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Original Studies |
Department of Internal Medicine, University of Pisa School of Medicine, 56126 Pisa, Italy
Address all correspondence and requests for reprints to: Fabio Monzani, M.D., Department of Internal Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy. E-mail: fmonzani{at}med.unipi.it
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients had a significantly higher isovolumic relaxation time (3.1 ± 0.5 vs. 2.6 ± 0.6; P < 0.03), peak A (0.77 ± 0.16 vs. 0.56 ± 0.13 m/s; P < 0.01), and preejection/ejection time (PEP/ET) ratio (0.72 ± 0.05 vs. 0.57 ± 0.06; P < 0.03) and a lower CVI (P < 0.0001) than controls. CVI was inversely related to TSH level (P < 0.0001) and PEP/ET ratio (P < 0.01). L-T4-treated patients showed a significant reduction of the PEP/ET ratio (P < 0.05), peak A (P < 0.05), and isovolumic relaxation time (P < 0.05) along with a normalization of CVI. Conversely, no changes were observed in the placebo-treated group.
In conclusion, sHT affects both myocardial structure and contractility. These alterations may be reversed by L-T4 therapy.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Recently, we demonstrated that sHT is associated with early alterations in both myocardial function and structure, as investigated by conventional echocardiography and videodensitometric analysis (15). In the present study we report the effect of L-T4 replacement therapy on myocardial function and structure in 20 consecutive sHT patients.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). Cardiovascular and
respiratory diseases were excluded in both patients and controls by a
complete clinical work-up. Routine laboratory chemistry was normal in
all, and none was taking any drug. Before inclusion in the protocol, a
blood sample for the determination of FT4,
FT3, antithyroglobulin, and antithyroid
peroxidase antibodies (TPO-Ab), and TSH was obtained at 0800 h
after an overnight fast. Patients were randomly assigned to receive
either L-T4 (Eutirox, Bracco S.p.A.,
Milan, Italy) replacement therapy (0.05 mg daily as two 0.025-mg
tablets), or two identical placebo tablets in a blinded manner. All
patients returned after 3 months for repeat thyroid function tests. One
of us (N.C.) had access to the treatment code and increased the dose of
L-T4 by 0.025 mg if the TSH level was
still greater than 3.6 mIU/L. This process continued until euthyroidism
was reached; the mean final replacement dose of
L-T4 was 0.065 mg daily. Patients
taking placebo completed an identical protocol; some of them were given
additional placebo tablets to maintain the blindness of the study. Six
months after the serum TSH level had become normal (in the
L-T4-treated patients) or 6 months
after the final dosage was assigned (in the placebo-treated patients),
the patients were readmitted for repeat evaluations of all parameters.
The L-T4-treated patients continued
to take the same dose of L-T4 until 6
months later, when they returned for a third and final evaluation. As
at the 6-month control point a significant improvement of myocardial
function was observed in the
L-T4-treated patients, the other
group of patients discontinued placebo and started
L-T4 replacement therapy. The study
protocol was reviewed and approved by the institutional ethics
committee; all patients gave their informed written consent to the
study.
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M-mode and 2D echocardiograms and Doppler analysis were performed in all subjects by means of a commercially available apparatus (Sonos 1000, Hewlett-Packard Co., Palo Alto, CA; equipped with a 2.5- or 3.5-MHz transducer). 2D images were obtained in parasternal long axis and short axis views and apical two- and four-chamber views using standard transducer positions. The following parameters were obtained from the M-mode echocardiographic tracings under the guide of 2D imaging: end-diastolic diameter, percent fractional left ventricle shortening, septal and posterior wall thickness at end-diastole, and left ventricular mass index. Cardiac output was calculated according to the formula (end diastolic volume - end systolic volume) x heart rate. Each of these parameters was the mean of five readings over consecutive cardiac cycles and was corrected for body surface area; the left ventricular volumes were derived by Teicholtz’s formula. Systemic vascular resistances were then calculated according to the formula (80 x mean blood pressure)/cardiac output, where 80 is a conversion factor from millimeters of Hg per min/L to dynes per s/cm-5.
Pulsed Doppler systolic aortic flow measurements were obtained as previously described (16). Preejection period (PEP) and ejection time (ET) were measured in milliseconds; the PEP/ET ratio was also calculated. The peak transmitral flow velocity in early diastole (peak E) and late diastole (peak A), the mitral acceleration and deceleration times, and the isovolumic relaxation time (IVRT) were measured. Each of these parameters was the mean of five readings over consecutive cardiac cycles and was corrected for heart rate according to Bazett’s formula (i.e. by the square root of the R-R interval). Intra- and interobserver coefficients of variation averaged 7.5% and 10%, respectively. As expected, the reproducibility of measurements on the posterior wall was lower than the corresponding measurements on the septum.
