Circadian Influences on Sudden Cardiac Death and Cardiac Electrophysiology

Authors, Journal, Affiliations, Type, DOI

• Authors: Brian P. Delisle, Abhilash Prabhat, Don E. Burgess, Isabel G. Stumpf, John J. McCarthy, Spencer B. Procopio, Xiping Zhang, Karyn A. Esser, Elizabeth A. Schroder
• Journal: Journal of Molecular and Cellular Cardiology, Volume 200 (2025), pp. 93–112
• Affiliations: Department of Physiology, University of Kentucky, Lexington, KY; University of Florida, Gainesville, FL; Department of Internal Medicine, University of Kentucky, Lexington, KY
• Type: Narrative review
• DOI: https://doi.org/10.1016/j.yjmcc.2025.01.006

Overview

This narrative review synthesizes the evidence that both extrinsic (SCN/autonomic) and intrinsic (cardiomyocyte BMAL1/CLOCK) circadian signaling generate day-night rhythms in cardiac ion channel expression and electrophysiology, providing a mechanistic substrate for time-of-day variation in sudden cardiac arrest (SCA) risk. The historically observed morning SCA peak is no longer evident in modern populations, likely reflecting widespread beta-blocker use and lifestyle changes, but overall daytime SCA incidence persists. The authors use a trigger-versus-substrate framework — daytime arrhythmogenic triggers interacting with time-of-day-variable myocardial substrate protection — to explain circadian arrhythmia risk. A comprehensive cross-database gene expression table (CircaDB, CircaAge, CircaMET, GEO GSE262714) catalogues circadian expression patterns for ~60 cardiac ion channel genes and regulators, with Kcnh2 (IKr), Gja1 (Cx43), Scn5a (Nav1.5), and Hcn4 identified as the most robust rhythmically expressed genes (REGs). A key translational insight concerns mRNA-to-protein fidelity: proteins with short half-lives (≤6 h) show meaningful circadian protein oscillations, while Kv11.1 (t½ ~12 h) generates only a blunted protein rhythm under normal conditions — but LQT2 mutations shortening t½ to <6 h paradoxically amplify time-of-day APD swings while also reducing steady-state channel levels.

Keywords

Circadian clock, Ion channels, Arrhythmias, Triggers, Myocardial substrate, Sudden cardiac death

Key Takeaways

1. Introduction — Epidemiology of Circadian SCA

• Historically, SCA showed a morning peak in both ischemic and non-ischemic heart disease; recent studies (Oregon SUDS, SCD-HeFT) fail to confirm this morning peak in contemporary populations.
• Proposed explanations for the loss of morning peak: widespread beta-blocker use blunting morning sympathetic surge; modern lifestyle changes (irregular sleep-wake cycles, shift work, altered feeding patterns); improved cardiovascular risk factor management.
• Overall higher SCA incidence during daytime hours persists regardless of age, gender, or coronary artery disease status; daytime coincides with peaks in sympathetic signaling, catecholamines, heart rate, afterload, and platelet aggregation.
• A working model: increased frequency of arrhythmogenic triggers during the day leads to higher sustained arrhythmia incidence in individuals with compromised myocardial substrate.

2. Day-Night Rhythms in Cardiac Electrophysiology (Extrinsic Regulation)

• Day-night rhythms in cardiac electrophysiology are measured under non-constant conditions (not true "circadian" per chronobiological definition); the term "circadian" is reserved for rhythms persisting in constant conditions (D:D).
• RR and QT intervals follow day-night rhythms peaking in the early morning and nadiring in the midafternoon.
• SCN lesion studies: disrupts day-night rhythms in RR and QT intervals in mice — SCN is central to autonomically driven rhythms.
• Heart transplant recipients with denervated hearts have very low amplitude heart rate day-night rhythms (5–10 bpm) vs. reinnervated transplant patients (20–25 bpm); residual amplitude reflects body temperature, catecholamines, and extracellular K⁺ cycling, as well as possible intrinsic cardiac clock disruption from absent sympathetic entrainment.
• QTc interval day-night rhythm is heavily confounded by correction formula and body temperature fluctuations; a morning QTc spike was historically reported but its persistence in contemporary populations is uncertain.
• Pharmacological inhibition of cardiac autonomic receptors disrupts day-night rhythms in HR and QT intervals in mice, confirming autonomic predominance.

