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Original Studies |
Department of Internal Medicine (C.L., S.V., G.L.V., F.F.), Endocrine Unit, Department of Clinical Physiopathology (M.L.D.F., M.L.B.), University of Florence Medical School; and Cardiovascular Echography Unit (G.B., R.D.B.), Azienda Ospedaliera Careggi, 50139 Firenze, Italy
Address correspondence and requests for reprints to: Maria Luisa Brandi, M.D., Department of Clinical Physiopathology, University of Florence, Viale Pieraccini, 6, 50139 Firenze, Italy.
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Abstract |
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In pHPT patients the echocardiographic parameters were normal; left ventricular isovolumetric relaxation time was always in the normal range, but significantly shorter than in control subjects, suggesting an increased sympathetic stimulation. Arterial diameters and thickness, blood pressure, and QT interval were not significantly different with respect to normal subjects and were unchanged 6 months after surgery. pHPT patients lacked the circadian rhythm of the low frequency to high frequency ratio, suggesting an increased sympathetic drive to the heart at nighttime. In normal subjects there were no significant differences in basal echocardiographic measurements during PTH infusion with respect to placebo and in the hemodynamic response to tilt.
These results suggest that cardiovascular function is substantially normal in normotensive pHPT patients with mild hypercalcemia. A modulation of the adrenergic control of circulation seems to be associated with hypercalcemia and/or chronic PTH excess, but its biological relevance needs further investigations.
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Introduction |
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Changes in the clinical spectrum of pHPT observed in the last decade led to an increased frequency of mild or asymptomatic cases for which only clinical follow-up is advised (12). In this new scenario, potential damages to the cardiovascular system by increased circulating PTH associated with serum calcium levels in the high-normal range need to be evaluated.
The aims of this study were to evaluate: 1) cardiovascular function, as assessed by noninvasive ultrasound, and the autonomic drive to the heart, as assessed by heart rate variability (HRV) analysis, in normotensive patients affected by mild pHPT and in age- and sex-matched control subjects; and 2) the effects of an acute increase in plasma PTH levels on cardiovascular function and HRV in a group of healthy volunteers in basal conditions and during physiological activation of the sympathetic nervous system by head-up tilt.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The study was carried out in accordance with the Declaration of Helsinki, approved by the local Ethics Committee, and all pHPT patients and healthy subjects gave their informed written consent to participate.
Protocol 1: cardiovascular function and HRV in pHPT.Twenty-four consecutive patients with mild asymptomatic pHPT, diagnosed at the Ambulatory of Metabolic Bone Diseases of the Endocrine Unit, University of Florence, between 1994 and 1996 during the screening procedures for osteoporosis, were considered for this study. All patients had persistently raised serum calcium levels (2.62–3.15 mmol/L), inappropriately high levels of PTH, and high turnover bone disease (osteopenia/osteoporosis) in the absence of other secondary causes of osteoporosis, so fulfilling indications for a surgical approach (complicated asymptomatic pHPT) (12). Ten patients were excluded because of impaired renal function (n = 2), arterial hypertension [grade 1 (n = 2) and grade 2 (n = 3), according to 1993 WHO guidelines], or other coexisting diseases (n = 3). The remaining 14 patients (12 women, mean age, 60 ± 11 yr; range, 36–71 yr) were included in the study. Twenty age- and sex-matched healthy subjects (17 women, mean age, 60 ± 8 yr; range, 34–71 yr) were recruited as controls. Neither pHPT patients nor healthy subjects smoked more than five cigarettes per day. In all patients and controls, previous medications, if any, were withheld at least 1 month before the study. Smoking was not allowed in the 5 days before and during the whole study period.
On the day of the study, at 0800 h, after overnight fasting, blood samples were obtained to measure serum total and ionized calcium, plasma PTH, and PRA. After a 2-h rest, all subjects underwent standard 12-lead electrocardiogram (EKG), echocardiographic assessment of left ventricular (LV) function and measurement of the mechanical properties of the brachial and the carotid arteries. Thereafter, a 24-h Holter recording was obtained in all subjects to evaluate HRV and QT interval. All patients included in the study underwent surgery 1- to-3 months after the study. Histopathological examination showed a single parathyroid adenoma in 12 patients and primary parathyroid hyperplasia in 2 patients (in 1 patient as the only manifestation of multiple endocrine neoplasia type I). Serum total and ionized calcium and PTH levels remained in the normal range during follow-up for at least 1 yr after surgery. Cardiovascular function and analysis of HRV and QT interval were repeated 6 months after surgery in 10 female patients (mean age, 61 ± 9 yr; range, 36–71 yr).
