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Original Studies |
Nuklearmedizinische Klinik und Poliklinik der Technischen Universität München, 81675 Munich, Germany
Address all correspondence and requests for reprints to: Frank M. Bengel, M.D., Nuklearmedizinische Klinik und Poliklinik, Technische Universität München, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 Munich, Germany. E-mail: frank.bengel{at}lrz.tu-muenchen.de
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Kinetics of 11C-labeled acetate, measured in vivo by positron emission tomography (PET), have been used for noninvasive assessment of tricarboxylic acid cycle flux and thus of myocardial oxidative metabolism. In both experimental (8) and human studies (9), a direct relationship between [11C]acetate turnover and measures of myocardial oxygen consumption has been established. Electrocardiographically gated magnetic resonance imaging (MRI), on the other hand, provides high spatial resolution and high reproducibility to assess cardiac contractile performance (10, 11, 12). The clinical usefulness of this technique to measure global as well as regional left ventricular function has been demonstrated previously (13, 14). Recently, it has been suggested that a combination of PET measurements of oxidative metabolism and studies of cardiac contractile function may be used for noninvasive estimation of cardiac efficiency (15), facilitating the application of serial measurements at different time points. The relation of these noninvasive parameters to invasive measurements of mechanical efficiency has been demonstrated (15). This concept has been successfully employed to assess the beneficial effects of afterload reduction and dobutamine infusion on the efficiency of the failing human heart (15, 16). It has, however, not yet been applied to describe changes in oxidative metabolism and cardiac efficiency in thyroid dysfunctional states.
To study the effects of thyroid hormones in vivo, patients with a history of total thyroidectomy for thyroid cancer present a unique model. For whole body radioiodine scanning, thyroid hormone replacement therapy is withheld to stimulate TSH production and thereby increase radioiodine uptake into tumor cells. As all patients are athyroid, severe hypothyroidism develops quickly. Additionally, the duration of the hypothyroid state is known, and hypothyroidism is readily reversible by reinstitution of thyroid hormone replacement therapy, representing advantages compared to the study of cardiac effects in patients with long term hyper- or hypothyroidism.
Thus, using this model, it was the aim of the present study to noninvasively estimate changes in cardiac oxidative metabolism and contractile function in the hypothyroid state by a serial application of PET with [11C]acetate along with functional measurements by electrocardiographically gated cine MRI.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The study group consisted of 10 patients (4 men and 6 women; aged 50 ± 8 yr) with a history of total thyroidectomy for follicular (n = 4) or papillary (n = 6) thyroid cancer. The patients had no clinical or electrocardiographic evidence of cardiac disease and no evidence of any other severe non-cardiac or nonthyroid disease.
According to the study protocol, patients underwent PET with [11C]acetate and cine MRI twice. The first study was carried out in the severe hypothyroid state when patients withheld thyroid hormone replacement therapy for a diagnostic or therapeutic application of radioiodine as part of their clinical work-up. T4 medication was discontinued 43 ± 9 days (range, 35–64 days) before PET and MRI. The second study was then performed 40 ± 13 days (range, 28–62 days) later under thyroid hormone replacement therapy consisting of oral intake of 175–225 µg T4/day, depending on individual body mass. No other cardioactive medication was taken by any of the patients. At both time points, blood samples for immunoradiometric in vitro measurement of levels of free T3, free T4, and TSH were taken. Although nine patients completed the protocol, one patient underwent only PET at both time points and refused to undergo the second MRI scan due to claustrophobia.
The study protocol was approved by the ethical committee of the medical faculty of the Technische Universität Muenchen. Before inclusion, all patients gave written informed consent.
PET
Myocardial oxidative metabolism was quantified noninvasively by dynamic PET and 11C-labeled acetate. [1-11C]Acetate was synthesized according to the method of Pike et al. (17). PET imaging was performed using an ECAT EXACT or ECAT 951 scanner (CTI/Siemens, Knoxville, TN). Performance characteristics of these scanners have been described previously (18, 19). After adequate positioning, a transmission scan was acquired for correction of photon attenuation. Subsequently, 300–500 megabecquerels [11C]acetate were injected as a slow bolus over 30 s, and a dynamic imaging sequence of 21 frames over 30 min (10 times, 10 s; 1 time, 60 s; 5 times, 100 s; 3 times, 180 s; and 2 times, 300 s) was initiated. Heart rate and blood pressure were monitored continuously throughout the imaging procedure by electrocardiogram and arm cuff measurements.
