Central Role of Macrophages and Nucleic Acid Release in Myasthenia Gravis Thymus.

OBJECTIVE: Myasthenia gravis (MG) is a neuromuscular disease mediated by antibodies against the acetylcholine receptor (AChR). The thymus plays a primary role in AChR-MG and is characterized by a type I interferon (IFN) signature linked to IFN-ß. We investigated if AChR-MG was characterized by an IFN-I signature in the blood, and further investigated the chronic thymic IFN-I signature. METHODS: Serum levels of IFN-ß and IFN-α subtypes, and mRNA expression for IFN-I subtypes and IFN-stimulated genes in peripheral mononuclear blood cells (PBMCs) were analyzed. The contribution of endogenous nucleic acids in thymic expression of IFN-I subtypes was investigated in human thymic epithelial cell cultures and the mouse thymus. By immunohistochemistry, thymic CD68+ and CD163+ macrophages were analyzed in AChR-MG. To investigate the impact of a decrease in thymic macrophages, mice were treated with an anti-CSF1R antibody. RESULTS: No IFN-I signature was observed in the periphery emphasizing that the IFN-I signature is restricted to the MG thymus. Molecules mimicking endogenous dsDNA signalization (Poly(dA:dT) and 2'3'-cGAMP), or dexamethasone-induced necrotic thymocytes increased IFN-ß and α-AChR expression by thymic epithelial cells, and in the mouse thymus. A significant decrease in thymic macrophages was demonstrated in AChR-MG. In mice, a decrease in thymic macrophages led to an increase of necrotic thymocytes associated with IFN-ß and α-AChR expression. INTERPRETATION: These results suggest that the decrease of thymic macrophages in AChR-MG impairs the elimination of apoptotic thymocytes favoring the release of endogenous nucleic acids from necrotic thymocytes. In this inflammatory context, thymic epithelial cells may overexpress IFN-ß, which specifically induces α-AChR, resulting in self-sensitization and thymic changes leading to AChR-MG. ANN NEUROL 2023;93:643-654.

Early and Midterm Outcomes of Endovascular Aortic Arch Repair Using In Situ Laser Fenestration.

INTRODUCTION: The aim of this study is to present single-center outcomes in patients treated with in situ laser fenestration thoracic endovascular aortic repair (LFTEVAR) for various aortic arch pathologies and assess the impact of increasing experience. METHODS: The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement was followed. A retrospective analysis of prospectively collected single aortic center data was conducted, including baseline information and peri- and post-operative outcomes of consecutive patients managed with LFTEVAR for aortic arch pathologies. Patients were enrolled from April 1, 2017 to January 31, 2023. The cohort was dichotomized to compare early (2017-2019) and late experience (2020-2023). Primary outcomes were peri-operative mortality and cerebrovascular morbidity. RESULTS: Thirty patients were included (63.3% males, mean age 69.8±9.6 years); 21.4% presented with aortic ruptures. Aortic aneurysm involving the aortic arch was the most frequent pathology (53.3%). Forty target vessels (TVs) were revascularized, including 19 left subclavian arteries (47.5%) and 17 left common carotid arteries (42.5%). Double fenestrations were performed in 10 patients. The proximal landing zone was Ishimaru zone 0 in 5 patients (16.7%) and zone 1 in 13 patients (43.3%). Technical success was 93%. No spinal cord ischemia was recorded, and 3 patients (10%) suffered a post-operative stroke, of which 1 was major (3.3%). The median follow-up was 12 months (range=1-48 months). Thirty-day and follow-up mortality rates were 13.5% and 15.3%, respectively. Target vessel instability was 10%, of which 3.8% required reintervention. There was no statistically significant difference in outcomes between the early and late experience groups. CONCLUSIONS: Laser fenestration thoracic endovascular aortic repair of the aortic arch performed in experienced aortic centers is associated with low early mortality and stroke rates. It is a safe and effective therapeutic option in patients considered unfit for open repair. CLINICAL IMPACT: Custom-made devices for arch pathologies requiring urgent repair are not an option because of manufacturing delays. Off-the-shelf devices with single branch arch prostheses, and outside IFU techniques such as parallel-grafts and surgeon-modified endografts have been proposed in this setting. Another off-the-shelf alternative is in situ laser fenestration thoracic endovascular repair (LFTEVAR), which addresses many limitations of the other off-the-shelf options. Our study reports the outcomes of 30 patients treated with LFTEVAR, showing that it is a viable therapeutic option in patients considered unfit for open repair acknowledging that sufficient experience with complex endovascular aortic repair is mandatory to achieve acceptable outcomes in these high-risk patients with challenging aortic anatomies.

