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Thrombolysis remains a very acceptable reperfusion option for ST-elevated acute myocardial infarction (STEMI); however, it fails relatively frequently and unpredictably.To investigate correlates of lytic failure (according to the standard ST resolution criterion) in current pharmacointensive STEMI care (dual antiplatelets with antithrombin), we analyzed retrospectively clinical data and echocardiographic left ventricular systolic function before initiation of reperfusion treatment in Killip I-III STEMI patients admitted to our 'spoke' intensive cardiac care unit between 1 January and 31 December 2010.Of the 53 STEMI patients enrolled, 28% failed thrombolysis. Patients who did not reperfuse were less frequently active smokers (P0.05, odds ratio 4.33) and had a higher prevalence of hemodynamic instability [heart rate/SBP (i.e. shock index)0.75; P0.05, odds ratio 13.45) and left ventricular systolic dysfunction (ejection fraction45%; P0.005, odds ratio 11.14). In an exploratory multivariable logistic regression analysis, those variables were the only discriminators independently associated with lytic failure (adjusted odds ratio 8.74, 230.10, and 18.22, respectively, all P0.05). Moreover, the combined variables had a high accuracy for prediction of failed thrombolysis (all discriminators positive, 99% specificity and 83% positive predictive value).Our pilot study indicates that thrombolysis still fails in about one-third of STEMI patients despite the current pharmacointensive approach and suggests that failed ST resolution might be independently associated with nonsmoking habit and pretreatment hemodynamic instability and left ventricular systolic dysfunction. Larger trials are needed to verify the potential clinical implications of our preliminary observation.

BACKGROUND: Thyroid fine-needle aspiration (FNA) samples belonging to the follicular neoplasm/suspicious for malignancy classes are controversial. The authors identified UbcH10 as a marker useful in the diagnosis of several neoplasms, including thyroid cancer. Here, analysis of UbcH10 expression by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry was applied to FNAs. METHODS: A series of 84 follicular neoplasm/suspicious for malignancy FNAs with histological follow-up (30 malignant) was prospectively collected. UbcH10 immunostaining was performed on cell blocks and compared with that of the proliferation marker Ki-67. At the mRNA level, UbcH10 was compared with CCND2 and PCSK2 expression, these latter being the best performing components of the previously reported 3-gene assay; to determine the diagnostic accuracy, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for each gene individually and in combination was evaluated. RESULTS: UbcH10 and Ki-67 shared a similar pattern; although UbcH10 expression was higher in malignant than in benign lesions (P < .001), staining was sporadic, and the cutoff value derived by the ROC analysis was too low (1.25%) for routine application. Conversely, UbcH10 expression assessment by quantitative RT-PCR was effective. UbcH10 mRNA levels associated with malignant histology were significantly higher than those associated with benign histology (P = .02). The AUC was 0.74 for UbcH10, 0.81 for CCDN2, 0.62 for PCSK2, and 0.84 for UbcH10 and CCND2 combination. CONCLUSIONS: UbcH10 quantitative RT-PCR analysis, rather than immunohistochemistry, is useful to increase the detection of malignancy in thyroid FNAs. UbcH10 may be added as a panel component in quantitative RT-PCR–based assays. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.

Aims To evaluate the reliability of a regional wall motion score index (WMSI)-based method for assessment of left ventricular (LV) ejection fraction (EF). Methods and results Two-dimensional (2D) echocardiography was used to assess a LV 16-segment-based regional wall motion. Each segment received a score based on contractility status: 4, normal kinesis; 3, mild; 2.5, moderate; and 1.5, severe hypo-kinesis; 0, akinesis; −1, dyskinesis; 3.5 and 4.5 were used for low-normal and high-normal kinesis; 5 for hyper-kinesis. Hence, WMSI-based EF was derived by summing the score assigned to each segment. Contextually, EF was evaluated by real-time three-dimensional (3D) echocardiography and by traditional Simpson's method (2D). Global longitudinal strain (GLS) by speckle-tracking method was derived as a volume-independent indicator of LV chamber contractility sensitive to regional wall motion abnormalities. In 40 subjects with 3D-EF ranging from 14 to 80%, including clinically healthy hypertensive and patients with Stage B–D congestive heart failure with global or segmental wall motion abnormalities, on average, WMSI-EF did not differ from EF measured by 3D or 2D (all P > 0.5). By intraclass correlation coefficients, reliability of WMSI-EF vs. 3D method was as good as the reliability of 2D method vs. 3D method. GLS correlated with WMSI-EF as strongly as with 3D-EF (both r 2 = 0.90). Moderate–severe mitral regurgitation was associated with increased difference between WMSI-EF and 3D-EF, independent to potential confounders. Intra-observer and inter-observer reproducibility of WMSI-EF was comparable to the reproducibility of EF estimated by 3D echocardiography. Feasibility (WMSI, 3D, 2D, and GLS all available) was 78%; however, feasibility of WMSI per se was ∼92% in clinical series. Conclusion Trained readers may rapidly estimate EF by a novel WMSI system, which was found to be accurate compared with 3D method and GLS.

Aims Myocardial inotropism is considered to be reduced under beta-1 adrenoreceptor blockage (β1-block). However, relationships between components of left ventricular (LV) systolic mechanics under β1-block accounting for physiological correlates are only partially explored. Methods and results Hypertensive outpatient without previous cardiovascular events and with normal LV ejection fraction (EF) at rest underwent echocardiographic evaluations of LV size and systolic function by standard, tissue-Doppler, and speckle-tracking methods before and after 2 weeks of treatment with bisoprolol to obtain change in LV systolic mechanics at a stable heart rate reduction (−20 ± 10% from baseline) without significant change in LV mass. In the study sample ( n = 26, 62% women, mean age 52 ± 10 years), under bisoprolol, afterload [i.e. circumferential (CESS) and meridional (MESS) end-systolic stress], LV mass, left atrial volume, and EF did not change significantly; LV chamber contractility [i.e. CESS/LV end-systolic volume index (CESS/ESVi) as well as MESS/ESVi] and relative wall thickness (RWT) decreased; stroke volume increased (all P < 0.05). Circumferential LV contractility (i.e. stress-corrected midwall shortening) increased, whereas regional longitudinal strain and strain rate, and global longitudinal strain decreased (all P < 0.05). Peak velocities of the systolic displacement of the lateral and medial mitral anulus did not change under bisoprolol. Parameters of longitudinal LV systolic function did not correlate with preload, afterload, RWT, or with stoke volume. Conclusion In hypertensive subjects with preserved LV EF, parameters of longitudinal LV systolic mechanics may not reflect the LV myocardial contractility status in steady-state conditions under short-term treatment with β1-block.

