Search

Background In addition to scalability, human embryonic stem cells (hESCs) have the unique advantage of allowing their directed differentiation toward lineage-specific cells. Objectives This study tested the feasibility of leveraging the properties of hESCs to generate clinical-grade cardiovascular progenitor cells and assessed their safety in patients with severe ischemic left ventricular dysfunction. Methods Six patients (median age 66.5 years [interquartile range (IQR): 60.5 to 74.7 years]; median left ventricular ejection fraction 26% [IQR: 22% to 32%]) received a median dose of 8.2 million (IQR: 5 to 10 million) hESC-derived cardiovascular progenitors embedded in a fibrin patch that was epicardially delivered during a coronary artery bypass procedure. The primary endpoint was safety at 1 year and focused on: 1) cardiac or off-target tumor, assessed by imaging (computed tomography and fluorine-18 fluorodeoxyglucose positron emission tomography scans); 2) arrhythmias, detected by serial interrogations of the cardioverter-defibrillators implanted in all patients; and 3) alloimmunization, assessed by the presence of donor-specific antibodies. Patients were followed up for a median of 18 months. Results The protocol generated a highly purified (median 97.5% [IQR: 95.5% to 98.7%]) population of cardiovascular progenitors. One patient died early post-operatively from treatment-unrelated comorbidities. All others had uneventful recoveries. No tumor was detected during follow-up, and none of the patients presented with arrhythmias. Three patients developed clinically silent alloimmunization. All patients were symptomatically improved with an increased systolic motion of the cell-treated segments. One patient died of heart failure after 22 months. Conclusions This trial demonstrates the technical feasibility of producing clinical-grade hESC-derived cardiovascular progenitors and supports their short- and medium-term safety, thereby setting the grounds for adequately powered efficacy studies. (Transplantation of Human Embryonic Stem Cell-derived Progenitors in Severe Heart Failure [ESCORT]; NCT02057900)

Heart failure is a little-known disease which is both frequent and serious. It is particularly concerned by therapeutic education as it is linked to a high level of avoidable hospitalisations and requires daily monitoring of simple clinical parameters. It also imposes a change of lifestyle on the patient.

Cardiovascular risk factors (CVRFs) self-perception by women may be inaccurate.A questionnaire was completed anonymously Online by women who self-reported their personal CVRF levels including age, weight, contraceptive use, menopausal status, smoking, diet and physical activities. Self-perceived risk was matched to actual cardiovascular risk according to the Framingham score.Among 5,240 young and middle-aged women with a high educational level, knowledge of personal CVRFs increased with age, from 51-90% for blood pressure (BP), 22-45% for blood glucose and 15-47% for blood cholesterol levels, between 30 and 65 years, respectively. This knowledge was lower for smoking compared with nonsmoking women: 62.5% vs. 74.5% for BP (P0.001), 22.7% vs. 33.8% for blood glucose (P0.001), 21.9% vs. 32.0% for cholesterol levels (P0.001). Knowledge of BP level was reduced among women using an estrogen-progestogen contraception (56.8% vs. 62.1%, P = 0.0031) and even more reduced among smokers (52.2%, P0.001). Conversely, women with leisure-time physical or sportive activity (60.5%), were less overweight or obese (22.4% vs. 34.2%, P0.001). They reported better knowledge of BP (72.4% vs. 68.3%, P0.001), blood cholesterol (31.1% vs. 26.4%, P0.001) and glucose levels (32.7% vs. 27.8%, P0.001). Self-perceived cardiovascular risk was rated low by 1,279 (20.4%), moderate by 3,710 (63.3%) and high by 893 (16.3%) women. Among 3,386 women tested using the Framingham score, 40.8% were at low, 25.2% at moderate and 33.8% at high risk.Knowledge of CVRFs and self-perception of individual risk are inaccurate in women. Educational interventions should be emphasized.

RESUME La cardio-oncologie (ou onco-cardiologie) est un nouveau champ medical a developpement rapide qui a pour but de prevenir et prendre en charge les affections cardiovasculaires chez les patients atteints de cancer, avant pendant et apres leur traitement. L’augmentation de l’incidence des cancers s’accompagne d’une amelioration de leur pronostic, au prix d’une cardiotoxicite frequente liee aux chimiotherapies et a la radiotherapie. Cette nouvelle population grandissante de patients n’est pas aujourd’hui prise en charge de facon optimale et justifie la mise en place d’equipes soignantes dediees avec des programmes de soins et de surveillance communs multidisciplinaires et structures. Cette nouvelle thematique interdisciplinaire medicale et scientifique, genere par ailleurs un inepuisable champ de recherche.

International audience; Background - Our knowledge of hypertrophic cardiomyopathy (HCM) mainly originates from quarternary centres. The objective is to assess the current management of HCM patients in a large multicentre French register according to the level of expertise. Methods and results - A total of 1431 HCM patients were recruited across 26 (11 expert and 15 non-expert) centres in REMY, a prospective hospital-based register of adult HCM patients. A sarcomeric origin was suspected in 1284 (89.7%) patients [261 (20.3%) with a reported gene mutation, 242 (18.8%) genotype-negative], while 107 (7.5%) had a diagnosis of non-sarcomeric HCM. Patients managed in non-expert centres were older (P

We report the case of a patient who had undergone injections of myoblasts in an infarct area 16 years before being referred for heart transplantation. The pathological examination of the explanted heart found persisting myotubes embedded in fibrosis. This finding supports the ability of myoblasts to survive in harsh environments, which can make them appealing candidates for transplantation in diseases requiring supply of new myogenic cells.

Heart failure is a little-known disease which is both frequent and serious. It is particularly concerned by therapeutic education as it is linked to a high level of avoidable hospitalisations and requires daily monitoring of simple clinical parameters. It also imposes a change of lifestyle on the patient.

L’education therapeutique est un element-cle de la prise en charge de tout patient souffrant d’une pathologie chronique. Il existe de nombreuses preuves de son efficacite pour eviter les hospitalisations, reduire les couts, et dans certaines pathologies baisser la mortalite. L’accompagnement therapeutique est une extension du concept d’education therapeutique aux nouvelles technologies qui laisse entrevoir (enfin) la diffusion de cette forme de soins beneficiant de recommandations tres fortes des societes de cardiologie nationale et internationales.

