Apical hypertrophic cardiomyopathy (HC) has been considered a “benign” form of HC, with limited data on long-term outcome. We compared apical HC patients with a non-HC, age- and gender-matched Minnesota white population to identify outcomes and prognostic factors. Between 1976 and 2006, 193 patients (62% men) with apical HC were seen at our clinic. Their most recent echocardiographic examinations were reviewed. Mean ± SD age at first presentation was 58 ± 17 years. A family history of HC or sudden cardiac death (SCD) was reported by 43 patients (22%); coronary artery disease was known in 22 (11%). An apical pouch was present in 29 patients, including an apical aneurysm in 6 and apical dilatation with hypokinesis in 23. Median follow-up (187 patients [97%]) was 78 months (range, 1–350). Death from all causes occurred in 55 patients (29%; 33 women) at a mean age of 72 years (range, 20–92). During follow-up, more women had heart failure (p = 0.001), atrial fibrillation (p = 0.009), or died (p <0.001) than men. Survival was worse than expected (p = 0.001); the observed versus expected 20-year survival was 47% versus 60%. SCD, resuscitated cardiac arrest, and/or defibrillator discharge was observed in 11 patients (6%) during follow-up. Multivariate predictors of decreased survival were higher age at baseline (p <0.001), female gender (p <0.001), and atrial fibrillation at baseline (p = 0.06). In conclusion, apical HC in this population was associated with increased mortality, especially in women. Because apical HC is less benign than previously suspected, careful longitudinal care is warranted.
Apical hypertrophic cardiomyopathy (HC) is a phenotype variant of HC, with hypertrophy predominantly affecting the apex, that was initially described 30 years ago. Patients with apical HC comprise approximately 25% of the total HC population in Asian populations and 1% to 10% in non-Asian populations. Apical HC may have different clinical implications compared with other subsets of HC. In Asian populations, apical HC seems to have a more benign prognosis than other types of HC; in whites, outcome data are limited. However, sudden cardiac death can occur in patients with HC, and the incidence of sudden cardiac death did not differ between apical HC and other HC subtypes in 1 North American population. In many risk-assessment studies, populations with HC either have not been analyzed separately, or patients with apical HC were a minor subset of HC patients. Recently, in a study of patients with apical HC and apical aneurysms, the adverse event rate was 10.5% per year during a mean ± SD of 4.1 ± 3.7 years of follow-up; adverse events included sudden death, appropriate implantable cardioverter-defibrillator (ICD) discharges, nonfatal thromboembolic stroke, and progressive heart failure and death. Another recent study showed an increased rate of adverse outcomes in patients with apical HC and abnormal apical contractility. The current study assessed the outcome of apical HC in a large population of patients evaluated at a tertiary care center in North America to identify predictors of adverse events.
Methods
This study was approved by the Mayo Clinic Institutional Review Board. Patients were retrospectively identified through the HC and echocardiographic databases at Mayo Clinic (Rochester, Minnesota). From June 1976 through September 2006, 2,662 patients were referred to the HC clinic at our institution. Of these, 210 patients (7.9%) initially were classified as having apical HC by a clinical evaluator with subspecialty interest in HC.
For all patients, the most recent echocardiographic study and all medical records were reviewed. Patients were excluded if they had (1) a history of severe, chronic, uncontrolled arterial hypertension with evidence of end-organ disease, (2) hemodynamically significant moderate or severe aortic valve disease, (3) infiltrative disorders (e.g., amyloidosis, hypereosinophilic syndrome), or (4) were an elite endurance athlete. After echocardiographic review, patients were excluded from this study if (1) criteria for apical HC were not fulfilled (n = 9) or (2) features were compatible with isolated left ventricular noncompaction (n = 3), endocardial fibroelastosis (n = 3), restrictive cardiomyopathy (n = 1), or pheochromocytoma (n = 1). The remaining 193 patients constituted the study cohort.
The following data were abstracted from the clinical record: demographic characteristics, family history of HC, presenting symptoms (including New York Heart Association classification), coronary risk factors, proof of coronary artery disease at the initial presentation, details of ICD implantation, and follow-up findings.
