From the Division of Pediatric Endocrinology, Department of Pediatrics, Department of Cardiology, Cardiothoracic Center*, and Department of Radiodiagnosis**, All India Institute of Medical Sciences, New Delhi 110 029, India.

Reprint requests: Dr. P.S.N. Menon, Additional Professor of Pediatrics, Division of Pediatric Endocrinology and Genetics, All India Institute of Medical Sciences, New Delhi 110 029, India. Fax: 91 11 686 2663 . e-mail: psnmenon@hotmail.com

Manuscript received: July 29, 1998; Initial review completed: October 9, 1998; Revision accepted: March 10, 1999.

Objective: To evaluate prospectively cardiac function in children with primary hypothyroidism before and after replacement therapy with L-thyroxine. Design: Prospective clinical and laboratory cardiac evaluation of children with hypothyroidism before and after therapy. Setting: Hospital based. Subjects: 20 consecutive children aged 6 months - 14 years with primary hypothyroidism.
Methods: Assessment of cardiac status by clinical, radiological, ECG, echocardiography, M-mode and 2 dimensional echo-Doppler study and phonocardiography for systolic and diastolic functions and structural anomalies.
Results: Indices of myocardial contractility like ejection fraction (EF), velocity of circumferential fibre shortening (VCF) did not change with therapy. However, systolic time intervals, both left ventricular (before therapy 0.32 ± 0.03 msec; after therapy 0.25 ± 0.03 msec; p <0.001) showed a significant change. In diastolic functions, isovolumic relaxation time fell from 62 ± 9 msec before therapy to 50 ± 5 msec after therapy (p <0.001). Pericardial effusion was found in 10 children before treatment which disappeared in 7 following therapy.
Conclusion: Subtle evidence of alteration of myocardial function is thus seen in children with primary hypothyroidism which reverses with treatment.                                            Key words: Cardiac function, Echocardiography, Hypothyroidism.


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Primary hypothyroidism is known to be associated with structural and functional alterations in the myocardium. Studies in adults with primary hypothyroidism have demonstrated abnormalities in systolic and diastolic functions which correlate with the severity of the deficiency(1,2). Structural changes such as asymmetric septal hyper trophy have also been demonstrated(3). However, very few studies have been done to evaluate cardiac function in children with primary hypothyroidism. These have yielded conflicting results(4-7). Prolonged systolic time interval or normal cardiac function was reported by most workers. Abnormalities of diastolic function have not been studied extensively in children nor the effect of replacement therapy on cardiac function. The objective of this study was to evaluate prospectively cardiac function in children with primary hypothyroidism before and after replacement therapy with L-thyroxine.

Subjects and Methods

Twenty consecutive newly diagnosed children with primary hypothyroidism attending the Pediatric Endocrinology clinic were evaluated. These included 8 boys and 12 girls in the age group ranging from 6 months to 14 years. The diagnosis of hypothyroidism was made on the basis of clinical features of hypothyroidism coupled with elevated serum TSH levels (normal <5 mu/ml) and low total thyroxine (T4) levels (normal 4-12 mg/dl). Both hormones were measured by radioimmunoassay using commercially available kits obtained from Bhabha Atomic Research Center, Mumbai. None of the children had any evidence of congenital heart disease and none of them had received L-thyroxine (Eltroxin: Glaxo Allenburys) before entry to the study.

Cardiovascular evaluation included detailed clinical evaluation for any evidence of abnormalities of cardiac rhythm, congestive heart failure (CHF) or pericardial effusion. Chest X-ray was done for evaluating cardiothoracic ratio (CT ratio) and radiological features of CHF and pericardial effusion. A 12-lead electrocardiogram was done in all cases and heart rate, PR interval, total amplitude of R and S waves, QRS complex voltage, Q-Tc interval, QRS axis in frontal plane, and evidence of ventricular hypertrophy were analyzed. A detailed echocardiographic analysis was done using Advanced Techno-logy Laboratory (ATL) machine and 3.5 - 5 MHz (mega hertz) transducer. M-mode and 2-dimensional and echo-Doppler findings were used to measure systolic and diastolic functions. Ejection fraction (EF), velocity of circumferential fibre shortening (VCF), systolic time intervals (STI), pre-ejection period (PEP) and ejection time (ET) were calculated using established criteria(8-10) as given below:

            (LVIDd)3 - (LVIDs)3
EF  = ---------------------------------- ´ 100
                     (LVIDd)3

                 LVIDd - LVIDs
VCF = -----------------------------
                 LVIDd ´ LVET

STI = PEP/ET

(LVIDd - Left ventricular internal dimension in diastole, LVIDs - Left ventricular internal dimension in systole, LVET - left ventricular ejection time)

PEP and ET were corrected by using the following formula:

Corrected PEP = Observed PEP + 0.4 ´ Heart rate(11).

