Fadi Gabriel Akar, PhD

1. The mission of the Akar Cardiac Bioelectricity Research laboratory at the Yale School of Medicine is to uncover the mechanisms underlying sudden cardiac death across a variety of clinically relevant structural heart diseases. We use integrative tools that allow us to undertake a systems biology approach to the investigation of arrhythmia mechanisms and to test novel treatment strategies. Specific areas of active research include mechanisms of mechano-electrical feedback, the interaction of myocardial bioenergetics and electrical function in post-ischemic remodeling and reperfusion related arrhythmias, and the role of altered gene expression and targeted gene delivery on ion channel function and arrhythmogenesis in cardiovascular diseases. Our long-term research goals are to: 1) elucidate mechanistic links between altered metabolic, mechanical, electrical, and structural properties that promote disease progression and regression, and 2) identify novel targets for treating electrical dysfunction. We specialize in the study of arrhythmia mechanisms at multiple levels of integration. A major focus of our work is the use of novel gene therapy approaches targeting metabolic pathways or calcium cycling proteins for combating arrhythmias caused by ischemia/reperfusion injury and heart failure.

The mission of the Akar Basic and Translational Arrhythmia Research 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

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