Virend K. Somers, MD, DPhil
What is the connection between sleep apnea and heart disease?
The connection between sleep apnea and heart disease is evolving very rapidly. People with cardiovascular problems such as high blood pressure, heart failure and stroke, have a high prevalence of sleep apnea. Whether sleep apnea actually causes heart disease is still unclear, but we do know that if you have sleep apnea today, the chance that you will develop hypertension in the future increases significantly.
One of the problems in defining the relationship between sleep apnea and heart disease is that people with sleep apnea often have other co-existing diseases as well.
If you treat people with high blood pressure and sleep apnea, or heart failure and sleep apnea, the measures of blood pressure or heart failure are significantly improved. There is good evidence to think there is a cause-and-effect relationship between hypertension and sleep apnea.
Why does your blood pressure go up when your sleep is disrupted by sleep apnea?
Your blood pressure will go up because when you're not breathing, the oxygen level in your body falls and excites receptors that alert the brain. In response, the brain sends signals through the nervous system and essentially tells the blood vessels to "tighten up" in order to increase the flow of oxygen to the heart and the brain, because they have priority.
The problem is that things that go on at night tend to carry over in the daytime, even when the sleep apnea patient is awake. The low oxygen levels at night seem to trigger multiple mechanisms that persist during the daytime, even when the patient is breathing normally.
How can CPAP (continuous positive airway pressure) reduce the cardiovascular consequences of sleep apnea?
The available evidence tells us that when you treat people with sleep apnea using CPAP, their blood pressure is not only lower at night—it's also lower during the day. That's a very good thing. Moreover, people with atrial fibrillation [a common type of irregular heart beat] with sleep apnea that is appropriately treated have only a 40% chance of coming back for further treatment of their atrial fibrillation. If their sleep apnea is untreated, the chance of a recurrence of atrial fibrillation goes up to 80%. The message to heart patients with sleep apnea is: With treatment of your sleep apnea, your chances of improvement are considerably better.
--Dr. Somers is Professor of Internal Medicine in the Division of Cardiovascular Diseases at the Mayo Clinic in Rochester, MN.
Sleep-Related Breathing Disorders in Heart Failure
by Shahrokh Javaheri, M.D.
Epidemiology of Heart Failure
Heart failure is a highly prevalent problem affecting approximately 5 million Americans, or 2% of the population. Multiple factors contribute to the rising incidence of heart failure. Among these are an increased average life span, improved therapy of ischemic coronary artery disease, and hypertension. Not surprisingly, therefore, the incidence and prevalence of heart failure is very much age-dependent with the prevalence increasing two-fold after 45 years of age. It is estimated that 10% of adults, 80 years or older, have heart failure. The incidence and prevalence of heart failure will continue to rise into the 21st century.
Heart failure with left ventricular systolic dysfunction is associated with excessive mortality. Due to loss of cardiac myocytes and fibrosis, death eventually follows. The annual mortality rate of patients with severe heart failure and systolic dysfunction is about 36%.
Depending on age, a considerable number of patients with symptoms of congestive heart failure may have isolated diastolic heart failure. Similar to systolic heart failure, isolated diastolic heart failure is also associated with excessive morbidity and repeated hospitalization.
The economic impact of heart failure is significant. The estimated cost of heart failure in the US is about $20 billion annually.
Epidemiology of sleep-related breathing disorders in heart failure
Prevalence of Sleep-Related Breathing Disorders in Heart Failure with Systolic Dysfunction
Fifty percent of ambulatory patients with treated, stable heart failure with left ventricular systolic dysfunction have periodic breathing during sleep. Approximately 40% have predominately central sleep apnea-hypopnea and 11% have obstructive sleep apnea-hypopnea (1-5).
Prevalence of Sleep-Related Breathing Disorders in Diastolic Heart Failure
Systematic studies to define the prevalence and impact of sleep-related breathing disorders in isolated diastolic heart failure are lacking. Chan et al (6) studied 20 patients (mean age 65±6), 85% of whom had systemic hypertension. Polysomnography showed that fifty-five percent (11/20) of the patients had 10 or more abnormal breathing events as measured by an overnight sleep study.
Since prevalence of both isolated diastolic heart failure and sleep apnea increase with age, it might be expected that a large percent of the senior population may have both disorders, resulting in a vicious cycle between heart failure and sleep apnea.
