Chemical Engineering of Cell Therapy for Heart Diseases. Li Zhenhua,Hu Shiqi,Cheng Ke Accounts of chemical research Cardiovascular disease (CVD) is a major health problem worldwide. Since adult cardiomyocytes irreversibly withdraw from the cell cycle soon after birth, it is hard for cardiac cells to proliferate and regenerate after myocardial injury, such as that caused myocardial infarction (MI). Live cell-based therapies, which we term as first generation of therapeutic strategies, have been widely used for the treatment of many diseases, including CVD. However, cellular approaches have the problems of poor retention of the transplanted cells and the significant entrapment of the cells in the lungs when delivered intravenously. Another big problem is the low storage/shipping stability of live cells, which limits the manufacturability of living cell products. The field of chemical engineering focuses on designing large-scale processes to convert chemicals, raw materials, living cells, microorganisms, and energy into useful forms and products. By definition, chemical engineers conceive and design processes to produce, transform, and transport materials. This matches the direction that cell therapies are heading toward: "produce", from live cells to synthetic artificial cells; "transform", from bare cells to cell/matrix/factor combinations; and "transport". from simple systemic injections to targeted delivery. Thus, we hereby introduce the "chemical engineering of cell therapies" as a concept. In this Account, we summarize our recent efforts to develop chemical engineering approaches to repair injured hearts. To address the limitations of poor cellular retention and integration, the first step was the artificial manipulation of stem cells before injections (we term this the second generation of therapeutic strategies). For example, we took advantage of the natural infarct-targeting ability of platelet membranes by fusing them onto the surface of cardiac stromal/stem cells (CSCs). By doing so, we improved the rate at which they were delivered through the vasculature to sites of MI. In addition to modifying natural CSCs, we described a bioengineering approach that involved the encapsulation of CSCs in a polymeric microneedle patch for myocardium regeneration. The painless microneedle patches were used as an in situ delivery device, which directly transported the loaded CSCs to the MI heart. In addition to low cell retention, there are some other barriers that need to be addressed before further clinical application is viable, including the storage/shipping stability of and the evident safety concerns about live cells. Therefore, we developed the third generation of therapeutic strategies, which utilize cell-free approaches for cardiac cell therapies. Numerous studies have indicated that paracrine mechanisms reasonably explain stem cell based heart repair. By imitating or adapting natural stem cells, as well as their secretions, and using them in conjunction with biocompatible materials, we can simulate the function of natural stem cells while avoiding the complications association with the first and second generation therapeutic options. Additionally, we can develop approaches to capture endogenous stem cells and directly transport them to the infarct site. Using these third generation therapeutic strategies, we can provide unprecedented opportunities for cardiac cell therapies. We hope that our designs will promote the use of chemical engineering approaches to transform, transport, and fabricate cell-free systems as novel cardiac cell therapeutic agents for clinical applications. 10.1021/acs.accounts.9b00137
    Hydrogels for therapeutic cardiovascular angiogenesis. Rufaihah Abdul Jalil,Seliktar Dror Advanced drug delivery reviews Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. While growth factor or cell therapy is promising, the retention of bioactive agents in the highly vascularized myocardium is limited and prevents sustained activation needed for adequate cellular responses. Various types of biomaterials with different physical and chemical properties have been developed to improve the localized delivery of growth factor and/or cells for therapeutic angiogenesis in ischemic tissues. Hydrogels are particularly advantageous as carrier systems because they are structurally similar to the tissue extracellular matrix (ECM), they can be processed under relatively mild conditions and can be delivered in a minimally invasive manner. Moreover, hydrogels can be designed to degrade in a timely fashion that coincides with the angiogenic process. For these reasons, hydrogels have shown great potential as pro-angiogenic matrices. This paper reviews a few of the hydrogel systems currently being applied together with growth factor delivery and/or cell therapy to promote therapeutic angiogenesis in ischemic tissues, with emphasis on myocardial applications. 10.1016/j.addr.2015.07.003
