Arterial Stiffness and Central Hemodynamics in Thyroidectomized Patients on Long-Term Substitution Therapy with Levothyroxine

Abstract

Background:

Long-term levothyroxine (LT4) therapy targeting thyrotropin (TSH) suppression in hypothyroid patients treated for thyroid cancer has been associated with increased arterial stiffness and increased cardiovascular mortality. However, most patients with hypothyroidism receive LT4 therapy targeting TSH in the reference range. The long-term vascular effects of this strategy have never been evaluated.

Methods:

Arterial stiffness and central hemodynamics were studied in 30 thyroidectomized patients (M _age = 54.5 ± 10.2 years; 80% female) on long-term (median = 11 years; range 3–41 years) LT4 replacement therapy targeting TSH in the reference range and 30 sex- and age-matched controls. Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (PWV) and central hemodynamics by pulse wave analysis using the SphygmoCor system.

Results:

TSH levels were comparable in patients and controls (median = 1.99 × 10³ IU/L [range 0.24–5.64 × 10³ IU/L] vs. median = 2.13 × 10³ IU/L [range 0.59–5.63 × 10³ IU/L]; p = 0.69), but patients had higher plasma thyroxine and lower plasma triiodothyronine levels than controls (median = 108 nmol/L [range 84–149 nmol/L] vs. 86 nmol/L [range 59–141 nmol/L]; p < 0.001 and median = 1.49 nmol/L [range 1.00–2.37 nmol/L] vs. 1.62 nmol/L [range 1.18–2.09 nmol/L]; p = 0.04, respectively). PWV was not significantly higher in patients compared to controls (8.2 ± 1.9 vs. 7.9 ± 1.9 m/s, p = 0.69). Similarly, no group differences were observed in central systolic/diastolic blood pressure (120 ± 16 mmHg vs. 119 ± 12 mmHg, p = 0.77; and 80 ± 11 mmHg vs. 80 ± 10 mmHg, p = 0.98, respectively), the augmentation index (28 ± 13% vs. 29 ± 8%, p = 0.72), or the pulse pressure amplification ratio (129 ± 17% vs. 124 ± 13%, p = 0.18).

Conclusion:

Despite subtle differences in plasma levels of thyroid hormones, long-term LT4 replacement therapy targeting TSH in the reference range does not seem to cause adverse effects on arterial stiffness and central hemodynamics.

Introduction

Thyroid hormones exert profound effects on the heart and the blood vessels. Thyroid hormones have been shown to affect the vascular hemodynamics and arterial stiffness through effects on vascular smooth muscle (VSM) tone (1), endothelial function (2,3), and mechanisms affecting calcification of the arterial wall (4). Reductions in cardiac output, heart rate, and blood pressure (BP), as well as increased arterial stiffness and systemic vascular resistance, are seen in patients with untreated hypothyroidism, and the opposite effects are observed in untreated hyperthyroidism (2,5 –7).

Short-term medical treatment of the underlying thyroid disease has been shown to restore the hemodynamic changes in both hyperthyroid (2,8) and hypothyroid (6) patients, whereas less unequivocal data have been reported for treatment effects on arterial stiffness in hyperthyroid (9,10) and hypothyroid (11 –13) patients.

After euthyroidism has been restored, many patients with thyroid diseases face lifelong treatment with levothyroxine (LT4) replacement therapy. Two recent studies found that long-term thyrotropin (TSH) suppression therapy in patients treated for thyroid cancer was associated with increased arterial stiffness (14) and a more than threefold increase in cardiovascular mortality compared with healthy controls (15).

However, the majority of patients receiving LT4 replacement therapy follow regimens targeting TSH in the reference range. The long-term cardiovascular effects of this treatment strategy remain largely unknown. LT4 replacement therapy is often characterized by relatively high thyroxine (T4) levels, despite TSH levels in the reference range. Consequently, the normal balance between plasma values for triiodothyronine (T3) and T4 is not fully restored, and this could affect arterial stiffness and vascular hemodynamics.

In this context, the present study aimed to assess arterial stiffness and central hemodynamics in patients on long-term LT4 replacement therapy targeting TSH in the reference range compared to sex- and age-matched controls.

