Abstract
Context
The prevalence of both heart failure and vitamin D deficiency increases with age and is associated with poor outcome in the elderly.
Objectives
We aimed to investigate the relationship between all-cause mortality and vitamin D deficiency in elderly patients with chronic heart failure.
Design
It is a retrospective, observational cross-sectional study. Median follow-up time was 497 days.
Subjects and Methods
302 patients aged ≥65 years heart failure patients was categorized into tertiles based on the 25-hydroxy-vitamin D levels. Clinical and laboratory parameters were evaluated according to tertiles. Hospitalization rates and overall survival were compared between tertiles. Independent predictors of all cause mortality were defined.
Results
Patients with low vitamin D tertile were mostly women (p=0.001), and had a worse NYHA functional class (p=0.005). During follow-up, deaths were more frequent in the first tertile (p = 0.001). All-cause mortality increased significantly with decreasing vitamin D tertiles (from third tertile 7.9%, to 11.9%, to 26%; log rank test p=0.003). No significant difference was observed at the composite endpoint of mortality or HF hospitalizations (P=0.451). Multivariate analysis supported that low vitamin D concentration was an independent predictor of all causes of mortality (HR 0.93; 95% CI 0.89-0.97; p=0.004).
Conclusions
Low vitamin D levels were independent predictors of all-cause mortality in the elderly population with chronic heart failure.
Keywords: Heart failure, Vitamin D, Mortality, Elderly
Introduction
Heart failure (HF) is a global problem with an increasing prevalence, affecting at least 23 million people worldwide (1). Despite all treatments, HF remains an important cause of morbidity and mortality, and its incidence and prevalence increase with age (2). Therefore, searches for biomarkers and supportive treatments that may affect prognosis continues.
Vitamin D is an important micronutrient that plays an important role in autocrine and paracrine regulation of cellular functions and for various organs including the heart. Vitamin D levels have been shown to be highly associated with cardiovascular events such as coronary artery disease, myocardial infarction, HF, hypertension and stroke (3). Correlation between vitamin D deficiency and high New York Heart Association (NYHA) functional classes, shorter 6-minute walking distance, increased N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and poor outcome have been reported in patients with HF (4, 5).
It is estimated that 30-50% of the world population is vitamin D deficient, and its incidence is increasing in the elderly population (6) as 40-80% of the elderly population exhibits Vitamin D deficiency (7). The frequency of vitamin D deficiency increases in the elderly due to poor exposure to sunlight and decreased skin synthesis of the conversion of 7 dehydrocholesterol to previtamin D (8).
In addition, it has been observed that vitamin D deficiency is very common in 80% to 95% of the HF population (9). The prevalence of both HF and vitamin D deficiency increases with age, and this appears to be associated with poor outcome in the elderly. Studies have reported that low vitamin D levels are associated with adverse outcomes such as hospital readmission or death because of HF, sudden cardiac death, or all cause mortality (5, 10, 11).
However, the relation of vitamin D deficiency with mortality and hospitalization in elderly patients with HF is not clearly known. In this study, we aimed to show the prevalence of vitamin D deficiency in elderly patients with chronic HF and the relationship between hospitalizations and all cause mortality.
Materials and Methods
Patient population and clinical / biochemical assessment
For this study, 1104 patients who were followed up in an outpatient HF clinic in a tertiary hospital between April 2016 and December 2019 were evaluated retrospectively. Medical records of 354 patients ≥65 aged were reviewed; 52 patients who received vitamin D replacement were excluded from the study, and 302 patients were included in the study.The study complies with the Declaration of Helsinki (2013). It was approved by the Antalya Training and Research Hospital ethics committee with the decision numbered 10/12. Inclusion criteria are listed below: (i) diagnosis of HF (ii) NYHA functional classes I–IV, (iii) left ventricular ejection fraction (LVEF) < 50%, (iv) age ≥ 65 years, (v) sex both male and female. Patients who were already taking vitamin D supplements were excluded. Demographic, clinical and biochemical parameters and information about hospitalization and mortality were collected from medical records. Since there is no international consensus about 25-hydroxy-vitamin D (25(OH)D) levels cut-off points and reference values, we categorized patients into tertiles of 25(OH)D levels. Tertiles were calculated according to the 25(OH)D concentration of the whole study population. Clinical and biochemical properties of all patients were evaluated including 25(OH)D, hemoglobin, creatinine, estimates glomerular filtration rate (eGFR), serum electrolytes, NT-proBNP, C-reactive protein (CRP), albumin, serum calcium, iron profiles, parathormone (PTH), electrocardiogram, echocardiography findings and medications. All parameters were measured with standard methods. eGFR was calculated as using the following formula= 186.3 × (serum creatinine mg/dL) - 1.154 × age - 0.203 × (0.742 for women). All patients were classified according to NYHA functional classification as NYHA class I–IV.
