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

Randomized controlled trials have been unable to detect a cardiovascular benefit of continuous positive airway pressure (CPAP) in unselected patients with obstructive sleep apnea (OSA). We hypothesize that deleterious cardiovascular outcomes are concentrated in a subgroup of patients with heightened apnea/hypopnea-related pulse rate response. We measured the pulse rate response to apneas/hypopneas (∆HR) in the Multi-Ethnic Study of Atherosclerosis (MESA, N=1395) and the Sleep Heart Health Study (SHHS, N=4575). MESA data were used to determine the functional form of association between ∆HR and subclinical cardiovascular biomarkers, while primary analyses tested the association of ∆HR with non-fatal/fatal CVD and all-cause mortality in longitudinal data from the SHHS. In MESA, U-shaped relationships were observed between subclinical CVD biomarkers (coronary artery calcium; NT-proBNP; Framingham risk score) and ∆HR; notably, high ∆HR (upper quartile) was associated with elevated biomarker scores compared to mid ∆HR (25th-75th centiles). In SHHS, individuals with high ∆HR compared to mid ∆HR were at increased risk of non-fatal/fatal CVD and all-cause mortality (non-fatal: 1.60 [1.28-2.00]; fatal: 1.68 [1.22-2.30]; all-cause: 1.29 [1.07-1.55], adjusted hazard ratio [95%CI]). The risk associated with high ∆HR was particularly high in those with substantial hypoxic burden (non-fatal: 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 non-sleepy individuals. Individuals with OSA who demonstrate elevated pulse rate response 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.