Scholarly article on topic 'Cardiac remodeling and apoptosis before and after restoration of euthyroidism in Graves’ thyrotoxicosis'

Cardiac remodeling and apoptosis before and after restoration of euthyroidism in Graves’ thyrotoxicosis Academic research paper on "Basic medicine"

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{"Cardiac remodeling" / Apoptosis / "Graves’ thyrotoxicosis"}

Abstract of research paper on Basic medicine, author of scientific article — Wael Refaie, Fawzya El Demerdash, Ehsan Refaie, Ahmed Elewa

Abstract Background Thyrotoxicosis is usually associated with cardiovascular morphological and functional changes (remodeling) which may lead to cardiac decompensation secondary to the apoptotic process. Autoimmune initiation may be a triggering factor. Aim Identifying the structural and functional cardiac changes in Graves’ toxicosis before and after restoration of euthyroidism and to illustrate the role of apoptosis if any on cardiac remodeling. Study design Prospective controlled study. Subjects and methods Thirty young females with Graves’ toxicosis and positive thyroid antibody tests, were selected from outpatient clinics of Mansoura University Hospital. The studied cases were evaluated by clinical examination, electrocardiography and echocardiography for cardiac changes before and after restoration of the euthyroid state and compared to a control group of age and sex matched euthyroid individuals. The anti apoptotic serum marker (Bcl-2) level was estimated on inclusion and after control of the thyrotoxicosis. Correlation of the anti apoptotic serum marker with thyroid function test and the cardiac remodeling changes was undertaken. Results Sinus tachycardia, prolonged QTc interval and increased QTd were evident. Echocardiographic evidences of increased left ventricular mass, diastolic dysfunction and some systolic dysfunction were common and these positively correlated with thyroid function tests but negatively correlated with serum anti apoptotic marker (Bcl-2). Conclusion Structural cardiac and functional changes are usual findings in Graves’ toxicosis that can be manifested by diastolic and systolic dysfunctional changes. Identifying remodeling and apoptosis and early management of thyrotoxicosis can halt the cardiac changes.

Academic research paper on topic "Cardiac remodeling and apoptosis before and after restoration of euthyroidism in Graves’ thyrotoxicosis"

The Egyptian Heart Journal (2012) 64, 75-80

Egyptian Society of Cardiology The Egyptian Heart Journal

www.elsevier.com/locate/ehj www.sciencedirect.com

ORIGINAL ARTICLE

Cardiac remodeling and apoptosis before and after restoration of euthyroidism in Graves' thyrotoxicosis

Wael Refaie a *, Fawzya El Demerdash a, Ehsan Refaie b, Ahmed Elewa c

a Department of Cardiology, Mansoura University, Egypt b Department of Obstetric and Gynecology, Mansoura University, Egypt c Department of Clinical Pathology, Mansoura University, Egypt

Available online 20 March 2012

KEYWORDS

Cardiac remodeling; Apoptosis;

Graves' thyrotoxicosis

Abstract Background: Thyrotoxicosis is usually associated with cardiovascular morphological and functional changes (remodeling) which may lead to cardiac decompensation secondary to the apoptotic process. Autoimmune initiation may be a triggering factor.

Aim: Identifying the structural and functional cardiac changes in Graves' toxicosis before and after restoration of euthyroidism and to illustrate the role of apoptosis if any on cardiac remodeling. Study design: Prospective controlled study.

Subjects and methods: Thirty young females with Graves' toxicosis and positive thyroid antibody tests, were selected from outpatient clinics of Mansoura University Hospital. The studied cases were evaluated by clinical examination, electrocardiography and echocardiography for cardiac changes before and after restoration of the euthyroid state and compared to a control group of age and sex matched euthyroid individuals. The anti apoptotic serum marker (Bcl-2) level was estimated on inclusion and after control of the thyrotoxicosis. Correlation of the anti apoptotic serum marker with thyroid function test and the cardiac remodeling changes was undertaken. Results: Sinus tachycardia, prolonged QTc interval and increased QTd were evident. Echocardio-graphic evidences of increased left ventricular mass, diastolic dysfunction and some systolic dysfunction were common and these positively correlated with thyroid function tests but negatively correlated with serum anti apoptotic marker (Bcl-2).

Corresponding author. E-mail address: refaie_wael@yahoo.com (W. Refaie).

