The relationship between vitamin D and PTH levels ...

http://informahealthcare.com/ceh ISSN: 1064-1963 (print), 1525-6006 (electronic) Clin Exp Hypertens, 2014; 36(1): 52–57 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10641963.2013.783054

ORIGINAL ARTICLE

The relationship between vitamin D and PTH levels and cardiovascular risk in the elderly hypertensives Sena Memnune Ulu1, Alper Ulaslı2, Fatima Yaman2, Go¨khan Yaman1, Gulay Ozkececi3, and S¸ eref Yuksel1 Department of Internal Medicine and Nephrology, 2Department of Physical Medicine and Rehabilitation, and 3Department of Cardiology, Afyon Kocatepe University, Faculty of Medicine, Afyonkarahisar, Turkey Abstract

Keywords

Introduction and objective: In this study, we aimed to investigate the relationship between vitamin D, parathyroid hormone (PTH) and cardiovascular risk (CVR) in hypertensive patients aged 65 years and over. Patients and methods: This study was performed with 84 hypertensive patients and 68 normotensive control group in Afyon Kocatepe University Faculty of Medicine Hospital. The determined cardiovascular risk degrees and the stages of blood pressure were compared with the levels of 25-(OH) vitamin D and PTH. Results: Mean systolic and diastolic blood pressure (BP) levels of the patients with vitamin D deficiency (VDD) were significantly higher than those without VDD (p50.001 for both). Mean systolic and diastolic BP levels of the patients with hyperparathyroidism were significantly higher than those without hyperparathyroidism (p ¼ 0.012, p ¼ 0.036, respectively). CVR was reversely correlated with vitamin D but the correlation with hyperparathyroidism did not reach statistically significant level (r ¼ –0.752, p50.001) and (r ¼ 0.210, p ¼ 0.055), respectively. Conclusion: These results indicate that the presence of hypertension is associated with VDD, as well as the stage of hypertension contributes to insufficiency, hyperparathyroidism and increased CVR. Clinicians should be aware and perhaps more aggressive for the treatment of HT and VDD in patients over 65 years of age.

Cardiovascular risk, elderly patients, hyperparathyroidism, hypertension, vitamin D, vitamin D deficiency

Introduction Vitamin D deficiency (VDD) is a common condition all over the world, especially in the population aged 65 and over (1–3). Number of patients with low vitamin D levels increases with advanced age (4). The vast majority of people with VDD, which is a cardiovascular risk factor alone are asymptomatic, and with regards to this situation, the importance of VDD increases (5,6). Vitamin D contributes to the regulation of the blood pressure (BP) by various mechanisms (7–11). These mechanisms include renin–angiotensin system (RAS) suppression, renoprotective effect, the effect on vascular cells and the metabolism of calcium and the protective effect on vascular calcification (12). Hypertension (HT) may be seen with the disruption of these mechanisms in VDD (3,13–20). An inverse relationship has been found between the levels of vitamin D and renin activation in hypertensive patients (7,21). A decrease in renin and angiotensin II levels have been reported in several studies which investigated the RAS Correspondence: Sena Memnune Ulu, MD, Department of Internal Medicine, Afyon Kocatepe University, Faculty of Medicine, 03200, Afyonkarahisar, Turkey. Tel: 0272 2463303. Fax: 0272 2463300. E-mail: [email protected]

History Received 10 January 2013 Revised 30 January 2013 Accepted 1 February 2013 Published online 17 May 2013

activation after treatment with vitamin D or its analogues (22,23). Although there have been conflicting results in the studies, an inverse relationship was found between vitamin D levels and HT (16,20). Secondary hyperparathyroidism occurs in VDD, and HT risk was found to be higher in patients with hyperparathyroidism in previous studies (12,15,24–26). Although a significant correlation was observed between PTH and BP in patients without hyperparathyroidism, there have been limited studies investigating the association between HT and VDD in the literature (3,13–18,27). This relationship has not been studied in Turkish population. We aimed to investigate the relationship between HT and VDD in elderly aged Turkish population.

