Vitamin D and Cardiovascular Disease
Vitamin D and Cardiovascular Disease
Although evidence confirms a robust association between vitamin D status and several cardiovascular disorders, a causal relationship remains to be fully elucidated. Mechanisms by which vitamin D deficiency may confer increased cardiovascular risk include the development of electrolyte imbalances, pancreatic β-cell dysfunction, and RAS activation. In addition, disrupted adaptive immune responses with severe vitamin D deficiency result in an inflammatory milieu that promotes vascular dysfunction and insulin resistance. Indeed, most epidemiological studies have reported an inverse relationship between vitamin D status and the prevalence of established cardiovascular risk factors such as age, hypertension, diabetes, and hypertriglyceridaemia (Table 1). Serum 25-OH D levels are also lower in women, in obesity, and in those with decreased physical activity.
The association between vitamin D deficiency and elevated blood pressure perhaps offers the most convincing evidence for the involvement of vitamin D metabolism in the pathogenesis of cardiovascular disease. A cause–effect relationship is postulated based on experimental and translational evidence demonstrating vital modulatory effects of vitamin D on the RAS axis.
For example, studies in normotensive and hypertensive subjects reveal an inverse relationship between vitamin D metabolites and plasma renin activity, regardless of baseline renin levels or salt intake. In addition, dietary salt loading results in blood pressure increases that are worse with vitamin D deficiency, and are positively correlated with calcitriol synthesis. Importantly, high-dose cholecalciferol therapy (15 000 IU/day for 1 month) in obese, hypertensive patients increased renal plasma flow (RPF) and decreased mean arterial pressure. Moreover, infusion of angiotensin II following cholecalciferol therapy resulted in a greater RPF decline and higher aldosterone secretion when compared with pre-treatment infusions. This is similar to established findings of increased tissue sensitivity to angiotensin following RAS antagonist therapy.
RAS activation and subsequent synthesis of angiotensin II are known to increase vascular tone and arterial stiffness, which precede and contribute to the development of hypertension and are also strong predictors of overall CVD risk. In this context, we observed a higher augmentation index (AIX) and a lower subendocardial viability ratio (SEVR), both considered as complex and composite markers of arterial wave reflections and systemic stiffening with lower 25-OH D levels, independent of concomitant vascular risk factors in healthy subjects (Figure 3). Furthermore, those with a normalized vitamin D status after 6 months exhibited significant improvements in vascular function measurements.
(Enlarge Image)
Figure 3.
Relationship between 25-OH D levels, arterial stiffness, and vascular function. 25-OH D, 25-hydroxyvitamin D. RHI, reactive hyperaemia index; FMD, brachial artery flow-mediated dilation (percentage points); PWV, pulse wave velocity; AIX, augmentation index; SEVR, subendocardial viability ratio. Error bars represent mean and standard error of predicted values adjusted for age, gender, race, body mass index, total cholesterol, low-density lipoprotein, triglycerides, C-reactive protein, and medication use. r, Pearson's correlation. n = 554 (54% men).
In the same way, measures of arterial stiffness inversely correlated with vitamin D status in the Baltimore Longitudinal Study of Aging and in a British multiethnic study, as well as in studies looking specifically at patients with diabetes, rheumatological conditions, peripheral arterial disease, and renal insufficiency. However, only a few studies examined effects of vitamin D therapy on vascular function, and so far results have been contradictory.
Thus, current evidence indicates that vitamin D deficiency may promote vascular dysfunction and sustained RAS activation, while sufficient levels may afford "endogenous," proximal inhibition.
The third National Health and Nutrition Examination (NHANES III) looked at serum 25-OH D in relation to CVD risk factors in over 13 000 US adults. After multivariable adjustment, those with 25-OH D levels in the lowest quartile had a significantly higher prevalence of hypertension compared with those in the highest quartile, and sufficient levels attenuated the expected age-related increases in blood pressure. Other population studies, including the 1958 British Birth Cohort and the German National Health Survey and Examination, confirm this inverse relationship.
Moreover, in two prospective cohorts of healthcare professionals, the risk of incident hypertension was increased by three-fold in those with 25-OH D <15 ng/mL compared with those with levels >30 ng/mL. Similarly, in a study that estimated 25-OH D levels based on dietary surveys in over 110 000 healthcare professionals, those with low "predicted" 25-OH D levels had a higher incidence of hypertension during nearly 16 years of follow-up.
The cardiovascular benefits of vitamin D therapy in those with chronic kidney disease and hyperparathyroidism have been long recognized, including blood pressure reduction, improved electrolyte balance, and an overall reduced cardiovascular mortality in haemodialysis patients.
