Diversité fonctionnelle du facteur de transcription Tbx5 dans le coeur

Le cœur des vertébrés est un organe modulaire qui requiert le " patterning " complexe des champs morphogénétiques cardiogènes et la convergence coordonnée des diverses sous-populations de progéniteurs cardiogéniques. Au moins 7 facteurs de transcription de la famille T-box coopèrent au sein de ces nombreuses sous-populations de progéniteurs cardiogéniques afin de réguler la morphogenèse et l’agencement de multiples structures le long de l’ébauche cardiaque, ce qui explique que les mutations humaines de ces gènes engendrent diverses malformations congénitales cardiaques (MCCs). L’un de ces gènes T-box, Tbx5, dont l’haploinsuffisance génère le syndrome de Holt-Oram (SHO), intervient dans une grande variété de réseaux de régulation géniques (RRGs) qui orchestrent la morphogenèse des oreillettes, du ventricule gauche, de la valve mitrale, des septums inter-auriculaire et inter-ventriculaire, ainsi que du système de conduction cardiaque. La diversité des RRGs impliqués dans la formation de ces structures cardiaques suggère que Tbx5 détient une profusion de fonctions qui ne seront identifiables qu’en répertoriant ses activités moléculaires dans chaque lignée cardiaque examinée isolément. Afin d’aborder cette problématique, une ablation génétique de Tbx5 dans l’endocarde a été réalisée. Cette expérience a démontré le rôle crucial de Tbx5 dans la survie des cellules endocardiques bordant le septum primum et des cardiomyocytes au sein de cette structure embryonnaire qui contribuera à la morphogenèse du septum inter-auriculaire. En outre, cette étude a révélé l’existence d’une communication croisée entre la sous-population de cellules endocardiques Tbx5+ et le myocarde au niveau du septum primum, afin d’assurer la survie des cardiomyocytes, et ultimement de garantir la maturation du septum inter-auriculaire. Nos résultats confirment aussi l’importance de l’interdépendance génétique (Tbx5 et Gata4 ainsi que Tbx5 et Nos3) entre différents loci dans la morphogenèse de la cloison inter-auriculaire, et particulièrement de l’influence que peut avoir l’environnement sur la pénétrance et l’expressivité des communications inter-auriculaires (CIAs) dans le SHO. En outre, puisque les fonctions d’un gène dépendent ordinairement des différents isoformes qu’il peut générer, une deuxième étude a focalisé davantage sur l’aspect transcriptionnel de Tbx5. Cette approche a mené à la découverte de 6 transcrits alternatifs exhibant des fonctions à la fois communes et divergentes. La caractérisation de 2 de ces isoformes a révélé le rôle de l’isoforme long (Tbx5_v1) dans la régulation de la croissance des cardiomyocytes durant la cardiogénèse, tandis que l’isoforme court (Tbx5_v2), préférentiellement exprimé dans le cœur mature, réprime la croissance cellulaire. Il est donc entièrement concevable que les mutations de TBX5 entraînant une troncation de la région C-terminale accroissent la concentration d’une protéine mutée qui, à l’instar de Tbx5_v2, interfère avec la croissance de certaines structures cardiaques. En revanche, la divergence de fonctions de ces isoformes, caractérisée par les disparités de localisation subcellulaire et de d’interaction avec d’autres cofacteurs cardiaques, suggère que les mutations affectant davantage un isoforme favoriseraient l’émergence d’un type particulier de MCC. Finalement, un dernier objectif était d’identifier le ou les mécanisme(s) moléculaire(s) par le(s)quel(s) Tbx5 régule son principal gène cible, Nppa, et d’en extraire les indices qui éclairciraient sa fonction transcriptionnelle. Cet objectif nécessitait dans un premier lieu d’identifier les différents modules cis-régulateurs (MCRs) coordonnant la régulation transcriptionnelle de Nppa et Nppb, deux gènes natriurétiques dont l’organisation en tandem et le profil d’expression durant la cardiogénèse sont conservés dans la majorité des vertébrés. L’approche d’empreinte phylogénétique employée pour scanner le locus Nppb/Nppa a permis d’identifier trois MCRs conservés entre diverses espèces de mammifères, dont un (US3) est spécifique aux euthériens. Cette étude a corroboré que la régulation de l’expression du tandem génique Nppb/Nppa requérait l’activité transcriptionnelle d’enhancers en complément aux promoteurs de Nppa et Nppb. La concordance quasiment parfaite entre les profils d’expression de Tbx5 et de ces deux gènes natriurétiques chez les mammifères, suggère que le gradient d’expression ventriculaire de Tbx5 est interprété par le recrutement de ce facteur au niveau des différents enhancers identifiés. En somme, les études présentées dans cette thèse ont permis de clarifier la profusion de fonctions cardiaques que possède Tbx5. Certaines de ces fonctions émanent de l’épissage alternatif de Tbx5, qui favorise la synthèse d’isoformes dotés de propriétés spécifiques. Les diverses interactions combinatoires entre ces isoformes et d’autres facteurs cardiaques au sein des diverses sous-populations de progéniteurs cardiogènes contribuent à l’émergence de RRGs cardiaques divergents.