MRI
For precise measurement of left ventricular function, MRI was carried out after PET imaging on the same day using a 1.5 Tesla Philips Gyroscan ACS2 or NT (Philips Medical Systems, Best, The Netherlands). Short axis multislice multiphase cine gradient echo sequences were applied with electrocardiographic triggering of R waves to cover the cardiac cycle in 12 phases. The entire left ventricle was imaged from apex to base in 12 slices with a thickness of 7–10 mm and a 128 x 128 pixel matrix.
Data analysis
PET. Attenuation-corrected transaxial PET images were reconstructed by filtered backprojection and a Hanning filter with 0.3 cycles/bin cut-off frequency. A previously validated volumetric sampling tool (20) was then applied to a summed dataset of frames 11–13 of the dynamic imaging sequence to create polar maps of static myocardial activity distribution at 2–4 min after the injection of [11C]acetate. Because the early uptake of [11C]acetate has been shown to be proportional to myocardial blood flow, these polar maps were normalized to their maximum and used for qualitative assessment of regional myocardial perfusion according to a previously validated approach (21).
Myocardial sectors defined by the polar map were then transferred to
the whole dynamic imaging sequence, and time-activity curves were
obtained. The early phase of tracer washout in these curves was fitted
monoexponentially to obtain the clearance constant k(mono), as a
previously validated measure of tricarboxylic acid cycle flux, and thus
of oxidative metabolism (8), expressed in another polar map. The
average of k(mono) for the whole map was calculated to define global
myocardial oxidative metabolism. In addition, regional analysis using a
model of five myocardial regions representing anterior, lateral,
septal, inferior, and apical walls was performed (Fig. 1
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Additionally, three midventricular slices were chosen for regional analysis of wall thickness and thickening. A modified centerline algorithm was applied to define 100 myocardial chords along the circumference of each transaxial slice using the posterior insertion of the right ventricle as a starting point. Four segments for septal, anterior, lateral, and inferior walls, including 25 chords/slice, were defined. Segmental wall thickness was calculated as the average length of all chords in the respective segment of the 3 slices in end-diastolic phase. Wall thickening was characterized by the percent increase in thickness from end diastole to end systole. The high reproducibility of this technique is supported by the data reported below.
To demonstrate the reproducibility of global and regional parameters derived from cine MRI, 10 healthy normal subjects (6 women and 4 men; aged 40 ± 13 yr) were imaged using protocols for acquisition and data analysis as described above. All image sets were analyzed by two independent observers, and absolute values as well as agreement between observers were calculated.
Overall, left ventricular mass ranged from 66–142 g (mean, 106 ± 29 g), end-diastolic volume ranged from 69.8–151.2 mL (mean, 104.0 ± 30.0 mL), end-systolic volume ranged from 20.4–53.0 mL (mean, 34.1 ± 11.8 mL), and ejection fraction ranged from 59–72% (mean, 67 ± 4%). Regional end-diastolic wall thickness ranged from 4.2–8.7 mm (mean, 5.8 ± 0.9 mm), and regional wall thickening ranged from 58–184% (mean, 97 ± 27%).
The interobserver agreement for functional parameters is shown in Table 1A. Correlation coefficients were
excellent for all global parameters, and sufficiently high for regional
parameters, suggesting high reproducibility of MRI data in accordance
with previous studies (10, 11, 12).
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End-diastolic and end-systolic volumes were used to calculate left ventricular ejection fraction (EF) and stroke volume (SV). Cardiac output (CO) was then obtained by multiplying SV times heart rate (HR). Systemic vascular resistance (SVR) was estimated as mean arterial blood pressure divided by CO and converted to dynes per s/cm5 (22).
By dividing SV by left ventricular mass, a stroke volume index (SVI) was obtained. Subsequently, left ventricular stroke work was estimated by a stroke work index (SWI), the product of SVI and peak systolic blood pressure (PSP) (15).
The mechanical efficiency of the left ventricle is defined as the relation between cardiac work and oxygen consumption. To noninvasively estimate myocardial efficiency, stroke work data were combined with data from [11C]acetate PET, and a previously validated work metabolic index (WMI) (15) was calculated by WMI = (SVI x PSP x HR)/k(mono) (mm Hg/mL·g), where k(mono) is the myocardial clearance constant for 11C derived from PET.
