Skip main navigation

Fibroblast Growth Factor 23 Is Associated With Carotid Plaque Presence and Area

The Northern Manhattan Study
Originally publishedhttps://doi.org/10.1161/ATVBAHA.115.305945Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;35:2048–2053

Abstract

Objective—

Elevated fibroblast growth factor 23 (FGF23), a hormone that regulates phosphate homeostasis, has been associated with mortality, cardiovascular events, and stroke, and to arterial calcification in chronic kidney disease, but its role in atherosclerosis is unclear and population-based studies are lacking. We hypothesized that elevated FGF23 would associate with carotid plaque presence, area, and echogenicity in the race/ethnically diverse community-based Northern Manhattan Study (NOMAS) sample.

Approach and Results—

There were 1512 stroke-free NOMAS participants with FGF23 and 2-dimensional carotid ultrasound data (mean age, 68±9 years; 61% women; 62% Hispanic, 18% black, and 18% white). We used multivariable linear and logistic regression to evaluate FGF23, continuously and by quintiles, as a correlate of carotid plaque, plaque area (cubic root transformed), and echogenicity adjusting for sociodemographic and vascular risk factors. Participants with FGF23 levels in the top quintile were more likely to have carotid plaque (odds ratio, 1.49; 95% confidence interval, 1.02–2.19; P=0.04) and larger plaque area (β=0.32 mm2, 95% confidence interval, 0.10–0.53 mm2; P=0.004) than those in the lowest quintile, adjusting for estimated glomerular filtration rate, demographics, and vascular risk factors. Linear regression models also showed that log transformed FGF23 (LnFGF23) associated with greater odds of plaque presence (odds ratio, 1.26 per LnFGF23; 95% confidence interval, 1.01–1.58; P=0.04), and plaque area (β=0.19 mm2 per LnFGF23; 95% confidence interval, 0.07–0.31 mm2; P=0.002).

Conclusions—

Higher FGF23 associated with greater likelihood and burden of carotid atherosclerosis independent of CKD. Atherosclerosis may be a mechanism through which FGF23 increases cardiovascular events and stroke.

Introduction

Elevated fibroblast growth factor 23 (FGF23), a hormone that regulates phosphate homeostasis, is a novel risk factor associated with cardiovascular events, stroke, and mortality in chronic kidney disease (CKD).1,2 Despite reported associations between elevated FGF23 levels and cardiovascular disease in CKD, and increasingly in the general population, the underlying mechanisms remain unclear.37 A potential cause is suggested by cross-sectional studies showing that elevated FGF23 is associated with greater carotid plaque across CKD stages, but data on the association with carotid plaque in the general population are lacking.6,810

Carotid plaque is a significant risk factor for cerebrovascular and cardiovascular disease.11,12 Given previous findings that elevated FGF23 is a risk factor for incident stroke,13,14 an association with carotid plaque would provide one possible mechanism. In light of previous pathological and in vitro studies, we hypothesized that elevations of plasma FGF23 would associate with greater carotid plaque prevalence and plaque burden.10,15 In addition, given the possible role of FGF23 in arterial calcification, we also hypothesized that elevated FGF23 would be associated with greater plaque echogenicity. We tested these hypotheses in the race/ethnically diverse community-based Northern Manhattan Study (NOMAS) sample because race/ethnic differences in the impact of carotid plaque on stroke risk have been reported, but their causes are not clear, and little is known about the role of FGF23.16,17

Materials and Methods

Materials and Methods are available in the online-only Data Supplement.

