The general focus of the Jalife lab is the understanding of the cellular and molecular mechanisms of arrhythmias and sudden cardiac death.
During the last 30 years the Jalife lab has been at the forefront in the study of the mechanisms underlying cardiac fibrillation. We developed novel technological approaches and algorithms, including phase mapping and dominant frequency mapping that enabled investigators to quantify the complex spatiotemporal patterns of atrial and ventricular fibrillation. Using a potentiometric dye and video imaging to record the dynamics of transmembrane potentials at many sites during fibrillation we demonstrated that transmembrane signals at each site exhibit a strong periodic component. This periodicity is seen as an attractor in two-dimensional-phase space and each site can be represented by its phase around the attractor. Spatial phase maps at each instant reveal the 'sources' of fibrillation in the form of topological defects, or phase singularities that rotate at very high speeds. Using our method of identifying phase singularities, we elucidated the mechanisms for the formation and termination of these singularities called “rotors. Altogether our results published in multiple journals indicate an unprecedented amount of temporal and spatial organization during cardiac fibrillation. Emerging evidence clearly supports a major role for rotors as the drivers of cardiac fibrillation both in animal models and humans.
Sudden cardiac death (SCD) in the young is a relatively rare but tragic event whose pathophysiology is poorly understood. A specific goal of the lab is to understand the emerging role of macromolecular ion channel complexes in the mechanisms of SCD in heritable diseases of young individuals. Our recent identification of the interplay of the main cardiac Na+ channel (NaV1.5) and a strong inward rectifier K+ channel (Kir2.1) in the control of cardiac excitability offers an exceptional opportunity to define the molecular bases of SCD. Evidence indicates that these two vastly different ion channels form “channelosomes” and physically interact with common partners that include adapter, scaffolding and regulatory proteins. Both channels have direct links with human disease. Trafficking deficient mutations in the gene encoding Kir2.1 (KCNJ2) yield the Andersen-Tawil syndrome (long-QT syndrome type 7); trafficking deficient mutations in the gene coding NaV1.5 (SCN5A) result in Brugada syndrome. Further, defects in the dystrophin gene (DMD) lead to cardiac ion channel dysfunction and SCD, which further highlights the relevance of macromolecular ion channel interplay in cardiac diseases. We have demonstrated that NaV1.5 and Kir2.1 regulate each other’s expression via PDZ-mediated binding to either SAP97 or the dystrophin protein complex member a-syntrophin, both of which help to stabilize both channels at the cell membrane. Using mutant channels that disrupt Golgi trafficking of Kir2.1 or NaV1.5 we have recently made the exciting discovery that NaV1.5 and Kir2.1 may travel together to their eventual membrane micro-domains. We will use adeno-associated virus–mediated gene transfer in mice, proteomics, and CRISPR/Cas9 gene editing in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to define for the first time the mechanistic framework for NaV1.5-Kir2.1 interactions in the heart in-vivo, and how dysregulation of the channelosome results in arrhythmias and SCD.