Adults with congenital heart disease (ACHD) are frequently affected by thyroid diseases (TDs). However, the clinical relevance of TD in ACHD remains unknown. We aimed to describe the prevalence of TD in the ACHD population and to ascertain whether TD are associated with worse outcome. Patients with ACHD >18 years attending our tertiary center for a day-case between 2014 and 2019 were included. Clinical data between patients’ first visit and December 2020 were collected. Primary end point was a combination of death, hospitalization for heart failure (HF), and new-onset of arrhythmic events. Secondary end points were each part of the primary outcome as separate end points. A total of 495 patients with ACHD (32.2 [24.5 to 45.6] years; 54% women) were included. Median follow-up was 9.4 (4.5 to 13.1) years. The prevalence of TD was 30%. TD group showed worse clinical status, as demonstrated by N-terminal pro b-type natriuretic peptide values (243.5 [96.5 to 523] vs 94 [45 to 207] pg/ml, p <0.001) and New York Heart Association class (27% vs 13% in class III to IV, p <0.0001) with higher incident rate of adverse events at follow-up (4.45 [3.43 to 5.69] % vs 1.29[0.94 to 1.75] % per person-year, p <0.001). TD were independently associated with higher risk of death (hazard ratio [HR] 4.1, p = 0.009), arrhythmic events (HR 3.8, p <0.0001), and hospitalization for HF (HR 8.02, p <0.0001). There was a fourfold increased risk of primary end point in the TD group even after propensity score matching for clinical variables including age, gender, disease complexity, physiological stage, previous palliative surgery, ventricular function, pulmonary arterial hypertension, cyanosis, and presence of systemic right ventricle (HR 4.47, p <0.0001). In conclusion, TD are predictive of adverse outcome in the ACHD population. Routine screening of thyroid function during follow-up in this population may be helpful to identify those with higher risk of death, arrhythmias, and HF.
Advances in cardiac surgery allowed to a greater proportion of patients with congenital heart disease to reach adulthood. Adults with congenital heart disease (ACHD) frequently present also thyroid disease (TD), which is known to potentially exacerbate arrhythmias, heart failure (HF), and atherosclerotic disease, thus contributing to premature mortality and morbidity. The aim of the present study is to describe the prevalence and clinical relevance of TD in patients with ACHD.
Methods
Data on consecutive patients with ACHD, >18 years, attending our tertiary center between 2014 and 2019 were retrospectively collected. The study population was divided in 2 groups according to the history of TD at baseline, defined as clinical manifest or subclinical (abnormal serum thyroid stimulating hormone [TSH] level) thyroid dysfunction including iatrogenic disease after thyroidectomy, goiter, and thyroid malformation. Electronic records were reviewed for clinical data between patients’ first clinical assessment and December 2020. For patients in the TD group, follow-up data were collected from the first clinical assessment after diagnosis of TD. The study was conducted according to the Declaration of Helsinki and obtained approval from the institutional ethics committee. As this study involved the retrospective analysis of data collected during clinical activity, the institutional review board waived the need for written informed consent.
The primary end point was the occurrence of cardiac events during follow-up including death, hospitalization for HF, and new-onset of arrhythmic events such as ventricular tachycardia (VT), atrial arrhythmia (AA) (atrial tachycardia, atrial flutter, atrial fibrillation), and bradyarrhythmic events requiring medical intervention. Secondary end points were each part of primary outcome as separate outcomes.
