Circadian rhythm of cardiac electrophysiology, arrhythmogenesis, and the underlying mechanisms

Abstract

Cardiac arrhythmias are a leading cause of cardiovascular death. It has long been accepted that life-threatening cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, and sudden cardiac death) are more likely to occur in the morning after waking. It is perhaps less well recognized that there is a circadian rhythm in cardiac pacemaking and other electrophysiological properties of the heart. In addition, there is a circadian rhythm in other arrhythmias, for example, bradyarrhythmias and supraventricular arrhythmias. Two mechanisms may underlie this finding: (1) a central circadian clock in the suprachiasmatic nucleus in the hypothalamus may directly affect the electrophysiology of the heart and arrhythmogenesis via various neurohumoral factors, particularly the autonomic nervous system; or (2) a local circadian clock in the heart itself (albeit under the control of the central clock) may drive a circadian rhythm in the expression of ion channels in the heart, which in turn varies arrhythmic substrate. This review summarizes the current understanding of the circadian rhythm in cardiac electrophysiology, arrhythmogenesis, and the underlying molecular mechanisms.

Keywords: Arrhythmia; Autonomic nervous system; Cardiac conduction system; Cardiac pacemaking; Circadian rhythm; Ion channel remodeling.

Figure 1

Schematic diagrams of the relationship between the environment, the central clock in the SCN, and the local clock in the heart (A) and the molecular pathways of the circadian clock (B). SCN = suprachiasmatic nucleus.

Figure 2

Circadian rhythm of ECG variables in the healthy human. A: Circadian rhythm of heart rate in 31 healthy men. BPM = beats/min. From Degaute et al, with permission. B: Circadian rhythm of PR interval in 50 healthy volunteers. From Dilaveris et al, with permission. C: Circadian rhythm in QRS duration in 20 healthy subjects. From Nakagawa et al with permission. D: Circadian rhythm of QT interval. From Bonnemeier et al, with permission.

Figure 3

Contribution of local cardiac clock (via ion channel remodeling) and central SCN clock toward circadian rhythm in heart rate. A: Circadian rhythm in the expression of HCN4 mRNA (as determined by quantitative polymerase chain reaction) in the mouse sinus node at 4 time points over 24 hours (light and dark indicated by shading). Values given as mean ± SEM (n = 6–8). Data fitted with a sinusoidal curve. From D’Souza et al, with permission. B: Heart rate over 42 hours in control mice and mice in which the SCN has been lesioned (n = 3–6 mice). From Tong et al, with permission. SCN = suprachiasmatic nucleus; ZT = zeitgeber time.

Figure 4

Evidence that the autonomic nervous system is not responsible for the circadian rhythm in heart rate. A: Complete autonomic blockade does not abolish the circadian rhythm in heart rate. BRS, MAP, and HR shown over 24 hours in spontaneously hypertensive rats during saline infusion (control) and during infusion of metoprolol and methyl-atropine (n = 9 rats per group). From Oosting et al, with permission. B: Pharmacologic blockade of the autonomic ganglia does not abolish the circadian rhythm in heart rate. BRS, MAP, and HR shown over 24 hours in spontaneously hypertensive rats during saline infusion (control) and during ganglionic blockade with hexamethonium (n = 8 rats per group). From Oosting et al, with permission. C: Circadian rhythm in heart rate is unaffected by knocking out the cardiac autonomic receptors. Heart rate is shown over 20 hours in control mice, mice deficient in cardiac sympathetic tone (lacking all 3 β-receptors), and mice deficient in cardiac vagal tone (lacking the M2 receptor) (∼8 mice per group). From Swoap et al, with permission. D: Cardiac transplant recipients still have a circadian rhythm in heart rate. Data from 17 heart transplant patients (11–36 months after transplantation) and 17 healthy volunteers matched for age and gender. From Idema et al, with permission. BRS = baroreceptor sensitivity; HR = heart rate; MAP = mean arterial pressure.

Figure 5

Unexpected role of the autonomic nervous system in mediating transcriptional effects in the heart. A: Complete autonomic blockade in the mouse by intraperitoneal injection of atropine and propranolol every 6 hours for 2 weeks abolishes the circadian rhythm in heart rate. Heart rate shown over 42 hours in control mice and mice with complete autonomic blockade (n = 3–6 mice). From Tong et al, with permission. B: Complete autonomic blockade in the mouse by intraperitoneal injection of atropine and propranolol every 6 hours for 2 weeks also abolishes the circadian rhythm in ventricular K⁺ channels. Expression of a range of K⁺ channel subunits shown over 42 hours in control mice and mice with complete autonomic blockade (n = 3–6 mice). From Tong et al, with permission.

Figure 6

Circadian rhythm in bradyarrhythmias and atrial tachycardia/flutter and atrial fibrillation (AT/AF). A: Circadian variation in asystolic pauses throughout 24 hours in 19 veteran athletes (human). Solid line shows the distribution in a veteran athlete with 846 pauses in 24 hours, which only occurred between the hours of 01:00 and 08:00. From Northcote et al, with permission. B: Circadian variation of bradyarrhythmia episodes and duration of heart block episodes in the healthy rat (bradyarrhythmia episodes analyzed for 94 days in 14 rats). From Otsuka et al, with permission. C: Circadian rhythm of AT/AF onset stratified by frequency of AT/AF events. Data from 72 (1–3 AT/AF events per hour), 72 (4–9 AT/AF events per hour), 69 (10–50 AT/AF events per hour), and 7 (51–119 AT/AF events per h) patients. From Shusterman et al, with permission.

Figure 7

Circadian rhythm in VPCs, VT/VF, and sudden cardiac death. A: Circadian rhythm in the number of hourly VPCs in 38 patients during 2 days of Holter monitoring. From Lanza et al, with permission. B: Circadian rhythm of VT/VF time of onset. From Tofler et al, with permission. C: Circadian rhythm in time of death of definite or possible sudden cardiac death (n = 429). From Willich et al, with permission. D: Circadian rhythm in ventricular arrhythmia events in 80 catecholaminergic polymorphic ventricular tachycardia patients recorded using Holter monitoring, ICD, or ILR. From Miyake et al, with permission. CAD = coronary artery disease; ICD = implantable cardioverter–defibrillator; ILR = implantable loop recorder; VF = ventricular fibrillation; VPC = ventricular premature complex; VT = ventricular tachycardia.

Figure 8

A: Schematic summary of circadian rhythm of ECG and arrhythmias in humans. The sleep period is illustrated as 23:00–05:59 and awake period as 06:00–22:59. B: Summary of mechanisms underlying circadian rhythm in heart rate and arrhythmias. Dotted arrow indicates possible actions of autonomic nervous system in synchronizing the local cardiac clock and mediating ion channel remodeling. AV = atrioventricular; SA = sinoatrial; SCN = suprachiasmatic nucleus.