Researchers from the University of Guelph say they are working on a potential new drug to treat heart attacks and prevent heart failure. Tami Martino, PhD, professor of biomedical sciences and director of the Centre for Cardiovascular Investigations, and PhD student Cristine Reitz have discovered what they believe is a novel drug target controlling the body’s repair responses after a heart attack.
A leading cause of death worldwide, heart attacks trigger inflammatory responses that cause a scar to form in the heart. Over time, that damage eventually leads to incurable heart failure. Administered within hours of an attack, the potential drug would prevent scarring. It would also eliminate the need for patients to take possibly debilitating heart medication for the rest of their lives.
“This research is really exciting because it opens the door to use circadian medicine therapies to heal heart attacks after they occur and to prevent the subsequent development of heart failure,” said Martino, a specialist in circadian medicine.
The circadian clock is found in virtually all cells of the body. It consists of genes and proteins that interact during 24-hour day and night cycles to regulate key functions such as heart rate and blood pressure. In the heart, that clock mechanism controls healthy cardiovascular physiology as well as how the heart responds to damage and undergoes repair.
The researchers’ paper (“SR9009 administered for one day after myocardial ischemia-reperfusion prevents heart failure in mice by targeting the cardiac inflammasome”) appears in Nature Communications Biology.
“Reperfusion of patients after myocardial infarction (heart attack) triggers cardiac inflammation that leads to infarct expansion and heart failure (HF). We previously showed that the circadian mechanism is a critical regulator of reperfusion injury. However, whether pharmacological targeting using circadian medicine limits reperfusion injury and protects against HF is unknown,” the investigators wrote.
“Here, we show that short-term targeting of the circadian driver REV-ERB with SR9009 benefits long-term cardiac repair post-myocardial ischemia reperfusion in mice. Gain and loss of function studies demonstrate specificity of targeting REV-ERB in mice. Treatment for just one day abates the cardiac NLRP3 inflammasome, decreasing immunocyte recruitment, and thereby allowing the vulnerable infarct to heal. Therapy is given in vivo, after reperfusion, and promotes efficient repair. This study presents downregulation of the cardiac inflammasome in fibroblasts as a cellular target of SR9009, inviting more targeted therapeutic investigations in the future.”
The researchers used a drug called SR9009, which targets a key component of the cellular clock mechanism. The medication disrupts expression of genes that trigger adverse immune responses after a heart attack.
In Martino’s experiments with mice, the treatment reduced production of a cellular sensor called the NLRP3 inflammasome that contributes to scarring. The University of Guelph researchers showed that giving this treatment after a heart attack along with conventional therapy such as reperfusion led to less inflammation and better cardiac repair. That allowed healing almost as though no heart attack had happened, noted Martino.
“No scar, no heart damage, no heart failure. People can survive heart attacks because the heart won’t even be damaged. We were amazed to see how quickly it worked, and how effective it was at curing heart attacks and preventing heart failure in our mouse models of the disease,” she said.
The discovery might ultimately help in other heart therapies involving early adverse inflammatory responses such as organ transplant or valve replacement, she added. More generally, it may also help with profound adverse inflammatory responses, such as treatment of traumatic brain injury, strokes, or severe burns, according to the scientists.
Martino’s lab will now begin preclinical trials on a potential therapy.
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