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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-1400
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 6 3326-3330
Copyright © 2005 by The Endocrine Society

Arterial Stiffness in Mild Primary Hyperparathyroidism

Mishaela R. Rubin, Mathew S. Maurer, Donald J. McMahon, John P. Bilezikian and Shonni J. Silverberg

Departments of Medicine (M.R.R., M.S.M., D.J.M., J.P.B., S.J.S.) and Pharmacology (J.P.B.), College of Physicians & Surgeons, Columbia University, New York, New York 10032

Address all correspondence and requests for reprints to: Shonni J. Silverberg, M.D., Columbia University, College of Physicians & Surgeons, Department of Medicine, PH8-864, 630 West 168th Street, New York, New York 10032. E-mail: sjs5{at}columbia.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
When primary hyperparathyroidism was a more symptomatic disease, it was often associated with increased cardiovascular risk. As the clinical manifestations of the disease have changed to a milder, more asymptomatic disorder, investigation is shifting to more subtle cardiovascular abnormalities. We measured arterial stiffness in 39 patients with mild primary hyperparathyroidism [serum calcium, 2.66 ± 0.2 mmol/liter (10.7 ± 0.6 mg/dl); PTH, 21.7 ± 9.5 pmol/liter (89 ± 39 pg/ml)] and in 134 controls. Arterial stiffness was measured mathematically at the radial artery with a noninvasive device as the "augmentation index" (AIx). The AIx measures the difference between the second and first systolic peaks in the pressure waveform and correlates with increased cardiovascular risk. When physiological variables affecting augmentation index and potentially confounding cardiovascular risk factors (age, gender, heart rate, height, blood pressure, diabetes mellitus, smoking, and hyperlipidemia) were adjusted for, primary hyperparathyroidism was an independent predictor of increased augmentation index (B = 3.37; P < 0.03). A matched-pair analysis showed that 15% of the variance in AIx was uniquely accounted for by the presence of primary hyperparathyroidism. The presence of primary hyperparathyroidism was a stronger predictor of elevated AIx than age, gender, smoking, hypertension, hyperlipidemia, or diabetes mellitus. AIx was also directly correlated with evidence of more active parathyroid disease, including higher PTH levels (r = +0.42; P < 0.05) and lower bone mineral density at the distal one-third radius (r = –0.33; P < 0.05). The diagnosis of primary hyperparathyroidism was therefore an independent predictor of increased AIx, an early measure of arterial stiffness, and the increase was associated with evidence of more active parathyroid disease.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
WHEN PRIMARY HYPERPARATHYROIDISM (PHPT) was a more symptomatic disease, it was often associated with increased cardiovascular risk (1, 2). Current data about the cardiovascular consequences of PHPT are often conflicting, in part due to the decrease in disease severity in the United States over the last several decades (3). As the clinical findings in PHPT have become more subtle over time, the investigation of cardiovascular manifestations of the disease has turned to less clinically overt abnormalities. In particular, studies of vascular function have focused on vascular reactivity, which measures small-vessel, or endothelial, function, as well as vascular compliance and capacitance, measures of large-vessel function (4, 5, 6).

Augmentation of the pressure waveform is caused by peripheral reflection of the initial pressure wave, generated by ventricular ejection. It is an actual echo of this wave, returning late in diastole when the arteries are very distensible and pulse-wave velocity is slow. It returns progressively earlier during systole as the arteries stiffen and aortic-wave velocity increases. The augmentation index (AIx) is measurable through identification of the shoulder or early systolic peak of pressure, which corresponds to peak flow in the aorta, and measurement from this point to the second peak, or shoulder of the wave in late systole. AIx has been shown to be a strong, independent risk marker for premature coronary artery disease (7).