Aims Comparative studies suggest that stem cells committed to a cardiac lineage are more effective for improving heart function than those featuring an extra-cardiac phenotype. We have therefore developed a population of human embryonic stem cell (ESC)-derived cardiac progenitor cells. Methods and results Undifferentiated human ESCs (I6 line) were amplified and cardiac-committed by exposure to bone morphogenetic protein-2 and a fibroblast growth factor receptor inhibitor. Cells responding to these cardio-instructive cues express the cardiac transcription factor Isl-1 and the stage-specific embryonic antigen SSEA-1 which was then used to purify them by immunomagnetic sorting. The Isl-1 + SSEA-1+ cells were then embedded into a fibrin scaffold which was surgically delivered onto the infarct area in a 68-year-old patient suffering from severe heart failure [New York Heart Association [NYHA] functional Class III; left ventricular ejection fraction (LVEF): 26%]. A coronary artery bypass was performed concomitantly in a non-infarcted area. The implanted cells featured a high degree of purity (99% were SSEA-1+), had lost the expression of Sox-2 and Nanog , taken as markers for pluripotency, and strongly expressed Isl-1 . The intraoperative delivery of the patch was expeditious. The post-operative course was uncomplicated either. After 3 months, the patient is symptomatically improved (NYHA functional Class I; LVEF: 36%) and a new-onset contractility is echocardiographically evident in the previously akinetic cell/patch-treated, non-revascularized area. There have been no complications such as arrhythmias, tumour formation, or immunosuppression-related adverse events. Conclusion This observation demonstrates the feasibility of generating a clinical-grade population of human ESC-derived cardiac progenitors and combining it within a tissue-engineered construct. While any conclusion pertaining to efficacy would be meaningless, the patient's functional outcome yet provides an encouraging hint. Beyond this case, the platform that has been set could be useful for generating different ESC-derived lineage-specific progenies.

Summary Background While occasional reports of mitral valve chordal rupture have been described in hypertrophic cardiomyopathy, the exact prevalence and characteristics of this event in a large medical cohort have not been reported. Aim To assess the prevalence of mitral valve chordal rupture in hypertrophic cardiomyopathy and the clinical, echocardiographic, surgical and histological profiles of those patients. Methods We searched for patients with mitral valve chordal rupture diagnosed by echocardiography among all electronic files of patients admitted to our centre for hypertrophic cardiomyopathy between 2000 and 2010. Results Among 580 patients admitted for hypertrophic cardiomyopathy, six patients (1%, 5 men, age 68–71 years) presented with mitral valve chordal rupture, symptomatic in five cases, always involving the posterior mitral leaflet. In all cases, echocardiography before rupture showed mitral valve systolic anterior motion, with anterior (and not posterior) leaflet elongation compared with a random sample of patients with non-obstructive hypertrophic cardiomyopathy ( P = 0.006) (and similar to that observed in obstructive hypertrophic cardiomyopathy). Significant resting left ventricular outflow tract obstruction was always present before rupture and disappeared after rupture in the five cases requiring mitral valve surgery for severe mitral regurgitation. Histological findings were consistent with extensive myxomatous degeneration in all cases. Conclusion Mitral valve chordal rupture is: infrequent in hypertrophic cardiomyopathy; occurs in aged patients with obstructive disease; involves, essentially, the posterior mitral leaflet; and causes, in general, severe mitral regurgitation requiring surgery. Myxomatous degeneration may be the substrate for rupture in these patients.

SummaryTherapeutic patient education programmes on heart failure have been widely proposed for many years for heart failure patients, but their efficiency remains questionable, partly because most articles lack a precise programme description, which makes comparative analysis of the studies difficult. To analyse the degree of precision in describing therapeutic patient education programmes in recent randomized controlled trials. Three major recent recommendations on therapeutic patient education in heart failure inspired us to compile a list of 23 relevant items that an ‘ideal’ description of a therapeutic patient education programme should contain. To discover the extent to which recent studies into therapeutic patient education in heart failure included these items, we analysed 19 randomized controlled trials among 448 articles published in this field from 2005 to 2012. The major elements required to describe a therapeutic patient education programme were present, but some other very important pieces of information were missing in most of the studies we analysed: the patient's educational needs, health literacy, projects, expectations regarding therapeutic patient education and psychosocial status; the educational methodology used; outcomes evaluation; and follow-up strategies. Research into how therapeutic patient education can help heart failure patients will be improved if more precise descriptions of patients, educational methodology and evaluation protocols are given by authors, ideally in a standardized format.

L’insuffisance cardiaque chronique est une maladie frequente et grave. Malgre les progres des derniers annees avec l’emergence de nouvelles therapeutiques, de nouveaux biomarqueurs et l’amelioration de nos possibilites diagnostiques en particulier en echographie, le taux de rehospitalisation et de deces reste particulierement eleve. Une autre specificite de cette maladie est que plus de 50 % des patients presentent des signes cliniques devant alerter celui-ci 5 jours avant son passage aux urgences. Tous ces elements font de l’insuffisance cardiaque une cible de choix pour la telemedecine. Dans le cadre de cette pathologie, la telemedecine s’est preferentiellement orientee, d’une part, vers le suivi de protheses electriques (pacemakers, defibrillateurs) et, d’autre part, vers le suivi de signes de decompensation, que ce soit au moyen de protheses embarquees (implantees) ou bien de modules externes connectes. Cependant, les resultats des etudes publiees ont ete tres variables et discutes. Actuellement, une nouvelle generation de dispositifs de telemedecine voit le jour, integrant non seulement des parametres cliniques, mais aussi des parametres biologiques, mais cette generation comme les autres doit prouver son utilite et sa population cible avant son deploiement.

