Long-term Results of Drug and Interventional Treatment in Patients with Morphologically Verified Idiopathic Arrhythmias

Aim. To study the late results of medical and interventional treatment in patients with morphologically verified nature of idiopathic arrhythmias.Methods. The prospective study included 20 patients (mean age 43.1±11.3 years, 10 female) with atrial fibrillation (AF), supraventricular and ventricular extrasystole, supraventricular and ventricular tachycardia, conduction disturbance without structural heart changes. In addition to the standard examination, the level of anti-heart antibodies was initially determined; endomyocardial biopsy (EMB) of the right ventricle with PCR study for the viral genome; DNA diagnostics (n=4), coronary angioraphy (n=6), skin biopsy (n=1) were performed. The median follow-up was 134 [128; 138] months.Results. By EMB in the initial examination were diagnosed: active (n=8)/borderline (n=3) infectious immune myocarditis; parvovirus-positive endomyocarditis (n=1); undifferentiated vasculitis (n=2); myocardial vasculitis (n=1); Fabry disease (n=1); arrhythmogenic right ventricular dysplasia (n=1); unspecified cardiomyopathy (n=2). Anti-heart antibodies were the most important in myocarditis diagnosis and monitoring. All patients with myocarditis/vasculitis (n=15) received its basic therapy: acyclovir (n=10); immunoglobulin G 10-12.5 g (n=2); hydroxychloroquine 200 mg/day (n=15); glucocorticoids (n=14); azathioprine 150 mg/day (n=2). The late results were evaluated in all patients with myocarditis. Initially, in 62.5% of patients a resistance of AF to all antiarrhythmic drugs was noted. After treatment the average frequency of AF paroxysms decreased (from 8 [5; 8] to 3 [1,25; 7,75] points). By the end of the follow-up, six patients underwent radiofrequency ablation (RFA) for AF, the full effect was achieved once. All patients without RFA have AF partially or completely resistant to drugs. Two patients (without RFA) died from ischemic stroke/ pulmonary embolism.Conclusion. Using EMB the causes of idiopathic arrhythmias (mainly AF) were diagnosed: immune inflammatory diseases in 75% and genetic in 25% of patients. As a result of complex treatment, the general burden of arrhythmias has decreased. But the presence of myocarditis and primary cardiomyopathy, without reducing the cardiac contractility and dilatation, does not allow achieving a stable antiarrhythmic effect. Lethality for 11 years was 10%. The causes of death were thromboembolic complications.

Attenuated Structural Transformation of Aconitine during Sand Frying Process and Antiarrhythmic Effect of Its Converted Products

The transformation pathways of diterpenoid alkaloids have been clarified in the boiling and steaming process. Aconitine, a famous diterpenoid alkaloid, is successively transformed into benzoylaconine and aconine during the processes of boiling and steaming, but the transformation pathway remains to be determined in the sand frying process. The present study aims at investigating the transformation pathways of aconitine in the process of sand frying, as well as assessing the cardiotoxicity and antiarrhythmic activity of aconitine and its converted products. The parameters of temperature and time for the structural transformation of aconitine were confirmed by HPLC. The converted products were further separated and identified by column chromatography, NMR, and HR-ESI-MS. Furthermore, by observing the lead II electrocardiogram (ECG) changes in rats under an equivalent dose, the cardiotoxicity of aconitine and its converted products were compared. Ultimately, the antiarrhythmic effect of the converted products was investigated by employing the model of aconitine-induced arrhythmia. Consequently, the structure of aconitine was converted when processed at 120°C–200°C for 1–40 min. Two diterpenoid alkaloids, a pair of epimers, namely, pyroaconitine and 16-epi-pyroaconitine, were further isolated from processed aconitine. 0.03 mg/kg aconitine induced arrhythmias in normal rats, while the converted products did not exhibit arrhythmias under an equal dose. In the antiarrhythmic assay, 16-epi-pyroaconitine could dose-dependently delay the onset time of VPB, reduce the incidence of VT, and increase the arrhythmia inhibition rate, demonstrating comparatively strong antiarrhythmic activity. Conclusively, compared with the prototype compound aconitine, the converted products exhibited lower cardiotoxicity. Further investigations on the cardiotoxicity indicated that pyroaconitine with β configuration had a stronger cardiotoxicity than 16-epi-pyroaconitine with α configuration. Furthermore, 16-epi-pyroaconitine could antagonize the arrhythmogenic effect caused by the prototype compound aconitine; the antiarrhythmic effect of 16-epi-pyroaconitine was stronger than lidocaine and propafenone, which had the potential to be developed as antiarrhythmic drugs.

