The MIDA-Q Mortality Risk Score: A Quantitative Prognostic Tool for the Mitral Valve Prolapse Spectrum.

BACKGROUND: Mitral valve prolapse (MVP) is responsible for a considerable disease burden but is widely heterogeneous. The lack of a comprehensive prognostic instrument covering the entire MVP spectrum, encompassing the quantified consequent degenerative mitral regurgitation (DMR), hinders clinical management and therapeutic trials. METHODS: The new Mitral Regurgitation International Database Quantitative (MIDA-Q) registry enrolled 8187 consecutive patients (ages 63±16 years, 47% women, follow-up 5.5±3.3 years) first diagnosed with isolated MVP, without or with DMR quantified prospectively (measuring effective regurgitant orifice [ERO] and regurgitant volume) in routine practice of 5 tertiary care centers from North America, Europe, and the Middle East. The MIDA-Q score ranges from 0 to 15 by accumulating guideline-based risk factors and DMR severity. Long-term survival under medical management was the primary outcome end point. RESULTS: MVP was associated with DMR absent/mild (ERO <20 mm2) in 50%, moderate (ERO 20-40 mm2) in 25%, and severe or higher (ERO ≥40 mm2) in 25%, with mean ERO 24±24 mm2, regurgitant volume 37±35 mL. Median MIDA-Q score was 4 with a wide distribution (10%-90% range, 0-9). MIDA-Q score was higher in patients with EuroScore II ≥1% versus <1% (median, 7 versus 3; P < 0.0001) but with wide overlap (10%-90% range, 4-11 versus 0-7) and mediocre correlation (R2 0.18). Five-year survival under medical management was strongly associated with MIDA-Q score, 97±1% with score 0, 95±1% with score 1 to 2, 82±1% with score 3 to 4, 67±1% with score 5 to 6, 60±1% with score 7 to 8, 44±1% with score 9 to 10, 35±1% with score 11 to 12, and 5±4% with MIDA-Q score ≥13, with hazard ratio 1.31 [1.29-1.33] per 1-point increment. Excess mortality with higher MIDA-Q scores persisted after adjustment for age, sex, and EuroScore II (adjusted hazard ratio, 1.13 [1.11-1.15] per 1-point increment). Subgroup analysis showed persistent association of MIDA-Q score with mortality in all possible subsets, in particular, with EuroScore II<1% (hazard ratio, 1.08 [1.02-1.14]) or ≥1% (hazard ratio, 1.11 [1.08-1.13]) and with no/mild DMR (hazard ratio, 1.14 [1.10-1.19]) or moderate/severe DMR (hazard ratio, 1.13 [1.10-1.16], all per 1-point increment with P<0.0001). Nested-model and bootstrapping analyses demonstrated incremental prognostic power of MIDA-Q score (all P<0.0001). CONCLUSIONS: This large, international cohort of isolated MVP, with prospective DMR quantification in routine practice, demonstrates the wide range of risk factor accumulation and considerable heterogeneity of outcomes after MVP diagnosis. The MIDA-Q score is strongly, independently, and incrementally associated with long-term survival after MVP diagnosis, irrespective of presentation, and is therefore a crucial prognostic instrument for risk stratification, clinical trials, and management of patients diagnosed with all forms of MVP.

Factors influencing post-surgical survival in degenerative mitral regurgitation.