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Materials and methods This study was conducted between April 2012 and September 2012 in departments of Internal medicine and Physical Medicine and Rehabilitation of Afyon Kocatepe University Faculty of Medicine Hospital. The study was conducted retrospectively using hospital records and included 84 patients diagnosed with HT whose vitamin D levels were measured with any reason at the follow-up visits. The control group was composed of 68 age and sex matched normotensive patients. Patients with the secondary causes of hypertension (such as renal hypertension, any endocrine disorders causing

Vitamin D, PTH and cardiovascular risk in the elderly


DOI: 10.3109/10641963.2013.783054

hypertension such as hypothyroidism, hyperthyroidism, Cushing’s syndrome, acromegaly, adrenal pathologies), with renal failure, liver failure, parathyroid related disease, receiving vitamin D therapy and those who did not want to participate in the study were excluded. Patients and control group were recalled to the hospital and those who agreed to be included in the study were questioned for age, sex, hyperlipidemia, smoking, family history, heart disease, any risk factors, dietary compliance, used drugs and whether they exercise regularly. Their medical histories were taken, and a general physical examination, including heart rate and arterial blood pressure, was performed. BP was classified according to the Seventh Report of the Joint National Committee on High BP (JNC-7) categories (28). Cardiovascular risk factors were determined and total cardiovascular risk was categorized as low, moderate, high and very high risk as recommended in the guidelines (29,30). Plasma 25-(OH) vitamin D, PTH, calcium, phosphorus levels were received from the recorded data of the patients. The level of 25-(OH) vitamin D was measured by RIA (Nichols Institute Diagnostics). Serum PTH was measured by immunoradiometric assay (Allegro Intact PTH, Nichols Institute, San Juan, Capistrano, CA). Plasma 25-(OH) D levels and PTH levels were measured in the last 1 month the other data belonged to the previous week. Statistical methods Continuous variables were presented as mean SD and categorical variables were expressed as percentage. Kolmogorov– Smirnov test was used to evaluate of the distribution of variables. Student’s t-test was used for continuous variables Table 1. Demographic data of the groups and the significance level of the differences.

Variables Age (year) Sex* Male Female

Patient group (n ¼ 84)

Control group (n ¼ 67)

p

70.77 5.31

71.68 6.53

0.345

18 (21.4%) 66 (78.6%)

14 (20.9%) 53 (79.1%)

0.937

All parameters are expressed as mean standard deviation) unless otherwise stated. *Data are expressed as number (%).

those with normal distribution and Mann–Whitney U test was used for continuous variables those without normal distribution. Chi-square test was used for categorical variables. The parameters affecting BP were investigated using Spearman/Pearson correlation where appropriate. A multiple linear regression model was used to identify independent predictors of BP. p50.05 value was accepted as significant level. For statistical calculations, SPSS statistical software (SPSS for Windows, version 17.0. Inc. Chicago, IL) was used.

Results The mean age of the patient and control groups, the distribution according to gender and the significance level of the differences between groups are outlined in Table 1. Of the 84 hypertensive patients, 33 (21.9%) were diagnosed with CAD alone, 10 of them (6.6%) had DM alone and 41 of them had both CAD and DM. The mean duration of HT diagnosis of the patients was 10.64 6.83 years. The mean vitamin D level was significantly lower in hypertensive patients compared to control group (38.03 19.47 and 44.79 19.47, p ¼ 0.03). VDD was detected in 40.5% of the patients; 23.8% of them had a vitamin D level between 20 and 30 ng/ml and 16.7% had a vitamin D level between 10 and 20 ng/ml, while none of them had a vitamin D level below 10 ng/ml. The mean systolic BP (SBP) value was 132.67 19.85 mm/Hg and the mean diastolic BP (DBP) value was 88.80 15.45 mm/Hg. Laboratory data of the patient and the control groups are shown in Table 2. The mean PTH level was 65.74 35.05 pg/ml in patient group while this was 37.36 14.03 pg/ml in control group and the difference was statistically significant (p50.001) (Table 2). Mean BMI of the patient group was higher compared to control group and because of the possible confounding effect of BMI on BP, we further analyzed the effect of vitamin D, BMI and PTH on BP with regression analysis. BMI and PTH had no effect on systolic BP whereas with 1 ng/ml decrease in vitamin D level there was 0.76 mmHg increase in BP (p50001). The patients were divided according to HT levels and compared in terms of vitamin D and PTH levels. Mean vitamin D level was significantly low in patients with stage 1 HT compared to high-normal stage (p50.001) while it was similar in stage 1 and 2 HT (p ¼ 0.946).

