March 02, 2016

UAB continues to be a powerhouse in cardiovascular research

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cardiovascular researchAccording to the Centers for Disease Control and Prevention, approximately 610,000 people die of heart disease in the United States every year — that’s one in every four deaths. The impact of cardiovascular diseases is quite large.

The University of Alabama at Birmingham is home to many talented investigators who study various aspects of heart disease within the School of Medicine’s Division of Cardiovascular Disease, at the Comprehensive Cardiovascular Center and across UAB . A primary goal of both the division and CCVC is to actively promote innovative, interdisciplinary and translational cardiovascular research. Many distinct — yet often complementary — basic and clinical studies are ongoing at UAB. With Alabama’s ranking among states with the most heart-related deaths, this innovative research is providing benefits to patients now and in the future.

UAB researchers are focusing on five key areas with an ultimate goal of improving the care of CVD patients. 

sumanth prabhu 2012Sumanth PrabhuHeart failure

Heart failure is a chronic, progressive condition in which the heart muscle is unable to function adequately and distribute sufficient oxygen and nutrients to meet the body’s needs. In other words, the heart cannot maintain its workload.

Multiple researchers at UAB are investigating the mechanisms by which heart failure occurs, as well as searching for ways to prevent heart failure and devise improved treatment strategies.

Heart failure can arise as a consequence of ischemic events, such as a heart attack — indeed, heart attack survivors are at increased risk for heart failure development. Ongoing research is trying to uncover the nature of this relationship.

During ischemic events, the immune system becomes activated, which is essential for the repair of the heart. However, inappropriate activation of immune cells results in chronic inflammation, which worsens damage to the heart, thereby contributing to heart failure development. Director of the UAB Cardiovascular Disease Division and the CCVC Sumanth Prabhu, M.D., is currently focusing on the role of specific immune cell populations in producing heart damage, and on finding a way to manipulate immune systems so they do not become hyperactivated.

Similarly, research in the laboratory of Ganesh Halade, Ph.D., is studying novel lipid species, known as resolvins, which are able to reverse inflammation in the heart. Roger White, Ph.D., and his collaborator, G.M. Anantharamaiah, Ph.D., are exploring the anti-inflammatory properties of high-density lipoprotein mimetic compounds in atherosclerosis and other disease states.

Other important areas of heart failure research involve energetics, regeneration, cellular survival and remodeling. Studies in the laboratory of Min Xie, M.D., are currently defining whether activation of self-preservation mechanisms such as autophagy promote survival of heart cells, thereby attenuating contractile dysfunction following a heart attack. In terms of remodeling, Louis Dell’Italia, M.D., is studying the mechanisms of extracellular matrix remodeling during heart failure, which can lead to stiffening of the heart. Both Xie and Dell’Italia have identified novel therapeutic targets that improve cardiac function in pre-clinical models.

Heart failure research further extends to the clinic, with multiple active clinical studies assessing the intramyocardial delivery of mesenchymal stem cells as a novel therapeutic in patients with heart failure, genomic determinants of patient response to pharmacological therapy, immune cell activation in chronic disease, heart failure outcomes research using the INTERMACS registry, and testing of novel circulatory support devices and other therapeutics in patients with advanced heart failure. The studies are led by multiple investigators, including Prabhu, Salpy Pamboukian, M.D., Jose Tallaj, M.D., Britta Brott, Renzo Loyaga-Rendon, M.D., and Deepak Acharya, M.D.

Clinical researchers including Massoud Leesar, M.D., Seun Alli, M.D., and Brott are examining interventional approaches to ischemic and valvular heart disease and associated cardiomyopathy. These include novel strategies for coronary intervention and stent design, outcomes after percutaneous structural (valvular) interventions, and developing paradigms for adjunctive anti-platelet therapy after interventional procedures. Nita Limdi, Ph.D., is leading an institutional precision medicine effort to uncover the clinical impact of genomic variation in the metabolism of anti-platelet drugs after coronary intervention.

suzanne oparil 2016Suzanne OparilHypertension research

Hypertension, or high blood pressure, typically has no symptoms, but can have deadly health consequences if not treated. According to the American Heart Association, nearly 80 million U.S. adults have been diagnosed with high blood pressure.

Suzanne Oparil, M.D., professor of medicine and past president of the American Heart Association , is part of a groundbreaking study called the SPRINT trial that suggests changing blood pressure guidelines could cause the falling death rate from heart attacks and stroke to drop even more. The trial found that a pressure below 120 was preferable for high-risk patients.

A number of hypertension patients are unresponsive to conventional treatment strategies. These individuals, known as resistant hypertensive patients, require three or more anti-hypertension treatments, to help manage their blood pressure. David Calhoun, M.D., professor of medicine in the Division of Cardiovascular Disease, is a pioneer in translational studies designed to identify underlying mechanisms causing resistant hypertension, as well as in the management of this disease.

