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Objective: Myocardial ischemia reperfusion is a major cause of cell injury during cardiac transplantation and is responsible for increased graft rejection. Several in vitro studies demonstrated the protective effect of P2Y11-like purinoreceptor stimulation in the context of myocardial ischemia/reperfusion. In this study, we hypothesized a possible cardioprotective role of P2Y11R stimulation against ischemia/reperfusion lesions and validated its clinical effect in vivo in a heart transplantation model., Methods: We subjected H9c2 rat cardiomyocyte-derived cell line to 5 hours of hypoxia and 1 hour of reoxygenation. P2Y11R selective agonist NF546 and antagonist NF340 were added at the onset of reoxygenation. Cell injuries were assessed by microculture tetrazolium reduction and intracellular adenosine triphosphate level. Clinical effect of P2Y11R stimulation was further investigated in vivo. Hearts from BALB/c mice were transplanted intra-abdominally into allogenic C57BL/6 mice (n = 104). Recipient mice were injected with P2Y11R agonist. Mice in the sham group were injected with saline solution. In the control group, hearts from C57BL/6 were transplanted into syngeneic C57BL/6 mice. Rejection lesions were investigated using histology and immunohistochemistry at days 3, 5, and 7 after transplantation. We measured caspase activities to quantify apoptosis. Production of proinflammatory and anti-inflammatory cytokines was investigated., Results: P2Y11R stimulation at the onset of reoxygenation significantly reduced in vitro hypoxia/reoxygenation injuries. This protection was suppressed with P2Y11R antagonist. In vivo, cardiac allograft survival was significantly prolonged after P2Y11R stimulation. Rejection lesions, classified according to the International Society of Heart Lung Transplantation guidelines and quantified using the mean number of inflammatory cells per field, were significantly reduced in the treated group. At day 5 after transplantation, P2Y11R agonist pretreated allografts also demonstrated less apoptotic lesions., Conclusions: Our data suggest a novel cardioprotective role of P2Y11R at the onset of reoxygenation/reperfusion against reperfusion injuries. Pharmacologic conditioning using P2Y11 agonist may be beneficial after cardiac transplantation in improving myocardial ischemia/reperfusion outcomes and decreasing graft rejection lesions., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The diagnosis of acute rejection in cardiac transplant recipients requires invasive technique with endomyocardial biopsy (EMB) which has risks and limitations. Cardiovascular magnetic resonance imaging (CMR) with T2 and T1 mapping is a promising technique for characterizing myocardial tissue. The purpose of the study was to evaluate T2, T1 and extracellular volume fraction (ECV) quantification as novel tissue markers to diagnose acute rejection., Methods: CMR was prospectively performed in 20 heart transplant patients providing 31 comparisons EMB-CMR. CMR was performed close to EMB. Images were acquired on a 1.5 Tesla scanner including T2 mapping (T2 prepared balanced steady state free precession) and T1 mapping (modified Look-Locker inversion recovery sequences: MOLLI) at basal, mid and apical level in short axis view. Global and segmental T2 and T1 values were measured before and 15 min (for T1 mapping) after contrast administration., Results: Acute rejection was diagnosed in seven patients: six cellular rejections (4 grade IR, 2 grade 2R) and one antibody mediated rejection. Patients with acute rejection had significantly higher global T2 values at 3 levels: 58.5 ms [55.0-60.3] vs 51.3 ms [49.5-55.2] (p = 0.007) at basal; 55.7 ms [54.0-59.7] vs 51.8 ms [50.1-53.6] (p = 0.002) at median and 58.2 ms [54.0-63.7] vs 53.6 ms [50.8-57.4] (p = 0.026) at apical level. The area under the curve (AUC) for each level was 0.83, 0.79 and 0.78 respectively. Patients with acute rejection had significantly higher ECV at basal level: 34.2% [32.8-37.4] vs 27.4% [24.6-30.6] (p = 0.006). The AUC for basal level was 0.84. The sensitivity, specificity and diagnosis accuracy for basal T2 (cut off: 57.7 ms) were 71, 96 and 90% respectively; and for basal ECV: (cut off 32%) were 86, 85 and 85% respectively. Combining basal T2 and basal ECV allowed diagnosing all acute rejection and avoiding 63% of EMB., Conclusions: In heart transplant patients, a combined CMR approach using T2 mapping and ECV quantification provides a high diagnostic accuracy for acute rejection diagnosis and could potentially decrease the number of routine EMB.