Results

There were 1512 stroke-free NOMAS participants with FGF23 levels and 2D carotid ultrasound data available. There were minor differences between NOMAS participants in the study sample and those not included (Table I in the online-only Data Supplement). The characteristics of the sample are shown in Table 1. Carotid plaque was present in 57% of the study group, which is similar to the prevalence in the overall NOMAS sample (mean total plaque area, 12±18 mm2).18

Table 1. Characteristics of Analytic Sample (Total and by the Quintiles of FGF23)

CharacteristicTotal (n=1512)FGF23 Quintiles 1–4 (Range, 6.6–80.3 RU/mL), n=1210FGF23 Quintile 5 (Range, 80.5–1340 RU/mL), n=302
Demographics
 Age, mean±SD, y68.9±9.068.5±8.9)70.6±9.2
 Male, n (%)587 (38.8)419 (40.6)96 (31.8)
 Race/ethnicity, n (%)
  Hispanic932 (61.6)741 (61.2)191 (63.2)
  Black276 (18.3)219 (18.1)57 (18.9)
  White269 (17.8)219 (18.1)50 (16.6)
  Other35 (2.3)31 (2.6)4 (1.3)
CV risk factors
 Smoking, n (%)
  Current239 (15.8)183 (15.1)56 (18.5)
  Former546 (36.1)430 (35.5)116 (38.4)
  Never727 (48.1)597 (49.3)130 (43.0)
 Moderate alcohol intake, n (%)611 (40.4)510 (42.1)101 (33.4)
 Anti-hypertension medication use, n (%)626 (42.1)475 (39.3)161 (53.3)
 Anti-diabetes mellitus medication use, n (%)194 (12.8)142 (11.7)52 (17.2)
 Lipid-lowering medication use, n (%)262 (17.3)193 (16.0)69 (22.8)
 BMI, mean±SD, kg/m228.2±5.027.9±4.829.4±5.8
 SBP, mean±SD, mm Hg141±20.1140.5±19.9142.8±21.2
 DBP, mean±SD, mm Hg83.1±10.983.1±10.882.8±11.3
 BS, mean±SD, mg/dL101.4±41.2101.1±41.1102.6±41.6
 LDL-C, mean±SD, mg/dL128.3±34.8129.1±33.9125.3±38.2
 HDL-C, mean±SD, mg/dL46.7±14.346.7±14.246.8±14.9
Biomarkers
 FGF23, mean±SD, RU/mL74.6±102.850.3±13.6172.0±201.1
 Phosphate, mean±SD, mg/dL3.0±0.53.0±0.53.1±0.5
 PTH, mean±SD, pg/mL55.7±24.853.9±22.563.1±31.5
 eGFR, mean±SD, mL/min per 1.73 m282.8±20.784.4±2076.2±22.1
Carotid plaque measures
 Plaque presence, n (%)862 (57.0)668 (55.2)194 (64.2)
 TCPA, mean±SD, mm211.7±18.810.8±17.815.4±22.1
 Time interval*, mean±SD, y2.9±3.43.1±3.42.4±3

BMI indicates body mass index; BS, fasting blood glucose; CV, cardiovascular; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; FGF23, fibroblast growth factor 23; GSM, gray scale median; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PTH, parathyroid hormone; SBP, systolic blood pressure; and TCPA, total carotid plaque area (cube root transformed).

*Time interval between FGF23 measure and carotid ultrasound examination.

Examining FGF23 (mean=74.6±102.8, RU/mL) as a continuous variable, we found that each unit increase in natural log-transformed FGF23 levels was associated with significantly greater odds of having carotid plaque and with greater total carotid plaque area (TCPA) after adjusting for estimated glomerular filtration rate (eGFR) and sociodemographic and vascular risk factors (Tables 2 and 3, Model 3). When we adjusted for serum phosphate and parathyroid hormone levels, the associations were attenuated and were nonsignificant for plaque presence, but remained significant for total plaque area (β=0.17 mm2; 95% confidence interval [CI], 0.06–0.30 mm2; P=0.006) per unit increase in natural log-transformed FGF23 levels.

