JOURNAL OF BONE AND MINERAL RESEARCH Volume 5, Number 5, 1990 Mary Ann Liebert, Inc., Publishers
Normal Left Ventricular Performance in Children with X-Linked Hypophosphatemic Rickets: A Doppler Echocardiography Study IRIS VERED,',3 ZVI VERED,',4 JULIO E. PEREZ,' ALLAN S. JAFFE,' and MICHAEL P. WHYTE'
ABSTRACT
To determine if chronic hypophosphatemia causes myocardial dysfunction, we explored one model for this metabolic derangement by prospectively investigating 11patients (aged 5-18 years) with X-linked hypophosphatemic rickets (XLH) by M-mode, two-dimensional, and Doppler echocardiography. Inorganic phosphate and calcitriol (1,25-dihydroxyvitamin Dj) treatment was withheld 72 h prior to study. None of the patients had cardiovascular symptoms. Fasting serum inorganic phosphate concentrations were subnormal in all: 2.6 f 0.5 mg/dl (SD). Serum total and ionized calcium, magnesium, sodium, potassium, and creatine kinase myocardial fraction (CK-MB) levels were unremarkable. Electrocardiograms revealed early repolarization abnormalities in 3 of the 11 patients: 1 had significant QT prolongation (corrected for heart rate), and 2 had T wave abnormalities. Exaggerated U waves occurred in 4 subjects. Resting echocardiograms were normal in 9 patients. In 1subject there was mitral valve prolapse, and 1patient possibly had an atrial septa1 defect (these findings were considered unrelated to hypophosphatemia). All M-mode measurements were normal. The two-dimensionally derived end-diastolic and end-systolic left ventricular volumes were 60.3 f 18.0 and 20.5 f 6.9 ml, respectively. Left ventricular ejection fraction was 66.1 f 4.79'0, and the cardiac index by Doppler study was 4.1 f 0.8 liters/min per m' (both values were within normal limits). Although the precise pathogenesis of XLH is unknown and our findings suggest that some electrocardiographic abnormalities may be common in this disorder, we found no evidence for left ventricular dysfunction in this human model of clinically significant long-standing hypophosphatemia.
INTRODUCTION VARIETY OF ADVERSE EFFECTS from hypophosphatemia and phosphate depletion are well Experimental phosphate deprivation impairs myocardial energy metabolism and contractility in a reversible fashi0n,(15)and several possible mechanisms have been suggested.(+") Only a small number of clinical studies, how-
A
ever, have investigated the significance of hypophosphatemia upon myocardial performance. Some authors(1z-14) have suggested that severe hypophosphatemia may cause cardiac decompensation, whereas others have demonstrated normal left ventricular f u n ~ t i o n . ( ~ ~ . ' ~ ) To explore the effects of phosphate depletion on the myocardium, we prospectively evaluated left ventricular performance in 11 pediatric patients with X-linked hypo-
'Metabolic Research Unit, Shriners Hospital for Crippled Children, St. Louis, MO 63131, and Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO 63110. zDivision of Cardiology, Washington University School of Medicine, St. Louis, MO 631 10. 3Pre~entaddress: Department of Medicine, The Chaim Sheba Medical Center, Tel Hashomer, Israel 52621. 'Present address: Heart Institute, The Chaim Sheba Medical Center, Tel Hashomer, Israel 52621.
469
470
VERED ET AL.
