On the other hand, where does our intake of Vitamin D come from? The most obvious source of Vitamin D is sun exposure. However, this may be limited in some areas and with people who stay indoors most of the time. Another source is dietary intake; some of the foods that contain noteworthy amounts of Vitamin D include Milk, Salmon, Tuna, and Eggs (National institutes of health, 2009). Finally, the last possible source of Vitamin D is supplements which are becoming more and more available (National institutes of health, 2009).
The findings that linked Vitamin D deficiency and primary hypertension (Wang, 2008) have therefore raised important research questions. Being considered a risk factor if diminished, is it possible therefore that the proper intake of Vitamin D will decrease hypertension?
To begin with, some studies did in fact find a positive correlation between Vitamin D deficiency and increased risk of hypertension.
Wang et al. (2008) showed that the risk for hypertension was decreased in the higher quintiles of dietary vitamin d in US women aged over 45 years with a multivariate relative risk of 0.95.
Another study by Wang, Manson, Buring, Lee, and Sesso (2008) that was conducted in the U.S on 1739 participants found that those who had a 25-OH D that is less than 15 ng/mL had a multivariable ratio of 1.62 for developing cardiovascular events (including hypertension).
On the other hand, other studies have shown contradictory evidence in which it was claimed that Vitamin D intake does not in fact reduce blood pressure in hypertensive patients:
As a matter of fact, in a study published in 2008, Margolis et al. (2008) found that Vitamin D did not have a significant result in lowering blood pressure (p-value=0.14). It was published that:”calcium plus vitamin D3 supplementation (1000 mg plus 400 IU daily, respectively) did not reduce BP over 7 years of follow-up” (Margolis et al, 2008).
However, in this same study by Margolis et al., the only population that showed statistically significant results in the effect of vitamin D on lowering blood pressure were those who were hypertensive and taking antihypertensive medications (p-value= 0.09).
On the other hand, another article that was also published by the American Heart Association (2005) stated that the administration of Vitamin D does not lower the risk of hypertension. Authors stated” we found no evidence that higher vitamin D consumption altered the risk of incident hypertension”. (Forman,Bischoff-Ferrari, Willett, Stampfer, &Curhan, 2005).
And finally, in a review article of recent clinical studies about Vitamin D deficiency and hypertension that was published in 2009, it was declared that:
Results of recent interventional studies that investigated the potential benefit of vitamin D supplementation on blood pressure have not been promising. Further studies are needed to find out if and when vitamin D supplementation should be used for treating patients with hypertension. (Ullah, Uwaifo, Nicholas, &Koch, 2009).
After a review of all these different studies it is worth noting that there should be a differentiation between vitamin D deficiency and risk of hypertension and vitamin D administration and decrease of hypertension. As a matter of fact there are a lot of contradictory results when it comes to these two research areas. In addition to that, more subgroups may be found under these research areas that further complicate the research conduction and that include all the possible different sources of vitamin D. Therefore, we will be aiming in our study to differentiate between the different sources of vitamin D.
Moreover, the role of vitamin D as an antihypertensive agonist has not been fully researched. Therefore, in the proposed study, the focus will be on vitamin D as an agonist to antihypertensives in patients that are known to be hypertensive. And only if a positive effect is found, will the different Vitamin D resources be investigated.
Methods
This is a double blind, randomized quantitative study. It is a placebo-controlled, longitudinal, and within subject design type of study.
Population
Between 2011 and 2012, 250 to 300 participants will be recruited to the study. This number would be appropriate enough to have a representative sample of the population and to allow for a relatively short and convenient period of time for the recruitment and the execution of the study. Around fifty participants will be assigned to each group. The study will be conducted in Lebanon; this will allow reducing the costs of the study and would be a representative sample of the population. At the same time it would be a helpful addition to researches conducted by expert scholars such as Dr. Asma Arabi, Dr. Rania Tohme, and Dr. Ghada el Hajj Fuleihan, who studied hypertension and vitamin D deficiency in the Lebanese population. Posters that present the study will be posted in different hospitals in Lebanon, in addition to cardiovascular physician’s clinics. Interested subjects will therefore have the opportunity to contact the researchers through the telephone and email to participate in the study. As mentioned previously, this recruitment phase will be conducted in one year.