    Inflammatory processes in cardiovascular disease: a route to targeted therapies. Ruparelia Neil,Chai Joshua T,Fisher Edward A,Choudhury Robin P Nature reviews. Cardiology Inflammatory processes are firmly established as central to the development and complications of cardiovascular diseases. Elevated levels of inflammatory markers have been shown to be predictive of future cardiovascular events. The specific targeting of these processes in experimental models has been shown to attenuate myocardial and arterial injury, reduce disease progression, and promote healing. However, the translation of these observations and the demonstration of clear efficacy in clinical practice have been disappointing. A major limitation might be that tools currently used to measure 'inflammation' are insufficiently precise and do not provide information about disease site and activity, or discriminate between functionally important activation pathways. The challenge, therefore, is to make measures of inflammation that are more meaningful, and which can guide specific targeted therapies. In this Review, we consider the roles of inflammatory processes in the related pathologies of atherosclerosis and acute myocardial infarction, by providing an evaluation of the known and emerging inflammatory pathways. We highlight contemporary techniques to characterize and quantify inflammation, and consider how they might be used to guide specific treatments. Finally, we discuss emerging opportunities in the field, including their current limitations and challenges that are the focus of ongoing study. 10.1038/nrcardio.2016.185
    New Myocyte Formation in the Adult Heart: Endogenous Sources and Therapeutic Implications. Vagnozzi Ronald J,Molkentin Jeffery D,Houser Steven R Circulation research Death of adult cardiac myocytes and supportive tissues resulting from cardiovascular diseases such as myocardial infarction is the proximal driver of pathological ventricular remodeling that often culminates in heart failure. Unfortunately, no currently available therapeutic barring heart transplantation can directly replenish myocytes lost from the injured heart. For decades, the field has struggled to define the intrinsic capacity and cellular sources for endogenous myocyte turnover in pursuing more innovative therapeutic strategies aimed at regenerating the injured heart. Although controversy persists to this day as to the best therapeutic regenerative strategy to use, a growing consensus has been reached that the very limited capacity for new myocyte formation in the adult mammalian heart is because of proliferation of existing cardiac myocytes but not because of the activity of an endogenous progenitor cell source of some sort. Hence, future therapeutic approaches should take into consideration the fundamental biology of myocyte renewal in designing strategies to potentially replenish these cells in the injured heart. 10.1161/CIRCRESAHA.118.311208
    Stem cells and injectable hydrogels: Synergistic therapeutics in myocardial repair. Sepantafar Mohammadmajid,Maheronnaghsh Reihan,Mohammadi Hossein,Rajabi-Zeleti Sareh,Annabi Nasim,Aghdami Nasser,Baharvand Hossein Biotechnology advances One of the major problems in the treatment of cardiovascular diseases is the inability of myocardium to self-regenerate. Current therapies are unable to restore the heart's function after myocardial infarction. Myocardial tissue engineering is potentially a key approach to regenerate damaged heart muscle. Myocardial patches are applied surgically, whereas injectable hydrogels provide effective minimally invasive approaches to recover functional myocardium. These hydrogels are easily administered and can be either cell free or loaded with bioactive agents and/or cardiac stem cells, which may apply paracrine effects. The aim of this review is to investigate the advantages and disadvantages of injectable stem cell-laden hydrogels and highlight their potential applications for myocardium repair. 10.1016/j.biotechadv.2016.03.003
