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Prevalence of Hypertrophic Cardiomyopathy in a General Population of Young Adults

Echocardiographic Analysis of 4111 Subjects in the CARDIA Study
Originally publishedhttps://doi.org/10.1161/01.CIR.92.4.785Circulation. 1995;92:785–789

    Abstract

    Background Hypertrophic cardiomyopathy (HCM) is a genetically transmitted disease and an important cause of morbidity and sudden cardiac death in young people, including competitive athletes. At present, however, few data exist to estimate the prevalence of this disease in large populations.

    Methods and Results As part of the Coronary Artery Risk Development in (Young) Adults (CARDIA) Study, an epidemiological study of coronary risk factors, 4111 men and women 23 to 35 years of age selected from the general population of four urban centers had technically satisfactory echocardiographic studies during 1987 through 1988. Probable or definite echocardiographic evidence of HCM was present in 7 subjects (0.17%) on the basis of identification of a hypertrophied, nondilated left ventricle and maximal wall thickness ≥15 mm that were not associated with systemic hypertension. Prevalence in men and women was 0.26:0.09%; in blacks and whites, 0.24:0.10%. Ventricular septal thickness was 15 to 21 mm (mean, 17 mm) in the 7 subjects. Only 1 of the 7 subjects had ever experienced important cardiac symptoms attributable to HCM, had previously been suspected of having cardiovascular disease, or had obstruction to left ventricular outflow; 4 other subjects had relatively mild systolic anterior motion of the mitral valve that was insufficient to produce dynamic basal outflow obstruction. ECGs were abnormal in 5 of the 7 subjects. Five other study subjects had left ventricular wall thicknesses of 15 to 21 mm that were a consequence of systemic hypertension.

    Conclusions HCM was present in about 2 of 1000 young adults. These unique population-based data will aid in assessments of the impact of HCM-related mortality and morbidity in the general population and the practicality of screening large populations for HCM, including those comprising competitive athletes.

    Hypertrophic cardiomyopathy (HCM) is a genetically transmitted cardiac disease with a broad clinical and morphological spectrum123456789 that has generated intense investigation since its initial description in 1958.10 Indeed, HCM has been cited as the most frequent cause of sudden cardiac death in young people, including competitive athletes,111213141516171819 stimulating an interest in the screening of large populations for this disease.2021

    However, most of the information available in the scientific literature on the expression, clinical course, and treatment of HCM has emanated from tertiary referral centers investigating highly selected populations of patients.12315161722232425 Although regarded as uncommon, the frequency with which HCM occurs in the general population is, at present, largely unknown. In the present investigation, we have estimated the prevalence of echocardiographically defined HCM in a large cohort of apparently healthy young adults selected from a community-based general population in four urban areas.

    Methods

    Selection of Subjects

    This investigation used the population of subjects defined in the Coronary Artery Risk Development in (Young) Adults (CARDIA) Study. The overall study design was described previously in detail26 but is also summarized briefly here. CARDIA was initiated in 1983 by the NHLBI to prospectively establish a large biracial cohort to investigate longitudinally over a number of years lifestyle and other variables that influence the evolution of coronary risk factors during young adulthood. A total study group of 10 143 subjects was contacted randomly in relatively equal numbers from four geographically diverse urban field centers: Birmingham, Ala; Chicago, Ill; Minneapolis, Minn; and the Kaiser Permanente Medical Care Program, Oakland, Calif.

    Recruitment of subjects was limited to men and women 18 to 30 years of age, and the population was stratified to achieve approximately equal numbers of blacks and whites, male and female subjects <25 and ≥25 years of age, and individuals with (or less than) a high school education. Study subjects were recruited from community-based target populations in census tracts (identified as racially diverse) through telephone company lists and random digit dialing or through either telephone or door-to-door contact after selection from commercial mailing lists in Birmingham, Chicago, and Minneapolis. In Oakland, participants were drawn from the membership rosters of the prepaid Kaiser Permanente Medical Care Program, which served about one quarter of the local population; potential subjects were randomly selected for telephone contact from the roster of subscribers through zip-code groupings or records of multiphasic health checkups.

