A new four-year, $2.8 million grant from the National Institutes of Health will allow researchers at the University of Illinois at Chicago, together with colleagues from Johns Hopkins University and the University of Texas at Houston, to evaluate the efficacy of two drugs that have the potential to vastly improve survival and cognitive outcomes in people who experience sudden cardiac arrest.
The two drugs, called TAT-PHLPP9c and TAT-PIF, mimic the effects of rapid cooling on the body, which is known to help prevent cardiac damage and mitigate the neurological effects of a heart attack. But cooling the body during and immediately after sudden cardiac arrest is difficult because the vests used to bring down the body’s core temperature are not available in all ambulances or hospitals.
“The best time to cool the body is during CPR, but out in the real world, that is very difficult,” said Dr. Terry Vanden Hoek, professor and head of emergency medicine at the UIC College of Medicine and lead investigator on the grant. “Cooling after the heart has been revived is also beneficial, although cooling during CPR appears to have the most profound benefits.
“Our goal is to deliver these two new biological agents intravenously during CPR so that the patient’s body is ‘cooled’ when it is most beneficial.”
Unlike for other leading causes of death, there are no drugs to treat cardiac arrest, which affects more than 500,000 people annually in the United States. Survival for cardiac arrest outside a hospital is about 7%.
“There are a few things we know help increase survival for out-of-hospital cardiac arrest,” Vanden Hoek said. “One is bystander CPR. Others are emergency responder CPR and cooling the body as soon as possible, preferably starting when CPR starts. But we also need drugs that have the potential to improve survival and long term outcomes and that can be delivered easily on the scene.”
During cardiac arrest, heart cells are unable to contract normally. They also cannot use their normal fuel source — fatty acids — properly. Instead, glucose, a type of sugar, becomes the major fuel source. But using glucose causes cellular stress and leads to increased production of another sugar called sorbitol, which is toxic in large amounts. To dampen the effects of sorbitol, cardiac cells release a compound called taurine, which helps reduce cellular stress. Taurine is very important for both heart and brain health. When taurine leaves the brain, it can lead to cognitive impairment and neurological issues.
In previous work, Vanden Hoek and UIC colleagues identified a small protein that was able to mimic the effects of cooling at the cellular level and is able to quickly permeate cardiac cells to activate an enzyme that supports the metabolism of glucose, preventing damaging cellular stress and toxic sorbitol production. The two new protein drugs are second-generation versions of the original protein, and they target metabolism more precisely and with fewer side effects.
“In mouse studies, our drugs are profoundly protective when it comes to the heart and brain, which take the biggest hits in cardiac arrest,” Vanden Hoek said. In mouse studies, animals given the drugs during cardiac arrest lasting up to 12 minutes were able to be revived and showed no signs of heart or brain damage.
“We are essentially bringing these animals back from the dead with virtually no negative effects,” Vanden Hoek said.
In the new studies, Vanden Hoek and colleagues will test the effects of the two drugs on the heart and brain as well as on cognitive functioning in mouse and pig models of cardiac arrest. They will also use a technique that measures the circumference of the optic nerve as a proxy for brain swelling to see if the drugs can help reduce swelling in the brain during cardiac arrest — a major contributor to negative neurological and neurocognitive outcomes of cardiac arrest. They also will look for biomarkers in the blood that will help them predict outcomes of cardiac arrest and track the effects of their two peptide drugs on outcomes.
Vanden Hoek and colleagues also will explore using their peptides in conjunction with extracorporeal membrane oxygenation, or ECMO. ECMO uses a pump to circulate blood through an artificial lung back into the bloodstream. It is used in some cardiac arrest patients to give the heart a break and a chance to heal.
“We expect to see a synergistic effect in terms of outcomes when using ECMO and our peptides together,” Vanden Hoek said.
Dr. Henry Halperin of Johns Hopkins University is a co-principal investigator and Dr. Henry Wang of the University of Texas at Houston is a co-investigator on the grant.