High serum phosphorus levels have been linked with vascular calcification and greater cardiovascular morbidity and mortality. We assessed whether serum phosphorus was associated with the atrial fibrillation (AF) incidence in a large community-based cohort in the United States. Our analysis included 14,675 participants (25% black, 45% men) free of AF at baseline (1987 to 1989) and with measurements of fasting serum phosphorus from the Atherosclerosis Risk In Communities (ARIC) study. The incidence of AF was ascertained through the end of 2008 from study visit electrocardiograms, hospitalizations, and death certificates. Cox proportional hazard models were used to estimate the hazard ratios of AF by the serum phosphorus levels, adjusting for potential confounders. During a median follow-up of 19.7 years, we identified 1,656 incident AF cases. Greater serum phosphorus was associated with a greater AF risk: the hazard ratio of AF with a 1-mg/dl increase in serum phosphorus was 1.13 (95% confidence interval 1.02 to 1.26). No significant interaction was seen by race (p = 0.88) or gender (p = 0.51). The risk of AF was increased in association with greater serum phosphorus in those with an estimated glomerular filtration rate of ≥90 ml/min/1.72 m 2 but not among those with an estimated glomerular filtration rate of <90 ml/min/1.72 m 2 . The total corrected calcium levels were not related to AF risk; however, greater levels of the calcium-phosphorus product were associated with greater AF risk. In conclusion, in the present large population-based study, greater levels of serum phosphorus and the related calcium-phosphorus product were associated with a greater incidence of AF.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with an increased risk of heart failure, stroke, and cardiovascular death. The established risk factors include age, white race, obesity, heart failure, coronary heart disease, left ventricular hypertrophy, hypertension, certain lifestyle factors, and, recently, chronic kidney disease (CKD). Increased phosphatemia because of impaired phosphorus excretion with decreased kidney function could help explain the relation between AF and CKD if phosphorus is an independent predictor of AF. Phosphorus is essential for numerous biologic functions, including cellular signal transduction, mineral metabolism, and energy exchange. Elevated phosphorus levels have been independently linked with calcification of the aorta and coronary arteries, increased arterial stiffness, elevated left ventricular mass, carotid atherosclerosis, and increased cardiovascular morbidity and mortality in subjects with and without CKD. The present study estimated the association of serum phosphorus levels with the incidence of AF in the Atherosclerosis Risk In Communities (ARIC) study cohort. We also assessed whether the related serum calcium and calcium-phosphorus product were associated with AF risk.
Methods
The ARIC study was a biracial, prospective cohort study of cardiovascular disease and atherosclerosis risk factors. The participants at baseline (1987 to 1989) included 15,792 men and women aged 45 to 64 years, recruited from 4 communities in the United States (Washington County, Maryland; northwest suburbs of Minneapolis, Minnesota; Jackson, Mississippi; and Forsyth County, North Carolina). Additional details on the ARIC study can be found in the online supplement . The institutional review board at each participating center approved the present study, and all study participants provided written informed consent.
The AF diagnoses were ascertained by 3 different sources in the ARIC study: electrocardiograms performed at study visits, hospital discharge codes, and death certificates. Additional details of AF ascertainment can be found in the online supplement .
In the present analysis, the incidence date of AF was defined as the date for the first electrocardiogram showing AF, the first hospital discharge coded as AF, or when AF was listed as a cause of death, whichever occurred earlier.
Blood samples were collected at each visit after a fast of ≥8 hours and sent to the ARIC Central Lipid Laboratory. The phosphorus, calcium, and creatinine levels were measured in frozen serum samples, using methods based on ammonium molybdate, o -cresolphthalein complexone, and modified kinetic Jaffe-picric acid, respectively. The coefficient of variation was 2.4% for phosphorus, 1.9% for calcium, and 3.7% for creatinine. Detailed procedures on baseline covariate measurements have been previously published and are also available in the online supplement .
Of the 15,792 participants who attended visit 1 in the ARIC study, we excluded those who were of a racial group other than white or black and nonwhites in the Minneapolis and Washington County field centers (n = 103), those with prevalent AF at visit 1 (n = 37), low-quality or missing electrocardiograms (n = 242), those missing phosphorus levels (n = 124), those with nonfasting blood samples (n = 485), those missing covariates (n = 108), and those with an estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m 2 (n = 18). The final sample included 14,675 participants (25% black, 45% men).
