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Left ventricular assist device (LVAD) implantation may be an attractive alternative therapeutic option for elderly patients with heart failure who are ineligible for heart transplantation.We aimed to describe the characteristics and outcomes of elderly patients (i.e. aged≥70 years) receiving an LVAD.This observational study was conducted in 19 centres between 2006 and 2016. Patients were divided into two groups-younger (aged70 years) and elderly (aged≥70 years), based on age at time of LVAD implantation.A total of 652 patients were included in the final analysis, and 74 patients (11.3%) were aged≥70 years at the time of LVAD implantation (maximal age 77.6 years). The proportion of elderly patients receiving an LVAD each year was constant, with a median of 10.6% (interquartile range 8.0-15.4%) per year, and all were implanted as destination therapy. Elderly and younger patients had similar durations of hospitalization in intensive care units and total lengths of hospital stays. Both age groups experienced similar rates of LVAD-related complications (i.e. stroke, bleeding, driveline infection and LVAD exchange), and the occurrence of LVAD complications did not impact survival in the elderly group compared with the younger group. Lastly, when compared with younger patients implanted as destination therapy, the elderly group also exhibited similar mid-term survival.This work strongly suggests that selected elderly adults can be scheduled for LVAD implantation.

OBJECTIVES Our goal was to provide a picture of left ventricular assist device (LVAD) activity in France between 2007 and 2016 based on the multicentric ASSIST-ICD registry. METHODS We retrospectively collected 136 variables including in-hospital data, follow-up survival rates and adverse events from 671 LVAD recipients at 20 out of 24 LVAD implant centres in France. The average follow-up time was 1.2 years (standard deviation: 1.4); the total follow-up time was 807.5 patient-years. RESULTS The included devices were the HeartMate II®, HeartWare LVAS® or Jarvik 2000®. The overall likelihood of being alive while on LVAD support or having a transplant (primary end point) at 1, 2, 3 and 5 years postimplantation was 65.2%, 59.7%, 55.9% and 47.7%, respectively, given a cumulative incidence of 29.2% of receiving a transplant at year 5. At implantation, 21.5% of patients were on extracorporeal life support. The overall rate of cardiogenic shock at implantation was 53%. The major complications were driveline infection (26.1%), pump pocket or cannula infection (12.6%), LVAD thrombosis (12.2%), ischaemic (12.8%) or haemorrhagic stroke (5.4%; all strokes 18.2%), non-cerebral haemorrhage (9.1%) and LVAD exchange (5.2%). The primary end point (survival) was stratified by age at surgery and by the type of device used, with inference from baseline profiles. The primary end point combined with an absence of complications (secondary end point) was also stratified by device type. CONCLUSIONS The ASSIST-ICD registry provides a real-life picture of LVAD use in 20 of the 24 implant centres in France. Despite older average age and a higher proportion of patients chosen for destination therapy, survival rates improved compared to those in previous national registry results. This LVAD registry contrasts with other international registries because patients with implants have more severe disease, and the national policy for graft attribution is distinct. We recommend referring patients for LVAD earlier and suggest a discussion of the optimal timing of a transplant for bridged patients (more dismal results after the second year of support?).

International audience; The impact of uncommon etiology cardiomyopathies on Left-ventricular assist device (LVAD)-recipient outcomes is not very well known. This study aimed to characterize patients with uncommon cardiomyopathy etiologies and examine the outcomes between uncommon and ischemic/idiopathic dilated cardiomyopathy. This observational study was conducted in 19 centers between 2006 and 2016. Baseline characteristics and outcomes of patients with uncommon etiology were compared to patients with idiopathic dilated/ischemic cardiomyopathies. Among 652 LVAD-recipients included, a total of 590 (90.5%) patients were classified as ischemic/idiopathic and 62 (9.5%) patients were classified in the "uncommon etiologies" group. Main uncommon etiologies were: hypertrophic (n = 12(19%)); cancer therapeutics-related cardiac dysfunction (CTRCD) (n = 12(19%)); myocarditis (n = 11(18%)); valvulopathy (n = 9(15%)) and others (n = 18(29%)). Patients with uncommon etiologies were significantly younger with more female and presented less co-morbidities. Additionally, patients with uncommon cardiomyopathies were less implanted as destination therapy compared with ischemic/idiopathic group (29% vs 38.8%). During a follow-up period of 9.1 months, both groups experienced similar survival. However, subgroup of hypertrophic/valvular cardiomyopathies and CTRCD had significantly higher mortality compared to the ischemic/idiopathic or myocarditis/others cardiomyopathies. Conversely, patients with myocarditis/others etiologies experienced a better survival. Indeed, the 12-months survival in the myocarditis/others; ischemic/idiopathic and hypertrophic/CTRCD/valvulopathy group were 77%; 65%, and 46% respectively. In conclusion, LVAD-recipients with hypertrophic cardiomyopathy, valvular heart disease and CTRCD experienced the higher mortality rate.

International audience; Objectives: To characterize the clinical presentation and outcomes of invasive mold infections (IMI) in solid organ transplant (SOT) recipients.Methods: Inclusion of all SOT recipients with IMI diagnosed between 2008 and 2016 at a referral center for SOT. Univariable analyses identified factors associated with death at one year, and logistic regression models retained independent predictors.Results: Of the 1739 patients that received a SOT during this period, 68 developed IMI (invasive aspergillosis [IA] in 58). Cumulative incidence of IMI at 1 year ranged from 1.2% to 18.8% (kidney and heart transplantation, respectively). At baseline, compared with other IMI, the need for vasoactive drugs was more frequent in patients with IA. During follow-up, 35 patients (51%) were admitted to the ICU and required mechanical ventilation (n = 27), vasoactive drugs (n = 31), or renal replacement therapy (n = 31). The need for vasoactive drugs (OR 7.34; P = .003) and a positive direct examination (OR 10.1; P = .004) were independently associated with the risk of death at 1 year in patients with IA (n = 33; 57%) CONCLUSIONS: Characteristics of IMI at presentation varied according to the underlying transplanted organ and the mold species. Following IA, one-year mortality may be predicted by the need for hemodynamic support and initial fungal load

