Phosphorus and Vitamin D Metabolism and Cardiovascular Outcomes: The multi-ethni

Summary

Principal Investigator: Bryan R Kestenbaum
Affiliation: University of Washington
Country: USA
Abstract: DESCRIPTION (provided by applicant): Evolving evidence suggests that phosphorous excess and vitamin D insufficiency contribute to cardiovascular disease (CVD) and premature death. Phosphorous excess directly transforms vascular smooth muscle tissue into osteoblast-like cells, which calcify the medial vessel wall. Vitamin D insufficiency activates the renin-angiotensin-aldosterone system, stimulates atherogenic cytokine expression, and directly promotes cardiomyocyte growth. Important gaps in existing knowledge constrain full understanding of mineral metabolism-CVD relationships in humans. First, current ascertainment of the phosphorous and vitamin D metabolic axes is crude, obscuring relationships with CVD outcomes and impeding translation to clinical application. Second, CVD pathways through which disturbed mineral metabolism may promote CVD are incompletely evaluated in humans. Third, phosphorous and vitamin D metabolism vary strongly by race/ethnicity, but knowledge of cardiovascular consequences of mineral metabolism disorders derive from populations with limited diversity. The overall goal of this proposal is to define relationships of phosphorous excess and vitamin D insufficiency with pathophysiologically relevant clinical and subclinical CVD outcomes in a community based, multi-ethnic population. We will characterize the phosphorous and vitamin D metabolic axes using multiple serum and urine biomarkers measured from previously collected baseline samples obtained from 6,736 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). MESA offers a unique opportunity to comprehensively evaluate novel CVD risk factors because of its multi-ethnic sampling strategy, exclusion of clinical CVD at baseline, state-of-the-art subclinical CVD measurements, and adjudicated cardiovascular events. We hypothesize that biomarkers of phosphorous excess (higher concentrations of serum phosphorous, serum fibroblast growth factor-23, and urine phosphorous) and vitamin D deficiency (lower 25- hydroxyvitamin D and higher parathyroid hormone concentrations) will be associated with incident cardiovascular events, incident hypertension, and incident chronic kidney disease. We further hypothesize that biomarkers of phosphorous excess and vitamin D deficiency will be associated with subclinical cardiovascular disease measurements that are directly relevant to mineral metabolism: coronary artery calcification, thoracic aorta calcification, arterial stiffness, and left ventricular mass. PUBLIC HEALTH RELEVANCE: Cardiovascular diseases (CVD) are the major cause of eath in the industrialized world for both men and women. Disturbances in phosphorous and vitamin D metabolism may be novel risk factors for CVD and may offer new opportunities for preventive or therapeutic intervention. The proposed studies will determine whether phosphorus excess and vitamin D deficiency are linked with clinically relevant CVD in a racially and ethnically diverse population. Findings will help clarify optimal serum concentrations of phosphorous and vitamin D biomarkers with respect to cardiovascular health and inform clinical trials which target mineral metabolism to prevent and reduce CVD.
Funding Period: ----------------2010 - ---------------2014-
more information: NIH RePORT

