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International audience; Aims: We documented the midterm prognosis of left ventricular thrombus (LVT) in heart failure (HF) patients with dilated cardiomyopathy (DCM) and ischaemic cardiomyopathy (ICM). We aimed to characterize patients with LVT in the context of HF with reduced (≤40%) left ventricular ejection fraction and evaluate their risk for death and/or embolic events, overall, and specifically in patients with ischaemic or non-ischaemic aetiology. We also intended to identify risk factors for LVT in patients with DCM.Methods and results: We included all HF patients (N = 105, age 56 ± 13) admitted from 2005 to 2018 in our institution for LVT without significant valve disease/prosthesis, heart transplant/left ventricular assist device, congenital heart disease, or acute myocardial infarction. Our primary endpoint was the 1 year risk of the composite of all-cause mortality (ACM) and symptomatic embolic events. Mean left ventricular ejection fraction was 23 ± 9%, and median BNP was 1795 pg/mL. Most (97%) patients were treated with vitamin K anticoagulants, and 64% had ICM. Symptomatic embolic events and/or ACM occurred in 20% of the population [embolic events (all within 30 days of LVT diagnosis) 15% and ACM 6%] and was similarly frequent in DCM or ICM (P > 0.05). Suspected/transient embolic events were more frequent in DCM (overall 13%; 29% in DCM vs. 5% in ICM, P < 0.01). Major bleeding occurred in 5% of patients. Left ventricular reverse remodelling occurred in 65% of patients, more frequently in DCM (86% in DCM vs. 65% in ICM, P = 0.02). In a case-control analysis matching DCM patients, BNP level was the only factor significantly associated with LVT (2447 pg/mL in LVT vs. 347 pg/mL, P < 0.001).Conclusions: Patients with LVT have markedly high natriuretic peptides and experience a 20% 1 year risk for embolic events and/or death following diagnosis despite anticoagulant treatment. Most patients have favourable remodelling/recovery. As all symptomatic embolic events occurred within 30 days of LVT diagnosis, a very careful initial management is warranted.

Nowadays, the detection of sucralose sodium adduct under electrospray ionization in mass spectrometry analysis is a common analysis method, but its high chemical stability is not fully understood. In this work, we use quantum chemistry calculations and mass spectrometry data to understand why sodiated sucralose presents this behavior in mass spectrometry conditions. The potential energy and the position of sodium ions were evaluated using different basis sets in order to comprehend the importance of sodiation in sucralose properties. Quantum-chemical calculations show higher reliability to explain the behavior of sucralose sodium adduct under mass spectrometry conditions, especially when its molecular geometry and potential energies are evaluated.

Structural remodeling is a common consequence of chronic pathological stresses imposed on the heart. Understanding the architectural and compositional properties of diseased tissue is critical to determine their interactions with arrhythmic behavior. Microscale tissue remodeling, below the clinical resolution, is emerging as an important source of lethal arrhythmia, with high prevalence in young adults. Challenges remain in obtaining high imaging contrast at sufficient microscale resolution for preclinical models, such as large mammalian whole hearts. Moreover, tissue composition-selective contrast enhancement for three-dimensional high-resolution imaging is still lacking. Non-destructive imaging using micro-computed tomography shows promise for high-resolution imaging. The objective was to alleviate sufferance from X-ray over attenuation in large biological samples. Hearts were extracted from healthy pigs (N = 2), and sheep (N = 2) with either induced chronic myocardial infarction and fibrotic scar formation or induced chronic atrial fibrillation. Excised hearts were perfused with: a saline solution supplemented with a calcium ion quenching agent and a vasodilator, ethanol in serial dehydration, and hexamethyldisilizane under vacuum. The latter reinforced the heart structure during air-drying for 1 week. Collagen-dominant tissue was selectively bound by an X-ray contrast-enhancing agent, phosphomolybdic acid. Tissue conformation was stable in air, permitting long-duration microcomputed tomography acquisitions to obtain high-resolution (isotropic 20.7 µm) images. Optimal contrast agent loading by diffusion showed selective contrast enhancement of the epithelial layer and sub-endocardial Purkinje fibers in healthy pig ventricles. Atrial fibrillation (AF) hearts showed enhanced contrast accumulation in the posterior walls and appendages of the atria, attributed to greater collagen content. Myocardial infarction hearts showed increased contrast selectively in regions of cardiac fibrosis, which enabled the identification of interweaving surviving myocardial muscle fibers. Contrast-enhanced air-dried tissue preparations enabled microscale imaging of the intact large mammalian heart and selective contrast enhancement of underlying disease constituents.