Background Acute type A aortic dissection is one of the most hazardous acute vascular pathology. Purpose To investigate trends in the management of acute type A aortic dissections on the last 15 years. Methods All consecutive patients who were operated on for an acute type A aortic dissection at the CHU of Toulouse, France, between 2005 and 2019 were retrospectively included. We compared demographics, diagnostic methods and surgical techniques between 3 periods: 2005–2009, 2010–2014 and 2015–2019 ( Table 1 ). Results A total of 507 patients were included, mean age was 63 ± 12 years, 354 (70%) were male and 299 (59%) had hypertension. Demographics were similar across periods. About clinical presentation, the proportion of patients admitted to the operating room with cardiac arrest has increased between the 3 periods (12% vs 5% vs7%; P Fig. 1 ). Conclusion Over a 15-years period, the demographics of patients operated on for type A aortic dissection has not significantly changed. However, there is a trend towards the management of patients in a more life-threatening condition. Most of the shifts relate to surgical techniques, with a more proactive approach to the treatment of associated aortic regurgitation.

Background: Extracorporeal life support (ECLS) holds the promise of significant improvement of the survival of patient in refractory cardiogenic shock (CS) or cardiac arrest (CA). Nevertheless, it remains to be shown to which extent these highly invasive supportive techniques could improve long-term patient's outcome. Methods: The outcomes of 82 adult ECLS patients at our institution between January 2012 and December 2013 were retrospectively analyzed. Results: Patients were essentially men (64.7%) and are 54 years old. Preexisting ischemic (53.7%) and dilated cardiomyopathy (14.6%) were frequent. ECLS indications were shared equally between CA and CS. ECLS-specific adverse effects as hemorrhage (30%) and infection (50%) were frequent. ECLS was effective for 43 patients (54%) with recovery for 35 (43%), 5 (6%) heart transplant, and 3 (4%) left ventricular assist device support. Mortality rate at 30 days was 59.8%, but long-term and 3-month survival rates were similar of 31.7%. Initial plasma lactate levels >5.3 mmol/L and glomerular filtration rate

International audience; Background - Ventricular arrhythmias (VAs) can occur after continuous flow left ventricular assist device (LVAD) implantation as a single arrhythmic event or as electrical storm (ES) with multiple repetitive VA episodes. Objective - We aimed at analyzing the incidence, predictors, and clinical impact of ES in LVAD recipients. Methods - Patients analyzed were those included in the multicenter ASSIST-ICD observational study. ES was consensually defined as occurrence of ≥3 separate episodes of sustained VAs within a 24-hour interval. Results - Of 652 patients with an LVAD, 61 (9%) presented ES during a median follow-up period of 9.1 (interquartile range [IQR] 2.5-22.1) months. The first ES occurred after 17 (IQR 4.0-56.2) days post LVAD implantation, most of them during the first month after the device implantation (63%). The incidence then tended to decrease during the initial years of follow-up and increased again after the third year post LVAD implantation. History of VAs before LVAD implantation and heart failure duration > 84 months were independent predictors of ES. The occurrence of ES was associated with an increased early mortality since 20 patients (33%) died within the first 2 weeks of ES. Twenty-two patients (36.1%) presented at least 1 recurrence of ES, occurring 43.0 (IQR 8.0-69.0) days after the initial ES. Patients experiencing ES had a significantly lower 1-year survival rate than did those free from ES (log-rank, P = .039). Conclusion - There is a significant incidence of ES in patients with an LVAD. The short-term mortality after ES is high, and one-third of patients will die within 15 days. Whether radiofrequency ablation of arrhythmias improves outcomes would require further studies.

International audience; Background - Left ventricular assist device (LVAD)-associated infections may be life-threatening and impact patients' outcome. We aimed to identify the characteristics, risk factors, and prognosis of LVAD-associated infections. Methods - Patients included in the ASSIST-ICD study (19 centers) were enrolled. The main outcome was the occurrence of LVAD-associated infection (driveline infection, pocket infection, or pump/cannula infection) during follow-up. Results - Of the 652 patients enrolled, 201 (30.1%) presented a total of 248 LVAD infections diagnosed 6.5 months after implantation, including 171 (26.2%), 51 (7.8%), and 26 (4.0%) percutaneous driveline infection, pocket infection, or pump/cannula infection, respectively. Patients with infections were aged 58.7 years, and most received HeartMate II (82.1%) or HeartWare (13.4%). Most patients (62%) had implantable cardioverter-defibrillators (ICDs) before LVAD, and 104 (16.0%) had ICD implantation, extraction, or replacement after the LVAD surgery. Main pathogens found among the 248 infections were Staphylococcus aureus (n = 113' 45.4%), Enterobacteriaceae (n = 61; 24.6%), Pseudomonas aeruginosa (n = 34; 13.7%), coagulase-negative staphylococci (n = 13; 5.2%), and Candida species (n = 13; 5.2%). In multivariable analysis, HeartMate II (subhazard ratio, 1.56; 95% CI, 1.03 to 2.36; P = .031) and ICD-related procedures post-LVAD (subhazard ratio, 1.43; 95% CI, 1.03-1.98; P = .031) were significantly associated with LVAD infections. Infections had no detrimental impact on survival. Conclusions - Left ventricular assist device-associated infections affect one-third of LVAD recipients, mostly related to skin pathogens and gram-negative bacilli, with increased risk with HeartMate II as compared with HeartWare, and in patients who required ICD-related procedures post-LVAD. This is a plea to better select patients needing ICD implantation/replacement after LVAD implantation.

