Dietary Supplementation with Homoarginine Preserves Cardiac Function in a Murine Model of Post-Myocardial Infarction Heart Failure
2017; Lippincott Williams & Wilkins; Volume: 135; Issue: 4 Linguagem: Inglês
10.1161/circulationaha.116.025673
ISSN1524-4539
AutoresDorothee Atzler, Debra J. McAndrew, Kathrin Cordts, Jürgen E. Schneider, Sevasti Zervou, Edzard Schwedhelm, Stefan Neubauer, Craig A. Lygate,
Tópico(s)Cardiovascular Function and Risk Factors
ResumoHomeCirculationVol. 135, No. 4Dietary Supplementation with Homoarginine Preserves Cardiac Function in a Murine Model of Post-Myocardial Infarction Heart Failure Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBDietary Supplementation with Homoarginine Preserves Cardiac Function in a Murine Model of Post-Myocardial Infarction Heart Failure Dorothee Atzler, PhD, Debra J. McAndrew, BS, Kathrin Cordts, BS, Jürgen E. Schneider, PhD, Sevasti Zervou, PhD, Edzard Schwedhelm, PhD, Stefan Neubauer, MD and Craig A. Lygate, PhD Dorothee AtzlerDorothee Atzler From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (D.A., D.J.M., J.E.S., S.Z., S.N., C.A.L.); Division of Vascular Biology, Institute for Stroke and Dementia Research, Ludwig Maximilians-University Munich, Germany (D.A.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Deutsches Zentrum füz-Kreislauf-Forschung e.V., partner site Munich Heart Alliance, Germany (D.A.); Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Germany (K.C., E.S.); and Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., partner site Hamburg/Kiel/Lübeck, Germany (K.C., E.S.). , Debra J. McAndrewDebra J. McAndrew From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (D.A., D.J.M., J.E.S., S.Z., S.N., C.A.L.); Division of Vascular Biology, Institute for Stroke and Dementia Research, Ludwig Maximilians-University Munich, Germany (D.A.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Deutsches Zentrum füz-Kreislauf-Forschung e.V., partner site Munich Heart Alliance, Germany (D.A.); Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Germany (K.C., E.S.); and Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., partner site Hamburg/Kiel/Lübeck, Germany (K.C., E.S.). , Kathrin CordtsKathrin Cordts From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (D.A., D.J.M., J.E.S., S.Z., S.N., C.A.L.); Division of Vascular Biology, Institute for Stroke and Dementia Research, Ludwig Maximilians-University Munich, Germany (D.A.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Deutsches Zentrum füz-Kreislauf-Forschung e.V., partner site Munich Heart Alliance, Germany (D.A.); Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Germany (K.C., E.S.); and Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., partner site Hamburg/Kiel/Lübeck, Germany (K.C., E.S.). , Jürgen E. SchneiderJürgen E. Schneider From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (D.A., D.J.M., J.E.S., S.Z., S.N., C.A.L.); Division of Vascular Biology, Institute for Stroke and Dementia Research, Ludwig Maximilians-University Munich, Germany (D.A.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Deutsches Zentrum füz-Kreislauf-Forschung e.V., partner site Munich Heart Alliance, Germany (D.A.); Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Germany (K.C., E.S.); and Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., partner site Hamburg/Kiel/Lübeck, Germany (K.C., E.S.). , Sevasti ZervouSevasti Zervou From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (D.A., D.J.M., J.E.S., S.Z., S.N., C.A.L.); Division of Vascular Biology, Institute for Stroke and Dementia Research, Ludwig Maximilians-University Munich, Germany (D.A.