Gene transfer of interleukin-18-binding protein attenuates cardiac allograft rejection.

Interleukin (IL) 18 is a potent pro-inflammatory Th1 cytokine that exerts pleiotropic effector functions in both innate and acquired immune responses. Increased IL-18 production during acute rejection has been reported in experimental heart transplantation models and in kidney transplant recipients. IL-18-binding protein (IL-18BP) binds IL-18 with high affinity and neutralizes its biologic activity. We have analyzed the efficacy of an adenoviral vector expressing an IL-18BP-Ig fusion protein in a rat model of heart transplantation. IL-18BP-Ig gene transfer into Fisher (F344) rat donor hearts resulted in prolonged graft survival in Lewis recipients (15.8 +/- 1.4 days vs. 10.3 +/- 2.5 and 10.1 +/- 2.1 days with control virus and buffer solution alone, respectively; P < 0.001). Immunohistochemical analysis revealed decreased intra-graft infiltrates of monocytes/macrophages, CD4(+), CD8alpha(+) and T-cell receptor alphabeta(+) cells after IL-18BP-Ig versus mock gene transfer (P < 0.05). Real-time reverse transcriptase polymerase chain reaction analysis showed decreased cytokine transcripts for the RANTES chemokine and transforming growth factor-beta after IL-18BP-Ig gene transfer (P < 0.05). IL-18BP-Ig gene transfer attenuates inflammatory cell infiltrates and prolongs cardiac allograft survival in rats. These results suggest a contributory role for IL-18 in acute rejection. Further studies aiming at defining the therapeutic potential of IL-18BP are warranted.

Integrating postoperative value of cardiac Troponin I for a better correlation with in-hospital outcomes after congenital heart surgery.

Objective: Cardiac Troponin-I (cTnI) is a well-recognized early postoperative marker for myocardial damage in adults and children after heart surgery. The present study was undertaken to evaluate whether the integrated value (area under the curve(AUC)) of postoperative cTnI is a better mode to predict long-term outcome than post operative cTnI maximum value, after surgery for congenital heart defects (CHD). Methods: retrospective cohort study. 279 patients (mean age 4.6 years; range 0-17 years-old, 185 males) with congenital heart defect repair on cardiopulmonary by-pass were retrieved from our database including postoperative cTnI values. Maximal post operative cTnI value, post operative cTnI AUC value at 48h and total post operative cTnI AUC value were calculated and then correlated with duration of intubation, duration of ICU stay and mortality. Results: the mean duration of mechanical ventilation was 5.1+/-7.2 days and mean duration of ICU stay was 11.0+/- 13.3 days,11 patients (3.9%) died in post operative period. When comparing survivor and deceased groups, there was a significant difference in the mean value for max cTnI (16.7+/- 21.8 vs 59.2+/-41.4 mcg/l, p+0.0001), 48h AUC cTnI (82.0+/-110.7 vs 268.8+/-497.7 mcg/l, p+0.0001) and total AUC cTnI (623.8+/-1216.7 vs 2564+/-2826.0, p+0.0001). Analyses for duration of mechanical ventilation and duration of ICU stay by linear regression demonstrated a better correlation for 48h AUC cTnI (ventilation time r+0.82, p+0.0001 and ICU stay r+0.74, p+0.0001) then total AUC cTnI (ventilation time r+0.65, p+0.0001 and ICU stay r+0.60, p+0.0001) and max cTnI (ventilation time r+0.64, p+0.0001 and ICU stay r+0.60, p+0.0001). Conclusion: Cardiac Troponin I is a specific and sensitive marker of myocardial injury after congenital heart surgery and it may predict early in-hospital outcomes. Integration of post operative value of cTnI by calculation of AUC improves prediction of early in-hospital outcomes. It probably takes into account, not only the initial surgical procedure, but probably also incorporates the occurrence of hypoxic-ischemic phenomena in the post-operative period.

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.

Respiratory infection in congenital cardiac disease. Hospitalizations in young children in Spain during 2004 and 2005: the CIVIC Epidemiologic Study.

OBJECTIVES To evaluate the rate of hospitalization for acute respiratory tract infection in children less than 24 months with haemodynamically significant congenital cardiac disease, and to describe associated risk factors, preventive measures, aetiology, and clinical course. MATERIALS AND METHODS We followed 760 subjects from October 2004 through April 2005 in an epidemiological, multicentric, observational, follow-up, prospective study involving 53 Spanish hospitals. RESULTS Of our cohort, 79 patients (10.4%, 95% CI: 8.2%-12.6%) required a total of 105 admissions to hospital related to respiratory infections. The incidence rate was 21.4 new admissions per 1000 patients-months. Significant associated risk factors for hospitalization included, with odds ratios and 95% confidence intervals shown in parentheses: 22q11 deletion (8.2, 2.5-26.3), weight below the 10th centile (5.2, 1.6-17.4), previous respiratory disease (4.5, 2.3-8.6), incomplete immunoprophylaxis against respiratory syncytial virus (2.2, 1.2-3.9), trisomy 21 (2.1, 1.1-4.2), cardiopulmonary bypass (2.0, 1.1-3.4), and siblings aged less than 11 years old (1.7, 1.1-2.9). Bronchiolitis (51.4%), upper respiratory tract infections (25.7%), and pneumonia (20%) were the main diagnoses. An infectious agent was found in 37 cases (35.2%): respiratory syncytial virus in 25, Streptococcus pneumoniae in 5, and Haemophilus influenzae in 4. The odds ratio for hospitalization due to infection by the respiratory syncytial virus increases by 3.05 (95% CI: 2.14 to 4.35) in patients with incomplete prophylaxis. The median length of hospitalization was 7 days. In 18 patients (17.1%), the clinical course of respiratory infection was complicated and 2 died. CONCLUSIONS Hospital admissions for respiratory infection in young children with haemodynamically significant congenital cardiac disease are mainly associated with non-cardiac conditions, which may be genetic, malnutrition, or respiratory, and to cardiopulmonary bypass. Respiratory syncytial virus was the most commonly identified infectious agent. Incomplete immunoprophylaxis against the virus increased the risk of hospitalization.

