CYTOSKELETAL ROLE IN THE TRANSITION FROM COMPENSATED TO DECOMPENSATEDHYPERTROPHY DURING ADULT CANINE LEFT-VENTRICULAR PRESSURE OVERLOADING

Increased microtubule density causes cardiocyte contractile dysfunctio n in right ventricular (RV) pressure overload hypertrophy, and these l inked phenotypic and contractile abnormalities persist and progress du ring the transition to failure. Although more severe in cells from fai ling than hypertrophied RVs, the mechanical defects are normalized in each case by microtubule depolymerization. To define the role of incre ased microtubule density in left ventricular (LV) pressure-overload hy pertrophy and failure, in a given LV we examined ventricular mechanics , sarcomere mechanics, and free tubulin and microtubule levels in cont rol dogs and in dogs with aortic stenosis both with LV hypertrophy alo ne and with initially compensated hypertrophy that had progressed to L V muscle failure. In comparing initial values with those at study 8 we eks later, dogs with hypertrophy alone had a very substantial increase in LV mass but preservation of a normal ejection fraction and mean sy stolic wall stress. Dogs with hypertrophy and associated failure had a substantial but lesser increase in LV mass and a reduction in ejectio n fraction, as well as a marked increase in mean systolic wall stress. Cardiocyte contractile function was equivalent, and unaffected by mic rotubule depolymerization, in cells from control LVs and those with co mpensated hypertrophy. In contrast, cardiocyte contractile function in cells from failing LVs was quite depressed but was normalized by micr otubule depolymerization. Microtubules were increased only in failing LVs. These contractile and cytoskeletal changes, when assayed longitud inally in a given dog by biopsy, appeared in failing ventricles only w hen wall stress began to increase and function began to decrease. Thus , the microtubule-based cardiocyte contractile dysfunction characteris tic of pressure-hypertrophied myocardium, originally described in the RV, obtains equally in the LV but is shown here to have a specific ass ociation with increased wall stress.