Hemorrhagic Transformation during Thrombolytic Therapy and Reperfusion: Effects of Age, Blood Pressure, and Matrix Metalloproteinases

Background: Despite the increasing use of thrombolytic therapy for acute ischemic stroke, hemorrhagic transformation remains a significant complication. Transformation appears to occur more frequently with age, diabetes, and hypertension, but clinical data are mixed. In addition to risk factors, matrix metalloproteinase expression mediates hemorrhage. We sought to test the effects of age, hypertension, and matrix metalloproteinases during recombinant tissue plasminogen activator (rt-PA) treatment in a standard model of filament occlusion of the middle cerebral artery. Methods: We compared young and aged rats who were genetically predisposed to hypertension to similar and dissimilar strains to separate the effect of hypertension and age. Results: Hemorrhagic transformation occurred significantly more frequently in chronically hypertensive animals-23 of 53 (44%) compared to 2 of 23 (9%) normotensive, genetically similar rats (Chi-square; P < .001; Mantel-Haenszel common odds ratio estimate 12.33 [95% confidence interval 2.7-57.0]). Hemorrhage rates were comparable in aged and young chronically hypertensive animals. Induced acute hypertension during reperfusion did not appear to alter rates of transformation. In hypertensive (n = 26) compared to genetically similar normotensive (n = 12) animals, rt-PA treatment increased mortality to 35% from 0% (Chi-square; P < .05), while hemorrhage occurred in 50% of the rt-PA-treated hypertensive subjects compared to 8% of the normotensive animals (Chi-square; P < .05). Two different inhibitors of matrix metalloproteinases significantly reduced mortality but not hemorrhage rates. Conclusions: Our data suggest for the first time an effect of chronic hypertension separate from age on the risk of hemorrhagic transformation. In addition, inhibitors of matrix metalloproteinases may protect the neurovascular unit directly, even without reducing hemorrhage risk. These findings will require additional research.