Frecuencia de presentación de cardiopatía estructural detectada por ecocardiografía en pacientes que consultan a urgencias por síncope

Introducción. El síncope es una patología frecuente en urgencias, afecta adolescentes y adultos mayores, en estos últimos se asocia con mayor frecuencia a cardiopatía estructural y riesgo de desenlace adverso, el ecocardiograma juega un papel importante en su diagnóstico etiológico. Objetivo. Establecer la frecuencia de cardiopatía estructural detectada por ecocardiografía, en pacientes que consultaron a urgencias por síncope. Métodos. Es un estudio descriptivo retrospectivo en el cual se revisaron las historias clínicas de pacientes adultos que consultaron a urgencias por síncope y a los cuales se les realizó ecocardiograma, estableciéndose la frecuencia de presentación de las más importantes cardiopatías estructurales. Resultados. Evaluados 149 pacientes, 60 presentaron un ecocardiograma normal (40%); 89 un ecocardiograma anormal, de estos las cardiopatías más frecuentes fueron: alteraciones contráctiles del ventrículo izquierdo (35,0%), hipertrofia concéntrica severa (27,5%), cardiopatía dilatada (15,0%), fracción de eyección del ventrículo izquierdo <40% (12,5%), hipertrofia excéntrica severa (7,5%), estenosis aórtica severa (2,5%). Discusión. Los resultados probablemente están relacionados con las características de la población atendida en un centro cardiovascular de referencia, esto podría explicar además la baja frecuencia de cardiopatía típicamente asociada a sincope cardiogénico detectada en el estudio al compararla con estudios hechos sobre población general. Conclusión. El ecocardiograma es una herramienta diagnóstica útil en la detección de causas cardiogénicas y no cardiogénicas de sincope. Las cardiopatías estructurales más frecuentemente halladas están relacionadas con enfermedades cardiovasculares prevalentes en la población atendida. Mientras la sospecha clínica del médico tratante sea justificada, el estudio debería realizarse.

Cardioprotective effects of insulin: how intensive insulin therapy may benefit cardiac surgery patients

Interest in the effects of insulin on the heart came with the recognition that hyperglycemia in the context of myocardial infarction is associated with increased risks of mortality, congestive heart failure, or cardiogenic shock. More recently, instigated by research findings on stress hyperglycemia in critical illness, this interest has been extended to the influence of insulin on clinical outcome after cardiac surgery. Even in nondiabetic individuals, stress hyperglycemia commonly occurs as a key metabolic response to critical illness, eg, after surgical trauma. It is recognized as a major pathophysiological feature of organ dysfunction in the critically ill. The condition stems from insulin resistance brought about by dysregulation of key homeostatic processes, which implicates immune/inflammatory, endocrine, and metabolic pathways. It has been associated with adverse clinical outcomes, including increased mortality, increased duration of mechanical ventilation, increased intensive care unit (ICU) and hospital stay, and increased risk of infection. Hyperglycemia in critical illness is managed with exogenous insulin as standard treatment; however, there is considerable disagreement among experts in the field as to what target blood glucose level is optimal for the critically ill patient. Conventionally, the aim of insulin therapy has been to maintain blood glucose levels below the renal threshold, typically 220 mg/dL (12.2 mmol/L). In recent years, some have advocated tight glycemic control (TGC) with intensive insulin therapy (IIT) to normalize blood glucose levels to within the euglycemic range, typically 80 to 110 mg/dL (4.4–6.1 mmol/L).

