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Butler J, Hammonds K, Talha KM, Alhamdow A, Bennett MM, Bomar JVA, Ettlinger JA, Traba MM, Priest EL, Schmedt N, Zeballos C, Shaver CN, Afzal A, Widmer RJ, Gottlieb RL, Mack MJ, Packer M. Incident heart failure and recurrent coronary events following acute myocardial infarction. Eur Heart J 2025; 46:1540-1550. [PMID: 39874177 PMCID: PMC12011519 DOI: 10.1093/eurheartj/ehae885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 09/12/2024] [Accepted: 12/06/2024] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND AND AIMS Recurrent myocardial infarction (MI) and incident heart failure (HF) are major post-MI complications. Herein, contemporary post-MI risks for recurrent MI and HF are described. METHODS A total of 6804 patients with a primary discharge diagnosis of MI at 28 Baylor Scott & White Health hospitals (January 2015 to December 2021) were studied. Patient characteristics, treatment, and outcomes, including incident HF, recurrent MI, all-cause death, and all-cause and cardiovascular rehospitalizations, were assessed. Landmark approach anchored at 3 months post-discharge was used to assess 1-year outcomes. RESULTS Median age was 69 years, 59.7% were male, and 76.7% had non-ST-elevation MI. Comorbidities included hypertension (89%), dyslipidaemia (87%), Type 2 diabetes (48%), and chronic kidney disease (34%); 17% had a history of MI and 23% of HF; 63% underwent percutaneous/surgical revascularization. In landmark-anchored 1-year outcomes (N = 6210), 413 (6.7%) patients died, 1730 (27.9%) had all-cause and 735 (11.8%) cardiovascular hospitalizations, 234 (3.8%) had recurrent MI. Of patients without history of HF, 1160 (23.8%) developed incident HF [42.2%, 26.7%, and 31.1% with ejection fraction (EF) < 40%, 41-49%, and >50%, respectively) within 3 months of discharge. Patients who developed HF had higher risk of death and hospitalizations (all P < .001), irrespective of EF. Of 2179 patients with EF > 50% without prevalent HF or HF during index hospitalization, 257 (11.8%) developed HF and 77 (3.5%) recurrent MI within 1 year. CONCLUSIONS In a contemporary post-MI cohort, the risk for incident HF was greater than recurrent MI, even among those with normal EF and no HF at discharge.
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Affiliation(s)
- Javed Butler
- Baylor Scott & White Research Institute, 3434 Live Oak St Ste 501, Dallas, TX 75204, USA
- Department of Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
| | - Kendall Hammonds
- Baylor Scott & White Research Institute, 3434 Live Oak St Ste 501, Dallas, TX 75204, USA
| | - Khawaja M Talha
- Department of Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
| | - Ayman Alhamdow
- Boehringer Ingelheim International GmbH, Binger Straße 173, Ingelheim, 55218 Ingelheim am Rhein, Germany
| | - Monica M Bennett
- Baylor Scott & White Research Institute, 3434 Live Oak St Ste 501, Dallas, TX 75204, USA
| | - J Vee Anne Bomar
- Baylor Scott & White Research Institute, 3434 Live Oak St Ste 501, Dallas, TX 75204, USA
| | - Jason A Ettlinger
- Baylor Scott & White Research Institute, 3434 Live Oak St Ste 501, Dallas, TX 75204, USA
| | - Monica Martinez Traba
- Boehringer Ingelheim International GmbH, Binger Straße 173, Ingelheim, 55218 Ingelheim am Rhein, Germany
| | - Elisa L Priest
- Baylor Scott & White Research Institute, 3434 Live Oak St Ste 501, Dallas, TX 75204, USA
| | - Niklas Schmedt
- Boehringer Ingelheim International GmbH, Binger Straße 173, Ingelheim, 55218 Ingelheim am Rhein, Germany
| | - Cecilia Zeballos
- Boehringer Ingelheim International GmbH, Binger Straße 173, Ingelheim, 55218 Ingelheim am Rhein, Germany
| | - Courtney N Shaver
- Baylor Scott & White Research Institute, 3434 Live Oak St Ste 501, Dallas, TX 75204, USA
| | - Aasim Afzal
- Departments of Cardiology and Cardiothoracic Surgery, Baylor Scott &White The Heart Hospital, 1100 Allied Dr, Plano, TX 75093, USA
- Center for Advanced Heart and Lung Disease and Baylor Heart and Vascular Institute, Baylor University Medical Center, 3410 Worth St, Ste 250, Dallas, TX 75226, USA
- Department of Medicine, Texas A&M Health Science Center, 3302 Gaston Avenue, Dallas, TX 75246, USA
| | - Robert J Widmer
- Department of Cardiology, Baylor Scott & White Medical Center—Temple, 2401 S 31st St, Temple, TX 76508, USA
| | - Robert L Gottlieb
- Baylor Scott & White Research Institute, 3434 Live Oak St Ste 501, Dallas, TX 75204, USA
- Departments of Cardiology and Cardiothoracic Surgery, Baylor Scott &White The Heart Hospital, 1100 Allied Dr, Plano, TX 75093, USA
- Center for Advanced Heart and Lung Disease and Baylor Heart and Vascular Institute, Baylor University Medical Center, 3410 Worth St, Ste 250, Dallas, TX 75226, USA
- Department of Medicine, Texas A&M Health Science Center, 3302 Gaston Avenue, Dallas, TX 75246, USA
- Department of Medicine, Burnett School of Medicine, Texas Christian University, 1100 W. Rosedale St., Fort Worth, TX 76104, USA
| | - Michael J Mack
- Baylor Scott & White Research Institute, 3434 Live Oak St Ste 501, Dallas, TX 75204, USA
- Departments of Cardiology and Cardiothoracic Surgery, Baylor Scott &White The Heart Hospital, 1100 Allied Dr, Plano, TX 75093, USA
| | - Milton Packer
- Center for Advanced Heart and Lung Disease and Baylor Heart and Vascular Institute, Baylor University Medical Center, 3410 Worth St, Ste 250, Dallas, TX 75226, USA
- Department of Medicine, Texas A&M Health Science Center, 3302 Gaston Avenue, Dallas, TX 75246, USA
- Department of Cardiology, Baylor Scott & White Medical Center—Temple, 2401 S 31st St, Temple, TX 76508, USA
- The Imperial College, London, UK
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Kaur SD, Choudhary S, Sen S, Pemmaraju DB, Singh SK, Kapoor DN. Microneedle patches: the next frontier in cardiovascular care. Drug Deliv Transl Res 2025:10.1007/s13346-025-01802-2. [PMID: 39881106 DOI: 10.1007/s13346-025-01802-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2025] [Indexed: 01/31/2025]
Abstract
Myocardial infarction is a condition where the heart muscle is damaged due to clogged coronary arteries. There are limited treatment options for treating myocardial infarction. Microneedle patches have recently become popular as a possibly viable therapy for myocardial. By adhering to the surface of the heart, these microneedle patches provide mechanical support, regenerative medicines, or cells directly to the injured tissue allowing for targeted treatment. These microneedle patches resolve the drawbacks of systemic therapy by facilitating targeted administration and integration with the goal of restoring damaged heart function. Recent advances in fabrication methods and current perspectives on the therapeutic advantages of cardiac microneedles patches used in the treatment of myocardial infarction are summarized in this review. Although the data is less in this area this review provides an avenue for the formulation scientist working in biomedical science to develop such microneedle patches for clinical applications in cardiology.
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Affiliation(s)
- Simran Deep Kaur
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, 173229, India
| | - Shivanshu Choudhary
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, 173229, India
| | - Santimoy Sen
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Guwahati, Assam, 781101, India
| | - Deepak B Pemmaraju
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Guwahati, Assam, 781101, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi Gt Road, Phagwara, Punjab, 144411, India
| | - Deepak N Kapoor
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, 173229, India.
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Piccolo EB, Ge ZD, Filipp ME, Sullivan DP, Thorp EB, Sumagin R. Hypoxia-inducible factor-2α enhances neutrophil survival to promote cardiac injury following myocardial infarction. Am J Physiol Heart Circ Physiol 2024; 327:H1230-H1243. [PMID: 39331023 PMCID: PMC11559636 DOI: 10.1152/ajpheart.00392.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 09/04/2024] [Accepted: 09/18/2024] [Indexed: 09/28/2024]
Abstract
Heart failure is a major cause of mortality following myocardial infarction. Neutrophils are among the first immune cells to accumulate in the infarcted region. Although beneficial functions of neutrophils in heart injury are now appreciated, neutrophils are also well known for their ability to exacerbate inflammation and promote tissue damage. Myocardial infarction induces hypoxia, where hypoxia-inducible factors (HIFs) are activated and play critical roles in cellular functions. In this context, the role of Hif2α in neutrophils during myocardial infarction is unknown. Here, we demonstrate that neutrophil Hif2α deletion markedly attenuates myocardial infarct size, improves cardiac function, reduces neutrophil survival and tissue accumulation, and correlates with increased macrophage engulfment rates. Mechanistic studies revealed that Hif2α promotes neutrophil survival through binding to hypoxia response element (HRE) in the promoter region of Birc2 to regulate expression of the prosurvival factor, cellular inhibitor of apoptosis protein-1 (cIAP1). Inhibition of cIAP1 in neutrophils using the pharmacological agent, Birinapant resulted in increased cell death, establishing a critical role of cIAP1 downstream of Hif2α in neutrophil survival. Taken together, our data demonstrate a protective effect of Hif2α deletion in neutrophils on cardiac injury outcomes through modulation of neutrophil cell survival.NEW & NOTEWORTHY Hif2α in neutrophils increases infarct size, cardiac dysfunction, and ventricular scar after myocardial infarction. Hif2α in neutrophils supports neutrophil survival via cIAP-1 signaling and delays macrophage engulfment.
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Affiliation(s)
- Enzo B Piccolo
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
| | | | - Mallory E Filipp
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
| | - David P Sullivan
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
| | - Edward B Thorp
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
| | - Ronen Sumagin
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
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Yao J, Li J, Zhu D, Li Y, Tasoudis P, Liu S, Mei X, Popowski K, Caranasos TG, Wang H, Xu M, Jiang T, Shen K, Li H, Huang K. An infusible biologically active adhesive for chemotherapy-related heart failure in elderly rats. Bioact Mater 2024; 40:571-581. [PMID: 39161907 PMCID: PMC11331816 DOI: 10.1016/j.bioactmat.2024.06.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 06/06/2024] [Accepted: 06/11/2024] [Indexed: 08/21/2024] Open
Abstract
Chemotherapy-induced cardiotoxicity with subsequent heart failure (HF) is a major cause of morbidity and mortality in cancer survivors worldwide. Chemotherapy-induced HF is exceptionally challenging as it generally manifests in patients who are typically not eligible for left ventricular device implantation or heart transplantation. To explore alternative treatment strategies for cancer survivors suffering from chemotherapy-induced HF, we developed a minimally invasive infusible cardiac stromal cell secretomes adhesive (MISA) that could be delivered locally through an endoscope-guided intrapericardial injection. To mimic the typical clinical presentation of chemotherapy-induced HF in elder patients, we established an aged rat model in which restrictive cardiomyopathy with sequential HF was induced via consecutive doxorubicin injections. In vitro, we prove that MISA not only enhanced cardiomyocytes proliferation potency and viability, but also inhibited their apoptosis. In vivo, we prove that MISA improved the ventricular contractility indexes and led to beneficial effects on histological and structural features of restrictive cardiomyopathy via promoting cardiomyocyte proliferation, angiogenesis, and mitochondrial respiration. Additionally, we also evaluated the safety and feasibility of MISA intrapericardial delivery in a healthy porcine model with an intact immune system. In general, our data indicates that MISA has a strong potential for translation into large animal models and ultimately clinical applications for chemotherapy-induced HF prior to the final option of heart transplantation.
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Affiliation(s)
- Jialu Yao
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Junlang Li
- Joint Department of Biomedical Engineering, University of North Carolina Chapel Hill and North Carolina State University, Raleigh, NC, USA
| | - Dashuai Zhu
- Department of Molecular Biomedical Sciences, NC State University, Raleigh, NC, USA
| | - Yuan Li
- Department of Molecular Biomedical Sciences, NC State University, Raleigh, NC, USA
- Joint Department of Biomedical Engineering, University of North Carolina Chapel Hill and North Carolina State University, Raleigh, NC, USA
| | - Panagiotis Tasoudis
- Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Shuo Liu
- Department of Molecular Biomedical Sciences, NC State University, Raleigh, NC, USA
| | - Xuan Mei
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA
| | - Kristen Popowski
- Department of Molecular Biomedical Sciences, NC State University, Raleigh, NC, USA
| | - Thomas G. Caranasos
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA
| | - Haipeng Wang
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Mingzhu Xu
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Tingbo Jiang
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Kan Shen
- Department of Critical Care Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Hongxia Li
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Ke Huang
- Department of Molecular Biomedical Sciences, NC State University, Raleigh, NC, USA
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Ueno K, Kamiya K, Hamazaki N, Nozaki K, Ichikawa T, Yamashita M, Uchida S, Noda T, Miki T, Hotta K, Maekawa E, Yamaoka-Tojo M, Matsunaga A, Ako J. Leg strength and incidence of heart failure in patients with acute coronary syndrome. Eur J Prev Cardiol 2024; 31:834-842. [PMID: 38150177 DOI: 10.1093/eurjpc/zwad406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/17/2023] [Accepted: 12/18/2023] [Indexed: 12/28/2023]
Abstract
AIMS The risk of developing heart failure (HF) after acute coronary syndrome (ACS) remains high. It is unclear whether skeletal muscle strength, in addition to existing risk factors, is a predictor for developing HF after ACS. We aimed to clarify the relationship between quadriceps isometric strength (QIS), a skeletal muscle strength indicator, and the risk of developing HF in patients with ACS. METHODS AND RESULTS We included 1053 patients with ACS without a prior HF or complications of HF during hospitalization. The median (interquartile range) age was 67 (57-74) years. The patients were classified into two groups-high and low QIS-using the sex-specific median QIS. The endpoint was HF admissions. During a mean follow-up period of 4.4 ± 3.7 years, 75 (7.1%) HF admissions were observed. After multivariate adjustment, a high QIS was associated with a lower risk of HF [hazard ratio: 0.52, 95% confidence interval (CI): 0.32-0.87]. Hazard ratio (95% CI) per 5% body weight increment increase of QIS for HF incidents was 0.87 (0.80-0.95). Even when competing risks of death were taken into account, the results did not change. The inclusion of QIS was associated with increases in net reclassification improvement (0.26; 95% CI: 0.002-0.52) and an integrated discrimination index (0.01; 95% CI: 0.004-0.02) for HF. CONCLUSION The present study showed that a higher level of QIS was strongly associated with a lower risk of developing HF after ACS. These findings suggest that skeletal muscle strength could be one of the factors contributing to the risk of developing HF after ACS.