Table 2. Association Between FGF23 and Carotid Plaque Presence

FGF23 levelModel 1Model 2Model 3
OR (95% CI)P ValueOR (95% CI)P ValueOR (95% CI)P Value
per LnFGF231.26 (1.04–1.52)0.021.26 (1.02–1.56)0.031.26 (1.01–1.58)0.04
Plaque presence
 Quintile 1ReferenceReferenceReference
 Quintile 20.94 (0.68–1.30)0.710.96 (0.68–1.35)0.820.94 (0.66–1.34)0.73
 Quintile 31.14 (0.83–1.57)0.421.27 (0.89–1.80)0.191.16 (0.81–1.67)0.41
 Quintile 41.22 (0.89–1.69)0.221.33 (0.93–1.90)0.121.24 (0.86–1.79)0.28
 Quintile 51.56 (1.13–2.17)0.0071.57 (1.09–2.26)0.021.49 (1.02–2.19)0.04
P for trend=0.002P for trend=0.003P for trend=0.01

Model 1: unadjusted; Model 2: adjusted for age, sex, race/ethnicity, eGFR, and time interval between FGF23 and carotid examination; Model 3: adjusted for age, sex, race/ethnicity, eGFR, and time interval between FGF23 and carotid examination plus vascular risk factors. CI indicates confidence interval; eGFR, estimated glomerular filtration rate; FGF23, fibroblast growth factor 23; LnFGF23, log transformed FGF23; and OR, odds ratio.

Table 3. Association Between FGF23 and TCPA

FGF23 levelModel 1Model 2Model 3
β (95% CI)P Valueβ (95% CI)P Valueβ (95% CI)P Value
per LnFGF230.21 (0.08–0.33)0.0010.20 (0.08–0.32)0.0010.19 (0.07–0.31)0.002
TCPA
 Quintile 1ReferenceReferenceReference
 Quintile 2−0.06 (−0.28 to 0.16)0.61−0.02 (−0.22 to 0.19)0.89−0.02 (−0.23 to 0.17)0.77
 Quintile 30.10 (−0.12 to 0.31)0.390.18 (−0.02 to 0.39)0.080.12 (−0.08 to 0.32)0.24
 Quintile 40.14 (−0.08 to 0.36)0.200.22 (0.01 to 0.43)0.040.15 (−0.05 to 0.36)0.15
 Quintile 50.38 (0.17 to 0.60)0.00060.38 (0.17 to 0.60)0.00050.32 (0.10 to 0.53)0.004
P for trend=0.0001P for trend <0.0001P for trend=0.0007

Model 1: unadjusted; Model 2: adjusted for age, sex, race/ethnicity, eGFR, and time interval between FGF23 and carotid examination; Model 3: adjusted for age, sex, race/ethnicity, eGFR, and time interval between FGF23 and carotid examination plus vascular risk factors. CI indicates confidence interval; eGFR, estimated glomerular filtration rate; FGF23, fibroblast growth factor 23; LnFGF23, log transformed FGF23; and TCPA, total carotid plaque area (cube root transformed).

We also looked for a dose effect by dividing FGF23 into quintiles. Compared with the lowest quintile of FGF23, there was a significant positive linear trend across increasing quintiles of FGF23 for its association with plaque presence (P for trend=0.01) and TCPA (P for trend=0.0007), adjusting for demographic and vascular risk factors (Tables 2 and 3). However, only participants with FGF23 values in the top quintile were significantly more likely to have carotid plaque, or greater TCPA, than those in the lowest quintile, adjusting for sociodemographic and vascular risk factors.

Restricting our analysis to participants without evidence of CKD (eGFR>59 mL/min per 1.73 m2), participants with FGF23 levels in the top quintile had greater TCPA (P=0.02 for the top quintile versus the lowest quintile; P for trend=0.009), but the association with carotid plaque presence no longer reached significance (P=0.13 for the top quintile versus the lowest quintile; P for trend=0.05). The association between FGF23 and carotid plaque presence and area did not differ by race/ethnicity.