The study sample will include both men and women; both genders will be included to eliminate any gender-related influence on the results. In addition, the participants should be 50 years of age or older since the risk of hypertension is increased in men who are at least 45 years old and in women who are 55 years old or older (U.S Department of Health and Human services, 2009). The participants would be all from the same ethnic group (white) to eliminate the influence of ethnic-related differences on our study results. All the participants should have been diagnosed as hypertensive by their primary physician.
History taking will be done through the phone and those with exclusion criteria will not be included in the study. Exclusion criteria include those who are not taking their prescribed antihypertensive medications, those who don’t plan on staying in Lebanon for the entire duration of the study that consists of two years, and those with a predicted survival rate of two years or less.
Assignment to Groups
After the one year recruitment period, participants’ 25-hydroxy vitamin D levels will be taken on their first visit, after which they will be first divided into two groups: those with a normal level of vitamin D, and those with vitamin D deficiency. Afterwards, the assignment to the other groups will be done in a randomized fashion to ensure adequate representation in each group. The different groups will be therefore:
Group 1: Participants with a normal level of vitamin D + placebo administration
Group 2: Participants with a normal level of vitamin D + controlled dietary intake of vitamin D
Group 3: Participants with a normal level of vitamin D + supplemental vitamin D administration
Group 4: Participants with vitamin D deficiency + primary dietary intake of vitamin D
Group 5: Participants with vitamin D deficiency + supplemental vitamin D pills administration
Measuring Levels of Vitamin D
When the 25-hydroxy vitamin D is present in the kidney, it changes into vitamin D. A widely used method to know the level of vitamin D in the human body is therefore measuring the level of 25-hydroxy vitamin D. This is performed by a blood test. For a person to be considered as having Vitamin D deficiency he/she should have a level of 25-hydroxy vitamin D that is less than 30 ng/mL, knowing that the normal range is 30-74 ng/mL (Melamed, 2010). Before assigning the participants to the groups, each participant will have his Vitamin D level measured. A certified physician will afterwards diagnose the participants as being Vitamin D deficient or not. Then after beginning the interventions, Vitamin D levels will be measured for each participant every six months for the duration of one year using the same technique. They will be coming to a rented clinic in the American University of Beirut-Medical Center for measuring their level of vitamin D.
Measuring Blood Pressure
After recruitment, each participant will have his blood pressure measured. The measurement will be made using a sphygmomanometer. To control for possible variations in the results, the same arm for each participant will be used for each measurement, an appropriately sized cuff will be used, and the participants will have to be seated. In addition, an assigned group of registered nurses will be the ones measuring the blood pressure in every visit. Blood pressure measurements will be done every two months for the duration of one year. Before assigning the participants to the different groups, a thorough history will be taken from each one. The history will include the date on which they were diagnosed with hypertension, how long they have been taking antihypertensive medications, and the names and classes of each medication being taken. They will be coming to a rented clinic in the American University of Beirut-Medical Center for measuring their blood pressure.
Execution of the Study
A total number of three researchers will be conducting the study. Three research assistants will have the role of recruiting the participants and entering data to the database. Three registered nurses will be performing blood tests, measuring blood pressure and educating the participants about the use of the sphygmomanometers. Three physicians will also participate with duties that include diagnosing vitamin D deficiency, monitoring the general health of the participants, identifying any emerging diseases, and referring participants to specialized physicians when needed. Three dieticians will also be present and their roles include monitoring the diet of the participants, with special focus on vitamin D intake in addition to nutritional education for the participants. Three psychologists will also be available to assess any psychological influence on the participants (e.g. stressful events) that may affect them and subsequently affect their blood pressure. And finally, three social workers will evaluate any socioeconomic limitations that may have an effect on the participants and consequently on the results (primarily blood pressure measurements). All participants will be provided with the phone number and email of each member of the multidisciplinary to facilitate communication. Any concerns or questions will be answered by this team.