We estimated the association between the baseline serum phosphorus and calcium levels and the incidence of AF using Cox proportional hazards models, with the interval to AF as the main outcome variable. Initially, we explored the association between phosphorus and calcium and AF risk using restricted cubic splines. Next, we categorized the serum phosphorus and calcium levels and the calcium-phosphorus product by quintiles for the categorical analysis. p Values for trend were calculated across the quintile categories using the quintile term. The follow-up period was defined as the interval elapsed between baseline and the date of AF incidence, death, lost to follow-up, or December 31, 2008, whichever came earlier. Models for the association of the phosphorus levels with AF risk were adjusted for the baseline covariates, including age, gender, race, study site, education (less than completed high school, high school diploma, at least some college), height (continuous), smoking (never, former, current), alcohol drinking (never, former, current), body mass index (continuous), diabetes (dichotomous), serum calcium (adjusted for albumin), systolic blood pressure (continuous), diastolic blood pressure (continuous), use of antihypertensive medications, eGFR (modeled as a spline), prevalent stroke, prevalent heart failure, and prevalent coronary heart disease. An additional model was performed, adjusting for incident heart failure and incident coronary heart disease as time-varying covariates. Models considering calcium as the main exposure included the same covariates, except for adjusting for phosphorus instead of calcium.
Because both excess phosphorus and an increased risk of AF have been independently linked with CKD, we also examined the association of phosphorus and AF stratified by the eGFR. Effect measure modification on the multiplicative scale was formally tested in the multivariate model, including an interaction term between gender, race, and eGFR categories and the phosphorus levels. The proportional hazards assumption was tested using time interaction terms and inspection of log negative log survival curves. All statistical analyses were performed with SAS, version 9.2 (SAS Institute, Cary, North Carolina).
Results
Selected characteristics for the ARIC participants by quintile of serum phosphorus level are listed in Table 1 . Women, blacks, current smokers, and those with prevalent heart failure were more likely to have higher phosphorus levels. The mean ± SD of serum phosphorus was 3.4 ± 0.5 mg/dl (interquartile range 3.1-3.7). The mean ± SD of calcium and the calcium-phosphorus product was 9.9 ± 0.4 mg/dl and 33.9 ± 5.2, respectively. The correlation coefficient between phosphorus and calcium was 0.16 and between phosphorus and the calcium-phosphorus product was 0.96.
| Variable | Serum Phosphorus Levels (mg/dl) | ||||
|---|---|---|---|---|---|
| ≤3.0 (n = 3,201) | 3.1–3.3 (n = 3,287) | 3.4–3.5 (n = 2,483) | 3.6–3.8 (n = 3,048) | ≥3.9 (n = 2,656) | |
| Age (yrs) | 54.2 ± 5.8 | 54.1 ± 5.8 | 54.1 ± 5.8 | 54.2 ± 5.7 | 54.4 ± 5.6 |
| Women | 33.2% | 46.0% | 56.4% | 66.4% | 79.0% |
| Black race | 23.4% | 23.4% | 25.5% | 25.6% | 26.8% |
| High school degree | 75.0% | 77.8% | 78.3% | 77.5% | 77.3% |
| Height (cm) | 171.4 ± 9.2 | 169.8 ± 9.3 | 168.4 ± 9.2 | 166.9 ± 9.0 | 165.1 ± 8.4 |
| Current smoker | 20.7% | 22.5% | 25.5% | 28.1% | 33.2% |
| Current alcohol drinker | 56.2% | 57.9% | 56.8% | 56.1% | 56.6% |
| Body mass index (kg/m 2 ) | 28.2 ± 5.0 | 27.8 ± 5.3 | 27.5 ± 5.2 | 27.6 ± 5.6 | 27.0 ± 5.4 |
| Diabetes mellitus | 11.0% | 10.2% | 9.9% | 9.8% | 11.9% |
| Hypertensive medication | 30.3% | 27.5% | 29.6% | 30.1% | 32.3% |
| Systolic blood pressure (mm Hg) | 123.2 ± 18.5 | 121.3 ± 18.7 | 120.8 ± 18.3 | 119.8 ± 18.4 | 119.5 ± 19.1 |
| Diastolic blood pressure (mm Hg) | 75.1 ± 11.0 | 74.0 ± 11.3 | 73.6 ± 10.9 | 72.8 ± 11.2 | 72.4 ± 11.3 |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 95.1 ± 14.5 | 95.8 ± 14.9 | 95.6 ± 14.6 | 96.2 ± 14.9 | 95.8 ± 16.2 |
| Estimated glomerular filtration rate category | |||||
| >90 ml/min/1.73 m 2 | 67.0% | 69.3% | 69.4% | 70.9% | 69.4% |
| 60–90 ml/min/1.73 m 2 | 31.7% | 29.1% | 29.3% | 27.5% | 28.5% |
| <60 ml/min/1.73 m 2 | 1.3% | 1.6% | 1.3% | 1.6% | 2.1% |
| Calcium ∗ (mg/dl) | 9.8 ± 0.5 | 9.9 ± 0.4 | 9.9 ± 0.4 | 9.9 ± 0.4 | 10.0 ± 0.4 |
| Calcium-phosphorus product (mg/dl) | 27.3 ± 2.5 | 31.6 ± 1.5 | 34.1 ± 1.5 | 36.7 ± 1.7 | 41.3 ± 3.1 |
| Prevalent stroke | 1.8% | 1.9% | 1.1% | 2.0% | 1.8% |
| Prevalent coronary heart disease | 5.6% | 4.8% | 4.9% | 3.9% | 4.1% |
| Prevalent heart failure | 4.4% | 3.6% | 4.1% | 4.8% | 5.2% |
During a median follow-up of 19.7 years, we identified 1,656 incident AF cases. The association between the serum phosphorus level and incident AF was examined using cubic splines, showing a slight J -shaped or reversed L -shaped association ( Figure 1 ), with a nonsignificant phosphorus quadratic term (p = 0.32). The multivariate adjusted hazard ratio of AF associated with 1-mg/dl higher serum phosphorus level was 1.13 (95% confidence interval 1.02 to 1.26). Categorizing serum phosphorus in quintiles, a 20% greater risk of AF was observed in the top quintiles compared to the lowest quintile, even after adjustment for potential confounders ( Table 2 ). The results were slightly attenuated in the uppermost quintile with additional adjustment for time-varying heart failure and coronary heart disease. The results did not differ with additional adjustment for incident hypertension, diuretic use, vitamin D intake, or after adjustment for eGFR at visit 4 (data not shown).
