Stephan Burkhard Felix

Background: Left ventricular (LV) remodeling is associated with impaired cardiac function and future cardiovascular disease (CVD). Current remodeling definitions use broad categorizations based on hypertrophy and mean wall thickness. Cardiac magnetic resonance (CMR) imaging provides detailed characterization of regional myocardial wall properties, which may enhance sex-specific cardiovascular disease (CVD) risk stratification. Objectives: We aimed to identify detailed LV remodeling patterns, their associations with CVD risk, and their clinical predictors. Methods: LV wall thickness data were obtained by CMR in three independent population-based cohorts (SHIP-TREND-0, n=931; SHIP-START-2, n=490; KORA-FF4, n=368). Sex-specific remodeling patterns were identified by k-means clustering and associated with established CVD risk scores and incident morbidity and all-cause mortality. Bootstrapped multinomial regression with LASSO regularization was used to select relevant clinical predictors of remodeling patterns. Results: The sample comprised 991 men (mean age 52.9 years, prevalent CVD 7.8%) and 798 women (52.5 years, 2%). Four remodeling clusters were found for men and women, respectively. For a subset of these clusters, significant associations with an increased CVD risk were found, e.g. in women, the high-risk cluster was associated with a 10.6 (95% confidence interval: 8.9, 12.3) percentage point increase in the 10-year Framingham Risk Score. Associations were independent of blood pressure and myocardial mass. Only in women, associations were also independent of average wall thickness and LV concentricity. Variable selection identified distinct clinical predictors of remodeling patterns. Conclusion: Particularly in women, regional LV wall thickness patterns detect unfavorable cardiac remodeling and might improve CVD risk stratification beyond existing strategies. Automated implementation during image acquisition and integration with shape-based models may facilitate clinical application. Graphical

Background and Aims: Associations of hyperlipidaemia and inflammation with the risk for incident major adverse cardiovascular events (MACEs) were analysed in individuals with and without cholesterol-lowering medication therapy. Methods: Data from 322,922 participants (55.9% women) aged 38 to 73 years from the UK Biobank were included. Longitudinal associations of low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) [Lp(a)], and high-sensitivity C-reactive protein (Hs-CRP), both individually and in combination, were analysed with the risk for incident MACEs using Cox regression models, stratified by cholesterol-lowering medication use. Results: During a median follow-up of 13.7 years, 31,295 (9.69%) participants had incident MACEs. The incidence was 8.32% in non-users and 18.6% in users of cholesterol-lowering medication. Higher LDL-C levels were associated with the highest risk for MACEs, followed by Lp(a) and Hs-CRP. One higher standard deviation in LDL-C, Lp(a), and Hs-CRP was associated with a 13%, 8%, and 6% greater risk for MACEs in non-users and 11%, 7%, and 6% in cholesterol-lowering medication users, respectively. When combined, LDL-C, Lp(a), and Hs-CRP demonstrated a synergistic effect. Compared with individuals with all three biomarkers at or below the 75th percentile, those with all three biomarkers above the 75th percentile had a 77% higher risk for incident MACEs among non-users and a 58% higher risk among those on cholesterol-lowering medications. Conclusions: Hyperlipidaemia and inflammation independently and synergistically contribute to an increased risk for incident cardiovascular events. The magnitude of risk is more closely related to serum biomarker concentrations than to the use or not of cholesterol-lowering medications.

Objectives: This retrospective study examines midkine, an inflammatory cytokine, as a potential serological biomarker to distinguish dilated cardiomyopathy (DCM) and inflammatory dilated cardiomyopathy (DCMi). Identifying such a biomarker is crucial for effective treatment of these two entities. Methods: The study included 54 patients with heart failure, reduced left ventricular systolic function, and suspected cardiac inflammation. Endomyocardial biopsies were obtained from all 54 patients to differentiate between DCM and DCMi. Blood sera were collected from these patients the same day the endomyocardial biopsy was performed and compared with those of 13 age-matched healthy individuals for different measurements such as midkine and NT-proBNP. Patients were followed up to a median of 194 days after the baseline visit. Results: Endomyocardial biopsies from patients with DCMi were associated with more infiltrating immune cells such as CD68⁺ macrophages and CD3⁺ T cells and a more frequent presence of a viral genome than those from patients with DCM. Both groups showed similar improvements in LV function and dimensions over time. MK serum levels were significantly higher in DCM/ DCMi patients than in healthy individuals but did not differ significantly between DCM and DCMi. MK levels did not significantly correlate with NYHA class, NT-proBNP, LVEDD, or LVEF, except for a weak correlation with LVEF at follow-up. Conclusions: Midkine serum levels were significantly higher in patients with a DCM phenotype and severely reduced systolic function. However, these levels could not distinguish between DCM and DCMi and showed no correlation with baseline or follow-up parameters. Therefore, midkine cannot be used as a biomarker to distinguish between DCM and DCMi.