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Deutsches Zentrum füz-Kreislauf-Forschung e.V., partner site Munich Heart Alliance, Germany (D.A.); Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Germany (K.C., E.S.); and Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., partner site Hamburg/Kiel/Lübeck, Germany (K.C., E.S.). , Edzard SchwedhelmEdzard Schwedhelm From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (D.A., D.J.M., J.E.S., S.Z., S.N., C.A.L.); Division of Vascular Biology, Institute for Stroke and Dementia Research, Ludwig Maximilians-University Munich, Germany (D.A.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Deutsches Zentrum füz-Kreislauf-Forschung e.V., partner site Munich Heart Alliance, Germany (D.A.); Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Germany (K.C., E.S.); and Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., partner site Hamburg/Kiel/Lübeck, Germany (K.C., E.S.). , Stefan NeubauerStefan Neubauer From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (D.A., D.J.M., J.E.S., S.Z., S.N., C.A.L.); Division of Vascular Biology, Institute for Stroke and Dementia Research, Ludwig Maximilians-University Munich, Germany (D.A.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Deutsches Zentrum füz-Kreislauf-Forschung e.V., partner site Munich Heart Alliance, Germany (D.A.); Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Germany (K.C., E.S.); and Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., partner site Hamburg/Kiel/Lübeck, Germany (K.C., E.S.). and Craig A. LygateCraig A. Lygate From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (D.A., D.J.M., J.E.S., S.Z., S.N., C.A.L.); Division of Vascular Biology, Institute for Stroke and Dementia Research, Ludwig Maximilians-University Munich, Germany (D.A.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Deutsches Zentrum füz-Kreislauf-Forschung e.V., partner site Munich Heart Alliance, Germany (D.A.); Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Germany (K.C., E.S.); and Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., partner site Hamburg/Kiel/Lübeck, Germany (K.C., E.S.). Originally published24 Jan 2017https://doi.org/10.1161/CIRCULATIONAHA.116.025673Circulation. 2017;135:400–402IntroductionLow plasma homoarginine (HA) is an emerging biomarker for cardiovascular disease and an independent predictor of mortality in patients with heart failure.1 Plasma levels appear to reflect cardiac dysfunction, positively correlating with ejection fraction and inversely with circulating brain natriuretic peptide.2 However, whether this outcome is a bystander or cause-and-effect has yet to be established. Within the context of stroke, a direct causal relationship has been inferred because normal mice pretreated with 14 mg/L HA had a smaller stroke size.3 In the present study, we show for the first time that dietary supplementation with HA improves cardiac function in the setting of chronic heart failure, suggesting a novel preventive strategy and inferring that low HA levels may be inherently detrimental because of a loss of this effect.We first confirmed that oral supplementation of C57BL/6J mice (Harwell, UK) with 14 mg/L L-HA hydrochloride (Sigma-Aldrich) in the drinking water for 4 weeks increased HA concentrations in both plasma (0.29±0.03 vs 0.89±0.07 µmol/L) and myocardial tissue (17.6±2.7 vs 48.8±6.8 nmol/g protein; n=5–10; P<0.01 for both), demonstrating a strong correlation between levels in plasma and myocardium (r=0.74, P<0.01). This dose did not significantly alter cardiac haemodynamic parameters or body weight and was chosen to match the dosing strategy previously shown to be cerebroprotective.3To investigate the influence of HA supplementation on heart failure development, adult female C57BL/6J mice were given drinking water with or without 14 mg/L HA for 4 weeks before myocardial infarction surgery and throughout the remaining 6 weeks follow-up. Echocardiography was performed 