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Original Studies |
Departments of Molecular and Clinical Endocrinology and Oncology (P.M., D.F., R.P., G.L., A.Co.) and Nuclear Medicine Center, National Council of Research, Department of Biomorphological and Functional Sciences, University Federico II (A.Cu., M.S.), I-80131 Naples; and Scientific Institute for Research and Care Neuromed (A.Cu.), Pozzilli 86077, Italy
Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, Federico II, University of Naples, Via S. Pansini 5, I-80131 Naples, Italy. E-mail: colao{at}unina.it
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Abstract |
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To further investigate this issue, we designed this two-arm study. In the first cross-sectional study, we compared echocardiography and radionuclide angiography results obtained in eight hyperthyroid acromegalic patients, eight hyperthyroid nonacromegalic patients, and eight healthy subjects. All acromegalic patients were receiving treatment for acromegaly at the onset of hyperthyroidism. In the second longitudinal study, performed in the group of acromegalic patients, we compared the cardiovascular results obtained during hyperthyroidism with the retrospective data obtained at the initial diagnosis of acromegaly and after 1-yr treatment for this disease and those prospective data obtained during the remission of hyperthyroidism.
In the cross-sectional study, hyperthyroid acromegalic patients showed an increase in the left ventricular (LV) mass index (LVMi) compared to healthy and hyperthyroid controls (P < 0.05), with evidence of LVMi hypertrophy in five of them (62.5%). A significant correlation was found between LVMi and GH levels (r = 0.785; P < 0.05). The LV ejection fraction (LVEF) at rest was higher in the control hyperthyroid population than in healthy controls (P < 0.05), whereas the LVEF response to exercise was reduced in acromegalic patients (P < 0.05 vs. healthy controls). In acromegalics, the exercise-induced change in LVEF was significantly reduced compared to that in healthy controls (P < 0.001), but not to that in hyperthyroid controls (P < 0.07), being abnormal (<5% increase vs. baseline values) in six patients. Four of these six patients (66%) had elevated GH and insulin-like growth factor I levels during the treatment of acromegaly. An inverse correlation between GH and LVEF at rest (r = -0.896; P < 0.05) and at peak exercise (r = -0.950; P < 0.001) was recorded. The peak filling rate was reduced in hyperthyroid acromegalic patients compared to those in both control populations (P < 0.05).
In the longitudinal study, acromegalic patients showed an increased LVMi during hyperthyroidism compared to that observed after successful treatment of acromegaly (P < 0.05); resting LVEF was increased compared to both basal (P < 0.001) and posttreatment values (P < 0.05). However, the exercise-induced change in LVEF was reduced (P < 0.05 vs. previous follow-up values). Remission of hyperthyroidism led to significant reduction of LVMi (P < 0.05) and resting LVEF (P < 0.05) and an increase in exercise-induced LVEF (P < 0.05).
In light of these findings, hyperthyroidism produces a detrimental effect on the cardiovascular system of acromegalic patients, particularly in those with uncontrolled disease. Thus, control of GH and insulin-like growth factor I should be a major objective, as cardiovascular risk persists in patients with ineffective hormonal suppression, and constant endocrine and cardiovascular surveillance remain crucial steps in patient follow-up.
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Introduction |
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Similarly, thyrotoxicosis can play per se a key role in cardiac performance. The effects of thyroid hormones are prompt on both heart contractility and systemic vascular system. In these conditions, increased heart rate, reduction of systemic vascular resistance, and enhancement of diastolic function have been reported (6, 17, 18, 19, 20, 21, 22). These factors contribute to increase the preload and the cardiac output (6). When prolonged, this condition may impair ventricular filling capacities and induce cardiac failure (18, 19, 20, 21, 22, 23, 24, 25), which can be accelerated by aging and preexisting cardiovascular disorders (17, 19, 25).
Accordingly, we investigated the hypothesis that the concomitant presence of acromegaly and hyperthyroidism could enhance the risk of developing cardiovascular complications. This objective was supported by the demonstration that thyroid disorders can frequently occur in acromegalic patients; goiter is recorded in up to 92% (7, 26, 27, 28, 29) and hyperthyroidism in 3.5–26% of cases (7, 26, 28).
This report describes the changes in cardiac structure and function in eight patients who developed hyperthyroidism after acromegaly. The development of thyrotoxicosis represented a worsening of both cardiac hypertrophy and diastolic and systolic function.
