Hypertrophic Cardiomyopathy

Practical Steps for Preventing Sudden Death

Barry J. Maron, MD

Exercise and Sports Cardiology Series
Editor: Paul D. Thompson, MD

THE PHYSICIAN AND SPORTSMEDICINE - VOL 30 - NO.1 - JANUARY 2002

In Brief: Hypertrophic cardiomyopathy (HCM) is a rare cause of death among the many participants in sports and recreational athletics, but it attracts widespread attention because the deaths occur in young, apparently healthy people. Differentiating HCM from conditioning hypertrophy (athlete's heart) remains a challenge. Routine detection of HCM patients is most commonly done with family history, physical examination, electrocardiography, and echocardiograhy. Keys to the differential diagnosis include evidence of heterogenous left ventricle hypertrophy, left atrial enlargement, unusual ECG patterns, and family history or gene mutations. Molecular detection methods for known defective genes in HCM have not yet become routine clinical tools. Athletes with unequivocal HCM should not participate in competitive sports, except for perhaps some low-intensity ones.

Sudden death from cardiovascular disease during competitive sports in young athletes appears to be rare, affecting about 1 in 200,000 high school athletes per academic year (1). Higher estimates of the risk for sudden death have been calculated in apparently healthy male athletes, joggers, and marathon racers (eg, 1 in 15,000 to 1 in 50,000) (2-4).

While such estimates might suggest to some that public concern about these tragic events is disproportionate to their impact on the population, the emotional and social impact of athletic-field catastrophes remains high. To the public and physicians alike, competitive athletes symbolize the healthiest segment of our society, and the unexpected collapse of these young people always has a profound psychological impact (5). As such, sudden death continues to represent an important medical issue.

Profile of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM, figure 1: not shown) is the single most common cardiovascular cause of sudden death in young athletes (table 1) (6-9). It usually occurs in the nonobstructive form and accounts for about 35% of these deaths (6). The disorder is a primary and familial cardiac malformation with a heterogeneous expression and a diverse clinical course for which disease-causing mutations in 10 genes encoding sarcomeric and regulatory proteins have been reported (10-19). HCM is a relatively uncommon cardiac malformation in the general population, recognizable clinically in about 1 in 500 (0.2%) (20).

TABLE 1. Causes of Sudden Cardiac Death in Young, Competitive Athletes in the United States
Cause	Percent
Hypertrophic cardiomyopathy (HCM)	36
Cornary anomalies	19
Increased cardiac mass (not diagnostic of HCM)	10
Ruptured aorta	5
Tunneled left anterior descending coronary artery	5
Aortic stenosis	4
Arrhythmogenic right ventricular dysplasia	3
Dilated cardiomyopathy	3
Myocarditis	3
Coronary artery disease	2
Mitral valve prolapse	2
Other	6
Noncardiac	2

Clinical profile. HCM-related sudden death in nonathletes (as well as athletes) has been most common in young, asymptomatic individuals, occurring frequently during moderate or severe exertion, similar to its demographic profile in athletes (10,11,21). Despite intense investigation, however, reliable identification of the individual HCM patient at high risk remains a major challenge. This stems, in part, from the fact that most data on risk stratification were compiled at referral institutions and derived from selected patient populations known to be at increased risk (22).

Nevertheless, variables that currently appear to identify young HCM patients at greatly increased risk include prior aborted cardiac arrest or sustained ventricular tachycardia, family history of sudden or other premature HCM-related death, or identification of a high-risk genotype, multiple-repetitive or prolonged nonsustained ventricular tachycardia on ambulatory (Holter) electrocardiogram (ECG) recordings, recurrent or exertional syncope, and massive (>=30-mm wall thickness) left ventricular hypertrophy (LVH) (14,15). Magnitude of the left ventricular (LV) outflow tract pressure gradient has not been independently associated with an increased risk for sudden death.

Demographics of sudden death. Studies (6-9,23-25) of young, competitive US athletes who died suddenly show that they participated in a variety of sports, most often basketball and football (about 70%), a fact that probably reflects the popularity and intensity of these sports. About 90% of athletic-field deaths occurred in males; the relative rarity in females probably reflects lower participation levels, and sometimes less-intense levels of training. About 60% of athletes were high school age at the time of death.

