The effect of n-3 enriched nutrition therapy on post-operative cognitive dysfunction after cardiac surgery

Background: Postoperative cognitive dysfunction (POCD) occurs frequently after cardiac surgery. Some data suggest that inflammation plays a key role in the development of POCD. N-3 fatty acids have been shown to have a beneficial effect on inflammation. We hypothesised that perioperative n-3 enriched nutrition therapy would reduce the incidence of POCD in this group of patients. Methods: Randomized, double blind placebo controlled trial in patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. 2x 250 mL placebo (Ensure Plus™, Abbott Nutrition) or n-3 enriched nutrition therapy (ProSure™ Abbott Nutrition) were administered for ten days starting 5 days prior to surgery. Cognition was assessed preoperatively and 7 days after surgery with the Consortium to Establish a Registry for Alzheimer's Disease - Neuropsychological Assessment Battery (CERAD-NAB) [1]. Results: 16 patients were included. Mean age was 72 } 5.3 for placebo and 75 } 4.8 for ProSure™ respectively. CRP and IL-6 did not differ significantly between groups preoperatively and on postoperative days 1, 3, and 7. Preoperative CERAD total scores were 86 } 10 and 81 } 9 (p = n.s.) for Placebo and ProSure™, respectively. Postoperative scores were 88 } 12, and 77 } 19 (p = n.s.) The change in score was not different between the two groups (Placebo: +3 } 5; ProSure: -5 } 11). Conclusion: In this very small sample no effect of preoperatively started n-3 enriched nutritional supplements on inflammation or cognitive functions were detected. However, there is a large likelihood of a type II error and more patients need to be included to assess possible beneficial effects of this intervention in elderly patients undergoing elective cardiac surgery. 1 Chandler MJ, et al. Neurology. 2005;65:102-6.

