Topic of the Month

Vitamin D and cardiovascular disease: a potential novel agent for reducing cardiovascular risk

May 31, 2016

Vitamin D deficiency is often found in patients with cardiovascular disease. Vitamin D may have a role in reducing the incidence of strokes and has a metabolic role in the process of coronary collateral circulation development, which occurs when minor blood vessels enlarge and join up to enable blood flow when an adjacent major vein or artery has been blocked. There are also studies that show Vitamin D supplementation may be useful to assist patients with muscle pain due to intolerance of certain statins. However many more trials and studies need to be made before Vitamin D can be recommended as a therapeutic agent for cardiovascular disease.

Vitamin D not only assists good bone health, as there is growing evidence that it can protect against cardiovascular disease too. Vitamin D deficiency has been associated with a range of manifestations of cardiovascular disease, including: high blood pressure, stroke, myocardial infarction, diabetes, congestive heart failure, atherosclerosis and endothelial dysfunction (2).

Vitamin D deficiency underlines a series of metabolic processes that can initiate and progress atherosclerosis in blood vessels (1), these include: proliferation and migration of vascular smooth muscle cells, adverse re-modelling of connective tissue matrix in the vascular wall; increased platelet aggregation, increased vascular calcification, increased production of inflammatory cytokines and acceleration of foam cell formation. However, randomised clinical trials are still required to see whether Vitamin D supplementation could improve vascular function.  The largest trial to date, the Women’s Health Initiative trial, which looked at a seven year intervention of Vitamin D and Calcium in post-menopausal women did not show a reduction in adverse cardiovascular events, but the study was actually designed to look at bone fracture and the Vitamin D dose used was very low at 400 IU per day (3).

A meta-analysis by Schöttker et al. (4) in 2014 followed up 6,695 participants aged 50 to 79 years from eight prospective studies in USA and Europe. There were 2,624 who eventually died of cardiovascular disease. The quintile with the lowest Vitamin D blood serum levels had the highest level of cardiovascular mortality. There was a general statistically-valid, inverse association between the Vitamin D levels in the quintile and death due to cardiovascular disease. There were no specific effects regarding gender, geographic region or age.

Vitamin D is known to help restore muscle strength. Therefore it seems plausible, it could be a useful adjunct in approximately 20% of patients who take taking statins, but suffer from some form of side effects, most commonly muscle ache and memory disturbance.  A meta-analysis of seven studies with 2420 statin-treated patients (6) provided evidence that low Vitamin D levels are associated with muscle pain in patients on statin therapy.  Khayznikov et al. (5) found that if statin intolerant patients with low serum Vitamin D levels (˂ 32 ng/mL) were treated with a weekly total Vitamin D therapy dose of 50,000 to 100,000 IU/week, the muscle related problems could be resolved in around 9 out of 10 cases.

However, the effect may depend on the type of statin. Backs et al. (7) reported that replenishment of Vitamin D deficient patients intolerant to rosuvastatin to a minimum serum level of 30ng/mL only produced alleviation of muscle pain related intolerance in around half of cases.

The thickness of the carotid intima-media (IMT) is a biomarker of structural atherosclerosis, where higher values, indicating thicker tissue and hence less flexibility, are strongly associated with the risk of heart disease. Further, IMT measurements during childhood have been shown to be predictive of adverse cardiovascular events in adults. Juonala et al. (8) compared IMT measurements of a cohort from Finland in 1980 (when they were children aged 3 – 18 years), then re-examined them in 2007 (when they were adults aged 30-45 years).  This study showed a significant association between 25-OH Vitamin D levels (in childhood) in blood serum and lower IMT in females. Overall, a blood serum level of 25-OH vitamin D of below 43 nmol/L in childhood was associated with increased IMT. US Guidelines recommend a level of 50 nmol/L or more during childhood (9).

Ischaemic stroke occurs where a blood clot blocks blood vessels and starves local tissues of oxygen and is the third most common cause of death in the industrialised world, and responsible for ca 10% of total mortality. A biomarker called “infarct volume”, which is a measure of the permanently damaged tissues surrounding the clot, is commonly used to assess the extent of ischemic brain injury after an ischemic stroke. Turetsky et al. (10) examined the data of 96 ischemic stroke patients to determine whether serum 25-OH vitamin D levels were an independent predictor of infarct volume and 90-day outcome status.

