This Article Full Text Full Text (PDF) Correction (v116,pe556) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tonelli, M. Search for Related Content PubMed PubMed Citation Articles by Tonelli, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLESTEROL Related Collections Risk Factors Acute coronary syndromes Acute myocardial infarction Epidemiology

(Circulation. 2005;112:2627-2633.)
© 2005 American Heart Association, Inc.

Coronary Heart Disease

Relation Between Serum Phosphate Level and Cardiovascular Event Rate in People With Coronary Disease

Marcello Tonelli, MD, SM; Frank Sacks, MD; Marc Pfeffer, MD, PhD; Zhiwei Gao, MSc; Gary Curhan, MD, ScD, for the Cholesterol And Recurrent Events (CARE) Trial Investigators

From the Department of Medicine (M.T.), Department of Critical Care (M.T.), Institute of Health Economics (M.T.), and Department of Public Health Sciences (M.T., Z.G.), University of Alberta, Edmonton, Alberta, Canada; Departments of Epidemiology (F.S., G.C.) and Nutrition (F.S.), Harvard School of Public Health, Boston, Mass; and Department of Medicine (M.P.) and Channing Laboratory (G.C.), Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Dr Marcello Tonelli, University of Alberta, Division of Nephrology and Immunology, 7-129 Clinical Science Bldg, 8440 112 St, Edmonton, Alberta T6B 2B7, Canada. E-mail mtonelli{at}ualberta.ca

Received March 31, 2005; revision received June 27, 2005; accepted August 3, 2005.

Background— Higher levels of serum phosphate are associated with adverse cardiovascular outcomes, especially in the setting of overt hyperphosphatemia. Given the biological importance of phosphorus, it is plausible that higher levels of serum phosphate within the normal range may also be associated with adverse outcomes.

Methods and Results— We performed a post hoc analysis of data from the Cholesterol And Recurrent Events (CARE) study. Baseline serum phosphate levels were measured in 4127 fasting participants who were randomized to receive pravastatin 40 mg daily or placebo and followed up for a median of 59.7 months. We used Cox proportional-hazards models to examine the association between serum phosphate and adverse clinical outcomes after adjustment for potential confounders. During nearly 60 months of follow-up, 375 participants died. A significant association was noted between baseline serum phosphate level and the age-, race-, and sex-adjusted risk of all-cause death (hazard ratio per 1 mg/dL, 1.27; 95% confidence interval, 1.02 to 1.58). After categorization based on baseline phosphate level (<2.5, 2.5 to 3.4, 3.5 to 3.9, and 4 mg/dL) and further adjustment, a graded independent relation between phosphate and death was observed (P for trend=0.03). For instance, participants with serum phosphate 3.5 mg/dL had an adjusted hazard ratio for death of 1.27 (95% confidence interval, 1.02 to 1.59) compared with those with serum phosphate of <3.5 mg/dL. Higher levels of serum phosphate were also associated with increased risk of new heart failure, myocardial infarction, and the composite of coronary death or nonfatal myocardial infarction, but not the risk of stroke.

Conclusions— We found a graded independent relation between higher levels of serum phosphate and the risk of death and cardiovascular events in people with prior myocardial infarction, most of whom had serum phosphate levels within the normal range. Given the ready availability and low cost of serum phosphate assays, this finding may prove clinically useful.

Key Words: cardiovascular diseases • kidney failure • myocardial infarction • phosphates

This article has been cited by other articles:

				M. Tonelli, G. Curhan, M. Pfeffer, F. Sacks, R. Thadhani, M. L. Melamed, N. Wiebe, and P. Muntner Relation Between Alkaline Phosphatase, Serum Phosphate, and All-Cause or Cardiovascular Mortality Circulation, November 3, 2009; 120(18): 1784 - 1792. [Abstract] [Full Text] [PDF]

				C J Ferro, C D Chue, R P Steeds, and J N Townend Is lowering phosphate exposure the key to preventing arterial stiffening with age? Heart, November 1, 2009; 95(21): 1770 - 1772. [Abstract] [Full Text] [PDF]

				Y. Sabbagh, S. P. O'Brien, W. Song, J. H. Boulanger, A. Stockmann, C. Arbeeny, and S. C. Schiavi Intestinal Npt2b Plays a Major Role in Phosphate Absorption and Homeostasis J. Am. Soc. Nephrol., November 1, 2009; 20(11): 2348 - 2358. [Abstract] [Full Text] [PDF]

