Coronary Vasoreactivity in Subjects with Thyroid Autoimmunity and Subclinical Hypothyroidism Before and After Supplementation with Thyroxine

Abstract

Background:

The association of subclinical hypothyroidism (SCH) with increased risk for cardiovascular disease is still controversial. This study aimed to examine coronary vascular reactivity by positron emission tomography (PET) in asymptomatic patients with SCH before and after levothyroxine (LT4) supplementation.

Methods:

Ten patients (7 women and 3 men; mean age 43±15 years) with untreated autoimmune SCH, defined by elevated levels of thyroid-stimulating hormone (mean TSH: 16.9±11.3 μU/mL), normal levels of free thyroxine (0.9±0.1 μg/mL), free triiodothyronine (3.2±0.4 pg/mL), and positive thyroid peroxidase antibodies were studied. Eight euthyroid subjects with similar low-risk cardiovascular risk profile served as controls. Myocardial blood flow (MBF) and coronary flow reserve (CFR) were quantitatively assessed with rest/stress N-13 ammonia PET at baseline and after 6 months of LT4 replacement therapy (given only to patients).

Results:

At baseline, stress MBF and CFR corrected (c) for rate pressure product (RPP) and myocardial vascular resistance (MVR) during stress were significantly reduced in SCH compared with controls (stress MBF: 2.87±0.93 vs. 4.79±1.16 mL/g/min, p=0.003; CFR: 2.6±0.73 vs. 4.66±1.38, p=0.004; MVR: 40.14±18.76 vs. 20.47±6.24 mmHg/mL/min, p=0.02). Supplementation therapy with LT4 normalized TSH in all subjects and was associated with an increase in CFR (2.6±0.73 vs. 3.81±1.19, p=0.003) and with a tendency toward a decrease in MVR. Differences in CFR between SCH and controls were also seen after correction of resting MBF for RPP.

Conclusions:

In asymptomatic subjects with SCH due to thyroid autoimmunity, coronary microvascular function is impaired and improves after supplementation with LT4. This may partially explain the increased cardiovascular risk attributed to SCH.

Introduction

S ubclinical hypothyroidism (SCH), defined as an elevated serum thyroid-stimulating hormone (TSH) but normal free thyroid hormone level, occurs in 5%–15% of the general population (1,2), and is most prevalent in elderly women (3,4). Thyroid hormone acts on the heart and peripheral vasculature in multiple nongenomic and genomic ways (5,6).

It may enhance cardiac output via direct effects on the heart by increasing contractility (7) and heart rate (8) and via indirect effects on peripheral vascular resistance (9,10). SCH has been associated with dyslipidemia (11), left ventricular diastolic dysfunction at rest (12), impaired systolic dysfunction on effort (13), increased incidence of coronary atherosclerosis, and myocardial infarction (14,15). Despite some evidence that SCH increases cardiovascular risk, the need of lifelong treatment with levothyroxine (LT4) is controversial (16,17), since most intervention studies were of short duration, noncontrolled, and small in sample size.

Positron emission tomography (PET) has emerged as the most sensitive technique for the noninvasive quantification of myocardial blood flow (MBF) and coronary flow reserve (CFR) (18). N-13 ammonia PET has been used to document an impaired CFR in patients with cardiovascular risk factors and a familiar history of coronary artery disease (CAD) (19 –22), as well as for the monitoring of therapeutic interventions (23 –26).

The aim of this study was to investigate MBF regulation at rest and during pharmacological stress as a marker of coronary vasoreactivity in asymptomatic patients with SCH due to autoimmunity at baseline and to assess the effects of a 6 month course of LT4-supplementation therapy.