The primary outcomes of this study were all cause mortality and hospitalization. Secondary outcomes was composite endpoint of all-cause mortality or hospitalization due to worsening of HF.
Statistical analysis
The distribution of the data was tested with the Kolmogorov–Smirnov test. Non-normally distributed data were logarithmically transformed. Results are expressed as means with standard deviations if normally distributed or medians with interquartile ranges if non-normally distributed. Categorical variables are reported as percentage of observations. Analyses of variance, Kruskall–Wallis test or chi-square test were used as appropriate. Spearman’s correlation analysis was used for vitamin D related factors. Kaplan-Meier survival analysis with log rank test was used to compare survival between vitamin D tertiles. Multivariate Cox regression analysis was performed to define independent predictors of all cause mortality. For the multivariate Cox regression, among the parameters determined to be significant in the univariate regression analysis, those previously examined in the literature were used. Results are presented as hazard ratios (HR) with 95% confidence intervals. A P-value of 0.05 was considered statistically significant. Statistical analyses were performed with SPSS version 22.0 software version.
Results
The study population was 204 men (67.5%) and 98 women (32.5%) with a median age of 72 [IQR 69-78]. The median vitamin D level of the study group was 16.35 ng/mL [IQR 11.53-22.60]. When evaluated according to the criteria determined by the endocrine society (12), the vitamin D level was <20 ng/mL in 198 individuals (65.6%), and the vitamin D level was >20 ng/mL in 104 individuals (34.4%).
Basal characteristics by tertiles vitamin D
Baseline characteristics according to 25(OH)D tertiles are presented in Table 1. Patients with low tertile according to vitamin D levels were mostly women (p=0.001), and had a worse NYHA functional class (p=0.005). Patients with lower vitamin D levels had higher heart rate (p=0.011), lower QRS duration (p=0.012), lower eGFR (p=0.017), lower albumin level (p<0.001), lower calcium level (p=0.001), higher parathormone levels (p=0.001), lower haemoglobin levels (p=0.01), lower serum iron levels (p=0.017), lower transferrin saturation (p=0.009) and higher CRP levels (p=0.048). When the treatment modalities were compared, it was seen that ß-Blockers were used less in lower tertile (P=0.029). However, there was no significant difference in age, body mass index, diabetes, hypertension, blood pressure, LVEF, creatinine, sodium, uric acid, total cholesterol, ferritin, transferrin, NT-proBNP, high sensitive troponin levels, and the use of renin angiotensin system blockers.
Table 1.
