Ana M. González

Diagnosis of subacute ventricular wall rupture after acute myocardial infarction: Sensitivity and specificity of clinical, hemodynamic and echocardiographic criteria☆

When ventricular free wall rupture after acute myocardial infarction is not followed by sudden death, it is referred to as subacute ventricular rupture. The sensitivity and specificity of clinical, hemodynamic and echocardiographic diagnostic variables obtained at bedside are unknown and were therefore prospectively studied in 1,247 consecutive patients with acute myocardial infarction including 33 patients with subacute ventricular rupture diagnosed at operation (group A) and 1,214 patients without ventricular rupture (at operation, postmortem study or at discharge) (group B). The incidence of syncope, recurrent chest pain, hypotension, electromechanical dissociation, cardiac tamponade, pericardial effusion, high acoustic intrapericardial echoes, right atrial and right ventricular wall compression identified in two-dimensional echocardiograms and hemopericardium demonstrated during pericardiocentesis was higher in group A than in group B (p less than 0.00001). The presence of cardiac tamponade, pericardial effusion greater than 5 mm, high density intrapericardial echoes or right atrial or right ventricular wall compression had a high diagnostic sensitivity (greater than or equal to 70%) and specificity (greater than 90%). The number of false positive diagnoses was always high for each diagnostic variable alone (greater than 20%), but the combination of clinical (hypotension), hemodynamic (cardiac tamponade) and echocardiographic variables allowed a sensitivity of greater than or equal to 65% with a small number of false positive diagnoses (less than 10%) and provided useful information for therapeutic decisions. The diagnosis of subacute ventricular rupture requires a surgical decision. Twenty-five (76%) of the 33 patients with subacute ventricular rupture survived the surgical procedure and 16 (48.5%) are long-term survivors. Thus, subacute ventricular wall rupture is a relatively frequent complication after acute myocardial infarction that can be accurately diagnosed and successfully treated.

Predisposing conditions for atrial fibrillation in atrial septal defect with and without operative closure

The aims of this study were to determine the prevalence and predisposing conditions for atrial fibrillation (AF) in adults with atrial septal defect (ASD) and to evaluate the influence of age at surgical repair. The study population consisted of 286 adults with ASD (mean age 39.5 +/- 19 years). All patients had >or = 1 follow-up visit and a Doppler echocardiographic study. One hundred ninety-two of the patients underwent surgical closure 1 to 34 years before the study. Analyzed variables were entered into univariate (Mann-Whitney U) and multivariate (stepwise logistic regression) models to assess independent predictors for AF. The prevalence of AF was similar in surgically treated patients (15.6%) and in the nonsurgical group (13.8%) (p = 0.69). Multivariate analysis showed that current age (RR 1.9 per each decade of age, 95% confidence interval [CI] 1.3 to 2.7, p = 0.001), mitral regurgitation (RR 3.0 per each degree of regurgitation, 95% CI 1.6 to 5.8, p = 0.001), left atrial enlargement (RR 2.8 per each 10 mm increase in size, 95% CI 1.5 to 5.2, p = 0.001), and tricuspid regurgitation (RR 1.9 per each degree of regurgitation, 95% CI 1.0 to 3.7, p = 0.04) were independent predictors of AF; however, gender, anatomic type, defect size, Qp:Qs, pulmonary artery pressure, right ventricular dimension, left ventricular shortening fraction, and prior surgical repair were not related to late AF development. In the surgical group, age >25 years at the time of surgery was the only predictor for AF independent of age at the time of the study (p = 0.02).

Sinus venosus syndrome: atrial septal defect or anomalous venous connection? A multiplane transoesophageal approach