Materials and Methods

Patients

Ten patients with SCH due to Hashimoto thyroiditis, evidenced by antithyroid peroxidase (TPO) antibodies (confirmed at least once) from our thyroid disease clinic in the Department of Nuclear Medicine of the University Hospital of Vienna, were enrolled in this study. Baseline characteristics are summarized in Table 1. Subjects with a positive stress test or known CAD, untreated and uncontrolled hypertension (>140/90 mmHg), familial hypercholesterolemia, chronic obstructive pulmonary disease, asthma, or diabetes mellitus were excluded from the study. Three patients with SCH and two controls had suffered from borderline hypertension but were adequately controlled by life-style modifications (weight control and dietary salt restriction) before the study. Six of 10 patients (age ranging from 25 to 70 years) had mild untreated SCH (TSH>5 μU/mL, confirmed twice), and 4 patients (1 man and 3 women, age ranging from 35 to 55 years) severe SCH (TSH: 18 to 34 μU/mL, confirmed twice) diagnosed 6 to 12 weeks before initiation of therapy. The median duration of untreated SCH as evidenced by first available clinical chemistry report was 4 months with a range from 2 to 9 months. Two patients had a history of slight fatigue; the remainder were asymptomatic. Smoking habits, body mass index, as well as medical history and concomitant medication were recorded. Blood pressure was assessed as the average of 2 measurements at separate visits in supine position at rest and 2, 4, 6, and 20 minutes after starting adenosine during the stress study. Serum total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, and triglycerides were determined according to standardized methods. Hypercholesterolemia was defined as total cholesterol>5.2 mM. Eight subjects with atypical chest pain, confirmed by negative coronary angiography and a similar cardiovascular risk profile but no history of thyroid disease, served as controls for the baseline PET evaluation. Written informed consent was obtained from all study participants of the approved protocol. The study was in accordance with the Declaration of Helsinki. PET studies were performed in premenopausal women only after a negative pregnancy test.

Table 1.

Demographic Data of 10 Patients with Subclinical Hypothyroidism and Positive Antithyroid Peroxidase Autoantibodies and 8 Controls

	N (%) or mean±SD (median; range)
Variable	SCH	Controls	p-value
Age (years)	43±15	49±11	n.s.
Gender (f/m)	7/3	2/6	n.s.
Body mass index	25±2	24±1	n.s.
Smoking	4/10 (40%)	2/8 (25%)	n.s.
Diabetes mellitus	0/8	0/8	n.s.
Uncontrolled hypertension	0/10	0/8	n.s.
Hypercholesterolemia	5/8 (56%)	3/8 (38%)	n.s.
TSH (μU/mL)	16.9±11.3	1.24±0.5	0.0006
FT4 (μg/mL)	0.9±0.1	1.12±0.2	0.01
FT3 (pg/mL)	3.2±0.4	3.7±0.5	0.04

SD, standard deviation; SCH, subclinical hypothyroidism; TSH, thyroid-stimulating hormone; n.s., not significant; FT4, thyroxine; FT3, triiodothyronine.

Thyroid examination

Thyroid palpation, sonography, and Tc-99m thyroid scintigraphy with measurement of thyroid hormones, TSH, and TPO autoantibodies were performed in all patients. For the quantitative measurements of non-protein-bound thyroxine (fT4) and triiodothyronine (fT3) IMMULITE^® 2000 Free T4 and IMMULITE 2000 Free T3 (EURO/DPC, Gwynedd LL55 4EL) were used. Serum levels of TSH, and TPO autoantibodies were measured using IMMULITE 2000 Third Generation TSH and IMMULITE 2000 Anti-TPO (EURO/DPC, Gwynedd LL55 4EL).

Rest/stress N-13 ammonia PET

SCH patients underwent a rest/stress N-13 PET at baseline and a second rest/stress N-13 PET after 6 months of LT4-supplementation therapy (0.15–0.5 mg/day) targeted to TSH levels between 1 and 2 μU/mL.

PET imaging protocol

All medication was stopped more than 12 hours before examination. PET imaging was performed using a whole-body PET scanner (Advance, General Electric Medical Systems). Dynamic N-13 ammonia PET scanning and image processing was performed for the noninvasive evaluation of regional and global MBF and quantification of CFR as previously published (19). After placement of the patient in the scanner and performance of a scout scan for localization of the heart, a 20-minute transmission scan was acquired for correction of photon attenuation. All patients underwent 2 emission scans each lasting∼20 minutes. A median dose of 800 MBq N-13 ammonia was injected as a slow bolus through an indwelling venous cannula followed by a saline flush and immediate dynamic imaging (12×10 seconds, 6×30 seconds, and 3×300 seconds). To allow for sufficient decay of N13 activity (physical half-life: 9.9 minutes) to>3% of the original activity, a break of at least 50 minutes was made between the rest and the stress study. For the stress studies adenosine was applied as previously reported (19).

