Research

Our clinical research programs have provided innovative information regarding the rehabilitation of older patients with heart disease, prevention of disability, the cost-effectiveness of cardiac rehabilitation, the treatment of high cholesterol and other risk factors in cardiac rehabilitation, and the treatment of obesity in heart patients

 As an NIH funded investigator since 2019, Dr. Sherrie Khadanga’s research pertains to ways to improve participation of cardiac rehabilitation as well as optimizing exercise training among those in cardiac rehab. Her research group has examined ways to improve aerobic fitness among women as well as interventions to increase cardiac rehab participation for low income individuals.

Our clinical strength in multimodality imaging and patient-centered cardiac testing translates into multiple research endeavors.  We benefit from close intra-divisional and inter-departmental collaboration.  For example, there are ongoing projects involving Echocardiography and Interventional Cardiology around structural interventions.  Further, we collaborate closely with the Department of Radiology for Cardiac Computed Tomography (CCT), Cardiac Magnetic Resonance Tomography (CMR), and Nuclear Myocardial Perfusion Imaging (MPI), resulting in joint clinical and research efforts.

Echocardiography:  Our high-volume echo laboratory has a long record of research activities ranging from assessment of mitral valve morphology to resistive force determination in heart failure. Technology includes 2D and 3D transthoracic and transesophageal echocardiography, stress echocardiography, and the full range of Doppler imaging, with strain and 3D modeling. Current projects include diagnosis and management of coronary artery occlusion in TAVR (M Tischler), echocardiographic parameters informing exercise capacity (M Meyer), and heart rate in heart failure with preserved ejection fraction (M Meyer). 

Cardiac Magnetic Resonance Tomography (CMR): The cardiac MRI laboratory provides a strong research commitment to advancing the field of cardiac imaging. Multiple CMR systems are in use. As a Philips demonstration site, we have early access to novel technologies. Accordingly, research efforts have included technical protocol enhancements and validation. 

Multimodality imaging research (Echo and CMR) has focused on the natural history and pathophysiology of mitral regurgitation and the differential effects of mitral valve repair and replacement surgeries. We have also elucidated effects of alteration in ventricular geometry on exercise performance and ventricular filling in patients with congestive heart failure and have been quantifying the extent of myocardial infarction, determinants of favorable responses to resynchronization therapy, and regional myocardial viability.  

Nuclear Stress Testing / Myocardial perfusion imaging (MPI): The nuclear cardiology laboratory has a long history of research in coronary artery disease prognosis with MPI.  Technology includes several SPECT cameras and PET perfusion and metabolic imaging. Recently, research efforts have included patient-centered PET and SPECT imaging, optimizing resolution recovery algorithms, improvement of PET scatter correction, and imaging of Cardiac Sarcoidosis.

At the University of Vermont, our clinician-scientists are conducting cutting-edge translational research to better understand the mechanism underlying atrial fibrillation and improve treatment for patients with cardiac arrhythmias and heart failure. These efforts include the development of new technologies for mapping of atrial fibrillation as well as clinical studies focused on innovative pacemaker treatments such as Bachmann Bundle pacing and heart rate modulation in heart failure with preserved ejection fraction. Additionally, the cardiac electrophysiology team is working on advancing ablation energy delivery methods for ventricular tachycardia ablation. These initiatives aim to translate scientific discoveries into better, more effective patient care.

 Participation in clinical investigations and multi-center trials is essential for advancing medical science. By joining these studies, patients gain access to cutting-edge technology and treatments that may not be available elsewhere. Additionally, participants can find satisfaction in knowing they are contributing to the development of therapies that will benefit future generations with similar health conditions. Patients at the University of Vermont have the opportunity to participate in these clinical trials, helping to shape the future of healthcare while receiving advanced, potentially life-changing care.

 The following clinical studies and trials are a few examples of our cardiac arrhythmia research:

• Cardiac Resynchronization Therapy using His/Left Bundle Pacing vs Left Ventricular Epicardial Pacing in Patients with Heart Failure, NCT05650658
• His-Bundle Corrective Pacing in Heart Failure, NCT05265520
• Physiologic accelerated pacing as a treatment in patients with heart failure with preserved ejection fraction (PACE HFpEF), NCT04546555
• Improving outcomes in atrial fibrillation: Evaluation of chronic beta-blocker use versus as-needed pharmacological rate control, NCT05745337
• Exercise capacity in patients with heart failure with preserved ejection fraction before and after ablation of atrial fibrillation, NCT05376748
• Multipolar ablation for the treatment of midmyocardial ventricular tachycardia

Our faculty and colleagues in the Departments of Molecular Physiology and Biophysics, Pharmacology and Biology have developed an internationally renowned Program in Cardiomyopathy and Heart Failure. The participating scientists currently attract over $7,000,000 annually in NIH funding to support research in these areas. This support includes two Program Project Grants and two NIH Research Training Grants.