    Pathophysiology of ST-segment elevation myocardial infarction: novel mechanisms and treatments. Montecucco Fabrizio,Carbone Federico,Schindler Thomas H European heart journal Despite major advances in mechanical and pharmacological reperfusion strategies to improve acute myocardial infarction (MI) injury, substantial mortality, morbidity, and socioeconomic burden still exists. To further reduce infarct size and thus ameliorate clinical outcome, the focus has also shifted towards early detection of MI with high-sensitive troponin assays, imaging, cardioprotection against pathophysiological targets of myocardial reperfusion injury with mechanical (ischaemic post-conditioning, remote ischaemic pre-conditioning, therapeutic hypothermia, and hypoxemia) and newer pharmacological interventions (atrial natriuretic peptide, cyclosporine A, and exenatide). Evidence from animal models of myocardial ischaemia and reperfusion also demonstrated promising results on more selective anti-inflammatory compounds that require additional validation in humans. Cardiac stem cell treatment also hold promise to reduce infarct size and negative remodelling of the left ventricle that may further improves symptoms and prognosis in these patients. This review focuses on the pathophysiology, detection, and reperfusion strategies of ST-segment elevation MI as well as current and future challenges to reduce ischaemia/reperfusion injury and infarct size that may result in a further improved outcome in these patients. 10.1093/eurheartj/ehv592
    2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Levine Glenn N,Bates Eric R,Bittl John A,Brindis Ralph G,Fihn Stephan D,Fleisher Lee A,Granger Christopher B,Lange Richard A,Mack Michael J,Mauri Laura,Mehran Roxana,Mukherjee Debabrata,Newby L Kristin,O'Gara Patrick T,Sabatine Marc S,Smith Peter K,Smith Sidney C Circulation 10.1161/CIR.0000000000000404
    2015 ACC/AHA/SCAI Focused Update on Primary Percutaneous Coronary Intervention for Patients With ST-Elevation Myocardial Infarction: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention and the 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction. Levine Glenn N,Bates Eric R,Blankenship James C,Bailey Steven R,Bittl John A,Cercek Bojan,Chambers Charles E,Ellis Stephen G,Guyton Robert A,Hollenberg Steven M,Khot Umesh N,Lange Richard A,Mauri Laura,Mehran Roxana,Moussa Issam D,Mukherjee Debabrata,Ting Henry H,O'Gara Patrick T,Kushner Frederick G,Ascheim Deborah D,Brindis Ralph G,Casey Donald E,Chung Mina K,de Lemos James A,Diercks Deborah B,Fang James C,Franklin Barry A,Granger Christopher B,Krumholz Harlan M,Linderbaum Jane A,Morrow David A,Newby L Kristin,Ornato Joseph P,Ou Narith,Radford Martha J,Tamis-Holland Jacqueline E,Tommaso Carl L,Tracy Cynthia M,Woo Y Joseph,Zhao David X Journal of the American College of Cardiology 10.1016/j.jacc.2015.10.005
    Comparative efficacy and safety of reperfusion therapy with fibrinolytic agents in patients with ST-segment elevation myocardial infarction: a systematic review and network meta-analysis. Jinatongthai Peerawat,Kongwatcharapong Junporn,Foo Chee Yoong,Phrommintikul Arintaya,Nathisuwan Surakit,Thakkinstian Ammarin,Reid Christopher M,Chaiyakunapruk Nathorn Lancet (London, England) BACKGROUND:Fibrinolytic therapy offers an alternative to mechanical reperfusion for ST-segment elevation myocardial infarction (STEMI) in settings where health-care resources are scarce. Comprehensive evidence comparing different agents is still unavailable. In this study, we examined the effects of various fibrinolytic drugs on clinical outcomes. METHODS:We did a network meta-analysis based on a systematic review of randomised controlled trials comparing fibrinolytic drugs in patients with STEMI. Several databases were searched from inception up to Feb 28, 2017. We included only randomised controlled trials that compared fibrinolytic agents as a reperfusion therapy in adult patients with STEMI, whether given alone or in combination with adjunctive antithrombotic therapy, against other fibrinolytic agents, a placebo, or no treatment. Only trials investigating agents with an approved indication of reperfusion therapy in STEMI (streptokinase, tenecteplase, alteplase, and reteplase) were included. The primary efficacy outcome was all-cause mortality within 30-35 days and the primary safety outcome was major bleeding. This study is registered with PROSPERO (CRD42016042131). FINDINGS:A total of 40 eligible studies involving 128 071 patients treated with 12 