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Association between serum Klotho concentration and heart failure in adults, a cross-sectional study from NHANES 2007–2016

  • Author Footnotes
    1 These authors contributed equally to the work.
    Jiasheng Cai
    Footnotes
    1 These authors contributed equally to the work.
    Affiliations
    Departments of Cardiology, Fudan University Zhongshan Hospital, Qingpu Branch, 1158 Park East Road, Shanghai 60518120, China
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  • Author Footnotes
    1 These authors contributed equally to the work.
    Lingyun Zhang
    Footnotes
    1 These authors contributed equally to the work.
    Affiliations
    Department of Nephrology, Huadong Hospital affiliated to Fudan University, 221 Yanan West Road, Shanghai 200040, China
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  • Author Footnotes
    1 These authors contributed equally to the work.
    Conggai Chen
    Footnotes
    1 These authors contributed equally to the work.
    Affiliations
    Department of Stroke Center, the First Affiliated Hospital of Soochow University, 188 Shizi Street Suzhou, Jiangsu Province 215006, China
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  • Jin Ge
    Affiliations
    Department of General medicine, Renji Hospital affiliated to JiaoTong University, 1630 Pujian Road, Shanghai 200127, China
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  • Mingxuan Li
    Affiliations
    Departments of Cardiology, Fudan University Zhongshan Hospital, Qingpu Branch, 1158 Park East Road, Shanghai 60518120, China
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  • Yi Zhang
    Affiliations
    Departments of Cardiology, Fudan University Zhongshan Hospital, Qingpu Branch, 1158 Park East Road, Shanghai 60518120, China
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  • Haibo Liu
    Affiliations
    Departments of Cardiology, Fudan University Zhongshan Hospital, Qingpu Branch, 1158 Park East Road, Shanghai 60518120, China
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  • Bin Song
    Correspondence
    Corresponding author: Department of Chronic Diseases Management, Clinical Medical College, Yangzhou University, 98 Nantong West Road, Yangzhou 225001, China.
    Affiliations
    Department of Chronic Diseases Management, Clinical Medical College, Yangzhou University, 98 Nantong West Road, Yangzhou 225001, China
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  • Author Footnotes
    1 These authors contributed equally to the work.
Published:November 06, 2022DOI:https://doi.org/10.1016/j.ijcard.2022.11.010

      Highlights

      • Limited data exists on the association between serum Klotho concentration and heart failure;
      • Serum Klotho concentration was negatively associated with the presence of heart failure in middle-aged and older adults;
      • The soluble Klotho might protect the diseased heart and ameliorates symptoms among patients with heart failure;
      • Jiasheng Cai isresponsible for data curation, formal analysis and writing original draft; Lingyun Zhang and Conggai Chen contributed tothe data curation, investigation, and formal analysis equal

      Abstract

      Background

      Limited data exist on the association between serum Klotho concentration and heart failure (HF).

      Methods and results

      We conducted a cross-sectional study of 13,625 participants aged 40–79 years in the National Health and Nutrition Examination Survey (NHANES) 2007–2016. Multivariable logistic regression models were used to examine the association between serum Klotho concentration (ln transformation) and HF. A total of 533 (2.9%) participants were identified to have HF, and participants with the lowest tertiles of serum Klotho concentration had the highest percentage of HF (T1: 3.8% vs. T2: 2.8% and T3: 2.1%, P < 0.001). After adjusting for potential confounders, ln (Klotho) was negatively and independently associated with the risk of HF (OR= 0.55, 95% CI 0.36–0.84). Meanwhile, compared with the T1 group, a higher serum Klotho concentration was associated with a lower risk of HF (tertile 2: OR = 0.93, 95% CI: 0.69–1.29, tertile 3: OR = 0.75, 95% CI: 0.52–1.09, P for trend 0.022). Finally, subgroup analyses indicated that lower Klotho concentrations significantly correlated with an increased risk of HF in half of the subgroups.

      Conclusion

      Serum Klotho concentration was consistently and negatively associated with the presence of HF among US middle-aged and older adults.

