Sinus Rhythm Control Research Articles

Impaired Intracellular Calcium Buffering Contributes to the Arrhythmogenic Substrate in Atrial Myocytes From Patients With Atrial Fibrillation.

Alterations in the buffering of intracellular Ca2+, for which myofilament proteins play a key role, have been shown to promote cardiac arrhythmia. It is interesting that although studies report atrial myofibrillar degradation in patients with persistent atrial fibrillation (persAF), the intracellular Ca2+ buffering profile in persAF remains obscure. Therefore, we aimed to investigate the intracellular buffering of Ca2+ and its potential arrhythmogenic role in persAF. Transmembrane Ca2+ fluxes (patch-clamp) and intracellular Ca2+ signaling (fluo-3-acetoxymethyl ester) were recorded simultaneously in myocytes from right atrial biopsies of sinus rhythm (Ctrl) and patients with persAF, alongside human atrial subtype induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). Protein levels were quantified by immunoblotting of human atrial tissue and induced pluripotent stem cell-derived cardiac myocytes. Mouse whole heart and atrial electrophysiology were measured on a Langendorff system. Cytosolic Ca2+ buffering was decreased in atrial myocytes of patients with persAF because of a depleted amount of Ca2+ buffers. In agreement, protein levels of selected Ca2+ binding myofilament proteins, including cTnC (cardiac troponin C), a major cytosolic Ca2+ buffer, were significantly lower in patients with persAF. Small interfering RNA (siRNA)-mediated knockdown of cTnC (si-cTNC) in atrial iPSC-CM phenocopied the reduced cytosolic Ca2+ buffering observed in persAF. Si-cTnC treated atrial iPSC-CM exhibited a higher predisposition to spontaneous Ca2+ release events and developed action potential alternans at low stimulation frequencies. Last, indirect reduction of cytosolic Ca2+ buffering using blebbistatin in an ex vivo mouse whole heart model increased vulnerability to tachypacing-induced atrial arrhythmia, validating the direct mechanistic link between impaired cytosolic Ca2+ buffering and atrial arrhythmogenesis. Our findings suggest that loss of myofilament proteins, particularly reduced cTnC protein levels, causes diminished cytosolic Ca2+ buffering in persAF, thereby potentiating the occurrence of spontaneous Ca2+ release events and atrial fibrillation susceptibility. Strategies targeting intracellular buffering may represent a promising therapeutic lead in persAF management.

Investigating tRNA-Derived Small RNA Expression Patterns and Bioinformatics Analysis in Epicardial Fat of Atrial Fibrillation Patients

Abstract: The intricate mechanisms underlying atrial fibrillation (AF) remain elusive. It is proposed that epicardial adipose tissue (EAT) may play a role in arrhythmias by releasing bioactive molecules, including exosomes containing tRNA-derived small RNAs (tsRNAs). Although tsRNAs are known to significantly influence cellular functions, their relationship with AF remains unexplored. To investigate this, we conducted RNA sequencing on EAT samples from 6 AF patients and 6 sinus rhythm control subjects. Our analysis identified 146 upregulated and 126 downregulated tsRNAs in AF. Four tsRNAs (tRF-SeC-TCA001, tiRNAGly–CCC–003, tRF-Gly-GCC-002, and tRF-Tyr-GTA-007) were validated via quantitative reverse transcriptionpolymerase chain reaction. Bioinformatic analysis revealed these tsRNAs target genes associated with cell adhesion and various cellular processes mediated by plasma membrane adhesion molecules. KEGG analysis suggested these target genes may contribute to AF pathogenesis through processes such as glycosaminoglycan biosynthesis, AMP-activated protein kinase activity, and the insulin signaling pathway. Our findings unveil altered tsRNA expression profiles in EAT from AF patients, hinting at potential interactions between tsRNAs and mRNA within EAT that could impact AF pathogenesis.

Risk and Protective Factors of Recurrence after Catheter Ablation for Atrial Fibrillation.

Atrial fibrillation (AF) is a common disease and is effectively managed through catheter ablation (CA). However, post-ablation AF recurrence can compromise patient outcomes, making the identification of associated risk factors crucially important. Factors influencing poor clinical outcomes include age, female sex, body mass index (BMI), non-paroxysmal AF, and comorbidities including diabetes mellitus (DM) and obstructive sleep apnea (OSA). Furthermore, the selected ablation strategy and employed technology are pivotal to long-term success in maintaining sinus rhythm control. The mechanisms of AF recurrence are complex and multifactorial; no single predictor is definitive. Thus, a personalized assessment of each patient should be tailored to the individual situation. A high risk of relapse does not preclude the option of ablation therapy, but rather underscores the necessity to address and manage underlying conditions contributing to AF pathogenesis, aiming to mitigate the risk of recurrence.

