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(Circulation. 1995;92:2488-2495.)
© 1995 American Heart Association, Inc.

Articles

Natural History of Hypertrophic Cardiomyopathy

A Population-Based Study, 1976 Through 1990

Charles R. Cannan, MBChB; Guy S. Reeder, MD; Kent R. Bailey, PhD; L. Joseph Melton, III, MD; Bernard J. Gersh, MBChB DPhil

From the Division of Cardiovascular Diseases (C.R.C., G.S.R.) and the Department of Health Sciences Research (K.R.B., L.J.M.), Mayo Clinic and Mayo Foundation, Rochester, Minn, and the Division of Cardiology, Georgetown University Medical Center (B.J.G.), Washington, DC.

Correspondence and reprint requests to Guy S. Reeder, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Hypertrophic cardiomyopathy is a disease entity characterized by marked heterogeneity in morphology and natural history. Most of our knowledge of the natural history of this disorder derives from the study of hospital-based populations and is influenced by referral bias. Therefore, this population-based study was undertaken to examine the natural history of hypertrophic cardiomyopathy among unselected residents of Olmsted County, Minnesota.

Methods and Results Patients with hypertrophic cardiomyopathy, confirmed by echocardiography, were identified by use of the resources of the Rochester Epidemiology Project. Patients with the echocardiographic features of hypertrophic cardiomyopathy but with long-standing hypertension requiring drug therapy were categorized as having hypertensive hypertrophic cardiomyopathy. Baseline clinical details and follow-up events were obtained by retrospective chart review. Thirty-seven patients were diagnosed with hypertrophic cardiomyopathy and 24 with hypertensive hypertrophic cardiomyopathy. Eight additional patients were first diagnosed at autopsy. The mean age of the 37 patients with hypertrophic cardiomyopathy was 59±20 years (range, 1 week to 92 years); the mean ventricular septal thickness was 17.5±3 mm. Follow-up was obtained for a median of 7.7 years (range, 45 days to 17.2 years). The 1- and 5-year survival rates were 95% and 92%, respectively; these rates did not differ from those of an age- and sex-matched population (P=NS). The annual risk of cardiac death was 0.7%. The mean age of patients with hypertensive hypertrophic cardiomyopathy was 79±8 years (range, 62 to 91 years), and the mean ventricular septal thickness was 19±2.5 mm. Follow-up was obtained for a median of 2.8 years (range, 4 days to 16.7 years). The 1- and 5-year survival rates were 75% and 43%, respectively, which differed sharply from the expected rates of 94% and 70% (P=.0028). The annual risk of cardiac death was 5%. Atrial fibrillation and evidence for myocardial infarction on ECG, use of digoxin and diuretics, and a high New York Heart Association functional class at presentation were all associated with decreased survival by multivariate analysis for both groups combined. A history of myocardial infarction, atrial fibrillation, and mitral annular calcification at presentation were associated with cardiac death.

Conclusions Hypertrophic cardiomyopathy is a more benign disease than previously reported from tertiary referral centers. Patients assessed as having hypertensive hypertrophic cardiomyopathy represent a subset at higher risk for cardiac and noncardiac death, with an overall decreased survival rate.

Key Words: cardiomyopathy • prognosis • follow-up studies

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Hypertrophic cardiomyopathy is a disease entity characterized by marked heterogeneity in morphology and natural history. Patients range in age from infants¹ to the elderly,² and the clinical spectrum varies from the asymptomatic form to sudden death as an initial presentation. In addition, hypertensive hypertrophic cardiomyopathy has been recognized recently as a distinct subtype of hypertrophic cardiomyopathy.³ An additional difficulty relates to the fact that most of our knowledge of the natural history of this diverse disorder derives from the study of hospital-based populations^{4 5 6 7 8} and thus may be biased by selective patient referral.^{9 10} More recent studies of the clinical course of hypertrophic cardiomyopathy, for example, suggest a more benign course,^{11 12 13 14} which contrasts with the 2% to 6% annual mortality reported in prior clinical investigations.^{4 5 6 7 8} This study was undertaken to examine the natural history of hypertrophic cardiomyopathy among unselected residents of Olmsted County, Minnesota, initially diagnosed during 1976 through 1990 who had ready access to high-quality medical care and were followed meticulously. The clinical spectrum and outcome among these patients should not have been distorted by referral bias.