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Subjects and Methods |
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In 1990 we started a program of cardiological evaluation in all patients admitted to our department for pituitary tumors. Among 93 patients with acromegaly admitted between 1990 and 1999, 10 (10.7%) developed hyperthyroidism after the initial diagnosis of acromegaly, but 8 (8.6%; 6 women and 2 men; age, 53 ± 5 yr; mean ± SEM) had complete hormone, echocardiography, and gated blood pool radionuclide angiography records and constituted the study population. Disease duration was deduced by the patient’s clinical history and photograph records; in this series it was 17 ± 3 yr. Hyperthyroidism was diagnosed on the basis of clinical features, elevated free thyroid hormone levels, and suppressed TSH levels. No patient had previously received thyroid hormone supplementation. No iodine had been administered for diagnostic/therapeutic procedures within the previous 6 months. All acromegalic patients developed hyperthyroidism after the diagnosis and treatment of acromegaly. The presumed interval occurring between the onset of hyperthyroidism and diagnosis was 6.7 ± 0.7 months. The study was approved by the local ethics committee, and all patients gave informed consent to participate.
Study design
To address the role of hyperthyroidism in acromegalic cardiomyopathy, the study was designed in two arms: a cross-sectional study aimed at comparing the results of the patient group with those obtained in 8 age- and sex-matched healthy controls free of thyroid disorders and in 8 nonacromegalic hyperthyroid patients. In these 24 subjects endocrine evaluation of pituitary and thyroid hormones, echocardiography, and gated blood pool radionuclide angiography were carried out. A longitudinal study was performed in the group of acromegalic patients by comparing the data obtained retrospectively in patients when they received the initial diagnosis of acromegaly (study 0) with those obtained respectively after 1 yr of treatment for this disease (study 1), when they received diagnosis of hyperthyroidism (study 2), and after 6–8 months of biochemical remission of hyperthyroidism (study 3).
Hormonal assessment and thyroid evaluation
Hormonal profiles included assay of GH (calculated as the mean of three consecutive samples drawn at 15-min intervals), ethanol-extracted IGF-I, free T4 (fT4) and T3 (fT3), and TSH levels in the basal condition and when suppressed after 200-µg iv TRH injection (TSH peak normal when >3 mIU/mL). Assay of anti-TSH receptor antibodies was performed when Graves’ disease was suspected. As cure criteria for acromegaly, fasting GH values below 2.5 µg/L and/or glucose-suppressed GH levels below 1 µg/L together with normal IGF-I values for age were taken into consideration (3); biochemical remission of hyperthyroidism was considered when normalization of fT3 and fT4 levels as well as restoration of normal TSH secretion was obtained. All hormonal profiles were assessed by immunoradiometric assay, using commercially available kits. Normal IGF-I ranges in our laboratory in 20- to 30-, 31- to 40-, 41- to 50-, and over 50-yr-old subjects were 110–502, 100–494, 100–303, and 78–258 µg/L. Normal ranges for fT3, fT4, and TSH were, respectively, 1.6–3.4 pg/mL, 7.1–18.5 pg/mL, and 0.5–4.7 µU/mL. Thyroid morphology was investigated by means of ultrasonography and 99Tc scintigraphy.
Cardiovascular evaluations
A preliminary exercise electrocardiogram and thallium-201 myocardial scintigraphy excluded concomitant coronary arterieal disease in patients who had experienced chest pain resembling angina pectoris. Patients received a careful physical examination at each step of the study. Assessment of the cardiovascular morphology by M- and B-mode Doppler echocardiography and of cardiac function by measuring left ventricular ejection fraction and assessment of peak filling rate by gated blood pool radionuclide angiography were performed in all subjects. Radionuclide angiography was chosen as a useful operator-independent method to study left ventricle performance, because it can provide direct and objective evaluation of ventricular function.
Echocardiography
All subjects were studied when lying in the left lateral recumbent position after a 10-min resting period, according to the recommendations provided by the American Society of Echocardiography (30). A complete M-mode, two-dimensional analysis was performed using an ultrasound mechanical system equipped with 3.5 MHz transducer (Apogee CX, Interspec, Ambler, PA), and evaluation of left ventricle mass was obtained using Devereux’s formula during the M-mode measurement, according to Penn’s convention (31). Left ventricle hypertrophy was considered when left ventricular myocardial mass, corrected for the body surface area (LVMi), was greater than 135 g/m2 in males and 110 g/m2 in females (31).