Objective: To discuss the anatomical features of sinus venosus atrial defect on the basis of a comprehensive transoesophageal echocardiography (TOE) examination and its relation to surgical data. Methods: 24 patients (13 men, 11 women, mean (SD) age 37 (17) years, range 17–73 years) with a posterior interatrial communication closely related to the entrance of the superior (SVC) or inferior vena cava (IVC) who underwent TOE before surgical repair. Records of these patients were retrospectively reviewed and compared with surgical assessments. Results: In 13 patients, TOE showed a deficiency in the extraseptal wall that normally separates the left atrium and right upper pulmonary vein from the SVC and right atrium. This deficiency unroofed the right upper pulmonary vein, compelling it to drain into the SVC, which overrode the intact atrial septum. In three patients, TOE examination showed a defect in the wall of the IVC, which continued directly into the posterior border of the left atrium. Thus, the intact muscular border of the atrial septum was overridden by the mouth of the IVC, which presented a biatrial connection. In the remaining eight patients, the defect was located in the muscular posterior border of the fossa ovalis. A residuum of atrial septum was visualised in the superior margin of the defect. Neither caval vein overriding nor anomalous pulmonary vein drainage was present. Conclusions: Sinus venosus syndrome should be regarded as an anomalous venous connection with an interatrial communication outside the confines of the atrial septum, in the unfolding wall that normally separates the left atrium from either caval vein. It results in overriding of the caval veins across the intact atrial septum and partial pulmonary vein anomalous drainage. It should be differentiated from posterior atrial septal defect without overriding or anomalous venous connections.

Bioprosthetic mitral valve thrombosis: Clinical profile, transesophageal echocardiographic features, and follow-up after anticoagulant therapy

Cardiac bioprosthetic valve thrombosis is frequently found on pathologic examination, but preoperative diagnosis is rarely performed. Four hundred six patients with mitral porcine xenograft bioprostheses were examined by transthoracic echocardiography. Transesophageal echocardiography (TEE) was performed in 161 of the patients, with clinical or echocardiographic criteria of prosthetic malfunction. Fairly homogeneous and echodense masses, attached to the ventricular surface of the mitral bioprosthetic cusps, were detected by TEE in 15 patients. Only 10 patients, in whom diagnosis of bioprosthetic thrombosis was confirmed, are included in this study. After TEE, two patients underwent prosthetic replacement and eight patients received anticoagulants. A new TEE was performed 85.6 +/- 29.8 days after anticoagulation in these eight patients. Clinical follow-up was continued for 13.6 +/- 8.6 months, and one additional patient underwent surgery during the follow-up. Pathologic examination of removed grafts (three cases) identified these masses as being thrombotic tissue. TEE examination after therapeutic anticoagulation demonstrated complete disappearance of the echogenic masses on bioprosthetic cusps and normal mobility of all leaflets in six cases. In the other two cases, cusp masses were notably reduced, but partially restrictive mobility of affected leaflets persisted, suggesting incomplete resolution of thrombi. Mitral valve prosthetic mean gradient decreased from 11.8 +/- 4.5 to 7.6 +/- 3.7 mm Hg (p < 0.001), and mitral valve area increased from 1.13 +/- 0.3 to 1.72 +/- 0.6 cm2 (p < 0.001). Long-term symptomatic improvement after anticoagulation was obtained in seven patients. Thus this study shows that mitral bioprosthetic thrombosis is a relatively frequent cause of valve dysfunction, TEE is useful for detecting thrombus in relation to mitral bioprosthetic valves, and oral anticoagulation is effective in resolving thrombosis on bioprostheses.

Dual role of Ras and Rho proteins: At the cutting edge of life and death

Small GTP‐binding proteins of the Ras superfamily are master controllers of the cell physiology. The range of processes in which these proteins are involved include cell cycle progression, cell division, regulation of cell morphology and motility and intracellular trafficking of molecules and organelles. The study of apoptosis, the physiological form of cell suicide, is progressively linking the functions of small G proteins to the control of the mechanisms that trigger the genetic programmes of cell death. To date, isoforms of the Ras and Rho groups have been related to both promotion and suppression of apoptosis. Further, signalling pathways driven by these proteins have been associated with the function and/or expression of molecules that regulate apoptotic responses. Thus, all available evidence points to a critical role for Ras and Rho proteins as major gatekeepers of the decision between cellular life and death.

The Bcl-2 gene is differentially regulated by IL-2 and IL-4: role of the transcription factor NF-AT.

