Abstract
In recent years, there has been increasing awareness of the high prevalence and clinical significance of sleep-disordered breathing (SDB) and its effects on a range of cardiovascular conditions, including hypertension, heart failure (HF), myocardial infarction (MI), atrial fibrillation (AF), and type 2 diabetes.
SDB describes a group of disorders characterized by abnormalities in the frequency and/or depth of breathing while asleep. These intermittent episodes cause partial or complete obstruction of the upper airway, disrupting normal ventilation and sleep architecture.[1] It not only causes poor sleep quality and daytime sleepiness, but has clinical consequences too.
Obstructive sleep apnea (OSA) is the most extreme variant, but other forms of SDB are highly prevalent, too. An analysis of 154 original investigations and reviews of sleep-related breathing disorders estimated that one in five adults has at least mild OSA and one in 15 adults has at least moderate OSA.[2] Central sleep apnea is the most common SDB in patients with HF, occurring in an estimated 40-63% of HF patients.[3,4] However, it may be more difficult to identify individuals with central sleep apnea since it does not tend to be associated with the typical excessive daytime sleepiness of OSA.
Case-control and retrospective studies first suggested that SDB is associated with an increased prevalence of coronary heart disease (CHD) and CHD-related outcomes, and large-scale cohort studies subsequently confirmed these findings. In the Sleep Heart Health Study (SHHS), for example, several cardiovascular disease outcomes, including MI and stroke, were associated with SDB.[5] Also, the Nurses Health Study prospectively observed that self-reported snoring, a cardinal symptom of SDB, may be an independent risk factor for the development of CHD.[6]
Cardiovascular Effects
There are several physiologic disturbances that can lead to cardiovascular consequences. As for specific cardiovascular effects, OSA places a strain on cardiac output by virtue of hypoxemia, large negative intrathoracic pressures, and high swings in systemic blood pressure. Here are other ways that SDB clinically affects specific heart conditions:
Heart Failure. As noted, central sleep apnea is highly prevalent in patients with left ventricular (LV) dysfunction and it often occurs before the development of overt HF.[7] The main clinical significance of central sleep apnea is its association with increased mortality independent of other known risk factors. Also, OSA has the potential to worsen ventricular dysfunction in patients with overt HF.[8]
Myocardial Infarction. Recently, investigators analyzed 1,660 patients with a first acute MI and found a strong association in the first 28 days after infarction between snoring and mortality. Occasional and regular heavy snorers had a 2.04 (95% confidence interval [CI], 1.50 to 2.79) and 3.30 (95% CI, 2.37 to 4.58) hazard ratio for mortality respectively within the first 28 days after controlling for age, gender, obesity, history of diabetes and hypertension, physical activity, smoking, and education.
Atrial Fibrillation. In a cohort of 3,542 people who underwent complete polysomnography, obesity and OSA were independent risk factors for incident AF over an average of about 5 years of follow-up (Figure 2).[10] Both obesity and OSA may contribute to the looming epidemic of AF and both conditions should be recognized as independent risk factors for incident AF.
Figure 2.
In another recent study, investigators prospectively evaluated SDB in a relatively young patient population (mean age 55 years) with paroxysmal or persistent AF and normal LV function.[11] The control population was comprised of patients referred to the same tertiary arrhythmia center during the same 18-month period but without AF. Among the AF group, there was a high prevalence of SDB (Figure 3) and more patients with significant SDB than the controls. After adjusting for relevant covariates, the odds ratio for the association between AF and SDB was 3.04 (95% CI 1.24-7.46, p = 0.02). In general, the authors said, OSA should be considered in patients with arrhythmias (including bradyarrhythmias) and — like the large cohort study above — particularly those individuals who are obese or hypertensive, regardless of the presence or absence of LV dysfunction.
Type 2 Diabetes. SDB is associated with insulin resistance and glucose intolerance, plus it is frequently found in individuals with type 2 diabetes. In a paper published in July 2008, the International Diabetes Federation Task Force on Epidemiology and Prevention "strongly recommends" that health professionals working in both type 2 diabetes and SDB adopt clinical practices to ensure that a patient presenting with one condition is considered for the other.[12]
Is Intervention Effective? The adverse effects of OSA on LV function can be at least partially reversed with continuous positive airway pressure (CPAP). In a 2007 issue of the Journal of the American College of Cardiology, Wang et al. reported a single-center prospective observational study comparing the mortality of patients with coexistent HF and OSA with that of patients with only HF.[13] Nearly 25% of the patients had OSA and risk of death was nearly three times higher in those with OSA versus those with mild or no OSA (Figure 4). None of the patients with HF and treated OSA died during 39-month follow-up. An accompanying editorial noted that "early diagnosis of OSA and initiation of effective CPAP therapy are of paramount importance in patients with coexistent HF and OSA."[14]
 | Figure 4. |
Evidence also suggests that CPAP decreases health care costs in moderate-to-severe OSA[15,16] and is associated with lower recurrence of AF.[17] Importantly, in patients with OSA, CPAP reduces the risk of car accidents from an excess risk of two to seven times greater than the background population to a level comparable to the general population.[18]
It should be noted that current data do not support routine use of CPAP in chronic stable congestive cardiac failure unless there is co-existent OSA. Bi-level pressure support using newer devices that may more effectively treat both OSA and central sleep apnea are being evaluated.