Data processing

Using the transmission scan, both rest and stress data were corrected for attenuation. Transaxial images were reconstructed using filtered backprojection. Vertical and horizontal cardiac long-axis angles were defined and used subsequently in the volumetric analysis for three-dimensional reorientation of all frames into 12 images in the short-axis view of the heart (thickness 0.8 cm).

Image analysis and calculation of MBF

For analysis of PET data a method employing automated region definition was used (21). The algorithm automatically defines myocardial regions of interest based on radial activity profiles including a blood volume fraction of ∼50%. This definition allows for correction of in-plane partial volume effects and tissue cross contamination in the model equation. The volumetric motion-tracking algorithm is used to delineate the myocardial contours from a late frame toward the earlier time points. After extraction of those motion-corrected time activity curves, numerically efficient nonlinear fitting algorithms estimate the partial volume-corrected MBF with user-selective spatial resolution. For the calculation of MBF the tracer kinetic model for N-13 ammonia developed by Hutchins was used (18). This model allows for precise calculation of myocardial perfusion as previously documented (27). By using a range of starting values for those parameters depending on a priori information, the overall stability was improved. The resulting MBF values are stored in polar maps that are spatially co-registered for a stress/rest protocol. Estimates of regional MBF were derived from the relationship of K1 to the tissue extraction fraction (EF): K1=MBF × EF. Based on experimental data by Schelbert et al. the initial extraction fraction has been shown to be <90%, even for flow values up to 5 mL/g/min (28). Therefore, MBF can be expressed as follows: MBF NH3 (in mL/g/min)=K1 (in mL/g/min). The quantitative polar maps for K1 were analyzed globally or divided into three myocardial regions each in 21 subjects. Baseline resting and stress MBF values are given as raw data and the former corrected for rate pressure product (RPP). CFR is defined by the difference in blood flow at rest compared with maximum coronary vasodilation. CFR was calculated as the ratio of segmental stress MBF divided by corresponding rest MBF in polar map analysis.

Calculation of myocardial vascular resistance and RPP

Myocardial vascular resistance (MVR) and RPP were calculated by dividing the mean blood pressure [2×(DBP+SBP)/3] by MBF, where DBP and SBP are diastolic and systolic blood pressure, respectively. Stress BP values obtained 2 minutes after start of adenosine infusion were used to calculate MVR. As there were no clinical symptoms indicating an increased central venous pressure in the subjects, we assumed the possible influence of right atrial pressure on MVR to be negligible.

Statistical analysis

We estimated that eight patients and eight controls would need to be enrolled to achieve an 80% power to detect a difference in CFR of 1.5 between patients and controls, assuming a standard deviation of 0.8 in each group, using t-test and a two-sided significance level of 0.05. For all continuous variables, means and standard deviations were calculated. Hemodynamic variables and MBF before and after LT4 supplementation were compared within the group in rest and stress conditions and between the groups using student's t-test. Fisher's exact test was used for categorical variables. Linear regression analysis was performed to evaluate the relationship between thyroid function, age, MBF, CFR, and lipid parameters. A p-value of <0.05 was considered statistically significant.

Results

Cardiovascular risk factors and thyroid hormones under LT4 supplementation

The cardiovascular risk profile of the participants is detailed in Table 1. After a 6-month LT4 supplementation, TSH, fT4, and fT3 were in normal range. Cholesterol, LDL cholesterol, and HDL cholesterol were not significantly altered (Table 2).

Table 2.

Thyroid Hormones, Lipid Profile, and Hemodynamics of Patients with Subclinical Hypothyroidism Before and After Levothyroxine-Supplementation Treatment and in Comparison to Controls