phosphatemic rickets (XLH) by M-mode, two-dimen- cardial fraction; CK-MB) levels. An age- and sex-adjusted sional, and Doppler echocardiography. Our results indi- normal range of fasting serum phosphate level for each pacate that cardiac function is unimpaired in this human tient was used according to Greenberg et al.(") Resting 12-lead electrocardiograms (EKG) and echocardiographic model of long-standing hypophosphatemia. studies were performed on the same day. EKGs were interpreted in accordance with the patient's age and sex, and the QT segment was corrected for heart rate (QTc).('*) METHODS Echocardiography by M-mode, two-dimensional, and Patients Doppler studies was performed with a commercially availA group of 11 pediatric patients with XLH were studied able (Hewlett-Packard, Andover, MA) system containing a (Table 1). Of these, 8 had family histories consistent with 2.5 or 3.5 MHz phased-array transducer. The dimensions the diagnosis; the other 3 were considered sporadic cases. of the left ventricle during diastole and systole, left atrium, All subjects had clinical, biochemical, radiographic, and aorta, left ventricular posterior wall, and intraventricular histologic evidence typical of XLH with varying degrees of septal thickness were measured according to the criteria of skeletal deformity. In each, there was selective renal phos- the American Society of Echocardiography.' 19) The bullet phate wasting; that is, no other significant renal tubular formula(zo)was used to calculate left ventricular end-diadefects (Fanconi's syndrome) were noted. All were patients stolic and end-systolic volumes and left ventricular ejection who were being followed at the Metabolic Research Unit, fraction. Cardiac output was obtained from Doppler echoShriners Hospital for Crippled Children (St. Louis, MO). cardiography at the left ventricular outflow tract level.(*') None had been diagnosed with a cardiovascular disorder. All EKGs and echocardiograms were analyzed by two inInformed consent was obtained from the parents and/or dependent observers. A consensus was reached for each legal guardians in accordance with a research protocol ap- measurement. Results are presented throughout the text proved by the Human Studies Committee, Washington and tables as mean f SD. University School of Medicine. Patients were admitted to the Metabolic Research Unit, and fasting specimens of serum were obtained before and RESULTS then 72 h after phosphate supplements (K-Phos Neutral, Beach Pharmaceuticals, Tampa, FL) and calcitriol (RocalA total of two boys and nine girls, mean age 9.7 f 4.2 trol, Hoffmann-LaRoche, Inc., Nutley, NJ) were with- years (range 5.6-17.7 years), were studied. The results of the biochemical analyses are summarized in Table 2. Fastheld. ing serum inorganic phosphate levels were below the normal range both at baseline and 72 h following withholding Biochemical studies of medication (2.8 f 0.4 and 2.6 f 0.5 mg/dl; p = NS). Serum was assayed for total and ionized calcium, mag- Serum total and ionized calcium, sodium, potassium, and nesium, sodium, potassium, and creatine kinase (myo- plasma CK-MB levels were all within their normal ranges.
TABLE1. DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF THE XLH STUDYPOPULATION
Patient no. 1 2 3 4 5 6 7 8 9 10 11
Age (years) 5.6 5.7 5.9 6.3 7.0 8.3 10.5 12.4 12.6 15.2 17.7
Sex M F F F F F
M F F F F
Body surface area (m2)
Diagnosisa
0.68 0.85 0.80 0.81 0.83 1.10 1.15 1.17 1.13 1.30 1.64
XLH XLH XLH Sporadic XLH XLH Sporadic Sporadic XLH XLH XLH
aXLH: consistent family history. Sporadic: sporadic hypophosphatemia (probable XLH). bReceiving vitamin D, (S0,OOO units/day).