different fibrinolytic regimens were assessed. Compared with accelerated infusion of alteplase with parenteral anticoagulants as background therapy, streptokinase and non-accelerated infusion of alteplase were significantly associated with an increased risk of all-cause mortality (risk ratio [RR] 1·14 [95% CI 1·05-1·24] for streptokinase plus parenteral anticoagulants; RR 1·26 [1·10-1·45] for non-accelerated alteplase plus parenteral anticoagulants). No significant difference in mortality risk was recorded between accelerated infusion of alteplase, tenecteplase, and reteplase with parenteral anticoagulants as background therapy. For major bleeding, a tenecteplase-based regimen tended to be associated with lower risk of bleeding compared with other regimens (RR 0·79 [95% CI 0·63-1·00]). The addition of glycoprotein IIb or IIIa inhibitors to fibrinolytic therapy increased the risk of major bleeding by 1·27-8·82-times compared with accelerated infusion alteplase plus parenteral anticoagulants (RR 1·47 [95% CI 1·10-1·98] for tenecteplase plus parenteral anticoagulants plus glycoprotein inhibitors; RR 1·88 [1·24-2·86] for reteplase plus parenteral anticoagulants plus glycoprotein inhibitors). INTERPRETATION:Significant differences exist among various fibrinolytic regimens as reperfusion therapy in STEMI and alteplase (accelerated infusion), tenecteplase, and reteplase should be considered over streptokinase and non-accelerated infusion of alteplase. The addition of glycoprotein IIb or IIIa inhibitors to fibrinolytic therapy should be discouraged. FUNDING:None. 10.1016/S0140-6736(17)31441-1
    Acute Myocardial Infarction. Anderson Jeffrey L,Morrow David A The New England journal of medicine 10.1056/NEJMra1606915
    Thrombus aspiration in acute myocardial infarction. Mahmoud Karim D,Zijlstra Felix Nature reviews. Cardiology The success of primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) is often hampered by incomplete microvascular myocardial reperfusion owing to distal embolization of thrombus resulting in microvascular obstruction. To address this problem, thrombus aspiration devices have been developed that can be used to evacuate coronary thrombus either manually or mechanically. Thrombus aspiration has the potential to reduce the local thrombus load, minimize the need for balloon predilatation, facilitate direct stenting, prevent distal embolization, and ultimately improve myocardial reperfusion. Furthermore, thrombus aspiration has enabled us to study coronary thrombus in vivo, and has facilitated recognition of distinct mechanisms of coronary thrombosis. Clinical trials focusing on manual thrombus aspiration in primary PCI have generally shown improved myocardial reperfusion. However, in two large trials powered for clinical end points, no reduction in 1-year mortality or other adverse clinical events was observed with the use of this strategy. Moreover, one of these trials showed a marginally increased risk of stroke. Consequently, current guidelines do not recommend routine use of thrombus aspiration. Future studies should focus on the identification of subgroups of patients with STEMI who might derive benefit from manual thrombus aspiration, and establish the effect of operator performance on the efficacy and safety of the procedure. 10.1038/nrcardio.2016.38
    In-Hospital ST-Segment Elevation Myocardial Infarction: Improving Diagnosis, Triage, and Treatment. Levine Glenn N,Dai Xuming,Henry Timothy D,Calfon Press Marcella,Denktas Ali E,Garberich Ross F,Jacobs Alice K,Jaski Brian E,Kaul Prashant,Kontos Michael C,Stouffer George A,Smith Sidney C, JAMA cardiology Importance:In-hospital ST-segment elevation myocardial infarction (STEMI) is a unique clinical entity with epidemiology, incidence, and outcomes distinct from that of out-of-hospital STEMI and has only within the past 10 years begun to receive increased attention and research. Patients with in-hospital STEMI are older, have more comorbidities, and more frequently have coagulopathies and contraindications for anticoagulation and fibrinolytic therapy. A standardized clinical definition of in-hospital STEMI is lacking. The objectives of this special communication are to (1) summarize the knowledge base regarding in-hospital STEMI; (2) review the challenges of diagnosis and treatment of patients with in-hospital STEMI; (3) present a standardized clinical definition for in-hospital STEMI; and (4) provide a quality improvement protocol to improve diagnosis, triage, and