TGR5 activation induces cytoprotective changes in the heart and improves myocardial adaptability to physiologic, inotropic, and pressure‐induced stress in mice

Introduction Administration of cholic acid, or its synthetic derivative, 6‐alpha‐ethyl‐23(S)‐methylcholic acid (INT‐777), activates the membrane GPCR, TGR5, influences whole body metabolism, reduces atherosclerosis, and benefits the cardiovascular physiology in mice. Direct effects of TGR5 agonists,...

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Published inCardiovascular therapeutics Vol. 36; no. 5; pp. e12462 - n/a
Main Authors Eblimit, Zeena, Thevananther, Sundararajah, Karpen, Saul J., Taegtmeyer, Heinrich, Moore, David D., Adorini, Luciano, Penny, Daniel J., Desai, Moreshwar S.
Format Journal Article
LanguageEnglish
Published England Hindawi Limited 01.10.2018
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Abstract Introduction Administration of cholic acid, or its synthetic derivative, 6‐alpha‐ethyl‐23(S)‐methylcholic acid (INT‐777), activates the membrane GPCR, TGR5, influences whole body metabolism, reduces atherosclerosis, and benefits the cardiovascular physiology in mice. Direct effects of TGR5 agonists, and the role for TGR5, on myocardial cell biology and stress response are unknown. Methods Mice were fed chow supplemented with 0.5% cholic acid (CA) or 0.025% INT‐777, a specific TGR5 agonist, or regular chow for 3 weeks. Anthropometric, biochemical, physiologic (electrocardiography and echocardiography), and molecular analysis was performed at baseline. CA and INT‐777 fed mice were challenged with acute exercise‐induced stress, acute catecholamine‐induced stress, and hemodynamic stress induced by transverse aortic constriction (TAC) for a period of 8 weeks. In separate experiments, mice born with constitutive deletion of TGR5 in cardiomyocytes (CM‐TGR5del) were exposed to exercise, inotropic, and TAC‐induced stress. Results Administration of CA and INT‐777 supplemented diets upregulated TGR5 expression and activated Akt, PKA, and ERK1/2 in the heart. CA and INT‐777 fed mice showed improved exercise tolerance, improved sensitivity to catecholamine and attenuation in pathologic remodeling of the heart under hemodynamic stress. In contrast, CM‐TGR5del showed poor response to exercise and catecholamine challenge as well as higher mortality and signs of accelerated cardiomyopathy under hemodynamic stress. Conclusions Bile acids, specifically TGR5 agonists, induce cytoprotective changes in the heart and improve myocardial response to physiologic, inotropic, and hemodynamic stress in mice. TGR5 plays a critical role in myocardial adaptability, and TGR5 activation may represent a potentially attractive treatment option in heart failure.
AbstractList Introduction Administration of cholic acid, or its synthetic derivative, 6‐alpha‐ethyl‐23(S)‐methylcholic acid (INT‐777), activates the membrane GPCR, TGR5, influences whole body metabolism, reduces atherosclerosis, and benefits the cardiovascular physiology in mice. Direct effects of TGR5 agonists, and the role for TGR5, on myocardial cell biology and stress response are unknown. Methods Mice were fed chow supplemented with 0.5% cholic acid (CA) or 0.025% INT‐777, a specific TGR5 agonist, or regular chow for 3 weeks. Anthropometric, biochemical, physiologic (electrocardiography and echocardiography), and molecular analysis was performed at baseline. CA and INT‐777 fed mice were challenged with acute exercise‐induced stress, acute catecholamine‐induced stress, and hemodynamic stress induced by transverse aortic constriction (TAC) for a period of 8 weeks. In separate experiments, mice born with constitutive deletion of TGR5 in cardiomyocytes (CM‐TGR5del) were exposed to exercise, inotropic, and TAC‐induced stress. Results Administration of CA and INT‐777 supplemented diets upregulated TGR5 expression and activated Akt, PKA, and ERK1/2 in the heart. CA and INT‐777 fed mice showed improved exercise tolerance, improved sensitivity to catecholamine and attenuation in pathologic remodeling of the heart under hemodynamic stress. In contrast, CM‐TGR5del showed poor response to exercise and catecholamine challenge as well as higher mortality and signs of accelerated cardiomyopathy under hemodynamic stress. Conclusions Bile acids, specifically TGR5 agonists, induce cytoprotective changes in the heart and improve myocardial response to physiologic, inotropic, and hemodynamic stress in mice. TGR5 plays a critical role in myocardial adaptability, and TGR5 activation may represent a potentially attractive treatment option in heart failure.
