The Role of RhoA/Rho-kinase System in the Deterioration of Coronary Microcirculation in Ischemic Heart Disease

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Effective treatment of patients with angina who have normal coronary arteriograms (microvascular angina) has not yet been established. Rho-kinase-mediated calcium sensitization of the myosin light chain in smooth muscle cells has been implicated as substantially contributing to vascular hyperconstriction. Accordingly, we sought to determine whether a potent Rho-kinase inhibitor fasudil prevents the occurrence of myocardial ischemia in patients with microvascular angina attributable to coronary microvascular spasm. We studied consecutive 18 patients with angina and normal epicardial coronaries in whom intracoronary acetylcholine (Ach) induced myocardial ischemia (ischemic electrocardiographic ahnges, myocardial lactate production, or both) without angiographically demonstrable epicardial coronary vasospasm. All patients underwent a second Ach challenge test after pretreatment with either saline (n=5) or fasudil (4.5mg intracoronarily, n=13). Myocardial ischemia was reproducibly induced by Ach in the saline group. In contrast, 11 of the 13 patients pretreated with fasudil had no evidence of myocardial ischemia during the second infusion of Ach (p<0.01). The lactate extraction ratio (median value [interquartile range]) during Ach infusion was improved by fasudil pretreatment, from -0.16 (-0.25 tp 0.04), to 0.09 (0.05 to 0.18) (p=0.0125). These results suggest that the inhibition of Rho-kinase may be a novel therapeutic strategy for this group of patients with microvascular angina.