AIx was found previously to be increased in 21 patients with mild PHPT compared with controls by Smith et al. (8). However, AIx is affected by a number of variables, such as heart rate and height, which were not fully considered in the previous study. A higher heart rate lowers AIx because of an earlier arrival of the reflected wave (9), whereas decreased height increases AIx because the site of the reflected wave is closer to the proximal aorta, leading to a greater reflected wave (10). Demographic features also limited the interpretation of the previous study, because the PHPT subjects were older than the controls [AIx increases with age because of increased arterial wall thickening and decreased elasticity (11)] and had a high frequency of abnormal carbohydrate and lipid metabolism, classic cardiovascular risk factors that can independently influence vascular stiffness (12, 13, 14). Increased AIx occurs in diabetes mellitus and hypercholesterolemia, probably as a result of alterations in the arterial wall elastin and collagen (14, 15). Other factors known to increase AIx are female sex (16), smoking (17), and hypertension (18). The aim of the present study was to examine the augmentation index in mild PHPT while adjusting for potentially confounding factors, including age, gender, heart rate, height, blood pressure, diabetes mellitus, smoking, and hyperlipidemia.


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

Thirty-nine consecutive patients (35 females, 4 males) with mild PHPT, as defined by elevated serum calcium and PTH concentrations, were evaluated in our Metabolic Bone Disease Unit at the time of a routine clinic visit. To exclude patients with such marked hypercalcemia that vascular calcification would be a clearly expected finding, we limited PHPT patients to those with serum calcium levels less than 3 mmol/liter (<12 mg/dl) and PTH levels less than 50 pmol/liter (<200 pg/ml) by the intact immunoradiometric assay. No exclusion criteria were used. One hundred thirty-four healthy controls (88 females, 46 males) were evaluated at a Health Awareness Fair at Columbia University. Control subjects were excluded if they reported a history of an elevated serum calcium. The presence of cardiovascular risk factors including diabetes mellitus, hyperlipidemia, and hypertension, which can influence augmentation index, was ascertained by questioning in addition to medication review. Patients smoking at least one cigarette daily for 1 yr within the last 5 yr were considered smokers. Diabetes was defined by the use of oral hypoglycemic agents or insulin therapy. Hyperlipidemia was defined by the use lipid-lowering medication. Hypertension was defined by either a systolic blood pressure more than 140 mm Hg or diastolic blood pressure more than 90 mm Hg or the use of antihypertensive medication. Measurements of height and resting heart rate, variables that influence augmentation index, were obtained in each subject. Informed written consent was obtained for each subject, and approval for the study was obtained from the Columbia University Institutional Review Board.

Pulse-wave analysis

Arterial stiffness and central aortic pressure were measured noninvasively by the technique of pulse-wave analysis using the SphygmoCor apparatus (version 6.01; AtCor, Sydney, Australia) (19). 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 entered directly into a computer and processed by system software to allow accurate on-line recording of the radial artery waveform. The corresponding aortic pressure waveform was then generated from an averaged radial artery waveform (derived from ~11 sec of sequentially recorded radial artery waveforms) using a validated transfer function (19, 20, 21). The AIx was determined from a computerized analysis of the central aortic waveform. It is defined as the difference between the first and second peaks of the central arterial waveform, expressed as a percentage of the pulse pressure (19). Larger values of AIx indicate increased wave reflection from the periphery as a result of increased arterial stiffness.

Radial blood pressure was calibrated against brachial blood pressure, which was measured using conventional mercury sphygmomanometry. 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 wave were outside the predetermined acceptable limits (<100 mV for pulse height, >10% for systolic or diastolic variability), then the recording was excluded. Reproducibility of the AIx using the SphygmoCor apparatus was determined as described previously (22). The precision in our laboratory between repeated measurements of the AIx is 2.2 ± 1.5% (mean difference ± SD).

