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Assessment of Left Ventricular Hypertrophy in a Trained Athlete: Differential Diagnosis of Physiologic Athlete's Heart From Pathologic Hypertrophy
Progress in Cardiovascular Diseases 54 (2012) 387 – 396 www.onlinepcd.com
Assessment of Left Ventricular Hypertrophy in a Trained Athlete: Differential Diagnosis of Physiologic Athlete's Heart From Pathologic Hypertrophy Antonio Pelliccia a,⁎, Martin S. Maron b , Barry J. Maron c a
The Institute of Sport Medicine and Science, Italian National Olympic Committee, Rome, Italy b Hypertrophic Cardiomyopathy Center, Tufts Medical Center, Boston, MA c The Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN
Abstract
Physiologic LV remodeling in young trained athletes as a consequence of chronic training can occasionally mimic certain pathologic conditions associated with sudden death, such as HCM. A small but important subset ofelite male athletes may show a borderline increased LV wall thickness of 13 to 15 mm, which defines a gray zone of overlap between the extreme expressions of athlete's heart and a mild HCM phenotype. Such diagnostic ambiguity can be resolved by using the paradigm of noninvasive parameters including testing with echocardiography (and, more recently, with CMR): left atrial and LV chamber dimensions and shape, brief periods of deconditioning to alter LV mass, measurement of oxygen consumption and diastolic filling, and recognition of familial occurrence of HCM or a pathogenic HCM-causing sarcomere mutation. Such distinctions between physiologic/benign athlete's heart and HCM, the most common cause of sudden death in the young in the United States, can be crucial. The recognition of HCM leads to disqualification from intense competitive sports to reduce sudden death risk and, when appropriate, permits initiation of therapeutic interventions. (Prog Cardiovasc Dis 2012;54:387-396) © 2012 Elsevier Inc. All rights reserved.
Keywords:
Left ventricular hypertrophy; Trained athlete; Pathologic hypertrophy
Historical perspectives The concept that the cardiovascular system of trained athletes differs structurally and functionally from that of untrained, normal individuals is remarkably more than 100 years old. 1 Henschen 1 is credited with the first description in 1899, using only a basic physical examination with careful percussion to recognize enlargement of the heart due to athletic activity in cross-country skiers. Henschen 1 concluded that both dilatation and hypertrophy were
Statement of Conflict of Interest: see page 395. ⁎ Address reprint requests to Antonio Pelliccia, MD, Institute of Sports Medicine and Science, Largo Piero Gabrielli, 1, 00197 Rome, Italy. E-mail address: [email protected] (A. Pelliccia).
0033-0620/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pcad.2012.01.003
present in trained athletes, involving the left and right sides of the heart and that these changes were normal and favorable: “skiing causes an enlargement of the heart which can perform more work than a normal heart.” In the mid-20th century, investigators used quantitative chest radiography to demonstrate that heart size was increased in athletes, particularly in those engaged in endurance sports with large aerobic capacity. Some observers regarded the heart of the trained athlete to be weakened because of the “strain” created by continuous and strenuous training, subject to deteriorating cardiac function and possible heart failure. 2 From that time, there has been periodic controversy regarding the intrinsic nature of an athlete's heart—that is, whether the morphologic alterations evident are benign physiologic adaptations and the consequence of the training or,
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Abbreviations and Acronyms
alternatively, are potentially pathologic and the AGT = angiotensin harbinger of disease and CMR = cardiovascular future disability. magnetic resonance In the last 2 decades, imaging techniques have HCM = hypertrophic allowed direct assesscardiomyopathy ment of the morphologic LGE = late gadolinium and functional cardiac enhancement changes induced by athLV = left ventricle letic conditioning, and several investigations, TDI = tissue Doppler imaging largely based on the long-standing cardiovascular program of the Institute of Sport Medicine and Science in Rome, have provided extensive information in a variety of athlete populations including elite competitors. 3-11 Determinants of cardiac remodeling Type of sport Morphologic cardiac changes in athletes have been attributed primarily to the type of sport and, specifically, to the hemodynamic overload induced by various conditioning programs 3-9 (Fig 1). Specifically, endurance sports (ie, cycling, cross-country skiing, and rowing) are associated with a predominant volume overload, whereas power disciplines (ie, weight and power lifting, shot put, and discus) are associated with a predominant pressure overload. In our experience, elite athletes engaged in endurance sports demonstrate the greatest alterations in left ventricular (LV) cavity size, wall thickness, and mass. 5,9 Athletes engaged in power disciplines show a disproportionately larger impact on LV wall thickness than cavity size; whereas LV cavity dimensions remain
within normal limits; the relative wall thickness is increased. Other disciplines such as soccer, rugby, hockey, those involving mixed (aerobic and anaerobic) exercise programs show a moderate impact on LV cavity size, with absolute dimensions that commonly exceed the normal limits; however, LV wall thicknesses usually remain within normal limits. 9,10 Finally, skill and technical disciplines (such as golfing, equestrian, or yachting) have only a minimal remodeling effect, if any, on cardiac morphology. 9 Body size and composition Cardiac dimensions are closely related to body size and composition. Body surface area has proven to be the strongest determinant of cardiac dimensions. 5,9 Indeed, athletes with the greatest body surface area (and largest lean body mass), such as those engaged in rowing, rugby, basketball, and water polo, usually have the greatest absolute LV cavity dimensions. 4,5 Sex Women athletes have larger LV cavity dimension (average, +6%) and maximal wall thickness (average, +14%) compared with sedentary female controls. 11 However, the extent of LV remodeling in absolute terms is usually mild in trained women athletes, and specifically, LV wall thickness do not exceed the upper normal limits (ie, 12 mm) and do not usually fall into a “gray zone” of borderline LV hypertrophy. 11 Not unexpectedly, women athletes show smaller absolute LV cavity dimensions (average, −10%) and wall thicknesses (average, −20%) in comparison with male athletes of the same age, ethnic origin, and sporting disciplines. 11 These differences are likely the consequence of several determinants including the smaller body size (and lean body mass) and the lower absolute cardiac output and systolic
Fig 1. Effect of specific sports training on either LV cavity dimension or wall thickness in elite athletes representing different types of sport disciplines.