Morphometrical features of left atrial appendage in the atrial fibrillation patients subjected to left atrial appendage closure.

This study aimed to evaluate the morphometrical features of left atrial appendage (LAA) in patients with atrial fibrillation, subjected to LAA percutaneous closure (LARIAT) for stroke prevention. Computed tomography (CT) scans of 51 patients with atrial fibrillation subjected to LARIAT procedure were comparatively evaluated with 50 patients with sinus rhythm (control group). Three-dimensional reconstructions were created using volume-rendering for evaluation. No differences were found in LAA types of distribution (cauliflower: 25.5 vs. 34.0%, chicken wing: 45.1 vs. 46.0%, arrowhead: 29.4 vs. 20.0%, all p > 0.05) between groups. However, the study group was characterized by LAAs with a lower number of lobes. The LAA orifice anteroposterior and transverse diameters (19.3 ± 4.12 vs. 17.2 ± 4.0 mm, p = 0.01 and 25.1 ± 5.1 vs. 20.5 ± ± 4.4 mm, p = 0.001), orifice area (387.2 ± 133.9 vs. 327.1 ± 128.3 mm2, p = 0.02) and orifice perimeter (70.2 ± 12.5 vs. 61.2 ± 11.6 mm, p = 0.04) was significantly larger in atrial fibrillation patients. More oval LAA orifices was found in atrial fibrillation group (94.0 vs. 70.4%, p = 0.001). No statistically significant differences were found in LAA body length (47.4 ± 15.4 vs. 43.7 ± 10.9 mm, p = 0.17), body width (24.7 ± 5.6 vs. 24.4 ± 5.8 mm, p = 0.81), and chamber depth (17.7 ± 3.5 vs. 16.5 ± 3.8 mm, p = 0.11). Calculated LAA ejection fraction was significantly lower in study group compared to healthy patients (16.4 ± 14.9 vs. 48.2 ± 12.9%, p = 0.001). Important morphometrical differences in LAA orifice have been found, which was significantly larger and more oval in patients with atrial fibrillation compared to healthy controls. Although no difference in LAA body type and size was observed; the LAA ejection fraction was significantly lower in atrial fibrillation rhythm patients.

Evaluation of left atrial and ventricular remodeling in atrial fibrillation subtype by using speckle tracking echocardiography.

Atrial fibrillation (AF) is associated with cardiac structural and functional remodeling. We investigated the left atrial (LA) and left ventricular (LV) changes in AF subtypes by using two-dimensional echocardiography strain techniques. The study population consisted of 102 subjects with sinus rhythm (control group) and 463 patients with AF, among which 284 patients had paroxysmal AF (PAF) and 179 patients had persistent AF (PerAF). A speckle tracking automatic functional imaging software was used to perform the strain analysis. Patients with AF had dilated LA maximum and minimum volume, decreased LA reservoir strain, lower LV ejection fraction (LVEF), and impaired global longitudinal strain (GLS) compared to those of the sinus rhythm control group. In patients with PerAF, the LA maximum and minimum volumes were larger, and the LA reservoir strain [PAF vs. PerAF, 28% (21,33) vs. 19% (14, 28), P < 0.05], LVEF, and absolute GLS value (PAF vs. PerAF, -16.9 ± 3.3 vs. -14.1 ± 3.5%) were lower than those in patients with PAF. Patients with AF regardless of LA enlargement had decreased LA reservoir strain and lower LVEF and absolute GLS value than those in the sinus rhythm control group. Compared with those with normal sinus rhythm, patients with AF had dilated LA volume and impaired LA function, which were further worsened in patients with PerAF than those in patients with PAF. LA functional impairment occurred before LA enlargement. Left atrioventricular remodeling happened across different stages of AF development.

