Unique non-invasive pace-mapping system to identify subjects at risk of arrhythmic sudden death

Project Information

HELP

Grant agreement ID: 101054717

DOI

10.3030/101054717

EC signature date 9 September 2022

Start date 1 September 2022

End date 31 August 2027

Funded under

• European Research Council (ERC)

Total cost

€ 2 488 400,00

EU contribution

€ 2 488 400,00

Coordinated by

UNIVERSITE DE BORDEAUX
France

Periodic Reporting for period 1 - HELP (Unique non-invasive pace-mapping system to identify subjects at risk of arrhythmic sudden death)

Reporting period: 2022-09-01 to 2025-02-28

Summary of the context and overall objectives of the project

Sudden Sudden cardiac death (SCD) is a common cause of adult mortality in western countries, accounting in Europe for about 350 000 cases annually. Most SCDs are caused by ventricular arrhythmias generated from an arrhythmogenic ‘substrate’ present within the heart. Paradoxically, despite the existence of efficient preventive therapies, the sole available predictor of SCD is a measure of cardiac contractility, an indirect metric, which applies only to a subset of patients. At present, most patients at risk cannot be identified pre-emptively to prevent sudden death.

The main objective of the HELP project is to develop a novel non-invasive body-surface mapping and pacing system, which will allow detection of cardiac signals related directly to the substrate responsible for lethal arrhythmias, for efficient SCD prediction. The unique approach proposed to achieve this objective will consist in: (1) combining electrocardiographic mapping and ultrasonic pacing technologies during cardiac signal acquisition from a high-density array of body surface electrodes; (2) characterizing micro-scale temporal, spectral and spatial features of substrate signals, at baseline and during pacing to unmask hidden signals; (3) establishing critical signal features specific of arrhythmogenic substrates using multi-parametric signal analysis on the body surface, based on unique electrophysiological data from explanted human hearts and from SCD survivors; (4) developing risk prediction scores from well-phenotyped groups of patients monitored by implanted devices.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have performed an experimental study aiming at characterizing the specific electrical signatures of localized heterogeneities and their role in arrhythmogenesis. For this, local repolarization, conduction and microstructural heterogeneities were created in ex vivo right ventricles. We found that microstructural substrates have the most pronounced impact on electrograms, especially when combined with sodium channel blockers, whereas local action potential duration (APD) shortening does not lead to electrogram fragmentation even though it is associated with the highest prevalence of spontaneous arrhythmias. We subsequently performed a dedicated study on the spontaneous arrhythmias occurring in the latter model (APD heterogeneity). Sixteen ventricular fibrillation (VF) initiations were optically mapped and showed triggers originating in all cases from the border zone between altered and normal repolarization areas. Importantly, our study in a model of localized repolarization heterogeneity demonstrates that VF triggers originate consistently from the border zone of the repolarization dispersion.

We have been able to produce computer models of hearts with small structural anomalies which can sustain re-entries. Using tools developed in our group, we could remove a portion of a coarse heart mesh, place the re-entrant structure within it, and then remesh the space in between the two. The heart was then paced as in sinus rhythm and body surface potentials calculated along with electrograms as recorded from clinical omnipole catheters. We also investigated the morphology of electrograms near the entrance sites of structural abnormalities which create channels. Using a simple sheet model, we compared our results with clinical electrograms recorded near the entrance of re-entrant channel. We were able to reproduce and explain the intaQRS activation alternans behaviour seen in the clinical recordings, relating it to the specific tissue conditions needed.

Building upon the challenges of accurately localizing ECG electrodes in clinical environments, two AI- and camera-based methods for automating electrode localization in body surface potential maps (BSPMs) were developed, eliminating the need for MRI or CT scans. These approaches provide safer alternatives to traditional imaging techniques, making advanced ECG mapping more practical in clinical environments.

Based on our prior work on noninvasive stimulation, we have developed a dedicated system for intercostal sonication, which has been validated in a series of pre-clinical studies. We showed that with such a transducer, intercostal sonication could be carried out without significant losses when the intercostal distance was 1 cm or more, which is within the range of values observed in vivo in man. This was quantified using dedicated MRI methods developed in the laboratory.

We conducted a clinical study to evaluate the characteristics of recurrent VF recorded on implantable defibrillator electrograms, associated with idiopathic VF. We found three variables to be the most discriminant of the underlying mechanisms: Sinus tachycardia was more frequent in microstructural substrates, whereas short-coupled triggers were most frequent in Purkinje-related VF, which also had shorter VF cycle lengths. The multivariable combination provided the highest prediction, discriminating 81% of VF substrates with a high probability (>80%). Interestingly, ectopy were inconsistently present before VF. Characteristics of arrhythmia recurrences on implantable cardioverter-defibrillators can thus provide phenotypic markers of the distinct and hidden substrates underlying IVF.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

An important breakthrough has been the validation of the hypothesis that triggers and substrates of VF are often co-localized. Indeed, we showed in a model of localized repolarization heterogeneities that spontaneous triggers of VF occurred at the border zone between the normal and abnormal repolarization regions. Targeted treatment of these areas can thus be effective in eliminating both the initiating mechanisms and the substrates maintaining the arrhythmias.

An unexpected, but significant breakthrough has been the discovery that recordings from implantable cardioverter-defibrillators contain important information on the mechanisms underlying VF and can provide, with high accuracy, improved phenotyping of patients. This is especially relevant in idiopathic VF populations, where this information can have major implications in terms of curative treatment options and help advance genetic screening.