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Aims This network meta-analysis aimed to assess the effect of early coronary angiography (CAG) compared with selective CAG (late and no CAG) for patients after out-of-hospital cardiac arrest without ST-elevation myocardial infarction (NSTE-OHCA). Methods and results A systematic literature search was performed using the EMBASE, MEDLINE and Web of Science databases without restrictions on publication date. The last search was performed on 15 July 2022. Randomized controlled trials (RCTs) and non-randomized studies (NRS) comparing the effect of early CAG to selective CAG after NSTE-OHCA on survival and/or neurological outcomes were included. Meta-analyses were performed based on a DerSimonian-Laird random effects model. A total of 18 studies were identified by the literature search. After the exclusion of two studies due to high risk of bias, 16 studies (six RCTs, ten NRS) were included in the final analyses. Meta-analyses showed a statistically significant increase in survival after early CAG compared with selective CAG in the overall analysis [OR: 1.40, 95% confidence interval (CI): (1.12-1.76), P < 0.01, I-2 = 68%]. This effect was lost in the subgroup analysis of RCTs [OR: 0.89, 95% CI: (0.73-1.10), P = 0.29, I-2 = 0%]. Random effects model network meta-analysis of NRS based on a Bayesian method showed statistically significant increased survival after late compared with early CAG [OR: 4.20, 95% CI: (1.22, 20.91)]. Conclusion The previously reported superiority of early CAG after NSTE-OHCA is based on NRS at high risk of selection and survivorship bias. The meta-analysis of RCTs does not support routinely performing early CAG after NSTE-OHCA.

Aims Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene. It is associated with formation of thoracic aortic aneurysms that can potentially be a life-threatening condition due to aortic rupture or dissection. Excessive non-canonical transforming growth factor beta signalling, mediated by activation of extracellutar signal-regulated kinases 1/2 (ERK1/2), as well as inducible nitric oxide synthase (NOS2)-dependent nitric oxide production, have been identified to drive aortic pathology in MFS through induction of elastin fragmentation and smooth muscle cell apoptosis. Despite promising results in animal studies, specific pharmacological interventions approved for clinical use in patients with MFS-related aortic disease are rare. Nitro-oleic acid (NO2-OA) is an endogenously generated signalling modulator, which is available as an oral compound and has been shown to inhibit ERK1/2 activation and NOS2 expression in different disease models, thereby exerting promising therapeutic effects. In this study, we investigated whether NO2-OA decreases aortic dilation in MFS. Methods and results Eight-week-old MFS (Fbn1(C1041G+)) mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneously implanted osmotic minipumps. Echocardiography indicated progressive ascending aortic dilation and wall stiffening in MFS mice, which was significantly attenuated by NO2-OA treatment. This protective effect was mediated by inhibition of aortic ERK1/2, Smad2 as well as nuclear factor kappa B overactivation and consequent attenuation of etastin fragmentation by matrix metattoproteinase 2, apoptosis, and collagen deposition. Critically, the therapeutic efficacy of NO2 -OA in MFS was further emphasized by demonstrating its capability to reduce lethal aortic complications in Fbn1(C1041G/+) mice challenged with Angiotensin II. Conclusion NO2-OA distinctly attenuates progression of aortic dilation in MFS via modulation of well-established disease-m

Atherosclerosis is a chronic, lipid-driven disease of medium sized arteries which causes myocardial infarction and stroke. Recently, an adaptive immune response against the plaque-associated autoantigen Apolipoprotein B100 (ApoB), the structural protein component of low-density lipoprotein, has been implicated in atherogenesis. In healthy individuals, CD4(+) T cells responding to ApoB mainly comprised regulatory T cells, which confer immune tolerance and atheroprotection. Mice and patients with atherosclerosis harbor increased numbers of proatherogenic ApoB-reactive T-helper cell subsets. Given the lack of therapies targeting proatherogenic immunity, clarification of the underlying mechanisms is of high clinical relevance. T cells develop in the thymus, where strong autoreactive T cells are eliminated in the process of negative selection. Herein, we investigated whether the transcription factor autoimmune regulator (AIRE), which controls expression of numerous tissue-restricted self-antigens in the thymus, is involved in mediating tolerance to ApoB and whether Aire deficiency might contribute to atherogenesis. Mice deficient for Aire were crossbred to apolipoprotein E-deficient mice to obtain atherosclerosis-prone Aire(-/-) Apoe(-/-) mice, which were fed a regular chow diet (CD) or western-type diet (WD). CD4(+) T cells responding to the ApoB peptide p6 were analyzed by flow cytometry. We demonstrate that Aire deficiency influences neither generation nor activation of ApoB-reactive T cells and has only minor and overall inconsistent impacts on their phenotype. Furthermore, we show that atherosclerotic plaque size is not affected in Aire(-/-) Apoe(-/-) compared to Aire(+/+) Apoe(-/-), irrespective of diet and gender. In conclusion, our data suggests that AIRE is not involved in regulating thymic expression of ApoB or atherosclerosis. Alternative mechanisms how ApoB-reactive CD4 T cells are selected in the thymus will have to be investigated.

