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How Vitamin D Protects the Cardiovascular System


How Vitamin D Protects the Cardiovascular System

Vitamin D receptors (VDRs) were found in many cells throughout the body, including endothelium, vascular smooth muscle, and cardiomyocytes, so the role of vitamin D in health role maintenance is beginning to expand, even though its classic function has been to increase the intestinal absorption of calcium for proper bone health.

Individuals with vitamin D deficiency have increased incidence of CVD, and this was the result of studies conducted recently. There are two biologically inactive precursors in the term "vitamin D"; while vitamin D2 (ergocalciferol) is produced exogenously and enters the circulation solely after gastrointestinal absorption, vitamin D3 (cholecalciferol) is produced mainly in the skin post exposure to UV radiation.  To form the biologically active metabolite of vitamin D, 1,25 (OH) 2D (calcitriol), hydroxylation reactions in the liver and kidney are required by both vitamin  D2 and  D3; these reactions are closely regulated by the parathyroid hormone (PTH). 25(OH)D concentrations or levels are the best in measuring vitamin D status, and they are better than calcitriol levels in this for many reasons such as higher circulating serum concentrations, longer half-life, i.e. 3 weeks compared to 8 hours for calcitriol, and tight regulation of calcitriol by PTH, which causes false elevation of calcitriol levels despite vitamin D deficiency. It has been suggested that concentrations above 30 ng/mL are associated with decreased fracture rates and maximal parathyroid suppression, even though until now there are no "normal" measure of 25(OH)D levels that is universally accepted.

 

Prevalence:

Vitamin D deficiency is more prevalent than previously anticipated, as indicated by a large body of evidence. Vitamin D deficiency accounts for over 40% in men and over 50% in women in the U.S., according to data from the Third National Health and Nutrition Examination Survey (NHANES III). Moreover, it was revealed that vitamin D deficiency (less than 30 ng/mL) was more common in old people, women, and ethnic or racial minorities, and in patients with diabetes mellitus, hypercholesterolemia, hypertension, and hypertriglyceridemia. Up to 50% of young adults and healthy children have vitamin D deficiency as well according to other studies.

 

Foods that naturally contain vitamin D are limited, such as sardines, mackerel, cod liver oil, and salmon; and there are a few foods that are fortified with vitamin D, such as some breads and cereals, orange juice, and milk; this causes the increase in prevalence of deficiency in patients of all age groups in some countries.

 

The risk of vitamin D deficiency depends on latitude, altitude, geography and seasonality, which links increased prevalence to reduced exposure to sunlight. In areas of increased geographic latitude and during the winter months, CVD risk is noted to be higher as well, so the need for investigation of the relationship between vitamin D and CVD risk is further supported with these notes.

 

Hyperparathyroidism and Increased CVD Risk:

In humans, secondary hyperparathyroidism (SHPT) in end-stage renal disease (ESRD) originates from vitamin D deficiency, resulting in increased risk for CVD; this is supported with strong evidence. With the threshold for PTH elevation being the 25(OH)D concentration of less than 30 ng/mL, the concentrations of 25(OH)D are inversely related to PTH levels. The decrease in calcium levels triggers PTH release when 25(OH)D concentrations decrease below 30 ng/mL, and this results in transport of calcium from bone and an increase in renal tubular calcium reabsorption in an attempt to elevate serum calcium levels; all of this inevitably leads to elevating renal production of 1,25(OH)D.

 

SHPT will result when sufficient amounts of 1,25(OH)D cannot be produced in dialysis patients, and those with stage 4 or 5 chronic kidney disease CKD with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m. SHPT is considered an important risk factor for the development of CVD in patients with ESRD. Patients who receive hemodialysis or peritoneal dialysis are at 10 to 20 times more susceptible to adjusted cardiovascular mortality when compared with general population.

 

There is a large body of evidence explaining that the increase in CVD is related to calcification of the heart valves, myocardium and mitral annulus, even though the link between ESRD and CVD is likely multifactorial. One study has revealed that the incidence of CVD was two times higher in patients with a PTH level more than 250 pg/mL, than in patients with PTH levels of less than 250 pg/mL, demonstrating the effect of SHPT on CVD outcomes. Compared to patients with normal PTH levels, CVD-related mortality rates doubled in those patients with elevated PTH, which was demonstrated in another observational study in elderly individuals. Moreover, improved outcomes were demonstrated by studies that evaluated the repletion of vitamin D levels in patients with CKD. One study found that supplementation with 1alpha-hydroxyvitamin D3 at 0.25 to 1.5 mcg in patients with ESRD who were undergoing hemodialysis significantly lowered the risk of death from CVD (P = .003). Supplementation with oral 1,25(OH)2D3 (calcitriol) has been shown in a recent study in patients with CKD and SHPT to improve overall survival significantly.

