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Background & Aims: A substantial proportion of patients with chronic hepatitis C virus infection treated with pegylated interferon α/ribavirin fail to achieve sustained virological response (SVR). Since growing evidence suggests that innate immunity may influence treatment responses, we examined natural killer (NK) cell phenotypic and functional changes during standard antiviral therapy., Methods: Expression of several NK-cell regulatory molecules was evaluated by flow cytometry in 37 consecutive patients with chronic HCV infection at baseline and at different time points during and after discontinuation of treatment. Cytokine production was evaluated by intracellular staining. Cytolytic potential was assessed as degranulation and as antibody-dependent cytotoxicity., Results: Baseline frequencies of CD56(dim) NK cells and perforin content were significantly higher, whereas CD16 expression was lower in SVR vs. non-responder subjects. Analysis by linear regression for repeated measures during the first 12 weeks showed significantly increased frequencies of activated (CD69(+)) NK cells in rapid virological responders (RVR) and identified a typical NK cell profile associated with SVR, featuring higher NK perforin content, lower CD16 expression, and higher proportion of CD56(dim)/CD16(-) cells. Moreover, SVR patients displayed higher natural and antibody-dependent NK cell cytotoxicity. IL28B rs12979860 CC homozygosis was significantly associated with SVR, independently of NK-cell phenotype and function., Conclusions: Different NK-cell phenotypic and functional features, in patients with chronic hepatitis C treated with standard therapy, were observed between non-responder vs. SVR patients, suggesting a potential role of NK cells in the response to treatment., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Improved knowledge of the structure and function of the aortic wall, as well as its pathophysiology and histopathology, will result in an increasing impact on clinical evaluation and treatment of thoracic aortic diseases. This opinion paper highlights the main "paradigmatic shifts" in this field, providing cardiologists with some novel clues for the clinical approach to patients with thoracic aortic disease.

Aims: Asynchronous myocardial contraction adversely influences left ventricular (LV) function and is therefore associated with a poor prognosis in heart failure. Exercise-induced change in ventricular dyssynchrony may be an important determinant of dynamic changes in cardiac output and mitral regurgitation., Methods and Results: A prospective, longitudinal study was designed with pre-defined dyssynchrony index and outcome variables to test the hypothesis that dynamic dyssynchrony is associated with worse long-term event-free survival in patients with dilated cardiomyopathy (DCM) and 'narrow' QRS complex. One-hundred eighty patients (62 ± 8 years; 110 males) with NYHA class II-III, idiopathic DCM, ejection fraction ≤35%, and QRS duration <120 ms were selected. All the patients underwent standard Doppler echo, colour tissue velocity imaging (DTI), and supine bicycle exercise stress echocardiography. Cardiac synchronicity was defined, at rest and at peak exercise, as DTI velocity opposing-wall delay (significant if ≥65 ms). Outcome was defined as freedom from death, heart transplantation, or LV-assist device implantation, over a median follow-up of 48 months, and a Cox proportional hazards model was used for survival analysis. At baseline examination, DCM patients showed a reduced LV ejection fraction (31 + 4%). A significant electromechanical delay in 58 patients (32%). At the peak of physical exercise, a significant electromechanical delay was detected in 103 patients (57%). There were 41 events during the follow-up (23%): 28 cardiac deaths, 8 heart transplantations, and 5 LV-assist device implantations over 4 years. When adjusted for confounding baseline variables, LV end-diastolic volume, restrictive mitral flow pattern, severity of mitral regurgitation, and the presence of exercise-induced intraventricular dyssynchrony were the only independent determinants of an adverse outcome., Conclusion: In patients with idiopathic DCM and narrow QRS, the increase in echocardiographic dyssynchrony during exercise was the strongest predictor of less favourable event-free survival.

Isolated left ventricular noncompaction in adults is uncommon. The most frequent clinical manifestations are heart failure due to left ventricular systolic dysfunction and supraventricular and ventricular arrhythmias, which may be sustained and associated with sudden death. Thromboembolic complications are also possible. We report the case of an adult patient with isolated left ventricular noncompaction who came to our observation because of acute cerebral ischemia, an initial presentation of the disease only rarely described.

Ejection fraction (EF) is the most widely used instrumental parameter in clinical cardiology for the evaluation of left ventricular systolic function and prognostic stratification of various cardiac diseases, including ischemic heart disease and heart failure. EF has some advantages but also many limitations, which may favor an incorrect use of this parameter. Moreover, the different cardiac imaging techniques available for EF calculation can be an additional source of errors and inaccuracies. This article will review in detail the pathophysiological features and intrinsic limitations of EF, with the aim to clarify how to properly use this parameter.

Natural killer (NK) cells are involved in innate immune responses to viral infections either via direct cytotoxicity which destroys virus-infected cells or production of immunoregulatory cytokines which modulate adaptive immunity and directly inhibit virus replication. These functions are mediated by different NK subpopulations, with cytotoxicity being generally performed by CD56(dim) NK cells, whereas CD56(bright) NK cells are mainly involved in cytokine secretion. NK functional defects are usually combined so that impaired degranulation is often associated with deficient cytokine production. Innate immunity is thought to be relevant in the control of hepatitis virus infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV), and recent findings reproducibly indicate that NK cells in chronic viral hepatitis are characterized by a functional dichotomy, featuring a conserved or enhanced cytotoxicity and a reduced production of interferon (IFN)-γ and tumor necrosis factor-α. In chronic HCV infection this appears to be caused by altered IFN-α signaling resulting from increased signal transducer and activator of transcription 1 (STAT1) phosphorylation, which polarizes NK cells toward cytotoxicity, and a concomitantly reduced IFN-α induced STAT4 phosphorylation yielding reduced IFN-γ mRNA levels. These previously unappreciated findings are compatible on the one hand with the inability to clear HCV and HBV from the liver and on the other they may contribute to understand why these patients are often resistant to IFN-α-based therapies.

