Improved exercise tolerance after losartan and enalapril in heart failure: Correlation with changes in skeletal muscle myosin heavy chain composition

Background - In congestive heart failure, fatigue-resistant, oxidative, slow type I fibers are decreased in leg skeletal muscle, contributing to exercise capacity (EC) limitation. The mechanisms by which ACE inhibitors and AII antagonists improve EC is still unclear. We tested the hypothesis that improvement in EC is related to changes in skeletal muscle composition toward type I fibers. Methods and Results - Eight patients with congestive heart failure, NYHA classes I through IV, were treated for 6 months with enalapril (E) 20 mg/d, and another 8 with losartan (L) 50 mg/d. EC was assessed with maximal cardiopulmonary exercise testing at baseline and after treatment. Myosin heavy chain (MHC) composition of the gastrocnemius was studied after electrophoretic separation of slow MHC1, fast oxidative MHC2a, and fast glycolytic MHC2b isoforms from needle microbiopsies obtained at baseline and after 6 months. EC improved in both groups. Peak V̇O₂ increased from 21.0±4.7 to 27.6±4.3 mL · kg^-1 · min^-1 (P=0.011) in the L group and from 17.5±5.0 to 25.0±5.5 mL · kg^-1 · min^-1 (P=0.014) in the E group. Similarly, ventilatory threshold changed from 15.0±4.0 to 19.9±4.9 mL (P=0.049) with L and from 12.0±1.9 to 15.4±3.5 mL (P=0.039) with E. MCH1 increased from 61.2±11.2% to 75.4±7.6% with L (P=0.012) and from 60.6±13.1% to 80.1±10.9% (P=0.006) with E. Similarly, MHC2a decreased from 21.20±9.5% to 12.9±4.4% (P=0.05) with L and from 19.9±7.8% to 11.8±7.9% (P=0.06) with E. MHC2b changed from 17.5±6.5% to 11.7±5.2% (P=0.07) with L and from 19.5±6.4% to 8.1±4.6% (P=0.0015) with E. There was a significant correlation between net changes in MHC1 and absolute changes in peak V̇O₂ (r²=0.29, P=0.029) and a trend to significance for MHC2a and 2b. Conclusions - Six months' treatment with L and with E produces an improvement in EC of similar magnitude. These changes are accompanied by a reshift of MHCs of leg skeletal muscle toward the slow, more fatigue-resistant isoforms. Magnitude of MHC1 changes correlates with the net peak V̇O₂ gain, which suggests that improved EC may be caused by favorable biochemical changes occurring in the skeletal muscle.