treatment of patients with in-hospital STEMI. Observations:Patients with in-hospital STEMI less frequently present with typical angina symptoms, and an electrocardiogram is often obtained owing to changes in clinical status, changes on telemetry, or a finding of elevated cardiac biomarker. The frequent nontypical presentations often lead to substantial delays in the diagnosis of STEMI. Only 34% to 71% of patients with in-hospital STEMI undergo diagnostic catheterization, and only 22% to 56% undergo percutaneous coronary intervention. Even in contemporary reports, some studies report in-hospital mortality in the range of 31% to 42%. Three areas of delay in the treatment of patients with in-hospital STEMI that merit particular attention are (1) delays in electrocardiogram acquisition, (2) delays in electrocardiogram interpretation, and (3) delays in activation of existing STEMI systems of care. Conclusions and Relevance:Treatment of patients with in-hospital STEMI is more complex and challenging than treatment of patients who develop out-of-hospital STEMI, leading to delays in diagnosis and triage and less frequent use of reperfusion therapy. Quality improvement programs targeted at decreasing delays and streamlining treatment of such patients may improve treatment and outcome. 10.1001/jamacardio.2017.5356
    Alginate biomaterial for the treatment of myocardial infarction: Progress, translational strategies, and clinical outlook: From ocean algae to patient bedside. Ruvinov Emil,Cohen Smadar Advanced drug delivery reviews Alginate biomaterial is widely utilized for tissue engineering and regeneration due to its biocompatibility, non-thrombogenic nature, mild and physical gelation process, and the resemblance of its hydrogel matrix texture and stiffness to that of the extracellular matrix. In this review, we describe the versatile biomedical applications of alginate, from its use as a supporting cardiac implant in patients after acute myocardial infarction (MI) to its employment as a vehicle for stem cell delivery and for the controlled delivery and presentation of multiple combinations of bioactive molecules and regenerative factors into the heart. Preclinical and first-in-man clinical trials are described in details, showing the therapeutic potential of injectable acellular alginate implants to inhibit the damaging processes after MI, leading to myocardial repair and tissue reconstruction. 10.1016/j.addr.2015.04.021
    Management of cardiogenic shock complicating myocardial infarction. Mebazaa Alexandre,Combes Alain,van Diepen Sean,Hollinger Alexa,Katz Jaon N,Landoni Giovanni,Hajjar Ludhmila Abrahao,Lassus Johan,Lebreton Guillaume,Montalescot Gilles,Park Jin Joo,Price Susanna,Sionis Alessandro,Yannopolos Demetris,Harjola Veli-Pekka,Levy Bruno,Thiele Holger Intensive care medicine Up to 10% of acute coronary syndromes are complicated by cardiogenic shock (CS) with contemporary mortality rates of 40-50%. The extent of ischemic myocardium has a profound impact on the initial, in-hospital, and post-discharge management and prognosis in this patient population. Individualized patient risk assessment plays an important role in determining appropriate revascularization, drug treatment with inotropes and vasopressors, mechanical circulatory support, intensive care support of other organ systems, hospital level of care triage, and allocation of clinical resources. This review will outline the underlying causes and diagnostic criteria, pathophysiology, and treatment of CS complicating acute coronary syndromes with a focus on (a) potential therapeutic issues from the perspective an interventional cardiologist, an emergency physician, and an intensive care physician, (b) the type of revascularization, and (c) new therapeutic advancements in pharmacologic and mechanical percutaneous circulatory support. 10.1007/s00134-018-5214-9
