Fibroblast Growth Factor 23 and Incident Cardiovascular Disease and Mortality in Middle-Aged Adults.
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ABSTRACT:
SUBMITTER: Paul S
PROVIDER: S-EPMC8475041 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Blacks have the highest prevalence of hypertension in the United States. Higher levels of FGF23 (fibroblast growth factor-23) have been associated with worse cardiovascular outcomes. Whether FGF23 is associated with rising blood pressure (BP) and racial differences in incident hypertension is unclear. We studied 1758 adults (45.0±3.7 years; 57.8% female; 36.9% black) without hypertension or cardiovascular disease who participated in the year 20 (2005-2006) follow-up examination of the CARDIA study (Coronary Artery Risk Development in Young Adults). We investigated the associations of baseline (year 20) cFGF23 (C-terminal FGF23) levels with longitudinal BP patterns and incident hypertension (defined as being on antihypertensive medication, systolic BP ?130 or diastolic BP ?80 mm?Hg) during 2 follow-up visits (years 25 and 30). During follow-up, 35.2% of participants developed hypertension. In multivariable linear mixed models, there were greater increases in systolic BP from year 20 to 25 and year 25 to 30 in the highest FGF23 quartile relative to the lowest quartile (+2.1 mm?Hg, P=0.0057 and +2.2 mm?Hg, P=0.0108, respectively for each time period), whereas there were greater increases in diastolic BP from year 20 to 25 in the highest quartile relative to the lowest (+1.6 mm?Hg; P=0.0024). In multivariable modified Poisson regression analyses, the highest FGF23 quartile was associated with a 45% greater risk of developing hypertension during follow-up compared with the lowest quartile (relative risk, 1.45 [1.18-1.77]). Results did not vary by race (Pinteraction=0.1523). Higher FGF23 levels are independently associated with rising BP over time and an increased risk of incident hypertension but not racial differences in hypertension.
| S-EPMC6002950 | biostudies-literature
Project description:An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44±15 ml/min per 1.73 m(2)). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4.
| S-EPMC3904568 | biostudies-literature
Project description:High levels of fibroblast growth factor 23 are associated with accelerated progression of CKD. Whether high fibroblast growth factor 23 levels also predict incident CKD is uncertain.A prospective case-cohort study was conducted within the Action to Control Cardiovascular Risk in Diabetes Trial. The analytic sample consisted of a random subcohort of 590 patients with type 2 diabetes without prevalent CKD at baseline, 124 of whom developed incident CKD during follow-up, and 520 additional patients with incident CKD outside the random subcohort. The association between serum intact fibroblast growth factor 23 and incident CKD, defined as the new onset of eGFR<60 ml/min per 1.73 m(2) that represented a ?25% decrease from baseline in an individual with eGFR?60 ml/min per 1.73 m(2) and no microalbuminuria (<30 mg/g creatinine) at baseline, was tested.The mean baseline eGFR in the random subcohort was 90.9±22.7 ml/min per 1.73 m(2). During a median follow-up of 4.7 years, there was a total of 644 patients with incident CKD. The median baseline fibroblast growth factor 23 level was modestly higher among patients with incident CKD versus controls (43.5, interquartile range=34.7-55.1 versus 39.8, interquartile range=31.9-49.5 pg/ml; P<0.001). Higher baseline fibroblast growth factor 23 levels were associated with higher risk of incident CKD in unadjusted and demographics-adjusted models, but the effect was attenuated after additional adjustment for clinical risk factors and baseline eGFR (hazard ratio per SD of natural log fibroblast growth factor 23, 1.09; 95% confidence interval, 0.94 to 1.27), which was the strongest predictor of incident CKD. Consistent with the results of primary analyses, baseline fibroblast growth factor 23 was not associated with eGFR slope.Higher fibroblast growth factor 23 levels are not independently associated with higher risk of incident CKD in patients with type 2 diabetes.
