Abstract
Thyroid hormone stimulates cardiac inotropy and chronotropy via direct genomic and non-genomic mechanisms. Hyperthyroidism magnifies these effects, resulting in an increase in heart rate, ejection fraction and blood volume. Hyperthyroidism also affects thrombogenesis and this may be linked to a probable tendency toward thrombosis in patients with hyperthyroidism. Patients with hyperthyroidism are therefore at higher risk for atrial fibrillation, heart failure and cardiovascular mortality. Similarly, TSH suppressive therapy for differentiated thyroid cancer is associated with increased cardiovascular risk. In this review, we present the latest insights on the cardiac effects of thyroid suppression therapy for the treatment of thyroid cancer. Finally, we will show new clinical data on how to implement this knowledge into the clinical practice of preventive medicine.
Introduction
Thyroid hormones and the cardiac system are closely related. This is illustrated by the fact that most characteristics and common symptoms of hyperthyroidism − such as palpitations, excitability, and perspiration − are the result of the effects of thyroid hormones on the cardiovascular and nervous system. In this review, we will explain these effects, first describing some general aspects of the relation between the thyroid and the cardiovascular system, and then clarifying the impact of overt and subclinical hyperthyroidism on the cardiovascular system. We will thereafter present the latest insights on the cardiac effects of thyroid suppression therapy for the treatment of thyroid cancer. Finally, we will show new clinical data on how to implement this knowledge into the clinical practice of preventive medicine.
Effects of thyroid hormones
Thyroid hormones influence the cardiovascular system via direct and indirect mechanisms. The most direct mechanism is the presence of thyroid hormone receptors on the myocardium and vascular endothelial cells (1). Indirect mechanisms include the cardiovascular effects of thyroid hormones via inflammatory cytokines and lipid metabolism.
Vascular effects
Triiodothyronine (T3) is the physiologically active thyroid hormone produced by de-iodination of the inactive hormone thyroxine (T4). T3 increases cardiac output by reducing systemic vascular resistance. First, T3 stimulates the endothelium of the vascular smooth muscle cells to synthesize and secrete nitric oxide (2). This results in relaxation of the smooth muscles, which reduces systemic vascular resistance, thereby diminishing the volume of effective arterial filling. This results in a release of renin and activation of the angiotensin–aldosterone axis, leading to an increase in plasma volume by renal sodium reabsorption. Finally, this increased plasma volume increases the cardiac output by an increase in preload (3).
The pathological state of hyperthyroidism magnifies the aforementioned effects, resulting in an increase in heart rate, ejection fraction, and blood volume, and in a decrease in systemic vascular resistance and isovolumic relaxation time (4).
Cardiac effects
T3 influences cardiac inotropy and chronotropy via direct genomic and non-genomic mechanisms. A direct genomic effect of T3, mediated by thyroid hormone nuclear receptors, is a modulation of the transcription rate of multiple cardiac genes involved in – among others – the kinetics of the influx and efflux of the calcium ions in the sarcoplasmatic reticulum. This is an essential contribution to optimal contraction and relaxation of the cardiomyocyte. Non-genomic effects of T3 are not receptor-dependent and may influence the performance characteristics of various sodium potassium and calcium channels. This changes the intracellular levels of calcium and potassium, thereby influencing inotropy and chronotropy (1).
Haemostatic system
For the thyrotoxic state, an extensive meta-analysis has illustrated a relation between thyroid hormone levels and the haemostatic system. Analysis revealed in thyrotoxicosis evidence of a hypercoagulable and hypofibrinolytic state, in both endogenous and exogenous thyrotoxicosis, and also in clinical and subclinical hyperthyroidism (5).
