Left ventricular myofilament dysfunction in rat experimental hypertrophy and congestive heart failure

Abstract

It is currently unclear whether left ventricular (LV) myofilament function is depressed in experimental LV hypertrophy (LVH) or congestive heart failure (CHF). To address this issue, we studied pressure overload-induced LV hypertrophy (POLVH) and myocardial infarction-elicited congestive heart failure (MICHF) in rats. LV myocytes were isolated from control, POLVH, and MICHF hearts by mechanical homogenization, skinned with Triton, and attached to micropipettes that projected from a sensitive force transducer and high-speed motor. A subset of cells was treated with either unphosphorylated, recombinant cardiac troponin (cTn) or cTn purified from either control or failing ventricles. LV myofilament function was characterized by the force-[Ca2+] relation yielding Ca2+-saturated maximal force (Fmax), myofilament Ca2+ sensitivity (EC50), and cooperativity (Hill coefficient, nH) parameters. POLVH was associated with a 35% reduction in Fmax and 36% increase in EC50. Similarly, MICHF resulted in a 42% reduction in Fmax and a 30% increase in EC50. Incorporation of recombinant cTn or purified control cTn into failing cells restored myofilament Ca2+ sensitivity toward levels observed in control cells. In contrast, integration of cTn purified from failing ventricles into control myocytes increased EC50 to levels observed in failing myocytes. The Fmax parameter was not markedly affected by troponin exchange. cTnI phosphorylation was increased in both POLVH and MICHF left ventricles. We conclude that depressed myofilament Ca2+ sensitivity in experimental LVH and CHF is due, in part, to a decreased functional role of cTn that likely involves augmented phosphorylation of cTnI.