Association of ivabradin use with ventricular arrhythmias in heart failure patients

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction Heart failure patients with reduced left ventricular function are at high risk for ventricular arrhythmias and sudden cardiac death. Ivabradine, a specific inhibitor of the If current in the sinoatrial node, provides heart rate reduction in sinus rhythm and angina control in chronic coronary syndromes. Purpose The effect of ivabradine on ventricular arrhythmias in heart failure patients has not been fully elucidated. In this study, we aimed to investigate the effect of ivabradine use on life-threatening arrhythmias and long-term mortality in heart failure patients. Methods In this retrospective study, 1639 patients with heart failure were included. Patients were divided into two groups as ivabradine users and non-users. Patients presenting with ventricular tachycardia, presence of ventricular extra systole and ventricular tachycardia in 24-hour rhythm monitoring, appropriate ICD shocks and long-term mortality outcomes were evaluated according to ivabradine use. Results After adjustment for clinical variables, admission with ventricular tachycardia had 3.0 higher rates in ivabradine non-users (95% CI: 1.5 – 10.2). According to the adjusted model for all variables, approximately 4.1 times more appropriate ICD shocks were observed in the ivabradine non-users than the users (95% CI: 1.8 – 9.6). Long-term mortality did not differ between these groups after adjustment for all covariates. Conclusion The use of ivabradine reduced the appropriate ICD discharge in heart failure patients with low ejection fraction. Ivabradine has a potential in the treatment of ventricular arrhythmias in heart failure patients.

Enhanced Ca2+-Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation.

Small-conductance Ca2+-activated K+ (SK)-channel inhibitors have antiarrhythmic effects in animal models of atrial fibrillation (AF), presenting a potential novel antiarrhythmic option. However, the regulation of SK-channels in human atrial cardiomyocytes and its modification in patients with AF are poorly understood and were the object of this study. Apamin-sensitive SK-channel current (ISK) and action potentials were recorded in human right-atrial cardiomyocytes from sinus rhythm control (Ctl) patients or patients with (long-standing persistent) chronic AF (cAF). ISK was significantly higher, and apamin caused larger action potential prolongation in cAF- versus Ctl-cardiomyocytes. Sensitivity analyses in an in silico human atrial cardiomyocyte model identified IK1 and ISK as major regulators of repolarization. Increased ISK in cAF was not associated with increases in mRNA/protein levels of SK-channel subunits in either right- or left-atrial tissue homogenates or right-atrial cardiomyocytes, but the abundance of SK2 at the sarcolemma was larger in cAF versus Ctl in both tissue-slices and cardiomyocytes. Latrunculin-A and primaquine (anterograde and retrograde protein-trafficking inhibitors) eliminated the differences in SK2 membrane levels and ISK between Ctl- and cAF-cardiomyocytes. In addition, the phosphatase-inhibitor okadaic acid reduced ISK amplitude and abolished the difference between Ctl- and cAF-cardiomyocytes, indicating that reduced calmodulin-Thr80 phosphorylation due to increased protein phosphatase-2A levels in the SK-channel complex likely contribute to the greater ISK in cAF-cardiomyocytes. Finally, rapid electrical activation (5 Hz, 10 minutes) of Ctl-cardiomyocytes promoted SK2 membrane-localization, increased ISK and reduced action potential duration, effects greatly attenuated by apamin. Latrunculin-A or primaquine prevented the 5-Hz-induced ISK-upregulation. ISK is upregulated in patients with cAF due to enhanced channel function, mediated by phosphatase-2A-dependent calmodulin-Thr80 dephosphorylation and tachycardia-dependent enhanced trafficking and targeting of SK-channel subunits to the sarcolemma. The observed AF-associated increases in ISK, which promote reentry-stabilizing action potential duration shortening, suggest an important role for SK-channels in AF auto-promotion and provide a rationale for pursuing the antiarrhythmic effects of SK-channel inhibition in humans.

Choice of sinus rhythm control strategy in patients with atrial fibrillation: why, when and how? A review

After 20 years of dubious notions of parity between sinus rhythm control and ventricular rate control strategies in patients with atrial fibrillation, there is evidence of the prognostic superiority of the former. The review article presents the results of randomized trials that support early rhythm control in patients with atrial fibrillation, possible pharmacological and non-pharmacological methods of such treatment in real clinical practice.

Angiotensin II Mediates Cardiomyocyte Hypertrophy in Atrial Cardiomyopathy via Epigenetic Transcriptional Regulation.

