Overview of Research Programs
The research activities of the Cardiovascular Medicine Division are best viewed within the broader context of the Case Cardiovascular Center (CCC). The mission of the CCC is to develop premier clinical, research, and education programs in heart and vascular disease. The structure of the Center includes research (Case Cardiovascular Research Institute—CVRI) and clinical (University Hospitals Harrington Heart & Vascular Institute—UH-HHVI) arms.
One of the primary missions of the CCC is the development of premier research programs that span the full spectrum of activities from basic bench-side research to translational research (“first-in-man”) and clinical trials. The CVRI is focused on basic and translational studies. The Research & Innovation Center (RIC) of the UH-HHVI is dedicated to innovative clinical trials and applied technology. Investigators in the CVRI and RIC are faculty members at UH Cleveland Medical Center, CWRU, and the VA. The CVRI/RIC are closely linked with the Institute for Transformative Molecular Medicine (ITMM) and the newly established Harrington Discovery Institute (HDI) that are focused on discovery of fundamental mechanisms governing cellular function at the molecular level and advancing those discoveries by developing novel therapeutic approaches to treat human disease. In addition, research faculty and trainees in other Divisions (Pulmonary, Hematology-Oncology, Endocrinology, General Medicine), other CWRU School of Medicine Departments (Physiology & Biophysics, Genetics, Biomedical Engineering, Pathology, Neuroscience, and Radiology) as well as Departments with the Lerner Research Institute (Cell Biology, Molecular Cardiology) collaborate with investigators in the CVRI and RIC
The net result of these efforts has been (1) the establishment of premier research programs in basic/translational/and clinical research, (2) recruitment of outstanding clinician-scientists and research scientists, (3) acquisition of robust funding including multiple K-grants, R01s, and a T32 Cardiovascular training grant.
Major Research Areas:
(a) Basic & Translational Research:
- Vascular Biology – Research efforts focus on the role of vascular cells in blood vessel development, angiogenesis, inflammation, injury & repair.
- Cardiac Myocyte Biology – Research efforts are focused on understanding fundamental mechanisms governing the development, progression, and complications of cardiac hypertrophy and failure.
- Gene Regulation – Research efforts are directed towards understanding basic molecular mechanisms governing gene regulation with a focus on DNA-binding proteins and chromatin-modifying factors.
- Inflammation & Immunity – The main focus is on the role of innate immunity – especially the development, differentiation and activation of myeloid lineage cells and their impact on the development of atherosclerosis, myocardial infarction, and insulin resistance syndromes.
- Stem Cell & Regenerative Medicine – These research efforts are investigating the potential of several types of adult stem cell (umbilical cord, bone marrow, and circulating EPCs) in the treatment of cardiovascular disease. These efforts include elucidating molecular mechanisms aimed at reprogramming, expanding and genetically modifying adult stem cells and evaluating their therapeutic potential.
- Arrhythmias – Using cardiac electrophysiological and pharmacological techniques, research efforts are focused on understanding mechanisms underlying the development of atrial flutter/fibrillation as well as novel pharmacologic and mechanical approaches to the treatment of this arrhythmia. In collaboration with the Department of BioMedical Engineering in the School of Engineering, faculty members are investigating OCT-based methods to image the atrial wall and monitor ablation procedures. Further, a novel OCT-based pace-maker is under development.
(b) Clinical Research (Center for Research & Innovation):
Academic year 2012-2013 was notable for continued growth in clinical research. All clinical research activities in Cardiovascular Medicine, Cardiac Surgery, and Vascular Surgery are within the umbrella of the Center for Research & Innovation under the direction of Marco Costa, MD, PhD. The Center is supported by a lead administrator (Stacey Mazzurco, RN), 8 nurse coordinators, 1 research assistant, 2 regulatory and grants specialists and 1 grant accountant. At present, the CIR conducts a total of ~77 trials (~1650 patients) with an estimated total budget of more than 11.0 million dollars.
- Preventive Cardiovascular Medicine – Research efforts are focused on subclinical atherosclerosis testing using coronary calcium scoring. This program will also examine the correlation between coronary calcium scoring and novel cellular and molecular biomarkers, non-invasive vascular function testing and dual energy radiographic imaging.
- Advanced Heart Failure & Transplant - The primary research focus of this section is clinical investigation through participation in heart failure clinical trials, registries, and investigator initiated protocols. Major research areas include diastolic heart failure, mechanical circulatory support, sleep disordered breathing and heart failure, Vitamin D and heart failure, novel percutaneous ventricle restoration therapy, stem cell therapy and novel genetic and biomarker correlations.
- Electrophysiology - The primary research focus is clinical investigation through participation in clinical trials assessing new antiarrhythmic drugs, new oral anticoagulants, and advanced cardiac devices (including pacemakers, defibrillators, and special catheter electrodes) and ablation procedures to treat Atrial Fibrillation.
- Interventional Cardiovascular Medicine – Research activities include clinical trials testing novel coronary and vascular (renal, iliac, limb ischemia) devices, cardiac and vascular stem cell therapy, percutaneous repair of structural heart disease (PFO closure) transcatheter aortic valve replacement, left atrial appendage closure to prevent stroke, biodegradable stents to treat coronary artery disease, and catheter-based renal denervation to treat hypertension. Currently, faculty members of the CVRI serve as overall PIs of 5 multicenter, multinational trials testing novel drug-eluting stents to treat coronary artery disease as well as optical coherence tomography and percutaneous ventricle restoration therapy. The experimental Cath Lab is also involved with development and pre-clinical testing of novel devices and imaging systems, such as optical coherence tomography and novel drug-eluting stents, including biodegradable stents. The experimental lab also serves as a training site for both local and national/international physicians. A new experimental cathlab was purchased through a CTSC grant to investigate MSCT-based coronary physiology. There were 3 training activities (devices: Impella, Parachute, OCT) in 2012.