Summary Background Ventricular arrhythmia is common after left ventricular assist device (LVAD) implantation, especially in the early postoperative phase ( Aim To identify the incidence of and risk factors for electrical storm (ES) occurring within 30 days of HeartMate ® II implantation. Methods We reviewed data from all consecutive patients undergoing HeartMate ® II device implantation at our institution from January 2008 to December 2014. Patient demographic data, pharmacotherapies and outcomes were collected. The primary endpoint was occurrence of early ES (within 30 days of surgery), defined as three or more separate episodes of sustained ventricular arrhythmia within a 24-hour interval, requiring appropriate therapy. Results Forty-three patients (mean age 56.7 ± 11.2 years; 39 men) were included. At HeartMate ® II implantation, mean left ventricular ejection fraction was 20 ± 5%, 32 (74.4%) patients had ischaemic cardiomyopathy and 31 (72.1%) were implanted with an indication of bridge to cardiac transplantation. During follow-up, 12 (27.9%) patients experienced early ES after HeartMate ® II implantation (median delay 9.1 ± 7.8 days). Early ES was more frequent in larger patients (body surface area 1.99 vs 1.81 m 2 ; P P = 0.08), previous implantable cardioverter-defibrillator implantation (66.7% vs 38.7%; P = 0.09), discontinuation of long-term beta-blocker therapy (75.0% vs 45.2%; P = 0.08), weaning of adrenergic drugs after the third day (66.7% vs 35.5%; P = 0.06) and the use of extracorporeal life support (50% vs 22.6%; P = 0.079), but was not associated with the cardiomyopathy aetiology or the indication for assistance. Catheter ventricular tachycardia ablation was performed in six (14.0%) patients. Early ES was associated with a significantly higher all-cause mortality rate at the 30th day (33.3% vs 6.5%; P = 0.02). Conclusion ES is a common and pejorative feature in the early postoperative period.

The FRANCE-2 registry (French Aortic National Corevalve and Edwards) previously reported good early- and medium-term clinical and echocardiographic efficacy for transcatheter aortic valve replacement. We here report 5-year follow-up results from the registry.The registry includes all consecutive patients undergoing transcatheter aortic valve replacement for severe aortic stenosis in France. Follow-up is scheduled at 30 days, 6 months, then annually from 1 to 5 years. Clinical events were defined according to the Valve Academic Research Consortium criteria, and hemodynamic structural valve deterioration (SVD) was defined according to the consensus statement by the European Association of Percutaneous Cardiovascular Interventions.Between January 2010 and January 2012, 4201 patients were enrolled in 34 centers. Five-year vital status was available for 95.5% of patients; 88.1% had clinical evaluation or died. Overall, at 5 years, all-cause mortality was 60.8% (n=2478; 95% CI, 59.3% to 62.3%). The majority of cardiovascular events occurred in the first month after valve implantation, and incidence remained low thereafter, at2% per year up to 5 years, except for heart failure. The rate of heart failure was 14.3% at 1 year, then decreased over time to5% per year. In cumulative incidence function, the rates of severe SVD and moderate/severe SVD at 5 years were 2.5% and 13.3%, respectively. Mortality did not differ between patients with or without severe SVD (hazard ratio, 0.71; 95% CI, 0.47-1.07; P=0.1). Finally, in the population of patients with severe SVD, 1 patient (1.7%) experienced a stroke, and 8 patients presented ≥1 heart failure event (13.3%).The 5-year follow-up results of the FRANCE-2 registry represent the largest long-term data set available in a high-risk population. In surviving patients, the low rate of clinical events and the low level of SVD after 1 year support the long-term efficacy of transcatheter aortic valve replacement in both types of transcatheter prosthesis featuring in the registry.

BACKGROUND Transcatheter aortic valve replacement (TAVR) has revolutionized management of high-risk patients with severe aortic stenosis. However, survival and the incidence of severe complications have been assessed in relatively small populations and/or with limited follow-up. OBJECTIVES This report details late clinical outcome and its determinants in the FRANCE-2 (FRench Aortic National CoreValve and Edwards) registry. METHODS The FRANCE-2 registry prospectively included all TAVRs performed in France. Follow-up was scheduled at 30 days, at 6 months, and annually from 1 to 5 years. Standardized VARC (Valve Academic Research Consortium) outcome definitions were used. RESULTS A total of 4,201 patients were enrolled between January 2010 and January 2012 in 34 centers. Approaches were transarterial (transfemoral 73%, transapical 18%, subclavian 6%, and transaortic or transcarotid 3%) or, in 18% of patients, transapical. Median follow-up was 3.8 years. Vital status was available for 97.2% of patients at 3 years. The 3-year all-cause mortality was 42.0% and cardiovascular mortality was 17.5%. In a multivariate model, predictors of 3-year all-cause mortality were male sex (p = 2 of 4 (p < 0.001). Severe events according to VARC criteria occurred mainly during the first month and subsequently in < 2% of patients/year. Mean gradient, valve area, and residual aortic regurgitation were stable during follow-up. CONCLUSIONS The FRANCE-2 registry represents the largest database available on late results of TAVR. Late mortality is largely related to noncardiac causes. Incidence rates of severe events are low after the first month. Valve performance remains stable over time. (J Am Coll Cardiol 2016; 68: 1637-47) (C) 2016 by the American College of Cardiology Foundation.