Aims European Heart Rhythm Association established an expert consensus to define, characterize, and classify atrial cardiomyopathy into four subgroups based on their histopathological features. The predominant pathological feature of classes I and III is the hypertrophy of atrial cardiomyocytes. Here, we aim to investigate the mechanism of epigenetic transcriptional regulation of cardiomyocyte hypertrophy in atrial cardiomyopathy. Methods and Results Compared with that of sinus rhythm control individuals, the myocardium of patients with atrial fibrillation exhibited increased levels of angiotensin II (AngII), chromatin-bound myocyte enhancer factor 2 (MEF2), acetylated histone H4 (H4ac), and H3K27ac; upregulation of hypertrophy-related genes; and decreased levels of histone deacetylase (HDAC) 4 and HDAC5 bound to the promoters of hypertrophy-related genes. Furthermore, incubation of atrial cardiomyocytes with AngII increased their cross-sectional area and improved the expression of hypertrophy-related genes. AngII also promoted the phosphorylation of HDAC4 and HDAC5 and induced their nuclear export. RNA sequencing analyses revealed that AngII significantly upregulated genes associated with cardiac hypertrophy. Chromatin immunoprecipitation showed that this correlated with increased levels of chromatin-bound MEF2, H4ac, and H3K27ac and decreased HDAC4 and HDAC5 enrichment in the promoters of hypertrophy-related genes. Moreover, these AngII-induced prohypertrophic effects could be partially reverted by treatment with the AngII receptor blocker losartan. Conclusions AngII had a prohypertrophic effect on atrial cardiomyopathy which was epigenetic-dependent. Patients with atrial fibrillation manifest an increased susceptibility to hypertrophy and exhibit epigenetic characteristics that are permissive for the transcription of hypertrophy-related genes. AngII induces histone acetylation via the cytoplasmic-nuclear shuttling of HDACs, which constitutes a novel mechanism of atrial hypertrophy regulation and might provide a promising therapeutic strategy for atrial cardiomyopathy.

Pharmacologic Rate versus Rhythm Control for Atrial Fibrillation in Heart Failure Patients.

Atrial fibrillation (AF) and Heart failure (HF) constitute two frequently coexisting cardiovascular diseases, with a great volume of the scientific research referring to strategies and guidelines associated with the best management of patients suffering from either of the two or both of these entities. The common pathophysiological paths, the adverse outcomes, the hospitalization rates, and the mortality rates that occur from various reports and trials indicate that a targeted therapy to the common background of these cardiovascular conditions may reverse the progression of their interrelating development. Among other optimal treatments concerning the prevalence of both AF and HF, the introduction of rhythm and rate control strategies in the guidelines has underlined the importance of sinus rhythm and heart rate control in the prevention of deleterious complications. The use of these strategies in the clinical practice has led to a debate about the superiority of rhythm versus rate control. The current guidelines as well as the published randomized trials and studies have not proved that rhythm control is more beneficial than the rate control treatments in the terms of survival, all-cause mortality, hospitalization rates, and quality of life. Therefore, the current therapeutic strategy is based on the therapy guidelines and the clinical judgment and experience. The aim of this review was to elucidate the endpoints of pharmacologic randomized clinical trials and the clinical data of each antiarrhythmic or rate-limiting medication, so as to promote their effective, individualized, evidence-based clinical use.

