Serum phosphate is associated with aortic valve calcification in the Multi-ethnic Study of Atherosclerosis (MESA)

doi:10.1016/j.atherosclerosis.2013.12.051

Atherosclerosis

Volume 233, Issue 2, April 2014, Pages 331-337

https://doi.org/10.1016/j.atherosclerosis.2013.12.051 Get rights and content

Highlights

•
We investigated phosphate metabolism biomarkers with aortic valve calcification.
•
Serum phosphate levels are significantly associated with AVC prevalence.
•
Phosphate metabolism was not associated with AVC severity or progression.

Abstract

Objectives

This study sought to investigate associations of phosphate metabolism biomarkers with aortic valve calcification (AVC).

Background

Calcific aortic valve disease (CAVD) is a common progressive condition that involves inflammatory and calcification mediators. Currently there are no effective medical treatments, but mineral metabolism pathways may be important in the development and progression of disease.

Methods

We examined associations of phosphate metabolism biomarkers, including serum phosphate, urine phosphate, parathyroid hormone (PTH) and serum fibroblast growth factor (FGF)-23, with CT-assessed AVC at study baseline and in short-term follow-up in 6814 participants of the Multi-Ethnic Study of Atherosclerosis (MESA).

Results

At baseline, AVC prevalence was 13.2%. Higher serum phosphate levels were associated with significantly greater AVC prevalence (relative risk 1.3 per 1 mg/dL increment, 95% confidence incidence: 1.1 to 1.5, p < 0.001). Serum FGF-23, serum PTH, and urine phosphate were not associated with prevalent AVC. Average follow-up CT evaluation was 2.4 years (range 0.9–4.9 years) with an AVC incidence of 4.1%. Overall, phosphate metabolism biomarkers were not associated with incident AVC except in the top FGF-23 quartile.

Conclusions

Serum phosphate levels are significantly associated with AVC prevalence. Further study of phosphate metabolism as a modifiable risk factor for AVC is warranted.

Section snippets

Background

Calcific aortic valve disease (CAVD) is a common condition that affects more than a quarter of adults over the age of 65 [1]. The presence of aortic valve calcification (AVC) is predictive of future cardiovascular events and motality [2], [3], and is associated with the severity of hemodynamic stenosis [4], [5]. Currently there is no medical treatment for CAVD, and valve replacement remains the only therapy for advanced symptomatic disease.

CAVD is now well understood to be an active metabolic

Study population

We evaluated participants from the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study of 6814 people who were free from clinical cardiovascular disease aged 45–84 years. Individuals were recruited between July 2000 and August 2002 from six U.S. communities (Baltimore, Maryland; Chicago, Illinois; Forsyth County, North Carolina; Los Angeles, California; New York, New York; and St. Paul, Minnesota) and were composed of four different ethnic groups (Black, Chinese, Hispanic

Baseline characteristics

There were 6814 participants in MESA with 2 individuals missing baseline AVC scores. Participants who had prevalent AVC were older, more likely to be male, and had more comorbidities than those who were free of AVC (Table 1). Phosphate metabolism biomarkers were adequately measurable in serum samples of 6544 individuals. Serum phosphate levels were normally distributed with a mean of 3.67 ± 0.52 mg/dL. The majority of phosphate levels were in the normal range; only 52 (0.8%) of participants had

Discussion

In this large, multi-ethnic population that was free of clinical cardiovascular disease, higher serum phosphate levels were associated with a greater prevalence of AVC independent of demographics, atherosclerotic risk factors, kidney function, and other mineral metabolism markers. This result validates previous epidemiologic associations of serum phosphate with early CAVD in a larger, more diverse study population that includes gold-standard measurements of aortic valve calcium and adjustment

Funding

This research was supported by R01 HL096875, R01 HL071739 and contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute.

Disclosures

None.

Acknowledgments

The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.