Statistical analysis
Values are expressed as the mean ± SD. Student’s paired two-tailed t test was applied to compare results in the hypothyroid state with those under thyroid hormone replacement therapy. P < 0.05 was defined as significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Table 1 depicts the results of
in vitro measurements of the thyroid functional state at
both imaging time points. During the first PET and MRI study, both
levels of free thyroid hormones were expectedly well below normal
range, and TSH was increased, confirming the severe hypothyroid state.
Commencement of T4 medication then resulted in a
euthyroid state at the time of the second study. Thyroid hormone levels
increased significantly to the upper normal range, and TSH
concomitantly decreased to the lower normal range.
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Parameters are summarized in Table 2. Heart rate was significantly lower in
the hypothyroid state compared to that during replacement therapy.
Although there was no difference in systolic and mean aortic blood
pressures, a nonsignificant trend toward higher diastolic blood
pressures in hypothyroidism was found.
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The results of regional wall thickness and thickening are shown in Fig. 2, A and B. Significantly greater
thickness was found for all four myocardial segments in hypothyroidism,
whereas the septal wall was thickest at both time points. Thickening as
a measure of contractility was reduced in all four segments during
hypothyroidism and increased significantly during replacement
therapy.
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Polar maps of [11C]acetate uptake at 2–4 min as a qualitative measure of regional myocardial perfusion expectedly revealed homogeneous perfusion in all patients at both imaging time points. Perfusion defects, defined as an uptake less than 50% of the maximum, were not identified in any individual.
Global values for the myocardial 11C clearance
constant, k(mono), as a measure of oxidative metabolism were 0.050
± 0.011/min in the hypothyroid state and increased significantly to
0.061 ± 0.016/min during replacement therapy (P =
0.01; Fig. 1
). The results of regional analysis are depicted in Fig. 2C, confirming that all myocardial segments contributed to the increase in
oxidative metabolism.
Estimates of myocardial efficiency
Figure 3 depicts individual changes
in the WMI as a noninvasive estimate of cardiac efficiency. Although
both cardiac work and oxidative metabolism increased during replacement
therapy, the WMI still increased significantly from 76,496 ±
39,847 mm Hg/mL·g in the hypothyroid state to 118,065 ± 47,867
mm Hg/mL·g during thyroid hormone medication (P <
0.001).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Changes in hemodynamic parameters and left ventricular geometry
The observed decrease in cardiac work in hypothyroidism has been well recognized and confirms several previous studies (1, 3, 4). Both chronotropic and inotropic effects of thyroid hormone medication contribute to this observation.
In part, the decrease in myocardial contractile performance under thyroid hormone deprivation may be a result of direct thyroid hormone action on a molecular level. T3 has been shown to influence the expression of several myocyte-specific genes encoding contractile proteins (23). Furthermore, diastolic function can be modulated via the expression of calcium-adenosine triphosphatase in the sarcoplasmic reticulum (24).
In addition to direct molecular effects, hemodynamic parameters, such as systemic vascular resistance and heart rate, also contribute to changes in myocardial performance (25). Systemic vascular resistance was higher in hypothyroidism compared to that in the normal state in the present study, confirming that thyroid hormones also affect peripheral vessel tone and thereby indirectly affect the heart (1). Furthermore, heart rate was expectedly lower during thyroid hormone deficiency. This effect is well described and, besides a potential negative effect on contractility, directly results in decreased cardiac work (3).
In addition to increases in stroke volume and heart rate, the increase in stroke work index (calculated per g tissue) in the present study is further pronounced by a decrease in ventricular mass from the hypothyroid to the euthyroid state. With respect to the short term model of hypothyroidism in the present study, this significant change within the observation period of approximately 40 days is surprising. The reproducibility and accuracy of MRI for determination of ventricular mass have been demonstrated extensively in previous studies (10, 12). Furthermore, high reproducibility in our laboratory, as demonstrated in Materials and Methods, renders inaccuracy of the method as a potential explanation unlikely. Previously, asymmetrical septal myocardial hypertrophy has been described in long term hypothyroid patients (26). Consistently, regional analysis in the present study revealed that septal wall thickness was greatest, whereas a decrease in thickness was found in all myocardial segments during thyroid hormone replacement. Due to the short time between the two observations, muscular hypertropy as a potential reaction to increased peripheral resistance seems unlikely. Although speculative, a reversible increase in the extracellular matrix may explain the increase in mass in the present study, as some previous experimental studies have suggested increased synthesis of collagen (27) and glycosaminoglycan (28) in the hypothyroid state. This mechanism could then also contribute to the reduced contractile performance. However, further detailed studies are necessary for improved understanding of the interaction between myocardial mass and thyroid state.