Radionuclide angiography
The study was performed at rest and after exercise and was
accompanied by measurements of heart rate and blood pressure as
previously reported in detail (16). The procedure of in vivo
labeling of red blood cells was performed with 555 MBq (15 mCi) of
99 mTc. Acquisition was performed at rest and
during dynamic physical exercise in the 45° left anterior projection
with a 15° craniocaudal tilt, with the patient in the supine
position, using a small field of view 
-camera (Starcam 300 A/M,
General Electric, Milwaukee, WI) and a low energy collimator. Data were
recorded at a rate of 30 frames/cardiac cycle for the resting study and
16 frames/cardiac cycle for the exercise study on a dedicated computer
system (General Electric). At least 200,000 counts/frame were acquired.
Exercise studies were performed using a bicycle ergometer with a
restraining harness to minimize the patient’s motion under the camera.
Exercise loads were increased by 25 watts every 2 min up to submaximal
exercise. Radionuclide angiography studies were analyzed using a
standard commercial software system (General Electric). Left
ventricular regions of interests were automatically drawn for each
frame, and a background region of interest was also computer delineated
on the end-systolic frame. After background correction, a left
ventricular time-activity curve was generated. Indexes of left
ventricular function were derived by computer analysis of the
background-corrected time-activity curve. The ejection fraction (EF)
was computed relatively to end-diastolic and end-systolic counts. Peak
left ventricular ejection and filling rates were also calculated after
a Fourier expansion with four harmonics. The peak ejection rate was
computed as the minimum negative peak before end-systole, and the peak
filling rate (PFR) was calculated as the maximum positive peak after
end-systole on the first derivative of the left ventricular
time-activity curve. Both peak ejection rate and PFR were computed as
left ventricular counts per s, normalized for the number of counts at
end-diastole and expressed as end-diastolic volume per s; to minimize
the influence of the ejection fraction, the PFR was also expressed
relative to the left ventricular stroke volume and as the ratio of PFR
to peak ejection rate (32). Time to peak ejection rate was determined
from the R wave, and time to peak filling rate was determined relative
to end systole (minimal volume on the time-activity curve).
Statistical analysis
Data are the mean ± SEM; one-way ANOVA, followed by Newman-Keuls test, was employed for comparison among acromegalic patients in hyperthyroidism with healthy and hyperthyroid controls (cross-sectional study) and with remaining follow-up evaluations (longitudinal study), applying Bonferroni’s correction. Pearson’s analysis was used to correlate cardiovascular results with hormonal data during the different intervals in acromegalic patients’ group. P < 0.05 was considered statistically significant.
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Results |
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Patients’ data are included in Tables 1
and 2,
respectively. At the time of diagnosis of hyperthyroidism, one patient
had been cured of acromegaly after surgery and radiotherapy. Of the
remaining seven patients, all were subjected to chronic sc octreotide
treatment, and normal GH and IGF-I levels were recorded in three of
them (43%). Two patients suffered from both arterial hypertension and
glucose intolerance, one from hypertension, and another from diabetes
mellitus. Hyperthyroidism presented with clinical and biochemical
features suggestive of Graves’ disease in four patients (50%),
showing elevated Tr-Ab levels (in all) or ophthalmopathy (in three
patients). Multinodular goiter with elevated uptake at scintigraphy was
documented in two of them and in all of the remaining patients.
Diastolic blood pressure at rest was higher (P < 0.05)
in hyperthyroid acromegalic patients than in healthy controls. Heart
rate was significantly higher in hyperthyroid acromegalic than in
healthy controls both at rest (P < 0.001) and after
exercise (P < 0.05), due to the presence of overt
tachyarrhythmia in four and atrial fibrillation in two patients, and
supplementation with ß-adrenergic antagonists was provided after they
had completed the cardiological evaluation.
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Cardiovascular data
Cross-sectional study (Table 3).
LVMi values were significantly higher in the group of the hyperthyroid
acromegalic patients than in either healthy subjects or control
hyperthyroid population (P < 0.05 in both cases; Fig. 1). During hyperthyroidism,
echocardiographic evidence of LV hypertrophy was detected in five
acromegalic patients (62.5%; no. 2–5 and 8; Figs. 1 and 2), four of whom (80%) showed elevated
GH levels despite being subjected to chronic octreotide treatment. LVMi
was higher in patients with elevated GH levels than in patients showing
GH suppression (157.2 ± 7.2 vs. 97.2 ± 6.2
g/m2; P < 0.001) at the onset of
hyperthyroidism. As a consequence, a significant correlation was
observed between GH levels and LVMi (r = 0.785; P
< 0.05).