Timing of collapse. Most athletes who experience sudden death (with HCM or other diseases) had been symptom free and not suspected of having cardiovascular disease. Sudden collapse was usually associated with exercise, predominantly in the late afternoon or early evening (6). Nonathletes with HCM, in contrast, had a prominent early- to mid-morning peak, similar to that of patients with coronary artery disease (26). In HCM, intense athletic participation may trigger potentially lethal tachyarrhythmias.

Racial differences. Although most reported sudden deaths in competitive athletes have been in white males, more than 40% have occurred in African-American athletes (6,25,27). This contrasts sharply with the very infrequent identification of black patients with HCM in hospital-based populations (25) and highlights the disparity in access to subspecialty healthcare for diagnosis. Consequently, young African-American athletes with HCM are less likely to be disqualified from competition (28).

Morphology and Heterogeneity

LVH has traditionally been regarded as the gross anatomic marker and likely determinant of many of the clinical features and course in most patients with HCM (see figure 1: not shown) (10-13,15). Since the LV cavity is usually small or normal in size, increased LV mass is due almost entirely to an increase in wall thickness.

Morphology. The clinical diagnosis of HCM has been based on the definition (by two-dimensional echocardiography) of the disease's most characteristic morphologic feature: LV wall thickening associated with a nondilated cavity and—in the absence of another cardiac or systemic disease—capable of producing the magnitude of hypertrophy present (eg, systemic hypertension or aortic stenosis) (10-13). Because the nonobstructive form of HCM is predominant (13-15), the well-described clinical features of dynamic obstruction to LV outflow—such as a loud systolic ejection murmur, systolic anterior motion of the mitral valve, or partial premature closure of the aortic valve—are not required for diagnosis.

HCM heterogeneity. Based on both ECG and necropsy analyses in many patients, the HCM disease spectrum has been characterized by vast structural diversity of patterns and extent of LVH (13,29). While the anterior ventricular septum is usually the predominant region of hypertrophy, virtually all possible patterns of LVH occur in HCM, and no single phenotypic expression can be considered "classic" or typical. For example, although many patients show diffusely distributed hypertrophy, about 30% demonstrate localized wall thickening confined to only one LV segment.

Absolute thickness of the LV wall varies greatly, though the average reported value in HCM is usually 21 to 22 mm (13). Wall thickness is profoundly increased in many patients, up to 60 mm (30). In contrast, the HCM phenotype is not always expressed as a greatly thickened left ventricle, and some patients show only a mild increase of up to 15 mm, including a few genetically affected individuals with normal thicknesses (¾12 mm) (18,31). Patterns of wall thickening in HCM are often strikingly heterogeneous, involving noncontiguous LV segments. Transitions between thickened areas and regions of normal thickness are often sharp and abrupt, not infrequently creating right-angled contours. Even first-degree relatives with the disease usually show considerable dissimilarities in the pattern of LV wall thickening (32).

Detection During Preparticipation Screening

While HCM may be suspected during preparticipation sports evaluations by the prior occurrence of exertional syncope, family history of the disease or of premature cardiac death, or by a loud heart murmur, such clinical features are relatively uncommon among all affected individuals. Of note, most HCM patients have the nonobstructive disease form that characteristically has no murmur or only a soft heart murmur (15). Consequently, the history and physical exam alone cannot be expected to reliably and consistently identify this disease (33). One study (3) showed that potentially lethal cardiovascular abnormalities, including HCM, were suspected by the standard preparticipation exam in only 3% of 115 high school and collegiate athletes who ultimately died suddenly of such diseases.

Even when noninvasive testing (eg, echocardiography) is employed, false-negatives may occur in athletes who have HCM but an incomplete phenotypic expression, usually during adolescence (34,35). Indeed, in individuals with HCM younger than age 13 to 15, LVH is often absent or mild, and therefore ECG findings (and phenotypic expression) may not be diagnostic during preparticipation screening (see "Lessons From an HCM Case Report," page 21).

Differentiating Between HCM and Athlete's Heart

In some young athletes, hypertrophy involving the anterior ventricular septum (wall thicknesses of 13 to 15 mm) is consistent with a relatively mild morphologic expression of HCM, and it may be difficult to distinguish from physiologic LVH that arises from athletic training (ie, athlete's heart) (36). While this distinction cannot always be resolved with certainty, careful analysis of echocardiographic and clinical features permits diagnostic differentiation in most instances (figure 2: not shown) (36).

