News Article | April 20, 2017
A Massachusetts General Hospital (MGH)-led research team has identified a surprising new role for macrophages, the white blood cells primarily known for removing pathogens, cellular debris and other unwanted materials. In their paper published in Cell the investigators describe discovering that macrophages are also essential to the healthy functioning of the heart, helping conduct the electric signals that coordinate the heartbeat. "Our finding that a new cell type is involved in cardiac conduction may lead to better understanding of normal heart function. What really surprised me was that macrophages can depolarize -- change their electric charge -- when coupled to a myocyte. Down the line, this work on the role of macrophages in conduction may lead to new treatments for cardiac arrhythmias," says corresponding author Matthias Nahrendorf, MD, PhD, of the MGH Center for Systems Biology. Best known for their immune system activity of engulfing and digesting microbes, damaged cells and foreign substances, macrophages are found in tissues throughout the body and have recently been shown to have additional functions related to the tissues where they reside. While macrophages are required for healing damaged tissues in the heart, their presence within healthy heart muscle suggests a role in normal heart function. Nahrendorf's study was designed to investigate their potential role in transmitting and coordinating the electrical signals that stimulate heart muscle contraction. Initial experiments in mice revealed that cardiac macrophages are more abundant in the atrioventicular (AV) node -- a key structure connecting the atria (upper chambers) to the ventricles (lower chambers) -- which coordinates contraction timing for the upper and lower chambers. Similarly high concentrations of macrophages were found in AV nodes from human autopsy samples. Subsequent animal experiments found that macrophages connect to heart muscle cells via gap junctions -- pore-like structures known to coordinate heart muscle contractions -- and that the shifts in electric charge that carry the conduction signal are synchronized between macrophages and adjacent heart muscle cells called myocytes. Mice lacking a key gap junction protein showed an abnormal slowing of signal conduction through the AV node, and a complete depletion of tissue macrophages led to the development of AV block -- a delay in conduction between the atria and ventricles that, in human patients, requires pacemaker implantation. Overall, the findings suggest that cardiac macrophages are essential participants in the cardiac conduction system and that changes in their numbers or properties may contribute to heart rhythm abnormalities. Nahrendorf and his colleagues are continuing to explore the role of macrophages in both the healthy heart and in common disorders of signal conduction. He adds that the cells' natural propensity to surround and take up materials for disposal could be used to induce macrophages to ingest drugs carried on nanoparticles. The co-lead authors of the Cell paper are Maarten Hulsmans, PhD, of the MGH Center for Systems Biology and Sebastian Clauss, MD, and Ling Xiao, PhD, of the MGH Cardiovascular Research Center. Additional co-authors include David Milan, MD, and Patrick Ellinor, MD, PhD, of the CVRC. Support for the study includes National Institutes of Health grants NS084863, HL128264, HL114477, HL117829, HL092577, HL105780, and HL096576. The MGH has filed a patent application covering the work described in this paper. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
News Article | October 31, 2016
NEW YORK, NY (Oct. 31) -- A major international study has found that drug-eluting stents, a less-invasive alternative to bypass surgery, are as effective as surgery for many patients with a blockage in the left main coronary artery. Findings from the EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial were published this morning online in the New England Journal of Medicine and presented at the annual Transcatheter Cardiovascular Therapeutics conference in Washington, DC. The trial research team included interventional cardiologists and cardiac surgeons from 126 centers in 17 countries. Coronary artery bypass graft (CABG) surgery has long been considered the definitive treatment for patients with left main coronary artery disease (LMCAD), in which the artery that supplies oxygen-rich blood to most of the heart muscle is clogged with atherosclerotic plaque. About two-thirds of all LMCAD patients have mild to moderate disease in the remainder of the coronary arteries. "Our study has shown that many patients with left main coronary artery disease who prefer a minimally invasive approach can now rest assured that a stent is as effective as bypass surgery for at least 3 years, and is initially safer, with fewer complications from the procedure," said first author Gregg W. Stone, MD, professor of medicine at Columbia University Medical Center and director of cardiovascular research and education at the Center for Interventional Vascular Therapy at NewYork-Presbyterian/Columbia. Stents, which are placed into the diseased artery via a catheter that is inserted through a small opening in a blood