Early Outcomes on Triple-Branch Arch Device With Retrograde Left Common Carotid Branch: A Case Series.

INTRODUCTION: Endovascular aortic arch repair using multibranch devices has been applied in patients considered at high risk for open repair. The aim of this case series was to report the early outcomes in patients managed with a new design 3 branch arch custom-made device, including a retrograde left common carotid artery (LCCA) branch. METHODS: The Preferred Reporting Of CaSe Series in Surgery (PROCESS) guidelines were followed. All consecutive patients undergoing endovascular repair of an aortic arch lesion with a custom-made triple-branch device, including a retrograde LCCA branch (Cook Medical, Bloomington, IN, USA), between October 27, 2022, and February 28, 2023, were included. The presence of an arch aneurysm (degenerative or post-dissection) with diameter ≥55 mm and high risk for a conventional open repair set the indication for treatment. The primary outcomes were technical success and mortality at 30 days. Early morbidity and reinterventions were considered as secondary outcomes. RESULTS: Eight elective patients (87.5% men, mean age 72.3±27.0 years) were included. Five of them (62.5%) had undergone a previous ascending aorta repair of an acute type A aortic dissection. All patients were asymptomatic, except one, with left recurrent laryngeal nerve compression. The mean maximum aortic diameter was 70.4±21.0 mm. Percutaneous femoral and axillary access was used in all cases except three in which a cut down for right carotid access was performed. Technical success was 100%. Femoral access to the LCCA and implantation of the bridging stent was performed without technical challenges. No death nor cerebrovascular event was recorded during the 30 day follow-up. Five patients (62.5%) presented major complications, 3 related to access needing reintervention and the remaining related to congestive heart failure (CHF), which were managed successfully with medical treatment. Follow-up (range 1-4 month) was uneventful, except for one patient who presented a secondary type Ia endoleak. CONCLUSIONS: According to our early experience, the presence of a retrograde branch facilitated the revascularization of the LCCA through femoral access, decreasing the risk of cerebrovascular morbidity. Further analyses with longer follow-up are needed to evaluate the safety and efficacy of the device. CLINICAL IMPACT: Data arising mainly from the retrograde branch for the revascularization of the LSA are encouraging from a variety of devices. The premiminary experience with a triple-branched arch device, with a retrograde branche for the LSA but also for the LCCA, was associated with no 30 day mortality and 100% technical success.The device's design allowed swift catheterization and completion of the LCCA revascularization using femoral access exclusively.

In Situ Fenestrated Thoracic Endovascular Repair Using the Upstream Peripheral Go BackTM Re-Entry Catheter.

