Cardiac effects of l -thyroxine administration in borderline hypothyroidism

International Journal of Cardiology 126 (2008) 190 – 195 www.elsevier.com/locate/ijcard

Cardiac effects of L-thyroxine administration in borderline hypothyroidism Stefano Mariotti a,⁎, Sandra Zoncu b , Francesca Pigliaru a , Claudia Putzu a , Valentina M. Cambuli a , Sara Vargiu b , Martino Deidda b , Giuseppe Mercuro b b

a Endocrinology, Department of Medical Sciences, University of Cagliari, Sardinia, Italy Department of Cardiovascular and Neurological Sciences, University of Cagliari, Sardinia, Italy

Received 18 October 2006; received in revised form 17 February 2007; accepted 30 March 2007 Available online 11 May 2007

Abstract Objective: To investigate the clinical relevance of L-thyroxine (L-T4) substitution therapy in borderline hypothyroidism. Design: To assess whether and to what extent administration of L-T4 is able to modify systolic and diastolic function in patients with subclinical hypothyroidism and in subjects with autoimmune thyroiditis and normal serum TSH. Methods: We studied 26 patients with classical Hashimoto's thyroiditis [18 with increased serum TSH (N 3 mU/ml — Group A), and 8 with normal serum TSH (b 3 mU/ml) — Group B]; a third group (C) included 13 healthy controls. All subjects underwent Pulsed Wave Tissue Doppler Imaging (PWTDI) to accurately quantify the global and regional left ventricular function. Results: In both groups A and B we confirmed a significant impairment of systolic ejection ( p b 0.001 and p b 0.05, respectively), a delay in diastolic relaxation ( p b 0.001 and p b 0.05, respectively) and a decrease in the compliance to the ventricular filling ( p b 0.05). Administration of 50 μg/day of L-T4 produced a progressive reduction of serum TSH (within the normal range) and normalization of all PWTDI parameters, which began after 6 months and finished after 12 months. Conclusion: Our data confirm previous evidence that subclinical hypothyroidism is associated with a cardiac dysfunction, even when this is very mild (i.e. with serum TSH still comprised in the normal range), and show that these abnormalities are reversible with L-T4 replacement therapy. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Cardiac function; PWDTI; Hypothyroidism; L-thyroxine

1. Introduction Subclinical hypothyroidism is a frequent condition defined by elevated TSH secretion in the presence of normal concentrations of circulating thyroid hormones [1–3]. It is associated with several mild cardiac abnormalities, such as impairment of left ventricular diastolic function at rest and of systolic function on effort [4–7]. In a recent study, we confirmed the presence of a diastolic dysfunction in patients with subclinical hypothyroidism and provided further evidence of impairment of systolic function in mild thyroid failure, also at rest [8]. Moreover, in the same investigation ⁎ Corresponding author. Endocrinology, Department of Medical Sciences, University of Cagliari, S.S. 554, bivio di Sestu, 09042 Monserrato (Cagliari), Sardinia, Italy. Tel.: +39 70 5109 6430; fax: +39 70 5109. E-mail address: [email protected] (S. Mariotti). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.03.130

we demonstrated that a slight impairment in both systolic and diastolic function is also detectable in patients with euthyroid autoimmune thyroiditis and a serum TSH still comprised within the normal range [8]. Aim of the present study was to assess the effect of L-thyroxine (L-T4) administration on cardiac function as compared to baseline in patients with borderline hypothyroidism. For this purpose, we used Pulsed Wave Tissue Doppler Imaging (PWTDI), an extremely sensitive technique in assessing the effects of subtle thyroid failure on heart contractility [8]. 2. Subjects and methods 2.1. Study population We studied 26 consecutive patients (25 females, 1 male) with Hashimoto's thyroiditis (for the diagnostic criteria, see

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below [9,10]) seen at the outpatient Endocrinology Clinic of Cagliari University Hospital. Eighteen of them had subclinical hypothyroidism with increased (N3 μU/ml) serum TSH (5.69 ± 2.16 μU/ml, range 3.51–10.7 μU/ml; Group A), and 8 had normal (b3 μU/ml) serum TSH (2.53 ± 0.35 μU/ml, 1.43–2.89 μU/ml; Group B). Serum free-T3 (FT3) concentration was within the normal range in both groups. A third group included thirteen healthy age- and sex-matched euthyroid controls (12 females, 1 male), randomly selected from subjects evaluated in our outpatient Endocrinology Service with no clinical, echographic or laboratory evidence of thyroid dysfunction. Controls were studied only once, in order to obtain standard reference values for any cardiac parameter evaluated. None of the patients or control subjects was affected by cardiovascular risk factors, namely diabetes, hypertension, dyslipidemia and cigarette smoking. The basal features of patients and controls are reported in Table 1. No significant differences were observed among the groups in heart rate, blood pressure and serum FT3 concentration. Mean serum free-T4 (FT4) concentration was significantly lower in patients belonging to Group A as compared to Group B and controls ( p b 0.001). Mean serum TSH was significantly increased in patients of Group A when compared to Group B ( p b 0.01). Although individual serum TSH concentration in patients of Group B was comprised within the normal range, the mean was significantly higher when compared with control subjects ( p b 0.01). 2.2. Study protocol The Ethical Committee of our University approved the present study, and informed written consent was obtained

