Frequent Premature Atrial Contractions Lead to Adverse Atrial Remodeling and Atrial Fibrillation in a Swine Model.

BACKGROUND: Frequent premature atrial complexes (PACs) are associated with future incident atrial fibrillation (AF), but whether PACs contribute to development of AF through adverse atrial remodeling has not been studied. This study aimed to explore the effect of frequent PACs from different sites on atrial remodeling in a swine model. METHODS: Forty swine underwent baseline electrophysiologic studies and echocardiography followed by pacemaker implantations and paced PACs (50% burden) at 250-ms coupling intervals for 16 weeks in 4 groups: (1) lateral left atrium (LA) PACs by the coronary sinus (Lat-PAC; n=10), (2) interatrial septal PACs (Sep-PAC; n=10), (3) regular LA pacing at 130 beats/min (Reg-130; n=10), and (4) controls without PACs (n=10). At the final study, repeat studies were performed, followed by tissue histology and molecular analyses focusing on fibrotic pathways. RESULTS: Lat-PACs were associated with a longer P-wave duration (93.0±9.0 versus 74.2±8.2 and 58.8±7.6 ms; P<0.001) and greater echocardiographic mechanical dyssynchrony (57.5±11.6 versus 35.7±13.0 and 24.4±11.1 ms; P<0.001) compared with Sep-PACs and controls, respectively. After 16 weeks, Lat-PACs led to slower LA conduction velocity (1.1±0.2 versus 1.3±0.2 [Sep-PAC] versus 1.3±0.1 [Reg-130] versus 1.5±0.2 [controls] m/s; P<0.001) without significant change in atrial ERP. The Lat-PAC group had a significantly increased percentage of LA fibrosis and upregulated levels of extracellular matrix proteins (lysyl oxidase and collagen 1 and 8), as well as TGF-ß1 (transforming growth factor-ß1) signaling proteins (latent and monomer TGF-ß1 and phosphorylation/total ratio of SMAD2/3; P<0.05). The Lat-PAC group had the longest inducible AF duration (terminal to baseline: 131 [interquartile range 30, 192] seconds versus 16 [6, 26] seconds [Sep-PAC] versus 22 [11, 64] seconds [Reg-130] versus -1 [-16, 7] seconds [controls]; P<0.001). CONCLUSIONS: In this swine model, frequent PACs resulted in adverse atrial structural remodeling with a heightened propensity to AF. PACs originating from the lateral LA produced greater atrial remodeling and longer induced AF duration than the septal-origin PACs. These data provide evidence that frequent PACs can cause adverse atrial remodeling as well as AF, and that the location of ectopic PACs may be clinically meaningful.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Predictors of first pass isolation of the pulmonary veins in real world ablations: An analysis of 2671 patients from the REAL-AF registry.

INTRODUCTION: During atrial fibrillation ablation (AFA), achievement of first pass isolation (FPI) reflects effective lesion formation and predicts long-term freedom from arrhythmia recurrence. We aim to determine the clinical and procedural predictors of pulmonary vein FPI. METHODS: We reviewed AFA procedures in a multicenter prospective registry of AFA (REAL-AF). A multivariate ordinal logistic regression, weighted by inverse proceduralist volume, was used to determine predictors of FPI. RESULTS: A total of 2671 patients were included with 1806 achieving FPI in both vein sides, 702 achieving FPI in one, and 163 having no FPI. Individually, age, left atrial (LA) scar, higher power usage (50 W), greater posterior contact force, ablation index >350 posteriorly, Vizigo™ sheath utilization, nonstandard ventilation, and high operator volume (>6 monthly cases) were all related to improved odds of FPI. Conversely sleep apnea, elevated body mass index (BMI), diabetes mellitus, LA enlargement, antiarrhythmic drug use, and center's higher fluoroscopy use were related to reduced odds of FPI. Multivariate analysis showed that BMI > 30 (OR 0.78 [0.64-0.96]) and LA volume (OR per mL increase = 1.00 [0.99-1.00]) predicted lower odds of achieving FPI, whereas significant left atrial scarring (>20%) was related to higher rates of FPI. Procedurally, the use of high power (50 W) (OR 1.32 [1.05-1.65]), increasing force posteriorly (OR 2.03 [1.19-3.46]), and nonstandard ventilation (OR 1.26 [1.00-1.59]) predicted higher FPI rates. At a site level, high procedural volume (OR 1.89 [1.48-2.41]) and low fluoroscopy centers (OR 0.72 [0.61-0.84]) had higher rates of FPI. CONCLUSION: FPI rates are affected by operator experience, patient comorbidities, and procedural strategies. These factors may be postulated to impact acute lesion formation.

