July/August 2020

Sleep Apnea and Heart Disease: What’s the Connection?
By Jamie Santa Cruz
Today’s Geriatric Medicine
Vol. 13 No. 4 P. 14

Evidence suggests that treating apnea improves cardiac outcomes.

Cardiovascular disease (CVD) remains a leading cause of death in the United States and around the world. Accordingly, there’s a strong emphasis on identifying and preventing risk factors, one of which is sleep apnea. Current evidence shows an association between sleep apnea and CVD but doesn’t definitively indicate a causal link between the two. Nevertheless, there are some hints that treating sleep apnea could improve cardiovascular outcomes.

Sleep Apnea Overview
There are two forms of sleep apnea. In obstructive sleep apnea (OSA), individuals experience episodes of partial or complete obstruction of the airway during sleep. By contrast, in central sleep apnea (CSA), an individual simply stops breathing momentarily during sleep.1 OSA is by far the more common form. Approximately 17% of US adults are thought to have OSA,1 whereas CSA has a prevalence of only roughly 0.9%.2

The prevalence of OSA has increased over time, paralleling increases in the average body mass index of the population.3 Many cases of OSA are mild, but nearly 1 in 15 American adults are thought to have at least a moderately severe form of the condition.1 OSA is very common in individuals with CVD, with a prevalence ranging from 30% to 60%, depending on the specific type of cardiovascular condition.4 That said, most individuals with OSA are never diagnosed.1

As for pathophysiology of OSA, the fundamental issue is the lack of oxygen flow. “The episodes of partial or total upper airway obstructions during sleep usually last from 10 seconds up to three minutes (in very severe cases), promoting recurrent drops in the oxygen saturation,” says Luciano Drager, MD, PhD, a professor of medicine at the University of Sao Paulo Medical School in Brazil. These intermittent decreases in oxygen levels, in turn, cause an increase in the activity of the autonomic nervous system, which governs the release of stress hormones. Importantly, this increase in activity persists even during wakefulness.1 In addition to causing oxygen desaturation, apneic episodes prompt intrathoracic pressure swings, which have the effect of forcing the heart to work harder. All of these factors, in turn, contribute to systemic inflammation and oxidative stress, which are significant predictors of cardiovascular risk.

Although apneic episodes typically last less than one minute, repeated episodes every night over the course of years or decades can lead to long-term effects on the heart and circulation. If untreated, OSA can eventually result in structural remodeling of the heart and enlargement of its chambers.5

CSA interrupts breathing by a different mechanism than does OSA, and some of its pathophysiology is also different. However, many of the qualitative impacts of the two forms are the same—especially in that both cause oxygen desaturation and increased activity of the sympathetic nervous system. Like OSA, CSA is common in individuals with CVD.5

Cardiovascular Conditions Associated With Sleep Apnea
According to Jeremy Tietjens, MD, a clinical fellow at the University of California, San Francisco School of Medicine, sleep apnea is associated with a variety of cardiovascular conditions and outcomes, but the strongest associations are with high blood pressure, arrhythmias (especially atrial fibrillation), and heart failure.

High Blood Pressure
The link between sleep apnea and high blood pressure is well established in observational studies.6,7 This association is dose dependent: The greater the severity of OSA, the greater the likelihood of eventually developing hypertension.8 The link between sleep apnea and hypertension is especially strong for resistant hypertension (that is, hypertension that remains uncontrolled even after use of three different antihypertensives). In a case-control study of 126 patients, the prevalence of hypertension was 38% among individuals who had hypertension that was controlled with medication, but the prevalence was nearly double (71%) in individuals with resistant hypertension.9

The link between sleep apnea and hypertension is also strong for pulmonary hypertension: Only 10% to 20% of individuals with OSA have pulmonary hypertension, but 70% to 80% of those diagnosed with pulmonary hypertension have OSA. When OSA is the primary cause of pulmonary hypertension, the pressure elevation is generally mild, but OSA can also exacerbate pulmonary hypertension stemming from other causes.10 Patients with severe pulmonary hypertension who have OSA are at higher risk for mortality than are those who do not have OSA.11

