Activation of the renin angiotensin system resulting in stimulation of angiotensin-II (AngII) type I receptor (AT1R) is an important factor in the development of liver fibrosis. Here, we investigated the role of Janus kinase 2 (JAK2) as a newly described intra-cellular effector of AT1R in mediating liver fibrosis. Fibrotic liver samples from rodents and humans were compared to respective controls. Transcription, protein expression, activation, and localization of JAK2 and downstream effectors were analyzed by realtime polymerase chain reaction, western blotting, immunohistochemistry, and confocal microscopy. Experimental fibrosis was induced by bile duct ligation (BDL), CCl4 intoxication, thioacetamide intoxication or continuous AngII infusion. JAK2 was inhibited by AG490. In vitro experiments were performed with primary rodent hepatic stellate cells (HSCs), Kupffer cells (KCs), and hepatocytes as well as primary human and human-derived LX2 cells. JAK2 expression and activity were increased in experimental rodent and human liver fibrosis, specifically in myofibroblastic HSCs. AT1R stimulation in wild-type animals led to activation of HSCs and fibrosis in vivo through phosphorylation of JAK2 and subsequent RhoA/Rho-kinase activation. These effects were prevented in AT1R–/– mice. Pharmacological inhibition of JAK2 attenuated liver fibrosis in rodent fibrosis models. In vitro, JAK2 and downstream effectors showed increased expression and activation in activated HSCs, when compared to quiescent HSCs, KCs, and hepatocytes isolated from rodents. In primary human and LX2 cells, AG490 blocked AngII-induced profibrotic gene expression. Overexpression of JAK2 led to increased profibrotic gene expression in LX2 cells, which was blocked by AG490.
Conclusion
Our study substantiates the important cell-intrinsic role of JAK2 in HSCs for development of liver fibrosis. Inhibition of JAK2 might therefore offer a promising therapy for liver fibrosis.
This study shows a high incidence of silent micro-embolic events after PV ablation. CAD, left ventricular dilatation, and hypertrophy were potential predictors of this complication.
PV ablation with the cryoballoon technique is feasible and seems to have a similar success rate in comparison to RF ablation. Procedure- and fluoroscopy duration are not longer than in conventional RF ablation.
Background:
There is limited knowledge about the impact of anatomic gaps as assessed by delayed gadolinium enhancement cardiac magnetic resonance on atrial fibrillation (AF) recurrence after first pulmonary vein (PV) isolation.
Methods:
Consecutive patients underwent delayed gadolinium enhancement cardiac magnetic resonance 3 months after radiofrequency circumferential PV isolation. Delayed gadolinium enhancement cardiac magnetic resonance images were assessed from 360 PV resulting in 2880 segments in the 2×8-segment model from 94 patients (52±11 years, 62% paroxysmal AF). Left atria were segmented using dedicated software. Anatomic gap was defined as discontinuation of the ablation line by ≥3 mm. Relative gap length was calculated as absolute gap length divided by the total length of the ablation line. AF recurrence was assessed after a mean follow-up duration of 15±10 months
Results:
Mean number of anatomic gaps was 5.4 per patient. Recurrence within the first year of ablation was observed in 21 patients with paroxysmal AF (36%) and 19 patients with persistent AF (53%). In the univariate analysis, CHA
2
DS
2
-VASc score, AF type, and relative gap length were predictive of recurrence. In the multivariate analysis, only relative gap length was significantly associated with recurrence (hazard ratio, 1.16 [1.02–1.31] per each 10% of gap).
Conclusions:
The total relative gap length but not the number of anatomic gaps in the PV ablation line as assessed by delayed gadolinium enhancement cardiac magnetic resonance was associated with AF recurrence 1 year after first PV isolation. An increase of 10% relative gap length increased the likelihood of AF recurrence by 16%.
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