Sleep and CVD Part V: Mechanisms Linking Short Sleep to Cardiovascular Disease

In this installment of the sleep and CVD series, we will explore potential mechanisms by which insufficient sleep may lead to cardiovascular dysfunction and disease.

Hello friends,

Last week, I released part IV of my blog series on sleep and cardiovascular disease. You can read that post HERE.

This week, in part V of the series, we will talk about the mechanisms responsible for the effects of insufficient sleep on cardiovascular disease processes.

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Here’s what to look forward to in the remaining parts of this series:

Part I: Sleep and Cardiovascular Disease: The Epidemiological Evidence (published 1/3/22)

Part II: Sex Differences in Sleep Loss and Cardiovascular Health Outcomes (published 1/10/22)

Part III: Circadian Rhythms & Cardiovascular Disease: The Role of Biological Clocks in Sleep and Health (published 1/17/22)

Part IV: Sleep Deprivation and Blood Vessel Health (published 1/24/22)

Part V: How Sleep Loss Causes Cardiovascular Disease (this post!)

Part VI: Exercise as a Strategy to Protect Against the Negative Effects of Sleep Loss

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In part V of this series, I’m going to explore some of the mechanisms that might 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. 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. 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 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. 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 pathways, as shown below.

The role of inflammation in causing arterial stiffness. Jain 2014.

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 causes us to produce less NO.

 The role of oxidative stress in endothelial/cardiac dysfunction. Munzel 2017.

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 reduces NO (Nox) availability. Kim 2011.

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). This has been demonstrated in human and 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” and reset. 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.