Atrial Fibrillation
The prevalence of atrial fibrillation is increasing in the United States.12 This is partly due to the aging population and the increase in established risk factors, but some of the rise in rates may be due to increasing rates of sleep apnea.1

Sleep apnea and atrial fibrillation share several risk factors, including obesity. Thus, it could be that both sleep apnea and atrial fibrillation are triggered by other causes, rather than sleep apnea being causative in atrial fibrillation. However, the association between sleep apnea and atrial fibrillation is stronger than the association between obesity and atrial fibrillation.13 The Sleep Heart Health Study found that individuals with severe OSA are at two to five times the risk of arrhythmias compared with individuals without sleep apnea, even after adjusting for obesity.14

As with hypertension, the relationship between sleep apnea and arrhythmias appears to be dose dependent.15 It’s thought that the increase in inflammation and oxidative stress caused by apneic episodes alters the electrophysiology of the heart, contributing to structural remodeling and thereby prompting the development of such arrhythmias.1 Individuals who have both atrial fibrillation and sleep apnea have more symptoms of arrhythmia and are more likely to be hospitalized than are those without sleep apnea.16 Although the link between OSA and atrial fibrillation is strong, at least one study suggests that CSA could put patients at greater risk of atrial fibrillation than will OSA.17

Heart Failure
Approximately 50% to 70% of individuals with heart failure have some form of sleep apnea.18,19 Apneas are prevalent not only in patients with overt heart failure but also in those with asymptomatic left ventricular dysfunction.20 Importantly, while OSA is the more common form of sleep apnea overall, CSA is the more common form of sleep apnea in heart failure patients in particular, accounting for approximately two-thirds of sleep apnea observed in this population.10

Not only is sleep apnea associated with heart failure, but it’s also linked to poorer outcomes. Individuals with heart failure who also experience sleep apnea (either OSA or CSA) have a higher risk of mortality following hospital discharge as well as a higher risk of readmission, compared with heart failure patients without sleep apnea.21

Is the Connection Causal?
The link between sleep apnea and cardiovascular risk is “extremely strong,” according to Deepak Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital, a professor of medicine at Harvard Medical School, and an American Heart Association volunteer expert. However, it’s an open question whether sleep apnea plays a causal role in CVD. “What isn’t quite as clear is how much of that link is really causative and how much of it is just associative,” says Bhatt, who suspects it’s a bit of both. “Sleep apnea and cardiovascular disease share several risk factors, so it’s not surprising that both would exist in the same person. Obesity, for example, is a powerful risk factor for sleep apnea, of course, but it’s also a risk factor for cardiovascular disease.”

According to Tietjens, the strongest indication of a causal connection is in the literature on hypertension. “There is some evidence that it can be causal in high blood pressure specifically, which can lead into some other diseases,” Tietjens says. “In studies of patients with resistant hypertension, … treating sleep apnea with CPAP can lower high blood pressure beyond what medications can do. [But] beyond contributing causally to high blood pressure—which I think we’re pretty confident of—we probably don’t have a lot of direct evidence that there is causality as far as other cardiovascular diseases because of the overlap with risk factors.”

Does Treatment of Sleep Apnea Reduce Cardiovascular Risk?
For OSA, the standard treatment is continuous positive airway pressure (CPAP). For CSA, additional treatment options also include adaptive servo-ventilation (ASV) or transvenous phrenic nerve stimulation. But how effective are these treatments at reducing cardiovascular risk?

