(Circulation. 1997;96:1696-1700.)
© 1997 American Heart Association, Inc.
Articles |
Complex Causes of Fatal Myocardial Infarction
From the World Health Organization Cardiovascular Center and the Departments of Medicine and Pathology at the University of Texas Medical Branch, Galveston.
Correspondence to Thomas N. James, MD, Office of the President, The University of Texas Medical Branch, Galveston, TX 77555-0129.
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Abstract |
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 Top Abstract IntroductionPotential Pitfalls in Routine...Contributions of Cardiogenic...Factors Altering Myocardial...Isolated Acute Infarction of...ApoptosisThree Special Considerations for...References |
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Abstract It is too often deduced that myocardial infarction is due to coronary occlusion and that subsequent death needs no other explanation. But the great majority of myocardial infarctions are not fatal, whether treated or untreated. There is, of course, some relation to the size of the infarct and the presence or absence of complicating conditions such as diabetes mellitus or hypertension, but little attention has been directed at the myriad of other events and processes influencing the clinical course. Examples include the exact anatomic territory infarcted and whether it includes the sinus node or AV node or important neuroreceptors; whether many small arteries are occluded (especially downstream of narrowed main coronary branches); whether the heart is hypertrophied, dilated, infected, or infiltrated; and whether there may be intracardiac, extracardiac, or intracranial neuropathological conditions that could destabilize cardiac electrical activity. It is now known that apoptosis plays a major role in myocardial infarction or ischemia, but it also occurs within the heart completely independently of infarction. There is also the vexing dilemma that an effective coronary collateral circulation, which is determined primarily by transanastomotic pressure gradient, is made less effective by exactly those treatments that reestablish flow in an occluded coronary artery. Since thrombolysis and angioplasty are automatically considered urgent treatment for an occluded coronary artery, it is prudent to remember the complex causes that determine whether the patient lives or dies.
Key Words: reperfusion • apoptosis • conduction
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Introduction |
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TopAbstractIntroductionPotential Pitfalls in Routine...Contributions of Cardiogenic...Factors Altering Myocardial...Isolated Acute Infarction of...ApoptosisThree Special Considerations for...References |
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Death hath so many doors by which to let life out. Beaumont and Fletcher, The Custom of the Country
When a person suffers an acute myocardial infarction and dies, death is customarily attributed to the infarction. This is a simple and understandable association that is legally and medically acceptable. But most people who have such an infarction not only do not die but even recover to a fully active life. In fact, despite dramatic modern emergency treatments of a powerful and increasingly sophisticated nature, we must keep in mind that the great majority of myocardial infarctions are not fatal with or without elaborate medical treatment.
The purpose of this brief review is to examine those numerous other factors that would help explain why some infarcts prove fatal but most do not. In this context, it is essential to understand that nearly all examples of sudden death are the result of multiple contributing causes and that most of them act together almost entirely by chance.1 Some of these causes may be harmless when they occur alone; others are serious but usually not fatal. Some such causes are readily detected by careful clinical examination, some by various laboratory and investigative procedures, some only with a careful routine autopsy study, and still others are not apparent except with special examinations of the heart that are seldom used in routine autopsies. This unusual variety of contributing causes forms a complex mosaic that is ultimately fatal, and cardiologists should be more aware of the entire pattern in this mosaic.
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Potential Pitfalls in Routine Postmortem Studies of the Heart |
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TopAbstractIntroductionPotential Pitfalls in Routine...Contributions of Cardiogenic...Factors Altering Myocardial...Isolated Acute Infarction of...ApoptosisThree Special Considerations for...References |
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The cardiac conduction system is seldom examined; yet, except for the obvious examples, such as rupture of the heart, the terminal event in fatal myocardial infarction is usually associated with such electrical instability as heart block or various arrhythmias. Proper examination of the sinus node, AV node, and His bundle is not exceptionally difficult. This should include a determination of whether the coronary occlusion causing infarction was located proximal or distal to the origin of the special arteries supplying the conduction system. Furthermore, numerous abnormalities of the conduction system (unrelated to coronary disease) may be undetectable during life; these will be discussed later. Unless the conduction system is examined, there is a large gap in our consideration of possible events that may importantly contribute to any sudden death, very much including that associated with myocardial infarction.
