IJCA-18039; No of Pages 5 International Journal of Cardiology xxx (2014) xxx–xxx
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studies Yunjun Xiao ⁎,1, Xianru Luo 1, Wei Huang, Jinzhou Zhang, Chaoqiong Peng Department of Nutrition and Food Hygiene, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
a r t i c l e
i n f o
Article history: Received 8 April 2014 Accepted 12 April 2014 Available online xxxx Keywords: Cardiovascular disease Cohort studies Fibroblast growth factor 23 Meta-analysis
Fibroblast growth factor 23 (FGF23), a hormone that is secreted by osteoblasts, is an important regulator of phosphorus and vitamin D metabolism [1]. The past few years have seen a rapidly growing interest in testing the hypothesis that increased FGF23 level is an independent risk factor of mortality and cardiovascular disease (CVD). Crosssectional studies have found higher circulating FGF23 concentrations were associated with severity of coronary artery disease (CAD) [2], prevalent CVD [3], left ventricular hypertrophy [4], total body atherosclerosis [5], endothelial dysfunction [6], and metabolic syndrome [7]. However, the reports from two nest case–control studies have been inconsistent; one concluded a positive association between FGF23 and mortality in hemodialysis patients [8], whereas the other concluded no association between FGF23 and risk of coronary heart disease (CHD) [9]. Recently, epidemiologic prospective cohort studies have investigated the link between FGF23 and risk of mortality and CVD events in different populations including kidney disease [10–17], diabetes [18], CAD patients [19], and community-based adults [20–23]. Some studies found a positive association, but the magnitudes of the association varied between these studies, and others reported no association. The inconsistent results of cohort studies prompted us to conduct a meta-analysis of prospective cohort studies to evaluate the association between FGF23 and risk of all-cause mortality and CVD events. We followed a standardized protocol and conducted and reported this analysis according to the guidelines of the Meta-analysis of Observation
⁎ Corresponding author at: Department of Nutrition and Food Hygiene, Shenzhen Center for Disease Control and Prevention, 8 Longyuan Road, Nanshan District, 518055 Shenzhen, China. Tel.: +86 755 25617321; fax: +86 755 25500660. E-mail address: [email protected] (Y. Xiao). 1 The authors contributed equally to this work.
Studies in Epidemiology group [24]. We conducted a systematic literature search of PubMed database through November 2013 for relevant articles that reported the association between FGF23 and risk of all-cause mortality and CVD events. To avoid missing any relevant study, we also searched the bibliographies of retrieved papers and recent reviews in the field. We did our search by using the following medical subject headings and keywords, such as Fibroblast Growth Factor-23, FGF23, and cardiovascular diseases, coronary disease, myocardial infarction, myocardial ischemia, coronary stenosis, coronary restenosis, cerebrovascular disorders, stroke, heart failure, death, mortality, all-cause mortality, cardiovascular mortality, and cohort studies, prospective studies, and follow-up studies. No restrictions were imposed. Two reviewers (Y.X. and X.L.) independently screened the abstracts and titles of the search results and eliminated articles only if they did not meet pre-stated inclusion criteria. The same 2 reviewers independently evaluated the remaining full-text articles for eligibility on the basis of a predefined set of eligibility criteria. Disagreements were resolved by discussion. Studies were considered eligible if they met the following criteria: 1) the study was a full-text, published prospective cohort study; 2) the exposure of interest was plasma or serum FGF23 concentrations; 3) the outcome of interest was all-cause or cardiovascular mortality or CVD events, myocardial infarction, stroke, or heart failure; and 4) relative risk (RR) and the corresponding 95% confidence interval (CI) or sufficient data to calculate them were provided. In addition, studies were excluded if they met the exclusion criteria that the sample size of a study was less than 200 and the duration of follow-up was less than one year. Two reviewers independently abstracted data on participant characteristics and study results with adjustment factors by using a standardized data collection form. Discrepancies in data extraction between reviewers were resolved by consensus. We extracted any reported RRs, HRs, or incidence density ratios of outcomes and study characteristics for each trial. We also systematically assessed key indicators of study quality: methods of outcome adjudication and ascertainment that account for confounders and completeness of follow-up ascertainment. To calculate summary estimates and 95% CIs of the risk for FGF23, we pooled both RRs and HRs by using either fixed-effects models or, in the presence of heterogeneity, random-effects models [25]. The presence of heterogeneity across studies was evaluated by using the Q statistic with a conservative p value of 0.10. Potential publication bias was evaluated by Begg and Egger tests at the p b 0.10 level of significance. All analyses were performed using STATA version 11.0 (StataCorp LP, College Station, Texas). A p value b 0.05 was considered statistically significant, except where otherwise specified.
