In two large US general population samples, QT interval was positively associated with serum phosphorus and inversely associated with total and ionized calcium.
Abstract
Context:
Disturbances in 25-hydroxyvitamin D, calcium, and phosphorus concentrations have been associated with increased risks of total and cardiovascular mortality. It is possible that changes in electrocardiographic QT interval duration may mediate these effects, but the association of 25-hydroxyvitamin D, phosphorus, and calcium concentrations with QT interval duration has not been evaluated in general population samples.
Objective:
The objective of the study was to evaluate the association of 25-hydroxyvitamin D, phosphorus, and calcium concentrations with QT interval duration in two large samples of the U.S. general population.
Design:
This study included cross-sectional analyses the Third National Health and Nutrition Survey (NHANES III) and the Atherosclerosis Risk in Communities (ARIC) study.
Setting:
The study was conducted in the general community.
Patients or Other Participants:
Patients included 7,312 men and women from NHANES III and 14,825 men and women from the ARIC study.
Interventions:
Serum 25-hydroxyvitamin D, total and ionized calcium, and inorganic phosphorus were measured in NHANES III, and serum total calcium and inorganic phosphorus were measured in ARIC.
Main Outcome Measure:
QT interval duration was obtained from standard 12-lead electrocardiograms.
Results:
In NHANES III, the multivariate adjusted differences in average QT interval duration comparing the highest vs. the lowest quartiles of serum total calcium, ionized calcium, and phosphorus were −3.6 msec (−5.8 to −1.3; P for trend = 0.005), −5.4 msec (−7.4 to −3.5; P for trend <0.001), and 3.9 msec (2.0–5.9; P for trend <0.001), respectively. The corresponding differences in ARIC were −3.1 msec (−4.3 to −2.0; P for trend <0.001), −2.9 msec (−3.8 to −1.9; P for trend <0.001), and 2.3 msec (1.3–3.3; P for trend <0.001). No association was found between 25-hydroxyvitamin D concentrations and QT interval duration.
Conclusions:
In two large samples of the general population, QT interval duration was inversely associated with the serum total and ionized calcium and positively associated with serum phosphorus.
Disturbances in serum calcium and phosphorus concentrations have been associated with increased risks of total and cardiovascular mortality (1–6). Low concentrations of vitamin D [25-hydroxyvitamin D (25[OH] D) and its active metabolite 1,25-dihydroxyvitamin D (1,25 [OH]2D)] have also been associated with an increased risk of death (7, 8). In addition, 1,25(OH)2D regulates calcium and phosphorus metabolism (9), and abnormalities in serum calcium concentrations affect electrocardiographic QT interval duration (10–12). Therefore, it is possible that changes in QT interval duration might mediate the mortality effects of vitamin D, calcium, and phosphorus. The association of 25(OH)D, phosphorus, and calcium concentrations with electrocardiographic QT interval duration, however, has not been evaluated in general population samples. The purpose of this analysis was to evaluate these associations in two large samples of the U.S. general population, the Third National Health and Nutrition Examination Survey (NHANES III), and the Atherosclerosis Risk in Communities (ARIC) study.
Materials and Methods
Study population
NHANES III was a cross-sectional study conducted between 1988 and 1994 using a multistage stratified clustered sampling design to select a representative sample of the civilian noninstitutionalized U.S. population (13). The NHANES III analysis was restricted to participants 40 yr of age and older as 12-lead electrocardiograms (ECG) were only performed in this age group. Of the 8561 participants 40 yr of age or older who had available ECG measurements, we excluded 194 participants with missing QT interval duration or heart rate, 535 participants with electrocardiographic QRS interval duration 120 msec or longer, and 520 participants with missing 25(OH)D, total calcium, or phosphorus concentrations. The final NHANES III sample included 7312 men and women. We further excluded 656 participants with missing ionized calcium because these serum samples could not be normalized (pH < 6.9 or > 8.0). The final sample size for analysis of ionized calcium in NHANES III was 6656.
The ARIC study was a population-based, prospective cohort study of 15,792 individuals 45–64 yr of age (14). Participants were drawn through probability sampling from four U.S. communities (Forsyth County, NC; Jackson, MS; suburban Minneapolis, MN; and Washington County, MD). We used electrocardiographic data collected at the baseline examination, conducted between 1987 and 1989. In the present study, we excluded 243 participants with missing QT interval duration or heart rate, 553 participants with QRS 120 msec or longer, and 124 participants with missing serum calcium or phosphorus concentrations. In addition, because of the small number, we also excluded 47 non-Caucasian, non-African-American participants. The final ARIC sample included 14,825 men and women.
Data collection
NHANES III included a standardized questionnaire administered at home by a trained interviewer and a detailed physical examination at a mobile examination center. Demographics, education, smoking status, alcohol consumption, medical history, and medication use were assessed by interview. QT-prolonging medications were defined as any QT-prolonging medication (definite, possible, or conditional) according to the Arizona Center for Education and Research on Therapeutics database (accessed September 1, 2009) (15). Height and weight were measured and body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Blood pressure was measured three times during the in-home interview and three additional times during the visit to the mobile examination center. We averaged all blood pressure measurements for each participant and defined hypertension as systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, and/or current use of blood pressure-lowering medication. Diabetes was defined as a fasting plasma glucose 126 mg/dl or greater, a nonfasting plasma glucose 200 mg/dl or greater, and/or current use of oral hypoglycemic agents or insulin. Laboratory test results included total cholesterol, high-density lipoprotein (HDL) cholesterol, serum albumin, and plasma glucose. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease Study formula, reexpressed for standardized serum creatinine (16–18).
