DOI: 10.1161/CIRCULATIONAHA.113.005499
Fibroblast Growth Factor-23 and Incident Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS) Running title: Mathew et al.; FGF-23 and Atrial Fibrillation Jehu S. Mathew, MD1,2; Michael C. Sachs, PhD2; Ronit Katz, DPhil2; Kristen K. Patton, MD1; Susan R. Heckbert, MD, PhD3,4; Andrew N. Hoofnagle, MD, PhD5; Alvaro Alonso, MD, PhD6; Michel Chonchol, MD7; Rajat Deo, MD, MTR8; Joachim H. Ix, MD, MAS9; David S. Siscovick, MD, MPH3; Bryan Kestenbaum, MD, MS2,4; Ian H. de Boer, MD, MS2,4 1
Division of Cardiology, University of Washington, Seattle, WA; 2Division off Nephrology Neph Ne phro ph ro olo logy gy and and Kidney Research Institute, University of Washington, Seattle, WA; 3Cardiovascular Health Research Unit, Depts of Medicine and Epidemiology, University of Washington, Seattle, WA; 4 Dept De ept of of Ep Epid Epidemiology, i em id mio iolo l gy, University of Washingt Washington, gtton, on, Seattle, WA;; 5De Dept ept ooff Laboratory Medicine, 6 Univ Un University iversi sity ty y off Wa Wash Washington, shin ingt gton on, Se Seat Seattle, attl tle, e, W WA; A; Di Division Divi vissioon off Ep Epid Epidemiology idem mio iolo logy gy aand nd C Community ommu om muni nity ty H Health, ealt lth, h School off Public Pubblicc Health, Pu Hea ealt lth, lt h, University Uni nive ivers rsiity off Minne M Minnesota, i eso esota, a,, M Minneapolis, inn in nneap apol oliis, is, MN MN; 7Di Division Divi visi sion si onn ooff Re Rena Renal nall na D Diseases iseases and and Hypertension, Hypeerttenssio on, University Uni nive verrsiity of of Colorado, Colo oradoo, Denver, Denv De nvver,, C CO; O; 8Di Division D iviisioon on off C Cardiology, ard dio ologgy,, E El ectr ec trop ophy op hyssioolog ologgy Se Sect tio ion, n, University Uni n verssit ityy off P ennsyylvvani vani nia,, P hi ade hila delp lp phia, P A; 9Di A; Division Div vissionn of of Electrophysiology Section, Pennsylvania, Philadelphia, PA; Neph Ne Nephrology phro ph rolo ro logy lo g and andd Hypertension, Hyp yper ertten tensio ion, n Dept n, Dept of M Medicine, ediicin ed icinee, U University niive vers rsit ityy off Cali it C California aliifo forn rnia ia S San an D Diego, iego ie go, and and San Sa n Diego Dieg Di eg go VA Healthcare Hea eallth lthcare hc System, Syst Sy stem em,, San Sa Di Dieg Diego, ego, o,, C CA A Address for Correspondence: Jehu Mathew, MD Division of Cardiology University of Washington 1959 NE Pacific Street Box 356422, Seattle, WA 98195 Tel: 206-685-1397 Fax: 206-685-9394 E-mail: [email protected] Journal Subject Codes: Etiology:[5] Arrhythmias, clinical electrophysiology, drugs, Heart failure:[10] Cardio-renal physiology/pathophysiology 1
DOI: 10.1161/CIRCULATIONAHA.113.005499
Abstract
Background—Fibroblast growth factor-23 (FGF-23) is a hormone that promotes urinary phosphate excretion and regulates vitamin D metabolism. Circulating FGF-23 concentrations increase markedly in chronic kidney disease and are associated with increased risk of clinical cardiovascular events. FGF-23 may promote atrial fibrillation (AF) by inducing left ventricular hypertrophy and diastolic and left atrial dysfunction. Methods and Results—We tested associations of circulating FGF-23 concentration with incident AF among 6,398 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 1,350 participants in the Cardiovascular Health Study (CHS), all free of clinical cardiovascular cardio ovasc s ul sc ular arr disease dis isea ease at baseline. Over 7.7 and 8.0 years median follow-up, we observed 291 and 229 