Case Analysis

This is an instructive case for understanding the pathophysiology and the pathogenesis of acute myocardial infarction. A number of critical events took place over a brief period of time, in someone who was seemingly healthy despite being an insulin-dependent diabetic (presumably type II diabetes mellitus). He developed a fulminant course that led to his death within hours of symptom onset. The analysis of these events can teach us much about ischemic heart disease.

We know little about this man prior to his presentation to the emergency room early in the morning. He had complaints of chest pain that were not characterized in the record as to their nature or radiation, but clearly sufficient to bring him to the hospital. It is noteworthy that the pain developed in the early morning hours, obviously when he was at rest, since this is the most common time for acute myocardial ischemia to develop. Although this is counterintuitive in that it is often assumed that myocardial infarction is most often associated with exercise; development of acute ischemia and/or sudden arrhythmia leading to death occurs more frequently in the hours between midnight and 6 A.M. Why this is so, is not entirely understood, but some postulate that there may be acute hormonal or neural effects on the coronary circulation, possibly related to rapid eye movement (REM) sleep. We do know about his diabetes mellitus, but there is no report as to whether he was chronically hypertensive. This is an important piece of information lacking in the record, since it may affect the decision to use thrombolytic therapy, which carries somewhat more risk in hypertensive patients because of the potential for hemorrhagic cerebral infarctions. Regardless, we are told that his blood pressure was normal in the emergency room (140/70 mmHg), but this may represent a fall in pressure in someone with evidence of left ventricular failure.

He did have findings that were strongly suggestive of heart failure despite maintaining normal blood pressure and pulse rate. His complaints of chest pain were associated with shortness of breath, consistent with pulmonary congestion secondary to left heart failure. The chest X-ray demonstrated an enlarged heart, which may be secondary to pre-existing cardiomegaly, or to an increase of the cardiac silhouette due to dilatation. However, it also showed increased vascular congestion and interstitial edema, which is one of the earliest signs of elevated left atrial pressure, presumably due to increased end-diastolic pressure in a failing left ventricle. Moreover, he had an S4 gallop rhythm, which is a pre-systolic extra sound due to atrial contraction with blood forced into a less compliant left ventricle. Myocardial infarction decreases the compliance of the left ventricle due to the stiffness of non-contracting myocytes, and the presence of interstitial edema. Although not specific for myocardial infarction because other conditions may lead to stiffness of the ventricular wall (e.g. sarcoidosis and scarring), an S3 and/or S4 gallop is a frequent finding in patients with myocardial infarction. In addition, the patient presented with jugular venous distention, which is a sign of elevated pressure in the right atrium, most likely due to right ventricular failure.

On clinical grounds, was there sufficient information to support the diagnosis of an acute myocardial infarction? The acute onset of heart failure with chest pain is presumptive evidence; however, unstable angina pectoris may be associated with ventricular failure due to stunned myocardium (e.g. ischemia-induced contractile dysfunction without myocardial necrosis), and cannot be used as an absolute indicator of infarction. The electrocardiographic findings of ST elevation in the anterior leads V2-V5 are supportive of acute ischemia, but whether the ischemia was transient or associated with actual tissue damage cannot be determined from this information. The creatine kinase (CK) was within normal limits (22 U/L). Does this mean there was no myocardial necrosis, or was the enzyme drawn too early in the course of events to be abnormal? Creatine kinase is an intracellular enzyme that is only released into the interstitium from necrotic cells. It is then mobilized in the cardiac lymph, where it is eventually drained from cardiac lymphatics into the venous system through the thoracic duct. The measured enzyme activity of CK is thus dependent on the volume of myocardium undergoing damage, the time it takes for the enzyme to reach the circulation, and the velocity of the lymphatic drainage. The latter is at least, partially dependent on blood flow and interstitial pressure in the affected tissue. This generally correlates with whether there is blood flow (e.g. in an infarction due to coronary occlusion with profound ischemia, versus a transient occlusion of the coronary artery with subsequent re-perfusion). In the situation where profound ischemia develops, the CK may peak at 12-24 hours after the onset of infarction. In contrast, with a reperfusion infarction, the CK may be "washed out" of the tissues more rapidly, thereby leading to an earlier peak elevation, which by 12-24 hours post- injury may already return to baseline values. The fact that the CK was normal within several hours after the onset of pain may be due to the early time course of events. Within the last several years, another more sensitive, early marker for myocardial necrosis has been identified: Troponin I enters the serum earlier than CK, and it persists there longer. The other clinical laboratory finding in this man that may support a presumptive diagnosis of myocardial infarction is the elevated white blood count (WBC) of 10,900 cells/nL. Non-specific mild elevations of the WBC are often present in early myocardial infarction but generally not with anginal chest pain without myocardial necrosis.