	Methods

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Data Source
Study subjects were identified through the resources of the Rochester Epidemiology Project, which provides a valuable database for large-scale population-based investigations of the natural histories of diseases. Such studies are possible because medical care is delivered by a limited number of providers and is virtually self-contained within the community.¹⁵ The Mayo Clinic and its two large affiliated hospitals (St Mary's and Rochester Methodist), together with the Olmsted Medical Group and its affiliated Olmsted Community Hospital, provide almost all the medical care delivered to Rochester residents, including cardiology services. Each provider uses a unit or dossier type of medical record system that is based on the patient's unique identification number. Identification and retrieval of all potential cases are possible because diagnoses and surgical procedures recorded in these records have been coded at Mayo since 1910. This index includes outpatient office or clinic consultations, emergency room visits, and nursing home care, as well as diagnoses recorded for hospital inpatients, on death certificates, and at autopsy examination. The Rochester Epidemiology Project supports a comparable index to the health care delivered by the other providers of medical services to community residents. It is estimated that in any 3-year period about 95% of the population of Olmsted County is seen for routine medical examination or for minor or major illness at the Mayo Clinic or its affiliates.¹⁶ This medical-record linkage system has been used in many studies of cardiovascular and other diseases.^{15 17} In addition, the databases of the echocardiography and cardiac catheterization laboratories at the Mayo Clinic were screened for Olmsted County residents. Echocardiography has become the cornerstone for the diagnosis of hypertrophic cardiomyopathy, and use of this procedure increased in Olmsted County during the time period of this study.¹⁸ These resources ensured complete ascertainment of clinically diagnosed cases of hypertrophic cardiomyopathy in the population and provided a reliable basis for follow-up.

With the described database, all Olmsted County residents with an initial diagnosis of hypertrophic cardiomyopathy, idiopathic hypertrophic subaortic stenosis, or asymmetrical septal hypertrophy in the 15-year period of 1976 through 1990 were identified. Review of a sample of 100 cases with the broader diagnosis of cardiomyopathy did not reveal any further cases. Exclusion criteria included any concomitant cardiac disorders that could produce left ventricular hypertrophy. Potential patients with hypertrophic cardiomyopathy with systemic hypertension were not excluded from the screening process. Patients were assigned to either hypertrophic cardiomyopathy (obstructive, nonobstructive, or apical) or hypertensive hypertrophic cardiomyopathy on the basis of clinical and echocardiographic findings, as outlined below. All potential cases confirmed by echocardiography that met residency requirements were included. Established residence in Olmsted County for at least 1 year before diagnosis was required; thus, those individuals who may have moved to the area for treatment of underlying diseases were excluded.

Hypertrophic Cardiomyopathy Cohort
Echocardiographic diagnosis of hypertrophic cardiomyopathy required the presence of asymmetrical septal hypertrophy (septal-to-free-wall ratio of 1.3) and a nondilated left ventricle with normal or hyperdynamic function or concentric hypertrophy with features of outflow tract obstruction. In patients with inadequate M-mode measurements at the initial echocardiogram, the presence of septal hypertrophy was confirmed on two-dimensional imaging. Supportive criteria included systolic anterior motion of the mitral valve in those patients with outflow tract obstruction and demonstration of a left ventricular outflow tract gradient by Doppler echocardiography. Localized basal septal hypertrophy was not considered to represent hypertrophic cardiomyopathy unless septal thickness was 20 mm or accompanied by mitral systolic anterior motion and/or evidence of left ventricular outflow obstruction. Patients with a questionable history of hypertension or a short duration of mild or borderline hypertension were included in the hypertrophic cardiomyopathy cohort.

