Cardiac Repolarization in Health and Disease

Authors, Journal, Affiliations, Type, DOI

• Christian Krijger Juárez, BSc; Ahmad S. Amin, MD, PhD; Joost A. Offerhaus, MD; Connie R. Bezzina, PhD; Bastiaan J. Boukens, PhD
• JACC: Clinical Electrophysiology, Vol. 9, No. 1, January 2023, pp. 124–138
• Department of Experimental Cardiology and Cardiology, Amsterdam University Medical Center; Department of Medical Biology, Amsterdam UMC; Department of Physiology, Maastricht University
• State-of-the-art review article
• DOI: https://doi.org/10.1016/j.jacep.2022.09.017

Overview

This state-of-the-art review comprehensively covers the genetic and electrophysiological basis of cardiac repolarization in health and disease. It details the ClinGen-curated gene landscape for congenital LQTS and SQTS, explains how regional differences in ion channel expression govern T-wave morphology and genotype-phenotype correlations, and characterises the mechanisms by which repolarization abnormalities generate arrhythmia triggers (EADs, R-from-T) and substrates (heterogeneous refractoriness, functional re-entry). The review then addresses the emerging field of GWAS-derived common genetic variants and polygenic risk scores (PRS) modulating QTc and LQTS susceptibility/severity, acquired repolarization disorders (drug-induced LQTS and SQTS), and the growing role of AI-based ECG analysis for detecting concealed repolarization disorders.

Keywords

Cardiac repolarization, long-QT syndrome, short-QT syndrome, genome-wide association studies, polygenic risk score, repolarization, Torsade de Pointes, early afterdepolarizations, T-wave morphology, ion channels, action potential duration

Key Takeaways

Congenital LQTS — Genetics and Gene Curation

• LQTS prevalence: 1 in 2,000–2,500; one of the main causes of SCD in patients younger than 35.
• 17 genes have been reported to cause LQTS; ClinGen 2020 reappraisal (Adler et al.) classified only 3 genes as definitive for autosomal-dominant isolated LQTS: KCNQ1 (LQT1, ~35%), KCNH2 (LQT2, ~30%), SCN5A (LQT3, ~10%).
• Four additional genes have strong/definitive evidence for atypical LQTS with multiorgan features: CALM1, CALM2, CALM3 (calmodulinopathy — neonatal bradycardia, AV block, severe QTc prolongation), and TRDN (triadin — QTc prolongation + negative T-waves + exercise-induced arrhythmias, autosomal recessive).
• CACNA1C has moderate evidence for isolated LQTS; AKAP9, ANK2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1 have limited or disputed evidence.
• ~10–20% of LQTS patients remain genotype-negative after comprehensive genetic testing.
• Syndromal LQTS: Jervell-Lange-Nielsen syndrome (KCNQ1 or KCNE1 homozygous/compound heterozygous — deafness + LQTS); Timothy syndrome (CACNA1C G406R GOF — syndactyly, autism, cardiac malformations); Andersen-Tawil syndrome (KCNJ2 — dysmorphic features + periodic paralysis).

Genotype-Phenotype Correlations and T-Wave Morphology

• T-wave shape reflects potential gradients from local differences in action potential duration (APD) across the heart — and is different across the three major LQTS subtypes because of the regional expression patterns of KCNQ1, KCNH2, and SCN5A.
• LQT1 (KCNQ1): IKs higher in subepicardium and right ventricle. At resting heart rates, IKs is roughly absent → QT prolongation minor at rest vs. LQT2/LQT3. At higher rates, IKs becomes major repolarizing force and KCNQ1 mutations unmask QT prolongation dramatically. Exercise/swimming are the primary triggers.
• LQT2 (KCNH2): IKr relatively large at low heart rates → long QT at baseline. IKs compensates and is more prominent in RV; IKr reduction causes more APD prolongation in LV than RV → bifid T-wave morphology. Sudden noise is the trigger; females have disproportionate risk.
• LQT3 (SCN5A): Increased INaLate prolongs phase 2 (plateau) → prolonged ST-segment with delayed T-wave onset. Arrhythmias at rest/during sleep. Mexiletine (late Na⁺ blocker) effectively shortens QTc.
• Location/domain of mutation modulates severity: LQT1 transmembrane pore variants > carboxy-terminus variants for cardiac event risk; LQT2 pore-region KCNH2 missense mutations > non-pore mutations.
• Age/sex interactions: LQT1 males have higher risk in childhood; LQT2 and LQT3 become symptomatic around puberty with female predominance — reflecting hormonal influence on QTc.

