Cardiac Arrhythmia

The general focus of Dr. Jalife's laboratory is the understanding of the cellular and molecular mechanisms of arrhythmias and sudden cardiac death (SCD).

The objective is to understand the emerging role of macromolecular ion channel complexes in the mechanisms of SCD in inherited diseases. Our recent identification of the interaction of the main sodium channel in the ventricles (NaV1.5) with the rectifying potassium channel (Kir2.1) in the control of cardiac excitability offers an exceptional opportunity to define the molecular basis of SCD. Evidence indicates that NaV1.5 and Kir2.1 form "channelosomes" and that they physically interact with partner proteins (adapters, scaffolds, and enzymes that regulate the function of electrical currents). Both channels have direct links to inherited diseases known as “channelopathies”. The Andersen-Tawil Syndrome (ATS), also known as Long QT Syndrome type 7, is mediated by loss-of-function mutations in the gene KCNJ2 that encodes the inward rectifier potassium channel Kir2.1. Gain-of-function mutations in the same gene cause Short QT Syndrome type 3 (SQTS3). Loss-of-function defects in SCN5A, the gene that encodes the main cardiac sodium channel NaV1.5, give rise to Brugada Syndrome (BrS). On the other hand, defects in the dystrophin gene that result in Duchenne Muscular Dystrophy (DMD) lead to dysfunction of both Kir2.1 and NaV1.5, leading to arrhythmias and SCD, which further highlights the relevance of the interaction of ion channels with other multiple proteins in the mechanisms of  heart diseases.

Unraveling the molecular mechanisms of different arrhythmogenic syndromes produced by mutations in the same ion channel gene

Our approach is multidisciplinary, it includes the use of transgenic mouse models generated by adeno-associated virus (AAV) mediated gene transfer, as well as the use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) made from somatic cells (epithelial fibroblasts) of patients carrying a given mutation or normal hiPSC-CMs modified by CRISPR/Cas9 genomic editing. We can implement this technology thanks to established collaborations with three different hospitals in Spain, Virgen de las Nieves Hospital in Granada, La Fe Hospital in Valencia and Central University Hospital of Asturias in Oviedo. We use a wide variety of mutually complementary technologies to understand the electrophysiological mechanisms underlying the inheritable disease under study, including electrocardiogram (ECG), intracardiac stimulation, patch-clamping, optical mapping, RNAseq, Western blotting, proteomics and immunocytochemistry. Our studies are complemented with computational modeling of ion channel structure, channel-ligand interactions, and more recently antiarrhythmic drug design in parallel with experimentation in human and animal models. Altogether, our studies are expected to yield essential information that should improve antiarrhythmic therapy toward prevention of SCD in patients suffering from inheritable cardiac diseases.