Antiarrhythmic Research Articles

Long-term follow-up after catheter ablation of atrial fibrillation and atrial tachycardia in patients with pulmonary hypertension

Abstract Introduction Catheter ablation of atrial fibrillation and atrial tachycardia (AF / AT) is established treatment in selected population. Only limited data, including long-term results, exist in patients with pulmonary hypertension (PH). Recently published prospective multicentric trial showed that more extensive radiofrequency catheter ablation of the bi-atrial arrhythmogenic substrate instead of clinical arrhythmia ablation alone is not beneficial in terms of arrhythmia recurrence in patients with AF / AT and PH. Now, we present the results of an extended, long-term follow-up from one of the study centres. Methods Patients with combined post- and pre-capillary or isolated pre-capillary PH and AF / AT indicated to catheter ablation were enrolled and randomised 1:1 into two parallel treatment arms. Patients underwent either clinical arrhythmia ablation only (Limited ablation group) or clinical arrhythmia plus substrate-based ablation (Extended ablation group). The primary endpoint was arrhythmia recurrence >30 s without antiarrhythmic drugs after the 3-month blanking period. Results A total of 52 patients (median age 71 years (IQR 62-75); 27 males) were enrolled. The presumable clinical arrhythmia was AF in 20 and AT in 32 patients, including typical AFL in 22 patients. Limited and extended ablation group included 28 and 24 patients, respectively. During the extended follow-up period of median 31 (IQR: 18; 46) months, the primary endpoint occurred in 17 patients (71 %) vs. 13 patients (46 %) in the Extended vs. Limited ablation group (p = 0.096). In parallel, overall mortality was comparable between groups (9 [38 %] vs. 11 [39 %]). Only 2 patients had recurrence of AFL during the extended follow-up. However, new different arrhythmia was documented in another 7 patients after the AFL ablation. Conclusion In PH patients, recurrence of AF / AT after a catheter ablation is frequent and the recurrence rate increases with the duration of follow-up. Ablation strategy seems to have no impact on arrhythmia free survival. Patients with typical atrial flutter have significantly higher chance to maintain sinus rhythm after a catheter ablation compared to AF or other AT.

Combined class I and class III antiarrhythmic effects of sotagliflozin - insights from heterologous expressions systems and atrial cardiomyocytes

Abstract Background The demand for more effective treatment options for atrial fibrillation (AF), the most common sustained arrhythmia, is driven by its direct impact on morbidity and mortality. Current therapies, such as antiarrhythmic drugs and catheter ablation, are limited by suboptimal efficacy and adverse effects or periinterventional complications. Therefore, safe and effective treatment of AF remains a major unmet clinical need. Sodium-glucose cotransporter (SGLT) inhibitors have shown promise in reducing the incidence of AF in large cardiovascular endpoint trials. However, the exact mechanisms of action remain unclear. While only two SGLT2 inhibitors are approved and clinically used in Europe, sotagliflozin, which inhibits both SGLT1 and SGLT2, might also have potential for the treatment of AF. Purpose This study aims to elucidate the effects of sotagliflozin on cardiac action potential formation. This understanding could optimise its clinical use, identify new targets for the treatment of atrial fibrillation and ultimately improve the quality of life of patients suffering from AF. Methods The effects of sotagliflozin on cardiac ionic currents were assessed using two-electrode voltage clamp measurements of several sodium and potassium channels heterologously expressed in Xenopus laevis oocytes. Subsequently, ascending concentrations of sotagliflozin were administered to isolated human atrial cardiomyocytes during patch-clamp measurements to investigate its effect on atrial action potential morphology. Results At a concentration of 100 µM, sotagliflozin showed significant inhibitory effects on three out of ten ion channels tested: NaV1.5 sodium channel current was reduced by 22,3 % %, hERG and KV4.3 potassium currents were reduced by 30,4 % and 22,5 % respectively. Patch-clamp experiments, performed on isolated human atrial cardiomyocytes showed a dose-dependent reduction in upstroke velocity and action potential amplitude by 20,8 % and 13,8 % at a concentration of 20 µM, reflecting class-I-antiarrhythmic effects. Furthermore, a prolongation of AP duration measured at 50 % (APD50) and 90 % (APD90) of repolarization by 57,7 % and 27,9 % at a sotagliflozin concentration of 20 µM was noted, implying additional class-III-antiarrhythmic action. Conclusions Sotagliflozin exerts direct inhibitory effects on heterologously expressed NaV1.5, hERG and KV4.3 channels, resulting in a reduction in upstroke velocity and action potential amplitude, as well as a prolongation of APD50 and APD90 levels in isolated human atrial cardiomyocytes. These results extend the pharmacological profile of sotagliflozin and suggest a potential role for the clinical use of combined SGLT1/SGLT2 inhibitors in the treatment of AF.

Impact of paroxysmal atrial fibrillation ablation on cardiac sympathetic nervous system: a prospective stratified randomized comparative study in patients with and without heart failure

