ANTOINE CAPEL - Academia.edu (original) (raw)

Papers by ANTOINE CAPEL

Arteriosclerosis, Thrombosis, and Vascular Biology

Background: Carmat bioprosthetic total artificial heart (Aeson; A-TAH) is a pulsatile and autoreg... more Background: Carmat bioprosthetic total artificial heart (Aeson; A-TAH) is a pulsatile and autoregulated device. The aim of this study is to evaluate level of hemolysis potential acquired von Willebrand syndrome after A-TAH implantation. Methods: We examined the presence of hemolysis and acquired von Willebrand syndrome in adult patients receiving A-TAH support (n=10) during their whole clinical follow-up in comparison with control subjects and adult patients receiving Heartmate II or Heartmate III support. We also performed a fluid structure interaction model coupled with computational fluid dynamics simulation to evaluate the A-TAH resulting shear stress and its distribution in the blood volume. Results: The cumulative duration of A-TAH support was 2087 days. A-TAH implantation did not affect plasma free hemoglobin over time, and there was no association between plasma free hemoglobin and cardiac output or beat rate. For VWF (von Willebrand factor) evaluation, A-TAH implantation di...

- La presente invention concerne un procede pour la realisation d'un materiau hemocompatible ... more - La presente invention concerne un procede pour la realisation d'un materiau hemocompatible comportant un substrat synthetique et un tissu biologique animal, procede selon lequel on deshydrate ledit tissu biologique animal et on le colle sur ledit substrat synthetique au moyen d'une dispersion de la matiere constitutive dudit substrat synthetique. - Selon l'invention, la deshydratation du tissu biologique animal est obtenue uniquement par voie chimique par immersion dudit tissu biologique animal dans un bain constitue d'une solution de polyethylene glycol a au moins 80% en poids.

- hemocompatible composite material and method of obtention.- According to the invention, the blo... more - hemocompatible composite material and method of obtention.- According to the invention, the blood compatible material comprises a synthetic substrate, durable and waterproof, having adhered a biological tissue.

Circulation, 2016

We report here the results of haemocompatibility in 3 patients from the feasibility study of the ... more We report here the results of haemocompatibility in 3 patients from the feasibility study of the first-in-man trail of a novel total artificial heart (C-TAH) containing bioprosthetic blood-contacti...

- tissue endoprosthesis and method for its realization. - According to the present invention, sai... more - tissue endoprosthesis and method for its realization. - According to the present invention, said tissue stent includes an expandable support structure or stent (2), trapped between an internal tissue structure (4) and an outer coating (10) consists of a flexible synthetic material hemocompatible, which permeates said inner structure (4) through days of said support structure (2).

Cite this article as: Christian Latrémouille, Alain Carpentier, Pascal Leprince, Jean-Christian R... more Cite this article as: Christian Latrémouille, Alain Carpentier, Pascal Leprince, Jean-Christian Roussel, Bernard Cholley, Elodie Boissier, Eric Epailly, Antoine Capel, Piet Jansen and David M. Smadja, A bioprosthetic Total Artificial Heart for end-stage heart failure: results from the pilot studyBioprosthetic Total Artificial Heart Pilot Study, Journal of Heart and Lung Transplantation, http://dx.doi.org/10.1016/j.healun.2017.09.002

Archives of Cardiovascular Diseases Supplements

Introduction Bioprosthetic heart valves (BV) made of xenogenic pericardium fixed with glutaraldeh... more Introduction Bioprosthetic heart valves (BV) made of xenogenic pericardium fixed with glutaraldehyde have been developed more than 30 years ago. The concept of cross linking collagenous fibers to ensure in-vivo stability of the scaffold and reducing antigenic immune response by fixation resulted in successful clinical evaluations and a lower risk of thromboembolism thus eliminating the need for a lifelong anticoagulation. To explain these clinical results, an acquired hemocompatibility process has been proposed but never extensively studied because of the impossibility to access not degenerated material. Objective To study and understand mechanisms of acquired hemocompatibility, we explored non degenerated BV from 9 different patients implanted with a Carmat total artificial heart (C-TAH) and four BV duration from 45 to 270 days. Method We performed classic histopathology and immunophenotypic characterization of explanted BV. Biological deposit has been also explored by Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). Result In short implantation duration time, we observed a fibrin deposit with inflammatory cells and pseudotubes formation. Histological sections showed superficial infiltration of cells, persisting in long duration but not damaging integrity of the pericardium. The fibrin deposit is then organized in a compacted smooth fibrin network in longer implantation durations. Endothelial cells (EC) monolayer covering has also been observed on this fibrin cap, the percentage of the BV surface with EC covering increasing along months. This endothelial cells covering is positive for VE-Cadherin, with flat nucleus and tight junctions. Conclusion Healthy BV implanted with C-TAH enabled us to study, for the first time, non-degenerated implanted valve in human. Biomaterial passivation by an organized fibrin deposit and formation of EC monolayer on top achieve an optimal hemocompatibility without any modification of pericardial tissue.

