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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.

Our results indicate that preoperative left ventricular systolic function continues to influence postoperative prognosis and suggest that the discordant conclusions of previous studies probably resulted from interpretive differences and differences in patient selection.

No abstract

While aortic root dilatation and valvular dysfunction have been well-documented in osteogenesis imperfecta (01), the nature and extent of cardiovascular involvement in 01

SUMMARY Many patients with hypertrophic cardiomyopathy die suddenly and unexpectedly, a significant number perhaps due to arrhythmia. Of 100 patients initially evaluated for signs or symptoms suggestive of heart disease or a family history of hypertrophic cardiomyopathy, 51 were selected solely because they met the echocardiographic criteria for the disease, and 49 patients were selected primarily because they had: 1) normal sinus rhythm despite left atrial enlargement, 2) a history of syncope, 3) a family history of premature death, or 4) a history of paroxysmal atrial fibrillation. All 100 patients were studied by 24-hour ambulatory electrocardiographic monitoring and 74 of them also underwent treadmill exercise testing. More than 50% of patients in all subgroups (with or without symptoms or left ventricular outflow tract obstruction) had multiform or repetitive ventricular premature depolarizations, including 19% who had ventricular tachycardia. Monitoring was superior to exercise testing for exposing these arrhythmias. Two patients experienced cardiac arrest within 2 months of monitoring; in each, monitoring had revealed ventricular tachycardia. Two patients with paroxysms of supraventricular tachycardia during monitoring developed fixed atrial fibrillation within 1 year. These preliminary observations suggest that monitoring may help identify patients at increased risk for significant arrhythmic events.MANY SYMPTOMATIC PATIENTS with hypertrophic cardiomyopathy die suddenly and unexpectedly during the course of their disease.'`' We have identified several people with hypertrophic cardiomyopathy in whom sudden death was the initial manifestation of disease.5 Despite the clinical importance of this problem and the likelihood that many of these sudden deaths are arrhythmic in origin,6 surprisingly little is known about the propensity of patients with hypertrophic cardiomyopathy to develop arrhythmias.In the present investigation we used 24-hour ambulatory electrocardiographic monitoring and treadmill exercise testing to examine the frequency and types of arrhythmias that occur in a large population of patients with hypertrophic cardiomyopathy. We sought to determine whether subgroups of patients with this disease are particularly susceptible to the development of arrhythmias. We also compared the sensitivity of 24-hour ambulatory electrocardiographic monitoring with that of treadmill exercise testing in detecting arrhythmias. Finally, we made a preliminary attempt to determine whether any electrocardiographic findings were predictive of subsequent mortality.From the Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20014. Presented in part at the 50th Annual Scientific Sessions, American Heart Association, Miami Beach, Florida, November, Methods Patient PopulationOne hundred patients with hypertrophic cardiomyopathy (asymmetric septal hypertrophy (ASH)) were studied after informed consent was secured. ASH was defined echocardiographically by a ven...

The presence of numerous abnormally arranged cardiac muscle cells in the ventricular septum has been considered a characteristic anatomic feature of hypertrophic cardiomyopathy. However, it has been suggested that the ventricular septum of infants with certain congenital cardiac diseases (such as aortic or pulmonic valve atresia) contains disorganized cardiac muscle cells similar to those in patients with hypertrophic cardiomyopathy. To test the validity of this concept and the true specificity and sensitivity of septal disorganization for hypertrophic cardiomyopathy, sections of ventricular septum were obtained at necropsy from 276 patients and the extent of ventricular septal disorganization was determined quantitatively. Disorganization was most marked in infants, children and adults with hypertrophic cardiomyopathy (i.e., present in 95% of 60 patients); the mean area of septum disorganized was 31 ± 3%. Although disorganized cells were present in 64% of 33 infants with aortic or pulmonic valve atresia, these cells occupied extremely small areas of ventricular septum (mean area of septum disorganized 2.8 ± 0.7%; p < 0.001). Furthermore, the minimal septal disorganization present in aortic or pulmonic valve atresia was similar to that found in 91 infants with other congenital heart malformations and in 92 normal fetuses or infants (mean area of septum disorganized was 1.4 ± 0.6 and 0.3 ± 0.1%, respectively). Hence, extensive ventricular septal disorganization is a highly sensitive and specific finding for hypertrophic cardiomyopathy, although small areas of disorganization may occur in infants with other heart diseases, including aortic or pulmonic valve atresia.

SUMMARY Important cardiac manifestations in the idiopathic hypereosinophilic syndrome include mitral regurgitation and peripheral embolization. To determine the anatomic basis of these abnormalities, real-time, wide-angle, two-dimensional echocardiography (2-D echo) was performed in 21 patients with the hypereosinophilic syndrome. Nine patients (43%) had clinical evidence of mitral regurgitation, and each had localized thickening of the posterobasal left ventricular wall behind the posterior mitral leaflet and absent (seven patients) or diminished (two patients) motion of the posterior leaflet. Anatomic observations at operation or necropsy in four patients with mitral regurgitation demonstrated that the echocardiographic abnormalities resulted from posterior mitral leaflet thickening and adherence of the leaflet to the underlying mural endocardium of the posterobasal wall. On 2-D echo, each of the six patients with peripheral emboli had either apical left ventricular echo-dense targets consistent with thrombus or thickening of the posterobasal wall of the left ventricle, and these findings were validated at autopsy or operation in three patients.Hence, in patients with the hypereosinophilic syndrome, 2-D echo is useful in identifying the probable etiology of two important cardiac manifestations. Thickening of the posterobasal wall is usually associated with impairment of posterior mitral leaflet function, resulting in mitral regurgitation. Because the hypereosinophilic syndrome is associated with peripheral embolization, thrombus formation and subsequent endocardial scarring, the noninvasive identification of intracavitary ventricular thrombi may be important.