Bioprosthetic Total Artificial Heart Research Articles

PB1371 Platelet Activation with the Aeson Bioprosthetic Total Artificial Heart: Insight from Aspirin Treatment and Outcomes

PB1371 Platelet Activation with the Aeson Bioprosthetic Total Artificial Heart: Insight from Aspirin Treatment and Outcomes

Bioprosthetic Total Artificial Heart Implantation Does Not Induce Chronic Inflammation.

The Aeson total artificial heart (A-TAH) has been developed for patients at risk of death from biventricular failure. We aimed to assess the inflammatory status in nine subjects implanted with the A-TAH in kinetics over one year. Laboratory assessment of leukocyte counts, inflammatory cytokines assay, and peripheral blood mononuclear cell collection before and after A-TAH implantation. Leukocyte counts were not significantly modulated according to time after A-TAH implantation (coefficient of the linear mixed effect model with 95% CI, -0.05 (-0.71 to -0.61); p = 0.44). We explored inflammatory cytokine after A-TAH and did not observe, at any time, a modified profile compared to pre-implantation values (all p -values > 0.05). Finally, we compared the distribution of circulating immune cell subpopulations identified based on sequential expression patterns for multiple clusters of differentiation. None of the population explored had significant modulation during the 12-month follow-up (all p -values > 0.05). In conclusion, using a cytokine multiplex assay combined with a flow cytometry approach, we demonstrated the absence of inflammatory signals in peripheral blood over a period of 12 months following A-TAH implantation.

Bioprosthetic Total Artificial Heart in Autoregulated Mode Is Biologically Hemocompatible: Insights for Multimers of von Willebrand Factor.

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. 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. 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 did not modify multimers profile of VWF in contrast to Heartmate II and Heartmate III. Furthermore, fluid structure interaction coupled with computational fluid dynamics showed a gradually increase of blood damage according to increase of cardiac output (P<0.01), however, the blood volume fraction that endured significant shear stresses was always inferior to 0.03% of the volume for both ventricles in all regimens tested. An inverse association between cardiac output, beat rate, and high-molecular weight multimers ratio was found. We demonstrated that A-TAH does not cause hemolysis or AWVS. However, relationship between HMWM and cardiac output depending flow confirms relevance of VWF as a biological sensor of blood flow, even in normal range.

Elevated Circulating Stem Cells Level is Observed One Month After Implantation of Carmat Bioprosthetic Total Artificial Heart.

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 includedin 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 month after A-TAH implantation regardless of the expression of CD133 or c-Kit. We then visualized data for the resulting clusters on a uniform manifold approximation and projection (UMAP) plot showing all single cells of the live Lin- and CD34+ events selected from down sampled files concatenated at T0 and T1. The three clusters upregulatedat T1 are CD45dim clusters, confirming our results. In conclusion, using a flow cytometry approach, we demonstrated in A-TAH-transplanted patients a significant mobilization of Lin-CD34+CD45dim in peripheral blood one month after A-TAH implantation. Using a flow cytometry approach, we demonstrated in A-TAH transplanted patients a significant mobilization of Lin-CD34+CD45dim in peripheral blood one month after A-TAH implantation. This cell population could be at the origin of newly formed endothelial cells on top of hybrid membrane in Carmat bioprosthetic total artificial heart.

Autoregulation of Pulsatile Bioprosthetic Total Artificial Heart is Involved in Endothelial Homeostasis Preservation.

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 endothelial protein C receptor (sEPCR) levels were found in patients after implantation with autoregulated C-TAH, whereas they significantly increased in the manual mode, as compared with pretransplant values (p = 0.005 and 0.001, respectively). In the autoregulated mode, a significant increase in the mobilization of cytokine stromal cell-derived factor 1 was found (p = 0.03). After adjustment on the mode of C-TAH, creatinine or C-reactive protein level, sEndoglin, and sEPCR, were found significantly associated with plasma total protein levels. Moreover, a significant decrease in pseudotubes formation and migration ability was observed in vitro in ECFCs receiving sEndoglin activation. Our combined analysis of endothelial biomarkers confirms the favorable impact of blood flow variation achieved with autoregulation in patients implanted with the bioprosthetic total artificial heart.

Hemocompatibility and safety of the Carmat Total Artifical Heart hybrid membrane

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 in-house 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.

