Platelet preservation in cardiac surgery using minimally invasive extracorporeal circulation versus optimized cardiopulmonary bypass.

BACKGROUND: Minimally invasive extracorporeal circulation (MiECC) is employed as a strategy to attenuate the physiologic disturbance caused by cardiopulmonary bypass. The aim of this study was to compare the coagulation profile of MiECC to an optimized conventional extracorporeal circuit (OpECC) with regards to platelet function, rotational thromboelastometry and blood product usage. METHODS: A retrospective analysis of coronary artery bypass grafting operations using either MiECC or OpECC was performed at a single institution. RESULTS: A total of 112 patients were included, with 61 receiving MiECC and 51 OpECC patients. OpECC patients had a significantly larger BSA (1.95+/- 0.22m2 vs 1.88 +/- 0.18m2, p = 0.034), than those who received MiECC. No difference between groups was observed regarding red blood cell, plasma, and platelet transfusions. Functional platelet count during the warming phase of cardiopulmonary bypass was found to be higher in the MiECC group ((136 (102-171) x109/L vs 109 (94-136) x109/L), p = 0.027), as were functional platelets as a percent of total platelet count ((86 (77-91)% vs 76 (63-82)%), p = 0.003). There were no significant differences between other outcomes such as operative mortality, incidence of stroke, and intensive care unit length of stay. CONCLUSION: While we did not see a difference in blood transfusions, MiECC resulted in a statistically significant advantage over OpECC with regards to preservation of functional platelets.

Outcomes of expanded polytetrafluoroethylene pericardial membrane implantation in left ventricular assist device explantation and heart transplantation.

OBJECTIVES: Redo sternotomy and explantation of left ventricular assist devices (LVAD) for heart transplantation (HT) involve prolonged dissection, potential injury to mediastinal structures and/or bleeding. Our study compared a complete expanded polytetrafluoroethylene (ePTFE) wrap versus minimal or no ePTFE during LVAD implantation, on outcomes of subsequent HT. METHODS: Between July 2005 and July 2018, 84 patients underwent a LVAD implant and later underwent HT. Thirty patients received a complete ePTFE wrap during LVAD implantation (Group 1), and 54 patients received either a sheet of ePTFE placed in the anterior mediastinum or no ePTFE (Group 2). RESULTS: Baseline characteristics were similar between Groups 1 and 2. Surgeons reported subjective improvements in speed, predictability, and safety of dissection with complete ePTFE compared with minimal or no ePTFE. Time from incision to initiation of cardiopulmonary bypass (CPB) were similar between groups (97 ± 38 vs. 89 ± 29 min, p = .3). Injury to mediastinal structures during the dissection was similar between groups (10% vs. 11%, p > .9). While surgeons reported less intraoperative bleeding in Group 1 (43% vs. 61%), this trend did not reach significance (p = .1). In-hospital mortality, intensive care unit length of stay and hospital length of stay were similar between both groups. CONCLUSIONS: In patients undergoing LVAD explant-HT, there was a trend toward reduced surgeon reported intraoperative bleeding with ePTFE placement. Despite qualitatively reported greater ease and speed of mediastinal dissection with ePTFE membrane placement, time to initiation of CPB did not differ, likely because surgeons remained cautious, allowing extra time for unanticipated difficulties.

Heart Failure and Drug Therapies: A Metabolic Review.

Cardiovascular disease is the leading cause of mortality globally with at least 26 million people worldwide living with heart failure (HF). Metabolism has been an active area of investigation in the setting of HF since the heart demands a high rate of ATP turnover to maintain homeostasis. With the advent of -omic technologies, specifically metabolomics and lipidomics, HF pathologies have been better characterized with unbiased and holistic approaches. These techniques have identified novel pathways in our understanding of progression of HF and potential points of intervention. Furthermore, sodium-glucose transport protein 2 inhibitors, a drug that has changed the dogma of HF treatment, has one of the strongest types of evidence for a potential metabolic mechanism of action. This review will highlight cardiac metabolism in both the healthy and failing heart and then discuss the metabolic effects of heart failure drugs.