The small coronary arteries are also generally ignored during autopsy studies, even though these special vessels are often the site of nonatherosclerotic narrowing lesions.2 "Small" coronary arteries, ie, 0.1 to 1.0 mm in diameter, include all the coronary anastomoses, the blood supply to the coronary chemoreceptor (of which more later), the specific blood supply to every part of the conduction system, and actually the terminal distribution of every large coronary artery. Significant occlusions can be as short as 1 mm, especially in the proximal portion of a small artery. Focal fibromuscular dysplasia, which is often the cause,3 is known to occur as "skip lesions," with multiple separate sites sometimes being present in the same small artery.
There is growing appreciation of "diminished coronary reserve" downstream of the site at which coronary angioplasty or thrombolysis was done.4 5 This becomes a crucial determinant of the eventual size of an infarct in unsalvaged myocardium. But when one speaks of diminished coronary reserve, what is actually being considered is the distal array of small terminating coronary branches. Diminished coronary reserve as just discussed must be caused in large part by downstream showering of debris produced by the thrombolytic breakup of a coronary thrombus or fracturing of a coronary atheroma by angioplasty, or by the spontaneous rupture of a coronary plaque.
Neural structures of the heart receive little attention during autopsy. These include not only nerves and ganglia but also certain important neuroreceptors, abnormalities of which are collectively called cardioneuropathy.6 Although cardioneuropathy is often secondary to an infarction, it may also be primary, eg, caused by preexisting disease such as viral neuritis or ganglionitis. Given the powerful control of mechanical and electrical activity normally exerted by nerves of the heart, one can see how cardioneuropathy may play a significant role in the pathogenesis of arrhythmias or conduction disturbances.
Significant other cardiac abnormalities may potentially coexist with but not be caused by the coronary occlusion or myocardial infarction. Persistent fetal dispersion of the AV node and His bundle represents a failure of normal morphogenesis of these structures7 8 and can be related to sudden unexpected death with or without significant coronary disease. A fibroma critically located in the central fibrous body and compressing the His bundle may contribute to sudden unexpected death,9 whether associated with myocardial infarction or not. Still other problems, most of them readily assessed with even routine careful autopsy, include ventricular hypertrophy, myocarditis of even a "mild" degree, and focal fibrosis or diffuse infiltration of the myocardium. Any or all of these may contribute to electrical instability of the heart and thus help explain why a myocardial infarction proved to be fatal, even though such pathological conditions present alone may not have caused death.
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Contributions of Cardiogenic Chemoreflexes |
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TopAbstractIntroductionPotential Pitfalls in Routine...Contributions of Cardiogenic...Factors Altering Myocardial...Isolated Acute Infarction of...ApoptosisThree Special Considerations for...References |
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There are at least two important chemoreflexes that are often a part of the clinical course of acute myocardial infarction and may participate in its fatal outcome. The first and more familiar is the Bezold-Jarisch reflex so often encountered in the early phase of an acute posterior infarction.10 Both bradycardia and hypotension are characteristic features of this chemoreflex, and both may be arrhythmogenic. Heart block also participates in these events for which excess vagal activity is partially responsible. Although the Bezold-Jarisch events are usually brief even untreated, they can have dangerous consequences while they are present.
Less familiar but exceptionally powerful is a cardiogenic
hypertensive chemoreflex first described by Comroe11 and
imaginatively studied by Horwitz and Sjoerdsma12 in human
subjects with angina and coronary disease. In the
anesthetized dog, the most powerful agent we found to elicit
this reflex experimentally was serotonin,13 14
confirming earlier observations by Eckstein et al.15
Serotonin is normally transported in the blood almost
entirely by platelets and is liberated by them during their
aggregative clumping. Today all cardiologists are keenly aware of the
major role platelets play in coronary thrombosis and in
complicating events after either angioplasty or
thrombolysis. The blood supply to the responsible
chemoreceptor is from the proximal left coronary
circulation,13 14 15 16 and serotonin selectively
administered in this region during experiments causes a doubling of
central aortic pressure within 
5 seconds. This abrupt hypertension
is due to the simultaneous occurrence of massive
arterial vasoconstriction and a powerful positive inotropic
effect on the left ventricular myocardium, both
mediated through efferent sympathetic neural pathways.