Table 1 Biophysical characteristics, cardiovascular measurements and hormonal data of patients and controls Patients

Age (years) Male/female Weight (kg) Height (cm) BMI (kg/m2) HR (bpm) SBP (mmHg) DBP (mmHg) FT3 (pg/ml) FT4 (pg/ml) TSH (mUI/l)

Group A

Group B

TSH N 3 mU/l

TSH b 3 mU/l

(n = 18)

(n = 8)

42.0 ± 8.9 1/17 65.3 ± 10.0 158.8 ± 5.2 25.9 ± 4.1 70.5 ± 9.7 129.2 ± 12.1 80.7 ± 7.9 3.19 ± 0.46 8.38 ± 1.89*ƒ 5.69 ± 2.16§#

39.0 ± 10.0 0/8 60 ± 7.9 162.2 ± 5.2 23.0 ± 3.1 74.0 ± 14.1 125.0 ± 9.3 75.0 ± 4.1 3.08 ± 0.39 11.43 ± 1.08 2.53 ± 0.35#

Controls (n = 13)

39.0 ± 8.2 1/12 62.1 ± 11.4 162.6 ± 10.5 23.5 ± 3.7 76.2 ± 11.6 125.2 ± 7.1 77.8 ± 7.1 3.5 ± 0.2 10.2 ± 1.7 1.2 ± 0.5

⁎p b 0.001 vs Group B; ƒp b 0.001 vs controls; §p b 0.01 vs Group B; #p b 0.01 vs controls. BMI: body mass index; DBP: diastolic blood pressure; HR: heart rate; SBP: systolic blood pressure.

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Table 2 Left ventricle morphological and functional 2D and Doppler echocardiographic indexes in patients and controls Baseline

L-T4

50 μg

L-T4

50 μg

Controls (n = 13)

6 months

12 months

Group A (TSH N 3 mU/l; n = 18) 81 ± 11 LVMI (g/m2) EF (%) 62 ± 5 Em (cm/s) 61 ± 13⁎ Am (cm/s) 59 ± 10 Em/Am 1.0 ± 0.2⁎ IVRT (ms) 87 ± 11

88 ± 14# 64 ± 4 64 ± 13 63 ± 14⁎ 1.0 ± 0.3⁎ 82 ± 8

90 ± 11# ⁎ 64 ± 3 67 ± 13 64 ± 14⁎ 1.1 ± 0.3⁎ 81 ± 6#

81 ± 12 66 ± 6 70 ± 10 53 ± 11 1.4 ± 0.3 84 ± 10

Group B (TSH b 3 mU/l; n = 8) LVMI (g/m2) 89 ± 9 EF (%) 63 ± 3 Em (cm/s) 65 ± 12 Am (cm/s) 57 ± 16 Em/Am 1.2 ± 0.4 IVRT (ms) 88 ± 10

86 ± 10 66 ± 3 74 ± 12 63 ± 12 1.2 ± 0.1 84 ± 10

88 ± 9 67 ± 2 74 ± 12 63 ± 12 1.2 ± 0.2 82 ± 5 #

81 ± 12 66 ± 6 70 ± 10 53 ± 11 1.4 ± 0.3 84 ± 10

⁎p b 0.05, vs controls; #p b 0.05 vs baseline. Am: mitral late diastolic peak velocity; EF: ejection fraction; Em: mitral early diastolic peak velocity; IVRT: isovolumic relaxation time; LVMI: left ventricle mass index.

