Vitamin D Deficiency is a Predictor of Survival in HF
Vitamin D Deficiency is a Predictor of Survival in HF
In the present study, we report the prevalence of vitamin D deficiency in a large cohort of HF patients, and describe the seasonal variation in vitamin D levels and the impact of vitamin D deficiency and supplementation on mortality in this population. The present study demonstrates that vitamin D levels are low in the general population and even lower in HF patients. More importantly, vitamin D deficiency was a significant predictor of reduced survival in patients with HF as well as in the control group. Moreover, vitamin D supplementation in HF patients was associated with improved outcome.
Median 25(OH)D levels among patients with HF in the present study were far below what is generally accepted as optimal levels (>75 nmol/L). Twent-eight per cent of this population had significant vitamin D deficiency (<25 nmol/L) and only 8.8% had optimal levels. HF patients had lower levels of vitamin D compared with the general population, although the differences were small. Mean levels reported in a recent small study in the healthy Israeli population >50 years old were quite similar to the levels in our control group. A larger recent study of vitamin D levels in the general Israeli population also showed a high prevalence of vitamin D deficiency, although the reported prevalence was lower than that reported in our study. Nevertheless, the data from this and previous studies give an indication of the magnitude of vitamin D deficiency in a country with abundant solar radiation.
Vitamin D deficiency in the present study was a significant and independent predictor of reduced survival in the HF and the control group, even when adjusted for significant predictors of vitamin D deficiency. Previous studies have shown this to be the case in the general population. However, until recently there was a paucity of data regarding this in patients with HF. A recent study demonstrated that vitamin D deficiency was a significant predictor of all-cause mortality and HF re-hospitalization in patients with mild to moderate HF. The present study demonstrates in a large community cohort of HF patients that vitamin D deficiency was a significant independent predictor of mortality.
Is this finding a marker of more severe disease, or is there a possible contribution of vitamin D deficiency to the pathogenesis of HF or to deterioration in function? Several mechanisms may explain this association. Vitamin D is a fat-soluble hormone, formed from 7-dehydrocholesterol in the skin during exposure to solar ultraviolet B radiation or ingested from dietary sources. It is converted to the active metabolite calcitriol (1,25-hydroxyvitamin D3) in the kidney. Calcitriol binds to a specific nuclear receptor, the vitamin D receptor, which is expressed in most cells, exerting its effects through gene transcription. It primarily regulates calcium homeostasis, but has numerous additional biological effects. Calcitriol is a negative regulator of the renin–angiotensin system and cardiomyocyte proliferation, and suppresses immune and inflammatory responses. All of these processes are important in the development and progression of HF. Calcitriol is also directly involved in calcium-dependent cellular processes, including the synthesis of calcium-binding protein, the activation of adenylate cyclase, the rapid activation of voltage-dependent calcium channels, and the influx, reuptake, and release of calcium from the sarcoplasmic reticulum. This altered intracellular handling of ionized calcium could also contribute to the impaired contractility of the myocardium in HF patients. Strong support for the involvement of vitamin D in the pathogenesis of HF comes from vitamin D receptor knockout mice. These mice develop typical signs of HF including activation of the renin–angiotensin–aldosterone system, cardiac hypertrophy, high blood pressure, and increased levels of atrial natriuretic peptide. In addition, parathyroid hormone is elevated in patients with vitamin D deficiency. Parathyroid hormone has been shown to be an independent predictor of all-cause and cardiovascular mortality in the general population, as well in patients with HF.
Vitamin D deficiency was shown to be a significant predictor of outcome in our study, but vitamin D levels are strongly influenced by the time of the year during which the test is done. Could this influence the outcome? We found that timing of the test in patients with vitamin D deficiency had no influence on outcome, and prognosis was very similar between different seasons. This analysis suggests that vitamin D levels confer prognostic information regardless of the timing of the test.
Although the vitamin D level is an independent predictor of survival in HF patients, insufficient and contradictory data exist regarding the benefit of vitamin D supplementation in this group. In the present study, we found an independent association between vitamin D supplementation and improved outcome in patients with HF. However, this is an association and does not prove a causative effect. A recent meta-analysis demonstrated that vitamin D supplementation in the form of vitamin D(3) decreased mortality in the general population (predominantly elderly women), in agreement with our results. A previous study demonstrated that vitamin D supplementation in HF patients modulated the inflammatory cytokine profile, with a reduction in the pro-inflammatory cytokine tumour necrosis factor-α and an increase in the anti-inflammatory cytokine interleukin-10. However, vitamin D supplementation was not found to improve functional capacity or quality of life in a short-term trial of 105 older patients with HF and vitamin D insufficiency, despite a decrease in brain natriuretic peptide. In addition, vitamin D3 supplement had no additional beneficial effects on markers of bone metabolism in 102 HF patients with low initial 25(OH)D concentrations if an adequate daily calcium intake was guaranteed. Thus, more evidence is needed to prove a benefit of regular vitamin D supplementation to improve cardiac function, quality of life, or mortality in HF patients. Furthermore, a recent public health report on dietary intake requirements for calcium and vitamin D from the American Institute of Medicine emphasizes that there are insufficient data regarding the benefits of vitamin D supplementation on extraskeletal health outcomes, and randomized trials are urgently needed.