Therefore, based on the initial presentation, it is not absolutely certain that a completed myocardial infarction had developed by the time the patient reached the emergency room. This may explain why the physicians elected to treat him with TPA, despite the potential risks in an older patient with diabetes mellitus and possible hypertension. The efficacy of treatment with TPA or streptokinase is directly related to the time in which re-perfusion is achieved, and this is dependent on the pathophysiology of myocardial infarction. Myocardial infarction is the end result of tissue damage, which is blood flow and time dependent. What this means is that when coronary flow to the tissue is suddenly interrupted, the tissue supplied by that vessel becomes acutely ischemic. Assuming that the tissue is not protected by sufficient collateral blood flow to prevent ischemic injury (a situation that is not common in the human heart), or that the myocardium has not been preconditioned with previous transient episodes of ischemia in the hours or days prior to the acute coronary occlusion (this may have the effect of providing partial myocardium protection, and eventually slow the progression of the injury), then the myocardium will begin to undergo necrosis.

Myocardial necrosis occurs sequentially from the inner subendocardial layer of the ventricular wall, through the mid and subepicardial layers of the ventricle until the infarction is transmural (more than 50% of the ventricular thickness). This process of inner wall to outer wall progression is known as the 'wave-front' phenomenon. Originally described by Reimer and Jennings, it relates the necrosis of the myocardium to the blood flow and the time in which the blood flow is decreased below a critical level. The progression of the 'wave-front' phenomenon is accelerated by severe ischemic conditions, mainly low collateral blood flow, hypotension, or increased myocardial oxygen demand (i.e. tachycardia, fever). In contrast to experimental infarctions where a coronary artery can be occluded suddenly in a completely normal heart, humans will have variable amounts of time required for actual necrosis. In addition, this time can be affected by other coexistent medical conditions (i.e. coronary atherosclerosis, hypertension, myocardial hypertrophy, and ventricular scarring). Nonetheless, in most cases, the infarction of the inner myocardial layers ensues within hours. The clinical implications of the wave-front phenomenon are profound, for it explains why some individuals develop a subendocardial and others a transmural myocardial infarction. Spontaneous interruption of coronary occlusion (e.g. intrinsic thrombolysis, or relaxation of a coronary artery spasm) leads to a cessation of the myocardial ischemia, and reperfusion of the necrotic tissue by blood. Hence, subendocardial myocardial infarctions are generally hemorrhagic. Complete coronary occlusion by thrombus, may be treated by thrombolysis or emergency angioplasty, leading to patency of the vessel, and the transformation of what would have been a transmural infarction into a subendocardial infarction. However, this is only effective if the reperfusion occurs within a time frame in which all of the myocardium destined to die has not done so. If the tissue is already necrotic, reperfusion only leads to the development of a hemorrhagic transmural infarction, which also has some increased risk because such infarctions are somewhat more susceptible to the fatal complication of ventricular rupture. It is particularly difficult in clinical situations to be cognizant of the time course of myocardial ischemia and infarction, because, as in this case, it is not clear that the symptoms were secondary to unstable angina pectoris, or actual myocardial infarction.

The treatment of this patient with TPA appeared to lead to initial improvement, suggesting that thrombolysis had been achieved. It is only a suggestion because his improvement may have been the result of treatment with nitroglycerin and subsequent anginal pain relief. It is noteworthy that he did not develop acute arrhythmias when TPA was infused, as sudden reperfusion following thrombolysis may decrease the sensitivity of the ischemic but not infarcted myocardium to electrical instability, leading to ventricular tachycardia or fibrillation, among other rhythms. It is also possible that the absence of initial arrhythmia was related to delayed thrombolysis, and that the sudden cardiac arrest he developed three hours after TPA administration was due to sudden reperfusion of the tissue at that point. Had CK enzymes been drawn sequentially every hour after TPA administration, it is possible that the time course of thrombolysis might have been marked by a sudden elevation of the enzyme as it was washed out of the necrotic myocardium. It is also conceivable that the TPA played no role in his death, and that the sudden arrhythmia was a spontaneous event associated with extensive myocardial infarction.

The autopsy clarified some of the pathophysiological and pathogenetic events. He had mild cardiomegaly; a 70 kg male should have a heart that weighs no more than 350-400 g (approximately 0.5% of the body weight expressed in kilograms). The heart weight of 430 g is most likely a reflection of pre-existent hypertension and prior myocardial damage. He had critical atherosclerotic narrowing (generally defined as more than 75%) of his entire left coronary artery system (left main, left anterior descending, and left circumflex), with moderate stenosis of his right coronary artery. With such severe disease of his left coronary artery, he was at extremely high risk for myocardial infarction and/or sudden cardiac death. The fact that he may not have experienced prior symptoms could be related to his diabetes mellitus, which is frequently associated with silent ischemia. The microscopic observation of multifocal replacement fibrosis was consistent with remote, presumably silent myocardial infarction, as well as myocardial damage associated with intramyocardial small vessel disease (a frequent finding in diabetic patients). He had a transmural myocardial infarction that grossly involved 60 % of the ventricular wall thickness, and microscopically was up to 80 %; however, its appearance clearly indicated it was a reperfusion infarction, since it was hemorrhagic. Thus, it would appear that the TPA had been effective, but it most likely was given too late to prevent a transmural infarction. On the other hand, since the infarction had been aborted at only 60-80% of the ventricular wall, and had he not developed a sudden arrhythmic death, the treatment might have had a positive effect on his subsequent ventricular function.