BACKGROUND: Because GH exerted beneficial effects in various experimental models of heart failure, we investigated the effects of GH on physical exercise capacity and cardiopulmonary performance in patients with dilated cardiomyopathy and chronic heart failure (CHF). METHODS: Twenty-two patients with CHF (New York Heart Association functional class II-III) underwent spirometry and a symptom-limited, cardiopulmonary exercise testing before and after 3 months of GH (n = 11; seven males; seven idiopathic; 57 +/- 11 yr; 4 IU sc every other day) or placebo (n = 11; eight males; six idiopathic; 54 +/- 10 yr) administration, in a randomized, double-blind trial. Background CHF therapy remained unchanged. RESULTS: GH, but not placebo, increased IGF-I serum concentration (from 144 +/- 35 to 293 +/- 58 ng/ml; P < 0.005) and improved New York Heart Association functional class (from 2.4 +/- 0.5 to 1.8 +/- 0.4; P < 0.005), exercise duration (from 831 +/- 273 to 925 +/- 266 sec; P < 0.005), peak power output (from 245 +/- 127 to 280 +/- 132 W; P < 0.05), peak minute ventilation (from 52.5 +/- 16.1 to 61.3 +/- 17.3 liters/min; P < 0.05), peak oxygen consumption (from 19.8 +/- 5.6 to 25.1 +/- 5.6 ml/kg.min; P < 0.005), and anaerobic threshold (from 14.9 +/- 4.8 to 20.0 +/- 4.5 ml/kg.min; P < 0.005) without affecting lung function parameters. Furthermore, the slope of the relationship between minute ventilation and pulmonary carbon dioxide production (ventilatory efficiency) decreased from 34.7 +/- 5.1 to 31.7 +/- 5.3 (P < 0.005), whereas the slope of the relation between percent predicted heart rate reserve used and percent observed metabolic reserve used (chronotropic index) rose from 0.57 +/- 0.20 to 0.69 +/- 0.18 (P < 0.005). CONCLUSION: Given the predictive value of physical exercise capacity and cardiopulmonary performance in CHF progression, these data provide additional insights into the mechanisms by which GH may potentially benefit CHF patients.

The down regulation of protein p27(kip1) (p27) in most cases of thyroid cancer has relevant diagnostic and prognostic implications. However, the oxyphilic (Hurthle cell) variant of follicular thyroid carcinoma expresses more p27 than benign oxyphilic lesions do.To evaluate the mechanism underlying this difference in expression of p27.Because high levels of cyclin D3 lead to p27 accumulation in cell lines and clinical samples of thyroid cancer, the immunocytochemical pattern of cyclin D3 in oxyphilic (n = 47) and non-oxyphilic (n = 70) thyroid neoplasms was investigated.In the whole study sample, there was a significant correlation between p27 and cyclin D3 expression (Spearman's r: 0.64; p0.001). The expression of cyclin D3 and p27 was significantly higher in the oxyphilic variant of follicular carcinomas than in non-oxyphilic carcinomas (p0.001). In the former, cyclin D3 overexpression and p27 accumulation were observed in a median of 75% and 55% of cells, respectively. In co-immunoprecipitation experiments, the level of p27-bound cyclin D3 was much higher in oxyphilic neoplasias than in normal thyroids and other thyroid tumours.These results show that increased p27 expression in the oxyphilic (Hurthle cell) variant of follicular thyroid carcinoma results from cyclin D3 overexpression.

Clinical relevance of left ventricular (LV) diastolic dysfunction in the absence of congestive heart failure (CHF) and LV systolic dysfunction is not fully established.Asymptomatic outpatients, sedentary, with cardiovascular risk factors but no history of cardiovascular events, underwent echocardiographic evaluation of LV structure and function by standard Doppler, color M-mode, and Doppler tissue methods, and exercise testing with simultaneous noninvasive assessment of LV stroke index and cardiac index. LV ejection fraction less than 50% and significant valvular disease or stress test suggestive of coronary disease were additional exclusion criteria.In 70 patients selected (40 +/- 10 years old, 63% men, 34% hypertensive, 34% diabetic, 4% diabetic and hypertensive, 11% with LV hypertrophy), LV diastolic dysfunction was detected in 26%, which was associated with hypertension, higher LV mass index, lower systolic function, lower peak exercise heart rate, and chronotropic reserve (all P.05), and with lower peak exercise stroke index and cardiac index (both covariates adjusted P.05), but not with lower peak exercise metabolic equivalents (P.5). Abnormal LV relaxation was independently correlated with lower peak exercise cardiac index and stroke index (both P.05). Peak exercise systolic and cardiac indices were comparable between patients with CHF risk factors (74%) versus those without.Isolated LV diastolic dysfunction was independently associated with lower peak exercise LV systolic performance in patients without CHF. Its diagnosis may provide a target for aggressive CHF risk management.

In older healthy men, aerobic exercise capacity is related to postischemic flow-mediated dilation of the brachial artery (FMD), but corresponding data in a younger population is not available. In addition, whether submaximal aerobic exercise performance also correlates with this kind of vasomotor reactivity is not known. Therefore, in 15 nonsmoking young healthy men [age 27 (5) years; body mass index: 24 (2) kg/m(2); mean (SD)] with different levels of ordinary physical activity, but not performing upper-extremity training, we measured FMD at 1 min after reactive hyperemia, and pulmonary oxygen uptake (VO(2)) at ventilatory anaerobic threshold (VO(2)AT) and at peak effort (peak VO(2)) during an incremental exercise on a treadmill. In our participants, FMD was 9.1 (3.4)%, VO(2)AT was 40.72 (5.92) ml/kg per min, and peak VO(2) was 52.95 (8.13) ml/kg per min. Using bivariate Pearson's correlation, and in separate multivariate regression analyses, VO(2)AT and peak VO(2) showed a significant and reasonably good correlation with FMD (r = 0.84, P0.001 and r = 0.77, P = 0.001, respectively), independent of age, body mass index and serum total cholesterol (beta = 0.77, P0.001, R(2) of the overall model = 0.79 and beta = 0.70, P0.005, R(2) of the overall model = 0.69, respectively). Our data provide evidence suggesting that in young healthy men a higher submaximal and maximal aerobic exercise performance is associated with a greater FMD of peripheral conduit arteries.

