Current evidence on the safety and efficacy of combined atrial fibrillation ablation and left atrial appendage closure.

PURPOSE OF REVIEW: Combined atrial fibrillation (AF) ablation and left atrial (LA) appendage (LAA) closure (LAAC) has been practiced for management of both the symptoms and the high stroke risk of AF. The purpose of this review is to review recent evidence regarding the combined procedure. RECENT FINDINGS: Newly acquired long-term data of combined AF ablation and LAAC supplied satisfactory evidence on the safety and efficacy of the combined procedure. Studies also showed LA structural remodeling following combined procedure was mainly affected by sinus rhythm status post catheter ablation, not by LAAC. A cost-effectiveness study revealed that combined procedure was a cost-effective therapeutic option in symptomatic AF patients with high stroke and bleeding risk. Due to recent evidence of high incidences of LAA thrombus formation after LAA electrical isolation (LAAEI) and benefit of LAAC after LAAEI, an extended combined procedure of standard AF ablation plus LAAEI and LAAC was considered as a potential therapeutic option for persistent AF patients with high stroke risk. SUMMARY: In conclusion, combined AF ablation and LAAC serve as a promising option for patients with symptomatic AF and high risk of stroke and/or bleeding.

A Clinical Perspective: Contribution of Dysfunctional Perivascular Adipose Tissue (PVAT) to Cardiovascular Risk.

Perivascular adipose tissue (PVAT) is now recognized as an important paracrine organ influencing the homeostasis of the vessel wall, regional blood flow and peripheral arterial resistance. There is remarkable phenotypic variability and plasticity of PVAT among various vascular beds, exhibiting phenotypes from white to brown and beige adipocytes. PVAT dysfunction is characterized by disturbed secretion of various adipokines, which, together with endothelial dysfunction, contribute to hypertension and cardiovascular disease (CVD). This brief review describes our current knowledge on PVAT in health and cardiovascular disease, with a special focus on different phenotypes and signaling pathways in adipocytes of PVAT associated with hypertension, obesity and cardiovascular disorders.

Accuracy of the Injection-Based Occlusion Tool Utilizing Saline and Glucose Solution in Cryoballoon Ablation Guided by a Novel Dielectric Imaging System.

Introduction: The aim of this study is to assess the accuracy of the injection-based occlusion (IBO) tool utilizing saline and glucose solution in verifying pulmonary vein (PV) occlusion during cryoballoon ablation guided by a novel dielectric system (KODEX-EPD system). Methods: In this retrospective study, we enrolled 34 consecutive patients with paroxysmal atrial fibrillation (AF) who underwent their initial cryoballoon ablation procedure guided by the KODEX-EPD system. PV occlusion was firstly assessed by the IBO tool utilizing saline or glucose solution and then verified by direct contrast angiography. Patients were divided into two groups according to the fluid used in the IBO tool: the Saline Group and the Glucose Group. Results: The overall procedure time and fluoroscopy time were comparable between the Saline Group and the Glucose Group (113.7 ± 18.3 vs. 108.4 ± 15.9 min; p = 0.375 and 10.1 ± 3.7 vs. 9.3 ± 3.5 min; p = 0.559). The IBO tool was utilized a total of 138 times in the Saline Group and 135 times in the Glucose Group. When assessing PV occlusion, the IBO tool using saline demonstrated a sensitivity of 92.6% and a specificity of 95.2% compared to angiography. Similarly, the IBO tool utilizing glucose solution showed a sensitivity of 93.2% and a specificity of 96.1%. Conclusions: The IBO tool utilizing non-contrast fluid, saline and glucose solution, demonstrates a high level of sensitivity and specificity in accurately predicting PV occlusion during cryoablation procedures. Both the saline and glucose solutions used in the IBO tool show promising results in effectively assessing PV occlusion.

Long-term outcome of combined catheter ablation and left atrial appendage closure in atrial fibrillation patients.