3. Intrinsic Cardiac Circadian Clock

• Isolated heart preparations (at constant temperature, after 1 hour ex vivo perfusion to remove autonomic residue) show significant time-of-day differences in APD, effective refractory period, Ca²⁺ transient duration, and adrenergic responsiveness.
• At the start of the dark cycle: shorter APD and refractory period, less adrenergic responsiveness, greater resistance to arrhythmias — suggesting a time-of-day peak in myocardial substrate protection.
• Aged mice (18–20 months) lose this time-of-day difference in cardiac electrophysiological properties — aging may reduce circadian amplitude and substrate protection.
• Core circadian clock: BMAL1/CLOCK (positive limb) transactivate Per/Cry genes; REV-ERBα (direct BMAL1/CLOCK target) and ROR compete at RORE elements to regulate Bmal1 (auxiliary loop); generates robust ~24-h rhythms.
• Cardiomyocyte-specific Bmal1 knockout prolongs RR and QT intervals, decreases circadian and steady-state levels of cardiac ion channel mRNA, reduces depolarizing/repolarizing current amplitudes, and alters pacemaking activity.
• Forced desynchrony protocol in humans (20-h day): 24-h rhythms in heart rate persist, confirming intrinsic circadian control of cardiac function in humans.

4. Bioinformatic Databases and Table 1 — Circadian Expression of Cardiac Ion Channel Genes

• Four databases were queried: (1) CircaDB — D:D and L:D male mouse heart; (2) CircaAge — D:D male mouse heart, Young/Aged/Old comparison; (3) CircaMET — L:D female mouse heart, DRF vs. NRF; (4) GEO GSE262714 — D:D male and female Bmal1 KO vs. control.
• Key distinction: D:D (constant darkness) allows true circadian "free-running" assessment; L:D data includes masking effects (direct behavioral/physiological responses to light, not intrinsic circadian).
• Genes rhythmic under L:D but not D:D (Kcna5, Kcnab1, Kcnb1, Kcnk2, Kctd17) likely driven by masking, not intrinsic clock.
• Most robust REGs (consistent across databases, strong p-values):
  • Kcnh2 (IKr/Kv11.1): strong rhythmicity in D:D (p=2.36e-7), L:D, all DRF/NRF, and both sexes in GEO; declines in Old (27-month) mice
  • Gja1 (Cx43): rhythmic in D:D (p=3.24e-5), L:D, NRF, and both sexes in GEO; BMAL1-dependent (eliminated in Bmal1 KO)
  • Scn5a (Nav1.5): rhythmic in D:D (p=5.01e-3) only; rhythmicity in female Bmal1 WT (p=1.56e-4) but not male WT
  • Hcn4 (If): rhythmic in D:D (p=9.22e-3); not in GEO dataset (ventricular tissue, Hcn4 primarily in SA node)
  • Clock genes: Arntl1 (Bmal1), Clock, Per2, Cry2, Nr1d1 — all robustly rhythmic across all databases and conditions
• ARVC-linked structural genes are robust REGs:
  • Pkp2 (plakophilin-2): rhythmic in D:D (p=3.02e-3), L:D, DRF, NRF, and both sexes in GEO; BMAL1-dependent
  • Dsg2 (desmoglein-2): rhythmic in young CircaAge, old CircaAge, NRF, and female Bmal1 WT
  • Dsc2 (desmocollin-2): rhythmic in D:D (p=4.35e-4), young CircaAge, old CircaAge, NRF, female Bmal1 WT
• Age-dependent changes: Kcnh2 weakens with advanced age (Young p=1.5e-3, Aged p=1.0e-4, Old p=0.056); Kcnj15 gains rhythmicity only in Old mice — diverse trajectories with age
• Sex differences: Kcnh2 rhythmicity in both sexes but different amplitude (female stronger p=1.4e-8 vs. male p=1.81e-3); Kcna4 rhythmic in females only; Kcnj3 rhythmic in males only; some sex differences are BMAL1-independent

5. Direct and Indirect Clock Regulation of Ion Channel Expression

• Direct regulation (BMAL1/CLOCK transactivation demonstrated):
  • Kcnh2 (Kv11.1/IKr): circadian mRNA in ventricular tissue; Bmal1 KO → smaller IKr current; promoter luciferase assay confirms BMAL1/CLOCK transactivation
  • Scn5a (Nav1.5/INa): circadian mRNA in ventricle; Bmal1 KO → smaller INa; promoter luciferase assay confirms transactivation
  • Hcn4 (If): circadian mRNA in SA node; Bmal1 KO → smaller If current
• Indirect regulation via transcriptional intermediaries:
  • KLF15 (Krüppel-like factor 15): directly clock-controlled by BMAL1/CLOCK; KLF15 protein regulates Kcnip2 (KChIP2) → modulates Kv4.2 → influences cardiac repolarization (Jeyaraj et al.)
  • E4BP4: additional clock-controlled transcription factor regulating Kcnip2 — demonstrates multi-layer clock-to-channel regulation
  • Tbx5 and Gata4: exhibit circadian expression patterns; critical cardiac ion channel transcription factors — rhythmic regulation may have broad effects on myocardial substrate
• miRNA regulation: Cardiomyocyte-specific Bmal1 KO → upregulation of ~70% of differentially expressed miRNAs; double REV-ERBα/β KO increases cardiomyocyte miRNA levels; miRNAs regulate Gja1 (Cx43) and Kcnj2 (Kir2.1) — post-transcriptional layer of circadian control
• Steroid hormone regulation: Estrogen and testosterone regulate K⁺ channels important for repolarization; glucocorticoids via GR modulate ion channel expression; steroid receptors themselves may be subject to circadian regulation; non-genomic effects (seconds to minutes) on L-type Ca²⁺ channels (estrogen, glucocorticoids) and Na⁺/K⁺ currents (aldosterone)
• Other indirect pathways: Day-night rhythms in core body temperature impact HR and ventricular repolarization; circadian changes in intracellular soluble protein abundance can alter ionic gradients across the sarcolemma

