MU Drives Collaboration Developing New Heart-Failure Drug

Your life depends on a muscle the size of a fist weighing 8 to 12 ounces.

Your heart never sleeps. It beats about 100,000 times per day, feeding your tissues with crucial oxygen and nutrients, and then doing double duty as it takes out the trash — removing carbon dioxide and other wastes.

Heart failure contributes to the death of about one in eight Americans. Despite improvements in the care of heart failure patients, the disease is currently associated with a 50 percent chance of death within five years of the onset of symptoms.

According to the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH), heart failure is a condition in which the heart cannot pump enough blood to meet the body’s needs. It is a heart that cannot keep up with its workload. Heart failure is a serious, chronic, progressive condition, and there is usually no cure.

“In some heart-failure patients, the heart has difficulty pumping out enough blood to support other organs in the body under normal resting conditions,” says Craig Emter, PhD, an associate professor in the Department of Biomedical Sciences at MU’s College of Veterinary Medicine. “Now, however, a large and growing number of patients have a different type heart failure. In these patients, the heart’s ability to pump blood at rest appears normal, but the ability of the heart to relax and fill with blood is impaired, which impacts the organ’s ability to respond to conditions of increasing cardiovascular stress, such as exercise or activities of daily living like climbing a flight of stairs. This condition is known as heart failure with preserved ejection fraction (HFpEF).”

An ejection fraction is an important measurement of how well your heart is pumping. In a healthy heart, the ejection fraction is 50 percent or higher — meaning that more than half of the blood that fills the left ventricle is pumped out with each beat.

“Typically in heart-failure scenarios, the heart remodels, or changes shape in a way that negatively impacts its function,” Emter says. “In HFpEF, the walls of the heart often become thick and more fibrotic. The cells themselves can change in size and shape, affecting the structure inside the cell that allows it to contract and relax. It alters the heart in a way that it doesn’t fill as well as it usually does and, as a result, it doesn’t pump blood as well as it should. The heart is struggling and trying to adapt, but the long-term effect of those changes is a negative impact.”

About 50 percent of patients with clinical heart failure have HFpEF, according to the NIH National Center for Biotechnology Information. Further, the proportion of those with HFpEF has been increasing steadily over the past 15 years.

Importantly, the disease affects women more than men, particularly older women, highlighting gender-specific issues in treating cardiovascular disease.

“The disease itself has a pretty significant sex component,” says Emter. “The prevalence of the type of heart failure we’re studying is two times higher in women, so you have a pretty big disparity between males and females. There is a serious imbalance in who gets this particular type of heart failure and who doesn’t.”

The curious sex disparity of the disease may have an aspect related to military service. As a result, a U.S. Department of Defense (DOD) grant funds work under way in Emter’s laboratory and among its partners. The goal is to obtain evidence-based feasibility for a new biologic drug intended to treat chronic heart disease, and that drug could hold promise as a new therapy for HFpEF.

“One thing my fellow grantee and I started reading about when we were relating this to the DOD and their call for this type of science, was that a lot of women in the military are exposed to high levels of stress during their service,” Emter says. “Many are subsequently diagnosed with PTSD. These women are more likely to hit menopause early, or face increased risk for needing a hysterectomy, which increases their risk of becoming menopausal earlier than they might have normally. The sooner you become menopausal, that increases your chances of having high blood pressure. These factors could potentially set women on a course for this disease.”

To address the current lack of treatments for HFpEF, Emter is the co-leader of a wide-ranging collaboration that reaches across campus and the nation.

“We have two partners here at Missouri,” Emter says. “Scott Rector, at the VA, and Tim Domeier at the School of Medicine. Dr. Michael Kapiloff is our collaborator at Stanford, and Dr. Roger Hajjar, at Mount Sinai Hospital in New York, is consulting with us to help us move this forward. Dr. Hajjar is probably the worldwide leader in gene therapy as it relates to the heart.”

Rector, PhD, is an associate professor at MU’s School of Medicine with co-appointments in Nutrition and Exercise Physiology and Gastroenterology and Hepatology. Domeier, PhD, is an associate professor in Medical Pharmacology and Physiology at the School of Medicine.

