Sleep and CVD Part III: Circadian Rhythms and CVD

In Parts I and II of this series, we established that sleep deprivation (i.e. not getting enough sleep) is associated with adverse cardiovascular outcomes. In addition, we looked at studies showing sex-differences in the strength of the association among insufficient sleep duration and CVD. The conclusion, it seems, is that women might suffer more from the effects of short sleep than men.

Exploring associations is fun, but where research really gets interesting is when we start to explore what might be underlying these associations — that is — by what mechanism(s) does a lack of sleep promote adverse cardiovascular health?

While we will talk about some specific biochemical and hormonal mechanisms in a future post, another plausible mechanism linking sleep and CVD involves circadian rhythms.

I won’t go too in depth on circadian rhythms here. But briefly, circadian rhythms (from circa dia meaning “about one day”) are internal 24 hour “clocks” that are present in nearly all of our cells. They control things like sleep and eating behavior, hormonal release, and even some aspects of muscle performance.

We have circadian rhythms in our cardiovascular system too. Throughout any given day, there is a considerable variation in things like blood pressure, blood clotting, and the ability of our blood vessels to relax (something called endothelial function). One well-known example of this is the fact that our blood pressure drops during the night (called “blood pressure dipping”). Interestingly, people who are “non-dippers” are shown to be at an increased cardiovascular disease risk.

Figure 1. Graphic of the circadian rhythm in blood pressure. Source: Douma 2018 (7)

Endothelial function also exhibits a circadian rhythm. Our vessels have a greater ability to dilate in the afternoon compared to the morning (1). No surprisingly, reduced endothelial function in the morning also corresponds to a morning surge in blood pressure.

Perhaps even more interesting is the nearly universal observation that there is a higher prevalence of cardiovascular “events” (i.e. heart attacks) in the morning (2). It’s perhaps no coincidence. This statistic can likely be explained, in part, by circadian rhythms.

Disruption of the internal circadian clock might be expected to further increase this morning risk…along with the risk at other times during the day. If internal clocks become “desynchronized” to the external environment and daily activities, our body becomes unable to “anticipate” what it needs to do, and dysfunction can occur.

There are data to indicate that circadian disruption can impair cardiovascular function. For instance, disruption of the internal circadian clock in mice leads to vascular dysfunction and disrupts the proper rhythm of the production of nitric oxide (NO), which we need to help relax our blood vessels (3).

Animals who have had their internal circadian clocks deleted or “knocked out” have impaired vascular function and show evidence of accelerated aging of their blood vessels (4).

How do sleep deprivation and sleep loss contribute to circadian disruption?

Interestingly, one could theoretically be sleep deprived while still maintaining a “normal” rhythm. Poor sleep habits and “social jetlag” may better explain circadian misalignment than simply “not getting enough sleep.”

However, some studies have shown that even a single night of sleep deprivation can lead to altered gene expression for important proteins involved in the circadian rhythm system. In addition to affecting clock genes, sleep deprivation also induces metabolic dysfunction in healthy young men (5).

Figure 2. Acute sleep loss reduces circadian rhythm genes in healthy young men. Source: Cedernaes 2015 (5)

Sleep-deprived mice show reduced expression of the circadian clock gene CRY1 and higher levels of inflammation after sleep deprivation (6).

Circadian rhythms likely play a profound role in maintaining cardiovascular health. In the setting of circadian misalignment due to long term shift work or continuous irregular sleep patterns, we likely will see both acute cardiovascular dysfunction and later, chronic disease as a result.

It makes sense that all kinds of diseases would result when our rhythms are out of line. The human body is a complex machine that works best when all signals are communicating properly, and metabolically synchronized. There are a lot of environmental and lifestyle factors that can throw this system out of whack, which is why being prudent about sleep, diet, and exercise are crucial.

In Part IV, we will look at experimental studies of sleep deprivation, and how acute sleep loss impacts vascular function and arterial stiffness!

References

1. Thosar SS, Butler MP, Shea SA. Role of the circadian system in cardiovascular disease. The Journal of clinical investigation. 2018;128(6):2157–2167.

2. Crnko S, Du Pré BC, Sluijter JPG, Van Laake LW. Circadian rhythms and the molecular clock in cardiovascular biology and disease. Nature reviews. Cardiology. 2019;16(7):437–447.

3. Rudic RD. Time is of the essence: Vascular implications of the circadian clock. Circulation. 2009;120(17):1714–1721.

4. Thosar S, Berman A, Herzig M, et al. Circadian rhythm of vascular function in midlife adults. Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39(6):1203–1211.

5. Cedernaes J, Osler ME, Voisin S, et al. Acute sleep loss induces tissue-specific epigenetic and transcriptional alterations to circadian clock genes in men. The Journal of Clinical Endocrinology & Metabolism. 2015;100(9):E1255-E1261.

6. Qin B, Deng Y. Overexpression of circadian clock protein cryptochrome (CRY) 1 alleviates sleep deprivation-induced vascular inflammation in a mouse model. Immunology Letters. 2014;163(1):76–83.

7. Douma LG, Gumz ML. Circadian clock-mediated regulation of blood pressure. Free Radical Biology and Medicine. 2018;119:108–114.