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Open Access 01-12-2022 | Research

Fibroblast growth factor 21 is associated with widening QRS complex and prolonged corrected QT interval in patients with stable angina

Authors: Wei-Chin Hung, Teng-Hung Yu, Chao-Ping Wang, Chia-Chang Hsu, Yung-Chuan Lu, Ching-Ting Wei, Fu-Mei Chung, Yau-Jiunn Lee, Cheng-Ching Wu, Wei-Hua Tang

Published in: BMC Cardiovascular Disorders | Issue 1/2022

Abstract

Background

Fibroblast growth factor 21 (FGF21) is produced by cardiac cells, may acts in an autocrine manner, and was suggested to has a cardioprotective role in atherosclerosis. Wide QRS complex and heart rate-corrected QT interval (QTc interval) prolongation are associated to dangerous ventricular arrhythmias and cardiovascular disease mortality. Yet, the role of FGF21 in cardiac arrhythmia has never been studied. The aim of the study was to investigate the relationship between plasma FGF21 and the QRS duration and QTc interval in patients with stable angina.

Methods

Three hundred twenty-one consecutive stable angina patients were investigated. Plasma FGF21 was measured through ELISA, and each subject underwent 12-lead electrocardiography.

Results

FGF21 plasma levels were positively associated with the QRS duration (β = 0.190, P = 0.001) and QTc interval (β = 0.277, P < 0.0001). With increasing FGF21 tertiles, the patients had higher frequencies of wide QRS complex and prolonged QTc interval. After adjusting for patients’ anthropometric parameters, the corresponding odd ratios (ORs) for wide QRS complex of the medium and high of FGF21 versus the low of FGF21 were 1.39 (95% CI 0.51–3.90) and 4.41 (95% CI 1.84–11.59), respectively, and p for trend was 0.001. Furthermore, multiple logistic regression analysis also showed the corresponding odd ratios (ORs) for prolonged QTc interval of the medium and high of FGF21 versus the low of FGF21 were 1.02 (95% CI 0.53–1.78) and 1.93 (95% CI 1.04–3.60) respectively with the p for trend of 0.037. In addition, age- and sex-adjusted FGF21 levels were positively associated with fasting glucose, HbA1c, creatinine, and adiponectin, but negatively associated with albumin, and the estimated glomerular filtration rate.

Conclusions

This study indicates that plasma FGF21 is associated with wide QRS complex and prolonged corrected QT interval in stable angina patients, further study is required to investigate the role of plasma FGF21 for the underlying pathogenesis.

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Benchimol D, Dubroca B, Bernard V, Lavie J, Paviot B, Benchimol H, et al. Short- and long-term risk factors for sudden death in patients with stable angina. Int J Cardiol. 2000;76:147–56.PubMedCrossRef

Narayanan K, Chugh SS. The 12-lead electrocardiogram and risk of sudden death: current utility and future prospects. Europace. 2015;17(Suppl 2):7–13.CrossRef

Cuddy TE, Tate RB. Sudden unexpected cardiac death as a function of time since the detection of electrocardiographic and clinical risk factors in apparently healthy men: the Manitoba follow-up study, 1948 to 2004. Can J Cardiol. 2006;22:205–11.PubMedPubMedCentralCrossRef

Ohkubo K, Watanabe I, Okumura Y, Ashino S, Kofune M, Nagashima K, et al. Prolonged QRS duration in lead V2 and risk of life-threatening ventricular Arrhythmia in patients with Brugada syndrome. Int Heart J. 2011;52:98–102.PubMedCrossRef

Moss AJ. Measurement of the QT interval and the risk associated with QTc interval prolongation: a review. Am J Cardiol. 1993;72:23B-25B.PubMedCrossRef

Passman R, Kadish A. Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes. Med Clin North Am. 2001;85:321–41.PubMedCrossRef

Wang NC, Maggioni AP, Konstam MA, Zannad F, Krasa HB, Burnett JC Jr, et al. Efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan (EVEREST) investigators. Clinical implications of QRS duration in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction. JAMA. 2008;299:2656–66.PubMedCrossRef

Robbins J, Nelson JC, Rautaharju PM, Gottdiener JS. The association between the length of the QT interval and mortality in the cardiovascular health study. Am J Med. 2003;115:689–94.PubMedCrossRef

Planavila A, Redondo-Angulo I, Villarroya F. FGF21 and cardiac physiopathology. Front Endocrinol. 2015;6:133.CrossRef

10.

