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Journal of Human Hypertension (2005) 19, 901–906 & 2005 Nature Publishing Group All rights reserved 0950-9240/05 $30.00 www.nature.com/jhh

ORIGINAL ARTICLE

Ambulatory monitoring of blood pressure (AMBP) in patients with primary hyperparathyroidism C Letizia1,2, P Ferrari1,2, D Cotesta1,2, C Caliumi1,2, R Cianci1, S Cerci1, L Petramala1,2, M Celi1,2, S Minisola1, E D’Erasmo1,2 and GF Mazzuoli1 1

Department of Clinical Science, University of Rome ‘La Sapienza’, Rome, Italy; 2Day Hospital of Internal Medicine and Arterial Hypertension, University of Rome ‘La Sapienza’, Rome, Italy

The purpose of our study was to evaluate the behaviour of blood pressure (BP) by ambulatory monitoring of blood pressure (AMBP) in 53 patients with primary hyperparathyroidism (PHPT) compared to 100 essential hypertensive (EH) and 31 healthy subjects (HS). The correlations between calcium–phosphorus metabolism and haemodynamic parameters in all groups are included in the study. AMBP was performed using the oscillometric technique (Space-Labs, 90207, Redmond, WA, USA) and the following AMBP parameters were evaluated: average day time systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) (when awake), average night time SBP, DBP and HR (when asleep) and average 24-h-SBP, DBP and HR. The definition of ‘dipper’ or ‘non-dipper’ subjects was established if night time SBP and DBP fall was 410% and o10%, respectively. In total, 25 PHPT patients (47.2%) were hyperten-

sive (HT-PHPT) and 28 PHPT (52.8%) were normotensive (NT-PHPT). Mean 24-h-SBP and DBP obtained by AMBP was higher in HT-PHPT (Po0.05) and EH (Po0.05) than in NT-PHPT and HS. The multiple linear regression has shown that in PHPT-HT patients ionized calcium is an independent factor for the rise of 24-h-DBP values (r: 0.497; Po0.05) and daytime DBP values (r: 0.497; Po0.05). In 56% of HT-PHPT patients there is an absence of physiological BP nocturnal fall (‘non-dipper’), which is statistically significant (Po0.05) compared with ‘nondipper’ EH patients (30%). In conclusion, in our study the prevalence of hypertension in PHPT was 47%. AMBP revealed that the ‘non-dipping ‘pattern was much higher in HT-PHPT patients in respect to EH patients. Journal of Human Hypertension (2005) 19, 901–906. doi:10.1038/sj.jhh.1001907; published online 7 July 2005

Keywords: blood pressure; ambulatory monitoring blood pressure; essential hypertension; primary hyperparathyroidism; dipper and non-dipper

Introduction Primary hyperparathyroidism (PHPT) is a pathological condition characterized by excessive secretion of the parathyroid hormone (PTH) from one or more parathyroid glands, not related to homeostatic requirements and associated with hypercalcaemia.1 PHPT is more prevalent in women over 50 years and in most cases is due to adenoma (80–85%), hyperplasia (15–20%), multiple adenoma (4–5%) and carcinoma (1%).2 In the literature, there is evidence, which shows that PHPT is associated with an increase in cardiovascular risk. An association between PHPT and hypertension has been accepted for 40 years, Correspondence: Professor C Letizia, Department of Clinical Science, Policlinico Umberto I, Viale del Policlinico 155, 00156 Rome, Italy. E-mail: [email protected] Received 11 September 2004; revised and accepted 20 May 2005; published online 7 July 2005

with a prevalence of the latter that varies between 20 and 80%.3–5 In some studies, most patients with PHPT and hypertension have blood pressure (BP) values that significantly decrease after parathyroidectomy.6 That allows these patients to reduce antihypertensive treatment or even to stop it definitively.3,7–9 Ambulatory monitoring of blood pressure (AMBP), using either invasive or noninvasive recorders, has shown that BP tends to be higher during the day and lower at night in normotensive subjects.10–14 In particular, some hypertensive patients do not exhibit the normal nocturnal BP fall, and they have been called ‘non-dippers’, whereas those with normal circadian rhythm have been called ‘dippers’.15–18 Moreover, studies that used AMBP showed that the reduction in night time BP seems to lower in secondary forms of hypertension.17–21 The aim of our study was to assess the behaviour of BP by ABPM in patients with PHPT, evaluating