 

Atherosclerosis and Inflammation:

The effect of elevated PTH levels induced by vitamin D deficiency on CVD risk in the absence of ESRD continues to be under investigation, despite the fact that the association of ESRD and increased CVD risk has been well documented. 654 adults between the ages of 55 and 96 years without a history of stroke, coronary heart disease, or revascularization were evaluated in a recent cross-sectional study, with results showing that those with higher concentrations of 25(OH)D had a significantly dose-dependent decrease of the intima-media wall thickness of the carotid artery (P = .036), linking vitamin D deficiency to the development of subclinical atherosclerosis. Research stating that vitamin D deficiency increases systemic inflammation, as confirmed by elevated levels of C-reactive protein and inerleukin-10, supported this finding. Moreover, it has been shown that administration of vitamin D analogues downregulated the inflammatory markers and reduced plaque production and instability.

 

Hypertension:

Hypertension is a well-known risk factor for CVD, and it may be the result of the upregulating in rennin-angiotensin-aldosterone system (RAAS), which is in turn the result of vitamin D deficiency and insufficiency. Increased serum angiotensin-converting enzyme levels, tissue rennin content, and increased blood pressure were observed in vitamin D receptor knockout mouse models in an animal study emulating vitamin D deficiency. Studies that were conducted on humans showed that 1,25(OH)2D has an inhibitory effect on rennin synthesis that decreases blood pressure. In a study conducted on patients that were exposed to UVB radiation in a tanning bed 3 times per week for a total of 3 months, serum 25(OH)D levels elevated above 100 nmol/L and blood pressure decreased by 6 mmHg in hypertensive patients, as a result of their exposure to UVB, but not UVA, radiation on a regular basis. Compared to calcium alone, supplementation with vitamin D and calcium resulted in a significant increase in 25(OH)D concentrations (P <.01), a decrease in blood pressure by 9.3% (P <.025), a decrease in  heart rate by 5.4% (P <.025), and a decrease in  PTH levels (P <.05), as shown by another study in elderly women. Moreover, compared to patients with lower concentrations, individuals with higher serum 25(OH)D concentrations had a self-reported mean systolic blood pressure approximately 3 mmHg lower; this was found by  NHANES III study.

 

In contrast, no such benefits of vitamin D supplementation on blood pressure decline were noted in many smaller studies. In women randomized to receive vitamin D (400 IU) and calcium at the end of a 7-year follow-up period, no blood pressure changes were noted, and this was in the Women's Health Initiative study that was recently conducted. But the vitamin D dose administered to study subjects was lower than recommended in clinical practice; supplementation is recommended to be at least 800 IU daily for adults who are over 70 years. Besides, study subjects had low adherence to the study drug, as the authors reported. To clarify the clinical importance of vitamin D supplementation as an antihypertensive agent, further studies are needed, but these results should not be ignored.

 

Diabetes and Metabolic Syndrome:

The association between vitamin D deficiency and metabolic syndrome, glucose intolerance, and obesity is another proposed mechanism for increased CVD risk, as shown in many animal and human cross-sectional studies. There is a relationship between normal insulin secretion from the pancreatic beta-cells and vitamin D, which is a fact that has been known for several years. Resulting in increased insulin production, it is proposed that the pancreas possesses the VDR gene and therefore has the ability to convert circulating 25(OH)D to 1,25(OH)2D. The risk of developing both obesity and diabetes mellitus increase by allelic variation in the VDR gene as shown in studies. Other studies have proposed that increased body fat causes sequestration of vitamin D in adipose tissue, which lowers serum vitamin D concentrations and ultimately leads to metabolic syndrome and insulin resistance. A 60% increase in insulin sensitivity in individuals with serum concentrations of 25(OH)D of 30 ng/mL compared to 10 ng/mL was observed in one study, and concentrations less than 20 ng/mL were associated with decreased beta-cell function. Compared to individuals with concentrations above 37 ng/mL, those with a 25(OH)D concentrations of less than 21 ng/mL doubled their odds ratio for diabetes, as found by the NHANES III study. Additionally, the risk of type 2 diabetes was reduced in individuals receiving higher doses of vitamin D daily by one-third, in a study comparing daily intake of 800 IU of vitamin D vs. less than 400 IU of vitamin D. Even though the evidence is limited, but it is intriguing. To determine the role of vitamin D in the prevention or treatment of diabetes and metabolic syndrome, future clinical trials are needed.

 

Correlation between Vitamin D and Cardiovascular Events:

A low 25(OH)D concentration is closely associated with CVD, an observation indicated by the literature. The protective effects of vitamin D on the cardiovascular system is explained by several mechanisms, including the regulation of inflammation with its link to atherosclerosis, involvement of the vitamin D-PTH axis, regulation of the RAAS system, and the effect of insulin secretion, metabolic syndrome, and insulin sensitivity. Pharmacists and other health care providers are assisted by understanding these mechanisms in interpreting the studies that were recently conducted to evaluate vitamin D deficiency and adverse cardiovascular events.