Background: Insulin-like Growth Factor Binding Protein 2 (IGFBP2) showed greater heart failure (HF) diagnostic accuracy than the "grey zone" B-type natriuretic peptides, and may have prognostic utility as well.Objectives: To determine if IGFBP2 provides independent information on cardiovascular mortality in HF.Methods: A retrospective study of 870 HF patients from 3 independent international cohorts. Presentation IGFBP2 plasma levels were measured by EUSA, and patients were followed from 1 year (Maastricht. Netherlands) to 6 years (Atlanta, GA, USA and Toulouse, France). Multivariate analysis, Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) were performed in the 3 cohorts. The primary outcome was cardiovascular mortality.Results: In multivariate Cox proportional hazards analysis, the highest quartile of IGFBP2 was associated with mortality in the Maastricht cohort (adjusted hazard ratio 1.69 (95% CI 1.18-2.41), p = 0.004) and in the combined Atlanta and Toulouse cohorts (adjusted hazard ratio 2.04 (95%CI, 13-3.3), p = 0.003). Adding IGFBP2 to a clinical model allowed a reclassification of adverse outcome risk in the Maastricht cohort (NRI - 18.7% p = 0.03; IDI - 3.9% p = 0.02) and with the Atlanta/Toulouse patients (NRI of 40.4% p = 0.01, 31,2% p = 0.04, 315% p = 0,02 and IDI of 2,9% p = 0,0005, 3.1% p = 0,0005 and 4,2%, p = 0.0005, fora follow-up of 1, 2 and 3 years, respectively).Conclusion: In 3 international cohorts, IGFBP2 level is a strong prognostic factor for cardiovascular mortality in HF, adding information to natriuretic monitoring and usual clinical markers, that should be further prospectively evaluated for patients optimized care. (C) 2019 Elsevier B.V. All rights reserved.

International audience; Objectives - This study aimed to evaluate the incidence, clinical impact, and predictors of late ventricular arrhythmias (VAs) in left ventricular assist device (LVAD) recipients aiming to clarify implantable cardioverter-defibrillator (ICD) indications. Background - The arrhythmic risk and need for ICD in patients implanted with an LVAD are not very well known. Methods - This observational study was conducted in 19 centers between 2006 and 2016. Late VAs were defined as sustained ventricular tachycardia or fibrillation occurring >30 days post-LVAD implantation, without acute reversible cause and requiring appropriate ICD therapy, external electrical shock, or medical therapy. Results - Among 659 LVAD recipients, 494 (median 58.9 years of age; mean left ventricular ejection fraction 20.7 ± 7.4%; 73.1% HeartMate II, 18.6% HeartWare, 8.3% Jarvik 2000) were discharged alive from hospital and included in the final analysis. Late VAs occurred in 133 (26.9%) patients. Multivariable analysis identified 6 independent predictors of late VAs: VAs before LVAD implantation, atrial fibrillation before LVAD implantation, idiopathic etiology of the cardiomyopathy, heart failure duration >12 months, early VAs (

Left ventricular assist devices (LVADs) require serial assessment of right and left ventricular (RV & LV) volumes and function. Because the RV is not assisted, its function is a critical determinant of the hemodynamic and contributes significantly to postoperative morbidity and mortality. We evaluated the feasibility and the accuracy of tomographic-equilibrium radionuclide ventriculography (t-ERV) for the assessment of patients with LVADs. Twenty-four patients with LVAD underwent t-ERV. Because of the limited acoustic window, transthoracic echocardiography (TTE) was only feasible in 19 patients. Functional evaluation including six-minute walk test (6MWT) and peak oxygen consumption (POC) was performed in 18 patients. Nine patients underwent a cardiac multidetector computed tomography (MDCT). Eight patients underwent a second evaluation by ERV 4.3 ± 1.4 months later. Reliability between t-ERV and MDCT for LV end-diastolic volume, LV end-systolic volume, LV ejection fraction, RV end-diastolic volume, RV end-systolic volume, and RV ejection fraction (RVEF) was 0.900 (P = .001), 0.911 (P = .001), 0.765 (P = .021), 0.728 (P = .042), 0.875 (P = .004), and 0.781 (P = .023), respectively. There was no correlation between t-ERV and RV systolic parameters assessed by TTE. RVEF was correlated with POC (R = 0.521; P = .027). A cut-off value of 40% for RVEF measured by t-ERV could discriminate patients with poor functional status (P = .048 for NYHA stage; P = .016 for 6MWT and P = .007 for POC). t-ERV is a simple, reproducible, and an accurate technique for the assessment of RV function in patients with LVADs and warrants consideration in the evaluation and monitoring of symptomatic patients.

International audience; Aims: This study explored the lateral crest structures of adult cardiomyocytes (CMs) within healthy and diseased cardiac tissue.Methods and results: Using high-resolution electron and atomic force microscopy, we performed an exhaustive quantitative analysis of the three-dimensional (3D) structure of the CM lateral surface in different cardiac compartments from various mammalian species (mouse, rat, cow, and human) and determined the technical pitfalls that limit its observation. Although crests were observed in nearly all CMs from all heart compartments in all species, we showed that their heights, dictated by the subsarcolemmal mitochondria number, substantially differ between compartments from one species to another and tightly correlate with the sarcomere length. Differences in crest heights also exist between species; for example, the similar cardiac compartments in cows and humans exhibit higher crests than rodents. Unexpectedly, we found that lateral surface crests establish tight junctional contacts with crests from neighbouring CMs. Consistently, super-resolution SIM or STED-based immunofluorescence imaging of the cardiac tissue revealed intermittent claudin-5-claudin-5 interactions in trans via their extracellular part and crossing the basement membrane. Finally, we found a loss of crest structures and crest–crest contacts in diseased human CMs and in an experimental mouse model of left ventricle barometric overload.Conclusion: Overall, these results provide the first evidence for the existence of differential CM surface crests in the cardiac tissue as well as the existence of CM–CM direct physical contacts at their lateral face through crest–crest interactions. We propose a model in which this specific 3D organization of the CM lateral membrane ensures the myofibril/myofiber alignment and the overall cardiac tissue cohesion. A potential role in the control of sarcomere relaxation and of diastolic ventricular dysfunction is also discussed. Whether the loss of CM surface crests constitutes an initial and common event leading to the CM degeneration and the setting of heart failure will need further investigation.