vessel in the groin, arm, or neck, are a less-invasive treatment option for many people with coronary artery disease. However, coronary artery bypass surgery (CABG) has long been considered the definitive treatment for patients with LMCAD, which affects a large portion of the heart muscle. Previously, randomized clinical trials suggested that first-generation drug-eluting stents, which release antiproliferative medications to prevent the artery from becoming re-occluded after stent placement, might be appropriate for patients with LMCAD without extensive blockages in the remainder of the heart arteries. The trial results, however, were inconclusive. "Since that time, stents have gotten better, and so has cardiac bypass surgery," said Dr. Stone. "That required us to take a fresh look at the relative safety and effectiveness of the two approaches." In the current study, 1,905 patients with LMCAD and low or intermediate coronary artery disease complexity (as determined by the SYNTAX score, an angiographic tool for measuring disease severity) were randomized to receive a drug-eluting stent that releases the antiproliferative agent everolimus (XIENCE, made by Abbott Vascular of Santa Clara, CA) or bypass surgery. The patients were followed for at least two years, with a median follow-up of three years. "We found that approximately 15 percent of patients in both groups had a heart attack, stroke, or died within three years," said Dr. Stone, lead author of the paper. "In other words, stents were equally effective as bypass surgery." The researchers also analyzed what happened to the patients in the first 30 days after treatment, when serious complications are most likely to occur. Within that period, stent patients had a significantly lower incidence (4.9 percent) of death, stroke, heart attack, or revascularization than those who had bypass surgery (7.9 percent). In addition, fewer stent patients had major bleeding, infections, kidney failure, or severe abnormal heart rhythms compared to those treated with surgery. The researchers reported that bypass surgery should still be considered standard therapy for those with LMCAD and extensive blockages in the remainder of the heart arteries, although the study did not include patients with severe disease. "Our study establishes stents as an acceptable or preferred alternative for patients with LMCAD and low or moderate disease complexity in the other 3 coronary arteries--about two-thirds of all LMCAD patients," said Dr. Stone. "While bypass is still considered a more durable repair, patients and doctors may prefer a percutaneous treatment approach, which is associated with better upfront results, fewer complications, and quicker recovery." Coronary artery disease (CAD), the most common form of heart disease in the US, results from the buildup of atherosclerotic plaques in the arteries that supply oxygenated blood to the heart. CAD frequently leads to strokes or heart attacks, killing more than 370,000 people annually, according to the Centers for Disease Control and Prevention. The left main artery, the primary supply of blood to the heart, is affected in about 10 percent of people with CAD. The study is titled, "Comparison of Everolimus-Eluting Stents and Bypass Graft Surgery in Selected Patients with Left Main Coronary Artery Disease." The other contributors are: Joseph F. Sabik (Cleveland Clinic Foundation, Cleveland, OH); Patrick W. Serruys (International Centre for Circulatory Health, NHLI, Imperial College London, London, UK); Charles A. Simonton (Abbott Vascular, Santa Clara, CA); Philippe Généreux, Erick Schampaert, and Pierre Pagé (Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada); John Puskas and Roxana Mehran (Mount Sinai Hospital, New York, NY); Nicholas Lembo, David E. Kandzari, and W. Morris Brown, III (Piedmont Hospital, Atlanta, GA); Marie-Claude Morice (Générale de Santé, Hopital Privé Jacques Cartier, Massy, France); David Taggart and Adrian Banning (John Radcliffe Hospital, Oxford, UK); Béla Merkely and Ferenc Horkay (Semmelweis University, Budapest, Hungary); Piet W. Boonstra and Ad Johannes van Boven (Medisch Centrum Leeuwarden, Leeuwarden, The Netherlands); Imre Ungi and Gabor Bogáts (University of Szeged, Szeged, Hungary); Samer Mansour and Nicolas Noiseux (Hôpital Hôtel-Dieu de Montréal, Montréal, Québec, Canada); Manel Sabaté and Jose Pomar (Hospital Clinic, Barcelona, Spain); Mark Hickey and Anthony Gershlick (University Hospitals of Leicester NHS Trust, Leicester, UK); Pawel Buszman and Andrzej Bochenek (Medical University of Silesia, Katowice, Poland and American Heart of Poland, Ustron, Poland); Ovidiu Dressler (Cardiovascular Research Center, New York, NY); Ioanna Kosmidou (NewYork-Presbyterian, New York, NY); Stuart J. Pocock (London School of Hygiene and Tropical Medicine, London, UK); and Arie Pieter Kappetein (Erasmus Medical Center, Rotterdam, The Netherlands). The study was sponsored and funded by Abbott Vascular, Santa Clara, CA. Additional authors' disclosures are included in the article. 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Vila O.F.,Cardiovascular Research Center UAB |
Vila O.F.,CIBER ISCIII |
Bago J.R.,Cardiovascular Research Center UAB |
Bago J.R.,CIBER ISCIII |
And 14 more authors.