Protocol 2: acute effects of PTH on cardiac function and HRV.Five healthy nonsmoker volunteers (one female, mean age 32 yr; range, 26–40 yr) participated in this single blind, placebo-controlled, random order, crossover study. Physical examination, blood pressure, urinalysis, blood cell count, routine biochemical parameters, EKG, and echocardiographic findings were normal. All subjects were on a standard, 100-mmol sodium diet in the week before and throughout the whole study period and were studied on two different occasions, 1 week apart, to receive PTH or placebo, respectively.
On the 1st day of the study, a 24-h urine collection was obtained to measure urinary sodium excretion. The next day, subjects had breakfast at about 0730 h. Thereafter, they remained supine until 1330 h, when they were placed on the tilt table (Type 1.73–006; Elektro-Werke, Hanning Germany). Two antecubital veins were cannulated for infusion of substances and blood sampling. The cuff of a semiautomatic oscillometric apparatus (Siemens-Sirecust 888) validated against standard sphygmomanometer before each test was positioned in the nondominant arm to measure arterial pressure. An EKG was continuously recorded to evaluate HRV. To obtain adequate urine flow rates, subjects were given an oral water load (200 mL/h) in the 2 h preceding the test and an infusion of 5% dextrose in water (250 mL/h) throughout the study. After a 2-h equilibration period, urine was obtained by spontaneous voiding and discarded. Then, teriparatide acetate [hPTH (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34), 200 U; Rorer Pharmaceutical Corporation, Fort Washington, PA], dissolved in 0.9% saline (30 mL), or placebo (the vehicle) was administered over 5 min. Ultrasound assessment of LV function and carotid artery distension was performed between the 25th and the 30th min after the start of the infusion (time 0). Thereafter, subjects were tilted at 60 degrees for 15 min, and ultrasound examination was repeated between the 10th and the 15th min of tilting (i.e. at 40–45 min from time 0). This schedule was chosen because preliminary experiments showed that the maximum urinary cAMP increase is evident 30–60 min after this schedule of injection of human PTH (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34). Blood and urine samples were obtained just before and 45 min after PTH infusion to measure calcium, creatinine and PTH, urine volume and urinary calcium, creatinine, and cAMP.
Echocardiographic assessment of cardiac function
M-mode, two-dimensional, and Doppler echocardiography was performed as described previously (13), allowing measurements and/or calculation of the following parameters (14, 15, 16, 17, 18, 19, 20): 1) LV end diastolic and end systolic diameters and volumes; 2) LV fractional shortening and LV ejection fraction (indices of LV systolic function); 3) LV mass index (LVMI); 4) cardiac index; 5) systemic vascular resistance (SVR); 6) atrial volumes; 7) mitral E/A ratio; 8) deceleration time of mitral E wave (DTE); 9) LV isovolumic relaxation time (IVRT); and 10) pulmonary vein systolic fraction (an indirect estimate of mean left atrial pressure).
Mean arterial pressure (MAP) was calculated as diastolic pressure + 1/3 pulse pressure.
Mechanical properties of the arteries
Wall geometry of the left common carotid artery (1 cm below
bifurcation) and the left brachial artery at the elbow was evaluated by
ultrasound (21), with measurements of end-diastolic (dD) and
end-systolic (sD) diameters (i.e. minimum and maximum
internal diameter, respectively) and end-diastolic intimal-medial
thickness of the far wall. Arterial distension was measured as percent
systolic increase of vessel diameter [(sD-dD)/dD
* 100]. Arterial pressure was used to calculate:
1) the arterial elastic modulus (EM): EM =
{[(SBP-DBP)/(sD-dD)]·dD}, (22); and 2) the index of arterial
stiffness (SI): SI = ln (SBP/DBP) *
(sD-dD)/dD (23), where SBP and DBP are systolic and diastolic blood
pressure, respectively. Arterial compliance (Cm) was determined from
pulse wave velocity (PWV), which was graphically measured on brachial
and radial pulse tracings, simultaneously recorded by using two
piezoelectric transducers connected to an ink-jet recorder, using the
formula Cm (cm/mm Hg) = (1.334 * mD)/(2
* PWV 2), where is blood density = 1.06
(24) and mD is the mean arterial diameter. In protocol 2, only the
carotid arterial distension was evaluated.