Characterization of remodeling processes in the atria of atrioventricular block dogs: Utility as an early-stage atrial fibrillation model.

To characterize utility of atrioventricular block (AVB) dogs as atrial fibrillation (AF) model, we studied remodeling processes occurring in their atria in acute (<2 weeks) and chronic (>4 weeks) phases. Fifty beagle dogs were used. Holter electrocardiogram demonstrated that paroxysmal AF occurred immediately after the production of AVB, of which duration tended to be prolonged in chronic phase. Electrophysiological analysis showed that inter-atrial conduction time and duration of burst pacing-induced AF increased in the chronic phase compared with those in the acute phase, but that atrial effective refractory period was hardly altered. Echocardiographic study revealed that diameters of left atrium, right pulmonary vein and inferior vena cava increased similarly in the acute and chronic phases. Histological evaluation indicated that hypertrophy and fibrosis in atrial tissue increased in the chronic phase. Electropharmacological characterization showed that i.v. pilsicainide effectively suppressed burst pacing-induced AF with increasing atrial conduction time and refractoriness of AVB dogs in chronic phase, but that i.v. amiodarone did not exert such electrophysiological effects. Taken together, AVB dogs in chronic phase appear to possess such pathophysiology as developed in the atria of early-stage AF patients, and therefore they can be used to evaluate drug candidates against early-stage AF.

Left atrial remodeling and voltage-guided ablation outcome in persistent atrial fibrillation patients according to CHA2DS2-VASc score.

BACKGROUND: CHA2DS2-VASc score-related differences have been reported in atrial fibrotic remodeling and prognosis of atrial fibrillation (AF) patients after ablation. There are currently no data on the efficacy of low voltage zone (LVZ)-guided ablation in persistent AF patients according to CHA2DS2-VASc score. We assessed in a cohort of persistent AF patients the extent of LVZ, the regional distribution of LA voltage and the outcome of LA voltage-guided substrate ablation in addition to PVI according to CHA2DS2-VASc score. METHODS: 138 consecutive persistent AF patients undergoing a first voltage-guided catheter ablation were enrolled. 58 patients with CHAD2DS2-VASc score ≥ 3 and 80 patients with CHAD2DS2-VASc score ≤ 2 were included. LA voltage maps were obtained using 3D-electroanatomical mapping system in sinus rhythm. LVZ was defined as < 0.5 mV. RESULTS: In the high CHAD2DS2-VASc score group, LA voltage was lower (1.5 [1.1-2.5] vs. 2.3 [1.5-2.8] mV, p = 0.02) and LVZs were more frequently identified (40% vs. 18%), p < 0.01). Female with CHA2DS2-VASc score ≥ 3 (p = 0.031), LA indexed volume (p = 0.009) and P-wave duration ≥ 150 ms (p = 0.001) were predictors of LVZ. After a 36-month follow-up, atrial arrhythmia-free survival was similar between the two groups (logrank test, P = 0.676). CONCLUSIONS: AF patients with CHAD2DS2-VASc score ≥ 3 display more LA substrate remodeling with lower voltage and more LVZs compared with those with CHAD2DS2-VASc score ≤ 2. Despite this atrial remodeling, they had similar and favorable 36 months results after one single procedure. Unlike male with CHAD2DS2-VASc score ≥ 3, female with CHAD2DS2-VASc score ≥ 3 was predictor of LVZ occurrence.

Atrial electrical remodeling and function after transcatheter aortic valve replacement in patients with aortic stenosis.