Abstract Background Catheter ablation of atrial fibrillation (AF) might influence the cardiac sympathetic nervous system (CSNS). We sought to investigate the impact of AF ablation with 2nd generation cryoballoon catheter (CB) and contact force sensing radiofrequency ablation catheter (RF) on CSNS and the association of this effect with early AF recurrence in patients with and without heart failure (HF), using cardiac iodine-123-metaiodobenzylguanidine (MIBG) scintigraphy. Methods and Results One hundred sixty-five paroxysmal AF patients who were scheduled for ablation were enrolled. All patients were categorized into two groups: one with HF (n=31), defined as left ventricular ejection fraction ≤ 40% or previous history of hospitalization for worsening HF, and the other without HF (n=134). They were then randomly assigned to CB (17 patients with HF and 68 without HF) or RF (14 with HF and 66 without HF). MIBG scintigraphy was performed at baseline and 3 months post-ablation and the washout rate (WR) was measured. There were no significant changes in WR from baseline to 3 months after RF and CB ablation (28.7±18.6% to 27.9±16.7% in RF and 29.4±16.7% to 30.5±16.4% in CB). WR decreased more in patients with HF at 3 months after ablation than without HF, while WR significantly increased in patients without HF and there was a significant interaction in WR change between with or without HF (interaction p<0.001). WR change from the baseline to 3 months after ablation (dWR) was not significantly different between CB and RF, irrespectively of the HF presence. In the blanking period of 3 months after ablation, early AF recurrence (EAR) was observed in 37 (22%) patients with no antiarrhythmic drugs (17(21%) patients in RF and 20(24%) in CB). dWR was significantly greater in patients with than without EAR (4.0±14.1% vs -0.9±11.0%, p=0.027). Higher dWR (≥ 6.9% (AUC 0.644, 95%CI [0.535-0.753]) by ROC curve analysis) was independently associated with EAR (adjusted odds ratio = 4.15, 95%CI [1.87-9.22], p<0.001, adjusted for age, sex, and left atrial diameter). Conclusions Irrespectively of CB and RF, AF ablation might reduce adrenergic tone in patients with HF, while it might induce more adrenergic tone in patients without HF. Excessive adrenergic tone might be associated with early AF recurrence.WR changes before and after ablationdWR in patients with or without HF

The CNP analogue vosoritide reduces arrhythmia in diabetic cardiomyopathy via cGMP-dependent PDE2 stimulation on cellular and organ level

Abstract Background Detrimental arrhythmia occurs frequently in patients with diabetic cardiomyopathy (DiabCM), but safe and effective therapies are limited. Diabetes-associated neuropathological alterations increase the sympathetic tone, leading to hyperactivation of β-adrenoceptor-mediated cAMP signalling in cardiomyocytes (CM). Increased activity of deleterious cAMP-dependent kinases causes pro-arrhythmic dysregulation of intracellular Ca2+ homeostasis. Phosphodiesterases (PDE) can reduce cAMP levels. Exceptionally, the cAMP-hydrolysing activity of PDE2 can be cGMP-dependently increased by C-type natriuretic peptide (CNP). Thus, the CNP analogue vosoritide (approved for the treatment of achondroplasia) might mediate this cGMP/cAMP crosstalk, reducing arrhythmia. Purpose Here, we aim to study whether the cGMP-dependent activation of PDE2 by vosoritide (VO) is sufficient to reduce arrhythmia and arrhythmogenic triggers in DiabCM. Methods Diabetes was induced by 5 consecutive injections of streptozotocin (50 mg/kg) in control (WT) mice and mice with a CM-specific PDE2 knockout (KO). All experiments were performed 5 weeks later. Cardiac function was characterised by echocardiography. Primary ventricular CM were isolated to assess protein expression and phosphorylation levels by Western blot (WB) and cAMP levels by ELISA. Patch-clamp and Ca2+ imaging experiments were used to investigate pro-arrhythmic triggers. Arrhythmic events were quantified in ex vivo perfused hearts after ischaemia-reperfusion (I/R) injury. Results Compared to healthy controls, diabetic animals showed impaired systolic function with a ~9 % reduction in ejection fraction. The significant increase in E/E’ ratio by ~34 % indicated a diastolic dysfunction. Interestingly, the cardiac function was further worsened in diabetic PDE2 KO. WB analysis revealed upregulation of the CNP receptor NPR-B and PDE2 in diabetic CM and altered regulation of proteins involved in cAMP-dependent Ca2+ cycling such as protein kinase A, Ca2+/calmodulin-dependent kinase II and phospholamban. Interestingly, VO significantly reduced isoprenaline (Iso)-induced cAMP levels in diabetic CM. The effect of VO was prevented by specific PDE2 inhibition with BAY 60-7550 (BAY). Furthermore, VO was able to reduce the Iso-induced increase in L-type Ca2+ current, whereas BAY or genetic PDE2 deletion counteracted this effect. Accordingly, VO significantly decreased the Iso-triggered Ca2+ spark frequency by ~40 %. Concomitant PDE2 inhibition or PDE2 KO prevented this anti-arrhythmic effect. Finally, ECG analysis revealed that VO clearly reduced arrhythmia development after I/R in ex vivo perfused diabetic hearts via PDE2 activation. Conclusion Our data indicate that vosoritide-induced PDE2 stimulation may attenuate abnormal cardiac Ca2+ cycling and thereby reduce arrhythmia in diabetic hearts. Thus, vosoritide may be repurposed as a novel anti-arrhythmic drug in DiabCM.

No reimbursement policy and implantable loop recorders in the real world setting

Abstract Background Prolonged heart rhythm evaluation is indicated in patients with suspected arrhythmias. Routine electrocardiographic Holter monitoring is often associated with poor adherence and may lead to little to no clinically relevant findings. Implantable loop recorders (ILRs) are small, subcutaneous cardiac devices providing semi-continuous electrocardiographic recording. Despite strong evidence supporting their effectiveness, ILRs are yet to be fully reimbursed by the National Health Fund- the public insurer in Poland. Purpose We aimed to investigate the feasibility, as well as the diagnostic yield of ILRs in a real world setting of a tertiary cardiovascular center. Methods We retrospectively analyzed data of consecutive patients admitted for ILR implantation between March 2013 nad November 2023. Hospitalization and procedural costs were covered by the clinic's statutory and hospital funds and not by the National Health Fund, the public payer. All patients were remotely monitored for device follow-up. Baseline demographic characteristics, as well as data regarding observation period, clinical outcomes and safety were collected. Results Data for 51 ILR implants in 50 patients was assessed. Insertion success rate was 100% on first attempt with no complications. Mean age was 54,43 ±18,56 years old. 52,94% of patients were female. Coronary artery disease was present in 21,57% patients, hypertension in 50,98%, diabetes in 13,73%. The indications for ILR implantation were unexplained syncope (n= 42; 82,35%), palpitations (n= 16; 31,37%), ischemic stroke of unknown origin (n= 6; 11,76%), monitoring of ventricular arrhythmia (n= 2; 3,92%). Mean time between occurrence of first symptoms and ILR implantation was 80,86 ±112,95 months. Mean monitoring period was 1067,62 ±668,89 days. 23 (45,1%) patients had an actionable event detected. Mean time to clinical outcome was 190,34 ±514,85 days. Based on the obtained recordings, in 13 (25,49%) patients a cardiac electronic device was implanted and 6 (11,76%) underwent an electrophysiological procedure. Time to intervention was 435,17 ± 542,9 days and 338,8 ± 273,44 days, respectively. ILR prompted medication modification in 14 (27,45%) patients. Antiarrhythmic drugs were modified in 6 (11,76%) patients. Oral anticoagulation was initiated in 3 (5,88%) patients. Mean time to any pharmacotherapy modification was 654,68 ± 604,32 days. Skin infections occurred in 2 patients, leading to early device removal. Conclusions This is the first study to present a comprehensive evaluation of ILR patients in Poland, along with a substantial observation period. We report a high prevalence of treatable cardiac conditions in patients with previous unsuccessful diagnostic work up. In the light of the upcoming favourable changes in governmental healthcare policy, demonstrating evidence supporting ILR application in everyday clinical practice is crucial for advocating their wider utilization and reimbursement.

