Novel Therapeutic Targets in Myocardial Infarction

Novel Therapeutic Targets in Myocardial Infarction

Friday, December 14, 2012

The New York Academy of Sciences

Presented By

 

Myocardial infarction (MI) is a leading cause of death worldwide. 20 million people die from cardiovascular disease each year and patients that survive are at high risk of a recurrent MI and heart failure. Although there are treatments to mitigate the initial cardiac damage during an acute myocardial infarction, there is a need for novel treatments to minimize subsequent cardiac remodeling that can adversely affect heart function. In this context, identifying new targets to improve tissue repair—including preservation of the cardiac microvasculature, clearance of apoptotic cells and tissue regeneration- might become of great interest to improve cardiac remodeling and function after MI. This symposium brings together leading experts in the field to discuss the best strategy to prevent microvascular damage and improve tissue regeneration after MI.

Reception to follow.

This event will also be broadcast as a webinar; registration is required.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City where possible.

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Agenda

* Presentation times are subject to change.


December 14, 2012

8:00 AM

Registration and Continental Breakfast

8:30 AM

Welcome
Jennifer Henry, PhD, The New York Academy of Sciences

 

Introduction to morning session Inflammation and Repair in Myocardial Infarction
Laurent Yvan-Charvet, PhD, Pfizer Global R&D

8:40 AM

Heart Repair with Bone Marrow Cells: Ready for Prime Time?
Buddhadeb Dawn, MD, University of Kansas Medical Center

9:20 AM

Targeting Phagocytic Clearance Pathways to Promote Heart Repair Post Myocardial Infarction
Edward Thorp, PhD, Northwestern University

10:00 AM

Coffee Break

10:30 AM

Inflammation Rules in Myocardial Infarction
Filip Swirski, PhD, Massachusetts General Hospital and Harvard Medical School

11:10 AM

Nanomedicine for Cardiovascular Disease Detection and Treatment
Zahi A. Fayad, PhD, Mount Sinai School of Medicine

11:50 AM

Networking Lunch

12:50 PM

Introduction to afternoon session: Vasculature and Myocardial Infarction
Mark Kaplan, PhD, Pfizer Global R&D

12:55 PM

Genetics of Cardiomyopathies
Elizabeth McNally, MD, PhD, The University of Chicago Medicine

1:35 PM

Circulating Endothelial Cells: A New Focus in Myocardial Infarction
Paddy Barrett, MD, Scripps Translational Science Institute

2:15 PM

Coffee Break

2:45 PM

Neurotrophins and Proneurotrophins in Cardiac Remodeling
Barbara Hempstead, MD, PhD, Weill Cornell Medical College

3:25 PM

Endothelial Microparticles: Potential Biomarkers for Vascular Damage
Sharon Sokolowski, PhD, Pfizer Global R&D

4:05 PM

Networking Reception

5:00 PM

Close

Speakers

Organizers

Mercedes Beyna, MS

Pfizer Global R&D

Mercedes Beyna is a research scientist at Pfizer, where she is using biochemical and imaging approaches in the quest to understand the biology underlying various psychiatric disorders. She also performs molecular and cellular biology-based target identification and assay development functions. Captivated by neuroscience, she has worked in the field for over 10 years, in both academic and industrial laboratory settings. Before joining pharmaceutical R&D, Mercedes held lab manager and senior lab technician positions at New York University (NYU). Her experience includes molecular neurobiology, synapse formation and plasticity, neurotrophin signaling, and developmental neurobiology areas. Mercedes attended Binghamton University, earning her undergraduate degree in Biology, and subsequently received her Master's Degree in Biology from NYU. As the Pfizer lead in the Biochemical Pharmacology Discussion Group at the New York Academy of Sciences, she enjoys developing interesting and educational symposia.

Mark Kaplan, PhD

Pfizer Global R&D

Mark Kaplan is a Senior Principal Scientist at Pfizer’s Centers for Therapeutic Innovation (CTI). He obtained his PhD in biophysics at the University of California, San Francisco in 1998. Subsequently, he was a Leukemia Society Postdoctoral Fellow in Genetics at the University of Wisconsin. Dr. Kaplan transitioned into industry and has worked as a scientist at Deltagen, Exelixis, Celera Genomics, and Roche, focusing on both oncology and RNAi. He recently joined Pfizer’s CTI New York organization and is leading a collaboration with Weill Cornell Medical College to develop a monoclonal antibody to mitigate cardiac remodeling following an acute myocardial infarction.