| S-EPMC4284418 | biostudies-literature
Project description:ImportanceHigher circulating fibroblast growth factor 23 (FGF23) concentrations are associated with cardiovascular disease events linked to heart failure, but associations of FGF23 with coronary heart disease (CHD) have been less consistent.ObjectiveTo determine the association of plasma FGF23 concentrations with incident CHD and whether this association differs by race, sex, or chronic kidney disease status.Design, setting, and participantsWe examined the association of FGF23 concentrations with incident CHD risk within the Reasons for Geographic and Racial Differences in Stroke study, a prospective cohort of black and white adults 45 years and older enrolled between January 2003 and October 2007 with follow-up through December 31, 2011. Using a case-cohort design, we measured FGF23 concentrations in 829 participants who developed incident CHD and in 812 participants randomly selected from the Reasons for Geographic and Racial Differences in Stroke study cohort (cohort random sample). To account for the stratified sampling design, the cohort random sample was weighted back to the original cohort overall (n?=?22?127). Cox proportional hazards models were used to examine the association of FGF23 concentration with incident CHD, adjusting for CHD risk factors and kidney function. In prespecified analyses, we examined whether race, sex, or chronic kidney disease modified the association of FGF23 concentration with incident CHD.ExposuresPlasma C-terminal FGF23 concentrations.Main outcomes and measuresInvestigator-adjudicated incident CHD events.ResultsOf the 22?127 participants in the weighted cohort random sample, 13?059 (58.9%) were female and 9435 (42.6%) were black, and the mean age was 64.3 (95% CI, 63.7-64.9) years. Greater age, lower estimated glomerular filtration rate, higher urine albumin to creatinine ratio, and female sex were associated with higher FGF23 concentration at baseline. In multivariable models adjusted for established CHD risk factors and kidney function, higher FGF23 concentrations were associated with greater risk of CHD (hazard ratio [HR] comparing fourth with first quartile, 2.15; 95% CI, 1.35-3.42). The magnitude and strength of these associations differed by sex. However, these differences were no longer observed when adjusting for hormone therapy in women (men: HR comparing fourth with first quartile, 2.40; 95% CI, 1.30-4.42; women: HR comparing fourth with first quartile, 2.34; 95% CI, 1.04-5.27) or when using sex-specific FGF23 quartiles (men: HR comparing fourth with first quartile, 2.65; 95% CI, 1.43-4.90; women: HR comparing fourth with first quartile, 2.26; 95% CI, 1.02-5.03).Conclusions and relevanceHigher FGF23 concentrations were associated with greater risk of CHD. Heterogeneity in the association by sex may be caused by differences in the distribution of plasma FGF23 concentrations or the use of hormone therapy in men vs women.
| S-EPMC5875372 | biostudies-literature
Project description:Both the activation of the renin angiotensin aldosterone system (RAAS) and elevations of circulating Fibroblast Growth Factor-23 (FGF-23) have been implicated in the pathogenesis of left ventricular hypertrophy (LVH) in chronic kidney disease. To investigate potential cross-talk between RAAS and FGF-23, we administered angiotensin II (Ang II) to wild-type rodents and the Hyp mouse model of excess FGF-23. Ang II administration for four weeks to wild-type rodents resulted in significant increases in systolic blood pressure and LVH. Unexpectedly, FGF-23 circulating levels were increased by 1.5-1.7 fold in Ang II treated animals. In addition, Ang II treatment increased expression of FGF-23 message levels in bone, the predominant tissue for FGF-23 production, and induced expression of FGF-23 and its co-receptor ?-Klotho in the heart, which normally does not express FGF-23 or ?-Klotho in physiologically relevant levels. Hyp mice with elevated FGF-23 exhibited increased blood pressure and LVH at baseline. Ang II administration to Hyp mice resulted further increments in blood pressure and left ventricular hypertrophy, consistent with additive cardiovascular effects. These findings suggest that FGF-23 may participate in unexpected systemic and paracrine networks regulating hemodynamic and myocardial responses.
