Cardiomyocyte-specific RXFP1 overexpression protects against pressure overload-induced cardiac dysfunction independently of relaxin.

Heart failure (HF) prevalence is rising due to reduced early mortality and demographic change. Relaxin (RLN) mediates protective effects in the cardiovascular system through Relaxin-receptor 1 (RXFP1). Cardiac overexpression of RXFP1 with additional RLN supplementation attenuated HF in the pressure-overload transverse aortic constriction (TAC) model. Here, we hypothesized that robust transgenic RXFP1 overexpression in cardiomyocytes (CM) protects from TAC-induced HF even in the absence of RLN. Hence, transgenic mice with a CM-specific overexpression of human RXFP1 (hRXFP1tg) were generated. Receptor functionality was demonstrated by in vivo hemodynamics, where the administration of RLN induced positive inotropy strictly in hRXFP1tg. An increase in phospholamban-phosphorylation at serine 16 was identified as a molecular correlate. hRXFP1tg were protected from TAC without additional RLN administration, presenting not only less decline in systolic left ventricular (LV) function but also abrogated LV dilation and pulmonary congestion compared to WT mice. Molecularly, transgenic hearts exhibited not only a significantly attenuated fetal and fibrotic gene activation but also demonstrated less fibrotic tissue and CM hypertrophy in histological sections. These protective effects were evident in both sexes. Similar cardioprotective effects of hRXFP1tg were detectable in a RLN-knockout model, suggesting an alternative mechanism of receptor activation through intrinsic activity, alternative endogenous ligands or crosstalk with other receptors. In summary, CM-specific RXFP1 overexpression provides protection against TAC even in the absence of endogenous RLN. This suggests RXFP1 overexpression as a potential therapeutic approach for HF, offering baseline protection with optional RLN supplementation for specific activation.

[Digitalization and clinical decision tools]. / Digitalisierung und Clinical Decision Tools.

Digitalization in cardiovascular emergencies is rapidly evolving, analogous to the development in medicine, driven by the increasingly broader availability of digital structures and improved networks, electronic health records and the interconnectivity of systems. The potential use of digital health in patients with acute chest pain starts even in the prehospital phase with the transmission of a digital electrocardiogram (ECG) as well as telemedical support and digital emergency management, which facilitate optimization of the rescue pathways and reduce critical time intervals. The increasing dissemination and acceptance of guideline apps and clinical decision support tools as well as integrated calculators and electronic scores are anticipated to improve guideline adherence, translating into a better quality of treatment and improved outcomes. Implementation of artificial intelligence to support image analysis and also the prediction of coronary artery stenosis requiring interventional treatment or impending cardiovascular events, such as heart attacks or death, have an enormous potential especially as conventional instruments frequently yield suboptimal results; however, there are barriers to the rapid dissemination of corresponding decision aids, such as the regulatory rules related to approval as a medical product, data protection issues and other legal liability aspects, which must be considered.

Ythdf2 regulates cardiac remodeling through its mRNA target transcripts.

m6A mRNA methylation controls cardiomyocyte function and increased overall m6A levels are a stereotyping finding in heart failure independent of the underlying etiology. However, it is largely unknown how the information is read by m6A reader proteins in heart failure. Here we show that the m6A reader protein Ythdf2 controls cardiac function and identified a novel mechanism how reader proteins control gene expression and cardiac function. Deletion of Ythdf2 in cardiomyocytes in vivo leads to mild cardiac hypertrophy, reduced heart function, and increased fibrosis during pressure overload as well as during aging. Similarly, in vitro the knockdown of Ythdf2 results in cardiomyocyte growth and remodeling. Mechanistically, we identified the eucaryotic elongation factor 2 as post-transcriptionally regulated by Ythdf2 using cell type specific Ribo-seq data. Our study expands our understanding on the regulatory functions of m6A methylation in cardiomyocytes and how cardiac function is controlled by the m6A reader protein Ythdf2.

[Deep vein thrombosis as a primary symptom of abdominal aortic aneurysm : Bilateral deep vein thrombosis caused by infrarenal abdominal aortic aneurysm (15 cm in diameter) with complete compression of the inferior vena cava]. / Tiefe Venenthrombose als Primärsymptom eines abdominellen Aortenaneurysmas : Beidseitige 4-Etagen-TVT durch infrarenales Bauchaortenaneurysma (15 cm Durchmesser) mit vollständiger Kompression der V. cava inferior.

This article presents the case of a 70-year-old obese patient with severe bilateral leg pain due to deep vein thrombosis. After unsuccessful venous recanalization, computed tomography angiography revealed an abdominal aortic aneurysm 15 cm in diameter with total compression of the inferior vena cava. For venous decompression as well as rupture prophylaxis, conventional open surgical repair was performed.

[Quality indicators and structural requirements for Cardiac Arrest Centers-Update 2021]. / Qualitätskriterien und strukturelle Voraussetzungen für Cardiac Arrest Zentren ­ Update 2021: Deutscher Rat für Wiederbelebung/German Resuscitation Council (GRC).