Paul Muntner, vice chair of the UAB Department of Epidemiology in the School of Public Health, recently received a prestigious grant from the American Heart Association to study 24-hour patterns in blood pressure. Blood pressure usually decreases during sleep, an event termed dipping. However, in some individuals, blood pressure does not decrease during the night. This non-dipping event is associated with increased risk of cardiovascular disease. The study by Muntner and colleagues Calhoun, Orlando Gutierrez, M.D.,Edward Inscho, Ph.D., Oparil, David Pollock, Ph.D., Jennifer Pollock, Ph.D., and Martin Young, Ph.D., is investigating the incidence of non-dipping in distinct racial groups, as well as the potential mechanisms leading to this condition.

paul mutnerPaul MuntnerElectrophysiology

An important aspect of cardiac biology relates to the circuits involved in transmission of electrical signals into mechanical work, which is broadly termed electrophysiology. Abnormalities in these complex circuits can lead to arrhythmias and sudden cardiac death. Through the use of state-of-the-art imaging and other methodological strategies, research at UAB is untangling these circuits, and translating the findings directly toward novel therapeutics.

Heart failure patients have an increased incidence of arrhythmias. Steven Pogwizd, M.D., professor of medicine, is coupling three-dimensional imaging technology with molecular techniques to gain insight into mechanistic links driving this increased risk. Possibilities include impairment of the normal electrical properties of heart cells — termed cardiomyocytes — or a loss of proper communication between these cells, a concept that is being investigated by Sabine Huke, Ph.D., associate professor of medicine.

Studies within the laboratory of Lufang Zhou, Ph.D., are utilizing a sophisticated ‘optogenetic’ approach, to modify electrical circuits simply in response to light pulses. An underlying theme in Zhou’s research involves the idea that impairments in energy metabolism during heart failure negatively impact the maintenance of normal electrical properties of the heart.

A robust clinical and translational electrophysiology research program is active on several fronts, including testing new device- and catheter-based therapeutics for ventricular and atrial arrhythmias. These studies are led by Tom McElderry, M.D., and Greg Walcott, M.D.

Studies in Prabhu’s laboratory are also underway examining novel genomic determinants of inflammation in atrial fibrillation and the contribution of immune cell populations to ventricular arrhythmias in heart failure.

jianyi zhangJianyi ZhangRegenerative medicine

Regenerative medicine is an interdisciplinary research and development program focusing on development of tissue constructs, regenerative matrices, and novel technologies and therapies to replace or repair both soft and mineralized tissues.

The potential positive impact of this new area of research for the eventual treatment of both vascular and cardiac diseases is considered high. For example, following a heart attack, it is important to replace both heart cells, as well as blood vessels, in order to prevent heart failure.  NIH-funded research in the laboratories of Prabhu and Yu-Fai Chen, Ph.D., is designed to employ novel strategies for the delivery, survival and integration of precursor (stem) cells into the heart following a heart attack, for the repair and replacement of dead and/or damaged tissue.

Researchers like Jianyi Zhang, M.D., chair of the UAB Department of Biomedical Engineering, and Palaniappan Sethu, Ph.D., associate professor of medicine, are considering the possibilities of making tissue artificially outside the body, and subsequently implanting tissue patches or grafts into the region of the heart that was affected by the heart attack.

martin youngMartin YoungCardio-metabolic diseases

Metabolic imbalance and mitochondrial dysfunction have been associated with the development of various cardio-metabolic diseases that are rampant in the U.S., such as obesity, Type 2 diabetes and cardiovascular disease. Restoration of normal metabolic balance and mitochondrial function are therefore important factors to eradicating this disorder.

Glenn C. Rowe, Ph.D., assistant professor in the Department of Medicine, is currently researching the study of mitochondrial dynamics in response to exercise, the effect of exercise on angiogenesis and mitochondrial metabolism, and the characterization of new regulators of mitochondrial metabolism in striated muscle. 

Researchers like Anath Shalev, M.D., director of the UAB Comprehensive Diabetes Center, are studying why people who have diabetes are at a higher risk of developing heart disease, and are also currently investigating whether a classic anti-hypertensive drug improves metabolic balance in those with Type 2 diabetes.

The failing heart has been described as ‘an engine without fuel.’ In order to develop sufficient force during each beat, the heart must use various fuels as energy sources. At the same time, metabolites affect heart function in ways that are independent of energy. Research in the laboratories of Dell’Italia, Rowe, Young and Zhou in the Division of Cardiovascular Disease, as well as in the Department of Pathology, is actively investigating links between metabolism and contractility of the heart, and how this relationship is impaired during cardio-metabolic diseases such as obesity and diabetes.