Recently, investigators reported that 6 months of aerobic exercise training increased exercise capacity and improved central sleep apnea in patients with chronic HF from systolic dysfunction.[19] Whether reducing central sleep apnea in this manner reduces the independent risk for poor long-term prognosis associated with SDB in this setting is unknown.
Investigators also have compared blood pressure response to nasal CPAP in a group of middle-aged men with mild-to-moderate untreated hypertension.[20] Nearly half of the study group had SDB and 3 weeks of nasal CPAP treatment caused a substantial lowering of nocturnal systolic (-7.8 mm Hg, p = 0.02 versus no SDB) and diastolic (-5.3 mm Hg, p = 0.03 versus no SDB) blood pressure values. The authors noted that a reduction in blood pressure similar to that obtained with CPAP has been associated with a substantial reduction in the incidence of cerebrovascular accidents and MI in previous studies.
Finally, in late 2007, investigators published a retrospective cohort study of patients with OSA who subsequently underwent percutaneous coronary intervention (PCI).[21] Patients were stratified according to whether they were treated for OSA (n = 175) or not (n = 196). Patients treated for OSA had a statistically significant decreased number of cardiac deaths on follow-up compared to untreated OSA patients (3% [95% CI 0% to 6%] vs. 10% [95% CI 5% to 14%] after 5 years, p = 0.027) (Figure 5), as well as a trend toward decreased all-cause mortality (p = 0.058). The authors concluded that screening for and treating OSA in patients with CHD who may undergo PCI may result in decreased cardiac death.
 | Figure 5. |
In this interview, Dr. Bernard J. Gersh, who participated in several of the studies summarized here, discusses the cardiovascular mechanisms of sleep-disordered breathing and the diagnosis and management of this large population of patients.
Transcript
Dr. Conti: I'm Richard Conti here in Snowmass, Colorado, and with me is Dr. Bernard Gersh. We're talking about "Sleep-Disordered Breathing and Cardiovascular Disease." Bernard, do most cardiovascular specialists think about sleep disorders?
Dr. Gersh: More are starting to, but most do not – including me not that long ago. Five or 6 years ago sleep-disordered breathing, particularly obstructive sleep apnea, really was not part of my decision-making process. I didn't think about it as a diagnosis nor about how it might complicate treatment; to me it just was something specialists in sleep disorders take care of.
Then, for reasons still unclear to me, I was asked to co-chair a National Heart, Lung, and Blood Institute panel of cardiologists and sleep doctors on sleep-disordered breathing and cardiovascular disease.[1] It was absolutely fascinating and at the end of the 3 days I realized that sleep apnea or sleep-disordered breathing is a very important co-factor in cardiovascular disease and we, as clinical cardiologists, have to learn more about sleep-disordered breathing.
Dr. Conti: Let's start with the epidemiology of this condition.
Dr. Gersh: The statistics are compelling: Somewhere in the range of 40 million Americans have sleep-disordered breathing and some 20 million Americans probably have sleep apnea. Of those, 60-80% are undiagnosed. I might add: one of the great ways to start thinking about the possibility of sleep apnea is to ask the spouse whether the other has sleep apnea.
The Wisconsin Sleep Study, a prospective longitudinal follow-up study, demonstrated that about 9% of women and about 24% of men have at least mild sleep apnea.[22] What is staggering is the cost to society, both direct and indirect, through accidents, litigation, and lack of productivity; it's somewhere in the range $50 billion to $100 billion dollars a year.
Dr. Conti: Please talk about the potential pathophysiologic mechanisms of this disorder.