The murine TS1αβ T cell line expresses the anti-apoptotic protein Bcl-2 upon IL-2 stimulation, whereas IL-4-mediated growth of this cell line proceeds in the absence of Bcl-2 expression. In addition, IL-4 stimulation inhibits Bcl-2 expression and modulates its mRNA level. IL-2-induced DNA binding activity for these transcription factors is sensitive to phosphatidylinositol 3 kinase inhibitor wortmannin and to Rho inhibitor Clostridium difficile toxin B, which inhibit IL-2-induced Bcl-2 expression. NF-AT transcription factor appears to be the most important in the control Bcl-2 expression, since inhibition of the calcium-calmodulin-dependent phosphatase calcineurin, which regulates NF-AT activity, downregulates Bcl-2 expression in IL-2-stimulated cells. Constitutive expression of this phosphatase also upregulates Bcl-2 expression in IL-4-stimulated cells. In addition, a dominant negative NF-AT expression vector downregulates Bcl-2 expression in IL-2-stimulated cells. These results suggest that IL-2 induction of Bcl-2 expression may be directly or indirectly mediated by NF-AT.

Linomide prevents the lethal effect of anti-Fas antibody and reduces Fas-mediated ceramide production in mouse hepatocytes.

Fas is an apoptosis-signaling receptor molecule expressed in vivo on thymocytes, liver, heart, and ovary. In vivo administration of the anti-Fas Jo2 antibody in mice induces severe apoptotic liver damage leading to fulminant hepatitis and death. Linomide, a quinoline 3-carboxamide, inhibits apoptosis of B and T cells induced by various stimuli including viruses, superantigens, and glucocorticoids. Mice treated with linomide survived the lethal effect of anti-Fas antibody, did not accumulate ceramide in hepatocytes, and recovered liver structure and function within 96 h of anti-Fas injection, as confirmed by histology and glutamic oxalacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase levels. Surviving mice showed severe depletion of cortical thymocytes, but medullar thymic cells expressing high CD3 and Fas levels also survived the treatment with anti-Fas in the presence of linomide. Heart, lung, and ovary showed no signs of apoptosis promoted by Fas ligation. These results suggest that linomide prevents cell death triggered by Fas ligation and can be useful for therapeutic intervention in fulminant hepatitis.

Synthesis and characterization of homo-dimetallic ferrocendiynyl-bridged bis(ethenylphthalocyaninato complexes)

Abstract Conjugated phthalocyanine-ferrocene systems 1 and 2 have been prepared. Homo-dimetallic ferrocendiynyl-bridged bismetallophthalocyanines 2 show a stacked conformation of the macrocycles in solution.

IL-2 deprivation triggers apoptosis which is mediated by c-Jun N-terminal kinase 1 activation and prevented by Bcl-2

A variety of environmental stresses, as well as inflammatory cytokines, induce activation of c-Jun N-terminal kinases. We describe here that IL-2 deprivation-induced apoptosis in TS1αβ cells does not modify c-Jun protein levels and correlates Bcl-2 downregulation and an increase in JNK1, but not JNK2, activity directly related to the induction of apoptosis. Indeed, downregulation of JNK1 expression using antisense oligonucleotides inhibits apoptosis induced by IL-2 withdrawal. Overexpression of Bcl-2 promotes cell survival and blocks JNK1 activation as well as apoptosis caused by IL-2 deprivation. This suggests that inhibition of the JNK1 signaling pathway may be a mechanism through which Bcl-2 promotes cell survival and prevents apoptosis triggered by growth factor withdrawal.

Cell-Based Fuzzy Metrics Enhance High-Content Screening (HCS) Assay Robustness

High-content screening (HCS) allows the exploration of complex cellular phenotypes by automated microscopy and is increasingly being adopted for small interfering RNA genomic screening and phenotypic drug discovery. We introduce a series of cell-based evaluation metrics that have been implemented and validated in a mono-parametric HCS for regulators of the membrane trafficking protein caveolin 1 (CAV1) and have also proved useful for the development of a multiparametric phenotypic HCS for regulators of cytoskeletal reorganization. Imaging metrics evaluate imaging quality such as staining and focus, whereas cell biology metrics are fuzzy logic–based evaluators describing complex biological parameters such as sparseness, confluency, and spreading. The evaluation metrics were implemented in a data-mining pipeline, which first filters out cells that do not pass a quality criterion based on imaging metrics and then uses cell biology metrics to stratify cell samples to allow further analysis of homogeneous cell populations. Use of these metrics significantly improved the robustness of the monoparametric assay tested, as revealed by an increase in Z′ factor, Kolmogorov-Smirnov distance, and strict standard mean difference. Cell biology evaluation metrics were also implemented in a novel supervised learning classification method that combines them with phenotypic features in a statistical model that exceeded conventional classification methods, thus improving multiparametric phenotypic assay sensitivity.