OBJECTIVES: To ascertain whether myocardial contractility and total arterial stiffness are significantly altered in human thyrotoxicosis, and to what extent they are affected by acute beta(1)-adrenergic blockade. METHODS: Doppler-echocardiography was used to assess left ventricular (LV) structure and function, hemodynamics and total arterial stiffness in untreated overt hyperthyroid patients before and 2 h after 5 mg bisoprolol given orally compared with age- and sex-matched healthy euthyroid controls. RESULTS: Compared with controls, untreated patients (n=20) had a higher heart rate (HR) and LV stroke index (SI), which were associated with higher pulse pressure (PP), larger LV end-diastolic volume index (EDVI, an index of preload,+11%, P

Echocardiography can be used to estimate myocardial contractility by the assessment of the circumferential end-systolic stress-corrected left ventricular (LV) fractional shortening measured at midwall level (stress-corrected MWS). Whether stress-corrected MWS at rest predicts exercise peak oxygen uptake (peak VO2) is unknown. Also, it is not known whether the propagation rate of the early LV filling wave (E wave propagation rate, V p), a new pre-load insensitive index of LV diastolic function, and echocardiographically assessed indices of arterial stiffness correlate to peak VO2. Accordingly, we performed echocardiographic studies and exercise tests with respiratory gas analysis in 15 young healthy male subjects (mean age 27 years, range 18–36). Neither stress-corrected-MWS (r=0.20, P=NS) nor ejection fraction (r=−0.05, P=NS) correlated significantly with peak VO2. Adjustment for age and resting heart rate had no effect on the results. In separate multiple regression models adjusting for standard covariates (age, LV size and heart rate), peak VO2 correlated with V p (beta=0.98, P

The progressive reduction in p27Kip1 (p27) protein immunohistochemical staining with increasing histological grading is a well-established finding occurring in breast cancer, and its role as diagnostic complement and prognostic marker has been thoroughly evaluated. To clarify whether this test may be applied to breast cytopathology, we performed p27 immunostaining on fresh fine-needle cytology (FNC) samples from 10 benign and 40 malignant breast lesions. On average, p27 immunostaining was significantly lower in carcinomas than in benign lesions (P < 0.005). In particular, among carcinomas, p27 immunostaining progressively reduced from well-to poorly differentiated lesions (G1 vs. G2, P < 0.05; G1 vs. G3, P < 0.001; G2 vs. G3; P < 0.001). A similar trend was noted in a subgroup of 20 matched FNCs and histological samples of breast carcinomas, when p27 immunostaining on FNCs was stratified according to the histological grading (G1 vs. G2, P = 0.18; G1 vs. G3, P < 0.05; G2 vs. G3, P < 0.05). In addition, p27 immunostaining on FNCs showed a good positive correlation with that on histology (Spearman R = 0.58; P < 0.01), with a diagnostic concordance between samples of 85%, by using the standard 50% positive cell cutoff. Taken in concert, our data suggest that p27 immunostaining is a reliable marker of tumor cell differentiation in breast cytopathology as well as in histopathology. Accordingly, staining FNCs for p27 may be an useful complement in addition to cytological grading in the preoperative assessment of breast cancer. Diagn. Cytopathol. 2004;30:375–380. © 2004 Wiley-Liss, Inc.

PATZ is a transcriptional repressor affecting the basal activity of different promoters, whereas RNF4 is a transcriptional activator. The association of PATZ with RNF4 switches the activation to repression of selected basal promoters. Because RNF4 interacts also with the androgen receptor (AR) functioning as a coactivator and, in turn, RNF4 associates with PATZ, we investigated whether PATZ functions as an AR coregulator. We demonstrate that PATZ does not influence directly the AR response but acts as an AR corepressor in the presence of RNF4. Such repression is not dependent on histone deacetylases. A mutant RNF4 that does not bind PATZ but enhances AR-dependent transcription is not influenced by PATZ, demonstrating that the repression by PATZ occurs only upon binding to RNF4. We also demonstrate that RNF4, AR, and PATZ belong to the same complex in vivo also in the presence of androgen, suggesting that repression is not mediated by the displacement of RNF4 from AR. Finally, we show that the repression of endogenous PATZ expression by antisense expression plasmids in LNCaP cells results in a stronger androgen response. Our findings demonstrate that PATZ is a novel AR coregulator that acts by modulating the effect of a coactivator. This could represent a novel and more general mechanism to finely tune the androgen response.

Mounting evidence suggests that increased circulating aldosterone levels, despite angiotensin-converting-enzyme inhibitors therapy, may exert deleterious cardiovascular effects in heart failure, leading to clinical deterioration and poor prognosis. In the past decades, a number of experimental investigations have provided major insight into the mechanism(s) of action and the biological effects of aldosterone on the cardiovascular system, indicating that aldosterone participates in the structural and functional remodeling of cardiac and vascular tissue. In particular, it has emerged that aldosterone plays a key role in the regulation of myocardial extracellular matrix composition and endothelial function with important pathophysiological implications. Such evidence, coupled with the recent beneficial effects of spironolactone, a competitive aldosterone receptor antagonist, in reducing cardiac mortality and morbidity in patients with severe chronic heart failure treated with angiotensin-converting-enzyme inhibitors and loop diuretics, highlights the importance of aldosterone in the pathophysiology of human heart failure. The purpose of this review is to provide an overview of the regulation of aldosterone production and metabolism in heart failure, the basic mechanism of aldosterone action, and the pathophysiological implications of aldosterone in heart failure, and to discuss recent evidence supporting the efficacy of aldosterone receptor blockade in the treatment of chronic heart failure in humans.

To determine the clinical impact of endogenous subclinical hyperthyroidism, specific symptoms and signs of thyroid hormone excess and quality of life were assessed in 23 patients (3 males and 20 females; mean age, 43 +/- 9 yr) and 23 age-, sex-, and lifestyle-matched normal subjects by using the Symptoms Rating Scale and the Short Form 36 Health Survey questionnaires. Because the heart is one of the main target organs of the thyroid hormone, cardiac morphology and function were also investigated by means of standard 12-lead electrocardiogram (ECG), 24-h Holter ECG, and complete Doppler echocardiography. Stable endogenous subclinical hyperthyroidism had been diagnosed in all patients at least 6 months before the study (TSH, 0.15 +/- 0.1 mU/L; free T(3), 6.9 +/- 1.1, pmol/L; free T(4), 17.2 +/- 2.3, pmol/L). Fifteen patients were affected by multinodular goiter, and eight patients by autonomously functioning thyroid nodule. The mean Symptoms Rating Scale score (9. 8 +/- 5.5 vs. 4.3 +/- 2.2, P:0.001) and both the mental (36.1 +/- 9.5 vs. 50.0 +/- 8.5, P:0.001) and physical (42.6 +/- 8.0 vs. 55. 6 +/- 4.1, P:0.001) component scores of Short Form 36 Health Survey documented a significant prevalence of specific symptoms and signs of thyroid hormone excess and notable impairment of quality of life in patients. Holter ECG showed a higher prevalence of atrial premature beats in endogenous subclinical hyperthyroid patients than in the controls, but the difference was not statistically significant, although the average heart rate was significantly increased in the patients (P:0.001). An increase of left ventricular mass (162 +/- 24 vs. 132 +/- 22 g, P:0.001) due to the increase of septal (P: = 0.025) and posterior wall (P: = 0.004) thickness was observed in patients. Systolic function was enhanced in patients as shown by the significant increase of both fractional shortening (P: = 0.005) and mean velocity of heart rate-adjusted circumferential fiber shortening (P: = 0.036). The Doppler parameters of diastolic function were significantly impaired in the patients as documented by the reduced early to late ratio of the transmitral flow velocities (P:0.001) and the prolonged isovolumic relaxation time (P: = 0.006). These data indicate that endogenous subclinical hyperthyroidism has a relevant clinical impact and that it affects cardiac morphology and function. Moreover, they suggest that treatment of persistent endogenous subclinical hyperthyroidism should be considered also in young and middle-aged patients to attenuate specific symptoms and signs of thyroid hormone excess, ameliorate the quality of life, and avoid the consequences to the heart of long exposure to a mild excess of thyroid hormone.