Unlabelled: Hepatitis C virus (HCV) persistence in the host results from inefficiencies of innate and adaptive immune responses. Most studies addressing the role of innate immunity concentrated on peripheral blood (PB) natural killer (NK) cells, whereas only limited information is available on intrahepatic (IH) NK cells. We therefore examined phenotypic and functional features of IH and PB NK cells in paired liver biopsy and venous blood samples from 70 patients with chronic HCV infection and 26 control persons subjected to cholecystectomy for gallstones as controls. Ex vivo isolated IH NK cells from HCV-infected patients displayed unique phenotypic features, including increased expression of NKp46-activating receptor in the face of reduced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cluster of differentiation (CD) 107a expression, which resulted in impaired degranulation compared with controls. To gain insights into the effect of HCV on NK cells, we exposed peripheral blood mononuclear cells (PBMCs) from patients and healthy donors to cell-culture-derived HCV (HCVcc) and measured NK cell degranulation, TRAIL, and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression. Exposure of PBMCs to HCVcc significantly boosted NK degranulation, pERK1/2, and TRAIL expression in healthy donors, but not in patients with chronic HCV infection, a defect that was completely reversed by interferon-alpha. Purified NK cells showed a minimal, though significant, increase in degranulation and TRAIL expression, both in patients and controls, after exposure to HCVcc., Conclusions: These findings indicate dysfunctional IH NK cell cytotoxicity associated with TRAIL down-regulation in chronic HCV infection, which may contribute to virus persistence. PB NK cell impairment upon exposure to HCVcc suggests the existence of an accessory cell-dependent NK cell lytic defect in chronic HCV infection predominantly involving the TRAIL pathway., (Copyright © 2012 American Association for the Study of Liver Diseases.)

A prospective randomized controlled study was designed to evaluate the effects of recombinant human follicle-stimulating hormone (rFSH) treatment on sperm DNA fragmentation in men with idiopathic oligoasthenoteratozoospermia (iOAT). One hundred twenty-nine men with sperm count less than 10 × 10(6) spermatozoa/mL and forward motility <25% were included; normal serum levels of FSH, luteinizing hormone (LH), and testosterone, and no other causes of infertility were enrolled. The patients were randomized into 2 groups: 65 men were treated on alternate days for 90 days with injections of 150 IU rFSH, and 64 subjects received nonantioxidant vitamin supplements. Main outcome measures were serum levels of FSH, LH, testosterone, and inhibin B and DNA fragmentation index (DFI) at baseline and after 90 days. No significant differences were observed between the 2 groups with regard to sperm parameters and hormone values. The DFI was similar between the 2 groups at the time of the enrollment but reduced significantly (P < .05) after rFSH therapy in study group, whereas no significant variation occurred in the control group. In the subgroup of patients with high basal DFI values (>15%), rFSH treatment significantly increased DFI (P < .01), whereas no significant variation occurred after 90 days of vitamin supplements. We conclude that rFSH administration improves sperm DNA integrity in iOAT men with increased DFI values. The degree of sperm DFI might be useful to identify those iOAT patients in which rFSH treatment can be advantageous.

Objective: To evaluate treatment efficacy and patient acceptability of the new Radiographic Tubal Assessment Set (RTAS) (Cook Ireland Ltd., Limerick, Ireland) for selective salpingography (SSG)., Study Design: 33 women, between 23 and 38 years old, referred to the Fertility Centre of the Department of Obstetrics, Gynecology and Reproductive Science, Second University of Naples, for sterility problems, underwent an office operative SSG with the RTAS. Of the 33 women, 12 had bilateral tubal obstruction (Group A) and 21 had unilateral tubal obstruction (Group B). Patients who did not regain tubal patency were referred for laparoscopic surgery. To verify patient acceptability, a visual analogue score (VAS 1-10) of pain was completed immediately after the procedure., Results: From a total of 45 obstructed fallopian tubes, 34 were recanalized, giving a success rate for the procedure of 75.6% (p<0.001). Nine patients with bilateral tubal obstruction (Group A) had the tubes recanalized and five obtained a spontaneous pregnancy. Sixteen patients with monolateral tubal obstruction (Group B) had the tubes recanalized and nine obtained a spontaneous pregnancy. A total of seven patients were sent for operative laparoscopy: four of them had the tubes recanalized and two obtained a spontaneous pregnancy. One patient was lost to follow-up. The evaluation of the level of pain felt during the procedure on the 10 cm VAS showed mean pelvic pain 2.9 ± 2.2, and an incidence of no discomfort±low pain significantly higher than moderate±severe pain (p<0.0001)., Conclusion: The RTAS can be considered a safe and effective tool to perform this office operative procedure for tubal recanalization, with a high acceptability for the patient. The "see and treat" approach in patients with proximal tubal obstruction (PTO) suggests for the future the use of this device under sonographic guidance, taking into account accurate patient selection., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Aims: To evaluate left ventricular (LV) systolic and diastolic myocardial function, and their relation to coronary flow reserve in patients with non-insulin-dependent diabetes mellitus (DM) and microvascular angina., Methods and Results: We selected a population of 45 normotensive patients with DM (56.3 ± 8.2 years; 25 males) with LV ejection fraction >50% and microvascular angina (anginal pain, positive imaging stress test and normal coronary angiography). Thirty-five age- and sex-matched healthy controls were also enrolled. All the patients underwent standard echocardiography, Tissue Doppler (TDI), two-dimensional strain (2DSE) imaging, and coronary flow reserve (CFR) measurement. LV myocardial early diastolic peak velocities (E(m)) and peak systolic 2DSE were reduced in both interventricular septum (IVS) and LV lateral wall (p<0.01) in DM, as well as CFR (1.89 ± 0.7 vs 2.55 ± 0.56, p<0.0001) compared with controls. By multivariate analysis, the independent determinants of E(m) were glycated haemoglobin (β coefficient=-0.36; p<0.01) and age (β=-0.46, p<0.001), while global longitudinal strain was predicted by glycated haemoglobin (β=0.48, P<0.001) and by the duration of the disease (β=0.38, P<0.005). An independent association between LV global longitudinal strain and CFR (β coefficient=-0.47, p<0.001) in DM patients was also evidenced., Conclusions: TDI, 2DSE and CFR are valuable non-invasive and easy-repeatable tools for detecting LV myocardial and coronary function in DM patients with microvascular angina., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Perivalvular leak following implant of aortic or mitral prosthetic valves or rings is a relatively common complication, sometimes leading to significant clinical and hemodynamic consequences, such as severe valvular insufficiency, heart failure and hemolysis. In these cases, a second surgical operation, which typically involves the replacement of the dehiscent prosthesis, is the procedure of choice, but sometimes it cannot be performed. The alternative to reoperation can be the percutaneous closure of the perivalvular leak guided by transesophageal echocardiography before and during the closure procedure. In this review, the current role of echocardiography in the study of perivalvular leaks, with particular reference to guiding percutaneous transcatheter closure, is discussed. Also, the advantages and limitations of conventional two-dimensional and real-time three-dimensional transesophageal echocardiography are compared.