International audience; Background: We have been intrigued by the observation that aortic stenosis (AS) may be associated with characteristic features of mitral drug-induced valvular heart disease (DI-VHD) in patients exposed to valvulopathic drugs, thus suggesting that beyond restrictive heart valve regurgitation, valvulopathic drugs may be involved in the pathogenesis of AS. Methods: Herein are reported echocardiographic features, and pathological findings encountered in a series of patients suffering from both AS (mean gradient > 15 mm Hg) and mitral DI-VHD after valvulopathic drugs exposure. History of rheumatic fever, chest radiation therapy, systemic disease or bicuspid aortic valve disease were exclusion criteria. Results: Twenty-five (19 females, mean age 62 years) patients having both AS and typical features of mitral DI-VHD were identified. Mean transaortic pressure gradient was 32+/-13 mm Hg. Aortic regurgitation was >= mild in 24 (96%) but trivial in one. Known history of aortic valve regurgitation following drug initiation prior the development of AS was previously diagnosed in 17 patients (68%). Six patients underwent aortic valve replacement and 3 both aortic and mitral valve replacement. In the 9 patients with pathology analysis, aortic valvular endocardium was markedly thickened by dense non-inflammatory fibrosis, a characteristic feature of DI-VHD. Conclusion: The association between AS and typical mitral DI-VHD after valvulopathic drug exposure may not be fortuitous. Aortic regurgitation was usually associated to AS and preceded AS in most cases but may be lacking. Pathology demonstrated the potential role of valvulopathic drugs in the development of AS. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Objectives The right ventricular failure (RVF) is a severe complication after implantation of a left ventricular assist device (LVAD), difficult to predict and treat. The purpose of this study was to identify risk factors of RVF after mechanical circulatory support. Methods This is a single-center prospective cohort of patients with long-term electrical intracorporeal continuous flow LVAD type HeartMate II between January 2008 and September 2014. We searched predictors of RVF, defined by a need of inhaled nitric oxide ≥48 hours and / or intravenous inotropes ≥14 days. Results 42 devices were implanted in 36 men and 6 women with a mean age of 57.3 years, for 30 ischemic and 12 primitive cardiomyopathies, 10 cases in “Destination Therapy” and 32 cases in “Bridge-to-Transplantation.” The 30-day mortality was 6 patients, 1-year survival of 84%, the mean last of intubation was 7 days and ICU stay of 16.3 days. There were 16 cases of RVF (38.1%). The significantly associated factors (p 2 ), capillary (26.3 versus 18.3mmHg) and mean pulmonary arterial pressures (38.7 versus 27.2mmHg), transpulmonary gradient (14 versus 8.5mmHg), pulmonary arterial resistances (3.7 versus 2.7 UW), right ventricular (26 versus 8.1mmHg) and atrial pressures (11 versus 5.5mmHg), bilirubin (28.3 versus 15.7 µmol/l), INTERMACS score (3.3 versus 4.4), non-ischemic etiologies (50 versus 85%) and preoperative inotropic drugs (56 versus 15%). Conclusion RVF remains a major complication in implantable LVAD. According to the literature, preoperative pulmonary hypertension, right systolic dysfunction and cavitary dilation seem to favor its appearance.

Stent graft has resulted in major advances in the treatment of trauma patients with blunt traumatic aortic injury (TAI) and has become the preferred method of treatment at many trauma centers. In this review, we provide an overview of the place of stent grafts for the management of this disease. As a whole, TEVAR repair of TAIs offers a survival advantage and reduction in major morbidity, including paraplegia, compared with open surgery. However, endovascular procedures in trauma require a sophisticated multidisciplinary and experienced team approach. More research and development of TAI-specific endograft devices is needed and large, multicenter studies will help to clarify the role of TEVAR compared with open repair of TAI.

Points essentiels Le syndrome aortique aigu (SAA) regroupe differentes entites pouvant potentiellement mettre en jeu la survie des patients. Le syndrome aortique aigu regroupe les hematomes de paroi, les ulceres de l’aorte et les dissections aortiques. Les progres de l’imagerie et des techniques endovasculaires permettent une meilleure prise en charge de cette maladie. La place actuelle des stent-grafts pour la prise en charge des SAA se definit sur la base des donnees de la litterature la plus recente.

We report the first case of percutaneous radio-frequency (RF) ablation procedure in a patient implanted with a HeartMate II left ventricular assist device for refractory heart failure. This procedure was performed for poorly tolerated recurrent atrial arrhythmias. No harmful consequence happened during or after the procedure despite the potential electromagnetic interferences existing between the RF delivery and the functioning of the device.

With the shortage of grafts, mechanical circulatory support has emerged as an alternative to heart transplantation. But one of the main disadvantages is the percutaneous source of energy that exposes to the risk of infection. We studied driveline infections occurred in a single-center prospective cohort of patients with long-term intracorporeal and continuous-flow left assist device type HeartMate II, between January 2008 and January 2014. Among the 34 devices implanted, we identified 9 cases of infection of the power cable (26.5%). The diagnosis was defined by the combination of a positive bacteriological sample with local inflammatory signs, ranging from skin redness to frank pus. The germs found included: 5 aureus staphylococci, 3 white staphylococci, 3 gram-negative bacilli including a pseudomonas aeruginosa, and a citrobacter. The median time to onset of infection was 15 months, ranging from 3 weeks to 2.5 years after implantation. Associated factors were: surgical re-opening, prolonged ICU stay, acute renal failure, the existence of a concomitant infection, malnutrition, duration of assistance and dressing changes at home. The treatment was based on a broad-spectrum antibiotics, secondarily adapted to the antibiogram and long lasting. Among these patients, two were transplanted, including one in the context of a Type 2 Super Emergency, two others died of a non-infectious cause, one patient is now cured and four are still carrying a chronic related-device infection. The management of end-stage heart failure has improved thanks to our growing experience in the field of long-term assistance, but the driveline infection is a major complication. It greatly affects the quality of life of the patients and transplantation may be the only prospect of recovery.

