Effect of exercise training and carvedilol treatment on cardiac function and structure in mice with sympathetic hyperactivity-induced heart failure

Abstract

The present investigation was undertaken to study the effect of β-blockers and exercise training on cardiac structure and function, respectively, as well as overall functional capacity in a genetic model of sympathetic hyperactivity-induced heart failure in mice (α 2A /α 2C ArKO). α 2A /α 2C ArKO and their wild-type controls were studied for 2 months, from 3 to 5 months of age. Mice were randomly assigned to control (N = 45), carvedilol-treated (N = 29) or exercise-trained (N = 33) groups. Eight weeks of carvedilol treatment (38 mg/kg per day by gavage) or exercise training (swimming sessions of 60 min, 5 days/week) were performed. Exercise capacity was estimated using a graded treadmill protocol and HR was measured by tail cuff. Fractional shortening was evaluated by echocardiography. Cardiac structure and gastrocnemius capillary density were evaluated by light microscopy. At 3 months of age, no significant difference in fractional shortening or exercise capacity was observed between wild-type and α 2A / α 2C ArKO mice. At 5 months of age, all α 2A /α 2C ArKO mice displayed exercise intolerance and baseline tachycardia associated with reduced fractional shortening and gastrocnemius capillary rarefaction. In addition, α 2A /α 2C ArKO mice presented cardiac myocyte hypertrophy and ventricular fibrosis. Exercise training and carvedilol similarly improved fractional shortening in α 2A / α 2C ArKO mice. The effect of exercise training was mainly associated with improved exercise tolerance and increased gastrocnemius capillary density while β-blocker therapy reduced cardiac myocyte dimension and ventricular collagen to wildtype control levels. Taken together, these data provide direct evidence for the respective beneficial effects of exercise training and carvedilol in α 2A /α 2C ArKO mice preventing cardiac dysfunction. The different mechanisms associated with beneficial effects of exercise training and carvedilol suggest future studies associating both therapies.

Aerobic exercise training in heart failure: impact on sympathetic hyperactivity and cardiac and skeletal muscle function

“…In this context, we have demonstrated an additional reduction in muscular sympathetic nerve activity by exercise training in HF patients optimized with carvedilol, a third generation β-blocker (β 1 -and β 2 -blockade) with an α-blockade and vasodilatory effect (14). Additionally, while β-blocker therapy had no impact on exercise capacity in humans or animals with HF (6,9), a β-blocker combined with exercise training improved exercise capacity (14,19).…”

“…These effects include reduction of sympathetic outflow in exercised humans (14,15) and animals (16)(17)(18) with HF. The sympathetic toxicity of cardiac (17)(18)(19)(20)(21) and skeletal (22)(23)(24) muscles in HF is also reduced by exercise training. Since morbidity and mortality in cardiovascular disease are often associated with increases of sympathetic nerve activity, exercise training becomes a potent nonpharmacological strategy for HF therapy.…”

Associação de betabloqueadores e treinamento físico na insuficiência cardíaca de camundongos

“…The treatments were carried out by gavage, and the doses used were previously tested in order to adjust them and to obtain equipotent doses for reducing the heart rate of animals, which corresponded to 135 mg/kg and 68 mg/kg for metoprolol and carvedilol, respectively 20,21 .…”

“…By using the pressure pulses recorded, we calculated the heart rate of the mice, as had already been done in previous studies 13,20,21,23 .…”

“…The collagen volume fraction was calculated as the percent ratio between the myocardial tissue area positively stained for collagen fibers (the absolute amount of collagen) and the total 13,20,21,23,24 .…”