Microtubule depolymerization normalizes in vivo myocardial contractile function in dogs with pressure-overload left ventricular hypertrophy

Background-Because initially compensatory myocardial hypertrophy in respons e to pressure overloading may eventually decompensate to myocardial failure , mechanisms responsible for this transition have long been sought. One suc h mechanism established in vitro is densification of the cellular microtubu le network, which imposes a viscous load that inhibits cardiocyte contracti on. Methods and Results-In the present study, we extended this in vitro finding to the in vivo level and tested the hypothesis that this cytoskeletal abno rmality is important in the in vivo contractile dysfunction that occurs in experimental aortic stenosis in the adult dog. In 8 dogs in which gradual s tenosis of the ascending aorta had caused severe left ventricular (LV) pres sure overloading (gradient, 152+/-16 mm Hg) with contractile dysfunction, L V function was measured at baseline and 1 hour after the intravenous admini stration of colchicine. Cardiocytes obtained by biopsy before and after in vivo colchicine administration were examined in tandem. Microtubule depolym erization restored LV contractile function both in vivo and in vitro. Conclusions-These and additional corroborative data show that increased car diocyte microtubule network density is an important mechanism for the ventr icular contractile dysfunction that develops in large mammals with adult-on set pressure-overload-induced cardiac hypertrophy.