When applying echo-Doppler imaging for either clinical or research purposes it is very important to select the most adequate modality/technology and choose the most reliable and reproducible measurements. Quality control is a mainstay to reduce variability among institutions and operators and must be obtained by using appropriate procedures for data acquisition, storage and interpretation of echo-Doppler data. This goal can be achieved by employing an echo core laboratory (ECL), with the responsibility for standardizing image acquisition processes (performed at the peripheral echo-labs) and analysis (by monitoring and optimizing the internal intra- and inter-reader variability of measurements). Accordingly, the Working Group of Echocardiography of the Italian Society of Cardiology decided to design standardized procedures for imaging acquisition in peripheral laboratories and reading procedures and to propose a methodological approach to assess the reproducibility of echo-Doppler parameters of cardiac structure and function by using both standard and advanced technologies. A number of cardiologists experienced in cardiac ultrasound was involved to set up an ECL available for future studies involving complex imaging or including echo-Doppler measures as primary or secondary efficacy or safety end-points. The present manuscript describes the methodology of the procedures (imaging acquisition and measurement reading) and provides the documentation of the work done so far to test the reproducibility of the different echo-Doppler modalities (standard and advanced). These procedures can be suggested for utilization also in non referall echocardiographic laboratories as an "inside" quality check, with the aim at optimizing clinical consistency of echo-Doppler data.

In a prospective observational study, 50 healthy patients aged 18-39 years, with regular ovulatory cycle and normal hormone levels, underwent endometrial biopsy in the proliferative and secretory phase of the menstrual cycle for semiquantitative reverse-transcription polymerase chain reaction analysis of mRNA for LGR7, the classic relaxin receptor. LGR7 is constitutively expressed in human endometrium, and an increased LGR7 immunostaining is demonstrated in the secretory phase, confirming the involvement of relaxin in the physiology of endometrium and suggesting its role in implantation., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Speckle-tracking echocardiography has recently emerged as a quantitative ultrasound technique for accurately evaluating myocardial function by analyzing the motion of speckles identified on routine 2-dimensional sonograms. It provides non-Doppler, angle-independent, and objective quantification of myocardial deformation and left ventricular systolic and diastolic dynamics. By tracking the displacement of the speckles during the cardiac cycle, strain and the strain rate can be rapidly measured offline after adequate image acquisition. Data regarding the feasibility, accuracy, and clinical applications of speckle-tracking echocardiography are rapidly accumulating. This review describes the fundamental concepts of speckle-tracking echocardiography, illustrates how to obtain strain measurements using this technique, and discusses their recognized and developing clinical applications.

Muscular fatigue and dyspnoea on exertion are among the most common symptoms in chronic heart failure; however their origin is still poorly understood. Several studies have shown that cardiac dysfunction alone cannot fully explain their origin, but the contribution of the multiorgan failure present in this syndrome must be highlighted. We aimed to summarize the existing evidence and the most controversial aspects of the complex interplay of different factors involved in the symptom generation. In the first part of the review, six key factors were revised (the heart, the lung, the skeletal muscle, the hormonal changes, the O2 delivery to the periphery, the endothelium). In this second part, the role of the excitatory reflexes and the cardiac cachexia are presented. Finally, potential therapeutic implications are discussed here. We believe that a better knowledge of the pathophysiology of this syndrome may contribute to the management of the patients and to the improvement in their stress tolerance and quality of life.

Background: Similar to power-to-weight ratio and weight-to-power ratio, which are measurements of the actual performance of any engine, the ratios of peak power output to left ventricular (LV) mass (peak power/mass) and of peak LV mass to power output (peak mass/power) are indices of LV performance potentially useful in heart failure (HF). This Doppler echocardiographic study was designed to evaluate peak power/mass and peak mass/power in patients with advanced HF compared with healthy subjects and to assess their prognostic value., Methods: Power output was measured at rest and at peak exercise in 75 subjects, 60 patients with advanced HF (LV ejection fraction ≤ 35%) and 15 controls. Peak LV power output (W) was calculated as the maximal product of (133 × 10⁻⁶) × stroke volume (mL) × mean arterial pressure (mm Hg) × heart rate (beats/min). LV mass was assessed using a standard M-mode echocardiographic method., Results: Peak power/mass was 1.84 ± 0.46 W/100 g and 0.76 ± 0.31 W/100 g, and peak mass/power was 32 ± 10 g/m²/W and 84 ± 38 g/m²/W in controls and in patients with HF, respectively (both P values < .0001). Peak power/mass was a powerful predictor of outcome on multivariate logistic regression analysis (hazard ratio, 0.907; P = .009). On receiver operating characteristic curve analysis, the areas under the curve for HF-related events were greater for peak power/mass (P = .002) and peak mass/power (P = .011) with respect to resting ejection fraction. Comparisons of Cox models showed that peak power/mass added prognostic value to a model that included age, New York Heart Association class, etiology, ejection fraction, and diastolic dysfunction (P < .0001)., Conclusion: Peak power/mass is useful to discriminate and risk stratify patients with advanced HF with additional power with respect to ejection fraction., (Copyright © 2010 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

Echocardiography is the most commonly used imaging technique in current clinical cardiology practice and is usually performed using a monoplane approach. In recent years new matrix-array transducers have become available that allow the real-time simultaneous display of two or more echocardiographic scanning planes from the same acoustic window. This multiplane approach is particularly interesting as it may reduce, during the examination, the number of probe movements and consequently facilitate image acquisition. In some clinical applications, moreover, the multiplane approach improves both accuracy and reproducibility of echocardiography. This review evaluates the state of the art of multiplane echocardiography and discusses possible clinical applications, advantages and limitations of this technique.

Cardiac resynchronization therapy (CRT) is a therapeutic option with proven efficacy in improving symptoms and reducing both hospitalization and mortality in patients with refractory heart failure. However, a significant number of patients do not respond to CRT and this may be due to incomplete or inappropriate selection and characterization of patients before pacemaker implant. Cardiac magnetic resonance imaging (CMRI) is an imaging technique that may assist cardiologists in this regard. This technique has the potential to improve the success rate of CRT, due to pre-interventional evaluation of left ventricular function, mechanical dyssynchrony, and characterization and quantification of scar tissue. Recently, venous coronary anatomy has also been successfully evaluated by CMRI. In this review the role of CMRI in patients with heart failure who are candidates for CRT is discussed and potential future developments are indicated.

