SEARCH

SEARCH BY CITATION

Keywords:

  • VITAMIN D–RESISTANCE RICKETS (VDRR);
  • VITAMIN D RECEPTOR KNOCKOUT MICE (VDR KO MICE);
  • RENIN-ANGIOTENSIN SYSTEM (RAS);
  • HYPERTENSION;
  • LEFT VENTRICULAR MASS (LVM)

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Vitamin D deficiency has been linked to hypertension and an increased prevalence of cardiovascular risk factors and disease. Studies in vitamin D receptor knockout (VDR KO) mice revealed an overstimulated renin-angiotensin system (RAS) and consequent high blood pressure and cardiac hypertrophy. VDR KO mice correspond phenotypically and metabolically to humans with hereditary 1,25-dihydroxyvitamin D–resistant rickets (HVDRR). There are no data on the cardiovascular system in human HVDRR. To better understand the effects of vitamin D on the human cardiovascular system, the RAS, blood pressure levels, and cardiac structures were examined in HVDRR patients. Seventeen patients (9 males, 8 females, aged 6 to 36 years) with hereditary HVDRR were enrolled. The control group included age- and gender-matched healthy subjects. Serum calcium, phosphorous, creatinine, 25-hydroxyvitamin D [25(OH)D],1,25-dihydroxyvitamin D3 [1,25(OH)2D3], parathyroid hormone (PTH), plasma rennin activity (PRA), aldosterone, angiotensin II (AT-II), and angiotensin-converting enzyme (ACE) levels were determined. Ambulatory 24-hour blood pressure measurements and echocardiographic examinations were performed. Serum calcium, phosphorus, and alkaline phosphatase values were normal. Serum 1,25(OH)2D3 and PTH but not PRA and ACE levels were elevated in the HVDRR patients. AT-II levels were higher than normal in the HVDRR patients but not significantly different from those of the controls. Aldosterone levels were normal in all HVDRR patients. No HVDRR patient had hypertension or echocardiographic pathology. These findings reveal that 6- to 36-year-old humans with HVDRR have normal renin and ACE activity, mild but nonsignificant elevation of AT-II, normal aldosterone levels, and no hypertension or gross heart abnormalities. © 2011 American Society for Bone and Mineral Research


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Understanding of the physiologic functions of vitamin D has extended beyond the regulation of calcium homeostasis and mineralization of bone to include regulation of the immune system and the proliferation and differentiation of normal and malignant cells. Recent cross-sectional studies have found low serum levels of 25-hydroxyvitamin D [25(OH)D] to be associated with an increased prevalence of hypertension and cardiovascular risk factors and disease.1, 2 Impaired ventricular function and dilated cardiomyopathy also have been documented in pediatric patients with rickets resulting from vitamin D deficiency.3–5

Mice with genetic disruption of the 1α-hydroxylase gene or of the vitamin D receptor (Vdr) gene (Vdr knockout) have an overstimulated renin-angiotensin system (RAS) and consequently developed high blood pressure accompanied by an increase in the heart-weight-to-body-weight ratio.6, 7 Furthermore, studies in mice with targeted deletion of the 25(OH)D 1α-hydroxylase demonstrated that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] treatment affords cardiovascular protection by repressing the RAS independent of extracellular calcium or phosphorus metabolism.7

It was shown recently that the vitamin D receptor (VDR) in adult rat and mouse cardiomyocytes is located in the T-tubular structure. Ablation of the VDR in mice resulted in chronic changes in contractile kinetics: Specifically, 1,25(OH)2D3 had rapid effects on myocyte contraction that were absent in Vdr knockout myocytes.8 It was proposed that calcitriol acts directly on the heart as a tranquilizer by blunting cardiomyocyte hypertrophy.9

Hereditary 1,25(OH)2D3-resistant rickets (HVDRR) owing to a generalized resistance to 1,25(OH)2D3 is caused by heterogeneous mutations in the VDR gene that cause loss of function of the receptor, ultimately leading to complete or partial target organ resistance to 1,25(OH)2D3. HVDRR in humans is due to mutations in the VDR gene.10 Patients with HVDRR and VDR knockout mice share many phenotypic and metabolic features, such as alopecia, hypocalcemia, elevated 1,25(OH)2D3 and parathyroid hormone (PTH) levels, and severe rickets.11 However, there are no studies or published clinical observations on the cardiovascular system in patients with HVDRR. The aim of this study was to investigate the RAS, blood pressure levels, and cardiac structure in HVDRR patients.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Patients

Seventeen consecutive patients with HVDRR (9 males and 8 females, aged 6 to 36 years) comprised the study group. Their characteristics are presented in Table 1. Two males were prepubertal (6 and 7.3 years old), and 4 females were in the course of puberty (twin sisters aged 11.8, 15.9, and 17 years old). Of the 11 adult patients, 7 were males (21 to 34 years old), and 4 were females (22 to 36 years old).