To examine reverse atrial electrical remodeling in patients with aortic stenosis (AS) after trans-catheter aortic valve replacement (TAVR). In 65 consecutive patients with severe AS (83 ± 4 years, 47 (72.3%) females), we analyzed ECG records for the P wave duration (PWD) in lead II and P-terminal force (PTFV1) in V1, and measured cardiac dimensions and function by echocardiography (ECHO) following TAVR. Biomarkers were measured to assess myocardial injury by TAVR. TAVR was successfully performed without major complications: the aortic valve area increased from 0.62 ± 0.14 cm2 to 1.52 ± 0.24cm2, and the trans-aortic pressure gradient decreased from 58.4 ± 15.9 mmHg to 15.0 ± 19.6 mmHg. PWD and PTFV increased immediately after TAVR and returned to the pre-TAVR levels on the next day. Then, the PWD declined toward 6 months after TAVR non-significantly in all patients, but significantly in 25 patients with baseline PWD ≥ 130 ms (P = 0.039). PTFV1 showed no long-term change. Improvement was observed in the ejection fraction, all thickness of the left ventricle and in the left atrial dimensions on ECHO. After recovery from transient aggravation by TAVR procedure, PWD reversed slowly, and the change was significant in those with baseline PWD ≥ 130 ms while change in PTFV1 was not significant at 6 months of follow-up. ECHO showed a reversal of remodeling in the left ventricle and in the left atrial dimension after TAVR.

Inhibition of ferroptosis by icariin treatment attenuates excessive ethanol consumption-induced atrial remodeling and susceptibility to atrial fibrillation, role of SIRT1.

Ferroptosis contributes to the pathogenesis of atrial fibrillation (AF), although the mechanisms are still largely uncovered. The current study was designed to explore the pharmacological effects of icariin against ethanol-induced atrial remodeling, if any, and the mechanisms involved with a focus on SIRT1 signaling. Excessive ethanol-treated animals were administered with Ferrostatin-1, Erastin or icariin to evaluate the potential effects of icariin or ferroptosis. Then, the underling mechanisms was further explored in the in vitro experiments using HL-1 atrial myocytes. Excessive ethanol administration caused significant atrial damage as evidenced by increased susceptibility to AF, altered atrial conduction pattern, atrial enlargement, and enhanced fibrotic markers. These detrimental effects were reversed by Ferrostatin-1 or icariin treatment, while Erastin co-administration markedly abolished the beneficial actions conferred by icariin. Mechanistically, ethanol-treated atria exhibited markedly up-regulated pro-ferroptotic protein (PTGS2, ACSL4, P53) and suppressed anti-ferroptotic molecules (GPX4, FTH1). Icariin treatment inhibited ethanol-induced atrial ferroptosis by reducing atrial mitochondrial damage, ROS accumulation and iron overload. Interestingly, the in vivo and in vitro data showed that icariin activated atrial SIRT1-Nrf-2-HO-1 signaling pathway, while EX527 not only reversed these effects, but also abolished the therapeutic effects of icariin. Moreover, the stimulatory effects on GPX4, SLC7A11 and the suppressive effects on ACSL4, P53 conferred by icariin were blunted by EX527 treatment. These data demonstrate that ferroptosis plays a causative role in the pathogenesis of ethanol-induced atrial remodeling and susceptibility to AF. Icariin protects against atrial damage by inhibiting ferroptosis via SIRT1 signaling. Its role as a prophylactic/therapeutic drug deserves further clinical study.

An objective tool for quantifying atrial fibrillation substrate in rats.

The utility of rodents for research related to atrial fibrillation (AF) is growing exponentially. However, the obtained arrhythmic waveforms are often mixed with ventricular signals and the ability to analyze regularity and complexity of such events is limited. Recently, we introduced an implantable quadripolar electrode adapted for advanced atrial electrophysiology in ambulatory rats. Notably, we have found that the implantation itself leads to progressive atrial remodeling, presumably because of mechanical loading of the atria. In the present study, we developed an algorithm to clean the atrial signals from ventricular mixing and thereafter quantify the AF substrate in an objective manner based on waveform complexity. Rats were sequentially examined 1-, 4-, and 8-wk postelectrode implantation using a standard AF triggering protocol. Preburst ventricular mixing was sampled and automatically subtracted based on QRS detection in the ECG. Thereafter, the "pure" atrial signals were analyzed by Lempel-Ziv complexity algorithm and a complexity ratio (CR) was defined for each signal by normalizing the postburst to the preburst values. Receiver operating characteristic (ROC) curve analysis indicated an optimal CR cutoff of 1.236 that detected irregular arrhythmic events with high sensitivity (94.5%), specificity (93.1%), and area under the curve (AUC) (0.96, 95% confidence interval, 0.945-0.976). Automated and unbiased analysis indicated a gradual increase in signal complexity over time with augmentation of high frequencies in power spectrum analysis. Our findings indicate that CR algorithm detects irregularity in a highly efficient manner and can also detect the atrial remodeling induced by electrode implantation. Thus, CR analysis can strongly facilitate standardized AF research in rodents.NEW & NOTEWORTHY Rodents are increasingly used in AF research. However, because of technical difficulties including atrial waveform mixing by ventricular signals, most studies do not discriminate between irregular (i.e., AF) and regular atrial arrhythmias. Here, we develop an unbiased computerized tool to "pure" the atrial signals from ventricular mixing and thereafter analyze AF substrate based on the level of irregularity in an objective manner. This novel tool can facilitate standardized AF research in rodents.

