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.

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.

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.

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.

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.

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).

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.

Pulsed Cavitational Ultrasound Softening: a new non-invasive therapeutic approach of calcified bioprosthetic valve stenosis.

BACKGROUND: The majority of prosthetic heart valves currently implanted are tissue valves that can be expected to calcify with time and eventually fail. Surgical or percutaneous redux valve replacement is associated with higher rate of complications. We propose a novel non-invasive therapeutic approach based on the use of pulsed cavitational ultrasound (PCU) to improve the valvular function of degenerative calcified bioprosthesis. OBJECTIVES: Our study aims to demonstrate in vitro and in vivo on an ovine model that PCU can significantly improve the bioprosthesis opening by softening remotely the calcified stiff cusps. METHODS: All the experiments were performed on calcified bioprosthetic valves explanted from human patients. PCU was performed in vitro on calcified bioprosthesis mounted on a hydraulic bench with pulsatile flow (n=8) and in vivo on an ovine model with implanted calcified bioprosthesis (n=7). We used 3D echocardiography, pressure and flow sensors, quantitative stiffness evaluation using shear wave elastography, micro-CT imaging and histology to evaluate in vitro and in vivo the effect of PCU. RESULTS: The transvalvular gradient was found to decrease by a mean of 50% after PCU in both in vitro (from 21.1±3.9 to 9.6±1.7 mmHg, p<0.001) and in vivo setup (from 16.2±3.2 to 8.2±1.3 mmHg, p<0.001), with a decrease of valve stiffness (in vitro: from 105.8±9 to 46.6±4 kPa, p<0.001; in vivo: from 82.6±10 to 41.7±7 kPa, p<0.001) and an increase of valve area (from 1.10±0.1 to 1.58±0.1 cm2, p<0.001). Histology and micro-CT imaging showed modifications of calcification structure without loss of calcification volume or alteration of the leaflet superficial structures. CONCLUSIONS: We have demonstrated in vitro and in vivo that PCU can decrease a calcified bioprosthesis stenosis by softening the leaflets remotely. This new non-invasive approach has the potential to improve the outcome of patients with severe bioprosthesis stenosis.

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.

Sensitivity Analysis of Vagus Nerve Stimulation Parameters on Acute Cardiac Autonomic Responses: Chronotropic, Inotropic and Dromotropic Effects.

Although the therapeutic effects of Vagus Nerve Stimulation (VNS) have been recognized in pre-clinical and pilot clinical studies, the effect of different stimulation configurations on the cardiovascular response is still an open question, especially in the case of VNS delivered synchronously with cardiac activity. In this paper, we propose a formal mathematical methodology to analyze the acute cardiac response to different VNS configurations, jointly considering the chronotropic, dromotropic and inotropic cardiac effects. A latin hypercube sampling method was chosen to design a uniform experimental plan, composed of 75 different VNS configurations, with different values for the main parameters (current amplitude, number of delivered pulses, pulse width, interpulse period and the delay between the detected cardiac event and VNS onset). These VNS configurations were applied to 6 healthy, anesthetized sheep, while acquiring the associated cardiovascular response. Unobserved VNS configurations were estimated using a Gaussian process regression (GPR) model. In order to quantitatively analyze the effect of each parameter and their combinations on the cardiac response, the Sobol sensitivity method was applied to the obtained GPR model and inter-individual sensitivity markers were estimated using a bootstrap approach. Results highlight the dominant effect of pulse current, pulse width and number of pulses, which explain respectively 49.4%, 19.7% and 6.0% of the mean global cardiovascular variability provoked by VNS. More interestingly, results also quantify the effect of the interactions between VNS parameters. In particular, the interactions between current and pulse width provoke higher cardiac effects than the changes on the number of pulses alone (between 6 and 25% of the variability). Although the sensitivity of individual VNS parameters seems similar for chronotropic, dromotropic and inotropic responses, the interacting effects of VNS parameters provoke significantly different cardiac responses, showing the feasibility of a parameter-based functional selectivity. These results are of primary importance for the optimal, subject-specific definition of VNS parameters for a given therapy and may lead to new closed-loop methods allowing for the optimal adaptation of VNS therapy through time.

