 Cardiac Surgery Research LaboratoryThe Cardiac Surgery Research Laboratory consists of an approximately 4,106 square foot research facility in Medical Science Research Building II. This laboratory supports the majority of basic research of the Section of Cardiac Surgery. The major areas of research focus on cardiac myocellular biology and cardiac myofilament structure and function. The Cardiac Surgery Myocellular Research Program is conducting studies on ischemic myocyte biology. Basic research in myocardial cellular physiology has focused on the metabolic alterations of the myocyte during ischemia, specifically with regard to stunning, preconditioning and cell signaling mechanisms. These studies have involved the use of both a retrograde perfused Langendorf rabbit heart model as well as a large animal model examining myocardial cellular physiology during global ischemia. Currently, the role of opioid receptors and cell signal transduction is being studied intensively at a molecular level. It has been noted that mammalian hibernation cellular physiology very closely parallels that of the altered cardiac cellular physiology seen with hypothermic ischemia utilized during cardiac surgery. However, these drastic subcellular and molecular changes seen with hypothermic mammalian hibernation, which include reduction of coronary flow with intracellular acidosis, hypoxia, hypothermia, ATP and energy store depletion and volume shifts, are well tolerated by hibernating animals, and in particular by the mammalian myocardium. Recent studies have revealed that opiate-like hibernation triggering or induction factors may play a role in maintaining cellular energy status and membrane integrity during hibernation, which could provide for "natural" cellular protection and metabolic inhibition for cardiac surgery or during other times when organ and cellular damage may occur. As evidence, plasma from deeply hibernating woodchucks containing a hibernation induction trigger (HIT) molecule which mimics natural hibernation, has been used to extend survival time of multiorgan autoperfusion systems. The opiate nature of HIT is well established and induces profound physiological depression mimicking natural hibernation: an anesthetized state, profound hypothermia, bradycardia, decreased renal function and feeding inhibition, which can be reversed or retarded by the opiate antagonists naloxone and naltrexone. Evidence indicates that the HIT molecule may initiate its potent metabolic inhibitory effects through specific membrane opioid receptors, and HIT may alter membrane geometry and potentially may be a membrane stabilizing agent. There is also evidence to suggest that the HIT molecule and the delta opioid DADLE may influence ATPases and preservation of ATP during ischemia, thereby potentially augmenting cellular and myocardial ischemic tolerance. Finally, in vitro cellular assays monitoring DNA and protein synthesis have noted profound alteration with HIT use. To determine the potential cellular protective effects of HIT molecules, or the synthetic delta opioid DADLE (D-Ala2-Leu5-Enkephalin), we have employed an isolated rabbit heart model, designed to simulate the cellular ischemic conditions found during cardiac surgery. In these studies, the delta opioids DADLE and DPDPE or the kappa opioids U50488H and Butorphanol have been administered into rabbits with remarkable cardiac preservation following ischemia. In addition, the mechanisms of this effect are also being examined at the cellular level. We first characterized the presence of functional opioid receptors in an immortalized mouse atrial cell line, HL-1. We utilize both HL-1 and primary cells from rabbit ventricle. This cellular format allows us to measure many simultaneous parameters of metabolism and viability. The Cardiac Myocyte Structure and Function Laboratory is investigating the role of troponin I (TnI) in the adult cardiac myocyte contractile response to protein kinase C. Protein kinase C (PKC) is activated in myocardium by several acute physiological stimuli and under several important chronic pathophysiological conditions, including ischemia. Acute activation of PKC by physiological agonists generally increases contractile function in cardiac myocytes. The cardiac isoform of TnI (cTnI) is one of the target proteins phosphorylated by PKC, and this regulatory thin filament phosphoprotein is postulated to have an important role in the positive inotropic response to PKC agonists. Ongoing experiments in the laboratory have recently determined that cTnI