Despite therapeutic advances, heart failure remains a common and serious event characterized by initial and progressive loss of cardiac myocytes, a loss that is currently untreatable. Cell therapy has emerged as a promising new approach to the treatment of heart failure, with very encouraging experimental results. Since 2000, when human stem cell therapy was first attempted in France, clinical trials with adult stem cells (myoblasts, bone-marrow derived cells, mesenchymal stem cells) have given variable results. The inconsistent and modest therapeutic benefit observed in these studies is due more to paracrine effects than to the hoped-for cell replacement, as adult stem cells do not turn into cardiomyocytes and their survival rate after transplantation is very low. In order to be effective, cell therapy should use heart muscle cells derived from pluri- or multipotent cells (human embryonic stem cells, induced pluripotent stem cells, resident cardiac cells), which are likely to have a higher survival rate in a hostile biological environment and deteriorated tissue scaffold. Cardiac tissue engineering assisted by nanotechnologies may eventually help to meet this challenge.

Aims Characteristics of sudden cardiac arrest (SCA) during sports offers a novel (and unexplored) setting to assess factors associated with disparities in outcomes across regions. Methods and results From a prospective 5-year community-based French registry concerning SCA during sports in 10–75 year-olds, we evaluated whether outcomes differed significantly between geographic regions. We then determined the extent to which variations in community-related early interventions were associated with regional variations in survival. Among 820 SCA cases studied, overall survival at hospital discharge was 15.7% (95% confidence interval, 13.2–18.2%), with considerable regional disparities (from 3.4 to 42.6%, P < 0.001). Major differences were noted regarding bystander initiation of cardiopulmonary resuscitation (15.3–80.9%, P < 0.001) and presence of initial shockable rhythm (28.6–79.1%, P < 0.001), with higher values of these being associated with better survival rates. The proportion of survivors with favourable neurological outcome at discharge was fairly uniform among survival groups (CPC–1/2, varying from 77.4 to 90.0%, P = 0.83). No difference was observed regarding subjects' characteristics and circumstances of SCA occurrence, including delays in resuscitation (collapse-to-call period). With a comparable in-hospital mortality ( P = 0.44), survival at hospital discharge was highly correlated with that at hospital admission (regional variations from 7.4 to 75.0%, P < 0.001). Conclusion Major regional disparities exist in survival rates (up to 10-fold) after SCA during sports. SCA cases from regions with the highest levels of bystander resuscitation had the best survival rates to hospital admission and discharge.

International audience; AIMS: Mutations in PRKAG2, the gene encoding for the γ2 subunit of 5'-AMP-activated protein kinase (AMPK), are responsible for an autosomal dominant glycogenosis with a cardiac presentation, associating hypertrophic cardiomyopathy (HCM), ventricular pre-excitation (VPE), and progressive heart block. The aim of this study was to perform a retrospective time-to-event study of the clinical manifestations associated with PRKAG2 mutations.METHODS AND RESULTS: A cohort of 34 patients from 9 families was recruited between 2001 and 2010. DNA were sequenced on all exons and flanking sequences of the PRKAG2 gene using Sanger sequencing. Overall, four families carried the recurrent p.Arg302Gln mutation, and the five others carried private mutations among which three had never been reported. In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%. The global survival at 60 years of age was 66%. Thirty-two per cent of patients (N = 10) required a device implantation (5 pacemakers and 5 defibrillators) at a median age of 66 years, and two patients required heart transplant. Only one patient presented with significant skeletal muscle symptoms. No significant differences regarding the occurrence of VPE, ablation complications, or death incidence were observed between different mutations.CONCLUSION: This study of patients with PRKAG2 mutations provides a more comprehensive view of the natural history of this disease and demonstrates a high risk of cardiac complications. Early recognition of this disease appears important to allow an appropriate management.

RESUME La cardiomyopathie hypertrophique est une maladie myocardique caracterisee par une hypertrophie ventriculaire gauche sans cause apparente (c’est-a-dire en l’absence d’une hypertension arterielle severe, d’une stenose valvulaire aortique...) Le diagnostic clinique repose sur l’imagerie cardiaque, habituellement l’echographie et de plus en plus la resonance magnetique nucleaire. La cardiomyopathie hypertrophique est la cause la plus frequente de mort subite chez les jeunes, particulierement lors des competitions athletiques. La majorite des patients reste asymptomatique durant la vie mais d’autres developpent des signes d’insuffisance cardiaque, une fibrillation auriculaire et des accidents vasculaires cerebraux. C’est la maladie cardiovasculaire genetique la plus frequente (a transmission autosomique dominante) avec une penetrance et une expression variables, causee par des mutations des genes codant les proteines sarcomeriques cardiaques. Les conseils genetiques et la stratification du risque sont indispensables chez tous les patients. Le traitement medical avec les betabloqueurs ou le verapamil ameliore les symptomes mais ne modifie pas la progression de la maladie. Les patients ayant une obstruction systolique et des symptomes severes ne repondant pas au traitement medical sont candidats a l’alcoolisation septale ou a la myectomie chirurgicale. L’approche actuelle est focalisee sur la prevention de la mort subite par le defibrillateur implantable indique chez les patients a haut risque.

Background— Although such data are available for young competitive athletes, the prevalence, characteristics, and outcome of sports-related sudden death have not been assessed previously in the general population. Methods and Results— A prospective and comprehensive national survey was performed throughout France from 2005 to 2010, involving subjects 10 to 75 years of age. Case detection for sports-related sudden death, including resuscitated cardiac arrest, was undertaken via national ambulance service reporting and Web-based screening of media releases. The overall burden of sports-related sudden death was 4.6 cases per million population per year, with 6% of cases occurring in young competitive athletes. Sensitivity analyses used to address suspected underreporting demonstrated an incidence ranging from 5 to 17 new cases per million population per year. More than 90% of cases occurred in the context of recreational sports. The age of subjects was relatively young (mean±SD 46±15 years), with a predominance of men (95%). Although most cases were witnessed (93%), bystander cardiopulmonary resuscitation was only commenced in 30.7% of cases. Bystander cardiopulmonary resuscitation (odds ratio 3.73, 95% confidence interval 2.19 to 6.39, P P Conclusions— Sports-related sudden death in the general population is considerably more common than previously suspected. Most cases are witnessed, yet bystander cardiopulmonary resuscitation was only initiated in one third of cases. Given the often predictable setting of sports-related sudden death and that prompt interventions were significantly associated with improved survival, these data have implications for health services planning.

