Initiation and development of a percutaneous left atrial appendage closure programme: A French centre's experience and literature review.

BACKGROUND: Percutaneous left atrial appendage closure may be considered in selected patients with atrial fibrillation at significant risk of both thromboembolism and haemorrhage. AIMS: To report the experience of a tertiary French centre in percutaneous left atrial appendage closure and to discuss the outcomes compared with previously published series. METHODS: This was a retrospective observational cohort study of all patients referred for percutaneous left atrial appendage closure between 2014 and 2020. Patient characteristics, procedural management and outcomes were reported, and the incidence of thromboembolic and bleeding events during follow-up were compared with historical incidence rates. RESULTS: Overall, 207 patients had left atrial appendage closure (mean age 75.3±8.6 years; 68% men; CHA2DS2-VASc score 4.8±1.5 ; HAS-BLED score 3.3±1.1), with a 97.6% (n=202) success rate. Twenty (9.7%) patients had at least one significant periprocedural complication, including six (2.9%) tamponades and three (1.4%) thromboembolisms. Periprocedural complication rates decreased from earlier to more recent periods (from 13% before 2018 to 5.9% after; P=0.07). During a mean follow-up of 23.1±20.2 months, 11 thromboembolic events were observed (2.8% per patient-year), a 72% risk reduction compared with the estimated theoretical annual risk. Conversely, 21 (10%) patients experienced bleeding during follow-up, with almost half of the events occurring during the first 3 months. After the first 3 months, the risk of major bleeding was 4.0% per patient-year, a 31% risk reduction compared with the expected estimated risk. CONCLUSION: This real-world evaluation emphasizes the feasibility and benefit of left atrial appendage closure, but also illustrates the need for multidisciplinary expertise to initiate and develop this activity.

Efficacy and Safety of Direct Oral Anticoagulants in Kidney Transplantation: A Single-center Pilot Experience.

BACKGROUND: Oral anticoagulation therapy is frequently prescribed to kidney transplant recipients (KTRs) for prevention and treatment of thrombotic events. Over the past 10 y, direct oral anticoagulants (DOACs) have shown similar efficacy with a safety profile equal or superior to that of vitamin K antagonist anticoagulants (VKAs) in the general population. However, little data are available on kidney transplantation. METHODS: We investigated the efficacy (thrombotic events) and safety (hemorrhagic and other adverse events and graft outcomes) of DOACs in a cohort of KTRs with a renal function >30 mL/min. We then compared these patients to a control group treated by VKA. RESULTS: Fifty-two KTRs treated by DOACs between 2013 and 2018 at Necker Hospital were included. Patients were with a mean age of 62 ± 13 y old and a mean glomerular filtration rate of 59 ± 20 mL/min/1.73m. The major indication was atrial fibrillation (n = 31 [60%]). Apixaban was the most commonly used agent (n = 36 [69%]). No thrombotic complications were reported under DOAC until last follow-up (14.1 ± 13 mo). In comparison to 50 controls under VKA during the same period, the bleeding rate under DOAC was significantly lower (11.5 versus 22.9 per 100 patient-y, P = 0.037) with a hazard ratio of 0.39 (95% confidence interval, 0.19-0.85, P = 0.041). No significant changes in kidney function, rejection rate, or hemoglobin level were reported. CONCLUSIONS: DOACs appear to be effective and safe anticoagulants in KTRs with stable renal function.

The Association Between Fibroblast Growth Factor 23 and Renal Transplantation Outcome Is Modified by Follow-up Duration and Glomerular Filtration Rate Assessment Method.

