Michael J. Sole

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.

Sleep deprivation, shift work, and jet lag all disrupt normal biological rhythms and have major impacts on health; however, circadian disorganization has never been shown as a causal risk factor in organ disease. We now demonstrate devastating effects of rhythm disorganization on cardiovascular and renal integrity and that interventions based on circadian principles prevent disease pathology caused by a short-period mutation (tau) of the circadian system in hamsters. The point mutation in the circadian regulatory gene, casein kinase-1epsilon, produces early onset circadian entrainment with fragmented patterns of behavior in +/tau heterozygotes. Animals die at a younger age with cardiomyopathy, extensive fibrosis, and severely impaired contractility; they also have severe renal disease with proteinuria, tubular dilation, and cellular apoptosis. On light cycles appropriate for their genotype (22 h), cyclic behavioral patterns are normalized, cardiorenal phenotype is reversed, and hearts and kidneys show normal structure and function. Moreover, hypertrophy does not develop in animals whose suprachiasmatic nucleus was ablated as young adults. Circadian organization therefore is critical for normal health and longevity, whereas chronic global asynchrony is implicated in the etiology of cardiac and renal disease.

Recent molecular studies have suggested that viral myocarditis frequently underlies human congestive cardiomyopathy; however, only moderately sensitive and specific techniques were used. Polymerase chain reaction (PCR) gene amplification is a sensitive, specific technique ideally suited for the diagnosis of viral disease in small tissue samples where low copy numbers of the viral genome may be present. Using PCR and high stringency condition, we screened biopsies taken from 48 patients with clinically suspected myocarditis or dilated cardiomyopathy. Five patients demonstrated positive enteroviral signals by PCR; two of them had myocarditis by pathology, whereas the other three had changes consistent with cardiomyopathy. Four other patients had myocarditis diagnosed by pathology from 3 months to 1 year earlier but were now negative by both PCR and pathology. Both pathology and PCR were negative for active myocarditis in all other patients. Ventricular samples taken from left ventricular myectomy in four additional patients with hypertrophic cardiomyopathy, normal human ventricle samples, and uninfected monkey kidney cells were also negative by PCR. This study supports a link between viral infection and dilated cardiomyopathy in some patients. PCR gene amplification provides a new diagnostic approach to patients with suspected myocarditis.

Cardiac arrhythmias, myocardial necrosis and ECG abnormalities in stroke may result from abnormally high levels of sympathetic activity. To examine this possibility, plasma norepinephrine, epinephrine and dopamine were measured in 74 patients with cerebral infarction, 18 with transient ischemic attacks and 33 non-stroke controls. Mean norepinephrine, epinephrine and dopamine values (pg/ml) in cerebral infarction (433.2, 81.6, 75.6 were higher (p less than 0.01) than in controls (281.1, 60.1, 40.5, respectively). Transient ischemic attacks produced values intermediate to these two groups (391.3, 80.9, 54.9). The elevated catecholamine concentrations in cerebral infarction could not be explained by differences in age, blood pressure, heart rate, stress, type or severity of stroke. The high plasma norepinephrine in the stroke group is consistent with an increase in peripheral sympathetic activity which could produce the cardiac abnormalities of cerebral infarction.