http://dx.doi.org/10.1016/j.ijcard.2014.04.138 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Xiao Y, et al, Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studi..., Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.138
2
Y. Xiao et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Fig. 1. Flow chart of study selection. CVD, cardiovascular disease; FGF23, fibroblast growth factor 23.
Fourteen prospective cohort studies were finally included in our present meta-analysis. Fig. 1 shows details of the study selection. The main characteristics of studies in the meta-analysis were presented in
Table 1. Among the 14 studies included here, 12 studies reported allcause mortality and 6 studies reported CVD events. Outcome assessments, duration of follow up, assessment of FGF23, and methodological quality varied across studies. Overall, high FGF23 levels were associated with a significantly increased risk of all-cause mortality (RR: 1.34 [95% CI: 1.20 to 1.48]; p b 0.001). Substantial heterogeneity was observed (I2 = 71.1%, p b 0.001) (Fig. 2). The overall combined RR in relation to FGF23 was 1.21 (95% CI: 1.11 to 1.31; p b 0.001) for CVD events. There was no evidence of heterogeneity for CVD events (I2 = 16.9%, p = 0.305) (Fig. 3). The combining RRs for cardiovascular mortality, myocardial infarction, stroke, and heart failure from fixed-effects models are presented in Fig. 4. Subgroup and sensitivity analyses were conducted to explore potential sources of heterogeneity in the association between FGF23 and risk of all-cause mortality and to examine the influence of various exclusion criteria on the overall risk estimate. The overall combined RRs in relation to FGF23 remained significant in various subgroups stratified by publication year, mean age, sample size, duration of follow-up, and pre-existing disease (Fig. 5). Additional sensitivity analyses with exclusion of 2 studies [21,22] that only enrolled male participants did not change the overall risk estimate (RR: 1.37 [95% CI: 1.29 to 1.44]; p b 0.001), but no significant heterogeneity was observed among the remaining studies (I2 = 38.1%, p = 0.104). The Begg and Egger tests also showed no evidence of publication bias among studies of FGF23 and all-cause mortality (Begg, p = 0.373; Egger, p = 0.163). In the present study we found that high FGF23 level was significantly and independently associated with an increased risk of 34% for all-cause mortality, 21% for CVD events, 24% for cardiovascular mortality, 15% for stroke, and 38% for heart failure. But no independent association was observed between FGF23 and risk of myocardial infarction. Subgroup analyses showed that C-terminal but not intact FGF23 was significantly
Table 1 Characteristics of 14 prospective cohort studies of FGF23 and all-cause mortality and cardiovascular events. Source
Location
Population
Sex/age, yrs
Recruitment time
Duration
FGF23 measurement
Outcomes
Jean (2009) [10]
France
695 days
2000–2002
6.0 yrs
Olauson (2010) [12]
Sweden United States
December 1994– April 2008 February–August 2007
23 months
Wolf (2011) [13] Kendrick (2011) [14]
United States
229 incident dialysis patients 984 stable kidney transplant recipients 1099 advanced CKD patients
C-terminal, 2740 (1192–8667) RU/ml C-terminal, 43.1 (28.9–72.3) RU/ml Intact, 2526 (431–19495) ng/L C-terminal, 28 (20–43) RU/ml C-terminal, 392 (216–945) RU/ml
All-cause death
United States
Male/female, 66.6 ± 14 Male/female, 67 ± 11 Male/female, 55 (33, 68) Male/female, 51 ± 13 Male/female, 69 ± 11
September 2006
Parker (2010) [19]
219 long haemodialysis patients 833 CAD patients
Isakova (2011) [11]
United States
Arnlov (2012) [21]
Sweden
Ix (2012) [20]
United States
Nakano (2012) [15]
Japan
Baia (2013) [16]
Netherlands
3879 CKD stages 2–4 patients 727 community-based men 3107 community-based adults 738 predialysis outpatients 593 stable kidney transplant recipients
Lee (2013) [18]
United States
Westerberg (2013) [22]
Sweden
Scialla (2013) [17]
United States
Arnlov (2013) [23]
Sweden
37 months
September 2001 –October 2003
2.9 yrs
