Signifiant decrease in in-hospital mortality and major adverse cardiac events in Swiss STEMI patients between 2000 and December 2007

Rapport de synthèse : Objectifs : évaluer la survie intra-hospitalière des patients présentant un infarctus du myocarde avec sus-décalage du segment ST admis dans les hôpitaux suisses entre 2000 et 2007, et identifier les paramètres prédictifs de mortalité intra-hospitalière et d'événements cardio-vasculaires majeurs (infarctus, réinfarctus, attaque cérébrale). Méthode : utilisation des données du registre national suisse AMIS Plus (Acute Myocardial lnfarction and Unstable Angina in Switzerland). Tous les patients admis pour un infarctus du myocarde avec sus-décalage du segment ST ou bloc de branche gauche nouveau dans un hôpital suisse participant au registre entre janvier 2000 et décembre 2007 ont été inclus. Résultats: nous avons étudié 12 026 patients présentant un infarctus du myocarde avec sus-décalage du segment ST ou bloc de branche gauche nouveau admis dans 54 hôpitaux suisses différents. L'âge moyen est de 64+-13 ans et 73% des patients inclus sont des hommes. L'incidence de mortalité intra-hospitalière est de 7.6% en 2000 et de 6% en 2007. Le taux de réinfarctus diminue de 3.7% en 2000 à 0.9% en 2007. L'utilisation de médicaments thrombolytiques chute de 40.2% à 2% entre 2000 et 2007. Les paramètres prédictifs cliniques de mortalité sont : un âge> 65-ans, une classe Killips Ill ou IV, un diabète et un infarctus du myocarde avec onde Q (au moment de la présentation). Les patients traités par revascularisation coronarienne percutanée ont un taux inférieur de mortalité et de réinfarctus (3.9% versus 11.2% et 1.1% versus 3.1%, respectivement, p<0.001) sur la période de temps étudiée. Le nombre de patients traités par revascularisation coronarienne percutanée augmente de 43% en 2000 à 85% en 2007. Les patients admis dans les hôpitaux bénéficiant d'une salle de cathétérisme cardiaque ont un taux de mortalité plus bas que les patients hopitalisés dans les centres sans salle de cathétérisme cardiaque. Mais les caractéristiques démographiques de ces deux populations sont très différentes. La mortalité intra-hospitalière ainsi que le taux de réinfarctus diminuent significativement au cours y de la période étudiée, parallèlement à l'augmentation de |'utilisation de la revascularisation coronarienne percutanée. La revascularisation coronarienne percutanée est le paramètre prédictif de survie le plus important. Conclusion: la mortalité intra-hospitalière et le taux de réinfarctus du myocarde ont diminué de manière significative chez les patients souffrant d'un infarctus du myocarde avec sus-décalage du segment ST au cours de ces sept dernières années, parallèlement à l'augmentation significative de la revascularisation coronarienne percutanée en plus de la thérapie médicamenteuse. La survie n'est È pas liée au lieu d'hospitalisation mais à l'accès à une revascularisation coronarienne percutanée.

Influence of deep sternal wound infection on long-term survival after cardiac surgery.

BACKGROUND: This study aimed to investigate the influence of deep sternal wound infection on long-term survival following cardiac surgery. MATERIAL AND METHODS: In our institutional database we retrospectively evaluated medical records of 4732 adult patients who received open-heart surgery from January 1995 through December 2005. The predictive factors for DSWI were determined using logistic regression analysis. Then, each patient with deep sternal wound infection (DSWI) was matched with 2 controls without DSWI, according to the risk factors identified previously. After checking balance resulting from matching, short-term mortality was compared between groups using a paired test, and long-term survival was compared using Kaplan-Meier analysis and a Cox proportional hazard model. RESULTS: Overall, 4732 records were analyzed. The mean age of the investigated population was 69.3±12.8 years. DSWI occurred in 74 (1.56%) patients. Significant independent predictive factors for deep sternal infections were active smoking (OR 2.19, CI95 1.35-3.53, p=0.001), obesity (OR 1.96, CI95 1.20-3.21, p=0.007), and insulin-dependent diabetes mellitus (OR 2.09, CI95 1.05-10.06, p=0.016). Mean follow-up in the matched set was 125 months, IQR 99-162. After matching, in-hospital mortality was higher in the DSWI group (8.1% vs. 2.7% p=0.03), but DSWI was not an independent predictor of long-term survival (adjusted HR 1.5, CI95 0.7-3.2, p=0.33). CONCLUSIONS: The results presented in this report clearly show that post-sternotomy deep wound infection does not influence long-term survival in an adult general cardio-surgical patient population.