- Cardiovascular Imaging – Research efforts in this area range from pre-clinical work, clinical work and offline analysis of images acquired in outside institutions and submitted to the cardiovascular imaging core laboratories. The UH Cardiovascular Imaging Core Laboratories is one of the most comprehensive core laboratories in the world by offering services in a wide range of imaging modalities from invasive to non-invasive methods (e.g., angiography, intravascular ultrasound, optical coherence tomography, MRI, and CT), supporting both local physicians and national and international clinical trials. The core lab is the world leader in the development and application of OCT as a surrogate method for clinical trials, with > 2500 OCT images of human coronary arteries in its database. The core laboratory is also pioneering the use of multislice CT (MSCT) for structural heart disease guidance and device selection, MSCT for novel minimally invasive therapies like Transcatheter Aortic Valve Implantation (TAVI), and transcatheter left atrial appendage occlusion. It is also the only imaging laboratory providing imaging review and device recommendation for Parachute therapy (the first transcatheter device for heart failure of ischemic etiology). These efforts are supported by robust funding from the NIH as the state of Ohio.
- Cardiovascular and Pulmonary Rehabilitation – Research efforts include participation in a variety of NIH funded clinical trials focused on the exercise rehabilitation process, patient education, biobehavioral correlates of cardiovascular disease, and patient adherence to recommended therapy. Much of the research is multidisciplinary, and performed in conjunction with colleagues at the Francis Payne Bolton School of Nursing and Kent State University.
- Vascular Medicine – The primary research focus in Vascular Medicine is clinical research. Vascular medicine plays a primary role in supporting the critical limb ischemia program. The inaugural protocol for this program (IRB protocol #11931-02 Injection of autologous CD34-positive cells for improved symptomatic relief and ischemic wound healing in subjects with moderate or high-risk critical limb ischemia) was completed in 2010. IRB Protocol #10-11-16, a multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy, safety, and tolerability of ixmyelocel-T in subjects with critical limb ischemia and no options for revascularization. Aastrom REVIVE CLI was initiated in 2012. Additionally, both cardiovascular medicine and vascular surgery faculty are co-investigators in trials comparing the effect of various anti-platelet agents n PAD.
The Center for Wound Care actively supports protocols in dermatology as well as a Phase II trial investigating a novel therapy for patients with peripheral arterial disease (IRB #06-11-15), a randomized, double-blinded, placebo-controlled, phase IIa dose-ranging study to assess the safety, pharmacokinetics, and tolerability of multiple does of sodium nitrite in diabetic patients with peripheral arterial disease (PAD) – SONIC.
The endothelial function testing program with carotid intima-media thickness (CIMT) measurement and brachial artery reactivity testing (BART) currently supports research in collaboration with Infectious Disease, Dermatology, School of Dentistry. and CV Medicine. There are several on-going protocols using these techniques in the context of HIV disease (SATURN trial) and psoriasis. Finally, collaborative physician-investigator studies in collaboration with the radiology department are developing imaging and circulating biomarkers for PAD.
(c) Clinical Research (Louis Stokes Cleveland VA Medical Center):
Increased focus on research and innovation has increasingly become a priority in the Department of Cardiology at the Louis Stokes Cleveland VA Medical Center. To ensure success, a full time research nurse with secured payment from the VA has been employed. Current research activities include participation in clinical trials in the areas of Interventional Cardiology/Cardiac Surgery (Coronary Artery Revascularization Study – CARDS), Heart Failure (including an Investigator Initiated study in HF-ID) and Electrophysiology (Prospective Implanatable Cardioverter Defibrillation Study – PROVIDE).
(d) Institute for Transformative Molecular Medicine (ITMM):
The Institute for Transformative Molecular Medicine began operations in the Wolstein Research Building at the turn of 2010 under the Directorship of Jonathan Stamler, MD, who holds the Robert S. and Sylvia K. Reitman Family Foundation Chair in Cardiovascular Innovation. The mission of the ITMM is to generate fundamental insights into cellular function at the molecular level that will inform the conceptualization of therapeutic approaches to human disease. The ITMM currently houses faculty in the Departments of Medicine and Anesthesiology as well as clinical fellows and post-doctoral trainees.
The UH Harrington Discovery Institute (HDI, or the Institute) is a national model dedicated to physicians-scientists, enabling them to transform their extensive, cross-cutting knowledge into therapies and medicines that improve patients’ lives. It supports physician-scientists as they undertake fundamental research uniquely capable of changing the standard of care, generating insights into the clinical condition, and developing new treatments. Major areas of research focus within the ITMM & HDI include:
- The regulation of cellular signal transduction by endogenously generated NO that operates through the posttranslational modification of cysteine residues within proteins, and the role of dysregulation of this mechanism in a wide range of cellular pathologies.
- The regulation of blood flow and tissue oxygenation by nitric oxide (NO) that is processed and dispensed by red blood cells, and the role of dysregulation of this mechanism in a range of clinical issues including cardiovascular and pulmonary diseases and the deleterious consequences of blood transfusion.
- The regulation of skeletal and cardiac muscle contractility by NO and reactive oxygen species and the role of dysregulation of this mechanism in musculoskeletal diseases and in myocardial dysfunction.
- The cellular mechanisms that protect against the deleterious effects of endogenously generated NO, and the potential role of dysfunction of those mechanisms in pathophysiology.
- Identification and characterization of molecular alterations underlying the development and progression of cancer for the development of better diagnosis and treatments.