In ARIC, comprehensive information regarding demographics, lifestyle characteristics, medication use, and medical history were obtained by trained interviewers at the baseline visit during home interviews. Three seated blood pressure measurements were taken during a clinical examination, and the average of the last two measurements was used. Laboratory tests results included total cholesterol, HDL cholesterol, serum albumin, serum potassium, and serum magnesium. BMI, hypertension, diabetes, eGFR, and use of QT-prolonging medications were defined or calculated in the same way as in NHANES III.
Serum 25(OH)D, calcium, and phosphorus
In NHANES III, blood samples collected during the examination were centrifuged, aliquoted, frozen to −70 C on site, and shipped on dry ice to central laboratories at which they were stored at −70C until analysis (19). 25(OH)D was measured by a RIA kit after extraction with acetonitrile (DiaSorin, Inc., Stillwater, MN) at the National Center for Environmental Health (Atlanta, GA). Serum total and ionized calcium were measured using a NOVA 7 + 7 electrolyte analyzer (Nova Biomedical, Waltham, MA). Ionized calcium concentrations were normalized at serum pH 7.4 because ionized calcium is pH dependent (19). Fasting serum phosphorus was measured using a Hitachi model 737 multichannel analyzer (Roche Molecular Biochemicals Diagnostics, Indianapolis, IN). In this method, inorganic phosphorus reacts with ammonium molybdate in an acidic solution to form ammonium phosphomolybdate, which is quantified in the UV range (340 nm) through the use of a sample-blanked end point method. Coefficients of variation for quality control samples were 14–20% for 25(OH)D, 0.6–2.8% for total calcium, 0.8–3.3% for ionized calcium, and 1.8–2.8% for phosphorus.
In ARIC, blood samples were obtained after fasting for 8 h following standardized procedures (20, 21). Samples were frozen to −70 C and shipped to the ARIC central laboratory at the University of Minnesota. Serum total calcium and serum inorganic phosphorus were measured using a Coulter discrete analyzer with continuous optical scanning (Coulter Electronics, Inc., Hialeah, FL). Serum ionized calcium was calculated based on serum total calcium and albumin concentrations (22). Total coefficients of variation for calcium and phosphorus were 1.9–2.2 and 2.1–2.4%, respectively. Serum 25(OH)D concentration was not measured in ARIC.
QT interval
In NHANES III, standard 12-lead resting ECG recordings were performed using a Marquette MAC 12 electrocardiograph (Marquette Medical Systems, Inc., Milwaukee, WI) with signals sampled at 250 samples per second per channel. A representative P-QRS-T cycle was then derived by selective averaging using the Dalhousie ECG analysis program (23). Baseline resting heart rate and QT interval were obtained from the ECG. In ARIC, a standard 12-lead ECG was recorded using MAC PC personal cardiography equipment (Marquette Electronics, Inc., Milwaukee, WI). Baseline QT interval from the digital 12-lead ECG was determined by the Dalhousie ECG analysis program and later updated to the GE Marquette 12-SL analysis program, which generated an average waveform derived from all 12 simultaneously measured leads (24). NHANES III and ARIC ECG were read centrally at the same reading center, the Epidemiological Cardiology Research Center, EPICARE (Wake Forest University, Winston-Salem, NC).
Statistical analysis
Data from NHANES III and ARIC were analyzed separately. In both studies, we used QT interval duration as the primary metric in models with concomitant adjustment for age, race, sex, and RR-interval duration. In addition, we performed a sensitivity analysis using Bazett's equation-corrected QT interval, with similar results (data not shown) (25).
In NHANES III, ECG sampling weights, primary sampling units, and stratification variables were used to account for the complex sampling design including unequal probabilities of selection, oversampling, clustering, and stratification (13). We categorized the distributions of serum 25(OH)D, total calcium, ionized calcium, and phosphorus into quartiles based on the weighted population distribution. Marginally adjusted means and 95% confidence intervals (CI) for QT interval duration by quartile of 25(OH)D, calcium, and phosphorus were calculated from multivariable linear regression models. Tests for linear trends across quartiles of exposure were computed by including a variable with the median value for each quartile of 25(OH)D, total and ionized calcium, and phosphorus in the linear regression models. We also conducted analyses using 25(OH)D, total and ionized calcium, and phosphorus concentrations as continuous variables. In addition, restricted quadratic spline models with knots at the fifth, 50th, and 95th percentiles of the distribution of 25(OH)D, total and ionized calcium, and phosphorus concentrations were used to provide a smooth yet flexible description of the dose-response relationship.
We used four models with progressive degrees of adjustment. First, we adjusted for age, race-ethnicity (non-Hispanic white, non-Hispanic black, Mexican-American, and other in NHANES III and Caucasian and African-American in ARIC), sex, RR-interval (restricted quadratic splines with knots at the fifth, 50th, and 95th percentiles of the overall study population) and, in ARIC, study center. Second, we further adjusted for BMI, smoking (current, former, and never), alcohol consumption (<12, ≥12 drinks in the past year in NHANES III, and current, former, and never in ARIC), high school education (yes, no), annual household income (<$20,000 and ≥$20,000 in NHANES III and <$25,000 and ≥$25,000 in ARIC), and use of QT-prolonging medications (yes, no). Third, we further adjusted for systolic blood pressure, total and HDL cholesterol, diabetes, history of myocardial infarction, history of congestive heart failure, creatinine-based eGFR, serum potassium, and serum albumin and, in ARIC, serum magnesium. Finally, fully adjusted models further included total calcium and phosphorus in the model for 25(OH)D, phosphorus and 25(OH)D in the model for calcium, and 25(OH)D and total calcium in the model for phosphorus. Subgroup analyses were also performed in clinically relevant subgroups of study participants and interactions were tested. Statistical analyses of NHANES III survey data were conducted using SUDAAN (version 10.0; Research Triangle Institute, Research Triangle Park, NC). Analyses of ARIC were conducted using STATA (version 11; Stata Corp., College Station, TX).