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Matrix Gla protein (MGP) is an inhibitor of calcification that requires carboxylation by vitamin K for activity. The inactive form of MGP, dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP), has been associated with increased calcification. However, it is not known whether there is a longitudinal relationship between dephosphorylated-uncarboxylated matrix Gla protein levels and coronary and aortic calcification in large population cohorts.
The Multi-Ethnic Study of Atherosclerosis (MESA) followed participants with serial cardiac computed tomography (CT) measures of vascular calcification. Dp-ucMGP was measured at baseline in a subset of participants who completed baseline and follow-up CTs approximately 10 years later and had available plasma specimens (n = 2663). Linear mixed effects models (LMMs) were used to determine the association of dp-ucMGP with the simultaneous incidence and progression of coronary artery, ascending thoracic aortic, or descending thoracic aortic calcification (CAC, ATAC, DTAC)].
For every one standard deviation (SD, 178 pmol/L) increment in dp-ucMGP, CAC increased by 3.44 ([95% CI = 1.68, 5.21], p < 0.001) Agatston units/year (AU/year), ATAC increased by 0.63 ([95% CI = 0.27, 0.98], p = 0.001) AU/year, and DTAC increased by 8.61 ([95% CI = 4.55, 12.67], p < 0.001) AU/year. The association was stronger for DTAC in those ≥65 years and with diabetes.
We found a positive association of the inactive form of matrix Gla protein, dp-ucMGP, and long-term incidence/progression of CAC, ATAC, and DTAC. Future studies should investigate dp-ucMGP as a calcification regulator and MGP as a possible therapeutic target to slow progression of calcification in the vasculature.
Kidney function, bone-mineral metabolism markers, and calcification of coronary arteries, aorta, and cardiac valves in older adults
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The contribution of kidney dysfunction, especially at mild-to-moderate stages, and bone-mineral metabolism (BMM) markers to vascular calcification remains controversial or unclear. We comprehensively evaluated the association of kidney and BMM markers with coronary artery calcification (CAC) and extra-coronary calcification (ECC).
In 1931 ARIC participants (age 73–95 years) without coronary heart disease at visit 7 (2018–19), we investigated the associations of estimated glomerular filtration rate (eGFR) (with creatinine, cystatin C, and both) and five serum BMM markers (calcium, fibroblast growth factor 23, magnesium, parathyroid hormone, and phosphorus) with high CAC and ECC (sex-race specific ≥75th vs. <75th percentile Agatston score) or any vs. zero CAC and ECC using multivariable logistic regression. For eGFR and BMM markers, we took their weighted cumulative averages from visit 1 (1987–89) to visit 5 (2011–13).
Lower eGFR, regardless of equations used, was not robustly associated with high CAC or ECC. Among BMM markers, only higher phosphorus levels, even within the normal range, showed robust associations with high CAC (only when modeled continuously) and ECC, independently of kidney function (e.g., odds ratio 1.94 [95%CI 1.38–2.73] for high aortic valve calcification, in the highest vs. lowest quartile). Results were generally consistent when analyzing any CAC or ECC, although cystatin C-based eGFR <60 mL/min/1.73 m² became significantly associated with mitral valve calcification (odds ratio 1.69 [1.10–2.60]).
Among kidney and BMM measures tested, only serum phosphorus demonstrated robust associations with both CAC and ECC, supporting a key role of phosphorus in the pathophysiology of vascular calcification.
Risk Markers for Limited Coronary Artery Calcium in Persons With Significant Aortic Valve Calcium (From the Multi-ethnic Study of Atherosclerosis)
2021, American Journal of Cardiology
Citation Excerpt :
Serum phosphate was measured on a Beckman-Coulter UniCel DxC instrument using time-rated colorimetry.15 Parathyroid hormone and serum 25-hydroxyvitamin D were measured in serum through liquid chromatography-mass spectroscopy on a Quattro Micro mass spectrometer.15 A sandwich immunoassay was used to measure full-length serum fibroblast growth factor-23 (FGF-23) (Kainos ELISA 96-well plate).15
