Case Analysis

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Cardiac pathology tends to be a descriptive specialty, but it also allows for an analysis of cardiac function (e.g. pathophysiology) based on the interpretation of changes in the heart and blood vessels. In some instances, one can even identify specific genetic abnormalities based on the pathology alone. This case is an example where even without meaningful clinical history, the diagnosis is reachable, and the genetic defect can be predicted.

Therefore, and most importantly, guidance can be provided for family members to possibly prevent future adverse outcomes.

The patient was a relatively young woman who died suddenly at home. The only significant medical history was hypertension (unknown whether it had been treated), and a diagnosis of dilated cardiomyopathy (DCM). It is unclear how the diagnosis of DCM was made, and what it was based on. Regardless, after the autopsy, it seemed certain that she did not have DCM, though it is possible that she had symptoms of congestive heart failure (CHF). Perhaps, because of CHF symptoms, she was classified clinically as having DCM, although this diagnosis usually requires sophisticated cardiological tests including echocardiography, and studies to rule out ischemic coronary disease. Endomyocardial biopsy is the confirmatory test. We do not know whether any cardiac work-up was carried out. However, with the autopsy findings, we can deduce the condition that presumably led to this woman's sudden death; and we can infer what her pre-mortem cardiac function was.

This woman had severe concentric left ventricular hypertrophy, with a total cardiac mass of 760 g, and a left ventricular wall of 2.7 cm (Figure 14). She weighed 64 kg, and therefore an expected heart weight for her should have been 250-300 g, and the wall thickness should have been less than 1.5 cm. Could the hypertrophy have been due to hypertension? It is certainly possible, though with the other findings discussed below, it would be very unlikely. Hypertension, in some predisposed individuals, can lead to severe concentric hypertrophy, associated with myocardial fibrosis and potentially CHF. In this case, she had several other alterations that are not typically seen in hypertensive cardiac disease. In particular, there was fibrous thickening of the sub-aortic endocardium, also known as the outflow tract of the left ventricle. There was fibrous thickening of the ventricular surface of the anterior leaflet of the mitral valve, with fibrosis and focal fusion of chordae tendineae attached to that leaflet. The posterior leaflet and its chordae were unaffected. The sparing of the posterior leaflet rules out a diffuse valvulopathy of the mitral valve, such as rheumatic heart disease. There was also mild fibrous thickening of the aortic valve cusps, with sparing of the commissures. These findings were not characteristic of a specific valvulopathy, but most likely were secondary to outflow tract turbulence. Finally, microscopic examination of the myocardium revealed severe myocyte hypertrophy; multiple foci of interstitial and replacement fibrosis; markedly thickened small muscular arteries; and numerous foci of myocyte disorganization, known as whorls (Figures 15 and 16). The totality of the pathological changes allows us to make a specific diagnosis. This woman had hypertrophic cardiomyopathy (HCM), which is also known as familial hypertrophic cardiomyopathy (FHC). The features are absolutely diagnostic, as described below. In addition, the strong association of HCM with fatal arrhythmia, provides an explanation for this woman's sudden death.

The findings of massive left ventricular hypertrophy in association with a subaortic endocardial plaque and anterior mitral valve leaflet thickening, indicate that this woman had obstructive HCM. This means that during systolic contraction, there was a rapid expulsion of blood across the prominent subaortic bulging muscle, which led to two related phenomena. The anterior leaflet of the mitral valve was literally swept or sucked into the outflow tract where it came in contact with the outflow tract endocardium. This is called systolic anterior motion of the mitral valve, or SAM. The markers of this process are the fibrous thickening of the outflow tract (endocardial plaque), and the fibrosis of the anterior leaflet. The pathological degeneration results from the trauma of the leaflet striking the endocardium during each systolic contraction, but particularly during periods of increased heart rate and more forceful contraction (e.g. during stress or exercise). Why does the anterior leaflet, which normally moves in a posterior direction to coapt with the posterior leaflet occluding the atrial-ventricular orifice, move in the opposite direction to strike the septum? Although there is still controversy over the explanation, most investigators believe that the rapid expulsion of blood over the convex bulging septum leads to a pressure drop over the curved surface (Venturi effect, similar to the decreased pressure over the curved upper surface of an airplane wing). The movement of the leaflet in the anterior direction, together with the hypertrophied muscle that narrows the outflow tract, leads to late systolic obstruction. The obstruction, together with turbulence causes a late systolic ejection murmur (the obstruction occurs late in systole because sufficient acceleration of the blood has to occur before the leaflet is sucked anteriorly).

