Proinflammatory Cytokines
2003; Lippincott Williams & Wilkins; Volume: 107; Issue: 11 Linguagem: Inglês
10.1161/01.cir.0000060808.79274.0c
ISSN1524-4539
AutoresDavid R. Murray, Gregory L. Freeman,
Tópico(s)Protease and Inhibitor Mechanisms
ResumoHomeCirculationVol. 107, No. 11Proinflammatory Cytokines Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBProinflammatory CytokinesPredictors of a Failing Heart? David R. Murray, MD and Gregory L. Freeman, MD David R. MurrayDavid R. Murray From the Department of Medicine/Cardiology, University of Texas Health Science Center at San Antonio, and South Texas Veterans Healthcare System, Audie L. Murphy Division, San Antonio. and Gregory L. FreemanGregory L. Freeman From the Department of Medicine/Cardiology, University of Texas Health Science Center at San Antonio, and South Texas Veterans Healthcare System, Audie L. Murphy Division, San Antonio. Originally published25 Mar 2003https://doi.org/10.1161/01.CIR.0000060808.79274.0CCirculation. 2003;107:1460–1462Congestive heart failure (CHF) is a complex clinical syndrome characterized by exercise intolerance, fatigability, dyspnea, and volume retention occurring as a consequence of myocardial injury and subsequent dysfunction. Progression of this disease is thought to be mediated by neurohormones, such as norepinephrine and angiotensin II, by virtue of the toxic effects that they exert on the heart and the peripheral vasculature.1 These mediators are capable of altering the function and structure of the left ventricle (LV), ie, remodeling, via direct effects on cardiomyocyte biology and extracellular matrix composition and via indirect effects on the loading conditions under which the heart must function.1 Indeed, antagonizing the activation of the renin angiotensin system and the adrenergic system has become the mainstay of contemporary pharmacologic management of patients with this disease.1,2 β-blockers and angiotensin converting enzyme inhibitors have been shown to improve ventricular performance and clinical outcomes in patients with symptomatic heart failure due to LV systolic dysfunction, thus supporting the "neurohormonal hypothesis".1,2See p 1486Another group of peptides, the proinflammatory cytokines, are upregulated in patients with CHF and have been implicated in the pathophysiology of this disease. The most well studied of these cytokines is tumor necrosis factor (TNF).3 Comparatively less is known about interleukin (IL)-1, IL-2, IL-6, and interferon-γ in the setting of heart failure. Cardiomyocytes as well as other nucleated cell types within the myocardium are capable of synthesizing TNF in response to various forms of cardiac stress such as myocardial infarction4 and LV pressure or volume overload.5 Neither TNF mRNA nor TNF protein appear to be constitutively expressed in the nonfailing heart; in contrast, TNF mRNA and protein appear to be uniformly expressed in failing human hearts.6 Both types of TNF receptors have been identified in human myocardium and they are dynamically regulated.6 When given exogenously7,8 or expressed in transgenic models9 at sufficiently high concentrations, TNF recapitulates several aspects of the heart failure phenotype. TNF provokes cardiomyocyte hypertrophy and sarcomeric protein synthesis,10 triggers apoptosis in isolated cardiomyocytes through activation of the neutral sphingomyelinase pathway,11 promotes fetal gene expression,9 blunts adrenergic responsiveness,12 and impairs contractile function.7,8 Without altering preload or afterload, TNF induces LV dilation, perhaps as a result of extracellular matrix degradation, allowing for rearrangement ("slippage") of bundles or groups of cardiac myocytes.7,8 These alterations in LV geometry are accompanied by systolic and diastolic dysfunction.8 Thus, excessive activation of TNF, and possibly of other proinflammatory cytokines, may