Inhibiton of L-Type Calcium Channels leading to heart failure via QT interval prolongation and Torsades de Pointes (TdP)

Sun-Woong Kang^a, Myeong Hwa Song^b  ,Do-Sun Lim ^b and Kim Young Jun^c 

^aCenter for Biomimetic Research, Korea Institute of Toxicology, Daejeon 34114, Korea

^bCardiovascular Center, Department of Cardiology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea

^cEnvironemental Safety Group, KIST Europe, campus E 71 Saarbruecken, Germany 

The dysfunction of L-type calcium channels (LTCCs) is a critical molecular initiating event (MIE) in the progression to severe cardiac outcomes, including ventricular fibrillation and cardiomyopathy, mediated by QT interval prolongation and Torsades de Pointes (TdP). LTCCs regulate calcium influx during the plateau phase of the cardiac action potential, essential for excitation-contraction coupling. Dysfunctional LTCCs, caused by genetic mutations, pharmacological agents, or electrolyte imbalances, lead to reduced or altered calcium currents (ICa,L), disrupting cardiac electrophysiology. This dysfunction prolongs action potential duration (APD), resulting in QT interval prolongation, a critical marker of delayed ventricular repolarization. QT prolongation predisposes cardiomyocytes to early afterdepolarizations (EADs), which create a substrate for TdP, a life-threatening polymorphic ventricular arrhythmia. Sustained TdP episodes can progress to ventricular fibrillation, characterized by chaotic electrical activity and ineffective ventricular contraction, leading to hemodynamic collapse. Repeated or prolonged episodes of TdP and ventricular fibrillation impose chronic stress on the myocardium, culminating in cardiomyopathy through structural remodeling, fibrosis, and reduced cardiac function. This AOP framework provides insights into the dose-response relationships between LTCC dysfunction and cardiac outcomes, supporting its application in regulatory toxicology, drug development, and risk assessment. It underscores the importance of screening pharmacological agents and environmental chemicals for QT prolongation and TdP risks to  cardiomyopathy. 

The dysfunction of L-type calcium channels (LTCCs) plays a central role in the pathogenesis of severe cardiac arrhythmias and structural heart disease. LTCCs are pivotal in regulating calcium influx during the plateau phase of the cardiac action potential, maintaining normal cardiac excitation-contraction coupling. Dysfunctional LTCCs, whether due to genetic mutations (e.g., CACNA1C variants), pharmacological agents, or electrolyte imbalances, can disrupt the delicate balance of ionic currents necessary for proper cardiac function.

This AOP is particularly relevant in the context of QT interval prolongation, a widely recognized marker of delayed ventricular repolarization. QT prolongation, whether congenital or acquired, predisposes individuals to Torsades de Pointes (TdP), a potentially fatal ventricular arrhythmia. TdP is often episodic and can degenerate into ventricular fibrillation (VF), characterized by disorganized electrical activity and hemodynamic collapse. Furthermore, chronic or repeated arrhythmic episodes can impose sustained stress on the myocardium, leading to cardiomyopathy characterized by fibrosis, chamber dilation, and impaired contractility.

This AOP framework provides a mechanistic understanding of the progression from LTCC dysfunction to adverse cardiac outcomes, offering a valuable tool for multiple applications:

• Regulatory Toxicology: Screening  chemicals for proarrhythmic risks, particularly QT prolongation and TdP potential.
• Risk Assessment: Assessing the cardiotoxic potential of pharmacological agents and environmental toxins.

Understanding this AOP is critical for advancing cardiovascular safety and guiding regulatory and clinical decision-making, especially in drug discovery and toxicology evaluations. It bridges the gap between molecular events and clinical outcomes, fostering better risk management strategies for heart failuare.

1. Problem Formulation

Biological Context:

LTCCs are essential for cardiac action potential propagation and excitation-contraction coupling. Dysfunction in these channels is directly linked to cardiac arrhythmias and structural abnormalities.

The AOP focuses on the progression from LTCC dysfunction to ventricular fibrillation and cardiomyopathy, mediated by intermediate events such as QT interval prolongation and Torsades de Pointes (TdP).

Regulatory Relevance:

This AOP addresses cardiotoxicity risks in pharmacological agents, environmental chemicals, and genetic predispositions (e.g., congenital Long QT syndrome).

Applications include drug safety evaluation, regulatory toxicology, and therapeutic target discovery.

2. Key Components of the AOP

Molecular Initiating Event (MIE)

Dysfunction of L-Type Calcium Channels:

LTCC dysfunction can result from genetic mutations (e.g., CACNA1C), pharmacological blockade, or electrolyte imbalances (e.g., hypocalcemia).

Leads to impaired calcium influx (ICa,L), disrupting the cardiac action potential.

Key Events (KEs)

Altered Action Potential Duration (APD):

Reduced LTCC activity prolongs the repolarization phase, leading to increased action potential duration (APD90).

QT Interval Prolongation:

The prolongation of ventricular repolarization extends the QT interval on ECG, predisposing the heart to early afterdepolarizations (EADs).

Torsades de Pointes (TdP):

QT prolongation and EADs create conditions for reentrant circuits, leading to TdP, a polymorphic ventricular arrhythmia.

Ventricular Fibrillation (VF):

Sustained TdP progresses to VF, characterized by disorganized electrical activity and ineffective contraction.

