Brain imaging determinants of functional prognosis after severe endocarditis: a multicenter observational study.

OBJECTIVE: We developed a detailed imaging phenotype of the cerebral complications in critically ill patients with infective endocarditis (IE) and determine whether any specific imaging pattern could impact prognostic information. METHODS: One hundred ninety-two patients admitted to the intensive care units of seven tertiary centers with severe, definite left IE and neurological complications were included. All underwent cerebral imaging few days after admission to define the types of lesions, their volumes, and their locations using voxel-based lesion-symptom mapping (VLSM). We employed uni- and multi-variate logistic regression analyses to explore the associations among imaging features and other prognostic variables and the 6-month modified Rankin Scale (mRS) score. RESULTS: Ischemic lesions were the most common lesions (75%; mean volume, 15.3 ± 33 mL) followed by microbleeds (50%; mean number, 4 ± 7.5), subarachnoidal hemorrhages (20%), hemorrhagic strokes (16%; mean volume, 14.6 ± 21 mL), and hemorrhagic transformations (10%; mean volume, 5.6 ± 11 mL). The volume of hemorrhagic transformations, the severity of leukopathy, and the compromises of certain locations on the motor pathway from the VLSM were associated with a poor 6-month mRS score on univariate analyses. However, upon multivariate analyses, no such specific imaging pattern independently predicted the mRS; this was instead influenced principally by age (OR = 1.03 [1.004-1.06]) and cardiac surgery status (OR = 0.06 [0.02-0.16]) in the entire cohort, and by age (OR = 1.04 [1.01-1.08]) and Staphylococcus aureus status (OR = 2.86 [1.19-6.89]) in operated patients. CONCLUSIONS: In a cohort of severely ill IE patients with neurological complications, no specific imaging pattern could be highlighted as a reliable predictor of prognosis.

Local abnormal ventricular activity detection in scar-related VT: Microelectrode versus conventional bipolar electrode.

BACKGROUND: Conventional bipolar electrodes (CBE) may be suboptimal to detect local abnormal ventricular activities (LAVAs). Microelectrodes (ME) may improve the detection of LAVAs. This study sought to elucidate the detectability of LAVAs using ME compared with CBE in patients with scar-related ventricular tachycardia (VT). METHODS: We included consecutive patients with structural heart disease who underwent radiofrequency catheter ablation for scar-related VT using either of the following catheters equipped with ME: QDOTTM or IntellaTip MIFITM. Detection field of LAVA potentials were classified as three types: Type 1 (both CBE and ME detected LAVA), Type 2 (CBE did not detect LAVA while ME did), and Type 3 (CBE detected LAVA while ME did not). RESULTS: In 16 patients (68 ± 16 years; 14 males), 260 LAVAs electrograms (QDOT = 72; MIFI = 188) were analyzed. Type 1, type 2, and type 3 detections were 70.8% (QDOT, 69.4%; MIFI, 71.3%), 20.0% (QDOT, 23.6%; MIFI, 18.6%) and 9.2% (QDOT, 6.9%; MIFI, 10.1%), respectively. The LAVAs amplitudes detected by ME were higher than those detected by CBE in both catheters (QDOT: ME 0.79 ± 0.50 mV vs. CBE 0.41 ± 0.42 mV, p = .001; MIFI: ME 0.73 ± 0.64 mV vs. CBE 0.38 ± 0.36 mV, p < .001). CONCLUSIONS: ME allow to identify 20% of LAVAs missed by CBE. ME showed higher amplitude LAVAs than CBE. However, 9.2% of LAVAs can still be missed by ME.

Electrogram morphology discriminators in implantable cardioverter defibrillators: A comparative evaluation.