BACKGROUND: The combined procedure of catheter ablation and left atrial appendage closure (LAAC) aims to simultaneously control the heart rhythm and reduce the risk of strokes in patients with atrial fibrillation (AF). The study aims to evaluate the procedural safety and long-term outcome of the combined procedure in a large patient cohort. METHODS: Clinical data of AF patients who underwent the combined procedure was retrospectively analyzed. Procedural and imaging follow-up parameters were compared between the transesophageal echocardiography-guided standard process and fluoroscopy-guided modified process, and between the single-seal WATCHMAN and dual-seal LACBES devices. Long-term outcomes included all-cause mortality, thromboembolic events, major bleeding, and recurrence of atrial tachyarrhythmias. RESULTS: A total of 1114 patients were included. The rates of procedure-related major complications were comparable between the standard and modified processes (3.7% vs. 2.2%, p = 0.219), except for a higher incidence of respiratory depression in standard process group (0.9% vs 0%, p = 0.037), and between WATCHMAN and LACBES devices (2.4% vs. 3.3%, p = 0.535). The follow-up imaging evaluation revealed a high rate of satisfactory seals (99.7%) and a low rate of device related thrombus (1.9%), which were similar between two process groups and devices. The follow-up of over 1960 patient-years revealed low rates of mortality, thromboembolism, and nonprocedural major bleeding (1.8, 3.2, and 0.9 per 100 patient-years, respectively). Recurrent atrial tachyarrhythmias was observed in 23.9% patients. CONCLUSIONS: The results supported the safety and long-term efficacy of the combined procedure of catheter ablation and LAAC. Fluoroscopy-guided LAAC device implantation may be considered in experienced centers.

Pathophysiological Role of Caveolae in Hypertension.

Caveolae, flask-shaped cholesterol-, and glycosphingolipid-rich membrane microdomains, contain caveolin 1, 2, 3 and several structural proteins, in particular Cavin 1-4, EHD2, pacsin2, and dynamin 2. Caveolae participate in several physiological processes like lipid uptake, mechanosensitivity, or signaling events and are involved in pathophysiological changes in the cardiovascular system. They serve as a specific membrane platform for a diverse set of signaling molecules like endothelial nitric oxide synthase (eNOS), and further maintain vascular homeostasis. Lack of caveolins causes the complete loss of caveolae; induces vascular disorders, endothelial dysfunction, and impaired myogenic tone; and alters numerous cellular processes, which all contribute to an increased risk for hypertension. This brief review describes our current knowledge on caveolae in vasculature, with special focus on their pathophysiological role in hypertension.

Distinct roles of angiotensin receptors in autonomic dysreflexia following high-level spinal cord injury in mice.

Autonomic dysreflexia (AD), a syndrome caused by loss of supraspinal control over sympathetic activity and amplified vascular reflex upon sensory stimuli below injury level, is a major health problem in high-level spinal cord injury (SCI). After supraspinal sympathetic control of the vasculature below the lesion is lost, the renin-angiotensin system (RAS) is thought to be involved in AD by regulating blood pressure and vascular reactivity. In this study, we aimed to assess the role of different RAS receptors during AD following SCI. Therefore, we induced AD by colorectal distention (CRD) in wild-type mice and mice deficient in the RAS components angiotensin (Ang) II type 1a receptor (AT1a) (Agtr1a-/-) and Ang-(1-7) receptor Mas (Mas-/-) four weeks after complete transection of spinal cord at thoracic level 4 (T4). Systemic blood pressure measurements and wire myography technique were performed to assess hemodynamics and the reactivity of peripheral arteries, respectively. CRD increased mean arterial blood pressure (MAP) and decreased heart rate (HR) in all three animal groups. However, we found less increases in MAP in Mas-/- mice compared to control mice after CRD, whereas AT1a deficiency did not affect the hemodynamic response. We found that the reactivity of wild-type and Mas-/- mesenteric arteries, which are innervated from ganglia distal but close to thoracic level T4, was diminished in response to Ang II in AD after T4-SCI, but this difference was not observed in the absence of AT1a receptors. CRD did not influence the reactivity of femoral arteries which are innervated from ganglia more distal to thoracic level T4, in response to Ang II in AD. In conclusion, we identified a specific role of the Ang-(1-7) receptor Mas in regulating the systemic blood pressure increase in AD in T4-SCI mice. Furthermore, AT1a signaling is not involved in this hemodynamic response, but underlies increased vascular reactivity in mesenteric arteries in response to Ang II, where it may contribute to adaptive changes in regional blood flow.

eNOS-NO-induced small blood vessel relaxation requires EHD2-dependent caveolae stabilization.