CARDIAC AND MUSCLE CHANNELOPATHIES: ROLES AND REGULATION OF VOLTAGE-GATED SODIUM CHANNELS

Abstract :The contraction of the heart or skeletal muscles is mainly due to the propagation, through excitable cells, of an electrical influx called action potential (AP). The AP results from the sequential opening of ion channels that generate inward or outward currents through the cell membrane. Among all the channels involved, the voltage-gated sodium channel is responsible for the rising phase of the action potential. Ten genes encode the different isoforms of these channels (from Nav1.1 to Nav1.9 and an atypical channel named NavX). Nav1.4 and Nav1.5 are the main skeletal muscle and cardiac sodium channels respectively. Their importance for muscle and heart function has been highlighted by the description of mutations in their encoding genes SCN4A and SCNSA. They lead respectively to neuromuscular disorders such as myotonia or paralysis (for Nav1.4), and to cardiac arrhythmias that can deteriorate into sudden cardiac death (for Nav1.5).The general aim of my PhD work has been to study diseases linked with channels dysfunction, also called channelopathies. In that purpose, I investigated the function and the regulation of the muscle and cardiac voltage-gated sodium channels. During the two first studies, I characterized the effects of two mutations affecting Nav1.4 and Nav1.5 function. I used the HEK293 model cells to express wild-type or mutant channels and then studied their biophysical properties with the patch-clamp technique, in whole cell configuration. We found that the SCN4A mutation produced complex alterations of the muscle sodium channel function, that could explain the myotonic phenotype described in patients carrying the mutation. In the second study, the index case was an heterozygous carrier of a SCNSA mutation that leads to a "loss of function" of the channel. The decreased sodium current measured with mutated Nay 1.5 channels, at physiological temperature, was a one of the factors that could explain the observed Brugada syndrome. The last project aimed at identifying a new potential protein interacting with the cardiac sodium channel. We found that the protein SAP97 binds the three last amino-acids of the C-terminus of Na,, 1.5. Our results also indicated that silencing the expression of SAP97 in HEK293 cells decreased the sodium current. Sodium channels lacking their three last residues also produced a reduced INa. These preliminary results suggest that SAP97 is implicated in the regulation of sodium channel. Whether this effect is direct or imply the action of an adaptor protein remains to be investigated. Moreover, our group has previously shown that Nav1.5 channels are localized to lateral membranes of cardiomyocytes by the dystrophin multiprotein complex (DMC). This suggests that sodium channels are distributed in, at least, two different pools: one targeted at lateral membranes by DMC and the other at intercalated discs by another protein such as SAP97.These studies reveal that cardiac and muscle diseases may result from ion channel mutations but also from regulatory proteins affecting their regulation.Résumé :La contraction des muscles et du coeur est principalement due à la propagation, à travers les cellules excitables, d'un stimulus électrique appelé potentiel d'action (PA). C'est l'ouverture séquentielle de plusieurs canaux ioniques transmembranaires, permettant l'entrée ou la sortie d'ions dans la cellule, qui est à l'origine de ce PA. Parmi tous les canaux ioniques impliqués dans ce processus, les canaux sodiques dépendant du voltage sont responsables de la première phase du potentiel d'action. Les différentes isoformes de ces canaux (de Nav1.1 à Nav1.9 et NavX) sont codées par dix gènes distincts. Nav1.4 et Nav1.5 sont les principaux variants exprimés respectivement dans le muscle et le coeur. Plusieurs mutations ont été décrites dans les gènes qui codent pour ces deux canaux: SCN4A (pour Nav1.4) et SCNSA (pour Nav1.5). Elles sont impliquées dans des pathologies neuromusculaires telles que des paralysies ou myotonies (SCN4A) ou des arythmies cardiaques pouvant conduire à la mort subite cardiaque (SCNSA).Mon travail de thèse a consisté à étudier les maladies liées aux dysfonctionnements de ces canaux, aussi appelées canalopathies. J'ai ainsi analysé la fonction et la régulation des canaux sodiques dépendant du voltage dans le muscle squelettique et le coeur. A travers les deux premières études, j'ai ainsi pu examiner les conséquences de deux mutations affectant respectivement les canaux Nav1.4 et Nav1.5. Les canaux sauvages ou mutants ont été exprimés dans des cellules HEK293 afin de caractériser leurs propriétés biophysiques par la technique du patch clamp en configuration cellule entière. Nous avons pu déterminer que la mutation trouvée dans le gène SCN4A engendrait des modifications importantes de la fonction du canal musculaire. Ces altérations fournissent des indications nous permettant d'expliquer certains aspects de la myotonie observée chez les membres de la famille étudiée. Le patient présenté dans la deuxième étude était hétérozygote pour la mutation identifiée dans le gène SCNSA. La perte de fonction des canaux Nav1.5 ainsi engendrée, a été observée lors d'analyses à températures physiologiques. Elle représente l'un des éléments pouvant potentiellement expliquer le syndrome de Brugada du patient. La dernière étude a consisté à identifier une nouvelle protéine impliquée dans la régulation du canal sodique cardiaque. Nos expériences ont démontré que les trois derniers acides aminés de la partie C-terminale de Nav1.5 pouvaient interagir avec la protéine SAP97. Lorsque que l'expression de la SAP97 est réduite dans les cellules HEK293, cela induit une baisse importante du courant sodique. De même, les canaux tronqués de leurs trois derniers acides aminés génèrent un flux ionique réduit. Ces résultats préliminaires suggèrent que SAP97 est peut-être impliquée dans la régulation du canal Na,,1.5. Des expériences complémentaires permettront de déterminer si ces deux protéines interagissent directement ou si une protéine adaptatrice est nécessaire. De plus, nous avons préalablement montré que les canaux Nav1.5 étaient localisés au niveau de la membrane latérale des cardiomyocytes par le complexe multiprotéique de la dystrophine (DMC). Ceci suggère que les canaux sodiques peuvent être distribués dans un minimum de deux pools, l'un ciblé aux membranes latérales pax le DMC et l'autre dirigé vers les disques intercalaires par des protéines telles que SAP97.L'ensemble de ces études met en évidence que certaines maladies musculaires et cardiaques peuvent être la conséquence directe de mutations de canaux ioniques, mais que l'action de protéines auxiliaires peut aussi affecter leur fonction.

Troponin-based risk stratification of patients with acute nonmassive pulmonary embolism: systematic review and metaanalysis.

