Understanding the changes in ryanodine receptor organisation and calcium handling following myocardial infarction

Abstract

Ischaemic heart disease (IHD) is a leading cause of mortality worldwide. MI is associated with complications such as ventricular arrhythmias (VAs) and contractile dysfunction which have also been observed in HF and attributed to altered intracellular calcium (Ca2+) handling. Within the myocyte, the excitation-contraction (EC) coupling process facilitates the rise and fall of Ca2+ with resultant cardiac contraction and relaxation and relies on key structures such as the ryanodine receptor (RyR) and thus, ultrastructural alterations can affect Ca2+ handling. Whilst these changes have been extensively studied in HF, there is limited information on Ca2+ handling and RyR organizational changes following MI. This study has developed a large mammal MI model to elucidate the temporal evolution of Ca2+ handling and RyR organizational changes following MI, with a focus on the MI border zone (BZ) to determine the association with arrhythmogenesis and contractile dysfunction. A large mammal MI model was established demonstrating the typical ST-T segment electrocardiographic changes with VAs observed on MI induction along with the rise and fall of serum troponin levels and an established infarct on cardiac extraction. Following MI, contractile and electrical remodelling changes were observed during the acute, latent and chronic phases, with some contractile dysfunction present at 8 weeks (chronic phase). Compared to control, spontaneous Ca2+ sparks were increased in amplitude and size in 8 week MI BZ cells, with an increased incidence of potentially arrhythmogenic Ca2+ waves at all time points following MI. In contrast to HF, the Ca2+ transient amplitude, rate of decay and synchronicity of Ca2+ rise were unaltered in this model, potentially explaining the modest degree of LV dysfunction seen. At 8 weeks, there was increased RyR inter-cluster distances with a greater number of clusters separated by more than 1 µm and an increased number of single receptor clusters. Additionally, cluster size variation was also increased at 8 weeks. Taken together, this suggests cluster fragmentation and dispersion with increased cluster size heterogeneity which has been associated with altered Ca2+ handling and increased propensity for Ca2+ waves. In conclusion, a large mammal MI model has been established demonstrating changes in Ca2+ handling and RyR organization potentially explaining the increased arrhythmogenicity following MI. This model has the potential to be a highly translatable model of IHD which may allow the discovery of novel therapeutic targets.

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andy Trafford (Supervisor), Katharine Dibb (Supervisor) & Christian Pinali (Supervisor)