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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThis article delves into the early gains that were made in the treatment of AMI, noting that the field has changed dramatically since 1912, when James B. Herrick, MD, postulated that thrombosis in the coronary artery leads to the symptoms and abnormalities that are associated with heart attacks [Herrick JB. \u003Cem\u003EJAMA\u003C\/em\u003E 1912]. It further covers the major advances over the subsequent 100 years and provided a vision for cardiovascular medicine in the coming century.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EMyocardial Infarction Genomics\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003ECardiovascular leader and innovator Eugene Braunwald, MD, MACC, Harvard Medical School, Boston, Massachusetts, USA, launched The Legends of Cardiovascular Medicine series by delivering the 2012 Simon Dack Lecture, which focused on the treatment of acute myocardial infarction (AMI) \u2013 into the second century after Herrick.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThe lecture delved into the early gains that were made in the treatment of AMI, noting that the field has changed dramatically since 1912, when James B. Herrick, MD, postulated that thrombosis in the coronary artery leads to the symptoms and abnormalities that are associated with heart attacks [Herrick JB. \u003Cem\u003EJAMA\u003C\/em\u003E 1912]. Dr. Braunwald covered the major advances over the subsequent 100 years and provided a vision for cardiovascular medicine in the coming century.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EMyocardial Infarction: The Early Days\u003C\/h2\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EEarly pioneers in cardiovascular medicine were faced with a highly lethal disease, as patients with myocardial infarction (MI) experienced a 30% in\u2013hospital mortality rate or frequently died before they could get to a hospital. The first major therapeutic advance occurred in 1961, with Dr. Desmond Julian\u0027s creation of the coronary care unit [Julian DG. \u003Cem\u003ELancet\u003C\/em\u003E 1961] which segregated patients with AMI, carefully monitored them with alarms, and performed closed chest resuscitation of previously fatal arrhythmias. This development reduced the mortality rate by half.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EOther breakthroughs have included reperfusion therapy, which has been associated with a 75% decrease in mortality over a 25\u2013year period; the addition of aspirin therapy to the MI treatment regimen; balloon angioplasty; and the use of both bare\u2013metal and drug\u2013eluting stents. These advances have continued to make impressive reductions in the mortality rate, but MI still exacts a high toll in morbidity and mortality in the United States (US) and around the world.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EA Relentless Foe\u003C\/h2\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EEven with these impressive gains, MI remains a major health concern, with almost 1 million new cases a year in the US alone. An American citizen experiences an MI approximately every 34 seconds, and the attack will be fatal about 15% of the time [Roger VL et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2012].\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EThe estimated annual incidence of MI among Americans is 610,000 new attacks and 325,000 recurrent ones; the annual mortality rate is 134,000. Worldwide, the figures are even more staggering. Every year, 17.1 million lives\u201482% of which are in the developing world\u2014are claimed by the global burden of cardiovascular disease (CVD) [World Heart Federation. \u003Cem\u003EState of the Heart Cardiovascular Disease Report\u003C\/em\u003E 2012].\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ETherapeutic Approaches to MI\u003C\/h2\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EThree important targets for therapy in AMI are the prevention of lethal myocardial reperfusion injury, post\u2013MI inhibition of thrombin generation, and post\u2013AMI cell therapy.\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EIn a 1985 article in the \u003Cem\u003EJournal Clinical Investigation\u003C\/em\u003E, Braunwald and Kloner described the double\u2013edged nature of reperfusion\u2014how it can limit infarct size but also lead to irreversible myocardial damage or death. The challenge of this dichotomy has led researchers to investigate options such as ischemic preconditioning [Murry CE et al. \u003Cem\u003ECirculation\u003C\/em\u003E 1986], remote ischemic preconditioning [Przyklenk K et al. \u003Cem\u003ECirculation\u003C\/em\u003E 1993], and perconditioning [Schmidt MR et al. \u003Cem\u003EAm J Physiol Heart Circ\u003C\/em\u003E 2007; Botker HE. \u003Cem\u003ELancet\u003C\/em\u003E 2010]. A small proof\u2013of\u2013concept trial by Piot et al. [\u003Cem\u003EN Engl J Med\u003C\/em\u003E 2008] found that the use of cyclosporin A was associated with approximately 40% smaller infarcts, presumably by inhibiting the opening of mitochondrial permeability transition pores.