Hypertensive Hypertrophic Cardiomyopathy
Patients meeting the echocardiographic diagnostic criteria described above but with long-standing histories of hypertension requiring drug therapy were included in the hypertensive hypertrophic cardiomyopathy cohort. Patients with uncontrolled hypertension were excluded from the study. Hypertension was defined as >140/90 mm Hg for patients younger than 65 years of age and >160/95 mm Hg for patients 65 years of age or older. The 8 patients with ambiguous diagnoses and a predominantly concentric pattern of left ventricular hypertrophy were assigned to the hypertensive hypertrophic cardiomyopathy cohort.

Data Collection
Clinical details and follow-up were obtained by review of each subject's complete (inpatient and outpatient) medical records and by mail or telephone contact when necessary. In addition to demographic data and vital status at last follow-up, information was collected on presenting history, medications used, physical examination findings, and results of ECGs, chest radiographs, and echocardiograms. The results of cardiac catheterization, 24-hour Holter monitoring, and functional testing were recorded when available. Primary clinical end points included sudden cardiac death (within 1 hour of presentation), nonsudden cardiac death, and death from noncardiac causes. The occurrence of presyncope, syncope, tachyarrhythmias, myocardial infarction, cerebrovascular accidents and transient ischemic attacks, infective endocarditis, systemic embolization, and cardiac hospitalization was also recorded during the follow-up period. Specific therapy aimed at hypertrophic cardiomyopathy through the study period and New York Heart Association (NYHA) classification of functional status at last follow-up were also recorded.

Data Analysis
Demographic and clinical data were summarized by mean±SD or percentages. Comparisons between the hypertrophic cardiomyopathy and hypertensive hypertrophic cardiomyopathy groups were performed with the two-sample t test or Pearson's ² test of proportions. Survival was estimated by the Kaplan-Meier¹⁹ product-limit method, and comparisons to survival rates of the US white population were made with the one-sample log-rank test.

Associations of variables with survival and cardiac death were estimated and tested with simple and multiple Cox proportional-hazards models. After a multiple regression model (not including the group variable) was selected for the overall cohort, a risk score based on this model was calculated for each individual. The two groups were compared with respect to this risk score, and a Cox model was fitted by use of the risk score, group, and interaction. This analysis was intended to detect an effect of the subdiagnostic group on risk independent of these other baseline factors and to detect whether the risk score had a similar impact in both groups. Finally, a separate set of analyses of survival was done in which survival time was replaced by a pseudotime variable based on the actuarial life tables for each given age and sex. This pseudotime variable, the negative logarithm of the age- and sex-specific survival probability for the observed follow-up time, was chosen to make the survival time distribution independent of age and sex.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Thirty-seven Olmsted County residents were initially diagnosed during life with hypertrophic cardiomyopathy and 24 with hypertensive hypertrophic cardiomyopathy during 1976 through 1990. Eight additional patients were first identified at autopsy (6 with hypertrophic cardiomyopathy and 2 with hypertensive hypertrophic cardiomyopathy). Table 1 gives further details on the patients diagnosed at autopsy. For the purposes of this study, subsequent discussion relates to the 61 patients diagnosed during life.

View this table: [in this window] [in a new window]   Table 1. Characteristics of 8 Olmsted County, Minnesota, Residents First Recognized With HCM at Autopsy

Hypertrophic Cardiomyopathy
Patient Characteristics
The mean age of these 37 patients (16 men, 21 women) was 59±20 years (range, 1 week to 92 years). At presentation, 16 patients (43%) had a history of chest pain, 6 patients (16%) had symptoms of dyspnea, and 4 patients (11%) had a history of syncope. Although 17 patients (46%) had a history of hypertension, mean systolic and diastolic pressures at the time of diagnosis were 142±24 and 83±13 mm Hg, respectively. Four patients (11%) had a history of myocardial infarction; 10 patients (27%) had additional medical conditions, including chronic obstructive airways disease, diabetes, malignancy, Parkinson's disease, and respiratory distress syndrome in a premature neonate. At the time of presentation, 3 patients (8%) were taking ß-adrenergic blocking drugs, 2 patients (5%) were taking calcium channel antagonists, and 11 patients (30%) were using diuretics. Table 2 gives further detail on baseline characteristics.

