Cardiac Clocks -circadian medicine: role of HA-TA (sun & moon) in HearT.

Circadian rhythms are fundamentally important for cardiovascular health, including heart rate, blood pressure, and molecular gene and protein responses. Rhythms also play a direct role in the pathophysiology of heart disease, such as in the timing of onset and severity of myocardial infarction, sudden cardiac death, ventricular arrhythmias, and stroke. Importantly, a flurry of new studies reveals translational applications for circadian biology to clinical medicine, and especially cardiology. Circadian medicine is a promising new approach that targets the heart’s daily physiologic and molecular rhythms to benefit the treatment of patients with cardiovascular disease.

Staying in synchrony with the earth’s 24-hour day and night (diurnal) cycle provides benefits to the daily functioning of our cardiovascular system. Conversely, desynchrony with the external environment, for example, through jet lag, shift work, or sleep disorders, has profound adverse effects on our cardiovascular system. Importantly, this has led a flurry of recent investigations with a translational focus, specifically on how circadian biology can be applied to benefit treatment of heart disease. For example, time-of-day therapy (chronotherapy) with angiotensin-converting enzyme inhibitors (ACEi) benefits treatment in experimental murine models of heart disease. Moreover, clinical cardiology benefits from chronotherapy and recent successes include evening administration of antihypertensives for non-dippers, aspirin at night to reduce morning risk of myocardial infarction (MI), nocturnal hemodialysis, and nocturnal continuous positive airway pressure (CPAP) for patients with obstructive sleep apnea (OSA). Evidence is also emerging that short-term circadian and sleep disruption, as occurs in intensive care units (ICUs), may hamper recovery after MI. Maintaining the diurnal environment and patients biological rhythms is a promising nonpharmaceutic approach to reduce scar expansion and improve outcomes after MI. Finally, recent studies give rise to 3 new frontiers for translational research: (1) applications to benefit cardiovascular disease in the aging population; (2) new understanding of circadian mitophagy in regulating cardiac bioenergetics; and (3) links between the circadian clock mechanism and cognitive impairment or depression in heart disease. Recognizing the fundamental role that the circadian mechanism plays in cardiovascular health and disease is leading to new translational applications for clinical cardiology.

The output of the circadian mechanism is observed as diurnal physiologic rhythms, many crucial to the cardiovascular system. For example, there is daily cyclic variation in heart rate (HR), which is highest in the day and lowest during the night.  Blood pressure (BP) also displays a daily rhythm that is highest in the morning, falls progressively throughout the day and early evening, and then reaches a nadir around 3:00 am .  Diurnal rhythms in BP are considered especially important for cardiovascular health, because clinically, humans with 24-hour BP profiles that do not follow the normal diurnal pattern are at a higher risk of heart disease. That is, most people have a nocturnal dip in BP of approximately 10% as compared with the daytime.  However, hypertensive non-dippers (patients who do not experience the anticipated drop in BP at night),  or patients without hypertension but still a diminished nocturnal decline in BP,  exhibit an increased risk of heart disease. These diurnal rhythms in HR and BP parallel the sympathetic and parasympathetic biases of our autonomic nervous system, and they are endogenously generated.

Chronotherapy and Clinical Applications for Treatment of Heart Disease

There is also a growing clinical appreciation that timing of therapy can be applied to several different cardiovascular therapies. Recent successes include the following: (1) Nocturnal BP: BP has a circadian rhythm that is high in the day and dips down by approximately 10% at night. This dipper profile is important for cardiovascular health, and hypertensive non-dippers have significantly increased heart size as compared with hypertensive dippers or normotensive dippers. Manfredini and Fabbian  have compiled a vast array of clinical reports and reviews supporting the notion that evening administration of antihypertensive drugs helps to maintain the dipper profile and can reduce cardiovascular risk. (2) Aspirin at night: Aspirin taken at night time, as compared with on awakening, may reduce the morning peak in platelet reactivity and thus may reduce cardiovascular risk. (3) Nocturnal hemodialysis: Cardiovascular disease is a significant cause of death in patients with end-stage renal disease. Intriguingly, nocturnal hemodialysis, as compared with conventional daytime therapy, is accompanied by regression of left ventricular cardiac hypertrophy.  (4) OSA: OSA is a common sleep disorder with cardiovascular consequences, and it is treated during nighttime by CPAP therapy. Nocturnal CPAP therapy attenuates some of the adverse effects of OSA on the cardiovascular system

