From malignant mutations to malignant domains: the continuing search for prognostic significance in the mutant genes causing hypertrophic cardiomyopathy.

The genetic causes of hypertrophic cardiomyopathy are diverse and thus present challenges in the development of genetic tests to identify patients at risk

Ventricular arrhythmias, sudden death, and prevention in patients with hypertrophic cardiomyopathy.

Sudden unexpected death, often occurring in young asymptomatic patients, is the most devastating facet of the natural history of hypertrophic cardiomyopathy (HCM). It appears to be the consequence of primary ventricular tachyarrhythmias arising in an electrically unstable myocardial substrate characterized by disorganized cellular architecture, ischemia, cell death, and replacement scarring. Although identification of the HCM patient subset at high risk for a catastrophic event with precision continues to present challenges, treatment strategies for the prevention of sudden death are now available. In particular, the implantable cardioverter-defibrillator has a high degree of efficacy in sensing and terminating potentially lethal ventricular tachyarrhythmias and a life-saving role in both the primary and secondary prevention of sudden cardiac death in HCM.

Preparticipation cardiovascular screening for US collegiate student-athletes.

CONTEXT: Sudden death in young competitive athletes due to unsuspected cardiovascular disease has heightened interest in preparticipation screening. OBJECTIVE: To assess screening practices for detecting potentially lethal cardiovascular diseases in college-aged student-athletes. DESIGN, SETTING, AND PARTICIPANTS: A total of 1110 National Collegiate Athletic Association member colleges and universities were surveyed between 1995 and 1997, with 879 (79%) responding to the questionnaire. MAIN OUTCOME MEASURES: Information on the administration and scope of the preparticipation screening process was obtained from the team physician or athletic director; preparticipation screening forms were evaluated for content and compared with 12 items recommended by the 1996 American Heart Association (AHA) consensus panel screening guidelines. RESULTS: Preparticipation screening was a requirement at 855 (97%) of 879 schools, was performed on campus at 713 schools (81 %), and was required annually by 446 schools (51 %). Team physicians were responsible for examinations at 603 (85%) of 713 schools with on-campus screening, although 135 of these schools (19%) also approved nurse practitioners and 244 schools (34%) allowed athletic trainers to perform examinations. Of the history and physical examination screening forms analyzed from 625 institutions, only 163 schools (26%) had forms that contained at least 9 of the recommended 12 AHA screening guidelines and were judged to be adequate, whereas 150 (24%) contained 4 or fewer of these parameters and were considered to be inadequate. Smaller Division III schools were more likely than larger Division I schools to have inadequate screening forms (30% vs 14%; P<.001). Relevant items that were omitted from more than 40% of the screening forms included history of exertional chest pain, dyspnea, or fatigue; familial heart disease or premature sudden death; and physical stigmata or family history of Marfan syndrome. CONCLUSION: The preparticipation screening process used by many US colleges and universities may have limited potential to detect (or raise the suspicion of) cardiovascular abnormalities capable of causing sudden death in competitive student-athletes.

Selective activation of the K(+)(ATP) channel is a mechanism by which sudden death is produced by low-energy chest-wall impact (Commotio cordis).

BACKGROUND: Sudden death due to relatively innocent chest-wall impact has been described in young individuals (commotio cordis). In our previously reported swine model of commotio cordis, ventricular fibrillation (with T-wave strikes) and ST-segment elevation (with QRS strikes) were produced by 30-mph baseball impacts to the precordium. Because activation of the K(+)(ATP) channel has been implicated in the pathogenesis of ST elevation and ventricular fibrillation in myocardial ischemia, we hypothesized that this channel could be responsible for the electrophysiologic findings in our experimental model and in victims of commotio cordis. METHODS AND RESULTS: In the initial experiment, 6 juvenile swine were given 0.5 mg/kg IV glibenclamide, a selective inhibitor of the K(+)(ATP) channel, and chest impact was given on the QRS. The results of these strikes were compared with animals in which no glibenclamide was given. In the second phase, 20 swine were randomized to receive glibenclamide or a control vehicle (in a double-blind fashion), with chest impact delivered just before the T-wave peak. With QRS impacts, the maximal ST elevation was significantly less in those animals given glibenclamide (0.16+/-0.10 mV) than in controls (0.35+/-0.20 mV; P=0.004). With T-wave impacts, the animals that received glibenclamide had significantly fewer occurrences of ventricular fibrillation (1 episode in 27 impacts; 4%) than controls (6 episodes in 18 impacts; 33%; P=0.01). CONCLUSIONS: In this experimental model of commotio cordis, blockade of the K(+)(ATP) channel reduced the incidence of ventricular fibrillation and the magnitude of ST-segment elevation. Therefore, selective K(+)(ATP) channel activation may be a pivotal mechanism in sudden death resulting from low-energy chest-wall trauma in young people during sporting activities.

Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (M-PATHY).

BACKGROUND: Dual-chamber pacing (DDD) has been proposed as a treatment alternative to surgery for severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), based largely on uncontrolled studies. METHODS AND RESULTS: This prospective, multicenter trial assessed pacing in 48 symptomatic HCM patients with >/=50 mm Hg basal gradient, refractory to drug therapy. Patients were randomized to 3 months each of DDD pacing and pacing backup (AAI-30) in a double-blind, crossover study design, followed by an uncontrolled and unblinded 6-month pacing trial. With randomization, no significant differences were evident between pacing and no pacing for subjective or objective measures of symptoms or exercise capacity, including NYHA functional class, quality of life score, treadmill exercise time or peak oxygen consumption. After 6 additional months of unblinded pacing, functional class and quality of life score were improved compared with baseline (P<0.01), but peak oxygen consumption was unchanged. Outflow gradient decreased 40%, 82+/-32 mm Hg to 48+/-32 mm Hg (P<0. 001), and was reduced in 57% of patients but showed no change or an increase in 43%. At 12 months, 6 individual patients (12%) showed improved functional capacity; each was 65 to 75 years of age. Left ventricular wall thicknesses in the overall study group showed no remodeling between baseline (22+/-5 mm) and 12 months (21+/-5 mm; P=NS). CONCLUSIONS: (1) Pacing cannot be regarded as a primary treatment for obstructive HCM; (2) with randomization, perceived symptomatic improvement was most consistent with a substantial placebo effect; (3) longer, uncontrolled pacing periods were associated with some subjective benefit but unaccompanied by objective improvement in cardiovascular performance and should be interpreted cautiously; (4) modest reduction in outflow gradient was achieved in most patients; and (5) a small subset (12%) >/= 65 years of age showed a clinical response, suggesting that DDD pacing could be a therapeutic option for some elderly patients.

Pitfalls in clinical recognition and a novel operative approach for hypertrophic cardiomyopathy with severe outflow obstruction due to anomalous papillary muscle.

BACKGROUND: Ventricular septal myotomy/myectomy (Morrow procedure) is the standard surgical option for severely symptomatic patients with hypertrophic cardiomyopathy (HCM) and marked basal obstruction to left ventricular outflow due to mitral valve systolic anterior motion. In some patients, however, congenital malformations of the mitral apparatus may be responsible for outflow obstruction; the failure to recognize this morphology before operation could have adverse consequences. METHODS AND RESULTS: We recently evaluated 2 patients with obstructive HCM operated on at Mayo Medical Center in 1997 who demonstrated direct anomalous papillary muscle insertion into the anterior mitral leaflet, producing muscular midcavity obstruction. This anomaly is potentially identifiable with echocardiography by exaggerated anterior displacement of hypertrophied papillary muscles within the left ventricular cavity and the direct continuity between papillary muscle and anterior leaflet associated with a rigid motion pattern of the mitral apparatus. Echocardiographic diagnosis, however, was confused in both patients by the association of systolic anterior motion of the mitral valve, probably produced by freely mobile margins of the mitral leaflet unencumbered by papillary muscle insertion, and in 1 patient probably representing a second and more basal level of obstruction. Because outflow tract morphology was judged unsuitable for conventional myotomy/myectomy, a novel surgical strategy was designed to remove the outflow gradient in which an extensive myectomy trough (wider at its apical than basal extent) was created within the ventricular septum to papillary muscle level; also, in 1 patient, attachment of anterolateral papillary muscle with the lateral free wall was partially severed to increase mobility of the mitral apparatus. After surgery, both patients reported substantial relief of symptoms and improved exercise tolerance and also showed reduced or abolished basal outflow obstruction. CONCLUSIONS: In HCM, outflow obstruction due to anomalous papillary muscle insertion directly into anterior mitral leaflet is challenging to identify but should always be contemplated before operative intervention. This important (but often unsuspected) congenital malformation may require alternative surgical strategies to standard myotomy/myectomy, similar to those described here.

Cardiovascular risks to young persons on the athletic field.

