Researchers Target Heart Failure

Researchers Target Heart Failure

Researchers Target Heart Failure

The odds are daunting. According to the Centers for Disease Control and Prevention, about 5.1 million people in the U.S. suffer from heart failure, a condition in which the heart loses its ability to pump effectively. Sadly, about half of those diagnosed with the condition will lose their battle within five years.

In this issue, meet two rising stars of research who are striking back at th is deadly disease with innovative therapies.

Hardworking, intelligent, creative—these are words that colleagues use to describe Antonio Abbate, M.D., Ph.D., and Fadi Salloum, Ph.D. Both are devoted to translational research, conducting basic science experiments with the goal of developing clinical therapies to improve the odds for patients with cardiovascular disease. The two doctors are friends—both have young families and grew up in Mediterranean countries (Abbate in Italy, Salloum in Lebanon). They collaborate on numerous research projects. Both have received American Heart Association (AHA) Young Investigator awards and other national recognitions and are principal investigators for several important research projects funded by entities including the National Institutes of Health (NIH) and the AHA.

Salloum-colleagueIt is a Thursday morning in August and Dr. Abbate, the James C. Roberts, Esquire, Professor of Cardiology, is making his rounds on VCU Medical Center’s 10th floor Coronary Intensive Care Unit (ICU). Most of the patients in this ICU have experienced an acute cardiac incident or are in the later stages of heart failure. One patient who suffered cardiac arrest breathes with the support of a ventilator’s pale blue tubing. At the nurses’ station in the center of it all, monitors continuously beep.

Abbate stops by the room of a longtime patient, who he notices has missed several appointments over the past few months. “I should be upset with you,” he says, teasing. The 53-year-old man has a critical blockage that will require a bypass and a pacemaker. Standing at the man’s bedside, Abbate says gently, “Well, it seems like it’s time for that surgery.”

“Dr. Abbate is like a spoonful of sugar. He can take care of the sickest of patients in the intensive care unit that you can imagine,” said Alpha “Berry” Fowler III, M.D., chair of VCU’s Department of Internal Medicine. “He is an amazing clinician.”

In addition to his work with patients, Abbate conducts research with Fowler and others as part of a multidisciplinary team focused on pulmonary and critical care at the Victoria Johnson Research Laboratories. He is the lead investigator in several preclinical (“basic science”) studies and the principal investigator or co-investigator in numerous clinical studies, in which he is examining the role of inflammation in heart disease. He has also published over 200 articles in scientific journals.

“He does everything. He’s the paradigm of a clinical researcher—from bench to bedside. His research takes him from the lab bench and molecules all the way to patient care and making it better,” said Kenneth Ellenbogen, M.D., chair of the Division of Cardiology.

Abbate grew up in the small town of Fondi, Italy (where his wife, Vera, is also from). As a young child, he lost his mother to cancer, which he believes drew him to medicine. “I realized how many people were ill and sick and required care. I thought [medicine] was something important to do. … I thought it would be a way to have my passion for science and doing something useful merge,” he said.

He received his medical degree from the University Campus Bio-Medico in Rome, graduating magna cum laude in 2000, and later obtained his Ph.D. in cellular and molecular cardiology from Catholic University, also in Rome. He completed his specialty training at Catholic University and VCU. He joined the VCU faculty in 2007, after one of his mentors, George Vetrovec, M.D., director of the Adult Cardiac Catheterization Lab, helped recruit him.

“I first met Dr. Abbate [in the summer of 1998] when he was a medical student in Italy, and he was just one of the most enthusiastic, intelligent folks that I’ve had the opportunity to be around. He just had huge energy and enthusiasm, and I thought, `This is the sort of person that we really want to have as a part of our faculty,’” said Vetrovec. “He’s been remarkable.”

“Dr. Vetrovec has given me so much guidance, opportunities, support and encouragement,” said Abbate. Once, after his grants were initially declined a few years ago, “Dr. Vetrovec told me, `Don’t worry—keep trying. You will succeed. They will come.’”

They did. Over the past six years, Abbate has collaborated with Benjamin Van Tassell, Pharm.D., an assistant and research professor with the VCU School of Pharmacy. Together, they have received over $3 million in NIH and other funding to develop a successful therapy using the drug anakinra to prevent or improve heart failure in patients who either have heart failure or have suffered a heart attack.

Their research involves Interleukin-1 (IL-1), a harmful pro-inflammatory agent that kicks into action following a heart attack. “Inflammation is a complex response to injury or infection,” explained Abbate. While initially IL-1 may contribute to healing, it also causes molecular and cellular changes to the myocardium “that may be compensatory at first but ultimately lead to heart failure,” he said. Anakinra is an IL-1 blocker that can prevent this further damage.

