Obstructive sleep apnea (OSA) is an independent risk factor for development of diabetes and cardiovascular (CV) disease and is associated with worse CV outcomes. With the increase in obese and aging populations, the prevalence of OSA is also increasing. Therefore, strategies that reduce cardiometabolic risk in OSA will have high public health impact. The need for alternate approaches to mitigate CV risk in OSA is also highlighted by the inconsistent effects of CPAP therapy in improving insulin sensitivity, lowering blood pressure (BP), and reducing CV events. In recent years, the role of cellular damage and senescence in the development of obesity- and age-related metabolic disorders has been demonstrated, and therapeutics aimed at clearing senescent cells are being developed. More specifically, the role of cellular senescence in causing adipose tissue dysfunction and thereby contributing to chronic inflammation, increased BP, and insulin resistance (IR) is now recognized. Among the factors known to trigger cellular senescence, oxidative stress, AngII, and inflammation are elevated in OSA. Therefore it is likely that OSA will be associated with increased cellular damage and senescence. Our overall hypothesis is that intermittent hypoxia (IH) in OSA triggers cellular damage via increases in AngII, inflammation, and generation of reactive oxygen species (ROS) in adipose tissue. The increase in damaged cells in adipose tissue would, in turn, further increase AngII, inflammation, and ROS. These may together alter adipose tissue function, and contribute to IR, hypertension, and CV disease. This hypothesis is supported by our compelling preliminary data showing: i) increased presence of damaged p16 and ?H2AX positive cells in adipose tissue of OSA subjects; ii) IH mediated increases in inflammation, AngII, ROS and senescence in cultured primary human preadipocytes; iii) attenuation of IH-dependent increases in senescent cells by atorvastatin and iv) lower prevalence of damaged cells in adipose tissue of OSA patients taking statin+CPAP. We will test our hypothesis using comprehensive characterization of blood and adipose tissue samples from 30 non-OSA (AHI<5) and 90 OSA (AHI>15) subjects to determine the presence of cellular damage (Aim 1). We will also identify potential mechanisms through which OSA causes cellular senescence, using in-vitro and ex-vivo approaches (Aim 2). Further, using a double blind randomized clinical trial design, we will evaluate the effects of 6 months of CPAP therapy and 80 mg atorvastatin on adipose tissue cellular damage, inflammation, BP, IR, and vascular function (Aim 3). The novelty and strengths of our proposal include the identification of adipose tissue cellular damage and senescence as a mediator of OSA-related cardiometabolic pathology, the multi-disciplinary translational approach, and the longitudinal randomized controlled trial in comprehensively phenotyped subjects, complemented by mechanistic in-vitro studies in primary human preadipocytes. Our study will provide important insights into pathways that may prove pivotal in reducing cardiometabolic burden in OSA patients.

Public Health Relevance

Obstructive sleep apnea (OSA) is a sleep breathing disorder associated with increased risk of developing diabetes and cardiovascular disease. Clinical management of sleep apnea using continuous positive airway pressure is not optimal and a need for development of new treatment strategies exists. The proposed studies will investigate the role of cellular damage and senescence (premature aging of cells) in increasing risk for diabetes and cardiovascular disease in OSA patients, and further evaluate the ability of statin therapy to reduce cell damage.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL065176-13A1
Application #
9379555
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Shi, Yang
Project Start
1999-09-30
Project End
2022-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
13
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Xie, Jiang; Covassin, Naima; Chahal, Anwar A et al. (2018) Effect of Adaptive Servo-Ventilation on Periodic Limb Movements in Sleep in Patients With Heart Failure. Am J Cardiol :
Singh, Prachi; Zhang, Yuebo; Sharma, Pragya et al. (2018) Statins decrease leptin expression in human white adipocytes. Physiol Rep 6:
Medina-Inojosa, Jose R; Batsis, John A; Supervia, Marta et al. (2018) Relation of Waist-Hip Ratio to Long-Term Cardiovascular Events in Patients With Coronary Artery Disease. Am J Cardiol 121:903-909
Covassin, Naima; Sert-Kuniyoshi, Fatima H; Singh, Prachi et al. (2018) Experimental Weight Gain Increases Ambulatory Blood Pressure in Healthy Subjects: Implications of Visceral Fat Accumulation. Mayo Clin Proc 93:618-626
Cundrle Jr, Ivan; Somers, Virend K; Singh, Prachi et al. (2018) Low leptin concentration may identify heart failure patients with central sleep apnea. J Sleep Res 27:240-243
Xie, Jiang; Sert Kuniyoshi, Fatima H; Covassin, Naima et al. (2018) Excessive Daytime Sleepiness Independently Predicts Increased Cardiovascular Risk After Myocardial Infarction. J Am Heart Assoc 7:
Chahal, Anwar A; Alhurani, Rabe E; Mohamed, Essa A et al. (2017) Are there sex differences following treatment of left ventricular outflow tract obstruction in adults with hypertrophic cardiomyopathy? Eur Heart J Qual Care Clin Outcomes 3:249-250
Watanabe, Eiichi; Kiyono, Ken; Matsui, Shojiro et al. (2017) Prognostic Importance of Novel Oxygen Desaturation Metrics in Patients With Heart Failure and Central Sleep Apnea. J Card Fail 23:131-137
Polonis, Katarzyna; Somers, Virend K; Becari, Christiane et al. (2017) Moderate-to-severe obstructive sleep apnea is associated with telomere lengthening. Am J Physiol Heart Circ Physiol 313:H1022-H1030
Wang, Ling; Chen, Jiyan; Li, Guangxi et al. (2017) The Prevalence of Sleep Apnea in Type B Aortic Dissection: Implications for False Lumen Thrombosis. Sleep 40:

Showing the most recent 10 out of 202 publications