1. Sleep Apnea and Cardiovascular Disease Randy A. Jordan, M.D. Interventional Cardiologist CMO-Jack Stephens Heart Institute CHI St. Vincent Heart Clinic Arkansas April 25, 2015

2. Common Problems Referred For Cardiology Evaluation Fatigue/ Malaise Palpitations Dyspnea Syncope Uncontrolled Hypertension Edema

3. Sleep Apnea Syndrome Fatigue Hypersomnolence Snoring Obesity BMI >30 Large Neck Circumference >16 inches in women >17 inches in men Morning Headaches Memory or Learning Difficulties Sexual Dysfunction

4. Complications and Commorbidities Death * 4 X Stroke * 3.7 X Cancer * 3.4 X Refractory Epilepsy (30% have OSA) Parkinson’s Disease (>20% have OSA) Cardiovascular Disease Busselton Health Study 20 year follow up

5. Definitions Apnea: Cessation of Airflow > 10 sec Hyponea: >50% reduction in airflow for >10 sec AHI: Apnea Hypopnea Index: the number of apneas and hypopneas per hour of sleep Severity: –Normal: AHI < 5 –Mild: AHI 5 – 15 –Moderate: AHI 15 – 30 –Severe: AHI >30 Sleep Apnea Syndrome (SAS) 3 : AHI of > 5 with symptoms.

6. Types of Sleep Apnea Obstructive (OSA): –Apnea with ventilatory efforts due to pharyngeal collapse –~90% of sleep apnea cases 4 Central (CSA): –Apnea without ventilatory effort due to withdrawal of central drive –Thought to be due to decreased cardiac output –Cheyne-Stokes respiration a subset of CSA –~10% of sleep apnea cases 4 Mixed: –Apnea with central component followed by obstructive component –Often classified as obstructive sleep apnea

7. Prevalence of Sleep Apnea in the General Population In individuals aged 30-60 years 5 : –9% of women and 24% of men have AHI > 5 –2% of women and 4% of men have Sleep Apnea Syndrome AHI > 5 + symptoms of daytime sleepiness –4% of women and 9% of men have AHI>15 –Common threshold for treatment –>10% of individuals over the age of 65 years 6,7 –Vast majority undiagnosed >12 million people in the U.S. alone 8

8. Prevalence of Sleep Disordered Breathing in the General Population Young T, et al. Predictors of Sleep-Disordered Breathing in Community-Dwelling Adults. Arch Intern Med 2002; 162: 893-900.

9. Sleep Apnea and Cardiovascular Abnormalities Sleep Apnea Dyslipidemias Increased fibrinogen, Leptin, Insulin resistance Abnormal Endothelial function Autonomic Dysfunction Arrhythmias Hypertension

10. Sleep Apnea and Hypertension ~30% of patients with hypertension have sleep apnea 61-67 >60% of sleep apnea patients have hypertension 68 *Hypertension was defined as a BP > 140/90 mmHg or the use of antihypertensive medications. Data extracted from Table 3: Peppard P et al. N Engl J Med 2000; 342: 1378-84.

11. Sleep Apnea and Coronary Artery Disease 30-50% of patients with CAD 2.7 fold increase in coronary calcification in non-obese patients with SA

12. Sleep Apnea and CHF Prevalence of CHF is 4.9 MM Americans 82 ~50% of patients with heart failure have sleep apnea 83, 84 >60% of patients with LVEF 15) 85 High co-morbid incidence of SDB 86 –End stage CHF – Cheyne Stokes Respirations –Obstructive SAS probably grossly under recognized –Vascular reactivity abnormalities –Renal perfusion and sodium retention

13. Sleep Apnea and CHF Potential interaction of SDB and CHF include: –Activation of Sympathetic nervous system –Vascular reactivity abnormalities –Renal perfusion and sodium retention –Dietary and medication compliance issues Bradley, Floras, Journal of Cardiac Failure, 2:223-240

14. Sleep Apnea and CHF: Clinical Observations Patients with OSA and CHF may be prone to volume related changes in upper airway resistance. Changes in effectiveness of CPAP may diminish renal perfusion and augment unwanted sodium and fluid retention. Patients with OSA and volume overload do not respond as well to oral diuretics and may have worsening renal function. Documenting and treating increases in airway resistance have important and dramatic clinical effects on CHF. Effectively treating OSA can have a positive impact on HF status. 87

