Research Interests in Cardiovascular Medicine

Brian Annex

Dr Brian Annex’s laboratory is a true bench to bedside translational research laboratory that focuses on angiogenesis (the growth and proliferation of blood vessels from existing vascular structures) in the context of peripheral arterial disease (PAD). With this as a focus, they have launched a research program that focuses on specific microRNAs that may serve as unique therapeutic approaches for the treatment of PAD in mouse, cell culture, and selected human studies. They have maintained continuing NIH funding. Additionally, they have two active projects in the area of computational modeling for angiogenesis in PAD. All four grants have a non-clinical and clinical component. Two new grants are looking at novel mechanism of angiogenesis.

Dr Alexander Klibanov’s laboratory has been active in pre-clinical research in the field of targeted imaging and drug delivery for over 25 years. Ultrasound imaging is a widespread and inexpensive non-invasive diagnostic technique. Ultrasound contrast agents offer a flexible platform that can be used for diagnostic imaging as a blood pool marker (tissue perfusion), as a targeted marker for imaging of inflammation, angiogenesis, and also as adjunct microdevices for enhanced targeted drug delivery and gene therapy. In diagnostic imaging, detection of contrast material offers high sensitivity (individual micron-sized particles can be visualized in vitro and in vivo by ultrasound medical imaging systems).

They prepare and analyze such ultrasound contrast materials, attach targeting ligands (antibodies, peptides) and plasmid DNA to their surface for targeting and ultrasound-enhanced delivery. Using colloid chemistry-based approaches, stable microbubbles with extended circulation lifetime are designed; polymer brush coating is applied to ensure enhanced stability.

Dr Michael Salerno’s laboratory’s research involves the development and evaluation of novel magnetic resonance imaging (MRI) pulse sequences and techniques to improve the clinical utility of cardiovascular MRI (CMR). His lab is an interdisciplinary group which includes undergraduate and graduate engineering students as well as clinical cardiologists and cardiovascular imaging fellows with the goal of bringing new advances into clinical practice. From an engineering perspective they are actively involved in the design and implementation of MRI pulse sequences and the development of new advanced image reconstruction and image processing techniques. The current clinical focus of the research is on myocardial perfusion imaging, imaging of myocardial fibrosis, and rapid free-breathing data acquisition. The group develops novel pulse sequences and applies these techniques in human subjects with the goal of creating robust clinically relevant techniques.

Dr Jamie Bourque has an active research program examining the population of patients with chest pain and negative coronary arteries. He is studying the long-term prognosis impact of non-obstructive CAD and has completed a K23 analyzing the effects of exercise on diagnosis, treatment, and prognosis in coronary microvascular dysfunction. He is studying the relationship of coronary flow reserve and extent of CAD by CT coronary angiography, and remains interested in prognostic factors with exercise stress, including high frequency QRS analysis and changes in lead AVR. A new area of interest for him is predictive analytics, and he is serving as principal investigator for a randomized controlled clinical trial of real-time predictive monitoring to reduce decompensation requiring ICU and adverse events in patients cared for on the acute cardiology care ward. Finally, he is interested in patient-centered imaging and is performing a decision analysis study to use patient preferences and utilities to guide the optimal pathway for assessment of coronary artery disease.

Dr Angela Taylor’s research, in collaboration with Dr McNamara, is managing the Human Phenotyping and Immune Cell Core. The function of Core is to provide human and immune cell phenotyping for each project that will be critical to the translation of mechanistic findings into the human model.

The effects of immune cell variations on atherosclerosis in humans represents a poorly understood area of atherogenesis and possible atheroprotection. The goal of the Human Phenotyping and Immune Cell Core (Core B) is to provide the resources necessary for translation of novel immune mechanisms of atherosclerosis that are well defined in murine models into the human model.

Genotype to Phenotype studies: Have discovered a single nucleotide polymorphism (SNP) in the human inhibitor of differentiation 3 (ID3) gene at rs11574 that results in attenuated ID3 function (Cir Res) and is associated with CVD in 3 distinct human cohorts. They have shown that knockout of the Id3 gene in mice regulates vascular smooth muscle cell (VSMC) proliferation in vitro and in vivo, and that Id3 overexpression reduces VSMC differentiation gene activation. VSMC growth and differentiation are key processes involved in atherogenesis. Ongoing work in the lab is utilizing CRISPR/Cas9 gene editing of human iPSC-derived VSMC to determine the impact of this CV disease-associated SNP on VSMC phenotypes linked to CVD.

