α1A-Adrenergic Receptor-Directed Autoimmunity Induces Left Ventricular Damage and Diastolic Dysfunction in Rats.

Background: Agonistic autoantibodies to the α₁-adrenergic receptor occur in nearly half of patients with refractory hypertension; however, their relevance is uncertain. Methods/Principal Findings: We immunized Lewis rats with the second extracellular-loop peptides of the human α_1A-adrenergic receptor and maintained them for one year. α_1A-adrenergic antibodies (α_1A-AR-AB) were monitored with a neonatal cardiomyocyte contraction assay by ELISA, and by ERK1/2 phosphorylation in human α_1A-adrenergic receptor transfected Chinese hamster ovary cells. The rats were followed with radiotelemetric blood pressure measurements and echocardiography. At 12 months, the left ventricles of immunized rats had greater wall thickness than control rats. The fractional shortening and dp/dt_max demonstrated preserved systolic function. A decreased E/A ratio in immunized rats indicated a diastolic dysfunction. Invasive hemodynamics revealed increased left ventricular end-diastolic pressures and decreased dp/dt_min. Mean diameter of cardiomyocytes showed hypertrophy in immunized rats. Long-term blood pressure values and heart rates were not different. Genes encoding sarcomeric proteins, collagens, extracellular matrix proteins, calcium regulating proteins, and proteins of energy metabolism in immunized rat hearts were upregulated, compared to controls. Furthermore, fibrosis was present in immunized hearts, but not in control hearts. A subset of immunized and control rats was infused with angiotensin (Ang) II. The stressor raised blood pressure to a greater degree and led to more cardiac fibrosis in immunized, than in control rats. Conclusions/Significance: We show that α_1A-AR-AB cause diastolic dysfunction independent of hypertension, and can increase the sensitivity to Ang II. We suggest that α_1A-AR-AB could contribute to cardiovascular endorgan damage. [ABSTRACT FROM AUTHOR]