Table 1. Characteristics and Metabolic Parameters of the HVDRR Patients and Controls
 HVDRR femalesHVDRR malesControl femalesControl males
Age
 Pre-pubertal (Age, yr) 6.6 ± 0.9 7.5 ± 2.1
  n = 2 (6, 7.3) n = 2 (6, 9)
 Pubertal (Age, yr)13.1 ± 23 14.2 ± 2.2 
 n = 4 (11.8, 11.8, 15.9, 17) n = 4 (12, 13, 15, 17) 
 Adults (Age, yr)26.6 ± 8.427.7 ± 4333 ± 3.126.2 ± 4.15
 n = 4 (22, 23, 35, 36)n = 7 (21, 25, 26, 27, 29, 32, 34)n = 4 (29, 32, 35, 36)n = 7 (20, 25, 25, 26, 27, 27, 34)
Height cm (Z-score)
 Pre-pubertal 114.5 ± 4.5 (−1.45 ± 0.2) 129 ± 1.4 (0.75 ± 1.7)
 Pubertal140.2 ± 14.6 (−2.6 ± 1) 157 ± 6.5 (−0.06 ± 0.42) 
 Adults149 ± 9.5 (−1.9 ± 1.88)161.6 ± 10 (−2.49 ± 1.5)160 ± 1.25 (−0.42 ± 0.15173.9 ±v5.6.5 (−032 ± 0.87)
BMI & BMI Z-score
 Pre-pubertal 16.7 ± 0.7 (0.27 ± 0.17) 17.4 ± 1.2 (1.17 ± 0.6)
 Pubertal18 ± 2.8 (0.03 ± 0.3) 24.3 ± 3.1 (1.12 ± 0.4) 
 Adults24.8 ± 5.9 (0.12 ± 1.3)26.2 ± 3.4 (1.0 ± 0.9)25 ± 3.7 (0.8 ± 0.5)248 ± 43 (0.8 ± 1.22)

These patients' phenotypes and genotypes have been described previously.12, 13 Fourteen of them belong to an Arab extended pedigree with a nonsense mutation in exon 8 (c.C885A) resulting in a stop codon, Tyr295stop,14 that was expressed consequently in a truncated receptor unable to bind 1,25(OH)2D3 and devoid of any biologic function.14, 15 One patient of Persian-Jewish origin had the same mutation that had been found in the extended Arab pedigree. A missense mutation in exon 2 (c.G98A) that encodes the first zinc module of the DNA binding domain (DBD) was found in 2 Arab siblings. This missense mutation changed glycine to aspartic acid at amino acid residue 33 in the first zinc finger module (Gly33Asp).16

All 6 pubertal and prepubertal patients were diagnosed at birth or during infancy and were treated with 5 g/m2 of calcium orally, which succeeded in preventing rickets and bone deformities.

The 11 adult HVDRR patients were diagnosed during childhood and early puberty. They were treated with high doses of elemental calcium (range 0.4 to 1.4 g/m2) through indwelling intracaval catheters for periods ranging from 1.8 to 3.8 years. Oral calcium therapy in doses of 5 g/m2 was initiated after radiologic evidence of healing of the rickets was seen.17, 18 Eight patients started treatment during early childhood (3 to 6 years) and reached normal adult height, whereas 3 patients (2 females and 1 male) reached very short final heights of 137, 140, and 137 cm, respectively [−3, −4.42, and −5.5 height standard deviation score (SDS)]. All adult patients stopped calcium supplement at 18 to 20 years of age, and although they consume less than 1 g of calcium per day on dietary calcium, they have almost normocalcemic and normophosphatemic blood levels with moderate elevation of PTH.

All patients were born with sparse hair surrounded by clusters of bald scalp areas, eyebrows, and eyelashes. They all lost most of their scalp hair at 1 to 6 months of age. There was no sign of pubic hair at puberty. During puberty, small milia restricted to skin areas, such as the upper body or the scalp and face, appeared and became prominent during adulthood. Adults had nearly normal eyelashes and sparse eyebrows.

All 17 patients who participated in this study maintain a normal lifestyle and are currently normocalcemic. All have normal liver and kidney functions, and none has diabetes or is being treated with any medication other than calcium. Ultrasonography of the neck failed to demonstrate any case of enlarged parathyroid glands. Two adult male patients practice high-endurance sport activities.