Dr Christopher Kramer’s research is focused on further development of cardiovascular magnetic resonance imaging (CMR) for clinical use. He is co-principal investigator of the Hypertrophic Cardiomyopathy Registry (HCMR), a natural history study of 2755 patients recruited from 6 countries and 44 sites to improve risk prognostication in HCM using a combination of clinical markers, CMR, genetics, and biomarkers. A second major area of interest is developing new CMR-based endpoints for clinical trials in peripheral arterial disease in collaboration with investigators in Radiology and Biomedical Engineering. These endpoints include atherosclerotic plaque imaging in the superficial femoral artery as well as calf muscle physiology (perfusion and energetics). These endpoints are being used in NIH and pharma-sponsored trials of lipid lowering therapies including PCSK9 inhibitors, exercise, as well as other novel therapeutics.

Dr Matthew Wolf’s laboratory investigates signaling mechanisms that contribute to cardiomyopathies and heart failure. Cardiomyopathies are diseases of the heart that lead to cardiac hypertrophy, impaired left ventricular systolic function, heart failure, and death. Many etiologies cause cardiomyopathies including myocardial infarction that results in scar formation, genetic predisposition related to inherited genetic variants that confer increased risk of developing disease, and environmental exposures including chemotherapeutic agents. Despite advances in pharmacologic and device-based treatment, ~50% of individuals who have heart failure do not survive beyond five years, highlighting the need for additional therapies. To address this important clinical need, research in the lab focuses on the following areas:

1.Signaling pathways that cause or modify cardiomyopathies identified in genetic screens of Drosophila

2.Mechanisms to induce transient cardiomyocyte proliferation to enhance myocardial regeneration after injury

The Precision Medicine: lab has developed the pipeline for high dimensional analysis of human PBMCs to identify unique immunophenotypes associated with disease burden and therapeutic responses. They are applying them to clinical scenarios to aid in the development of personalized approaches to therapy.

Dr Ken Walsh’s laboratory investigates the signaling and transcriptional-regulatory mechanisms that control both normal and pathological tissue growth in the cardiovascular system. Their studies were among the first to document that the eNOS/PI3-kinase/Akt/GSK/Forkhead signaling axis is of critical importance in the regulation of the cardiovascular system. Signaling through this pathway controls cellular enlargement (hypertrophy), cell death (apoptosis), and blood vessel recruitment and growth (angiogenesis). Major projects in the Walsh laboratory have analyzed mechanisms of inter-tissue communication within the cardiovascular system and how these regulatory mechanisms are perturbed by obesity-induced metabolic dysfunction. A new project in the laboratory investigates how acquired mutations in blood cells contribute to the development of cardiovascular disease. Somatic DNA mutations accumulate over time in many tissues, and this is a hallmark of the aging process. In particular, somatic mutations in preleukemic “driver” genes within hematopoietic stem cells can confer “fitness” advantages leading to the clonal amplification of these cells. Finally, the laboratory has examined how age-associated loss of skeletal muscle mass affects metabolic and cardiovascular function, and is exploring the possibility that muscle-secreted factors (myokines) confer some of the benefits of exercise training on cardiovascular and metabolic diseases. This process is referred to as clonal hematopoiesis, and it is remarkably prevalent in the elderly population. A number of recent studies have associated advanced clonal hematopoiesis with increased mortality and elevated risk of cardiovascular disease and stroke.

Dr Coleen McNamara’s laboratory has been active in three focus areas: Inflammation and Cardiovascular Disease (CVD). A wealth of studies have clearly shown that atherosclerosis is a chronic inflammatory disease. As such, immunomodulatory therapy has been proposed as the next stage for improving prevention of atherosclerotic CVD. Indeed, a recent large human trial (CANTOS) provided proof of concept data that treating inflammation could reduce CV events. Yet, not all immune cells are pro-inflammatory. This group is actively pursuing both human and murine studies on the role of immune cells in CVD and development of precision and personalized immunomodulation approaches.

