Increased serum phosphorus has been associated with increased mortality from cardiovascular (CV) disease. However, information is scant regarding the influence of serum phosphorus within the normal range on vascular risk in subclinical atherosclerosis in asymptomatic young adults. Serum phosphorus and other CV risk factor variables were measured in 856 white and 354 black subjects without known CV disease or renal disease. Carotid intima–media thickness (IMT) was measured by B-mode ultrasonography. Significant race and gender differences were noted for serum phosphorus (blacks > whites) and carotid IMT (black women > white women; men > women). In bivariate analyses, serum phosphorus was correlated with carotid IMT (p <0.001), and smokers showed higher phosphorus levels than nonsmokers (p = 0.008). In multivariate regression analyses, carotid IMT was significantly associated with serum phosphorus (regression coefficient beta = 0.028, p <0.001) and smoking (beta = 0.032, p <0.001), adjusting for other CV risk factors and estimated glomerular filtration rate. In addition, a significant interaction effect of cigarette smoking and serum phosphorus on carotid IMT was noted, with a greater increasing trend of carotid IMT with phosphorus in smokers than in nonsmokers (p = 0.019 for interaction). In conclusion, serum phosphorus within the normal range is an important correlate of carotid IMT in asymptomatic young adults, with smoking potentiating this adverse association.
Phosphorus is essential for diverse biological functions and is tightly regulated within the physiologic range in healthy subjects. An excess amount of phosphorus has been associated with increased mortality from cardiovascular (CV) disease in subjects with chronic kidney disease, from moderate to end-stage renal failure. Recently, it has been found that phosphorus levels within a normal range are independently associated with risk of all-cause mortality and CV events in patients with previous myocardial infarction. Phosphorus levels are also associated with increased risk of chronic kidney disease and may be a potentially modifiable risk factor for stroke and death in a general population. However, only a few studies have examined the relation between phosphorus levels and subclinical atherosclerosis in asymptomatic patients. The present study examined the relation between serum phosphorus and carotid intima–media thickness (IMT), a validated indicator of subclinical atherosclerosis and future CV risk, in clinically asymptomatic white and black young adults.
Methods
As part of the Bogalusa Heart Study, a biracial (black–white) community-based investigation of the early nature history of CV disease, 1,210 subjects (856 white and 354 black, 43.1% men) 24 to 44 years of age, residing in the community of Bogalusa, Louisiana, were examined for carotid IMT by ultrasound and CV risk factor variables, including serum phosphorus. All subjects in this study gave informed consent for examination. Study protocols were approved by the institutional review board of the Tulane University Medical Center (New Orleans, Louisiana).
Examinations of study subjects followed protocols and procedures described elsewhere. Subjects were instructed to fast for 12 hours before screening, and compliance was determined by an interview on the morning of examination. Height and weight were measured 2 times to ±0.1 cm and to ±0.1 kg, respectively. Body mass index (weight in kilograms divided by the square of the height in meters) was used as a measurement of overall adiposity. Blood pressure levels were measured using mercury sphygmomanometers on the right arm of subjects in a relaxed, sitting position by 2 randomly assigned nurses (3 replicates each). The first and fifth Korotkoff phases were used to determine systolic and diastolic blood pressures, respectively. Means of replicate readings were used for analyses. Forced values (140/90 mm Hg) were assigned for systolic and diastolic blood pressures, respectively, to subjects (n = 81) who were on antihypertension medication at the time of examination. Mean arterial pressure (diastolic blood pressure + 1/3 pulse pressure) was used as a measurement of hemodynamic status. Information on smoking status was obtained by questionnaires. Those who smoked ≥1 cigarette per week during the previous 1 year were considered current smokers.
