Cardiac Repolarization

Definition

Cardiac repolarization is the restoration of the resting membrane potential in cardiomyocytes following depolarization, mediated by coordinated outward K⁺ currents (IKs, IKr, IK1) that overcome residual inward Ca²⁺ and Na⁺ currents during action potential phases 2 and 3. On the surface ECG, ventricular repolarization is captured as the T-wave; its duration is approximated by the QT interval.

Key Concepts

Ion Currents and Regional Heterogeneity

• Ventricular repolarization is governed by the net balance of outward K⁺ currents (IKs/KCNQ1, IKr/KCNH2, IK1/KCNJ2) against inward currents (ICaL/CACNA1C, INaLate/SCN5A). (sources/repolarisation-jaccep-2023, rating: high)
• Regional heterogeneity in ion channel expression creates spatial gradients in action potential duration (APD) across the heart: subepicardium vs. subendocardium, right vs. left ventricle, base vs. apex. These APD gradients generate the potential differences that manifest as the T-wave on the ECG. (sources/repolarisation-jaccep-2023)
• The T-wave shape (not just QT duration) reflects these regional repolarization gradients and differs systematically between LQTS genetic subtypes as a consequence of where each gene's channel is most abundantly expressed. (sources/repolarisation-jaccep-2023)
• KCNQ1/IKs: Higher expression in subepicardium and right ventricle; relatively inactive at low heart rates; becomes dominant at higher rates. At rest, IKs contributes minimally to repolarization — mutations in KCNQ1 cause little QT prolongation at rest but unmask dramatically with exercise (LQT1 pattern). (sources/repolarisation-jaccep-2023)
• KCNH2/IKr: Relatively large at low heart rates; IKr reduction causes greater APD prolongation in LV than RV (where IKs compensates) → bifid T-wave seen in LQT2. (sources/repolarisation-jaccep-2023)
• SCN5A/INaLate: Gain-of-function mutation produces persistent late Na⁺ influx throughout phase 2, prolonging the plateau → delayed T-wave onset and long ST-segment (LQT3 pattern). (sources/repolarisation-jaccep-2023)
• Heart-rate dependence: QTc correction formulas (Bazett: QT/√RR; Fridericia: QT/∛RR) adjust for the inverse QT-heart rate relationship. IKs increases at higher rates, shortening APD — this is the basis of exercise testing in LQTS. (sources/repolarisation-jaccep-2023)

ECG Parameters of Repolarization

• QTc interval is the primary clinical parameter; Bazett formula used most commonly but Fridericia preferred at higher heart rates. (sources/repolarisation-jaccep-2023)
• Tpeak-to-T-end (TpTe): Reflects transmural dispersion of repolarization; distinguishes LQTS mutation carriers from controls and differentiates LQTS subtypes — but is not sensitive enough to separate symptomatic from asymptomatic LQTS patients. (sources/repolarisation-jaccep-2023)
• T-wave morphology: Small variations in T-wave shape independently predict life-threatening arrhythmias in both low- and moderate-risk populations. AI-based morphology analysis achieves AUC 0.741 for identifying concealed LQTS (normal QTc). (sources/repolarisation-jaccep-2023)
• In SQTS: Short/absent ST segments; tall asymmetrical T-waves; prolonged TpTe; shorter J-point-to-Tpeak interval in symptomatic patients. QTc shortening severity does NOT correlate with arrhythmia risk. (sources/repolarisation-jaccep-2023)

Arrhythmogenesis from Repolarization Abnormalities

• Trigger — EADs (prolonged repolarization): Prolonged APD → reactivation of ICaL and/or spontaneous SR Ca²⁺ release → depolarising INCX current → early afterdepolarizations. ~700,000 synchronised cardiomyocytes required to propagate an EAD to tissue-level triggered action potential. (sources/repolarisation-jaccep-2023)
• Trigger — R-from-T phenomenon: Spontaneous wavefront arising at the border between long and short repolarization regions, independent of EADs per se. (sources/repolarisation-jaccep-2023)
• Trigger — SQTS (shortened repolarization): APD shortening relative to calcium transient duration → elevated intracellular Ca²⁺ remains when the cell repolarizes → reverse-mode NCX provides inward INCX → afterdepolarization → triggered activity. Tracked clinically by the electromechanical window (negative EM window = increased arrhythmia risk). (sources/repolarisation-jaccep-2023)
• Substrate: Spatial heterogeneity in refractoriness → unidirectional conduction block → functional re-entry. Shortened QTc (SQTS) facilitates re-entry because refractory periods are abbreviated. (sources/repolarisation-jaccep-2023)
• TdP mechanism (LQTS): Initiated by focal beats in the long-repolarization zone. Multiple premature focal beats in this zone shorten APD locally more than in surrounding myocardium → reversal of the repolarization gradient → substrate for unidirectional block → transition from focal to re-entrant mechanism. (sources/repolarisation-jaccep-2023)
• Post-repolarization refractoriness (ischaemia): During ischaemia, the refractory period extends beyond the end of the action potential → APD is no longer a reliable estimate of refractoriness → T-wave duration does not reflect heterogeneity in refractoriness during acute ischaemia. (sources/repolarisation-jaccep-2023)