Archives of Cardiovascular Diseases Supplements

European Journal of Cardio-Thoracic Surgery, 2012

OBJECTIVES: The CARMAT total artificial heart (TAH) is an implantable, electro-hydraulically driv... more OBJECTIVES: The CARMAT total artificial heart (TAH) is an implantable, electro-hydraulically driven, pulsatile flow device with four bioprosthetic valves. Its blood-pumping surfaces consist of processed bioprosthetic pericardial tissue and expanded polytetrafluorethylene (ePTFE), potentially allowing for the reduction of anti-coagulation. This pre-clinical study assessed the in vitro haemocompatibility of these surfaces. METHODS: Coupons of pericardial tissue and ePTFE were placed in closed tubular circuits filled with 12.5 ml of fresh human blood exposed to the pulsatile flow at 120 ml/min for 4 h (37°C). Silicone-and heparin-coated polyvinyl chloride (PVC) tubes served as positive and negative controls, respectively. Fresh blood from six donors was used to fill four sets of 12 circuits. Blood samples were taken at baseline and from each circuit after 4 h. Coupons of materials were examined with scanning electron microscopy. RESULTS: The platelet count was 202 ± 45 × 10 9 l −1 at baseline. Four hours after circulation, the platelet counts were 161 ± 30 × 10 9 l −1 (compared with baseline, P = 0.0207) for pericardial tissue, 162 ± 35 × 10 9 l −1 (P = 0.0305) for ePTFE and 136 ± 42 × 10 9 l −1 for positive controls (P = 0.0021). Baseline plasma fibrinogen was 2.9 ± 0.5 mg/dl compared with 3.0 ± 0.5 mg/dl for pericardial tissue and 3.1 ± 0.7 mg/dl for ePTFE, indicating no marked fibrinogen consumption. Thromboxane B2 levels for positive controls were 33.3 ± 8.7 ng/ml compared with 16.2 ± 11.5 ng/ml for pericardial tissue (P = 0.0015) and 15.2 ± 4.7 ng/ml for ePTFE (P < 0.0001). Platelet adhesion was 2.87 ± 1.01 × 10 9 cm −2 for positive controls compared with 1.06 ± 0.73 × 10 9 cm −2 for pericardial tissue (P < 0.0001) and 0.79 ± 0.75 × 10 9 cm −2 for ePTFE (P < 0.0001). Thrombin-antithrombin III complex levels were 3.8 ± 0.5 μg/ml for positive controls compared with 1.9 ± 0.9 for pericardial tissue (P < 0.0001) and 2.1 ± 1.0 for ePTFE (P < 0.0001). With an electro-microscopic examination at ×600, only small depositions of platelets, erythrocytes and fibrin were noticed on the pericardial tissue samples and ePTFE samples. Silicone surfaces showed marked areas of thrombi, and PVC tubings a thin protein layer. CONCLUSIONS: Haemocompatibility of the TAH blood-contacting surfaces was confirmed by in vitro studies showing a limited consumption of fibrin, limited thromboxane B2 release and platelet adhesion, and minor blood cell depositions on the surfaces. These results will be validated in clinical studies, with the aim of reducing anti-coagulation when using the CARMAT TAH.

