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Related Concept Videos

Mechanism of Cardiac Arrhythmias01:28

Mechanism of Cardiac Arrhythmias

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Arrhythmias are irregular heart rhythms occurring when the heart's electrical impulses become abnormal. These disturbances can lead to various symptoms, depending on their severity and the underlying cause. Some common factors contributing to arrhythmias include hypoxia, ischemia, electrolyte imbalances, excessive catecholamine exposure, drug toxicity, and muscle overstretching. Arrhythmias can be classified into two main types based on the rate and site of origin of abnormal heart rhythms.
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Antiarrhythmic Drugs: Class I Agents as Sodium Channel Blockers01:22

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Class I antiarrhythmic drugs are used to treat various types of arrhythmias or irregular heart rhythms. These drugs block the sodium (Na+) channels in the cardiac cells, thereby affecting the movement of electrical impulses across the heart. Class I antiarrhythmic drugs are divided into three subgroups: Class IA, Class IB, and Class IC, each with distinct mechanisms of action and effects on the heart.
Class 1A Antiarrhythmic Drugs: These drugs work by moderately blocking sodium channels,...
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Related Experiment Video

Updated: Sep 10, 2025

Measurement of Heart Contractility in Isolated Adult Human Primary Cardiomyocytes
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Nonclinical Human Cardiac New Approach Methodologies (NAMs) Predict Vanoxerine-Induced Proarrhythmic Potential.

M Iveth Garcia1, Bhavya Bhardwaj1, Keri Dame1

  • 1Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.

Journal of Cardiovascular Development and Disease
|August 27, 2025
PubMed
Summary
This summary is machine-generated.

New approach methodologies (NAMs) accurately predicted vanoxerine

Keywords:
calcium handlingcardiomyocytescomplex in vitro modelcontractilityelectrophysiologyhiPSC-CMmicrophysiological systems (MPSs)new approach methodologies (NAMs)nonclinical study

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Area of Science:

  • Cardiovascular toxicology
  • In vitro pharmacology
  • Stem cell biology

Background:

  • Vanoxerine caused cardiac events in clinical trials, but not in earlier nonclinical studies.
  • New approach methodologies (NAMs) offer advanced in vitro models for drug safety assessment.
  • Cardiac microphysiological systems (MPSs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide human-relevant data.

Purpose of the Study:

  • To evaluate vanoxerine's cardiac effects using human cardiac NAMs.
  • To assess the predictive capacity of cardiac NAMs for clinical outcomes.
  • To investigate vanoxerine-induced changes in cardiac excitation-contraction coupling.

Main Methods:

  • Utilized a cardiac MPS with hiPSC-CMs to measure voltage, calcium handling, and contractility.
  • Employed the hiPSC-CM comprehensive in vitro proarrhythmia assay (CiPA) using multielectrode arrays (MEAs).
  • Assessed vanoxerine's concentration-dependent effects on cardiac function and repolarization.

Main Results:

  • Vanoxerine delayed repolarization and induced proarrhythmic events in both NAM platforms.
  • Cardiac MPS showed frequency-dependent effects, with EADs eliminated at 1.5 Hz pacing.
  • Exposure analysis indicated significant vanoxerine loss in the cardiac MPS.
  • TdP risk analysis suggested high to intermediate risk at clinical concentrations.

Conclusions:

  • Cardiac NAMs successfully recapitulated clinical outcomes for vanoxerine.
  • These models detected vanoxerine-induced delayed repolarization and proarrhythmia.
  • This study supports NAMs for evaluating drug safety and reducing animal testing.