Impact of Atrial Fibrillation on the Symptoms and Echocardiographic Evaluation of Patients With Aortic Stenosis.

Atrial fibrillation (AF) is common in patients with aortic stenosis (AS) and complicates the assessment of AS severity. The overlapping of symptoms in these 2 conditions may postpone valve replacement. This study aimed to evaluate the effect of AF on the severity assessment of AS and its impact on symptoms and quality of life (QoL). Patients with severe AS were prospectively recruited. Echocardiography, symptom questionnaires, and RAND-36 QoL assessment were performed preoperatively and 3 months postoperatively. The aortic valve calcium score (AVC) was measured using computed tomography. Of the 279 patients, 74 (26.5%) had AF. Patients with AF had lower mean gradients and 45.9% had a low-gradient phenotype, with a mean gradient <40 mm Hg, compared with 22.4% of those without AF (p <0.001). The AVC measurements revealed severe valve calcification equally in patients with or without AF (85.7% vs 87.7%, p = 0.78). Patients with AF were more symptomatic at baseline, with 50.0% versus 27.3% in New York Heart Association class III or higher (p <0.001), and after intervention. Patients with AF had more residual dyspnea (27.3% vs 12.0%, p = 0.007) and exercise intolerance (36.4% vs 17.0%, p = 0.002). The QoL improved significantly in both groups but was worse at baseline in patients with AF and remained impaired after intervention. In conclusion, low-gradient AS phenotype is overrepresented in patients with AF, but they have equally severe stenosis determined using AVC, despite the lower gradients. Patients with AF have more symptoms and worse QoL, but they improve significantly after intervention. In patients with AF, multimodality imaging is important in the assessment of AS severity.

Heterologous boosting of nonrelated toxoid immunity during acute Puumala hantavirus infection.

Persistence of immune memory in humans is a crucial yet poorly understood aspect of immunology. Here we have studied the effect of Puumala hantavirus infection on unrelated, pre-existing immune memory by studying T cell- and antibody responses against toxoid vaccine antigens of diphtheria, tetanus and pertussis in a cohort of 45 patients. We found that tetanus- and pertussis -specific IgG concentrations elevate during acute Puumala virus infection. Increase in vaccine IgG was associated with proliferation of heterologous T cells. Interestingly, increases in tetanus-specific IgG persisted a year after the infection while pertussis-specific IgG declined rapidly; a difference in IgG kinetics resembling the difference seen after vaccination against tetanus and pertussis. These results suggest that persistence of immune memory is facilitated by heterologous boosting of old memory during memory formation against newly encountered antigens. They also show that different toxoid antigens may be treated differently. Our study gives new insight into how immune memory formation may alter pre-existing immune memory, and also shows that heterologous immunity may have an impact on vaccination outcomes.

Novel 6p21.3 Risk Haplotype Predisposes to Acute Coronary Syndrome.

BACKGROUND: The HLA-DRB1*01 allele of the human leukocyte antigen has been associated with acute coronary syndrome. Genome-wide association studies have revealed associations with human leukocyte antigen and non-human leukocyte antigen genes of 3 major histocompatibility complex gene classes but not at allelic level. METHODS AND RESULTS: We conducted a large-scale genetic analysis on a case-control cohort comprising 5376 acute coronary syndrome cases and 4852 unrelated controls from 4 populations of 2 European countries. We analyzed the risk candidate allele of HLA-DRB1*01 by genomic real-time polymerase chain reaction together with high-density single nucleotide polymorphisms of the major histocompatibility complex to precisely identify risk loci for acute coronary syndrome with effective clinical implications. We found a risk haplotype for the disease containing single nucleotide polymorphisms from BTNL2 and HLA-DRA genes and the HLA-DRB1*01 allele. The association of the haplotype appeared in 3 of the 4 populations, and the direction of the effect was consistent in the fourth. Coronary samples from subjects homozygous for the disease-associated haplotype showed higher BTNL2 mRNA levels (r=0.760; P<0.00001).We localized, with immunofluorescence staining, BTNL2 in CD68-positive macrophages of the coronary artery plaques. In homozygous cases, BTNL2 blocking, in T-cell stimulation assays, enhanced CD4(+)FOXP3(+) regulatory T cell proliferation significantly (blocking versus nonblocking; P<0.05). CONCLUSIONS: In cases with the risk haplotype for acute coronary syndrome, these results suggest involvement of enhanced immune reactions. BTNL2 may have an inhibitory effect on FOXP3(+) T cell proliferation, especially in patients homozygous for the risk alleles. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov; Unique Identifier: NCT00417534.

A normal T cell receptor beta CDR3 length distribution in patients with APECED.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the AIRE gene. Murine studies suggest that AIRE controls thymic expression of tissue-restricted antigens, its absence allowing nonselected autoreactive cells to escape. We tested this in humans using the TCRß CDR3 length repertoire as a surrogate of thymic selection, as it shortens during the process. Analysis of healthy thymuses showed an altogether 1.9 base pair shortening, starting at the CD4(+)CD8(+)CD3(low) stage and continuing until the CD4(+) subset, likely encompassing both the positive and negative selection. Comparison of five APECED patients with eight healthy controls showed a skewed repertoire with oligoclonal expansions in the patients' CD4(+) and CD8(+) populations. The average CDR3 length, however, was normal and unaffected by the skewing. This was also true of the hypothesized autoreactive CD8(+)CD45RA(+) population. We failed to detect a subset with an abnormally long CDR3 repertoire, as would be predicted by a failure in selection.