Dr. El Refaey’s research focuses on cardiovascular physiology and molecular mechanisms underlying heart rhythm regulation. Her research pursues new strategies to target arrhythmogenesis, specifically new roles, and mechanisms underlying ion channel-membrane protein regulation in heart rhythm, ultimately leading to new diagnostics and novel therapies for human arrhythmias. Her team utilizes a combination of molecular, biochemical, imaging, and surgical approaches to study the mechanisms of arrhythmias.
Project 1: Determining Novel Regulatory Molecules to Target Ventricular Arrhythmias
Sudden cardiac death and arrhythmias account for ~15-20% of all deaths worldwide. Voltage-gated sodium channels (Nav) in the heart are major regulators of myocyte excitability and cardiac function. The Nav channel current (INa) is a large amplitude and short duration inward current that is regulated by rapid channel activation and immediate inactivation. However, a small late component of this current (INa,L) is present at baseline but increases in response to heightened adrenergic challenge and has been correlated with fatal forms of congenital and acquired arrhythmia. Most work on Nav1.5 has focused on molecular pathways for positive regulation of INa,L. However, less is known about the pathways for negative regulation. These pathways are critical and can be targeted to alter the pathogenic INa,L in potentially fatal forms of arrhythmia.
For this project, we have generated novel tools including mouse models and pharmacological agents to identify the impact of PP2A-B56α on cardiac action potential and arrhythmias in vivo. Combining molecular, biochemical, pharmacological, patch clamping, and Ca2+ imaging approaches, this project will generate critical information and clinically relevant data for INa,L regulation, and arrhythmias.
Project 2: Defining Molecular Pathways and Establishing Novel Therapeutic Interventions to Manage Atrial Fibrillation
Atrial fibrillation (AF) is the most prevalent sustained clinical arrhythmia and is associated with morbidity and mortality. It increases the risk of heart failure, myocardial infarction, chronic kidney disease, stroke, and death. Many factors including limited efficacy and the risk of side effects have diminished AF drug development. Previous reports showed aberrant IK,ACh function in atria from patients with persistent AF. In addition, human variants in KCNJ5 have been identified and correlated to AF. There is particular interest in the K+ channels such as the muscarinic potassium channels (K,ACh), formed of G-protein-gated inwardly rectifying potassium subunits (GIRK1 and GIRK4) and predominantly expressed in the atria to avoid ventricular pro-arrhythmic side effects.
Our approach combines computational, biochemical, pharmacological, imaging, electrophysiological, molecular, and in vivo animal studies. This project has an impact on the understanding of the molecular structure of the IK,ACh, the molecular basis of constitutively active IK,ACh channels. It will allow the development of atrial-selective and pathology-specific therapies for the management of AF.