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Affiliation(s)
- Kensuke Ueno
- Department of Rehabilitation Sciences, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Kentaro Kamiya
- Department of Rehabilitation Sciences, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
- Department of Rehabilitation, School of Allied Health Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Nobuaki Hamazaki
- Department of Rehabilitation, Kitasato University Hospital, Sagamihara, Japan
| | - Kohei Nozaki
- Department of Rehabilitation, Kitasato University Hospital, Sagamihara, Japan
| | - Takafumi Ichikawa
- Department of Rehabilitation, Kitasato University Hospital, Sagamihara, Japan
| | - Masashi Yamashita
- Department of Rehabilitation Sciences, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
- Division of Research, ARCE Inc., Sagamihara, Japan
| | - Shota Uchida
- Department of Rehabilitation Sciences, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
- Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Takumi Noda
- Department of Rehabilitation Sciences, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Takashi Miki
- Department of Rehabilitation Sciences, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Kazuki Hotta
- Department of Rehabilitation Sciences, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
- Department of Rehabilitation, School of Allied Health Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Emi Maekawa
- Department of Cardiovascular Medicine, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Minako Yamaoka-Tojo
- Department of Rehabilitation Sciences, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
- Department of Rehabilitation, School of Allied Health Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Atsuhiko Matsunaga
- Department of Rehabilitation Sciences, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
- Department of Rehabilitation, School of Allied Health Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Junya Ako
- Department of Cardiovascular Medicine, School of Medicine, Kitasato University, Sagamihara, Japan
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Rosellini E, Cascone MG, Guidi L, Schubert DW, Roether JA, Boccaccini AR. Mending a broken heart by biomimetic 3D printed natural biomaterial-based cardiac patches: a review. Front Bioeng Biotechnol 2023; 11:1254739. [PMID: 38047285 PMCID: PMC10690428 DOI: 10.3389/fbioe.2023.1254739] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/16/2023] [Indexed: 12/05/2023] Open
Abstract
Myocardial infarction is one of the major causes of mortality as well as morbidity around the world. Currently available treatment options face a number of drawbacks, hence cardiac tissue engineering, which aims to bioengineer functional cardiac tissue, for application in tissue repair, patient specific drug screening and disease modeling, is being explored as a viable alternative. To achieve this, an appropriate combination of cells, biomimetic scaffolds mimicking the structure and function of the native tissue, and signals, is necessary. Among scaffold fabrication techniques, three-dimensional printing, which is an additive manufacturing technique that enables to translate computer-aided designs into 3D objects, has emerged as a promising technique to develop cardiac patches with a highly defined architecture. As a further step toward the replication of complex tissues, such as cardiac tissue, more recently 3D bioprinting has emerged as a cutting-edge technology to print not only biomaterials, but also multiple cell types simultaneously. In terms of bioinks, biomaterials isolated from natural sources are advantageous, as they can provide exceptional biocompatibility and bioactivity, thus promoting desired cell responses. An ideal biomimetic cardiac patch should incorporate additional functional properties, which can be achieved by means of appropriate functionalization strategies. These are essential to replicate the native tissue, such as the release of biochemical signals, immunomodulatory properties, conductivity, enhanced vascularization and shape memory effects. The aim of the review is to present an overview of the current state of the art regarding the development of biomimetic 3D printed natural biomaterial-based cardiac patches, describing the 3D printing fabrication methods, the natural-biomaterial based bioinks, the functionalization strategies, as well as the in vitro and in vivo applications.
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Affiliation(s)
| | | | - Lorenzo Guidi
- Department of Civil and Industrial Engineering, University of Pisa, Pisa, Italy
| | - Dirk W. Schubert
- Department of Materials Science and Engineering, Institute of Polymer Materials, Friedrich-Alexander-University (FAU), Erlangen, Germany
- Bavarian Polymer Institute (BPI), Erlangen, Germany
| | - Judith A. Roether
- Department of Materials Science and Engineering, Institute of Polymer Materials, Friedrich-Alexander-University (FAU), Erlangen, Germany
| | - Aldo R. Boccaccini
- Bavarian Polymer Institute (BPI), Erlangen, Germany
- Department of Materials Science and Engineering, Institute of Biomaterials, Friedrich-Alexander-University (FAU), Erlangen, Germany
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Guo J, Wang H, Li Y, Zhu S, Hu H, Gu Z. Nanotechnology in coronary heart disease. Acta Biomater 2023; 171:37-67. [PMID: 37714246 DOI: 10.1016/j.actbio.2023.09.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/17/2023] [Accepted: 09/08/2023] [Indexed: 09/17/2023]
Abstract
Coronary heart disease (CHD) is one of the major causes of death and disability worldwide, especially in low- and middle-income countries and among older populations. Conventional diagnostic and therapeutic approaches have limitations such as low sensitivity, high cost and side effects. Nanotechnology offers promising alternative strategies for the diagnosis and treatment of CHD by exploiting the unique properties of nanomaterials. In this review, we use bibliometric analysis to identify research hotspots in the application of nanotechnology in CHD and provide a comprehensive overview of the current state of the art. Nanomaterials with enhanced imaging and biosensing capabilities can improve the early detection of CHD through advanced contrast agents and high-resolution imaging techniques. Moreover, nanomaterials can facilitate targeted drug delivery, tissue engineering and modulation of inflammation and oxidative stress, thus addressing multiple aspects of CHD pathophysiology. We discuss the application of nanotechnology in CHD diagnosis (imaging and sensors) and treatment (regulation of macrophages, cardiac repair, anti-oxidative stress), and provide insights into future research directions and clinical translation. This review serves as a valuable resource for researchers and clinicians seeking to harness the potential of nanotechnology in the management of CHD. STATEMENT OF SIGNIFICANCE: Coronary heart disease (CHD) is the one of leading cause of death and disability worldwide. Nanotechnology offers new strategies for diagnosing and treating CHD by exploiting the unique properties of nanomaterials. This review uses bibliometric analysis to uncover research trends in the use of nanotechnology for CHD. We discuss the potential of nanomaterials for early CHD detection through advanced imaging and biosensing, targeted drug delivery, tissue engineering, and modulation of inflammation and oxidative stress. We also offer insights into future research directions and potential clinical applications. This work aims to guide researchers and clinicians in leveraging nanotechnology to improve CHD patient outcomes and quality of life.
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Affiliation(s)
- Junsong Guo
- Academician Workstation, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China; Department of Cardiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China
| | - Hao Wang
- Academician Workstation, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China; Department of Cardiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China
| | - Ying Li
- Academician Workstation, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China; Department of Cardiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China
| | - Shuang Zhu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nano-safety, Institute of High Energy Physics, Beijing 100049, China; CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Chinese Academy of Sciences, Beijing 100190, China; Center of Materials Science and Optoelectronics Engineering, College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Houxiang Hu
- Academician Workstation, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China; Department of Cardiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China.
| | - Zhanjun Gu
- Academician Workstation, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China; CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nano-safety, Institute of High Energy Physics, Beijing 100049, China; Center of Materials Science and Optoelectronics Engineering, College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing 100049, China.
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8
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Elendu C, Amaechi DC, Elendu TC, Ashna M, Ross-Comptis J, Ansong SO, Egbunu EO, Okafor GC, Jingwa KA, Akintunde AA, Ogah CM, Edeko MO, Ibitoye AV, Ogunseye MO, Alakwe-Ojimba CE, Omeludike EK, Oguine CA, Afuh RN, Olawuni CA, Ekwem OR, Oyedele BA, Pius EI, Asekhauno MO, Ladele JA, Okoro CB, Monika Pouekoua BC, Adenikinju JS, Agu-ben CM, Aborisade O. Heart failure and diabetes: Understanding the bidirectional relationship. Medicine (Baltimore) 2023; 102:e34906. [PMID: 37713837 PMCID: PMC10508577 DOI: 10.1097/md.0000000000034906] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 08/03/2023] [Indexed: 09/17/2023] Open
Abstract
Heart failure and diabetes mellitus are 2 common and closely intertwined chronic conditions that often coexist in individuals. The relationship between heart failure and diabetes is bidirectional, meaning that each condition can influence the development and progression of the other. Understanding this complex interplay is crucial for optimizing the management and outcomes of patients with these comorbidities. This review comprehensively analyzed the literature to examine the bidirectional relationship between heart failure and diabetes. We searched various electronic databases and included studies that explored the pathophysiological mechanisms, epidemiology, clinical implications, and therapeutic considerations associated with this relationship. The bidirectional relationship between heart failure and diabetes is multifactorial and involves several interconnected mechanisms. Diabetes is a recognized risk factor for heart failure, increasing the risk of its development and accelerating its progression. On the other hand, heart failure can contribute to the development of insulin resistance and worsen glycemic control in patients with diabetes. Shared risk factors, such as obesity, hypertension, and dyslipidemia, contribute to development of both conditions. Additionally, hyperglycemia, insulin resistance, chronic inflammation, oxidative stress, and mitochondrial dysfunction play significant roles in the pathogenesis of heart failure in individuals with diabetes. The bidirectional relationship between heart failure and diabetes has important clinical implications. Patients with heart failure and diabetes have worse outcomes, including higher hospitalization rates, morbidity, and mortality, than those without diabetes. Optimal management strategies should target both conditions simultaneously, focusing on lifestyle modifications, pharmacotherapy, glycemic control, and cardiovascular risk reduction.
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9
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Docherty KF, Lam CSP, Rakisheva A, Coats AJS, Greenhalgh T, Metra M, Petrie MC, Rosano GMC. Heart failure diagnosis in the general community - Who, how and when? A clinical consensus statement of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur J Heart Fail 2023; 25:1185-1198. [PMID: 37368511 DOI: 10.1002/ejhf.2946] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/17/2023] [Accepted: 06/19/2023] [Indexed: 06/29/2023] Open
Abstract
A significant proportion of patients experience delays in the diagnosis of heart failure due to the non-specific signs and symptoms of the syndrome. Diagnostic tools such as measurement of natriuretic peptide concentrations are fundamentally important when screening for heart failure, yet are frequently under-utilized. This clinical consensus statement provides a diagnostic framework for general practitioners and non-cardiology community-based physicians to recognize, investigate and risk-stratify patients presenting in the community with possible heart failure.
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Affiliation(s)
- Kieran F Docherty
- BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Carolyn S P Lam
- National Heart Centre Singapore, Duke-National University of Singapore, Singapore, Singapore
| | - Amina Rakisheva
- Scientific Research Institute of Cardiology and Internal Medicine, Almaty, Kazakhstan
| | | | - Trisha Greenhalgh
- Nuffield Department of Primary Care Health Sciences, Medical Sciences Division, University of Oxford, Oxford, UK
| | - Marco Metra
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Cardiology. ASST Spedali Civili, University of Brescia, Brescia, Italy
| | - Mark C Petrie
- BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
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10
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Xu Y, Hu Y, Geng Y, Zhao N, Jia C, Song H, Bai W, Guo C, Wang L, Ni Y, Qi X. Pentraxin 3 depletion (PTX3 KD) inhibited myocardial fibrosis in heart failure after myocardial infarction. Aging (Albany NY) 2022; 14:4036-4049. [PMID: 35522573 PMCID: PMC9134954 DOI: 10.18632/aging.204070] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 04/04/2022] [Indexed: 11/25/2022]
Abstract
Background: HF is a common complication of MI. The underlying mechanisms of myocardial fibrosis in HF after MI are incompletely defined. Here, this study aims to investigate the role of PTX3 KD in HF after MI. Methods: Bioinformatics analysis based on GSE86569 dataset was performed to explore the potential role of PTX3 in HF. Male C57/BL6J mice were administered with lentiviral vector encoding PTX3 KD or empty vector, and then underwent either coronary ligation or sham surgery. Echocardiography, Masson staining, and immunofluorescence counterstaining were conducted to evaluate the cardiac function and fibrosis. Cardiac fibroblasts were isolated and transfected with lentiviral vector encoding PTX3 KD in vitro to verify the in vivo findings. Results: Bioinformatics analysis based on GSE86569 revealed the aberrant expression of PTX3 in HF patients. Echocardiography showed that PTX3 KD reversed the HF-induced cardiac dysfunction with better cardiac function parameters. Masson staining demonstrated that the obvious infarct and high fibrosis ratio in HF mice were remarkably improved after PTX3 KD. Immunofluorescence staining indicated that the HF-induced increase expression of α-SMA was significantly suppressed by PTX3 KD. Additionally, both in vivo and in vitro results confirmed that PTX3 KD decreased the fibrosis-related up-regulation of collagen I, collagen III, and p-STAT3. However, the result was opposite after IL-6 treatment. Conclusions: PTX3 KD protects the cardiac function and counteracts the myocardial fibrosis by down-regulating IL-6/STAT3 pathway in HF.
