Using the repeated coronary occlusion model, we investigated the effect of heparin treatment on collateral development. In eight control dogs, 2 min coronary occlusions were repeated 129±44 times until acute occlusion was no longer accompanied by a reduction in systolic shortening of the ischemic area. In a further eight dogs pre-treated with heparin, however, only 81±33 occlusions were necessary to produce the same results. These findings indicate that heparin has the potential to accelerate and potentiate collateral development in vivo.

　 Ten patients with coronary artery disease and effort angina were exercised 10 to 20 min following pre-treatment with a single intravenous dose of heparin (5000 units) twice a day for 10 days. The rate-pressure product at the onset of 0.1 mV ST depression and anginal pain increased by 19% and 35%, respectively. The angiographic collateral score also increased in these patients. In contrast, none of these indexes changed significantly in patients with exercise alone.

　 In a subsequent randomized study, 52 patients with effort angina were randomly assigned to receive one of two intravenous doses of enoxaparin (40 mg or 60 mg) or a placebo. Each patient underwent 20 treadmill exercise sessions 10 to 20 min following pre-treatment with enoxaparin or a placebo. Only in patients who received 60 mg enoxaparin pretreatment, did the rate-pressure product at the onset of angina increase significantly, by 16%. The extent of angiographically demonstrable collateral circulation to the area perfused by the completely obstructed coronary artery increased in 47% of the enoxaparin-treated patients, but only in 25% of the placebo patients. These findings are compatible with a hypothesis that a combination of exercise and enoxaparin induces collateral growth to the jeopardized myocardium.

　 The clarification of the precise mechanisms of the interaction of angiogenic growth factors with heparin would provide a new therapeutic strategy for coronary artery disease.