Background— One of the key targets in treating mitral regurgitation (MR) is reducing the otherwise progressive left ventricular (LV) remodeling that exacerbates MR and conveys adverse prognosis. We have previously demonstrated that severing 2 second-order chordae to the anterior mitral leaflet relieves tethering and ischemic MR acutely. The purpose of this study was to test whether this technique reduces the progression of LV remodeling in the chronic ischemic MR setting. Methods and Results— A posterolateral MI was created in 18 sheep by obtuse marginal branch ligation. After chronic remodeling and MR development at 3 months, 6 sheep were randomized to sham surgery (control group) and 12 to second-order chordal cutting (6 each to anterior leaflet [AntL] and bileaflet [BiL] chordal cutting, techniques that are in clinical application). At baseline, chronic infarction (3 months), and follow-up at a mean of 6.6 months post-myocardial infarction (MI) (euthanasia), we measured LV end-diastolic (EDV) and end-systolic volume (ESV), ejection fraction, wall motion score index, and posterior leaflet (PL) restriction angle relative to the annulus by 2D and 3D echocardiography. All measurements were comparable among groups at baseline and chronic MI. At euthanasia, AntL and BiL chordal cutting limited the progressive remodeling seen in controls. LVESV increased relative to chronic MI by 109±8.7% in controls versus 30.5±6.1% with chordal cutting ( P P P P Conclusions— Reduced leaflet tethering by chordal cutting in the chronic post-MI setting substantially decreases the progression of LV remodeling with sustained reduction of MR over a chronic follow-up. These benefits have the potential to improve clinical outcomes.

Summary Background Chest pain units (CPUs) are very popular in the USA for the triage of low-to-intermediate-risk chest pains. However, CPUs do not yet exist in France. Aims To determine the prevalence and clinical characteristics of patients admitted to a new CPU in France, and to assess the quality of care with regard to identification and exclusion of an acute coronary syndromes (ACS). Methods This prospective study included 906 consecutive patients with non-traumatic chest pain admitted to our CPU between September 2006 and August 2008. Patients were managed according to their probability of presenting with an ACS. Clinical characteristics, diagnostic tests, final diagnosis, destination and length of stay were recorded. We also assessed the 30-day outcome of patients in whom an ACS was excluded. Results Of the 906 patients, 27.9% had an ACS (1.3% with and 26.6% without ST-segment elevation, respectively). Non-ischaemic cardiac aetiologies and non-cardiac aetiologies were found in 123 (12.6%) and 63 (7.0%) patients, respectively. A final diagnosis of chest pain of undetermined origin was made in 51.5% of patients; among these, 17 (6.5%) patients were re-admitted to the CPU between September 2006 and September 2007. Thirty-day follow-up revealed that only one patient had subsequent confirmation of coronary artery disease requiring further hospitalization. Conclusions This prospective study reports the first experience of a CPU in a cardiology department in France. Our preliminary results suggest that our CPU can exclude an ACS safely. Further studies are warranted to assess the value of CPUs in France.

Aims The aim of this study involves the early identification, among apparently healthy individuals, of those at high risk for sudden cardiac death. We tested the hypothesis that individuals who respond to mild mental stress in preparation for exercise test with the largest heart rate increases might be at highest risk. Methods and results Data from 7746 civil servants participating in the Paris Prospective Study I, followed-up for 23 years, allowed to compare heart rate changes between rest and mild mental stress (preparation prior to an exercise test) between subjects who suffered sudden cardiac death ( n = 81), non-sudden ( n = 129) coronary death, or death from any cause ( n = 1306). The mean heart rate increase during mild mental stress was 8.9 ± 10.8 b.p.m. Risk of sudden cardiac death increased progressively with heart rate increase during mental stress and the relative risk of the third vs. the first tertile was 2.09 (95% confidence interval, 1.13–3.86) after adjustment for confounders. This relationship was not observed for non-sudden coronary death. Conclusion An important heart rate increase produced by a mild mental stress predicts long-term risk for sudden cardiac death. Heart rate changes before an exercise test may provide a simple tool for risk stratification.

Mesenchymal stem cells (MSCs) are reported to be immune privileged. We assessed whether their transplantation (Tx) could create a suppressive microenvironment mitigating rejection of coinjected human embryonic stem cells (hESCs). Three weeks after ligation-induced myocardial infarction, 40 immunocompetent rats received 150 microl of cardiac-specified hESCs (5 x 10(6)), MSCs (5 x 10(6)), hESC + MSC (5 x 10(6) for each), or control medium. Two months after Tx, left ventricle (LV) function was assessed by echocardiography, and hearts were processed for the detection of human cells by immunostaining and quantitative RT-PCR, patterns of rejection, fibrosis, and angiogenesis. Two months after Tx, LV ejection fraction (LVEF) was significantly higher in the ESC and ESC + MSC groups compared with controls. There were few engrafted cells, which expressed markers of endothelial, smooth muscle, and ventricular cardiac cells, particularly in the MSC group. Hearts of all groups demonstrated a similar infiltration by CD4(+) and CD3(+) cells but MSC-Tx resulted in a greater infiltration of FoxP3 compared with the control and ESC-alone groups. No teratoma was observed. Thus, cotransplantation of ESCs and MSCs provided better functional preservation compared with single-cell treatment alone. However, there was only modest evidence for an immunosuppressive effect of coinjected MSCs and their beneficial effects seemed rather mediated by trophic effects on the host tissue.