Journal of Biomedical Materials Research - Part A | Year: 2013
The angiogenic capacity of a new biomaterial composite of poly(lactic acid) and calcium phosphate glass (PLA/CaP) was analyzed by noninvasive bioluminescence imaging (BLI) and histological procedures. Human adipose tissuederived mesenchymal stromal cells expressing cytomegalovirus (CMV) promoter regulated Photinus pyralis luciferase (hAMSC-PLuc) grew up to 30 times the initial cell load, in vitro, when seeded in PLA/CaP scaffolds, but suffered an initial growth crisis followed by recovery when the scaffolds were subcutaneously implanted in SCID mice. To analyze changes in gene expression, hAMSC-PLuc cells were double labeled with a CMV promoter regulated Renilla reniformis luciferase and a Photinus pyralis luciferase reporter regulated by either the PECAM promoter or a hypoxia response element (HRE) artificial promoter and seeded in PLA/CaP and PLA scaffolds implanted in SCID mice. Analysis by BLI showed that hAMSCs in scaffolds were induced to differentiate to the endothelial lineage and did this faster in PLA/CaP than in PLA scaffolds. Endothelial differentiation correlated with a decrease in the activity of HRE regulated luciferase expression, indicative of a reduction of hypoxia. Histological analysis showed that PLA/CaP scaffolds were colonized by a functional host vascular system. Moreover, colonization by isolectin B 4 positive host cells was more effective in PLA/CaP than in PLA scaffolds, corroborating BLI results. © 2012 Wiley Periodicals, Inc.
PubMed | Cardiovascular Research Center UAB
Type: Clinical Trial | Journal: Journal of biomedical materials research. Part A | Year: 2013
The angiogenic capacity of a new biomaterial composite of poly(lactic acid) and calcium phosphate glass (PLA/CaP) was analyzed by noninvasive bioluminescence imaging (BLI) and histological procedures. Human adipose tissue-derived mesenchymal stromal cells expressing cytomegalovirus (CMV) promoter regulated Photinus pyralis luciferase (hAMSC-PLuc) grew up to 30 times the initial cell load, in vitro, when seeded in PLA/CaP scaffolds, but suffered an initial growth crisis followed by recovery when the scaffolds were subcutaneously implanted in SCID mice. To analyze changes in gene expression, hAMSC-PLuc cells were double labeled with a CMV promoter regulated Renilla reniformis luciferase and a Photinus pyralis luciferase reporter regulated by either the PECAM promoter or a hypoxia response element (HRE) artificial promoter and seeded in PLA/CaP and PLA scaffolds implanted in SCID mice. Analysis by BLI showed that hAMSCs in scaffolds were induced to differentiate to the endothelial lineage and did this faster in PLA/CaP than in PLA scaffolds. Endothelial differentiation correlated with a decrease in the activity of HRE regulated luciferase expression, indicative of a reduction of hypoxia. Histological analysis showed that PLA/CaP scaffolds were colonized by a functional host vascular system. Moreover, colonization by isolectin B(4) positive host cells was more effective in PLA/CaP than in PLA scaffolds, corroborating BLI results.