Zhang J, Li Y. Fibroblast growth factor 21, the endocrine FGF pathway and novel treatments for metabolic syndrome. Drug Discov Today. 2014;19:579–89.PubMedCrossRef

11.

Tanajak P, Chattipakorn SC, Chattipakorn N. Effects of fibroblast growth factor 21 on the heart. J Endocrinol. 2015;227:R13-30.PubMedCrossRef

12.

Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 2007;5:426–37.PubMedCrossRef

13.

Kharitonenkov A, Dunbar JD, Bina HA, Bright S, Moyers JS, Zhang C, et al. FGF-21/FGF-21 receptor interaction and activation is determined by betaKlotho. J Cell Physiol. 2008;215:1–7.PubMedCrossRef

14.

Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. FGF-21 as a novel metabolic regulator. J Clin Invest. 2005;115:1627–35.PubMedPubMedCentralCrossRef

15.

Sarruf DA, Thaler JP, Morton GJ, German J, Fischer JD, Ogimoto K, et al. Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes. 2010;59:1817–24.PubMedPubMedCentralCrossRef

16.

Planavila A, Redondo I, Hondares E, Vinciguerra M, Munts C, Iglesias R, et al. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun. 2013;4:2019.PubMedCrossRef

17.

Li J, Xu C, Liu Y, Li Y, Du S, Zhang R, et al. Fibroblast growth factor 21 inhibited ischemic arrhythmias via targeting miR-143/EGR1 axis. Basic Res Cardiol. 2020;115:9.PubMedCrossRef

18.

Yan X, Chen J, Zhang C, Zhou S, Zhang Z, Chen J, et al. FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation. J Cell Mol Med. 2015;19:1557–68.PubMedPubMedCentralCrossRef

19.

Joki Y, Ohashi K, Yuasa D, Shibata R, Ito M, Matsuo K, et al. FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism. Biochem Biophys Res Commun. 2015;459:124–30.PubMedCrossRef

20.

Chou RH, Huang PH, Hsu CY, Chang CC, Leu HB, Huang CC, et al. Circulating fibroblast growth factor 21 is associated with diastolic dysfunction in heart failure patients with preserved ejection fraction. Sci Rep. 2016;6:33953.PubMedPubMedCentralCrossRef

21.

Shen Y, Zhang X, Xu Y, Xiong Q, Lu Z, Ma X, et al. Serum FGF21 is associated with future cardiovascular events in patients with coronary artery disease. Cardiology. 2018;139:212–8.PubMedCrossRef

22.

Shen Y, Zhang X, Pan X, Xu Y, Xiong Q, Lu Z, et al. Contribution of serum FGF21 level to the identification of left ventricular systolic dysfunction and cardiac death. Cardiovasc Diabetol. 2017;16:106.PubMedPubMedCentralCrossRef

23.

Wang CP, Lu LF, Yu TH, Hung WC, Chiu CA, Chung FM, et al. Serum levels of total p-cresylsulphate are associated with angiographic coronary atherosclerosis severity in stable angina patients with early stage of renal failure. Atherosclerosis. 2010;211:579–83.PubMedCrossRef

24.

Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations. A report of the American college of cardiology/american heart association task force on practice guidelines (Committee on management of patients with chronic stable Angina). Circulation. 1999;99:2829–48.PubMedCrossRef

25.

The thrombolysis in myocardial infarction (TIMI) trial. Phase I findings. TIMI study group. N Engl J Med. 1985;312:932–6.

