Arterial Stiffness in Mild Primary Hyperparathyroidism

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					                 Arterial Stiffness in Mild Primary Hyperparathyroidism
      Mishaela R. Rubin, Mathew S. Maurer, Donald J. McMahon, John P. Bilezikian and Shonni J. Silverberg

J. Clin. Endocrinol. Metab. 2005 90:3326-3330 originally published online Mar 15, 2005; , doi: 10.1210/jc.2004-1400

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0021-972X/05/$15.00/0                                                                 The Journal of Clinical Endocrinology & Metabolism 90(6):3326 –3330
Printed in U.S.A.                                                                                               Copyright © 2005 by The Endocrine Society
                                                                                                                                 doi: 10.1210/jc.2004-1400

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

When primary hyperparathyroidism was a more symptomatic dis-           justed for, primary hyperparathyroidism was an independent pre-
ease, it was often associated with increased cardiovascular risk. As   dictor of increased augmentation index (B        3.37; P      0.03). A
the clinical manifestations of the disease have changed to a milder,   matched-pair analysis showed that 15% of the variance in AIx was
more asymptomatic disorder, investigation is shifting to more subtle   uniquely accounted for by the presence of primary hyperparathyroid-
cardiovascular abnormalities. We measured arterial stiffness in 39     ism. The presence of primary hyperparathyroidism was a stronger
patients with mild primary hyperparathyroidism [serum calcium,         predictor of elevated AIx than age, gender, smoking, hypertension,
2.66 0.2 mmol/liter (10.7 0.6 mg/dl); PTH, 21.7 9.5 pmol/liter         hyperlipidemia, or diabetes mellitus. AIx was also directly correlated
(89 39 pg/ml)] and in 134 controls. Arterial stiffness was measured    with evidence of more active parathyroid disease, including higher
mathematically at the radial artery with a noninvasive device as the   PTH levels (r      0.42; P 0.05) and lower bone mineral density at
“augmentation index” (AIx). The AIx measures the difference between    the distal one-third radius (r     0.33; P    0.05). The diagnosis of
the second and first systolic peaks in the pressure waveform and       primary hyperparathyroidism was therefore an independent predic-
correlates with increased cardiovascular risk. When physiological      tor of increased AIx, an early measure of arterial stiffness, and the
variables affecting augmentation index and potentially confounding     increase was associated with evidence of more active parathyroid
cardiovascular risk factors (age, gender, heart rate, height, blood    disease. (J Clin Endocrinol Metab 90: 3326 –3330, 2005)
pressure, diabetes mellitus, smoking, and hyperlipidemia) were ad-

           was a more symptomatic disease, it was often associ-
ated with increased cardiovascular risk (1, 2). Current data
                                                                          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
about the cardiovascular consequences of PHPT are often con-           heart rate and height, which were not fully considered in the
flicting, in part due to the decrease in disease severity in the       previous study. A higher heart rate lowers AIx because of an
United States over the last several decades (3). As the clinical       earlier arrival of the reflected wave (9), whereas decreased
findings in PHPT have become more subtle over time, the                height increases AIx because the site of the reflected wave is
investigation of cardiovascular manifestations of the disease          closer to the proximal aorta, leading to a greater reflected
has turned to less clinically overt abnormalities. In particular,      wave (10). Demographic features also limited the interpre-
studies of vascular function have focused on vascular reactivity,      tation of the previous study, because the PHPT subjects were
which measures small-vessel, or endothelial, function, as well         older than the controls [AIx increases with age because of
as vascular compliance and capacitance, measures of large-             increased arterial wall thickening and decreased elasticity
vessel function (4 – 6).                                               (11)] and had a high frequency of abnormal carbohydrate and
   Augmentation of the pressure waveform is caused by pe-              lipid metabolism, classic cardiovascular risk factors that can
ripheral reflection of the initial pressure wave, generated by         independently influence vascular stiffness (12–14). Increased
ventricular ejection. It is an actual echo of this wave, return-       AIx occurs in diabetes mellitus and hypercholesterolemia,
ing late in diastole when the arteries are very distensible and        probably as a result of alterations in the arterial wall elastin
pulse-wave velocity is slow. It returns progressively earlier          and collagen (14, 15). Other factors known to increase AIx are
during systole as the arteries stiffen and aortic-wave velocity        female sex (16), smoking (17), and hypertension (18). The aim
increases. The augmentation index (AIx) is measurable                  of the present study was to examine the augmentation index
through identification of the shoulder or early systolic peak          in mild PHPT while adjusting for potentially confounding
of pressure, which corresponds to peak flow in the aorta, and          factors, including age, gender, heart rate, height, blood pres-
measurement from this point to the second peak, or shoulder            sure, diabetes mellitus, smoking, and hyperlipidemia.
of the wave in late systole. AIx has been shown to be a strong,
                                                                                            Subjects and Methods
independent risk marker for premature coronary artery dis-
ease (7).                                                              Subjects
                                                                          Thirty-nine consecutive patients (35 females, 4 males) with mild
                                                                       PHPT, as defined by elevated serum calcium and PTH concentrations,
   First Published Online March 15, 2005                               were evaluated in our Metabolic Bone Disease Unit at the time of a
   Abbreviations: ACE, Angiotensin-converting enzyme; AIx, augmen-     routine clinic visit. To exclude patients with such marked hypercalcemia
tation index; PHPT, primary hyperparathyroidism.                       that vascular calcification would be a clearly expected finding, we lim-
JCEM is published monthly by The Endocrine Society (http://www.        ited PHPT patients to those with serum calcium levels less than 3, the foremost professional society serving the en-   mmol/liter ( 12 mg/dl) and PTH levels less than 50 pmol/liter ( 200
docrine community.                                                     pg/ml) by the intact immunoradiometric assay. No exclusion criteria