PURPOSE: The aim is to present a case of in situ fenestrated thoracic endovascular repair, using a re-entry peripheral catheter, needing urgent repair due to recurrent episodes of hemoptysis because of an aorto-bronchial fistula after previous thoracic endovascular aortic repair (TEVAR). TECHNIQUE: A 74-year-old male with a previous TEVAR presented with hemoptysis, fever, and cachexia. An aorto-bronchial fistula and type Ia endoleak were depicted on computed tomography angiography (CTA). Due to the patient's frail general condition, a proximal TEVAR extension was planned, prior to thoracotomy for debridement, and long-term antibiotics. An in situ fenestrated TEVAR was performed to provide proximal sealing and revascularize the left common carotid and subclavian arteries. For fenestration creation, an Upstream Peripheral Go Back catheter (Bentley, Hechingen, Germany) was used. The Go Back catheter has been approved as a re-entry tool for complex peripheral arterial revascularization. In this case, both fenestrations were successfully created. Proximal seal and target vessel patency were confirmed on CTA. Thoracotomy confirmed aortic exclusion. A wedge lobectomy was performed in combination with pediculated omentectomy to exclude the exposed endograft. CONCLUSION: In urgent cases, where custom-made thoracic devices are unavailable, in situ fenestrations with the Go Back catheter are an alternative to laser fenestrations. CLINICAL IMPACT: Fenestrations are often required in acute TEVAR to achieve a proximal seal in the arch. In situ fenestrations with the Go Back catheter are an alternative to laser fenestrations and PMEGs in this setting.

Impact of the COVID-19 Pandemic on Complex Aortic Aneurysm Surgery.

INTRODUCTION: This study aimed to evaluate the impact of COVID on total case load and peri-operative outcomes in patients undergoing open surgical repair (OSR) and endovascular repair (ER) of complex aortic aneurysms (cAAs). METHODS: A single-center retrospective analysis of prospective data of patients managed with elective cAA ER or OSR from January 2018 to December 2021 was conducted. A comparative analysis on the impact of the COVID-19 pandemic on the case volume and on the 30-day outcomes was assessed using time periods, before (2018-2019) and during the pandemic (2020-2021). RESULTS: During the 4-year study period, 255 patients with cAA were managed with ER and 576 with OSR. The pandemic did not reduce the cAA ER volume (p=0.12), but a statistically significant reduction in OSR case load was recorded (p=0.04). Following OSR, hospital length of stay (11.1 vs 10.3 days), and early mortality (6.94% vs 4.63%), were similar before and during the pandemic. In the ER cohort, baseline characteristics, early mortality (3.6% vs 4.1%, p=0.976), and morbidity (10% vs 14%, p=0.44), were comparable during the 2 periods. For ER cases, the hospital and intensive care unit (ICU) stay both decreased significantly (8±8-6±7 days, p<0.001 and 2±4 vs 1±6 days p=0.01, respectively) during the pandemic. CONCLUSION: Resource pressures drove modifications in clinical practice to reduce the length of hospitalization, without compromising the clinical outcomes, in patients undergoing ER of cAA. This modification was not effective in patients undergoing OSR that resulted in a significant decrease of this activity. CLINICAL IMPACT: The pandemic did not reduce complex endovascular repair (ER) volume (p=0.12) while a significant reduction in open surgical repair (OSR) case load was recorded (p=0.04). For the endovascular cohort, early mortality (p=0.976) and morbidity (p=0.44) remained stable, while the hospital and intensive care unit (ICU) stay decreased (p<0.001 and p=0.01, respectively) during the pandemic.

A Review: Single and MultiBranch Devices for the Treatment of Aortic Arch Pathologies with Proximal Sealing in Ishimaru Zone 0.

Recently published experience has shown that endovascular management of the aortic arch, including sealing in the proximal zones, can be a viable option for patients considered unfit for conventional open repair. Endograft designs vary and include single or multibranch devices, with or without the addition of surgical debranching. Initial reports show that both techniques can be performed with high technical success and acceptable perioperative morbidity and mortality rates in high volume centers. Single branch devices, available off-the-shelf, may provide a treatment option for emergent presentations where patients cannot wait for the design and manufacture of a customized endograft. Double or triple branched endografts are now increasingly implanted in high-volume aortic centers. The purpose of this review is to describe the single and multibranched endovascular devices currently available for aortic arch repair, their associated published outcomes, and to discuss their relative advantages and disadvantages.

Extracorporeal Membrane Oxygenation for Respiratory Failure Related to COVID-19: A Nationwide Cohort Study.