1110-2608 © 2012 Egyptian Society of Cardiology. Production and hosting by Elsevier B.V. All rights reserved.

Peer review under responsibility of Egyptian Society of Cardiology. doi:10.1016/j.ehj.2012.02.001

Conclusion: Structural cardiac and functional changes are usual findings in Graves' toxicosis that can be manifested by diastolic and systolic dysfunctional changes. Identifying remodeling and apop-tosis and early management of thyrotoxicosis can halt the cardiac changes.

© 2012 Egyptian Society of Cardiology. Production and hosting by Elsevier B.V. All rights reserved.

1. Introduction

Thyroid hormones have profound effects on virtually all tissues and the cardiovascular (CV) system is a predominant one.1 Thyrotoxicosis has long been known to be associated with cardio-megaly and heart failure (HF).2 Recent studies revealed the presence of a flow mediated type non-autoimmune form of a reversible pulmonary hypertension (PHTN) in Graves' toxicosis (GT),3'4 and it is recommended to investigate thyroid status in patients with right sided HF especially in the presence of PHTN.5 About 6% of thyrotoxic patients develop symptoms of heart failure and less than 1% develop a reversible form of dilated cardiomyopathy with biventricular or four chamber dila-tation.6'7 The congestive heart failure occurring in Graves' toxicosis in spite of the associated hyperdynamic circulation could be due to direct damage by autoimmune myocarditis.8 Thyrotoxicosis may elicit acute myocardial ischemia even in patients with angiographically normal coronary vessels. The left ventricular apical akinesis and the impaired global systolic function can be normalized by successful medical treatment of thyrotoxicosis.9 Moreover, subclinical thyrotoxicosis may be associated with changes in cardiac performance and morphology with increased LV mass index, increased cardiac contractility with tachycardia, diastolic dysfunction, induction of atrial arrhythmia and impaired cardiac performance.10

HF has become the dominant CV disorder worldwide and there is an urgent need to clarify the mechanism covering pathological remodeling mediated through cell death and to identify the ways of preventing and treating HF.11 The progression of compensated hypertrophy to HF is still debated. The hypothesis that structural remodeling as well as cell death, contribute to the transition to HF is accepted.12

There are 3 types of cell death (apoptosis, autophagy and necrosis). Apoptosis is a form of programed cell death. Autophagy is a cell survival mechanism that involves degradation and recycling of cytoplasmic components.11 The role of apoptosis in heart during ischemic and non ischemic cardiomyopathies has been under investigation and reported to contribute to ventricular remodeling13 and studies on apoptosis have proved new insights into autoimmune target destruction. Apoptosis secondary to chronic remodeling is implicated as a mediator to HF14 but there are still many controversies about the presence and significance of apoptosis in HF. These controversies are partially attributed to the limitation of the technique used to detect apoptosis in HF.15

2. Aim

It was aimed to:

- Identify the cardiac structural and functional sequel of Graves' toxicosis;

- Correlation between thyroid function, electrocardiographic and echocardiographic changes before and after medical restoration of euthyroidism;

- Illustrate the correlation between serum antiapoptotic factor (Bcl-2) and the cardiac changes.

3. Subjects and methods

Thirty young females (25-32 years) were selected from the medical, endocrinal, cardiovascular and gynecology departments, Mansoura Faculty of Medicine. Criteria for qualification of Graves' disease included presence of goiter, ophthalmopathy of any degree and symptoms and signs of thyrotoxicosis.

Thirty apparently age and body weight- matched healthy females were included as a reference group. Neither the thyro-toxic, nor the reference group were smokers, diabetics. None had hypertension, kidney or liver disorders.

The clinical diagnosis of GT was confirmed by the presence of elevated FT3, FT4 and depressed sTSH besides the presence of positive serum thyroid antibodies (TPOab, TSHRab). Pregnant, lactating women and those receiving hormonal contraception, antithyroid, iodine containing drugs (expectorants, amiodarone, lithium or radio contrast exposure) were excluded. Women with low Hb, low platelet count and/or leuco-penia and those with elevated hepatic serum enzymes were also excluded. Post-prandial serum glucose, serum urea, serum cre-atinine and liver functions (serum bilirubin, AST, ALT and ALP) were performed on automated analyzer Hitachi 911 Kits supplied by Roche diagnostics.

