Antiarrhythmic Amiodarone Research Articles

Artemisinin conferred cytoprotection to human retinal pigment epithelial cells exposed to amiodarone-induced oxidative insult by activating the CaMKK2/AMPK/Nrf2 pathway

BackgroundOcular toxicity is a severe adverse effect that limits the chronic clinical use of the antiarrhythmic drug amiodarone. Here, we aimed to evaluate the cytoprotective effect of artemisinin and explore the potential signalling pathways in human retinal pigment epithelial (RPE) cell cultures.MethodsD407 cell cultures were exposed to amiodarone and the impact of artemisinin was evaluated. The key parameters included lactate dehydrogenase (LDH) release, intracellular reactive oxygen species (ROS) generation, and the mitochondrial membrane potential (MMP). We also assessed the protein levels of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), phosphorylated adenosine monophosphate-activated protein kinase (AMPK)ɑ (p-AMPK), calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), and nuclear factor erythroid 2-related factor 2 (Nrf2).ResultsArtemisinin reduced the cytotoxicity induced by amiodarone, as reflected by decreased LDH release, ROS generation, and MMP disruption. Additionally, artemisinin increased p-AMPK, CaMKK2, and Nrf2 protein levels. Inhibition of AMPK, CaMKK2, or Nrf2 abolished the cytoprotective effect of artemisinin. AMPK activation and Nrf2 knockdown further supported its protective role.ConclusionsArtemisinin protected RPE cells from amiodarone-induced damage via the CaMKK2/AMPK/Nrf2 pathway. The in vivo experiments in mice confirmed its efficacy in preventing retinal injury caused by amiodarone. These results suggest that an artemisinin-based eye formulation could be repurposed for treating amiodarone-induced ocular toxicity.

The effects of empagliflozin on ventricular arrhythmias in heart failure patients with an implantable cardioverter-defibrillator: a double-blind randomized controlled trial.

Sodium-glucose transporter 2 (SGLT2) inhibitors such as empagliflozin are one of the main treatments for type 2 diabetes mellitus (DM2) and heart failure (HF). They have also demonstrated anti-arrhythmic effects in some preclinical and clinical studies. The purpose of this study was to assess the effects of empagliflozin on ventricular arrhythmias in HF patients with an implantable cardioverter-defibrillator (ICD). In a prospective double-blinded, randomized controlled trial of Iran County, Mashhad (72 patients 1:1), we compared the frequency and proportion of ventricular arrhythmias and ICD therapies during the 24weeks to the prior 24weeks. Results revealed that empagliflozin significantly reduced the frequency and proportion of ventricular tachycardia (VT)/fibrillation (VF) episodes (P = 0.019 and 0.039, respectively). Moreover, it tended to reduce the frequency and proportion of ICD therapies, including anti-tachycardia pacing (ATP) and shock. Subgroup analysis of patients with or without any antiarrhythmic drugs (digoxin, mexiletine, amiodarone, or sotalol) revealed that only patients who were previously on the antiarrhythmic drugs benefit from empagliflozin antiarrhythmic effects. In conclusion, empagliflozin exhibits anti-arrhythmic effects in HF patients with an ICD. Larger and long-term clinical studies are still needed to investigate and confirm all positive effects of SGLT2 inhibitors in this regard. Trial registration number: IRCT20120520009801N7 (Approval date: June 11, 2022).

The antiarrhythmic drugs amiodarone and dronedarone inhibit intoxication of cells with pertussis toxin.

Pertussis toxin (PT) is a virulent factor produced by Bordetella pertussis, the causative agent of whooping cough. PT exerts its pathogenic effects by ADP-ribosylating heterotrimeric G proteins, disrupting cellular signaling pathways. Here, we investigate the potential of two antiarrhythmic drugs, amiodarone and dronedarone, in mitigating PT-induced cellular intoxication. After binding to cells, PT is endocytosed, transported from the Golgi to the endoplasmic reticulum where the enzyme subunit PTS1 is released from the transport subunit of PT. PTS1 is translocated into the cytosol where it ADP-ribosylates inhibitory α-subunit of G-protein coupled receptors (Gαi). We showed that amiodarone and dronedarone protected CHO cells and human A549 cells from PT-intoxication by analyzing the ADP-ribosylation status of Gαi. Amiodarone had no effect on PT binding to cells or in vitro enzyme activity of PTS1 but reduced the signal of PTS1 in the cell suggesting that amiodarone interferes with intracellular transport of PTS1. Moreover, dronedarone mitigated the PT-mediated effect on cAMP signaling in a cell-based bioassay. Taken together, our findings underscore the inhibitory effects of amiodarone and dronedarone on PT-induced cellular intoxication, providing valuable insights into drug repurposing for infectious disease management.

