bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dapagliflozin downregulates G protein-coupled receptor Kinase-2 and upregulates regulator of g protein signaling-4 in adrenals to exert sympatholysis in heart failure
Authors: Lymperopoulos A , Del Calvo G , Baggio Lopez T , Carbone A , Borges J , Suster M , Maning J , Iacobellis G , Goldberger J 
Published: November 2023

Abstract
Dapagliﬂozin is a sodium-glucose co-transporter (SGLT)-2 inhibitor with beneficial cardiovascular effects independent of its anti-diabetic actions. Among these is sympatholysis, i.e., norepinephrine (NE) lowering which is beneficial in chronic human heart failure (HF). Adrenal G protein-coupled receptor kinase (GRK)-2 upregulation is a major driver of circulating catecholamine (CA) elevation and sympathetic nervous system (SNS) hyperactivity in HF due to dysregulation of adrenal sympatho-inhibitory α2-adrenergic receptors (ARs) [1]. On the other hand, we recently reported that signaling by neuronal free fatty acid receptor (FFAR)-3, which stimulates NE release from sympathetic neurons, is blocked by Regulator of G protein Signaling (RGS)-4 [2,3]. We hypothesized herein that dapagliﬂozin may lower SNS hyperactivity in the adrenal gland by improving α2AR, and antagonizing FFAR3 signaling in adrenal chromafﬁn cells. We used the rat pheochromocytoma PC12 cell line expressing human α2A-AR, as well as freshly isolated adrenal glands from rats treated with dapagliﬂozin in vivo. Dapagliﬂozin treatment for 7 consecutive days (20 mg/kg/d in drinking water) led to a signiﬁcant reduction in blood circulating NE levels (217+67 pg/ml, n=6), compared to control, vehicle-treated rats (363+77 pg/ml, n=6, p&lt;.05), suggesting reduced SNS activity. This was accompanied by reduced GRK2 and tyrosine hydroxylase (TH) mRNA and protein levels in dapagliﬂozin-treated rat adrenals vs. vehicle-treated animal-derived glands. In contrast, RGS4 mRNA levels were increased in dapagliflozin-treated adrenals. Adrenal α2AR density was higher in dapagliﬂozin- vs. vehicle-treated rats (51.3+7.3 vs. 26.1+8.1 fmol/mg of protein, respectively; n=12 glands from 6 animals per group, p&lt;.05). These results (i.e., GRK2 & TH downregulation with RGS4 upregulation) were completely recapitulated in PC12 cells in culture, treated with 5 microM dapagliﬂozin (or vehicle) for 24 hours. Importantly, α2AR-dependent G protein-mediated signaling towards inhibition of CA secretion was markedly enhanced, whereas FFAR3-dependent phospholipase C/calcium signaling was reduced, at 24 hrs post-dapagliﬂozin treatment of PC12 cells. GRK2 overexpression partially reversed dapagliflozin`s effect on cholinergic-induced CA secretion. In conclusion, dapagliﬂozin exerts a sympatholytic action in the adrenal medulla via a) downregulation of TH, which reduces CA biosynthesis, and GRK2, which reduces α2AR desensitization; and b) upregulation of RGS4 to block FFAR3-stimulated CA secretion (Figure).Figure
Effective cardiac mRNA delivery using lipid nanoparticles
Authors: Labonia M C I , Estape Senti M , Van Der Kraak P H , Brans M A D , Deshantri A K , Dokter I , Schiffelers R M , Sluijter J P G , Vader P 
Published: November 2023

Abstract

Background/Introduction
Heart failure is a global health burden for which there is no curative treatment available that aims to recover the impaired cardiac function.(1) Messenger RNA (mRNA) has emerged as a promising tool for protein replacement therapy. Endogenous mechanisms that enable repairing the heart can potentially be triggered by cardiac messenger RNA (mRNA) delivery.(2,3) Furthermore, the mRNA molecule can be modified in its secondary structure in order to reduce its immunogenicity and susceptibility to degradation by RNases. Clinical application of modified mRNA (modRNA) is challenged by the lack of effective and safe delivery systems. Lipid nanoparticles (LNPs) represent a well characterized class of mRNA delivery systems, which were recently approved for clinical usage in mRNA-based covid-19 vaccines.

