The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 8 2450-2454
Copyright © 1997 by The Endocrine Society
Cardiovascular Abnormalities in Patients with X-Linked Hypophosphatemia
Rodrigo Nehgme,
John T. Fahey,
Cynthia Smith and
Thomas O. Carpenter
Department of Pediatrics, Sections of Pediatric Cardiology (R.N.,
J.T.F.) and Endocrinology (C.S., T.O.C.), Yale University School of
Medicine, New Haven, Connecticut 06520
Address all correspondence and requests for reprints to: Rodrigo Nehgme, M.D., Department of Pediatrics (Cardiology), Yale University School of Medicine, Room 302 LLCI, 333 Cedar Street, New Haven, Connecticut 06520.
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Abstract
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Treatment for X-linked hypophosphatemia (XLH; vitamin D metabolites and
phosphate salts) may result in hypercalcemia, hypercalciuria,
nephrocalcinosis, and hyperparathyroidism. Cardiovascular abnormalities
occur in association with these complications, but have not been
reported in XLH. We hypothesized that such abnormalities may occur in
XLH and evaluated cardiovascular status in 13 patients with this
disease.
All patients were asymptomatic and had normal cardiovascular physical
examinations and Holter studies. Serum calcium and creatinine clearance
were normal in all. However, all patients had mild to moderate
nephrocalcinosis. Left ventricular hypertrophy was diagnosed by
electrocardiogram in three and by ultrasonography in seven children.
Baseline blood pressure (BP) was normal (mean ± SD,
116 ± 15/74 ± 6 mm Hg). During exercise stress testing,
systolic BP increased in all patients, but the maximal systolic
pressure was less than that in healthy age- and sex-matched controls
(156 ± 20 vs. 175 ± 23;
P = 0.002, by t test). An abnormal
increase in diastolic BP occurred at all levels of work load in XLH
patients; their peak exercise diastolic BP was 91 ± 12
vs. 72 ± 6 mm Hg in controls
(P < 0.0001, by t test).
Whether these abnormal findings are primary defects in XLH or represent
complications of treatment is unclear. Patients with XLH should be
monitored closely for the development of hypertension and left
ventricular hypertrophy. Investigation of the mechanisms involved and
establishment of therapeutic guidelines are indicated.
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Introduction
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THE PRIMARY metabolic disturbances in
patients with X-linked hypophosphatemia (XLH) are decreased renal
tubular reabsorption of phosphate (1, 2) and failure to generate
elevated circulating levels of 1,25-dihydroxyvitamin D during
hypophosphatemia (3). The standard treatment for XLH (vitamin D
metabolites and phosphate salts) may result in the complications of
hypercalcemia, hypercalciuria, nephrocalcinosis (4, 5, 6, 7, 8, 9, 10), and
hyperparathyroidism (11, 12, 13). Cardiovascular abnormalities, such as
valvular disease, myocardial dysfunction, and hypertension, occur in
association with these complications (14, 15, 16, 17, 18, 19, 20), but have not been
reported in XLH. We, therefore, hypothesized that cardiovascular
complications may occur in patients with XLH and performed a complete,
noninvasive cardiac evaluation in 13 affected patients.
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Subjects and Methods
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Thirteen subjects (nine females and four males) with XLH were
studied. Serum phosphate and renal tubular phosphate threshold maxima
were low in all, characteristic of XLH. The mean age of the subjects
was 13.5 yr (range, 8–20 yr), the mean weight was 50.62 ± 16.75
kg, and the mean height was 145.69 ± 19.07 cm. Ten subjects had
affected family members. Otherwise, family history revealed the
presence of hypertension only in the XLH-affected mother of two
patients. All patients were receiving standard therapy (Table 1
).
Informed consent was obtained from the patients or their parents. The
study protocol was approved by the human investigation committee at the
Yale University School of Medicine.