| Variable | Data Stratified by Quintile | p for Trend | ||||
|---|---|---|---|---|---|---|
| Serum phosphorus quintiles (mg/dl) | ≤3.0 | 3.1–3.3 | 3.4–3.5 | 3.6–3.8 | 3.9+ | |
| AF cases | 380 | 373 | 260 | 360 | 283 | |
| Person-yrs | 55,853 | 57,758 | 43,533 | 53,924 | 46,220 | |
| AF incidence rate ∗ | 5.31 | 5.38 | 5.30 | 6.16 | 5.99 | |
| Model 1 | 0.02 | |||||
| Hazard ratio | 1 | 1.02 | 1.01 | 1.17 | 1.15 | |
| 95% Confidence interval | Referent | 0.88–1.17 | 0.86–1.18 | 1.01–1.36 | 0.98–1.35 | |
| Model 2 | 0.02 | |||||
| Hazard ratio | 1 | 1.08 | 1.05 | 1.20 | 1.17 | |
| 95% Confidence interval | Referent | 0.94–1.25 | 0.90–1.23 | 1.03–1.39 | 0.99–1.38 | |
| Model 3 | 0.03 | |||||
| Hazard ratio | 1 | 1.14 | 1.11 | 1.23 | 1.15 | |
| 95% Confidence interval | Referent | 0.99–1.31 | 0.94–1.30 | 1.06–1.43 | 0.98–1.36 | |
| Serum calcium quintiles (mg/dl) | ≤9.55 | 9.56–9.8 | 9.81–10.0 | 10.01–10.29 | ≥10.3 | |
| AF cases | 322 | 383 | 323 | 372 | 256 | |
| Person-yrs | 54,242 | 60,939 | 51,686 | 55,409 | 35,012 | |
| AF incidence rate ∗ | 5.05 | 5.46 | 5.38 | 5.94 | 7.06 | |
| Model 1 | 0.0002 | |||||
| Hazard ratio | 1 | 1.10 | 1.09 | 1.22 | 1.36 | |
| 95% Confidence interval | Referent | 0.95–1.28 | 0.93–1.27 | 1.05–1.41 | 1.15–1.61 | |
| Model 2 | 0.09 | |||||
| Hazard ratio | 1 | 1.06 | 1.02 | 1.12 | 1.15 | |
| 95% Confidence interval | Referent | 0.92–1.24 | 0.88–1.20 | 0.96–1.31 | 0.97–1.37 | |
| Model 3 | 0.38 | |||||
| Hazard ratio | 1 | 1.04 | 0.98 | 1.06 | 1.08 | |
| 95% Confidence interval | Referent | 0.89–1.20 | 0.84–1.15 | 0.91–1.24 | 0.91–1.28 | |
| Calcium-phosphorus product quintiles | ≤29.5 | 29.6–32.5 | 32.6–35 | 35.1–38 | ≥38.1 | |
| AF cases | 348 | 318 | 331 | 323 | 336 | |
| Person-yrs | 50,894 | 53,428 | 50,070 | 51,056 | 51,840 | |
| AF incidence rate ∗ | 4.57 | 4.33 | 4.94 | 5.01 | 5.46 | |
| Model 1 | 0.003 | |||||
| Hazard ratio | 1 | 0.96 | 1.09 | 1.12 | 1.23 | |
| 95% Confidence interval | Referent | 0.82–1.12 | 0.94–1.27 | 0.95–1.30 | 1.05–1.44 | |
| Model 2 | 0.006 | |||||
| Hazard ratio | 1 | 1.03 | 1.18 | 1.14 | 1.22 | |
| 95% Confidence interval | Referent | 0.88–1.20 | 1.01–1.38 | 0.97–1.33 | 1.04–1.43 | |
| Model 3 | 0.02 | |||||
| Hazard ratio | 1 | 1.12 | 1.21 | 1.18 | 1.21 | |
| 95% Confidence interval | Referent | 0.96–1.31 | 1.04–1.41 | 1.01–1.38 | 1.03–1.43 | |
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