Top Publications

  1. pmc A partnership approach for Electronic Data Capture in small-scale clinical trials
    Joshua D Franklin
    University of Washington, Box 357420, 1959 NE Pacific St, Seattle, WA 98195, USA
    J Biomed Inform 44:S103-8. 2011
  2. pmc Estimating mean annual 25-hydroxyvitamin D concentrations from single measurements: the Multi-Ethnic Study of Atherosclerosis
    Michael C Sachs
    Kidney Research Institute and Division of Nephrology, University of Washington, Seattle, WA, USA
    Am J Clin Nutr 97:1243-51. 2013
  3. pmc Invited commentary: Quantifying salt in urine--a complex solution
    Ian H De Boer
    Am J Epidemiol 177:1193-5; discussion 1196-8. 2013
  4. pmc 25-Hydroxyvitamin D and parathyroid hormone are not associated with carotid intima-media thickness or plaque in the multi-ethnic study of atherosclerosis
    Marc Blondon
    From the Department of Epidemiology M B, D S S, J D K, B K, I H d B, Division of Nephrology and Kidney Research Institute M S, B K, I H d B, Department of Laboratory Medicine A N H, Department of Environmental and Occupational Health Sciences J D K, Department of Medicine D S S, J D K, B K, I H d B, Cardiovascular Health Research Unit M B, D S S, University of Washington, Seattle, WA Department of Medicine, Geneva University Hospitals, Geneva, Switzerland M B Division of Nephrology, University of California, San Diego, CA J H I Department of Medicine, Johns Hopkins University, Baltimore, MD E D M and Divison of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI C K, A D G, J H S
    Arterioscler Thromb Vasc Biol 33:2639-45. 2013
  5. pmc Influence of estrogen therapy on calcium, phosphorus, and other regulatory hormones in postmenopausal women: the MESA study
    Nisha Bansal
    MD, MAS, Kidney Research Institute, University of Washington, 908 Jefferson Street, Third Floor, Seattle, WA 98104
    J Clin Endocrinol Metab 98:4890-8. 2013
  6. pmc Association of 25-hydroxyvitamin D and parathyroid hormone with incident hypertension: MESA (Multi-Ethnic Study of Atherosclerosis)
    Adriana J van Ballegooijen
    Department of Health Sciences and the EMGO Institute, VU University Amsterdam, Amsterdam, The Netherlands Electronic address
    J Am Coll Cardiol 63:1214-22. 2014
  7. pmc Serum phosphate is associated with aortic valve calcification in the Multi-ethnic Study of Atherosclerosis (MESA)
    Jason P Linefsky
    Division of Cardiology, Emory University Atlanta VA Medical Center, 1639 Pierce Drive, Suite 319, Atlanta, GA 30322, USA Electronic address
    Atherosclerosis 233:331-7. 2014
  8. pmc Fibroblast growth factor-23 and cardiovascular disease in the general population: the Multi-Ethnic Study of Atherosclerosis
    Bryan Kestenbaum
    From the Kidney Research Institute, Department of Medicine, Division of Nephrology B K, M C S, C R C, J R, D R, I H d B, Department of Laboratory Medicine A N H, Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology D S S, and Department of Epidemiology M B, University of Washington, Seattle Division of Nephrology, Department of Medicine, University of California at San Diego J H I Nephrology Section, Veterans Affairs San Diego Healthcare System, CA J H I and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego J H I Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD J A C L and Department of Radiology, Tufts New England Medical Center, Boston, MA J F P
    Circ Heart Fail 7:409-17. 2014
  9. pmc Impaired vitamin D metabolism in CKD
    Cortney Bosworth
    Division of Nephrology and Kidney Research Institute, University of Washington, Seattle, WA, USA
    Semin Nephrol 33:158-68. 2013
  10. pmc Parathyroid hormone and arterial dysfunction in the multi-ethnic study of atherosclerosis
    Cortney Bosworth
    Division of Nephrology and Kidney Research Institute, Department of Medicine, University of Washington, Seattle, WA, USA
    Clin Endocrinol (Oxf) 79:429-36. 2013

Scientific Experts

  • Ian H De Boer
  • Bryan Kestenbaum
  • David S Siscovick
  • Joachim H Ix
  • Andrew N Hoofnagle
  • Michael C Sachs
  • Cortney Bosworth
  • Cassianne Robinson-Cohen
  • Marc Blondon
  • Gregory P Levin
  • Jason P Linefsky
  • Adriana J van Ballegooijen
  • Joao A C Lima
  • Erin D Michos
  • Michael Sachs
  • John Eng
  • Ronit Katz
  • John Ruzinski
  • Nisha Bansal
  • Maryam Afkarian
  • Kalani T Yamamoto
  • Jonathan Himmelfarb
  • Cortney R Bosworth
  • Gregory Levin
  • Bruce M Psaty
  • Abigail B Shoben
  • Joshua D Franklin
  • Marjolein Visser
  • Andy N Hoofnagle
  • Joseph F Polak
  • Kevin D O'Brien
  • Denise Rock
  • Ingeborg A Brouwer
  • Matthew J Budoff
  • Nancy Swords-Jenny
  • Mathew J Budoff
  • Claudia Korcarz
  • Jennifer A Nettleton
  • James H Stein
  • Katherine R Tuttle
  • Cassy Robinson-Cohen
  • Joel D Kaufman
  • Russell Tracy
  • Ha Nguyen
  • Carmen A Peralta
  • Irl B Hirsch
  • Alina Kostina
  • Adam D Gepner
  • David R Jacobs
  • Pamela L Lutsey
  • Matthew Budoff
  • Marcia C de Oliveira
  • Daniel Duprez
  • Noel S Weiss
  • Dong Li
  • Gail A Laughlin
  • Michael H Criqui
  • Abigail Shoben
  • Luigi Ferrucci
  • Bessie Young
  • Denise K Houston
  • Kushang V Patel
  • Yongmei Liu
  • David Siscovick
  • Karl Michaelsson
  • Jane A Cauley
  • Stephen B Kritchevsky
  • Toshiko Tanaka
  • Stephen M Schwartz
  • Thomas Wang
  • Kurt Lohman
  • Emil Hagström
  • Stefania Bandinelli
  • Hakan Melhus
  • Myles Wolf
  • Alicia Guidry
  • James F Brinkley