To assess the association of elevated FGF23 with plaque echogenicity, we examined FGF23 in relation to GSM maximum values. First, we examined potential dose effects by analyzing the top 4 quintiles (Q2, Q3, Q4, and Q5) of FGF23 compared with the bottom quintile (Q1) as correlates of GSM. We found a threshold effect for Q5. We then compared participants with FGF23 levels in Q5 to those below and found those in Q5 to have significantly greater GSM adjusting for age, sex, race/ethnicity, and eGFR (β=2.6; 95% CI, 0.7–4.6; P=0.008). Adjusting further for vascular risk factors, the positive association remained but no longer reached significance (β=1.9; 95% CI, –0.1 to 3.8; P=0.06). In a sensitivity analysis, when limited to participants with eGFR≥60 and FGF23<400, all the associations with plaque area remained similar and significant.

In a sensitivity analysis excluding participants with probable primary hyperparathyroidism (n=4), those with FGF23 levels in the top quintile had greater odds of having carotid plaque (odds ratio, 1.48; CI, 1.01–2.18; P=0.04) and had greater plaque areas (β=0.31; CI, 0.09–0.52; P=0.004) than those with FGF23 levels in the lowest quintile. None of the sociodemographic or vascular risk factors were found to be effect modifiers of the associations between FGF23 and the markers of carotid atherosclerosis.

Discussion

Although cross-sectional and observational, these are the first population-based data that we are aware of to support FGF23 as a possible risk factor for large vessel atherosclerosis. In this stroke-free community-based sample of Latino, black, and white people living in the same community, participants with elevated FGF23 levels were more likely to have carotid plaque and greater TCPA, after adjusting for estimated kidney function, sociodemographic, and vascular risk factors. The association between FGF23 and TCPA remained significant even in those without evidence of CKD.

The role of elevated FGF23 in atherosclerosis is controversial. The Cardiovascular Health Study found that FGF23 was not associated with ankle brachial index, a measure of peripheral artery disease, or with related events after controlling for vascular risk factors and kidney function.19 Conversely, elevated FGF23 has been associated with impaired radial and brachial vasoreactivity in a community population, suggesting a link with disease of medium-sized arteries.20

A recent histopathologic analysis of calcified carotid plaques from patients who underwent carotid endarterectomy found that FGF23 was present in 48 of 53 resected plaques even though only 28 patients had detectable serum C-terminal FGF23. They also found that 45 of 48 plaques stained positive for intracellular FGF23. FGF23 was not found in healthy segments of the vessel, suggesting FGF23 is produced locally in plaques and selectively in diseased arteries. To our knowledge, no studies have evaluated associations of serum and local FGF23 production, and in our study all patients had detectable FGF23.

Mechanisms through which elevated FGF23 may cause atherosclerosis are unclear. To date, there has been mixed clinical evidence to support elevated FGF23 as a risk factor for arterial calcification, including in the aorta, coronary artery, and carotid, across CKD stages.8,21,22 The community-based Multi-Ethnic Study of Atherosclerosis did not find FGF23 levels to be associated with atherosclerosis.23 However, there is recent evidence that elevated FGF23 plays a role in fat mass and pathological lipid metabolism that might help explain how FGF23 might have an impact on atherosclerosis since FGF23 null mice have both cardiovascular calcifications because of dysregulated parathyroid hormone, Vitamin D, and calcium metabolism in addition to abnormal lipids.24,25 In model 3, LDL was significantly associated with echogenicity, and therefore a potential mediator along with smoking, blood pressure, and treatment for diabetes mellitus (data not shown). Lipid-lowering medication was not a significant contributor.

Further study is also needed to investigate the role of other factors, such as phosphorus intake. Because FGF23 tightly regulates serum phosphate, it is not surprising that we found no significant correlation between levels of the 2 markers. In vitro studies suggest that isolated FGF23 overexpression does not potentiate vascular calcification.6 However, in vitro elevated serum phosphate can increase expression of genes that predispose to calcification.26 Other in vitro evidence has demonstrated that FGF23 potentiates arterial smooth muscle calcification when local phosphate levels increase.15,27 Calcified tissue increases echogenicity, and calcified plaque has been associated with a greater risk of vascular events in this cohort.28 In this study, FGF23 was associated with greater echogenicity after adjusting for demographics and eGFR, but this was no longer significant after adjusting for vascular risk factors. Also, there was no association between FG23 and echogenicity when we restricted the analysis to those with plaque. Therefore, we are unable to link FGF23 to calcified plaque.

