Sleep Apnea and Cardiovascular Risk Presented by Akshay Mahadevia, M.D. Diplomate American Board of Sleep Medicine
Objectives Pathogenesis of obstructive sleep apnea, central sleep apnea and Cheyne-Stokes respirations Mechanisms by which sleep apnea has been linked with cardiovascular diseases Cardiovascular diseases associated with sleep apnea Does treating sleep apnea make any difference in outcomes of CV diseases More questions, then answers
OSA Pathogenesis Anatomic abnormalities of upper airways Regulations of pharyngeal dilator muscle activation Unstable ventilatory control (High loop gain)
Central Sleep Apnea (less common than OSA) Cessation of airflow without respiratory effort during sleep Primary alveolar hypoventilation, sleep transition apneas, high altitude, CVA, treatment emergent. Central apneas and Cheyne-Stokes respirations
Cheyne-Stokes Respirations (CSR) CSR is a form of central apnea that is common in CHF (Javahari,, Ann Intern Med 1995) 20 to 40% in patients with systolic heart failure Risks factors included male gender, age, hypocapnia and atrial fibrillation (Sin D et al, Am J Respir Crit Care Med 1999; 160:1101-1106) 1106) CSR is the best independent predictor of mortality in patients with CHF (Lanfranchi:: PA, circulation 1999; 99:1435-1440) 1440)
CSR (con( con t) High ventilatory drive Elevated chemo sensitivity Increased cardiac filling pressures Circulatory delay
Evidence and Mechanisms Linking OSA to Cardiovascular Disease: Over the past two decades, emerging evidence has implicated OSA as a comorbidity in a number of CV conditions (JAMA 2003; 290: 1906-1914) 1914) The effects of OSA have been linked to the activation of a number of mechanisms that may contribute to the development and progression of CV disease Treatment of OSA in patients with existing CV disease conditions has been associated with improvements in these conditions
Mechanisms by which OSA may elicit cardiac and vascular dysfunction: Sympathetic activation Endothelial dysfunction Inflammation Oxidative stress Production of vasoactive substances Metabolic mechanisms Changes in intrathoracic pressure
Sympathetic Activation: In otherwise healthy patients with sleep apnea, sympathetic nerve traffic even during normoxic quiet resting daytime wakefulness is substantially higher than that which is seen in normal control subjects (Somers VK J Clin Invest 1995; 9: 1894-1904) 1904)
Sympathetic Activation (con( con t) During apnea, when the inhibitory influence of hyperventilation is absent, the sympathetic neural response to hypoxia and hypercapnia is potentiated. (Somers VK J Appl Physiol 1989; 67: 2095-2600) 2600) High catecholamine levels indicating high sympathetic activity leads to vasoconstriction causing elevated blood pressure, development of hypertension
Endothelial Dysfunction Carlson JTet al Attenuated endothelium- dependent vascular relaxation in patients with sleep apnea (J Hypertens 1996; 14: 577-584) 584) Kato, Robert-Thomson P, Phillips BA Impairment of endothelium-dependent dependent vasodilation of resistance vessels in patients with OSA (Circulation 2000; 102:2607-2610) 2610)
Endothelial Dysfunction Smaller arterioles do not dilate in response to acetylcholine indicating resistance vessel endothelial dysfunction Some studies have noted decreased conduit vessel endothelial function, with improvement after CPAP therapy (Ipms,, TSC H, Tsengkur,, Endothelial function in obstructive sleep apnea and response to treatment (Am J Respir Crit Care Med 2003; 169:348-353) 353) It is unclear whether endothelial dysfunction is related to sleep apnea independent of hypertention, diabetes, smoking and hyperlipidemia.