HRV
HRV was evaluated using a computer-based system (ELA Medical, Segrate, Italy), as reported previously (25, 26). In the frequency-domain, we calculated the ratio between the low frequency (LF; power in the band from 0.04–0.15 Hz) and the high frequency (HF; the power in the band from 0.16–0.40 Hz) spectral components, as an index of the sympatho-vagal balance to the heart. In the time-domain, we calculated the proportion of adjacent (RR) intervals differentiated by more than 50 ms (pNN50), as an expression of the vagal tone of the heart (27). In protocol 1, the LF/HF ratio was calculated in the whole 24-h period, as well as in a daytime (0800–1200 h) and a nighttime (0–0400 h) period, to evaluate the circadian rhythm of the sympatho-vagal balance to the heart. In protocol 2, because the recordings were short-lasting and stationary was lacking (27), pNN50 was not calculated.
QT interval
QT interval (from the onset of the QRS to the end of the T wave) was measured in a standard 12-lead EKG recorded at 50 mm/sec and corrected for heart rate (QTLC) according to Sagie et al. (28). QTLC was considered abnormal when longer than 440 ms. Dynamic QT was analyzed using a dedicated algorithm (ELA Medical), as described previously (26), with evaluation of the early portion of QT interval (QT apex: QTa), the entire QT interval (Qtend:QTe), and the SD) of both QTa and QTe. Linear regression slopes (QTa/RR and QTe/RR) were also computed, with a correlation coefficient more than 0.70. The latter parameters are indices of QT variability (29).
Analytical methods
Intact PTH (1–84), PRA, and urinary cAMP were measured using commercial kits from Nichols Institute Diagnostics (San Juan Capistrano, CA) (for PTH) and New England Nuclear (Boston, MA) (for both PRA and cAMP).
Statistical analysis
Data are reported as mean value ± SD. Statistical analysis was performed using the SPSS, Inc. for Windows statistical package 7.5 (SPSS, Inc., Chicago, IL). Basal data were compared after Levene’s test by t test (independent data). Data before and after parathyroidectomy were compared by the paired t test. Results of the acute administration of PTH and placebo were analyzed using the two-way ANOVA for repeated measures, followed by the t test, as appropriate. Relationships were assessed by using the Pearson’s correlation coefficients. A P value less than 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Table 1
shows serum calcium and
plasma PTH in healthy subjects and pHPT patients, including the
subgroup of patients studied before and after parathyroidectomy. In
pHPT patients, plasma PTH ranged between 65 and 993 pg/mL, and serum
calcium was high normal or slightly increased. All biochemical
parameters normalized after surgery.
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. LVMI was within the normal range in
all patients. No differences were observed between pHPT and healthy
subjects in any parameters of cardiovascular function, except IVRT,
which was significantly shorter in pHPT patients, indicating an
abnormal LV relaxation. Surgery did not reverse this abnormality.
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). Patients with pHPT had elastic
properties and stiffness of both the carotid and the brachial artery
comparable with those of healthy subjects. Parathyroidectomy did not
modify any of the morphological and mechanical properties of the
arteries.
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. No significant
differences were observed between pHPT patients and healthy subjects
with respect to any of the measured parameters. At difference with
healthy subjects, however, pHPT patients lacked the circadian rhythm of
the LF/HF ratio. Analysis of individual data showed that the circadian
rhythm of the LF/HF ratio was absent in 7 of the 14 patients included
in the study. Patients with a blunted day-night LF/HF rhythm had a
higher LF/HF ratio at nighttime than those with a normal rhythm
(4.43 ± 0.8 vs. 2.36 ± 1,
P < 0.05). No differences were observed between
these two subgroups of pHPT patients in either the clinical/biochemical
characteristics or the other measured parameters of HRV. In the five
patients without circadian LF/HF rhythm submitted to surgery, this
alteration was reversed by parathyroidectomy.
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Protocol 2: PTH infusion in normal subjects
All volunteers completed the protocol. The biochemical effects of
PTH infusion are reported in Table 5. As
expected, urinary cAMP increased and circulating PTH (1–84) decreased
following PTH (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) infusion, whereas serum calcium levels did not
change.