Serum TSH concentration was measured by immunometric assay. Serum free T3 and T4 were estimated using a solid phase competitive chemiluminescent enzyme immunoassay. All thyroid hormone profile were measured on Immunlite automated analyzer. Serum thyroid hormones kits were supplied by DPC (Diagnostic Products Corporation), Los Angeles, CA 900455597. Serum B-cell lymphoma-2 antiapoptotic (Bcl-2) level kits were supplied by IBL (Immuno-Biological Laboratories).

Clinical examination was performed stressing on history of Palpitation and tachycardia. Cases with advanced Graves' oph-thalmopathy were not included as most of them were either under corticosteroid therapies and/or immune modulating drugs. A standard 12 lead ECG was recorded at 25 mm/s and 1 mV/ cm standardization, stressing on heart rate, rhythm, QTc and QTd. Two-dimensional and Doppler echocardiography (para-sternal and apical 4 chamber views) were undertaken.

The examined cases were advised rest with no undue effort and to receive carbimazole 60 mg/day for 3 months with clinical, CBC, serum hepatic enzymes every fortnight when indicated. The studied thyroid function, the anti apoptotic (Bcl-2) ECG and Echo-Doppler were reevaluated.

4. Statistical analysis

Statistical analysis was performed by using SPSS statistical package for Social Science Program version "10" 1999. Qualitative data were presented as frequency and percentages. The

Table 1 The clinical manifestation of the studied Grave' toxicosis patients.

Before ttt No. of cases (%) After ttt No. of cases (%) P

Losing weight in spite of good appetite 24 cases (80) 3 cases (10) <0.001

Sense of hotness 22 cases (73.3) 2 cases (6.6) <0.001

Palpitation 22 cases (73.3) 3 cases (10) <0.001

Tachycardia 22 cases (73.3) 3 cases (10) <0.001

Menstrual irregularity 18 cases (60) 1 case (3.3) <0.001

Neck swelling 25 cases (83.3) 3 cases (10) <0.001

Table 2 Serum apoptotic marker (Bcl-2) level in thyrotoxicosis patients before and after treatment.

Parameter (mean ± SD) Control (C) Before ttt (B) After ttt (A) P P P

C vs B C vs A B vs A

Serum Bcl-2 (U/ml) 3.99 ± 2.9 24.80 ± 11.6 12.1 ± 26.7 <0.001 0.10 0.02

Table 3 ECG findings in Graves' thyrotoxic patients before and after treatment.

Before ttt After ttt P

Sinus tachycardia 83.3% (25 cases) 10% (3 cases) <0.001

Voltage changes for LVH 26.6% (8 cases) 3.3% (one case) 0.02

QTc dispersion > 80 ms 66.6% (20 cases) 10% (3 cases) <0.001

Prolonged QTc interval 66.6% (20 cases) 10% (3 cases) <0.001

Table 4 Correlation between serum Bcl-2 and LV diastolic function in Graves' thyrotoxic patients before and after treatment.

Serum Bcl-2 before ttt Serum Bcl-2 after ttt P

Peak E velocity(cm/s) Before ttt r = -0.918 <0.001

After ttt r = -0.419 <0.001

Peak A velocity(cm/s) Before ttt r = -0.851 <0.001

After ttt r = -0.329 <0.01

Declaration time (ms) Before ttt r = -0.752 <0.001

After ttt r = -0.289 NS

Isovolumic relaxation time (ms) Before ttt r = -0.930 <0.001

After ttt r = -0.720 <0.001

quantitative data were examined by using Kolmogorov-Smir-nov test to test for normal distribution of the data when parametric, expressed as mean and standard deviation. Student's t test was used, to test for difference in normally distributed quantitative data between the two groups. Mann-Whitney-U test was used for comparison between two groups when data are not normally distributed. Significance was considered when P value less than 0.05.

5. Results

In the present study, ECG evidences of cardiac affection included presence of significant sinus tachycardia, prolonged QTc and frequent QTd which were significantly ameliorated after treatment (Table 3).

The echocardiographic finding in GT before and after treatment compared to the control group is illustrated in (Table 5), which showed a significant increase of both the interventricular septum thickness at diastole (IVSD) and the posterior wall

thickness at diastole (PWTD) in the GT group before treatment compared to the control group. The increased thickness of the IVSD and PWTD was significantly decreased by anti-thyroid medical treatment.