Renal arteries denervation: from the treatment of resistant hypertension to the treatment of atrial fibrillation

Renal denervation (RDN) is a therapeutic strategy for patients with uncontrolled arterial hypertension characterized by considerable fluctuations during its progression. After initial strong enthusiasm, the procedure came to an abrupt halt following the publication of the Symplicity HTN-3 study results. The results of recently published studies highlight the reduction in blood pressure values after RDN and justify the inclusion in the Guidelines of new recommendations for the use of RDN in clinical practice, in selected patients. Additionally, RDN findings are summarized in view of other potential indications such as atrial fibrillation. Six prospective, randomized studies are presented that evaluated RDN as an adjunct therapy to pulmonary vein isolation for the treatment of atrial fibrillation. In five studies, patients had uncontrolled hypertension despite therapy with three antihypertensive drugs. The analysis of these studies showed that RDN reduced the recurrence of atrial fibrillation (AF) by 57% compared to patients with pulmonary vein isolation (PVI) only. Modulation of the autonomic nervous system by RDN has been shown not only to reduce blood pressure but also to have an antiarrhythmic effect in symptomatic AF patients when the strategy is combined with PVI, thus opening up new therapeutic scenarios.

The reinvented old player – an antazoline is effective in pharmacological cardioversion of atrial fibrillation

Introduction Antazoline (ANT) is an old antihistaminic medication with antiarrhythmic properties. After intravenous administration ANT exerts rapid antiarrhythmic effect often resulting in conversion of atrial fibrillation (AF) to sinus rhythm (SR) and is widely used in Poland for this purpose in the last years. However, published data on its effectiveness, safety and clinical utility for rapid AF termination are limited and ANT is not recognized as a cardioversion drug. Aim To assess the real-world efficacy of ANT for pharmacological cardioversion of paroxysmal and persistent non-valvular AF. Methods Our single center, retrospective, observational study included patients (pts) with history paroxysmal or persistent AF episode lasting less than 6 months, in stable cardiopulmonary condition who were qualified for elective pharmacological cardioversion with intravenous ANT. The primary end-point was the conversion of AF to SR confirmed in electrocardiography (ECG) during the 6-hours observation. Results A total of 176 pts (mean age 68.4±12.0 years, 49% male) were enrolled into the study. In 93 patients (52%) AF duration was shorter than 48 hours and median AF duration time was 24 (7–432) hours. The overall success rate of pharmacological cardioversion of AF with intravenous ANT was 45.5% (80/176 pts). The mean used dose of ANT was 250.9±65.4mg. The subgroup analysis, regarding the AF duration, suggested the effectiveness of ANT mainly in in short-lasting AF (effectiveness of antazoline based cardioversion for AF lasting <48h vs others: 75.3% vs 12.0%, p<0.001). In multivariable logistic regression model AF duration (for every 24h in AF – OR=0.97; 95% CI 0.96–0.98), the left atrium antero-posterior diameter (OR=0.92; 95% CI 0.86–0.99) and the serum creatinine level (OR=0.15; 95% CI 0.03–0.73) were identified as independent predictors of antazoline based pharmacological cardioversion effectiveness, even after adjustment for comorbidities. The ROC curves revealed that the optimal cut-off value for AF duration time predicting ANT's effectiveness was 48h (AUC=0.876; 95% CI 0.815–0.922) – Figure 1. There were only one episode of bradycardia <45 bpm related to ANT administration. Conclusions Antazoline is effective and safe in rapid pharmacological cardioversion of paroxysmal AF, especially in the short-lasting AF (<48 hours) and in patients without the left atrium enlargement and significant renal disease. FUNDunding Acknowledgement Type of funding sources: None. Figure 1. ROC curve analysis

Extracellular vesicles secreted by human cardiosphere-derived cells attenuate electrophysiological remodelling in an in vitro model of atrial fibrillation

