The following are key points to remember from this state-of-the-art review on sleep disordered breathing (SDB) and cardiovascular disease (CVD):

1. SDB entails a variety of sleep-related breathing disorders including obstructive sleep apnea (OSA) and central sleep apnea (CSA). These result in apnea or hypopnea and subsequent recurrent episodes of nocturnal hypoxemia, sympathetic nervous activation, and cortical arousal, all of which are associated with excessive daytime sleepiness.
   • Apnea: Absence of airflow for ≥10 seconds.
   • Hypopnea: ≥30% reduction in airflow for ≥10 seconds AND either PaO₂ drop ≥3% OR cortical arousal.
   • Apnea hypopnea index (AHI): AHI = number of events per hour of sleep.
2. OSA is a heterogeneous disorder characterized by repetitive narrowing or closure of the upper airway during sleep.
3. CSA is a complex group of disorders characterized by breathing instability due to repetitive loss of respiratory drive. There is often some concomitant degree of upper airway narrowing.
   • CSA-Cheyne-Stokes breathing (CSB) is commonly associated with heart failure (HF), atrial fibrillation (AF), stroke, or brain stem/high cervical cord injury.
   • Treatment-emergent CSA is CSA that emerges when predominantly OSA is treated.
   • Opioid (or other substance)-related CSA.
4. The presence of characteristic symptoms and associated risk factors should prompt further screening. Nocturnal breathing disturbances include snoring, gasping, and breathing pauses. Daytime symptoms include excessive daytime sleepiness, fatigue, and difficulty concentrating.
   • Index of suspicion for SDB should be particularly high for those with refractory hypertension, or AF.
5.  The gold standard for diagnosis is in-hospital polysomnography, which includes an EEG. These can identify apneas and hypopneas, the different stages of sleep, sleep fragmentations, as well as other sleep-related issues such as arrhythmias and periodic leg movements.
   • The more widely available home sleep apnea test measures oxygen saturation and other respiratory measures, but lacks precise sleep data, and as such, an actual AHI cannot be calculated. The main metric used is the respiratory event index (REI), which can underestimate the AHI by 12%.
   • Severity grading is based on AHI/REI cutoffs with <5 (normal), 5-≤15 (mild), 15-30 (moderate), ≥30 (severe) with the addition of the severity of overnight hypoxemia, sleep fragmentation, and daytime sleepiness.
6. SBD is associated with several major pathophysiological abnormalities, including swings in intrathoracic pressure, reduced and fragmented sleep, cyclical hypoxemia and re-oxygenation, activation of the sympathetic nervous system, endothelial dysfunction, and increased thrombosis.
7. SDB and CVD often co-exist, indicating both the causal relationship as well as underlying risk factors. Risk factors for SDB include:
   • Sex: Two- to four-fold more prevalent in men; more prevalent in women after menopause.
   • Age: Increasing prevalence with age due to reduced airway stiffness.
   • Obesity: 40-60% of people with OSA are obese; four-fold increase in OSA in obese middle-aged people; however, 20% of people with OSA are not obese.
   • Craniofacial features: Narrower oropharyngeal airway increases risk; small/recessed jaw.
   • Systemic Inflammation: Increased plasma C-reactive protein and interleukin-6; insulin levels increase SDB risk.
   • Genetics: Two-fold risk of OSA when first-degree relative has OSA.
8. Associations between OSA and CVD: A diagnosis of OSA confers a higher risk of mortality and higher CVD incidence, and increases when AHI >30. Studies have shown two- to three-fold greater mortality rates, most notably in women with severe untreated OSA. Some studies have shown that levels of overnight hypoxemia are better at predicting mortality than the AHI findings, implicating the strong central role of hypoxemia contributing to inflammation, oxidative stress, and sympathetic nervous system activation.
   • Hypertension: Up to 50% of OSA patients may have hypertension, and 30% of patients with hypertension will likely have OSA. OSA is a particularly important cause in resistant hypertension.
   • Cardiac arrhythmias:  Pathophysiological changes due to acute transient electrophysiological changes as well as chronic progressive cardiac remodeling increase the likelihood of developing atrial arrhythmias.  The prevalence of SDB in AF patients is higher, while severe OSA is also associated with decreased efficacy of antiarrhythmic drug therapy. In observational studies, continuous positive airway pressure (CPAP) use is associated with a 42% decreased risk of AF recurrence, while weight loss alone can also be effective. Coexistent sleep apnea and HF increase the risk of developing ventricular arrhythmias.