	SCH				Comparison of subjects with SCH and controls
	Before LT4	After LT4	p-value	Controls	p-value before LT4	p-value after LT4
TSH (μU/mL)	16.9±11.3	1.85±1.0	0.001	1.24±0.5	0.0006	n.s
FT4 (μg/mL)	0.9±0.1	1.5±0.4	0.001	1.12±0.2	0.01	n.s.
FT3 (pg/mL)	3.2±0.4	3.9±0.4	0.01	3.7±0.5	0.04	n.s.
LDL cholesterol (mg/dl)	141±39	133±25	n.s.	114±22	n.s.	n.s.
HDL cholesterol (mg/dl)	46±7	49±11	n.s.	55±11	n.s.	n.s.
Triglycerides (mg/dl)	225±44	164±111	n.s.	194±31	n.s.	n.s.
HR rest	63±20	67±10	n.s.	68±11	n.s.	n.s.
DBP rest	86±8	79±8	0.04	75±7	0.01	n.s.
SBP rest	141±20	126±17	0.03	119±16	0.04	n.s.
RPP rest	7539±1447	6456±1165	0.001	6064±1571	n.s.	n.s.
HR stress	93±13	89±15	n.s.	92±14	n.s.	n.s.
DBP stress	83±8	78±11	n.s.	78±10	n.s.	n.s.
SBP stress	141±21	129±23	0.04	121±20	n.s.	n.s.
RPP stress	9557±2166	8783±2030	n.s.	8642±2498	n.s.	n.s.
% change	31±11	33±19	n.s.	39±10	n.s.	n.s.

HR, heart rate; DBP, diastolic blood pressure (mmHg); RPP, rate pressure product; LT4, levothyroxine; LDL, low-density lipoprotein; HDL, high-density lipoprotein; SBP, systolic blood pressure (mmHg).

PET studies

Baseline PET studies could be evaluated in 9 of 10 patients and were compared to controls. In one subject scintigraphic information could not be completed for technical reasons. Comparison of PET data before and after LT4 supplementation was available in 8 patients. One patient could not finish the follow-up study because of claustrophobia.

Hemodynamic response to pharmacological stress in patients and controls

Differences between patients and controls as well as changes in hemodynamic responses to pharmacodynamic stress in patients before and after LT4 supplementation are shown in Table 2.

MBF and CFR before and after LT4 supplementation

Noncorrected MBF

At baseline, stress MBF and CFR were significantly reduced in patients with SCH compared with controls (stress MBF 2.87±0.93 vs. 4.79±1.16 mL/mg/min, p=0.003; CFR: 2.6±0.73 vs. 4.66±1.38, p=0.004). These differences were not seen after LT4 supplementation. Furthermore, CFR increased significantly (2.6±0.73 vs. 3.81±1.19, p=0.003), mainly due to the increase in stress MBF (stress MBF 2.87±0.93 vs. 3.69±1.34 mL/100 g/min, n.s.) after hormone replacement therapy. For further details see Table 3.

Table 3.

Myocardial Blood Flow, Coronary Flow Reserve, and Myocardial Vascular Resistance in Patients with Subclinical Hypothyroidism Before and After Levothyroxine Therapy and Controls

	SCH
	Before LT4	After LT4	p-value	Controls	p-value before LT4	p-value after LT4
MBF rest	1.09±0.32	1.07±0.29	n.s.	1.07±0.31	n.s.	n.s.
MBF stress	2.87±0.93	3.69±1.34	n.s.	4.79±1.16	0.003	n.s.
CFR	2.6±0.73	3.81±1.19	0.003	4.66±1.38	0.004	n.s.
MBFc rest	1.21±0.49	1.33±0.54	n.s.	1.11±0.44	n.s.	n.s.
CFRc	2.53±1.15	3,52±1,08	0.043	5.26±2.64	0.01	n.s.
MVR rest	106.00±26.58	96.1±20.47	n.s.	94.35±39.36	n.s.	n.s.
MVR stress	40.14±18.76	29.4±4.75	n.s.	20.47±6.24	0.02	n.s.

MBF, myocardial blood flow (mL/g/min); CFR, coronary flow reserve; MBFc, myocardial blood flow corrected for RPP; CFRc, coronary flow reserve (MBF stress divided MBF at rest corrected for rest RPP); MVR, myocardial vascular resistance (mmHg/mL/min).

MBF corrected for RPP

At baseline, stress MBF and global CFRc were significantly reduced by 35% and 46% compared with controls (CFRc 2.53±1.15 vs. 5.26±2.64, p=0.01). After LT4 supplementation, CFRc increased significantly by 24% in patients (CFRc 3.52±1.08, p=0.043).

Five patients presented with an abnormal CFRc (cut-off 2.5) before LT4 treatment with normalization in 2 patients after LT4-therapy.

