Abstract Platelet activation plays a critical role in thrombosis. Inhibition of platelet activation is a cornerstone in treatment of acute organ ischemia. Platelet ACKR3 surface expression is independently associated with all-cause mortality in CAD patients. In a novel genetic mouse strain, we show that megakaryocyte/platelet-specific deletion of ACKR3 results in enhanced platelet activation and thrombosis in vitro and in vivo. Further, we performed ischemia/reperfusion experiments (transient LAD-ligation and tMCAO) in mice to assess the impact of genetic ACKR3 deficiency in platelets on tissue injury in ischemic myocardium and brain. Loss of platelet ACKR3 enhances tissue injury in ischemic myocardium and brain and aggravates tissue inflammation. Activation of platelet-ACKR3 via specific ACKR3 agonists inhibits platelet activation and thrombus formation and attenuates tissue injury in ischemic myocardium and brain. Here we demonstrate that ACKR3 is a critical regulator of platelet activation, thrombus formation and organ injury following ischemia/reperfusion.
Abstract Funding Acknowledgements Type of funding sources: None. Introduction Local impedance (LI) drop can predict sufficient lesion formation during radiofrequency ablation (RF). Recently, a novel ablation catheter technology able to measure LI and contact force has been made available for clinical use. High power short duration (HPSD) RF ablation has been shown to be feasible for atrial fibrillation (AF) ablation with short procedure time. We used LI drop and plateau formation to guide duration of 50 Watt RF power applications for circumferential pulmonary vein isolation (PVI). Methods Consecutive patients with indication for de novo AF ablation (n = 32, age 65 ± 10 years) with paroxysmal (n = 16) or persistent (n = 16) AF underwent ultra high density 3D mapping of the left atrium and catheter ablation. Thereafter, ipsilateral PV encircling with 50 Watt RF-applications targeting an interlesion distance of ≤ 6mm and a contact force of 10-30g was performed. Duration of HPSD RF application between 7-15s was guided by impedance drop >20 Ohm and plateau formation of LI. Further ablation strategy was left to the investigator’s discretion. Esophageal temperature measurement was performed using a three thermistor catheter with temperature cut off 39.0°C. In case of temperature rise or very near esophageal contact to the circumferential line, RF application time was shortened to 7s. Patients underwent adenosine testing after PVI. Previously we performed all types of AF ablation using an LI guided HPSD ablation without contact force measurement capability in 80 patients. Results Complete PVI was achieved in all pts with only 13.5 ± 4.3 min cumulative RF application duration and an ablation procedure duration of 46.5 ± 10.4 min with the novel LI measuring catheter. First-pass isolation of ipsilateral veins was achieved in 75% of circles. Recurrence of PV conduction during waiting period (20min) and adenosine testing occured in 25% of circles, and was reablated in most patients with a single spot of HPSD application. Using 94 ± 36 RF application per patient, mean maximum LI drop was 23.6 ± 4.0 Ohm. Reconnected fibers were associated with low LI drop due to instability of contact in most cases due to breathing in case of difficult sedation of the patients. No serious complications occurred in all 32 pts using HPSD with the novel contact force catheter design. Conclusion Guiding of HPSD RF ablation by LI is highly efficient and safe. A novel local impedance algorithm in combination with contact force sensing enable short PVI times with low early recurrence of PV conduction. Prediction of permanent lesions seems possible and the only limitation seems to be unstable RF catheter contact due patients breathing. Follow up have to be waited.
Abstract Background Short duration 50 Watt radiofrequency (RF) ablation has been shown to be feasible for atrial fibrillation (AF) ablation with short procedure times. Purpose We evaluated 50 Watt RF power with a different fixed short application duration at the anterior and posterior left atrial wall using contact force (CF) sensing catheters for circumferential pulmonary vein isolation (PVI). Methods Consecutive patients (pts) with indication for de novo AF ablation (n=40, age 64±12 years) with paroxysmal (n=23) or persistent (n=17) AF underwent high density 3D mapping of the left atrium. Low voltage areas of more than 5% of the left atrium were only found in 20% of pts. Thereafter, circumferential PVI using CF sensing catheters was performed. For each RF application (50 Watt, RF duration 11–13s at the anterior wall, 9–11s at the posterior wall) a stable catheter tip position with minimal mean CF of 3g was required and application was stopped in case of CF more than 30g. Esophageal temperature measurement was performed with temperature cut off 39.0°C. In case of temperature rise, ablation protocol was switched to conventional 20 Watt RF applications for ablation adjacent to the esophagus. Results Complete PVI was achieved in all pts with 81±29 short RF applications resulting in cumulative RF applications duration of 13.1±4.2min and an ablation duration of 59±17min for complete PVI. Even RF application with low CF (3–5g) were effective. Due to esophageal temperature rise, switch to conventional RF application with 20 Watt was performed in 43% of pts at least at one posterior PV entrance. After a waiting period of 20 min only in 33% of pts any PV conduction recurs, in 28% of pts only at a single spot and reconnected fibers were not associated with low CF application at that spot, but clearly associated with low energy application at the posterior wall. All PV were successfully re-isolated in most of pts with a single spot high energy RF application. No serious complications occurred in association with PVI. Follow up will be available at presentation time. Conclusion RF ablation with 50 Watt fixed short duration is efficient and safe for circumferential PVI. Ablation procedure durations are shorter and early recurrence rates are lower compared to reported conventional ablation procedures. The importance of CF titration seems to be diminished by 50 Watt RF applications in the left atrium. Further follow up have to be waited.