BACKGROUND: Despite expanding use, knowledge on extracorporeal membrane oxygenation support during the COVID-19 pandemic remains limited. The objective was to report characteristics, management, and outcomes of patients receiving extracorporeal membrane oxygenation with a diagnosis of COVID-19 in France and to identify pre-extracorporeal membrane oxygenation factors associated with in-hospital mortality. A hypothesis of similar mortality rates and risk factors for COVID-19 and non-COVID-19 patients on venovenous extracorporeal membrane oxygenation was made. METHODS: The Extracorporeal Membrane Oxygenation for Respiratory Failure and/or Heart failure related to Severe Acute Respiratory Syndrome-Coronavirus 2 (ECMOSARS) registry included COVID-19 patients supported by extracorporeal membrane oxygenation in France. This study analyzed patients included in this registry up to October 25, 2020, and supported by venovenous extracorporeal membrane oxygenation for respiratory failure with a minimum follow-up of 28 days after cannulation. The primary outcome was in-hospital mortality. Risk factors for in-hospital mortality were analyzed. RESULTS: Among 494 extracorporeal membrane oxygenation patients included in the registry, 429 were initially supported by venovenous extracorporeal membrane oxygenation and followed for at least 28 days. The median (interquartile range) age was 54 yr (46 to 60 yr), and 338 of 429 (79%) were men. Management before extracorporeal membrane oxygenation cannulation included prone positioning for 411 of 429 (96%), neuromuscular blockage for 419 of 427 (98%), and NO for 161 of 401 (40%). A total of 192 of 429 (45%) patients were cannulated by a mobile extracorporeal membrane oxygenation unit. In-hospital mortality was 219 of 429 (51%), with a median follow-up of 49 days (33 to 70 days). Among pre-extracorporeal membrane oxygenation modifiable exposure variables, neuromuscular blockage use (hazard ratio, 0.286; 95% CI, 0.101 to 0.81) and duration of ventilation (more than 7 days compared to less than 2 days; hazard ratio, 1.74; 95% CI, 1.07 to 2.83) were independently associated with in-hospital mortality. Both age (per 10-yr increase; hazard ratio, 1.27; 95% CI, 1.07 to 1.50) and total bilirubin at cannulation (6.0 mg/dl or more compared to less than 1.2 mg/dl; hazard ratio, 2.65; 95% CI, 1.09 to 6.5) were confounders significantly associated with in-hospital mortality. CONCLUSIONS: In-hospital mortality was higher than recently reported, but nearly half of the patients survived. A high proportion of patients were cannulated by a mobile extracorporeal membrane oxygenation unit. Several factors associated with mortality were identified. Venovenous extracorporeal membrane oxygenation support should be considered early within the first week of mechanical ventilation initiation.

"First in Man" Total Percutaneous Aortic Arch Repair With 3-Inner-branch Endografts: A Report of Two Cases.

SUMMARY BACKGROUND DATA: Aneurysms of the arch are a complex clinical problem and a technical challenge. Currently, over 40% of patients are considered unfit for conventional open surgery, requiring a cardiopulmonary bypass and hypothermic circulatory arrest. In experienced hands and appropriate anatomic conditions, arch-branched graft technology has shown to be a safe and effective alternative to open conventional surgery to patients that historically have had no surgical options. OBJECTIVES: This report summarizes the first in man implant of a three-vessel arch branch stent graft using a total percutaneous approach without the need for exposure of the cervical arteries-a surgical step with inherent problems and risks. METHODS: This approach was performed in two consecutive patients, a 66-year-old woman with a chronic post type A dissection 60 mm diameter aneurysm of the aortic arch, and a 72-year-old man with a 70 mm saccular degenerative atheromatous aortic arch aneurysm. RESULTS: Technical success was obtained in both cases. The patients were extubated in the operating theatre. Neither suffered any pre- or postoperative neurological deficits. Both were discharged home after remarkably uneventful hospital stays. There were no access complications. Postoperative computerized tomography scans and ultra-sound confirmed patent supra-aortic branches and completely excluded aneurysms. CONCLUSIONS: Our new truly minimally invasive approach demonstrates that it is possible to manage one of the most challenging treatments of aortic pathologies without any surgical incision. Further, evaluation and experience are required to confirm these promising results.