Eighteen Months Follow-up In Patients With Tachycardia-induced Cardiomyopathy

One of the causes of chronic heart failure (HF) may be tachycardia-induced cardiomyopathy (TIC) - a heart disease that occurs with persistent supraventricular tachyarrhythmia, characterized by partially or completely reversible dysfunction and dilatation of the ventricles. The long-term prognosis in these patients is poorly understood. Objective: To evaluate the rate of rehospitalisation and the dynamics of the left ventricular ejection fraction in patients with TIC in 6 to 18 months after discharge from the hospital. Materials and methods: A retrospective analysis of patients diagnosed with TIC was carried out from January 2019 to February 2021. The diagnosis of TIC corresponded to the following signs: a stable tachycardia with more 100 beats per min; left ventricular ejection fraction (LVEF) <45%; exclusion of other causes of heart failure; partial or complete restoration of LVEF after restoration and maintenance of sinus rhythm or heart rate control. Patients were monitored by phone calls and called for follow-up of a transthoracic echocardiography. A total of 52 patients were examined, including 40 men (76.9%) 64.4 ± 10.3 (33; 88) years old. The most common cause of TIC was atrial fibrillation, recorded in 48 (92.3%) patients, in 4 (7.69%) patients - atrial flutter. In 46 (88.5%) patients, arterial hypertension was previously diagnosed, and in 12 (23.1%) cases - type 2 diabetes mellitus. Initial LVEF at hospitalization was 40.3 ± 8.2%, while LVEF <35% was recorded in 15 (28.85%) patients. Patient management was in accordance with clinical guidelines. Patients were treated during an episode of tachyarrhythmia and after restoration of sinus rhythm. Dynamic monitoring of echocardiography was possible in 26 patients. Differences were considered statistically significant at p <0.05. Results: The average follow-up period was 18,4 ± 6 [4; 27] months. With control echocardiography in 17 (32.69%) people the LVEF was more than 45%. During the observation period, 7 patients (13.46%) died, non-cardiovascular causes predominated in the mortality structure: in 4 patients (7.69%), death was due to oncopathology and in 1 patient (1.92%) due to coronavirus infection. The mean value of LVEF with control echocardiography was 47.8 ± 9.3% [31; 66] (p <0.0001) (Pic.1). In 3 (3.85%) patient, LVEF remained <35%. In 5 (9.62%) patients, LVEF after treatment increased, but remained <45%. Conclusion: The data of the presented long-term follow-up of patients with TIC indicate a favorable course in most cases, regardless of (or in despite of) the initial LVEF. One of the causes of chronic heart failure (HF) may be tachycardia-induced cardiomyopathy (TIC) - a heart disease that occurs with persistent supraventricular tachyarrhythmia, characterized by partially or completely reversible dysfunction and dilatation of the ventricles. The long-term prognosis in these patients is poorly understood. Objective: To evaluate the rate of rehospitalisation and the dynamics of the left ventricular ejection fraction in patients with TIC in 6 to 18 months after discharge from the hospital. Materials and methods: A retrospective analysis of patients diagnosed with TIC was carried out from January 2019 to February 2021. The diagnosis of TIC corresponded to the following signs: a stable tachycardia with more 100 beats per min; left ventricular ejection fraction (LVEF) <45%; exclusion of other causes of heart failure; partial or complete restoration of LVEF after restoration and maintenance of sinus rhythm or heart rate control. Patients were monitored by phone calls and called for follow-up of a transthoracic echocardiography. A total of 52 patients were examined, including 40 men (76.9%) 64.4 ± 10.3 (33; 88) years old. The most common cause of TIC was atrial fibrillation, recorded in 48 (92.3%) patients, in 4 (7.69%) patients - atrial flutter. In 46 (88.5%) patients, arterial hypertension was previously diagnosed, and in 12 (23.1%) cases - type 2 diabetes mellitus. Initial LVEF at hospitalization was 40.3 ± 8.2%, while LVEF <35% was recorded in 15 (28.85%) patients. Patient management was in accordance with clinical guidelines. Patients were treated during an episode of tachyarrhythmia and after restoration of sinus rhythm. Dynamic monitoring of echocardiography was possible in 26 patients. Differences were considered statistically significant at p <0.05. Results: The average follow-up period was 18,4 ± 6 [4; 27] months. With control echocardiography in 17 (32.69%) people the LVEF was more than 45%. During the observation period, 7 patients (13.46%) died, non-cardiovascular causes predominated in the mortality structure: in 4 patients (7.69%), death was due to oncopathology and in 1 patient (1.92%) due to coronavirus infection. The mean value of LVEF with control echocardiography was 47.8 ± 9.3% [31; 66] (p <0.0001) (Pic.1). In 3 (3.85%) patient, LVEF remained <35%. In 5 (9.62%) patients, LVEF after treatment increased, but remained <45%. Conclusion: The data of the presented long-term follow-up of patients with TIC indicate a favorable course in most cases, regardless of (or in despite of) the initial LVEF.

