Integrative Effect of Carvedilol and Aerobic Exercise Training Therapies on Improving Cardiac Contractility and Remodeling in Heart Failure Mice

Abstract

The use of β-blockers is mandatory for counteracting heart failure (HF)-induced chronic sympathetic hyperactivity, cardiac dysfunction and remodeling. Importantly, aerobic exercise training, an efficient nonpharmacological therapy to HF, also counteracts sympathetic hyperactivity in HF and improves exercise tolerance and cardiac contractility; the latter associated with changes in cardiac Ca2+ handling. This study was undertaken to test whether combined β–blocker and aerobic exercise training would integrate the beneficial effects of isolated therapies on cardiac structure, contractility and cardiomyocyte Ca2+ handling in a genetic model of sympathetic hyperactivity-induced HF (α2A/α2C- adrenergic receptor knockout mice, KO). We used a cohort of 5–7 mo male wild-type (WT) and congenic mice (KO) with C57Bl6/J genetic background randomly assigned into 5 groups: control (WT), saline-treated KO (KOS), exercise trained KO (KOT), carvedilol-treated KO (KOC) and, combined carvedilol-treated and exercise-trained KO (KOCT). Isolated and combined therapies reduced mortality compared with KOS mice. Both KOT and KOCT groups had increased exercise tolerance, while groups receiving carvedilol had increased left ventricular fractional shortening and reduced cardiac collagen volume fraction compared with KOS group. Cellular data confirmed that cardiomyocytes from KOS mice displayed abnormal Ca2+ handling. KOT group had increased intracellular peak of Ca2+ transient and reduced diastolic Ca2+ decay compared with KOS group, while KOC had increased Ca2+ decay compared with KOS group. Notably, combined therapies re-established cardiomyocyte Ca2+ transient paralleled by increased SERCA2 expression and SERCA2:PLN ratio toward WT levels. Aerobic exercise trained increased the phosphorylation of PLN at Ser16 and Thr17 residues in both KOT and KOCT groups, but carvedilol treatment reduced lipid peroxidation in KOC and KOCT groups compared with KOS group. The present findings provide evidence that the combination of carvedilol and aerobic exercise training therapies lead to a better integrative outcome than carvedilol or exercise training used in isolation.

Exercise training on cardiovascular diseases: Role of animal models in the elucidation of the mechanisms

“…In 5-7-month old α 2A /α 2Ca ARKO mice, it is possible to observe increased heart height, LV mass, cardiomyocyte width and CSA, as well as cardiac fibrosis and collagen volume, suggesting a phenotype generally observed in remodeled hearths 89,91,94,95,102 . In the study of Pereira et al 90 , quantitative morphometric analyses indicated that cardiomyocyte width and cardiac collagen were, respectively, 28% and 55% increased in α 2A /α 2Ca ARKO mice in comparison with age-matched control 90 .…”

“…This phenotype is not well established in 3-month old α 2A /α 2Ca ARKO mice 90,92,102 . However, from the 5 th month of life, these animals present suggestible muscle profile of skeletal myopathy due to decreased motor performance (i.e., Rotard test), increased oxidative stress (i.e., lipid hydroperoxidation and protein carbonylation), gastrocnemius capillary rarefaction, muscle atrophy of type I and type II fibers and, due to all these factors, exercise intolerance 89,91,93,95,101,102 .…”

Molecular Mechanisms Underlying Cardiac Adaptation to Exercise

“…Low intensity exercise training has been shown to delay the onset of heart failure in the spontaneously hypertensive heart failure rat without effects on hypertension (Emter et al, 2005). Training also improved cardiac function in surgical and genetic models of heart failure or hypertrophic cardiomyopathy in mice (Konhilas et al, 2006; McMullen et al, 2007; Vanzelli et al, 2013). In humans, the largest study to examine the effects of exercise in heart failure patients was the HF-ACTION trial that examined the safety and efficacy of exercise in over 2300 patients with heart failure with reduced ejection fraction (HFrEF) (O'Connor et al, 2009).…”

Impact of exercise training on redox signaling in cardiovascular diseases

“…Moderate exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure mice (Medeiros et al, 2008;Oliveira et al, 2009;Vanzelli et al, 2013). Kavazis and co-workers have recently shown that short-term exercise training protects the heart against doxorubicin-induced heart failure by preventing cardiac mitochondrial dysfunction and increased oxidant stress .…”