Effect of endovascular hypothermia on acute ischemic edema: morphometric analysis of the ICTuS trial.

INTRODUCTION: Pilot studies of hypothermia for stroke suggest a potential benefit in humans. We sought to test whether hypothermia decreases post-ischemic edema using CT scans from a pilot trial of endovascular hypothermia for stroke. METHODS: Eighteen patients with acute ischemic stroke underwent therapeutic hypothermia (target = 33 degrees C) for 12 or 24 h followed by a 12-h controlled re-warm using an endovascular system. CT scans obtained at baseline, 36-48 h (right after cooling and re-warming) and 30 days were digitized, intracranial compartment volumes measured using a validated stereological technique, and the calculated change in CSF volume between the three time-points were used as an estimate of edema formation in each patient. Patients were grouped retrospectively for analysis based on whether they cooled effectively (i.e., to a temperature nadir of less than 34.5 degrees C within 8 h) or not. RESULTS: Eleven patients were cooled partially or not at all, and seven were effectively cooled. Baseline demographics and compartment volumes and densities were similar in both groups. At 36-48 h, the total CSF volume had significantly decreased in the not-cooled group compared to the cooled group (P < 0.05), with no significant difference in mean volume of ischemia between them (73 +/- 73 ml vs. 54 +/- 59 ml, respectively), suggesting an ameliorative effect of hypothermia on acute edema formation. At 30 days, the difference in CSF volumes had resolved, and infarct volumes (73 +/- 71 ml vs. 84 +/- 102 ml, respectively) and functional outcomes were comparable. CONCLUSIONS: Endovascular hypothermia decreases acute post-ischemic cerebral edema. A larger trial is warranted to determine if it affects final infarct volume and outcome in stroke.

Matrix metalloproteinase-2 cleavage of adrenomedullin produces a vasoconstrictor out of a vasodilator.

MMPs (matrix metalloproteinases) play a major role in the pathogenesis of hypertension by altering the extracellular matrix during cardiovascular remodelling. In the present study we show that MMP-2, but not MMP-9, cleaves the vasodilator peptide AM (adrenomedullin). Addition of the AM-binding protein, complement factor H, prevents this cleavage, providing a hitherto unknown mechanism of action for this binding protein. We identified the signature cleavage fragments and found some of them in human urine, suggesting that MMP-2 processing of AM may occur in vivo. Synthetic AM fragments regulated blood pressure in rats. The larger peptides are vasodilators, as is intact AM, whereas intermediate fragments did not affect blood pressure. In contrast, AM(11-22) elicited vasoconstriction. Studies of AM receptor activation in Rat2 cells confirm that the larger AM cleavage peptides activated this receptor, whereas AM(11-22) did not. The present study defines a new mechanism through which MMP-2 may regulate blood pressure by simultaneously eliminating a vasodilator and generating a vasoconstrictor.