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Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica (G.V., G.A.L., G.L.), Cattedra di Medicina d’Urgenza, Dipartimento di Medicina e Clinica Sperimentale (M.G., A.C., I.P., N.P., O.d.D.), Università degli Studi Federico II, 80131 Naples, Italy
Abstract
Pulsed tissue Doppler (TD) is a new ultrasound tool that allows quantification of myocardial regional wall motion. To investigate the cardiac effects of subclinical hypothyroidism (SH), the present study assessed left ventricular (LV) myocardial regional function in SH by pulsed TD. Twenty women with SH and 20 healthy women underwent standard Doppler echocardiograms and pulsed TD, placing a sample volume at the level of posterior septum and LV mitral annulus. Myocardial systolic and diastolic velocities and time intervals were determined for both levels. Doppler-echocardiographic and TD measurements were adjusted for body surface area and heart rate.
Standard Doppler showed an increases in LV preejection period, preejection period/LV ejection time ratio, and isovolumic relaxation time (IVRT) in SH. By TD analysis, myocardial precontraction time (PCTm), PCTm/myocardial contraction time ratio, and myocardial relaxation time (RTm) were prolonged at the level of both posterior septum and mitral annulus in SH. In the whole population, IVRT, PCTm, and RTm were negatively related to FT4, whereas IVRT, PCTm/myocardial contraction time ratio, and RTm were positively correlated to TSH.
In conclusion, this study underscores the usefulness of TD to detect cardiac functional abnormalities due to stable SH, mainly by changes in myocardial time intervals in several LV segments.
SUBCLINICAL HYPOTHYROIDISM (SH) is a common disorder characterized by increased serum TSH and its response to TRH, whereas serum free T4 (FT4) and free T3 (FT3) concentrations are within the normal range for the general population (1, 2). In view of the minor thyroid hormone secretion impairment, it is predictable that metabolic and organ function indexes of SH will show only marginal alterations. Nevertheless, such changes may be clinically relevant when they affect target organs over a period of several years (3). In particular, heart and vessels are very sensitive to thyroid hormones, as cardiovascular disorders are often associated with both overt hypothyroidism and hyperthyroidism (4, 5, 6, 7, 8). Several noninvasive techniques (9, 10, 11, 12, 13, 14, 15, 16) have been used to assess cardiac involvement in SH, but all of them provide information about left ventricular (LV) global chamber function without exploring changes occurring at the level of the regional myocardial walls.
Pulsed tissue Doppler (TD) is a new noninvasive ultrasound tool that allows measurement of myocardial regional wall motion. Although standard echocardiography collects data about cardiac function either from parameters measured from the blood-myocardial boundaries or from Doppler flow, TD has the peculiarity of directly measuring velocities and time intervals of myocardium by placing a sample volume within the chosen myocardial walls. It is noteworthy that TD evaluation is performed on line during a simple echocardiographic examination by modifying filter settings and reducing velocity ranges of the standard Doppler signal (17, 18, 19).
On these grounds the present study was designed to investigate myocardial regional function in SH by using pulsed TD to identify possible LV myocardial systolic and diastolic involvement in relation to a reference population of euthyroid healthy subjects.
Subjects and Methods
Study protocol
Twenty female patients (mean age ± SD, 38.5 ± 12.4 yr) with newly diagnosed, untreated, autoimmune primary SH and no previous history of thyrotoxicosis were included in the study. SH was diagnosed in those cases where TSH values were above normal and associated with a supranormal response to TRH (change in TSH, >30 mU/liter) and FT3 and FT4 levels in the lower limit of the normal range. Only patients with TSH and thyroid hormone levels stable for at least 6 months before enrolment were included. TSH and thyroid hormones were considered stable if their variations were lower than 20% in 3 consecutive evaluations performed in the 6 months preceding the current study. Twenty female healthy subjects, recruited among the staff and relatives of medical doctors attending the present study, were included in the control group. All subjects gave informed consent, and the study was approved by the institutional ethical committee. Exclusion criteria were history of any acquired and/or congenital cardiac disease; arterial systemic hypertension; diabetes mellitus; respiratory, hematological, liver, and/or kidney diseases; pregnancy; administration of cardiac medications or any drug known to interfere with myocardial function; and echocardiograms of inadequate quality. At study admission, demographic and anthropometric data; serum FT3, FT4, and TSH levels; clinical arterial blood pressure (BP); 12-lead surface electrocardiogram; 2-dimensional guided M-mode and standard Doppler echocardiographic evaluations; and TD assessment were performed in all participants.