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Fig 2. Impact of different variables on LV end-diastolic cavity dimensions in a large population of male and female elite athletes. The relative impacts of the examined variables (body size, sex, age, and type of sport) are shown here as a proportion of overall variability in LV cavity size. Reproduced with permission from Pelliccia A, Thompson PD. 14
blood pressure attained during exercise by women compared with men. Genetic determinants Evidence for a genetic influence on cardiac remodeling in athletes has been suggested for the renin-angiotensin (AGT) system. 12,13 Specifically, military recruits undergoing 10-week exercise training had an LV mass increased by 42%, if they harbored an ACE-DD genotype and only 2% (P b .001) if an ACE-II genotype. 12 Also, the AGT M235T polymorphism may regulate the rate of transcription and secretion of AGT and the extent of cardiac remodeling; elite endurance athletes with the AGT-TT expression had larger LV mass in comparison with those with AGT-MM genotype (+10%; P b .004), independent of sex and intensity of training. 13 The relative contribution of demographic and environmental or genetic variables to LV remodeling in trained athletes has long been the subject of controversy. 14 Data assembled in large athlete populations analyzed with multivariate analysis show that about 75% of variability in LV cavity size is attributable to nongenetic factors such as body size, type of sport, sex, and age, with the body surface area being the largest of these components 14 (Fig 2). The remaining 25% of cavity size variability is otherwise unexplained and possibly caused by genetic factors. Left ventricular remodeling Responses of individual athletes to systematic conditioning are not uniform. Training induces some evidence of cardiac remodeling in about one half of trained athletes,
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consisting of alterations in ventricular chamber dimensions, namely, increased LV and right ventricular and left atrial cavity size (and volume), associated with normal systolic and diastolic function (Fig 3A-C). However, there is a considerable overlap in cardiac dimensions between a trained athlete population and age- and sex-matched sedentary controls. 3,4 Overall, athletes show relatively small (but statistically significant) increases of about 10% to 20% for wall thickness or cavity size, and these values in most individual athletes remain within accepted normal limits. 4 The magnitude of physiologic LV remodeling may become substantial when the multiple determinants, as described before, are present at the same time. The most extreme increases in cavity dimension and/or wall thickness have been observed in elite male athletes with large body size who are training in rowing, cross-country skiing, cycling, and swimming. 9,15,16 Absolute LV cavity dimensions in these instances usually exceed normal limits (ie, end-diastolic diameter ≥55 mm) and, not infrequently, were markedly increased (ie, ≥60 mm). 16 Left ventricular wall thicknesses are also increased and, in a small but important subset of elite male athletes, exceed the upper normal limits (ie, ≥13 mm). 15 Of note, some misunderstanding persists as to whether purely strength training results in LV hypertrophy. Such sports are associated with only mildly increased wall thicknesses (often disproportionate relative to cavity size). However, although increased in comparison with matched untrained controls, absolute LV wall thicknesses rarely exceed the upper normal limits (ie, usually remaining b13 mm). 9,10 It should be recalled that LV remodeling is dynamic in nature and may appear to develop relatively gradually after the initiation of vigorous conditioning. Such changes are reversible with cessation of training and are most impressive in endurance athletes. 17-19
Athlete's heart and cardiovascular disease Because of the potentially adverse consequences of underlying cardiovascular disease in young athletes, considerable attention has focused on the clinical distinction of physiologically based athlete's heart from a variety of structural heart diseases. 20,21 This differential diagnosis has critical implications for dedicated athletes (and their physicians) because cardiovascular disease, namely, cardiomyopathies, may represent the basis for disqualification from competitive sports as a strategy to reduce sudden death risk. Furthermore, athletes with cardiac disease judged to be at high risk may subsequently become candidates for an implantable defibrillator and prophylactic prevention of sudden death. These diagnostic dilemmas arise when the remodeling of athlete's heart mimics certain pathologic conditions
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Fig 3. Distribution of cardiac dimensions in large populations of highly trained male and female athletes. A, LV end-diastolic cavity dimension; 14% of athletes have an enlargement of 60 to 70 mm. B, Transverse left atrial dimension; 20% of athletes have an enlargement of 40 mm or more. C, Maximum LV wall thickness; 2% of men and 0% of women have an enlargement of 13 mm or more. Reproduced with permission from Maron BJ, Pelliccia A. 3
such as hypertrophic cardiomyopathy (HCM), when absolute cardiac dimensions fall outside clinically accepted partition values (eg, LV wall thickness N12 mm; some-
what lower cut points apply to female and adolescent athletes). 21,22 Actually, a small but substantial subset of elite male athletes show an increased LV wall thickness
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Left ventricular wall thickness
Fig 4. Clinical criteria used to distinguish nonobstructive HCM from athlete's heart when maximal LV wall thickness is within shaded gray area of overlap, consistent with both diagnoses.
of 13 to 15 mm or more, which defines a gray zone of overlap between the extreme expressions of athlete's heart and a mild HCM phenotype (without outflow obstruction). 21 This ambiguity can usually be resolved by applying a number of noninvasive parameters as shown in Fig 4.
Maximum LV wall thickness of 15 mm in young trained athletes likely represents the upper limit of physiologic LV hypertrophy. 15 Instead, in patients with HCM, including those who are asymptomatic and regularly involved in active lifestyles, maximum LV wall thickness averages 21 to 22 mm and even 30 mm or more in about 10% of patients. 23 However, an important minority of patients with HCM show no or only mild wall thickening in a gray zone of 13 to 15 mm, which overlaps with that found in elite athletes. Therefore, absolute LV wall thickness itself may not differentiate physiologic from pathologic hypertrophy. In physiologic hypertrophy of the athlete, although the anterior ventricular septum is usually the segment of the LV wall that is maximally thickened, the overall pattern is symmetric and homogeneous, usually with a difference of 2 mm or less between all portions of the LV. 15 In contrast, in patients with HCM, the distribution of LV hypertrophy is usually strikingly asymmetric. 23 Although the anterior ventricular septum is generally the most thickened segment, not uncommonly, other areas (such as posterior ventricular septum, anterior free wall, or apex) may show the most marked degree of thickening. In addition, contiguous portions of the LV wall may show strikingly
Fig 5. Comparative echocardiographic images obtained from an elite marathon runner with physiologic LV remodeling vs an elite water polo player with HCM. A and B, Parasternal long-axis (A) and short-axis (B) views in elite marathon runner show increased LV wall thickness (maximum, 15 mm), with homogeneous distribution in transverse and longitudinal planes, associated with a mildly increased cavity size (diastolic diameter, 57 mm). C and D, Parasternal long-axis (C) and short-axis (D) views in the water polo player show LV wall thickening of a similar magnitude (maximum, 14 mm), but the posterior free wall is spared from hypertrophy (10 mm), and the cavity size is mildly reduced in size (diastolic diameter, 45 mm).