Results and Discussion
Results
The average age of study participants was 56.4 yr in NHANES III and 54.1 yr in ARIC (Table 1). In NHANES III, 45.4% of participants were men, and 44.2% in ARIC were men. The average concentrations of serum 25(OH)D, total calcium, ionized calcium, and phosphorus in NHANES III were 70.6 nmol/liter, 2.3 mmol/liter, 1.2 mmol/liter, and 1.1 mmol/liter, respectively. In ARIC, the average concentrations of serum total calcium, estimated ionized calcium, and phosphorus were 2.5, 1.2, and 1.1 mmol/liter, respectively. Males and whites were more likely to have higher concentrations of serum 25(OH)D and lower concentrations of phosphorus, whereas current smokers were more likely to have lower concentrations of 25(OH)D and higher concentrations of phosphorus in both NHANES III and ARIC (Supplemental Appendix Tables 1 and 2, published on The Endocrine Society's Journals Online web site at http://jcem.endojournals.org).
Table 1.
Baseline characteristics
| Characteristic | NHANES III (n = 7,312) | ARIC (n = 14,825) |
|---|---|---|
| Age (yr)a | 56.4 (12.4) | 54.1 (5.7) |
| Male | 45.4 | 44.2 |
| Race/ethnicity | ||
| White | 81.2 | 73.7 |
| Black | 8.5 | 26.3 |
| Other | 10.4 | 0 |
| High school education | 71.2 | 76.5 |
| Smoking | ||
| Current | 22.6 | 26.1 |
| Former | 35.0 | 32.0 |
| Never | 42.4 | 41.7 |
| Current alcohol use | 46.4 | 55.9 |
| Use of QT-prolonging medication | 12.1 | 9.4 |
| Diabetes | 8.7 | 11.6 |
| Myocardial infarction | 5.0 | 3.6 |
| Hypertension | 36.4 | 34.3 |
| Total cholesterol (mg/dl) | 217.9 (42.0) | 214.9 (42.0) |
| HDL (mg/dl) | 51.0 (16.0) | 51.7 (17.1) |
| BMI (kg/m2) | 27.3 (5.5) | 27.7 (5.3) |
| eGFR (ml/min per 1.73 m2) | 84.5 (22.5) | 93.1 (21.4) |
| Heart rate (beats/min) | 68.1 (11.4) | 66.7 (10.3) |
| QT interval (msec) | 406.2 (30.7) | 409.2 (28.4) |
| QTc (msec)b | 429.1 (23.3) | 428.7 (23.8) |
| Serum potassium (mmol/liter) | 4.1 (0.3) | 4.42 (0.48) |
| Serum 25(OH)D (nmol/liter) | 70.6 (27.3) | NA |
| Serum calcium (mmol/liter) | 2.30 (0.12) | 2.45 (0.11) |
| Ionized calcium (mmol/liter) | 1.23 (0.05) | 1.24 (0.05) |
| Serum phosphorus (mmol/liter) | 1.10 (0.16) | 1.11 (0.16) |
NA, Not available; QTc, equation-corrected QT interval.
Values are means (sd) or percentages unless otherwise noted.
QTc used Bazett equation.
After adjusting for age, race, sex, and RR-interval, the average differences in QT interval duration comparing the highest vs. the lowest quartiles of serum 25(OH)D, total and ionized calcium, and phosphorus in NHANES III were −0.1 msec (95% CI −2.1 to 2.0; P for trend = 0.99), −3.7 msec (−5.8 to −1.7; P for trend = 0.001), −6.3 msec (−8.2 to −4.5; P for trend <0.001), and 1.8 msec (0.1 to 3.5; P for trend = 0.02), respectively (Table 2). Adjusting for other cardiovascular risk factors did not materially affect the differences, but including 25(OH)D, calcium, and phosphorus in the same model further strengthens the associations for calcium and phosphorus. The average differences in QT interval duration in fully adjusted models comparing the highest vs. the lowest quartiles of serum 25(OH)D, total calcium, ionized calcium, and phosphorus were 1.3 msec (95% CI −1.0 to 3.5; P for trend = 0.20), −3.6 msec (−5.8 to −1.3; P for trend = 0.005), −5.4 msec (−7.4 to −3.5; P for trend <0.001), and 3.9 msec (2.0 to 5.9; P for trend <0.001), respectively.
Table 2.
