Desmoplakin mutations in cardiac fibroblasts cause TGFß1-mediated pathological fibrogenesis in desmoplakin cardiomyopathy via beclin-1 regulation.

Background: Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy (ACM). Among ACM, pathogenic desmoplakin ( DSP ) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction. DSP variants are also linked to other fibrotic diseases. Whether DSP plays any role in pathological fibrosis remain unknown. Methods: Mesenchymal stromal cells (MSCs) are resident fibroblast-like cells that are responsible for fibrogenesis in most organs, including hearts. We first used unbiased genome-wide analyses to generate cardiac fibroblasts-like, induced pluripotent stem cell-derived MSCs from normal donors and ACM patients with DSP mutations. We then studied the fibrogenic responses of cardiac MSCs to transforming growth factor beta-1 (TGF-ß1) using Western/Co-IP, autophagy assay, gene knockdowns/over-expressions, genomic analyses, mouse DSP knockdown models, immunostaining, and qPCR. Results: TGFß1 induced excessive accumulations of vimentin (VIM)/fibrillar collagens, and over-activated fibrotic genes in DSP- mutant MSCs when compared to normal MSCs. In normal MSCs, VIMs bind to wild-type DSP during normal fibrogenesis after TGFß1. DSP- mutant MSCs exhibited a haplo-insufficient phenotype with increased DSP-unbound VIMs that sequestered beclin-1 (BECN1) from activating autophagy and caveolin-1 (CAV1)-mediated endocytosis. Decreased autophagy caused collagen accumulations and diminished CAV1 endocytosis resulted in abnormal CAV1 plaque formation that over-activated fibrotic genes [ COL1A1, COL3A1, and fibronectin ( FN )] via heightened p38 activities after TGFß1. Genome-wide analysis and DSP knockdown in mouse fibroblasts confirmed this novel role of DSP mutations in pathological fibrosis. Overexpression of VIM-binding domains of DSP could suppress pathological fibrosis by increasing collagen autophagic degradation and decreasing fibrotic gene expressions. Conclusions: Our data reveal that DSP deficiency in MSCs/fibroblasts leads to exaggerated fibrogenesis in DSP-cardiomyopathy by decreasing BECN1 availability for autophagy and CAV1-endocytosis. Overexpression of VIM binding domains of DSP could be a new strategy to treat pathological fibrosis.

Relationship Between Insurance Status and Receipt of Cardiac Tests and Procedures During Hospitalization: A Cross-Sectional Study.

BACKGROUND: Prior analyses of the relationship between insurance status and receipt of tests and procedures have yielded conflicting findings and have focused on outpatient care. We sought to characterize the relationship between primary payer and diagnostic and procedural intensity, comparing rates of cardiac tests and procedures in matched hospitalized Medicaid and commercially insured patients. METHODS AND RESULTS: We created a propensity score-matched sample of Medicaid and commercially insured adults hospitalized at all acute care hospitals in Kentucky, Maryland, New Jersey, and North Carolina from 2016 to 2018. The main outcome was receipt of a cardiac test or procedure: echocardiogram, stress test, cardiac catheterization (elective, in acute coronary syndrome, in ST-segment-elevation myocardial infarction), and pacemaker and subcutaneous cardiac rhythm monitor implantation. Generalized linear models with a hospital-specific indicator variable were estimated to calculate the adjusted odds of a commercially insured patient receiving a given test or procedure relative to a Medicaid patient. Models controlled for race, ethnicity, and zip code income quartile. Commercially insured patients were more likely to receive each cardiac test or procedure, with adjusted odds ratios ranging from 1.16 (95% CI, 1.00-1.34) for cardiac catheterization in ST-segment-elevation myocardial infarction to 1.40 (95% CI, 1.27-1.54) for pacemaker implantation. CONCLUSIONS: Hospitalized commercially insured patients were more likely to undergo a range of cardiac tests and procedures, some of which may represent low-value care. This may be driven by a combination of physician and patient preference, financial incentives, and social determinants of health. Our findings support the need for hospital payment models focused on increasing value and reducing inequities.

Anatomical Ablation of the Atrioventricular Node.