Purpose
We compared cardiac delivery efficiency between different mRNA-LNPs formulations and naked mRNA in citrate buffer upon intramyocardial administration in mice. Furthermore, we aimed to identify cardiac cell types that were targeted. Finally, we assessed whether LNP administration induces a local immunogenic response.

Methods
Different LNP formulations were tested in vitro and in vivo for luciferase or GFP – encoding modRNA delivery. In vitro, LNP mediated modRNA delivery was assessed in human endothelial cells (HMEC-1), induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) and induced pluripotent stem cell -derived fibroblasts (iPS-FBs). In vivo, mice undergoing open chest heart surgery under general anaesthesia were intramyocardially injected with 2.5μg modRNA in LNPs or in citrate buffer. In order to quantify tissue distribution of mRNA delivery levels, luciferase expression was measured in various organs 24h after administration. Moreover, to identify cellular uptake specificity, histology was performed on mice treated with GFP modRNA.

Results
mRNA-LNPs outperformed naked mRNA upon intramyocardial administration in mice (figure 1 a, d-i). Although LNPs were mainly in the injection site in the left ventricular wall (Figure 1 b), the liver showed to be the main mRNA-LNP target organ(figure 1 a,b). mRNA-LNPs showed targeting of epicardial and interstitial cardiac cells (figure 1c). Among the tested C12-200 LNP formulations, no differences in in vivo delivery efficiency were observed (Figure 1 a, d). Most importantly, variations on the ionizable lipid LNP component determined the LNP local immune response.

Conclusion(s)
We present a proof of concept of a promising strategy for delivering mRNA to the heart by using LNPs as delivery systems, which proved to be more efficient than the current state of the art (mRNA in citrate buffer). LNP optimization to better target the heart could introduce a novel approach to achieve cardiac tissue repair.
Changes in study enrollment of patients with non-ischemic cardiomyopathy receiving an ICD for primary prevention: Insights from the APPRAISE ATP study
Authors: Mont L , Daubert J , Zareba W , Kutyifa V , Ando K , Wold N , Yong P , Schuger C 
Published: November 2023

Abstract

Introduction
The DANISH study called into question the effectiveness of the ICD in patients (pts) with non-ischemic cardiomyopathy (NIC) and resulted in a downgrade in ESC guidelines from Class I to Class IIA. The effect of these findings on implantation of ICDs in NIC pts in clinical studies has not been well established.

Methods
Two clinical studies were analyzed before and after the publication of DANISH: MADIT-RIT (2009-2012) and APPRAISE ATP (2017-present). These two studies enrolled globally and implanted ICDs in pts with primary prevention (PP) indications. The proportion of pts with NIC were analyzed between the two studies, both globally and by region: North America (NA) and European Union (EU). In addition, the APPRAISE ATP study was divided into halves to determine if any changes were observed whilst the study was in progress. Continuous variables were analyzed with a t-test and categorical variables were analyzed with a Chi-square test. Due to small numbers, implanted pts outside NA and the EU were not entered into the analysis.

Results
Demographics for the NIC subgroups are shown in the table below [MADIT-RIT (n=284) and APPRAISE ATP (n=1084)]. When compared to MADIT-RIT, pts in APPRAISE ATP were significantly older, had a higher mean LVEF, and greater prevalence of AF and diabetes. Globally, the proportion of pts with NIC who received ICDs was unchanged between the current APPRAISE ATP study and MADIT-RIT 10 years previously (38.1% vs 39.3%, p=0.91). When analyzed by geography, there was no change in North America (38.0% vs 41.6%, p=0.27). In Europe, however, there was a drop in enrollment of NIC ICD pts from 38.6% in MADIT-RIT to 29.1% in APPRAISE ATP. This decline was 24.6% in relative terms and approached, but did not achieve, statistical significance (p=0.074).
Implant rates in NIC ICD pts were stable overall when comparing the first half of APPRAISE ATP to its second half. Rates were also stable across both halves in NA and while implant rates of NIC ICD pts appeared to rebound in the second half in the EU, that late increase was not statistically significant.