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different thicknesses, with hypertrophied segments separated by regions of normal thickness 23 (Fig 5). Left ventricular cavity In trained athletes, LV cavity dimension is commonly enlarged (ie, end-diastolic diameter ≥55 mm) 15 but only occasionally associated with absolute increase in LV wall thickness. Conversely, in patients with HCM, LV cavity size is characteristically normal or reduced (ie, end-diastolic diameter usually ≤50 mm). 23 In HCM, the LV chamber is enlarged (ie, 55-60 mm) only in the “end-stage,” characterized by progressive heart failure and systolic dysfunction. 24 Therefore, in most instances, it is possible to resolve the diagnostic ambiguity of borderline LV wall thickening based solely on LV cavity dimension, either small or enlarged (Fig 5). Indeed, the enlarged LV cavity in athletes maintains its normal ellipsoid shape, with the mitral valve normally positioned; whereas in patients with HCM, LV geometry is greatly distorted. 23 Resting or provocable LV outflow tract obstruction due to systolic anterior motion of the mitral valve is present in about two thirds of patients with HCM associated with a small LV outflow tract. On the contrary, LV outflow tract is normal in size or enlarged in trained athletes as a part of physiologic LV remodeling, and systolic anterior motion is absent. Left atrium Left atrial remodeling is a common consequence of athletic training with enlarged dimensions and volume. In a large cohort of 1823 elite athletes, left atrial transverse dimension was increased (≥40 mm) in 20% and markedly increased (≥45 mm) in only 2%. 20 In trained athletes, left atrial enlargement is consistently associated with LV cavity enlargement and normal or supranormal diastolic function. On the contrary, left atrium enlargement in patients with HCM is usually associated with impaired LV relaxation and filling and small LV cavity dimension. Therefore, the relationship between LV cavity and left atrial size is useful in the differential diagnosis of athlete's heart vs HCM. Diastolic LV filling and relaxation Most patients with HCM, including those most likely to be confused with “athlete's heart” because of the mild LV hypertrophy, show abnormal Doppler diastolic indexes of LV filling, independent of whether symptoms or outflow obstruction is present. 25 Typically, early peak transmitral flow velocity (E wave) is decreased, E-wave deceleration time is prolonged, late (atrial, A wave) peak is increased, and E/A ratio is reversed. 25 In contrast, trained athletes with LV hypertrophy consistently show normal LV filling pattern. 26
Tissue Doppler imaging (TDI) may aid in distinguishing physiologic LV remodeling in athletes from HCM. Comparative TDI investigations in individuals with different forms of LV hypertrophy showed that systolic and early diastolic velocities are decreased in patients with pathologic hypertrophy but were preserved in athletes. Specifically, the systolic and early diastolic gradient of velocity between the endocardium and epicardium in ventricular septum and posterior wall is significantly lower in HCM compared with athletes. The most useful TDI parameters for differentiating HCM from physiologic hypertrophy appear to be the gradient of velocity in early diastole of the posterior wall 27 and systolic annular velocity (b9 cm/s is associated with a sensitivity of 87% and a specificity of 97%). 28 Consequently, in a trained athlete with suspected LV hypertrophy, a distinctly abnormal LV filling or relaxation pattern strongly suggests the diagnosis of HCM. A normal diastolic LV filling or relaxation pattern, however, is not particularly useful for differential diagnosis because it can be compatible with both athlete's heart and HCM. Cardiovascular magnetic resonance Cardiovascular magnetic resonance (CMR) is as an advanced imaging modality with an expanding role in the differential diagnosis of HCM from physiologic LV remodeling in trained athletes. Contemporary CMR sequences produce truly tomographic, 3-dimensional, high-spatial-resolution images with full ventricular coverage and, therefore, the opportunity to inspect the LV myocardium for limited, focal hypertrophy without being encumbered by the limitations inherent in echocardiographic imaging. As a result, CMR is often superior to echocardiography for identifying the presence of LV hypertrophy, particularly when increased wall thickness is completely (or predominantly) limited to focal areas of the anterior free wall, posterior septum, and apex. 29,30 On the other hand, in trained athletes with physiologic cardiac remodeling, CMR consistently shows right ventricular and LV cavity enlargement, which maintains the normal shape, in the absence of localized wall thickening. 31 Finally, contrast-enhanced CMR with late gadolinium enhancement (LGE) can detect areas of myocardial fibrosis after the intravenous injection of gadolinium. Most patients with HCM demonstrate LGE, often in a patchy, multifocal mid–myocardial (or transmural) distribution, particularly in regions of LV hypertrophy, and unrelated to coronary artery distribution. The association of LGE and ventricular tachyarrhythmias on ambulatory Holter electrocardiogram (ECG) suggests a possible causative link between myocardial fibrosis, arrhythmia, and, ultimately, sudden cardiac death in patients with HCM. 32 Although some contrast-enhanced CMR studies are available in athletes, there is currently no evidence to
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suggest that LGE is present in physiologically remodeled hearts. Therefore, in patients for whom it is ambiguous as to whether mildly increased LV wall thickness is a result of athletic conditioning or HCM, the presence of LGE would favor the diagnosis of HCM. In this regard, CMR can provide important diagnostic information in differentiating patients with HCM from those with hypertrophy secondary to systematic athletic training.
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diffuse T-wave inversion. Occurrence of such abnormal patterns in an athlete with LV hypertrophy should be viewed with suspicion and mandate careful diagnostic investigation and periodical follow-up. 35 On the other hand, about 5% of trained athletes without LV hypertrophy or overt heart disease show distinctly abnormal ECG patterns consistent with HCM. 34 Regression of hypertrophy with deconditioning
Twelve-lead ECG Abnormal ECG patterns are common in patients with HCM (up to 90% of probands) and may be present in advance of the appearance of LV hypertrophy on imaging studies. 33 A variety of ECG alterations have been reported in patients with HCM, but no single pattern can be considered as a hallmark of the disease. Although a variety of ECG changes are commonly observed in trained athletes with physiology LV remodeling, 34 particular suspicion for HCM is raised by certain abnormalities such as marked left-axis deviation, left atrial enlargement pattern, deep Q waves, ST-segment depression, and
The most reliable demonstration that LV hypertrophy is a consequence of athletic training is the demonstration of its regression with brief periods of complete deconditioning. In our experience, highly trained athletes examined at peak conditioning (when echocardiography shows LV wall thicknesses of 13-15 mm) can demonstrate a significant reduction (by 2-5 mm) after a 3-month deconditioning period. 18 This observation is further supported by our longitudinal study, in which we prospectively evaluated athletes with LV hypertrophy during a 6 year-period after cessation of their athletic careers. 19 We observed normalization of LV wall
Fig 6. Role of CMR in the evaluation of athletes with borderline LV wall measurements. An asymptomatic 19-year-old US collegiate basketball player was identified on preparticipation evaluation to have an abnormal 12-lead ECG (A). During the initial cardiovascular evaluation, CMR demonstrated a focal area of increased LV wall thickness (ie, 14 mm) in the posterior septum at mid-LV level (B; asterisk). After a 3-month period of deconditioning from competitive sport and training, a repeated CMR showed no change in the posterior septal thickness (C). In addition, on contrast-enhanced CMR images (D), an area of LGE was present in the area of mild LV wall thickening. The presence of LGE and an area of LV hypertrophy confined to posterior septum, unchanged in thickness after athletic deconditioning, support the diagnosis of HCM in this athlete. Abbreviations: VS, ventricular septum; PW, posterior free wall; LV, LV cavity; LA, left atrium.
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thickness and no occurrence of adverse cardiovascular events. 19 Conversely, no substantial alteration in wall thickness would be expected to occur in patients with HCM in response to changes in physical activity. However, it should be emphasized that identification of changes in wall thickness with deconditioning requires high-quality serial imaging (preferably, CMR) studies, skilled operators, and compliance of the athlete for a temporary and complete interruption of the training program. Cardiovascular magnetic resonance images produce sharp contrast between the interface of darkened myocardium and bright blood pool, permitting precise wall thickness measurements in any location of the LV chamber. As a result, CMR can be particularly helpful in detecting serial changes in LV wall thickness over short periods of complete deconditioning (Fig 6).
LV wall thickness greater than 12 mm in a female athlete should raise suspicion for HCM.
