Ventricular Repolarization: Key Factors and ECG Implications

The heart’s electrical activity relies on precise coordination between depolarization and repolarization. Ventricular repolarization resets cardiac cells after contraction, ensuring readiness for the next heartbeat. Disruptions can lead to arrhythmias and other complications, making it a critical focus in research and clinical practice.

Understanding ventricular repolarization aids in diagnosing and managing heart conditions. The electrocardiogram (ECG) is a key tool for assessing normal and abnormal repolarization patterns.

Cellular Basis Of Ventricular Repolarization

Ventricular repolarization restores the electrical state of cardiac myocytes following depolarization. This phase is governed by ion movement across the cell membrane, primarily potassium (K⁺) efflux, which counteracts the preceding influx of sodium (Na⁺) and calcium (Ca²⁺). The controlled return to resting membrane potential ensures the ventricles are prepared for the next cycle. Disruptions can prolong or shorten repolarization, increasing the risk of arrhythmias such as torsades de pointes or ventricular fibrillation.

Voltage-gated potassium channels open in response to prior depolarization, allowing K⁺ to exit the cell and gradually restore the negative resting potential. The Na⁺/K⁺ ATPase pump and inward rectifier K⁺ channels maintain this state. Delayed rectifier potassium currents, particularly I_Kr (rapid) and I_Ks (slow), shape repolarization duration. I_Kr contributes to initial repolarization, while I_Ks ensures completion, particularly at higher heart rates. Mutations or pharmacological blockade of these channels can prolong repolarization, manifesting as a lengthened QT interval on an ECG.

Calcium handling also influences repolarization. While Ca²⁺ influx through L-type calcium channels is associated with the plateau phase, its removal via the sodium-calcium exchanger (NCX) and sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) affects repolarization timing. Excess intracellular calcium can prolong repolarization by modulating potassium currents, contributing to afterdepolarizations that may trigger arrhythmias. Maintaining ionic homeostasis is crucial, as even minor imbalances can have significant electrophysiological consequences.

Phases Of The Cardiac Action Potential

The cardiac action potential progresses through distinct phases dictated by ion movement across ventricular myocyte membranes. This electrical cycle ensures coordinated contraction and relaxation, enabling efficient blood circulation.

Phase 0, rapid depolarization, is driven by sodium influx through voltage-gated Na⁺ channels. As membrane potential rises, these channels inactivate, transitioning to phase 1, where transient outward potassium (I_to) currents briefly repolarize the membrane. This notch in the action potential waveform shapes subsequent electrical activity.

Phase 2, the plateau phase, balances inward calcium currents through L-type Ca²⁺ channels and outward potassium currents. Sustained Ca²⁺ influx prolongs depolarization, ensuring adequate ventricular contraction. Excess intracellular Ca²⁺ can extend depolarization and predispose to afterdepolarizations. Calcium channel blockers, such as verapamil, shorten this phase and reduce myocardial contractility.

Phase 3 initiates final repolarization, dominated by potassium efflux through delayed rectifier K⁺ channels. I_Kr primarily governs early repolarization, while I_Ks becomes more prominent at higher heart rates. Mutations in KCNH2 (hERG) and KCNQ1, which encode these channels, are linked to congenital long QT syndrome, characterized by delayed repolarization and increased risk of torsades de pointes.

Ion Channels In Ventricular Myocytes

Ion channels in ventricular myocytes regulate sodium, calcium, and potassium movement, ensuring controlled action potential progression. Even minor functional alterations can have significant electrophysiological consequences.

Voltage-gated Naᵥ1.5 sodium channels, encoded by SCN5A, initiate rapid depolarization. These channels open transiently during phase 0, allowing Na⁺ influx and driving membrane potential upward. Rapid inactivation prevents prolonged depolarization, ensuring timely repolarization. SCN5A mutations can lead to Brugada syndrome or type 3 long QT syndrome, both increasing ventricular arrhythmia risk. Sodium channel blockers like flecainide reduce excitability in arrhythmogenic substrates.

L-type Ca²⁺ channels (Caᵥ1.2), regulated by CACNA1C, sustain depolarization during the plateau phase. Ca²⁺ entry triggers excitation-contraction coupling by activating ryanodine receptors, releasing stored Ca²⁺ for contraction. Dysregulation can cause conditions such as Timothy syndrome, characterized by prolonged repolarization and severe arrhythmias. Calcium channel blockers like diltiazem reduce intracellular Ca²⁺ levels and decrease myocardial contractility, useful in hypertension and arrhythmia management.

