Extracellular-cAMP suppresses pulmonary arterial hypertension-induced ventricular arrhythmias.

Abstract

Pulmonary Arterial Hypertension (PAH), a major cause of right ventricular failure, is associated with a high 5-year mortality rate. Arrhythmias account for a significant proportion of morbidity and mortality in PAH patients. Hence, there is a critical need for new therapies to effectively treat PAH-related cardiac arrhythmias. The purpose of this study was to evaluate the efficacy of extracellular cyclic adenosine monophosphate (e-cAMP) treatment in reversing pathophysiological electrophysiological (EP) remodeling and arrhythmia propensity caused by PAH. Ex-vivo optical action potential (AP) mapping, real-time reverse transcription-polymerase chain reaction, immunostaining, morphological and histologic analyses were performed on two different models of pulmonary hypertension (Monocrotaline and Sugen/pneumonectomy) to test the impact of e-cAMP treatment in suppressing ventricular arrhythmias in PAH. PAH diseased rats from both models exhibited a high propensity of inducible ventricular tachycardia (VT). Remarkably, e-cAMP treatment suppressed the incidence of VT in both models. Examination of the EP substrate revealed action potential duration prolongation and marked conduction slowing in PAH-diseased animals. These features, however, were significantly reversed by e-cAMP treatment. Moreover, e-cAMP reversed the development of AP alternans in PAH. Extracellular cAMP-treated rats exhibited a significant decrease in myocardial fibrosis and hypertrophic remodeling. Reversal of EP remodeling by e-cAMP was accompanied by decreased pulmonary vascular remodeling and by restored cardiac expression of key ion channel transcripts. Extracellular cAMP treatment reduces the incidence of ventricular arrhythmias and suppresses pathological EP remodeling by restoring cardiac and pulmonary vascular remodeling. This approach may represent a new therapeutic modality for arrhythmia suppression in PAH patients.