Pulmonary arterial hypertension has a poor prognosis quoad vitam et valitudinem. Herein, we report on a middle-aged woman affected by idiopathic pulmonary arterial hypertension whose quality of life and exercise tolerance improved remarkably after a six-month course of treatment with the long-acting phosphodiesterase-5 inhibitor tadalafil.

Objective: We evaluated the performance of cytologic p16INK4a (p16) immunostaining within a cervical cancer screening program for the categories of atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LS after triage with high-risk human papillomavirus (HR-HPV) testing and atypical squamous cells, cannot exclude high-grade intraepithelial squamous lesion (ASC-H) and high-grade squamous intraepithelial lesion (HSIL). We also verified whether the routine introduction of p16 staining might enhance the specificity and positive predictive value (PPV) for cervical intraepithelial neoplasia grade 2 or higher (CIN2+) lesions predicted by a cytological screening test. Study Design: Performance of the p16 cytology test was estimated in 578 cytological samples, of which 213 were HR-HPV+ ASC-US, 186 were HR-HPV+ LSIL, 74 were ASC-H, 56 were HSIL-CIN2 and 49 were HSIL-CIN3. All samples had histological follow-up. Results: In the ASC-US category, p16 sensitivity was 91% for CIN2+ and 100% for CIN3, while specificity was 64 and 58%, respectively, negative predictive value (NPV) was 96 and 100%, respectively, and PPV was 39%. In the LSIL category, sensitivity was 77 and 75%, respectively, for CIN2+ and CIN3, while specificity was 64 and 57%, NPV was 93 and 98% and PPV was 30%. Sensitivity for ASC-H and HSIL-CIN3 was 100% for CIN2+ and CIN3, while for HSIL-CIN2 it was 91 and 95%, respectively; NPV for ASC-H was 100%, and for HSIL-CIN2 it was 43 and 86%, respectively. Follow-up examinations of 8 cases diagnosed as p16+ ASC-H and HSIL-CIN3, but histologically negative or CIN1 on the first biopsy, showed 4 CIN2 and 4 CIN3 lesions. Conclusions: Sensitivity, specificity, PPV and NPV confirm the importance of the utilization of p16 in the categories ASC-US and LSIL after triage with an HR-HPV test. In the ASC-H and HSIL-CIN3 lesions, p16 was shown to be an excellent marker for picking up CIN2+ lesions, especially in cases with cytohistological discordance.

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. Methods and results: Cell lines and tissue samples of Hodgkin’s lymphoma (HL) and of non-Hodgkin’s lymphoma (NHL) were screened for UbcH10 expression at transcriptional and translational levels. UbcH10 expression was related to the grade of malignancy. In fact, it was low in indolent tumours and high in a variety of HL and NHL cell lines and in aggressive lymphomas. It was highest in Burkitt’s lymphoma, as shown by quantitative real-time polymerase chain reaction and by tissue microarray immunohistochemistry. Flow cytometry of cell lines confirmed that UbcH10 expression is cell-cycle dependent, steadily increasing in S phase, peaking in G2/M phase and dramatically decreasing in G0/G1 phases. We also showed that UbcH10 plays a relevant role in lymphoid cell proliferation, since blocking of its synthesis by RNA interference inhibited cell growth. Conclusions: Taken together, these results indicate that UbcH10 is a novel lymphoid proliferation marker encompassing the cell cycle window associated with exit from mitosis. Its overexpression in aggressive lymphomas suggests that UbcH10 could be a therapeutic target in this setting.

Background: The clinical manifestations of resistance to thyroid hormone (RTH) are highly variable, and the impact of RTH on the cardiovascular system has been poorly investigated. Aim: The objective of the study was to evaluate the cardiovascular characteristics of 16 untreated and asymptomatic patients with RTH compared with 16 euthyroid healthy controls to define the cardiovascular involvement in RTH syndrome. Patients and Methods: Sixteen untreated and asymptomatic RTH patients (eight males; aged 33 ± 12 yr, range 21–45 yr) and 16 controls (nine males; aged 33 ± 5 yr, range 24–42 yr) were enrolled. Clinical data, thyroid status, and echocardiographic results were recorded. Results: Heart rate was comparable with that of controls, whereas arterial pressure was higher than controls. Mean interventricular septum diastolic thickness and mean left ventricular (LV) posterior wall diastolic thickness were significantly lower in RTH patients than controls with a consequent significant decrease of the mean LV mass and LV mass indexed by body surface area. Patients also had abnormalities of myocardial relaxation as indicated by a significant increase of peak A and consequent reduction of the early to late ratio. Finally, systemic vascular resistance was significantly higher in RTH patients than controls. Conclusions: Our results suggest the presence of cardiovascular alterations in asymptomatic and untreated RTH patients similar to those reported in hypothyroid patients. Our strict selection likely created a bias in the inclusion of a particular type of RTH patients, who could represent a minority of patients with RTH. However, no correlation was found between the type of mutation and cardiovascular characteristics of RTH patients.