Background: The aim of this study was to compare speckle-tracking echocardiography-derived left ventricular (LV) systolic mechanics and their relationships with LV diastolic properties in young patients with hypertension and in young competitive athletes in relation to their respective alterations of LV structure., Methods: Nineteen sedentary controls, 22 top-level rowers, and 18 young newly diagnosed, never-treated patients with hypertension, all male, underwent Doppler echocardiography including pulsed tissue Doppler of the mitral annulus and speckle-tracking echocardiography. Peak longitudinal strain was calculated in apical long-axis, four-chamber, and two-chamber views, and values of the three views were averaged (global longitudinal strain [GLS]). Regional circumferential and radial strain were calculated at the LV basal, middle, and apical levels, and values were averaged (global circumferential strain and global radial strain). LV torsion was determined as the net difference in the mean rotation between the apical and basal levels., Results: The three groups were comparable for age, whereas body mass index and blood pressure were higher in patients with hypertension, and heart rate was lower in rowers. LV mass index was higher in rowers and in patients with hypertension than in controls, without differences in relative wall thickness, ejection fraction, and midwall shortening. Left atrial volume index was greater in rowers than in controls and patients with hypertension. Annular systolic velocity (s') (P < .001) and early diastolic velocity (e') (P < .0001) were lower and the E/e' ratio was higher (P < .0001) in patients with hypertension. GLS was lower in patients with hypertension (-17.5 ± 2.8%) than in rowers (-22.2 ± 2.7%) and in controls (-21.1 ± 2.0%) (P < .0001). Global circumferential strain, global radial strain, and torsion were similar among the three groups. In the pooled population, GLS was an independent contributor to E/e' ratio (P < .0001) after adjusting for age, heart rate, meridional end-systolic stress, LV mass index and left atrial volume index. By receiver operating characteristic curve analyses, both GLS and E/e' ratio appeared to be accurate in discriminating patients with hypertension from healthy controls, with the E/e' ratio being more sensitive (77.8%) and GLS more specific (89.5%)., Conclusions: The hearts of young patients with hypertension are characterized by reduced GLS, whereas global circumferential strain, global radial strain, and torsion are similar to those of athletes' hearts. The extent of GLS is strongly associated with LV diastolic function, independently of afterload changes and the degree of LV hypertrophy., (Copyright © 2010 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

The introduction of three-dimensional echocardiography and its evolution from time-consuming and cumbersome off-line reconstruction to real-time volumetric technique (real-time three-dimensional echocardiography) are one of the most significant advances in ultrasound imaging of the heart of the past decade. This imaging modality currently provides realistic views of cardiac valves capable of demonstrating the anatomy of various heart valve diseases in a unique, noninvasive manner. In addition, real-time three-dimensional echocardiography offers completely new views of the valves and surrounding structures, and allows accurate quantification of severity of valve disease. This article reviews the advantages of real-time three-dimensional echocardiography in assessing heart valves and shows also technological limitations in order to provide the scientific basis for its clinical use.

Tricuspid valve (TV) morphology and function evaluation plays a key role in several cardiac diseases, including left-sided valvular diseases and heart failure. However, TV is structurally complex and, differently from aortic and mitral valves, cannot be visualized in a single two-dimensional echocardiographic view, neither transthoracic nor transesophageal (i.e., simultaneous imaging of the three TV leaflets and their attachment to the annulus is not feasible). Conversely, real-time three-dimensional transthoracic echocardiography allows complete visualization of the TV apparatus from multiple views. This can lead to an improvement of our understanding about the pathophysiological mechanisms underlying TV diseases and functional tricuspid regurgitation, and may suggest new surgical techniques in order to improve surgical outcomes. The present review focuses on the state-of-the-art of real-time three-dimensional transthoracic echocardiography in TV morphology and function evaluation with its clinical applications and limits.

Real-time three-dimensional transesophageal echocardiography (RT3DTEE) is now commonly used in daily clinical practice. The transesophageal, compared to the transthoracic approach, allows the visualization of the whole spectrum of the mitral valve apparatus and the posterior cardiac structures. Moreover, images obtained by RT 3D TEE provide a unique and complete visualization of the mitral valve prosthetic elements. Indeed, the possibility to visualize guidewires and catheters in cardiac chambers and their relationship with cardiac structures during percutaneous transcatheter procedures reduces the time of radiation exposure and simplifies the approach becoming the reference method for monitoring. This review aims to underline the potential clinical applications and the advantages of RT3DTEE compared to other methods.

Hypertrophic cardiomyopathy (HCM) is one of the most common inherited cardiomyopathy. The identification of patients with HCM is sometimes still a challenge. Moreover, the pathophysiology of the disease is complex because of left ventricular hyper-contractile state, diastolic dysfunction, ischemia and obstruction which can be coexistent in the same patient. In this review, we discuss the current and emerging echocardiographic methodology that can help physicians in the correct diagnostic and pathophysiological assessment of patients with HCM.

The definition of the athlete's heart includes the mechanisms of cardiac adaptation to training, characterized by the increase of internal chamber dimensions, ventricular wall thickness, and atrial chambers. The morphology of the athlete's heart is intermediate between concentric and eccentric left ventricular hypertrophy (LVH), in relation to the large prevalence of mixed sports activities and training protocols (including both aerobic and anaerobic exercise). Echocardiography is the tool of choice for the assessment of the athlete's heart and also for the differentiation of physiologic and pathologic LVH (hypertrophic cardiomyopathy and LVH due to arterial hypertension). The initial echocardiographic approach includes the quantitative analysis of the left ventricle, in order to calculate left ventricular mass, left ventricular mass index and relative wall thickness for diagnosing concentric or eccentric LVH. Tissue Doppler (pulsed or color modality) and strain rate imaging (Doppler or two-dimensional modality) may give additional information to the standard indices of systolic function. Diastolic function can be evaluated not only by standard Doppler transmitral inflow measurements but also using pulsed tissue Doppler, which may allow to distinguish the athlete's LVH from diastolic impairment of hypertensive patients or hypertrophic cardiomyopathy by the simple determination of myocardial early diastolic velocity. Also the morphological and functional features of the left atrium and of the right ventricle can be assessed in the athlete's heart by combining standard echocardiography with new echocardiographic technologies.

