Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry

Background: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients\u2019 clinical phenotypes and analyse the differential clinical course. Methods: We performed a hierarchical cluster analysis based on Ward\u2019s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients\u2019 prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P <.001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27\u20133.62; HR 3.42, 95%CI 2.72\u20134.31; HR 2.79, 95%CI 2.32\u20133.35), and Cluster 1 (HR 1.88, 95%CI 1.48\u20132.38; HR 2.50, 95%CI 1.98\u20133.15; HR 2.09, 95%CI 1.74\u20132.51) reported a higher risk for the three outcomes respectively. Conclusions: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes

Molecular characterization of leukocyte adhesion deficiency in six patients

Leukocyte adhesion deficiency (LAD) is caused by defects in the CD18 gene, which codes for the common β2 subunit of the leukocyte integrins LFA-1, Mac-1 and p150,95. Failure to produce a functional β2 subunit results in the defective expression of all three leukocyte integrins, and the leukocytes of LAD patients have subnormal adhesion properties. Six patients with LAD were studied. Patient B was homozygous and carried a G284S mutation. A two-bp (GA) deletion at position 1256 (1256ΔGA) was found in the cDNA of patient C, who also had an abnormally large mRNA of 4.3 kb. Patients E and K were siblings and were heterozygous at the genomic level. One defective allele contained a mutation in intron 6/7 which created a preemptive 3' splice site. The resulting mRNA has 12 extra bases at the junction of exons 6 and 7, coding for four extra residues PSSQ in the protein. The same allele also carried a R586W mutation. The other allele was transcribed at a low level and was not characterized. Patient G carried a L149P mutation in one allele; again, the other allele was not characterized due to low transcription levels. Patient R carried two mutant alleles with G284S and R593C mutations respectively. The G284S mutation and the 1256ΔGA deletion have not been reported previously. CD18 cDNA carrying the abnormalities were cotransfected with normal CD11a or CD11b cDNA into COS cells. Expression of the LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) antigens on COS cells was not detected, suggesting that these two mutations are sufficient to account for LAD.link_to_subscribed_fulltex

A CR1 polymorphism associated with constitutive erythrocyte CR1 levels affects binding to C4b but not C3b

The erythrocyte type one complement receptor (E-CR1) mediates erythrocyte binding of complement-opsonized immune complexes (IC), and helps protect against random deposition of circulating IC. Two linked CR1 polymorphisms occur in binding domains, at I643T and Q981H. In Caucasians, the variant alleles (643T, 981H) are associated with low constitutive E-CR1 expression levels. This study was conducted to determine if these polymorphisms affect ligand binding, and if so, represent risk factors for the autoimmune IC disease, systemic lupus erythematosus (SLE). In an ELISA comparing relative ligand binding differences, E-CR1 from individuals homozygous for the variant residues (643TT/981HH) exhibited greater binding to C4b, but not C3b, than homozygous wild-type E-CR1. Analysis of single-binding domain CR1 constructs demonstrated that the 981H residue imparted this enhanced C4b binding. No differences were observed in the 981H allele frequency between Caucasian controls (0·170, n = 100) and SLE patients (0·130, n = 150, P = 0·133), or between African American controls (0·169, n = 71) and SLE patients (0·157, n = 67). In a subset of individuals assessed for CR1 size, excluding from this analysis those expressing at least one B allele revealed a trend for over-representation of the 981H allele in Caucasian controls (0·231 frequency, n = 26) versus SLE patients (0·139, n = 83, P = 0·089), but again no difference between African American controls (0·188, n = 24) and SLE patients (0·191, n = 34). These data suggest that the 981H residue compensates for low constitutive expression of E-CR1 in Caucasians by enhancing C4b binding. This may contribute protection against SLE