Thank you, reader, for returning to (or just beginning) this series where we have been exploring the link between sleep and cardiovascular disease (CVD). You can read this and previous posts here, but also by visiting my Patreon page (where you can find other content and maybe become a monthly supporter of my work!)
Our focus thus far has been on the strong associations between insufficient sleep (aka sleep deprivation) and a greater risk for CVD morbidity and mortality. In addition, we have discussed the fact that men and women seem to display different risk profiles when it comes to CVD and sleep — in that women seem to experience a higher CVD risk than men when they don’t get enough sleep.
The two most recent posts dive into circadian rhythms (Part III) and blood vessel health (Part IV), and how these factors probably play a large role in the sleep-CVD relationship. Since my research focus is specifically on blood vessel health and function, this is a particularly interesting and important topic to me.
In part V, the final post in this series, I’m going to explore some of the cellular mechanisms that might actually be causing dysfunction and disease in people who don’t get enough sleep. The list is non-exhaustive, but I’ll cover three of the primary pathways that have been given the most research attention.
It is important to explore mechanisms for a variety of reasons, not the least of which is that this allows us to then explore potential “treatments” or interventions to prevent or reverse the health complications caused by insufficient sleep.
In other ways, it’s just very interesting, if not necessary, to know what is going on in the body in response to a lack of sleep — which really is a physiological stress. What happens inside our body after a single “all-nighter” or years and years of insufficient sleep?
We’ve already covered endothelial dysfunction and arterial stiffness as potential causes of the increased CVD risk associated with poor sleep, but the mechanisms go deeper than these two higher-level processes. This post will talk about what’s going on at a cellular level.
Below are some of the more well-known and well-studied mechanisms that increase the risk of poor CVD health in short-sleepers. Some of these data come from association studies, but a large portion are based on experimentally-derived data in humans and sometimes in rodents.
Inflammation and Oxidative Stress
Inflammation, at least chronic, low-grade inflammation, plays a role in several diseases, not just CVD. Acute inflammation serves a crucial role in our body by responding to infections, injury, etc., and helping us to adapt, heal, and grow more resilient. On the other hand, chronic inflammation is no good — it’s as if our body is constantly responding and “attacking” itself; a constant state of “stress.” For this reason, inflammation can lead to a lot of issues, and contributes to the development of cardiovascular and cardiometabolic diseases (Donath 2019).
As it turns out, sleep duration is negatively correlated with several pro-inflammatory cytokines — i.e. people with shorter sleep have higher resting levels of inflammation (Ferrie 2013, Miller 2009). Not only that, but experimentally restricting sleep (sleep deprivation) raises levels of pro-inflammatory cytokines including IL-6, TNF-α, Interferon-y, and C-reactive protein (Irwin 2006, Irwin 2015, Sauvet 2015, Tobaldini 2013, Meier-Ewert 2004, van Leeuwen 2009, Ferrie 2013, Miller 2009).
Some studies have even found that total sleep deprivation for 29–40 hours increases inflammatory markers, but only after a day of recovery sleep! (Sauvet 2010, Sauvet 2017) This means that, perhaps, some sort of “delayed” response to stress (lack of sleep) is happening. This is a bit concerning, because it suggests that even a night of recovery sleep isn’t enough to return you to “normal” after a bout of sleep deprivation — at least as far as inflammation is concerned.
High levels of inflammation promote negative changes to blood vessel structure and function through multiple divergent and convergent pathways.
For instance, acute inflammation increases arterial stiffness and reduces elastic properties of our arteries (Vlachopoulos 2005). Chronic inflammation is a major cause of the age-related increase in arterial stiffness. This occurs through processes like increasing growth factors and how much collagen we have in our artery walls, leaving them stiffer and less elastic. Essentially, high levels of inflammation can cause structural remodeling of blood vessels, leading to poor cardiovascular health and impaired or reduced function. Inflammation also reduces the capacity of our blood vessels to dilate and increases the tone of our vascular smooth muscle — both of which are associated with artery stiffening.
Oxidative stress is generally classified as an imbalance of antioxidants and pro-oxidants in the body. Oxidants, aka reactive oxygen species (ROS), are highly-reactive molecules that cause cellular damage and inactivate beneficial molecules in the cardiovascular system, among other effects.
Oxidative stress can be increased by high levels of inflammation, but also lead to inflammatory responses. Inflammation and oxidative stress perpetuate a vicious cycle in our body.
