Emiliano A. Palmieri

Effects of Subclinical Thyroid Dysfunction on the Heart

The cardiovascular system is very sensitive to thyroid hormone, and a wide spectrum of cardiac changes has long been recognized in overt thyroid dysfunction (1-5). In contrast, cardiovascular impairment in patients with subclinical thyroid dysfunction has only recently been studied in detail (6-9). This condition, characterized by normal levels of circulating free thyroxine (FT4) and free triiodothyronine (FT3) and elevated (subclinical hypothyroidism) or below-normal (subclinical hyperthyroidism) thyroid-stimulating hormone (TSH) concentrations, is associated with changes in several cardiovascular measures. These changes support the view that subclinical thyroid dysfunction is not a compensated biochemical change sensu strictu. To clarify this process, we reviewed clinical studies of the consequences of subclinical thyroid dysfunction on the heart. Methods Data sources were articles in our collection about the cardiovascular effects of subclinical thyroid dysfunction in humans published between 1970 and September 2001. We checked that articles had not been overlooked by searching the MEDLINE database (keywords were thyroid hormone, heart, subclinical hypothyroidism, subclinical hyperthyroidism, and cardiovascular risk), references of relevant articles, textbooks, and abstracts of presentations at international thyroid meetings. Given the relatively few studies on the effect of subclinical thyroid disease on the cardiovascular system, we are confident that we considered all English-language peer-reviewed reports. All authors assessed the reports and agreed about article content. Subclinical Hypothyroidism Subclinical hypothyroidism, defined as increased serum TSH concentrations associated with normal FT4 and FT3 concentrations, may be caused by exogenous (l-thyroxine under-replacement in hypothyroid patients; medication with lithium, cytokines, iodine, or antithyroid drugs; and iodine 131 therapy or thyroidectomy) or endogenous (Hashimoto thyroiditis and previous subacute or silent thyroiditis) factors (8). Its prevalence ranges from 1.3% to 17.5%, depending on age, sex, and iodine intake (10-14). A large cross-sectional study from Colorado reported a mean prevalence of 9% (15). People with thyroid antibodies caused by Hashimoto thyroiditis are prone to subclinical hypothyroidism. The incidence of subclinical hypothyroidism, derived from a review (14) of three longitudinal studies that included a total of 2956 patients (with 6-, 10-, and 20-year follow-up, respectively) (16-18), is 2.1% to 3.8% per year in thyroid antibodypositive patients and about 0.3% per year in thyroid antibodynegative patients. The annual risk for developing overt hypothyroidism after 20 years is 4.3% in women with increased TSH concentrations and thyroid antibodies and 2.6% in women with subclinical hypothyroidism without thyroid antibodies (18). Cardiac Manifestations Table 1 lists the cardiovascular abnormalities reported in subclinical hypothyroidism (19-33). Resting heart rate was normal in all patients in whom it was evaluated (21, 22, 25, 28-30, 33). Cardiac function, evaluated from systolic time intervals, was also normal in patients with subclinical hypothyroidism (19, 27). In contrast, the preejection period and the interval from Q wave to pulse arrival at the brachial artery were prolonged, and the preejection periodleft ventricular ejection time ratio was higher in 20 patients with subclinical hypothyroidism than in the same patients after l-thyroxine replacement therapy (20). Table 1. Cardiovascular Abnormalities in Subclinical Hypothyroidism In the first double-blind study of the effects of 1 year of l-thyroxine therapy compared with placebo in 17 patients with subclinical hypothyroidism of different origins, the preejection periodleft ventricular ejection time ratio was significantly decreased after l-thyroxine therapy, particularly in patients with the highest ratio (>0.390) (21). In 18 patients, l-thyroxine caused a small but significant increase in left ventricular ejection fraction (evaluated by radionuclide ventriculography) during maximal exercise but caused no change at rest or during moderate exercise (22). In 10 patients evaluated before and after TSH concentrations were normalized with l-thyroxine, the treatment did not affect left ventricular ejection fraction at rest but did enhance the increase in ejection fraction during exercise (23). In the same study, sodium nitroprusside produced similar increases in cardiac output in patients with subclinical hypothyroidism and in euthyroid persons. However, in the former group, enhanced cardiac output was due to a large increase in heart rate and reduced stroke volume, whereas euthyroid persons had a smaller increase in heart rate and no change in stroke volume. Therefore, restoration of euthyroidism by l-thyroxine improves systolic function on effort in patients with subclinical hypothyroidism. This could have resulted from