The prognostic implications of heart rate (HR) change over years have never been assessed. It was hypothesized that an increase in HR in apparently healthy persons observed over years could be associated with an increase in mortality risk and conversely. A total of 5,139 asymptomatic working men (aged 42 to 53 years) free of clinically detectable cardiovascular disease were recruited from 1967 to 1972 and had their HRs measured at rest in standardized conditions every year for 5 consecutive years. HR change was defined as the difference between HR at examination 5 and HR at inclusion, and subjects were divided into tertiles according to decrease >4 beats/min, unchanged (from -4 to +3 beats/min), and increase >3 beats/min. After >20 years of mortality surveillance, 1,219 deaths were observed. After adjustments were made for confounding factors, including baseline HR at rest, and compared with subjects with unchanged HRs, subjects with decreased HRs during the 5 years had a 14% decreased mortality risk (RR 0.86, 95% confidence interval 0.74 to 1.00, p=0.05), whereas subjects with increased HRs during the 5 years had a 19% increased mortality risk (RR 1.19, and 95% confidence interval 1.04 to 1.37, p

Despite therapeutic advances, heart failure remains a common and serious event characterized by initial and progressive loss of cardiac myocytes, a loss that is currently untreatable. Cell therapy has emerged as a promising new approach to the treatment of heart failure, with very encouraging experimental results. Since 2000, when human stem cell therapy was first attempted in France, clinical trials with adult stem cells (myoblasts, bone-marrow derived cells, mesenchymal stem cells) have given variable results. The inconsistent and modest therapeutic benefit observed in these studies is due more to paracrine effects than to the hoped-for cell replacement, as adult stem cells do not turn into cardiomyocytes and their survival rate after transplantation is very low. In order to be effective, cell therapy should use heart muscle cells derived from pluri- or multipotent cells (human embryonic stem cells, induced pluripotent stem cells, resident cardiac cells), which are likely to have a higher survival rate in a hostile biological environment and deteriorated tissue scaffold. Cardiac tissue engineering assisted by nanotechnologies may eventually help to meet this challenge.

Comparative studies suggest that stem cells committed to a cardiac lineage are more effective for improving heart function than those featuring an extra-cardiac phenotype. We have therefore developed a population of human embryonic stem cell (ESC)-derived cardiac progenitor cells.Undifferentiated human ESCs (I6 line) were amplified and cardiac-committed by exposure to bone morphogenetic protein-2 and a fibroblast growth factor receptor inhibitor. Cells responding to these cardio-instructive cues express the cardiac transcription factor Isl-1 and the stage-specific embryonic antigen SSEA-1 which was then used to purify them by immunomagnetic sorting. The Isl-1(+) SSEA-1(+) cells were then embedded into a fibrin scaffold which was surgically delivered onto the infarct area in a 68-year-old patient suffering from severe heart failure [New York Heart Association [NYHA] functional Class III; left ventricular ejection fraction (LVEF): 26%]. A coronary artery bypass was performed concomitantly in a non-infarcted area. The implanted cells featured a high degree of purity (99% were SSEA-1(+)), had lost the expression of Sox-2 and Nanog, taken as markers for pluripotency, and strongly expressed Isl-1. The intraoperative delivery of the patch was expeditious. The post-operative course was uncomplicated either. After 3 months, the patient is symptomatically improved (NYHA functional Class I; LVEF: 36%) and a new-onset contractility is echocardiographically evident in the previously akinetic cell/patch-treated, non-revascularized area. There have been no complications such as arrhythmias, tumour formation, or immunosuppression-related adverse events.This observation demonstrates the feasibility of generating a clinical-grade population of human ESC-derived cardiac progenitors and combining it within a tissue-engineered construct. While any conclusion pertaining to efficacy would be meaningless, the patient's functional outcome yet provides an encouraging hint. Beyond this case, the platform that has been set could be useful for generating different ESC-derived lineage-specific progenies.

International audience; Aim This paper describes the multi-step translational approach that has resulted in the generation of clinical-grade human embryonic stem cell-derived cardiac progenitor cells for transplantation in patients with severe ischaemic heart failure. There is now compelling evidence that cells committed to a cardiac lineage are most effective for improving the function of infarcted hearts. This has been confirmed by our pre-clinical studies entailing transplantation of human embryonic stem cell (hESC)-derived cardiac progenitors in rat and non-human primate models of myocardial infarction. These data have paved the way for a translational programme aimed at a phase I clinical trial. Methods and results The main steps of this programme have included (i) the expansion of a clone of pluripotent hESC to generate a master cell bank under good manufacturing practice conditions (GMP); (ii) a growth factor-induced cardiac specification; (iii) the purification of committed cells by immunomagnetic sorting to yield a stage-specific embryonic antigen (SSEA)-1-positive cell population strongly expressing the early cardiac transcription factor Isl-1; (iv) the incorporation of these cells into a fibrin scaffold; (v) a safety assessment focused on the loss of teratoma-forming cells by in vitro (transcriptomics) and in vivo (cell injections in immunodeficient mice) measurements; (vi) an extensive cytogenetic and viral testing; and (vii) the characterization of the final cell product and its release criteria. The data collected throughout this process have led to approval by the French regulatory authorities for a first-in-man clinical trial of transplantation of these SSEA-1(+) progenitors in patients with severely impaired cardiac function. Conclusion Although several facets of this manufacturing process still need to be improved, these data may yet provide a useful platform for the production of hESC-derived cardiac progenitor cells under safe and cost-effective GMP conditions.

After a decade of experimental work, skeletal myoblast transplantation has now entered the clinical arena as a potentially new means of improving the function of the chronically infarcted heart through regeneration of fibrotic scars. Because the engrafted myoblasts do not connect with the host cardiomyocytes, it is increasingly considered that the functional benefits of myogenic cell transplantation are more related to limitation of adverse post-infarction remodelling and/or paracrine signalling on recipient tissue rather than to a synchronous contribution of the graft to the heart's systolic function. The initial clinical studies of intra-operative myoblast transplantation have primarily documented the feasibility of the procedure and unravelled a potential pro-arrhythmic risk that needs to be further characterized. It is now critical to assess whether the functional benefits observed in the laboratory setting translate into meaningful improvements in local and global contractility and ultimate patient outcomes. The results of ongoing randomized trials should soon help clarifying this efficacy issue. In parallel, experimental studies need to be actively pursued to address some remaining key issues including the means of optimizing myoblast delivery, engraftment and survival, and the development of a second-line generation of cells featuring the potential of a true electromechanical integration within the recipient myocardium.

