Influence of sleep on physiological systems in atherosclerosis

Abstract

Sleep is a fundamental requirement of life and is integral to health. Deviation from optimal sleep associates with numerous diseases including those of the cardiovascular system. Studies, spanning animal models to humans, show that insufficient, disrupted or inconsistent sleep contribute to poor cardiovascular health by disrupting body systems. Fundamental experiments have begun to uncover the molecular and cellular links between sleep and heart health while large-scale human studies have associated sleep with cardiovascular outcomes in diverse populations. Here, we review preclinical and clinical findings that demonstrate how sleep influences the autonomic nervous, metabolic and immune systems to affect atherosclerotic cardiovascular disease.

Fig. 1 |. Sleep and atherosclerotic cardiovascular disease are connected through the integration of the nervous, immune and metabolic systems.

Sleep calibrates ASCVD by modulating multiple core body systems. Interference of adequate sleep including sleep duration, quality and timing adversely affects the function of the nervous, metabolic and immune systems, which predisposes to ASCVD and its complications, including myocardial infarction and stroke. Emerging studies suggest these connections between ASCVD and sleep are bidirectional and peripheral metabolic, nervous and immune imbalance alter sleep.

Fig. 2 |. Sleep and autonomic nervous balance.

Sleep exerts a modulatory effect on the activity of the autonomic nervous system. Persistent sleep disturbances lead to elevated SNS and HPA activity during sleep and wakefulness and modulate the tone of the PNS. Consequently, desynchronization of the HPA axis compromises heart electrophysiology leading to extremities in heart rate variability, while aberrant SNS and PNS activation triggers nocturnal non-dipping of blood pressure (BP) and daytime HTN. In addition, sleep manipulates SNS/PNS equilibrium instigating adverse immune responses in the heart including accentuated inflammatory cytokine production. Altogether, sleep deficiencies promote heart rate alterations, HTN and inflammation via compromising the autonomic nervous system, thus exacerbating ASCVD.

Fig. 3 |. Sleep and the metabolic system.

Sleep and the metabolic system share a bidirectional relationship. While sleep disturbances promote food intake and can cause subsequent weight gain, excess consumption of a sugar-rich and cholesterol-rich diet increases sleep drive with curtailed sleep quality. On the one hand, insufficient or irregular sleep can fuel metabolic syndrome by affecting hepatic triglyceride and cholesterol output via the modulation of hypoxia-dependent metabolic genes in the liver. Consequently, persistent sleep disruption may result in an atherogenic lipid profile with heightened LDL-c and triglyceride and lower HDL-c levels. On the other hand, suboptimal sleep hygiene propagates fat mass accumulation, adipocyte progenitor cell production and adipose tissue inflammation. Prolonged metabolic reprogramming of the adipose tissue contributes to leptin resistance as well as glucose intolerance and insulin resistance, thereby predisposing to cardiometabolic complications.

Fig. 4 |. Sleep protects from ASCVD by modulating inflammation.

The beneficial impacts of proper sleep on the immune system are manifold; thus, insufficient or poor-quality sleep exerts various adverse effects on inflammation that underlies atherosclerosis. Prolonged sleep disruption compromises neuroimmune communication axes that modulate leukocyte numbers and function via neuropeptide, SNS or PNS innervations. (1) Blunted hypocretin signaling from the lateral hypothalamus to bone marrow pre-neutrophils following sleep fragmentation heightens colony-stimulating factor-1 (CSF-1)-mediated medullary hematopoiesis and results in subsequent monocytosis and neutrophilia. Consequently, increased aortic immune cell infiltration drives exacerbated atherosclerotic lesion formation. (2) Enhanced sympathetic and compromised anti-inflammatory parasympathetic inputs to secondary lymphoid organs and neuroimmune cardiovascular interfaces at the adventitia — that is, artery tertiary lymphoid organs (ATLOs) — augment the production of pro-inflammatory cytokines including IL-6, TNF and IL-1β, further inciting an inflammatory milieu. Whether this affects local lymphocyte function and repertoire remains unknown. (3) Sleep disturbances promote endothelial cell dysfunction characterized by enhanced chemoattractant activity, including CCL2 release and increased expression of adhesion molecules, such as ICAM-1, VCAM-1 or E-selectin. Circulating exosomes promote endothelial cell injury via increased miR-182-5p-dependent NF-κB and NLRP3 signaling, thus licensing IL-1β and IL-18 production. These effects compromise endothelial cell integrity and further facilitate immune cell entry into the atheroma. (4) Persistent sleep fragmentation poses profound and lasting changes on hematopoietic stem cells via epigenetic restructuring, leading to exaggerated myeloid-biased inflammatory bursts. Consequently, aortic macrophages derived from recruited monocytes may be strongly pro-inflammatory, defective of rate-limiting processes, such as lipid handling or efferocytosis and more prone to necrotic death, further fueling plaque growth and instability. ACh, acetylcholine; CORT, corticosterone; HCRTR1, hypocretin receptor 1; NA, noradrenaline.