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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 10 3515-3519
Copyright © 2000 by The Endocrine Society

Special Articles

Augmentation of Central Arterial Pressure in Mild Primary Hyperparathyroidism

J. C. Smith, M. D. Page, R. John, M. H. Wheeler, J. R. Cockcroft, M. F. Scanlon and J. S. Davies

Departments of Medicine (J.C.S., M.D.P., M.F.S., J.S.D.), Biochemistry (R.J.), Surgery (M.H.W.), and Cardiology (J.R.C.), University Hospital of Wales, Cardiff CF14 4XW, United Kingdom

Address all correspondence and requests for reprints to: Dr. J. C. Smith, Department of Medicine, University Hospital of Wales, Cardiff CF14 4XW, United Kingdom.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Primary hyperparathyroidism (PHPT) is associated with increased cardiovascular risk, although the mechanisms involved remain unclear. Recent evidence has shown increased pulse pressure to be a powerful predictor of cardiovascular events. As increases in pulse pressure are due largely to arterial stiffening, we measured arterial stiffness in 21 subjects with PHPT (18 women and 3 men; 46–71 yr old) and 21 age- and sex-matched healthy controls using pulse wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and augmentation index, a measure of vessel stiffness. Metabolic parameters were also measured.

The serum calcium level among PHPT subjects was (mean ± SD) 2.74 ± 0.14 mmol/L. pulse wave analysis showed that both augmentation and the augmentation index were significantly higher in the PHPT group vs. controls [16 ± 5 vs. 10 ± 4 mm Hg (P < 0.001) and 36 ± 9% vs. 25 ± 6% (P < 0.001)] despite comparable brachial systolic pressures between groups (136 ± 13 vs. 134 ± 18 mm Hg). Patients with PHPT had higher fasting serum insulin levels [median (range), 15.8 (7.4–39.4) vs. 11.6 (5.1–23) mU/L; P < 0.05] and triglyceride (1.6 ± 0.6 vs. 1.2 ± 0.4 mmol/L; P < 0.05), but lower high density lipoprotein cholesterol (1.4 ± 0.4 vs. 1.6 ± 0.3 mmol/L; P < 0.05).

These data indicate that subjects with mild PHPT (calcium, <3.0 mmol/L) have increased arterial stiffness, as evidenced by higher augmentation of central aortic pressures. Enhanced vessel stiffness may arise from a combination of structural and functional vascular changes due to hypercalcemia and/or metabolic abnormalities. Increased vascular stiffness in subjects with PHPT may account in part for the increased cardiovascular risk in this group.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DESPITE INCREASING evidence that primary hyperparathyroidism (PHPT) is associated with an increased risk of a cardiovascular event (1, 2, 3), the pathophysiological mechanisms involved remain unclear, and the need for treatment in mild and/or asymptomatic PHPT is controversial. A number of cardiovascular abnormalities are associated with PHPT, including systolic hypertension (1, 4), accelerated coronary atherosclerosis (5), arrhythmias (6, 7), myocardial structural changes (8, 9, 10), and left ventricular hypertrophy (LVH), a strong independent predictor of cardiovascular morbidity (11, 12). The cause of these cardiac abnormalities remains poorly understood. The demonstration of LVH in normotensive subjects with PHPT (13, 14) suggests increased left ventricular afterload, independent of brachial systolic pressures. LVH may arise as a direct consequence of pathological changes in the vasculature leading to arterial stiffening. Recent evidence has shown increased pulse pressure to be a powerful predictor of cardiovascular events (15, 16, 17). Increases in pulse pressure are due largely to arterial stiffening. In addition to being a marker for degenerative physical changes, increased vascular stiffness has important hemodynamic consequences, and evidence is mounting that vascular stiffness is an independent marker of cardiovascular risk (18, 19).

Healthy arteries are compliant structures, capable of buffering the pressure changes that occur during the cardiac cycle. Energy is absorbed during systole and released during diastole, resulting in smooth peripheral blood flow and the maintenance of diastolic coronary perfusion. Antegrade arterial pressure waves are reflected back from the periphery, arriving in the central arteries after the central systolic pressure peak (20). However, as arteries stiffen, profound changes occur in the arterial pressure waveform. Pulse wave velocity increases, and this results in the reflected wave arriving earlier, thus adding to the central pressure wave to produce an augmented central systolic pressure (21). Central pressure is the major determinant of left ventricular afterload and the subsequent development of LVH (21, 22). It is therefore becoming apparent that increased large artery stiffness is an important contributor to the development of cardiovascular disease. This is further supported by the clear association demonstrated with other classical risk factors, including age, smoking, hypercholesterolemia, diabetes, and atherosclerosis (18, 22, 23).

