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How broken sleep promotes cardiovascular disease

The link between sleep and cardiovascular disease is poorly understood. Findings in mice now show that disrupted sleep causes the brain to signal the bone marrow to boost white blood cell production, damaging blood vessels.
Alan R. Tall is in the Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
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Sanja Jelic is in the Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
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Most people have at some point echoed Macbeth’s complaint about the loss of “sleep that knits up the ravelled sleeve of care”. Sleep disorders, such as obstructive sleep apnoea (when breathing temporarily stops, causing both sleep disruption and lack of oxygen in blood) and sleep deprivation, have been associated with an increased risk of atherosclerosis and its harmful cardiovascular effects1,2. Atherosclerosis is characterized by the formation of ‘plaques’ in arteries, as white blood cells enter the artery wall, take up cholesterol and other substances from the blood and trigger an inflammatory response. However, the mechanisms linking sleep disruption and atherosclerosis have been largely unknown. Writing in Nature, McAlpine et al.3 show that persistent sleep disruption causes the brain to signal the bone marrow to increase the production of white blood cells.

McAlpine et al. studied mice that were prone to developing atherosclerosis. The authors induced sleep fragmentation by moving a bar intermittently across the bottom of the animals’ cages during their sleep period (Fig. 1), and compared these animals with animals that slept normally. They found that mice with sleep fragmentation had more-severe atherosclerosis, which was paralleled by increases in the production of white blood cells in the bone marrow and in the numbers of monocytes and neutrophils — two types of white blood cell — in the blood. These effects were absent if the bar was moved when the mice were fully awake. Stress activates the sympathetic nervous system (which is associated with the ‘fight-or-flight’ response), and such activation increases the production of white blood cells and atherosclerosis in other experimental settings4. However, the authors did not find evidence for a role of sympathetic activation in their setting.

Figure 1 | Sleep fragmentation accelerates atherosclerosis. McAlpine et al.3 induced long-term sleep fragmentation in mice by moving a bar across the bottom of their cages during their sleep period. Such treatment reduces the levels of the protein hypocretin, which is produced in the brain’s hypothalamus. Hypocretin receptors are present on cells in the bone marrow (pre-neutrophils) that will develop into a type of white blood cell called a neutrophil. Pre-neutrophils sense the lack of hypocretin and produce increased amounts of a protein known as colony-stimulating factor-1 (CSF-1). Uninhibited CSF-1 production stimulates stem cells that give rise to all types of white blood cell (haematopoietic stem cells; HSCs) to produce increased numbers of pre-neutrophils and pre-monocytes (white blood cells that will develop into monocytes). Mature neutrophils and monocytes migrate to arterial walls, where the monocytes develop into macrophage cells. Macrophages and, to a lesser extent, neutrophils promote the formation of plaques, a hallmark of atherosclerosis — a condition that can have harmful cardiovascular effects.

Next, McAlpine and colleagues performed a systematic examination of sleep-regulating proteins in the hypothalamus, a part of the brain that controls metabolic responses in the body. They discovered that expression of the protein hypocretin (also called orexin) was markedly reduced in the sleep-disturbed mice, compared with the control mice. Hypocretin promotes wakefulness, and increases food intake and the activity of the sympathetic nervous system5. Low expression of hypocretin has been seen in individuals with narcolepsy, a rare disorder that makes people fall asleep during the day5.

McAlpine et al. observed that, like the mice with sleep fragmentation, genetically engineered mice unable to express hypocretin produced more white blood cells and had increased atherosclerosis compared with mice that were able to express hypocretin. Giving hypocretin to mice that had sleep disruption reduced white blood cell production and decreased the severity of atherosclerosis, suggesting that reduced hypocretin levels have a major role in atherosclerosis driven by sleep fragmentation.

Probing further, McAlpine et al. found that sleep disruption decreased hypocretin levels in the animals’ blood and bone marrow. This protein has two receptors in cells, one of which is highly expressed in the subset of bone marrow cells that gives rise to neutrophils. These pre-neutrophils responded to decreased amounts of hypocretin by increasing the production of colony-stimulating factor 1 (CSF-1), a protein that promotes the production of white blood cells from stem cells in the bone marrow. The authors also found that CSF-1 deficiency in bone marrow cells counteracted the increased production of monocytes and the accelerated atherosclerosis caused by hypocretin deficiency or sleep fragmentation. These results suggest that the reduction of hypocretin levels caused by sleep disruption stimulates CSF-1 production, and that this increases the production of monocytes and promotes atherosclerosis.

Although the hypocretin–CSF-1 pathway seems to be the major mechanism linking sleep fragmentation to the production of white blood cells and atherosclerosis, there are hints that other mechanisms could also be involved. For example, McAlpine et al. observed that CSF-1 deficiency in bone marrow cells did not reduce the elevated numbers of neutrophils in blood caused by hypocretin deficiency or sleep fragmentation. This suggests that other, CSF-1-independent, pathways increase neutrophil production during sleep disruption. Of note, neutrophils can contribute to the formation of atherosclerotic plaques, even if their role is less important than that of monocytes. Furthermore, in addition to increasing monocyte numbers in blood, CSF-1 affects the artery wall directly, for example by stimulating the maturation of monocytes into macrophage cells6. This influence of CSF-1 on artery walls might have contributed to the protective effects of CSF-1 deficiency in mice with sleep fragmentation.

McAlpine et al. observed a decrease in hypocretin expression and an increase in the production of white blood cells only after 12 weeks of sleep disruption. Although this might suggest that the brain undergoes structural changes that lead to loss of hypocretin-producing neurons, this possibility was not supported by the authors’ assessment of the number of dead cells in the hypothalamus. Narcolepsy can be caused by the loss of hypocretin-producing neurons5, and one of the hallmarks of this disease is fragmented sleep7. Together with the present study’s findings, which indicate that sleep fragmentation causes hypocretin deficiency, this suggests that a bidirectional relationship might exist between the two conditions.

Although sleep disruption did not affect the animals’ body weight, it reduced food intake, as expected when hypocretin levels are low. The maintenance of body weight despite reduced food intake implies that the mice used less energy. Given that hypocretin increases energy expenditure through signalling by the hormone leptin8, these findings indicate that hypocretin deficiency might lead to reduced leptin signalling in mice that have sleep fragmentation. Moreover, white blood cell production is increased in leptin-deficient mice9. This suggests that metabolic disturbances beyond those studied by McAlpine et al. might contribute to the increased production of these cells and the worsening atherosclerosis in mice with sleep disruption.

Study of the relationships between sleep disorders and metabolic and cardiovascular disorders is in its infancy. McAlpine et al. have uncovered a previously unknown mechanism that has possible therapeutic implications. The drug suvorexant, a blocker of hypocretin receptors, was approved in 2014 for the treatment of insomnia. The present study raises the question of whether such therapies could have harmful cardiovascular consequences. Effects observed in mouse studies often do not translate well to humans, and suvorexant did not increase total white blood cell counts in one observational human study10. Nevertheless, continued surveillance of people receiving this drug might be warranted. Future studies might further unravel the links between sleep disorders and cardiometabolic risk, and lead to new therapeutic strategies for treating these highly prevalent disorders.

Nature 566, 329-330 (2019)

doi: 10.1038/d41586-019-00393-6

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