Preventing heart failure by altering the circadian clock

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Targeting the circadian clock in the heart could prevent the chronic inflammation that leads to heart failure, Canadian researchers suggested. (Bing)

When people suffer heart attacks, the resulting scarring of the heart tissue often leads to chronic heart failure. Researchers at the University of Guelph in Canada have discovered a drug that they believe can prevent that scarring and the progression to chronic heart failure.

The drug, SR9009, works by capitalizing on the circadian clock inside the heart—the genes that turn on and off at specific times to regulate heart rate, blood pressure and other functions. In mouse models, administering SR9009 shortly after a heart attack reduced inflammation and scarring, allowing the heart to better repair itself. The researchers reported the results in Nature Communications Biology.

SR9009 works by disrupting genes that would normally activate immune responses after a heart attack. In mice, it tamped down the production of the NLRP3 inflammasome, a protein complex that promotes scarring. When they combined the drug with conventional therapies used to promote blood flow after heart attacks, the animals’ hearts healed to the point where it almost looked as if no cardiac event had happened at all, the researchers reported.

"No scar, no heart damage, no heart failure,” said Tami Martino, Ph.D., professor and director of the Centre for Cardiovascular Investigations at the University of Guelph, in a statement. “We were amazed to see how quickly it worked,” she added.

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Several companies are targeting the NLRP3 inflammasome to treat a variety of diseases. Late last year, U.K. and Ireland-based startup Inflazome raised €40 million ($46 million) to develop its pipeline of NLRP3-targeted drugs to treat diseases marked by excessive inflammation such as Alzheimer’s disease and inflammatory bowel disease. Another U.K. startup, Nodthera, raised £28 million ($40 million) to develop an NLRP3 inflammasome inhibitor for conditions such as nonalcoholic steatohepatitis.

What makes the University of Guelph approach distinctive is its focus on the circadian clock. SR9009 specifically targets REV-ERB, a family of nuclear receptors that regulate the circadian clock. The researchers showed that activating REV-ERB with SR9009 in mice lowered the production of NLRP3, when they administered the drug after conventional heart attack treatments.

Because REV-ERB is most active during sleep, they gave the drug to some of the mice at bedtime. Those animals showed better heart healing than did mice who were given SR9009 at wake time, the researchers reported. They suggested that in people, the first dose could be given during the initial treatment after a heart attack with a follow-up dose at sleep time, they said.

The University of Guelph scientists believe the research could inspire new approaches to treating patients immediately following heart attacks. “We hope our experimental study will stimulate the initiation of translational research targeting REV-ERB, and indeed explore an emerging class of drugs that target the circadian mechanism, to benefit treatment of patients clinically,” they wrote in the study.