incident AF events multivariable ev ven ents ts in in MESA MESA and and nd CHS, respectively. In mult tiv ivaariable Cox proportional prop oporti op tiion onal a hazards models, each two-fold higher with higher wo-fold ohigheer FGF-23 FGFFG F-23 23 concentration con once cent ce ntra raatiionn was was associated asssociiatted w ithh a 41 it 41% % hi high gherr rrisk gh issk of of incident inci in cide ci dentt AF de AF in in MESA ME ESA (HR (HR R 1.41 1.4 .411 [95% [9 95% % CI CI 1.13-1.76], 1.13 13-1 13 -1.7 -1 .76] .7 6],, p=0.003) p=00.0 p= 0.003) 3) and and a 30% 30% higher hig ighe heer risk risk s off incident inci in c de ci dent ntt AF AF in in CHS CHS HS (HR [95% potential characteristics HR 1.30 [95 5% CII 11.05-1.61], .0055-1.61 6 ], 61 ] pp=0.016), =0 0.0016 6), ) aadjusting djus dj usti us t ng ti n fo forr po pote teent ntia iaal co cconfounding nfou nf ound ou ndin nd ingg ch in char arac ar acte ac teristics te including kidney disease. Serum phosphate concentration was significantly associated with incident AF in MESA (HR 1.15 per 0.5 mg/dL [CI 1.02-1.31], p-value=0.023) but not CHS. In MESA, an association of low estimated glomerular filtration rate with incident AF was partially attenuated by adjusting for FGF-23. Conclusions—Higher circulating FGF-23 concentration is associated with incident AF and may, in part, explain the link between chronic kidney disease and AF.
Key words: atrial fibrillation, fibroblast growth factor, mineral, chronic kidney disease
2
DOI: 10.1161/CIRCULATIONAHA.113.005499
Introduction The global prevalence of atrial fibrillation (AF) and its associated costs are growing1-7. The identification of novel, modifiable risk factors may reveal new therapeutic targets for arrhythmia prevention. Alterations in mineral metabolism are particularly promising8-11. Fibroblast growth factor-23 (FGF-23) is a bone-derived hormone that plays a central role in phosphate homeostasis. FGF-23 acts on the kidney to promote urinary phosphate excretion and inhibit the production of 1,25-dihydroxyvitamin D, thereby reducing gastrointestinal absorption of dietary phosphate. FGF-23 may directly induce left ventricular hypertrophy12. In human studies, higher circulating concentrations of FGF-23 have been associated with increased left eft ventricular mass13 as well as incident heart failure, myocardial infarction, an and nd ca cardiovascular ard dio iova vasc va scuular sc death14-17. Increased cardiac hypertrophy can lead to diastolic dysfunction and a rise in left-sided fill llin ingg pres in ppressures res essu s ress re su resu sulting in left atrial dilation an nd ffibrosis ibrosis – an im mport rttan antt structural precipitant filling resulting and important 1 ffor or A AF F initiatio initiation ionn18 . Circulating Cirrcul Ci ulat ul atin at in ng FG FGF-23 GF-2 F-23 cconcentrations onccen centraatioonss ri rise ise substantially suubst ubsttan nti tial allly l with witth chronic chro ch ro oni nicc kidney kidn dney ey y
disease dise di seas se asse (CKD) (CKD (C KD)) and KD and FGF-23 FG GF-23 F-2 excess excces esss may may pa part partially rtiaall rt llyy explain expl ex xpl p ai a n the the known know kn ownn associations ow assso soci ciat atio at io ons n ooff CKD CK KD with wiith h incident ncident AF19. We tested the associations of FGF-23 with incident AF in longitudinal studies of the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). We secondarily examined whether associations of CKD with incident AF can be explained, in part, by elevated concentrations of FGF-23.