Since this reflex can be eliminated by cooling or cutting the vagus nerves, its afferent pathway must be through them. However, the efferent activity is both vagal and sympathetic. This combination is itself powerfully arrhythmogenic, and both atrial fibrillation and transient heart block are frequently observed during the initial hypertensive response in dogs. The cardiogenic hypertensive chemoreflex can be seen as a mirror image of the Bezold-Jarisch reflex, the former accompanying anterior infarcts (blood supply to the chemoreceptor coming from the proximal left coronary system) just as the latter occurs with posterior infarcts. However, in reviewing the clinical course of patients with acute myocardial infarction in whom major new-onset hypertension was observed, we found that the hypertension was not consistently related to the location of the infarct, but in every such "new hypertensive" patient, there were always significant narrowing lesions in the proximal left coronary system.17
It is simple to visualize how either of these chemoreflexes could destabilize cardiac electrical activity or contribute to other problems, such as cardiac rupture. Each reflex is normally brief and occurs early in the course of acute myocardial infarction, being most often recognized by examining the patient in the office, at home, in the ambulance, or on arrival in the emergency room.
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Factors Altering Myocardial Repolarization |
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TopAbstractIntroductionPotential Pitfalls in Routine...Contributions of Cardiogenic...Factors Altering Myocardial...Isolated Acute Infarction of...ApoptosisThree Special Considerations for...References |
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It is well known that delayed repolarization (prolonged QT interval) and widened dispersion of myocardial refractory periods are both arrhythmogenic. Of course, during acute myocardial infarction, as illustrated by the familiar ECG changes in the T wave and ST segment, both delayed repolarization and increased dispersion of refractory periods come into play. However, numerous additional potential causes of altered repolarization may independently coincide with myocardial infarction. Cardioneuropathy,6 which may play a special arrhythmogenic role in patients with the long-QT syndrome,18 19 is one of these. Numerous other factors that are not caused by the myocardial infarction but can powerfully influence myocardial repolarization include injury or disease in the brain, myocardial hypertrophy, focal myocardial fibrosis, pericarditis or myocarditis, and a wide assortment of medications or hormonal changes. In our attempts to understand the differences that may determine whether or not a given myocardial infarction ends fatally, all these and other factors should be kept in mind.
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Isolated Acute Infarction of the Bundle of His |
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TopAbstractIntroductionPotential Pitfalls in Routine...Contributions of Cardiogenic...Factors Altering Myocardial...Isolated Acute Infarction of...ApoptosisThree Special Considerations for...References |
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Too often, it is thought that an infarct is an infarct and that its significance is primarily in relation to its size (the mass of myocardium infarcted). But that is simplistic. As an intriguing example of this point, let me illustrate how an acute myocardial infarction no more than 1 mm in maximal dimensions may cause sudden death. This is exactly the situation encountered in the sudden death of a young man thought to be in excellent health until he fell over dead while tying his young daughter's shoes as she prepared to go to school.20 In his heart, there was a marked narrowing by focal fibromuscular dysplasia of the specific small artery supplying the His bundle, which was transected by a hemorrhagic infarct. The adjacent myocardium of the ventricular septum was normal, as was the rest of his heart and the remainder of the autopsy.
Why would such a tiny infarct cause sudden death? In the circumstances, there was no opportunity to obtain an ECG or even a terminal clinical examination, but it may reasonably be anticipated that complete heart block developed. If so, why was there no survivable escape rhythm?
There are several considerations in this special case, a clinical course now also described by others.21 First, the abrupt onset of complete heart block presumably interrupted conduction of all sinus beats to the ventricles. Normal sinus rate will suppress ("overdrive") most potential escape rhythms, and the abruptness of heart block in this young man precluded early emergence of a survivable AV junctional escape rhythm. Second, and perhaps even more important, there is experimental evidence22 that the first and major source of escape rhythms after failure of sinus rhythm is located near the junction of the AV node and His bundle, a site unfortunately located just proximal to the particular infarct that destroyed the His bundle. Thus, neither sinus rhythm nor an AV junctional escape rhythm could be effectively transmitted to the ventricles when the His bundle was transected by infarction.