Segmental analysis per vascular territory

Overall, no significant differences in regional CFR or stress MBF were detected. None of the patients exhibited a significant difference (exceeding 2 SD) between any of three vascular territories analyzed, which would strongly indicate CAD with stenosis of hemodynamic relevance.

MVR before and after LT4 supplementation

Rest/stress MVR was increased in SCH by 12% and by 96% (p=0.02), respectively, compared with controls. Comparison of MVR before and after LT4 supplementation showed a decrease by 10% and 27%, respectively (see Table 3).

Correlation analysis between thyroid function, MBF, CFR, and cardiovascular risk factors

Neither baseline TSH nor peripheral free hormones were significantly related to rest or stress MBF or CFR. After LT4 supplementation there was a weak relation between the increase in fT3 levels and (i) the improvement in CFR (r=0.539; p: n. s.) and (ii) a decrease in resting MBF (r=0.559, p: n. s.). No significant correlations were found between lipids, lipoproteins, or BMI and rest or stress MBF or levels of thyroid autoantibodies. Among observed changes in thyroid hormones and lipoproteins, the closest relation was found between the increase in fT3 levels and the increase in HDL (r=0.66; p: n.s.)

Neither change in blood flow parameters was significantly related to changes in lipid or lipoprotein levels. The LDL/HDL ratio was weakly associated with an improvement of CFR (r=0.49, n.s.).

Discussion

The importance of SCH as a risk factor for cardiovascular disease is still controversial. The Rotterdam study suggested that in an aging female population, SCH is independently associated with aortic atherosclerosis and with an increased incidence of myocardial infarction (14). However, decreased survival benefit was reported in another study in elderly patients (>80 years) with mildly elevated TSH (29). This report raises the possibility that at least in older cases, LT4 supplementation or rather normalization of TSH may not have survival benefit, and the opposite may be the case (30,31). A recent meta-analysis also showed a higher cardiovascular risk in younger individuals with SCH (32), supporting the concept that LT4 replacement should be considered in the younger patients with SCH (16). Another randomized, cross-over trial in a large population of patients has also shown that LT4 supplementation in SCH subjects led to a significant improvement in cardiovascular risks (33). It is notable that our study population consisted of young to middle-aged individuals with SCH, a target population for pharmacological intervention with LT4 supplementation. However, due to the inconsistent reports and the large numbers of populations afflicted by SCH, there is an urgent need for further clarification of adverse effects of SCH on cardiovascular system and their reversibility.

There are multiple mechanisms by which SCH may increase cardiovascular risk. This study demonstrates the presence and partial reversibility of abnormal coronary microvascular reactivity in SCH due to Hashimoto thyroiditis. Patients with SCH showed a marked impairment of CFR that was attributable to an attenuated increase in MBF and increased vascular resistance during adenosine stress. It is important to state that quantitative perfusion myocardial imaging under pharmacological stress with adenosine is an integrated marker of both epicardial and resistance vessel reactivity, while cold pressure testing reflects endothelial function only. An altered vascular reactivity is a key event in early atherosclerosis and precedes the development of obstructive lesions (34). During the last years, evidence has accumulated on the nongenomic and genomic effects of T3 on the regulation of cardiac function and cardiovascular hemodynamics (5,6). Many studies stress the role of T3 in decreasing systemic vascular resistance by relaxation of vascular smooth muscle cells via nongenomic action (35).

Our findings fit to these experimental and clinical data on the importance of thyroid hormones in the regulation of vascular reactivity by demonstrating altered vascular reactivity in SCH.

Some studies reported the presence and reversibility of endothelial dysfunction or vascular reactivity in SCH mostly by employing Doppler echocardiographic methods (36 –38). Biondi et al. reported signs of endothelial dysfunction in patients with SCH by using color Doppler visualization of coronary flow in the distal left anterior descending artery before and after cold pressure testing. In contrast, PET imaging representing one of the most accurate noninvasive methods of quantification of MBF offers the unique opportunity to quantify MBF both globally and regionally in defined myocardial segments.

The studies by Lekakis et al. and Taddei et al. reported an impaired endothelium-dependent vasodilation not only in SCH (39,40) but also in patients with high-normal serum TSH (39). Of note, our findings of an altered vascular reactivity were seen in patients with more severe forms of SCH, since mean TSH levels exceed 10 μU/mL by far.

As in another study, abnormal flow-mediated vasodilation was not related to the presence of dyslipidemia (40). Our findings suggest that possible changes in blood lipids in patients with SCH do not explain the finding of disturbed coronary microvascular function. Potential pathological mechanisms involved in this process relate to impairment in coronary microvascular reserve, which are supported by the finding of an increase in MVR during stress in SCH patients compared to controls. This, in turn, may be caused by an increase in left ventricular mass and/or increased collagen content as suggested by previous studies (13,41).

Some studies have shown that SCH is associated with a reduced cardiac output and an increase in systemic vascular resistance, and that these abnormalities were significantly improved after LT4 supplementation (42). However, our measurements were restricted to the assessment MVR but not systemic vascular resistance.

Hypertension is associated with an abnormal coronary vasoreactivity (43,44). The finding of a relationship between blood pressure regulation and thyroid hormone concentration has been demonstrated in subjects with normal thyroid function (45) and SCH (42). In concordance, our patients with SCH exhibited significantly higher DBP and SBP than controls with corresponding alterations in circulatory hemodynamics as indicated by an increased MVR. However, it is notable that alterations in stress MBF and CFR persisted after normalization of hemodynamic differences in RPP and were more pronounced than previously found in (borderline) hypertensive patients in studies also employing PET methodology (43,44). Thus, in patients with SCH, alterations in MVR may partially be related to changes in blood pressure regulation. Whether impaired vasoreactivity can be already detected in subjects with high-normal TSH levels exhibiting altered blood pressure homeostasis remains to be elucidated.

Our findings seem to be independent of lipid levels as baseline cholesterol was not different from controls and cholesterol levels did not change significantly after a mean of 6 months of LT4 supplementation in patients either. Therefore, neither baseline lipid levels nor the small decrease in total cholesterol under hormone replacement therapy was related to stress MBF and CFR.

In five patients an abnormal CFR (cut-off 2.5) was found, which was normalized in two patients under hormone replacement therapy. Concomitantly, SBP and stress MVR dropped significantly, while DBP did not. It is not unlikely that CFR could have been normalized in more patients if the interval between both PET studies had been longer. There is evidence that lipid lowering by statins causes substantial improvements in myocardial vascular reactivity with a latency of about 6 to 9 months (46). LT4 supplementation causes small improvements in lipid parameters (47,48) and blood pressure regulation, and therefore it might take much longer to improve coronary vasoreactivity. Alternatively, the incomplete reversibility of impaired vasoreactivity in our study could be due to a prolonged history of SCH causing irreversible structural abnormalities in the heart and vessel wall or represent an age-related effect. In fact, the abnormal CFR did not change in two of three patients aged>50 years, while the CFR did completely recover in a 35-year-old male patient with a maximum TSH of 34 μU/mL in the presence of normal thyroxine and triiodothyronine levels.

Limitations

Our small but well-defined study group was confined to those with SCH due to thyroid autoimmunity. Most of our asymptomatic study patients had a very low pretest probability of CAD. Although the presence of subclinical CAD cannot be ruled out, it is very unlikely to be the reason for an abnormal CFR compared with control subjects with a similar cardiovascular risk profile.

Although the study population was large enough to detect significant differences in vascular reactivity between patients and controls, the sample size is too small to demonstrate the extent of their reversibility.

Clinical Implications

This study supports the strategy of identifying subjects with SCH due to thyroid autoimmunity because of their increased cardiovascular risk. Current guidelines for SCH focus on case finding in premenopausal females in whom its prevalence is up to 15%. Supplementation with LT4 is recommended in this patient population since conversion rate into manifested hypothyroidism is high and for the prevention of deterioration in atherogenic lipoprotein metabolism. Furthermore, SCH is associated with altered hemodynamics as evidenced by an increased MVR. However, the need of lifelong treatment with LT4 is still debated (17). Although there is no consensus on which subjects with SCH should receive supplementation therapy (49,50), the data of our study support previous (16,32) findings that LT4 replacement may have more potential benefit in younger SCH patients who are at the risk of microvascular coronary disease. Future research should focus on the long-term cardiovascular effects of LT4 supplementation by employing randomized clinical end-point trials.

Footnotes

Author Disclosure Statement

The authors declare that no competing financial interests exist.

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