Components include extensive bench research focused on the contractile machinery, excitation-contraction coupling, myocardial relaxation and diastolic function, skeletal muscle myopathy, gene transfer and proteomics of cardiomyopathic and failing myocardium. Programmatic areas include:

• hypertrophic and familial dilated cardiomyopathy, for which genetically engineered animals are used to simulate human disease;
   
• animal preparations exhibiting acquired hypertrophy and the transition to failure; and
   
• cardiomyopathic and failing human myocardium.

The latter work utilizes myocardial tissue from explanted hearts as well as biopsy tissue obtained in the operating room by our cardiac surgeons. These have allowed study of tissue from diverse patients including those who do not have end-stage disease such as those with diabetes, cardiomyopathy, and variably-compensated valvular heart disease. A new program focusing on the biology of reverse remodeling during resynchronization therapy for heart failure has recently been funded.

Clinical research emphasizes investigation of contractile reserve and diastolic function in cardiac hypertrophy and failure, valvular disease and diabetes, characterized with resting and stress echocardiography. A novel project examining mechanisms of cardiovascular maladaptation in relation to natriuretic hormone secretion in patients with congenital heart disease and acquired heart failure is well-established. Along with the new above program described above, magnetic resonance imaging will be employed to predict responses to resynchronization therapy in heart failure patients. Patients are also considered for participation in clinical trials, including both investigator-initiated local research and multi-center trials of novel treatments.

Dr. Martin LeWinter has had a longstanding interest in ventricular and myocardial function. Current areas of interest include mechanoenergetics of the myocardium in acquired heart failure and genetic models of cardiomyopathy. The goal is to use whole heart mechanoenergetic, skinned strip and in vitro motility and force analyses to provide a comprehensive understanding of abnormalities of the myofilament in disease.

A second area is diastolic left ventricular function, in particular the role of the giant cytoskeleton protein titin as a determinant of left ventricular stiffness and restoring forces. A third area is the effect of diabetes on myocardial function, both calcium handing and the myofilament. These studies utilize samples of human myocardium obtained in the operating room.

The Interventional Cardiology program at the University of Vermont Medical Center is at the forefront of clinical research with the goal of bringing cutting edge therapies to our community.

Our faculty are engaged in both investigator-initiated research and multicenter clinical trials across a broad spectrum of Interventional Cardiology practice. We are one of the leading clinical trial sites in the country in the field of coronary intervention and structural heart disease intervention. Through these ongoing projects, our faculty is regionally and nationally recognized for leadership in research, publication and device development.

Multicenter Clinical Trials

Our program participates in clinical trials investigating new device therapies and new treatment indications for established therapies in the field. We are recognized as a leading clinical trial site in the country. Many of the trials we have participated in have led to Food and Drug Administration (FDA) approval of new treatments.

Some of the trials that we are actively recruiting in are:

• The RESTORE TAV trial is studying the safety and effectiveness of repeat transcatheter aortic valve replacement (TAVR) in patients with previously implanted but failing transcatheter heart valves.
• The EXPAND TAVR II trial is a global study evaluating the safety and effectiveness of the Evolut™ TAVR system in patients with moderate, symptomatic aortic stenosis, aiming to determine if early intervention with TAVR, alongside guideline-directed medical therapy, can improve outcomes compared to medical therapy alone.
• The APOLLO Trial is a global study evaluating the safety and efficacy of the Medtronic Intrepid™ Transcatheter Mitral Valve Replacement (TMVR) System in patients with severe symptomatic mitral regurgitation who are unsuitable for conventional surgery.
• The COMPLETE TAVR trial is evaluating whether performing staged coronary stenting (PCI) improves outcomes compared to medical therapy alone in patients with severe aortic stenosis and coronary artery disease undergoing TAVR.
• The SPYRAL Renal Denervation Registry is a global study tracking the long-term safety and effectiveness of the Symplicity Spyral system in reducing blood pressure in patients with uncontrolled hypertension.

Investigator-Initiated Research

Our group translates mechanistic research in thrombosis from the bench to the cardiac catheterization suite. Our group is actively involved in conducting validation studies for a novel biomarker of platelet activation, FcyRIIa, developed by our division chief Dr. David Schneider. The study aims to determine whether platelet expression of this biomarker is associated with increased cardiovascular risk.