Arrhythmogenesis — Trigger and Substrate

• Trigger mechanism (LQTS): Prolonged APD → reactivation of ICaL and spontaneous Ca²⁺ release from SR → depolarising INCX current → early afterdepolarizations (EADs). ~700,000 cardiomyocytes must synchronise to propagate an EAD to tissue-level triggered action potential.
• R-from-T phenomenon: Alternative trigger model — spontaneous wavefront arises at the border between long and short repolarization regions (not from EADs per se).
• Trigger mechanism (SQTS): Shortened APD → APD-to-calcium transient mismatch → elevated intracellular Ca²⁺ during late-AP → reverse NCX → inward INCX → afterdepolarization → triggered action potential. Tracked by the electromechanical window (electrical QT systole subtracted from mechanical systole); a negative electromechanical window predicts arrhythmia risk.
• Substrate: Heterogeneity in refractoriness → unidirectional block → functional re-entry. Short QTc facilitates easier re-entry → VF in SQTS. During ischemia, post-repolarization refractoriness dissociates APD from refractory period — T-wave is NOT a reliable measure of refractoriness during ischemia.
• TdP initiation and perpetuation: TdP starts with focal beats in the area with long repolarization, then transitions to re-entry. Premature focal beats in the long-repolarization zone shorten APD there more than in surrounding myocardium → reversal of the repolarization gradient → unidirectional block → functional re-entry substrate.

SQTS — Genetics and ECG

• Very rare autosomal dominant condition; diagnosed with QTc ≤340 ms, or QTc ≤360 ms + additional criteria (family history of SQTS or family history of SCD <40 years).
• ClinGen-curated genes: KCNH2 (SQT1, gain-of-function) — definitive; KCNQ1 (SQT2), KCNJ2 (SQT3), SLC4A3 — strong to moderate evidence. CACNA1C and CACNB2 (loss-of-function) — disputed for isolated SQTS; associated with combined Brugada + short QTc phenotype.
• ECG features in SQTS: Short/absent ST segments; prolonged Tpeak-to-T-end; asymmetrical tall T-waves with high amplitude. Symptomatic patients tend to have shorter J-point-to-Tpeak interval and higher Tpeak-to-T-end/QTc ratio compared to asymptomatic patients.
• Severity of QTc shortening does NOT predict arrhythmia risk in SQTS (unlike LQTS where QTc correlates with risk).

Common Genetic Variants and Polygenic Risk Scores

• QT interval heritability in the general population: 25–50%.
• 2014 GWAS (European ancestry): 68 independent QT-SNPs at 35 loci. 2022 multiancestry GWAS meta-analysis (n=252,977): 176 independent QT-SNPs (114 novel); 62 of 68 prior SNPs replicated.
• X-chromosome locus in males associated with QT/JT interval — nearest gene expressed only in testis, suggesting testosterone as driver.
• Many QT-SNPs are at or near known LQTS/SQTS genes (KCNQ1, KCNH2, KCNJ2, KCNE1, SCN5A); many are at novel loci with unexplored biology.
• Tpeak-to-T-end GWAS (n=30,000): multiple SNPs identified at rest and with exercise; some loci do not overlap with QTc-SNPs.
• PRS in LQTS susceptibility (Lahrouchi et al. 2020): Case-control GWAS (1,656 LQTS vs 9,890 controls); 3 genome-wide significant loci; common SNPs account for ~15% of variance in LQTS susceptibility. PRS was higher in genotype-negative LQTS vs. genotype-positive → suggests genotype-negative patients have a more complex, non-Mendelian genetic aetiology.
• PRS modulation of disease severity: Kolder et al.: PRS (22 QT-SNPs) associated with QTc in LQT2 patients; higher PRS quartile may confer higher arrhythmia risk. Turkowski et al.: PRS (61 SNPs) higher in LQTS probands with QTc ≥480 ms vs <480 ms; higher in probands vs. gene-positive family members.
• Low-frequency variant example: KCNE1 p.Asp85Asn (MAF ~1%) — 7.42 ms/allele effect; predisposes to LQTS and modulates disease severity in LQT1 families with Finnish founder mutation.
• UK Biobank (n=130,000): >75% of individuals with deleterious KCNQ1 or KCNH2 variants had QTc <480 ms — underlining extensive low penetrance of established LQTS genes.