INTRODUCTIONAdministration of cholic acid, or its synthetic derivative, 6-alpha-ethyl-23(S)-methylcholic acid (INT-777), activates the membrane GPCR, TGR5, influences whole body metabolism, reduces atherosclerosis, and benefits the cardiovascular physiology in mice. Direct effects of TGR5 agonists, and the role for TGR5, on myocardial cell biology and stress response are unknown. METHODSMice were fed chow supplemented with 0.5% cholic acid (CA) or 0.025% INT-777, a specific TGR5 agonist, or regular chow for 3 weeks. Anthropometric, biochemical, physiologic (electrocardiography and echocardiography), and molecular analysis was performed at baseline. CA and INT-777 fed mice were challenged with acute exercise-induced stress, acute catecholamine-induced stress, and hemodynamic stress induced by transverse aortic constriction (TAC) for a period of 8 weeks. In separate experiments, mice born with constitutive deletion of TGR5 in cardiomyocytes (CM-TGR5del ) were exposed to exercise, inotropic, and TAC-induced stress. RESULTSAdministration of CA and INT-777 supplemented diets upregulated TGR5 expression and activated Akt, PKA, and ERK1/2 in the heart. CA and INT-777 fed mice showed improved exercise tolerance, improved sensitivity to catecholamine and attenuation in pathologic remodeling of the heart under hemodynamic stress. In contrast, CM-TGR5del showed poor response to exercise and catecholamine challenge as well as higher mortality and signs of accelerated cardiomyopathy under hemodynamic stress. CONCLUSIONSBile acids, specifically TGR5 agonists, induce cytoprotective changes in the heart and improve myocardial response to physiologic, inotropic, and hemodynamic stress in mice. TGR5 plays a critical role in myocardial adaptability, and TGR5 activation may represent a potentially attractive treatment option in heart failure.
Administration of cholic acid, or its synthetic derivative, 6-alpha-ethyl-23(S)-methylcholic acid (INT-777), activates the membrane GPCR, TGR5, influences whole body metabolism, reduces atherosclerosis, and benefits the cardiovascular physiology in mice. Direct effects of TGR5 agonists, and the role for TGR5, on myocardial cell biology and stress response are unknown. Mice were fed chow supplemented with 0.5% cholic acid (CA) or 0.025% INT-777, a specific TGR5 agonist, or regular chow for 3 weeks. Anthropometric, biochemical, physiologic (electrocardiography and echocardiography), and molecular analysis was performed at baseline. CA and INT-777 fed mice were challenged with acute exercise-induced stress, acute catecholamine-induced stress, and hemodynamic stress induced by transverse aortic constriction (TAC) for a period of 8 weeks. In separate experiments, mice born with constitutive deletion of TGR5 in cardiomyocytes (CM-TGR5 ) were exposed to exercise, inotropic, and TAC-induced stress. Administration of CA and INT-777 supplemented diets upregulated TGR5 expression and activated Akt, PKA, and ERK1/2 in the heart. CA and INT-777 fed mice showed improved exercise tolerance, improved sensitivity to catecholamine and attenuation in pathologic remodeling of the heart under hemodynamic stress. In contrast, CM-TGR5 showed poor response to exercise and catecholamine challenge as well as higher mortality and signs of accelerated cardiomyopathy under hemodynamic stress. Bile acids, specifically TGR5 agonists, induce cytoprotective changes in the heart and improve myocardial response to physiologic, inotropic, and hemodynamic stress in mice. TGR5 plays a critical role in myocardial adaptability, and TGR5 activation may represent a potentially attractive treatment option in heart failure.