Materials and Methods

The study population has been described previously (16). In a cross-sectional study design, 49 patients who had undergone total or partial thyroidectomy and who were on long-term treatment with levothyroxine and 49 age- and sex-matched controls were recruited. Central hemodynamics and arterial stiffness were assessed in 35 patients and 33 controls. Matched data on central hemodynamics were available in 30 patients and controls, and data on arterial stiffness in 29 patients and controls.

The patients were recruited from a patient population of 219 patients who had undergone thyroid surgery (total/partial thyroidectomy) at Aarhus University Hospital during 1971–2009. The mean duration from surgery and start of substitution to inclusion in this study was 11 years (range 3–41 years). Patients were only included if they had received levothyroxine treatment continuously for more than two years and were well-managed at the time of inclusion (defined as ≥1 plasma TSH within the reference range and none above during the last six months prior to inclusion). Controls were identified from the Danish Civil Registration System, which generated a list with the names and addresses of 100 people of mixed sex for each birth year between 1932 and 1982, giving a total of 5000 individuals. The individuals were selected randomly from the population living in the vicinity of Aarhus, Denmark. When a hypothyroid patient was included, 5–10 randomly chosen sex- and age-matched (±2 years) controls were invited by letter to participate. Patients and controls were excluded if they had hypo- or hyperparathyroidism, severely impaired renal function (estimated glomerular filtration rate <30 mL/min/1.73 m²), a history of malignant disease within the last two years, or if they had been hospitalized due to chronic alcohol or drug abuse. Other exclusion criteria were sarcoidosis, pregnancy, untreated malabsorption, treatment with lithium, amiodarone, systemic corticosteroids and activated vitamin D analogues, and >1200 mg calcium or >50 μg vitamin D. Moreover, controls with a prior history of thyroid disease or a plasma TSH outside the reference range were excluded. All participants provided written informed consent. The study was performed in accordance with the Declaration of Helsinki II and approved by The Central Denmark Region Committees on Health Research Ethics (M-20110260), the Danish Data Protection Agency (2007-58-0010), and the Central Denmark Region (1-72-76-12).

Vascular assessment

Arterial stiffness and hemodynamics were assessed non-invasively using the SphygmoCor system. Carotid-femoral pulse wave velocity (PWV) is considered the gold-standard method for non-invasive assessment of arterial stiffness (17). PWV expresses the travel speed of the pulse wave between the carotid and the femoral artery and increases with increasing stiffness of the arterial wall. Increased PWV prognosticates cardiovascular risk above and beyond conventional cardiovascular risk factors (18). Hemodynamics at the level of the aorta can be assessed by pulse wave analysis (PWA). Peripheral pressure wave forms are recorded at the level of the radial artery by applanation tonometry, and the central pressure waveforms are derived by Fourier analysis of the waveforms using the generalized transfer-function software of the SphygmoCor system (17). The major indexes of the central wave form are reported: the aortic systolic and diastolic blood pressure, the augmentation index (Aix), and the pulse pressure amplification. The Aix is the difference between the first and the second systolic peaks of the central waveform expressed as a percentage of pulse pressure. The pulse pressure amplification expresses the ratio of the brachial pulse pressure to the aortic pulse pressure.

Examinations were conducted between 9:00 a.m. and 1:00 p.m. after a minimum of five minutes rest in a quiet room. The study subjects had abstained from smoking and intake of tea, coffee, or other caffeinated beverages for at least three hours before the examinations. At least two hours elapsed between breakfast and the examinations.

Measurements of PWV and PWA were performed using an applanation tonometer (SPT-301B; Millar, Houston, TX) and SphygmoCor equipment and software v8.0 (AtCor Medical, Sydney, Australia). After a minimum of five minutes rest in the supine position, three office BP were measured at the right arm with an appropriately sized cuff using a Riester Champion N automatic BP monitor (Riester GmbH, Jungingen, Germany). The mean of three systolic and diastolic BP were used for calibration of the SphygmoCor for the PWV and PWA measurements. Carotid-femoral PWV was assessed based on sequential electrocardiogram-referenced tonometry based recordings of the pulse wave at the carotid and the femoral artery determined the PWV. The transit time was determined by the intersecting tangent algorithm method (19), and the path length was calculated by subtracting the distance between the site of the carotid artery pulse measurement and the sternal notch from the distance between the site of the femoral artery pulse measurement and the sternal notch, all measured directly using a tape measure. The mean of two PWV measurements was calculated.

