Case Analysis

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Mr. S. had a large subendocardial myocardial infarction (SEMI) that showed organizational changes that dated the infarct to approximately 10-14 days before death. Subsequently, he had transmural extension of the original SEMI that occurred 1-2 days before death. The extension resulted from acute thrombotic occlusion of a severely atherosclerotic coronary artery affected by plaque hemorrhage and rupture. Since the thrombus was 1-2 days old, it was temporally related to the infarct extension. We will focus on several aspects of this case in this discussion:

1. Subendocardial versus transmural myocardial infarction;

2. Transmural extension of an infarction, and why this is different from lateral extension;

3. Coronary artery lesion(s) accounting for the myocardial pathology;

4. Histological dating of infarction and thrombus

This case illustrates basic cardiac pathophysiology and pathology. It reflects what occurs in vivo in humans, as a counterpart of what has been demonstrated convincingly in the animal laboratory. It also provides a rationale for some of the interventional approaches currently being employed to prevent the unfortunate outcome that resulted in the death of Mr. S. As we have discussed earlier, myocardial infarction is not a sudden, 'all-or-none' phenomenon. There is a progression of necrosis across the ventricular wall from the endocardium towards the epicardium. It develops in stages or waves, giving rise to the term 'wavefront', described by Reimer and Jennings in several classic papers. Although based on experimental studies, the concept has been amply verified in humans. It represents the conceptual underpinning for the use of thrombolytic agents, acute catheterization with balloon angioplasty and stenting, and acute coronary artery bypass grafting, during myocardial infarction. In the present case, Mr. S. received the thrombolytic agent TP A, and this led to the development of a SEMI. The reasons for this will become obvious.

Acute myocardial infarction occurs with temporal and spatial determinants. This means that the progression across the ventricular wall is time-dependent, and the volume of myocardium affected by ischemia and its evolution to necrosis, is spatially limited by the coronary artery anatomy and flow. The myocardium affected by ischemia is also referred to as myocardium at risk, or vulnerable myocardium. Not all of the myocardium at risk will infarct; the actual volume will depend on the collateral circulation to support it, and whether intervention(s) allow reperfusion of the obstructed coronary vessel. As long as reperfusion occurs sufficiently early in the course of the MI, the wavefront will be aborted and a potential transmural infarction will be limited to the subendocardium. Consequently, a SEMI by definition represents a reperfusion injury, whereas transmural infarctions are ischemic lesions resulting from the total absence or marked diminution of blood flow to the tissue.

There are other implications that result from this pathophysiology. SEMIs are hemorrhagic, and are associated with ischemic injury to capillaries, which results in interstitial leakage of blood. Since there is reperfusion that follows a period of ischemia, the re-introduced oxygenated blood interacts with damaged sarcolemmal proteins and lipids. This generates oxygen and hydroxyl free radicals that irreversibly perforate the sarcolemma, leading to a massive influx of extracellular fluid and calcium. The perforations prevent the myocardial cell maintenance of fluid and electrolyte balance, and the calcium causes hypercontraction of the actin-myosin filaments. The end result is contraction band necrosis, which is a characteristic feature of SEMI (Figure 7). Moreover, since the infarction process has been aborted by the reperfusion, a pathological definition of a SEMI is an infarct that extends less than 50% through the ventricular wall (starting from the subendocardium).

The clinical definition of a SEMI depends on its electrocardiographic findings. It generally does not produce Q-waves in the leads identifying the area of ischemia. Accordingly, it is clinically termed a non-Q-wave MI. In practical terms, some non-Q-wave infarctions may progress beyond 50% of the ventricular wall. Consequently, there may not be an absolute correlation between the clinical and pathological terminology. The explanation for the absence of Q-waves is of significant interest: the Q-wave represents the negative deflection below the iso-electric line on the ECG. Necrotic muscle does not generate any electrical impulses, positive or negative (the dead muscle is electrically invisible). It allows the ECG leads to 'see through' the necrotic tissue to the viable myocardium on the opposite side of the ventricular wall, which is able to generate upward positive deflections, or R-waves, in the ECG leads directly facing this zone. In the opposite leads, and facing the electrically negative infarct zone, the deflections are downward negative, or Q-waves. Since a SEMI has a viable zone of myocardium overlying the infarct, it is not electrically neutral. Therefore, no Q-waves are seen.