phosphorylation by PKC causes accelerated relaxation in cardiac myocytes. This enhancement in the rate of relaxation is removed in myocytes expressing the slow skeletal isoform of TnI, which is not phosphorylated by protein kinase C. Future studies are planned to define the cTnI site(s) phoshorylated by protein kinase C in the intact myofilament. Information gained from these studies can now be used to determine whether TnI phosphorylation and/or the TnI-mediated enhancement of relaxation produced in response to PKC is altered under physiological and pathophysiological conditions. Studies also are being carried out to understand the role individual protein kinase C isoforms play in the contractile response. In ongoing studies, we are examining the effects of protein kinase C isoform over-expression using viral-mediated gene transfer into adult rat and rabbit myocytes. The effects of dominant negative mutants for each isoform on contractile performance are also being examined in these cells. Increased expression is observed within 24 hrs of gene transfer and preliminary results indicate that basal contractile function is not altered significantly in myocytes over-expressing inidividual protein kinase C isoforms or dominant negative constructs. Future studies will focus on agonist-mediated changes in contraction within these cells, as well as determination of isoform localization under basal and agonist-mediated conditions. Many of the above basic research projects are being performed in collaboration with other departments including: Internal Medicine, Physiology, and Pharmacology. Techniques
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Location/Contact Opioid Hibernation Factors for Myocardial PreservationInvestigators: Steven F. Bolling, MD, Surgery; and John Traynor, PhD, Pharmacology The use of natural and synthetic hibernation factors for preserving the heart during surgery and for transplant. The CAM Research Center for Cardiovascular DiseasesInvestigators: Steven F. Bolling, MD, Surgery and Sara Warber, MD, Family Medicine (Center); Martin Stevens, MD, Endocrinology (Project 1); Keith Aaronson, MD, Internal Medicine (Project 2); and Sara Warber, MD, Family Medicine (Project 3) This study investigates complementary and alternative medicine (CAM) modalities used to treat cardiovascular disease and promote cardiovascular health. Qigong and Psychosocial Effects during Rehabilitation after Cardiac SurgeryInvestigators: Sara Warber, MD, Family Medicine; Steven F. Bolling, MD, Amy Ai, PhD, Surgery; and Christopher Peterson, PhD, Psychology This interdisciplinary project explores two apects; the first objective is to explore the role of spirituality and religiousness in the adjustment of midlife and older aged patients following cardiac surgery. A second objective of this study is to investigate the effects of External Qigong, an ancient Energy Healing Therapy, which may improve incisional wound healing and the overall sensation of pain for patients recovering from cardiac surgery. Clinical Evaluation of Acorn Cardiac Support Device Therapy in Patients with Dilated Cardiomyopathy: A Pivotal Randomized Trial in the United StatesInvestigators: Steven F. Bolling, MD, Francis D. Pagani, MD, PhD, Iva A. Smolens, MD, MS, Surgery; Keith D. Aaronson, MD, and David Bach, MD, Internal Medicine This research focuses on patients, 18 years or older who are in NYHA class III or IV status. The purpose of the research is to Evaluate the safety and efficacy of Acorn Cardiac Support Device therapy in a prospective, randomized study in patients with dilated cardiomyopathy of either ischemic or non-ischemic origin who may or may not be candidates for mitral valve repair/replacement (MVR). The Acorn Cardiac Support Device is intended to support the heart, preventing further dilation that is associated with progressive heart failure, thereby preserving or improving functional status. The EXPEDITION Trial (Na+/H+ EXchange Inhibition to Prevent Coronary Events in Acute Cardiac Conditions)(A double-blind, placebo-controlled, multinational trial to investigate the effect of IV treatment with the Na+/H+ exchange inhibitor cariporide (HOE642) on all-cause mortality and non-fatal myocardial infarction in patients at risk of myocardial necrosis during and after coronary artery bypass graft (CABG) surgery) Cariporide (HOE642) is a potent and selective inhibitor of the Na+/H+ exchange (NHE) subtype 1, an ion exchanger that plays a pivotal role in the setting of myocardial ischemia and reperfusion. Blocking the NHE-1 ion exchange