Serum phosphorus levels were determined by an ammonium molybdate method, glucose and creatinine by an enzymatic method, as part of multiple chemistry profile (SMA20) by the multichannel Olympus Au-5000 Analyzer (Olympus, Lake Success, New York). Serum cholesterol and triglycerides (TGs) were determined enzymatically on a Hitachi 902 Automatic Analyzer (Roche Diagnostics, Indianapolis, Indiana). Serum lipoprotein cholesterols were analyzed by a combination of heparin–calcium precipitation and agar–agarose gel electrophoresis procedures. The laboratory is monitored for precision and accuracy by the Lipid Standardization Program of the Centers for Disease Control and Prevention (Atlanta, Georgia). Plasma insulin was measured by a commercial radioimmunoassay kit (Padebas insulin kits, Pharmacia, Diagnostics, Piscataway, New Jersey); intraclass correlation coefficients, a measurement of reproducibility of the entire process from blood collection to data processing, between blind duplicate values (n = 97) were 0.98 for low-density lipoprotein (LDL) cholesterol, 0.99 for high-density lipoprotein (HDL) cholesterol, 0.97 for TGs, 0.98 for glucose and insulin, 0.98 for creatinine, and 0.99 for serum phosphorus. Estimated glomerular filtration rate was estimated as a function of age, serum creatinine, gender, and race using the simplified Modified Diet in Renal Disease equation: estimated glomerular filtration rate (milliliters per minute per 1.73 m 2 ) = 186.3 × creatinine −1.154 × age −0.203 × (0.742 if a woman) × (1.21 if black), where m 2 denotes body surface area in square meters. An index of insulin resistance (homeostasis model assessment of insulin resistance) was calculated according to the formula: fasting insulin (microunits per milliliter) × fasting glucose (millimoles per liter)/22.5. Forced values of 160 mg/dl for LDL cholesterol and 126 mg/dl for glucose were assigned to subjects who were on medications for hypercholesterolemia (n = 26) and diabetes (n = 19) at the time of examination, respectively.
Carotid ultrasound measurements were done by an experienced and highly trained technician on ultrasound instrument (Power Vision Toshiba SSH-380 ultrasound system, Toshiba American Medical Systems, Carrollton, Texas) using a 7.5-MHz linear array transducer. Images were recorded at the common carotid, carotid bulb (bifurcation), and internal carotid arteries bilaterally according to previously developed protocols for the Atherosclerosis Risk In Communities study. Images were recorded on Super VHS videotapes and read by certified readers from the Vascular Ultrasound Research Laboratory in Wake Forest Medical Center (Wake Forest, North Carolina) using semiautomatic ultrasound imaging. Maximum carotid IMT readings of left and right far walls were averaged for each segment; if bilateral images could not be obtained, 1 side was used as the average. Then, the averaged carotid IMT of the common, bulb, and internal segments was calculated as mean carotid IMT. Common carotid IMT, carotid bulb IMT, internal carotid IMT, and mean carotid IMT were used for analyses. Based on repeated measurements of 75 study subjects, intraclass correlation coefficients for repeat scans were 0.72 for the common carotid, 0.69 for the carotid bulb, and 0.80 for the internal carotid.
All data analyses were performed using SAS 9.1 (SAS Institute, Cary, North Carolina). Homeostasis model assessment of insulin resistance and TG/HDL cholesterol were logarithmically transformed to improve the normality of distribution for correlation and regression analyses; however, their mean values in original scales are presented in Table 1 for description. Differences in mean values of study variables between race–gender groups and serum phosphorus between smokers and nonsmokers were tested by analysis of covariance models. Correlation of serum phosphorus with CV risk factor variables and carotid IMT was assessed using Pearson correlation coefficients. The independent relation of serum phosphorus to carotid IMT was examined by multivariate regression models, adjusting for other CV risk factor variables and estimated glomerular filtration rate; because cigarette smoking, which contains substantial amounts of nicotine, free radicals, and pro-oxidants to produce oxidative stress, and higher serum phosphorus may confound the results, 2 separate models without (model I) and with (model II) smoking status were used. Further, the interaction of serum phosphorus and smoking on carotid IMT was tested by including an interaction term.