Acquired Repolarization Disorders

• Drug-induced LQTS: Antiarrhythmics, antimicrobials, SSRIs, antipsychotics are main culprits. IKr channel blockade is the primary mechanism — heterogeneous APD prolongation → dispersion of repolarization → EADs → TdP.
• Repolarization reserve concept: Predisposing genetic variants remain subclinical until IKr blockade depletes the reserve, unmasking QT prolongation and TdP. Explains why ~10–20% of drug-induced TdP patients carry LQTS gene variants. KCNE1 p.Asp85Asn and NOS1AP SNPs enriched in drug-induced TdP cohorts.
• PRS comprising 60 QT-SNPs predicted drug-induced TdP and explained a substantial proportion of QTc response to dofetilide, quinidine, and ranolazine in healthy individuals.
• PI3K pathway inhibition prolongs QTc by affecting multiple ion currents — proposed as the mechanism in diabetes mellitus (↓ insulin activation of PI3K).
• Acquired SQTS: Main causes — acidosis, hypercalcemia, hyperkalemia, hypothermia, cardioversion. Drug-induced SQTS: rare; rufinamide (antiepileptic) causes QTc shortening; carnitine deficiency associated with short QTc.

Artificial Intelligence in ECG Analysis

• Up to 40% of LQTS patients have QTc <450 ms — many are undetectable by QTc alone.
• Deep neural networks have been applied to identify repolarization disorders beyond human ECG reading capacity.
• AI accurately detected long-QT intervals in genetic heart disease patients (Giudicessi et al. 2021).
• Deep learning model (Aufiero et al. 2022) identified concealed LQTS (normal QTc) with AUC 0.741; also discriminated LQT1 from LQT2.
• Input occlusion technique revealed mechanistic ECG footprints used by the network — corresponding to predicted T-wave changes from IKr inhibition — validating the biological basis of AI detection.
• AI is expected to become an established tool for ECG analysis in the coming decade.

Limitations of the Document

• Review article — no primary data from the authoring group; evidence synthesis may reflect author emphasis.
• GWAS PRS data largely derived from European ancestry populations; limited multiancestry validation of PRS for LQTS risk prediction.
• AI ECG studies cited are small (limited n); AUC of 0.741 for concealed LQTS represents moderate discrimination — clinical utility not yet established.
• Acquired SQTS section is very brief; evidence base for drug-induced SQTS is limited to case reports and small series.
• Common variant studies in SQTS are absent — a knowledge gap explicitly acknowledged by the authors.

Key Concepts Mentioned

• concepts/Cardiac-Repolarization — central topic; T-wave physiology, EAD mechanisms, re-entry substrate
• concepts/Torsades-de-Pointes — TdP initiation/perpetuation mechanism, focal-to-reentry transition
• concepts/Cardiac-Action-Potential — ion currents and regional APD heterogeneity
• concepts/Ion-Channel-Mutations — ClinGen curation of LQTS/SQTS genes
• concepts/Polygenic-Risk-Score — PRS for LQTS susceptibility and QTc modulation
• concepts/Drug-Induced-Arrhythmia — drug-induced LQTS, repolarization reserve
• concepts/Schwartz-Score — Tpeak-to-T-end as diagnostic parameter
• concepts/Left-Cardiac-Sympathetic-Denervation — referenced as invasive therapy for high-risk LQTS

Key Entities Mentioned

• entities/Long-QT-Syndrome — primary entity; genotype-phenotype correlations, PRS, AI ECG
• entities/Short-QT-Syndrome — secondary entity; ECG features, acquired causes, gene curation
• entities/Brugada-Syndrome — mentioned in context of CACNA1C/CACNB2 combined phenotype with short QTc

Wiki Pages Updated

• Created: wiki/sources/repolarisation-jaccep-2023.md
• Created: wiki/concepts/Cardiac-Repolarization.md
• Created: wiki/concepts/Polygenic-Risk-Score.md
• Updated: wiki/entities/Long-QT-Syndrome.md
• Updated: wiki/entities/Short-QT-Syndrome.md
• Updated: wiki/concepts/Torsades-de-Pointes.md
• Updated: wiki/concepts/Cardiac-Action-Potential.md
• Updated: wiki/wikiindex.md
• Updated: wiki/sourceindex.md
• Updated: log.md