Pathophysiology
Effects of Sleep-Related Breathing Disorders on Sleep
Sleep is not homogenous and consists of two neurophysiologically distinct states of non-rapid and rapid eye movements. Stages 1, 2, 3 and 4 constitute approximately 80% of sleep and are collectively called non-rapid eye movement (NREM) sleep. Approximately 20% of sleep is REM (rapid eye movement) sleep. Sleep becomes progressively deeper from stage 1 to 4, and characteristically sympathetic nervous activity decreases. In REM sleep, however, sympathetic activity intermittently increases. In order to have normal sleep, it is important that interruption does not occur. In the presence of sleep apnea, however, sleep continuity is disrupted. Many arousals and excess light sleep lead to daytime sleepiness in these patients.
Consequences of Sleep-Related Breathing Disorders on Heart Failure
Recurrent episodes of apnea and hypopnea may result in blood gas abnormalities, excessive arousals, and large negative deflections in pressure surrounding the heart (7-8). These adversely affect cardiac function and are briefly discussed below.
Hypoxemia has both direct and indirect effects on cardiovascular function. Hypoxemia results in a decreased myocardial oxygen delivery, which could impair both systolic and diastolic function of the heart. Indirectly, hypoxemia may affect cardiac function by a host of neuro-hormonal mechanisms such has increased sympathetic activity and endothelin, a potent vasoconstrictor. Hypoxemia may also act as a promoter of the inflammatory process, which in turn may play a role in coronary atherosclerosis.
Arousals cause sympathetic nervous system activity, and therefore, recurrent arousals along with hypoxemia and hypercapnia result in further nocturnal sympathetic activity in patients with sleep apnea and heart failure. Since reduction in sympathetic activity is an important therapeutic measure, residual excessive nocturnal sympathetic overload due to sleep apnea may adversely affect cardiac function.
Large negative deflection in pleural pressure occurs during obstructive sleep apnea and to a lesser extent during hyperpnea following central apnea. The negative pressure surrounding the heart increases the work the heart must do to pump blood, and this may have deleterious effects on left ventricular function.
In conclusion, the consequences of sleep apnea and hypopnea could potentially affect cardiac function adversely (7), contributing to an increase in morbidity and mortality of patients with heart failure. Several studies have shown increased mortality in heart failure patients with central sleep apnea when compared to heart failure patients without this disorder (9-11). There are no studies regarding the effects of obstructive sleep apnea on survival of heart failure patients. However, studies of the general population have shown that obstructive sleep apnea is associated with increased mortality, (12) and this most likely applies to those with heart failure as well.
Clinical Presentation
The clinical presentation of obstructive sleep apnea in subjects with heart failure is similar to that of subjects without heart failure. Obesity and habitual snoring (snoring every night or almost every night) are the hallmarks of obstructive sleep apnea (2, 3). In contrast, subjects with heart failure and central sleep apnea are commonly thin and the majority do not snore habitually (2). Furthermore, since many symptoms of heart failure such as nocturnal dyspnea, nocturia and daytime fatigue and sleepiness overlap with symptoms of sleep apnea, clinical suspicion for sleep apnea, particularly central sleep apnea in heart failure, is difficult.
There are several markers, however, that when present should increase suspicion for central sleep apnea (2, 3). These include the presence of low arterial PCO2 (below 35 mm Hg), atrial fibrillation, and ventricular arrhythmias. As is the case with obstructive sleep apnea, the presence of witnessed apnea, nocturnal dyspnea, waking up unrefreshed, and excessive daytime sleepiness should also increase suspicion for the presence of central sleep apnea.
Investigation
Formal sleep study (polysomnography) is the gold standard and most reliable diagnostic method to confirm a sleep-related breathing disorder both in the general population and in subjects with heart failure. Accredited sleep facilities in the US usually have an individual on staff who is a diplomate of the American Board of Sleep Medicine, and technologists who have special training in sleep and are qualified to conduct sleep studies. In polysomnography, brain waves, muscle and eye movements, breathing and oxygen levels, snoring, heart rate and leg movements are recorded. From these recordings, stages of sleep, the number of arousals, apneas and hypopneas, and the magnitude of desaturation can be calculated. The role of less comprehensive, limited monitoring, for example, nocturnal pulse oximetry with or without respiratory effort (thoracoabdominal excursions), and naso-oral airflow need to be fully elucidated. Specifically, when oximetry alone is used, a negative study does not necessarily rule out the presence of sleep-related breathing disorders.
Treatment of Sleep-Related Breathing Disorders in Heart Failure
There are no established treatments for sleep apnea in heart failure. Large scale randomized controlled studies to determine morbidity and mortality of heart failure patients with sleep apnea are still lacking. However, preliminary studies on a small number of patients show that surrogates of mortality of heart failure such as norepinephrine level, ejection fraction and exercise tolerance, may improve with treatment. The following summarizes the present approach to treatment (7).