The SEMI is hemorrhagic and initially is composed of myocardium with contraction band necrosis. Time-dependent necrosis of the ventricular layers extending towards the epicardium is associated with time-dependent survival of the immediate subendocardial layers. Normally, if one examines the myocardium just under the endocardium from a heart with a transmural infarction, there will be 3-5 myocardial cell layers that survive. They are maintained viable by direct diffusion of oxygen across the endocardium into the tissue (oxygen can diffuse approximately 30-50 microns, or about the distance of 3-5 myocardial cell diameters). If the myocytes are hypertrophied, the endocardium is fibrosed, or the zone underlying the infarction is blocked by a mural thrombus, there is no myocardial cell survival. Although these cells probably have no functional role, the immediate subendocardial zone is also where the Purkinje cells are found; thus, the survival of this tissue through oxygen diffusion may permit normal ventricular conduction. The same zone, in a SEMI, is initially much larger, representing as many as 10-20 myocardial cells, which are potentially ischemic and represent vulnerable myocardium. Furthermore, this subendocardial myocardium is most likely 'stunned', is non-contractile, and with time, may even undergo necrosis. However, it can generate electrical activity, and as such may be a source of malignant and possibly fatal arrhythmias. Hence, the association of SEMI and lethal rhythm disturbances.

The other consequence of the different pathophysiology between a SEMI and a transmural myocardial infarction (TMMI), is that the TMMI occurs following complete occlusion of a coronary artery. In contrast to contraction bands characteristic of SEMI, the myocardium undergoes coagulative necrosis, which is a denaturing process of the cellular proteins secondary to oxygen deprivation. This leads to a smudgy 'cooked' appearance of the myocardium, with intense red staining with the dye eosin, or hypereosinophilia. Since this may take as long as 4-6 hours to become evident, it may be very difficult to ascertain whether any patient dying suddenly actually had a myocardial infarction as the precipitating event.

Clearly, then, there are pathophysiological, pathological, and functional differences between a SEMI and a TMMI. We will next turn to the issue of infarct extension:

Ordinarily, coronary vessels in humans have limited collateral branches. This is particularly true when the obstruction is more distal in the coronary artery, thereby providing fewer branches to bridge the zone of ischemia. However, the prediction as to whether any patient will or will not have adequate collaterals to support the myocardium is not possible prior to obstruction. Generally, collaterals are more likely to be present in the immediate subepicardial myocardium, decreasing from epicardium to endocardium. Accordingly, the myocardium at risk following coronary occlusion is spatially determined in an inside-outside dimension, and is sharply delimited along the lateral margins. The infarction is broader along the endocardium, and angles inward toward the epicardium. There are minimal collaterals that maintain the lateral margins. This means that there is no significant lateral border zone. The latter observation was a source of major controversy 20 years ago, but now is a widely accepted concept.

The myocardium at risk for infarction remains vulnerable even if the initiating coronary artery occlusion is transformed into a patent vessel. Even after reperfusion, the surviving subepicardial myocardium remains vulnerable to necrosis. If the vessel re-occludes at the same level, the surviving myocardium will then infarct as if the coronary artery was initially blocked in its entirety, and remained so for many hours. This is what is known as transmural extension; and it is precisely what occurred in the present case. Mr. S. had re-establishment of flow with TPA, and then he re-occluded many days later leading to a TMMI found at autopsy. The vulnerable infarct zone does not extend laterally, since distinct and separate vessels or branches supply that myocardium. If the myocardium lateral to an infarct undergoes necrosis, it would represent an extension to a new vascular territory. It is not unusual for additional vessels to become thrombosed or occluded by spasm in the setting of a TMMI. This would lead to new lateral or distant lesions from the initial focus.

As a final point, there is one concept that relates to post-occlusion modification of an MI and that is the term infarct expansion. It refers to the modification of the ventricular wall affected by a TMMI that undergoes remodeling. This leads to mural thinning and aneurysmal bulging of the wall. This process has significant effects on ventricular function, susceptibility to endocardial thrombus, and the potential for ventricular rupture. Expansion is usually associated with a large TMMI, but not a SEMI. When it occurs, it has a relatively poor prognosis.