To provide a model close to the human heart, and to study intrinsic cardiac function at the same time as electromechanical coupling, we developed a magnetic resonance (MR)-compatible setup of isolated working perfused pig hearts. Hearts from pigs (40 kg, n = 20) and sheep ( n = 1) were blood perfused ex vivo in the working mode with and without loaded right ventricle (RV), for 80 min. Cardiac function was assessed by measuring left intraventricular pressure and left ventricular (LV) ejection fraction (LVEF), aortic and mitral valve dynamics, and native T1 mapping with MR imaging (1.5 Tesla). Potential myocardial alterations were assessed at the end of ex vivo perfusion from late-Gadolinium enhancement T1 mapping. The ex vivo cardiac function was stable across the 80 min of perfusion. Aortic flow and LV-dP/d tmin were significantly higher ( P < 0.05) in hearts perfused with loaded RV, without differences for heart rate, maximal and minimal LV pressure, LV-dP/d tmax, LVEF, and kinetics of aortic and mitral valves. T1 mapping analysis showed a spatially homogeneous distribution over the LV. Simultaneous recording of hemodynamics, LVEF, and local cardiac electrophysiological signals were then successfully performed at baseline and during electrical pacing protocols without inducing alteration of MR images. Finally, 31P nuclear MR spectroscopy (9.4 T) was also performed in two pig hearts, showing phosphocreatine-to-ATP ratio in accordance with data previously reported in vivo. We demonstrate the feasibility to perfuse isolated pig hearts in the working mode, inside an MR environment, allowing simultaneous assessment of cardiac structure, mechanics, and electrophysiology, illustrating examples of potential applications.

The onset of right ventricular dysfunction in patients presenting with congenital heart disease is associated with a dismal long-term outcome and often represents a therapeutic dead end. Our study had several objectives: (1) to analyse the anatomical, functional, histological and cellular characteristics of an animal model of repaired tetralogy of Fallot with right ventricular dysfunction (2) to test the new electrical treatment known as cardiac contractility modulation in this animal model. Seven sheep underwent a first surgery at the age of three weeks aiming to mimic the characteristics of a repaired tetralogy of Fallot. Five controls were sham-operated. Experimental studies were performed 12 months after the initial operation. The hemodynamic, echocardiographic, and mitochondrial function studies were carried out before and after cardiac contractility modulation in closed- and open-chest conditions. In this animal model of right ventricular dysfunction, short-term cardiac contractility modulation was associated with a significant improvement in (a) right ventricular function, as evidenced by a significant increase in right ventricular dP/dt (p

Background: The FRANCE-2 registry (French Aortic National Corevalve and Edwards) previously reported good early- and medium-term clinical and echocardiographic efficacy for transcatheter aortic valve replacement. We here report 5-year follow-up results from the registry. Methods: The registry includes all consecutive patients undergoing transcatheter aortic valve replacement for severe aortic stenosis in France. Follow-up is scheduled at 30 days, 6 months, then annually from 1 to 5 years. Clinical events were defined according to the Valve Academic Research Consortium criteria, and hemodynamic structural valve deterioration (SVD) was defined according to the consensus statement by the European Association of Percutaneous Cardiovascular Interventions. Results: Between January 2010 and January 2012, 4201 patients were enrolled in 34 centers. Five-year vital status was available for 95.5% of patients; 88.1% had clinical evaluation or died. Overall, at 5 years, all-cause mortality was 60.8% (n=2478; 95% CI, 59.3% to 62.3%). The majority of cardiovascular events occurred in the first month after valve implantation, and incidence remained low thereafter, at P =0.1). Finally, in the population of patients with severe SVD, 1 patient (1.7%) experienced a stroke, and 8 patients presented ≥1 heart failure event (13.3%). Conclusions: The 5-year follow-up results of the FRANCE-2 registry represent the largest long-term data set available in a high-risk population. In surviving patients, the low rate of clinical events and the low level of SVD after 1 year support the long-term efficacy of transcatheter aortic valve replacement in both types of transcatheter prosthesis featuring in the registry.

Severe asthma is a major public health issue throughout the world. Increased bronchial smooth muscle (BSM) mass, a characteristic feature of airway remodeling in severe asthma, is associated with resistance to high-intensity treatment and poor prognosis. In vitro, the Ca(2+)-channel blocker gallopamil decreased the proliferation of BSM cells from patients with severe asthma.We conducted a double-blind, randomized, placebo-controlled study to evaluate the effect of gallopamil on airway remodeling in patients with severe asthma.Subjects received either gallopamil (n = 16) or placebo (n = 15) for 1 year and were monitored for an additional 3-month period. Airway remodeling was analyzed at baseline and after treatment phase using both fiberoptic bronchoscopy and computed tomography scan. The primary end point was the BSM area. Secondary end points included normalized BSM thickness and frequency of asthma exacerbations.BSM area was reduced in the gallopamil group (baseline vs. end of treatment) but was unchanged in the placebo group. Between-group differences in BSM area were not significantly different in gallopamil versus placebo groups. By contrast, between-group differences in normalized BSM thickness were significantly different between the two groups. The mean number of exacerbations per month was not different during the treatment phase in gallopamil versus placebo group but was significantly lower in patients previously treated with gallopamil during the follow-up period. There were no differences between the groups with respect to overall side effects.Gallopamil treatment for 12 months reduces BSM remodeling and prevents the occurrence of asthma exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT 00896428).

