Background: Cardiovascular response to stressful respiratory maneuvers has been shown to differ in patients with significant coronary artery disease (S-CAD).An innovative test, using the Respiratory Stress Response (RSR), has been developed by SPIROCOR ? for the detection of S-CAD.The RSR is calculated from spectral analysis of finger pulse wave modulations, recorded by photoplethysmography (PPG) during deep, paced breathing at a rate of 6 breaths per minute (0.1Hz) over 70 seconds.Four separate studies (Ⅰ, Ⅱ, Ⅲ, and Ⅳ) in 3 different medical centers (2 in Israel, 1 in the US) were conducted throughout the development and testing of this new test.Methods: Overall 466 consecutive patients (Ⅰ=123, Ⅱ=98, Ⅲ=150, Ⅳ=95) referred for coronary angiography, were enrolled and underwent the RSR test prior to angiography.RSR was calculated by proprietary software analyzing the relative spectral power of the respiratory peak area at 0.1 Hz.The angiograms were analyzed visually (Ⅰ, Ⅱ) and by Quantitative Coronary angiography (Ⅲ, Ⅳ) by a single cardiologist who was blinded to the RSR results.S-CAD was defined in accordance to AHA Guidelines as luminal stenosis>70% of at least one coronary artery or LM stenosis>50%.Receiver operating curve methodology was applied to determine the optimal cut-offpoint and accuracy of RSR in indicating S-CAD.Results: In all studies S-CAD pts had significantly lower RSR compared to pts without S-CAD, p<0.001.Sensitivity of the RSR for detection of S-CAD ranged between 75-87 percent, while specificity ranged between 63-85 percent in the 4 studies.Multivariate logistic regression analysis, adjusted risk factors, showed that RSR is a strong independent indicator of S-CAD in all studies.Conclusion: The novel RSR test is a simple accurate non-invasive tool for detection of S-CAD.Figure-1-Reduced Respiratory Stress Response in significant CAD Legend: The modulations in the PPG signal, represented by RSR, are the 0.1 Hz (cycle time=10 sec), "large waves" correlating with the frequency of breathing, rather than the ~1Hz oscillations correlating to each heart beat.It can clearly be seen that these "large wave" modulations and the spectral peak are significantly reduced in the patient with S-CAD as compared to the patient without S-CAD.