Adjusted mean (95% CI) of QT interval (milliseconds) by quartiles of serum 25(OH)D, total calcium, ionized calcium, and phosphorus (NHANES III)
| Serum 25(OH)D (nmol/liter) |
|||||
|---|---|---|---|---|---|
| <50.8 | 50.8–67.7 | 67.7–85.9 | >85.9 | P value for trend across quartiles | |
| Model 1a | 406.2 (404.9–407.5) | 406.1 (404.3–407.9) | 406.2 (404.4–408.1) | 406.1 (404.4–407.8) | 0.99 |
| Model 2b | 405.7 (404.1–407.3) | 405.5 (403.7–407.3) | 406.7 (404.7–408.6) | 406.3 (404.5–408.2) | 0.49 |
| Model 3c | 405.7 (404.2–407.3) | 405.4 (403.6–407.2) | 406.7 (404.7–408.7) | 406.5 (404.7–408.3) | 0.36 |
| Model 4d | 405.4 (403.9–407.0) | 405.5 (403.7–407.2) | 406.7 (404.7–408.7) | 406.7 (404.9–408.5) | 0.20 |
| Serum total calcium (mmol/liter) |
|||||
|---|---|---|---|---|---|
| <2.23 | 2.23–2.30 | 2.30–2.36 | >2.36 | ||
| Model 1a | 408.2 (406.4–410.1) | 406.0 (404.6–407.4) | 406.2 (404.7–407.7) | 404.5 (402.6–406.4) | 0.001 |
| Model 2b | 407.7 (405.7–409.7) | 405.8 (404.4–407.3) | 406.4 (404.7–408.0) | 404.5 (402.6–406.4) | 0.01 |
| Model 3c | 407.7 (406.0–409.4) | 405.9 (404.4–407.3) | 406.5 (404.8–408.2) | 404.5 (402.4–406.6) | 0.01 |
| Model 4e | 407.9 (406.2–409.7) | 406.0 (404.5–407.5) | 406.4 (404.7–408.1) | 404.3 (402.3–406.4) | 0.005 |
| Serum ionized calcium (mmol/liter) |
|||||
|---|---|---|---|---|---|
| <1.20 | 1.20–1.23 | 1.23–1.26 | >1.26 | ||
| Model 1a | 409.7 (407.8–411.6) | 407.1 (405.2–409.0) | 405.6 (404.0–407.2) | 403.4 (401.9–404.8) | <0.001 |
| Model 2b | 409.7 (407.7–411.7) | 407.0 (405.0–409.1) | 405.1 (403.3–406.9) | 403.3 (402.0–404.6) | <0.001 |
| Model 3c | 409.2 (407.4–411.1) | 406.7 (404.6–408.8) | 405.2 (403.3–407.0) | 403.7 (402.3–405.1) | <0.001 |
| Model 4e | 409.2 (407.3–411.0) | 406.7 (404.7–408.8) | 405.1 (403.3–407.0) | 403.8 (402.4–405.1) | <0.001 |
| Serum phosphorus (mmol/liter) |
|||||
|---|---|---|---|---|---|
| <0.98 | 0.98–1.08 | 1.08–1.19 | >1.19 | ||
| Model 1a | 404.9 (403.1–406.7) | 405.8 (404.3–407.3) | 407.0 (405.3–408.7) | 406.7 (405.1–408.3) | 0.02 |
| Model 2b | 404.2 (402.5–406.0) | 405.5 (403.9–407.2) | 406.9 (405.0–408.8) | 407.3 (405.6–408.9) | 0.001 |
| Model 3c | 403.9 (402.2–405.7) | 405.6 (404.1–407.2) | 406.7 (404.8–408.7) | 407.7 (405.8–409.5) | <0.001 |
| Model 4f | 403.8 (402.1–405.5) | 405.5 (404.0–407.1) | 406.8 (404.9–408.7) | 407.8 (405.9–409.6) | <0.001 |
Adjusted for age (continuous), sex, race (non-Hispanic white, non-Hispanic black, Mexican-American, and other), and RR interval (restricted quadratic splines with knots at the fifth, 50th, and 95th percentile).
Further adjusted for BMI (continuous), smoking (current, former, never), alcohol consumption (<12, ≥12 drinks in the past year), high school education, annual household income (<$20,000, ≥$20,000), and QT prolongation medications.
Further adjusted for systolic blood pressure (continuous), total cholesterol (continuous), HDL (continuous), serum potassium (continuous), serum albumin (continuous), eGFR (continuous), diabetes, history of myocardial infarction, and history of congestive heart failure.
Further adjusted for serum calcium and serum phosphorus.
Further adjusted for serum 25(OH)D and serum phosphorus.
Further adjusted for serum calcium and serum 25(OH)D.
When using 25(OH)D, calcium, and phosphorus as continuous variables in fully adjusted models, the differences in QT interval associated with an increase from the 10th to the 90th percentile of the NHANES III distribution of 25(OH)D, total calcium, ionized calcium, and phosphorus were 1.3 msec (95% CI −0.7 to 3.4), −3.3 msec (−5.1 to −1.5), −6.3 msec (−8.1 to −4.5), and 3.8 msec (2.1 to 5.5) (Fig. 1).
Fig. 1.
Multivariate adjusted difference in QT interval associated with an increase in serum total calcium, ionized calcium, and phosphorus from the 10th to the 90th percentile of the population distribution. The sizes of the squares are inversely proportional to the variance of the point estimate (NHANES III).
In ARIC, the average differences in QT interval duration in fully adjusted models comparing the highest vs. the lowest quartiles of total calcium, ionized calcium, and phosphorus were −3.1 msec (−4.3 to −2.0; P for trend <0.001), −2.9 msec (−3.8 to −1.9; P for trend <0.001), and 2.3 msec (1.3 to 3.3; P for trend <0.001), respectively (Table 3). When using calcium and phosphorus as continuous variables in fully adjusted models, the change in QT interval associated with an increase from the 10th to the 90th percentile of the ARIC distribution of total calcium, ionized calcium, and phosphorus were −3.3 msec (−4.2 to −2.4), −3.6 msec (−4.6 to −2.7), and 2.8 msec (1.9 to 3.8), respectively (Fig. 2).