Male/female, 58.2 ± 11.0 Male, 77.6 ± 0.76 Male/female, 78 ± 5 Male/female, 64 (54, 72) Male/female, 52 ± 12
June 2003–September 2008 1998–2001
3.5 yrs 9.7 yrs
1996–1997
10.5 yrs
May 2005–July 2007
4.4 yrs
August 2001–July 2003
7.0 yrs
380 Type 2 diabetes patients
Male/female, 54 ± 10
1991–1995
8–12 yrs
3014 population-based men 3860 CKD stages 2–4 patients 973 community-based men
Male, 75.5 ± 3.2 Male/female, 21–74 Male, 70
2001–2004
4.5 yrs
2003–2008
3.7 yrs
January 2001–June 2004
5.1 yrs
C-terminal, 145.5 (96–239) RU/ml Intact, 44 (9–162) pg/ml C-terminal, 70 (53–99) RU/ml Intact, 49.5 (31.7–80.5) pg/ml C-terminal, 140 (95–219) RU/ml C-terminal, Alive 50 (36–75), ESRD 117 (65–238), Death 84 (53–133) RU/ml Intact, 43.5 (32.4–57.5) pg/ml C-terminal, 145.4 (96.0–238.8) RU/ml Intact, 47 ± 24 pg/ml
All-cause death, CVD events All-cause death All-cause death, allograft loss All-cause death, CVD events, initiation of chronic dialysis All-cause mortality and ESRD All-cause and cardiovascular death All-cause death, heart failure, CVD events All-cause death, CVD events All-cause and cardiovascular death, graft failure All-cause and cardiovascular death, ESRD All-cause and cardiovascular death Atherosclerotic events, congestive heart failure CVD events
CAD, coronary artery disease; CKD, chronic kidney disease; CVD, cardiovascular disease; ESRD, end-stage renal disease; FGF23, fibroblast growth factor 23.
Please cite this article as: Xiao Y, et al, Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studi..., Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.138
Y. Xiao et al. / International Journal of Cardiology xxx (2014) xxx–xxx
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Fig. 2. Association between FGF23 and risk of all-cause mortality. FGF23, fibroblast growth factor 23.
associated with risk of all-cause mortality. On the basis of our findings, several questions arise. First, is the association of FGF23 with mortality and CVD causal? To answer this question, several issues should be considered, including different measurements of FGF23 and adequate control for confounding factors. Second, could treating high FGF23 level with drug intervention or dietary therapy protect against mortality or CVD events? On the contrary, a recent study found FGF23 neutralization with a monoclonal FGF23 antibody likely contributed to the increased mortality in mineral and bone disorder rat model [26]. Third, by what exact mechanisms does FGF23 independently increase the risk of CVD? Several factors such as left ventricular hypertrophy, arterial calcification, hyperphosphatemia and vitamin D deficiency, and endothelial dysfunction, may offer insights. Further studies, including well-designed clinical trials, are
warranted to address these questions for a better understanding of the association and to provide convincing evidence for clinical practice in CVD prevention. In summary, this meta-analysis of prospective cohort studies suggests that FGF23 significantly increases the risk of all-cause mortality and CVD events, and the increase is probably independent of conventional cardiovascular risk factors. Y.X., W.H., and C.P. developed the study concept and designed the study; Y.X., X.L., J.Z. conducted the data extraction and analyzed the data. Y.X. and X.L. wrote the paper. J.Z., W.H., and C.P. reviewed and edited the manuscript. This work was supported by grants from the Guangdong Provincial Traditional Chinese Medicine Research Fund (20131037) and the Shenzhen Municipal Science and Technology Project (201302139).
Fig. 3. Association between FGF23 and risk of CVD events. FGF23, fibroblast growth factor 23.
Please cite this article as: Xiao Y, et al, Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studi..., Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.138
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Y. Xiao et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Fig. 4. Association between FGF23 and risk of cardiovascular mortality, myocardial infarction, stroke, and heart failure. FGF23, fibroblast growth factor 23.