We found a definite seasonal variation in vitamin D levels in both HF patients and the control group, with increased levels of 25(OH)D in the summer months compared with the winter months. There was a strong direct relationship between the solar radiation and vitamin D levels in both groups. In addition, decreased solar radiation exposure was a predictor of vitamin D deficiency. In HF patients, the average level was lower than in the control group during most months of the year, but the difference was more pronounced during the summer. It is possible that the lower levels seen in patients with HF are partially related to a greater reduction in sun exposure due to limited functional capacity and outdoor activities, which is more evident in the summer when there is abundant solar radiation. Direct data regarding actual individual sun exposure were not available in this study. The current data emphasize the importance of sun exposure on vitamin D levels in patients with HF and suggest that sun exposure may significantly increase vitamin D levels in these patients.
There was an association between 25(OH)D deficiency and an increased pulse. This is of interest as a previous randomized study showed that treatment with vitamin D supplementation decreased heart rate.
The present study was an observational study with its known limitations. Vitamin D levels were taken from patients at the discretion of the treating physician, and, thus, the data may not reflect the actual prevalence of vitamin D deficiency in the whole population. In particular, there were a higher proportion of females in this cohort (HF and control groups). In addition, the prevalence of diseases such as diabetes and ischaemic heart disease was higher in our control group than the rates reported in the general population.
Another limitation is that this study analysed a single measurement of 25(OH)D and this may not adequately reflect the long-term vitamin D status in these patients. We also did not have data on the specific causes of mortality. The decision to administer vitamin D supplementation was also at the discretion of the treating physician.
In conclusion, vitamin D deficiency is highly prevalent in HF patients as well as in the general population, even in a geographic location with exposure to abundant solar radiation. Vitamin D deficiency was a significant predictor of reduced survival in both HF patients and the control groups. In addition, vitamin D supplementation was associated with increased survival in HF patients.
Discussion
In the present study, we report the prevalence of vitamin D deficiency in a large cohort of HF patients, and describe the seasonal variation in vitamin D levels and the impact of vitamin D deficiency and supplementation on mortality in this population. The present study demonstrates that vitamin D levels are low in the general population and even lower in HF patients. More importantly, vitamin D deficiency was a significant predictor of reduced survival in patients with HF as well as in the control group. Moreover, vitamin D supplementation in HF patients was associated with improved outcome.
Median 25(OH)D levels among patients with HF in the present study were far below what is generally accepted as optimal levels (>75 nmol/L). Twent-eight per cent of this population had significant vitamin D deficiency (<25 nmol/L) and only 8.8% had optimal levels. HF patients had lower levels of vitamin D compared with the general population, although the differences were small. Mean levels reported in a recent small study in the healthy Israeli population >50 years old were quite similar to the levels in our control group. A larger recent study of vitamin D levels in the general Israeli population also showed a high prevalence of vitamin D deficiency, although the reported prevalence was lower than that reported in our study. Nevertheless, the data from this and previous studies give an indication of the magnitude of vitamin D deficiency in a country with abundant solar radiation.
Vitamin D deficiency in the present study was a significant and independent predictor of reduced survival in the HF and the control group, even when adjusted for significant predictors of vitamin D deficiency. Previous studies have shown this to be the case in the general population. However, until recently there was a paucity of data regarding this in patients with HF. A recent study demonstrated that vitamin D deficiency was a significant predictor of all-cause mortality and HF re-hospitalization in patients with mild to moderate HF. The present study demonstrates in a large community cohort of HF patients that vitamin D deficiency was a significant independent predictor of mortality.