The early stages of aortic valve calcification (AVC) and coronary artery calcification (CAC) include shared ASCVD risk factors, yet there is considerable heterogeneity between the burden of AVC, and CAC. We sought to identify the markers associated with limited CAC among persons with significant AVC. There were 325 participants from the Multi-Ethnic Study of Atherosclerosis without clinical ASCVD and with AVC ≥100 Agatston units (AU) at Visit 1. Multivariable-adjusted prevalence ratios for limited CAC (0 to 99 AU) were calculated using modified Poisson regression. Participants had a mean age of 72.1 years, median AVC score of 209, and 34% were women. A total of 133 (41%) participants had CAC <100, of whom 46/133 had CAC = 0. Younger age (PR = 1.40, 95% CI: 1.22 to 1.62, per 10-years), female gender (PR = 1.68, 95% CI: 1.28 to 2.20), and low 10-year ASCVD risk (PR = 2.30, 95% CI: 1.85 to 2.85) were most strongly associated with limited CAC. Neither a normal lipoprotein(a) nor normal measures of inflammation were significantly associated with limited CAC. Lower serum phosphate (PR = 1.15, 95% CI: 1.01 to 1.31; per 0.5 mg/dl lower) and calcium-phosphate product (PR = 1.16, 95% CI: 1.02 to 1.34; per SD lower) were associated with an approximately 15% higher prevalence of limited CAC. In conclusion, more than 40% of persons with significant AVC had CAC. Beyond traditional risk factors, lower serum phosphate, and lower calcium-phosphate product were associated with a higher prevalence of limited CAC.
Serum levels of C-terminal FGF23 (cFGF23) are associated with 1-year-mortality in patients undergoing transcatheter aortic valve replacement (TAVR)
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Serum levels of FGF23 have been associated with adverse outcomes in cardiovascular diseases in patients with and without impaired renal function. Hence, this study aimed to explore the prognostic relevance of intact FGF23 (iFGF23) and its derivate C-terminal FGF23 (cFGF23) in patients undergoing transcatheter aortic valve replacement (TAVR) with regard to renal function.
A total of 274 patients undergoing transfemoral TAVR were enrolled in this study. Blood samples were obtained preinterventionally and analyzed for iFGF23 and cFGF23 by means of enzyme linked immunosorbent assay (ELISA). Follow-up was obtained for 12 months.
Serum levels of cFGF23 and iFGF23 both correlated positively with serum creatinine and inversely with estimated glomerular filtration rate (eGFR). Cox regression analysis revealed a significant association of cFGF23 with 1-year-mortality in patients with eGFR ≥45ml/min/1.73m², but not in patients with an eGFR <45ml/min/1.73m². A cut-off was calculated for cFGF23 (6.82 pmol/l) and patients with eGFR ≥45ml/min/1.73m² were retrospectively divided into two groups (above/below cut-off). Patients above the cut-off had a significantly worse 1-year-mortality than patients below the cut-off (33.3% vs. 19.6%; OR 2.05 (95%CI 1.03-4.07), p= 0.038). The association of cFGF23 with 1-year-mortality in patients with eGFR ≥45ml/min/1.73m² remained statistically significant even after correction for possible confounders in a multivariate Cox regression analysis.
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Calcific aortic valve disease (CAVD), previously thought to represent a passive degeneration of the valvular extracellular matrix (VECM), is now regarded as an intricate multistage disorder with sequential yet intertangled and interacting underlying processes. Endothelial dysfunction and injury, initiated by disturbed blood flow and metabolic disorders, lead to the deposition of low-density lipoprotein cholesterol in the VECM further provoking macrophage infiltration, oxidative stress, and release of pro-inflammatory cytokines. Such changes in the valvular homeostasis induce differentiation of normally quiescent valvular interstitial cells (VICs) into synthetically active myofibroblasts producing excessive quantities of the VECM and proteins responsible for its remodeling. As a result of constantly ongoing degradation and re-deposition, VECM becomes disorganised and rigid, additionally potentiating myofibroblastic differentiation of VICs and worsening adaptation of the valve to the blood flow. Moreover, disrupted and excessively vascularised VECM is susceptible to the dystrophic calcification caused by calcium and phosphate precipitating on damaged collagen fibers and concurrently accompanied by osteogenic differentiation