    Self-assembling peptide-based delivery of therapeutics for myocardial infarction. French Kristin M,Somasuntharam Inthirai,Davis Michael E Advanced drug delivery reviews Cardiovascular disease, including myocardial infarction, is the number one cause of death. Current treatments are palliative and slow the progression toward heart failure, but to not regenerate healthy tissue. Self-assembling peptides are biomimietic, readily produced, non-immunogenic and non-cytotoxic. They do not assemble into hydrogels until triggered, allowing them to be injected into the myocardium and providing opportunities for minimally invasive therapies. The ability to tune the mechanical and bioactive properties of self-assembling peptides will continue to make them readily adaptable for mimicking natural microenvironments. To date, a variety of growth factors and signaling moieties have been incorporated into self-assembling peptide hydrogels, enhancing cell behavior and tissue function. Furthermore, the hydrogels serve as delivery vehicles for cells in vivo and platforms for improved cell culture. In addition to a brief review of self-assembling peptides, we will discuss a variety of their approaches for myocardial infarction therapy. Moreover, we will assess approaches taken in other tissue and discuss how these could benefit therapies for myocardial infarction. 10.1016/j.addr.2015.04.023
    Left Ventricular Thrombus After Acute Myocardial Infarction: Screening, Prevention, and Treatment. McCarthy Cian P,Vaduganathan Muthiah,McCarthy Killian J,Januzzi James L,Bhatt Deepak L,McEvoy John W JAMA cardiology Importance:Left ventricular (LV) thrombus is a complication of acute myocardial infarction (MI) and is associated with systemic thromboembolism. With randomized clinical trials investigating the optimal antithrombotic regimen in patients with MI who require concomitant chronic anticoagulation and with the emergence of the direct-acting oral anticoagulants, treatment options for post-MI LV thrombus have become more complicated. Herein, we review the epidemiology, pathogenesis, diagnosis, prevention, and treatment of LV thrombus after acute MI. Observations:Contemporary epidemiologic data suggest the incidence of LV thrombus, detected using optimal imaging modalities, may be as high as 15% in patients with ST-segment elevation MI and up to 25% in patients with anterior MI. While a standard transthoracic echocardiogram is commonly used for screening, it is limited by low sensitivity for LV thrombus detection, necessitating the addition of contrast (unless contraindicated) and/or use of cardiac magnetic resonance imaging when pretest probability is high. To our knowledge, there are no existing randomized clinical trials evaluating the safety and efficacy of anticoagulation in the prevention or treatment of LV thrombus after MI, and clinicians must rely on available epidemiologic and trial-generated data from related entities to guide treatment. Randomized clinical trials have confirmed that triple therapy increases bleeding rates compared with less potent antithrombotic regimens after MI, and observational data suggest that triple therapy regimens may not prevent LV thrombus formation. On the other hand, if an LV thrombus is detected, anticoagulation is essential to prevent systemic thromboembolism. We offer 1 approach to treatment, grounded in the best available data. Conclusions and Relevance:Uncertainties remain regarding the optimal screening pathway, frequency of follow-up imaging, candidate selection for thromboprophylaxis, and treatment strategies for post-MI LV thrombus. Ongoing studies from related therapeutic areas of varying antithrombotic regimens will continue to inform the optimal approach to treatment; however, more dedicated study of this clinical conundrum is also needed. 10.1001/jamacardio.2018.1086
    Management of cardiogenic shock complicating myocardial infarction: an update 2019. Thiele Holger,Ohman E Magnus,de Waha-Thiele Suzanne,Zeymer Uwe,Desch Steffen European heart journal Cardiogenic shock (CS) remains the most common cause of death in patients admitted with acute myocardial infarction (AMI) and mortality remained nearly unchanged in the range of 40-50% during the last two decades. Early revascularization, vasopressors and inotropes, fluids, mechanical circulatory support, and general intensive care measures are widely used for CS management. However, there is only limited evidence for any of the above treatment strategies except for revascularization and the relative ineffectiveness of intra-aortic balloon pumping. This updated review will outline the management of CS complicating AMI with major focus on state-of-the art treatment. 10.1093/eurheartj/ehz363