Risk and causes of hospital admission in patients with atrial fibrillation on treatment with oral anticoagulants

Abstract Background Atrial fibrillation (AF) is associated with an increased risk of hospitalisation, although the main reasons for hospital admission and the role of antiarrhythmic drugs are not clarified. Objective The aim of our study was to assess the incidence rate and the factors associated with all-cause, cardiovascular and AF-related causes of hospitalisation in patients suffering from AF. Methods This is a prospective single-centre ongoing study (ATHERO-AF cohort) which included 2782 patients affected by non-valvular AF on oral anticoagulants. The primary endpoints were all-cause, cardiovascular and AF-related hospitalisation. Cardiac hospitalizations were defined as (non-AF) arrhythmias, acute coronary syndromes, heart failure (HF), systemic embolism, hypertensive urgency, vascular/cardiac surgery. The AF-related hospitalisation was defined as a recurrence of AF in paroxysmal pattern or as a high-rate symptomatic AF episode in persistent/permanent patterns. Multivariable Cox proportional hazards regression analysis was used to calculate the hazard ratio (HR) with 95% Confidence interval (95%CI) for each factor in relation to risk of hospitalisation. Results Overall, 43.5% of patients were women with a mean age of 74.6±9.1year. Patients were followed for a mean of 31±26.8 months. We registered 1205 (12.1%/year) hospitalisations for any reason, 533 (5.7%/year) for cardiovascular causes and 180 (2.0%/year) were AF-related hospitalisations (Central illustration). Among the anti-arrhythmic drug use, we highlighted that flecainide and propafenone were associated with AF-related hospitalisations in paroxysmal and in persistent/permanent patterns (HR 1.861, 95%CI 1.116-3.101 and HR 1.947, 95%CI 1.069-3.548, respectively). Amiodarone (HR 3.012, 95%CI 1.835-4.943) and verapamil or diltiazem (HR 2.067, 95%CI 1.117-3.825) were associated with an increased risk of AF-related hospitalisations in persistent/permanent AF pattern. Furthermore, cancer was associated (HR 1.802, 95%CI 1.057-3.070) with increased risk of hospitalisation due to AF-related causes. Conversely, beta-blockers and digoxin were not associated with increased risk of hospital admission. Conclusions Hospitalisations of patients with AF are frequent for both cardiovascular and non-cardiovascular causes. Among the AF-related ones, the use of antiarrhythmic drugs emerged as associated with increased risk of hospitalisations, hypothesizing their poor effect in preventing AF episodes. For these reasons, we suggest carefully considering their use, reserving them for symptomatic patients with frequent AF recurrences.Central Illustration

Low levels of apolipoprotein M are associated with increased risk of ventricular arrhythmias

Abstract Background Ventricular arrhythmia (VA) is a frequent cause of sudden cardiac death (SCD). Treatment to prevent SCD includes device therapy with implantable cardioverter defibrillator (ICD). Although the electrophysiology underlying VA have been described, the molecular understanding of VA risk remains unclear. Purpose To identify proteins that are associated with higher and lower risk of VA. Methods SMASH 1 Study was a prospective observational study of 490 patients treated with ICD. The plasma proteome was analyzed with the Olink Explore 384 Cardiometabolic platform at study inclusion, and patients were followed for mean 3.1± 0.7 years. VA events were defined as adjudicated ventricular fibrillation or sustained ventricular tachycardia registered from ICD recordings and clinical events were recorded from electronic health records. Protein concentrations were quantified relatively as normalized protein expression on a log2-transformed concentrations where a large number represents higher protein level in the sample. Results The mean age was 66±12 years, 83% were male and 51% had a primary prevention ICD-indication. Episode(s) of VA occurred in 137 patients (28%) during follow-up. In total, 353 distinct proteins were successfully analyzed in all patients. Among these, high B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels were associated with a higher risk of VA, while Apolipoprotein M (APOM) was the only protein significantly associated with a lower risk of VA after multiple testing using Benjamini-Hochberg correction (Figure, Panel A). After adjusting for age, sex, body mass index, coronary artery disease, heart failure, renal function, left ventricular ejection fraction and antiarrhythmic medication, only low APOM levels remained significantly associated with VA: HR 0.51 (95%CI 0.32-0.79] per log unit increase, p=0.003. Patients in the lowest quartile of APOM had a particularly high risk of incident VA: HR 2.26 (95%CI 1.60-3.19), p=3.61x10-6, compared to quartile 2-4 (Figure, Panel B). High APOM levels were also associated with a lower risk of HF hospitalizations (HR 0.25 [95%CI 0.16-0.40], p<0.001) and all-cause mortality (HR 0.36 [95%CI 0.22-0.60], p<0.001), and these associations remained significant in adjusted models. Conclusions Low levels of APOM are associated with a greater risk of incident VA, independently of established risk factors. Low APOM also predicted risk of HF hospitalizations and mortality in our cohort, which suggest protective cardiovascular effects of APOM. Figure: Association of individual proteomic measures with risk of ventricular arrhythmias (VA).A:Volcano plots of the associations of individual plasma proteins with incident VA. The dotted line represents the significance level at false discovery rate <0.05 and the red dots are significant proteins after multiple testing using Benjamini-Hochberg correction.B: Risk of VA by quartile of Apolipoprotein M.