Corrected ET = Observed ET + 1.6 ´ Heart rate(12).

Isovolumic relaxation time (IVRT) and early and the late filling ratios were the diastolic functions evaluated using echo and phonocardiography. In addition thickness of the interventricular septum and posterior wall were measured. Pericardial effusion was evaluated and its severity also was evaluated.

All the parameters were reevalauted after 8 weeks of replacement therapy with L - thyroxine in a dose of 5-15 mg/kg/day (mean 9.2 ± 3.1 mg/kg/day) when the total T4 and TSH were within normal limits. Thus each patient served as his/her control. The pediatric car-diologist who had done the echo both pre- and post-therapy was not aware of the thyroid status of the patient.

Statistical analysis of significance was performed by paired ‘t’ test for quantitative variables and McNieman’s Chi square test for qualitative variables such as pericardial effusion.
 

Subjects and Methods

Results

Discussion

References

Mean serum thyroxine level before therapy was 1.3 mg/dl and following replacement therapy with L-thyroxine increased to 6.8 mg/dl, while that of TSH decreased from 80.5 mu/ml to 5.0 mu/ml. Both the levels of T4 and TSH were in the euthyroid state at the time of second cardiologic assessment (Table I). The heart rate showed a rise with therapy, while the blood pressure both systolic and diastolic remained almost unaltered. There were no significant alterations in PR interval, Q-Tc interval and QRS axis in the electrocariogram recordings both before and after therapy.

The most significant change was observed in the systolic time intervals; both right and left ventricular STI showed a significant change with therapy (Table II). The mean LVSTI fell from 0.32 ± 0.03 msec to 0.29 ± 0.03 msec (p<0.001). However, EF and VCF which are the indicators of myocardial contractility did not alter with therapy. Among the diastolic functions studied isovolumic relaxation time (IVRT) could be assessed in all children while early and late filling time was evaluated in 18 children. Mean IVRT fell from 62 ± 9 msec to 50 ± 5 msec with therapy (p <0.001). However, E/A ratio (ratio of early to late filling of left ventricle) and velocity of deceleration did not show any significant change.

The mean thickness of the interventricular septum reduced from 6.40 ± 1.07 mm to 5.90 ± 1.07 mm with therapy. Similary the left ventricular posterior wall thickness also reducd from 5.70 ± 0.70 mm to 5.30 ± 0.70 mm. There was no evidence of asymmetric septal hypertrophy or left ventricular outflow obstruction. Pericardial effusion was found in 10 out of the 20 children, with two children having significant large effusions. These two children were the oldest in the study. With replacement therapy the effusion disappeared in 7 out of the 10 children.
 
 

Table I__ Parameters of Thyroid and Cardiac Function. Parameter                 Before therapy After therapy

Mean T4 (mg/dl)	1.3	6.8*
Mean TSH (mu/ml)	80.5	5.0*
Mean heart rate/min	82 ± 17	99 ± 13*
Mean systolic BP (mm Hg)	97 ± 5	97 ± 5
Mean diastolic BP (mm Hg)	68 ± 5	63 ± 5
Cardio-thoracic ratio	50 ± 4	48 ± 5
P R interval	0.14 ± 0.02	0.11 ± 0.08
Q-Tc interval	0.16 ± 0.03	0.15 ± 0.04
R wave (mm)	6.0 ± 2.0	8.0 ± 2.0
QRS axis	80.0 ± 15.0	80.0 ± 15.0

  Table II__ Systolic and Diastolic Cardiac Functions (Mean ± SD).