Myocardial oxidative metabolism
Myocardial oxygen consumption is closely coupled to cardiac work (8). With the decreases in contractility and heart rate, it can be assumed that oxygen consumption also decreases in hypothyroidism. The relationship between work and oxygen consumption as a measure of efficiency, however, remains elusive without direct measurements of both. Using PET with [11C]acetate for the first time in hypothyroid patients, noninvasive assessment of myocardial oxidative metabolism in the present study confirms the assumption of lower values during hypothyroidism.
In a previous study in hyperthyroid patients, elevated levels of myocardial oxidative metabolism compared to those in normal controls have been described, which decreased during propranolol treatment, but remained elevated compared to those in normal subjects (29). In contrast to the present study, however, no simultaneous information about left ventricular contractile function was acquired, and interpretation of the results with regard to efficiency remained difficult.
Effect of thyroid hormones on cardiac mechanical efficiency
Although it has been suggested previously that performance of the hypothyroid heart may be less efficient (2), the present study is the first to describe effects of hypothyroidism on cardiac efficiency noninvasively. The results demonstrate that the decrease in cardiac work in short term hypothyroidism is more pronounced compared to the decrease in oxygen consumption. The mechanisms underlying this decreased efficiency in hypothyroidism may be manifold.
As mentioned above, T3 influences the myocardial expression of a variety of gene-encoded proteins (23). It has been speculated previously that abnormally high levels of ATP-consuming enzymes in hyperthyroidism may lead to less chemical energy being used for contractile purposes and more being used for heat production, resulting in decreased efficiency (30). In hypothyroidism, on the other hand, other energy-demanding enzymatic changes that reduce mechanical efficiency of the heart may occur. Impaired diastolic function as a result of altered calcium handling may be another contributor (24). A major factor for the reduced efficiency, however, may be the rise in peripheral vascular resistance (1). An inverse relationship between peripheral resistance as a measure of afterload and cardiac efficiency has been demonstrated previously (16).
Clinical implications
It has been suggested previously that hypothyroidism may contribute to aggravation or exacerbation of intrinsic cardiac disease, resulting in heart failure (2, 3). The observed decrease in myocardial efficiency in hypothyroidism can be assumed to contribute to this observation and further points out the importance of adequate thyroid hormone substitution.
Limitations
Some limitations of the present study need to be taken into account. First, the present study has been conducted using a short term model of hypothyroidism. Although this model provides unique advantages because of low interindividual differences and predictability of the thyroid state, caution has to be used when transferring results to different situations, such as long term hypothyroidism or hyperthyroidism. Nevertheless, they provide valuable new insights into the cardiac effects of thyroid hormones.
Methodologically, it needs to be pointed out that the applied combination of noninvasive measurements of blood pressure by arm cuff and ventricular function by MRI allows only a rough estimation of cardiac work. Due to the longitudinal study design, accurate quantification by invasive procedures was not performed. However, the relationship between noninvasive estimates of cardiac work and invasive quantitative parameters has been established previously (15), and the applied technique for MR imaging has been shown to be valid and reproducible (10, 11, 12). Furthermore, noninvasive serial measurements indicated highly significant changes despite the methodological limitations. The results, therefore, support sufficient accuracy of the applied techniques.
Conclusions
Serial noninvasive measurements of myocardial oxidative metabolism and ventricular function suggest a decrease in cardiac work and oxygen consumption in a model of short term hypothyroidism. The decrease in oxidative metabolism was less pronounced, resulting in a reduction of estimates of myocardial efficiency. Both direct effects of thyroid hormone deprivation on the heart as well as indirect effects via the peripheral circulation may contribute to these findings. The observed results may have clinical implications by serving as an explanation for development or worsening of heart failure in hypothyroid patients with preexisting cardiac disease and point out the importance of adequate thyroid hormone substitution.
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Acknowledgments |
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Received August 13, 1999.
Revised November 8, 1999.
Accepted December 16, 1999.
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References |
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