Endothelial nitric oxide synthase (eNOS)-related vessel relaxation is a highly coordinated process that regulates blood flow and pressure and is dependent on caveolae. Here, we investigated the role of caveolar plasma membrane stabilization by the dynamin-related ATPase EHD2 on eNOS-nitric oxide (NO)-dependent vessel relaxation. Loss of EHD2 in small arteries led to increased numbers of caveolae that were detached from the plasma membrane. Concomitantly, impaired relaxation of mesenteric arteries and reduced running wheel activity were observed in EHD2 knockout mice. EHD2 deletion or knockdown led to decreased production of nitric oxide (NO) although eNOS expression levels were not changed. Super-resolution imaging revealed that eNOS was redistributed from the plasma membrane to internalized detached caveolae in EHD2-lacking tissue or cells. Following an ATP stimulus, reduced cytosolic Ca2+ peaks were recorded in human umbilical vein endothelial cells (HUVECs) lacking EHD2. Our data suggest that EHD2-controlled caveolar dynamics orchestrates the activity and regulation of eNOS/NO and Ca2+ channel localization at the plasma membrane.

RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a Gαi2-Protein/PI3Kß/γ/Nitric Oxide-Coupled Pathway.

Background: Relaxins are small peptide hormones, which are novel candidate molecules that play important roles in cardiometablic syndrome. Relaxins are structurally related to the insulin hormone superfamily, which provide vasodilatory effects by activation of G-protein-coupled relaxin receptors (RXFPs) and stimulation of endogenous nitric oxide (NO) generation. Recently, relaxin could be demonstrated to activate Gi proteins and phosphoinositide 3-kinase (PI3K) pathways in cultured endothelial cells in vitro. However, the contribution of the Gi-PI3K pathway and their individual components in relaxin-dependent relaxation of intact arteries remains elusive. Methods: We used Gαi2- (Gnai2-/-) and Gαi3-deficient (Gnai3-/-) mice, pharmacological tools and wire myography to study G-protein-coupled signaling pathways involved in relaxation of mouse isolated mesenteric arteries by relaxins. Human relaxin-1, relaxin-2, and relaxin-3 were tested. Results: Relaxin-2 (∼50% relaxation at 10-11 M) was the most potent vasodilatory relaxin in mouse mesenteric arteries, compared to relaxin-1 and relaxin-3. The vasodilatory effects of relaxin-2 were inhibited by removal of the endothelium or treatment of the vessels with N (G)-nitro-L-arginine methyl ester (L-NAME, endothelial nitric oxide synthase (eNOS) inhibitor) or simazine (RXFP1 inhibitor). The vasodilatory effects of relaxin-2 were absent in arteries of mice treated with pertussis toxin (PTX). They were also absent in arteries isolated from Gnai2-/- mice, but not from Gnai3-/- mice. The effects were not affected by FR900359 (Gαq protein inhibitor) or PI-103 (PI3Kα inhibitor), but inhibited by TGX-221 (PI3Kß inhibitor) or AS-252424 (PI3Kγ inhibitor). Simazine did not influence the anti-contractile effect of perivascular adipose tissue. Conclusion: Our data indicate that relaxin-2 produces endothelium- and NO-dependent relaxation of mouse mesenteric arteries by activation of RXFP1 coupled to Gi2-PI3K-eNOS pathway. Targeting vasodilatory Gi-protein-coupled RXFP1 pathways may provide promising opportunities for drug discovery in endothelial dysfunction and cardiometabolic disease.

SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling.

Medial vascular calcification, associated with enhanced mortality in chronic kidney disease (CKD), is fostered by osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Here, we describe that serum- and glucocorticoid-inducible kinase 1 (SGK1) was upregulated in VSMCs under calcifying conditions. In primary human aortic VSMCs, overexpression of constitutively active SGK1S422D, but not inactive SGK1K127N, upregulated osteo-/chondrogenic marker expression and activity, effects pointing to increased osteo-/chondrogenic transdifferentiation. SGK1S422D induced nuclear translocation and increased transcriptional activity of NF-κB. Silencing or pharmacological inhibition of IKK abrogated the osteoinductive effects of SGK1S422D. Genetic deficiency, silencing, and pharmacological inhibition of SGK1 dissipated phosphate-induced calcification and osteo-/chondrogenic transdifferentiation of VSMCs. Aortic calcification, stiffness, and osteo-/chondrogenic transdifferentiation in mice following cholecalciferol overload were strongly reduced by genetic knockout or pharmacological inhibition of Sgk1 by EMD638683. Similarly, Sgk1 deficiency blunted vascular calcification in apolipoprotein E-deficient mice after subtotal nephrectomy. Treatment of human aortic smooth muscle cells with serum from uremic patients induced osteo-/chondrogenic transdifferentiation, effects ameliorated by EMD638683. These observations identified SGK1 as a key regulator of vascular calcification. SGK1 promoted vascular calcification, at least partly, via NF-κB activation. Inhibition of SGK1 may, thus, reduce the burden of vascular calcification in CKD.