We have assessed the function of large arteries in subjects with PHPT using arterial pulse wave analysis (PWA) (24) and have studied biochemical indicators of glucose and lipid metabolism in this condition. The aim of the study was to determine whether increased arterial stiffness is associated with PHPT, thus contributing to the increased cardiovascular risk.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients and controls

Twenty-one patients (18 women and 3 men; age range, 46–71 yr) with untreated mild PHPT, as defined by serum calcium within the range 2.6–3.0 mmol/L in association with elevated PTH, and 21 healthy volunteers as controls were studied. The control group was drawn from hospital staff and colleagues at the University Hospital of Wales and was carefully selected so that each control was matched with an individual patient with regard to sex, similar age (within 5 yr), and similar brachial systolic blood pressure (within 10 mm Hg). In addition, smoking status was equivalent in both groups. Patients with overt evidence of coronary heart disease or known diabetes mellitus were excluded. Five patients in the PHPT group and 4 subjects in the control group had documented hypertension and were taking established (>1 yr) antihypertensive medication. In the PHPT group, 2 patients received calcium channel blockers, and 1 patient each took a ß-blocker, a diuretic, and an angiotensin-converting enzyme inhibitor plus diuretic combination. Two subjects in the control group took ß-blockers, and 2 of the subjects took an angiotensin-converting enzyme inhibitor. Two PHPT patients and 2 control subjects were cigarette smokers. The study had approval from the local research ethics committee, and all subjects gave informed consent to participate.

Pulse wave analysis (PWA)

Arterial stiffness and central aortic pressure were measured noninvasively by the technique of PWA using the Sphygmocor apparatus (BPAS-1, PWV Medical, Sydney, Australia) as developed by O’Rourke (24). All measurements were taken from the radial artery at the wrist using a micromanometer (SPC-301, Millar Instruments, Houston, TX) applying the principle of applanation tonometry to flatten the artery by gentle pressure. Data were collected directly into a desktop computer and were processed by the system software to allow accurate on-line recording of the radial artery waveform. The corresponding aortic pressure waveform can then be generated from an averaged radial artery waveform (derived from 20 sequentially recorded radial artery waveforms) using a validated transfer factor (24, 25, 26). Computerized analysis of the central waveform allows determination of augmentation, the augmentation index, and the central blood pressure (Fig. 1Go). The augmentation index is defined as the difference between the first and second peaks of the central arterial waveform, expressed as a percentage of the pulse pressure (24). Radial blood pressure was calibrated against brachial blood pressure, which was measured using an Omron automated sphygmomanometer (HEM-705CP, Omron Corp., Kyoto, Japan). Although the operator was not blinded to the identification of subjects, the software allowed for objectivity of measurements by setting quality control parameters on the radial artery waveform recordings. These parameters were mean pulse height and systolic and diastolic variability. If any of the parameters on a given recording were outside the predetermined acceptable limits (<100 mV for pulse height, >10% for systolic or diastolic variability), then the recording was excluded. The first 3 readings obtained within quality control limits were taken as the accepted recordings. All subjects were studied in the fasting state. Three sequential measurements were taken for each subject, and from these the mean augmentation, augmentation index, and central aortic pressure were calculated. A single operator performed all measurements. The reproducibility of the augmentation index using the Sphygmocor apparatus was determined before the study in a separate group of 25 control subjects using the methodology described previously (27, 28). The reproducibility data for the augmentation index showed a mean difference ± SD between repeated measurements of 0.84 ± 4.0% (95% confidence interval, -0.81 to +2.49).



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  		Figure 1. Computerized analysis of the central waveform allows determination of augmentation, the augmentation index, and the central blood pressure.

 
Biochemical measurements

Intact PTH was measured by a two-site immunochemiluminometric assay (Bayer Corp.-Chiron Corp., Halstead, UK). The between-assay precision at a PTH concentration of 1.8 pmol/L was 19.2%, and that at a PTH concentration of 43.6 pmol/L was 11.3%.