Purpose Heart failure (HF) is a common, serious, and still poorly known illness, which might benefit from studies in claims databases. However, to provide reliable estimates, HF patients must be adequately identified. This validation study aimed to estimate the diagnostic accuracy of the International Classification of Diseases, Tenth Revision (ICD-10) codes I50.x, heart failure, in the French hospital discharge diagnoses database. Methods This study was performed in two university hospitals, comparing recorded discharge diagnoses and electronic health records (EHRs). Patients with discharge ICD-10 codes 150.x were randomly selected. Their EHRs were reviewed to classify HF diagnosis as definite, potential, or miscoded based on the European Society of Cardiology diagnostic criteria, from which the codes' positive predictive value (PPV) was computed. To estimate sensitivity, patients with an EHR HF diagnosis were identified, and the presence of the I50.x codes was sought for in the hospital discharge database. Results Two hundred possible cases of HF were selected from the hospital discharge database, and 229 patients with an HF diagnosis were identified from the EHR. The PPV of I50.x codes was 60.5% (95% CI, 53.7%-67.3%) for definite HF and 88.0% (95% CI, 83.5%-92.5%) for definite/potential HF. The sensitivity of I50.x codes was 64.2% (95% CI, 58.0%-70.4%). PPV results were similar in both hospitals; sensitivity depended on the source of EHR: Departments of cardiology had a higher sensitivity than had nonspecialized wards. Conclusions Diagnosis codes I50.x in discharge summary databases accurately identify patients with HF but fail to capture some of them.

A expansão tecnológica e comunicacional propiciou o surgimento de novas práticas de visualização e apropriação de informações, de modo a afetar a visibilidade e as práticas das comunidades de fãs, que se constituem a partir de uma participação ativa dos membros que as integram. Este trabalho procura inserir-se no contexto da cultura participativa a fim de melhor compreender o fenômeno de cultura de fãs e contribuir para os estudos que a ele estão relacionados. Para isto, utiliza-se o filme Batman vs Superman – A Origem da Justiça com o objetivo de demonstrar como os fãs se organizam e quais as suas práticas em uma comunidade virtual. O método empregado é o da netnografia apoiada à observação das práticas online e à elaboração de questionários destinados aos membros da comunidade. A base teórica é composta por autores como Henry Jenkins (1992;2006;2009;2015), Matt Hills (2002), Clay Shirky (2011), Paul Booth (2010), Mark Duffett (2013), dentre outros que procuram compreender a participação como o fator fundamental da cultura de fãs. The technological and communicational expansion provided the emergence of new practices of preview and appropriation of information, affecting the visibility and the practices of the fans communities, which stabilish from an active participation of members that integrate them. This paper seeks to insert in the culture participatory context in order of better understand the fans culture phenomenon and contribute to the studies that are related to it. Therefore, I use Batman vs Superman – Down of Justice film to demonstrate how the fans organize themselves and which are their practices in a virtual community. The used method is the netnography with the observation of online practices and the elaboration of quizzes for the community members. The theoretical basis is composed of authors like Henry Jenkins (1992; 2006; 2009; 2015), Matt Hills (2002), Clay Shirky (2011), Paul Booth (2010), Mark Duffett (2013), and others that try to understand the participation as the key factor of the fans culture.

Ventricular arrhythmia is common after left ventricular assist device (LVAD) implantation, especially in the early postoperative phase (30 days).To identify the incidence of and risk factors for electrical storm (ES) occurring within 30 days of HeartMateWe reviewed data from all consecutive patients undergoing HeartMateForty-three patients (mean age 56.7±11.2 years; 39 men) were included. At HeartMateES is a common and pejorative feature in the early postoperative period.

Background Left ventricular (LV) afterload could be associated with reduced myocardial contractility. The aim of this study was to evaluate the relative impact of increased afterload on LV myocardial deformation indices in chronic aortic constriction, with regard to hypertrophy, myocardial fibrosis, and mitochondrial function, and to differentiate acute versus chronic afterload effect. Methods Young pigs underwent aortic banding ( n = 11) or sham ( n = 7) operations. Nineteen weeks later, LV morphology and systolic function, including myocardial deformation, were assessed by echocardiography before and after banding release or acute aortic constriction (in the sham group). After the animals were euthanized, mitochondrial function and LV interstitial fibrosis were assessed. Results The chronic banding group ( n = 8) presented with significant LV hypertrophy compared with the sham group ( n = 7), and longitudinal strain (LS) was significantly altered (16.9 ± 0.7% vs 20.3 ± 0.7%, P = .001) while circumferential, radial strain, and ejection fraction were not. LS abnormalities were situated mostly on the basal and mid segments and on the septal wall. There was also significantly more myocardial fibrosis in the chronic banding group compared with the sham group, while mitochondrial function was preserved. The relative contributions of hypertrophic and fibrotic remodeling and of afterload to alter global LS were 62%, and 38%, respectively. Acute aortic banding also significantly altered LS. The ratio of LS to septal wall thickness enabled differentiation between chronic and acute afterload increase (1.9 ± 0.2 in the chronic group vs 2.9 ± 0.3 in the acute group, P = .001). Conclusions LS is susceptible to both hypertrophic and fibrotic remodeling and afterload increase, particularly on the basal and mid LV segments of the septum. The ratio of LS to septal wall thickness enables differentiation of acute from chronic afterload LS alteration.

Severe anaphylactoid reaction after the use of iodinated contrast media are rare but can contraindicate the use of contrast agent. It was the case of a 53-year-old woman suffering from symptomatic severe aortic stenosis, recused for cardiac surgery because of deleterious effects of chest-wall irradiation, with porcelain aorta. We decided to implant a 23-mm Edwards® SAPIEN® transcatheter aortic valve via a femoral route without using any contrast media. The implantation was successful after surgical approach of the femoral artery, transesophageal echocardiography guiding, and localization of native leaflets and coronary trunk with catheters. Immediate and one month post-interventional follow-up was favorable and echocardiography showed a good functioning of the aortic bioprosthesis. Although conventional angiography is the best way to visualize the good positioning of the valve before deployment, our case suggests that, in special situations, transfemoral implantation of an Edwards® SAPIEN® aortic bioprosthesis is feasible without any contrast injection. © 2012 Wiley Periodicals, Inc.