BACKGROUND: Controversy exists regarding the usefulness of troponin testing for the risk stratification of patients with acute pulmonary embolism (PE). We conducted an updated systematic review and a metaanalysis of troponin-based risk stratification of normotensive patients with acute symptomatic PE. The sources of our data were publications listed in Medline and Embase from 1980 through April 2008 and a review of cited references in those publications. METHODS: We included all studies that estimated the relation between troponin levels and the incidence of all-cause mortality in normotensive patients with acute symptomatic PE. Two reviewers independently abstracted data and assessed study quality. From the literature search, 596 publications were screened. Nine studies that consisted of 1,366 normotensive patients with acute symptomatic PE were deemed eligible. Pooled results showed that elevated troponin levels were associated with a 4.26-fold increased odds of overall mortality (95% CI, 2.13 to 8.50; heterogeneity chi(2) = 12.64; degrees of freedom = 8; p = 0.125). Summary receiver operating characteristic curve analysis showed a relationship between the sensitivity and specificity of troponin levels to predict overall mortality (Spearman rank correlation coefficient = 0.68; p = 0.046). Pooled likelihood ratios (LRs) were not extreme (negative LR, 0.59 [95% CI, 0.39 to 0.88]; positive LR, 2.26 [95% CI, 1.66 to 3.07]). The Begg rank correlation method did not detect evidence of publication bias. CONCLUSIONS: The results of this metaanalysis indicate that elevated troponin levels do not adequately discern normotensive patients with acute symptomatic PE who are at high risk for death from those who are at low risk for death.

Défibrillateur automatique implantable (DAI): principes de base et indications cliniques actuelles [Implantable cardiac defibrillator (ICD): basics and present clinical guidelines].

An implantable cardiac defibrillator (ICD) is a cardiac implantable electronic device that is capable of identifying and treating ventricular arrhythmias. Consideration about the type of ICD to select for a given patient include whether the patient has bradycardia requiring pacing support, has associated atrial tachyarrhythmias, or would benefit from cardiac resynchronization therapy. The ICD functions by continuously monitoring the patient's cardiac rate and delivering therapies (anti-tachycardia pacing, shocks) when the rate exceeds the programmed rate "cutoff". Secondary prevention trials have demonstrated that ICDs reduce the incidence of arrhythmic death and total mortality in patients presenting with a cardiac arrest. ICDs are also indicated for primary prevention of sudden cardiac death in specific high-risk subgroups of patients.

Persistent left superior vena cava in cardiac congenital surgery

La persistance d'une veine cave supérieure gauche (VCSG) est une entité relativement fréquente dans le cadre des malformations cardiaques congénitales. Le but de cette étude est d'analyser à quel moment le diagnostic de la persistance de la VCSG est effectué, à quel moment le diagnostic des éventuelles anomalies du sinus coronarien associées est effectué, et de l'impact global de la persistance d'une VCSG sur la mortalité et la morbidité des patients après chirurgie cardiaque pour une malformation cardiaque congénitale. Analyse rétrospective d'une cohorte d'enfants ayant subi une chirurgie cardiaque avec circulation extracorporelle pour une malformation cardiaque congénitale. Trois-cent septante et un patients ont été inclus dans l'étude avec un âge médian de 2.75 ans (IQR 0.65-6.63). Parmi eux, 47 patients présentaient une persistance de la VCSG (12.7%), et cette persistance de la VCSG a été identifiée par échocardiographie dans le cadre du bilan préopératoire chez 39 patients (83%). Trois patients (6.4%) présentant une persistance de la VCSG, ont développé après chirurgie cardiaque, une obstruction significative de la voie d'entrée du ventricule gauche qui a aboutit à un débit cardiaque anormal ou à une hypertension pulmonaire secondaire. Chez huit patients (17%), la persistance de la VCSG, était associée à un défaut partiel ou total de fermeture du sinus coronarien et dans deux cas (4%) à une atrésie de l'ostium du sinus coronarien. La durée de la ventilation mécanique était plus courte de façon significative dans le groupe contrôle (1.2 vs. 3.0 jours, p = 0.004), tandis que la durée de séjour aux soins intensifs ne différait pas. La mortalité était significativement moins élevée dans le groupe contrôle que dans le groupe de patient avec persistance de la VCSG (2.5 vs. 10.6 %, p = 0.004). Les résultats de cette étude montrent que la persistance de la VCSG en association avec une malformation cardiaque congénitale augmente le risque de mortalité chez les enfants qui subissent une chirurgie cardiaque avec circulation extracorporelle. La mise en évidence d'une persistance de la VCSG et des anomalies associées, s'impose pour éviter des complications pendant et après une chirurgie cardiaque.

