The Sleep Apnea-Specific Pulse-Rate Response Predicts Cardiovascular Morbidity and Mortality

Rationale: Randomized controlled trials have been unable to detect a cardiovascular benefit of continuous positive airway pressure in unselected patients with obstructive sleep apnea (OSA). We hypothesize that deleterious cardiovascular outcomes are concentrated in a subgroup of patients with a heightened pulse-rate response to apneas and hypopneas (Delta HR). Methods: We measured the Delta HR in the MESA (Multi-Ethnic Study of Atherosclerosis) (N = 1,395) and the SHHS (Sleep Heart Health Study) (N= 4,575). MESA data were used to determine the functional form of the association between the Delta HR and subclinical cardiovascular biomarkers, whereas primary analyses tested the association of the Delta HR with nonfatal or fatal cardiovascular disease (CVD) and all-cause mortality in longitudinal data from the SHHS. Measurements and Main Results: In the MESA, U-shaped relationships were observed between subclinical CVD biomarkers (coronary artery calcium, NT-proBNP [N-terminal prohormone BNP], and Framingham risk score) and the Delta HR; notably, a high Delta HR (upper quartile) was associated with elevated biomarker scores compared with a midrange Delta HR (25th-75th centiles). In the SIMS, individuals with a high Delta HR compared with a midrange Delta HR were at increased risk of nonfatal or fatal CVD and all-cause mortality (nonfatal adjusted hazard ratio [95% confidence interval (CI)], 1.60 [1.28-2.00]; fatal adjusted hazard ratio [95% CI], 1.68 [1.22-2.30]; allcause adjusted hazard ratio [95% CI], 1.29 [1.07-1.55]). The risk associated with a high Delta HR was particularly high in those with a substantial hypoxic burden (nonfatal, 1.93 [1.36-2.73]; fatal, 3.50 [2.15-5.71]; all-cause, 1.84 [1.40-2.40]) and was exclusively observed in nonsleepy individuals. Conclusions: Individuals with OSA who demonstrate an elevated Delta HR are at increased risk of cardiovascular morbidity and mortality. This study identifies a prognostic biomarker for OSA that appears useful for risk stratification and patient selection for future clinical trials.