6. mRNA-to-Protein Translation: The Half-Life Problem

• mRNA rhythmicity does not reliably translate to protein rhythmicity; in other tissues (e.g., liver), many REGs do not show direct mRNA-protein correlation; amplitude of cycling proteins is generally much smaller than mRNA counterparts.
• Protein half-life is the critical determinant of whether rhythmic mRNA generates rhythmic protein: proteins with longer half-lives accumulate over time and buffer mRNA oscillations, attenuating protein amplitude.
• Kv11.1 (KCNH2): wild-type t½ ≈ 12 h → small amplitude protein rhythm under normal conditions; both reduced amplitude mRNA oscillations and loss of steady-state protein would reduce myocardial substrate protection.
• LQT2 mutations (KCNH2 nonsense/missense): shorten Kv11.1 t½ to <6 h → two consequences: (1) lower median/steady-state Kv11.1 protein levels (less IKr overall) → longer APD; (2) larger protein oscillation amplitude → larger time-of-day variation in APD and arrhythmia risk. This may explain why some LQT2 patients have arrhythmias at predictable times of day.
• Speculative implication: mutations shortening the half-life of proteins encoded by other circadian-regulated genes may unmask daily rhythms in cellular function and physiology in other channelopathies.
• The rhythmic proteome is primarily regulated at translational and posttranslational levels (not just transcriptional), meaning only a subset of REGs will produce rhythmically expressed proteins.

Limitations of the Document

• Narrative (not systematic) review; evidence synthesis is selective and expert-curated rather than pre-registered/exhaustive.
• Animal data (mostly mouse) dominate the mechanistic evidence; circadian gene expression data are largely from rodents; translation to human circadian cardiology remains limited.
• mRNA-to-protein model (Fig. 2) uses a simplified translation model and estimated protein half-lives; direct measurement of circadian protein oscillations for most cardiac ion channels in humans does not exist.
• Epidemiological data on SCA circadian patterns are from specific populations (Oregon SUDS, SCD-HeFT) and may not generalize globally.
• The loss of the morning SCA peak is proposed but not fully explained mechanistically — causal attribution to beta-blockers, lifestyle, or other factors is speculative.
• Table 1 databases are cross-sectional snapshots; gene expression patterns vary by sex, age, feeding schedule — conditions may not reflect human clinical contexts.
• No interventional or clinical translation data presented; chronotherapy implications remain theoretical.

Key Concepts Mentioned

• concepts/Circadian-Rhythm-Cardiac-Electrophysiology — central topic: how extrinsic/intrinsic circadian signals regulate myocardial substrate properties
• concepts/Sudden-Cardiac-Death — circadian distribution of SCA/SCD events; trigger-substrate model
• concepts/Cardiac-Action-Potential — APD, ERP, IKr, INa, If circadian modulation
• concepts/Cardiac-Action-Potential — Kv11.1 half-life → APD oscillation in LQT2
• concepts/Electrical-Remodeling — circadian transcriptional remodeling of ion channel expression

Key Entities Mentioned

• entities/Long-QT-Syndrome — LQT2/KCNH2 mutations, protein half-life, time-of-day APD variation
• entities/ARVC — Pkp2, Dsg2, Dsc2 are robust cardiac REGs; circadian structural gene expression implications
• entities/Atrial-Fibrillation — Gja1/Cx43 is a circadian REG (relevant to conduction/AF substrate)

Wiki Pages Updated

• wiki/sources/circadian-scd-jmcc-2025.md — created (this file)
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — updated
• wiki/concepts/Circadian-Rhythm-Cardiac-Electrophysiology.md — created
• wiki/concepts/Sudden-Cardiac-Death.md — updated
• wiki/entities/Long-QT-Syndrome.md — updated
• wiki/entities/ARVC.md — updated