Echocardiographic images and data were retrieved from the prospectively acquired echocardiographic database. The most recent echocardiographic examination for each patient was reviewed. For patients who had undergone apical myectomy (n = 16) or heart transplantation (n = 1), the last echocardiographic examination before that intervention was reviewed. The following criteria for apical HC were applied: (1) hypertrophy predominantly involving the apex, (2) hypertrophy that may extend from the apex to the level of the papillary muscles, and (3) hypertrophy without predominant basal left ventricular involvement. Wall thickness had to be at least 12 mm in a single segment. Patients were not excluded if they additionally showed hypertrophy of the basal septum or other basal segment, provided there was no evidence of left ventricular outflow tract obstruction. All patients in the study had nonobstructive HC, with predominant apical hypertrophy; those with typical asymmetric basal septal HC were excluded.
We assessed data on wall thickness of basal septum, basal posterior wall, maximal apical wall thickness, ejection fraction, presence of hypokinetic segments, midventricular or apical obstruction, presence of an apical pouch, and left atrial size. Left atrial dilatation was defined as either left atrial dilatation in the parasternal long axis by M-mode measurement (>4 cm) or in the apical views by biplane measurement of the left atrial volume (left atrial volume index >28 mL/m 2 body surface area). Diastolic function was assessed as previously described. Right atrial pressure was estimated as previously described. Pulmonary hypertension was defined as an estimated right ventricular systolic pressure >35 mm Hg.
We reviewed the 12-lead electrocardiograms that were recorded closest to the echocardiographic examination. We measured standard intervals, the number of leads showing negative T waves, and voltage of negative T waves in precordial leads. The ST-T wave segments were studied to determine whether T-wave inversion was present; when it was, the maximum T-wave depth in any anterior lead was recorded. Giant T-wave negativity was defined as a negative T-wave voltage of at least 10 mm (≥1 mV).
Last follow-up was obtained in 187 patients (97%) by clinical visits (n = 69), by other contact (e.g., a computer search, telephone contact, letter from outside physicians, prescription refill [n = 22]), by survey (n = 40), or by notice of death (n = 55) or heart transplantation (n = 1). End of follow-up was censored on September 30, 2006.
Cause of death was classified as cardiovascular if it was attributable to myocardial infarction, arrhythmia, sudden cardiac death, congestive heart failure, or stroke. Sudden cardiac death was defined as instantaneous and unexpected death within 1 hour after a previously stable condition.
We also noted whether the patient had any of the following morbidity parameters: atrial fibrillation or flutter, ventricular tachycardia or ventricular fibrillation, transient ischemic attack or stroke, or congestive heart failure. Implantation of an automatic ICD was noted when present.
Continuous data values were expressed as mean ± SD. Contingency tables were analyzed for association with a chi-squared or Fisher exact test (where appropriate). Comparison of continuous variables was made with the appropriate 2-sample test: a 2-sample t test when the variable distributions were symmetric and a Wilcoxon rank-sum test otherwise. Survival was evaluated by Kaplan-Meier analysis, with 95% confidence intervals. Expected survival was calculated on the basis of rates observed in the Minnesota white population with the same age and gender distribution as those in the study group. Cox proportional hazards regression was used to test for associations with long-term survival. Stepwise selection techniques were used to identify variables independently associated with the end points in these analyses, including age, gender, functional class III or IV symptoms, hypertension, family history of HC, family history of sudden cardiac death, giant negative T waves, maximal left ventricular wall thickness, history of syncope, and chronic or paroxysmal atrial fibrillation. For all analyses, statistical significance was established as p ≤0.05.
