#channelopathies #inherited-arrhythmias #long-qt-syndrome #brugada-syndrome #cpvt #short-qt-syndrome #sudden-cardiac-death #genetics

Inherited cardiac arrhythmias

Authors, Journal, Affiliations, Type, DOI

Authors: Peter J. Schwartz, Michael J. Ackerman, Charles Antzelevitch, Connie R. Bezzina, Martin Borggrefe, Bettina F. Cuneo, Arthur A. M. Wilde
Journal: Nature Reviews Disease Primers, 2020;6:58 (article citation ID 6:58)
Affiliations: Istituto Auxologico Italiano IRCCS and University of Milan (Schwartz, Bezzina, Wilde); Mayo Clinic (Ackerman); Lankenau Institute for Medical Research and Thomas Jefferson University (Antzelevitch); University Medical Center Mannheim and DZHK (Borggrefe); Children's Hospital Colorado (Cuneo); Amsterdam UMC and Columbia University (Wilde)
Type: Review article — Disease Primer
DOI: https://doi.org/10.1038/s41572-020-0188-7

Overview

A multi-author Primer on the four major cardiac channelopathies — long QT, short QT, catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome — covering epidemiology, genetics, electrophysiological mechanism, diagnosis, risk stratification and therapy, with sections on pregnancy and quality of life. Its distinctive feature is that the Brugada mechanism debate is argued by its two principal proponents, Antzelevitch (repolarisation hypothesis) and Wilde (depolarisation hypothesis), rather than adjudicated. It is also unusually explicit that inherited arrhythmias cause a substantial share of sudden death in the young — 40% of autopsies in 1–35-year-olds show a structurally normal heart — and that roughly 10% of sudden infant deaths carry an LQTS-causing variant. Management is presented as gene-specific wherever the evidence allows, with propranolol/nadolol, mexiletine, quinidine, left cardiac sympathetic denervation and the ICD as the five therapeutic pillars.

Keywords

Long QT syndrome; short QT syndrome; catecholaminergic polymorphic ventricular tachycardia; Brugada syndrome; sudden cardiac death; ion channel; KCNQ1; KCNH2; SCN5A; RYR2; calmodulin; spatial dispersion of repolarization; beta-blocker; mexiletine; quinidine; left cardiac sympathetic denervation; ICD; pregnancy

Key Takeaways

Epidemiology

SCD under 35 years occurs at 1.3–3.2 per 100,000 person-years in US, Danish and Dutch studies. A 3-year prospective Australian/New Zealand study of ages 1–35 found male predominance and death predominantly during sleep (38%) or at rest (27%); autopsy showed a structurally normal heart in 40%, coronary artery disease in 24% and inherited cardiomyopathy in 16%.
General-population SCD is a different disease: 0.6 to >1.4 per 1,000 per year, mean age 65, ~75% male, coronary disease in ~80%.
LQTS prevalence is 1 in 2,534 apparently healthy live births (95% CI 1 in 1,583 to 1 in 4,350) in the prospective 44,596-infant Italian ECG study; because infants with QTc 450–470 ms were not all genotyped, the authors estimate the true ECG-positive prevalence at ≥1 in 2,000. Disease-causing variants were found in 29% of infants with QTc 451–460 ms and 49% of those with QTc >470 ms.
Brugada prevalence has a strong ethnic gradient: Asians 0.0–0.94%, Japanese-Americans 0.15%, Europeans 0.0–0.02%, North Americans 0.005–0.1%. Founder mutations for LQTS are described in Finland, South Africa, Canada, the Netherlands and Sweden.
The channelopathy prevalence figures in guidelines are educated guesses — population studies exist only for LQTS; SQTS has just over 200 reported patients.