Sudden cardiac deaths of young athletes, which are usually associated with physical exertion, continue to achieve high public visibility and generate considerable concern. Despite broad community participation in sports, such catastrophes are uncommon, occurring in about 1/200000 high school athletes per academic year. Various unsuspected congenital cardiovascular diseases are usually responsible; the most common lesions are hypertrophic cardiomyopathy and several congenital coronary artery anomalies. Selected reports suggest that arrhythmogenic right ventricular dysplasia may be a more common cause of these deaths than previously suspected. In some trained athletes with borderline increases in thickness of the left ventricular wall, mild morphologic expression of hypertrophic cardiomyopathy can often be distinguished from the physiologic consequences of athlete's heart by noninvasive clinical assessment and testing. In addition, the recognized cardiovascular risks of the athletic field are now extended to include cardiac arrest resulting from relatively modest, nonpenetrating chest blows produced by projectiles (such as baseballs) or bodily contact in the absence of underlying cardiac disease and without structural injury to the chest wall or heart. These uncommon but usually fatal events seem to result when chest impact occurs precisely during the vulnerable phase of repolarization, and they may be reduced by use of softer baseballs. Preparticipation screening for cardiovascular disease, consisting of standard history and physical examination, is customary practice for most high school and college athletes in the United States. Evidence suggests, however, that the present screening process for cardiovascular disease in high school athletes may be largely inadequate, given the content of the approved screening questionnaires (which serve as guidelines for the process) and the use of examiners with little cardiovascular training. This emphasizes the need for national standardization of preparticipation screening. The recommendations of the 26th Bethesda Conference for disqualification from competitive athletics are now a standard for management decisions when cardiovascular abnormalities are identified in trained athletes.

Profile of preparticipation cardiovascular screening for high school athletes.

CONTEXT: Sudden death in young competitive athletes due to unsuspected cardiovascular disease has heightened concern and interest in the preparticipation screening available to high school athletes in the United States. OBJECTIVE: To assess the potential adequacy of the preparticipation screening process for detecting or increasing the suspicion of cardiovascular abnormalities. DESIGN: Current guidelines and requirements for implementation of preparticipation screening from each of the high school jurisdictions in the 50 states and the District of Columbia were analyzed and compared with the 1996 American Heart Association (AHA) consensus panel guidelines on screening. OUTCOME MEASURES: Items contained on preparticipation screening questionnaires; the examiners designated to perform screening. RESULTS: Eight states (16%) have no approved history and physical examination questionnaires to guide examiners, including 1 state without a formal screening requirement. Of the remaining 43 states, several items relevant to cardiac-related problems were frequently omitted from the questionnaires. Exertional dyspnea or chest pain, prior limitation from sports, family history of heart disease, or Marfan syndrome were included in 0% to 56% of the state forms. Specific cardiovascular items on physical examination were included in forms from only 5% to 37% of states, including documentation of a heart murmur, irregular heart rhythm, peripheral pulses, or stigmata of Marfan syndrome. Seventeen (40%) of 43 states had history and physical questionnaires judged to be most adequate with at least 9 of the 13 AHA recommendations, whereas 12 states (28%) were least adequate with 4 or less of these recommended items. Therefore, a total of 20 (40%) of the 51 states have no approved history and physical examination questionnaires, or formal screening requirement, or forms that were judged to be inadequate. In addition to physicians, 21 states also permit nurses or physician assistants to administer examinations, and 11 states specifically provide for practitioners with limited cardiovascular training (such as chiropractors). CONCLUSIONS: Preparticipation athletic screening for cardiovascular disease with standard history and physical examination, as presently employed in US high schools, is highly dependent on the state-approved questionnaires, which frequently are abbreviated and may be inadequate; is implemented by a variety of health care workers with varying levels of expertise; and may be severely limited in its power to detect potentially lethal cardiovascular abnormalities. These observations should represent an impetus for change and improvement in the preparticipation cardiovascular screening process for high school athletes.

Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.

BACKGROUND: Mutations in the gene for cardiac myosin-binding protein C account for approximately 15 percent of cases of familial hypertrophic cardiomyopathy. The spectrum of disease-causing mutations and the associated clinical features of these gene defects are unknown. METHODS: DNA sequences encoding cardiac myosin-binding protein C were determined in unrelated patients with familial hypertrophic cardiomyopathy. Mutations were found in 16 probands, who had 574 family members at risk of inheriting these defects. The genotypes of these family members were determined, and the clinical status of 212 family members with mutations in the gene for cardiac myosin-binding protein C was assessed. RESULTS: Twelve novel mutations were identified in probands from 16 families. Four were missense mutations; eight defects (insertions, deletions, and splice mutations) were predicted to truncate cardiac myosin-binding protein C. The clinical expression of either missense or truncation mutations was similar to that observed for other genetic causes of hypertrophic cardiomyopathy, but the age at onset of the disease differed markedly. Only 58 percent of adults under the age of 50 years who had a mutation in the cardiac myosin-binding protein C gene (68 of 117 patients) had cardiac hypertrophy; disease penetrance remained incomplete through the age of 60 years. Survival was generally better than that observed among patients with hypertrophic cardiomyopathy caused by other mutations in the genes for sarcomere proteins. Most deaths due to cardiac causes in these families occurred suddenly. CONCLUSIONS: The clinical expression of mutations in the gene for cardiac myosin-binding protein C is often delayed until middle age or old age. Delayed expression of cardiac hypertrophy and a favorable clinical course may hinder recognition of the heritable nature of mutations in the cardiac myosin-binding protein C gene. Clinical screening in adult life may be warranted for members of families characterized by hypertrophic cardiomyopathy.

