In a report in the journal Nature, an international consortium of researchers that includes Case Western Reserve University School of Medicine in Cleveland and Baylor College of Medicine explains the molecular linkage between the circadian clock and the deadly heart rhythms that lead to sudden death.
The answer begins with a controller of the circadian clock – krüppel-like factor 15 (Klf15), which has been a long-time target of the laboratory of Dr. Mukesh Jain of Case Western, said Dr. Xander Wehrens, professor of molecular physiology and biophysics and cardiology at BCM, also an author. (Jain is corresponding author of the report.)
Klf15, in turn, controls the level of a potassium channel-interacting protein (KChIP2), which affects how potassium flows out of heart muscle cells called cardiac myocytes.
Changes affect potassium current
Because the level of this KChIP2 protein fluctuates during the circadian or daily cycle, it can change the size of the potassium current in cardiac myocytes. Changes in this subunit or Klf15 can affect the potassium current that governs repolarization of the cardiac myocyte. Overall, this can shorten or lengthen the time the heart muscle has to empty the heart’s pumping chamber (ventricle) of blood. This time interval for repolarization is critical. Too much or too little can result in abnormal heart rhythms called arrhythmias. As the heart loses the regularity of the beat, it cannot pump blood efficiently.
Studies of mice that lacked Klf15 and mice with a genetic change that caused them to make more Klf15 than normal increased the risk of deadly arrhythmias.
This was a proof of principle, said Wehrens.
“It is the first example of a molecular mechanism for the circadian change in susceptibility to cardiac arrhythmias,” he said.
“If there was too much Klf15 or none, the mice were at risk for developing the arrhythmias,” he said.
Long QT or Short QT
Because Klf15 is regulated by the circadian “clock,” the rate of flow through the potassium channel goes up and down and if disrupted, can lead to a change that results in one of two known heart problems linked to sudden death – long QT or short QT syndrome. (QT refers to an interval measured from an electrocardiogram or ECG, which corresponds to the electrical recovery time of heart.)
Wehrens credits Jain’s laboratory with accomplishing much of the work. His laboratory performed the electrophysiology experiments with the mice that lacked Klf15 and those who produced too much, he said.
Much of the BCM work was done by Dr. Mark McCauley, a cardiology fellow who was a post-doctoral fellow in the laboratory at the time, said Wehrens.
Others who took part in this work include first author Darwin Jeyaraj, Saptarsi Haldar, Xiapoing Wan, Yuan Lu, Betty Eapen, Nikunj Sharma, Eckhard Ficker, Michael Cutler, and David Rosenbaum, all of Case Western; Jurgen A. Ripperger and Urs Albrecht of University of Fribourg in Switzerland; Kun Hu and Steven A. Shea of Brigham and Women’s Hospital and Harvard Medical School in Boston; James Gulick, Atusushi Sanbe, and Jeffrey Robbins of Cincinnati Children’s Hospital Medical Center; Sophie Demolombe of Universite de Nice Sophia Antipolis in Valbonne, France; and Roman Kondratov of Cleveland State University in Ohio.
Funding for this work came from the National Institutes of Health, the Heart Rhythm Society, the American Heart Association, the Swiss National Science Foundation, the Centre National de la Recherche Scientifique, and the Leducq Foundation.