Baseline demographics according to tertiles of 25-hydroxy-vitamin D
| Variable |
All patients
(n:302) |
First tertile
Vitamin D <13.3 ng/mL (n:100) |
Second tertile
Vitamin D 13.3-20.3 ng/mL (n:101) |
Third tertile Vitamin D >20.3 ng/mL (n:101) | P-value |
|---|---|---|---|---|---|
| 25(OH)D level (ng/mL) | 16.35 (11.53-22.60) | 9.60 (6.99-11.53) | 16.31 (14.49-18.46) | 24.80 (22.50-27.93) | <0.001 |
| Age (years) | 72 (69-78) | 73 (68-80.75) | 74.5 (70-78) | 72 (68-75) | 0.138 |
| Female (%) | 32,5 | 46 | 30 | 22 | 0.001 |
| BMI (kg/m2) | 26.1 (23.1-29.3) | 26.6 (23.1-29.8) | 26.2 (23-29.9) | 25.7 (23-28.1) | 0.368 |
| NYHA class (%) | 0.005 | ||||
| NYHA I | 22.5 | 16 | 29.7 | 21.8 | |
| NYHA II | 46 | 36 | 46.5 | 52.5 | |
| NYHA III-IV | 31.5 | 45 | 23.8 | 25.8 | |
| Diabetes (%) | 36.4 | 37 | 43 | 30 | 0.162 |
| Hypertension (%) | 57 | 59 | 61 | 57 | 0.388 |
| ACE-I/ARB (%) | 73.9 | 74 | 73.3 | 74.2 | 0.573 |
| ß-blockers (%) | 90.4 | 84 | 93.1 | 94.1 | 0.029 |
| Systolic BP (mmHg) | 120 (100-130) | 120 (100-130) | 110 (110-120) | 120 (100-130) | 0.976 |
| Diastolic BP (mmHg) | 60 (60-70) | 60 (60-78.75) | 60 (60-70) | 60 (60-70) | 0.764 |
| Heart rate (b.p.m) | 73 (64-84) | 78 (68-85) | 73.5 (63-83) | 70 (60-80) | 0.011 |
| QRS duration, msn | 110 (64-139.5) | 104 (92-124) | 117 (96-145.5) | 111.5 (94.5-147.5) | 0.012 |
| LVEF (%) | 30 (24-35) | 30 (20-35) | 30 (23-35) | 30 (25-30) | 0.640 |
| Creatinine (mg/dL) | 1.17 (0.98-1.43) | 1.16 (0.94-1.53) | 1.19 (1.03-1.44) | 1.17 (0.96-1,36) | 0.308 |
| eGFR (mL/min/1.73m2) | 54.5 (44.3-69.1) | 51.9 (40.8-60.4) | 54.6 (43.5-66.6) | 59 (48.8-74.7) | 0.017 |
| Sodium (mmol/L) | 139 (136-140) | 139 (136.2-141) | 139 (136-140.5) | 139 (136-140) | 0.951 |
| Albumin (g/dL) | 4.1 (3.8-4.4) | 3.9 (3.7-4.2) | 4.2 (4-4.5) | 4.2 (3.9-4.5) | <0.001 |
| Calcium (mg/dL) | 9.4 (9-9.7) | 9.1 (8.8-9.6) | 9.4 (9.1-9.8) | 9.5 (9.12 -9.70) | 0.001 |
| Uric acid (mg/dL) | 7.05 (5.7-8.6) | 7.3 (5.6-9.2) | 7.3 (5.9-8.55) | 6.65 (5.7-8) | 0.215 |
|
Total cholesterol
(mg/dL) |
166 (133-200) | 161 (127-192) | 177 (142-210) | 163 (132-192) | 0.960 |
| PTH (ng/L) | 74 (47-108) | 96 (66-129) | 66 (45-100.25) | 61 (40.25-93) | <0.001 |
| Haemoglobin (g/dL) | 12.6±1.8 (8.3-17.4) | 12.2±1.6 (8.3-15.9) | 12.9±1.9 (8.6-17.3) | 12.87±1.8 (8.6-17.4) | 0.01 |
| Serum iron (μg/dL) | 65.5 (41-92.2) | 58 (35.7-82) | 68 (42.5-91.5) | 72 (53-107) | 0.017 |
| Ferritin (μg/L) | 58 (31-106) | 55 (34-102) | 59 (26-109.5) | 62 (31-105.5) | 0.830 |
| Transferrin (mg/dL) | 272 (232-311.5) | 272.5 (228.5-313.2) | 275 (232.5-315.5) | 269 (232-301) | 0.851 |
| Transferrin saturation (%) | 20 (12.2-28.8) | 16.2 (11.3-24.6) | 19.9 (12.4-20.1) | 22.4 (16.6-32.5) | 0.009 |
| NT-proBNP (ng/L) | 2460.5 (1014.7-5912.2) | 3243(1573.2-6352.2) | 1913 (940.6-5936.5) | 2324 (733.1-5234.5) | 0.056 |
| High sensitive troponin (ng/L) | 20 (14-36.5) | 20 (12-45) | 22 (15.5-39.5) | 20 (13.25-34.5) | 0.780 |
| CRP (mg/dL) | 4.9 (2-11) | 6 (2.35-14.8) | 4 (1.8-16) | 4 (2-8) | 0.048 |
25(OH)D,=25-hydroxy-vitamin D; BMI= body mass index; NYHA,=New York Heart Association; ACE-I,=angiotensin converting enzyme inhibitor; ARB,=angiotensin receptor blocker; BP= blood pressure; b.p.m.,=beats per minute; LVEF=left ventricular ejection fraction; eGFR=estimated glomerular filtration rate; PTH=parathyroid hormone; NT-proBNP=N-terminal pro-brain natriuretic peptide; CRP= C-reactive protein.Normally distributed data are presented as mean+SD. Non-normally distributed data are presented as median (interquartile range).
