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. Author manuscript; available in PMC: 2019 Dec 30.
Published in final edited form as: Curr Opin Endocrinol Diabetes Obes. 2016 Dec;23(6):423–429. doi: 10.1097/MED.0000000000000294

FGF-23 and Cardiovascular Disease: Review of Literature

Jasveen Batra 1, Rupinder Singh Buttar 1, Pardeep Kaur 1, Jacqueline Kreimerman 1, Michal L Melamed 1
PMCID: PMC6936216  NIHMSID: NIHMS941338  PMID: 27652999

Abstract

Purpose of Review

This review examines associations between FGF-23 and cardiovascular disease.

Recent findings

FGF-23 is a hormone produced by osteocytes and osteoblasts which aids with phosphate excretion by the kidney and acts as a negative feedback regulator for activated vitamin D synthesis. Recent studies have found associations between elevated FGF-23 levels and a number of cardiovascular diseases including hypertension, left ventricular hypertrophy, endothelial dysfunction and cardiovascular events and mortality.

Summary

Recent studies have explored the possible effects of FGF-23 on the cardiovascular system. In animal and observational human studies, there is a link between elevated FGF-23 levels and multiple cardiovascular outcomes, including hypertension, left ventricular hypertrophy and cardiovascular events and mortality. Further studies are required to evaluate whether decreasing FGF-23 levels improves cardiovascular outcomes.

Keywords: FGF-23, Cardiovascular disease, vitamin D, Phosphorus, chronic kidney disease

Introduction

Fibroblast growth factor 23 (FGF-23), a ~32 kDa hormone secreted by osteocytes and osteoblasts, is a major regulator of vitamin D and phosphate homeostasis. In the kidney, FGF-23 most commonly binds to an FGF receptor and α-klotho together in order to have biologic activity. The Klotho null mouse and the FGF-23 null mouse exhibit a similar rapid aging phenotype, with hyperphosphatemia, increased 1,25 dihydroxyvitamin D levels, and ectopic calcification.1,2 High levels of FGF-23 produced by tumors or due to constant activation of FGF-23 receptors by missense gene mutations, can cause increased phosphate urinary excretion by downregulating NPT2a in the proximal tubule and hypophosphatemia.3–5 High levels of FGF-23 also suppress the renal expression of 1- α hydroxylase (CYP27B1) and increase activity of the 24-hydroxylase enzyme (CYP24A1),6 which together result in decreased levels of the active 1, 25-dihydroxyvitamin D, decreased phosphate absorption in the intestines and rickets or osteomalacia.7

FGF-23 has been associated with numerous different manifestations of cardiovascular disease (CVD). Animal studies reveal direct toxicities of an infusion of FGF-23 in the form of myocyte hypertrophy and left ventricular hypertrophy (LVH).8 Previous studies have linked LVH, cardiovascular and all-cause mortality to higher levels of FGF-23.8–10 Results of several studies reveal associations between higher FGF-23 and an increased risk of cardiovascular events, independent of kidney function or serum levels of other mineral metabolites.11–14 An independent risk of heart failure as well as cardiovascular death has been seen in stable ischemic heart disease patients with elevated levels of FGF-23 regardless of renal function.15 Interestingly, recent data also reveals associations between elevated FGF-23 levels and hypertension.16 The aim of this review is to present the most updated research on FGF-23 and its associations with CVD.