It is less clear if vitamin D therapy in essential hypertension, without overt kidney disease or electrolyte disturbances, will provide similar benefits. Trials reporting these measurements have either shown no blood pressure changes or small reductions in BP; however, these were limited by small and heterogeneous study samples, widely variable dosing strategies, and a short duration of follow-up. Several meta-analyses and systematic reviews have also arrived at conflicting conclusions; while a net significant hypotensive effect of vitamin D replacement was reported by some, others found either no change or only reductions in systolic BP, which may be apparent in specific subgroups such as those with vitamin D deficiency at baseline.
Another complication in determining effects of vitamin D on blood pressure is that exposure to UV light also causes reductions in blood pressure, independent of vitamin D photosynthesis. Significant, immediate hypotensive effects of erythaemal and pre-erythaemal doses of UV irradiation have been demonstrated in both normotensive and hypertensive subjects. These effects are likely to be the result of overall decreases in vascular resistance with diffuse skin vasodilatation, and this "photorelaxation" is thought to be partly mediated by increased nitric oxide release in cutaneous vascular beds.
Vitamin D deficiency is associated with disorders of insulin synthesis, secretion, and sensitivity. Experimental evidence highlights mechanisms by which vitamin D may influence glycaemic control; these include modulation of pancreatic RAS activity and regulation of calcium ion traffic across β-cells that directly affect insulin synthesis and secretion. Furthermore, vitamin D deficiency results in aberrant immune responses that precipitate an inflammatory milieu and subsequent insulin resistance.
However, discrepancies in experimental and clinical evidence underscore knowledge gaps in determining the relationship between vitamin D metabolism and glycaemic control. For example, while human adipocytes express membrane-bound VDR that modulates lipolysis and lipogenesis activity in vitro, VDR null murine models exhibit a lean phenotype and increased energy expenditure, associated with adipose tissue atrophy. Further, models heterozygous for VDR show a similar, albeit less severe phenotype. Alternatively, increased adiposity and body fat mass observed in most insulin-resistant subjects may partly account for the lower 25-OH D levels seen in this population, as lipid-soluble vitamin D may be sequestered in adipose tissue, thus decreasing 25-OH D bioavailability.
Many retrospective, cross-sectional, case–control, and prospective studies demonstrate a higher incidence and prevalence of type I diabetes mellitus with depressed vitamin D status. Similarly, low serum 25-OH D correlates with insulin resistance, obesity, aberrant phasing of insulin responses to glucose loading, glucose intolerance, fasting hyperglycaemia, and frank type II diabetes mellitus.
Observational, case–control, and prospective evidence strongly suggests that supplementing infants with vitamin D may significantly reduce the future incidence of type I diabetes. Dosage and timing of therapy appear to modulate this protective effect. The evidence for type II diabetes is weaker. Recent results from the Women's Health Initiative in which 33 591 postmenopausal women were randomized to both daily calcium and cholecalciferol (1 g and 400 IU, respectively) or placebo demonstrated no primary prevention benefit of vitamin therapy in 2291 incident cases of diabetes mellitus after 7 years of follow-up. Limitations of this study include study subjects' enrolment in additional dietary and hormonal interventions, inclusion of subjects already taking vitamin D supplements and the exclusion of men.
While several smaller and non-randomized clinical trials show promising improvements in glycaemic control with vitamin D therapy, a recent Endocrine Society statement emphasized the lack of solid evidence supporting benefits of vitamin D therapy in diabetes mellitus.
Other potential consequences of vitamin D metabolism on human vasculature derive from several lines of experimental investigation and include exacerbation of atherogenesis and acceleration of arterial calcification. For example, the established anti-lymphoproliferative effects of vitamin D extend to regulation of monocyte/macrophage differentiation and the concomitant response to, and secretion of, inflammatory cytokines. This in turn may determine monocyte infiltration and cholesterol retention in the vascular wall and may corroborate clinical evidence of increased plaque instability and incident myocardial infarctions in vitamin D-deficient patients, in addition to the observed improvements in inflammatory biomarker levels in heart failure patients following vitamin D therapy.
Additionally, aberrant vitamin D signalling induced in murine models caused extensive calcification of medium and small sized arteries, resembling human age-related Mönckeberg's disease. In humans, vitamin D deficiency independently predicted prevalence, incidence, and progression of coronary calcification in 374 diabetic patients over 6 years of follow-up. Similar to experimental studies that show endothelial cell function modulation by vitamin D analogues; indices of endothelial function and microvascular reactivity assessed as brachial-artery flow-mediated dilation and reactive hyperaemia index, respectively, were independently correlated with 25-OH D levels in a study we conducted in asymptomatic individuals (Figure 3).