Mechanisms and Pathophysiology

LQTS genetics

LQT1 (KCNQ1/IKs) 30–35%, LQT2 (KCNH2/IKr) 25–40%, LQT3 (SCN5A/INa) 5–10%; the three genes explain ~90% of genotype-positive patients. 15–20% of clinically definite LQTS remains genotype-negative; 5–10% carry multiple mutations, which present younger and more severely.
Genotype–phenotype within genes: KCNQ1 variants in transmembrane-encoding sequence carry higher risk than C-terminus variants, and dominant-negative variants higher risk than haploinsufficiency; KCNH2 pore-region missense variants are more severe than non-pore variants.
ClinGen designations in this Primer: disputed evidence for KCNE2, KCNJ5, SCN4B, SNTA1, AKAP9 and ANK2; limited evidence for CAV3, KCNE1 and KCNJ2; strong for TRDN; definitive for CALM1, CALM2 and CALM3. This is a stricter reading than later curations and conflicts with KCNE1's established role in Jervell–Lange-Nielsen syndrome.
Calmodulinopathy: CALM1/2/3 lie on different chromosomes, share 85% nucleotide homology and encode an identical 149-amino-acid protein, yet one mutant allele out of six is sufficient to cause LQTS. The International Calmodulinopathy Registry had 74 patients; among 29 families screened, the variant was de novo in 93%, with germline mosaicism in a parent in the remainder. Presentation is early with profound QTc prolongation, often 2:1 AV block and high risk of arrest.
Extracardiac LQTS variants: Jervell and Lange-Nielsen (biallelic KCNQ1 or KCNE1; KCNE1 milder), Timothy syndrome (recurrent de novo CACNA1C G406R; syndactyly, congenital heart disease, immune deficiency, hypoglycaemia, autism) and Andersen–Tawil (KCNJ2 loss-of-function). The Primer argues Andersen–Tawil is not part of LQTS: the apparent QT prolongation comes from including a prominent U wave in the QTc calculation.

SQTS, CPVT and BrS genetics

SQTS is autosomal dominant; gain-of-function KCNH2 (SQT1), KCNQ1 (SQT2) and KCNJ2 (SQT3) shorten the action potential. CACNA1C/CACNB2/CACNA2D1 loss-of-function is described but causality is limited. A single SLC4A3 missense (anion exchanger AE3) was found in a large SQTS family and a smaller unrelated family.
CPVT: RYR2 missense variants cause 65% (CPVT1). CASQ2 causes the recessive, rarer and more severe CPVT2; CALM1, CALM2 and TRDN cause overlapping LQTS/CPVT phenotypes; TECRL is recessive with mixed features. The recommended panel covers all 105 translated RYR2 exons plus CASQ2, KCNJ2, CALM1/2/3, TRDN, TECRL and PKP2, because PKP2-mediated ARVC has a pre-cardiomyopathic electrical phase that mimics CPVT.
BrS: SCN5A is the only unequivocally implicated gene, found in ~20% of probands; the >20 other reported genes come almost entirely from candidate-gene studies in single individuals or small families. GWAS common variants near SCN5A and HEY2 support complex, non-Mendelian inheritance; more than four of six risk alleles makes a type 1 ECG more likely.

Genetic modifiers

The same KCNQ1-A341V founder mutation produces a wide QTc spectrum, including values within the normal range — direct evidence that additional genetic and non-genetic factors determine repolarisation. Modifier research is most advanced in LQTS and is a route to better risk stratification.

