Apoptosis in human acute myocardial infarction: The rationale for clinical trials of apoptosis inhibition in acute myocardial infarction

Abstract

The objective of the present review was to examine apoptosis in patients with acute myocardial infarction (MI) and to address (i) the prevalence of apoptosis in acute MI, (ii) techniques to determine apoptosis, (iii) time period from the onset of acute MI to the detection of apoptosis, (iv) criticisms about apoptosis in acute MI. A systematic literature search identified over 20 publications comprising over 400 patients. The prevalence of apoptosis varied from over 90 in nuclear imaging studies using annexin binding to 0.25 in an autopsy study using monoclonal antibody to single-stranded DNA. Apoptosis was present in 50-60 of infarcted hearts within 24 hours of MI (detected by Bax and activated caspase-3), 26 of myocytes in patients who died within 11 days of MI (pooled mean from 5 studies using only TUNEL staining), and 12 of the myocytes of patients who died, on average, 20 days after onset of MI (pooled mean from eight studies using dual staining with caspase-3 plus TUNEL). Criticisms of the TUNEL assay appear unjustified as TUNEL is at least 85 specific using caspase-3 activation as a marker of apoptosis. Taken together, DNA fragmentation on agarose gel electrophoresis, TUNEL staining of nuclei, caspase-3 activation, bcl-2 and Bax expression, and annexin V binding overwhelming support apoptotic cell death as an important component of MI. The amount of cardiac apoptosis correlates with the presence of heart failure and fatal arrhythmias. Heart failure as a complication of MI carries a high mortality and indicates the amount of myocardium lost during the infarct. Taken together, these findings suggest the need for clinical trials in acute MI to confirm whether inhibition of apoptosis can reduce patient morbidity and mortality.