A prospective analysis of the efficacy and safety of ethacizine during premature atrial contractions and premature ventricular contractions

Abstract Background Ethacizine, a class Ic antiarrhythmic agent, is prescribed for managing severe or refractory supraventricular and ventricular arrhythmias, including premature atrial (PACs) and ventricular contractions (PVCs). Despite its use, there is a lack of substantial research exploring the therapeutic effects of ethacizine at present. Purpose The study evaluated the efficacy and safety of ethacizine in addressing PACs and PVCs, in cases where other antiarrhythmic medications proved ineffective. Methods We performed a prospective analysis of ethacizine treatment (50 mg. b.i.d.) for early (30-45 days) and late periods (150-210 days), in male (n=58; 59.2%) and female (n=40; 40.8%) patients aged ≥ 18 years (18-72 y.o; mean age 45 years), with 46 cases of PACs and 52 cases of PVCs, who had previously been treated with another antiarrhythmic medication (bisoprolol, metoprolol, sotalol, verapamil, amiodarone, or propafenone) and had not achieved the target rate of extrasystoles (≤1000/24h). Results The findings reveal a substantial decrease in the mean parameters of PACs during both, the early period (initial 6877 ± 2432, following 761 ± 341); (88,9%); t([45]) = [13,336], p = [< .001) and the late period (initial 6877 ± 2432, following 574 ± 294); (91,7%); t([45]) = [15,124], p = [< .001). The quantitative reduction in PACs reached a maximum of 93.8% in the early period (19406 PACs □ 1211 PACs) and 94.3% in the late period (19406 PACs □ 1105 PACs). The mean parameters of PVCs in the early period experienced a significant reduction (initial 3205 ± 1145, following 550 ± 194); (82,8%); t([51]) = [8,284], p = [< .001). Similarly, the mean PVC values in the late period exhibited a noteworthy decrease (initial 3205 ± 1145, following 490 ± 181); (84,8%); t([51]) = [8,553], p = [< .001). For PVCs, the maximum effect observed in the early period was 94.8% (18929 PVCs □ 989 PVCs), and in the late period, it reached 95% (18929 PVCs □ 950 PVCs). The target rate in the late period (≤1000/24h.) for PACs reached 89%, and for PVCs - 86% (Figure 1). Adverse effects were noted in a mere four subjects (4%). These events manifested as 2nd-degree AV block (Mobitz 1), sustained ventricular tachycardia, asymptomatic nonsustained polytopic ventricular tachycardia, and asymptomatic transient ST-segment elevation observed through 24-hour ECG holter monitoring. Conclusion A prospective study on ethacizine treatment (50 mg. b.i.d.) confirmed its effectiveness and safety in reducing PACs and PVCs. It demonstrated a sustained reduction in extrasystole occurrences for an extended period, achieving the target rate with minimal side effects. Ethacizine merits consideration for addressing extrasystolic arrhythmia, particularly in cases where other antiarrhythmic medications prove ineffective.Results of the study

Left atrial and left ventricular positive and negative remodeling after catheter ablation of atrial fibrillation

Abstract Introduction Atrial fibrillation (AF) is associated with negative remodeling of left atrium (LA) and in later stages of diseases with negative remodeling of left ventricle (LV). Can radiofrequency ablation (RFA) of pulmonary veins cure AF and retain progression of arrhythmia? Purpose This study evaluated positive and negative remodeling of LA and LV after RFA of pulmonary veins and a 7-year follow-up. The patients were divided into 4 groups on the basis of Pulmonary Vein Isolation Outcome Degree (PVIOD 1-4), a new measure for the efficacy of catheter ablation of AF. Methods One hundred seventeen patients with symptomatic drug-refractory paroxysmal and persistent AF were treated with RFA. At baseline and after a 7 years of follow-up, 2-dimensional echocardiography was performed to assess LA diameter, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD) and left ventricular ejection fraction (LVEF). Results After a 7-year follow-up 32.5% patients with successful single RFA of AF (PVIOD 1) showed significant positive LA and LV remodeling: LA diameter 39.3±0.6 vs 36.5±0.6 mm, p=0.0007; LVEDD 53.1±0.6 vs 50.9±0.7 mm, p=0.008; LVESD 34.7±0.8 vs 32.0±0.1 mm, p=0.005 and LVEF 56.8±0.8 vs 62.1±1.1 %, p=0.000008. In 29.1% of patients with success after multiple procedures (PVIOD 2) occurred significant reverse LA remodeling: LA diameter 41.9±0.7 vs 40.2±0.6 mm, p=0.04. Clinical success (PVIOD 3) after RFA was defined as a significant reduction in the number and duration of AF episodes with or without previously ineffective antiarrhythmic drugs (AAD) class I and III. In 14.5% of subjects with long-term clinical success (PVIOD 3 and baseline LA diameter 43.2±1.0 mm) remodeling of LA and LV was not occurred. In 23.9% of patients with procedural and clinical failure after RFA (PVIOD 4) long-term follow-up showed significant negative remodeling of LA and LV: LA diameter 44.7±0.7 vs 47.4±0.7 mm, p=0.006; LVEDD 52.8±0.9 vs 57.1±0.6 mm, p=0.0006; LVESD 36.5±1.1 vs 40.7±1.2 mm, p=0.006 and LVEF 50.7±1.7 vs 43.8±1.8 %, p=0.004. Conclusions Single successful RFA of pulmonary veins in early stage of AF with normal LA diameter cure arrhythmia, which was proved with LA and LV positive remodeling after a 7-year follow-up. With increase of LA diameter, the success of RFA decrease. The multiple procedures slow the progression of AF, but are less effective because of long periods of time between them. Clinical success and role of AAD therapy are also important in AF management. If AF is not treated with RFA properly on time it becomes progressive disease.