Elevated FGF23 has been linked to an increased risk of stroke and several mechanism could underlie this association.29 We recently reported that elevated FGF23 was associated with an increased risk of incident hemorrhagic stroke in NOMAS.13 Although the underlying causes of the intracerebral hemorrhages in our sample were unknown, the high prevalence of hypertension in NOMAS suggests that most were because of microvascular disease, perhaps due to rupture of vessels previously damaged by arteriolosclerosis. Although the causes of small and large vessel disease do not overlap entirely, it is possible that inflammation is a common underlying process. Inflammation is known to potentiate atherosclerosis.30 We have previously shown that markers of inflammation are associated with carotid atherosclerosis and white matter lesions, a marker of cerebral small vessel disease, in NOMAS.3133 Recently, other studies have shown that FGF23 is associated with elevation of inflammatory markers, and we plan future studies with NOMAS to explore these relationships.5,34

Several limitations are noteworthy. Our data are cross-sectional, and no causal conclusions can be made about the temporal relationship between elevated FGF23 and carotid plaque formation. Half of participants had FGF23 and carotid ultrasound on the same day, so we are unable to account for potential changes in FGF23 over time, however longitudinal studies of FGF23 levels demonstrate that they are stable.35 To account for changes in time, we adjusted for the time difference between FGF23 and carotid ultrasound. Strengths of our study include the race/ethnically diverse urban population-based prospective design and the stroke-free status of participants at the time of the carotid and FGF23 measurements. We also adjusted for important confounders, including comorbid vascular risk factors and kidney function.

Our study provides cross-sectional evidence of a relationship between elevated FGF23 and carotid plaque presence, as well as greater plaque burden, after adjusting for estimated kidney function. Furthermore, those with elevated FGF23 but without evidence of CKD also had greater carotid plaque burden. These associations suggest FGF23 may be a risk factor for large vessel atherosclerosis. If prospective observational and clinical studies further implicate FGF23 in atherosclerotic plaque formation and progression, this hormone could become a target for therapeutic interventions designed to lower it for prevention of large vessel disease.36

Nonstandard Abbreviations and Acronyms

CKD

chronic kidney disease

eGFR

estimated glomerular filtration rate

FGF23

fibroblast growth factor 23

NOMAS

Northern Manhattan Study

TCPA

total carotid plaque area

Acknowledgments

We would like to thank the NOMAS staff, especially Janet DeRosa, the project manager.

Footnotes

The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.115.305945/-/DC1.

Correspondence to Clinton Wright, MD, MS, 1120 NW 14th St, CRB 1349, Miami, FL 33136. E-mail