Cardiomyopathy:

Repeated or chronic arrhythmias impose structural and functional stress on the myocardium, resulting in fibrosis, dilation, and reduced contractility.

Adverse Outcomes (AOs)

Cardiac Ventricular Fibrillation:

A life-threatening arrhythmia leading to sudden cardiac death if untreated.

Cardiomyopathy:

Structural and functional myocardial damage leading to heart failure.

3. Evidence Gathering and Integration

Identification of Evidence

Molecular-Level Data:

Studies on LTCC function and dysfunction due to pharmacological agents, mutations, or electrolyte imbalances.

Electrophysiological Data:

Evidence linking ICa,L reductions to prolonged APD and arrhythmogenesis.

Clinical and Preclinical Studies:

QT prolongation and TdP occurrences in response to drugs, toxins, or genetic conditions.

Screening and Prioritization

Use of high-throughput screening platforms (e.g., ToxCast, Tox21) to identify compounds affecting LTCCs.

Prioritize evidence demonstrating dose-response relationships and temporal concordance.

Weight of Evidence Assessment

Apply the OECD’s weight-of-evidence approach:

Biological plausibility of each KE.

Empirical support for KERs.

Reproducibility across species and models.

1. Molecular Initiating Event (MIE)

• Dysfunction of L-Type Calcium Channels (LTCCs):
  • LTCCs play a crucial role in regulating calcium influx during the plateau phase (phase 2) of the cardiac action potential.
  • Dysfunction (e.g., due to blockade, mutations, or altered regulation) reduces calcium currents (ICa,L) or disrupts their timing, impairing cardiac excitation-contraction coupling.

2. Key Events (KEs)

KE1: Altered Action Potential Duration (APD)

• Mechanism:
  • Reduced LTCC activity prolongs the repolarization phase (phase 3) of the cardiac action potential by altering the balance between inward (ICa,L) and outward (potassium) currents.
  • This leads to prolonged action potential duration, which predisposes myocytes to arrhythmogenic conditions.
• Measurement:
  • Patch-clamp electrophysiology to measure action potential duration (e.g., APD90).

KE2: QT Interval Prolongation

• Mechanism:
  • Prolonged action potential duration extends the QT interval on an electrocardiogram (ECG), reflecting delayed ventricular repolarization.
  • QT interval prolongation increases susceptibility to early afterdepolarizations (EADs), which can trigger arrhythmias.
• Measurement:
  • ECG assessment of the QT interval.
  • Corrected QT interval (QTc) > 450 ms in men and > 460 ms in women indicates prolongation.

KE3: Torsades de Pointes (TdP)

• Mechanism:
  • EADs and heterogeneity in repolarization create a substrate for reentrant circuits, resulting in TdP, a polymorphic ventricular tachyarrhythmia.
  • TdP is episodic and may self-terminate or progress to ventricular fibrillation.
• Measurement:
  • ECG showing characteristic twisting QRS complexes around the isoelectric line.

KE4: Ventricular Fibrillation

• Mechanism:
  • Sustained TdP progresses to ventricular fibrillation (VF), a lethal arrhythmia characterized by chaotic electrical activity and ineffective ventricular contraction.
• Measurement:
  • ECG showing rapid, irregular, and uncoordinated electrical activity.

KE5: Cardiomyopathy

• Mechanism:
  • Repeated episodes of TdP and VF, or prolonged QT interval without effective correction, result in chronic myocardial stress, hypoxia, and structural remodeling, leading to cardiomyopathy.
• Measurement:
  • Echocardiography or cardiac MRI showing reduced ejection fraction, chamber dilation, or fibrosis.

3. Adverse Outcomes (AOs)

• Cardiac Ventricular Fibrillation:
  • A life-threatening arrhythmia leading to sudden cardiac arrest if not corrected.
• Cardiomyopathy:
  • Chronic structural and functional impairment of the myocardium, leading to heart failure and reduced quality of life.

4. Key Event Relationships (KERs)

• MIE → KE1 (LTCC Dysfunction → Altered APD):

  • Dysfunctional LTCCs reduce inward calcium currents, prolonging repolarization and action potential duration.
  • Supported by experimental studies using LTCC blockers like verapamil and diltiazem.

• KE1 → KE2 (Altered APD → QT Interval Prolongation):

  • Prolonged action potentials extend the QT interval on ECG, a well-documented marker of delayed ventricular repolarization.

• KE2 → KE3 (QT Interval Prolongation → TdP):

  • QT prolongation increases the likelihood of EADs, which trigger TdP under conditions of repolarization heterogeneity.

• KE3 → KE4 (TdP → Ventricular Fibrillation):

  • Sustained TdP degenerates into ventricular fibrillation, leading to hemodynamic collapse.

• KE4 → AO (Ventricular Fibrillation → Cardiomyopathy):

  • Recurrent or sustained VF episodes result in myocardial damage and structural remodeling, culminating in cardiomyopathy.

The evidence assessment for this AOP demonstrates strong biological plausibility and empirical support for the progression from LTCC dysfunction to cardiomyopathy via QT prolongation and TdP. Quantitative understanding of the dose-response and temporal relationships supports its predictive value in regulatory toxicology and risk assessment. Addressing identified evidence gaps will further enhance the robustness and applicability of this AOP.

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