Ali Azarbarzin1, Scott A Sands2, Magdy Younes3, Luigi Taranto-Montemurro4,5, Tamar Sofer6,7, Daniel Vena4,5, Raichel M Alex2, Sang-Wook Kim2, Daniel J Gottlieb5, David P White2, Susan Redline8,9, Andrew Wellman4,5. 1. Brigham and Women's Hospital, 1861, Boston, Massachusetts, United States; aazarbarzin@bwh.harvard.edu. 2. Brigham and Women's Hospital, 1861, Boston, Massachusetts, United States. 3. University of Manitoba, 8664, Winnipeg, Manitoba, Canada. 4. Brigham and Women's Hospital, 1861, Departments of Medicine and Neurology, Boston, Massachusetts, United States. 5. Harvard Medical School, 1811, Boston, Massachusetts, United States. 6. Brigham and Women's Hospital, 1861, Medicine, Boston, Massachusetts, United States. 7. Harvard Medical School, 1811, Medicine, Boston, Massachusetts, United States. 8. Brigham and Women's Hospital, 1861, Division of Sleep and Circadian Disorders, Boston, Massachusetts, United States. 9. Harvard Medical School, 1811, Division of Sleep Medicine, Boston, Massachusetts, United States.
Abstract
RATIONAL: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
RATIONAL: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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