Repolarization Reserve

• The concept of repolarization reserve (Roden 1998) holds that multiple redundant mechanisms (IKr, IKs, IK1, INa-L, etc.) maintain normal repolarization. When one mechanism is already perturbed (e.g., by a latent LQTS mutation or low-frequency variant), the addition of an IKr-blocking drug depletes reserve and unmasks QT prolongation and TdP risk. (sources/repolarisation-jaccep-2023)
• The KCNE1 p.Asp85Asn variant (MAF ~1%, European) exerts a 7.42 ms/allele QTc effect and has been shown to predispose to both congenital LQTS and drug-induced TdP — exemplifying the role of low-frequency modulatory variants in depleting repolarization reserve. (sources/repolarisation-jaccep-2023)
• Concomitant factors that further deplete reserve: hypokalemia, hypomagnesemia, bradycardia, female sex (estrogen inhibits IKr), disease-related ion channel remodeling. (sources/repolarisation-jaccep-2023)

Common Genetic Variants and Heritability

• QT interval heritability in the general population: 25–50%. (sources/repolarisation-jaccep-2023)
• 2022 multiancestry GWAS meta-analysis (n=252,977) identified 176 independent QT-SNPs; common variants have small individual effects (<1–2 ms/allele). (sources/repolarisation-jaccep-2023)
• Many QT-SNPs cluster near known LQTS/SQTS ion channel genes; many are at novel loci representing unexplored biology relevant to repolarization. (sources/repolarisation-jaccep-2023)
• Genome-wide genetic correlation exists between QT interval in the general population and congenital LQTS susceptibility — confirming a shared biology. (sources/repolarisation-jaccep-2023)
• See concepts/Polygenic-Risk-Score for details on PRS application in LQTS.

Primary vs Secondary ST-T Classification

• Primary ST-T changes are repolarization abnormalities: myocardial ischemia, electrolyte disturbances (hyperkalemia, hypokalemia), tachycardia, sympathetic activation, and drug effects. In primary changes, the QRS complex is normal — the abnormal force originates in the repolarization process itself.
• Secondary ST-T changes are activation (depolarization) abnormalities: LBBB, LVH, pre-excitation, PVCs, pacemaker. In all secondary cases, the mechanism is the same — slow, abnormal endocardium-to-epicardium depolarization → subendocardium repolarizes before subepicardium → reversed repolarization direction → discordant ST-T relative to QRS. (sources/STT-mechanism-ACA-2026, rating: medium)
• Ischemia injury current mechanism: Partial depolarization of ischemic myocardium creates a voltage gradient at rest; during the TP/PQ period (when normal myocardium is fully repolarized), current flows between ischemic and normal zones. In subendocardial ischemia, this elevates the TP/PQ baseline, making the ST segment (which remains at its true position during AP phase II) appear depressed. In transmural ischemia, the baseline is depressed, making ST appear elevated. (sources/STT-mechanism-ACA-2026)

Contradictions / Open Questions

• Injury current theory completeness: The diastolic/systolic injury current model of ST displacement (TP/PQ baseline shift) is the dominant teaching model, but quantitative accuracy in human ischemia has been questioned. Alternative models exist (systolic injury current — ST shift during depolarisation rather than baseline during rest). (sources/STT-mechanism-ACA-2026)

• T-wave as refractoriness surrogate fails in ischaemia: The T-wave is used clinically as an estimate of repolarization heterogeneity and refractoriness, but post-repolarization refractoriness during acute ischaemia makes the T-wave an unreliable guide. This limits the use of ECG repolarization parameters for arrhythmia risk prediction during acute coronary events. (sources/repolarisation-jaccep-2023)

• EADs vs. R-from-T — relative contribution unresolved: Both EADs and the R-from-T phenomenon have been proposed as the primary trigger for LQTS arrhythmias. Their relative contributions in human disease (vs. ex vivo/in silico models) remain unresolved. (sources/repolarisation-jaccep-2023)

• Electromechanical window direction paradox: Logic predicts that a longer mechanical systole relative to electrical systole (positive EM window) should be protective. However, clinical data show that a decreased or negative EM window is the risk factor for arrhythmias. The exact mechanism — implicating stretch-activated ion channels — is not yet fully understood. (sources/repolarisation-jaccep-2023)

• SQTS: QTc severity does not predict arrhythmia risk — unlike LQTS. This distinction is clinically important but lacks mechanistic explanation at the individual-patient level and has no clinical risk stratification tool equivalent to the Schwartz Score or LQTS 1-2-3 calculator. (sources/repolarisation-jaccep-2023)

• Related to concepts/ST-T-Changes

• Related to sources/STT-mechanism-ACA-2026

Connections

• Related to concepts/Cardiac-Action-Potential
• Related to concepts/Torsades-de-Pointes
• Related to concepts/Ion-Channel-Mutations
• Related to concepts/Polygenic-Risk-Score
• Related to concepts/Drug-Induced-Arrhythmia
• Related to concepts/Schwartz-Score
• Related to entities/Long-QT-Syndrome
• Related to entities/Short-QT-Syndrome
• Related to entities/Brugada-Syndrome

Sources

• sources/STT-mechanism-ACA-2026
• sources/repolarisation-jaccep-2023