Abstract
Besides regulating calcium-phosphate metabolism, fibroblast growth factor-23 (FGF23) and Klotho have been proposed to have other roles in heart and vasculature. For example, FGF23 has been associated with cardiac hypertrophy and reduced left ventricular ejection fraction among patients with chronic kidney disease and cardiovascular disorders. The purpose of the study was to investigate whether serum FGF23 and α-Klotho concentrations are associated with cardiac diastolic dysfunction and related parameters among cardiac patients with preserved left ventricular ejection fraction. The current study enrolled 269 patients (69 women, 200 men) who were admitted to our cardiology department between October 2012 and January 2014 and had a left ventricular ejection fraction of >50 %. Cardiac diastolic function was assessed by blood flow and tissue Doppler velocities, plasma B-type natriuretic peptide (BNP) concentration, and cardiac hypertrophy. After adjusting for sex, and age, logistic regression analysis showed that log(α-Klotho), but not log(FGF23), was significantly associated with diastolic dysfunction. After further adjustment for renal function, blood hemoglobin, and serum albumin levels, the negative association between log(α-Klotho) and diastolic dysfunction retained statistical significance with an odds ratio of 0.50 (95 % confidence interval 0.31–0.81, P = 0.005, per 1 standard deviation). Among patients with preserved LVEF, serum α-Klotho concentrations were negatively associated with diastolic dysfunction. Whether modulation of serum levels α-Klotho will ameliorate cardiac diastolic function among patients with this disorder awaits further investigation.
Similar content being viewed by others
References
Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T (2004) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435
Fukumoto S (2014) Phosphate metabolism and vitamin D. Bonekey Rep 3:497
Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444:770–774
Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M (2006) Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281:6120–6123
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51
Hu MC, Kuro-o M, Moe OW (2013) Renal and extrarenal actions of Klotho. Semin Nephrol 33:118–129
Ky B, Shults J, Keane MG, Sutton MS, Wolf M, Feldman HI, Reese PP, Anderson CA, Townsend RR, Deo R, Lo J, Gadegbeku C, Carlow D, Sulik MJ, Leonard MB (2013) FGF23 modifies the relationship between vitamin D and cardiac remodeling. Circ Heart Fail 6:817–824
Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutierrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John Sutton M, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro OM, Kusek JW, Keane MG, Wolf M (2011) FGF23 induces left ventricular hypertrophy. J Clin Invest 121:4393–4408
Seiler S, Rogacev KS, Roth HJ, Shafein P, Emrich I, Neuhaus S, Floege J, Fliser D, Heine GH (2014) Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2-4. Clin J Am Soc Nephrol 9:1049–1058
Xie J, Cha SK, An SW, Kuro OM, Birnbaumer L, Huang CL (2012) Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun 3:1238
Shibata K, Fujita S, Morita H, Okamoto Y, Sohmiya K, Hoshiga M, Ishizaka N (2013) Association between circulating fibroblast growth factor 23, alpha-Klotho, and the left ventricular ejection fraction and left ventricular mass in cardiology inpatients. PLoS One 8:e73184
Fujita S, Okamoto Y, Shibata K, Morita H, Ito T, Sohmiya K, Hoshiga M, Ishizaka N (2013) Serum uric acid is associated with left ventricular hypertrophy independent of serum parathyroid hormone in male cardiac patients. PLoS One 8:e82735
Matsubara T, Miyaki A, Akazawa N, Choi Y, Ra SG, Tanahashi K, Kumagai H, Oikawa S, Maeda S (2014) Aerobic exercise training increases plasma Klotho levels and reduces arterial stiffness in postmenopausal women. Am J Physiol Heart Circ Physiol 306:H348–H355
Kitzman DW, Daniel KR (2007) Diastolic heart failure in the elderly. Heart Fail Clin 3:437–453
Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53:982–992
Devereux RB, Reichek N (1977) Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation 55:613–618
Wachtell K, Bella JN, Liebson PR, Gerdts E, Dahlof B, Aalto T, Roman MJ, Papademetriou V, Ibsen H, Rokkedal J, Devereux RB (2000) Impact of different partition values on prevalences of left ventricular hypertrophy and concentric geometry in a large hypertensive population : the LIFE study. Hypertension 35:6–12
Roman MJ, Pickering TG, Schwartz JE, Pini R, Devereux RB (1996) Relation of arterial structure and function to left ventricular geometric patterns in hypertensive adults. J Am Coll Cardiol 28:751–756