26.

Tang WH, Wang CP, Chung FM, Huang LLH, Yu TH, Hung WC, et al. Uremic retention solute indoxyl sulfate level is associated with prolonged QTc interval in early CKD patients. PLoS One. 2015;10: e0119545.PubMedPubMedCentralCrossRef

27.

American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2012;35(Suppl 1):S64–71.CrossRef

28.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult treatment panel III). JAMA. 2001;285:2486–97.CrossRef

29.

Levy D, Savage DD, Garrison RJ, Anderson KM, Kannel WB, Castelli WP. Echocardiographic criteria for left ventricular hypertrophy: the Framingham heart study. Am J Cardiol. 1987;59:956–60.PubMedCrossRef

30.

Kong X, Ma Y, Chen J, Luo Q, Yu X, Li Y, et al. Chinese eGFR Investigation Collaboration. Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating glomerular filtration rate in the Chinese population. Nephrol Dial Transplant. 2013;28:641–51.PubMedCrossRef

31.

Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol. 1983;51:606.PubMedCrossRef

32.

Friedman HH. Diagnostic electrocardiography and vectorcardiography. New York: McGraw-Hill; 1971.

33.

Sokolow M, Lyon TO. The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J. 1949;37:161–86.PubMedCrossRef

34.

Maron BJ, Wolfson JK, Ciró E, Spirito P. Relation of electrocardiographic abnormalities and patterns of left ventricular hypertrophy identified by 2-dimensional echocardiography in patients with hypertrophic cardiomyopathy. Am J Cardiol. 1983;51:189–94.PubMedCrossRef

35.

Salvi V, Karnad DR, Panicker GK, Natekar M, Hingorani P, Kerkar V, et al. Comparison of 5 methods of QT interval measurements on electrocardiograms from a thorough QT/QTc study: effect on assay sensitivity and categorical outliers. J Electrocardiol. 2011;44:96–104.PubMedCrossRef

36.

Malik M, Hnatkova K, Batchvarov V, Gang Y, Smetana P, Camm AJ. Sample size, power calculations, and their implications for the cost of thorough studies of drug induced QT interval prolongation. Pacing Clin Electrophysiol. 2004;27:1659–69.PubMedCrossRef

37.

Straus SM, Kors JA, De Bruin ML, van der Hooft CS, Hofman A, Heeringa J, et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol. 2006;47:362–7.PubMedCrossRef

38.

Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS, et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes. 2010;59:2781–9.PubMedPubMedCentralCrossRef

39.

Patel V, Adya R, Chen J, Ramanjaneya M, Bari MF, Bhudia SK, et al. Novel insights into the cardio-protective effects of FGF21 in lean and obese rat hearts. PLoS One. 2014;9: e87102.PubMedPubMedCentralCrossRef

40.

Shen Y, Ma X, Zhou J, Pan X, Hao Y, Zhou M, et al. Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease. Cardiovasc Diabetol. 2013;12:124.PubMedPubMedCentralCrossRef

41.

Lin Z, Wu Z, Yin X, Liu Y, Yan X, Lin S, et al. Serum levels of FGF-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile. PLoS One. 2010;5: e15534.PubMedPubMedCentralCrossRef

42.

Lee Y, Lim S, Hong ES, Kim JH, Moon MK, Chun EJ, et al. Serum FGF21 concentration is associated with hypertriglyceridaemia, hyperinsulinaemia and pericardial fat accumulation, independently of obesity, but not with current coronary artery status. Clin Endocrinol. 2014;80:57–64.CrossRef

43.

Lenart-Lipińska M, Matyjaszek-Matuszek B, Gernand W, Nowakowski A, Solski J. Serum fibroblast growth factor 21 is predictive of combined cardiovascular morbidity and mortality in patients with type 2 diabetes at a relatively short-term follow-up. Diabetes Res Clin Pract. 2013;101:194–200.PubMedCrossRef

44.