Conclusions
The results of the DANISH study appear to have had a limited global impact on enrollment of NIC pts requiring implant of a PP ICD into the APPRAISE ICD clinical study. Whilst there was no change in North America before and after DANISH, there is a signal in the data that investigators in the EU may have restricted implants initially but eventually relaxed as time progressed. Further investigation is needed to confirm whether physicians in general practice have altered their referral patterns.
Poor glycemic control is associated with the prevalence of left atrial low-voltage areas in patients with atrial fibrillation ablation
Authors: Matsuda Y , Masuda M , Uematsu H , Sugino A , Ooka H , Kudo S , Fujii S , Asai M , Iida O , Okamoto S , Ishihara T , Nanto K , Tsujimura T , Hata Y , Mano T 
Published: November 2023

Abstract

Background
Although glycemic control before atrial fibrillation (AF) ablation is associated with AF recurrence after the procedure, the mechanism has not been fully clarified. Left atrial low-voltage areas (LVAs) were known to be correlated with atrial scarring and AF recurrence after ablation, and a preliminary study showed that the past history of diabetes mellitus (DM) was an independent predictor of LVAs. However, the association between LVAs and glycemic control before ablation has not been elucidated.

Purpose
The purpose of this study was to investigate the association between glycemic control before AF ablation and the prevalence of LVAs in patients with AF ablation.

Methods
The study design was a single center, retrospective observational study. Between December 2014 and December 2018, 782 (age, 68 ± 10 years; female, 262 [34%]; persistent AF, 414 [53%]) consecutive patients who underwent initial AF ablation were included. Glycated hemoglobin A1c (HbA1c) levels were measured before the procedure, and HbA1c ≥ 7% was set as the cut-off value of poor glycemic control in patients with DM. The definition of LVAs was sites with a left atrial bipolar amplitude &lt; 0.5 mV covering as ≥ 5 cm². Rhythm outcome after the procedure was followed for 24 months.

Results
Of 782 patients, 162 (21%) patients had LVAs, and 135 (17%) patients had past history of DM. LVAs were found more frequently in patients with poor glycemic control (Figure 1). On multivariate analysis, DM with HbA1c ≥7% was an independent predictor of LVAs (odds ratio, 3.6; 95% confidence interval: 1.8–7.0; p &lt; 0.001). In patients with LVAs, freedom from AF recurrence during the study periods tended to be lower in patients who had DM with HbA1c ≥7% than in those with non-DM (40.3% versus 51.6%, p = 0.06) (Figure 2).

Conclusions
In patients with AF ablation, LVAs were found more frequently in patients with poor glycemic control. In particular, DM with HbA1c ≥7% was an independent predictor of LVAs.Prevalence of LVAs and glycemic controlAF recurrence and glycemic control
Appropriate selection of substrate ablation in patients with persistent atrial fibrillation using an on-day assessment of baseline rhythm and trigger origin
Authors: Matsunaga Y , Egami Y , Ukita K , Yasumoto K , Okamoto N , Yano M , Tanaka N , Masuda M , Watanabe T , Inoue K , Sunaga A , Hikoso S , Sakata Y , Nishino M , Tanouchi J 
Published: November 2023

Abstract

Background
It has not been fully elucidated which patients with persistent atrial fibrillation (PerAF) should undergo substrate ablation.

Purpose
To identify the appropriate patients with PerAF who required an additional substrate ablation plus pulmonary vein isolation (PVI) using an on-day assessment of the baseline rhythm during the procedure and origin of the AF trigger.

