Cytoskeletal role in the contractile dysfunction of cardiocytes from hypertrophied and failing right ventricular myocardium.

We have shown on the levels of the sarcomere and the cardiocyte that increased microtubule density accounts, to a remarkable degree, for the contractile dysfunction characteristic of pressure-overload right ventricular hypertrophy. In this study, we have asked whether these linked phenotypic and contractile abnormalities persist during the transition to right heart failure in this model and whether, following this transition, microtubule depolymerization remains effective in restoring normal cellular contractile function when characterized in terms of sarcomere mechanics. The feline right ventricle was pressure overloaded by pulmonary artery banding. The quantity of microtubules was estimated from immunoblots and immunofluorescent micrographs, and their mechanical effects were assessed by measuring sarcomere motion during microtubule depolymerization. These measurements were made in control cats and in operated cats having right ventricular hypertrophy alone or hypertrophy with associated right heart failure; the left ventricle from each heart served as a normally loaded same-animal control. We show here both that alterations in microtubule density and sarcomere mechanics are a persistent and progressive feature of the hypertrophied and then failing cat right ventricle and that the ratio of polymerized to free tubulin is selectively increased in the failing right ventricle. The mechanical defect, though more severe in failing than in hypertrophied right ventricles, was normalized by microtubule depolymerization. Because we find persistent and progressive increases both in microtubules and in the functional consequence of aberrant sarcomere mechanics during the transition from hypertrophy to failure when right ventricular pressure overloading is severe, this cytoskeletal abnormality may well contribute to the contractile dysfunction characteristic of right heart failure in this model.