Background— Contact force (CF) is an important determinant of lesion formation for atrial endocardial radiofrequency ablation. There are minimal published data on CF and ventricular lesion formation. We studied the impact of CF on lesion formation using an ovine model both endocardially and epicardially. Methods and Results— Twenty sheep received 160 epicardial and 160 endocardial ventricular radiofrequency applications using either a 3.5-mm irrigated-tip catheter (Thermocool, Biosense-Webster, n=160) or a 3.5 irrigated-tip catheter with CF assessment (Tacticath, Endosense, n=160), via percutaneous access. Power was delivered at 30 watts for 60 seconds, when either catheter/tissue contact was felt to be good or when CF>10 g with Tacticath. After completion of all lesions, acute dimensions were taken at pathology. Identifiable lesion formation from radiofrequency application was improved with the aid of CF information, from 78% to 98% on the endocardium ( P P =0.02). The mean total force was greater on the endocardium (39±18 g versus 21±14 g for the epicardium; P 3 versus 209±131 mm 3 ; P =0.02) probably because of the absence of the heat sink effect of the circulating blood and covered a greater area (41±27 mm 2 versus 29±17 mm 2 ; P =0.03) because of catheter orientation. Conclusions— In the absence of CF feedback, 22% of endocardial radiofrequency applications that are thought to have good contact did not result in lesion formation. Epicardial ablation is associated with larger lesions.

Introduction: Patients who have undergone repair of Tetralogy of Fallot (TOF) often present with right bundle branch block. Cardiac resynchronization therapy (CRT) with right ventricular (RV) or biventricular (BiV) stimulation has been proposed as a modality to correct electrical abnormalities and improve cardiac contractility in patients with repaired TOF. We aimed to 1) compare ventricular electrical activation in adults with repaired TOF during RV versus BiV stimulation, using a non-invasive epicardial mapping system, and 2) examine the clinical mid-term effects of BiV resynchronization. Methods: 9 adults with repaired TOF were implanted with a CRT system and underwent 1) a non-invasive epicardial mapping (n = 9) during sinus intrinsic rhythm, RV and BiV pacing 2) a clinical evaluation (n = 7) before and after 6 months CRT with assessment of NYHA class and exercise capacity. Results: During intrinsic rhythm, non-invasive mapping demonstrated delayed activation of the right compared with the left ventricle in all patients, with the greatest activation delay noted near the infundibulum. However, we observed important differences among patients, in the severity of activation delays. Global activation time and an index of dyssynchrony were improved (p < 0.05) during BiV pacing compared with RV pacing and spontaneous rhythm. BiV pacing increased (p < 0.05) exercise tolerance and lowered the mean NYHA functional class at 6 months of follow up. Conclusion: Patients with corrected TOF present with different patterns of ventricular activation. RV stimulation modestly improved RV activation sequence and was associated with a delayed LV activation. Biventricular stimulation significantly decreased right and left ventricular dyssynchrony. © 2011 Elsevier Ireland Ltd.

The comprehensive study of human pathologies has revealed the complexity of the interactions involved in cardiovascular physiology. The recent validation of system's biology approaches – like our Modular Control and Regulation Analysis (MoCA) – motivates the current interest for new integrative and non-invasive analyses that could be used for medical study of human heart contraction energetics. By considering heart energetics as a supply–demand system, MoCA gives access to integrated organ function and brings out a new type of information, the “elasticities”, which describe in situ the regulation of both energy demand and supply by cellular energetic status. These regulations determine the internal control of contraction energetics and may therefore be a key to the understanding of the links between molecular events in pathologies and whole organ function/dysfunction. A wider application to the effects of cardiac drugs in conjunction with the direct study of heart pathologies may be considered in the near future. MoCA can potentially be used not only to detect the origin of the defects associated with the pathology (elasticity analyses), but also to provide a quantitative description of how these defects influence global heart function (regulation analysis) and therefore open new therapeutic perspectives. Several key examples of current applications to intact isolated beating heart are presented in this paper. The future application to human pathologies will require the use of non-invasive NMR techniques for the simultaneous measurement of energy status (31P NMR) and heart contractile activity (3D MRI). This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.

Rhythmic complications seem common after left ventricular (LV) assist device (LVAD), especially in the early phase of implantation (

In vivo phage display selection is a powerful strategy for directly identifying agents that target the vasculature of normal or diseased tissues in living animals. We describe here a new in vivo biopanning strategy in which a human phage single-chain antibody (scFv) library was injected into high-fat diet-fed ApoE(-/-) mice. Extracellular and internalized phage scFvs were selectively recovered from atherosclerotic vascular endothelium and subjacent tissues. After three successive biopanning rounds, a panel of six clones with distinct gene sequences was isolated. Four scFvs produced and purified in soluble form were shown to interact in vitro with a rabbit atheromatous protein extract by time-resolved fluorescence resonance energy transfer and to target the endothelial cell surface and inflamed intima-related regions of rabbit and human tissue sections ex vivo. These new scFvs selected in a mouse model recognized both rabbit and human tissue, underlying the interspecies similarities of the recognized epitopes. By combining immunoprecipitation and mass spectrometry, one of the selected scFvs was shown to recognize carbonic anhydrase II, an up-regulated enzyme involved in resorption of ectopic calcification. These results show that in vivo biopanning selection in hypercholesterolemic animals makes it possible to identify both scFvs homing to atherosclerotic endothelial and subendothelial tissues, and lesion-associated biomarkers. Such scFvs offer promising opportunities in the field of molecular targeting for the treatment of atherosclerosis.

