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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096875-04
Application #
8448210
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Olson, Jean
Project Start
2010-06-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$484,835
Indirect Cost
$169,324
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Blondon, Marc; Cushman, Mary; Jenny, Nancy et al. (2016) Associations of Serum 25-Hydroxyvitamin D With Hemostatic and Inflammatory Biomarkers in the Multi-Ethnic Study of Atherosclerosis. J Clin Endocrinol Metab 101:2348-57
Jenny, Nancy Swords; Olson, Nels C; Allison, Matthew A et al. (2016) Biomarkers of Key Biological Pathways in CVD. Glob Heart 11:327-336.e3
van Ballegooijen, Adriana J; Rhee, Eugene P; Elmariah, Sammy et al. (2016) Renal Clearance of Mineral Metabolism Biomarkers. J Am Soc Nephrol 27:392-7
Hoofnagle, Andrew N; Laha, Thomas J; de Boer, Ian H (2016) Recalibration of 24,25-Dihydroxyvitamin D3 Results Based on NIST Standard Reference Material 972a. Am J Kidney Dis 67:812-3
Manichaikul, Ani; Rich, Stephen S; Allison, Matthew A et al. (2016) KCNK3 Variants Are Associated With Hyperaldosteronism and Hypertension. Hypertension 68:356-64
Kendrick, Jessica B; Zelnick, Leila; Chonchol, Michel B et al. (2016) Serum Bicarbonate Is Associated with Heart Failure in the Multi-Ethnic Study of Atherosclerosis. Am J Nephrol 45:118-126
Criqui, Michael H; Aboyans, Victor; Allison, Matthew A et al. (2016) Peripheral Artery Disease and Aortic Disease. Glob Heart 11:313-326
Hansen, Joyanna G; Tang, Wenbo; Hootman, Katie C et al. (2015) Genetic and environmental factors are associated with serum 25-hydroxyvitamin D concentrations in older African Americans. J Nutr 145:799-805
van Ballegooijen, Adriana J; Robinson-Cohen, Cassianne; Katz, Ronit et al. (2015) Vitamin D metabolites and bone mineral density: The multi-ethnic study of atherosclerosis. Bone 78:186-93
Bertisch, Suzanne M; Sillau, Stefan; de Boer, Ian H et al. (2015) 25-Hydroxyvitamin D Concentration and Sleep Duration and Continuity: Multi-Ethnic Study of Atherosclerosis. Sleep 38:1305-11

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