    ST-segment elevation myocardial infarction. Vogel Birgit,Claessen Bimmer E,Arnold Suzanne V,Chan Danny,Cohen David J,Giannitsis Evangelos,Gibson C Michael,Goto Shinya,Katus Hugo A,Kerneis Mathieu,Kimura Takeshi,Kunadian Vijay,Pinto Duane S,Shiomi Hiroki,Spertus John A,Steg P Gabriel,Mehran Roxana Nature reviews. Disease primers ST-segment elevation myocardial infarction (STEMI) is the most acute manifestation of coronary artery disease and is associated with great morbidity and mortality. A complete thrombotic occlusion developing from an atherosclerotic plaque in an epicardial coronary vessel is the cause of STEMI in the majority of cases. Early diagnosis and immediate reperfusion are the most effective ways to limit myocardial ischaemia and infarct size and thereby reduce the risk of post-STEMI complications and heart failure. Primary percutaneous coronary intervention (PCI) has become the preferred reperfusion strategy in patients with STEMI; if PCI cannot be performed within 120 minutes of STEMI diagnosis, fibrinolysis therapy should be administered to dissolve the occluding thrombus. The initiation of networks to provide around-the-clock cardiac catheterization availability and the generation of standard operating procedures within hospital systems have helped to reduce the time to reperfusion therapy. Together with new advances in antithrombotic therapy and preventive measures, these developments have resulted in a decrease in mortality from STEMI. However, a substantial amount of patients still experience recurrent cardiovascular events after STEMI. New insights have been gained regarding the pathophysiology of STEMI and feed into the development of new treatment strategies. 10.1038/s41572-019-0090-3
    Acute myocardial infarction. Reed Grant W,Rossi Jeffrey E,Cannon Christopher P Lancet (London, England) Acute myocardial infarction has traditionally been divided into ST elevation or non-ST elevation myocardial infarction; however, therapies are similar between the two, and the overall management of acute myocardial infarction can be reviewed for simplicity. Acute myocardial infarction remains a leading cause of morbidity and mortality worldwide, despite substantial improvements in prognosis over the past decade. The progress is a result of several major trends, including improvements in risk stratification, more widespread use of an invasive strategy, implementation of care delivery systems prioritising immediate revascularisation through percutaneous coronary intervention (or fibrinolysis), advances in antiplatelet agents and anticoagulants, and greater use of secondary prevention strategies such as statins. This seminar discusses the important topics of the pathophysiology, epidemiological trends, and modern management of acute myocardial infarction, focusing on the recent advances in reperfusion strategies and pharmacological treatment approaches. 10.1016/S0140-6736(16)30677-8
    Cardiovascular Magnetic Resonance in Acute ST-Segment-Elevation Myocardial Infarction: Recent Advances, Controversies, and Future Directions. Bulluck Heerajnarain,Dharmakumar Rohan,Arai Andrew E,Berry Colin,Hausenloy Derek J Circulation Although mortality after ST-segment elevation myocardial infarction (MI) is on the decline, the number of patients developing heart failure as a result of MI is on the rise. Apart from timely reperfusion by primary percutaneous coronary intervention, there is currently no established therapy for reducing MI size. Thus, new cardioprotective therapies are required to improve clinical outcomes after ST-segment-elevation MI. Cardiovascular magnetic resonance has emerged as an important imaging modality for assessing the efficacy of novel therapies for reducing MI size and preventing subsequent adverse left ventricular remodeling. The recent availability of multiparametric mapping cardiovascular magnetic resonance imaging has provided new insights into the pathophysiology underlying myocardial edema, microvascular obstruction, intramyocardial hemorrhage, and changes in the remote myocardial interstitial space after ST-segment-elevation MI. In this article, we provide an overview of the recent advances in cardiovascular magnetic resonance imaging in reperfused patients with ST-segment-elevation MI, discuss the controversies surrounding its use, and explore future applications of cardiovascular magnetic resonance in this setting. 10.1161/CIRCULATIONAHA.117.030693
