Cardiovascular Research

Jean Marie Ruddy MD in CV lab

The Cardiovascular Research Laboratory is nationally recognized for their contributions and expertise toward understanding the dynamic relationships between changes in tissue composition and resident cellular phenotype that occur in cardiovascular disease development. The laboratory is designed to be a functional platform to facilitate both basic and clinical research studies carried out by interested members of the Cardiothoracic Surgery and Vascular Surgery Divisions. Using an integrative bedside-to-bench-to-bedside approach, our investigators study the pathological mechanisms underlying a broad range of cardiovascular diseases including thoracic and abdominal aortic aneurysms, myocardial infarction, diastolic heart failure, and mechanisms of arrhythmogenesis. We use a wide array of biochemical and molecular biological approaches, as well as small and large animal models, to assess cellular signaling pathways and signaling intermediates that contribute to the pathogenesis of cardiovascular disease, with the primary goal of developing new technologies to treat these conditions. This is accomplished in an inclusive and supportive environment designed to train and equip surgeon scientists, whether they are established clinicians, seasoned basic/translational scientists, new faculty, or residents just starting their careers.

The Cardiovascular Research Laboratory is located on the 3rd floor of the Thurmond/Gazes Research Building, and houses the biochemistry laboratory, the tissue culture facility, and the Volpe Multidisciplinary Mouse Physiology Laboratory. In addition, we have direct access to small and large animal housing, as well as, large animal chronic and acute operating suites. Please contact Dr. Jones or Dr. Ruddy if you any questions or are interested in any research opportunities; we always have openings for interested graduate/medical students and post-doctoral fellows.

The overall goals of the laboratory are focused on advancing scientific knowledge and clinical care through training and equipping surgeon scientists, whether they are established clinicians, basic/translational scientists, new faculty, surgery residents, or graduate and medical students, just starting their careers.

Research in the Jones Laboratory:

1) Pathogenesis of thoracic aortic aneurysms. This area of research focus examines the initiation and progression of thoracic aortic aneurysms (TAAs), with emphasis on understanding the regulation of fibroblast phenotype and the role (production, release, signaling) of transforming growth factor-beta (TGF-beta) in aneurysm development. There are three specific projects areas we are working on: a) understanding the time-dependent (early vs. late) and cell-type specific (fibroblast vs. macrophage) expression of membrane type-1 matrix metalloproteinase (MT1-MMP) during TAA formation and progression and its mechanistic role as a mediator of TGF-beta release in TAA development; b) elucidating the post-transcriptional (microRNA) and post-translational (phosphorylation) regulation of MT1-MMP and how its abundance, activity, and cellular localization affect cellular signaling and peri-cellular proteolysis; and c) understanding the mechanisms of how alterations in the extracellular matrix changes the mechanical environment, and how that translates to modifications in cellular phenotype and function. We utilize a murine surgical model of TAA, taking advantage of various transgenic and inducible-conditional mouse strains, to examine the cellular, molecular, and structural properties of aortic dilatation.  

2) Mechanisms of acute and chronic myocardial toxicity following anthracycline treatment. This area of research focuses on the development of a small animal model of myocardial toxicity. These studies will utilize the delivery of a chemotherapeutic agent (Doxorubicin) in mice by osmotic pump over a 2-week prolonged delivery period, in order to examine myocardial changes by echocardiography during the acute (during + 1-2 wks post-treatment) and chronic (2-4 months post-treatment) phases of myocardial toxicity. The ultimate goal is to identify pathways involved in late-onset myocardial fibrosis leading to cardiomyopathy, and intervening in those pathways in order to prolong disease-free survival.

3) Clinical outcomes research & basic science. During the COVID-19 pandemic, the laboratory established a close collaboration with several of our CT Division Surgeons to initiate new projects mining local and national surgical outcomes databases and combining the results with basic science principles to: 1) establish relationships between common clinical parameters and the risk of death due to arrhythmia following left ventricular assist device implantation; and 2) to identify circulating inflammatory profiles that may predict difficult post-operative recovery following major cardiac procedures. While the goals of both projects are focused on improving clinical care, they clearly represent the new avenues of research, combining both clinical and basic science, providing academic support to our surgeon scientists.


Research in the Ruddy Laboratory:

1) Pathogenesis of Abdominal Aortic Aneurysms. This project area examines hypertensive vascular remodeling as it relates to the formation and growth of infrarenal abdominal aortic aneurysm (AAA). We focus on the role of inflammation as a biomechanical link between these two pathologies with particular interest in the serum and glucocorticoid-regulated kinase-1 (SGK-1). Activation of SGK-1 in abdominal aortic vascular smooth muscle cells (VSMCs) is hypothesized to result in the production of proinflammatory cytokines that recruit macrophages to secrete proteases and propagate AAA growth. We utilize murine models of hypertension (AngiotensinII-derived versus spontaneous), have developed a model of chronic inflammation with Interluekin-6 infusion that independently influences aortic remodeling, and employ the validated periadventitial calcium chloride model of AAA, thereby allowing our investigations to apply multiple biomechanical stressors and more closely replicate the pathology of patients with AAA. Harvested aortic tissue can then undergo molecular analysis and by elucidating the mechanism of macrophage infiltration into the aortic wall, we expect to identify pharmacotherapeutic targets which may be utilized to treat small AAA and prevent growth.

2) The Mechanics of Aortic Dissection. Uncomplicated type B aortic dissection (TBAD) are managed medically, but many progress to aneurysmal degeneration and ultimately require surgical repair of this complex anatomy. Understanding how the flow in the true versus false lumen influences progressive dilation may allow providers to predict which patients are at high risk for aneurysmal degeneration and may therefore benefit from endovascular surgical repair early in their course. We hypothesize that the number and location of intimal flap fenestrations significantly influences these hemodynamic parameters and are utilizing silicone models as well as porcine aortic tissue to study TBAD with 4D flow MRI.

3) Preserving Vessels for Biologic Conduit. As patients with peripheral artery disease (PAD) progress to critical limb ischemia (CLI), open surgical bypass is often required. In cases where patients have inadequate autologous vein, prosthetic conduits are utilized but are known to have inferior rates of patency. Utilizing a proprietary solution that has already been demonstrated to preserve lung tissue with minimal endothelial and stromal cell damage, we are investigating preservation of superficial femoral artery and saphenous vein with a focus on maintaining both the native matrix structure and the functional cellular components in order to provide an improved off-the-shelf cellularized biologic conduit. This investigation employs tissue myograph experimentation to quantify vessel compliance and contractility and plans to employ a large animal extremity bypass model to demonstrate patency.


Current Laboratory Members:

Jeff Jones, Ph.D......................... PI/Laboratory Director, Division of Cardiothoracic Surgery

Jean Ruddy, M.D........................ PI/Laboratory Co-Director, Division of Vascular Surgery

Rupak Mukherjee, Ph.D............. Staff Scientist/Statistician

Ying Xiong, Ph.D........................ Staff Scientist/ Laboratory Manager

Nagarajan Muthu, M.D.............. Surgical Resident/Post-doctoral Trainee

SaraRose Hall, BS...................... Laboratory Technician

Lena Emrich, M.D...................... Visiting Scholar/Cardiothoracic Surgeon

Sanford Zeigler, M.D................. Cardiothoracic Surgeon

Nicholas Pope, M.D................... Cardiothoracic Surgeon