For evaluation of the RAS components, 17 healthy age- and gender-matched normal subjects from the patients' extended families were recruited to form the control group. Their anthropometric characteristics are presented in Table 1. Some were the siblings of the HVDRR patients and therefore may have been heterozygote carriers of the disease. Such heterozygote carriers were shown previously to express normal VDR,14 to have in vitro VDR activity, and to be indistinguishable from normal subjects both clinically and biochemically.15

The Rambam Health Care Campus Helsinki Committee approved this study. Written informed consent was obtained from the participants or the parents of minor participants.

Methods

Serum calcium, phosphorous, creatinine, 25(OH)D, 1,25(OH)2D3, PTH, plasma renin activity (PRA), aldosterone, angiotensin II (AT-II), and angiotensin-converting enzyme (ACE) were determined after 1 hour of supine rest. Serum 25(OH)D and 1,25(OH)2D3 concentrations were measured by radioassay (DiaSorin, Inc., Stillwater, MN, USA). Plasma PTH was measured by an immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA). Blood samples for PRA, aldosterone, AT-II, and ACE were collected under ice 1 hour after an antecubital vein catheterization and 1 hour of bed rest. PRA was determined by RIA (DiaSorin, Inc.), and plasma aldosterone was measured by RIA (DPC, Los Angeles, CA, USA). AT-II was determined by the AT-II (human) AssayMax ELISA Kit, and ACE activity was measured with the ACE Trinity Biotech Procedure 305-UV Instrument (Cobas Mira, Roche, Basel, Switzerland). 25(OH)D and 1,25(OH)2D3, plasma PTH, calcium, phosphorus, androsterone, PRA, AT-II, and ACE values were compared with those of age- and gender-matched normal subjects from the extended families.

Echocardiography

M-mode 2D echocardiographic examinations were performed by commercially available instruments (Philips SONOS 7500, Koninklijke Philips Electronics N.V., Eindhoven, The Netherlands) equipped with 2.25- to 7.5-MHz imaging transducers. End-diastolic and end-systolic left ventricular internal diameter (LVED and LVES), interventricular septum thickness (IVST), and posterior wall thickness (PWT) were measured. Left ventricular mass (LVM) was estimated by Devereux's formula normalized by body surface area (BSA) and height. Heart measurements, adjusted to age, gender, and body surface area (BSA), were compared with published normal reference data that were obtained by echocardiography and cardiac magnetic resonance imaging (MRI).19–21

Relative wall thickness (RWT) was calculated as PWT/internal radius at end-diastole in order to assess LV geometry. Endocardial shortening was calculated as the ratio LVED-LVES/LVED. Increased RWT was identified as an RWT of 0.42 or more.22 All patients were in sinus rhythm at the time of their echocardiographic examinations. All echocardiographic examinations were performed by the same cardiologist. All heart measurements were compared with those of normal white subjects from Europe and North America. That is because the values of individuals of the same genetic background as the current HVDRR patients were shown not to be significantly different from European and North American subjects.23

Ambulatory blood pressure monitoring

Ambulatory blood pressure monitors (ABPMs) were used to record for 24 hours on the nondominant arm using an Oscar 2 device (SunTech Medical, Inc., Morrisville, NC, USA). The device was set to obtain blood pressure readings at 15-minute intervals during the day (7:00 to 23:00) and at 30-minute intervals during the night (23:00 to 7:00). Each ABPM data set was scanned automatically to remove artifactual readings according to preselected editing criteria. Mean 24-hour, daytime, and nighttime heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) values were obtained, as were percent nocturnal decreases (dips) in these measures. A dip was defined as a greater than 10% reduction at night in the mean HR, SBP, and DBP values.

Statistics

BP measurements in children and pubertal patients were adjusted for age and gender and are expressed as Z-scores.24 All heart compartment measurements were adjusted to BSA and presented as Z-scores.25 Measurements that reached a Z-score of more than 2 were suspected of being abnormal. The results were compared with normal reference values.21, 26

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Minerals, electrolytes, and calcium-regulating hormones

The mean (±SDM) serum calcium, phosphorous, creatinine, potassium, and sodium concentrations and serum alkaline phosphatase activity of the patients and the controls are presented in Fig. 1. The data are given according to age (ie, prepubertal, pubertal, and adult) and gender. Calcium levels were significantly lower in HVDRR adult male patients than in control adult males (p < .01; Fig. 1A). PTH levels were elevated in the prepubertal and pubertal patients (p < .025). The highest PTH values were detected in the prepubertal patients, whereas they tended toward normal values in adulthood (Fig. 1D). The levels of 1,25(OH)2D3, the hallmark of HVDRR,12 were significantly elevated in all patients except adult females (Fig. 1F).

thumbnail image

Figure 1. Metabolic parameters of the HVDRR patients and controls (mean ± SDM). The open bars represent the patients, and the black bars represent the controls. The dashed lines represent the lower limits for calcium, phosphorous, and 25(OH)D and the upper limits for alkaline phosphatase, PTH, and 1,25(OH)D. The asterisks represent the difference in magnitude between HVDRR patients and controls. Calcium levels were normal in the prepubertal and pubertal HVDRR patients during calcium supplement, whereas they were normal in adult HVDRR patients without any calcium supplement.