Background: Atrioventricular (AV) conduction ablation has been achieved by targeting the area of penetration of the conduction axis as defined by recording a His bundle potential. Ablation of the His bundle may reduce the possibility of a robust junctional escape rhythm. It was hypothesised that specific AV nodal ablation is feasible and safe. Methods: The anatomical position of the AV node in relation to the site of penetration of the conduction axis was identified as described in dissections and histological sections of human hearts. Radiofrequency (RF) ablation was accomplished based on the anatomical criteria. Results: Specific anatomical ablation of the AV node was attempted in 72 patients. Successful AV nodal ablation was accomplished in 63 patients (87.5%), following 60 minutes (IQR 50-70 minutes) of procedure time, 3.4 minutes (IQR 2.4-5.5 minutes) of fluoroscopy time, and delivery of 4 (IQR 3-6) RF lesions. An escape rhythm was present in 45 patients (71%), and the QRS complex was similar to that before ablation in all 45 patients. Atropine was administered in six patients after the 10-min waiting period and did not result in restoration of conduction. In nine patients, AV conduction could not be interrupted, and AV block was achieved with ablation of the His after delivery of 12 (IQR 8-15) RF lesions. No cases of sudden death were encountered, and all patients had persistent AV block during a median 10.5 months (IQR 5-14 months) of follow-up. Conclusion: Anatomical ablation of the AV node is feasible and safe, and results in an escape rhythm similar to that before ablation.

Optimizing the Distribution of Ablation Lesions to Prevent Postablation Atrial Tachycardia: A Personalized Digital-Twin Study.

BACKGROUND: Although targeting atrial fibrillation (AF) drivers and substrates has been used as an effective adjunctive ablation strategy for patients with persistent AF (PsAF), it can result in iatrogenic scar-related atrial tachycardia (iAT) requiring additional ablation. Personalized atrial digital twins (DTs) have been used preprocedurally to devise ablation targeting that eliminate the fibrotic substrate arrhythmogenic propensity and could potentially be used to predict and prevent postablation iAT. OBJECTIVES: In this study, the authors sought to explore possible alternative configurations of ablation lesions that could prevent iAT occurrence with the use of biatrial DTs of prospectively enrolled PsAF patients. METHODS: Biatrial DTs were generated from late gadolinium enhancement-magnetic resonance images of 37 consecutive PsAF patients, and the fibrotic substrate locations in the DT capable of sustaining reentries were determined. These locations were ablated in DTs by representing a single compound region of ablation with normal power (SSA), and postablation iAT occurrence was determined. At locations of iAT, ablation at the same DT target was repeated, but applying multiple lesions of reduced-strength (MRA) instead of SSA. RESULTS: Eighty-three locations in the fibrotic substrates of 28 personalized biatrial DTs were capable of sustaining reentries and were thus targeted for SSA ablation. Of these ablations, 45 resulted in iAT. Repeating the ablation at these targets with MRA instead of SSA resulted in the prevention of iAT occurrence at 15 locations (18% reduction in the rate of iAT occurrence). CONCLUSIONS: Personalized atrial DTs enable preprocedure prediction of iAT occurrence after ablation in the fibrotic substrate. It also suggests MRA could be a potential strategy for preventing postablation AT.

Assessing the arrhythmogenic propensity of fibrotic substrate using digital twins to inform a mechanisms-based atrial fibrillation ablation strategy.

Atrial fibrillation (AF), the most common heart rhythm disorder, may cause stroke and heart failure. For patients with persistent AF with fibrosis proliferation, the standard AF treatment-pulmonary vein isolation-has poor outcomes, necessitating redo procedures, owing to insufficient understanding of what constitutes good targets in fibrotic substrates. Here we present a prospective clinical and personalized digital twin study that characterizes the arrhythmogenic properties of persistent AF substrates and uncovers locations possessing rotor-attracting capabilities. Among these, a portion needs to be ablated to render the substrate not inducible for rotors, but the rest (37%) lose rotor-attracting capabilities when another location is ablated. Leveraging digital twin mechanistic insights, we suggest ablation targets that eliminate arrhythmia propensity with minimum lesions while also minimizing the risk of iatrogenic tachycardia and AF recurrence. Our findings provide further evidence regarding the appropriate substrate ablation targets in persistent AF, opening the door for effective strategies to mitigate patients' AF burden.

Effects of Glucagon-Like Peptide-1 Receptor Agonists on Atrial Fibrillation Recurrence After Catheter Ablation.