A cardiovascular symptoms questionnaire was completed by all patients,
and a complete physical examination was performed by a pediatric
cardiologist. A 12-lead electrocardiogram (ECG) with rhythm strip was
obtained and interpreted according to standards for age (21). A
two-dimensional, M-mode, Doppler, and color Doppler cardiac ultrasound
(128/XP-10, Acuson, Mountain View, CA) was performed, with assessment
of left ventricular function by standard M-mode techniques. The left
ventricular mass was determined as described by Daniels et
al. (22) for pediatric patients; this measurement was standardized
to each patient’s height, and the upper limit of normal was considered
33.6 g/m3 (23). Baseline cardiac rhythm and potential
arrhythmias were evaluated by a 24-h continuous ECG monitoring system
(Prodigy Cardiodata, Northboro, MA) or Holter. Maximal exercise stress
tests were performed with a stationary bicycle ergometer (Cardiodata
Max-1, Yorba Linda, CA) using a James II or III protocol depending on
body surface area (24). Continuous monitoring of work load, whole body
oxygen consumption (VO2), and carbon dioxide production
(VCO2) by expiratory gas analysis, and 12-lead ECG were
performed during the test. The respiratory exchange ratio was
calculated as VCO2/VO2 and monitored throughout
the test. Blood pressure (BP) was obtained using an arm cuff and
auscultatory technique with a mercury sphigmomanometer at rest, at
progressively increasing work loads, and during recovery.
The results of exercise stress tests in XLH patients were compared with
those obtained concurrently in our exercise laboratory in an age- and
sex-matched control group without cardiovascular disease. Blood
chemistry tests were not obtained in this group. The control group of
28 subjects (18 females and 10 males) had a mean age of 14.3 ±
2.5 yr (range, 9–19 yr), a mean weight of 56.5 ± 12.8 kg, and a
mean height of 161.1 ± 11.9 cm. This group underwent maximal
exercise stress testing, achieving maximal VO2 (mean,
38.1 ± 8.1 mL/min·kg; range, 23.5–53.5 mL/min·kg) and peak
exercise work load comparable to those in the XLH subjects.
All XLH patients underwent renal ultrasonography and blood sampling for
determination of serum calcium, phosphate, and creatinine. Creatinine
clearance was calculated using 24-h urine collections. Immunoreactive
PTH was measured using a sensitive assay recognizing intact hormone and
midmolecule fragments (11). Data are expressed as the mean ±
SD. Two-factor ANOVA was used to compare BP between groups
at all exercise levels. Two-tailed unpaired Student’s t
tests were used to compare rest, peak exercise, and recovery values
between groups. P < 0.05 was considered
significant.
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Results
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Low serum phosphate (2.19 ± 0.36 mg/dL) was present in all
patients. Serum calcium (9.55 ± 0.36 mg/dL), serum creatinine,
and creatinine clearance were normal in all subjects. Previous
elevation in PTH levels had been recorded in all but two patients;
however, only 5 of the 13 patients had elevated PTH values at the time
of this study. All patients had nephrocalcinosis by renal
ultrasonography. All patients appeared to be reasonably compliant with
therapy.
All patients were free of cardiovascular symptoms, and physical cardiac
examinations were normal. The resting 12-lead ECG showed normal sinus
rhythm in 12 patients and wandering atrial pacemaker with low right
atrial rhythm alternating with sinus rhythm, a normal variant, in 1
patient. Cardiac intervals including PR, QRS duration, and QTc (range,
0.362–0.438), were all normal. P wave voltages were normal, but QRS
voltage amplitudes suggested left ventricular hypertrophy in 3
patients. ST-T segments were normal. Holter studies revealed normal
sinus rhythm with normal atrioventricular conduction and absence of
significant atrial or ventricular ectopy.
Cardiac ultrasonography revealed normal heart structure with good left
ventricular function. Similarly, Doppler studies did not indicate any
valvular obstructive lesions, intracardiac shunting, or significant
valvular regurgitation. Cardiac calcifications were not observed.