Laurent Yvan-Charvet, PhD

Pfizer Global R&D

Laurent Yvan-Charvet is a Lab Head in the CVMED research unit at Pfizer, Inc He obtained his PhD in Endocrinology from the University of Paris XI (France) in 2005 and received a postdoctoral cardiovascular training at Columbia University (New York) on the role of cholesterol efflux pathways in inflammation and stem cell biology. In 2012, he joined Pfizer Inc, for a lab head position in the CVMED research unit and hopes to contribute to the development of new therapeutics for cardiovascular diseases. Dr. Yvan-Charvet was the recipient of the Roger Davis Award in 2010 and has been a finalist of the I.H. Page Young Investigator Award in 2011.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Paddy Barrett, MD

Scripps Translational Science Institute

Paddy Barrett, MD MRCPI is the winner of the A. Menarini/Irish Cardiac Society Travelling Research Scholarship, the McArdle Prize in surgery for outstanding academic performance and is a member of the prestigious Royal College of Physicians of Ireland. His research interests lie mainly in the fields of personalized medicine and wireless health technologies with particular focus on the molecular and genomic characterization of circulating endothelial cells released during myocardial infarction. He firmly believes that this and other ground breaking research being carried out at the Scripps Translational Science Institute will revolutionize how we will tailor the diagnostics and therapeutics of today and the future. After graduating from University College Dublin, Ireland he went on to do residency training in major tertiary centers in both Sydney, Australia and Dublin, Ireland. In 2009 he became a member of the Royal College of Physicians of Ireland and was accepted on to the Irish Cardiology Fellowship training program. Dr. Barrett has published previously on topics ranging from the echocardiographic strain patterns in cardiotoxic chemotherapeutics to the mortality trends in the end stage kidney disease population with peripheral artery disease.

Buddhadeb Dawn, MD

University of Kansas Medical Center

Buddhadeb Dawn, MD, is the Maureen and Marvin Dunn Professor and Director of the Division of Cardiovascular Diseases at the University of Kansas Medical Center. He is also the Vice Chair for research in the Department of Medicine, and Director of the Cardiovascular Research Institute at KU. A graduate of Calcutta Medical College, Dr. Dawn completed medicine residency at the University of Missouri-Columbia and cardiology fellowship at the University of Louisville. He is a clinician-scientist with research interests focused primarily on heart repair by adult stem cells. He has authored more than 100 articles and his research has been funded by the NIH and the American Heart Association for many years. A Fellow of the American Heart Association as well as the American College of Cardiology, Dr. Dawn serves on various scientific committees, grant review panels, and editorial boards of several leading cardiovascular journals. His clinical interests include echocardiography and atrial fibrillation.

Zahi A. Fayad, PhD

Mount Sinai School of Medicine

Dr. Fayad attended Johns Hopkins University and the University of Pennsylvania. From 1996 to 1997, he was junior faculty in the Department of Radiology at the University of Pennsylvania. He joined the faculty of Mount Sinai School of Medicine in 1997. Dr. Fayad serves as professor of Radiology and Medicine (Cardiology) at the Mount Sinai School of Medicine. He is the Director of the Translational and Molecular Imaging Institute and vice Chair for Research in the Department of Radiology at the Mount Sinai School of Medicine and Mount Sinai Medical Center. Dr. Fayad’s interdisciplinary and discipline bridging research - from engineering to biology and from pre-clinical to clinical investigations - has been dedicated to the detection and prevention of cardiovascular disease with many seminal contributions in the field of biomedical imaging.

Barbara Hempstead, MD, PhD

Weill Cornell Medical College

Dr. Barbara Hempstead is a Professor of Medicine and Associate Dean for Faculty Development at Weill Cornell Medical College. She obtained her MD/PhD training at Washington University in St. Louis, followed by clinical training in Internal Medicine and Hematology and Medical Oncology at New York Hospital-Cornell Medical Center. She has studied the biological actions of neurotrophins for more than 20 years. She was a member of the team that initially identified Trk as the survival promoting NGF receptor, and more recently identified proneurotrophins as distinct signaling molecules that selectively bind p75 to induce cell death. In addition to evaluating roles for the neurotrophins in the nervous system, her laboratory has described important roles for these molecules in the vasculature. She is a member of the American Society for Clinical Investigation, the Association of American Physicians, prior Chair of the Gordon Research Conference on “Neurotrophic Factors”, and a Member of the Board of Scientific Counselors of the NICHD.