Methods Study Population MESA and CHS are community-based cohort studies designed to assess risk factors for
3
DOI: 10.1161/CIRCULATIONAHA.113.005499
cardiovascular disease.20, 21 Between 2000 and 2002, MESA enrolled 6,814 participants ages 45-84 years who were free of baseline cardiovascular disease, defined as physician-diagnosed myocardial infarction, angina or nitroglycerin use, stroke or transient ischemic attack, heart failure, current AF, or having undergone cardiovascular procedures (coronary artery bypass grafting, angioplasty, valve replacement, pacemaker or defibrillator implantation, any surgery on the heart or arteries). Participants were recruited by race/ethnicity (Caucasian, African-American, Hispanic, and Chinese descents) and were drawn from six U.S. regions. FGF-23 concentrations were measured for 6,552 MESA participants with frozen serum available at baseline. From this group, we excluded two participants with estimated glomerular r filtration rate (e GFR)
Fibroblast Growth Factor-23 and Incident Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS) Running title: Mathew et al.; FGF-23 and Atrial Fibrillation Jehu S. Mathew, MD1,2; Michael C. Sachs, PhD2; Ronit Katz, DPhil2; Kristen K. Patton, MD1; Susan R. Heckbert, MD, PhD3,4; Andrew N. Hoofnagle, MD, PhD5; Alvaro Alonso, MD, PhD6; Michel Chonchol, MD7; Rajat Deo, MD, MTR8; Joachim H. Ix, MD, MAS9; David S. Siscovick, MD, MPH3; Bryan Kestenbaum, MD, MS2,4; Ian H. de Boer, MD, MS2,4 1
Division of Cardiology, University of Washington, Seattle, WA; 2Division off Nephrology Neph Ne phro ph ro olo logy gy and and Kidney Research Institute, University of Washington, Seattle, WA; 3Cardiovascular Health Research Unit, Depts of Medicine and Epidemiology, University of Washington, Seattle, WA; 4 Dept De ept of of Ep Epid Epidemiology, i em id mio iolo l gy, University of Washingt Washington, gtton, on, Seattle, WA;; 5De Dept ept ooff Laboratory Medicine, 6 Univ Un University iversi sity ty y off Wa Wash Washington, shin ingt gton on, Se Seat Seattle, attl tle, e, W WA; A; Di Division Divi vissioon off Ep Epid Epidemiology idem mio iolo logy gy aand nd C Community ommu om muni nity ty H Health, ealt lth, h School off Public Pubblicc Health, Pu Hea ealt lth, lt h, University Uni nive ivers rsiity off Minne M Minnesota, i eso esota, a,, M Minneapolis, inn in nneap apol oliis, is, MN MN; 7Di Division Divi visi sion si onn ooff Re Rena Renal nall na D Diseases iseases and and Hypertension, Hypeerttenssio on, University Uni nive verrsiity of of Colorado, Colo oradoo, Denver, Denv De nvver,, C CO; O; 8Di Division D iviisioon on off C Cardiology, ard dio ologgy,, E El ectr ec trop ophy op hyssioolog ologgy Se Sect tio ion, n, University Uni n verssit ityy off P ennsyylvvani vani nia,, P hi ade hila delp lp phia, P A; 9Di A; Division Div vissionn of of Electrophysiology Section, Pennsylvania, Philadelphia, PA; Neph Ne Nephrology phro ph rolo ro logy lo g and andd Hypertension, Hyp yper ertten tensio ion, n Dept n, Dept of M Medicine, ediicin ed icinee, U University niive vers rsit ityy off Cali it C California aliifo forn rnia ia S San an D Diego, iego ie go, and and San Sa n Diego Dieg Di eg go VA Healthcare Hea eallth lthcare hc System, Syst Sy stem em,, San Sa Di Dieg Diego, ego, o,, C CA A Address for Correspondence: Jehu Mathew, MD Division of Cardiology University of Washington 1959 NE Pacific Street Box 356422, Seattle, WA 98195 Tel: 206-685-1397 Fax: 206-685-9394 E-mail: [email protected] Journal Subject Codes: Etiology:[5] Arrhythmias, clinical electrophysiology, drugs, Heart failure:[10] Cardio-renal physiology/pathophysiology 1
DOI: 10.1161/CIRCULATIONAHA.113.005499
Abstract
Background—Fibroblast growth factor-23 (FGF-23) is a hormone that promotes urinary phosphate excretion and regulates vitamin D metabolism. Circulating FGF-23 concentrations increase markedly in chronic kidney disease and are associated with increased risk of clinical cardiovascular events. FGF-23 may promote atrial fibrillation (AF) by inducing left ventricular hypertrophy and diastolic and left atrial dysfunction. Methods and Results—We tested associations of circulating FGF-23 concentration with incident AF among 6,398 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 1,350 participants in the Cardiovascular Health Study (CHS), all free of clinical cardiovascular cardio ovasc s ul sc ular arr disease dis isea ease at baseline. Over 7.7 and 8.0 years median follow-up, we observed 291 and 229 incident AF events