guanosine-monophosphate and Cardiomyopathies

Treatment for chronic hepatitis C virus (HCV) infection is evolving from interferon (IFN)-based therapy to direct-acting antiviral (DAA) agents, yet some safety concerns have arisen involving cardiac toxicity. In this study, we sought to better understand the potential off-target toxicities of new DAAs. We retrospectively evaluated the clinical and pathological findings of the sentinel case in a phase II study that led to clinical development discontinuation for BMS-986094, an HCV nucleotide polymerase (nonstructural 5B) inhibitor. We also report on outcomes from other patients in the same study, including electrocardiogram changes, cardiovascular biomarkers, and transthoracic echocardiograms. Thirty-four patients received IFN-free BMS-986094 regimens. Six patients had left ventricular ejection fractions (LVEFs) <30%, 8 had LVEFs 30%-50%, and 11 required hospitalization for suspected cardiotoxicity. Of the patients with LVEF <50%, 6 had normalization of systolic function after a median of 20 days. T-wave inversions were the most sensitive predictor of LVEF dysfunction. B-type natriuretic peptide levels increased over time and correlated with the degree of LVEF dysfunction. Pathological analysis of cardiac tissue revealed severe myocyte damage with elongated myofibrils without gross necrosis. These findings were consistent with some results of recent primate studies that were conducted to further investigate the potential mechanisms of BMS-986094 toxicity.. A novel nucleotide analog polymerase inhibitor developed for HCV treatment may cause a toxic cardiomyopathy. Ongoing surveillance of DAAs for cardiotoxicities may be beneficial, especially among patients at higher risk for cardiovascular disease.

Topics: Adult; Aged; Antiviral Agents; Cardiomyopathies; Cohort Studies; Female; Follow-Up Studies; Guanosine Monophosphate; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Protease Inhibitors; Retrospective Studies; Risk Assessment

Cardiac hypertrophy is a major risk factor for morbidity and mortality in a number of cardiovascular diseases. Consequently, the signaling pathways that inhibit cardiac hypertrophy are currently receiving much interest. Among them, nitric oxide (NO), signaling via cGMP and cGMP-dependent protein kinase I, has been recognized as a negative regulator of cardiac hypertrophy. The present study investigated the in-vivo effect of sildenafil as a phosphodiestrase-5A (PDE-5A) inhibitor on the hypertrophic response of rat heart to isoproterenol and the relation of this effect to the level of myocardial cGMP and integrity of the constitutive nitric oxide synthase (cNOS) activity.. The results showed that daily intraperitoneal administration of sildenafil per se for 10 days was without noticeable adverse effects on survival or myocardium. Conversely, daily subcutaneous administration of isoproterenol for 10 days caused significant myocardial hypertrophy, cell injury and decline in survival. When sildenafil was injected daily, one hour before isoproterenol, survival was significantly improved and the myocardium didn't show significant hypertrophy or cell injury. Interestingly, sildenafil was accompanied by significant rise in myocardial cGMP level, a parameter which was found in the present study to possess a significant negative correlation with cardiac hypertrophy and leak of cardiac troponin T into serum. At the same time, cGMP was found to possess a positive correlation with myocardial creatine kinase activity that reflects the efficiency of the energy utilization processes in the myocardium. However, in rats given Nomega-nitro-L-arginine (L-NNA) as a competitive inhibitor of cNOS, sildenafil failed to show any favorable effect on survival or the myocardial injury parameters used to assess isoproterenol-induced injury.. The present study suggests that increased cardiac cGMP level by sildenafil have a cardioprotective effect probably through acting as a post-receptor negative regulator of cardiac sympathetic responsiveness. Integrity of NOS function was an essential prerequisite for sildenafil's mediated cardioprotection encountered in the present study.

Topics: Adrenergic beta-Agonists; Animals; Cardiomyopathies; Creatine Kinase; Guanosine Monophosphate; Isoproterenol; Linear Models; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Sildenafil Citrate; Sulfones; Troponin T