The investigators evaluated the cardiac effects of Thyroid-stimulating hormone (TSH) over-suppression in women with differentiated thyroid cancer (DTC) frequently encountered during suppression therapy.

The aim of this study was to evaluate the cardiac effects of TSH over-suppression in women with DTC during TSH suppressive therapy for 5 to 9 years relative to their risk of recurrence.

Methods

1. Patients

   From chart review, the investigators selected 96 female differentiated thyroid cancer patients who received total- or near-total thyroidectomy, and thereafter regularly visited the endocrine out-patient department (OPD) of Chuncheon Sacred Heart Hospital. Majority of papillary thyroid cancer tends to present between 30 and 50 years old and their risk of recurrence is low or intermediate. Menopause also might affect on the cardiovascular risk factors in women. According to guidelines, the dose of thyroxine would be reduced after 10 years of thyroidectomy in DTC patients. Therefore, additional enrollment criteria were as follows: 1) age less than 45 years old when receiving total or near-total thyroidectomy, 2) serum level of TSH<0.1 mU/L in the intermediate -risk or TSH<0.3 mU/L in the low recurrence-risk group, over 2 years before study entry, 3) receiving TSH suppressive therapy for 5 to 9 years with fixed dose of LT4 more than 2 years before study entry, and 4) no history of structural heart disease, arrhythmia, or cardiac symptoms (palpitation, exertional dyspnea and chest discomfort) during therapy. Of the 17 patients who met the criteria, three patients did not consent to this study. Candidates who satisfied all the enrollment criteria took an electrocardiogram to rule out patients with arrhythmia. Finally, 14 DTC patients were enrolled and studied from September 2009 to March 2010. As each patient was enrolled, control subjects were selected from patients who visited endocrinology department for thyroid nodule work-up. The control group had to meet the following criteria: 1) the subject matched to a patient by age (±2 years), sex, and body mass index (BMI) (±2 kg/m2), 2) within the reference range of serum TSH (0.3-4.6 mU/L), 3) no history of structural heart disease, arrhythmia, or cardiac symptoms, 4) no history of comorbid diseases which affect thyroxine metabolism and cardiac structure, including hepatic or renal disease, anemia, and hypertension. All subjects who met the enrollment criteria took an electrocardiogram to rule out arrhythmias. Control subjects were recruited and tested from January 2010 to July 2011. All participants provided written informed consent.

2. Assays

   On the examination day, all participants were prohibited from smoking and consuming caffeine. After a light breakfast and medication, including levo-thyroxine (LT4) in cancer patients, participants visited the hospital before 9 AM. The investigators evaluated the comorbid conditions of the participants. Body weight and height were measured while the participants wore light clothing without shoes. The body mass index (BMI) was calculated as the weight in kilograms divided by the height in meters squared. Their blood pressure was taken after a 10 minute rest period. Subsequently, each subject underwent a 2-dimensional echocardiogram carried out by one examiner. After the cardiac work-up, blood samples were drawn to test of thyroid function. Blood samples were collected in pre-chilled tubes containing EDTA, immediately placed on ice, and promptly centrifuged at 4°C. After separation, plasma was stored at -80°C for the N-terminal pro-brain natriuretic peptide (NT-pro-BNP).

   Serum thyroid function tests were performed by a chemiluminescent immunoassay (UNICELL DXI800, Beckman Coulter, USA). Serum TSH (reference value: 0.3-4.6 mU/L, detection limit: 0.0025 mU/L), free T4 (reference value: 7.0-20.0 pmol/L), and free T3 (reference value: 4.0-5.9 pmol/L) were measured. Plasma NT-pro-BNP measurements were done using chemiluminescent immunoassay method (Roche E170, Roche diagnostics, Germany)

3. Echocardiography

Comprehensive transthoracic echocardiography was performed using commercially available equipment (IE33, Philips Medical System, Andover, Massachusetts). Standard 2-dimensional measurements were obtained as recommended by the American Society of Echocardiography (ASE) in the left lateral position. Left atrial volume index was measured by the biplane area-length method. Left ventricular (LV) mass was calculated using the following equation: LV mass = 0.8 (1.04 { [LVIDd + PWTd + IVSd]3 - [LVIDd]3 } )+ 0.6, where LVID is LV end-diastolic dimension, PWT is posterior wall thickness, IVS is interventricular septal wall thickness, and d is diastole. Tissue Doppler-derived early diastolic mitral annular velocity (e') and late diastolic mitral annular velocity (a') were measured from the septal corner of the mitral annulus in the apical 4-chamber view. To evaluate the global longitudinal strain (GLS) of the left ventricle, echocardiographic images were obtained at the apical 4-chambers view and the strain was analyzed based on routine DICOM (Digital Imaging and Communications in Medicine) data sets using software (2D Cardiac Performance Analysis, TomTec, Munich, Germany). A region of interest was manually placed on the endocardial and epicardial borders. The echocardiographic data were gathered and analyzed by 2 experienced echocardiographers who were unaware of any corresponding clinical data.

Statistical analysis Data were reported as means and standard deviation (SD). For the comparison of means between groups, we used the Mann-Whitney test because the sample size was small (n=14 for each group).

All P values calculated are two-tailed and considered significant at P < 0.05. All statistical analysis was performed using SPSS 20.0 software (SPSS Inc, Chicago, USA).

Inclusion Criteria:

• thyroid cancer group

  1. age less than 45 years old when receiving total or near-total thyroidectomy,
  2. serum level of TSH<0.1 mU/L in the intermediate -risk or TSH<0.3 mU/L in the low recurrence-risk group over 2 years before study entry,
  3. receiving TSH suppressive therapy for 5 to 9 years with fixed dose of LT4 more than 2 years before study entry, and
  4. no history of structural heart disease, arrhythmia, or cardiac symptoms (palpitation, exertional dyspnea and chest discomfort) during therapy.

• control group

  1. the subject matched to a patient by age (±2 years), sex, and body mass index (BMI) (±2 kg/m2),
  2. within the reference range of serum TSH (0.3-4.6 mU/L),
  3. no history of structural heart disease, arrhythmia, or cardiac symptoms,
  4. no history of comorbid diseases which affect thyroxine metabolism and cardiac structure, including hepatic or renal disease, anemia, and hypertension.

Exclusion Criteria:

• who had arrhythmia in electrography or history of cardiac disease

female differentiated thyroid cancer patients who received total- or near-total thyroidectomy, and thereafter regularly visited the endocrine out-patient department (OPD) of Chuncheon Sacred Heart Hospital. Finally, 14 DTC patients were enrolled and studied from September 2009 to March 2010. As each patient was enrolled, control subjects were selected from patients who visited endocrinology department for thyroid nodule work-up. All subjects who met the enrollment criteria took an electrocardiogram to rule out arrhythmias.

We have no plan to share the data with other investigator.