BACKGROUND: Morphology algorithms are currently recommended as a standalone discriminator in single-chamber implantable cardioverter defibrillators (ICDs). However, these proprietary algorithms differ in both design and nominal programming. OBJECTIVE: To compare three different algorithms with nominal versus advanced programming in their ability to discriminate between ventricular (VT) and supraventricular tachycardia (SVT). METHODS: In nine European centers, VT and SVTs were collected from Abbott, Boston Scientific, and Medtronic dual- and triple-chamber ICDs via their respective remote monitoring portals. Percentage morphology matches were recorded for selected episodes which were classified as VT or SVT by means of atrioventricular comparison. The sensitivity and related specificity of each manufacturer discriminator was determined at various values of template match percentage from receiving operating characteristics (ROC) curve analysis. RESULTS: A total of 534 episodes were retained for the analysis. In ROC analyses, Abbott Far Field MD (area under the curve [AUC]: 0.91; P < .001) and Boston Scientific RhythmID (AUC: 0.95; P < .001) show higher AUC than Medtronic Wavelet (AUC: 0.81; P < .001) when tested for their ability to discriminate VT from SVT. At nominal % match threshold all devices provided high sensitivity in VT identification, (91%, 100%, and 90%, respectively, for Abbott, Boston Scientific, and Medtronic) but contrasted specificities in SVT discrimination (85%, 41%, and 62%, respectively). Abbott and Medtronic's nominal thresholds were similar to the optimal thresholds. Optimization of the % match threshold improved the Boston Scientific specificity to 79% without compromising the sensitivity. CONCLUSION: Proprietary morphology discriminators show important differences in their ability to discriminate SVT. How much this impact the overall discrimination process remains to be investigated.

Acute and mid-term outcome of ethanol infusion of vein of Marshall for the treatment of perimitral flutter.

AIMS: We hypothesized that an epicardial approach using ethanol infusion in the vein of Marshall (EIVOM) may improve the result of ablation for perimitral flutter (PMF). METHODS AND RESULTS: We studied 103 consecutive patients with PMF undergoing high-resolution mapping. The first 71 were treated with radiofrequency (RF) ablation alone (RF-group), and the next 32 underwent EIVOM followed by RF on the endocardial and epicardial mitral isthmus (EIVOM/RF-group). Contact force was not measured during ablation. Acute and 1-year outcomes were compared. Flutter termination rates were similar between the RF-group (63/71, 88.7%) and EIVOM/RF-group (31/32, 96.8%, P = 0.27). Atrial tachycardia (AT) terminated with EIVOM alone in 22/32 (68.6%) in the EIVOM/RF-group. Bidirectional block of mitral isthmus was always achieved in the EIVOM/RF-group, but significantly less frequently achieved in the RF-group (62/71, 87.3%; P = 0.05). Median RF duration for AT termination/conversion was shorter [0 (0-6) s in the EIVOM/RF-group than 312 (55-610) s in the RF-group, P < 0.0001], as well as for mitral isthmus block in the EIVOM/RF-group [246 (0-663) s] than in the RF-group [900 (525-1310) s, P < 0.0001]. Pericardial effusion was observed in 1/32 (3.2%) in EIVOM/RF-group and 5/71 (7.0%) in RF-group (P = 0.66); two in RF-group required drainage and one of them developed subsequent ischaemic stroke. One-year follow-up demonstrated fewer recurrences in the EIVOM/RF-group [6/32 (18.8%)] than in the RF-group [29/71 (40.8%), P = 0.04]. By multivariate analysis, only EIVOM was significantly associated with less AT recurrence (hazard ratio = 0.35, P = 0.018). CONCLUSION: Ethanol infusion in the vein of Marshall may reduce RF duration required for PMF termination as well as for mitral isthmus block without severe complications, and the mid-term outcome may be improved by this approach.

Detailed comparison between the wall thickness and voltages in chronic myocardial infarction.