Objective The study's objective was to comparatively evaluate surgery and stent-graft repair of acute or subacute traumatic aortic rupture. Methods A total of 76 patients (14–76 years old; mean, 37 years; male/female ratio, 63/11) with a traumatic aortic injury were admitted to our hospital between 1981 and 2003. Six patients died within 1 to 9 days of another associated severe traumatic lesion. The 70 remaining patients were divided according to the type of rupture repair. In group 1, 35 patients were treated surgically: 28 with immediate repair and 7 with delayed repair (average time interval 66 days, 5–257 days). In group 2, 29 patients were treated with stent grafting of the aortic isthmus. In group 3, 6 patients with minor aortic lesions were treated medically with a close follow-up. Results In the 28 patients treated surgically in the emergency department, the mortality and paraplegia rates were 21% and 7%, respectively. No death or paraplegia was observed in the group with delayed surgical repair. With stent grafting, complete exclusion of the pseudoaneurysmal sac was observed in all patients. Except for 1 iliac rupture treated during the same procedure, there was no major morbidity or mortality during the mean follow-up of 46 months (13–90 months). No major complication was observed in group 3. Conclusions In stable rupture of the aorta, initial conservative treatment is safe and allows management of the major associated lesions. Stent grafting of the aortic isthmus is a valuable therapeutic alternative to surgical repair, especially in patients considered high risk for conventional thoracotomy.

Graft vascular disease (GVD) remains the major limitation to long-term survival after solid organ transplantation. Aortic or carotid allografts in rats have been shown to be useful models because similar changes to those observed in man develop within weeks. Both immunological and non-immunological factors influence the process of GVD and a method that could permit rapid multiple arterial allotransplantation in the rat would be of great value. We performed simultaneous orthotopic aortic and carotid allotransplantations in 25 rats. The vessels were anastomosed using a sleeve technique. No immunosuppression was given. The animals were killed at 15, 30, or 60 days and histological analyses of the grafts were performed. The overall survival rate was 80% and the incidence of technical failure was very low. The histopathological aspect revealed typical progressive GVD. In conclusion, we have developed a new model of simultaneous aortic and carotid transplantation in rats. This model, which incorporates a modification of the sleeve anastomosis, is rapid and yields an easy tool to investigate immunological and non-immunological processes driving GVD.

International audience; Diabetic cardiomyopathy is a secondary complication of diabetes with an unclear etiology. Based on a functional genomic evaluation of obesity-associated cardiac gene expression, we previously identified and cloned the gene encoding apolipoprotein O (APOO), which is overexpressed in hearts from diabetic patients. Here, we generated APOO-Tg mice, transgenic mouse lines that expresses physiological levels of human APOO in heart tissue. APOO-Tg mice fed a high-fat diet exhibited depressed ventricular function with reduced fractional shortening and ejection fraction, and myocardial sections from APOO-Tg mice revealed mitochondrial degenerative changes. In vivo fluorescent labeling and subcellular fractionation revealed that APOO localizes with mitochondria. Furthermore, APOO enhanced mitochondrial uncoupling and respiration, both of which were reduced by deletion of the N-terminus and by targeted knockdown of APOO. Consequently, fatty acid metabolism and ROS production were enhanced, leading to increased AMPK phosphorylation and Ppara and Pgc1a expression. Finally, we demonstrated that the APOO-induced cascade of events generates a mitochondrial metabolic sink whereby accumulation of lipotoxic byproducts leads to lipoapoptosis, loss of cardiac cells, and cardiomyopathy, mimicking the diabetic heart-associated metabolic phenotypes. Our data suggest that APOO represents a link between impaired mitochondrial function and cardiomyopathy onset, and targeting APOO-dependent metabolic remodeling has potential as a strategy to adjust heart metabolism and protect the myocardium from impaired contractility.

Background Graft arteriosclerosis is a major cause of death after allotransplantation of organs such as the heart or the kidney. Aortic allotransplantation in mice is a useful experimental model to study the mechanisms of this pathology. However, the conventional heterotopic aortic model is limited by a high morbidity and is technically difficult to perform. We developed a new simple method for aortic transplantation in mice. Methods The infrarenal aorta from the donor mouse was anastomosed to the recipient’s aorta at the same position using a sleeve technique. Orthotopic aortic transplantation was performed in 45 mice, 5 isografts and 40 allografts. No immunosuppression was given, and the mice were killed at day 15 or 30. The graft was examined macroscopically, and several histologic sections were made. Results The overall survival rate was 78%. The incidence of thrombosis was low (4 cases) compared with previously published series. Histology of aortas revealed typical aspects of rejection in the allografts with a chronic picture at day 30. No significant lesion was observed in isografts. Conclusions We have developed a model of orthotopic aortic transplantation in mice. This new model is easy to carry out and has a low incidence of thrombosis, probably because there is no size discrepancy between donor and recipient aortic segment.

The heterotopic heart of rats has been a useful model in the evaluation of immunomodulatory protocols. Graft palpation usually determines the day of rejection. We present in this paper an original method of graft monitoring in allograft rejection.Heterotopic cardiac abdominal transplantation was performed in Lewis isografts (n = 15) and in ACI to Lewis allograft (n = 15). A balloon connected to a measurement device was inserted in the left ventricle, and calculation of Dp/Dtmax was possible by recording the intra-left ventricular pressure. A ten-day follow-up was achieved with a daily comparison of palaption, ECG, and Dp/Dtmax.In transplanted hearts, Dp/Dtmax did not change in isografts but significantly decreased in allograft on posttransplantation Day 5 (PTD 5) vs PTD 0.1 and 3 (p.01). Dp/Dtmax values on PTD 5 and 6 were also statistically significant in allograft vs isograft group (p.01). Histological analysis at this time showed the occurrence of acute rejection in the allograft group. Graft palpation, and ECG remained normal until PTD 10 and no difference was observed between iso and allo groups.This study shows that daily measurement of Dp/Dtmax in heterotopic heart is made possible by our implantable system without interrupting the graft, and gives a more accurate definition of graft rejection than a combination of palpation and ECG. In addition, this method would seem desirable when differences in survival may be expected to be of lesser magnitude.

A 70-year-old patient presented a large saccular aneurysm involving the whole aortic arch. Because of a past history of left thoracotomy and a high co-morbidity profile, we opted for a combined strategy, consisting of an extra-anatomic bypass of the supra-aortic vessels, followed by the endovascular implantation of a covered thoracic stent-graft. Endovascular stent grafting of aortic arch aneurysm, after extra anatomic bypass of supra-aortic vessels, appears as an attractive alternative strategy for high surgical risk patients.