REGULATORS OF THE RELEASE OF FGF-23

There appear to be several key regulators of FGF-23 including 1, 25-dihydroxyvitamin D, parathyroid hormone (PTH), phosphate intake and possibly others. FGF-23 levels increase as GFR falls, likely due to the need for more phosphate excretion as nephrons fail. Therapy with activated vitamin D compounds, such as calcitriol, paricalcitol or doxercalciferol, cause FGF-23 elevations.17,18 Treatment with nutritional vitamin D compounds, such as cholecalciferol and ergocalciferol, has been shown to increase FGF-23 in some studies19–21 but not in others.22 Therefore, it is somewhat unclear at this time whether nutritional vitamin D affects FGF-23 levels. Dietary phosphate and PTH are other important regulator of FGF-23.23,24 Activated vitamin D, dietary phosphate and PTH are regulators that are physiologically consistent with the actions of FGF-23. Newer regulators have been described that need further exploration. In a pilot study of 20 patients with CKD, therapy with sodium bicarbonate elevated FGF-23 over a 6 week period.25 Experimental induction of a myocardial infarction in a rat model also led to elevation of FGF-23 levels, independent of changes in PTH and klotho.26 In addition, patients with acute decompensated heart failure had much higher levels of FGF-23 compared to controls but the excess FGF-23 was not of myocardial origin, suggesting that control of FGF-23 is more complicated than previously thought.27 Further research is needed to evaluate the mechanisms behind these observations.

FGF-23 AND CHRONIC KIDNEY DISEASE

FGF-23 levels increase as CKD progresses and elevated FGF-23 levels are often the first mineral metabolic marker that changes in CKD.28 Alongside this change, renal klotho levels are also seen to decrease in patients with CKD prior to FGF-23 elevation.29 As the kidneys fail, they become less able to excrete the body’s phosphate load. Elevated phosphate levels have been associated with early mortality and cardiovascular disease in patients with kidney disease and in the general population.30–32 As kidney disease progresses and the body is less able to excrete phosphate, FGF-23 levels increase to aid the body by increasing excretion of phosphate by the kidney but this increase appears to be, in the long-term, maladaptive.33

Much of the early work on associations between elevated FGF-23 and cardiovascular events and mortality was performed in patients with kidney disease.10,34 In most studies of mortality and cardiovascular events, the magnitude of the effect of FGF‐23 was larger than, and independent of, serum phosphate.12,28,34,35 Phosphate and FGF-23 have been hypothesized to have distinct effects on the cardiovascular system, with elevated FGF-23 directly promoting cardiac remodeling and hyperphosphatemia directly promoting arterial injury36,37, although other studies have suggested a synergism between FGF-23 and phosphate.38 In addition to elevated cardiovascular risk, elevated FGF-23 levels have been associated with a faster progression to end-stage renal disease.12,28

FGF-23 AND HYPERTENSION

Recently, elevated FGF-23 levels have been associated with increased plasma volume and hypertension in animal and human studies.16,39 Higher sodium intake is a fairly well-established independent risk factor on elevations in blood pressure.40–42 In mouse models, infusion of FGF-23 was found to increase sodium reabsorption.39 Mice lacking the FGF-23 gene excreted more sodium in their urine, whereas mice with elevated FGF-23 levels had higher plasma volumes, hypertension and cardiac hypertrophy.39 This study suggested that FGF-23 stimulates sodium re-absorption and volume expansion through Na-Cl co-transporter (NCC) in the distal convoluted tubule.39 In addition, a high phosphate diet in the 5/6 nephrectomized rat model increased FGF-23 levels and angiotensin-converting enzyme expression, possibly leading to hypertension through direct activation of the renin-angiotensin system.43

Several patient and epidemiologic studies also show an association between high FGF-23 levels and hypertension. In a small study of 42 pediatric hypertensive patients, urinary FGF-23/creatinine ratios were higher than in healthy children.44 The positive correlation of FGF-23 was seen with systolic but not diastolic blood pressure.44 In the Atherosclerosis Risk in Communities (ARIC) study, among 7,948 middle-aged individuals without hypertension at baseline, higher FGF-23 levels were associated with the development of hypertension over a median follow-up of 5.9 years. After adjustment for demographics, behaviors and clinical factors (including kidney function), the final hazard ratio for incident hypertension was 1.21 (95% confidence interval: 1.08, 1.35) for the highest decile of FGF-23 compared with the lowest.16 Adjustment for serum PTH, calcium and 25-hydroxyvitamin D levels did not alter the association. Thus, both animal models and epidemiological studies suggest that elevated FGF-23 levels may play a role in hypertension.