AMBP in patients with primary hyperparathyroidism C Letizia et al 902

the prevalence of hypertension and the ‘dipper’ phenomenon. Patients affected by essential hypertension (EH) and healthy subjects (HS) were recruited as controls. Moreover, correlations between some calcium–phosphorus metabolism and haemodynamics parameters were evaluated in all groups studied.

Methods

DBP and average 24-h HR. Periods were determined by the subjects diarics. The definition of ‘dipper’ and ‘non-dipper’ subjects was established where night time SBP and DBP fall was 410% and o10%, respectively.23–25 Ambulatory hypertension was defined as 24-h BP 4135/ 85 mmHg.23,24 Subjects missing more than 4-h of measurement were considered to be noninformative and were excluded from the study.

Study population

From January 1999 to December 2003, we examined 53 consecutive patients with clinical and biochemical PHPT (12 M, 41 F; mean age 58.879 years). The control group consisted of 100 patients with EH (23 M, 77 F; mean age 56.378 years), without any sign of organ damage, and 31 HS (7 M, 24 F; mean age 55.876 years). The diagnosis of PHPT was established according to laboratory data (PTH, ionized calcium, phosphorus, urinary calcium). All patients underwent ultrasonography (US) and Tc-MIBI-imaging. All patients were diagnosed with sporadic-type PHPT. The diagnosis of EH was made after the exclusion of secondary hypertension by studying the renin– angiotensin–aldosterone system, plasma cortisol, chromogranin A and urinary excretion of vanillilmandelic acid (VMA). This study was performed according to the Declaration of Helsinki and approved by the local Ethics Committee: all participants gave informed consent. Methods

All participants in the study followed a normosodic and normokaliemic diet for at least 2 weeks and compliance to the diet was evaluated with 24-h sodium and potassium excretion. After an overnight fast, at 0800–0900 blood samples were obtained for determination of ionized calcium (Ca2 þ ), creatinine and PTH. Ambulatory monitoring of blood pressure (AMBP)

AMBP was performed using the oscillometric technique, which involves a portable, lightweight, noninvasive monitor with a self-insufflating cuff (Space Labs, 90207, Redmond, WA, USA). This system has been validated by the British Hypertension Society22 and AMBP readings were obtained at 15 min intervals from 0600 to midnight, and at 30 min intervals from midnight to 0600. The following AMBP parameters were evaluated: average daytime systolic blood pressure (SBP), average daytime diastolic blood pressure (DBP) and daytime heart rate (HR) (when awake), average night time SBP, average night time DBP and night time HR (when asleep), and average 24-h SBP, average 24-h Journal of Human Hypertension

Statistical analysis

All data are expressed as mean7standard deviation (s.d.). The statistical analysis was performed using Sigmastat software (Jandel Corporation, USA) and all values were analysed using the ANOVA test, followed by Student’s t-test, whenever appropriate. Correlations between haemodynamic values and calcium phosphorus parameters were calculated using the Pearson coefficient of linear correlation. Multiple regression analysis with backward elimination of independent variables was performed to evaluate predictors of changes in cardiovascular parameters. A P-value o0.05 was considered significant.