 

25(OH)D deficiency (lowest quartile, less than 17.8 ng/mL) increases the risk of all-cause mortality by 26%, and increases the risk of CVD mortality as well, although this is not statistically significant, as found in a recent investigation of the general U.S. population. Adults with lower 25(OH)D concentrations were more likely to have CVDs such as heart failure, peripheral arterial disease, coronary heart disease, and stroke, according to data from NHANES (2001–2004). It was discussed that due to limited physical activity, the lower vitamin D levels may have been observed in patients with heart failure and heart disease, which leads to decreased sunlight exposure, suggesting that lower vitamin D was a result of CVD and not the other way round. But subjects with low vitamin D levels without CVD at baseline had a 53% to 80% higher rates of a CVD end point (fatal or nonfatal myocardial infarction MI, heart failure, stroke, and ischemia), found by another prospective observational study with a mean follow-up period of 5.4 years. Moreover, a two-fold increase rate of MI during 10-year follow-up period was experienced by men without CVD at baseline but with vitamin D deficiency, defined as 25(OH)D less than 15 ng/mL; this was found in the Health Professionals Follow-up Study.

 

Future research is necessary to reveal the relationship between vitamin D and cardiovascular health, even though these trials are important stepping-stones to our insight into this widely debated topic in the literature. For patients at risk for CVD, there are currently no universal guidelines that standardize screening, prevention, or treatment of vitamin D deficiency, but there are recommendations for serum 25(OH)D concentrations that have been found to maintain optimal bone health and prevent rickets. Pharmacists can assist in identifying patients at highest risk for vitamin D deficiency and provide recommendations for appropriate screening and treatment, based on current literature. Dietary consumption of vitamin D is not the optimal choice to increase vitamin D levels, because few foods naturally contain vitamin D, and some foods are fortified. However, the best natural source of vitamin D is UVB exposure. "Sensible" sun exposure is 5-10 minutes of exposure of arms and legs, or hands, arms, and face, 2 to 3 times per week, and it is documented that this exposure is recommended daily to maintain adequate vitamin D levels, but this recommendation is extremely controversial since there is a growing concern about any exposure to sunlight causing skin damage, including skin cancer and wrinkling.

 

The risk for vitamin D deficiency is increased in patients who don’t receive adequate exposure to sunlight, as well as those who are obese; have skin pigmentation; use sunscreen; are elderly; cover all of the skin with clothing; use certain medications, such as anticonvulsants, glucocorticoids, drugs that activate the steroid and xenobiotic receptor; or have hepatic failure and intestinal-fat malabsorption syndrome. To help reveal vitamin D deficiency, these patients are recommended to have their 25(OH)D concentrations checked yearly; this check is preferred at the end of the fall season. 400 IU daily is currently recommended by the FDA for children and adults of all ages, but this supplementation is found to be inadequate; to achieve optimal supplementation, most people, particularly elderly adults and those living in higher altitudes and in extreme winter climates, need at least 800 to 2,000 IU of vitamin D daily. To determine the effect of vitamin D supplementation on potential benefits in CVD prevention, it would be beneficial if future trials use adequate dosages, i.e. 800 IU at least. To assess the effect of vitamin D on the mortality risk associated with CVD, prospective studies are warranted. Health care professionals and patients need to be educated by pharmacists on the available data regarding this potential association.

 

Noting that the percentage of daily value is 400 IU/day recommended by the FDA for adults and children aged 4 years and older, the  following is a list of select sources of vitamin D, the IUs per serving, and the percentage of daily value:

 

  • 5-10 minutes of sun exposure between 10 am and 3 pm at least twice a week to the face, arms, legs, or back without sunscreen, is  400 IUs and the daily value is 100%
  • Vitamin D supplement (1 softgel or tablet), is 400-2,000 IUs, 100-500%
  • Cod liver oil (1 tbsp), 1,360 IUs, 340%
  • Salmon (sockeye, cooked, 3 oz), 794 IUs, 199%
  • Tuna fish (canned, drained in water, 3 oz), 154 IUs, 39%
  • Milk (fortified, 1 cup), 115–124 IUs, 29–31%
  • Orange juice (fortified, 1 cup), 100 IUs, 25%
  • Yogurt (fortified, 6 oz) 80 IUs, 20%
  • Ready-to-eat cereal (fortified, 1 cup) 40 IUs, 10%

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Prepared By: Dr. Mehyar Al-khashroum
Edited By: Miss Araz Kahvedjian


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