FGF-23 LEVELS AND SUBCLINICAL ATHEROSCLEROSIS

Associations have been found between high FGF-23 levels and subclinical atherosclerosis including coronary artery calcification and carotid artery intima-media thickness. A study of 282 African American patients with type 2 diabetes mellitus but without significant kidney disease showed an association of higher FGF-23 levels with coronary artery calcified atherosclerotic plaque, but not carotid artery or aorto-illiac calcified plaque.45 A different study in different ethnic groups (68% Hispanic) did show an association between higher FGF-23 levels and carotid calcification.46 Similar associations between high FGF-23 levels and coronary artery calcification scores were seen in a study of 150 patients with CKD stages 3-5D in China47 and in a study of 142 French patients.48 The study from China also found that patients with the highest FGF-23 levels and the most coronary calcification had the highest risk of all-cause mortality.47 In a study done on children with stage 2 CKD and hypertension, findings were consistent in showing that higher FGF-23 levels were associated with arterial wall stiffness.49 Higher FGF-23 levels are also associated with higher carotid artery intima-media thickness, another marker of subclinical atherosclerosis, in peritoneal dialysis patients.50

The mechanisms for association between FGF-23 and subclinical atherosclerosis remain unclear. If elevated FGF-23 levels are associated with hypertension and hypertension is a risk for atherosclerosis, elevated FGF-23 levels could be associated with atherosclerosis and vascular dysfunction through hypertension. Another hypothesis suggests that FGF-23 enhances phosphate induced vascular calcification.38 A study using rat aortas showed that FGF-23 may enhance vascular calcification by causing aortic cells to differentiate into osteoblastic cells.38

FGF-23 LEVELS AND LEFT VENTRICULAR HYPERTROPHY (LVH)

The correlation between FGF- 23 and LVH has been well established through animal studies8,51,52 and epidemiologic and patient studies.53 A series of experiments has established that infusion of FGF-23 results in LVH through apparently a blood pressure independent mechanism,8 that the receptor responsible for the hypertrophy is the FGF Receptor 4,51 and that treatment with an FGF receptor blocker can lead to regression of LVH.52 Other authors have found that phosphate loading and Klotho deficiency, in addition to FGF-23, may also play a role in cardiac remodeling.54

Multiple epidemiological and patient studies have shown an association between high FGF-23 levels and LVH. In a study of 162 patients with CKD, higher FGF-23 levels were associated with higher odds of LVH.10 In a study of 3070 participants of the CRIC study (Chronic Renal Insufficiency Cohort), higher FGF-23 levels at baseline were associated with decrease ejection fraction, and higher mean left ventricular mass index after one year of follow-up.8 The previous studies were in patients with kidney disease, but the association between higher FGF-23 levels and LVH and cardiovascular events has also been shown in the Cardiovascular Health Study, a community-based cohort study.53,55 These epidemiologic investigations cannot distinguish whether FGF-23 acts directly on the myocardium or via elevations in blood pressure to cause left ventricular hypertrophy. Interestingly, due to these effects of FGF-23, it is interesting to evaluate studies of vitamin D therapy, such as the PRIMO trial.56 The primary hypothesis of the PRIMO trial was that therapy with activated vitamin D compounds would improve LVH in patients with kidney disease. This hypothesis was not proven by the trial and one potential explanation is that the activated vitamin D compound made the FGF-23 levels increase which then potentially led to LVH through the FGF-23 pathway.

FGF-23 LEVELS AND ATRIAL FIBRILLATION

Evaluating the potential association between FGF-23 and atrial fibrillation has yielded conflicting results.57,58 Several mechanisms have been proposed including direct effects of FGF-23 on the atrial myocardium and the induction of atrial enlargement leading to fibrillation of the atria.59–61 Analysis of data in one study demonstrated a tight connection between higher FGF-23 levels and incident atrial fibrillation in CKD patients, which was reinforced in a pooled meta-analysis showing higher FGF-23 levels as an independent predictor of atrial fibrillation risk (OR 1.35, 95% CI 1.09 to 169).60,62