    Of the 10 143 eligible contacts, 5115 were examined and ultimately entered in the study. The study subjects were distributed in relatively equal numbers among the four centers. The initial examination (during 1985 through 1986) included standardized assessments of psychosocial, dietary, and exercise-related characteristics; measurement of blood pressure, height, and weight; total plasma cholesterol determination; and an ECG. Five years later (during 1990 through 1991), when the subjects were 23 to 35 years of age, this assessment was repeated. At that time, echocardiographic examinations were performed in 4243 subjects. Of these, 4111 (97%) had technically satisfactory echocardiographic studies that permitted reliable assessment of left ventricular wall thickness and morphology. Subjects were excluded from the study if they were physically unable to participate in the 3-hour examination (which included an exercise test) because of cardiac or systemic symptoms and functional limitation.

    Echocardiographic Methods

    The echocardiography protocol used in CARDIA was similar to that used in the Cardiovascular Health Study.27 Echocardiographic studies were performed with respiration suspended at midexpiration in the left lateral decubitus position by use of standard methodology at all four field centers with commercially available Acuson-128 phased array sector scanners (Acuson Inc) and 2.5- and 3.75-MHz transducers. Stop-frame M-mode and real-time two-dimensional (2D) images were recorded at 30 frames per second on 1/2-in super VHS videotape. Eight trained technicians (two from each center) performed the echocardiographic studies. In addition, these eight technicians participated in a 5-day centralized training and orientation session focused on the objectives and design of the CARDIA Study held at the Echocardiography Reading Center (University of California, Irvine).

    In addition to standardized training of the echocardiography technicians and readers, quality control measures incorporated into the CARDIA Study design included regular technician observation by a trained echocardiographer and periodic blind duplicate readings associated with reader review sessions.27 Interobserver and intraobserver reproducibilities for M-mode measurements of cardiac dimensions made by both technicians and readers were evaluated as previously described for the Cardiovascular Health Study.27 In CARDIA, technical errors for components of variability for left ventricular mass measurements were as follows: intratechnician performance, 10% (from 60 paired studies); intertechnician performance, 10% (from 44 paired studies); intrareader, 8% (from 158 paired studies); and interreader, 14% (from 350 paired studies).

    M-mode echocardiograms were derived from the 2D images under direct anatomic visualization and were recorded at 50 mm/s on super VHS videotape. Cardiac dimensions were measured from M-mode echocardiograms directly from the video screen, according to the recommendations of the American Society of Echocardiography28 that utilize cutting-edge methodology for the recognition of borders. These measurements were made with the aid of a Dextra D-200 (Dextra, Inc) off-line image analysis system, and the data were stored in a master computer in d-base iv database format.

    Echocardiographic images (2D) were obtained in the parasternal long- and short-axis views and apical two- and four-chamber views with standard transducer positions.29 In those subjects suspected of having HCM (from the primary echocardiographic analysis at the Reading Center), the extent and distribution of left ventricular hypertrophy were assessed from the 2D echocardiogram by one of the investigators (B.J.M.) primarily from the parasternal short-axis planes1930 ; however, the parasternal long-axis and the apical views were also used to integrate the observations made from the short-axis planes. In the parasternal short-axis view, the left ventricle was divided into four regions that identified the anterior and posterior ventricular septa and the lateral and posterior free walls. Wall thicknesses were assessed directly from the television monitor with the aid of calipers and the calibration scale produced by the instrument. Endocardial and epicardial borders were identified by viewing of the pertinent portions of videotape in slow-motion and real-time modes. A particular effort was made to exclude overlying trabeculae in the measurement of left ventricular wall thickness. Maximal wall thickness was defined in each patient as the greatest thickness identified in any of the four segments into which the left ventricle had been divided. Anterior ventricular septal thickness was assessed by an integrated analysis of the 2D and the M-mode recordings.1930 Degree and duration of systolic anterior motion of the mitral valve31 were assessed from the echocardiogram by use of previously described criteria.