Background: Little is known about the epidemiology of acute decompensated heart failure (ADHF) in patients admitted to intensive and coronary care units (ICU/CCU). Observational data may improve disease management and guide the design of clinical trials. Aims: EFICA is an observational study of the clinical profile, management and survival of ADHF patients admitted to ICU/CCU. Methods: The study included 599 patients admitted to 60 ICU/CCUs across France. Relevant data was recorded during hospitalisation. Survival was assessed at 4 weeks and 1 year. Results: The main cause of ADHF was ischaemic heart disease (61%); 29% of patients had cardiogenic shock. Mortality was 27.4% at 4 weeks and 46.5% at 1 year, increasing to 43.2% and 62.5%, respectively, when including pre-admission deaths. Shock patients had the highest [57.8% vs. 15.2% without shock (p

This study reports a family affected by a new phenotype associated with dilated cardiomyopathy and quadriceps myopathy. 1 Methods: 29 family members underwent a physical and neurological examination, including an electromyogram and biopsy of muscle abnormalities. A cardiac examination was performed in all subjects. 2 Results: The family pedigree (n=72) demonstrated that transmission was autosomal dominant. Eleven subjects had cardiac involvement, only four had quadriceps muscle involvement. Cardiac impairment preceded neurological involvement. The mean age for neurological involvement was 44±0.8 years (range 43–45) and cardiac involvement was 37±7.9 years (range: 24–45). Cardiac involvement consisted of: hypokinetic dilated cardiomyopathy (64%); atrial fibrillation (100%); ventricular arrhythmias (64%); impaired conduction with bundle branch or complete atrio ventricular block (73%). Four patients required pacemakers and anti arrhythmic therapies. Four patients died: two of refractory heart failure and two of sudden death; two patients were resuscitated following cardiac arrest. Three patients required a prophylactic implantable cardiac defibrillator (ICD). Muscle morphological abnormalities were characterized by a variable number of fibers with rimmed vacuoles. The quadriceps deteriorated progressively without impairment of other muscles. Genotypic study showed a lamin A/C gene mutation. 3 Conclusions: This family was affected by a new phenotype composed of an autosomal dominant severe dilated cardiomyopathy with conduction defects or arrhythmias and quadriceps myopathy. Cardiac abnormalities preceded neuromuscular disorders and defined the prognosis of this disease.

Aims This study was designed to assess the functional effects of a transvenous coronary sinus technique of skeletal myoblast delivery in infarcted myocardium. Methods and results An anterior myocardial infarction was created percutaneously in 14 sheep. Simultaneously, a muscle biopsy was harvested and expanded. Two weeks later, sheep were instrumented percutaneously with a dedicated catheter incorporating an extendable needle for puncture of the venous wall and, under endovascular ultrasound guidance, a microcatheter was advanced through the needle into the target scar for cell delivery. Following the baseline echocardiographic assessment of left ventricular (LV) function, sheep were randomly allocated to receive four-staged in-scar injections of either autologous cells (n ¼ 7) or culture medium (n ¼ 7). Two months later, LV function was reassessed blindly and hearts were explanted for subsequent histological and immunohistochemical analysis. There were no acute procedural complications. Baseline LV ejection fraction (EF) was significantly lower in transplanted sheep than in controls [38% (35‐48) vs. 51% (38‐55), respectively, P ¼ 0.03; median (range)]. Two months later, LVEF was significantly higher in the transplanted group than in controls [50% (47‐56) vs. 39% (36‐47), respectively, P ¼ 0.002]. Clusters of myoblasts were identified by histology and immunohistochemistry in three of the seven transplanted sheep. Conclusion These data suggest the functional efficacy of the transvenous coronary sinus technique as a less invasive means of cell delivery to infarcted myocardium.

Background: Reactive oxygen species (ROS) production increases after injury and potentially contributes to restenosis after angioplasty. We therefore evaluated the effect of adenovirus-mediated gene transfer (Ad) of superoxide dismutase (SOD) and catalase (CAT) on ROS production and restenosis after balloon angioplasty. Methods: O2– and H2O2 production was quantified in cultured cells after incubation with either LPS or CuSO4. Angioplasty and gene transfer were performed in rabbit atherosclerotic iliac arteries. One artery was injected with AdSOD and AdCAT, while the contralateral artery was injected with an adenovirus carrying no transgene, and served as control. Results: ROS production was significantly decreased after adenovirus-mediated gene transfer of SOD and CAT as compared with control. Treated arteries showed less restenosis (32 ± 27 vs. 63 ± 19%, p = 0.003) and less constrictive remodeling (1.2 ± 0.3 vs. 0.9 ± 0.2, p = 0.02) than control arteries. Arteries injected with AdSOD and AdCAT showed better vasoreactivity to acetylcholine (11 ± 4 vs. –1 ± 6%, p < 0.05), lower collagen density (43 ± 16 vs. 53 ± 23%, p = 0.03), and lower inflammatory cell infiltration (22 ± 6 vs. 36 ± 11%, p = 0.04) than control arteries. Conclusions: Our data suggest that adenovirus-mediated gene transfer of SOD and CAT reduced oxidative stress, restenosis, collagen accumulation, and inflammation and improved endothelial function after angioplasty.

Resume Le traitement betabloquant est actuellement recommande par l'ensemble des guidelines concernant le traitement de l'insuffisance cardiaque systolique. Pourtant, leur prescription reste limitee. Une des possibles raisons de cette relative faible prescription est le risque de survenue d'une decompensation cardiaque induite par l'effet a court terme du traitement betabloquant. Parmi les autres elements limitatifs on retrouve l'apparition d'une bradycardie ou d'une hypotension symptomatique. Si les donnees cliniques peuvent permettre d'identifier assez facilement les patients susceptibles de presenter une hypotension ou une bradycardie, ils ne peuvent permettre d'identifier ceux allant presenter une poussee d'insuffisance cardiaque secondaire a l'introduction d'un traitement betabloquant. En revanche l'existence d'un BNP superieur a 490 pg/ml avant l'introduction du traitement betabloquant permet d'identifier ces patients avec une sensibilite de 90 %, un taux de BNP superieur a 1000 pg/ml etant associe a un risque de 40 % de presenter une poussee d'insuffisance cardiaque. A ce titre, il convient d'etre prudent lors de l'introduction d'un traitement betabloquant chez les patients insuffisants cardiaques presentant des taux de BNP eleves.

