Impact of Circadian Disruption on Cardiovascular Function and Disease

Abstract

The circadian system, that is ubiquitous across species, generates ∼24 h rhythms in virtually all biological processes, and allows them to anticipate and adapt to the 24 h day/night cycle, thus ensuring optimal physiological function. Epidemiological studies show time-of-day variations in adverse cardiovascular (CV) events, and controlled laboratory studies demonstrate a circadian influence on key markers of CV function and risk. Furthermore, circadian misalignment, that is typically experienced by shift workers as well as by individuals who experience late eating, (social) jet lag, or circadian rhythm sleep-wake disturbances, increases CV risk factors. Therefore, understanding the mechanisms by which the circadian system regulates CV function, and which of these are affected by circadian disruption, may help to develop intervention strategies to mitigate CV risk.

Keywords: cardiovascular risk; circadian misalignment; circadian rhythms; shiftwork.

Figure 1:. Conceptual framework of circadian misalignment effects on cardiovascular risk

A: Circadian rhythms are driven by molecular clocks centered around core clock genes such as BMAL1, CLOCK and NPAS2, which regulate rhythms of their own transcription/expression via negative (and positive) feedback loops (see top left inset for schematic, see ref# [71] for review). B: These molecular clocks are present in almost every cell in the body, including cardiac/vascular tissues, adrenal glands, kidneys, the immune system, and importantly, the “master clock” in the SCN. The SCN clock can affect cardiovascular function independently of peripheral clocks (e.g. via autonomic nervous system outflow/endocrine outflow) and by acting to synchronize peripheral clocks (e.g. via circadian rhythms in body temperature/endocrine outflow). Peripheral circadian clocks provide feedback to each other and the SCN clock via their modulatory effects on cardiovascular and endocrine physiology. Endogenous circadian rhythms also influence daily patterns in behavior/exposure to environmental factors, which in turn also impact cardiovascular physiology. C: Disruptions to the circadian system can impact cardiovascular risk without necessarily disrupting behavioral/environmental cycles (e.g. via tissue-specific circadian clock-gene mutations). Behavioral/environmental cycles can impact cardiovascular risk even when said rhythms are entrained/aligned to the endogenous circadian cycle (e.g. via disrupted sleep in individuals who maintain regular schedules). However, in the most common/epidemiologically relevant scenarios, behavioral/environmental cycles become misaligned relative to the endogenous circadian cycle and it is this circadian misalignment that impacts cardiovascular risk. Known risk contributors are shown in black, putative ones in gray. “Non 24h” – any scenario with individuals living on non-24 schedules; “ASPS/DSPS” – advanced sleep phase syndrome/delayed sleep phase syndrome.

Figure 2:. Circadian system influences cardiovascular risk factors: Possible contribution to morning peak in CV events

Displayed here are cardiovascular risk factors shown to be under endogenous circadian control. They are grouped according to temporal alignment with the window of increased cardiovascular vulnerability in the morning hours. “Risk factors” (red lines) are those whose elevation may be correlated with increased acute risk for adverse cardiovascular events, while elevation of “protective factors” (green lines) are considered to decrease acute risk for adverse cardiovascular events. “Risk factors” are considered contributing if the peak in their circadian rhythm occurs during the vulnerable window (biological morning), intermediate if they rise during the vulnerable window, and not contributing if they are at their minimum during the vulnerable window. “Protective factors” are considered not contributing if the peak in their circadian rhythm occurs during the vulnerable window (biological morning), intermediate if they fall during the vulnerable window during the vulnerable window. PAI-1 – plasminogen activating factor 1; Epinephrine (SNS) – epinephrine used here as a marker of sympathetic nervous system activation/sympathetic cardiac modulation; lnHF (PNS) – the natural log of high frequency power in the electrocardiogram, used here as a marker of parasympathetic nervous system activation/vagal cardiac modulation. This a qualitative summary of quantitative data collected during circadian unmasking (forced desynchrony) experiments in human participants [21, 33, 37-39]. These studies suggest rhythms of the hemostatic (blood clotting) system and of cortisol contribute to the morning peak in adverse cardiovascular events, that rhythms in blood pressure and lnHF (PNS) do not contribute and that circadian rhythms in melatonin, heart rate and epinephrine (SNS) may contribute to an intermediate extent.

