CALCIUM SENSITIVITY OF ISOMETRIC TENSION IS INCREASED IN CANINE EXPERIMENTAL HEART-FAILURE

To examine the role of alterations in myofibrillar function in chronic heart failure, we determined isometric tension-pCa relations in perme abilized myocardium from a canine model of dilated cardiomyopathy (DCM ) produced by chronic rapid pacing. In the initial series of experimen ts, seven dogs were paced at 250 beats per minute for 28.9+/-7.0 days, resulting in ventricular dilatation and reduced ejection fractions by echocardiography and elevated intracardiac filling pressures. Isometr ic tension-pCa relations were measured by using mechanically disrupted and permeabilized myocyte-sized preparations obtained from left ventr icular biopsies before (n=11) and after (n=10) chronic rapid pacing-in duced heart failure. Resting sarcomere length (SL) was set at 2.35 mu m, and preparations had low end compliance (SL was 2.23+/-0.03 mu m du ring maximal activation). Passive tension (2.1+/-1.0 versus 2.4+/-0.6 mN/mm(2)) and maximal Ca2+-activated tension (25.9+/-9.3 versus 27.8+/ -6.8 mN/mm(2)) were similar for control and DCM preparations, respecti vely. However, the calcium sensitivity of isometric tension was increa sed in failing myocardium (pCa(50) 5.95+/-0.11 [DCM] versus 5.83+/-0.1 0 [control], P=.001). Treatment of myofibrillar preparations with the catalytic subunit of protein kinase A decreased calcium sensitivity of tension to a greater degree in failing preparations (shift of pCa(50) from 6.04+/-0.06 to 5.75+/-0.09, n=7) than in nonfailing preparations (5.91+/-0.08 to 5.74+/-0.07, n=8), and isometric tension-pCa relation s in the two groups were not significantly different after protein kin ase A treatment. These data suggest that the increased calcium sensiti vity in DCM may be due at least in part to a reduction of the adrenerg ically mediated phosphorylation of myofibrillar regulatory proteins. T his increased calcium sensitivity of isometric tension may partially c ompensate for decreases in systolic calcium transients in DCM but may also contribute to the diastolic dysfunction that accompanies this con dition.