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). No differences were
observed in carotid distension in response to either head-up tilt or
PTH infusion (Table 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, cardiovascular morphology and function and autonomic control of heart rate were evaluated in normotensive patients with asymptomatic pHPT, and responses to acute PTH infusions were obtained in a group of healthy subjects. Our results show that in these patients with mild hypercalcemia the cardiovascular system is minimally, or not at all, affected. In fact, they had normal cardiac morphology; differently than in previous reports (5), no increases in LV mass were found. Systolic and diastolic function of the left ventricle were normal, and the IVRT was always in the normal range, although significantly shorter than in control subjects, suggesting an increased sympathetic stimulation that is known to shorten LV relaxation time (33). Accordingly, acute administration of PTH does not seem to influence cardiovascular homeostasis in normal subjects. We could not observe the early, short-lasting, vasodilating, inotropic, and chronotropic effects of the infusion of PTH and PTH-related protein shown in isolated, perfused rat hearts (34) (data not shown).
The possibility that hypercalcemia and/or a chronic exposure to high PTH levels might affect the arterial tone prompted us to evaluate systemic hemodynamics and the mechanical properties of the carotid and the brachial artery in pHPT patients with mild hypercalcemia. Normotensive pHPT patients showed no differences in the mechanical properties of the carotid artery with respect to either healthy subjects or postsurgery evaluation. Similarly, PTH infusion did not modify systemic hemodynamics or the mechanical properties of the carotid artery in healthy subjects, in agreement with the report by Mok et al. (35).
In the present study, we also evaluated the hypothesis that mild hypercalcemia and/or PTH excess could influence the autonomic drive to the heart (and/or heart responsiveness to sympathetic and parasympathetic stimulation), offering an explanation for the increased susceptibility to cardiac arrhythmias described in patients with pHPT. To this purpose, we performed time- and frequency-domain analysis of HRV, a reliable, noninvasive tool for quantitative evaluation of the neural control to the heart (27, 36). We found that half of the pHPT patients included in the study exhibited a blunted day-night rhythm of the LF/HF ratio, suggesting an increased sympathetic drive to the heart at night-time. This finding seems particularly intriguing because a blunted day-night rhythm of LF/HF has also been described in hypertension and liver cirrhosis (25, 26, 37). Interestingly, surgery restored the physiological rhythm of sympatho-vagal balance. On the contrary, a short-term PTH infusion, in the absence of hypotensive response, prevented the physiological increase in the LF/HF ratio in response to head-up tilt. The physiological interpretation and the biological relevance of this finding warrant further elucidation. During PTH infusion, the time-domain parameter was not calculated, as in all cases of short-lasting recordings, in which frequency-domain methods should be preferred. The analysis of HRV in transient physiological phenomena still represents a challenging research topic. In some conditions associated either with autonomic withdrawal or high levels of sympathetic excitations, a decrease in the absolute power of LF component can be observed, with decreased HRV (27, 36). Moreover, HRV measures fluctuations in autonomic inputs to the heart, rather than the mean level of autonomic inputs. On the contrary, the data available to date suggest great stability of HRV measures derived from 24-h ambulatory monitoring (27).
These observations point to a role for hypercalcemia and/or chronically elevated PTH levels as causative factor(s) for the increased sympathetic drive to the heart observed in our pHPT patients. Pertinent to this observation are data by Vlachakis et al. (38), who found that pHPT patients had a greater catecholamine response to calcium infusion than healthy subjects and patients with hypertension, and by Gennari et al. (39) who showed that calcium infusion did not cause any rise in plasma norepinephrine in parathyroidectomized patients. These observations suggest a permissive role for PTH in the stimulation of norepinephrine release caused by acute hypercalcemia.
Finally, in this study, patients affected by pHPT did not show any differences in conventional and dynamic QT interval when compared with healthy subjects. This could be simply due to the mild hypercalcemia of our patients, because pHPT patients with higher calcemic levels are known to have a short QT interval and alterations in dynamic QT have been described (40).
In conclusion, the results of this investigation show that cardiovascular function is substantially normal in a subset of normotensive pHPT patients with mild hypercalcemia. The cardiovascular abnormalities reported in previous studies might be related to longer-lasting and/or higher calcemic levels, to the coexistence of hypertension, and/or to other unknown associated factors. The occurrence of mild abnormalities in LV relaxation and in the circadian rhythm of cardiac sympatho-vagal balance suggests a slightly increased sympathetic drive to the heart in normocalcemic patients with mild pHPT. The implications of this alteration in the long-term outcome of cardiovascular function in asymptomatic pHPT patients need to be evaluated by prospective studies, taking also into account the genetic substrate, the associated risk factors for cardiovascular diseases, and the different biohumoral pattern (PRA, aldosterone, vitamin D levels) in the single pHPT patient.
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Footnotes |
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Received August 12, 1999.
Accepted December 20, 1999.
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References |
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