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

Center for Cardiovascular Research, ¹Department of Physiology and Biophysics, Department of Medicine; and ²Section of Cardiology, University of Illinois, Chicago, Illinois

Submitted 26 May 2006 ; accepted in final form 28 June 2006

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 (F_max), myofilament Ca²⁺ sensitivity (EC₅₀), and cooperativity (Hill coefficient, n_H) parameters. POLVH was associated with a 35% reduction in F_max and 36% increase in EC₅₀. Similarly, MICHF resulted in a 42% reduction in F_max 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 F_max 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.

left ventricle; troponin; phosphorylation; cardiac disease

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