The peripheral pulse wave was assessed by applanation tonometry at the right radial artery, and the central pulse waves were derived by the in-built transfer function of the SphygmoCor device. Only measurement with an operator index >80 was accepted. The mean of two PWA measurements were calculated.

Biochemistry

Fasting blood samples were drawn in the morning, as previously described (16). Briefly, TSH, T3, and T4 were measured using electrochemiluminiscence immunoassays (ECLIA) on an automated instrument (Cobas e 601; Roche Diagnostics GmbH, Mannheim, Germany). For TSH, the lower detection limit is 0.005 × 10³ IU/L, with a total imprecision (CV%) of 8.6%, 2.1%, and 1.8% at serum values of 0.034 × 10³ IU/L, 0.91 × 10³ IU/L, and 3.96 × 10³ IU/L, respectively. For T3, the lower detection limit is 0.300 nmol/L, with a CV% of 3.6%, 4.2%, and 5.3% at serum levels of 1.22 nmol/L, 2.87 nmol/L, and 5.09 nmol/L, respectively. The lower detection limit for T4 is 5.40 nmol/L, with a CV% of 1.8%, 1.3%, and 1.7% at 63.1 nmol/L, 84.3 nmol/L, and 243 nmol/L, respectively.

Statistics

The distributions of continuous variables were tested with histograms and QQ-plots. Skewed data were log-transformed. Means of two groups were compared with a Student's unpaired t-test and means of three groups with one-way analysis of variance (ANOVA). Dichotomous variables were compared with a chi-square test. Associations between thyroid parameters and vascular parameters within the patient and control group were assessed by linear regression analysis in crude and multivariate models. All multivariate models were adjusted for the matching parameters age and sex. Additionally, the following parameters were tested one at a time for inclusion in the models: Body mass index (BMI), office systolic and diastolic BP, resting heart rate, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, creatinine, estimated glomerular filtration rate, antihypertensive treatment (yes/no), statin treatment (yes/no), smoking (active/previous/never), and, in the patients, levothyroxine dose. Office systolic and BP were not tested for inclusion in the models with aortic systolic and diastolic BP due to collinearity. Based on this assessment, the final model for PWV was adjusted for age, sex, systolic BP, and BMI, and the models with PWA indexes were adjusted for age, sex, and resting heart rate. The remaining parameters were not associated with the PWV and PWA indexes at a statistically significant level. Variables with a normal distribution are presented with mean ± standard deviation (SD), and skewed data are presented as median (range). Dichotomous data are presented as number and percentage. The results of the regression analysis are presented as β-coefficient (confidence interval [CI]). A sample size of 30 patients and 30 controls, an alpha level of 0.05, and an expected standard deviation of 1.3 m/s would confer a power of 83% to detect a difference in PWV of 1 m/s. All analyses were performed using the statistical software Stata v14 (Stata Corp LP, College Station, TX).

Results

The characteristics of the patients and controls are shown in Table 1. The age, sex, BMI distribution, systolic and diastolic BP resting heart rate, proportion of patients smoking, and proportion of patients receiving antihypertensive or lipid-lowering treatment was comparable in the patients and controls. None of the patients or controls had a history of cardiovascular disease, and no significant differences were observed with regard to cholesterol levels or kidney function. No significant difference in TSH was observed between the patients and controls. Patients had lower plasma T3 and higher plasma T4 levels and consequently a higher T4/T3 ratio than the controls did.

Table 1.