Author Thevananther, Sundararajah
Moore, David D.
Adorini, Luciano
Desai, Moreshwar S.
Taegtmeyer, Heinrich
Penny, Daniel J.
Eblimit, Zeena
Karpen, Saul J.
AuthorAffiliation 6 Intercept Pharmaceuticals Inc., San Diego, California
5 Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
1 Section of Pediatric Critical Care, Baylor College of Medicine, Houston, Texas
3 Pediatric Gastroenterology, Emory School of Medicine, Atlanta, Georgia
4 Department of Internal Medicine, Division of Cardiology, McGovern Medical School, University of Texas Health Science Center, Houston, Texas
2 Pediatric Gastroenterology and Liver Center, Baylor College of Medicine, Houston, Texas
7 Department of Pediatric Cardiology, Baylor College of Medicine, Houston, Texas
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Issue 5
Keywords TGR5
cholic acid
myocardial adaptation
INT-777
preconditioning
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MSD, SJK, DDM, HT, and DJP conceived of the presented idea; ZE and MSD conducted the actual experiments and wrote the manuscript; ST, HT, LA, and DDM gave scientific help, guidance and proof read the manuscript. All authors discussed the results and contributed to the final manuscript.
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References 2015; 35
2010; 55
2012; 167
2011; 54
2011; 13
2004; 2
1998; 83
2011; 14
2003; 278
2017; 113
2001; 104
2001; 103
2001; 42
2014; 129
2009; 14
2018; 8
2009; 52
2018; 1864
2009; 10
2013; 99
2009; 50
2015; 131
2006; 25
2013; 97
2014; 13
1999; 96
2010; 151
2006; 126
2010; 5
2011; 123
2014; 11
2003; 284
2006; 439
2008; 18
2017; 65
2013; 304
2013; 91
2001; 29
2008; 51
2007; 12
2014; 42
2002; 29
2006; 45
2013; 33
2005; 288
2005; 5
2005; 329
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2005; 15
2010; 51
2008; 294
References_xml – volume: 8
  start-page: 7110
  issue: 1
  year: 2018
  article-title: Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR5
  publication-title: Sci Rep
– volume: 104
  start-page: 2923
  issue: 24
  year: 2001
  end-page: 2931
  article-title: Metabolic gene expression in fetal and failing human heart
  publication-title: Circulation
– volume: 11
  start-page: 10
  issue: 1
  year: 2014
  article-title: The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility
  publication-title: Nutr Metab (Lond)
– volume: 51
  start-page: 2097
  issue: 6
  year: 2010
  end-page: 2107
  article-title: Hypertrophic cardiomyopathy and dysregulation of cardiac energetics in a mouse model of biliary fibrosis
  publication-title: Hepatology
– volume: 288
  start-page: H971
  issue: 2
  year: 2005
  end-page: H976
  article-title: Ischemic preconditioning protects by activating prosurvival kinases at reperfusion
  publication-title: Am J Physiol Heart Circ Physiol
– volume: 126
  start-page: 789
  issue: 4
  year: 2006
  end-page: 799
  article-title: Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network
  publication-title: Cell
– volume: 10
  start-page: 167
  issue: 3
  year: 2009
  end-page: 177
  article-title: TGR5‐mediated bile acid sensing controls glucose homeostasis
  publication-title: Cell Metab
– volume: 45
  start-page: 337
  issue: 2
  year: 2006
  end-page: 338
  article-title: The emerging role of bile acids as integrators of intermediary metabolism
  publication-title: J Hepatol
– volume: 97
  start-page: 393
  issue: 3
  year: 2013
  end-page: 403
  article-title: FoxO1 is crucial for sustaining cardiomyocyte metabolism and cell survival
  publication-title: Cardiovasc Res
– volume: 42
  start-page: 55
  issue: 1
  year: 2001
  end-page: 62