Cardiovascular Diseases and Vitamin D
Although evidence confirms a robust association between vitamin D status and several cardiovascular disorders, a causal relationship remains to be fully elucidated. Mechanisms by which vitamin D deficiency may confer increased cardiovascular risk include the development of electrolyte imbalances, pancreatic β-cell dysfunction, and RAS activation. In addition, disrupted adaptive immune responses with severe vitamin D deficiency result in an inflammatory milieu that promotes vascular dysfunction and insulin resistance. Indeed, most epidemiological studies have reported an inverse relationship between vitamin D status and the prevalence of established cardiovascular risk factors such as age, hypertension, diabetes, and hypertriglyceridaemia (Table 1). Serum 25-OH D levels are also lower in women, in obesity, and in those with decreased physical activity.
Vitamin D and Hypertension
The association between vitamin D deficiency and elevated blood pressure perhaps offers the most convincing evidence for the involvement of vitamin D metabolism in the pathogenesis of cardiovascular disease. A cause–effect relationship is postulated based on experimental and translational evidence demonstrating vital modulatory effects of vitamin D on the RAS axis.
For example, studies in normotensive and hypertensive subjects reveal an inverse relationship between vitamin D metabolites and plasma renin activity, regardless of baseline renin levels or salt intake. In addition, dietary salt loading results in blood pressure increases that are worse with vitamin D deficiency, and are positively correlated with calcitriol synthesis. Importantly, high-dose cholecalciferol therapy (15 000 IU/day for 1 month) in obese, hypertensive patients increased renal plasma flow (RPF) and decreased mean arterial pressure. Moreover, infusion of angiotensin II following cholecalciferol therapy resulted in a greater RPF decline and higher aldosterone secretion when compared with pre-treatment infusions. This is similar to established findings of increased tissue sensitivity to angiotensin following RAS antagonist therapy.
RAS activation and subsequent synthesis of angiotensin II are known to increase vascular tone and arterial stiffness, which precede and contribute to the development of hypertension and are also strong predictors of overall CVD risk. In this context, we observed a higher augmentation index (AIX) and a lower subendocardial viability ratio (SEVR), both considered as complex and composite markers of arterial wave reflections and systemic stiffening with lower 25-OH D levels, independent of concomitant vascular risk factors in healthy subjects (Figure 3). Furthermore, those with a normalized vitamin D status after 6 months exhibited significant improvements in vascular function measurements.
(Enlarge Image)
Figure 3.
Relationship between 25-OH D levels, arterial stiffness, and vascular function. 25-OH D, 25-hydroxyvitamin D. RHI, reactive hyperaemia index; FMD, brachial artery flow-mediated dilation (percentage points); PWV, pulse wave velocity; AIX, augmentation index; SEVR, subendocardial viability ratio. Error bars represent mean and standard error of predicted values adjusted for age, gender, race, body mass index, total cholesterol, low-density lipoprotein, triglycerides, C-reactive protein, and medication use. r, Pearson's correlation. n = 554 (54% men).
In the same way, measures of arterial stiffness inversely correlated with vitamin D status in the Baltimore Longitudinal Study of Aging and in a British multiethnic study, as well as in studies looking specifically at patients with diabetes, rheumatological conditions, peripheral arterial disease, and renal insufficiency. However, only a few studies examined effects of vitamin D therapy on vascular function, and so far results have been contradictory.
Thus, current evidence indicates that vitamin D deficiency may promote vascular dysfunction and sustained RAS activation, while sufficient levels may afford "endogenous," proximal inhibition.
Vitamin D Deficiency and Epidemiology of Hypertension
The third National Health and Nutrition Examination (NHANES III) looked at serum 25-OH D in relation to CVD risk factors in over 13 000 US adults. After multivariable adjustment, those with 25-OH D levels in the lowest quartile had a significantly higher prevalence of hypertension compared with those in the highest quartile, and sufficient levels attenuated the expected age-related increases in blood pressure. Other population studies, including the 1958 British Birth Cohort and the German National Health Survey and Examination, confirm this inverse relationship.
Moreover, in two prospective cohorts of healthcare professionals, the risk of incident hypertension was increased by three-fold in those with 25-OH D <15 ng/mL compared with those with levels >30 ng/mL. Similarly, in a study that estimated 25-OH D levels based on dietary surveys in over 110 000 healthcare professionals, those with low "predicted" 25-OH D levels had a higher incidence of hypertension during nearly 16 years of follow-up.
Vitamin D Therapy in Hypertension
The cardiovascular benefits of vitamin D therapy in those with chronic kidney disease and hyperparathyroidism have been long recognized, including blood pressure reduction, improved electrolyte balance, and an overall reduced cardiovascular mortality in haemodialysis patients.
