Central sleep apnea and cardiovascular disease state-of-the-art

Abstract

Central sleep apnea, a rare polysomnographic finding in the general population, is prevalent in certain cardiovascular conditions including systolic and diastolic left ventricular dysfunction, atrial fibrillation, coronary artery disease, carotid artery stenosis, stroke, and use of certain cardiac-related medications. Polysomnographic findings of central sleep apnea with adverse cardiovascular impacts include nocturnal hypoxemia and arousals, which can lead to increased sympathetic activity both at night and in the daytime. Among cardiovascular diseases, central sleep apnea is most prevalent in patients with left ventricular systolic dysfunction; a large study of more than 900 treated patients has shown a dose-dependent relationship between nocturnal desaturation and mortality. Multiple small randomized controlled trials have shown mitigation of sympathetic activity when central sleep apnea is treated with nocturnal oxygen, continuous positive airway pressure, and adaptive servoventilation. However, two early randomized controlled trials with positive airway pressure devices have shown either a neutral effect on survival or excess premature mortality in the active treatment arm, compared to untreated central sleep apnea. In contrast, the results of the most recent trial using an advanced adaptive servoventilation device showed improved quality of life and no signal for mortality suggesting that treatment of central sleep apnea was at least safe. In addition to positive airway pressure devices, multiple medications have been shown to improve central sleep apnea, but no long-term trials of pharmacologic therapy have been published. Currently, phrenic nerve stimulation is approved for the treatment of central sleep apnea, and the results of a randomized controlled trial showed significant improvement in sleep metrics and quality of life.

Keywords: hypoxemia; pap devices; phrenic nerve stimulation; sleep apnea; ticagrelor.

Figure 1.

Central apnea in a patient with HF with reduced ejection fraction during stage 2 non-REM sleep. From top to bottom: first two tracings are eye movements; the third is chin electromyogram, fourth and fifth are electroencephalogram, sixth is electrocardiogram; the next two lines are idle. The remaining lines are in order and represent airflow measured by thermocouple and carbon dioxide (CO₂), rib cage (RC) and abdominal (ABD) traces, esophageal pressure, and oxyhemoglobin saturation measured by pulse oximetry. Note that during obstructive apnea, airflow is absent while breathing effort continues. Note also the crescendo–decrescendo changes in thoracoabdominal excursion and oronasal airflow that sandwich central apnea. There is absence of any pressure changes in the esophageal pressure during apnea, and large negative swings during the hyperventilation period following central apnea. Taken and adapted with permission from reference [1].

Figure 2.

Prevalence of sleep apnea in patients with left ventricular dysfunction. ACPE: acute cardiogenic pulmonary edema; ADHF: acute decompensated HF; LVDD: left ventricular diastolic dysfunction; LVSD: left ventricular systolic dysfunction; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction. Taken and adapted with permission from reference [1].

Figure 3.

A 5-min epoch of a patient with systolic HF and HCSB. Note the periodic breathing with recurrent central apneas that are of the same length resulting in recurrent hypoxia/reoxygenation because of CSA. Note presence of atrial fibrillation. The tracings are similar to Figure 1.

Figure 4.

Central apneas in a patient with acute coronary syndrome treated with ticagrelor. Results of 20-min samples taken from 24-h home respiratory polygraphy of a patient with acute coronary syndrome experiencing periodic breathing on ticagrelor (panel a), 1 week (panel b) and 1 month after ticagrelor discontinuation, with progressive increase in ventilation stability and disappearance of central apneas. Taken and adapted with permission from Giannoni et al. [54].

Figure 5.

Potential therapeutic approach for the treatment of central apneas and HCSB in patients with HF. *These include angiotensin converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitor (i.e. sacubitril/valsartan), beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors, for patients with HF and HFrEF and HFmrEF, while only nonsteroidal mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors for HFpEF. ASV: assisted servoventilation; CA: central apneas; CO₂: carbon dioxide; CPAP: continuous positive airway pressure; CRT: cardiac resynchronization therapy; HCSB: Hunter-Cheyne-Stokes breathing; LVAD: left ventricular assist device; O₂: oxygen; SGLT2-i: sodium-glucose cotransporter-2 inhibitors.

Figure 6.

Components of a modern ASV device. EPAP: end-expiratory positive airway pressure; IPS: inspiratory pressure support; OSA: obstructive sleep apnea; HCSB: Huntter-Cheyne-Stokes breathing; CSA: central sleep apnea. Taken and adapted with permission from Javaheri et al. [97].

Figure 7.

Anticyclic pressure changes of an ASV device. Please note that the device pressure support increases when the subject’s intrinsic breathing decreases (i.e. during hypopnea).

Figure 8.

Impact of time spent with oxygen saturation below 90% on survival in patients with HF and reduced ejection fraction. SaO₂: oxygen saturation; T90: time spent with SaO₂ < 90%. Taken and adapted with permission from Oldenburg et al. [13].

Figure 9.

Mortality in the SERVE-HF trial and ADVENT-HF trial. Kaplan-Meier curves for mortality in the SERVE-HF and ADVENT-HF trials. The lower panel displays data from the SERVE-HF trial, showing an excess mortality in patients treated with ASV. The upper panel presents data from the ADVENT-HF trial, where no statistically significant difference in mortality was observed between the ASV-treated and control groups. Taken and adapted with permission from references [98] and [110].

Figure 10.

Elimination of CSA by phrenic nerve stimulation. Periodic breathing with CSA associated with desaturation (SPO₂), are eliminated with phrenic nerve stimulation. Taken and adapted with permission from reference [115].

Figure 11.

Long-term positive effects of phrenic nerve stimulation on the apnea–HI and sleep architecture in patients with central apneas. Upper panel: median AHI and its components—CAI, Obstructive Apnea Index, Mixed Apnea Index, and HI—are shown by visit. Polysomnography (PSG) was performed at baseline, 1 and 2 years; polygraphy (PG) at 3 years; and PSG/PG at 5 years (smaller sample size due to study closure, COVID-19, and subject decline). The right panel includes only patients with paired baseline and 5-year data. Lower panel: sleep stages by visit: median percentages of total sleep time in N1 (light sleep), N2 (intermediate sleep), N3 (deep sleep), and REM (rapid eye movement) are shown. N1 decreased over time, while deeper stages (N2, N3, REM) increased. Smaller sample size at year 5; the right panel includes only paired data. Sleep stage medians do not sum to 100%. Taken and adapted with permission from Costanzo et al. [118].

Figure 12.

Positive effects of buspirone on central apneas at nighttime and daytime. Oral administration of buspirone (bus, 15 mg three times daily) reduces central apneas in patients with HF across the 24 h compared to placebo (pla) (and baseline—bas), as evidenced by the significant reduction of daytime and nighttime AHI index and the CAI. Taken and adapted with permission from Giannoni et al. [139].