Advanced Development in Arrhythmia Mechanisms and Therapy

The Advanced Development in Arrhythmia Mechanisms and Therapy (ADAM-T) laboratory focuses on investigating from a multidisciplinary approach, the mechanisms underlying cardiac arrhythmias that occur in highly prevalent cardiovascular diseases in the general population, as well as in specific subsets at particular risk of sudden cardiac death.

The group of scientists and their collaborators have the primary goal of providing rigorous and detailed understanding of different factors, either at the molecular and cellular level or at the macroscopic and structural level, which are involved in the dynamic behavior of the electrical cardiac activity and may lead to cardiac arrhythmias. Such an endeavor is accomplished by facilitating fluent collaborations between departments, research institutions and universities, and different professional profiles from students to physicians. All together make it possible to establish solid basis for identifying populations at risk of cardiac arrhythmias, as well as for studying and applying new therapies that aim at controlling and eliminating such a risk. All laboratory members work as a multidisciplinary team to achieve translational impact in all the projects that are currently on going. The laboratory has demonstrated significant contributions in the field of cardiac electrophysiology during the last 8 years. A significant number of publications support the advances in the understanding of complex cardiac arrhythmias, mapping strategies and sudden cardiac death.

Since 2016, the ADAM-T laboratory has been continuously funded by the Instituto de Salud Carlos III (ISCIII) (https://eng.isciii.es/eng.isciii.es/InformacionCiudadanos/DivulgacionCulturaCientifica/DivulgacionISCIII/Paginas/Divulgacion/Que-es-el-ISCIII.html). First, we studied complex wave propagation dynamics during atrial fibrillation in a novel translational pig model of persistent and long-standing persistent atrial fibrillation. The model does not develop heart failure as many commonly reported animal models of atrial fibrillation, which need to be stopped after 1-2 months of follow up because of severe heart failure. This first project reported novel and clinically relevant findings on single-signal detection of rotational-footprints and leading-driver regions to identify atrial areas associated with long-term atrial fibrillation maintenance (see Figure 1 below). The results showed that the combination of frequency and amplitude modulations (iFM and iAM, respectively) of electrical or optical signals enabled us to identify specific atrial areas as targets for atrial fibrillation ablation in both the pig model and in patients with persistent atrial fibrillation. This highly innovative approach has been developed using a complete translational strategy from 2D computational simulations and optical mapping imaging in isolated hearts, to in vivo studies in pigs and further demonstration of its clinical impact in patients with persistent atrial fibrillation. This approach also enables cardiac electrophysiologists to identify patients in whom catheter ablation of limited extension is unlikely to provide any benefit.

 

Amplitude modulation (AM) / frequency modulation n (FM) concept

Figure 1. A and B: Amplitude modulation (AM) / frequency modulation (FM) concept. A, AM and FM in radio broadcasting. B, Left, during cardiac fibrillation, scroll wave/rotor drifting gives rise to AM and FM. When a drifting scroll wave filament/rotor core approaches the square, the amplitude of the action potential decreases increasing instantaneous AM (iAM; in red). Simultaneously, as the wave-emitting source (scroll wave filament/rotor core) approaches, the perceived instantaneous FM (iFM; in blue) at the spot increases (Doppler Effect). Therefore, simultaneous iAM/iFM increase indicates drifting scroll waves/rotors in the surroundings. Additionally, the areas with the highest average iFM are those potentially driving fibrillation in a hierarchical fashion. Right, average iFM is estimated from its median and mean values (8 Hz both) and with the conventional dominant frequency (DF) spectral approach (5.6 Hz). Interestingly, the time intervals with the highest iFM usually show the lowest amplitudes and vice versa, which conditions the height of their corresponding power spectral peaks and limits the value of DF-based hierarchical approaches. Full paper here.