    Echocardiographic Data Analysis

    CARDIA echocardiographic data was analyzed in a two-tier fashion as described. First, the initial echocardiographic interpretations made at or near the time when the studies were recorded by a team of three trained echocardiographic technician-readers at the Echocardiography Reading Center facility.27 From these interpretations, seven screening codes were judged to be consistent with (or suggestive of) the diagnosis of HCM, including four based on quantitative measurements: (1) left ventricular wall thickness ≥12 mm, (2) left ventricular end-diastolic cavity dimension <45 mm, (3) percent left ventricular fractional shortening >25%, and (4) systolic anterior motion of the mitral valve. Three other codes were assessed qualitatively by visual inspection of the real-time 2D movie: (1) concentric left ventricular hypertrophy, (2) basal ventricular septal hypertrophy, and (3) hypertrophic cardiomyopathy. A total of 128 echocardiographic studies were identified in one or more of these seven categories. Each of these studies was then analyzed a second time by one investigator (B.J.M.) specifically for the presence or absence of HCM; these measurements were used for all prevalence estimates.

    In addition, the same investigator similarly analyzed 1102 other echocardiographic studies for HCM. Each of these latter studies had been assigned diagnostic codes other than the aforementioned seven and included all those echocardiographic studies recorded on the same VHS videotapes as the coded echocardiograms (about 10 to 20 per tape). Therefore, one investigator independently analyzed a total of 1230 echocardiograms (representing 29% of the suitable CARDIA echocardiographic studies) to make the echocardiographic diagnosis of HCM and also to validate the original coding diagnoses made at the Echocardiography Reading Center.

    Criteria for Diagnosis

    The standard definition of HCM was used in this analysis, ie, a hypertrophied nondilated left ventricle in the absence of another cardiac or systemic disease capable of producing left ventricular hypertrophy.32 Specifically, HCM was identified by echocardiography (in probable or definite terms) by virtue of a maximal left ventricular wall thickness ≥15 mm present in any left ventricular segment,1451932 representing an unambiguous and conservative cutoff value that substantially exceeded the mean ventricular septal thickness for the overall study group (8.7±1.5 mm) and the generally accepted upper limit for normal left ventricular wall thickness in adult subjects (≤12 mm).33

    The presence of mitral valve systolic anterior motion343536 was used as a confirmatory diagnostic finding, but its absence did not exclude the diagnosis of HCM because the nonobstructive form of the disease is characteristically associated with no or only mild systolic anterior motion.131

    Results

    Of the 4111 study subjects, 7 (0.17%) were identified as having probable or definite echocardiographic evidence for HCM (the Table). The 95% CI for this prevalence was 0.07% to 0.35%.

    The 7 subjects with HCM (4 black men, 1 black woman, 1 white man, and 1 white woman) were 25 to 33 years of age at the time of the echocardiographic study. The frequency of HCM was 5 in 1913 (0.26%) in men, 2 of 2198 (0.09%) in women, 5 in 2081 (0.24%) in blacks, and 2 in 2030 (0.10%) in whites. Each of the 7 subjects with HCM was free of important cardiac symptoms at the time of echocardiographic study, although one had reported having palpitations. Of the 7 subjects, 6 had not previously been suspected of having cardiovascular disease; however, 1 subject (No. 2 in Table 1), a 25-year-old woman, had been identified as having HCM and underwent ventricular septal myotomy-myectomy 8 months before the CARDIA echocardiographic study. Before the operation, she experienced exertional dyspnea, chest pain, and presyncope. Of the 5 subjects with HCM, 3 came from the Chicago field center and 1 each from Minneapolis, Oakland, and Birmingham.

