1345Prognostic impacts of impaired coronary vasodilatation and enhanced coronary vasoconstricting responses in patients with angina and unobstructive coronary arteries

Background: Coronary vasomotor abnormalities, including impaired vasodilatation and enhanced vasoconstriction of epicardial and microvascular coronary arteries, play important roles in the pathogenesis of angina with unobstructive coronary arteries. However, the prognostic impacts of these disorders and their combination remains to be fully elucidated. Purpose: We examined the prognostic impacts of impaired vasodilatation, enhanced vasoconstriction of coronary arteries, and both of them in patients with angina and unobstructive coronary arteries. Methods and results: We enrolled 187 consecutive patients with suspected angina and unobstructive coronary arteries (M/F 113/74, 63.2±12.3 [SD] year-old). To assess coronary vasoconstricting responses, we performed acetylcholine provocation tests. Then, to evaluate coronary microvascular dilator function, we measured coronary flow reserve (CFR) and index of microcirculation resistance (IMR) during hyperemic state induced by intravenous adenosine administration. For the analysis, we divided the subjects into 4 groups according to CFR (<2.0) and IMR (>20) levels; high CFR and low IMR (Group 1, n=84), high CFR and high IMR (Group 2, n=37), low CFR and low IMR (Group 3, n=39), and low CFR and high IMR (Group 4, n=27). Among the 4 groups, there was no significant difference in age, sex, or prevalence of traditional coronary risk factors, whereas Group 4 had the highest levels of high-sensitive troponin T (P=0.04) and high-sensitive C-reactive protein (P=0.01). Although abnormal vasoconstricting responses to intracoronary acetylcholine were noted in all the 4 groups as defined by CFR and IMR, Group 4 had the highest incidence of epicardial coronary spasm (P=0.02) and the lowest incidence of microvascular spasm (P=0.046) (Figure A). Moreover, we analyzed the incidence of major adverse cardiac events (MACE), including cardiac death, non-fatal myocardial infarction, hospitalization due to unstable angina pectoris, during the median follow-up period of 619 days (IQR 373, 814). Kaplan-Meier survival analysis showed a significantly worse prognosis in Group 4 compared with other 3 groups (HR 9.14, 95% CI 1.17–184.75, P=0.03) (Figure B). Multivariable Cox proportional hazard analysis showed that a combination of epicardial spasm and coronary microvascular dilator dysfunction with low CFR and high IMR was significantly correlated with poor outcomes (HR 11.87, 95% CI 1.85–66.64, P=0.005). Importantly, intracoronary administration of fasudil, a selective Rho-kinase inhibitor, significantly ameliorated CFR and IMR in Group 4 as compared with other 3 groups (both P<0.001).