The coronary lesion that accounted for the events affecting this patient is fairly common. He had a high-grade atherosclerotic plaque, which presumably led to an acute luminal thrombosis. The thrombus was then lysed with TP A, re-establishing adequate coronary flow and aborting the infarct progression across the ventricular wall. Subsequently, the same plaque ruptured leading to re-thrombosis of the vessel at the same level, extending his SEMI into a TMMI. This was a clinically silent event, most likely because of his diabetes mellitus. If these events had occurred today, he would have undergone coronary catheterization following the development of the SEMI. An angiogram would have demonstrated persistent high-grade coronary occlusion, and he would have had balloon angioplasty and stent placement, if clinically feasible. If not, he might have had coronary artery bypass grafting. With either approach, the vulnerable myocardium would have been well-perfused, and he would not have extended his SEMI.

The pathology of the initial infarction and the subsequent extension could be dated histologically. This is possible because of the use of well-established criteria that define the time course for the inflammatory response, the development of granulation tissue, and the deposition of connective tissue until the entire infarct is replaced by mature scar tissue. Similar dating of the thrombi can be done, as documented in this case with the coronary artery thrombus that correlated with the TMMI. Although the dating is not precise to the minute and hour (in contrast to the frequent impression one gets from television or fictional depictions of pathological investigation, where the fatal event is identified to the minute and hour), it can provide a rough 6-12 hour time frame for most of the cellular events affecting the infarcting myocardium. It is beyond the scope of this book to provide the details of the dating procedure, although they are adequately described in numerous pathology and cardiology texts. In most cases, such an evaluation is of academic interest, with some clinical implications. It is often of great importance in the medico-legal sphere where the determination of the precise time of an infarct and correlation with clinical signs and symptoms may be significant. For instance, this approach may help establish whether a fatal motor vehicle accident occurred due to a MI and fatal arrhythmia, or trauma directly caused the death of the driver.

In summary, the extension of a SEMI into a TMMI in this patient, serves as clinical verification for many of the major insights into myocardial ischemia and coronary thrombosis, which have been developed over the past 2 decades with animal studies. These insights have provided a firm scientific grounding for the interventional cardiology and cardiac surgery treatments of coronary ischemia and myocardial infarction. Over the last years, these treatment options have had a tremendous impact on disease prognosis, quality of life and survival of patients with ischemic coronary artery disease.

Suggested Readings

1. Villablanca AC, McDonald JM; Rutledge JC. Smoking and cardiovascular disease. Clin Chest Med. 2000; 21:159-72.

2. Reimer KA, Jennings RB. Biologic basis for limitation of infarct size. Adv Exp Med Biol. 1986; 194:315-30.

3. Ravn HB, Falk E. Histopathology of plaque rupture. Cardiol Clin. 1999; 17:263-70.

4. Schroeder AP, Falk E. Pathophysiology and inflammatory aspects of plaque rupture. Cardiol Clin. 1996; 14:211-20.

5. Becker RC, Bovill EG, Seghatchian MJ, Samama MM. Pathobiology of thrombin in acute coronary syndromes. Am Heart J. 1998; 136:S19-31

6. Stern S, Cohn PF, Pepine CJ. Silent myocardial ischemia. Curr Probl Cardiol. 1993; 18:301-59.

7. Okun EM, Factor SM, Kirk ES. End-capillary loops in the heart: An explanation for discrete myocardial infarctions without border zones. Science 1979; 206:565-67.

8. Factor SM, Okun EM, Kirk ES. The histological lateral border of acute canine myocardial infarction: a function of the microcirculation. Circ Res 1981; 48:640-49.

9. Factor SM, Okun EM, Minase T, Kirk ES. The microcirculation of the human heart: end capillary loops with discrete perfusion fields. Circulation 1982; 66:1241-48.

10. Forman R, Cho S, Factor SM, Kirk ES. Acute myocardial infarct extension into a previously preserved subendocardial region at risk in dogs and patients. Circulation 1982; 67:117-24.

Figure 5. Transverse section of the right coronary artery showing intraplaque hemorrhage and luminal thrombotic occlusion.
Right Coronary Artery Plaque

Figure 6. Section of right coronary artery partially occluded by a ruptured atheromatous plaque with hemorrhage (arrow) (Hematoxylin and Eosin, 40X). Distal sections of

Figure 6. Section of right coronary artery partially occluded by a ruptured atheromatous plaque with hemorrhage (arrow) (Hematoxylin and Eosin, 40X). Distal sections of

Figure 7. Contraction bands (arrows) are present in reperfusion injury, catecholamine induced damage and as a result of resuscitation efforts. (Hematoxylin and Eosin, 60X)

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