Myocardial angiogenesis and coronary perfusion in left ventricular pressure-overload hypertrophy in the young lamb: Evidence for inhibition with chronic protamine administration

Abstract

In contrast to young growing animals, pressure-overload hypertrophy in adults is frequently associated with diminished myocardial capillary density and maximal coronary flow per gram. To determine the role of angiogenesis in maintaining perfusion capacity in the hypertrophying heart, the angiogenesis inhibitor protamine sulfate was administered to young lambs during the development of left ventricular (LV) pressure-overload hypertrophy. Baseline and maximum (adenosine) myocardial perfusion was measured in four groups of chronically instrumented 10-week-old lambs subjected to 1) ascending aortic bands since the age of 4 weeks (LVH group, n = 10), 2) sham operation at the age of 4 weeks (SHAM group, n = 8), 3) aortic bands and twice daily injections of protamine since the age of 4 weeks (LVH+P group, n = 9), 4) sham operation and injection of protamine (SHAM+P group, n = 8). Capillary density was measured postmortem. Peak LV pressure and the LV/body weight ratio were similarly increased in LVH and LVH+P compared with sham-operated lambs (p < 0.001). In LVH lambs, LV capillary number increased by 32% compared with sham-operated lambs (p < 0.05), and capillary density, coronary flow reserve, and minimal coronary resistance remained normal. In contrast, LVH+P lambs had no significant increase over SHAM lambs in LV capillaries and total maximum coronary flow. The LVH+P lambs had lower LV subendomyocardial capillary density and higher minimal coronary resistance per gram (p < 0.05 versus LVH lambs). Right ventricular capillary density and minimal resistance were similar in all groups. These findings support the hypotheses that myocardial angiogenesis with pressure-overload hypertrophy is important in maintaining maximal LV coronary flow in the young and that impairment of angiogenesis results in diminished coronary flow capacity.