How We Breathe During Sleep Affects Health, Wellness and Longevity Susan Redline, MD, MPH Peter C. Farrell Professor of Sleep Medicine Program Director- Sleep Medicine Epidemiology Harvard Medical School Brigham and Women s Hospital Beth Israel Deaconess Medical Center Boston, MA
Overview Normal and abnormal breathing during sleep Obstructive sleep apnea Physiological impacts of apnea/hypoxemia Impact on cardiovascular disease, stroke, diabetes, mortality Impact on sleepiness, cognition, and frailty Vulnerability of women?
Normal Breathing Breathing During Sleep Apneas Obstructive Sleep Apnea (OSA): Frequent episodes of airway collapse (apneas)
Hypoxia and Sympathetic Activation Recurrent hypoxia and reoxygenation Increase flux of free radicals Induce endothelin expression Suppress NO generation, local vasoconstriction Oxidation of serum proteins Hypoxemia, hypercapnia, and arousal Sympathetic Nervous System overdrive Systemic and pulmonary vasoconstriction Inflammation, endothelial dysfunction and oxidative stress IL6, sil6r, IL-8, TNFα, CRP,(NF-Kappa B) Insulin resistance and dyslipidemia Somers et al. J Clin Invest. 1995;96:1897.
Sleep Apnea: Sleep Disruption and Autonomic System Activation Neubauer DN Am Fam Phy 1999 Increased arousals/awakenings Decreased Slow Wave Sleep and REM Sleep Cardiovascular responses Blood pressure surges-non-dipping Fluctuations in: heart rate, cardiac output, coronary/cerebral blood flow, myocardial oxygen demand Decreased coronary perfusion pressure Increased cardiac oxygen demand Cardiac ischemia, Electrical instability Brain responses Impaired synaptic plasticity, accumulation of toxins, neuroinflammation, apoptosis Sleepiness, Cognitive Impairment
Sleep Apnea and Health 50% increased risk of hypertension 50% increased risk coronary heart disease 70% increased risk of heart failure 3-4-fold increased arrhythmias 2-3-fold increased risk of stroke 30-50% increased risk of diabetes 2-fold increased mortality 20-50% increase in MCI Decreased QoL, sleepiness, functional impairment Emerging recognition of overnight hypoxic burden as a driving factor for mortality and morbidity Reviewed: Drager, Circ; 2017
OSA and Incident Diabetes Meta-Analysis: Moderate-Severe OSA and Incident Diabetes 6 prospective cohort studies N=5953 Mild OSA Follow up: 3 to 16 yrs Overall OR: 1.63 (1.09, 2.45) Wang Respir 2013 Anothaisintawee Sleep Med Rev 2016
OSA and Cardio-cerebral Vascular Diseases Meta-Analysis Stroke and OSA Coronary Artery Disease and OSA Men Women Loke YK Circ Cardiovasc Qual Out 2012
Increased HF/Death In Older Women Kaplan Meier survival curves for the risk of HF or death of moderate/severe OSA vs none/mild OSA stratify by sex. Gabriela Querejeta Roca et al. Circulation. 2015;132:1329-1337
OSA severity is independently associated with hs-tnt in women but not men and partially explains increase risk of HF Hs-TroponinT (pg/l) 0.2 0.3 0.5 0.7 1 1.4 3 4 P value for women= 0.03 P value for men= 0.94 0.3 [0.3-0.5] 0.6 [0.4-0.9] 0.6 [0.4-1] 0.3 [0.3-0.6] 0.4 [0.3-0.6] WOMEN (N=893) MEN (N=752) 0.7 [0.5-1.3] NONE MILD MODERATE SEVERE OSA categories 0.6 [0.4-1] 0.5 [0.3-0.7] Fully adjusted Elevated TnT levels partially mediated the association between OSA and CVD Querejeta Roca, Redline, Shah et al. Circulation 2015;132:1329-37.
CVD Mortality In Clinic-Based Samples In Men and Women N=1,652 MEN, followed for 10 yrs OR 2.9 for incident fatal CVD for severe OSA after multiple risk factor adjustment Marin, Lancet 2005 N=1,116 WOMEN followed for 6 yrs OR 3.5 for incident fatal CVD for severe OSA after multiple risk factor adjustment Campos-Rodriguez Ann In Med 2012 *CVD outcomes include stroke, HF
Hypoxemia, Inflammation and Mortality 2531 (MrOS) men followed for 7.4 yrs; 628 deaths SDB and Inflammation AHI>30 associated with: IL-6, CRP >10%SaO 2 TST<90%: IL-6,CRP, IFN-g Inflammation and mortality Number of elevated inflammatory markers SDB and mortality No association with AHI (HR 1.08) >10%SaO 2 TST<90%: HR 1.32 (1.06,1.64) Mediation of SDB and mortality by inflammation Inflammatory burden attenuated association by 42% Smagula, Sleep, 2016
Smoking-Related CVD Stronger In Women with OSA vs Men Women with OSA have more endothelial dysfunction than men with OSA Smoking increases CVD partly via endothelial dysfunction Nieto 2003; Faulx 2004 Sleep Heart Health Study Incident CVD, 3852 followed for 10 years Compared to Non-smokers, AHI < 5 Men, Current Smokers, AHI >15: 1.07 (0.47,2.40) Women, Current Smokers, AHI>15: 4.17 (1.80,9.66) Donovan, L; in review
JAGS 2014
JAGS 2009
Cognitive Deficits and Sleep Apnea Systematic Reviews and Meta-Analyses 298 older women, followed for 4.7 years SDB (AHI>15): aor 1.85 (1.11,3.08) for MCI Meta-Analysis Yaffe JAMA 2011 Meta OR: 1.26 (1.11,1.65) Leng JAMA Neuro 2017 Olaithe M et al Sleep Med Rev 2018
Summary Repetitive breathing disturbances and hypoxemia activate multiple pathophysiological pathways implicated in cardio-metabolic function, inflammation, and brain function Sleep Disordered Breathing (esp hypoxemia) associated with incident diabetes, CAD, stroke, MCI/cognitive decline, frailty and functional decline Associations in women more apparent with long term follow-up SDB and smoking may be interactive risk factors in women SDB is a prevalent and potentially modifiable target to promote health and longevity WHISPER will provide pivotal data in a diverse sample on sleep exposures that increase risk for MCI, HF, and cancer outcomes in older women
Starr County Health Study Study of Osteoporetic Fractures in Older Women (SOF) Sleep Study Sleep Heart Health Study Cleveland Children s Sleep and Health Study Cleveland Family Study WHISPER Sleep Apnea Patient Centered Outcomes Network (MyApnea.Org) and our patient leaders Transomics In Precision Medicine (TOPMed) Dozens of collaborators and staff NIH, NHLBI