Statistical analysis was carried out using R version 4.0.5. Continuous variables were reported as mean ± SD or median (interquartile range), according to data distribution. Comparisons between groups were assessed with t test or Wilcoxon rank-sum test. Categorical variables were presented as frequencies (percentage of total). Differences in proportions were evaluated with chi-square. Kaplan–Meier survival curves were plotted with censoring at the time of first event occurrence. The relation between clinical parameters and outcome was assessed using univariable Cox proportional hazard regression analyses. Variables significant on univariate analysis were included in the multivariable model. In order to adjust for baseline clinical differences between groups, propensity scores were computed using logistic regression, with presence of TD as dependent variable and clinical variables as independent variables, including age, gender, disease complexity, and physiological stage (according to American Heart Association ACHD guidelines ), previous palliative surgery, ejection fraction (EF), pulmonary arterial hypertension, cyanosis, and systemic right ventricle to perform 1:1 nearest neighbor matching within a caliper of 0.25 SDs. Once balance was verified, matched pairs were used as strata in the Cox model. A p <0.05 was considered statistically significant.
Results
A total of 495 patients (32.2 [24.5 to 45.6] years, 54% women) were included. Baseline clinical details are summarized in Table 1 . The majority (414 = 84%) had moderate/complex disease. A total of 151 patients (30.5%) had a diagnosis of TD ( Table 2 ). Of them, 115 were on replacement therapy (76%) and 7 were on suppressive treatment (5%) at last clinical assessment. Laboratory data of thyroid function obtained on an outpatient basis at last assessment were available for 73 patients. A total of 29 of 73 had a decompensated thyroid function (40%): 20 showed increased values of TSH (7.9 [5.8 to 11.2] nmol/L) and 9 suppressed TSH values (0.22 [0.07 to 0.3] nmol/L). None of the patients with a diagnosis of thyroid cancer and previous thyroidectomy had a history of cancer-related complications. Patients in the TD group were older, mostly females, and with higher proportion of genetic disorders. There was no significant difference in the number of cardiac surgeries between the 2 groups; however, a higher proportion of patients with TD had undergone at least 2 cardiac catheterizations. In the TD group, there was a higher prevalence of palliative surgical procedures, such as Glenn/Fontan palliation, aortopulmonary shunt, and pulmonary banding. Accordingly, the TD group comprised a higher proportion of patients with cyanosis. At latest follow-up, patients with TD had higher N-terminal pro b-type natriuretic peptide values, more advanced New York Heart Association class, and lower EF. Moreover, patients with TD were more likely on diuretics, angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers, and antiarrhythmic treatment.
| Variables | All patients N=495 | Thyroid disease | p-Value | |
|---|---|---|---|---|
| Yes N=151 | No N=344 | |||
| Age (years) | 32.1[25.5-45.6] | 41.2[29.7-53.5] | 30.2[24.3-39] | <0.0001 |
| Male | 226(46%) | 35(23%) | 191(56%) | <0.0001 |
| Number of cardiac surgeries | 0 →156 (32%) 1→206 (42%) 2→76 (15%) 3→50 (10%) 4→7 (1.4%) | ≥2→40 (26%) | ≥2→93 (27%) | 0.8 |
