We use an integrative bedside-to-bench-to-bedside approach to translational research. Investigators in the Division of Cardiothoracic Surgery study mechanisms underlying several key cardiovascular diseases including: thoracic aortic aneurysms, myocardial infarction and ischemia-reperfusion, non-ischemic dilated cardiomyopathy, pressure overload hypertrophy, arrhythmias (atrial fibrillation), and the development of pulmonary arteriovenous malformations. We use a wide array of biochemical and molecular biological techniques, to assess cellular signaling pathways and signaling intermediates that contribute to the pathogenesis of cardiovascular disease. We typically obtain patient samples for initial hypothesis testing, then move to animal models and cell culture systems to establish mechanisms. The primary goal of our mechanistic studies is to translate our findings back into animal models, and ultimately back into patients in the form of novel treatment that address critical need areas. Our key research interests and ongoing projects in the laboratory include:
Thoracic Aortic Aneurysms. The primary focus of the laboratory is the study of thoracic aortic aneurysms (TAAs), or the unanticipated dilatation of the major vessel delivering blood from the heart to the body. There are numerous etiologies of TAAs including genetic disorders, such as Marfan syndrome and congenital cardiovascular malformations such as a bicuspid aortic valve, however most commonly TAAs are idiopathic. TAAs often remain asymptomatic and are usually diagnosed serendipitously during a routine physical examination or work-up for another medical issue. Once diagnosed, a “watch and wait” surveillance program is initiated until the risk of aortic rupture outweighs the risk of the surgical repair. This approach results in a progressively weakened aortic wall which is manifested as gross dilatation that progresses to rupture if left untreated. Current treatment options are limited and consist of surgical reconstruction or endovascular intervention; neither of which addresses the underlying pathways which drive this devastating disease. TAA development is influenced by a series of interrelated mechanisms that disrupt extracellular matrix (ECM) homeostasis through the stimulation of proteolytic pathways mediated by the matrix metalloproteinases, and dysregulation of the production and deposition of ECM proteins. Importantly, these mechanisms are associated in part with changes in the resident aortic cellular phenotype. Using a large biorepository of TAA tissue and plasma specimens, collected through collaborative agreements with surgeons at Duke University, the University of Pennsylvania, and Yale University, basic hypotheses are tested to identify signaling pathways and intermediates that are associated with TAA presence. Then both a small (mouse) and large (pig) animal model of TAA serve as the test bed for validating specific mechanisms, through the use of targeted transgenics and knockouts, specific interventional studies, and novel medical device testing. Ongoing TAA studies include:
Identification of specific biomarkers capable of predicting the presence of TAA in patients
Use of biomarker profiles to determine the optimal time for surgical intervention, or efficacy of an applied intervention
Identification of critical signaling pathways and intermediates involved in the regulation of ECM homeostasis
Identification of novel therapeutics to intervene in the ECM remodeling process in an effort to attenuate TAAprogression
Use of advanced imaging techniques to predict regional ECM remodeling within the aortic wall in order to predictrupture risk in patients with TAA
Ex vivo mechanical testing to examine age-dependent physiological changes in aortic structure, function, and cellular phenotype
Use of bioengineering principles to develop novel drug delivery systems (spheroids)
Use of tissue engineering techniques to develop biocompatible vascular conduits for aortic grafting
Myocardial Infarction and Ischemia-Reperfusion. Myocardial infarction (MI), commonly known as a heart attack, results from the interruption of blood supply to a part of the myocardium (ischemia), causing the myocytes in the afflicted region to become damaged or die. While state of the art reperfusion techniques have dramatically improved the outcome from acute MIs, the MI region becomes the nidus for long term remodeling, which includes activation of the matrix metalloproteinases. This laboratory previously demonstrated that pharmacological inhibition of the matrix metalloproteinases can prevent expansion of the MI region and left ventricular dilation after MI. In addition, transgenic mice deficient in the expression of key matrix metalloproteinases, show similar results demonstrating the attenuation of left ventricular dilation. These studies were the rationale for a large multi-center clinical trial (PREMIER), which tested the efficacy of matrix metalloproteinase inhibition in post-MI subjects. Ongoing MI/I-R studies include:
Studying the role of microRNA regulation of the matrix metalloproteinases in the left ventricle remodeling after MI.
Elucidation of the role of the matrix metalloproteinases on development of post-MI ventricular arrhythmias; the leading cause of sudden death in patients who have had an MI.
