New Therapy Could Preserve Vessel Function After Heart Attack

Scientists have identified the process that causes blood vessels to constrict during and after a heart attack. They’ve also demonstrated that delivering a vital molecule that is depleted during this process directly to those blood vessels can reverse damage and help restore blood flow.

The Ohio State University medical researchers say these findings have the potential to improve outcomes for patients with acute coronary episodes related to ischemia, and to ameliorate the restriction of blood supply to the heart.

The study is published online this week in the journal Proceedings of the National Academy of Sciences.

“This is a useful therapeutic approach and should be easy to translate,” said Jay L. Zweier, director of the Davis Heart and Lung Research Institute at Ohio State University Medical Center and senior author of the study. “This should enable improved treatment of patients with unstable coronary syndromes and heart attacks, allowing enhanced restoration of blood flow and preservation of heart muscle at risk.”

Scientists have known that following a heart attack blood vessels around the heart do not properly dilate and may constrict because of problems in the cells that line the vessel walls. But until now, they did not precisely understand why. Zweier and colleagues set out to determine the cascade of events that leads to the loss of vessel vasodilatory function and, in the process, identified a potential solution that would dilate and reopen vessels, improving blood flow.

In examining isolated hearts, the research team observed that in hearts subjected to a lack of blood flow, or the ischemia that occurs during a heart attack, the ability of the vessels to remain dilated is impaired because production of the nitric oxide molecule that dilates the vessel stops. This stoppage can be traced to depletion during ischemia of a molecule that is a critical cofactor required to activate the enzyme nitric oxide synthase (NOS), which produces the potent vasodilator nitric oxide. This critical cofactor is a molecule called tetrahydrobiopterin, or BH4.

In fact, the loss of BH4 during ischemia not only prevents production of nitric oxide and the dilation it causes, but actually causes the enzyme NOS to completely reverse course and instead produce an oxidant called superoxide that leads to constriction of the vessels.

Zweier noted that the longer that blood flow is stopped during a cardiac event, the more severe the loss of BH4 – meaning the chances of restoring blood flow are increasingly reduced. The study showed a marked loss of BH4 after 30 minutes without blood flow, and more than 90 percent depletion after 45 minutes.

“What wasn’t known before was that as the time of ischemia progresses, the function of the enzyme is impaired and subsequent coronary flow is reduced. There is loss of enzyme function plus the switch from dilation to constriction,” said Zweier, also a professor of internal medicine. “Following a heart attack, vessels tend to constrict and mircovascular occlusion occurs, but what you need is a patent circulation with dilated vessels for restoration of coronary flow, or the muscle will die.”