Atrial fibrillation (AF)

is the most common arrhythmia and has considerable impact on public health, yet is poorly understood. Present therapy is inadequate and new mechanistic insights are needed to develop more effective and safe therapeutic approaches.

Traditionally, AF has been attributed to multiple re-entry circuits due to conduction and refractoriness abnormalities. Recent work, however, points to the importance of focal mechanisms and a crucial role of Ca²⁺-handling impairments. The present application addresses the hypothesis that Ca²⁺-handling abnormalities underlie the development and progression of AF. Recent evidence suggests that maladaptive changes in Ca²⁺-handling precede, promote and sustain AF. Accordingly, identification and characterisation of the culprit atrial Ca²⁺-handling abnormalities will lead to novel mechanistically-based therapeutic targets. We have assembled a group of world-leading laboratories with complementary high-level expertise over all levels from gene through patient in AF pathophysiology, arrhythmia genetics, fundamental cellular and sub-cellular Ca²⁺-handling and cardiac remodeling, in a co-ordinated effort to elucidate the role of Ca²⁺-handling dysfunction in AF.

Background, Specific Aims, and Research Plan

Electrical and structural remodeling have emerged as key elements in AF-substrate development. However, there are crucial intermediate, presently-unidentified factors in AF perpetuation. Growing evidence from genetic, cell-biology and molecular-pathophysiology studies points to abnormalities in intracellular Ca²⁺-handling as a missing link in AF-initiating focal activity and in perpetuation by both rapidly-discharging foci and re-entrant mechanisms.

Despite this extensive evidence for Ca²⁺ as a key mediator in AF-pathophysiology, the Ca²⁺-related abnormalities that lead to the occurrence and maintenance of AF are poorly understood. We will significantly advance knowledge in this important but underdeveloped field.