Results All patients included in the study had good technical quality AMBP recordings. In total, 25 patients with PHPT were found to be hypertensive (HT-PHPT; 7 M, 18 F) and 28 were normotensive (NT-PHPT; 5 M, 23 F). The demographic, biochemical and haemodynamic parameters of the studied groups are reported in Table 1; furthermore, Table 1 shows serum ionized calcium (Ca2 þ ) and PTH mean levels. As expected, in patients with PHPT, serum Ca2 þ and PTH levels were higher than in other groups (Po0.001). No statistical difference was found for biochemical parameters between EH patients and HS (P40.05). Moreover, all patients with PHPT presented higher SBP and DBP values than HS (Po0.001), whereas patients with EH showed higher SBP and DBP than PHPT (Po0.001) and HS (Po0.001). Our results demonstrate that in PHPT patients, hypertensive status was present in 47.2% patients. Mean values for 24-h, daytime and night time SBP, and for 24-h, daytime and night time DBP, and for 24-h, daytime and night time HR in all patients affected by PHPT, EH patients and NS, respectively, are reported in Table 2. In Table 3 the AMBP values in HT-PHPT and NT-PHPT subgroups are reported. As expected, mean 24-h BP (24-h-SBP and 24-hDBP) obtained by AMBP was higher in the HT-PHPT subgroup (Po0.05) and the EH patients’ group (Po0.05) than in the NT-PHPT subgroup and HS group. No statistically significant difference


Table 1 Demographic, haemodynamic and laboratory parameters in all study groups Group

Sex (m/f)

Age (years)

PHPT-HT (n ¼ 25) PHPT-NT (n ¼ 28) EH (n ¼ 100) HS (n ¼ 31)

7/18 5/23 23/77 7/24

58.379 60.179 56.378 55.876

SBP (mmHg)

DBP (mmHg)

HR (b/min)

Calcium (mmol/l)

7277 7079 7676 6773

2.770.1* 2.7770.15 2.470.2 2.2770.1

142712* 8677* 11475 7576 165723*,** 10075* 11975 7974

Ca2+ (mmol/l)

P (mmol/l)

1.4570.1 0.8970.11 1.3870.1 0.9170.13 1.2170.02 1.1370.1*** 1.2270.21 1.170.2***

Creat (mmol/l)

PTHi (pg/ml)

93726.5 97717.7 75717.2 72727.4

94.4712* 83.3715 20.6711.4 29.0711.0

*Po0.001 vs PHPT-NT, HS and EH; **Po0.001 vs PHPT and HS; ***Po0.001 vs PHPT-HT and PHPT-NT. PHPT-NT ¼ primary hyperparathyroidism-normotensive; PHPT-HT ¼ primary hyperparathyroidism-hypertensive; EH ¼ essential hypertensive; HS ¼ healthy subjects; SBP ¼ systolic blood pressure; DBP ¼ diastolic blood pressure; HR ¼ heart rate; Ca2+ ¼ ionized serum calcium; P ¼ phosphorus; Creat ¼ creatinine; PHTi ¼ intact-parathyroid hormone.

Table 2 Ambulatory monitoring blood pressure 24 h (AMBP24 h) measurements in all studied groups AMBP

PHPT (n ¼ 53)

EH (n ¼ 100)

HS (n ¼ 31)

24-h BP average SBP 131.6714* 146.3711* 115.9711 (mmHg) 24-h BP average DBP 80.477* 92.475* 70.075 (mmHg) 24-h BP average HR (b/min) 70.878 78.378* 75.076 Daytime SBP (mmHg) 135.679* 150.578* 119.174 Daytime DBP (mmHg) 89.277* 95.076* 77.275 Daytime HR (b/min) 74.376 80.779 77.777 Night time SBP (mmHg) 130.4718* 136.8712* 109.5710 Night time DBP (mmHg) 76.079* 84.674* 69.176 Night time HR (b/min) 64.677 71.679 69.775 Data are expressed as mean7s.d. PHPT ¼ patients with primary hyperparathryroidism; EH ¼ patients with essential hypertension; HS ¼ healthy subjects; SBP ¼ systolic blood pressure; DBP ¼ diastolic blood pressure; HR ¼ heart rate; *Po0.001 vs HS.

