We aimed to examine associations between serum 25-hydroxyvitamin D (25[OH]D) concentration and mortality from heart failure (HF) and cardiovascular disease (CVD) and premature death from all causes using data from the Third National Health and Nutrition Examination Survey, which included 13,131 participants (6,130 men, 7,001 women) ≥35 years old at baseline (1988 to 1994) and followed through December 2000. Premature death was defined all-cause death at <75 years of age. Results indicated that during an average 8-year follow-up, there were 3,266 deaths (24.9%) including 101 deaths from HF, 1,451 from CVD, and 1,066 premature all-cause deaths. Among HF deaths, 37% of decedents had serum 25(OH)D levels <20 ng/ml, whereas only 26% of those with non-HF deaths had such levels (p <0.001). Multivariate-adjusted Cox model indicated that subjects with serum 25(OH)D levels <20 ng/ml had 2.06 times higher risk (95% confidence interval 1.01 to 4.25) of HF death than those with serum 25(OH)D levels ≥30 ng/ml (p <0.001). In addition, hazard ratios (95% confidence intervals) for premature death from all causes were 1.40 (1.17 to 1.68) in subjects with serum 25(OH)D levels <20 ng/ml and 1.11 (0.93 to 1.33) in those with serum 25(OH)D levels of 20 to 29 ng/ml compared to those with serum 25(OH)D levels ≥30 ng/ml (p <0.001, test for trend). In conclusion, adults with inadequate serum 25(OH)D levels have significantly higher risk of death from HF and all CVDs and all-cause premature death.
Heart failure (HF) has posed an enormous public health burden in the United States and in other industrialized countries. It is estimated that about 6 million Americans live with HF, >67,000 new cases are diagnosed yearly in adults >35 years of age, and HF accounts for about 300,000 deaths each year. Although nutritional factors have long been implicated in the risk of cardiomyopathies, only during the previous decade has rapidly accumulating epidemiologic evidence indicated an inverse association between vitamin D status and risk for cardiovascular disease (CVD), diabetes mellitus, and certain forms of cancers. Few of these previous studies have been a prospective study design or analyzed prospectively. The long-term impact of vitamin D insufficiency and deficiency on risk of HF and all forms of CVDs are not well studied. To fill these gaps, the present study examined associations between serum 25-hydroxyvitamin D concentration (25[OH]D; a biomarker of vitamin D level in the circulation) and risk of death from HF and CVD in subjects ≥35 years old and risk of death from all causes in subjects <75 years old (the average life expectancy from the 1980s through the 1990s).
Methods
We used data from the Third National Health and Nutrition Examination Survey (NHANES III 1988 to 1994) and the NHANES III Mortality-Linked File (2000). The NHANES III is a nationwide survey conducted by the National Center for Health Statistics (NCHS) of the Centers of Disease Control and Prevention in the United States from October 1988 through October 1994, gathering information representing the health and nutritional status of the noninstitutionalized civilian United States population ≥2 months of age. The study consists of interviews, physical examinations, and data from blood sample analysis. Household interviews were conducted before the examination to collect demographic, medical history, and health behavior information. Examinations were carried out in mobile examination centers. Blood samples were obtained at mobile examination centers for measurements of serum biomarkers. To ensure the quality of blood sample collection and to minimize hemolysis of blood samples, participants were asked to fast for 12 hours before a morning examination or 6 hours before an afternoon or evening examination. All phlebotomists were certified and trained in standardized laboratory procedures. Serum 25(OH)D levels were assessed using a radioimmunoassay kit (DiaSorin Inc, Stillwater, Minnesota). The NHANES III Mortality-Linked File was done by the NCHS working with the state’s Offices of Vital Statistics to link NHANES III data with death certificate records using the National Death Index. The National Death Index is a central computerized index of death record information on file. This linkage provides a unique opportunity to conduct longitudinal analysis between measurements at baseline and outcomes through the period of follow-up (i.e., survival or mortality). In the present study, we used the Mortality-Linked File, which recorded NHANES III participants’ (1988 to 1994) survival status or causes of death through December 31, 2000. The NHANES III survey was approved by the Centers of Disease Control and Prevention NCHS institutional review board. Data obtained from the NCHS for the present study were de-identified for participants’ private information security. In total 13,131 participants (6,130 men, 7,001 women) ≥35 years old were included in the present study. We restricted the study to those ≥35 years old because prevalence of CVD and mortality is substantially lower at <35 years of age. Detailed information on the NHANES III has been provided elsewhere.