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Affiliation(s)
- Yufang Xu
- Department of Pharmacy, Hebei People's Hospital, Shijiazhuang 050051, Hebei, China
| | - Yiting Hu
- Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050051, Hebei, China
| | - Yanping Geng
- Cardiovascular Medicine, Hebei General Hospital, Shijiazhuang 050051, Hebei, China
| | - Na Zhao
- Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050051, Hebei, China
| | - Caiyun Jia
- Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050051, Hebei, China
| | - Haojing Song
- Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050051, Hebei, China
| | - Wanjun Bai
- Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050051, Hebei, China
| | - Caihui Guo
- Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050051, Hebei, China
| | - Lili Wang
- Cardiovascular Medicine, Hebei General Hospital, Shijiazhuang 050051, Hebei, China
| | - Yanhui Ni
- Cardiovascular Medicine, Hebei General Hospital, Shijiazhuang 050051, Hebei, China
| | - Xiaoyong Qi
- Cardiovascular Medicine, Hebei General Hospital, Shijiazhuang 050051, Hebei, China
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11
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Neef K, Drey F, Lepperhof V, Wahlers T, Hescheler J, Choi YH, Šarić T. Co-transplantation of Mesenchymal Stromal Cells and Induced Pluripotent Stem Cell-Derived Cardiomyocytes Improves Cardiac Function After Myocardial Damage. Front Cardiovasc Med 2022; 8:794690. [PMID: 35071360 PMCID: PMC8770928 DOI: 10.3389/fcvm.2021.794690] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 11/22/2021] [Indexed: 01/01/2023] Open
Abstract
Induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) represent an attractive resource for cardiac regeneration. However, survival and functional integration of transplanted iPS-CM is poor and remains a major challenge for the development of effective therapies. We hypothesized that paracrine effects of co-transplanted mesenchymal stromal cells (MSCs) augment the retention and therapeutic efficacy of iPS-CM in a mouse model of myocardial infarction (MI). To test this, either iPS-CM, MSC, or both cell types were transplanted into the cryoinfarction border zone of syngeneic mice immediately after injury. Bioluminescence imaging (BLI) of iPS-CM did not confirm enhanced retention by co-application of MSC during the 28-day follow-up period. However, histological analyses of hearts 28 days after cell transplantation showed that MSC increased the fraction of animals with detectable iPS-CM by 2-fold. Cardiac MRI analyses showed that from day 14 after transplantation on, the animals that have received cells had a significantly higher left ventricular ejection fraction (LVEF) compared to the placebo group. There was no statistically significant difference in LVEF between animals transplanted only with iPS-CM or only with MSC. However, combined iPS-CM and MSC transplantation resulted in higher LVEF compared to transplantation of single-cell populations during the whole observation period. Histological analyses revealed that MSC increased the capillarization in the myocardium when transplanted alone or with iPS-CM and decreased the infarct scar area only when transplanted in combination with iPS-CM. These results indicate that co-transplantation of iPS-CM and MSC improves cardiac regeneration after cardiac damage, demonstrating the potential of combining multiple cell types for increasing the efficacy of future cardiac cell therapies.
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Affiliation(s)
- Klaus Neef
- Department of Cardiac and Thoracic Surgery, Heart Center, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Florian Drey
- Department of Cardiac and Thoracic Surgery, Heart Center, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Vera Lepperhof
- Institute for Neurophysiology, Center for Physiology and Pathophysiology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Thorsten Wahlers
- Department of Cardiac and Thoracic Surgery, Heart Center, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Jürgen Hescheler
- Institute for Neurophysiology, Center for Physiology and Pathophysiology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Yeong-Hoon Choi
- Department of Cardiac and Thoracic Surgery, Heart Center, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Clinic for Cardiac Surgery and Surgical Intensive Care Medicine, Kerckhoff Clinic Bad Nauheim, Kerckhoff Campus, Justus Liebig University Giessen, Giessen, Germany
| | - Tomo Šarić
- Institute for Neurophysiology, Center for Physiology and Pathophysiology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- *Correspondence: Tomo Šarić
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12
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Wischmann P, Chennupati R, Solga I, Funk F, Becher S, Gerdes N, Anker S, Kelm M, Jung C. Safety and efficacy of iron supplementation after myocardial infarction in mice with moderate blood loss anaemia. ESC Heart Fail 2021; 8:5445-5455. [PMID: 34636175 PMCID: PMC8712778 DOI: 10.1002/ehf2.13639] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 09/12/2021] [Accepted: 09/19/2021] [Indexed: 11/28/2022] Open
Abstract
Aims Iron deficiency is frequently observed in patients with acute coronary syndrome and associates with poor prognosis after acute myocardial infarction (AMI). Anaemia is linked to dysregulation of iron metabolism, red blood cell dysfunction, and increased reactive oxygen species generation. Iron supplementation in chronic heart failure is safe and improves cardiac exercise capacity. Increases in iron during ischaemia or immediately after reperfusion are associated with detrimental effects on left ventricular (LV) function. The safety and applicability of iron during or immediately after reperfusion of AMI in anaemia are not known. We aimed to study the safety and efficacy of iron supplementation within 1 h or deferred to 24 h after reperfusion of AMI by analysing LV function and infarct size. Methods and results In a mouse model of moderate blood loss anaemia (n = 6–8 mice/group), the effects of iron supplementation (20 mg iron as ferric carboxymaltose per kg body weight) within 1 h and deferred to 24 h after ischaemia/reperfusion were assessed. Cardiac function was analysed in vivo by echocardiography at baseline (Day 3) with and without anaemia, after AMI (24 h), and after administration of intravenous iron. Anaemia was characterized by iron deficiency and a trend towards increased haemolysis, which was supported by increased plasma free‐haemoglobin [sham vs. anaemia (n = 8/group): P < 0.05]. Anaemia increased heart rate, LV end‐diastolic volume, stroke volume, and cardiac output, while LV end‐systolic volume remained unchanged at baseline. Superimposition of AMI deteriorated global LV function, whereas infarct sizes remained unaffected [sham vs. anaemia (n = 6/group): P = 0.9]. Deferred iron supplementation 24 h after ischaemia/reperfusion resulted in reversal of end‐systolic volume increase and reduced infarct size [% of area at risk: sham vs. anaemia + iron after 24 h; (n = 6/group); 48 ± 7 vs. 38 ± 7; P < 0.05], whereas administration within 1 h after reperfusion was neutral [sham vs. anaemia + iron; (n = 6/group); 48 ± 7 vs. 42 ± 8; P = 0.56]. Moreover, iron application after reperfused AMI showed unaltered mortality compared with sham. Conclusions Iron supplementation 24 h after reperfusion of AMI is safe and reversed enlargement of end‐systolic volume after AMI resulting in increased stroke volume and cardiac output. This highlights its potential as adjunctive treatment in anaemia with ID after reperfused AMI. Time point of iron application after reperfusion appears critical.
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Affiliation(s)
- Patricia Wischmann
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Moorenstr. 5, Düsseldorf, 40225, Germany
| | - Ramesh Chennupati
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Moorenstr. 5, Düsseldorf, 40225, Germany
| | - Isabella Solga
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Moorenstr. 5, Düsseldorf, 40225, Germany
| | - Felix Funk
- Department of Nanomedicines, Vifor Pharma Management Ltd, Glattbrugg, Switzerland
| | - Stefanie Becher
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Moorenstr. 5, Düsseldorf, 40225, Germany
| | - Norbert Gerdes
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Moorenstr. 5, Düsseldorf, 40225, Germany
| | - Stefan Anker
- Department of Cardiology, Charité Campus Virchow-Klinikum, Berlin, Germany
| | - Malte Kelm
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Moorenstr. 5, Düsseldorf, 40225, Germany
| | - Christian Jung
- Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Moorenstr. 5, Düsseldorf, 40225, Germany
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13
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Fischesser DM, Bo B, Benton RP, Su H, Jahanpanah N, Haworth KJ. Controlling Reperfusion Injury With Controlled Reperfusion: Historical Perspectives and New Paradigms. J Cardiovasc Pharmacol Ther 2021; 26:504-523. [PMID: 34534022 DOI: 10.1177/10742484211046674] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Cardiac reperfusion injury is a well-established outcome following treatment of acute myocardial infarction and other types of ischemic heart conditions. Numerous cardioprotection protocols and therapies have been pursued with success in pre-clinical models. Unfortunately, there has been lack of successful large-scale clinical translation, perhaps in part due to the multiple pathways that reperfusion can contribute to cell death. The search continues for new cardioprotection protocols based on what has been learned from past results. One class of cardioprotection protocols that remain under active investigation is that of controlled reperfusion. This class consists of those approaches that modify, in a controlled manner, the content of the reperfusate or the mechanical properties of the reperfusate (e.g., pressure and flow). This review article first provides a basic overview of the primary pathways to cell death that have the potential to be addressed by various forms of controlled reperfusion, including no-reflow phenomenon, ion imbalances (particularly calcium overload), and oxidative stress. Descriptions of various controlled reperfusion approaches are described, along with summaries of both mechanistic and outcome-oriented studies at the pre-clinical and clinical phases. This review will constrain itself to approaches that modify endogenously-occurring blood components. These approaches include ischemic postconditioning, gentle reperfusion, controlled hypoxic reperfusion, controlled hyperoxic reperfusion, controlled acidotic reperfusion, and controlled ionic reperfusion. This review concludes with a discussion of the limitations of past approaches and how they point to potential directions of investigation for the future.
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Affiliation(s)
- Demetria M Fischesser
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, College of Medicine, 2514University of Cincinnati, Cincinnati, OH, USA
| | - Bin Bo
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, College of Medicine, 2514University of Cincinnati, Cincinnati, OH, USA
| | - Rachel P Benton
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, College of Medicine, 2514University of Cincinnati, Cincinnati, OH, USA
| | - Haili Su
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, College of Medicine, 2514University of Cincinnati, Cincinnati, OH, USA
| | - Newsha Jahanpanah
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, College of Medicine, 2514University of Cincinnati, Cincinnati, OH, USA
| | - Kevin J Haworth
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, College of Medicine, 2514University of Cincinnati, Cincinnati, OH, USA
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14
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Das S, Nam H, Jang J. 3D bioprinting of stem cell-laden cardiac patch: A promising alternative for myocardial repair. APL Bioeng 2021; 5:031508. [PMID: 34368602 PMCID: PMC8318604 DOI: 10.1063/5.0030353] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 06/01/2021] [Indexed: 12/18/2022] Open
Abstract
Stem cell-laden three-dimensional (3D) bioprinted cardiac patches offer an alternative and promising therapeutic and regenerative approach for ischemic cardiomyopathy by reversing scar formation and promoting myocardial regeneration. Numerous studies have reported using either multipotent or pluripotent stem cells or their combination for 3D bioprinting of a cardiac patch with the sole aim of restoring cardiac function by faithfully rejuvenating the cardiomyocytes and associated vasculatures that are lost to myocardial infarction. While many studies have demonstrated success in mimicking cardiomyocytes' behavior, improving cardiac function and providing new hope for regenerating heart post-myocardial infarction, some others have reported contradicting data in apparent ways. Nonetheless, all investigators in the field are speed racing toward determining a potential strategy to effectively treat losses due to myocardial infarction. This review discusses various types of candidate stem cells that possess cardiac regenerative potential, elucidating their applications and limitations. We also brief the challenges of and an update on the implementation of the state-of-the-art 3D bioprinting approach to fabricate cardiac patches and highlight different strategies to implement vascularization and augment cardiac functional properties with respect to electrophysiological similarities to native tissue.
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Affiliation(s)
- Sanskrita Das
- Department of Convergence IT Engineering, POSTECH, 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea
| | - Hyoryung Nam
- Department of Convergence IT Engineering, POSTECH, 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea
| | - Jinah Jang
- Author to whom correspondence should be addressed:
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15
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Xu LN, Wang SH, Su XL, Komal S, Fan HK, Xia L, Zhang LR, Han SN. Targeting Glycogen Synthase Kinase 3 Beta Regulates CD47 Expression After Myocardial Infarction in Rats via the NF-κB Signaling Pathway. Front Pharmacol 2021; 12:662726. [PMID: 34349643 PMCID: PMC8327268 DOI: 10.3389/fphar.2021.662726] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/12/2021] [Indexed: 12/13/2022] Open
Abstract
The aim of this study was to investigate the effects of the GSK-3β/NF-κB pathway on integrin-associated protein (CD47) expression after myocardial infarction (MI) in rats. An MI Sprague Dawley rat model was established by ligating the left anterior descending coronary artery. The rats were divided into three groups: Sham, MI, and SB + MI (SB216763) groups. Immunohistochemistry was used to observe the changes in cardiac morphology. A significant reduction in the sizes of fibrotic scars was observed in the SB + MI group compared to that in the MI group. SB216763 decreased the mRNA and protein expression of CD47 and NF-κB during MI. Primary rat cardiomyocytes (RCMs) and the H9c2 cell line were used to establish in vitro hypoxia models. Quantitative real-time PCR and western blotting analyses were conducted to detect mRNA and protein expression levels of CD47 and NF-κB and apoptosis-related proteins, respectively. Apoptosis of hypoxic cells was assessed using flow cytometry. SB216763 reduced the protein expression of CD47 and NF-κB in RCMs and H9c2 cells under hypoxic conditions for 12 h, and alleviated hypoxia-induced apoptosis. SN50 (an NF-κB inhibitor) also decreased CD47 protein expression in RCMs and H9c2 cells under hypoxic conditions for 12 h and protected cells from apoptosis. GSK-3β upregulates CD47 expression in cardiac tissues after MI by activating NF-κB, which in turn leads to myocardial cell damage and apoptosis.