				G. J. Becker, R. G. Walker, T. D. Hewitson, and E. Pedagogos Phosphate levels--time for a rethink? Nephrol. Dial. Transplant., August 1, 2009; 24(8): 2321 - 2324. [Full Text] [PDF]

				E. Shuto, Y. Taketani, R. Tanaka, N. Harada, M. Isshiki, M. Sato, K. Nashiki, K. Amo, H. Yamamoto, Y. Higashi, et al. Dietary Phosphorus Acutely Impairs Endothelial Function J. Am. Soc. Nephrol., July 1, 2009; 20(7): 1504 - 1512. [Abstract] [Full Text] [PDF]

				M. Kuro-o Klotho in chronic kidney disease--What's new? Nephrol. Dial. Transplant., June 1, 2009; 24(6): 1705 - 1708. [Full Text] [PDF]

				R. N. Foley Phosphate Levels and Cardiovascular Disease in the General Population Clin. J. Am. Soc. Nephrol., June 1, 2009; 4(6): 1136 - 1139. [Abstract] [Full Text] [PDF]

				S. Anderson, J. B. Halter, W. R. Hazzard, J. Himmelfarb, F. M. Horne, G. A. Kaysen, J. W. Kusek, S. G. Nayfield, K. Schmader, Y. Tian, et al. Prediction, Progression, and Outcomes of Chronic Kidney Disease in Older Adults J. Am. Soc. Nephrol., June 1, 2009; 20(6): 1199 - 1209. [Abstract] [Full Text] [PDF]

				O. M. Gutierrez, J. L. Januzzi, T. Isakova, K. Laliberte, K. Smith, G. Collerone, A. Sarwar, U. Hoffmann, E. Coglianese, R. Christenson, et al. Fibroblast Growth Factor 23 and Left Ventricular Hypertrophy in Chronic Kidney Disease Circulation, May 19, 2009; 119(19): 2545 - 2552. [Abstract] [Full Text] [PDF]

				A. Covic, P. Kothawala, M. Bernal, S. Robbins, A. Chalian, and D. Goldsmith Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease Nephrol. Dial. Transplant., May 1, 2009; 24(5): 1506 - 1523. [Abstract] [Full Text] [PDF]

				S. C. Palmer, J. C. Craig, and G. F. M. Strippoli Taking aim at targets Nephrol. Dial. Transplant., May 1, 2009; 24(5): 1358 - 1361. [Full Text] [PDF]

				J. H. Ix, I. H. De Boer, C. A. Peralta, K. L. Adeney, D. A. Duprez, N. S. Jenny, D. S. Siscovick, and B. R. Kestenbaum Serum Phosphorus Concentrations and Arterial Stiffness among Individuals with Normal Kidney Function to Moderate Kidney Disease in MESA Clin. J. Am. Soc. Nephrol., March 1, 2009; 4(3): 609 - 615. [Abstract] [Full Text] [PDF]

				C. Sullivan, S. S. Sayre, J. B. Leon, R. Machekano, T. E. Love, D. Porter, M. Marbury, and A. R. Sehgal Effect of Food Additives on Hyperphosphatemia Among Patients With End-stage Renal Disease: A Randomized Controlled Trial JAMA, February 11, 2009; 301(6): 629 - 635. [Abstract] [Full Text] [PDF]

				R. N. Foley, A. J. Collins, C. A. Herzog, A. Ishani, and P. A. Kalra Serum Phosphorus Levels Associate with Coronary Atherosclerosis in Young Adults J. Am. Soc. Nephrol., February 1, 2009; 20(2): 397 - 404. [Abstract] [Full Text] [PDF]

				T. Isakova, O. M. Gutierrez, Y. Chang, A. Shah, H. Tamez, K. Smith, R. Thadhani, and M. Wolf Phosphorus Binders and Survival on Hemodialysis J. Am. Soc. Nephrol., February 1, 2009; 20(2): 388 - 396. [Abstract] [Full Text] [PDF]

				S. J. Onufrak, A. Bellasi, F. Cardarelli, V. Vaccarino, P. Muntner, L. J. Shaw, and P. Raggi Investigation of Gender Heterogeneity in the Associations of Serum Phosphorus With Incident Coronary Artery Disease and All-Cause Mortality Am. J. Epidemiol., January 1, 2009; 169(1): 67 - 77. [Abstract] [Full Text] [PDF]