Pathophysiology of the individual arrhythmias

Spatial dispersion of repolarisation (SDR) is the common final pathway across all four syndromes, lowering the threshold for reentry. The hypothesis derives largely from canine wedge preparations, and the Primer notes that electrophysiologists do not interpret those experiments uniformly.
LQTS: reduced net repolarising current prolongs APD; transmural/trans-septal dispersion plus early afterdepolarisation-triggered activity initiate TdP. Short TdP episodes may be focal, but long non-terminating episodes are maintained by reentry. Sympathetic activation amplifies dispersion, and neurally released noradrenaline differs from circulating adrenaline/isoprenaline — a distinction with therapeutic consequences.
SQTS: heterogeneous AP abbreviation, preferential in epicardium, raises SDR and shortens wavelength, promoting reentry and atrial fibrillation. The mechanism of the PVC that precipitates polymorphic VT is unresolved.
CPVT: RYR2/CASQ2/calmodulin/triadin defects cause SR calcium overload and spontaneous diastolic release → transient inward current → delayed afterdepolarisations → triggered activity. Two competing accounts of the transition to polymorphic VT remain: epicardial ectopy producing SDR and reentry (wedge experiments; suppressed by propranolol and verapamil) versus His–Purkinje DAD-triggered focal activity (transgenic mice).
BrS: the J wave reflects a transmural Ito gradient, greatest in RVOT epicardium, which is why BrS is a right ventricular disease; early repolarisation is its left ventricular inferior-wall counterpart. Epicardial mapping shows fractionated signals in 75% of early-repolarisation patients, which one camp reads as delayed depolarisation and the other as delayed repolarisation.

Diagnosis, Screening and Prevention

LQTS: upper limits of normal QTc are 440 ms in males and 460 ms in females; mean is 400 ± 20 ms. The 1993–2011 Schwartz score is reproduced (QTc 450–459 in males 1 point, 460–479 2, ≥480 3; recovery QTc ≥480 1; TdP 2; T-wave alternans 1; notched T in three leads 1; bradycardia 0.5; stress syncope 2, non-stress 1; deafness 0.5; family LQTS 1; unexplained SCD <30 0.5). The tangent method can underestimate QT when the T-wave descent is slow — common in IKs/IKr impairment — and should not be used when LQTS is suspected. The exercise test almost never induces arrhythmia in LQTS (unlike CPVT) but shows impaired QT adaptation, recovery T-wave changes and blunted heart-rate deceleration; Holter captures night-time T-wave lability. Echocardiography can show mechanical alterations.
SQTS: QTc ≤340 ms is the 2015 ESC Class I threshold (level C); QTc ≤360 ms with a pathogenic variant, family history of SQTS, family history of SCD <40 or documented VT/VF warrants consideration (Class IIa C). Prevalence of QTc <340 ms is 0.4% in a Finnish cohort and <320 ms 0.1%; QTc ≤340 ms is 0.05% in children. Short QT alone is not associated with arrhythmic risk, so the threshold overlaps healthy people. Measure at heart rate 50–70 bpm; supportive features are PQ-segment deviation (81%), tall symmetrical T waves with absent ST segment, early repolarisation (65%), apparent U waves and impaired QT adaptation. A mutation is found in only ~20%.
CPVT: diagnosis requires a structurally normal heart, normal resting ECG and exercise-induced bidirectional VT or polymorphic PVCs. The typical sequence begins with unifocal PVCs at 110–130 bpm, progressing to bigeminy, couplets, bidirectional couplets and then non-sustained or bidirectional VT, often resolving at peak exercise or immediately in recovery. A rare RYR2 missense is present in 3% of healthy people, so a compelling phenotype gives ~20:1 odds that the variant is causal. Per the 2013 HRS/EHRA/APHRS consensus, a CPVT1 pathogenic variant is equivalent to a clinical diagnosis and mandates cascade testing and consideration of prophylactic beta-blockade in asymptomatic carriers.
BrS: a spontaneous type 1 coved pattern (J-point ≥2 mm, negative T) in V1/V2 at the 2nd–4th intercostal space is mandatory; type 2/3 patterns are saddleback and non-diagnostic. High lead placement, sodium-channel blockade (ajmaline most effective, sensitivity/specificity unknown) or vagal loading (post-meal or post-exercise ECG) increase sensitivity; additional clinical criteria are needed when the type 1 appears only after drug or fever. Phenocopies must be excluded.