Elizabeth McNally, MD, PhD

The University of Chicago Medicine

Dr. Elizabeth McNally is a Professor in the Department of Medicine, Section of Cardiology and in the Department of Human Genetics at the University of Chicago. Dr. McNally directs the Institute for Cardiovascular Research and the Cardiovascular Genetics Clinic at the University of Chicago. Dr. McNally earned her undergraduate degree in biology and philosophy at Barnard College at Columbia University. She remained in New York as part of an NIH sponsored Medical Scientist Training Program at Albert Einstein College of Medicine where she received her MD and PhD degrees. Dr. McNally completed training in Internal Medicine and Cardiovascular Medicine at Brigham and Women's Hospital and at Harvard Medical School in Boston. Her research fellowship was under Louis Kunkel, PhD, in the Genetics Division at Children's Hospital in Boston. Dr. McNally joined the faculty of the University of Chicago in 1996 where she is now a tenured professor. She is principal investigator on NIH grants to discern genetic disease mechanisms in heart and muscle disease. She also leads the Cardiovascular Training Program. Her special clinical interests are in treating patients with inherited forms of cardiovascular disease including cardiomyopathy, cardiovascular complications of neuromuscular disease, and inherited aortic vascular disease. She received an American Heart Association Established Investigator Award, a Charles E. Culpeper Scholar Award, Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation, and Burroughs Wellcome Clinical Translational Award. She most recently served as the President of the American Society for Clinical Investigation.

Sharon Sokolowski, PhD

Pfizer Global R&D

Sharon Sokolowski is a Senior Principal Scientist in Drug Safety Research and Development at Pfizer Inc. and leads the Biomarkers Flow Cytometry Laboratory in Groton, Connecticut. For the past 28 years, Sharon has been employed with Pfizer, holding positions ranging from bench scientist to laboratory manager. After spending several years in Infectious Disease and Immunology, Sharon initiated her career in Drug Safety. Currently the Biomarker Flow Cytometry Lab supports safety / efficacy biomarker development, support of Regulatory Toxicity studies, as well as mechanistic investigations. She obtained her bachelor’s degree in Biology from Cornell University and completed her Master’s at the University of Vermont.

Filip Swirski, PhD

Massachusetts General Hospital and Harvard Medical School

Dr. Swirski is Assistant Professor at Harvard Medical School and Massachusetts General Hospital (MGH). Dr. Swirski obtained his PhD in Immunology from McMaster University in Canada in 2004. In 2007, he completed his postdoctoral studies in Vascular Biology at Brigham and Women’s Hospital and MGH. His lab focuses on leukocytedynamics in cardiovascular disease. He is currently working on how extramedullary myelopoiesis influences the evolution of atherosclerotic lesions.

Edward Thorp, PhD

Northwestern University

Dr. Thorp received his PhD in Microbiology and Immunology from Loyola University Chicago with Dr. Tom Gallagher for studies of virus infection and assembly in cholesterol-rich membrane micro-domains. His interests in cholesterol led to studies of atherosclerosis as an American Heart Association postdoctoral fellow in the laboratory of Dr. Ira Tabas in the Department of Medicine at Columbia University in New York. During this time, he focused on the Unfolded Protein stress Response and resolution of inflammation by macrophages. Dr. Thorp is now back in Chicago as Assistant Professor in the Department of Pathology and associate of the Feinberg Cardiovascular Research Institute in the Feinberg School of Medicine at Northwestern University.

Dr. Thorp's current research focus is on myocardial cell stress and inflammation-resolution post myocardial infarction. He has published in multiple basic and translational journals including Cell Metabolism and Circulation and reviews articles for the Journal of Experimental Medicine, ATVB, Circulation Heart Failure, Journal of Immunology, and others. Dr. Thorp also serves as peer reviewer for American Heart Association grant submissions. Dr. Thorp is currently an NIH Pathway to Independence Fellow.