The left ventricular mass (LVM) was increased before treatment compared to the control group and although decreased after treatment yet the differences were insignificant. The left ventricular mass and dimension revealed significant changes together with the left ventricular systolic and diastolic functions in comparison to the control group. The LV diastolic functions; were significantly ameliorated with antithyroid treatment together with peak E velocity, peak A velocity, declaration time (DT) and isovolumic relation T (IVRT) (Table 5).

The correlation between serum antiapoptotic (Bcl-2) and LV diastolic function was stressed upon. Before treatment, the peak E velocity, the peak A velocity, the DT and IVRT were significantly correlated with Bcl-2 level, but after treatment significant correlation was only related to peak E and A velocity and IVRT. The DT was insignificantly changed

Table 5 Echocardiographic findings in Graves' thyrotoxicosis patients before and after treatment.

Parameter (mean ± SD) Control (C) Before ttt (B) After ttt (A) P P P

C vs B C vs A B vs A

LV systolic function

Fractional shortening (FS%) 39.32 ± 4.03 44.1 ± 11.1 39.98 ± 0.2 0.035 0.373 0.046

Ejection fraction (EF%) 74 ± 18.1 81.01 ± 1.1 77.97 ± 6.18 0.038 0.26 0.010

Stroke volume (SV) (ml/beat) 74 ± 10.6 84.13 ± 52.43 70.9 ± 26.88 0.032 0.558 0.044

Cardiac output (COP) (l/min) 5.2 ± 1.2 8.99 ± 1.6 5.87 ± 2.2 <0.001 0.14 <0.001

Cardiac index (CI) (l/min/m2) 3.3 ± 2.1 6.11 ± 3.12 3.8 ± 1.6 <0.001 0.30 <0.001

Peripheral vascular resistance PVR (dyne.sx cm-5) 1521.2 ± 261.1 1089.41 ± 445.1 1399.9 ± 211.1 <0.001 0.052 <0.001

Correlated mean velocity of circumferential fiber 1.2 ± 0.19 1.4 ± 0.2 1.19 ± 0.20 <0.001 0.84 <0.001

shortening (MVCFc) (circ/s)

End- systolic wall stress (ESWS) (103 dyn/cm2) 54.9 ± 5.1 63 ± 1.1 58.1 ± 11.1 <0.001 0.156 0.01

LV dimensions and mass

End diastolic diameter EDD (cm) 4.7 ± 0.4 4.5 ± 0.5 4.6 ± 0.4 0.92 0.33 0.39

End systolic diameter (ESD) (cm) 2.8 ± 0.4 2.5 ± 1.1 2.6 ± 0.8 0.16 0.22 0.68

Interventricular septum thickness at diastole 0.72 ± 0.10 0.82 ± 0.01 0.78 ± 0.1 0.017 0.023 0.033

(IVSD) (cm)

Posterior wall thickness at diastole (PWTD) (cm) 0.85 ± 0.10 0.97 ± 0.2 0.89 ± 0.02 0.018 0.035 0.033

Left ventricular mass (LVM) (g) 112.6 ± 11.2 150 ± 77.3 135 ± 60.1 0.011 0.045 0.404

Left ventricular mass index (LVMI) (g) 80.6 ± 50.9 105.90 ± 30.7 83.9 ± 50.1 0.023 0.801 0.044

LV diastolic function

Peak E velocity (cm/s) 74.9 ± 15.8 67.9 ± 8.9 73.9 ± 9.5 0.038 0.767 0.014

Peak A velocity (cm/s) 51 ± 3.1 53.9 ± 1.1 52.9 ± 1.8 <0.001 0.131 0.011

Declaration time (DT) (ms) 170.5 ± 4.1 181.8 ± 11.2 170.6 ± 3.5 <0.001 0.919 <0.001

Isovolumic relaxation time (IVRT) (ms) 54.7 ± 2.5 84. 9 ± 18.1 68.6 ± 16.2 <0.001 <0.001 <0.001

Table 6 Correlation between thyroid hormones & TSH levels and serum Bcl-2 in Graves' thyrotoxic patients before and after

treatment.