FGF-23 LEVELS AND CARDIOVASCULAR EVENTS AND MORTALITY

Other studies have shown associations between high FGF-23 levels and coronary and other ischemic cardiovascular events. In a study of 704 patients with coronary artery disease, higher FGF-23 levels were associated with a combined outcome of acute coronary syndrome, stroke or transient ischemic attack, heart failure and death in patients with T2DM at baseline.63 An analysis of the Cardiovascular Health Study revealed that participants with higher FGF-23 levels were more likely to experience non-sudden cardiac death (cardiovascular deaths that were not sudden such as myocardial infarctions and strokes).64 Among dialysis patients, higher FGF-23 levels have been associated with cardiovascular mortality and all-cause mortality.34,35 Higher baseline FGF-23 levels were associated with incident heart failure in the CRIC cohort.9 High levels of FGF-23 were also shown to be associated with an increased risk of mortality, regardless of kidney function, in patients with heart failure with reduced ejection fraction.50 Thus, higher FGF-23 levels have been associated with multiple different cardiovascular events in multiple different populations.

POSSIBLE TREATMENT STRATEGIES FOR ELEVATED FGF-23 LEVELS

Low phosphate diets and the use of phosphate binders should theoretically lower FGF-23 levels. However, small clinical trials have not consistently shown this.65,66 Eating a plant based diet compared to eating a meat diet with the same nutrient content for one week led to lower phosphate and FGF-23 levels.67 Treatment with cincalcet in hemodialysis patients with secondary hyperparathyroidism lowered FGF-23 levels and this lowering of FGF-23 was associated with lower rates of cardiovascular events in a re-analysis of the EVOLVE clinical trial.68 Further research is required to evaluate whether lowering FGF-23 levels is associated with lower rates of cardiovascular events consistently.

CONCLUSION

FGF-23 is a bone-derived hormone that we believe primarily acts as a negative feedback on the activation of vitamin D and increases phosphate excretion, thereby decreasing phosphate levels. FGF-23, the FGF receptor and the obligate co-receptor α-klotho work in concert to effect FGF-23 actions. Low α-klotho levels have also been associated with cardiovascular disease.69 Elevations of FGF-23 occur early in the course of chronic kidney disease, likely due to several factors, and help to control phosphate levels. Elevated FGF-23 levels have been associated with several different forms of cardiovascular disease including hypertension, subclinical atherosclerotic disease, left ventricular hypertrophy, atrial fibrillation and other cardiovascular events (Figure). The next step in our understanding of FGF-23 pathophysiology is ascertaining whether decreasing FGF-23 levels leads to improved outcomes in patients. Table 1.

Fig 1.

Fig 1

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Highlights of the associations described in the review. Phosphate, PTH and 1,25-dihydroxyvitamin D lead to increased FGF-23 levels. Elevated FGF-23 levels may lead to hypertension through effects in the kidney and cardiovascular diseases and mortality.

Table 1. Determinants of FGF-23 levels.

Putative factors whose effect is either unclear or novel are designated with a question mark.

Positive Regulators Negative Regulators
Dietary Phosphate23 Cinacalcet68
Activated vitamin D (calcitriol, paricalcitol, doxercalciferol)17,18 Phosphate binders?65,66
Nutritional vitamin D (ergocalciferol, cholecalciferol)?19–22 Low phosphate diet?65,66
PTH24 Plant based diet?67
Sodium bicarbonate?25
Experimental myocardial infarction?26
Acute decompensated heart failure?27
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KEY POINTS.

  • - FGF-23 is a hormone produced by osteocytes and osteoblasts which acts to increase phosphate excretion by the kidney and decrease 1,25-dihydroxyvitamin D levels as a negative feedback.

  • - FGF-23 levels are higher in patients with kidney disease and may be the first biomarker of chronic kidney disease-bone mineral disorder.

  • - High FGF-23 levels have been associated with multiple adverse cardiovascular outcomes including hypertension, left ventricular hypertrophy, subclinical atherosclerosis and cardiovascular events and mortality.

  • - Studies are needed to evaluate whether decreasing FGF-23 levels in humans may decrease cardiovascular events, especially in the setting of kidney disease.

Acknowledgments

None

Financial support: None

Dr. Melamed is supported by grant R01 DK102952 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

Footnotes

CONFLICTS OF INTEREST

None of the authors report any conflicts of interest.

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