| S-EPMC6098163 | biostudies-literature
Project description:BackgroundFibroblast growth factor 23 (FGF-23) is a hormone that increases the rate of urinary excretion of phosphate and inhibits renal production of 1,25-dihydroxyvitamin D, thus helping to mitigate hyperphosphatemia in patients with kidney disease. Hyperphosphatemia and low 1,25-dihydroxyvitamin D levels are associated with mortality among patients with chronic kidney disease, but the effect of the level of FGF-23 on mortality is unknown.MethodsWe examined mortality according to serum phosphate levels in a prospective cohort of 10,044 patients who were beginning hemodialysis treatment and then analyzed FGF-23 levels and mortality in a nested case-control sample of 200 subjects who died and 200 who survived during the first year of hemodialysis treatment. We hypothesized that increased FGF-23 levels at the initiation of hemodialysis would be associated with increased mortality.ResultsSerum phosphate levels in the highest quartile (>5.5 mg per deciliter [1.8 mmol per liter]) were associated with a 20% increase in the multivariable adjusted risk of death, as compared with normal levels (3.5 to 4.5 mg per deciliter [1.1 to 1.4 mmol per liter]) (hazard ratio, 1.2; 95% confidence interval [CI], 1.1 to 1.4). Median C-terminal FGF-23 (cFGF-23) levels were significantly higher in case subjects than in controls (2260 vs. 1406 reference units per milliliter, P<0.001). Multivariable adjusted analyses showed that increasing FGF-23 levels were associated with a monotonically increasing risk of death when examined either on a continuous scale (odds ratio per unit increase in log-transformed cFGF-23 values, 1.8; 95% CI, 1.4 to 2.4) or in quartiles, with quartile 1 as the reference category (odds ratio for quartile 2, 1.6 [95% CI, 0.8 to 3.3]; for quartile 3, 4.5 [95% CI, 2.2 to 9.4]; and for quartile 4, 5.7 [95% CI, 2.6 to 12.6]).ConclusionsIncreased FGF-23 levels appear to be independently associated with mortality among patients who are beginning hemodialysis treatment. Future studies might investigate whether FGF-23 is a potential biomarker that can be used to guide strategies for the management of phosphorus balance in patients with chronic kidney disease.
| S-EPMC2890264 | biostudies-literature
Project description:Background Previous studies have documented the cardiometabolic health benefits of plant-based diets; however, these studies were conducted in selected study populations that had narrow generalizability. Methods and Results We used data from a community-based cohort of middle-aged adults (n=12 168) in the ARIC (Atherosclerosis Risk in Communities) study who were followed up from 1987 through 2016. Participants' diet was classified using 4 diet indexes. In the overall plant-based diet index and provegetarian diet index, higher intakes of all or selected plant foods received higher scores; in the healthy plant-based diet index, higher intakes of only the healthy plant foods received higher scores; in the less healthy plant-based diet index, higher intakes of only the less healthy plant foods received higher scores. In all indexes, higher intakes of animal foods received lower scores. Results from Cox proportional hazards models showed that participants in the highest versus lowest quintile for adherence to overall plant-based diet index or provegetarian diet had a 16%, 31% to 32%, and 18% to 25% lower risk of cardiovascular disease, cardiovascular disease mortality, and all-cause mortality, respectively, after adjusting for important confounders (all P<0.05 for trend). Higher adherence to a healthy plant-based diet index was associated with a 19% and 11% lower risk of cardiovascular disease mortality and all-cause mortality, respectively, but not incident cardiovascular disease (P<0.05 for trend). No associations were observed between the less healthy plant-based diet index and the outcomes. Conclusions Diets higher in plant foods and lower in animal foods were associated with a lower risk of cardiovascular morbidity and mortality in a general population.
