A Randomized, Double-Blind, Placebo-Controlled Trial of Simvastatin on Subarachnoid Hemorrhage-Induced Vasospasm

The mortality rate of aneurysmal subarachnoid hemorrhage (SAH) approaches 50% within the 1st 24 hours of ictus. Patients who survive can subsequently develop a progressive vasospasm of large cerebral arteries, which is a major cause of morbidity and mortality. Vasospasm can be of varying severity, and only a small portion of patients with vasospasm develop clinical signs or symptoms. Patients with severe vasospasm are prone to develop ischemic deficits, which, if untreated, will progress into ischemic infarcts.

The mechanisms of vasospasm have been subject to intense investigation. Nitric oxide (NO)-cGMP system has attracted particular attention. Under normal physiological conditions, NO synthesized by endothelia NO synthase (eNOS) stimulates vascular smooth muscle cGMP production, which in turn causes smooth muscle relaxation. Vasospasm impairs endothelium-dependent dilations, suggesting that SAH induces a state of NO deficiency within cerebral arteries.

There are several potential mechanisms of such an NO deficiency. Hemoglobin is a potent scavenger of NO, and when applied extraluminal it binds NO and inhibits its action. Presence of perivascular hemoglobin may contribute to development of vasospasm by reducing the availability of NO. It has been shown that adventitial applied hemoglobin can inhibit basal NO activity and that in vivo adventitial exposure to whole blood leads to a reduction in basal cGMP levels in association with vasospasm of cerebral arteries. Similarly, superoxide also reacts with NO and acts as an NO scavenger. Superoxide production is increased after SAH, which may in part be responsible for inhibition of NO-dependent vasodilation. Free radical scavengers and manipulations to reduce free radical formation reduce vasospasm after SAH.

NOS is constitutively expressed in endothelium and adventitial perivascular nerve fibers. SAH-induced vasospasm in monkeys has been associated with diminished constitutive NOS immunoreactivity in the perivascular nerves around the spastic arteries. Endothelial NOS mRNA has also been decreased in monkey cerebral arteries 7d after SAH. Therefore, data suggest that there is a relative reduction in NO synthesis after SAH, in addition to increased breakdown.

In summary, the reduction in NO tonus around the cerebral arteries induced by decreased expression of endothelial NOS as well as increased NO scavenger substances in the subarachnoid space, and a relative resistance to NO-induced vasodilation in SAH appears to be one of the key events in the development of vasospasm. Therefore, therapeutic interventions that enhance endothelial NO production may compensate for these changes and reverse or reduce vasospasm.