Overt hyperthyroidism
The cardiovascular effects of overt hyperthyroidism have been observed for decades. In fact, some examples of pioneering publications were published >25 years ago. One example is a paper by Sawin et al., which showed a low serum thyrotropin (thyroid-stimulating hormone (TSH)) concentration in people aged 60 or older to be associated with a three times higher incidence of atrial fibrillation in the subsequent decade (6). The group of Franklyn showed that a low serum TSH is associated with increased mortality from all causes, and in particular mortality due to cardiovascular diseases (7). In the studies by both Sawin and Franklyn, low TSH was considered to be the best marker of thyroid hormone excess. However, neither researcher could show an association between serum free T3 and T4 concentrations, and they suggested a greater specificity of serum TSH as a tissue marker of thyroid hormone status. A more recent meta-analysis showed a 20% increase in all-cause mortality in patients diagnosed with hyperthyroidism (8). Moreover, a later study by the same authors showed a significant increase particularly in cardiovascular mortality, especially in Graves patients (9).
The increased mortality in overt hyperthyroidism can be explained by both heart failure and atrial fibrillation. In overt hyperthyroidism, congestive circulation results in high output failure. In addition, the associated atrial fibrillation may increase the risk of heart failure and stroke. Clinical data have already confirmed the relation between hyperthyroidism and heart failure. Thirteen percent of patients with new-onset atrial fibrillation were found to have biochemical hyperthyroidism, and conversely, 10–15% of patients with hyperthyroidism are known to develop atrial fibrillation – a rate much higher than the 1% atrial fibrillation present in the general population (10).
Hyperthyroidism also affects thrombogenesis with a rise in factors VIII and IX, fibrinogen, von Willebrand factor, and plasminogen activator inhibitor-1 factor, whereas these factors are not increased in euthyroid patients. This may be linked to a probable tendency toward thrombosis in patients with hyperthyroidism. Increasing levels of T4 have been shown to be a risk factor for venous thrombosis (11). Although a specific mechanism remains to be elucidated (12), the procoagulant effects observed in hyperthyroidism have been shown to be mediated via the TRβ (13).
Subclinical hyperthyroidism
Subclinical hyperthyroidism is defined as a subnormal serum TSH level while serum levels of T3 and T4 remain within the normal range. The prevalence of subclinical hyperthyroidism ranges from 0.6 to 1.8% in adults, depending on age, sex and iodine status (14). Although patients with subclinical hyperthyroidism often do not experience symptoms of hyperthyroidism, they are nevertheless at increased risk of cardiovascular disease, osteoporosis, and dementia (14). A landmark study with pooled data from 10 large prospective cohorts showed subclinical hyperthyroidism to be associated with an increased risk of atrial fibrillation (HR 1.68; 95% CI: 1.16–2.43). The strength of this meta-analysis was that it included only prospective studies, and selected cohorts using second- and third-generation TSH assays (15). Especially TSH levels lower than 0.10 mIU/L were associated with an increase in cardiovascular events and atrial fibrillation. The risk of atrial fibrillation had already been illustrated in the earlier mentioned study of Sawin, who also included patients with subclinical hyperthyroidism in his study (6).
In general, subclinical hyperthyroidism is associated with a higher incidence of major adverse cardiovascular events. This could be the result of a hypercoagulable state, because increased factor X activity has been measured in patients with subclinical hyperthyroidism (16). Moreover, in subclinical hyperthyroidism, an increased carotid intima-media thickness has also been reported (17). Altogether, subclinical hyperthyroidism results in an increased risk of death from cardiovascular disease (HR 1.29; 95% CI: 1.02–1.62), as well as leading to other effects, such as an increased left ventricular mass, sinus tachycardia, and diastolic dysfunction (15).
TSH suppression in differentiated thyroid cancer
Adults
Differentiated thyroid cancer, consisting of papillary and follicular thyroid cancer, is common at a relatively young age, with a peak incidence at ages 35–50 years. DTC has a relatively good prognosis (18). Thyroid cancer is the fifth most common type of cancer in women (19). For all patients, the standard initial treatment for DTC has consisted of thyroidectomy, radioactive iodine (RAI) adjuvant therapy, and TSH suppression therapy. Nowadays, this treatment is given mainly to patients with a high risk of recurrence. In the past, TSH suppression was standard follow-up therapy for all patients with thyroid cancer, regardless of the cancer stage. This has provided insight regarding long-term effects of this suppression therapy, including the increased risk of cardiovascular disease and mortality. As a result, moderate and complete suppression is currently recommended for patients with biochemically or structurally incomplete disease, whereas the other stages are treated with mild or no suppression (20).