| S-EPMC6759882 | biostudies-other
Project description:BackgroundElevated serum concentrations of fibroblast growth factor 23 (FGF23) are associated with cardiovascular mortality in patients with chronic kidney disease and those undergoing dialysis.ObjectivesWe tested the hypotheses that polymorphisms in FGF23, its co-receptor alpha-klotho (KL), and/or FGF23 receptors (FGFR) are associated with cardiovascular events and/or mortality.MethodsWe used 1,494 DNA samples collected at baseline from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events Trial, in which patients were randomized to the calcimimetic cinacalcet or placebo for the treatment of secondary hyperparathyroidism. We analyzed European and African Ancestry samples separately and then combined summary statistics to perform a meta-analysis. We evaluated single-nucleotide polymorphisms (SNPs) in FGF23, KL, and FGFR4 as the key exposures of interest in proportional hazards (Cox) regression models using adjudicated endpoints (all-cause and cardiovascular mortality, sudden cardiac death, and heart failure [HF]) as the outcomes of interest.Resultsrs11063112 in FGF23 was associated with cardiovascular mortality (risk allele = A, hazard ratio [HR] 1.32, meta-p value = 0.004) and HF (HR 1.40, meta-p value = 0.007). No statistically significant associations were observed between FGF23 rs13312789 and SNPs in FGFR4 or KL genes and the outcomes of interest.Conclusionsrs11063112 was associated with HF and cardiovascular mortality in patients receiving dialysis with moderate to severe secondary hyperparathyroidism.
| S-EPMC6473180 | biostudies-literature
Project description:BackgroundIn the Multicenter AIDS Cohort Study, we examined whether fibroblast growth factor-23 (FGF-23), a bone-derived phosphaturic hormone involved in bone metabolism, is associated with incident frailty. Furthermore, we examined whether this association differs by HIV serostatus and race.MethodsOf 715 men assessed for frailty and selected for FGF-23 measurements using stored blood samples (2007-2011), 512 men were nonfrail at/before the baseline visit. Frailty was defined by the presence of ≥3 of the following on 2 consecutive 6-month visits within 1 year: unintentional weight loss ≥10 pounds, weakness, slowness, low energy, and low physical activity. We determined the association of FGF-23 levels with incident frailty using proportional hazards models adjusting for sociodemographics, comorbidities, and kidney function.ResultsSixty-five percent were HIV-infected; 29% were black. Median baseline FGF-23 levels were lower in HIV-infected vs. HIV-uninfected men (33.7 vs. 39.9 rU/mL, P = 0.006) but similar by race. During a median follow-up of 6.6 years, 32 men developed frailty; they had higher baseline FGF-23 levels vs. men who remained nonfrail (45 vs. 36 rU/mL, P = 0.02). FGF-23 (per doubling) was associated with a 1.63-fold risk of frailty [95% confidence interval (CI): 1.19 to 2.23]; results did not differ by HIV serostatus. Conversely, FGF-23 was associated with a 2.72-fold risk of frailty among blacks (95% CI: 1.51 to 4.91) but had minimal association among nonblacks (hazard ratio = 1.26, 95% CI: 0.77 to 2.05; p-interaction = 0.024).ConclusionsAmong men with or at-risk of HIV infection, higher FGF-23 was associated with greater risk of frailty, particularly in blacks. The mechanisms by which FGF-23 may contribute to frailty warrant further study.
| S-EPMC6289864 | biostudies-literature
Project description:BackgroundFibroblast 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 resultsWe tested the associations of circulating FGF-23 concentration with incident AF among 6398 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 1350 participants in the Cardiovascular Health Study (CHS), all free of clinical cardiovascular disease at baseline. Over a median of 7.7 and 8.0 years of follow-up, we observed 291 and 229 incident AF events in MESA and CHS, respectively. In multivariable Cox proportional hazards models, each 2-fold-higher FGF-23 concentration was associated with a 41% higher risk of incident AF in MESA (hazard ratio, 1.41; 95% confidence interval, 1.13-1.76; P=0.003) and a 30% higher risk of incident AF in CHS (hazard ratio, 1.30; 95% confidence interval, 1.05-1.61; P=0.016) after adjustment for potential confounding characteristics, including kidney disease. Serum phosphate concentration was significantly associated with incident AF in MESA (hazard ratio, 1.15 per 0.5 mg/dL; 95% confidence interval, 1.02-1.31; P=0.023) but not CHS. In MESA, an association of low estimated glomerular filtration rate with incident AF was partially attenuated by adjustment for FGF-23.ConclusionHigher circulating FGF-23 concentration is associated with incident AF and may, in part, explain the link between chronic kidney disease and AF.
| S-EPMC4108550 | biostudies-literature