Thyrotropin Over-suppression and Heart
Condition: Malignant Neoplasm of Thyroid; Heart Diseases; Thyrotoxicosis on Thyroxine Therapy
MeSH terms: Neoplasms; Thyroid Neoplasms; Heart Diseases; Thyroid Diseases; Thyrotoxicosis
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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).
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        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.
      
Biospecimen description: 
      serum and plasma
    
Keywords: thyroid neoplasms; heart; thyroxine; thyrotoxicosis