Download figure to PowerPoint

Renin-angiotensin-aldosterone axis

The mean PRA levels were normal in all HVDRR patients (Fig. 2A). ACE levels were similar for the two groups (Fig. 2B). AT-II levels were higher than the normal reference values in all HVDRR patients but without significant differences between HVDRR patients and control individuals (Fig. 2C). Aldosterone levels were within the normal range in all HVDRR patients (Fig. 2D).

thumbnail image

Figure 2. The renin angiotensin aldosterone system in HVDRR patients and controls (mean ± SDM). The open bars represent the patients, and the black bars represent the controls. The hatched line represents the upper normal values. The asterisks represent the difference in magnitude between HVDRR patients and controls. Aldosterone levels in HVDRR adult females were normal but significantly higher than in normal adult females (p < .02).

Download figure to PowerPoint

Blood pressure and heart rate

Neither systolic nor diastolic hypertension was detected in any of the adults or children during the 24 hours of continuous BP recording (Fig. 3). SBP Z-scores in the prepubertal males and pubertal females were 0.75 ± 0.73 and −0.24 ± −0.18, respectively, whereas their DBP Z-scores were 0.04 ± 0.01 and −0.021 ± 0.008, respectively.

thumbnail image

Figure 3. Mean 24-hour daytime and nighttime systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR). The open bars represent daytime measurements, and the black bars represent the nighttime measurements (mean ± SDM). F = female; M = male.

Download figure to PowerPoint

There was a significant correlation between day and night SBPs (r = 0.94, p < .001) and DBPs (r = 0.7, p < .01) among the males. In contrast, while there was a significant correlation between day and night SBPs among the females (r = 0.74, p ≤ .05), none was demonstrated between day and night DBPs.

thumbnail image

Figure 4. Left ventricular (LV) mass for height percentile curves generated by Foster and colleagues26 (used with permission). The 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles are depicted. All 17 patients are plotted. Black dots represent male patients, and open dots represent female patients. The five dots between the 90th and 95th percentiles were two short adult patients (male 140 cm, −5.7 SDS, and female 134 cm, −4.42 SDS), two adult patients who practice high-endurance sport activities (27 years old, 164 cm, −2 SDS and 27 years old, 163.4 cm, −2.11 SDS), and a 17-year-old female (150 cm, −2.21 SDS).

Download figure to PowerPoint

None had blunted nocturnal dipping during normal night sleep (ie, nondipper profile), which is an early, sensitive sign of general tendency toward hypertension. Two males, 6 and 21 years of age, and one 36-year-old female had an SBP dip lower than −10% (ie, 5.3%, 7.1%, and 6.9%, respectively). DBP dips were more prominent than SBP dips (−22.2% ± 11.2% and −11.1% ± 4.9% in males and females, respectively, p < .02). Two males, 25 and 32 years old and one 36-year-old female had a DBP dip lower than −10% (ie, −4.4%, −6.6%, and −4.4%, respectively), and all three reported difficulty sleeping during BP measurements at night.

HR measurements are presented in Table 2. All the males had an HR dip greater than −10% compared with 4 females who had a dip lower than −10% (ages 15.9, 17, 23, and 35 years). All four of these females reported difficulty sleeping during BP measurements at night. The only patient who had neither SBP nor DBP dips was a 36-year-old female who was very short and obese [134 cm, body mass index (BMI) 35 kg/m2]. Her LVM adjusted to BSA Z-score was 0.27, her RWT was less than 0.42 mm, and her adjusted aortic root diameter to BSA was 0.77 SDS.

Table 2. Heart Measurements as Recorded by M-Mode 2D Echocardiographic Examinations, Adjusted to Body Surface Area (BSA) and Height, and Expressed in Z-Scores
 FemalesMales
PubertalAdultsPre-pubertalAdults
  1. SDS = standard deviation score; LVED = left ventricular end-diastolic; LVES = left ventricular end-systolic; IVST = interventricular septum thickness; PWT = posterior wall thickness; AR = aortic root; LA = left atrium; RV = right ventricle.

