Ageing and dysfunction of the heart

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.

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:

• Al Benson, University of Leeds
• Matthew Lancaster, University of Leeds
• Jurgen Schneider and Irvin Teh from the ePIC facility , University of Leeds
• Izzy Jayasinghe, University of Sheffield
• Blanca Rodriguez, University of Oxford
• Esther Pueyo, University of Zaragoza
• Yohannes Shiferaw, California State University, Northridge

This project has only recently started; key results, models and data will be posted here.