Detail Information

Publications21

  1. pmc A partnership approach for Electronic Data Capture in small-scale clinical trials
    Joshua D Franklin
    University of Washington, Box 357420, 1959 NE Pacific St, Seattle, WA 98195, USA
    J Biomed Inform 44:S103-8. 2011
    ..EDC systems we evaluated were Catalyst Web Tools, OpenClinica and REDCap. We also found that two other systems, Caisis and LabKey, did not meet the specific user needs of the study group...
  2. pmc Estimating mean annual 25-hydroxyvitamin D concentrations from single measurements: the Multi-Ethnic Study of Atherosclerosis
    Michael C Sachs
    Kidney Research Institute and Division of Nephrology, University of Washington, Seattle, WA, USA
    Am J Clin Nutr 97:1243-51. 2013
    ..Single measurements may misclassify annual exposure, which may lead to bias in research and complicate clinical decision making...
  3. pmc Invited commentary: Quantifying salt in urine--a complex solution
    Ian H De Boer
    Am J Epidemiol 177:1193-5; discussion 1196-8. 2013
    ..Further work is needed to extend estimation to additional populations and improve individual-level assessment...
  4. pmc 25-Hydroxyvitamin D and parathyroid hormone are not associated with carotid intima-media thickness or plaque in the multi-ethnic study of atherosclerosis
    Marc Blondon
    From the Department of Epidemiology M B, D S S, J D K, B K, I H d B, Division of Nephrology and Kidney Research Institute M S, B K, I H d B, Department of Laboratory Medicine A N H, Department of Environmental and Occupational Health Sciences J D K, Department of Medicine D S S, J D K, B K, I H d B, Cardiovascular Health Research Unit M B, D S S, University of Washington, Seattle, WA Department of Medicine, Geneva University Hospitals, Geneva, Switzerland M B Division of Nephrology, University of California, San Diego, CA J H I Department of Medicine, Johns Hopkins University, Baltimore, MD E D M and Divison of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI C K, A D G, J H S
    Arterioscler Thromb Vasc Biol 33:2639-45. 2013
    ..Observational evidence supports independent associations of 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) with cardiovascular risk. A plausible hypothesis for these associations is accelerated development of atherosclerosis...
  5. pmc Influence of estrogen therapy on calcium, phosphorus, and other regulatory hormones in postmenopausal women: the MESA study
    Nisha Bansal
    MD, MAS, Kidney Research Institute, University of Washington, 908 Jefferson Street, Third Floor, Seattle, WA 98104
    J Clin Endocrinol Metab 98:4890-8. 2013
    ..Other biomarkers of mineral metabolism may help understand the biological basis of these actions...
  6. pmc Association of 25-hydroxyvitamin D and parathyroid hormone with incident hypertension: MESA (Multi-Ethnic Study of Atherosclerosis)
    Adriana J van Ballegooijen
    Department of Health Sciences and the EMGO Institute, VU University Amsterdam, Amsterdam, The Netherlands Electronic address
    J Am Coll Cardiol 63:1214-22. 2014
    ..This study investigated whether lower 25-hydroxyvitamin D and higher parathyroid hormone concentrations are associated with incident hypertension...
  7. pmc Serum phosphate is associated with aortic valve calcification in the Multi-ethnic Study of Atherosclerosis (MESA)
    Jason P Linefsky
    Division of Cardiology, Emory University Atlanta VA Medical Center, 1639 Pierce Drive, Suite 319, Atlanta, GA 30322, USA Electronic address
    Atherosclerosis 233:331-7. 2014
    ..This study sought to investigate associations of phosphate metabolism biomarkers with aortic valve calcification (AVC)...
  8. pmc Fibroblast growth factor-23 and cardiovascular disease in the general population: the Multi-Ethnic Study of Atherosclerosis
    Bryan Kestenbaum
    From the Kidney Research Institute, Department of Medicine, Division of Nephrology B K, M C S, C R C, J R, D R, I H d B, Department of Laboratory Medicine A N H, Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology D S S, and Department of Epidemiology M B, University of Washington, Seattle Division of Nephrology, Department of Medicine, University of California at San Diego J H I Nephrology Section, Veterans Affairs San Diego Healthcare System, CA J H I and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego J H I Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD J A C L and Department of Radiology, Tufts New England Medical Center, Boston, MA J F P
    Circ Heart Fail 7:409-17. 2014
    ..The role of FGF-23 in cardiovascular disease development in the general population is unclear. We tested associations of FGF-23 with major subclinical and clinical cardiovascular disease outcomes in a large prospective cohort...
  9. pmc Impaired vitamin D metabolism in CKD
    Cortney Bosworth