Sex
Genetics
Although maximum absolute LV wall thickness in athletes may occasionally exceed 13 mm in male athletes, 15 LV wall thicknesses do not usually exceed 11 mm in female white athletes and 12 mm in female black athletes. 11,36 These observations suggest that intense athletic conditioning is an insufficient stimulus to place women within the morphologic gray zone of LV wall thickness, defined as 13 to 15 mm. Therefore, an increased
At present, a variety of mutations in 11 or more genes encoding proteins of the cardiac sarcomere have been reported to cause HCM, 38-40 with the 2 most common of these being β-myosin heavy-chain and myosin-binding protein C. At present, more than 1400 individual diseasecausing mutations have been reported for these genes, demonstrating the vast genetic heterogeneity responsible for HCM. Commercial genetic testing for HCM has now
Peak oxygen consumption Other useful criterion for differential diagnosis is the peak oxygen consumption. Marked physiologic LV wall thickening is virtually limited to elite, highly trained athletes engaged in endurance disciplines (primarily rowing, canoeing, and cycling) who usually have a superior exercise performance and attain high peak oxygen consumption (ie, VO2 max N50 mL kg −1 min −1 and often ≥70 mL kg −1 min −1). On the other hand, asymptomatic patients with HCM and only mild LV hypertrophy (in a range of 13-15 mm) usually attain lower peak oxygen consumption (ie, VO2 max b40-45 mL kg −1 min −1). 37
Fig 7. Genetic testing in the differential diagnosis of HCM from physiologic remodeling in trained athletes. A 20-year-old collegiate long-distance runner was evaluated for HCM after the diagnosis of this disease in his older brother and father. The athlete was found to have borderline abnormal 12-lead ECG; CMR demonstrated a maximal LV wall thickness of 13 mm in the basal anterior ventricular septum (⁎) and 11 mm in the lateral free wall, without systolic anterior motion of the mitral valve. After a period of deconditioning, the athlete's maximal LV wall thickness remained unchanged. Genetic testing was then undertaken in an effort to provide support to the diagnosis of HCM. A disease-causing sarcomere mutation (MYBC3Arg 502Trp) was initially identified in both affected family members and, subsequently, in the athlete. Therefore, genetic testing provided confirmatory evidence supporting HCM as the cause of LV hypertrophy in this individual. As a result, recommendations were made for disease management, including exclusion from competitive sport based on this diagnosis. Square represents males; circle, females; solid black symbols, clinically affected by HCM; clear symbols, without cardiac evaluation; gray symbol, borderline HCM after initial assessment by CMR; +, positive for mutation. Abbreviations: MYBPC, myosin-binding protein C.
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penetrated into cardiovascular clinical practice with automated DNA sequencing providing rapid, reliable, and comprehensive molecular diagnosis on a fee-forservice basis, although not yet available throughout the world. However, the likelihood of obtaining a positive test result in the proband is only about 50% because all genes causing HCM have not been identified. A negative test result is common and nondiagnostic. If a pathogenic mutation is identified in a proband (probably only a 25% likelihood), family members can be tested to identify those at risk for developing disease, a strategy that underscores the predominant role for genetic testing in HCM. Another potential application for genetic testing is in providing a definitive diagnosis of HCM in the individual athlete with borderline LV wall thickening (Fig 7). Although obtaining a positive genetic test result in this particular clinical scenario in the absence of a HCM family history is quite low (about 10%-20%), the identification of a disease-causing sarcomere mutation would definitively resolve the diagnosis. Therefore, the power of molecularbased diagnosis to potentially impact such difficult diagnostic situations confirms the emerging role for genetic testing in the contemporary differential diagnosis of athlete's heart vs HCM. However, physicians and patients should be fully informed regarding the potential implications of performing genetic testing, including the possibility for high out-of-pocket costs (up to $5500), wait time for test results (usually, 8 weeks in the United States), and confidentiality concerns related to discriminatory practice based on genetic testing results. Clinical implications Differentiating the clinically innocent athlete's heart from a pathologic condition has obvious important implications. Remodeling due to athletic training does not itself have adverse consequences even if long term and intense. 4,5,19,41 On the other hand, HCM is the most common genetic heart disease and cause of sudden death in young people including competitive athletes in the United States. 42 The recognition of HCM in trained athletes unavoidably triggers 2 major clinical initiatives. First, HCM is disqualifying from most intense competitive sports to lower risk, independent of the presence or absence of other conventional risk markers for this disease. 43,44 Therefore, participation in intense competitive sports is itself considered a modifiable sudden death risk factor in HCM. 45 Second, the diagnosis of HCM creates the opportunity for close long-term surveillance and institution of treatment modalities, when appropriate, such as consideration for primary prevention of sudden death with the implantable defibrillator. 46 Statement of Conflict of Interest All authors declare that there are no conflicts of interest.
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Disclosure Dr Barry J. Maron is a consultant for Gene Dx.
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21. Maron BJ, Pelliccia A, Spirito P: Cardiac disease in young trained athletes: insights into methods for distinguishing athlete's heart from structural heart disease, with particular emphasis on hypertrophic cardiomyopathy. Circulation 1995;91:1596-1601. 22. Sharma S, Maron BJ, Whyte G, et al: Physiologic limits of left ventricular hypertrophy in elite junior athletes: relevance to differential diagnosis of athlete's heart and hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;40:1431-1436. 23. Klues HG, Schiffers A, Maron BJ: Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphologic observations and significance as assessed by twodimensional echocardiography in 600 patients. J Am Coll Cardiol 1995;26:1699-1708. 24. Spirito P, Maron BJ, Bonow RO, et al: Occurrence and significance of progressive left ventricular wall thinning and relative cavity dilatation in patients with hypertrophic cardiomyopathy. Am J Cardiol 1987;60:123-129. 25. Maron BJ, Spirito P, Green KJ, et al: Noninvasive assessment of left ventricular diastolic function by pulsed Doppler echocardiography in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1987;10:733-742. 26. Lewis JF, Spirito P, Pelliccia A, et al: Usefulness of Doppler echocardiographic assessment of diastolic filling in distinguishing “athlete's heart” from hypertrophic cardiomyopathy. Am J Cardiol 1992;68:296-300. 27. Derumeaux G, Douillet R, Troniou A, et al: Distinguishing between physiologic hypertrophy in athletes and primary hypertrophic cardiomyopathies. Importance of tissue color Doppler. Arch Mal Coeur Vaiss 1999;92:201-210. 28. Vinereanu D, Florescu N, Schulthorpe N, et al: Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol 2001;88:53-58. 29. Rickers C, Wilke NM, Jerosch-Herold M, et al: Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation 2005;112:855-861. 30. Maron MS, Maron BJ, Harrigan C, et al: Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance. J Am Coll Cardiol 2009;54:220-228. 31. Scharhag J, Schneider G, Urhausen A, et al: Athlete's heart: right and left ventricular mass and function in male endurance athletes and untrained individuals determined by magnetic resonance imaging. J Am Coll Cardiol 2002;410:1856-1863. 32. Adabag AS, Maron BJ, Appelbaum E, et al: Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol 2008;51:1369-1374.