Regulation of the cardiac voltage-gated sodium channel Nav1.5 : regulation of Nav1.5 by ubiquitin-protein ligases of the Nedd4/Nedd4-like family and characterisation of two novel mutations in the gene encoding Nav1.5 (SCN5A) implicated in the Brugada syndrome triggered by fever

Abstract: The genesis of the cardiac action potential, which accounts for the cardiac contraction, is due to the sodium current INa mediated by the voltage-gated sodium channel Nav1.5. Several cardiac arrhythmias such as the Brugada syndrome are known te be caused by mutations in SCN5A, the gene encoding Nav1.5. Studies of these mutations allowed a better understanding of biophysical and functional properties of Nav1.5. However, only few investigations have been performed in order to understand the regulation of Nav1.5. During my thesis, I investigated different mechanisms of regulation of Nav1.5 using a heterologous expression system, HEK293 cells, coupled with a technique of sodium current recording: the patch clamp in whole cell configuration. In previous studies it has been shown that an enzyme of the Nedd4 family (Nedd4-2) regulates an epithelial sodium channel via the interaction with PY-motifs present in the latter. Interestingly, Nav1.5 contains a similar PY-motif, which motivated us to study the role of Nedd4-2 expressed in heart for the regulation of Nav1.5. In a second study, we investigated the implication of two Nav1.5 mutants, which were either less functional or net functional (Nav1.5 R535X and Nav1.5 L325R respectively) implied in the genesis of the Brugada syndrome by fever. Our results established two mechanisms implied in Nav1.5 regulation. The first one implies that following the interaction between the PY-motif of Nav1.5 and Nedd4- 2 Nav1.5 is ubiquitinated by Nedd4-2. This ubiquitination leads to the internalization of Nav1 .5. The second mechanism is a phenomenon called the "dominant negative" effect of Nav1.5 L325R on Nay1.5 where the decrease of 'Na is potentially due to the retention of Nav1.5 by Nav1.5 L325R in an undefined intracellular compartment. These studies defined two mechanisms of Nav1.5 regulation, which could play an important role for the genesis of cardiac arrhythmias where molecular processes are still poorly understood. Résumé La genèse du potentiel d'action cardiaque, permettant la contraction cardiaque, est due au courant sodique INa issu des canaux sodiques cardiaques dépendants du voltage Nav1.5. Nombreuses arythmies cardiaques telles que le syndrome de Brugada sont connues pour être liées à des mutations du gène SCN5A, codant pour Nav1.5. L'étude de ces mutations a permis une meilleure compréhension des propriétés structurelles et fonctionnelles de Nav1.5 et leurs implications dans la genèse de ces pathologies. Néanmoins peu d'études ont été menées afin de comprendre les mécanismes de régulation de Nav1.5. Mon travail de thèse a consisté à étudier des mécanismes de régulation de Nav1.5 en utilisant un système d'expression hétérologue, les cellules HEK293, couplé à une technique d'enregistrement des courants sodiques, le "patch clamp" en configuration cellule entière. La présence sur Nav1.5 d'un motif-PY similaire à ceux nécessaires pour la régulation d'un canal épithélial sodique par une enzyme de la famille de Nedd4, nous a amenée à étudier le rôle de ces ubiquitine-ligases, en particulier Nedd4-2, dans la régulation de Nav1.5. La seconde étude s'est intéressée aux conséquences de deux mutations de SCN5A codant pour deux mutants peu ou pas fonctionnels (Nav1.5 L325R et Nav1.5 R535X respectivement) retrouvées chez des patients présentant un syndrome de Brugada exacerbé par un état fébrile. Nos résultats ont permis d'établir deux mécanismes de régulation de Nav1.5 L'un par Nedd4-2 qui implique rubiquitination de Nav1.5 par cette ligase suite à l'interaction entre le motif-PY de Nav1.5 et Nedd4-2. Cette modification déclenche l'internalisation du canal impliquée dans la diminution d'INa. Le second mécanisme quant à lui est un effet "dominant négatif" de Nav1.5 L325R sur Nav1.5 aboutissant à une diminution d'INa suite à la séquestration intracellulaire potentielle de Nav1.5 par Nav1.5 L325R. Ces études ont mis en évidence deux mécanismes de régulation de Nav1.5 pouvant jouer un rôle majeur dans la genèse et/ou l'accentuation des arythmies cardiaques dont les processus moléculaires au sein des cardiomyocytes, impliquant des modifications du courant sodiques, sont encore mal compris. Résumé destiné à un large public La dépolarisation électrique de la membrane des cellules cardiaques permet la contraction du coeur. La génèse de cette activité électrique est due au courant sodique issu d'un type de canal à sodium situé dans la membrane des cellules cardiaques. De nombreuses pathologies provoquant des troubles du rythme cardiaque sont issues de mutations du gène qui code pour ce canal à sodium. Ces canaux mutants, entrainant diverses pathologies cardiaques telles que le syndrome de Brugada, ont été largement étudiées. Néanmoins, peu de travaux ont été réalisés sur les mécanismes de régulation de ce canal à sodium non muté. Mon travail de thèse a consisté à étudier certains des mécanismes de régulation de ce canal à sodium en utilisant une technique permettant l'enregistrement des courants sodiques issus de l'expression de ces canaux à sodium à la membrane de cellules mammifères. La présence sur ce canal à sodium d'une structure spécifique, similaire à celle nécessaire pour la régulation d'un canal épithélial à sodium par une enzyme appelée Nedd4-2, nous a amenée à étudier le rôle de cette enzyme dans la régulation de ce canal à sodium. La seconde étude s'est intéressée aux rôles de deux mutations du gène codant pour ce canal à sodium retrouvées chez des patients présentant un syndrome de Brugada exacerbé par la fièvre. Nos résultats nous ont permis d'établir deux mécanismes de régulation de ce canal à sodium diminuant le courant sodique l'un par l'action de l'enzyme Nedd4-2, suite à son interaction avec ce canal, qui modifie ce canal à sodium (ubiquitination) diminuant de ce fait la densité membranaire du canal. L'autre par un mécanisme suggérant un effet négatif de l'un des canaux mutants sur l'expression à la membrane du canal à sodium non muté. Ces études ont mis en évidence deux mécanismes de régulation de ce canal à sodium pouvant jouer un rôle majeur dans la genèse et/ou l'accentuation des troubles du rythme cardiaques dont les mécanismes cellulaires sont encore incompris.