Impact of the Advisa MRI pacing system on the diagnostic quality of cardiac MR images and contraction patterns of cardiac muscle during scans: Advisa MRI randomized clinical multicenter study results.

BACKGROUND: The Advisa MRI system is designed to safely undergo magnetic resonance imaging (MRI). Its influence on image quality is not well known. OBJECTIVE: To evaluate cardiac magnetic resonance (CMR) image quality and to characterize myocardial contraction patterns by using the Advisa MRI system. METHODS: In this international trial with 35 participating centers, an Advisa MRI system was implanted in 263 patients. Of those, 177 were randomized to the MRI group and 150 underwent MRI scans at the 9-12-week visit. Left ventricular (LV) and right ventricular (RV) cine long-axis steady-state free precession MR images were graded for quality. Signal loss along the implantable pulse generator and leads was measured. The tagging CMR data quality was assessed as the percentage of trackable tagging points on complementary spatial modulation of magnetization acquisitions (n=16) and segmental circumferential fiber shortening was quantified. RESULTS: Of all cine long-axis steady-state free precession acquisitions, 95% of LV and 98% of RV acquisitions were of diagnostic quality, with 84% and 93%, respectively, being of good or excellent quality. Tagging points were trackable from systole into early diastole (360-648 ms after the R-wave) in all segments. During RV pacing, tagging demonstrated a dyssynchronous contraction pattern, which was not observed in nonpaced (n = 4) and right atrial-paced (n = 8) patients. CONCLUSIONS: In the Advisa MRI study, high-quality CMR images for the assessment of cardiac anatomy and function were obtained in most patients with an implantable pacing system. In addition, this study demonstrated the feasibility of acquiring tagging data to study the LV function during pacing.

Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction.

AIMS: Recent evidence suggests that cardiac progenitor cells (CPCs) may improve cardiac function after injury. The underlying mechanisms are indirect, but their mediators remain unidentified. Exosomes and other secreted membrane vesicles, hereafter collectively referred to as extracellular vesicles (EVs), act as paracrine signalling mediators. Here, we report that EVs secreted by human CPCs are crucial cardioprotective agents. METHODS AND RESULTS: CPCs were derived from atrial appendage explants from patients who underwent heart valve surgery. CPC-conditioned medium (CM) inhibited apoptosis in mouse HL-1 cardiomyocytic cells, while enhancing tube formation in human umbilical vein endothelial cells. These effects were abrogated by depleting CM of EVs. They were reproduced by EVs secreted by CPCs, but not by those secreted by human dermal fibroblasts. Transmission electron microscopy and nanoparticle tracking analysis showed most EVs to be 30-90 nm in diameter, the size of exosomes, although smaller and larger vesicles were also present. MicroRNAs most highly enriched in EVs secreted by CPCs compared with fibroblasts included miR-210, miR-132, and miR-146a-3p. miR-210 down-regulated its known targets, ephrin A3 and PTP1b, inhibiting apoptosis in cardiomyocytic cells. miR-132 down-regulated its target, RasGAP-p120, enhancing tube formation in endothelial cells. Infarcted hearts injected with EVs from CPCs, but not from fibroblasts, exhibited less cardiomyocyte apoptosis, enhanced angiogenesis, and improved LV ejection fraction (0.8 ± 6.8 vs. -21.3 ± 4.5%; P < 0.05) compared with those injected with control medium. CONCLUSION: EVs are the active component of the paracrine secretion by human CPCs. As a cell-free approach, EVs could circumvent many of the limitations of cell transplantation.

Atrial arrhythmias in adult patients with right- versus left-sided congenital heart disease anomalies.