The intellectual property developed in CNIC (related to this project) to efficiently identify and target atrial fibrillation drivers during persistent atrial fibrillation is under further clinical assessment in the ongoing TAILOR-AF study (NCT05169320) conducted at the Hospital Clínico San Carlos (official partner of the patent PCT/EP2019/077610). The main objective of this study is to identify (via iAM/iFM maps), target and ablate atrial fibrillation leading drivers in patients with symptomatic persistent atrial fibrillation recurrences despite ≥2 previous pulmonary vein isolation procedures. The methods include a percutaneous catheter mapping and ablation approach followed by a minimally invasive surgical approach via thoracoscopy, if necessary. As a secondary objective we will study the association of underlying blood biomarkers, atrial imaging and surface ECG parameters, with advanced remodeling stages requiring a surgical approach to target leading driver regions. This study illustrates the strong motivation of the laboratory to achieve clinical impact with the research activities performed in animal models.

Successful rhythm control in patients with atrial fibrillation is highly dependent on the underlying atrial remodeling stage for each patient. Such remodeling includes structural, electrical and mechanical changes that make the arrhythmia persistent in the long term. Interestingly, these remodeling changes follow patient-specific patterns that cannot be fully characterize with regular clinical tools. Recently, we have used remote monitoring technology to improve remodeling progression characterization in individual patients. More specifically, standard data transmission technology installed in current implantable devices such as pacemakers can be used to monitor cardiac electrical activity during episodes of atrial fibrillation, thus establishing disease status and the rate of progression. Results from a multicenter study in collaboration with 51 centers in Spain have shown that cardiac electrical signals from patients fitted with pacemakers or implantable cardioverter–defibrillators can be used to monitor and predict the progression of the arrhythmia in a personalized and specific manner. Figure 2 below shows a schematic view of the study methodology and representative results. Full paper here.

Study methodology and medical application of the new technology

Figure 2. Study methodology and medical application of the new technology.

Interestingly, we have documented that our pig animal model of persistent atrial fibrillation also follows individual-specific patterns which are strikingly similar to the remodeling patterns observed in patients. These results motivated a second funded project by the ISCIII, which is currently ongoing since 2020 to study the molecular bases of individual-specific progression and maintenance of atrial fibrillation. The main objective of this second project is to prospectively study the predictive value of early serum and imaging biomarkers in animal- and patient-specific remodeling patterns during atrial fibrillation progression. We also aim to determine the underlying molecular, functional and structural properties of leading driver areas that sustain the overall arrhythmia in our translational pig model of long-standing persistent atrial fibrillation.

The highly translational value of the pig model, and current gaps in knowledge to characterize atrial remodeling progression and atrial myopathy using novel biomarkers, led to further funding from the European Commission, under the H2020 programme and the Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation (MAESTRIA) consortium. The MAESTRIA project team focuses on developing novel approaches for timely detection of atrial myopathy to improve care management and identifying novel therapeutic targets for personalized medicine of atrial fibrillation and stroke.

Atrial remodeling also involves other parameters like structural and mechanical changes as atrial fibrillation evolves. We have recently signed a Master Research Agreement between the CNIC (ADAM-T laboratory) and Philips Ibérica to use non-invasive transthoracic echocardiography as a tool to simultaneously assess electrical and mechanical remodeling during atrial fibrillation. Specifically, we used the capability of tissue Doppler imaging to quantify the mechanical behavior of different regions of the free wall of both atria during atrial fibrillation. Such mechanical data in combination with simultaneous surface ECG data provide information about electrical and mechanical remodeling progression during atrial fibrillation. Although the research activities are currently ongoing, this new approach provides information about two important parameters during atrial fibrillation remodeling (electrical and mechanical activity) that might have a significant impact in clinical outcomes.

Overall, atrial fibrillation has been one of the main research areas of interest, in which all lab members and collaborators have significantly contributed to provide new insights into the mechanisms underlying atrial fibrillation and new therapeutic strategies to prevent and terminate this arrhythmia. Cardiac fibrillation, and more specifically atrial fibrillation is a complex phenomenon that requires software and imaging tools to understand the dynamics and wave-propagation patterns that can be targeted to terminate the arrhythmia. A simplified schema of the complexity of atrial fibrillation dynamics is shown in Figure 3 below. More information can be found in Jorge G. Quintanilla et al. Cardiovasc. Res. 2021;117:1662-1681.