Особенности клинических проявлений ишемической болезни сердца у больных с амиодаронассоциированным гипотиреозом

Coronary heart disease (CHD) is an acute problem of modern medicine. Primarily, it is determined by the high prevalence of the disease among the working-age population, as well as by the considerable mortality and disability associated with it. Amiodarone (Am) is the drug of choice in the treatment of cardiac arrhythmias (CA), one of the frequent and threatening manifestations of CHD. Long-term use of the drug can lead to the development of primary hypothyroidism (HT), which significantly aggravates the course of cardiovascular diseases. Objective. To assess the cardiovascular system (CVS) of CHD patients with the development of amiodarone-associated hypothyroidism (AmHT). Material and methods. Analysis of case histories of 810 patients with CHD and various CA who were taking Am for sinus rhythm control was performed. The case histories were examined and a retrospective analysis was performed on the clinical course of CHD in 28 patients with AmHT before and after the development of thyreopathy. To evaluate the state of cardiovascular system the patients' complaints, objective examination data, electrocardiography (ECG) and echocardiography (EchoCG) were assessed. Results. Long-term intake of Am by patients with CHD results in primary HT in 3.4% of cases. The formation of thyreopathy significantly affects the course of the disease. Patients show a 19.6% increase in myocardial volume indices and a 22.7% decrease in myocardial contractility, with a 30.2% increase in left ventricular myocardial mass (LVMM). Conclusion. Amiodarone-associated hypothyroidism is one of the significant complications developing in patients taking the drug for a long period of time. The formation of thyreopathy in patients with CHD significantly aggravates the course of the underlying disease, which should be taken into account when prescribing treatment and dynamic monitoring

Biomarkers of Metabolic Syndrome: Role in Pathogenesis and Pathophysiology Of Atrial Fibrillation.

The relationship between Metabolic syndrome and Atrial Fibrillation is confirmed by many studies. The components of Metabolic syndrome cause remodeling of the atrial. Metabolic syndrome and metabolic derangements of the syndrome could be the cause of the pathogenesis of AF. This review article discusses the major biomarkers of Metabolic syndrome and their role in the pathogenesis of AF. The biomarkers are adiponectin, leptin, Leptin/ Adiponectin ratio, TNF-α, Interleukin-6, Interleukin-10, PTX3, ghrelin, uric acid, and OxLDL.The elevated plasma levels of adiponectin were linked to the presence of persistent AF. Leptin signaling contributes to angiotensin-II evoked AF and atrial fibrosis. Tumor necrosis factor-alpha involvement has been shown in the pathogenesis of chronic AF. Similarly, Valvular AF patients showed high levels of TNF-α. Increased left atrial size was associated with the interleukin-6 because it is a well-known risk factor for AF. Interleukin-10 as well as TNF-α were linked to AF recurrence after catheter ablation. PTX3 could be superior to other inflammatory markers that were reported to be elevated in AF. The serum ghrelin concentration in AF patients was reduced and significantly increased after treatment. Elevated levels of uric acid could be related to the burden of AF. Increased OxLDL was found in AF as compared to sinus rhythm control.

Epicardial fat and the risk of atrial tachy-arrhythmia recurrence post pulmonary vein isolation: a computed tomography study.

Epicardial and Pericardia fat have been hypothesized to exert local and systemic pathogenic effects on nearby cardiac structures. The present study aimed to evaluate the impact of epicardial and pericardial fat volumes on the outcome of patients that underwent a first pulmonary vein isolation (PVI) with cryoablation. We included 130 consecutive patients with atrial fibrillation (AF) that underwent contrast enhanced ECG-gated cardiac computed tomography (CCT) before a PVI. The control group included 50 patients in normal sinus rhythm that underwent ECG-gated CT to rule out coronary artery disease. Epicardial and pericardial fat volumes were quantified with CCT. Patients with AF compared to patients with normal sinus rhythm (control group) had significantly larger epicardial (140.3 ± 58.1 vs. 55.9 ± 17.7ml; respectively, P < 0.001) and pericardial (77.0 ± 35.5ml vs. 27.2 ± 9.5ml; respectively, P < 0.001) fat volumes. Among patients that underwent PVIs, those with AF recurrence had a greater epicardial (175.0 ± 54.4ml vs. 130.7 ± SD 54.2ml; respectively, P < 0.001) and pericardial (93.7 ± SD 42.8 vs. 72.5 ± SD 31.9ml; respectively, P < 0.001) fat volumes, compared to patients with no AF recurrence. Multivariate analyses revealed that epicardial fat was an independent predictor of recurrence post-ablation (HR = 1.08, 95% CI 1.02-1.16 per 10-ml increase in volume; P = 0.009). Pericardial fat was associated with 7% increase in risk of recurrent AF (HR = 1.07, 95% CI 0.98-1.18; P = 0.117). Epicardial fat, assessed with contrast enhanced CCT, is an independent predictor of AF recurrence after PVI ablation.