4 weeks after surgery to exclude infarcts <25% because these mice do not develop heart failure. High-resolution cine-magnetic resonance imaging under isoflurane anesthesia was applied in vivo 5.5 weeks after surgery to assess infarct size, left ventricular (LV) structure, mass, and volumes. After 6 weeks, haemodynamic measurements were obtained by LV catheterization and contractile reserve assessed under maximal dobutamine infusion (16ng/g body weight/min) via the jugular vein. All surgery and in vivo phenotyping was as previously described.4 Cardiac blood, lungs, and scar-free LV tissue were collected and stored at −80°C. Myocardial and plasma HA concentrations were measured using tandem-mass spectrometry.3 This investigation was approved by the Ethical Review Committee at the University of Oxford and conforms to the UK Animals (Scientific Procedures) Act, 1986, incorporating Directive 2010/63/EU.No difference was found in the overall survival between groups (control myocardial infarction 64% vs HA supplementation 68%, P=0.69). For all subsequent analyses, experimental groups were retrospectively matched for infarct size, which is necessary to determine the effect of HA on heart failure development independent of effects on myocardial injury.4 Cine-magnetic resonance imaging revealed profound LV remodeling, which is indicative of heart failure (ie, dilatation and hypertrophy), but to a similar extent in both control and HA-supplemented animals (Table). Similarly, global function assessed by magnetic resonance imaging (eg, ejection fraction) was severely impaired but did not differ between groups most likely because magnetic resonance imaging could only be performed under basal (nonstimulated) conditions. In contrast, haemodynamic measures of isovolumetric function were better preserved with HA supplementation, as evidenced by higher LV contractility (dP/dtmax) at baseline and upon β-adrenergic stimulation, manifesting as preserved contractile reserve (ΔdP/dtmax). Furthermore, diastolic indices (dP/dtmin, tau) were also improved under stimulated conditions in the HA-supplemented animals (Table). These findings are unlikely to reflect altered loading conditions because markers for afterload (LV systolic pressure) and preload (LV end-diastolic pressure) did not differ significantly between groups, and tau is relatively load-insensitive.Table. In Vivo Cardiac Function 6 Weeks After Myocardial Infarction (MI) in Female C57BL/6J Mice With (+HA) and Without (−HA) Dietary Homoarginine Supplementation (14 mg/L Drinking Water)MIP Value−HA+HACine-Magnetic Resonance Imaging(n=19)(n=23) Infarct size (%)39.3±9.139.8±7.00.84 Heart rate (bpm)461±34454±340.54 Ejection fraction (%)17±515±50.39† End diastolic volume (µL)140±35147±280.40† End systolic volume (µL)118±36125±290.50 Stroke volume (µL)22±522±50.90 Cardiac output (mL/min)10 130±25179893±26530.67†Haemodynamics (baseline)(n=19)(n=23) LV systolic pressure (mm Hg)84±688±60.06 LV end-diastolic pressure (mm Hg)14.6±5.313.3±4.20.36 Tau (ms)15.0±2.813.4±3.40.11 dP/dtmax (mm Hg/s)4753±10735515±12920.03†* dP/dtmin (mm Hg/s)−3308±998−4029±14470.051†Haemodynamics (stimulated‡)(n=19)(n=23) LV systolic pressure (mm Hg)84±688±70.06 LV end-diastolic pressure (mm Hg)13.5±5.310.8±3.90.069 Tau (ms)11.8±2.49.9±2.50.014* dP/dtmax (mm Hg/s)5710±17917421±26430.006†* dP/dtmin (mm Hg/s)-4048±1358-5357±20380.009†* Δ dP/dtmax (mm Hg/s)956±8811906±15700.014†*Postmortem morphology(n=19)(n=23) Tibial length (mm)18.2±0.318.3±0.20.17 Lung/tibial length (mg/mm)9.2±2.99.6±2.50.28† LV/tibial length (mg/mm)7.1±0.87.7±1.00.06All values are presented as mean±SD. *P<0.05 for −HA versus +HA using Student's t test when normally distributed or †Mann-Whitney-U test when normality assumption is violated. Haemodynamic measurements assessed at baseline