Multiple randomized controlled trials have examined the impact of CPAP treatment on hypertension, and many of these suggest that treating sleep apnea with CPAP results in lower systemic blood pressure. In Spain, a large, multicenter randomized control trial of patients with moderate to severe OSA found that treatment with CPAP did not result in a statistically significant reduction in the incidence of hypertension or cardiovascular events after four years. However, stratified analysis showed that participants who used CPAP for a greater number of hours per night did see a statistically significant reduction in both hypertension and cardiovascular events.22 A meta-analysis of five other randomized trials found that individuals treated with CPAP showed a reduction both in 24-hour ambulatory blood pressure and in nocturnal diastolic blood pressure.23 The effect size of the treatment in the meta-analysis was modest, but research suggests that even modest reductions in blood pressure are associated with lower risk of cardiovascular events.24

With respect to arrhythmias, too, there’s evidence that CPAP treatment may reduce risk. A large cohort of more than 10,000 participants demonstrated that OSA patients treated with CPAP were significantly less likely to progress to permanent atrial fibrillation than were those who didn’t receive CPAP.16 In addition, a number of observational studies also show that patients with OSA who are treated with CPAP after ablation have a substantially lower risk of recurrent atrial fibrillation than do those who aren’t receiving CPAP.10

“When you have an individual with sleep apnea and atrial fibrillation who is either not treated or not effectively treated, when you try to restore the rhythm to normal, the likelihood of maintaining a normal rhythm is pretty low,” says Lee Surkin, MD, founder of the American Academy of Cardiovascular Sleep Medicine and one of few physicians board certified in both CVD and sleep medicine. However, “treating that patient with sleep apnea will give that patient the same statistical chance of maintaining a normal rhythm as if they didn’t have sleep apnea at all.”

In the context of heart failure, studies have produced inconsistent findings about the benefit of treating sleep apnea. Several randomized controlled trials have found that treatment of CSA with CPAP does not improve survival in heart failure patients.25,26 On the other hand, adherence to treatment is often a problem, and some analyses suggest that patients receiving CPAP treatment who are more adherent and who have effective suppression of their CSA do have improved survival.26,27

The results are similarly ambiguous in studies examining the impact of ASV rather than CPAP. Several randomized trials have found that ASV treatment in patients who have CSA may improve quality of life, but it does not improve cardiac function, reduce hospitalization for heart failure, or reduce mortality.28-30

One of the most significant trials to date on the question of how sleep apnea treatment affects cardiovascular outcomes is the SAVE trial (Sleep Apnea Cardiovascular Endpoints), a large, multicenter, open-label trial with blinded assessment of endpoints. The trial, which included more than 2,700 patients with a history of coronary artery disease or cerebrovascular disease and untreated moderate to severe OSA, had a mean follow-up of 3.7 years.29

Unfortunately, treatment with CPAP did not impact the primary endpoint, which was a composite of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina. However, it did improve quality of life. Furthermore, a secondary analysis found that patients with high adherence to treatment had a lower risk of stroke and other cerebrovascular events than did patients who received usual care, implying that lack of adherence may explain the lack of benefit in the study population as a whole.29

In sum, treatment of sleep apnea appears to have a beneficial impact on intermediate outcomes in cardiovascular health, including blood pressure and arrhythmic burden. But there’s no definitive evidence that treatment has a meaningful impact on adverse cardiac events or mortality.

The major problem at present, according to Surkin, is that so many studies on the effects of treatment have suffered from poor adherence to treatment. “With CPAP, you have to place it on at bedtime and keep it on all night long in order for you to breathe consistently during the night. If you put the CPAP machine mask on and then remove it a few hours later, you are potentially missing events that happen in the second half of the night.” Thus, Surkin believes future studies with better adherence may still demonstrate that treating sleep apnea improves mortality. “The jury is still out, and studies are ongoing to tease that out more accurately,” he says.