Methods
This study was a post hoc sub-analysis of the EARNEST-PVI (Effect of Extensive Ablation on Recurrence in Patients with Persistent AF Treated with Pulmonary Vein Isolation) trial, which was a prospective, multicenter, randomized, open-label trial, comparing the PVI-alone and PVI-plus arms. The patients were divided into 2 groups according to the baseline rhythm and origin of the AF trigger. AF trigger was induced before catheter ablation using isoproterenol infusion (maximum dose of 0.4 μg/kg/min). Proven pulmonary vein (PV) triggers were defined as reproducible AF triggers from only the PVs. Group A consisted of patients with sinus rhythm at the baseline or proven PV triggers. Proven PV triggers were defined as reproducible AF triggers from only the PVs. Group B consisted of the remaining patients, who were AF at baseline and had non-proven PV triggers. The arrhythmia-free survival after a 3-month blanking period was assessed.

Results
Among the group A patients (n=327, Figure 1), the arrhythmia-free survival did not significantly differ between the PVI-alone and PVI-plus arms (p=0.276, HR 1.22, 95% CI: 0.85-1.76) (Figure 2, upper panel). Among the group B patients (n-166, Figure 1), who had AF at baseline and non-PV triggers, the arrhythmia-free survival was significantly lower in the PVI-alone than PVI-plus arm (p=0.032, HR 1.68, 95% CI: 1.04-2.70) (Figure 2 lower panel).

Conclusion
The on-day assessment of the baseline rhythm and trigger origin could distinguish patients who benefited from an additional ablation plus PVI. With an additional ablation plus PVI, the patients with sinus rhythm at baseline or who had proven PV triggers did not receive any benefit, whereas those with AF at baseline and no proven PV triggers received a benefit.Figure 1Figure 2
Incidence and predictors of asymptomatic cerebral infarction following radiofrequency catheter ablation for atrial fibrillation
Authors: Watanabe T , Yamada T , Morita T , Kawasaki M , Kikuchi A , Kondou T , Kawai T , Nishimoto Y , Seo M , Nakamura J , Kayama K , Fujita T , Tamura Y , Fukunami M 
Published: November 2023

Abstract

Backgrounds
Left atrial catheter ablation has been established as an important treatment option for atrial fibrillation (AF), but it carries the risk of periprocedural thromboembolism. Periprocedural major stroke is rare, but silent stroke does not appear to be rare. Accurate risk stratification for stroke and appropriate anticoagulation management are essential.

Purpose
We aimed to investigate the incidence and predictors of silent cerebral infarction (CI) associated with AF catheter ablation, detected by diffusion-weighted magnetic resonance imaging (DW-MRI).

Methods and Results
We performed a retrospective analysis of 618 consecutive patients (age 72±10 years, persistent atrial fibrillation (PEF) 45%, CHA2DS2-VASc score 2.6±1.4) with persistent or paroxysmal AF that underwent pulmonary vein (PV) or additional ablation and post-procedural cerebral MRI 1 day after ablation. During the ablation procedure, activated clotting time (ACT) was checked every 20 minutes, and additional heparin boluses were administered as needed to maintain ACT &gt;320 seconds. Patients were analyzed for possible demographical, medical, echocardiographic, and procedural predictors of infarction events. Post-procedure DW-MRI detected new infarction lesions in 83 patients (13.4%:CI-group). There were no differences between the CI and non-CI groups with respect to age, type of anticoagulant and complex fractionated atrial electrogram ablation. Body weight, brain natriuretic peptide and left atrial diameter were significantly higher in the CI group. Left ventricular ejection fraction (LVEF) was significantly lower in the CI than non-CI group (58.6±12.6 vs. 64.2±11.8, P&lt;0.001). PEF was more frequent in patients with CI than non-CI group (63.9 vs. 42.1%, P&lt;0.001). In a multivariate regression model revealed only EF was a significant predictor for the occurrence of new asymptomatic lesions on post-procedural DW-MRI (OR 0.949, 95% CI 0.92-0.98, P=0.001).