View this table: [in this window] [in a new window]   Table 2. Clinical Characteristics of Olmsted County, Minnesota, Residents With HCM and HT HCM at Presentation During 1976 Through 1990

Echocardiographic Data
Two-dimensional echocardiography was performed in all 37 patients, and Doppler studies were obtained in 20 patients (54%). Adequate M-mode measurements of the ventricular septum were available in 27 patients (73%) at the time of the diagnostic study. The mean ventricular septal diastolic thickness was 17.5±3 mm (normal, 12 mm). Systolic anterior motion of the mitral valve was present in 21 patients (57%), and mitral annular calcification was observed in 5 patients (14%). The most common pattern of left ventricular hypertrophy was asymmetrical septal hypertrophy (46%). Eight patients (22%) had concentric hypertrophy with septal prominence, 6 patients (16%) had concentric hypertrophy, 3 patients (8%) had basal septal hypertrophy, and 3 patients (8%) had apical hypertrophy. Of the 20 patients undergoing Doppler echocardiography, 15 (75%) had a left ventricular outflow gradient (mean maximal instantaneous gradient, 39±32 mm Hg). Table 3 gives more echocardiographic data.

View this table: [in this window] [in a new window]   Table 3. Echocardiographic Data at Presentation Among Olmsted County, Minnesota, Residents With HCM and HT HCM During 1976 Through 1990

Angiographic Data
Ten patients (27%) underwent cardiac catheterization; a left ventricular outflow tract gradient was observed at rest in 3 patients. Moderate coronary artery disease was present in 1 patient.

Ambulatory ECG
Twenty patients (54%) had 24-hour ambulatory ECGs; sinus rhythm was present in 18 patients, and a wandering atrial pacemaker was documented in the remaining 2 patients. Paroxysmal supraventricular tachycardia was noted in 13 patients; complex ventricular ectopy (ventricular premature complexes, >700 per hour, in pairs or in bigeminy) was documented in 6 patients.

Treadmill Exercise Test
Fourteen patients (38%) underwent treadmill exercise testing; an ischemic exercise ECG was documented in 1 patient.

Follow-up Data
Patients were followed for a median of 7.6 years (mean, 8.0 years; range, 23 days to 17.2 years). At least 5 years of follow-up was obtained for 17 patients. The mean NYHA functional class at presentation was 1.3. Among patients who initially presented with class I symptoms, 43% progressed to class II, III, or IV symptoms during the course of the follow-up period (Fig 1). The mean functional class at last clinical follow-up was 1.75 for the 36 patients in whom this information was available. Five patients (14%) had at least one syncopal episode, 4 patients (11%) had documented myocardial infarctions, 2 patients (5%) suffered cerebrovascular accidents, and 15 patients (41%) had one or more cardiac hospitalizations during the follow-up period (Table 4). The most common reason for cardiac hospitalization was management of chest pain. No patient underwent myectomy for the surgical relief of obstruction. There were 8 deaths (2 cardiac and 6 noncardiac). One of the cardiac deaths was assessed as sudden death although it was not witnessed and the exact circumstances of death were not clear. Another 2 patients suffered sudden cardiac arrest but were successfully resuscitated and had automatic implantable cardiac defibrillators inserted. Medical therapy during follow-up included ß-blockers, calcium channel antagonists, or both in 33 patients (89%). Two patients had permanent cardiac pacemakers implanted for complete heart block and sick sinus syndrome during the follow-up period.

View larger version (21K): [in this window] [in a new window]   Figure 1. Chart showing New York Heart Association classification of 36 patients from Olmsted County, Minnesota, with hypertrophic cardiomyopathy at presentation (left) vs time of last follow-up (right).