Like inflammation, oxidative stress biomarkers are elevated in people with a short sleep duration (Kanagasabai 2015, Faraut 2011, Boudjeltia 2011).
ROS are also enemies of the vasculature, at least when present in high levels and unopposed by protective antioxidants. Thus, high and uncontrolled levels of ROS in response to insufficient sleep could mediate vascular dysfunction. We have already covered how levels of ROS (and inflammation) increase after periods of sleep deprivation. Additionally, it has been demonstrated that high levels of ROS lead to endothelial dysfunction. They do this by reacting with and inactivating nitric oxide (NO) which we need to help blood vessels relax. ROS also cause us to produce less NO.
In fact, NO bioavailability is reduced after sleep deprivation (Kim 2011), and people with a short sleep duration have lower levels of NO than people who get a normal amount of sleep (Bain 2017). Reduced levels of NO likely explain a greater CVD risk in these individuals, since this molecule has several protective effects for our cardiovascular system, and a loss of NO bioavailability is one factor that plays a role in the development of vascular dysfunction and CVD.
Sleep deprivation also causes us to produce less antioxidants — which are what our body uses to fight and protect against the negative effects of ROS (Trivedi 2017). Similar findings have been shown in animal models.
Exactly why inflammation and oxidative stress increase after sleep loss is unclear. However, one hypothesis is that sleep is a period where our cardiovascular system can “rest”, replenish, and reduce its overall load. When this doesn’t occur, we maintain an “activated” vascular system, fail to decrease blood pressure during the night (blood pressure “dipping”) and throw off crucial maintenance systems like antioxidant synthesis and nervous system balance. This high level of activation causes an inflammatory response, increases ROS production, and leaves our body unable to deal with physiological stressors. You can see how, over time, this could increase the risk for diseases of the cardiovascular system.
Autonomic Nervous System
We have two branches of our autonomic nervous system (ANS) — the sympathetic (SNS) and parasympathetic (PNS) systems. In general, sympathetic activity in the cardiovascular system is associated with an increased heart rate, elevated blood pressure, and endothelial dysfunction and arterial stiffness. On the other hand, parasympathetic activity is associated with a lower heart rate, vasodilation and reduced blood pressure, and better endothelial function and reduced arterial stiffness.
Alterations in the balance of these systems due to poor sleep are a probable cause of cardiovascular dysfunction. Indeed, acute sleep deprivation increases sympathetic activity in adults (Sauvet 2010, Tobaldini 2013, Zhong 2005), and even chronic moderate sleep restriction has been shown to raise levels of SNS activity (Dettoni 2012, Takase 2004, Grimaldi 2016, Spiegel 1999). As we covered earlier, some studies even show that SNS activity is elevated in older women, but not men, following acute sleep deprivation (Carter 2019).
This makes sense, because sleep is the major time during the day when our parasympathetic system dominates and sympathetic activity withdraws a bit. This is why blood pressure and heart rate fall at night. In this way, depriving yourself of this parasympathetic-dominant time would elevate the other arm of the ANS disproportionately — both at night and during the day — and research shows this to be true.
How does increased SNS activity promote cardiovascular disease? For one, activation of the SNS causes elevations in arterial stiffness. This occurs through the binding of epinephrine and norepinephrine (adrenaline and noradrenaline; i.e. the “stress hormones”) to alpha receptors on our blood vessels, causing them to constrict and increase their stiffness/reduce their elasticity. This can happen both in the short term, but also in response to chronically high levels of SNS activity.
The SNS is also implicated in endothelial dysfunction. For instance, if you acutely raise sympathetic activity, endothelial function declines (Bruno 2012), and high resting SNS activity is inversely associated with endothelial function in healthy adults. Therefore, when SNS activity is elevated due to insufficient or poor sleep, endothelial dysfunction is likely to result. However, there are some studies showing that endothelial dysfunction occurs before the increase in SNS activity following a bout of sleep deprivation. This is to say that elevated sympathetic activity might have a sufficient, but not necessary role in endothelial dysfunction due to sleep deprivation.
It might be useful to think about sympathetic activity as having a “restraining” function on blood vessels that prevents their proper function. A higher resting vascular tone and a stiffer, less-compliant vessel will be less capable of relaxing when it needs to. In contrast, a “parasympathetic” state where our vessels are relaxed and responsive is more prone to function properly and in a healthy manner. This is why the SNS/PNS balance is so important for cardiovascular health, and likely a mechanism behind the relationship between sleep and CVD.
