Work and oxygen consumption of isolated right ventricular papillary muscle in experimental pulmonary hypertension

Abstract

Right-sided myocardial mechanical efficiency (work output/metabolic energy input) in pulmonary hypertension can be severely reduced. We determined the contribution of intrinsic myocardial determinants of efficiency using papillary muscle preparations from monocrotaline-induced pulmonary hypertensive (MCT-PH) rats. The hypothesis tested was that efficiency is reduced by mitochondrial dysfunction in addition to increased activation heat reported previously. Right ventricular muscle preparations were subjected to 5 Hz sinusoidal length changes at 37°C. Work and suprabasal oxygen consumption ( ${\dot{V}}_{O_2}$ ) were measured before and after cross-bridge inhibition by blebbistatin. Cytosolic cytochrome c concentration, myocyte cross-sectional area, proton permeability of the inner mitochondrial membrane and monoamine oxidase and glucose 6-phosphate dehydrogenase activities and phosphatidylglycerol/cardiolipin contents were determined. Mechanical efficiency ranged from 23% to 11% in control (n = 6) and from 22% to 1% in MCT-PH (n = 15) and correlated with work (r² = 0.68, P < 0.0001) but not with ${\dot{V}}_{O_2}$ (r² = 0.004, P = 0.7919). ${\dot{V}}_{O_2}$ for cross-bridge cycling was proportional to work (r² = 0.56, P = 0.0005). Blebbistatin-resistant ${\dot{V}}_{O_2}$ (r² = 0.32, P = 0.0167) and proton permeability of the mitochondrial inner membrane (r² = 0.36, P = 0.0110) correlated inversely with efficiency. Together, these variables explained the variance of efficiency (coefficient of multiple determination r² = 0.79, P = 0.0001). Cytosolic cytochrome c correlated inversely with work (r² = 0.28, P = 0.0391), but not with efficiency (r² = 0.20, P = 0.0867). Glucose 6-phosphate dehydrogenase, monoamine oxidase and phosphatidylglycerol/cardiolipin increased in the right ventricular wall of MCT-PH but did not correlate with efficiency. Reduced myocardial efficiency in MCT-PH is a result of activation processes and mitochondrial dysfunction. The variance of work and the ratio of activation heat reported previously and blebbistatin-resistant ${\dot{V}}_{O_2}$ are discussed. KEY POINTS: Mechanical efficiency of right ventricular myocardium is reduced in pulmonary hypertension. Increased energy use for activation processes has been demonstrated previously, but the contribution of mitochondrial dysfunction is unknown. Work and oxygen consumption are determined during work loops. Oxygen consumption for activation and cross-bridge cycling confirm the previous heat measurements. Cytosolic cytochrome c concentration, proton permeability of the mitochondrial inner membrane and phosphatidylglycerol/cardiolipin are increased in experimental pulmonary hypertension. Reduced work and mechanical efficiency are related to mitochondrial dysfunction. Upregulation of the pentose phosphate pathway and a potential gap in the energy balance suggest mitochondrial dysfunction in right ventricular overload is a resiult of the excessive production of reactive oxygen species.

Keywords: blebbistatin; cardiolipin; cytochrome c release; mitochondria; monocrotaline; myocardial efficiency; oxygen consumption; papillary muscle; pulmonary hypertension; right-sided heart failure; work loop.