      Keywords

      Abbreviations:

      Klotho (soluble α-Klotho), HF (heart failure), CHF (chronic heart failure), AHF (acute heart failure), CHD (coronary heart disease), AP (angina pectoris), MI (myocardial infarction), CVDs (cardiovascular diseases), CKD (chronic kidney disease), BMI (body mass index), eGFR (glomerular filtration rate), TC (total cholesterol), TG (triglycerides), Cr (serum creatinine), BUN (blood urea nitrogen), UA (uric acid), K (serum potassium), Na (serum sodium), P (serum phosphorus), Hg (hemoglobin), WBC (white blood cell)
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      References

        • Miura S.
        • Yoshihisa A.
        • Takiguchi M.
        • Shimizu T.
        • Nakamura Y.
        • Yamauchi H.
        • et al.
        Association of Hypocalcemia with Mortality in hospitalized patients with heart failure and chronic kidney disease.
        J. Card. Fail. 2015; 21: 621-627
        • McDonagh T.A.
        • Metra M.
        • Adamo M.
        • Gardner R.S.
        • Baumbach A.
        • Böhm M.
        • et al.
        2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure.
        Eur. Heart J. 2021; 42: 3599-3726
        • Welsh P.
        • Kou L.
        • Yu C.
        • Anand I.
        • van Veldhuisen D.J.
        • Maggioni A.P.
        • et al.
        Prognostic importance of emerging cardiac, inflammatory, and renal biomarkers in chronic heart failure patients with reduced ejection fraction and anaemia: RED-HF study.
        Eur. J. Heart Fail. 2018; 20: 268-277
        • Greene S.J.
        • Butler J.
        • Fonarow G.C.
        • Subacius H.P.
        • Ambrosy A.P.
        • Vaduganathan M.
        • et al.
        Pre-discharge and early post-discharge troponin elevation among patients hospitalized for heart failure with reduced ejection fraction: findings from the ASTRONAUT trial.
        Eur. J. Heart Fail. 2018; 20: 281-291
        • Demissei B.G.
        • Postmus D.
        • Cleland J.G.
        • O’Connor C.M.
        • Metra M.
        • Ponikowski P.
        • et al.
        Plasma biomarkers to predict or rule out early post-discharge events after hospitalization for acute heart failure.
        Eur. J. Heart Fail. 2017; 19: 728-738
        • Kurosu H.
        • Yamamoto M.
        • Clark J.D.
        • Pastor J.V.
        • Nandi A.
        • Gurnani P.
        • et al.
        Suppression of aging in mice by the hormone klotho.
        Science. 2005; 309: 1829-1833
        • Poelzl G.
        • Ghadge S.K.
        • Messner M.
        • Haubner B.
        • Wuertinger P.
        • Griesmacher A.
        • et al.
        Klotho is upregulated in human cardiomyopathy independently of circulating klotho levels.
        Sci. Rep. 2018; 8: 8429
        • Bergmark B.A.
        • Udell J.A.
        • Morrow D.A.
        • Jarolim P.
        • Kuder J.F.
        • Solomon S.D.
        • et al.
        Klotho, fibroblast growth factor-23, and the renin-angiotensin system - an analysis from the PEACE trial.
        Eur. J. Heart Fail. 2019; 21: 462-470
        • Hu M.C.
        • Shi M.
        • Gillings N.
        • Flores B.
        • Takahashi M.
        • Kuro-O M.
        • et al.
        Recombinant α-klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy.
        Kidney Int. 2017; 91: 1104-1114
        • Nie F.
        • Wu D.
        • Du H.
        • Yang X.
        • Yang M.
        • Pang X.
        • et al.
        Serum klotho protein levels and their correlations with the progression of type 2 diabetes mellitus.
        J. Diabetes Complicat. 2017; 31: 594-598
        • Kuro O.M.
        The klotho proteins in health and disease.
        Nat. Rev. Nephrol. 2019; 15: 27-44
        • Ter Braake A.D.
        • Smit A.E.
        • Bos C.
        • van Herwaarden A.E.
        • Alkema W.
        • van Essen H.W.
        • et al.
        Magnesium prevents vascular calcification in klotho deficiency.
        Kidney Int. 2020; 97: 487-501
        • Lanzani C.
        • Citterio L.
        • Vezzoli G.
        Klotho: a link between cardiovascular and non-cardiovascular mortality.
        Clin. Kidney J. 2020; 13: 926-932
        • Cianciolo G.
        • Galassi A.
        • Capelli I.
        • Schillaci R.
        • La Manna G.
        • Cozzolino M.
        Klotho-FGF23, cardiovascular disease, and vascular calcification: black or white?.
        Curr. Vasc. Pharmacol. 2018; 16: 143-156
        • von Jeinsen B.
