Hypertrophic Cardiomyopathy Pathology

HCM is a condition characterized by marked LV hypertrophy (LVH) with asymmetrical hypertrophy of the interventricular septum when compared to the posterior free wall. In approxi-

Table 4-2 Pathologic Features of Hypertrophic Cardiomyopathy

Left ventricular hypertrophy Asymmetrical septal hypertrophy

Systolic anterior motion of the septal leaflet of the mitral valve Myofibrillar disarray

Table 4-3 Historical Features Deserving Aggressive Evaluation

Family history of sudden death at an early age

Family history of heart disease

History of a heart murmur

Syncope with exertion

Presyncope with exertion

Chest pain with exertion

Palpitations with exertion mately 20% to 25% of individuals, this asymmetrical hypertrophy will cause obstruction of the LV outflow tract. Significant variability in hypertrophy of the left ventricle can be seen; this is the result of the unique genetic mutations that cause this disease as described later. For the most part, higher mortality is associated with greater degrees of hypertrophy. Paradoxical anterior motion of the septal leaflet of the mitral valve can be seen during systole. Microscopically, myofibrillar disarray and fibrosis can be demonstrated and is a hallmark of this disorder. This disarray provides the underlying substrate for electrical instability and the lethal arrhythmias that lead to SCD in athletes. A summary of the salient pathologic features of HCM can be found in Table 4-2.

Genetics

The genetics of this disorder are well understood. Half of all cases result from inherited mutations, while the other half are the result of sporadic mutations. Fifty percent of these mutations occur in the beta cardiac myosin heavy chain on chromosome 14. Watkins et al9 screened beta cardiac myosin heavy chain genes for mutations in 25 unrelated families with HCM. Seven missense mutations were uncovered in 12 families. Six of these mutations resulted in a change in the electrical charge of the altered amino acid, and these were found to be associated with a shorter life expectancy. Patients with the mutation that did not produce a change in charge had almost normal survival.

Mutations have also been discovered in other myocardial contractile elements, including troponin T, tropomyosin, and myosin-binding protein C. Further evidence of the variability in the lethality of specific mutations has been shown in these contractile elements. Watkins et al10 assessed mutations in the tro-ponin T and tropomyosin genes in 27 families with familial HCM. Troponin T mutations accounted for 15% of the cases; while these mutations were characterized by mild to subclinical hypertrophy, they were uncharacteristically associated with a high incidence of sudden death.

Clinical Evaluation

The majority of patients with HCM will not have symptoms nor will they have a positive family history for the disease. Therefore, careful attention must be paid to any of the historical features noted in Table 4-3, and an aggressive workup should be pursued in any athlete for whom such a history can be elicited. The physical examination also may provide little information to support the diagnosis of HCM. Only 20% of patients will demonstrate the auscultatory features suggestive of this disorder. These characteristic findings include a late systolic, harsh, crescendo/decrescendo murmur that can be accentuated with a Valsalva maneuver, and an accompanying S4 gallop. Those with pronounced LV hypertrophy will have a sustained and displaced LV impulse on palpation.

Diagnostic Studies

While ECG and a chest radiograph may be abnormal in those athletes with HCM, it is important to note that the findings typically demonstrated in these studies are not specific for the disease. The electrocardiogram is abnormal in approximately 90% of those with HCM. While the tracings in those with this disorder may be quite bizarre, typical findings include evidence of ventricular hypertrophy and associated ST segment and T-wave changes. On the other hand, the majority of those with HCM will not have an abnormal chest radiograph. Those athletes with positive radiographs will demonstrate an enlarged cardiac silhouette with evidence of LV hypertrophy. Given the poor specificity of these two studies, a more sensitive and specific test must be used to assess those athletes in whom the diagnosis of HCM is being considered. Echocardiography is a highly sensitive and specific test for HCM, and the characteristic findings of asymmetrical septal hypertrophy and paradoxical systolic anterior motion of the septal leaflet of the mitral valve are pathognomonic for this disease.

Differentiating Hypertrophic Cardiomyopathy from the Athletic Heart

Occasionally, differentiating HCM from the athletic heart can be challenging. In fact, considering the data presented earlier in this section with regard to the magnitude of LV hypertrophy that can be seen in the elite athlete's heart, it is obvious that when considering this feature alone, considerable overlap can exist between those LV dimensions seen in HCM and those seen in the athletic heart. This concept can best be appreciated by viewing the Venn diagram in Figure 4-2.