An update of the first description of quality indicators and structural requirements for Cardiac Arrest Centers from 2017 based on first experiences and certifications is presented. Criteria were adjusted, substantiated and in some parts redefined for feasibility in everyday clinical use.

Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK).

Systemic forms of amyloidosis affecting the heart are mostly light-chain (AL) and transthyretin (ATTR) amyloidoses. The latter is caused by deposition of misfolded transthyretin, either in wild-type (ATTRwt) or mutant (ATTRv) conformation. For diagnostics, specific serum biomarkers and modern non-invasive imaging techniques, such as cardiovascular magnetic resonance imaging (CMR) and scintigraphic methods, are available today. These imaging techniques do not only complement conventional echocardiography, but also allow for accurate assessment of the extent of cardiac involvement, in addition to diagnosing cardiac amyloidosis. Endomyocardial biopsy still plays a major role in the histopathological diagnosis and subtyping of cardiac amyloidosis. The main objective of the diagnostic algorithm outlined in this position statement is to detect cardiac amyloidosis as reliably and early as possible, to accurately determine its extent, and to reliably identify the underlying subtype of amyloidosis, thereby enabling subsequent targeted treatment.

Gene transfer to the vascular system: Novel translational perspectives for vascular diseases.

Although vessels are directly exposed to the bloodstream, vascular gene transfer is rarely used as a tool for preclinical studies for several reasons: (i) viral and non-viral vectors show a low transduction efficiency in the vascular system; (ii) classical vascular gene therapy approaches such as treatment of peripheral or cardiac ischemia are focusing on non-vascular target cells; and (iii) vascular diseases are rarely monogenetic, thus gene replacement approaches are uncommon. Here, we provide an overview of recent approaches in developing novel vectors and modes of application for improved transduction efficiency of large and small vessels. Increased availability of such tools for vascular gene transfer has already facilitated preclinical studies addressing a broad variety of vascular diseases like transplant vasculopathy, atherosclerosis, and hereditary aortic diseases such as Marfan syndrome.

AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies.

Mutations in the human desmin gene cause autosomal-dominant and recessive cardiomyopathies and myopathies with marked phenotypic variability. Here, we investigated the effects of adeno-associated virus (AAV)-mediated cardiac wild-type desmin expression in homozygous desmin knockout (DKO) and homozygous R349P desmin knockin (DKI) mice. These mice serve as disease models for two subforms of autosomal-recessive desminopathies, the former for the one with a complete lack of desmin protein and the latter for the one with solely mutant desmin protein expression in conjunction with protein aggregation pathology in striated muscle. Two-month-old mice were injected with either a single dose of 5 × 1012 AAV9-hTNT2-mDes (AAV-Des) vector genomes or NaCl as control. One week after injection, mice were subjected to a forced swimming exercise protocol for 4 weeks. Cardiac function was monitored over a period of 15 month after injection and before the mice were sacrificed for biochemical and morphological analysis. AAV-mediated cardiac expression of wild-type desmin in both the homozygous DKO and DKI backgrounds reached levels seen in wild-type mice. Notably, AAV-Des treated DKO mice showed a regular subcellular distribution of desmin as well as a normalization of functional and morphological cardiac parameters. Treated DKI mice, however, showed an aberrant subcellular localization of desmin, unchanged functional cardiac parameters, and a trend toward an increased cardiac fibrosis. In conclusion, the effect of a high-dose AAV9-based desmin gene therapy is highly beneficial for the heart in DKO animals, but not in DKI mice.

Correction to: Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel.

The original article contains several small errors. The errors & concurrent corrections are listed below [1].

Antithrombotic therapy in patients with non-valvular atrial fibrillation undergoing percutaneous coronary intervention: should we change our practice after the PIONEER AF-PCI and RE-DUAL PCI trials?

The number of patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) is increasing. Since these patients have a CHA2DS2-VASc score of 1 or higher, they should be treated with oral anticoagulation to prevent stroke. However, combination therapy with oral anticoagulation for prevention of embolic stroke and dual platelet inhibition for prevention of coronary thrombosis significantly increases bleeding complications. The optimal combination, intensity and duration of antithrombotic combination therapy is still not known. In the rather small randomized WOEST trial, the combination of a vitamin K antagonist (VKA) and clopidogrel decreased bleeding compared to the conventional triple therapy with VKA, clopidogrel and aspirin. In the PIONEER AF-PCI trial, two rivaroxaban-based treatment regimens significantly reduced bleeding complications compared to conventional triple therapy without increasing embolic or ischemic complications following PCI. Dual therapy with rivaroxaban and clopidogrel appeared to provide an optimal risk-benefit ratio. In the RE-DUAL PCI trial, dual therapy with dabigatran also reduced bleeding complications compared to conventional triple therapy. With respect to the composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization dabigatran-based dual therapy was non-inferior to VKA-based triple therapy. The upcoming trials AUGUSTUS with apixaban and ENTRUST-PCI with edoxaban will further examine the use of NOACs in this setting. While recent guidelines recommend NOAC-based dual therapy in only a subset of patients (those who are at increased risk of bleeding), the available data now suggest that this should be the preferred choice for the majority of patients. Adding aspirin to this primary choice for up to 4 weeks in patients at especially high ischemic risk would likely prevent atherothrombotic events, but this needs further investigation. Taken together, it is time to adjust our practice and move to dual therapy consisting of a NOAC plus clopidogrel in most patients.

