Our laboratory investigates the cellular and molecular mechanisms of arrhythmias with the objective to generate novel treatments that can prevent sudden cardiac death (SCD), which is a major public health problem. SCD accounts for almost 20% of total mortality in Europe, and the majority of individuals who experience a sudden cardiac arrest will not survive.¹ SCD in the young remains a particularly daunting problem. While relatively uncommon, SCD in a previously healthy child or young adult is always a tragedy that may have a devastating impact on the families and the community.² Yet the mechanisms are unknown, and the only effective treatment is the urgent application of an electric shock. Genetic (inheritable) cardiac disorders comprise a substantial proportion of SCD cases aged £40 years. These include primary arrhythmogenic disorders, known as ion channel diseases (also known as channelopathies) such as Andersen-Tawil syndrome type 1 (ATS1), catecholaminergic polymorphic ventricular tachycardia (CPVT) and Brugada Syndrome (BrS); as well as inherited cardiomyopathies, such as hypertrophic cardiomyopathy and Duchene’s muscular Dystrophy (DMD), both of which can lead to arrhythmias and SCD by mechanisms yet unknown.^3-5 Traditionally, ion channel diseases have been treated as “monogenic” based on the assumption that there is a direct relationship between the ion channel mutation and the disease phenotype. However, ion channels do not function in isolation, but are part of large, multi-protein complexes, comprising not only their auxiliary subunits, but also components of the cytoskeleton, regulatory kinases and phosphatases, trafficking proteins, extracellular matrix proteins, and even other ion channels.

We are exploring the pivotal role of macromolecular ion channel complexes in the pathogenesis of sudden cardiac death (SCD) across both inherited and acquired cardiac diseases. We have uncovered that cardiac excitability is intricately regulated by interactions between NaV1.5—the primary sodium channel in ventricular myocytes—and Kir2.1, a key inward rectifier potassium channel. These channels form macromolecular assemblies known as channelosomes, which closely interact with various partner proteins, including adapters, scaffolds, and enzymes, to modulate electrical signaling in the heart. Both NaV1.5 and Kir2.1 are directly involved in arrhythmogenic conditions, such as channelopathies and cardiomyopathies. For example, loss-of-function mutations in KCNJ2 (encoding Kir2.1) cause Andersen-Tawil syndrome type 1 (ATS1), also known as long QT syndrome type 7, while gain-of-function mutations in the same gene cause short QT syndrome type 3 (SQTS3). Similarly, loss-of-function mutations in SCN5A (encoding NaV1.5) lead to Brugada syndrome (BrS). Furthermore, mutations in the dystrophin gene associated with Duchenne muscular dystrophy (DMD) disrupt both Kir2.1 and NaV1.5, resulting in arrhythmias and increasing the risk of SCD. The altered channel interactions observed in DMD highlight the fundamental significance of ion channel complexes and their associated proteins in cardiac disease mechanisms. Such findings suggest that disruptions in NaV1.5-Kir2.1 channelosomes, whether due to inherited mutations or acquired disease processes, underpin the development of arrhythmogenic disorders like ATS1 and DMD, both of which can precipitate SCD. Consequently, we propose the Kir2.1-NaV1.5 channelosome as a promising therapeutic target for innovative interventions to restore cardiac excitability and reduce the incidence of life-threatening arrhythmias in patients with cardiovascular disease.

Our multidisciplinary strategy integrates transgenic mouse models produced via adeno-associated virus (AAV)–mediated gene delivery with complementary investigations using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). These hiPSC-CMs are generated either from patient-derived somatic cells (such as epithelial fibroblasts) carrying disease-specific mutations or from wild-type hiPSC-CMs subsequently engineered through CRISPR/Cas9 genome editing. The implementation of hiPSC-CM–based studies is supported by collaborations with three Spanish hospitals: Virgen de las Nieves Hospital (Granada), La Fe Hospital (Valencia), and Central University Hospital of Asturias (Oviedo).The broad set of complementary techniques we use to investigate the electrophysiological mechanisms of inheritable arrhythmias includes electrocardiography (ECG), intracardiac stimulation, patch-clamping, optical mapping, RNA sequencing, western blotting, proteomics, and immunocytochemistry.

We also use AI based computer modeling of ion channel structure and channel–ligand interactions. We design and characterize novel antiarrhythmic drugs in parallel with experimental testing in human and animal models. We expect our studies to yield important information with potential to improve antiarrhythmic therapy and help prevent SCD in patients suffering from inheritable and other cardiac diseases.