Stem Cell Reviews and Reports

Endothelial progenitor cells (EPCs) are involved in vasculogenesis and cardiovascular diseases. H... more Endothelial progenitor cells (EPCs) are involved in vasculogenesis and cardiovascular diseases. However, the phenotype of circulating EPCs remains elusive but they are more often described as CD34 + KDR +. The aim of the study was to extensively characterize circulating potential vasculogenic stem cell candidates in two populations of patients with cardiovascular disease by powerful multidimensional single cell complementary cytometric approaches (mass, imaging and flow). We identified cellular candidates in one patient before and after bioprosthetic total artificial heart implantation and results were confirmed in healthy peripheral and cord blood by mass cytometry. We also quantified cellular candidates in 10 patients with different COVID-19 severity. Both C-TAH implantation and COVID-19 at critical stage induce a redistribution of circulating CD34 + and CD19 + sub-populations in peripheral blood. After C-TAH implantation, circulating CD34 + progenitor cells expressed c-Kit stem marker while specific subsets CD34 + CD133 −/+ CD45 −/dim c-Kit + KDR − were mobilized. KDR was only expressed by CD19 + B-lymphocytes and CD14 + monocytes subpopulations in circulation. We confirmed by mass cytometry this KDR expression on CD19 + in healthy peripheral and cord blood, also with a VE-cadherin expression, confirming absence of endothelial lineage marker on CD34 + subtypes. In COVID-19, a significant mobilization of CD34 + c-Kit + KDR − cells was observed between moderate and critical COVID-19 patients regardless CD133 or CD45 expression. In order to better evaluate EPC phenotype, we performed imaging flow cytometry measurements of immature CD34 + KDR + cells in cord blood and showed that, after elimination of non-circular events, those cells were all CD19 +. During COVID-19, a significant mobilization of CD19 + KDR + per million of CD45 + cells was observed between moderate and critical COVID-19 patients regardless of CD34 expression. CD34 + c-Kit + cells are mobilized in both cardiovascular disease described here. KDR cells in peripheral blood are CD19 positive cells and are not classic vasculogenic stem and/or progenitor cells. A better evaluation of c-Kit and KDR expressing cells will lead to the redefinition of circulating endothelial progenitors.

The Aeson® total artificial heart (A-TAH) has been developed as a total heart replacement for pat... more The Aeson® total artificial heart (A-TAH) has been developed as a total heart replacement for patients at risk of death from biventricular failure. We previously described endothelialization of the hybrid membrane inside A-TAH probably at the origin of acquired hemocompatibility. We aimed to quantify vasculogenic stem cells in peripheral blood of patients with long-term A-TAH implantation. Four male adult patients were included in this study. Peripheral blood mononuclear cells were collected before A-TAH implantation (T0) and after implantation at one month (T1), between two and five months (T2), and then between six and twelve months (T3). Supervised analysis of flow cytometry data confirmed the presence of the previously identified Lin−CD133+CD45− and Lin−CD34+ with different CD45 level intensities. Lin−CD133+CD45−, Lin−CD34+CD45− and Lin−CD34+CD45+ were not modulated after A-TAH implantation. However, we demonstrated a significant mobilization of Lin−CD34+CD45dim (p = 0.01) one m...

Thrombosis and Haemostasis

Pulsatile Carmat bioprosthetic total artificial heart (C-TAH) is designed to be implanted in pati... more Pulsatile Carmat bioprosthetic total artificial heart (C-TAH) is designed to be implanted in patients with biventricular end-stage heart failure. Since flow variation might contribute to endothelial dysfunction, we explored circulating endothelial biomarkers after C-TAH implantation in seven patients and compared the manual and autoregulated mode. Markers of endothelial dysfunction and regeneration were compared before and during a 6- to 9-month follow-up after implantation. The follow-up was divided into three periods (< 3, 3–6, and > 6 months) and used to estimate the temporal trends during the study period. A linear mixed model was used to analyze repeated measures and association between tested parameters according to the mode of C-TAH and the time. Relevance of soluble endoglin (sEndoglin) level increase has been tested on differentiation and migration potential of human vasculogenic progenitor cells (endothelial colony forming cells [ECFCs]). Normal sEndoglin and soluble...

Heliyon

The Carmat bioprosthetic total artificial heart (C-TAH) is a biventricular pump developed to mini... more The Carmat bioprosthetic total artificial heart (C-TAH) is a biventricular pump developed to minimize drawbacks of current mechanical assist devices and improve quality of life during support. This study aims to evaluate the safety of the hybrid membrane, which plays a pivotal role in this artificial heart. We investigated in particular its blood-contacting surface layer of bovine pericardial tissue, in terms of mechanical aging, risks of calcification, and impact of the hemodynamics shear stress inside the ventricles on blood components. Hybrid membranes were aged in a custom-designed endurance bench. Mechanical, physical and chemical properties were not significantly modified from 9 months up to 4 years of aging using a simulating process. Exploration of erosion areas did not show risk of oil diffusion through the membrane. Blood contacting materials in the ventricular cavities were subcutaneously implanted in Wistar rats for 30 days as a model for calcification and demonstrated that the inhouse anti-calcification pretreatment with Formaldehyde-Ethanol-Tween 80 was able to significantly reduce the calcium concentration from 132 μg/mg to 4.42 μg/mg (p < 0.001). Hemodynamic simulations with a computational model were used to reproduce shear stress in left and right ventricles and no significant stress was able to trigger hemolysis, platelet activation nor degradation of the von Willebrand factor multimers. Moreover, explanted hybrid membranes from patients included in the feasibility clinical study were analyzed confirming preclinical results with the absence of significant membrane calcification. At last, blood plasma bank analysis from the four patients implanted with C-TAH during the feasibility study showed no residual glutaraldehyde increase in plasma and confirmed hemodynamic simulation-based results with the absence of hemolysis and platelet activation associated with normal levels of plasma free hemoglobin and platelet microparticles after C-TAH implantation. These results on mechanical aging, calcification model and hemodynamic simulations predicted the safety of the hybrid membrane used in the C-TAH, and were confirmed in the feasibility study.

