Failure of pindolol and metoprolol to reduce the size of non-reperfused infarcts in dogs using area at risk techniques

Summary: Recent studies have shown that long term mortality after acute myocardial infarction is reduced by chronic beta-blocker therapy, however, the mechanism is not well understood. Our objective was to determine whether the selective beta blocker, metoprolol, or the nonselective intrinsic sympathomimetic activity (ISA)-blocker pindolol, reduce infarct size as a function of an area at risk (AR) in a permanent infarction model in dogs and which blocker is preferable in regards to myocardial function. Dogs were instrumented with ultrasonic crystals to measure regional function in nonischaemic and infarct margin segments. Left ventricular (LV) pressures, LV dP/dt and heart rate (HR) were monitored. Dogs were subjected to a 6 h LAD coronary artery occlusion and were randomised to a control (n = 9), pindolol (n = 10), and metoprolol (n = 9) group. At 30 and 90 min post occlusion saline, pindolol (3 μg·kg^-1 and 12 μg·kg^-1) or metoprolol (12 μg·kg^-1 and 48 μg·kg^-1) were given intravenously. The in vivo AR was determined by autoradiography, the in vitro AR by postmortem dye infusion and the area of necrosis by tetrazolium staining. Pindolol and metoprolol decreased LV dP/dt by 20% (P<0.05). Metoprolol also decreased HR by 20% (P<0.05) and shortening of nonischaemic segments by 12% (P<0.05) following the 1st and 2nd dose. Function in infarct margin segments was not changed in either group. Blood flow, measured by microspheres, was similar in the three groups. Infarct size as a function of the in vivo AR was 61 ± 9% (control), 64 ± 10% (pindolol) and 57 ± 9% (metoprolol). Infarct size of the in vitro AR was 20 to 40% smaller according to the larger in vitro AR which does not take collateral flow into account. Hence, pindolol and metoprolol failed to reduce infarct size despite a significant reduction of LV dP/dt in both groups and of HR in the metoprolol group. In regards to myocardial function pindolol could be preferable because it does not effect HR or regional function of noninfarcted myocardium. It seems unlikely that infarct size reduction of non-perfused infarcts is the primary mechanism for the observed reduction in mortality in clinical trials.