Myocarditis, often initiated by viral infection, may progress to autoimmune inflammatory heart disease, dilated cardiomyopathy and heart failure. Although cardiac myosin is a dominant autoantigen in animal models of myocarditis and is released from the heart during viral myocarditis, the characterization, role and significance of anti-cardiac myosin autoantibodies is poorly defined. In our study, we define the human cardiac myosin epitopes in human myocarditis and cardiomyopathies and establish a mechanism to explain how anti-cardiac myosin autoantibodies may contribute to heart disease. We show that autoantibodies to cardiac myosin in sera from myocarditis and dilated cardiomyopathies in humans targeted primarily epitopes in the S2 hinge region of cardiac myosin. In addition, anti-cardiac myosin antibodies in sera or purified IgG from myocarditis and cardiomyopathy targeted the beta-adrenergic receptor and induced antibody-mediated cAMP-dependent protein kinase A (PKA) cell signaling activity in heart cells. Antibody-mediated PKA activity in sera was abrogated by absorption with anti-human IgG. Antibody-mediated cell signaling of PKA was blocked by antigen-specific inhibition by human cardiac myosin or the beta-adrenergic receptor but not the alpha adrenergic receptor or bovine serum albumin. Propranolol, a beta blocker and inhibitor of the beta-adrenergic receptor pathway also blocked the antibody-mediated signaling of the beta-adrenergic receptor and PKA. The data suggest that IgG antibody against human cardiac myosin reacts with the beta-adrenergic receptor and triggers PKA signaling in heart cells. In-summary, we have identified a new class of crossreactive autoantibodies against human cardiac myosin and the beta-adrenergic receptor in the heart. In addition, we have defined disease specific peptide epitopes in the human cardiac myosin rod S2 region in human myocarditis and cardiomyopathy as well as a mechanistic role of autoantibody in the pathogenesis of disease.
We used multiple linear regression to study predictors of systolic blood pressure response (SBPR), i.e., the increase in pressure above baseline after 3, 6, and 9 min of treadmill exercise, in 4262 men and women. Predictors considered were usual SBP, the difference (
A study of the effect of congenital sporadic hypothyroidism (CSH) on hearing dysfunction was undertaken. Fifteen female and six male CSH patients were evaluated audiometrically. All of these patients had a protein bound iodine quotient (PBI) of less than 4 mg% at the time of diagnosis and were currently under treatment. The patients ranged in age from four and one-half years to 40 years old; eight had sensorineural hearing loss; three had mixed hearing loss; only two had conductive loss and eight had essentially normal hearing. Special audiometric studies were performed including SISI, Rosenberg threshold tone decay, Békésy tracings, and evoked response audiometry (ERA). The SISI and tone decay test results were equivocal. However, statistically abnormal Békésy tracings, with unusually wide excursions were noted. This may be explained by a prolonged nerve conduction time. Evoked response audiometry, which is objective and is independent of cortical neuromuscular function, demonstrated that the unusually wide Békésy excursions were not the result of sluggish motor responses alone. A statistically significant prolonged latency period measured by ERA (without sedation) was found in four patients who were under compensatory hormonal treatment. A parallel preliminary animal experiment was performed in an attempt to confirm these clinical ERA findings. Guinea pigs were induced to hypothyroidism by propylthiouracil. After two months of continuous treatment the ERA was measured. All six guinea pigs had prolonged nerve conduction times at two frequencies. The latency periods were generally 2.5 to 3 times greater than control guinea pigs. A case report is presented of a patient who developed increased hearing loss when replacement therapy was stopped. The hearing levels improved when a euthyroid state was medically reestablished. The results of ERA and Békésy tracings suggest that abnormally prolonged nerve conduction time can play an important role in the hearing dysfunction of CSH patients.
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