In the study, for practice in clinical settings, we applied the commonly accepted cut-off points to classify serum 25(OH)D level into 3 groups: (1) vitamin D deficiency was defined as serum 25(OH)D concentrations <20 ng/ml; (2) vitamin D insufficiency was defined as serum 25(OH)D concentration 20 to 29 ng/ml; and (3) vitamin D sufficiency was defined as serum 25(OH)D concentrations ≥30 ng/ml (normal).
Study outcomes included mortality from (1) HF ( International Classification of Disease, Tenth Revision code I50), (2) all forms of CVD ( International Classification of Disease, Tenth Revision codes I20 to I69), and (3) all causes. Follow-up time (years) was calculated from the baseline interview to the end of follow-up (December 31, 2000) or until the date of death if a participant died before the end of follow-up, whichever occurred first. Premature death was defined as those who died at <75 years of age because the United States life expectancy in the study period from the 1980s through the 1990s was around 75 years.
In the study, we conducted a serial analysis. First, we described the characteristics of study participants across 3 groups of serum 25(OH)D concentration (i.e., <20, 20 to 29, and ≥30 ng/ml). Differences were tested using chi-square test for categorical variables and analysis of variance for continuous variables. Leading cause of death was analyzed according to the proportions of death from HF, CVD, and all causes. Second, hazard ratios (i.e., relative risk) and 95% confidence intervals of serum 25(OH)D for risk of mortality from HF and CVD and among all ages and premature death from all causes were estimated using Cox proportional hazard regression models (Cox model). In the analysis, follow-up time (years) and survival status (yes or no) were the dependent variables, and serum 25(OH)D concentration and covariates were the independent variables. To control potential confounders (i.e., covariates), 2 sets of multivariate Cox models were conducted: model 1 was adjusted for age (year), gender (men vs women), and race/ethnicity (White, African-American, Hispanic, and others) and model 2 was adjusted for covariates used in model 1 plus marital status (married vs not married), education level (recoded 0, 1, and 2 for those with more than high school, high school, and less than high school level, respectively), smoking status (current smokers vs nonsmokers), alcohol consumption (yes vs no), physical activity (less, about the same, or more compared to the same age group), body mass index (kilograms per meter squared), and diabetes mellitus (yes vs no). The hazard function (measurement of risk; the greater the value, the greater the mortality at follow-up time) of premature death from all causes and death from HF by serum 25(OH)D levels were depicted using Kaplan–Meier curves.
All statistical analyses were performed using SAS 9.1 (SAS Institute, Cary, North Carolina). Analysis for complex sample surveys were used taking into consideration the NHANES III’s complex survey designs. Cox proportional hazard assumption was examined using plots of log(−log) survival curves and Schoenfeld residuals methods. A 2-sided p value ≤0.05 was considered statistically significant in all data analyses.
Results
Of 13,131 participants, 3,266 died during an average 8-year follow-up (range 0 to 12). CVD contributed to 44.4% and cancer to 21.4 of total deaths. HF as a single cause of death (n = 101) contributed 3.1% of total deaths. Of premature deaths (n = 1,066), CVD contributed to 34.2% and cancer to 30.1% of all deaths. HF as a single cause of death contributed to 1.0% of total premature deaths.
As presented in Table 1 , overall, <1/2 of participants ≥35 years old had normal serum 25(OH)D concentrations (≥30 ng/ml). Subjects ≥75 years old had the lowest rate of having normal 25(OH)D levels (31.0%). Significant distributions across serum 25(OH)D levels were observed by race/ethnicity, education, and behavior factors.