Targeted proteomics of right heart adaptation to pulmonary arterial hypertension.

No prior proteomic screening study has centred on the right ventricle (RV) in pulmonary arterial hypertension (PAH). This study investigates the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH.Plasma proteomic profiling was performed using multiplex immunoassay in 121 (discovery cohort) and 76 (validation cohort) PAH patients. The association between proteomic markers and RHMP, defined by the Mayo right heart score (combining RV strain, New York Heart Association (NYHA) class and N-terminal pro-brain natriuretic peptide (NT-proBNP)) and Stanford score (RV end-systolic remodelling index, NYHA class and NT-proBNP), was assessed by partial least squares regression. Biomarker expression was measured in RV samples from PAH patients and controls, and pulmonary artery banding (PAB) mice.High levels of hepatocyte growth factor (HGF), stem cell growth factor-ß, nerve growth factor and stromal derived factor-1 were associated with worse Mayo and Stanford scores independently from pulmonary resistance or pressure in both cohorts (the validation cohort had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added value to the REVEAL score in the prediction of death, transplant or hospitalisation at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams.High plasma HGF levels are associated with RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH. Assessing plasma HGF levels might identify patients at risk of heart failure who warrant closer follow-up and intensified therapy.

Urgent desensitization in patients bridged to heart transplantation under extracorporeal membrane oxygenation support: A preliminary experience.

Antihuman leukocyte antigen (HLA) antibodies restrict the access to cardiac allografts. Desensitization therapy is a major challenge in patients with cardiogenic shock waiting for urgent heart transplantation (HT). We retrospectively reviewed six patients (mean age of 37.5 years [16-70]) who underwent plasmapheresis (PP) under extracorporeal membrane oxygenation (ECMO) before transplant between January 2017 and September 2018. The average duration of follow-up was 25 months [20-32]. Mean fluorescence intensity (MFI) of HLA-specific antibodies was reported as follows: score 4 for MFI < 1000, score 6 for 1000 < MFI < 3000 and score 8 for MFI > 3000. The mean duration of ECMO support was 29 days [1-74] and 6.8 [1-29] PP sessions were performed per patient before transplant. The mean number of HLA-specific antibodies before HT was 9.6 for score 6 [4-13] and 5.8 for score 8 [1-12]. Four patients had major complications after transplantation (2 hemorrhagic shocks, 5 infectious events). Mean MFI reduction rate was 94% [79-100] for Class I and 44.2% for Class II [0-83]. Hospital survival was 100%, and early antibody-mediated rejection was diagnosed in one patient at 7 days after HT. Plasmapheresis under ECMO support was associated with favorable early outcomes in highly sensitized candidates for urgent heart transplantation.

Surgical aortic valve replacement in the modern era: Insights from the French Registry EPICARD.