Durable mechanical circulatory support as bridge to heart transplantation.

PURPOSE OF REVIEW: Durable mechanical circulatory support (MCS) technology has changed over time as devices have evolved from pulsatile to continuous flow support. In this review, we discuss recent data and substantial changes to current practice as it pertains to the subject of current era durable left ventricular assist devices (LVADs) as a bridge to heart transplantation. RECENT FINDINGS: The results of heart transplantation in patients bridged with durable LVAD support are satisfactory even after prolonged duration of support. Reports of recent experience with LVAD related infection suggest that this complication has limited impact on post-transplant outcomes. Important sex-related disparities continue to exist following durable LVAD implantation. Recent changes in the United Network for Organ Sharing donor heart allocation policy have resulted in a drastic decline in the use of durable LVAD support for Bridge to Transplant in the United States. SUMMARY: Durable MCS in the form of LVAD as a BTT strategy continues to evolve over time. Optimization of its role in the treatment of end-stage heart failure, particularly in females will need to be the focus of future research.

Heart donation and transplantation after circulatory determination of death: expert guidance from a Canadian consensus building process.

Controlled donation after circulatory determination of death (DCD), where death is determined after cardiac arrest, has been responsible for the largest quantitative increase in Canadian organ donation and transplants, but not for heart transplants. Innovative international advances in DCD heart transplantation include direct procurement and perfusion (DPP) and normothermic regional perfusion (NRP). After death is determined, DPP involves removal and reanimation of the arrested heart on an ex situ organ perfusion system. Normothermic regional perfusion involves surgically interrupting (ligating the aortic arch vessels) brain blood flow after death determination, followed by restarting the heart and circulation in situ using extracorporeal membrane oxygenation. The objectives of this Canadian consensus building process by a multidisciplinary group of Canadian stakeholders were to review current evidence and international DCD heart experience, comparatively evaluate international protocols with existing Canadian medical, legal, and ethical practices, and to discuss implementation barriers. Review of current evidence and international experience of DCD heart donation (DPP and NRP) determined that DCD heart donation could be used to provide opportunities for more heart transplants in Canada, saving additional lives. Although candid discussion identified a number of potential barriers and challenges for implementing DCD heart donation in Canada, it was determined that DPP implementation is feasible (pending regulatory approval for the use of an ex situ perfusion device in humans) and in alignment with current medical guidelines for DCD. Nevertheless, further work is required to evaluate the consistency of NRP with current Canadian death determination policy and to ensure the absence of brain perfusion during this process.

RéSUMé: Le don contrôlé après un décès circulatoire (DDC), cas dans lequel le décès est déterminé après un arrêt cardiaque, est à l'origine de la plus forte augmentation quantitative des dons et des transplantations d'organes au Canada, sauf pour les transplantations cardiaques. Parmi les progrès internationaux novateurs dans la transplantation cardiaque après DDC, citons l'obtention directe et perfusion (ODP) et la circulation régionale normothermique (CRN). Une fois le décès déterminé, l'ODP consiste à retirer et réanimer le cœur arrêté sur un système de perfusion ex situ. La circulation régionale normothermique consiste à interrompre de manière chirurgicale (en ligaturant les vaisseaux de l'arc aortique) le flux sanguin au cerveau après la détermination du décès, puis à redémarrer le cœur et la circulation in situ utilisant l'oxygénation par membrane extracorporelle (ECMO). Les objectifs de ce processus canadien d'établissement de consensus par un groupe multidisciplinaire d'intervenants canadiens étaient d'examiner les données probantes et les expériences internationales actuelles en matière de DDC, d'évaluer comparativement les protocoles internationaux par rapport aux pratiques médicales, juridiques et éthiques canadiennes existantes, et de discuter des obstacles à la mise en œuvre de tels protocoles. L'examen des données probantes et des expériences internationales actuelles en matière de don de cœur après DDC (ODP et CRN) a permis de déterminer que le don de cœur après DDC pourrait être utilisé afin de faire de plus nombreuses transplantations cardiaques au Canada, sauvant ainsi des vies supplémentaires. Bien que des discussions aient permis d'identifier plusieurs obstacles et défis potentiels à la mise en œuvre du don cardiaque après DDC au Canada, il a été déterminé que la mise en œuvre de l'ODP est réalisable (en attente de l'approbation réglementaire pour l'utilisation d'un dispositif de perfusion ex situ chez l'humain) et en accord avec les directives médicales actuelles concernant le DDC. Néanmoins, d'autres travaux sont nécessaires pour évaluer la conformité de la CRN aux politiques canadiennes actuelles de détermination de la mort et pour garantir l'absence de perfusion cérébrale au cours de ce processus.