Focal fibromuscular dysplasia that narrows either the sinus node artery or AV node artery has been observed in relation to sudden unexpected death.23 24 Focal fibromuscular dysplasia has no recognized dependent coexistence with disease of the large coronary artery, but there is no reason to think that they cannot coincidentally coexist. That is the essential point for the subject at hand. Some cases of fatal posterior myocardial infarction have massive destruction of the AV node and coincidental marked narrowing of the AV node artery, a situation that must compound the usual dromotropic effect of such infarcts by causing even more extensive damage to the AV node.
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Apoptosis |
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TopAbstractIntroductionPotential Pitfalls in Routine...Contributions of Cardiogenic...Factors Altering Myocardial...Isolated Acute Infarction of...ApoptosisThree Special Considerations for...References |
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With the seminal description of this form of cell death by Kerr et al25 and the later meticulous definition of the important difference between necrosis and apoptosis,26 an exciting new era of understanding of how and why cells die was quickly seized upon by oncologists, immunologists, developmental biologists, and gastroenterologists, but cardiologists were late to enter the field. Now there is an exponential growth of interest and imaginative investigations examining the role of apoptosis (programmed cell death) in various cardiac diseases, including the importance of both apoptosis and necrosis in myocardial infarction itself.27 28 Of the numerous major differences in cell death by the two modalities, one of the most important is that necrosis is typically associated with extensive inflammation, whereas apoptosis typically is not. Thus, any area of infarction with necrosis has the compounded noxious results of attracting many leukocytes, which themselves can cause further injury to local tissue.
It has been shown that mild hypoxia leads to apoptosis and severe hypoxia for the same type of cells causes necrosis and that the same graded response was true of injury by radiation or hyperthermia.29 From this, it was expected that mild ischemia would be associated predominantly or exclusively with apoptosis and more severe ischemia with necrosis. However, it is now known that both types of cell death are present in myocardial infarction,27 28 which is not surprising when one considers the multiple separate determinants of either distribution or delivery of collateral circulation in the human heart.30 It is unlikely that most examples of coronary occlusion would be followed by a homogeneous area of distal damage but more likely that the perfused territory would be heterogeneous, making the infarcted area appear patchy, with generally more severe injury centrally (necrosis) than peripherally (apoptosis).
Another reason for this heterogeneous histological appearance, with a mixture of apoptosis and necrosis, deals with why apoptosis is typically devoid of inflammatory response. Lack of inflammation is because of two factors: (1) rapid phagocytosis by neighboring macrophages or even by like cells such as myocytes and (2) the finite duration for morphological preservation of the integrity of an apoptotic cell or the integrity of debris in the form of apoptotic bodies, which are themselves membrane bound. When the extent of apoptosis becomes sufficiently massive, then the potential for scavenging phagocytosis is simply overwhelmed, and both the apoptotic cells and apoptotic bodies eventually break down to release their intracellular contents, which quickly evoke the usual inflammatory response.
In the human heart, apoptosis can be triggered by a variety of signals, only one of which is ischemia. Postnatal morphogenesis of the cardiac conduction system is a normal process that may and often does recur intermittently throughout life and not simply in youth.8 31 This morphogenesis is most likely genetically programmed, and its prevalence and actual extent at any given time vary among individuals. Since the morphogenesis per se is independent of coronary disease or myocardial infarction, its chance concurrence is difficult to predict but can nevertheless serve as a powerful factor compounding the other determinants of electrical instability in the infarcted heart.
Morphological identification of apoptosis is not difficult if properly sought. For example, the usual absence of any inflammatory response to apoptotic cell death means that the late residual of apoptosis exhibits little major scarring but more often an abnormally located focus of fat mixed with thin strands of collagen. Such foci attract little attention and can easily be misinterpreted as normal tissue. Immunohistochemical staining permits the accurate recognition of apoptosis in progress.32 After apoptotic cells are engulfed by phagocytosis, either entire cells or fragments of them (apoptotic bodies) can still be recognized with the immunohistochemical stain. Electron microscopic features of apoptosis are also distinctive, but they are more difficult to apply at routine autopsy.