BACKGROUND: The relationship between the local electrograms (EGMs) and wall thickness (WT) heterogeneity within infarct scars has not been thoroughly described. The relationship between WT and voltages and substrates for ventricular tachycardia (VT) was examined. METHODS: In 12 consecutive patients with myocardial infarction and VT, WT, defined by a multidetector computed tomography, and voltage were compared. In multicomponent EGMs, amplitudes of both far- and near-field components were manually measured, and the performance of the three-dimensional-mapping system automatic voltage measurement was assessed. RESULTS: Of 15 748 points acquired, 2677 points within 5 mm of the endocardial surface were analyzed. In total, 909 (34.0%) multicomponent EGMs were identified; 785 (86.4%) and 883 (97.1%) were distributed in the WT less than 4 and 5 mm, respectively. Far-field EGM voltages increased linearly from 0.14 mV (0.08-0.28 mV) in the WT: 0 to 1 mm to 0.70 mV (0.43-2.62 mV) in the WT: 4 to 5 mm (ρ = 0.430; P < 0.001), and a significant difference was demonstrated between any two WT-groups (P ≤ 0.001). In contrast, near-field EGM voltages varied from 0.27 mV (0.11-0.44 mV) in the WT: 0 to 1 mm to 0.29 mV (0.17-0.53 mV) in the WT: 4 to 5 mm with a poorer correlation (ρ = 0.062, P = 0.04). The proportion of points where the system automatically measured the voltage on near-field EGMs increased from less than 10% in areas of WT: 4 to 5 mm to 50% in areas less than 2 mm. Of 21 VTs observed, seven hemodynamically stable VTs were mapped and terminated in WT: 1 to 4 mm area. CONCLUSIONS: Although far-field voltages gradually increase with the WT, near-field does not. The three-dimensional-mapping system preferentially annotates the near-field components in thinner areas (center of the scar) and the far-field component in thicker areas when building a voltage map. Critical sites of VT are distributed in WT: 1 to 4 mm areas.

Anti-αIIb ß3 immunization in Glanzmann thrombasthenia: review of literature and treatment recommendations.

Glanzmann thrombasthenia (GT) is caused by inherited defects of the αIIb ß3 platelet glycoprotein. This bleeding disorder can be treated with platelet transfusion therapy, but some patients will be immunized and begin to form anti-human leucocyte antigen (HLA) and/or anti-αIIb ß3 antibodies. These antibodies can bind and interfere with the function of the transfused platelets, rendering treatment ineffective. However, platelet transfusion refractoriness attributable to HLA antibodies may be managed by the selection of compatible donors, although they are not always readily available, particularly in an emergency. Thus, anti-αIIb ß3 antibodies represent one of the most severe complications in GT. Both genetic and environmental factors may contribute to the risk of anti-αIIb ß3 development, but the underlying pathogenic mechanisms are still unknown. This review will summarize the current knowledge of the risk factors for development of anti-αIIb ß3 antibodies in patients with GT and discuss how these findings may influence the clinical management of patients.

Mutations of the integrin αIIb/ß3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α-granules.

Rare gain-of-function mutations within the ITGA2B or ITGB3 genes have been recognized to cause macrothrombocytopenia (MTP). Here we report three new families with autosomal dominant (AD) MTP, two harboring the same mutation of ITGA2B, αIIbR995W, and a third family with an ITGB3 mutation, ß3D723H. In silico analysis shows how the two mutated amino acids directly modify the salt bridge linking the intra-cytoplasmic part of αIIb to ß3 of the integrin αIIbß3. For all affected patients, the bleeding syndrome and MTP was mild to moderate. Platelet aggregation tended to be reduced but not absent. Electron microscopy associated with a morphometric analysis revealed large round platelets; a feature being the presence of abnormal large α-granules with some giant forms showing signs of fusion. Analysis of the maturation and development of megakaryocytes reveal no defect in their early maturation but abnormal proplatelet formation was observed with increased size of the tips. Interestingly, this study revealed that in addition to the classical phenotype of patients with αIIbß3 intracytoplasmic mutations there is an abnormal maturation of α-granules. It is now necessary to determine if this feature is a characteristic of all mutations disturbing the αIIb R995/ß3 D723 salt bridge.

Clinical and Laboratory Findings in Patients with δ-Storage Pool Disease: A Case Series.