AIMS: Indications for surgery in patients with degenerative mitral regurgitation (DMR) are increasingly liberal in all clinical guidelines but the role of secondary outcome determinants (left atrial volume index ≥60 mL/m2, atrial fibrillation, pulmonary artery systolic pressure ≥50 mmHg and moderate to severe tricuspid regurgitation) and their impact on post-operative outcome remain disputed. Whether these secondary outcome markers are just reflective of the DMR severity or intrinsically affect survival after DMR surgery is uncertain and may have critical importance in the management of patients with DMR. To address these gaps of knowledge the present study gathered a large cohort of patients with quantified DMR, accounted for the number of secondary outcome markers and examined their independent impact on survival after surgical correction of the DMR. METHODS AND RESULTS: The Mitral Regurgitation International DAtabase-Quantitative registry includes patients with isolated DMR from centres across North America, Europe, and the Middle East. Patient enrolment extended from January 2003 to January 2020. All patients undergoing mitral valve surgery within 1 year of registry enrolment were selected. A total of 2276 patients [65 (55-73) years, 32% male] across five centres met study eligibility criteria. Over a median follow-up of 5.6 (3.6 to 8.7) years, 278 patients (12.2%) died. In a comprehensive multivariable Cox regression model adjusted for age, EuroSCORE II, symptoms, left ventricular ejection fraction (LVEF), left ventricular end-systolic diameter (LV ESD) and DMR severity, the number of secondary outcome determinants was independently associated with post-operative all-cause mortality, with adjusted hazard ratios of 1.56 [95% confidence interval (CI): 1.11-2.20, P = 0.011], 1.78 (95% CI: 1.23-2.58, P = 0.002) and 2.58 (95% CI: 1.73-3.83, P < 0.0001) for patients with one, two, and three or four secondary outcome determinants, respectively. A model incorporating the number of secondary outcome determinants demonstrated a higher C-index and was significantly more concordant with post-operative mortality than models incorporating traditional Class I indications alone [the presence of symptoms (P = 0.0003), or LVEF ≤60% (P = 0.006), or LV ESD ≥40 mm (P = 0.014)], while there was no significant difference in concordance observed compared with a model that incorporated the number of Class I indications for surgery combined (P = 0.71). CONCLUSION: In this large cohort of patients treated surgically for DMR, the presence and number of secondary outcome determinants was independently associated with post-surgical survival and demonstrated better outcome discrimination than traditional Class I indications for surgery. Randomised controlled trials are needed to determine if patients with severe DMR who demonstrate a cardiac phenotype with an increasing number of secondary outcome determinants would benefit from earlier surgery.

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

BACKGROUND: Carmat bioprosthetic total artificial heart (Aeson; A-TAH) is a pulsatile and autoregulated device. The aim of this study is to evaluate level of hemolysis potential acquired von Willebrand syndrome after A-TAH implantation. METHODS: We examined the presence of hemolysis and acquired von Willebrand syndrome in adult patients receiving A-TAH support (n=10) during their whole clinical follow-up in comparison with control subjects and adult patients receiving Heartmate II or Heartmate III support. We also performed a fluid structure interaction model coupled with computational fluid dynamics simulation to evaluate the A-TAH resulting shear stress and its distribution in the blood volume. RESULTS: The cumulative duration of A-TAH support was 2087 days. A-TAH implantation did not affect plasma free hemoglobin over time, and there was no association between plasma free hemoglobin and cardiac output or beat rate. For VWF (von Willebrand factor) evaluation, A-TAH implantation did not modify multimers profile of VWF in contrast to Heartmate II and Heartmate III. Furthermore, fluid structure interaction coupled with computational fluid dynamics showed a gradually increase of blood damage according to increase of cardiac output (P<0.01), however, the blood volume fraction that endured significant shear stresses was always inferior to 0.03% of the volume for both ventricles in all regimens tested. An inverse association between cardiac output, beat rate, and high-molecular weight multimers ratio was found. CONCLUSIONS: We demonstrated that A-TAH does not cause hemolysis or AWVS. However, relationship between HMWM and cardiac output depending flow confirms relevance of VWF as a biological sensor of blood flow, even in normal range.

Comparison of Short and Midterm Aortic Reinterventions in Acute Type A Aortic Dissection Treated by Frozen Elephant Trunk or Conventional Arch Repair.

BACKGROUND: Long-term outcomes after acute type A aortic dissection (ATAAD) are related to remodelling of the descending thoracic aorta and aortic reinterventions. We compared the impact of an extensive repair at the index procedure using the Frozen Elephant Trunk (FET) technique, versus a conventional arch repair, on long-term remodelling of the descending thoracic and reintervention related to the aorta. METHODS: Consecutive patients who underwent conventional arch repair (conventional group) or FET repair (FET group) for an ATAAD from September 2018 to November 2021 were included. Patients who died before discharge or were lost to follow-up prior to the first appointment were excluded from the analysis. Preoperative and postoperative computed tomography angiography was reconstructed and diameter of the true/false lumen of the remaining aorta was compared up to 1 year. Negative (increased total diameter ≥ 5 mm) aortic remodelling was collected for each computed tomography angiography, as well as aortic reinterventions. Comparison of demographic, anatomical, and perioperative complications data were performed using Wilcoxon test for continuous variables or Chi-square test for categorical covariates. The Kaplan-Meier method estimator was used to assess survival rates. The Log rank test was used to compare survival curves between the 2 groups. RESULTS: Thirty nine patients were included, 22 in the conventional group and 17 in the FET group (82% males, mean age 60 ± 12 years). In the FET group, distal anastomosis was performed in zone 0 or 1 for 82% of patients using the simplified delivery technique. Median maximum preoperative descending aortic diameter was larger in the FET group (33 mm [30; 37] vs. 30 mm [28; 32] [P = 0.0172]). At 30 days, the rate of negative remodelling on the descending thoracic aorta was significantly higher in the conventional group (50%) than in the FET group (8%, P = 0.02). At 1 year, Kaplan-Meier analysis shown a freedom from descending aortic negative remodeling of 35.1% (95% confidence interval (CI) 18.7-66.1%) in conventional group and 44.9% (CI 95% 26.1-77.2%) in FET group with no significant difference. However, early negative remodelling was observed for the conventional group. Within a year, freedom from reintervention was observed for 74.4% (95% CI 57.1-97%) of patients in the conventional group and 75.5 (95% CI 57.1-99.7%) of patients in the FET group with no significant difference. CONCLUSIONS: Negative evolution of descending aorta remains a challenge after ATAAD. An extensive repair using the FET technique during the index procedure seems to be associated with satisfying short-term remodelling of descending aorta.