Table 3.
Adjusted mean (95% CI) of QT interval (milliseconds) by quartiles of serum total calcium, ionized calcium, and phosphorus (ARIC)
| Serum total calcium (mmol/liter) |
|||||
|---|---|---|---|---|---|
| <2.38 | 2.38–2.45 | 2.45–2.53 | >2.53 | P value for trend across quartiles | |
| Model 1a | 411.1 (410.4–411.7) | 409.6 (409.0–410.2) | 408.6 (408.1–409.1) | 407.6 (406.9–408.3) | <0.001 |
| Model 2b | 411.0 (410.3–411.7) | 409.5 (408.9–410.1) | 408.7 (408.2–409.3) | 407.8 (407.1–408.6) | <0.001 |
| Model 3c | 410.8 (410.1–411.5) | 409.5 (408.9–410.1) | 408.8 (408.2–409.3) | 407.9 (407.2–408.7) | <0.001 |
| Model 4d | 411.0 (410.3–411.7) | 409.6 (409.0–410.2) | 408.7 (408.2–409.2) | 407.8 (407.0–408.6) | <0.001 |
| Estimated ionized calcium (mmol/liter) |
|||||
|---|---|---|---|---|---|
| <1.20 | 1.20–1.24 | 1.24–1.28 | >1.28 | ||
| Model 1a | 410.8 (410.2–411.4) | 409.5 (408.8–410.2) | 408.3 (407.7–408.9) | 408.4 (407.8–409.0) | <0.001 |
| Model 2b | 411.0 (410.4–411.6) | 409.6 (408.9–410.4) | 408.4 (407.8–409.0) | 408.2 (407.6–408.9) | <0.001 |
| Model 3c | 410.9 (410.2–411.5) | 409.4 (408.7–410.1) | 408.6 (408.0–409.2) | 408.3 (407.6–408.9) | <0.001 |
| Model 4d | 411.0 (410.4–411.7) | 409.4 (408.7–410.2) | 408.5 (407.9–409.1) | 408.1 (407.5–408.8) | <0.001 |
| Serum phosphorus (mmol/liter) |
|||||
|---|---|---|---|---|---|
| <1.00 | 1.00–1.10 | 1.10–1.20 | >1.20 | ||
| Model 1a | 408.7 (408.1–409.4) | 409.0 (408.5–409.6) | 409.5 (408.9–410.2) | 409.6 (408.9–410.2) | 0.05 |
| Model 2b | 408.6 (407.9–409.3) | 409.1 (408.5–409.6) | 409.6 (408.9–410.2) | 409.8 (409.1–410.4) | 0.01 |
| Model 3c | 408.2 (407.5–408.9) | 409.0 (408.4–409.6) | 409.6 (408.9–410.3) | 410.1 (409.5–410.8) | <0.001 |
| Model 4e | 408.0 (407.3–408.7) | 408.9 (408.4–409.5) | 409.7 (409.0–410.3) | 410.3 (409.7–411.0) | <0.001 |
Adjusted for age (continuous), sex, race (Caucasian, African-American), and RR interval (restricted quadratic splines with knots at the fifth, 50th, and 95th percentile).
Further adjusted for BMI (continuous), smoking (current, former, never), alcohol consumption (current, former, never), high school education, annual household income (<$25,000, ≥$25,000), and QT prolongation medications.
Further adjusted for hypertension, total cholesterol (continuous), HDL (continuous), serum potassium (continuous), serum magnesium (continuous), serum albumin (continuous), eGFR (continuous), diabetes, history of myocardial infarction, and study center.
Further adjusted for serum phosphorus.
Further adjusted for serum calcium.
Fig. 2.
Multivariate adjusted difference in QT interval associated with an increase in serum total calcium, ionized calcium, and phosphorus from the 10th to the 90th percentile of the population distribution. The sizes of the squares are inversely proportional to the variance of the point estimate (ARIC).
The associations of calcium and phosphorus with QT interval duration were consistent across subgroups of the study population in NHANES III and ARIC (Figs. 1 and 2). The spline regression models confirmed a linear dose-response relationship of QT interval with calcium and phosphorus, with no clear threshold effect (Fig. 3).
Fig. 3.
Multivariate-adjusted difference in QT interval associated with different concentrations of ionized calcium and phosphorus using restricted quadratic spline models.
Discussion
In NHANES III and ARIC studies, two large general population studies conducted in the United States, QT interval duration was inversely associated with serum total and ionized calcium concentration and positively associated with serum phosphorus. No association was found between 25(OH)D and QT interval in NHANES III. For calcium, the association was progressive throughout the full range of serum calcium concentrations, and it was not restricted to the extremes of hyper- or hypocalcemia. Consistent with electrophysiological mechanisms, the association for ionized calcium was stronger than that for total calcium concentration. The observed relationship between serum phosphorus and QT interval duration has not been described previously in the literature, and replication in two independent large samples adds to the strength of the findings. In addition, the associations maintained when calcium and phosphorus were adjusted for one another, suggesting these associations reflect independent effects.
Most calcium and phosphorus in the body is stored in bones, predominantly as hydroxyapatite crystals (26, 27). In plasma, about 50% of calcium is in the biologically active ionized form; 40% is bound to proteins primarily albumin; and 10% is complexed with citrate, sulfate, bicarbonate, lactate and phosphate (27). Plasma phosphorus circulates as either organic phosphorus bound to lipids and esters or as inorganic phosphorus (27). Under physiological conditions, plasma calcium and phosphorus concentrations are determined by dietary intake, intestinal absorption, renal excretion, and bone formation and resorption, which are tightly regulated by a number of hormones including 1,25(OH)2D (1, 27).
