Chronic heart failure is characterized as a clinical disorder by exercise intolerance. There are two factors that are independently responsible for the reduced exercise capacity: (a) a shift from myosin heavy chain 1 (MHC1) to MHC2a and MHC2b and (b) muscle atrophy. We have demonstrated, both in experimental models of heart failure and in man, that the more severe the heart failure, the greater the magnitude of skeletal muscle apoptosis. In the monocrotaline treated rat, that develops a severe right-sided heart failure, the increased number of apoptotic nuclei was paralleled by increasing levels of circulating TNFalpha. In agreement with some recent observations showing that sphingolipids can mediate programmed cell death, we found that in animals with heart failure and high number of apoptotic nuclei, circulating levels of sphingosine were significantly increased. In a study conducted in patients with heart failure we found a correlation between exercise capacity limitation and skeletal myocytes apoptosis. There was also a correlation between degree of muscle atrophy and magnitude of apoptosis. The shift in MHCs, although with a different mechanism, is also responsible for the reduced exercise capacity in these patients. In fact there is a strong correlation between indices of severity of CHF and MHC composition. Muscle fatigue, appears earlier in patients that have a greater skeletal muscle expression of 'fast' MHCs. We have also demonstrated that MHCs shift and apoptosis can be prevented by using angiotensin II converting enzyme inhibitors and angiotensin II receptor blockers.