Functional reserve and contractile phenotype of atrial myocardium from patients with atrial remodeling without and with atrial fibrillation.

Atrial contractility and functional reserve in atrial remodeling (AR) without (AR/-AF) or with atrial fibrillation (AR/+AF) are not well characterized. In this study, functional measurements were performed in right atrial muscle strips (n = 71) obtained from patients (N = 22) undergoing routine cardiac surgery with either no AR [left atrial (LA) diameter < 40 mm and no history of AF (hAF)], AR/-AF (LA diameter ≥ 40 mm, no hAF), or AR/+AF (hAF and LA diameter ≥ 40 mm or LAEF < 45%). AR/-AF and AR/+AF were associated with a prolongation of half-time-to-peak (HTTP, P < 0.001) and time-to-peak (TTP) contraction (P < 0.01) when compared with no AR. This effect was seen at baseline and during ß-adrenergic stimulation with isoproterenol (Iso). Early relaxation assessed by half-relaxation time (HRT) was prolonged in AR/-AF (P = 0.03) but not in AR/+AF when compared with no AR at baseline, but this delay in relaxation in AR/-AF was attenuated with Iso. Late relaxation (τ) did not differ between AR/-AF and no AR but was consistently shorter in AR/+AF than no AR before (P = 0.04) and during Iso (P = 0.01), indicating accelerated late relaxation in AR/+AF. Relative force increase during Iso was higher (P = 0.01) and more dispersed (P = 0.047) in patients with AR/+AF. Relative adrenergic response was unaltered in the myocardium of patients with AR/-AF and AR/+AF. In conclusion, AR/-AF and AR/+AF are associated with changes in myocardial inotropic reserve and contractility. The changes are particularly pronounced in patients with AR/+AF, suggesting that the progression from AR/-AF to AR/+AF is associated with progressive alterations in atrial function that may contribute to arrhythmogenesis.NEW & NOTEWORTHY Mechanical alterations in atrial remodeling without (AR/-AF) and with atrial fibrillation (AR/+AF) have not been studied in detail in human atrial tissue preparations. To our knowledge, this is the first study to compare the mechanical phenotype and inotropic reserve in human atrial myocardial preparations from patients with no atrial remodeling, AR/-AF, and AR/+AF. We identify specific patterns of contractile dysfunction and heterogeneity for both, AR/-AF and AR/+AF, indicating the progression of atrial disease.

Atrial fibrillation: Epidemiology, pathophysiology, and clinical complications (literature review).

The last three decades have been characterized by an exponential increase in knowledge and advances in the clinical management of atrial fibrillation. The purpose of the study is to provide an overview of the pathogenesis of nonvalvular atrial fibrillation and a comprehensive investigation of the epidemiological data associated with various risk factors for atrial fibrillation. The leading research methods are analysis and synthesis, comparison, observation, induction and deduction, and grouping method. Research has shown that old age, male gender, and European descent are important risk factors for developing atrial fibrillation. Other modifiable risk factors include a sedentary lifestyle, smoking, obesity, diabetes mellitus, obstructive sleep apnea, and high blood pressure predisposing to atrial fibrillation, and each has been shown to induce structural and electrical atrial remodeling. Both heart failure and myocardial infarction increase the risk of developing atrial fibrillation and vice versa creating feedback that increases mortality. The review is a comprehensive study of the epidemiological data linking nonmodifiable and modifiable risk factors for atrial fibrillation, and the pathophysiological data supporting the relationship between each risk factor and the occurrence of atrial fibrillation. This may be necessary for the practice of the treatment of the cardiac system.

Impact of unipolar voltage criteria for left atrial posterior wall on atrial fibrillation recurrence after pulmonary vein isolation.