Scores on the cardiovascular fingerprint at the time of DTC diagnosis for patients who did/did not develop a cardiovascular event.
Citation: Endocrine Connections 10, 1; 10.1530/EC-20-0539
In the early nineties, adult patients on TSH suppression therapy for thyroid cancer or multi-nodular goiter were already shown to have diastolic dysfunction and an increased left ventricular mass (21). A significantly lower left ventricular ejection fraction (within reference range) was found in 25 thyroid cancer patients after more than 10 years of TSH suppressive therapy, compared to controls. A randomized study in these 25 patients showed the diastolic dysfunction, also reported in this study, to be partly reversible after 6-month restoration of euthyroidism (22). Patients on TSH suppression therapy also are at risk of overt cardiovascular disease, according to increasing evidence presented from several points of view. Table 1 summarizes the most important studies on the cardiovascular effects of exogeneous TSH suppression since 2010. Our group showed in more than 500 DTC patients, compared to 1500 controls, a 2.5-fold increase in AF that was independent from the well-known AF risk factors (23). Other studies also showed a higher prevalence of AF in thyroid cancer patients (24, 25). One study also showed a higher risk of stroke (26). However, none of these studies could find an association between TSH level and AF.
Studies on cardiovascular endpoints in DTC patients on TSH suppression therapy.
| Author/year of publication | Patients | Outcome parameters | Type of study |
|---|---|---|---|
| Abdulrahman (2010) (47) | 25 DTC patients, 40 controls | Systolic and diastolic dysfunction after prolonged subclinical hyperthyroidism reversible after euthyroidism | Prospective, single-blinded, placebo-controlled randomized trial |
| Abonowara (2012) (24) | 136 DTC patients | TSH suppression associated with high AF prevalence | Cross-sectional |
| Klein Hesselink (2013) (33) | 524 DTC patients | Increased cardiovascular and all-cause mortality, independent from established risk factors, relation lower TSH | Retrospective |
| 1572 controls | |||
| Klein Hesselink (2015) (23) | 518 DTC patients | Increased risk atrial fibrillation, independent from established AF risk factors | Retrospective |
| 1563 controls | |||
| Klein Hesselink (2017) (39) | 266 DTC patients | NT-proBNP levels associated with increased risk cardiovascular events and all-cause mortality | Prospective |
| 798 controls | |||
| Klein Hesselink 2017 (31) | 66 adult pediatric DTC survivors | 21% diastolic dysfunction (e’ septal and e’ lateral) | Cross-sectional |
| Pajamaki (2018) (36) | 901 DTC patients | Increased cardiovascular morbidity, accountable to atrial fibrillation and TSH < 0.1 | Retrospective |
| 4485 controls | |||
| Toulis (2018) (26) | 3009 DTC patients | Significantly higher risk of atrial fibrillation and stroke | Prospective |
| 11303 controls | |||
| Park (2018) (37) | 3822 DTC patients | Year and age at cancer diagnosis, sex, cancer stage, TSH suppression therapy, baseline BMI, and baseline comorbidity were risk factors for CVD | Cohort |
| Wang (2018) (48) | 105 DTC patients (subdivided in TSH ≤0.1 and > 0.1 and duration of TSH suppression 0.5; 1; >1 year) | Prolonged suppression time associated with decrease left ventricular diastolic function, systolic synchrony and myocardial perfusion | Observational |
Children
Although thyroid cancer during childhood is rare, it is nevertheless the most common endocrine malignancy in children and its incidence is increasing (19). At the time of diagnosis children often have a larger tumors and higher prevalence of cervical lymph nodes and distant (mostly pulmonary) metastases, and show a higher recurrence rate compared to adults (27, 28). Nevertheless, their prognosis is even better than that of adults, with 15-year survival rates above 95% (29, 30). In the last decade more attention has also been given to late effects in survivors of pediatric differentiated thyroid cancer. This underscores the need for data to evaluate in children the effects of cancer treatment consisting of a total thyroidectomy and, if necessary, extensive lymph node dissection, radioactive iodine (RAI) adjuvant therapy, and TSH suppression comparable to the treatment in adults.