33. Maron BJ, Wolfson JK, Cirò E, et al: Relation of electrocardiographic abnormalities and patterns of left ventricular hypertrophy identified by 2-dimensional echocardiography in patients with hypertrophic cardiomyopathy. Am J Cardiol 1983;51:189-194. 34. Pelliccia A, Maron BJ, Culasso F, et al: Clinical significance of abnormal electrocardiographic patterns in trained athletes. Circulation 2000;102:278-284. 35. Pelliccia A, Di Paolo FM, Quattrini FM, et al: Outcomes in athletes with marked ECG repolarization abnormalities. N Engl J Med 2008;358:152-161. 36. Rawlins J, Carre F, Kervio G, et al: Ethnic differences in physiological cardiac adaptation to intense physical exercise in highly trained female athletes. Circulation 2010;121:1078-1085. 37. Sharma S, Elliott PM, Whyte G, et al: Utility of metabolic exercise testing in distinguishing hypertrophic cardiomyopathy from physiologic left ventricular hypertrophy in athletes. J Am Coll Cardiol 2000;36:864-870. 38. Wang L, Seidman JG, Seidman CE: Narrative review: harnessing molecular genetics for the diagnosis and management of hypertrophic cardiomyopathy. Ann Intern Med 2010;152:513-520. 39. Wordsworth S, Leal J, Blair E, et al: DNA testing for hypertrophic cardiomyopathy: a cost-effectiveness model. Eur Heart J 2010; 31:926-935. 40. Bos JM, Towbin JA, Ackerman MJ: Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol 2009;54:201-211. 41. Pelliccia A, Kinoshita N, Pisicchio C, et al: Long-term clinical consequences of intense, uninterrupted endurance training in Olympic athletes. J Am Coll Cardiol 2010;55:1619-1625. 42. Maron BJ, Doerer JJ, Haas TS, et al: Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006. Circulation 2009;119:1085-1092. 43. Maron BJ, Zipes DP: 36th Bethesda Conference: eligibility recommendations for competitive athletes with cardiovascular abnormalities. J Am Coll Cardiol 2005;45:2-64. 44. Pelliccia A, Fagard R, Bjørnstad HH, et al: Recommendations for competitive sports participation in athletes with cardiovascular disease. A consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology, and the Working Group of Myocardial and Pericardial diseases of the European Society of Cardiology. Eur Heart J 2005;26:1422-1445. 45. Maron BJ: Contemporary insights and strategies for risk stratification and prevention of sudden death in hypertrophic cardiomyopathy. Circulation 2010;121:445-456. 46. Maron BJ, Spirito P, Shen WK, et al: Implantable cardioverterdefibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007;298:405-412.
Assessment of Left Ventricular Hypertrophy in a Trained Athlete: Differential Diagnosis of Physiologic Athlete's Heart From Pathologic Hypertrophy Antonio Pelliccia a,⁎, Martin S. Maron b , Barry J. Maron c a
The Institute of Sport Medicine and Science, Italian National Olympic Committee, Rome, Italy b Hypertrophic Cardiomyopathy Center, Tufts Medical Center, Boston, MA c The Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN
Abstract
Physiologic LV remodeling in young trained athletes as a consequence of chronic training can occasionally mimic certain pathologic conditions associated with sudden death, such as HCM. A small but important subset ofelite male athletes may show a borderline increased LV wall thickness of 13 to 15 mm, which defines a gray zone of overlap between the extreme expressions of athlete's heart and a mild HCM phenotype. Such diagnostic ambiguity can be resolved by using the paradigm of noninvasive parameters including testing with echocardiography (and, more recently, with CMR): left atrial and LV chamber dimensions and shape, brief periods of deconditioning to alter LV mass, measurement of oxygen consumption and diastolic filling, and recognition of familial occurrence of HCM or a pathogenic HCM-causing sarcomere mutation. Such distinctions between physiologic/benign athlete's heart and HCM, the most common cause of sudden death in the young in the United States, can be crucial. The recognition of HCM leads to disqualification from intense competitive sports to reduce sudden death risk and, when appropriate, permits initiation of therapeutic interventions. (Prog Cardiovasc Dis 2012;54:387-396) © 2012 Elsevier Inc. All rights reserved.
Keywords:
Left ventricular hypertrophy; Trained athlete; Pathologic hypertrophy
Historical perspectives The concept that the cardiovascular system of trained athletes differs structurally and functionally from that of untrained, normal individuals is remarkably more than 100 years old. 1 Henschen 1 is credited with the first description in 1899, using only a basic physical examination with careful percussion to recognize enlargement of the heart due to athletic activity in cross-country skiers. Henschen 1 concluded that both dilatation and hypertrophy were
Statement of Conflict of Interest: see page 395. ⁎ Address reprint requests to Antonio Pelliccia, MD, Institute of Sports Medicine and Science, Largo Piero Gabrielli, 1, 00197 Rome, Italy. E-mail address: [email protected] (A. Pelliccia).
0033-0620/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pcad.2012.01.003
present in trained athletes, involving the left and right sides of the heart and that these changes were normal and favorable: “skiing causes an enlargement of the heart which can perform more work than a normal heart.” In the mid-20th century, investigators used quantitative chest radiography to demonstrate that heart size was increased in athletes, particularly in those engaged in endurance sports with large aerobic capacity. Some observers regarded the heart of the trained athlete to be weakened because of the “strain” created by continuous and strenuous training, subject to deteriorating cardiac function and possible heart failure. 2 From that time, there has been periodic controversy regarding the intrinsic nature of an athlete's heart—that is, whether the morphologic alterations evident are benign physiologic adaptations and the consequence of the training or,
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Abbreviations and Acronyms
alternatively, are potentially pathologic and the AGT = angiotensin harbinger of disease and CMR = cardiovascular future disability. magnetic resonance In the last 2 decades, imaging techniques have HCM = hypertrophic allowed direct assesscardiomyopathy ment of the morphologic LGE = late gadolinium and functional cardiac enhancement changes induced by athLV = left ventricle letic conditioning, and several investigations, TDI = tissue Doppler imaging largely based on the long-standing cardiovascular program of the Institute of Sport Medicine and Science in Rome, have provided extensive information in a variety of athlete populations including elite competitors. 3-11 Determinants of cardiac remodeling Type of sport Morphologic cardiac changes in athletes have been attributed primarily to the type of sport and, specifically, to the hemodynamic overload induced by various conditioning programs 3-9 (Fig 1). Specifically, endurance sports (ie, cycling, cross-country skiing, and rowing) are associated with a predominant volume overload, whereas power disciplines (ie, weight and power lifting, shot put, and discus) are associated with a predominant pressure overload. In our experience, elite athletes engaged in endurance sports demonstrate the greatest alterations in left ventricular (LV) cavity size, wall thickness, and mass. 5,9 Athletes engaged in power disciplines show a disproportionately larger impact on LV wall thickness than cavity size; whereas LV cavity dimensions remain
within normal limits; the relative wall thickness is increased. Other disciplines such as soccer, rugby, hockey, those involving mixed (aerobic and anaerobic) exercise programs show a moderate impact on LV cavity size, with absolute dimensions that commonly exceed the normal limits; however, LV wall thicknesses usually remain within normal limits. 9,10 Finally, skill and technical disciplines (such as golfing, equestrian, or yachting) have only a minimal remodeling effect, if any, on cardiac morphology. 9 Body size and composition Cardiac dimensions are closely related to body size and composition. Body surface area has proven to be the strongest determinant of cardiac dimensions. 5,9 Indeed, athletes with the greatest body surface area (and largest lean body mass), such as those engaged in rowing, rugby, basketball, and water polo, usually have the greatest absolute LV cavity dimensions. 4,5 Sex Women athletes have larger LV cavity dimension (average, +6%) and maximal wall thickness (average, +14%) compared with sedentary female controls. 11 However, the extent of LV remodeling in absolute terms is usually mild in trained women athletes, and specifically, LV wall thickness do not exceed the upper normal limits (ie, 12 mm) and do not usually fall into a “gray zone” of borderline LV hypertrophy. 11 Not unexpectedly, women athletes show smaller absolute LV cavity dimensions (average, −10%) and wall thicknesses (average, −20%) in comparison with male athletes of the same age, ethnic origin, and sporting disciplines. 11 These differences are likely the consequence of several determinants including the smaller body size (and lean body mass) and the lower absolute cardiac output and systolic
Fig 1. Effect of specific sports training on either LV cavity dimension or wall thickness in elite athletes representing different types of sport disciplines.