Optimization of Cardiopulmonary Function
Our initial approach is to optimize treatment of heart failure itself, since improvement in cardiopulmonary function may resolve or improve sleep-related breathing disorders.
Treatment of Obstructive Sleep Apnea-Hypopnea in Patients with Heart Failure
Treatment of obstructive sleep apnea-hypopnea in heart failure is similar to that of obstructive sleep apnea without heart failure. Weight loss and mechanical ventilatory devices such as continuous positive airway pressure (CPAP) are the therapeutic choice. CPAP is the most common effective treatment for obstructive sleep apnea. Wearing a mask over the nose during sleep, pressure from an air blower forces air through the nasal passages to prevent upper airway closure. The use of CPAP may decrease the number of nocturnal ventricular arrhythmias (13) and also increases left ventricular ejection fraction (14). Supplemental nasal O2 administered at night might be helpful for CPAP noncompliant subjects.
Treatment of Central Sleep Apnea in Patients with Heart Failure
After optimization of cardiopulmonary function, if periodic breathing persists, several approaches are possible (7).
Three practical therapeutic options include use of oxygen, mechanical ventilatory devices and theophylline.
Oxygen
Oxygen is an effective drug, and in some patients virtually eliminates central apneas (15).
In a randomized, single-blind, placebo-controlled crossover study, Hanly and associates (16) showed that one night administration of 2 to 3 l/min nasal oxygen (when compared to compressed air) improved sleep disordered breathing events, desaturation and sleep quality. In a randomized, double-blind, placebo-controlled, crossover trial, Andreas and associates (17) showed that one week treatment with nocturnal oxygen improved exercise capacity of heart failure patients with sleep apnea. Another study (18) has shown that use of nocturnal O2 decreases urinary norepinephrine levels by about 50%.
Mechanical Devices
Nasal continuous positive airway pressure (CPAP) has been most extensively studied (13, 19, 20). However, other mechanical devices such as bilevel ventilatory support and adaptive pressure support servo-ventilation have been also used. The latter device (21) could be promising particularly in subjects with severe central sleep apnea.
Virtually all these studies have been conducted in patients with heart failure and left ventricular systolic dysfunction. We studied 21 patients with central sleep apnea, nine of whom responded to CPAP (43% of patients with CSA) (13). In these patients, CPAP virtually eliminated disordered breathing (apnea-hypopnea index decreased from 36 per hour to 4 per hour) and reduced arterial oxyhemoglobin desaturation. An important finding in our study was the effect of CPAP on ventricular irritability during sleep. In patients whose sleep apnea responded to CPAP, the number of premature ventricular contractions, couplets and ventricular tachycardias decreased with CPAP. In contrast, CPAP had no significant effect on ventricular irritability in patients whose disordered breathing did not improve.
Other studies demonstrated that long-term use of CPAP decreased sympathetic activity and increased left ventricular ejection fraction (19-20).
Since sudden death (presumably caused by ventricular arrhythmias) and pump failure are the two major causes of death in heart failure patients, chronic use of CPAP by decreasing ventricular arrhythmias and improving ejection fraction may improve survival (22). Large-scale systematic studies, however, are needed.
Theophylline
In a double blind, placebo-controlled, crossover study in 15 patients with heart failure and systolic dysfunction, we observed that theophylline at therapeutic serum concentrations improved central sleep apnea (23). However, before widespread use of theophylline, long-term studies are necessary to assure its safety in the setting of congestive heart failure.
Summary
Heart failure with systolic and diastolic dysfunction is highly prevalent, has major health economical impact, and is associated with excessive morbidity and mortality.
Multiple factors may contribute to the progressively declining course of heart failure. One such cause could be the occurrence of disordered breathing during sleep. Several studies have shown a high prevalence of central and obstructive sleep apnea in heart failure. The pathological consequences of sleep apnea may adversely affect the natural history of heart failure. Diagnosis and treatment of sleep-related breathing disorders may improve survival of heart failure patients. Preliminary studies on a small number of patients with systolic heart failure are consistent with this notion. However, long-term studies on a large number of subjects with heart failure are needed.
Diagnosis of sleep-related breathing disorders requires a sleep study (polysomnography). Several treatment options including mechanical devices, oxygen and theophylline are available. Preliminary studies show that these therapeutic options decrease the number of sleep-related breathing disorders, improve sleep quality, improve oxygen desaturation, decrease urinary norepinephrine excretion, increase left ventricular ejection fraction, and may improve survival. However, large systematic studies need to be performed to better define the impact of treatment on morbidity and mortality.
