Prognostic value of abnormal vasoreactivity of epicardial coronary arteries to sympathetic stimulation in patients with normal coronary angiograms

Objective - We aimed to evaluate prospectively whether patients with normal coronary angiogram but abnormal epicardial vasoreactivity to cold pressor test (CPT) are at increased risk for cardiovascular events. Methods and Results - Vasoreactivity in response to CPT and dilation of epicardial arteries to intracoronary application of nitroglycerin were assessed quantitatively (percent change of luminal area, ΔLA%) in 130 patients with normal coronary angiograms. Cardiovascular events (cardiovascular death, acute coronary syndrome, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary bypass grafting, ischemic stroke, or peripheral revascularization) were assessed as clinical outcome parameters over a mean follow-up period of 45±9 months. Based on their vascular responses to CPT, patients were assigned into the following 3 groups: group 1, patients with normal vasodilator response (ΔLA >0%; n=37); group 2, patients with moderate vasoconstrictor response (ΔLA between 0% and - 15%; n=42); and group 3, patients with severe vasoconstrictor response (ΔLA ≤-15%; n=51). Although patients from groups 2 and 3 had significantly increased vasoconstrictor response to CPT (group 2, ΔLA ≤6±3% and group 3, ΔLA -24±6% versus group 1, ΔLA 11±9%; P≤0.0001), they showed normal endothelial-independent epicardial vasodilation to intracoronary application of nitroglycerin similar to patients from group 1 (ΔLA 39±16% and 34±14% versus 41±14%; P=NS, respectively). During follow-up, none of the patients from group 1 developed cardiac events. However, 7 cardiovascular events occurred in group 2 and 30 occurred in group 3 in 4 and 22 patients, respectively (P≤0.0001, univariate by log-rank test). After adjustment for known risk factors for coronary artery disease, impaired epicardial coronary vasoreactivity to CPT remained significantly associated with the risk of developing cardiovascular events (P=0.040, multivariate by Cox regression model). Conclusions - In patients with normal coronary angiogram, abnormal vasoreactivity of epicardial coronary arteries in response to sympathetic stimulation is associated with the risk of developing cardiovascular events.