Strategic timing- early and delayed catheter ablation in atrial fibrillation

Abstract Background Atrial fibrillation (AF) is the most common sustained arrhythmia. AF catheter ablation (CA) is superior to antiarrhythmic drug (AAD) therapy in maintaining sinus rhythm. However, not much is known regarding the optimal timing of the ablation. Purpose This review aims to examine the evidence supporting both early and delayed ablation approaches, as well as explore their respective disadvantages. Methods We performed an electronic search in databases such as PubMed, ScienceDirect, Springer, Wiley Online Library, focusing on studies published from 2013 until 2022 and including both observational studies and randomized controlled trials (RCTs). Left atrial diameter and ejection fraction (EF) were assessed. The limit between early and delayed ablation was set to be 3 years, considering delayed CA studies with a diagnosis-to-ablation-time (DAT) of 3 years or more, and early CA studies with a DAT of less than 3 years. Included studies were selected according to our eligibility criteria: observational studies or RCTs that included patients with symptomatic paroxysmal or persistent AF that underwent ablation using either radiofrequency or cryoballoon approach or both approaches, studies that reported DAT, studies that included a follow-up period, studies that evaluated AF recurrence or AF burden. Studies that included a surgical ablation, a hybrid ablation approach, or ablation for arrhythmias other than AF were excluded. Results Ten studies were selected out of 1387 identified records. After a follow-up period of 1 year, the early ablation subgroup had a lower mean AF recurrence rate (31.1%) compared to that of the delayed ablation subgroup (37.7%) ( p<0.0004). The median AF recurrence rate in radiofrequency ablation group was (47.8%) in comparison to the AF recurrence rate in cryoablation group which was (27.4%) (p<0.0001). In studies that included paroxysmal AF patients exclusively, the AF recurrence rate was directly proportional to the DAT(R=0.95). Conclusion Our results demonstrate that DAT correlates with recurrence rate at 1 year following AF CA, the shorter the DAT the better the outcome especially in paroxysmal AF population.Prisma study selection flow diagramCorrelation between DAT-AF recurrence

Procedural outcomes of fluoroscopy-less catheter ablation for atrial fibrillation

Abstract Background Radiofrequency catheter ablation is superior therapy to antiarrhythmic drugs for maintaining sinus rhythm in atrial fibrillation (AF) patients. Traditional fluoroscopy-guided AF ablation poses risks of prolonged radiation exposure for both patients and medical staff. Recent advancements in fluoroscopy-less catheter ablation techniques offer potential solutions, but comprehensive data on their effectiveness and safety are lacking. Purpose To evaluate the procedural outcomes and safety of fluoroscopy-less catheter ablation for AF compared to fluoroscopy-guided ablation. Methods Retrospective observational study of consecutive AF ablations (N=881) conducted at a university teaching hospital (Hamilton Health Sciences, Hamilton, Ontario) from November 2017 to September 2022. An electro-anatomical mapping system and ICE was used in all cases. Baseline characteristics and procedural outcomes between the fluoroscopy-less and fluoroscopy-guided groups were compared. Cases that used <60 seconds of fluoroscopy (occasionally used by operators during the placement of an esophageal probe) were included in the fluoroscopy-less group (N= 68). Results Mean age of individuals was 60.6 ± 11 years, 71.7% were male, 72.6% had paroxysmal AF, mean CHA2DS2-VASc score was 1.6 ± 1.4, 11.1% had prior heart failure, and mean left ventricular ejection fraction was 57.5 ± 15%. There were no significant differences in patient baseline characteristics between the fluoroscopy-less and fluoroscopy groups. Total procedure and fluoroscopy times were lower in the fluoroscopy-less group compared to the fluoroscopy-guided group (169.3 ±42 minutes vs. 192.1 ±54 minutes, p<0.0001 and 0.024 ±0.10 vs. 10.0 ±7.4 minutes , p<0.0001). Fluoroscopy-less AF ablation remained an independent predictor of lower procedure times following adjusting for the use of general anesthesia, high-power short-duration, presence of trainees, AF pattern, redo cases, and type of mapping system. Complication rates were similar between fluoroscopy-less and fluoroscopy-guided ablation (1.9% vs. 3.8%, p=0.11). Conclusion Fluoroscopy-less catheter ablation for AF appears to have similar procedural outcomes and safety than fluoroscopy-guided AF ablation.

Real world data on SVT ablation in Denmark Higher risk of need for reablation in todays patient population a Nationwide registry based Danish study

Abstract Introduction Supraventricular tachycardias (SVTs) are a common reason for healthcare contacts and can have significant impact on patient’s quality of life. Today, ablation therapy is considered the treatment of choice for many cardiac tachyarrhythmias, and it is increasingly utilized to treat SVT-patients with chronic symptoms. Ablation therapy for SVTs is considered a safe procedure with high periprocedural success rates. However, recent studies on today’s patient population have shown a tendency towards higher age and more comorbidity, which might affect these success rates. Therefore, there is a need to explore more real-world data on long-term outcomes of catheter ablations in today’s population. Purpose To examine the long-term success rates of ablation therapy by investigating risk of reablation in patients treated for either an accessory pathway (AP), atrioventricular nodal re-entry tachycardia (AVNRT) or ectopic atrial tachycardia (EAT). Methods Using Danish nationwide registries, patients of 18 years or older who underwent RFA for AP, AVNRT or EAT between January 1st 2010 and January 1st 2019 were included. Comorbidities and use of antiarrhythmic drugs were analyzed. The cumulative incidences of reablation for either AP, AVNRT or EAT were estimated at 5-year follow-up. Results Figure 1 shows the baseline characteristics of the study population. A total of 5.905 patients were included in the study, with a median age of 52 [38, 65], and 47% were male. Among them, the AP group comprised 1.575 patients, with a mean age of 42 [29, 55], and 61% were male. The AVNRT group consisted of 3.598 patients, with a mean age of 56 [43, 67], and 42% were male. In the EAT group, there were 732 patients, with a mean age of 57 [42, 67], and 44% were male. The comorbidity burden was generelly higher in EAT patients, who also had the highest use of antiarrhythmic drugs. Figure 2 shows the 5-year cumulative incidence of reablation for AP, AVNRT or EAT-patients. Risk of reablation after 5 years was 12%, 5% and 12% for AP-, AVNRT- and EAT patients respectively. After 1 year the risk was 9%, 3% and 9% for AP-, AVNRT- and EAT patients respectively. Conclusion Despite the generally safe nature of ablation therapy with high periprocedural success rates, our findings highlight a notable risk of reablation, particularly for AP and EAT patients, after 5 years of follow-up.Baseline Characteristics5year cumulative incidence of reablation