Correlations
The concentration of vitamin D was significantly correlated in univariate analyses with several parameters (Table 2). Vitamin D was positively correlated with QRS duration, eGFR, calcium, albumin, haemoglobin, transferrin saturation, serum iron level, while negative correlation was found with age, heart rate, uric acid, PTH, NT-proBNP.
Table 2.
Univariate correlations for 25-hydroxy-vitamin D
| Variable | R=Correlation coefficient (Spearman’s rho) | P-value |
|---|---|---|
| Age | -0.132 | 0.022 |
| Heart rate | -0.198 | 0.001 |
| QRS duration | 0.154 | 0.007 |
| eGFR | 0.168 | 0.003 |
| Calcium | 0.216 | <0.001 |
| Albumin | 0.247 | <0.001 |
| Haemoglobin | 0.180 | 0.002 |
| Transferrin saturation | 0.170 | 0.003 |
| Uric acid | -0.115 | 0.046 |
| Parathyroid hormone | -0.339 | <0.001 |
| NT-proBNP | -0.140 | 0.015 |
| Serum iron | 0.159 | 0.006 |
eGFR,=estimated glomerular filtration rate; NT-proBNP,=N-terminal pro-brain natriuretic peptide.
All cause mortality and hospitalization
Median follow-up time was 497 days [IQR 308-841]. During the follow-up, 46 (15.2%) patients died and 121 (40.1%) patients were rehospitalized. The number of patients who died was significantly higher in the first tertil (number of deaths by tertile, respectively; 26, 12, 8, P=0.001). There was no difference about hospitalization rates in tertiles (P=0.242). All-cause mortality increased significantly with decreasing vitamin D tertiles (from third tertile 7.9%, to 11.9%, to 26%; log rank test P=0.003; Fig. 1). Although it increased in the first tertile of hospitalization because of HF, there was no significant difference between the tertiles (from first tertile 45%, to 33.7%, to 41.6%; log rank test P=0.714). Similarly when the composite endpoint of mortality or HF hospitalizations was evaluated, no significant difference was observed between vitamin D tertiles (from first tertile 60%, to 42.6%, to 45.5%; log rank test P=0.451).
Figure 1.
Survival for all-cause mortality according to tertiles of 25-hydroxy-vitamin D. First tertile vitamin D level <13.3 ng/mL, second tertile 13.3-20.3 ng/mL, and third tertile >20.3 ng/mL. Log-rank test P = 0.003. The endpoint of mortality increased significantly across decreasing 25(OH)D tertiles, from 7.9%, to 11.9%, to 26%.
In Cox regression analysis, vitamin D level was seen to be an important predictor of all-cause mortality. It was found that higher vitamin D levels were associated with reduced mortality rates (HR 0.93; 95% CI 0.89-0.97; P=0.001, Table 3). Multivariable Cox regression analysis showed that lower vitamin D concentration remained an independent predictor of the all cause mortality (HR 0.93; 95% CI 0.89–0.97; P=0.004; Table 2). However, NT-proBNP and sodium appeared to be independent predictors of all cause mortality (respectively; HR 2.90; 95% CI 1.54-5.45; P=0.001, HR 0.87; 95% CI 0.82-0.93; P<0.001, Table 3).
Table 3.