Table 2. Laboratory data of the patients and the control group. Variables 2

BMI (kg/m ) Hb (g/dl) Htc (%) CRP (mg/dl) BUN (mg/dl) Creat (mg/dl) Systolic (mm/Hg) Diastolic (mm/Hg) Ca (mg/dl) P (mg/dl) D vit (ng/ml) PTH (pg/ml)

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Patient group (n ¼ 84)

Control group (n ¼ 67)

p

28.28 4.00 (22–39) 12.87 2.00 (11.70–15.80) 39.42 5.92 0.55 0.38 (0.10–1.70) 16.88 5.55 (0.87–25.37) 0.79 0.20 (0.17–1.22) 132.67 19.85 (90.00–175.00) 88.80 15.45 (60.00–115.00) 9.28 0.63 (7.06–10.90) 3.49 0.70 (2.30–6.70) 38.03 19.47 (10.09–93.20) 65.74 35.05 (23.17–215.00)

26.34 2.29 (21–30) 12.97 1.35 (8.00–15.40) 39.9 3.74 (27.30–46.80) 0.82 1.06 (0.10 5.77) 17.14 4.96 (7.71–31.73) 0.82 0.18 (0.54–1.32) 105.52 9.89 (90.00–125.00) 83.58 74.20 (60.00–68.00) 9.38 0.43 (8.55 10.45) 4.09 4.13 (2.10 37.00) 44.79 19.47 (22.00–93.19) 37.36 14.03 (3.00–85.00)

50.001 0.747 0.552 0.003 0.769 0.340 50.001 0.530 0.268 0.194 0.03 50.001

All parameters were expressed as mean standard deviation (Min–Max) unless otherwise stated. *Data were expressed as number (%). p values 50.05 were accepted as significant. The significant differences between the groups were shown in bold.


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Clin Exp Hypertens, 2014; 36(1): 52–57

Patients were divided into two groups according to the presence of vitamin D deficiency (vitamin D deficiency (VDD) ¼ serum vitamin D level 530 ng/ml and without vitamin D deficiency ¼ serum vitamin D level 430 ng/ml). Mean blood pressure levels of the patients with VDD were significantly higher than those without VDD (p50.001) (Figure 1). Mean vitamin D and PTH levels according to the stages of HT of the patients were shown in Table 3. Patients were divided into two groups according to the presence of hyperparathyroidism (hyperparathyroidism ¼ PTH450 pg/ml and normal PTH levels ¼ PTH: 12–50 pg/ ml). Mean systolic and diastolic blood pressure levels of the patients with hyperparathyroidism were significantly higher than those with normal PTH levels (p ¼ 0.012, p ¼ 0.036, respectively) (Figure 2). Vitamin D levels were reversely correlated with SBP and DBP (r ¼ –0.741, p50.001); (r ¼ –0.745, p50.001, respectively). Positive relationship was determined between PTH levels and SBP (r ¼ 0.875, p50.001). CVR was reversely correlated with vitamin D but the correlation with hyperparathyroidism did not reach statistically significant level (r ¼ –

0.752, p50.001) and (r ¼ 0.210, p ¼ 0.055) respectively (see Figure 3). CVR was positively correlated with SBP and DBP (r ¼ 0.877, p50.001) and (r ¼ 0.842, p50.001), respectively. There were no correlations between age, gender, smoking, BMI, hypertension, PTH levels and vitamin D levels.

Discussion This study was the first investigating the relationship between vitamin D and PTH levels according to the stages of SBP, DBP and the CVR in a population aged 65 and over in Turkey. The most important finding in the study was that a decrease in the mean level of vitamin was observed with the increase in the level of both SBP and DBP. An inverse relationship between plasma vitamin D levels and the development risk of hypertension was shown in the previous studies (31,32). Inverse correlations were reported between vitamin D levels and systolic BP and diastolic BP (3,33). Later, He et al. demonstrated the same result between only SBP in a study which was carried out with 7561 participants aged 20 years and over (12). However, there have been opinions defending

Figure 1. The relationship between blood pressure and vitamin D levels.

Table 3. Mean vitamin D and PTH levels according to the stages of HT patients. HT stage High-normal HT Stage 1 Stage 2

D vit (ng/ml)

PTH (pg/ml)

55.50 16.87(28.61–93.20) 26.25 7.59 (10.76–45.51 26.06 11.82 (10.09–46.00)

57.98 28.10 (23.17–169.90 67.99 40.86 (29.11–215.00) 74.29 36.24 (25.27–166.00)

All parameters were expressed as mean standard deviation (Minimum–Maximum) unless otherwise stated.