Replacement Myocardial Fibrosis in Patients With Mitral Valve Prolapse: Relation to Mitral Regurgitation, Ventricular Remodeling, and Arrhythmia.

BACKGROUND: Mitral valve prolapse (MVP) is a frequent disease that can be complicated by mitral regurgitation (MR), heart failure, arterial embolism, rhythm disorders, and death. Left ventricular (LV) replacement myocardial fibrosis, a marker of maladaptive remodeling, has been described in patients with MVP, but the implications of this finding remain scarcely explored. We aimed at assessing the prevalence, pathophysiological and prognostic significance of LV replacement myocardial fibrosis through late gadolinium enhancement (LGE) by cardiac magnetic resonance in patients with MVP. METHODS: Four hundred patients (53±15 years of age, 55% male) with MVP (trace to severe MR by echocardiography) from 2 centers, who underwent a comprehensive echocardiography and LGE cardiac magnetic resonance, were included. Correlates of replacement myocardial fibrosis (LGE+), influence of MR degree, and ventricular arrhythmia were assessed. The primary outcome was a composite of cardiovascular events (cardiac death, heart failure, new-onset atrial fibrillation, arterial embolism, and life-threatening ventricular arrhythmia). RESULTS: Replacement myocardial fibrosis (LGE+) was observed in 110 patients (28%; 91 with myocardial wall including 71 with basal inferolateral wall, 29 with papillary muscle). LGE+ prevalence was 13% in trace-mild MR, 28% in moderate MR, and 37% in severe MR, and was associated with specific features of mitral valve apparatus, more dilated LV and more frequent ventricular arrhythmias (45% versus 26%, P<0.0001). In trace-mild MR, despite the absence of significant volume overload, abnormal LV dilatation was observed in 16% of patients and ventricular arrhythmia in 25%. Correlates of LGE+ in multivariable analysis were LV mass (odds ratio, 1.01 [95% CI, 1.002-1.017], P=0.009) and moderate-severe MR (odds ratio, 2.28 [95% CI, 1.21-4.31], P=0.011). LGE+ was associated with worse 4-year cardiovascular event-free survival (49.6±11.7 in LGE+ versus 73.3±6.5% in LGE-, P<0.0001). In a stepwise multivariable Cox model, MR volume and LGE+ (hazard ratio, 2.6 [1.4-4.9], P=0.002) were associated with poor outcome. CONCLUSIONS: LV replacement myocardial fibrosis is frequent in patients with MVP; is associated with mitral valve apparatus alteration, more dilated LV, MR grade, and ventricular arrhythmia; and is independently associated with cardiovascular events. These findings suggest an MVP-related myocardial disease. Last, cardiac magnetic resonance provides additional information to echocardiography in MVP.

Management and outcomes of ventricular septal defects after acute myocardial infarction: A multicenter retrospective study.

BACKGROUND AND AIM: The mortality rate of patients with post-myocardial infarction (MI) ventricular septal defects (VSDs) is high, and the benefit of surgery is unclear. We aimed to investigate the management and outcomes of post-MI VSD over a 10-year period in a large cohort. METHODS: Data of patients with post-MI VSD admitted in three French university hospitals from 2008 to 2019 were examined. The characteristics of those who underwent surgery were compared with those who received medical treatment. Mortality risk factors, survival curves, and outcomes at 30 days and 1 year after treatment were determined. RESULTS: Of the 92 patients whose data were examined, 50 underwent surgery and 42 received exclusive medical treatment. All patients were critically ill. Overall, 76.1% of patients received inotropic support, and 63% received mechanical ventilation. Circulatory assistance, mainly via intra-aortic balloon pump and extra-corporeal membrane oxygenation, was provided to 46.7% patients, with 14.1% requiring a second assistance. The median time to surgery was 4 days. At 1 year, mortality was 46% in those who underwent surgery and 83.3% in those treated medically (p < .001). Survival curves at 1 and 3 months showed major differences, and the survival rate showed little change 30 days after treatment. Cardiogenic shock and cardiac arrest emerged as risk factors for mortality. CONCLUSIONS: In our retrospective, multicenter study, the mortality resulting from post-MI VSD did not seem to improve over the last decade. Although surgery carried considerable risks, it improved survival.