--Shahrokh Javaheri, MD, is Professor of Medicine at the University of Cincinnati and Director of the Sleep Disorders Laboratory at the Veterans Affairs Medical Center and Consultant, Sleep Disorders Program, University of Cincinnati and Sleepcare Diagnostics. He is recognized as an international expert on the heart and sleep disorders. E-mail: Shahrokh.Javaheri@med.va.gov.
References
1. Javaheri S, Parker TJ, Wexler L, Michaels SE, Stanberry E, Nishyama H, Roselle GA. Occult sleep-disordered breathing in stable congestive heart failure. Ann Intern Med 1995; 122:487-492. [Erratum, Ann Intern Med 1995;123:77.]
2. Javaheri S, Parker TJ, Liming JD, Corbett BS, Nishiyama H, Wexler L, Roselle GA. Sleep apnea in 81 ambulatory male patients with stable heart failure: Types and their prevalences, consequences, and presentations. Circulation 1998; 97:2154-2159.
3. Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999; 160:1101-1106.
4. Tremel F, Pépin J-L, Veale D, Wuyam B, Siche J-P, Mallion JM, Lévy P. High prevalence and persistence of sleep apnea in patients referred for acute left ventricular failure and medically treated over 2 months. Eur Heart J 1999; 20:1201-1209.
5. Solin P, Bergin P, Richardson M, Kaye D, Walters EH, Naughton MT. Influence of pulmonary capillary wedge pressure on central apnea in heart failure. Circulation 1999; 99:1574-1579.
6. Chan HS, Chiu HF, Tse LK, Woo KS. Obstructive sleep apnea presenting with nocturnal angina, heart failure, and near-miss sudden death. Chest. 1991; 99:1023-1025.
7. Javaheri S. Treatment of central sleep apnea in heart failure. Sleep 2000; 23 (Supplement 4):S224-S227.
8. Kryger M.H. Sleep and heart failure. Eur J Respir Dis 1990; 3:1103-1104.
9. Hanly P, Zuberi-Khokhar N. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med 1996; 153:272-276.
10. Fries R, Bauer D, Heisel A, Juhasz j, Fichter J, Schieffer H, Sybrecht GW. Clinical significance of sleep-related breathing disorders in patients with implantable cardioverter defibrillators. Pace 1999; 22:223-227.
11. Lanfranchi PA, Braghiroli A, Bosimini E, Mazzuero G, Colombo R, Donner CF, Giannuzzi P. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation 1999; 99:1435-1440.
12. He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea. Chest 1988; 94:9-14.
13. Javaheri S. Effects of continues positive airway pressure on sleep apnea and ventricular irritability in patients with heart failure. Circulation 2000; 101:392-397.
14. Malone S, Liu PP, Holloway R, Rutherford R, Xie A, Bradley TD. Obstructive sleep apnoea in patients with dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet 1991; 338:1480-84.
15. Javaheri S, Ahmed M, Parker TJ, Brown CR. Effects of nasal O2 on sleep-related disordered breathing in ambulatory patients with stable heart failure. Sleep 1999; 22:1101-1106.
16. Hanly PJ, Millar TW, Steljes DG, Baert R, Frais MA, Kryger MH. The effect of oxygen on respiration and sleep in patients with congestive heart failure. Ann Intern Med 1989; 111:777-782.
17. Andreas S, Clemen C, Sandholzer H, Figulla HR, Kreuzer H. Improvement of exercise capacity with treatment of Cheyne-Stokes respiration in patients with congestive heart failure. J Am Coll Cardiol 1996; 27:1486-1490.
18. Staniforth AD, Kinneart WJM, Starling R, Hetmanski DJ, Cowley AJ. Effects 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.
19. Naughton MT, Liu PP, Bernard DC, Goldstein RS, Bradley TD. Treatment of congestive heart failure and Cheyne-Stokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit Care Med 1995; 151:92-97.
20. Naughton MT, Benard DC, Liu PP, Rutherford R, Rankin F, Bradley TD. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1995; 152:473-479.
21. Teschler H, Döhring J, Wang YM, Berthon-Jones M. Adaptive
pressure support servo-ventilation: A novel treatment for Cheyne-Stokes
respiration in heart failure. Am J Respir Crit Care Med Vol 2001; 164:614-619.
22. Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation, 2000;102:61-66.
23. Javaheri S, Parker TJ, Wexler L, Limining JD, Lindower P, Roselle GA. Effect of theophylline on sleep-disordered breathing in heart failure.
N Eng J Med 1996; 335:562-567.
Sleep Medicine Alert is a publication of the National Sleep Foundation. Comments, suggestions and letters to the editor are welcome.