Form Of Familial Hypertrophic Cardiomyopathy Research Articles

Apical hypertrophic cardiomyopathy and hepatitis C virus infection.

The familial form of hypertrophic cardiomyopathy (HCM) is attributed to mutations in the genes for contractile proteins, but the etiology of non-familial form remains unknown. This study was designed to examine the clinical features, histopathologic changes, and hepatitis C virus (HCV) genomes in patients with HCM associated with HCV infection. Anti-HCV antibody was present in the sera of 9 of 65 patients (13.8%) with HCM versus 2.41% in a control population of voluntary blood donors in Japan, a statistically significant difference (p<0.0001). Among these 9 patients, 6 had ace-of-spades-shaped deformities of the left ventricle with apical hypertrophy. Myocardial fibrosis was found in all patients, and mild cellular infiltration was observed in 5 patients. Type 1b HCV RNA was present in the sera of 5 of the 9 patients. The copy number of HCV was 5.5x10(3)-8.6x10(5) genomes/ml serum, and multiple clones of HCV were detected in the sera of each patient by an analysis of the hypervariable regions using fluorescent single-strand conformation polymorphism. Positive strands of HCV were found in the hearts of 5 patients, and negative strands in the hearts of 2 patients. A high prevalence of HCV infection was found in patients with HCM, particularly of the apical variety, suggesting that HCV is an important causal agent in the pathogenesis of the disease.

Diastolic dysfunction and altered energetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy.

An arginine to glutamine missense mutation at position 403 of the beta-cardiac myosin heavy chain causes familial hypertrophic cardiomyopathy. Here we study mice which have this same missense mutation (alphaMHC403/+) using an isolated, isovolumic heart preparation where cardiac performance is measured simultaneously with cardiac energetics using 31P nuclear magnetic resonance spectroscopy. We observed three major alterations in the physiology and bioenergetics of the alphaMHC403/+ mouse hearts. First, while there was no evidence of systolic dysfunction, diastolic function was impaired during inotropic stimulation. Diastolic dysfunction was manifest as both a decreased rate of left ventricular relaxation and an increase in end-diastolic pressure. Second, under baseline conditions alphaMHC403/+ hearts had lower phosphocreatine and increased inorganic phosphate contents resulting in a decrease in the calculated value for the free energy released from ATP hydrolysis. Third, hearts from alphaMHC403/+ hearts that were studied unpaced responded to increased perfusate calcium by decreasing heart rate approximately twice as much as wild types. We conclude that hearts from alphaMHC403/+ mice demonstrate work load-dependent diastolic dysfunction resembling the human form of familial hypertrophic cardiomyopathy. Changes in high-energy phosphate content suggest that an energy-requiring process may contribute to the observed diastolic dysfunction.

A molecular map of the interactions between titin and myosin-binding protein C. Implications for sarcomeric assembly in familial hypertrophic cardiomyopathy.

The thick filaments of vertebrate striated muscles contain with myosin a number of accessory proteins of the intracellular immunoglobulin superfamily, which are localized in a distinct pattern of stripes 43 nm apart. The specific localization of these proteins is believed to be due partly to their interaction with the giant muscle protein titin (also called connectin), which spans the entire sarcomere and may act as a molecular ruler. We have used recombinant fragments of titin covering the thick filament region to investigate their interaction with myosin-binding protein C (MyBP-C) from skeletal and cardiac muscle. The interaction of titin and MYBP-C is directed by a subset of titin immunoglobulin domains that are specific for the C-region of the thick filament, supporting the ruler hypothesis for the myosin-binding proteins. The interaction of recombinant titin with overlapping fragments of human cardiac MyBP-C maps the titin-binding site within the C-terminal region, which is deleted in patients suffering from the chromosome-11-associated form of familial hypertrophic cardiomyopathy. This disorder is therefore likely to be the result of thick-filament misassembly by abolishing the ternary interaction of titin, myosin and MyBP-C.

An advanced form of familial hypertrophic cardiomyopathy showing massive myocardial fibrosis with intramural small arterial thickening An autopsy case.

An autopsy case of an advanced form of hypertrophic cardiomyopathy (HCM) showing marked fibrosis with intramural small arterial abnormalities is presented in this report. A 52-year-old woman, who had a positive family history of HCM, was admitted because of palpitations. The chest roentgenogram showed a mildly enlarged cardiac silhouette and the electrocardiogram revealed abnormal Q waves and R wave and T wave abnormalities. The echocardiogram revealed hypokinesis with thinning of the interventricular septum and the anterior wall of the left ventricle. Percutaneous right ventricular endomyocardial biopsies demonstrated moderate interstitial fibrosis with small arterial thickening. At necropsy, the anterior and posterior walls of the left ventricle and the interventricular septum were markedly thinned and showed a massive transmural fibrosis. Moreover, the intramural small arteries, 50-300 microns in diameter, showed marked intimal and medial hypertrophy with proliferation of elastic fibers and smooth muscle cells. From these findings, it is suggested that this was originally a case of HCM which progressed to a decompensated stage because of the abnormal intramural small arteries. The significance of small arterial lesions in HCM is discussed.