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 microns, and preparations had low end compliance (SL was 2.23 +/- 0.03 microns during maximal activation). Passive tension (2.1 +/- 1.0 versus 2.4 +/- 0.6 mN/mm2) and maximal Ca(2+)-activated tension (25.9 +/- 9.3 versus 27.8 +/- 6.8 mN/mm2) were similar for control and DCM preparations, respectively. However, the calcium sensitivity of isometric tension was increased in failing myocardium (pCa50 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 pCa50 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.(ABSTRACT TRUNCATED AT 250 WORDS)