Background— The mechanisms of thrombosis on plaque erosion are poorly understood. We examined the potential role of endothelial apoptosis in endothelial erosion and vessel thrombosis. Methods and Results— Segments of New Zealand White rabbit femoral arteries were temporarily isolated in vivo. One artery was incubated with staurosporin for 30 minutes, whereas the contralateral artery was incubated with saline and served as control. Three days later, thrombosis was evaluated angiographically and histologically. TUNEL score in the endothelial layer was significantly increased in staurosporin-treated arteries compared with controls (2.43±0.30 versus 0.93±0.44, respectively; P =0.001). Large areas of endothelial denudation were detectable in staurosporin-treated vessels, whereas endothelium integrity was almost preserved in the saline group. Vessel thrombosis occurred in 58% of staurosporin-treated arteries (7 of 12) but in only 8% of saline-treated segments ( P P =0.04). These results were confirmed in balloon-injured atheromatous arteries. Conclusions— In vivo induction of endothelial apoptosis leads to both vessel thrombosis and endothelial denudation. Endothelial apoptosis may be a critical step in the transition from a stable endothelialized plaque to plaque erosion and thrombosis.

Resume L’insuffisance cardiaque est une pathologie grave ou la compliance du patient joue un role crucial. Cette compliance passe par une formation du patient vis-a-vis de sa maladie et de son traitement. Cette formation peut etre realisee au sein d’un centre hospitalier general au prix d’un investissement important en temps et en personnels. L’education therapeutique est neanmoins un element de plus en plus indispensable dans le cadre d’une prise en charge de qualite et est ressentie comme extremement benefique par les patients chez qui elle permet d’ameliorer les connaissances et l’implication d’une part et de diminuer la duree des sejours hospitaliers d’autre part.

Resume Les peptides natriuretiques de type B comme le BNP ou le NT Pro BNP sont des marqueurs diagnostiques et pronostiques reconnus et de plus en plus largement utilises en pratique courante. L’âge provoque une augmentation significative de ces peptides en particulier du fait de l’existence de nombreuses co-pathologies comme l’hypertension ou l’insuffisance renale et necessite une adaptation des normes utilisees. La valeur diagnostique et pronostique du BNP semble cependant preservee meme s’il faut rester encore plus prudent que chez le sujet jeune avant d’evoquer le diagnostic d’insuffisance cardiaque en cas de BNP moderement eleve.

Natriuretic Peptides like BNP or NT Pro BNP are diagnostic and prognostic makers largely used in clinical practice. Ageing may increase these peptides, especially in case of comorbidities like renal failure or hypertension and require adjustment for age. Diagnostic value of natriuretic peptides seems however preserved in elderly people.

Heritable dilated cardiomyopathy is a genetically highly heterogeneous disease. To date 17 different chromosomal loci have been described for autosomal dominant forms of dilated cardiomyopathy with or without additional clinical manifestations. Among the 10 mutated genes associated with dilated cardiomyopathy, the lamin A/C (LMNA) gene has been reported in forms associated with conduction-system disease with or without skeletal muscle myopathy. For the first time, we report here a French family affected with a new phenotype composed of an autosomal dominant severe dilated cardiomyopathy with conduction defects or atrial/ventricular arrhythmias, and a specific quadriceps muscle myopathy. In all previously reported cases with both cardiac and neuromuscular involvement, neuromuscular disorders preceded cardiac abnormalities. The screening of the coding sequence of the LMNA gene on all family members was performed and we identified a missense mutation (R377H) in the lamin A/C gene that cosegregated with the disease in the family. Cell transfection experiments showed that the R377H mutation leads to mislocalization of both lamin and emerin. These results were obtained in both muscular (C2C12) and non-muscular cells (COS-7). This new phenotype points out the wide spectrum of neuromuscular and cardiac manifestations associated with lamin A/C mutations, with the functional consequence of this mutation seemingly associated with a disorganization of the lamina.

Objectives: To determine if B-type natriuretic peptide (BNP) measurement could be useful in determination of functional capacity in patients suffering from chronic heart failure. Background: Evaluating functional capacity is a crucial factor in the follow-up of patients with chronic heart failure. There are numerous methods for measuring functional capacity and their relative merits remain under discussion. Clinical classifications are very subjective and other methods are difficult to use in clinical practice. Methods: We evaluated functional capacity in 151 consecutive patients using the 6-min walk test. All patients were clinically classified using the New York Heart Association (NYHA) classification. We measured BNP plasma levels using a bedside BNP test. Results: Six minute walk test performance decreased through NYHA classes 1 to 4 (469±87, 411±82, 325±83 and 196±63 m, respectively, P

Chronic heart failure patients education to self-management is recommended by international guidelines but is still underuse by clinicians. Actually only 5–10% of CHF patients benefit from multidisciplinary education in Europe. Many studies have underline the short- or mild-term impact of education on hospitalization but only few on mortality. The aim of our study was to analyse the long-term impact (8 years) of a structured multidisciplinary education of CHF patients and relatives using simple tools (paperboard, games, quiz) on all causes mortality. Methods We have prospectively included 803 consecutive CHF patients referred to our heart failure center since 2001. Patient education was proposed to all patients and was done only in 264. Education was done on Monday and Tuesday. Some refused and some were referred out of the education days. Education was based on an educational diagnostic done by a nurse, a discussion between doctor and a group of 6 patients and relatives and a discussion between physiotherapist and patients. At the end of the session, patients use a game tool analyzing reactivity and knowledge. We have followed the patients in the same way with the same clinicians in charge of optimizing HF therapy. Mean follow up was 8 ± 4 years. The main end point was all cause mortality. Results The two groups (Education vs no education) were comparable in term of age, LVEF (33 ± 11 vs 38 ± 13%) left ventricular filling (E/A 0,9 ± 0,2 vs 1,31 ± 1) renal function (creatininemia 114 ± 94 vs 116 ± 113 μmol/l) and BNP (313 ± 463 vs 533 ± 770 pg/mL)) and comparable in term of CH F therapies. During follow up, annual mortality rate was 3,19% in therapeutic education group versus 4,8% in the no education group ( p : 0,0369). Conclusion Education of CHF patients is a long-term effective tool in order to reduce long-term mortality. Our HF tool kit using face to face discussions and reactivity based games is not really time consuming (3 hours nurse/1 hour physiotherapist for a group from 6 to 8 patients) and is effective in order to reduce long term all cause mortality by 1/3. Due to its impact in real life, patient education to self-management should be promoted in CHF patient management and done in every HF center.