Figure 3. Schematic of structurally and electrically remodeled atria, where several reported patterns might coexist. However, atrial fibrillation may still be driven in a hierarchical fashion by specific regions with higher than surrounding activation rate (leading drivers). Such regions would host reentrant drivers in many cases, albeit not all reentrant activity would act as a driver, since rotors are commonly found in passive bystander regions.

Figure 3. Schematic of structurally and electrically remodeled atria, where several reported patterns might coexist. However, atrial fibrillation may still be driven in a hierarchical fashion by specific regions with higher than surrounding activation rate (leading drivers). Such regions would host reentrant drivers in many cases, albeit not all reentrant activity would act as a driver, since rotors are commonly found in passive bystander regions.

Unlike unipolar or bipolar electrical recordings, optical mapping recordings provide action potential data, which potentially should improve the accuracy of our novel methodology to identify specific atrial regions driving the atrial fibrillation maintenance. In fact, at the experimental level optical mapping approaches are the most widely-used tools for studying fibrillation and drug-action at high spatiotemporal resolution in isolated-heart preparations. Such ex vivo preparations permit the use of interventions (e.g., the use of motion uncouplers) that greatly improve fluorescence signal acquisition but are not viable in vivo. New methods for in vivo studies have the potential to generate a tremendous impact in the understanding of complex cardiac arrhythmia in the clinic. We recently developed an experimental method that utilizes near-infrared voltage-sensitive dyes (di-4-ANBDQBS / di-4-ANEQ(F)PTEA) optimized for imaging blood-perfused tissue. A representative movie with dye injection and loading via percutaneous catheterization of the left descending coronary artery in vivo is shown below.

A representative movie with dye injection and loading using percutaneous catheterization of the left descending coronary artery in vivo

The excitation-ratiometric properties of di-4-ANBDQBS and di-4-ANEQ(F)PTEA ex vivo demonstrated that ratiometry permits the recording of action potentials with minimal motion artifacts in the contracting heart. In vivo application of excitation-ratiometric properties and high-performance optical technology in the translational pig model enabled high-resolution imaging of action potentials and wave propagation dynamics during both ventricular fibrillation (motion minimal) and electrical pacing (motion substantial). Extensive toxicity studies showed that coronary dye injection did not generate systemic nor cardiac damage, although di-4-ANBDQBS injection induced transient hypotension, which was not observed with di-4-ANEQ(F)PTEA. Full paper here. The data show the potential of achieving cardiac optical mapping in clinical cardiac electrophysiology. We are currently developing this technology to achieve in vivo optical mapping from the endocardial surface of cardiac chambers using minimally invasive catheter technology. The latter will represent a significant breakthrough in the field of cardiac electrophysiology, since optical action potentials provide the highest standards of tissue and cellular electrophysiology, potentially moving the field to a new era of high-performance mapping in the clinic.

Animal models and research areas are complemented with research activities in the clinic. The laboratory is also carrying out other two clinical trials related to atrial fibrillation (https://clinicaltrials.gov/ct2/show/NCT03005366?term=Filgueiras-Rama&rank=2) and ventricular fibrillation (https://clinicaltrials.gov/ct2/show/NCT03248557?term=Filgueiras-Rama&rank=1). The laboratory also works on big data analysis from a multicenter registry of cardiac implantable devices to identify electrical parameters associated with ventricular arrhythmic events in patients with implantable cardioverter defibrillator. This project has been approved by the UMBRELLA scientific committee, which represents a multicenter Spanish observational registry (https://clinicaltrials.gov/ct2/show/NCT01561144?term=UMBRELLA&rank=3), ensuring the legal, normative, and scientific data exploitation.