LV mass (gr)79.6 ± 31.998.3 ± 22.952 ± 3111 ± 12
 (range)(49–131)(78–125)(49.1–55.2)(92–126)
 [Normal][107 ± 20][76–162] [88–224]
LV mass Z-score−0.77 ± 1.0−0.17 ± 0.840.02 ± 0.17−0.67 ± 0.43
 (range)(−1.97–1.0)(−0.9–0.8)(−0.1–01)(−1.3–(−0.1))
LVSF%42.2 ± 4.442.2 ± 3.443.5 ± 2.539.5 ± 6.8
 (range)(34.6–46)(38–46)(41–46)(32.5–50)
 [Normal] [25–43] [27–45]
LVED/BSASDS−0.46 ± 1.10.6−0.28 ± 1.151.42 ± 0.540.35 ± 1.72
 (range)(1.9–0.44)(−1–1.4)(1–1.8)(−2.6–1.43)
LVES/BSASDS−0.29 ± 1.49−0.97 ± 1.22−0.28 ± 0.56−0.33 ± 0.91
 (range)(−1.3–1.9)(−2–0.7)−0.6–0.1(−1.2–1.4)
LA/BSASDS0.22 ± 1.15−0.68 ± 0.611.0 ± 0.720.86 ± 1.16
 (range)(−1.4–1.0)(−1.58–(−10))(0.5–1.52)(−0.4–2.6)
AR/BSASDS0.33 ± 1.120.01 ± 0.80.95 ± 0.61.3 ± 0.8
 (range)(−1–1.6)(−1–0.8)(0.46–1.44)(0.39–2.5)
RV/BSASDS1.86 ± 1.050.2 ± 0.90.73 ± 0.460.57 ± 1.29
 (range)(0.6–1.9)(−1.4–0.8)(0.4–1)(−0.8–1.4)

Echocardiography

All heart measurements adjusted for age, gender, and BSA were within the normal ranges (Table 2). None of the HVDRR patients' LVM measurements indicated LVH. The highest LVM measured in adult males was 180 g. The highest LVM in females, 131 g, was measured in a 17-year-old female. This value was close to the 95th percentile according to the early LVM estimations by Daniels and colleagues27 and less than 2 SDS, as estimated recently with MRI by Cain and colleagues.20, 21

LVED and LVES diameters were normal in all patients. The highest LVED/BSA measurements were those of the two adult males who practice high-endurance sport activities (1.8 SDS) and in the 17-year-old female (2 SDS). The highest LVES/BSA was measured in the same 17-year-old female (1.76 SDS).

IVS/BSA Z-scores and left PWT measurements were normal in all patients. None had a relative PWT > 0.42. The mean aortic root (AR) diameter at the sinuses of Valsalva level was within the normal range in all adult males and females.25, 28, 29 The AR diameter was 20.5 ± 2.1 mm in the prepubertal males and 30.5 ± 3.3 in the adult males, and it was 23 ± 4.6 mm and 25 ± 1.8 mm in the pubertal and adult females, respectively. The AR diameter adjusted to BSA was at 2.5 SDS in one patient with severe kyphosis, who was extremely short (−5.7 height SDS). The right ventricle and left atrium diameters adjusted to BSA were normal in all patients, except for one adult male who practices high-endurance sport activities: He had a left atrium/BSA of +2.6 SDS. The mean prepubertal (43.5% ± 2.5%) and pubertal (44.7% ± 1.5%) ventricular shortening fractions were higher than those in adults (p < .05), as expected.

LVM was plotted against height, as proposed by Foster and colleagues26 (Fig. 4). The LVM adjusted to height in 5 HVDRR patients was between the 90th and 95th percentiles. Two of these 5 patients were males who practice high-endurance sport activities, and a third patient was a very short adult male (140 cm, −5.7 height SDS). The remaining 2 patients were females, one who was a very short adult (134 cm, −4.42 height SDS) and the other who was the 17-year-old with an LVM of 131 g and an LVM Z-score of 0.9.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Accumulating evidence from clinical and epidemiologic studies in humans indicates that low vitamin D status is associated with increased prevalence of arterial hypertension.1, 2 Similarly, Vdr null mice and 1α-hydroxylase knockout mice develop high-renin hypertension and cardiac hypertrophy.30 However, recent systematic reviews concluded that the association between vitamin D status and hypertension is still uncertain and that vitamin D supplementation showed minimal or no effect on BP.31, 32 Thus it remains to be established whether there is a causal association between vitamin D deficiency and hypertension in humans.

HVDRR is a rare disease. Fewer than 100 patients have been reported in the literature.33 Therefore, the 17 patients who participated in this study provide a unique opportunity to examine the role of vitamin D and that of VDR in humans in order to elucidate and extend current understanding of the role of vitamin D in the cardiovascular system.

