Education and Innovation in Cardiovascular Medicine
Literature

Alkaline phosphatase, but not serum phosphate, associated with increased CV risk

6-3-2013

Alkaline Phosphatase, Serum Phosphate, and Incident Cardiovascular Disease and Total Mortality in Older Men.

Wannamethee SG, Sattar N, Papcosta O et al
Arterioscler Thromb Vasc Biol. 2013 Feb 21.


Background

End-stage renal disease often comes with altered mineral metabolism such as changes in alkaline phosphatase (ALP) and circulating phosphate concentrations [1-3]. Several studies have linked elevated circulating phosphate levels and serum ALP levels to increased coronary calcification and cardiovascular risk in persons with chronic kidney disease [1-4]. Also for the general population serum phosphate has been described to be associated with increased risk of cardiovascular disease (CVD) [5-9]. However, some studies did not find an association between phosphate and coronary heart disease (CHD) events in the general population [7,8,10]. Population studies that looked at ALP and CVD, found a that increased levels are associated with increased CVD mortality and hospitalization [11-13]. ALP is associated with a marker of inflammation [14], but the role of inflammation in the relationship between ALP and CVD is unclear.
This prospective study investigated the association between serum phosphatase and ALP with CHD risk, stroke, CVD mortality and total mortality, in 3381 men aged 60 to 79 year, without a history of myocardial infarction or stroke.


Main results

  • High ALP was significantly associated with increased risk of major CHD events and CVD events and CVD mortality, which could partly be explained by CV risk factors and inflammation.
  • Serum phosphatise was only significantly associated with CVD mortality not due to CHD or stroke (HR:1.35 [1.01, 1.83]; P=0.04), but showed no associations with CHD or stroke risks.
  • ALP and serum phosphate were both associated with increased total mortality, even after adjustment for inflammation and exclusion of men with chronic kidney disease.


Conclusions

This study confirms some earlier findings on the associations of ALP and phosphate with CHD/CVD events and total mortality, and extends these findings to older men without CVD. The authors discuss the potential contribution of inflammation, but further research is needed to elucidate the nature of the association between ALP and phosphate with CHD and CVD outcomes.


References:

1.Covic A, Kothawala P, Bernal M, Robbins S, Chalian A, Goldsmith D. 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. 2009;24:1506–1523.
2. Palmer SC, Hayen A, Macaskill P, Pellegrini F, Craig JC, Elder GJ, Strippoli GF. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with
chronic kidney disease: a systematic review and meta-analysis. JAMA.2011;305:1119–1127.
3. Regidor DL, Kovesdy CP, Mehrotra R, Rambod M, Jing J, McAllister CJ, Van Wyck D, Kopple JD, Kalantar-Zadeh K. Serum alkaline phosphatase predicts mortality among maintenance hemodialysis patients. J
Am Soc Nephrol. 2008;19:2193–2203.
4. Adeney KL, Siscovick DS, Ix JH, Seliger SL, Shlipak MG, Jenny NS, Kestenbaum BR. Association of serum phosphate with vascular and valvular calcification in moderate CKD. J Am Soc Nephrol. 2009;20:381–387.
6 Larsson TE, Olauson H, Hagström E, Ingelsson E, Arnlöv J, Lind L, Sundström J. Conjoint effects of serum calcium and phosphate on risk of total, cardiovascular, and noncardiovascular mortality in the community.
Arterioscler Thromb Vasc Biol. 2010;30:333–339.
7. Foley RN, Collins AJ, Ishani A, Kalra PA. Calcium-phosphate levels and cardiovascular disease in community-dwelling adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J. 2008;156:556–563.
8. Onufrak SJ, Bellasi A, Cardarelli F, Vaccarino V, Muntner P, Shaw LJ, Raggi P. Investigation of gender heterogeneity in the associations of serum phosphorus with incident coronary artery disease and all-cause
mortality. Am J Epidemiol. 2009;169:67–77.
9. Dhingra R, Sullivan LM, Fox CS, Wang TJ, D’Agostino RB Sr, Gaziano JM, Vasan RS. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med.
2007;167:879–885.
10. Slinin Y, Blackwell T, Ishani A, Cummings SR, Ensrud KE; and for the MORE Investigators. Serum calcium, phosphorous and cardiovascular events in post-menopausal women. Int J cardiol 2011;149:335–340.
11.Tonelli M, Curhan G, Pfeffer M, Sacks F, Thadhani R, Melamed ML, Wiebe N, Muntner P. Relation between alkaline phosphatase, serum phosphate, and all-cause or cardiovascular mortality. Circulation. 2009;120:
1784–1792.
12. Ryu WS, Lee SH, Kim CK, Kim BJ, Yoon BW. Increased serum alkaline phosphatase as a predictor of long-term mortality after stroke.Neurology. 2010;75:1995–2002.
13. Abramowitz M, Muntner P, Coco M, Southern W, Lotwin I, Hostetter TH, Melamed ML. Serum alkaline phosphatase and phosphate and risk of mortality and hospitalization. Clin J Am Soc Nephrol. 2010;5:1064–1071.
14.Webber M, Krishnan A, Thomas NG, Cheung BM. Association between serum alkaline phosphatase and C-reactive protein in the United States National Health and Nutrition Examination Survey 2005–2006. Clin
Chem Lab Med. 2010;48:167–173.

Abstract

Objective:
We have examined the association between serum phosphate and alkaline phosphatase (ALP) with incident cardiovascular disease (CVD) outcomes and total mortality in older men.

Approach and Results
A prospective study of 3381 men, aged 60 to 79 years, without a history of myocardial infarction or stroke followed up for an average 11 years during which there were 605 major CVD events (fatal coronary heart disease and nonfatal myocardial infarction, stroke, and CVD death) and 984 total deaths. ALP but not serum phosphate was associated with increased risk of coronary heart disease and overall CVD events which persisted after adjustment for CVD risk factors and markers of inflammation and after exclusion of men with chronic kidney disease (adjusted hazard ratio per SD, 1.19 [1.05, 1.34]; P=0.007 and 1.10 [1.01, 1.21]; P=0.04). In contrast, serum phosphate was only associated with increased CVD mortality owing to noncoronary heart disease or stroke causes (adjusted hazard ratio per SD, 1.35 [1.01, 1.83]; P=0.04). Both raised phosphate and ALP were associated with significantly increased total mortality after full adjustment and exclusion of men with chronic kidney disease.

Conclusions:
ALP but not serum phosphate is associated with coronary heart disease risk in elderly men. High levels of ALP and serum phosphate are both associated with increased total mortality.


AlkalineALPArteriosclerassociationsCHDmenMortalityphosphatasephosphateProspectiveserumThrombVASc

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