Aims: Right ventricular failure after left ventricular assist device (LVAD) implantation is a major concern that remains challenging to predict. We sought to investigate the relationship between preoperative pulmonary artery pulsatility index (PAPi) and mortality after LVAD implantation. Methods and results: A retrospective analysis of the ASSIST‐ICD multicentre registry allowed the assessment of PAPi before LVAD according to the formula [(systolic pulmonary artery pressure − diastolic pulmonary artery pressure)/central venous pressure]. The primary endpoint was survival at 3 months, according to the threshold value of PAPi determined by the receiver operating characteristic (ROC) curve. A multivariate analysis including demographic, echographic, haemodynamic, and biological variables was performed to identify predictive factors for 2 year mortality. One hundred seventeen patients were included from 2007 to 2021. The mean age was 58.45 years (±13.16), with 15.4% of women (sex ratio 5.5). A total of 53.4% were implanted as bridge to transplant and 43.1% as destination therapy. Post‐operative right ventricular failure was observed in 57 patients (48.7%), with no significant difference between survivors and non‐survivors at 1 month (odds ratio 1.59, P = 0.30). The median PAPi for the whole study population was 2.83 [interquartile range 1.63–4.69]. The threshold value of PAPi determined by the ROC curve was 2.84. Patients with PAPi ≥ 2.84 had a higher survival rate at 3 months [PAPi < 2.84: 58.1% [46.3–72.8%] vs. PAPi ≥ 2.84: 89.1% [81.1–97.7%], hazard ratio (HR) 0.08 [0.02–0.28], P < 0.01], with no significant difference after 3 months (HR 0.67 [0.17–2.67], P = 0.57). Other predictors of 2 year mortality were systemic hypertension (HR 4.22 [1.49–11.97], P < 0.01) and diabetes mellitus (HR 4.90 [1.83–13.14], P < 0.01). LVAD implantation as bridge to transplant (HR 0.18 [0.04–0.74], P = 0.02) and heart transplantation (HR 0.02 [0.00–0.18], P < 0.01) were associated with a higher survival rate at 2 years. Conclusions: Preoperative PAPi < 2.84 was associated with a higher risk of early mortality after LVAD implantation without impacting 2 year outcomes among survivors. [ABSTRACT FROM AUTHOR]

Sterile inflammation is a key determinant of myocardial reperfusion injuries. It participates in infarct size determination in acute myocardial infarction and graft rejection following heart transplantation. We previously showed that P2Y11 exerted an immunosuppressive role in human dendritic cells, modulated cardiofibroblasts' response to ischemia/reperfusion in vitro and delayed graft rejection in an allogeneic heterotopic heart transplantation model. We sought to investigate a possible role of P2Y11 in the cellular response of cardiomyocytes to ischemia/reperfusion. We subjected human AC16 cardiomyocytes to 5 h hypoxia/1 h reoxygenation (H/R). P2Y11R (P2Y11 receptor) selective agonist NF546 and/or antagonist NF340 were added at the onset of reoxygenation. Cellular damages were assessed by LDH release, MTT assay and intracellular ATP level; intracellular signaling pathways were explored. The role of P2Y11R in mitochondria-derived ROS production and mitochondrial respiration was investigated. In vitro H/R injuries were significantly reduced by P2Y11R stimulation at reoxygenation. This protection was suppressed with P2Y11R antagonism. P2Y11R stimulation following H2O2-induced oxidative stress reduced mitochondria-derived ROS production and damages through PKCε signaling pathway activation. Our results suggest a novel protective role of P2Y11 in cardiomyocytes against reperfusion injuries. Pharmacological post-conditioning targeting P2Y11R could therefore contribute to improve myocardial ischemia/reperfusion outcomes in acute myocardial infarction and cardiac transplantation. [ABSTRACT FROM AUTHOR]