A nationwide study was performed to evaluate the outcome, surgical complications and late effects of 131-I treatment and TSH suppressive therapy, as well as quality of life in survivors of pediatric DTC in the Netherlands, treated between 1970 and 2013 (30). The outcomes of more than 100 survivors were studied, and the majority showed no evidence of disease; 8 had recurrent and 9 persistent disease. In 66 subjects, all of them long-term adult survivors of pediatric DTC with a median follow-up of 17 years, the prevalence of cardiac dysfunction was studied in relation to treatment variables, and compared with reference data for echocardiography based on the recommendations of the American Society of Echocardiography, and using retrospective data of 66 unaffected sex- and age-matched Dutch controls. The most striking observation was diastolic dysfunction in 14 out of these 66 asymptomatic survivors (21.2%) without an association with the available TSH levels during their medical history (31). Higher attained age and larger waist circumference were associated with decreased diastolic function, whereas TSH levels and cumulative administered radioiodine dose were not. The biomarkers (N-terminal pro-brain natriuretic peptide, high-sensitive Troponin-T, galectin-3), were also not associated with diastolic dysfunction. Atrial fibrillation was not observed during a 24-h Holter electrocardiography.
Recently, 47 of these 66 survivors were re-evaluated with echocardiography, and this assessment of cardiac function established a further worsening, after 5 years, of the earlier found impaired diastolic function. The main finding was a further deterioration of the diastolic function, illustrated in the early diastolic lateral tissue velocity, the e’ lateral and e’ septal, as a hemodynamic determinant of left ventricle relaxation, restoring forces, and filling pressure. Diastolic dysfunction was present in the e’ septal in 23.9% of the survivors, and in the e’ lateral in 40.4%. However, in these data an association with TSH level could not be confirmed, possibly because of insufficient lab data to cover the entire follow-up period adequately (Reichert, submitted data). However, these data may have a clinical impact, because diastolic dysfunction has been considered as a possible primary manifestation of more overt heart failure (32).
So far, these data support the presence of cardiovascular damage and risk of cardiovascular disease, although the pathophysiological background is not yet clear; evidence of an obvious relation with TSH suppression is still lacking.
Relation TSH suppression
However, other data have shown a relationship between the risk of cardiovascular mortality and TSH level. In a cohort of 524 adult patients with DTC, a 3.3-fold increase in cardiovascular mortality, independent of cardiovascular risk factors, was shown when they were compared with more than 1500 age- and sex-matched controls (33). This study reported an association between lower TSH levels and higher risk. Moreover, after adjustment for cardiovascular risk factors, DTC risk (based on the TNM classification), histology, cumulative radioiodine dose and neck radiotherapy, TSH level remains predictive of cardiovascular mortality. The specific mechanism of the effects of suppressed TSH levels, thereby accompanied by increased free thyroxin levels, is still unknown. After all, the effect of altered thyroid hormone status may also have thus far unknown results on a cellular level, as circulating free T3 and free T4 concentrations do not reflect intracellular concentration. This was illustrated more than 20 years ago in a study on thyroidectomized rats treated with T4; the study showed that euthyroidism could not be restored in the rat tissues (34). Thus, intracellular thyroid metabolism in patients on thyroxine replacement therapy may also differ from that in subjects with normal thyroid function. These pathophysiological gaps do not eliminate the clinical relevance of the risk of cardiovascular disease in patients treated with a suppressive dosage of thyroxine for thyroid cancer. Cardiovascular disease is a significant challenge for thyroid cancer survivors, and a long existing problem, as already shown in the study by MD Anderson among adult thyroid cancer survivors. Of patients reporting by questionnaires, 9.7, 6.9 and 19.1% developed cardiovascular disease after, respectively, <10, 10–20, and >20 years of follow-up. Especially considering the excellent prognosis of this disease, this is a large group of patients (35). Furthermore, other cohort studies also indicate that administration of TSH suppression therapy is associated with increased cardiovascular risk (36, 37).
