SIMVASTATIN TREATMENT ATTENUATES INCREASED RESPIRATORY VARIABILITY AND APNEA/HYPOPNEA INDEX IN RATS WITH CHRONIC HEART FAILURE RR

摘要

Cheyne-Stokes respiration (CSR) and cardiac arrhythmias are associated with increased morbidity and mortality in patients with congestive heart failure (CHF). Enhanced carotid body chemoreflex (CBC) sensitivity is associated with these abnormalities in CHF. Reduced carotid body nitric oxide and nitric oxide synthase (NOS) levels play an important role in the enhanced CBC. In other disease models, Simvastatin (statin) treatment increases endothelial NOS (eNOS) in part by increasing Kruppel like Factor 2 (KLF2) expression. We hypothesized that statin treatment would ameliorate enhanced CBC sensitivity as well as increased respiratory variability (RV), apnea/hypopnea index (AHI), and arrhythmia index (AI), in a rodent model of CHF. Resting breathing pattern, cardiac rhythm, and the ventilatory and carotid body (CB) chemoreceptor afferent responses to hypoxia (CBC) were assessed in rats with CHF induced by coronary ligation. CHF was associated with enhanced ventilatory and CB afferent responses to hypoxia as well as increased RV, AHI, and AI. Statin treatment prevented the increases in CBC sensitivity and the concomitant increases in RV, AHI, and AI. KLF2 and eNOS protein were decreased in the CB and nucleus tractus solitarii (NTS) of CHF animals and statin treatment increased the expression of these proteins. Our findings demonstrate that the increased CBC sensitivity, respiratory instability and cardiac arrhythmias observed in CHF are ameliorated by statin treatment and suggest that statins may be an effective treatment for CSR and arrhythmias in patient populations with high chemoreflex sensitivity.