The Funny Thing About Ivabradine and Heart Failure

The report earlier this week by cardiologists of results from the SHIFT trial, a major advance in treating heart failure by slowing patients’ hearts with the drug ivabradine, came complete with a funny, fascinating footnote. 

The footnote literally is funny, a myocardial mechanism know as the “funny” current and written as “If”–f as in funny–that supplies the “I” in the trial name SHIFT and also provides the physiologic sweet spot where ivabradine works its therapeutic magic. 

image courtesy Flickr user The Capt'n

The funny current is an ever-recurring movement of sodium and potassium ions across membranes in the sinus node of a beating heart, the trigger for each heartbeat, the heart’s spontaneous pacemaker, which means the lifespan of each funny current is less than a second. Chemists formulated ivabradine as a highly specific and selective inhibitor of the funny current, an action that slows the heart beat without any other clinical effect. This produced ivabradine’s impressive reduction in heart failure deaths and hospitalizations in the SHIFT results, reported August 29 at the annual congress of the European Cardiology Society in Stockholm. 

The story of how the funny current got found and named comes from the source, Dario DiFrancesco, Ph.D., professor of physiology and biochemistry at the University of Milan, who a few years ago recorded a charming, brief reminiscence about the episode. As Dr. DiFrancesco recalls, he began studying the heart’s pacemaker current as a postdoc junior researcher in 1976, first in Cambridge and then, starting in 1977, in Oxford. He made ex vivo preps of rabbit sinus-node tissue, which he stuck with microelectrodes and treated with voltage clamps. 

This led, in 1979, to his discovery of “a very unusual current,” an inward current that activated on hyperpolarization. All other known, inward currents in heart muscle activate on depolarization. “We termed it funny because of its odd properties,” Dr. DiFrancesco said. “We realized this was landmark data that established a new dogma for pacemaker activity. Funny current is responsible for the heart beat and for controlling heart rate. It is an essential mechanism in initiation of the heart beat.” According to his vignette, Dr. DiFrancesco’s discovery rested on his chance treatment of the rabbit-tissue prep with a hyperpolarizing current. 

He and his collaborators, Hilary Brown and Susan Noble, reported their discovery and coined the funny current, If name in a 1979 Nature paper

Somehow funny current became evolution’s solution to how hearts beat, and somehow the Oxford group stumbled onto the current’s existence. Developing ivabradine and showing its efficacy in a major trial with 6,500 heart failure patients turned funny current into serious medicine. 

—Mitchel Zoler (on Twitter @mitchelzoler)

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Filed under Cardiovascular Medicine, IMNG, Internal Medicine

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