bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatiotemporal stability of digital twin-guided atrial fibrillation dominant frequency sites and the clinical outcome of catheter ablation
Authors: Hwang T , Kwon O , Lim B , Yang S , Kim M , Kim D , Park J , Yu H , Kim T , Uhm J , Joung B , Lee M , Pak H
Published: May 2024

Background

Although the dominant frequency (DF) may localize the reentrant drivers of atrial fibrillation (AF), its meandering nature makes it difficult to localize as an extra-pulmonary vein (extra-PV) target.

Purpose

We explored and quantified the spatiotemporal stability of DF by sophisticated digital-twin maps and the association with the rhythm outcome of clinical AF catheter ablation (AFCA).

Methods

We retrospectively examined the DF sites in the digital twin integrated by high-density electroanatomical maps (EAM) of 170 patients previously included in the CUVIA-AF2 trial (male 70.6%, 59.2±11.3 years old, 100% persistent AF). We monitored 34 seconds of virtual AF and analyzed DF sites in 10 different left atrial (LA) regions at 3 consecutive periods (6 seconds each after 16sec induction and blanking periods). The spatiotemporal stability index (STSI) was calculated to quantify mean DF's spatial and temporal variability. During protocol-based rhythm follow-up, we assessed the atrial arrhythmia recurrence rate by dividing patients into two groups based on STSI 0.75.

Results

During the simulation, 108 out of 170 (63.5%) patients obtained mean DF values in all three consecutive periods. There were 26 (24.1%) patients in the stable DF group (STSI ≥0.75, Stable group) and 82 (75.9%) patients in the unstable DF group (STSI <0.75, Unstable group). Although the proportion of patients with hypertension (73.1 vs. 47.6%, p=0.041) was higher and left ventricular end-diastole diameter (51.3±3.9 vs. 49.0±4.4 mm, p=0.020) was larger in the stable DF group than in the unstable DF group, other parameters, including LA size, LA voltage, or AF ablation targets, did not differ between two groups. During the median 19 [15-22] months follow-up, the atrial arrhythmia recurrence rate of the Stable group is higher than that of the Unstable group (log-rank p=0.031, HR = 2.06, CI [1.06-4.01])

Conclusions

We found that the temporally stable DF in EAM-integrated virtual AF, the potential extra-PV AF drivers, is a surrogate marker of the adverse rhythm outcome of AFCA. A prospective clinical trial targeting the spatiotemporally stable DF will be warranted.
Initial experience with a virtual atrial fibrillation clinic after pulmonary vein isolation
Authors: Reijrink-De Boer M , Wolsink I , Frenaij I , Beukema K F , Brouns B , Van Dijk V F , Liebregts M , Wijffels M C E F , Boersma L V A , Balt J C
Published: May 2024

Introduction

To detect recurrent atrial fibrillation (AF), a variety of methods are used, ranging from incidental electrocardiogram to rhythm monitoring with implantable loop recorders (ILRs). In clinical practice, routine use of ILRs is not feasible due to cost. Repeated (week)-Holters cause a considerable burden, both on patients and hospitals, and moreover are inadequate for detecting recurrent AF.

Purpose

To investigate whether remote monitoring (RM) is feasible in patients with AF after pulmonary vein isolation.

Methods

We set up a virtual AF clinic. Patients were equipped with a photopletysmography (PPG) application and asked to perform a recording when symptomatic. Recordings uploaded to the Hospital Electronic Patient Dossier and monitored by dedicated eNurses. The number of hospital contacts, hospital visits, electrocardiograms and Holter recordings were noted. Patient satisfaction and quality of life was measured by (validated) questionnaires. Comparisons were made with a historic control group from Jan-March 2019 with a traditional follow up of outpatient visits, electrocardiograms and Holters.

Results

157 patients were studied, 78 in the RM group and 79 in the control group. Mean age was 63 ± 10 years, 64% male. AF was paroxysmal in 68% of patients. Follow-up was 1 year and completed in all patients. In the RM group, patients performed 16±29 recordings/year. AF was detected in 37 (47%) patients on RM. While more planned remote contacts were performed in the RM group, significantly less planned and unplanned outpatient clinic visits, AF-related hospital admissions, and Holters took place. Patients report a high satisfaction with this form of remote monitoring.

Conclusions

A virtual AF clinic is feasible. When asked to record when symptomatic, patients perform few measurements. Compared to patients with a traditional follow-up, patients on PPG-based RM need fewer hospital visits and admissions, and undergo fewer Holters. Patient satisfaction with RM is high.
Digital patient care program following successful ablation or cardioversion of patients with atrial fibrillation
Authors: Von Degenfeld G , Langbein A , Boscheri A , Weyh P , Ziegler M O , Leber A , Schreier S , Spitzer S
Published: May 2024

Background

The current ESC guidelines on atrial fibrillation recommend the assessment of disease burden and the rigorous management of cardiovascular risk factors. A digital patient care program (Digital Health Program Atrial Fibrillation) was offered to patients following pulmonary vein isolation or cardioversion in cooperation with a major German statutory health insurer and a leading cardiology clinic. The 12 month program consists of the following functions: (1) self-recording of 1-channel-ECGs by patients with the possibility to receive short-term assessment by a teledoctor; (2) Patient education on health literacy, management of risk factors and lifestyle optimization via an App; (3) Monitoring of blood pressure and body weight; (4) Medication management via the App; und (5) videoconsultations on demand. When needed, medication was optimized by the teledoctors, or patients were referred to their family practice or cardiologists.

