Obstructive sleep apnea (OSA) is associated with a range of comorbidities, worse quality of life, and an elevated risk of all-cause and cardiovascular mortality compared withto the general population.1 Some findings have demonstrated an association between OSA and the risk of sudden cardiac death (SCD), which affects as many as 450,000 individuals annually in the United States.2

To further explore this connection, the authors of a meta-analysis published in June 2021 in BMJ Open Respiratory Research examined 22 observational studies comporised of 42,099 total participants with a mean age of 62 years (64% menale).3 They found that OSA was linked to all-cause sudden death (risk ratio [RR], 1.74; 95% CI, 1.44-2.10; I2=72%) and cardiovascular mortality (RR, 1.94; 95% CI, 1.39-2.70; I2=32%).

The results also showed a marginally significant dose-–response relationship between OSA severity and the risk of death (P =.05) as follows: mild (RR, 1.16; 95% CI, 0.70-1.93), moderate (RR, 1.72; 95% CI, 1.11-2.67) and severe (RR, 2.87; 95% CI, 1.70-4.85) OSA. Older age was identified as a significant factor contributing to the link between OSA and mortality.3


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The various comorbidities affecting patients with OSA, especially cardiovascular disease, likely influence the risk of sudden death in these individuals. “If there is pre-existing damage to the heart, such as from hypertension, diabetes, or congenital heart disease, then the susceptible areas are more prone to further damage,” Kin Yuen, MD, MS, sleep medicine specialist and assistant professor at the University of California, San Francisco, School of Medicine, told us in an interview.

Along with the elevated burden of cardiovascular disease and arrhythmias – including higher rates of nocturnal arrhythmias – among individuals with OSA compared withto the general population, the clinical features of OSA may also increase the risk of SCD. “Possible mechanisms include low oxygen levels causing hypoxic damage to the heart muscle or electricity circuit that controls the heart rhythm,” according to Dr Yuen.

The Role of Hypoxemia

Of the limited epidemiologic data regarding the association between OSA and SCD, a 2013 cohort study demonstrated that OSA predicted incident SCD in a sample of 10,701 patients who underwent sleep studies in at an academic center.2

After a follow-up period of up to 15 years (average 5.3) in which 142 patients had fatal or resuscitated SCD, classification and regression tree  (CART) analysis identified the following factors as the best predictors of SCD in OSA: age older than >60 years (HR, 5.53), apnea-hypopnea index (AHI) >20 (HR, 1.60), mean nocturnal oxygen saturation (O2sat) <93% (HR, 2.93), and lowest nocturnal O2sat <78% (HR, 2.60; P <.0001 for all).

In multivariate analysis, nocturnal hypoxemia severity was found to be a strong predictor of SCD independently of the other well-established risk factors including age and comorbidities such as cardiovascular diseaseCVD and hypertension. The lowest nocturnal O2sat threshold determined by CART (78%) predicted an 81% increase in SCD risk (HR, 1.81; 95% CI, 1.28-2.56; P =.0008).2

The Role of Arrhythmias

Noting the increased risk of cardiovascular mortality associated with arrhythmias, the authors of a study published in April 2021 in Brain Sciences examined the relationship between OSA incidence and severity and the parameters of 24-hour electrocardiogram (ECG) Holter monitoring in 94 patients (mean age, 53.7 years) with suspected OSA.4

In a group of participants with confirmed OSA, more frequent episodes of supraventricular tachycardia (SVT) and ventricular arrhythmias were observed. Regression analysis revealed that higher AHI independently predicted SVT, supraventricular arrhythmia pairs, and the number of pauses longer than >2.5 seconds in ECG monitoring.4

“Routine Holter monitoring in patients with OSA would allow for implementation of early prevention and treatment of coexisting cardiac disorders, and therefore a reduction in cardiovascular risk,” as stated in the paper.4 Other studies using Holter monitoring have shown that CPAP [continuous positive airway pressure] treatment led to significant reductions in various arrhythmias after 3 and 6 months in OSA patients.5,6

In addition to the appropriate treatment of OSA and regular follow-ups to check for arrhythmias, especially for high-risk patient groups such as those with pre-existing heart valve disease, Dr Yuen said that any patient with a family member who died passed away in their sleep with no known cause should be evaluated.