About 77.9 million (1 in 4) American adults have high blood pressure. High blood pressure is the primary cause of left ventricular hypertrophy (LVH), which represents a strong predictor of future heart failure and cardiovascular mortality. Previous studies have shown an altered metabolic profile in hypertensive patients with LVH. The goal of this study was to identify blood metabolomic LVH biomarkers by 1H NMR to provide novel diagnostic tools for rapid LVH detection in populations of hypertensive individuals. This cross-sectional study included 48 hypertensive patients with LVH matched with 48 hypertensive patients with normal LV size, and 24 healthy controls. Two-dimensional targeted M-mode echocardiography was performed to measure left ventricular mass index. Partial least squares discriminant analysis was used for the multivariate analysis of the 1H NMR spectral data. From the 1H NMR-based metabolomic profiling, signals coming from methylene (–CH2–) and methyl (–CH3) moieties of aliphatic chains from plasma lipids were identified as discriminant variables. The –CH2–/–CH3 ratio, an indicator of the mean length of the aliphatic lipid chains, was significantly higher (P

s S163 Multivariate analysis model of maximum likelihood estimates Covariate Hazard Ratio 95% Confidence

Acute aortic syndrome (AAS) describes several life threatening aortic pathologies. Acute aortic syndrome include intramural haematoma, penetrating aortic ulcer and acute aortic dissection. Advances in both imaging and endovascular treatment has led to an increase in diagnosis and improved management of these often catastrophic pathologies. The current place of stent-grafts for the AAS management is defined on the basis of the most recent literature.

Objective We sought to determine the midterm results of endovascular repair of atherosclerotic aneurysms of the thoracic descending aorta by using second-generation, commercially available stent grafts. Methods Between 1996 and 2005, 45 patients (mean age, 68 ± 11 years) with aneurysms of the descending thoracic aorta underwent endovascular repair. Aortic dissections, penetrating ulcers, and traumatisms were excluded. The mean follow-up was 24.7 ± 21.6 months (maximum, 6.7 years). Results No patients died, and no conversion to surgical intervention was required during the procedures. Three (6.7%) patients died during the first month, and 6 (14.7%) died later on. The main complications were strokes (13.3%), vascular access complications (8.9%), aortic complications (6.6%), paraplegia (4.4%), and sudden deaths (4.4%). Nineteen (42%) primary endoleaks were encountered: 3 required reinterventions, 15 spontaneously thrombosed, and 1 patient died. Except for 2 sudden unexplained deaths, no aortic complications were observed after 1 month. Actuarial survival estimates at 1, 3, and 5 years were 87.6% ± 5.3%, 76.9% ± 7.4%, and 70.6% ± 9.2%, respectively. Actuarial freedom from death related to the treated aortic disease was 94.3% ± 4.0%, 94.3% ± 4.0%, and 86.4% ± 8.4% at 1, 3, and 5 years, respectively. Aspirin status of greater than 3 ( P = .005), high aortic diameter ( P = .007), and long covered lengths ( P = .02) were determinant for mortality. Actuarial freedom from complication was 62.6% ± 7.7%, 58.9% ± 8.1%, and 58.9% ± 8.1% at 1, 3, and 5 years, respectively. The location of the aneurysm ( P = .05) and a high aortic diameter ( P = .04) were both determinants for endoleaks. Conclusions Stent grafting of atherosclerotic aneurysm of the thoracic descending aorta is safe and effective. Further studies are mandatory to determine the most relevant indications and the long-term efficacy of such treatment.

Background Chronic vascular rejection (CVR) is a major problem in clinical transplantation. Studies in experimental animals have been important to understand some of its mechanisms, but they are hampered by the difficulty of extrapolating the results into clinical practice. Methods We created a new experimental model for the study of human CVR by grafting multiple human mesenteric arteries from the same human donor into different SCID/beige mice in the infrarenal aortic position. Twenty-seven different mice were successfully grafted with a human artery from 6 donors. One week later, 23 of the mice received an intraperitoneal injection of 40 million human spleen cells, either from the same donor (autologous) or from another donor (allogeneic). Results In 81% of the mice an immune reconstitution was obtained, shown by the presence of human T, B and NK cells and IgG in circulating blood. At the time of sacrifice, 5 weeks after the arterial transplantation, a typical CVR with infiltration of human immune cells and deposit of human immunoglobulin was observed in the reconstituted mice that received allogeneic cells, whereas only minor lesions were noted in autologous combinations. No CVR was observed without injection of human splenocytes. We did not observe lymphoma or graft-vs-host reactions during the experiment. Conclusions We show that it is feasible to graft multiple human arteries from the same donor into SCID/beige mice, and that a specific and typical CVR is observed after reconstitution with allogeneic spleen cells. Our method allows for pre-clinical testing of new therapeutics in controlled series.

Background We developed an original experimental model to study chronic vascular rejection (CVR) consisting of a graft of human mesenteric artery followed by human immune reconstitution into CB.17 SCID/Beige mice. Human immune reconstitution achieved after human PBMC injection has often been variable and incomplete. The aim of this work was to develop an alternative method to achieve a complete, functional human immune reconstitution. Method After institutional authorizations, spleen cells were recovered from cadaveric organ donors. Single intraperitoneal injections of various doses of spleen cells were made into 70 CB.17 SCID/Beige mice. Reconstitution of the human immune system was monitored by flow cytometry (circulating human cells) and ELISA (human IgG). Colonization of murine lymphoid organs by human cells was studied by immunohistochemistry and flow cytometry. Evaluation of the immune function consisted of examination of CVR lesions in human arterial grafts. The animals were humanely killed at day 28. Results After injection of 30 to 40 × 106 spleen cells, the mice showed significant human CD3+, CD19+, and CD56+ populations in peripheral blood. The mean human cells levels were, respectively, 8.2% ± 5.4%, 2.9% ± 1.2%, and 5.3% ± 5.1%. Murine spleen and mesenteric lymph nodes were colonized by human T and B cells, while the murine thymus was only colonized by human T cells. Human IgG was detected in murine serum (65.9 ± 63.3 mg/L) and typical CVR lesions were observed within the allogeneic grafts. Conclusion Intraperitoneal injection of 30 to 40 × 106 human spleen cells into CB.17 SCID/Beige mice induces complete and functional human immune reconstitution allowing the study of CVR under human allogeneic conditions.