BACKGROUND: 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. METHODS: Fifty-one FNA samples that were suspicious for Hurtle cell neoplasia and that had histologic follow-up (19 malignant cases) were examined. Cyclin D3 expression levels were evaluated in cell block preparations and were compared with levels of the closely related cyclin D1 protein. RESULTS: Greater than 25% positive cells were used as the cutoff point, as suggested by previous studies. Cyclin D1 and cyclin D3 were highly specific (100% for both) and fairly accurate (75% and 92%, respectively) in distinguishing between benign and malignant oncocytic lesions; the positive predictive value (PPV) for each was 100%. However, both cyclins D1 and D3 had low sensitivity (32% and 79%, respectively) and low negative predictive value (NPV) (71% and 89%, respectively). In contrast, by adopting balanced receiver operating characteristic-derived positive cutoff values, cyclin D1 (� 6.5%) and cyclin D3 (� 7.5%) were found to be highly sensitive (100% for both) and accurate (90% and 94%, respectively); and the NPV was 100% for both. In contrast, cyclins D1 and D3 had low specificity (84% and 91%, respectively) and a low PPV (79% and 86%, respectively); however, these values improved in samples that were positive for both cyclins (sensitivity, 100%; specificity, 94%; PPV, 90%; NPV, 100%; and accuracy, 96%). CONCLUSIONS: Cyclin D3 increased the suspicion of malignancy in indeterminate oncocytic lesions; its diagnostic performance depended on the cutoff point used and was enhanced further when combined with cyclin D1. Cancer (Cancer Cytopathol) 2009;117:522–9. V C 2009 American Cancer Society.

OBJECTIVE: To compare the molecular, histological, and functional characteristics of growth hormone (GH)- and pressure overload-induced cardiac hypertrophy, and their responses to ischemia-reperfusion and mechanical stretch. DESIGN: Four groups of male Wistar rats were studied: aortic banding (n=24, AB) or sham (n=24, controls) for 10 weeks, and GH treatment (n=24; 3.5mg/kg/day, GH) or placebo (n=24, controls) for 4 weeks. At 13 weeks, the rats were randomly subjected to: (i) assessment of basal left ventricular mRNA expression of sarcoplasmic reticulum calcium-ATPase (SERCA-2), phospholamban (PLB), and Na(+)-Ca(2+) exchanger (NCX) and collagen volume fraction (CVF) (Protocol A, 8 rats in each group); (ii) left ventricular no-flow ischemia with simultaneous evaluation of intracellular Ca(2+) handling and ATP, phosphocreatine (PCr) and inorganic phosphate (Pi) content (Protocol B, 12 rats in each group); or (iii) left ventricular mechanical stretch for 40 min with assessment of tumor necrosis-alpha (TNF-alpha) mRNA (Protocol C, 4 rats in each group). Protocol B and C were carried out in a Langendorff apparatus. RESULTS: In Protocol A, no difference was found as to myocardial mRNA content of Ca(2+) regulating proteins and CVF in GH animals vs controls. In contrast, in the AB group, myocardial mRNA expression of SERCA-2 and PLB was downregulated while that of NCX and CVF were increased vs. controls (p

Although many observers consider the cardiovascular risk associated with isolated prehypertension to be low and not worth pharmacological treating, the cardiovascular disease rate is increased among individuals within this blood pressure stratum.We performed Doppler echocardiography and submaximal bicycle ergometry in 20 nonsmoking sedentary prehypertensive subjects and 20 age- and sex-matched nonsmoking sedentary normotensive subjects, and investigated the association between the systolic blood pressure response to exercise (SBPRE) and hypertensive target organ damage. An exaggerated SBPRE (E-SBPRE) and a normal SBPRE (N-SBPRE) were diagnosed using the mean +2 standard deviations of systolic blood pressure at 100 W in normotensives.Body mass index was similar in the two groups. Resting blood pressure and systemic vascular resistance were higher in prehypertensives. Almost half the latter had an E-SBPRE. There were no differences in age, gender, and body mass index between normotensives and prehypertensives with an E-SBPRE or a N-SBPRE. Resting blood pressure and systemic vascular resistance were similarly increased in prehypertensives with an E-SBPRE and a N-SBPRE vs normotensives. Compared with normotensives, prehypertensives with an E-SBPRE showed: (a) a significantly greater left ventricular relative wall thickness, mostly due to a smaller cavity, (b) a significantly longer left ventricular isovolumic relaxation time, and (c) a significantly greater global arterial stiffness, as estimated by the pulse pressure/left ventricular stroke volume ratio.Our findings suggest that an E-SBPRE is frequent among prehypertensive subjects and is associated with cardiovascular remodeling, which may herald cardiovascular disease.

The relationship between peripheral circulation and blood pressure (BP) response to maximal exercise is an intriguing and not yet well defined topic.Aims of the present study were to investigate in well trained young healthy males the possible relationships between the endothelial or the smooth muscle component of the peripheral circulation and 1) the BP response to physical exercise on treadmill 2) the body mass composition.Fifteen subjects (18-36 years), regularly performing physical activity 3 times weekly underwent the following examinations: body composition by bioelectrical impedance analysis; measurement of the forearm blood flow (FBF) at rest and during post-ischemic hyperemia by strain-gauge plethysmography at the upper arm; measurement of brachial artery diameter (BAD) at rest and after 4-min ischemia by echography; BP response to maximal exercise on treadmill with the determination of maximal oxygen consumption and the measurement of lactic acid serum concentration.BAD was significantly increased during post-ischemic hyperemia up to the 4th minute of observation with a peak at 60 s (+8.5%); FBF increased at 30 s after ischemia (+210%) and returned to baseline levels at the 2nd minute. In the linear correlation analysis, systolic BP increase at the end of the maximal exercise was significantly and inversely related to the increase in FBF (r=-0.663, p0.01) and to the early FMD (r=0.503, p0.05). In the multiple regression analysis, however, only FBF independently affected SBP increase during exercise (t=-3.268, p0.02). Systolic BP increase at the end of the maximal exercise was significantly related to the increase in FBF but not to that of BAD. Among parameters of body composition, fat-free mass was closely related to changes only in BAD.These data indicate that FBF, which depends on the smooth muscle component of the peripheral circulation, is closely related to BP response to exercise while the endothelial function, which has been determined as changes in BAD, is related to the fat-free mass of the body, possibly through the peripheral insulin sensitivity.

Background G1/S cell cycle progression requires p27Kip1 (p27) proteolysis, which is triggered by its phosphorylation on threonine (Thr) 187. Since its levels are abundant in quiescent and scarce in cycling cells, p27 is an approved marker for quiescent cells, extensively used in histopathology and cancer research. Methods However here we showed that by using a specific phosphorylation site (pThr187) antibody, p27 is detectable also in proliferative compartments of normal, dysplastic and neoplastic tissues. Results In fact, whereas un-phosphorylated p27 and MIB-1 showed a significant inverse correlation (Spearman R = -0.55; p < 0,001), pThr187-p27 was positively and significantly correlated with MIB-1 expression (Spearman R = 0.88; p < 0,001). Thus proliferating cells only stain for pThr187-p27, whereas they are un-reactive with the regular p27 antibodies. However increasing the sensitivity of the immunocytochemistry (ICH) by the use of an ultra sensitive detection system based on tiramide signal amplification, simultaneous expression and colocalisation of both forms of p27 was shown in proliferating compartments nuclei by double immunofluorescence and laser scanning confocal microscopy studies. Conclusion Overall, our data suggest that p27 expression also occurs in proliferating cells compartments and the combined use of both regular and phospho- p27 antibodies is suggested.