View this table: [in this window] [in a new window]   Table 4. Clinical Events During Follow-up of Olmsted County, Minnesota, Residents With HCM and HT HCM During 1976 Through 1990

Hypertensive Hypertrophic Cardiomyopathy
Patient Characteristics
This group consisted of 24 patients (3 men, 21 women) with a mean age of 77±8 years (range, 62 to 91 years). At presentation, 11 patients (46%) had a history of chest pain, 13 patients (54%) had symptoms of dyspnea, and 3 patients (13%) had a history of syncope. All had a history of hypertension, and the mean systolic and diastolic pressures were 157±27 and 83±13 mm Hg, respectively, at the time of diagnosis. Seven patients (29%) had a history of myocardial infarction; 11 patients (46%) had additional medical conditions, including chronic obstructive airways disease, diabetes, renal impairment, malignancy, liver cirrhosis, and alcohol abuse. At the time of presentation, 3 patients (13%) were taking ß-adrenergic blocking drugs, 4 patients (17%) were taking calcium channel antagonists, and 19 patients (79%) were using diuretics. Table 2 gives additional details on baseline characteristics.

Echocardiographic Data
Two-dimensional echocardiography was performed in all patients, and Doppler studies were obtained in 18 patients (75%). Adequate M-mode measurements of the ventricular septum were available in 12 patients (48%) at the time of the diagnostic study. The mean ventricular septal diastolic thickness was 19±3 mm (normal, 12 mm). Systolic anterior motion of the mitral valve was present in 9 patients (38%), and mitral annular calcification was observed in 6 patients (25%). The most common pattern of left ventricular hypertrophy was concentric hypertrophy (50%). Eleven patients (46%) had concentric hypertrophy with septal prominence, and 1 patient (4%) had asymmetrical septal hypertrophy. Of the 18 patients undergoing Doppler echocardiography, 13 (72%) had a left ventricular outflow gradient (mean maximal instantaneous gradient, 15±17 mm Hg). Table 3 gives further echocardiographic data.

Angiographic Data
Three patients (13%) underwent cardiac catheterization; no left ventricular outflow tract gradient was observed at rest in any patient. Severe coronary artery disease was present in 1 patient.

Ambulatory ECG
Eight patients (33%) had 24-hour ambulatory ECGs recorded; sinus rhythm was present in 6 patients, atrial fibrillation and a nodal rhythm were present in the remaining 2 patients. Paroxysmal supraventricular tachycardia was noted in 5 patients; complex ventricular ectopy (as defined above) was documented in 2 patients. One patient had a run of nonsustained ventricular tachycardia.

Treadmill Exercise Test
Five patients (21%) underwent treadmill exercise testing; an ischemic exercise ECG was documented in 2 patients.

Follow-up Data
Patients were followed for a median of 2.8 years (mean, 4.6 years; range, 4 days to 16.7 years). At least 5 years of follow-up was obtained for 8 patients. The mean NYHA functional class at presentation was 1.95. Among patients who initially presented with class I symptoms, 73% progressed to class II, III, or IV symptoms during the course of follow-up (Fig 2). The mean functional class at the last clinical follow-up was 2.2. Five patients (21%) had at least one syncopal episode, 3 patients (13%) had documented myocardial infarctions, 4 patients (17%) suffered cerebrovascular accidents, and 1 patient (4%) had a transient ischemic attack. Nine (42%) had one or more cardiac hospitalizations during the follow-up period (Table 4). The most common reason for cardiac hospitalization was management of chest pain. There were 15 deaths (6 cardiac and 9 noncardiac). One of the cardiac deaths was assessed as sudden death even though it was not witnessed and the exact circumstances of death were not clear. Medical therapy during follow-up included ß-blockers, calcium channel antagonists, or both in 19 patients (79%).

View larger version (17K): [in this window] [in a new window]   Figure 2. Chart showing New York Heart Association classification of 24 patients from Olmsted County, Minnesota, with hypertensive hypertrophic cardiomyopathy at presentation (left) vs time of last follow-up (right).

Survival Analysis
Survival rates of patients with hypertrophic cardiomyopathy at 1 and 5 years were 95% and 92%, respectively, compared with an expected 97% and 87%. The difference between observed and expected survival rates was not significant at the 5-year follow-up (P=.4; Fig 3). By contrast, survival rates for the hypertensive hypertrophic cardiomyopathy cohort were only 75% and 43% at 1 and 5 years, respectively, which differed sharply from the expected 1- and 5-year survival rates of 94% and 70% (P=.0028; Fig 4). Of the deaths occurring in the hypertensive hypertrophic cardiomyopathy cohort, 60% were assessed as noncardiac. When the survival rates between the two groups were compared without age adjustment, the difference was highly significant (P=.0002), but the hypertensive hypertrophic cardiomyopathy patients were much older (mean age, 77 years) than the hypertrophic cardiomyopathy patients (mean age, 59 years). When survival was reanalyzed with a pseudotime variable corresponding to the actuarial probability of death, the difference between groups remained significant (P=.02) despite this correction for age and sex.

View larger version (8K): [in this window] [in a new window]   Figure 3. Plot showing survival among Olmsted County, Minnesota, residents with hypertrophic cardiomyopathy (solid line) first diagnosed during 1976 through 1990 vs an age- and sex-matched population (dotted line) (P=.4).

View larger version (9K): [in this window] [in a new window]   Figure 4. Plot showing survival among Olmsted County, Minnesota, residents with hypertensive hypertrophic cardiomyopathy (solid line) first diagnosed during 1976 through 1990 vs an age- and sex-matched population (dotted line) (P=.0028).

A survival analysis within the hypertrophic cardiomyopathy subgroup between patients with a history of hypertension (1- and 5-year survival rates, 100% and 94%, respectively) and those without hypertension (90% and 90%, respectively) did not reveal any difference (P=.86; Fig 5).

View larger version (8K): [in this window] [in a new window]   Figure 5. Plot showing survival among Olmsted County, Minnesota, residents with hypertrophic cardiomyopathy with no history of hypertension (solid line) vs those with hypertrophic cardiomyopathy with a history of hypertension (dotted line) (P=.86).

Clinical, ECG, and echocardiographic variables were examined for an association with decreased survival during the follow-up period for both groups combined because numbers were insufficient to allow multivariate analysis for each group separately. The 1-week-old neonate was not included in the multivariate analysis. Atrial fibrillation and evidence for myocardial infarction on ECG, use of digoxin and diuretics, and a high NYHA functional class at presentation were all associated with decreased survival by multivariate analysis for both groups combined (Table 5). By use of a risk score, these variables were significantly associated with decreased survival within each group, with a higher risk score noted in the hypertensive cardiomyopathy group. However, despite correction for the above parameters in multivariate analysis, the diagnosis of hypertensive hypertrophic cardiomyopathy itself remained a significant prognostic indicator for survival.

View this table: [in this window] [in a new window]   Table 5. Predictors of Survival by Multivariate Analysis for Olmsted County, Minnesota, Residents With HCM and HT HCM During 1976 Through 1990

Cardiac Death
The risk of cardiac death was 0.7%/y and 5%/y among the hypertrophic cardiomyopathy and hypertensive hypertrophic cardiomyopathy patients, respectively. The risk of sudden cardiac death was not assessed separately because the clinical circumstances surrounding the possible sudden deaths were unclear. Atrial fibrillation on presentation ECG, a history of myocardial infarction, and mitral annular calcification on the initial echocardiogram were associated with an increased incidence of cardiac death by multivariate analysis for both groups combined (Table 6).

View this table: [in this window] [in a new window]   Table 6. Predictors of Survival to Cardiac Death by Multivariate Analysis for Olmsted County, Minnesota, Residents With HCM and HT HCM During 1976 Through 1990

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Our study is the first population-based assessment of the natural history of hypertrophic cardiomyopathy. The annual risk of cardiac death was 0.7% for hypertrophic cardiomyopathy, and there was no significant difference in overall survival compared with an age- and sex-matched population. This is in striking contrast to the poor prognosis among patients with hypertensive hypertrophic cardiomyopathy, whose survival rates were greatly reduced compared with that expected for people of like age and sex.