Tucker B, Li H, Long X, Rye KA, Ong KL. Fibroblast growth factor 21 in non-alcoholic fatty liver disease. Metabolism. 2019;101: 153994.PubMedCrossRef

45.

Itoh N, Ohta H, Nakayama Y, Konishi M. Roles of FGF signals in heart development, health, and disease. Front Cell Dev Biol. 2016;4:110.PubMedPubMedCentral

46.

Cheng P, Zhang F, Yu L, Lin X, He L, Li X, et al. Physiological and pharmacological roles of FGF21 in cardiovascular diseases. J Diabetes Res. 2016;2016:1540267.PubMedPubMedCentralCrossRef

47.

Dzikowicz DJ, Carey MG. Obesity and hypertension contribute to prolong QRS complex duration among middle-aged adults. Ann Noninvasive Electrocardiol. 2019;24: e12665.PubMedPubMedCentralCrossRef

48.

Devi MR, Arvind T, Kumar PS. ECG changes in smokers and non smokers-a comparative study. J Clin Diagn Res. 2013;7:824–6.PubMedPubMedCentral

49.

Lira MMP, de Medeiros Filho JEM, Baccin Martins VJ, da Silva G, de Oliveira Junior FA, de Almeida Filho ÉJB, et al. Association of worsening of nonalcoholic fatty liver disease with cardiometabolic function and intestinal bacterial overgrowth: a cross-sectional study. PLoS One. 2020;15: e0237360.PubMedPubMedCentralCrossRef

50.

Grisanti LA. Diabetes and arrhythmias: pathophysiology, mechanisms and therapeutic outcomes. Front Physiol. 2018;9:1669.PubMedPubMedCentralCrossRef

51.

Elffers TW, de Mutsert R, Lamb HJ, Maan AC, Macfarlane PW, Willems van Dijk K, et al. Association of metabolic syndrome and electrocardiographic markers of subclinical cardiovascular disease. Diabetol Metab Syndr. 2017. https://doi.org/10.1186/s13098-017-0238-9.CrossRefPubMedPubMedCentral

52.

Kashani A, Barold SS. Significance of QRS complex duration in patients with heart failure. J Am Coll Cardiol. 2005;46:2183–92.PubMedCrossRef

53.

Thomsen MB, Nielsen MS, Aarup A, Bisgaard LS, Pedersen TX. Uremia increases QRS duration after β-adrenergic stimulation in mice. Physiol Rep. 2018;6: e13720.PubMedPubMedCentralCrossRef

54.

Cetin M, Kocaman SA, Canga A, Durakoglugil ME, Erdogan T, Satiroglu O, et al. The independent relationship between systemic inflammation and fragmented QRS complexes in patients with stable angina pectoris. Kardiol Pol. 2012;70:668–75.PubMed

55.

Woo YC, Xu A, Wang Y, Lam KS. Fibroblast growth factor 21 as an emerging metabolic regulator: clinical perspectives. Clin Endocrinol. 2013;78:489–96.CrossRef

56.

Nakanishi K, Ishibashi C, Ide S, Yamamoto R, Nishida M, Nagatomo I, et al. Serum FGF21 levels are altered by various factors including lifestyle behaviors in male subjects. Sci Rep. 2021;11:22632.PubMedPubMedCentralCrossRef

57.

Lin Z, Pan X, Wu F, Ye D, Zhang Y, Wang Y, et al. Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice. Circulation. 2015;131:1861–71.PubMedPubMedCentralCrossRef

58.

Yılmaz AS, Çinier G, Çırakoğlu ÖF, Çetin M. Epicardial adipose tissue predicted prolonged QTc interval in patients with arterial hypertension. Clin Exp Hypertens. 2021;43:230–6.PubMedCrossRef

59.