from all subjects. Participants were familiarized with instrumentation and medical environment of echocardiographic laboratory before testing. All subjects underwent physical examination, a complete M-Mode, 2D, spectraland color-Doppler and PWTDI study. Patients from groups A and B were studied at baseline and after 6 and 12 months of therapy with a fixed dose of L-T4 (50 μg/die). 2.3. Doppler echocardiography Recordings were performed by using a 2.5-MHz transducer. Left ventricular mass (LVM), LVM index (LVMI) and ejection fraction (EF) were calculated by conventional methods [11,12]. Pulsed Doppler transmitral flow velocities were recorded from 4-chamber apical view, with the sample volume placed at the level of the mitral valve leaflet tips. Early (Em) and late (Am) diastolic velocities of transmitral flow were measured and Em/Am ratio was derived. Isovolumic relaxation time (IVRT) was measured as the time interval between the end of systolic output flow and transmitral Em wave onset, by placing the sample volume between the outflow tract and the mitral valve. 2.4. PWTDI For this procedure we used an ultrasound system equipped with TDI capabilities (SSA-380A; Toshiba Corp., Tochigi, Japan). PWTDI mapping of systolic and diastolic velocities was assessed in the mitral annulus, with subjects in the left lateral decubitus position. By means of a 4-chamber apical view, a 3-mm sample volume was placed at level of both basal lateral and infero-septal mitral annulus, with the ultrasonic Doppler beam in a position as parallel as possible

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to the motion of the myocardial wall. A detailed description of methods is reported in a previous publication of ours [8]. The following measurements were made from the PWTDI recordings: peak systolic velocity (Sa, cm/s), acceleration time of S (ATSa, s), deceleration time of S (DTSa, s), peak early diastolic velocity (Ea, cm/s), peak late diastolic velocity (Aa, cm/s), acceleration time of E (ATEa, s), and deceleration time of E (DTEa, s). Ea/Aa ratio was then calculated. Mean acceleration and deceleration rates of S (ARSa, cm/s2; DRSa, cm/s2) and of E (AREa, cm/s2; DREa, cm/s2) were obtained as Sa and Ea divided by their respective time intervals. We considered the peak early diastolic velocity of lateral mitral annulus (Eal, cm/s) as a relaxation index. Finally, we calculated the ratio between Em and Eal (Em/Eal), a parameter that allows to estimate the influence of cardiac relaxation on mitral flow [13]. The same experienced echocardiographer, unaware of thyroid condition of subjects, carried out all examinations. Reproducibility of PWTDI parameters in our laboratory had been previously documented [14]. 2.5. Assessment of thyroid function Serum TSH, FT4, FT3, TPOAb, TgAb were measured in all subjects. FT4 and FT3 were assayed by a direct, label antibody, competitive immunoassay technique (Ortho-Clinical Diagnostic, Amersham, UK). The normal range for FT4

was 7.7–21.9 pg/ml and for FT3 2.7–5.27 pg/ml. Serum TSH was measured by immunometric assay (Ortho-Clinical Diagnostic, Amersham, UK). The normal range was 0.2– 3.0 mU/l. TPOAb and TgAb were determined by a enzymelabelled, chemiluminescent sequential immunometric assay (DPC, Los Angeles, USA) using IMMULITE 2000 devices (Medical System). The normal range for TPOAb was b 10 UI/ml, for TgAb was b 40 UI/ml. TPOAb ranged 64– 3000 UI/ml (median 369) in group A, and 134–3000 UI/ml (median 379) in Group B and were negative in controls. Thyroid ultrasound was performed in all cases using a 7.5 MHz linear electronic transducer and thyroid echogenicity subjectively evaluated by a conventional gray scale. The diagnosis of Hashimoto's thyroiditis was made on the basis of hypoechoic goiter [15] associated to high levels of TPOAb [10,11]. 2.6. Statistical analysis Data of all groups are reported as mean ± S.D. Differences between control subjects and patients, and those between basal condition and therapy with L-T4 (6 and 12 months) were assessed by the Student's 2-tailed t test for unpaired or paired observations, as appropriate. All calculated p values are considered as significant when b 0.05.

Fig. 1. Systolic mitral annulus indexes assessed by PWTDI in patients with borderline hypothyroidism (at baseline and after 6- and 12-months L-T4) and in control subjects (only baseline data). ⁎p b 0.05, #p b 0.001 vs controls; ∫p b 0.05, †p b 0.001 vs basal.