Impacto clínico e econômico da redefinição dos critérios diagnósticos de infarto do miocárdio

Introdução: Estudos sobre implicações clínicas da nova definição de infarto do miocárdio (IAM), incorporando novos marcadores de lesão miocárdica, são escassos na literatura. A prevalência de IAM e das suas complicações são diretamente dependentes do critério diagnóstico utilizado. Objetivo: Avaliar o impacto diagnóstico, prognóstico e econômico da nova definição de IAM proposta pela AHA/ ESC usando troponina T (TnT) como marcador de lesão cardíaca. Métodos: Um total de 740 pacientes com dor torácica admitidos na Emergência do Hospital de Clínicas de Porto Alegre no período de julho/ 1999 a janeiro/ 2002 foram incluídos no estudo. Creatina quinase total (CK), CK-MB atividade e TnT foram dosados em uma amostra de 363 pacientes, representativa de toda a coorte. Para redefinição de IAM foram utilizados como ponto de corte valores pico de TnT > 0,2 mg/dl. Os desfechos avaliados foram classificados como eventos cardíacos maiores (angina recorrente, insuficiência cardíaca congestiva, choque cardiogênico e óbito) e como procedimentos de revascularização. Também foram avaliados o manejo prescrito, os custos e o faturamento hospitalar. Resultados: Nos 363 pacientes com marcadores dosados, foram diagnosticados 59 casos de IAM (16%) pelos critérios clássicos; enquanto 40 pacientes (11%) tiveram o diagnóstico de IAM pelo critério redefinido, o que corresponde a um incremento de 71% na incidência. Pacientes com IAM redefinido eram significativamente mais idosos e do sexo masculino, apresentaram mais dor atípica e diabetes mellitus. Na análise multivariada, pacientes com infarto redefinido tiveram um risco 5,1 [IC 95% 1,0-28] vezes maior para óbito hospitalar e 3,4 [IC 95% 1,1-10] vezes maior para eventos combinados em relação aqueles sem IAM. O manejo dos casos de IAM redefinido foi semelhante ao manejo daqueles com IAM tradicional, exceto pelos procedimentos de revascularização que foram menos freqüentes (25% vs. 51%, P < 0,001). O grupo com IAM redefinido permaneceu mais tempo internado e foi submetido a procedimentos mais tardiamente. Do ponto de vista institucional, o uso dos novos critérios para IAM poderia resultar em um aumento de 9% (mais R$ 2.756,00 por grupo de 100 pacientes avaliados) no faturamento baseado em diagnóstico segundo a tabela do SUS. Conclusões: O novo diagnóstico de IAM acrescenta um número expressivo de indivíduos com infarto aos serviços de emergência. A incorporação deste critério é importante na medida que estes pacientes têm um prognóstico semelhante aos demais casos tradicionalmente diagnosticados. Como a identificação destes casos poderia resultar em um manejo mais qualificado e eficiente destes pacientes, esforços deveriam ser adotados para reforçar a adoção da redefinição de IAM.

Clinical Profile, Predictors of Mortality, and Treatment of Patients after Myocardial Infarction, in an Academic Medical Center Hospital

OBJECTIVE: To evaluate clinical profiles, predictors of 30-day mortality, and the adherence to international recommendations for the treatment of myocardial infarction in an academic medical center hospital. METHODS: We retrospectively studied 172 patients with acute myocardial infarction, admitted in the intensive care unit from January 1992 to December 1997. RESULTS: Most patients were male (68%), white (97%), and over 60 years old (59%). The main risk factor for coronary atherosclerotic disease was systemic blood hypertension (63%). Among all the variables studied, reperfusion therapy, smoking, hypertension, cardiogenic shock, and age were the predictors of 30-day mortality. Most commonly used medications were: acetylsalicylic acid (71%), nitrates (61%), diuretics (51%), angiotensin-converting enzyme inhibitors (46%), thrombolytic therapy (39%), and beta-blockers (35%). CONCLUSION: The absence of reperfusion therapy, smoking status, hypertension, cardiogenic shock, and advanced age are predictors of 30-day mortality in patients with acute myocardial infarction. In addition, some medications that are undoubtedly beneficial have been under-used after acute myocardial infarction.