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Affiliation(s)
- Li-Na Xu
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Shu-Hui Wang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xue-Ling Su
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Sumra Komal
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Hong-Kun Fan
- Department of Physiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Li Xia
- Department of Anesthesiology in Surgery Branch, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Li-Rong Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Sheng-Na Han
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
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16
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Jering KS, Claggett B, Pfeffer MA, Granger C, Køber L, Lewis EF, Maggioni AP, Mann D, McMurray JJV, Rouleau JL, Solomon SD, Steg PG, van der Meer P, Wernsing M, Carter K, Guo W, Zhou Y, Lefkowitz M, Gong J, Wang Y, Merkely B, Macin SM, Shah U, Nicolau JC, Braunwald E. Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI): design and baseline characteristics. Eur J Heart Fail 2021; 23:1040-1048. [PMID: 33847047 DOI: 10.1002/ejhf.2191] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 03/29/2021] [Accepted: 04/08/2021] [Indexed: 11/11/2022] Open
Abstract
AIMS Patients surviving an acute myocardial infarction (AMI) are at risk of developing symptomatic heart failure (HF) or premature death. We hypothesized that sacubitril/valsartan, effective in the treatment of chronic HF, prevents development of HF and reduces cardiovascular death following high-risk AMI compared to a proven angiotensin-converting enzyme (ACE) inhibitor. This paper describes the study design and baseline characteristics of patients enrolled in the Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) trial. METHODS AND RESULTS PARADISE-MI, a multinational (41 countries), double-blind, active-controlled trial, randomized patients within 0.5-7 days of presentation with index AMI to sacubitril/valsartan or ramipril. Transient pulmonary congestion and/or left ventricular ejection fraction (LVEF) ≤40% and at least one additional factor augmenting risk of HF or death (age ≥70 years, estimated glomerular filtration rate <60 mL/min/1.73 m2 , diabetes, prior myocardial infarction, atrial fibrillation, LVEF <30%, Killip class ≥III, ST-elevation myocardial infarction without reperfusion) were required for inclusion. PARADISE-MI was event-driven targeting 708 primary endpoints (cardiovascular death, HF hospitalization or outpatient development of HF). Randomization of 5669 patients occurred 4.3 ± 1.8 days from presentation with index AMI. The mean age was 64 ± 12 years, 24% were women. The majority (76%) qualified with ST-segment elevation myocardial infarction; acute percutaneous coronary intervention was performed in 88% and thrombolysis in 6%. LVEF was 37 ± 9% and 58% were in Killip class ≥II. CONCLUSIONS Baseline therapies in PARADISE-MI reflect advances in contemporary evidence-based care. With enrollment complete PARADISE-MI is poised to determine whether sacubitril/valsartan is more effective than a proven ACE inhibitor in preventing development of HF and cardiovascular death following AMI.
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Affiliation(s)
- Karola S Jering
- Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
| | - Brian Claggett
- Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
| | - Marc A Pfeffer
- Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
| | | | | | - Eldrin F Lewis
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA
| | | | - Douglas Mann
- Washington University Medical Center, St Louis, MO, USA
| | - John J V McMurray
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | | | - Scott D Solomon
- Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
| | - Philippe G Steg
- Université de Paris, AP-HP (Assistance Publique-Hôpitaux de Paris), FACT (French Alliance for Cardiovascular Trials) and INSERM U-1148, Paris, France
| | - Peter van der Meer
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | | | | | - Weinong Guo
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
| | - Yinong Zhou
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
| | | | - Jianjian Gong
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
| | - Yi Wang
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
| | - Bela Merkely
- Semmelweis University, Heart and Vascular Center, Budapest, Hungary
| | - Stella M Macin
- Instituto de Cardiología JF Cabral Corrientes, Corrientes, Argentina
| | - Urmil Shah
- Care Institute of Medical Sciences, Ahmedabad, India
| | - Jose C Nicolau
- Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Eugene Braunwald
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
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17
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Zhang R, Guo T, Han Y, Huang H, Shi J, Hu J, Li H, Wang J, Saleem A, Zhou P, Lan F. Design of synthetic microenvironments to promote the maturation of human pluripotent stem cell derived cardiomyocytes. J Biomed Mater Res B Appl Biomater 2020; 109:949-960. [PMID: 33231364 DOI: 10.1002/jbm.b.34759] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/08/2020] [Accepted: 11/10/2020] [Indexed: 12/19/2022]
Abstract
Cardiomyocyte like cells derived from human pluripotent stem cells (hPSC-CMs) have a good application perspective in many fields such as disease modeling, drug screening and clinical treatment. However, these are severely hampered by the fact that hPSC-CMs are immature compared to adult human cardiomyocytes. Therefore, many approaches such as genetic manipulation, biochemical factors supplement, mechanical stress, electrical stimulation and three-dimensional culture have been developed to promote the maturation of hPSC-CMs. Recently, establishing in vitro synthetic artificial microenvironments based on the in vivo development program of cardiomyocytes has achieved much attention due to their inherent properties such as stiffness, plasticity, nanotopography and chemical functionality. In this review, the achievements and deficiency of reported synthetic microenvironments that mainly discussed comprehensive biological, chemical, and physical factors, as well as three-dimensional culture were mainly discussed, which have significance to improve the microenvironment design and accelerate the maturation of hPSC-CMs.
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Affiliation(s)
- Rui Zhang
- School and hospital of Stomatology, Lanzhou University, Lanzhou, China.,College of Life Sciences, Lanzhou University, Lanzhou, China
| | - Tianwei Guo
- Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Yu Han
- School and hospital of Stomatology, Lanzhou University, Lanzhou, China
| | - Hongxin Huang
- School and hospital of Stomatology, Lanzhou University, Lanzhou, China
| | - Jiamin Shi
- College of Life Sciences, Lanzhou University, Lanzhou, China
| | - Jiaxuan Hu
- College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China
| | - Hongjiao Li
- School and hospital of Stomatology, Lanzhou University, Lanzhou, China
| | - Jianlin Wang
- College of Life Sciences, Lanzhou University, Lanzhou, China
| | - Amina Saleem
- Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Ping Zhou
- School and hospital of Stomatology, Lanzhou University, Lanzhou, China
| | - Feng Lan
- National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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18
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Valkov N, Das S. Y RNAs: Biogenesis, Function and Implications for the Cardiovascular System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1229:327-342. [PMID: 32285422 DOI: 10.1007/978-981-15-1671-9_20] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
In recent years, progress in the field of high-throughput sequencing technology and its application to a wide variety of biological specimens has greatly advanced the discovery and cataloging of a diverse set of non-coding RNAs (ncRNAs) that have been found to have unexpected biological functions. Y RNAs are an emerging class of highly conserved, small ncRNAs. There is a growing number of reports in the literature demonstrating that Y RNAs and their fragments are not just random degradation products but are themselves bioactive molecules. This review will outline what is currently known about Y RNA including biogenesis, structure and functional roles. In addition, we will provide an overview of studies reporting the presence and functions attributed to Y RNAs in the cardiovascular system.
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Affiliation(s)
- Nedyalka Valkov
- Cardiovascular Research Center of Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Saumya Das
- Cardiovascular Research Center of Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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19
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Kim CW, Kim CJ, Park EH, Ryu S, Lee Y, Kim E, Kang K, Lee KY, Choo EH, Hwang BH, Youn HJ, Park KD, Chang K. MSC-Encapsulating in Situ Cross-Linkable Gelatin Hydrogels To Promote Myocardial Repair. ACS APPLIED BIO MATERIALS 2020; 3:1646-1655. [DOI: 10.1021/acsabm.9b01215] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Chan Woo Kim
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Chan Joon Kim
- Division of Cardiology, Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 11765, Republic of Korea
| | - Eun-Hye Park
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Seungbae Ryu
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea
| | - Yunki Lee
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea
| | - Eunmin Kim
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Kwonyoon Kang
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Kwan Yong Lee
- Division of Cardiology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon 21431, Republic of Korea
| | - Eun-Ho Choo
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Byung-Hee Hwang
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Ho-Joong Youn
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Ki Dong Park
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea
| | - Kiyuk Chang
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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Wu L, Dalal R, Cao CD, Postoak JL, Yang G, Zhang Q, Wang Z, Lal H, Van Kaer L. IL-10-producing B cells are enriched in murine pericardial adipose tissues and ameliorate the outcome of acute myocardial infarction. Proc Natl Acad Sci U S A 2019; 116:21673-21684. [PMID: 31591231 PMCID: PMC6815157 DOI: 10.1073/pnas.1911464116] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Acute myocardial infarction (MI) provokes an inflammatory response in the heart that removes damaged tissues to facilitate tissue repair/regeneration. However, overactive and prolonged inflammation compromises healing, which may be counteracted by antiinflammatory mechanisms. A key regulatory factor in an inflammatory response is the antiinflammatory cytokine IL-10, which can be produced by a number of immune cells, including subsets of B lymphocytes. Here, we investigated IL-10-producing B cells in pericardial adipose tissues (PATs) and their role in the healing process following acute MI in mice. We found that IL-10-producing B cells were enriched in PATs compared to other adipose depots throughout the body, with the majority of them bearing a surface phenotype consistent with CD5+ B-1a cells (CD5+ B cells). These cells were detected early in life, maintained a steady presence during adulthood, and resided in fat-associated lymphoid clusters. The cytokine IL-33 and the chemokine CXCL13 were preferentially expressed in PATs and contributed to the enrichment of IL-10-producing CD5+ B cells. Following acute MI, the pool of CD5+ B cells was expanded in PATs. These cells accumulated in the infarcted heart during the resolution of MI-induced inflammation. B cell-specific deletion of IL-10 worsened cardiac function, exacerbated myocardial injury, and delayed resolution of inflammation following acute MI. These results revealed enrichment of IL-10-producing B cells in PATs and a significant contribution of these cells to the antiinflammatory processes that terminate MI-induced inflammation. Together, these findings have identified IL-10-producing B cells as therapeutic targets to improve the outcome of MI.
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Affiliation(s)
- Lan Wu
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
| | - Rajeev Dalal
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Connie D Cao
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - J Luke Postoak
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Guan Yang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Qinkun Zhang
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Zhizhang Wang
- Vanderbilt-NIH Mouse Metabolic Phenotyping Center, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Hind Lal
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Luc Van Kaer
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
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21
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Tosun V, Korucuk N, Güntekin Ü. Akut anterior ST segment miyokard infarktüsü sonrası GRACE risk skorunun sol ventrikül ejeksiyon fraksiyonundaki prediktif değeri. CUKUROVA MEDICAL JOURNAL 2019. [DOI: 10.17826/cumj.459500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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22
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Kitmitto A, Baudoin F, Cartwright EJ. Cardiomyocyte damage control in heart failure and the role of the sarcolemma. J Muscle Res Cell Motil 2019; 40:319-333. [PMID: 31520263 PMCID: PMC6831538 DOI: 10.1007/s10974-019-09539-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/03/2019] [Indexed: 01/07/2023]
Abstract
The cardiomyocyte plasma membrane, termed the sarcolemma, is fundamental for regulating a myriad of cellular processes. For example, the structural integrity of the cardiomyocyte sarcolemma is essential for mediating cardiac contraction by forming microdomains such as the t-tubular network, caveolae and the intercalated disc. Significantly, remodelling of these sarcolemma microdomains is a key feature in the development and progression of heart failure (HF). However, despite extensive characterisation of the associated molecular and ultrastructural events there is a lack of clarity surrounding the mechanisms driving adverse morphological rearrangements. The sarcolemma also provides protection, and is the cell's first line of defence, against external stresses such as oxygen and nutrient deprivation, inflammation and oxidative stress with a loss of sarcolemma viability shown to be a key step in cell death via necrosis. Significantly, cumulative cell death is also a feature of HF, and is linked to disease progression and loss of cardiac function. Herein, we will review the link between structural and molecular remodelling of the sarcolemma associated with the progression of HF, specifically considering the evidence for: (i) Whether intrinsic, evolutionary conserved, plasma membrane injury-repair mechanisms are in operation in the heart, and (ii) if deficits in key 'wound-healing' proteins (annexins, dysferlin, EHD2 and MG53) may play a yet to be fully appreciated role in triggering sarcolemma microdomain remodelling and/or necrosis. Cardiomyocytes are terminally differentiated with very limited regenerative capability and therefore preserving cell viability and cardiac function is crucially important. This review presents a novel perspective on sarcolemma remodelling by considering whether targeting proteins that regulate sarcolemma injury-repair may hold promise for developing new strategies to attenuate HF progression.