Potassium channels govern repolarization. Delayed rectifier currents (I_Kr and I_Ks) restore resting membrane potential by facilitating K⁺ efflux. I_Kr, mediated by the hERG (KCNH2) channel, plays a key role in terminating the action potential. Blockade of this channel by certain medications can cause drug-induced long QT syndrome, increasing torsades de pointes risk. Inward rectifier K⁺ channels (I_K1) help maintain resting potential, preventing spontaneous depolarization and stabilizing electrical activity.

Influence Of Electrolyte Balance

Electrolyte concentrations significantly impact ventricular repolarization, with potassium, calcium, and sodium levels influencing repolarization duration and stability. Imbalances contribute to arrhythmogenic risks, making regulation a clinical priority.

Potassium is the primary determinant of repolarization speed. Hyperkalemia shortens the QT interval and can cause conduction abnormalities, while hypokalemia prolongs repolarization, increasing torsades de pointes risk. Clinical guidelines recommend maintaining serum potassium between 3.5 and 5.0 mmol/L to minimize arrhythmic risk.

Calcium affects repolarization by modulating the plateau phase. Hypercalcemia shortens the QT interval, while hypocalcemia prolongs it by reducing L-type calcium channel activity. Sodium, though primarily responsible for depolarization, influences repolarization through Na⁺/K⁺ ATPase and sodium-calcium exchanger activity. Hyponatremia and hypernatremia can alter intracellular calcium levels, further affecting repolarization.

Common ECG Markers

ECG analysis provides key insights into ventricular repolarization. The QT interval, representing the time from ventricular depolarization to complete repolarization, is a crucial marker. A prolonged QT interval, typically over 450 ms in men and 470 ms in women, increases the risk of torsades de pointes. Causes include congenital ion channel mutations, electrolyte imbalances, and medications that inhibit potassium currents, particularly hERG (I_Kr) blockers.

T wave morphology also reflects repolarization integrity. Abnormalities such as inversion, biphasic patterns, or flattening indicate ischemia, electrolyte disturbances, or structural heart disease. Early afterdepolarizations, often linked to prolonged repolarization, may appear as U waves or notched T waves, particularly in hypokalemia or drug-induced QT prolongation. The Tpeak-Tend interval, measuring repolarization dispersion, is an emerging metric for arrhythmic risk. Increased dispersion suggests heightened vulnerability to reentrant arrhythmias.

Genetic Determinants

Genetic variations in ion channel genes significantly impact ventricular repolarization, predisposing individuals to long QT syndrome (LQTS), short QT syndrome (SQTS), and Brugada syndrome. These mutations disrupt ion currents, altering repolarization duration and increasing arrhythmia risk.

LQTS is primarily caused by mutations in KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3). Loss-of-function mutations in KCNQ1 or KCNH2 delay repolarization, prolonging the QT interval, while gain-of-function mutations in SCN5A enhance sodium influx, further extending repolarization. Patients may experience syncope or sudden cardiac arrest, particularly in response to triggers like exercise (LQT1), emotional stress (LQT2), or sleep (LQT3).

SQTS results from gain-of-function mutations in potassium channels like KCNH2 and KCNQ1, accelerating repolarization and shortening the QT interval. This condition increases atrial and ventricular fibrillation risk. Brugada syndrome, linked to loss-of-function mutations in SCN5A, reduces sodium channel activity, causing early repolarization abnormalities. Its characteristic ECG pattern of right precordial ST-segment elevation reflects impaired conduction and heterogeneous repolarization. Genetic testing is crucial for identifying at-risk individuals and guiding treatment strategies, such as beta-blockers for LQTS, quinidine for Brugada syndrome, or implantable cardioverter-defibrillators (ICDs) for high arrhythmic risk patients.

Heart Rate And Autonomic Modulation

Repolarization varies with autonomic nervous system activity and heart rate fluctuations. Sympathetic stimulation accelerates repolarization by enhancing I_Ks potassium currents and increasing L-type calcium influx, shortening the QT interval. Excessive sympathetic activation, as seen in pheochromocytoma or emotional distress, may heighten repolarization heterogeneity and trigger arrhythmias.

Parasympathetic activity prolongs repolarization through acetylcholine-sensitive potassium currents (I_KAch), particularly during sleep, which can unmask latent repolarization abnormalities, as seen in Brugada syndrome. QT adaptation to heart rate changes is critical; impaired adaptation, as in diabetic autonomic neuropathy or congenital LQTS, increases arrhythmic risk. Beta-blockers and ivabradine help stabilize repolarization by modulating autonomic tone.