   • Coronary artery disease: OSA increases the risk of coronary events, up to a two-fold increase in several observational studies. In patients with ST-segment elevation myocardial infarctions, the prevalence of undiagnosed severe OSA can be about 40%, typically having their acute coronary syndrome occur at nighttime. It has been shown that patients with OSA have increased arterial stiffness, earlier atherosclerosis, worse coronary artery calcification, and more plaque instability.
   • HF: SBD has prevalence rates of 50-75% in patients with both HF with reduced ejection fraction (HrEF) and HF with preserved EF (HFpEF). The prevalence of CSA increases as severity of HF symptoms increase.
   • Pulmonary arterial hypertension: It remains unclear to what extent the transient increases in pulmonary vascular resistance culminate in sustained vasoconstriction. Nonetheless, it remains very important to identify pulmonary hypertension in patients with OSA, as this confers an increased mortality risk.
9. Management:
   • Lifestyle changes include weight loss in obese/overweight patients, smoking cessation, moderate exercise, and improved sleep hygiene. Increased physical activity was associated with a decreased prevalence of OSA, irrespective of body mass index. Weight loss had a more variable effect on the severity of OSA. Interventions combining weight loss and exercise training were more effective though full remission was not achieved in moderate or severely affected patients.
   • CPAP is the first-line therapy for OSA patients with moderate or severe OSA, improving both symptoms and overall quality of life. Improvements in mask and device design have improved adherence, but tolerating CPAP remains a big problem for many patients.
     • Primary prevention of CV events: In a few trials, CPAP improved hypertension, but CVD and cerebrovascular events were unchanged.
     • Secondary prevention of CV events: Multiple randomized trials have not shown improvements in CVD outcomes, though they typically do improve daytime sleepiness.
   • Mandibular advancement splints can be used in patients with mild or moderate OSA and have shown similar reductions in BP when compared to CPAP.
   • Evidence for upper airway surgery has been mixed, but has been shown to improve the degree of AHI and sleepiness, but did affect hypertension.
   • Adaptive servo-ventilation (ASV) increases inspiratory support during hypopnea and withdraws it during hyperventilation, providing mandatory breaths during apnea while generating background positive airway pressure. It is effective in both CSA and OSA. Some early studies suggest that ASV can improve cardiac diastolic dysfunction, symptoms, and decrease plasma BNP in HFpEF patients.
   • Oxygen therapy for CSA-CSB may improve overnight desaturations, but prolongs apneas and hypopneas in the OSA subgroup.
   • Phrenic nerve stimulation for severe CSA in one trial did improve oxygen desaturation and daytime sleepiness, but the trial was not powered for CV events.
10. Conclusions:
    • SDB should be considered in anyone with symptoms of snoring, daytime sleepiness, and fatigue, especially in obese patients or those with a history of CVD.
    • Weight loss and CPAP therapy can improve daytime sleepiness and quality of life, and may help improve hypertension and AF. However, CPAP treatment in randomized trials has not been shown to improve CV outcomes.
    • CSA is typically seen in patients with HF and/or AF and while mask-based therapy can improve the breathing disorder, it also has not been shown to improve CV outcomes and may be harmful in HFrEF.
    • Ongoing research should focus on better phenotyping and quantification of SDB, targeting those at highest CV risk, and offering a broader range of more personalized therapies. 

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Exercise, Hypertension, Sleep Apnea

Keywords: Arrhythmias, Cardiac, Atherosclerosis, Atrial Fibrillation, Continuous Positive Airway Pressure, Coronary Artery Disease, Exercise, Fatigue, Heart Failure, Hypertension, Obesity, Overweight, Primary Prevention, Secondary Prevention, Quality of Life, Risk Factors, Sleep Apnea Syndromes, Sleep Apnea, Central, Sleep Apnea, Obstructive, Smoking Cessation, Sympathetic Nervous System, Vascular Diseases, Ventricular Remodeling, Weight Loss

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