Serum Bcl-2 before ttt Serum Bcl-2 after ttt P

Serum free T3 Before ttt r = -0.186 NS

After ttt r = -0.101 NS

Serum freeT4 Before ttt r = -0.009 NS

After ttt r = -0.393 <0.01

Serum TSH Before ttt r = 0.026 NS

After ttt r = 0.053 NS

(Table 4). Studying the correlation between thyroid hormones, TSH and serum Bcl-2 before and after treatment revealed significant correlation only with FT4 (Table 6).

6. Discussion

Apoptosis; one of the forms of programed cell death is a physiological occurrence and is a requisite to the correct functioning of every organ.16,17 The signal to apoptosis can be started practically in any cell of any organ. Disturbance of apoptosis regulation determine the essential link of pathogenesis of many diseases including the studied cases of autoimmune Graves' toxicosis.

Thyroid disorders including subclinical toxicosis are becoming very common. Fortunately they can be easily diagnosed and treated, thus arresting cardiac changes and apoptosis. In the present study, the cardiovascular changes in GT were detected clinically, also by ECG and echocardiography (Tables 1, 3 and 5). Poulsen and coworkers, 200118 reported that echocardiogra-phy has become a well established practical and safe non invasive maneuver for diagnosing cardiovascular dysfunction.

The electrocardiographic changes (Table 3) revealed significant sinus tachycardia, voltage changes for LVH, prolonged QTc, increased QTcd before treatment and significant improvement after restoration of euthyroidism. The QTc was significantly longer in the studied cases of GT in comparison to the control group before and after treatment thus confirming the findings of Etinarslan et al. 1998.19 QTd >80 ms in the present study before treatment and its significant improvement after restoration of euthyroidism may indicate regional inho-mogeneity of ventricular repolarization time.20 The present electrocardiographic changes are in agreement with the finding of Lambardi, 199821 who reported that for the QTc intervals and QTd, the smaller the better. The prolonged QTc and the increased occurrence of QTd may be due to the shift of sympathetic predominance and/or reduced vagal modulation which are constant phenomena of thyrotoxicosis.22

The echocardiographic changes (Table 5) are in agreement with Ching et al. 199623 who described cardiac hypertrophy as a result of thyrotoxicosis and/or long term thyroxine therapy. Cardiac remodeling involves increased rates of cardiomyocyte cell death that precedes HF.24 The serum antiapoptotic marker

(Bcl-2) level in the studied cases showed significant elevation in comparison to the control group and was markedly diminished after antithyroid treatment (Table 2). The expression of anti-apoptotic molecules (Bcl-2) is regulated in thyroid cells to avoid apoptotic cell death25 and there is up regulation of antiapoptotic molecules (Bcl-2) protecting thyrocytes from apoptotic cell death.26

Bcl-2, the first example of an oncogene that inhibits cell death rather than promoting cell proliferation, was found in follicular lymphoma and is frequently linked to an immuno-globulin by chromosome location.25 A correlation between serum antiapoptotic Bcl-2 level and LV diastolic dysfunction before and after antithyroid treatment was evident (Table 4). Before treatment, the peak E velocity, the peak A velocity, the DT and IVRT revealed significant correlation with Bcl-2 level. However after restoration of euthyroidism the significant negative correlation was only related to peak A velocity and IVRT.

In the present work beta blocker (propranolol) was combined with carbimazole but ACE inhibitors were not used. This could explain the relatively common persistence of features of remodeling in the present study. Previous studies showed that metoprolol, carvedilol over a time course of 318 months led to regression of cardiac hypertrophy and dilatation with progressive increase in EF and restoration of a more elliptical chamber shape.27-29 Novel pharmacological approaches for reverse remodeling in heart failure have been developed by pharmacological blockade of the sarcolemmal Na/hydrogen exchanger.30

The anti apoptotic function of Bcl-2 differs and may be stimulus dependent31 or cell specific.32 The anti apoptotic Bcl-2 had a positive consequence on the viability of ischemia of the brain and myocardium although it was believed to exert minimal or no detectable changes in these organs.33 Salmaso and coworkers (2002)34 found that Bcl-2 promoted hypertrophy in thyroid cells while attenuating the heart muscle cell.

7. Conclusion

Structural and functional cardiac changes are common findings in Graves' toxicosis that can lead to many apoptotic changes including diastolic and systolic dysfunction and cardiac hypertrophy. Early diagnosis and prompt treatment of Graves' toxicosis can halt these cardiovascular changes. Search for anti apoptotic measures is awaited.

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