University of Illinois. Most importantly, the Foundation has funded the postdoctoral work of Chris Masterjohn, PhD, working with Fred Kummerow, PhD, head of the research lab.
With these funds, Chris initiated a research program focused on the interaction between fat-soluble vitamins A, D, and K. This program is an outgrowth of the work on fat-soluble vitamins that Chris laid out in the pages of Wise Traditions between 2005 and 2007. The program has two long-term goals: first, to enrich our understanding of how to utilize the fat-soluble vitamins in the form of nutrient-dense whole foods to prevent and treat degenerative disease and to optimize performance and well-being; second, to lay down solid evidence for the complex interactions between food nutrients that will move the nutritional science community toward embracing the value of the nutrient-dense foods so deeply valued by the traditionally living societies studied by Weston Price.
Chris’s first study within this program explored the effect of vitamin D on the metabolism of vitamin K in rats. The study showed that high doses of vitamin D harm the kidneys by increasing soft tissue calcification and impair vitamin K status, consistent with the hypothesis that Chris first developed in the pages of Wise Traditions, but it also generated a number of surprising findings. One was that the true response of rats to excess vitamin D takes six months to become clear, while most rat studies in this area only last for several weeks. Another was that, despite poor kidney health, and despite higher serum undercarboxylated osteocalcin—usually considered a marker of poor bone health—the rats dosed with extra vitamin D actually had improved bone health. This introduces a major caveat into the typical interpretation of this marker in human studies, and highlights the importance of understanding why a blood marker is changed rather than simply observing that it has changed, just as is true of serum 25(OH)D or serum cholesterol. Chris plans to publish two peer-reviewed papers from this study by the end of this year, and ultimately to publish a third paper from this study on the effect of vitamin D on vitamin A metabolism. Ultimately, this study provides a preliminary foundation for further studies investigating the protective effects of vitamins A and K on vitamin D-induced soft tissue calcification, and for human studies examining the ability of these vitamins to prevent and reverse cardiovascular calcification.
Chris was also able to use these funds to mentor Grace Hile, a medical student interested in ancestral health and integrative medicine, who took the lead this summer in examining the bone health of the vitamin D-dosed rats. This was part of Southern Illinois University’s Mentored Professional Enrichment Experience.
Finally, the postdoctoral grant also enabled Chris, through his position at the university, to teach the first-year veterinary students about vitamins and minerals. As a result of his student evaluations, he was included in the University of Illinois’s Spring 2014 “List of Teachers Ranked as Excellent by Their Students.”
In addition, contributions paid for studies that looked at the levels of trans fats in common processed foods (www.
westonaprice.org/health-topics/trans-fats-in-the-food-supply/) and the fatty acid profile of grass-fed versus grain-fed beef tallow (www.westonaprice.org/health-topics/fatty-acid-analysis-of-grass-fed-and-grain-fed-beef-tallow/). The results of a WAPF-funded study on hexane levels in common foods will soon be published in a peer reviewed scientific journal, to be followed by a report in Wise Traditions.
The traditional purpose of a postdoctoral grant is to provide a young researcher with the ability to establish a reputation as an independent researcher and thus to become well-positioned to obtain a tenure-track faculty position and thereby establish a career in research and other contributions to academia. Chris’s independent research, conducted with funds from WAPF and generous support from Dr. Fred Kummerow and the University of Illinois College of Veterinary Medicine, together with the experience he gained mentoring and teaching in that position, allowed him to obtain a position beginning this fall as assistant professor of health and nutrition sciences at Brooklyn College.
The focus of our research funding will now enter a new phase as Chris settles into this new position. He will be teaching undergraduate courses in nutritional chemistry for students aiming to become registered dietitians and mentoring graduate students. Most importantly, Chris will be running a laboratory where he will have access to the latest testing equipment. Thus, he will be in an excellent position to continue and expand his research on fat-soluble vitamins.
The BurnsidesLaboratory at the University of Illinois does not have the expensive modern testing equipment that would allow us to continue research in the field most important to us—testing the levels of fat-soluble vitamins in foods grown and prepared by various methods. Therefore, while we will continue to support Dr. Kummerow’s research to a limited extent, especally for performing fatty acid analyses, our primary support will now go to Chris Masterjohn at Brooklyn College.
We will keep our members informed of the progress of our research with the new opportunities presented to us with Chris’s move to Brooklyn College.
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2. Saphir O, Priest WS, Hamburger WW, Katz LN. Coronary arteriosclerosis, coronary thrombosis, and the resulting myocardial changes. An evaluation of their respective clinical pictures including the electrocardiographic records, based on the anatomical findings. Am Heart J. 1935;10:567-95.
3. Constantinides. Plaque Fissures in Human Coronary Thrombosis. J Atheroscler Res. 1996;6:1-17.
4. Davies MJ, Thomas A. Plaque fissuring – the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Heart J. 1985;53:363-73.
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7. DeWood MA, Spres J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med. 1980;303(16):897-902.
8. Kelly-Arnold A, Maldonado N, Laudier D, Aikawa E, Cardoso L, Weinbaum S. Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries. Proc Natl Acad Sci USA. 2013;110(26):10741-6.
9. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316(22):1371-5.
10. Libby P. Lesion versus lumen. Nat Med. 1995;1(1):17-8.
11. Libby P, DiCarli M, Weissleder R. The Vascular Biology of Atherosclerosis and Imaging Targets. J Nucl. Med. 2010; 51:33S-37S.
12. Camici PH, Rimoldi OE, Gaemperli O, Libby P. Non-invasive anatomic and functional imaging of vascular inflammation and unstable plaque. Eur Heart J. 2012;33(11):1309-17.
13. Cliqiuri G, Levy B, Pernow J, Thoren P, Hansson GH,. Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice. Proc Nat Acad Sci USA. 1999;96:6920-4.
14. Shiomi M, Ishida T, Kobayashi T, Nitta N, Sonada A, Yamada S, Kolke T, Kuniyoshi N, Murata K, Hirata K, Ito T, Libby P. Vasospasm of atherosclerotic coronary arteries precipitates acute ischemic myocardial damage in myocardial infarction-prone strain of the Watanabe heritable hyperlipidemic rabbits. Arterioscler Thromb Vasc Biol. 2013;33(11):2518-23.
15. Kostapanos MS, Florentin M, Elisaf MS, Mikhailidis DP. Hemostatic factors and the metabolic syndrome. Curr Vasc Pharmacol. 2013; 11(6):880-905.