Ultrasonic videodensitometry
Quantitative analysis of the 2D spatial pattern of the echocardiographic images provides a morphological characterization of myocardial tissue. The technique has proven useful in the identification of various cardiomyopathies in experimental animals and humans (17, 18, 19, 20, 21) and was carried out as previously described (15). To achieve a precise and reproducible sampling of textural parameters, during the echocardiographic examination the gain settings and compensation profiles were adjusted for all study subjects to obtain apparently uniform myocardial brightness throughout the echocardiogram. The gray scale transfer function was adjusted to be linear for the entire video signal range, and no reject, enhancement, or dynamic range was used. The echocardiographic images were recorded on videotape (SVHS Panasonic AG-7350; Panasonic, Secaucus, NJ) and then directly transferred to a calibrated video digitization system. These images were converted into 256 x 256 pixels of 256 gray levels each (0 = black, 255 = white), with 8 bits of intensity range by using a commercial real-time videodigitizer (Tomtec Imaging Systems, Inc., Boulder, CO). One cardiac cycle (RR wave) was automatically divided into 12 frames independently of heart rate. End-diastole was defined as the point in the cardiac cycle at the onset of the electrocardiographic R wave. End-systole was defined as the time of apparent minimal left ventricular chamber size and occurred near the peak of the T wave. The images of end-diastole and end-systole were selected with an optimal visualization of both the interventricular septum and the left ventricular posterior wall. The regions of interest for texture analysis were chosen by the consensus of two observers, who were blinded to the results of conventional echocardiography, by using an interactive computer program. The region of interest, always of the same size (32 x 42 pixels), was placed in the same location in the septum (midseptum) and the posterior wall (midposterior) at both end-systolic and end-diastolic frames. Only the myocardium was included; endocardial and pericardial specular echoes were excluded to avoid artifacts. A histogram of the echocardiographic gray level distribution was generated for each region of interest. The mean gray level (MGL) of each cavity region (background signal) was subtracted from the absolute MGL obtained for each region of interest. A quantitative analysis of the shape of each distribution was also performed using skewness and kurtosis. The CVI was calculated as follows: (MGLend-diastole - MGLend-systole)/MGLend-systole and was expressed as a percentage (17, 18). Measurements were averages of at least 5 consecutive cardiac cycles.
Serological parameters
Serum FT3 and FT4 levels were measured by specific RIA (Techno-Genetics Recordati, Milan, Italy). TSH was determined with an ultrasensitive immunoradiometric assay method (Cis Diagnostici, Tronzano Vercellese, Italy). The coefficients of variation were 3.8% or less (intraassay) and 5% or less (interassay). Anti-Tg antibodies were measured by a specific immunoradiometric assay (TG-Ab IRMA, Biocode, Sclessin, Belgium); anti-TPO antibodies were measured by specific RIA (AB-TPO, Sorin Biomedica, Saluggia, Italy). Normal values in our laboratory are: FT4, 7.2–20 pmol/L; FT3, 3.7–8.6 pmol/L; TSH, 0.30–3.6 mIU/L, antithyroglobulin, less than 50 IU/mL; and TPO-Ab, less than 10 IU/mL.
Statistical analysis
Data are given as the mean ± SD unless
otherwise stated. Statistical analysis was performed by Student’s
t test for paired data, ANOVA for repeated measures, or
2 test, as appropriate; statistical
significance was set at P < 0.05. Correlation
coefficients were calculated by standard methods.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The thyroid hormone profiles of patients and controls are reported
in Table 1
. At baseline, TSH levels were significantly higher in sHT
patients than controls (P < 0.001), whereas
FT3 and FT4 were
comparable. No significant differences in serum TSH,
FT4, or FT3 levels were
observed between the placebo- and
L-T4-treated groups of sHT
patients. At the 6-month follow-up, serum TSH levels had returned
within the normal range in the
L-T4-treated group and were
now significantly lower than those in the placebo-treated group
(P = 0.0001). At 1 yr, no further modification in the
serum TSH level was observed. Serum FT3 and
FT4 levels remained within the normal range
during the entire treatment course in both placebo- and
L-T4-treated patients.
Conventional echo-Doppler parameters
At baseline, sHT patients had a significantly higher IVRT
(3.1 ± 0.5 vs. 2.6 ± 0.6 ms; P
< 0.03), and peak A values (0.77 ± 0.16 vs. 0.56
± 0.13 m/s; P < 0.01) than controls. Moreover, PEP
(6.8 ± 0.4 vs. 5.0 ± 0.5 ms; P
< 0.02) as well as the PEP/ET ratio (0.72 ± 0.05 vs.
0.57 ± 0.06; P < 0.03) were significantly longer
in patients than controls. In contrast, systemic vascular resistances
were similar in the two groups (Table 2).
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). By
contrast, no significant change in any of these parameters was observed
in the placebo-treated group (Table 4).
Systemic vascular resistances did not significantly change in either
group of patients during the entire treatment course.
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At baseline, patients had lower CVI than controls at both septum (-9.2 ± 15.4% vs. 35 ± 10.3%; P < 0.0001) and posterior wall (-2.7 ± 19.3% vs. 45.0 ± 16.2%; P < 0.0001). CVI was directly related to serum FT3 level (at septum: r = 0.42; P < 0.005; at posterior wall: r = 0.38; P < 0.002) and was inversely related to TSH levels (at septum: r = -0.59; P < 0.001; at posterior wall: r = -0.48; P < 0.003). Furthermore, at both sites CVI showed an inverse correlation with left ventricular mass index (r = -0.50; P < 0.05 and r = -0.48: P < 0.05, respectively) and the PEP/ET ratio (r = -0.43; P < 0.03 and r = -0.42; P < 0.05, respectively).