  article-title: An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro‐6‐thia‐heptadecanoic acid and [18F]FDG in Patients with Congestive Heart Failure
  publication-title: J Nucl Med
– volume: 29
  start-page: 272
  issue: Pt 2
  year: 2001
  end-page: 278
  article-title: Fuel‐sensing mechanisms integrating lipid and carbohydrate utilization
  publication-title: Biochem Soc Trans
– volume: 329
  start-page: 386
  issue: 1
  year: 2005
  end-page: 390
  article-title: Bile acids promote glucagon‐like peptide‐1 secretion through TGR5 in a murine enteroendocrine cell line STC‐1
  publication-title: Biochem Biophys Res Commun
– volume: 304
  start-page: H1103
  issue: 8
  year: 2013
  end-page: H1113
  article-title: ANG II causes insulin resistance and induces cardiac metabolic switch and inefficiency: a critical role of PDK4
  publication-title: Am J Physiol Heart Circ Physiol
– volume: 55
  start-page: 932
  issue: 4
  year: 2010
  end-page: 938
  article-title: Accelerated development of pressure overload‐induced cardiac hypertrophy and dysfunction in an RyR2‐R176Q knockin mouse model
  publication-title: Hypertension
– volume: 129
  start-page: 399
  issue: 3
  year: 2014
  end-page: 410
  article-title: Executive summary: heart disease and stroke statistics–2014 update: a report from the American Heart Association
  publication-title: Circulation
– volume: 96
  start-page: 857
  issue: 6
  year: 1999
  end-page: 868
  article-title: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor
  publication-title: Cell
– volume: 50
  start-page: 1509
  issue: 8
  year: 2009
  end-page: 1520
  article-title: Bile acids as regulatory molecules
  publication-title: J Lipid Res
– volume: 51
  start-page: 1831
  issue: 6
  year: 2008
  end-page: 1841
  article-title: Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure‐activity relationships, and molecular modeling studies
  publication-title: J Med Chem
– volume: 65
  start-page: 189
  issue: 1
  year: 2017
  end-page: 201
  article-title: Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart
  publication-title: Hepatology
– volume: 42
  start-page: 244
  issue: 2
  year: 2014
  end-page: 249
  article-title: TGR5 in inflammation and cardiovascular disease
  publication-title: Biochem Soc Trans
– volume: 103
  start-page: 2441
  issue: 20
  year: 2001
  end-page: 2446
  article-title: Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure
  publication-title: Circulation
– volume: 131
  start-page: e29
  issue: 4
  year: 2015
  end-page: e322
  article-title: Heart disease and stroke statistics–2015 update: a report from the American Heart Association
  publication-title: Circulation
– volume: 13
  start-page: 825
  issue: 8
  year: 2011
  end-page: 829
  article-title: AKT signalling in the failing heart
  publication-title: Eur J Heart Fail
– volume: 18
  start-page: 167
  issue: 2
  year: 2008
  end-page: 174
  article-title: Bile acids and the membrane bile acid receptor TGR5–connecting nutrition and metabolism
  publication-title: Thyroid
– volume: 35
  start-page: 1464
  issue: 4
  year: 2015
  end-page: 1477
  article-title: Cardiomyopathy reverses with recovery of liver injury, cholestasis and cholanemia in mouse model of biliary fibrosis
  publication-title: Liver Int
– volume: 14
  start-page: 747
  issue: 6
  year: 2011
  end-page: 757
  article-title: TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading
  publication-title: Cell Metab
– volume: 54
  start-page: 1303
  issue: 4
  year: 2011
  end-page: 1312
  article-title: Dual farnesoid X receptor/TGR5 agonist INT‐767 reduces liver injury in the Mdr2‐/‐ (Abcb4‐/‐) mouse cholangiopathy model by promoting biliary HCO(‐)(3) output
