Thoracic Endovascular Repair after Total Aortic Arch Replacement with Frozen Elephant Trunk for Type a Aortic Dissection.

BACKGROUND: The management of residual aortic dissection after initial type A repair with the Frozen elephant trunk technique remains mostly unexplored. This work aimed to evaluate endovascular second-stage surgery for patients with residual aortic dissection. METHODS: A retrospective analysis of consecutive patients that underwent Type A aortic repair with Frozen elephant trunk, followed by a second-stage endovascular procedure was done from March 2016 to December 2021. The primary outcome was aortic-related adverse events or mortality, and secondary outcomes were aortic remodeling and perioperative complications. Remodeling was assessed by comparing the difference in ratios for true lumen/total aortic diameters on pre-operative and follow-up scans. RESULTS: Thirty-four patients underwent second-stage surgery after Type A repair during the study period (7 thoracic endovascular aortic repair extensions, 1 STABLE/PETTICOAT, and 26 STABILISE). Median follow-up was 23 months (range 2-66 months). There were no perioperative deaths or major complications and 1 reoperation for left subclavian re-embolization. At the last follow-up, there was no aortic-related mortality. There were 5 aortic-related adverse events, including another subclavian re-embolization and a preplanned open conversion. Risk factors were connective tissue disorders (P = 0.01) and aortic aneurysms >55 mm (P = 0.03). Distal remodeling reached statistical significance in all segments (P < 0.01) and was greater for patients treated with the STABILISE technique when compared to extended thoracic endovascular aortic repair (P = 0.01). CONCLUSIONS: Second-stage endovascular management of residual aortic dissection after initial Frozen elephant trunk repair showed excellent perioperative and good midterm outcomes and induced significant remodeling of the entire aorta in most cases, particularly with the STABILISE procedure.

Tetraplegia after branched frozen elephant trunk implantation for acute type A aortic dissection.

A 58-year-old male patient presented with acute type A aortic dissection. Complete arch and ascending aorta replacement were performed using a Thoraflex Hybrid prosthesis. The left subclavian artery was ligated and the remaining supra-aortic trunks were reimplanted using the branches of the prosthesis. After an uneventful early postoperative period, sudden onset of hypotension and bradycardia occurred, with severe vasoplegia, requiring vasopressors. Ischemia of the upper left limb and compartment syndrome ensued, leading to left carotid subclavian bypass. After discontinuation of sedation, tetraplegia was noted due to spinal cord ischemia from C3 to C7.

Technical Aspects of Open Repair for Degenerative Aneurysmal Evolution Despite Early Thoracic Endovascular Repair of Type B Aortic Dissection.

BACKGROUND: Closure of the proximal tear by thoracic endovascular aortic repair (TEVAR) at the acute phase appears to be a safe effective treatment to prevent aneurysmal degeneration type B dissection. However, it appears to be inefficient in up to a third of the patient. We report the technical aspects of our experience with patients undergoing secondary open repair after TEVAR for dissecting thoracoabdominal aneurysm despite early closure proximal tear by TEVAR. METHODS: During a period of 5 years, 96 patients presenting acute type B aortic dissections were treated by TEVAR and followed-up in our institution. Among them, 5 patients experienced an evolution to a dissecting thoracoabdominal aortic aneurysm. Their demographic data and initial medical conditions, delay to reintervention, operative technical details, perioperative and mid-term outcomes were collected and analyzed. RESULTS: All 5 patients (4 male, mean age 58 ± 9) were operated under peripheral normothermic bypass without deep circulatory arrest using the thoracic stent graft as an elephant trunk for completion of the proximal anastomosis. In cases of patency, the false lumen was reapproximated in the anastomosis, 6 visceral arteries were revascularized selectively. One patient died at day 1 of perioperative ventricular fibrillation due to an acute myocardial infarction. The 4 others are alive without complication after a median of 30 months, range (13-22). CONCLUSIONS: In our experience, TEVAR was not only efficient at the acute phase to deal with complications, but in cases of subsequent aneurysmal evolution, it made open repair even easier by avoiding very proximal cross-clamping/anastomosis and circulatory arrest.

Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report.

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

Towards a clinical use of human embryonic stem cell-derived cardiac progenitors: a translational experience.

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

Comprehensive annular and subvalvular repair of chronic ischemic mitral regurgitation improves long-term results with the least ventricular remodeling.