Molecular characterization of signalling complexes involved in G-protein coupled receptor-induced cardiac hypertrophy

In response to pathological stresses, the heart undergoes a remodelling process associated with cardiac hypertrophy. Since sustained hypertrophy can progress to heart failure, there is an intense investigation about the intracellular signalling pathways that control cardiomyocyte growth. Accumulating evidence has demonstrated that most stimuli known to initiate pathological changes associated with the development of cardiac hypertrophy activate G protein-coupled receptors (GPCRs) including the αl-adrenergic- (αl-AR), Angiotensin II- (AT-R) and endothelin-1- (ET-R) receptors. In this context, we have previously identified a cardiac scaffolding protein, called AKAP-Lbc (Α-kinase anchoring protein), with an intrinsic Rho specific guanine nucleotide exchange factor activity, that plays a key role in integrating and transducing hypertrophic signals initiated by these GPCRs (Appert-Collin, Cotecchia et al. 2007). Activated RhoA controls the transcriptional activation of genes involved in cardiomyocyte hypertrophy through signalling pathways that remain to be characterized. Here, we identified the nuclear factor-Kappa Β (NF-κΒ) activating kinase ΙΚΚβ as a novel AKAP-Lbc interacting protein. This raises the hypothesis that AKAP-Lbc might promote cardiomyocyte growth by maintaining a signalling complex that promotes the activation of the pro-hypertrophic transcription factor NF-κΒ. In fact, the activation of NF- κΒ-dependent transcription has been detected in numerous disease contexts, including hypertrophy, ischemia/reperfusion injury, myocardial infarction, allograft rejection, myocarditis, apoptosis, and more (Hall, Hasday et al. 2006). While it is known by more than a decade that NF-κΒ is a critical mediator of cardiac hypertrophy, it is currently poorly understood how pro-hypertrophic signals controlling NF-κΒ transcriptional activity are integrated and coordinated within cardiomyocytes. In this study, we show that AKAP-Lbc and ΙΚΚβ form a transduction complex in cardiomyocytes that couples activation of αl-ARs to NF-κB-mediated transcriptional reprogramming events associated with cardiomyocyte hypertrophy. In particular, we can show that activation of ΙΚΚβ within the AKAP-Lbc complex promotes NF-κB-dependent production of interleukine-6 (IL-6), which, in turn, enhances foetal gene expression. These findings indicate that the AKAP-Lbc/ΙΚΚβ complex is critical for selectively directing catecholamine signals to the induction of cardiomyocyte hypertrophy.