OBJECTIVE: We sought to assess the demographic changes and postoperative outcomes of surgical aortic valve replacement (SAVR) in recent years since the advent of trans-catheter aortic valve implantation (TAVI) in France. METHODS: Demographic, surgical data, and early outcomes of patients undergoing SAVR for AS were reviewed from The French registry EPICARD before (2007-2012) and after (2013-2018) approval of TAVI by French health authorities. We included patients with less than 20% of missing data per variable and per patient. Univariate and multivariate analysis were conducted to assess for risk factors of mortality and acute kidney failure (AKF) requiring renal replacement therapy (RRT). RESULTS: A total of 27,398 patients from the EPICARD registry were included: 8819, in the early cohort (2007-2012) and 18,579 in the recent cohort (2013-2018). In-hospital and 30-day mortality rates were lower in the recent cohort compared to the early cohort, respectively 1.22% versus 2.20 (p < .001) and 1.22% versus 2.34% (p < .001). The bioprosthesis-to-mechanical prosthesis ratio significantly increased over the time: from 5.3 to 8.1. In the recent cohort, rates of postoperative blood transfusions, prolonged mechanical ventilation, and AKF requiring RRT were lower. In-hospital and 30-day mortality risks were decreased in the recent cohort, with odds ratio respectively of 0.668 [0.466-0.958] and 0.66 [0.460-0.945] in multivariate (p ≤ .005) and univariate analysis (p < .001). Risk of AKF with RRT was unchanged. CONCLUSION: This nationwide study from the French registry EPICARD shows significant reduced hospital mortality and persistent favourable early outcomes of SAVR since TAVI implementation.

Decreased expression of miR-29 family associated with autoimmune myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune disease mainly mediated by autoantibodies against the acetylcholine receptor (AChR) at the neuromuscular junction. The thymus is the effector organ, and its removal alleviates the symptoms of the disease. In the early-onset form of MG, the thymus displays functional and morphological abnormalities such as B cell infiltration leading to follicular hyperplasia, and the production of AChR antibodies. Type-I interferon (IFN-I), especially IFN-ß, is the orchestrator of thymic changes observed in MG. As Dicer and miR-29 subtypes play a role in modulating the IFN-I signalization in mouse thymus, we investigated their expression in MG thymus. METHODS: The expression of DICER and miR-29 subtypes were thoroughly investigated by RT-PCR in human control and MG thymuses, and in thymic epithelial cells (TECs). Using miR-29a/b-1-deficient mice, with lower miR-29a/b-1 expression, we investigated their susceptibility to experimental autoimmune MG (EAMG) as compared to wild-type mice. RESULTS: DICER mRNA and all miR-29 subtypes were down-regulated in the thymus of MG patients and DICER expression was correlated with the lower expression of miR-29a-3p. A decreased expression of miR-29 subtypes was similarly observed in MG TECs; a decrease also induced in TECs upon IFN-ß treatment. We demonstrated that miR-29a/b-1-deficient mice were more susceptible to EAMG without higher levels of anti-AChR IgG subtypes. In the thymus, if no B cell infiltration was observed, an increased expression of Ifn-ß associated with Baff expression and the differentiation of Th17 cells associated with increased expression of Il-6, Il-17a and Il-21 and decreased Tgf-ß1 mRNA were demonstrated in miR-29a/b-1-deficient EAMG mice. CONCLUSIONS: It is not clear if the decreased expression of miR-29 subtypes in human MG is a consequence or a causative factor of thymic inflammation. However, our results from the EAMG mouse model indicated that a reduction in miR-29a/b1 may contribute to the pathophysiological process involved in MG by favoring the increased expression of IFN-ß and the emergence of pro-inflammatory Th17 cells.

Proximal outflow graft extrinsic compression of the Heartmate 3 centrifugal flow left ventricular assist device resulting in pump dysfunction.

We herein report an unusual life-threatening complication with the Hearmate 3 centrifugal ventricular assist device: proximal outflow graft extrinsic compression due to external thrombus leading to pump dysfunction and urgent heart transplantation. Low flow alarms without other abnormalities lead to the diagnosis of outflow occlusion. There was no evidence for a twist of the outflow graft, and no evidence for outflow thrombosis. The location of the outflow occlusion was particularly difficult to diagnose due to metallic artifacts around the pump. This report underscores that this complication should be screened in case of persistent low-flow alarms with the Heartmate 3 centrifugal pump.

Valve-sparing aortic root replacement in a patient with retroaortic course of the left circumflex artery.