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). By contrast, an
abnormal LVEF response to exercise (<5% increase vs.
baseline values) was observed in six acromegalic patients, among whom
four (66%) had unsuppressed GH levels. In these four patients, the
LVEF response to exercise was significantly lower than that in patients
with suppressed GH during therapy (49.2 ± 4.7% vs.
64.2 ± 3.8%; P < 0.05). With respect to the
healthy population, the EF response to exercise was reduced in both
acromegalic patients and hyperthyroid patients (P <
0.05 in both cases; Fig. 3). The exercise-induced change in LVEF (
LVEF) was significantly lower in hyperthyroid acromegalic patients than
in healthy controls (P < 0.001), but not in
hyperthyroid controls (P < 0.07; Fig. 3). In the group
of hyperthyroid acromegalic patients, a significant correlation was
found between GH values and LVEF at rest (r = -0.896;
P < 0.05), at peak exercise (r = -0.950;
P < 0.001), and as LVEF (r = -0.888;
P < 0.05). LVEF was correlated with PFR at rest
(r = 0.740; P < 0.05). PFR was significantly
lower in the patient population compared with those in healthy and
hyperthyroid controls (P < 0.05 and < 0.001,
respectively) and inversely correlated with age (r = -0.718;
P < 0.05) and disease duration (r = -0.745;
P < 0.05). Hyperthyroid status exerted a precocious
muscular exhaustion in acromegalic patients, with reduced exercise
capacity and duration compared with both healthy controls
(P < 0.05 and < 0.001) and control hyperthyroid
patients (P < 0.05). Remarkably, three acromegalic
patients precociously concluded their workout due to muscular
exhaustion.
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). In
study 2, LVMi values were higher than those in study 1
(P < 0.05), whereas LVMi values were lower compared to
data recorded in study 0 (P < 0.05; Fig. 2
). A direct
correlation was found between LVMi values obtained in study 0 and those
recorded in study 2 (r = 0.705; P < 0.05).
Resting LVEF was significantly enhanced compared to both previous
follow-up values (P < 0.001 and 0.05, respectively),
but the response to exercise was impaired, and the LVEF was lower
compared to values recorded in study 1 (P < 0.05 and
0.001, respectively; Fig. 4).
Additionally, exercise capacity and duration were reduced compared to
results obtained during study 1 (P < 0.05 in both
cases). The achievement of euthyroidism (study 3) was followed by a
significant reduction of LVMi (P < 0.05) in all
patients, and a normalization of LVMi was observed in one patient (no.
2, Fig. 2). A prompt improvement of cardiac performance at peak
exercise was similarly obtained, with an increase in LVEF at peak
exercise as well as in LVEF (P < 0.05 in both
cases; Fig. 4). An exercise-induced change in LVEF was correlated to
PFR (r = 0.780; P < 0.05). Additionally, exercise
capacity and duration improved (P < 0.05 in both
cases).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Although a limited number of investigations of the coexistence of acromegaly and hyperthyroidism currently exist (7, 26, 28), growing evidence has accumulated that the thyroid can be enlarged in up to 92% of acromegalic patients (26, 27, 28, 29), independently of TSH levels (28, 33). Data concerning the prevalence of hyperthyroidism in the setting of acromegaly are not uniform, as it was reported to range between 3.5–26% (7, 26, 28). In our experience, 9 patients presenting hyperthyroidism after having received a diagnosis of acromegaly and 1 other patient coming to our attention with both diseases concomitantly accounted for a prevalence of 10.7%. Of these 10 patients, 8 were included in the present study and were receiving treatment for acromegaly at the onset of hyperthyroidism. In particular, 1 patient had been cured by surgery and radiotherapy, whereas the remaining 7 were subjected to chronic octreotide therapy. Whether octreotide treatment could have triggered thyroid hyperfunction is difficult to estimate. Neither previous report supports this evidence (26, 27, 28, 29). Instead, it has been proposed that chronic GH and IGF-I excess could stimulate the thyroid to develop morphological and functional changes, in a fashion that would be TSH independent (26, 27, 28, 29). Therefore, in our series of hyperthyroid acromegalic patients, hyperthyroidism seems to have occurred as a complication in the natural course of acromegaly itself. Among our patients, biochemical and clinical features suggestive of Graves’ disease were present in 4 subjects, 2 of whom showed ultrasonographic and scintigraphic features of toxic multinodular goiter, at variance with the classical presentation of Graves’ disease (34). All of the remaining hyperthyroid patients had toxic multinodular goiter.
