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Current Research

Our Mission

The mission of the Akar Electro-Biology and Arrhythmia Therapeutics Laboratory at Yale University is to advance our understanding of the basic biology of sudden cardiac death with a view towards identifying novel targets for treatment of acquired and congenital arrhythmic disorders. We seek mechanism-based molecular therapies for electrical diseases that are not amenable for treatment by conventional anti-arrhythmic approaches. We are actively pursuing studies on the pathophysiology of complex arrhythmias that arise in the following settings:

  • Hypertrophy and heart failure
  • Myocardial Infarction and ischemia-reperfusion injury
  • Obesity and diabetes mellitus
  • Atrial fibrillation
  • Pulmonary hypertension
  • Arrhythmogenic cardiomyopathy and other Inherited Arrhythmia Syndromes
The laboratory’s experimental pipeline consists of studies along the full translational scale from identifying novel targets through their validation in proof-of-concept studies and ultimately their advanced testing in pre-clinical large animal models. Ongoing studies in the lab include:
  • Target identification: These studies focus on identifying novel targets that control excitability and arrhythmias in the heart. For these, we use a combination of in vitro approaches, including heterologous cell lines, human inducible pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), tissue engineered constructs and genetic mouse models (cardiac-restricted conditional knockdown and overexpression).
  • Target validation: These proof-of-concept studies rely on the use of cardiotropic gene delivery to uncover the electro-mechanical and structural effects of manipulating the expression of a given molecular target in rodent animal models.
  • Pre-clinical testing: These studies are designed to explore the efficacy of a given therapeutic strategy in either preventing or reversing arrhythmic risk in porcine models of cardiac disease using approaches that are readily translatable to humans.

Cognizant of lessons learned from the CAST and SWORD trials, we guide our work by the over-arching principal that effective and safe management of rhythm disorders requires interfering with the upstream root causes of the disease rather than the down-stream end-effectors of excitability (or the ion channels themselves). In that regard, we are interested in pursuing studies that elucidate fundamental mechanisms by which ion channel function is regulated by:
  • Metabolic signaling and mitochondrial bioenergetics
  • Mechano-transduction and mechano-electrical feedback
  • Biochemical cues

Current Projects

Arrhythmia mechanisms in hypertrophy and heart failure

A long-standing interest in the lab is the unraveling of mechanisms of sudden cardiac death in various etiologies of heart failure. We demonstrated the role of repolarization heterogeneity and conduction abnormalities in promoting arrhythmias across the failing heart. Our work highlighted the importance of gap junction remodeling including altered phosphorylation of Cx43 in the conduction defects that we uncovered in small and large animals of ischemic and non-ischemic heart failure. We also identified the time-course of electrophysiological changes during the early stages of hypertrophy. We studied the mechanisms by which mechanical dyssynchrony and cardiac resynchronization therapy regulate electrophysiological function at the cellular and tissue levels. We are developing myocardial gene therapy approaches to prevent adverse post-myocardial infarction remodeling.

Post-ischemic Arrhythmias

A major focus of my lab has been on the identification of mechanisms by which mitochondrial bioenergetics control electrical function. We were among the first groups to highlight the central role of mitochondria in the regulation of excitability and arrhythmias through a mechanism termed ‘metabolic sink’. We further identified novel strategies for treating post-ischemic arrhythmias by targeting key mitochondrial ion channels.

Arrhythmia Mechanisms in Obesity and Diabetes Mellitus

We have been pursuing studies to elucidate the mechanisms that underlie electrical dysfunction in the setting of diabetes mellitus. We are working towards identifying which mitochondrial pathways are protective and which are defective in diabetes.
We are also testing novel approaches for arrhythmia suppression in the diabetic heart by targeting the mitochondrial translocator protein which controls the regenerative process of ROS-induced ROS-release as well as mitochondrial network dynamics through fission/fusion events.

Inherited Arrhythmia Syndromes

Our work is focused on elucidating the mechanisms by which spatio-temporal repolarization gradients form arrhythmogenic substrates in the structurally normal heart. We were the first to define the functional topography of M-cells and establish their role in promoting transmural dispersion of repolarization and arrhythmias in acquired forms of the Long QT Syndrome. We are also pursuing studies aimed at uncovering the role of understudied molecular targets and pathways that control electro-mechanical function in the structurally normal heart in order to develop next generation therapeutics for inherited arrhythmias.

Pulmonary Hypertension

We are pursuing studies aimed at elucidating arrhythmia mechanisms in the context of right ventricular hypertrophy and failure secondary to pulmonary hypertension. In collaborative studies we are also pursuing novel therapeutic approaches to ameliorate those arrhythmias.