Sex Differences in Drug-Induced Arrhythmogenesis

Area of Science:

• Cardiovascular Physiology
• Pharmacology
• Computational Biology

Background:

• Heart electrical activity exhibits significant sex-specific variations, leading to differential drug responses.
• Women are over twice as likely as men to experience potentially fatal drug-induced arrhythmias, yet underlying mechanisms are poorly understood.

Purpose of the Study:

• To investigate the mechanistic origins of sex-specific drug-induced cardiac arrhythmia using multiscale modeling and machine learning.
• To identify critical drug concentrations and key ion channels contributing to arrhythmogenesis in male versus female hearts.

Main Methods:

• Integration of multiscale cardiac modeling with machine learning algorithms.
• Development and training of a sex-specific multi-fidelity arrhythmogenic risk classifier.
• Quantification of ion channel activity, tissue conductivity, and cardiac dimensions.

Main Results:

• Sex differences in ion channel function, tissue conductivity, and heart dimensions contribute to longer QT-intervals in women.
• The critical concentration of dofetilide, a high-risk drug, is found to be seven times lower in women compared to men.
• Identified key ion channels responsible for sex-specific arrhythmogenesis.

Conclusions:

• Sex must be considered an independent biological variable in drug development and risk assessment.
• Understanding sex differences in drug safety is crucial for personalized medicine and developing safer therapeutics.
• Findings have broad implications for the development of new drugs and the safe prescription of existing medications.