Ageing and dysfunction of the heart

Summary

The healthcare challenges of ageing populations are a major concern of the 21st century. At substantial socio-economic costs, ageing limits quality of life and is associated with significantly higher risk of sudden death. Dysfunction of the heart has been implicated as a major driving factor for both of these considerations; cardiac-ageing is associated with mechanical dysfunction, which limits daily activities, and increased vulnerability to arrhythmia, which can be immediately life-threatening.

The function of the heart is determined by the interplay of cellular and tissue structures from the smallest (billionth of a metre) to the largest (whole-heart) scales; remodelling of (i.e. adaptations to) these cellular and tissue structures observed in ageing is a critical factor which underlies ageing-associated dysfunction and resulting cardiovascular disease. Moreover, whereas prescription rates in the aged are substantially higher than the general population, safety and efficacy testing is typically performed on young animal, clinical and/or in-silico models; ageing-associated remodelling may have a substantial impact on both the safety and efficacy of various pharmacological compounds.

This project aims to provide systems-level understanding of the structural remodelling from the sub-cellular to whole-organ scales which occurs with ageing, the mechanisms by which it underlies cardiac dysfunction, and how this modulates the impact of pharmacological intervention. This will be achieved through systems approach, utilising multiple experimental techniques integrated directly with computational modelling to explore ageing-related remodelling from the nanodomain to whole-heart scales.



Project overview

Title: Remodelling of structure-function relationships underlying cardiac dysfunction in ageing: A multi-scale, systems approach
Source: MRC Career Development Award
Total value: £1,504,340.00
Tenure: October 2021 - September 2026

Description: This project brings together many of the different areas of research in our group. It will use a combination of simulations and experiments to characterise the nature of ageing-associated remodelling of the structures of cardiac cells and tissues, and mechanistically link these remodelled structures to emergent dysfunction.

Structural remodelling and ageing


Cardiac-ageing is associated with mechanical dysfunction, which reduces the heart’s pumping efficiency and limits daily activities, and an increased vulnerability to arrhythmia, which can be immediately life-threatening. For example, the incidence of ventricular ectopic excitation, which can act as a trigger for fatal arrhythmia events, is 17-fold higher in men aged over 60 than those aged 20-40. Remodelling of the structure-function relationships in cardiac cells and tissues can explain both this mechanical and electrical dysfunction.

A major challenge in dissecting the mechanisms of this dysfunction is that ageing is associated with remodelling of structure-function relationships across multiple spatial scales - from the sub-cellular nanodomain right up to the whole-heart. It is ultimately the multi-scale interaction of these remodelled structure-function relationships which causes dysfunction.

Approaches and collaborators


This project will use a combination of experimental and simulation approaches to acheive its aims; experiments will characterise structural remodelling at multiple scales, and simulations will provide the mechanistic link between structure and function at each scale individually as well as between scales.

Experiments include super-resolution microscopy, patch-clamp, optical mapping and MRI. Computational models include spatial models at each scale as well as new approaches to integrated between the scales.

I am delighted to have onboard many local, national and international collaborators to support in the delivery of this project:

Results and data

Sub-cellular structure and calcium dynamics

The heart must beat continuously throughout our lives to pump blood around the body. Each heartbeat is controlled by the movement of calcium within heart muscle cells. Calcium acts as a signal telling the cells when to contract and relax. As we age, the heart undergoes structural changes that can reduce its ability to function effectively and increase the risk of abnormal heart rhythms. Changes in the way heart cells store, organise and release calcium may contribute to these age-related problems, but how these changes develop is not fully understood.

In this study, we investigated how ageing affects the structures responsible for calcium release within heart muscle cells, and how these changes influence functional calcium release. We studied heart cells from male rats aged 6, 18 and 24 months. We measured individual calcium release events in the cells, both under normal conditions and following stimulation with isoprenaline, a drug which increases heart activity. Using advanced microscopy techniques, we then examined the organisation of the ryanodine receptor, a protein responsible for calcium release.

We found that ageing changed how heart cells responded to increased stimulation. In older cells, stimulation produced larger and wider calcium release events, indicating that the way calcium is handled becomes altered with age. We also found that ageing altered the structural organisation of the calcium release channel. In older animals, the ryanodine receptor was more fragmented, less densely organised and more disordered. Interestingly, these changes were most pronounced in the 18-month group, suggesting that remodelling may not occur in a simple, gradual pattern with age. Instead, ageing may increase the variation in how local calcium-release structures are organised, with some cells retaining a relatively healthy structure while others become increasingly disrupted.

Together, these findings show that within the heart, ageing changes both the way calcium is released and the organisation of calcium-release structures. These changes may contribute to reduced heart function and the increased risk of abnormal heart rhythms that occur with ageing.

Data availability
Imaging data and our custom tools for image analysis can be found on the Zenodo page

Related publications

[40] Hurley ME, Conesa D, Benson AP Colman MA (2026). Sedentary ageing remodels the structure–function relationships that underlie calcium signalling at super-resolution scales in the heart. The Journal of Physiology; DOI: 10.1113/JP290679 The Joutnal of Physiology (in press)