INTRODUCTION: Fibroblast growth factor 23 (FGF23) could contribute to cardiovascular morbidity in chronic kidney disease. In studies of kidney transplant recipients, a high circulating level of FGF23 has been associated with death and graft loss independently of estimated glomerular filtration rate (GFR). Whether FGF23 is associated with adverse outcomes in the early posttransplantation period is unknown. METHODS: We analyzed a cohort of 845 kidney transplant recipients in stable condition who had GFR measured in the first years after transplantation with a median follow-up of 71 months. RESULTS: A high FGF23 concentration was associated with death or graft loss in univariate analysis, but this association was lost after adjustment for measured GFR. In contrast, FGF23 remained significantly associated with the composite outcome when estimated GFR was substituted for measured GFR. We also observed that follow-up duration modified the association between FGF23 and outcome. Although FGF23 was not associated with any endpoint in the full duration of the study, we found an independent association between FGF23 and the incidence of graft loss within the 4 years after FGF23 measurement. We did not find an association between FGF23 levels and left ventricular mass in a subgroup of 227 patients who had echocardiography performed within 3 months of FGF23 measurement. DISCUSSION: This study demonstrates that FGF23 measured during the first year after transplantation is not an independent predictor of death and graft loss and is not associated with left ventricular hypertrophy in the posttransplantation period. It further unveils important factors modifying the association between FGF23 and outcome in this population.

Arterio-venous fistula for automated red blood cells exchange in patients with sickle cell disease: Complications and outcomes.

Erythrocytapheresis (ER) can improve outcome in patients with sickle cell disease (SCD). A good vascular access is required but frequently it can be difficult to obtain for sickle cell patients. Arterio-venous fistulas (AVFs) have been suggested for ER in SCD supported by limited evidence. We report the largest cohort of ER performed with AVFs from three French SCD reference centers. Data of SCD patients undergoing ER with AVFs in the French SCD reference center were retrospectively collected. The inclusion criteria were: SS or Sß-Thalassemia and AVF surgery for ER. SCD-related complications, transfusion history, details about AVF surgical procedure, echocardiographic data before and after AVF, AVF-related surgical and hemodynamical complications were collected. Twenty-six patients (mean age 20.5 years, mean follow-up 68 months [11-279]) were included. Twenty-three patients (88.5%) required central vascular access before AVF. Fifteen AVFs (58%) were created on the forearm and 11 (42%) on the arm. Nineteen patients (73%) had stenotic, thrombotic or infectious AVF complications. A total of 0.36 stenosis per 1,000 AVF days, 0.37 thrombosis per 1,000 AVF days and 0.078 infections per 1.000 AVF days were observed. The mean AVF lifespan was 51 months [13-218]. One patient with severe pulmonary hypertension worsened after AVF creation and died. We report the first series of SCD patients with AVF for ER, demonstrating that AVFs could be considered as a potential vascular access for ER. Patients with increased risk for hemodynamic intolerance of AVFs must be carefully identified, so that alternative vascular accesses can be considered. Am. J. Hematol. 92:136-140, 2017. © 2016 Wiley Periodicals, Inc.

Prevalence and predictors of early cardiovascular events after kidney transplantation: evaluation of pre-transplant cardiovascular work-up.

INTRODUCTION: Cardiovascular disease is the leading cause of mortality after renal transplantation. The purpose of this study was to analyze cardiovascular risk factors at transplantation, occurrence of cardiovascular events in the first year after transplantation and evaluate pre-transplant work-up. MATERIAL AND METHOD: In total, 244 renal transplant recipients older than 50 years were included. The results of pre-transplant work-up, including clinical evaluation, electrocardiogram, echocardiography, myocardial perfusion testing and coronary angiography were analyzed. RESULTS: Patients had multiple risk factors at inclusion on renal transplantation waiting list as high blood pressure (94.7%), dyslipidemia (81.1%), smoking (45.3%), diabetes (23.6%), past history of cardiovascular disease (21.3%) and obesity (12.7%). Following transplantation, 15.5% (n = 38) of patients experienced a cardiovascular event, including 2.8% (n = 7) acute coronary syndrome, 5.8% (n = 14) isolated increase in troponin level and 5.3% (n = 13) new onset atrial fibrillation. The pre-transplant parameters associated with a cardiovascular event were a past medical history of cardiovascular disease (HR = 2.06 [1.06-4.03], p = 0.03), echocardiographic left ventricular hypertrophy (HR = 2.04 [1.04-3.98], p = 0.037) and abnormal myocardial perfusion testing (HR = 2.25 [1.09 -5.96], p = 0.03). Pre-transplantation evaluation allowed the diagnosis of unknown coronary artery lesions in 8.9% of patients.