Prevention of thromboembolic complications during cardioversion and catheter ablation in patients with atrial fibrillation: review of key randomized trials

This review focuses on the relevance of sinus rhythm control in patients with atrial fibrillation in real-life clinical practice and specific clinical features of patients with this arrhythmia. The authors presented current guidelines on prevention of thromboembolic complications and a review of results from major clinical studies of direct oral anticoagulants. The search for literature and selection of clinical studies for 2009-2020 were performed on websites of the European and Russian Societies of Cardiology, the All-Russian Scientific Society of Arrhythmologists, and in online databases PubMed, EMBASE, eLibrary, and Google Scholar using the key words atrial fibrillation, anticoagulants, ablation, cardioversion, and efficacy and safety.

PLK2 is a novel regulator of osteopontin-driven fibrosis and diastolic dysfunction in permanent atrial fibrillation

Abstract Background and aim Atrial fibrillation (AF) is frequently accompanied by cardiac fibrosis and diastolic heart failure. Due to the heterogeneous nature and complexity of fibrosis, the knowledge of the underlying pathomechanisms is limited. Thus, effective antifibrotic pharmacotherapy is missing. The objective of this study was to decipher the role of polo-like kinase 2 (PLK2) in the pathogenesis of cardiac fibrosis and left ventricular diastolic dysfunction. We put particular emphasis on the identification of profibrotic downstream targets of PLK2, which can serve as therapeutic targets. Methods and results This study was based on human atrial tissue biopsies and peripheral blood samples, a PLK2 knockout mouse model, a canine tachy-pacing model and specific pharmacological interventions on cardiac fibroblasts. In human atrial AF tissue samples, PLK2 was 50% downregulated by hypoxia-induced promoter methylation compared to sinus rhythm (SR) control. Confirmatory analysis of a canine tachy-pacing model showed PLK2 downregulation exclusively in the atria but not in the ventricles. Specific pharmacological inhibition as well as genetic deletion of PLK2 led to a striking myofibroblast phenotype. Discovery proteomics revealed that the global knockout of PLK2 resulted in de novo secretion of the inflammatory cytokine osteopontin (OPN) in cardiac fibroblasts and concomitant ventricular fibrosis in the PLK2 knockout mouse model. An ELISA analysis of peripheral blood samples of AF patients with electrophysiologically proven fibrosis, confirmed significantly increased OPN plasma concentrations compared to SR and non-fibrosis AF controls. Consequently, echocardiography on PLK2 KO mice revealed left ventricular diastolic dysfunction, tachycardia and fibrosis-typical surface ECG anomalies (PQ and QRS prolongation). Mechanistically, we identified the ERK1/2 signaling pathway as the molecular link between reduced expression of PLK2 and elevated osteopontin transcription. In a reverse translational attempt, we successfully tested the capability of 5-amino-salicylic acid (5-ASA) to inhibit osteopontin transcription and to reverse a TGF-β-induced myofibroblast phenotype in vitro. Currently the long-term administration of 5-ASA is tested in PLK2 knockout mice to evaluate the therapeutic potential to prevent cardiac fibrosis and diastolic heart failure development. Conclusion and clinical impact We identified PLK2 as an epigenetically regulated kinase involved in the pathophysiology of fibrosis in AF. PLK2 knockout mice can serve as a model of diastolic heart failure wherein OPN is a promising therapeutic target. Our results strengthen the current hypothesis that atrial fibrillation is not only an ion channel disease but a complex systemic disorder. Restoration of physiological PLK2 expression and blockade of osteopontin release with 5-ASA may constitute valuable new drug targets for the prevention and treatment of fibrosis and diastolic heart failure in AF. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Faculty of Medicine, Carl Gustav Carus, Dresden, “MeDDrive Start” Grant

Clinical Pharmacology-Driven Translational Research to Optimize Bedside Therapeutics of Sotalol Therapy.