Biochemical and densitometric measurements

Biochemical and densitometric measurements were obtained at the time of the study visit or within the 6 months preceding the visit. Serum total calcium was measured by automated techniques (Technicon Instruments, Tarrytown, NY). Serum PTH was measured by immunoradiometric assay (Nichols Institute Diagnostics, San Jaun Capistrano, CA). Bone-specific alkaline phosphatase activity was measured by a solid phase, two-site immunoradiometric assay (Hybritech Inc., San Diego, CA). Urinary N-telopeptide excretion was measured by a competitive-inhibition ELISA (Ostex, Seattle, WA). Bone mineral density was obtained by dual-energy x-ray absorptiometry (model QDR-4500 bone densitometer; Hologic, Waltham, MA.)

Statistical analyses

All statistical analyses were performed using SPSS for Windows (version 11.0; SPSS, Chicago, IL). All continuous data are presented as mean value ± SD, and all categorical data are reported as percentage or absolute number. Student’s t tests and Fisher’s exact tests were used to assess differences between groups. A Pearson’s correlation coefficient was used to assess the relationship between variables. The multivariate relationship among variables was evaluated by multiple-regression analysis. With AIx as the dependent variable, the following independent variables were entered in the model, along with a dummy code for the presence of a diagnosis of PHPT: age, sex, height, heart rate, systolic and diastolic blood pressure, tobacco use, history of hypertension, hyperlipidemia, and diabetes mellitus. P < 0.05 was considered significant. Matched-pair analysis was performed with the use of "propensity scores" for the analysis of nonrandomized cohorts (23). A propensity score was calculated for each subject (i.e. the likelihood of being in the PHPT or control group, calculated from a logistic regression model that included heart rate, height, gender, blood pressure, age, diabetes mellitus, smoking, and hyperlipidemia), and the largest number of pairs of cases and controls with adjacent propensity scores was used for the matched-pair analysis.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The characteristics of the PHPT and control groups are shown in Table 1Go. Mean serum calcium [2.66 ± 0.2 mmol/liter (10.7 ± 0.6 mg/dl)] and PTH levels [21.7 ± 9.5 pmol/liter (89 ± 39 pg/ml)] were in the range typical for a cohort of patients with mild PHPT. Five patients (13%) had a history of nephrolithiasis, although none had active stone disease at the time they were studied. The remaining 34 patients were asymptomatic. The frequencies of tobacco use, hyperlipidemia, and diabetes mellitus were similar among the two groups. Compared with the control group, the PHPT group was younger, had more women, and had lower peripheral brachial artery systolic pressures and less frequent histories of hypertension. Resting heart rate and peripheral brachial artery diastolic pressure were similar among the two groups. The proportion of patients using angiotensin-converting enzyme (ACE) inhibitors and ß blockers did not differ between the two groups. Serum creatinine was available in 36 of the patients and in 63 of the controls and did not differ between the groups (patients, 0.9 ± 0.2 vs. controls, 1.0 ± 1.1 mg/dl; P = 0.4). The 63 controls for whom serum creatinine data were available do not represent a biased, younger sample because more than half (n = 39) were above the mean age of 67.1 yr of the control population. Indices of PHPT are shown in Table 2Go.


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  		TABLE 1. Characteristics of subjects and controls

 

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  		TABLE 2. Biochemical and densitometric indices in PHPT subjects

 
Pulse-wave analysis revealed a higher AIx in the PHPT group (28 ± 10 vs. 25 ± 10%), although it was not statistically significant without adjustment for factors that influence AIx. Because large-artery stiffness can be influenced by a variety of physical and metabolic factors and because the control group was significantly older and more hypertensive, a multiple-regression analysis was performed in which the following factors potentially altering central hemodynamic indices were entered into the model: presence of PHPT, heart rate, height, gender, blood pressure, age, diabetes mellitus, smoking, and hyperlipidemia. With these adjustments, there was a significant relationship between PHPT and AIx. The presence of PHPT was an independent predictor of increased AIx (B = 3.37; P < 0.03). PHPT remained an independent predictor of AIx in the subgroup of patients with asymptomatic disease (n = 34; B = 3.17; P < 0.05). The attributable unique contribution of the presence of PHPT to the variance in AIx (r2) in this sample, after controlling for other variables, was 5%. Details of this model are shown in Table 3Go. The presence of PHPT contributed to the risk of arterial stiffness more than other known risk factors, including diabetes mellitus, hyperlipidemia, smoking, and diastolic blood pressure. When the analysis was performed with only female subjects, the same pattern of multiple-regression results was seen (data not shown).