Conclusions
This study shows a high incidence of silent micro-embolic events after AF ablation. Lower LVEF were potential predictors of this complication.
Catheter ablation of atrial fibrillation: three-dimensional transesophageal echocardiography versus magnetic resonance imaging for pre-interventioal pulmonary vein imaging (8-year follow-up)
Authors: Kettering K 
Published: November 2023

Abstract

Catheter ablation has become the first line of therapy in patients with symptomatic, recurrent, drug-refractory atrial fibrillation (AF). However, it is still challenging because of the high degree of variability of the pulmonary vein (PV) anatomy. Three-dimensional transesophageal echocardiography (TEE) is a promising new technique for cardiac imaging. Therefore, we have evaluated the usefulness of 3-D TEE for analysing the left atrial anatomy prior to an ablation procedure in comparison to magnetic resonance imaging (MRI).

Methods
In 240 patients, 3-D TEE and cardiac MRI were performed immediately prior to an ablation procedure (paroxysmal AF: 110 patients, persistent AF: 130 patients). The image quality provided by 3-D TEE and by cardiac MRI was compared in all patients. Two different ablation strategies were used. In patients with paroxysmal AF, the cryoablation technique was used. In the other patients, a circumferential pulmonary vein ablation was performed using a three-dimensional mapping system.

Results
A 3-D TEE and a cardiac MRI could be performed successfully in all patients prior to the ablation procedure. Several variations of the PV anatomy could be visualized precisely by 3-D TEE and cardiac MRI (e.g. accessory PVs, common PV ostia, varying diameter of the left atrial appendage and its distance to the left superior PV). The image quality was good in the majority of patients even if AF with rapid ventricular response was present during the examination. The image quality provided by 3-D TEE was acceptable in 230/240 patients (95.8 %). The TEE findings correlated well with the PV angiographies performed using cardiac MRI. There was a good correlation with regard to the diameter of the PV ostia assessed by these two imaging techniques. All ablation procedures could be performed successfully (mean number of completely isolated PVs: 3.9 (cryo group), 3.9 (radiofrequency catheter ablation group)). At 96-month follow-up, 64.6 % of all patients were free from an arrhythmia recurrence (cryo group: 70.0 %, Carto group: 60.0 %). There were no major complications.

Conclusions
AF ablation procedures can be performed safely and effectively based on prior 3-D TEE imaging. The image quality was acceptable in the vast majority of patients.
Comparison of myocardial injury and inflammation between ablation index-guided and conventional contact force-guided ablation in atrial fibrillation patients
Authors: Yano M , Egami Y , Kawanami S , Sugae H , Ukita K , Kawamura A , Nakamura H , Yasumoto K , Tsuda M , Okamoto N , Matsunaga-Lee Y , Nishino M , Tanouchi J 
Published: November 2023

Abstract

Background
Ablation index (AI)-guided ablation improves the incidence of arrhythmia recurrence as compared to conventional contact force (CF)-guided ablation.

Purpose
The aim of this study was to elucidate the differences in the biomarkers associated with myocardial injury and inflammation between conventional CF-guided and AI-guided ablation.

Methods
Atrial fibrillation (AF) patients who underwent pulmonary vein isolation (PVI) from the Osaka Rosai Atrial Fibrillation ablation (ORAF) registry were enrolled. We divided the patients into two groups: conventional CF-guided PVI (CF group) and AI-guided PVI (AI group). The differences in biomarkers associated with myocardial injury and inflammation, and long-term durability of PVI between the two groups were evaluated.