BACKGROUND: Undersized ring annuloplasty for ischemic mitral regurgitation (MR) is associated with variable results and >30% MR recurrence. We tested whether subvalvular repair by severing second-order mitral chordae can improve annuloplasty by reducing papillary muscle tethering. METHODS AND RESULTS: Posterolateral myocardial infarction known to produce chronic remodeling and MR was created in 28 sheep. At 3 months, sheep were randomized to sham surgery versus isolated undersized annuloplasty versus isolated bileaflet chordal cutting versus the combined therapy (n=7 each). At baseline, chronic myocardial infarction (3 months), and euthanasia (6.6 months), we measured left ventricular (LV) volumes and ejection fraction, wall motion score index, MR regurgitation fraction and vena contracta, mitral annulus area, and posterior leaflet restriction angle (posterior leaflet to mitral annulus area) by 2-dimensional and 3-dimensional echocardiography. All groups were comparable at baseline and chronic myocardial infarction, with mild to moderate MR (MR vena contracta, 4.6±0.1 mm; MR regurgitation fraction, 24.2±2.9%) and mitral annulus dilatation (P<0.01). At euthanasia, MR progressed to moderate to severe in controls but decreased to trace with ring plus chordal cutting versus trace to mild with chordal cutting alone versus mild to moderate with ring alone (MR vena contracta, 5.9±1.1 mm in controls, 0.5±0.08 with both, 1.0±0.3 with chordal cutting alone, 2.0±0.4 with ring alone; P<0.01). In addition, LV end-systolic volume increased by 108% in controls versus 28% with ring plus chordal cutting, less than with each intervention alone (P<0.01). In multivariate analysis, LV end-systolic volume and mitral annulus area most strongly predicted MR (r(2)=0.82, P<0.01). CONCLUSIONS: Comprehensive annular and subvalvular repair improves long-term reduction of both chronic ischemic MR and LV remodeling without decreasing global or segmental LV function at follow-up.

Evaluation of rat heart microvasculature with high-spatial-resolution susceptibility-weighted MR imaging.

PURPOSE: To demonstrate that strandlike hypointense signals seen in the myocardium of normal rat hearts correspond to myocardial microvessels with high-spatial-resolution susceptibility-weighted (SW) magnetic resonance (MR) imaging without injection of contrast medium. MATERIALS AND METHODS: Animal experiments were performed with institutional animal care committee approval. Ex vivo cardiac MR imaging was performed in 10 normal Wistar rats with a 4.7-T imager and a cryogenic probe. The hypothesis that thin tubular hypointense signals in the myocardium of rat hearts at SW MR imaging sequences (group 1, n = 6; in-plane resolution, 39 µm) represent intramyocardial microvessels was tested. A superparamagnetic intravascular contrast agent (ferumoxsil; Lumirem) was used to explore the distribution of the intramyocardial microvessels (group 2, n = 4; three-dimensional fast imaging with steady-state free precession sequences). Nonparametric Mann-Whitney tests were performed to compare groups 1 and 2 both for microvascular densities (MVD) on histologic sections and for MR imaging signal intensities (SIs). Wilcoxon signed rank tests were used for paired comparison of subepicardial and subendocardial MVD and SI within groups. RESULTS: Ferumoxsil opacified the coronary microvasculature (group 2) on MR-matched histologic sections. No statistically significant difference was found between groups 1 and 2 for either MVD or MR imaging SI expressed as ratios between subendocardium and subepicardium (P = .40 and P = .46, respectively). The comparison of mean subendocardial and subepicardial SI within groups revealed significantly more microvessels in the subepicardium with MR (group 1: P = .01; group 2: P = .004). CONCLUSION: Myocardial microvessels appear as strandlike structures on high-spatial-resolution SW MR images without the aid of contrast medium injection.

Spot stenting of the tear in type B aortic dissection.

BACKGROUND: In selected type B acute aortic dissection with aortic growth and patent false lumen, an intervention may be required to prevent aortic rupture. Apart from stent grafting of the thoracic aorta, aimed at occluding the primary intimal tear, some have advocated closure of reentry tears by stent grafting of the aortic true lumen after hybrid revascularization of the excluded viscera or by branched aortic endografts. METHODS: We describe a simple technique for occluding a major reentry tear in the visceral abdominal aorta, using on-the-shelf covered stent grafts, arising from the aortic true lumen, crossing the dissection septum tear and aortic false lumen, and being distally anchored in the visceral branch vessel, acting as a rivet on the dissection septum tear, achieving aortic false lumen thrombosis. RESULTS: In selected cases, we achieved aortic false lumen thrombosis by spot stenting of the tear. CONCLUSIONS: This spot stenting technique may be a useful way of achieving complete false lumen thrombosis or lowering the false lumen pressure of degenerating dissecting aneurysms.

