Beating against the clock

Shift work has been associated with adverse cardiometabolic effects, such as increased risk for coronary artery disease, diabetes and metabolic syndrome, hypertension and dyslipidemia (1). Although it has been suggested that circadian misalignment may contribute to disease, dissecting the impact of the circadian clock versus social and behavioral influences has been difficult. In PNAS, Morris et al. use simulated short-term shift work in a well-controlled laboratory setting to demonstrate that circadian misalignment impacts blood pressure (BP) and inflammation markers, two important cardiovascular risk factors (2). These findings provide cogent support for the importance of altered circadian rhythms on cardiovascular disease risk.

Circadian rhythmicity affects all living organisms on earth. In mammals, molecular components of the clock machinery exist in the brain and peripheral tissues. The central clock exists in the suprachiasmatic nucleus in the hypothalamus and is mainly entrained by light; it coordinates the physiology and behavior of the organism (3). The clocks in peripheral tissues are coupled to the central clock, but can also be entrained to oscillate autonomously by other environmental cues (or zeitgebers), such as food (4). Thus, it is possible to dys-synchronize the central and peripheral clocks as seen in the jet-travel or shift-work paradigm.

To directly assess the effect of circadian misalignment in humans, Morris et al. (2) designed a sophisticated laboratory-based human study with two 8-d protocols and a cross-over design that comprehensively tested the acute effect of misalignment in a variety of physiological parameters. In the first report of this series, the authors found that circadian misalignment reduces glucose tolerance by decreasing insulin sensitivity, whereas the diurnal variation of glucose tolerance is a result of variable β-cell function (5). More recently, in PNAS, Morris et al. (2) report findings regarding cardiovascular risk factors, including the blood pressure, heart rate, and inflammation markers.

Blood Pressure

One major observation is that circadian misalignment per se leads to increased 24-h systolic blood pressure (SBP), which is mainly attributed to nighttime SBP elevation (and reduced SBP dipping). Normally, SBP falls during the nighttime and failure to do so (termed “nondippers”) has been associated with increased risks for cardiovascular events and adverse outcomes, including stroke, heart failure, and myocardial infarction (6). The magnitude of sleep SBP elevation observed as a result of a single shift, in the present study, was almost 6 mmHg and lasted 3 d in this acute experimental paradigm (2). Although seemingly modest, this magnitude of change is comparable to many BP-reducing agents when used as monotherapy (e.g., β-blockers and calcium-channel blockers). Indeed, a meta-analysis of over 600,000 patients showed that a 10-mmHg drop in SBP significantly reduced the risk of major cardiovascular events (20%), coronary heart disease (17%), stroke (27%), and heart failure (28%), as well as all-cause mortality (13%). More recently, a landmark randomized trial of intensive versus standard BP control in patients with cardiovascular risk factors was shown to significantly reduce major cardiovascular events (25%) and all-cause mortality (27%) (7), suggesting even small effects of the BP in the prehypertension range can be of pathological significance. The increased SBP during circadian misalignment may be partially mediated by the shortened total sleep duration (∼1 h) and increased nighttime epinephrine, and are not associated with changes in melatonin or cortisol level (2). The contribution of each of these factors is worth investigating, as it will direct future management aimed at reducing the cardiovascular risks associated with shift work or frequent jet travel.

Inflammation

Another interesting finding is the increase in inflammatory factors [IL-6, C-reactive protein (CRP), resistin, and TNF-α] after acute misalignment (2). Although some of these markers, such as IL-6, quickly returned to baseline, they may still contribute to the long-term health of shift workers through repeated exposure. A large body of experimental work supports the importance of inflammation in the development of cardiovascular disease (8). Clinically, the emergence of inflammatory markers, such as high-sensitivity CRP (hsCRP), has been particularly helpful in predicting cardiovascular risks (9). Furthermore, the JUPITER trial and others have shown a reduction in absolute vascular events with rosuvastatin in apparently healthy individuals with low levels of LDL cholesterol but elevated hsCRP (10). Genetic studies demonstrated that the causality likely lies in the proinflammatory IL-1 and IL-6 cascade (11, 12) and not CRP itself. As a result, two large clinical trials (Cardiovascular Inflammation Reduction Trial “CIRT” and Canakinumab Anti-inflammatory Thrombosis Outcomes Study “CANTOS”) aimed to recruit over 25,000 people total are ongoing to answer the ultimate question of whether therapy targeted to reduction of inflammation can decrease cardiovascular events independently of known factors, such as lipoprotein.

The study by Morris et al. (2) provides the long-awaited direct evidence from human studies regarding the cardiovascular risks associated with circadian dys-synchrony. It confirms the notion from previous epidemiological studies and animal studies that dys-synchrony leads to increased BP and inflammation. It should be noted that the BP or inflammatory marker changes in the Morris et al. study did not exceed the normal range. The present work was performed in young healthy volunteers; the changes are likely to be of great significance in middle-age to older patients, with baseline hypertension or higher level of baseline hsCRP. It is noteworthy that both elevated BP and inflammation have been associated with a number of other late-onset disorders, such as dementia and cancer. Although the body of literature on the relationship between shift work and these conditions is still emerging (13, 14), understanding the effect of misalignment may have a far-reaching impact beyond the field of cardiovascular biology.

The present study also opens up the discussion for possible therapeutic options. Chronotherapy targeted for the sleep-time blood pressure might be of particular benefit. Indeed, several clinical studies have discovered that nighttime angiotensin-converting enzyme inhibitor achieves better BP control and is associated with lower risk for total cardiovascular disease events (15–18). Furthermore, study in mice showed that rest-time angiotensin-converting enzyme inhibitor results in improved cardiac remodeling even when controlled for BP (19). Additional therapy aimed at facilitating the resynchronization using both behavioral (e.g., feeding, exercise, lighting conditions) and pharmacological modifications (melatonin) may be effective. Finally, directly manipulating the molecular clock has now become possible and offers novel therapeutic opportunities.