Sex-specific responses to drug therapy in atrial fibrillation: Mechanisms, efficacy, and personalised treatment

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major contributor to stroke and heart failure. Despite its prevalence, current pharmacological therapies remain only moderately effective and are associated with significant side effects. Notably, male and female patients exhibit distinct responses to anti-arrhythmic drugs, yet most current treatments do not account for these sex-based differences.

This PhD project aims to investigate the mechanistic basis of sex-specific responses to drug therapy in AF, with a focus on calcium (Ca²⁺) handling, electrical remodelling, and structural differences in atrial tissue. Using a robust rabbit model of AF induced by rapid atrial pacing, we will evaluate how male and female hearts respond differently to anti-fibrotic and Ca²⁺-modulating drugs, such as pirfenidone and RyR2-targeting agents.

The project will combine in vivo and ex vivo drug testing, optical mapping of electrical activity, and confocal/super-resolution imaging to assess how pharmacological interventions influence atrial electrical properties and subcellular Ca²⁺ dynamics in a sex-specific manner. Structural remodelling—particularly changes in atrial tubular networks and expression of key ion channels and calcium-handling proteins—will be examined in detail.

This research will advance our understanding of how biological sex influences drug efficacy and mechanism of action in AF and will contribute to the development of more effective, personalised, and equitable treatment strategies for both men and women.

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