Pulsed cavitational ultrasound for non-invasive chordal cutting guided by real-time 3D echocardiography.

AIMS: Basal chordae surgical section has been shown to be effective in reducing ischaemic mitral regurgitation (IMR). Achieving this section by non-invasive mean can considerably decrease the morbidity of this intervention on already infarcted myocardium. We investigated in vitro and in vivo the feasibility and safety of pulsed cavitational focused ultrasound (histotripsy) for non-invasive chordal cutting guided by real-time 3D echocardiography. METHODS AND RESULTS: Experiments were performed on 12 sheep hearts, 5 in vitro on explanted sheep hearts and 7 in vivo on beating sheep hearts. In vitro, the mitral valve (MV) apparatus including basal and marginal chordae was removed and fixed on a holder in a water tank. High-intensity ultrasound pulses were emitted from the therapeutic device (1-MHz focused transducer, pulses of 8 µs duration, peak negative pressure of 17 MPa, repetition frequency of 100 Hz), placed at a distance of 64 mm under 3D echocardiography guidance. In vivo, after sternotomy, the same therapeutic device was applied on the beating heart. We analysed MV coaptation and chordae by real-time 3D echocardiography before and after basal chordal cutting. After sacrifice, the MV apparatus were harvested for anatomical and histological post-mortem explorations to confirm the section of the chordae. In vitro, all chordae were completely cut after a mean procedure duration of 5.5 ± 2.5 min. The procedure duration was found to increase linearly with the chordae diameter. In vivo, the central basal chordae of the anterior leaflet were completely cut. The mean procedure duration was 20 ± 9 min (min = 14, max = 26). The sectioned chordae was visible on echocardiography, and MV coaptation remained normal with no significant mitral regurgitation. Anatomical and histological post-mortem explorations of the hearts confirmed the section of the chordae. CONCLUSIONS: Histotripsy guided by 3D echo achieved successfully to cut MV chordae in vitro and in vivo in beating heart. We hope that this technique will open the door in the near future to the non-invasive treatment of functional IMR.

Shear Wave Imaging of Passive Diastolic Myocardial Stiffness: Stunned Versus Infarcted Myocardium.

OBJECTIVES: The aim of this study was to investigate the potential of shear wave imaging (SWI), a novel ultrasound-based technique, to noninvasively quantify passive diastolic myocardial stiffness in an ovine model of ischemic cardiomyopathy. BACKGROUND: Evaluation of diastolic left ventricular function is critical for evaluation of heart failure and ischemic cardiomyopathy. Myocardial stiffness is known to be an important property for the evaluation of the diastolic myocardial function, but this parameter cannot be measured noninvasively by existing techniques. METHODS: SWI was performed in vivo in open-chest procedures in 10 sheep. Ligation of a diagonal of the left anterior descending coronary artery was performed for 15 min (stunned group, n = 5) and 2 h (infarcted group, n = 5). Each procedure was followed by a 40-min reperfusion period. Diastolic myocardial stiffness was measured at rest, during ischemia, and after reperfusion by using noninvasive shear wave imaging. Simultaneously, end-diastolic left ventricular pressure and segmental strain were measured with a pressure catheter and sonomicrometers during transient vena caval occlusions to obtain gold standard evaluation of myocardial stiffness using end-diastolic strain-stress relationship (EDSSR). RESULTS: In both groups, the end-systolic circumferential strain was drastically reduced during ischemia (from 14.2 ± 1.2% to 1.3 ± 1.6% in the infarcted group and from 13.5 ± 3.0% to 1.9 ± 1.8% in the stunned group; p <0.01). SWI diastolic stiffness increased after 2 h of ischemia from 1.7 ± 0.4 to 6.2 ± 2.2 kPa (p < 0.05) and even more after reperfusion (12.1 ± 4.2 kPa; p < 0.01). Diastolic myocardial stiffening was confirmed by the exponential constant coefficient of the EDSSR, which increased from 8.8 ± 2.3 to 25.7 ± 9.5 (p < 0.01). In contrast, SWI diastolic stiffness was unchanged in the stunned group (2.3 ± 0.4 kPa vs 1.8 ± 0.3 kPa, p = NS) which was confirmed also by the exponential constant of EDSSR (9.7 ± 3.1 vs 10.2 ± 2.3, p = NS). CONCLUSIONS: Noninvasive SWI evaluation of diastolic myocardial stiffness can differentiate between stiff, noncompliant infarcted wall and softer wall containing stunned myocardium.

