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

冠状动脉造影正常的心绞痛患者（微血管心绞痛）的有效治疗方法尚未确定。平滑肌细胞中rho激酶介导的肌球蛋白轻链钙致敏被认为是血管过度收缩的主要原因。因此，我们试图确定一种有效的rho激酶抑制剂法舒地尔是否能预防冠状动脉微血管痉挛引起的微血管心绞痛患者心肌缺血的发生。我们研究了连续18例心绞痛和正常心外膜冠状动脉患者，其中冠状膜内乙酰胆碱（Ach）诱导心肌缺血（缺血性心电图增强，心肌乳酸生成，或两者兼有），但没有血管造影显示的心外膜冠状动脉痉挛。所有患者在用生理盐水（n=5）或法舒地尔（4.5mg冠状动脉内注射，n=13）预处理后进行第二次乙酰胆碱激发试验。生理盐水组乙酰胆碱可重复诱导心肌缺血。法舒地尔预处理的13例患者中，11例在第二次输注乙酰胆碱时无心肌缺血迹象（p<0.01）。法舒地尔预处理提高了乙酰氨基酚输注过程中乳酸提取率（中位数[四分位数范围]），从-0.16（-0.25 - 0.04）提高到0.09 (0.05 - 0.18)（p=0.0125）。这些结果表明，抑制rho激酶可能是这组微血管心绞痛患者的一种新的治疗策略。

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.