Several studies have demonstrated the usefulness of B-type natriuretic peptide (BNP) dosage in patients referring for acute dyspnea in the emergency department. BNP is strongly associated not only with the evidence but even with the degree of heart failure, and BNP values are particularly increased in the advanced NYHA classes and in patients with poor prognosis. High BNP levels correlate with echocardiographic indexes of left ventricular and right ventricular systolic dysfunction but even better with diastolic dysfunction and degree of left ventricular filling pressure. However, in presence of some clinical confounders, such as obesity, renal insufficiency and anemia, BNP dosage itself cannot be interpretable. Under these circumstances, Doppler echocardiography is able to identify with better accuracy patients affected by heart failure. Algorithms built taking into account clinical and echocardiographic parameters as well as BNP measurements are already available in the guidelines of the European Society of Cardiology on heart failure with normal ejection fraction. They will lead to a better and earlier identification, better risk stratification and management of patients referring for heart failure.

In the last decades the introduction and development of echocardiography allowed a significant improvement in the diagnosis as well as in the morphological and functional evaluation of several heart diseases, and today many therapeutic decisions are taken based on the results of the echocardiographic examination. One of the most important development in the field of echocardiography is three-dimensional imaging, which has evolved from the slow and labor-intense off-line reconstruction techniques to the faster and simpler real-time volumetric imaging, which has the potential to be integrated in routine clinical practice. One of the major proven advantages of real-time three-dimensional echocardiography is the evaluation of left ventricular volume, mass and function, which is achieved by eliminating the need for geometric modeling and the errors caused by foreshortened views. In this review we discuss the state-of-the-art and anticipate future developments of real-time three-dimensional echocardiography that are relevant to its application to the left ventricle.

Background: Because echocardiography is routinely applied for left ventricle (LV) evaluation before cardiac resynchronization therapy (CRT), it is important to know whether echocardiographic assessment of myocardial scar burden may also help to predict CRT response in patients with drug-refractory systolic heart failure of ischemic origin., Methods: Seventy-one patients with ischemic heart failure who underwent CRT were retrospectively analyzed. The number of LV scar segments was evaluated in each patient, defining transmural scar as an end-diastolic wall thickness < or = 5 mm associated with increased acoustic reflectance. CRT response was defined by LV end-systolic volume decrease by at least 10% after 6 months of treatment. The role of pacing site with respect to scar location was also assessed., Results: Thirty-nine patients (55%) were responders and 32 patients (45%) were nonresponders to CRT. At baseline, responders had a lower number of scar segments (1.7 +/- 1.6 vs 3.5 +/- 2.5, P = .001). The number of scar segments was significantly associated with CRT response and correlated significantly with end-systolic volume variation (r = 0.57, P = .0001). The presence of 3 or more scar segments allowed the identification of nonresponders with a sensitivity of 62% and specificity of 71%. In responders, the pacing stimulus was more frequently delivered remote from scar segments, whereas in nonresponders it was more often delivered over the scar segments., Conclusion: Echocardiographic evaluation of transmural scar burden predicts CRT response after 6 months of treatment and should be performed in all candidates for CRT with ischemic heart failure before biventricular pacemaker implantation.

Aims: It is unclear whether myocardial velocity or deformation indices of dyssynchrony are better at predicting response to cardiac resynchronization therapy (CRT). Therefore, two indices of left ventricular (LV) dyssynchrony based on myocardial velocity and deformation were compared to predict success of CRT., Methods and Results: Sixty patients with dilated cardiomyopathy, New York Heart Association class III-IV, LV ejection fraction (EF) < or =35%, QRS >120 ms underwent CRT. The standard deviation of the averaged time-to-peak longitudinal negative strain (Tepsilon-SD) and positive systolic velocity (Tv-SD) of 12 LV segments were calculated before and after 6 months of CRT. Responders were defined at month 6 by > or =20% EF increase and/or > or =15% end-systolic volume (ESV) decrease with respect to baseline. On univariable analysis, baseline Tepsilon-SD and Tv-SD were both significantly associated with CRT response; however, the area under the receiver operating characteristic curve was better for Tepsilon-SD. On bivariable analysis, only Tepsilon-SD retained an independent prognostic value for CRT response. Results of the analysis did not change when the logistic models were adjusted for aetiology., Conclusion: Baseline dyssynchrony of longitudinal myocardial peak deformation (Tepsilon-SD) appears to be better than dyssynchrony of longitudinal myocardial peak systolic velocities (Tv-SD) for the identification of CRT responders.

Bullying almost always occurs in the presence of peers, most of whom do not intervene to stop it. This study examined the role of attachment, empathy, and gender in predicting the behavior of 105 middle school students who reported being either (a) defenders who actively intervened to stop bullying, or (b) outsiders who were either not involved or stood by passively. It was hypothesized that gender, attachment to mother, attachment to father, and empathy would predict whether children nominated themselves as defenders in bullying situations. A hierarchical logistic regression analysis indicated that these variables together significantly predicted whether children nominated themselves as defenders or outsiders. Gender was not a unique significant predictor. Attachment to mother contributed significant unique variance to the model, but attachment to father did not after accounting for gender and attachment to mother. Empathy contributed significant unique variance to the model even after accounting for all other variables. Results suggest that middle school personnel should openly discuss with students their roles in bullying interactions. In addition, teaching empathy towards others and involving parents may be critical components in comprehensive prevention programs.

Objective: To verify whether myocardial impairment can be detected by tissue Doppler imaging (TDI) in patients with asymptomatic systemic sclerosis (SSc), 35 patients with SSc with normal left ventricular (LV) ejection fraction and 35 control subjects were studied., Methods: Myocardial longitudinal peak systolic velocity, strain, and strain rate (SR) were measured by TDI at a regional level, and for each parameter the average value was calculated using an LV 12-segment model. In addition, the mitral annulus diastolic velocities and the E/Ea ratio were obtained. Myocardial calibrated integrated backscatter (cIB) was used as an index of fibrosis., Results: Compared with controls, patients with SSc showed lower peak strain (-19.5% +/- 2.3% vs -26.1% +/- 2.4%, P < .001), peak SR (-1.34 +/- 0.14 s(-1) vs -1.59 +/- 0.14 s(-1), P < .001), septal cIB (-19.5 +/- 3.1 dB vs -23.8 +/- 1.6 dB, P < .001), and posterior wall cIB (-23.4 +/- 2.9 dB vs -28.6 +/- 2.5 dB, P = .001), and higher E/Ea (11.7 +/- 2.5 vs 9.8 +/- 1.1, P < .001), whereas peak systolic velocities did not differ. Strain, SR, and E/Ea correlated better with cIB than systolic velocities., Conclusion: TDI-derived strain, SR, and E/Ea can detect impairment of LV myocardial function in asymptomatic patients with SSc with normal LV ejection fraction better than TDI systolic velocities.