Inhibition of Clostridioides difficile toxins TcdA and TcdB by the amiodarone derivative dronedarone.

The dreaded nosocomial pathogen Clostridioides difficile causes diarrhea and severe inflammation of the colon, especially after the use of certain antibiotics. The bacterium releases two deleterious toxins, TcdA and TcdB, into the gut, which are mainly responsible for the symptoms of C.difficile-associated diseases (CDADs). Both toxins are capable of entering independently into various host cells, e.g., intestinal epithelial cells, where they mono-O-glucosylate and inactivate Rho and/or Ras GTPases, important molecular switches for various cellular functions. We have shown recently that the cellular uptake of the Clostridioides difficile toxins TcdA and TcdB (TcdA/B) is inhibited by the licensed class III antiarrhythmic drug amiodarone (Schumacher et al. in Gut Microbes 15(2):2256695, 2023). Mechanistically, amiodarone delays the cellular uptake of both toxins into target cells most likely by lowering membrane cholesterol levels and by interfering with membrane insertion and/or pore formation of TcdA/B. However, serious side effects, such as thyroid dysfunction and severe pulmonary fibrosis, limit the clinical use of amiodarone in patients with C. difficile infection (CDI). For that reason, we aimed to test whether dronedarone, an amiodarone derivative with a more favorable side effect profile, is also capable of inhibiting TcdA/B. To this end, we tested in vitro with various methods the impact of dronedarone on the intoxication of Vero and CaCo-2 cells with TcdA/B. Importantly, preincubation of both cell lines with dronedarone for 1h at concentrations in the low micromolar range rendered the cells less sensitive toward TcdA/B-induced Rac1 glucosylation, collapse of the actin cytoskeleton, cell rounding, and cytopathic effects, respectively. Our study points toward the possibility of repurposing the already approved drug dronedarone as the preferable safer-to-use alternative to amiodarone for inhibiting TcdA/B in the (supportive) therapy of CDADs.

Amiodarone chewable gels as a potential appproach for paediatric congenital cardiopathies treatment: Comparison between animal and vegetal gelling agents

The difficulty in swallowing is a frequent problem when oral solid dosage forms (conventional tablets or capsules) are administered to paediatric population or patients with dysphagia. An interesting alternative to overcome these problems are non-conventional formulations like chewable gels, commonly known as ’gummies’. Therefore, this work addresses the design, development and characterization of gummies using gelatine and pectin, for the vehiculization of the antiarrhythmic amiodarone (AMIO). Applying a Design of Experiments (DoE) approach, four gelatine (GG1-GG4) and eight pectin formulations (PG1-PG8) were developed. Considering the obtained results for responses during DoE evaluation (i.e., volume, syneresis, hardness, and gumminess), GG3 and PG8 were selected for complete characterization. Water activity, pH, drug content, texture parameters (adhesiveness, springiness, cohesiveness, and fracturability), disintegration time, in vitro dissolution, and microbiological features were evaluated. The obtained results were within the expected values for this type of formulation. The dissolution profiles showed a 94 % − 99 % of the AMIO content released for GG3 and PG8, respectively, so they could be considered suitable as immediate release dosage forms. In conclusion, the chewable gels were successfully developed and characterised, suggesting a potential means to accomplish a final prototype for the improvement of congenital cardiopathies treatment.