Results

an interim analysis of 72 patients that have participated in the first 6 months of the program showed:

1.) Over 20,000 ECGs were written, or a mean of approx. 1.5 ECGs/patient/day. Based on the teledoctor assessment of the ECGs and the videoconsultation over the platform recurring atrial fibrillation could be detected early and with high reliability, and patients could be advised.

2.) Figure A.: In patients with known, but insufficiently controlled arterial blood pressure at baseline (systolic blood pressure > 130 mmHg), blood pressure was reduced by 7.2 ±7.8 mmHg (mean ± std); n = 20.

3.) Figure B.: In obese patients at baseline (BMI ≥ 30) the body weight was reduced by 3.03 ±4.71 KG (mean ± std); n = 26.

Summary: The combination self-recorded ECGs with high adherence, the feedback by the App and the possibility to book a short-term teledoctor appointment made it possible to perform quick and reliable assessment and give concrete recommendations to the patient. Furthermore, the accompanying education program led to reduced blood pressure and body weight.

This systematic analysis of a real world digital patient care program indicates that the program is feasible and effective. These results need to be confirmed in a controlled study.Figure 1
Inhalation exposure to flavored electronic nicotine delivery systems (vaping) negatively impacts cardiac electrophysiology
Authors: Abou-Assali O , Ebner M , Chams J , Chang M , Zhang Y , Calcul L , Chidipi B , Noujaim S
Published: May 2024

Background

Electronic nicotine delivery systems (ENDS) heat "e-liquids" to generate "e-vapor", an inhalable aerosol. E-liquids contain nicotine and flavors in a solvent of 70% vegetable glycerin, 30% propylene glycol (70VG/30PG). Flavored ENDS are very popular among teens vapers, however, the possible cardiac electrophysiological harm of inhalation exposure to flavored ENDS are not fully understood.

Purpose

To test if inhalation exposure to e-liquids or their constituents compromises mitochondrial integrity, increases oxidative stress, and leads to cardiac electrophysiological toxicity.

Methods

Gas chromatography mass spectrometry (GC/MS), and flow cytometry, in-vivo programmed electrical stimulation (PES), and transmission electron microscopy (TEM) were used in atrial like HL-1 myocytes and in mice overexpressing the antioxidant mitochondrial catalase (MCAT) which underwent inhalation exposure to e-vapor.

Results

We compared the toxicity of e-vapor exposure to 30 differently flavored e-liquids (70VG/30PG, with 6 mg/ml nicotine) in HL-1 cells using annexinV flow cytometry. Most e-liquids were toxic. We then quantified the concentrations of major flavoring carbonyls (cinnamaldehyde, vanillin, ethyl-vanillin, maltol, and ethyl-maltol) in the 30 e-liquids using GC/MS. Toxicity of the e-liquids in HL-1 cells correlated with their flavoring carbonyls concentration. We assessed oxidative stress (OS) via CellROX flow cytometry in HL-1 cells exposed to vanilla flavored e-vapor. OS increased in exposed cells but this was blunted by N-acetylcycteine pretreatment. In-vivo inhalation exposure to e-vapor of vanilla flavored e-liquid with 6 mg/ml nicotine increased inducible ventricular tachycardia duration in WT but not in MCAT mice versus control. In TEM, mitochondrial perimeter was unaffected, but cristae thickness decreased in exposed WT, but not in exposed MCAT hearts versus controls. We then investigated whether adverse cardiac effects of vaping are due only to nicotine. Mice were exposed to the e-vapor of 70VG/30PG base alone or base plus vanillin WITHOUT nicotine. In telemetric ECG analysis of heart rate variability, exposure to base plus vanillin decreased parasympathetic indices more than exposure to base alone. In PES, the effective refractory periods of base alone and base plus vanillin groups tended to be shortened vs air controls. While exposure to base alone and to base plus vanillin significantly increased inducible ventricular tachycardia duration compared to air controls, the increase in the base plus vanillin group was more significant compared to that of base alone.

Conclusions

Inhalation exposure to flavored ENDS or to their NON-NICOTINE constituents negatively affects ventricular electrophysiology, possibly via adverse mitochondrial remodeling, and increased oxidative stress.
A new hiPSC-based viral expression system to study virus host-cell interaction in hiPSC-derived cardiomyocytes
Authors: Peischard S , Strutz-Seebohm N , Seebohm G
Published: May 2024