International audience; This review describes developments in historical perspective as well as recent results of investigations of cellular mechanisms of regulation of energy fluxes and mitochondrial respiration by cardiac work - the metabolic aspect of the Frank-Starling law of the heart. A Systems Biology solution to this problem needs the integration of physiological and biochemical mechanisms that take into account intracellular interactions of mitochondria with other cellular systems, in particular with cytoskeleton components. Recent data show that different tubulin isotypes are involved in the regular arrangement exhibited by mitochondria and ATP-consuming systems into Intracellular Energetic Units (ICEUs). Beta II tubulin association with the mitochondrial outer membrane, when co-expressed with mitochondrial creatine kinase (MtCK) specifically limits the permeability of voltage-dependent anion channel for adenine nucleotides. In the MtCK reaction this interaction changes the regulatory kinetics of respiration through a decrease in the affinity for adenine nucleotides and an increase in the affinity for creatine. Metabolic Control Analysis of the coupled MtCK-ATP Synthasome in permeabilized cardiomyocytes showed a significant increase in flux control by steps involved in ADP recycling. Mathematical modeling of compartmentalized energy transfer represented by ICEUs shows that cyclic changes in local ADP, Pi, phosphocreatine and creatine concentrations during contraction cycle represent effective metabolic feedback signals when amplified in the coupled non-equilibrium MtCK-ATP Synthasome reactions in mitochondria. This mechanism explains the regulation of respiration on beat to beat basis during workload changes under conditions of metabolic stability. This article is part of a Special Issue entitled Local Signaling in Myocytes SI.

Background In the past 5years a few number of studies and case reports have come out focusing on biventricular (BiV) stimulation for treatment of congenital heart disease related ventricular dysfunction. The few available studies include a diverse group of pathophysiological entities ranging from a previously repaired tetralogy of Fallot (TOF) to a functional single ventricle anatomy. Patient's status is too heterogeneous to build important prospective study. To well understand the implication of prolonged electromechanical dyssynchrony we performed a chronic animal model that mimics essential parameters of postoperative TOF. Methods Significant pulmonary regurgitation, mild stenosis, as well as right ventricular outflow tract (RVOT) scars were induced in 15 piglets to mimic repaired TOF. 4months after hemodynamics and dyssynchrony parameters were compared with a control group and with a population of symptomatic adult with repaired TOF. Results Comparing the animal model with the animal control group on echocardiography, RV dilatation, RV and LV dysfunction, broad QRS complex and dyssynchrony were observed on the animal model piglets. Moreover, epicardial electrical mapping showed activation consistent with a right bundle branch block. The animal models displayed the same pathophysiological parameters as the post TOF repair patients in terms of QRS duration, pulmonary regurgitation biventricular dysfunction and dyssynchrony. Conclusion This chronic swine model mimics electromechanical ventricular activation delay, RV and LV dysfunction, as in adult population of repair TOF. It does appear to be a very useful and interesting model to study the implication of dyssynchrony and the interest of resynchronization therapy in TOF failing ventricle.

Background. Metaboreflex overactivation has been proprosed to explain exaggerated hyperventilation in heart failure population. We investigated the metaboreflex activation after cardiac resynchronization therapy (CRT). Methods. 10 heart failure patients (mean left ventricular ejection fraction (LVEF) 2 7 ± 4 %) schedulded for CRT implantation were prospectively studied. At baseline and after 6 month follow up two maximal cardiopulmonary exercise tests with and without regional circulatory occlusion (RCO) during recovery were performed. RCO was achieved by inflation of bilateral upper thigh tourniquets 30 mmHg above peak systolic blood pressure during 3 minutes after peak exercise. Metaboreflex contribution to the ventilatory response was assessed as the difference in ventilatory data at the third minute during recovery between the two tests (Δ). Results. Patients had enhanced VE/VCO2 slope ( 4 0 ± 9 ) and an evident metaboreflex contribution to the high ventilatory response (ΔVE: 3 ± 4 L/min; 𝑃 = 0 . 0 5 , ΔRR: 4 . 5 ± 4 /min; 𝑃 = 0 . 0 0 3 and ΔVE/VCO2: 5 . 5 ± 4 ; 𝑃 = 0 . 0 0 7 ). 6 months after CRT implantation, NYHA class, LVEF, peak VO2 and VE/VCO2 were significantly improved ( 1 . 4 ± 0 . 5 ; 𝑃 < 0 . 0 0 1 , 4 2 ± 7 %; 𝑃 < 0 . 0 0 1 , 1 6 . 5 ± 3 mL/kg/min; 𝑃 = 0 . 0 0 3 ; 3 3 ± 1 0 ; 𝑃 = 0 . 0 1 ). Metaboreflex contribution to VE, RR, and VE/VCO2 was reduced compared with baseline ( 𝑃 = 0 . 0 8 , 𝑃 = 0 . 0 1 and 𝑃 = 0 . 4 resp.). Conclusion. 6 months after CRT metaboreflex contribution to the ventilatory response is reduced.