Toxicologic analysis of 35 drugs in post mortem human blood samples with focus on antihypertensive and antiarrhythmic drugs

Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in therapeutic doses, and if they were taken in accidental, intentional, or suicidal overdose scenarios. Therefore, a novel analytical method was developed and validated for the quantification of 35 drugs with toxicological relevance, including antihypertensive and antiarrhythmic drugs (ajmaline, amlodipine, amiodarone, atenolol, bisoprolol, carvedilol, clonidine, desethylamiodarone, diltiazem, donepezil, doxazosin, dronedarone, esmolol, flecainide, lercanidipine, lidocaine, metoprolol, nebivolol, nimodipine, pindolol, prajmaline, propafenone, propranolol, sotalol, urapidil, and verapamil), as well as other medications commonly found in combination (sildenafil, tadalafil, atorvastatin, clopidogrel, dapoxetine, memantine, pentoxifylline, rivastigmine, and ivabradine). The method enables simultaneous identification and quantification in blood samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS).Validation exhibited excellent linearity across the concentration range for all analytes. Precision and accuracy were within acceptable limits, with bias and relative standard deviation (RSD) values consistently below 9 % and 10 %, respectively. Selectivity and specificity assessments confirmed the absence of any interference from contaminants or co-extracted drugs. The method demonstrated very high sensitivity, with limits of detection (LOD) as low as 0.01 ng/ml and limits of quantification (LOQ) as low as 0.04 ng/ml. Extraction recovery exceeded 57.5 % for all analytes except atenolol, and matrix effects were <17 % for all analytes except pindolol. Processed sample stability evaluations revealed consistent results with acceptable deviations for all analytes. In addition, the method was specifically tested for the use in post mortem analysis. The applicability of our method was demonstrated by the analysis of two authentic human autopsy blood samples.

Comparative analysis of antiarrhythmic drugs following atrial fibrillation ablation

Abstract Background Atrial fibrillation (AF) ablation has become an established therapeutic modality for rhythm control. However, the optimal post-ablation pharmacological strategy remains uncertain. The present study addresses this gap by conducting a comparative analysis of four commonly used antiarrhythmic drugs (amiodarone, propafenone, sotalol, and flecainide), both as standalone treatments and in combination with beta blockers, to determine their impact on mortality, hospitalization rates, and AF recurrence. Methods A multi-center, retrospective cohort study was conducted, including patients who underwent successful AF ablation between 20010 to 2020. The study population was divided into groups based on the prescribed antiarrhythmic drug regimen: amiodarone, propafenone, sotalol, flecainide, and respective combinations with beta blockers. Patient demographics, comorbidities, and procedural details were collected. Endpoints included all-cause mortality, hospitalization due to cardiovascular events, MACE and AF recurrence. Results A total of 908 patients were included in this study. The mean age was 66 years old, and 33% (n=297) were female patients. Of 908 patients, 35% (n=316) were prescribed amiodarone, 34% (n=305) propafenone, 8% (n=76) sotalol, and 6%% (n=51) flecainide post AF ablation. Association with beta blockers were observed in 55% (n=496) of cases. Amiodarone group had a 0,3% (n=1) mortality, 9% (n=27) of hospitalizations, 2% (n=5) of major cardiovascular events (MACE) and 32% (n=101) of AF recurrence. Propafenone group had a 1,3% (n=4) mortality, 4% (n=12) hospitalizations, 2% (n=5) of MACE and 27% (n=81) of AF recurrence. Sotalol group had a 4% (n=3) mortality, 6% (n=4) of hospitalizations, 3% (n=2) of MACE and 44% (n=32) of AF recurrence. Flecainide group had 0 cases of death, 2% (n=1) of hospitalization, 0 cases of MACE and 35% of recurrence. Amiodarone is associated with a lower risk of death (p=0,018 OR 0,13). The presence of betablockers did not affect the endpoints, namely, death, hospitalization, MACE or AF recurrence. There were no other statistically significant associations between variables. Conclusion This study evaluated the effectiveness of common antiarrhythmics, such as amiodarone, propafenone, sotalol, and flecainide, with and without beta blockers, in the post-AF ablation setting. In this study, amiodarone showed a lower risk of death. There were no other statistically significant associations between either antiarrhythmic drug and each endpoint. The presence of betablocker therapy did not interfere with the endpoints. The findings contribute to the ongoing discourse on the optimal pharmacological strategy for AF management post-ablation. Further prospective studies with larger sample sizes are warranted to validate and refine these observations, paving the way for evidence-based guidelines in tailoring antiarrhythmic drug regimens for improved patient outcomes

