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 permeabilized myocardium from a canine model of dilated cardiomyopathy (DCM) produced by chronic rapid pacing. In the initial series of experiments, 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. Isometric tension-pCa relations were measured by using mechanically disrupted and permeabilized myocyte-sized preparations obtained from left ventricular biopsies before (n=11) and after (n=10) chronic rapid pacing-induced 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 during 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, respectively. However, the calcium sensitivity of isometric tension was increased in failing myocardium (pCa(50) 5.95+/-0.11 [DCM] versus 5.83+/-0.10 [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 relations in the two groups were not significantly different after protein kinase A treatment. These data suggest that the increased calcium sensitivity in DCM may be due at least in part to a reduction of the adrenergically mediated phosphorylation of myofibrillar regulatory proteins. This increased calcium sensitivity of isometric tension may partially compensate for decreases in systolic calcium transients in DCM but may also contribute to the diastolic dysfunction that accompanies this condition.