Coxsackievirus B3 (CVB3) belongs to the Picornaviridae family and is a member of the enterovirus genus. CVB3 is the most frequently detected pathogen in viral myocarditis, which leads to acute heart infections in 20-40% of cases and to dilated cardiomyopathy (DCM) in cases of prolonged viral persistence. Complex arrhythmias and sudden deaths due to CVB infections have also been reported, particularly in newborns and children. Observed arrhythmias include bradycardia, AV block and junctional ectopic tachycardia, suggesting that in addition to the functioning myocardium, the pacemaker cells and cardiac conduction system may also be impaired by CVB3 infection. The symptomatic phenotype is highly variable and depends on unclear host factors. It ranges from inconspicuous inflammation and rapid healing to acute congestive heart failure or viral persistence with progressive chronic disease. Despite the increasing and profound knowledge about viral myocarditis, it is still a challenge to identify further host factors that contribute to acute and chronic myocarditis, as science lacks sensitive and controllable disease models. The presented project shows the generation of a controlled, inducible virus-expressing hiPSC line that provides a solution for the beforementioned problems. The new human induced pluripotent stem cell line (hiPSC) i can be used to carry out virologic experiments in a controlled manner and without risk to the user. For this purpose, the modified and non-infectious genome of the enterovirus Coxsackievirus B3 (CVB3) is stably integrated into the genome of a wild-type hiPSC line. The CVB3 genome to be stably integrated was modified to prevent the formation of functional capsids by a DVP0 mutation. In addition, the 3'UTR and 5'UTR regions of the CVB3 genome were removed, which prevents uncontrolled self-replication of viral RNA. As a result, work with this CVB3DVP0-UTR genome is classified as S1 compliant. The expression of the CVB3DP0-UTR virus genome can be controlled by adding doxycycline to the cell culture medium by a TeT-On System. The transfected cells are then cultivated as clones and tested for virus expression. The dose-dependent CVB3DVP0 expression is verified using qPCR and FACS after 1 day of doxycycline application in the cell culture medium. Clones isolated and positively tested for CVB3 expression are used to carry out initial experiments on the interaction of the expressed viral proteins with the cell. Particular focus is placed on the induction of cell death, remodelling of the cytoskeleton and increase of reactive oxygen species (ROS) in mitochondria after CVB3DVP0-UTR induction in order to validate the cell system for application. Differentiation of the CVB3-expressing hiPSC-line into cardiomyocytes with subsequent virus induction results in the elevation of mitochondrial ROS, degradation of the cytoskeleton and arrhythmic behaviour of the cells.
The entrainment of action potential duration and contraction amplitude by recapitulation of respiratory sinus arrhythmia in isolated cardiac myocytes
Authors: Carpenter A , Pannell L M K , Fowler E D , Butler A S , Paton J F R , Hancox J C , James A F
Published: May 2024

Introduction

Respiratory sinus arrhythmia (RSA) is the oscillation of heart rate in phase with ventilation and represents the high frequency component of heart rate variability. RSA is prevalent in the young and the endurance-trained and its loss is considered a prognostic indicator for sudden cardiac death. The recapitulation of RSA improves cardiac function in animal models of heart failure1,2. However, the precise mechanisms by which RSA affects cardiac function are unknown.

Hypothesis: We examined the hypothesis that the recapitulation of RSA in isolated ventricular myocytes affects the stimulus interval-dependence of action potential duration (APD) and sarcomere shortening through mechanisms involving sarcoplasmic reticulum (SR) Ca2+ release.

Methods

Hearts were excised from adult male guinea pigs under general anaesthesia (140 mg/kg bodyweight euthatal, i.p.) and left ventricular myocytes isolated. Isolated myocytes were superfused with Tyrode’s solution for perforated patch whole-cell current clamp recording and action potentials and sarcomere length measured simultaneously. Sample sizes are presented as n/N (cell/animal number) and nested hierarchical analysis applied using a generalized linear mixed model (P<0.05).

Results

Pacing at a basic cycle length (CL, 350 ms) induced APD, Ca2+ transient amplitude (CaT) and sarcomere shortening alternans. The recapitulation of RSA through oscillatory pacing (OP), in which CL was set to 20% below and 20% above the corresponding basic CL in a 2-short, 2-long stimulus train, reduced the incidence of alternans. Furthermore, OP entrained APD, CaT and sarcomere shortening and this entrainment persisted in voltage clamp experiments with fixed APD. Using a three-step protocol to examine the dependence of APD and sarcomere shortening on both preceding (CLn-1) and anteceding (CLn-2) stimulus intervals, both APD and sarcomere shortening were found to depend directly on the preceding cycle length (CLn-1, P<0.001). In contrast, sarcomere shortening depended inversely on the anteceding CL (CLn-2, P<0.001; n/N = 24/4). Following treatment of the cells with caffeine (50 µM) to sensitise ryanodine receptors, the dependence of APD and sarcomere shortening on CLn-1 was markedly suppressed, and the inverse dependence of sarcomere shortening on CLn-2 was lost (P<0.001, n/N = 6/3). The effects of OP are akin to post-extrasystolic potentiation3 and mathematical simulation4 supports the involvement of changes in the sarcoplasmic reticulum Ca2+ content.

Conclusion

These data are consistent with an obligatory role for the SR in the entrainment of APD, CaT and sarcomere shortening and the suppression of alternans by the recapitulation of RSA. We hypothesise that recapitulation of RSA would be protective against ventricular tachyarrhythmia and further work is required to test this.
Right atrial endomysial fibrosis is associated with higher POAF-burden
Authors: Winters J , Kawczynski M J , Gilbers M D , Isaacs A , Zeemering S , Bidar E , Maesen B , Verheule S , Schotten U
Published: May 2024

Background

Atrial endomysial fibrosis, rather than overall connective tissue content, determines the complexity of conduction in human atrial fibrillation (AF). Moreover, the AF-specific blood biomarker BMP10 is associated with atrial endomysial fibrosis, but not overall connective tissue content. It is unclear whether pre-operative atrial endomysial fibrosis predicts post-operative AF (POAF) incidence and burden.

Objective

To determine the predictive value of atrial fibrosis for early and late POAF burden.

Methods

Patients with and without AF history were included in the RACE V tissue bank study (n=134). Post-operative rhythm was monitored continuously for 2.5 years with implantable loop recorders. Late POAF-burden was investigated following a 90-day blanking period. Left (n=89) and/or right (n=92) atrial appendage biopsies (LAA/RAA) were snap-frozen and histologically investigated following WGA-staining.

Results

Logistic regression, corrected for age, sex and AF history, showed that left (st.β = 0.54 [0.23-0.85], p=0.001) and right (st.β=0.35 [0.07-0.64], p=0.017) atrial endomysial fibrosis were associated with early POAF burden in the blanking period. Only right atrial endomysial fibrosis, however, predicted late POAF-burden (st.β=0.44 [-], p=0.009). Adjusted Cox proportional hazards analyses indicated that patients in the highest tertile of right atrial endomysial fibrosis, in particular, are at risk for late POAF (HR T3 vs T1: 2.47 [1.18-5.17], p=0.016, Fig 1). Overall connective tissue content in both atria was not associated with POAF-burden.