Atrial arrhythmias (AAs) are a common complication in adult patients with congenital heart disease. We sought to compare the lifetime prevalence of AAs in patients with right- versus left-sided congenital cardiac lesions and their effect on the prognosis. A congenital heart disease diagnosis was assigned using the International Disease Classification, Ninth Revision, diagnostic codes in the administrative databases of Quebec, from 1983 to 2005. Patients with AAs were those diagnosed with an International Disease Classification, Ninth Revision, code for atrial fibrillation or intra-atrial reentry tachycardia. To ensure that the diagnosis of AA was new, a washout period of 5 years after entry into the database was used, a period during which the patient could not have received an International Disease Classification, Ninth Revision, code for AA. The cumulative lifetime risk of AA was estimated using the Practical Incidence Estimators method. The hazard ratios (HRs) for mortality, morbidity, and cardiac interventions were compared between those with right- and left-sided lesions after adjustment for age, gender, disease severity, and cardiac risk factors. In a population of 71,467 patients, 7,756 adults developed AAs (isolated right-sided, 2,229; isolated left-sided, 1,725). The lifetime risk of developing AAs was significantly greater in patients with right- sided than in patients with left-sided lesions (61.0% vs 55.4%, p <0.001). The HR for mortality and the development of stroke or heart failure was similar in both groups (HR 0.96, 95% confidence interval [CI] 0.86 to 1.09; HR 0.94, 95% CI 0.80 to 1.09; and HR 1.10, 95% CI 0.98 to 1.23, respectively). However, the rates of cardiac catheterization (HR 0.63, 95% CI 0.55 to 0.72), cardiac surgery (HR 0.40, 95% CI 0.36 to 0.45), and arrhythmia surgery (HR 0.77, 95% CI 0.6 to 0.98) were significantly less for patients with right-sided lesions. In conclusion, patients with right-sided lesions had a greater lifetime burden of AAs. However, their morbidity and mortality were no less than those with left-sided lesions, although the rate of intervention was substantially different.

Myocardial MIBG scintigraphy: a useful clinical tool? : A retrospective study in 50 parkinsonian patients.

Meta-iodbenzylguanidine scintigraphy (MIBG scintigraphy) shows reduced uptake in idiopathic Parkinson's disease (IPD), idiopathic REM sleep behavior disorder (IRBD) and Lewy body dementia (LBD), but not in other parkinsonian or dementia syndromes. We retrospectively reevaluated 50 patients. Concordance rate between last clinical diagnosis and scintigraphy diagnosis was only given in two-thirds of the patients. Confounding factors were: decreasing heart/mediastinum ratio (HMR) with progressive age, higher HMR in women and possibly interference with antihypertensive medication. Standardization of the methods and precise clinical guidelines are warranted for better clinical use.

Association of early repolarization with risk of cardiac mortality in the general population

Early repolarization, which is characterized by an elevation of the J-point on 12-lead electrocardiography, is a common finding that has been considered as benign for decades. However, in the last years, it has been related with vulnerability to idiopathic ventricular fibrillation and with cardiac mortality in the general population. Recently, 4 potential ECG predictors that could differentiate the benign from the malignant form of early repolarization have been suggested. Any previous study about early repolarization has been done in Spain. Aim. To ascertain whether the presence of early repolarization pattern in a resting electrocardiogram is associated with a major risk of cardiac death in a Spanish general population and to determine whether the presence of potential predictors of malignancy in a resting electrocardiogram increases the risk of cardiac mortality in patients with early repolarization pattern. Methods. We will analyse the presence of early repolarization and the occurrence of cardiac mortality in a retrospective cohort study of 4,279 participants aged 25 to 74 years in the province of Girona. This cohort has been followed during a mean of 9.8 years. Early repolarization will be stratified according to the degree of J-point elevation (≥0.1 mV or ≥0.2 mV), the morphology of the J-wave (slurring, notching or any of these two), the ST-segment pattern (ascending or descending) and the localization (inferior leads, lateral leads, or both). Association of early repolarization with cardiac death will be assessed by adjusted Cox-proportional hazards models

