Association between the severity of heart failure and the susceptibility of myocytes to apoptosis in patients with idiopathic dilated cardiomyopathy

Background: Bcl-2 proto-oncogene, an inhibitor of apoptosis and Bax proto-oncogene, an inducer of apoptosis play critical roles in the molecular circuit controlling apoptosis in cardiac muscle. The ratio of Bax to Bcl-2 proto-oncogene determines survival or death after an apoptotic stimulus. We speculated that susceptibility of myocytes to apoptosis determined as the Bax/Bcl-2 ratio might vary with the severity of heart failure. Methods and results: We studied immunohistochemically 108 endomyocardial biopsy specimens from 30 patients with idiopathic dilated cardiomyopathy (mild heart failure, n=14; moderate or severe heart failure, n=16) with the use of Bcl-2 and Bax monoclonal antibodies. The expression of each protein was determined semiquantitatively as the fraction of myocytes labeled with specific monoclonal antibodies using a digital morphometric analysis system. Patients with mild heart failure showed significantly increased Bax/Bcl-2 ratio than the patients with advanced heart failure (1.59±1.26 vs. 0.34±0.43, P=0.002). The expression of Bcl-2 was found to be independent of the severity of heart failure whereas the expression of Bax was significantly higher in patients with mild heart failure compared to the patients with moderate or severe heart failure (52.1±29.3 vs. 21.6±22.4%, P=0.005). Additionally, Bax/Bac-2 ratio was inversely correlated with the mitral E-interventricular septum distance, left ventricular end-systolic and end-diastolic diameter. Conclusion: The susceptibility of myocytes to apoptosis is significantly increased in the early phase of heart failure but it decreases with worsening of the disease due to depressed expression of Bax onco-protein. Increased myocyte susceptibility to apoptosis may have a role in the transition from mild heart failure to severe in patients with idiopathic dilated cardiomyopathy.