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.

Percutaneous venopulmonary artery extracorporeal membrane oxygenation for right heart failure after left ventricular assist device insertion.

OBJECTIVES: Right ventricular failure after left ventricular assist device (LVAD) insertion is associated with significant mortality and morbidity. Mechanical support options include right ventricular assist devices, venoarterial extracorporeal membrane oxygenation (ECMO) and venopulmonary artery ECMO, the latter often involving central cannulation. We sought to evaluate the feasibility and early outcomes of a truly percutaneous venopulmonary artery (pVPA) ECMO strategy, with the potential advantage of bedside removal once weaned. METHODS: Data from a single tertiary centre were reviewed retrospectively from January 2014 to January 2019. During this time, 54 patients underwent LVAD insertion, with 19 requiring mechanical support for right ventricular failure. Among them, 10 patients received pVPA ECMO. Implantation of the pVPA ECMO was performed under transoesophageal echocardiography and fluoroscopy guidance, with an inflow cannula placed in the right atrium via the right femoral vein and an outflow cannula placed in the left pulmonary artery (PA) via the right internal jugular vein. RESULTS: Cannula insertion was 100% successful with no need for repositioning. Eight patients (80%) were able to be successfully weaned (at the bedside); 6 were discharged from the hospital and there were no cases of early sepsis, mediastinitis or thromboembolism. At follow-up, 5 patients had received transplants (50%), with 1 on LVAD support as destination therapy (10%). Survival was 60 ± 15% and 50 ± 16% at 6 and 12 months, respectively. CONCLUSIONS: pVPA ECMO is 100% technically feasible and is an efficient method for temporary right ventricular support after LVAD insertion with the advantage of simple bedside removal and avoidance of a PA graft remnant in the chest cavity.

Stent-assisted balloon dilatation of chronic aortic dissection.

BACKGROUND: The treatment of complicated chronic aortic dissection remains controversial. We previously reported encouraging early results with the stent-assisted balloon-induced intimal disruption and relamination of aortic dissection (STABILISE) technique for treating complicated acute aortic dissections. However, to date there have been no specific reports on the treatment of complicated chronic aortic dissections with this technique. The aim of this study was to assess the results of the STABILISE technique to treat complicated chronic aortic dissection. METHODS: A single-center prospectively maintained database enrolled all patients hospitalized for aortic dissection at our institution. Inclusion criteria for the STABILISE procedure at the chronic stage of dissection (>3 months) were postdissection aneurysm with a diameter >55 mm or rapid aortic diameter growth >5 mm/6 months. We reviewed all patients treated for complicated chronic aortic dissection with the STABILISE technique. Patients were monitored at 3, 6, and 12 months and annually thereafter with clinical, imaging, and laboratory studies. Outcome analyses included survival, rupture, spinal cord ischemia, endoleak, morbidity (cardiac, renal, or pulmonary), reinterventions, false lumen patency, and aneurysm growth. RESULTS: Between September 2015 and December 2018, 17 patients underwent a STABILISE procedure for complicated chronic aortic dissection of the descending aorta. Fifteen patients were treated for remaining chronic distal thoracoabdominal aortic dissection after acute DeBakey type I aortic dissection repair, and 2 patients were treated for chronic type B aortic dissection. The median patient age was 61 years (range, 46-67 years). The median interval between the onset of acute symptoms and the procedure was 9 months (range, 3-67 months). Indications for the STABILISE procedure were a rapidly growing dissected aortic diameter >5 mm/6 months in 13 patients and aneurysmal evolution of the descending thoracic aorta >55 mm in 4 patients. There were no cases of in-hospital death, stroke, spinal cord ischemia, ischemic colitis, or renal failure necessitating dialysis. The median duration of follow-up was 17 months (range, 5-28.5 months). At the last computed tomography scan, 15 patients (88%) had complete false lumen thrombosis of the treated thoracoabdominal aorta down to the renal arteries. None of the patients had aortic growth at treated thoracoabdominal aorta level. One patient developed a proximal type 1 endoleak and required reintervention. Regarding the untreated aortoiliac level below the renal arteries, 11 patients had persistent false lumen patency, and 1 patient developed a common iliac artery aneurysm. All the other patients had stable infrarenal aortoiliac diameters. No late deaths were reported during follow-up. CONCLUSIONS: The STABILISE technique is a safe and effective means of performing immediate, complete aortic remodeling of the thoracoabdominal aorta in patients with complicated chronic aortic dissection, stabilizing the diameter of the dissected aorta.