Platelet δ-storage pool disease (δ-SPD) is a platelet function disorder characterized by a reduction in the number or content of dense granules. Reports on δ-SPD are mostly limited to case presentations. We aimed to retrospectively describe a series of patients with δ-SPD to better characterize the disease. We studied 16 patients with congenital or acquired δ-SPD. Lumiaggregometry, α- and δ-granules content, platelet ultrastructure, αIIbß3 integrin, and glycoprotein Ib (GPIb) activation were assessed. Most of the patients generally demonstrate mild to moderate bleeding diathesis. Platelet aggregation studies showed moderate abnormalities with variable profiles, while all the individuals had almost complete absence of adenosine triphosphate release. Mepacrine capture, CD63 expression, and study of dense granules by electron microscopy enabled to distinguish different subtypes of δ-SPD with quantitative or qualitative defect. Surprisingly, significantly decreased GPIb expression levels after platelet activation with thrombin receptor activating peptide 50 µM were found, suggesting that GPIb-impaired mobilization may represent an additional feature of the disorder. In conclusion, δ-SPD represents a complex disorder with various clinical and biological aspects, requiring a great deal of expertise to be properly diagnosed.

Long-term follow-up after left atrial appendage occlusion with comparison of transesophageal echocardiography versus computed tomography to guide medical therapy and data about postclosure cardioversion.

AIMS: The use of left atrial appendage (LAA) occluders in atrial fibrillation is increasing. There are few data on the comparison between transesophageal echocardiography (TEE) and computed tomography (MDCT) assessing peridevice flow and outcome of electrical cardioversion (ECV) in these patients. METHODS AND RESULTS: Single-center prospective registry from 2009 to 2015 including all LAA occluders to analyze success and complications during implantation and follow-up. Patients having ≥1 ECV were further analyzed. TEE was performed during implantation and at 6 weeks. In a subgroup of 77 patients, we compared MDCT with TEE at 6 weeks. Overall, 135 patients (69 ± 9 years; 70% male; CHA2 DS2 -VASc score: 3.6 ± 1.4; HAS-BLED score: 2.5 ± 0.6) received a LAA occluder (Watchman, n = 73; ACP-1, n = 59; Amulet, n = 3; PVI + LAA occluder, n = 91; and LAA occluder only, n = 44). Device implantation was successful in 131 (97%). Eight patients (5.9%) had major periprocedural complications (ischemic stroke/transient ischemic attacks, n = 4, tamponade, n = 2, device thrombosis, n = 2, Dressler syndrome, n = 1). The periprocedural complication rate was similar between concomitant procedure and LAA occluder only (8/91 vs. 5/44; P = 0.6). Twelve patients (9%) died (procedure-related, n = 2; 1%) during follow-up of 44 months (IQR: 43). MDCT (n = 77) at 6 weeks showed similar peridevice flow compared to TEE (TEE: 1.5 ± 1.9 mm vs. MDCT: 1.1 ± 2.2 mm, P = 0.25). Thromboembolic events occurred in 3 patients (CVA, n = 1; TIA, n = 2) during follow-up. In total, 41 ECV were performed in 26 patients (1.6 ± 0.9/patient), 13 months (IQR: 24) after implantation (<1 month: n = 8). No ECV-related clinical complications were observed. CONCLUSION: LAA occlusion is feasible with an acceptable safety profile and few events during long-term follow-up. ECV after LAA occlusion is feasible. MDCT could help to evaluate peridevice flow.

A new cryoenergy for ventricular tachycardia ablation: a proof-of-concept study.

INTRODUCTION: Lack of transmural lesion formation during radiofrequency (RF) ablation for ventricular tachycardia (VT) is an important determinant of arrhythmia recurrence. The aim of this proof-of-concept study was to evaluate safety and efficacy of a new and more powerful cryoablation system for ventricular ablation. METHODS AND RESULTS: Five healthy female sheep (59 ± 6 kg) underwent a surgical sternotomy for epicardial and endocardial access [endocardial access via right atrial appendage and left ventricular (LV) apex]. A cryoablation system with liquid nitrogen (IceCure) was used to create 3 min freezes at the right ventricle (RV). Left ventricular cryoablation was performed with either a 6 min or 2 × 4 min freezes. To assess safety, ablation was also performed on the mid left anterior descending artery and the proximal coronary sinus. A total of 45 lesions were created (RV epicardial, n = 12; LV epicardial, n = 18; RV endocardial, n = 7; LV endocardial, n = 8; LAD, n = 4; and CS, n = 4). The mean lesion volume was 5055 ± 92 mm3 (length: 32 ± 4.6 mm, width: 16.0 ± 6.4 mm, and depth: 11.2 ± 4.4 mm). Lesions were transmural in 28/45 (62%) and >10 mm in depth in 35/45 (78%). Of the endocardial lesions, 12/15 were transmural (80%). There was no benefit of the bonus freeze in LV lesions (6 vs. 2 × 4 min: 6790 ± 44 vs. 5595 ± 63 mm3; P = 0.44). All ablated vascular structures appeared macroscopically normal without acute stenosis. One animal died due to incessant Ventricular fibrillation (VF). CONCLUSION: Our results indicate that a more powerful cryoablation system is able to create large, transmural ventricular lesions from both the endocardium and the epicardium. The technology may hold potential for both surgical and catheter-based VT ablation in humans.