Interestingly, left ventricular mass was greater than the 95th
percentile for height3 (23) in 7 subjects (Fig. 1). In most patients this was secondary to increased
wall thickness, i.e. concentric left ventricular
hypertrophy, with only two subjects showing elevated left ventricular
end diastolic volumes. Left ventricular hypertrophy was independent of
parathyroid status in patients with XLH (P > 0.25, by
2 analysis).
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Figure 1. Distribution of left ventricular mass (grams
per m3) in patients with XLH. Seven patients had values
greater than the 95th percentile (18, 19).
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During a maximal exercise stress test, each subject achieved at least
95% of the predicted maximal heart rate for age. Maximal
VO2 ranged from 25.8–45.3 mL/min·kg with a mean of
34.1 ± 6.8 mL/min/kg, indicating an average level of physical
conditioning. The maximum respiratory exchange ratio was 1 or greater
in all subjects, indicating a significant lactate load and a
near-maximal effort.
As expected, systolic BP increased progressively with exercise at
increasing work loads in both XLH and control subjects; however, the
increase was slightly attenuated in the XLH group at high work loads
(Fig. 2). In contrast to the constant or slight decrease
in diastolic BP seen in control subjects, an increase in diastolic BP
was observed in XLH subjects at almost all exercise levels (Fig. 3). This abnormal pattern was present in all but one of
the XLH subjects.
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Figure 2. Mean systolic BP at different work loads in
13 patients with XLH (filled circles) and in 28 controls
(open circles). As expected, systolic BP increased in
both groups with exercise. Although a tendency to an attenuated
increase at high work loads was seen in XLH patients, the two curves
were not significantly different for a James II (P
= 0.396) or James III (P = 0.494) exercise protocol
(by two-factor ANOVA).
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Figure 3. Mean diastolic BP at different work loads in
13 patients with XLH (filled circles) and in 28 controls
(open circles). A significant abnormal increase in
diastolic BP was seen in XLH patients performing a James II
(P = 0.034) or James III (P <
0.001) exercise protocol compared to that in the control group (by
two-factor ANOVA).
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At peak exercise specifically, systolic BP was lower in XLH patients
than in controls (P = 0.002; Fig. 4),
whereas diastolic BP in XLH patients was higher than that in controls
(P < 0.0001; Fig. 5). Diastolic BP was
higher at peak exercise than at rest in the XLH group
(P = 0.0003), but not in controls (Fig. 5). Diastolic
BP returned to normal, preexercise values in both groups during
recovery. All patients with left ventricular hypertrophy had an
abnormal diastolic BP response to exercise; however, no significant
correlation between the maximum increment in diastolic BP and the
magnitude of left ventricular hypertrophy was found (P
= 0.83, by Pearson correlation).
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Figure 4. Systolic BP at rest, peak exercise, and
recovery in XLH patients (n = 13; hatched bars)
vs. controls (n = 28; open bars).
Systolic BP was significantly lower in the XLH group at peak exercise
(*, P = 0.002, by t test).
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Figure 5. Mean diastolic BP at rest, peak exercise,
and recovery in XLH patients (n = 13; hatched bars)
vs. controls (n = 28; open bars).
Diastolic BP increased abnormally during exercise in the XLH group (*,
P = 0.0003, by t test), but not in
controls. It was also significantly higher than that in control
children at peak exercise ( , P < 0.0001, by
t test).
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Discussion
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Despite the absence of cardiovascular symptoms or physical
findings, this group of patients with XLH demonstrated diastolic
hypertension and attenuated increases in systolic BP with exercise.
Furthermore, left ventricular hypertrophy was documented in seven
patients (54%) by cardiac ultrasonography, a finding not previously
reported. In contrast to our normal ECG intervals, Vered et
al. (25) reported prolongation of the QTc interval in 2 of 11 XLH
patients. Ventricular hypertrophy, diagnosed by voltage criteria in
23% (3 of 13) of our patients, was not mentioned in their study.