        • Sopova K.
        • Palapies L.
        • Leistner D.M.
        • Fichtlscherer S.
        • Seeger F.H.
        • et al.
        Bone marrow and plasma FGF-23 in heart failure patients: novel insights into the heart-bone axis.
        ESC Heart Fail. 2019; 6: 536-544
        • Taneike M.
        • Nishida M.
        • Nakanishi K.
        • Sera F.
        • Kioka H.
        • Yamamoto R.
        • et al.
        Alpha-klotho is a novel predictor of treatment responsiveness in patients with heart failure.
        Sci. Rep. 2021; 11: 2058
        • Xu C.
        • Liang J.
        • Xu S.
        • Liu Q.
        • Xu J.
        • Gu A.
        Increased serum levels of aldehydes are associated with cardiovascular disease and cardiovascular risk factors in adults.
        J. Hazard. Mater. 2020; 400123134
        • Yao X.
        • Xu X.
        • Jin F.
        • Zhu Z.
        The correlation of type 2 diabetes status with bone mineral density in middle-aged adults.
        Diabetes Metab Syndr Obes. 2020; 13: 3269-3276
        • Yamazaki Y.
        • Imura A.
        • Urakawa I.
        • Shimada T.
        • Murakami J.
        • Aono Y.
        • et al.
        Establishment of sandwich ELISA for soluble alpha-klotho measurement: age-dependent change of soluble alpha-klotho levels in healthy subjects.
        Biochem. Biophys. Res. Commun. 2010; 398: 513-518
        • Sattler E.L.P.
        • Ishikawa Y.
        • Trivedi-Kapoor R.
        • Zhang D.
        • Quyyumi A.A.
        • Dunbar S.B.
        Association between the prognostic nutritional index and dietary intake in community-dwelling older adults with heart failure: findings from NHANES III.
        Nutrients. 2019; : 11
        • Levey A.S.
        • Stevens L.A.
        • Schmid C.H.
        • Zhang Y.L.
        • Castro 3rd, A.F.
        • Feldman H.I.
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann. Intern. Med. 2009; 150: 604-612
        • Jaddoe V.W.
        • de Jonge L.L.
        • Hofman A.
        • Franco O.H.
        • Steegers E.A.
        • Gaillard R.
        First trimester fetal growth restriction and cardiovascular risk factors in school age children: population based cohort study.
        Bmj. 2014; 348g14
        • Truby L.K.
        • Rogers J.G.
        Advanced heart failure: epidemiology, diagnosis, and therapeutic approaches.
        JACC Heart Fail. 2020; 8: 523-536
        • Regan J.A.
        • Kitzman D.W.
        • Leifer E.S.
        • Kraus W.E.
        • Fleg J.L.
        • Forman D.E.
        • et al.
        Impact of age on comorbidities and outcomes in heart failure with reduced ejection fraction.
        JACC Heart Fail. 2019; 7: 1056-1065
        • Bohula E.A.
        • Wiviott S.D.
        • McGuire D.K.
        • Inzucchi S.E.
        • Kuder J.
        • Im K.
        • et al.
        Cardiovascular safety of Lorcaserin in overweight or obese patients.
        N. Engl. J. Med. 2018; 379: 1107-1117
        • Fukui A.
        • Kaneko H.
        • Okada A.
        • Yano Y.
        • Itoh H.
        • Matsuoka S.
        • et al.
        Semiquantitative assessed proteinuria and risk of heart failure: analysis of a nationwide epidemiological database.
        Nephrol. Dial. Transplant. 2022; 37: 1691-1699
        • Kuro-o M.
        • Matsumura Y.
        • Aizawa H.
        • Kawaguchi H.
        • Suga T.
        • Utsugi T.
        • et al.
        Mutation of the mouse klotho gene leads to a syndrome resembling ageing.
        Nature. 1997; 390: 45-51
        • Shimada T.
        • Kakitani M.
        • Yamazaki Y.
        • Hasegawa H.
        • Takeuchi Y.
        • Fujita T.
        • et al.
        Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism.
        J. Clin. Invest. 2004; 113: 561-568
        • Kawarazaki W.
        • Mizuno R.
        • Nishimoto M.
        • Ayuzawa N.
        • Hirohama D.
        • Ueda K.
        • et al.
        Salt causes aging-associated hypertension via vascular Wnt5a under klotho deficiency.
        J. Clin. Invest. 2020; 130: 4152-4166
        • Pan Q.
        • Lin S.
        • Li Y.
        • Liu L.
        • Li X.
        • Gao X.
        • et al.
        A novel GLP-1 and FGF21 dual agonist has therapeutic potential for diabetes and non-alcoholic steatohepatitis.
        EBioMedicine. 2021; 63103202
        • Zhao Y.
        • Zeng C.Y.
        • Li X.H.
        • Yang T.T.
        • Kuang X.
        • Du J.R.