Intraoperative cerebral perfusion in geriatric patients

Background: It is unknown whether cerebral perfusion in geriatric and younger patients under general anaesthesia differs. Methods: We compared 2 groups of patients undergoing elective major non-cardiac surgery under standardized general anaesthesia (thiopental, sevoflurane, fentanyl, atracurium). Group 1: 18-40 yrs (n = 20), Group 2: >65 yrs (n = 37). Cerebral perfusion was investigated with transcranial Doppler and near-infrared spectroscopy (NIRS). Arterial blood pressure was monitored continuously with a Finapres device. Mx, an index allowing continuous monitoring of cerebrovascular autoregulation based on the changes in mean arterial blood pressure (MAP) and cerebral blood flow velocity was calculated. Data are shown as mean } SD. Results: MAP (86 } 9.6 vs 79 } 10.9 mm Hg, p = 0.02), end-tidal concentration of sevoflurane (1.9 } 0.3 vs 1.6 } 0.3%, p <0.01), and the cerebral tissue oxygenation index measured by NIRS (72 } 4 vs 68 } 5%, p = 0.01), were significantly lower in Group 2. The end-tidal concentration of O2 was significantly higher in Group 2 (46 } 4 vs 48 } 4% p = 0.04). There were no significant differences between Group 1 and 2 for cerebral blood flow velocity (41 } 10 vs 43 } 18 cm/s), end tidal CO2 (4.7 } 0.3 vs 4.6 } 0.3 kPa) and cerebrovascular autoregulation (Mx 0.42 } 0.2 vs 0.48 } 0.2). In Group 1 35% and in Group 2 43% of the patients had an index of autoregulation suggesting disturbed cerebrovascular autoregulation (p = n.s.). Conclusions: In elderly patients under general anaesthesia with sevoflurane the cerebral tissue oxygenation index was significantly lower than in younger patients despite higher end-tidal oxygen concentrations. Our data suggest subtle differences in cerebral perfusion between geriatric and younger

Effects of bisoprolol fumarate on left ventricular size, function, and exercise capacity in patients with heart failure: analysis with magnetic resonance myocardial tagging.

BACKGROUND: Recent data suggest that beta-blockers can be beneficial in subgroups of patients with chronic heart failure (CHF). For metoprolol and carvedilol, an increase in ejection fraction has been shown and favorable effects on the myocardial remodeling process have been reported in some studies. We examined the effects of bisoprolol fumarate on exercise capacity and left ventricular volume with magnetic resonance imaging (MRI) and applied a novel high-resolution MRI tagging technique to determine myocardial rotation and relaxation velocity. METHODS: Twenty-eight patients (mean age, 57 +/- 11 years; mean ejection fraction, 26 +/- 6%) were randomized to bisoprolol fumarate (n = 13) or to placebo therapy (n = 15). The dosage of the drugs was titrated to match that of the the Cardiac Insufficiency Bisoprolol Study protocol. Hemodynamic and gas exchange responses to exercise, MRI measurements of left ventricular end-systolic and end-diastolic volumes and ejection fraction, and left ventricular rotation and relaxation velocities were measured before the administration of the drug and 6 and 12 months later. RESULTS: After 1 year, heart rate was reduced in the bisoprolol fumarate group both at rest (81 +/- 12 before therapy versus 61 +/- 11 after therapy; P <.01) and peak exercise (144 +/- 20 before therapy versus 127 +/- 17 after therapy; P <.01), which indicated a reduction in sympathetic drive. No differences were observed in heart rate responses in the placebo group. No differences were observed within or between groups in peak oxygen uptake, although work rate achieved was higher (117.9 +/- 36 watts versus 146.1 +/- 33 watts; P <.05) and exercise time tended to be higher (9.1 +/- 1.7 minutes versus 11.4 +/- 2.8 minutes; P =.06) in the bisoprolol fumarate group. A trend for a reduction in left ventricular end-diastolic volume (-54 mL) and left ventricular end-systolic volume (-62 mL) in the bisoprolol fumarate group occurred after 1 year. Ejection fraction was higher in the bisoprolol fumarate group (25.0 +/- 7 versus 36.2 +/- 9%; P <.05), and the placebo group remained unchanged. Most changes in volume and ejection fraction occurred during the latter 6 months of treatment. With myocardial tagging, insignificant reductions in left ventricular rotation velocity were observed in both groups, whereas relaxation velocity was reduced only after bisoprolol fumarate therapy (by 39%; P <.05). CONCLUSION: One year of bisoprolol fumarate therapy resulted in an improvement in exercise capacity, showed trends for reductions in end-diastolic and end-systolic volumes, increased ejection fraction, and significantly reduced relaxation velocity. Although these results generally confirm the beneficial effects of beta-blockade in patients with chronic heart failure, they show differential effects on systolic and diastolic function.

Multiplex targeted high-throughput sequencing for Mendelian cardiac disorders.