Amiodarone-induced thyrotoxicosis type 2: the role of differential diagnosis in patient management

The antiarrhythmic drug amiodarone can affect the function of the thyroid gland, contributing to the development of thyrotoxicosis or hypothyroidism. The development of thyrotoxicosis exacerbates the cardiovascular pathology present in patients: it leads to the progression of left ventricular dysfunction, recurrence of rhythm disturbances, increasing the risk of adverse outcomes. Timely diagnosis of thyrotoxicosis in the treatment of amiodarone is of fundamental importance in choosing the right therapeutic tactics, which is determined by the type of amiodarone-induced thyrotoxicosis (AmIT), the state of the cardiovascular system, and the risk of recurrent arrhythmias. In type 1 AMIT, the main method of controlling the relief of thyrotoxicosis is thyroostatic therapy with the possibility of subsequent radical treatment (radioiodine therapy, thyroidectomy). Type 2 AmIT is a self-limiting process, however, for the treatment of patients with moderate to severe amiodarone-induced thyrotoxicosis type 2, glucocorticoids are the first-line drugs. With a mixed version of AmIT, a combination of antithyroid drugs and glucocorticoids is recommended. This review presents a clinical case of a patient with type 2 AmIT who was treated with thyrostatic drugs for a long time without achieving an effect.

Amiodarone Advances the Apoptosis of Cardiomyocytes by Repressing Sigmar1 Expression and Blocking KCNH2-related Potassium Channels.

Heart failure (HF) is the ultimate transformation result of various cardiovascular diseases. Mitochondria-mediated cardiomyocyte apoptosis has been uncovered to be associated with this disorder. This study mainly delves into the mechanism of the anti-arrhythmic drug amiodarone on mitochondrial toxicity of cardiomyocytes. The viability of H9c2 cells treated with amiodarone at 0.5, 1, 2, 3, and 4 μM was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and Sigmar1 expression was examined by quantitative real-time PCR (qRTPCR). After transfection, the viability, apoptosis, reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), and potassium voltage-gated channel subfamily H member 2 (KCNH2) expression in H9c2 cells were assessed by MTT, flow cytometry, ROS assay kit, mitochondria staining kit, and Western blot. Amiodarone at 1-4 μM notably weakened H9c2 cell viability with IC50 value of 2.62 ± 0.43 μM. Amiodarone at 0.5-4 μM also evidently suppressed the Sigmar1 level in H9c2 cells. Amiodarone repressed H9c2 cell viability and KCNH2 level and triggered apoptosis, ROS production and mitochondrial depolarization, while Sigmar1 upregulation reversed its effects. Moreover, KCNH2 silencing neutralized the combined modulation of amiodarone and Sigmar1 up-regulation on H9c2 cell viability, apoptosis, and ROS production. Amiodarone facilitates the apoptosis of H9c2 cells by restraining Sigmar1 expression and blocking KCNH2-related potassium channels.

State-independent inhibition of the oncogenic Kv10.1 channel by desethylamiodarone, a comparison with amiodarone

Kv10.1 is a voltage-dependent K channel whose ectopic expression is associated with several human cancers. Additionally, Kv10.1 has structure–function properties which are not yet well understood. We are using drugs of clinical importance in an attempt to gain insight on the relationship between pharmacology and characteristic functional properties of this channel. Herein, we report the interaction of desethylamiodarone (desAd), the active metabolic product of the antiarrhythmic amiodarone with Kv10.1: desAd binds to both closed and open channels, with most inhibition taking place from the open state, with affinity ~ 5 times smaller than that of amiodarone. Current inhibition by desAd and amiodarone is not synergistic. Upon repolarization desAd becomes trapped in Kv10.1 and thereafter dissociates slowly from closed-and-blocked channels. The addition of the Cole-Moore shift plus desAd open-pore-block time courses yields an increasing phase on the steady-state inhibition curve (H∞) at hyperpolarized holding potentials. In contrast to amiodarone, desAd does not inhibit the Kv10.1 Cole-Moore shift, suggesting that a relevant hydrophobic interaction between amiodarone and Kv10.1 participates in the inhibition of the Cole-Moore shift, which is lost with desAd.