The obstruction and the murmur can be accentuated by tachycardia, increased contractility, and decreased end-diastolic volume. Increasing the velocity of the flow leads to a greater pressure fall across the septum, and decreasing the chamber dimensions shortens the distance the valve leaflet must traverse to strike the septum. End-diastolic volume can fall if there is a decrease in circulating blood volume, which may result from the inappropriate use of diuretics in a patient with congestive symptoms who is not identified as having HCM. End-diastolic volume will also decrease transiently during the Valsalva maneuver (increasing intra-thoracic pressure against a closed glottis), which is a good way to accentuate the murmur when auscultating the heart in a patient suspected of having HCM. In contrast, a patient with structural aortic stenosis may have a diminution of murmur intensity with a fall in end-diastolic volume. Any process that increases end-diastolic volume, thereby increasing the left ventricular dimensions and enhancing the separation of the anterior mitral valve leaflet and the septal endocardium, will lead to a decrease of the subaortic obstruction and the late systolic murmur. Similarly, decreasing contractility or slowing the heart rate (as with calcium channel blocking agents or beta adrenergic blockers) will decrease the obstruction and the murmur. The concomitant effect of the anterior mitral valve leaflet being swept into the outflow tract, is that it does not coapt with the posterior leaflet. Thus, individuals with SAM, also have mitral regurgitation, which may further compromise cardiac function and may enhance pulmonary congestion.

Usually, individuals with HCM who have CHF, do not have significant symptomatology due to the subaortic obstruction or the mitral valve regurgitation. Rather, they generally have severe diastolic dysfunction as a result of the marked ventricular hypertrophy, in association with extensive scarring in the myocardium. These hearts are also affected by an increased interstitial connective tissue matrix, although the pathogenesis of this process is not understood. The result is a markedly stiffened ventricle, with small ventricular volumes. The ventricle fills poorly, and there is an elevation of left atrial pressure, which is increased even further if there is significant mitral valve regurgitation. Thus, congestive symptoms are secondary to diastolic dysfunction. In fact, systolic function is relatively well maintained and even super-normal, in most patients with HCM. The pathophysiologic problem is one of inadequate ventricular filling. It is likely that the diagnosis of DCM in this case was based on congestive symptoms that she had secondary to diastolic dysfunction. Had an echocardiogram been performed, it would have been obvious immediately that she did not have DCM, but she had HCM.

Microscopically, patients with HCM have extensive areas of disorganized muscle fibers called whorls. This pattern of disorganization is not pathognomonic of HCM, as it can be seen in normal hearts and in areas around myocardial scars; but its extent in HCM is greater than in any other condition. Ordinarily, myocardial fibers are aligned in parallel within the 3 layers of the ventricular wall (each of the layers is oriented obliquely to the adjacent layer, but within the layers, the myocytes line-up in parallel). However, in myocyte whorls, the fibers are arranged at random, and are therefore unlikely to be capable of generating meaningful forceful contraction. The etiology for this fiber disposition is unknown, but one possible explanation is that it develops as a result of localized abnormal contraction patterns in the myocardium, secondary to the basic defect in this disease (see below).