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Affiliation(s)
- Ashraf Kitmitto
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, AV Hill, Dover Street, Manchester, M13 9PL, UK.
| | - Florence Baudoin
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, AV Hill, Dover Street, Manchester, M13 9PL, UK
| | - Elizabeth J Cartwright
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, AV Hill, Dover Street, Manchester, M13 9PL, UK
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Ferreira JP, Duarte K, McMurray JJV, Pitt B, van Veldhuisen DJ, Vincent J, Ahmad T, Tromp J, Rossignol P, Zannad F. Data-Driven Approach to Identify Subgroups of Heart Failure With Reduced Ejection Fraction Patients With Different Prognoses and Aldosterone Antagonist Response Patterns. Circ Heart Fail 2019; 11:e004926. [PMID: 29997240 DOI: 10.1161/circheartfailure.118.004926] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 05/16/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Patients with heart failure with reduced ejection fraction have a poor prognosis. The identification of subgroups with different outcomes and treatment response patterns may help to tailor strategies to each individual patient. We present an exploratory study of patients enrolled in the EMPHASIS-HF trial (Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms) using latent class analysis with validation using the EPHESUS trial (Eplerenone, a Selective Aldosterone Blocker, in Patients With Left Ventricular Dysfunction After Myocardial Infarction) to identify subgroups of patients with different prognosis and response to eplerenone therapy. METHODS AND RESULTS Latent class analysis identifies mutually exclusive groups of individuals maximizing within-group similarities and between-group differences. In the EMPHASIS-HF trial, 2279 heart failure with reduced ejection fraction patients were randomized to eplerenone or placebo and were characterized according to 18 clinical features. Subgroup definitions were applied to 6472 patients enrolled in the EPHESUS trial to validate observations. Event-free survival and effect of eplerenone on the composite of cardiovascular death and heart failure hospitalization were determined for each subgroup. Four subgroups were identified with significant differences in event-free survival (P=0.002). The subgroup C had the worst event-free survival in both studies and was characterized by older age, lower body mass index, worse renal function, higher baseline potassium levels, high prevalence of anemia, diabetes mellitus, previous revascularization and higher rates of eplerenone discontinuation, and hyperkalemia during follow-up. Two subgroups (B and C) showed a poorer response to eplerenone in both studies and these groups shared common features such as lower body mass index and high prevalence of anemia. Clinical profiles, prognosis, and treatment response patterns of the 4 subgroups applied in EPHESUS trial presented similarities to those observed in EMPHASIS. CONCLUSIONS Using a data-driven approach, we identified heart failure with reduced ejection fraction subgroups with significantly different prognoses and potentially different responses to eplerenone. However, these data should be regarded as hypothesis-generating and prospective validation is warranted, to assess the potential clinical implications of these subgroups. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT00232180.
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Affiliation(s)
- João Pedro Ferreira
- Université de Lorraine INSERM, Centre, d'Investigations Cliniques Plurithématique 1433, INSERM U1116, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., K.D., P.R., F.Z.).,Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Portugal (J.P.F.)
| | - Kevin Duarte
- Université de Lorraine INSERM, Centre, d'Investigations Cliniques Plurithématique 1433, INSERM U1116, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., K.D., P.R., F.Z.)
| | - John J V McMurray
- BHF Cardiovascular Research Centre, University of Glasgow, Scotland, United Kingdom (J.J.V.M)
| | - Bertram Pitt
- Department of Medicine, University of Michigan School of Medicine, Ann Arbor (B.P.)
| | - Dirk J van Veldhuisen
- Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands (D.J.v.V., J.T.)
| | | | - Tariq Ahmad
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (T.A.)
| | - Jasper Tromp
- Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands (D.J.v.V., J.T.)
| | - Patrick Rossignol
- Université de Lorraine INSERM, Centre, d'Investigations Cliniques Plurithématique 1433, INSERM U1116, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., K.D., P.R., F.Z.)
| | - Faiez Zannad
- Université de Lorraine INSERM, Centre, d'Investigations Cliniques Plurithématique 1433, INSERM U1116, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., K.D., P.R., F.Z.).
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24
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Welsh P, Papacosta O, Ramsay S, Whincup P, McMurray J, Wannamethee G, Sattar N. High-Sensitivity Troponin T and Incident Heart Failure in Older Men: British Regional Heart Study. J Card Fail 2019; 25:230-237. [PMID: 30103019 PMCID: PMC7083232 DOI: 10.1016/j.cardfail.2018.08.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Indexed: 12/25/2022]
Abstract
OBJECTIVE The aim of this work was to study the association of high-sensitivity troponin T (hsTnT) with incident heart failure (HF), and implications for its use in prediction models. METHODS AND RESULTS In the British Regional Heart Study, 3852 men aged 60-79years without baseline HF (3165 without baseline chronic heart disease) were followed for a median of 12.6years, during which 295 incident cases of HF occurred (7.7%). A 1-SD increase in log-transformed hsTnT was associated with a higher risk of incident HF after adjusting for classic risk factors (hazard ratio [HR] 1.58, 95% confidence interval [CI] 1.42-1.77) and after additional adjustment for N-terminal pro-B-type natriuretic peptide (NT-proBNP; HR 1.34, 95% CI 1.19-1.52). The strength of the association between hsTnT and incident HF did not differ by strata of other risk factors. An hsTnT concentration of <5ng/L had a sensitivity of 99.7% (95% CI 98.1%-99.9%) and a specificity of 3.4% (95% CI 2.8%-4.0%). A risk-prediction model including classic risk factors and NT-proBNP yielded a C-index of 0.791, but addition of hsTnT did not further improve prediction (P = .28). CONCLUSIONS Elevated hsTnT is consistently associated with risk of HF in older men. HF occurred rarely over 12years when baseline hsTnT was below the limit of detection. hsTnT measurement, however, does not improve HF prediction in a model already containing NT-proBNP.
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Affiliation(s)
- Paul Welsh
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
| | - Olia Papacosta
- Department of Primary Care and Population Health, University College London, London, United Kingdom
| | - Sheena Ramsay
- Department of Primary Care and Population Health, University College London, London, United Kingdom,Institute of Health and Society, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Peter Whincup
- Department of Primary Care and Population Health, University College London, London, United Kingdom,Population Health Research Institute, St George's, University of London, London, United Kingdom
| | - John McMurray
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Goya Wannamethee
- Department of Primary Care and Population Health, University College London, London, United Kingdom
| | - Naveed Sattar
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
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25
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Mikrani R, Liang C, Naveed M, Kamboh AA, Abbas M, Chaurasiya B, Xue L, Xiaohui Z. A cardiac troponin I study in a minimally invasive myocardial infarction canine model. J Appl Biomed 2019; 17:39. [PMID: 34907744 DOI: 10.32725/jab.2018.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 09/18/2018] [Indexed: 01/26/2023] Open
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An W, Yu Y, Zhang Y, Zhang Z, Yu Y, Zhao X. Exogenous IL-19 attenuates acute ischaemic injury and improves survival in male mice with myocardial infarction. Br J Pharmacol 2019; 176:699-710. [PMID: 30460984 DOI: 10.1111/bph.14549] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 10/21/2018] [Accepted: 10/24/2018] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND PURPOSE Myocardial infarction (MI) is one of the leading causes of death in China and often results in the development of heart failure. In this work, we tested the therapeutic role of Interleukin-19 (IL-19) in mice with MI and investigated the underlying molecular mechanism. EXPERIMENTAL APPROACH Mice were subjected to MI by ligation of left anterior descending coronary artery (LAD) and treated with IL-19 (10ng g-1 ; i.p.). KEY RESULTS Protein expression of IL-19 and its receptor in myocardium were upregulated 24 hrs post-MI in male mice. IL-19 treatment decreased infarct and apoptosis in myocardium, accompanied by enhanced haem oxygenase-1 (HO-1) activities and reduced malondialdehyde (MDA) formation. Pretreatment with IL-19 upregulated HO-1 expression in cultured neonatal mouse ventricular myocytes and attenuated oxygen-glucose deprivation (OGD)-induced injuries in vitro. Furthermore, IL-19 preserved cardiac function and improved survival of mice with MI. IL-19 reduced inflammatory infiltrates and suppressed formation of TNF-α, IL-1β, and IL-6. More importantly, IL-19 inhibited polarization toward proinflammatory M1 macrophages and stimulated M2 macrophage polarization in myocardium of mice with MI. IL-19 enhanced protein levels of vascular endothelial growth factor (VEGF) and promoted angiogenesis in myocardium of mice with MI. In addition, IL-19 treatment increased DNA-binding of the transcription factor STAT3 in myocardium of mice with MI. CONCLUSIONS AND IMPLICATIONS Treatment with exogenous IL-19 attenuated acute ischemic injury and improved survival of mice with MI. The mechanisms underlying these effects involved induction of HO-1, M2 macrophage polarization, angiogenesis, and STAT3 activation.
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Affiliation(s)
- Weishuai An
- Department of Cardiovasology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yongsheng Yu
- Department of Cardiovasology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yuefan Zhang
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Zhigang Zhang
- Department of Cardiology, Putuo Center Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yunhua Yu
- Department of Geriatrics, Fuzhou General Hospital, Fujian Medical University, Fuzhou, China
| | - Xianxian Zhao
- Department of Cardiovasology, Changhai Hospital, Second Military Medical University, Shanghai, China
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Huang K, Hu S, Cheng K. A New Era of Cardiac Cell Therapy: Opportunities and Challenges. Adv Healthc Mater 2019; 8:e1801011. [PMID: 30548836 PMCID: PMC6368830 DOI: 10.1002/adhm.201801011] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 11/05/2018] [Indexed: 12/15/2022]
Abstract
Myocardial infarction (MI), caused by coronary heart disease (CHD), remains one of the most common causes of death in the United States. Over the last few decades, scientists have invested considerable resources on the study and development of cell therapies for myocardial regeneration after MI. However, due to a number of limitations, they are not yet readily available for clinical applications. Mounting evidence supports the theory that paracrine products are the main contributors to the regenerative effects attributed to these cell therapies. The next generation of cell-based MI therapies will identify and isolate cell products and derivatives, integrate them with biocompatible materials and technologies, and use them for the regeneration of damaged myocardial tissue. This review discusses the progress made thus far in pursuit of this new generation of cell therapies. Their fundamental regenerative mechanisms, their potential to combine with other therapeutic products, and their role in shaping new clinical approaches for heart tissue engineering, are addressed.
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Affiliation(s)
- Ke Huang
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, 27607, USA
| | - Shiqi Hu
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, 27607, USA
| | - Ke Cheng
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, 27607, USA
- Pharmacoengineeirng and Molecular Pharmaceutics Division, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Tang J, Wang J, Huang K, Ye Y, Su T, Qiao L, Hensley MT, Caranasos TG, Zhang J, Gu Z, Cheng K. Cardiac cell-integrated microneedle patch for treating myocardial infarction. SCIENCE ADVANCES 2018; 4:eaat9365. [PMID: 30498778 PMCID: PMC6261659 DOI: 10.1126/sciadv.aat9365] [Citation(s) in RCA: 192] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 10/26/2018] [Indexed: 05/17/2023]
Abstract
We engineered a microneedle patch integrated with cardiac stromal cells (MN-CSCs) for therapeutic heart regeneration after acute myocardial infarction (MI). To perform cell-based heart regeneration, cells are currently delivered to the heart via direct muscle injection, intravascular infusion, or transplantation of epicardial patches. The first two approaches suffer from poor cell retention, while epicardial patches integrate slowly with host myocardium. Here, we used polymeric MNs to create "channels" between host myocardium and therapeutic CSCs. These channels allow regenerative factors secreted by CSCs to be released into the injured myocardium to promote heart repair. In the rat MI model study, the application of the MN-CSC patch effectively augmented cardiac functions and enhanced angiomyogenesis. In the porcine MI model study, MN-CSC patch application was nontoxic and resulted in cardiac function protection. The MN system represents an innovative approach delivering therapeutic cells for heart regeneration.
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Affiliation(s)
- Junnan Tang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
| | - Jinqiang Wang
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
| | - Ke Huang
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
| | - Yanqi Ye
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
| | - Teng Su
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
| | - Li Qiao
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
- Department of Cardiology, The Second Affiliated Hospital of Hebei Medicial University, Shijiazhuang, Hebei 050000, China
| | - Michael Taylor Hensley
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
| | - Thomas George Caranasos
- Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Jinying Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Zhen Gu
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
- Department of Bioengineering, University of California, Los Angeles, CA, USA
- California NanoSystems Institute, Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA, USA
- Corresponding author. (K.C.); (Z.G.)
| | - Ke Cheng
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Corresponding author. (K.C.); (Z.G.)
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Tran DT, Welsh RC, Ohinmaa A, Thanh NX, Kaul P. Resource Use and Burden of Hospitalization, Outpatient, Physician, and Drug Costs in Short- and Long-term Care After Acute Myocardial Infarction. Can J Cardiol 2018; 34:1298-1306. [PMID: 30170782 DOI: 10.1016/j.cjca.2018.05.022] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 05/25/2018] [Accepted: 05/28/2018] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Little is known about the resource use and cost burden of acute myocardial infarction (AMI) beyond the index event. We examined resource use and care costs during the first and each subsequent year, among patients with incident AMI. METHODS Patients aged ≥18 years who were admitted with incident AMI at emergency departments or hospitals in Alberta, Canada, between April 2004 and March 2014 were included. Incident cases were defined as those without an AMI hospitalization in the previous 10 years. Inpatient, outpatient, practitioner claims, drug claims, and vital statistics were linked and follow-up data were available until March 2016. Resource use and care costs per patient for each year after the AMI were calculated. RESULTS The analysis included 41,210 patients with incident AMI (non-ST-segment elevation myocardial infarction [NSTEMI] = 50.8%, ST-segment elevation myocardial infarction = 36.8%, and undefined myocardial infarction [MI] = 12.5%). Resource use and care costs were highest during the first year. Compared with other MI groups, patients with ST-segment elevation myocardial infarction had more frequent outpatient visits (mean 1.64 vs 0.99 [NSTEMI] and 0.87 [undefined MI] visits) but spent fewer days in hospital (mean 7.72 vs 9.23 [NSTEMI] and 8.5 [undefined MI] days) during the first year. AMI costs were $19,842 during the first year and $845 per year for the next 5 years. Hospitalization costs accounted for the majority of costs during the first year (81.1%), whereas drug costs did for the next 5 years (62.1%). CONCLUSIONS The long-term annual cost burden of AMI is modest compared with care costs during the first year. Although hospitalization dominates first year costs, pharmaceuticals do so in the long term.
