Impairment of Diastolic Function by Lack of Frequency-Dependent Myofilament Desensitization in Rabbit Right Ventricular Hypertrophy

Background—Ventricular hypertrophy is a physiological response to pressure overload that, if left untreated, can ultimately result in ventricular dysfunction, including diastolic dysfunction. The aim of this study was to test the hypothesis that frequency-dependent myofilament desensitization, a physiological response of healthy myocardium, is altered in hypertrophied myocardium. Methods and Results—New Zealand white rabbits underwent a pulmonary artery banding procedure to induce pressure overload. After 10 weeks, the animals were euthanized, hearts removed, and suitable trabeculae harvested from the free wall of the right ventricle. Twitch contractions, calibrated bis-fura-2 calcium transients, and myofilament calcium sensitivity (potassium contractures) were measured at frequencies of 1, 2, 3, and 4 Hz. The force frequency response, relaxation frequency response, and calcium frequency relationships were significantly blunted, and diastolic tension significantly increased with frequency in the pulmonary artery banding rabbits compared with sham-operated animals. Myofilament calcium sensitivity was virtually identical at 1 Hz in the treatment versus sham group (pCa 6.11 0.03 versus 6.11 0.06), but the frequency-dependent desensitization that takes place in the sham group ( pCa 0.14 0.06, P 0.05) was not observed in the pulmonary artery banding animals ( pCa 0.02 0.05). Analysis of myofilament protein phosphorylation revealed that the normally observed frequency-dependent phosphorylation of troponin-I is lost in pulmonary artery banding rabbits. Conclusions—The frequency-dependent myofilament desensitization is significantly impaired in right ventricular hypertrophy and contributes to the frequency-dependent elevation of diastolic tension in hypertrophy. (Circ Heart Fail. 2009;2:472-481.)