Background Stem cells and their secreted extracellular vesicles (EVs) have shown different cardioprotective effects. However, their impact on the electrophysiological properties of the heart tissue remains controversial. While the use of some progenitor cells seems to have antiarrhythmic potential, the use of cardiomyocyte-like cells may be proarrhythmic. The mechanisms behind, and whether these effects are linked to cell engraftment and not to their secreted products is not fully known. Purpose The aim of this study was to investigate the electrophysiological modifications induced by extracellular vesicles secreted by human cardiosphere-derived cells (CDC-EVs) in an in vitro model of atrial fibrillation in order to explore their potential antiarrhythmic effect. Methods CDCs were derived from cardiac biopsies of patients who underwent cardiac surgery for other reasons. Purified CDC-EVs resuspended in serum-free media (SFM) vs. SFM alone were added to HL-1 atrial myocyte monolayers presenting spontaneous fibrillatory activity. After 48 hours, the monolayers were fully confluent, and the electrophysiological properties were analysed through optical mapping in both the treated (n=9) and control plates (n=9). Optical mapping recordings of the monolayers were analysed with Matlab for the activation frequency, activation complexity, rotor dynamics (curvature and meandering) and conduction velocity. Results CDC-EVs reduced activation complexity of the fibrillating atrial monolayers by ∼40% (2.74±0.59 vs. 1.61±0.16 PS/cm2, p<0.01). This reduction in activation complexity was accompanied by larger rotor meandering (1.47±0.82 vs. 4.32±2.25 cm/s, p<0.01) and decreased curvature (1.79±0.40 vs. 0.87±0.24 rad/cm, p<0.01) in the treated group. Despite reduction in the activation complexity, activation frequency did not change significantly between both groups. This could be in part because CDC-EVs increased conduction velocity by 80% (1.32±0.57 vs. 2.65±0.87 cm/s, p<0.01). Low conduction velocity has been linked to higher reentry recurrence, and lower meandering and higher curvature to higher rotor stability and harder AF termination. Therefore, CDC-EVs seem to drive cardiomyocytes to a less arrhythmic profile reducing activation complexity and preventing remodelling by increasing conduction velocity and modifying rotor dynamics. Conclusions CDC-EVs significantly modify conduction velocity and rotor dynamics, therefore reducing fibrillation complexity and remodelling to drive atrial myocytes to a less arrhythmogenic profile. Testing CDC-EVs in more robust models of atrial fibrillation, the most common sustained arrhythmia in humans with significant morbidity and mortality, is of special interest. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III, Ministerio de Ciencia e Innovaciόn,CIBERCV, Spain Figure 1

Protective effects of omega-3 fatty acids in dogs with myxomatous mitral valve disease stages B2 and C

Myxomatous mitral valve disease (MMVD) is characterized by thickening of the valve leaflets and omega-3 (ω-3) supplementation has been associated with modulation of blood pressure (BP) and heart rate, improvement of doppler echocardiographic indices, antiarrhythmic, anti-inflammatory and anti-dislipidemic effects in dogs and humans, although prospective studies of it single use are still absent in the veterinary literature. The objective of this study was to evaluate the influence of ω-3 supplementation in dogs with MMVD. Twenty-nine dogs were followed quarterly for 12 months by clinical evaluation, arterial blood pressure, electrocardiography, doppler echocardiography, thoracic radiography and laboratory tests including inflammatory mediators and cardiac biomarker blood concentrations. The dogs were classified in stages B2 and C, according to the classification proposed by ACVIM 2019. They were randomly assigned to either ω-3 group (ω-3G) or control group (CG). The ingestion of ω-3 reduced the chance of developing arrhythmias by 2.96 times (p = 0.003). The vertebral heart size (VHS) measurements were higher in the control group (p = 0.033). In conclusion, at the dosages used in this study, ω-3 dietary supplementation reduces the volumetric overload, has antiarrhythmic effect and keeps dogs with B2 and C stages of MMVD in milder stages of the disease.

Antiarrhythmic effect of 9-week hybrid comprehensive telerehabilitation and its influence on cardiovascular mortality in long term follow-up - subanalysis of the TELEREHabilitation in Heart Failure Patients - TELEREH-HF Randomized Clinical Trial.