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Affiliation(s)
- Dat T Tran
- School of Public Health, University of Alberta, Edmonton, Alberta, Canada; Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada.
| | - Robert C Welsh
- Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada; Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, University of Alberta Hospital, Edmonton, Canada
| | - Arto Ohinmaa
- School of Public Health, University of Alberta, Edmonton, Alberta, Canada; Institute of Health Economics, Edmonton, Alberta, Canada
| | - Nguyen X Thanh
- School of Public Health, University of Alberta, Edmonton, Alberta, Canada; Institute of Health Economics, Edmonton, Alberta, Canada
| | - Padma Kaul
- Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada; Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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30
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Effect of Tivorel on the level of matrix metalloproteinases-2 and 9, galectin-3, final glycation products and functional state of the endothelium in patients with postinfarction chronic heart failure with preserved ejection fraction. Fam Med 2018. [DOI: 10.30841/2307-5112.2.2018.145642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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31
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Wang S, Fan Y, Feng X, Sun C, Shi Z, Li T, Lv J, Yang Z, Zhao Z, Sun D. Nicorandil alleviates myocardial injury and post-infarction cardiac remodeling by inhibiting Mst1. Biochem Biophys Res Commun 2018; 495:292-299. [PMID: 29127009 DOI: 10.1016/j.bbrc.2017.11.041] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 11/06/2017] [Indexed: 11/21/2022]
Abstract
BACKGROUND Cardiomyocyte autophagy and apoptosis are crucial events underlying the development of cardiac abnormalities and dysfunction after myocardial infarction (MI). A better understanding of the cell signaling pathways involved in cardiac remodeling may support the development of new therapeutic strategies for the treatment of heart failure (HF) after MI. METHODS A cardiac MI injury model was constructed by ligating the left anterior descending (LAD) coronary artery. Neonatal cardiomyocytes were isolated and cultured to investigate the mechanisms underlying the protective effects of nicorandil on MI-induced injury. RESULTS Nicorandil reduced cardiac enzyme release, mitigated left ventricular enlargement and cardiac dysfunction after MI, as evaluated by echocardiography and hemodynamic measurements. According to the results of the western blot analysis and immunofluorescence staining, nicorandil enhanced autophagic flux and reduced apoptosis in cardiomyocytes subjected to hypoxic injury. Interestingly, nicorandil increased Mst1 and p-Mst1 levels in cardiomyocytes subjected to MI injury. Mst1 knockout abolished the protective effects of nicorandil on cardiac remodeling and dysfunction after MI. Mst1 knockout also abolished the beneficial effects of nicorandil on cardiac enzyme release and cardiomyocyte autophagy and apoptosis. CONCLUSIONS Nicorandil alleviates post-MI cardiac dysfunction and remodeling. The mechanisms were associated with enhancing autophagy and inhibiting apoptosis through Mst1 inhibition.
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Affiliation(s)
- Shanjie Wang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yanhong Fan
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xinyu Feng
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Chuang Sun
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhaofeng Shi
- Department of Traditional Chinese Medicine, Xijing Hospital Affiliated to Fourth Military Medical University, Xi'an, China
| | - Tian Li
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jianjun Lv
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhi Yang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhijing Zhao
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
| | - Dongdong Sun
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
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32
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Stelzle D, Shah ASV, Anand A, Strachan FE, Chapman AR, Denvir MA, Mills NL, McAllister DA. High-sensitivity cardiac troponin I and risk of heart failure in patients with suspected acute coronary syndrome: a cohort study. EUROPEAN HEART JOURNAL. QUALITY OF CARE & CLINICAL OUTCOMES 2018; 4:36-42. [PMID: 29045610 PMCID: PMC5805120 DOI: 10.1093/ehjqcco/qcx022] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 06/24/2017] [Accepted: 07/14/2017] [Indexed: 12/24/2022]
Abstract
Aims Heart failure may occur following acute myocardial infarction, but with the use of high-sensitivity cardiac troponin assays we increasingly diagnose patients with minor myocardial injury. Whether troponin concentrations remain a useful predictor of heart failure in patients with acute coronary syndrome is uncertain. Methods and results We identified all consecutive patients (n = 4748) with suspected acute coronary syndrome (61 ± 16 years, 57% male) presenting to three secondary and tertiary care hospitals. Cox-regression models were used to evaluate the association between high-sensitivity cardiac troponin I concentration and subsequent heart failure hospitalization. C-statistics were estimated to evaluate the predictive value of troponin for heart failure hospitalization. Over 2071 years of follow-up there were 83 heart failure hospitalizations. Patients with troponin concentrations above the upper reference limit (URL) were more likely to be hospitalized with heart failure than patients below the URL (118/1000 vs. 17/1000 person years, adjusted hazard ratio: 7.0). Among patients with troponin concentrations Conclusion Cardiac troponin is an excellent predictor of heart failure hospitalization in patients with suspected acute coronary syndrome. The strongest associations were observed in patients with troponin concentrations in the normal reference range, in whom high-sensitivity cardiac troponin assays identify those at increased risk of heart failure who may benefit from further investigation and treatment.
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Affiliation(s)
- Dominik Stelzle
- BHF Centre for Cardiovascular Science, University of Edinburgh, 49 Little Fracne Cresc, Edinburgh EH16 4SB, UK
| | - Anoop S V Shah
- BHF Centre for Cardiovascular Science, University of Edinburgh, 49 Little Fracne Cresc, Edinburgh EH16 4SB, UK
| | - Atul Anand
- BHF Centre for Cardiovascular Science, University of Edinburgh, 49 Little Fracne Cresc, Edinburgh EH16 4SB, UK
| | - Fiona E Strachan
- BHF Centre for Cardiovascular Science, University of Edinburgh, 49 Little Fracne Cresc, Edinburgh EH16 4SB, UK
| | - Andrew R Chapman
- BHF Centre for Cardiovascular Science, University of Edinburgh, 49 Little Fracne Cresc, Edinburgh EH16 4SB, UK
| | - Martin A Denvir
- BHF Centre for Cardiovascular Science, University of Edinburgh, 49 Little Fracne Cresc, Edinburgh EH16 4SB, UK
| | - Nicholas L Mills
- BHF Centre for Cardiovascular Science, University of Edinburgh, 49 Little Fracne Cresc, Edinburgh EH16 4SB, UK
| | - David A McAllister
- The Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
- The Usher Institute of Population Health and Informatics, University of Edinburgh, Edinburgh, UK
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33
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Predictors of high Killip class after ST segment elevation myocardial infarction in the era of primary reperfusion. Int J Cardiol 2017; 248:46-50. [DOI: 10.1016/j.ijcard.2017.07.038] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 06/30/2017] [Accepted: 07/12/2017] [Indexed: 01/12/2023]
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Farías JG, Molina VM, Carrasco RA, Zepeda AB, Figueroa E, Letelier P, Castillo RL. Antioxidant Therapeutic Strategies for Cardiovascular Conditions Associated with Oxidative Stress. Nutrients 2017; 9:nu9090966. [PMID: 28862654 PMCID: PMC5622726 DOI: 10.3390/nu9090966] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 08/17/2017] [Accepted: 08/18/2017] [Indexed: 12/14/2022] Open
Abstract
Oxidative stress (OS) refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability to scavenge these ROS by endogenous antioxidant systems, where ROS overwhelms the antioxidant capacity. Excessive presence of ROS results in irreversible damage to cell membranes, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Oxidative stress plays a crucial role in the pathogenesis of cardiovascular diseases related to hypoxia, cardiotoxicity and ischemia-reperfusion. Here, we describe the participation of OS in the pathophysiology of cardiovascular conditions such as myocardial infarction, anthracycline cardiotoxicity and congenital heart disease. This review focuses on the different clinical events where redox factors and OS are related to cardiovascular pathophysiology, giving to support for novel pharmacological therapies such as omega 3 fatty acids, non-selective betablockers and microRNAs.
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Affiliation(s)
- Jorge G Farías
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4780000, Chile.
| | - Víctor M Molina
- Unidad de Cuidados Intensivos, Hospital de Niños Roberto del Río, Santiago 7500922, Chile.
- Unidad de Cuidados Intensivos Pediátricos, Hospital Clínico Pontificia Universidad Católica de Chile, Santiago 7500922, Chile.
| | - Rodrigo A Carrasco
- Laboratorio de Investigación Biomédica, Departamento de Medicina Interna, Hospital del Salvador, Santiago 7500922, Chile.
- Departamento de Cardiología, Clínica Alemana, Santiago 7500922, Chile.
| | - Andrea B Zepeda
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4780000, Chile.
| | - Elías Figueroa
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4780000, Chile.
- Núcleo de Investigación en Producción Alimentaria, BIOACUI, Escuela de Acuicultura, Universidad Católica de Temuco, Temuco 4780000, Chile.
| | - Pablo Letelier
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4780000, Chile.
- School of Health Sciences, Universidad Católica de Temuco, Temuco 4780000, Chile.
| | - Rodrigo L Castillo
- Laboratorio de Investigación Biomédica, Departamento de Medicina Interna, Hospital del Salvador, Santiago 7500922, Chile.
- Programa de Fisiopatología Oriente, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 7500922, Chile.
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35
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Chami B, Jeong G, Varda A, Maw AM, Kim HB, Fong G, Simone M, Rayner B, Wang XS, Dennis J, Witting P. The nitroxide 4-methoxy TEMPO inhibits neutrophil-stimulated kinase activation in H9c2 cardiomyocytes. Arch Biochem Biophys 2017; 629:19-35. [DOI: 10.1016/j.abb.2017.07.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 06/23/2017] [Accepted: 07/03/2017] [Indexed: 12/12/2022]
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36
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Ferreira JP, Duarte K, Montalescot G, Pitt B, de Sa EL, Hamm CW, Flather M, Verheugt F, Shi H, Turgonyi E, Orri M, Rossignol P, Vincent J, Zannad F. Effect of eplerenone on extracellular cardiac matrix biomarkers in patients with acute ST-elevation myocardial infarction without heart failure: insights from the randomized double-blind REMINDER Study. Clin Res Cardiol 2017; 107:49-59. [DOI: 10.1007/s00392-017-1157-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 08/22/2017] [Indexed: 10/19/2022]
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37
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Giustino G, Redfors B, Brener SJ, Kirtane AJ, Généreux P, Maehara A, Dudek D, Neunteufl T, Metzger DC, Crowley A, Mehran R, Gibson CM, Stone GW. Correlates and prognostic impact of new-onset heart failure after ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention: insights from the INFUSE-AMI trial. EUROPEAN HEART JOURNAL-ACUTE CARDIOVASCULAR CARE 2017; 7:339-347. [DOI: 10.1177/2048872617719649] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background: The determinants and significance of early (30-day) heart failure symptoms after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI) remain unclear. We investigated the clinical and imaging correlates of early post-discharge heart failure in patients with STEMI, and evaluated its impact on clinical outcomes. Methods: Patients from the INFUSE-AMI trial were categorized according to New York Heart Association (NYHA) functional classification at their 30-day visit (NYHA class ≥2 versus 1). Independent correlates of NYHA class ≥2 were determined by multivariable logistic regression. A landmark analysis beyond 30 days was performed to assess the impact of 30-day NYHA class ≥2 on 1-year risk of death or hospitalization for heart failure. Results: Among 402 patients enrolled in the INFUSE-AMI trial with data on NYHA class at 30 days, 76 (18.9%) had NYHA class ≥2. Independent correlates of 30-day NYHA class ≥2 were age, Killip class ≥2 at presentation, heart rate at presentation, intraprocedural no-reflow, and 30-day infarct size (% total ventricular mass). After adjustment for infarct size, patients with NYHA class ≥2 remained at higher risk of death or hospitalization for heart failure at 1-year follow-up compared to those in NYHA class 1 (11.8% vs. 2.8%, adjusted hazard ratio 3.78, 95% confidence interval 1.16–12.22, P=0.03). Conclusions: Clinical, procedural, and imaging variables predict the development of clinical heart failure after primary percutaneous coronary intervention in patients with STEMI. Early post-discharge heart failure symptoms identify a high-risk patient cohort for subsequent heart failure hospitalization and death, independent of infarct size. Trial Registration: ClinicalTrials.gov ; NCT00976521
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Affiliation(s)
- Gennaro Giustino
- Zena and Michael A Wiener Cardiovascular Institute, The Icahn School of Medicine at Mount Sinai, USA
- Clinical Trials Center, Cardiovascular Research Foundation, USA
| | - Björn Redfors
- Clinical Trials Center, Cardiovascular Research Foundation, USA
| | - Sorin J Brener
- Clinical Trials Center, Cardiovascular Research Foundation, USA
- Department of Medicine, New York Methodist Hospital, USA
| | - Ajay J Kirtane
- Clinical Trials Center, Cardiovascular Research Foundation, USA
- Department of Cardiology, NewYork-Presbyterian Hospital/Columbia University Medical Center, USA
| | - Philippe Généreux
- Clinical Trials Center, Cardiovascular Research Foundation, USA
- Department of Medicine, Hôpital du Sacré-Coeur de Montréal, Canada
| | - Akiko Maehara
- Clinical Trials Center, Cardiovascular Research Foundation, USA
- Department of Cardiology, NewYork-Presbyterian Hospital/Columbia University Medical Center, USA
| | - Dariusz Dudek
- Department of Medicine, Department of Interventional Cardiology, Jagiellonian University Medical College, Poland
| | | | | | - Aaron Crowley
- Clinical Trials Center, Cardiovascular Research Foundation, USA
| | - Roxana Mehran
- Zena and Michael A Wiener Cardiovascular Institute, The Icahn School of Medicine at Mount Sinai, USA
- Clinical Trials Center, Cardiovascular Research Foundation, USA
| | | | - Gregg W Stone
- Clinical Trials Center, Cardiovascular Research Foundation, USA
- Department of Cardiology, NewYork-Presbyterian Hospital/Columbia University Medical Center, USA
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38
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Zhang S, Yeap XY, DeBerge M, Naresh NK, Wang K, Jiang Z, Wilcox JE, White SM, Morrow JP, Burridge PW, Procissi D, Scott EA, Frazier W, Thorp EB. Acute CD47 Blockade During Ischemic Myocardial Reperfusion Enhances Phagocytosis-Associated Cardiac Repair. JACC Basic Transl Sci 2017; 2:386-397. [PMID: 28920097 PMCID: PMC5595371 DOI: 10.1016/j.jacbts.2017.03.013] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Our data suggest that, after a myocardial infarction, integrin-associated protein CD47 on cardiac myocytes is elevated. In culture, increased CD47 on the surface of dying cardiomyocytes impairs phagocytic removal by immune cell macrophages. After myocardial ischemia and reperfusion, acute CD47 inhibition with blocking antibodies enhanced dead myocyte clearance by cardiac phagocytes and also improved the resolution of cardiac inflammation, reduced infarct size, and preserved cardiac contractile function. Early targeting of CD47 in the myocardium after reperfusion may be a new strategy to enhance wound repair in the ischemic heart.