Laboratory determinations
All blood samples for circulating serum FT3, FT4, and TSH were collected from antecubital vein between 0800 and 0900 h after an overnight fast. Evaluation of TSH levels was performed by a chemiluminescent microparticle immunoassay assay (Architect System, Abbott Spa, Rome, Italy) with a sensitivity of 0.0025 mIU/liter or less and an intraassay variation of 1.2% at 2.00 mIU/liter; the normal range was 0.35–4.94 mIU/liter. Serum FT3 and FT4 were measured using a chemiluminescent microparticle immunoassay (Architect System, Abbott Laboratories, Chicago, IL). The intraassay coefficients of variation were 3.6% at 4.95 pmol/liter for FT3 and 2.3% at 15.70 pmol/liter for FT4. The sensitivities were less than 1.54 pmol/liter and less than 5.15 pmol/liter for FT3 and FT4, respectively. The normal range for FT3 was 2.63–5.70 pmol/liter, and that for FT4 was 9.01–19.05 pmol/liter.
Doppler echocardiographic and TD examinations
Standard Doppler echocardiography and TD were performed with the subjects in partial left decubitus using Vingmed System 5 (GE, Horten, Norway) equipped with TD capabilities. A variable frequency phased array transducer (2.5–3.5–4.0 MHz) was used for echo-Doppler and TD. At the end of the study, cuff BP (mean of three measurements) was estimated by a physician blinded to the examination. Doppler echocardiographic and TD tracings were recorded on super VHS videotapes and high fidelity paper strip at a velocity of 50–100 mm/sec. All measurements were analyzed by two experienced sonographers, who were unaware of clinic and laboratory data, on and average of three to five cardiac cycles.
M-mode quantitative analysis was performed according to the American Society of Echocardiography in parasternal long axis view (20). LV mass (in grams) was indexed for both body surface area (21) and height2.7 (Cornell adjustment) (22). Relative diastolic wall thickness was determined as the ratio between the sum of wall thickness (septal wall plus posterior wall) and LV end-diastolic diameter. Endocardial fractional shortening was calculated as the percent change in LV internal dimension between systole and diastole. Pulsed Doppler of LV systolic outflow tract was performed by placing the sample volume close to the aortic valve. The LV preejection period (PEP; milliseconds; from electrocardiogram QRS to the beginning of systolic ejection), LV ejection time (LVET; milliseconds; from the beginning to the end of LV ejection), and PEP/LVET ratio were determined as systolic time intervals. Stroke volume (milliliters) was estimated according to the outflow tract method using the formula: systolic TVI x LV output diameter (in centimeters), where TVI is the time velocity integral of systolic wave (23). Cardiac output (liters per minute) was calculated as SV (milliliters) x heart rate (beats per minute). Pulsed Doppler LV inflow recording was performed in an apical four-chamber view by placing the sample volume at the tip level. Early (E) and atrial (A) peak velocities (meters per second) and their ratio, E wave deceleration time (milliseconds), isovolumic relaxation time (IVRT; milliseconds; the time interval between the end of systolic output flow and transmitral E wave onset, by placing the sample volume between outflow tract and the mitral valve) were measured as indexes of LV global diastolic function. Our methods and reproducibility of LV Doppler indexes were previously reported (24).
Pulsed TD extend Doppler applications beyond the analysis of intracardiac flow velocities until the quantitative assessment of the regional myocardial LV wall motion. It has been used in various heart diseases and is an accurate and reproducible method (25, 26, 27). By measuring myocardial wall velocities through spectral analyses, pulsed TD presents a high temporal resolution that allows the calculation of time intervals throughout the cardiac cycle (28, 29, 30, 31). In the present study pulsed TD was performed by transducer frequencies of 3.5–4.0 MHz, adjusting the spectral pulsed Doppler signal filters until they reached a Nyquist limit of 15–20 cm/sec, and using the minimum optimal gain. In an apical four-chamber view, a 5-mm pulsed Doppler sample volume was subsequently placed at the level of basal septum and basal LV lateral mitral annulus. The apical view was chosen to obtain a quantitative assessment of regional wall motion almost simultaneous with Doppler LV inflow and to minimize the incidence angle between the Doppler beam and LV longitudinal wall motion. The pulsed TD of a chosen segment (i.e. posterior septum) characterized by a positive myocardial systolic velocity (Sm) and two negative diastolic velocities, early (Em) and atrial (Am), of a normal subject is shown in Fig. 1
. The peak velocity of Sm (meters per second), precontraction time (PCTm; from the onset of electrocardiogram QRS to the beginning of Sm), contraction time (CTm; from the beginning to the end of the Sm wave; both in milliseconds), and PCTm/CTm ratio were calculated as myocardial systolic indexes. Em and Am peak velocities (meters per second), Em/Am ratio, and regional relaxation time (RTm; milliseconds), as the time interval occurring between the end of Sm and the onset of Em, were determined as myocardial diastolic measurements. Our TD methods and reproducibility were previously described (28); the intra- and interobserver regression coefficients were more than 0.85 (P < 0.00001) for all TD measurements in a population of 16 subjects.