Univariable and multivariable analyses by Cox regression analysisfor all-cause mortality
| Variables | χ2 | Univariable analysis | Multivariable analysis | ||
|---|---|---|---|---|---|
| Hazard ratio (95% CI) | P-value | Hazard ratio (95% CI) | P-value | ||
| Age | 10.8 | 1.06 (1.02-1.11) | 0.001 | 1.01 (0.97-1.06) | 0.43 |
| eGFR | 13.8 | 0.97 (0.95-0.98) | 0.001 | 0.99 (0.97-1.01) | 0.46 |
| Sodium | 19.8 | 0.88 (0.83-0.93) | <0.001 | 0.87 (0.82-0.93) | <0.001 |
| Albümin | 36.3 | 0.12 (0.06-0.25 | <0.001 | ||
| Transferrin saturation | 6.8 | 0.96 (0.93-0.99) | 0.009 | ||
| CRP | 12.7 | 1.01 (1.004-1.01) | 0.001 | ||
| NT-proBNP | 28.6 | 4.25 (2.49-7.25) | <0.001 | 2.90 (1.54-5.45) | 0.001 |
| 25(OH)D | 10.4 | 0.93 (0.89-0.97) | 0.001 | 0.93 (0.89-0.97) | 0.004 |
eGFR=estimated glomerular filtration rate; CRP= C-reactive protein; NT-proBNP=N-terminal pro-brain natriuretic peptide;25(OH)D=25-hydroxy-vitamin D. Values for NT-proBNP were log transformed before analysis.
Discussion
We think that this study is an important study showing the relationship between vitamin D levels and mortality in the elderly patients with chronic HF. We have shown that low vitamin D levels are common in elderly HF patients and are independently associated with an increased risk of all-cause mortality. Like low vitamin D concentrations, sodium and NT-proBNP were independent predictors of mortality in elderly HF patients too.
Vitamin D is a steroid hormone in the group of fat soluble vitamins. It is estimated that around 30-50% of them are affected by vitamin D deficiency worldwide (6) and that 40-80% of the elderly population is vitamin D deficient (7). With aging, the susceptibility to vitamin D deficiency increases due to the decrease in eating, the decrease in the absorption of nutrients including vitamins from the intestines, and the decrease in vitamin D skin synthesis. In addition, since elderly people spend a short time outside the home, the conversion of 7-dehydrocholesterol to vitamin D by the ultraviolet light of the sun decreases (8,13).
It is also known that vitamin D deficiency is very common in the HF population, ranging from about 80% to 95% (9). The prevalence of vitamin D deficiency in the elderly population with HF is not clearly known. In our study, the frequency in this population was 65.6% (<20 ng/mL). Although our study was conducted in a city located on the 36th parallel in southwest Turkey in a region that receives sufficient sunlight all year round, we encountered vitamin D deficiency quite frequently.
The role of vitamin D in cardiovascular disease has received increasing attention in recent years. Several observational studies have shown that vitamin D deficiency is common in patients with cardiovascular disease and may increase the risk of developing HF (14,15). Low vitamin D levels have been shown to be associated with poor outcomes in patients with HF (5, 10, 11).
According to the epidemiological data of the National Health and Nutrition Examination Survey (NHANES) 2001-2004, when 8351 adults were evaluated, the proportion of those with 25 (OH) D <30 ng/ml was 74%. They showed that it was more common in patients with both coronary heart disease and heart failure (89%; OR 3.52, 95% CI 1.58 to 7.84) after controlling for age, race, and gender. The burden of HF was higher at <20 ng/mL, reported as 3.2% (16). A previous study found that the lowest quartile of the 25 (OH) D level (<17.ng/mL) was independently associated with all-cause deaths in the general population (17). While the studies we have mentioned now are general population studies, Kestenbaum et al. reported that a serum 25 (OH) level of <15 ng/mL in older adults without initial cardiovascular disease was associated with a 29% risk of mortality (18). However, the median follow-up time for this study was 14 years much longer than ours. In our study, the lowest tertile (vitamin D <13.3 ng/mL) all-cause mortality was 26% and was significantly higher than other tertiles, but ours were performed in the elderly HF population, not in the general population without HF.