Evaluation of the impact of the recent controversy over statins in France: the EVANS study.

BACKGROUND: The effect of statins on the prevention of cardiovascular events is well-established. However, a recent controversy in France questioned the value of statins, especially in primary prevention. AIMS: To evaluate the impact of this controversy on patient adherence to statin therapy and its potential clinical impact. METHODS: All patients on statins were recruited consecutively from consultations over a period of 1 month (from March 2013) by five physicians in three centres. Patient demographics and co-morbidities were collected and adherence to statin therapy was evaluated with a questionnaire. We estimated the number of deaths and major cardiovascular events that could be induced per year. RESULTS: A total of 142 patients were included: 37 in primary prevention (mean age, 68.0±13.1 years; 41% women); 105 in secondary prevention (mean age, 67.6±12.1 years; 20% women). In primary prevention, 24.3% of patients intended to stop statins versus 8.6% in secondary prevention (P<0.001). In France, if the percentages of medication discontinuations following the controversy were actually similar to those we found in our survey, 4992 major cardiovascular events, including 1159 deaths, would be induced in 1 year. CONCLUSION: Recent controversy over statins could induce a large proportion of patients to stop their medication and generate a large number of major cardiovascular events.

[Senile systemic amyloidosis: definition, diagnosis, why thinking about?]. / Amylose systémique sénile : définition, diagnostic, pourquoi y penser ?

Senile systemic amyloidosis (SSA) is characterized by infiltration of amyloid transthyretin fibrils in the myocardium. SSA occurs mainly (but not always) in elderly men. SSA leads to hypertrophic and/or restrictive cardiomyopathy complicated by conduction disturbances, atrial arrhythmia and systemic embolization (stroke…). That is why SSA needs a special care and to be diagnosed. Cardiac SSA diagnosis needs to exclude two other forms of cardiac amyloidosis: AL amyloidosis (light chain) and hereditary transthyretin amyloidosis (genetic testing). Scintigraphic 99mTc-DPD heart retention is observed in cardiac amyloidosis. DPD heart retention is more frequent in cardiac transthyretin amyloidosis than in cardiac AL amyloidosis. Specific treatments of cardiac TTR amyloidosis are in development.

Composite cell sheets: a further step toward safe and effective myocardial regeneration by cardiac progenitors derived from embryonic stem cells.

BACKGROUND: The safety and efficacy of myocardial regeneration using embryonic stem cells are limited by the risk of teratoma and the high rate of cell death. METHODS AND RESULTS: To address these issues, we developed a composite construct made of a sheet of adipose tissue-derived stroma cells and embryonic stem cell-derived cardiac progenitors. Ten Rhesus monkeys underwent a transient coronary artery occlusion followed, 2 weeks later, by the open-chest delivery of the composite cell sheet over the infarcted area or a sham operation. The sheet was made of adipose tissue-derived stroma cells grown from a biopsy of autologous adipose tissue and cultured onto temperature-responsive dishes. Allogeneic Rhesus embryonic stem cells were committed to a cardiac lineage and immunomagnetically sorted to yield SSEA-1(+) cardiac progenitors, which were then deposited onto the cell sheet. Cyclosporine was given for 2 months until the animals were euthanized. Preimplantation studies showed that the SSEA-1(+) progenitors expressed cardiac markers and had lost pluripotency. After 2 months, there was no teratoma in any of the 5 cell-treated monkeys. Analysis of >1500 histological sections showed that the SSEA-1(+) cardiac progenitors had differentiated into cardiomyocytes, as evidenced by immunofluorescence and real-time polymerase chain reaction. There were also a robust engraftment of autologous adipose tissue-derived stroma cells and increased angiogenesis compared with the sham animals. CONCLUSIONS: These data collected in a clinically relevant nonhuman primate model show that developmentally restricted SSEA-1(+) cardiac progenitors appear to be safe and highlight the benefit of the epicardial delivery of a construct harboring cells with a cardiomyogenic differentiation potential and cells providing them the necessary trophic support.