contribute to the LV remodeling observed in CHF via mechanisms that involve both myocyte and nonmyocyte elements of the myocardium.Circulating levels of TNF and IL-6 are elevated in patients with heart failure, particularly those with cardiac cachexia13 and edematous decompensation.14 Studies have consistently shown a direct relationship between levels of these cytokines and deteriorating functional classes of heart failure.15,16 Circulating TNF and its soluble receptors (sTNFR1 and sTNFR2) as well as IL-6 (but not its soluble receptor) predict mortality independent of age, gender, etiology of heart failure, NYHA Class, ejection fraction and serum sodium.17 Of interest, the circulating level of sTNFR2, a biologically "inert" protein cleaved from the cell surface membrane by TNF-α-converting enzyme (TACE), appears to be the most accurate predictor of mortality.17 Although these clinical studies cannot address whether the findings represent an epiphenomenon that is associated with, but not causally related to worsening disease severity and outcomes, the preponderance of data suggests that TNF and IL-6 (a promoter of cardiomyocyte hypertrophy and a negative inotrope)18 exert direct toxic effects on the heart and peripheral circulation. Conceivably, even sTNFR2 may be a surrogate marker for worsening LV function and/or LV remodeling: TACE levels correlate with the degree of LV systolic dysfunction in patients with dilated cardiomyopathy.19Until now, clinical studies evaluating cytokines and heart failure have been limited to patients with symptomatic disease in the setting of documented systolic dysfunction. In the current issue of Circulation,20 Vasan and colleagues sought to determine whether elevated levels of inflammatory markers antedate the development of CHF in individuals free of the condition. A subgroup of 732 elderly Framingham study subjects (mean age 78 years, 67% women) without prior myocardial infarction (MI) and CHF participated in this study. Blood was obtained to determine baseline levels of IL-6, C-reactive protein (CRP, low sensitivity immunoprecipitation assay), and spontaneous production of TNF by peripheral blood mononuclear cells (PBMC). Subjects with a history of MI were excluded because prior MI is a known powerful trigger for cytokine activation, progressive LV remodeling and CHF.4 Over a mean follow-up of 5.2 years, 56 subjects (35 women) developed CHF as defined by Framingham criteria. After adjustments for established risk factors, including the occurrence of MI during follow-up, the investigators found that the risk of developing CHF increased ≈1.6-fold to 1.7-fold per tertile increment in PBMC TNF and IL-6 levels, respectively. Participants with serum CRP levels ≥5 mg/dL (only 9% of subjects) experienced a 2.2-fold increased risk of CHF. Subjects with elevated serum IL-6 and PBMC TNF > median values as well as CRP ≥5 mg/dL had a 4.1-fold risk for developing CHF.The result of this study must be interpreted with caution. The study population consisted of predominantly elderly, white subjects (67% female) with a high prevalence of hypertension (≈70%), atrial fibrillation (≈7%), and preexisting cardiovascular disease (≈25% with history of angina, cerebrovascular or peripheral vascular disease without prior documented MI). As pointed out by the authors, the results cannot be generalized to include other ethnicities, younger age groups, and patients with different co-existing conditions.A more important limitation of this study is the lack of data related to the status of ventricular function at the time of baseline assessment. Although patients with confirmed prior MI (presumably diagnosed on the basis of history, cardiac enzymes and/or Q-waves on ECG) were excluded, subjects with preexistent cardiovascular disease, LV hypertrophy, left bundle branch block, atrial fibrillation, valvular