Abstracts

Heart Repair with Bone Marrow Cells: Ready for Prime Time?
Buddhadeb Dawn, MD, University of Kansas Medical Center

A new therapy for heart repair has gained momentum in the recent years – transplantation of bone marrow cells. On the basis of strong evidence from animal studies, several clinical trials of cardiac repair with adult bone marrow-derived cells (BMC) have been completed. These relatively smaller studies employed different BMC types with highly variable numbers, routes, and timings of transplantation, and included patients with acute myocardial infarction (MI), chronic ischemic heart disease (IHD), as well as ischemic cardiomyopathy. Although the outcomes have been predictably disparate, analysis of pooled data indicates that BMC therapy in patients with acute MI and chronic IHD results in modest improvements in cardiac parameters and clinical outcomes without any increase in untoward effects. However, a number of questions remain to be addressed in order to make cell therapy a routine clinical practice. The purpose of this talk is to summarize the available clinical evidence regarding the efficacy and safety of therapeutic cardiac repair with adult BMCs, and discuss select aspects of ongoing basic research aimed at further improving the results.

Targeting Phagocytic Clearance Pathways to Promote Heart Repair Post Myocardial Infarction
Edward Thorp, PhD, Northwestern University

Increasing incidences of heart failure after myocardial infarction (MI) requires new and complementary strategies to combat associated morbidity and mortality. Accumulating evidence highlights the importance of the innate immune response post MI in modulating subsequent heart remodeling and function. A primary task of recruited monocytes to sites of injury is the phagocytic clearance of dead and dying cells. Importantly, mechanisms of clearance are directly linked to downstream signaling pathways that control inflammation resolution and tissue repair. Surprisingly, the causal significance of how clearance signaling shapes subsequent heart remodeling, as well as the principle molecular determinants that are required, remain unclear. Elucidation of clearance pathways post MI carries the potential for enhanced myocardial salvage and repair after ischemic injury.

Inflammation Rules in Myocardial Infarction
Filip Swirski, PhD, Massachusetts General Hospital and Harvard Medical School

Atherosclerosis is the main underlying cause of myocardial infarction. Ischemic injury induces a massive inflammatory response characterized by the influx of neutrophils and monocyte subsets into the myocardium. Healing depends on a coordinated biphasic influx of inflammatory and reparative monocytes. During atherosclerosis, monocytes develop in the bone marrow as part of steady-state hematopoiesis, and in the spleen in a process called extramedullary hematopoiesis. The accelerated production of monocytes during atherosclerosis leads to poor healing after myocardial infarction. Conversely, the immune response after myocardial infarction fuels an inflammatory cycle and accelerates atherosclerosis. The development of monocytes, therefore, links atherosclerosis and myocardial infarction. In this talk, I will discuss the latest developments of monocyte biology in atherosclerosis and its complications, with a focus on potential therapies.

Nanomedicine for Cardiovascular Disease Detection and Treatment
Zahi A. Fayad, PhD, Mount Sinai School of Medicine

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. New diagnostic and therapeutic strategies are needed to mitigate this public health issue. Advances in nanotechnology have generated innovative strategies for diagnosis and therapy in a variety of diseases, foremost in cancer. Based on these studies, a novel concept referred to as nanomedical theranostics, or the combinatory application of nanoparticulate agents to allow diagnostic therapy, is being explored to enable image-guided, personalized, or targeted treatment. Preclinically, theranostics have been gradually applied to CVD with several interesting and encouraging findings. We will review the studies and challenges of nanotheranostic strategies in CVD. Wewill demonstrate nanotheranostic strategies that may potentially be utilized to benefit patients.

Genetics of Cardiomyopathies
Elizabeth McNally, MD, PhD, The University of Chicago Medicine