Dilated cardiomyopathy (DCM) is characterized by reduced left ventricular ejection fraction (LVEF) and left or biventricular dilatation. We evaluated sex-specific associations of circulating proteins and metabolites with structural and functional heart parameters in DCM. Plasma samples (297 men, 71 women) were analyzed for proteins using Olink assays (targeted analysis) or LC-MS/MS (untargeted analysis), and for metabolites using LC MS/MS (Biocrates AbsoluteIDQ p180 Kit). Associations of proteins (n = 571) or metabolites (n = 163) with LVEF, measured left ventricular end diastolic diameter (LVEDD^measured), and the dilation percentage of LVEDD from the norm (LVEDD^{acc. to HENRY}) were examined in combined and sex-specific regression models. To disclose protein–metabolite relations, correlation analyses were performed. Associations between proteins, metabolites and LVEF were restricted to men, while associations with LVEDD were absent in both sexes. Significant metabolites were validated in a second independent DCM cohort (93 men). Integrative analyses demonstrated close relations between altered proteins and metabolites involved in lipid metabolism, inflammation, and endothelial dysfunction with declining LVEF, with kynurenine as the most prominent finding. In DCM, the loss of cardiac function was reflected by circulating proteins and metabolites with sex-specific differences. Our integrative approach demonstrated that concurrently assessing specific proteins and metabolites might help us to gain insights into the alterations associated with DCM.

Previous studies provided evidence for the importance of cardiac structure abnormalities, in particular greater left ventricular (LV) mass, for brain aging, but longitudinal studies are lacking to date. We included 926 individuals (median age 48 years; 53% women) from the TREND cohort of the Study of Health in Pomerania (SHIP) without reduced ejection fraction or a history of myocardial infarction. LV mass index (LVMI) was determined by echocardiography at baseline. Brain morphometric measurements were derived from magnetic resonance images at baseline and 7‐year follow‐up. Direct effects of baseline LVMI on brain morphometry at follow‐up were estimated using linear regression models with adjustment for baseline brain morphometry. At baseline, median LVMI was 40 g/m^2.7 and 241 individuals (26%) met the criterion of LV hypertrophy. After correction for multiple testing, baseline LVMI was directly associated with reduced global cortical thickness and increased cortical brain age at follow‐up independent from hypertension and blood pressure. Exposure‐outcome relations were nonlinear and significantly stronger in the upper half of the exposure distribution. Specifically, an increase in baseline LVMI from the 50% quantile to the 95% quantile was associated additional 2.7 years (95% confidence interval = [1.5 years, 3.8 years]) of cortical brain age at follow‐up. Additional regional analyses yielded bilateral effects on multiple frontal cortical regions. Our findings highlight the role of cardiac structure in brain aging. LVMI constitutes an easily measurable marker that might help to identify persons at risk for cognitive impairment and dementia.

The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles. The main elements of the DZHK infrastructure are web-based and central units for data management, LIMS, IDMS, and transfer office, embedded in a framework consisting of the DZHK Use and Access Policy, and the Ethics and Data Protection Concept. This framework is characterised by a modular design allowing a high standardisation across all studies. For studies that require even tighter criteria additional quality levels are defined. In addition, the Public Open Data strategy is an important focus of DZHK. The DZHK operates as one legal entity holding all rights of data and biological sample usage, according to the DZHK Use and Access Policy. All DZHK studies collect a basic set of data and biosamples, accompanied by specific clinical and imaging data and biobanking. The DZHK infrastructure was constructed by scientists with the focus on the needs of scientists conducting clinical studies. Through this, the DZHK enables the interdisciplinary and multiple use of data and biological samples by scientists inside and outside the DZHK. So far, 27 DZHK studies recruited well over 11,200 participants suffering from major cardiovascular disorders such as myocardial infarction or heart failure. Currently, data and samples of five DZHK studies of the DZHK Heart Bank can be applied for.

The evolutionary conserved NEAT1-MALAT1 gene cluster generates large noncoding transcripts remaining nuclear, while tRNA-like transcripts (mascRNA, menRNA) enzymatically generated from these precursors translocate to the cytosol. Whereas functions have been assigned to the nuclear transcripts, data on biological functions of the small cytosolic transcripts are sparse. We previously found NEAT1^−/− and MALAT1^−/− mice to display massive atherosclerosis and vascular inflammation. Here, employing selective targeted disruption of menRNA or mascRNA, we investigate the tRNA-like molecules as critical components of innate immunity. CRISPR-generated human ΔmascRNA and ΔmenRNA monocytes/macrophages display defective innate immune sensing, loss of cytokine control, imbalance of growth/angiogenic factor expression impacting upon angiogenesis, and altered cell–cell interaction systems. Antiviral response, foam cell formation/oxLDL uptake, and M1/M2 polarization are defective in ΔmascRNA/ΔmenRNA macrophages, defining first biological functions of menRNA and describing new functions of mascRNA. menRNA and mascRNA represent novel components of innate immunity arising from the noncoding genome. They appear as prototypes of a new class of noncoding RNAs distinct from others (miRNAs, siRNAs) by biosynthetic pathway and intracellular kinetics. Their NEAT1-MALAT1 region of origin appears as archetype of a functionally highly integrated RNA processing system.