disease, and hypertension were included. Surely some of these patients must have had subclinical LV systolic and/or diastolic dysfunction at the time of cytokine assessment, related to occult MI, myocardial hibernation, pressure or volume overload, or other forms of injury. Elevated inflammatory markers in this study may have identified patients with vascular disease at risk for myocardial infarction21,22 or patients with preexisting subclinical LV dysfunction.23 Without a baseline assessment of ventricular structure and function, the study cannot address whether IL-6, TNF, and CRP predicts the de novo development of cardiomyopathy versus foreshadowing the transition between subclinical LV dysfunction and overt congestion.The study does, however, offer some clues suggesting that inflammatory mediators can predict a transition toward a congested state. Determination of whether the patient had CHF was based on Framingham criteria.20 These criteria rely heavily on the presence of signs (eg, rales, jugular venous distension, hepatojugular reflux, peripheral edema, hepatomegaly) and symptoms (eg, paroxysmal nocturnal dyspnea, orthopnea, dyspnea on exertion) related to volume overload characterizing the congestive state. Lacking in these criteria are measures of exercise intolerance (unrelated to dyspnea), fatigability, generalized weakness, and energy depletion—symptoms that are more subtle and less specific in an elderly population vulnerable to the confounding factors of orthopedic and neurologic injury as well as the debilitating effects of aging. This study does not define whether inflammatory markers predict the development of "noncongestive" heart failure. Of interest, limited follow-up echocardiographic data showed that 6 of the 14 CHF patients (43%) with serum IL-6 levels in the top tertile had preserved systolic function, suggesting that IL-6 might interact with the vasculature and/or with other neurohormonal systems to promote congestion. The influence of IL-6 on ventricular systolic performance may actually be less important.Although this study suggests that TNF, CRP, and especially IL-6 levels are predictors for the development of CHF, several limitations preclude the routine use of these markers for risk stratification in clinical practice. First, many neurohormonal and clinical markers have been linked to outcomes in patients with CHF but comparative data regarding which ones are redundant and which ones are incremental in an asymptomatic patient population are limited. As a case in point, Vasan and colleagues found that serum IL-6 levels were related to CRP levels.20 This result was not as surprising as IL-6 is a central mediator of the acute-phase response and a primary determinant of the hepatic production of C-reactive protein.24 Furthermore, the authors did not provide hazard ratios for the other known predictors of CHF such as LV hypertrophy, hypertension, coronary artery disease, valvular disease, diabetes, and obesity.20 As such, side-by-side comparison of the value of elevated cytokines and these known predictors is not possible. Whether any of the inflammatory markers provide meaningful information over and above established variables remains to be proven. Secondly, to be useful for a large, general population, a screening test should be sensitive, accurate, reliable, easily standardized and inexpensive. Whether these features apply to tests used to detect this set of biochemical parameters is not clear. The sensitivity, specificity, negative and positive predictive values of IL-6, TNF, and CRP were not analyzed. Moreover, elevated levels of all three inflammatory markers were present in only 12 out of the 56 patients diagnosed with CHF, suggesting limited clinical utility. Finally, identification of risk should ideally lead to a treatment intervention that modifies that risk. Treatment