Thrombus of the Aorta and SARS-CoV-2 Infection: Cause or Trigger?

Objective: Coronavirus disease 19 is a well-established cause of rare arterial thrombosis. Nevertheless, the exact mechanism of arterial thrombosis remains to be elucidated. We herein report the case of a large floating thrombus of the aortic arch, its surgical management and histological analysis. Case: A 65-year-old patient presented to the emergency department with a suspected stroke. He was non-smoker, but presented cardiovascular risk factors, namely hypertension, type 2 diabetes and hyperlipidaemia. A computed tomography of the aorta revealed a large floating thrombus of the aortic arch, at the base of the brachiocephalic trunk, suspected to be the etiology of stroke. Therapeutic anticoagulation was immediately started. The decision was made to perform an open aortic replacement surgery because of the symptomatic thromboembolic event with recent cerebral infarction and the potential harmfulness of the thrombus due to its size. A mobile thrombus was observed at the base of the brachiocephalic trunk by echocardiography. It was attached to a small area of the upper aortic wall and had an irregular surface. Histology revealed a platelet-rich thrombus lying on an aortic atherosclerotic plaque without pronounced inflammation. No plaque ulceration was present but endothelial cell desquamation was observed consistent with plaque erosion. Conclusion: In our case, there was a thrombus lying on an atherosclerotic plaque with intact thick fibrous cap, but associated with a plaque erosion mechanism. The thrombus formation appeared more likely to relate to a very localized endothelial injury.

Does the human skeletal muscle harbor the murine equivalents of cardiac precursor cells?

The limited plasticity of adult muscle- or bone marrow- derived stem cells intended for cardiac regeneration impedes their conversion into cardiomyocytes. Since murine skeletal muscle was reported to harbor cardiac precursor cells, we assessed whether similar cells exist in man. Skeletal muscle biopsies obtained from 39 patients were sorted by flow cytometry which generated three populations (CD90+/CD34(-), CD34+/CD90(-), CD90(-)/CD34(-)) expressing similar levels of cardiac (Nkx2.5, cTn-T, cTn-I, Cx43) and skeletal muscle (Myf-5, MyoD, myogenin) mRNAs, as assessed by quantitative reverse transcriptase-PCR. However, compared to unpurified myoblasts, CD34+/CD90(-) cells expressed greater amounts of endothelium-specific mRNAs and were, therefore, selected for transplantation experiments. Thirty immunosuppressed rats then underwent coronary artery ligation and, 4 weeks later, were intramyocardially injected with culture medium, myoblasts, or CD34+/CD90(-) cells. After 1 month, left ventricular ejection fraction was significantly higher in the CD34+/CD90(-) group than in the control and myoblast-injected hearts, which was associated with smaller fibrosis and greater angiogenesis. The low engraftment rate suggested a paracrine mechanism supported by the greater release of growth factors by CD34+/CD90(-) cells than by unsorted myoblasts. In conclusion, the human skeletal muscle does not harbor cardiac-specified cells but contains a CD34+ fraction endowed with an angiogenic potential providing superior functional and structural benefits.

Feasibility and safety of non-invasive ultrasound therapy (NIUT) on an porcine aortic valve.

