Susan A. Casey

EFFICACY OF IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS FOR THE PREVENTION OF SUDDEN DEATH IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY

BACKGROUND Hypertrophic cardiomyopathy is a genetic disease associated with a risk of ventricular tachyarrhythmias and sudden death, especially in young patients. METHODS We conducted a retrospective multicenter study of the efficacy of implantable cardioverter-defibrillators in preventing sudden death in 128 patients with hypertrophic cardiomyopathy who were judged to be at high risk for sudden death. RESULTS At the time of the implantation of the defibrillator, the patients were 8 to 82 years old (mean [+/-SD], 40+/-16), and 69 patients (54 percent) were less than 41 years old. The average follow-up period was 3.1 years. Defibrillators were activated appropriately in 29 patients (23 percent), by providing defibrillation shocks or antitachycardia pacing, with the restoration of sinus rhythm; the average age at the time of the intervention was 41 years. The rate of appropriate defibrillator discharge was 7 percent per year. A total of 32 patients (25 percent) had episodes of inappropriate discharges. In the group of 43 patients who received defibrillators for secondary prevention (after cardiac arrest or sustained ventricular tachycardia), the devices were activated appropriately in 19 patients (11 percent per year). Of 85 patients who had prophylactic implants because of risk factors (i.e., for primary prevention), 10 had appropriate interventions (5 percent per year). The interval between implantation and the first appropriate discharge was highly variable but was substantially prolonged (four to nine years) in six patients. In all 21 patients with stored electrographic data and appropriate interventions, the interventions were triggered by ventricular tachycardia or fibrillation. CONCLUSIONS Ventricular tachycardia or fibrillation appears to be the principal mechanism of sudden death in patients with hypertrophic cardiomyopathy. In high-risk patients with hypertrophic cardiomyopathy, implantable defibrillators are highly effective in terminating such arrhythmias, indicating that these devices have a role in the primary and secondary prevention of sudden death.

Epidemiology of Hypertrophic Cardiomyopathy–Related Death Revisited in a Large Non–Referral-Based Patient Population

BACKGROUND Death resulting from hypertrophic cardiomyopathy (HCM), particularly when sudden, has been reported to be largely confined to young persons. These data emanated from tertiary HCM centers with highly selected referral patterns skewed toward high-risk patients. METHODS AND RESULTS The present analysis was undertaken in an international population of 744 consecutively enrolled and largely unselected patients more representative of the overall HCM spectrum. HCM-related death occurred in 86 patients (12%) over 8+/-7 years (mean+/-SD). Three distinctive modes of death were as follows: (1) sudden and unexpected (51%; age, 45+/-20 years); (2) progressive heart failure (36%; age, 56+/-19 years); and (3) HCM-related stroke associated with atrial fibrillation (13%; age, 73+/-14 years). Sudden death was most common in young patients, whereas heart failure- and stroke-related deaths occurred more frequently in midlife and beyond. However, neither sudden nor heart failure-related death showed a statistically significant, disproportionate age distribution (P=0.06 and 0.5, respectively). Stroke-related deaths did occur disproportionately in older patients (P=0.002). Of the 45 patients who died suddenly, most (71%) had no or mild symptoms, and 7 (16%) participated in moderate to severe physical activities at the time of death. CONCLUSIONS HCM-related cardiovascular death occurred suddenly, or as a result of heart failure or stroke, largely during different phases of life in a prospectively assembled, regionally based, and predominantly unselected patient cohort. Although most sudden deaths occurred in adolescents and young adults, such catastrophes were not confined to patients of these ages and extended to later phases of life. This revised clinical profile suggests that generally held epidemiological tenants for HCM have been influenced considerably by skewed reporting from highly selected populations. These data are likely to importantly affect risk stratification and treatment strategies importantly for the prevention of sudden death in HCM.

Utility of Cardiac Magnetic Resonance Imaging in the Diagnosis of Hypertrophic Cardiomyopathy