We wanted to establish a preclinical model of chronic vascular rejection (CVR) by transplanting small arteries from the mesentery of cadaveric organ donors by the rapid "sleeve" technique into SCID/beige mice reconstituted with human allogeneic spleen cells. After institutional authorization and with informed consent from relatives, we obtained tissues and cells from cadaveric organ donors. A piece of mesentery was recovered from the donor and kept in buffered solution at 4 degrees C until use. After dissection of the mesentery, small arteries of suitable size were transplanted in place of the infrarenal aorta of the mice. Cells for the immunological reconstitution of the mice were spleen cells from the same or other organ donors. Twenty-three suitable arterial segments were obtained from the mesentery of three cadaveric donors. Ten of the mice received 3 x 10(7) human spleen cells intraperitoneally 1 week after the arterial graft and they all showed circulating human CD3+ and CD19+ cells 2 weeks after injection. The mice were sacrificed 5 weeks after the arterial graft. SCID/beige mice reconstituted with allogeneic spleen cells showed a typical CVR, whereas mice that received no cells had a normal vascular anatomy. We believe our model is well suited for the study of treatment of CVR under human allograft conditions.

Ehlers-Danlos syndrome (EDS) is a rare inherited disorder of connective tissue characterized by hyperextensible skin, hypermobile joints, and abnormalities of the cardiovascular system. Most patients are unaware of their disease until a catastrophic event such as arterial rupture or bowel perforation occurs. Aortic disruption accounts for many of the deaths in EDS type IV cases and only two cases of survival after spontaneous aortic rupture have previously been reported. We report on a third case of a survivor of spontaneous abdominal aortic rupture in EDS type IV.

Failure to control chronic graft dysfunction [e.g. graft vascular disease (GVD)] is the primary cause of immunologic graft failure. This is the first study of mycophenolate mofetil (MMF) for the treatment of GVD in non-human primate recipients of aortic allografts. Abdominal aortic allografts were exchanged between mixed leukocyte reaction (MLR) -mismatched, blood-group-compatible cynomolgus monkeys. Six control recipients were untreated. Individualized treatment with frequent dose adjustments of MMF insured that treatment was close to the maximum tolerated dose (mean 99.2 mg/kg/day). Immune-mediated injury proceeded unhindered until day 45, after which MMF treatment began. Changes in intimal volume (IV) were quantified by intravascular ultrasound (IVUS) and compared to histology on day 105. Serial IVUS measurements of IV (mm(3)) in controls showed progressive GVD. In four out of six animals, MMF was well tolerated, thus enabling optimum treatment; in all these animals, IV was significantly less than in the control animals (p = 0.02). In the two remaining animals, high doses were not tolerated; at day 105, there was no significant difference in IV between them and the controls. We found a significant correlation between the mean MMF tolerated dose and the inhibition of progression of IV (r = -0.88, p = 0.015). When high MMF doses were tolerated, MMF slowed progression of GVD.

Background: FK778, a malononitrilamide analog of leflunomide, is currently being investigated for use in clinical transplantation. Methods: Whole blood from cynomolgus monkeys (n=4) and healthy human volunteers (n=4) was incubated with different concentrations of FK778 and stimulated with mitogens in culture medium. Lymphocyte proliferation was assessed by tritium-labeled thymidine incorporation and by flow-cytometric analysis of expression of proliferating cell nuclear antigen on cells in S/G2M phase. Flow cytometry was also used to assess expression of T and B lymphocyte activation surface antigens and production of intracellular cytokines by T cells. Results: Not only lymphocyte proliferation, but also expression of various T cell surface antigens (CD25, CD11a, CD95, CD154) was suppressed by FK778. Fifty percent effective concentration values for the different immune functions were lower in human blood than in blood from cynomolgus monkeys. Conclusions: FK778 inhibits multiple immune functions. Their flow cytometric evaluation can be used to assess the effects of the drug in vivo.

Background— Delayed treatment with sirolimus (SRL) halts progression of graft vascular disease (GVD) in nonhuman primate (NHP) aortic allograft recipients. In this study, we investigated whether SRL monotherapy prevents the development of GVD. Methods and Results— Pairs of 3-cm infrarenal aortic segments were exchanged between mixed lymphocyte reaction–mismatched, blood group–compatible NHPs (n=12). Six NHPs were untreated controls, and 6 were treated orally with SRL starting on the day of transplantation. Follow-up was 105 days. SRL doses were adjusted individually by assessing SRL blood concentrations, immune function, and clinical status. The severity of GVD was determined every 3 weeks by intravascular ultrasound, which quantified intimal area (IA) and intimal volume (IV) for the middle 1-cm graft segments. The mean±SEM SRL plasma levels were 14.5±9 ng/mL. In grafts from treated NHPs, IA and IV values on days 63, 84, and 105 were significantly lower than for controls ( P P 2 , P 3 , P Conclusions— We show that SRL monotherapy prevented GVD in NHP aortic allograft recipients, suggesting the value of SRL for controlling GVD in clinical transplantation.

A-285222 (A-285) is a bis-trifluoromethyl-pyrazole (BTP), a novel class of immunosuppressive agents that inhibit NFAT activity in vitro in human and non-human primate cells through a calcineurin-independent mechanism. In this preliminary study, we treated cynomolgus monkeys with different doses of A-285 for several days. Blood was collected from all animals at different times during the study. From these samples, plasma concentrations of A-285 were measured by liquid chromatography/mass spectrometry (LC/MS), and intracellular T-cell production of the cytokines IL-2, IFN-gamma, and TNF-alpha was quantified by flow cytometry using a mitogen-stimulated whole blood assay. Marked inhibition of cytokine production occurred after administration of the first dose of A-285, and this effect was comparable to that of cyclosporine. While neurological toxic side effects were seen when the plasma concentration of A-285 exceeded 4 microg/ml, at lower plasma levels the drug was well tolerated over 2 weeks and its pharmacodynamic effects were sustained throughout this time.