Protective role of Nrf2 against ischemia reperfusion injury and cardiac allograft vasculopathy.

Ischemia-reperfusion injury (IRI) and cardiac allograft vasculopathy (CAV) remain unsolved complications post-heart transplant (Tx). The antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) has been suggested to inhibit reactive oxygen species-mediated NF-κB activation. We hypothesized that Nrf2 inhibits NF-κB activation post-Tx and suppresses IRI and the subsequent development of CAV. IRI and CAV were investigated in murine heterotopic Tx models, respectively. Nrf2 wild-type (WT) and KO mice were used as donors. Sulforaphane was used as an Nrf2 agonist. In saline-treated animals following 24 hours of reperfusion in isogenic grafts, Nrf2-KO showed significantly less SOD1/2 activity compared with WT. Nrf2-KO displayed significantly high total and phosphorylated p65 expressions and percentage of cells with nuclear p65. mRNA levels of NF-κB-mediated proinflammatory genes were also high. Graft dysfunction, apoptosis, and caspase-3 activity were significantly higher in Nrf2-KO. In the allograft studies, graft beating score was significantly weaker in Nrf2-KO compared with WT. Nrf2-KO also demonstrated significantly more coronary luminal narrowing. In WT animals, sulforaphane successfully augmented all the protective effects of Nrf2 with increase of SOD2 activity. Nrf2 inhibits NF-κB activation and protects against IRI via its antioxidant properties and suppresses the subsequent development of CAV.

Risk prediction models for survival after heart transplantation: A systematic review.

Risk prediction scores have been developed to predict survival following heart transplantation (HT). Our objective was to systematically review the model characteristics and performance for all available scores that predict survival after HT. Ovid Medline and Epub Ahead of Print and In-Process & Other Non-Indexed Citations, Ovid Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Clinical Trials were searched to December 2018. Eligible articles reported a score to predict mortality following HT. Of the 5392 studies screened, 21 studies were included that derived and/or validated 16 scores. Seven (44%) scores were validated in external cohorts and 8 (50%) assessed model performance. Overall model discrimination ranged from poor to moderate (C-statistic/area under the receiver operating characteristics 0.54-0.77). The IMPACT score was the most widely validated, was well calibrated in two large registries, and was best at discriminating 3-month survival (C-statistic 0.76). Most scores did not perform particularly well in any cohort in which they were assessed. This review shows that there are insufficient data to recommend the use of one model over the others for prediction of post-HT outcomes.

Maintaining the permanence principle for death during in situ normothermic regional perfusion for donation after circulatory death organ recovery: A United Kingdom and Canadian proposal.

There is international variability in the determination of death. Death in donation after circulatory death (DCD) can be defined by the permanent cessation of brain circulation. Post-mortem interventions that restore brain perfusion should be prohibited as they invalidate the diagnosis of death. Retrieval teams should develop protocols that ensure the continued absence of brain perfusion during DCD organ recovery. In situ normothermic regional perfusion (NRP) or restarting the heart in the donor's body may interrupt the permanent cessation of brain perfusion because, theoretically, collateral circulations may restore it. We propose refinements to current protocols to monitor and exclude brain reperfusion during in situ NRP. In abdominal NRP, complete occlusion of the descending aorta prevents brain perfusion in most cases. Inserting a cannula in the ascending aorta identifies inadequate occlusion of the descending aorta or any collateral flow and diverts flow away from the brain. In thoracoabdominal NRP opening the aortic arch vessels to atmosphere allows collateral flow to be diverted away from the brain, maintaining the permanence standard for death and respecting the dead donor rule. We propose that these hypotheses are correct when using techniques that simultaneously occlude the descending aorta and open the aortic arch vessels to atmosphere.

