P129Mechanical efficiency of hypertrophied rat papillary muscle related to phosphatidylglycerol/cardiolipin and cytosolic cytochrome c

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Abstract

Hypertrophied hearts are inefficient, i.e. consume more oxygen per unit of myocardial work than normal. The inefficiency may increase myocardial oxygen demand several fold and can be a major contributor to the development of hypoxia in hypertrophied myocytes and reduced cardiac output. We hypothesize that the inefficiency is due to mitochondrial dysfunction.

Papillary muscles were dissected from the right ventricle of control (n = 5) and monocrotaline-induced (60mg/kg sc) pulmonary hypertensive Wistar rats (n = 7). Mechanical efficiency was determined in a 0.038 ml glass chamber from work loops and oxygen uptake during 5 Hz sinusoidal length changes, peak-to-peak amplitude 15% of optimal length, at 37C. The efficiency was 35 (SD 5) % in control and 14 (SD 14) % in hypertrophied preparations (P=0.006). Experiments using blebbistatin to inhibit cross-bridge interaction demonstrated that the inefficiency is not due to sarcomere dysfunction. The right ventricular free wall was used to determine the phosphatidylglycerol/cardiolipin ratio using HPLC mass spectroscopy and cytosolic cytochrome c by quantitative immunohistochemistry. Mechanical efficiency of papillary muscles correlated with phosphatidylglycerol/cardiolipin (r = -0.82, P < 0.01) and cytosolic cytochrome c concentration (r = -0.78, P=0.01).

Cardiolipin is an essential component of the mitochondrial innermembrane - regulating its permeability, respiratory chain complexes and cytochrome c release - and is synthesized from phosphatidylglycerol. Our results suggest that the mechanical inefficiency of hypertrophied myocardium is caused by mitochondrial dysfunction due to a disturbance of cardiolipin metabolism.

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