It is less clear if vitamin D therapy in essential hypertension, without overt kidney disease or electrolyte disturbances, will provide similar benefits. Trials reporting these measurements have either shown no blood pressure changes or small reductions in BP; however, these were limited by small and heterogeneous study samples, widely variable dosing strategies, and a short duration of follow-up. Several meta-analyses and systematic reviews have also arrived at conflicting conclusions; while a net significant hypotensive effect of vitamin D replacement was reported by some, others found either no change or only reductions in systolic BP, which may be apparent in specific subgroups such as those with vitamin D deficiency at baseline.
Another complication in determining effects of vitamin D on blood pressure is that exposure to UV light also causes reductions in blood pressure, independent of vitamin D photosynthesis. Significant, immediate hypotensive effects of erythaemal and pre-erythaemal doses of UV irradiation have been demonstrated in both normotensive and hypertensive subjects. These effects are likely to be the result of overall decreases in vascular resistance with diffuse skin vasodilatation, and this "photorelaxation" is thought to be partly mediated by increased nitric oxide release in cutaneous vascular beds.
Vitamin D and Diabetes Mellitus
Vitamin D deficiency is associated with disorders of insulin synthesis, secretion, and sensitivity. Experimental evidence highlights mechanisms by which vitamin D may influence glycaemic control; these include modulation of pancreatic RAS activity and regulation of calcium ion traffic across β-cells that directly affect insulin synthesis and secretion. Furthermore, vitamin D deficiency results in aberrant immune responses that precipitate an inflammatory milieu and subsequent insulin resistance.
However, discrepancies in experimental and clinical evidence underscore knowledge gaps in determining the relationship between vitamin D metabolism and glycaemic control. For example, while human adipocytes express membrane-bound VDR that modulates lipolysis and lipogenesis activity in vitro, VDR null murine models exhibit a lean phenotype and increased energy expenditure, associated with adipose tissue atrophy. Further, models heterozygous for VDR show a similar, albeit less severe phenotype. Alternatively, increased adiposity and body fat mass observed in most insulin-resistant subjects may partly account for the lower 25-OH D levels seen in this population, as lipid-soluble vitamin D may be sequestered in adipose tissue, thus decreasing 25-OH D bioavailability.
Vitamin D Deficiency and Epidemiology of Diabetes Mellitus
Many retrospective, cross-sectional, case–control, and prospective studies demonstrate a higher incidence and prevalence of type I diabetes mellitus with depressed vitamin D status. Similarly, low serum 25-OH D correlates with insulin resistance, obesity, aberrant phasing of insulin responses to glucose loading, glucose intolerance, fasting hyperglycaemia, and frank type II diabetes mellitus.
Vitamin D Therapy in Diabetes Mellitus
Observational, case–control, and prospective evidence strongly suggests that supplementing infants with vitamin D may significantly reduce the future incidence of type I diabetes. Dosage and timing of therapy appear to modulate this protective effect. The evidence for type II diabetes is weaker. Recent results from the Women's Health Initiative in which 33 591 postmenopausal women were randomized to both daily calcium and cholecalciferol (1 g and 400 IU, respectively) or placebo demonstrated no primary prevention benefit of vitamin therapy in 2291 incident cases of diabetes mellitus after 7 years of follow-up. Limitations of this study include study subjects' enrolment in additional dietary and hormonal interventions, inclusion of subjects already taking vitamin D supplements and the exclusion of men.
While several smaller and non-randomized clinical trials show promising improvements in glycaemic control with vitamin D therapy, a recent Endocrine Society statement emphasized the lack of solid evidence supporting benefits of vitamin D therapy in diabetes mellitus.
The Role of Vitamin D in Modulating Adaptive Immunity, Vascular Inflammation, and Endothelial Function
Other potential consequences of vitamin D metabolism on human vasculature derive from several lines of experimental investigation and include exacerbation of atherogenesis and acceleration of arterial calcification. For example, the established anti-lymphoproliferative effects of vitamin D extend to regulation of monocyte/macrophage differentiation and the concomitant response to, and secretion of, inflammatory cytokines. This in turn may determine monocyte infiltration and cholesterol retention in the vascular wall and may corroborate clinical evidence of increased plaque instability and incident myocardial infarctions in vitamin D-deficient patients, in addition to the observed improvements in inflammatory biomarker levels in heart failure patients following vitamin D therapy.
Additionally, aberrant vitamin D signalling induced in murine models caused extensive calcification of medium and small sized arteries, resembling human age-related Mönckeberg's disease. In humans, vitamin D deficiency independently predicted prevalence, incidence, and progression of coronary calcification in 374 diabetic patients over 6 years of follow-up. Similar to experimental studies that show endothelial cell function modulation by vitamin D analogues; indices of endothelial function and microvascular reactivity assessed as brachial-artery flow-mediated dilation and reactive hyperaemia index, respectively, were independently correlated with 25-OH D levels in a study we conducted in asymptomatic individuals (Figure 3).