The implementation of physiological afterload during ex situ heart perfusion augments prediction of posttransplant function.

Ex situ heart perfusion (ex situ heart perfusion) is an emerging technique that aims to increase the number of organs available for transplantation by augmenting both donor heart preservation and evaluation. Traditionally, ex situ heart perfusion has been performed in an unloaded Langendorff mode, though more recently groups have begun to use pump-supported working mode (PSWM) and passive afterload working mode (PAWM) to enable contractile evaluation during ex situ heart perfusion. To this point, however, neither the predictive effectiveness of the two working modes nor the predictive power of individual contractile parameters has been analyzed. In this article, we use our previously described system to analyze the predictive relevance of a multitude of contractile parameters measured in each working mode. Ten porcine hearts were excised and perfused ex situ in Langendorff mode for 4 h, evaluated using pressure-volume catheterization in both PSWM and PAWM, and transplanted into size-matched recipient pigs. After 3 h, hearts were weaned from cardiopulmonary bypass and evaluated. When correlating posttransplant measurements to their ex situ counterparts, we report that parameters measured in both modes show sufficient power (Spearman rank coefficient > 0.7) in predicting global posttransplant function, characterized by cardiac index and preload recruitable stroke work. For the prediction of specific posttransplant systolic and diastolic function, however, a large discrepancy between the two working modes was observed. With 9 of 10 measured posttransplant parameters showing stronger correlation with counterparts measured in PAWM, it is concluded that PAWM allows for a more detailed and nuanced prediction of posttransplant function than can be made in PSWM.NEW & NOTEWORTHY Ex situ heart perfusion has been proposed as a means to augment the organ donor pool by improving organ preservation and evaluation between donation and transplantation. Using our multimodal perfusion system, we analyzed the impact of using a "passive afterload working mode" for functional evaluation as compared with the more traditional "pump-supported working mode." Our data suggests that passive afterload working mode allows for a more nuanced prediction of posttransplant function in porcine hearts.

Intraoperative and Early Postoperative Management of Heart Transplantation: Anesthetic Implications.

The gold standard treatment for end-stage heart failure, with 50% mortality within 5 years of diagnosis, is considered heart transplantation. Despite the improvements in immunosuppression, the period of highest mortality risk in the heart transplantation population is during the first year post-transplantation, with primary graft dysfunction being the leading cause of mortality. After adequate preoperative assessment of the recipient, including patients on mechanical support, the intraoperative care of heart transplantation patients requires extensive monitoring followed by proficient management of anesthesia induction and maintenance, ventilation, and fluid therapy. The focus on weaning from cardiopulmonary bypass should be on preventing right ventricular failure and high pulmonary vascular resistances, with protocolized blood conservation strategies and transfusion protocols. The early postoperative care of a heart transplantation patient is focused on the post-cardiopulmonary bypass and transplantation status, with particular attention to the presence of primary graft dysfunction, right ventricular performance, pulmonary pressures, and vasoplegia. The aim is early extubation, inotropic and chronotropic support weaning, and chest tube removal to facilitate discharge of the patient from the intensive care unit. The increased complexity of heart transplantation recipients, including the incremental use of pre- transplantation mechanical circulatory support and extended criteria donor hearts, requires extensive and sophisticated preparation of the cardiac anesthesiologist. This article aims to provide an overview of the intraoperative and early postoperative anesthesia management of heart transplantation patients.

New Strategies to Expand and Optimize Heart Donor Pool: Ex Vivo Heart Perfusion and Donation After Circulatory Death: A Review of Current Research and Future Trends.