Insulin was measured by RIA (Medgenix, Appligene-Oncor-Lifescreen, Watford, UK). The between-assay precision at an insulin concentration of 18.2 mU/L was 14.2%, and that at an insulin concentration of 126 mU/L was 18.4%. Serum lipids, calcium, and plasma glucose were measured using standard techniques.

Statistical analysis

All statistical analyses were performed using SPSS (version 6.1, SPSS, Inc., Chicago, IL) for Windows. Data are expressed as the mean ± SD for normally distributed values and as the median (range) for data with a nonnormal distribution. The unpaired t test was used for parametric data, and the Mann-Whitney test was used for nonparametric data. The correlation between variables was evaluated using Spearman’s and Pearson’s correlation coefficients and stepwise regression analysis. P < 0.05 was considered significant. Reproducibility data for PWA were expressed in terms of the mean difference ± SD between paired measurements for a single operator.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The physical and hemodynamic data are summarized in Table 1Go. PWA showed that the augmentation (difference between the first and second systolic pressure peaks) in the PHPT group was significantly higher than that in the control group (16 ± 5 vs. 10 ± 4 mm Hg; P < 0.001) despite similar peripheral systolic pressures (136 ± 13 vs. 134 ± 19 mm Hg) and pulse pressures. The augmentation index was also significantly higher in the PHPT group (36 ± 9% vs. 25 ± 6%; P < 0.001). Central aortic systolic pressure was elevated in the PHPT group, with a mean difference of 5 mm Hg between groups, although this difference did not reach statistical significance.


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  		Table 1. Hemodynamic and physical characteristics of subjects

 
Biochemical results are shown in Table 2Go. These data indicate that there were no significant differences in glucose concentrations between the groups. Five PHPT patients did, however, have fasting glucose levels in the range of 6–7 mmol/L, fulfilling American Diabetes Association criteria for impaired fasting glucose. None of these patients had previous documented hyperglycemia or impaired glucose tolerance. Fasting serum insulin concentrations were significantly elevated in the PHPT group compared with those in the controls [15.8 (7.4–39.4) vs. 11.6 (5.1–23.0) mU/L; P < 0.05].


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  		Table 2. Biochemical characteristics

 
Although there were no differences in total serum cholesterol or low density lipoprotein cholesterol between the two groups, high density lipoprotein cholesterol was significantly lower in the PHPT group (1.4 ± 0.4 vs. 1.6 ± 0.3 mmol/L; P < 0.05), and consequently, the total cholesterol/HDL ratio was higher in the PHPT group (4.7 ± 1.9 vs. 3.7 ± 0.8; P < 0.05). Furthermore, serum triglyceride was higher in the PHPT group compared to that in controls (1.6 ± 0.6 vs. 1.2 ± 0.4 mmol/L; P < 0.05), and in three patients serum triglyceride was greater than 2.5 mmol/L. There were no significant differences in body weight or body mass index between the groups, and no correlation was noted among body mass index, triglyceride, or serum insulin concentrations. For the combined group of PHPT and control subjects, a significant correlation was noted between serum insulin concentration and augmentation index (r = 0.49; P < 0.01; Fig. 2Go). A multiple regression analysis model applied to determine the strongest predictors of the augmentation index revealed serum calcium to be the most significant determinant of the augmentation index (Table 3Go); PTH and insulin were not identified as independent predicting variables.



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  		Figure 2. For the combined group of PHPT and control subjects, a significant correlation was noted between serum insulin concentration and augmentation index (r = 0.49; P < 0.01).

 

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  		Table 3. Results of multiple regression analysis for the dependent variable: augmentation index

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The pathophysiological mechanisms responsible for the increased cardiovascular risk associated with PHPT are poorly understood (1, 2, 3). We have demonstrated that PHPT is associated with an increase in arterial stiffness assessed using PWA. Patients with PHPT had significantly increased augmentation of their central aortic pressure waveform and augmentation index compared with controls matched for brachial blood pressure. Such changes contribute to an increased hemodynamic afterload, which may result in maladaptive changes such as left ventricular hypertrophy. Similar changes in left ventricular structure are encountered in aging, normotensive individuals, in whom ventricular concentric remodeling can occur (29). Indeed, the increase in left ventricular mass seen in patients with a dominant late systolic peak appears to be directly related to the shape of the aortic pressure waveform (22). The effect of stiff arteries on brachial pressure is often much less conspicuous, and consequently, routine brachial spygmomanometry is likely to underestimate the true extent of cardiac afterload. This observation may explain the increased prevalence of echocardiographic LVH among hypertensive and normotensive patients with PHPT (13, 14). Furthermore, higher central arterial pressures would be expected to adversely affect overall cardiovascular function and may also explain the increased risk of cerebrovascular disease reported in PHPT (30).

