Previous studies have suggested that vitamin D deficiency might contribute to the pathogenesis of heart failure (HF); however, limited data are available on the association of vitamin D-binding protein (VDBP)—a major transport protein for vitamin D—and the development of HF. Thus, we investigated whether plasma VDBP is inversely associated with HF risk. Using a prospective nested case-control design, we selected 464 cases and 464 matched controls from the Physicians’ Health Study for the present analyses. VDBP was determined using an enzyme-linked immunoassay. Self-reported HF was obtained through annual follow-up questionnaires and validated in a subsample by a review of the medical records. We used conditional logistic regression analyses to compute the adjusted odds ratios. The mean age was 58.6 years, and the median VDBP was 307.8 μg/ml (interquartile range 265.2 to 354.6). Plasma VDBP was not associated with HF in our study. Across the consecutive quintiles of VDBP, the odds ratio was 1.0 (95% confidence interval [CI] reference), 1.05 (95% CI 0.66 to 1.65), 1.28 (95% CI 0.80 to 2.06), 1.07 (95% CI 0.65 to 1.75), and 1.28 (95% CI 0.76 to 2.15); p for linear trend = 0.41, after adjustment for matching factors, body mass index, diabetes, atrial fibrillation, hypertension, and high-sensitivity C-reactive protein. In conclusion, our data have shown no significant association between the plasma levels of VDBP and HF risk in apparently healthy male physicians.
Heart failure (HF) remains a major public health burden in the United States, with a lifetime risk of 1 in 5 at 40 years of age, and mortality ranging from 20% to 50%. Emerging research has suggested an association between HF risk and vitamin D deficiency. In a prospective study of 41,504 health records, low serum 25-hydroxyvitamin D (25-OHD) was associated with a 31% higher risk of HF compared with normal levels. Such a relation could be partially explained by the role of vitamin D on parathyroid hormone, renin, vascular endothelial growth factor, calcium influx, inflammation, and platelet aggregation; all of which can affect myocardial function and the development of HF. However, administering vitamin D supplementation in patients with HF has produced mixed results. One hypothesis for these results is not a lack of 25-OHD, but a low level of vitamin D-binding protein (VDBP), an abundant Gc-globulin, whose major function is to bind and transport 25-OHD from plasma into target cells. VDBP protects against vitamin D deficiency and is essential for normal vitamin D homeostasis. It is currently unknown whether the relation between vitamin D and the risk of HF is partly due to low levels of circulating plasma VDBP. If true, VDBP could serve as a novel pharmacologic target for new drugs. Therefore, in the present study, we sought to examine whether lower plasma VDBP levels are associated with a higher risk of HF in a prospective nested case-control study of United States (US) male physicians.
Methods
The present ancillary study was a nested case-control study using data from the Physicians’ Health Study (PHS), a completed, randomized, double-blind, placebo-controlled trial designed to study low-dose aspirin and β-carotene for the primary prevention of cardiovascular disease and cancer among US male physicians. A detailed description of the PHS has been previously published. Of the 22,071 participants, we randomly selected 464 incident HF cases that occurred after baseline blood collection (1982). We used a risk set technique to match each incident HF case to a control by age at randomization (within 1 year), race (white or non-Hispanic, Hispanic, African-American or black, Asian or Pacific Islander, other [whenever possible given the presence of missing values for this variable]), year of birth (within 1 year), and time of blood collection (within 288 days). Each case was eligible to serve as a control before the HF diagnosis. Similarly, each control was eligible to later become a HF case to ensure that the controls were representative of the total population from which the HF cases came. Each participant gave written informed consent, and the institutional review board at Brigham and Women’s Hospital approved the study protocol.
VDBP was determined in human plasma (1:20,000) using a sandwich immunoassay from Alpco Diagnostics (Salem, New Hampshire). The interassay coefficient of variation was 6%. HF outcome in the PHS was ascertained by annual follow-up questionnaires. Specifically, a questionnaire was mailed to each participant every 6 months during the first year and annually thereafter to obtain information on compliance with the intervention and the occurrence of new medical diagnoses, including HF. A detailed description of HF validation in the PHS using a review of the medical records in a subsample has been previously published. Information on the demographic variables, body mass index, cigarette smoking, exercise, alcohol consumption, and a history of diabetes mellitus, atrial fibrillation, and hypertension were collected at baseline. High-sensitivity C-reactive protein (hs-CRP) was measured in human plasma using a latex particle–enhanced immunoturbidimetric assay (Roche Diagnostics, Indianapolis, Indiana) and analyzed using a Roche Modular P Chemistry Analyzer (Roche Diagnostics). The interassay coefficient of variation was 4.5%.