  publication-title: Hepatology
– volume: 83
  start-page: 117
  issue: 2
  year: 1998
  end-page: 132
  article-title: Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease
  publication-title: Circ Res
– volume: 129
  start-page: e28
  issue: 3
  year: 2014
  end-page: e292
  article-title: Heart disease and stroke statistics–2014 update: a report from the American Heart Association
  publication-title: Circulation
– volume: 83
  start-page: 1336
  issue: 6
  year: 2008
  end-page: 1344
  article-title: Atherogenic diet‐induced hepatitis is partially dependent on murine TLR4
  publication-title: J Leukoc Biol
– volume: 5
  start-page: e9689
  issue: 3
  year: 2010
  article-title: Bile acid‐induced arrhythmia is mediated by muscarinic M2 receptors in neonatal rat cardiomyocytes
  publication-title: PLoS One
– volume: 25
  start-page: 1419
  issue: 7
  year: 2006
  end-page: 1425
  article-title: Endocrine functions of bile acids
  publication-title: EMBO J
– volume: 29
  start-page: 346
  issue: 4
  year: 2002
  end-page: 350
  article-title: Mitochondrial proteins in hypertrophy and atrophy: a transcript analysis in rat heart
  publication-title: Clin Exp Pharmacol Physiol
– volume: 33
  start-page: 1663
  issue: 7
  year: 2013
  end-page: 1669
  article-title: Bile acid receptor TGR5 agonism induces NO production and reduces monocyte adhesion in vascular endothelial cells
  publication-title: Arterioscler Thromb Vasc Biol
– volume: 52
  start-page: 7958
  issue: 24
  year: 2009
  end-page: 7961
  article-title: Discovery of 6alpha‐ethyl‐23(S)‐methylcholic acid (S‐EMCA, INT‐777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity
  publication-title: J Med Chem
– volume: 13
  start-page: 570
  issue: 2
  year: 2014
  end-page: 580
  article-title: Bariatric surgery modulates circulating and cardiac metabolites
  publication-title: J Proteome Res
– volume: 12
  start-page: 217
  issue: 3‐4
  year: 2007
  end-page: 234
  article-title: Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection
  publication-title: Heart Fail Rev
– volume: 1864
  start-page: 1345
  issue: 4 Pt B
  year: 2018
  end-page: 1355
  article-title: Heart and bile acids ‐ Clinical consequences of altered bile acid metabolism
  publication-title: Biochim Biophys Acta
– volume: 151
  start-page: 2306
  issue: 5
  year: 2010
  end-page: 2318
  article-title: The increase in cardiac pyruvate dehydrogenase kinase‐4 after short‐term dexamethasone is controlled by an Akt‐p38‐forkhead box other factor‐1 signaling axis
  publication-title: Endocrinology
– volume: 294
  start-page: H936
  issue: 2
  year: 2008
  end-page: H943
  article-title: Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin‐induced cardiomyopathy
  publication-title: Am J Physiol Heart Circ Physiol
– volume: 167
  start-page: 1563
  issue: 7
  year: 2012
  end-page: 1572
  article-title: Regulation of apoptosis in HL‐1 cardiomyocytes by phosphorylation of the receptor tyrosine kinase EphA2 and protection by lithocholic acid
  publication-title: Br J Pharmacol
– volume: 15
  start-page: 69
  issue: 2
  year: 2005
  end-page: 75
  article-title: The reperfusion injury salvage kinase pathway: a common target for both ischemic preconditioning and postconditioning
  publication-title: Trends Cardiovasc Med
– volume: 91
  start-page: 333
  issue: 3
  year: 2013
  end-page: 346
  article-title: FOXO1‐mediated upregulation of pyruvate dehydrogenase kinase‐4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate
  publication-title: J Mol Med (Berl)
– volume: 278
  start-page: 9435
  issue: 11
  year: 2003
  end-page: 9440
