Exercise Can Prevent and Reverse the Severity of Hypertrophic Cardiomyopathy

Abstract

Abstract-Hypertrophic cardiomyopathy (HCM) is the most common form of sudden death in young competitive athletes.However, exercise has also been shown to be beneficial in the setting of other cardiac diseases. We examined the ability of voluntary exercise to prevent or reverse the phenotypes of a murine model of HCM harboring a mutant myosin heavy chain (MyHC). No differences in voluntary cage wheel performance between nontransgenic (NTG) and HCM male mice were seen. Exercise prevented fibrosis, myocyte disarray, and induction of "hypertrophic" markers including NFAT activity when initiated before established HCM pathology. If initiated in older HCM animals with documented disease, exercise reversed myocyte disarray (but not fibrosis) and "hypertrophic" marker induction. In addition, exercise returned the increased levels of phosphorylated GSK-3␤ to those of NTG and decreased levels of phosphorylated CREB in HCM mice to normal levels. Exercise in HCM mice also favorably impacted components of the apoptotic signaling pathway, including Bcl-2 (an inhibitor of apoptosis) and procaspase-9 (an effector of apoptosis) expression, and caspase-3 activity. Remarkably, there were no differences in mortality between exercised NTG and HCM mice. Thus, not only was exercise not harmful but also it was able to prevent and even reverse established cardiac disease phenotypes in this HCM model. (Circ Res. 2006;98:540-548.)Key Words: apoptosis Ⅲ exercise Ⅲ hypertrophic cardiomyopathy Ⅲ remodeling T reatment strategies for hypertrophic cardiomyopathy (HCM) depend on clinical symptoms and stratification of sudden death risk with little evidence supporting prophylactic treatment of asymptomatic HCM. 1 It is becoming increasingly evident that cardiac rehabilitation for patients with other forms of cardiac disease such as ischemic heart disease, hypertension, and congestive heart failure (CHF) includes regular exercise, particularly aerobic exercise, and that exercise reduces cardiovascular morbidity and mortality in these subjects. 2,3 Yet there are no reports in the literature that discuss the impact of mild, monitored exercise as a therapeutic measure for HCM patients. Exercise rehabilitation in HCM patients, however, is somewhat counterintuitive considering the high incidence of sudden cardiac death in young athletes and that both the American Heart Association and the European Society of Cardiology strongly encourage preparticipation cardiovascular screening of HCM for young competitive athletes. 4,5 However, we hypothesized that voluntary cage wheel running as a form of mild exercise would improve and/or prevent the pathologic cardiac phenotype in a murine model of HCM. Voluntary cage wheel was chosen as the exercise intervention because it eliminates physical and psychological stressors associated with forced exercise paradigms that may exacerbate the HCM syndrome, and we have previously demonstrated cardiac adaptation to voluntary cage wheel exercise. 6 The particular HCM mouse model developed by our group 7 is ideal to addres...

Inhibition of Glycogen Synthase Kinase 3β During Heart Failure Is Protective

“…21 Although swimming significantly increased HW/BW in both groups, expression of GSK-3␤-DN failed to exert an additive effect on the swimming-induced hypertrophy observed in NTg (supplemental Figure VIII). Together with recent evidence that GSK-3␤ is phosphorylated in response to exercise, 22 these results suggest that GSK-3␤-DN-and exercise-induced (physiological) hypertrophy are mediated in part through a common signaling mechanism.…”

“…These observations are relevant to the mechanism of heart failure because physiological hypertrophy could negatively regulate the development of pathological hypertrophy. 22 GSK-3␤ phosphorylates GATA4 and eIF2B, thereby inhibiting cardiac hypertrophy through inhibition of either gene expression or protein translation. 4,6 Because GATA4 protects the heart from load-induced heart failure, 27 the Figure 5.…”

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

“…Of interest, exercise training promoted the same beneficial effects as induced by sustained treatment with cyclosporine (a selective inhibitor of the calcineurin/NFAT pathway) in HF (20). In agreement with our findings, Konhilas et al (49) demonstrated that voluntary exercise decreased NFAT activation and reversed cardiac disease phenotypes in an animal model of hypertrophic cardiomyopathy. These findings clearly demonstrate that deactivation of the calcineurin/NFAT signaling pathway is a key process involved in the exercise training-induced cardiac anti-remodeling effect in HF.…”

Impact of Demographic Features, Lifestyle, and Comorbidities on the Clinical Expression of Hypertrophic Cardiomyopathy

“…There are no data to support a detrimental effect of exercise in patients with HCM and no evidence that long‐term athletic training may promote an exacerbation of the underlying disease process. In animal models, routine exercise before the development of cardiac phenotype prevented subsequent fibrosis, myocyte disarray, and induction of markers of hypertrophy in mutant myosin heavy chain mice 46. Conversely, in non‐mutant rats conditioned to run vigorously for up to 16 weeks, cardiac fibrosis, changes in ventricular function, and increased arrhythmic propensity were observed 47.…”