				S. M. Sprague, H. Abboud, P. Qiu, M. Dauphin, P. Zhang, and W. Finn Lanthanum Carbonate Reduces Phosphorus Burden in Patients with CKD Stages 3 and 4: A Randomized Trial Clin. J. Am. Soc. Nephrol., January 1, 2009; 4(1): 178 - 185. [Abstract] [Full Text] [PDF]

				E. Ritz and A. Remppis CHAPTER 15b Cardiovascular Problems in Chronic Kidney Disease ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text]

				C. S Shinaberger, S. Greenland, J. D Kopple, D. Van Wyck, R. Mehrotra, C. P Kovesdy, and K. Kalantar-Zadeh Is controlling phosphorus by decreasing dietary protein intake beneficial or harmful in persons with chronic kidney disease? Am. J. Clinical Nutrition, December 1, 2008; 88(6): 1511 - 1518. [Abstract] [Full Text] [PDF]

				A. Levin MD, B. Hemmelgarn MD PhD, B. Culleton MD MSc, S. Tobe MD, P. McFarlane MD PhD, M. Ruzicka MD PhD, K. Burns MD, B. Manns MD MSc, C. White MD, F. Madore MD MSc, et al. Guidelines for the management of chronic kidney disease Can. Med. Assoc. J., November 18, 2008; 179(11): 1154 - 1162. [Full Text] [PDF]

				M. Rodriguez and A. J. Felsenfeld PTH, FGF-23 and early CKD Nephrol. Dial. Transplant., November 1, 2008; 23(11): 3391 - 3393. [Full Text] [PDF]

				P. A. McCullough, V. Agrawal, E. Danielewicz, and G. S. Abela Accelerated Atherosclerotic Calcification and Monckeberg's Sclerosis: A Continuum of Advanced Vascular Pathology in Chronic Kidney Disease Clin. J. Am. Soc. Nephrol., November 1, 2008; 3(6): 1585 - 1598. [Abstract] [Full Text] [PDF]

				J. Andrade, L. Er, A. Ignaszewski, and A. Levin Exploration of Association of 1,25-OH2D3 with Augmentation Index, a Composite Measure of Arterial Stiffness Clin. J. Am. Soc. Nephrol., November 1, 2008; 3(6): 1800 - 1806. [Abstract] [Full Text] [PDF]

				O. M. Gutierrez, M. Mannstadt, T. Isakova, J. A. Rauh-Hain, H. Tamez, A. Shah, K. Smith, H. Lee, R. Thadhani, H. Juppner, et al. Fibroblast Growth Factor 23 and Mortality among Patients Undergoing Hemodialysis N. Engl. J. Med., August 7, 2008; 359(6): 584 - 592. [Abstract] [Full Text] [PDF]

				O. Phan, O. Ivanovski, I. G. Nikolov, N. Joki, J. Maizel, L. Louvet, M. Chasseraud, T. Nguyen-Khoa, B. Lacour, T. B. Drueke, et al. Effect of oral calcium carbonate on aortic calcification in apolipoprotein E-deficient (apoE-/-) mice with chronic renal failure Nephrol. Dial. Transplant., January 1, 2008; 23(1): 82 - 90. [Abstract] [Full Text] [PDF]

				G. Saab, A. T. Whaley-Connell, R. Khanna, and J. R. Sowers Review: Therapy for the altered mineral metabolism of chronic kidney disease: implications for vascular calcification Therapeutic Advances in Cardiovascular Disease, December 1, 2007; 1(2): 107 - 112. [Abstract] [PDF]

				D. Fliser, B. Kollerits, U. Neyer, D. P. Ankerst, K. Lhotta, A. Lingenhel, E. Ritz, F. Kronenberg, and for the MMKD Study Group Fibroblast Growth Factor 23 (FGF23) Predicts Progression of Chronic Kidney Disease: The Mild to Moderate Kidney Disease (MMKD) Study J. Am. Soc. Nephrol., September 1, 2007; 18(9): 2600 - 2608. [Abstract] [Full Text] [PDF]

				E. L. Schiffrin, M. L. Lipman, and J. F.E. Mann Chronic Kidney Disease: Effects on the Cardiovascular System Circulation, July 3, 2007; 116(1): 85 - 97. [Abstract] [Full Text] [PDF]

				R. Dhingra, L. M. Sullivan, C. S. Fox, T. J. Wang, R. B. D'Agostino Sr, J. M. Gaziano, and R. S. Vasan Relations of Serum Phosphorus and Calcium Levels to the Incidence of Cardiovascular Disease in the Community Arch Intern Med, May 14, 2007; 167(9): 879 - 885. [Abstract] [Full Text] [PDF]