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Affiliation(s)
- Shuang Zhang
- Department of Pathology and Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Xin-Yi Yeap
- Department of Pathology and Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Matthew DeBerge
- Department of Pathology and Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Nivedita K Naresh
- Department of Pathology and Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Kevin Wang
- Department of Pathology and Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Zhengxin Jiang
- Department of Pathology and Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Jane E Wilcox
- Department of Pathology and Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Steven M White
- Department of Pathology and Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | | | - Paul W Burridge
- Department of Pharmacology and Center for Pharmacogenomics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Daniel Procissi
- Department of Pathology and Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Evan A Scott
- Department of Pathology and Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - William Frazier
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri
| | - Edward B Thorp
- Department of Pathology and Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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Abstract
Reperfusion therapy decreases myocardium damage during an acute coronary event and consequently mortality. However, there are unmet needs in the treatment of acute myocardial infarction, consequently mortality and heart failure continue to occur in about 10% and 20% of cases, respectively. Different strategies could improve reperfusion. These strategies, like generation of warning sign recognition and being initially assisted and transferred by an emergency service, could reduce the time to reperfusion. If the first electrocardiogram is performed en route, it can be transmitted and interpreted in a timely manner by a specialist at the receiving center, bypassing community hospitals without percutaneous coronary intervention capabilities. To administer thrombolytic therapy during transport to the catheterization laboratory could reduce time to reperfusion in cases with expected prolonged transport time to a percutaneous coronary intervention center or to a center without primary percutaneous coronary intervention capabilities with additional expected delay, known as pharmaco-invasive strategy. Myocardial reperfusion is known to produce damage and cell death, which defines the reperfusion injury. Lack of resolution of ST segment is used as a marker of reperfusion failure. In patients without ST segment resolution, mortality triples. It is important to note that, until recently, reperfusion injury and no-reflow were interpreted as a single entity and we should differentiate them as different entities; whereas no-reflow is the failure to obtain tissue flow, reperfusion injury is actually the damage produced by achieving flow. Therefore, treatment of no-reflow is obtained by tissue flow, whereas in reperfusion injury the treatment objective is protection of susceptible myocardium from reperfusion injury. Numerous trials for the treatment of reperfusion injury have been unsuccessful. Newer hypotheses such as “
controlled reperfusion”, in which the interventional cardiologist assumes not only the treatment of the culprit vessel but also the way to reperfuse the myocardium at risk, could reduce reperfusion injury.
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Affiliation(s)
- Alejandro Farah
- Interventional Cardiology Department, San Bernardo Hospital, Salta, Argentina
| | - Alejandro Barbagelata
- Universidad Católica de Buenos Aires, Buenos Aires, Argentina.,Department of Medicine, Duke University School of Medicine, Durham, NC, USA
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40
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Liu Y, Baumgardt SL, Fang J, Shi Y, Qiao S, Bosnjak ZJ, Vásquez-Vivar J, Xia Z, Warltier DC, Kersten JR, Ge ZD. Transgenic overexpression of GTP cyclohydrolase 1 in cardiomyocytes ameliorates post-infarction cardiac remodeling. Sci Rep 2017; 7:3093. [PMID: 28596578 PMCID: PMC5465102 DOI: 10.1038/s41598-017-03234-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Accepted: 04/20/2017] [Indexed: 12/19/2022] Open
Abstract
GTP cyclohydrolase 1 (GCH1) and its product tetrahydrobiopterin play crucial roles in cardiovascular health and disease, yet the exact regulation and role of GCH1 in adverse cardiac remodeling after myocardial infarction are still enigmatic. Here we report that cardiac GCH1 is degraded in remodeled hearts after myocardial infarction, concomitant with increases in the thickness of interventricular septum, interstitial fibrosis, and phosphorylated p38 mitogen-activated protein kinase and decreases in left ventricular anterior wall thickness, cardiac contractility, tetrahydrobiopterin, the dimers of nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and the expression of sarcoplasmic reticulum Ca2+ handling proteins. Intriguingly, transgenic overexpression of GCH1 in cardiomyocytes reduces the thickness of interventricular septum and interstitial fibrosis and increases anterior wall thickness and cardiac contractility after infarction. Moreover, we show that GCH1 overexpression decreases phosphorylated p38 mitogen-activated protein kinase and elevates tetrahydrobiopterin levels, the dimerization and phosphorylation of neuronal nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and sarcoplasmic reticulum Ca2+ handling proteins in post-infarction remodeled hearts. Our results indicate that the pivotal role of GCH1 overexpression in post-infarction cardiac remodeling is attributable to preservation of neuronal nitric oxide synthase and sarcoplasmic reticulum Ca2+ handling proteins, and identify a new therapeutic target for cardiac remodeling after infarction.
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Affiliation(s)
- Yanan Liu
- Departments of Anesthesiology, Medical College of Wisconsin, Milwaukee, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA.,Department of Medicine, Columbia University, 630 W. 168th Street, New York, New York, 10032, USA
| | - Shelley L Baumgardt
- Departments of Anesthesiology, Medical College of Wisconsin, Milwaukee, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA
| | - Juan Fang
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA
| | - Yang Shi
- Aurora Research Institute, Aurora Health Care, 750 W. Virginia Street, Milwaukee, Wisconsin, 53234, USA
| | - Shigang Qiao
- Departments of Anesthesiology, Medical College of Wisconsin, Milwaukee, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA
| | - Zeljko J Bosnjak
- Departments of Anesthesiology, Medical College of Wisconsin, Milwaukee, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA.,Department of Physiology, Medical College of Wiscosin, Milwaukee, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA
| | - Jeannette Vásquez-Vivar
- Department of Biophysics, Medical College of Wisconsin, Milwaukee, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA
| | - Zhengyuan Xia
- Department of Anesthesiology, University of Hong Kong, Hong Kong, People's Republic of China
| | - David C Warltier
- Departments of Anesthesiology, Medical College of Wisconsin, Milwaukee, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA
| | - Judy R Kersten
- Departments of Anesthesiology, Medical College of Wisconsin, Milwaukee, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA
| | - Zhi-Dong Ge
- Departments of Anesthesiology, Medical College of Wisconsin, Milwaukee, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA.
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41
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Bera A, Sen D. Promise of adeno-associated virus as a gene therapy vector for cardiovascular diseases. Heart Fail Rev 2017; 22:795-823. [DOI: 10.1007/s10741-017-9622-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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42
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D'Amario D, Leone AM, Borovac JA, Cannata F, Siracusano A, Niccoli G, Crea F. Granulocyte colony-stimulating factor for the treatment of cardiovascular diseases: An update with a critical appraisal. Pharmacol Res 2017; 127:67-76. [PMID: 28602846 DOI: 10.1016/j.phrs.2017.06.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 05/30/2017] [Accepted: 06/06/2017] [Indexed: 01/22/2023]
Abstract
Heart failure and acute myocardial infarction are conditions that are associated with high morbidity and mortality. Significant dysfunction of the heart muscle can occur as the consequence of end-stage chronic cardiovascular diseases or acute ischemic events that are marked by large infarction area and significant tissue necrosis. Despite the remarkable improvement of conventional treatments, a substantial proportion of patients still develops severe heart failure that can only be resolved by heart transplantation or mechanical device implantation. Therefore, novel approaches based on stem-cell therapy can directly modify the disease process and alter its prognosis. The ability of the stem-cells to modify and repair the injured myocardium is a challenging but intriguing concept that can potentially replace expensive and invasive methods of treatment that are associated with increased risks and significant financial costs. In that sense, granulocyte colony-stimulating factor (G-CSF) seems as an attractive treatment approach. Based on the series of pre-clinical experiments and a limited amount of clinical data, it was demonstrated that G-CSF agents possess the ability to mobilize stem-cells from bone marrow and induce their differentiation into cardiomyocytes or endothelial cells when brought into contact with injured regions of the myocardium. However, clinical benefits of G-CSF use in damaged myocardium remain unclear and are the topic of expert discussion. The main goal of this review is to present relevant and up-to-date evidence on G-CSF therapy use in pre-clinical models and in humans and to provide a rationale for its potential clinical applications in the future.
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Affiliation(s)
- Domenico D'Amario
- Institute of Cardiology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 8, Rome, 00168, Italy
| | - Antonio Maria Leone
- Institute of Cardiology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 8, Rome, 00168, Italy
| | - Josip Anđelo Borovac
- Department of Pathophysiology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia
| | - Francesco Cannata
- Institute of Cardiology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 8, Rome, 00168, Italy
| | - Andrea Siracusano
- Institute of Cardiology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 8, Rome, 00168, Italy
| | - Giampaolo Niccoli
- Institute of Cardiology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 8, Rome, 00168, Italy
| | - Filippo Crea
- Institute of Cardiology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 8, Rome, 00168, Italy.
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Zhang D, Tu H, Wang C, Cao L, Muelleman RL, Wadman MC, Li YL. Correlation of Ventricular Arrhythmogenesis with Neuronal Remodeling of Cardiac Postganglionic Parasympathetic Neurons in the Late Stage of Heart Failure after Myocardial Infarction. Front Neurosci 2017; 11:252. [PMID: 28533740 PMCID: PMC5420597 DOI: 10.3389/fnins.2017.00252] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Accepted: 04/20/2017] [Indexed: 01/06/2023] Open
Abstract
Introduction: Ventricular arrhythmia is a major cause of sudden cardiac death in patients with chronic heart failure (CHF). Our recent study demonstrates that N-type Ca2+ currents in intracardiac ganglionic neurons are reduced in the late stage of CHF rats. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG) and sinoatrial ganglion. Only AVG nerve terminals innervate the ventricular myocardium. In this study, we tested the correlation of electrical remodeling in AVG neurons with ventricular arrhythmogenesis in CHF rats. Methods and Results: CHF was induced in male Sprague-Dawley rats by surgical ligation of the left coronary artery. The data from 24-h continuous radiotelemetry ECG recording in conscious rats showed that ventricular tachycardia/fibrillation (VT/VF) occurred in 3 and 14-week CHF rats but not 8-week CHF rats. Additionally, as an index for vagal control of ventricular function, changes of left ventricular systolic pressure (LVSP) and the maximum rate of left ventricular pressure rise (LV dP/dtmax) in response to vagal efferent nerve stimulation were blunted in 14-week CHF rats but not 3 or 8-week CHF rats. Results from whole-cell patch clamp recording demonstrated that N-type Ca2+ currents in AVG neurons began to decrease in 8-week CHF rats, and that there was also a significant decrease in 14-week CHF rats. Correlation analysis revealed that N-type Ca2+ currents in AVG neurons negatively correlated with the cumulative duration of VT/VF in 14-week CHF rats, whereas there was no correlation between N-type Ca2+ currents in AVG neurons and the cumulative duration of VT/VF in 3-week CHF. Conclusion: Malignant ventricular arrhythmias mainly occur in the early and late stages of CHF. Electrical remodeling of AVG neurons highly correlates with the occurrence of ventricular arrhythmias in the late stage of CHF.
