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Cardiology›Condition·Updated Jul 11, 2026·v1

Cardiac Action Potential

The cardiac action potential is the electrical waveform driving each heartbeat, and its disruption, through genetic mutations, drugs, or metabolic disturbances, underlies the majority of arrhythmias. Understanding the five phases and their ion channels enables targeted diagnosis and management of channelopathies, reducing the risk of sudden cardiac death.

High Evidence89 references·6,865 words·28 min read·v1
cardiac action potentialchannelopathylong QT syndromeBrugada syndromearrhythmiaelectrophysiologysudden cardiac death

Quick Reference

RxDrug of choiceLQTS: nadolol 1-2 mg/kg/day or propranolol 2-4 mg/kg/day; Brugada syndrome: quinidine 600-1200 mg/day for arrhythmia suppression; acute torsades: IV magnesium sulfate 2 g.
AltAlternativesMexiletine 150-300 mg TID for LQT3; amiodarone for acute ventricular arrhythmias; flecainide for MEPPC syndrome; AICAR (AMPK activator) for ibrutinib-induced arrhythmia (preclinical).
⊘AvoidClass Ic antiarrhythmics in ischemic heart disease or LV dysfunction; non-dihydropyridine CCBs in heart failure; QT-prolonging drugs in LQTS; pure Class III agents (d-sotalol) due to increased mortality.
DxTest of choice12-lead ECG with QTc measurement (Bazett's formula); for Brugada, ajmaline/flecainide challenge; for CPVT, exercise stress test; for drug-induced QT, toxicology screen and hERG assay.
ScKey scoreSchwartz score for LQTS (≥3.5 high probability); spontaneous type 1 ECG pattern for Brugada syndrome; QTc ≥500 ms as risk threshold for torsades.
→When to referPrior cardiac arrest, recurrent syncope despite therapy, QTc >500 ms with symptoms, family history of sudden death, spontaneous type 1 Brugada pattern with syncope, or for ICD/ablation evaluation.
The cardiac action potential, with its five phases governed by specific ion channels, provides the mechanistic framework for diagnosing and managing inherited and acquired arrhythmias; early recognition of channelopathies and genotype-guided therapy reduce sudden death risk.
The cardiac action potential is the fundamental electrical waveform that drives each heartbeat, and its disruption underlies the majority of arrhythmias. Understanding its five phases and the ion channels governing them is essential for diagnosing and managing inherited and acquired channelopathies, which collectively account for a significant proportion of sudden cardiac death in young individuals. This overview covers the key facts, mechanisms, and clinical relevance of the cardiac action potential, emphasizing the diagnostic approach and therapeutic strategies for QT prolongation, Brugada syndrome, and other disorders.

Overview and Recommendations

Key Facts

  • •The cardiac action potential is a transient electrical waveform that coordinates cardiomyocyte contraction, divided into five phases (0-4) based on predominant ion currents: phase 0 (rapid depolarization, Na⁺ influx via ), phase 1 (early repolarization, transient outward K⁺ current Iₜₒ), phase 2 (plateau, L-type Ca²⁺ current balancing delayed rectifier K⁺ currents), phase 3 (repolarization, rapid I_Kr and slow I_Ks), and phase 4 (resting potential, maintained by I_K1 and Na⁺/K⁺-ATPase).
  • •Inherited channelopathies, long QT syndrome (LQTS), , , and catecholaminergic polymorphic ventricular tachycardia (CPVT), affect approximately 1 in 2000 individuals and account for up to 20% of sudden cardiac deaths in structurally normal hearts.
  • •The QT interval on ECG is the clinical surrogate for action potential duration; a QTc >500 ms confers a 2- to 3-fold increased risk of torsades de pointes, especially when combined with hypokalemia or hypomagnesemia.
  • •The hERG potassium channel (I_Kr) is the most common target of drug-induced QT prolongation; regulatory safety margins (C_max vs. hERG IC₅₀ >30-fold) are used to predict proarrhythmic risk, and the Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm now integrates multiple ion channel effects for more accurate risk assessment.
  • •The four pillars of antiarrhythmic therapy, β-blockers, sodium channel blockers, potassium channel modulators, and device therapy (ICD, ablation), are guided by genotype-specific risk stratification, with emerging gene therapy (e.g., KCNQ1-SupRep, KCNH2-SupRep, MOG1 gene therapy) offering potential molecular cure in preclinical models.