Linkage disequilibrium amongst ITGA2B and ITGB3 gene variants in patients with Glanzmann thrombasthenia confirms that most disease-causing mutations are recent.

We recently reported mutation analysis of the largest cohort of Glanzmann thrombasthenia (GT) patients so far examined. Sanger sequencing of coding regions, splice sites, upstream and downstream regions of the ITGA2B and ITGB3 genes identified 78 causal genetic variants (55 novel); 4 large deletions or duplications were also detected. We have now analysed the expression of non-causal gene polymorphisms in the sequenced regions of both genes in selected members of this cohort. We identified 10 mostly silent variants in ITGA2B and 37 in ITGB3; all were present in control donor databases. Three non-synonymous single nucleotide polymorphisms present were human platelet alloantigen (HPA) variants. A series of haplogroups, often including HPA-3b in ITGA2B, repeated with little variation across unrelated families of wide geographical origins and with different GT-causing mutations whether in ITGA2B or ITGB3. In contrast, a deleterious heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B shared a common ITGA2B haplogroup composed of at least five gene polymorphisms and re-occurred in seven European families with no known family relationships. Our results highlight the value of gene polymorphism analysis in GT and are consistent with the bulk of disease-causing mutations in GT being of recent origin.

A diagnostic approach that may help to discriminate inherited thrombocytopenia from chronic immune thrombocytopenia in adult patients.

Inherited thrombocytopenia (IT) is a heterogeneous group of rare diseases that are often confused with immune thrombocytopenia (ITP). The objective of this study was to supply clinicobiological elements that allow a distinction to be drawn between IT and chronic ITP. We then compared 23 adult patients with IT and 9 patients with chronic ITP. Our study revealed six discriminating criteria: (i) an age of discovery <34 years: positive predictive value (PPV) = 88.2% [63.6; 98.5], (ii) a family history of thrombocytopenia: PPV = 100.0% [82.4; 100.0], (iii) a personal history of bleeding: PPV = 100% [76.8; 100.0], (iv) a mean platelet volume >11 fL: PPV = 93.3% [68.1; 99.8], (v) an excess of giant platelets on blood smear: 100.0% [76.8; 100.0], and (vi) a percentage >44% of platelets with a surface area >4 µm(2) in electron microscopy: PPV = 83.3% [58.6; 96.4]. If at least three of these criteria were combined, it was possible to distinguish IT from chronic ITP with 91.3% [72.0; 98.9] sensitivity and PPV = 100.0% [66.4; 100.0] specificity. The secondary objective of this study was to assess the prevalence of potential IT diagnosis in patients with chronic thrombocytopenia of uncertain origin. Applying our diagnostic approach to a series of 20 cases allowed us to estimate that 40% of them could be suffering from IT. Finally, our diagnostic approach may help to correctly distinguish IT from chronic ITP, particularly in the context of macrothrombocytopenia.

Expanding the Mutation Spectrum Affecting αIIbß3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort.

We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbß3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real-time PCR. Families with mutations in either gene were indistinguishable in terms of bleeding severity that varied even among siblings. Families were grouped into type I and the rarer type II or variant forms with residual αIIbß3 expression. Variant forms helped identify genes encoding proteins mediating integrin activation. Splicing defects and stop codons were common for both ITGA2B and ITGB3 and essentially led to a reduced or absent αIIbß3 expression; included was a heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B causing exon skipping in seven unrelated families. Molecular modeling revealed how many missense mutations induced subtle changes in αIIb and ß3 domain structure across both subunits, thereby interfering with integrin maturation and/or function. Our study extends knowledge of GT and the pathophysiology of an integrin.