IntroductionCardiac rehabilitation is a component of heart failure (HF) management but its effect on ventricular arrhythmias is not well recognized. We analyzed the antiarrhythmic effect of a 9-week hybrid comprehensive telerehabilitation (HCTR) and its influence on long term cardiovascular mortality in HF patients taken from TELEREH-HF trial.Material and methodsWe evaluated the presence of non-sustained ventricular tachycardia (nsVT) and frequent premature ventricular complexes≥10 beats/hour (PVCs≥10) in 24-hour ECG monitoring at baseline and after 9-week HCTR or usual care(UC) of 773 HF patients (NYHA I-III, LVEF≤40%). Functional response for HCTR was assessed by changes-delta(Δ) in peak oxygen consumption(pVO2) as a result of comparing pVO2 from the beginning and the end of the program.ResultsAmong 143 patients with nsVT, arrhythmia subsided in 30.8% after HCTR, similarly among 165 patients randomized to UC who had nsVT 34.5% did not show them after 9 weeks (p=0.481). There was no significant difference in the decrease in PVC≥10 over 9 weeks between randomization arms (14.9%vs17.8%, respectively p=0.410). Functional response for HCTR in ΔpVO2>2.0 ml/kg/min did not affect occurrence of arrhythmias. Multivariable analysis did not identify HCTR as an independent factor determining improvement of nsVT or PVCs≥10. However, only in HCTR group, the achievement of the antiarrhythmic effect significantly reduced the cardiovascular mortality in 2-year follow-up (p<0.001).ConclusionsSignificant improvement in physical capacity after 9 weeks of HCTR did not correlate with the antiarrhythmic effect in terms of incidence of nsVT or PVCs≥10. An antiarrhythmic effect after the 9-week HCTR affected long term cardiovascular mortality in HF patients.

Cinderella drug: an antazoline is effective in pharmacological cardioversion of atrial fibrillation - Single center experience

Funding Acknowledgements Type of funding sources: None. Introduction Antazoline (ANT) is an old antihistaminic medication with antiarrhythmic properties. After intravenous administration ANT exerts rapid antiarrhythmic effect often resulting in conversion of persistent atrial fibrillation (AF) to sinus rhythm (SR). However, published data on its effectiveness, safety and clinical utility for rapid AF termination are limited and ANT is not recognized as a cardioversion drug. Aim To assess the real-world efficacy of ANT for pharmacological cardioversion of paroxysmal and persistent non-valvular AF. Methods We conducted a single center, retrospective, observational study including patients (pts) with history paroxysmal or persistent AF episode lasting less than 6 months, in stable cardiopulmonary condition who were qualified for elective pharmacological cardioversion with intravenous ANT. The primary end-point was the conversion of AF to SR confirmed in electrocardiography (ECG) during the 6-hours observation. Results A total of 176 pts (mean age 68.4 ± 12.0 years, 49% male) were enrolled into the study. In 93 patients (52%) AF duration was shorter than 48 hours and median AF duration time was 24 (7 – 432) hours. The overall success rate of pharmacological cardioversion of AF with intravenous ANT was 45.5% (80/176 pts). The mean used dose of ANT was 250.9 ± 65.4mg. The subgroup analysis, regarding the AF duration, suggested the effectiveness of ANT mainly in in short-lasting AF (effectiveness of antazoline based cardioversion for AF lasting &lt;48h vs others: 75.3% vs 12.0%, p &lt; 0.001). In multivariable logistic regression model AF duration (for every 24h in AF - OR = 0.97; 95% CI 0.96 – 0.98), the left atrium antero-posterior diameter (OR = 0.92; 95% CI 0.86 – 0.99) and the serum creatinine level (OR = 0.15; 95% CI 0.03 – 0.73) were identified as independent predictors of antazoline based pharmacological cardioversion effectiveness, even after adjustment for comorbidities. The ROC curves revealed that the optimal cut-off value for AF duration time predicting ANT’s effectiveness was 48h (AUC = 0.876; 95% CI 0.815 – 0.922). There were only one episode of bradycardia &lt;45 bpm related to ANT administration. Conclusions Intravenous antazoline administration is effective and safe in rapid pharmacological cardioversion of paroxysmal AF, especially in the short-lasting AF (&lt;48 hours) and in patients without the left atrium enlargement and significant renal disease. Abstract Figure.

Ablation scar in a single pulmonary vein causes proarrhythmic mechanical destabilization in healthy sheep atria