Tissue kallikrein deficiency and renovascular hypertension in the mouse.

The kallikrein kinin system (KKS) is involved in arterial and renal functions. It may have an antihypertensive effect in both essential and secondary forms of hypertension. The role of the KKS in the development of two-kidneys, one-clip (2K1C) hypertension, a high-renin model, was investigated in mice rendered deficient in tissue kallikrein (TK) and kinins by TK gene inactivation (TK-/-) and in their wild-type littermates (TK+/+). Four weeks after clipping the renal artery, blood flow was reduced in the clipped kidney (2K1C-TK+/+: -90%, 2K1C-TK-/-: -93% vs. sham-operated mice), and the kidney mass had also decreased (2K1C-TK+/+: -65%, 2K1C-TK-/-: -66%), whereas in the unclipped kidney, blood flow (2K1C-TK+/+: +19%, 2K1C-TK-/-: +17%) and kidney mass (2K1C-TK+/+: +32%, 2K1C-TK-/-: +30%) had both increased. The plasma renin concentration (2K1C-TK+/+: +78%, 2K1C-TK-/-: +65%) and renal renin content of the clipped kidney (2K1C-TK+/+: +58%, 2K1C-TK-/-: +65%) had increased significantly. There was no difference for these parameters between 2K1C-TK+/+ and 2K1C-TK-/- mice. Blood pressure monitored by telemetry and by plethysmography, rose immediately after clipping in both genotypes, and reached similar levels (2K1C-TK+/+: +24%, 2K1C-TK-/-: +21%). 2K1C-TK+/+ and 2K1C-TK-/- mice developed similar concentric left ventricular hypertrophy (+24% and +17%, respectively) with normal cardiac function. These findings suggest that in the context of chronic unilateral reduction in renal blood flow, TK and kinins do not influence the trophicity of kidneys, the synthesis and secretion of renin, blood pressure increase, and cardiac remodeling due to renin angiotensin system activation.

Self-assembling peptide nanofibers and skeletal myoblast transplantation in infarcted myocardium.

Cell transplantation is currently limited by poor graft retention and survival in the postinfarction scar. Because this issue could potentially be addressed by embedding cells in bioinjectable scaffolds and boosting cell survival pathways, we induced a myocardial infarction in 72 rats to assess the effects of different self-assembling peptides with or without platelet-derived growth factor (PDGF-BB) on survival of transplanted skeletal myoblasts. Two weeks after coronary artery ligation, rats were randomized to receive in-scar injections of culture medium (controls, n = 11), self-assembling peptide (RAD16-I) nanofibers (NF, n = 9), skeletal myoblasts (n = 12), or skeletal myoblasts in combination with NF (n = 8). In separate experiments with different self-assembling peptides (RAD16-II), rats received in-scar injections of culture medium (controls, n = 6), skeletal myoblasts (n = 10), PDGF-loaded peptides (n = 7), or skeletal myoblasts (5 x 10(6)) in combination with PDGF-loaded peptides (n = 9). After 1 month, left ventricular function, as assessed by echocardiography, was not improved in either of the experimental groups compared with controls. This correlated with the failure of RAD16-I peptides or PDGF-loaded RAD16-II peptides to improve myoblast survival despite a greater angiogenesis. In vitro experiments confirmed that the number of myoblasts decreased over time when seeded on nanofiber gels. These data suggest that the optimal use of biomaterial scaffolds for survival of transplanted cells will require specific tailoring of the biomaterial to the cell type.

Is xenotransplantation of embryonic stem cells a realistic option?