Impact of Electrode Type on Mapping of Scar-Related VT.

BACKGROUND: Substrate-based VT ablation is mostly based on maps acquired with ablation catheters. We hypothesized that multipolar mapping catheters are more effective for identification of scar and local abnormal ventricular activity (LAVA). METHODS AND RESULTS: Phase1: In a sheep infarction model (2 months postinfarction), substrate mapping and LAVA tagging (CARTO® 3) was performed, using a Navistar (NAV) versus a PentaRay (PR) catheter (Biosense Webster). Phase2: Consecutive VT ablation patients from a single center underwent NAV versus PR mapping. Point pairs were defined as a PR and a NAV point located within a 3D-distance of ≤3 mm. Agreement was defined as both points in a pair being manually tagged as normal or LAVA. Four sheep (4 years, 50 ± 4.8 kg) and 9 patients were included (53 ± 14 years, 8 male, 6 ischemic cardiomyopathy). Mapping density was higher within the scar with PR versus NAV (3.2 vs. 0.7 points/cm2 , P = 0.001) with larger bipolar scar area (68 ± 55 cm2 vs. 58 ± 48 cm2 , P = 0.001). In total, 818 point pairs were analyzed. Using PR, far-field voltages were smaller (PR vs. NAV; bipolar: 1.43 ± 1.84 mV vs. 1.64 ± 2.04 mV, P = 0.001; unipolar; 4.28 ± 3.02 mV vs. 4.59 ± 3.67 mV, P < 0.001). More LAVA were also detected with PR (PR vs. NAV; 126 ± 113 vs. 36 ± 29, P = 0.001). When agreement on LAVA was reached (overall: 72%; both LAVA, 40%; both normal, 82%) higher LAVA voltages were recorded on PR (0.48 ± 0.33 mV vs. 0.31 ± 0.21 mV, P = 0.0001). CONCLUSION: Multipolar mapping catheters with small electrodes provide more accurate and higher density maps, with a higher sensitivity to near-field signals. Agreement between PR and NAV is low.

In vitro characterization of rare anti-αIIbß3 isoantibodies produced by patients with Glanzmann thrombasthenia that severely block fibrinogen binding and generate procoagulant platelets via complement activation.

Background: Glanzmann thrombasthenia (GT) is a rare bleeding disorder caused by inherited defects of the platelet αIIbß3 integrin. Platelet transfusions can be followed by an immune response that can block integrin function by interfering with fibrinogen binding. Objectives: In this study, we aimed to determine the prevalence of such isoantibodies and better characterize their pathogenic properties. Methods: Twelve patients with GT were evaluated for anti-αIIbß3 isoantibodies. Sera from patients with GT with or without anti-αIIbß3 isoantibodies were then used to study their in vitro effect on platelets from healthy donors. We used several approaches (IgG purification, immunofluorescence staining, and inhibition of signaling pathways) to characterize the pathogenic properties of the anti-αIIbß3 isoantibodies. Results: Only 2 samples were able to severely block integrin function. We observed that these 2 sera caused a reduction in platelet size similar to that observed when platelets become procoagulant. Mixing healthy donor platelets with patients' sera or purified IgGs led to microvesiculation, phosphatidylserine exposure, and induction of calcium influx. This was associated with an increase in procoagulant platelets. Pore formation and calcium entry were associated with complement activation, leading to the constitution of a membrane attack complex (MAC) with enhanced complement protein C5b-9 formation. This process was inhibited by the complement 5 inhibitor eculizumab and reduced by polyvalent human immunoglobulins. Conclusion: Our data suggest that complement activation induced by rare blocking anti-αIIbß3 isoantibodies may lead to the formation of a MAC with subsequent pore formation, resulting in calcium influx and procoagulant platelet phenotype.