of hypertension, coronary artery disease, and valvular disease can prevent the development of CHF. Whether the same can be said for neutralizing the biologic activity of proinflammatory cytokines remains unclear, and early interventional trials in patients with established CHF have not been encouraging.25Notwithstanding these limitations, Vasan and colleagues have provided data implicating inflammatory mediators as independent predictors of the onset of congestion in an elderly cohort. This study provides further support for the hypothesis that cytokines, namely, IL-6 and TNF, are maladaptive proteins that participate in the development and progression of heart failure by virtue of their toxic effects on the heart and peripheral vasculature. As with other neurohormonal markers which predict adverse outcomes in patients with heart failure, the ultimate distinction between whether the elevated level of a cytokine is a parallel phenomenon or a true causal mediator of disease rests on the demonstration that antagonizing or suppressing the cytokine results in beneficial effects. For the proinflammatory cytokines, illumination of this important point will require further investigation.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to David R. Murray, MD, Department of Medicine/Cardiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, MSC 7872, San Antonio, TX 78229 to 3900. E-mail [email protected] References 1 Eichhorn EJ. Medical therapy of chronic heart failure: role of ACE-inhibitors and beta-blockers. Cardiol Clin. 1998; 16: 711–725.CrossrefMedlineGoogle Scholar2 Murray DR, Dugan J. Overview of recent clinical trials in heart failure: what is the current standard of care? Cardio in Rev. 2000; 8: 340–347.CrossrefMedlineGoogle Scholar3 Mann DL. Recent insights into the role of tumor necrosis factor in the failing heart. Heart Fail Rev. 2001; 6: 71–80.CrossrefMedlineGoogle Scholar4 Prabhu SD, Chandrasekar B, Murray DR, et al. Beta-adrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling. Circulation. 2000; 101: 2103–2109.CrossrefMedlineGoogle Scholar5 Kapadia S, Oral H, Lee J, et al. Hemodynamic regulation of tumor necrosis factor-α gene and protein in adult feline myocardium. Circ Res. 1997; 81: 187–195.CrossrefMedlineGoogle Scholar6 Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factor-α and tumor necrosis factor receptors in the failing human heart. Circulation. 1996; 93: 704–711.CrossrefMedlineGoogle Scholar7 Bozkurt B, Kribbs S, Clubb Jr FJ, et al. Pathophysiologically relevant concentrations of tumor necrosis factor-α promote progressive left ventricular dysfunction and remodeling in rats. Circulation. 1998; 97: 1382–1391.CrossrefMedlineGoogle Scholar8 Murray DR, Freeman GL. Tumor necrosis factor-α induces a biphasic effect on myocardial contractility in conscious dogs. Circ Res. 1996; 78: 154–160.CrossrefMedlineGoogle Scholar9 Kubota T, McTiernan CF, Frye CS, et al. Dilated cardiomyopathy in transgenic mice with cardiac specific overexpression of tumor necrosis factor-alpha. Circ Res. 1997; 81: 627–635.CrossrefMedlineGoogle Scholar10 Yokoyama T, Nakano M, Bednarczyk JL, et al. Tumor necrosis factor-α provokes a hypertrophic growth response in adult cardiac myocytes. Circulation. 1997; 95: 1247–1252.CrossrefMedlineGoogle Scholar11 Krown KA, Page MT, Nguyen C, et al. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes: involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest. 1996; 98: 2854–2865.CrossrefMedlineGoogle Scholar12 Gulick TS, Chung MK, Pieper SJ, et al. Interleukin-1 and tumor necrosis factor inhibit cardiac myocyte β-adrenergic responsiveness. Proc Natl Acad Sci U S A. 1989; 86: 6753–6757.CrossrefMedlineGoogle Scholar13 Anker SD, Ponikowski PP, Clark AL, et al. Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heart failure. Eur Heart J. 1999; 20: 683–693.CrossrefMedlineGoogle Scholar14 Niebauer J, Volk HD, Kemp M, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet. 1999; 353: 1838–1842.CrossrefMedlineGoogle Scholar15 Torre-Amione G, Kapadia S, Benedict C, et al. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol. 1996; 27: 1201–1206.CrossrefMedlineGoogle Scholar16 Tsutamoto T, Hisanaga T, Wada A, et al. Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol. 1998; 31: 391–398.CrossrefMedlineGoogle Scholar17 Deswal A, Petersen NJ, Feldman AM, et al. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the vesnarinone trial (VEST). Circulation. 2001; 103: 2055–2059.CrossrefMedlineGoogle Scholar18 Wollert KC, Drexler H. The role of interleukin-6 in the failing heart. Heart Fail Rev. 2001; 6: 95–103.CrossrefMedlineGoogle Scholar19 Satoh M, Nakamura M, Saitoh H, et al. Tumor necrosis factor-α-converting enzyme and tumor necrosis factor-α in human dilated cardiomyopathy. Circulation. 1999; 99: 3260–3265.CrossrefMedlineGoogle Scholar20 Vasan RS, Sullivan LM, Roubenoff R, et al. Inflammatory markers and risk of heart failure in elderly subjects without a prior myocardial infarction: the Framingham Study. Circulation. 2003; 107: 1486–1491.LinkGoogle Scholar21 Ridker PM, Rifai N, Stampfer MJ, et al. Plasma concentrations of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000; 101: 1767–1772.CrossrefMedlineGoogle Scholar22 Ridker PM, Rifai N, Pfeffer M, et al. Elevation of tumor necrosis factor-α and increased risk of recurrent coronary events after myocardial infarction. Circulation. 2000; 101: 2149–2153.CrossrefMedlineGoogle Scholar23 Raymond RJ, Dehmer GJ, Theoharides TC, et al. Elevated interleukin-6 levels in patients with asymptomatic left ventricular systolic dysfunction. Am Heart J. 2001; 141: 435–438.CrossrefMedlineGoogle Scholar24 Baumann H, Gauldie J. Regulation of hepatic acute phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammation. Mol Biol Med. 1990; 7: 147–159.MedlineGoogle Scholar25 Krum H. Tumor necrosis factor-α blockade as a therapeutic strategy in heart failure (RENEWAL and ATTACH): unsuccessful, to be specific. J Card Fail. 2003; 8: 365–368.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByYang Y, Kurian J, Schena G, Johnson J, Kubo H, Travers J, Kang C, Lucchese A, Eaton D, Lv M, Li N, Leynes L, Yu D, Yang F, McKinsey T, Kishore R, Khan M, Mohsin S and Houser S (2021) Cardiac Remodeling During Pregnancy With Metabolic Syndrome, Circulation, 143:7, (699-712), Online publication date: 16-Feb-2021. Sato A, Kato T, Kasai T, Ishiwata S, Yatsu S, Matsumoto H, Shitara J, Murata A, Shimizu M, Suda S, Matsue Y, Naito R, Hiki M and Daida H (2020) Relationship between inflammatory biomarkers and sleep-disordered breathing in patients with heart failure, Sleep and Biological Rhythms, 10.1007/s41105-020-00287-5, 19:1, (55-61), Online publication date: 1-Jan-2021. Kim G and Park Y (2021) Accelerated diastolic dysfunction in premenopausal women with rheumatoid arthritis, Arthritis Research & Therapy, 10.1186/s13075-021-02629-1, 23:1, Online publication date: 1-Dec-2021. Sun S, Cao H, Yao N, Zhao L, Zhu X, Ni E, Zhu Q and Zhu W (2019) β-Arrestin 2 mediates arginine vasopressin-induced IL-6 induction via the ERK1/2-NF-κB signal pathway in murine hearts, Acta Pharmacologica Sinica, 10.1038/s41401-019-0292-y, 41:2, (198-207), Online publication date: 1-Feb-2020. Lu C, Ou H, Day C, Chen H, Pai P, Lee C, Chen R, Chang R, PadmaViswanadha V, Hsieh D and Huang C (2019) Deep sea minerals ameliorate diabetic‐induced inflammation via inhibition of TNFα signaling pathways, Environmental Toxicology, 10.1002/tox.22882, 35:4, (468-477), Online publication date: 1-Apr-2020. Borow K, Yaroshinsky A, Greenberg B and Perin E (2019) Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure, Circulation Research, 125:3, (265-281), Online publication date: 19-Jul-2019. Burrai