    Maximal left ventricular wall thicknesses (of anterior ventricular septum in each) were 15 to 21 mm (mean, 17 mm), including a septal thickness of 21 mm in the patient with a prior myotomy-myectomy. Distribution of left ventricular wall thickening was diffuse, involving the anterior ventricular septum, posterior septum, and anterolateral free wall in 4 subjects and was confined to the anterior septum in the other 3. Left ventricular end-diastolic cavity dimensions were 40 to 51 mm. Relatively mild mitral valve systolic anterior motion was present in 4 subjects. In each of these instances, the mitral valve approached but did not make contact with the septum. ECGs were judged to be abnormal in 5 of the 7 subjects with HCM: 3 had ST-segment and T-wave changes, 1 had left ventricular hypertrophy (“strain”) pattern, and 1 also had abnormal Q waves.

    All 7 subjects with HCM were among the 114 subjects initially identified at the Echocardiographic Reading Center with echocardiographic abnormalities. Of the 1102 echocardiograms reanalyzed as validation for the primary readings of the Reading Center, none met the aforementioned criteria for HCM.

    Five other subjects in the cohort were identified as having left ventricular hypertrophy. Maximal wall thicknesses in the anterior ventricular septum were 15 to 21 mm (mean, 17 mm). In each of these subjects, however, elevated blood pressures (systolic, 145 to 190 mm Hg; diastolic, 96 to 143 mm Hg) were recorded on the CARDIA examination during which the echocardiogram had been performed; therefore, the left ventricular hypertrophy present in these subjects was considered to be a consequence of systemic hypertension.37

    Discussion

    The present study assesses the frequency with which HCM occurs in the general population by use of a large, prospectively established youthful population (23 to 35 years of age) initially recruited to investigate the impact of lifestyle and other variables on the evolution of coronary risk factors.26 That this study involved a large cohort designed to be representative of the general population of young people, uncontaminated by any referral bias, and in which all subjects had undergone systematic echocardiographic examinations suggests that the CARDIA Study might well be uniquely suited to study the prevalence of HCM. Furthermore, the age of the study subjects (23 to 35 years) appears to be optimal for a study of the prevalence of HCM because the echocardiographic studies were performed at a time in life when the disease could be expected to have complete morphological expression.38

    The principal finding of the present study is that HCM occurs in about 0.2% of a general population of young adults. Of the 7 study subjects judged to have probable or definite echocardiographic evidence of HCM, 6 had the nonobstructive form of the disease and only 1 had experienced important cardiac symptoms; except for the latter patient, none had been previously suspected of having cardiovascular disease. Each subject showed relatively mild morphological expression of HCM, with an average maximum left ventricular wall thickness of 17 mm, somewhat less than that previously encountered in large hospital-based referral populations with HCM,519 and none demonstrated a particularly marked morphological expression of the disease.539

    However, our reported prevalence figure in subjects 23 to 35 years of age may represent an overestimation of the overall occurrence of HCM because the disease may not be as common in other age groups such as the elderly. On the other hand, other factors could have underestimated the true occurrence of HCM in a young adult population. For example, some patients with HCM would not have met the established entry criteria for selection into the CARDIA Study owing to the presence of marked symptoms and functional limitation, while others may have died suddenly of their disease before having the opportunity to be entered. Also, our relatively strict morphological criteria for probable or definite HCM (maximal left ventricular wall thickness ≥15 mm) could have excluded those occasional patients with mild morphological expressions of the disease and “borderline” wall thickness of only 13 or 14 mm.4 The low prevalence of HCM in the present study population limited the statistical power to detect differences with respect to sex and race.