of VICs. Being combined, passive calcification and biomineralisation synergistically induce ossification of the aortic valve ultimately resulting in its mechanical incompetence requiring surgical replacement. Unfortunately, multiple attempts have failed to find an efficient conservative treatment of CAVD; however, therapeutic regimens and clinical settings have also been far from the optimal. In this review, we focused on interactions and transitions between aforementioned mechanisms demarcating ascending stages of CAVD, suggesting a predisposing condition (bicuspid aortic valve) and drug combination (lipid-lowering drugs combined with angiotensin II antagonists and cytokine inhibitors) for the further testing in both preclinical and clinical trials.
Biomarkers of mineral metabolism and progression of aortic valve and mitral annular calcification: The Multi-Ethnic Study of Atherosclerosis
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Citation Excerpt :
Accordingly, there were no significant differences in baseline characteristics in participants who underwent cardiac CT in Exam 2 versus those who did so in Exam 3 (data not shown). Cardiac CTs at Exam 1 (baseline) and Exam 2/3 were read for AVC (n = 6812 at baseline, n = 6058 at visits 2/3) and MAC (n = 6814 at baseline, n = 5895 at visits 2/3) [21,25]. FGF-23 and phosphate measurements were completed in baseline specimens from n = 6547 participants [21], while fetuin-A was also measured in baseline specimens from a random subset of n = 2550 participants [26].
Previous research has implicated dysregulation of phosphate metabolism and calcium-phosphate solubilization in cardiovascular calcification, but epidemiologic studies evaluating longitudinal associations with valvular or annular calcification by computed tomography (CT), a highly sensitive imaging modality, are lacking. Our primary aim was to investigate the associations of mineral biomarkers with incidence and progression of aortic valve calcification (AVC) and mitral annular calcification (MAC).
We evaluated the associations of serum FGF-23 (n = 6547 participants), phosphate (n = 6547), and fetuin-A (n = 2550) measured at baseline in the community-based Multi-Ethnic Study of Atherosclerosis with AVC and MAC on CT performed at baseline and at a median of 2.4 (1.6, 3.1) years later. We used linear mixed-effects models to account simultaneously for prevalence, incidence and progression of AVC and MAC.
After adjustment for demographic and clinical characteristics, a significant association was documented for FGF-23 with accelerated annual progression of MAC (2.83 Agatston units (AU), 95% CI = 0.49, 5.17 AU, per standard deviation (18.46 pg/mL) of FGF-23), but this was not seen for phosphate or fetuin-A. None of these biomarkers was associated with accelerated annual progression of AVC.
This study provides evidence relating serum FGF-23 to accelerated annual MAC progression. Whether this mineral regulator is a risk marker or is involved in pathogenesis merits further investigation.

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Published by Elsevier B.V.

Serum phosphate is associated with aortic valve calcification in the Multi-ethnic Study of Atherosclerosis (MESA)

Highlights

Abstract

Objectives

Background

Methods

Results

Conclusions

Section snippets

Background

Study population

Baseline characteristics

Discussion

Funding

Disclosures

Acknowledgments

JACC Cardiovasc Imaging

Clin Radiol

J Am Coll Cardiol

Am J Kidney Dis

Acad Radiol

Acad Radiol

Acad Radiol

J Am Coll Cardiol

JACC Cardiovasc Imaging

Am J Cardiol

Ann Thorac Surg

J Biol Chem

J Am Coll Cardiol

Kidney Int

Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly

N Engl J Med

Predictors of outcome in severe, asymptomatic aortic stenosis

N Engl J Med

Measurement of aortic valve calcification using multislice computed tomography: correlation with haemodynamic severity of aortic stenosis and clinical implication for patients with low ejection fraction

Heart

Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: calcific aortic valve disease-2011 update

Circulation

Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis. Histological and immunohistochemical studies

Circulation

Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial

Circulation

Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis

N Engl J Med