The marked coronary atherosclerosis and the observation of a ruptured atherosclerotic plaque, provide insight into a pathophysiologic conundrum regarding coronary artery disease. How can patients, such as this one, progress for years with significant occlusive coronary artery disease, and then suddenly have an acute event that takes place over minutes to hours leading to myocardial infarction and sudden arrhythmic death? The simple answer, but one that has only become evident over the last approximately 25 years, is that the chronic atherosclerotic plaque must be affected by a sudden acute event, such as plaque rupture with or without luminal thrombosis, or plaque rupture with spasm of the vessel. It is now recognized that the atherosclerotic plaque is not stable, particularly when it is composed of cholesterol, fibrous tissue, calcium, and inflammatory cells (the so-called complex plaque). The plaque contents are often overlain by a fibrous cap, that may be thick and relatively immune to rupture, or thin and susceptible to rupture. The thin fibrous cap may be affected by the plaque materials, and specifically collagenases (tissue metalloproteinases, or TMPs), elaborated by inflammatory cells, and capable of degrading the cap collagen. This may lead to plaque rupture, and the release of thrombosis promoting material into the coronary lumen. Alternatively, the plaque may be affected by mechanical disruption secondary to spasm of intact smooth muscle in the coronary artery wall (particularly if the plaque is eccentrically localized in the vessel circumference). Thus, stimulation of vessel contraction that may occur secondary to the release of stress related hormones, or secondary to vasogenic substances such as nicotine or cocaine, can lead to plaque rupture, also. The ruptured plaque in this case was not associated with luminal thrombosis, which may be explained by the efficacy of the TPA that led to thrombolysis. However, as noted by the presence of a transmural myocardial infarction, there must have been complete left coronary artery occlusion for at least two to four hours before TPA treatment was instituted. It would appear that the treatment was appropriate but the extent and severity of the infarction, particularly in a patient with underlying, and probably silent, myocardial disease, led to his death.

A final comment pertains to the microscopic incidental finding of multifocal amyloid deposition in the myocardium. In the absence of systemic amyloidosis associated with a plasma cell dyscrasia, or chronic inflammation, it is most likely that this amyloid represents the so-called senile amyloidosis. This condition, which tends to increase in frequency with age, is of unknown etiology. It is generally due to the abnormal accumulation of transthyreitin, which develops the beta pleated sheet conformation of all of the amyloid proteins, and therefore stains with Congo red dye, producing apple-green birefringence when viewed by polarized microscopy. Why this particular type of amyloid has a predilection for the myocardium is unknown. It usually is asymptomatic, but it may occasionally be associated with a restrictive cardiomyopathy characterized by diastolic dysfunction. It is unlikely that amyloidosis played a direct role in this patient's course, although it may have made him more susceptible to develop acute congestive heart failure when his myocardial infarction developed.

Suggested Readings

1. Jennings RB, Steenbergen C Jr, Reimer KA. Myocardial ischemia and reperfusion. Monogr Pathol. 1995; 37:47-80.

2. Reimer KA, Vander Heide RS, Jennings RB. Ischemic preconditioning slows ischemic metabolism and limits myocardial infarct size. Ann N Y Acad Sci. 1994; 723:99-115.

3. Jennings RB, Reimer KA. The cell biology of acute myocardial ischemia. Annu Rev Med. 1991; 42:225-46.

4. Reimer KA, Jennings RB. The "wavefront phenomenon" of myocardial ischemic cell death. II. Transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest. 1979; 40:633-44.

5. Brockington CD, Lyden PD. Criteria for selection of older patients for thrombolytic therapy. Clin Geriatr Med. 1999; 15:721-39.

6. Hamm CW. New serum markers for acute myocardial infarction. N Engl J Med. 1994; 331:607-8.

7. Straznicky IT, White HD. Thrombolytic therapy for acute myocardial infarction in the elderly. Coron Artery Dis. 2000; 11:299-304.

8. Zhao M, Zhang H, Robinson TF, Factor SM, Sonneblick H, Eng C. Profound structural alterations of the extracellular collagen matrix in post-ischemic dysfunctional ("stunned") but viable myocardium. J Am Coll Cardiol l987; 10:1322-34.

9. Factor SM, Bache R. " Pathophysiology of Myocardial Ischemia". In Hurt's The Heart. Ninth Edition. Alexander WR, Schlant RC, and Fuster V eds. McGraw-Hill Co, Inc., 1998.

Figure 2. Reperfusion injury. Extravasated blood percolates between necrotic myocytes (Hematoxylin and Eosin, 40X)
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