system shuts down the initial step of the ionic exchanges in the heart which cause sodium/calcium overload and consequently cell necrosis. Cariporide is the first substance in this new class of NHE inhibitors. The primary objective is to demonstrate that cariporide reduces the combined incidence of all-cause mortality and non-fatal MI by Day 5 compared to placebo in patients at risk of myocardial necrosis during and after CABG surgery. The secondary objective is to demonstrate that cariporide reduces the combined incidence of all-cause mortality and non-fatal MI by Day 5 compared to placebo in patients at risk of myocardial necrosis during and after CABG surgery. PREMIUM: Prospective Randomized Evaluation of Mitral Insufficiency at the University of MichiganInvestigators: Steven F. Bolling, MD, Iva A. Smolens, MD, MS, Francis D. Pagani, MD, PhD, Seema S. Sonnad, PhD, Vinay Badhwar, MD, Surgery; Keith D. Aaronson, MD, MS, Todd Koelling, MD, David Bach, MD, and Robert Cody, MD, Internal Medicine, Cardiology The aim of this research study is to determine the effects of mitral reconstruction and medical therapy compared to optimal medical therapy alone in patients with New York Heart Association class III to IV heart failure, moderate or severe mitral regurgitation and left ventricular ejection fraction < 30 percent with respect to: functional status (peak oxygen consumption, six minute walk distance, NYHA class), left ventricular function and remodeling (ejection fraction, ventricular volumes, regurgitant volumes, mass, and wall stress), disease-specific (Minnesota Living with Heart Failure Questionnaire) and generic (EQ5D) quality of life, hospitalizations, costs, cost effectiveness, and cost utility, mortality Mitral Valve Repair Using the Da Vinci™ Surgical SystemInvestigators: Steven F. Bolling, MD, Richard L. Prager, MD, Richard G. Ohye, MD, Surgery In this study, safety and effectiveness of the da Vinci™ Surgical System and Endoscopic Instruments will be evaluated for repair of the mitral valve in subjects with significant mitral valve disease requiring surgical management. Structural and Functional Effects of Protein Kinase C-mediated Troponin I Phosphorylation in Adult Rat Cardiac MyocytesInvestigators: Margaret V. Westfall, PhD, Surgery Activation of protein kinase C (PKC) by several agonists has previously been demonstrated to cause phosphorylation of cardiac troponin I (cTnI), as well as other myofilament proteins. A primary goal of this research is to characterize acute and long-term PKC phosphorylation of myofilament proteins in the intact cardiac myocyte. A second goal is to determine the relative contribution of acute PKC-mediated cTnI phosphorylation to myofilament force generation in permeabilized adult cardiac myocytes. These studies are being accomplished by expressing slow skeletal TnI in adult myocytes using viral-mediated gene transfer, and then comparing TnI phosphorylation and myofilament function to myocytes expressing the endogenous cTnI. Experiments are also being carried out to determine whether long term activation of PKC continues to phosphorylate cTnI, and whether these changes in cTnI phosphorylation correlate with the onset of myofibrillar degradation. Protein Kinase C. Signaling Through Troponin I in Adult Cardiac MyocytesInvestigators: Margaret V. Westfall, PhD, Surgery The overall aim of this group of experiments is to ascertain the direct influence of phosphorylated cTnI on adult myocyte contractile function in response to PKC activation by physiological agonists. Phosphorylation of myofilament proteins and myocyte sarcomere shortening responses to the PKC agonist endothelin are being examined for these studies. The time-dependence myofilament protein phosphorylation and myocyte shortening in response to different doses of ET are currently under investigation. Ongoing studies have determined that cTnI phosphorylation by PKC causes accelerated relaxation in intact cardiac myocytes. This enhancement in the rate of relaxation is removed in myocytes expressing the slow skeletal isoform of TnI, which is not phosphorylated by protein kinase C. Information gained from these studies can now be used to determine whether TnI phosphorylation and/or the TnI-mediated enhancement of relaxation produced in response to PKC is altered under physiological and pathophysiological conditions. Influence of Troponin I Phosphorylation by Protein Kinase C on Cardiac Myocyte Contractile FunctionInvestigator: Margaret V. Westfall, PhD, Surgery The overall objective of this proposal is