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Fig 2. Impact of different variables on LV end-diastolic cavity dimensions in a large population of male and female elite athletes. The relative impacts of the examined variables (body size, sex, age, and type of sport) are shown here as a proportion of overall variability in LV cavity size. Reproduced with permission from Pelliccia A, Thompson PD. 14
blood pressure attained during exercise by women compared with men. Genetic determinants Evidence for a genetic influence on cardiac remodeling in athletes has been suggested for the renin-angiotensin (AGT) system. 12,13 Specifically, military recruits undergoing 10-week exercise training had an LV mass increased by 42%, if they harbored an ACE-DD genotype and only 2% (P b .001) if an ACE-II genotype. 12 Also, the AGT M235T polymorphism may regulate the rate of transcription and secretion of AGT and the extent of cardiac remodeling; elite endurance athletes with the AGT-TT expression had larger LV mass in comparison with those with AGT-MM genotype (+10%; P b .004), independent of sex and intensity of training. 13 The relative contribution of demographic and environmental or genetic variables to LV remodeling in trained athletes has long been the subject of controversy. 14 Data assembled in large athlete populations analyzed with multivariate analysis show that about 75% of variability in LV cavity size is attributable to nongenetic factors such as body size, type of sport, sex, and age, with the body surface area being the largest of these components 14 (Fig 2). The remaining 25% of cavity size variability is otherwise unexplained and possibly caused by genetic factors. Left ventricular remodeling Responses of individual athletes to systematic conditioning are not uniform. Training induces some evidence of cardiac remodeling in about one half of trained athletes,
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consisting of alterations in ventricular chamber dimensions, namely, increased LV and right ventricular and left atrial cavity size (and volume), associated with normal systolic and diastolic function (Fig 3A-C). However, there is a considerable overlap in cardiac dimensions between a trained athlete population and age- and sex-matched sedentary controls. 3,4 Overall, athletes show relatively small (but statistically significant) increases of about 10% to 20% for wall thickness or cavity size, and these values in most individual athletes remain within accepted normal limits. 4 The magnitude of physiologic LV remodeling may become substantial when the multiple determinants, as described before, are present at the same time. The most extreme increases in cavity dimension and/or wall thickness have been observed in elite male athletes with large body size who are training in rowing, cross-country skiing, cycling, and swimming. 9,15,16 Absolute LV cavity dimensions in these instances usually exceed normal limits (ie, end-diastolic diameter ≥55 mm) and, not infrequently, were markedly increased (ie, ≥60 mm). 16 Left ventricular wall thicknesses are also increased and, in a small but important subset of elite male athletes, exceed the upper normal limits (ie, ≥13 mm). 15 Of note, some misunderstanding persists as to whether purely strength training results in LV hypertrophy. Such sports are associated with only mildly increased wall thicknesses (often disproportionate relative to cavity size). However, although increased in comparison with matched untrained controls, absolute LV wall thicknesses rarely exceed the upper normal limits (ie, usually remaining b13 mm). 9,10 It should be recalled that LV remodeling is dynamic in nature and may appear to develop relatively gradually after the initiation of vigorous conditioning. Such changes are reversible with cessation of training and are most impressive in endurance athletes. 17-19
Athlete's heart and cardiovascular disease Because of the potentially adverse consequences of underlying cardiovascular disease in young athletes, considerable attention has focused on the clinical distinction of physiologically based athlete's heart from a variety of structural heart diseases. 20,21 This differential diagnosis has critical implications for dedicated athletes (and their physicians) because cardiovascular disease, namely, cardiomyopathies, may represent the basis for disqualification from competitive sports as a strategy to reduce sudden death risk. Furthermore, athletes with cardiac disease judged to be at high risk may subsequently become candidates for an implantable defibrillator and prophylactic prevention of sudden death. These diagnostic dilemmas arise when the remodeling of athlete's heart mimics certain pathologic conditions
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Fig 3. Distribution of cardiac dimensions in large populations of highly trained male and female athletes. A, LV end-diastolic cavity dimension; 14% of athletes have an enlargement of 60 to 70 mm. B, Transverse left atrial dimension; 20% of athletes have an enlargement of 40 mm or more. C, Maximum LV wall thickness; 2% of men and 0% of women have an enlargement of 13 mm or more. Reproduced with permission from Maron BJ, Pelliccia A. 3
such as hypertrophic cardiomyopathy (HCM), when absolute cardiac dimensions fall outside clinically accepted partition values (eg, LV wall thickness N12 mm; some-
what lower cut points apply to female and adolescent athletes). 21,22 Actually, a small but substantial subset of elite male athletes show an increased LV wall thickness
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Left ventricular wall thickness
Fig 4. Clinical criteria used to distinguish nonobstructive HCM from athlete's heart when maximal LV wall thickness is within shaded gray area of overlap, consistent with both diagnoses.
of 13 to 15 mm or more, which defines a gray zone of overlap between the extreme expressions of athlete's heart and a mild HCM phenotype (without outflow obstruction). 21 This ambiguity can usually be resolved by applying a number of noninvasive parameters as shown in Fig 4.
