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.
0021-972X/97/$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1997 by The Endocrine Society
Vol. 82, No. 8 Printed in U.S.A.
Cardiovascular Abnormalities in Patients with X-Linked Hypophosphatemia RODRIGO NEHGME, JOHN T. FAHEY, CYNTHIA SMITH, THOMAS O. CARPENTER
AND
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 ABSTRACT 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 6 SD,
T
HE 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 –10), and hyperparathyroidism (11–13). Cardiovascular abnormalities, such as valvular disease, myocardial dysfunction, and hypertension, occur in association with these complications (14 –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. Subjects and Methods 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 6 16.75 kg, and the mean height was 145.69 6 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 Received January 16, 1997. Revision received May 7, 1997. Accepted May 15, 1997. 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.
116 6 15/74 6 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 6 20 vs. 175 6 23; P 5 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 6 12 vs. 72 6 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. (J Clin Endocrinol Metab 82: 2450 –2454, 1997)
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 ageand 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 6 2.5 yr (range, 9 –19 yr), a mean weight of 56.5 6 12.8 kg, and a mean height of 161.1 6 11.9 cm. This group underwent maximal exercise stress testing, achieving maximal VO2 (mean, 38.1 6 8.1 mL/minzkg; range, 23.5–53.5 mL/ minzkg) 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
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CARDIOVASCULAR ABNORMALITIES IN XLH
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TABLE 1. Patient treatment information Patient no.
Age (yr)
Gender
Treatment duration (yr)
1,25(OH)2D (mg/day)
Phosphorus (g/day)
1 2 3 4 5 6 7 8 9 10 11 12 13
16 17 17 18 10 10 14 16 20 9 11 8 9
Male Female Male Male Female Female Male Female Female Female Female Female Female
16 16 15 12 9 10 12 14 19 8 11 8 7
0.50 0.75 1.00 0.50 0.75 0.20a 0.50 1.00 0.75 1.00 0.75 0.75 1.50
0 1.5 1.0 0.5 1.0 0 1.0 0.25 0.5 1.25 0.75 0.75 0.75
12.1 6 3.7
0.77 6 0.32
0.71 6 0.45
Mean 6 a
SD
13.5 6 4.1
Dihydrotachysterol (in milligrams per day)
the mean 6 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.
Results
Low serum phosphate (2.19 6 0.36 mg/dL) was present in all patients. Serum calcium (9.55 6 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 12lead 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 x2 analysis). 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/minzkg with a mean of 34.1 6 6.8 mL/min/kg, indicating an average level of physical conditioning. The maximum respiratory ex-
FIG. 1. Distribution of left ventricular mass (grams per m3) in patients with XLH. Seven patients had values greater than the 95th percentile (18, 19).
change 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. At peak exercise specifically, systolic BP was lower in XLH patients than in controls (P 5 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 5 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 5 0.83, by Pearson correlation).
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FIG. 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 5 0.396) or James III (P 5 0.494) exercise protocol (by two-factor ANOVA).
FIG. 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 5 0.034) or James III (P , 0.001) exercise protocol compared to that in the control group (by two-factor ANOVA).
Discussion
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
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FIG. 4. Systolic BP at rest, peak exercise, and recovery in XLH patients (n 5 13; hatched bars) vs. controls (n 5 28; open bars). Systolic BP was significantly lower in the XLH group at peak exercise (*, P 5 0.002, by t test).
FIG. 5. Mean diastolic BP at rest, peak exercise, and recovery in XLH patients (n 5 13; hatched bars) vs. controls (n 5 28; open bars). Diastolic BP increased abnormally during exercise in the XLH group (*, P 5 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).
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 ab-
CARDIOVASCULAR ABNORMALITIES IN XLH
normally 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 (5–10), 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-angiotensinaldosterone 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 –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
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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. Acknowledgments The authors gratefully acknowledge the technical assistance of Richard DeStefano in the Pediatric Exercise Laboratory and that of David Silver with the statistical analysis.
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