| Variable | <20 ng/ml | 20–29 ng/ml | ≥30 ng/ml | p Value |
|---|---|---|---|---|
| (n = 4,170) | (n = 3,890) | (n = 3,260) | ||
| Percentage (SEP) | Percentage (SEP) | Percentage (SEP) | ||
| Age (years) | ||||
| 35–44 | 26.3% (1.2) | 33.4% (1.4) | 40.2% (1.4) | |
| 45–54 | 23.2% (1.2) | 35.9% (1.6) | 40.9% (1.7) | |
| 55–64 | 27.3% (1.3) | 33.7% (1.5) | 38.9% (1.5) | <0.001 |
| 65–74 | 25.2% (1.3) | 37.1% (1.5) | 37.7% (1.5) | |
| ≥75 | 30.7% (1.3) | 38.3% (1.4) | 31.0% (1.4) | |
| Race/ethnicity | ||||
| White | 20.0% (0.7) | 35.8% (0.8) | 44.1% (0.9) | |
| African-American | 62.3% (1.0) | 27.0% (0.9) | 10.7% (0.6) | <0.001 |
| Hispanic | 38.7% (1.2) | 38.5% (1.2) | 22.8% (1.1) | |
| Others | 36.4% (2.9) | 36.4% (3.0) | 27.2% (2.8) | |
| Marital status | ||||
| Married | 22.6% (0.7) | 35.7% (0.9) | 41.7% (0.9) | |
| Widow | 35.8% (1.5) | 35.4% (1.6) | 28.9% (1.5) | <0.001 |
| Separated/divorced | 34.4% (1.9) | 31.4% (2.0) | 34.2% (2.1) | |
| Never married | 31.9% (2.7) | 35.0% (2.9) | 33.0% (3.0) | |
| Education | ||||
| <High school | 30.0% (1.3) | 34.7% (1.4) | 35.3% (1.5) | |
| High school | 27.5% (0.9) | 34.7% (1.0) | 37.8% (1.0) | <0.001 |
| >High school | 23.1% (1.0) | 35.7% (1.2) | 41.2% (1.3) | |
| Body mass index (kg/m 2 ) | ||||
| <25 | 23.9% (1.0) | 32.4% (1.1) | 43.7% (1.2) | |
| 25–29 | 23.6% (0.9) | 36.0% (1.2) | 40.4% (1.2) | <0.001 |
| ≥30 | 33.0% (1.2) | 38.0% (1.3) | 29.0% (1.3) | |
| Current smoking | 28.9% (1.1) | 33.5% (1.3) | 37.6% (1.4) | <0.001 |
| Alcohol consumption | 22.4% (0.9) | 34.6% (1.1) | 43.0% (1.1) |
As presented in Table 2 , participants with a self-rated health of excellent had the highest rate of having normal 25(OH)D levels (45.2%), and those with poor health had the lowest rate (25.3%). Overall, subjects with chronic conditions had smaller proportions of normal 25(OH)D levels than those who had no chronic conditions.
| Variable | <20 ng/ml | 20–29 ng/ml | ≥30 ng/ml | p Value |
|---|---|---|---|---|
| (n = 4,170) | (n = 3,890) | (n = 3,260) | ||
| Percentage (SEP) | Percentage (SEP) | Percentage (SEP) | ||
| Self-rated health | ||||
| Excellent | 21.4% (1.4) | 33.4% (1.7) | 45.2% (1.8) | |
| Very good | 20.3% (1.1) | 35.8% (1.4) | 43.9% (1.5) | <0.001 |
| Good | 28.6% (1.0) | 34.9% (1.2) | 36.6% (1.2) | |
| Fair | 33.4% (1.5) | 36.5% (1.6) | 30.1% (1.5) | |
| Poor | 40.8% (2.9) | 33.9% (3.0) | 25.2% (2.6) | |
| Blood pressure | ||||
| Normal | 23.7% (1.2) | 34.2% (1.4) | 42.1% (1.4) | |
| Prehypertension ⁎ | 24.5% (1.2) | 35.5% (1.4) | 40.0% (1.4) | <0.001 |
| Hypertension † | 29.0% (0.9) | 35.5% (1.0) | 35.6% (1.0) | |
| Self-report of condition ‡ | ||||
| Coronary heart disease | ||||
| No | 25.8% (0.6) | 35.0% (0.7) | 39.2% (0.8) | 0.21 |
| Yes | 27.6% (2.2) | 37.9% (2.6) | 34.5% (2.5) | |
| Stroke | ||||
| No | 25.8% (0.6) | 35.2% (0.7) | 39.0% (0.7) | 0.002 |
| Yes | 36.3% (3.2) | 30.1% (3.0) | 33.6% (3.3) | |
| Heart failure | ||||
| No | 26.1% (0.6) | 34.8% (0.7) | 39.1% (0.7) | 0.09 |
| Yes | 27.7% (2.7) | 40.0% (3.3) | 32.3% (3.1) | |
| Diabetes mellitus | ||||
| No | 25.1% (0.6) | 35.1% (0.7) | 39.8% (0.8) | <0.001 |
| Yes | 37.9% (2.2) | 35.2% (2.3) | 26.9% (2.1) |
⁎ Systolic blood pressure 120 to 139 mm Hg or diastolic blood pressure 80 to 89 mm Hg.
† Systolic blood pressure/diastolic blood pressure ≥140/90 mm Hg or use of antihypertensive drugs.
As presented in Table 3 , subjects ≥35 years old with serum 25(OH)D deficiency (<20 ng/ml) had a significantly higher risk of deaths from HF and CVD than those who had a normal serum 25(OH)D level (≥30 ng/ml).
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