Heart transplantation remains the definitive management for end-stage heart failure refractory to medical therapy. While heart transplantation cases are increasing annually worldwide, there remains a deficiency in organ availability with significant patient mortality while on the waiting list. Attempts have therefore been made to expand the donor pool and improve access to available organs by recruiting donors who may not satisfy the standard criteria for organ donation because of donor pathology, anticipated organ ischemic time, or donation after circulatory death. "Ex vivo" heart perfusion (EVHP) is an emerging technique for the procurement of heart allografts. This technique provides mechanically supported warm circulation to a beating heart once removed from the donor and before implantation into the recipient. EVHP can be sustained for several hours, facilitate extended travel time, and enable administration of pharmacological agents to optimize cardiac recovery and function, as well as allow assessment of allograft function before implantation. In this article, we review recent advances in expanding the donor pool for cardiac transplantation. Current limitations of conventional donor criteria are outlined, including the determinants of organ suitability and assessment, involving transplantation of donation after circulatory death hearts, extended criteria donors, and EVHP-associated assessment, optimization, and transportation. Finally, ongoing research relating to organ optimization and functional ex vivo allograft assessment are reviewed.

Practical valvular issues in patients requiring ventricular assist devices.

PURPOSE OF REVIEW: As ventricular assist device (VAD) therapy in patients with advanced heart failure continues to grow, experience with concomitant valvular diseases present either before or after VAD implantation continues to accrue. In this review, we discuss recent data and current practice as it pertains to the subject of concomitant valvular disease in patients requiring VADs. RECENT FINDINGS: Persistent aortic valve closure has been identified as a potential contributor to aortic valve 'disuse atrophy' resulting in valve degeneration. Dilation of the aortic root may be predictive of future development of aortic insufficiency. Novel echocardiographic parameters to identify the severity of aortic insufficiency following VAD implantation may be useful for risk stratification. Concomitant repair of significant mitral regurgitation may confer benefit to pulmonary vascular resistance and right ventricular function; however, this remains controversial. Concomitant repair of significant tricuspid regurgitation has not demonstrated early postoperative benefit nor survival benefit. Atrial fibrillation has emerged as a risk factor that may predict accelerated progression of postoperative tricuspid regurgitation. SUMMARY: Management of aortic insufficiency, mitral regurgitation or tricuspid regurgitation in patients requiring VADs continues to be the source of controversy. As experience accrues with varying strategies to prevent or manage these valvular lesions, our understanding of the impact of these strategies continues to evolve.

Description of a Novel Set-up for Functional Echocardiographic Assessment of Left Ventricular Performance During Ex Vivo Heart Perfusion.

Ex vivo heart perfusion (EVHP) is a new technology aimed at decreasing cold ischemia time and evaluating cardiac function before transplanting a donor heart. In an experimental EVHP swine model, we tested a 3D-printed custom-made set-up to perform surface echocardiography on an isolated beating heart during left ventricular loading. The views obtained at any time point were equivalent to standard transesophageal and transthoracic views. A decrease in left ventricular function during EVHP was observed in all experiments.

Left ventricular assist device exchange: the Toronto General Hospital experience.

BACKGROUND: As support times for left ventricular assist devices (LVADs) become longer, several complications requiring device exchange may occur. To our knowledge, this is the first Canadian report regarding implantable LVAD exchange. METHODS: We retrospectively reviewed the cases of consecutive, unique patients implanted with an LVAD between June 2006 and October 2015 at Toronto General Hospital. RESULTS: In total, 122 patients were impanted with an LVAD during the study period. Eight patients required LVAD exchange, and 1 patient had 2 replacements (9 of 122, 7.3%). There were 7 HeartMate II (HMII), 1 HVAD and 1 DuraHeart pumps exchanged. Two of these exchanges occurred early at the time of initial implant, whereas 7 occurred late (range 8-623 d). Six exchanges were made owing to pump thrombosis. Of the 3 exchanges made for other causes, 1 HMII exchange was owing to a driveline fracture, 1 DuraHeart patient had early inflow obstruction requiring exchange to HMII at the initial implant, and the third had a suspected inflow obstruction with no evidence of thrombosis at the time of the procedure. The mean support time before exchange was 225 days, and time from exchange to transplant, death or ongoing support was 245 days. Three patients were successfully bridged to transplant, and at the time of data collection 2 were supported awaiting transplant. Three patients died after a mean duration of 394.3 days (range 78-673 d) of support postreplacement. Four cases were successfully performed using a subcostal approach. CONCLUSION: Pump thrombosis is the most common cause for LVAD exchange, which can be performed with acceptable morbidity and mortality. The subcostal approach may be the preferred procedure for an HMII exchange when indicated.