Is this finding a marker of more severe disease, or is there a possible contribution of vitamin D deficiency to the pathogenesis of HF or to deterioration in function? Several mechanisms may explain this association. Vitamin D is a fat-soluble hormone, formed from 7-dehydrocholesterol in the skin during exposure to solar ultraviolet B radiation or ingested from dietary sources. It is converted to the active metabolite calcitriol (1,25-hydroxyvitamin D3) in the kidney. Calcitriol binds to a specific nuclear receptor, the vitamin D receptor, which is expressed in most cells, exerting its effects through gene transcription. It primarily regulates calcium homeostasis, but has numerous additional biological effects. Calcitriol is a negative regulator of the renin–angiotensin system and cardiomyocyte proliferation, and suppresses immune and inflammatory responses. All of these processes are important in the development and progression of HF. Calcitriol is also directly involved in calcium-dependent cellular processes, including the synthesis of calcium-binding protein, the activation of adenylate cyclase, the rapid activation of voltage-dependent calcium channels, and the influx, reuptake, and release of calcium from the sarcoplasmic reticulum. This altered intracellular handling of ionized calcium could also contribute to the impaired contractility of the myocardium in HF patients. Strong support for the involvement of vitamin D in the pathogenesis of HF comes from vitamin D receptor knockout mice. These mice develop typical signs of HF including activation of the renin–angiotensin–aldosterone system, cardiac hypertrophy, high blood pressure, and increased levels of atrial natriuretic peptide. In addition, parathyroid hormone is elevated in patients with vitamin D deficiency. Parathyroid hormone has been shown to be an independent predictor of all-cause and cardiovascular mortality in the general population, as well in patients with HF.
Vitamin D deficiency was shown to be a significant predictor of outcome in our study, but vitamin D levels are strongly influenced by the time of the year during which the test is done. Could this influence the outcome? We found that timing of the test in patients with vitamin D deficiency had no influence on outcome, and prognosis was very similar between different seasons. This analysis suggests that vitamin D levels confer prognostic information regardless of the timing of the test.
Although the vitamin D level is an independent predictor of survival in HF patients, insufficient and contradictory data exist regarding the benefit of vitamin D supplementation in this group. In the present study, we found an independent association between vitamin D supplementation and improved outcome in patients with HF. However, this is an association and does not prove a causative effect. A recent meta-analysis demonstrated that vitamin D supplementation in the form of vitamin D(3) decreased mortality in the general population (predominantly elderly women), in agreement with our results. A previous study demonstrated that vitamin D supplementation in HF patients modulated the inflammatory cytokine profile, with a reduction in the pro-inflammatory cytokine tumour necrosis factor-α and an increase in the anti-inflammatory cytokine interleukin-10. However, vitamin D supplementation was not found to improve functional capacity or quality of life in a short-term trial of 105 older patients with HF and vitamin D insufficiency, despite a decrease in brain natriuretic peptide. In addition, vitamin D3 supplement had no additional beneficial effects on markers of bone metabolism in 102 HF patients with low initial 25(OH)D concentrations if an adequate daily calcium intake was guaranteed. Thus, more evidence is needed to prove a benefit of regular vitamin D supplementation to improve cardiac function, quality of life, or mortality in HF patients. Furthermore, a recent public health report on dietary intake requirements for calcium and vitamin D from the American Institute of Medicine emphasizes that there are insufficient data regarding the benefits of vitamin D supplementation on extraskeletal health outcomes, and randomized trials are urgently needed.
We found a definite seasonal variation in vitamin D levels in both HF patients and the control group, with increased levels of 25(OH)D in the summer months compared with the winter months. There was a strong direct relationship between the solar radiation and vitamin D levels in both groups. In addition, decreased solar radiation exposure was a predictor of vitamin D deficiency. In HF patients, the average level was lower than in the control group during most months of the year, but the difference was more pronounced during the summer. It is possible that the lower levels seen in patients with HF are partially related to a greater reduction in sun exposure due to limited functional capacity and outdoor activities, which is more evident in the summer when there is abundant solar radiation. Direct data regarding actual individual sun exposure were not available in this study. The current data emphasize the importance of sun exposure on vitamin D levels in patients with HF and suggest that sun exposure may significantly increase vitamin D levels in these patients.
There was an association between 25(OH)D deficiency and an increased pulse. This is of interest as a previous randomized study showed that treatment with vitamin D supplementation decreased heart rate.
Limitations of This Study
The present study was an observational study with its known limitations. Vitamin D levels were taken from patients at the discretion of the treating physician, and, thus, the data may not reflect the actual prevalence of vitamin D deficiency in the whole population. In particular, there were a higher proportion of females in this cohort (HF and control groups). In addition, the prevalence of diseases such as diabetes and ischaemic heart disease was higher in our control group than the rates reported in the general population.
Another limitation is that this study analysed a single measurement of 25(OH)D and this may not adequately reflect the long-term vitamin D status in these patients. We also did not have data on the specific causes of mortality. The decision to administer vitamin D supplementation was also at the discretion of the treating physician.
In conclusion, vitamin D deficiency is highly prevalent in HF patients as well as in the general population, even in a geographic location with exposure to abundant solar radiation. Vitamin D deficiency was a significant predictor of reduced survival in both HF patients and the control groups. In addition, vitamin D supplementation was associated with increased survival in HF patients.
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