DOI: 10.3109/10641963.2013.783054

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Figure 2. The relationship between blood pressure levels and PTH levels (Levels on x axis corresponds to number of patients).

Figure 3. The relationship between vitamin D levels and CVR.

vice versa (26,34–38). Snijder et al. did not find any significant relationship between vitamin D levels and blood pressure in their study with 1205 subjects aged 65 and over (39). Also, Chan et al. reported no significant relationship between vitamin D levels and blood pressure in their study that included 939 male patients aged 65 and over (25).

There was no relationship between blood pressure stages and vitamin D levels in the study by Skaaby et al. with 6784 people between the ages of 30–60 (34). In our study, vitamin D levels of the hypertensive patients were significantly lower than the normotensive control group. In addition, a negative correlation was found between the


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values of vitamin D and BP stages. Mean vitamin D levels were decreased with the increase in systolic and diastolic BP. In addition, with 1 ng/ml decrease in vitamin D level, there was 0.76 mmHg increase in BP. Our findings were consistent with the studies in general; however, more reliable results can be obtained in this subject with the large numbered prospective controlled studies. It was shown that vitamin D levels were lower in the population of 65 years and over than other age groups in National Health and Nutrition Survey (NHANES III), which was carried out with more than 15 000 people in America by Zadshir et al. (40). The percentage of the patients aged 65 years or over with a level of vitamin D 10 ng/ml or below was 34.6% in a study conducted with 127 people who had not any disease affecting the level of vitamin D in Spain (41). In another study with post-menopausal women between the ages of 47–66, VDD ratio was 64% (42). In our study, VDD ratio was found as 40.5%; 23.8% of them had a vitamin D level between 20 and 30 ng/ml and 16.7% had a vitamin D level between 10 and 20 ng/ml, but none of them had a vitamin D level below 10 ng/ml. The association between VDD and CVR have been shown in several recent reports (43–45). However, studies which reported no relationship between VDD and CVR are also available (46,47). In our study, we found a significant relationship between VDD and CVR. This finding can be considered as a natural consequence of the positive relationship between VDD and HT or the stages of hypertension. Although PTH’s effect on blood pressure has not been fully understood, its prosclerotic effect on smooth muscle cells, contributing to vessel wall thickening and high blood pressure, is well known (8,39). BP values are correlated with PTH levels (12,15,25,26). This correlation was shown in a study with patients with normal PTH levels (27). In another study with 1205 people aged 65 and over, systolic and diastolic blood pressure were associated with high serum PTH levels (39). In addition, it was shown that, PTH infusion raises blood pressure in healthy individuals (48). In this study, mean blood pressure of patients with hyperparathyroidism was higher than those without hyperparathyroidism. As well as, the highest PTH values were observed in patients with stage II HT. In a study by Chan et al. with 939 male patients of 65 years, high serum PTH levels was associated with the increase in SBP and DBP levels (25). In our study, positive correlations were found between PTH levels and SBP. The underlying mechanism is not completely known for now but, this finding was supported by the other studies in the literature (39,48). Studies investigating the pathophysiology of the relationship between hypertension and hyperparathyroidism will provide us further detailed information. In the previous studies, hyperparathyroidism (both primary and secondary) was shown to increase CVR (46,49–51). This finding was supported by another study which reported the decrease in CVR after parathyroidectomy (52). In our study, we found a poor relationship between hyperparathyroidism and CVR, but it did not reach a significant level. More comprehensive studies investigating the relationship between hyperparathyroidism and CVR will shed light on this issue.

Clin Exp Hypertens, 2014; 36(1): 52–57

These results indicate that the presence of hypertension is associated with VDD, as well as the stage of hypertension contributes to insufficiency, hyperparathyroidism and increased CVR. Clinicians should be aware and perhaps more aggressive for the treatment of HT and VDD in patients over 65 years of age. As a result, regarding the potential risks and associations of vitamin D deficiency, hyperparathyroidism, HT and CVR, more extensive studies are needed in order to understand the relationship between vitamin D levels, CVR and HT in patients aged 65 years and over and as well as need for vitamin D supplementation.

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