Sleep Apnea: Types, Mechanisms, and Clinical Cardiovascular Consequences

Abstract

Sleep apnea is highly prevalent in patients with cardiovascular disease. These disordered breathing events are associated with a profile of perturbations that include intermittent hypoxia, oxidative stress, sympathetic activation, and endothelial dysfunction, all of which are critical mediators of cardiovascular disease. Evidence supports a causal association of sleep apnea with the incidence and morbidity of hypertension, coronary heart disease, arrhythmia, heart failure, and stroke. Several discoveries in the pathogenesis, along with developments in the treatment of sleep apnea, have accumulated in recent years. In this review, we discuss the mechanisms of sleep apnea, the evidence that addresses the links between sleep apnea and cardiovascular disease, and research that has addressed the effect of sleep apnea treatment on cardiovascular disease and clinical endpoints. Finally, we review the recent development in sleep apnea treatment options, with special consideration of treating patients with heart disease. Future directions for selective areas are suggested.

Keywords: central sleep apnea; hypertension; obstructive sleep apnea.

FIGURE 1. Polysomnographic Example of OSA

First tracing is chin electromyogram, second and third are electroencephalogram, fourth is electrocardiogram, fifth and sixth are airflow measured by thermocouple (fifth) and CO₂ (sixth), seventh and eighth are rib cage (RC, seventh) and abdominal (ABD, eighth), ninth is oxyhemoglobin saturation measured by pulse oximetry, and tenth is esophageal pressure. Please note that during obstructive apnea, airflow is absent while breathing effort continues. Breathing resumes with the onset of arousal. Reprinted with permission from Javaheri (8). OSA = obstructive sleep apnea.

FIGURE 2. Polysomnographic Example of Hunter-Cheyne-Stokes Breathing

The first 2 tracings are electro-occulogram; otherwise tracings as in Figure 1. Note the smooth and gradual changes in the thoracoabdominal excursions and esophageal pressure in the crescendo and decrescendo arms of the cycle. There is an intervening central apnea, absence of naso-oral airflow, and excursions in pleural pressure, thorax, and abdomen. The arousal occurs at the peak of hyperventilation. Desaturation is delayed because of long circulation time in heart failure. Reprinted with permission from Dowdell WT, Javaheri S, McGinnis W. Cheyne-Stokes respiration presenting as sleep apnea syndrome: clinical and polysomnographic features. Am Rev Respir Dis 1990;141:871-9.

FIGURE 3. Normal Cardiovascular Changes in NREM and REM Sleep

During NREM sleep sympathetic activity decreases whereas parasympathetic activity increases with consequent decrease in BP and HR. The reverse occurs in phasic REM sleep. BP = blood pressure; COP = cardiac output; HR = heart rate; NREM = non–rapid eye movement; REM = rapid eye movement.

FIGURE 4. Pathophysiological Consequences of Sleep Apnea and Hypopnea

Pleural pressure (Ppl) is a surrogate of the pressure surrounding the heart and other vascular structures. [ = increased; Y = decreased. Reprinted with permission from Javaheri (8). CV = cardiovascular; H₂O = water; L = left; O₂ = oxygen; PCO₂ = partial pressure of carbon dioxide in the blood; PO₂ = partial pressure of oxygen in the blood; R = right.

FIGURE 5. Prevalence (%) of OSA in CVD

The lower limit is invariably using an AHI of ≥15/h, indicating presence of moderate-to-severe OSA. The upper part of the range relates to a lower threshold of ≥5/h. CVD = cardiovascular disease; OSA = obstructive sleep apnea.

FIGURE 6. Effect of CPAP Therapy on BP in Patients With Hypertension

Summary of different meta-analyses of RCTs. Positive figures mean improvement in BP level with CPAP (net changes) *Number of studies included (number of patients included). §Patients without daytime hypersomnia. BP = blood pressure; CI = confidence interval; CPAP = continuous positive airway pressure; DBP = diastolic blood pressure; RCT = randomized controlled trial; SBP = systolic blood pressure.

FIGURE 7. Effect of CPAP Therapy on BP in Patients With Resistant Hypertension

The figure shows 5 randomized controlled trials and 2 meta-analyses. The differences between the 2 meta-analyses depend on the most updated references included in the 2015 meta-analysis. Positive figures mean improvement in BP level with CPAP (net changes) *Number of studies included (number of patients included). !Daytime BP values. Abbreviations as in Figure 6.

FIGURE 8. Effect of CPAP Treatment on CV Risk

The figure shows the incidence risk for the primary composite endpoints in 3 RCTs (49,63,64) in the CPAP compared with the control group (hazard ratio or incidence density ratio, 95% CI) in the intention-to-treat analysis and in the adherence analysis (patients with CPAP adherence ≥4 h/day). *In the McEvoy study (49), the significant CV improvement in patients who used CPAP ≥4 h/day was only achieved in the risk of a cerebrovascular event, but not in the primary composite outcome. CV = cardiovascular; other abbreviations as in Figure 6.

FIGURE 9. Sleep Apnea is Prevalent in Left Ventricular Dysfunction

Prevalence (%) of moderate-to-severe sleep apnea (AHI ≥15) in asymptomatic left ventricular systolic dysfunction (LVSD) or left ventricular diastolic dysfunction (LVDD), heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF), and acutely decompensated heart failure (ADHF). AHI = apnea-hypopnea index; CSA = central sleep apnea; OSA = obstructive sleep apnea.

FIGURE 10. Effects of Sleep Apnea and HF on Central Sympathetic Outflow

Heart failure is a hyperadrenergic state. Sleep apnea further contributes to increased central sympathetic outflow. Locus ceruleus is the brainstem arousal network, and norepinephrine is the neurotransmitter. HF = heart failure.

FIGURE 11. Comparative Survival of 258 HF Patients Treated for Sleep Apnea and 30,000 Patients Not Tested for Sleep Apnea

Adapted with permission from Javaheri et al. (92). HF = heart failure.

FIGURE 12. Prevalence of OSA in 45 of 60 Consecutive Cardiac Transplant Recipients

Those who developed sleep apnea had gained the most weight after transplantation. Adapted with permission from Javaheri et al. (95). CI = confidence interval; HF = heart failure; OSA = obstructive sleep apnea.

CENTRAL ILLUSTRATION. Potential Etiological Risk Factors for Sleep Apnea and the Downstream Consequences

The illustration depicts the multietiological risk factors for sleep apnea and its downstream consequences, which include increased sympathetic nerve activity, metabolic dysregulation, inflammation, oxidative stress, vascular endothelial dysfunction, and intermittent hypoxia. These mechanistic pathways are critical for the pathogenesis of coronary heart disease, hypertension, and atrial fibrillation, all of which are etiological risk factors for end-stage cardiovascular disease. The figure is a schematic representation to illustrate important concepts, but does not fully depict the complex interactions between the various key variables.