Prevention of cardiovascular events in differentiated thyroid carcinoma
The question arises which DTC patients are at risk of developing cardiovascular events, and whether screening and primary prevention are useful in this patient category. The use of TSH suppressive therapy is currently tempered in both adult and pediatric patients who have long-term disease-free survival. However, especially in high and intermediate-risk groups, TSH suppression is still being applied during the first 5 years of follow-up and for long-term follow-up during persistent disease. Also, for children, long-term suppression therapy is still being recommended (38). As has been suggested in one small study, cardiac remodeling may be triggered by chronic hemodynamic overload, caused by the subclinical hyperthyroidism, and may recover after euthyroidism (22). However, it is unclear whether this recovery occurs in all patients. In patients with longstanding TSH suppression, cardiac damage may be more permanent.
The question is, how can we find the patients at risk of a cardiovascular event? A more stringent approach and treatment of cardiovascular risk factors may prevent cardiovascular events and improve the survival and quality of life of patients with thyroid cancer.
In this context, the biomarker N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) has been studied in DTC patients. Elevated levels of circulating concentrations of NT-proBNP in DTC patients were associated with an increased risk of cardiovascular events and all-cause mortality. This was shown in 266 DTC patients without a history of cardiovascular events, comparing each patient with three age- and sex-matched selected controls (39). The median age of patients and controls was 54 years, and one of the inclusion criteria was DTC survival of at least 1 year. NT-proBNP levels were evaluated median 10 years (IQR: 4.1–18.8) after DTC diagnosis. Median NT-proBNP level was significantly higher, with 70 ng/L (IQR: 40–119) for DTC patients and 49 ng/L (IQR: 25–89) for controls. DTC patients in quartile 4 (NT-proBNP > 119 ng/mL) had the worst prognosis for all-cause mortality and cardiovascular events during a median follow-up of 8.6 years (IQR: 6.6–9.0) after serum sample collection. However, this finding remains to be translated into clinical practice.
Recently, the European Society of Cardiology (ESC) provided recommendations regarding cardiovascular monitoring and decision-making regarding cancer therapies with potential cardiovascular side effects (40). However, these recommendations were limited to patients diagnosed with cancer types that are treated with chemotherapy and radiation therapy. Those therapies are not usually involved in the treatment of DTC. For DTC specific guidelines for monitoring and treatment of cardiovascular risk are lacking.
Furthermore, the available risk estimations for non-cancer patients are not appropriate for DTC patients. Ten-year cardiovascular risk estimates, such as SCORE and the Framingham risk score, are used to identify patients at high risk of cardiovascular events (41, 42). However, these estimates have not been validated in cancer patients. Furthermore, when using 10-year risk estimates, only patients above the age of 50–55 years (50 in men, 55 in women) are eligible for primary cardiovascular prevention (41). Thus, especially for cancer types with the peak incidence at ages <50 years, these cardiovascular risk estimates are not appropriate to assess the cardiovascular risk.
An example of a cancer type with the peak incidence at a young age and increased cardiovascular mortality is testicular cancer. Lubberts et al. developed a tool called the vascular fingerprint to identify patients at high cardiovascular risk in a primary prevention setting. This tool involves assessing five risk factors: high BMI, smoking, hypertension, dyslipidemia and impaired fasting glucose. A high-risk vascular fingerprint (≥3 risk factors) before the start of chemotherapy identified patients at the highest risk of arterial cardiovascular events. Although not externally validated, these factors promised to be useful for selection of patients who might benefit from preventive strategies (43). In line with this approach, we reanalyzed the results of the earlier mentioned cohort of DTC patients (33), and developed a cardiovascular fingerprint specifically for survivors of DTC. For this thyroid cancer cardiovascular fingerprint, we added two risk factors that were not relevant to the series of young male patients with testicular cancer: sex and age. The components of this thyroid cancer cardiovascular fingerprint are shown in Table 2.