and ‡after stimulation with dobutamine (16 ng/g body weight/min). dP/dtmax indicates contractility; dP/dtmin, relaxation; Δ dP/dtmax, contractile reserve; and LV, left ventricle.Conceivably, our results will stimulate further research. For example, the precise molecular mechanism remains elusive, and it has yet to be established whether presupplementation is necessary or HA has an additional effect on infarct size. Maintaining functional reserve would clearly be desirable for patient quality of life, but whether this is truly beneficial in the long term will need to be tested in the clinical setting. In this context, it is notable that a beneficial effect was obtained from a 3-fold increase in plasma HA using a human dose equivalent of ≈250 mg daily. Recently, we investigated kinetic and dynamic properties of oral HA supplementation in healthy humans demonstrating a 7-fold elevation in plasma HA levels when 125 mg HA was given daily for 4 weeks,5 suggesting that a relatively low dose would be sufficient to elevate plasma HA into the therapeutic range for at-risk patients. This contrasts with the known pharmacokinetic profile for L-arginine supplementation, suggesting that HA is not a straightforward substitution for L-arginine metabolism.5 Nevertheless, future studies should determine the effect of HA on nitric oxide bioavailability.Our study questioned whether, for the same extent of myocardial injury, dietary HA supplementation modifies the subsequent development of chronic heart failure. Specifically, we can conclude that HA did not alter structural LV remodeling after myocardial infarction but that dietary HA supplementation preserved contractile reserve, with treated hearts maintaining higher responses to β–adrenergic stimulation. This finding suggests that HA is more than a bystander biomarker because higher levels directly influence heart failure pathophysiology. Because it is safe, cheap, and easily administered,5 dietary supplementation with homoarginine represents a promising approach for clinical translation.Sources of FundingDr Atzler acknowledges the support of the European Community under a Marie Curie Intra-European Fellowship for Career Development (623127). This work was funded by Ludwig Maximilians-University Munich's Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative (to D.A.) and by a British Heart Foundation Programme Grant (RG/13/8/30266 to C.L., J.E.S., and S.N.). Dr Schneider is a Senior BHF Basic Science Research Fellow (FS/11/50/29038). The authors acknowledge a Wellcome Trust Core Award (grant number 090532/Z/09/Z).DisclosuresNone.FootnotesCirculation is available at http://circ.ahajournals.org.Correspondence to: Dorothee Atzler, PhD, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 17, D-81377 Munich, Germany; or Craig Lygate, PhD, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Dr, Oxford, OX3 7BN UK. E-mail [email protected] or [email protected]References1. Atzler D, Schwedhelm E, Choe CU.L-homoarginine and cardiovascular disease.Curr Opin Clin Nutr Metab Care. 2015; 18:83–88. doi: 10.1097/MCO.0000000000000123.CrossrefMedlineGoogle Scholar2. Pilz S, Meinitzer A, Gaksch M, Grübler M, Verheyen N, Drechsler C, Hartaigh BÓ, Lang F, Alesutan I, Voelkl J, März W, Tomaschitz A.Homoarginine in the renal and cardiovascular systems.Amino Acids. 2015; 47:1703–1713. doi: 10.1007/s00726-015-1993-2.CrossrefMedlineGoogle Scholar3. Choe CU, Atzler D, Wild PS, Carter AM, Böger RH, Ojeda F, Simova O, Stockebrand M, Lackner K, Nabuurs C, Marescau B, Streichert T, Müller C, Lüneburg N, De Deyn PP, Benndorf RA, Baldus S, Gerloff C, Blankenberg S, Heerschap A, Grant PJ, Magnus T, Zeller T, Isbrandt D, Schwedhelm E.Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies.Circulation. 