1,25-(0H)2D3 dose (ng/kg/day) 24.2 10.8 16.8 31.2 11.3 0 0 11.5 28.2 11.6 -b
Phosphate dose (as phosphorus, mg/kg/day) 14.3 21.7 22.5 31.1 22.7 0 0 11.6 28.4 35.0 5.6
VENTRICULAR PERFORMANCE IN HYPOPHOSPHATEMICRICKETS
471
and was significantly prolonged (> 0.44 s) in 2 patients (6 and 8). Prominent U waves were noted in 4 subjects (3-5 and 11). Doppler echocardiograms were normal in nine patients. In one subject (3) mitral valve prolapse was present, and in
Serum magnesium concentration was normal in all but one patient,(10)in whom it was only minimally decreased (1.7 mg/dl). EKG findings for the 11 subjects are shown in Table 3. The mean duration of the QTc segment was 0.42 0.03 s
TABLE2. SERUM BIOCHEWSTRY~ OF 11 PEDIATRIC
PATIENTS WITH
XLH
~~
Inorganic phosphate (mg/dl) Patient no. 1 2 3 4 5
6 7 8 9 10 11 Mean f SD
Baseline
72 hb
Normal lower limit c
2.5 3.3 2.6 3.0 2.9
3.2 2.8 2.8 3.0 2.8 3.2 2.1 2.2 3.1 1.8 2.0
3.6 3.7 3.6 3.6 3.5 3.4 3.4 3.2 3.2 3.0 2.9
-d -d
2.5 3.3 2.7 2.1 2.8 0.4
Ionized calcium
Magnesium
(8.5-1 0.5)
(4.20-5.40)
(1.8-2.9)
(mg/dl)
(W/dl)
(mg/dl)
9.3 9.7 9.9 9.8 9.8 9.8 10.0 9.2 10.1 9.6 9.2
4.55 4.62 4.71 4.62 4.69 4.76 4.61 4.66 4.80 4.73 4.28
1.8 1.8 1.8 1.8 1.8 2.0 1.8 1.8 2.1 1.7 2.0
9.7 0.3
2.6 0.5
f
Total calcium
f
f
aUnits and normal range given in parentheses as b72 hours after therapy withheld. CAge and sex adjusted."61 duntreated prior to study.
f
4.63 0.14
1.9 0.1
f
f
2 SD mean.
TABLE3. ELECTROCARDIOGRAPHIC RESULTS IN 11 PEDIATRIC PATIENTS WITH XLH
Patient no. 1 2 3 4 5 6 7 8 9 10 11 Mean
QT/ma
0.42 0.39 0.41 0.39 0.43 0.45b 0.38 0.48b 0.40 0.39 0.43 f
SD
0.42
* 0.03
aQT corrected for heart rate. bProlonged according to age and sex.
T-wave abnormalities
Prominent U waves
-
+
CK-MB (0-11) (IU/liter) 2
Normal Left Ventricular Performance in Children with X-Linked Hypophosphatemic Rickets: A Doppler Echocardiography Study IRIS VERED,',3 ZVI VERED,',4 JULIO E. PEREZ,' ALLAN S. JAFFE,' and MICHAEL P. WHYTE'
ABSTRACT
To determine if chronic hypophosphatemia causes myocardial dysfunction, we explored one model for this metabolic derangement by prospectively investigating 11patients (aged 5-18 years) with X-linked hypophosphatemic rickets (XLH) by M-mode, two-dimensional, and Doppler echocardiography. Inorganic phosphate and calcitriol (1,25-dihydroxyvitamin Dj) treatment was withheld 72 h prior to study. None of the patients had cardiovascular symptoms. Fasting serum inorganic phosphate concentrations were subnormal in all: 2.6 f 0.5 mg/dl (SD). Serum total and ionized calcium, magnesium, sodium, potassium, and creatine kinase myocardial fraction (CK-MB) levels were unremarkable. Electrocardiograms revealed early repolarization abnormalities in 3 of the 11 patients: 1 had significant QT prolongation (corrected for heart rate), and 2 had T wave abnormalities. Exaggerated U waves occurred in 4 subjects. Resting echocardiograms were normal in 9 patients. In 1subject there was mitral valve prolapse, and 1patient possibly had an atrial septa1 defect (these findings were considered unrelated to hypophosphatemia). All M-mode measurements were normal. The two-dimensionally derived end-diastolic and end-systolic left ventricular volumes were 60.3 f 18.0 and 20.5 f 6.9 ml, respectively. Left ventricular ejection fraction was 66.1 f 4.79'0, and the cardiac index by Doppler study was 4.1 f 0.8 liters/min per m' (both values were within normal limits). Although the precise pathogenesis of XLH is unknown and our findings suggest that some electrocardiographic abnormalities may be common in this disorder, we found no evidence for left ventricular dysfunction in this human model of clinically significant long-standing hypophosphatemia.