    Heart regeneration and repair after myocardial infarction: translational opportunities for novel therapeutics. Cahill Thomas J,Choudhury Robin P,Riley Paul R Nature reviews. Drug discovery Current therapies for heart failure after myocardial infarction are limited and non-curative. Although regenerative approaches are receiving significant attention, clinical efforts that involve transplantation of presumed stem and progenitor cells have largely failed to deliver. Recent studies of endogenous heart regeneration in model organisms, such as zebrafish and neonatal mice, are yielding mechanistic insights into the roles of cardiomyocyte proliferation, resident stem cell niches, neovascularization, the immune system and the extracellular matrix. These findings have revealed novel pathways that could be therapeutically targeted to stimulate repair following myocardial infarction and have provided lessons to guide future efforts towards heart regeneration through cellular reprogramming or cardiomyocyte transplantation. 10.1038/nrd.2017.106
    Optimized Treatment of ST-Elevation Myocardial Infarction. Niccoli Giampaolo,Montone Rocco A,Ibanez Borja,Thiele Holger,Crea Filippo,Heusch Gerd,Bulluck Heerajnarain,Hausenloy Derek J,Berry Colin,Stiermaier Thomas,Camici Paolo G,Eitel Ingo Circulation research Primary percutaneous coronary intervention is nowadays the preferred reperfusion strategy for patients with acute ST-segment-elevation myocardial infarction, aiming at restoring epicardial infarct-related artery patency and achieving microvascular reperfusion as early as possible, thus limiting the extent of irreversibly injured myocardium. Yet, in a sizeable proportion of patients, primary percutaneous coronary intervention does not achieve effective myocardial reperfusion due to the occurrence of coronary microvascular obstruction (MVO). The amount of infarcted myocardium, the so-called infarct size, has long been known to be an independent predictor for major adverse cardiovascular events and adverse left ventricular remodeling after myocardial infarction. Previous cardioprotection studies were mainly aimed at protecting cardiomyocytes and reducing infarct size. However, several clinical and preclinical studies have reported that the presence and extent of MVO represent another important independent predictor of adverse left ventricular remodeling, and recent evidences support the notion that MVO may be more predictive of major adverse cardiovascular events than infarct size itself. Although timely and complete reperfusion is the most effective way of limiting myocardial injury and subsequent ventricular remodeling, the translation of effective therapeutic strategies into improved clinical outcomes has been largely disappointing. Of importance, despite the presence of a large number of studies focused on infarct size, only few cardioprotection studies addressed MVO as a therapeutic target. In this review, we provide a detailed summary of MVO including underlying causes, diagnostic techniques, and current therapeutic approaches. Furthermore, we discuss the hypothesis that simultaneously addressing infarct size and MVO may help to translate cardioprotective strategies into improved clinical outcome following ST-segment-elevation myocardial infarction. 10.1161/CIRCRESAHA.119.315344
    Assessment and Treatment of Patients With Type 2 Myocardial Infarction and Acute Nonischemic Myocardial Injury. DeFilippis Andrew P,Chapman Andrew R,Mills Nicholas L,de Lemos James A,Arbab-Zadeh Armin,Newby L Kristin,Morrow David A Circulation Although coronary thrombus overlying a disrupted atherosclerotic plaque has long been considered the hallmark and the primary therapeutic target for acute myocardial infarction (MI), multiple other mechanisms are now known to cause or contribute to MI. It is further recognized that an MI is just one of many types of acute myocardial injury. The Fourth Universal Definition of Myocardial Infarction provides a taxonomy for acute myocardial injury, including 5 subtypes of MI and nonischemic myocardial injury. The diagnosis of MI is reserved for patients with myocardial ischemia as the cause of myocardial injury, whether attributable to acute atherothrombosis (type 1 MI) or supply/demand mismatch without acute atherothrombosis (type 2 MI). Myocardial injury in the absence of ischemia is categorized as acute or chronic nonischemic myocardial injury. However, optimal evaluation and treatment strategies for these etiologically distinct diagnoses have yet to be defined. Herein, we review the epidemiology, risk factor associations, and diagnostic tools that may assist in differentiating between nonischemic myocardial injury, type 1 MI, and type 2 MI. We identify limitations, review new research, and propose a framework for the diagnostic and therapeutic approach for patients who have suspected MI or other causes of myocardial injury. 10.1161/CIRCULATIONAHA.119.040631