References [1] Bhattacharyya N, Chong WH, Gafni RI, et al. Fibroblast growth factor 23: state of the field and future directions. Trends Endocrinol Metab 2012;23:610–8. [2] Xiao Y, Peng C, Huang W, et al. Circulating fibroblast growth factor 23 is associated with angiographic severity and extent of coronary artery disease. PLoS One 2013;8:e72545. [3] Dalal M, Sun K, Cappola AR, et al. Relationship of serum fibroblast growth factor 23 with cardiovascular disease in older community-dwelling women. Eur J Endocrinol 2011;165:797–803. [4] Mirza MA, Larsson A, Melhus H, et al. Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis 2009;207:546–51. [5] Mirza MA, Hansen T, Johansson L, et al. Relationship between circulating FGF23 and total body atherosclerosis in the community. Nephrol Dial Transplant 2009; 24:3125–31. [6] Mirza MA, Larsson A, Lind L, et al. Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. Atherosclerosis 2009; 205:385–90. [7] Mirza MA, Alsio J, Hammarstedt A, et al. Circulating fibroblast growth factor-23 is associated with fat mass and dyslipidemia in two independent cohorts of elderly individuals. Arterioscler Thromb Vasc Biol 2011;31:219–27. [8] Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008;359:584–92. [9] Taylor EN, Rimm EB, Stampfer MJ, et al. Plasma fibroblast growth factor 23, parathyroid hormone, phosphorus, and risk of coronary heart disease. Am Heart J 2011;161: 956–62. [10] Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast growth factor (FGF)23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant 2009;24:2792–6. [11] Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 2011;305:2432–9. [12] Olauson H, Qureshi AR, Miyamoto T, et al. Relation between serum fibroblast growth factor-23 level and mortality in incident dialysis patients: are gender and cardiovascular disease confounding the relationship? Nephrol Dial Transplant 2010;25: 3033–8.
[13] Wolf M, Molnar MZ, Amaral AP, et al. Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. J Am Soc Nephrol 2011;22:956–66. [14] Kendrick J, Cheung AK, Kaufman JS, et al. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. J Am Soc Nephrol 2011;22:1913–22. [15] Nakano C, Hamano T, Fujii N, et al. Intact fibroblast growth factor 23 levels predict incident cardiovascular event before but not after the start of dialysis. Bone 2012;50:1266–74. [16] Baia LC, Humalda JK, Vervloet MG, et al. Fibroblast growth factor 23 and cardiovascular mortality after kidney transplantation. Clin J Am Soc Nephrol 2013;8:1968–78. [17] Scialla JJ, Xie H, Rahman M, et al. Fibroblast growth factor-23 and cardiovascular events in CKD. J Am Soc Nephrol 2014;25:349–60. [18] Lee JE, Gohda T, Walker WH, et al. Risk of ESRD and all cause mortality in type 2 diabetes according to circulating levels of FGF-23 and TNFR1. PLoS One 2013;8: e58007. [19] Parker BD, Schurgers LJ, Brandenburg VM, et al. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann Intern Med 2010;152:640–8. [20] Ix JH, Katz R, Kestenbaum BR, et al. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J Am Coll Cardiol 2012;60:200–7. [21] Arnlov J, Carlsson AC, Sundstrom J, et al. Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community. Kidney Int 2012;83:160–6. [22] Westerberg PA, Tivesten A, Karlsson MK, et al. Fibroblast growth factor 23, mineral metabolism and mortality among elderly men (Swedish MrOs). BMC Nephrol 2013;14:85. [23] Arnlov J, Carlsson AC, Sundstrom J, et al. Serum FGF23 and risk of cardiovascular events in relation to mineral metabolism and cardiovascular pathology. Clin J Am Soc Nephrol 2013;8:781–6. [24] Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008–12. [25] DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7: 177–88. [26] Shalhoub V, Shatzen EM, Ward SC, et al. FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. J Clin Invest 2012;122:2543–53.
Please cite this article as: Xiao Y, et al, Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studi..., Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.138
Y. Xiao et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Fig. 5. Analyses of subgroups relating FGF23 to all-cause mortality. FGF23, fibroblast growth factor 23.