Heparin Anti-Xa Activity, a Readily Available Unique Test to Quantify Apixaban, Rivaroxaban, Fondaparinux, and Danaparoid Levels.

BACKGROUND: Despite their usefulness in perioperative and acute care settings, factor-Xa inhibitor-specific assays are scarcely available, contrary to heparin anti-Xa assay. We assessed whether the heparin anti-Xa assay can (1) be used as a screening test to rule out apixaban, rivaroxaban, fondaparinux, and danaparoid levels that contraindicate invasive procedures according to current guidelines (>30 ng·mL-1, >30 ng·mL-1, >0.1 µg·mL-1, and >0.1 IU·mL-1, respectively), (2) quantify the anticoagulant level if found significant, that is, if it exceeded the abovementioned threshold. METHODS: In the derivation cohort then in the validation cohort, via receiver operating characteristics (ROC) curve analysis, we evaluated the ability of heparin anti-Xa assay to detect levels of factor-Xa inhibitors above or below the abovementioned safety thresholds recommended for an invasive procedure (screening test). Among samples with relevant levels of factor-Xa inhibitor, we determined the conversion factor linking the measured level and heparin anti-Xa activity in a derivation cohort. In a validation cohort, the estimated level of each factor-Xa inhibitor was thus inferred from heparin anti-Xa activity. The agreement between measured and estimated levels of factor-Xa inhibitors was assessed. RESULTS: Among 989 (355 patients) and 756 blood samples (420 patients) in the derivation and validation cohort, there was a strong linear relationship between heparin anti-Xa activities and factor-Xa inhibitors measured level (r = 0.99 [95% confidence interval {CI}, 0.99-0.99]). In the derivation cohort, heparin anti-Xa activity ≤0.2, ≤0.3, <0.1, <0.1 IU·mL-1 reliably ruled out a relevant level of apixaban, rivaroxaban, fondaparinux, and danaparoid, respectively (area under the ROC curve ≥0.99). In the validation cohort, these cutoffs yielded excellent classification accuracy (≥96%). If this screening test indicated relevant level of factor-Xa inhibitor, estimated and measured levels closely agreed (Lin's correlation coefficient close to its maximal value: 95% CI, 0.99-0.99). More than 96% of the estimated levels fell into the predefined range of acceptability (ie, 80%-120% of the measured level). CONCLUSIONS: A unique simple test already widely used to assay heparin was also useful for quantifying these 4 other anticoagulants. Both clinical and economic impacts of these findings should be assessed in a specific study.

A simplified delivery frozen elephant trunk technique to reduce circulatory arrest time in hybrid aortic arch surgery.

A simplified delivery technique for the frozen elephant trunk procedure allows the distal suture to be performed on a perfused and loaded aorta in moderate hypothermia-or even normothermia-reducing circulatory arrest time to just a few minutes. Two surgical sealing tourniquets are placed around the aortic arch, usually between the brachiocephalic trunk (BCT) and the left common carotid artery and the aorta is cross-clamped and cardioplegia started. Once in mild hypothermia, the BCT is disconnected and circulatory arrest is initiated while cerebral perfusion is maintained. This modified technique can be used in all pathologies, including dissections.

Celsior® crystalloid cardioplegia versus standard hyperkalemic normothermic blood cardioplegia: Analysis of myocardial protection in elective mitral valve repair.