2013; 128:1451–1461. doi: 10.1161/CIRCULATIONAHA.112.000580.LinkGoogle Scholar4. Lygate CA, Bohl S, ten Hove M, Faller KM, Ostrowski PJ, Zervou S, Medway DJ, Aksentijevic D, Sebag-Montefiore L, Wallis J, Clarke K, Watkins H, Schneider JE, Neubauer S.Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction.Cardiovasc Res. 2012; 96:466–475. doi: 10.1093/cvr/cvs272.CrossrefMedlineGoogle Scholar5. Atzler D, Schönhoff M, Cordts K, Ortland I, Hoppe J, Hummel FC, Gerloff C, Jaehde U, Jagodzinski A, Böger RH, Choe CU, Schwedhelm E.Oral supplementation with L-homoarginine in young volunteers.Br J Clin Pharmacol. 2016; 82:1477–1485. doi: 10.1111/bcp.13068.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Jensen M, Müller C, Hübner N, Patone G, Saar K, Choe C, Schwedhelm E and Zeller T (2022) Expression of cardiovascular-related microRNAs is altered in L-arginine:glycine amidinotransferase deficient mice, Scientific Reports, 10.1038/s41598-022-08846-1, 12:1, Online publication date: 1-Dec-2022. Nitz K, Lacy M, Bianchini M, Wichapong K, Kücükgöze I, Bonfiglio C, Migheli R, Wu Y, Burger C, Li Y, Forné I, Ammar C, Janjic A, Mohanta S, Duchene J, Heemskerk J, Megens R, Schwedhelm E, Huveneers S, Lygate C, Santovito D, Zimmer R, Imhof A, Weber C, Lutgens E and Atzler D (2022) The Amino Acid Homoarginine Inhibits Atherogenesis by Modulating T-Cell Function, Circulation Research, 131:8, (701-712), Online publication date: 30-Sep-2022. Koch V, Gruenewald L, Gruber‐Rouh T, Martin S, Eichler K, Booz C, Yel I, Vogl T, Buchner K, Hagenmueller M, März W, Frey N, Hardt S and Riffel J (2022) Homoarginine treatment of rats improves cardiac function and remodeling in response to pressure overload, Fundamental & Clinical Pharmacology, 10.1111/fcp.12808 Fulghum K, Collins H, Jones S and Hill B (2022) Influence of biological sex and exercise on murine cardiac metabolism, Journal of Sport and Health Science, 10.1016/j.jshs.2022.06.001, Online publication date: 1-Jun-2022. Porro B, Eligini S, Conte E, Cosentino N, Capra N, Cavalca V and Banfi C (2022) An Optimized MRM-Based Workflow of the l-Arginine/Nitric Oxide Pathway Metabolites Revealed Disease- and Sex-Related Differences in the Cardiovascular Field, International Journal of Molecular Sciences, 10.3390/ijms23031136, 23:3, (1136) Koch V, Weber C, Riffel J, Buchner K, Buss S, Hein S, Mereles D, Hagenmueller M, Erbel C, März W, Booz C, Albrecht M, Vogl T, Frey N, Hardt S and Ochs M (2022) Impact of Homoarginine on Myocardial Function and Remodeling in a Rat Model of Chronic Renal Failure, Journal of Cardiovascular Pharmacology and Therapeutics, 10.1177/10742484211054620, 27, (107424842110546), Online publication date: 1-Jan-2022. Rodionov R, Beyer-Westendorf J, Bode-Böger S, Eggebrecht L, Konstantinides S, Martens-Lobenhoffer J, Nagler M, Prochaska J and Wild P (2021) Homoarginine and methylarginines independently predict long-term outcome in patients presenting with suspicion of venous thromboembolism, Scientific Reports, 10.1038/s41598-021-88986-y, 11:1, Online publication date: 1-Dec-2021. Lygate C (2021) The Pitfalls of in vivo Cardiac Physiology in Genetically Modified Mice – Lessons Learnt the Hard Way in the Creatine Kinase System, Frontiers in Physiology, 10.3389/fphys.2021.685064, 12 Mokhaneli M, Botha‐Le Roux S, Fourie C, Böger R, Schwedhelm E and Mels C (2020) L‐homoarginine is associated with decreased cardiovascular‐ and all‐cause mortality, European Journal of Clinical Investigation, 10.1111/eci.13472, 51:5, Online publication date: 1-May-2021. Wetzel M, Stanley K, Maity S, Madesh M, Bopassa J and Awad A (2021) Homoarginine ameliorates diabetic nephropathy independent of nitric oxide synthase‐3, Physiological Reports, 10.14814/phy2.14766, 9:5, Online publication date: 1-Mar-2021. Jensen M, Müller C, Choe C, Schwedhelm E and Zeller T (2020) Analysis of