F, Hasan W, Luppi M and Micheluzzi V (2018) A Conceptual Framework Encompassing the Psychoneuroimmunoendocrinological Influences of Listening to Music in Patients With Heart Failure, Holistic Nursing Practice, 10.1097/HNP.0000000000000253, 32:2, (81-89), Online publication date: 1-Mar-2018. António N (2018) Reduction of systemic inflammation after cardiac resynchronization therapy: A new form of response?, Revista Portuguesa de Cardiologia (English Edition), 10.1016/j.repce.2018.01.005, 37:2, (115-116), Online publication date: 1-Feb-2018. António N (2018) Redução da inflamação sistémica após terapêutica de ressincronização cardíaca: uma nova forma de resposta?, Revista Portuguesa de Cardiologia, 10.1016/j.repc.2018.01.004, 37:2, (115-116), Online publication date: 1-Feb-2018. Edmonston D, Morris J and Middleton J (2018) Working Toward an Improved Understanding of Chronic Cardiorenal Syndrome Type 4, Advances in Chronic Kidney Disease, 10.1053/j.ackd.2018.08.010, 25:5, (454-467), Online publication date: 1-Sep-2018. Xu F, Sun S, Wang X, Ni E, Zhao L and Zhu W (2017) GRK2 Mediates Arginine Vasopressin-Induced Interleukin-6 Production via Nuclear Factor-κB Signaling Neonatal Rat Cardiac Fibroblast, Molecular Pharmacology, 10.1124/mol.116.107698, 92:3, (278-284), Online publication date: 1-Sep-2017. Yanagisawa S, Inden Y, Yoshida N, Kato H, Miyoshi-Fujii A, Mizutani Y, Ito T, Kamikubo Y, Kanzaki Y, Hirai M and Murohara T (2015) Body mass index is associated with prognosis in Japanese elderly patients with atrial fibrillation: an observational study from the outpatient clinic, Heart and Vessels, 10.1007/s00380-015-0765-y, 31:9, (1553-1561), Online publication date: 1-Sep-2016. Altara R and Blankesteijn W (2015) Technological Aspects of Measuring Inflammatory Markers Inflammation in Heart Failure, 10.1016/B978-0-12-800039-7.00008-6, (117-130), . Aramburu-Bodas Ó, García-Casado B, Salamanca-Bautista P, Guisado-Espartero M, Arias-Jiménez J, Barco-Sánchez A, Santamaría-González J, Formiga F, Montero-Pérez-Barquero M and Manzano L (2015) Relationship between osteoprotegerin and mortality in decompensated heart failure with preserved ejection fraction, Journal of Cardiovascular Medicine, 10.2459/JCM.0000000000000229, 16:6, (438-443), Online publication date: 1-Jun-2015. Güder G and Rutten F (2014) Comorbidity of Heart Failure and Chronic Obstructive Pulmonary Disease: More than Coincidence, Current Heart Failure Reports, 10.1007/s11897-014-0212-x, 11:3, (337-346), Online publication date: 1-Sep-2014. Avci A, Alizade E, Fidan S, Yesin M, Guler Y, Kargin R and Esen A (2014) Neutrophil/lymphocyte ratio is related to the severity of idiopathic dilated cardiomyopathy, Scandinavian Cardiovascular Journal, 10.3109/14017431.2014.932922, 48:4, (202-208), Online publication date: 1-Aug-2014. Calle M and Fernandez M (2012) Inflammation and type 2 diabetes, Diabetes & Metabolism, 10.1016/j.diabet.2011.11.006, 38:3, (183-191), Online publication date: 1-Jun-2012. Kurita A, Takase B, Shinagawa N, Kodani E, Okada K, Iwahara S, Kusama Y and Atarashi H (2011) Spiritual Activation in Very Elderly Individuals Assessed as Heart Rate Variability and Plasma IL/10/IL-6 Ratios, International Heart Journal, 10.1536/ihj.52.299, 52:5, (299-303), . O'Dell K, Masters K, Spielmans G and Maisto S (2011) Does type-D personality predict outcomes among patients with cardiovascular disease? A meta-analytic review, Journal of Psychosomatic Research, 10.1016/j.jpsychores.2011.01.009, 71:4, (199-206), Online publication date: 1-Oct-2011. Fadini G and Avogaro A (2011) Cardiovascular effects of DPP-4 inhibition: Beyond GLP-1, Vascular Pharmacology, 10.1016/j.vph.2011.05.001, 55:1-3, (10-16), Online publication date: 1-Jul-2011. Okada K, Kurita A, Takase B, Otsuka T, Kodani E, Kusama Y, Atarashi H and Mizuno K (2009) Effects of Music Therapy on Autonomic