INTRODUCTION VARIETY OF ADVERSE EFFECTS from hypophosphatemia and phosphate depletion are well Experimental phosphate deprivation impairs myocardial energy metabolism and contractility in a reversible fashi0n,(15)and several possible mechanisms have been suggested.(+") Only a small number of clinical studies, how-
A
ever, have investigated the significance of hypophosphatemia upon myocardial performance. Some authors(1z-14) have suggested that severe hypophosphatemia may cause cardiac decompensation, whereas others have demonstrated normal left ventricular f u n ~ t i o n . ( ~ ~ . ' ~ ) To explore the effects of phosphate depletion on the myocardium, we prospectively evaluated left ventricular performance in 11 pediatric patients with X-linked hypo-
'Metabolic Research Unit, Shriners Hospital for Crippled Children, St. Louis, MO 63131, and Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO 63110. zDivision of Cardiology, Washington University School of Medicine, St. Louis, MO 631 10. 3Pre~entaddress: Department of Medicine, The Chaim Sheba Medical Center, Tel Hashomer, Israel 52621. 'Present address: Heart Institute, The Chaim Sheba Medical Center, Tel Hashomer, Israel 52621.
469
470
VERED ET AL.
phosphatemic rickets (XLH) by M-mode, two-dimen- cardial fraction; CK-MB) levels. An age- and sex-adjusted sional, and Doppler echocardiography. Our results indi- normal range of fasting serum phosphate level for each pacate that cardiac function is unimpaired in this human tient was used according to Greenberg et al.(") Resting 12-lead electrocardiograms (EKG) and echocardiographic model of long-standing hypophosphatemia. studies were performed on the same day. EKGs were interpreted in accordance with the patient's age and sex, and the QT segment was corrected for heart rate (QTc).('*) METHODS Echocardiography by M-mode, two-dimensional, and Patients Doppler studies was performed with a commercially availA group of 11 pediatric patients with XLH were studied able (Hewlett-Packard, Andover, MA) system containing a (Table 1). Of these, 8 had family histories consistent with 2.5 or 3.5 MHz phased-array transducer. The dimensions the diagnosis; the other 3 were considered sporadic cases. of the left ventricle during diastole and systole, left atrium, All subjects had clinical, biochemical, radiographic, and aorta, left ventricular posterior wall, and intraventricular histologic evidence typical of XLH with varying degrees of septal thickness were measured according to the criteria of skeletal deformity. In each, there was selective renal phos- the American Society of Echocardiography.' 19) The bullet phate wasting; that is, no other significant renal tubular formula(zo)was used to calculate left ventricular end-diadefects (Fanconi's syndrome) were noted. All were patients stolic and end-systolic volumes and left ventricular ejection who were being followed at the Metabolic Research Unit, fraction. Cardiac output was obtained from Doppler echoShriners Hospital for Crippled Children (St. Louis, MO). cardiography at the left ventricular outflow tract level.(*') None had been diagnosed with a cardiovascular disorder. All EKGs and echocardiograms were analyzed by two inInformed consent was obtained from the parents and/or dependent observers. A consensus was reached for each legal guardians in accordance with a research protocol ap- measurement. Results are presented throughout the text proved by the Human Studies Committee, Washington and tables as mean f SD. University School of Medicine. Patients were admitted to the Metabolic Research Unit, and fasting specimens of serum were obtained before and RESULTS then 72 h after phosphate supplements (K-Phos Neutral, Beach Pharmaceuticals, Tampa, FL) and calcitriol (RocalA total of two boys and nine girls, mean age 9.7 f 4.2 trol, Hoffmann-LaRoche, Inc., Nutley, NJ) were with- years (range 5.6-17.7 years), were studied. The results of the biochemical analyses are summarized in Table 2. Fastheld. ing serum inorganic phosphate levels were below the normal range both at baseline and 72 h following withholding Biochemical studies of medication (2.8 f 0.4 and 2.6 f 0.5 mg/dl; p = NS). Serum was assayed for total and ionized calcium, mag- Serum total and ionized calcium, sodium, potassium, and nesium, sodium, potassium, and creatine kinase (myo- plasma CK-MB levels were all within their normal ranges.
