Remodelling of structure-function relationships underlying cardiac dysfunction in ageing: A multi-scale systems approach

BACKGROUND

The healthcare challenges of ageing populations are a major concern of the 21st century. Dysfunction of the heart has been implicated as a causative factor which both limits quality of life and increases the risk of sudden death; 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 models or in healthy volunteers; ageing-associated remodelling may have a substantial impact on both the safety and efficacy of various pharmacological compounds not currently revealed by existing studies.

AIMS

My 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.

RESEARCH PROJECT

I will develop a novel computational modelling framework which will be combined with state-of-the-art experimental approaches. This integrative, multi-disciplinary approach will quantify and characterise the remodelled structures from the sub-cellular to whole-heart scales, and provide novel mechanistic analysis which links structural and functional data and ultimately explains emergent dysfunction. Animal model experiments will be performed to provide detailed, controllable and comprehensive data; this will be supplemented by human data collected as part of project collaborators' independent research, in order to provide the translational relevance.

Wet-lab imaging experiments, quantifying cellular and tissue structures in young and aged rats, will be undertaken by a post-doctoral research assistant; these data will inform image-based simulations which will predict how these structures affect mechanical and electrical function at the cellular and tissue scales.

I will develop novel computational modelling methods to allow simultaneous study of structures from the nanometre to whole-heart scales. These methods will be applied to provide the systems-level perspective on cardiac dysfunction in ageing, revealing the relative importance and contributions of multiple remodelled structures and, importantly, their interaction.

Finally, the computational models will be combined with previously developed models of multiple common anti-arrhythmic agents in order to assess the interaction of ageing-associated remodelled structures and pharmacological intervention, and how this affects both the safety and efficacy of these treatment options.

IMPORTANCE

The insight gained from my project will give a much better understanding of the mechanisms of cardiac dysfunction in ageing, and reveal the link between ageing and cardiovascular disease. Importantly, this insight will be from cell-to-organ and on fundamental mechanisms - by revealing the most relevant and modifiable components of this dysfunction, these insights will help identify the optimum targets for successful management of dysfunction, as well as identify potential diagnostic biomarkers which may be indicative of the transition from healthy state to cardiovascular disease. This knowledge will underpin future research into pharmacology and diagnostics which will significantly improve the management of cardiovascular disease in the aged.

The primary goals of my project are to: (1) Quantify ageing-associated remodelling of sub-cellular calcium-handling structures, and the extent to which it underlies cellular pro-arrhythmia and the loss of excitation-contraction-coupling; (2) quantify tissue remodelling at the local (mm) and global (cm) scales, and elucidate how these features interact with cellular remodelling to ultimately determine dysfunction; (3) assess the impacts of these remodelling components on the safety and efficacy of pharmacological modulation.
These research goals will be addressed through the development of a joint simulation-experimental approach to compare structure and function between young and aged ventricular myocytes and myocardium.

Super-resolution microscopy will be used to reconstruct intracellular structure, pertaining to ion channel distribution and membrane structure; histology, optical mapping and MRI will characterise tissue remodelling, pertaining to myocyte arrangement and electrical coupling, fibrosis, chamber size, wall thickness, myocyte orientation organisation; image-based biophysically detailed computational models of cardiac cells and tissues will be used to relate these structures to emergent function.

Novel computational modelling approaches will be developed to enable true simultaneous mechanistic analysis of the interactions of structural remodelling across all of the relevant scales and provide the systems-interaction perspective of global function.

The computational models will then be integrated with an in silico pharmacology testing platform to determine the interactions of ageing-associated remodelling with pharmacological intervention.

Experimental animals will be randomly assigned to one of three groups: young and two time-points of aged; image-based modelling will be performed directly using reconstructions and in the wider space; all computer model code and structural data will be made freely available open-source.