Intoxicação por veneno de sapo em um canino

O sapo do gênero Bufo possui nas suas glândulas paratóides uma secreção mucóide contendo toxinas como bufaginas e Bufotoxinas, que são esteróides cardiogênicos. Os cães podem atacar os sapos, entrando em contato com o veneno por meio das mucosas. Um canino, da raça Bulldog Francês, foi encaminhado ao Setor de Patologia Veterinária da Universidade Federal do Rio Grande do Sul (UFRGS) para a necropsia com histórico de provável intoxicação por veneno de sapo. Na necropsia o canino apresentava pulmões aumentados de volume, avermelhados e com edema, e rins de coloração vermelho-escura. As alterações microscópicas indicaram congestão, hemorragia e edema pulmonar. Nos rins, no baço e nos linfonodos foi observada congestão. As análises toxicológicas para os venenos de rotina foram negativas. Porém, a investigação do veneno de sapo a partir de cromatografia por camada delgada e gasosa demonstrou resultado positivo, revelando ser esta a causa da morte do canino.

Edema agudo pulmonar associado à obstrução das vias aéreas. Relato de caso

BAKGROUND AND OBJECTIVES: Negative pressure pulmonary edema has been defined as non-cardiogenic edema, with transudation of fluid to the interstitial space of the lungs due to an increase in negative intrathoracic pressure secondary to obstruction of the upper airways. This is the case of a healthy patient who underwent general anesthesia and developed acute pulmonary edema after extubation. CASE REPORT: A 23-year old female patient, physical status ASA II, underwent gynecologic videolaparoscopy under general anesthesia. The procedure lasted 3 hours without intercurrence. After extubation the patient developed laryngeal spasm and reduction in oxygen saturation. The patient improved after placement of an oral cannula and administration of oxygen under positive pressure with a face mask. Once the patient was stable she was transferred to the recovery room where, shortly after her arrival, she developed acute pulmonary edema with elimination of bloody serous secretion. Treatment consisted of elevation of the head, administration of oxygen via a face mask, furosemide and fluid restriction. Chest X-ray was compatible with acute pulmonary edema and normal cardiac area. Electrocardiogram (ECG), echocardiogram and cardiac enzymes were normal. The condition of the patient improved and she was discharged from the hospital the following day, asymptomatic. CONCLUSIONS: Acute pulmonary edema associated with obstruction of the upper airways can aggravate surgical procedures with low morbidity, affecting mainly young patients. Early treatment should be instituted because it has a fast evolution and, in most cases, resolves without lasting damages. © Sociedade Brasileira de Anestesiologia, 2008.

Cardiomiopatia hipertrófica felina: revisão bibliografica

Hypertrophic cardiomyopathy (HCM) is the most common heart disease in the feline specie, more frequently affecting pure-breed males such as Ragdolls and Maine Coons. HCM can be primary (idiopathic) or secondary, when other diseases such as hyperthyroidism are involved. The disease is characterized by an increase in the diameter and thickness of the left ventricular wall, with consequent diastolic dysfunction. Mitral regurgitation happens due to compromised ventricular filling, leading to an increased left atrium size and consequent cardiogenic pulmonary edema. Along with the progress of modern veterinary medicine, many diseases could be addressed more successfully on small animal internal medicine, such as feline HCM. This article brings a literature review of the feline hypertrophic cardiomyopathy, focusing on its etiology, physiopathology, clinical presentations, diagnostic methods, therapeutics and prognosis

Choque

The shock, now known as a clinical syndrome due to a systemic breakdown in tissue perfusion leading to cellular hypoxia, metabolic changes and consequently organ dysfunction, is a condition that affects both humans and animals and should be classified as an emergency. For its dynamic course the therapy becomes a challenge, all the time time spared in diagnosis and treatment is essential to save the patient's life, so knowledge of its physiopathology can become of great value, and in order to clarify it better, shock has been divided didactically into: cardiogenic, hypovolemic, distributive, and obstructive, so the best approach may be chosen to this situation, noting that the therapy in general is the sum of several procedures that aims to compensate for the animal so that the underlying cause of shock may be treated

