Researchers harness the heart’s natural defense against heart attack damage

Previous research from the team prompted them to investigate whether activating certain proteins in the early morning hours could improve protection against heart damage. 

Researchers are investigating whether the body’s built-in response to low oxygen can be harnessed to reduce heart damage during heart attacks and surgery, using drugs that are already available. 

Published recently in Nature Reviews Cardiology, the review led by corresponding author Holger Eltzschig, MD, PhD, professor and John P. and Kathrine G. McGovern Distinguished University Chair in the Department of Anesthesiology, Critical Care, and Pain Medicine at McGovern Medical School at UTHealth Houston, focuses on proteins called hypoxia-inducible factors, or HIFs, which act as the body’s oxygen sensors. When oxygen levels drop, such as during a heart attack, HIFs switch on a network of protective genes that help cells survive. These genes allow the heart to adapt to low-oxygen conditions by changing how it produces energy, reducing stress on cells, and activating other protective pathways. 

“Myocardial infarction, or a heart attack, is one of the leading causes of perioperative death in patients. For decades, my lab has been interested in finding new ways to protect the heart muscle from damage caused by a lack of oxygen,” said Eltzschig, who also serves as associate vice president of translational medicine and director of the Institute of Perioperative Medicine at McGovern Medical School. 

A heart attack occurs when blood flow to the heart muscle is reduced or blocked by partially or completely blocked arteries. This oxygen shortage can kill heart cells and trigger inflammation. Although restoring blood flow is critical, the sudden return of oxygen can also cause additional injury, a phenomenon known as ischemia-reperfusion injury. 

Previous research by Eltzschig and his team revealed that the time of day a heart attack occurs can influence the severity of heart damage. He found the effect was driven by an interaction between BMAL1, a key circadian rhythm protein, and HIF2A, a protein that helps the body adapt to low oxygen. Together, these proteins influence how heart cells respond after a heart attack and may affect the extent of injury. 

The findings showed that HIF2A provides greater protection in the afternoon than in the early morning hours, helping explain why some heart attacks may cause more damage depending on when they occur. Those findings prompted the team to investigate whether activating HIF2A in the early morning hours could improve protection against heart damage. 

The review takes a broader view, highlighting HIF proteins as key regulators of the heart’s response to low oxygen and proposing that HIF-activating drugs could one day be used to protect the heart during heart attacks and surgery. 

The researchers highlighted two proteins, HIF1A and HIF2A, that may help protect the heart through different mechanisms. HIF1A is especially important in a phenomenon known as ischemic preconditioning, in which brief, controlled periods of reduced blood flow appear to “train” the heart to better withstand a future heart attack. HIF2A may provide additional protection that varies according to the body's natural circadian rhythms. 

In animal and laboratory studies, drugs that boost HIF activity have consistently reduced heart damage caused by heart attacks. However, these treatments have not yet become standard care for heart patients, although some HIF-activating therapies are already approved by the FDA for other conditions. 

Researchers expect future clinical trials to test whether HIF-activating drugs can reduce heart damage during acute heart attacks, protect the heart during major cardiac surgery, and prevent heart injury during other surgical procedures. 

Other UTHealth Houston authors include Cong Luo, MD, PhD, instructor; Tao Li, PhD, instructor; Jihoon Tak, PhD, postdoctoral research fellow; Matthew DeBerge, PhD, assistant professor; and Kuang-Lei Tsai, PhD, associate professor at McGovern Medical School.