TABLE1. DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF THE XLH STUDYPOPULATION
Patient no. 1 2 3 4 5 6 7 8 9 10 11
Age (years) 5.6 5.7 5.9 6.3 7.0 8.3 10.5 12.4 12.6 15.2 17.7
Sex M F F F F F
M F F F F
Body surface area (m2)
Diagnosisa
0.68 0.85 0.80 0.81 0.83 1.10 1.15 1.17 1.13 1.30 1.64
XLH XLH XLH Sporadic XLH XLH Sporadic Sporadic XLH XLH XLH
aXLH: consistent family history. Sporadic: sporadic hypophosphatemia (probable XLH). bReceiving vitamin D, (S0,OOO units/day).
1,25-(0H)2D3 dose (ng/kg/day) 24.2 10.8 16.8 31.2 11.3 0 0 11.5 28.2 11.6 -b
Phosphate dose (as phosphorus, mg/kg/day) 14.3 21.7 22.5 31.1 22.7 0 0 11.6 28.4 35.0 5.6
VENTRICULAR PERFORMANCE IN HYPOPHOSPHATEMICRICKETS
471
and was significantly prolonged (> 0.44 s) in 2 patients (6 and 8). Prominent U waves were noted in 4 subjects (3-5 and 11). Doppler echocardiograms were normal in nine patients. In one subject (3) mitral valve prolapse was present, and in
Serum magnesium concentration was normal in all but one patient,(10)in whom it was only minimally decreased (1.7 mg/dl). EKG findings for the 11 subjects are shown in Table 3. The mean duration of the QTc segment was 0.42 0.03 s
TABLE2. SERUM BIOCHEWSTRY~ OF 11 PEDIATRIC
PATIENTS WITH
XLH
~~
Inorganic phosphate (mg/dl) Patient no. 1 2 3 4 5
6 7 8 9 10 11 Mean f SD
Baseline
72 hb
Normal lower limit c
2.5 3.3 2.6 3.0 2.9
3.2 2.8 2.8 3.0 2.8 3.2 2.1 2.2 3.1 1.8 2.0
3.6 3.7 3.6 3.6 3.5 3.4 3.4 3.2 3.2 3.0 2.9
-d -d
2.5 3.3 2.7 2.1 2.8 0.4
Ionized calcium
Magnesium
(8.5-1 0.5)
(4.20-5.40)
(1.8-2.9)
(mg/dl)
(W/dl)
(mg/dl)
9.3 9.7 9.9 9.8 9.8 9.8 10.0 9.2 10.1 9.6 9.2
4.55 4.62 4.71 4.62 4.69 4.76 4.61 4.66 4.80 4.73 4.28
1.8 1.8 1.8 1.8 1.8 2.0 1.8 1.8 2.1 1.7 2.0
9.7 0.3
2.6 0.5
f
Total calcium
f
f
aUnits and normal range given in parentheses as b72 hours after therapy withheld. CAge and sex adjusted."61 duntreated prior to study.
f
4.63 0.14
1.9 0.1
f
f
2 SD mean.
TABLE3. ELECTROCARDIOGRAPHIC RESULTS IN 11 PEDIATRIC PATIENTS WITH XLH
Patient no. 1 2 3 4 5 6 7 8 9 10 11 Mean
QT/ma
0.42 0.39 0.41 0.39 0.43 0.45b 0.38 0.48b 0.40 0.39 0.43 f
SD
0.42
* 0.03
aQT corrected for heart rate. bProlonged according to age and sex.
T-wave abnormalities
Prominent U waves
-
+
CK-MB (0-11) (IU/liter) 2