Journal of the American College of Cardiology, Jan 15, 2018

The main risk factor for bleeding in patients with continuous-flow mechanical circulatory support... more The main risk factor for bleeding in patients with continuous-flow mechanical circulatory support (CF-MCS) is the acquired von Willebrand factor (VWF) defect related to the high shear-stress forces developed by these devices. Although a higher bleeding rate has been reported in CF-MCS recipients who had reduced pulsatility, the relation between pulsatility and the VWF defect has never been studied. The purpose of this study was to investigate the relation between pulsatility and VWF under CF-MCS. We assessed the effect of 2 CF-MCS on VWF multimer degradation in a mock circulatory loop (model 1). Using these devices, we investigated in a dose-effect model (model 2) 3 levels of pulsatility in 3 groups of swine. In a cross-over model (model 3), we studied the effects of sequential changes of pulsatility on VWF. We reported the evolution of VWF multimerization in a patient undergoing serial CF-MCS and/or pulsatile-MCS. We demonstrated the proteolytic degradation of VWF multimers by high...

The Journal of Heart and Lung Transplantation

BACKGROUND: The electro-hydraulically actuated Carmat total artificial heart (C-TAH) is designed ... more BACKGROUND: The electro-hydraulically actuated Carmat total artificial heart (C-TAH) is designed to replace the heart in patients with end-stage heart failure, either as bridge to transplant or destination therapy. It provides pulsatile flow and contains bio-prosthetic blood contacting materials. A clinical feasibility study was conducted to evaluate the C-TAH safety and performance. METHODS: Hospitalized patients, at imminent risk of death from irreversible biventricular failure despite optimal medical management, and not eligible for transplant or eligible but on extracorporeal life support, were enrolled. The primary endpoint was 30-days survival. RESULTS: Four patients were implanted with the C-TAH, three as destination therapy (ages 76, 68, 74) and one as bridge to transplant (age 58). They had implant times of 74, 270, 254 and 20 days respectively. All patients were free from hemolysis, clinical neurologic events, clinical evidence of thrombus and device-related infections. Hemodynamic and physical recovery allowed two patients to be discharged home for a cumulative duration of 7 months. The anticoagulation management strategy comprised initial unfractionated heparin, from postoperative day 2, followed by low molecular weight heparin and aspirin. An increased D-dimer level was observed in all patients during months 1 to 4. Temporary suspension of heparin anticoagulation resulted in thrombocytopenia and increased fibrin monomer, reversed by resuming anticoagulation with heparin. Causes of death were device-related (2 cases), respiratory failure and multi-organ failure. CONCLUSIONS: Preliminary clinical results with the C-TAH demonstrated good safety and performance profiles in patients suffering from biventricular failure, which need to be confirmed in a pivotal study.

Journal of Cardiothoracic and Vascular Anesthesia

To determine hemostasis perturbations, including von Willebrand factor (VWF) multimers, after imp... more To determine hemostasis perturbations, including von Willebrand factor (VWF) multimers, after implantation of a new bioprosthetic and pulsatile total artificial heart (TAH). Preclinical study SETTING: Single-center biosurgical research laboratory. Female Charolais calves, 2-to-6 months old, weighing 102-to-122 kg. Surgical implantation of TAH through a mid-sternotomy approach. Four of 12 calves had a support duration of several days (4, 4, 8, and 10 days), allowing for the exploration of early steps of hemostasis parameters, including prothrombin time; coagulation factor levels (II, V, VII+X, and fibrinogen); and platelet count. Multimeric analysis of VWF was performed to detect a potential loss of high-molecular weight (HMW) multimers, as previously described for continuous flow rotary blood pumps. Despite the absence of anticoagulant treatment administered in the postoperative phase, no signs of coagulation activation were detected. Indeed, after an immediate postsurgery decrease of prothrombin time, platelet count, and coagulation factor levels, most parameters returned to baseline values. HMW multimers of VWF remained stable either after initiation or during days of support. Coagulation parameters and platelet count recovery in the postoperative phase of the Carmat TAH (Camat SA, Velizy Villacoublay Cedex, France) implantation in calves, in the absence of anticoagulant treatment and associated with the absence of decrease in HMW multimers of VWF, is in line with early hemocompatibility that is currently being validated in human clinical studies.