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At baseline, in comparison to control subjects, Em and Em/Am ratio were significantly lower ( p b 0.05) in Group A and comparable in Group B (Table 2). After 6- and 12-month therapy with L-T4, Em progressively increased in Group A, becoming comparable with that of controls (Table 2). In the same group L-T4 also induced a significant increase of LVMI and a significant reduction of IVRT, when compared to basal values. The mean LVMI at the end of treatment (12 months) was also slightly, but significantly, higher when compared to controls. In contrast, L-T4 administration did not produce significant modification of echocardiographic parameters in Group B patients, with the exception of IRVT, which was significantly reduced after 12 months.

baseline abnormalities, with mean Sa and DRSa still significantly ( p b 0.05) reduced, and TSa and DTSa significantly ( p b 0.05) increased when compared to controls. None of the systolic PWTDI indexes showed significant differences between Groups A and B. Fig. 1 also shows the variations of selected PWTDI systolic parameters in comparison with basal findings after 6- and 12-month therapy with L-T4. During hormone administration, most systolic indexes revealed a progressive trend towards normalization, not significantly differentiating from the respective control values at the end of the observation period. In detail, Sa, ARSa and DRSa showed a significant increase in patients of Group A ( p b 0.001) and Sa ( p b 0.05) and DRSa ( p b 0.001) in those of Group B; moreover, TSa and DTSa progressively decreased in both Group A ( p b 0.001) and Group B ( p b 0.001 and p b 0.05, respectively).

3.2. PWTDI systolic function

3.3. PWTDI diastolic function

Selected PWTDI systolic parameters are depicted in Fig. 1 and compared with those of the control group. In Group A patients, baseline Sa, ARSa and DRSa were significantly reduced ( p b 0.001) and DTSa and TSa significantly increased ( p b 0.001), as compared to controls. Patients of Group B showed similar, although milder,

Selected PWTDI diastolic parameters are summarized in Fig. 2. At baseline, Ea, Ea/Aa ratio, AREa, DREa and Eal were significantly lower in patient of Group A ( p b 0.01) and Group B ( p b 0.01), as compared to controls. Furthermore, DTEa and the Em/Eal ratio resulted significantly increased in both Group A ( p b 0.05) and Group B ( p b 0.01 and p b 0.05,

3. Results 3.1. Doppler echocardiography

Fig. 2. Diastolic mitral annulus indexes assessed by PWTDI in patients with borderline hypothyroidism (at baseline and after 6- and 12-months L-T4) and in control subjects (only baseline data). ⁎p b 0.05, #p b 0.001 vs controls; ∫p b 0.05, †p b 0.001 vs basal.

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Table 3 Hormonal data in patients and in controls Baseline

L-T4

50 μg

6 months

L-T4

50 μg

12 months

Controls (n = 13)

Group A (TSH N 3 mU/l; n = 18) FT3 (pg/ml) 3.2 ± 0.5⁎ 3.4 ± 0.6 FT4 (pg/ml) 8.4 ± 1.9⁎ 11.0 ± 2.6# TSH (mUI/l) 5.7 ± 2.2⁎⁎ 3.2 ± 2.3⁎⁎##

3.7 ± 0.4# 11.0 ± 1.6# 2.7 ± 1.8⁎⁎##

3.5 ± 0.2 10.0 ± 1.6 1.2 ± 0.5

Group B (TSH b 3 mU/l; n = 8) FT3 (pg/ml) 3.1 ± 0.4⁎ 3.2 ± 0.1⁎ FT4 (pg/ml) 11.4 ± 1.1 10.7 ± 1.3# TSH (mUI/l) 2.5 ± 0.3⁎⁎ 1.9 ± 0.9⁎

3.5 ± 0.3# 11.7 ± 0.6 0.9 ± 0.9#

3.5 ± 0.2 10.0 ± 1.6 1.2 ± 0.5

⁎p b 0.05, ⁎⁎p b 0.01 vs controls; #p b 0.05, ##p b 0.01 vs baseline.

respectively). None of the diastolic PWTDI indexes showed significant differences between Group A and Group B. After 12 months of L-T4 administration, all parameters became comparable with those of controls: Ea, Ea/Aa ratio, AREa, DREa and Eal showed a significant increase ( p b 0.001) and DTEa and Em/Eal a decrease ( p b 0.05) in Group A. The same trend was observed in Group B patients, in whom the Ea, AREa, DREa, Eal and Em/Eal values had already normalized after 6 months of treatment. No relevant ECG morphological abnormalities and rhythm disturbances were observed in L-T4-treated groups. 3.4. Hormonal data In patients of Group A, serum TSH significantly and progressively decreased with L-T4 administration, although it remained significantly higher than that of euthyroid controls ( p b 0.01; Table 3). Serum FT3 and FT4 were significantly lower than controls before treatment ( p b 0.05), while always in the normal range, and became comparable with those of controls on L-T4, both at 6 and 12 months of treatment. In patients of Group B, L-T4 administration was associated to a significant decrease of serum TSH, which reached a level not significantly different from that of normal controls after 12 months of treatment (Table 3). Administration of L-T4 was also associated in this group of patients to a marginal increase in serum FT3. In no case serum TSH, FT3 and FT4 was outside the normal range during L-T4 administration, in both groups. 4. Discussion In the present study, carried out with both 2D echocardiography and PWTDI, we investigated the cardiac function in borderline hypothyroidism. In accordance with our previous investigation [8], and in comparison with healthy euthyroid controls, we detected a subtle but significant impairment of both systolic and diastolic function in patients with typical subclinical hypothyroidism. This occurred also in subjects with echographic and serological evidence of Hashimoto's thyroiditis, and serum TSH still comprised in