Inflammation: Hypoxemia and sleep deprivation seen in sleep apnea causes increases in C-reactive C protein (Shamsuzzanan AS et al, Elevated C AS et al, Elevated C-reactiave protein in patients with OSA. Circulation 2002; 105:2462-2464) 2464)
Inflammation (con( con t): Evidence of systemic inflammatory state in patients with sleep apnea include elevated levels of amyloid A, cytokines, adhesion molecules and increased leukocyte binding to endothelial cells (Svatikova A, et al, Serum amyloid A in obstructive sleep apnea. Circulation 2003; 108:1451-1454; 1454; El-Solh AA, Medor MJ, Sikka P. Adhesion molecules in patients with coronary artery disease and moderate-to to-severe sleep apnea; Chest 2002; 121:1541-1547) 1547)
Oxidative Stress: Repetitive nocturnal hypoxemia causes enhanced release of superoxide from polymorphonuclear neutropils in OSA with inprovement after CPAP therapy. (Schultz R (Schultz R. Am J Resp Crit Care Med 2000; 162:566-570) 570)
Production of Vasoactive Substances: Severe hypoxemia in OSA has been implicated as a possible cause for the release of vasoactive substances such as endothelin (Phillips BA, Narkiewicz K, Pesek al.) Effects of obstructive sleep apnea on endothelin and blood pressure (J 1999; 17:61-66) 66) Pesek OA et (J Hypertens
Production of Vasoactive Substances (con( con t): Sleep apnea may trigger release of atrial natriuretic peptide but brain natriuretic peptide does not appear to increase in OSA patients. (Svatikova A, Shamsuzzanan AS, Wolk R et al. Plasma brain natriuretic peptide in obstructive Sleep Apnea. Am J Cardiol 2004; 94:529-532) 532)
Metobolic Mechanisms: Extensive data have suggested that sleep apnea is accompanied by a state of metabolic dysregulation and that sleep apnea may be an important part of metabolic syndrome (Coughlin S, Mawdsley C, Magarza JA et al.) Obstructive sleep apnea is independently associated with an increased prevalence of metabolic syndrome. EMR Heart J 2004; 25:735-741) 741)
Metobolic Mechanisms (con( con t): Sleep apnea patients have been noted to have increased insulin resistance. This has been proven to be independent of presence of obesity. (IP MS, Lam B, Ply Mon et al. Obstructive sleep apneas is independently associated with insulin resistence.. Am J Respir Crit Care Med 2002; 165:670-676) 676) Enhanced leptin resistance so that leptin levels in male sleep apneics are higher than in similarly obese men without sleep apnea. (Phillis BK.. Am J Physiol Heart Circ Physiol 2000; 279:h234-h237.) h237.)
Changes in Intrathoracic Pressure: In OSA during repetitive Mueller maneuvers, very significant negative intrathoracic pressure are generated causing cardiac transmural pressure gradient which may cause cardiac wall stress and other hemodynamic effects.
Cardiovascular Diseases Associated with OSA: Hypertension Atrial fibrillation Other cardiac dysrhythmias Heart failure Cardiac ischemia
Hypertension: The Wisconsin Cohort study has shown that over a 4 year followup,, OSA is independently linked with a threefold increase in the likelihood of new hypertension developing, as compared to patients without sleep apnea. (N Engl J Med 2000; 342:1378-1384) 1384) Treatment of OSA has resulted in significant reduction in blood pressure not only at night but also in the morning. (Circulation 2003; 107:68-73) 73)
The association between OSA and hypertension has prompted the most recent Joint National Committee 7 guidelines for the management of hypertension to list OSA as first of the identifiable causes of hypertension.
Atrial Fibrillation: The patients with OSA are more likely to develop AF postoperatively after bypass surgery. (Coronary Art Disease 1996; 7:475-478). 478). About 50% of patients coming for cardioversion respond to questionnaires assessing risk for OSA in favor of having OSA (Circulation 2004; 110:364-367.) 367.) Of those who are cardioverted successfully, the presence of untreated OSA is accompanied over 1 year, about double compared to risk of recurrance of AF in patients whose OSA has been treated (Circulation 2003; 107:2589-2594) 2594)
Mechanisms of Developing Atrial Fibrillation in Patients with OSA: Hypoxemia Sympathetic activation Increased blood pressure Abrupt increase in negative intrathoracic pressure
Other Cardiac Dysrrhythmias: OSA has also been linked to PVC s s and ventricular tachycardia Diving reflex in OSA has been shown to cause bradyarrythmias Diving reflex consists of increased cardiac vagal drive along with sympathetic activation to peripheral blood vessels except to the brain and to the heart. Severe bradyarrythmias can occur in the setting of a completely normal cardiac conduction system. (Lancet 1979; (1) 81119:764-767) 767)
Heart Failure While central sleep apnea is the most prominent type of sleep-disordered breathing in heart failure, OSA may be present in 10% or more of heart failure patients. Treatment of OSA improves ejection fraction in heart failure patients (N Engl J Med 2003; 348:1233-1241; Am J Respir Crit Care med 2004; 169:361-366) 366) Even though several studies have shown significant benefit of nasal CPAP therapy in terms of cardiac function in patients with CHF and OSA, mortality benefits from treatment of OSA in heart failure patients is not known.