Arteriosclerosis, Thrombosis, and Vascular Biology

Background: Carmat bioprosthetic total artificial heart (Aeson; A-TAH) is a pulsatile and autoreg... more Background: Carmat bioprosthetic total artificial heart (Aeson; A-TAH) is a pulsatile and autoregulated device. The aim of this study is to evaluate level of hemolysis potential acquired von Willebrand syndrome after A-TAH implantation. Methods: We examined the presence of hemolysis and acquired von Willebrand syndrome in adult patients receiving A-TAH support (n=10) during their whole clinical follow-up in comparison with control subjects and adult patients receiving Heartmate II or Heartmate III support. We also performed a fluid structure interaction model coupled with computational fluid dynamics simulation to evaluate the A-TAH resulting shear stress and its distribution in the blood volume. Results: The cumulative duration of A-TAH support was 2087 days. A-TAH implantation did not affect plasma free hemoglobin over time, and there was no association between plasma free hemoglobin and cardiac output or beat rate. For VWF (von Willebrand factor) evaluation, A-TAH implantation di...

- La presente invention concerne un procede pour la realisation d'un materiau hemocompatible ... more - La presente invention concerne un procede pour la realisation d'un materiau hemocompatible comportant un substrat synthetique et un tissu biologique animal, procede selon lequel on deshydrate ledit tissu biologique animal et on le colle sur ledit substrat synthetique au moyen d'une dispersion de la matiere constitutive dudit substrat synthetique. - Selon l'invention, la deshydratation du tissu biologique animal est obtenue uniquement par voie chimique par immersion dudit tissu biologique animal dans un bain constitue d'une solution de polyethylene glycol a au moins 80% en poids.

- hemocompatible composite material and method of obtention.- According to the invention, the blo... more - hemocompatible composite material and method of obtention.- According to the invention, the blood compatible material comprises a synthetic substrate, durable and waterproof, having adhered a biological tissue.

Circulation, 2016

We report here the results of haemocompatibility in 3 patients from the feasibility study of the ... more We report here the results of haemocompatibility in 3 patients from the feasibility study of the first-in-man trail of a novel total artificial heart (C-TAH) containing bioprosthetic blood-contacti...

- tissue endoprosthesis and method for its realization. - According to the present invention, sai... more - tissue endoprosthesis and method for its realization. - According to the present invention, said tissue stent includes an expandable support structure or stent (2), trapped between an internal tissue structure (4) and an outer coating (10) consists of a flexible synthetic material hemocompatible, which permeates said inner structure (4) through days of said support structure (2).

Cite this article as: Christian Latrémouille, Alain Carpentier, Pascal Leprince, Jean-Christian R... more Cite this article as: Christian Latrémouille, Alain Carpentier, Pascal Leprince, Jean-Christian Roussel, Bernard Cholley, Elodie Boissier, Eric Epailly, Antoine Capel, Piet Jansen and David M. Smadja, A bioprosthetic Total Artificial Heart for end-stage heart failure: results from the pilot studyBioprosthetic Total Artificial Heart Pilot Study, Journal of Heart and Lung Transplantation, http://dx.doi.org/10.1016/j.healun.2017.09.002

Archives of Cardiovascular Diseases Supplements

Introduction Bioprosthetic heart valves (BV) made of xenogenic pericardium fixed with glutaraldeh... more Introduction Bioprosthetic heart valves (BV) made of xenogenic pericardium fixed with glutaraldehyde have been developed more than 30 years ago. The concept of cross linking collagenous fibers to ensure in-vivo stability of the scaffold and reducing antigenic immune response by fixation resulted in successful clinical evaluations and a lower risk of thromboembolism thus eliminating the need for a lifelong anticoagulation. To explain these clinical results, an acquired hemocompatibility process has been proposed but never extensively studied because of the impossibility to access not degenerated material. Objective To study and understand mechanisms of acquired hemocompatibility, we explored non degenerated BV from 9 different patients implanted with a Carmat total artificial heart (C-TAH) and four BV duration from 45 to 270 days. Method We performed classic histopathology and immunophenotypic characterization of explanted BV. Biological deposit has been also explored by Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). Result In short implantation duration time, we observed a fibrin deposit with inflammatory cells and pseudotubes formation. Histological sections showed superficial infiltration of cells, persisting in long duration but not damaging integrity of the pericardium. The fibrin deposit is then organized in a compacted smooth fibrin network in longer implantation durations. Endothelial cells (EC) monolayer covering has also been observed on this fibrin cap, the percentage of the BV surface with EC covering increasing along months. This endothelial cells covering is positive for VE-Cadherin, with flat nucleus and tight junctions. Conclusion Healthy BV implanted with C-TAH enabled us to study, for the first time, non-degenerated implanted valve in human. Biomaterial passivation by an organized fibrin deposit and formation of EC monolayer on top achieve an optimal hemocompatibility without any modification of pericardial tissue.