Impacto de diferentes métodos de avaliação da obesidade abdominal após síndromes coronarianas agudas

Background: Abdominal obesity is an important cardiovascular risk factor. Therefore, identifying the best method for measuring waist circumference (WC) is a priority. Objective: To evaluate the eight methods of measuring WC in patients with acute coronary syndrome (ACS) as a predictor of cardiovascular complications during hospitalization. Methods: Prospective study of patients with ACS. The measurement of WC was performed by eight known methods: midpoint between the last rib and the iliac crest (1), point of minimum circumference (2); immediately above the iliac crest (3), umbilicus (4), one inch above the umbilicus (5), one centimeter above the umbilicus (6), smallest rib and (7) the point of greatest circumference around the waist (8). Complications included: angina, arrhythmia, heart failure, cardiogenic shock, hypotension, pericarditis and death. Logistic regression tests were used for predictive factors. Results: A total of 55 patients were evaluated. During the hospitalization period, which corresponded on average to seven days, 37 (67%) patients had complications, with the exception of death, which was not observed in any of the cases. Of these complications, the only one that was associated with WC was angina, and with every cm of WC increase, the risk for angina increased from 7.5 to 9.9%, depending on the measurement site. It is noteworthy the fact that there was no difference between the different methods of measuring WC as a predictor of angina. Conclusion: The eight methods of measuring WC are also predictors of recurrent angina after acute coronary syndromes. Key words: Evaluation; Acute Coronary Syndrome; Abdominal Circumference

Summary of the II Brazilian Guideline Update on Acute Heart Failure 2009/2011

In the past two years we observed several changes in the diagnostic and therapeutic approach of patients with acute heart failure (acute HF), which led us to the need of performing a summary update of the II Brazilian Guidelines on Acute Heart Failure 2009. In the diagnostic evaluation, the diagnostic flowchart was simplified and the role of clinical assessment and echocardiography was enhanced. In the clinical-hemodynamic evaluation on admission, the hemodynamic echocardiography gained prominence as an aid to define this condition in patients with acute HF in the emergency room. In the prognostic evaluation, the role of biomarkers was better established and the criteria and prognostic value of the cardiorenal syndrome was better defined. The therapeutic approach flowcharts were revised, and are now simpler and more objective. Among the advances in drug therapy, the safety and importance of the maintenance or introduction of beta-blockers in the admission treatment are highlighted. Anticoagulation, according to new evidence, gained a wider range of indications. The presentation hemodynamic models of acute pulmonary edema were well established, with their different therapeutic approaches, as well as new levels of indication and evidence. In the surgical treatment of acute HF, CABG, the approach to mechanical lesions and heart transplantation were reviewed and updated. This update strengthens the II Brazilian Guidelines on Acute Heart Failure to keep it updated and refreshed. All clinical cardiologists who deal with patients with acute HF will find, in the guidelines and its summary, important tools to help them with the clinical practice for better diagnosis and treatment of their patients.

Left ventricular free wall impeding rupture in post-myocardial infarction period diagnosed by myocardial contrast echocardiography: Case report

Abstract Background: Left ventricular free wall rupture occurs in up to 10% of the in-hospital deaths following myocardial infarction. It is mainly associated with posterolateral myocardial infarction and its antemortem diagnosis is rarely made. Contrast echocardiography has been increasingly used for the evaluation of myocardial perfusion in patients with acute myocardial infarction, with important prognostic implications. In this case, we reported its use for the detection of a mechanical complication following myocardial infarction. Case presentation: A 50-year-old man with acute myocardial infarction in the lateral wall underwent myocardial contrast echocardiography for the evaluation of myocardial perfusion in the third day post-infarction. A perfusion defect was detected in lateral and inferior walls as well as the presence of contrast extrusion from the left ventricular cavity into the myocardium, forming a serpiginous duct extending from the endocardium to the epicardial region of the lateral wall, without communication with the pericardial space. Magnetic resonance imaging confirmed the diagnosis of impending rupture of the left ventricular free wall. While waiting for cardiac surgery, patient presented with cardiogenic shock and died. Anatomopathological findings were consistent with acute myocardial infarction in the lateral wall and a left ventricular free wall rupture at the infarct site. Conclusion: This case illustrates the early diagnosis of left ventricular free wall rupture by contrast echocardiography. Due to its ability to be performed at bedside this modality of imaging has the potential to identify this catastrophic condition in patients with acute myocardial infarction and help to treat these patients with emergent surgery.