Major perioperative cardiac complications, including cardiac death, nonfatal myocardial infarction and nonfatal cardiac arrest, can occur in patients undergoing noncardiac surgery. To reduce the risk of these complications, some authors have reported on the utility of intraoperative transesophageal echocardiography as a complementary monitoring tool in noncardiac surgery. However, although this approach is now well established in patients undergoing cardiac surgery, there are no guidelines for intraoperative transesophageal echocardiography application in noncardiac surgery, and little literature exists on patient outcome, logistics, financial impact, medico-legal implications and safety. In this review, we discuss published information about the use of intraoperative transesophageal echocardiography during noncardiac surgery with an attempt to clarify whether this approach may offer potential benefits compared with conventional intraoperative monitoring systems. In addition, perioperative risk determinants in noncardiac surgery are briefly summarized and information derived from intraoperative transesophageal echocardiography for evaluation of cardiac morphology and function is schematically presented.

The possibilities of applying the laws of dynamics to the study of myocardial mechanics are remarkable and to some extent neglected to characterize ventricular performance by the imaging techniques. There are potentially useful applications derived from the analyses of Doppler flow velocity profiles of left ventricular outflow to be applied to the study of cardiovascular dynamics. They include ejection force, pressure-volume work and ventricular power. All these variables require measurements that are easy to obtain even during a standard examination, like stroke volume, ventricular outflow velocity, and the velocity-time integral.

The objective of this review was to explore the clinical relevance of Doppler echocardiographic techniques in the evaluation of right and left ventricular function. It is well known that echocardiographic and Doppler analysis are able to provide information about several hemodynamic parameters, such as cardiac output, diastolic filling pressure, vascular resistances and pulmonary arterial pressures. This integrated approach, completely reliable and non-invasive, could allow to obtain useful information not only from a diagnostic and prognostic point of view but also for a potential therapeutic management, either pharmacological or surgical. This review summarizes the current knowledge and the emerging applications of echocardiographic and Doppler techniques focusing on the close correlation between Doppler-derived data and those coming from invasive techniques. On the basis of these evidences, the importance, even in daily clinical practice, of a non-invasive catheterization laboratory is clear and able to supply key information about ventricular function and, at the same time, to avoid expensive and unpleasant invasive procedures for patients.

Aortic valve stenosis is a common disease. Despite this, the diagnosis may often be missed; a significant proportion of patients are still identified at post-mortem examination, and 5% of operations are performed at end stage. Unrecognized aortic valve stenosis is an important cause of anesthetic mortality. One reason for failing to make a diagnosis is that the clinical signs can be difficult to interpret due to the confounding association with arterial hypertension, coronary artery disease and systemic arteriosclerosis, potentially blunting the effects of aortic valve stenosis on the circulation. Moreover, most patients with aortic valve stenosis have a long asymptomatic period and may not seek medical attention. In patients with severe, symptomatic, calcific aortic valve stenosis, aortic valve replacement is the only effective treatment; much evidence suggests that it should be offered to patients regardless of age, after appropriate clinical evaluation. Doppler echocardiography plays a pivotal role in confirming the diagnosis of aortic valve stenosis in assessing the severity of the disease and, ultimately, in giving prognostically relevant information. Moreover, echocardiography is suitable for monitoring of disease progression and left ventricular function in these patients, and is of fundamental support for clinical follow-up. Accurate noninvasive quantification of aortic valve stenosis is, however, a technically demanding and time-consuming procedure, with several potential pitfalls. Considering the frequency and importance of aortic valve stenosis, a comprehensive echocardiographic study should be offered and carefully performed in all patients with noteworthy murmurs and repeated regularly (at appropriate time intervals), together with clinical review, in patients in whom aortic valve stenosis has been diagnosed.

Functional mitral regurgitation (FMR) is a common finding in patients with ischemic or nonischemic dilated cardiomyopathy as a complication of left ventricular (LV) dysfunction and remodeling associated with a fibrotic remodeling response of mitral leaflets to abnormal valvular loading. Although mitral valve tenting is the main determinant of FMR, clinical and experimental observations suggest that intraventricular delay could be a potential co-determinant of FMR. LV dyssynchrony can potentially contribute to FMR by several mechanisms, such as creating an uncoordinated regional LV mechanical activation in segments supporting the papillary muscles, determining diastolic mitral regurgitation, reducing the sphincteric function of the mitral annulus, and decreasing the efficiency of LV contraction and closing forces. Cardiac resynchronization therapy has been demonstrated to reduce FMR with correction of some of the underlying pathophysiological mechanisms. The present review article focuses on the role of mechanical dyssynchrony as a pathophysiological determinant of FMR, and on the potential role of cardiac resynchronization therapy as a therapeutic option for treatment of FMR in patients with severe heart failure and advanced LV dysfunction.

Although cardiac resynchronization therapy is currently used for treatment of refractory heart failure in patients with low ejection fraction and cardiac dyssynchrony, there is a substantial number of non-responders. This indicates that, in addition to cardiac dyssynchrony, there are other factors affecting response to cardiac resynchronization therapy. Pre-implant identification of these factors appears of crucial importance in order to finalize the resynchronization treatment to those patients who have the highest probability of a positive response. In this review the main non-dyssynchrony determinants of response to cardiac resynchronization therapy are presented and discussed.

Cardiac resynchronization therapy (CRT) is currently used for treatment of refractory heart failure and is effective in reducing symptoms and increasing quality of life and exercise tolerance. Data from the literature also show that CRT may prolong event-free survival and reduce heart failure mortality. This therapy is also highly cost-effective as compared to optimized medical treatment. The reduction of the risk of death occurs in both nonischemic and ischemic heart failure, although in this latter group CRT benefit seems to be less. It is still controversial whether a back-up defibrillator should be implanted to all patients undergoing CRT. Finally, left ventricular reverse remodeling occurring after 3 to 6 months of treatment predicts long-term benefit of CRT on mortality.