Dr. Gersh: There are several plausible mechanisms and a lot of good circumstantial evidence. First, remember that many of these patients with sleep-disordered breathing have comorbidities. For example, sleep apnea coexists with hypertension, obesity, diabetes, cigarette smoking, and so on. Aside from that, there's a considerable body of evidence looking at the events that occur with obstructive sleep apnea, particularly the apneic phase followed by arousal. During the apneic phase, there are tremendously negative intrathoracic pressures, so the transmural pressure in the left ventricle is very high and one of the mechanisms is increased left ventricular afterload.
Also, during the cycles of sleep apnea, there's sympathetic overactivity, rebound hypertension, catecholamine surge, release of inflammatory markers, elevated levels of C-reactive protein and interleukin-6, and an increase in free-oxygen radicals. All these so-called bad actors appear to be released during these cycles of sleep apnea and arousal.
There is other interesting work suggesting metabolic dysregulation associated with sleep-disordered breathing. I don't know whether it's a result of leptin metabolism or leptin release; it's not clearly understood, but the effects are clearly there.
One interesting aspect of sleep apnea is that in the year before diagnosis the patient often admits to a recent marked weight gain. That may be related to some disorder of leptin, satiety, and appetite suppression, but it's fair to say there are hosts of plausible physiological mechanisms related to hypoxia, hypocarbia, negative intrathoracic pressures, the sympathetic activity associated with arousal, and possibly pulmonary vasoconstriction. It hasn't been completely sorted out yet, but the evidence is pretty strong.
Dr. Conti: What are the main diseases that are directly related to obstructive sleep apnea?
Dr. Gersh: We owe a lot to the Wisconsin Sleep Study, which showed unequivocally that obstructive sleep apnea causes hypertension. A very important long-term follow-up study strongly suggests that obstructive sleep apnea is associated with an increase in stroke.[23] There clearly is a relationship with heart failure, particularly central sleep apnea.
Although the data are a little inconsistent, some studies suggest that the treatment of sleep apnea may improve left ventricular function in people with heart failure. Many of these patients who I would have once said had mild cardiomyopathy – an ejection fraction 40% – now I suspect many have sleep apnea.
The evidence for coronary artery disease is a little more speculative but I'm pretty sure there's a relationship. Then there is a very strong relationship between obstructive sleep apnea and arrhythmias and this has been an area of, great interest to us at the Mayo Clinic. I have no doubt that obstructive sleep apnea is strongly associated with the development of atrial fibrillation and recurrence after treatment. My colleague, Virend Somers at the Mayo Clinic, with Dr. Apoor Gami, one of our fellows, published a study in the New England Journal of Medicine, showing that the diurnal rhythm of sudden cardiac death is completely reversed in sleep apnea.[24] In other words, among people with obstructive sleep apnea, the highest incidence of sudden cardiac death is at night, whereas the normal diurnal rhythm's in the day. In addition there is a clear increase in bradyarrhythmias. I'm not sure if it's "heart block" but bradycardias and pauses. This may be related to the diving reflex; that's a reflex we all have to prevent asphyxia. It may well be that people with obstructive sleep apnea are getting bradycardias at night, secondary to the initiation or triggering of this diving reflex.
Probably the final question before we get onto treatment is this: Does treatment of sleep apnea reduce cardiovascular events? Or is the association with cardiovascular events because sleep apnea is a surrogate for other risk factors? Data suggest that the treatment of sleep apnea with CPAP independently reduces cardiovascular events and closes that loop, so to speak.
Dr. Conti: What about treatment?
Dr. Gersh: The indications to treat a patient right now would be symptoms, such as daytime somnolence or motor vehicle accidents. A key part of treatment is lifestyle modification: even a small amount of weight loss may have a big effect; other suggestions include avoidance of alcohol at night and avoidance of sedatives. One of our sleep doctors gave me a useful tip. He said, "Tell them to lie on their side when sleeping."
As for CPAP, more and more patients will comply if they are sent to centers with expertise in the use of this technology. It's not an easy treatment, but there's a lot going on to modify current forms of CPAP. However, right now patients need referral to a sleep center; this is not for the cardiologist.
Dr. Conti: What about surgical intervention?
Dr. Gersh: The data for surgical approaches are not convincing. One area that is very dynamic at the moment relates to diagnosis. Our sleep centers have a huge waiting list for sleep studies and there's a lot of discussion about ambulatory polysomnography. This may be available soon.
Dr. Conti: Bernard, thank you for sharing this with our ACCEL audience. This information should heighten the level of awareness of all of us about the problem of obstructive sleep apnea and its relationship to cardiovascular disease and events.
Dr. Gersh: Thank you so much, Dick.
Guidelines
Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008;51:e1-62.
Source : http://www.medscape.com/viewarticle/579521
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