Desfechos intra-hospitalares e preditores de mortalidade no infarto agudo do miocárdio com choque cardiogênico tratados por angioplastia primária: dados do registro InCor

INTRODUÇÃO: O choque cardiogênico é a maior causa de morte em pacientes com infarto agudo do miocárdio com supradesnivelamento do segmento de ST (IAMCSST). O presente estudo avaliou pacientes com IAMCSST e choque cardiogênico submetidos a intervenção coronária percutânea primária com o objetivo de estabelecer seu perfil e os preditores de mortalidade hospitalar. MÉTODOS: Registro unicêntrico, incluindo 100 pacientes avaliados no período de 2001 a 2009 quanto a características clínicas, angiográficas e do procedimento, e a desfechos intra-hospitalares. Por análise multivariada foram determinados preditores independentes da mortalidade hospitalar. RESULTADOS: Com relação às características clínicas, foi observada alta prevalência de fatores de risco, sendo a taxa de sucesso angiográfico de 92%, apesar da complexidade das lesões (83,1% do tipo B2/C). A artéria mais acometida foi a descendente anterior (45%), tendo o padrão multiarterial ocorrido em 73% dos casos. A taxa de mortalidade foi de 45%, sendo seus preditores independentes o padrão multiarterial [odds ratio (OR) 2,62; intervalo de confiança de 95% (IC 95%) 1,16-5,90] e o fluxo coronário TIMI < 3 ao final do procedimento (OR 2,11, IC 95% 1,48-3,02). CONCLUSÕES: Os pacientes com IAMCSST complicado por choque cardiogênico apresentaram características clínicas e angiográficas de alto risco e, apesar do alto sucesso angiográfico do procedimento, altas taxas de mortalidade. Foram preditores independentes de mortalidade o padrão multiarterial e fluxo TIMI < 3 ao final do procedimento.

Key issues in diagnosing and treating acute aortic syndromes: results from the metropolitan area of Bologna network

Background: Survival of patients with Acute Aortic Syndrome (AAS) may relate to the speed of diagnosis. Diagnostic delay is exacerbated by non classical presentations such as myocardial ischemia or acute heart failure (AHF). However little is known about clinical implications and pathophysiological mechanisms of Troponin T elevation and AHF in AAS. Methods and Results: Data were collected from a prospective metropolitan AAS registry (398 patients diagnosed between 2000 and 2013). Troponin T values (either standard or high sensitivity assay, HS) were available in 248 patients (60%) of the registry population; the overall frequency of troponin positivity was 28% (ranging from 16% to 54%, using standard or HS assay respectively, p = 0.001). Troponin positivity was associated with a twofold increased risk of long in-hospital diagnostic time (OR 1.92, 95% CI 1.05-3.52, p = 0.03), but not with in-hospital mortality. The combination of positive troponin and ACS-like ECG abnormalities resulted in a significantly increased risk of inappropriate therapy due to a misdiagnosis of ACS (OR 2.48, 95% CI 1.12-5.54, p = 0.02). Patients with AHF were identified by the presence of dyspnea as presentation symptom or radiological signs of pulmonary congestion or cardiogenic shock. The overall frequency of AHF was 28 % (32% type A vs. 20% type B AAS, p = 0.01). AHF was due to a variety of pathophysiological mechanisms including cardiac tamponade (26%), aortic regurgitation (25%), myocardial ischemia (17%), hypertensive crisis (10%). AHF was associated with increased surgical delay and with increased risk of in-hospital death (adjusted OR 1.97 95% CI1.13-3.37,p=0.01). Conclusions: Troponin positivity (particularly HS) was a frequent finding in AAS. Abnormal troponin values were strongly associated with ACS-like ECG findings, in-hospital diagnostic delay, and inappropriate therapy. AHF was associated with increased surgical delay and was an independent predictor of in-hospital mortality.