Calcium plays a key role in determining the duration of the action potential of cardiac cells (10). The inward calcium current is a depolarizing current that prolongs the ventricular action potential duration. Furthermore, intracellular calcium will influence the opening and closing of the calcium channel such that increases in intracellular Ca2+ will hasten channel closure by a process called calcium-induced inactivation (28). In addition, there are a number of other calcium-sensitive currents and electrogenic exchangers in the heart. Both mechanisms likely contribute to the changes in action potential duration and therefore the QT interval in response to changes in serum calcium concentrations. Patients with hypocalcaemia [serum calcium concentrations below 2.2 mmol/liter or 9 mg/dl (29, 30)] have prolonged QT interval durations due to a longer phase 2 of the cardiac action potential. Conversely, the QT interval is shortened in patients with hypercalcemia (serum calcium concentrations above 2.6 mmol/liter or 10.5 mg/dl) (11, 12, 31). Beyond the effects of pathological variations in serum calcium concentrations on QT interval duration, our findings show that calcium concentration is inversely associated with QT interval duration across the full range of the calcium distribution and suggest that serum calcium is an important physiological regulator of QT interval duration. In addition, the effect of ionized calcium appeared to be stronger in NHANES III compared with ARIC, possibly due to the differences in how ionized was measured in the two studies (directly by electrolyte analyzer in NHANES III and calculated by formula from total calcium in ARIC).
The literature on phosphorus and ECG parameters is scant, and we were not able to identify any study that examined the relationship between serum phosphorus and QT interval. Laboratory studies are thus needed to identify the mechanisms underlying the association between phosphorus and QT interval duration. In rats, hyperphosphatemia was associated with cardiac fibrosis and myocardial hypertrophy (32, 33), and the latter may then lead to longer QT intervals (34, 35). It is unlikely, however, that this mechanism explains an association identified across the whole range of phosphorus concentrations in the general population. In addition, increasing phosphorus concentrations may stimulate PTH release (36–38), which has been associated with hypertension and glucose intolerance (39–41), but the impact of these downstream changes on QT interval duration are uncertain.
The observed association between phosphorus and QT may partly explain some previous epidemiological observations. Increased serum phosphorus concentrations have been associated with increased cardiovascular (1) and total mortality (2, 3, 5, 6) in various study populations, including patients with chronic kidney disease (6), established coronary heart disease (2, 3), diabetes (1), and the general population (2, 4, 5, 42). Although it has been postulated that the association of phosphorus with cardiovascular events may be mediated by vascular calcification (1–6), our study suggests that electrocardiographic abnormalities may also contribute to increased risk of mortality. In particular, phosphorus-induced changes in QT interval duration may contribute to the substantial increase in sudden cardiac death observed in chronic kidney disease and renal failure.
The biologically active metabolite of vitamin D, 1,25(OH)2D, plays an important role in regulating calcium and phosphorus balance. In case of low serum calcium or phosphorus, 1,25(OH)2D enhances their concentrations by increasing bone resorption, intestinal absorption, and renal tubular reabsorption (26, 27). However, 1,25(OH)2D was not measured in NHANES III or ARIC; we used 25(OH)D in the current analysis. 25(OH)D is the predominant circulating form of vitamin D and is the most widely used biomarker used in biomonitoring of vitamin D status, reflecting the sum of vitamin D absorbed from the intestine and produced in the skin. On the other hand, 1,25(OH)2D has a short half-life and is not commonly used to determine vitamin D status. Of note, the levels of 25(OH)D and 1,25(OH)2D tend to correlate well with each other, although there are situations in which the levels of 25(OH)D do not reflect those of 1,25(OH)2D [e.g. in disorders of 1α-hydroxylation of 25(OH)D]. Because calcium and phosphorus affect the QT interval in opposite directions, this may explain the lack of association between 25(OH)D and QT interval duration because the effects of calcium and phosphorus cancel out. In addition, 25(OH)D measurement had a very high coefficient of variation, which suggests an imprecise assay and might also be the reason that no association was found.
A major strength of our study is the independent replication of the associations of calcium and phosphorus with QT interval duration in two large samples of the general U.S. population, NHANES III and ARIC. Both studies used carefully standardized methods and laboratory procedures, with detailed quality control and assurance. Even though NHANES III and ARIC used different protocols for participant sampling and recruitment, ECG recording and processing, and biochemistry measurements, the consistency of the findings in both studies supports the validity of the observed associations. Several limitations of this study also need to be considered. Measurement of the QT interval and of serum concentrations of 25(OH)D, calcium, and phosphorus at a single time may result in nondifferential measurement error because there is substantial within-person variability. The cross-sectional design also limited our ability to make statements regarding the causality of the observed associations between QT interval and serum phosphorus because of potential uncontrolled confounding. Finally, the mechanisms underlying the association of phosphorus with QT interval duration need to be established in mechanistic studies.
In conclusion, data from two large studies of the general population, NHANES III and ARIC, showed that QT interval duration was inversely associated the serum total and ionized calcium and positively associated with serum phosphorus. Additional randomized trials as well as biological studies should be conducted to confirm these findings, elucidate the mechanisms of the association between phosphorus and QT interval duration, and evaluate whether a higher dietary intake of phosphorus contributes to a prolonged QT interval and a greater risk of arrhythmias by increasing serum phosphorus concentrations.
