Abstract Rationale 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. Methods After three weeks of subcutaneous injection of Monocrotaline (MCT) or left pneumonectomy within VEGFR inhibition by Sugen-5416 (Su/Pn), rats were randomly assigned to receive miniosmotic pumps containing cAMP or a saline solution. At the 5-week terminal time-point, Ex-vivo optical action potential (AP) mapping, real-time reverse transcription–polymerase chain reaction, immunostaining, morphological and histologic analyses were performed on both models to test the impact of e-cAMP treatment in suppressing ventricular arrhythmias in PAH. Results As expected, PAH diseased rats from both models exhibited a high propensity of inducible ventricular tachycardia. Remarkably, e-cAMP treatment suppressed the incidence of ventricular tachycardia in both models. Examination of the EP substrate revealed action potential duration (APD) prolongation and marked conduction slowing in PAH-diseased animals. These features, however, were significantly reversed by e-cAMP treatment. Moreover, the analysis of alternans showed that e-cAMP treatment prevented the incidence of alternans behavior altogether (P = 0.0291 for e-cAMP-treated MCT vs. MCT group, P = 0.021 for e-cAMP-treated Su/Pn vs. Su/Pn group). PAH-diseased rats displayed right ventricular as well as cardiomyocyte hypertrophy, whereas e-cAMP-treated rats exhibited a significant decrease in hypertrophic remodeling both at the chamber and cellular levels. We also uncovered a marked decrease in myocardial fibrosis by e-cAMP treatment in PAH-diseased rats. Reversal of EP remodeling by e-cAMP was accompanied by decreased cardiac and pulmonary vascular remodeling and by restored cardiac expression of key ion channel transcripts. Conclusion Extracellular cAMP treatment reduces the incidence of ventricular arrhythmias and suppresses pathological EP remodeling. This approach may represent a new therapeutic modality for arrhythmia suppression in PAH patients. This abstract is funded by: NIH
Parajuli et al. (Fri,) studied this question.