INTRODUCTION: With the increase and refinement of video assisted mitral valve surgery, cristalloïd cardioplegia started regaining popularity. The aim of our study was to evaluate the effectiveness of Celsior®, a crystalloid cardioplegic solution, on myocardial protection in elective surgical mitral valve repair in comparison to blood based hyperkalemic cardioplegia. METHODS: In this observational retrospective study, all consecutive elective isolated surgical mitral valve repair where Celsior® or normothermic hyperkalemic blood cardioplegia were used were included. Primary endpoint was any sign of myocardial protection failure (troponin levels, need for inotropic or mechanical support, rhythm disturbances, mortality). Secondary endpoint was Celsior® safety (allergic reactions, bleeding, organ toxicities). RESULTS: From January 2009 to August 2016, 382 patients underwent elective isolated mitral valve repair in whom normothermic hyperkalemic blood cardioplegia (n = 181) or Celsior® (n = 201) were used. There were no statistically significant differences in baseline characteristics including Euroscore 2. Peak troponin (pg/ml) release and 30-days mortality were not statistically different. Need for cardioversion was significantly more frequent in the Celsior® group (47% vs 13%, p < 0.001). There was no statistical difference in post-operative atrial fibrillation, permanent pacemaker implantation, reoperation for bleeding, transfusion, acute kidney injury, haemoglobin at discharge or length of stay. No allergic reaction to Celsior® occurred. CONCLUSION: Effective myocardial protection was achieved with the Celsior® cardioplegic solution with no unexpected toxicity. Celsior® may be an efficacious and safe cardioprotective strategy in mitral valve repair.

Association between Neu5Gc carbohydrate and serum antibodies against it provides the molecular link to cancer: French NutriNet-Santé study.

BACKGROUND: High consumption of red and processed meat is commonly associated with increased cancer risk, particularly colorectal cancer. Antibodies against the red meat-derived carbohydrate N-glycolylneuraminic acid (Neu5Gc) exacerbate cancer in "human-like" mice. Human anti-Neu5Gc IgG and red meat are both independently proposed to increase cancer risk, yet how diet affects these antibodies is largely unknown. METHODS: We used world global data to demonstrate that colorectal cancer incidence and mortality are associated with increased national meat consumption. In a well-defined large cohort, we used glycomics to measure daily Neu5Gc intake from red meat and dairy, and investigated serum as well as affinity-purified anti-Neu5Gc antibodies. Based on 24-h dietary records, daily Neu5Gc intake was calculated for 19,621 subjects aged ≥ 18 years of the NutriNet-Santé study. Serum and affinity-purified anti-Neu5Gc antibodies were evaluated by ELISA and glycan microarrays in representative 120 individuals, each with at least eighteen 24-h dietary records (aged 45-60, Q1-Q4; aged > 60, Q1 and Q4; 10 men/women per quartile). RESULTS: We found that high-Neu5Gc diet, gender, and age affect the specificity, levels, and repertoires of anti-Neu5Gc IgG immune responses, but not their affinity. Men consumed more Neu5Gc than women, mostly from red meat (p = 0.0015), and exhibited higher overall serum anti-Neu5Gc IgG levels by ELISA (3.94 ng/µl versus 2.22 ng/µl, respectively; p = 0.039). Detailed glycan microarray analysis against 56 different glycans revealed high Neu5Gc-specificity with increased anti-Neu5Gc IgG and altered repertoires, associated with higher consumption of Neu5Gc from red meat and cow dairy. Affinity purification of serum anti-Neu5Gc antibodies revealed increased levels and biased array repertoire patterns, without an increase in antibody affinity, in individuals consuming higher Neu5Gc levels. Furthermore, in a high-meat diet, antibody diversity patterns on glycan microarrays shifted towards Neu5Gcα3-linked glycans, increasing the α3/α6-glycans ratio score. CONCLUSIONS: We found a clear link between the levels and repertoire of serum anti-Neu5Gc IgG and Neu5Gc intake from red meat and dairy. These precise rational methodologies allowed to develop a Gcemic index to simplify the assessment of Neu5Gc in foods that could potentially be adapted for dietary recommendations to reduce cancer risk.

Pig endothelial protein C receptor is functionally compatible with the human protein C pathway.