CONTEXTE: À mesure que la durée d'utilisation des dispositifs d'assistance ventriculaire gauche (DAVG) augmente, plusieurs complications nécessitant un remplacement du dispositif peuvent survenir. À notre connaissance, il s'agit du premier rapport canadien concernant le remplacement des DAVG implantables. MÉTHODES: Nous avons passé en revue de manière rétrospective les cas individuels consécutifs de patients à qui on a implanté un DAVG entre juin 2006 et octobre 2015 à l'Hôpital Général de Toronto. RÉSULTATS: En tout, 122 patients ont reçu un DAVG pendant la période de l'étude. Huit patients ont eu besoin d'un remplacement de DAVG et 1 patient a eu besoin de 2 remplacements (9 sur 122, 7,3 %). Sept dispositifs HeartMate II (HMII), 1 dispositif HVAD et 1 dispositif DuraHeart ont été remplacés. Deux de ces remplacements sont survenus peu de temps après la pose initiale du dispositif, tandis que les 7 autres se sont produits plus tardivement (dans les 8 à 623 jours suivants). Six remplacements ont été effectués en raison d'une thrombose de la pompe. Parmi les 3 remplacements effectués pour d'autres raisons, 1 dispositif HMII a été remplacé en raison d'un bris de la ligne d'activation, 1 dispositif DuraHeart a présenté une obstruction précoce du flux entrant nécessitant la pose d'un HMII dès l'implantation initiale, et le troisième présentait une obstruction présumée du flux entrant sans signe de thrombose au moment de l'intervention. La durée moyenne d'utilisation avant le remplacement du dispositif a été de 225 jours, et l'intervalle entre le remplacement et la transplantation, le décès ou la décision de maintenir l'assistance a été de 245 jours. L'appareil a permis une transition réussie jusqu'à la transplantation chez 3 patients, et au moment de la collecte des données, 2 patients porteurs d'un DAVG étaient en attente d'une transplantation. Trois patients sont décédés après une durée moyenne de 394,3 jours (entre 78 et 673 jours) d'assistance post-remplacement. Quatre remplacements ont été effectués avec succès par une approche sous-costale. CONCLUSION: La thrombose de la pompe est la cause la plus fréquente de remplacement d'un DAVG; le remplacement peut être effectué avec des taux de morbidité et de mortalité acceptables. L'approche sous-costale serait à privilégier lorsqu'un remplacement de HMII est indiqué.

A New Multi-Mode Perfusion System for Ex Vivo Heart Perfusion Study.

Ex vivo heart perfusion has been shown to be an effective means of facilitating the resuscitation and assessment of donor hearts for cardiac transplantation. Over the last ten years however, only a few ex vivo perfusion systems have been developed for this application. While results have been promising, a system capable of facilitating multiple perfusion strategies on the same platform has not yet been realized. In this paper, the design, development and testing of a novel and modular ex vivo perfusion system is described. The system is capable of operating in three unique primary modes: the traditional Langendorff Mode, Pump-Supported Working-Mode, and Passive Afterload Working-Mode. In each mode, physiological hemodynamic parameters can be produced by managing perfusion settings. To evaluate heart viability, six experiments were conducted using porcine hearts and measuring several parameters including: pH, aortic pressure, lactate metabolism, coronary vascular resistance (CVR), and myocardial oxygen consumption. Pressure-volume relationship measurements were used to assess left ventricular contractility in each Working Mode. Hemodynamic and metabolic conditions remained stable and consistent across 4 h of ex vivo heart perfusion on the ex vivo perfusion system, validating the system as a viable platform for future development of novel preservation and assessment strategies.

Year in review: complex valve reconstruction.

