MYOSIN HEAVY-CHAIN SYNTHESIS IS INCREASED IN A RABBIT MODEL OF HEART-FAILURE

Chronic ventricular tachycardia (chronic VT) causes left ventricular ( LV) dysfunction and is associated with increased LV wall stress and ne urohormonal activation, but no LV hypertrophy. The mechanisms responsi ble for the lack of myocardial growth with chronic VT are unknown. Acc ordingly, this study examined contractile protein [myosin heavy chain (MHC)] synthesis in a rabbit model of chronic VT. MHC mRNA levels, pro tein concentration, and synthesis rates were examined in control rabbi ts (n = 18) and in rabbits with chronic VT (400 beats/min, 3 wk, n = 1 8). With chronic VT, LV end-diastolic volume increased (8.2 +/- 0.8 vs . 5.3 +/- 0.6 mi, P < 0.05), ejection fraction decreased (12 +/- 3 vs. 38 +/- 4%, P < 0.05) and peak systolic wall stress increased (963 +/- 93 vs. 262 +/- 42 g/cm(2), P < 0.05). Plasma catecholamine and endoth elin levels also increased threefold, and renin activity increased two fold. Despite these stimuli for hypertrophy, LV mass-to-body weight ra tio was unchanged (1.15 +/- 0.07 vs. 1.25 +/- 0.05 g/kg). At the myocy te level, chronic VT caused myocyte lengthening (159.6 +/- 1.8 vs. 121 .6 +/- 1.4 mu m, P < 0.05), but a reduction in myocyte cross-sectional area (199 +/- 6 vs. 249 +/- 7 mu m(2), P < 0.0001), as well as a redu ced velocity of shortening (42.6 +/- 1.6 vs. 74.1 +/- 2.8 mu m/s, P < 0.05). Chronic VT resulted in a significant increase in the rate of MH C synthesis, but paradoxically, there was no change in LV MHC content. Despite increased MHC synthesis, relative levels of MHC mRNA were not increased in chronic VT (2.79 +/- 0.23 vs. 2.44 +/- 0.20 AU, relative to glyceraldehyde-3-phosphate dehydrogenase), suggesting an increase in MHC translational efficiency. These unique findings suggest acceler ated degradative processes must contribute to the failure of myocardia l growth in this model of LV dysfunction in which increased LV wall st ress, neurohormonal activation, and increased protein synthesis occurr ed.