BACKGROUND: Endothelial protein C receptor (EPCR) plays an anticoagulant and anti-inflammatory role by promoting the activation of protein C by thrombin bound to thrombomodulin (TBM). Incompatibility between pig TBM and human/primate thrombin is thought to contribute to dysregulated coagulation in pig-to-primate organ xenografts, and expression of human TBM (hTBM) in pigs has shown benefit in preclinical models. However, it is not known whether there are incompatibilities-or molecular barriers-between endogenous pig EPCR (pEPCR) and transgenically expressed human TBM. AIM: To clone and express pEPCR, and determine its function in the human protein C pathway in vitro. METHODS: Pig endothelial protein C receptor cDNA was generated from pig lung RNA by RT-PCR. Primate COS-7 transfectants expressing various combinations of human and pig TBM and EPCR were incubated with human thrombin and human protein C, and tested for TBM cofactor activity. RESULTS: The predicted protein sequence of pEPCR shared 72.3% amino acid sequence identity with hEPCR, and residues critical for protein C binding were conserved. COS-7 cells transfected with hEPCR, pEPCR or vector showed minimal TBM cofactor activity (0.13 ± 0.04, 0.13 ± 0.02 and 0.14 ± 0.06 U, respectively). The cofactor activity of hTBM-transfected cells (1.18 ± 0.29 U) was 8-fold higher than vector-transfected cells (P = .004) and further increased 4-fold and 3-fold by co-transfection with hEPCR (5.01 ± 1.12 U, P = .004) or pEPCR (3.73 ± 0.65 U, P = .003), respectively. CONCLUSIONS: Our data show that pEPCR is largely compatible with the human TBM/thrombin complex, when expressed on COS-7 cells in vitro, promoting the activation of human protein C. These findings suggest that endogenous pEPCR will enhance the activity of transgenic hTBM in the xenograft setting.

High-Flow Therapy by Nasal Cannulae Versus High-Flow Face Mask in Severe Hypoxemia After Cardiac Surgery: A Single-Center Randomized Controlled Study-The HEART FLOW Study.

OBJECTIVE: To determine whether high-flow oxygen therapy by nasal cannulae (HFNC) is more effective than a high-flow face mask (HFFM) in severe hypoxemia. DESIGN: Randomized, single-center, open-labeled, controlled trial. SETTING: University Hospital of Nantes, France. PARTICIPANTS: Cardiac surgery patients presenting oxygen saturation <96% with Venturi mask 50%. INTERVENTION: Oxygenation by HFNC (45 L/min, FIO2 100%) or Hudson RCI non-rebreather face mask with a reservoir bag (15 L/min). MEASUREMENTS AND MAIN RESULTS: The co-primary outcomes were the PaO2/FIO2 ratio at 1 and 24 hours. In the intent-to-treat analysis (90 patients), the mean (standard deviation) PaO2/FIO2 ratios were: after 1 hour, 113.4 (50.2) in HFFM versus 137.8 (57.0) in HFNC (mean difference 24.4, CI 97.5% [2.9-45.9], p = 0.03), and after 24 hours, 106.9 (62.6) in HFFM versus 129.9 (54.0) in HFNC (mean difference 23.0, CI 97.5% [1.5-44.6], p = 0.04). After adjustment on baseline PaO2/FIO2, this difference persisted at 24 hours (p = 0.04). For secondary outcomes, the PaO2/FIO2 ratio after 6 hours was 108.7 (47.9) in HFFM versus 136.0 (45.2) in HFNC (p = 0.01), without difference after 48 hours (p = 0.95). Refractory hypoxemia requiring noninvasive ventilation occurred in 13 (28%) patients in HFNC versus 24 (56%) patients in HFFM (p = 0.007). The HFNC improved satisfaction (p = 0.0002) and reduced mucus dryness (p = 0.003) compared with HFFM. CONCLUSION: In patients with severe hypoxemia after cardiac surgery, PaO2/FIO2 at 1 and 24 hours were higher and the use of noninvasive ventilation was reduced in HFNC compared with HFFM.

Romiplostim as a transfusion saving strategy in 20 patients after heart or lung transplantation: a single centre before-after pilot study.

BACKGROUND: Thrombocytopenia is a common disorder after heart or lung transplantation. Platelet transfusion is often required to maintain haemostasis but represents a specific cause of morbidity and mortality in this setting including alloimmunisation and graft rejection. STUDY DESIGN AND METHODS: As part of a health-care quality improvement project, in a single-centre before-after pilot study, the relevance of a platelet transfusion saving strategy based on romiplostim administration after transplantation was assessed in patients with platelet count <100 × 109/L. Transfusions on days 28 and 90 were compared using propensity matched score for adjustment of demographic characteristics at baseline. The primary outcome was platelet transfusion until day 28 after transplantation. RESULTS: Ninety-three patients were analysed (73 before vs. 20 after). The median [interquartile range] number of platelet concentrate was 1 [0;4.0] before versus 0.5 [0;2.0] in the after period, mean difference 0.5 confidence interval 95% [-0.7 to 1.7], p = 0.39. On day 28, median [interquartile range] red blood cell transfusion was significantly higher in the before versus the after period, 7 [2.0;13.5] versus 6 [1.5;8.5], mean difference 3.2 CI 95% [0.4-6.0], p = 0.02. At 6 months, the rate of patients with de novo anti-human leukocyte antigen alloimmunisation was 45% before versus 53% in the after period (p = 0.56). Deep venous thrombosis was detected in nine patients (12%) before versus seven patients (35%) in the after period (p = 0.04). CONCLUSION: Romiplostim did not significantly reduce platelet transfusion after heart or lung transplantation. Its relevance and safety in a global transfusion strategy remains to be studied in this setting in a large randomised study.