They found that higher serum 25(OH)D  status was significantly associated with smaller infarct volumes (p < .05).  There was also an association with low serum status and 90 day outcome. The risk of a poor outcome was found to double with each 10 ng/ml decrease in vitamin D status. Hence low vitamin D status can be used to help identify stoke patients at risk of a poor outcome.

In an animal model, a study (11) has shown that Vitamin D can help restore blood circulation and enable vascular repair in rats with induced type 1 diabetes. The study also shows that the presence of Vitamin D is a necessary factor in the formation of new blood capillaries from epithelial cells in a process known as angiogenesis. The active form of Vitamin D, 1,25-di hydroxyl Vitamin D3 restores vascular repair and angiogenesis in type 1 diabetic mice. The mechanism involves, active vitamin D3 inducing and activating nitric oxide synthase and NADPH oxidase (NOX1), mobilises homing of angiogenic myeloid cells (AMCs), and the production of stromal cell-derived factor (SDF1) and vascular epithelial growth factor 1 (VEGF1).  Further, it has been shown that a small number of human volunteers fed for 6 weeks with 4000 IU per day of Vitamin D3 are able to increase their levels of circulating angiogenic myeloid cells. It seems likely that Vitamin D plays an important role in regulation of the process of coronary collateral circulation development, which is when minor blood vessels enlarge and join up to enable blood flow when an adjacent major vein or artery has been blocked (12).

Whilst the scientific evidence for benefits of Vitamin D to patients with cardiovascular disease is encouraging, further clinical and experimental studies are required before it can be recommended as a therapeutic option.

References

  1. Brewer, LC, Michos ED  & Reis JP, “Vitamin D in Atherosclerosis, Vascular Disease, and Endothelial Function”; Current Drug Targets 2011; 12: 54-60.
  2. Anagnostis P, Athyros VG, Amididou F et al , “Vitamin D and cardiovascular disease: a novel agent for reducing cardiovascular risk?”; Curr Vasc Pharmacol. 2010 Sep;8(5):720-30.
  3. Hsia J, Heiss G, Ren H et al., “Calcium/Vitamin D supplementation and cardiovascular events”;  Circulation  2007; 115: 846-54.
  4. Schöttker B, Jorde R, Peasey A et al., “Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States, BMJ 2014; 348g3656 .
  5. Khayznikov M, Hemachrandra K, Pandit R, Kumar A, Wang P, Glueck CJ, “Statin Intolerance Because of Myalgia, Myositis, Myopathy, or Myonecrosis  Can in Most Cases be Safely Resolved by Vitamin D Supplementation”; N Am J Med Sci. 2015 Mar;7(3):86-93. doi: 10.4103/1947-2714.153919
  6. Michalska-Kasiczak M, Sahebkar A, Mikhailidis DP, Rysz J, Munter P, Toth PP et al. Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group; Analysis of Vitamin D levels in patients with and without statin-associated myalgia – A systematic review and meta-analysis of 7 studies with 220 patients. Int J Cardiol 2015; 178:111-6 .
  7. Backes JM, Barnes BJ, Moriarty PM; “Statin intolerance and Vtamin D supplementation: Sunny, but a few clouds remain”; N Am J Med Sci. 2015; 241:15.
  8. Juonala M, Voipio A, Pahkala K et al.; “Childhood 25-OH vitamin D levels and carotid intima-media thickness in adulthood: The cardiovascular Risk in Young Finns Study”; Journal of Clinical Endocrinology and Metabolism 2015: 100(4), 1469–1476. http://doi.org/10.1210/jc.2014-3944
  9. Wagner CL & Greer FR; “Prevention of rickets and Vitamin D deficiency in infants, children and adolescents”; Pediatrics 2008; 122: 1142-1152.
  10. Turetsky A, Goddeau R, & Hinninger N, Low Serum Vitamin D Is Independently Associated with Larger Lesion Volumes after Ischemic Stroke. Journal of Stroke and Cerebrovascular Diseases, May 22, 2015.
  11. Wong MS, Leisegang MS, Kruse C  et al; “Vitamin D promotes vascular regeneration”; Circulation 2014; 130:976-86.
  12. Lima J & Kunadian V; “Vitamin D:evidence for an association with coronary collateral circulation de Postepy W Kardiologii Interwencyjnej 2015; 11(3)174-176.NUTRI-FACTS