All patients had normal BP measurements during ambulatory blood pressure monitoring, which is the recommended method of choice for effectively screening, diagnosing, and monitoring hypertension in all age groups. Furthermore, none had blunted nocturnal dipping during normal night sleep (nondipper profile), which is an early sensitive sign of general tendency toward hypertension.34 None of our HVDRR patients was found to have any evidence of increased RAS activity or pathologic hypertrophy of the heart, at least until the age of 36 years. This is contrary to the findings of many clinical and epidemiologic studies that demonstrated a link between vitamin D deficiency and hypertension and the findings in Vdr and 1α-hydroxylase knockout mice models.

Tishkoff and colleagues8 and Zhao and Simpson35 have shown recently that part of the VDR specifically interacts with T-tubules in adult rat and mouse cardiomyocytes and that 1,25(OH)2D3 induces a decreased peak sarcomere shortening within minutes, effects that are considered to be nongenomic. The possibility that the truncated VDR in our HVDRR patients still poses a secondary ligand-binding pocket that is responsible for the normal blood pressure and heart structure was excluded by Malloy and colleagues,14 who showed that the point mutation in the VDR gene at nucleotide c.C885A, as found in the 15 patients in this study, results in a premature stop, Tyr295stop, and consequently expresses no VDR owing to instability and degradation of the abnormal mRNA.

As for the role of 1,25(OH)2D3 and VDR in renin metabolism, several studies have emphasized the important role of 1,25(OH)2D3 in suppressing rennin.7 Yuan and colleagues36 have shown that 1,25(OH)2D3 liganded to the VDR downregulates renin gene transcription by suppressing, at least in part, cAMP-responsive element–mediated transcriptional activity in the renin gene promoter. In addition to studies on the effect of 1,25(OH)2D3 liganded to the VDR on renin suppression, others have revealed the involvement of multiple regulatory proteins that suppress renin expression, such as nuclear receptors Retinoid X receptor (RXR) α and β,37 ERBE-Related 2 (Ear2),38 and Nuclear Transcription Factor-Y (NF-Y).39 One possible explanation for the differences in renin levels between Vdr knockout mice and HVDRR patients may relate to the possibility that among the factors that suppress renin in humans, the relative effect of 1,25(OH)2D3 liganded to the VDR on renin is lower in humans than in mice. Recent human investigations of the association between vitamin D and the RAS did not find any significant relation between plasma 25-hydroxyvitamin D and the RAS in 184 normotensive individuals.40

We are currently unable to provide any explanation or mechanism for the differences between Vdr null mice and HVDRR patients other than the possibility that humans may activate redundant mechanisms to maintain normal blood pressure, RAS activity, and cardiac structure in the absence of VDR activity. One example for a compensatory mechanism is the change in the extent of calcium supplement doses required by our adult HVDRR patients to maintain normocalcemic levels. During infancy and childhood, our HVDRR patients who lacked a functional VDR suffered from severe hypocalcemia and rickets and were treated successfully with huge doses of calcium, whereas the same patients now maintain normocalcemic levels without calcium supplement as adults. The observation that HVDRR patients can maintain normal serum calcium levels without calcium supplement after puberty, once growth has ended and calcium demand is lower,41 was reported previously,42–45 but the mechanism behind this change over time is not fully understood. The results of studies on humans46 and Vdr knockout mice47–49 raised the possibility that sex hormones are involved in enhancing increased intestinal calcium absorption through VDR-independent mechanisms.

The possibility that the high therapeutic calcium dose taken by the prepubertal and pubertal patients in this study prevented activation of the RAS, hypertension, and heart hypertrophy was addressed by Li and colleagues,30 who showed that the elevation of renin expression in Vdr knockout mice is not due to hypocalcemia but resulted from VDR inactivation per se and/or hyperparathyroidism.

PTH has been shown to indirectly regulate renin expression, and intravenous infusion of PTH was shown to increase PRA and renin release in both humans and animals.50, 51 Despite high PTH levels in almost all the currently described patients, none of them had elevated levels of PRA.

In summary, a cohort of patients with HVDRR, aged 6 to 36 years, was evaluated and shown to have normal PRA, aldosterone, and ACE activity and mild but nonsignificant elevation of AT-II. None had hypertension or gross heart abnormities.