References

  • 1. Kendrick J, Cheung AK, Kaufman JS, Greene T, Roberts WL, Smits G, Chonchol M; HOST Investigators. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis.J Am Soc Nephrol. 2011; 22:1913–1922. doi: 10.1681/ASN.2010121224.CrossrefMedlineGoogle Scholar
  • 2. Gutiérrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Jüppner H, Wolf M. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis.N Engl J Med. 2008; 359:584–592. doi: 10.1056/NEJMoa0706130.CrossrefMedlineGoogle Scholar
  • 3. van Venrooij NA, Pereira RC, Tintut Y, Fishbein MC, Tumber N, Demer LL, Salusky IB, Wesseling-Perry K. FGF23 protein expression in coronary arteries is associated with impaired kidney function.Nephrol Dial Transplant. 2014; 29:1525–1532. doi: 10.1093/ndt/gft523.CrossrefMedlineGoogle Scholar
  • 4. Ix JH, Katz R, Kestenbaum BR, de Boer IH, Chonchol M, Mukamal KJ, Rifkin D, Siscovick DS, Sarnak MJ, Shlipak MG. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study).J Am Coll Cardiol. 2012; 60:200–207. doi: 10.1016/j.jacc.2012.03.040.CrossrefMedlineGoogle Scholar
  • 5. Gutiérrez OM, Wolf M, Taylor EN. Fibroblast growth factor 23, cardiovascular disease risk factors, and phosphorus intake in the health professionals follow-up study.Clin J Am Soc Nephrol. 2011; 6:2871–2878. doi: 10.2215/CJN.02740311.CrossrefMedlineGoogle Scholar
  • 6. Scialla JJ, Lau WL, Reilly MP, et al; Chronic Renal Insufficiency Cohort Study Investigators. Fibroblast growth factor 23 is not associated with and does not induce arterial calcification.Kidney Int. 2013; 83:1159–1168. doi: 10.1038/ki.2013.3.CrossrefMedlineGoogle Scholar
  • 7. Taylor EN, Rimm EB, Stampfer MJ, Curhan GC. Plasma fibroblast growth factor 23, parathyroid hormone, phosphorus, and risk of coronary heart disease.Am Heart J. 2011; 161:956–962. doi: 10.1016/j.ahj.2011.02.012.CrossrefMedlineGoogle Scholar
  • 8. Nakayama M, Kaizu Y, Nagata M, Ura Y, Ikeda H, Shimamoto S, Kuma K. Fibroblast growth factor 23 is associated with carotid artery calcification in chronic kidney disease patients not undergoing dialysis: a cross-sectional study.BMC Nephrol. 2013; 14:22. doi: 10.1186/1471-2369-14-22.CrossrefMedlineGoogle Scholar
  • 9. Balci M, Kirkpantur A, Gulbay M, Gurbuz OA. Plasma fibroblast growth factor-23 levels are independently associated with carotid artery atherosclerosis in maintenance hemodialysis patients.Hemodial Int. 2010; 14:425–432. doi: 10.1111/j.1542-4758.2010.00480.x.CrossrefMedlineGoogle Scholar
  • 10. Voigt M, Fischer DC, Rimpau M, Schareck W, Haffner D. Fibroblast growth factor (FGF)-23 and fetuin-A in calcified carotid atheroma.Histopathology. 2010; 56:775–788. doi: 10.1111/j.1365-2559.2010.03547.x.CrossrefMedlineGoogle Scholar
  • 11. Rundek T, Arif H, Boden-Albala B, Elkind MS, Paik MC, Sacco RL. Carotid plaque, a subclinical precursor of vascular events: the Northern Manhattan Study.Neurology. 2008; 70:1200–1207. doi: 10.1212/01.wnl.0000303969.63165.34.CrossrefMedlineGoogle Scholar
  • 12. Spence JD. Carotid plaque measurement is superior to IMT Invited editorial comment on: carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis-Yoichi Inaba, M.D., Jennifer A. Chen M.D., Steven R. Bergmann M.D., Ph.D.Atherosclerosis. 2012; 220:34–35. doi: 10.1016/j.atherosclerosis.2011.07.006.CrossrefMedlineGoogle Scholar