Generation of cattle knockout for galactose-α1,3-galactose and N-glycolylneuraminic acid antigens.

Two well-characterized carbohydrate epitopes are absent in humans but present in other mammals. These are galactose-α1,3-galactose (αGal) and N-glycolylneuraminic acid (Neu5Gc) which are introduced by the activities of two enzymes including α(1,3) galactosyltransferase (encoded by the GGTA1 gene) and CMP-Neu5Gc hydroxylase (encoded by the CMAH gene) that are inactive in humans but present in cattle. Hence, bovine-derived products are antigenic in humans who receive bioprosthetic heart valves (BHVs) or those that suffer from red meat syndrome. Using programmable nucleases, we disrupted (knockout, KO) GGTA1 and CMAH genes encoding for the enzymes that catalyse the synthesis of αGal and Neu5Gc, respectively, in both male and female bovine fibroblasts. The KO in clonally selected fibroblasts was detected by polymerase chain reaction (PCR) and confirmed by Sanger sequencing. Selected fibroblasts colonies were used for somatic cell nuclear transfer (SCNT) to produce cloned embryos that were implanted in surrogate recipient heifers. Fifty-three embryos were implanted in 33 recipients heifers; 3 pregnancies were carried to term and delivered 3 live calves. Primary cell cultures were established from the 3 calves and following molecular analyses confirmed the genetic deletions. FACS analysis showed the double-KO phenotype for both antigens confirming the mutated genotypes. Availability of such cattle double-KO model lacking both αGal and Neu5Gc offers a unique opportunity to study the functionality of BHV manufactured with tissues of potentially lower immunogenicity, as well as a possible new clinical approaches to help patients with red meat allergy syndrome due to the presence of these xenoantigens in the diet.

Elicited and pre-existing anti-Neu5Gc antibodies differentially affect human endothelial cells transcriptome.

Humans cannot synthesize N-glycolylneuraminic acid (Neu5Gc) but dietary Neu5Gc can be absorbed and deposited on endothelial cells (ECs) and diet-induced anti-Neu5Gc antibodies (Abs) develop early in human life. While the interaction of Neu5Gc and diet-induced anti-Neu5Gc Abs occurs in all normal individuals, endothelium activation by elicited anti-Neu5Gc Abs following a challenge with animal-derived materials, such as following xenotransplantation, had been postulated. Ten primary human EC preparations were cultured with affinity-purified anti-Neu5Gc Abs from human sera obtained before or after exposure to Neu5Gc-glycosylated rabbit IgGs (elicited Abs). RNAs of each EC preparation stimulated in various conditions by purified Abs were exhaustively sequenced. EC transcriptomic patterns induced by elicited anti-Neu5Gc Abs, compared with pre-existing ones, were analyzed. qPCR, cytokines/chemokines release, and apoptosis were tested on some EC preparations. The data showed that anti-Neu5Gc Abs induced 967 differentially expressed (DE) genes. Most DE genes are shared following EC activation by pre-existing or anti-human T-cell globulin (ATG)-elicited anti-Neu5Gc Abs. Compared with pre-existing anti-Neu5Gc Abs, which are normal component of ECs environment, elicited anti-Neu5Gc Abs down-regulated 66 genes, including master genes of EC function. Furthermore, elicited anti-Neu5Gc Abs combined with complement-containing serum down-regulated most transcripts mobilized by serum alone. Both types of anti-Neu5Gc Abs-induced a dose- and complement-dependent release of selected cytokines and chemokines. Altogether, these data show that, compared with pre-existing anti-Neu5Gc Abs, ATG-elicited anti-Neu5Gc Abs specifically modulate genes related to cytokine responses, MAPkinase cascades, chemotaxis, and integrins and do not skew the EC transcriptome toward a pro-inflammatory profile in vitro.

New insights into mitral valve dystrophy: a Filamin-A genotype-phenotype and outcome study.