Chronic heart failure is linked to high rate of death and hospitalization. Some studies have highlighted the beneficial effect of heart failure clinics on morbidity and mortality. We have developed this type of structure at CHR Dubos since 3 years and we have recently created an heart failure clinic (10 beds). It's based on a concept including an experienced medical and nurse team, patient's and patient's family education and evaluation of the structure.

OBJECTIVES We sought to evaluate whether cellular mass changes (including apoptosis and proliferation) after arterial injury could interact with restenosis and arterial remodeling. BACKGROUND The mechanisms controlling arterial remodeling after angioplasty remain poorly understood. Apoptosis and cell proliferation have been previously described after balloon angioplasty. However, their importance in the occurrence of arterial remodeling and restenosis is unknown. METHODS Atherosclerosis was induced in 48 femoral arteries of New Zealand White rabbits by air-desiccation and a high-cholesterol diet. One month later, angioplasty was performed in 40 arteries. Apoptosis, cell proliferation, residual stenosis and arterial remodeling were evaluated at 2 h and 3, 7, 14, 21 and 28 days after angioplasty. RESULTS Cell proliferation and apoptosis profiles were similar, but the peak in cell proliferation occurred approximately four days earlier than the peak in apoptosis in the neointima and media. Apoptosis density was positively correlated with arterial remodeling in the neointima and media (r = 0.69, p = 0.005 and r = 0.50, p = 0.05, respectively). Moreover, residual stenosis was inversely correlated with apoptosis density in the neointima and media (r = -0.62, p = 0.008 and r = -0.52, p = 0.04, respectively). In contrast, cell proliferation was independent of restenosis and arterial remodeling. CONCLUSIONS In this model, cell proliferation preceded apoptosis throughout the four weeks after angioplasty. Apoptosis was inversely correlated with restenosis. Interestingly, apoptosis was also related to enlargement remodeling after balloon angioplasty.

We sought to evaluate frequency, characteristics, and outcomes of sudden cardiac arrest (SCA) during sports activities according to the location of occurrence (in sports facilities vs those occurring outside of sports facilities).This is an observational 5-year prospective national French survey of subjects 10 to 75 years old presenting with SCA during sports (2005-2010), in 60 French administrative regions (covering a population of 35 million people). Of the 820 SCA during sports, 426 SCAs (52%) occurred in sports facilities. Overall, a substantially higher survival rate at hospital discharge was observed among SCA in sports facilities (22.8%, 95% CI 18.8-26.8) compared to those occurring outside (8.0%, 95% CI 5.3-10.7) (P.0001). Patients with SCA in sports facilities were younger (42.1 vs 51.3 years, P.0001) and less frequently had known cardiovascular diseases (P.0001). The events were more often witnessed (99.8% vs 84.9%, 0.0001), and bystander cardiopulmonary resuscitation was more frequently initiated (35.4% vs 25.9%, P = .003). Delays of intervention were significantly shorter when SCA occurred in sports facilities (9.3 vs 13.6, P=0.03), and the proportion of initially shockable rhythm was higher (58.8% vs 33.1%, P.0001). Better survival in sports facilities was mainly explained by concomitant circumstances of occurrence (adjusted odds ratio 1.48, 95% CI 0.88-2.49, P = .134).Sports-related SCA is not a homogeneous entity. The 3-fold higher survival rate reported among sports-related SCA is mainly due to cases that occur in sports facilities, whereas SCA during sports occurring outside of sports facilities has the usual very low rate of survival.

Background— Although the benefits of automatic external defibrillators are undeniable, their effectiveness could be dramatically improved. One of the key issues is the disparity between the locations of automatic external defibrillators and sudden cardiac arrests (SCAs). Methods and Results— From emergency medical services and other Parisian agencies, data on all SCAs occurring in public places in Paris, France, were prospectively collected between 2000 and 2010 and recorded using 2020 grid areas. For each area, population density, population movements, and landmarks were analyzed. Of the 4176 SCAs, 1255 (30%) occurred in public areas, with a highly clustered distribution of SCAs, especially in areas containing major train stations (12% of SCAs in 0.75% of the Paris area). The association with population density was poor, with a nonsignificant increase in SCAs with population density ( P =0.4). Occurrence of public SCAs was, in contrast, highly associated with population movements ( P P P Conclusions— Using a systematic analysis of determinants of SCA in public places, we demonstrated the extent to which population movements influence SCA distribution. Our findings also suggested that beyond this key risk factor, some areas are dramatically associated with a higher risk of SCA.

Background In ischemic conditions, concentration of circulating nonesterified fatty acids (NEFA) is increased and has a proarrhythmic effect that is responsible for ventricular tachyarrhythmias. In nonischemic patients, high NEFA plasma concentration has been shown to be associated with frequent premature ventricular complexes and increased familial risk of cardiovascular disease, but its relation to sudden death has not been studied. We assessed the role of circulating NEFA in sudden death in asymptomatic men in a long-term cohort study. Methods and Results A total of 5250 men employed by the city of Paris, aged 42 to 53 in 1967 to 1972, free of known ischemic cardiac disease, and included in the Paris Prospective Study I, completed a second annual examination and had fasting plasma circulating NEFA measured. Each subject underwent a physical examination and ECG, provided blood for laboratory tests, and answered questionnaires administered by trained interviewers. Vital status was obtained for each subject from specific inquiries until he retired; after retirement, it was obtained from death certificates. Body mass index, systolic and diastolic blood pressures, tobacco consumption, parental history of sudden death, fasting cholesterol level, and circulating NEFA concentration were independent factors associated with sudden death during follow up (average, 22 years). When adjusted for confounding factors, circulating NEFA concentration remained an independent risk factor for sudden death (relative risk, 1.70; 95% confidence interval, 1.21 to 2.13) but not for fatal myocardial infarction. Conclusions Circulating NEFA concentration is an independent risk factor for sudden death in middle-aged men. Some form of primary prevention could be envisaged in subjects at high risk of sudden death.