UA Team Tackles Better Brain Health

Sep 5, 2017

The human heart is not cut out for bypass surgery. It beats and it moves. So, it must be quieted beforehand.

To accomplish this, a surgeon puts a patient in circulatory arrest — that is, the heart is stopped and the patient placed on a bypass machine. The machine takes the patient's blood and circulates it through a pump and an oxygenator and then returns it to the patient. Instead of the heart and lungs doing the pumping and the oxygenating, the machine is doing the work.

However, the human body is "incredibly sensitive," says Dr. Nancy Sweitzer, director of the University of Arizona Sarver Heart Center and chief of cardiology at the UA College of Medicine – Tucson.

"As the blood re-enters the body after passing through the machine, the body knows that the blood has been exposed to the plastic and the tubing and the metal," Sweitzer says. "It senses something about that blood being different and then activates the body's inflammatory mechanisms."

Some patients have a profound response to this procedure, others a minor one.

"After bypass surgery, some people tell us that they feel different, they think differently and things have changed for them even though their heart is better," Sweitzer says.

Some people don't notice anything all. Studies have shown, however, that if cognition and memory are carefully evaluated, tests detect cognitive deficits in a substantial number of people after bypass surgery, says Sweitzer, an expert in heart failure.

The cognitive deficits may be so subtle that people don't notice them, but some do, and so do their families. Other times, studies have shown significant or even permanent memory loss in patients who have undergone bypass surgery, says Meredith Hay, professor of physiology at the College of Medicine – Tucson.

As it stands now, there are no effective treatments for cognitive impairments, including memory loss.

Introducing: Angiotensin 1-7

That's why Sweitzer is collaborating with Hay and Lee Ryan, a UA professor of psychology and department head, on the Phase 2 trial to determine whether a particular peptide administered before and after coronary bypass surgery mitigates — or even reverses — cognitive deficits thought to be connected to the procedure.

The peptide is known as angiotensin 1-7 — or ang 1-7, for short. A derivative of angiotensin 2, it is a naturally occurring compound that relaxes vascular tone, diminishes the dilation of blood vessels, decreases inflammation and is considered safe in normal amounts.

"Our body makes angiotensin, which is cleaved to angiotensin 2," Hay explains.

Angiotensin 2 is involved in the body's water balance, an important matter. Many patients with high blood pressure have too much angiotensin 2. However, our bodies have the ability to break down angiotensin 2 into angiotensin 1-7.

"It was discovered around 20 years ago that there's this beautiful yin-yang relationship between angiotensin 2 (a vasoconstrictor that raises blood pressure and increases inflammation) and angiotensin 1-7 (which decreases inflammation)," Hay says. 

"People who have studied cardiovascular sciences have studied angiotensin 2 for years," she says. "We know that angiotensin 1-7 is anti-inflammatory, and we know that it's protective of the brain. People have studied it in the kidneys, in the heart, in the blood vessels, but nobody has studied its effect on memory function."

Until very recently, that is.

The UA researchers are just starting the Phase 2 clinical trial, involving patients who come to Banner – University Medical Center Tucson in need of bypass surgery. Last month, the researchers enrolled their first participant.

John Konhilas, UA associate professor of physiology; Carol Barnes, director of the UA Evelyn F. McKnight Brain Institute and Regents' Professor of Psychology, and Hay previously conducted preclinical studies in mice with heart failure that laid the foundation for the human trial. These pivotal studies showed that angiotensin 1-7 reversed memory loss in mice with heart failure.

"Important to our understanding of why disease in the heart results in memory loss requires scientists and doctors from different disciplines to work together," Hay says. 

Generally speaking, cardiologists and cardiac surgeons make sure the heart is working, so careful evaluation for brain function may not occur. Meanwhile, neurologists are concentrating on the brain and not the heart.

"We want to see what happens when we bring these two important areas of science and medicine together — the brain and the heart — and study the patient as a whole," Hay says.

Quality of Patient Health at Stake

Researchers know that when patients have cognitive impairment, it can significantly affect the quality of their health, says Ryan, a clinical neuropsychologist and expert in neuroimaging and the aging brain.

"Patients who have cognitive impairment after bypass surgery are less likely to maintain their regimens of medication, to engage in self-care, are more likely to be re-hospitalized, and have a higher mortality rate," says Ryan, who is heading up the study's cognitive testing and brain imaging.

"We think ang 1-7 has a specific impact on an area of the brain called the hippocampus," she says.

Based on animal studies, researchers know the kinds of memories that should be most affected by damage to the hippocampus. Ryan will use targeted neurological tests that will tap into what the researchers think ang 1-7 might be doing.

In the double-blind, clinical trial, participants will be given ang 1-7 or a placebo two hours before bypass surgery and will take the drug or placebo every day for 21 days thereafter.

"The drug has got to be onboard and dispersed throughout the body before the patient goes on cardiopulmonary bypass," notes Dr. David Bull, chief of cardiothoracic surgery in the College of Medicine  – Tucson. Bull and Dr. Zain Khalpey, associate professor of surgery in the College of Medicine – Tucson, are the partner surgeons in the Phase 2 study.

"Participants in the trial are going to be patients whose bypass is elective because there are requirements for certain lab tests and imaging," Bull says. "With someone who needs urgent surgery, there isn't going to be enough time to get the testing done before they have to have surgery."

In fact, participants will undergo a series of tests to evaluate their memory before surgery and periodically following surgery, with the last test administered one year after bypass. Imaging of the brain with MRI scans also will take place before and after surgery.

Nothing Ventured, Nothing Gained

"We don't know if the drug is going to work in humans," Hay says. "But if we don't do a study like this, we won't know if it will work or not."

But even if it doesn't work, Ryan says, "we're going to have a really strong dataset, and a broad and in-depth analysis of these participants pre- to post-surgery. The whole connection between cardiovascular health and brain health is relatively new, but it's a major focus of the National Heart, Lung and Blood Institute, which funded the study."

Says Sweitzer: "I've never done anything with memory and heart disease. But right after I moved to Arizona, Lee and Meredith came to my office and said, 'We have this compound, and we think it's ready to move into humans, but we don't have any expertise in doing human clinical trial studies.' And that's what I do.

"I think it's a great Arizona story that we had this confluence of expertise across very different and complementary disciplines. This isn't one of those situations where if we don't hurry somebody else will do this. Nobody else can do this. We have this unique combination of expertise right here in Tucson."

Original story: https://uanews.arizona.edu/story/ua-team-tackles-better-brain-health

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