Patient and Control Characteristics

	Patients (n = 30)	Controls (n = 30)	p
Sex
Male, n (%)	6 (20)	6 (20)
Female, n (%)	24 (80)	24 (80)
Age, years	54.5 ± 10.2	55.8 ± 9.9	0.62
Body mass index, kg/m²	26.2 ± 4.1	25.8 ± 4.9	0.76
Office systolic BP, mmHg	130 ± 16	127 ± 14	0.46
Office diastolic BP, mmHg	79 ± 11	79 ± 9	1.00
Resting heart rate, beats/min	63 ± 11	62 ± 10	0.68
Total cholesterol, mmol/L	5.5 ± 1.0	5.1 ± 1.0	0.08
HDL-cholesterol, mmol/L	1.7 ± 0.5	1.6 ± 0.5	0.61
LDL-cholesterol, mmol/L	3.3 ± 0.9	3.0 ± 0.9	0.18
Triglycerides, mmol/L, median (range)	1.15 (0.5–5.1)	1.0 (0.4–3.0)	0.21
Creatinine, μmol/L	72.1 ± 12.2	68.5 ± 8.7	0.20
Estimated GFR, mL/min/1.73 m²	78.8 ± 10.6	81.1 ± 9.0	0.38
Antihypertensive treatment, n (%)	7 (23)	8 (27)	0.77
Statin treatment, n (%)	4 (13)	5 (17)	0.72
History of cardiovascular disease,^a n (%)	0 (0)	0 (0)
Smoking, n (%)
Current	4 (14)	5 (18)	0.10
Previous	14 (48)	6 (21)
Never	11 (38)	17 (61)
Etiology
Non-toxic goiter, n (%)	10 (33)	—
Toxic goiter, n (%)	17 (57)	—
Thyroid cancer, n (%)	3 (10)	—
Treatment
Levothyroxine dose
μg/day, median (range)	136 (50–357)	—
μg/day/kg, median (range)	1.83 (0.68–4.60)	—
Plasma TSH, 10³ IU/L, median (range)	1.99 (0.24–5.64)	2.13 (0.59–5.63)	0.69
Plasma T3, nmol/L, median (range)	1.49 (1.00–2.37)	1.62 (1.18–2.09)	0.04
Plasma T4, nmol/L, median (range)	108 (84–149)	86 (59–141)	<0.001
Plasma T4/T3 ratio, median (range)	73 (53–107)	53 (42–69)	<0.001

Continuous data are reported as mean ± standard deviation (SD) or median (range).

History of myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting.

BP, blood pressure; GFR, glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; T3, triiodothyronine; T4, thyroxine; TSH, thyrotropin.

No significant differences were observed for the PWV or for the PWA indexes of aortic systolic and diastolic BP, Aix and pulse pressure amplification when comparing patients and controls (Table 2) or when comparing subgroups of thyroidectomized patients (Supplementary Table S1; Supplementary Data are available online at www.liebertpub.com/thy).

Table 2.

Comparison of Pulse Wave Analyses Indexes and Carotid-Femoral Pulse Wave Velocity in Patients and Controls

	Patients (n = 30)	Controls (n = 30)	p
Estimated aortic systolic BP (mmHg)	120 ± 16	119 ± 12	0.77
Estimated aortic diastolic BP (mmHg)	80 ± 11	80 ± 10	0.98
Augmentation index (%)	28 ± 13	29 ± 8	0.72
Pulse pressure amplification ratio (%)	129 ± 17	124 ± 13	0.18
Carotid-femoral pulse wave velocity (m/s)^a	8.2 ± 1.9	7.9 ± 1.9	0.69

Data are reported as mean ± SD.

29 observations in each group.

TSH, T3, T4, and T4/T3 ratio were not associated with PWV or the PWA indexes in either patients or controls in crude linear regression analyses (Table 3). With adjustment for the covariates age, sex, systolic BP, and BMI for the PWV model, and age, sex, and heart rate for the PWA models, all associations remained non-significant in the patients, whereas as significant inverse association between TSH and PWV was observed in the controls (β = −0.6 [CI −1.0 to −0.1] m/s per 10³ IU/L TSH. All associations with PWA indices remained insignificant in the controls.

Table 3.