Please cite this article as: Xiao Y, et al, Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studi..., Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.138
5
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studies Yunjun Xiao ⁎,1, Xianru Luo 1, Wei Huang, Jinzhou Zhang, Chaoqiong Peng Department of Nutrition and Food Hygiene, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
a r t i c l e
i n f o
Article history: Received 8 April 2014 Accepted 12 April 2014 Available online xxxx Keywords: Cardiovascular disease Cohort studies Fibroblast growth factor 23 Meta-analysis
Fibroblast growth factor 23 (FGF23), a hormone that is secreted by osteoblasts, is an important regulator of phosphorus and vitamin D metabolism [1]. The past few years have seen a rapidly growing interest in testing the hypothesis that increased FGF23 level is an independent risk factor of mortality and cardiovascular disease (CVD). Crosssectional studies have found higher circulating FGF23 concentrations were associated with severity of coronary artery disease (CAD) [2], prevalent CVD [3], left ventricular hypertrophy [4], total body atherosclerosis [5], endothelial dysfunction [6], and metabolic syndrome [7]. However, the reports from two nest case–control studies have been inconsistent; one concluded a positive association between FGF23 and mortality in hemodialysis patients [8], whereas the other concluded no association between FGF23 and risk of coronary heart disease (CHD) [9]. Recently, epidemiologic prospective cohort studies have investigated the link between FGF23 and risk of mortality and CVD events in different populations including kidney disease [10–17], diabetes [18], CAD patients [19], and community-based adults [20–23]. Some studies found a positive association, but the magnitudes of the association varied between these studies, and others reported no association. The inconsistent results of cohort studies prompted us to conduct a meta-analysis of prospective cohort studies to evaluate the association between FGF23 and risk of all-cause mortality and CVD events. We followed a standardized protocol and conducted and reported this analysis according to the guidelines of the Meta-analysis of Observation
⁎ Corresponding author at: Department of Nutrition and Food Hygiene, Shenzhen Center for Disease Control and Prevention, 8 Longyuan Road, Nanshan District, 518055 Shenzhen, China. Tel.: +86 755 25617321; fax: +86 755 25500660. E-mail address: [email protected] (Y. Xiao). 1 The authors contributed equally to this work.
Studies in Epidemiology group [24]. We conducted a systematic literature search of PubMed database through November 2013 for relevant articles that reported the association between FGF23 and risk of all-cause mortality and CVD events. To avoid missing any relevant study, we also searched the bibliographies of retrieved papers and recent reviews in the field. We did our search by using the following medical subject headings and keywords, such as Fibroblast Growth Factor-23, FGF23, and cardiovascular diseases, coronary disease, myocardial infarction, myocardial ischemia, coronary stenosis, coronary restenosis, cerebrovascular disorders, stroke, heart failure, death, mortality, all-cause mortality, cardiovascular mortality, and cohort studies, prospective studies, and follow-up studies. No restrictions were imposed. Two reviewers (Y.X. and X.L.) independently screened the abstracts and titles of the search results and eliminated articles only if they did not meet pre-stated inclusion criteria. The same 2 reviewers independently evaluated the remaining full-text articles for eligibility on the basis of a predefined set of eligibility criteria. Disagreements were resolved by discussion. Studies were considered eligible if they met the following criteria: 1) the study was a full-text, published prospective cohort study; 2) the exposure of interest was plasma or serum FGF23 concentrations; 3) the outcome of interest was all-cause or cardiovascular mortality or CVD events, myocardial infarction, stroke, or heart failure; and 4) relative risk (RR) and the corresponding 95% confidence interval (CI) or sufficient data to calculate them were provided. In addition, studies were excluded if they met the exclusion criteria that the sample size of a study was less than 200 and the duration of follow-up was less than one year. Two reviewers independently abstracted data on participant characteristics and study results with adjustment factors by using a standardized data collection form. Discrepancies in data extraction between reviewers were resolved by consensus. We extracted any reported RRs, HRs, or incidence density ratios of outcomes and study characteristics for each trial. We also systematically assessed key indicators of study quality: methods of outcome adjudication and ascertainment that account for confounders and completeness of follow-up ascertainment. To calculate summary estimates and 95% CIs of the risk for FGF23, we pooled both RRs and HRs by using either fixed-effects models or, in the presence of heterogeneity, random-effects models [25]. The presence of heterogeneity across studies was evaluated by using the Q statistic with a conservative p value of 0.10. Potential publication bias was evaluated by Begg and Egger tests at the p b 0.10 level of significance. All analyses were performed using STATA version 11.0 (StataCorp LP, College Station, Texas). A p value b 0.05 was considered statistically significant, except where otherwise specified.
