ROLE OF MICROTUBULES IN CONTRACTILE DYSFUNCTION OF HYPERTROPHIED CARDIOCYTES

Cardiac hypertrophy in response to systolic pressure overloading frequ ently results in contractile dysfunction, the cause for which has been unknown. Since, in contrast, the same degree and duration of hypertro phy in response to systolic volume overloading does not result in cont ractile dysfunction, we postulated that the contractile dysfunction of pressure hypertrophied myocardium might result from a direct effect o f stress as opposed to strain loading on an intracellular structure of the hypertrophied cardiocyte. The specific hypothesis tested here is that the microtubule component of the cytoskeleton is such an intracel lular structure, which, forming in excess, impedes sarcomere motion. T he feline right ventricle was either pressure overloaded by pulmonary artery banding or volume overloaded by atrial septotomy. The quantity of microtubules was estimated from immunoblots and immunofluorescent m icrographs, and their mechanical effects were assessed by measuring sa rcomere motion during microtubule depolymerization. We show here that stress loading increases the microtubule component of the cardiac musc le cell cytoskeleton; this apparently is responsible for the entirety of the cellular contractile dysfunction seen in our model of pressure- hypertrophied myocardium. No such effects were seen in right ventricul ar cardiocytes from normal or volume-overloaded cats or in left ventri cular cardiocytes from any group of cats. Importantly, the linked micr otubule and contractile abnormalities are persistent and thus may be f ound to have significance for the deterioration of initially compensat ory cardiac hypertrophy into the congestive heart failure state.