A mutant tropomyosin that causes hypertrophic cardiomyopathy is expressed in vivo and associated with an increased calcium sensitivity.

Mutant contractile protein genes that cause familial hypertrophic cardiomyopathy (FHC) are presumed to encode mutant proteins that interfere with contractile function. However, it has generally not been possible to show mutant protein expression and incorporation into the sarcomere in vivo. This study aimed to assess whether a mutant alpha-fast tropomyosin (TM) responsible for FHC is actually expressed and determines abnormal contractile function. Since alpha-fast TM is expressed in heart and skeletal muscle, samples from vastus lateralis muscles were studied from two FHC patients carrying an Asp175Asn alpha-fast TM mutation and two healthy control subjects. TM isoforms from whole biopsy samples and single fibers were identified by gel electrophoresis and Western blot analysis. An additional faster-migrating TM band was observed in both FHC patients. The aberrant TM was identified as the Asp175Asn alpha-fast TM by comigration with purified recombinant human Asp175Asn alpha-fast TM. Densitometric quantification of mutant and wild-type alpha-fast TMs suggested equal expression of the two proteins. Contractile parameters of single skinned muscle fibers from FHC patients and healthy control subjects were compared. Calcium sensitivity was significantly increased in muscle fibers containing Asp175Asn alpha-fast Tm compared with fibers lacking the mutant TM. No discernible difference was found regarding cooperativity, maximum force, and maximum shortening velocity. This is the first demonstration that the mutant TM that causes FHC is indeed expressed and almost certainly incorporated into muscle in vivo and does result in altered contractile function; this confirms a dominant-negative, rather than null allele, action. Since the mutant TM was associated with increased calcium sensitivity, this mutation might be associated with an enhancement and not a depression of cardiac contractile performance. If so, this contrasts with the hypothesis that FHC mutations induce contractile impairment followed by compensatory hypertrophy.

Risk profiles and cardiovascular preparticipation screening of competitive athletes.

There has been heightened interest in the design and role of preparticipation screening for high school and college athletes. An American Heart Association consensus panel, composed of cardiovascular specialists and other physician experts having extensive clinical experience with athletes of all ages as well as a legal expert, assessed the benefits and limitations of preparticipation screening for early detection of cardiovascular abnormalities in competitive athletes. The panel addressed cost-efficiency and feasibility issues as well as the medicolegal implications of screening; and developed consensus recommendations and guidelines for the most prudent, practical, and effective screening procedures and strategies.

Clinical and morphologic expression of hypertrophic cardiomyopathy in patients > or = 65 years of age.

Hypertrophic cardiomyopathy (HC) is most often identified in patients in the second through fifth decades of life, but has been increasingly recognized in older patients. The present report characterizes morphologic and clinical features of HC in 134 consecutively studied patients aged > or = 65 years referred to a tertiary center. Echocardiographic or clinical evaluation, or both, was performed in 134 patients aged 65 to 85 years (mean 72) at most recent evaluation. Selected findings were compared with those in 64 youthful patients with HC aged 15 to 35 years (mean 25). Most elderly patients (120 of 134, 90%) developed marked symptoms that usually became evident after age 55 years; 94 of 120 experienced sustained improvement with medical treatment or operation. Elderly patients had relatively mild left ventricular (LV) wall thickening (20 +/- 3 mm), generally confined to the septum. In most (i.e., 68%), septal hypertrophy was uniformly distributed with parallel right and left borders and associated with elliptical LV cavity shape; however, in 32%, an inhomogeneously hypertrophied septum bulged into the left ventricle, disrupting normal cavity shape. Dynamic subaortic obstruction was present under basal or provocable conditions in a particularly small LV outflow tract in 103 of 134 patients (77%), and was usually produced by relatively restricted excursion of the anteriorly displaced mitral leaflets and posterior septal motion. HC is characterized by age-related differences in both clinical and morphologic expression. Elderly patients with HC characteristically demonstrate onset of cardiac symptoms late in life, as well as distinctive LV morphology and dynamics of outflow obstruction.

