Sandra Freitag-Wolf

Background and Aim: Genetic susceptibility plays a particularly important role in early‐onset (EO) and severe periodontitis (PD). The genetic risk remains largely unexplained because of limited sample sizes and heterogeneous phenotypes in genome‐wide association studies (GWAS). This study investigates whether current GWAS data can be used to construct a polygenic score (PGS) capturing genetic susceptibility to severe PD. Materials and Methods: A PGS was developed in a three‐step design, using a German EO‐III/IV‐C‐PD GWAS ( n = 692 cases, ≤ 35 years at diagnosis) as the base dataset, a Spanish EO‐III/IV‐C‐PD GWAS ( n = 441 cases) to optimise the score, and as validation a Dutch EO‐III/IV‐C‐PD GWAS ( n = 171 cases) and a German population‐based GWAS with later‐onset III/IV‐PD (Studies of Health in Pomerania [SHIP], n = 2941 cases). Results: The PGS showed a trend towards association with disease status in the Spanish sample (Nagelkerke R ² = 0.4%, p = 0.06; AUC = 0.52; 95% confidence interval [CI]: 0.49–0.56), but not in the smaller Dutch dataset ( R ² = 0.2%, p = 0.18; AUC = 0.52; 95% CI: 0.48–0.57) or in the SHIP dataset (AUC = 0.50, 95% CI: 0.48–0.52). Case–control distributions overlapped substantially. Genetic correlation analyses revealed no strong overlap with other associated traits. Conclusions: Current PGS models have limited case–control discriminative ability for PD. Larger harmonised studies are needed to enhance genetic risk prediction and clarify pleiotropic relationships.

Purpose: Thymic involution, a hallmark of immune ageing, is associated with chronic low-grade inflammation (“inflammaging”) and has been implicated in age-associated inflammatory diseases, including atherosclerosis. This study aimed to evaluate the association between persistent thymus and coronary artery calcification based on the Agatston score. Materials and Methods: In an exploratory effort, we retrospectively analyzed 206 patients aged 40–64 years who underwent ECG-triggered thoracic CT between 2019 and 2024. Coronary artery calcifications were quantified on virtual non-contrast reconstructions using the Agatston score. Thymic tissue was graded on a five-point scale based on the extent of fatty replacement, with higher grades indicating greater thymic preservation. Results: The cohort included 126 men and 80 women. Complete fatty replacement of the thymus (Grade 0) was seen more often in men compared to women (51/126 vs. 18/80; p = 0.011). Linear regression analysis revealed a significant inverse association between thymus grade and coronary Agatston score (Beta (B) = −28.8 (95% CI −45.3 to −12.3); p = 0.001). After adjusting for age and sex, higher thymic grades remained significantly associated with lower coronary Agatston scores (B = −22.2 (95% CI: −41.7 to −2.6); p = 0.03). Further analysis with adjustments for cardiovascular risk factors was not performed. Conclusions: Residual thymic tissue was significantly inversely associated with coronary artery calcification, and this association persisted after adjustment for age and sex. These findings support the hypothetical concept that morphologically detectable thymic remnants may reflect interindividual differences in immune ageing and inflammaging that are associated with age-related inflammatory disease phenotypes. The results of this hypothesis-generating study give incentive to further investigate the nature and strength of these associations in prospective studies.

Background. The significance of concomitant tricuspid regurgitation (TR) in the context of transcatheter aortic valve replacement (TAVR) remains unclear. This study aimed to analyze the severity of TR before and after TAVR with regard to short- and long-term survival and to analyze the influencing factors. Methods. In our retrospective analysis, TR before and after TAVR was examined and patients were classified into groups accordingly. Special attention was paid to patients with post-interventional changes in TR. Mortality after TAVR was considered the primary endpoint of the analysis and major complications according to the Valve Academic Research Consortium 3 (VARC3) were compared. Moreover, biomarkers and risk factors for worsening or improvement of TR through TAVR were analyzed. Results. Among 775 patients who underwent TAVR in our center between January 2009 and December 2019, 686 patients (89%) featured low- and 89 patients (11%) high-grade TR. High-grade pre-TAVR TR was associated with worse short- (30-day), mid- (2-year) and long-term survival up to 8 years. Even though in nearly half of the patients with high-grade TR the regurgitation improved within seven days after TAVR (n = 42/89), this did not result in a survival benefit for this subgroup. On the other hand, a worsening of low-grade TR was seen in more than 10% of the patients (n = 73/686), which was also associated with a worse prognosis. Predictors of worsening of TR after TAVR were adipositas, impaired right ventricular function and the presence of mild TR. Age, atrial fibrillation, COPD, impaired renal function and elevated cardiac biomarkers were risk factors for mortality after TAVR independent from the grade of TR. Conclusions. Not only pre-interventional, but also post-TAVR high-grade TR is associated with a worse prognosis after TAVR. TAVR can change concomitant tricuspid regurgitation, but improvement does not have any impact on short- and long-term survival. Worsening of TR after TAVR is possible and impairs the prognosis.