Anomalous origin of the left circumflex artery (LCA) arising from the right coronary sinus was observed in a 45-year-old man with aortic root aneurysm. Valve-sparing aortic root replacement (VSARR) was decided despite the subannular course of the LCA. A modified Tirone David procedure was performed with specific consideration for distribution of the proximal suture line due to the periaortic and subannular course of the LCA. Due to the risk of LCA injury, a coronary artery bypass grafting was performed using the left internal thoracic artery to secure the perfusion of the LCA. The challenging association of aortic root aneurysm and anomalous origin and course of the LCA was managed successfully during VSARR.

Orthotopic tracheal transplantation using human bronchus: an original xenotransplant model of obliterative airway disorder.

Bronchiolitis obliterans syndrome (BOS) is a main cause of allograft dysfunction and mortality after lung transplantation (LTx). A better understanding of BOS pathogenesis is needed to overcome this treatment-refractory complication. Orthotopic tracheal transplantation using human bronchus was performed in Brown Norway (BN) and nude (RNU) rats. Allografts were recovered in both strains at Day 7 (BN7 , n = 6; RNU7 , n = 7) or Day 28 (BN28 , n = 6; RNU28 , n = 6). Immune response of the host against the bronchial graft was assessed. Human samples from BOS patients were used to compare with the histological features of the animal model. Obstruction of the allograft lumen associated with significant infiltration of CD3+ and CD68+ cells was observed in the BN group on Day 28. Immune response from type 1 T-helper cells against the tracheal xenograft was higher in BN animals compared to nude animals on Days 7 and 28 (P < 0.001 and P = 0.035). Xenoreactive antibodies were significantly higher at Day 7 (IgM) and Day 28 (IgG) in the BN group compared to RNU (respectively, 37.6 ± 6.5 vs. 5.8 ± 0.7 mean fluorescence, P = 0.039; and 22.4 ± 3.8 vs. 6.9 ± 1.6 mean fluorescence, P = 0.011). Immunocompetent animals showed a higher infiltration of S100A4+ cells inside the bronchial wall after 28 days, associated with cartilage damage ranging from invasion to complete destruction. In vitro expression of S100A4 by human fibroblasts was higher when stimulated by mononuclear cells (MNCs) from BN rats than from RNU (2.9 ± 0.1 vs. 2.4 ± 0.1 mean fluorescence intensity, P = 0.005). Similarly, S100A4 was highly expressed in response to human MNCs compared to stimulation by T-cell-depleted human MNCs (4.3 ± 0.2 vs. 2.7 ± 0.1 mean fluorescence intensity, P < 0.001). Obliterative bronchiolitis has been induced in a new xenotransplant model in which chronic airway obstruction was associated with immune activation against the xenograft. Cartilage infiltration by S100A4+ cells might be stimulated by T cells.

Right ventricular reserve in a piglet model of chronic pulmonary hypertension.

Right ventricular (RV) response to exercise or pharmacological stress is not well documented in pulmonary hypertension (PH). We investigated the relationship between RV reserve and ventricular-arterial coupling. Surgical ligation of the left pulmonary artery was performed in 13 Large White piglets (PH group), thereafter weekly embolisations of the right lower lobe were performed for 5 weeks. A control group of six piglets underwent sham procedures. Right heart catheterisation and echocardiography were performed at week 6. Pressure-volume loops were recorded before and after dobutamine infusion. Induction of experimental PH resulted in a higher mean ± sd pulmonary artery pressure (34 ± 9 versus 14 ± 2 mmHg; p<0.01) and in a lower ventricular-arterial coupling efficiency (0.66 ± 0.18 versus 1.24 ± 0.17; p<0.01) compared with controls at 6 weeks. Dobutamine-induced relative changes in RV stroke volume index (SVI) and end-systolic elastance were lower in the PH group (mean ± SD 47 ± 5% versus 20 ± 5%, p<0.01, and 81 ± 37% versus 32 ± 14%, p<0.01, respectively). Change in SVI was strongly associated with resting ventricular-arterial coupling (R(2)=0.74; p<0.01). RV reserve was associated with ventricular-arterial coupling in a porcine model of chronic pressure overload.

