Prognostic significance of impaired chronotropic response to pharmacologic stress Rb-82 PET

Background: An impaired chronotropic response to exercise is an accepted risk marker but the relationship between heart rate reserve (HRR) with pharmacologic stress is less well-established. The primary aim of this analysis was to evaluate the prognostic significance of HRR in patients undergoing rest/stress myocardial perfusion positron emission tomography (PET) in estimating coronary artery disease (CAD) mortality. Methods: This subset analysis from the PET Prognosis Multicenter Registry includes a total of 2,398 patients undergoing rest/stress Rb-PET from three participating sites. The HRR from rest to peak stress was categorized into tertiles of >4, 5-14, and <15 beats per minute (bpm). At stress, the % abnormal myocardium was categorized as ;ltand5 %, 5-9.9 %, and <10 %. We estimated CAD mortality using univariable and multivariable Cox proportional hazard models. Results: CAD mortality was 12.8 %, 3.4 %, and 0.8 %, respectively, for HRR measurements of ≤;4, 5-14, and <15 bpm (P < 0.0001). In a multivariable model, the HRR was independently predictive of CAD mortality (P < 0.0001) with adjusted hazard ratios elevated 3.5- and 8.4-fold for HRR of 5-14 and >4 versus <15 bpm. In a multivariable model, both the HRR and stress MPI % abnormal myocardium were independently and highly predictive of CAD mortality. Moreover, the net reclassification improvement was 0.18 for the HRR when compared to a model including risk factors, symptoms, rest HR, and PET variables (P = 0.0008). For those with <10 % abnormal myocardium on stress PET, there was a graded relationship between HRR and CAD mortality with adjusted hazards exceeding 50-fold for measurements of 5-14 and ≤;4 bpm (P < 0.0001) compared to stress MPI with <5 % abnormal myocardium and a HRR <15 bpm. Conclusion: A diminished HRR to vasodilator stress is a novel but increasingly important predictor of CAD mortality. HRR measurements of >4, 5-14, and <15 bpm were independently predictive of CAD mortality and underscore the importance of optimizing readily available novel markers of risk as highly relevant to identifying high and low risk patient subsets.