Operative treatment of pediatric obstructive hypertrophic cardiomyopathy: a 26-year experience.

We retrospectively reviewed the 26-year National Institutes of Health experience with operative treatment of obstructive hypertrophic cardiomyopathy in pediatric patients. Operative criteria were either severe obstructive symptoms (New York Heart Association functional class III or IV) or sudden death. Seventeen patients underwent 19 open procedures, of which the present study is comprised. Complete follow-up was available 10.1 +/- 1.4 years (mean +/- standard error; range, 0.8 to 26.2 years) after operation. The mean ages at diagnosis and operation were 11.9 +/- 1.3 years (range, 1 to 17 years) and 14.8 +/- 0.7 years (range, 9 to 17 years), respectively. The preoperative intraventricular septum mean dimension was 23.2 +/- 1.3 mm (range, 11 to 36 mm). The left ventricular outflow tract gradient was 74 +/- 9 mm Hg (range, 20 to 175 mm Hg) at rest and 94 +/- 7 mm Hg (range, 55 to 175 mm Hg) with provocation. Fifteen patients (88%) underwent left ventricular myotomy and myectomy, and 2 underwent mitral valve replacement. Two patients who initially received left ventricular myotomy and myectomy later underwent mitral valve replacement. There were one perioperative death (6%) and five late sudden deaths (31%) at 3.8, 8.7, 9.6, 14.1, and 21 years postoperatively. Kaplan-Meier survival was 86% +/- 8% at 5 years and 77% +/- 12% at 10 years. After operation, the left ventricular outflow tract gradient decreased almost 80% to 21 +/- 15 mm Hg (p = 0.0001). In 8 patients, the left ventricular outflow tract gradient completely resolved.(ABSTRACT TRUNCATED AT 250 WORDS)

Echocardiographic assessment of mitral valve size in obstructive hypertrophic cardiomyopathy. Anatomic validation from mitral valve specimen.

BACKGROUND: In patients with hypertrophic cardiomyopathy, obstruction to left ventricular outflow is produced by systolic anterior motion of the mitral valve. In many of these patients, the mitral leaflets are elongated and increased in overall size. Mitral valve size may be responsible, in part, for the presence and magnitude of the outflow gradient and the pattern of systolic anterior motion of the leaflets. It may also influence the effectiveness of ventricular septal myotomy-myectomy in relieving subaortic obstruction. Therefore, the present study was undertaken to determine whether mitral valve dimensions could be assessed in quantitative terms from the echocardiogram in patients with hypertrophic cardiomyopathy. METHODS AND RESULTS: A group of 37 patients with hypertrophic cardiomyopathy was selected for this study by virtue of having a high-quality transthoracic or intraoperative echocardiogram suitable for certain quantitative measurements from stop-frame images as well as a morphologically intact mitral valve specimen (removed during surgery). Seven measurements of mitral valve dimensions were obtained from the two-dimensional and M-mode echocardiograms. A univariate regression analysis identified the mitral valve opening area as the best single predictor of actual mitral leaflet area measured from the specimen (r2 = .75; r = .87). The linear relation between mitral valve opening area as assessed by two-dimensional echocardiography and actual mitral leaflet area measured from the mitral valve specimen accounted for approximately 75% of the variability in mitral leaflet area. With such statistical models, it was possible to reliably identify from the echocardiogram enlarged mitral valves (> or = 12.0 cm2) in 16 of 19 patients (84%) and normal-sized valves in 15 of 18 patients (83%). CONCLUSIONS: In a selected group of patients with obstructive hypertrophic cardiomyopathy, a model derived from a regression analysis of quantitative echocardiographic measurements permitted (with good precision) estimation of actual mitral leaflet area and consequently overall mitral valve size and the discrimination of enlarged from normal-sized mitral valves.

Hypertrophic Cardiomyopathy in Athletes.

In brief Hypertrophic cardiomyopathy brief (HCM) accounts for a large proportion of sudden deaths in young athletes. HCM is a complex disease with a broad clinical and morphologic spectrum. Most patients with HCM have impaired diastolic filling of the left ventricle, and about 25% have left ventricular outflow tract obstruction. Cardiac symptoms and/or signs are often present, and the condition is most effectively identified with echocardiography. Propranolol or verapamil relieves symptoms in many patients; surgery may benefit patients who have outflow obstruction associated with symptoms that persist after pharmacologic therapy. Patients with HCM should not engage in organized competitive sports or particularly strenuous exercise, although moderate recreational exercise is likely to be acceptable for such individuals.