Atrial fibrillation recurrence rates in patients with transthyretin cardiac amyloidosis undergoing pulmonary vein isolation: a comparative retrospective study with propensity score matching

Abstract Background Atrial fibrillation (AF) affects up to 70% of individuals diagnosed with transthyretin cardiac amyloidosis (ATTR CA) [1]. AF ablation is frequently considered in the management of these patients, but there is a lack of data about outcomes of the procedure in this population. Purpose This study aims to evaluate AF recurrence rates and long-term AF recurrence-free survival in patients with ATTR CA undergoing pulmonary vein isolation (PVI). Methods A single-center retrospective study was conducted, including all patients diagnosed with ATTR CA who underwent PVI from 2016 to 2023. We compared patients with amyloidosis (cases) to those without (controls), employing propensity score matching for age, gender, AF type (paroxysmal vs. persistent), BMI, diabetes, arterial hypertension diagnosis, antiarrhythmic drug therapy post-index ablation, and left atrium (LA) volume assessed by 3D rotational angiography (3DRA). Results 16 patients with CA were matched to 16 patients without (32 patients in total). After matching, the populations demonstrated comparable baseline characteristics (figure 1). The study consistently revealed a higher AF recurrence rate, after PVI, in the CA group (81.3%) compared to the control group (37.5%) at the last follow-up (p-value 0.01) (median follow-up 1255 ± 1055 days in CA and 1491 ± 464 days in control group), as well as a significantly lower long-term AF-recurrence free survival (log-rank p = 0.01 – figure 2). Additionally, the recurrence rate at 1-year post-procedure was 56.25% in the CA group and 18.75% in the control group (p-value 0.03). Conclusions Pulmonary vein isolation remains a viable treatment option for individuals with ATTR CA. However, it proved less effective (or less durable) than in the general population without the disease, both at 1-year follow-up and for longer periods, as shown also with recurrence-free survival rate. Further studies are warranted to determine the optimal treatment strategy for this specific population.Baseline Characteristics fig. 1Kaplan Meyer fig. 2

Potential use of pharmacogenetics in cardiology: genome-wide association studies of amiodarone-induced thyroid disorders

Abstract Background Amiodarone is a commonly prescribed antiarrhythmic drug used to manage supraventricular and ventricular arrhythmias. The use of amiodarone is associated with a broad range of adverse effects, including amiodarone-induced hypothyroidism (AIH) or amiodarone-induced thyrotoxicosis (AIT) (1). Both conditions are linked with increased mortality and have no known reliable risk predictors (2). Purpose We investigated the genetic underpinnings of amiodarone-induced thyroid disorders, and the clinical validity and utility of screening for genetic variants. Methods We conducted the first genome-wide association studies (GWAS) of AIH and AIT using data from three large biobanks. We compared the AUCs for SNPs identified through the above GWAS with polygenic risk scores for both hypo- and hyperthyroidism. Finally, we tested the clinical validity and utility of screening for risk variants. Results We found two risk loci for AIH. The lead variant at the first locus, rs1443438, was intronic to FOXE1 (OR 0.39, MAF = 35%, P = 1.59 × 10-42). The other lead variant, rs2209796, was located 93 kb upstream to FOXA2 (OR 0.56, MAF = 29%, P = 2.64 × 10-15: Figure 1). For AIT, we found one risk locus. The lead variant, rs2268803, was intronic to CAPZB (OR 1.81, MAF = 42%, P = 2.43 × 10-8: Figure 1). Next, we added GWAS SNPs or polygenic risk scores to risk prediction models consisting of age, sex and 4 principal components (PCs), and compared AUC estimates between risk models. Using GWAS SNPs, we found that the AIT variant increased the AUC with 6% (95%CI 1.1 – 10.3, AUC: 0.72) and 9% (95%CI 6.2 – 11.2, AUC: 0.75) for AIH, compared to the benchmark model. Both GWAS SNP models were superior to polygenic risk scores in terms of AUC (P for difference <0.05). The positive and negative predictive value (PPV and NPV) for the AIT-variant was 14.6% and 95.7%, respectively. For the AIH-variants combined, we found a PPV of 17% and a NPV of 95%. Conclusions Common genetic variants are associated with both amiodarone-induced hypo- and hyperthyroidism and are at this point, superior to polygenic risk scores in predicting amiodarone-induced thyroid disorders. These findings add to the potentials of pharmacogenetics in cardiology. Figure 1. Double Manhattan plot of amiodarone induced thyroid disorders. The Y-axis is the negative log10 of the P-value for each single nucleotide polymorphism. The X-axis is the chromosome, with positions on each chromosome ranging from lower to higher (left to right). The dotted line marks the threshold for genome-wide significance. Amiodoarone-induced hypothyroidism at the top, and amiodarone-induced thyrotoxicosis at the bottom.Figure 1

Prediction of atrial fibrillation recurrence after ablation: the impact of machine learning and recurrence during the blanking period