Rubin et al. • Arterial Stiffness in Hyperparathyroidism                                    J Clin Endocrinol Metab, June 2005, 90(6):3326 –3330          3327

were used. One hundred thirty-four healthy controls (88 females, 46          analysis. With AIx as the dependent variable, the following independent
males) were evaluated at a Health Awareness Fair at Columbia Uni-            variables were entered in the model, along with a dummy code for the
versity. Control subjects were excluded if they reported a history of an     presence of a diagnosis of PHPT: age, sex, height, heart rate, systolic and
elevated serum calcium. The presence of cardiovascular risk factors          diastolic blood pressure, tobacco use, history of hypertension, hyper-
including diabetes mellitus, hyperlipidemia, and hypertension, which         lipidemia, and diabetes mellitus. P     0.05 was considered significant.
can influence augmentation index, was ascertained by questioning in          Matched-pair analysis was performed with the use of “propensity
addition to medication review. Patients smoking at least one cigarette       scores” for the analysis of nonrandomized cohorts (23). A propensity
daily for 1 yr within the last 5 yr were considered smokers. Diabetes was    score was calculated for each subject (i.e. the likelihood of being in the
defined by the use of oral hypoglycemic agents or insulin therapy.           PHPT or control group, calculated from a logistic regression model that
Hyperlipidemia was defined by the use lipid-lowering medication. Hy-         included heart rate, height, gender, blood pressure, age, diabetes mel-
pertension was defined by either a systolic blood pressure more than 140     litus, smoking, and hyperlipidemia), and the largest number of pairs of
mm Hg or diastolic blood pressure more than 90 mm Hg or the use of           cases and controls with adjacent propensity scores was used for the
antihypertensive medication. Measurements of height and resting heart        matched-pair analysis.
rate, variables that influence augmentation index, were obtained in each
subject. Informed written consent was obtained for each subject, and                                         Results
approval for the study was obtained from the Columbia University
Institutional Review Board.                                                     The characteristics of the PHPT and control groups are
                                                                             shown in Table 1. Mean serum calcium [2.66          0.2 mmol/
Pulse-wave analysis                                                          liter (10.7 0.6 mg/dl)] and PTH levels [21.7 9.5 pmol/
   Arterial stiffness and central aortic pressure were measured nonin-
                                                                             liter (89 39 pg/ml)] were in the range typical for a cohort
vasively by the technique of pulse-wave analysis using the SphygmoCor        of patients with mild PHPT. Five patients (13%) had a history
apparatus (version 6.01; AtCor, Sydney, Australia) (19). All measure-        of nephrolithiasis, although none had active stone disease at
ments were taken from the radial artery at the wrist using a microma-        the time they were studied. The remaining 34 patients were
nometer (SPC-301; Millar Instruments, Houston, TX), applying the prin-       asymptomatic. The frequencies of tobacco use, hyperlipid-
ciple of applanation tonometry to flatten the artery by gentle pressure.
Data were entered directly into a computer and processed by system           emia, and diabetes mellitus were similar among the two
software to allow accurate on-line recording of the radial artery wave-      groups. Compared with the control group, the PHPT group
form. The corresponding aortic pressure waveform was then generated          was younger, had more women, and had lower peripheral
from an averaged radial artery waveform (derived from 11 sec of              brachial artery systolic pressures and less frequent histories
sequentially recorded radial artery waveforms) using a validated trans-
fer function (19 –21). The AIx was determined from a computerized
                                                                             of hypertension. Resting heart rate and peripheral brachial
analysis of the central aortic waveform. It is defined as the difference     artery diastolic pressure were similar among the two groups.
between the first and second peaks of the central arterial waveform,         The proportion of patients using angiotensin-converting en-
expressed as a percentage of the pulse pressure (19). Larger values of AIx   zyme (ACE) inhibitors and blockers did not differ between
indicate increased wave reflection from the periphery as a result of         the two groups. Serum creatinine was available in 36 of the
increased arterial stiffness.
   Radial blood pressure was calibrated against brachial blood pressure,     patients and in 63 of the controls and did not differ between
which was measured using conventional mercury sphygmomanometry.              the groups (patients, 0.9 0.2 vs. controls, 1.0 1.1 mg/dl;
The software allowed for objectivity of measurements by setting quality      P     0.4). The 63 controls for whom serum creatinine data
control parameters on the radial artery waveform recordings. These           were available do not represent a biased, younger sample
parameters were mean pulse height and systolic and diastolic variabil-
ity. If any of the parameters on a given recording wave were outside the
                                                                             because more than half (n 39) were above the mean age of
predetermined acceptable limits ( 100 mV for pulse height, 10% for           67.1 yr of the control population. Indices of PHPT are shown
systolic or diastolic variability), then the recording was excluded. Re-     in Table 2.
producibility of the AIx using the SphygmoCor apparatus was deter-              Pulse-wave analysis revealed a higher AIx in the PHPT
mined as described previously (22). The precision in our laboratory          group (28 10 vs. 25 10%), although it was not statistically
between repeated measurements of the AIx is 2.2 1.5% (mean differ-
ence sd).                                                                    significant without adjustment for factors that influence AIx.