http://dx.doi.org/10.1016/j.ijcard.2014.04.138 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Xiao Y, et al, Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studi..., Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.138
2
Y. Xiao et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Fig. 1. Flow chart of study selection. CVD, cardiovascular disease; FGF23, fibroblast growth factor 23.
Fourteen prospective cohort studies were finally included in our present meta-analysis. Fig. 1 shows details of the study selection. The main characteristics of studies in the meta-analysis were presented in
Table 1. Among the 14 studies included here, 12 studies reported allcause mortality and 6 studies reported CVD events. Outcome assessments, duration of follow up, assessment of FGF23, and methodological quality varied across studies. Overall, high FGF23 levels were associated with a significantly increased risk of all-cause mortality (RR: 1.34 [95% CI: 1.20 to 1.48]; p b 0.001). Substantial heterogeneity was observed (I2 = 71.1%, p b 0.001) (Fig. 2). The overall combined RR in relation to FGF23 was 1.21 (95% CI: 1.11 to 1.31; p b 0.001) for CVD events. There was no evidence of heterogeneity for CVD events (I2 = 16.9%, p = 0.305) (Fig. 3). The combining RRs for cardiovascular mortality, myocardial infarction, stroke, and heart failure from fixed-effects models are presented in Fig. 4. Subgroup and sensitivity analyses were conducted to explore potential sources of heterogeneity in the association between FGF23 and risk of all-cause mortality and to examine the influence of various exclusion criteria on the overall risk estimate. The overall combined RRs in relation to FGF23 remained significant in various subgroups stratified by publication year, mean age, sample size, duration of follow-up, and pre-existing disease (Fig. 5). Additional sensitivity analyses with exclusion of 2 studies [21,22] that only enrolled male participants did not change the overall risk estimate (RR: 1.37 [95% CI: 1.29 to 1.44]; p b 0.001), but no significant heterogeneity was observed among the remaining studies (I2 = 38.1%, p = 0.104). The Begg and Egger tests also showed no evidence of publication bias among studies of FGF23 and all-cause mortality (Begg, p = 0.373; Egger, p = 0.163). In the present study we found that high FGF23 level was significantly and independently associated with an increased risk of 34% for all-cause mortality, 21% for CVD events, 24% for cardiovascular mortality, 15% for stroke, and 38% for heart failure. But no independent association was observed between FGF23 and risk of myocardial infarction. Subgroup analyses showed that C-terminal but not intact FGF23 was significantly
Table 1 Characteristics of 14 prospective cohort studies of FGF23 and all-cause mortality and cardiovascular events. Source
Location
Population
Sex/age, yrs
Recruitment time
Duration
FGF23 measurement
Outcomes
Jean (2009) [10]
France
695 days
2000–2002
6.0 yrs
Olauson (2010) [12]
Sweden United States
December 1994– April 2008 February–August 2007
23 months
Wolf (2011) [13] Kendrick (2011) [14]
United States
229 incident dialysis patients 984 stable kidney transplant recipients 1099 advanced CKD patients
C-terminal, 2740 (1192–8667) RU/ml C-terminal, 43.1 (28.9–72.3) RU/ml Intact, 2526 (431–19495) ng/L C-terminal, 28 (20–43) RU/ml C-terminal, 392 (216–945) RU/ml
All-cause death
United States
Male/female, 66.6 ± 14 Male/female, 67 ± 11 Male/female, 55 (33, 68) Male/female, 51 ± 13 Male/female, 69 ± 11
September 2006
Parker (2010) [19]
219 long haemodialysis patients 833 CAD patients
Isakova (2011) [11]
United States
Arnlov (2012) [21]
Sweden
Ix (2012) [20]
United States
Nakano (2012) [15]
Japan
Baia (2013) [16]
Netherlands
3879 CKD stages 2–4 patients 727 community-based men 3107 community-based adults 738 predialysis outpatients 593 stable kidney transplant recipients
Lee (2013) [18]
United States
Westerberg (2013) [22]
Sweden
Scialla (2013) [17]
United States
Arnlov (2013) [23]
Sweden
