Apoptosis and changes in contractile protein pattern in the skeletal muscle in heart failure

Chronic heart failure is characterized as a clinical disorder by exercise i ntolerance. There are two factors that are independently responsible for th e reduced exercise capacity: (a) a shift from myosin heavy chain 1 (MHC1) t o MHC2a and MHC2b and (b) muscle atrophy. We have demonstrated, both in exp erimental models of heart failure and in man,that the more severe the heart failure, the greater the magnitude of skeletal muscle apoptosis. In the mo nocrotaline treated rat, that develops a severe right- sided heart failure, the increased number of apoptotic nuclei was paralleled by increasing leve ls of circulating TNF alpha. In agreement with some recent observations sho wing that sphingolipids can mediate programmed cell death, we found that in animals with heart failure and high number of apoptotic nuclei, circulatin g levels of sphingosine were significantly increased. in a study conducted in patients with heart failure we found a correlation between exercise capa city limitation and skeletal myocytes apoptosis. There was also a correlati on between degree of muscle atrophy and magnitude of apoptosis. The shift i n MHCs, although with a different mechanism, is also responsible for the re duced exercise capacity in these patients. In fact there is a strong correl ation between indices of severity of CHF and MHC composition. Muscle fatigu e, appears earlier in patients that have a greater skeletal muscle expressi on of 'fast' MHCs. We have also demonstrated that MHCs shift and apoptosis can be prevented by using angiotensin II converting enzyme inhibitors and a ngiotensin ii receptor blockers.