multivariable ev ven ents ts in in MESA MESA and and nd CHS, respectively. In mult tiv ivaariable Cox proportional prop oporti op tiion onal a hazards models, each two-fold higher with higher wo-fold ohigheer FGF-23 FGFFG F-23 23 concentration con once cent ce ntra raatiionn was was associated asssociiatted w ithh a 41 it 41% % hi high gherr rrisk gh issk of of incident inci in cide ci dentt AF de AF in in MESA ME ESA (HR (HR R 1.41 1.4 .411 [95% [9 95% % CI CI 1.13-1.76], 1.13 13-1 13 -1.7 -1 .76] .7 6],, p=0.003) p=00.0 p= 0.003) 3) and and a 30% 30% higher hig ighe heer risk risk s off incident inci in c de ci dent ntt AF AF in in CHS CHS HS (HR [95% potential characteristics HR 1.30 [95 5% CII 11.05-1.61], .0055-1.61 6 ], 61 ] pp=0.016), =0 0.0016 6), ) aadjusting djus dj usti us t ng ti n fo forr po pote teent ntia iaal co cconfounding nfou nf ound ou ndin nd ingg ch in char arac ar acte ac teristics te including kidney disease. Serum phosphate concentration was significantly associated with incident AF in MESA (HR 1.15 per 0.5 mg/dL [CI 1.02-1.31], p-value=0.023) but not CHS. In MESA, an association of low estimated glomerular filtration rate with incident AF was partially attenuated by adjusting for FGF-23. Conclusions—Higher circulating FGF-23 concentration is associated with incident AF and may, in part, explain the link between chronic kidney disease and AF.
Key words: atrial fibrillation, fibroblast growth factor, mineral, chronic kidney disease
2
DOI: 10.1161/CIRCULATIONAHA.113.005499
Introduction The global prevalence of atrial fibrillation (AF) and its associated costs are growing1-7. The identification of novel, modifiable risk factors may reveal new therapeutic targets for arrhythmia prevention. Alterations in mineral metabolism are particularly promising8-11. Fibroblast growth factor-23 (FGF-23) is a bone-derived hormone that plays a central role in phosphate homeostasis. FGF-23 acts on the kidney to promote urinary phosphate excretion and inhibit the production of 1,25-dihydroxyvitamin D, thereby reducing gastrointestinal absorption of dietary phosphate. FGF-23 may directly induce left ventricular hypertrophy12. In human studies, higher circulating concentrations of FGF-23 have been associated with increased left eft ventricular mass13 as well as incident heart failure, myocardial infarction, an and nd ca cardiovascular ard dio iova vasc va scuular sc death14-17. Increased cardiac hypertrophy can lead to diastolic dysfunction and a rise in left-sided fill llin ingg pres in ppressures res essu s ress re su resu sulting in left atrial dilation an nd ffibrosis ibrosis – an im mport rttan antt structural precipitant filling resulting and important 1 ffor or A AF F initiatio initiation ionn18 . Circulating Cirrcul Ci ulat ul atin at in ng FG FGF-23 GF-2 F-23 cconcentrations onccen centraatioonss ri rise ise substantially suubst ubsttan nti tial allly l with witth chronic chro ch ro oni nicc kidney kidn dney ey y
disease dise di seas se asse (CKD) (CKD (C KD)) and KD and FGF-23 FG GF-23 F-2 excess excces esss may may pa part partially rtiaall rt llyy explain expl ex xpl p ai a n the the known know kn ownn associations ow assso soci ciat atio at io ons n ooff CKD CK KD with wiith h incident ncident AF19. We tested the associations of FGF-23 with incident AF in longitudinal studies of the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). We secondarily examined whether associations of CKD with incident AF can be explained, in part, by elevated concentrations of FGF-23.
Methods Study Population MESA and CHS are community-based cohort studies designed to assess risk factors for
3
DOI: 10.1161/CIRCULATIONAHA.113.005499
cardiovascular disease.20, 21 Between 2000 and 2002, MESA enrolled 6,814 participants ages 45-84 years who were free of baseline cardiovascular disease, defined as physician-diagnosed myocardial infarction, angina or nitroglycerin use, stroke or transient ischemic attack, heart failure, current AF, or having undergone cardiovascular procedures (coronary artery bypass grafting, angioplasty, valve replacement, pacemaker or defibrillator implantation, any surgery on the heart or arteries). Participants were recruited by race/ethnicity (Caucasian, African-American, Hispanic, and Chinese descents) and were drawn from six U.S. regions. FGF-23 concentrations were measured for 6,552 MESA participants with frozen serum available at baseline. From this group, we excluded two participants with estimated glomerular r filtration rate (e GFR)