Interventions
The intervention phase will run over a period of one year. Registered nurses will be administering the placebo pills and supplemental Vitamin D in a double blind fashion. The amount of daily vitamin D intake for each person will be set at 600 IU. This amount is the required daily amount (RDA) and can be given to those who have no vitamin D deficiency with no risk of side effects (Refer to Table 1). The supplemental pills will be 300 IU each. Those in the supplemental group and not vitamin D deficient (group three) will receive two pills a day with no modification in their diet. Those who are in the supplemental group and are Vitamin D deficient (group five) will receive a bigger dose in order to reach the required daily intake amount of 600 IU. The dose will be adjusted according to their level of deficiency with no modification in their diet. Those in the dietary intake group and not vitamin D deficient (group two) will have their diet modified in order to receive a daily amount of 600 IU of Vitamin D from their diet. Those in the dietary intake of Vitamin D and are vitamin D deficient(group four) will receive supplemental Vitamin D pills of 200 IU and the remaining Vitamin D that is required will be received from the diet. Since dietary intake of Vitamin D might not be enough for those who are deficient, the supplemental Vitamin D will therefore ensure that they receive the required amount. Those in the placebo group will have no modification in their diet.
Confounding Variables
The amount of salt intake seems to have a great impact on the presence of hypertension and maintenance of blood pressure, where hypertension is prevalent in societies with salt intake of above 100 meq/day (equivalent to 2.3 g of sodium), as published by Elliot et al. (1996). An intake of a diet rich in salt (with at least 2.3 g of sodium per day) would make it hard to determine the effect of vitamin D on blood pressure, thus leading to inappropriate and possibly insignificant findings. In addition to that, the adherence of participants to their daily intake of vitamin D, whether supplemental or from dairy products, is a problem since their exact daily intake can’t be accurately measured. A definite concern would be the non adherence of the participants to their antihypertensive medications during the study; such non adherence would make it almost impossible to find the agonistic effect of vitamin D on these medications. Other confounding variables would be diabetes, heart disease, obesity, and problems in vitamin D malabsorption, and information on health status and lifestyle.
Covariates
Participants’ vitamin D levels will be measured every six months. Doing so will help in determining whether the participants are taking their daily vitamin D doses. In addition to that, participants will have to come to the clinic assigned for this research to have their blood pressures measured every 2 months. They will be provided with a sphygmomanometer and a daily flow sheet to record their measured blood pressure twice daily (once in the morning and once at night) at home. On their two months visit, the flow sheets will be taken from them and the data will be entered into the study’s database. This will allow the researchers to check if the patients are taking their daily doses of antihypertensive drugs as highly fluctuating blood pressures for a prolonged period of time would be an indicative of the participants’ adherence to their antihypertensive drugs.
Statistical Methods
Pearson’s r will be used to indicate the direction and the magnitude of the relationship between the different variables: Vitamin D supplementation and BP, dietary Vitamin D and BP, and placebo and BP. The relationship between these variables will be studied in both the Vitamin D deficient population and the population with the normal level of Vitamin D. In addition, the results will be run through analysis of variance (ANOVA) to test the difference between the different means.
Ethical Considerations
The study is expected to be approved by the institutional review board. An informed consent would be given for each participant to sign after explaining all the aspects of the study including all the possible side effects. In addition, a multidisciplinary team composed of physicians, registered nurses, dieticians, psychologists, and social workers would be available to answer all the participants’ questions and guide them throughout the study.
