1. Sleep and Cardiovascular Disease KD Weeks, MD, FACC, FAASM

2. No disclosures to report

3. Impact of Cardiovascular Disorders 900,000 deaths per year in USA Hypertension alone affects 75 million Americans, many misdiagnosed as “essential” Research has discovered evidence of bidirectional relationship of sleep apnea and c-v disorders Mechanisms: Arousals > neuro-hormonal activation > release of inflammatory mediators (cytokines) and adhesion molecules > reactive oxygen species and transcription factors due to oxidative stress Javaheri Principles and Practice of Sleep Medicine 2004

4. Web Traffic to www.acc.org Subsite on Sleep Apnea and Heart Failurewww.acc.org

5. Possible C-V Complications of OSA Endothelial dysfunction Hypertension Pulmonary hypertension Systolic or diastolic heart failure Arrhythmias Coronary artery disease TIA and stroke Dementia Death

6. Impact of Therapy Treatment of obstructive and central sleep apnea with PAP results in improvement of c-v morbidity and mortality Unclear whether OSA treatment reduces risk of sudden cardiac death Fanari ACC-Cardiosource 2014

8. Hypertension and OSA Known for decades but difficulty proving causal relationship and benefit of CPAP therapy Severity of OSA at baseline impacts future onset of hypertension (Wisconsin Sleep Cohort) Small but significant reduction in daytime blood pressure in normotensive patients after four weeks of PAP therapy Refractory hypertension, eg 3 drugs at maximum dose with persistent hypertensive pressure elevations, is associated with OSA in 83% of patients Non-sleepy patients with OSA may be immune to the bp lowering effect of therapy

10. Sleep Apnea and Stroke Chronic intermittent hypoxia is a key factor in vascular inflammation, atherosclerosis, and endothelial disease Cycle of inflammation Rise in sympathetic activity and blood pressure amplify the effect of the cycle of inflammation Impact of atrial fibrillation and patent foramen ovale also contributes to the risk of embolic stroke

11. Javaheri 2007 Sleep Medicine Clinics

13. Sleep Disordered Breathing and Atrial Fib New data on mechanisms and impact: Upper airway collapse > hypoxia > ventilator overshoot > hypercapnia > autonomic instability and intrathoracic pressure alterations Increased state of thrombosis, inflammation, and oxidative stress produce a pro-arhythmogenic milieu, atrial macro-reentry, and automaticity OSA is a powerful predictor of ablation failure, independent of atrial enlargement, obesity, or hypertension A fib will affect up to 16 million patients by 2050 A fib will cost $6.7 billion per year In a cardiology practice the majority of OSA patients have been referred by electrophysiologists Future strategies? Mehra ACC-Cardiosource 2014

14. Pulmonary Hypertension (PAH) and Sleep Apnea OSA recognized by WHO in 1998 as a secondary cause of PAH 15 – 70% of OSA patients have PAH COR pulmonale may occur in cases of severe OSA, especially if associated with high PaCO 2 Several but not all studies show compliant, effective treatment of OSA improves PAH

16. Obstructive and Central OSA and Heart Failure HF R EF HF P EF Major public health issue High mortality and morbidity Frequent hospital admissions and readmissions High economic impact Obstructive sleep apnea is the most common, least recognized co-morbidity -- 70% of HF patients have OSA/CSA Similar symptoms in heart failure and OSA CSA associated with higher mortality PAP may not improve mortality in HF patients

17. Obstructive and Central OSA and Heart Failure HF R EF HF P EF (cont’d) CSA is suppressed in 50% of HF patients by CPAP In HF patients OSA is not associated with daytime sleepiness ASV is recommended for CPAP non-responders with CSA

18. Meddic.jp

19. Coronary Heart Disease and Sleep Apnea CAD estimated to be present in 20– 25% of OSA patients Prevalence is 30% in case controlled studies with an independent association Direct causality is not well established Major cardiac events are more likely in patients with severe OSA CPAP may significantly reduce c-v events AHI severity is an independent predicator of mortality in patients with CAD Screening for both disorders in patients with risk factors for one is suggested as well as co-management strategies Impaired sleep in men and disturbed sleep in women may be related to moderately higher risk of poor cardiac prognosis after first AMI (A. Clark SLEEP2014)

21. Patent Foramen Ovale and Sleep Apnea Congenital cardiac defect present in approximately 25% of healthy adults and usually asymptomatic Patients with PFO might have left to right shunt which can lead to systemic embolization It is little known and poorly studied Severe OSA may raise the risk of complications in patients with elevated right heart pressures

23. Amplatzer PFO Occluder

25. Gore Helex PFO Occluder

26. Patent Foramen Ovale and Sleep Apnea Questions 1.Do patients with severe OSA have a higher prevalence of PFO compared to healthy individuals? 2.Does PFO combined with OSA result in higher stroke risk? 3.Does percutaneous PFO closure improve OSA symptoms?

27. Insomnia and C-V Disease Risk 20% of US adults are affected by insomnia but only 10% are chronic Death mechanism is unclear but inflammation due to stress can be measured by C-reactive protein which is associated with cardiovascular risk One 38 year study of 1,409 adults concluded that persistent but not intermittent insomnia was associated with increased all-cause and cardiopulmonary mortality, and a steeper increase in inflammatory markers (S. Parthasarathy American Journal of Medicine 2014)

28. Punjabi NM PLoS Med2009

29. Sleep Disorders and Mortality Many prospective long term studies suggest that untreated patients with OSA have higher risk of death from all causes, particularly cardiovascular There is a relationship between severity of the OSA and cardiovascular risk OSA predicts incident sudden cardiac death and the risk magnitude is predicted by multiple parameters characterizing OSA severity, independent of established risk factors Therapy with effective compliant PAP significantly reduces mortality from c-v disease and auto accidents

30. Sleep Apnea and the Association with Cancer Peppard PE; Nieto FJ. Here come the sleep apnea-cancer studies. SLEEP 2013;36(10):1409-1411.

31. Sleep and Cardiovascular Disease KD Weeks, MD, FACC, FAASM

32. Graphics Permissions Slide 2: Creative Commons Attribution License by Chris Potter on www.stockmonkey.com Slide 4: © American College of Cardiology Slide 7: © 2015 Kenneth D. Weeks, Jr., MD Slide 9: Public Domain image by the National Heart Lung and Blood Institute (NIH) on Wikimedia Commons Slide 11: © 2007 Shahrokh Javaheri, MD Slide 12: © 2015 Kenneth D. Weeks, Jr., MD Slide 15: © 2007 Shahrokh Javaheri, MD Slide 20: Creative Commons Attribution-NonCommercial 2.0 Generic. Some rights reserved by HeartBabyHome. Adapted with permission by cropping and resizing. Slide 22: © 2006 W. L. Gore & Associates, Inc. Slide 23: Crown Copyright by Capital & Coast District Health Board, New Zealand Slide 24: © 2006 W. L. Gore & Associates, Inc. Slide 25: © 2006 W. L. Gore & Associates, Inc. Slide 28: Creative Commons Attribution License by Punjabi et al. PLoS Med 2009 August.