Patients treated with placebo did not show any significant change in
CVI at either septum or posterior wall. In contrast, patients receiving
L-T4 therapy showed a significant
increase in CVI at both septum and posterior wall (P <
0.01 vs. baseline) at 6 months. A further significant
improvement was observed after 1 yr of therapy, when CVI values became
similar to those of controls (Table 5).
Finally, in L-T4-treated
patients the treatment-induced changes in serum TSH levels were
inversely related to CVI values at both septum and posterior wall
(r = -0.65; P < 0.0001; Fig. 1).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the present study we performed a strict selection of patients with stable sHT, excluding patients with confounding factors particularly affecting the cardiovascular system. The current results demonstrate that a significant impairment of both left ventricular diastolic and systolic function is present in subclinical hypothyroidism, and that these alterations are fully reversible with L-T4 replacement therapy. However, a longer period of treatment is needed to reverse the alterations of left ventricular diastolic function than that required to reverse those of systolic ventricular function. Overall, our data confirm the results reported by two previous randomized studies carried out with simultaneous recording of electrocardiogram, phonocardiogram, and carotid pulse tracing or conventional Doppler echocardiography (9, 13). However, one study (9) evaluated only systolic time intervals, and the other (13) was not performed with a placebo group.
The videodensitometric method has been previously used to describe preclinical abnormalities of myocardial texture in diverse conditions such as myocarditis, essential hypertension, myocardial ischemia, and amyloidosis (19, 20, 21, 31). In the present study by videodensitometric analysis we were able to detect a significantly lower variation in MGL during cardiac cycle in sHT patients than in controls. A decreased cyclic variation of the echo amplitude in the face of essentially normal load-dependent functional indexes (left ventricle fractional shortening and systemic vascular resistances) suggests that changes in CVI amplitude may be a distinct, early index of altered intramural myocardial function, i.e. impaired intrinsic myocardial contractility (32). This interpretation is in line with the observed inverse relationship between CVI and the PEP/ET ratio. As was the case for conventional echocardiographic parameters, a progressive improvement of the videodensitometric picture was observed during L-T4 treatment. In fact, a significant increase in CVI was already detectable at 6 months, and normalization was achieved after 1 yr of replacement therapy. It is noteworthy that the treatment-induced changes in CVI and serum TSH were quantitatively related to one another, suggesting a causal relationship. Thus, to our knowledge this is the first study to report the existence in sHT of both functional and textural myocardial alterations, which are reversible upon specific hormone replacement.
Thyroid hormone deficiency can alter cardiac muscle function by decreasing the activity of several enzymes involved in the regulation of myocyte calcium fluxes (33) and the expression of several contractile proteins (34). Cardiac muscle functional changes, such as alterations in calcium uptake and release jointly leading to depressed inotropism (35), have been documented to occur in hypothyroid animals. The definition of sHT implies that circulating thyroid hormone levels are still in the normal range. Therefore, it may seem puzzling to find cardiac alterations similar to those observed in frank hypothyroidism. However, minute decrements in hormone synthesis may over time lead to biochemical and functional signs qualitatively similar to those of overt hypothyroidism.
Our data suggest that myocardial dysfunction in sHT is also associated with modifications of the acoustic properties of myocardial tissue. Different structural components can influence the acoustic properties of the myocardium, such as collagen, ventricular muscle fiber orientation, tissue water content, and capillary blood flow distribution. A direct relation has been reported between integrated backscatter and hydroxyproline content in autopsied human hearts with fibrotic changes due to remote myocardial infarction (36). Furthermore, a correlation has been found between regional echo amplitude and myocardial collagen content as measured endobioptically (37). Scattered geometry is another determinant of myocardial reflectivity. In fact, myocardial scattering intensity depends directly on myocyte size; the microstructural arrangement of myocardial cells embedded in a collagen matrix may provide a sufficient local acoustic impedance mismatch to account for the scattering from normal myocardium (36). The end-diastolic MGL decrease observed in our sHT patients may reflect an altered myocardial composition, possibly due to increased albumin content in the extracellular space or to an increase in capillary permeability (38). In physical terms, the increase in tissue water content can influence the acoustic properties of the myocardium. Direct support for this interpretation would be provided by histological studies of myocardial tissue if they were feasible.
In conclusion, our data suggest that sHT is associated with a subtle, reversible impairment of both diastolic and systolic myocardial functions. Videodensitometric analysis confirms and extends these functional defects by displaying alterations in myocardial texture. Therefore, subclinical hypothyroidism is better considered a condition of minimal tissue hypothyroidism than a compensated state. Indeed, L-T4 replacement therapy should be advised for these patients with the aim to prevent both the progression to frank hypothyroidism and the development of clinically significant myocardial dysfunction.
Received July 28, 2000.
Revised October 6, 2000.
Accepted November 27, 2000.
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), and after 6 months (
) or 1 yr (
) of
L-T4 replacement therapy.