Figure 3:. Effects of circadian misalignment on circadian and cardiovascular risk markers

Shown is a visual, qualitative summary of quantitative data collected during in-lab circadian misalignment (night-shift work simulation) experiments in human participants [22, 23] (see blue panel on the right for clarification of the inverted light-dark schedule, and note that all other panels are plotted by time since scheduled lights-off). In the green box (left) we show the effect of acute/recurrent circadian misalignment on two classic phase markers of the central circadian pacemaker: melatonin and cortisol. Along with suppression of the amplitude of cortisol/melatonin (in part due to the ~90lux light exposure), acute and even short-term repeated misalignment leads to these two phase markers being ~12hours temporally offset relative to the sleep/wake cycle due to the inertia of the circadian system. In the purple box (middle) we show the effect of acute/recurrent circadian misalignment on two markers of cardiovascular risk: high sensitivity C-reactive protein (hs-CRP) and blood pressure (BP). Daily rhythms in these two profiles are primarily driven by the behavioral (sleep/wake); thus, unlike melatonin and cortisol, their rhythms are not 12-hours offset during misalignment. However, during misalignment hs-CRP and BP are elevated (in both non-shift workers and chronic shift workers). These observations may help to elucidate the underlying mechanisms by which shiftwork (or other forms of recurrent circadian misalignment) increases cardiovascular risk.

Figure 4:. Linking chronodisription to cardiovascular disease

Chronodisruption (see left figure panel) can take the form of circadian misalignment or disturbance of circadian clock function per se, either of which can lead to increased cardiovascular risk. Chronodisruption leads to physiological changes which are associated with and often precede cardiovascular disease (see middle figure panel), including adverse effects on thrombogenic pathways [22, 23], hemodynamic function [22, 53, 58, 72, 73], arterial stiffness [74], inflammation[22, 23, 49, 55, 75], and autonomic nervous system function [24, 37, 57]. Furthermore, chronodisruption has also been directly linked to many forms of cardiovascular disease (see right figure panel), including coronary artery disease (CAD) [76], cardiomyopathy [16, 18, 52, 58], hypertension [77], stroke [15, 60], and chronic kidney disease [16, 78]. Chronodisruption may also contribute to such physiological changes and/or cardiovascular disease via other classes of risk factors (e.g. alterations to behavioral patterns; see bottom figure panel).

Figure 5:. Prospects for circadian interventions to mitigate cardiovascular risk

A: Interventions to decrease morning peak in major adverse cardiovascular events (CV events). Top panel: Pharmacological chronotherapy here refers to timing of cardiovascular medication (via timing administration and/or delayed/slow-release formulations) aimed at maximizing the dose during the vulnerable time while minimizing the dose at other times to decrease adverse side effects. Middle Panel: Although exercise lowers overall/long-term cardiovascular risk, it may carry increased acute risk of an adverse event for patients with cardiovascular disease, which could be mitigated by optimal timing of exercise within the biological day. Bottom panel: There may be a multiplicative effect of CV event risk factors produced by certain tissues in the body at a given circadian phase (e.g., circadian morning peak in PAI-1 and coinciding peak in platelet activation). If so, tissue-specific phase shifting of peripheral clocks in one (but not the other) tissue could serve to blunt the overall CV event risk during the vulnerable time window. B: Interventions to mitigate overall risk/adverse CV effects of chronodisruption. Top panel: Mounting evidence suggests that optimally timed exogenous melatonin may decrease blood pressure. Middle panel: During circadian misalignment, evidence is developing that confining meals to the biological day may decrease metabolic/glucoregulatory sequelae of circadian misalignment. Bottom panel: A long-term goal of treating circadian misalignment is the development of therapeutics, e.g., small molecules, accelerating re-entrainment of the central and/or peripheral clocks to shifted behavioral and environmental cycles, e.g., for shift workers, jet lag, and circadian rhythm sleep/wake disorders.