In our prospective study, we observed no associations between plasma levels of FGF23, intact PTH, and phosphorus and subsequent risk for incident nonfatal MI or fatal CHD. The odds ratios for CHD associated with phosphorus were less than 1, and the upper bound of the 95% confidence interval excluded a clinically meaningful increase in risk.
Much of the interest in FGF23 as a potential biomarker for CVD was generated by studies in individuals with chronic kidney disease who have circulating levels of FGF23 several orders of magnitude higher than in our study population. For example, hemodialysis patients in the highest quartile of c-terminal FGF23 (FGF23 levels > 4010 RU/mL) had a multivariate odds ratio of 5.7 (95% CI 2.6-12.6) for 1-year all-cause mortality compared to participants in the lowest quartile (FGF23 < 1090 RU/mL).4
Recent data suggest that higher FGF23 also may be associated with cardiovascular disease in individuals with normal kidney function (and concomitantly much lower concentrations of plasma FGF23). In a prospective study of 833 individuals in the Heart and Soul Study (mean eGFR >70 mL/min per 1.73 m2
), participants in the highest tertile of plasma FGF23 had an 83% increase in cardiovascular disease events compared to the lowest tertile.8
The median plasma level of c-terminal FGF23 in Heart and Soul was 43.1 RU/mL.
There are several possible explanations for the apparent contradiction between the null associations we observed between FGF23 and CHD and the positive associations reported in Heart and Soul. First, unlike our study participants, individuals in Heart and Soul had CHD at baseline. Thus, it is possible that FGF23 is associated with severity of existing CHD but not development of CHD. Second, the majority of CVD events in Heart and Soul were heart failure and stroke or transient ischemic attack. Notably, FGF23 levels were not associated with risk of MI in Heart and Soul. Third, it is possible that the relatively long time of follow-up in our study (10 years) attenuated the magnitude of risk associated with a single plasma measurement of FGF23. The median follow-up in Heart and Soul was 6 years. However, restriction of our analyses to 6 years of follow-up did not change our results and we demonstrated low within-person variation in FGF23 levels over time.
Historically, interest in the potential effect of PTH on CHD risk was generated by the results of studies reporting increased rates of all cause and cardiovascular mortality in individuals with primary hyperparathyroidism.21, 22
Similarly, the higher PTH levels in individuals with chronic kidney disease led to speculation that PTH was a “uremic toxin” partly responsible for the high rates of CVD death in individuals with impaired kidney function.2, 3
To our knowledge, only one prospective study to date has reported an association between plasma PTH (independent of simultaneously measured plasma 25[OH]D) and CVD in a population of individuals with predominantly normal kidney function.5
In 958 male participants of the Uppsala Longitudinal Study of Adult Men (ULSAM) followed for a median of 9.7 years, each standard deviation increase in PTH was independently associated with a 38% greater risk for cardiovascular mortality.5
In contrast to ULSAM, we did not identify an association between plasma PTH and subsequent CVD. However, the numbers and definitions of outcomes in our study were substantially different than in ULSAM. The ULSAM investigators observed only 53 incident cases of cardiovascular mortality. In addition, the ICD-9 and ICD-10 administrative codes used to classify death as cardiovascular in ULSAM encompassed a wide array of potentially disparate diseases, including stroke, pulmonary embolus, pulmonary hypertension, and rheumatic heart disease. Our 422 cases of non-fatal MI and fatal CHD were confirmed by medical record review.
Hyperphosphatemia is an established risk factor for cardiovascular risk and mortality in individuals with chronic kidney disease.1, 3
and the impact of plasma phosphorus on mortality may be greater with higher plasma calcium levels.1
Data also suggest that higher levels of phosphorus are associated with adverse cardiovascular outcomes in individuals with normal renal function.6, 7
In the Framingham Offspring Study, the multivariate relative risk of incident CHD for individuals in the highest quartile of plasma phosphorus compared to the lowest quartile was 1.55 (95% CI 1.16-2.07).6
Plasma calcium was not associated with CHD, and the CHD risk associated with phosphorus did not vary by plasma calcium level. In secondary analyses of the Cholesterol And Recurrent Events (CARE) study, higher levels of plasma phosphorus (even in ranges considered normal) were associated with higher rates of cardiovascular events and death.7
In contrast to the Framingham Offspring Study and CARE, several recent large studies found no or inconsistent associations between plasma phosphorus and CVD. In 15,732 participants of the Atherosclerosis Risk in Communities Study (ARIC) with mean follow-up of 12.6 years, higher plasma phosphorus was associated with increased risk for stroke and death but not CHD.9
Although a subsequent analysis of ARIC reported that plasma phosphorus was associated with mortality in men but not women, there was no statistically significant variation by gender for associations between phosphorus and CHD.10
A secondary analysis of 7259 postmenopausal women in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial reported no associations between plasma phosphorus and incident CHD or stroke during 4 years of follow-up.11
We also observed no association between plasma phosphorus and risk of incident CHD. A potentially important difference between our study and the Framingham Offspring Study and CARE is the large number of smokers in the latter studies. In Framingham Offspring, 44.8% of participants in the highest quartile of phosphorus were current smokers compared to 27.4% in the lowest quartile, and in CARE 40.1% of participants in the highest quartile of phosphorus were current smokers compared to 6.9% in the lowest. Because current smoking is independently associated with higher levels of plasma phosphorus in a dose dependent fashion,9, 12
it is possible that adjusting for smoking as a binary variable without considering quantity or duration of smoking (as in Framingham Offspring and CARE) permits residual confounding by tobacco use in multivariate analyses of phosphorus and cardiovascular disease. Of note, over 50% of participants in ULSAM (a cohort in which a positive association was observed between phosphorus and cardiovascular mortality) were current smokers.23
Our study has limitations. First, the upper bounds of the 95% confidence intervals of odds for incident CHD associated with FGF23 and PTH did not exclude clinically meaningful increases in risk. However, ours is the largest prospective study to date examining independent associations between these factors and incident CHD. Second, the low number of smokers in our study did not allow us to examine the potential impact of quantity and duration of tobacco use on associations between phosphorus and incident CHD. Third, because we used EDTA as a plasma preservative, we could not measure plasma calcium. It is possible that the risk of CHD associated with plasma phosphorus varies by calcium. Finally, our study population was male and predominantly white.
We observed no associations between plasma FGF23, intact PTH, and phosphorus and subsequent incident nonfatal MI or fatal CHD. These data suggest that plasma levels of these factors have limited or no utility as biomarkers for incident CHD in men with normal renal function.