Influence of hyperoxia on diastolic myocardial and arterial endothelial function.

OBJECTIVE: Hyperoxia is known to influence cardiovascular and endothelial function, but it is unknown if there are differences between younger and older persons. The aim of this study was to monitor changes in myocardial diastolic function and flow-mediated dilatation (FMD) in younger and elderly volunteers, before and after exposure to relevant hyperbaric hyperoxia. METHODS: 51 male patients were separated into two groups for this study. Volunteers in Group 1 (n=28, mean age 26 ±6, "juniors") and Group 2 (n=23, mean age 53 ±9, "seniors") received standard HBO2 protocol (240kPa oxygen). Directly before and after hyperoxic exposure in a hyperbaric chamber we took blood samples (BNP, hs-troponin-t), assessed the FMD and echocardiographic parameters with focus on diastolic function. RESULTS: After hyperoxia we observed a high significant decrease in heart rate and systolic/diastolic FMD. Diastolic function varied in both groups: E/A ratio showed a statistically significant increase in Group 1 and remained unchanged in Group 2. E/e' ratio showed a slight but significant increase in Group 1, whereas e'/a' ratio increased in both groups. Deceleration time increased significantly in all volunteers. Isovolumetric relaxation time remained unchanged and ejection fraction showed a decrease only in Group 2. There were no changes in levels of BNP and hs-troponin-t in either group. CONCLUSION: Hyperoxia seems to influence endothelial function differently in juniors and seniors: FMD decreases more in seniors, possibly attributable to pre-existing reduced vascular compliance. Hyperoxia-induced bradycardia induced a more pronounced improvement in diastolic function in juniors. The ability of Group 1 to cope with hyperoxia-induced effects did not work in the same manner as with Group 2.

[Choosing wisely recommendations in cardiology]. / Klug-entscheiden-Empfehlungen in der Kardiologie.

This article describes controversially discussed Choosing wisely recommendations presented by the German Cardiac Society: anticoagulation therapy in patients with atrial fibrillation and "only" moderate stroke risk, on the one hand, and goal-directed low-density lipoprotein (LDL) cholesterol-lowering, on the other. Presuming an adequate regime, patients with atrial fibrillation and only moderate risk of stroke (CHA2DS2-VASc Score of 1 in men and of 2 in women) also benefit from anticoagulation therapy, even in elderly patients. In patients with coronary heart disease, the German Cardiac Society recommends reducing LDL-cholesterol serum levels with a statin to values lower than 70 mg/dl (1.8 mmol/l) or at least reducing the basal level by 50%. With this recommendation, the German Cardiac Society unequivocally prioritizes the "goal-oriented statin therapy" above the "statin strategy of fixed dose". The reasons for this preference are discussed.

Hyperlipidaemia and incident osteoarthritis of the hand: a population-based case-control study.

OBJECTIVE: Preclinical evidence suggests that increased cholesterol levels might be involved in the pathophysiology of osteoarthritis of the hand (HOA), but evidence from observational studies remains scarce. We aimed to analyse the association between hyperlipidaemia and incident HOA. DESIGN: We conducted a matched (1:1) case-control study using the UK-based Clinical Practice Research Datalink (CPRD). Cases were patients aged 30-89 years with an incident diagnosis of HOA between 1995 and 2014. In multivariable conditional logistic regression analyses, we calculated odds ratios (OR) for incident HOA in patients with hyperlipidaemia, categorized by gender, age, previous duration of hyperlipidaemia, and recent statin treatment. RESULTS: Among 19,590 cases and 19,590 controls, we observed an increased risk of HOA in patients with hyperlipidaemia (OR 1.37, 95% confidence intervals (CI) 1.28-1.47), when compared to patients without hyperlipidaemia. Thus, of all HOA cases in our study population, 3.6% may have been attributable to the presence of hyperlipidaemia (population attributable risk). Most patients with HOA were elderly, but the strength of the association between HOA and hyperlipidaemia inversely correlated with increasing age, with the highest OR of 1.72 (95% CI 1.24-2.38) in patients aged 29-49 years. Categorization by previous hyperlipidaemia duration, as well as sub-classification of patients with hyperlipidaemia into those with and without recent statin use did not meaningfully change the effect estimate. CONCLUSIONS: Our results suggest that hyperlipidaemia may be an independent risk factor for new onset HOA.