INTRODUCTION: Beyond pulmonary vein isolation (PVI), additional therapeutic strategies for atrial fibrillation (AF) have not been established. Remodeling of the left atrium (LA) could impact AF recurrence post-PVI. We investigated the impact of unipolar voltage (UV) criteria for the LA posterior wall (LA-PW) on AF recurrence post-PVI. METHODS: We reviewed the cases of 106 AF patients (mean age 63.8 years, nonparoxysmal AF: 59%) who underwent extensive encircling PVI by radiofrequency ablation guided by a 3-dimension mapping system, investigating the impact on AF recurrence of the UV criteria of the LA. RESULTS: Out of all patients, 26 patients had AF recurrence during post-PVI follow-up [median 603 days]. They showed a higher percentage of nonparoxysmal AF (80.8 vs. 52.5%, p = .011), longer AF duration (2.9 ± 2.7 vs. 1.0 ± 1.7 years, p = .002), and larger area size of UV < 2.0 mV in LA-PW (2.8 ± 1.8 vs. 1.0 ± 1.5 cm2 , p < .001) than those without recurrence. Cox Hazard analysis for AF recurrence adjusted by age, gender, AF duration, body mass index and left atrial volume index revealed that an area size over 2.0 cm2 of UV < 2.0 mV in LA-PW (HR 6.9 [95% CI:1.3-35.5], p = .021) posed independent risks for AF recurrence post-PVI. The atrial arrhythmia-free survival rate was higher in those with no area of UV < 3.0 mV in LA-PW compared to those with a sizable area (>2.0 cm2 ) of UV < 3.0 mV and <2.0 mV (95.0% vs. 74.2% vs. 57.1%, Log-Rank: p < .001). In the AF etiology of patients with AF recurrence, 9 of 14 patients who underwent the 2nd procedure had no PV reconnection, and 8 patients required the LA-PW isolation for their non-PV AF. CONCLUSION: UV criteria of LA-PW is a useful parameter for AF-recurrence post-PVI. Lower UV in LA-PW as an indication of electrical remodeling could indicate a higher risk of AF recurrence and the need for further therapeutic strategies.

Subfertility versus ART: unraveling the origins of fetal cardiac programming.