Nitro-oleic acid (NO2-OA), a nitric oxide (NO)- and nitrite (NO2-)-derived electrophilic fatty acid metabolite, displays anti-inflammatory and anti-fibrotic signaling actions and therapeutic benefit in murine models of ischemia-reperfusion, atrial fibrillation, and pulmonary hypertension. Muscle LIM protein-deficient mice (Mlp(-/-)) develop dilated cardiomyopathy (DCM), characterized by impaired left ventricular function and increased ventricular fibrosis at the age of 8 weeks. This study investigated the effects of NO2-OA on cardiac function in Mlp(-/-) mice both in vivo and in vitro. Mlp(-/-) mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneous osmotic minipumps. Wildtype (WT) littermates treated with vehicle served as controls. Mlp(-/-) mice exhibited enhanced TGF beta signalling, fibrosis and severely reduced left ventricular systolic function. NO2-OA treatment attenuated interstitial myocardial fibrosis and substantially improved left ventricular systolic function in Mlp(-/-) mice. In vitro studies of TGF beta-stimulated primary cardiac fibroblasts further revealed that the anti-fibrotic effects of NO2-OA rely on its capability to attenuate fibroblast to myofibroblast transdifferentiation by inhibiting phosphorylation of TGF beta downstream targets. In conclusion, we demonstrate a substantial therapeutic benefit of NO2-OA in a murine model of DCM, mediated by interfering with endogenously activated TGF beta signaling.

The six-transmembrane protein of prostate 2 (Stamp2) acts as an anti-inflammatory protein in macrophages by protecting from overt inflammatory signaling and Stamp2 deficiency accelerates atherosclerosis in mice. Herein, we describe an unexpected role of Stamp2 in polymorphonuclear neutrophils (PMN) and characterize Stamp2's protective effects in myocardial ischemic injury. In a murine model of ischemia and reperfusion (I/R), echocardiography and histological analyses revealed a pronounced impairment of cardiac function in hearts of Stamp2-deficient- (Stamp2(-/-)) mice as compared to wild-type (WT) animals. This difference was driven by aggravated cardiac fibrosis, as augmented fibroblast-to-myofibroblast transdifferentiation was observed which was mediated by activation of the redox-sensitive p38 mitogen-activated protein kinase (p38 MAPK). Furthermore, we observed increased production of reactive oxygen species (ROS) in Stamp2(-/-) hearts after I/R, which is the likely cause for p38 MAPK activation. Although myocardial macrophage numbers were not affected by Stamp2 deficiency after I/R, augmented myocardial infiltration by polymorphonuclear neutrophils (PMN) was observed, which coincided with enhanced myeloperoxidase (MPO) plasma levels. Primary PMN isolated from Stamp2(-/-) animals exhibited a proinflammatory phenotype characterized by enhanced nuclear factor (NF)-kappa B activity and MPO secretion. To prove the critical role of PMN for the observed phenotype after I/R, antibody-mediated PMN depletion was performed in Stamp2(-/-) mice which reduced deterioration of LV function and adverse structural remodeling to WT levels. These data indicate a novel role of Stamp2 as an anti-inflammatory regulator of PMN and fibroblast-to-myofibroblast transdifferentiation in myocardial I/R injury.

Novel cancer therapies are contributing to the steadily decreasing cancer mortality. However, many of these new therapies can have significant cardiovascular complications. These can appear during treatment and, in the worst case, may even require discontinuation of treatment. At the same time, chronic side effects of cancer therapies such as heart failure, valvular heart disease or coronary artery disease are becoming increasingly relevant due to improved long-term survival and are the most common non-cancer associated cause of death. Many of the cardiovascular complications can be treated effectively, resulting in an improved long-term survival of the patients. Knowledge of the agent-specific cardiovascular side effects and diagnostic options is essential for structured management of cardio-oncologic patients to further improve mortality and morbidity in cancer patients.