Maximum LV wall thickness of 15 mm in young trained athletes likely represents the upper limit of physiologic LV hypertrophy. 15 Instead, in patients with HCM, including those who are asymptomatic and regularly involved in active lifestyles, maximum LV wall thickness averages 21 to 22 mm and even 30 mm or more in about 10% of patients. 23 However, an important minority of patients with HCM show no or only mild wall thickening in a gray zone of 13 to 15 mm, which overlaps with that found in elite athletes. Therefore, absolute LV wall thickness itself may not differentiate physiologic from pathologic hypertrophy. In physiologic hypertrophy of the athlete, although the anterior ventricular septum is usually the segment of the LV wall that is maximally thickened, the overall pattern is symmetric and homogeneous, usually with a difference of 2 mm or less between all portions of the LV. 15 In contrast, in patients with HCM, the distribution of LV hypertrophy is usually strikingly asymmetric. 23 Although the anterior ventricular septum is generally the most thickened segment, not uncommonly, other areas (such as posterior ventricular septum, anterior free wall, or apex) may show the most marked degree of thickening. In addition, contiguous portions of the LV wall may show strikingly
Fig 5. Comparative echocardiographic images obtained from an elite marathon runner with physiologic LV remodeling vs an elite water polo player with HCM. A and B, Parasternal long-axis (A) and short-axis (B) views in elite marathon runner show increased LV wall thickness (maximum, 15 mm), with homogeneous distribution in transverse and longitudinal planes, associated with a mildly increased cavity size (diastolic diameter, 57 mm). C and D, Parasternal long-axis (C) and short-axis (D) views in the water polo player show LV wall thickening of a similar magnitude (maximum, 14 mm), but the posterior free wall is spared from hypertrophy (10 mm), and the cavity size is mildly reduced in size (diastolic diameter, 45 mm).
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different thicknesses, with hypertrophied segments separated by regions of normal thickness 23 (Fig 5). Left ventricular cavity In trained athletes, LV cavity dimension is commonly enlarged (ie, end-diastolic diameter ≥55 mm) 15 but only occasionally associated with absolute increase in LV wall thickness. Conversely, in patients with HCM, LV cavity size is characteristically normal or reduced (ie, end-diastolic diameter usually ≤50 mm). 23 In HCM, the LV chamber is enlarged (ie, 55-60 mm) only in the “end-stage,” characterized by progressive heart failure and systolic dysfunction. 24 Therefore, in most instances, it is possible to resolve the diagnostic ambiguity of borderline LV wall thickening based solely on LV cavity dimension, either small or enlarged (Fig 5). Indeed, the enlarged LV cavity in athletes maintains its normal ellipsoid shape, with the mitral valve normally positioned; whereas in patients with HCM, LV geometry is greatly distorted. 23 Resting or provocable LV outflow tract obstruction due to systolic anterior motion of the mitral valve is present in about two thirds of patients with HCM associated with a small LV outflow tract. On the contrary, LV outflow tract is normal in size or enlarged in trained athletes as a part of physiologic LV remodeling, and systolic anterior motion is absent. Left atrium Left atrial remodeling is a common consequence of athletic training with enlarged dimensions and volume. In a large cohort of 1823 elite athletes, left atrial transverse dimension was increased (≥40 mm) in 20% and markedly increased (≥45 mm) in only 2%. 20 In trained athletes, left atrial enlargement is consistently associated with LV cavity enlargement and normal or supranormal diastolic function. On the contrary, left atrium enlargement in patients with HCM is usually associated with impaired LV relaxation and filling and small LV cavity dimension. Therefore, the relationship between LV cavity and left atrial size is useful in the differential diagnosis of athlete's heart vs HCM. Diastolic LV filling and relaxation Most patients with HCM, including those most likely to be confused with “athlete's heart” because of the mild LV hypertrophy, show abnormal Doppler diastolic indexes of LV filling, independent of whether symptoms or outflow obstruction is present. 25 Typically, early peak transmitral flow velocity (E wave) is decreased, E-wave deceleration time is prolonged, late (atrial, A wave) peak is increased, and E/A ratio is reversed. 25 In contrast, trained athletes with LV hypertrophy consistently show normal LV filling pattern. 26
Tissue Doppler imaging (TDI) may aid in distinguishing physiologic LV remodeling in athletes from HCM. Comparative TDI investigations in individuals with different forms of LV hypertrophy showed that systolic and early diastolic velocities are decreased in patients with pathologic hypertrophy but were preserved in athletes. Specifically, the systolic and early diastolic gradient of velocity between the endocardium and epicardium in ventricular septum and posterior wall is significantly lower in HCM compared with athletes. The most useful TDI parameters for differentiating HCM from physiologic hypertrophy appear to be the gradient of velocity in early diastole of the posterior wall 27 and systolic annular velocity (b9 cm/s is associated with a sensitivity of 87% and a specificity of 97%). 28 Consequently, in a trained athlete with suspected LV hypertrophy, a distinctly abnormal LV filling or relaxation pattern strongly suggests the diagnosis of HCM. A normal diastolic LV filling or relaxation pattern, however, is not particularly useful for differential diagnosis because it can be compatible with both athlete's heart and HCM. Cardiovascular magnetic resonance Cardiovascular magnetic resonance (CMR) is as an advanced imaging modality with an expanding role in the differential diagnosis of HCM from physiologic LV remodeling in trained athletes. Contemporary CMR sequences produce truly tomographic, 3-dimensional, high-spatial-resolution images with full ventricular coverage and, therefore, the opportunity to inspect the LV myocardium for limited, focal hypertrophy without being encumbered by the limitations inherent in echocardiographic imaging. As a result, CMR is often superior to echocardiography for identifying the presence of LV hypertrophy, particularly when increased wall thickness is completely (or predominantly) limited to focal areas of the anterior free wall, posterior septum, and apex. 29,30 On the other hand, in trained athletes with physiologic cardiac remodeling, CMR consistently shows right ventricular and LV cavity enlargement, which maintains the normal shape, in the absence of localized wall thickening. 31 Finally, contrast-enhanced CMR with late gadolinium enhancement (LGE) can detect areas of myocardial fibrosis after the intravenous injection of gadolinium. Most patients with HCM demonstrate LGE, often in a patchy, multifocal mid–myocardial (or transmural) distribution, particularly in regions of LV hypertrophy, and unrelated to coronary artery distribution. The association of LGE and ventricular tachyarrhythmias on ambulatory Holter electrocardiogram (ECG) suggests a possible causative link between myocardial fibrosis, arrhythmia, and, ultimately, sudden cardiac death in patients with HCM. 32 Although some contrast-enhanced CMR studies are available in athletes, there is currently no evidence to
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suggest that LGE is present in physiologically remodeled hearts. Therefore, in patients for whom it is ambiguous as to whether mildly increased LV wall thickness is a result of athletic conditioning or HCM, the presence of LGE would favor the diagnosis of HCM. In this regard, CMR can provide important diagnostic information in differentiating patients with HCM from those with hypertrophy secondary to systematic athletic training.