Cardiac Ischemia: Hypoxemia and increased afterload in OSA can lead to nocturnal cardiac ischemia in patients with pre-existing existing coronary artery disease. ST depression has been noted to be more frequent in patients with CAD who have more severe OSA. (Lancet 1995; 305:1085-1087)
Cardiac Ischemia (con( con t) Patients with known CAD and OSA have an increased 5 year mortality compared with those who do not have OSA (Am J Respir Crit Care Med 2000; 162: 31-86) Duration of ST depression is attenuated by application of nasal CPAP therapy
Central Sleep Apnea: Implications for the Failing Heart: A number of studies have implicated CSA as a marker of poorer prognosis in heart failure patients. (Circulation 1999; 99:1435-1440, 1440, Am J Respir Crit Care Med 1996; 153;272-276) 276) In a population with moderate to severe heart failure, an AHI 30 is accompanied by very high 2 year cardiac mortality, independent of other risk factors. Central sleep apnea or CSA may be a consequence of heart failure, presence CSA has detrimental effect on cardiac function. (Am J Cardiol 1998; 81: 432-436) 436)
Mechanisms Affecting Cardiac Functions in Heart Failure Patients with CSA: Heart failure patients with CSA have higher levels of sympathetic activation, as evidenced by plasma and urine norepinephrine. (Am J Respir Crit Care Med 1995; 152: 473-479) 479) Higher sympathetic activity affects heart rate and blood pressure which may be more problematic in the context of failing heart
Mechanisms Affecting Cardiac Functions in Heart Failure Patients with CSA (con( con t): Bradyarrythmias caused by CSA due to diving reflex also may be less tolerated by failing heart. Higher prevalence of ventricular arrythmias has been demonstrated in patients with heart failure with CSA than without.
Treatment of CSA in Congestive Heart Failure: CSA occurring during heart failure may activate pathologic mechanisms that contribute to progression of heart failure and increased mortality. Improved heart failure management reduces central sleep apnea severity by Decrease in pulmonary congestion Improvement in circulation time Improvement in blunted neurohumoral activation Decrease cardiac filling pressures
Treating CSA improves heart failure, which includes: -Oxygen therapy -Theophylline -Acetazolamide -Positive pressure therapy -Cardiac pacing
Oxygen Therapy: Low level nocturnal oxygen therapy has shown to improve sleep quality, cognitive function, sympathetic activity and cardiac functional status. (Hanly PF et al. The Effect of oxygen on respiration and sleep in patients with congestive heart failure. Am Intern Med 1989; 111: 777-782. Staniforth AD et al. Effect of oxygen on sleep quality, cognitive function and sympathetic activity in patients with chronic heart failure and Cheyne-Stokes respiration. Eur Heart J 1998; 19: 922-928) 928)
Theophylline: A phosphodiesterase inhibitor, has been shown to significantly attenuate CSA in heart failure. Due to cardiovascular adverse effects of theophylline,, its use is limited. (Javaheri S, parker TJ, Wxler L, et al. Effects of theophylline on sleep-disordered breathing in heart failure N Eng J Med 1996; 335: 562-567) 567)
Acetazolamide: Carbonic anhydrous inhibitor decreases bicarbonate levels and changes CO 2 levels which stabilizes ventilatory control.
Positive Pressure Therapy: Nasal CPAP therapy leads to stabilization of breathing pattern, redness catacholamines, increases LV ejection fraction by reducing cardiac preload and afterload. Sin s s study demonstrated that over 5 years, heart failure patients with CSA randomly assigned to receive CPAP therapy treatment had an improved transplant force survival compared with those randomly assigned to receive no treatment. (Circulation 2000; 102 61 (Circulation 2000; 102 61-66) 66)
A large randomized study addressing this question, the CANPAP trial was prematurely discontinued, and outcome results are pending (CANPAP. Can J Cardiol 2001; 17: 677-684). 684). Adaptive ventilation (Heart PAP) has been shown to be better tolerated and more effective in treating CSA in heart failure patients. (Teschler H, Dohring J, Wang Yon et al. Adaptive pressure support servo-ventilation: ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med 2001; 164: 617-619) 619)
Pacing in Treatment of CSA with Heart Failure: Garrigne s study in 2002 demonstrated that atrial overdrive pacing significantly attenuated both central and obstructive sleep apnea (N Egnl J Med 2002; 346: 404 Cardiac resynchronization therapy with biventricular pacing has been shown to significantly decrease mortality in heart failure patients with EF below 30%. J Med 2002; 346: 404-411) 411)
Pacing in Treatment of CSA with Heart Failure (con( con t): Sinha s group demonstrated that in patients with a low EF of around 24% and LBBB, cardiac resynchronization therapy significantly lowered the severity of CSA and greatly improved sleep quality. (J Am Coll Cardiol 2004; 44: 68-71)