Supplementary Material
Acknowledgments
We thank the staff and the participants of the ARIC study for their important contributions.
This work was supported by grants from the National Center for Cardiovascular Research (CNIC Translational Cardiology Grant 2008-03), the National Institutes of Health (Grants ES015597 and HL091062), the Donald W. Reynolds Cardiovascular Clinical Research Center at Johns Hopkins University and the Fondation Leducq. The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute Contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022.
Disclosure Summary: The authors have nothing to disclose.
Footnotes
- ARIC
- Atherosclerosis Risk in Communities
- BMI
- body mass index
- CI
- confidence interval
- ECG
- electrocardiogram
- eGFR
- estimated glomerular filtration rate
- HDL
- high-density lipoprotien
- 1,25 (OH)2D
- 1,25-dihydroxyvitamin D
- 25(OH) D
- 25-hydroxyvitamin D
- NHANES III
- Third National Health and Nutrition Examination Survey.
References
- 1. Chonchol M, Dale R, Schrier RW, Estacio R. 2009. Serum phosphorus and cardiovascular mortality in type 2 diabetes. Am J Med 122:380–386 [DOI] [PubMed] [Google Scholar]
- 2. Tonelli M, Curhan G, Pfeffer M, Sacks F, Thadhani R, Melamed ML, Wiebe N, Muntner P. 2009. Relation between alkaline phosphatase, serum phosphate, and all-cause or cardiovascular mortality. Circulation 120:1784–1792 [DOI] [PubMed] [Google Scholar]
- 3. Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G. 2005. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 112:2627–2633 [DOI] [PubMed] [Google Scholar]
- 4. Dhingra R, Sullivan LM, Fox CS, Wang TJ, D'Agostino RB, Sr, Gaziano JM, Vasan RS. 2007. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 167:879–885 [DOI] [PubMed] [Google Scholar]
- 5. Foley RN, Collins AJ, Ishani A, Kalra PA. 2008. Calcium-phosphate levels and cardiovascular disease in community-dwelling adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 156:556–563 [DOI] [PubMed] [Google Scholar]
- 6. Kestenbaum B, Sampson JN, Rudser KD, Patterson DJ, Seliger SL, Young B, Sherrard DJ, Andress DL. 2005. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 16:520–528 [DOI] [PubMed] [Google Scholar]
- 7. Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W. 2008. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med 168:1340–1349 [DOI] [PubMed] [Google Scholar]
- 8. Melamed ML, Michos ED, Post W, Astor B. 2008. 25-Hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 168:1629–1637 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Dietary supplement fact sheet: vitamin D. National Institutes of Health Office of Dietary Supplements. Available at: http://ods.od.nih.gov/factsheets/vitamind.asp (accessed January 2011)
- 10. Surawicz B. 1967. Relationship between electrocardiogram and electrolytes. Am Heart J 73:814–834 [DOI] [PubMed] [Google Scholar]
- 11. Eryol NK, Colak R, Ozdoğru I, Tanriverdi F, Unal S, Topsakal R, Katlandur H, Bayram F. 2003. Effects of calcium treatment on QT interval and QT dispersion in hypocalcemia. Am J Cardiol 91:750–752 [DOI] [PubMed] [Google Scholar]
- 12. Saikawa T, Tsumabuki S, Nakagawa M, Takakura T, Tamura M, Maeda T, Ito S, Ito M. 1988. QT intervals as an index of high serum calcium in hypercalcemia. Clin Cardiol 11:75–78 [DOI] [PubMed] [Google Scholar]
- 13. 1994. Plan and operation of the Third National Health and Nutrition Examination Survey, 1988–94. Series 1: programs and collection procedures. Vital Health Stat 1:1–407 [PubMed] [Google Scholar]
- 14. 1989. ARIC Investigators: the Atherosclerosis Risk In Communities (ARIC) Study: design and objectives. Am J Epidemiol 129:687–702 [PubMed] [Google Scholar]
- 15. Drugs that prolong the QT interval and/or induce torsades de pointes ventricular arrhythmia. Available at: http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm (accessed September 2009)
- 16. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. 1999. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461–470 [DOI] [PubMed] [Google Scholar]
- 17. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F. 2006. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 145:247–254 [DOI] [PubMed] [Google Scholar]
- 18. NCHS note for correction of serum creatinine for NHANES III, NHANES, 1999–2000, 2001–2002, and 2003–2004. Available at: http://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/general_% 20note_for_serum_creatinine.pdf (accessed April 2010)
- 19. 1996. National Center for Health Statistics, Third National Health and Nutrition Examination Survey, 1988–1994. Reference manuals and reports (CD-ROM). Hyattsville, MD: National Center for Health Statistics [Google Scholar]
- 20. Papp AC, Hatzakis H, Bracey A, Wu KK. 1989. ARIC hemostasis study-I. Development of a blood collection and processing system suitable for multicenter hemostatic studies. Thromb Haemost 61:15–19 [PubMed] [Google Scholar]