Subclinical hyperthyroidism appears to be a common disorder. It may be caused by exogenous or endogenous factors: excessive TSH suppressive therapy withl-thyroxine (l-T4) for benign thyroid nodular disease, differentiated thyroid cancer, or hormone over-replacement in patients with hypothyroidism are the most frequent causes. Consistent evidence indicates that ‘subclinical’ hyperthyroidism reduces the quality of life, affecting both the psycho and somatic components of well-being, and produces relevant signs and symptoms of excessive thyroid hormone action, often mimicking adrenergic overactivity. Subclinical hyperthyroidism exerts many significant effects on the cardiovascular system; it is usually associated with a higher heart rate and a higher risk of supra-ventricular arrhythmias, and with an increased left ventricular mass, often accompanied by an impaired diastolic function and sometimes by a reduced systolic performance on effort and decreased exercise tolerance. It is well known that these abnormalities usually precede the onset of a more severe cardiovascular disease, thus potentially contributing to the increased cardiovascular morbidity and mortality observed in these patients. In addition, it is becoming increasingly apparent that subclinical hyperthyroidism may accelerate the development of osteoporosis and hence increased bone vulnerability to trauma, particularly in postmenopausal women with a pre-existing predisposition. Subclinical hyperthyroidism and its related clinical manifestations are reversible and may be prevented by timely treatment.

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 (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.

Increased or reduced action of thyroid hormone on certain molecular pathways in the heart and vasculature causes relevant cardiovascular derangements. It is well established that overt hyperthyroidism induces a hyperdynamic cardiovascular state (high cardiac output with low systemic vascular resistance), which is associated with a faster heart rate, enhanced left ventricular (LV) systolic and diastolic function, and increased prevalence of supraventricular tachyarrhythmias - namely, atrial fibrillation - whereas overt hypothyroidism is characterized by the opposite changes. However, whether changes in cardiac performance associated with overt thyroid dysfunction are due mainly to alterations of myocardial contractility or to loading conditions remains unclear. Extensive evidence indicates that the cardiovascular system responds to the minimal but persistent changes in circulating thyroid hormone levels, which are typical of individuals with subclinical thyroid dysfunction. Subclinical hyperthyroidism is associated with increased heart rate, atrial arrhythmias, increased LV mass, impaired ventricular relaxation, reduced exercise performance, and increased risk of cardiovascular mortality. Subclinical hypothyroidism is associated with impaired LV diastolic function and subtle systolic dysfunction and an enhanced risk for atherosclerosis and myocardial infarction. Because all cardiovascular abnormalities are reversed by restoration of euthyroidism ("subclinical hypothyroidism") or blunted by beta-blockade and L-thyroxine (L-T4) dose tailoring ("subclinical hyperthyroidism"), timely treatment is advisable in an attempt to avoid adverse cardiovascular effects. Interestingly, some data indicate that patients with acute and chronic cardiovascular disorders and those undergoing cardiac surgery may have altered peripheral thyroid hormone metabolism that, in turn, may contribute to altered cardiac function. Preliminary clinical investigations suggest that administration of thyroid hormone or its analogue 3,5-diiodothyropropionic acid greatly benefits these patients, highlighting the potential role of thyroid hormone treatment in patients with acute and chronic cardiovascular disease.

To the Editor: In their Scientific Review and Clinical Applications article about subclinical thyroid disease, Dr Surks and colleagues stated that numerous small studies reveal subtle decreases in myocardial contractility in patients with subclinical hypothyroidism. Although the authors cited our review article in making this claim, they did not mention that we found diastolic dysfunction to be the most consistent cardiac abnormality in this disease. Furthermore, we reported that it tends to regress with replacement of thyroid hormone. This finding has been independently reported elsewhere. Furthermore, diastolic dysfunction has been reported not only in patients with thyroid-stimulating hormone (TSH) levels greater than 10 mU/L but also in those with TSH values between 4.5 and 10 mU/L. In contrast to this pattern with diastolic dysfunction, Surks et al reported that whereas lipid profiles are frequently abnormal when TSH levels are greater than 10 mU/L, they are seldom so in the lower TSH range. Thus, there appears to be a different target organ sensitivity to thyroid hormone deficiency, which may become clinically relevant depending on the patient’s thyroid function set-point. Collectively, these observations suggest that the decision to treat, rather than being based on a cutoff TSH threshold, should depend on the patient’s overall condition. We recommend that in the presence of a background of cardiovascular risk, replacement treatment should be considered regardless of the TSH concentration. On the other hand, simple clinical follow-up may be warranted in patients without cardiovascular risk and no other indications for thyroid hormone replacement.

Introduction: The aim of the present study is to compare a hydrophilic catheter to the standard polyvinyl chloride catheter with regard to bacteriological safety and overall comfort in patients undergoing intravesical immuno- or chemotherapy for bladder cancer. Materials and Methods: One hundred patients (80 males, 20 females; median age 65.8 years, range 48–79 years) eligible for intravesical prophylaxis of superficial bladder cancer recurrences were randomized to receive intravesical therapy using a standard catheter (group A, n = 50) or a hydrophilic catheter (group B, n = 50). Urinalysis and urine culture were performed 2 days after catheterization. Comfort during catheterization was assessed by a 5-point visual analogue scale at the end of the first four instillations. Results: Urinary tract infection (UTI) was detected in 7.4% of catheterizations in group A, whereas it occurred in 3.5% of catheterizations in group B (p < 0.01). Escherichia coli was the most frequent pathogen regardless of the device used. At the end of each of the first four instillations, the mean score for discomfort was significantly higher in group A than in group B (p < 0.001), although catheterization was progressively better tolerated regardless of the device used (both p < 0.005). None of the patients were found to be suffering from orchitis, epididymitis or gross haematuria. Conclusion: Hydrophilic catheters may be used safely and are well tolerated by patients undergoing intravesical immuno- or chemotherapy. The hydrophilic catheter was associated with a significantly lower occurrence of UTI and higher acceptability compared to the standard device. These data should be considered with regard to patient compliance with intravesical therapy.

Herein we report on a young girl with recurrent, functioning paraganglioma of the organ of Zuckerkandl and severe and sustained arterial hypertension (systolic pressure > 200, diastolic pressure > 120 mmHg); with evidence of cardiac damage induced by chronic cathecolamine excess. She promptly and steadily improved after the institution of doxazosin (6 mg/day) plus atenolol (50 mg bid) treatment. This case demonstrates that a correct therapeutic strategy in the long-term management of patients with inoperable catecholamine-producing neuroendocrine tumors (pheochromocytomas and paragangliomas) can maintain arterial pressure in the normal range and reverse the cardiac damage induced by chronic cathecolamine excess.