Background—Two-dimensional echocardiography is currently the standard test for the clinical diagnosis of hypertrophic cardiomyopathy (HCM). The present study was undertaken to determine whether cardiac MRI (CMR) affords greater accuracy than echocardiography in establishing the diagnosis and assessing the magnitude of left ventricular (LV) hypertrophy in HCM. Methods and Results—Forty-eight patients (age 34±16 years) suspected of having HCM (or with a confirmed diagnosis) were imaged by both echocardiography and CMR to assess LV wall thickness in 8 anatomic segments (total n=384 segments) and compared in a blinded fashion. Maximum LV thickness was similar by echocardiography (21.7±9.1 mm) and CMR (22.5±9.6 mm; P=0.21). However, in 3 (6%) of the 48 patients, echocardiography did not demonstrate LV hypertrophy, and CMR identified otherwise undetected areas of wall thickening in the anterolateral LV free wall (17 to 20 mm), which resulted in a new diagnosis of HCM. In the overall study group, compared with CMR, echocardiography also underestimated the magnitude of hypertrophy in the basal anterolateral free wall (by 20±6%; P=0.001), as well as the presence of extreme LV wall thickness (≥30 mm) in 10% of patients (P<0.05). Conclusions—CMR is capable of identifying regions of LV hypertrophy not readily recognized by echocardiography and was solely responsible for diagnosis of the HCM phenotype in an important minority of patients. CMR enhances the assessment of LV hypertrophy, particularly in the anterolateral LV free wall, and represents a powerful supplemental imaging test with distinct diagnostic advantages for selected HCM patients.

Assessment of Diastolic Function With Doppler Tissue Imaging to Predict Genotype in Preclinical Hypertrophic Cardiomyopathy

Background—Unexplained left ventricular hypertrophy (LVH) is considered diagnostic of hypertrophic cardiomyopathy (HCM) but fails to identify all genetically affected individuals. Altered diastolic function has been hypothesized to represent an earlier manifestation of HCM before the development of LVH; however, data regarding the clinical utility of imaging techniques that assess this parameter are limited. Methods and Results—Echocardiographic studies including Doppler tissue imaging (DTI) were performed in a genotyped HCM population with &bgr;-myosin heavy chain (&bgr; -MHC) mutations. Genotype (+) individuals with LVH (G+/LVH+; n=18) and genotype (+) individuals without LVH (G+/LVH−; n=18) were compared with normal control subjects (n=36). Left ventricular ejection fraction (EF) was significantly higher in both genotype (+) groups (75±5% and 71±6%, respectively, versus 64± 5% in control subjects;P <0.0001). Mean early diastolic myocardial velocities (Ea) were significantly lower in both genotype (+) subgroups, irrespective of LVH (P <0.02). However, there was substantial overlap in Ea velocities between the G+/LVH− and control groups. An Ea velocity of ≤13.5 cm/s had 86% specificity and 75% sensitivity for identifying genotype-positive subjects. The combination of EF ≥68% and Ea velocity <15 cm/s was 100% specific and 44% sensitive in predicting affected genotype. Conclusions—Abnormalities of diastolic function assessed by Doppler tissue imaging precede the development of LVH in individuals with HCM caused by &bgr; -MHC mutations. Although Ea velocity alone was not sufficiently sensitive as a sole diagnostic criterion, the combination of Ea velocity and EF was highly predictive of affected genotype in individuals without overt manifestations of HCM.

Clinical profile of stroke in 900 patients with hypertrophic cardiomyopathy

OBJECTIVES We sought to assess the occurrence and clinical significance of stroke and peripheral arterial embolizations at non-central nervous system sites in a large, community-based cohort with hypertrophic cardiomyopathy (HCM). BACKGROUND Such vascular events are insufficiently appreciated complications of HCM for which there is limited information on occurrence, clinical profile and determinants. METHODS We assessed the clinical features of patients with stroke and other peripheral vascular events in a consecutive group of patients with HCM from four regional cohorts not subject to significant tertiary referral bias. RESULTS Of the 900 patients, 51 (6%) patients experienced stroke or other vascular events over 7 +/- 7 years, including 44 patients with stroke; 21 (41%) of these 51 patients died or were permanently disabled. The overall incidence was 0.8%/year and 1.9% for patients >60 years old. Age at first event ranged from 29 to 86 years (mean 61 +/- 14 years). Most (n = 37; 72%) events occurred in those >50 years, although 14 (28%) younger patients (< or = 50 years) also had events. Multivariate analysis showed stroke and other peripheral vascular events to be independently associated with congestive symptoms and advanced age, as well as with atrial fibrillation (in 45 [88%] of 51 patients), at the initial evaluation. The cumulative incidence of these events among patients with atrial fibrillation was significantly higher in non-anticoagulated patients as compared with patients receiving warfarin (31% vs. 18%; p < 0.05). CONCLUSIONS Stroke and peripheral embolizations showed a 6% prevalence rate and an incidence of 0.8%/year in a large, unselected HCM group. These profound complications of HCM, which may lead to disability and death, were substantially more common in the elderly, occurred almost exclusively in patients with paroxysmal or chronic atrial fibrillation and appeared to be reduced in frequency by anticoagulation.