Biochemical and densitometric measurements                                   TABLE 1. Characteristics of subjects and controls
   Biochemical and densitometric measurements were obtained at the                                                   PHPT                  Controls
time of the study visit or within the 6 months preceding the visit. Serum                                           (n 39)                (n 134)
total calcium was measured by automated techniques (Technicon In-
struments, Tarrytown, NY). Serum PTH was measured by immunora-                 Age (yr)                           63.3 8.8               67.1 11a
diometric assay (Nichols Institute Diagnostics, San Jaun Capistrano,           Female                               35 (90)                88 (66)a
CA). Bone-specific alkaline phosphatase activity was measured by a             Height (cm)                       163.6 7.0              165.2 9.0
solid phase, two-site immunoradiometric assay (Hybritech Inc., San             Resting heart rate (bpm)           71.4 11                72.6 11
Diego, CA). Urinary N-telopeptide excretion was measured by a com-             Brachial systolic blood           126.4 16.6             142.7 20.0a
petitive-inhibition ELISA (Ostex, Seattle, WA). Bone mineral density               pressure (mm Hg)
was obtained by dual-energy x-ray absorptiometry (model QDR-4500               Brachial diastolic blood           77.4        10         77.7        13
bone densitometer; Hologic, Waltham, MA.)                                          pressure (mm Hg)
                                                                               Tobacco use                            3 (8)                4 (3)
                                                                               Hypertension                          15 (39)              86 (64)a
Statistical analyses                                                           Hyperlipidemia                        15 (39)              38 (28)
                                                                               Diabetes mellitus                      3 (8)               11 (8)
   All statistical analyses were performed using SPSS for Windows
                                                                               Antihypertensive                      12 (31)              44 (33)
(version 11.0; SPSS, Chicago, IL). All continuous data are presented as
mean value sd, and all categorical data are reported as percentage or
                                                                                 B blockers                              4                      10
absolute number. Student’s t tests and Fisher’s exact tests were used to
                                                                                 ACE inhibitors                          5                       8
assess differences between groups. A Pearson’s correlation coefficient
was used to assess the relationship between variables. The multivariate        Data are expressed as the mean            SD   or number (%).
relationship among variables was evaluated by multiple-regression               P 0.05.
3328   J Clin Endocrinol Metab, June 2005, 90(6):3326 –3330                                Rubin et al. • Arterial Stiffness in Hyperparathyroidism