Critically ill patients with infective endocarditis, neurological complications and indication for cardiac surgery: a multicenter propensity-adjusted study.

BACKGROUND: The benefit-risk balance and optimal timing of surgery for severe infective endocarditis (IE) with ischemic or hemorrhagic strokes is unknown. The study aim was to compare the neurological outcome between patients receiving surgery or not. METHODS: In a prospective register-based multicenter ICU study, patients were included if they met the following criteria: (i) left-sided IE with an indication for heart surgery; (ii) with cerebral complications documented by cerebral imaging before cardiac surgery; (iii) with Sequential Organ Failure Assessment score ≥ 3. Exclusion criteria were isolated right-sided IE, in-hospital acquired IE and patients with cerebral complications only after cardiac surgery. In the primary analysis, the prognostic value of surgery in term of disability at 6 month was assessed by using a propensity score-adjusted logistic regression. RESULTS: 192 patients were included including ischemic stroke (74.5%) and hemorrhagic lesion (15.6%): 67 (35%) had medical treatment and 125 (65%) cardiac surgery. In the propensity score-adjusted logistic regression, a favorable 6-month neurological outcome was associated with surgery (odds ratio 13.8 (95% CI 6.2-33.7). The 1-year mortality was strongly reduced with surgery in the fixed-effect propensity-adjusted Cox model (hazard ratio 0.18; 95% CI 0.11-0.27; p < 0.001). These effects remained whether the patients received delayed surgery (n = 62/125) or not and whether they were deeply comatose (Glasgow Coma Scale ≤ 10) or not. CONCLUSIONS: In critically ill IE patients with an indication for surgery and previous cerebral events, a better propensity-adjusted neurological outcome was associated with surgery compared with medical treatment.

Glanzmann thrombasthenia: state of the art and future directions.

Glanzmann thrombasthenia (GT) is the principal inherited disease of platelets and the most commonly encountered disorder of an integrin. GT is characterized by spontaneous mucocutaneous bleeding and an exaggerated response to trauma caused by platelets that fail to aggregate when stimulated by physiologic agonists. GT is caused by quantitative or qualitative deficiencies of αIIbß3, an integrin coded by the ITGA2B and ITGB3 genes and which by binding fibrinogen and other adhesive proteins joins platelets together in the aggregate. Widespread genotyping has revealed that mutations spread across both genes, yet the reason for the extensive variation in both the severity and intensity of bleeding between affected individuals remains poorly understood. Furthermore, although genetic defects of ITGB3 affect other tissues with ß3 present as αvß3 (the vitronectin receptor), the bleeding phenotype continues to dominate. Here, we look in detail at mutations that affect (i) the ß-propeller region of the αIIb head domain and (ii) the membrane proximal disulfide-rich epidermal growth factor (EGF) domains of ß3 and which often result in spontaneous integrin activation. We also examine deep vein thrombosis as an unexpected complication of GT and look at curative procedures for the diseases, including allogeneic stem cell transfer and the potential for gene therapy.

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models.

Characterized by mucocutaneous bleeding arising from a lack of platelet aggregation to physiologic stimuli, Glanzmann thrombasthenia (GT) is the archetype-inherited disorder of platelets. Transmitted by autosomal recessive inheritance, platelets in GT have quantitative or qualitative deficiencies of the fibrinogen receptor, αIIbß3, an integrin coded by the ITGA2B and ITGB3 genes. Despite advances in our understanding of the disease, extensive phenotypic variability with respect to severity and intensity of bleeding remains poorly understood. Importantly, genetic defects of ITGB3 also potentially affect other tissues, for ß3 has a wide tissue distribution when present as αvß3 (the vitronectin receptor). We now look at the repertoire of ITGA2B and ITGB3 gene defects, reexamine the relationship between phenotype and genotype, and review integrin structure in the many variant forms. Evidence for modifications in platelet production is assessed, as is the multifactorial etiology of the clinical expression of the disease. Reports of cardiovascular disease and deep vein thrombosis, cancer, brain disease, bone disorders, and pregnancy defects in GT are discussed in the context of the results obtained for mouse models where nonhemostatic defects of ß3-deficiency or nonfunction are being increasingly described.