Table 3 Ambulatory monitoring blood pressure (AMBP) measurements in patients with primary hyperparathyroidism (PHPT) AMBP

PHPT

Table 4 Correlation between 24 h-diastolic blood pressure (24-hDBP) and calcium-phosphorus parameters in patients with primary hyperparathyroidism and hypertension. Multiple linear regression (Stepwise-Backward) Variables

P-value

Regression coefficient

Age Calcium Ca2+ Phosphorus PTH

0.0993 0.752 0.05 0.178 0.382

0.904 0.597 0.497 0.497 0.617

Table 5 Correlation between daytime diastolic blood pressure (D-DBP) and calcium-phosphorus parameters in patients with primary hyperparathyroidism and hypertension. Multiple linear regression (Stepwise-Backward) Variables Calcium Ca2+ Phosphorus PTH

P-value

Regression coefficient

0.679 0.05 0.265 0.348

0.569 0.497 0.497 0.593

P

Normotensive Hypertensive (n ¼ 25) (n ¼ 25) 24-h BP average SBP (mmHg) 24-h BP average DBP (mmHg) 24-h BP average HR (b/min)

114.5710 72.575 70.179

141.5712 85.677 71.276

o0.05 o0.05 NS

Daytime SBP (mmHg) Daytime DBP (mmHg) Daytime HR (b/min)

119.675 76.776 73.279

145.379 89.277 74.376

o0.05 o0.05 NS

Night time SBP (mmHg) Night time DBP (mmHg) Night time HR (b/min)

105.0710 64.475 64.976

130.4718 76.079 64.677

o0.05 o0.05 NS

of 24-H-DBP values (r: 0.497; Po0.05) and daytime DBP values (r: 0.497; Po0.05) (Tables 4 and 5). No correlation was found between PTH and mean BP and HR values in this group. In the HT-PHPT subgroup, 14 (56%) patients do not show the presence of the physiological BP nocturnal fall (non-dipper), whereas 11 patients (44%) present the nocturnal fall (‘dipper’), showing a statistically significant rate (Po0.05) when compared with non-dipper EH patients (30%). No correlation was found in the EH and NS groups between calcium–phosphorus metabolism parameters and haemodynamic parameters.

Data are expressed as mean7s.d. SBP ¼ systolic blood pressure; DBP ¼ diastolic blood pressure; HR ¼ heart rate.

Discussion (P40.05) was found for 24-h HR, daytime HR or night time HR in all examined groups. The multiple linear regression showed that in PHPT-HT patients, among the variables studied, ionized calcium is an independent factor for the rise

The prevalence of hypertension has been shown to be higher in PHPT than in the general population. According to some authors, this prevalence may vary from 20 to 80%.2–5 The results of our study confirm and extend these data reported in the Journal of Human Hypertension


literature; in fact, 47% of our patients with PHPT showed arterial hypertension. The mechanisms responsible for the rise of arterial hypertension in PHPT are still quite controversial. Some pathogenetic factors and mechanisms responsible for the rise of BP values in PHPT are represented by the following: (a) hypercalcaemia;3,4,26–29 (b) PTH;30,31 (c) renal function injury;7,8 (d) activation of the renin–angiotension–aldosterone system;32–34 (e) activation of the sympathetic nervous system;26,29 (f) activation of the endothelin35 and adrenomedullin36 systems. Calcium was studied first as a factor responsible for the pathogenesis of hypertension in PHPT. Fardella and Rodriguez-Portales4 in 1995 observed an important role of intracellular calcium in essential hypertension favouring smooth muscle cell contraction. The same authors also showed that in patients with PHPT (a condition in which the mean biochemical characteristics are the increase in serum ionized calcium and PTH levels), intracellular calcium was higher in normotensive patients with PHPT than in normal controls but was lower than in patients affected by essential hypertension.4 In patients with PHPT, intracellular calcium was closely correlated with PTH levels, but not with total serum calcium levels. In patients with essential hypertension, intracellular calcium was statistically correlated with mean, SBP and DBP.4 In conclusion, normotensive patients with PHPT, as well as EH patients, may have increased intracellular calcium concentrations. The correction of PTH normalizes intracellular calcium and the strong correlation between PTH and intracellular calcium suggests that PTH may act as a ionophore for the calcium entry into the cell.4 We found, in hypertensive patients with PHPT, that 24-h DBP and daytime DBP values correlate significantly with serum ionized calcium. These results confirm, in part, the pathogenetical hypothesis of the role of calcium in the rise of hypertension in patients affected by PHPT. Particularly, in these patients, calcium is thought to play a role in the