Als zentrales Stellglied ist die Herzfrequenz fundamental, um das Herzzeitvolumen aufrechtzuerhalten und an den Bedarf anzupassen. Die Bewertung einer abnormen Schlagfrequenz kann jedoch vor allem bei kritisch kranken Patienten eine Herausforderung sein, weil viele pathophysiologisch relevante Einflussfaktoren berücksichtigt werden müssen. Im Folgenden werden Zusammenhänge beleuchtet, die für therapeutische Entscheidungen relevant sind.
Cyclophilins are a group of highly conserved cytosolic enzymes that have a peptidylprolyl cis/trans isomerase activity. Cyclophilin A (CyPA) can be secreted in the extracellular space by inflammatory cells and upon cell death. The presence of CyPA in patients with non-ischemic cardiomyopathy is associated with poor clinical prognosis. Here, we investigated the inhibition of extracellular CyPA in a mouse model of troponin I-induced autoimmune myocarditis using the strictly extracellular CyPA-inhibitor MM284. Since A/J mice develop severe inflammation and fibrosis after immunization with murine cardiac troponin I (mcTn I), we used this model to analyze the effects of an extracellular CyPA inhibition. As extracellular CyPA-inhibitor we used the recently described CsA-derivate MM284. In vitro studies confirmed that MM284 inhibits CyPA-induced monocytic migration and adhesion. A/J mice immunized with mcTnI were treated with MM284 or vehicle every second day. After 28 days, we found a considerable reduction of myocardial injury and fibrosis. Further analysis revealed a reduced myocardial presence of T-cells and macrophages compared to control treated animals. Whereas MMP-9 expression was reduced significantly by MM284, we observed no significant reduction of inflammatory cytokines such as IL-6 or TNFα. Extracellular CyPA plays an important role in autoimmune myocarditis for myocardial damage and fibrosis. Our data suggest a new pharmacological approach for the treatment of myocardial inflammation and reduction of cardiac fibrosis by inhibition of extracellular CyPA.
Cardiac hypertrophy is characterized by remodeling of the myocardium, which involves alterations in the ECM (extracellular matrix) and cardiomyocyte structure. These alterations critically contribute to impaired contractility and relaxation, ultimately leading to heart failure. Emerging evidence implicates that extracellular signaling molecules are critically involved in the pathogenesis of cardiac hypertrophy and remodeling. The immunophilin CyPA (cyclophilin A) has been identified as a potential culprit. In this study, we aimed to unravel the interplay between eCyPA (extracellular CyPA) and myocardial dysfunction and evaluate the therapeutic potential of inhibiting its extracellular accumulation to improve heart function.
Abstract During megakaryopoiesis, megakaryocytes (MKs) undergo cellular morphological changes with strong modification of membrane composition and lipid signaling. Here, we adopt a lipid-centric multiomics approach to create a quantitative map of the MK lipidome during maturation and proplatelet formation. Data reveal that MK differentiation is driven by an increased fatty acyl import and de novo lipid synthesis, resulting in an anionic membrane phenotype. Pharmacological perturbation of fatty acid import and phospholipid synthesis blocked membrane remodeling and directly reduced MK polyploidization and proplatelet formation, resulting in thrombocytopenia. The anionic lipid shift during megakaryopoiesis was paralleled by lipid-dependent relocalization of the scaffold protein CKIP-1 and recruitment of the kinase CK2α to the plasma membrane, which seems to be essential for sufficient platelet biogenesis. Overall, this study provides a framework to understand how the MK lipidome is altered during maturation and the effect of MK membrane lipid remodeling on MK kinase signaling involved in thrombopoiesis.
The role of cryoballoon (CB) pulmonary vein isolation (PVI) for patients with persistent atrial fibrillation (AF) is controversial, since long-term success can be poor. We performed left atrial voltage mapping before CB PVI and determined AF-free survival depending on the extent of low-voltage areas (LVAs).We consecutively enrolled 60 patients with persistent AF (average age, 60.6 ± 12.9 years; CHA2 DS 2 VASc score, 2.3 ± 1.6; and left atrial size 46.0 ± 5.2 mm) who were planned for CB PVI. Before ablation, we performed left atrial voltage mapping (Abbott EnSite Precision or Velocity). LVAs were defined if local bipolar signal amplitudes were less than 0.5 mV during sinus rhythm. Thirty-seven patients did not show significant LVAs (<10%), while 12 patients had LVAs between 10% and 30% and 11 patients showed substantial LVAs greater than 30% of the left atrial area. CB PVI could be successfully performed in all patients. A 7-day holter monitoring was obtained 3, 6, and 12 months after ablation. After a 12-month follow-up time, 83.8% of patients without LVAs (<10%) were free of atrial fibrillation, while 50.0% of patients with 10% to 30% LVAs and 9.1% of patients with LVAs more than 30% had stable sinus rhythm. The degree of atrial fibrosis correlated with the risk of AF recurrence.In patients with persistent AF undergoing CB PVI, the extent of left atrial LVAs predicts an AF-free survival. CB PVI seems to be a highly effective treatment for patients with persistent AF without atrial fibrosis.
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