Mendelian cardiomyopathies and arrhythmias are characterized by an important genetic heterogeneity, rendering Sanger sequencing very laborious and expensive. As a proof of concept, we explored multiplex targeted high-throughput sequencing (HTS) as a fast and cost-efficient diagnostic method for individuals suffering from Mendelian cardiac disorders. We designed a DNA capture assay including all exons from 130 genes involved in cardiovascular Mendelian disorders and analysed simultaneously four samples by multiplexing. Two patients had familial hypertrophic cardiomyopathy (HCM) and two patients suffered from long QT syndrome (LQTS). In patient 1 with HCM, we identified two known pathogenic missense variants in the two most frequently mutated sarcomeric genes MYH7 and MYBPC. In patient 2 with HCM, a known acceptor splice site variant in MYBPC3 was found. In patient 3 with LQTS, two missense variants in the genes SCN5A and KCNQ were identified. Finally, in patient 4 with LQTS a known missense variant was found in MYBPC3, which is usually mutated in patients with cardiomyopathy. Our results showed that multiplex targeted HTS works as an efficient and cost-effective tool for molecular diagnosis of heterogeneous disorders in clinical practice and offers new insights in the pathogenesis of these complex diseases.

Persistent left superior vena cava in cardiac congenital surgery.

Persistent left superior vena cava (LSVC) is a relatively frequent finding in congenital cardiac malformation. The scope of the study was to analyze the timing of diagnosis of persistent LSVC, the timing of diagnosis of associated anomalies of the coronary sinus, and the global impact on morbidity and mortality of persistent LSVC in children with congenital heart disease after cardiac surgery. Retrospective analysis of a cohort of children after cardiac surgery on bypass for congenital heart disease. Three hundred seventy-one patients were included in the study, and their median age was 2.75 years (IQR 0.65-6.63). Forty-seven children had persistent LSVC (12.7 %), and persistent LSVC was identified on echocardiography before surgery in 39 patients (83 %). In three patients (6.4 %) with persistent LSVC, significant inflow obstruction of the left ventricle developed after surgery leading to low output syndrome or secondary pulmonary hypertension. In eight patients (17 %), persistent LSVC was associated with a partially or completely unroofed coronary sinus and in two cases (4 %) with coronary sinus ostial atresia. Duration of mechanical ventilation was significantly shorter in the control group (1.2 vs. 3.0 days, p = 0.04), whereas length of stay in intensive care did not differ. Mortality was also significantly lower in the control group (2.5 vs. 10.6 %, p = 0.004). The results of study show that persistent LSVC in association with congenital cardiac malformation increases the risk of mortality in children with cardiac surgery on cardiopulmonary bypass. Recognition of a persistent LSVC and its associated anomalies is mandatory to avoid complications during or after cardiac surgery.

Early predictors of outcome in comatose survivors of ventricular fibrillation and non-ventricular fibrillation cardiac arrest treated with hypothermia: a prospective study

OBJECTIVES: Current indications for therapeutic hypothermia (TH) are restricted to comatose patients with cardiac arrest (CA) due to ventricular fibrillation (VF) and without circulatory shock. Additional studies are needed to evaluate the benefit of this treatment in more heterogeneous groups of patients, including those with non-VF rhythms and/or shock and to identify early predictors of outcome in this setting. DESIGN: Prospective study, from December 2004 to October 2006. SETTING: 32-bed medico-surgical intensive care unit, university hospital. PATIENTS: Comatose patients with out-of-hospital CA. INTERVENTIONS: TH to 33 +/- 1 degrees C (external cooling, 24 hrs) was administered to patients resuscitated from CA due to VF and non-VF (including asystole or pulseless electrical activity), independently from the presence of shock. MEASUREMENTS AND MAIN RESULTS: We hypothesized that simple clinical criteria available on hospital admission (initial arrest rhythm, duration of CA, and presence of shock) might help to identify patients who eventually survive and might most benefit from TH. For this purpose, outcome was related to these predefined variables. Seventy-four patients (VF 38, non-VF 36) were included; 46% had circulatory shock. Median duration of CA (time from collapse to return of spontaneous circulation [ROSC]) was 25 mins. Overall survival was 39.2%. However, only 3.1% of patients with time to ROSC > 25 mins survived, as compared to 65.7% with time to ROSC < or = 25 mins. Using a logistic regression analysis, time from collapse to ROSC, but not initial arrest rhythm or presence of shock, independently predicted survival at hospital discharge. CONCLUSIONS: Time from collapse to ROSC is strongly associated with outcome following VF and non-VF cardiac arrest treated with therapeutic hypothermia and could therefore be helpful to identify patients who benefit most from active induced cooling.