Doppler echocardiography is a fundamental instrument to understand heart damage during essential arterial hypertension. Left ventricular (LV) hypertrophy may also be conveniently studied in its morphological and functional aspects by ultrasound application. Echocardiography can also provide important morphological and functional information in hypertensive patients for therapeutic management and prognostic stratification. In recent years, echocardiography has been enriched by very refined techniques that are capable of studying the physiopathological intramyocardial phenomena: (i) tissue Doppler (which studies intramyocardial velocities and time intervals and allows the analysis of strain and strain rate); (ii) integrated backscatter (which analyzes variations of myocardial reflectivity in decibels); (iii) transthoracic Doppler derived coronary flow reserve (which quantifies the vasodilator response of coronary velocities to a hyperaemic stimulation); (iv) myocardial echo-contrast-echocardiography (which studies the kinetics of ultrasound contrast microbubbles at the intramyocardial level); and (v) real-time three-dimensional (3-D) echocardiography [which allows a more precise evaluation of left ventricular (LV) volumes and LV mass]. These new methodological approaches have recently been used in the hypertensive clinical setting to provide a deeper knowledge of the complex physiopathological and histopathological mechanisms underlying the modifications induced by arterial hypertension at the myocardial tissue level (myocytes, collagen, microcirculation). This review shows the advancement of high-tech ultrasound applied to hypertensive heart disease, pointing out limitations and incremental potentialities in comparison with conventional echocardiography.

Sporadic colorectal cancer (CRC) is a major health concern worldwide. Epidemiologic evidence suggests a polygenic predisposition to CRC, but the genes responsible remain unknown. Here, we performed genome-wide scanning of male (ACI/SegHsd x Wistar-Furth)F2 (AWF2) rats to map susceptibility genes influencing the evolution of early colorectal lesions to adenocarcinoma following 1,2-dimethylhydrazine administration. Phenotypic analysis revealed higher incidence/multiplicity and lower size of adenomas in ACI/SegHsd (ACI) and (ACI/SegHsd x Wistar-Furth)F1 (AWF1) than Wistar-Furth (WF) rats and higher incidence/multiplicity of poorly differentiated adenocarcinomas in WF than ACI rats, with intermediate values in AWF1 rats. Linkage analysis of 138 AWF2 rats identified three loci on chromosomes 4, 15 and 18 in significant linkage with lesion multiplicity that were identified as rat Colon cancer resistance (rCcr) 1, rCcr2 and rCcr3, respectively. Seven other loci on chromosomes 5, 6, 15, 17, 18 and 20 were in suggestive linkage with adenoma/adenocarcinoma multiplicity/surface area. Six of them were identified as rCcr4-9 and a locus on chromosome 5 was identified as a susceptibility locus, rCcs1. Significant interactions between rCcr3 and rCcr6, rCcr6 and rCcr8 and rCcr5 and rCcr9, and four novel epistatic loci controlling multiplicity/size of colorectal lesions were discovered. Apc, located at rCcr3, did not show functional promoter polymorphisms. However, influence of susceptibility/resistance genes on Wnt/beta-catenin pathway was shown by defective beta-catenin inactivation in WF but not in ACI and AWF1 rat adenocarcinomas. These data indicate that inheritance of predisposition to CRC depends on interplays of several genetic factors, and suggest a possible mechanism of polygenic control of CRC progression.

Although left ventricular (LV) dyssynchrony assessed by ultrasound is emerging as superior to QRS duration in predicting response to cardiac resynchronization therapy (CRT), the role of conventional echocardiographic parameters of dyssynchrony is still debated. Forty-eight patients with heart failure in New York Heart Association classes III to IV, LV ejection fraction < or =35%, and QRS duration > or =120 ms were studied. LV dyssynchrony was evaluated by M-mode as septal-to-posterior wall motion delay and left lateral wall postsystolic displacement (LWPSD). Interventricular dyssynchrony was defined as the difference between the LV and right ventricular preejection periods measured by standard Doppler. Reverse remodeling was defined as an LV end-systolic volume decrease > or =15% after 6 months of CRT. Thirty-one patients (65%) were considered responders to CRT. At baseline responders differed from nonresponders by having less severe New York Heart Association class (p = 0.006), lower percentage of ischemic cause (p = 0.006), longer PR interval (p = 0.013), shorter LV diastolic filling time corrected for heart rate (p = 0.005), and presence of LWPSD (p = 0.003). At multivariate analysis, predictors of CRT response were LWPSD (odds ratio [OR] 1.045, 95% confidence interval [CI] 1.001 to 1.091; p = 0.043), LV diastolic filling time corrected for heart rate (OR 0.855, 95% CI 0.744 to 0.981, p = 0.026), and nonischemic cause (OR 0.109, 95% CI 0.018 to 0.657, p = 0.016). In conclusion, preimplantation assessment of cardiac dyssynchrony based on M-mode LWPSD may predict LV reverse remodeling after CRT, especially in patients with nonischemic cause and shorter diastolic filling time. This suggests the potential role of baseline postsystolic mechanical phenomena in determining response to CRT independently of QRS duration.

In cardiology, ventricular function has extensively been studied, whereas atrial function received less attention. For such a reason atrial function is less known. The aim of this review was to summarize the role of atrial function and to explain how echocardiography and new echocardiographic-derived techniques may be of help to better study atrial function.

Tissue Doppler is an ultrasound tool representing a useful completion of standard Doppler echocardiographic examination, The placement of pulsed tissue Doppler sample volume at the level of the different sites of the mitral annulus allows to obtain information on left ventricular global longitudinal (systolic and diastolic) function, whereas the sampling of tricuspid lateral annulus gives similar information on the right ventricular chamber. Myocardial early diastolic velocity (Em) is a marker of ventricular diastolic relaxation and the ratio obtainable between transmitral (or transtricuspid) E velocity and annular Em (E/Em ratio) is an accurate index of the level of filling pressure of the assessed ventricular chamber. Myocardial systolic velocity (Sm) as well as the frequency of acceleration of presystolic velocity, occurring during isovolumic contraction time, are indexes of systolic performance and their reduction is evident in several cardiac pathologies. Tissue Doppler-derived systolic and diastolic indexes have a recognized prognostic value in heart failure and after acute myocardial infarction. In these conditions they are able to predict both left ventricular remodeling and mortality.