In terms of future research and other remaining needs, “Longitudinal data of families that were affected by sudden death in sleep, with genetic analysis and sleep studies, would be invaluable,” she stated. “Technology that allows for easier, non-invasive monitoring of heart rhythm and oxygen levels in sleep would also be very helpful.”

To learn more about the OSA-SCD connection, we interviewed the following experts:

Younghoon Kwon, MD, MS, FACC, associate professor of medicine, director of Ccardiac ICU/ inpatient service at Harborview Medical Center, and associate director of cCardiac ICU at the University of Washington Medical Center in Seattle (and co-author of a 2019 review on the topic that appeared in Circulation Reports7).

Richard J. Castriotta, MD, FCCP, FAASM, pulmonologist, sleep medicine specialist, and professor of clinical medicine at the Keck School of Medicine at the University of Southern California in Los Angeles.

What are the proposed mechanisms by which OSA may increase the risk of SCD?  

Dr Kwon: Patients with OSA have a high prevalence of other cardiovascular risks that are all associated with a high risk of SCD, so the relationship is likely synergistic. OSA is a risk factor for hypertension and increased left ventricular mass, both of which are well-established risk factors for SCD.  To some extent, OSA is also associated with an increased risk of coronary heart disease and heart failure, although this evidence is weaker. These are also well-established risk factors for SCD, so OSA can increase the risk of SCD indirectly via these pathways.

On the other hand, OSA also increases arrhythmogenicity by affecting the electrophysiological properties of the heart. For example, OSA increases the expression of L-type calcium channels in the heart, which can affect ventricular repolarization and predispose patients to ventricular arrhythmias.  One study showed that OSA is associated with nocturnal peaking of SCD vs early morning peaking in the general population.7

Dr Castriotta: OSA causes bradycardia and a drop in arterial oxygen concentration during the apnea, and then at termination of the apnea and resumption of breathing, it results in tachycardia and stimulation of the sympathetic nervous system. This increases blood pressure and puts a strain on the heart while increasing the risk of arrhythmias.1 This increased sympathetic nervous system drive persists into wakefulness. 

In addition to these cyclic increases in blood pressure, there are cyclic increases in cerebral spinal fluid pressure in the brain. Up to 70% of people who have a stroke have sleep apnea.8

Those with OSA are significantly more likely to have heart rhythm problems and non-sustained ventricular tachycardia. OSA also causes altered blood coagulability, making it more likely to clot by causing platelet aggregation and activation. OSA causes an increase in blood pressure during sleep, and the most important correlations between cardiovascular disease and blood pressure are with sleep-time blood pressure.

OSA causes an inflammatory state with increased amounts of Cc-reactive protein (CRP), tumor necrosis factor alpha (TNF-a), interleukin-6, interleukin-8, intercellular adhesion molecules (ICAM), vascular cell adhesion molecules (VCAM), and selectin.9

How do comorbidities affect the risk of SCD in OSA?

Dr Castriotta: Those with OSA plus chronic lung disease are much more likely to develop pulmonary hypertension and heart failure, with pathology involving both the left and right sides of the heart.

Those with OSA and morbid obesity are at risk for development of obesity-hypoventilation syndrome (OHS). Individuals with OHS are 90 times more likely to develop pulmonary hypertension and  cor pulmonale  with an increased risk of sudden cardiac death.10

What are the recommended strategies to mitigate the risk of SCD in OSA patients?

Dr Kwon: A holistic approach is important. In addition to treating OSA, other comorbidities need to be addressed. In particular, weight loss and blood pressure control are important. 

Dr Castriotta: The European Society of Cardiology guidelines recommend treatment of obstructive sleep apnea.11 This is most often done with positive airway pressure, but other treatments include placement of a hypoglossal nerve stimulator, mandibular-advancing oral appliances, mandibular-advancement surgery and, especially for children, adenotonsillectomy.

What are some of the remaining gaps in this area that warrant further investigation?