The cardiovascular fingerprint.
| Risk factor | Score |
|---|---|
| Sex | Male = 1 |
| Age | >45 years = 1, >60 years = 2 |
| Body mass index | >25 kg/m2= 1 |
| Hypertension | Blood pressure >140/90 mmHg OR usage of antihypertensive drugs = 1 |
| Dyslipidemia | total cholesterol >5.1 mmol/L OR HDL <1.04 mmol/L OR LDL >2.5 mmol/L OR usage of lipid lowering drugs = 1 |
| Smoking | Current smoking = 1 |
| Diabetes | Usage of blood glucose lowering drugs = 1 |
| Total | 8 points, ≥ 4 points = ‘high cardiovascular fingerprint’ |
The following cut-off values or definitions were used: BMI >25 kg/m2, current smoking, blood pressure >140/90 mmHg (or use of antihypertensive drugs), dyslipidemia (total cholesterol >5.1 mmol/L, HDL <1.04 mmol/L, LDL >2.5 mmol/L or use of lipid-lowering drugs), and use of blood glucose-lowering drugs. We defined high risk as ≥4 points after testing with a receiver operating characteristic (ROC) curve. A cut-off score for the cardiovascular fingerprint was determined to differentiate between patients with a high or a low risk of developing cardiovascular events. We tested cut-off values of 3–5 with a receiver operating characteristic (ROC) curve (Supplementary Fig. 1, see section on supplementary materials given at the end of this article). The cut-off score of 4 was found to have the optimal discriminative power to identify DTC patients with high cardiovascular risk (sensitivity of 65.0% and specificity 72.5%).
We applied this simple tool to 619 consecutive DTC patients, diagnosed between 1980 and 2010 (Fig. 1). As we aimed to identify patients for primary cardiovascular prevention, we excluded patients who had experienced a cardiovascular event before the DTC diagnosis. A cardiovascular event was defined as a stroke (CVA or TIA), myocardial infarction, heart failure (NYHA 2-4), or revascularization procedure. After the diagnosis of DTC, 60 of the 619 DTC patients (9.7%) developed a first cardiovascular event within the follow-up time (median 12.6 years). The cardiovascular fingerprint identified 39 of those 60 patients (65.0%) as high risk.
Of 426 patients with a low score on the cardiovascular fingerprint, 21 (4.9%) developed a cardiovascular event. Of the other 193 patients with a high score, 39 (20.2%) developed a cardiovascular event. The cardiovascular fingerprint was compared to the traditional cardiovascular risk estimation of the European Society of Cardiology for non-cancer patients (41). Of the 60 patients with a cardiovascular event, 22 (36.7%) were classified as high risk by this traditional estimation. The cardiovascular fingerprint had a higher diagnostic odds ratio (4.8, 95% CI: 2.7–8.4) compared to the traditional risk estimation (3.0, 95% CI: 1.70–5.34). The cardiovascular fingerprint was more effective, particularly in identifying younger patients at risk of cardiovascular disease. Twenty patients with a cardiovascular event, classified as low-risk by the traditional risk estimation, had a positive cardiovascular fingerprint. Those patients were younger than the patients identified by the traditional risk estimation (mean 52.9 ± s.d. 10.5 vs mean 70.7 ± s.d. 7.5 years, P ≤ 0.001). Although preliminary, the cardiovascular fingerprint may be a simple and effective tool to identify DTC patients at increased risk of a first cardiovascular event. Nevertheless, this tool must be validated in another cohort of DTC patients.
Conclusion
This overview has illustrated that the cardiovascular risks of clinical and subclinical hyperthyroidism also apply to long-term survivors of DTC, in both adult and pediatric survivors. Therefore, for all DTC patients, cardiovascular risk management should be considered in line with their elevated risk factors. For example, lifestyle advice regarding smoking cessation, healthy dietary habits, and regular physical activity (44), could be offered to all DTC patients with high cardiovascular fingerprints. Furthermore, initiation of antihypertensive drugs could be considered for DTC patients found to have a blood pressure >140/90 mmHg upon several visits (45). In patients with dyslipidaemia, lipid-lowering drugs should be considered (46). However, further research is needed to establish the beneficial effect of cardiovascular prevention specifically in DTC patients. Moreover, the mechanisms of cardiovascular toxicity in DTC patients should be elucidated.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EC-20-0539.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work did not receive any specific grant from any agency in the public, commercial or non-profit sector.
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