Disclosures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

All the authors state that they have no conflicts of interest.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Authors' roles: Study design: DT, YW, and AL. Study conduct: DT and AL. Data collection: DT, YS, YB, AH, and VG. Data analysis: DT, YS, and YW. Data interpretation: DT, YS, and YW. Drafting manuscript: DT, YS, and YW. Revising manuscript content: DT and YW. Approving final version of manuscript: DT, YS, YB, AH, VG, and YW. AL takes responsibility for the integrity of the data analysis.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  • 1
    Pilz S, Marz W, Wellnitz B, et al. Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab. 2008; 93: 39273935.
  • 2
    Pilz S, Tomaschitz A, Ritz E, Pieber TR. Vitamin D status and arterial hypertension: a systematic review. Nat Rev Cardiol. 2009; 6: 621630.
  • 3
    Chen S, Glenn DJ, Ni W, et al. Expression of the vitamin D receptor is increased in the hypertrophic heart. Hypertension. 2008; 52: 11061112.
  • 4
    Bodyak N, Ayus JC, Achinger S, et al. Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals. Proc Natl Acad Sci USA. 2007; 104: 1681016815.
  • 5
    Lee JH, O'Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? J Am Coll Cardiol. 2008; 52: 19491956.
  • 6
    Xiang W, Kong J, Chen S, et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab. 2005; 288: E125132.
  • 7
    Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice. Kidney Int. 2008; 74: 170179.
  • 8
    Tishkoff DX, Nibbelink KA, Holmberg KH, Dandu L, Simpson RU. Functional vitamin D receptor (VDR) in the t-tubules of cardiac myocytes: VDR knockout cardiomyocyte contractility. Endocrinology. 2008; 149: 558564.
  • 9
    Simpson RU, Hershey SH, Nibbelink KA. Characterization of heart size and blood pressure in the vitamin D receptor knockout mouse. J Steroid Biochem Mol Biol. 2007; 103: 521524.
  • 10
    Malloy PJ, Feldman D. Genetic disorders and defects in vitamin d action. Endocrinol Metab Clin North Am. 2010; 39: 333346, table of contents.
  • 11
    Bouillon R, Carmeliet G, Verlinden L, et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev. 2008; 29: 726776.
  • 12
    Tiosano D, Weisman Y, Hochberg Z. The role of the vitamin D receptor in regulating vitamin D metabolism: a study of vitamin D-dependent rickets, type II. J Clin Endocrinol Metab. 2001; 86: 19081912.
  • 13
    Even L, Weisman Y, Goldray D, Hochberg Z. Selective modulation by vitamin D of renal response to parathyroid hormone: a study in calcitriol-resistant rickets. J Clin Endocrinol Metab. 1996; 81: 28362840.
  • 14
    Malloy PJ, Hochberg Z, Tiosano D, Pike JW, Hughes MR, Feldman D. The molecular basis of hereditary 1,25-dihydroxyvitamin D3 resistant rickets in seven related families. J Clin Invest. 1990; 86: 20712079.
  • 15
    Feldman D, Chen T, Cone C, et al. Vitamin D resistant rickets with alopecia: cultured skin fibroblasts exhibit defective cytoplasmic receptors and unresponsiveness to 1,25(OH)2D3. J Clin Endocrinol Metab. 1982; 55: 10201022.
  • 16
    Hughes MR, Malloy PJ, Kieback DG, et al. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science. 1988; 242: 17021705.
  • 17
    Hochberg Z, Tiosano D, Even L. Calcium therapy for calcitriol-resistant rickets. J Pediatr. 1992; 121: 803808.
  • 18
    Weisman Y, Bab I, Gazit D, Spirer Z, Jaffe M, Hochberg Z. Long-term intracaval calcium infusion therapy in end-organ resistance to 1,25-dihydroxyvitamin D. Am J Med. 1987; 83: 984990.
  • 19
    Daniels SR, Meyer RA, Liang YC, Bove KE. Echocardiographically determined left ventricular mass index in normal children, adolescents and young adults. J Am Coll Cardiol. 1988; 12: 703708.
  • 20
    Cain PA, Ahl R, Hedstrom E, et al. Age and gender specific normal values of left ventricular mass, volume and function for gradient echo magnetic resonance imaging: a cross sectional study. BMC Med Imaging. 2009; 9: 2.
  • 21
    Cain PA, Ahl R, Hedstrom E, et al. Physiological determinants of the variation in left ventricular mass from early adolescence to late adulthood in healthy subjects. Clin Physiol Funct Imaging. 2007; 27: 255262.
  • 22
    Ganau A, Devereux RB, Roman MJ, et al. Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol. 1992; 19: 15501558.
  • 23
    Mohammad MJM. Determination of left ventricular mass by echocardiography in normal Arab people. Med J Islamic. Acad Sci. 2001; 14: 5964.
  • 24
    National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. Pediatrics. 2004; 114: 555576.
  • 25
    Kampmann C, Wiethoff CM, Wenzel A, et al. Normal values of M mode echocardiographic measurements of more than 2000 healthy infants and children in central Europe. Heart. 2000; 83: 667672.