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All analyses were performed using SPSS for Windows, version 6.0 (SPSS, Inc., Chicago, IL). Variables are presented as the mean ± SD. In view of the recognized influence of body surface area and heart rate on cardiovascular parameters (32, 33), standard Doppler echocardiographic and TD measurements were adjusted for body surface area and heart rate by covariance analyses. A t test for unpaired data estimated intergroup differences. Linear regression analyses and partial correlation test by Pearson’s method were performed to assess univariate relations. Differences were significant at P < 0.05.
Results
The demographic, clinical, and laboratory characteristics of the study population are listed in Table 1. The two groups were comparable for age, body surface area, systolic, diastolic and mean BP, heart rate, FT3, and FT4, whereas TSH was significantly higher in SH (P < 0.0001).
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records the analysis of Doppler echocardiographic measurements adjusted for body surface area and heart rate. All M mode measurements were comparable between the two groups. By standard Doppler analysis, only PEP and the PEP/LVET ratio (both P < 0.05), among systolic indexes, and IVRT (P < 0.005), among diastolic indexes, were impaired in SH compared with controls.
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displays the adjusted TD measurements in the two groups. PCTm, PCTm/CTm ratio, and RTm were all higher at the level of both assessed regions in SH compared with controls. The peak velocity Em/Am ratio of SH was significantly lower only at the level of the posterior septum. Figure 2 shows the TD pattern of the posterior septum in a normal control (upper panel) and in a SH patient (lower panel); PCTm and RTm were both prolonged in the SH patient.
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Among standard Doppler echocardiographic measurements, the adjusted IVRT was related to FT4 (r = -0.34) and to TSH (r = 0.35; both P < 0.05). The relations of PEP and PEP/LVET to FT4 and TSH were not significant. No significant relation of other standard Doppler indexes to LV mass index, relative diastolic wall thickness with thyroid hormones, and TSH was observed.
Among TD indexes, adjusted PCTm was associated with FT4 at the level of the mitral annulus (r = -0.36; P < 0.05), but not at the septal level. The relation between adjusted PCTm and TSH was not significant at both chosen LV levels. The septal (but not mitral annular) adjusted PCTm/CTm ratio was associated with TSH (r = 0.32; P < 0.05). The adjusted RTm was related to FT4 (r = -0.37; P < 0.05) at the level of the mitral annulus and to TSH (r = 0.40; P < 0.01) at the posterior septum.
No significant association of FT3 with either adjusted standard Doppler echocardiographic or adjusted TD measurements was observed.
Discussion
LV systolic and diastolic function has been previously investigated by noninvasive techniques in SH, but the degree of cardiac involvement varies in different studies. Some researchers reported a prolongation of LV PEP and an increase in the PEP/LVET ratio evaluated by polygraphic techniques in SH (9, 10, 11), whereas other studies did not find any changes in LV systolic time intervals (12, 13). Similarly, Tseng et al. (34) found that LV PEP, PEP/LVET ratio, and IVRT, assessed by echocardiographic examination of the aortic and mitral valves, were normal in SH. Arem et al. (35) found normal cardiac structure and function, mild prolongation of LV PEP during exercise, and slightly smaller LV end-diastolic dimension at rest in eight patients with SH by M-mode and Doppler analyses. Recent reports have observed an impairment of LV diastolic relaxation in SH, demonstrated by a prolonged IVRT and a higher A velocity amplitude, that is an increased contribution of atrial systole to LV filling (14, 15, 16). Moreover, a mild impairment of myocardial structure has been observed by videodensitometric analysis in SH, which has shown how the extent of this damage is directly associated with the loss of thyroid function (15, 16). The results include a wide range of cardiac abnormalities also by using radionuclide ventriculography. Foldes et al. (36) found a lower LV ejection fraction in SH than in euthyroid controls, both at rest and during physical exercise, whereas Bell et al. (37) reported an LV ejection fraction decrease only during maximal exercise. These discrepancies might be in part related to the different selection (age, sex distribution, and inclusion of patients with previous hyperthyroidism or unstable SH), to the different diagnostic criteria (too wide range of TSH levels) and to the impossibility of defining the onset and length of thyroid failure in the majority of assessed populations.
By the tools routinely used in the clinical setting, all of the findings permit a reliable evaluation of LV global morphology and function, but do not provide information about myocardial systolic and diastolic properties in the different LV regional segments. Pulsed TD has the peculiarity of providing a quantitative analysis of myocardial wall motion by measuring regional (both systolic and diastolic) velocities and time intervals of different LV walls (25, 26, 27, 28, 29, 30, 31). It is a method with a good reproducibility (28), and normal reference values of its measurements have been reported (38, 39).