alteration of peripheral vascular resistance with affects in DBP. A second result shown in our study was the finding of a noteworthy rate of ‘non-dipper’ hypertensives in PHPT patients in comparison with EH subjects (56 and 30%, respectively). Our data are different from other studies (Table 6) and in particular Middeke et al19 who revealed a normal circadian BP profile with a nocturnal BP fall in nine patients with PHPT and elevated BP. The difference can be explained, in part, by the number of patients studied and, morever, the other studies that describe the circadian rhythm of BP in PHPT have been performed using the Cosinor method by Halberg.37 In our study the diurnal BP variation was characterized by the relative night decline calculated as follows: (daytimenight time value BP/daytime BP 100). This result needs some reflection on the role of hypertension, particularly if ‘non-dipper’, which could be an independent cardiovascular risk factor in PHPT. Regarding this, it was reported in the literature that the lack of a resting time BP drop of 10% or more was associated with several cardiovascular risks and thus represents an important predictive risk factor for cardiovascular morbidity. In particular, Verdecchia et al23,24,38 showed an increase of the cardiovascular events in ‘non-dipper’ patients, and Shimada et al39 found higher incidence of cerebrovascular injury, as documented by magnetic resonance (MRI), and finally Palatini et al40 detected a higher incidence of left ventricular hypertrophy in non-dipper hypertensive subjects. In particular, in patients with diabetes and patients with chronic renal failure,41 in whom a more important global cardiovascular risk for all daytime BP level is well known, a lack or a reduction in nocturnal pressure fall was observed. In conclusion, the results of our study have confirmed higher than 47% of hypertension in PHPT, as reported in the literature, and have shown that serum Ca2 þ seems to play an important role in the development of hypertensive condition. Further-

Table 6 What is known on this topic K The prevalence of arterial hypertension has been shown to be higher in PHPT than in general population: the prevalence may vary from 20 to 80%2–5 K Calcium was studied as a factor responsible for the pathogenesis of hypertension in PHPT4 K In the patients with PHPT, the circadian blood pressure rhythm (analysed in some studies with Cosinor method by Halberg F) is generally present19 and the 24 h ambulatory blood pressures and the intima media thickness of the carotid arteries failed to differ significantly between the PHPT patients and control subjects6 What this work adds K Results of our study confirm and extend the data of arterial hypertension in PHPT, in fact 47% of our patients with PHPT showed arterial hypertension K We found in hypertensive patients with PHPT that the 24-h DBP and daytime DBP values correlated significantly with serum ionized calcium (Ca2+) K In our study the AMBP was performed using the oscillometric technique (Space Labs 90207, Redmond, WA, USA) and we found in 14/25 hypertensive PHPT patients (56%) the absence of the physiological blood pressure nocturnal fall (non-dipper) showing a statistically significant rate when compared with non-dipper patients with essential hypertension

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more, a noteworthy number of ‘non-dipper’ hypertensive subjects (56%) has been reported in PHPT patients, much higher than in EH patients (30%). This result seems to suggest that in PHPT this condition may represent an independent cardiovascular risk factor. Further studies are necessary to confirm and extend these results.

Acknowledgements This work has been supported in part by Banca di Credito Cooperativo of Rome, Italy. We thank Mr Giovanni Clemente for his technical assistance.

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