Mechanism Summary

  • •Phase 0 is driven by the rapid inward Na⁺ current (I_Na) through voltage-gated Nav1.5 channels encoded by SCN5A; loss-of-function mutations reduce I_Na, causing Brugada syndrome and progressive conduction defects, while gain-of-function prolongs phase 2, causing LQT3 and multifocal ectopic Purkinje-related premature contractions (MEPPC).
  • •Phase 1 repolarization is mediated by the transient outward K⁺ current (I_to) through Kv4.2/Kv4.3 channels; gain-of-function mutations (e.g., KCND2 S447R) abbreviate action potential duration and predispose to nocturnal paroxysmal atrial fibrillation, while a de novo KCND3 mutation (Gly306Ala) augments I_to, causing early repolarization syndrome with J-point elevation and ventricular fibrillation.
  • •Phase 2 plateau is sustained by L-type Ca²⁺ current (I_Ca,L) through Cav1.2, modulated by calmodulin (CALM1-3); calmodulinopathies disrupt Ca²⁺-dependent modulation, producing severe LQTS and CPVT, and the plateau phase is also the target of dihydropyridine calcium channel blockers.
  • •Phase 3 repolarization is driven by the rapid (I_Kr, hERG/KCNH2) and slow (I_Ks, KCNQ1) delayed rectifier K⁺ currents; loss-of-function prolongs action potential duration (LQT1 from KCNQ1, LQT2 from KCNH2), while gain-of-function shortens it (short QT syndrome), and drug-induced I_Kr blockade is the most common cause of acquired QT prolongation.
  • •Phase 4 resting potential is set primarily by the inward rectifier K⁺ current (I_K1, Kir2.1/KCNJ2); loss-of-function causes Andersen-Tawil syndrome with prolonged QT, periodic paralysis, and dysmorphic features, while microRNA-1 can directly inhibit Kir2.1 via a non-canonical mechanism, depolarizing the resting membrane potential.
  • •The Na⁺-Ca²⁺ exchanger (NCX) plays a critical role in Ca²⁺ extrusion; upregulation in heart failure and diabetes prolongs action potential duration and promotes early afterdepolarizations (EADs) via spontaneous Ca²⁺ release from the sarcoplasmic reticulum, creating a substrate for triggered arrhythmias.
  • •Fever in Brugada syndrome reduces sodium channel conductance through temperature-dependent inactivation of Nav1.5, unmasking the type 1 ECG pattern in up to 30% of patients; this mechanism explains why febrile illness can precipitate life-threatening arrhythmias in children with Brugada syndrome.
  • •Autoantibodies against K⁺ channels (e.g., anti-Kv1.4) and inflammatory cytokines (TNF-α, IL-6) downregulate repolarizing currents, mimicking genetic channelopathies; this autoimmune mechanism can be identified through serologic testing and may respond to immunomodulation.
  • •Drug-induced action potential prolongation (e.g., loperamide, methadone, antipsychotics) results from I_Kr blockade, with QT prolongation and QRS widening; loperamide at high doses blocks both I_Kr and I_Na, producing a mixed phenotype that mimics congenital long QT syndrome.
  • •Gap junctional uncoupling (e.g., by carbenoxolone) slows conduction velocity by 27% in the right atrium and 23% in the right ventricle without affecting refractoriness, creating a substrate for reentry; this mechanism is relevant in heart failure and aging, where connexin 43 expression declines.