Urological surgery and antiplatelet drugs after cardiac and cerebrovascular accidents.

PURPOSE: The perioperative treatment of patients on dual antiplatelet therapy after myocardial infarction, cerebrovascular event or coronary stent implantation represents an increasingly frequent issue for urologists and anesthesiologists. We assess the current scientific evidence and propose strategies concerning treatment of these patients. MATERIALS AND METHODS: A MEDLINE and PubMed search was conducted for articles related to antiplatelet therapy after myocardial infarction, coronary stents and cerebrovascular events, as well as the use of aspirin and/or clopidogrel in the context of surgery. RESULTS: Early discontinuation of antiplatelet therapy for secondary prevention is associated with a high risk of coronary thrombosis, which is further increased by the hypercoagulable state induced by surgery. Aspirin has recently been recommended as a lifelong therapy. Clopidogrel is mandatory for 6 weeks after myocardial infarction and bare metal stents, and for 12 months after drug-eluting stents. Surgery must be postponed beyond these waiting periods or performed with patients receiving dual antiplatelet therapy because withdrawal therapy increases 5 to 10 times the risk of postoperative myocardial infarction, stent thrombosis or death. The shorter the waiting period between revascularization and surgery the greater the risk of adverse cardiac events. The risk of surgical hemorrhage is increased approximately 20% by aspirin and 50% by clopidogrel. CONCLUSIONS: The risk of coronary thrombosis when antiplatelet agents are withdrawn before surgery is generally higher than the risk of surgical hemorrhage when antiplatelet agents are maintained. However, this issue has not yet been sufficiently evaluated in urological patients and in many instances during urological surgery the risk of bleeding can be dangerous. A thorough dialogue among surgeon, cardiologist and anesthesiologist is essential to determine all risk factors and define the best possible strategy for each patient.

Role of innate immunity in cardiac inflammation after myocardial infarction.

Over the past two decades, inflammation has emerged as a key pathophysiological process during myocardial infarction. It develops consecutively to the activation of innate immune defense mechanisms, in response to the release of endogenous molecules by necrotic cells and the extracellular matrix. These danger signals are sensed by cellular receptors normally involved in antimicrobial defenses, including toll-like receptors and a subset of NOD-like receptors, which promote intracellular signaling dependent on nuclear factor kappaB and on the formation of the inflammasome. These mechanisms stimulate the expression of multiple inflammatory mediators and growth factors, sequentially inducing the recruitment of inflammatory cells, the clearance of injured tissue, angiogenesis, and the proliferation of fibroblasts, eventually resulting in scar formation and infarct healing. Dysregulation of these responses may result in continued cardiomyocyte loss, fibrosis beyond the limits of the infarcted area, reactive hypertrophy and chamber dilatation, a process termed adverse cardiac remodeling, leading to functional compromise and heart failure. This review presents the current state of knowledge on the process of immune activation within the infarcted myocardium and its consequences.

Increased blood glucose variability during therapeutic hypothermia and neurological recovery after cardiac arrest

INTRODUCTION. Recent studies suggest that increased blood glucose variability (BGV) is associated with ICU mortality1. Hypothermia is known to induce insulin resistance, thus potentially increasing BGV. No studies however have examined the effect of therapeutic hypothermia (TH) on insulin requirements and BGV. OBJECTIVES. To examine the effect of TH on BGV and its relationship to outcome in patients with coma after cardiac arrest (CA). METHODS. We prospectively studied 132 consecutive comatose CA patients treated with TH (target core temp 33_C for 24 h, using surface cooling). All patients were treated with intravenous insulin (blood glucose target 6-8 mM), according to a written algorithm, with nurse-driven adjustment of insulin dose. For each patient, standard deviation of repeated blood glucose samples was used to calculate BGV. Two time-points, comparable in duration, were studied: TH (stable maintenance phase, i.e. 6-24 h, core temp ± 33_C) vs. Normothermia (NT, i.e. after rewarming, stable normothermic phase, core temp ± 37_C). Mortality and neurological recovery (Glasgow-Pittsburgh Cerebral Performance Categories, CPC, dichotomized as good = CPC 1-2 vs. poor = CPC 3-5) were assessed at hospital discharge. Statistical analysis was performed with ANOVA for repeated measures. RESULTS. Compared to NT, TH was associated with increased intravenous insulin dose (0.8 ± 1.1 vs. 1.6 ± 2 U/h, P\0.0001), higher mean (6.9 ± 1.3 vs. 7.7 ± 1.8 mM, P\0.0001) and maximum (9.1 ± 3.7 vs. 10.9 ± 3.6 mM, P\0.0001) blood glucose, and increased BGV (1.3 ± 1.2 vs. 1.7 ± 1.1 mM, P = 0.004). Increased BGV was strongly associated with mortality (2.5 ± 1.5 mM in non-survivors vs. 1.6 ± 1 mM in survivors, P\0.001) and worse outcome (2.3 ± 1.4 mM in patients with poor vs. 1.5 ± 0.8 mM in those with good neurological recovery, P\0.0001). CONCLUSIONS. Therapeutic hypothermia is associated with increased insulin requirements and higher blood glucose variability,which in turn correlateswithworse prognosis in patientswith post- CA coma. Strategies aimed to maintain stable glycemic profile and avoid blood glucose variability might contribute to optimize the management of TH and may translate into better outcome.