Reduced vascular compliance may result from both structural and functional abnormalities in large and medium-sized vessels. Echocardiographic studies have demonstrated calcific deposits within the heart valves and myocardium of patients with PHPT (8, 13, 31), but it is unclear whether such structural changes may adversely affect cardiac performance. Similarly, structural changes within the arterial wall may contribute to vessel stiffening, but as yet there is no evidence demonstrating an association between large artery calcification and PHPT. However, functional abnormalities, most notably endothelial dysfunction, can also directly contribute to vessel stiffening. It has been shown that endogenous mediators such as nitric oxide can have profound effects on the shape of the pulse waveform and the timing of the wave reflection in animal (32) and human models (33, 34), implying that the endothelium is an important regulator of vessel stiffness. It is possible that endothelial function is impaired in PHPT as a result of the metabolic and lipid disturbances associated with this condition. A recent study has supported this hypothesis by demonstrating endothelial dysfunction in PHPT patients, which was reversible after parathyroidectomy (35). In addition, the observation that surgical cure of PHPT can result in partial regression of LVH (13, 14, 31) suggests that reversible functional changes may have an important role. However, these findings remain to be fully established given the contrasting observations by Neunteufl et al. (36) of normal endothelial-dependent dilatation of the brachial artery in PHPT subjects, suggesting intact endothelial function. It is unclear whether the cause of these functional abnormalities is related to hypercalcemia itself, or they occur through direct action of PTH. It has been shown that only minor elevations in serum calcium (2.79–2.94 mmol/L) are associated with increased mortality (37); therefore, it is understandable that our group of PHPT patients whose mean calcium was well within this range showed evidence of vascular dysfunction.

We also demonstrated higher fasting insulin concentrations in subjects with PHPT compared with those in age- and weight-matched controls together with a propensity to frank glucose intolerance. These results are in agreement with other studies that have also demonstrated a higher incidence of glucose intolerance and diabetes mellitus in PHPT (38, 39, 40). The abnormal lipoprotein profiles, in particular hypertriglyceridemia combined with low high density lipoprotein concentrations, are also typical of an insulin-resistant state (41). Reduced insulin sensitivity with abnormal glucose disposal have been reported in PHPT (42, 43), and the link between insulin resistance and calcium metabolism is further supported by the observation that defects in intracellular calcium homeostasis occur in type 2 diabetes (44). Defects in insulin and glucose metabolism play an important role in both the etiology and the natural course of hypertension (45), with insulin itself having important vascular effects on both central and peripheral vasculature (46, 47, 48). In the present study we have demonstrated a correlation between serum insulin concentrations and the augmentation index, thus supporting the hypothesis that insulin is an important regulator of vascular compliance. In healthy nonobese individuals, physiological concentrations of insulin have been shown to reduce wave reflection and hence augmentation, leading to a state of diminished vascular stiffness (46). However, in obese insulin-resistant individuals the ability of insulin to reduce aortic wave reflection is severely blunted. Thus, this phenomenon provides a link between insulin resistance and hypertension and may partially explain the increased wave reflection and augmentation encountered in our PHPT group, who displayed biochemical features of the metabolic syndrome X.

In conclusion, this study is the first to demonstrate that mild to moderate PHPT is associated with increased vascular stiffness. A combination of structural and functional vascular changes occurring as a result of altered calcium homeostasis together with metabolic and lipid perturbations may contribute to these vascular abnormalities. The demonstration of increased arterial stiffness provides a mechanism for the development of LVH in normotensive PHPT and is likely to contribute significantly to both cardiovascular morbidity and mortality. This finding has important implications for the management of patients with mild primary hyperparathyroidism in whom aggressive management of cardiovascular risk factors should be considered.

Received December 2, 1999.

Revised March 10, 2000.

Accepted June 28, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals