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Original Studies |
Institute of Cardiology (G.M., M.G.P., A.B., M.L.) and Endocrinology, Department of Medical Sciences (R.C., L.P., F.P., S.M.), University of Cagliari, 09124 Cagliari, Italy
Address all correspondence and requests for reprints to: Prof. Giuseppe Mercuro, M.D., Institute of Cardiology, University of Cagliari, Via S. Giorgio 12, 09124 Cagliari, Italy. E-mail: mercuro{at}pacs.unica.it
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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O2
achieved at peak exercise (maximum O2, 17.3 ±
3.3 vs. 21.9 ± 2.5 mL/min·kg), and anaerobic
threshold (expressed as a percentage of O2max,
46.5 ± 8.4 vs. 56.2 ± 6.6) were
significantly reduced in L-T4-treated patients.
The L-T4 dose was then reduced to the minimal
amount able to keep the serum TSH concentration at 0.1 mU/L or less in
7 patients who were reevaluated 6 months after the initial study. This
individual tailoring of the TSH-suppressive
L-T4 dose was in all cases associated with
normalization of all echocardiographic and ergometabolic parameters. In
conclusion, our findings show that abnormalities of heart morphology
associated with impaired exercise performance occur as a consequence of
long term therapy with fixed TSH-suppressive doses of
L-T4, but that these abnormalities improve or
disappear after careful tailoring of TSH-suppressive therapy. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To further elucidate the role of TSH-suppressive therapy in the development of cardiovascular disturbances, we carried out a detailed clinical, echocardiographic, and ergometabolic study in a group of patients who had received a standard TSH-suppressive therapy using a fixed dose of L-T4. The study was then repeated in a subgroup of patients in whom the L-T4 dose was individually reduced to the minimum required to suppress the serum TSH concentration.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Nineteen consecutive patients (16 women and 3 men; mean ±
SD age, 44 ± 12 yr; range, 27–69 yr) who had
received long term TSH-suppressive
L-T4 therapy at a mean weekly dose of
950 ± 270 µg (range, 700-1575 µg) for a period of 5.7 ±
3.5 yr (range, 2–20 yr) were enrolled in the present study. This
dosage corresponded to a fixed L-T4
dose of 1.8–4.0 µg/kg BW, a regimen previously judged adequate on
the basis of suppressed serum TSH concentration (
0.1 mU/L) with a
normal serum free T3 (FT3)
concentration and absence of overt thyrotoxic symptoms. No patient
suffered from any known cardiovascular disease or took drugs other than
L-T4. None had taken any
nonprescription sympatholytic medication for at least 1 week before the
study. Ten patients were athyreotic after surgery for differentiated
thyroid carcinoma, 5 had undergone subtotal thyroidectomy for nontoxic
goiter, and 4 had been operated upon for diffuse or nodular nontoxic
goiter. The control group consisted of 19 healthy untrained volunteers
(15 women and 4 men) matched for age (41 ± 12 yr; range, 26–65)
and body mass index (BMI). Further details on patients and controls are
reported in Table 1
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Serum thyroid hormone concentrations were determined by commercially available kits: total T3 (TT3) and total T4 (TT4) were measured by RIA (RIA-MAT T3 and RIA-MAT T4, respectively, Byk-Sangtec Diagnostica Radim, Rome, Italy; normal values: TT3, 110–210 ng/dL; TT4, 4.9–12.0 µg/dL); FT3 and free T4 (FT4) were measured using a chromatographic method based on separation of the free hormone on Lisophase columns (Technogenetics, Milan, Italy; normal values: FT4, 6.6–16 pg/mL; FT3, 2.8–5.6 pg/mL); serum TSH was determined by a chemiluminescent method (Ortho-Clinical Diagnostics, Amersham Pharmacia Biotech, Aylesbury, U.K.; normal values, 0.3–3.0 mU/L) with a functional sensitivity of 0.0125 mU/L in our laboratory. Plasma norepinephrine (NE) was assayed in duplicate by high-pressure liquid chromatography with electrochemical detection (11); normal values in our laboratory were less than 350 pg/mL in the supine position and less than 500 pg/mL in the standing position.
Cardiovascular and ergometabolic study
The present study was approved by the ethical committee of our university, and all subjects gave informed consent before participation. Patients and controls first underwent an anamnestic interview (Symptom Rating Scale) for assigning a clinical score of thyroid hyperactivity as devised by Klein et al. (12). According to this test, a score of 20 or more is consistent with overt hyperthyroidism, and a score of 7 or less is consistent with a euthyroid condition. Patients and control subjects were familiarized with instrumentation, medical environment, and bicycle ergometer before testing. In the 2 days immediately preceding each experimental session, all subjects were asked to refrain from smoking and drinking alcohol or coffee and to abstain from severe physical exercise. Subjects reported to our laboratory at approximately 0900 h after a light breakfast and were weighed and measured. They spent at least 20 min (acclimatization period) lying in a quiet room at a controlled temperature of 20 ± 1 C and a relative humidity of 65 ± 10%. At that time, blood samples for circulating NE were obtained via a large median basilic vein of the left arm. Soon after, blood pressure (BP) measurement, standard 12-lead electrocardiogram (ECG), and M-Mode and two-dimensional echocardiography were performed. Echocardiographic studies were performed by a single experienced echocardiographer with an ultrasound apparatus Acuson 128XP/10c (Acuson, Mountain View, CA) and a 2.5-MHz transducer. Complete M-Mode, two-dimensional, and spectral and color Doppler recordings were made with subjects in the left lateral decubitus position using conventional parasternal and apical views, according to the standardization of the American Society of Echocardiography (13).We measured left ventricular (LV) end-diastolic dimension (EDD), interventricular septum thickness (IST) and LV posterior wall thickness (PWT) at the apex of the R wave of an ECG recorded simultaneously. We measured ejection fraction, LV mass index (LVMi) in accordance with the method of Devereux et al. (14). Pulsed Doppler transmitral flow was determined from a four-chamber apical view, with the sample volume placed at the level of the mitral valve leaflet tips. Peak velocities at early (E) and late (A) mitral inflows were measured, and then the E/A ratio was calculated. The isovolumic relaxation time (IVRT) was measured as the interval from the aortic component of the second sound to the onset of the E wave.
Nine subjects (seven women and two men; aged 39 ± 8 yr; range, 27–60) and the same number of controls matched for age, sex, and BMI underwent an integrated cardiopulmonary exercise test. They sat on a case 15 computer-driven, electronically braked bicycle ergometer (Marquette, Milwaukee, WI) for a minimum rest period of 5 min and breathed quietly via a mouth/face mask to stabilize resting gas measurements. Subjects then cycled at a constant pedal frequency of 60 rpm. After a 3-min warm-up at a low workload, each subject carried out incremental and uninterrupted upright exercise. The initial external work of 10 watts was increased by 10 watts/min. Both patients and control subjects were encouraged to continue as long as possible and reach muscular exhaustion.
Electrocardiograms were monitored continuously and recorded every
30 s both during exercise and during a 10-min postexercise
recovery period. Arterial BP was ascertained using a mercury
sphygmomanometer. BP measurements were obtained every 3 min during
exercise and at the first, fifth and tenth minute of recovery.
Breathing rate (f), minute ventilation (Ve), oxygen consumption
(o2), and carbon dioxide production
(Vco2) were determined on a breath by breath
basis with a Medical Graphics System 2000 (Medical Graphics Corp., St.
Paul, MN). Before each test, the system was calibrated using a fixed
concentration of standard gases. Peak O2
consumption was defined as the highest value of
O2 achieved at the end of exercise
(maximum O2). Anaerobic threshold (AT) was
determined by means of a combination of multiple graphs. Finally, we
calculated the increase in O2 relative to
increase in work rate (
o2/WR), a
measurement used to estimate the amount of O2
used during incremental exercise in relation to the quantity of
external work performed.
Longitudinal study after individual tailoring of L-T4 dose
In a group of seven patients (five women and two men; mean ± SD age, 43 ± 11 yr; range, 27–60 yr), L-T4 was individually reduced so that from the initial fixed dose of 1.8–4.0 µg/kg (mean weekly dose, 1030 ± 293 µg; range, 700-1400 µg) the tailored dose of 1.6–3.1 µg/kg (mean weekly dose, 870 ± 180 µg; range, 650-1100) was reached. This was obtained by progressive lowering of the L-T4 dose until the serum TSH concentration reached values above 0.1 mU/mL, followed by a careful increase in L-T4 until serum TSH remained steady at 0.1 mU/mL or less. Echocardiographic measurements and ergometric sessions were then repeated 6 months after the basal evaluation.
Data analysis
Data are reported as the mean ± SD. Comparisons were made between the whole group of patients under TSH-suppressive L-T4 treatment at the time of enrollment and matched controls. In the patient cohort in whom individual titration of L-T4 was performed, the basal data for L-T4 were compared to those obtained after individualization of the dose. Differences between means were assessed using Student’s t test for paired data. All P values calculated are two-tailed and considered significant at P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Selected biophysical and clinical characteristics and the serum
thyroid hormone and TSH concentrations of patients and controls are
reported in Table 1
. No significant differences were revealed between
the groups with regard to age, BMI, or resting BP. The mean resting
heart rate of the study patients was slightly higher than that of the
normal subjects, although the difference was not statistically
significant. Patients submitted to TSH-suppressive therapy displayed a
significantly higher thyrotoxic score than euthyroid controls (9.6
± 3.7 vs. 5.3 ± 2.6; P < 0.01),
mostly due to the presence of palpitations and anxiety.
Individual FT3 values were always within the
normal range, and no significant difference was observed between the
means of patients and controls (Table 1). In contrast, as also shown in
Table 1, the mean FT4 concentration was
significantly higher in L-T4-treated
patients, and serum levels above the normal range (>16 pg/mL) were
observed in 5 cases. The serum TSH concentration was 0.1 mU/mL or less
in all cases, but was still measurable (0.03–0.1 mU/mL) in 14 patients
due to the high sensitivity of the assay.
Instrumental investigations
The ECG was normal in all patients receiving TSH-suppressive
therapy. The most significant morphological and functional
echocardiographic parameters observed in patients and controls are
shown in Table 2. We found a significant
increase in IST (P < 0.01), LVPWT (P
< 0.01), and LVMi (P < 0.01) in patients compared to
euthyroid controls, although no patient showed changes meeting criteria
for myocardial hypertrophy. Moreover, LVEDD was increased in patients
compared with controls (P < 0.05); the ejection
fraction did not show significant differences between the two groups.
In the patient group, IVRT was significantly prolonged
(P < 0.05). The E/A ratio remained unchanged. When the
results obtained in the subgroup of five patients with
FT4 above 16 pg/mL were separately analyzed and
compared to those of the remaining patients, no significant differences
were found for any of the parameters examined (data not shown).
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The subgroup of nine patients who were ergometrically tested
(Table 3) did not differ from respective
controls in heart rate. However, their mean systolic BP was higher than
that of the entire TSH-suppressed group (P < 0.05),
yielding a higher heart rate x SBP product (double product;
P < 0.05). Ventilation parameters (f, Ve, and
O2) measured at rest in the seated
position on the bicycle ergometer did not differ in the two groups.
Patients taking L-T4
displayed a significantly decreased effort tolerance, with lower
maximal workload than healthy controls (102 ± 14 vs.
117 ± 12 watts; P < 0.05). ECG findings obtained
during exercise were normal in all patients except in a 44-yr-old woman
who manifested an upright deflection of the S-T segment of ECG
in V5-V6 at the peak of
exercise without symptoms. All examined patients and controls exceeded
90% of the predicted maximal heart rate (96 ± 7% and 95 ±
2%, respectively) and were stopped for physical exhaustion. The mean f
and Ve at peak o2 utilization were higher
in patients taking L-T4
than in controls, but were not significantly different. In contrast, a
significant reduction of the maximum O2
and a lowering of the AT (expressed as a percentage of the theoretic
O2max) were found (P <
0.01 and P < 0.05, respectively; Table 3). Finally,
o2/WR was significantly lower in
patients than in controls (P < 0.05).
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Figure 1 shows plasma NE
concentrations measured at rest in the recumbent and standing positions
in patients and controls who underwent the ergometabolic test. NE
concentrations were significantly lower in TSH-suppressed patients in
both supine (102 ± 29 vs. 165 ± 35 pg/mL;
P < 0.01) and standing (175 ± 29 vs.
320 ± 41 pg/mL; P < 0.01) positions in
comparison with the euthyroid controls.
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Serum FT3, FT4, and TSH
concentrations before and after individual reduction of
L-T4 dose are reported in Table 4. Although the serum TSH concentration
remained at 0.1 mU/L or less in all cases, the reduction in
L-T4 dose was associated with a
slight, but significant, increase in the mean serum TSH concentration.
In contrast, no significant change was observed in serum
FT3 and FT4. As shown in
Fig. 2, individual titration
of the L-T4 dose was associated with
a significant improvement in the thyrotoxic score (from 12.8 ±
2.4 to 9.9 ± 2.8; P < 0.005). Reduction of the
L-T4 dose produced a change
in echocardiographic parameters. In particular, systolic indexes,
significantly decreased after
L-T4 dose adjustment
[LVMi, from 105 ± 19.5 to 88 ± 17.0
g/m2 (P < 0.010; LVEDD, from
46.4 ± 3.1 to 43.0 ± 3.0 mm (P < 0.05);
IST, from 10.0 ± 1.0 to 8.9 ± 1.0 mm (P <
0.005); LVPWT, from 8.9 ± 1.1 to 8.2 ± 0.8 mm
(P < 0.05)]. A nonsignificant improvement in
diastolic function, as assessed by shortening of IVRT, was also
observed after decreasing the
L-T4 dose (from 93 ±
13 to 84 ± 12 ms; P = NS). The response of
ergometabolic parameters to individual titration of
L-T4 displayed a
significant increase in maximal workload, achieved after 6 months of
individual dose tailoring (mean increase, 17.7 ± 5.4%;
P < 0.05). At that time, maximum
O2 and AT were increased [from 19.4
± 5.0 to 22.2 ± 5.6 mL/min·kg (P < 0.005) and
from 47 ± 7% to 57 ± 6% (P < 0.001),
respectively] and were no longer different from the respective values
recorded in control subjects (Fig. 3).
Circulating NE was not significantly increased by individually tailored
compared to fixed doses of
L-T4 [supine, 135 ±
40 vs. 110 ± 28 pg/mL (P = NS);
standing, 243 ± 52 vs. 181 ± 39 pg/mL
(P = NS)].
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TSH-suppressive therapy has also been found to be associated with mild
thyrotoxic symptoms (6), as assessed by standardized questionnaires
(12). To investigate further the basis for these symptoms, we carried
out investigations of the responses to physical exercise in
L-T4-treated subjects. Our patients
showed decreased exercise tolerance with lower maximal workload
compared to healthy controls. Clinical symptoms of poor exercise
capacity resulted in early exertional dyspnea and discomfort before
reaching peak exercise and maximum o2. In
addition, a lower AT was observed in subjects receiving fixed
L-T4 suppressive therapy compared to
normal controls. AT represents the exercise level above which aerobic
energy production is supplemented by anaerobic mechanisms. An early
occurrence of the latter in our patients seems to suggest an
anticipated beginning of the anaerobic phase of isotonic exercise.
Moreover, the peak o2 was decreased,
suggesting that the response to exercise was associated with an
impaired maximal aerobic function. Finally, patients showed lower
ratios of the increase in o2 consumption
to the increase in work rate. This together with the earlier AT and the
lower peak o2 during
L-T4 treatment suggest an unusually
high anaerobic contribution to exercise. These abnormalities are
milder, but similar to those recently found in hyperthyroid patients
(17, 18), in whom an impairment of the aerobic metabolic component of
exercise occurs. On the basis of our findings, it is difficult to
address questions about the pathophysiology of disorders limiting
exercise during TSH-suppressive therapy. A possible interpretation is
that diastolic dysfunction, which we found in our patients at rest, may
cause per se a systolic impairment during exercise, with the
inability to raise muscle blood flow for satisfying metabolic
requirements (19). We also observed a trend to an altered breathing
pattern with an increase in f and Ve either at rest or during exercise.
However, the changes in these parameters did not reach statistical
significance. Again, this trend recalls the alterations in Ve found in
hyperthyroid patients (17), in whom an increase in f, sometimes
associated with a reduced tidal volume, may be attributed both to an
increased tissue metabolism and to the acknowledged myopathy of
respiratory muscles induced by an excess of T3
(20).
It should be underlined that these alterations in cardiovascular and pulmonary function cannot be attributed to higher circulating catecholamine concentrations. During long term L-T4 TSH-suppressive therapy, we observed a significant reduction in plasma levels of NE in both basal and stimulated conditions. Our findings are again in keeping with previous reports of low NE levels in overt hyperthyroidism (21).
When TSH-suppressive L-T4 therapy is individually tailored to the lowest dose required to keep the serum TSH concentration below the normal range, it has been reported that there are no detectable cardiovascular abnormalities, with the possible exception of a very mild increased ventricular mass (10). Our study results confirm and extend those findings, showing a clear improvement in several cardiovascular parameters, including a significant increase in maximal workload and reversal of all impaired ergometabolic derangements. The reduction of the L-T4 dose was also associated with an improvement of the clinical thyrotoxic score, although the score remained substantially higher than that in controls. This was presumably due to the higher basal mean score (12.8 vs. 9.6) observed in the seven patients in whom the longitudinal study was performed. The reason for this selection bias is unclear, but as patients were chosen on the basis of spontaneous agreement, it is conceivable that this was at least partially due to the presence of higher basal thyrotoxic symptoms.
In conclusion, the present study shows that TSH-suppressive therapy with L-T4 can cause symptoms, modifications in myocardial structure, and altered cardiopulmonary function, primarily during physical activity. However, careful adjustment of the L-T4 dose can reverse and almost completely normalize cardiopulmonary function parameters and significantly reduce thyrotoxic symptoms, while still maintaining TSH suppression at 0.1 mU/L or less. The recognition of these problems provides the basis for suggesting a lower degree of TSH suppression in patients with benign thyroid disease and in those with low risk differentiated thyroid cancer, leaving the full serum TSH suppression to patients with a high risk of thyroid cancer. Finally, in cases where individual tailoring is not possible, other alternative strategies (e.g. ß-blockers) (6) can be envisaged in patients with thyroid cancer requiring full TSH suppression. On the basis of these observations, we conclude that TSH-suppressive therapy with L-T4, when individually tailored, prevented in our patients cardiac anatomical and functional modifications that are generally considered to represent a risk factor for cardiovascular morbidity.
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Acknowledgments |
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Received April 12, 1999.
Revised July 22, 1999.
Accepted September 17, 1999.
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References |
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