to understand the contribution of individual phosphorylation sites within cTnI to the PKC_mediated enhancement of relaxation in intact cardiac myocytes. The working hypothesis is that phosphorylation sites Ser43/45 and Thr144 within TnI each play a critical role in the relaxation phase of the contractile function response to PKC. This hypothesis will be tested using the potent PKC agonist endothelin-1 (ET), which reproducibly enhances myocyte contractile function in a largely PKC_dependent manner, and is released during several physiological/pathophysiological conditions. Phosphorylation of TnI and myocyte shortening will be followed in parallel experiments using myocytes expressing mutant cTnI proteins with Ala substitutions at Ser43, Ser45, and/or Thr144. These mutant cTnI proteins will be expressed in adult myocytes using viral_based gene transfer to express the unique TnI proteins in adult cardiac myocytes. Rapid, specific, and efficient gene transfer, protein expression and myofilament incorporation of delivered TnI genes previously has been achieved in fully differentiated adult myocytes with this powerful approach. Information from these studies will provide a direct understanding of the role specific phosphorylation sites within cTnI play in the PKC_mediated myocyte shortening response. Ultimately, knowledge gained from the proposed studies may be used to design and deliver unique TnI proteins to failing hearts experiencing altered responses to PKC. Influence of Troponin I Phosphorylation by PKC on Contractile FunctionInvestigators: Margaret V. Westfall, PhD, Surgery Phosphorylation of the cardiac isoform of troponin I (cTnI) in vitro is associated with enhanced contractile function during protein kinase C (PKC) activation in intact myocytes. However, the specific role of cTnI phosphorylation in the acute contractile response to PKC is controversial. The overall objective of this proposal is to understand the contribution of cTnI, as well as regions within cTnI, to the PKC-mediated contractile response in intact cardiac myocytes. The working hypothesis is that cTnI phosphorylation plays a critical role in the relaxation phase of the contractile function response to PKC. This hypothesis will be tested using the potent PKC agonist endothelin-1 (ET), which reproducibly enhances myocyte contractile function in a largely PKC-dependent manner, and is released during several physiological/ pathophysiological conditions. The first aim of this proposal is to characterize cTnI phosphorylation and determine its role in the adult rat cardiac myocyte contractile response to acute PKC activation. Initial experiments will evaluate temporal and dose-dependent associations between TnI phosphorylation and the myocyte contractile shortening response to PKC activation by ET. Results from these experiments will lay an essential foundation for subsequently determining the contribution of phosphorylated cTnI to the myocyte shortening response to PKC. This later goal will be achieved using viral-based gene transfer to express unique TnI proteins in adult cardiac myocytes and then comparing PKC-dependent TnI phosphorylation and shortening responses in myocytes. Rapid, specific, and efficient gene transfer, protein expression and myofilament incorporation of delivered TnI genes is achieved in fully differentiated adult myocytes using this powerful approach. The first unique TnI selected for determining the contribution of cTnI phosphorylation to the PKC-mediated shortening response will be a TnI isoform expressed during fetal cardiac development, which lacks at least two putative sites phosphorylated by PKC. Information from these studies will provide a direct understanding of the role phosphorylated cTnI plays in the PKC-mediated myocyte shortening response. Insight also will be gained into differential developmental responses to PKC activation. The second aim will be to identify site(s) within cTnI that are phosphorylated by PKC and determine the importance of each site in the myocyte contractile response to PKC. The relative importance of cTnI site(s) phosphorylated by PKC in the shortening response will be investigated in myocytes expressing mutant TnI containing substitutions in putative phosphorylation sites. A third aim of this proposal is to determine the effect of isoform-specific TnI region(s) on the ability of TnI to be phosphorylated and/or influence the contractile response to PKC. Ultimately, insights gained from the proposed studies may aid in the design and delivery of unique TnI proteins to failing