Clinical symptoms of right ventricular failure in experimental chronic pressure load are associated with progressive diastolic dysfunction

Background: Right ventricular failure (RVF) due to pressure load is a major cause of death in congenital heart diseases and pulmonary hypertension. The mechanisms of RVF are unknown. We used an experimental approach based upon clinical signs of RVF to delineate functional and biological processes associated with RVF.

Methods and results: Wistar rats were subjected to a pulmonary artery banding (PAB n = 12) or sham surgery (CON, n = 7). After 52 5 days, 5/12 PAB rats developed clinical symptoms of RVF (inactivity, ruffled fur, dyspnea, ascites) necessitating termination (PAR + CF). We compared these to PAR rats with RVF without clinical symptoms (PAB). PAB resulted in reduced cardiac output, RV stroke volume, TAPSE, and increased end diastolic pressure (all p <0.05 vs. CON) in all rats, but PAB + CF rats were significantly more affected than PAR, despite similar pressure load (p = ns). Pressure-volume analysis showed enhanced contractility (end systolic elastance) in PAB and PAR + CF, but diastolic function (end diastolic elastance, end diastolic pressure) deteriorated especially in PAB + CF. In PAB + CF capillary density was lower than in PAR. Gene-array analysis revealed down-regulation of both fatty acid oxidation and carbohydrate metabolism in PAB + CF.

Conclusion: Chronic PAR led to different degrees of RVF, with half of the rats developing severe clinical symptoms of RVF, associated with progressive deterioration of diastolic function, hypoxia-prone myocardium, increased response to oxidative stress and suppressed myocardial metabolism. This model represents clinical RVF and allows for unraveling of mechanisms involved in the progression from RV adaptation to RV failure and the effect of intervention on these mechanisms. (C) 2014 Elsevier Ltd. All rights reserved.