In the present study we investigated myocardial function in SH using standard Doppler echocardiography and pulsed TD. We applied pulsed TD to both LV lateral mitral annulus and posterior septal wall. Interestingly, LV mitral annulus provides information on longitudinal LV global chamber function, whereas posterior septal TD measures systolic and diastolic indexes of a myocardial wall. One can assume that the measurements of the posterior septum, where TD signal is very clear and the Doppler angle is optimal, might be extended to the longitudinal motion of the other LV myocardial walls when regional wall motion abnormalities are not evident (26, 27).
In the absence of any detectable change in LV systolic function (fractional shortening, stroke volume, or cardiac output), standard Doppler did not show any significant difference in LV global diastolic indexes (transmitral E and A peak velocities and E/A ratio) between SH and controls. TD showed significant mild impairment of the Em/Am ratio at the level of the posterior septum in SH. It is worth noting that Em and Am peak velocities are markers of LV myocardial relaxation and atrial activity, respectively. Also, TD velocities have been demonstrated to be preload independent (40, 41) and provide reliable estimation of LV filling pressures (42). Therefore, the regional Em/Am ratio is a reliable parameter to detect myocardial impairment of passive diastolic properties of LV walls (24, 43, 44).
The main information from the present study was obtained by the assessment of TD myocardial (both systolic and diastolic) time intervals. In agreement with previous reports (14, 15, 16), standard Doppler revealed a significant prolongation of LV PEP, PEP/LVET ratio (systolic time intervals), and IVRT (diastolic time interval) in SH compared with controls. By TD analysis, PCTm, PCTm/CTm ratio, and RTm, all myocardial indexes corresponding to LV chamber standard Doppler-derived PEP, PEP/LVET ratio, and IVRT, respectively, were significantly prolonged at the level of both assessed regions in SH. Moreover, IVRT was related negatively to FT4 and positively related to TSH in the whole population; similar relations were found between the homologous TD-derived myocardial time intervals and hormones, as RTm was related to both FT4 and TSH, and PCTm was related to FT4. In addition, although the standard Doppler PEP/LVET ratio was not correlated to thyroid hormones and TSH, the septal PCTm/CTm ratio was positively associated with TSH.
On the basis of these data, TD-derived PCTm, RTm, and PCTm/CTm ratio appear to be useful indexes for the evaluation of LV myocardial involvement in SH. PCTm is a myocardial systolic time interval corresponding to the isometric period before the onset of LV myocardial contraction, and RTm reflects the energy-dependent phase of myocardial isometric relaxation developing when the aortic valve is closed and the LV mitral valve is not yet open (45). These parameters depend on cytosolic calcium concentrations modulated by the sarcoplasmatic reticulum’s ATP-dependent calcium ion transport (46). Of note, calcium channel transport is controlled by thyroid hormones (8), and it is reasonable to suppose that thyroid action might modulate both the systolic contraction and the time occurring for diastolic relaxation by these mechanisms. On the other hand, the PCTm/CTm ratio corresponds to the PEP/LVET ratio obtainable by standard Doppler, an index whose magnitude is inversely related to myocardial contractility (47).
A limitation of the present study has to be mentioned, as it rises from the performance of pulsed TD only at the level of posterior septum and LV mitral annulus. TD analysis of all 16 LV wall segments used to calculate the wall motion score index (48) might have provided more extensive information of myocardial changes in SH. This kind of assessment, however, should be very time expensive for the determination of so many measurements in each LV segment. In addition, the two chosen regions might reflect similar changes in the other LV myocardial walls in the absence of patients affected by coronary artery who were excluded by selection in the present study.
In conclusion, the current investigation confirms that stable SH is associated with cardiac functional abnormalities of systolic and diastolic phases. TD may be useful to detect LV impairment in this clinical setting and suggests possible pathophysiological mechanisms underlying involvement of the heart in SH.
Acknowledgments
We thank Gabriella Granata and Philip Sands for their help with the preparation of the manuscript.
Footnotes
Address all correspondence and requests for reprints to: Prof. Giovanni Lupoli, Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università Federico II, Via Pansini 5, 80131 Naples. Italy. E-mail: .
Abbreviations: Am, Atrial diastolic velocity; BP, blood pressure; CTm, myocardial contraction time; Em, early diastolic velocity; ET, ejection time; FT3, free T3; FT4, free T4; IVRT, isovolumic relaxation time; LV, left ventricular; LVET, left ventricular ejection time; PCTm, myocardial precontraction time; PEP, preejection period; RTm, myocardial relaxation time; SH, subclinical hypothyroidism; TD, tissue Doppler.
Received November 2, 2001.
Accepted June 7, 2002.
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