It’s also possible that treatment of sleep apnea is more effective for primary prevention of cardiovascular events than it is for secondary prevention.31,32 According to Drager, “In patients with no previous history of cardiovascular events (primary prevention scenario), observational studies suggest that CPAP, the main treatment for OSA, is able to prevent hypertension incidence and to decrease nonfatal cardiovascular events in men and fatal cardiovascular events in men, women, and elderly [patients].” By contrast, “In patients with a previous history of cardiovascular events (secondary prevention scenario), recent randomized trials showed that CPAP was not able to prevent a new cardiovascular event.”

Takeaways for Clinicians
There are several ways health care providers can help safeguard their patients’ heart health, including the following.

• Screen patients with CVD for sleep apnea. Given the strong association between sleep apnea and cardiovascular risk, clinicians should keep in mind that many of their heart disease patients are likely to have sleep apnea. “A lot of the symptoms of sleep apnea … overlap with symptoms of cardiovascular disease—in terms of fatigue, erectile dysfunction, those types of symptoms that are nonspecific,” Tietjens says. Thus, “clinicians should have a lower threshold to test for sleep apnea in patients with cardiovascular disease and should consider a routine screen for it.”

• Consider sleep apnea as a potential explanation for unexplained cardiovascular abnormalities. “If someone’s got high blood pressure that seems really hard to control, if they have heart failure exacerbations with no other obvious causes, if they have heart rhythm problems that are just popping up with no good explanation, sometimes the cause … could be sleep apnea,” Bhatt says. Accordingly, clinicians should keep sleep apnea in mind as a possible diagnosis for patients who repeatedly present with such issues.

• Always treat sleep apnea—even if it won’t lower the risk of cardiovascular events. Tietjen acknowledges that studies examining the impact of sleep apnea treatment on cardiovascular outcomes have been “disappointing,” but argues that treatment still has value for other reasons. “All the studies that have looked at symptom benefits and quality of life benefits with respect to actual sleep apnea do support a benefit of treating sleep apnea,” he says. Even if patients don’t see cardiovascular benefits, they “do derive a lot of benefit from having their sleep apnea treated … in terms of overall quality of life and more energy.”

Bhatt concurs. Even if there’s no cardiovascular benefit, he says, a patient’s sleep apnea should be treated “just so that they get a good night’s sleep.”

— Jamie Santa Cruz is a health and medical writer in the greater Denver area.

References
1. Mehra R. Sleep apnea and the heart. Cleve Clin J Med. 2019;86(9 Suppl 1):10-18.

2. Donovan LM, Kapur VK. Prevalence and characteristics of central compared to obstructive sleep apnea: analyses from the sleep heart health study cohort. Sleep. 2016;39(7):1353‐1359.

3. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006-1014.

4. Cepeda-Valery B, Acharjee S, Romero-Corral A, Pressman GS, Gami AS. Obstructive sleep apnea and acute coronary syndromes: etiology, risk, and management. Curr Cardiol Rep. 2014;16(10):535.

5. Floras JS. Sleep apnea and cardiovascular disease: an enigmatic risk factor. Circ Res. 2018;122(12):1741-1764.

6. Nieto FJ, Young TB, Lind BK, et al. Association of sleep‐disordered breathing, sleep apnea, and hypertension in a large community‐based study. Sleep Heart Health Study [published correction appears in JAMA 2002;288(16):1985]. JAMA. 2000;283(14):1829-1836.

7. Marin JM, Agusti A, Villar I, et al. Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA. 2012;307(20):2169-2176.

8. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep‐disordered breathing and hypertension. N Engl J Med. 2000;342(19):1378-1384.

9. Gonçalves SC, Martinez D, Gus M, et al. Obstructive sleep apnea and resistant hypertension: a case‐control study. Chest. 2007;132(6):1858-1862.

10. Tietjens JR, Claman D, Kezirian EJ, et al. Obstructive sleep apnea in cardiovascular disease: a review of the literature and proposed multidisciplinary clinical management strategy. J Am Heart Assoc. 2019;8(1):e010440.

