- Introduction Respiratory maneuvers can uncover manifestations of myocardial ischemia. Some pulse wave characteristics are associated with significant coronary artery disease (S-CAD). An innovative test using the respiratory stress response (RSR) has been developed for the detection of S-CAD based on spectral analysis of finger pulse wave oscillations measured using photoplethysmography (PPG) during deep, paced breathing at a rate of 6 breaths per minute (0.1 Hz) for 70 seconds. We evaluated this test (RSR) as an indicator of S-CAD. Methods The study consisted of 2 stages—feasibility and validation—assessing RSR in patients referred for coronary angiography. RSR was calculated by proprietary software analysis of the relative spectral power of the respiratory peak area at 0.1 Hz. The coronary angiograms were analyzed visually (stage I) and by quantitative coronary angiography (stage II) by 1 cardiologist blinded to the RSR results. S-CAD was defined as luminal stenosis >70% of at least 1 coronary artery or LM stenosis >50%. Results A total of 193 consecutive patients (stage I: 98 and stage II: 95) with a mean age of 63.2 ± 11.9 years, 70% men, 112 (58%) with S-CAD, were included. S-CAD patients had significantly lower RSR compared with patients without S-CAD, P < 0.001. RSR yielded a sensitivity of 83% (95% confidence interval = 75–90) and specificity of 70% (95% confidence interval = 59–80) for indicating S-CAD. Multivariate logistic regression analysis, adjusted for risk factors, showed that RSR is a strong independent indicator of S-CAD [OR = 18.9 (7.2–49.5), P < 0.001]. Conclusion Reduced RSR is an accurate noninvasive indicator of S-CAD.