Wall thickness. Although the region of predominant LV wall thickening always involves the anterior septum, in highly trained athletes the thicknesses of other wall segments are similar (37). Absolute increases in LV wall thickness within the diagnostic "gray zone" from athletic training have been identified most commonly in sports such as rowing and cycling, but not as a consequence of isometric training (38). While the anterior portion of septum is also usually the region of maximal wall thickening, in HCM areas other than the anterior septum (eg, posterior septum and anterolateral free wall or apex) may show the most marked thickening (13,29).

Cavity dimension. An enlarged LV end-diastolic cavity dimension (>55 mm) is present in more than one third of highly trained, elite male athletes (39). Conversely, the diastolic cavity dimension is small (<45 mm) in most HCM patients and is greater than 55 mm only in those who proceed to end-stage disease with progressive heart failure and systolic dysfunction (40). Therefore, in some instances, it is possible to distinguish athlete's heart from HCM solely on the basis of this measure (36).

Doppler transmitral waveform. Abnormalities of LV diastolic filling have been identified noninvasively with pulsed Doppler echocardiography (41). Most patients with HCM, including those with relatively mild hypertrophy that could be confused with athlete's heart, show abnormal Doppler diastolic indexes of LV filling and relaxation independent of whether symptoms or outflow obstruction are present (41,42). In comparison, trained athletes have invariably demonstrated normal LV filling patterns (43-47). Consequently, in an athlete suspected of HCM, a distinctly abnormal Doppler transmitral flow-velocity pattern strongly supports this diagnosis, while a normal Doppler study is compatible with either HCM or athlete's heart (42).

Gender. Sex differences in cardiac dimensions and LV mass have been identified in trained athletes (48-50). For example, female athletes rarely show LV wall thicknesses greater than 12 mm (51). Therefore, female athletes with wall thicknesses within the diagnostic gray zone are most likely to have HCM.

Deconditioning. Increased LV cavity size or wall thickness can be shown to be a physiologic consequence of athletic training by serial echocardiographic exams. After a short period of athletic deconditioning, decreases in cardiac dimensions and mass are evident (52-54). Elite athletes with LVH may show a reduction in wall thickness of about 2 to 5 mm with 3 months of deconditioning (54). An unequivocal decrease in LV wall thickness with deconditioning is inconsistent with pathologic hypertrophy and HCM.

ECG findings. Because of the wide variety of ECG alterations in athletes without cardiovascular disease (55) and patients with HCM (53), the 12-lead ECG is not particularly useful in distinguishing between these two entities.

Familial aggregation and genetics. The most definitive evidence for the presence of HCM in an athlete with increased wall thickness comes from the demonstration of the disease in a relative (16-18,31,56-58). Therefore, in athletes in whom the distinction between HCM and athlete's heart cannot be achieved definitively by other methods, echocardiographic screening of family members may resolve the diagnosis (57). Absence of HCM in a family, however, does not exclude the diagnosis since HCM may be sporadic, presumably due to de novo mutation.

Identification of the genetic alterations causing HCM raises the possibility of DNA diagnosis in athletes suspected of having the disorder. At present, mutations responsible for HCM have been identified in 10 genes, each of which encode proteins of the sarcomere: beta-myosin heavy chain, alpha-myosin heavy chain, cardiac troponin T, troponin-1, myosin-binding protein C, alpha-tropomyosin, essential and regulatory myosin light chains, titin, and actin (16-19,31,56-61). This substantial genetic heterogeneity and the requisite expensive, time-intensive methods currently make using molecular biologic techniques difficult for routine clinical resolution of athlete's heart versus HCM.

Eligibility Considerations

When a cardiovascular abnormality such as HCM is identified in a competitive athlete, physicians must consider: (1) the magnitude of risk for sudden cardiac death associated with continued participation, and (2) the criteria used for determining whether individual athletes should be withdrawn from competition.

The 26th Bethesda Conference. This conference (28) offers recommendations for eligibility or disqualification, taking into account the severity of the cardiovascular abnormality as well as the nature of the sport.