11. Minai OA, Ricaurte B, Kaw R, et al. Frequency and impact of pulmonary hypertension in patients with obstructive sleep apnea syndrome. Am J Cardiol. 2009;104(9):1300-1306.

12. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285(18):2370-2375.

13. Trulock KM, Narayan SM, Piccini JP. Rhythm control in heart failure patients with atrial fibrillation: contemporary challenges including the role of ablation. J Am Coll Cardiol. 2014;64(7):710-721.

14. Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: the Sleep Heart Health Study. Am J Respir Crit Care Med. 2006;173(8):910-916.

15. Mehra R, Stone KL, Varosy PD, et al. Nocturnal arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med. 2009;169(12):1147-1155.

16. Holmqvist F, Guan N, Zhu Z, et al. Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation-Results from the outcomes registry for better informed treatment of atrial fibrillation (ORBIT-AF). Am Heart J. 2015;169(5):647.e2-654.e2.

17. May AM, Blackwell T, Stone PH, et al. Central sleep-disordered breathing predicts incident atrial fibrillation in older men. Am J Respir Crit Care Med. 2016;193(7):783-791.

18. Oldenburg O, Lamp B, Faber L, Teschler H, Horstkotte D, Töpfer V. Sleep‐disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients. Eur J Heart Fail. 2007;9(3):251-257.

19. Oldenburg O, Teerlink JR. Screening for sleep‐disordered breathing in patients hospitalized for heart failure. JACC Heart Fail. 2015;3(9):732-733.

20. Lanfranchi PA, Somers VK, Braghiroli A, Corra U, Eleuteri E, Giannuzzi P. Central sleep apnea in left ventricular dysfunction: prevalence and implications for arrhythmic risk. Circulation. 2003;107(5):727-732.

21. Khayat R, Jarjoura D, Porter K, et al. Sleep disordered breathing and post-discharge mortality in patients with acute heart failure. Eur Heart J. 2015;36(23):1463-1469.

22. Barbé F, Durán-Cantolla J, Sánchez-de-la-Torre M, et al. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA. 2012;307(20):2161-2168.

23. Liu L, Cao Q, Guo Z, Dai Q. Continuous positive airway pressure in patients with obstructive sleep apnea and resistant hypertension: a meta‐analysis of randomized controlled trials. J Clin Hypertens (Greenwich). 2016;18(2):153-158.

24. Turnbull F; Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood‐pressure‐lowering regimens on major cardiovascular events: results of prospectively‐designed overviews of randomised trials. Lancet. 2003;362(9395):1527-1535.

25. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med. 2005;353(19):2025-2033.

26. Peker Y, Glantz H, Eulenburg C, Wegscheider K, Herlitz J, Thunström E. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea; the RICCADSA randomized controlled trial. Am J Respir Crit Care Med. 2016;194(5):613-620.

27. Arzt M, Floras JS, Logan AG, et al. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation. 2007;115(25):3173-3180.

28. Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive servo‐ventilation for central sleep apnea in systolic heart failure. N Engl J Med. 2015;373(12):1095-1105.

29. Drager LF, McEvoy RD, Barbe F, Lorenzi-Filho G, Redline S; INCOSACT Initiative (International Collaboration of Sleep Apnea Cardiovascular Trialists). Sleep apnea and cardiovascular disease: lessons from recent trials and need for team science. Circulation. 2017;136(19):1840‐1850.

30. Momomura S, Seino Y, Kihara Y, et al. Adaptive servo‐ventilation therapy for patients with chronic heart failure in a confirmatory, multicenter, randomized, controlled study. Circ J. 2015;79(5):981-990.

31. O’Connor CM, Whellan DJ, Fiuzat M, et al. Cardiovascular outcomes with minute ventilation-targeted adaptive servo-ventilation therapy in heart failure: the CAT-HF trial. J Am Coll Cardiol. 2017;69(12):1577-1587.

32. McEvoy RD, Antic NA, Heeley E, et al. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med. 2016;375(10):919-931.