The effect of amiodarone on the spectral parameters of heart rate variability in patients with various forms of atrial fibrillation

In this study, spectral parameters in patients with various forms of atrial fibrillation and the effect of the class III antiarrhythmic drug amiodarone on these parameters were studied. The use of spectral analysis of heart rate variability (hereinafter referred to as HRV) when choosing a drug for the treatment of arrhythmia and arterial hypertension is becoming increasingly widespread in experimental and clinical practice. This method, thanks to the mathematical analysis of the time and frequency characteristics of heart rate variability, allows you to get an idea of slow oscillatory processes that constantly exist in the body and have the properties of autowaves. The use of this method gives an idea of the role of various departments of the autonomic nervous system (sympathetic and parasympathetic), as well as the implementation of humoral mechanisms in the implementation of the chronotropic function of the heart.

Abstract 16093: Hemodynamic Implications of Transseptal Access for Ventricular Tachycardia Ablation in Patients With Left Ventricular Assist Devices

Introduction: Ventricular tachycardia (VT) is common in patients with left ventricular assist devices (LVAD), and catheter ablation can be an effective treatment strategy. Although transseptal approach for LV mapping and ablation is often preferred, iatrogenic atrial septal defect (ASD) after transseptal access may theoretically result in clinically significant right-to-left shunting. The short- and long-term implications of transseptal puncture, including hemodynamic changes in LVAD patients, remain uncertain. Methods and Results: From 2013-2023, 15 LVAD patients (age 68.5±12 years; 2 women) underwent 18 VT ablation procedures with single transseptal access for LV ablation without ASD closure afterwards. Clinical VT was eliminated in 83%. No patients had prior PFO/ASD; Mean RVSP was 45mmHg, 6 (40%) had pulmonary hypertension, and 8 (53.3%) had moderate or severe RV dysfunction. All patients had previously failed at least 1 antiarrhythmic drug (amiodarone 100%; sotalol 33%; mexiletine 94%). Procedural complications occurred in 3 procedures (all related to vascular access, none directly related to transseptal access; 1 patient with interrupted IVC requiring transhepatic access had bleeding due to transection of intercostal artery requiring arterial embolization). Post-procedure echocardiograms (n=14; mean time to echo 90±116 days) showed no intra-cardiac shunting or persistent ASD. Right heart catheterization (pre: n=12; post: n=8, at mean follow-up 187±243 days) showed similar pre- and post-ablation RA pressures (11.6 vs 14.9 mmHg, p =0.24) and wedge pressures (14.9 vs 20.4 mmHg, p =0.8) with absence of significant shunting based on pre- and post-ablation arterial (95.2% vs 97.7%, p =0.06) and PA oxygen saturations (56.5% vs 51.3%, p =0.29). No episodes of clinically significant hypoxia occurred after ablation. Conclusion: Transseptal access for VT ablation can be safely performed in LVAD patients and is unlikely to result in clinically or hemodynamically significant residual shunting over long-term follow-up. Therefore, empiric ASD closure after transseptal access in all LVAD patients is likely unnecessary.

Interaction of the antiarrhythmic drug Amiodarone with the sodium channel Nav1.5 depends on the extracellular pH

IntroductionAmiodarone (AMD) is a clinically used drug to treat arrhythmias with significant effect upon the cardiac sodium channel Nav1.5. AMD has a pKa of 6.56, and changes in extracellular pH (pHe) may alter its pharmacological properties. Here we explored how changes in pHe impacts the pharmacological properties of AMD upon human-Nav1.5-sodium-current (INa) and in ex vivo rat hearts. MethodsEmbryonic-human-kidney-cells (HEK293) were used to transiently express the human alpha-subunit of NaV1.5 channels and the isolated heart of Wistar rats were used. Patch-Clamp technique was deployed to study INa and for electrocardiogram (ECG) evaluation the ex vivo heart preparation in the Langendorff system was applied. ResultsThe potency of AMD upon peak INa was ∼25x higher in pHe 7.0 when compared to pHe 7.4. Voltage dependence for activation did not differ among all groups. AMD shifted the steady-state inactivation curve to more hyperpolarized potentials, with similar magnitudes for both pHes. The recovery from INa inactivation was delayed in the presence of AMD with similar profile in both pHes. Interestingly, the use-dependent properties of AMD was distinct at pHe 7.0 and 7.4. Finally, AMD was able to change the ex vivo ECG profile, however at pHe 7.0+AMD a larger increase in the RR and QRS duration and in the QT interval when compared to pHe 7.4 was found. ConclusionsThe pharmacological properties of AMD upon NaV1.5 and isolated heart preparation depends on the pHe and its use in vivo during extracellular acidosis may cause a distinct biological response in the heart tissue.