Despite the presence of long-standing hypophosphatemia, Vered et
al. (25) also reported normal resting left ventricular ejection
fraction in all of their patients, consistent with our findings.
However, the attenuated increase in systolic BP noted in our subjects
at peak exercise could be secondary to a subtle decrease in ventricular
function related to hypophosphatemia (26). The abnormal BP response
observed with exercise in XLH patients suggests that vascular tone is
abnormally regulated in this population. This idea is further supported
by the finding of ventricular hypertrophy, the appropriate response to
a subtle chronic increase in peripheral vascular resistance. Whether
these findings represent a primary defect in XLH or are a function of
treatment is yet to be determined. We are not aware of other clinical
circumstances in which diastolic BP increases with isotonic bicycle
exercise. Normally, maximal aerobic exercise decreases systemic
vascular resistance, due to maximal dilation of resistance vessels in
exercising muscles. Thus, diastolic pressure is maintained or decreases
with increasing cardiac output. In contrast, during isometric exercise,
such as weight lifting, both systolic and diastolic BP increase due to
vasoconstriction in the isometrically tensed muscles, leading to
increased peripheral vascular resistance and greatly increased
afterload for the left ventricle (27). The hemodynamic effect of
isotonic aerobic exercise in our patient group was similar to the
normal response to isometric exercise.
Nephrocalcinosis, a common finding in patients with XLH (5, 6, 7, 8, 9, 10), was
present in all patients in this study; however, serum creatinine and
creatinine clearance were normal. Nevertheless, it is possible that
renal calcinosis may influence regulators of vascular tone, such as the
renin-angiotensin-aldosterone system, which, in turn, may mediate the
abnormal cardiovascular findings described herein. Further studies are
necessary to investigate this possibility.
Calcification of other soft tissues, such as ligaments and tendons, in
patients with XLH appears to be independent of treatment (28) and
raises the possibilities that abnormal calcium deposition in arterial
wall tissues may mechanically alter vessel compliance, affect the
production of local vasoactive factors, or alter responses to humoral
factors that regulate vascular tone. Indeed, arterial calcification has
been associated with hypertension in infants, children, and adults
(29, 30, 31). Cardiac ultrasonography did not reveal myocardial or great
vessel calcifications; however, the possibility of calcium
microdeposition at these sites or in peripheral blood vessels can not
be excluded. Such deposition could explain the abnormal BP response to
exercise seen in these patients.
It is more likely that the abnormally thick left ventricles of our
patients have abnormal diastolic function, with impaired ventricular
filling leading to an inability to augment stroke volume, particularly
at the high blood flows required by exercise. We speculate that left
ventricular hypertrophy in this population is due to a chronic,
unrecognized increase in systemic vascular resistance. Compensatory
hypertrophy due to a slight reduction in left ventricular function
during normal daily activities, such as exercising in children, is a
possible contributor as well.
Hyperparathyroidism has been associated with hypertension (17, 18) and
left ventricular hypertrophy (20). Stefenelli et al. (20)
described regression of ventricular hypertrophy after parathyroidectomy
and normalization of calcium and PTH in adult patients with primary
hyperparathyroidism. However, we could not demonstrate an association
between the presence of hyperparathyroidism and left ventricular mass
in our XLH patients.
The gene harboring the XLH mutation (PEX) encodes an endopeptidase with
40–60% homology to neutral endopeptidase and endothelin-converting
enzyme-1 (32). Such an endopeptidase is likely to process systemic
factors that regulate renal phosphate transport. Our findings raise the
possibility that vascular tone may be regulated by a substrate for the
PEX gene product. Interestingly, neutral endopeptidase is known to
down-regulate responses to angiotensin I and II (33), and
endothelin-converting enzyme-1 activates endothelin-1 (34); all of
these are vasoactive peptides with a significant role in the regulation
of vascular tone.