BACKGROUND: Relationship between glucagon-like peptide-1 receptor agonist (GLP-1 RA) use prior to atrial fibrillation (AF) ablation and subsequent AF recurrence is not well-understood. OBJECTIVES: This study investigated the effects of GLP-1 RA use within 1 year before ablation and its association with AF recurrence and associated outcomes. METHODS: The TriNetX research database was used to identify patients aged ≥18 years undergoing AF ablation (2014-2023). Patients were categorized into 2 groups, and propensity score matching (1:1) between preablation GLP-1 RA users and nonusers was performed based on demographics, comorbidities, body mass index, laboratory tests, AF subtype, and medications. Primary outcome was composite of cardioversion, new antiarrhythmic drug therapy, or repeat AF ablation after a 3-month blanking period following the index ablation. Additional outcomes included ischemic stroke, all-cause hospitalization, and mortality during 12-month follow-up period. RESULTS: After 1:1 propensity score matching, the study cohort comprised 1,625 GLP-1 RA users and 1,625 matched GLP-1 RA nonusers. Preablation GLP-1 RA therapy was not associated with a lower risk of cardioversion, new AAD therapy, and repeat AF ablation after the index procedure (HR: 1.04 [95% CI: 0.92-1.19]; log-rank P = 0.51). Furthermore, the risk of ischemic stroke, all-cause hospitalization, and mortality during the 12-month follow-up period did not differ between the 2 groups. CONCLUSIONS: These findings suggest that preprocedural use of GLP-1 RAs is not associated with a reduced risk of AF recurrence or associated adverse outcomes following ablation, and underscore the need for future research to determine whether these agents improve outcome in AF patients.

High-resolution mapping of the circuit of typical atrioventricular nodal reentrant tachycardia.

BACKGROUND: Recent anatomic and electrophysiologic evidence has provided new insight into the anatomic substrate. Previous reports on electroanatomic mapping (EAM) of the circuit of atrioventricular nodal reentrant tachycardia (AVNRT) have been limited by mapping only the triangle of Koch on the right side of the septum and by the use of conventional mapping tools. The objectives are to obtain comprehensive high-resolution mapping of typical AVNRT and to investigate the role of the atrioventricular ring tissues in the circuit. METHODS: We employed EAM with the use of novel modules and algorithms for studying typical AVNRT from the right and the left sides of the septum. RESULTS: We performed extensive mapping of both the atrial septum and the septal vestibule of the tricuspid valve during typical AVNRT in 9 (6 females) patients, aged 49.6 ± 12.1 years. In two of these, left septal mapping was also obtained through the aorta. The earliest initial activation was variable, emanating from the superior or medial septum. The impulse consistently appeared below the orifice of the coronary sinus, at the site where its inferoanterior margin merged with the septal vestibule of the tricuspid valve at its entrance to the right atrium. It then returned to the initial activation site, presumably through the septal vestibular myocardium. The left septal activation area corresponded to that recorded on the right side. CONCLUSIONS: Typical AVNRT uses a circuit confined within the pyramid of Koch from the AV node to the septal isthmus, involving the myocardial walls of the pyramidal space.

Pericarditis After Catheter Ablation for Atrial Fibrillation: Predictors and Outcomes.

BACKGROUND: Catheter ablation is a mainstay of atrial fibrillation (AF) treatment. Acute pericarditis after ablation is 1 of the frequently observed complications. There is a significant lack of data on the incidence and predictors of postablation pericarditis. OBJECTIVES: This study examines the incidence, characteristics, and predictors of pericarditis after AF ablation. METHODS: Patients undergoing AF ablation from January 1, 2016, to March 31, 2022, at Johns Hopkins were prospectively enrolled in an AF ablation registry. A clinical diagnosis of acute pericarditis was established in accordance with 2015 European Society of Cardiology guidelines by the presence of at least 2 of the following characteristics: pleuritic chest pain, friction rub, typical electrocardiographic changes, or pericardial effusion within 3 months after the ablation procedure. RESULTS: Of 1,540 patients who underwent AF ablation, 57 patients (3.7%) developed acute pericarditis. Baseline clinical characteristics including age, sex, and body mass index were comparable between the pericarditis and nonpericarditis groups. The median time to symptom onset was 1 day. Electrocardiographic changes were observed in 34 (59.6%) patients, pericardial effusion developed in 7 (12%) patients, and the mean duration of medical treatment was 7 days (25th-75th percentile: 3-14 days). Most pericarditis cases were treated medically with disease-specific nonsteroidal anti-inflammatory drugs (100%) and colchicine (81%). Effusion with tamponade necessitating pericardiocentesis was observed in 4 (7%) patients. Radiofrequency (RF) ablation was performed in 869 (58.6%) patients in the nonpericarditis group and 39 (68.4%) patients with pericarditis; cryoballoon ablation was performed in 486 (32.8%) patients in the nonpericarditis group and 11 (19.3%) patients with pericarditis. Multivariable logistic regression analysis identified RF ablation (OR: 2.09; 95% CI: 1.07-4.08; P = 0.03) as an independent predictor of acute pericarditis after AF ablation, whereas age per unit increase was associated with a decreased risk (OR: 0.97; 95% CI: 0.95-0.995; P = 0.02). CONCLUSIONS: The incidence of acute pericarditis after catheter ablation in our study population was 3.7%. RF ablation and younger age were independent risk factors for postablation acute pericarditis.