STUDY QUESTION: Do spontaneously conceived (SC) fetuses from subfertile couples show the same signs of cardiac remodeling as those observed after IVF treatments? SUMMARY ANSWER: As opposed to fetuses from IVF, SC fetuses from subfertile couples do not show cardiac remodeling and present a similar cardiac structure and function to those of SC fetuses from fertile couples. WHAT IS KNOWN ALREADY: Subjects conceived by IVF present signs of cardiac remodeling and suboptimal function in utero and during childhood, including larger atria, more globular and thicker ventricles, reduced longitudinal motion, and impaired relaxation as compared to SC individuals from fertile couples. There are no previous publications investigating the independent cardiac programming effects of infertility in SC fetuses from subfertile couples (with time-to-pregnancy (TTP) over 12 months). STUDY DESIGN, SIZE, DURATION: A prospective cohort study of 289 singleton pregnancies exposed and not exposed to subfertility recruited from 2019 to 2021, including 96 SC pregnancies from fertile couples (TTP under 12 months), 97 SC from subfertile couples (TTP over 12 months), and 96 from IVF after fresh embryo transfer. Fetal echocardiography was performed in all pregnancies. Epidemiological data and perinatal outcomes were collected in all pregnancies. The overall attrition rate was 15.7%. PARTICIPANTS/MATERIALS, SETTING, METHODS: SC from subfertile couples and IVF pregnancies were identified as eligible at pregnancy diagnosis, and eligible SC pregnancies from fertile couples who attended our maternal-fetal unit were invited to participate at third trimester, being matched to the other groups by maternal age. Fetal echocardiography was performed at 29-34 weeks of pregnancy to assess cardiac structure and function, and results were adjusted by parental age, maternal smoking status, child's birth order, birthweight centile, gestational age, and estimated fetal weight at scan. MAIN RESULTS AND THE ROLE OF CHANCE: Parental age, ethnicity, BMI, and smoking exposure, median gestational age and estimated fetal weight were similar in all study groups. There were no significant differences in infertility duration or etiology between the subfertile and the IVF populations (TTP: subfertile median 35 months (interquartile range 20-48) versus IVF: 47 (25-61); P-value = 0.051). While both fertile and subfertile SC groups presented similar fetal cardiac results, IVF fetuses showed larger atria (right atria-to-heart ratio: IVF mean 18.9% (SD 3.4) versus subfertile 17.8% (3.5) versus fertile 17.6% (3.3); adjusted P-value < 0.001), more globular ventricles (right ventricular sphericity index: IVF 1.56 (0.25) versus subfertile 1.72 (0.26) versus fertile 1.72 (0.26); <0.001), and thicker myocardial walls (relative wall thickness: IVF 0.86 (0.22) versus subfertile 0.64 (0.13) versus fertile 0.64 (0.18); <0.001). Whereas SC fetuses from fertile and subfertile couples had preserved cardiac function, IVF fetuses showed signs of suboptimal systolic and diastolic function, with reduced tricuspid ring displacement (IVF 7.26 mm (1.07) versus subfertile 8.04 mm (1.18) versus fertile 7.89 mm (1.51); <0.001) and increased left myocardial performance index (IVF 0.49 (0.08) versus subfertile 0.45 (0.09) versus fertile 0.45 (0.10); <0.001). A sub-analysis including only unexplained infertility cases in subfertile SC and IVF groups showed similar results. LIMITATIONS, REASONS FOR CAUTION: The fetal cardiac changes reported here are subclinical, and most of the cardiovascular parameters were within normal ranges. Although echocardiographic changes are recognized as potential cardiovascular risk factors, their association with long-term cardiovascular disease remains to be demonstrated. WIDER IMPLICATIONS OF THE FINDINGS: Subfertility per se does not seem to be associated to fetal cardiac remodeling, which has been previously described in IVF fetuses. Future studies are warranted to further investigate other factors related to the observed fetal cardiac changes associated with ART. STUDY FUNDING/COMPETING INTEREST(S): This project has been partially funded with support from the Erasmus + Programme of the European Union (Framework Agreement number: 2013-0040). This publication reflects the views only of the author, and the Commission cannot be held responsible for any use, which may be made of the information contained therein. Additionally, the research leading to these results has received funding from 'la Caixa' Foundation under grant agreement LCF/PR/GN18/10310003, the Instituto de Salud Carlos III (PI15/00130, PI16/00861, PI17/00675, PI18/00073, INT21/00027)-co-funded by the European Union, Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK) and AGAUR 2017 SGR grant no 1531. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Atrial fibrillation: Epigenetic aspects and role of sodium-glucose cotransporter 2 inhibitors.

Atrial fibrillation (AF) is the most frequent arrhythmia and is associated with substantial morbidity and mortality. Pathophysiological aspects consist in the activation of pro-fibrotic signaling and Ca2+ handling abnormalities at atrial level. Structural and electrical remodeling creates a substrate for AF by triggering conduction abnormalities and cardiac arrhythmias. The care of AF patients focuses predominantly on anticoagulation, symptoms control and the management of risk factors and comorbidities. The goal of AF therapy points to restore sinus rhythm, re-establish atrioventricular synchrony and improve atrial contribution to the stroke volume. New layer of information to better comprehend AF pathophysiology, and identify targets for novel pharmacological interventions consists of the epigenetic phenomena including, among others, DNA methylation, histone modifications and noncoding RNAs. Moreover, the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in diabetic and non-diabetic patients at cardiovascular risk as well as emerging evidence on the ability of SGLT2i to modify epigenetic signature in cardiovascular diseases provide a solid background to investigate a possible role of this drug class in the onset and progression of AF. In this review, following a summary of pathophysiology and management, epigenetic mechanisms in AF and the potential of sodium-glucose SGLT2i in AF patients are discussed.

Cardiac remodeling after tricuspid valve repair in Ebstein's anomaly: a magnetic resonance study.