    Division of Nephrology and Kidney Research Institute, University of Washington, Seattle, WA, USA
    Semin Nephrol 33:158-68. 2013
    ..New insights into the mechanisms and regulation of vitamin D metabolism may lead to novel approaches to assess and treat impaired vitamin D metabolism in chronic kidney disease...
  10. pmc Parathyroid hormone and arterial dysfunction in the multi-ethnic study of atherosclerosis
    Cortney Bosworth
    Division of Nephrology and Kidney Research Institute, Department of Medicine, University of Washington, Seattle, WA, USA
    Clin Endocrinol (Oxf) 79:429-36. 2013
    ..Impaired arterial function is a potential mechanism for these associations. We tested whether serum PTH concentration is associated with measures of arterial function...
  11. pmc Kidney disease and increased mortality risk in type 2 diabetes
    Maryam Afkarian
    Kidney Research Institute and Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA 98014, USA
    J Am Soc Nephrol 24:302-8. 2013
    ..2%-29.6%) when further adjusted. We observed similar patterns for cardiovascular and noncardiovascular mortality. In conclusion, those with kidney disease predominantly account for the increased mortality observed in type 2 diabetes...
  12. pmc The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease
    Cortney R Bosworth
    Department of Medicine, Division of Nephrology and Kidney Research Institute, University of Washington, Seattle, WA 98104, USA
    Kidney Int 82:693-700. 2012
    ..Thus, chronic kidney disease is a state of stagnant vitamin D metabolism characterized by decreases in both 1,25(OH)(2)D production and vitamin D catabolism...
  13. pmc Paricalcitol does not improve glucose metabolism in patients with stage 3-4 chronic kidney disease
    Ian H De Boer
    Division of Nephrology and Kidney Research Institute, Department of Medicine, University of Washington, Seattle, Washington 98104, USA
    Kidney Int 83:323-30. 2013
    ..Thus, despite substantial effects on vitamin D metabolism, paricalcitol did not improve glucose metabolism in nondiabetic patients with stage 3-4 chronic kidney disease...
  14. pmc Circulating vitamin D metabolites and kidney disease in type 1 diabetes
    Ian H De Boer
    Kidney Research Institute and Division of Nephrology, University of Washington, Box 359606, 325 Ninth Avenue, Seattle, Washington 98104, USA
    J Clin Endocrinol Metab 97:4780-8. 2012
    ..Impaired vitamin D metabolism may contribute to the development and progression of diabetic kidney disease...
  15. pmc Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes
    Gregory P Levin
    Department of Biostatistics, University of Washington, Seattle, USA
    JAMA 308:1898-905. 2012
    ....
  16. pmc Dietary phosphorus is associated with greater left ventricular mass
    Kalani T Yamamoto
    Division of Nephrology and Kidney Research Institute, University of Washington, Seattle, Washington 98104 2499, USA
    Kidney Int 83:707-14. 2013
    ..1 g greater LVM compared with the lowest quintile. Higher dietary phosphorus intake was associated with greater odds of LVH among women, but not men. These associations require confirmation in other studies...
  17. pmc Estimated GFR and Circulating 24,25-Dihydroxyvitamin D3 Concentration: A Participant-Level Analysis of 5 Cohort Studies and Clinical Trials
    Ian H De Boer
    Division of Nephrology, Department of Medicine, Seattle, WA Kidney Research Institute, Department of Medicine, Seattle, WA Department of Epidemiology, University of Washington, Seattle, WA Electronic address
    Am J Kidney Dis 64:187-97. 2014
    ..We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25[OH]2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFRs...
  18. pmc Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study
    Ian H De Boer
    University of Washington, Seattle, USA
    Ann Intern Med 156:627-34. 2012
    ..Current clinical 25-(OH)D targets based on associations with intermediate markers of bone metabolism may not reflect optimal levels for other chronic diseases and do not account for known seasonal variation in 25-(OH)D concentration...
  19. pmc Seasonal variation in 25-hydroxyvitamin D concentrations in the cardiovascular health study
    Abigail B Shoben
    The Ohio State University, 1841 Neil Avenue, Columbus, OH 43210 1240, USA
    Am J Epidemiol 174:1363-72. 2011
    ..Accounting for collection time may reduce bias in research studies and improve decision-making in clinical care...
  20. pmc Serum 25-hydroxyvitamin D and change in estimated glomerular filtration rate
    Ian H De Boer
    Department of Medicine, University of Washington, Seattle, WA 98195, USA Tele
    Clin J Am Soc Nephrol 6:2141-9. 2011
    ..Mounting evidence suggests that 1,25-dihydroxyvitamin D prevents the progression of chronic kidney disease (CKD). It is not clear whether "nutritional" forms of vitamin D affect GFR...