Safety validation study of the hybrid membrane in the Carmat bioprosthetic Total Artificial Heart

The Carmat bioprosthetic Total Artificial Heart (C-TAH) is a mechanical circulatory support device providing an alternative to the heart transplant for patients in advanced heart failure. One of the most original components of the C-TAH is its biocompatible hybrid membrane made of bovine pericardial tissue and polyurethane separating the actuating liquid of the pump from blood inside ventricles. The aim of our study is to evaluate safety of the hybrid membrane in terms of mechanical aging, risks of calcification, and impact on the hemodynamics inside ventricles on red blood cells, platelet and von willebrand factor (vWF) impairment. Hybrid membranes were aged in a custom-designed endurance bench then evaluated in terms of mechanical proprieties and physical degradation. Erosion areas were explored in electronic microscopy and surface topography. Samples were subcutaneously implanted in Wistar rats as a model for calcification. Hemodynamic simulation using computational model has been used to reproduce shear stress in both ventricles. Compliance of the membrane is not significantly modified from 9 month to a 4 years aging simulating process. Physical proprieties as glass transition temperature and infrared spectrum are not modified. Exploration of erosion areas showed no oil diffusion through the membrane. Implantation in wistar rats demonstrated that anticalcification pretreatment with FET was able to significantly reduce the calcium concentration. We confirmed the absence of calcification in the areas in contact with blood by microtomography in the feasability study. The hemodynamic simulation showed no significant stress able to trigger hemolysis, platelet activation or the degradation of the vWFmultimers, confirmed with the patients implanted in feasibility study. Mechanical aging, calcification model and hemodynamic simulation allowed us to confirm safety of the hybrid membrane used in the C-TAH.

A bioprosthetic total artificial heart for end-stage heart failure: Results from a pilot study

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. 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. 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. 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.

121 - Implantation of a bioprosthetic total artificial heart induces a profile of acquired hemocompatibility with recellularization of its blood-contacting membranes

121 - Implantation of a bioprosthetic total artificial heart induces a profile of acquired hemocompatibility with recellularization of its blood-contacting membranes

The Carmat Bioprosthetic Total Artificial Heart Is Associated With Early Hemostatic Recovery and no Acquired von Willebrand Syndrome in Calves

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.

First clinical use of a bioprosthetic total artificial heart: report of two cases

The development of artificial hearts in patients with end-stage heart disease have been confronted with the major issues of thromboembolism or haemorrhage. Since valvular bioprostheses are associated with a low incidence of these complications, we decided to use bioprosthetic materials in the construction of a novel artificial heart (C-TAH). We report here the device characteristics and its first clinical applications in two patients with end-stage dilated cardiomyopathy. The aim of the study was to evaluate safety and feasibility of the CARMAT TAH for patients at imminent risk of death from biventricular heart failure and not eligible for transplant. The C-TAH is an implantable electro-hydraulically actuated pulsatile biventricular pump. All components, batteries excepted, are embodied in a single device positioned in the pericardial sac after excision of the native ventricles. We selected patients admitted to hospital who were at imminent risk of death, having irreversible biventricular failure, and not eligible for heart transplantation, from three cardiac surgery centres in France. The C-TAH was implanted in two male patients. Patient 1, aged 76 years, had the C-TAH implantation on Dec 18, 2013; patient 2, aged 68 years, had the implantation on Aug 5, 2014. The cardiopulmonary bypass times for C-TAH implantation were 170 min for patient 1 and 157 min for patient 2. Both patients were extubated within the first 12 postoperative hours and had a rapid recovery of their respiratory and circulatory functions as well as a normal mental status. Patient 1 presented with a tamponade on day 23 requiring re-intervention. Postoperative bleeding disorders prompted anticoagulant discontinuation. The C-TAH functioned well with a cardiac output of 4·8-5·8 L/min. On day 74, the patient died due to a device failure. Autopsy did not detect any relevant thrombus formation within the bioprosthesis nor the different organs, despite a 50-day anticoagulant-free period. Patient 2 experienced a transient period of renal failure and a pericardial effusion requiring drainage, but otherwise uneventful postoperative course. He was discharged from the hospital on day 150 after surgery with a wearable system without technical assistance. After 4 months at home, the patient suffered low cardiac output. A change of C-TAH was attempted but the patient died of multiorgan failure. This preliminary experience could represent an important contribution to the development of total artificial hearts using bioprosthetic materials. CARMAT SA.

Animal studies with the Carmat bioprosthetic total artificial heart.

The Carmat bioprosthetic total artificial heart (TAH) contains bioprosthetic blood-contacting surfaces, and is designed for orthotopic cardiac replacement. In preparation for clinical studies, we evaluated the TAH performance and its effects on end-organ function in an animal model. Twelve female Charolais calves, 2-3 months of age and weighing 102-122 kg, were implanted with the TAH through a mid-sternotomy to ensure an adequate anatomic fit. The intended support duration was 4-10 days. Haematological values, creatinine, bilirubin and lactate levels were measured and mean arterial and central venous pressure, central venous oxygen saturation and TAH parameters were monitored. The calves were placed in a cage immediately postoperatively, and extubated on postoperative day 1 in most cases. Average support duration was 3 days, with 4 of 12 calves supported for 4, 4, 8 and 10 days. The initial procedures were used to refine surgical techniques and postoperative care. Pump output ranged from 7.3 to 10 l/min. Haemodynamic parameters and blood analysis were within acceptable ranges. No device failures occurred. No anticoagulation was used in the postoperative phase. The calves were euthanized in case of discomfort compromising the animal well-being, such as respiratory dysfunction, severe blood loss and cerebral dysfunction. Device explant analysis showed no thrombus formation inside the blood cavities. Histological examination of kidneys showed isolated micro-infarction in 2/12 animals; brain histology revealed no thromboembolic depositions. The Carmat bioprosthetic TAH implanted in calves up to 10 days provided adequate blood flow to organs and tissues. Low levels of haemolysis and no visible evidence of thromboembolic depositions in major organs and device cavities, without the use of anticoagulation, may indicate early-phase haemocompatibility of the TAH.