Relationship of race to sudden cardiac death in competitive athletes with hypertrophic cardiomyopathy

OBJECTIVES The goal of this study was to determine the impact of race on identification of hypertrophic cardiomyopathy (HCM). BACKGROUND Sudden death in young competitive athletes is due to a variety of cardiovascular diseases (CVDs) and, most commonly, HCM. These catastrophes have become an important issue for African Americans, although HCM has been previously regarded as rare in this segment of the U.S. population. METHODS We studied the relationship of race to the prevalence of CVDs causing sudden death in our national athlete registry, and compared these findings with a representative multicenter hospital-based cohort of patients with HCM. RESULTS Of 584 athlete deaths, 286 were documented to be due to CVD at ages 17 +/- 3 years; 156 (55%) were white, and 120 (42%) were African American. Most were male (90%), and 67% participated in basketball and football. Among the 286 cardiovascular deaths, most were due to HCM (n = 102; 36%) or anomalous coronary artery of wrong sinus origin (n = 37; 13%). Of the athletes who died of HCM, 42 (41%) were white, but 56 (55%) were African American. In contrast, of 1,986 clinically identified HCM patients, only 158 (8%) were African American (p < 0.001). CONCLUSIONS In this autopsy series, HCM represented a common cause of sudden death in young and previously undiagnosed African American male athletes, in sharp contrast with the infrequent clinical identification of HCM in a hospital-based population (i.e., by seven-fold). This discrepancy suggests that many HCM cases go unrecognized in the African American community, underscoring the need for enhanced clinical recognition of HCM to create the opportunity for preventive measures to be employed in high-risk patients with this complex disease.

Development of left ventricular hypertrophy in adults with hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations ☆

OBJECTIVES We sought to determine whether the development of left ventricular hypertrophy (LVH) can be demonstrated during adulthood in genetically affected relatives with hypertrophic cardiomyopathy (HCM). BACKGROUND Hypertrophic cardiomyopathy is a heterogeneous cardiac disease caused by mutations in nine genes that encode proteins of the sarcomere. Mutations in cardiac myosin-binding protein C (MyBPC) gene have been associated with age-related penetrance. METHODS To further analyze dormancy of LVH in patients with HCM, we studied, using echocardiography and 12-lead electrocardiography, the phenotypic expression caused by MyBPC mutations in seven genotyped pedigrees. RESULTS Of 119 family members studied, 61 were identified with a MyBPC mutation, including 21 genetically affected relatives (34%) who did not express the HCM morphologic phenotype (by virtue of showing normal left ventricular wall thickness). Of these 21 phenotype-negative individuals, 9 were children, presumably in the prehypertrophic phase, and 12 were adults. Of the 12 adults with normal wall thickness < or = 12 mm (7 also with normal electrocardiograms), 5 subsequently underwent serial echocardiography prospectively over four to six years. Of note, three of these five adults showed development of LVH in mid-life, appearing for the first time at 33, 34 and 42 years of age, respectively, not associated with outflow obstruction or significant symptoms. CONCLUSIONS In adults with HCM, disease-causing MyBPC mutations are not uncommonly associated with absence of LVH on echocardiogram. Delayed remodeling with the development of LVH appearing de novo in adulthood, demonstrated here for the first time in individual patients with prospectively obtained serial echocardiograms, substantiates the principle of age-related penetrance for MyBPC mutations in HCM. These observations alter prevailing perceptions regarding the HCM clinical spectrum and family screening strategies and further characterize the evolution of LVH in this disease.

Clinical course of hypertrophiccardiomyopathy with survival to advanced age

OBJECTIVES This study was designed to clarify and resolve the clinical profile of older patients with hypertrophic cardiomyopathy (HCM). BACKGROUND Adverse consequences of HCM such as sudden death and incapacitating symptoms have been emphasized for the young and middle-aged. METHODS Long-term outcome of HCM was assessed in a community-based cohort not subject to tertiary center referral bias. RESULTS Of 312 patients, 73 (23%) achieved normal life expectancy (> or =75 years; range to 96); 44 (14%) were > or =80 years old. Most patients > or =75 years (47; 64%) experienced no or only mild limiting symptoms and lived virtually their entire lives with few HCM-related clinical consequences; 26 patients (36%) experienced severe progressive symptoms. In elderly patients with HCM, diagnosis and symptom onset were considerably delayed to 74 +/- 8 and 70 +/- 11 years, respectively. For patients > or =50 years at diagnosis, the probability of survival for 5, 10, and 15 years was 85 +/- 3%, 74 +/- 4%, and 57 +/- 6%, respectively, and did not significantly differ from a matched general population (p = 0.20). Patients > or =75 years were predominantly women, and had less marked wall thickness and more frequently showed basal outflow obstruction > or =30 mm Hg (compared with those <75 years; p < 0.01 and 0.001, respectively). CONCLUSIONS Hypertrophic cardiomyopathy is frequently well tolerated and compatible with normal life expectancy, and may remain clinically dormant for long periods of time with symptoms and initial diagnosis deferred until late in life. These observations afford a measure of reassurance to many patients with HCM, a disease for which clinical course is often unfavorable and unpredictable.