Exploring the inhibitory potential of the antiarrhythmic drug amiodarone against Clostridioides difficile toxins TcdA and TcdB

ABSTRACT The intestinal pathogen Clostridioides difficile is the leading cause of antibiotic-associated diarrhea and pseudomembranous colitis in humans. The symptoms of C. difficile-associated diseases (CDADs) are directly associated with the pathogen’s toxins TcdA and TcdB, which enter host cells and inactivate Rho and/or Ras GTPases by glucosylation. Membrane cholesterol is crucial during the intoxication process of TcdA and TcdB, and likely involved during pore formation of both toxins in endosomal membranes, a key step after cellular uptake for the translocation of the glucosyltransferase domain of both toxins from endosomes into the host cell cytosol. The licensed drug amiodarone, a multichannel blocker commonly used in the treatment of cardiac dysrhythmias, is also capable of inhibiting endosomal acidification and, as shown recently, cholesterol biosynthesis. Thus, we were keen to investigate in vitro with cultured cells and human intestinal organoids, whether amiodarone preincubation protects from TcdA and/or TcdB intoxication. Amiodarone conferred protection against both toxins independently and in combination as well as against toxin variants from the clinically relevant, epidemic C. difficile strain NAP1/027. Further mechanistic studies suggested that amiodarone’s mode-of-inhibition involves also interference with the translocation pore of both toxins. Our study opens the possibility of repurposing the licensed drug amiodarone as a novel pan-variant antitoxin therapeutic in the context of CDADs.

Клинические случаи хирургического лечения катаракты при амиодароновой кератопатии

Amiodarone-induced keratopathy occurs against the background of systemic use of the antiarrhythmic drug amiodarone, due to deposition of iodine molecules in the lysosomes of corneal cell elements. Amiodaronic keratopathy is not a contraindication to the surgical treatment of cataract. In LLC “Tri-Z”, Moscow branch 2 patients were operated for cataracts on the background of stage 2 amiodarone keratopathy. High functional results were obtained: Visus = 0.9–1.0. Considering the possibility of progressing corneal changes with subsequent transition to the projection area of the pupil against the background of taking this drug, a consultation with a arrhythmologist was recommended in order to resolve the issue of replacing amiodarone with another antiarrhythmic drug. Key words: amiodarone; keratopathy; cataract surgery.

Impact of concomitant cardiovascular medications on overall survival in patients with liver cirrhosis

Objectives of the article Liver cirrhosis is the end-stage liver disease associated with poor prognosis and cardiovascular comorbidity could significantly impact mortality of cirrhotic patients. We conducted a large, retrospective study to investigate the survival impact of cardiovascular co-medications in patients with liver cirrhosis. Materials and methods A study-specific R package was processed on the local databases of partner institutions within the Observational Health Data Sciences and Informatics consortium, namely Columbia University, New York City (NYC), USA and Ajou University School of Medicine (AUSOM), South Korea. Patients with cirrhosis diagnosed between 2000 and 2020 were included. Final analysis of the anonymous survival data was performed at Medical Faculty Mannheim, Heidelberg University. Results We investigated a total of 32,366 patients with liver cirrhosis. Our data showed that administration of antiarrhythmics amiodarone or digoxin presented as a negative prognostic indicator (p = 0.000 in both cohorts). Improved survival was associated with angiotensin-converting enzyme inhibitor ramipril (p = 0.005 in NYC cohort, p = 0.075 in AUSOM cohort) and angiotensin II receptor blocker losartan (p = 0.000 in NYC cohort, p = 0.005 in AUSOM cohort). Non-selective beta blocker carvedilol was associated with a survival advantage in the NYC (p = 0.000) cohort but not in the AUSOM cohort (p = 0.142). Patients who took platelet inhibitor clopidogrel had a prolonged overall survival compared to those without (p = 0.000 in NYC cohort, p = 0.003 in AUSOM cohort). Conclusion Concomitant cardiovascular medications are associated with distinct survival difference in cirrhotic patients. Multidisciplinary management is needed for a judicious choice of proper cardiovascular co-medications in cirrhotic patients.