L'autopsie moléculaire de la mort subite cardiaque: de la salle d'autopsie au cabinet du praticien [Molecular autopsy of sudden cardiac death: from postmortem to clinical approach]

Sudden cardiac death is one of the most prevalent cause of death in developed countries. Its aetiology varies according to the age. Some cardiac diseases may explain sudden death with minimal or no anatomic findings. However, many cardiac diseases, as for example channelopathies and hypertrophic cardiomyopathy have a genetic basis. Therefore genetic analyses (molecular autopsy) are becoming a useful tool in forensic medicine to identify the cause of sudden cardiac death and to improve the early diagnosis of asymptomatic carriers among relatives.

Endothelial dependant coronary vasoreactivity measured by 82Rb cardiac PET in obstructive sleep apnea patients before and after CPAP treatment

Introduction: Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular diseases. Endothelial dysfunction is believed to be one of the pathophysiological mechanism underlying this association. Our aim was to compare endothelial dependent coronary vasoreactivity in obstructive sleep apnea (OSA) patients and controls by quantifying myocardial blood flow (MBF) response to cold pressure testing (CPT) with 82Rb cardiac PET/CT. Methods: Twenty-four OSA patients (2W/22M, mean age 58 yo, mean BMI 28.6 kg/m2) with an apnea-hypopnea index (AHI) >30/h and 9 healthy volunteers (AHI <10/h) underwent a full night sleep recording (PSG) and a dynamic 82 Rb cardiac PET/CT scan at rest, during CPT and adenosine stress. In OSA patients the same measurements (PSG and PET/CT) were respeated 6 weeks after initiating continuous positive airway pressure (autoCPAP) treatment. To reflect differences in baseline cardiac work, values were normalized according to ratepressure product (RPP). Results: At baseline, untreated OSA patients had a mean AHI of 48.8/h and showed a lower MBF response to CPT than controls (1.1 ± 0.2 mL/min/g vs. 1.3 ± 0.4 mL/min/g, P = 0.048). When treated with CPAP, CPT-MBF was not different between controls and well-treated OSA patients (1.2 ± 0.3 mL/min/g vs 1.3 ± 0.4 mL/min/g, P = 0.68), but it was significantly lower for insufficiently treated patients (n = 10) with a residual AHI >10/h (0.9 ± 0.2 mL/min/g vs 1.3 ± 0.4 mL/min/g, P = 0.03). There was also a trend toward a difference in CPT-MBF between insufficiently and well-treated OSA patients (1.2 ± 0.3 mL/min/g vs 0.9 ± 0.2 mL/min/g, P = 0.15). Conclusion: Untreated OSA patients have an impaired coronary endothelial function as measured by MBF response to CPT compared to control subjects. This difference disappears after 6 weeks of autoCPAP therapy but only in OSA patients showing a good response to CPAP (AHI <10/h). Further studies are needed to determine by which mechanism OSA and CPAP treatment influence coronary vasoreactivity.

Cardiac perforation after surgical repair of pectus excavatum.

Five days after surgical repair of pectus excavatum, this 7-year-old boy had a right-sided Kirschner wire protruding beneath the skin. The wire was repositioned blindly. Severe congestive heart failure developed. Surgical exploration showed a pierced right atrium, a torn septal leaflet of the tricuspid valve and noncoronary aortic cusp, and a large traumatic ventricular septal defect. The outcome and the indications and possible complications of surgery are discussed.