Conclusion

Patients with higher levels of right atrial endomysial fibrosis are at risk for developing late POAF with a higher POAF-burden.Figure 1
Bioenergetics and mitochondrial deregulation underlie self-sustained persistency of atrial fibrillation in an ovine model
Authors: Caluori G , Nattel S , Vaillant F , Charron S , Naud P , Guilloteau F , Claverol S , Abell E , Loyer V , Constantin M , Popa M A , Bernus O , Jais P , Dos Santos P , Pasdois P
Published: May 2024

Background

Atrial fibrillation (AF) often transitions from paroxysmal to more sustained forms in a 4-15/100 person-year range(1). It is well-recognized from both clinical and animal studies that some individuals undergo this transition much more readily than others, but the underlying mechanisms remain unclear.

Purpose

To identify potential differences in atrial bioenergetics between animals developing stable AF (AF-S) versus those resistant to this transition (AF-R) in a sheep AF-model.

Methods

AF was induced through repeated bursts of atrial tachystimulation (2). Stability of AF was monitored with telemetry. In-vivo electrophysiological remodeling was assessed via contact mapping. Metabolic and bioenergetic remodeling were evaluated using frozen left atrial appendage (LAA) tissues and isolated LAA mitochondria.

Results

AF-S sheep developed stable (>24-hour self-sustained) AF after 13 (range 5-22) days on average, whereas AF-R sheep failed to develop stable AF despite 120-day tachystimulation. Contact mapping and histological analysis revealed similar electro-anatomical remodeling in AF-S and AF-R groups, with the only significant difference observed in the decrease of activation time and conduction velocity in the AF-S atria. Both AF-S and AF-R animals displayed a notable increase in mitochondrial mass. Proteomic analysis showed significant differences in metabolism-related proteins and pathways between AF-S and AF-R, in particular concerning the anaplerotic supplementation of the tricarboxylic acid cycle at the level of α-ketoglutarate. Furthermore, compared to AF-R, AF-S LAA exhibited a 45% increase in succinate content, and a 23% decrease in ATP and Creatine Phosphate (PCr) content, suggesting a pathological metabolic alteration linked to a bioenergetic default. AF-S mitochondria presented abnormal succinate-oxidation, associated with a significant 20% decrease in ATP-synthesis rate, 22% increase in ROS-production, mitochondrial-membrane hyperpolarization, and decreased Complex I/II specific activity ratio. AF-S mitochondria alterations were prevented by complex I inhibitor S1QEL1.1, hinting to a participation of mitochondrial ROS into the mechanism of AF stabilization. In vivo acute intravenous perfusion of succinate in rats made them more susceptible to more frequent (OR 35 CI=[1.63-449.80]) and longer AF episodes upon treansesophageal stimulation; this vulnerability to AF was prevented by intraperitoneal pretreatment with SQEL1.1.

Conclusions

Resistance to AF-stabilization is associated with specific bioenergetic remodeling. These findings provide new mechanistic insights into AF-resistance and might open avenues for novel therapeutic strategies for AF-management.
In vivo KCNH2-suppression-replacement gene therapy attenuates the pathogenic phenotype in transgenic rabbits with short QT syndrome type 1
Authors: Nimani S , Bains S , Alerni N , Giammarino L , Louradour J , Horvath A , Beslac O , Tester D J , Christoforou N , Brunner M , Casoni D , Haeberlin A , Brooks G , Ackerman M J , Odening K E
Published: May 2024

Background

Short QT syndrome type 1 (SQT1) is a genetic channelopathy characterized by gain-of-function variants in the KCNH2-encoded potassium channel underlying the IKr current, leading to a pathologically shortened cardiac action potential duration (APD). Patients with SQT1 manifest shortening of the QT duration on 12-lead ECG and are prone to cardiac arrhythmias that can culminate in sudden cardiac death.

Purpose

To investigate the effect of a KCNH2-specific suppression-replacement (KCNH2-SupRep) gene therapy on the pathogenic phenotype in transgenic SQT1 rabbits.

Methods

A novel dual-component KCNH2-SupRep gene therapy was developed by combining a custom-designed KCNH2 shRNA (suppression) and an shRNA-immune (shIMM) KCNH2 cDNA (replacement) into AAV9. In vivo AAV9-mediated KCNH2-SupRep / sham treatment was performed by intra-aortic root injection of the KCNH2-SupRep AAV9 (1E10 vg/kg) / NaCl 0.9% during balloon occlusion using a Swan Ganz catheter. Three weeks after administration, 12-lead ECGs were assessed in adult transgenic SQT1 (KCNH2-N588K, gain of IKr due to impaired inactivation) and wild-type (WT) rabbits to determine the effect of KCNH2-SupRep / sham treatment on the rabbit’s QTc duration and QT index. Patch-clamp recordings were performed in isolated ventricular cardiomyocytes (CMs) to evaluate the effect of KCNH2-SupRep / sham treatment on the CM’s action potential duration at 90% repolarization (APD90).