These findings suggest that patients with XLH be monitored for the
development of hypertension and left ventricular hypertrophy. As the
abnormal findings were noted by cardiac ultrasonography and exercise
stress testing, and not routinely performed in the clinical setting,
periodic cardiology evaluation is indicated. Severe left ventricular
hypertrophy, resting hypertension, or hypertension during a 24-h BP
recording may warrant specific therapy. Further studies are necessary
to elucidate the mechanism of abnormal vascular tone regulation in
patients with XLH. Such studies may also help to provide a more
specific therapeutic approach.
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Acknowledgments
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The authors gratefully acknowledge the technical assistance of
Richard DeStefano in the Pediatric Exercise Laboratory and that of
David Silver with the statistical analysis.
Received January 16, 1997.
Revised May 7, 1997.
Accepted May 15, 1997.
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References
|
|---|
-
Chan JC, Alon U, Hirschman GM. 1985 Renal
hypophosphatemic rickets. J Pediatr. 106:533–544.[CrossRef][Medline]
-
Rasmussen H, Tenenhouse HS. 1989 Hypophosphatemias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds.
The metabolic basis of inherited disease, 6th ed. New York:
McGraw-Hill; 2581–2604.
-
Scriver CR, Reade TM, DeLuca HF, Hamstra AJ. 1978 Serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients
with hereditary rickets or bone disease. N Engl J Med. 299:976–979.[Abstract]
-
Latta K, Hisano S, Chan J. 1993 Therapeutics of
X-linked hypophosphatemic rickets. Pediatr Nephrol. 7:744–748.[CrossRef][Medline]
-
Alon U, Lovell HB, Donaldson DL. 1992 Nephrocalcinosis, hyperparathyroidism, and renal failure in familial
hypophosphatemic rickets. Clin Pediatr. 31:180–183.
-
Alon U, Donaldson DL, Hellerstein S, Warady BA, Harris
DJ. 1992 Metabolic and hystologic investigation of the nature of
nephrocalcinosis in children with hypophosphatemic rickets and in the
Hyp mouse. J Pediatr. 120:899–905.[CrossRef][Medline]
-
Kooh SW, Binet A, Daneman A. 1994 Nephrocalcinosis
in X-linked hypophosphatemic rickets: its relationship to treatment,
kidney function, and growth. Clin Invest Med. 17:123–130.[Medline]
-
Cole DE. 1994 Nephrocalcinosis in X-linked
hypophosphatemic rickets: just how serious is the problem? [Editorial
Comment]. Clin Invest Med. 17:131–132.[Medline]
-
Goodyer PR, Kronick JB, Jequier S, Reade TM, Scriver
CR. 1987 Nephrocalcinosis and its relationship to treatment of
hereditary rickets. J Pediatr. 111:700–704.[CrossRef][Medline]
-
Verge CF, Lam A, Simpson JM, Cowell CT, Howard NJ,
Silink M. 1991 Effects of therapy in X-linked hypophosphatemic
rickets. N Engl J Med. 325:1843–1848.[Abstract]
-
Carpenter TO, Mitnick MA, Ellison A, Smith C, Insogna
KL. 1994 Nocturnal hyperparathyroidism: a frequent feature of
X-linked hypophosphatemia. J Clin Endocrinol Metab. 78:1378–1383.[Abstract]
-
Rivkees SA, El-Hajj-Fuleihan G, Brown EM, Crawford
JD. 1992 Tertiary hyperparathyroidism during high phosphate
therapy of familial hypophosphatemic rickets. J Clin Endocrinol
Metab. 75:1514–1518.[Abstract]
-
Knutdtzon J, Halse J, Monn E, et al. 1995 Autonomous hyperparathyroidism in X-linked hypophosphataemia. Clin
Endocrinol. 42:199–203.[Medline]
-
Kaltreider HB, Baum GL, Bogaty G, McCoy MD, Tucker
M. 1969 So-called metastatic calcification of the lung. Am J
Med. 46:188–196.[CrossRef][Medline]
-
Roberts WC, Waller BF. 1981 Effect of chronic
hypercalcemia on the heart: analysis of 18 necropsy patients. Am J
Med. 71:371–384.[CrossRef][Medline]
-
Rostand SG, Sanders C, Kirk KA, Rustky EA, Fraser
RG. 1988 Myocardial calcification and cardiac dysfunction in
chronic renal failure. Am J Med. 85:651–657.[Medline]
-
Spiegel AM. 1991 Pathophysiology of primary
hyperparathyroidism. J Bone Miner Res. 6:S15–S17.