Septal curvature is marker of hemodynamic, anatomical, and electromechanical ventricular interdependence in patients with pulmonary arterial hypertension.

AIMS: The objective of this study was to determine the factors independently associated with septal curvature in patients with pulmonary arterial hypertension (PAH). METHODS: Eighty-five consecutive patients with PAH who had an echocardiogram and a right heart catheterization within 24 hours of each others were included in the study. Septal curvature was assessed at the mid-papillary level using the eccentricity index (EI). Marked early systolic septal anterior motion was defined as a change in EI > 0.2 between end-diastole and early systole. Inter-ventricular mechanical delay was calculated as the percent time difference between right ventricular (RV) to left ventricular (LV) end-ejection time normalized for the RR interval. RESULTS: Average age was 45 ± 11 years and the majority of patients were women (75%). Mean right atrial pressure was 11 ± 7 mmHg, mean PAP was 52 ± 13 mmHg, relative RV area 1.8 ± 0.9, and RV fractional area change 24 ± 8%. End-diastolic EI was 1.6 ± 0.4 and systolic EI was 2.5 ± 0.8. On multivariate analysis relative pulmonary pressure, relative RV area, and inter-ventricular mechanical delay were independently associated with systolic EI (R(2) = 0.72, P < 0.001). Independent determinants of diastolic EI included relative RV area and mean PAP (R(2) = 0.69, P < 0.001). A systolic EI >1.08 differentiated patients with PAH from healthy controls with an AUC = 0.99. Patients with early systolic septal anterior motion (44% of subjects) had lower exercise capacity, more extensive ventricular remodeling, and worst ventricular function. CONCLUSION: Septal curvature is a useful marker of structural, hemodynamic, and electromechanical ventricular interdependence in PAH.

Doppler echocardiography for surveillance of acute cardiac allograft rejection: a 28-year single-center experience.

Background: Endomyocardial biopsies (EMB) are recommended for the detection of acute cardiac rejection (ACR) despite limited sensitivity. We report the long-term post-transplant results of Doppler echocardiography as a noninvasive alternative of routine EMB. Methods: Two cohorts of heart transplantation (HT) recipients were chronologically defined as follows: the Dual Monitoring Cohort (DMC) from January 1990 to December 1997 included patients who underwent routine EMB and Doppler echocardiography within 24 hours for ACR surveillance; and the "Echo-First Cohort" (EFC), including patients transplanted from January 1998 to December 2018 with Doppler echocardiography as first-line approach for ACR surveillance. Echocardiographic measurements of interest were collected: early diastolic (E) wave peak velocity; pressure half time (PHT) and isovolumetric relaxation time (IVRT). Post-transplant outcomes were reviewed and the Kaplan-Meier approach was used for survival estimates. Inter-operator variability for ultrasound measurements was investigated. Data were collected from medical records from January 2019 to December 2020. Results: A total of 228 patients were included, 99 patients in the DMC and 129 in the EFC. Overall, 5-, 10- and 15-year survival rates were 65.4%, 55.5% and 44.1% respectively, without any significant difference between the two cohorts (log rank test, P=0.71). Echocardiography variables and EMB findings were associated with a mean area under the receiver operating characteristic curve (AUC-ROC) of 0.73 [95% confidence interval (CI): 0.54-0.91], 0.74 (95% CI: 0.54-0.94) and 0.75 (95% CI: 0.57-0.94) respectively for E wave, PHT and IVRT. IVRT and PHT were significantly decreased, and E wave significantly increased, in case of histologically proven ACR. Inter-operator variability was not significant for E wave and IVRT measurements (P=0.13 and 0.30 respectively). Conclusions: Doppler echocardiography as a first-line method for surveillance of ACR did not impair long-term results after HT. These findings suggest that this non-invasive approach might be a reasonable alternative to systematic EMB, limiting risk and improving the quality of life.