| Number of catheterizations | 0 →255 (51%) 1→141 (28%) 2→67 (14%) 3→29 (6%) ≥4→2 (0.4%) | ≥2→44 (29%) | ≥2→45 (13%) | <0.0001 |
| Disease complexity | 1→ 81(16%) 2→ 272(55%) 3→142(29%) | 1→ 35(23%) ≥2→ 116(77%) | 1→ 49(14%) ≥2→ 295(86%) | <0.0001 |
| Physiological stage | A→ 115(23%) B→ 140(28%) C→ 211(43%) D→ 29(6%) | A-B→69(46%) C-D→ 82(54%) | A-B→186(55%) C-D→ 158(45%) | 0.065 |
| Type of repair | Biventricular: 353(71%) Unrepaired 89(18%) Fontan 40(8%) Other palliation 7(1%) | Palliated 24(16%) | Palliated 29(8%) | 0.0135 |
| Genetic disorder | 39(8%) | 28(19%): -21 Down -2 Turner -1 Prader Willi -1 Kabuki -1Willliams -1 ring chromosome8 -1 Ehlers-Danlos | 11(3%) -7 Down -2 Pierre Robin -1 Charge -1 duplicated chromosome 8 | <0.0001 |
| Cyanosis | 25(5%) | 12(8%) | 13(4%) | 0.0013 |
| Pulmonary arterial hypertension | 81(16%) | 11(7%) | 70(20%) | 0.0004 |
| Systemic right ventricle | 73(15%) | 12(8%) | 61(18%) | 0.0047 |
| Pacemaker | 51(10%) | 18(12%) | 33(9.5%) | 0.4 |
| Implantable cardiac defibrillator | 13(3%) | 7(5%) | 6(1.7%) | 0.064 |
| Nt-proBNP (pg/ml) | 114[53-275](N=358) | 243.5[96.5-523] (n=96) | 94[45-207] (n=262) | <0.0001 |
| NYHA class | I→ 179(36%) II→ 228(46%) III→ 86(17%) IV→ 2(0.4%) | I-II→110(73%) III-IV →41(27%) | I-II→297(86%) III-IV→ 47(13%) | 0.0002 |
| 6 minute walking distance | 387±109 (n=56) | 372.4±95 (n=27) | 401.9±121 (n=29) | 0.3 |
| Ejection fraction(%) | 60[55-61.7] | 55[55-60] | 60[55-65] | 0.0002 |
| At least moderate valvular disease | 201(41%) | 71(47%) | 130(38%) | 0.69 |
| History of ventricular tachycardia | 7(1.5%) | 4(3%) | 3(0.9%) | 0.08 |
| Medications at last visit | Betablockers: 161(32%) Antiarrhythmic: 65(13%) Diuretics: 113(23%) Angiotensin-converting enzyme inhibitors/ aldosterone receptor antagonists: 228(46%) | 58(38%) 30(19.8%) 58(38%) 72(47.6%) | 103(30%) 35(10%) 55(16%) 156(18%) | 0.08 0.0029 <0.0001 <0.0001 |
| Main cardiac diagnosis | 12 (8%) Ventricular septal defect 21 (14%) Atrial septal defect 22 (15%) Atrioventricular septal defect 4 (3%) Partial anomalous pulmonary venous drainage 13 (9%) Aortic coarctation 11 (7%) Bicuspid aortic valve/congenital aortic stenosis 1 (0.6%) Aortopulmonary window 4 (3%) Mitral valve disease 3 (2%) Transposition of the great arteries 7 (5%) Congenitally corrected transposition of the great arteries 4 (3%) Pulmonary atresia 11 (7%) Pulmonary stenosis 16 (11%) Tetralogy of Fallot 3 (2%) Double outlet right ventricle 2 (1%) Double outlet left ventricle 5 (3%) Tricuspid atresia 7 (5%) Double inlet left ventricle 5 (3%) Ebstein’s anomaly |
| Thyroid diagnosis | 35 (23%) Hashimoto’s thyroiditis 5 (3%) Basedow-Graves disease 17 (11%) Amiodarone-related 1 (0.7%) Total thyroid agenesis 18 (12%) Multinodular goitre 1 (0.7%) Follicular adenoma 6 (4%) Carcinoma: 1 follicular carcinoma 2 papillary carcinoma 3 no histological data 69 (46%) unknown |
| Thyroid surgery | 15 (10%) |
| Radioactive iodine therapy | 1 |
| Thyroid function | 129(85%) hypo 7 (5%) hyper 5 (3%) both 10 (7%) normal |
| Thyroid hormone replacement therapy | 115 (76%) |
| Dosage | 75 [50-100] |
| Suppressive treatment | 7 (5%) |
| Laboratory results (N=73) | |
| Thyroid-stimulating hormone (nmol/L) | 3.7 [1.1.-5.1] |
| Free triiodothyronine (nmol/L) | 3 [2.5-3.1] |
| Free thyroxin (nmol/L) | 1.3 [1.2-1.6] |
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