OBJECTIVES: We aimed to evaluate immediate and midterm cardiac remodeling after surgery by cardiac magnetic resonance (CMR) in Ebstein's anomaly (EA), and also to investigate preoperative predictors of right ventricular (RV) normalization. METHODS: We retrospectively analyzed CMR parameters of the whole heart in adult patients with EA before surgery, at discharge and follow-up. RESULTS: A total of 26 patients were included and performed CMR at 7 days (interquartile range, 3-13 days) before surgery. Immediate postoperative CMR was finished at discharge (median: 8 [7-9] days; n = 18) and follow-up CMR at 187 days (interquartile range, 167-356 days; n = 17). RV and right atrial (RA) volumes promptly decreased immediately after surgery and at follow-up (all p < 0.05). RV ejection fraction decreased significantly at discharge (p < 0.05) but recovered at follow-up (p = 0.18). However, RV global longitudinal strain and RA reservoir strain were significantly impaired immediately and midterm after surgery (all p < 0.05). Indexed left ventricular (LV) end-diastolic volume, stroke volume, as well as global longitudinal strain increased from preoperative to follow-up (all p < 0.05). Patients who achieved normalization of RV volumes after surgery had smaller severity index and RV and RA volumes and higher LV ejection fraction and RA reservoir strain at baseline than patients without RV normalization (all p < 0.05). CONCLUSIONS: Reverse biventricular remodeling took place in EA after tricuspid valve surgery. Tricuspid valve reconstruction should be performed before deterioration of RV volume overload and LV function to achieve reverse RV remodeling. Key Points • After removing the volume load of tricuspid regurgitation in Ebstein's anomaly, reverse remodeling was detected by CMR in both left and right heart at midterm follow-up. • Tricuspid valve reconstruction should be performed before deterioration of RV volume overload and LV function to achieve reverse RV remodeling.

Iron and atrial fibrillation: A review.

Atrial fibrillation (AF), one of the most common arrhythmias in clinical practice, is classified into paroxysmal, persistent, and permanent AF according to its duration. The development of AF is associated with increased cardiovascular morbidity and mortality. However, the exact etiology of this disease remains poorly understood. Recent studies found disorders of iron metabolism might be involved in the progression of AF. Abnormal iron metabolism in cardiomyocytes provides arrhythmogenic substrates through a variety of mechanisms, including calcium mishandling, ion channel remodeling, and oxidative stress overaction. Interestingly, in AF patients with iron overload, interventions on iron metabolism, such as iron chelators and ferroptosis inhibitors, has been shown to prevent AF via reducing ferroptosis. Herein, we review the possible mechanisms, consequences, and therapeutic implications of altered atrial iron handling for AF pathophysiology.

Reverse structural left atrial remodeling and atrial tachycardia in patients with repeat ablation for atrial fibrillation.

BACKGROUND: Catheter ablation has been evolved to a cornerstone in the therapy of atrial fibrillation (AF); however, atrial tachycardias (AT) after AF ablation are still an important issue. Besides the electrical recurrence of atrial tachyarrhythmia after ablation, left atrial (LA) remodeling has received attention as a consequence of AF. OBJECTIVE: The aim of this study is to evaluate predictors for AT recurrence and LA remodeling in patients with repeat AF ablation procedures. METHODS AND RESULTS: One hundred thirteen patients who underwent repeat AF ablation with 3D electro-anatomical mapping system were evaluated. Mean age was 63.1 ± 9.3 years, and 2.3 ± 0.5 ablation procedures were performed during a time period of 22 [IQR 7;48] months. Reverse structural LA remodeling (LA volume decreased more than 15%) was observed in 25 (22.1%) patients. LA volume index (LAVI) during first procedure was the only predictor for positive reverse structural LA remodeling (hazard ratio (HR): 1.03, 95% CI: 1.00-1.07, p = .036) in multivariate analysis. Fifty-nine (52.2%) patients experienced only AF and 54 (47.8%) patients AT after first procedure. Female gender (HR: 5.21, 95% CI: 1.66-18.08, p = .006), LAVI (HR: 1.06, 95% CI: 1.02-1.11, p = .008) and LA scar percentage (HR: 1.08, 95% CI: 1.02-1.17, p = .019) were independent significant predictors for AT recurrence in multivariate analysis. CONCLUSIONS: Reverse structural LA remodeling occurred in a quarter of patients with repeat ablation procedures for AF. Only larger LAVI during first procedure predicted reverse structural LA remodeling. Half of the patients experienced AT between first and last ablation procedure. Female gender, larger LAVI and larger scar area were significant predictors for AT after catheter ablation for AF.

Study of ECG-derived atrial fibrillatory rate for prediction of the outcome of cardioversion of short duration atrial fibrillation (CASAF).

