MYOCARDIAL FORCE-FREQUENCY DEFECT IN MITRAL REGURGITATION HEART-FAILURE IS REVERSED BY FORSKOLIN

Background. Postoperative ejection phase parameters and patient surviv al rates for mitral valve replacement surgery are considerably lower t han for similar aortic valve surgery. While chordal transection probab ly is the major contributor to the lowered values, there is also evide nce for decreased preoperative myocardial contractile reserve in mitra l regurgitation patients. This study characterizes abnormalities in th e force-frequency relation that may underlie impaired function of myoc ardium isolated from mitral regurgitation patients with New York Heart Association class II-III heart failure. Methods and Results. Left ven tricular epicardial myocardium was obtained by surgical biopsy during mitral valve replacement surgery in patients with mitral regurgitation heart failure (left ventricular ejection fraction, 0.64+/-0.05) and d uring coronary artery bypass surgery in patients with normal ventricul ar function. The steady-state twitch tension versus frequency relation was measured in myocardial strip preparations (37 degrees C, 12 to 22 8 min(-1)) in the absence and presence of forskolin. Relative to norma l function, peak isometric twitch tension in mitral regurgitation is d epressed by 50% (P<.02) and 74% (P<.003) at contraction frequencies of 60 min(-1) and 168 min(-1), respectively. The slope of the tension-fr equency curve is blunted and its peak is shifted to a lower frequency (mitral regurgitation: 134 min(-1); normal function: 173 min(-1); P<.0 2). The myosin heavy chain concentration did not differ between mitral regurgitation and normal function strips (53+/-4 versus 54+/-4 nmol/g blotted wt). Forskolin (0.5 mu mol/L) completely reversed the tension depression, blunting, and the lowered peak frequency in the mitral re gurgitation preparations. Conclusions. Preoperatively, myocardial tens ion generation in mitral regurgitation patients is severely depressed, and the force frequency curve is blunted and has a negative slope in the exercise range of heart rates. The reversal of these defects by fo rskolin suggests that abnormal excitation-contraction coupling may und erlie the decreased contractile reserve in mitral regurgitation patien ts.