Archives of Cardiovascular Diseases Supplements

European Journal of Cardio-Thoracic Surgery, 2012

OBJECTIVES: The CARMAT total artificial heart (TAH) is an implantable, electro-hydraulically driv... more OBJECTIVES: The CARMAT total artificial heart (TAH) is an implantable, electro-hydraulically driven, pulsatile flow device with four bioprosthetic valves. Its blood-pumping surfaces consist of processed bioprosthetic pericardial tissue and expanded polytetrafluorethylene (ePTFE), potentially allowing for the reduction of anti-coagulation. This pre-clinical study assessed the in vitro haemocompatibility of these surfaces. METHODS: Coupons of pericardial tissue and ePTFE were placed in closed tubular circuits filled with 12.5 ml of fresh human blood exposed to the pulsatile flow at 120 ml/min for 4 h (37°C). Silicone-and heparin-coated polyvinyl chloride (PVC) tubes served as positive and negative controls, respectively. Fresh blood from six donors was used to fill four sets of 12 circuits. Blood samples were taken at baseline and from each circuit after 4 h. Coupons of materials were examined with scanning electron microscopy. RESULTS: The platelet count was 202 ± 45 × 10 9 l −1 at baseline. Four hours after circulation, the platelet counts were 161 ± 30 × 10 9 l −1 (compared with baseline, P = 0.0207) for pericardial tissue, 162 ± 35 × 10 9 l −1 (P = 0.0305) for ePTFE and 136 ± 42 × 10 9 l −1 for positive controls (P = 0.0021). Baseline plasma fibrinogen was 2.9 ± 0.5 mg/dl compared with 3.0 ± 0.5 mg/dl for pericardial tissue and 3.1 ± 0.7 mg/dl for ePTFE, indicating no marked fibrinogen consumption. Thromboxane B2 levels for positive controls were 33.3 ± 8.7 ng/ml compared with 16.2 ± 11.5 ng/ml for pericardial tissue (P = 0.0015) and 15.2 ± 4.7 ng/ml for ePTFE (P < 0.0001). Platelet adhesion was 2.87 ± 1.01 × 10 9 cm −2 for positive controls compared with 1.06 ± 0.73 × 10 9 cm −2 for pericardial tissue (P < 0.0001) and 0.79 ± 0.75 × 10 9 cm −2 for ePTFE (P < 0.0001). Thrombin-antithrombin III complex levels were 3.8 ± 0.5 μg/ml for positive controls compared with 1.9 ± 0.9 for pericardial tissue (P < 0.0001) and 2.1 ± 1.0 for ePTFE (P < 0.0001). With an electro-microscopic examination at ×600, only small depositions of platelets, erythrocytes and fibrin were noticed on the pericardial tissue samples and ePTFE samples. Silicone surfaces showed marked areas of thrombi, and PVC tubings a thin protein layer. CONCLUSIONS: Haemocompatibility of the TAH blood-contacting surfaces was confirmed by in vitro studies showing a limited consumption of fibrin, limited thromboxane B2 release and platelet adhesion, and minor blood cell depositions on the surfaces. These results will be validated in clinical studies, with the aim of reducing anti-coagulation when using the CARMAT TAH.

Stem Cell Reviews and Reports

Endothelial progenitor cells (EPCs) are involved in vasculogenesis and cardiovascular diseases. H... more Endothelial progenitor cells (EPCs) are involved in vasculogenesis and cardiovascular diseases. However, the phenotype of circulating EPCs remains elusive but they are more often described as CD34 + KDR +. The aim of the study was to extensively characterize circulating potential vasculogenic stem cell candidates in two populations of patients with cardiovascular disease by powerful multidimensional single cell complementary cytometric approaches (mass, imaging and flow). We identified cellular candidates in one patient before and after bioprosthetic total artificial heart implantation and results were confirmed in healthy peripheral and cord blood by mass cytometry. We also quantified cellular candidates in 10 patients with different COVID-19 severity. Both C-TAH implantation and COVID-19 at critical stage induce a redistribution of circulating CD34 + and CD19 + sub-populations in peripheral blood. After C-TAH implantation, circulating CD34 + progenitor cells expressed c-Kit stem marker while specific subsets CD34 + CD133 −/+ CD45 −/dim c-Kit + KDR − were mobilized. KDR was only expressed by CD19 + B-lymphocytes and CD14 + monocytes subpopulations in circulation. We confirmed by mass cytometry this KDR expression on CD19 + in healthy peripheral and cord blood, also with a VE-cadherin expression, confirming absence of endothelial lineage marker on CD34 + subtypes. In COVID-19, a significant mobilization of CD34 + c-Kit + KDR − cells was observed between moderate and critical COVID-19 patients regardless CD133 or CD45 expression. In order to better evaluate EPC phenotype, we performed imaging flow cytometry measurements of immature CD34 + KDR + cells in cord blood and showed that, after elimination of non-circular events, those cells were all CD19 +. During COVID-19, a significant mobilization of CD19 + KDR + per million of CD45 + cells was observed between moderate and critical COVID-19 patients regardless of CD34 expression. CD34 + c-Kit + cells are mobilized in both cardiovascular disease described here. KDR cells in peripheral blood are CD19 positive cells and are not classic vasculogenic stem and/or progenitor cells. A better evaluation of c-Kit and KDR expressing cells will lead to the redefinition of circulating endothelial progenitors.