improved myocardial contractility and, perhaps, lusitropic function. The preejection period was prolonged in only 5 of 17 patients with subclinical hypothyroidism compared with 50 euthyroid controls, whereas the mean left ventricular ejection fraction was reduced both at rest and during isometric exercise (24). In the first double-blind, crossover study of women with subclinical hypothyroidism due to Hashimoto thyroiditis, 20 randomly selected women with primary subclinical hypothyroidism received l-thyroxine and placebo for 6 months each (25). Left ventricular systolic function was assessed from systolic time intervals before and after l-thyroxine. Heart ratecorrected preejection period and the preejection periodleft ventricular ejection time ratio decreased significantly after treatment. In another study, left ventricular function, evaluated by echocardiography-derived systolic time intervals, was unchanged in 22 patients with subclinical hypothyroidism compared with normal controls (26). In eight subclinical hypothyroid patients evaluated at rest and during bicycle-ergometer exercise testing before and after l-thyroxine treatment, Doppler-derived systolic time intervals showed a more prolonged preejection period and a higher preejection periodleft ventricular ejection time ratio during pretreatment maximum exercise (28). Echocardiographic left ventricular end-diastolic dimension was slightly but significantly lower before l-thyroxine treatment. Left ventricular structure and function at rest were evaluated by using Doppler echocardiography in 26 selected patients with stable subclinical hypothyroidism due to Hashimoto thyroiditis and in 30 normal controls (29). In 10 randomly selected patients, the evaluation was repeated after 6 months of l-thyroxine therapy (daily dose, 68 g). No significant abnormality in left ventricular structure was seen, whereas Doppler-derived mean aortic acceleration, a reliable index of left ventricular systolic function, was significantly lower in patients than in controls. This acceleration normalized after l-thyroxine therapy. Furthermore, isovolumic relaxation time was prolonged, and the earlylate ratio of Doppler-derived transmitral peak flow velocities was lower in patients than in controls. Both measures of diastolic function returned to normal after l-thyroxine replacement. Doppler echocardiography and ultrasonic myocardial textural analysis confirmed these findings in 16 patients with subclinical hypothyroidism (30). They had a significantly increased left ventricular mass and lower cyclic variation measures (percentage systolic/diastolic change in mean gray levels) in both the interventricular septum and the left ventricular posterior wall (30). Radionuclide ventriculography revealed a longer time to peak filling rate in 10 patients with subclinical hypothyroidism than in 10 normal controls (32). This index of diastolic function normalized after l-thyroxine replacement. Using stress Doppler echocardiography and cardiopulmonary exercise testing, Kahaly (31) studied 20 patients with subclinical hypothyroidism before and after l-thyroxine therapy and 20 normal controls. At rest, the cardiac measures recorded in untreated patients approximated those obtained in controls and in euthyroid patients. However, patients had significantly lower stroke volume, cardiac index, and peak aortic flow velocity and significantly prolonged preejection period during exercise. All measures normalized after a euthyroid state was achieved. Furthermore, the oxygen pulse (oxygen uptake per heartbeat), an index of stroke volume, was significantly decreased both at the anaerobic threshold and at maximal work capacity, and work rate was reduced at the anaerobic threshold in patients versus controls. These measures normalized after replacement therapy. Finally, in a double-blind, placebo-controlled study of the effects of l-thyroxine replacement therapy on cardiac structure and function in subclinical hypothyroidism, cardiac measures, evaluated by Doppler echocardiography and videodensitometry, were almost normal after l-thyroxine therapy (33). Coronary Artery Disease Overt hypothyroidism increases serum cholesterol levels (15, 27, 34-36), but it is not known whether subclinical hypothyroidism affects serum lipid profiles. Serum cholesterol levels have been significantly higher in patients with subclinical hypothyroidism than in normal controls (31, 37-40). In other studies, levels were only marginally increased (41-43). In three studies, the prevalence of subclinical or overt hypothyroidism was higher in hypercholesterolemic patients (44-46), a finding not confirmed in a subsequent study (47). Other markers of atherosclerotic risk described in overt hypothyroidism (enhanced low-density lipoprotein oxidation, elevated lipoprotein[a] levels, and hyperhomocysteinemia) may also be responsible for an association between subclinical hypothyroidism and coronary artery disease (48-50). Of interest, a recent quantitative review of patients with s