Inhibition of factor IXa by the pegnivacogin system during cardiopulmonary bypass: a potential substitute for heparin. A study in baboons.

OBJECTIVES: Heparin and protamine are standard for anticoagulation and reversal for cardiopulmonary bypass (CPB). The REGADO biosciences protocol 1 (REG1) anticoagulant system, consisting of the Factor IXa (FIXa)-inhibitor pegnivacogin and its reversal agent (anivamersen), has been studied in patients undergoing coronary catheterization and in CPB in sheep and pigs. Prior to first human use in CPB, we wanted to test the safety and efficacy of REG1 in a primate model. METHODS: Fourteen baboons undergoing 2 h of CPB followed by 1 h of reperfusion were studied. Three received heparin/protamine and 11 received 1 of 2 doses of pegnivacogin followed by anivamersen. Thrombin-generating capacity was tested in additional in vitro experiments. RESULTS: Targeted drug levels and near-complete FIXa inhibition were achieved. Bypass was run uneventfully in all animals without any clotting in the circuit and bleeding was minimal in the two groups. However, in contrast to heparin-treated baboons, those receiving pegnivacogin/anivamersen displayed thrombi in the bypass cannulae upon cannulation and kidney cortical infarcts. Inter-species comparisons revealed that in the presence of high levels of FIXa inhibition, tissue factor-mediated thrombin generation in baboons was much higher than that in other species. CONCLUSIONS: These data highlight the limitations of the baboon model for assessing factor-specific coagulation inhibitors during CPB. The justification for Phase 1 human studies using REG1 for CPB is unclear.

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.

Long-term functional benefits of human embryonic stem cell-derived cardiac progenitors embedded into a fibrin scaffold.

BACKGROUND: Cardiac-committed cells and biomimetic scaffolds independently improve the therapeutic efficacy of stem cells. In this study we tested the long-term effects of their combination. METHODS: Eighty immune-deficient rats underwent permanent coronary artery ligation. Five to 7 weeks later, those with an echocardiographically measured ejection fraction (EF) ≤55% were re-operated on and randomly allocated to receive a cell-free fibrin patch (n = 25), a fibrin patch loaded with 700,000 human embryonic stem cells (ESC) pre-treated to promote early cardiac differentiation (SSEA-1(+) progenitors [n = 30]), or to serve as sham-operated animals (n = 25). Left ventricular function was assessed by echocardiography at baseline and every month thereafter until 4 months. Hearts were then processed for assessment of fibrosis and angiogenesis and a 5-component heart failure score was constructed by integrating the absolute change in left ventricular end-systolic volume (LVESV) between 4 months and baseline, and the quantitative polymerase chain reaction (qPCR)-based expression of natriuretic peptides A and B, myosin heavy chain 7 and periostin. All data were recorded and analyzed in a blinded manner. RESULTS: The cell-treated group consistently yielded better functional outcomes than the sham-operated group (p = 0.002 for EF; p = 0.01 for LVESV). Angiogenesis in the border zone was also significantly greater in the cell-fibrin group (p = 0.006), which yielded the lowest heart failure score (p = 0.04 vs sham). Engrafted progenitors were only detected shortly after transplantation; no grafted cells were identified after 4 months. There was no teratoma identified. CONCLUSIONS: A fibrin scaffold loaded with ESC-derived cardiac progenitors resulted in sustained improvement in contractility and attenuation of remodeling without sustained donor cell engraftment. A paracrine effect, possibly on innate reparative responses, is a possible mechanism for this enduring effect.