    Although HCM has been regarded largely as a relatively uncommon cardiac disease, few data are available that measure the prevalence of HCM in general or cardiac populations. Hada et al40 surveyed 12 000 adult Japanese workers initially with ECGs and subsequently with echocardiograms (in a subset of only about 12%); the reported prevalence of HCM was 0.2%. However, use of the ECG for primary screening could have resulted in an underestimation of the frequency of HCM in that particular population. In an early echocardiographic study (confined to the M-mode technique) in more than 3000 offspring of the original Framingham cohort, Savage et al41 found echocardiographic markers of HCM in 0.3%. Of note, while the present investigation and those of Hada et al40 and Savage et al41 are not directly comparable with respect to methodology and the precise criteria used to diagnose HCM, each study nevertheless achieved similar estimates for prevalence. Furthermore, a recent study in a community-based population of patients referred for echocardiography because of a suspicion of cardiovascular disease demonstrated a 0.5% prevalence for HCM.42 Finally, the population-based study of Olmsted County, Minn,43 described an age- and sex-adjusted prevalence of only 0.02% for HCM. The fact that this was a disease surveillance analysis of patients who came to medical attention for HCM (rather than identification by population screening such as in the present study) undoubtedly accounted for what would appear to be an underestimation of the true prevalence of HCM. Therefore, the findings of the present study show that recognition of HCM by morphological criteria yields a prevalence 10 times greater than prior estimates based on symptomatic presentation and about one half of that reported in some prior echocardiographic screening studies. Also, our data substantiate that most young patients identified with HCM have no symptoms.

    Even with the previously discussed epidemiological considerations, we believe that our findings in the present CARDIA population provide a reasonable estimate of the overall frequency with which HCM is encountered in the general population of young adults. The present prevalence data will aid in assessment of the impact of HCM within the broad spectrum of cardiovascular diseases12 and the feasibility and cost-effectiveness of screening large asymptomatic populations for HCM, including those comprising competitive athletes.2021

    Table 1. Clinical and Morphological Findings in Seven Subjects Identified With Echocardiographic Features Consistent With HCM

    PatientAge, yRaceSexVS Thickness, mmLV Free-Wall Thickness, mmLVD, mmLA, mmFS, %SAMECGBP, mm HgHt/Wt, in/lb
    AntPostALPost
    124BM15151511503943>0Diffuse ST-T112/7672/230
    225WF2121211440456601Elevated voltages, inverted T waves, abnormal QS100/5965/181
    330BF1721010104037361+Normal107/7362/179
    431BM1531010115137451+5Normal116/6572/197
    533BM18151684930390LVH, inverted T waves4112/5869/211
    633BM1731010115130371+Diffuse ST-T122/8967/151
    734WM171417114835462+5Elevated ST102/7871/211

    HCM indicates hypertrophic cardiomyopathy; VS, ventricular septum; Ant, anterior; Post, posterior; LV, left ventricular; AL, anterolateral; LVD, LV end-diastolic dimension; LA, left atrium; FS, fractional shortening; SAM, systolic anterior motion of mitral valve; BP, blood pressure; Ht, height; Wt, weight; and LVH, LV hypertrophy. SAM grading system is a modification of that of Gilbert et al31 : 1+ indicates mitral valve is >10 mm from ventricular septum; 2+, mitral valve <10 mm from ventricular septum but without mitral-septal contact; and 0, absent. ECG was recorded ≈1 year after the subject’s echocardiographic study as part of the CARDIA study design. BP measurements are the averages of two recordings at the same examination.

    1Preoperative (before myotomy-myectomy) LV outflow gradient was 50 mm Hg, caused by mitral valve systolic anterior motion.

    2Region of anterior septum bulges prominently into proximal portion of outflow tract.

    3Involving predominantly the distal portion of the anterior septum.

    4Giant T-wave inversion (up to 20 mm); tall voltages (up to 46 mm).

    5Appears to be due preferentially to posterior mitral leaflet.36

    This work was supported by contracts NO1-HC-48047 through NO1-HC-48050, NO1-HC-95095, and NO1-HC-95100 from the NHLBI.

    Footnotes

    Correspondence to Dr Barry J. Maron, Cardiovascular Research Division, Minneapolis Heart Institute Foundation, 920 E 28th St, Ste 40, Minneapolis, MN 55407.

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