hearts experiencing altered or pathophysiological responses to PKC. The "BEST" Trial: BioGlue Surgical Adhesive Efficacy and Safety Trial as a Surgical Adjunct in the Treatment of Type A Aortic DissectionInvestigator: G. Michael Deeb, MD, Steven F. Bolling, MD, Francis D. Pagani, MD, PhD, Surgery This research focuses on patients, 18 years or older, with a confirmed diagnosis of an acute Type A aortic dissection and who, in the opinion of the investigator, require emergent surgical repair. BioGlue Surgical Adhesive is intended to be used as an adjunct in the surgical repair of acute, Type A aortic dissections. It has been proposed that application of BioGlue to the repair site will decrease early hospital discharge mortalities, compared to that of patients receiving standard surgical repair. 29mm Freestyle Valve StudyInvestigators: G. Michael Deeb, MD, Steven F. Bolling, MD, Francis D. Pagani, MD, PhD, Surgery The FreeStyle valve is a stentless bioprosthesis (porcine) that is specially treated with an anti calcification agent and zero pressure fixated. The durability is hoped to be longer than the traditional porcine valves. The FreeStyle valve has been released for commercial use in sizes 19-27mm. Because the 29mm size was not used in the original clinical trial, the FDA has required specific study of this size with at least one year followup. This study is being performed at six clinical sites with enrollment up to 60 patients. A New Aortic Root Prosthesis: Outcome and Follow-Up(Edwards Prima Plus Stentless Bioprosthesis Model 2500P) The Edwards Life Science PRIMA valve is a stentless bioprosthesis valve size (21-29mm) used in the aortic position. The clinical trial was conducted in a multi-center setting. The valve has been released for market use. Long term follow-up is ongoing with the study patients. Randomized Evaluation of Mechanical Assistance in the Treatment of Congestive Heart Failure (REMATCH Trial)Investigators: Francis D. Pagani, MD, PhD, Surgery; and Keith Aaronson, MD, Internal Medicine This four-year, randomized, prospective, multi-center trial is designed to investigate the use of the HeartMate Left Ventricular Assist Device as an alternative to heart transplantation in patients with severe end-stage cardiomyopathy who because of comorbid conditions would not otherwise be heart transplant candidates. Autologus Myoblast Transplantation for the Treatment of End-Stage Heart Failure: A Pilot StudyInvestigators: Francis Pagani, MD, PhD, Himanshu Patel, MD, Surgery; and Keith Aaronson, MD, Internal Medicine The purpose of this study is to test the feasibility and safety of transplanting autologous myoblasts derived from skeletal muscle into the myocardium of subjects in end stage heart failure. The subjects enrolled will be candidates for heart transplant surgery and will be scheduled for placement of a left ventricle assist device as bridge to orthotopic transplantation. A secondary objective is to gain preliminary information on the autologous graft survival and the potential for improvement of cardiac function that might be associated with the myoblast transplantation. Positron Emission Tomography of the Heart in Patients Undergoing Chronic Implantation of the HeartMate Left Ventricular Assist DeviceInvestigators: Francis D. Pagani, MD, PhD, Surgery; Keith Aaronson, M.D.,Todd Koelling, MD, Claire Duvernoy, MD, Internal Medicine; and James Corbett, MD, Radiology This is a prospective study that will investigate changes in myocardial blood flow and metabolism that occur during chronic mechanical unloading of the left ventricle while being supported by the HeartMate Left Ventricular Assist Device. The purpose of this study is to identify whether chronic mechanical unloading of the heart can improve myocardial contractility. Autologous Myoblast Transplantation for the Treatment of Infarcted Myocardium - A Pilot StudyInvestigators: Francis D. Pagani, MD, PhD, Himanshu Patel, MD, Surgery; Philip Cascade, MD, Radiology; Keith Aaronson, MD, Internal Medicine The purpose of this study is to test the feasibility and safety of transplanting autologous myoblasts derived from skeletal muscle into and around the ischemic or scarred areas of the myocardium, post-myocardial infarction. The transplantation of the autologous myoblast cells will be performed while the subject is undergoing coronary artery bypass surgery (CABG). The subjects enrolled in the study will have had a myocardial infarction and also have left ventricular dysfunction. Continuous Access Protocol For REMATCH (CAP)Investigators: Francis D. Pagani, MD, PhD, Surgery; Keith Aaronson, MD, Internal Medicine, Susan Hickenbottom, MD, Neurology The purpose of C.A.P. is to allow patients at the original 20 REMATCH sites, who meet the inclusion/exclusion criteria for C.A.P., to be treated with the VE LVAD and continue to provide information on the safety and efficacy of the VE LVAD in this patient population. The primary objective of the trial is to assess survival, functional status, quality of life and rate of adverse events in patients with end-stage chronic heart failure who are on Optimal Medical Management (OM2), are not candidates for cardiac transplantation and have been implanted with the VE LVAD. A Phase II Randomized Multicenter Clinical Study To Evaluate the Safety and Efficacy of the TandemHeart™ pVAD System vs. Conventional Therapy for Treatment of Cardiogenic ShockInvestigators: Maura Moscucci, MD, Internal Medicine, Francis D. Pagani, MD, PhD, Surgery This is a randomized, multicenter clinical study of patients with persistent cardiogenic shock despite maximum medical therapy. The study will compare the safety and efficacy of the TandemHeart pVAD System versus IABP in providing short term circulatory support to patients with persistent cardiogenic shock despite conventional therapy. HeartMate XVE LVAS Support in Patients with Cardiogenic Shock Complicating an Acute Myocardial Infarction TrialInvestigators; Francis D. Pagani, MD, PhD, Surgery, Keith Aaronson, MD, Internal Medicine, David Dyke, MD, Internal Medicine The overall purpose of this clinical study is to evaluate the survival benefit of the HeartMate XVE LVAS as a treatment for patients who develop cardiogenic shock within 72 hours of an acute transmural myocardial infarction. Computational Fluid Dynamics in the Design and Evaluation Surgical Reconstruction for Single VentricleInvestigators: Edward L. Bove, MD, Surgery; Francesco Migliavacca, PhD, and Gabriele Dubini, PhD, Department of Bioengineering, the Politechnico di Milano (Italy), Surgery A computerized model which evaluates flow dynamics and optimal reconstructive techniques is being used to assess the hemi-Fontan and Fontan operations being utilized for reconstruction of the single ventricle. Investigational Use of the Contregra Pulmonary Conduit Study 9202-99CInvestigators: Edward L. Bove, MD, Richard G. Ohye, MD, Surgery; and Caren Goldberg, MD, Pediatric Cardiology The optimal conduit for right ventricular outflow tract reconstruction in congenital heart disease has not yet been identified. A new conduit, harvested from bovine jugular vein, is being evaluated to assess its utility in patients requiring right ventricular to pulmonary artery conduit insertion. Outcome of Infants with Functional Single Ventricle: Regional Cerebral Perfusion Versus Deep Hypothermic Circulatory ArrestInvestigators: Richard G. Ohye, MD, Surgery; and Caren S. Goldberg, MD, Pediatric Cardiology The current standard for the repair of complex congenital heart defects in children requiring aortic reconstruction includes the use of deep hypothermic circulatory arrest (DHCA). DHCA entails cooling the patient to 18oC and stopping all blood flow for a variable period of time. During this time, blood flow ceases to all vital organs, including the brain. Although the exact safe duration of DHCA is unknown, it is generally felt that 45-60 minutes is safe. While some studies have found few differences in the physical and mental development of children undergoing DHCA, others have found subtle changes in up to 50% of patients. Due to this uncertainty, several groups have described a new technique of regional cerebral perfusion (RCP) to supply blood to the brain during these periods, which would otherwise require DHCA. No study has shown any negative result from the use of RCP. Whether DHCA or RCP is better for the patient is currently unknown. The goal of RCP is to maintain a supply of blood and oxygen to the brain throughout the case. Outcome will be assessed based on the patient's immediate post-operative and long-term neurological development and survival. In addition, RCP also appears to supply some blood flow to other organs in the body. Therefore, other outcomes such as heart function, kidney function, liver function, lung function, post-operative bleeding, time on the ventilator, length of stay in the ICU and length of hospital stay will also be monitored during the hospitalization.   Three-dimensional model of a typical hemi-Fontan procedure based on anatomic data from magnetic resonance scans and angiocardiograms. |