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Cardiac Origin of Rhythm DISturbances: 3-Dimensional structural investigations

Final Report Summary - CORDIS3D (Cardiac Origin of Rhythm DISturbances: 3-Dimensional structural investigations)

Myocardial structure is important in the triggering and maintenance of many cardiac arrhythmias including atrial and ventricular fibrillation. Detailed knowledge of myocardial structure is essential to the understanding of these disorders and in the development of diagnostic and therapeutic strategies. This must include the normal and pathological distribution of key functional proteins such as connexins. There are a variety of structural imaging methodologies which can be used to study normal and pathological hearts: high spatial resolution MRI and CT, Diffusion Tensor MRI, three-dimensional volume histology from sections or from tissue block imaging. Furthermore, histological imaging can determine molecular distributions after labelling, which may be by immunohistochemistry, viral transfection or transgenics. In this exchange partnership we bring together four leading centres with unique and complementary expertise in order to systematically study the structural substrate of propagation and arrhythmia in the normal and failing heart and in heart failure. Research topics studied are the role of Purkinje Fibres in ventricular fibrillation, pulmonary venous cuff re-entry in atrial fibrillation, the role of structural changes in myocardial infarction in ventricular fibrillation and right ventricular outflow tract ventricular tachycardia. The overall hypothesis is that a leading contributor to cardiac re-entrant arrhythmias in disease is a change in the local structural properties of the myocardial substrate that together with other factors such as tissue electrophysiology and cardiac metabolism provide the required substrate.

Tissues studied include hearts from relevant animal disease models and post-mortem/operative human tissues. Disease models studied include small and large animal (rat, sheep & pig) models of infarction and right heart failure. Rat models have the advantage that the small cardiac size allows high spatial resolution imaging to be carried out of the whole cardiac volume, while the large animal models offer closer to man structure and electrophysiology. Structural imaging is accompanied by 3D-electrophysiological recording and computational modelling to enable investigation of the structure-function relationship.

The scientific project has achieved almost all its initial objectives. We have developed and validated novel non-destructive high-resolution imaging techniques of the cardiac microstructure based on MRI and microCT approaches, and linked those electrical conduction in the heart and to a potential role in arrhythmogenesis. This has allowed us to establish detailed anatomical models of the healthy and structurally normal rat atrial and ventricular tissues, including the pulmonary veins and Purkinje fibre network respectively. A rat model of right ventricular heart failure has also been investigated using these approaches to assess the degree of structural remodelling and its impact on arrhythmogenesis. Large animal models (including pig and sheep) have also been investigated using these imaging approaches and have allowed for translation of novel therapeutic and interventional techniques to be validated in vivo prior to translation to the clinic. The structural imaging has been supplemented with comprehensive electrical mapping data allowing detailed investigation of the structure-function relationship. We have used the experimental data to build large-scale computational models that are currently being validated and further developed to investigate the mechanisms of atrial and ventricular arrhythmias. The work performed in this project has also led to new scientific avenues, including the potential role of cardiac metabolism in fibro-fatty structural tissue remodeling, and the use of novel imaging tools such as superresolution microscopy and light-sheet imaging techniques.

The CORDIS3D network has enabled a more rigorous and fruitful investigation of the link between cardiac structure and cardiac arrhythmia than would be possible by each of the centres acting alone. The partnership has brought four centres with a strong track record in mechanistic investigations of arrhythmia into a synergistic network with multiple complementarities. The outcomes are a better understanding of the role of structure in lethal cardiac arrhythmias to develop novel therapeutic strategies, and a significant contribution to enhancing existing collaboration between the partners and building these into a complimentary multilateral collaboration network tackling an important health issue.