Objective: To compare the effects of GnRH-agonist/recombinant rFSH versus GnRH-antagonist/recombinant FSH stimulation on follicular fluid levels of soluble intercellular adhesion molecule (sICAM)-1 and vascular cell adhesion molecule-1 (sVCAM-1) during in vitro fertilization (IVF)., Design: Prospective, randomized study., Setting: University hospital., Patient(s): Seventy-three women underwent IVF., Intervention(s): GnRH-agonist/rFSH or GnRH-antagonist/rFSH administration and collection of follicular fluid from 3 small (11-14 mm in diameter) and 3 large (18-21 mm in diameter) follicles on the day of oocyte retrieval., Main Outcome Measure(s): Follicular fluid levels of sICAM-1 and sVCAM-1 and intrafollicular estradiol and progesterone were also measured., Result(s): Women who underwent GnRH-agonist/rFSH showed higher concentrations of sICAM-1 in both small and large follicles were compared with patients who received GnRH-antagonist/rFSH treatment; follicular fluid levels of sVCAM-1 were similar between the 2 stimulation protocols. Content of sICAM-1 in small and large follicles positively correlated with the number of follicles of > or =15 mm and the number of oocytes that were retrieved in both study groups. Concentrations of follicular fluid sVCAM-1 and progesterone were higher in large than in small follicles and were correlated positively to each other in both follicular classes., Conclusion(s): In IVF, GnRH-agonist/rFSH is associated with higher follicular fluid levels of sICAM-1 compared with GnRH-antagonist/rFSH regimen. Intrafollicular sICAM-1 content may predict ovarian response, and sVCAM-1 appears as an indicator of the degree of follicular luteinization.

Patients with heart failure, marked systolic dysfunction and dys-synchronous myocardial contraction are at increased risk for exacerbated pump failure and arrhythmias, and suffer higher mortality rates. In these patients, cardiac resynchronization therapy (CRT), achieved by a biventricular pacing, can lead to clinical improvement, reverse left ventricular remodeling and prolonged survival, although a substantial subset of non-responders has been reported. The electrocardiographic QRS width does not predict long-term CRT benefit, while direct measures of mechanical dyssynchrony obtained by various ultrasound techniques have been shown to have a better predictive value. However, currently there is no consensus on the optimal ultrasound technique to use for assessing mechanical dyssynchrony and select candidates for CRT. In this review, the clinical role of both conventional and new ultrasound techniques applied to the study of cardiac dyssynchrony will be discussed, focusing on patient selection for CRT.

Background: Tissue harmonic imaging (THI) reduces near-field and side-lobe artifacts. This could improve recognition of cardiac masses, including thrombi and spontaneous echocontrast (SEC), a known thromboembolic risk factor., Objectives: We tested the hypothesis that THI improves detection of left ventricular (LV) thrombi and SEC compared with transthoracic fundamental imaging in patients with recent myocardial infarction., Methods: In all, 118 consecutive patients with recent myocardial infarction were studied at predischarge. The echocardiographic examination was performed in both fundamental imaging and THI modality and evaluated by 3 skilled and 3 nonexperienced observers for recognition of LV thrombosis and SEC., Results: THI increased LV thrombi diagnosis by 25% by skilled observers and by 50% by nonexperienced readers, reducing the number of false-positive diagnoses by 67%. Also, compared with fundamental imaging, THI improved recognition of LV SEC by both experienced and nonexperienced observers by 56% and 62%, respectively., Conclusions: The improved recognition of LV thrombosis and SEC by THI in patients with myocardial infarction is clinically relevant allowing appropriate treatment and prognostic stratification. Therefore, routine use of THI should be recommended when studying such patients in clinical practice.

Aims: We tested the hypothesis that dyssynchrony of left ventricular (LV) myocardial deformation evaluated by ultrasound can predict success of cardiac resynchronization therapy (CRT) in patients with heart failure (HF)., Methods and Results: Thirty-seven patients with dilated cardiomyopathy, New York Heart Association class III-IV, LV ejection fraction (EF) < or =35%, QRS > 120 ms were studied before, at pre-discharge, and after 3 and 6 months of CRT. The M-mode peak septal-to-posterior wall motion and thickening delay (SPWMD and SPWTD, ms) and the standard deviation of the averaged time-to-peak strain (TPS-SD, ms) of 12 middle and basal LV segments obtained from the three standard apical views were calculated. Responders were defined at month 6 by > or =20% EF increase and/or > or =15% end-systolic volume (ESV) decrease with respect to baseline. Baseline SPWTD (not SPWMD) and TPS-SD differentiated responders from non-responders with good accuracy and reproducibility. A value > or =194 ms for SPWTD and > or =60 ms for TPS-SD was significantly associated with responder identification. Baseline dyssynchrony parameters correlated significantly with EF (r = 0.53 for SPWTD and r = 0.86 for TPS-SD) and ESV variations (r = -0.42 for SPWTD and r = -0.73 for TPS-SD)., Conclusion: Patients with chronic HF should undergo ultrasound evaluation to quantify dyssynchrony of LV myocardial deformation, which would help identifying CRT responders.

Background: Tumor necrosis factor alpha-alpha (TNF-alpha) activation is an independent prognostic indicator of mortality in patients with heart failure (HF). Despite the recognition that several TNF family cytokines are elevated during myocardial infarction, their role in predicting subsequent prognosis in these setting remains poorly understood., Methods and Results: We performed a systematic evaluation of TNF-alpha and its type 1 and 2 soluble receptors, together with interleukin (IL)-6, IL-1 receptor antagonist, and IL-10, in 184 patients (132 men; mean age, 64+/-12) consecutively admitted for myocardial infarction. We correlated their values to short- and long-term incidence of death and HF (primary outcome). In 10 patients, we also studied the presence of transcardiac gradients for TNF-alpha and its soluble receptors. The control group comprised 45 healthy subjects who were sex and age matched (33 men; mean age, 65+/-6 years) to the patients. All tested cytokines were increased in patients, and no transcardiac or systemic AV difference was found. After a median follow-up of 406 days (range, 346 to 696 days), 24 patients died and 32 developed HF. Univariate analysis showed that all cytokines were related to outcome, whereas after adjustment for baseline and clinical characteristics, sTNFR-1 remained the only independent predictor of death and HF (hazard ratio, 2.9; 95% CI, 1.9 to 3.8, tertile 1 versus 3), together with left ventricular ejection fraction, Killip class, and creatine kinase-MB at peak., Conclusions: sTNFR-1 is a major short- and long-term predictor of mortality and HF in patients with acute myocardial infarction.