The other microscopic finding typical of HCM, is that these patients generally have extensive myocardial scarring with areas of interstitial fibrosis, and infarct-like replacement fibrosis. Some of the scarring may in fact be related to myocardial ischemia, as the increased stiffness and thickness of the ventricular wall, and the enhanced contractility, lead to increased wall stress, which in turn may diminish myocardial perfusion. In addition, the intramyocardial muscular arteries are abnormally thickened and sclerotic, thereby causing a structural limitation to tissue perfusion. Patients with HCM may have complaints of atypical chest pain, and may have electrocardiographic abnormalities consistent with ischemia. However, although ischemic injury may be significant, and may even provoke arrhythmias, the most significant complication of this condition is sudden fatal arrhythmia. As in this patient, sudden death can be entirely unexpected, and may be the very first manifestation of the disease. Despite the relative rarity of HCM in the general population, it attains great notoriety because of it strong association with sudden death, often in otherwise healthy young people. Sudden death is also very predictable in individuals from families with known genetic mutations that have been shown to be particularly lethal.

Hypertrophic cardiomyopathy is an autosomal dominant hereditary disease. It can occur sporadically, presumably due to a unique mutation, but it occurs in families, often with variable penetrance. Prior to the last decade, HCM was thought to be due to a single mutation of the gene that codes for myosin heavy chain (MHC, a structural component of myosin, which is part of the contractile apparatus of the heart cell) in cardiac myocytes. A number of single amino acid mutations of MHC have now been identified in numerous families. Of interest, a particular mutation leads to similar phenotypic expression, including enhanced tendency to sudden death (thereby allowing for prediction and potential treatment in affected family members). The disease, however, has become far more complex than originally thought. Affected patients or families that did not have mutation of the MHC gene on chromosome 14 were identified. However, linkages to mutations on other chromosomes were found. This suggested that HCM is not a disease, but it is a syndrome.

In fact, 7 different forms of the condition have been found, often with phenotypic variability, and not all associated with marked ventricular hypertrophy, outflow tract obstruction, or other related findings. All 7 defects involve the sarcomere, thereby leading to the concept that HCM is a sarcomeric cardiomyopathy. The two most significant, and apparently most frequent in the population, are those that affect MHC, and troponin T. The latter is interesting because it does not lead to significant ventricular hypertrophy and obstruction, but it is associated with a very high prevalence of sudden death. Six of the 7 different abnormal proteins that cause HCM have been identified, with their specific mutant gene. The seventh that leads to HCM in association with a conduction defect known as the Wolf-Parkinson-White (WPW) syndrome is most likely the one that affected the patient in this case. This form of HCM has been linked to a gene on chromosome 7. Recently, an abnormal protein kinase encoded by this gene was identified.

At the completion of this autopsy, the family was contacted due to the fact that HCM was the final diagnosis, and because of the concern that other family members unknowingly might be affected. The patient had no siblings, and no other close relatives who had either been diagnosed with HCM, or had died unexpectedly and suddenly as a result of heart disease. However, she did have a single 29 year old daughter. Discussion with the daughter led to the information that she had been diagnosed with WPW as a child. Although WPW can occur sporadically, the association of HCM and WPW in first degree relatives did not appear to be a coincidence. Based on the likelihood of both mother and daughter having HCM, it was strongly suggested to the daughter that she have a cardiac work-up, including echocardiography. If the diagnosis was confirmed, then appropriate monitoring and treatment would be instituted. Pharmacologic treatment has been shown to be beneficial in symptomatic patients, although it may not prevent sudden arrhythmic death. To prevent the latter complication, an automated implantable defibrillator has been used with some success.

As a final note, WPW is an arrhythmic condition that can occur independently of HCM. It represents accelerated transmission of electrical activation from the atrium to the ventricle through an abnormal bypass (accessory) pathway. Thus, the ventricle is activated faster than normal, which may lead to disruption of the atrio-ventricular coordination. Electrophysiologically, the result is a shortened PR interval, and a slurring of the upstroke of the QRS complex leading to the formation of a delta wave. This delta wave is thought to represent the combined rapid transmission through the accessory bundle, and the normal transmission from the sino-atrial node through the atrial wall into the atrio-ventricular node. Drug treatment of WPW is available, along with surgical or interventional cardiologic ablation of the accessory bundle, if it can be identified. Sudden death may be a rare but recognized complication of WPW. It is not known whether sudden death in patients with HCM and WPW results from the WPW alone.

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