| Variable ⁎ | White | Black | p Value for Difference | |||
|---|---|---|---|---|---|---|
| Men | Women | Men | Women | Race | Gender | |
| (n = 377) | (n = 479) | (n = 144) | (n = 210) | |||
| Age (years) | 36 ± 4 | 36 ± 5 | 36 ± 4 | 35 ± 5 | NS | NS |
| Body mass index (kg/m 2 ) | 29 ± 6 | 28 ± 7 | 29 ± 7 | 31 ± 8 | <0.001 † | <0.05 |
| Homeostasis model assessment of insulin resistance | 3.0 ± 3.0 | 2.4 ± 2.2 | 2.8 ± 2.6 | 3.6 ± 5.5 | <0.001 † | <0.05 |
| Triglycerides/high-density lipoprotein cholesterol | 4.5 ± 4.7 | 2.8 ± 3.6 | 3.1 ± 3.6 | 1.8 ± 1.1 | <0.001 | <0.001 |
| Low-density lipoprotein cholesterol (mg/dl) | 130 ± 34 | 124 ± 33 | 125 ± 43 | 114 ± 30 | <0.002 † | <0.05 |
| Mean arterial pressure (mm Hg) | 93 ± 8 | 87 ± 9 | 99 ± 13 | 92 ± 12 | <0.001 | <0.001 |
| Smokers (%) | 29 | 28 | 42 | 29 | <0.001 ‡ | <0.05 § |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 97 ± 16 | 98 ± 22 | 105 ± 20 | 116 ± 25 | <0.001 | <0.001 § |
| Phosphorus (mg/dl) | 3.35 ± 0.54 | 3.37 ± 0.52 | 3.70 ± 0.59 | 3.61 ± 0.55 | <0.001 | NS |
| Carotid intima–media thickness (mm) | 0.85 ± 0.18 | 0.75 ± 0.12 | 0.87 ± 0.16 | 0.79 ± 0.14 | <0.001 † | <0.001 |
⁎ Mean ± SD for continuous variables.
Results
Table 1 lists levels of study variables by race and gender. Significant racial differences were noted for phosphorus (blacks > whites), carotid IMT (black women > white women), body mass index (black women > white women), homeostasis model assessment of insulin resistance (black women > white women), TG/HDL cholesterol (whites > blacks), LDL cholesterol (white women > black women), mean arterial pressure (blacks > whites), estimated glomerular filtration rate (blacks > whites), and number of smokers (black men > white men). Gender-related differences were significant for carotid IMT (men > women), body mass index (white men > white women and black women > Black men), homeostasis model assessment of insulin resistance (white men > white women and black women > black men), TG/HDL cholesterol (men > women), LDL cholesterol (men > women), mean arterial pressure (men > women), estimated glomerular filtration rate (black women > black men), and number of smokers (black men > black women).
Pearson correlation coefficients of serum phosphorus with carotid IMT and CV risk factor variables are presented in Table 2 . Serum phosphorus was significantly correlated with carotid IMT, adjusting for race, gender, and age. Importantly, smokers had significantly higher mean levels ± SD of serum phosphorus (3.52 ± 0.54 mg/dl) than nonsmokers (3.41 ± 0.56 mg/dl), adjusting for race, gender, and age (p = 0.008). In addition, serum calcium levels did not show a significant relation to carotid IMT (data not shown).
| r | p Value | |
|---|---|---|
| Age ⁎ | −0.014 | 0.599 |
| Body mass index † | 0.009 | 0.765 |
| Logarithmic homeostasis model assessment of insulin resistance † | −0.040 | 0.170 |
| Logarithmic triglycerides/high-density lipoprotein cholesterol † | −0.017 | 0.559 |
| Low-density lipoprotein cholesterol † | 0.028 | 0.333 |
| Mean arterial pressure † | 0.041 | 0.153 |
| Estimated glomerular filtration rate † | 0.034 | 0.244 |
| Carotid intima–media thickness † | 0.124 | <0.001 |
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