Oral sotalol, used in adults for sinus rhythm control, is initiated at 80 mg b.i.d. and titrated to a maximum safe dose. The US Food and Drug Administration recommends monitoring the corrected QT interval (QTc) for at least 3 days, until steady‐state exposure of the drug is reached, before patient discharge, which can significantly impact the total cost of treatment. The objectives of this research were to design an accelerated intravenous sotalol loading and maintenance therapy that will reduce the hospital length of stay and to also evaluate the pharmacoeconomic impact in a hospital setting. Pharmacokinetic simulations of sotalol plasma concentrations vs. times profiles were performed to determine the optimal intravenous/oral transition regimen. A cost minimization analysis from the health sector perspective was conducted to assess the cost savings for these proposed accelerated regimens. For a chosen target dose of 120 mg b.i.d., two infusions of 40 mg over 1 hour and 20 mg over 0.5 hour, each followed up by an evaluation of QTc, can be administered followed immediately by the target oral maintenance dose of 120 mg at the end of the second infusion. Consequently, steady‐state exposure and, therefore, steady‐state QTc are obtained on the first day of therapy, facilitating an earlier hospital discharge. Two and 1‐day mean total cost of −$3,123 (95% confidence interval (CI), −$3,640, −$2,607) −$4,820 (95% CI, −$5,352, −$4,288) were observed for this strategy, respectively. We are proposing an intravenous to oral transition strategy for sotalol that has the potential to significantly reduce cost and increase patient convenience.

Differentially expressed genes for atrial fibrillation identified by RNA sequencing from paired human left and right atrial appendages.

Atrial fibrillation is a significant worldwide contributor to cardiovascular morbidity and mortality. Few studies have investigated the differences in gene expression between the left and right atrial appendages, leaving their characterization largely unexplored. In this study, differential gene expression was investigated in atrial fibrillation and sinus rhythm using left and right atrial appendages from the same patients. RNA sequencing was performed on the left and right atrial appendages from five sinus rhythm (SR) control patients and five permanent AF case patients. Differential gene expression in both the left and right atrial appendages was analyzed using the Bioconductor package edgeR. A selection of differentially expressed genes, with relevance to atrial fibrillation, were further validated using quantitative RT-PCR. The distribution of the samples assessed through principal component analysis showed distinct grouping between left and right atrial appendages and between SR controls and AF cases. Overall 157 differentially expressed genes were identified to be downregulated and 90 genes upregulated in AF. Pathway enrichment analysis indicated a greater involvement of left atrial genes in the Wnt signaling pathway whereas right atrial genes were involved in clathrin-coated vesicle and collagen formation. The differing expression of genes in both left and right atrial appendages indicate that there are different mechanisms for development, support and remodeling of AF within the left and right atria.

Effect of β-blockers on triggering of symptomatic atrial fibrillation by anger or stress

Anger and stress can trigger episodes of atrial fibrillation (AF) in patients with a history of AF. The purpose of this study was to determine whether β-blockers can protect against emotionally triggered AF. In this prospective, controlled, electronic diary-based study of emotions preceding AF, patients with a history of paroxysmal or persistent AF (N = 91) recorded their rhythm on event monitors at the time of AF symptoms and completed a diary entry querying mood states (eg, anger and stress) for the preceding 30 minutes (pre-AF "case period") for 1 year. Also, patients underwent monthly 24-hour Holter monitoring during which they were prompted to complete a diary entry twice per hour. Diaries recorded during sinus rhythm comprise controls. Patients' exposure to each emotion was compared between the pre-AF case period and control periods by using generalized estimating equation modeling, as well as interactions between β-blocker use and emotion tested. Sixty percent were prescribed β-blockers. A total of 163 symptomatic AF episodes (in 34 patients) and 11,563 Holter-confirmed sinus rhythm control periods had associated diary data. Overall, the likelihood of an AF episode was significantly higher during anger or stress. This effect, however, was significantly attenuated in patients on β-blockers (odds ratio 22.5; 95% confidence interval 6.7-75.4, P < .0001 for patients not prescribed β-blockers vs odds ratio 4.0, 95% confidence interval 1.7-9.5, P= .002 for those prescribed β-blockers; P = .02 for the interaction). Exclusion of patients on sotalol did not affect findings. Anger or stress can trigger AF, but use of β-blockers greatly attenuates this deleterious physiological response.

INCREASED RISK OF CARDIAC DEATH WITH RECURRENT TACHYCARDIA MEDIATED CARDIOMYOPATHY DUE TO ATRIAL FIBRILLATION/FLUTTER

Tachycardia mediated cardiomyopathy is a rare consequence of atrial tachyarrhythmias, where reduced left ventricular ejection fraction (LVEF) recovers after achievement of sinus rhythm or rate control. A small proportion develop recurrent TMC with recurrence of arrhythmia and outcomes in this group