Results

After in vivo AAV9-mediated KCNH2-SupRep gene therapy injection (1E10 vg/kg) in 7 SQT1 rabbits, QTc duration and QT index significantly increased in all SQT1 rabbits (QTc: untreated(UT)-SQT1: 153.2±3.8ms vs treated-SQT1: 166.5±4.6ms, p=0.0002, N=7 each; QTi: UT-SQT1: 92.5±1.9% vs treated-SQT1: 99.7±2.7%, p=0.0007, N=7 each), reaching a QT index of ~100% typically observed in WT rabbits. No such changes were observed in the sham-SQT1 rabbits. Furthermore, cardiomyocytes isolated from 7 SQT1 rabbits that received in vivo SupRep gene therapy demonstrated APD90 prolongation closer to WT rabbits compared to UT-SQT1 and sham-SQT1 rabbits (APD90: UT-SQT1: 314.2±11.9ms, WT: 404.5±13.8ms, treated-SQT1: 362.9±10.6ms; UT-SQT1 vs WT: p<0.0001; UT-SQT1 vs treated-SQT1: p=0.019; WT vs Treated-SQT1: p=0.031). In line with these observations, first IKr measurements demonstrate smaller IKr currents in SupRep-SQT1 than in sham-SQT1 CMs.

Conclusion

In vivo KCNH2-SupRep gene therapy normalizes the pathologically shortened QTc duration and QT index in transgenic SQT1 rabbits. Moreover, KCNH2-SupRep treatment prolongs APD90 in SQT1 compared to UT-SQT1 and sham-SQT1 reaching levels closer to WT.
Angiotensin II-mediated oxidative stress increased the vulnerability of ventricular arrhythmia in cardiac hypertrophy rabbit model, which is suppressed by CaMKII inhibitor
Authors: Lee Y , Bae H J , Shin D G , Jung B C
Published: May 2024

Objectives

Angiotensin system is a major cause of heart failure and arrhythmia. Despite a lack of direct evidence that oxidative stress causes ventricular arrhythmia, reversal of oxidative stress is considered a plausible therapy. This study evaluated the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor could suppress arrhythmia in cardiac hypertrophy rabbit model.

Methods

Angiotensin II (Ang II) or saline was administrated for 2 weeks via osmotic minipumps implanted subcutaneously in the midclavicular region. Hearts were perfused, mapped optically to analyze action potential durations (APD), and restitution kinetics, and tested for VF vulnerability. The intracellular calcium dynamics were measured in cardiomyocyte treated with Ang II (10 ng/ml) for 1 hours.

Results

In Ang II rabbit groups, 2(30%) rabbits died and had ventricular arrhythmia and hearts had enlarged left ventricle, longer APD90, slower conduction velocity (CV; P<0.01 versus control) and higher levels of transcripts for CaMKII, PLB, RyR2 (P<0.05 versus control). N-acetylcysteine treatment reversed the transcripts for APD90 and CV (P<0.01). Programmed stimulation triggered VF in Ang II (n=5/6) and Ang II + saline (n=4/6), but not in control (n=0/10, P<0.01). Cardiomyocyte induced with Ang II showed increased spontaneous Ca2+ release (Ca2+ Wave Frequency; 1.0±0.0 vs. 5.1±0.5, p=0.001, Ca2+ Amplitude; 1.0±0.0 vs. 1.3±0.1, p=0.001) with control. CaMKII inhibitor reversed the change of Ca2+.

Conclusion

The Ang II group had an increased incidence of arrhythmia caused by increased phosphorylation of Ca2+ handling proteins. These changes were partially reversed by CaMKII inhibition.
Genetic characterization of drug-induced long QT syndrome in a large prospective cohort
Authors: Campos Garcia B , Rodriguez Santiago B , Salazar Blanco J , Hernandez Ontiveros H , Avila Parcet A , Garcia Hernando V , Carceller Sindreu M , Juanes Borrego A , Rodriguez Font E , Alonso Martin C , Mendez Zurita F , Moreno Weidmann Z , Vinolas Prat X , Guerra Ramos J M
Published: May 2024

Introduction

Drug-induced long QT syndrome (DI-LQTS) is a clinical entity with a poorly defined etiopathogenesis.

Purpose

The objective of the study was to determine the genetic basis of a prospective cohort of patients with DI-LQTS in the setting of a tertiary hospital center.

Methods

Prospective observational study with consecutive inclusion of patients with the diagnosis of DI-LQTS according to standard criteria, in a tertiary hospital, between 2018 and 2022. A genetic study was performed through massive DNA sequencing to identify variants in known genes associated with cardiopathy, arrhythmogenic and cardiomyopathy.

Results

86 patients (age 65±15 years, 59% men) were included. The mean corrected QT interval (QTc) of the entire cohort was 543±56 ms. The drugs associated with QTc interval prolongation were: psychotropics 51%, antiarrhythmics 38%, anesthetics 30%, antibiotics 16%, antineoplastics 5%, others 4%. Twenty-one patients (24%) presented with ventricular arrhythmias at the time of drug-induced QTc prolongation: 10 (12%) ventricular fibrillation, 7 (8%) sustained ventricular tachycardia, 3 (3%) non-sustained ventricular tachycardia, 1 (1%) frequent ventricular premature beats.

Genetic information was obtained in 83 (97%) patients. 17 pathogenic mutations associated with heart disease were identified in 15 (18%) patients: 4 (5%) patients with 5 mutations in ion channel genes (KCNE1, KCNE1B, KCNH2, RYR1, RYR2), and 12 (14%) patients with 12 mutations in genes associated with cardiomyopathy (NF1, PKD2, ABCC6, TTN, FHOD3, MYO6, COL11A1, CCDC40, CRELD1, COL4A1). Two patients had 2 pathogenic mutations each, one of them with both mutations associated with channelopathy, and another with a mutation associated with channelopathy and a second mutation related to cardiomyopathy. Only 1 patient carrying a pathogenic mutation related to cardiomyopathy had a clear phenotype, while in 3 carrier patients there was a history of transient systolic dysfunction, 2 due to tachycardiocardiopathy and 1 due to peripartum cardiomyopathy. The identification of a pathogenic mutation was not related to significant differences in QTc interval prolongation (544±63 vs 542±55 ms) or risk of ventricular arrhythmias (26% vs 24%).