Complex regulation of the cyclin-dependent kinase inhibitor p27kip1 in thyroid cancer cells by the PI3K/AKT pathway: regulation of p27kip1 expression and localization.

Functional inactivation of the tumor suppressor p27(kip1) in human cancer occurs either through loss of expression or through phosphorylation-dependent cytoplasmic sequestration. Here we demonstrate that dysregulation of the PI3K/AKT pathway is important in thyroid carcinogenesis and that p27(kip1) is a key target of the growth-regulatory activity exerted by this pathway in thyroid cancer cells. Using specific PI3K inhibitors (LY294002, wortmannin, and PTEN) and a dominant active AKT construct (myrAKT), we demonstrated that the PI3K/AKT pathway controlled thyroid cell proliferation by regulating the expression and subcellular localization of p27. Results obtained with phospho-specific antibodies and with transfection of nonphosphorylable p27(kip1) mutant constructs demonstrated that PI3K/AKT-dependent regulation of p27(kip1) mislocalization in thyroid cancer cells occurred via phosphorylation of p27(kip1) at T157 and T198 (but not at S10 or T187). Finally, we evaluated whether these results were applicable to human tumors. Analysis of 100 thyroid carcinomas indicated that p27(kip1) phosphorylation at T157/T198 and cytoplasmic mislocalization were preferentially associated with activation of the PI3K/AKT pathway. Thus the PI3/AKT pathway and its effector p27(kip1) play major roles in thyroid carcinogenesis.

Subclinical Hypothyroidism and Cardiac Function

The cardiovascular system is sensitive to the action of thyroid hormone. However, although a wide spectrum of cardiac abnormalities has long been recognized in patients with overt thyroid dysfunction, the question of cardiac involvement in patients with subclinical thyroid dysfunction has been investigated only in the last two to three decades. Most clinical studies have shown that subclinical hypothyroidism or hyperthyroidism is associated with changes in several cardiac parameters. More specifically, the literature on cardiac involvement in subclinical hypothyroidism consistently shows that patients have resting left ventricular diastolic dysfunction evidenced by delayed relaxation, and impaired systolic dysfunction on effort that results in poor exercise capacity. Whether or not subclinical hypothyroidism also affects left ventricular systolic function at rest remains controversial. Studies of subclinical hypothyroid patients before and after euthyroidism was achieved with levothyroxine replacement provided evidence of impaired resting left ventricular systolic function. Indeed, at-rest left ventricular systolic function was substantially normal in most studies of subclinical hypothyroid patients compared to normal control subjects. Drawing on these data, it appears that subclinical hypothyroidism should be considered a mild form of thyroid failure, associated with initial signs of cardiovascular hypothyroidism. Therefore, it would seem appropriate to initiate timely treatment of patients with mild thyroid failure to prevent cardiac involvement.

Growth hormone corrects vascular dysfunction in patients with chronic heart failure