131 * CHRONIC ANIMAL EXPERIENCE WITH THE CARMAT BIOPROSTHETIC ARTIFICIAL HEART

S 28 EACTS Left ventricular assist device 2 Monday, 13 October 2014 131 CHRONIC ANIMAL EXPERIENCE WITH THE CARMAT BIOPROSTHETIC ARTIFICIAL HEART C. Latremouille, D. Duveau, B. Cholley, L. Zilberstein, P. Bruneval, J. Perles, P. Jansen, A. Carpentier Cardiovascular Surgery, European Hospital Georges Pompidou, Paris, France; Cardiovascular and Thoracic Surgery, Hopital G. et R. Laennec, Nantes, France; Anesthesie-Reanimation, European Hospital Georges Pompidou, Paris, France; Anaesthesiology & Critical Care, Ecole Nationale Veterinaire d’Alfort, Maisons-Alfort, France; Pathology, European Hospital Georges Pompidou, Paris, France; Medical, CARMAT SA, Velizy, France Objectives: The CARMAT total artificial heart (TAH) contains bioprosthetic blood-contacting surfaces and is designed for orthotopic cardiac replacement. In preparation for clinical studies, we evaluated the TAH performance and its effects on end-organ function in an animal model. Methods: Twelve female Charolais calves, 2–8 months of age and weighing 102– 122 kg were implanted with the TAH through a mid-sternotomy to ensure an adequate anatomic fit. The intended support duration was 4–10 days. Haematologic values, creatinine, bilirubin and lactate levels were measured and mean arterial and central venous pressure, central venous oxygen saturation and TAH parameters were monitored. Results: All calves were placed in a cage immediately postoperatively and extubated on postoperative day 1. Average support duration was 3 days, with 4/12 calves supported for 4, 4, 8 and 10 days. The initial procedures were used to refine surgical techniques and postoperative care. Pump output ranged from 7.3 to 10 l/min. Haemodynamic parameters and blood analysis stayed within acceptable ranges (Table). No device failures occurred. The calves were euthanised because of respiratory insufficiency/infections in most cases. Kidney and brain histology showed no evidence of thrombo-embolic depositions. Device explant analysis showed no thrombus formation inside the blood cavities. Parameter Pre-op Post-op Day1 Day2 Day3 Day4 Haemoglobin (g/100 ml) 10.7 ± 1.8 10.4 ± 1.7 9.7 ± 2.3 8.8 ± 1.7 8.8 ± 0.7 8.4 ± 0.5 Platelets (10/μl) 253 ± 95 122 ± 92 124 ± 88 94 ± 24 66 ± 19 86 ± 20 Free Hgb (mg/dl) 11.1 ± 6 34.4 ± 31.6 31.6 ± 26.5 8.1 ± 4.4 5.5 ± 1.9 10.4 ± 3.4 Creatinine (mmol/l) 134 ± 23 230 ± 32 362 ± 96 317 ± 189 289 ± 184 255 ± 181 Total bilirubin (mmol/l) 5.5 ± 2.6 4.9 ± 3.3 4.9 ± 1.9 5.3 ± 1.7 7.5 ± 4.2 N/A SVO2 (%) 73 ± 8 81 ± 9 70 ± 17 69 ± 8 78 ± 3 73 ± 12 Lactate (mmol/l) 0.6 ± 0.3 5.4 ± 3.1 8.3 ± 7.6 1.9 ± 1.4 2.1 ± 1.9 2 ± 1.1 MAP (mmHg) 92 ± 20 96 ± 20 80 ± 19 92 ± 11 99 ± 9 N/A CVP (mmHg) 12 ± 6 13 ± 4 8 ± 6 11 ± 10 N/A N/A Pump flow (l/min) 7.3 ± 2.4 6.7 ± 2.3 7.2 ± 1 9 ± 0.5 9.4 ± 1.2 9.4 ± 1.3 MAP: mean arterial pressure; CVP: central venous pressure. Conclusion: The CARMAT bioprosthetic TAH implanted in calves up to 10 days provided adequate blood flow to organs and tissues. Haemocompatibility of the TAH was confirmed by low levels of haemolysis and no evidence of thromboembolic depositions in major organs and device cavities. Interactive CardioVascular and Thoracic Surgery Sunday A bsracts 01 –06

In vitro haemocompatibility of a novel bioprosthetic total artificial heart

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. 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. 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. 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.