Circadian Rhythm Disruption
We’ve discussed circadian rhythms before in Part III of this series. These 24-hour “clocks” in our vessels control everything from blood pressure to when our arteries are the most (and least) elastic. Interesting fact: vascular function is lower in the morning and displays its “peak” activity in the mid to late afternoon. Thus, vascular function is described as exhibiting “diurnal variation” (Thosar 2018, Thosar 2019).
Misaligned rhythms, whereby our “internal” clocks are out of sync with the “external” environment, promote physiological dysfunction. In terms of our discussion, this means increased inflammation, impaired blood pressure and ANS regulation, and endothelial dysfunction.
Indeed, circadian misalignment increases systolic and diastolic blood pressure, reduces parasympathetic activity, and elevates inflammatory cytokines including IL-6, C-reactive protein, and TNF-α (Challapah 2019). All of these are associated with an increased risk for CVD. The epidemiological data support this. Shift workers who demonstrate a misalignment of their circadian rhythms are at a greater risk for heart disease.
It is hard to directly impose circadian misalignment or study it completely in humans, but studies using rodent models of circadian system disruption show that these animals exhibit impaired vascular endothelial function and even show signs of accelerated vascular aging. Chronic sleep loss, potentially leading to circadian system disruption, is likely to replicate many of these changes in humans.
There are relatively few studies in humans looking at whether acute sleep deprivation leads to circadian misalignment and how this may influence vascular function, but it has been shown that a single night of sleep deprivation alters the transcription of genes that are crucial for circadian rhythm function in adult men (Cedernaes 2015).
Disruption of circadian rhythms could lead to a reduced ability to produce nitric oxide, since the enzyme that makes NO is under circadian control. This would cause endothelial dysfunction. But in general, an overall shifting of circadian rhythms alters our body’s “normal” vascular responses at different times of day, inducing vascular dysfunction and disturbing the oscillation of key enzymes involved in vascular health and regulation (Rudic 2009).
Again, while the studies were done in rodents, sleep deprivation leads to a reduced transcription of a gene known as cryptochrome 1 (CRY1) that is essential for proper circadian clock function. Reduced CRY1 in vascular cells in mice was accompanied by increased levels of inflammation and, presumably, endothelial dysfunction (though this wasn’t measured) (Qin 2014).
The role of the circadian system in CVD is a field that is benefitting from recent developments in molecular techniques that allow researchers to study mechanisms and genes involved in this process. It’s likely an area where publications and new data will continue to increase in the coming years.
When it comes to “causes” of a disease, we often like to play a version of “Clue” where there is one potential culprit — or in our case, one potential pathway. Vascular researchers want to blame endothelial dysfunction and inflammation researchers want to pin the blame on inflammation. However, the reality is that insufficient sleep likely leads to CVD through a combination of all of the above mechanisms…and probably more!
For instance, studies show that metabolism becomes dysregulated by poor sleep, and even appetite increases. Cardiovascular and metabolic health are intertwined in such a way that dysregulation in one is more than likely to cause dysfunction in the other.
But as far as cardiovascular mechanisms go, acute and chronic sleep deprivation affect our autonomic nervous system balance, inflammatory and oxidant/antioxidant systems, and our endogenous circadian systems in a way that primes our heart and blood vessels for dysfunction.
This series obviously hasn’t gotten into the “evolutionary” reasons for why we sleep, but it becomes clear when studying the above mechanisms that, as far as our cardiovascular system is concerned, we need this crucial period in order to “unload” our heart and vessels, reset our autonomic activity, and just give ourselves a “rest.” There are also some other repair pathways that start going to work when we sleep — helping to clear our cellular “detritus” (not a scientific term) and maintain homeostasis and vascular health.
When we skimp on sleep, we lose out on this period of rest and regeneration. Once or twice, it won’t kill us. But as with all “bad habits”, over time, the detrimental effects will pile up and increase our susceptibility to disease.
The good thing is, sleep hygiene might be the most simple habit to improve. Maintain a constant bedtime (and wake time), and try as best as you can for a solid 6–9 hours every night. It’s the least you can do for your heart, and likely every other organ in your body.
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