The Aeson® total artificial heart (A-TAH) has been developed as a total heart replacement for pat... more The Aeson® total artificial heart (A-TAH) has been developed as a total heart replacement for patients at risk of death from biventricular failure. We previously described endothelialization of the hybrid membrane inside A-TAH probably at the origin of acquired hemocompatibility. We aimed to quantify vasculogenic stem cells in peripheral blood of patients with long-term A-TAH implantation. Four male adult patients were included in this study. Peripheral blood mononuclear cells were collected before A-TAH implantation (T0) and after implantation at one month (T1), between two and five months (T2), and then between six and twelve months (T3). Supervised analysis of flow cytometry data confirmed the presence of the previously identified Lin−CD133+CD45− and Lin−CD34+ with different CD45 level intensities. Lin−CD133+CD45−, Lin−CD34+CD45− and Lin−CD34+CD45+ were not modulated after A-TAH implantation. However, we demonstrated a significant mobilization of Lin−CD34+CD45dim (p = 0.01) one m...

Thrombosis and Haemostasis

Pulsatile Carmat bioprosthetic total artificial heart (C-TAH) is designed to be implanted in pati... more Pulsatile Carmat bioprosthetic total artificial heart (C-TAH) is designed to be implanted in patients with biventricular end-stage heart failure. Since flow variation might contribute to endothelial dysfunction, we explored circulating endothelial biomarkers after C-TAH implantation in seven patients and compared the manual and autoregulated mode. Markers of endothelial dysfunction and regeneration were compared before and during a 6- to 9-month follow-up after implantation. The follow-up was divided into three periods (< 3, 3–6, and > 6 months) and used to estimate the temporal trends during the study period. A linear mixed model was used to analyze repeated measures and association between tested parameters according to the mode of C-TAH and the time. Relevance of soluble endoglin (sEndoglin) level increase has been tested on differentiation and migration potential of human vasculogenic progenitor cells (endothelial colony forming cells [ECFCs]). Normal sEndoglin and soluble...

Heliyon

The Carmat bioprosthetic total artificial heart (C-TAH) is a biventricular pump developed to mini... more The Carmat bioprosthetic total artificial heart (C-TAH) is a biventricular pump developed to minimize drawbacks of current mechanical assist devices and improve quality of life during support. This study aims to evaluate the safety of the hybrid membrane, which plays a pivotal role in this artificial heart. We investigated in particular its blood-contacting surface layer of bovine pericardial tissue, in terms of mechanical aging, risks of calcification, and impact of the hemodynamics shear stress inside the ventricles on blood components. Hybrid membranes were aged in a custom-designed endurance bench. Mechanical, physical and chemical properties were not significantly modified from 9 months up to 4 years of aging using a simulating process. Exploration of erosion areas did not show risk of oil diffusion through the membrane. Blood contacting materials in the ventricular cavities were subcutaneously implanted in Wistar rats for 30 days as a model for calcification and demonstrated that the inhouse anti-calcification pretreatment with Formaldehyde-Ethanol-Tween 80 was able to significantly reduce the calcium concentration from 132 μg/mg to 4.42 μg/mg (p < 0.001). Hemodynamic simulations with a computational model were used to reproduce shear stress in left and right ventricles and no significant stress was able to trigger hemolysis, platelet activation nor degradation of the von Willebrand factor multimers. Moreover, explanted hybrid membranes from patients included in the feasibility clinical study were analyzed confirming preclinical results with the absence of significant membrane calcification. At last, blood plasma bank analysis from the four patients implanted with C-TAH during the feasibility study showed no residual glutaraldehyde increase in plasma and confirmed hemodynamic simulation-based results with the absence of hemolysis and platelet activation associated with normal levels of plasma free hemoglobin and platelet microparticles after C-TAH implantation. These results on mechanical aging, calcification model and hemodynamic simulations predicted the safety of the hybrid membrane used in the C-TAH, and were confirmed in the feasibility study.