  • 26
    Foster BJ, Mackie AS, Mitsnefes M, Ali H, Mamber S, Colan SD. A novel method of expressing left ventricular mass relative to body size in children. Circulation. 2008; 117: 27692775.
  • 27
    Cuspidi C, Michev I, Meani S, et al. Reduced nocturnal fall in blood pressure, assessed by two ambulatory blood pressure monitorings and cardiac alterations in early phases of untreated essential hypertension. J Hum Hypertens. 2003; 17: 245251.
  • 28
    Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005; 18: 14401463.
  • 29
    Burman ED, Keegan J, Kilner PJ. Aortic root measurement by cardiovascular magnetic resonance: specification of planes and lines of measurement and corresponding normal values. Circ Cardiovasc Imaging. 2008; 1: 104113.
  • 30
    Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002; 110: 229238.
  • 31
    Pittas AG, Chung M, Trikalinos T, et al. Systematic review: Vitamin D and cardiometabolic outcomes. Ann Intern Med. 2010; 152: 307314.
  • 32
    Wang L, Manson JE, Song Y, Sesso HD. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010; 152: 315323.
  • 33
    Malloy PJ, Pike JW, Feldman D. The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr Rev. 1999; 20: 156188.
  • 34
    Urbina E, Alpert B, Flynn J, et al. Ambulatory blood pressure monitoring in children and adolescents: recommendations for standard assessment: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the council on cardiovascular disease in the young and the council for high blood pressure research. Hypertension. 2008; 52: 433451.
  • 35
    Zhao G, Simpson RU. Membrane localization, Caveolin-3 association and rapid actions of vitamin D receptor in cardiac myocytes. Steroids. 2009.
  • 36
    Yuan W, Pan W, Kong J, et al. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem. 2007; 282: 2982129830.
  • 37
    Murakami Y, Nobukuni T, Tamura K, et al. Localization of tumor suppressor activity important in nonsmall cell lung carcinoma on chromosome 11q. Proc Natl Acad Sci U S A. 1998; 95: 81538158.
  • 38
    Liu X, Huang X, Sigmund CD. Identification of a nuclear orphan receptor (Ear2) as a negative regulator of renin gene transcription. Circ Res. 2003; 92: 10331040.
  • 39
    Shi Q, Gross KW, Sigmund CD. NF-Y antagonizes renin enhancer function by blocking stimulatory transcription factors. Hypertension. 2001; 38: 332336.
  • 40
    Forman JP, Williams JS, Fisher ND. Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system in humans. Hypertension. 55: 12831288.
  • 41
    Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011; 96: 5358.
  • 42
    Hochberg Z, Benderli A, Levy J, et al. 1,25-Dihydroxyvitamin D resistance, rickets, and alopecia. Am J Med. 1984; 77: 805811.
  • 43
    Hirst MA, Hochman HI, Feldman D. Vitamin D resistance and alopecia: a kindred with normal 1,25-dihydroxyvitamin D binding, but decreased receptor affinity for deoxyribonucleic acid. J Clin Endocrinol Metab. 1985; 60: 490495.
  • 44
    Chen TL, Hirst MA, Cone CM, Hochberg Z, Tietze HU, Feldman D. 1,25-dihydroxyvitamin D resistance, rickets, and alopecia: analysis of receptors and bioresponse in cultured fibroblasts from patients and parents. J Clin Endocrinol Metab. 1984; 59: 383388.
  • 45
    Nicolaidou P, Tsitsika A, Papadimitriou A, et al. Hereditary vitamin D-resistant rickets in Greek children: genotype, phenotype, and long-term response to treatment. J Pediatr Endocrinol Metab. 2007; 20: 425430.
  • 46
    Mauras N, Vieira NE, Yergey AL. Estrogen therapy enhances calcium absorption and retention and diminishes bone turnover in young girls with Turner's syndrome: a calcium kinetic study. Metabolism. 1997; 46: 908913.
  • 47
    Colin EM, Van Den Bemd GJ, Van Aken M, et al. Evidence for involvement of 17beta-estradiol in intestinal calcium absorption independent of 1,25-dihydroxyvitamin D3 level in the Rat. J Bone Miner Res. 1999; 14: 5764.
  • 48
    Van Cromphaut SJ, Rummens K, Stockmans I, et al. Intestinal calcium transporter genes are upregulated by estrogens and the reproductive cycle through vitamin D receptor-independent mechanisms. J Bone Miner Res. 2003; 18: 17251736.
  • 49
    Fudge NJ, Kovacs CS. Pregnancy up-regulates intestinal calcium absorption and skeletal mineralization independently of the vitamin D receptor. Endocrinology. 2010; 151: 886895.
  • 50
    Silver J, Naveh-Many T, Mayer H, Schmelzer HJ, Popovtzer MM. Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest. 1986; 78: 12961301.
  • 51
    Broulik PD, Horky K, Pacovsky V. Effect of parathyroid hormone on plasma renin activity in humans. Horm Metab Res. 1986; 18: 490492.