Infraestructura de Medicina de Precisión asociada a la Ciencia y la Tecnología
Atrial fibrillation (AF) is one of the most prevalent cardiac pathologies, associated with a high risk of morbidity and mortality, with the consequent social and healthcare expenditure derived from clinical complications (dementia, stroke and heart failure (HF)) and the costs of its treatment. Its progression from paroxysmal to persistent forms is associated with a greater increase in morbidity and mortality. Genetic and cardiovascular concomitants (among them obesity) determine the underlying substrate that favors its onset and perpetuation. The lesion substrate is myocardial interstitial fibrosis (MIF), which is associated with progression and reduced effectiveness of ablation therapy. In this regard, members of this working group have described 1) The association between epicardial fat and its progression to fibrosis; 2) The presence of a complex MIF biochemical profile, an indicator of excessive collagen fiber deposition; and 3) That the completion time of electrical atrial remodeling can be estimated individually by analyzing changes in atrial activation frequency. However, the genetic factors underlying these processes are unknown. With this background, the primary objectives of this study are: 1) validation of AF risk markers in patients with HF (in those with subcutaneous Holter monitoring or pacing devices); 2) validation of markers predicting AF progression toward persistent forms; and finally, 3) validation of markers of response to AF ablation therapy.
The results of this study may provide clinically relevant information on the pathophysiology of AF that improves its diagnosis and treatment monitoring, contributing to stratifying the risk of adverse clinical evolution to implement preventive therapeutic strategies.
Main Objective: To identify the presence of clinical, imaging, biochemical and genetic markers (including PRSs) that allow for AF risk stratification in patients with HF with monitoring devices (subcutaneous Holter (WP1-A1) and pacemakers/defibrillators (WP1.A2).
Secondary objectives:
The clinical impact of this proposal is considerable, as it provides a better understanding of the underlying pathophysiological processes of AF, as well as new indicators that help stratify patients with HF according to the type of underlying atrial cardiomyopathy. It will allow for early and specific diagnosis of the AF mechanism, followed by the development of targeted treatments. The inclusion of disease risk prediction models will allow for estimates based on individual characteristics, including genetic, environmental, and clinical components, to provide a score for a given risk of developing AF.
Work Package 1 (WP1A1 and A2) will determine the exact burden of AF in patients with HF, identify risk predictors for its development, and analyze event-related relevance. It will also help determine differences in events between HF patients with device-based devices (A.2) and those without device-based devices (A.1).
The WP1.A3 package (since these will be patients with AF, the estimated time for AF progression is shorter) will allow us to determine the mechanisms that lead to AF progression, from self-limited (paroxysmal) to persistent forms, with the resulting atrial and ventricular remodeling (we could also analyze data from patients belonging to WP1 A1 and WP1 A2 who have presented AF). This question is as crucial, if not more so, than determining which patients will develop AF, since its progression is relevant for events (stroke, HF decompensation, and death). To date, we do not know the time required for AF progression or the mechanisms that lead to it. Animal models developed at the CNIC (Dr. David Filgueiras) will be translated into clinical practice. Furthermore, all the factors involved (genetic, environmental, clinical) will be comprehensively addressed in each specific individual, based on the analysis of blood samples, imaging, epicardial fat activity, and dominant frequencies. For the first time, different lines of research initiated by the coordinating centers (IDIS/CHUS – epicardial fat and genomics, CNIC – dominant frequencies, and FIMA/CUN – collagen metabolism) could be combined in a single study. This is therefore the most ambitious project undertaken in the field of heart failure and AF to date.
Furthermore, despite the vast amount of knowledge generated in recent years in the field of AF, the current approach ignores its etiology and focuses on generalized treatment of rate or rhythm control (antiarrhythmic drugs or ablation), based solely on the impact of symptoms on quality of life and the degree of cardiac impairment. Only atrial size and the time of arrhythmia progression are available as markers of ablation technique failure. The WP2 work package (B1 and B2) aims to identify new circulating biomarkers with the goal of generating a diagnostic and predictive panel applicable on an individualized basis to clinical decision-making regarding optimal treatment (rhythm vs. rate control).
It represents an approach to personalized medicine in the field of the most prevalent and impactful arrhythmia. Therefore, we believe the results obtained in this study may mark a turning point in the approach to AF, improving individualized clinical care.