Crude Linear Regression Associations Between Thyroid Parameters and Vascular Indexes in Patients and Controls

	Estimated aortic systolic BP (mmHg)	Estimated aortic diastolic BP (mmHg)	Augmentation index (%)	Pulse pressure amplification ratio (%)	Carotid-femoral pulse wave velocity (m/s)
Plasma TSH (10³ IU/L)
Patients	−0.2 [−4.7 to 4.2]	1.1 [−1.9 to 4.1]	−2.8 [−6.2 to 0.7]	3.9 [−0.5 to 8.3]	−0.1 [−0.7 to 0.5]
Controls	−0.2 [−4.7 to 4.2]	−1.5 [−4.9 to 1.9]	2.3 [−0.3 to 4.9]	−3.2 [−7.5 to 1.1]	−0.4 [−1.1 to 0.3]
Plasma T3 (nmol/L)
Patients	−0.9 [−24.4 to 22.6]	2.8 [−13.1 to 18.7]	−13.3 [−31.6 to 5.1]	14.0 [−9.6 to 37.6]	−0.9 [−3.6 to 1.9]
Controls	7.4 [−12.0 to 26.8]	−0.4 [−15.7 to 15.0]	−3.7 [−15.7 to 8.2]	13.3 [−5.9 to 32.6]	1.5 [−1.5 to 4.5]
Plasma T4 (nmol/L)
Patients	0.05 [−0.33 to 0.42]	−0.04 [−0.29 to 0.22]	−0.03 [−0.33 to 0.27]	−0.05 [−0.43 to 0.34]	−0.02 [−0.07 to 0.02]
Controls	0.04 [−0.26 to 0.33]	−0.05 [−0.28 to 0.18]	−0.05 [−0.23 to 0.14]	0.17 [−0.13 to 0.46]	0.03 [−0.01 to 0.07]
T4/T3 ratio (%)
Patients	0.03 [−0.37 to 0.42]	−0.09 [−0.36 to 0.17]	0.19 [−0.12 to 0.51]	−0.26 [−0.66 to 0.14]	−0.01 [−0.05 to 0.04]
Controls	−0.17 [−0.85 to 0.51]	−0.13 [−0.66 to 0.40]	0.03 [−0.39 to 0.45]	−0.04 [−0.73 to 0.65]	0.02 [−0.08 to 0.13]

Data are reported as β coefficient [confidence interval]. n = 30 in all groups, except carotid-femoral pulse wave velocity, which is n = 29. All associations are statistically non-significant.

Discussion

Long-term TSH-suppressive LT4 replacement therapy has been associated with increased arterial stiffness and increased cardiovascular mortality. We investigated patients treated with long-term LT4 replacement therapy targeting TSH in the reference range and found no indications of adverse effects on arterial stiffness and central hemodynamics.

The first major finding was that even though patients on LT4 replacement therapy were characterized by a significantly increased T4/T3 ratio, no significant differences in arterial stiffness or central hemodynamics were observed compared with age- and sex-matched controls. The second major finding was that arterial stiffness and central hemodynamics did not differ significantly across the three subtypes of thyroidectomized patients (non-toxic goiter, n = 10; toxic goiter, n = 17; and thyroid cancer, n = 3). Finally, no association was found between thyroid hormone levels and arterial stiffness and hemodynamic markers in the patients. In the controls, an inverse association between TSH levels and PWV was observed in the adjusted model.

Thyroid hormones have been shown to exert vascular effects through different pathways. T4, the major thyroid hormone secreted by the thyroid gland, is converted into T3 by iodothyronine deiodinases (ID). Type II ID provides local intracellular T3 and has been identified in VSM cells from both human aorta and coronary arteries regulating local T3 concentration (20,21). T3 has been found to induce VSM relaxation via direct effects in cultured aortic media (1) and via increased NO-mediated endothelial reactivity in patients with untreated hyperthyroidism (2). Conversely, decreased endothelial reactivity was observed in patients with untreated hypothyroidism (3). Thyroid hormones may also affect calcium deposits in the vascular wall (22) via the anti-calcifying matrix GLA protein (MGP) (23). MGP gene expression is upregulated by T3, and increased MGP levels were associated with reduced aortic calcification in rats (4).