Clinical Relevance

  • •Suspect a channelopathy in any young patient with unexplained syncope, palpitations, or sudden cardiac arrest, especially with a family history of sudden death; obtain a 12-lead ECG with careful measurement of QTc using Bazett's formula and assess for Brugada pattern in leads V1-V3.
  • •For LQTS, initiate β-blocker therapy as first-line: propranolol 2-4 mg/kg/day divided BID-TID or nadolol 1-2 mg/kg/day once daily; titrate to a resting heart rate of 50-60 bpm and avoid QT-prolonging drugs (check www.crediblemeds.org); maintain serum K+ >4.5 mEq/L and Mg2+ >2.0 mg/dL.
  • •For Brugada syndrome with spontaneous type 1 ECG and syncope or prior cardiac arrest, implant an ICD; quinidine 600-1200 mg/day in divided doses is used for arrhythmia suppression in patients who are ineligible for ICD or have recurrent VF despite device therapy.
  • •For CPVT, first-line therapy is nadolol 1-2 mg/kg/day or propranolol 2-4 mg/kg/day; left cardiac sympathetic denervation (LCSD) is effective for refractory cases; avoid catecholamines and stress, and consider exercise stress testing to guide therapy.
  • •For drug-induced QT prolongation with torsades de pointes, immediately discontinue the offending agent, administer IV magnesium sulfate 2 g over 1-2 minutes, and maintain serum K+ >4.5 mEq/L; for bradycardia-dependent TdP, consider temporary pacing at 80-100 bpm or isoproterenol infusion 1-2 mcg/min.
  • •For LQT3 (SCN5A gain-of-function), add mexiletine 150-300 mg TID to β-blocker therapy; mexiletine blocks the late Na+ current and can shorten QTc by 30-50 ms; monitor for gastrointestinal side effects and neurologic toxicity.
  • •In acute management of ventricular arrhythmias, amiodarone 150 mg IV over 10 minutes, then 1 mg/min for 6 hours, then 0.5 mg/min for 18 hours is first-line for stable patients; lidocaine 1-1.5 mg/kg IV is an alternative, especially for ischemic VT.
  • •Use the Schwartz score for clinical diagnosis of LQTS: assign points for QTc ≥480 ms (3 points), 460-479 ms (2), 450-459 ms (1), torsades de pointes (2), T-wave alternans (1), notched T wave (1), low heart rate (0.5), syncope with stress (2), congenital deafness (0.5), family history of LQTS (1), family history of sudden death <30 years (0.5); a score ≥3.5 indicates high probability.
  • •For Brugada syndrome, the type 1 ECG pattern (coved ST elevation ≥2 mm in V1-V3) is diagnostic; if not present, provocative testing with fever (induce hyperthermia) or sodium channel blocker (ajmaline 1 mg/kg IV over 5 min, flecainide 2 mg/kg IV over 10 min) can unmask the pattern with continuous ECG monitoring.
  • •In patients with drug-refractory atrial fibrillation, consider pulmonary vein isolation; preprocedural CT to assess left atrial appendage-left superior pulmonary vein proximity may identify non-PV sources, and electrocardiographic imaging (ECGI) can detect abnormal repolarization gradients.
  • •For mechanically ventilated patients with arrhythmias, correct acid-base disturbances and avoid hypokalemia/hypomagnesemia; use continuous telemetry monitoring and consider a 12-lead ECG daily for QTc assessment.
  • •In sepsis, action potential prolongation correlates with myocardial injury and elevated IL-6, CK-MB, and sST2 levels; consider tropisetron 5 mg IV as a 5-HT3 antagonist that may attenuate AP prolongation in preclinical models, though this is not yet standard of care.
  • •For elderly patients with diabetes and prolonged QT, suspect KCNH2 downregulation and increased NCX1 expression; optimize glycemic control and consider regular exercise to preserve connexin 43 expression and maintain electrical stability.
  • •Avoid class Ic antiarrhythmics (flecainide, propafenone) in patients with ischemic heart disease or LV dysfunction due to increased mortality in CAST trial; use amiodarone or sotalol instead if needed.
  • •Refer patients with high-risk features (prior cardiac arrest, recurrent syncope despite therapy, LQT3 with QTc >500 ms, spontaneous type 1 Brugada pattern with syncope) for ICD evaluation and electrophysiology consultation.
  • •Family screening is mandatory: first-degree relatives of probands with channelopathies should undergo ECG and targeted genetic testing; cascade screening can identify asymptomatic carriers who may benefit from preventive therapy.
  • •Emerging gene therapies (KCNQ1-SupRep, KCNH2-SupRep, MOG1 upregulation) are in preclinical development and may offer molecular cure in the future; these suppression-replacement constructs normalize APD in patient-derived iPSC-CMs and are moving toward clinical trials.

Board Review — High Yield

  • •Phase 0, Rapid depolarization via Na⁺ influx (Nav1.5/SCN5A); loss-of-function → Brugada syndrome; gain-of-function → LQT3 and MEPPC.
  • •Phase 2 plateau, L-type Ca²⁺ current (Cav1.2) balanced by delayed rectifier K⁺ currents; calmodulinopathies cause severe LQTS and CPVT.
  • •Phase 3 repolarization, Rapid (I_Kr, hERG) and slow (I_Ks, KCNQ1) K⁺ currents; drug-induced I_Kr block → torsades de pointes.
  • •QTc >500 ms, 2-3× increased risk of torsades; combined with hypokalemia/hypomagnesemia → emergency; IV magnesium 2 g is first-line.
  • •Brugada syndrome, Type 1 ECG pattern (coved ST elevation ≥2 mm in V1-V3); fever unmasks pattern; quinidine for arrhythmia suppression; ICD for high-risk patients.
  • •CPVT, Bidirectional VT during exercise; normal resting ECG; first-line therapy = β-blockers (nadolol); left cardiac sympathetic denervation for refractory cases.
  • •Drug-induced QT prolongation, IV magnesium 2 g for torsades; discontinue culprit; maintain K+ >4.5; avoid bradycardia with pacing or isoproterenol.
  • •Schwartz score, Points for QTc, torsades, T-wave alternans, syncope, family history; score ≥3.5 = high probability LQTS.
  • •Amiodarone, Multichannel blocker (Class I, II, III, IV); effective for acute VT/VF but long-term extracardiac toxicity (thyroid, lung, liver, cornea).
  • •Emerging gene therapy, SupRep constructs for KCNQ1/KCNH2 normalize APD in preclinical models; MOG1 gene therapy for Brugada; ML-277 (IKs activator) reverses drug-induced LQT2.

Deep Dive — Evidence Details

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