Failure to control chronic graft dysfunction (eg, graft vascular disease (GVD)) is the primary cause of graft failure. We have shown in rats that mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), inhibits: 1) smooth muscle proliferation in vitro, 2) intimal thickening in arterial and heart transplants and 3) neointima formation after balloon catheter injury in native arteries. We now report the first study of MMF for the treatment of GVD in nonhuman primates. MethodsAortic allografts were exchanged between MLR mismatched, blood group compatible cynomolgus monkeys. 6 control animals received no immunosuppression, 6 animals were treated with MMF from day 45 after transplantation on in an individual maximal tolerated dose (mean 99.2 mg/kg/day). Until day 45 the animals did not receive any immunosuppressive treatment. The progression of GVD was quantified by IVUS as changes in intimal volume (IV) in the midsegments of all grafts every 3 weeks until day 105 when the animals were euthanized and the grafts have been harvested for histopathological analysis. Pharmacokinetik and pharmacodynamic monitoring was used to optimize the immunosuppressive efficacy. ResultIn serial IVUS measurements IV progressed after day 42 from 25 ± 1 to 44 ± 4 on day 63 to 52 ± 4 on day 84 to 55 ± 3mm2 on day 105 in the control versus 25 ± 4, 40 ± 7, 43 ± 7 and 47 ± 7 mm2 in the treatment group (p = 0.3). Also the difference in IA failed to be significant overall between control and treatment group, there was a significant correlation between mean MMF dose and IA (r = − 0.88, P = 0.01): In four out of 6 animals no dose reduction due to toxicity was necessary and in all these animals IA was lower than in the control animals. In two animals with MMF toxicity and dose reduction, high IA was observed. ConclusionsIn this demanding model evaluating advanced graft vascular disease in non-human primates MMF was able to halt GVD when given in a high maximal tolerated dose. In case of toxicity and individual necessary dose reduction, progress of GVD was not altered.

ISA247 is a novel cyclosporine analog. In this study we compare, in vitro, the effects of ISA247 on immune function with those of cyclosporine. Whole blood from cynomolgus monkeys (n = 5) was incubated with different concentrations of ISA247 or cyclosporine and stimulated with different mitogens in culture medium. Lymphocyte proliferation was assessed by [3H]-TdR incorporation assay and by flow cytometry. Flow cytometry was also used to assess production of intracellular cytokines by T cells and expression of T cell activation surface antigens. The concentration of drug necessary to attain 50% of the maximum effect (EC50) was subsequently calculated. EC50 values for ISA247 were lower than for cyclosporine, and the differences were statistically significant for lymphocyte proliferation, T cell cytokine production, and expression of all T cell activation surface antigens but one. We conclude that ISA247 suppresses diverse immune functions more potently than cyclosporine in vitro.

The malononitrilamide FK778 is a leflunomide analogue with a shorter half-life than leflunomide. Groups of cynomolgus monkeys were treated orally with various doses of FK778 once daily for 7 days: group A, 10 mg/kg ( n=4); group B, 5 mg/kg ( n=3); and group C, one single loading dose of 20 mg/kg followed by 5 mg/kg once daily ( n=2). Trough plasma concentration of FK778 was measured by HPLC. Lymphocyte proliferation and expression of T-cell activation surface antigens were assessed by flow cytometry. In group A, trough plasma concentration of FK778 reached steady state at 48 h. After 7 days, lymphocyte proliferation was 23+/-7.4% (mean +/- SEM) and expression of CD71, CD25, CD11a and CD95 on T cells was less than 50% of pre-treatment baseline values. In group B, trough plasma levels of FK778 did not reach steady state, but dropped to near-zero levels after 3 days and on day 7 and lymphocyte proliferation and T-cell surface antigen expression were not different from pre-treatment baseline values. In group C, FK778 trough levels did not reach steady state, but drug exposure was evident over the entire period of treatment, and on day 7, lymphocyte proliferation was 11.4+/-8.6% of pre-treatment baseline values. We conclude that FK778 inhibits lymphocyte proliferation and expression of T-cell activation antigens in vivo in non-human primates after 1 week of treatment. These effects are related to the total drug exposure over the time of treatment. At doses lower than 10 mg/kg daily, FK778 is cleared from the circulation between the dosing intervals, thus failing to exert its inhibitory effects on immune functions.

We tested the hypothesis that sustained suppression of immune functions by mycophenolate mofetil (MMF) throughout the dosing interval reduces the severity of rejection.Four groups of rat heart allograft recipients were treated orally daily through Day 5 with either: "low-dose" MMF, 10 mg/kg once daily (QD) or 5 mg/kg twice daily (BID); or "high-dose" MMF, 20 mg/kg QD or 10 mg/kg BID. The following were determined for all animals on Day 6: pharmacokinetics (PK, using high-performance liquid chromatography) of mycophenolic acid (MPA); pharmacodynamics (PD, by flow cytometry quantitation of whole blood mitogen-stimulated lymphocyte proliferation and expression of diverse T-cell surface activation molecules); and histologic graft rejection scores (RS).RS correlated with PD for suppression of both lymphocyte proliferation and transferrin receptor expression (r2 = 0.85 and 0.81, respectively) more highly than with MPA plasma levels (r2 = 0.45), which shows the validity of PD as surrogate markers of MMF efficacy. MMF 5 mg/kg BID produced greater (p0.001) suppression of lymphocyte proliferation (area under the PD effect-time curve, AUE = 2,010% inhibition. hour) and sustained trough (E0) PD effect (86% suppression) than MMF 10 mg/kg QD (AUE = 1,436% inhibition. hour, E0 = 55%). RS did not differ between the 20 mg/kg QD and 10 mg/kg BID "high-dose" groups, because PD was maximally suppressed.PD were surrogate markers for MMF immunosuppressive efficacy. MMF 5 mg/kg BID produced more sustained suppression of both PD and rejection than MMF 10 mg/kg QD.