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In this paper, we describe the effects of voluntary cage wheel exercise on mouse cardiac and skeletal muscle. Inbred male C57/Bl6 mice (age 6-8 wk; n = 12) [corrected] ran an average of 4.3 h/24 h, for an average distance of 6.8 km/24 h, and at an average speed of 26.4 m/min. A significant increase in the ratio of heart mass to body mass (mg/g) was evident after 2 wk of voluntary exercise, and cardiac atrial natriuretic factor and brain natriuretic peptide mRNA levels were significantly increased in the ventricles after 4 wk of voluntary exercise. A significant increase in the percentage of fibers expressing myosin heavy chain (MHC) IIa was observed in both the gastrocnemius and the tibialis anterior (TA) by 2 wk, and a significant decrease in the percentage of fibers expressing IIb MHC was evident in both muscles after 4 wk of voluntary exercise. The TA muscle showed a greater increase in the percentage of IIa MHC-expressing fibers than did the gastrocnemius muscle (40 and 20%, respectively, compared with 10% for nonexercised). Finally, the number of oxidative fibers as revealed by NADH-tetrazolium reductase histochemical staining was increased in the TA but not the gastrocnemius after 4 wk of voluntary exercise. All results are relative to age-matched mice housed without access to running wheels. Together these data demonstrate that voluntary exercise in mice results in cardiac and skeletal muscle adaptations consistent with endurance exercise.

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How an individual's sex and genetic background modify cardiac adaptation to increased workload is a topic of great interest. We systematically evaluated morphological and physiological cardiac adaptation in response to voluntary and forced exercise. We found that sex/gender is a dominant factor in exercise performance (in two exercise paradigms and two mouse strains) and that females of one of these strains have greater capacity to increase their cardiac mass in response to similar amounts of exercise. To explore the biochemical mechanisms for these differences, we examined signaling pathways previously implicated in cardiac hypertrophy. Ca 2ϩ /calmodulin-dependent protein kinase (CaMK) activity was significantly greater in males compared with females and increased after voluntary cage-wheel exposure in both sexes, but the proportional increase in CaMK activity was twofold higher in females compared with males. Phosphorylation of glycogen synthase kinase-3␤ (GSK-3␤) was evident after 7 days of cage-wheel exposure in both sexes and remained elevated in females only by 21 days of exercise. Despite moderate increases in myocyte enhancer factor-2 (a downstream effector of CaMK) transcriptional activity and phosphorylation of Akt with exercise, there were no sex differences. Mitogen-activated protein kinase signaling components (p38 mitogenactivated protein kinase and extracellular regulated kinase 1/2) were not different between male and female mice and were not affected by exercise. We conclude that females have increased exercise capacity and increased hypertrophic response to exercise. We have also identified sex-specific differences in hypertrophic signaling within the cardiac myocyte that may contribute to sexual dimorphism in exercise and cardiac adaptation to exercise. hypertrophy; myocyte signaling; workload; glycogen; calmodulin DESPITE INCREASING KNOWLEDGE of the mechanisms of cardiac adaptation to increased workload, there are significant sex/ gender differences that remain poorly understood. For example, in response to pathological stimuli such as systemic hypertension or aortic stenosis, women respond with more left ventricular hypertrophy and augmented contractility than men (51, 54), whereas men progress to poor contractility, chamber dilation, and wall thinning (7,11,24,39,50). Yet in the face of ischemic heart disease, females fare worse than their male counterparts (12,14,21).Physiological stimuli such as exercise can also elicit a sexually dimorphic cardiac response. Despite conflicting reports on the functional impact of exercise on the heart, it is apparent that there is differential remodeling between the sexes in response to aerobic exercise (16,49). Moreover, the sexually dimorphic cardiac response to exercise likely depends on the type of activity performed (aerobic vs. anaerobic, chronic vs. acute) as demonstrated in exercise-trained male and female rats. Male and female animals exercised by treadmill running have similar heart mass compared with sedentary controls (42, 44). In both sexes, ...

Structural remodelling occurring before, due to the underlying heart disease, and during atrial fibrillation (AF) sets the stage for permanent AF. Current therapy in AF aims to maintain sinus rhythm in symptomatic patients, but outcome is unfortunately poor. Stretch of the atria is a main contributor to atrial remodelling. In this review, we describe different aspects of structural remodelling as seen in animal models and in patients with AF, including atrial enlargement, cellular hypertrophy, dedifferentiation, fibrosis, apoptosis, and loss of contractile elements. In the second part, we describe downstream signals of mechanical stretch and their contribution to AF and structural remodelling. Ultimately, knowledge of mechanisms underlying structural remodelling may help to identify new pharmacological targets for AF prevention.

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...

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This study demonstrates that the S-ICD is effective in terminating ventricular arrhythmias. There is, however, a considerable percentage of ICD related adverse events, which decreases as the therapy evolves and experience increases.