AIMS: The present study aimed at testing the hypothesis that atrial fibrillatory rate (AFR) is predictive of sinus rhythm maintenance after electrical cardioversion. METHODS AND RESULTS: The study comprised 32 patients admitted for cardioversion of atrial fibrillation of short duration (mean duration 3.8 ± 7.7 days). AFR was estimated using frequency power spectrum analysis of QRST-cancelled ECG. At six-weeks follow-up 22% of the patients had relapsed to AF. The pre-cardioversion mean AFR of those was 332 ± 64 fpm compared to 378 ± 59 fpm among patients maintaining sinus rhythm (p = 0.12). CONCLUSION: AFR was not predictive of sinus rhythm maintenance in patients of short duration AF undergoing cardioversion. This is in stark contrast with the earlier reported findings. CLINICAL TRIAL REGISTRATION: NCT02112318 (http://www. CLINICALTRIALS: gov).

Asymmetric remodeling between the left and right atria in patients with advanced interatrial block and atrial fibrillation.

BACKGROUND: Advanced interatrial block (A-IAB) on electrocardiography (ECG) represents the conduction delay between the left and right atria. We investigated the association of A-IAB with left and right atrial (LA/RA) remodeling in patients with atrial fibrillation (AF). METHODS: We enrolled 74 patients who underwent ECG, cardiac computed tomography (CCT), and echocardiography during sinus rhythm before catheter ablation of AF. A-IAB was defined as P-wave duration ≥120 ms with a biphasic morphology in leads III and aVF or notched morphology in lead II. We compared the maximum and minimum LA/RA volume indices (max and min LAV/RAVI), LA/RA expansion index (LAEI/RAEI), and total, passive, and active LA/RA emptying fraction (LAEF/RAEF) between patients with and without A-IAB. RESULTS: Of the 74 patients (mean age, 64.3 ± 9.6 years), 35 (47%) showed A-IAB. Patients with A-IAB had a significantly higher likelihood of hypertension and left ventricular diastolic dysfunction than those without. Patients with A-IAB had significantly larger max (69.2 [60.7-79.7]mL/m2 vs. 60.9 [50.4-68.3]mL/m2, P < 0.01) and min (44.0 [37.2-52.1]mL/m2 vs. 34.1 [29.2-43.5]mL/m2, P < 0.01) LAVI than those without. The max and min RAVI were not significantly different between groups. LAEI (55.1 [48.2-78.5]% vs. 72.1 [57.8-84.8]%, P < 0.05), total LAEF (35.5 [32.5-44.0]% vs. 41.9 [36.6-45.9]%, P < 0.05), and passive LAEF (12.2 [10.0-14.4]% vs. 15.5 [11.2-19.6]%, P < 0.05) were significantly lower in patients with A-IAB than without. CONCLUSIONS: A-IAB was associated with LA, but not RA enlargement, in patients with AF. A-IAB may indicate LA functional remodeling in the reservoir and conduit phases.

Correlation between Serum Myosin Light Chain 4 Levels and Recurrence after Radiofrequency Ablation in Patients with Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia that is harmful to human health. This study aims to explore the relationship between myosin light chain 4 (MYL4) and AF recurrence after radiofrequency ablation (RFA). Patients with AF (n = 85) were enrolled, and healthy subjects (n = 90) with normal sinus rhythm and no previous history of AF were selected as controls. The serum levels of MYL4, transforming growth factor (TGF) -ß1, and procollagen type-I C-terminal propeptide (PICP) were determined. The correlation between MYL4 and atrial fibrosis remodeling indicators (TGF-ß1/PICP) and left atrial diameter (LAD) was analyzed. The influence of MYL4 on AF recurrence after RFA was evaluated, and the independent correlation between them was assessed. Patients with AF and the controls showed no significant differences in age, gender, body mass index, systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, white blood cell count, neutrophil/lymphocyte ratio, brain natriuretic peptide, and history of smoking, drinking, hypertension, and diabetes (P > 0.05), but with increased LAD in patients with AF (P < 0.01). Serum MYL4 level was reduced in patients with AF (0.6 ± 0.2) compared with that of controls (0.1 ± 0.6) (P < 0.01), and it was negatively correlated with TGF-ß1, PICP, and LAD (r = -0.2389, P < 0.05; r = -0.5174, P < 0.01; r = -0.3191; P < 0.01). Low levels of MYL4 increased the risk of AF recurrence after RFA (χ2 = 16.64; P < 0.0001). A low MYL4 level in patients with AF showed a poorer prognosis. Serum MYL4 level and AF type were independent risk factors affecting AF recurrence after RFA.