Abstract 5512: Vascular Rhexis: A Potentially Modifiable Contributor to Negative Remodeling After Myocardial Infarction

Abstract

We previously noticed in studies of plasminogen activator inhibitor type-1 (PAI-1) knockout (PKO) mice that infarction was often hemorrhagic. Thus, we hypothesized that the intensified fibrinolysis was unmasking a loss of integrity of coronary vessels (vascular rhexis) potentially caused in part by inflammation. To test this hypothesis, in the present study we induced myocardial infarction (MI) in PKO and control C57BL6 mice by ligation of the left coronary artery for 48 hr, harvested the hearts for assessment of infarct size (measured based on depletion of left ventricular [LV] creatinine kinase activity), and quantified hemorrhage by assaying with non-cross reacting ELISAs hemoglobin content corrected for myoglobin content in LV myocardium. Normal mouse LV myocardium contains approximately 40 μ l blood/g. PKO mice (n = 9) had marked intramyocardial hemorrhage in infarct zones (432±27 SEM μ l blood/g). Vascular rhexis was evident in C57BL6 controls as well (n = 5) as judged from the presence of 51±3 μ l blood/g LV 48 hr after coronary occlusion despite less blood in the infarct zone within 4 hr after coronary occlusion (10±5 μ l blood/g, n = 13). Intramyocardial hemorrhage in PKO mice was significantly reduced (302±37 μ l blood/g, p < 0.01 vs control PKO) by treatment with cyclophosphamide (n = 12) before coronary occlusion sufficient to induce profound leukopenia and by treatment with aprotinin (n = 9) after coronary occlusion to inhibit plasmin (220±40 μ l blood/g, p < 0.01 vs control PKO). Treatment with the combination of both (n = 4) virtually eliminated hemorrhage (49±5 μ l blood/g, p < 0.01 vs control PKO). Treatment did not modify infarct size (PKO: 46±2% of LV mass; PKO with cycloposphamide: 45±1%; PKO with aprotinin: 43±2%). Thus, rupture of coronary vessels occurs within 48 hr after the onset of coronary occlusion leading to hemorrhage that may exacerbate late, negative ventricular remodeling; cyclophosphamide reduces vascular rhexis by attenuating inflammation; and aprotinin reduces hemorrhage associated with vascular rhexis unmasked by intensified fibrinolysis by inhibiting plasmin.