Safe, common chemical reduced reperfusion injury by up to 75 percent in mice, may hold potential for people
As if having a heart attack isn’t bad enough, cardiologists know that the worst damage may actually occur after it’s over.
Blocked arteries are typically the trigger, stopping the flow of blood and starving the heart muscle of oxygen. But when the blockage is removed, and the blood comes rushing back, it wreaks havoc of its own. The result is called reperfusion injury, a life-threatening flood of inflammation and cellular destruction that has stumped scientists for 40 years.
Now, however, a potentially groundbreaking study by Fred Hutchinson Cancer Research Center scientists suggests that the worst effects of reperfusion injury may be prevented with a safe, simple solution: a dose of iodide, a chemical form of the element iodine that’s added to ordinary table salt.
“If this turns out to be positive, it could transform medicine and the leading cause of death in the Western world,” said Dr. Mark B. Roth, the Fred Hutch cell biologist whose lab came up with the new technique.
When mice with induced heart attacks were given IV infusions of sodium iodide five minutes before reperfusion, it reduced myocardial infarction, or MI, damage by as much as 75 percent. And when mice were given sodium iodide in their drinking water for two days before the procedure, they showed similar significant protection against the damage.
That’s the latest finding from Roth, a 2007 MacArthur Foundation “genius” grant recipient best known for his work using hydrogen sulfide to induce a state of reversible suspended animation in mice and other organisms, with hopes of helping critically injured people. The new study was published Friday in the journal PLOS ONE.
The technique is still a long way from being used in the 720,000 Americans who suffer heart attacks annually, or in helping the 600,000 in the U.S. who die of heart disease – the top cause of death – each year. The extent of harm from reperfusion injury in humans is hard to estimate, said Dr. Graham Nichol, a professor of medicine at the University of Washington. But in animal models, it may contribute to up to a third of the size of the infarct, or heart damage.
But if the protective effect of the iodide infusions and oral iodide shown in mice is borne out in other animal models – and, eventually, in people – it could eventually change how doctors treat heart attacks and perform cardiac bypass procedures.
“If this works in other animals as effectively as it does in our own hands, I would guarantee you that it would be a big deal,” Roth said.
And that’s not just Roth talking.
‘It’s truly incredible’
Dr. Rakesh Kukreja, a member of the operations committee of CAESAR, the National Institutes of Health’s Cardioprotection Consortium, said he was “very impressed” with Roth’s findings.
“It’s truly incredible, in my opinion,” said Kukreja, who is also director of the molecular cardiology program at Virginia Commonwealth University.
The study by Roth and his laboratory associates, Dr. Akiko Iwata and Dr. Mike Morrison, provided a thoroughly researched and documented potential solution to the longstanding paradox of reperfusion injury, Kukreja said.
“Even today, after 40 years of research and spending billions of dollars of NIH money, there’s no accepted method of reducing infarct size,” he said, referring to the area of damage caused by a heart attack.
“These mouse studies are very, very encouraging.”
That’s a view echoed by Nichol, who is also medical director of the Resuscitation Outcome Consortium Clinical Trial Center.
“A 75 percent reduction in infarct size would be significant and important if it translates into humans,” Nichol said.
Still, that’s a big if. Experiments that succeed in smaller animals may not work in larger animals. And those that show promise in large animals may not translate to people, Nichol cautioned.
In addition to confirming the effect of iodide on reperfusion in other experiments, scientists need to nail down exactly how the chemical element works. In the paper, the authors suggested that iodide might impact thyroid hormone function:
“ … The benefit of iodide may be conferred by depressing thyroid hormone production and as a result decreasing cardiac metabolism that is linked to reperfusion injury.”
The iodide didn’t have the same protective effect in mice with depleted thyroid function, Roth noted. But, he added, that’s only a theory and must be proven in future studies.
The U.S. government’s Defense Advanced Research Projects Agency, or DARPA, funded the study. Heart attacks are such a significant public health problem that federal officials have supported Roth in considering research into the area, which started him thinking about using elemental reducing agents to prevent reperfusion injury.
Iwata and Morrison tested the iodide procedure on dozens of mice during the past 2 ½ years. Iwata, an expert in animal models of human injuries, said even she was taken aback by the findings.
“It’s surprising,” she said.
A superior safety profile
Roth and Morrison said there are several elemental reducing agents in what they call the “southeast corner of the Periodic Table,” including sulfide, bromide, selenide – and iodide.
But only iodide, boasts both a profound protective effect on reperfusion injury and a superior safety profile. Even in large quantities, iodide is very safe, the authors noted. And it’s already approved for human ingestion – and widely available. “You can buy it on Amazon right now,” Roth noted.
None of the experts could say how soon the iodide could – or would – proceed to trials in humans. They all cautioned that it’s far too early for people with heart problems to start ingesting iodide before surgery.
Roth said the Seattle company he started, Faraday Pharmaceuticals, is moving the work forward. With further research, the promise of dramatically reducing perfusion injury in people could become a reality, he added.
“I think this is well worth exploring further,” he said. “I am as encouraged as anyone could be.”