OBJECTIVES The goal of this study was to test the hypothesis that growth hormone (GH) administration to patients with chronic heart failure (CHF) corrects their vascular dysfunction. BACKGROUND Endothelial dysfunction is a prominent feature of CHF. Recent evidence indicates that GH plays a role in vascular reactivity. METHODS We studied vascular reactivity in 16 patients with CHF (New York Heart Association class II to III) before and after three months of GH (4 IU subcutaneously every other day) or placebo administration in a randomized, double-blind trial. We measured forearm blood flow (FBF) by strain-gauge plethysmography during intrabrachial, graded infusion of acetylcholine (ACh) and sodium nitroprusside (NP). We also measured the forearm balance of nitrite and cyclic guanosine monophosphate (cGMP) before and during ACh infusion. Maximal oxygen uptake (VO2max) was measured by breath-to-breath respiratory gas analysis. RESULTS Before treatment, the response of FBF to ACh was flat (p = NS). Growth hormone, but not placebo, greatly improved this response (p = 0.03) and, concomitantly, increased the forearm release of nitrite and cGMP (p < 0.05). Growth hormone also potentiated the FBF response to NP (p = 0.013). Growth hormone interacted with ACh response (p = 0.01) but not with the response to NP (p = NS). Accordingly, GH enhanced the slope of the dose-response curve to ACh (p < 0.05) but not to NP. The VO2max increased significantly after GH treatment (20 +/- 2 and 26 +/- 2 ml x Kg(-1) x min(-1) before and after GH treatment, respectively, p < 0.05) but not after placebo. CONCLUSIONS A three-month treatment with GH corrected endothelial dysfunction and improved non-endothelium-dependent vasodilation in patients with CHF. The data highlight the potential role of GH in the progression of congestive heart failure.

HMGA1 protein overexpression in human breast carcinomas: correlation with ErbB2 expression.

We measured, by immunohistochemistry, HMGA1 protein expression in 212 breast tissue specimens: 6 normal samples, 28 hyperplastic lesions (13 with cellular atypia), 11 fibroadenomas, 10 in situ ductal carcinomas, 144 ductal carcinomas, and 13 lobular carcinomas. HMGA1 was not expressed in normal breast tissue; HMGA1 staining was intense in 40% of hyperplastic lesions with cellular atypia and in 60% of ductal carcinomas and weak in fibroadenomas and in hyperplastic lesions without cellular atypia. Because HMGA1 expression was similar among ductal breast carcinomas with different histologic grading, we evaluated the association between HMGA1 expression and that of other markers of breast carcinoma invasion (estrogen and progesterone receptors, Ki-67 antigen, and ErbB2) in 21 cases of grade 3 breast ductal carcinomas and 7 cases of breast lobular carcinomas. We found that HMGA1 expression tended to be associated only with c-erbB-2 expression (Spearman rho: 0.36; P = 0.065). Taken together, these results suggest that HMGA1 expression might be a novel indicator for the diagnosis and prognosis of human breast cancer.

Improvement of left ventricular hypertrophy and arrhythmias after lanreotide-induced GH and IGF-I decrease in acromegaly. A prospective multi-center study

We report the results of a prospective Italian multi-center study of the effects of lanreotide, a slow-release somatostatin analog, on left ventricular morphology and function and on the prevalence of ventricular arrhythmic events in 19 patients with active, newly diagnosed, uncomplicated acromegaly. Cardiac features were evaluated with Doppler-echocardiography and 24-h Holter ECG monitoring at baseline and after 6 months of lanreotide therapy. Fifteen patients (78.9%) had left ventricular hypertrophy. Lanreotide treatment significantly decreased the left ventricular mass (127.8±6.9 vs 140.7±7.1 g/m2, p<0.001) and left ventricular hypertrophy significantly disappeared in 6 of these patients. Treatment did not significantly affect systolic function, whereas it increased the Doppler- derived early-to-late mitral flow velocity, (E/A) ratio, of early-to-late trans-mitral flow velocity (1.34±0.1 vs 1.09±0.06, p=0.001). Stroke volume was slightly but not significantly increased after treatment, whereas systolic BP was significantly higher (134±14 vs 129±13 mmHg, p<0.05). The 24-h mean heart rate was significantly reduced after treatment (66.5±11 vs 71.5±20 beats/min, p<0.05). Supra-ventricular premature beats (>50/24 h) occurred in 16.6% of patients and were unaffected by treatment. Differently, ventricular premature beats (>50/24 h) occurred in 33.3% of patients before treatment vs 16.5%, after treatment. In conclusion, lanreotide reduced the left ventricular mass, and improved ventricular filling and ventricular arrhythmic profile. (J.