15. Effect on CHF volume overload Daily weight monitoring – no change in diuretic medication Download of CPAP data: pressure dropped to 8 cm Initiation of Auto titrating CPAP: pressure 18 cm Data on file: Dr. Randall Williams, Northwestern University

16. Central Sleep Apnea and Heart Failure Bradley, Floras, Journal of Cardiac Failure, 2:223-240 Fatigue Left Ventricular Failure: Cardiac Output LV Filling Pressure Pulmonary edema Pulmonary afferent stimulation Hyperventilation Central Apnea Cardiac O 2 Supply vs. Demand PaO 2 PaCO 2 SNACatecholaminesHR Arousal Sleep Disruption Hypersomnolence PaCO 2

17. Sleep Apnea and Cardiac Arrhythmias Bradyarrhythmias: –AV Block and asystoles have been reported in up to 10% of patients with sleep apnea 74-77 Tachyarrhythmias and ventricular ectopy: –Ventricular ectopy has been reported in up to 66% of patients with sleep apnea syndrome 78-80 –Ventricular tachycardia more common in patients with sleep apnea (0-15%) vs. the general population (0-4%) 81

18. Figure 1. Comparison of the number of ventricular arrhythmias occurring simultaneous to disordered breathing (AI) and ventricular arrhythmias occurring during the time of normal breathing (NAI) in all patients with sleep-related breathing disorders and ventricular tachyarrhythmias during sleep. *Indicates patients with CSR. Fichter J, et al. Chest. 2002;122:558-561. Sleep Apnea and Cardiac Arrhythmias

19. Sleep Apnea and Atrial Fibrillation 25% of Atrila Fib patients have SA 3.65 Fold increase in stroke risk if SA is present SA not currently used in stroke risk stratification CHADS 2 score 0 2 x Risk CHA 2 DS 2 VAS C score 0 and 1 1.62 x Risk

20. Acute Effects of Sleep Apnea Acute Effects of Sleep Apnea 42 Negative intrathoracic pressure –Increased LV transmural pressure –Increased afterload –Increased venous return –Diminished LV relaxation and filling –Reduced Stroke Volume and Cardiac Output –Vasoconstriction Mediated through baroreceptor activation: Aortic and carotid

21. Acute Effects of Sleep Apnea Acute Effects of Sleep Apnea 43 Hypoxia –Pulmonary artery vasoconstriction –Increased sympathetic nerve activity (SNA) –Surges in HR and BP at end of apnea –The degree of desaturation is directly related to increase in BP –O 2 administration has little effect

22. Chronic Effects of Sleep Apnea Autonomic dysfunction 44-50 –Both sympathetic activation and parasympathetic withdrawal –Sleep and wake both effected –Increase in BP variability –Decrease in heart rate variability –Increased arrhythmia, V-Tach, Sudden Death –Hypoxia seems to exacerbate the dysfunction

23. Chronic Effects of Sleep Apnea Circulating hormones –Atrial natriuretic peptide increased 51-52 –Unclear results for renin, aldosterone, and vasopressin –Clear elevation in Endothelin-1 levels 53 Insulin resistance 54-55 Leptin resistance 56-57 Increased PAI-1 and fibrinogen levels 58-59 –Role in atherosclerosis and thrombosis

24. Effects of OSA on Cardiovascular System PaO 2, PaCO 2 Myocardial O 2 Delivery Cardiac Ischemia Hypertrophy Cardiac Failure Stroke Volume LV wall tension Cardiac O 2 demand Intrathoracic Pressure Arousal SNA Catecholamines Hypertension HR BP Bradley, Floras, Journal of Cardiac Failure, 2:223-240 Acute Chronic Obstructive Apnea

26. Conclusions Sleep Apnea is a highly prevalent, underdiagnosed disease with significant effects on the cardiovascular system. Many common problems referred to cardiologist are associated with sleep apnea and successful treatment frequently requires treatment of the underlying sleep disorder.