Journal of the American College of Cardiology, Jan 15, 2018

The main risk factor for bleeding in patients with continuous-flow mechanical circulatory support... more The main risk factor for bleeding in patients with continuous-flow mechanical circulatory support (CF-MCS) is the acquired von Willebrand factor (VWF) defect related to the high shear-stress forces developed by these devices. Although a higher bleeding rate has been reported in CF-MCS recipients who had reduced pulsatility, the relation between pulsatility and the VWF defect has never been studied. The purpose of this study was to investigate the relation between pulsatility and VWF under CF-MCS. We assessed the effect of 2 CF-MCS on VWF multimer degradation in a mock circulatory loop (model 1). Using these devices, we investigated in a dose-effect model (model 2) 3 levels of pulsatility in 3 groups of swine. In a cross-over model (model 3), we studied the effects of sequential changes of pulsatility on VWF. We reported the evolution of VWF multimerization in a patient undergoing serial CF-MCS and/or pulsatile-MCS. We demonstrated the proteolytic degradation of VWF multimers by high...

The Journal of Heart and Lung Transplantation

BACKGROUND: The electro-hydraulically actuated Carmat total artificial heart (C-TAH) is designed ... more BACKGROUND: The electro-hydraulically actuated Carmat total artificial heart (C-TAH) is designed to replace the heart in patients with end-stage heart failure, either as bridge to transplant or destination therapy. It provides pulsatile flow and contains bio-prosthetic blood contacting materials. A clinical feasibility study was conducted to evaluate the C-TAH safety and performance. METHODS: Hospitalized patients, at imminent risk of death from irreversible biventricular failure despite optimal medical management, and not eligible for transplant or eligible but on extracorporeal life support, were enrolled. The primary endpoint was 30-days survival. RESULTS: Four patients were implanted with the C-TAH, three as destination therapy (ages 76, 68, 74) and one as bridge to transplant (age 58). They had implant times of 74, 270, 254 and 20 days respectively. All patients were free from hemolysis, clinical neurologic events, clinical evidence of thrombus and device-related infections. Hemodynamic and physical recovery allowed two patients to be discharged home for a cumulative duration of 7 months. The anticoagulation management strategy comprised initial unfractionated heparin, from postoperative day 2, followed by low molecular weight heparin and aspirin. An increased D-dimer level was observed in all patients during months 1 to 4. Temporary suspension of heparin anticoagulation resulted in thrombocytopenia and increased fibrin monomer, reversed by resuming anticoagulation with heparin. Causes of death were device-related (2 cases), respiratory failure and multi-organ failure. CONCLUSIONS: Preliminary clinical results with the C-TAH demonstrated good safety and performance profiles in patients suffering from biventricular failure, which need to be confirmed in a pivotal study.

Journal of Cardiothoracic and Vascular Anesthesia

To determine hemostasis perturbations, including von Willebrand factor (VWF) multimers, after imp... more To determine hemostasis perturbations, including von Willebrand factor (VWF) multimers, after implantation of a new bioprosthetic and pulsatile total artificial heart (TAH). Preclinical study SETTING: Single-center biosurgical research laboratory. Female Charolais calves, 2-to-6 months old, weighing 102-to-122 kg. Surgical implantation of TAH through a mid-sternotomy approach. Four of 12 calves had a support duration of several days (4, 4, 8, and 10 days), allowing for the exploration of early steps of hemostasis parameters, including prothrombin time; coagulation factor levels (II, V, VII+X, and fibrinogen); and platelet count. Multimeric analysis of VWF was performed to detect a potential loss of high-molecular weight (HMW) multimers, as previously described for continuous flow rotary blood pumps. Despite the absence of anticoagulant treatment administered in the postoperative phase, no signs of coagulation activation were detected. Indeed, after an immediate postsurgery decrease of prothrombin time, platelet count, and coagulation factor levels, most parameters returned to baseline values. HMW multimers of VWF remained stable either after initiation or during days of support. Coagulation parameters and platelet count recovery in the postoperative phase of the Carmat TAH (Camat SA, Velizy Villacoublay Cedex, France) implantation in calves, in the absence of anticoagulant treatment and associated with the absence of decrease in HMW multimers of VWF, is in line with early hemocompatibility that is currently being validated in human clinical studies.