Subclinical hypothyroidism and cardiovascular risk: a reason to treat?

Subclinical hypothyroidism (SH), defined by elevated serum levels of thyroid stimulating hormone (TSH) with normal levels of free thyroid hormones, is common in adults, especially in women over 60 years of age. Among individuals with this condition, up to two-thirds have serum TSH levels between 5–10 mU/L and thyroid autoantibodies; almost half of them may progress to overt thyroid failure, the annual percent risk increasing with serum TSH level. There is evidence that elevated TSH levels in patients with SH do not reflect pituitary compensation to maintain euthyroidism, but a mild tissue hypothyroidism sensu strictu. When lasting more than 6–12 months, SH may be associated with an atherogenic lipid profile, a hypercoagulable state, a subtle cardiac defect with mainly diastolic dysfunction, impaired vascular function, and reduced submaximal exercise capacity. The deviation from normality usually increases with serum TSH level (‘dosage effect’ phenomenon). Restoration of euthyroidism by levothyroxine (LT4) treatment may correct the lipid profile and cardiac abnormalities, especially in patients with an initially higher deviation from normality and higher serum TSH levels. Importantly, a strong association between SH and atherosclerotic cardiovascular disease, independent of the traditional risk factors, has been recently reported in a large cross-sectional survey (the Rotterdam Study). However, whether SH confers a high risk for cardiovascular disease, and whether LT4 therapy has a long-term benefit that clearly outweighs the risks of overzealous treatment in these individuals, remain topics of controversy. Therefore, until randomized, controlled, prospective, and adequately powered trials provide unequivocal answers to these critical questions, it is advisable to prescribe LT4 therapy on a case-by-case basis, taking into account the risk of progressive thyroid failure and the risk of cardiovascular events

Cyclin D1 and D3 overexpression predicts malignant behavior in thyroid fine-needle aspirates suspicious for Hurthle cell neoplasms

Thyroid fine‐needle aspiration (FNA) samples that feature a follicular‐patterned, monotonous Hurthle (oncocytic) cell population cannot be diagnosed reliably. The authors of this report recently identified cyclin D3 overexpression on histologic sections of Hurthle cell carcinoma. In this study, they assessed the diagnostic value of cyclin D3 immunohistochemistry added to routine cytology.

UbcH10 expression in human lymphomas

Aims:  The UbcH10 ubiquitin‐conjugating enzyme plays a key role in regulating mitosis completion. We have previously reported that UbcH10 overexpression is associated with aggressive thyroid, ovarian and breast carcinomas. The aim of this study was to investigate UbcH10 expression in human lymphomas.

Circulating levels of growth hormone, insulin-like growth factor-I and prolactin in normal, growth retarded and anencephalic human fetuses

We measured growth hormone (GH), insulin-like growth factor-I (IGF-I), and both total and glycosylated prolactin (PRL) levels in 131 blood samples obtained by cordocentesis in normal and abnormal fetuses from 19 to 40 weeks of gestation. In normal fetuses, IGF-I and PRL levels showed a positive correlation and GH a negative correlation with gestational age. A negative relation between GH and IGF-I levels was observed, while PRL did not show any correlation with both GH and IGF-I concentrations. IGF-I increased from 5.6±3 (at 19–22 weeks) to 10.7±5 nmol/l at term; GH decreased from 31±10 to 7.7±4 μg/l and PRL increased from 16±18 to 139±76 μg/l. Glycosylated PRL accounted for about 15% of total PRL, a value similar to that found in normal adults. In 27 fetuses of 27–37 weeks with intra-uterine growth retardation, GH and PRL levels were higher and IGF-I levels lower than in normal fetuses matched for week of gestation. In 8 anencephalic fetuses of 19–26 weeks of gestation, both GH and IGF-I levels were lower, and PRL levels were higher than in matched controls. Altogether these data support the views that a) both GH and PRL secretion are under the hypothalamic control during fetal development, b) the serum GH decrease from midgestation to the end of pregnancy is mediated by the negative feed-back mechanism of increasing IGF-I levels and c) IGF-I production is mainly regulated by fuel supply and only partially by GH.