Abstract Introduction Pulmonary vein isolation is superior to antiarrhythmic drugs for rhythm control in patients with atrial fibrillation (AF). Nevertheless, recurrences within the first year are still significant. Several clinical risk scores were developed to predict AF recurrence; however, despite good results in development cohorts, the results in external validation are usually poor, limiting the general applicability of these scores. Purpose We aimed to develop machine learning (ML) models to predict AF recurrences within the first year after catheter ablation and compare their performance with conventional risk scores. Methods We used a retrospective dataset of a tertiary hospital center, including all consecutive patients submitted to the first AF ablation between 2017 and 2021. The dataset included 76 features: patient characteristics, medical history, baseline echocardiography, calcium score, procedure variables, and early recurrence (ER) during the 90-day blanking period. The outcome was defined as the occurrence of an electrocardiographically documented late recurrence (LR) of atrial tachycardia/AF > 30s between 3-12 months. Three different supervised ML models (penalized logistic regression, random forests, and XGBoost) were developed on the training cohort, and hyperparameters were tuned using 10-fold cross-validation. A testing dataset was held out to estimate the final performance (25%). The following risk scores were calculated: APPLE, CAAP-AF, and BASE-AF2 (the last includes ER). Areas under the curve (AUC) of receiver operating characteristic curves were compared using DeLong’s test. Results 679 patients were included: 62.7% males, median age of 59±16 years, and 78.2% with paroxysmal AF. The median time from diagnosis to ablation was 2±4 years. 74.2% underwent radiofrequency ablation and the remaining cryoablation. ER occurred in 12.5%, and most of these patients also experienced LR (68.7 vs 19.6% in those without ER, p<0.001). LR was observed in 25.6%. The XGBoost model showed the best performance with an AUC 0.774, 95% confidence interval (CI) 0.688–0.844) outperforming existing scores (picture 1): APPLE score AUC 0.607, 95% CI 0.562–0.653, p-value<0.001; CAAP-AF score AUC 0.622, 95% CI 0.576–0.668, p-value=0.002; BASE-AF2 AUC 0.628, 95% CI 0.581–0.675, p-value= 0.003. Variable importance analysis showed a significant drop in the performance of the models when ER was not considered, indicating its high importance in predicting LR (picture 2). Conclusions Recurrence during the blanking period was the most important predictor of LR in our population. The ML model was superior to conventional risk scores. ML models might be an essential tool to improve the prediction of outcomes and clinical decision-making for optimal follow-up.ROC curvesFeature Importance

Ablation strategy for patients with atrial fibrillation and heart failure - a Danish nationwide cohort study

Abstract Introduction Atrial fibrillation (AF) patients with heart failure (HF) face increased risks of AF recurrence and HF admission. Catheter ablation (CA) is a recognized treatment option. Due to observed atrial remodelling and fibrosis associated with ventricular remodelling in HF patients, it could be suggested that a more comprehensive ablation strategy should be applied for these patients. Purpose To examine the risk of AF recurrence and HF admission by ablation strategy for patients with AF and HF. Method This nationwide cohort study was conducted using real-life data from Danish healthcare registries. All patients above 18 years of age, with a diagnosis of AF and HF that underwent first-time CA from January 1st 2010 to December 31st 2018, were identified and included at the date of ablation. Exposure of interest was ablation strategy - pulmonary vein isolation (PVI) or additional ablation to PVI (PVI plus). PVI plus was defined as either roofline, mitral linear ablation, posterior wall isolation, complex fractionated atrial electrograms or ganglionated plexi ablation. Primary endpoint was HF admission and AF recurrence after a 3-months blanking period. AF recurrence was defined by a composite endpoint of first-reached endpoint of either use of antiarrhythmic drugs, AF admission, electrical cardioversions, or AF re-ablation. The relative rates of recurrent AF and HF admission by ablation strategy (PVI or PVI plus) were examined by Cox proportional models using PVI as reference. The analyses were adjusted for clinically important baseline characteristics including age, sex, AF type (paroxysmal or persistent), diagnosis-to-ablation time, procedural year, body mass index, size of left atrium, as well as co-morbidities such as ischemic heart disease, chronic obstructive pulmonary disease, chronic kidney disease, hypertension, and diabetes. Results The study cohort consisted of 1,270 patients diagnosed with AF and HF undergoing first-time CA, of which 1,119 (88%) received PVI and 151 (12%) received PVI plus. 80% where males in both groups. Median age was 62 for the PVI group and 64 for the PVI plus group. Severely enlarged left atrium, ischemic heart disease and use of amiodarone were more prevalent in the PVI plus group compared to the PVI group (Table 1). The relative risk of recurrent AF showed a hazard ratio of 1.02 (95% CI: 0.77-1.37) for the PVI plus group compared to the PVI group, and for HF admission the hazard ratio was 0.95 (95% CI: 0.55-1.65) for the PVI plus group compared to the PVI group (Figure 1). Conclusion No significant differences in AF recurrence and HF admission were observed between PVI and PVI plus strategy in AF and HF patients in this observational study. With a diagnosis-to-ablation time exceeding 3 years, it could be argued that advanced atrial remodelling may diminish the impact of reverse atrial remodelling after catheter ablation, irrespective of the ablation strategy employed.Table 1Figure 1

Evolving atrial fibrillation (AF) care in New Zealand (NZ): a nurse specialist-led clinic aiming to improve standardisation, equity, cost-effectiveness, and lifestyle modification in AF management

