New Promise for Treating Cardiac Arrhythmias

Ruxolitinib, a drug that is already approved by the U.S. Food and Drug Administration (FDA) for treating certain cancers and skin conditions, is effective at inhibiting CaMKII, a protein kinase linked to cardiac arrhythmias.

In a new study published June 21, 2023, in Science Translational Medicine, researchers from Johns Hopkins University and the University of Chicago invented a new reporting technique to monitor activity of CaMKII while screening the effects of nearly 5,000 FDA approved drugs on human cells that expressed the enzyme. The screen identified five previously unknown CaMKII inhibitors; ruxolitinib, which is used to treat cancers of the blood and bone marrow, along with skin conditions like atopic dermatitis and vitiligo, was the most effective.

CaMKII, or Calcium and calmodulin-dependent protein kinase II, is critical to cardiomyocytes, the muscle cells of the heart, where it maintains the balance of calcium. Activation of CaMKII helps facilitate rapid changes in heart activity, such as initiating a fight-or-flight response in the body. Overactivation can lead to impaired heart function and cell death, which can in turn lead to poor heart health outcomes like arrhythmia.

CaMKII is perhaps best known, however, for its role in the brain, where it is believed to play key roles in learning and memory. This has slowed the development of CaMKII inhibitors to treat arrythmia, for fear they could impact cognitive function.

Oscar Reyes Gaido, the study’s first author and an MD-PhD student in the lab, developed a new tool to measure activity of CaMKII in living cells. 

Using this tool, the researchers conducted a drug repurposing screen to test the effects of 4,475 approved compounds on cultured human cardiomyocytes. This identified five previously unknown CaMKII inhibitors: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib. Of the five, ruxolitinib was the most effective at inhibiting CaMKII activity in cell and mouse models of CaMKII-driven arrhythmias. A 10-minute application of the drug was enough to prevent catecholaminergic polymorphic ventricular tachycardia (CPVT), a congenital source of pediatric cardiac arrest, and rescue atrial fibrillation, the most common clinical arrhythmia. Crucially, the mice treated with ruxolitinib did not show any adverse cognitive effects when they were tested with memory and learning tasks.

“There’s been a long search for fundamental pathways that could be targets for therapeutics in arrhythmias,” Anderson said. “This could be a finding that will translate relatively rapidly into people now since it’s already been proven to be safe in humans.”

Sources:

Oscar E. Reyes Gaido, Nikoleta Pavlaki, Jonathan M. Granger, Olurotimi O. Mesubi, Bian Liu, Brian L. Lin, Alan Long, David Walker, Joshua Mayourian, Kate L. Schole, Chantelle E. Terrillion, Lubika J. Nkashama, Mohit M. Hulsurkar, Lauren E. Dorn, Kimberly M. Ferrero, Richard L. Huganir, Frank U. Müller, Xander H. T. Wehrens, Jun O. Liu, Elizabeth D. Luczak, Vassilios J. Bezzerides, Mark E. Anderson. An improved reporter identifies ruxolitinib as a potent and cardioprotective CaMKII inhibitor. Science Translational Medicine, 2023; 15 (701) DOI: 10.1126/scitranslmed.abq7839 

University of Chicago. (2023, June 22). Repurposed drug shows promise for treating cardiac arrhythmias. ScienceDaily. Retrieved June 26, 2023 from www.sciencedaily.com/releases/2023/06/230622182828.htm

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