Several distinguishing features may help separate these two clinical entities. First, the hypertrophy seen in the athletic heart is usually concentric. While HCM can also present with concentric LVH, it usually is asymmetrical. Second, the internal dimension of the left ventricle is usually large in the athletic heart (>55mm) and diminished in HCM (<45 mm). In HCM, an enlarged left atrium is usually seen in conjunction with the

Figure 4-2 Overlap of left ventricular hypertrophy in hypertrophic cardiomyopathy (HCM) and the athlete's heart.

alous artery must make an acute turn and pass between the aorta and pulmonary artery to provide distribution to the anterior heart. The acute angle that the anomalous artery makes before it turns between the two great vessels can lead to significant ischemia during exercise. This resultant ischemia may lead to the development of malignant arrhythmias, which can be fatal.

This pathophysiology has been demonstrated during noninvasive studies. In the previously cited study of Davis et al,11 the four patients with anomalies detected on echocardiography were studied further. All were asymptomatic at the time of the investigation. One patient with anomalous origin of the right coronary artery had decreased perfusion in the distribution of the right coronary artery and ventricular ectopy on ECG at rest. One patient with an anomalous origin of the left main coronary artery had atrial tachycardia with inferior and lateral ischemia with exercise on ECG.

Clinical Investigation

Detection of coronary abnormalities can be challenging. Most of these abnormalities are detected postmortem after an athlete dies suddenly. However, some athletes may manifest premonitory symptoms and careful attention to these may be life saving. A recent study by Basso et al12 underscores this important point. These authors reviewed two registries, collected in Italy and the United States, of athletes who died suddenly. Twenty-seven deaths were attributed to anomalous coronary arteries and identified solely at autopsy. Twenty-five athletes died during and two immediately after intense exercise. Twenty-three were found to have anomalous origin of the left main coronary artery and four had anomalous origin of the right coronary artery . Fifteen (55%) athletes had no cardiac manifestations or studies during life, but the remaining 12 had clinical data recorded in their medical records before the SCD that was subsequently collected pre-mortem. Premonitory symptoms occurred in 10 athletes, including syncope in four and chest pain in five. Premonitory symptoms occurred 3 to 24 months before death. All cardiovascular tests were within normal limits including ECG in nine athletes, maximal exercise tests in six, and two-dimensional echocardiography in two athletes.

It is important to discuss the role of two-dimensional echocardiography in the evaluation of athletes with suspected coronary artery abnormalities. Zeppilli et al13 used two-dimensional echocardiography to study the ostia and first tracts of coronary arteries in 3650 athletes. Clear visualization of them was obtained in 90% of the studies. Three asymptomatic athletes (0.09%) had abnormalities; angiography confirmed anomalous origin of the right coronary artery in two and the other had anomalous origin of the left main coronary artery.

These data are very instructive. They reinforce the notion that any symptoms previously noted in Table 4-3 must be investigated aggressively and suggest that invasive studies may need to be performed in those athletes presenting with such symptoms in order to exclude coronary artery abnormalities as the cause of their symptoms. Therefore, while the initial evaluation of athletes with premonitory symptoms should include a careful history, physical examination, and ECG, it is important to emphasize that these may be not be revealing. Stress echocar-diography and, if necessary, coronary angiography should be performed to either confirm or exclude the diagnosis of anomalous coronary arteries in these athletes.

Table 4-4 Most Common Coronary Artery Abnormalities in Athletes

Anomalous origin of the left coronary artery from the right sinus of Valsalva

Tunneled or intramural coronary arteries

Anomalous origin of the left coronary artery from the pulmonary artery

Anomalous origin of the right coronary artery from the left sinus of Valsalva

Hypoplastic coronary arteries hypertrophied left ventricle, and LV filling is abnormal. Finally, the bizarre electrocardiographic patterns sometimes seen with HCM are not seen in the athletic heart. However, it is important to note that occasionally none of these distinguishing features are present, and the clinician may be left with LV wall thicknesses that fall into the "gray zone." In these instances, a period of deconditioning may be useful in differentiating these two entities. The athlete with an athletic heart will demonstrate regression of hypertrophy after a period of detraining, while one with HCM will have no change in LV hypertrophy.

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