Parameter	Before therapy	After therapy
Systolic
LVSTI (msec)	0.32 ± 0.03	0.29 ± 0.03*
RVSTI (msec)	0.29 ± 0.03	0.25 ± 0.03*
VCF	1.58 ± 0.34	1.61 ± 0.30
EF (%)	77.00 ± 5.40	79.00 ± 5.80
Change in LV dimension (%)	38.00 ± 5.00	40.00 ± 5.00
Diastolic
IVRT (msec)	62.00 ± 9.00	50.00 ± 5.00*
E/A ratio	2.30 ± 2.90	2.00 ± 1.10
Structural
Interventricular septum (IVS) (mm)	6.40 ± 1.07	5.90 ± 1.07
Lt Posterior wall (PW) (mm)	5.70 ± 0.90	5.30 ± 0.70
Ratio of IVS/PW	1.12 ± 0.19	1.11 ± 0.10

 

Subjects and Methods

Results

Discussion

References

This is the first study prospectively evaluating both systolic and diastolic cardiac functions in children with primary hypothyroidism. The effects of hypothyroidism on cardiac function are relatively less studied in children as compared to adults. Studies in adult patients showed evidence of myocardial dysfunction such as deranged systolic time intervals, pro- longed relaxation time and structural changes.

We had studied systolic function in children with hypothyroidism using left and right STI, indices of myocaridal contractility such as ejection fraction, percentage change in left ventricle in systole and circumferential fiber shortening. Earlier studies in adults had shown correlation of severity of hypothyroidism with derangement in STI(1,2,13). These indicated the need of prompt replacement therapy in adults for optimal left ventricular function. However, studies conducted in children have shown contradicting results. Hayford et al. did not observe any significant change in LVSTI in 13 children with hypothyroidism(4). However, subsequent workers demonstrated that LVSTI was altered in infants and children with hypothyroidism compared to normal(5-7). Balducci et al. demonstrated that PEP/LVET ratio negatively correlated with log T4 and log T3 levels indicating that children with hypothyroidism have similar systolic function abnormalities compared to adults(7).

Subtle changes in systolic function were found in our study which were identified in systolic time intervals only. The ejection fraction and velocity of circumferential fibre shortening were not significantly affected. Systolic time intervals are load independent indices and therefore better indicators of intrinsic myocardial function than EF and VCF. Further STI were corrected for the heart rate, so the change seen is not due to increase in heart rate which is known to rise following replacement therapy with L-thyroxine. This indicates in-directly that there is an intrinsic alteration of myocardial function in children with primary hypothyroidism.

We evaluated diastolic function by IVRT, early and late diastolic filling ratios, expressed as E/A ratio and velocity of deceleration. Studies on diastolic function in children with hypothyroidism are very few and inconclusive. Vora et al.observed IVRT in hypothyroid adults was increased compared to normals and decreased with replacement therapy within 3-4 weeks(13). Another study in women with short term hypothyroidism observed that IVRT was prolonged but reversed on replacement therapy(14). This is the first study where an attempt was made to study the diastolic function in children with primary hypo-thyroidism. The evidence of diastolic dysfunction in children with hypothyroidism was clearly evident in our study with significant reduction in IVRT and therapy. The E/A ratio and velocity of deceleration were not significantly altered. There is scant information available on change in IVRT with heart rate. Hypothyroidism is known to elevate systemic vascular resistance. Blood pressure (diastolic), a crude indicator of systemic vascular resistance was not altered in the children in our study. Thus IVRT probably represents subtle diastolic dysfunction.

Santos et al. demonstrated structural changes in heart as a result of hypothyroidism evidenced by thickening of interventricular septum and left ventricular posterior wall as well as asymmetric septal hypertrophy in adults(15). Farooki et al. did not observe any significant structural changes in children with hypothyroidism(6). Our study shows evidence of structural changes in myocardium such as reduction in mean thickness of IVS with therapy. However, we did not observe any asymmetric septal hypertrophy.

Pericardial effusion is a recognized complication of severe untreated hypothyroidism in adults while it is rarely described in children. Various studies have shown an incidence of 30-33% in adults(1,16). The data from children have shown a higher incidence in most studies ranging from 30-74%(4,6,7,17,18). In a study conducted in infants upto 3 months, two groups observed negligible pericardial effusion whereas Balducci et al. showed an incidence of 36%(5,7). Rondanini et al. related effusions to the severity of hormonal defect particularly during fetal life(17). In our study also there was a high incidence of pericardial effusion. The effusion decreased or dis- appeared promplty with replacement therapy. The pericardial effusion was not related to etiology or severity of hypothyroidism. However, there was some suggestion that severe effusions are likely with long-standing untreated hypothyroidism.

In conclusion, subtle evidence of alteration of myocardial function both systolic and di-astolic was seen in children with primary hypothyroidism which reversed with replacement therapy. These changes do no appear to be related to the changes in heart rate. Evidence of structural changes seen in this study also reversed with replacement therapy.
 

Subjects and Methods

Results

Discussion

References