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  		TABLE 3. Multiple-regression summary for the dependent variable AIx (r2 = 0.58)

 
A matched-pair analysis was also performed in the 28 pairs with matched propensity scores (pairs of patients and control subjects comparable with regard to heart rate, height, gender, blood pressure, age, diabetes mellitus, smoking, and hyperlipidemia in a logistic regression model). When the original regression analysis was repeated on this restricted sample of matched pairs, 83% of the variance in AIx was accounted for, and 15% was uniquely accounted for by the presence of PHPT. Having PHPT was a stronger predictor of elevated AIx than age, gender, smoking, hypertension, hyperlipidemia, or diabetes mellitus.

For the PHPT group, a significant positive correlation was noted between PTH concentration and AIx (r = +0.42; P < 0.05) (Fig. 1AGo). A hallmark of target organ involvement in PHPT is a reduction in cortical bone density as measured at the distal one-third of the radius. When this feature of PHPT was studied in relationship to the AIx, the r value was significant (r = –0.33; P < 0.05) (Fig. 1BGo). There was no association between AIx and serum or urinary calcium, markers of bone turnover, or bone mineral density at the lumbar spine or femoral neck (data not shown).



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  		FIG. 1. A, A significant positive correlation was noted between AIx and PTH levels (r = +0.42; P < 0.05). The horizontal lines delineate the normal range of PTH (10–65 pg/ml); the relationship with AIx extends linearly into the normal range of PTH. B, A significant negative correlation was noted between AIx and the one-third radius T score (r = –0.33; P < 0.05).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Although symptomatic PHPT has been associated with adverse cardiovascular consequences, it is unclear whether mild PHPT has similar effects. We found that, when potential physiological confounders and classical cardiovascular risk factors were taken into account, the diagnosis of PHPT was an independent predictor of increased AIx, an early measure of arterial stiffness. The relationship between this measurement and classical indices of parathyroid disease activity, namely PTH level and distal forearm bone density, help to substantiate the likelihood that mild PHPT can be associated with cardiovascular abnormalities.

Symptomatic PHPT has been associated with vascular and myocardial calcification, arrhythmias, hypertension, and left ventricular hypertrophy (24) (25). Epidemiological studies in Scandinavian populations with PHPT support an increase in cardiovascular mortality (26, 27, 28, 29). In contrast to the European studies, the only study of a largely asymptomatic American cohort found markedly reduced cardiovascular mortality (relative risk 0.6) (3). In populations characterized primarily by asymptomatic disease, evidence for cardiovascular involvement has therefore turned to more subtle manifestations. Anatomic parameters, for example, have been measured with the use of high-resolution carotid ultrasonography (30). Carotid intima-medial thickness was markedly increased in 20 patients with PHPT compared with controls (1.6 ± 0.5 vs. 0.68 ± 0.3) (31). In populations in which the serum calcium did not extend to the markedly abnormal range, it was shown, in contrast, that carotid intima-medial thickness is not affected by PHPT (4, 6, 32, 33). The suggestion is that only in those with severe hypercalcemia or in those with established cardiovascular risk factors is one likely to find evidence for cardiovascular involvement in PHPT. Although these data are supported by a recent study by Fallo et al.,(34) that study was limited in the scope of the analysis of the carotid artery.