Results
The study group consisted of 193 patients (mean ± SD age, 58 ± 17 years; 120 men [62%]). The demographic and clinical characteristics at initial presentation are listed in Table 1 . The cohort was 91% white, 3% Asian, and 6% black or other race. Women were older than men at the time of their first visit. The prevalence of diabetes mellitus and hypertension were slightly higher in women (p = 0.02 for both); otherwise, no gender-based differences in personal cardiovascular risk factors or known coronary artery disease were identified. Compared with men, a greater proportion of women had a family history of coronary artery disease (p = 0.04) and reported dyspnea and a history of heart failure.
| Characteristic | All Patients (n = 193) | Men (n = 120) | Women (n = 73) | p Value |
|---|---|---|---|---|
| Mean ± SD age (yrs) | 58 ± 17 | 55 ± 18 | 62 ± 15 | 0.009 |
| Family history | ||||
| HC | 31 (16%) | 19 (16%) | 12 (16%) | 0.91 |
| Sudden cardiac death | 19 (10%) | 11 (9%) | 8 (11%) | 0.69 |
| HC and/or sudden cardiac death | 43 (22%) | 27 (23%) | 16 (22%) | 0.92 |
| Coronary artery disease | 29 (15%) | 13 (11%) | 16 (22%) | 0.04 |
| Arterial hypertension | 58 (30%) | 29 (24%) | 29 (40%) | 0.02 |
| Smoker (current or previous) | 96 (50%) | 61 (51%) | 35 (48%) | 0.70 |
| Hyperlipidemia | 128 (66%) | 78 (65%) | 50 (68%) | 0.62 |
| Diabetes mellitus | 15 (8%) | 5 (4%) | 10 (14%) | 0.02 |
| New York Heart Association functional class | ||||
| I | 96 (50%) | 66 (55%) | 30 (41%) | 0.16 |
| II | 63 (33%) | 36 (30%) | 27 (37%) | |
| III/IV | 34 (18%) | 18 (15%) | 16 (22%) | |
| Dyspnea on exertion | 74 (38%) | 39 (33%) | 35 (48%) | 0.03 |
| Angina pectoris | 55 (28%) | 34 (28%) | 21 (29%) | 0.95 |
| Syncope | 22 (11%) | 13 (11%) | 9 (12%) | 0.75 |
| Heart failure | 16 (8%) | 6 (5%) | 10 (14%) | 0.03 |
| Stroke | 13 (7%) | 8 (7%) | 5 (7%) | 0.96 |
| Proven coronary artery disease | 22 (11%) | 14 (12%) | 8 (11%) | 0.88 |
Electrocardiogram findings are summarized in Table 2 . Ninety percent of patients had the typical negative T waves. Compared with women, men had a greater number of leads with negative T waves (p = 0.007), deeper negative T waves (p = 0.007), and more frequently met criteria for giant negative T waves (p = 0.04). At baseline, there was no difference between men and women in the history of known ventricular tachycardia or prior ICD implantation. A greater proportion of women had a history of atrial fibrillation at baseline (p = 0.002), especially paroxysmal atrial fibrillation. More patients with an apical pouch formation had a family history of sudden cardiac death (p = 0.03).
| Finding or Arrhythmia | All Patients (n = 176) | Men (n = 111) | Women (n = 65) | p Value |
|---|---|---|---|---|
| Mean ± SD heart rate (beats/min) | 65 ± 13 | 64 ± 13 | 66 ± 13 | 0.28 |
| Sinus rhythm | 152 (86%) | 97 (87%) | 55 (85%) | 0.60 |
| Mean ± SD QRS duration (ms) | 101 ± 17 | 102 ± 17 | 100 ± 17 | 0.28 |
| Any negative T wave | 158 (90%) | 103 (93%) | 55 (85%) | 0.08 |
| Mean ± SD number of negative T waves | 3.8 ± 1.7 | 4.1 ± 1.7 | 3.3 ± 1.8 | 0.007 |
| Mean ± SD maximal negative T wave (mm) | 5.1 ± 4.2 | 5.8 ± 4.5 | 4.0 ± 3.4 | 0.007 |
| Giant T wave (>10 mm) | 19 (11%) | 16 (14%) | 3 (5%) | 0.04 |
| Any Q wave | 16 (9%) | 8 (7%) | 8 (12%) | 0.26 |
| Previous ventricular tachycardia | 21/193 (11%) | 13/120 (11%) | 8/73 (11%) | 0.98 |
| Previous automatic ICD | 4/193 (2%) | 2/120 (2%) | 2/73 (3%) | 0.61 |
| Previous atrial fibrillation, any | 43/193 (22%) | 18/120 (15%) | 25/73 (34%) | 0.002 |
| Paroxysmal | 28/193 (15%) | 10/120 (8%) | 18/73 (25%) | 0.002 |
| Chronic | 15/193 (8%) | 8/120 (7%) | 7/73 (10%) | 0.46 |
∗ Patient percentages for categories “All Patients,” “Men,” and “Women” were calculated using the denominator 176, 111, and 65, respectively, unless otherwise indicated.
† Electrocardiograms to measure or analyze QT interval and T-wave negativity were available in 176 patients (4 patients had pacemaker rhythm; 13 patients with missing data).
Echocardiographic characteristics are summarized in Table 3 . Both men and women had small left ventricles and significantly enlarged left atrial size. Men had a larger left ventricular end-diastolic diameter and a slightly greater posterior wall thickness than women. There were no sex-related differences in apical wall thickness, involvement of the midventricle, left atrial size, diastolic function, intraventricular systolic or diastolic gradients, or presence of an apical pouch. Pulmonary artery pressures were elevated in both genders. Pulmonary artery pressure could be calculated in 125 patients (mean ± SD, 41 ± 15 mm Hg). Women had higher pulmonary artery pressure compared with men (mean ± SD, 48 ± 18 vs 36 ± 10 mm Hg; p ≤0.001) and consequently more often had clinically significant valvular heart disease because of moderate or severe tricuspid regurgitation (10% and 0% in women and men, respectively; p<0.001). Diastolic dysfunction was frequent (79%); in the subset of 89 patients for whom pulmonary artery pressure could be estimated, we observed no association between elevated pulmonary artery pressure and diastolic dysfunction (p = 0.61).
| Finding | All Patients | Men (n = 120) | Women (n = 73) | p Value | |||
|---|---|---|---|---|---|---|---|
| n | Value | n | Value | n | Value | ||
| Mean ± SD age at echocardiographic examination (yrs) | 193 | 61 ± 17 | 120 | 59 ± 17 | 73 | 65 ± 15 | 0.02 |
| Mean ± SD LV end-diastolic diameter (mm) | 156 | 48 ± 6 | 95 | 50 ± 6 | 61 | 47 ± 7 | 0.002 |
| Mean ± SD septal wall thickness (mm) | 160 | 15 ± 5 | 96 | 15 ± 5 | 64 | 14 ± 4 | 0.12 |
| Mean ± SD posterior wall thickness (mm) | 152 | 12 ± 3 | 91 | 13 ± 3 | 61 | 12 ± 4 | 0.03 |
| Apical wall thickness (mm) | 177 | ||||||
| ≥20 | 72 (41%) | 112 | 51 (46%) | 65 | 21 (32%) | 0.08 | |
| ≥25 | 17 (10%) | 112 | 13 (12%) | 65 | 4 (6%) | 0.24 | |
| ≥30 | 2 (1%) | 112 | 2 (2%) | 65 | 0 | 0.53 | |
| Mean ± SD maximal thickness | 177 | 20 ± 5 | 112 | 20 ± 5 | 65 | 19 ± 4 | 0.07 |
| LV hypertrophy only at apex | 193 | 73 (38%) | 120 | 47 (39%) | 73 | 26 (36%) | 0.65 |
| Mean ± SD ejection fraction (%) | 191 | 67 ± 9 | 118 | 67 ± 8 | 73 | 67 ± 11 | 0.55 |
| Mean ± SD LA end-systolic diameter (mm) | 119 | 47 ± 9 | 73 | 46 ± 8 | 46 | 48 ± 11 | 0.79 |
| Mean ± SD LA volume index (mL/m 2 body surface area) | 84 | 43 ± 18 | 54 | 42 ± 16 | 30 | 46 ± 22 | 0.57 |
| LA dilatation | 186 | 133 (72%) | 116 | 77 (66%) | 70 | 56 (80%) | 0.05 |
| Abnormal diastolic function | 125 | 95 (76%) | 85 | 63 (74%) | 40 | 32 (80%) | 0.47 |
| Regional wall motion abnormality | 193 | 16 (8%) | 120 | 12 (10%) | 73 | 4 (5%) | 0.27 |