Conclusions

The genetic basis of drug-induced long QT syndrome is essentially different from that of the congenital form of the disease. The identification of pathogenic mutations in genes associated with cardiomyopathy is relatively frequent, while those associated with ion channel genes are uncommon.
CineECG analysis of body surface potential mapping performed in preclinical and clinical plakophilin-2-variant carriers
Authors: Van Der Schaaf I , Kloosterman M , Loh P , Van Dam P M
Published: May 2024

Background/introduction

Pathogenic variation of the plakophilin-2 (PKP2) gene is associated with arrhythmogenic cardiomyopathy (ACM). Disease manifestation in PKP2-pathogenic variant (PV) carriers differs greatly. Early detection of disease is crucial and could be of benefit in the risk stratification of this population. 67-lead body surface potential mapping (BSPM) could offer more insight into subtle electrical abnormalities. CineECG is a novel tool which can provide an estimation of the average pathway of ventricular activation based on the BSPM-signals, and could be of added value in the detection of electrical abnormalities.

Purpose

This study aimed to analyze 67-lead BSPM data with CineECG to ascertain the electrical activation pathway in PKP2-PV carriers and to compare these to the normal CineECG.

Methods

Ten PKP2-PV carriers underwent 67-lead BSPM. Six carriers were without definite ACM diagnosis (preclinical); no Task Force Criteria (TFC) were met apart from the identification of the pathogenic PKP2-variant. The other four carriers were all diagnosed with definite ACM (symptomatic). The average location and direction of ventricular activation was determined with CineECG, resulting in a CineECG trajectory throughout the ventricles. These results were compared to the normal CineECG trajectory, which was established in a previous study with normal ECG’s from the PTB-XL database. A CineECG trajectory that deviated more than 15% from the normal trajectory was considered abnormal. Additionally, to further determine the added diagnostic value of BSPM and CineECG beyond the standard 12-lead ECG, the 12-lead ECG’s were evaluated for abnormalities by three different ECG-experts.

Results

Expert evaluation of the 12-lead ECG showed that all preclinical PKP2-PV carriers had a normal ECG (no TFC and no other abnormalities such as abnormal electrical heart axis, pathological Q-waves or low voltage). In the symptomatic carriers, all ECG’s showed either presence of TFC or conduction abnormalities.

Of the ten PKP2-PV carriers, eight exhibited an abnormal CineECG trajectory. In the preclinical group, four out of six carriers had an abnormal activation trajectory, while all symptomatic carriers had an abnormal CineECG trajectory.

Conclusions

Through CineECG analysis of 67-lead BSPM, abnormal ventricular activation was identified in the majority of PKP2-PV carriers. Notably, abnormal activation was observed in four out of six preclinical PKP2-PV carriers while the standard 12-lead ECG showed no abnormalities. Future research in a larger group, which also includes follow-up data, is warranted to determine whether these results are an indication of early signs of disease.Figure 1
Diagnostic yield of cardiac monitors in patients with suspected arrhythmias: systematic literature review and network meta-analysis
Authors: Parikh P , Lukyanov V , Medic G , Wadhwa M
Published: May 2024

Objective

To demonstrate the diagnostic yield (DY) across cardiac rhythm monitors stratified by monitoring duration for symptomatic patients with suspected cardiac arrhythmias (palpitations, dizziness, syncope, presyncope, lightheadedness).

Methods

PubMed, Embase, and Scopus were searched to identify published randomized and observational studies between January 1, 2000, and November 28th, 2021. DY data were extracted for comparative studies. The DY of cardiac monitors in these patients was reviewed for Any Arrhythmia, Clinically Relevant Arrhythmia, Explained Episodes (symptomatic and clinically relevant), New Onset Atrial Fibrillation, and Symptomatic Events. Clinically Relevant Arrhythmia was defined by the study and included atrial fibrillation, atrial flutter, atrial tachycardia, other SVT, VT, pause, and bradycardia. Patients who had a history of prior stroke or transient ischemic attack were excluded. Network meta-analysis (NMA) was used to pool estimates. Cardiac monitoring duration was categorized into the following 3 timeframes: 3 days or less (≤3 d), greater than 3 days to less than 30 days (>3 d), and 30 days or greater (≥ 30 d).

Results

Inclusion and exclusion criteria identified a pooled population of 1696 patients in 6 comparative studies, 2 Randomized Controlled Trials (RCTs) and 4 non-RCTs (Figure 1). NMA results for comparative studies show that monitoring durations of >3 d and ≥30 d provided significant better DY than ≤3 d (Table 1). The odds ratio for DY of >3 d as compared to ≤3 d was 5.75 (95% CI 2.05-19.38) in patients with Any Arrhythmias, 5.99 (95% CI 2.10 - 7.79) in patients with Clinically Relevant Arrhythmias, 10.22 (95% CI 0.61 - 4343.00) in patients with Explained Episodes, and 2.74 (95% CI 1.12 - 7.53) in patients with New Onset Atrial Fibrillation. As only a single study provided results on Symptomatic Events, NMA was not possible for this measure. The odds ratio for DY of >3 d as compared to ≥30 d was 0.02 (95% CI 0.00 - 0.15) in patients with Any Arrhythmias, 0.03 (95% CI 0.00 - 0.10) in patients with Clinically Relevant Arrhythmias, 0.04 (95% CI 0.01 - 0.13) in patients with Explained Episodes, and 0.17 (95% CI 0.03 - 0.66) in patients with diagnosis of New Onset Atrial Fibrillation.

Conclusion

NMA indicates that >3 d and ≥30 d provide significantly better DY than ≤3 d for identifying Any Arrhythmia, Clinically Relevant Arrhythmia, and New Onset AF. Despite favorable odds ratios for ≥30 d over >3 d, these values were associated with uncertainty due to the limited studies available for monitoring durations of ≥30 d. Overall, in patients experiencing symptoms of palpitations, dizziness, syncope, and without prior stroke or transient ischemic arrest, >3 d of monitoring improved DY compared with shorter monitoring durations.Figure 1.Prisma Flow DiagramTable 1.Diagnostic Yield Comparison.
Continuing evaluation of atrial fibrillation detection after cryptogenic stroke: one-year findings from a multi-center study with confirm Rx ICM
Authors: Quartieri F Q , Baek Y S , Kim T H , Honma K , Shin S Y , Feng L , Lee K , Grammatico A , Morimoto M
Published: May 2024

Background

The detection of atrial fibrillation (AF) after a cryptogenic stroke (CS) carries crucial therapeutic implications. While clinical trials have meticulously explored the incidence of AF in CS patients, real-world data on this topic remain relatively sparse. In this study, we aimed to assess the incidence of AF among patients with cryptogenic stroke, who underwent the implantation of an insertable cardiac monitor (ICM). The abstract reports the interim results from the CS sub-study of the Smart Registry.

Methods

A prospective, single-arm, multi-center registry was conducted to identify AF in patients with cryptogenic stroke using the Confirm R ICM. Inclusion criteria comprised participants aged 40 years or older who had experienced cryptogenic strokes within a 90-day window. Prior to enrollment, comprehensive diagnostic assessments were performed to meticulously rule out all potential sources of embolism, in accordance with the minimal standards of the American and European Guidelines. At each follow-up visit, expert electrophysiologists reviewed and adjudicated ICM detected AF episodes. The primary endpoint was the cumulative incidence of true device-detected AF (lasting more than 30 seconds) at 6 months. Kaplan-Meier curves were employed to assess the cumulative incidence of true device-detected AF through 12 months.

Results

In our study, 117 patients were enrolled across 19 global sites from September 2021 to August 31, 2023. Kaplan-Meier analysis revealed a 21.3% probability (confidence interval (CI): 14.5%, 30.7%) of true AF episodes lasting more than 30 seconds at 6 months, increasing to 31.0% (CI: 22.0%, 42.5%) at 12 months. Similar results were observed in episodes lasting over 120 seconds at both 6 months (20.7%) and 12 months (30.5%). In average, 14.4 true AF episodes per patient were detected per year. The median time from implantation to AF detection (> 30 seconds) was 31.5 days (interquartile range, 7 to 191).

Conclusion

Our ongoing study illustrates the effectiveness of the Confirm Rx ICM in detecting atrial fibrillation after cryptogenic stroke. These results confirm the diagnostics value of long-term continuous AF monitoring in cryptogenic stroke patients.
Photoplethysmography recordings preceding onset atrial fibrillation show a higher heart rate variability - a TeleCheck-AF subanalysis
Authors: Hillmann H , Hermans A , Gawalko M , Mueller-Leisse J , Betz K , Van Der Velden R , Pluymaekers N , Evens S , De Cooman T , Sultan A , Gruwez H , Hendriks J , Manninger M , Linz D , Duncker D
Published: May 2024

Background

An increased heart rate variability (HRV), mostly assessed by 12-lead electrocardiogram (ECG) or long-term Holter monitoring, can be associated with the onset of atrial fibrillation (AF). Data evaluating HRV measurements using digital devices, especially those using photoplethysmography (PPG), in patients at risk for AF are sparse. In this analysis, we aimed to assess if hand-held-based non-continuous PPG measurements can provide short-term HRV to predict AF.

Methods

Patients from the TeleCheck-AF project with at least one PPG measurement in AF and one measurement in sinus rhythm (SR) were analyzed. Briefly, patients were provided with a PPG-based heart rate/rhythm monitoring smartphone app. They were instructed to record a PPG measurements three times daily and in case of symptoms for seven consecutive days. Short-term HRV using root mean square of successive normal-to-normal interval differences (RMSSD) was calculated in recordings in SR and compared between those not preceding and preceding an episode of AF (figure 1).

Results

Overall, 136 patients [56.3% men, median age 66 (59; 72) years] were included in the analysis. Median total number of recordings per patient was 24 (19; 30) including 4 (2;7) AF episodes per 1 week recording period. RMSSD was significantly higher in PPG measurements preceding an AF episode than in PPG measurements not preceding an AF episode [42.5 (33.2;70.7)ms vs. 41.1 (32.4;54.7)ms; p<0.001]. Between-group comparison revealed no significant difference for gender, age, previous ablation or betablocker therapy (p=0.824; p=0.484; p=0.519 and p=0.624, respectively).

Conclusion

Short-term HRV based on RMSSD, assessed by digital hand-held devices is significantly higher in PPG recordings preceding an AF episode than in measurements not preceding a consecutive AF episode. Whether PPG-recording derived short-term HRV can help to predict onset-AF warrants further study in larger populations.

Figure 1: Patient example and exemplary analysis scheme, depicting the total number of recordings (n=14). HRV of recordings in sinus rhythm (SR) not preceding an episode of atrial fibrillation (AF) (A; grey circles) were compared to recordings preceding a consecutive AF episode (B; blue circles).Figure 1
Efficacy of smart device heart rhythm monitoring to detect spontaneous conversion to sinus rhythm in patients scheduled for electric cardioversion of atrial fibrillation. Kardiover Study
Authors: Benezet Mazuecos J , Alonso P , Lozano J M , Salas J , Gonzalez O , Rodriguez-Manero M , Narvaez I , Barrio I , Iglesias J A
Published: May 2024

Introduction

the management of patients with recent-onset atrial fibrillation (AF) is to achieve sinus rhythm (SR) by electrical or pharmacological cardioversion (CV). However, frequently SR is spontaneously restored, making scheduled admission and/or transesophageal echocardiogram (TEE) unnecessary and therefore causing misutilization of healthcare resources. Emerging medical technology has allowed for monitoring of heart rhythm abnormalities.

Objective

A prospective multicenter study was designed to evaluate the diagnostic ability of a smart device ECG monitor to detect spontaneous conversion to SR in AF patients, preventing unnecessary admission and providing an earlier management.

Methods

A prospective multicenter study was designed including patients with first diagnosed, paroxysmal or persistent AF scheduled for ambulatory electrical cardioversion in cardiology departments of 7 hospitals of Spain. Patients were asked to submit ECG recordings to a central Corelab daily, twice a day and whenever they present symptoms, until cardioversion (spontaneous or scheduled) and a week afterwards. Whenever a spontaneous conversion to SR was detected, investigators were contacted to confirm SR and abort admission, likewise when AF recurrence after cardioversion was detected. Patients’ satisfaction was evaluated using a test for perceived utility and value, convenience, and accessibility.

Results

A total of 62 patients were enrolled (age 62±10 years). Baseline characteristics of the study population are described in the Table. Fifteen patients (24%) did not undergo CV as they showed spontaneous conversion to SR. Among 47 patients admitted for CV, it was successful in 41 (87%). One patient aborted CV because of atrial thrombus on TEE. During follow up after conversion to SR (spontaneous or electrical), recurrences of AF occurred in 20 of 56 patients (36%) correctly detected by the devices. At the end of the follow-up 41 of 56 patients (73%) remained in SR. Due to the early detection of spontaneous conversion to SR, a total of 15 admissions and 9 TEE were prevented and these resources used for other patients. Adherence was high with a rate of ECG transmission over 80% in 56 patients (90%). Perceived satisfaction was also high with an overall punctuation of 9 over 10 in the patient’s feedback test.

Conclusion

Digital devices for heart rhythm monitoring can optimize the management of AF patients scheduled for CV, avoiding unnecessary admissions and providing a more rational use of healthcare resources.Table
Non-invasive assessment of the ventricular tachycardia isthmus during sinus rhythm
Authors: Reventos-Presmanes J , Pellicer B , Serrano J , Invers-Rubio E , Regany M , Borras R , Tolosana J M , Guasch E , Guichard J B , Vazquez S , Guillem M S , Porta-Sanchez A , Mont L , Climent A M , Roca-Luque I
Published: May 2024

Background

The ablation of ventricular tachycardias (VT) presents significant challenges due to the complex and time-consuming approaches involved in identifying arrhythmogenic regions. Combining non-invasive electrocardiographic imaging (ECGI) with endocardial mapping could potentially enhance the efficacy of interventions.

Objective

To evaluate the capability of ECGI in guiding operators towards areas of VT isthmuses during sinus rhythm.

Methods

Patients with scar-related VT, confirmed by late gadolinium enhancement cardiac magnetic resonance, were prospectively enrolled. We compared the areas of slowed conduction identified by ECGI with the VT sustaining regions identified endocardially. Simultaneous Electroanatomical Mapping (EAM) and ECGI mapping were performed during VT ablation procedures. In patients in whom a hemodynamically stable VT was maintained, the reentry circuit was mapped endocardially, and the ablation target was identified. The left ventricle was segmented into 9 regions, categorized as either VT-isthmus or non-VT isthmus based on EAM findings. Prior to ablation, local activation times (LAT) and conduction velocity (CV) ECGI sinus maps were computed. Slow conduction was quantified non-invasively by computing different ECGI metrics per region, including the mean and the standard deviation (SD) of LAT and CV, the regional Total Activation Time (rTAT) – time span between the earliest and latest activated nodes–, and the Slow Conduction Velocity (SCV) – the percentage of nodes where velocity falls below 60 cm/s -.

Results

The study included 20 consecutive patients with ischemic cardiomyopathy who were referred for VT ablation. A total of 21 regions linked to the VT isthmus were identified endocardially in 17 patients (age: 66.1±8.8 years, 94.1% male, left ventricular ejection fraction: 26.4±7.3%). Figure 1 illustrates the correlation between the VT circuit and the ECGI sinus map in two patients with extensive left ventricular fibrosis. ECGI metrics related to VT isthmuses exhibited a higher standard deviation in both LAT (18.1±2.0 vs 9.8±1.2 ms; p=0.001), and CV (50.4±4.7 vs 37.1±2.8 cm/s; p=0.011), and a greater percentage of nodes with slowed conduction (13.7±2.7 vs 7.4±1.6 %; p=0.029), compared to non-VT isthmus regions, Figure 2. Multivariate logistic regression analysis revealed that SD-LAT was the strongest predictor of VT isthmus localization.

Conclusion

ECGI has demonstrated the capability to pinpoint slowed conduction areas responsible for VT in sinus rhythm, showing promise in planning and guiding VT ablation strategies. This advancement paves the way for further research into using this non-invasive tool to improve risk stratification methods for ventricular arrhythmias.