SummaryAdults with congenital heart lesions constitute a rapidly growing group of patients with cardiovascular disease. This nascent demographic phenomenon is creating major issues concerning the optimal management of these patients, in whom sudden death and progressive heart failure are predominant causes of death. Ventricular dyssynchrony appears to be very common in this population and can appear early in the history of the disease. Recently, cardiac resynchronization therapy (CRT) has emerged as a potential treatment option for patients with congenital heart disease (CHD). In this paper, we review the clinical evidence for the role of CRT in a number of different groups of patients with congenital heart lesions. In particular, we focus on whether there is a plausible mechanistic role for CRT and, if so, whether this results in acute and longer-term beneficial effects. We conclude that CRT shows promise as a potential treatment option for patients with CHD and ventricular impairment, but larger clinical outcome studies are required before definitive guidance can be issued.

Aims Ischaemic preconditioning (IPC) protects the heart against prolonged lethal ischaemia through a signalling cascade involving Akt, glycogen synthase kinase-3β (GSK-3β), and mitochondrial ATP-sensitive potassium channels (mitoKATP). We previously demonstrated the involvement of the Wnt pathway in IPC in vivo via GSK-3β. A downstream target might be mammalian target of rapamycin (mTOR) since Wnt can impair tuberous sclerosis complex-2 (TSC2) phosphorylation by inhibiting GSK-3β. Here, we investigate whether the mTOR pathway is involved in cardioprotection. Methods and results Isolated-perfused mouse hearts were subjected to IPC via four cycles of ischaemia/reperfusion or pharmacological preconditioning (PPC) by diazoxide, a selective mitoKATP activator. IPC, like PPC, induced an inhibition/phosphorylation of GSK-3β through Akt activation. Preconditioning also induced phosphorylation of mTOR, p70S6K, and 4E-BP1 that correlated with a significant reduction in infarct size after 40-min ischaemia and 120-min reperfusion when compared with non-preconditioned controls. Preconditioning was impaired in GSK3 knock-in mice. In transgenic mice hearts overexpressing secreted frizzled protein 1 (sFRP1, a Wnt/Frz antagonist), GSK-3β phosphorylation, mTOR activation, and cardioprotection were impaired. Cardioprotection and its signalling were also inhibited by rapamycin (an mTOR inhibitor), 5-HD (a mitoKATP blocker), and N -(2-mercaptopropionyl) glycine (MPG) as a reactive oxygen species (ROS) scavenger. Conclusions We propose that the preconditioning signalling pathway involving an amplification loop results in a downregulation of GSK-3β and a constant opening of mitoKATP with ROS generation to activate the mTOR pathway and induce cardioprotection. The disruption of the Wnt/Frz pathway by sFRP1 modulates this loop, inducing GSK-3β activation. This study provides evidence that cardioprotection involves both a pro-survival mTOR pathway and a developmental Wnt pathway targeting GSK-3β.

Conventionally, the evaluation of left ventricular (LV) systolic function is based on ejection fraction assessment, which may be supplemented by other echocardiographic techniques, such as tissue Doppler imaging, 3D evaluation, and speckle tracking strains. However, these imaging modalities have a high technicity and are time-consuming, while being associated with reproducibility limitations. In this context, the usefulness of simpler measurements such as sys- tolic time intervals (STI) by pulsed Doppler echocardiography must be emphasized. Methods and results In this multicentre study, left ventricular ejection fraction (LVEF), dP/dtmax, LV stroke volume, myocardial longitudinal deformation, aortic pre-ejectional period (PEP, ms), and left ventricular ejection time (LVET, ms) were prospectively investigated and compared in 134 consecutive heart failure (HF) patients and 43 control subjects. Feasibility of STI measurements was 100%. Intra-observer reproducibility was 98% for PEP, 96% for LVET, 87% for LVEF, and 93% for global longitudinal strain (GLS). By subgroup analyses, with increasingly altered LVEF or GLS, PEP significantly increased, whereas significantly LVET decreased, resulting in a significantly increased PEP/LVET ratio (P , 0.001). In the HF patients group, a correlation between LVEF and PEP/LVET was found, with r ¼ 0.55 (y ¼ 20.0083x + 0.75, P , 0.001). Based on receiver operating curve analyses, the area under the curve was 0.91 for PEP/LVET . 0.43, which allowed us to detect LVEF , 35% with a sensitivity of 87%, and a specificity of 84%. Conclusion STI can be easily and accurately measured in clinical practice, and may be used for detecting alterations in LV systolic function. Moreover, this method is likely to have potential applications in the management of HF patients.