Aims: Filamin-A (FLNA) was identified as the first gene of non-syndromic mitral valve dystrophy (FLNA-MVD). We aimed to assess the phenotype of FLNA-MVD and its impact on prognosis. Methods and results: We investigated the disease in 246 subjects (72 mutated) from four FLNA-MVD families harbouring three different FLNA mutations. Phenotype was characterized by a comprehensive echocardiography focusing on mitral valve apparatus in comparison with control relatives. In this X-linked disease valves lesions were severe in men and moderate in women. Most men had classical features of mitral valve prolapse (MVP), but without chordal rupture. By contrast to regular MVP, mitral leaflet motion was clearly restricted in diastole and papillary muscles position was closer to mitral annulus. Valvular abnormalities were similar in the four families, in adults and young patients from early childhood suggestive of a developmental disease. In addition, mitral valve lesions worsened over time as encountered in degenerative conditions. Polyvalvular involvement was frequent in males and non-diagnostic forms frequent in females. Overall survival was moderately impaired in men (P = 0.011). Cardiac surgery rate (mainly valvular) was increased (33.3 ± 9.8 vs. 5.0 ± 4.9%, P < 0.0001; hazard ratio 10.5 [95% confidence interval: 2.9-37.9]) owing mainly to a lifetime increased risk in men (76.8 ± 14.1 vs. 9.1 ± 8.7%, P < 0.0001). Conclusion: FLNA-MVD is a developmental and degenerative disease with complex phenotypic expression which can influence patient management. FLNA-MVD has unique features with both MVP and paradoxical restricted motion in diastole, sub-valvular mitral apparatus impairment and polyvalvular lesions in males. FLNA-MVD conveys a substantial lifetime risk of valve surgery in men.

Inverse probability weighting to control confounding in an illness-death model for interval-censored data.

Multistate models with interval-censored data, such as the illness-death model, are still not used to any considerable extent in medical research regardless of the significant literature demonstrating their advantages compared to usual survival models. Possible explanations are their uncommon availability in classical statistical software or, when they are available, by the limitations related to multivariable modelling to take confounding into consideration. In this paper, we propose a strategy based on propensity scores that allows population causal effects to be estimated: the inverse probability weighting in the illness semi-Markov model with interval-censored data. Using simulated data, we validated the performances of the proposed approach. We also illustrated the usefulness of the method by an application aiming to evaluate the relationship between the inadequate size of an aortic bioprosthesis and its degeneration or/and patient death. We have updated the R package multistate to facilitate the future use of this method.

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

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

Characterization of immunogenic Neu5Gc in bioprosthetic heart valves.

BACKGROUND: The two common sialic acids (Sias) in mammals are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated form N-glycolylneuraminic acid (Neu5Gc). Unlike most mammals, humans cannot synthesize Neu5Gc that is considered foreign and recognized by circulating antibodies. Thus, Neu5Gc is a potential xenogenic carbohydrate antigen in bioprosthetic heart valves (BHV) that tend to deteriorate in time within human patients. METHODS: We investigated Neu5Gc expression in non-engineered animal-derived cardiac tissues and in clinically used commercial BHV, and evaluated Neu5Gc immunogenicity on BHV through recognition by human anti-Neu5Gc IgG. RESULTS: Neu5Gc was detected by immunohistochemistry in porcine aortic valves and in porcine and bovine pericardium. Qualitative analysis of Sia linkages revealed Siaα2-3>Siaα2-6 on porcine/bovine pericardium while the opposite in porcine aortic/pulmonary valve cusps. Similarly, six commercial BHV containing either porcine aortic valve or porcine/bovine/equine pericardium revealed Siaα2-3>Siaα2-6 expression. Quantitative analysis of Sia by HPLC showed porcine/bovine pericardium express 4-fold higher Neu5Gc levels compared to the porcine aortic/pulmonary valves, with Neu5Ac at 6-fold over Neu5Gc. Likewise, Neu5Gc was expressed on commercial BHV (186.3±16.9 pmol Sia/µg protein), with Neu5Ac at 8-fold over Neu5Gc. Affinity-purified human anti-Neu5Gc IgG showing high specificity toward Neu5Gc-glycans (with no binding to Neu5Ac-glycans) on a glycan microarray, strongly bound to all tested commercial BHV, demonstrating Neu5Gc immune recognition in cardiac xenografts. CONCLUSIONS: We conclusively demonstrated Neu5Gc expression in native cardiac tissues, as well as in six commercial BHV. These Neu5Gc xeno-antigens were recognized by human anti-Neu5Gc IgG, supporting their immunogenicity. Altogether, these findings suggest BHV-Neu5Gc/anti-Neu5Gc may play a role in valve deterioration warranting further investigation.