the normal range. The latter subset of patients appears to be affected by a very mild form of thyroid failure; in keeping with this concept, the mean serum TSH was significantly higher than that of euthyroid controls, but still in the normal range. An additional finding of the present study is the demonstration that administration of L-T4 was able to restore the whole cardiac function in both groups of individuals with mild thyroid failure. The normalization of PWTDI parameters was partial after 6 months and complete after 12 months of therapy. In general, patients with increased basal serum TSH displayed normal parameters after 12 months, while most patients with basal serum TSH b 3 mU/l reached normal systolic and diastolic function by the 6th month. This phenomenon is probably accounted for the use of a fixed (50 μg) dose of L-T4, which was probably suboptimal in the majority of Group A patients, as shown by the mean serum TSH found at the end of the study, which remained significantly higher than that of euthyroid controls and of Group B patients. Accordingly, the changes of both systolic and diastolic PWTDI parameters were more evident in Group B as compared to Group A patients. We admit that the use of individually tailored L-T4 dose, aiming to bring the serum TSH to a same narrow normal range (e.g. between 0.5 and 1.0 mU/ml), would have been a more accurate approach. However, the main goal of the present study was to assess that the subtle cardiac abnormalities recently found in Hashimoto's patients with TSH comprised in the normal range [8] could be reversed by thyroid hormone administration. Therefore, we selected a simpler protocol with a fixed low dose of L-T4 (50 μg/day) to avoid over-treatment. The results obtained strongly support this concept, in spite of some differences in the final thyroid status obtained in the two study Groups. Taken together, our present and previous [8] data support the concept that patients with autoimmune thyroiditis and normal TSH levels (i.e. those at high risk to develop SH or overt thyroid failure) may actually be slightly hypothyroid. This hypothesis, although recently envisaged [16], has not been directly addressed with studies on heart contractility. Moreover, the observation that the degree of cardiac derangement in patients with autoimmune thyroiditis was intermediate between patients with SH and normal euthyroid controls, supports the concept of a continuum spectrum of cardiac function changes throughout the normal range of TSH. The present study provides also some important technical clues, confirming that PWTDI, a technique that uses the Doppler principle to assess the ventricular wall motion velocity [17], is more effective than 2D echocardiography in the identification of cardiac abnormalities [8]. Accordingly, conventional echocardiograms failed to demonstrate the impairment of the systolic phase in patients with subclinical hypothyroidism and did not recognise any dysfunction, either systolic or diastolic, in Group-A patients with TSH b 3. On the contrary, the study of PWTDI parameters, a reliable index of

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global left ventricle function [18], confirmed our previous findings of a significant impairment of left ventricular ejection (decreased Sa and DRSa), diastolic relaxation (decreased Ea, AREa, DREa and Eal) and ventricular filling (decreased Ea/Aa ratio and increased Em/Eal) in subtle hypothyroidism [8], and allowed to prove that these abnormalities could be reversed by L-T4 administration. For its part, conventional 2D and Doppler echocardiographic investigation documented a L-T4-induced shortening of IVRT, interpretable as an improvement of the diastolic function. On the other hand, the observation of an increased LVMI seems to represent an incidental finding, possibly related to the replacement therapy, able to promote per se a subtle increase in cardiac work [19] or a direct trophic effect on the myocardium [20]. In conclusion, the present study offers a further contribution to the growing evidence that subclinical hypothyroidism is associated to a cardiac dysfunction, even if in its mildest form and shows that this dysfunction is fully reversible by L-T4 administration. Further studies are needed to ascertain the actual benefits of substitution therapy in borderline thyroid failure. References [1] Cooper DS. Clinical practice. Subclinical hypothyroidism. N Engl J Med 2001;345:260–5. [2] Huber G, Staub JJ, Meier C, et al. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab 2002;87: 3221–6. [3] Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228–38. [4] Biondi B, Fazio S, Palmieri EA, et al. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 1999;84: 2064–7. [5] Monzani F, Di Bello V, Caraccio N, et al. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab 2001;86: 1110–5.

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