Eleven patients who had undergone total thyroidectomy for differentiated thyroid cancer and who were on chronic TSH-suppressive therapy with levothyroxine (l-T4), underwent 24-h Holter electrocardiogram and Doppler-echocardiography before and after acute recombinant human TSH (rhTSH) administration for disease staging. The treatment, which was generally well tolerated, did not affect circulating thyroid hormones levels, nor did it have measurable effects on heart rate, rhythm, left ventricular morphology, or systo-diastolic function. Notably, arterial blood pressure tended to be slightly reduced after rhTSH administration, although in no instance did the patients become frankly symptomatic. Our data demonstrate that rhTSH does not alter cardiovascular function acutely. Consequently, it can safely be used in the routine staging of patients affected by differentiated thyroid cancer.

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.

The cardiovascular manifestations of thyroid hormone excess, including tachycardia, a widened pulse pressure, a brisk carotid and peripheral arterial pulsation, a hyperkinetic cardiac apex, and loud first heart sound have long been recognized and are a cornerstone for clinical diagnosis (1–9). A number of studies in the past decades have provided critical insights into the mechanisms that are responsible for the hyperdynamic cardiocirculatory state in overt hyperthyroid patients, suggesting that it probably results from the combined effects of thyroid hormone on certain molecular pathways on the heart and vasculature, at both the genomic and nongenomic level (10). Despite these advances, it is not yet clear whether, in spontaneous human hyperthyroidism, the high cardiac output state (11–24) is sustained prevalently by changes in peripheral hemodynamics (vascular hypothesis), or by changes in myocardial contractility (myocardial hypothesis) (19, 21). This issue has major clinical and pathophysiological implications. In fact, although peripheral and myocardial mechanisms are not mutually exclusive, the major contribution of one of the two mechanisms may have important consequences with regard to the “economy” of the cardiovascular system, given the notion that increased cardiac performance due to inotropic stimulation is less efficient than that due to modulation of the loading status. Accordingly, here we review research on the effects of spontaneous human hyperthyroidism on heart rate, preload, afterload, and myocardial contractility in an attempt to establish how these factors interact with each other and to what extent they contribute to increasing cardiac performance at rest.

Subclinical Cushing's syndrome (SCS) is increasingly being reported in incidentally discovered adrenal adenomas; its hallmark is mild autonomous cortisol hyperproduction without specific clinical signs of cortisol excess. Increased prevalence of hypertension, obesity, and impaired glucose tolerance have been described in SCS, but there is no specific study of the risk factors for cardiovascular diseases. In this cross-sectional study we assessed the cardiovascular profile in 28 consecutive SCS patients (19 women and 9 men; aged 56 +/- 10.6 yr) compared with 100 controls matched for age, gender, and body mass index. Systolic (P < 0.001) and diastolic (P < 0.005) blood pressures were higher in patients, as were fasting glucose, insulin, total cholesterol, triglycerides (all P < 0.001), and fibrinogen (P < 0.05). Moreover, the insulin resistance index was increased in patients as was the waist to hip ratio and mean carotid artery intima-media thickness (all P < 0.001). Of the patients, 60.7% had arterial hypertension, 71.4% had lipid abnormalities, 28.6% had impaired glucose tolerance, 35.7% type 2 diabetes mellitus, and 53.6% had abnormalities in hemostatic parameters. Atherosclerotic plaques were more frequent in patients (P < 0.0001). Only 4 (14.3%) patients did not have multiple risk factors for cardiovascular events. Six (21.3%) had clinical evidence of cardiovascular disease; another 11 (39.3%) had cardiovascular abnormalities as revealed by ultrasound scanning of carotid arteries and/or electrocardiogram records. These results strongly suggest that an increased cardiovascular risk profile, similar to that described in overt Cushing's syndrome, is present in SCS subjects. This finding supports the concept that chronic mild endogenous cortisol excess may have important systemic effects on the human body.

Many studies have shown that acromegaly has relevant effects on cardiovascular system, but few data are available regarding the effects of short-term acromegaly on heart morphology and function. These data would help to clarify the natural history of acromegalic disease and could provide new insight into the mechanisms of GH action on the human heart. Therefore, we studied by Doppler echocardiography a group of 10 young subjects strictly selected as having short-term (

Growth hormone (GH) is a peptide hormone synthesized and secreted by the anterior pituitary gland. In normal conditions, its synthesis and secretion are strictly regulated by the integrated and coordinated actions of two hypothalamic neurohormones: GH releasing factor and GH inhibiting factor (i.e., somatostatin). The ratio between the hypothalamic secretion of these two factors represents the basic and dynamic mechanism by which neurologic as well as extraneurologic influences may functionally affect GH secretion under physiologic or pathophysiologic conditions (1). Biological effects of GH are mediated by the interaction with a specific transmembrane receptor (GHR), expressed in almost all cellular types. As a consequence of GH–GHR interaction on target tissues, GH may exert direct metabolic effects. However, the most relevant biological effects of GH are indirect and to a large extent mediated by the stimulation of expression of insulinlike growth factor-I (IGF-I), in the liver (endocrine action) and in peripheral tissues (autocrine/paracrine action). Only a small amount of liver-derived IGF-I circulates as a free hormone, which is responsible for the biological actions. Indeed, the bulk of circulating IGF-I is bound to its specific carrier proteins, called IGF-binding proteins (IGF-BPs), the most important of which seems to be IGF-BP-3, since it binds more than 95% of IGF-I in the blood (1, 2). Furthermore, the IGF-I/ IGF-BP-3 dimer forms a complex with another protein subunit, the acid-labile subunit, and in this ternary complex the IGF-I has a serum half-life of many hours. Both the acid-labile subunit and IGF-BP-3 are principally synthesized in the liver, and their serum concentrations are influenced by circulating GH levels. IGF-BPs serve not only to transport IGF-I in the circulation, but also to prolong its half-life, to modulate its tissue specificity, and to potentiate or neutralize its biological actions. Moreover, a number of studies have shown that IGF-BPs modify the biological effects of IGF-I on a variety of mammalian cells. The relative importance of circulating versus locally produced IGF-I in the anabolic and growth-promoting effects of GH has recently been addressed by Sjogren et al. and Yakar et al. (3, 4). By using a novel tissuespecific recombinant system, the two groups independently concluded that, although hepatic IGF-I is the major contributor to circulating IGF-I levels, it is not crucial for normal postnatal growth, providing direct evidence for the importance of an autocrine/paracrine role for IGF-I. In this scenario, a large body of evidence has accumulated to support the concept that the GH–IGF-I axis targets the heart (5–9). In particular, it has been demonstrated that GHRs are largely expressed in the myocardium (9) and that, by interacting with GH, they stimulate the local biosynthesis of IGF-I, which may act in an autocrine or paracrine manner by binding specifically to its high-affinity membrane-associated receptor (Fig. 1). In this regard, it has been shown that myocardial IGF-I expression and content strictly parallel circulating GH levels (5–8). Studies in both animals and humans have provided consistent evidence that the GH–IGF-I axis is involved in the regulation of myocardial structure and function. In particular, a large number of studies have consistently shown that GH and IGF-I are critically involved in the regulation of cardiomyocyte growth.