TABLE 2. Biochemical and densitometric indices in PHPT                    presence of PHPT. Having PHPT was a stronger predictor of
subjects                                                                  elevated AIx than age, gender, smoking, hypertension, hy-
                                              PHPT             Normal
                                                                          perlipidemia, or diabetes mellitus.
                                             (n 39)             range        For the PHPT group, a significant positive correlation was
 Serum calcium (mmol/liter)                2.66    0.2        2.1–2.4     noted between PTH concentration and AIx (r           0.42; P
 PTH (pmol/liter)                          21.7    9.5        2.4 –15.9   0.05) (Fig. 1A). A hallmark of target organ involvement in
 Urinary calcium (mg/24h)                 191.3    99             300     PHPT is a reduction in cortical bone density as measured at
 Lumbar spine BMD (gm/cm2)                0.920    0.22                   the distal one-third of the radius. When this feature of PHPT
   T score                                 1.48    1.5
 Total hip BMD (gm/cm2)                   0.760    0.15                   was studied in relationship to the AIx, the r value was sig-
   T score                                 1.52    1.1                    nificant (r     0.33; P 0.05) (Fig. 1B). There was no asso-
 Distal forearm BMD (gm/cm2)              0.614    0.11                   ciation between AIx and serum or urinary calcium, markers
   T score                                 1.48    1.4                    of bone turnover, or bone mineral density at the lumbar spine
 Urinary NTX (nmol/liter BCE)              50.5    31         20 –50
                                                                          or femoral neck (data not shown).
   (n 11)
 BSAP (ng/ml) (n 13)                        18.5   10         8.0 –16.6
  Data are expressed as the mean SD. BMD, Bone mineral density;
NTX, N-telopeptide; BSAP, bone-specific alkaline phosphatase.                Although symptomatic PHPT has been associated with
                                                                          adverse cardiovascular consequences, it is unclear whether
Because large-artery stiffness can be influenced by a variety             mild PHPT has similar effects. We found that, when potential
of physical and metabolic factors and because the control                 physiological confounders and classical cardiovascular risk
group was significantly older and more hypertensive, a mul-               factors were taken into account, the diagnosis of PHPT was
tiple-regression analysis was performed in which the fol-                 an independent predictor of increased AIx, an early measure
lowing factors potentially altering central hemodynamic in-               of arterial stiffness. The relationship between this measure-
dices were entered into the model: presence of PHPT, heart                ment and classical indices of parathyroid disease activity,
rate, height, gender, blood pressure, age, diabetes mellitus,             namely PTH level and distal forearm bone density, help to
smoking, and hyperlipidemia. With these adjustments, there                substantiate the likelihood that mild PHPT can be associated
was a significant relationship between PHPT and AIx. The                  with cardiovascular abnormalities.
presence of PHPT was an independent predictor of increased                   Symptomatic PHPT has been associated with vascular and
AIx (B      3.37; P    0.03). PHPT remained an independent                myocardial calcification, arrhythmias, hypertension, and left
predictor of AIx in the subgroup of patients with asymp-                  ventricular hypertrophy (24) (25). Epidemiological studies in
tomatic disease (n 34; B 3.17; P 0.05). The attributable                  Scandinavian populations with PHPT support an increase in
unique contribution of the presence of PHPT to the variance               cardiovascular mortality (26 –29). In contrast to the European
in AIx (r2) in this sample, after controlling for other variables,        studies, the only study of a largely asymptomatic American
was 5%. Details of this model are shown in Table 3. The                   cohort found markedly reduced cardiovascular mortality
presence of PHPT contributed to the risk of arterial stiffness            (relative risk 0.6) (3). In populations characterized primarily
more than other known risk factors, including diabetes mel-               by asymptomatic disease, evidence for cardiovascular involve-
litus, hyperlipidemia, smoking, and diastolic blood pressure.             ment has therefore turned to more subtle manifestations. An-
When the analysis was performed with only female subjects,                atomic parameters, for example, have been measured with the
the same pattern of multiple-regression results was seen                  use of high-resolution carotid ultrasonography (30). Carotid
(data not shown).                                                         intima-medial thickness was markedly increased in 20 patients
   A matched-pair analysis was also performed in the 28                   with PHPT compared with controls (1.6 0.5 vs. 0.68 0.3) (31).
pairs with matched propensity scores (pairs of patients and               In populations in which the serum calcium did not extend to the
control subjects comparable with regard to heart rate, height,            markedly abnormal range, it was shown, in contrast, that ca-
gender, blood pressure, age, diabetes mellitus, smoking, and              rotid intima-medial thickness is not affected by PHPT (4, 6, 32,
hyperlipidemia in a logistic regression model). When the                  33). The suggestion is that only in those with severe hypercal-
original regression analysis was repeated on this restricted              cemia or in those with established cardiovascular risk factors is
sample of matched pairs, 83% of the variance in AIx was                   one likely to find evidence for cardiovascular involvement in
accounted for, and 15% was uniquely accounted for by the                  PHPT. Although these data are supported by a recent study by