- 21. 1987. National Heart, Lung, and Blood Institute, Atherosclerosis Risk in Communities (ARIC) Study. Operation manual no. 9: hemostasis determinations. Version 1.0 Chapel Hill, NC: ARIC Coordinating Center, School of Public Health, University of North Carolina [Google Scholar]
- 22. Björkman MP, Sorva AJ, Tilvis RS. 2009. Calculated serum calcium is an insufficient surrogate for measured ionized calcium. Arch Gerontol Geriatr 49:348–350 [DOI] [PubMed] [Google Scholar]
- 23. Rautaharju PM, MacInnis PJ, Warren JW, Wolf HK, Rykers PM, Calhoun HP. 1990. Methodology of ECG interpretation in the Dalhousie program; NOVACODE ECG classification procedures for clinical trials and population health surveys. Methods Inf Med 29:362–374 [PubMed] [Google Scholar]
- 24. Rautaharju PM, Park LP, Chaitman BR, Rautaharju F, Zhang ZM. 1998. The Novacode criteria for classification of ECG abnormalities and their clinically significant progression and regression. J Electrocardiol 31:157–187 [PubMed] [Google Scholar]
- 25. Bazett HC. 1920. An analysis of time relations of electrocardiograms. Heart 7:353–367 [Google Scholar]
- 26. Peacock M. 2010. Calcium metabolism in health and disease. Clin J Am Soc Nephrol 5(Suppl 1):S23–S30 [DOI] [PubMed] [Google Scholar]
- 27. Taylor JG, Bushinsky DA. 2009. Calcium and phosphorus homeostasis. Blood Purif 27:387–394 [DOI] [PubMed] [Google Scholar]
- 28. Eckert R, Chad JE. 1984. Inactivation of Ca channels. Prog Biophys Mol Biol 44:215–267 [DOI] [PubMed] [Google Scholar]
- 29. Cunha DF, Cunha SF, Ferreira TP, Sawan ZT, Rodrigues LS, Prata SP, Silva-Vergara ML. 2001. Prolonged QTc intervals on the electrocardiograms of hospitalized malnourished adults. Nutrition 17:370–372 [DOI] [PubMed] [Google Scholar]
- 30. Narang R, Ridout D, Nonis C, Kooner JS. 1997. Serum calcium, phosphorus and albumin levels in relation to the angiographic severity of coronary artery disease. Int J Cardiol 60:73–79 [DOI] [PubMed] [Google Scholar]
- 31. Benoit SR, Mendelsohn AB, Nourjah P, Staffa JA, Graham DJ. 2005. Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey. Eur J Cardiovasc Prev Rehabil 12:363–368 [DOI] [PubMed] [Google Scholar]
- 32. Amann K, Törnig J, Kugel B, Gross ML, Tyralla K, El-Shakmak A, Szabo A, Ritz E. 2003. Hyperphosphatemia aggravates cardiac fibrosis and microvascular disease in experimental uremia. Kidney Int 63:1296–1301 [DOI] [PubMed] [Google Scholar]
- 33. Neves KR, Graciolli FG, dos Reis LM, Pasqualucci CA, Moysés RM, Jorgetti V. 2004. Adverse effects of hyperphosphatemia on myocardial hypertrophy, renal function, and bone in rats with renal failure. Kidney Int 66:2237–2244 [DOI] [PubMed] [Google Scholar]
- 34. Porthan K, Virolainen J, Hiltunen TP, Viitasalo M, Väänänen H, Dabek J, Hannila-Handelberg T, Toivonen L, Nieminen MS, Kontula K, Oikarinen L. 2007. Relationship of electrocardiographic repolarization measures to echocardiographic left ventricular mass in men with hypertension. J Hypertens 25:1951–1957 [DOI] [PubMed] [Google Scholar]
- 35. Salles G, Leocádio S, Bloch K, Nogueira AR, Muxfeldt E. 2005. Combined QT interval and voltage criteria improve left ventricular hypertrophy detection in resistant hypertension. Hypertension 46:1207–1212 [DOI] [PubMed] [Google Scholar]
- 36. Almaden Y, Hernandez A, Torregrosa V, Canalejo A, Sabate L, Fernandez Cruz L, Campistol JM, Torres A, Rodriguez M. 1998. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol 9:1845–1852 [DOI] [PubMed] [Google Scholar]
- 37. Pitts TO, Piraino BH, Mitro R, Chen TC, Segre GV, Greenberg A, Puschett JB. 1988. Hyperparathyroidism and 1,25-dihydroxyvitamin D deficiency in mild, moderate, and severe renal failure. J Clin Endocrinol Metab 67:876–881 [DOI] [PubMed] [Google Scholar]
- 38. Slatopolsky E, Finch J, Denda M, Ritter C, Zhong M, Dusso A, MacDonald PN, Brown AJ. 1996. Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 97:2534–2540 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Kristal-Boneh E, Froom P, Harari G, Ribak J. 1997. Association of calcitriol and blood pressure in normotensive men. Hypertension 30:1289–1294 [DOI] [PubMed] [Google Scholar]
- 40. Saleh FN, Schirmer H, Sundsfjord J, Jorde R. 2003. Parathyroid hormone and left ventricular hypertrophy. Eur Heart J 24:2054–2060 [DOI] [PubMed] [Google Scholar]
- 41. Wareham NJ, Byrne CD, Carr C, Day NE, Boucher BJ, Hales CN. 1997. Glucose intolerance is associated with altered calcium homeostasis: a possible link between increased serum calcium concentration and cardiovascular disease mortality. Metabolism 46:1171–1177 [DOI] [PubMed] [Google Scholar]
- 42. Onufrak SJ, Bellasi A, Shaw LJ, Herzog CA, Cardarelli F, Wilson PW, Vaccarino V, Raggi P. 2008. Phosphorus levels are associated with subclinical atherosclerosis in the general population. Atherosclerosis 199:424–431 [DOI] [PubMed] [Google Scholar]
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