To test the purported immune privilege of embryonic stem cells (ESC) in the challenging setting of xenotransplantation, 14 immunocompetent baboons were subjected to a coronary artery occlusion-reperfusion sequence and, two weeks later, randomized to receive in-scar injections of culture medium or cardiac-committed mouse ESC engineered to express fluorescent reporter genes driven by cardiac-specific promoters. Two months after transplantation, left ventricular function, as assessed by echocardiography, deteriorated to a similar extent in control and treated baboons. This correlated with failure to identify the grafted cells by X-gal histology and immunofluorescence. Rejection did not seem to be mediated by xenoantibodies, but rather by T lymphocytes and natural killer cells as suggested by positive immunostaining for CD3 and CD56 early after transplantation. There was no increase in circulating levels of regulatory T cells. These data raise a cautionary note about the immune privilege of ESC and suggest that from a mere immunologic standpoint, ESC xenotransplantation is likely to be an unrealistic challenge.

Can bone marrow-derived multipotent adult progenitor cells regenerate infarcted myocardium?

OBJECTIVES: To assess the functional effects of multipotent adult progenitor cells (MAPCs) transplanted in a rat model of chronic myocardial infarction. METHODS: Forty-four rats underwent coronary ligation and, 14 days later, were randomly allocated to receive in-scar injections (5 x 10(6) cells/150 microL) of green fluorescent protein (eGFP)-transduced allogeneic MAPCs (n = 25) or culture medium (controls, n = 19). Nine of the MAPC-treated hearts were employed for functional studies while the remaining 16 received cells co-labeled with Resovist and were only used for serial histological assessments. Left ventricular (LV) function was assessed echocardiographically before transplantation and 1 month thereafter in a blinded manner. Immunohistochemistry, electron microscopy and PCR were used to detect grafted cells. All data were compared by nonparametric tests. RESULTS: Baseline ejection fractions (EF, median;[interquartile range]) did not differ significantly among the groups: 30% [0.23;0.37] and 37% [0.32;0.38] in control and rMAPC-transplanted hearts, respectively. One month later, LV function of control hearts was found to have deteriorated, as reflected by a decline in EF to 24% [0.21;0.30], and although EF tended to remain more stable after cell transplantation (37% [0.27;0.41]), the difference between the two groups failed to achieve statistical significance (p = 0.06). While MAPCs could be identified early post-transplant, no evidence of engraftment was further observed at 1 month by immunohistochemistry, electron microscopy or PCR. CONCLUSIONS: In this model, MAPCs did not improve global pump function, and although some of these cells expressed endothelial markers during the early post-transplant period, we could not detect any evidence for differentiation into cardiomyocytes and no engraftment was further identified beyond 2 weeks after cell injections.

Can cold or heat shock improve skeletal myoblast engraftment in infarcted myocardium?

OBJECTIVE: Cell death remains a major limitation of skeletal myoblast (SM) transplantation but the patterns of cell survival and proliferation in heart and their potential modulation by thermic stresses like heat shock (HS) and cryopreservation (Cryo) are still incompletely characterized. METHODS: To track SMs in situ, we developed a dual-marker system based on the semiconservative expression of the foreign soluble protein, beta-Galactosidase (beta-Gal) and the constitutive expression of the Y chromosome in a myocardial infarction model. Control medium or Lewis male rat SMs (fresh or subjected to Cryo or HS) were injected in Lewis female rats. RESULTS: There was a massive cell loss early after transplantation in the fresh group, which was only partially compensated for by a subsequent proliferation. Conversely, both Cryo and HS significantly improved early cell survival but blunted subsequent proliferation so that, at 15 days posttransplantation, the total number of engrafted donor-derived Y-positive cells did not differ significantly between the three groups. Most of them expressed a skeletal muscle phenotype. CONCLUSIONS: These data confirm the high death rate of in-scar transplanted myoblasts, demonstrate the ability of those that survive to proliferate and differentiate along the myogenic pathway but do not support the efficacy of either Cryo or HS for increasing the ultimate magnitude of myoblast engraftment.