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Catharina Hospital, Eindhoven Medtronic (unrestricted research grant) Background Ablative pulmonary vein isolation (PVI) prevents AF in 60% of AF patients. The absence of an antiarrhythmic effect of PVI is poorly understood. Atrial and PV stretch is proarrhythmic but the mechanical effect of PV ablation scar on AF arrhythmogenesis is unknown. We hypothesize that single ablation scars are potentially proarrhythmic because they create heterogeneous stretch. Purpose To evaluate the mechanical effect of a purposely incomplete PVI ablation scar on left atrial (LA) electrophysiology. Methods Functional cardiac MRIs in vivo in sheep (n = 11) before and 3-months after incomplete PVI by radiofrequency in the right PV (RPV) were analyzed with a feature-tracking algorithm to obtain local strain in the LA. The ablated hearts were explanted and perfused with 1:5 blood:Krebs solution in a dual-chamber working-heart set-up. Diagnostic multi-electrode endocardial catheters were positioned in the RPV and left PV (LPV). Premature stimulation was performed in each PV in low (∼12mmHg) and high (∼25mmHg) LA pressure. Twelve control hearts without ablation scar underwent similar ex vivo investigation. Results The maximum longitudinal strain of the myocardial wall between the RPV and LPV increased from 20.2 ± 6.2% to 33.5 ± 16.0% (before vs. after ablation, respectively; p = 0.032), whereas the maximum radial strain of the LA septum close to the RPV decreased from 45.6 ± 9.7% to 35.8 ± 7.3% (before vs. after ablation, respectively; p = 0.035). Sustained AF (&gt;30s) was more often induced during stimulation in hearts with ablation scar than in control (25.0% and 11.5% of induction attempts (n = 76 and n = 87) in ablated and control hearts, respectively; p = 0.025). In ablated hearts, an increase in LA pressure augmented AF inducibility (12.8% vs. 37.8% of induction attempts (n = 39 vs. n = 37), low vs. high LA pressure, respectively; p = 0.023), whereas this was not the case in control hearts (4.4% vs. 19.0% of induction attempts (n = 45 vs. n = 42), low vs. high LA pressure; p = 0.289). The number of spontaneous premature atrial complexes (PACs) not leading to AF were similar in ablated and control hearts (0 ± 0 vs. 0 ± 2 total PACs within 20ms of refractory period during premature stimulation protocol, respectively; p = 0.411). The diastolic stimulation threshold of RPV was higher in the ablated than in control hearts (90 ± 63 vs. 79 ± 31mA, respectively; p = 0.049). The refractory period was similar in the ablated and control hearts (237 ± 62 vs. 235 ± 55ms, respectively; p = 0.873). Conclusion Local ablation scar caused regionally disparate bio-mechanical changes in proximity to ablative energy delivery and increased inducibility of sustained AF especially during increased LA stretch. This was associated with decreased tissue excitability without changes in refractoriness. A single incomplete PVI ablation scar therefore is proarrhythmic. Development of ablation lesion sets that homogenize atrial mechanics and electrophysiology may improve AF ablation success.

Antiarrhythmic effect of 9-week hybrid cardiac telerehabilitation - subanalysis of the TELEREHabilitation in Heart Failure patients - TELEREH-HF randomized clinical trial

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The National Centre for Research and Development, Warsaw, Poland. Background. Cardiac rehabilitation is a component of heart failure (HF) management but its effect on ventricular arrhythmias is not well recognized. Purpose. We analyzed the antiarrhythmic effect of a 9-week hybrid cardiac telerehabilitation (HCTR) and its influence on long term cardiovascular mortality in HF patients taken from the TELEREH-HF trial. Methods. We evaluated the presence of non-sustained ventricular tachycardia (nsVT) and frequent premature ventricular complexes ≥10 beats/hour (PVCs ≥10) with 24-hour ECG monitoring at the baseline and after 9-week HCTR or usual care (UC) of 773 HF patients (NYHA I-III, LVEF ≤ 40%). Results. Among 143 patients with nsVT, arrhythmia subsided in 30.8% after HCTR, similarly among 165 patients randomized to UC who had nsVT 34.5% did not show them after 9 weeks (p = 0.481). There was no significant difference in the decrease in PVC ≥10 over 9 weeks between randomization arms (14.9% vs. 17.8%, respectively p = 0.410). Functional response for HCTR (Δ peak oxygen consumption [pVO2] in cardiopulmonary exercise test &gt;2.0 ml/kg/min) did not affect occurrence of arrhythmias. The multivariable analysis of the entire population did not identify HCTR as an independent factor determining improvement in terms of nsVT or PVCs &gt;10. However, only in the HCTR group, the achievement of the antiarrhythmic effect significantly reduced the cardiovascular mortality in 2 years follow-up (Logrank p = 0.0009) (Figure). Conclusions. Significant improvement in physical capacity after 9 weeks of HCTR did not correlate with the antiarrhythmic effect in terms of incidence of nsVT or PVCs ≥10. An antiarrhythmic effect after the 9-week HCTR affected long term cardiovascular mortality in HF patients. Abstract Figure