  • 13. Wright CB, Dong C, Stark M, Silverberg S, Rundek T, Elkind MS, Sacco RL, Mendez A, Wolf M. Plasma FGF23 and the risk of stroke: the Northern Manhattan Study (NOMAS).Neurology. 2014; 82:1700–1706. doi: 10.1212/WNL.0000000000000410.CrossrefMedlineGoogle Scholar
  • 14. Panwar B, Jenny NS, Howard VJ, Wadley VG, Muntner P, Kissela BM, Judd SE, Gutiérrez OM. Fibroblast growth factor 23 and risk of incident stroke in community-living adults.Stroke. 2015; 46:322–328. doi: 10.1161/STROKEAHA.114.007489.LinkGoogle Scholar
  • 15. Jimbo R, Kawakami-Mori F, Mu S, Hirohama D, Majtan B, Shimizu Y, Yatomi Y, Fukumoto S, Fujita T, Shimosawa T. Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency.Kidney Int. 2014; 85:1103–1111. doi: 10.1038/ki.2013.332.CrossrefMedlineGoogle Scholar
  • 16. Tattersall MC, Gassett A, Korcarz CE, Gepner AD, Kaufman JD, Liu KJ, Astor BC, Sheppard L, Kronmal RA, Stein JH. Predictors of carotid thickness and plaque progression during a decade: the Multi-Ethnic Study of Atherosclerosis.Stroke. 2014; 45:3257–3262. doi: 10.1161/STROKEAHA.114.005669.LinkGoogle Scholar
  • 17. Sacco RL, Boden-Albala B, Abel G, Lin IF, Elkind M, Hauser WA, Paik MC, Shea S. Race-ethnic disparities in the impact of stroke risk factors: the Northern Manhattan Stroke Study.Stroke. 2001; 32:1725–1731.LinkGoogle Scholar
  • 18. Kuo F, Gardener H, Dong C, Cabral D, Della-Morte D, Blanton SH, Elkind MS, Sacco RL, Rundek T. Traditional cardiovascular risk factors explain the minority of the variability in carotid plaque.Stroke. 2012; 43:1755–1760. doi: 10.1161/STROKEAHA.112.651059.LinkGoogle Scholar
  • 19. Garimella PS, Ix JH, Katz R, Chonchol MB, Kestenbaum BR, de Boer IH, Siscovick DS, Shastri S, Hiramoto JS, Shlipak MG, Sarnak MJ. Fibroblast growth factor 23, the ankle-brachial index, and incident peripheral artery disease in the Cardiovascular Health Study.Atherosclerosis. 2014; 233:91–96. doi: 10.1016/j.atherosclerosis.2013.12.015.CrossrefMedlineGoogle Scholar
  • 20. Mirza MA, Larsson A, Lind L, Larsson TE. Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community.Atherosclerosis. 2009; 205:385–390. doi: 10.1016/j.atherosclerosis.2009.01.001.CrossrefMedlineGoogle Scholar
  • 21. Schoppet M, Hofbauer LC, Brinskelle-Schmal N, Varennes A, Goudable J, Richard M, Hawa G, Chapurlat R, Szulc P. Serum level of the phosphaturic factor FGF23 is associated with abdominal aortic calcification in men: the STRAMBO study.J Clin Endocrinol Metab. 2012; 97:E575–E583. doi: 10.1210/jc.2011-2836.CrossrefMedlineGoogle Scholar
  • 22. Desjardins L, Liabeuf S, Renard C, Lenglet A, Lemke HD, Choukroun G, Drueke TB, Massy ZA; European Uremic Toxin (EUTox) Work Group. FGF23 is independently associated with vascular calcification but not bone mineral density in patients at various CKD stages.Osteoporos Int. 2012; 23:2017–2025. doi: 10.1007/s00198-011-1838-0.CrossrefMedlineGoogle Scholar
  • 23. Kestenbaum B, Sachs MC, Hoofnagle AN, Siscovick DS, Ix JH, Robinson-Cohen C, Lima JA, Polak JF, Blondon M, Ruzinski J, Rock D, de Boer IH. Fibroblast growth factor-23 and cardiovascular disease in the general population: the Multi-Ethnic Study of Atherosclerosis.Circ Heart Fail. 2014; 7:409–417. doi: 10.1161/CIRCHEARTFAILURE.113.000952.LinkGoogle Scholar
  • 24. Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism.J Clin Invest. 2004; 113:561–568. doi: 10.1172/JCI19081.CrossrefMedlineGoogle Scholar