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Affiliation(s)
- Dongze Zhang
- Department of Emergency Medicine, University of Nebraska Medical CenterOmaha, NE, USA
| | - Huiyin Tu
- Department of Emergency Medicine, University of Nebraska Medical CenterOmaha, NE, USA
| | - Chaojun Wang
- Department of Emergency Medicine, University of Nebraska Medical CenterOmaha, NE, USA.,Department of Cardiovascular Disease, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an, China
| | - Liang Cao
- Department of Emergency Medicine, University of Nebraska Medical CenterOmaha, NE, USA.,Department of Cardiac Surgery, Second Xiangya Hospital, Central South UniversityChangsha, China
| | - Robert L Muelleman
- Department of Emergency Medicine, University of Nebraska Medical CenterOmaha, NE, USA
| | - Michael C Wadman
- Department of Emergency Medicine, University of Nebraska Medical CenterOmaha, NE, USA
| | - Yu-Long Li
- Department of Emergency Medicine, University of Nebraska Medical CenterOmaha, NE, USA.,Department of Cellular & Integrative Physiology, University of Nebraska Medical CenterOmaha, NE, USA
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44
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Pinali C, Malik N, Davenport JB, Allan LJ, Murfitt L, Iqbal MM, Boyett MR, Wright EJ, Walker R, Zhang Y, Dobryznski H, Holt CM, Kitmitto A. Post-Myocardial Infarction T-tubules Form Enlarged Branched Structures With Dysregulation of Junctophilin-2 and Bridging Integrator 1 (BIN-1). J Am Heart Assoc 2017; 6:e004834. [PMID: 28473402 PMCID: PMC5524063 DOI: 10.1161/jaha.116.004834] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 01/26/2017] [Indexed: 11/16/2022]
Abstract
BACKGROUND Heart failure is a common secondary complication following a myocardial infarction (MI), characterized by impaired cardiac contraction and t-tubule (t-t) loss. However, post-MI nano-scale morphological changes to the remaining t-ts are poorly understood. METHOD AND RESULTS We utilized a porcine model of MI, using a nonlethal microembolization method to generate controlled microinfarcts. Using serial block face scanning electron microscopy, we report that post-MI, after mild left-ventricular dysfunction has developed, t-ts are not only lost in the peri-infarct region, but also the remnant t-ts form enlarged, highly branched disordered structures, containing a dense intricate inner membrane. Biochemical and proteomics analyses showed that the calcium release channel, ryanodine receptor 2 (RyR2), abundance is unchanged, but junctophilin-2 (JP2), important for maintaining t-t trajectory, is depressed (-0.5×) in keeping with the t-ts being disorganized. However, immunolabeling shows that populations of RyR2 and JP2 remain associated with the remodeled t-ts. The bridging integrator 1 protein (BIN-1), a regulator of tubulogensis, is upregulated (+5.4×), consistent with an overdeveloped internal membrane system, a feature not present in control t-ts. Importantly, we have determined that t-ts, in the remote region, are narrowed and also contain dense membrane folds (BIN-1 is up-regulated +3.4×), whereas the t-ts have a radial organization comparable to control JP2 is upregulated +1.7×. CONCLUSIONS This study reveals previously unidentified remodeling of the t-t nano-architecture in the post-MI heart that extends to the remote region. Our findings highlight that targeting JP2 may be beneficial for preserving the orientation of the t-ts, attenuating the development of hypocontractility post-MI.
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Affiliation(s)
- Christian Pinali
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Nadim Malik
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - J Bernard Davenport
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Laurence J Allan
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Lucy Murfitt
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Mohammad M Iqbal
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Mark R Boyett
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Elizabeth J Wright
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Rachel Walker
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Yu Zhang
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Halina Dobryznski
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Cathy M Holt
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
| | - Ashraf Kitmitto
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
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45
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Saseendran A, Ally K, Gangadevi P, Banakar PS. Effect of supplementation of lecithin and carnitine on growth performance and nutrient digestibility in pigs fed high-fat diet. Vet World 2017; 10:149-155. [PMID: 28344396 PMCID: PMC5352838 DOI: 10.14202/vetworld.2017.149-155] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 01/03/2017] [Indexed: 11/16/2022] Open
Abstract
Aim: To study the effect of dietary supplementation of lecithin and carnitine on growth performance and nutrient digestibility in pigs fed high-fat diet. Materials and Methods: A total of 30 weaned female large white Yorkshire piglets of 2 months of age were selected and randomly divided into three groups allotted to three dietary treatments, T1 - Control ration as per the National Research Council nutrient requirement, T2 - Control ration plus 5% fat, and T3 - T2 plus 0.5% lecithin plus 150 mg/kg carnitine. The total dry matter (DM) intake, fortnightly body weight of each individual animal was recorded. Digestibility trial was conducted toward the end of the experiment to determine the digestibility coefficient of various nutrients. Results: There was a significant improvement (p<0.01) observed for pigs under supplementary groups T2 and T3 than that of control group (T1) with regards to growth parameters studied such as total DM intake, average final body weight and total weight gain whereas among supplementary groups, pigs reared on T3 group had better intake (p<0.01) when compared to T2 group. Statistical analysis of data revealed that no differences were observed (p>0.05) among the three treatments on average daily gain, feed conversion efficiency, and nutrient digestibility during the overall period. Conclusion: It was concluded that the dietary inclusion of animal fat at 5% level or animal fat along with lecithin (0.5%) and carnitine (150 mg/kg) improved the growth performance in pigs than non-supplemented group and from the economic point of view, dietary incorporation of animal fat at 5% would be beneficial for improving growth in pigs without dietary modifiers.
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Affiliation(s)
- Arathy Saseendran
- Department of Animal Nutrition, College of Veterinary and Animal Sciences, Kerala Veterinary and Animal Sciences University, Mannuthy, Thrissur - 680 651, Kerala, India
| | - K Ally
- Department of Animal Nutrition, College of Veterinary and Animal Sciences, Kerala Veterinary and Animal Sciences University, Mannuthy, Thrissur - 680 651, Kerala, India
| | - P Gangadevi
- Department of Animal Nutrition, College of Veterinary and Animal Sciences, Kerala Veterinary and Animal Sciences University, Mannuthy, Thrissur - 680 651, Kerala, India
| | - P S Banakar
- Department of Animal Nutrition, College of Veterinary and Animal Sciences, Kerala Veterinary and Animal Sciences University, Mannuthy, Thrissur - 680 651, Kerala, India
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46
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Ramjee V, Li D, Manderfield LJ, Liu F, Engleka KA, Aghajanian H, Rodell CB, Lu W, Ho V, Wang T, Li L, Singh A, Cibi DM, Burdick JA, Singh MK, Jain R, Epstein JA. Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction. J Clin Invest 2017; 127:899-911. [PMID: 28165342 DOI: 10.1172/jci88759] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 12/12/2016] [Indexed: 12/27/2022] Open
Abstract
Ischemic heart disease resulting from myocardial infarction (MI) is the most prevalent form of heart disease in the United States. Post-MI cardiac remodeling is a multifaceted process that includes activation of fibroblasts and a complex immune response. T-regulatory cells (Tregs), a subset of CD4+ T cells, have been shown to suppress the innate and adaptive immune response and limit deleterious remodeling following myocardial injury. However, the mechanisms by which injured myocardium recruits suppressive immune cells remain largely unknown. Here, we have shown a role for Hippo signaling in the epicardium in suppressing the post-infarct inflammatory response through recruitment of Tregs. Mice deficient in epicardial YAP and TAZ, two core Hippo pathway effectors, developed profound post-MI pericardial inflammation and myocardial fibrosis, resulting in cardiomyopathy and death. Mutant mice exhibited fewer suppressive Tregs in the injured myocardium and decreased expression of the gene encoding IFN-γ, a known Treg inducer. Furthermore, controlled local delivery of IFN-γ following MI rescued Treg infiltration into the injured myocardium of YAP/TAZ mutants and decreased fibrosis. Collectively, these results suggest that epicardial Hippo signaling plays a key role in adaptive immune regulation during the post-MI recovery phase.
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Abstract
The hearts of lower vertebrates such as fish and salamanders display scarless regeneration following injury, although this feature is lost in adult mammals. The remarkable capacity of the neonatal mammalian heart to regenerate suggests that the underlying machinery required for the regenerative process is evolutionarily retained. Recent studies highlight the epicardial covering of the heart as an important source of the signalling factors required for the repair process. The developing epicardium is also a major source of cardiac fibroblasts, smooth muscle, endothelial cells and stem cells. Here, we examine animal models that are capable of scarless regeneration, the role of the epicardium as a source of cells, signalling mechanisms implicated in the regenerative process and how these mechanisms influence cardiomyocyte proliferation. We also discuss recent advances in cardiac stem cell research and potential therapeutic targets arising from these studies.
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Affiliation(s)
| | - Nadia Rosenthal
- National Heart and Lung Institute, Imperial College London, London, UK Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia The Jackson Laboratory, Bar Harbor, ME, USA
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48
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Pinkham MI, Loftus MT, Amirapu S, Guild SJ, Quill G, Woodward WR, Habecker BA, Barrett CJ. Renal denervation in male rats with heart failure improves ventricular sympathetic nerve innervation and function. Am J Physiol Regul Integr Comp Physiol 2017; 312:R368-R379. [PMID: 28052866 DOI: 10.1152/ajpregu.00313.2016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 12/14/2016] [Accepted: 01/02/2017] [Indexed: 01/19/2023]
Abstract
Heart failure is characterized by the loss of sympathetic innervation to the ventricles, contributing to impaired cardiac function and arrhythmogenesis. We hypothesized that renal denervation (RDx) would reverse this loss. Male Wistar rats underwent myocardial infarction (MI) or sham surgery and progressed into heart failure for 4 wk before receiving bilateral RDx or sham RDx. After additional 3 wk, left ventricular (LV) function was assessed, and ventricular sympathetic nerve fiber density was determined via histology. Post-MI heart failure rats displayed significant reductions in ventricular sympathetic innervation and tissue norepinephrine content (nerve fiber density in the LV of MI+sham RDx hearts was 0.31 ± 0.05% vs. 1.00 ± 0.10% in sham MI+sham RDx group, P < 0.05), and RDx significantly increased ventricular sympathetic innervation (0.76 ± 0.14%, P < 0.05) and tissue norepinephrine content. MI was associated with an increase in fibrosis of the noninfarcted ventricular myocardium, which was attenuated by RDx. RDx improved LV ejection fraction and end-systolic and -diastolic areas when compared with pre-RDx levels. This is the first study to show an interaction between renal nerve activity and cardiac sympathetic nerve innervation in heart failure. Our findings show denervating the renal nerves improves cardiac sympathetic innervation and function in the post-MI failing heart.
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Affiliation(s)
| | - Michael T Loftus
- Department of Physiology, University of Auckland, Auckland, New Zealand
| | - Satya Amirapu
- Department of Anatomy and Radiology, University of Auckland, Auckland, New Zealand
| | - Sarah-Jane Guild
- Department of Physiology, University of Auckland, Auckland, New Zealand
| | - Gina Quill
- Department of Medicine, University of Auckland, Auckland, New Zealand; and
| | - William R Woodward
- Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon
| | - Beth A Habecker
- Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon
| | - Carolyn J Barrett
- Department of Physiology, University of Auckland, Auckland, New Zealand
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Ladejobi A, Wayne M, Martin-Gill C, Guyette FX, Althouse AD, Sharbaugh MS, Reis SE, Callaway CW, Kellum JA, Smith AJC, Toma C, Olafiranye O. Association of remote ischemic peri-conditioning with reduced incidence of clinical heart failure after primary percutaneous coronary intervention. CARDIOVASCULAR REVASCULARIZATION MEDICINE 2016; 18:105-109. [PMID: 28038863 DOI: 10.1016/j.carrev.2016.12.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 12/05/2016] [Accepted: 12/08/2016] [Indexed: 12/01/2022]
Abstract
BACKGROUND Clinical heart failure (HF) occurs frequently after ST-segment elevation myocardial infarction (STEMI), and is associated with increased mortality. We assessed the impact of remote ischemic peri-conditioning (RIPC) during inter-facility air medical transport of STEMI patients on clinical HF following primary percutaneous coronary intervention (pPCI). METHODS Data from Acute Coronary Treatment and Intervention Outcomes Network Registry®-Get With the Guidelines™ (ACTION Registry-GWTG) from two PCI-hospitals that are utilizing RIPC during inter-facility helicopter transport of STEMI patients for pPCI between March, 2013 and September, 2015 were used for this study. The analyses were limited to inter-facility STEMI patients transported by helicopter with LVEF <55% after pPCI. The outcome measures were occurrence of clinical HF and serum level of brain-type natriuretic peptide (BNP). RESULTS Out of the 150 STEMI patients in this analysis, 92 patients received RIPC and 58 did not. The RIPC and non-RIPC groups were generally similar in demographic and clinical characteristics except for lower incidence of cardiac arrest in the RIPC group (3/92 [3.3%] versus 13/58 [22.4%], p=0.002). STEMI patients who received RIPC were less likely to have in-hospital clinical HF compared to patients who did not receive RIPC (3/92 [3.3%] versus 7/58 [12.1%]; adjusted OR=0.22, 95% CI 0.05-0.92, p=0.038) after adjusting for baseline differences. In subgroup analysis, RIPC was associated with lower BNP (123 [interquartile range, 17.0-310] versus 319 [interquartile range, 106-552], p=0.029). CONCLUSION RIPC applied during inter-facility air transport of STEMI patients for pPCI is associated with reduced incidence of clinical HF and serum BNP.
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Affiliation(s)
- Adetola Ladejobi
- Department of Medicine, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Max Wayne
- Department of Medicine, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Francis X Guyette
- Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Andrew D Althouse
- Department of Medicine, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Michael S Sharbaugh
- Department of Medicine, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Steven E Reis
- Department of Medicine, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Clifton W Callaway
- Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - John A Kellum
- Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - A J Conrad Smith
- Department of Medicine, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Catalin Toma
- Department of Medicine, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Oladipupo Olafiranye
- Department of Medicine, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
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50
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Neutrophils recruited to the myocardium after acute experimental myocardial infarct generate hypochlorous acid that oxidizes cardiac myoglobin. Arch Biochem Biophys 2016; 612:103-114. [PMID: 27789204 DOI: 10.1016/j.abb.2016.10.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 10/11/2016] [Accepted: 10/19/2016] [Indexed: 11/17/2022]
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