We are also one of the founding sites for the Northern New England Cardiovascular Disease Group Consortium (NNECDSG), a regional registry of cardiology and cardiac surgery procedures. Some of the projects conducted by our trainees and faculty using the NNE registry include trends of TAVR and SAVR use in young adults, acute kidney injury in TAVR recipients, and impact of distance to PCI center on outcomes of STEMI patients.

Our faculty have conducted important practice-informing studies using data from a number of national databases such as NCDR TVT, Vizient Clinical Data Base, and Trinet X.

Extensive research focuses on the role of and mechanisms underlying thrombosis and inflammation in ischemic heart disease. Platelets are pivotal in thrombosis, and antiplatelet agents are pivotal in the treatment of ischemic heart disease. Paradoxically, however, our ability to assess platelet function and to quantify effects of antiplatelet agents is limited.

Our group has developed a sensitive and specific method to assess platelet function. With the assay developed, we have demonstrated that assessment of the potential for platelets to activate (i.e. platelet reactivity) can be used to identify patients at high and low risk of subsequent cardiac events. We have used this approach to define more effective modes of treatment for patients with acute coronary syndromes.

Our group is actively involved in defining optimal anti-thrombotic therapy with both anticoagulants, and antiplatelet agents. Research efforts range from mechanistic studies in vitro to translational studies designed to apply novel laboratory methods to improve treatment and clinical trials testing the efficacy of novel therapeutic agents and combinations.

We have developed and validated methods by which biochemical quantification of the extent of myocardial infarction can be accomplished in vivo based on sequential analyses of concentration in plasma of macromolecules (CK, MB CK isoenzymes, and other moieties such as troponin I and troponin T) and applied them to determine the extent of infarction is an important determinant of prognosis after myocardial infarction and furthermore, whether the extent of infarction can be modified by interventions that reduce myocardial oxygen requirements or increase myocardial oxygen supply.

This work has had a major impact on how patients with acute myocardial infarction are treated and led to a reduction of mortality secondary to treatments, such as thrombolysis that were validated initially with the methods developed.

We have contributed to the initial development of cardiac positron emission tomography with the use of positron-emitting radionuclides including carbon-11 labeled palmitate, the physiological fuel of myocardium, and applied it to further delineate the nature of evolution of infarction and its interdiction with interventions salvaging ischemic myocardium including coronary thrombolysis with clot-selective fibrinolytic agents.

We have pioneered coronary thrombolysis with the use of the clot-selective plasminogen activator, tissue-type plasminogen activator (t-PA), in studies of cells in culture, experimental animals, and mechanistic clinical studies in patients with acute myocardial infarction with quantification of the extent of infarction by positron emission tomography and analysis of time activity-curves in blood of enzymes liberated from myocardium. This work provided a foundation for subsequent large-scale, multicenter clinical trials in which Dr. Burton Sobel helped to demonstrate the efficacy of coronary thrombolysis with clot-selective agents, heparin, and aspirin in the reduction of death associated with coronary artery disease and acute myocardial infarction.

Recently we delineated altered fibrinolysis in blood and altered proteolytic activity in vessel walls as mediators of deleterious effects of hyperinsulinemia associated with insulin resistance, impaired glucose tolerance, and type 2 diabetes, thereby helping to elucidate the pathophysiology of macrovascular angiopathy in type 2 diabetes. This work, coupled with results of studies demonstrating that insulin sensitizers normalize fibrinolysis in patients with type 2 diabetes, is changing the approach to their treatment directed at reducing the risk of heart attack and cardiac death.

Platelet Biology, Coagulation, and Fibrinolysis

We have demonstrated that the combination of hyperinsulinemia, hyperglycemia and increased concentrations of free fatty acids in blood of healthy subjects increases the concentration and activity of the primary inhibitor of fibrinolysis, plasminogen activator inhibitor type-1.

In vitro studies delineated that increased concentrations in blood of insulin increase expression of PAI-1 through stabilization of mRNA. In addition, we demonstrated that free fatty acids increase expression of PAI-1 by increasing transcription of PAI-1 through a fatty acid response region in the 5’ untranslated region of the PAI-1 gene.

In addition, we have developed a semi-quantitative method to assess plaque morphology in mice. This approach has been implemented to determine the role of genetic modifications such as increased vascular smooth muscle expression of PAI-1 in the genesis of atherosclerotic lesions. We have developed and implemented a sensitive and specific means for assessment of platelet function that utilizes flow cytometry to characterize specific components of platelet reactivity. Our work has utilized this method to delineate the prognostic implications of platelet reactivity and to characterize the effects of selected treatment modalities on platelet function and prognosis.