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Evangelia Kranias, PhD, is shown in the UC College of Medicine.

Evangelia Kranias, PhD, is shown in the UC College of Medicine.

Evangelia Kranias, PhD, is shown in her laboratory at the UC College of Medicine.
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Publish Date: 07/18/18
Media Contact: Cedric Ricks, 513-558-4657
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Kranias Laboratory Leads Efforts to Tackle Sudden Cardiac Death

CINCINNATI—A University of Cincinnati (UC) College of Medicine researcher will lead an American network of researchers in a $6 million international study of a heart gene’s role in a genetic disorder that often leads to sudden cardiac death. 

Evangelia Kranias, PhD, professor in the UC Department of Pharmacology and Systems Physiology, will serve as the U.S. coordinator while Pieter Doevendans, MD, PhD, of the Netherlands Heart Institute will coordinate the network in the European Union. Kranias will work with researchers at Stanford University and the Icahn School of Medicine at Mount Sinai, along with European scientists at the Netherlands Heart Institute in Utrecht, the Biomedical Research Foundation of the Academy of Athens in Greece and University Medical Center in Goettingen, Germany. 

Other participating investigators from the College of Medicine working with Kranias on this project include Sakthivel Sadayappan, PhD, professor, and Deeptankar DeMazumder, MD, PhD, assistant professor, both in the UC Division of Cardiovascular Health and Disease.

The five-year project is funded by the Paris-based Fondation Leducq, which supports international efforts to research cardiovascular and neurovascular diseases through its Transatlantic Networks of Excellence Program. Each of the six institutions involved will share equally in the $6 million grant.

This project will investigate the role heart gene phospholamban (PLN) plays in the genetic heart disorder arrhythmogenic cardiomyopathy (ACM). The study titled, Cure Phospholanan-induced Cardiomyopathy (Cure-PLaN), will begin Jan. 1, 2019. 

"This consortium of scientists is really amazing because it brings expertise from different labs and countries together to address the disease problem,” says Kranias, a member of the UC Heart, Lung and Vascular Institute. "Everybody has complementary expertise. We are all working together under one umbrella.”

The pathogenesis of arrhythmogenic cardiomyopathy is largely unknown and the diagnosis remains challenging, but it is a leading cause of sudden cardiac death in young individuals, often related to exercise and adrenergic stimulation, says Kranias, who also holds the Hanna Chair of Cardiology at UC.

Sudden cardiac arrest (SCA) is a condition in which the heart suddenly stops beating due to a malfunction in the heart’s electrical system. The malfunction that causes SCA is a life-threatening abnormal rhythm. Sudden cardiac arrest can strike anyone without warning and is unpredictable leading to the loss of pulse, unconsciousness and the ability to breathe.

Kranias provided the first evidence that phospholamban plays an important role in regulating the heart’s ability to contract and pump blood. She identified the mutation of phospholamban—PLN R14del—in 2006 in Greece. Kranias says that recent evidence suggests that this mutation plays a central role in mediating ACM and its progression. Her laboratory uses knock-in animal models with humanized phospholamban and its mutation to further our understanding of ACM.

The phospholamban genetic mutation has also been found in populations in the Netherlands, Germany, Spain, the United States, Norway and Denmark, says Kranias.

"During this project, the research team will try to understand what goes wrong in the hearts of some human carriers with the phospholamban mutation causing them to develop heart disease while others do not,” says Kranias.

A better understanding of the factors influencing clinical variability will help for risk-stratification to select mutation carriers that need more careful follow up, but also for personalized evaluation and therapy, explains Kranias. Patient studies will be complemented by laboratory studies to examine the molecular and cellular mechanisms underlying the pathogenesis of the clinical phenotype. The team will use a shared platform of patient data coupled with lab experiments and animal models. These will include patient-specific induced pluripotent stem cell derived cardiomyocytes, human engineered cardiac tissues and animal models. 

The models are both mice and pigs with knock-in of human normal or mutant phospholamban (humanized animal models). This will enable the team to design novel therapeutic strategies for treating ACM, says Kranias. 

"The research is driven by a strong interaction between human carriers, patient representatives and established researchers, focusing on the unmet medical need to combat PLN-disease and potentially ACM in general,” says Kranias.

She says that patients impacted by the phospholamban mutation have formed the PLN Foundation: A Foundation of Patients for Patients to further research to develop preventive strategies and treatment therapies. 

"I have worked all my life on phospholamban and have really defined the function of this genes in the heart,” says Kranias. "Now I am able to see all my work moving from bench to bedside where we can apply all the knowledge from four decades of research to develop therapy for these patients.

"What an amazing thing for a scientist to see all their work coming to fruition in their career,” says Kranias. "Everything you have been building on from a basic science standpoint will be used in personalized evaluation and therapy.”

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