Following an 18-month follow-up of 548 HF patients, adjusted multivariate Cox regression analysis demonstrated that low 25 (OH) D concentration was an independent predictor of HF hospitalization and all cause mortality composite endpoint (HR 1.09 per 10 nmol/L decrease; 95% CI: 1.00-1.16; P=0.040) and all-cause mortality (HR 1.10 per 10 nmol/L decrease; 95% CI: 1.00-1.22; P=0.049) (19). We found low vitamin D concentration was an independent predictor of death from all causes (HR 0,93; 95% CI 0.89–0.97; P=0.004), but this relationship was not present for rehospitalization and composite endpoint. In a cross-sectional prospective study demonstrated a higher prevalence of vitamin D deficiency in patients on the emergency cardiac transplant list compared to those on the elective list (5). Lower vitamin D levels have been reported to be associated with higher adverse events defined as death or transplantation. Taken together, these studies clearly show that there is a high prevalence of vitamin D deficiency in HF patients and that vitamin D deficiency is associated with more severe disease and higher adverse outcome rates.
Vitamin D deficiency is also linked to increased production and release of inflammatory cytokines that can have a direct negative effect on the myocardium. They can induce myocardial apoptosis, hypertrophy, fibrosis, left ventricular remodeling and cause negative ionotropic effects (20,21). Previous studies reported that low 25 (OH) D status was associated with low exercise capacity and borderline significance in the Kansas City Cardiomyopathy Questionnaire, while in patients with NYHA class II or higher symptoms, vitamin D supplementation improved the inflammatory state but had no improvement in ventricular function or survival benefit (22,23). It has been previously shown that high CRP levels are a common finding in patients with HF and are associated with a poor prognosis (4,24). However, there was a significant difference between tertiles, no correlation was found between vitamin D levels and CRP in our study. Vitamin D was correlated with albumin and nutritional status such as calcium, haemoglobin, transferrin saturation, serum iron level. Vitamin D was negative correlation with PTH and NT-proBNP. Decreasing vitamin D leads to increasing levels of PTH (25). 25 (OH) D levels of less than 20 ng/mL are associated with increased serum parathyroid hormone (PTH) levels and hyperparathyroidism (26). In Japanese HF patients, 25 (OH) D levels were moderately correlated with albumin and nutritional status, but were not found to be a strong predictor of cardiac outcome compared to BNP levels (27).
The effect of vitamin D replacement on poor outcome of cardiovascular disorders was also evaluated in studies. In the Vitamin D Assessment Study, 5110 adults from the general population were randomized to vitamin D supplements or placebo for an average of 3.3 years. There was no significant difference in combined end point of incident cardiovascular disease or death and the incidence of HF (28). In The VITamin D and OmegA-3 TriaL (VITAL) study, 25.871 subjects given vitamin D3 (cholecalciferol, 2000 IU/day) and marine omega-3 fatty acids (1 g/day) were followed for a median 5.3 year of cancer and cardiovascular disease. In this large primary prevention study, it was reported that vitamin D3 supplementation did not significantly reduce total invasive cancer or the composition of major cardiovascular events (29). The EVITA study followed 400 HF patients for 3 years after vitamin D replacement. Although mortality did not significantly differ in treated and placebo group, there was a significant greater need for mechanical circulatory support implantation in treated patients compared to placebo (30). There are not many studies on the effect of vitamin D replacement in elderly HF patients with vitamin D deficiency. Witham et al. showed that vitamin D supplementation in 105 elderly (>70 years) patients did not improve functional capacity or quality of life in elderly HF patients with vitamin D deficiency (31).
Our study has some limitations. One limitation of this study is that it was performed retrospectively, the sample size was relatively small. These situations affect the overall consequences for the endpoints. Another limitation is that the study does not reflect the whole population for only performed in a single center. Because the center where the recordings are made is in the region with sufficient sunshine during all seasons of the year, further studies are needed for other regions or the whole country.
In conclusion, we have demonstrated in a relatively small population that low vitamin D levels were independent predictors of all-cause mortality in the elderly with chronic HF. This appears to be a treatable condition to improve poor prognosis. Elderly patients with HF may benefit from vitamin D supplementation. There is a need for large randomized studies on this subject in this population.
Conflict of interest
The authors declare that they have no conflict of interest.
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