Short-term treatment of hyper- and hypothyroidism have been shown to restore vascular reactivity and hemodynamics. Increased endothelial reactivity assessed by forearm strain-gauge plethysmography in eight patients with untreated hyperthyroidism was normalized six months after euthyroidism was restored (2). Similarly, increased augmentation index in 12 patients with untreated hypothyroidism was normalized after six months of LT4 treatment (6).

Data on short-term treatment effects on arterial stiffness in hyper- and hypothyroid patients are less clear.

Inaba et al. reported a significant reduction in common carotid artery stiffness in 27 Graves' disease patients after normalization of thyroid function (9), whereas increased arterial stiffness was observed in 47 patients with Graves' disease with ophthalmopathy who had been euthyroid for more than three months compared with 27 controls (10).

In 30 patients with hypothyroidism, increased baseline carotid arterial stiffness decreased to normal levels after a least one year of LT4 treatment (11). Dernellis et al. reported that in 15 normotensive hypothyroid patients, increased baseline aortic stiffness was normalized after a mean LT4 treatment period of nine months, whereas in 15 hypertensive hypothyroid patients, aortic stiffness was not normalized despite normalization of BP to lower levels than a control group (12). Increased baseline PWV was also normalized in 26 patients with severe hypothyroidism (defined as a TSH >70 IU/L) after six months LT4 therapy, but not in 15 patients with less severe hypothyroidism (TSH <15 mIU/L) (13).

The vascular effects of long-term LT4 replacement therapy have been sparsely investigated. Shargorodsky et al. found that TSH-suppressive therapy in 26 thyroidectomized patients with thyroid cancer treated with LT4 replacement therapy for a median of 6.7 years (range 3–21 years) was associated with significantly increased arterial stiffness in the patients compared with 26 controls of comparable age and sex distribution (14). T4 levels were higher and T3 level similar in the patients versus the controls (14). In a recent large Dutch retrospective cohort study of 524 patients with differentiated thyroid carcinoma and 1572 sex- and age-matched controls, TSH suppressive LT4 therapy was associated with a markedly increased cardiovascular mortality in the patients (hazard ratio 3.35 [CI 1.66–7.74]) during a median of 8.5 years of follow-up (15).

Thus, even though there is a clear need for prospective trials, these data suggest a potential harmful effect of LT4 used in suppression doses. However, the vast majority of patients are treated with LT4 replacement therapy targeting TSH in the reference range. The present study is the first to investigate the long-term effects of this treatment strategy, and the data do not indicate any adverse vascular effects as assessed by PWV and PWA indexes.

Strengths and limitations

The major strengths of the current study are the long duration of replacement therapy and the sex-and age-matched design. However, as this is a cross-sectional study, a cause–effect relationship cannot be established for the association between the thyroid hormones and the vascular indexes. Furthermore, current levels of thyroid hormones may not correlate closely with past levels and do not reflect temporal excursions in hormone levels during the treatment period. Analysis according to extent of surgery was not feasible, as detailed information regarding the surgical procedures was not available. A skewed distribution of diabetes and/or waist–hip ratio could potentially confound the between-group comparisons. However, data regarding these parameters were not available. Yet, adjustment for BMI did not affect the results. Lastly, a healthy survivor effect could confound the observed lack of association between thyroid hormone levels and vascular indices. However, this may be less likely, given that none of the patients or controls had a history of cardiovascular disease and the comparable distribution statin and antihypertensive use in patients and controls.

Conclusion

This study investigated patients treated with long-term LT4 replacement therapy targeting TSH in the reference range and found no indications of adverse effects on arterial stiffness or central hemodynamics.

Footnotes

Acknowledgments

The authors are indebted to the participants in the study that made it possible. The technical assistance of Lisa Buus, Merete Møller, Tove Stenum, Lisbeth Flyvbjerg, Christina Wiegers, Lene Sørensen, Mette Carstens, and Helle Thøgersen is greatly appreciated. This work was supported by Familien Hede Nielsens Fond, The Institute of Clinical Medicine, Aarhus, and The Danish Diabetes Academy supported by the Novo Nordisk Foundation.

Author Disclosure Statement

The authors declare no conflicts of interest regarding the publication of this paper.

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