L-arginine:glycine amidinotransferase-, creatine- and homoarginine-dependent gene regulation in the murine heart, Scientific Reports, 10.1038/s41598-020-61638-3, 10:1, Online publication date: 1-Dec-2020. Malle O, Trummer C, Theiler-Schwetz V, Meinitzer A, Keppel M, Grübler M, Tomaschitz A, Voelkl J, März W and Pilz S (2020) NO Synthesis Markers Are Not Significantly Associated with Blood Pressure and Endothelial Dysfunction in Patients with Arterial Hypertension: A Cross-Sectional Study, Journal of Clinical Medicine, 10.3390/jcm9123895, 9:12, (3895) Zaric B, Radovanovic J, Gluvic Z, Stewart A, Essack M, Motwalli O, Gojobori T and Isenovic E (2020) Atherosclerosis Linked to Aberrant Amino Acid Metabolism and Immunosuppressive Amino Acid Catabolizing Enzymes, Frontiers in Immunology, 10.3389/fimmu.2020.551758, 11 Maas R, Mieth M, Titze S, Hübner S, Fromm M, Kielstein J, Schmid M, Köttgen A, Kronenberg F, Krane V, Hausknecht B, Eckardt K and Schneider M (2018) Drugs linked to plasma homoarginine in chronic kidney disease patients—a cross-sectional analysis of the German Chronic Kidney Disease cohort, Nephrology Dialysis Transplantation, 10.1093/ndt/gfy342, 35:7, (1187-1195), Online publication date: 1-Jul-2020. Schwedhelm E, Song R, Vasan R, van den Heuvel E, Hannemann J, Xanthakis V and Böger R (2020) Association of Lower Plasma Homoarginine Concentrations with Greater Risk of All-Cause Mortality in the Community: The Framingham Offspring Study, Journal of Clinical Medicine, 10.3390/jcm9062016, 9:6, (2016) Jiménez Jiménez F, Jordá Miñana A and González Iglesias C (2020) Recommendations for specialized nutritional-metabolic treatment of the critical patient: Heart disease. Metabolism and Nutrition Working Group of the Spanish Society of Intensive and Critical Care Medicine and Coronary Units (SEMICYUC), Medicina Intensiva (English Edition), 10.1016/j.medine.2019.12.006, 44, (77-80), Online publication date: 1-Jun-2020. Jiménez Jiménez F, Jordá Miñana A and González Iglesias C (2020) Recomendaciones para el tratamiento nutrometabólico especializado del paciente crítico: patologia cardìaca. Grupo de Trabajo de Metabolismo y Nutrición de la Sociedad Española de Medicina Intensiva, Crítica y Unidades Coronarias (SEMICYUC), Medicina Intensiva, 10.1016/j.medin.2019.12.002, 44, (77-80), Online publication date: 1-Jun-2020. Jensen M, Müller C, Schwedhelm E, Arunachalam P, Gelderblom M, Magnus T, Gerloff C, Zeller T and Choe C (2020) Homoarginine- and Creatine-Dependent Gene Regulation in Murine Brains with l-Arginine:Glycine Amidinotransferase Deficiency, International Journal of Molecular Sciences, 10.3390/ijms21051865, 21:5, (1865) Grosse G, Schwedhelm E, Worthmann H and Choe C (2020) Arginine Derivatives in Cerebrovascular Diseases: Mechanisms and Clinical Implications, International Journal of Molecular Sciences, 10.3390/ijms21051798, 21:5, (1798) Sasani A, Hornig S, Grzybowski R, Cordts K, Hanff E, Tsikas D, Böger R, Gerloff C, Isbrandt D, Neu A, Schwedhelm E and Choe C (2019) Muscle phenotype of AGAT- and GAMT-deficient mice after simvastatin exposure, Amino Acids, 10.1007/s00726-019-02812-4, 52:1, (73-85), Online publication date: 1-Jan-2020. Jarzebska N, Georgi S, Jabs N, Brilloff S, Maas R, Rodionov R, Zietz C, Montresor S, Hohenstein B and Weiss N (2019) Kidney and liver are the main organs of expression of a key metabolic enzyme alanine:glyoxylate aminotransferase 2 in humans, Atherosclerosis Supplements, 10.1016/j.atherosclerosissup.2019.08.041, 40, (106-112), Online publication date: 1-Dec-2019. Hanff E, Said M, Kayacelebi A, Post A, Minovic I, van den Berg E, de Borst M, van Goor H, Bakker S and Tsikas D (2019) High plasma guanidinoacetate-to-homoarginine ratio is associated with high all-cause and cardiovascular mortality rate in adult renal