The majority of our patients exhibited signs and symptoms of cardiovascular involvement. In acromegaly, heart disorders are prominent factors in rising morbidity and mortality (7, 8, 9, 10). Nevertheless, patients may be clinically asymptomatic for long, that is because cardiac impairment develops stepwise (5). Initially, cardiac performance is increased and predisposes to concentric myocardial hypertrophy. This, in turn, weakens diastolic filling and impairs systolic performance (5, 11, 12, 13, 14, 15, 16), although other complications, such as arterial hypertension, arrhythmias, and coronary artery disease, may be synergistically harmful (5, 15). It is conceivable that unless a prompt suppression of GH and IGF-I excess is achieved (35, 36, 37), cardiac performance may progressively worsen, and in more advanced stage of disease, ventricular dilatation and congestive heart failure may occur (5, 12, 13, 14, 15).
There is general agreement, on the other hand, that cardiac arrhythmias and hyperdynamic circulatory state are integral parts of the hyperthyroid syndrome (19). It has been demonstrated that both thyroid hormone administration and hyperthyroidism can be accompanied by reduced vascular resistance and increased cardiac output (6, 17, 18, 19, 20, 21, 25). The overall effect of these changes is to alter the loading condition in the heart and to realize, in a sequence sharing some homology with that observed in the early stages of acromegaly (6, 20, 22), a hyperkinetic syndrome. Although in a very recent study the treatment with T3 was shown useful after surgery in chilidren with congenital heart disease (40), the hemodynamic change can contribute to cardiac hypertrophy (6, 25). It has been shown that not only is the contractile reserve reduced and the ejection fraction inadequate to effort (18, 19, 20), but heart failure may also develop (19, 24, 37, 38, 39). As aging and/or preexisting cardiac disorders have been claimed to increase the risk of congestive heart failure during hyperthyroidism (17, 19), it could be speculated that the concomitant presence of acromegalic cardiomyopathy might have accelerated cardiac impairment.
In our series of acromegalic patients, the increase in LVMi, the enhancement of cardiac performance at rest, and the presence of an overt failure at peak exercise were clearly observed. Four patients, showing unsuppressed GH values when hyperthyroidism was diagnosed, showed a significant increase in LVMi and a significant reduction of LVEF at peak exercise compared with patients showing controlled disease. A positive correlation was found between GH levels and cardiac mass, whereas they inversely correlated to the LVEF at peak exercise. These findings are emblematic of a reduction of the functional cardiac reserve when hyperthyroidism develops in the setting of acromegaly. As the worsening of cardiac morphology and function is particularly evident in patients with unsuppressed GH and IGF-I, this is indicative of persisting cardiovascular impairment unless hormone suppression is achieved. To this extent, effective and prolonged GH and IGF-I suppression undoubtedly represents a restraining factor for the patient’s well-being. The observations presented in this report are therefore in agreement both with data showing incomplete reversal of cardiac abnormalities after recovery of acromegaly (5, 12, 13, 36) and with other reports indicating a correlation between GH suppression and cardiovascular performance (35) or mortality (7, 8, 9, 10).
Although the results of this study could be biased by the limited number of patients, any randomized or prospective investigation seems inapplicable due to the scant prevalence of hyperthyroidism in acromegaly. Rather, these findings eventually support the concept that cardiovascular instability in acromegaly, which is aggravated by the presence of hypertension and glucose tolerance abnormalities (41), may benefit by prompt recognition of concomitant endocrine disorders and a combined curative approach. Although current therapeutic solutions for acromegaly can lead to clinical and cardiovascular improvement in many cases, incomplete hormonal suppression seems to limit further progression. Thus, a constant surveillance of other endocrine circuits as well as of the cardiovascular system remains a crucial step in the follow-up of acromegalic patients.
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Footnotes |
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Received June 29, 1999.
Revised November 29, 1999.
Accepted December 16, 1999.
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