Neurological complications of infective endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study.

BACKGROUND The purpose of this study was to assess the incidence of neurological complications in patients with infective endocarditis, the risk factors for their development, their influence on the clinical outcome, and the impact of cardiac surgery. METHODS AND RESULTS This was a retrospective analysis of prospectively collected data on a multicenter cohort of 1345 consecutive episodes of left-sided infective endocarditis from 8 centers in Spain. Cox regression models were developed to analyze variables predictive of neurological complications and associated mortality. Three hundred forty patients (25%) experienced such complications: 192 patients (14%) had ischemic events, 86 (6%) had encephalopathy/meningitis, 60 (4%) had hemorrhages, and 2 (1%) had brain abscesses. Independent risk factors associated with all neurological complications were vegetation size ≥3 cm (hazard ratio [HR] 1.91), Staphylococcus aureus as a cause (HR 2.47), mitral valve involvement (HR 1.29), and anticoagulant therapy (HR 1.31). This last variable was particularly related to a greater incidence of hemorrhagic events (HR 2.71). Overall mortality was 30%, and neurological complications had a negative impact on outcome (45% of deaths versus 24% in patients without these complications; P<0.01), although only moderate to severe ischemic stroke (HR 1.63) and brain hemorrhage (HR 1.73) were significantly associated with a poorer prognosis. Antimicrobial treatment reduced (by 33% to 75%) the risk of neurological complications. In patients with hemorrhage, mortality was higher when surgery was performed within 4 weeks of the hemorrhagic event (75% versus 40% in later surgery). CONCLUSIONS Moderate to severe ischemic stroke and brain hemorrhage were found to have a significant negative impact on the outcome of infective endocarditis. Early appropriate antimicrobial treatment is critical, and transitory discontinuation of anticoagulant therapy should be considered.

How Can Nanotechnology Help to Repair the Body? Advances in Cardiac, Skin, Bone, Cartilage and Nerve Tissue Regeneration

Nanotechnologists have become involved in regenerative medicine via creation of biomaterials and nanostructures with potential clinical implications. Their aim is to develop systems that can mimic, reinforce or even create in vivo tissue repair strategies. In fact, in the last decade, important advances in the field of tissue engineering, cell therapy and cell delivery have already been achieved. In this review, we will delve into the latest research advances and discuss whether cell and/or tissue repair devices are a possibility. Focusing on the application of nanotechnology in tissue engineering research, this review highlights recent advances in the application of nano-engineered scaffolds designed to replace or restore the followed tissues: (i) skin; (ii) cartilage; (iii) bone; (iv) nerve; and (v) cardiac.

Bilateral sequential nonarteritic anterior ischemic optic neuropathy: a comparison of visual outcomes in fellow eyes using quantitative analysis of goldmann visual fields.

OBJECTIVE To better define the concordance of visual loss in patients with nonarteritic anterior ischemic optic neuropathy (NAION). METHODS The medical records of 86 patients with bilateral sequential NAION were reviewed retrospectively, and visual function was assessed using visual acuity, Goldmann visual fields, color vision, and relative afferent papillary defect. A quantitative total visual field score and score per quadrant were analyzed for each eye using the numerical Goldmann visual field scoring method. RESULTS Outcome measures were visual acuity, visual field, color vision, and relative afferent papillary defect. A statistically significant correlation was found between fellow eyes for multiple parameters, including logMAR visual acuity (P = .01), global visual field (P < .001), superior visual field (P < .001), and inferior visual field (P < .001). The mean deviation of total (P < .001) and pattern (P < .001) deviation analyses was significantly less between fellow eyes than between first and second eyes of different patients. CONCLUSIONS Visual function between fellow eyes showed a fair to moderate correlation that was statistically significant. The pattern of vision loss was also more similar in fellow eyes than between eyes of different patients. These results may help allow better prediction of visual outcome for the second eye in patients with NAION.

Neuropathie optique rétrobulbaire post-actinique [Post-actinic retrobulbar optic neuropathy]

BACKGROUND: Radiation optic neuropathy (RON) is a rare, unpredictable, late complication of radiotherapy secondary to obliterative endarteritis. Tumor recurrence has to be ruled out by a clinical and neuroradiological examination. METHODS: Five patients with RON were investigated by magnetic resonance imaging (MRI) during 1992. RESULTS: Radiation-induced lesions of the intracranial visual pathways were easily visible on MRI. Without Gadolinium, a sectorial swelling was detectable, which markedly enhanced with Gadolinium. Intracranial optic nerve was affected in 5/5 cases, optic chiasm in 3/5 cases, and optic tract in 2/5 cases. CONCLUSIONS: MRI is the examination of choice when RON is suspected: it will easily delineate the extent of the lesion, and compression/infiltration by a recurrent tumor will be formally ruled out. A segmental swelling of visual pathway with marked Gadolinium enhancement on MRI is highly suggestive of radionecrosis.

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.