Nervous System Activity, Incidence of Heart Failure Events, and Plasma Cytokine and Catecholamine Levels in Elderly Patients With Cerebrovascular Disease and Dementia, International Heart Journal, 10.1536/ihj.50.95, 50:1, (95-110), . Hirasawa Y, Nakagomi A, Kobayashi Y, Katoh T and Mizuno K (2009) Short-Term Amiodarone Treatment Attenuates the Production of Monocyte Cytokines and Chemokines by C-Reactive Protein and Improves Cardiac Function in Patients With Idiopathic Dilated Cardiomyopathy and Ventricular Tachycardia, Circulation Journal, 10.1253/circj.CJ-08-0794, 73:4, (639-646), . Al-Sarraj T, Saadi H, Calle M, Volek J and Fernandez M (2009) Carbohydrate Restriction, as a First-Line Dietary Intervention, Effectively Reduces Biomarkers of Metabolic Syndrome in Emirati Adults, The Journal of Nutrition, 10.3945/jn.109.109603, 139:9, (1667-1676), Online publication date: 1-Sep-2009. Yuan M, Huang C, Tang Y, Wang X, Huang H, Chen Y and Wang T (2009) A novel peptide ghrelin inhibits neural remodeling after myocardial infarction in rats, European Journal of Pharmacology, 10.1016/j.ejphar.2009.07.015, 618:1-3, (52-57), Online publication date: 1-Sep-2009. Puglisi M and Fernandez M (2008) Modulation of C-Reactive Protein, Tumor Necrosis Factor-α, and Adiponectin by Diet, Exercise, and Weight Loss, The Journal of Nutrition, 10.3945/jn.108.097188, 138:12, (2293-2296), Online publication date: 1-Dec-2008. Xu Z, Lin S, Wu W, Tan H, Wang Z, Cheng C, Lu L and Zhang X (2008) Ghrelin prevents doxorubicin-induced cardiotoxicity through TNF-alpha/NF-κB pathways and mitochondrial protective mechanisms, Toxicology, 10.1016/j.tox.2008.02.018, 247:2-3, (133-138), Online publication date: 1-May-2008. Monsuez J, Escaut L, Teicher E, Charniot J and Vittecoq D (2007) Cytokines in HIV-associated cardiomyopathy, International Journal of Cardiology, 10.1016/j.ijcard.2006.11.143, 120:2, (150-157), Online publication date: 1-Aug-2007. Mercuro G, Cadeddu C, Piras A, Dessì M, Madeddu C, Deidda M, Serpe R, Massa E and Mantovani G (2007) Early Epirubicin-Induced Myocardial Dysfunction Revealed by Serial Tissue Doppler Echocardiography: Correlation with Inflammatory and Oxidative Stress Markers, The Oncologist, 10.1634/theoncologist.12-9-1124, 12:9, (1124-1133), Online publication date: 1-Sep-2007. Nicola P, Crowson C, Maradit-Kremers H, Ballman K, Roger V, Jacobsen S and Gabriel S (2005) Contribution of congestive heart failure and ischemic heart disease to excess mortality in rheumatoid arthritis, Arthritis & Rheumatism, 10.1002/art.21560, 54:1, (60-67), Online publication date: 1-Jan-2006. Bozkurt B (2006) Biomarkers of Inflammation Cardiovascular Biomarkers, 10.1007/978-1-59745-051-5_19, (295-318), . Qayyum R and Schulman P (2006) Cardiovascular effects of the thiazolidinediones, Diabetes/Metabolism Research and Reviews, 10.1002/dmrr.596, 22:2, (88-97), Online publication date: 1-Mar-2006. THEODORAKIS G, FLEVARI P, KROUPIS C, ADAMOPOULOS S, LIVANIS E, KOSTOPOULOU A, KOLOKATHIS F, PARASKEVAIDIS I, LEFTHERIOTIS D and KREMASTINOS D (2006) Antiinflammatory Effects of Cardiac Resynchronization Therapy in Patients with Chronic Heart Failure, Pacing and Clinical Electrophysiology, 10.1111/j.1540-8159.2006.00331.x, 29:3, (255-261), Online publication date: 1-Mar-2006. Bajaj G and Sharma R (2006) TNF-α-mediated cardiomyocyte apoptosis involves caspase-12 and calpain, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2006.05.059, 345:4, (1558-1564), Online publication date: 1-Jul-2006. Tsukamoto O, Minamino T, Sanada S, Okada K, Hirata A, Fujita M, Shintani Y, Yulin L, Asano Y, Takashima S, Yamasaki S, Tomoike H, Hori M and Kitakaze M (2006) The Antagonism of Aldosterone Receptor Prevents the Development of Hypertensive Heart Failure Induced by Chronic Inhibition of Nitric Oxide Synthesis in Rats, Cardiovascular Drugs and Therapy, 