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Ravi Dhingra, MD; Lisa M. Sullivan, PhD; Caroline S. Fox, MD; Thomas J. Wang, MD; Ralph B. D’Agostino Sr, PhD; J. Michael Gaziano, MD, MPH; Ramachandran S. Vasan, MD

Arch Intern Med. 2007;167(9):879-885.

Background  Higher levels of serum phosphorus and the calcium-phosphorus product are associated with increased mortality from cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) or prior CVD. However, it is unknown if serum phosphorus levels influence vascular risk in individuals without CKD or CVD.

Methods  We prospectively evaluated 3368 Framingham Offspring study participants (mean age, 44 years; 51% were women) free of CVD and CKD. We used multivariable Cox models to relate serum phosphorus and calcium levels to CVD incidence.

Results  On follow-up (mean duration, 16.1 years), there were 524 incident CVD events (159 in women). In multivariable analyses and adjusting for established risk factors and additionally for glomerular filtration rate and for hemoglobin, serum albumin, proteinuria, and C-reactive protein levels, a higher level of serum phosphorus was associated with an increased CVD risk in a continuous fashion (adjusted hazard ratio per increment of milligrams per deciliter, 1.31; 95% confidence interval, 1.05-1.63; P = .02; P value for trend across quartiles = .004). Individuals in the highest serum phosphorus quartile experienced a multivariable-adjusted 1.55-fold CVD risk (95% confidence interval, 1.16%-2.07%; P = .004) compared with those in the lowest quartile. These findings remained robust in time-dependent models that updated CVD risk factors every 4 years and in analyses restricted to individuals without proteinuria and an estimated glomerular filtration rate greater than 90 mL/min per 1.73 m². Serum calcium was not related to CVD risk.

Conclusion  Higher serum phosphorus levels are associated with an increased CVD risk in individuals free of CKD and CVD in the community. These observations emphasize the need for additional research to elucidate the potential link between phosphorus homeostasis and vascular risk.

Author Affiliations: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Mass (Drs Dhingra, Fox, Wang, D’Agostino, and Vasan); Massachusetts Veterans Epidemiology Research and Information Center, Veterans Administration Boston Healthcare System (Drs Dhingra and Gaziano), and Division of Aging, Brigham and Women's Hospital (Drs Dhingra and Gaziano), Boston; Department of Medicine, Alice Peck Day Memorial Hospital, Lebanon, NH (Dr Dhingra); Division of Cardiology, Massachusetts General Hospital, Boston (Dr Wang); Department of Biostatistics, School of Public Health (Drs Sullivan and D’Agostino), and Cardiology Section and Department of Preventive Medicine and Epidemiology, School of Medicine (Dr Vasan), Boston University, Boston; and National Heart, Lung and Blood Institute, Bethesda, Md (Dr Fox).

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