Prevention of Sudden Cardiac Death With Implantable Cardioverter-Defibrillators in Children and Adolescents With Hypertrophic Cardiomyopathy

OBJECTIVES The aim of this study was to determine the efficacy of implantable cardioverter-defibrillators (ICDs) in children and adolescents with hypertrophic cardiomyopathy (HCM). BACKGROUND HCM is the most common cause of sudden death in the young. The availability of ICDs over the past decade for HCM has demonstrated the potential for sudden death prevention, predominantly in adult patients. METHODS A multicenter international registry of ICDs implanted (1987 to 2011) in 224 unrelated children and adolescents with HCM judged at high risk for sudden death was assembled. Patients received ICDs for primary (n = 188) or secondary (n = 36) prevention after undergoing evaluation at 22 referral and nonreferral institutions in the United States, Canada, Europe, and Australia. RESULTS Defibrillators were activated appropriately to terminate ventricular tachycardia or ventricular fibrillation in 43 of 224 patients (19%) over a mean of 4.3 ± 3.3 years. ICD intervention rates were 4.5% per year overall, 14.0% per year for secondary prevention after cardiac arrest, and 3.1% per year for primary prevention on the basis of risk factors (5-year cumulative probability 17%). The mean time from implantation to first appropriate discharge was 2.9 ± 2.7 years (range to 8.6 years). The primary prevention discharge rate terminating ventricular tachycardia or ventricular fibrillation was the same in patients who underwent implantation for 1, 2, or ≥3 risk factors (12 of 88 [14%], 10 of 71 [14%], and 4 of 29 [14%], respectively, p = 1.00). Extreme left ventricular hypertrophy was the most common risk factor present (alone or in combination with other markers) in patients experiencing primary prevention interventions (17 of 26 [65%]). ICD-related complications, particularly inappropriate shocks and lead malfunction, occurred in 91 patients (41%) at 17 ± 5 years of age. CONCLUSIONS In a high-risk pediatric HCM cohort, ICD interventions terminating life-threatening ventricular tachyarrhythmias were frequent. Extreme left ventricular hypertrophy was most frequently associated with appropriate interventions. The rate of device complications adds a measure of complexity to ICD decisions in this age group.

Usefulness of B-Type Natriuretic Peptide Assay in the Assessment of Symptomatic State in Hypertrophic Cardiomyopathy

Background—Hypertrophic cardiomyopathy (HCM) has a diverse clinical spectrum that often includes progressive heart failure symptoms and disability. Assessment of symptom severity may be highly subjective, encumbered by the heterogeneous clinical presentation. Plasma B-type natriuretic peptide (BNP) has been used widely as an objective marker for heart failure severity and outcome, predominantly in coronary heart disease with ventricular dilatation and systolic dysfunction. Methods and Results—We prospectively assessed plasma BNP as a quantitative clinical marker of heart failure severity in 107 consecutive HCM patients. BNP showed a statistically significant relationship to magnitude of functional limitation, assessed by New York Heart Association (NYHA) functional class: I, 136±159 pg/mL; II, 338±439 pg/mL; and III/IV, 481±334 pg/mL (P <0.001). Multivariable analysis showed that BNP was independently related to NYHA class as well as age and left ventricular wall thickness (each with a value of P =0.0001). BNP ≥200 pg/mL was the most reliable predictor of heart failure symptoms, with positive and negative predictive values of 63% and 79%, respectively. BNP power in distinguishing patients with or without heart failure symptoms was less than that for differentiating between no (or only mild) and severe symptoms (area under receiver operating characteristic curve=0.75 and 0.83, respectively). Conclusions—Plasma BNP is independently related to the presence and magnitude of heart failure symptoms in patients with HCM. As a clinical marker for heart failure, BNP is limited by considerable overlap in values between categories of heart failure severity as well as confounding variables of left ventricular wall thickness and age.