2023 HRS/APHRS/LAHRS guideline on cardiac physiologic pacing for the avoidance and mitigation of heart failure.

Cardiac physiologic pacing (CPP), encompassing cardiac resynchronization therapy (CRT) and conduction system pacing (CSP), has emerged as a pacing therapy strategy that may mitigate or prevent the development of heart failure (HF) in patients with ventricular dyssynchrony or pacing-induced cardiomyopathy. This clinical practice guideline is intended to provide guidance on indications for CRT for HF therapy and CPP in patients with pacemaker indications or HF, patient selection, pre-procedure evaluation and preparation, implant procedure management, follow-up evaluation and optimization of CPP response, and use in pediatric populations. Gaps in knowledge, pointing to new directions for future research, are also identified.

Sex-based differences in safety and efficacy of catheter ablation for atrial fibrillation.

BACKGROUND: Studies have identified significant sex-based differences and disparities in the clinical presentation and treatment of atrial fibrillation (AF). Studies have shown women are less likely to be referred for catheter ablation, are older at the time of ablation, and are more likely to have recurrence after ablation. However, in most studies investigating AF ablation outcomes, the female cohorts were relatively small. The impact of sex on the outcome and safety of ablation procedures is still unclear. OBJECTIVE: To investigate sex-based differences in outcomes and complications after AF catheter ablation, with a significant female cohort METHOD: In this retrospective study, patients undergoing AF ablation from January 1, 2014, to March 31, 2021, were included. We investigated clinical characteristics, duration and progression of AF, number of EP appointments from diagnosis to ablation, procedural data, and procedure complications. RESULTS: Total of 1346 patients underwent first catheter ablation for AF during this period, including 896 (66.5%) male and 450 (33.4%) female patients. Female patients were older at the time of ablation (66.2 vs. 62.4 years; p < .001). Women had higher CHA2 DS2 -VASc (congestive heart failure, hypertension, age, diabetes, stroke, vascular disease, sex category) scores (3 vs. 2; p < .001) than men, expectedly, as the female sex warrants an additional point. 25.3% female patients had PersAF at the time of diagnosis versus 35.3% male patients (p < .001). At the time of ablation, 31.8% female patients had PersAF as compared to 43.1% male patients (p < .001), indicating progression of PAF to PersAF in both sexes. Women tried more AADs than men before ablation (1.13 vs. 0.98; p = .002). Male and female patients had no statistically significant difference in (a) arrhythmia recurrence at 1-year post ablation (27.7% vs. 30%; p = .38) or (b) procedural complication rate (1.8% vs. 3.1%; p = .56). CONCLUSION: Female patients were older and had higher CHA2 DS2 -VASc scores compared to males at the time of AF ablation. Women tried more AADs than men before ablation. One-year arrhythmia recurrence rates and procedural complications were similar in both sexes. No sex-based differences were observed in safety and efficacy of ablation.

2023 HRS/APHRS/LAHRS guideline on cardiac physiologic pacing for the avoidance and mitigation of heart failure.

Cardiac physiologic pacing (CPP), encompassing cardiac resynchronization therapy (CRT) and conduction system pacing (CSP), has emerged as a pacing therapy strategy that may mitigate or prevent the development of heart failure (HF) in patients with ventricular dyssynchrony or pacing-induced cardiomyopathy. This clinical practice guideline is intended to provide guidance on indications for CRT for HF therapy and CPP in patients with pacemaker indications or HF, patient selection, pre-procedure evaluation and preparation, implant procedure management, follow-up evaluation and optimization of CPP response, and use in pediatric populations. Gaps in knowledge, pointing to new directions for future research, are also identified.

Initial Findings From the National Cardiovascular Data Registry of Atrial Fibrillation Ablation Procedures.