Background The recent development of accurate methods to measure two-dimensional strain during dobutamine stress echocardiography has reactivated the debate as to the respective value of myocardial perfusion versus myocardial function assessment in detecting coronary stenoses. The aim of our study was to compare the effects of progressive coronary constrictions on two-dimensional strain and myocardial contrast echocardiography parameters during stress conditions. Methods Nine open-chest pigs were studied in the setting of various degrees of coronary constrictions. Two-dimensional strain and myocardial contrast echocardiography with Flash refilling sequence acquisitions were obtained at rest and during dobutamine infusion. Values of longitudinal strain (LS), circumferential strain (CS), radial strain (RS), and wall thickening, as well as myocardial perfusion parameter (A.b), were then calculated. Results At rest, accuracy for detecting coronary stenosis was higher for CS, LS, and A.b (74%, 67%, and 69%, respectively) than for RS or wall thickening (62% and 64%, respectively). Dobutamine stress echocardiography increased the accuracy of A.b and LS to 77% and to 73%, respectively. Sensitivity during stress was higher for CS (93%) and A.b (77%), whereas specificity was higher for LS (89%) than for other parameters. Combined evaluations (CS+A.b, CS+LS, and LS+A.b) during dobutamine stress echocardiography improved both sensitivity and accuracy for detecting coronary stenosis. Conclusion Quantitative evaluation of contraction by LS and CS analysis and perfusion (A.b) during stress echocardiography resulted in similar accuracy levels, whereas the radial component was less accurate. Maximal sensitivities and accuracies were obtained by combined evaluations during stress.

Mitochondria are central players in the pathophysiology of ischemia–reperfusion. Activation of plasma membrane G-coupled receptors or the Na,K-ATPase triggers cytosolic signaling pathways that result in cardioprotection. Our working hypothesis is that the occupied receptors migrate to caveolae, where signaling enzymes are scaffolded into signalosomes that bud off the plasma membrane and migrate to mitochondria. The signalosome–mitochondria interaction then initiates intramitochondrial signaling by opening the mitochondrial ATP-sensitive K + channel (mitoK ATP ). MitoK ATP opening causes an increase in ROS production, which activates mitochondrial protein kinase C epsilon (PKCɛ), which inhibits the mitochondrial permeability transition (MPT), thus decreasing cell death. We review the experimental findings that bear on these hypotheses and other modes of protection involving mitochondria.

International audience; AIMS: We sought to develop and validate a multiparametric algorithm by applying previously validated criteria to predict cardiac resynchronization therapy (CRT) response in a multicentre study. Thirty per cent of patients treated by CRT fail to respond to the treatment. Although dyssynchrony by echocardiography has been used to improve the selection of patients, the complexity of myocardial contraction has generated a moderate improvement using any of several individual parameters. METHODS AND RESULTS: Two hundred end-stage heart failure patients [NYHA 3-4 and left ventricular ejection fraction (LVEF)120 ms were included. Echocardiography analysis focused on the following parameters: atrioventricular dyssynchrony, interventricular dyssynchrony, and intraventricular dyssynchrony that integrated radial (PSAX M-mode) and longitudinal [tissue Doppler imaging (TDI)] evaluations for spatial (wall to wall) and temporal (wall end-systole to mitral valve opening) dyssynchrony diagnosis. Following CRT implantation, patients were monitored for 6 months with functional and echo evaluations defining responders by a 15% reduction in end-systolic volume. Mean QRS duration and LVEF were 152 +/- 17 ms and 25 +/- 8%. There was a CRT response in 57% of patients, independent of QRS width. Mean prevalence of positive criteria was 34 +/- 8%. Feasibility and variability averages were 81 +/- 20% and 9 +/- 4%. In a single parametric approach, ranges of sensitivities and specificities were 18-65% and 45-84% with a mean of 41% and 66%. A multiparametric approach by focusing on criteria combination decreased the mean rate of false-positive results to 14 +/- 12%, 5 +/- 4%, 2 +/- 2%, and 1 +/- 2% from one to four parameters, respectively. More than three parameters were associated with a specificity above 90% and a positive predictive value above 65%. Reproducibility of this global strategy was 91%. CONCLUSION: A multiparametric echocardiographic strategy based on the association of conventional criteria is a better indicator of CRT response than the existing single parametric approaches.

Perfusion of the heart with bradykinin triggers cellular signaling events that ultimately cause opening of mitochondrial ATP-sensitive K+(mitoKATP) channels, increased H2O2production, inhibition of the mitochondrial permeability transition (MPT), and cardioprotection. We hypothesized that the interaction of bradykinin with its receptor induces the assembly of a caveolar signaling platform (signalosome) that contains the enzymes of the signaling pathway and that migrates to mitochondria to induce mitoKATPchannel opening. We developed a novel method for isolating and purifying signalosomes from Langendorff-perfused rat hearts treated with bradykinin. Fractions containing the signalosomes were found to open mitoKATPchannels in mitochondria isolated from untreated hearts via the activation of mitochondrial PKC-ε. mitoKATPchannel opening required signalosome-dependent phosphorylation of an outer membrane protein. Immunodetection analysis revealed the presence of the bradykinin B2receptor only in the fraction isolated from bradykinin-treated hearts. Immunodetection and immunogold labeling of caveolin-3, as well as sensitivity to cholesterol depletion and resistance to Triton X-100, attested to the caveolar nature of the signalosomes. Ischemic preconditioning, ischemic postconditioning, and perfusion with ouabain also led to active signalosome fractions that opened mitoKATPchannels in mitochondria from untreated hearts. These results provide initial support for a novel mechanism for signal transmission from a plasma membrane receptor to mitoKATPchannels.