37 months
September 2001 –October 2003
2.9 yrs
Male/female, 58.2 ± 11.0 Male, 77.6 ± 0.76 Male/female, 78 ± 5 Male/female, 64 (54, 72) Male/female, 52 ± 12
June 2003–September 2008 1998–2001
3.5 yrs 9.7 yrs
1996–1997
10.5 yrs
May 2005–July 2007
4.4 yrs
August 2001–July 2003
7.0 yrs
380 Type 2 diabetes patients
Male/female, 54 ± 10
1991–1995
8–12 yrs
3014 population-based men 3860 CKD stages 2–4 patients 973 community-based men
Male, 75.5 ± 3.2 Male/female, 21–74 Male, 70
2001–2004
4.5 yrs
2003–2008
3.7 yrs
January 2001–June 2004
5.1 yrs
C-terminal, 145.5 (96–239) RU/ml Intact, 44 (9–162) pg/ml C-terminal, 70 (53–99) RU/ml Intact, 49.5 (31.7–80.5) pg/ml C-terminal, 140 (95–219) RU/ml C-terminal, Alive 50 (36–75), ESRD 117 (65–238), Death 84 (53–133) RU/ml Intact, 43.5 (32.4–57.5) pg/ml C-terminal, 145.4 (96.0–238.8) RU/ml Intact, 47 ± 24 pg/ml
All-cause death, CVD events All-cause death All-cause death, allograft loss All-cause death, CVD events, initiation of chronic dialysis All-cause mortality and ESRD All-cause and cardiovascular death All-cause death, heart failure, CVD events All-cause death, CVD events All-cause and cardiovascular death, graft failure All-cause and cardiovascular death, ESRD All-cause and cardiovascular death Atherosclerotic events, congestive heart failure CVD events
CAD, coronary artery disease; CKD, chronic kidney disease; CVD, cardiovascular disease; ESRD, end-stage renal disease; FGF23, fibroblast growth factor 23.
Please cite this article as: Xiao Y, et al, Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studi..., Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.138
Y. Xiao et al. / International Journal of Cardiology xxx (2014) xxx–xxx
3
Fig. 2. Association between FGF23 and risk of all-cause mortality. FGF23, fibroblast growth factor 23.
associated with risk of all-cause mortality. On the basis of our findings, several questions arise. First, is the association of FGF23 with mortality and CVD causal? To answer this question, several issues should be considered, including different measurements of FGF23 and adequate control for confounding factors. Second, could treating high FGF23 level with drug intervention or dietary therapy protect against mortality or CVD events? On the contrary, a recent study found FGF23 neutralization with a monoclonal FGF23 antibody likely contributed to the increased mortality in mineral and bone disorder rat model [26]. Third, by what exact mechanisms does FGF23 independently increase the risk of CVD? Several factors such as left ventricular hypertrophy, arterial calcification, hyperphosphatemia and vitamin D deficiency, and endothelial dysfunction, may offer insights. Further studies, including well-designed clinical trials, are
warranted to address these questions for a better understanding of the association and to provide convincing evidence for clinical practice in CVD prevention. In summary, this meta-analysis of prospective cohort studies suggests that FGF23 significantly increases the risk of all-cause mortality and CVD events, and the increase is probably independent of conventional cardiovascular risk factors. Y.X., W.H., and C.P. developed the study concept and designed the study; Y.X., X.L., J.Z. conducted the data extraction and analyzed the data. Y.X. and X.L. wrote the paper. J.Z., W.H., and C.P. reviewed and edited the manuscript. This work was supported by grants from the Guangdong Provincial Traditional Chinese Medicine Research Fund (20131037) and the Shenzhen Municipal Science and Technology Project (201302139).
Fig. 3. Association between FGF23 and risk of CVD events. FGF23, fibroblast growth factor 23.
Please cite this article as: Xiao Y, et al, Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studi..., Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.138
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Fig. 4. Association between FGF23 and risk of cardiovascular mortality, myocardial infarction, stroke, and heart failure. FGF23, fibroblast growth factor 23.