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

                Independent variable                            B                 SE                  t value                  P less than
        Height (cm)                                             0.35             0.09                   3.98                      0.01
        Heart rate (bpm)                                        0.43             0.06                   7.25                      0.01
        Systolic blood pressure (mm Hg)                         0.18             0.05                   3.59                      0.01
        Female gender                                           4.78             1.81                   2.65                      0.01
        Presence of PHPT                                        3.37             1.52                   2.21                      0.03
        Presence of diabetes mellitus                           5.08             1.98                   2.56                      0.01
        Age (increase per decade)                               0.96             0.70                   1.38                      0.18
        Smoking                                                 3.60             2.67                   1.38                      0.17
        Presence of hyperlipidemia                              1.61             1.26                   1.32                      0.19
        Diastolic blood pressure (mm Hg)                        0.02             0.07                   0.29                      0.77
Rubin et al. • Arterial Stiffness in Hyperparathyroidism                               J Clin Endocrinol Metab, June 2005, 90(6):3326 –3330     3329

                                                                        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 es-
                                                                        tablishing 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 propor-
                                                                        tion of use of ACE inhibitors or 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 pres-
                                                                        ence 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 fur-
                                                                        ther enhanced when pairs of patients and control subjects
                                                                        well matched with regard to age, gender, heart rate, height,
                                                                        blood pressure, diabetes mellitus, smoking, and hyperlipid-
                                                                        emia 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
FIG. 1. A, A significant positive correlation was noted between AIx     age, gender, smoking, hypertension, hyperlipidemia, or di-
and PTH levels (r      0.42; P 0.05). The horizontal lines delineate    abetes mellitus.
the normal range of PTH (10 – 65 pg/ml); the relationship with AIx         We also found that AIx was directly correlated with evi-
extends linearly into the normal range of PTH. B, A significant neg-    dence of more active parathyroid disease. The increased ar-
ative correlation was noted between AIx and the one-third radius T
score (r     0.33; P 0.05).                                             terial stiffness in the presence of higher PTH levels and
                                                                        greater cortical demineralization is consistent with overall
Fallo et al.,(34) that study was limited in the scope of the analysis   greater target organ involvement that now could include the
of the carotid artery.                                                  vasculature as well. This relationship extended into the “nor-
   Arterial stiffness is a strong, early predictor for cardio-          mal” range of PTH, but, for these subjects with hypercalce-
vascular disease. The normal central aortic pressure wave is            mia, levels of PTH, even if normal, are decidedly abnormal.
composed of a forward-traveling wave generated by left                  However, we did not find an association between AIx and
ventricular ejection and a later-arriving reflected wave from           serum or urinary calcium levels. Whether PTH has an effect
the periphery. As arterial stiffness increases, transmission            on the vasculature independent of ambient calcium levels
velocity of both forward and reflected waves increase, which            (36) is unknown.
causes the reflected wave to arrive earlier in the central aorta           In conclusion, PHPT was an independent predictor of
and augment pressure in late systole. This earlier arrival,             increased AIx, an early measure of arterial stiffness, and the
measured as the AIx, is associated with several cardiovas-              increase was associated with evidence of more active para-
cular risk factors (35), including age, smoking, hypertension,          thyroid disease. Additional studies are needed to establish
diabetes mellitus, and hypercholesterolemia. Other factors              whether the vasculature should become another key target
that can influence AIx include heart rate and height (9, 10).           organ for evaluation of patients with mild, asymptomatic
ACE inhibitors decrease AIx through vasodilatation,                     PHPT.
whereas blockers increase AIx by a reduction in heart rate.
In mild PHPT, AIx was found previously to be increased in                                        Acknowledgments
a study by Smith et al. (8). However, heart rate and height
were not controlled for. In addition, a younger control group              Received July 16, 2004. Accepted March 3, 2005.
was used, in whom the AIx might be lower simply as a                       Address all correspondence and requests for reprints to: Shonni J.
                                                                        Silverberg, M.D., Columbia University, College of Physicians & Sur-
function of age (11). Finally, subjects with PHPT were over-            geons, Department of Medicine, PH8-864, 630 West 168th Street, New
represented with respect to the expected incidence in this              York, New York 10032. E-mail:
population of diabetes mellitus and elevated total choles-
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