Dysbiosis of the gut microbiome is a hallmark of inflammatory bowel disease (IBD) and both, IBD risk and microbiome composition, have been found to be associated with genetic variation. Using data from families of IBD patients, we examined the association between genetic and microbiome similarity in a specific IBD context, followed by a genome-wide quantitative trait locus (QTL) linkage analysis of various microbiome traits using the same data. SNP genotypes as well as gut microbiome and phenotype data were obtained from the Kiel IBD family cohort (IBD-KC). The IBD-KC is an ongoing prospective study in Germany currently comprising 256 families with 455 IBD patients and 575 first- and second-degree relatives. Initially focusing upon known IBD risk loci, we noted a statistically significant (FDRBarnesiella (chromosome 4, region spanning 10.34 cM), Clostridium_XIVa (chr4, 3.86 cM; chr14, two regions spanning 7.05 and 13.02 cM respectively), Pseudoflavonifractor (chr7, 12.80 cM) Parasutterella (chr14, 8.26 cM), Ruminococcus (chr16, two overlapping regions spanning 8.01 and 16.87 cM, respectively), Roseburia (chr19, 7.99 cM), and Odoribacter (chr22, three regions spanning 0.89, 5.57 and 1.71 cM, respectively), as well as the Shannon index of α diversity (chr3, 1.47 cM). Our study thus shows that, in families of IBD patients, pairwise genetic similarity for at least one IBD risk locus is associated with overall microbiome dissimilarity among discordant pairs of relatives, and that hitherto unknown genetic modifiers of microbiome traits are located in at least 12 human genomic regions.

Cardiovascular Research, 2021, https://doi.org/10.1093/cvr/cvab290

A deficient epidermal barrier is a key feature of atopic dermatitis (AD) and comprises altered lipid and protein content and composition of the stratum corneum resulting in disturbed water balance. Clinically, eczematous lesions on dry skin and pruritus develop. Pruritic nodules occur in prurigo nodularis (PN), another chronic skin disease, which can be associated with atopy. We aimed at comparing the three clinical pictures, classic AD, atopic prurigo (AP), and non-atopic PN, to healthy controls regarding the epidermal barrier. We determined clinical parameters and performed biophysical measurements, histology/immunohistochemistry, electron microscopy, and molecular biological analysis. We found distinctively elevated clinical scores, reduced hydration and increased transepidermal water loss, epidermal hyperplasia and inflammation reduced filaggrin and increased loricrin and involucrin expression, as well as reduced intercellular lipid lamellae in all three disease groups. These findings show a severe disruption in epidermal barrier structure and function in all three disorders so that epidermal barrier impairment is now proven not only for AD but also for PN.

Cardiogenic shock (CS) is a life-threatening low cardiac output state resulting in pulmonary congestion, hypotension, critical end-organ hypoperfusion, and tissue hypoxia. ^1–3 Inadequate myocardial oxygenation triggers a downward spiral, further worsening cardiac function in CS. Acute myocardial infarction (MI) is the most common cause of CS. Despite reperfusion therapy, mortality remains high, and there are currently no targeted therapies that improve survival. ^1–3 Studies in large animals have been instrumental in defining CS pathophysiology and the potential role of mechanical circulatory support. For genetic manipulation and drug screens, a mouse model would be invaluable. Here we present such a model.