Trigger and substratE Mechanisms of Pulmonary vein ectOpy – TEMPO

Atrial fibrillation (AF) is the most common sustained arrhythmia. In France alone, AF affects 750000 people. AF results in a fivefold increase in the risk of stroke, and a threefold increase in the risk of heart failure with an increased hospitalization and mortality risk than otherwise. AF thus represents a major health problem and a significant burden on the healthcare system.
AF is mainly triggered by ectopic activity from the pulmonary veins (PV). This landmark discovery, made by members of the current project, led to a curative treatment based on radiofrequency (RF) ablation of the PVs, currently recommended by HRS/EHRA/ECAS and with over 200000 patients treated worldwide using this technique in 2010. However, the precise mechanisms underlying PV ectopy remain poorly understood and current treatment is indiscriminately applied to all PVs, irrespective of whether they show ectopic activity or not.
Several mechanisms, including automaticity, aftedepolarizations, and re-entry, have been proposed to underlie PV ectopic activity. These can occur under various stimuli including stretch and adrenergic stimulation. However, previous studies have used different species to investigate different mechanisms under different experimental conditions, which makes it difficult to extrapolate these results to the patient. Furthermore, the complex myofiber organization in the PVs, i.e. the structural substrate, is likely to play a significant role in arrhythmogenesis, yet it remains relatively unexplored. Finally, the lack of experimental or clinical data on human PVs represents a major challenge to our understanding of PV ectopy and AF initiation.
The main objective of the TEMPO research project is to gain a better understanding in the trigger and substrate mechanisms underlying PV ectopy and the onset of paroxysmal AF. Specifically, this project will consist of 4 workpackages that will aim at: (i) a comprehensive molecular, cellular and clinical characterization of PV electrophysiology with a special emphasis on afterdepolarizations as a mechanism of ectopy; (ii) determining the effects of stretch on PV ectopy from the molecular level to the clinical situation; (iii) investigating the effects of increased adrenergic and vagal stimulation upon PVs from the single cell to the patient; and (iv) reconstructing the complex myofiber architecture of the PVs, before and after ablation, and investigate its role on AF initiation.
In order to achieve these objectives, the TEMPO research project will be carried out as a collaborative effort between national (Bordeaux, Tours) and international (Ann Arbor, Leeds) academic partners spanning a wide range of expertise from molecular and cellular electrophysiology, optical mapping, to clinical imaging and electrophysiology; and four industrial partners, allowing to take full advantage of their clinical intracardiac mapping and navigation systems (St Jude Medical, Biosense Webster) and the development of novel technologies such as specially designed monophasic action potential catheters (Medtronic) and non-invasive electrocardiographic mapping (CardioInsight) that will allow to identify the culprit PV and greatly reduce procedure time and complications.
Major strengths of the TEMPO project will be: (i) the integrative approach from molecule to in vivo in a single large mammalian species (sheep) relevant to human electrophysiology; (ii) the combined experimental and clinical methodology allowing for direct translation of research result to the clinic; and (iii) the availability of a limited number of explanted human hearts (with approval from the bioethical agency “France-Transplant”) that will provide the ideal experimental testing ground.
In conclusion, TEMPO is an ambitious and innovative research project that will result in a better understanding of PV ectopy and an improved treatment of AF.