Background: Overall prognosis in patients with out-of-hospital cardiac arrest (OHCA) remains poor, especially when return of spontaneous circulation (ROSC) cannot be achieved at the scene. It is unclear if rapid transport to the hospital with ongoing cardiopulmonary resuscitation (CPR) improves outcome in patients with refractory OHCA (rOHCA). The aim of this study was to evaluate the effect of a novel fast track algorithm (FTA) in patients with rOHCA. Methods: This prospective single-center study analysed outcome in rOHCA patients treated with FTA. Historical patients before FTA-implementation served as controls. rOHCA was defined as: persistent shockable rhythm after three shocks and 300 mg of amiodarone or persistent non-shockable rhythm and continuous CPR for 10 min without ROSC after exclusion of treatable arrest causes. Results: 110 consecutive patients with rOHCA (mean age 56 +/- 14 years) were included. 40 patients (36%) were treated with FTA, 70 patients (64%) served as historical controls. Pre-hospital time was significantly shorter after FTA implementation (69 +/- 18 vs. 79 +/- 24 min, p = 0.02). Favourable neurological outcome (defined as cerebral performance categories Score 1 or 2) was significantly more frequent in FTA patients (27.5% vs. 11.4%, p = 0.038). FTA-implementation showed a trend towards improved mortality (70.0% vs. 82.9%, p = 0.151). Extracorporeal Life Support was similar between the two groups. Conclusion: Our study suggests that a rapid transport algorithm with ongoing CPR is feasible, improves neurological outcome and may improve survival in carefully selected patients with rOHCA.

Background: S100A4 has recently emerged as an important player in cardiac disease, affecting phenotype development in animal models of myocardial infarction and pathological cardiac hypertrophy, albeit it is unclear whether S100A4 exerts a detrimental or beneficial function. The goal of the current study was to analyze S100A4 expression in models of cardiac pathology, investigate its degradation by the ubiquitin-proteasome system (UPS), and furthermore examine the functional effects of S100A4 levels in a 3D model of engineered heart tissue (EHT). Methods and Results: S100A4 mRNA and protein levels were analyzed in different models of cardiac pathology via quantitative RT-PCR and Western blot, showing a higher S100A4 steady-state protein concentration in hearts of Mybpc3-knock-in (KI) hypertrophic cardiomyopathy (HCM) mice. COS-7 cells co-transfected with plasmids encoding mutant (MUT) Asb2 beta lacking the E3 ligase activity in combination with V5-tagged S100A4 plasmid presented higher S100A4-V5 protein steady-state concentrations than cells co-transfected with the Asb2 beta wild type (WT) plasmid. This effect was blunted by treatment with the specific proteasome inhibitor epoxomicin. Adeno-associated virus serotype 6 (AAV6)-mediated S100A4 overexpression in a 3D model of EHT did not affect contractile parameters. Immunofluorescence analysis showed a cytosolic and partly nuclear expression pattern of S100A4. Gene expression analysis in EHTs overexpressing S100A4-V5 showed markedly lower steady-state concentrations of genes involved in cardiac fibrosis and pathological cardiac hypertrophy. Conclusion: We showed that S100A4 protein level is higher in cardiac tissue of Mybpc3-KI HCM mice probably as a result of a lower degradation by the E3 ligase Asb2 beta. While an overexpression of S100A4 did not alter contractile parameters in EHTs, downstream gene expression analysis points toward modulation of signaling cascades involved in fibrosis and hypertrophy.

Novel cancer therapeutics contribute to a steadily declining cancer mortality. However, several of these new therapies target pathways also involved in the cardiovascular system thus causing cardiotoxic side effects such as chemotherapy-induced heart failure (CIHF). This might limit the applicability of these effective treatments in a relevant number of patients. Furthermore, given the improving cancer survival rates, chemotherapy-induced cardiotoxic complications receive increasing attention given their potential impact on long-term morbidity and mortality. The understanding of molecular mechanisms that underlie CIHF is crucial for future improvement of pharmacodynamics of these therapeutics but also for developing specific interventions to prevent CIHF. Here, we discuss molecular mechanisms underlying CIHF of novel cancer therapeutics including a short synopsis on clinical management of patients suffering from CIHF.

History and clinical findings We present a 31-year old woman with a 6-year history of cutaneous lupus erythematosus (CLE) who presented to the emergency room with typical chest pain. ECG and transthoracic echocardiography were normal. Her working diagnosis of pericarditis was made due to systemic progression of her lupus erythematosus (LE). Treatment with NSAIDs was initiated and her immunosuppressive regimen intensified. The patient was discharged after resolution of her symptoms. A week later, the patient was seen at the rheumatology clinic with recurrence and aggravation of her symptoms. She was found to have elevated troponin and cardiac enzymes and therefore underwent cardiac catheterization, revealing three vessel coronary artery disease. Therapy and course The patient underwent urgent open surgical myocardial revascularization. Despite the immunosuppressive therapy the postoperative course was uneventful. Conclusions The risk for coronary artery disease in LE patients is very high. Particularly in young women presenting with chest pain, regardless of typical cardiopulmonary manifestations of LE such as pericarditis and pleurisy, acute coronary syndrome should always be considered.