References [1] Bhattacharyya N, Chong WH, Gafni RI, et al. Fibroblast growth factor 23: state of the field and future directions. Trends Endocrinol Metab 2012;23:610–8. [2] Xiao Y, Peng C, Huang W, et al. Circulating fibroblast growth factor 23 is associated with angiographic severity and extent of coronary artery disease. PLoS One 2013;8:e72545. [3] Dalal M, Sun K, Cappola AR, et al. Relationship of serum fibroblast growth factor 23 with cardiovascular disease in older community-dwelling women. Eur J Endocrinol 2011;165:797–803. [4] Mirza MA, Larsson A, Melhus H, et al. Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis 2009;207:546–51. [5] Mirza MA, Hansen T, Johansson L, et al. Relationship between circulating FGF23 and total body atherosclerosis in the community. Nephrol Dial Transplant 2009; 24:3125–31. [6] Mirza MA, Larsson A, Lind L, et al. Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. Atherosclerosis 2009; 205:385–90. [7] Mirza MA, Alsio J, Hammarstedt A, et al. Circulating fibroblast growth factor-23 is associated with fat mass and dyslipidemia in two independent cohorts of elderly individuals. Arterioscler Thromb Vasc Biol 2011;31:219–27. [8] Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008;359:584–92. [9] Taylor EN, Rimm EB, Stampfer MJ, et al. Plasma fibroblast growth factor 23, parathyroid hormone, phosphorus, and risk of coronary heart disease. Am Heart J 2011;161: 956–62. [10] Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast growth factor (FGF)23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant 2009;24:2792–6. [11] Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 2011;305:2432–9. [12] Olauson H, Qureshi AR, Miyamoto T, et al. Relation between serum fibroblast growth factor-23 level and mortality in incident dialysis patients: are gender and cardiovascular disease confounding the relationship? Nephrol Dial Transplant 2010;25: 3033–8.
[13] Wolf M, Molnar MZ, Amaral AP, et al. Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. J Am Soc Nephrol 2011;22:956–66. [14] Kendrick J, Cheung AK, Kaufman JS, et al. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. J Am Soc Nephrol 2011;22:1913–22. [15] Nakano C, Hamano T, Fujii N, et al. Intact fibroblast growth factor 23 levels predict incident cardiovascular event before but not after the start of dialysis. Bone 2012;50:1266–74. [16] Baia LC, Humalda JK, Vervloet MG, et al. Fibroblast growth factor 23 and cardiovascular mortality after kidney transplantation. Clin J Am Soc Nephrol 2013;8:1968–78. [17] Scialla JJ, Xie H, Rahman M, et al. Fibroblast growth factor-23 and cardiovascular events in CKD. J Am Soc Nephrol 2014;25:349–60. [18] Lee JE, Gohda T, Walker WH, et al. Risk of ESRD and all cause mortality in type 2 diabetes according to circulating levels of FGF-23 and TNFR1. PLoS One 2013;8: e58007. [19] Parker BD, Schurgers LJ, Brandenburg VM, et al. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann Intern Med 2010;152:640–8. [20] Ix JH, Katz R, Kestenbaum BR, et al. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J Am Coll Cardiol 2012;60:200–7. [21] Arnlov J, Carlsson AC, Sundstrom J, et al. Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community. Kidney Int 2012;83:160–6. [22] Westerberg PA, Tivesten A, Karlsson MK, et al. Fibroblast growth factor 23, mineral metabolism and mortality among elderly men (Swedish MrOs). BMC Nephrol 2013;14:85. [23] Arnlov J, Carlsson AC, Sundstrom J, et al. Serum FGF23 and risk of cardiovascular events in relation to mineral metabolism and cardiovascular pathology. Clin J Am Soc Nephrol 2013;8:781–6. [24] Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008–12. [25] DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7: 177–88. [26] Shalhoub V, Shatzen EM, Ward SC, et al. FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. J Clin Invest 2012;122:2543–53.
Please cite this article as: Xiao Y, et al, Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studi..., Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.138
Y. Xiao et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Fig. 5. Analyses of subgroups relating FGF23 to all-cause mortality. FGF23, fibroblast growth factor 23.
Please cite this article as: Xiao Y, et al, Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studi..., Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.138
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