Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.

Estrogen status appears to play an important modulatory role in improvements in endothelial function with endurance exercise training in postmenopausal women. The restored endurance exercise training adaptation in estrogen-treated postmenopausal women may be related to mitigation of oxidative stress.

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, ...