  article-title: A G protein‐coupled receptor responsive to bile acids
  publication-title: J Biol Chem
– volume: 284
  start-page: E855
  issue: 5
  year: 2003
  end-page: E862
  article-title: Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs
  publication-title: Am J Physiol Endocrinol Metab
– volume: 113
  start-page: 564
  issue: 6
  year: 2017
  end-page: 585
  article-title: Novel targets and future strategies for acute cardioprotection: Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart
  publication-title: Cardiovasc Res
– volume: 99
  start-page: 1629
  issue: 22
  year: 2013
  end-page: 1630
  article-title: Bile acids induce arrhythmias: old metabolite, new tricks
  publication-title: Heart
– volume: 14
  start-page: 523
  issue: 9‐10
  year: 2009
  end-page: 530
  article-title: TGR5: an emerging bile acid G‐protein‐coupled receptor target for the potential treatment of metabolic disorders
  publication-title: Drug Discov Today
– volume: 2
  start-page: 4
  issue: 1
  year: 2004
  article-title: Endotoxin leads to rapid subcellular re‐localization of hepatic RXRalpha: A novel mechanism for reduced hepatic gene expression in inflammation
  publication-title: Nucl Recept
– volume: 123
  start-page: 979
  issue: 9
  year: 2011
  end-page: 988
  article-title: Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice
  publication-title: Circulation
– volume: 5
  start-page: 63
  issue: 1
  year: 2005
  end-page: 73
  article-title: Bile acids are toxic for isolated cardiac mitochondria: a possible cause for hepatic‐derived cardiomyopathies?
  publication-title: Cardiovasc Toxicol
– volume: 439
  start-page: 484
  issue: 7075
  year: 2006
  end-page: 489
  article-title: Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation
  publication-title: Nature
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Snippet Introduction Administration of cholic acid, or its synthetic derivative, 6‐alpha‐ethyl‐23(S)‐methylcholic acid (INT‐777), activates the membrane GPCR, TGR5,...
Administration of cholic acid, or its synthetic derivative, 6-alpha-ethyl-23(S)-methylcholic acid (INT-777), activates the membrane GPCR, TGR5, influences...
IntroductionAdministration of cholic acid, or its synthetic derivative, 6‐alpha‐ethyl‐23(S)‐methylcholic acid (INT‐777), activates the membrane GPCR, TGR5,...
INTRODUCTIONAdministration of cholic acid, or its synthetic derivative, 6-alpha-ethyl-23(S)-methylcholic acid (INT-777), activates the membrane GPCR, TGR5,...
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StartPage e12462
SubjectTerms Adaptation, Physiological
Animals
Bile
Cardiotonic Agents - pharmacology
Cells, Cultured
cholic acid
Cholic Acids - pharmacology
Cytoprotection
Disease Models, Animal
Exercise Tolerance - drug effects
Heart
Heart Failure - drug therapy
Heart Failure - metabolism
Heart Failure - pathology
Heart Failure - physiopathology
INT‐777
Male
Mice, Inbred C57BL
Mice, Knockout
myocardial adaptation
Myocardial Contraction - drug effects
Myocardium - metabolism
Myocardium - pathology
preconditioning
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - metabolism
Signal Transduction - drug effects
TGR5
Title TGR5 activation induces cytoprotective changes in the heart and improves myocardial adaptability to physiologic, inotropic, and pressure‐induced stress in mice
URI https://onlinelibrary.wiley.com/doi/abs/10.1111%2F1755-5922.12462
https://www.ncbi.nlm.nih.gov/pubmed/30070769
https://www.proquest.com/docview/2102311809
https://search.proquest.com/docview/2082088208
https://pubmed.ncbi.nlm.nih.gov/PMC6800140
Volume 36
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