Budget
- One Vitamin D measurement Kit costs 1 000 $ for each 40 participants. We will be needing eight kits for each assigned measurement time and a total of three measurements will be done for each participant= 1 000 $ х 8 х 3= 24 000 $
- 1000 $/RN х 5 = 5000 $
- 1000$/research assistant x 3 =3000$
- 1000 $/dietician х 3 = 3000$
- 1000 $/social worker х3 = 3000 $
- 1000 $/psychologist х 3 = 3000 $
- 1000 $/physician х 3 = 3000 $
- 20 $/sphygmomanometer(used by RNs) х 3 = 100 $
- 20 $/ sphygmomanometer(used by participants) х 300 = 6 000 $
- 10 $/100 pill of vitamin D = 153300 pills х (100/10) $ = 15 330 $
-
Total budget = 65,430 $
Dissemination of results
The results will be published in Nursing and Medical journals. In addition, conferences will be held in order to present the findings of this study.
Appendix A
Table 1. The recommended dietary allowance of vitamin D intake according to age
(Institute of medicine of the national academies, 2010)
References
El-Hajj Fuleihan, G, & Deeb, M. (1999). hypovitaminosis d in a sunny country. The New
England journal of medicine, 340(23), 1840-1841.
Elliott, P, Stamler, J, Nichols, R, Dyer, A.R, Stamler, R, Kesteloot, H, Marmot, M. (1996).
Intersalt revisited: further analyses of 24 hour sodium excretion and blood pressure
within and across populations. British medical journal, 312(7041), 1249-1253.
Forman, J.P, Bischoff-Ferrari, H.A, Willett, W.C, Stampfer, M.J , & Curhan, G.C. (2005).
Vitamin D Intake and Risk of Incident Hypertension: Results From Three Large Prospective Cohort Studies. Hypertension, 46 , 676-682.
, , , , , , A,
, . (2008). Prevalence and predictors of vitamin D inadequacy amongst Lebanese osteoporotic women. British Journal of Nutrition, 101, 487–49.
Holick, M.F. (2007). Vitamin d deficiency. New England Journal of Medicine, 357(3), 266-
281.
Jorde, R. , & Bønaa K.H. (2000). Calcium from dairy products, vitamin D intake, and blood
pressure: the Tromsø study. The American Journal of Clinical Nutrition, 71 , 1530-1535.
Li, Y. C. (2003). Vitamin D Regulation of the Renin–Angiotensin System. Journal of
Cellular Biochemistry ,88 , 327–331.
Margolis, K.L,Ray, R.M, Van Horn, L, Manson, J.E, Allison, M.A, Black, H.R, Beresford,
S.A, Connelly, S.A, Curb, J.D, Grimm, R.H,Kotchen, T.A, Kuller, L.H,& Wassertheil-Smolle, S. (2008). Effect of Calcium and Vitamin D Supplementation on Blood Pressure: The Women’s Health Initiative Randomized Trial. Hypertension, 52 , 847-855.
Melamed, M.L. National Institutes of Health, National Kidney and Urologic Diseases
Information Clearinghouse. (2010). low vitamin d levels linked to increased risk of kidney failure (10–4531)
Tohme, R.A, Jurjus, A.R, & Estephan, A. (2005). The prevalence of hypertension and its
association with other cardiovascular disease risk factors in a representative sample of
the Lebanese population. Journal of Human Hypertension, 19, 861-868.
Ullah, M.I, Uwaifo, G.I, Nicholas, W.C, &Koch, C.A. (2009). Does Vitamin D Deficiency
Cause Hypertension? Current Evidence from Clinical Studies and Potential Mechanisms. International Journal of Endocrinology , 1-11.
Wang, L., Manson, J. E., Buring, J. E., Lee, I. M., &Sesso, H. D . (2008). Dietary intake of
dairy products, calcium, and vitamin D and the risk of hypertension in middle-aged and older women. Hypertension, 51, 1073-1079.
Wang ,T.J,Pencina, M.J, Booth, S.L, Jacques, P.F, Ingelsson, E, Lanier, K, Benjamin,
E.J,D’Agostino, R.B, Wolf, M, &Vasan, R.S. (2008). Vitamin D Deficiency and Risk of Cardiovascular Disease. Circulation ,117 , 503-511.