We used conditional logistic regression analysis to calculate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs). We created quintiles of VDBP using its distribution in the control series. The lowest quintile of VDBP was used as the reference group. We assessed confounding by the body mass index (continuous), a history of atrial fibrillation (yes vs no), a history of diabetes (yes vs no), a history of hypertension (yes vs no), and the natural logarithm of hs-CRP (continuous). We obtained a p value for linear trend by creating a new variable that was assigned the median VDBP value from the control series in each quintile and fitting the new variable in the conditional logistic regression model. Spearman correlation coefficients between VDBP and hs-CRP, age, and body mass index were evaluated. In secondary analyses, we analyzed HF preceded by coronary heart disease (CHD) (n = 143) separately from HF without antecedent CHD (n = 321) and restricted the study sample to white participants (n = 864). All analyses were completed using Statistical Analysis Systems, version 9.2 (SAS Institute, Cary, North Carolina). All p values were 2-tailed, and the significance level was set at an α of 0.05.
Results
The characteristics of the 928 US male physicians obtained at baseline are listed in Table 1 according to the VDBP quintiles. The mean age of the study participants at baseline was 58.6 ± 8.2 years (range 39.9 to 82.7). Compared with the lowest quintile, the highest quintile of VDBP was associated with higher hs-CRP levels and a lower prevalence of atrial fibrillation ( Table 1 ). VDBP correlated positively with hs-CRP, and the Spearman correlation coefficient was 0.10 (p <0.01). In contrast, no correlation was found between VDBP and body mass index or age (r = −0.03, p = 0.41, and r = 0.02, p = 0.53, respectively).
| Characteristic | Plasma VDBP (μg/ml) | ||||
|---|---|---|---|---|---|
| Q1 (225.2; 108.5–251.1) | Q2 (273.4; 251.6–289.4) | Q3 (307.4; 290.1–324.4) | Q4 (345.2; 324.5–365.6) | Q5 (394.8; 365.8–1,222.1) | |
| Subjects (n) | 179 | 188 | 189 | 181 | 191 |
| Age (yrs) | 58.7 ± 8.0 | 58.3 ± 8.2 | 59.0 ± 8.0 | 58.2 ± 8.0 | 58.9 ± 8.7 |
| BMI (kg/m 2 ) | 25.5 ± 3.2 | 25.4 ± 3.4 | 25.3 ± 2.5 | 25.2 ± 2.7 | 25.2 ± 2.8 |
| hs-CRP (mg/dl) | 2.7 ± 7.6 | 2.3 ± 3.3 | 2.0 ± 2.8 | 2.4 ± 6.4 | 3.3 ± 5.9 |
| White race | 170 (97.1) | 170 (95.5) | 179 (98.4) | 168 (97.7) | 177 (96.7) |
| Current smoker | 17 (9.5) | 28 (15.0) | 19 (10.1) | 14 (7.8) | 23 (12.0) |
| Never smoked | 82 (45.8) | 87 (46.5) | 82 (43.4) | 78 (43.3) | 87 (45.6) |
| Current alcohol use | 149 (83.2) | 154 (82.4) | 161 (85.2) | 156 (86.7) | 158 (83.2) |
| Atrial fibrillation | 11 (6.2) | 10 (5.3) | 12 (6.4) | 1 (0.6) | 4 (2.1) |
| Vigorous exercise | 127 (71.0) | 143 (76.1) | 136 (72.0) | 143 (79.4) | 131 (70.1) |
| Diabetes mellitus | 8 (4.5) | 17 (9.0) | 7 (3.7) | 11 (6.1) | 10 (5.2) |
| Hypertension | 53 (29.9) | 73 (39.5) | 46 (24.5) | 58 (32.0) | 58 (30.5) |
In a conditional logistic regression model adjusting for matching factors, the ORs for HF was 1.0 (95% CI reference), 1.09 (95% CI 0.71 to 1.66), 1.12 (95% CI 0.72 to 1.73), 1.02 (95% CI 0.64 to 1.62), and 1.15 (95% CI 0.71 to 1.87) across the consecutive quintiles of plasma VDBP (p for linear trend = 0.68). The corresponding ORs after adjustment for body mass index and a history of atrial fibrillation, diabetes, and hypertension, and hs-CRP level were 1.0 (95% CI reference), 1.05 (95% CI 0.66 to 1.65), 1.28 (95% CI 0.80 to 2.06), 1.07 (95% CI 0.65 to 1.75), and 1.28 (95% CI 0.76 to 2.15); p for linear trend = 0.41.
In secondary analyses, VDBP was not associated with the risk of HF with antecedent CHD in a model adjusted for matching factors, body mass index, a history of atrial fibrillation, diabetes, hypertension, and hs-CRP. The OR was 1.0 (95% CI referent), 1.20 (95% CI 0.44 to 3.30), 2.22 (95% CI 0.78 to 6.31), 1.44 (95% CI 0.47 to 4.43), and 2.03 (95% CI 0.65 to 6.41) across consecutive quintiles of VDBP (p for linear trend = 0.28). For HF without previous CHD, the corresponding ORs were 1.0 (95% CI referent), 0.96 (95% CI 0.56 to 1.62), 0.94 (95% CI 0.54 to 1.64), 1.00 (95% CI 0.57 to 1.76), and 1.12 (95% CI 0.61 to 2.04); p for linear trend = 0.70. The results did not change when the restricted to white participants (data not shown).
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