Results
This study population included a total of 794 patients (CF-guided, 241 patients; AI-guided, 553 patients). Total application time was significantly shorter, and total application number was significantly smaller in AI than CF group. High-sensitive troponin I (hs-TnI) post-ablation was significantly higher in AI than CF group (p&lt;0.001), even after taking the total application number and total application time into consideration. No significant differences in inflammatory markers changes from pre- to post-ablation were observed between the two groups. Multiple regression analysis showed that age, AF type, AI-guided ablation and creatinine were significantly associated with the acute myocardial injury (hs-TnI value) after catheter ablation (standardized beta-coefficient=-0.096, p=0.013, standardized beta-coefficient=0.159, p&lt;0.001, standardized beta-coefficient=0.078, p=0.031 and standardized beta-coefficient=0.118, p=0.003, respectively). AI-guided ablation was significantly associated with the hs-TnI post-ablation by multiple regression analysis. The PV reconnection ratio was significantly smaller in AI than CF group (p=0.037).

Conclusion
According to the results of the biomarkers during AF ablation, AI-guided ablation had the ability to create larger lesions than CF-guided ablation, but had an equivalent inflammatory status to CF-guided ablation. The differences in myocardial injury and inflammation could be the mechanism of the better durability of PVI for AI-guided ablation.
Risk of complications in patients undergoing pulmonary vein antrum isolation: a single centre experience
Authors: Khaykin Y , Azizi Z , Alipour P , Gao-Kang J , Pirbaglou M , Falvey G , Khaykin M , Mooring A , Jasrai A , Zarifian Kamyab S , Narbonne M , Malcolm R , Timajchi E , Pantano A , Sadek M M 
Published: November 2023

Abstract

Background
Pulmonary vein antrum isolation (PVAI) is the gold standard approach to treat symptomatic atrial fibrillation (AF) refractory to medical therapy. While PVAI may result in a number of potential complications, there is a growing body of literature supporting safety of same day discharge post-PVAI.

Purpose
To retrospectively evaluate the incidence of post-procedure acute adverse events (AE), and elucidate factors associated with increased risk of such complications in patients undergoing PVAI.

Methods
Patients underwent PVAI between 2004-2021 at a tertiary care centre, and were followed-up at 3, 6 and 12 months post-PVAI. All procedures were performed utilizing intra-cardiac echocardiography. Baseline characteristics of patients who experienced acute AE were compared with those in patients who did not. Univariate and multivariate logistic regression models adjusted for age, sex, type of AF, left atrial size, and comorbidities were employed to evaluate risk factors for acute AE.

Results
2829 patients (mean age: 61.5±10.4 years, 33.7% female, 64.1% paroxysmal AF) were included in this study. Overall incidence of acute AE was 92 (3.3%), which included: 60 (2.1%) patients with access site hematoma, 20 (0.7%) patients with hematoma requiring treatment, and 12 (0.4%) patients with cardiac tamponade. Other complications included: 5 (0.18%) strokes or transient ischemic attacks (TIA), 3 (0.10%) esophageal fistulas, and 1 (0.03%) phrenic nerve injury. Females (4.2% vs 2%, P=0.001), patients older than 75 years (3.3% vs 2.7%, P=0.8), non-paroxysmal AF (3.4% vs 2.4%, P=0.1), body mass index ≥ 35 kg/m2 (3.6% vs 2.7%, p=0.04), those with an implanted device (6.7% vs 2.3%, p=0.004), and sinus node dysfunction (SND) (6.6% vs 2.5%, p=0.001) had a greater rate of acute AEs. Patients with comorbidities, including hypertension (3.4% vs 2%, P=0.04), Type 2 diabetes ( 3.2% vs 2.7%, p=0.7), congestive heart failure (5.6% vs 2.5%, P=0.008), and coronary artery disease (3.9% vs 2.6%, p=0.1) also manifested higher rate of acute AE. In the multivariate logistic regression model, female sex (OR= 2.5 [1.4, 4.4]), CHF (OR= 2.6 [1.3, 4.9]) and SND (OR=2.6 [1.1, 5.5] were associated with increased AE risk when adjusted for age, AF type, and other comorbidities.

Conclusion
In the multivariate model, female sex, a history of congestive heart failure, and SND were independently associated with a greater risk of AE following PVAI.