QT prolongation-related ventricular arrhythmia associated with atrial fibrillation electrical cardioversion

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Atrial fibrillation (AF) is the most common arrhythmia, a leading cause of strokes, and associated with an increased mortality. Although electrical cardioversion of AF is considered a relatively safe procedure, post cardioversion QT prolongation-related ventricular arrhythmias (VA) may appear due to the combination of QT-prolonging anti-arrhythmic drugs, acute heart rate change from rapid AF into sinus bradycardia, electrolyte imbalance, etc. To date, there is still no consensus regarding the actual prevalence of this complication. Given the global tendency for early discharge during the same day of AF cardioversion, there is a crucial need to define the true prevalence of this phenomenon and the characteristics of these patients. Purpose Evaluate the prevalence of post AF cardioversion prolonged QT-related VA, and describe the characteristics of patients developing this complication. Method Single center retrospective analysis of all AF electrical cardioversions, during the last 3 years, which were followed by documented prolonged QT-related VA or sudden cardiac death (SCD) within 72 hours from cardioversion. Post cardioversion VA was detected by a computerized search of hospitalization records, 24-hour Holter recordings, and EMS strips. Results Out of 950 AF electrical cardioversions performed at our hospital during the last 3 years there were 4 cases with Torsades de Pointes (TdP) and 1 case of SCD occurring within 72 hours from cardioversion (5/950; 0.5%). All five patients were females, 3/5 with low LVEF and 4/5 on class III anti-arrhythmic drug (Amiodarone or Sotalol). Electrolyte abnormalities (including hypokalemia, hypomagnesemia, and hypocalcemia) were found in 3/5 patients and post cardioversion sinus bradycardia in 2/5 patients. Conclusion The incidence of post-AF cardioversion life threatening VA is low although non-negligible. Prolonged ECG monitoring and cautious follow-up of QTc should be recommended among patients, especially females with low LVEF, treated by class III anti-arrhythmic drugs. Post AF cardioversion same day discharge should be discouraged in these patients.

Severe heart failure with rapid arrhythmia: Treatment with amiodarone and esmolol and its effect on TGF-β1, APN and PIIINP

Rapid arrhythmia (RA) is a major complication of severe heart failure (SHF). Treatment with anti-arrhythmic drug amiodarone though improves the myocardial blood supply and suppress arrhthmia, its clinical application is unsatisfactory. Amiodarone combined with another class II antiarrhythmic drug, esmolol shows rapid onset and good efficacy. Here, we studied the effects of amiodarone and esmolol in severe heart failure (SHF) with rapid arrhythmia (RA) and its effect on TGF-β1, APN and PIIINP. A total of 180 SHF patients with RA treated at Zhejiang Provincial Hospital of Traditional Chinese Medicine were selected and divided into experimental group (n = 90) and control group (n = 90) according to the random number table method. The control group was given routine therapy + amiodarone therapy, and the experimental group was given routine therapy + amiodarone + esmolol therapy. Cardiac function measures including cardiac index (CI), mean arterial pressure (MAP) and ejection fraction (LVEF), diastolic blood pressure (DBP), systolic blood pressure (SBP) and heart rate (HR), serum TGF-β1, APN and PIIINP levels were observed in both groups before and 48 h after treatment. After treatment, the CI, MAP and LVEF of the experimental group were greater than those of the control group (P&lt;0.05); DBP, SBP and HR were greater (or higher) in the experimental group than in the control group (P&lt;0.05); serum TGF-β1 and PIIINP levels in experimental groups were all lower than in control group and serum APN levels were higher (P&lt;0.05) than in control group. The total effective rate of the experimental group was less than that of the control group (P&lt;0.05). There was no difference in the incidence of adverse effects between the two groups (P&gt;0.05). The results indicate that treatment of severe heart failure (SHF) with rapid arrhythmia (RA) by amiodarone and esmolol may safely enhance cardiac function, blood pressure and heart rate, improve efficacy, inhibit the progression of myocardial fibrosis, and improve serum TGF-β1, APN and PIIINP levels.