Klapholz M, Maurer M, Lowe AM, Messineo F, Meisner JS, Mitchell J, Kalman J, Phillips RA, Steingart R, Brown EJ Jr, Berkowitz R, Moskowitz R, Soni A, Mancini D, Bijou R, Sehhat K, Varshneya N, Kukin M, Katz SD, Sleeper LA, Le Jemtel TH (2004) Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction: results of the New York Heart Failure Registry. J Am Coll Cardiol 43:1432–1438
Volpe M, McKelvie R, Drexler H (2010) Hypertension as an underlying factor in heart failure with preserved ejection fraction. J Clin Hypertens (Greenwich) 12:277–283
Negishi K, Kobayashi M, Ochiai I, Yamazaki Y, Hasegawa H, Yamashita T, Shimizu T, Kasama S, Kurabayashi M (2010) Association between fibroblast growth factor 23 and left ventricular hypertrophy in maintenance hemodialysis patients. Comparison with B-type natriuretic peptide and cardiac troponin T. Circ J 74:2734–2740
di Giuseppe R, Buijsse B, Hirche F, Wirth J, Arregui M, Westphal S, Isermann B, Hense HW, Dierkes J, Boeing H, Stangl GI, Weikert C (2013) Plasma fibroblast growth factor 23, parathyroid hormone, 25-hydroxyvitaminD3 and risk of heart failure: a prospective, case-cohort study. J Clin Endocrinol Metab jc20132963
Semba RD, Cappola AR, Sun K, Bandinelli S, Dalal M, Crasto C, Guralnik JM, Ferrucci L (2011) Plasma klotho and cardiovascular disease in adults. J Am Geriatr Soc 59:1596–1601
Song S, Gao P, Xiao H, Xu Y, Si LY (2013) Klotho suppresses cardiomyocyte apoptosis in mice with stress-induced cardiac injury via downregulation of endoplasmic reticulum stress. PLoS ONE 8:e82968
Kitagawa M, Sugiyama H, Morinaga H, Inoue T, Takiue K, Ogawa A, Yamanari T, Kikumoto Y, Uchida HA, Kitamura S, Maeshima Y, Nakamura K, Ito H, Makino H (2013) A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS One 8:e56695
Fernandes VR, Polak JF, Cheng S, Rosen BD, Carvalho B, Nasir K, McClelland R, Hundley G, Pearson G, O’Leary DH, Bluemke DA, Lima JA (2008) Arterial stiffness is associated with regional ventricular systolic and diastolic dysfunction: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol 28:194–201
Nair D, Shlipak MG, Angeja B, Liu HH, Schiller NB, Whooley MA (2005) Association of anemia with diastolic dysfunction among patients with coronary artery disease in the Heart and Soul Study. Am J Cardiol 95:332–336
Srivastava PM, Thomas MC, Calafiore P, MacIsaac RJ, Jerums G, Burrell LM (2006) Diastolic dysfunction is associated with anaemia in patients with Type II diabetes. Clin Sci (Lond) 110:109–116
Marechaux S, Six-Carpentier MM, Bouabdallaoui N, Montaigne D, Bauchart JJ, Mouquet F, Auffray JL, Le Tourneau T, Asseman P, LeJemtel TH, Ennezat PV (2011) Prognostic importance of comorbidities in heart failure with preserved left ventricular ejection fraction. Heart Vessels 26:313–320
Zhang Y, Safar ME, Iaria P, Agnoletti D, Protogerou AD, Blacher J (2010) Prevalence and prognosis of left ventricular diastolic dysfunction in the elderly: the PROTEGER study. Am Heart J 160:471–478
Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, Borbely A, Edes I, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG, Brutsaert DL (2007) How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 28:2539–2550
Jorge AJ, Ribeiro ML, Rosa ML, Licio FV, Fernandes LC, Lanzieri PG, Jorge BA, Brito FO, Mesquita ET (2012) Left atrium measurement in patients suspected of having heart failure with preserved ejection fraction. Arq Bras Cardiol 98:175–181
Masugata H, Senda S, Inukai M, Murao K, Tada S, Hosomi N, Iwado Y, Noma T, Kohno M, Himoto T, Goda F (2011) Association between high-sensitivity C-reactive protein and left ventricular diastolic function assessed by echocardiography in patients with cardiovascular risk factors. Tohoku J Exp Med 223:263–268
Perry GJ, Ahmed MI, Desai RV, Mujib M, Zile M, Sui X, Aban IB, Zhang Y, Tallaj J, Allman RM, Aronow WS, Fleg JL, Ahmed A (2011) Left ventricular diastolic function and exercise capacity in community-dwelling adults ≥65 years of age without heart failure. Am J Cardiol 108:735–740
Harada M, Hara F, Yamazaki J (2010) Correlation between plasma B-type natriuretic peptide levels and left ventricular diastolic function using color kinetic imaging. J Cardiol 56:91–96
Wan SH, Vogel MW, Chen HH (2014) Pre-clinical diastolic dysfunction. J Am Coll Cardiol 63:407–416
Kane GC, Karon BL, Mahoney DW, Redfield MM, Roger VL, Burnett JC Jr, Jacobsen SJ, Rodeheffer RJ (2011) Progression of left ventricular diastolic dysfunction and risk of heart failure. JAMA 306:856–863
Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ (2003) Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 289:194–202
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Okamoto, Y., Fujita, Si., Morita, H. et al. Association between circulating FGF23, α-Klotho, and left ventricular diastolic dysfunction among patients with preserved ejection fraction. Heart Vessels 31, 66–73 (2016). https://doi.org/10.1007/s00380-014-0581-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00380-014-0581-9