The role of vitamin D in the pathological mechanism of metabolic diseases. Vitamin D and cardiovascular diseases
Marlena Dudek-Makuch, Pharm. D., Development Expert, Curtis Health Caps
Vitamin D is primarily known for its role in the intestinal absorption of calcium and in bone mineralization. But the observation of seasonal changes in blood pressure and the subsequent identification of vitamin D receptor (VDR) and an enzyme involved in vitamin D metabolism (1α-hydroxylase) in cardiac muscle cells (cardiomyocytes), endothelial cells, and smooth muscle cells of the vascular walls suggest that vitamin D is also involved in the cardiovascular system. Animal studies have provided strong evidence that vitamin D is crucial for ensuring the integrity of the cardiovascular system, especially for regulating vascular tone and preventing fibrosis and hypertrophy. Epidemiological data suggest that vitamin D insufficiency in humans results in arterial stiffness, hypertension, left ventricular hypertrophy and endothelial dysfunction, lending credence to the belief that vitamin D can have a protective effect in cardiovascular diseases and reduce the risk of heart failure .
The observed correlation between high blood pressure and the levels of the vitamin D metabolite 25(OH)D served as a starting point for a debate over the role of vitamin D in the pathogenesis of cardiovascular diseases. As suggested by experimental data, a large number of observational studies confirm that vitamin D can protect against hypertension .
One of the factors contributing to hypertension is endothelial dysfunction. Experimental research prove the importance of vitamin D in regulating endothelial function. One of its suggested mechanisms of action is activating the renin-angiotensin-aldosterone system (RAAS). Vitamin D works as an endocrine regulator, inhibiting the expression of the renin gene. Reduced renin synthesis and RAAS inhibition contribute to the control of circulating blood volume and prevent hypertension [3, 4].
Another vitamin D-mediated mechanism of modulating vascular tone is inhibition of cyclooxygenase 1 (COX-1) synthesis in endothelial cells, which results in reduced synthesis of endothelium-derived vascular contracting factors .
It has been shown that hypertensive patients exposed to UVB radiation three times a week for six weeks during winter time exhibited increased vitamin D levels and a significant reduction in blood pressure values. A correlation has also been established between supplementation of vitamin D and calcium at 1600 IU and 800 mg, respectively, and a 9% reduction in blood pressure in elderly women .
A meta-analysis of prospective studies, which covered a total of 283,537 subjects, including 55,816 patients with hypertension, revealed that subjects with the highest levels of 25(OH)D had a 30% lower risk of developing arterial hypertension .
Atherosclerosis is caused by a multitude of factors, including genetic and environmental ones. Major contributors include hypertension and elevated blood levels of low density lipoprotein (LDL). A number of experimental and clinical studies confirm that vitamin D can modulate the pathogenesis of atherosclerosis.
Increased concentration of LDL causes it to be modified and absorbed by macrophages, which leads to the formation of foam cells, a characteristic feature of progressing atherosclerosis. Vitamin D has been shown to decrease LDL uptake and cholesterol accumulation in macrophages, slowing down atherosclerotic plaque formation and progression of the disease .
Vitamin D can also influence the pathophysiology of atherosclerosis by modulating inflammatory response and down-regulating the expression of proinflammatory factors such as TNFα, IL-6, IL-1, and IL-8 in isolated monocytes [5, 9]. In addition, vitamin D modulates the expression of thrombomodulin, regulating platelet aggregation and thrombogenic activity, and a deficiency of the vitamin can increase coagulation and the risk of embolism.
An extensive study by the National Health and Nutrition Examination Survey (2001–2004), which involved 4,839 subjects, revealed a higher prevalence of peripheral arterial disease (PAD), associated with reduced blood supply to the lower extremities, in subjects with low serum 25(OH)D levels .
While clinical evidence to support vitamin D’s beneficial effects in preventing atherosclerosis may not always be unequivocal, considering the well-established role of the vitamin in inhibiting the formation of foam cells and modulating the synthesis of prostaglandins, including vasoconstriction and coagulation factors, vitamin D can be assumed to contribute to reducing the risk of atherosclerosis.
Literature also suggests that hypovitaminosis D is associated with congestive heart failure, acute myocardial infarction and ischaemic heart disease. This is often explained by the fact that 1,25(OH)2D has a considerable metabolic effect on cardiomyocytes, smooth muscle cells, and vascular endothelium, and its deficiency can result in left ventricular hypertrophy, among other things .
Brøndum-Jacobsen et al. conducted a 29-year-long study aimed at demonstrating the association between vitamin D insufficiency and the incidence of ischaemic heart disease, myocardial infarction, and early death. The study covered 10,170 Danish residents. It demonstrated that low vitamin D levels were associated with an increased risk of heart disease; the risk of ischaemic heart disease was found to increase by 72%, the risk of myocardial infarction by 99% and that of early death by 88%.
In a meta-analysis of 18 observational studies involving 82,982 healthy individuals, the risk of ischaemic heart disease was found to be 39% higher in subjects with vitamin D insufficiency .
Another meta-analysis, covering 28 observational studies (a total of 99,745 subjects), revealed that high levels of 25(OH)D are associated with a lower incidence of cardiometabolic disorders .
Numerous studies conducted both on animal models and in humans suggest a number of possible mechanisms by which vitamin D can affect the cardiovascular system, either preventing or improving prognosis in conditions such as ischaemic heart disease, arterial hypertension, atherosclerosis or heart failure. Sadly, there are no specific guidelines for vitamin D supplementation in cardiovascular disease patients, who are therefore advised to follow the general recommendations, i.e. keeping the target serum 25(OH)D levels at 30-50 ng/ml (75–125 nmol/l). There is a significant need for more research into vitamin D’s role in the cardiovascular system, which could inform the development of guidance on preventive and therapeutic vitamin D supplementation in patients with cardiovascular diseases.
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Marlena Dudek-Makuch, PhD (Pharm.), MSc, has 20 years of professional experience in phytochemical and biological research, and scientific information (assistant professor at the Department of Pharmacognosy, Poznań University of Medical Sciences). She is an author of research and review papers on the isolation and identification of compounds of plant origin, and evaluation of their biological activity. Since 2015, she has been teaching a postgraduate course in “Herbs in practice and therapy”.
She is currently a member of the Regulatory Department, R&D Division, at CHC. In her position, she is in charge of preparing expert reports (clinical, non-clinical) for medicinal products, clinical reports for OTC switches, clinical assessments of medical devices, pharmacovigilance activities for medical devices, and safety assessment of plant-based raw materials used in medicinal products, medical devices, and dietary supplements.
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