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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Kidney, Nutrition, Obesity and Diabetes (KNOD)
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Olson, Jean
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Mathew, Jehu S; Leary, Peter J; Bansal, Nisha et al. (2015) Mineral metabolism and the right ventricle: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Kidney Dis 65:521-3
de Boer, Ian H; Sachs, Michael C; Chonchol, Michel et al. (2014) Estimated GFR and circulating 24,25-dihydroxyvitamin D3 concentration: a participant-level analysis of 5 cohort studies and clinical trials. Am J Kidney Dis 64:187-97
Linefsky, Jason P; O'Brien, Kevin D; Sachs, Michael et al. (2014) Serum phosphate is associated with aortic valve calcification in the Multi-ethnic Study of Atherosclerosis (MESA). Atherosclerosis 233:331-7
van Ballegooijen, Adriana J; Kestenbaum, Bryan; Sachs, Michael C et al. (2014) Association of 25-hydroxyvitamin D and parathyroid hormone with incident hypertension: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 63:1214-22
de Boer, Ian H; Mehrotra, Rajnish (2014) Insulin resistance in chronic kidney disease: a step closer to effective evaluation and treatment. Kidney Int 86:243-5
Hsu, Jeffrey J; Katz, Ronit; Ix, Joachim H et al. (2014) Association of fibroblast growth factor-23 with arterial stiffness in the Multi-Ethnic Study of Atherosclerosis. Nephrol Dial Transplant 29:2099-105
Kestenbaum, Bryan; Sachs, Michael C; Hoofnagle, Andy N et al. (2014) Fibroblast growth factor-23 and cardiovascular disease in the general population: the Multi-Ethnic Study of Atherosclerosis. Circ Heart Fail 7:409-17
de Boer, Ian H; Brunzell, John D (2014) HDL in CKD: how good is the "good cholesterol?". J Am Soc Nephrol 25:871-4
Bansal, Nisha; Zelnick, Leila; Robinson-Cohen, Cassianne et al. (2014) Serum parathyroid hormone and 25-hydroxyvitamin D concentrations and risk of incident heart failure: the Multi-Ethnic Study of Atherosclerosis. J Am Heart Assoc 3:e001278
Mathew, Jehu S; Sachs, Michael C; Katz, Ronit et al. (2014) Fibroblast growth factor-23 and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). Circulation 130:298-307

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