Our study had 2 main findings: 1) hypothyroidism is not associated with a higher risk of all-cause mortality in patients receiving CRT for HF, and 2) baseline TSH level is an independent predictor for appropriate ICD therapy. This is the first study to show that in patients who have HF, TSH level is associated with ventricular arrhythmic events after CRT.
Hypothyroidism and CRT outcomes
The prevalence of hypothyroidism in patients with HF is 4% to 24%2. Our study showed a higher incidence of hypothyroidism than previous reports. Hypothyroidism is associated with adverse effects on cardiac output, cardiac contractility, and vascular resistance12. A decrease in the thyroid hormone level may result in endothelial dysfunction, vascular smooth muscle cell apoptosis, atherosclerosis or ischemic heart disease, and cardiac atrophy with chamber dilatation by sarcomere lengthening13-15. One study showed that a decrease in the thyroid hormone level is proportional to the severity of HF symptoms16. These pathophysiologic factors may diminish an optimal response to CRT. In this study, the hypothyroidism group had less improvement in NYHA class than the euthyroidism group, yet the improvement in LVEF was similar between the two groups at 1-year follow-up.
Hypothyroidism is associated with a higher mortality rate, cardiovascular events, and progression of chronic kidney disease and diabetes1, 2, 10, 17-19. Similarly, Chen’s study found that a low-normal free triiodothyronine level was associated with HF rehospitalization and overall mortality in euthyroid patients with HF receiving CRT20. In contrast, similar risk of all-cause mortality was found in our patients with hypothyroidism or euthyordism. This might be explained by the similar CRT response rate between them, implying the effectiveness and importance of CRT for patients with HF and hypothyroidism.
OH is associated with increased cardiovascular risks, whereas the risk with SH is still controversial10, 21. There is no consensus on whether SH warrants treatment22. One important reason for the controversy is that observational studies show that TSH tends to increase with age23. While age-based cut-off points for hypothyroidism not yet been standardized, there might be a danger of overtreatment, especially in the elderly. A large observational study has corroborated that TRT may minimize the risk of coronary heart disease in younger patients (<70 years)24. A recent randomized, double-blind, placebo-controlled clinical trial found no difference in systolic or diastolic heart function after TRT compared with placebo in older adults ( ≥65 years) with subclinical hypothyroidism25. No comparison about TRT for SH patients was conducted in this study since no TRT was used for SH. Nevertheless, no differences were found in the outcomes between patients with SH and those with OH. Numerous studies have reported improvement in vascular and cardiac function and arterial stiffness in patients with SH26, 27. A meta-analysis showed a possible relationship between SH and an increased risk of coronary heart disease mortality compared with euthyroidism28. TRT was observed beneficial in preventing major adverse cardiovascular and cerebral events for hypothyroidism patients undergoing percutaneous coronary intervention15. Therefore, TRT should be individualized for SH patients, and more considered especially for those with high coronary heart diseases and younger age.
Hypothyroidism and ventricular arrhythmia
Hypothyroidism is associated with both supraventricular and ventricular arrhythmias29, 30. QT interval prolongation and dispersion have been observed in patients with decreased thyroid function, which might be responsible for the increased inhomogeneity of ventricular repolarization and myocardial vulnerability to ventricular arrhythmia31, 32. These changes can be reversed after levothyroxine treatment33, 34. Not surprisingly, our patients with more severe thyroid dysfunction (higher TSH level) had higher risk of ventricular arrhythmic events despite CRT, an indication that ventricular arrhythmia is substantially associated with systemic diseases and comorbidities in HF, especially thyroid dysfunction. Indeed, our study is the first to demonstrate an increased baseline TSH level is associated with increased ventricular tachyarrhythmic events. Furthermore, the TSH level was an independent predictor for sustained ventricular arrhythmia. The TSH level might be considered as an important biomarker to stratify the risk of sudden death. Female sex was an independent predictor for fewer appropriate ICD therapies in our study, consistent with a previous report35.
Amiodarone and hypothyroidism
Amiodarone therapy frequently causes thyroid dysfunction, most commonly hypothyroidism. This effect is largely related to the high iodine content of the medication and its effect on thyroid hormone synthesis and release. Patients who receive CRT for HF more often receive amiodarone therapy for control of ventricular or atrial arrhythmia, in whom hypothyroidism may occur as an adverse drug effect. As Amiodarone is the most effective drug in controlling ventricular arrhythmia, TRT is accepted to overcome the adverse effect. In this study abnormal TSH level were associated with worse prognosis regardless of amiodarone usage or TRT. Moreover, the survival rate was lower in the amiodarone group than in the non-amiodarone group. However, amiodarone was not an independent predictor for survival, suggesting the amiodarone group was more likely to be sicker, requiring antiarrhythmic drug to control ventricular or atrial arrhythmia associated with heart failure. Our finding was in agreement with the finding of previous study in which patients who took amiodarone for rhythm control of atrial fibrillation had a higher risk of cardiovascular hospitalization and mortality rates compared to the rate control group36. Despite amiodarone reducing ICD shocks according to previous study37, in our study the amiodarone group had a higher appropriate ICD therapy event rate than the non-amiodarone group, a suggestion of incomplete control of ventricular arrhythmia in this patient group.
This was a single-center retrospective cohort study without a 10 year follow-up schedule and was subject to the inherent limitations of retrospective study, like the missing data regarding therapy or TSH level changes during follow-up. Because triiodothyronine and thyroxine levels were not available, the thyroid status was assessed only by documented history and TSH levels. The TSH was measured only once before CRT implantation, the diagnosis of subclinical hypothyroidism may not be accurate. Finally, the national death and location database was used for survival analysis, with the limitation of knowing the cause of deaths.