Liu WY, Huang S, Shi KQ, Zhao CC, Chen LL, Braddock M, et al. The role of fibroblast growth factor 21 in the pathogenesis of liver disease: a novel predictor and therapeutic target. Expert Opin Ther Targets. 2014;18:1305–13.PubMedCrossRef

60.

Luo Y, Lu W. Serum levels of FGF21 and prediction of cardiovascular events. Cardiology. 2018;139:219–21.PubMedCrossRef

61.

Chow WS, Xu A, Woo YC, Tso AW, Cheung SC, Fong CH, et al. Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors. Arterioscler Thromb Vasc Biol. 2013;33:2454–9.PubMedCrossRef

62.

Xiao Y, Liu L, Xu A, Zhou P, Long Z, Tu Y, et al. Serum fibroblast growth factor 21 levels are related to subclinical atherosclerosis in patients with type 2 diabetes. Cardiovasc Diabetol. 2015;14:72.PubMedPubMedCentralCrossRef

63.

Zhang W, Chu S, Ding W, Wang F. Serum level of fibroblast growth factor 21 is independently associated with acute myocardial infarction. PLoS One. 2015;10: e0129791.PubMedPubMedCentralCrossRef

64.

An SY, Lee MS, Yi SA, Ha ES, Han SJ, Kim HJ, et al. Serum fibroblast growth factor 21 was elevated in subjects with type 2 diabetes mellitus and was associated with the presence of carotid artery plaques. Diabetes Res Clin Pract. 2012;96:196–203.PubMedCrossRef

65.

Yan X, Chen J, Zhang C, Zeng J, Zhou S, Zhang Z, et al. Fibroblast growth factor 21 deletion aggravates diabetes-induced pathogenic changes in the aorta in type 1 diabetic mice. Cardiovasc Diabetol. 2015;14:77.PubMedPubMedCentralCrossRef

66.

Goetz R. Metabolism: Adiponectin-a mediator of specific metabolic actions of FGF21. Nat Rev Endocrinol. 2013;9:506–8.PubMedCrossRef

67.

Wu CC, Chang CS, Hsu CC, Wang CP, Tsai IT, Lu YC, et al. Elevated plasma adiponectin levels are associated with abnormal corrected QT interval in patients with stable angina. Int Heart J. 2020;61:29–38.PubMedCrossRef

68.

Matsumoto T, Ohnishi H, Sato T, Miki T, Akasaka H, Hanawa N, et al. Insulin resistance is associated with longitudinal changes of cardiac repolarization heterogeneity in apparently healthy subjects. Cardiol Ther. 2019;8:239–51.PubMedCentralCrossRef

69.

Correa R, Arini PD, Correa LS, Valentinuzzi M, Laciar E. Novel technique for ST-T interval characterization in patients with acute myocardial ischemia. Comput Biol Med. 2014;50:49–55.PubMedCrossRef

70.

Tikkanen JT, Kenttä T, Porthan K, Huikuri HV, Junttila MJ. Electrocardiographic T wave abnormalities and the risk of sudden cardiac death: the finnish perspective. Ann Noninvasive Electrocardiol. 2015;20:526–33.PubMedPubMedCentralCrossRef

Title: Fibroblast growth factor 21 is associated with widening QRS complex and prolonged corrected QT interval in patients with stable angina
Authors: Wei-Chin Hung
Teng-Hung Yu
Chao-Ping Wang
Chia-Chang Hsu
Yung-Chuan Lu
Ching-Ting Wei
Fu-Mei Chung
Yau-Jiunn Lee
Cheng-Ching Wu
Wei-Hua Tang
Publication date: 01-12-2022
Publisher: BioMed Central
Published in: BMC Cardiovascular Disorders / Issue 1/2022
Electronic ISSN: 1471-2261
DOI: https://doi.org/10.1186/s12872-022-02868-3

2024 ASCO Annual Meeting

Springer Medicine

Fibroblast growth factor 21 is associated with widening QRS complex and prolonged corrected QT interval in patients with stable angina

Abstract

Background

Methods

Results

Conclusions

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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