BACKGROUND: The National Cardiovascular Data Registry (NCDR) AFib Ablation Registry was created to assess real-world prevalence, demographic characteristics, procedural management, and outcomes of patients undergoing atrial fibrillation (AF) ablation procedures. OBJECTIVES: The goal of this study was to characterize the patient, hospital, and physician characteristics and in-hospital outcomes related to AF ablation in the first 5 years of the registry. METHODS: This paper describes the AFib Ablation Registry structure and governance, outcome assessment processes, data quality, and data collection processes. The characteristics of the patient population, hospitals, and in-hospital outcomes are also described. RESULTS: A total of 76,219 patients were included in the registry between January 2016 and December 2020 (mean age 65.5 ± 10.3 years, 65.2% male, 55.8% paroxysmal AF, mean CHA2DS2-VASc score 2.7 ± 1.6) treated by 708 physicians in 162 hospitals. Successful isolation of all pulmonary veins was achieved in 92.4% of patients. The prevalence of any complication during procedural admission was 2.50% and major complication was 0.9%, including significant bradycardia in 0.47%, heart failure in 0.47%, and pericardial effusion requiring intervention in 0.44%. Hospitalization >1 day occurred in 11.8% of patients, and in-hospital death was rare (n = 41 [0.05%]). CONCLUSIONS: The NCDR AFib Ablation Registry is the largest multicenter, prospective cohort study of patients undergoing catheter ablation worldwide. Results in the first 5 years showed that successful pulmonary vein isolation is achieved in the majority of patients, with a low rate of complications. Future studies from the registry will assess practice trends, evaluate treatment patterns associated with different patient outcomes, and support development of evidence-based guidelines.

Growth Differentiation Factor-15 Predicts Mortality and Heart Failure Exacerbation But Not Ventricular Arrhythmias in Patients With Cardiomyopathy.

Background Heart failure (HF) has been increasing in prevalence, and a need exists for biomarkers with improved predictive and prognostic ability. GDF-15 (growth differentiation factor-15) is a novel biomarker associated with HF mortality, but no serial studies of GDF-15 have been conducted. This study aimed to investigate the association between GDF-15 levels over time and the occurrence of ventricular arrhythmias, HF hospitalizations, and all-cause mortality. Methods and Results We used a retrospective case-control design to analyze 148 patients with ischemic and nonischemic cardiomyopathies and primary prevention implantable cardioverter-defibrillator (ICD) from the PROSe-ICD (Prospective Observational Study of the ICD in Sudden Cardiac Death Prevention) cohort. Patients had blood drawn every 6 months and after each appropriate ICD therapy and were followed for a median follow-up of 4.6 years, between 2005 to 2019. We compared serum GDF-15 levels within ±90 days of an event among those with a ventricular tachycardia/fibrillation event requiring ICD therapies and those hospitalized for decompensated HF. A comparator/control group comprised patients with GDF-15 levels available during 2-year follow-up periods without events. Median follow-up was 4.6 years in the 148 patients studied (mean age 58±12, 27% women). The HF cohort had greater median GDF-15 values within 90 days (1797 pg/mL) and 30 days (2039 pg/mL) compared with the control group (1062 pg/mL, both P<0.0001). No difference was found between the ventricular tachycardia/fibrillation subgroup within 90 days (1173 pg/mL, P=0.60) or 30 days (1173 pg/mL, P=0.78) and the control group. GDF-15 was also significantly predictive of mortality (hazard ratio, 3.17 [95% CI, 2.33-4.30]). Conclusions GDF-15 levels are associated with HF hospitalization and mortality but not ventricular arrhythmic events.

Quantitative assessment of the fast pathway in atrioventricular nodal reentrant tachycardia.

BACKGROUND: Mathematical modelling has allowed calculation of the length of the slow and fast pathways in typical atrioventricular nodal reentrant tachycardia (AVNRT). The length of the slow pathway has been correlated with the measured length of the right inferior extension in human histologic specimens, but no histology data exist about the fast pathway. METHODS: In preparations of cadaveric human hearts, the AV node was identified, and the site of the fast pathway was projected according to both existing evidence and results of our electroanatomic mapping. This permitted measurement of the length of the fast pathway as a limb of the tachycardia circuit. RESULTS: Measurements of the length of the projected area of the fast pathway on histology specimens were performed in 8 hearts. The estimated length of the fast pathway was 39.6 ± 5.8 mm (range: 30.4-45.9 mm). These numbers are comparable to those produced by mathematical calculations of the length of the fast pathway. CONCLUSIONS: Typical AVNRT uses a circuit from the AV node to the septal isthmus of an average size of 5-6 cm, confined within the pyramid of Koch.