        Klotho overexpression improves amyloid-β clearance and cognition in the APP/PS1 mouse model of Alzheimer’s disease.
        Aging Cell. 2020; 19e13239
        • Shi M.
        • Flores B.
        • Gillings N.
        • Bian A.
        • Cho H.J.
        • Yan S.
        • et al.
        αKlotho mitigates progression of AKI to CKD through activation of autophagy.
        J. Am. Soc. Nephrol. 2016; 27: 2331-2345
        • de Borst M.H.
        • Vervloet M.G.
        • ter Wee P.M.
        • Navis G.
        Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease.
        J. Am. Soc. Nephrol. 2011; 22: 1603-1609
        • Kanbay M.
        • Demiray A.
        • Afsar B.
        • Covic A.
        • Tapoi L.
        • Ureche C.
        • et al.
        Role of klotho in the development of essential hypertension.
        Hypertension. 2021; 77: 740-750
        • Okamoto Y.
        • Fujita S.
        • Morita H.
        • Kizawa S.
        • Ito T.
        • Sakane K.
        • et al.
        Association between circulating FGF23, α-klotho, and left ventricular diastolic dysfunction among patients with preserved ejection fraction.
        Heart Vessel. 2016; 31: 66-73
        • Poveda J.
        • Vázquez-Sánchez S.
        • Sanz A.B.
        • Ortiz A.
        • Ruilope L.M.
        • Ruiz-Hurtado G.
        TWEAK-Fn14 as a common pathway in the heart and the kidneys in cardiorenal syndrome.
        J. Pathol. 2021; 254: 5-19
        • Cosentino N.
        • Resta M.L.
        • Somaschini A.
        • Campodonico J.
        • Lucci C.
        • Moltrasio M.
        • et al.
        Acute kidney injury and in-hospital mortality in patients with ST-elevation myocardial infarction of different age groups.
        Int. J. Cardiol. 2021; 344
        • Chen K.
        • Wang S.
        • Sun Q.W.
        • Zhang B.
        • Ullah M.
        • Sun Z.
        Klotho deficiency causes heart aging via impairing the Nrf2-GR pathway.
        Circ. Res. 2021; 128: 492-507
        • Ding J.
        • Tang Q.
        • Luo B.
        • Zhang L.
        • Lin L.
        • Han L.
        • et al.
        Klotho inhibits angiotensin II-induced cardiac hypertrophy, fibrosis, and dysfunction in mice through suppression of transforming growth factor-β1 signaling pathway.
        Eur. J. Pharmacol. 2019; 859172549
        • Seiler S.
        • Rogacev K.S.
        • Roth H.J.
        • Shafein P.
        • Emrich I.
        • Neuhaus S.
        • et al.
        Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2-4.
        Clin. J. Am. Soc. Nephrol. 2014; 9: 1049-1058
        • Schwantes-An T.H.
        • Liu S.
        • Stedman M.
        • Decker B.S.
        • Wetherill L.
        • Edenberg H.J.
        • et al.
        Fibroblast growth factor 23 genotype and cardiovascular disease in patients undergoing Hemodialysis.
        Am. J. Nephrol. 2019; 49: 125-132
        • Nowak A.
        • Friedrich B.
        • Artunc F.
        • Serra A.L.
        • Breidthardt T.
        • Twerenbold R.
        • et al.
        Prognostic value and link to atrial fibrillation of soluble klotho and FGF23 in hemodialysis patients.
        PLoS One. 2014; 9e100688
        • Paula R.S.
        • Souza V.C.
        • Machado-Silva W.
        • Almeida B.R.
        • Daros A.C.
        • Gomes L.
        • et al.
        Serum klotho (but not haplotypes) associate with the post-myocardial infarction status of older adults.
        Clinics (Sao Paulo). 2016; 71: 725-732
        • Sahu A.
        • Mamiya H.
        • Shinde S.N.
        • Cheikhi A.
        • Winter L.L.
        • Vo N.V.
        • et al.
        Age-related declines in α-klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration.
        Nat. Commun. 2018; 9: 4859
        • Maekawa Y.
        • Ishikawa K.
        • Yasuda O.
        • Oguro R.
        • Hanasaki H.
        • Kida I.
        • et al.
        Klotho suppresses TNF-alpha-induced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation.
        Endocrine. 2009; 35: 341-346
        • Hu M.-C.
        • Shi M.
        • Zhang J.
        • Quiñones H.
        • Kuro-o M.
        • Moe O.W.
        Klotho deficiency is an early biomarker of renal ischemia-reperfusion injury and its replacement is protective.
        Kidney Int. 2010; 78: 1240-1251
        • Hu M.-C.
        • Kuro-o M.
        • Moe O.W.
        Klotho and kidney disease.
        J Nephrol. 2010; 23 (S136-S44)