Dr ZhenYan’s laboratory focuses on two major areas: Molecular mechanism of exercise training-induced skeletal muscle adaptation – Exercise training (physical activity) has been known since antiquity to promote physical performance and health and prevent disease. The benefits are largely mediated by responses and adaptations in skeletal muscle. Mitochondria, the cellular powerplants which oxidize nutrients and generate ATP, are responsible for meeting the energetic demand of exercise in skeletal muscle. Research in this laboratory has focused on two opposite processes: addition (biogenesis) and removal (mitophagy) of mitochondria in skeletal muscle. They investigate the role of mitogen-activated protein kinase (MAPK) p38 in exercise training-induced mitochondrial biogenesis through peroxisome proliferator activated receptor co-activator-1 (Pgc-1) (NIH R01). In addition, they investigate the regulation and functional role of mitochondria-associated bioenergetic sensor AMPK (mitoAMPK) in striated muscles and other tissues. They have recently patented and developed a novel mouse voluntary weightlifting model and study the activation of mTOR and autophagy mechineries in contractile and metabolic adaptation to resistance exercise (Read more). The overall goal of these research efforts is to elucidate the fundamental molecular and signaling mechanisms of exercise training-induced contractile and metabolic adaptations and lay a solid foundation for the development of more efficacious interventions to promote health and prevent and treat chronic diseases.

Exercise benefits in protection against diseases – Exercise training is considered the most effective intervention against the development of non-communicable diseases, including cardiovascular, metabolic and neurodegenerative diseases and cancer; however, scientific evidence with experimental proof are often missing, and the underlying mechanisms are less well understood. To this end, we take advantage of animal models with molecular genetics and the state-of-the-art imaging and functional analyese to gain improved understanding of the benefits of exercise training in diesease prevention. We investigate the role of endurance exercise training-induced EcSOD expression in skeletal muscle in protection against oxidative damage in skeletal muscle and other peripheral tissues/organs in various disease settings, including catabolic muscle wasting, diabetic cardiomyopathy and multiple organ dysfunction syndrome induced by endotoxemia and sepsis and trauma (NIH R01). These and other collaborative projects will provide novel insights into the moledular mechanism by which exercise training elicits profound protection against the development of various diseases.

Dr Nishaki Mehta’s research is conducted in collaboration with the Division of Biomedical Engineering. Everyday clinical needs are identified and addressed to create simple, meaningful solutions for safe and effective patient care. For instance, her team has developed a device to reduce the risk of bleeding and possibly improve wound healing outcomes in patients undergoing cardiac implantable pacemaker and defibrillator placements. The clinical trial is currently pending approval from the hospital review board. She has also developed a patient centric compression stocking which will deliver the same compression with minimal effort owing to a fulcrum mechanism which can amplify the pressure to improve efficiency. Volunteer testing is underway to demonstrate the efficacy. Another active effort is development of a modified scalpel which can reduce injuries during cardiac procedures and deliver controlled incision depths. She is also working with the Division of Computer Engineering to develop and validate an algorithm that can improve diagnostic pathways for discrimination of tachycardia in cardiac implantable defibrillators.

Dr Mehta’s clinical research focusses on risk factor modification for atrial fibrillation. Her team has obtained a research grant to evaluate the impact of dietary patterns on the gut microbiota which can be the signature to systemic inflammation. This can impact atrial fibrillation outcomes. Patient enrollment will begin this fall.

Dr Kenneth Bilchick As UVA’s Director of Electrophysiology Research, Dr Bilchick oversees a broad program of research related to heart rhythm disorders and heart failure. Ongoing clinical trials and studies supported by the NIH, AHA, and other sources focus on the impact of advanced cardiac imaging modalities such as cardiac magnetic resonance on improving clinical outcomes and establishing mechanisms of disease in these patients. Many of these patients have conditions such as heart failure meeting criteria for cardiac resynchronization therapy, atrial fibrillation, ventricular tachycardia, and supraventricular tachycardia. Dr Bilchick has an active program related to evaluation of outcomes after ICDs in the National Cardiovascular Data Registry. He also has ongoing collaborations with Dr McNamara, Dr Epstein, Dr Holmes, and Dr Mazimba.

Dr J. Randall Moorman’s research focuses on using Big Data to improve clinical outcomes. Dr Moorman is inaugural director of the University of Virginia Center for Advanced Medical Analytics (UVA CAMA), a multi-disciplinary resource for UVA investigators, allowing clinicians and quantitative scientists to make efficient use of Big Data to solve emerging complex health system medical engineering problems. The Center fosters innovative ways of addressing widespread and potentially devastating illness and provides the framework to facilitate commercialization of any new transformative technologies. The ability to learn from Big Data has the potential to improve quality of patient care while reducing cost by providing the most robust evidence base for individualized patient management. Specifically, Big Data analytics can add information about effectiveness of current best practice methods, suggest improvements to care pathways and, in its most advanced application, provide early warning of specific threats to a patient’s health. Dr Moorman’s lab studies have predictive analytics modeling, and predictive monitoring can improve clinical outcomes in neonates, children and adults.

 

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