Management

Pharmacological

LQTS beta-blockade for every diagnosed patient, because the first event can be fatal. Only propranolol and nadolol are beyond doubt effective; metoprolol should not be used, atenolol is doubtful and other agents are unproven. Exceptions are asymptomatic males with LQT1 still event-free off therapy at 25 and genotype-positive phenotype-negative individuals. Beta-blockers are also effective in LQT3, correcting an old misconception.
Mexiletine is the first gene-specific therapy, for LQT3: add it when it shortens QTc by >40 ms in a patient with baseline QTc >500 ms. The test is simple — therapeutic levels are reached 90–120 minutes after half the daily dose, and a 2-hour ECG identifies responders without knowing the mutation's biophysics. Mayo and Milan now also use mexiletine in LQT2. Ranolazine data are insufficient. Lumacaftor–ivacaftor may rescue KCNH2 trafficking defects in LQT2, with supportive iPSC-CM and early clinical data.
SQTS: asymptomatic QTc 300–360 ms is monitored without prophylaxis; QTc ≤300 ms carries risk, especially at rest or during sleep. Quinidine is the only drug that lengthens QTc and reduces events — IIb C for primary prevention in high-risk families or after recurrent ICD shocks. Intravenous isoprenaline is used for electrical storm or refractory VF.
CPVT: beta-blockade is first-line for all symptomatic patients, nadolol preferred, carvedilol an alternative if nadolol is unavailable or not tolerated. Add flecainide, which both blocks sodium current and stabilises leaky RYR2; a small placebo-controlled RCT confirmed reduced exercise-induced ectopy. Therapeutic success is a normalised stress test, tolerating occasional bigeminy but escalating for bidirectional couplets or worse.
BrS: drug options are limited. Intravenous isoprenaline is the most effective acute treatment for electrical storm and can normalise the ECG; quinidine is the best-studied chronic drug; cilostazol and milrinone are alternatives. All sodium-channel blockers except quinidine should be avoided (brugadadrugs.org).

Non-pharmacological

LCSD interrupts noradrenaline release from the left cardiac sympathetic nerves and raises the VF threshold. It is preganglionic, so there is no reinnervation or post-denervation supersensitivity; thoracoscopy is the preferred approach. Indications include failure of beta-blockade, primary prevention with persistent QTc >500 ms or T-wave alternans, multiple ICD shocks and beta-blocker intolerance. To be effective it must section the lower half of the left stellate ganglion plus the first four thoracic ganglia; the commonest cause of breakthrough events is a procedure that removed only the stellate ganglion. If LCSD fails, add right-sided denervation sequentially — never start bilateral.
ICD: implant after cardiac arrest as a rule, but young LQT1 patients whose arrest occurred off beta-blockade may be managed with beta-blockers and/or LCSD alone. In the largest LQTS device study 31% had an adverse event within 5 years, and younger patients face more generator changes. The usual strategy is LCSD to prevent episodes with an ICD as safety net.
CPVT and the ICD: because each event is more lethal, practice has been aggressive, but CPVT is the one entity where the device may increase mortality — inappropriate shocks from sinus tachycardia or AF trigger an adrenergic storm. Contemporary centres reserve ICDs for arrest requiring external defibrillation and favour triple therapy (nadolol, flecainide, LCSD), which may match ICD survival without device morbidity. LCSD is recommended for recurrent sustained VT on stress testing or recurrent syncope despite optimal drugs.
BrS: ICD is Class I after cardiac arrest or documented VA. Epicardial RVOT ablation normalised the ECG in 8 of the first 9 severely symptomatic patients and prevented recurrence in 39 symptomatic patients over ~10 months; prophylactic ablation in asymptomatic patients is discouraged pending randomised trials.

Gene-specific lifestyle (LQTS)

LQT1: limit physical and emotional stress; swimming allowed only with a competent adult supervisor.
LQT2: remove alarms and telephones from the bedroom; replace potassium after diarrhoea and use potassium-sparing agents for chronic hypokalaemia; postpartum women should avoid sleep deprivation, with partners handling night feeds.
LQT3: events occur at rest/asleep; an intercom for affected children and an adult bed partner are advised because night-time deaths are often not silent.