Dr Kwon: The complex link between OSA and SCD involves multiple mechanisms such as maladaptive autonomic nervous system changes, myocardial ischemia, increased arrhythmogenicity, altered ion channel expression, and hemodynamic shifts that collectively point to the plausibility of a convincing link between these conditions.

However, at the population level, there is a dearth of evidence supporting a direct link between OSA and SCD. There is a need for more large-scale studies with long follow-up periods to clarify the relationship between SCD risk in OSA in specific patient populations, as well as research elucidating the role of OSA in arrhythmogenicity.

Another area warranting investigation is the influence of OSA treatment on SCD markers in the general population and in individuals with cardiovascular diseases.

Additionally, a major question is: Since OSA is so prevalent, which individuals should we treat? We cannot simply put CPAP on every patient with the diagnosis of OSA — it’s not realistic. This is something that researchers need to explore.

Dr Castriotta: Further studies are needed to identify the exact pathogenesis of sudden death and to identify the risk factors to facilitate early diagnosis and treatment.

Reference

1. Heilbrunn ES, Ssentongo P, Chinchilli VM, Oh J, Ssentongo AE. Sudden death in individuals with obstructive sleep apnoea: a systematic review and meta-analysisBMJ Open Respir Res. 2021;8(1):e000656. doi:10.1136/bmjresp-2020-000656

2. Gami AS, Olson EJ, Shen WK, et al. Obstructive sleep apnea and the risk of sudden cardiac death: a longitudinal study of 10,701 adults.  J Am Coll Cardiol. 2013;62(7):610-616. doi:10.1016/j.jacc.2013.04.080

3. Heilbrunn ES, Ssentongo P, Chinchilli VM, Oh J, Ssentongo AE. Sudden death in individuals with obstructive sleep apnoea: a systematic review and meta-analysis.  BMJ Open Respir Res. 2021;8(1):e000656. doi:10.1136/bmjresp-2020-000656

4. Urbanik D, Gać P, Martynowicz H, et al. Obstructive sleep apnea as a predictor of arrhythmias in 24-h ECG Holter monitoring. Brain Sci. 2021;11(4):486. doi:10.3390/brainsci11040486

5. Varga PC, Rosianu HS, Vesa ŞC, Hancu BGD, Beyer R, Pop CM. The impact of continuous positive airway pressure on cardiac arrhythmias in patients with sleep apnea. J Res Med Sci. 2020;25:42. doi:10.4103/jrms.JRMS_677_18

6. Abumuamar AM, Newman D, Dorian P, Shapiro CM. Cardiac effects of CPAP treatment in patients with obstructive sleep apnea and atrial fibrillation. J Interv Card Electrophysiol. 2019;54(3):289-297. doi:10.1007/s10840-018-0482-4

7. Blackwell JN, Walker M, Stafford P, Estrada S, Adabag S, Kwon Y. Sleep apnea and sudden cardiac death. Circ Rep. 2019;1(12):568–574. doi:10.1253/circrep.CR-19-0085

8. Davis AP, Billings ME, Longstreth WT Jr, Khot SP. Early diagnosis and treatment of obstructive sleep apnea after stroke: Are we neglecting a modifiable stroke risk factor? Neurol Clin Pract. 2013;3(3):192-201. doi:10.1212/CPJ.0b013e318296f274

9. Liu X, Ma Y, Ouyang R, et al. The relationship between inflammation and neurocognitive dysfunction in obstructive sleep apnea syndrome. J Neuroinflammation. 2020;17(1):229. doi:10.1186/s12974-020-01905-2

10. Athayde RAB, Oliveira Filho JRB, Lorenzi Filho G, Genta PR. Obesity hypoventilation syndrome: a current review.  J Bras Pneumol. 2018;44(6):510-518. doi:10.1590/S1806-37562017000000332

11.  Priori SG, Blomström-Lundqvist C, Mazzanti A, et al; ESC Scientific Document Group. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J. 2015;36(41):2793-2867. doi:10.1093/eurheartj/ehv316

This article originally appeared on Pulmonology Advisor