Although subclinical hypothyroidism is frequently diagnosed, the decision to institute a substitutive therapy with L-T4 remains controversial. Because the cardiovascular system is considered a main target for the action of thyroid hormone, we investigated whether subclinical hypothyroidism induces cardiovascular abnormalities. Twenty-six patients (mean age, 36 +/- 12 yr) were evaluated by Doppler-echocardiography, whereas a subgroup of 10 patients, randomly selected, were reevaluated after 6 months of L-T4 substitutive therapy (mean dose, 68 microg daily). Thirty subjects (matched for age, sex, and body surface area) served as controls. Mean plasma TSH was significantly higher in patients (P < 0.001), whereas mean serum free T4 and free T3 concentrations, although in the normal range, were significantly lower (P < 0.001 and P < 0.005, respectively). Blood pressure and heart rate did not differ from control values. Echocardiogram examination showed no abnormalities of the left ventricular morphology and a slight, but not significant, reduction in the systolic function in the patient group. In contrast, Doppler-derived indices of diastolic function showed significant prolongation of the isovolumic relaxation time (94 +/- 13 vs. 84 +/- 8 msec; P < 0.001), increased A wave (55 +/- 13 vs. 48 +/- 9 cm/sec; P < 0.05), and reduced early diastolic mitral flow velocity/late diastolic mitral flow velocity ratio (1.4 +/- 0.3 vs. 1.7 +/- 0.3; P < 0.001). In the subgroup of 10 patients, thyroid hormone profile was normalized by 6 months of L-T4 substitutive therapy, whereas no changes were observed in the left ventricular morphology. Systolic function was significantly enhanced, as compared with pretreatment values (P < 0.01) but did not differ from control values. Also, systemic vascular resistance was significantly decreased by L-T4 replacement therapy. Assessment of diastolic function showed significant shortening of isovolumic relaxation time (77 +/- 15 vs. 91 +/- 8; P < 0.05), reduction of A wave (51 +/- 13 vs. 60 +/- 12; P < 0.01), and increase of early diastolic mitral flow velocity/late diastolic mitral flow velocity ratio (1.7 +/- 0.4 vs. 1.3 +/- 0.3; P < 0.001). These indices, however, were comparable with those of control subjects. These findings indicate that subclinical hypothyroidism affects diastolic function and that this abnormality may be reversed by L-T4 substitutive therapy.

Acute pulmonary embolism (PE) is a syndrome with a significant annual incidence, potentially associated with an elevated morality rate.1 Patients presenting with acute PE and persistent systemic hypotension, cardiogenic shock, or cardiac arrest are classified as having massive PE; in the absence of haemodynamic instability, PE is defined generically as non-massive. The latter, however, is classified as submassive acute PE in the presence of right ventricular (RV) dysfunction,1 to indicate that patients with normotensive acute PE and RV dysfunction may suddenly need escalation of therapy (vasopressor and/or inotropic support, rescue fibrinolysis, cardiopulmonary resuscitation).2–4 While clinical manifestation of acute PE may vary widely and significantly between patients, acute RV dysfunction is more quantifiable and uniform objective information in PE with relation to the severity of pulmonary vascular impairment.5 RV failure is the prominent cause of death in acute PE. This is further supported by the fact that in the setting of non-massive acute PE, RV dysfunction correlates with brain natriuretic peptide and troponins, which are in turn biomarkers of the severity of RV overload,6 providing additional information for risk stratification of the heterogeneous group of patients with normotensive PE.7–11 However, whether aggressive treatment (i.e. fibrinolysis or catheter-based pulmonary embolectomy) should be employed in acute submassive PE in addition to anticoagulation is controversial.1 In fact, while fibrinolysis or thromboembolectomy are associated with partial recovery of RV dysfunction,12 … *Corresponding author. Tel: +39 081 2543536; fax: +39 081 2543536. E-mail address : vpalmier{at}med.cornell.edu

Even today, heart failure due to doxorubicin‐induced dilated cardiomyopathy seems to have a poor prognosis, as it is often irreversible and relatively unresponsive to standard medical treatment. This paper describes the first case of a patient complaining of severe symptoms of congestive heart failure due to doxorubicin‐induced dilated cardiomyopathy unresponsive to standard medical treatment (digoxin, diuretics, and angiotensin‐converting enzyme inhibitor), who showed complete clinical recovery and significant improvement of left ventricular dysfunction after carvedilol treatment. It also illustrates the possibility that carvedilol may be a first‐choice drug for the treatment of this disease.

Background: Mounting evidence indicates that subclinical thyroid dysfunction has important clinical effects and prognostic implications, supporting the view that it is not a compensated biochemical change sensu strictu. Purpose: To review clinical information on the effects of subclinical thyroid dysfunction on the heart. Data Sources: English-language articles identified from files and a MEDLINE search (1970–September 2001), references of relevant articles, textbooks, and meeting abstracts. Study Selection: Reports on the effects of subclinical hypothyroidism and subclinical hyperthyroidism on the cardiovascular system in humans. Data Extraction: Data on cardiac structure and performance, arrhythmias, and risk for coronary artery disease were independently assessed by all authors and summarized. Data Synthesis: Subclinical hypothyroidism is associated with impaired left ventricular diastolic function at rest, systolic dysfunction on effort, and enhanced risk for atherosclerosis and myocardial infarction. Subclinical hyperthyroidism is associated with increased heart rate, atrial arrhythmias, increased left ventricular mass with marginal concentric remodeling, impaired ventricular relaxation, reduced exercise performance, and increased risk for cardiovascular death. All abnormalities were reversed by restoration of euthyroidism (subclinical hypothyroidism) or were blunted by -blockade and tailoring of the L-thyroxine dose (subclinical hyperthyroidism). Conclusion: The heart responds to the minimal but persistent changes in circulating thyroid hormone levels typical of subclinical thyroid dysfunction. Thus, the condition is not a compensated biochemical change sensu strictu, and timely treatment should be considered in an attempt to avoid adverse cardiovascular effects