Rhythms in the Intensive Care Unit

Modern hospitals, and especially intensive and coronary care units, still use multi-bed rooms. Contemporary medicine seems to ignore the importance of undisturbed diurnal rhythms, even in the critically ill. Although the ICU benefits patient management, inadvertent noise, lighting, and frequent patient-staff interactions conspire to disturb sleep and circadian rhythms in acutely ill patients.The short-term disruption of diurnal rhythms, for just the few days after MI, worsened long-term outcomes (increased scar expansion and left ventricular dilation and decreased % ejection fraction) as compared with mice housed in a normal diurnal environment after MI. The short-term diurnal disruption had a profound adverse effect on outcome because the circadian rhythms of the immune system were disturbed. Normally there is coordinated removal of dead tissue through an early inflammatory phase, followed by remodeling of the myocardium, and scar maturation. However, when rhythms were disturbed, this early inflammatory response was altered. As a result, this led to a domino-like triggered a domino-like effect, whereby aberrant early remodeling set an inappropriate stage for the subsequent healing phases and ultimately worsened outcome. Maintaining the diurnal environment and patients’ biological rhythms is a promising nonpharmaceutic approach to improve outcomes.

The molecular circadian clock mechanism cycles-Circadian Rhythms and Cardiovascular Aging

 HF is a common cause for hospitalization in patients older than 65 years of age and is a considerable economic burden, and more than 50% of patients die within 5 years of diagnosis. Disturbing Clock in circadian mutant mice ( Clock Δ19/Δ19 ) leads to an age-dependent increase in heart size, cardiomyocyte hypertrophy, interstitial fibrosis, and maladaptive cardiac remodeling leading to HF (increased left ventricular dimensions, reduced % ejection fraction, and % fractional shortening). Cardiomyocyte-specific mutation of Clock can cause hypertrophy and fibrosis, and moreover, disruption in the vasculature in Clock Δ19/Δ19 mice contributes to reduced myogenic responsiveness and leads to decreased cardiac contractility.  Mechanistically, Clock is a key mediator in the PTEN-AKT signal pathways, and thus, it plays a crucial role in cardiac growth and renewal. Intriguingly, pharmacologic targeting of the circadian mechanism may provide a new opportunity for treating heart disease. The therapeutic implications may be particularly relevant for individuals subjected to circadian rhythms disruption, such as shift workers and individuals with sleep disorders in the aging population.The molecular circadian clock mechanism cycles

Circadian Rhythms and Mitophagy

The circadian mechanism component Rev-erb-a is key regulator of mitochondrial content and oxidative function in skeletal muscle, exerting control in part by repressing genes that trigger mitophagy. It is currently known that the PINK1-Parkin pathway plays an essential role in eliminating damaged mitochondria by mitophagy. Under basal conditions the E3-ligase Parkin is retained in the cytoplasm but rapidly translocates to damaged mitochondria in a manner dependent upon PINK1. Activation of parkin results in the ubiquitination of several proteins on the outer mitochondrial membrane, which targets ubiquitinated mitochondria for autophagic removal. Notably, defects in autophagy have been associated with contractile dysfunction and HF. For example, autophagy increases in cardiac myocytes following ischemia-reperfusion injury. In fact, activation of autophagy upon early phases of reperfusion is critical for removing damaged organelles, including mitochondria and averting proteotoxic stress. This mechanism is largely substantiated by studies in which delayed autophagy exacerbated reperfusion injury, resulting in cardiac-increased cell death and cardiac dysfunction.  Because mitochondria are highly dynamic organelles and continually undergoing fission and fusion, future investigations examining the role of the circadian mechanism on mitophagy in the heart are warranted.

Circadian Rhythms and Depression in Patients with Heart Disease

Depression is common in patients with coronary heart disease, and the comorbidity complicates treatment and worsens prognosis. Moreover, cognitive impairment, depression, or brain changes have all been frequently reported as coincidental in patients with HF. Although there is a complex interplay between pathophysiologic factors that can contribute to these mental health conditions in patients with heart disease, a role for the circadian mechanism may also be warranted. In support of this notion, several studies suggest that disruption of the circadian clock system plays a role in mood disorders, including depression and bipolar disorder.  Moreover, it has been shown experimentally that disruption of circadian rhythms in mice lowers dendritic length and decreases the complexity of neurons in the prelimbic frontal cortex, a brain region important for emotional control.

Summary

Recent epidemiologic, experimental, and clinical studies demonstrate the profound importance of circadian rhythms for healthy cardiovascular physiology. Disturbing rhythms is etiologically associated with heart disease and worse outcomes. Recent successes include optimizing the timing of cardiovascular medications to improve drug efficacy and maintaining circadian rhythms and sleep to benefit outcomes after MI. Upcoming areas for preclinical translation include targeting the circadian mechanism to reduce cardiac aging, targeting circadian-driven bioenergetics to improve heart function, and examining the complex interplay between neurophysiology and heart disease to improve outcomes for patients with heart disease.

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