Genetic mutations account for a significant percentage of cardiomyopathy, a leading cause of congestive heart failure. Nearly 75% of inherited hypertrophic cardiomyopathy (HCM) is explained by dominant mutations in two genes, MYH7 and MYBPC3. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium handling proteins. There are more than fifty single genes linked to inherited DCM, including many genes that also link to HCM. Notably, most of the mutations are rare or even unique within families or individuals with cardiomyopathy. To begin to assess the population-based variation in three common genes associated with cardiomyopathy, we queried the 1000 Genomes database. The 1000 Genomes project is an ongoing consortium designed to deliver whole genome sequence information from an ethnically diverse population and, therefore, is a rich source to determine both common and rare genetic variants. We focused our analysis on protein-altering variation in MHY7, MYBPC3, and TTN. We identified known and predicted pathogenic variation in MYBPC3 and MYH7 at a much higher frequency than what would be expected based on the known prevalence of cardiomyopathy. We also found substantial variation, including protein-disrupting sequences, in TTN. The frequency of predicted pathogenic protein altering variation in cardiomyopathy genes suggests that many of these variants may be insufficient to cause disease on their own but may modify phenotype in a genetically susceptible host. We propose that these variants, in combination with additional genetic variants or other pathological events such as myocardial infarction, identify those at risk for developing heart failure.

Circulating Endothelial Cells: A New Focus in Myocardial Infarction
Paddy Barrett, MD, Scripps Translational Science Institute

Markers of myocardial injury at the time of infarction have improved substantially over recent years. Markers of acute atherosclerotic plaque rupture however have lagged behind. Circulating endothelial cells are released at the time of acute coronary artery atherosclerotic plaque rupture but until recently these rare cells were difficult capture, enumerate and characterize. Leveraging developments in rare circulating tumor cell technology these cells can now be reliably obtained. Cell counting and morphological analysis have demonstrated excellent discriminative ability between those with myocardial infarction and healthy controls. Beyond enumeration and morphological analysis, molecular characterization at a genomic level is now possible. Circulating endothelial cell DNA sequencing, transcriptome sequencing and gene expression analysis will facilitate the development of a unique molecular signature, which could be utilized as a diagnostic tool at point of care for those presenting with chest pain. The ability to now focus on the atherosclerotic plaque rupture itself rather than the downstream effects of myocardial ischemia is a major step forward in the management of unstable coronary artery disease.

Neurotrophins and Proneurotrophins in Cardiac Remodeling
Barbara Hempstead, MD, PhD, Weill Cornell Medical College

Treatment of cardiac ischemia focuses on rapid reestablishment of coronary blood flow. Nonetheless, impaired microvascular perfusion despite artery patencydamages tissue in the peri-infarct area. Development of new, targeted strategies to promote recovery requires the identification of cytokines that induce microvascular dysfunction, and microvascular recovery. We will discuss the actions of brain derived neurotrophic factor (BDNF) to promote angiogenesis in the myocardium, via direct actions on endothelial cells, vascular smooth muscle cells and hematopoietic progenitors. Second, we will describe the actions of proNGF, the precursorof nerve growth factor. ProNGF is a cytokine that has been well-characterized in the brain, as it is induced by injury. ProNGF activates its receptors, p75NTR and sortilin, to mediate pro-apoptotic and stress responses. Following fatal myocardial infarction in humans,and in murine cardiac ischemia-reperfusion injury, proNGF and p75NTRare rapidly induced. To identify proNGF actions, we have evaluated a proNGF-expressing knock-in mouse. This mouse exhibits microvascularendothelial activation and increased vascular permeability in the heart, which progress to lethal cardiomyopathy in the adult. Furthermore, genetic deletion of p75 limits infarct size following ischemia reperfusion injury. These studies identify novel, non-neuronal actions for proNGF and suggest that proNGF represents a new target to limit microvascular dysfunction following ischemic injury.

Endothelial Microparticles: Potential Biomarkers for Vascular Damage
Sharon Sokolowski, PhD, Pfizer Global R&D

Endothelial cells (EC) are thin flattened cells that line blood and lymph vessel walls. Endothelial microparticles (EMPs) are small vesicles (0.1-1μm) that are released into circulating blood from activated, injured, or apoptotic endothelial cells and are found at elevated levels in a number of diseases associated with vascular / endothelial dysfunction. EMPs retain markers, or surface receptors, from the cell of origin such as FLK-1, CD144, CD146, CD105 and CD106 and can be identified by specific antibodies via flow cytometry. The surface receptors detected in the EMP assay may correspond to a cellular condition or event that caused the microparticle release such as stressed or damaged endothelium, endothelial activation, or inflammation. The EMP assay is being investigated as a biomarker for drug induced vascular injury and preclinical qualification of the EMP assay yielded promising results for large as well as small vascular damage. These results suggest the potential for clinical translation of the endothelial microparticle assay as a biomarker for microvascular damage after myocardial infarction.

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