CNP Promotes Antiarrhythmic Effects via Phosphodiesterase 2

Background: Ventricular arrhythmia and sudden cardiac death are the most common lethal complications after myocardial infarction. Antiarrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Here, we focus on the cardioprotective CNP (C-type natriuretic peptide) as a novel antiarrhythmic principle. We hypothesize that antiarrhythmic effects of CNP are mediated by PDE2 (phosphodiesterase 2), which has the unique property to be stimulated by cGMP to primarily hydrolyze cAMP. Thus, CNP might promote beneficial effects of PDE2-mediated negative crosstalk between cAMP and cGMP signaling pathways. Methods: To determine antiarrhythmic effects of cGMP-mediated PDE2 stimulation by CNP, we analyzed arrhythmic events and intracellular trigger mechanisms in mice in vivo, at organ level and in isolated cardiomyocytes as well as in human-induced pluripotent stem cell-derived cardiomyocytes. Results: In ex vivo perfused mouse hearts, CNP abrogated arrhythmia after ischemia/reperfusion injury. Upon high-dose catecholamine injections in mice, PDE2 inhibition prevented the antiarrhythmic effect of CNP. In mouse ventricular cardiomyocytes, CNP blunted the catecholamine-mediated increase in arrhythmogenic events as well as in ICaL, INaL, and Ca2+spark frequency. Mechanistically, this was driven by reduced cellular cAMP levels and decreased phosphorylation of Ca2+handling proteins. Key experiments were confirmed in human iPSC-derived cardiomyocytes. Accordingly, the protective CNP effects were reversed by either specific pharmacological PDE2 inhibition or cardiomyocyte-specific PDE2 deletion. Conclusions: CNP shows strong PDE2-dependent antiarrhythmic effects. Consequently, the CNP-PDE2 axis represents a novel and attractive target for future antiarrhythmic strategies

Should quinolones come first in Helicobacter pylori therapy?

New generations of fluoroquinolones, like levofloxacin and moxifloxacin, exhibit a broad-spectrum activity against Gram-positive and Gram-negative bacteria, and have been successfully introduced into the treatment of Helicobacter pylori infection. Based on a large body of evidence, current guidelines recommend the use of levofloxacin- or moxifloxacin-containing proton-pump inhibitor (PPI) triple therapies in second-line or rescue treatment of H. pylori infection. The efficacy of standard PPI triple therapies has substantially declined during the last decade, mainly due to increasing resistance against the key antibiotics clarithromycin and metronidazole. Therefore, alternative strategies for first-line therapy of H. pylori infection have been evaluated in a considerable number of clinical trials including sequential regimens, nonbismuth quadruple regimens, and quinolone-containing PPI triple therapy regimens. The aim of this paper is to summarize the current body of evidence of levofloxacin- and moxifloxacin-containing regimens in first-line treatment of H. pylori infection, and to discuss the risks and benefits of these strategies in the light of increasing resistance of H. pylori to quinolones

Factors associated with a high or low implantation of self-expanding devices in TAVR

Objectives!#!Optimizing valve implantation depth (ID) plays a crucial role in minimizing conduction disturbances and achieving optimal functional integrity. Until now, the impact of intraprocedural fast (FP) or rapid ventricular pacing (RP) on the implantation depth has not been investigated. Therefore, we aimed to (1) evaluate the impact of different pacing maneuvers on ID, and (2) identify the independent predictors of deep ID.!##!Methods!#!473 TAVR patients with newer-generation self-expanding devices were retrospectively enrolled and one-to-one propensity-score-matching was performed, resulting in a matching of 189 FP and RP patients in each cohort. The final ID was analyzed, and the underlying functional, anatomical, and procedural conditions were evaluated by univariate and multivariate analysis.!##!Results!#!The highest ID was reached under RP in severe aortic valve calcification and valve size 26 mm. Multivariate analysis identified left ventricular outflow (LVOT) calcification [OR 0.50 (0.31-0.81) p = 0.005*], a 'flare' aortic root [OR 0.42 (0.25-0.71), p = 0.001*], and RP (OR 0.49 [0.30-0.79], p = 0.004*) as independent highly preventable predictors of a deep ID. In a model of protective factors, ID was significantly reduced with the number of protective criteria (0-2 criteria: - 5.7 mm ± 2.6 vs. 3-4 criteria - 4.3 mm ± 2.0; p < 0.0001*).!##!Conclusion!#!Data from this retrospective analysis indicate that RP is an independent predictor to reach a higher implantation depth using self-expanding devices. Randomized studies should prove for validation compared to fast and non-pacing maneuvers during valve delivery and their impact on implantation depth.!##!Trail registration!#!Clinical Trial registration: NCT01805739.!##!Study design!#!Evaluation of the impact of different pacing maneuvers (fast ventricular pacing-FP vs. rapid ventricular pacing-RP) on implantation depth (ID). After one-to-one-propensity-score-matching, independent protective and risk factors for a very deep ID beneath 6 mm toward the LVOT (< - 6 mm) were identified. Stent frame pictures as a courtesy by Medtroni

Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL

Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a major therapeutic challenge. DLBCL can be classified into at least two major subtypes, i.e. germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL, each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad anti-tumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. Due to high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and JAK kinases. Interestingly, the BCL-2 specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCL

Superresolution microscopy in heart — Cardiac nanoscopy

Detailed understanding of the adaptive nature of cardiac cells in health and disease requires investigation of proteins and membranes in their native physiological environment, ideally by noninvasive optical methods. However, conventional light microscopy does not resolve the spatial characteristics of small fluorescently labeled protein or membrane structures in cells. Due to diffraction limiting resolution to half the wavelength of light, adjacent fluorescent molecules spaced at less than ~250 nm are not separately visualized. This fundamental problem has lead to a rapidly growing area of research, superresolution fluorescence microscopy, also called nanoscopy. We discuss pioneering applications of superresolution microscopy relevant to the heart, emphasizing different nanoscopy strategies towards new insight in cardiac cell biology. Here, we focus on molecular and structural readouts from subcellular nanodomains and organelles related to Ca2+ signaling during excitationcontraction (EC) coupling, including live cell imaging strategies. Based on existing data and superresolution techniques, we suggest that an important future aim will be subcellular in situ structure-function analysis with nanometric resolving power in organotypic cells.peerReviewe