Catheter ablation or medical therapy to delay progression of atrial fibrillation : The randomized controlled atrial fibrillation progression trial (ATTEST)

Funding Information: This work was supported by Biosense Webster, Inc. Publisher Copyright: © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.Aims: Delay of progression from paroxysmal to persistent atrial fibrillation (AF) is an important measure of long-term success of AF treatment. However, published data on the impact of catheter ablation on AF progression are limited. This study evaluates whether radiofrequency (RF) catheter ablation delays the progression of AF compared with antiarrhythmic drug (AAD) treatment using current AF management guidelines. Methods: This prospective, randomized, controlled, two-arm, open-label trial was conducted at 29 hospitals and medical centres across 13 countries. Patients were randomized 1: 1 to RF ablation or AAD treatment. The primary endpoint was the rate of persistent AF/atrial tachycardia (AT) at 3 years. Results: After early study termination following slow enrolment, 255 (79%) of the planned 322 patients were enrolled (RF ablation, n = 128, AAD, n = 127); 36% of patients in the RF ablation group and 41% in the AAD group completed 3 years of follow-up. For the primary endpoint, the Kaplan-Meier estimate of the rate of persistent AF/AT at 3 years was significantly lower with RF ablation [2.4% (95% confidence interval (CI), 0.6-9.4%)] than with AAD therapy [17.5% (95% CI, 10.7-27.9%); one-sided P = 0.0009]. Patients ≥65 years were ∼4 times more likely to progress to persistent AF/AT than patients <65 years, suggesting RF ablation can delay disease progression [hazard ratio: 3.87 (95% CI, 0.88-17.00); P = 0.0727]. Primary adverse events were reported for eight patients in the RF ablation group. Conclusions: Radiofrequency ablation is superior to guideline-directed AAD therapy in delaying the progression from paroxysmal to persistent AF.publishersversionPeer reviewe

Atomic Mechanisms of Timothy Syndrome-Associated Mutations in Calcium Channel Cav1.2

Timothy syndrome (TS) is a very rare multisystem disorder almost exclusively associated with mutations G402S and G406R in helix IS6 of Cav1.2. Recently, mutations R518C/H in helix IIS0 of the voltage sensing domain II (VSD-II) were described as a cause of cardiac-only TS. The three mutations are known to decelerate voltage-dependent inactivation (VDI). Here, we report a case of cardiac-only TS caused by mutation R518C. To explore possible impact of the three mutations on interdomain contacts, we modeled channel Cav1.2 using as templates Class Ia and Class II cryo-EM structures of presumably inactivated channel Cav1.1. In both models, R518 and several other residues in VSD-II donated H-bonds to the IS6-linked α1-interaction domain (AID). We further employed steered Monte Carlo energy minimizations to move helices S4–S5, S5, and S6 from the inactivated-state positions to those seen in the X-ray structures of the open and closed NavAb channel. In the open-state models, positions of AID and VSD-II were similar to those in Cav1.1. In the closed-state models, AID moved along the β subunit (Cavβ) toward the pore axis and shifted AID-bound VSD-II. In all the models R518 retained strong contacts with AID. Our calculations suggest that conformational changes in VSD-II upon its deactivation would shift AID along Cavβ toward the pore axis. The AID-linked IS6 would bend at flexible G402 and G406, facilitating the activation gate closure. Mutations R518C/H weakened the IIS0-AID contacts and would retard the AID shift. Mutations G406R and G402S stabilized the open state and would resist the pore closure. Several Cav1.2 mutations associated with long QT syndromes are consistent with this proposition. Our results provide a mechanistic rationale for the VDI deceleration caused by TS-associated mutations and suggest targets for further studies of calcium channelopathies

2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death the Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC)

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Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Bromhexine Hydrochloride Prophylaxis of COVID-19 for Medical Personnel: A Randomized Open-Label Study

Background: Bromhexine hydrochloride has been suggested as a TMPRSS2 protease blocker that precludes the penetration of the SARS-CoV-2 into cells. We aimed to assess the preventive potential of regular bromhexine hydrochloride intake for COVID-19 risk reduction in medical staff actively involved in the evaluation and treatment of patients with confirmed or suspected SARS-CoV-2 infection. Methods: In a single-center randomized open-label study medical staff managing patients with suspected and confirmed COVID-19 were enrolled and followed-up for 8 weeks. The study began at the initiation of COVID-19 management in the clinic. We enrolled 50 participants without a history of SARS-CoV-2 infection: 25 were assigned to bromhexine hydrochloride treatment (8 mg 3 times per day), and 25 were controls. The composite primary endpoint was a positive nasopharyngeal swab polymerase chain reaction (PCR) test to SARS-CoV-2 or the signs of clinical infection within 28 days and at week 8. Secondary endpoints included the symptomatic infection rate and positive nasopharyngeal swab (PCR) tests. Results: The rate of the combined primary endpoint did not differ significantly between the active treatment group (2/25 [8%]) and control group (7/25 [28%]); P = 0.07. A fewer number of participants developed symptomatic infection (confirmed COVID-19) in the treatment group compared to controls (0/25 vs 5/25; P = 0.02). Conclusion: Bromhexine hydrochloride prophylaxis was associated with a reduced rate of symptomatic COVID-19. However, the prophylactic treatment was not associated with a lower combined primary endpoint rate, a positive swab PCR test and/or COVID-19. (ClinicalTrials.gov number, NCT04405999