10.1007/s10557-006-8130-0, 20:2, (93-102), Online publication date: 1-Apr-2006. Nicola P, Maradit-Kremers H, Roger V, Jacobsen S, Crowson C, Ballman K and Gabriel S (2005) The risk of congestive heart failure in rheumatoid arthritis: A population-based study over 46 years, Arthritis & Rheumatism, 10.1002/art.20855, 52:2, (412-420), Online publication date: 1-Feb-2005. Chirinos J, Zambrano J, Chakko S, Schob A, Veerani A, Perez G and Mendez A (2005) Usefulness of C-reactive protein as an independent predictor of death in patients with ischemic cardiomyopathy, The American Journal of Cardiology, 10.1016/j.amjcard.2004.08.065, 95:1, (88-90), Online publication date: 1-Jan-2005. Crespo Leiro M, Marzoa Rivas R, Paniagua Martn M and Castro Beiras A (2005) Miocardiopat?as: concepto, clasificaci?n. Miocardiopat?a dilatada idiop?tica, Medicine - Programa de Formaci?n M?dica Continuada Acreditado, 10.1016/S0211-3449(05)73800-5, 9:42, (2765-2774), Online publication date: 1-Oct-2005. Smith R, Jiang H and Sun Y (2005) Developments in ghrelin biology and potential clinical relevance, Trends in Endocrinology & Metabolism, 10.1016/j.tem.2005.09.004, 16:9, (436-442), Online publication date: 1-Nov-2005. Li W, Gavrila D, Liu X, Wang L, Gunnlaugsson S, Stoll L, McCormick M, Sigmund C, Tang C and Weintraub N (2004) Ghrelin Inhibits Proinflammatory Responses and Nuclear Factor-κB Activation in Human Endothelial Cells, Circulation, 109:18, (2221-2226), Online publication date: 11-May-2004. Rma v, AA V, HWM P, WH v and DJ v (2004) New Pharmacological Strategies in Chronic Heart Failure, Cardiovascular Drugs and Therapy, 10.1007/s10557-004-6227-x, 18:6, (491-501), Online publication date: 1-Nov-2004. Feingold K, Kim M, Shigenaga J, Moser A and Grunfeld C (2004) Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response, American Journal of Physiology-Endocrinology and Metabolism, 10.1152/ajpendo.00205.2003, 286:2, (E201-E207), Online publication date: 1-Feb-2004. Libera L and Vescovo G (2004) Muscle wastage in chronic heart failure, between apoptosis, catabolism and altered anabolism: a chimaeric view of inflammation?, Current Opinion in Clinical Nutrition & Metabolic Care, 10.1097/01.mco.0000134374.24181.5b, 7:4, (435-441), Online publication date: 1-Jul-2004. Ware L, Fang X and Matthay M (2003) Protein C and thrombomodulin in human acute lung injury, American Journal of Physiology-Lung Cellular and Molecular Physiology, 10.1152/ajplung.00442.2002, 285:3, (L514-L521), Online publication date: 1-Sep-2003. Hatoum O, Miura H and Binion D (2003) The vascular contribution in the pathogenesis of inflammatory bowel disease, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00552.2003, 285:5, (H1791-H1796), Online publication date: 1-Nov-2003. Yolanda M, Donosepoetro M, Santoso A and Arif M (2011) Association among Soluble Tumor Necrosis Factor Receptor I, Matrix Metalloproteinase-9, Procollagen C-terminal Propeptide type I, and N-Terminal proBrain Natriuretic Peptide in Heart Failure, The Indonesian Biomedical Journal, 10.18585/inabj.v3i1.136, 3:1, (64-9) Liuba I, Ahlmroth H, Jonasson L, Englund A, Jonsson A, Safstrom K and Walfridsson H (2008) Source of inflammatory markers in patients with atrial fibrillation, Europace, 10.1093/europace/eun111, 10:7, (848-853) Svetikienė M, Trybė D, Strioga M, Veželienė J, Isajevas V, Malickaitė R, Jurgauskienė L, Ringaitienė D, Šerpytis M and Šipylaitė J (2021) Impact of Immunonutrition on T Cell Activation: A Randomized Control Study in Cardiac Surgery Patients, Acta medica Lituanica, 10.15388/Amed.2021.28.2.16, 28:2, (16) March 25, 2003Vol 107, Issue 11 Advertisement Article InformationMetrics https://doi.org/10.1161/01.CIR.0000060808.79274.0CPMID: 12654598 Originally publishedMarch 25, 2003 Keywordsinterleukinstumor necrosis factorcytokinesheart failureEditorialsPDF download Advertisement
Referência(s)