The natural history of hypertrophic cardiomyopathy has been described from several large studies. Most patients deteriorated clinically over various time spans, and a 2% to 6% annual mortality was reported.^{4 5 6 7 8} Patients from these studies were characterized by severe symptoms or a malignant family history and were predominantly referrals to tertiary care centers.^{4 5 8} Indeed, almost 50% of studies published on hypertrophic cardiomyopathy in the major cardiology journals originated from two centers.¹¹ Accordingly, these patients reflect the more severe spectrum of the disease, leading to early referral. More recent reports on the natural history of hypertrophic cardiomyopathy as it occurs in the community also reflect a more benign course. Shapiro and Zezulka¹⁴ studied 39 patients over a 5-year period at a community hospital. Mortality among these patients was no different from normal. A report of a small outpatient population of 25 patients followed for a mean of 4.4 years demonstrated a similarly benign course.¹¹ The largest series was a clinic population of 113 patients followed for a mean of 7 years¹² ; in this series, the annual cardiac mortality was only 1%. Despite the more benign course, this study still represented a population of referrals from surrounding areas and was therefore still subject to referral bias. Others have described the course of hypertrophic cardiomyopathy in the elderly population² and middle-aged asymptomatic patients.¹³ All concluded that the natural history of hypertrophic cardiomyopathy may be more benign than implied by earlier reports. Our results confirm their findings but identify a subgroup of patients at higher risk in a well-defined population in which very few patients went undiagnosed.

Multivariate analysis revealed NYHA functional class, use of digoxin and diuretics at presentation, and myocardial infarction and atrial fibrillation on baseline ECG to be associated with a poor prognosis. Not surprisingly, the decreased survival in the overall population was predicted by the severity of symptoms. The association with atrial fibrillation could be the consequence of severe disease or causal on the basis of the well-documented detrimental effects of atrial fibrillation in patients with diastolic dysfunction. The use of digoxin and diuretics is known to be detrimental in some instances of hypertrophic cardiomyopathy.³ Finally, the association of pathological Q waves on presentation ECG with prognosis is less certain but may pertain to the electrophysiological myocardial abnormalities known to occur in hypertrophic cardiomyopathy.²⁰ Prior studies reported left ventricular hypertrophy,²¹ functional class and young age at presentation,⁸ a strong family history of sudden death,⁸ syncope,⁸ and ventricular tachycardia on ambulatory ECG²² to be associated with a worse prognosis. Our study confirms the association of functional class on presentation with outcome. No patient with hypertrophic cardiomyopathy was demonstrated to have ventricular tachycardia on ambulatory ECG; however, others questioned the significance of ventricular tachycardia during 24-hour ambulatory monitoring.²³ Because only 46% of our patients had ambulatory monitoring performed, this result should be interpreted with caution. The prognostic significance of a family history of sudden death was not addressed because no reliable data on family history were available in this retrospective study. Although we did not find an association between prognosis and the other previously described parameters, the numbers in this study were small relative to the large referral center studies.

Although we believe that very few cases of hypertrophic cardiomyopathy in Olmsted County residents were missed, an important area of underdiagnosis was asymptomatic people who never seek medical care for any reason. These are usually young men, as emphasized by the finding of two young men who, with no known medical problems, presented at autopsy as having hypertrophic cardiomyopathy with sudden death. Thus, the younger patients included in this study could represent a more stable subgroup previously selected by sudden death and medical care. In our study, only 5 young patients (14%, <40 years of age) had hypertrophic cardiomyopathy, and no cardiac deaths were reported. In addition, the diagnosis of hypertrophic cardiomyopathy required the presence of ventricular hypertrophy on echocardiography; thus, patients in the early stages of the disease with no ventricular hypertrophy, as described by Maron et al,²⁴ or genetically affected patients without echocardiographic changes²⁵ would not be included. Despite this, we believe that this patient cohort accurately reflects the clinical spectrum of hypertrophic cardiomyopathy as identified by echocardiography in contemporary clinical practice.