Non-Ischemic Dilated cardiomyopathy. Dilated cardiomyopathy, the most common form of non-ischemic cardiomyopathies, is a condition in which the left ventricles (and other chambers as well) become enlarged and lose pumping efficiency. This results in decreased blood flow to the body and adversely affects other organ systems. In this process the left ventricle dilates, as does the mitral valve annulus, rendering the mitral valve incompetent and allowing regurgitant blood flow back into the left atrium. Our laboratory previously demonstrated that the change in left ventricular geometry and function with non-ischemic dilated cardiomyopathy was associated with induction of the matrix metalloproteinases in both human specimens, as well as in a porcine model, in which this form of cardiomyopathy was induced by chronic tachycardia. Moreover, myocytes isolated from the left ventricles after the development of this form of cardiomyopathy demonstrated reduced contractile function when subjected to electrical stimulation. Using a large animal translational model of dilated cardiomyopathy we tested the effects of therapies such as angiotensin converting enzyme inhibition, angiotensin receptor blockade, endothelin receptor blockade, calcium channel blockers, and matrix metalloproteinase inhibitors amongst others, on the progression of changes in left ventricular geometry, pump function, and isolated myocyte contractility. A number of these agents were subsequently examined in clinical trials for efficacy in patients. Ongoing studies include:
Investigating the effects of these agents on mitral valve regurgitation
Evaluating devices/surgical procedures designed to minimize regurgitant flow through the mitral valve, and to determine the effect on resident cellular form and function.
Pressure Overload Hypertrophy. Hypertrophic cardiomyopathy (HCM) is a primary disease of the myocardium in which the walls of the heart thicken (hypertrophy). The occurrence of HCM is a significant cause of sudden unexpected cardiac death in patients of all ages. Consequently, studies were performed in large and small animal models where left ventricular hypertrophy was induced secondary to aortic stenosis or banding of the transverse aorta. Results from these studies demonstrated that enhanced matrix metalloproteinases activity was counterintuitively associated with increased signaling in profibrotic pathways. Interestingly, in a transgenic mouse line which overexpresses a membrane-bound matrix metalloproteinase (MT1-MMP), this phenomenon was demonstrated further linking enhanced protease activity with increased left ventricular fibrosis and implicating a role for MT1-MMP. Ongoing studies include:
Examination of the mechanisms linking increase MT1-MMp activity with increased myocardial fibrosis in the setting of pressure overload hypertrophy
Identification of circulating biomarkers to be used to diagnose the presence of HCM.
Arrhythmias (atrial fibrillation). Atrial fibrillation (AF) is the most common cardiac arrhythmia (irregular heart beat). AF may be asymptomatic, but it is often associated with palpitations, fainting, chest pain, or heart failure. Atrial fibrillation may be treated with medications to either slow the heart rate to a normal range ("rate control") or revert the heart rhythm back to normal ("rhythm control"). Synchronized electrical cardioversion can be used to convert AF to a normal heart rhythm. AF is often associated with enlargement of the atria and structural remodeling of the atrial myocardium. Using patient specimens, this laboratory reported that AF was associated with significant changes in the myocardial abundance of the matrix metalloproteinases and their tissue inhibitors. Ongoing studies include:
Identification of circulating biomarkers that can be used to predict patients likely to relapse into AF following cardioversion
Elucidation of the role of matrix metalloproteinases and their inhibitors in the structural changes that enhance arrhythmogenicity
Pulmonary Arteriovenous Malformations. Congenital anomalies resulting in single ventricle physiology represent one of the most complicated and challenging defects encountered in children with congenital heart disease. As part of a three stage surgical palliation, the Glenn superior cavopulmonary anastomosis is commonly performed to decrease the volume overload in hypoplastic heart infants. However, the durability of this complex procedure is limited by the development pulmonary arteriovenous malformations (PAVMs); arising through aberrant angiogenesis. PAVM formation results in right-to-left shunting of blood through the lungs, bypassing gas exchange, and resulting in progressive cyanosis, hypoxia, and increased morbidity and mortality of the babies suffering from this condition. The prevalence of PAVMs has been reported to be as high as 60-70% in patients following introduction of the Glenn shunt. This laboratory has recently developed a large animal model to define mechanisms responsible for PAVM initiation and development. Ongoing studies include:
Identification of the underlying mechanisms that drive PAVM development
Evaluate the role of cellular phenotype change in pulmonary artery smooth muscle and endothelial cells isolated from Glenn shunt lungs versus normal lungs
Determine the contribution of pulsatile flow dynamics versus altered angiogenic signaling in driving PAVM development
Identification of circulating factors that contribute to PAVM development in babies who have undergone the Glenn Shunt procedure