Anti-Ischemic Effect of Leptin in the Isolated Rat Heart Subjected to Global Ischemia-Reperfusion: Role of Cardiac-Specific miRNAs

Background: Leptin is an obesity-associated adipokine that has been implicated in cardiac protection against ischemia-reperfusion injury (IRI). In this study, concentration-dependent effects of leptin on myocardial IRI were investigated in the isolated rat heart. In addition, we analyzed myocardial miRNAs expression in order to investigate their potential involvement in leptin-mediated cardioprotection. Methods: The effect of leptin on IRI was examined in Langendorff-perfused rat hearts preconditioned with two leptin concentrations (1.0 nM and 3.1 nM) for 60 min. The hearts were subjected to 30 min global ischemia and 120 min reperfusion with buffer containing leptin in the respective concentration. Heart function and arrhythmia incidence were analyzed. Infarct size was assessed histochemically. Expression of miRNA-144, -208a, -378, and -499 was analyzed in the ventricular myocardium using RT-PCR. Results: The addition of 1.0 nM leptin to the buffer exerted an infarct-limiting effect, preserved post-ischemic ventricular function, and prevented reperfusion arrhythmia compared to 3.1 nM leptin. Myocardial expression of miRNA-208a was decreased after heart exposure to 1.0 nM leptin and significantly elevated in the hearts perfused with leptin at 3.1 nM. Conclusion: Acute administration of leptin at low dose (1.0 nM) results in cardiac protection against IRI. This effect is associated with reduced myocardial expression of miRNA-208a

Evidence of Specialized Tissue in Human Interatrial Septum: Histological, Immunohistochemical and Ultrastructural Findings

<div><p>Background</p><p>There is a paucity of information on structural organization of muscular bundles in the interatrial septum (IAS). The aim was to investigate histologic and ultrastructural organization of muscular bundles in human IAS, including fossa ovalis (FO) and flap valve.</p><p>Methods</p><p>Macroscopic and light microscopy evaluations of IAS were performed from postmortem studies of 40 patients. Twenty three IAS specimens underwent serial transverse sectioning, and 17 - longitudinal sectioning. The transverse sections from 10 patients were immunolabeled for HCN4, Caveolin3 and Connexin43. IAS specimens from 6 other patients underwent electron microscopy.</p><p>Results</p><p>In all IAS specimens sections the FO, its rims and the flap valve had muscle fibers consisting of working cardiac myocytes. Besides the typical cardiomyocytes there were unusual cells: tortuous and horseshoe-shaped intertangled myocytes, small and large rounded myocytes with pale cytoplasm. The cells were aggregated in a definite structure in 38 (95%) cases, which was surrounded by fibro-fatty tissue. The height of the structure on transverse sections positively correlated with age (P = 0.03) and AF history (P = 0.045). Immunohistochemistry showed positive staining of the cells for HCN4 and Caveolin3. Electron microscopy identified cells with characteristics similar to electrical conduction cells.</p><p>Conclusions</p><p>Specialized conduction cells in human IAS have been identified, specifically in the FO and its flap valve. The cells are aggregated in a structure, which is surrounded by fibrous and fatty tissue. Further investigations are warranted to explore electrophysiological characteristics of this structure.</p></div

Electron micrographs of Purkinje-like cells in the IAS.

<p>The heart obtained from the same patient as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113343#pone-0113343-g006" target="_blank">figure 6</a>. Pc, Purkinje-like cell; n, nucleus; m, mitochondria; mf, myofilaments; pm, plasma membrane; rer - rough endoplasmic reticulum. <b>A.</b> A transverse section of several Purkinje-like cells. The large size of cells and localization of myofilaments at the cell periphery are appreciated. <b>B.</b> A longitudinal section of a Purkinje-like cell. The regular sarcomeric organization of myofilaments and plasma membrane undulations are visible. A T-like cell is also seen to the left from the Purkinje-like cell. <b>C.</b> Densely packed rough endoplasmic reticulum in Purkinje-like cell cytoplasm.</p

Characteristics of the patients and histological material.

<p>AF, atrial fibrillation; CAD, coronary artery disease; GI, gastrointestinal; COPD, chronic obstructive pulmonary disease; DCM, dilated cardiomyopathy; LV, left ventricle. P>0.05 for all parameters.</p><p>Characteristics of the patients and histological material.</p

Left atrial endocardial surface with an IAS and a part of the mitral valve.

<p>The heart obtained from a 55-year-old male patient. FO, fossa ovalis; FV, flap valve; RSVP, right superior pulmonary vein ostium; RIPV, right inferior pulmonary vein ostium; LSVP, left superior pulmonary vein ostium; LIVP, left inferior pulmonary vein ostium; MV, mitral valve. The distance between the RSPV and the flap valve is marked by the green arrow. The dotted oval denotes the most frequently encountered location of the structure.</p