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EAnother area of great promise is the inhibition of thrombin generation post\u2013MI, which can persist for months after an acute event. The ATLAS ACS 2\u2013TIMI 51 trial [Mega JL et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2011; Vinall M. \u003Cem\u003EMD Conference Express: AHA 2011\u003C\/em\u003E] randomized 15,526 patients to one of two doses of rivaroxaban (2.5 mg or 5 mg) or placebo for a mean of 13 months and up to 31 months. Rivaroxaban significantly reduced the primary efficacy endpoint, compared with placebo (8.9% vs 10.7%; HR, 0.84; p=0.008 mITT; p=0.002 ITT). The 2.5\u2013mg BID dose reduced the rate of death from cardiovascular causes (2.7% vs 4.1%; p=0.002) and from any cause (2.9% vs 4.5%; p=0.002). The primary safety endpoint of non\u2013CABG TIMI major bleeding was increased with rivaroxaban (2.1% vs 0.6%; HR, 3.96; p\u0026lt;0.001), with no excess of fatal intracranial hemorrhage or fatal bleeding with rivaroxaban 2.5 mg BID and no evidence of hepatotoxicity or posttreatment rebound ischemic events. The trial was a landmark study that culminated a 2\u2013decade search for another approach to combining antiplatelet and anticoagulant therapies.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-4\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EThe Next Frontiers\u003C\/h2\u003E\n         \u003Cp id=\u0022p-11\u0022\u003ESeveral active areas of investigation hold promise for future advances in cardiovascular science and medicine, including genetics and genomics, molecular targeting, pharmacogenomics, and stem cell biology and regenerative medicine [Nabel EG, Braunwald E. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2012].\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EPost\u2013AMI cell therapy, in particular the REPAIR\u2013AMI trial [Assmus B et al. \u003Cem\u003ECirc Heart Fail\u003C\/em\u003E 2010], showed that intracoronary infusion of bone marrow\u2013derived mononuclear cells in patients with reperfused AMI is associated with improved global contractile function; preferentially improves left ventricular function in patients with the most severely depressed contractility after AMI; and prevents left ventricular end\u2013systolic volume expansion within 4 months of therapy. The therapy holds great promise in limiting the development of postinfarction heart failure (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/4\/6\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Two\u0026#x2013;Year Event\u0026#x2013;Free Survival: REPAIR\u0026#x2013;AMI.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1293458650\u0022 data-figure-caption=\u0022Two\u0026#x2013;Year Event\u0026#x2013;Free Survival: REPAIR\u0026#x2013;AMI.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/4\/6\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/4\/6\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/4\/6\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14012\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-13\u0022 class=\u0022first-child\u0022\u003ETwo\u2013Year Event\u2013Free Survival: REPAIR\u2013AMI.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EAssmus B et al, Clinical Outcome 2 Years After Intracoronary Administration of Bone Marrow\u2013Derived Progenitor Cells in Acute Myocardial Infarction, \u003Cem\u003ECirculation Heart Failure\u003C\/em\u003E 2010, volume 3, issue number 1, page 89.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EThis lecture was inspiring both in recounting the tremendous progress that has been made in limiting the morbidity and mortality associated with AMI, and in highlighting the exciting innovations that hold promise in further reducing the global burden of AMI and its associated complications.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/4\/6\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022The editors would like to thank the many members of the American College of Cardiology presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1293458650\u0022 data-figure-caption=\u0022The editors would like to thank the many members of the American College of Cardiology presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure2\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/4\/6\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/4\/6\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure2\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/4\/6\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14013\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\n               \u003Cp id=\u0022p-15\u0022 class=\u0022first-child\u0022\u003EThe editors would like to thank the 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