Septic shock is characterized by increased vascular permeability and hypotension despite increased cardiac output. Numerous vasoactive cytokines are upregulated during sepsis, including angiopoietin 2 (ANG2), which increases vascular permeability. Here we report that mice engineered to inducibly overexpress ANG2 in the endothelium developed sepsis-like hemodynamic alterations, including systemic hypotension, increased cardiac output, and dilatory cardiomyopathy. Conversely, mice with cardiomyocyte-restricted ANG2 overexpression failed to develop hemodynamic alterations. Interestingly, the hemodynamic alterations associated with endothelial-specific overexpression of ANG2 and the loss of capillary-associated pericytes were reversed by intravenous injections of adeno-associated viruses (AAVs) transducing cDNA for angiopoietin 1, a TIE2 ligand that antagonizes ANG2, or AAVs encoding PDGFB, a chemoattractant for pericytes. To confirm the role of ANG2 in sepsis, we i.p. injected LPS into C57BL/6J mice, which rapidly developed hypotension, acute pericyte loss, and increased vascular permeability. Importantly, ANG2 antibody treatment attenuated LPS-induced hemodynamic alterations and reduced the mortality rate at 36 hours from 95% to 61%. These data indicate that ANG2-mediated microvascular disintegration contributes to septic shock and that inhibition of the ANG2/ TIE2 interaction during sepsis is a potential therapeutic target.

Aims Atrial fibrillation (AF) in patients suffering from heart failure with preserved ejection fraction (HFpEF) is associated with increased symptoms and higher morbidity and mortality. Effective treatment strategies for this patient population have not yet been established. Methods and results We analysed clinical outcomes and echocardiographic parameters of patients with AF and HFpEF who underwent pulmonary vein isolation (PVI). Out of 374 PVI patients, we identified 35 patients suffering from concomitant HFpEF. Freedom from atrial tachyarrhythmia (AT) after 1 year was 80%. Heart failure symptoms assessed by New York Heart Association class significantly improved from 2.7 ± 0.7 to 1.7 ± 0.9 (P < 0.001). We observed regression of diastolic dysfunction by echocardiography 12 months after the index procedure. Moreover, 15 patients (42.9%) experienced complete resolution of HFpEF after a single ablation procedure. Multivariate logistic regression revealed absence of AT recurrence as an independent predictor of recovery from HFpEF (hazard ratio 11.37, 95% confidence interval 1.70–75.84, P = 0.009). Furthermore, resolution of HFpEF by achieving freedom from AT recurrence by PVI, including multiple procedures, led to a significant reduction of hospitalizations. Conclusion Our results suggest that restoration of sinus rhythm by PVI in HFpEF patients with concomitant AF induces reverse remodelling, improvement of symptoms, resolution of HFpEF and subsequently decrease of hospitalizations. Randomized controlled trials are warranted to confirm our results.

Background Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are both common conditions associated with high morbidity and mortality, especially if they coexist. Catheter ablation (CA) for AF has been shown recently to induce reverse remodeling and improve symptoms in HFpEF patients. The aim of this study was to compare outcomes of AF patients with HFpEF, who either underwent CA for AF or received medical therapy only. Methods and Results We included all AF patients with HFpEF according to current guidelines treated at our hospital between 2013 and 2018. Out of 6614 AF patients, we identified 127 with confirmed HFpEF. After applying propensity score matching to balance patient groups, 43 patients treated by CA and 43 patients receiving medical treatment were compared. Patients in the CA group underwent a mean of 1.5 ± 0.8 ablation procedures. Arrhythmia recurrence occurred significantly less frequently in the CA group (hazard ratio [HR]: 0.47; 95% CI: 0.25–0.87; p = .016). The primary endpoint, a composite of heart failure hospitalization and death, was reduced significantly by CA compared to medical therapy (HR: 0.30; 95% CI: 0.13–0.67; p = .003). This was driven by a decrease in heart failure hospitalization. Clinical and echocardiographic parameters of HFpEF improved significantly only after CA. Remarkably, reassessment of diagnostic HFpEF criteria at the end of follow‐up demonstrated HFpEF resolution in 15 out of 43 patients (35%) treated by CA and only 4 out of 43 patients (9%) treated medically (p = .008). Conclusion Catheter ablation for AF in HFpEF patients in comparison to medical therapy decreases heart failure hospitalization, heart failure symptoms, and improves diastolic function. AF ablation should be considered in patients with HFpEF and concomitant AF.

Aims Pulmonary vein isolation (PVI) either by balloon devices or radiofrequency forms the cornerstone of invasive atrial fibrillation (AF) treatment. Although equally effective cryoballoon (CB)-based PVI offers shorter procedure duration and a better safety profile. Beside the worldwide established Arctic Front Advance system, a novel CB device, POLARx, was recently introduced. This CB incorporates unique features, which may translate into improved efficacy and safety. However, multicentre assessment of periprocedural efficacy and safety is lacking up to date. Methods and results A total of 317 patients with paroxysmal or persistent AF were included and underwent POLARx CB-based PVI in 6 centres from Germany and Italy. Acute efficacy and safety were assessed in this prospective multicenter observational study. In 317 patients [mean age: 64 ± 12 years, 209 of 317 (66%) paroxysmal AF], a total of 1256 pulmonary veins (PVs) were identified and 1252 (99,7%) PVs were successfully isolated utilizing mainly the short tip POLARx CB (82%). The mean minimal CB temperature was −57.9 ± 7°C. Real-time PVI was registered in 72% of PVs. The rate of serious adverse events was 6.0% which was significantly reduced after a learning curve of 25 cases (9.3% vs. 3.0%, P = 0.018). The rate of recurrence-free survival after mean follow-up of 226 ± 115 days including a 90-day blanking period was 86.1%. Conclusion In this large multicentre assessment, the novel POLARx CB shows a promising efficacy and safety profile after a short learning curve.

Mutations in the molecular co-chaperone Bcl2-associated athanogene 3 (BAG3) are found to cause dilated cardiomyopathy (DCM), resulting in systolic dysfunction and heart failure, as well as myofibrillar myopathy (MFM), which is characterized by protein aggregation and myofibrillar disintegration in skeletal muscle cells. Here, we generated a CRISPR/Cas9-induced Bag3 knockout zebrafish line and found the complete preservation of heart and skeletal muscle structure and function during embryonic development, in contrast to morpholino-mediated knockdown of Bag3. Intriguingly, genetic compensation, a process of transcriptional adaptation which acts independent of protein feedback loops, was found to prevent heart and skeletal muscle damage in our Bag3 knockout model. Proteomic profiling and quantitative real-time PCR analyses identified Bag2, another member of the Bag protein family, significantly upregulated on a transcript and protein level in bag3 -/- mutants. This implied that the decay of bag3 mutant mRNA in homozygous bag3 -/- embryos caused the transcriptional upregulation of bag2 expression. We further demonstrated that morpholino-mediated knockdown of Bag2 in bag3 -/- embryos evoked severe functional and structural heart and skeletal muscle defects, which are similar to Bag3 morphants. However, Bag2 knockdown in bag3 +/+ or bag3 +/- embryos did not result in (cardio-)myopathy. Finally, we found that inhibition of the nonsense-mediated mRNA decay (NMD) machinery by knockdown of upf1 , an essential NMD factor, caused severe heart and skeletal muscle defects in bag3 -/- mutants due to the blockade of transcriptional adaptation of bag2 expression. Our findings provide evidence that genetic compensation might vitally influence the penetrance of disease-causing bag3 mutations in vivo .