Following their initial animal model and early clinical trials, which received early support from VCU Pauley Heart Center and other sources, the pair is currently engaged in three larger NIH-funded trials in which they are providing anakinra therapy to three distinct groups of patients: 1) heart failure, 2) large heart attacks (STEMI) and 3) diastolic heart failure. These are Phase II clinical trials, which will hopefully guide the final Phase III studies for FDA approval.

His patients inspire his research. “They make it valuable. Knowing the patients, knowing the unmet needs in clinical practice, makes me approach research in a way to address those needs,” he said. “I realize how little we understand of disease and how much better we could be doing if we had more tools to treat patients.”

Hydrogen sulfide (H2S) is often associated with the rotten egg smell of swamps. Surprisingly, the noxious gas has healing properties too—and may prove a critical link to preventing heart failure, says Salloum, VCU assistant professor of medicine and physiology and biophysics.

“Hydrogen sulfide is toxic in certain concentrations—one whiff of it, and you’re dead. But it’s also something that enzymes naturally produce in our bodies,” Salloum says. After a person experiences a heart attack, his or her level of H2S drops. Of his research, Salloum says “I started looking at the physiological levels of hydrogen sulfide. … If the levels are too high, that will be bad. However, there’s a certain level we need to maintain, and if we go below that, it’s also bad.”

Salloum, a dedicated researcher who regularly puts in 10- to 12-hour days, stands in the bright, open lab room in the newly renovated Pauley Heart Center research laboratories in Sanger Hall. A long, white lab bench divides the room. Set on it are bottles of chemicals, test tubes and other tools that he uses to prepare doses of hydrogen sulfide for his preclinical studies.

Abbate-patientFor the past four years, he’s studied—with the support of a prestigious AHA National Scientist Development Grant—what happens to the body when hydrogen sulfide is given on a daily basis to animal subjects following a heart attack. He specifically traces inflammation and programmed cell death, two conditions that occur following a heart attack and can contribute to heart failure. “Both are significantly attenuated with hydrogen sulfide therapy,” he says.

Ranking his research proposal in the top 1%, the AHA recently provided Salloum with additional funding to further his work. He currently has two active grants as principal investigator to study heart failure prevention from the AHA and Novartis Pharmaceuticals and is co-investigator on three NIH grants. In addition to his AHA Young Investigator Award, he’s also received the American Association for the Advancement of Science’s Excellence in Science Award.

“His work is high impact. He’s looking at critical cellular and molecular mechanisms that address the transition from cardiac stress into heart failure, which really is still a challenging and difficult area,” said Edward Lesnefsky Jr., M.D., VCU professor of and chief of cardiology at McGuire V.A. Medical Center.

A native of Beirut, Salloum says his interest comes naturally. Growing up in a Mediterranean country, he has long heard about the sulfur-based hot springs in Europe and North Africa known for their healing properties. Interestingly, recent studies have shown the springs can alleviate edema and other symptoms of heart failure, he says. Additionally, garlic, a heart-healthy staple of the Mediterranean diet, also releases H2S.

He earned his B.S. in biology from the American University of Beirut in 1996. After graduation, he served in the Lebanese Army Medical Brigade and then emigrated to the U.S. in 1998 and moved to Richmond (where his wife, Lusene, is from) to pursue his doctorate in physiology from VCU School of Medicine. He completed his postdoctoral training in 2008 under the mentorship of Rakesh Kukreja, Ph.D., director of the VCU Molecular Cardiology Research Laboratories, and then joined the VCU staff in 2009.

As a young scientist, he has appreciated the creative and encouraging environment fostered by Kukreja. “There’s so much room to explore and advance the field in the vibrant research setting that we have here at Pauley Heart Center,” says Salloum.

Together, the two have been co-investigators on multiple NIH grants over the past 10 years and have jointly authored over 50 research papers. “Dr. Salloum’s extraordinary research productivity and work ethic impressed me the most when I recruited him as a faculty member. In fact, he is one of the most talented colleagues I have worked with during my 30 years at VCU,” Kukreja said. “He is very passionate about science and is very pleasant to work with. He thinks beyond his own work to support others.”

Another colleague, Fowler shares this perception. “Fadi Salloum, is first of all, a very good human being. He’s very polite. And most of all, he is a very intense scientist. When he goes into a research topic, he dives deep into the problem,” he said.

About 10 years ago, Fowler and Salloum joined efforts to create the very first mouse cardiac ischemia model at VCU—a blueprint on how to induce and treat the condition in mice, as a precursor to human studies. Salloum has taught the surgical skill to various research groups, including one in Rome.

Basic research is at the front end of a long process. After the animal studies come many years of clinical trials before FDA approval is possible. For instance, Salloum says it may be at least 10 years before his H2S therapy is available by prescription to humans.

“Dr. Salloum’s strength has been real dedication. He’s going to keep after it until he’s successful. … He’s also a very creative individual. And I think he’s just really getting started and that there’s much more that he will achieve,” said Vetrovec.

Kukreja added, “His research is going to have huge impact on the treatment of patients with myocardial infarction and heart failure in the future.”