PURPOSE OF REVIEW: In recent years, great emphasis has been placed on reconstructive techniques for the surgical management of heart valve disease. In this review, we discuss recent data and current practice as it pertains to the subject of reconstructive valve surgery. RECENT FINDINGS: New techniques and an improved understanding of the mechanisms of aortic insufficiency have led to marked improvement in the early and late outcomes of aortic valve repair. While mitral valve repair is the established approach for the management of degenerative mitral valve disease, surgical technique continues to be refined, with valve reconstruction principles applied to increasingly challenging anatomy. Moreover, the introduction of novel biomaterials has allowed extension of the indication for valve reconstruction to circumstances of extensive tissue defect, including infective endocarditis. SUMMARY: Valve reconstruction is increasingly being recognized as an alternative to valve replacement. It alleviates the risks of prosthesis-related complications and is especially appealing in young and middle-aged adults. While early and midterm outcomes appear promising, further studies are warranted to assess the clinical benefit and long-term durability of complex valve reconstruction procedures.

Severe Staphylococcus aureus Endocarditis Presenting as Peripartum Thrombotic Thrombocytopenic Purpura.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening illness that occurs in both pregnant and non-pregnant women. Several other conditions can mimic the disease, which makes the diagnosis challenging. CASE: We describe a case of severe Staphylococcus aureus endocarditis that initially presented as peripartum TTP in a 39-year-old woman at 29+6 weeks' gestation. We give an overview of the diagnostic considerations and management of thrombocytopenia in pregnancy and review the literature related to TTP and peripartum infective endocarditis. CONCLUSION: Given the significant differences in definitive therapies for the spectrum of thrombocytopenic conditions that occur in pregnancy, timely and accurate diagnosis of TTP is critical for optimal management.

Epidermal growth factor-like domain 7 is a novel inhibitor of neutrophil adhesion to coronary artery endothelial cells injured by calcineurin inhibition.

BACKGROUND: We investigated the effect of epidermal growth factor-like domain 7 (Egfl7) on nuclear factor-κB activation, intercellular adhesion molecule-1 expression, and neutrophil adhesion to human coronary artery endothelial cells after calcineurin-inhibition-induced injury. METHODS AND RESULTS: Human coronary endothelial cells were incubated with cyclosporine (CyA) 10 µg/mL with or without Egfl7 (100 ng/mL) or the Notch receptor activator Jagged1 (200 ng/mL) for 6 to 48 hours. CyA upregulated nuclear factor-κB (p65) activity (128 ± 2% of control, P<0.001) in nuclear extracts, as determined with a DNA-binding activity ELISA. This activity was inhibited by Egfl7 (86 ± 3% of control; P<0.001 versus CyA alone). Jagged1 blocked Egfl7-induced nuclear factor-κB inhibition (105 ± 4% of control; P<0.05 versus CyA plus Egfl7). CyA upregulated cell-surface intercellular adhesion molecule-1 expression (215 ± 13% of control; P<0.001), as determined by flow cytometry. This expression was suppressed by Egfl7 (148 ± 5%; P<0.001 versus CyA alone). Jagged1 attenuated the intercellular adhesion molecule-1-suppressive effect of Egfl7 when administered with CyA (193 ± 3% versus 148 ± 5%; P<0.01). CyA increased neutrophil adhesion to human coronary endothelial cells (control 20 ± 5%, CyA 37 ± 3%; P<0.001 versus control) in a nonstatic neutrophil adhesion assay. This increase was attenuated by Egfl7 (22 ± 6%; P<0.001 versus CyA alone). Jagged 1 attenuated the effect of Egfl7 on neutrophil adhesion (31±3%; P<0.001 versus Egfl7 plus CyA). CONCLUSIONS: Our study reveals that Egfl7 is a potent inhibitor of neutrophil adhesion to human coronary endothelial cells subsequent to calcineurin-inhibition-induced injury. Mechanistically, Egfl7 blocked nuclear factor-κB pathway activation and intercellular adhesion molecule-1 expression, which suggests that it may have significant antiinflammatory properties. Because Jagged1 blocked the effect of Egfl7, Notch receptor antagonism may contribute to the mechanism of action of Egfl7.