A CircRNA-miRNA-mRNA Network for Exploring Doxorubicin- and Myocet-Induced Cardiotoxicity in a Translational Porcine Model.

Despite the widespread use of doxorubicin (DOX) as a chemotherapeutic agent, its severe cumulative cardiotoxicity represents a significant limitation. While the liposomal encapsulation of doxorubicin (Myocet, MYO) reduces cardiotoxicity, it is crucial to understand the molecular background of doxorubicin-induced cardiotoxicity. Here, we examined circular RNA expression in a translational model of pigs treated with either DOX or MYO and its potential impact on the global gene expression pattern in the myocardium. This study furthers our knowledge about the regulatory network of circRNA/miRNA/mRNA and its interaction with chemotherapeutics. Domestic pigs were treated with three cycles of anthracycline drugs (DOX, n = 5; MYO, n = 5) to induce cardiotoxicity. Untreated animals served as controls (control, n = 3). We applied a bulk mRNA-seq approach and the CIRIquant algorithm to identify circRNAs. The most differentially regulated circRNAs were validated under cell culture conditions, following forecasting of the circRNA-miRNA-mRNA network. We identified eight novel significantly regulated circRNAs from exonic and mitochondrial regions in the porcine myocardium. The forecasted circRNA-miRNA-mRNA network suggested candidate circRNAs that sponge miR-17, miR-15b, miR-130b, the let-7 family, and miR125, together with their mRNA targets. The identified circRNA-miRNA-mRNA network provides an updated, coherent view of the mechanisms involved in anthracycline-induced cardiotoxicity.

Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification.

BACKGROUND: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. METHODS: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan (Bgn), Tlr3, and IFN-α/ß receptor alpha chain (Ifnar1)-deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. RESULTS: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn-/-, Tlr3-/-, and Ifnar1-/- mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1-BGN-TLR3-interferon-α/ß receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. CONCLUSIONS: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.

Effectiveness of radiation protection systems in the cardiac catheterization laboratory: a comparative study.

BACKGROUND: As numbers and complexity of percutaneous coronary interventions are constantly increasing, optimal radiation protection is required to ensure operator safety. Suspended radiation protection systems (SRPS) and protective scatter-radiation absorbing drapes (PAD) are novel methods to mitigate fluoroscopic scattered radiation exposure. The aim of the study was to investigate the effectiveness regarding radiation protection of a SRPS and a PAD in comparison with conventional protection. METHODS: A total of 229 cardiac catheterization procedures with SRPS (N = 73), PAD (N = 82) and standard radiation protection (N = 74) were prospectively included. Real-time dosimeter data were collected from the first operator and the assistant. Endpoints were the cumulative operator exposure relative to the dose area product [standardized operator exposure (SOE)] for the first operator and the assistant. RESULTS: For the first operator, the SRPS and the PAD significantly decreased the overall SOE compared to conventional shielding by 93.9% and 66.4%, respectively (P < 0.001). The protective effect of the SRPS was significantly higher compared to the PAD (P < 0.001). For the assistant, the SRPS and the PAD provided a not statistically significant reduction compared to conventional shielding in the overall SOE by 38.0% and 30.6%, respectively. CONCLUSIONS: The SRPS and the PAD enhance radiation protection significantly compared to conventional protection. In most clinical scenarios, the protective effect of SRPS is significantly higher than the additional protection provided by the PAD. Comparison of the additional radiation protection provided by protective scatter-radiation absorbing drapes (PAD) and the suspended radiation protection system (SRPS) system over standard protection with lead aprons.

Lockdown surgery: the impact of coronavirus disease 2019 measures on cardiac cases.

OBJECTIVES: The need to ration medical equipment and interventions during the coronavirus disease 2019 pandemic translated to an ever-lengthening wait list for surgical care. Retrospective analysis of lockdowns is of high importance to learn from the current situation for future pandemics. This monocentric study assessed the impact of lockdown periods on cardiac surgery cases and outcomes. METHODS: The single-centre cross-sectional descriptive observational study was conducted to investigate the first lockdown period and the following post-lockdown period in comparison to the same periods during the previous 3 years at the Department of Cardiac Surgery at the Medical University of Innsbruck. Data were prospectively collected and retrospectively analysed from the department-specific quality management system. The primary objective was to compare the number of open-heart procedures between the prelockdown and the lockdown period. The secondary objectives were to analyse the characteristics and the outcomes of open-heart procedures. RESULTS: There were no differences in patient demographics. A significant decrease of 29% in weekly surgical procedures was observed during the lockdown period. The surgical case-mix was unaffected: The numbers of aortic valve replacements, coronary artery bypass grafts, mitral valve repair or replacement procedures and others remained stable. The urgency of cases increased significantly, and the general health conditions of patients appeared to be worse. However, outcomes were unchanged. CONCLUSIONS: By implementing a rational patient selection process, the quality of open-heart procedures was maintained even though patients who underwent surgery during lockdown were sicker and more symptomatic.

Non-Coding RNAs in Stem Cell Regulation and Cardiac Regeneration: Current Problems and Future Perspectives.

Although advances in rapid revascularization strategies following acute myocardial infarction (AMI) have led to improved short and long-term outcomes, the associated loss of cardiomyocytes and the subsequent remodeling result in an impaired ventricular function that can lead to heart failure or death. The poor regenerative capacity of the myocardium and the current lack of effective regenerative therapies have driven stem cell research in search of a possible solution. One approach involves the delivery of stem cells to the site of injury in order to stimulate repair response. Although animal studies initially delivered promising results, the application of similar techniques in humans has been hampered by poor target site retention and oncogenic considerations. In response, several alternative strategies, including the use of non-coding RNAs (ncRNAs), have been introduced with the aim of activating and regulating stem cells or inducing stem cell status in resident cells. Circular RNAs (circRNAs) and microRNAs (miRNAs) are ncRNAs with pivotal functions in cell proliferation and differentiation, whose role in stem cell regulation and potential significance for the field of cardiac regeneration is the primary focus of this review. We also address the general advantages of ncRNAs as promising drivers of cardiac regeneration and potent stem cell regulators.