  • 25. Mirza MA, Alsiö J, Hammarstedt A, Erben RG, Michaëlsson K, Tivesten A, Marsell R, Orwoll E, Karlsson MK, Ljunggren O, Mellström D, Lind L, Ohlsson C, Larsson TE. Circulating fibroblast growth factor-23 is associated with fat mass and dyslipidemia in two independent cohorts of elderly individuals.Arterioscler Thromb Vasc Biol. 2011; 31:219–227. doi: 10.1161/ATVBAHA.110.214619.LinkGoogle Scholar
  • 26. Jono S, McKee MD, Murry CE, Shioi A, Nishizawa Y, Mori K, Morii H, Giachelli CM. Phosphate regulation of vascular smooth muscle cell calcification.Circ Res. 2000; 87:E10–E17.LinkGoogle Scholar
  • 27. Six I, Okazaki H, Gross P, Cagnard J, Boudot C, Maizel J, Drueke TB, Massy ZA. Direct, acute effects of Klotho and FGF23 on vascular smooth muscle and endothelium.PLoS One. 2014; 9:e93423. doi: 10.1371/journal.pone.0093423.CrossrefMedlineGoogle Scholar
  • 28. Prabhakaran S, Singh R, Zhou X, Ramas R, Sacco RL, Rundek T. Presence of calcified carotid plaque predicts vascular events: the Northern Manhattan Study.Atherosclerosis. 2007; 195:e197–e201. doi: 10.1016/j.atherosclerosis.2007.03.044.CrossrefMedlineGoogle Scholar
  • 29. Mathew JS, Sachs MC, Katz R, Patton KK, Heckbert SR, Hoofnagle AN, Alonso A, Chonchol M, Deo R, Ix JH, Siscovick DS, Kestenbaum B, de Boer IH. Fibroblast growth factor-23 and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS).Circulation. 2014; 130:298–307. doi: 10.1161/CIRCULATIONAHA.113.005499.LinkGoogle Scholar
  • 30. Ross R. Atherosclerosis–an inflammatory disease.N Engl J Med. 1999; 340:115–126. doi: 10.1056/NEJM199901143400207.CrossrefMedlineGoogle Scholar
  • 31. Alsulaimani S, Gardener H, Elkind MS, Cheung K, Sacco RL, Rundek T. Elevated homocysteine and carotid plaque area and densitometry in the Northern Manhattan Study.Stroke. 2013; 44:457–461. doi: 10.1161/STROKEAHA.112.676155.LinkGoogle Scholar
  • 32. Elkind MS, Cheng J, Boden-Albala B, Paik MC, Sacco RL; Northern Manhattan Stroke Study. Elevated white blood cell count and carotid plaque thickness: the Northern Manhattan Stroke Study.Stroke. 2001; 32:842–849.LinkGoogle Scholar
  • 33. Elkind MS, Cheng J, Boden-Albala B, Rundek T, Thomas J, Chen H, Rabbani LE, Sacco RL. Tumor necrosis factor receptor levels are associated with carotid atherosclerosis.Stroke. 2002; 33:31–37.LinkGoogle Scholar
  • 34. Munoz Mendoza J, Isakova T, Ricardo AC, Xie H, Navaneethan SD, Anderson AH, Bazzano LA, Xie D, Kretzler M, Nessel L, Hamm LL, Negrea L, Leonard MB, Raj D, Wolf M; Chronic Renal Insufficiency Cohort. Fibroblast growth factor 23 and Inflammation in CKD.Clin J Am Soc Nephrol. 2012; 7:1155–1162. doi: 10.2215/CJN.13281211.CrossrefMedlineGoogle Scholar
  • 35. Scialla JJ, Astor BC, Isakova T, Xie H, Appel LJ, Wolf M. Mineral metabolites and CKD progression in African Americans.J Am Soc Nephrol. 2013; 24:125–135. doi: 10.1681/ASN.2012070713.CrossrefMedlineGoogle Scholar
  • 36. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy.J Clin Invest. 2011; 121:4393–4408. doi: 10.1172/JCI46122.CrossrefMedlineGoogle Scholar

Significance

The hormone fibroblast growth factor 23 is a novel risk factor for stroke and cardiovascular outcomes. These are the first population-based data demonstrating that elevated fibroblast growth factor 23 is associated with the likelihood and burden of carotid atherosclerosis independent of chronic kidney disease. Carotid atherosclerosis is an important potentially modifiable stroke risk factor and may be a mechanism through which fibroblast growth factor 23 increases cardiovascular events and stroke.