transplant recipients, Amino Acids, 10.1007/s00726-019-02783-6, 51:10-12, (1485-1499), Online publication date: 1-Nov-2019. Wetzel M, Gao T, Venkatachalam M, Morris S and Awad A (2019) l ‐Homoarginine supplementation prevents diabetic kidney damage , Physiological Reports, 10.14814/phy2.14235, 7:18, Online publication date: 1-Sep-2019. Rodionov R, Begmatov H, Jarzebska N, Patel K, Mills M, Ghani Z, Khakshour D, Tamboli P, Patel M, Abdalla M, Assaf M, Bornstein S, Millan J, Bode‐Böger S, Martens‐Lobenhoffer J, Weiss N and Savinova O (2019) Homoarginine Supplementation Prevents Left Ventricular Dilatation and Preserves Systolic Function in a Model of Coronary Artery Disease, Journal of the American Heart Association, 8:14, Online publication date: 16-Jul-2019.Karetnikova E, Jarzebska N, Markov A, Weiss N, Lentz S and Rodionov R (2019) Is Homoarginine a Protective Cardiovascular Risk Factor?, Arteriosclerosis, Thrombosis, and Vascular Biology, 39:5, (869-875), Online publication date: 1-May-2019.Nitz K, Lacy M and Atzler D (2019) Amino Acids and Their Metabolism in Atherosclerosis, Arteriosclerosis, Thrombosis, and Vascular Biology, 39:3, (319-330), Online publication date: 1-Mar-2019. Niekamp C, Atzler D, Ojeda F, Sinning C, Lackner K, Böger R, Munzel T, Beutel M, Schmidtmann I, Pfeiffer N, Leuschner A, Blankenberg S, Wild P, Zeller T, Schwedhelm E and Schnabel R (2018) Cross-Sectional Associations between Homoarginine, Intermediate Phenotypes, and Atrial Fibrillation in the Community—The Gutenberg Health Study, Biomolecules, 10.3390/biom8030086, 8:3, (86) Baldassarri F, Schwedhelm E, Atzler D, Böger R, Cordts K, Haller B, Pressler A, Müller S, Suchy C, Wachter R, Düngen H, Hasenfuss G, Pieske B, Halle M, Edelmann F and Duvinage A (2018) Relationship between exercise intervention and NO pathway in patients with heart failure with preserved ejection fraction, Biomarkers, 10.1080/1354750X.2018.1460762, 23:6, (540-550), Online publication date: 18-Aug-2018. Zinellu A, Paliogiannis P, Carru C and Mangoni A (2018) Homoarginine and all-cause mortality: A systematic review and meta-analysis, European Journal of Clinical Investigation, 10.1111/eci.12960, 48:8, (e12960), Online publication date: 1-Aug-2018. Bahls M, Atzler D, Markus M, Friedrich N, Böger R, Völzke H, Felix S, Schwedhelm E and Dörr M (2018) Low-Circulating Homoarginine is Associated with Dilatation and Decreased Function of the Left Ventricle in the General Population, Biomolecules, 10.3390/biom8030063, 8:3, (63) Schönhoff M, Weineck G, Hoppe J, Hornig S, Cordts K, Atzler D, Gerloff C, Böger R, Neu A, Schwedhelm E and Choe C (2018) Cognitive performance of 20 healthy humans supplemented with L-homoarginine for 4 weeks, Journal of Clinical Neuroscience, 10.1016/j.jocn.2018.01.035, 50, (237-241), Online publication date: 1-Apr-2018. Faller K, Atzler D, McAndrew D, Zervou S, Whittington H, Simon J, Aksentijevic D, ten Hove M, Choe C, Isbrandt D, Casadei B, Schneider J, Neubauer S and Lygate C (2017) Impaired cardiac contractile function in arginine:glycine amidinotransferase knockout mice devoid of creatine is rescued by homoarginine but not creatine, Cardiovascular Research, 10.1093/cvr/cvx242, 114:3, (417-430), Online publication date: 1-Mar-2018. Chafai A, Fromm M, König J and Maas R (2017) The prognostic biomarker L-homoarginine is a substrate of the cationic amino acid transporters CAT1, CAT2A and CAT2B, Scientific Reports, 10.1038/s41598-017-04965-2, 7:1, Online publication date: 1-Dec-2017. January 24, 2017Vol 135, Issue 4 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.116.025673PMID: 28115416 Originally publishedJanuary 24, 2017 Keywordsargininecardiovascular disease preventionhomoargininepost-myocardial infarction heart failurePDF download Advertisement SubjectsHeart Failure
Referência(s)