Calcific aortic stenosis (CAS) is associated with advanced age and comorbidities, therefore a non-invasive therapy for it would be beneficial. We previously demonstrated that ultrasound therapy improved calcified bioprosthetic valve function in an open chest model. For translational applications, we tested non-invasive ultrasound therapy (NIUT) transthoracically on swine aortic valves and investigated the need for antithrombotic treatment as a follow-up. Primary objective: feasibility and safety of NIUT. Secondary objectives: occurrence, severity and evolution of side effects during therapy and at 1 month follow-up. The device (Valvosoft, Cardiawave) consisted of an electronically steered multi-element transducer and a 2D echocardiographic probe. Three groups of swine received treatment on aortic valves: NIUT (group 1; n = 10); NIUT and 1 month antithrombotic treatment (group 2; n = 5); sham group (group 3; n = 4). Feasibility was successfully reached in all treated swine (n = 15) and no life-threatening arrhythmia were detected. Non-sustained ventricular tachycardia occurred during the procedure in seven swine. Decrease or interruption of NIUT ended arrhythmia. Histopathology revealed no valve or surrounding tissue damage and echocardiography revealed no valvular dysfunction. Only one animal had side effects [right ventricle (RV) dilatation], but the RV normalized after therapy cessation with no sequelae at follow-up. No disturbance in biological markers nor valve thrombosis were observed at follow-up. Antithrombotic treatment did not demonstrate any advantage. Survival at 30 d was 100%. We demonstrated, in vivo, the feasibility and safety of transthoracic NIUT on aortic valves in a swine model without serious adverse events. We expect this first-time transthoracic delivery of NIUT to pave the way towards a new non-invasive approach to valve softening in human CAS to restore valve function.

Stent-assisted balloon-induced intimal disruption and relamination of distal remaining aortic dissection after acute DeBakey type I repair.

OBJECTIVES: Surgical repair in patients with acute DeBakey type I aortic dissection (ADIAD) achieves good short-term results, but in several patients the false lumen remains patent in the descending aorta because of distal intimal tears with persisting risk for distal aneurismal evolution. We report the short- and mid-term outcomes of the stent-assisted balloon-induced intimal disruption and relamination of aortic dissection (STABILISE) technique for the 16 first patients treated for a residual dissection of the descending thoracic aorta after repaired ADIAD. METHODS: We reviewed all patients treated with STABILISE for a remaining distal thoracoabdominal aortic dissection after ADIAD repair. RESULTS: From March 2016 to March 2018, 16 patients with previous surgery for ADIAD underwent the STABILISE procedure during the same hospitalization in a second-stage procedure to extend the repair within the descending thoracic aorta. The median age was 56 years (range, 43-65 years). Indication for the STABILISE procedure was persisting false lumen patency within the thoracic descending aorta associated with malperfusion symptoms in 13 patients and associated with dissecting aneurysm of the descending thoracic aorta >40 mm in 3 patients. Technical success was achieved in 100%. Eight (12.5%) renal arteries required stenting during the procedure. In-hospital mortality was 6% (n = 1). There was no stroke, spinal cord ischemia, ischemic colitis, or renal failure requiring dialysis. Median length of follow-up was 8 months (range, 3-24 months). One patient developed a proximal type 1 endoleak in the arch and required reintervention for proximal extension of the stent graft in zone 2. The primary visceral patency rate was 100%. There were no late deaths reported. At last computed tomography scan, all patients had complete aortic remodeling of the treated thoracoabdominal aorta with no aortic enlargement. CONCLUSIONS: The STABILISE technique, in patients with remaining distal thoracoabdominal aortic dissection at the acute stage of a type A repair, allowed an immediate remodeling of the thoracoabdominal aorta, which should improve their long-term outcomes in terms of aortic-related events.

Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction.

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

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.

A novel controller based on state-transition models for closed-loop vagus nerve stimulation: Application to heart rate regulation.

Vagus nerve stimulation (VNS) is an established adjunctive therapy for pharmacologically refractory epilepsy and depression and is currently in active clinical research for other applications. In current clinical studies, VNS is delivered in an open-loop approach, where VNS parameters are defined during a manual titration phase. However, the physiological response to a given VNS configuration shows significant inter and intra-patient variability and may significantly evolve through time. VNS closed-loop approaches, allowing for the optimization of the therapy in an adaptive manner, may be necessary to improve efficacy while reducing side effects. This paper proposes a generic, closed-loop control VNS system that is able to optimize a number of VNS parameters in an adaptive fashion, in order to keep a control variable within a specified range. Although the proposed control method is completely generic, an example application using the cardiac beat to beat interval (RR) as control variable will be developed in this paper. The proposed controller is based on a state transition model (STM) that can be configured using a partially or a fully-connected architecture, different model orders and different state-transition algorithms. The controller is applied to the adaptive regulation of heart rate and evaluated on 6 sheep, for 13 different targets, using partially-connected STM with 10 states. Also, partially and fully-connected STM defined by 30 states were applied to 7 other sheep for the same 10 targets. Results illustrate the interest of the proposed fully-connected STM and the feasibility of integrating this control system into an implantable neuromodulator.