Cardiac calcium buffering in health and disease

Abstract

Calcium fluxes in the heart have been extensively studied in both health and disease, yet calcium buffering, which plays a crucial role in regulating intracellular free calcium, remains underexplored. This thesis investigates the modulation of calcium buffering under physiological conditions, such as β-adrenergic stimulation, as well as in the disease states of heart failure (HF) and atrial fibrillation (AF). In healthy cardiac myocytes, calcium buffering adapts efficiently to maintain contractility during increased heart rates and β-adrenergic stimulation. This study demonstrates that in healthy hearts, β-adrenergic stimulation enhances calcium buffering facilitating efficient calcium cycling. In HF, calcium-binding affinity increases (reflected by a reduced Kd), while maximal binding capacity (Bmax) decreases, impairing contractility and increasing arrhythmogenic risk. PDE5 inhibition with tadalafil was found to partially restore calcium buffering. Whilst Bmax remains reduced, this restoration stabilises calcium transients despite an observed reduction in sarcoplasmic reticulum (SR) calcium content. This suggests a potential anti-arrhythmic mechanism of PDE5 inhibition while preserving the calcium transient amplitude. In AF, characterised by uncoordinated atrial electrical activity, calcium buffering is similarly disrupted, with increased calcium sensitivity contributing to a higher arrhythmia risk. This thesis highlights calcium buffering as a crucial factor in AF pathophysiology and a potential therapeutic target. Modulating calcium buffering may help reduce the arrhythmic burden in AF. Furthermore, the development of a novel echocardiographic protocol specifically designed to provide more comprehensive cardiovascular assessment in sheep, can be applied to study a variety of cardiac conditions with greater translatability to human physiology. In conclusion, this thesis demonstrates the critical role of calcium buffering in both health and disease and identifies calcium buffering as a promising therapeutic target for improving cardiac function in HF and arrhythmias.

Date of Award	29 Jan 2025
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andy Trafford (Main Supervisor), David Eisner (Co Supervisor) & Katharine Dibb (Co Supervisor)