| Elevated pulmonary artery systolic pressure (mm Hg) | 125 | 78 (62%) | 75 | 37 (49%) | 50 | 41 (82%) | <0.001 |
| Apical wall motion abnormality | 193 | 120 | 18 (15%) | 73 | 11 (15%) | 0.99 | |
| Apical aneurysm | 6 (3%) | ||||||
| Apical dilatation with hypokinesis | 23 (12%) | ||||||
| Systolic apical gradient | 186 | 75 (40%) | 116 | 45 (39%) | 70 | 30 (43%) | 0.58 |
| Diastolic gradient | 186 | 27 (15%) | 116 | 17 (15%) | 70 | 10 (14%) | 0.94 |
| Clinically significant valvular heart disease | 193 | 12 (6%) | 120 | 2 (2%) | 73 | 10 (14%) | <0.001 |
Follow-up was available in 187 patients (97%; Table 4 ). Median age at follow-up was 72 years (range, 20–92). More episodes of heart failure were observed in women than men (p = 0.001). Women had a higher incidence of atrial fibrillation (p = 0.009). There were no gender-based differences in documented ventricular tachycardia events, proven coronary artery disease, implantation of ICD, or stroke. However, when considering the combined end point of sudden cardiac death, ICD discharge, and resuscitated cardiac arrest, more men tended to be affected than women, although the difference was not significant (p = 0.11). The annual rate of sudden cardiac death and/or ICD discharge was 0.5% per year.
| Variable | All (n = 187) | Men (n = 114) | Women (n = 73) | p Value |
|---|---|---|---|---|
| Mean ± SD age (yrs) | 64 ± 18 | 62 ± 19 | 66 ± 16 | 0.13 |
| Mean ± SD length of follow-up (mos) | 94 ± 76 | 106 ± 79 | 76 ± 67 | 0.005 |
| New York Heart Association functional class | 0.22 | |||
| I or II | 147 (79%) | 93 (82%) | 54 (74%) | |
| III or IV | 40 (21%) | 21 (18%) | 19 (26%) | |
| Atrial fibrillation | 54 (29%) | 25 (22%) | 29 (40%) | 0.009 |
| Heart failure | 35 (19%) | 13 (11%) | 22 (30%) | 0.001 |
| History of ventricular tachycardia | 37 (20%) | 23 (20%) | 14 (19%) | 0.87 |
| Coronary artery disease | 39 (21%) | 26 (23%) | 13 (18%) | 0.41 |
| AICD implantation | ||||
| Ever | 21 (11%) | 13 (11%) | 8 (11%) | 0.93 |
| During follow-up | 16 (9%) | 10 (9%) | 6 (8%) | 0.90 |
| Discharge during follow-up | 5 (3%) | 5 (4%) | 0 | 0.16 |
| Syncope | 28 (15%) | 18 (16%) | 10 (14%) | 0.70 |
| Stroke | 21 (11%) | 12 (11%) | 9 (12%) | 0.70 |
| Death ∗ | ||||
| Any death | 55 (29%) | 22 (19%) | 33 (45%) † | <0.001 ‡ |
| Cardiac death or stroke | 9 (5%) | 5 (4%) | 4 (5%) | 0.56 |
| Cardiac death | 7 (4%) | 4 (4%) | 3 (4%) | 0.57 |
| SCD | 5 (3%) | 3 (3%) | 2 (3%) | >0.99 |
| AICD discharge | 5 (3%) | 5 (4%) | 0 (0%) | 0.16 |
| Resuscitated cardiac arrest | 3 (2%) | 3 (3%) | 0 (0%) | 0.29 |
| SCD, AICD discharge, or resuscitated cardiac arrest | 11 (6%) | 9 (8%) | 2 (3%) | 0.11 |
| SCD, AICD discharge, stroke, or resuscitated cardiac arrest | 20 (11%) | 14 (12%) | 6 (8%) | 0.63 |
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