Pregnancy-Associated Risk

LQTS is the only channelopathy with adequate pregnancy data. CPVT shows no increased maternal risk in the single available study; BrS event rates are not elevated, so management is fever control and drug avoidance.
Postpartum event rates are <1% in LQT1 but 16% in LQT2; there are no LQT3 data. Beta-blockers are safe in pregnancy, but atenolol is class D for growth restriction.
Fetal loss is higher when the mother carries the variant: fetal death 24.4% versus 3.4% when the father carries it.
Delivery: low-risk women on adequate beta-blockade can deliver vaginally; LQTS does not need intrapartum telemetry, but CPVT does. Caesarean with telemetry is considered for poorly controlled arrhythmia or prior arrest. Oxytocin can prolong QT — optimise potassium and magnesium, record an ECG at baseline and 1–2 h after starting, and stop if QTc exceeds 500 ms or rises >60 ms.
Neonatal ECG is unreliable until after the second week because QT is physiologically prolonged for 7–10 days, unless QTc >500 ms; genetic screening of the newborn is performed meanwhile. Pre-implantation genetic testing is an option when the familial variant is known.

Quality of Life

ICD shocks can initiate a vicious cycle of fear, catecholamine release and further VT/VF, especially in LQTS and CPVT; LCSD improves quality of life and is preferred where feasible.
Sport cessation is a major psychological event; advice should account for local law, sport type, team versus individual pressure and genotype (LQT2/LQT3 lower risk than LQT1).
Asymptomatic BrS with a spontaneous type 1 carries a ~1%/year device-use risk but is often told they may die in their sleep, producing chronic anxiety; quinidine data are used to reassure, and prophylactic RVOT ablation remains unproven.

Outlook

LQTS: outcomes are good except for infants with events in the first year; LCSD remains underused because few surgeons can perform it. Modifier genetics and patient-specific iPSC-CMs are the two research priorities.
SQTS: too few patients (<200) for risk stratification; the European registry should expand; quinidine adherence and tolerability are unresolved.
CPVT: one-third of clinically diagnosed patients have no identifiable gene; diagnosis is still delayed because exercise testing is omitted from the workup of young cardiac arrest. Universal lifelong beta-blockade based on genotype alone is unsatisfactory, and ICD monotherapy should never be recommended.
BrS: pathogenesis, risk stratification and therapy remain contested; large pooled registries and randomised trials of epicardial ablation are needed before it is offered to asymptomatic patients.

Limitations of the document

Published in 2020 and predates the guidelines that now govern practice — ESC 2022, the 2023 HRS/EHRA/APHRS consensus and current ClinGen curations. Its gene-disease statements (notably KCNE1 as "limited" evidence and the older Schwartz score) are not the current standard.
No systematic search or meta-analysis — it is an expert narrative Primer; prevalence figures for SQTS, CPVT and BrS are explicitly acknowledged as educated guesses, and CPVT/SQTS management rests on small registries and case series.
The Brugada section is intentionally adversarial, with the repolarisation and depolarisation hypotheses argued by their proponents and no adjudication; readers looking for a settled mechanism will not find one.
Pregnancy evidence is LQTS-centric; CPVT and BrS statements rest on single small studies.
Risk stratification is descriptive rather than quantitative — tools such as the 1-2-3 LQTS calculator and the Shanghai score are named but not modelled, and no event-rate table comparable to later reviews is provided.
Precision-therapy developments after 2020 are absent — no discussion of later gene therapy trials, newer devices or the current generation of risk calculators.
The converted text contains OCR artefacts in several figure legends and in the Andersen–Tawil paragraph, so some sentences were reconstructed from context; all quoted numbers were cross-checked against the prose where possible.

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The ingest entry is in log.md.