Circadian rhythms in cardiovascular disease

Abstract

Circadian rhythms, controlled by the suprachiasmatic nucleus and peripheral clocks, regulate 24-h cycles in biological processes such as the cardiovascular system. Circadian rhythms influence autonomic balance, with parasympathetic dominance during sleep supporting cardiac recovery and sympathetic activation during the day supporting circulatory demand. Congruent with systemic and cellular circadian rhythmicity, 24-h patterns arise in the pathophysiology of cardiovascular diseases, including ischaemic heart disease, heart failure, and arrhythmias. Daily variations influence the timing and outcome of myocardial infarction, with studies reporting patterns in infarct size depending on the time of onset. Similar daily patterns are observed in cardio- and cerebrovascular complications. In heart failure, circadian rhythms are dampened but remain intact, suggesting the potential for incorporating timing in diagnostics and therapies. Sudden cardiac death follows a distinct pattern, with a higher incidence in the morning. Atrial fibrillation onset, on the other hand, occurs more frequently at night. Risk factors and modifiers, such as physiological, psychological, lifestyle, and environmental factors and comorbidities interact with circadian rhythms, thereby impacting cellular pathomechanisms and development of cardiovascular health and disease. Chronotherapy, which aligns treatments with circadian rhythms, has demonstrated potential for improving the efficacy of cardiovascular therapies. This review examines the influence of circadian rhythms on cardiovascular health in the context of specific cardiac diseases and risk factors, and it highlights the therapeutic opportunities informed by circadian patterns.

Keywords: Cardiovascular Disease; Chronomodulation; Chronotherapy; Circadian Rhythms; Epidemiology; Heart Failure; Incidence; Myocardial Infarction; ischaemic Heart Disease.

Graphical Abstract

Circadian rhythms have an impact on cardiac disease, several evironmental and behavioural factors can induce circadian misalignment. Several opportunities can be considered to integrate circadian-based strategies, and to target and detect circadian rhythm variation.

Figure 1

Circadian regulation of molecular clock gene signalling and physiological regulation. Circadian regulation of molecular clock gene signalling and physiological processes. This overview illustrates the circadian control of molecular clock genes, clock-controlled genes, and physiological functions, including the autonomic nervous system's influence on heart rate variability, heart rate, and blood pressure. ANS, autonomic nervous system; SCN, suprachiasmatic nucleus

Figure 2

Incidence peaks of cardiovascular diseases during a 24-h period. A circular visualization summarizing the incidence peaks of various cardiovascular diseases. Timepoints corresponding to incidence peaks for several cardiovascular diseases are illustrated, with supporting literature provided in Supplementary data online, Tables S2–S4. Dashed lines represent second-highest peak of incidence. BP, blood pressure; HF, heart failure; hr, hour; OSAS, obstructive sleep apnoea

Figure 3

Overview of the circadian-cardiac interactome. An overview figure inspired by a directed acyclic graph, illustrating the key factors of the circadian-cardiac interactome. This visualization integrates the risk factors and risk modifiers influencing circadian rhythms and cardiac function. The red arrows indicate the direct influence of lifestyle, physiological, psychological and environmental factors on cardiovascular disease triggering key pathomechanisms by changes of key components of the interactome. Key pathomechanisms for cardiovascular diseases are higher levels in stress hormones, dysregulated expression of ROS producing and degrading enzymes leading to oxidative stress, activation of immune cells and increase in pro-inflammatory cytokines, exacerbated inflammation and progression of atherosclerosis, disturbed metabolism of glucose and fatty acids, impaired mitochondrial function (e.g. respiration, autophagy), dysregulated epigenetic pathways, enhanced thrombotic pathways and altered coagulation, phase shifts in blood pressure maximum and generally higher blood pressure levels, impaired vascular function, exacerbated arterial stiffness and promotion of fibrosis. The blue arrows indicate the influence of the risk factors and risk modifiers on circadian misalignment indirectly impacting cardiovascular risk. The black arrows indicate the influences between circadian misalignment, pathophysiology by interactome changes and cardiovascular disease. The latter can be beneficially influenced by chronotherapy approaches. CVD, cardiovascular disease; DAG, directed acyclic graph; SCN—suprachiasmatic nucleus;