Although not all patients with HCM incur the same risk for sudden cardiac death (14,15,21,25), differentiating subgroups with disparate risks has proved challenging. Although electrophysiologic testing with programmed electrical stimulation has provided some predictability of outcome in high-risk patients with coronary artery disease, using those data for inferences about patients with HCM is fraught with great uncertainty (14,15), particularly for trained athletes. Difficulty in assessing risk is reflected in the recommendations for athletic eligibility of young individuals that are necessarily conservative and homogeneous: "Athletes with the unequivocal diagnosis of HCM should not participate in most competitive sports, with the possible exception of those of low intensity. This recommendation includes those athletes with or without symptoms and with or without left ventricular outflow obstruction" (62). Patients with HCM judged to be at high risk should be considered for implantation of a cardioverter-defibrillator (63).

Patients with gene mutations. DNA-based diagnosis has identified increasing numbers of children and adults with a preclinical diagnosis of HCM (17,19,30,35,56,61). Although they possess a disease-causing genetic mutation, these individuals are nevertheless without clinical or phenotypic manifestations of HCM such as LV wall thickening on echocardiogram or cardiac symptoms (though various alterations may be evident on the 12-lead ECG) (29,61,64). From available data, it is possible that many such genotype positive-phenotype negative children will develop LVH when fully grown (34,25).

Genetically affected adults without phenotypic expression of LVH appear to be relatively uncommon and largely confined to those who have myosin-binding protein C (56,61,65) and cardiac troponin T mutations (58). The clinical implications of a primary molecular diagnosis of HCM, and the appropriate management of such individuals, are largely unresolved issues. Currently, no evidence exists to justify excluding most genetically affected individuals without the HCM phenotype (eg, without LVH on echocardiogram) from competitive athletics or most other life activities. However, possible exceptions are those who have a family history of frequent HCM-related death or a documented genotype regarded as adverse (30).

This article was adapted from the recently published book: Thompson PD (ed): Exercise and Sports Cardiology, New York City, McGraw-Hill Medical Publishing, 2001 (to order: 1-800-262-4729 [ISBN:0-07-134773-9]).

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Lessons From an HCM Case Report

Athlete's heart and hypertrophic cardiomyopathy (HCM) have characteristics that overlap and sometimes make differential diagnosis difficult.

During a high school basketball game, a male 17-year-old player stumbled off the court and collapsed. He was found to be pulseless and apneic. Cardiopulmonary resuscitation was initiated immediately by the boy's father (a cardiovascular surgeon) for about 5 minutes. Ventricular fibrillation was documented, and external defibrillation, performed three times, ultimately restored his sinus rhythm.

An echocardiogram performed the following day demonstrated a markedly increased left ventricular (LV) wall thickness compared with normal values 27 months earlier, anterior ventricular septum of 25 mm, posterior septum of 21 mm, and posterobasal LV free wall of 23 mm. Moderate mitral valve systolic anterior motion was present without mitral-septal contact or evidence of outflow obstruction under basal conditions. A 12-lead electrocardiogram showed a bizarre pattern with evidence of LV hypertrophy, including markedly increased voltages (eg, RV₆ = 41 mm) and a giant T-wave inversion (up to 18 mm in depth).

The patient recovered completely without neurologic impairment. An implantable cardioverter-defibrillator was placed for prevention of sudden death.

This case makes four important points about athletic participation:

• Sudden death occurs not infrequently in athletes with HCM during intense physical exertion, particularly in sports such as competitive basketball.
• Successful resuscitation and survival from ventricular fibrillation is possible if appropriate measures are undertaken promptly.
• Children with genetic forms of HCM usually show little or no LV wall thickening before age 14. However, abrupt and marked increases in wall thickness may occur before age 18, coinciding with growth and maturation. This scenario may create diagnostic uncertainty when echocardiography is performed in the prehypertrophic phase.
• Systolic anterior motion of the mitral valve, albeit mild and unassociated with outflow obstruction, may be a clinical clue suggestive of HCM in the prehypertrophic phase.

Dr Maron is Director of the Hypertrophic Cardiomyopathy Center at the Minneapolis Heart Institute Foundation. Address correspondence to Barry J. Maron, MD, Minneapolis Heart Institute Foundation, 920 E 28th St, Suite 40, Minneapolis, MN 55407; e-mail to hcm.maron@mhif.org.