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Three Special Considerations for Those Performing Angioplasty and/or Thrombolysis |
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TopAbstractIntroductionPotential Pitfalls in Routine...Contributions of Cardiogenic...Factors Altering Myocardial...Isolated Acute Infarction of...ApoptosisThree Special Considerations for...References |
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Opening an occluded human coronary artery is a highly logical procedure for which much evidence indicates a beneficial effect. However, increasing experience has also led to the troubling recognition that there are harmful side effects to be kept in mind. These include not only rupture of the coronary artery by a probe or balloon or the production of dissection in the arterial wall but also either local or distant hemorrhage (particularly in the brain) sometimes associated with thrombolysis. Many innovations and special considerations are continually being introduced to make such procedures both safer and more effective. However, there are three problems that, in my opinion, have received insufficient attention.
1. The first of these is the inescapable effect of either angioplasty or thrombolysis on the coronary collateral circulation. Kattus and Gregg33 long ago convincingly demonstrated that the most important determinant for successful establishment of coronary collateral flow is the transanastomotic pressure gradient. No other potential determinant they examined was nearly as important. When a coronary artery is narrowed or occluded, the level of pressure distal to the obstruction is quickly diminished, making the onset of flow through the numerous anastomoses that normally exist in human hearts34 optimally effective. With the passage of time, this new transanastomotic flow morphologically transforms the arterial anastomosis and substantially increases its lumen. Opening an occluded coronary artery immediately eliminates the potentially beneficial effect of an increased transanastomotic pressure gradient.
Do not misinterpret this caveat as an argument necessarily against either angioplasty or thrombolysis. Simply keep in mind that one side effect, ie, loss of trans-anastomotic pressure gradient, of both these procedures (and of coronary bypass surgery) is seldom considered but may be a source of either early or late failure to achieve an optimal result in preserving jeopardized myocardium. Certainly, one cannot argue that the cardiologist should always simply wait for the delayed development of an optimally effective collateral circulation, since the acute nature of most myocardial infarctions does not permit such delay of implementation. But both thrombolysis and angioplasty are increasingly performed "electively" in clinical circumstances in which any acute progression of events is not happening, and in many of those cases, choosing nature's balancing course can be an attractive alternative decision.
2. In the rapidly progressing events of acute myocardial infarction, there is still another harmful side effect of opening the occluded artery: the group of reperfusion phenomena. Reestablishment of arterial perfusion in myocardium recently made ischemic has its own deleterious consequences,35 36 and one of these is apoptosis.37 Whatever the triggering mechanism for reperfusion apoptosis in myocardium may be, there is little doubt that a variable and often substantial volume of cell death occurs after flow in an occluded coronary artery has been reestablished. Just as with the discussion of loss of transanastomotic pressure gradient, this is not necessarily an argument against opening an occluded coronary artery by either angioplasty or thrombolysis but simply a reminder that the beneficial results are mingled with certain important deleterious effects.
3. Finally, for thrombolysis, there is another seldom or insufficiently recognized harmful possibility. Apoplexy of the heart is a term I coined some years ago to describe the assortment of events within the cardiac conduction system ending in sudden death,38 spanning virtually an entire spectrum of events similar to those in the brain collectively known as apoplexy. These include both thrombosis and hemorrhage, however produced, but happening in the areas of electrical control of the heart (impulse formation and conduction) rather than in the electrical control systems in the brain. Just as cerebral hemorrhage is a potentially disastrous side effect of coronary thrombolysis, much feared and carefully guarded against, analogous events may be produced in different components of the cardiac conduction system by thrombolysis, and this very real hazard has not attracted the investigative attention it deserves. It will not be an easy matter to resolve, because some enhanced bleeding produced distal to the site at which thrombolysis was performed can be attributed to the ischemic injury previously caused by the coronary occlusion that is being eliminated. In posterior myocardial infarction, for example, hemorrhage in and near the AV node is an expected consequence of the responsible coronary occlusion. But if the initial hemorrhage in that region was, for whatever reason, minimal or less extensive, the subsequent introduction of a thrombolytic agent could augment the hemorrhagic injury in the AV node and His bundle, because it is predictable that the thrombolytic agent must be carried downstream in addition to being delivered in the area of the coronary thrombus itself.
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Acknowledgments |
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The work upon which this review is based was supported by the Pegasus Fund of the University of Texas Medical Branch.
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References |
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TopAbstractIntroductionPotential Pitfalls in Routine...Contributions of Cardiogenic...Factors Altering Myocardial...Isolated Acute Infarction of...ApoptosisThree Special Considerations for...References |
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