The mean age of patients in our hypertrophic cardiomyopathy cohort was 59 years. This age is significantly greater than the mean ages of 39 and 43 years reported by the two large referral centers¹¹ but reflects instead the age distribution of unselected patients from the general population. The diagnosis of hypertrophic cardiomyopathy in the elderly is not a new finding. As early as 1971, Whiting et al²⁶ reported that 32% of patients catheterized at the Massachusetts General Hospital were <60 years of age. In a community-based study, Petrin and Tavel²⁷ found that 85% of patients were >50 years of age and 82% of these were women. In the present study, 41% and 88% of patients in the hypertrophic cardiomyopathy and hypertensive hypertrophic cardiomyopathy cohorts, respectively, were 65 years of age or older. Increasing age is associated with an increase in left ventricular mass and septal thickness.²⁸ In the very old, the septum may be not only hypertrophied but also sigmoid, which may simulate the appearance of hypertrophic cardiomyopathy.²⁹ Lever and colleagues³⁰ highlighted the echocardiographic differences between young and old patients with hypertrophic cardiomyopathy and suggested that hypertrophic cardiomyopathy in the elderly may be a disease distinctly different from that which exists in the young. Thus, it is likely that the cardiac changes seen in various age groups of patients with hypertrophic cardiomyopathy reflect the spectrum of a heterogeneous disease.

We included all patients with mild or moderate hypertension. Hypertension is present in one third of the general population,³¹ and significant overlap with a rare condition such as hypertrophic cardiomyopathy should be expected, especially in the elderly population.^{2 3 26} Only a minority of patients with chronic mild or moderate hypertension develop detectable left ventricular hypertrophy.³² Furthermore, it has been shown that, except for increased posterior wall thickness, hypertensive patients with hypertrophic cardiomyopathy do not differ echocardiographically from an age- and sex-matched normotensive group of patients with the same disease.³² Patients with mild hypertension included in the hypertrophic cardiomyopathy cohort may well represent an inappropriate hypertrophy to an appropriate stimulus and possibly a milder subgroup. However, survival analysis between these patients and those without hypertension in the hypertrophic cardiomyopathy cohort did not reveal any difference.

The worse prognosis of the hypertensive hypertrophic cardiomyopathy cohort than the hypertrophic cardiomyopathy patients is not fully understood. The clinical entity of hypertensive hypertrophic cardiomyopathy may reflect an even more inappropriate response to hypertension. Furthermore, these patients were more symptomatic at presentation; patients with concomitant fatal disease were not excluded from the study and often had hypertensive hypertrophic cardiomyopathy diagnosed while in a hospital setting for other medical problems. Therefore, they may represent a sicker spectrum of hypertrophic cardiomyopathy patients with hypertension. Being older patients with hypertension, they would have been far more likely to have significant coronary artery disease, which might account for the increased incidence of cardiac death observed and the increased percentage with a history of myocardial infarction. This would concur with the finding of Lazzeroni et al³³ that coronary artery disease was more prevalent in older than younger patients and played an important role in the natural history and prognosis of hypertrophic cardiomyopathy. Finally, could hypertensive hypertrophic cardiomyopathy simply be severe hypertension with the same hypertrophic and hemodynamic features of hypertrophic cardiomyopathy, even though the two diseases are unrelated? Considerable overlap between the two can exist, and left ventricular hypertrophy secondary to severe hypertension can mimic hypertrophic cardiomyopathy in as many as one third of patients in one study.³⁴ We were careful to exclude patients with a record of severe or uncontrolled hypertension but acknowledge that this was a subjective assessment with a potential for error. Ultimately, the only way we could tell whether hypertensive hypertrophic cardiomyopathy is a forme fruste of hypertrophic cardiomyopathy or a different disease entity is genetic analysis,³⁵ which is beyond the scope of this study and current clinical practice.

The present study demonstrates that hypertrophic cardiomyopathy is generally a more benign disease than previously reported from tertiary referral centers. NYHA functional class, use of digoxin and diuretics at presentation, and atrial fibrillation and myocardial infarction on baseline ECG were associated with a decreased survival rate. Predictors of cardiac death included a history of myocardial infarction, atrial fibrillation, and mitral annular calcification. Although we cannot adequately explain the discrepancy in survival, it appears that patients assessed as having hypertensive hypertrophic cardiomyopathy represent a subset of patients at higher risk for cardiac and noncardiac death with an overall decreased survival rate.

	Acknowledgments

 
This work was supported in part by research grant AR-30582 from the NIH, US Public Health Service.

Received January 18, 1995; revision received April 4, 1995; accepted April 7, 1995.

	References

Top Abstract Introduction Methods Results Discussion References

 

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