“Dr. Michael Kapiloff, who we share the grant with, has thoroughly and exhaustively studied this problem in mice in a lot of different ways,” Emter says. “He has looked extensively at the signaling mechanisms that we’re addressing. That’s one reason we got interested in working with him.”

Kapiloff, MD, PhD, is an associate research professor of ophthalmology at Stanford, and he has many accomplishments in cardiovascular medicine. He holds an associate professorship, by courtesy, in cardiovascular medicine at Stanford’s School of Medicine.

Kapiloff’s Stanford lab has been identifying molecular and cellular regulatory mechanisms that are responsible for the deterioration of heart function in disease. They have identified two molecules as critical for the progression of heart disease in mice and have developed a new biologic drug that has been remarkably effective in mice at preventing heart failure.

Meanwhile, the Emter lab has been developing large animal models for heart failure.

“Dr. Kapiloff needed to see if the drug works in a preclinical animal model before we take it into the clinic,” Emter explains. “That’s why we’re moving on to pigs. The pig is a pretty good human model, as far as the heart goes. Pigs are very similar to humans — maybe the most similar animal species in terms of how the heart works — from the general size of the heart, blood pressures, how it pumps blood through the body and things like that.”

The pigs in question are Ossabaw pigs, a unique breed with a history with Mizzou. In 2002, Michael Sturek, then a professor at MU’s School of Medicine and an investigator at Dalton Cardiovascular Research Center, took a team to Ossabaw Island in the Atlantic Ocean off the coast of Georgia, and acquired 26 feral miniature pigs. The animals trace their lineage back to the 1500s, when Spanish sailors exploring the New World often released horses, cows and pigs to serve as food and transportation during future exploration or settlement. Isolated on an island that experiences seasonal shortages of food, the pigs developed an ability to store astounding amounts of body fat.

“They are a very interesting animal model,” Emter says. “Genetically, they hang on to every calorie of food they eat. When they have access to plenty of food, much like people who have bad diets and get caloric excess, they become a diabetic model. Their bodies still hang on to all that food, so they become obese and have many of the symptoms seen in Type 2 diabetes like insulin resistance, high glucose, high blood sugar and those sorts of general metabolic issues.”

Biologic drugs are transforming medicine. Unlike chemical drugs, biologics are produced by living cells, and harvested directly from biology. The roots of biologic medicine trace back to the original vaccines, but its contemporary application has revolutionized the treatment of many diseases, and Emter’s lab is joining the revolution.

“This is actually the first gene therapy study that we have ever done; this is a new thing for us,” Emter says. “It is a daunting challenge. Getting a virus into the heart is pretty difficult; it takes some doing. But, we are some of the very few people on Earth who get to do this kind of work, so it’s a tremendous privilege for us. We’re excited to see if this therapy can help a beating heart become well again.

“We’re trying to realize the promise of gene therapy, trying to design a gene that expresses or interacts only in the organ that you want it to,” Emter says. “This is a very specific virus that we’ve tailored to do this job. Our gene has certain ‘promoters’ that hopefully will allow only the heart to generate the protein that we’re trying to express in it.

“We hope the gene therapy we’re using interacts with a number of different signaling pathways within the cell that limits or prevents that ‘bad’ remodeling,” Emter says. “The protein that we’re putting in, which the body doesn’t normally produce, actually blocks an interactive place on the nucleus of the heart cells where a lot of different signaling pathways come together. Those signals coming in cause the nucleus to activate all of those changes to how the heart is shaped and the components that construct it. We’re going to block those signals so that changes in the shape of the heart don’t occur, so it doesn’t become more fibrotic and stiff, so that it relaxes and fills like it normally would. In a nutshell, that’s how our therapeutic virus is supposed to work.”

According to the NCBI, medical education researchers are inherently collaborators. The conceptual issues and challenges they often tackle require institutional resources. The process of theoretical frameworks, experimentation and empirical proof lends itself to building on the work of others. Emter says this embrace of teamwork is a characteristic found throughout the MU system.

“It’s important to recognize that this grant really embraces the collaborative spirit of Mizzou that has been around for a long time. That spirit and tradition of collaboration is an important aspect of this,” Emter says. “The outreach, and the way we’re doing things, really fits the reputation that the University of Missouri has.”