Interaction of Impaired Coronary Flow Reserve and Cardiomyocyte Injury on Adverse Cardiovascular Outcomes in Patients Without Overt Coronary Artery Disease

Background— Minimally elevated serum cardiac troponin reflects myocardial injury and is associated with increased mortality, even absent coronary artery disease (CAD). We sought to investigate the relationship between low-level troponin elevation and impaired coronary flow reserve (CFR), an integrated measure of coronary vasomotor function, and to assess their contributions to adverse outcomes in patients without overt CAD. Methods and Results— Consecutive patients (n=761) undergoing evaluation for suspected CAD with troponin before stress myocardial perfusion positron emission tomography were followed up (median, 2.8 years) for major adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, or late revascularization. Patients with flow-limiting CAD, left ventricular ejection fraction <40%, or revascularization within 60 days of imaging were excluded. CFR was quantified from stress/rest myocardial blood flow with the use of positron emission tomography. Compared with patients with negative troponin, those with at least 1 positive troponin (n=97) had higher pretest clinical scores, more renal dysfunction, and lower left ventricular ejection fraction and CFR. In adjusted analysis, impaired CFR remained independently associated with positive troponin (odds ratio, 2.18; 95% confidence interval, 1.37–3.47; P=0.001), and both impaired CFR and positive troponin were independently associated with major adverse cardiovascular events (hazard ratio, 2.25; 95% confidence interval, 1.31–3.86; P=0.003; and hazard ratio, 2.42; 95% confidence interval, 1.34–4.40; P=0.004, respectively). Impaired CFR and positive troponin identified patients at highest risk of major adverse cardiovascular events (log-rank P<0.0001), with a significant interaction (P<0.007) seen between CFR and troponin. Conclusions— In patients without overt CAD, impaired CFR was independently associated with minimally elevated troponin and major adverse cardiovascular events. Impaired CFR, here reflecting microvascular dysfunction, modified the effect of a positive troponin on adverse outcomes.