-
Heath H. 1991 Clinical spectrum of primary
hyperparathyroidism: evolution with changes in medical practice and
technology. J Bone Miner Res. 6:S63–S70.
-
Carpenter C, May ME. 1994 Case report: cardiotoxic
calcemia. Am J Med Sci. 307:43–44.[Medline]
-
Stefenelli T, Abela C, Frank H, et al. 1997 Cardiac
abnormalities in patients with primary hyperparathyroidism:
implications for follow-up. J Clin Endocrinol Metab. 82:106–112.[Abstract/Free Full Text]
-
Garson Jr A. 1983 The electrocardiogram in infants,
and children: a systematic approach. Philadelphia: Lea and Febiger.
-
Daniels SR, Meyer RA, Liang Y, Bove KE. 1988 Echocardiographically determined left ventricular mass index in normal
children, adolescents and young adults. J Am Coll Cardiol. 12:703–708.[Abstract]
-
Daniels SR, Kimbal TR, Morrison JA, Khoury P, Meyer
RA. 1995 Indexing left ventricular mass to account for differences
in body size in children and adolescents without cardiovascular
disease. Am J Cardiol. 76:699–701.[CrossRef][Medline]
-
James FW, Kaplan S, Glueck CJ, Tsay JY, Knight MJ,
Sarwar CJ. 1980 Responses of normal children and young adults to
controlled bicycle exercise. Circulation. 61:901–912.
-
Vered I, Vered Z, Perez JE, Jaffe AS, Whyte MP. 1990 Normal left ventricular performance in children with X-linked
hypophosphatemic rickets: a Doppler echocardiography study. J Bone
Miner Res. 5:469–474.[Medline]
-
Knochel JP. 1985 The clinical status of
hypophosphatemia. An update. N Engl J Med. 313:447–449.[Medline]
-
Ross RM. 1989 Interpreting exercise tests. Houston:
CSI Software; 173–174.
-
Polisson RP, Martinez S, Khoury M, et al. 1985 Calcification of entheses associated with X-linked hypophosphatemic
osteomalacia. N Engl J Med. 313:1–6.[Abstract]
-
Thomas P, Chandra M, Kahn E, McVicar M, Naidich J,
LaCorte M. 1990 Idiopathic arterial cacification of infancy: a
case with prolonged survival. Pediatr Nephrol. 4:233–235.[CrossRef][Medline]
-
Hodson EM, Antico VF, O’Neill P. 1992 Hypertension
associated with diffuse small artery calcification: a case report. Pediatr Nephrol. 6:556–558.[CrossRef][Medline]
-
Marchais SJ, Guerin AP, London GM. 1992 Arterial
calcinosis, chronic renal failure and calcium antagonism. Drugs.
44(Suppl 1):119–122.
-
The HYP Consortium. 1995 A gene (PEX) with
homologies to endopeptidases is mutated in patients with X-linked
hypophosphatemic rickets. Nat Genet. 11:130–136.[CrossRef][Medline]
-
Gafford JT, Skidgel RA, Erdos EG, Hersh LB. 1983 Human kidney "enkephalinase," a neutral metalloendopetidase that
cleaves active peptides. Biochemistry. 22:3265–3271.[CrossRef][Medline]
-
Xu D, Emoto N, Giaid A, et al. 1994 ECE-1: a
membrane-bound metalloprotease that catalizes the proteolytic
activation of big endothelin-1. Cell. 78:473–485.[CrossRef][Medline]
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Abstract
Introduction