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diffuse T-wave inversion. Occurrence of such abnormal patterns in an athlete with LV hypertrophy should be viewed with suspicion and mandate careful diagnostic investigation and periodical follow-up. 35 On the other hand, about 5% of trained athletes without LV hypertrophy or overt heart disease show distinctly abnormal ECG patterns consistent with HCM. 34 Regression of hypertrophy with deconditioning
Twelve-lead ECG Abnormal ECG patterns are common in patients with HCM (up to 90% of probands) and may be present in advance of the appearance of LV hypertrophy on imaging studies. 33 A variety of ECG alterations have been reported in patients with HCM, but no single pattern can be considered as a hallmark of the disease. Although a variety of ECG changes are commonly observed in trained athletes with physiology LV remodeling, 34 particular suspicion for HCM is raised by certain abnormalities such as marked left-axis deviation, left atrial enlargement pattern, deep Q waves, ST-segment depression, and
The most reliable demonstration that LV hypertrophy is a consequence of athletic training is the demonstration of its regression with brief periods of complete deconditioning. In our experience, highly trained athletes examined at peak conditioning (when echocardiography shows LV wall thicknesses of 13-15 mm) can demonstrate a significant reduction (by 2-5 mm) after a 3-month deconditioning period. 18 This observation is further supported by our longitudinal study, in which we prospectively evaluated athletes with LV hypertrophy during a 6 year-period after cessation of their athletic careers. 19 We observed normalization of LV wall
Fig 6. Role of CMR in the evaluation of athletes with borderline LV wall measurements. An asymptomatic 19-year-old US collegiate basketball player was identified on preparticipation evaluation to have an abnormal 12-lead ECG (A). During the initial cardiovascular evaluation, CMR demonstrated a focal area of increased LV wall thickness (ie, 14 mm) in the posterior septum at mid-LV level (B; asterisk). After a 3-month period of deconditioning from competitive sport and training, a repeated CMR showed no change in the posterior septal thickness (C). In addition, on contrast-enhanced CMR images (D), an area of LGE was present in the area of mild LV wall thickening. The presence of LGE and an area of LV hypertrophy confined to posterior septum, unchanged in thickness after athletic deconditioning, support the diagnosis of HCM in this athlete. Abbreviations: VS, ventricular septum; PW, posterior free wall; LV, LV cavity; LA, left atrium.
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thickness and no occurrence of adverse cardiovascular events. 19 Conversely, no substantial alteration in wall thickness would be expected to occur in patients with HCM in response to changes in physical activity. However, it should be emphasized that identification of changes in wall thickness with deconditioning requires high-quality serial imaging (preferably, CMR) studies, skilled operators, and compliance of the athlete for a temporary and complete interruption of the training program. Cardiovascular magnetic resonance images produce sharp contrast between the interface of darkened myocardium and bright blood pool, permitting precise wall thickness measurements in any location of the LV chamber. As a result, CMR can be particularly helpful in detecting serial changes in LV wall thickness over short periods of complete deconditioning (Fig 6).
LV wall thickness greater than 12 mm in a female athlete should raise suspicion for HCM.
Sex
Genetics
Although maximum absolute LV wall thickness in athletes may occasionally exceed 13 mm in male athletes, 15 LV wall thicknesses do not usually exceed 11 mm in female white athletes and 12 mm in female black athletes. 11,36 These observations suggest that intense athletic conditioning is an insufficient stimulus to place women within the morphologic gray zone of LV wall thickness, defined as 13 to 15 mm. Therefore, an increased
At present, a variety of mutations in 11 or more genes encoding proteins of the cardiac sarcomere have been reported to cause HCM, 38-40 with the 2 most common of these being β-myosin heavy-chain and myosin-binding protein C. At present, more than 1400 individual diseasecausing mutations have been reported for these genes, demonstrating the vast genetic heterogeneity responsible for HCM. Commercial genetic testing for HCM has now
Peak oxygen consumption Other useful criterion for differential diagnosis is the peak oxygen consumption. Marked physiologic LV wall thickening is virtually limited to elite, highly trained athletes engaged in endurance disciplines (primarily rowing, canoeing, and cycling) who usually have a superior exercise performance and attain high peak oxygen consumption (ie, VO2 max N50 mL kg −1 min −1 and often ≥70 mL kg −1 min −1). On the other hand, asymptomatic patients with HCM and only mild LV hypertrophy (in a range of 13-15 mm) usually attain lower peak oxygen consumption (ie, VO2 max b40-45 mL kg −1 min −1). 37
Fig 7. Genetic testing in the differential diagnosis of HCM from physiologic remodeling in trained athletes. A 20-year-old collegiate long-distance runner was evaluated for HCM after the diagnosis of this disease in his older brother and father. The athlete was found to have borderline abnormal 12-lead ECG; CMR demonstrated a maximal LV wall thickness of 13 mm in the basal anterior ventricular septum (⁎) and 11 mm in the lateral free wall, without systolic anterior motion of the mitral valve. After a period of deconditioning, the athlete's maximal LV wall thickness remained unchanged. Genetic testing was then undertaken in an effort to provide support to the diagnosis of HCM. A disease-causing sarcomere mutation (MYBC3Arg 502Trp) was initially identified in both affected family members and, subsequently, in the athlete. Therefore, genetic testing provided confirmatory evidence supporting HCM as the cause of LV hypertrophy in this individual. As a result, recommendations were made for disease management, including exclusion from competitive sport based on this diagnosis. Square represents males; circle, females; solid black symbols, clinically affected by HCM; clear symbols, without cardiac evaluation; gray symbol, borderline HCM after initial assessment by CMR; +, positive for mutation. Abbreviations: MYBPC, myosin-binding protein C.
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penetrated into cardiovascular clinical practice with automated DNA sequencing providing rapid, reliable, and comprehensive molecular diagnosis on a fee-forservice basis, although not yet available throughout the world. However, the likelihood of obtaining a positive test result in the proband is only about 50% because all genes causing HCM have not been identified. A negative test result is common and nondiagnostic. If a pathogenic mutation is identified in a proband (probably only a 25% likelihood), family members can be tested to identify those at risk for developing disease, a strategy that underscores the predominant role for genetic testing in HCM. Another potential application for genetic testing is in providing a definitive diagnosis of HCM in the individual athlete with borderline LV wall thickening (Fig 7). Although obtaining a positive genetic test result in this particular clinical scenario in the absence of a HCM family history is quite low (about 10%-20%), the identification of a disease-causing sarcomere mutation would definitively resolve the diagnosis. Therefore, the power of molecularbased diagnosis to potentially impact such difficult diagnostic situations confirms the emerging role for genetic testing in the contemporary differential diagnosis of athlete's heart vs HCM. However, physicians and patients should be fully informed regarding the potential implications of performing genetic testing, including the possibility for high out-of-pocket costs (up to $5500), wait time for test results (usually, 8 weeks in the United States), and confidentiality concerns related to discriminatory practice based on genetic testing results. Clinical implications Differentiating the clinically innocent athlete's heart from a pathologic condition has obvious important implications. Remodeling due to athletic training does not itself have adverse consequences even if long term and intense. 4,5,19,41 On the other hand, HCM is the most common genetic heart disease and cause of sudden death in young people including competitive athletes in the United States. 42 The recognition of HCM in trained athletes unavoidably triggers 2 major clinical initiatives. First, HCM is disqualifying from most intense competitive sports to lower risk, independent of the presence or absence of other conventional risk markers for this disease. 43,44 Therefore, participation in intense competitive sports is itself considered a modifiable sudden death risk factor in HCM. 45 Second, the diagnosis of HCM creates the opportunity for close long-term surveillance and institution of treatment modalities, when appropriate, such as consideration for primary prevention of sudden death with the implantable defibrillator. 46 Statement of Conflict of Interest All authors declare that there are no conflicts of interest.
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Disclosure Dr Barry J. Maron is a consultant for Gene Dx.
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