Arterial stiffness is a strong, early predictor for cardiovascular disease. The normal central aortic pressure wave is composed of a forward-traveling wave generated by left ventricular ejection and a later-arriving reflected wave from the periphery. As arterial stiffness increases, transmission velocity of both forward and reflected waves increase, which causes the reflected wave to arrive earlier in the central aorta and augment pressure in late systole. This earlier arrival, measured as the AIx, is associated with several cardiovascular risk factors (35), including age, smoking, hypertension, diabetes mellitus, and hypercholesterolemia. Other factors that can influence AIx include heart rate and height (9, 10). ACE inhibitors decrease AIx through vasodilatation, whereas ß blockers increase AIx by a reduction in heart rate. In mild PHPT, AIx was found previously to be increased in a study by Smith et al. (8). However, heart rate and height were not controlled for. In addition, a younger control group was used, in whom the AIx might be lower simply as a function of age (11). Finally, subjects with PHPT were over-represented with respect to the expected incidence in this population of diabetes mellitus and elevated total cholesterol, risk factors that can independently influence vascular stiffness (12, 13, 14).

In the present study, AIx was compared in 39 patients with mild PHPT and 134 healthy controls. When physiological variables affecting AIx and potentially confounding classical cardiovascular risk factors were taken into account, PHPT was an independent predictor of increased AIx. Although the controls were older and more hypertensive than the patients with PHPT, these differences, if anything, would tend to bias our results toward minimizing differences rather than establishing them. Other cardiovascular risk factors associated with increased AIx, including smoking, diabetes mellitus, and hypercholesterolemia, were not significantly different between patients and controls. The control subjects did not appear to have a greater degree of renal insufficiency, an important indicator of comorbidity that can be associated with increased AIx. There was also no difference in proportion of use of ACE inhibitors or ß blockers in the two groups. Moreover, all cardiovascular risk factors were adjusted for in the multiple-regression analysis, which showed that PHPT contributed 5% of the variance in arterial stiffness. The presence of PHPT contributed to the risk of arterial stiffness more than other known risk factors, including diabetes mellitus, hyperlipidemia, smoking, and diastolic blood pressure. The strength of the association between PHPT and AIx was further enhanced when pairs of patients and control subjects well matched with regard to age, gender, heart rate, height, blood pressure, diabetes mellitus, smoking, and hyperlipidemia were considered. In that analysis, 15% of the variance in AIx was uniquely accounted for by the presence of PHPT. Having PHPT was a stronger predictor of elevated AIx than age, gender, smoking, hypertension, hyperlipidemia, or diabetes mellitus.

We also found that AIx was directly correlated with evidence of more active parathyroid disease. The increased arterial stiffness in the presence of higher PTH levels and greater cortical demineralization is consistent with overall greater target organ involvement that now could include the vasculature as well. This relationship extended into the "normal" range of PTH, but, for these subjects with hypercalcemia, levels of PTH, even if normal, are decidedly abnormal. However, we did not find an association between AIx and serum or urinary calcium levels. Whether PTH has an effect on the vasculature independent of ambient calcium levels (36) is unknown.

In conclusion, PHPT was an independent predictor of increased AIx, an early measure of arterial stiffness, and the increase was associated with evidence of more active parathyroid disease. Additional studies are needed to establish whether the vasculature should become another key target organ for evaluation of patients with mild, asymptomatic PHPT.


   Footnotes
 
First Published Online March 15, 2005

Abbreviations: ACE, Angiotensin-converting enzyme; AIx, augmentation index; PHPT, primary hyperparathyroidism.

Received July 16, 2004.

Accepted March 3, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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E. Ambrogini, F. Cetani, L. Cianferotti, E. Vignali, C. Banti, G. Viccica, A. Oppo, P. Miccoli, P. Berti, J. P. Bilezikian, et al.
Surgery or Surveillance for Mild Asymptomatic Primary Hyperparathyroidism: A Prospective, Randomized Clinical Trial
J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3114 - 3121.
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J. Bollerslev, S. Jansson, C. L. Mollerup, J. Nordenstrom, E. Lundgren, O. Torring, J.-E. Varhaug, M. Baranowski, S. Aanderud, C. Franco, et al.
Medical Observation, Compared with Parathyroidectomy, for Asymptomatic Primary Hyperparathyroidism: A Prospective, Randomized Trial
J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1687 - 1692.
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