Abstract Background Management of atrial fibrillation (AF) in NZ is challenging and variable between regions. NZ has a diverse population with Māori and Pacific ethnic groups, in particular, facing significant difficulties with access to care and inequity in treatment. The integration of nurse specialists into the care of patients with AF is increasingly recognised and discussed in AF management, including the European Society of Cardiology (ESC) guidelines. This approach also allows emphasis on managing lifestyle factors, pivotal contributing factors in disease burden Objective This study assesses the efficacy of a nurse specialist-led AF clinic in a large regional centre in New Zealand. We look specifically at the standardisation of care, lifestyle management, the impact on health equity in managing AF, and the cost-effectiveness of these strategies. Methods A retrospective analysis of the first year of the clinic’s establishment was conducted reviewing the outcomes, attendance, and adherence to management guidelines. The clinic is running three days per week to follow up those presenting to the Emergency Department with a primary diagnosis of AF. After discharge, appointments are available within 48-72 hours of presentation. The clinics efficacy and ability to serve wider NZ populations will also be presented alongside a recently-published, similar initiative in Christchurch, NZ. Results Over the first year, 247 appointments were made (Median age 66, interquartile range 58-76, 48% male, 75% NZ European). 168 patients were established on a rhythm control strategy, with 20 directly referred for ablation, 26 receiving cardioversions, and the remainder established on anti-arrhythmic medication strategies. Lifestyle modifications were addressed with majority of these patients. Demographic data also highlighted once more, a need to focus on equity with only 17.4% of appointments attended by Māori and Pacific patients, lower than would be expected given population data and relative disease burden. Conclusions The Nurse Specialist-led AF clinic shows promising outcomes and is a positive step forward in AF management in this region of NZ. Incorporating ESC guidelines with emphasis on lifestyle factors and including rhythm control strategies to good effect. This clinic brings international standards to a local stage and throws a focus on our unique healthcare needs and an emphasis on equitable delivery of care. This clinic is scalable, effective, and an inclusive approach to AF care.

Dynamics of changes in heart rate, ST segment and T-wave on patients with ventricular rhythm disturbances on the background of type 2 diabetes mellitus according to the results of 24-hour cardiac monitoring

The aim of the study was to analyze the dynamics of heart rate, assess the morphogenesis of the ST segment and T wave in patients with ventricular arrhythmias associated with type 2 diabetes mellitus (type 2 DM) based on the results of daily cardiac monitoring against the background of two regimens of metabolitotropic treatment. The study included 133 patients with type 2 DM with ventricular arrhythmias. The inclusion criteria for the study were: moderately severe type 2 diabetes in the stage of sub-/compensation on the background of combined glucose-lowering therapy without insulin, the presence of ventricular arrhythmias of classes III–V according to Lown B. and Wolf M. (1971). By random sampling, patients were randomized into 3 observation groups, statistically homogeneous in age, sex, duration of the diabetic syndrome, classes of ventricular arrhythmias. Patients of the 1st group (n = 44) received amiodarone and beta-blocker. Patients of the 2nd group (n = 45) received the same antiarrhythmic treatment, but in combination with meldonium for 3 consecutive months with the next 3-month course repeated after 6 months. Representatives of the 3rd group (n = 44) received treatment with amiodarone, beta-blocker and trimetazidine of the same duration. 24-hour ECG monitoring was performed at baseline, 3 months later, and 1 year later. Statistica 6.0 software was used for statistical processing. The examination revealed tachycardia syndrome and signs of pain and painless myocardial ischemia. It has been established that ventricular arrhythmias in type 2 DM are of a secondary nature, largely dependent on ischemic manifestations. Trimetazidine compared with meldonium showed a greater anti-ischemic effect, which made it possible to obtain a better antiarrhythmic effect. Trimetazidine is considered as one of the justified components of the treatment of ventricular arrhythmias of ischemic origin in patients with type 2 DM.

Pharmacotherapy of acute ST-elevation myocardial infarction and the pharmacist's role, part 2: Complications, postrevascularization care, and quality improvement.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Key pharmacotherapeutic modalities and considerations for the patient with ST-elevation myocardial infarction (STEMI) across the later phases of inpatient care are reviewed. Published descriptions and validation of clinical pharmacist roles specific to the acute management of STEMI are limited. This high-risk period from presentation through revascularization, stabilization, and hospital discharge involves complex pharmacotherapeutic decision points, many operational medication needs, and multiple layers of quality oversight. A companion article reviewed STEMI pharmacotherapy from emergency department presentation through revascularization. Herein we complete the pharmacotherapy review for the STEMI patient across the inpatient phases of care, including the management of peri-infarction complications with vasoactive and antiarrhythmic agents, considerations for postrevascularization antithrombotics, and assessments of supportive therapies and secondary prevention. Key guideline recommendations and literature developments are summarized from the clinical pharmacist's perspective alongside suggested pharmacist roles and responsibilities. Considerations for successful hospital discharge after STEMI and pharmacist involvement in associated institutional quality improvement efforts are also provided. We aim to support inpatient pharmacy departments in advancing clinical services for this critical patient population and call for further research delineating pharmacists' impact on patient and institutional STEMI outcomes.

Pediatric Orally Disintegrating Tablets (ODTs) with Enhanced Palatability Based on Propranolol HCl Coground with Hydroxypropyl-β-Cyclodextrin.

Propranolol, largely prescribed as an antihypertensive and antiarrhythmic drug in pediatrics, is characterized by a bitter taste and an astringent aftertaste. Currently, the therapy requires crushing of tablets for adults and their dispersion in water many times a day, leading to loss of dosing accuracy, low palatability, and poor compliance for both patients and caregivers. This work aimed to exploit cyclodextrin complexation by cogrinding to develop orally disintegrating tablets (ODTs) endowed with reliable dosing accuracy, good palatability and safety, ease of swallowability, and ultimately better compliance for both pediatric patients and caregivers. Different formulation variables and process parameters were evaluated in preparing ODTs. The technological and morphological characterization and disintegration tests were performed according to official and alternative tests to select the ODT formulation based on the drug Hydroxypropyl-β-cyclodextrin (HPβCD) coground complex form containing Pearlitol® Flash as the diluent and 8% Explotab® as the superdisintegrant, which demonstrated the highest % drug dissolution in simulated saliva and acceptable in vitro palatability assessed by the electronic tongue, confirming the good taste-masking power of HPβCD towards propranolol. Such a new dosage form of propranolol could represent a valid alternative to the common extemporaneous preparations, overcoming the lack of solid formulations of propranolol intended for pediatric use.