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bioRxiv · 10.1101/2021.12.30.474521

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

van der Laarse, W. J.·Bogaards, S. J. P.·Schalij, I.·Vonk Noordegraaf, A.·Vaz, F. M.·van Groen, D.
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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 was tested that efficiency is reduced by mitochondrial dysfunction in addition to increased activation heat reported previously. Right ventricular (RV) muscle preparations were subjected to 5 Hz sinusoidal length changes at 37{degrees}C. Work and suprabasal oxygen consumption (VO2) 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 (PP IMM), and monoamine oxidase (MAO)-A and glucose 6-phosphate dehydrogenase (G-6-PDH) activities and phosphatidylglycerol (PG) and cardiolipin (CL) 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 VO2 (r2 = 0.004, P = 0.7919). VO2 for cross-bridge cycling was proportional to work (r2 = 0.56, P = 0.0005). Blebbistatin-resistant VO2 (r2 = 0.32, P = 0.0167) and IMM PP (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). G-6-PDH, MAO-A and PG/CL increased in the RV wall of MCT-PH but did not correlate with efficiency. Reduced myocardial efficiency in MCT-PH is due to activation processes and mitochondrial dysfunction. The variance of work and the ratio of activation heat reported previously and blebbistatin-resistant VO2 are discussed. Key pointsO_LIMechanical 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. C_LIO_LIWork and oxygen consumption is determined during work loops. Oxygen consumption for activation and cross-bridge cycling confirm the previous heat measurements. C_LIO_LICytosolic cytochrome c concentration, proton permeability of the mitochondrial inner membrane and phosphatidylglycerol/cardiolipin are increased in experimental pulmonary hypertension. C_LIO_LIMitochondrial dysfunction in right ventricular myocytes is related to reduced work and mechanical efficiency in experimental pulmonary hypertension. C_LIO_LIUpregulation of the pentose phosphate pathway and a potential gap in the energy balance suggest mitochondrial dysfunction in right ventricular overload is due to excessive production of reactive oxygen species. C_LI

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van der Laarse, W. J., Bogaards, S. J. P., Schalij, I., Vonk Noordegraaf, A., Vaz, F. M., van Groen, D.. 2021-12-30. Work and oxygen consumption of isolated right ventricular papillary muscle in experimental pulmonary hypertension. https://doi.org/10.1101/2021.12.30.474521

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