300 LITERATURE CASE SERIES REVIEW ON LANDIOLOL IN ACUTE DECOMPENSATED HEART FAILURE SECONDARY TO TACHYARRHYTHMIAS

Abstract Introduction Landiolol is a recently innovated ultra-short-acting beta-blocker. Landiolol is the only beta-blocker with a specific dose recommendation for patients with cardiac dysfunction and acute atrial fibrillation (Class I recommendation according to the ESC guidelines). Landiolol has a shorter elimination half-life than any other beta-blocker, and it can be administered safely to patients with various tachyarrhythmias. The short duration of action and titratability of landiolol makes it ideal for use in critically ill patients. Purpose of the Study Review the case reports in the literature on the administration of landiolol in critically ill patients with acute decompensated heart failure (ADHF) secondary to tachyarrhythmias. Methods 11 case reports of ADHF secondary to tachyarrhythmias were identified. Personal, clinical and humoral data were collected. The heart rate and systolic pressure values in the time before and after the administration of Landiolol were plotted in a summary graph. Results The mean age of the 11 patients was 55 years old with high proBNP values at admission. The etiological diagnosis of heart failure was heterogeneous but tachyarrhythmia was the trigger event in all patients. Patients were critically ill with a mean EF of 26 ± 16% and an initial shock index of 1.4 ±0.5. Landiolol administered together with other antiarrhythmic drugs (amiodarone in 4/11 patients), epinephrine/norepinephrine (9/11) and levosimendan (4/11) favoured heart rate lowering and an increase in systolic blood pressure.At discharge, 4/11 had improved EF, in 10/11 sinus rhythm was restored, and all patients recovered hemodynamic stability without adverse events related to Landiolol (Figure 1). Conclusion In this case series review, Landiolol was a useful strategy in patients with ADHF refractory to conventional therapy by facilitating rate/rhythm control, limiting the toxicity of inotropic drugs and improving the hemodynamic profile. Figure 1

Gender electrocardiographic features in patients with drug-induced long QT syndrome caused by antiarrhythmic therapy

Female gender is traditionally considered to be a risk factor for the QT interval prolongation and polymorphic ventricular tachycardia «torsades de pointes». However, despite a large number of studies on electrocardiographic features in patients with congenital long QT interval syndrome, there is relatively little information on gender ECG differences in the drug-induced QT interval prolongation.The aim of this study is to evaluate the gender characteristics of electrocardiographic parameters characterizing myocardial depolarization and repolarization in patients with drug-induced QT interval prolongation induced by class III antiarrhythmic drugs.67 patients with drug-induced QT interval prolongation induced class III antiarrhythmic drugs (amiodarone or sotalol) were examined, of which 38 (56.8 %) women and 29 (43.2 %) men, mean age – 57.1 ± 9.5 years. All patients underwent clinical laboratory and non-invasive electrophysiological studies, which included 12-lead ECG recording and 24-hour Holter monitoring. The patients of both genders were comparable in age and clinical characteristics, with the exception of a higher prevalence of AF in men (82.7 % vs 52.6 %, p = 0.03). The total duration of taking class III antiarrhythmic drugs in male patients was 3.79 ± 1.49 days, which significantly differed from female patients (3.11 ± 1.15 days, p = 0.044). When analyzing the initial standard ECG of patients recorded before starting antiarrhythmic drugs, there were no statistically significant differences between the groups, with the exception of large values of the corrected cardioelectrophysiological balance index (QTc/QRS) in female patients ( p = 0.037). While taking class III antiarrhythmic drugs, women had a higher duration of QTc ( p = 0.03) and JTc ( p = 0.023) intervals, as well as a dispersion of QT ( p = 0.012) and JT ( p = 0.006) intervals. According to Holter monitoring data, female patients were more likely to have an increased risk of developing non-sustained polymorphic VT ( p = 0.105).These results suggest a complex interplay between gender and repolarization that needs further investigation. Considering the gender characteristics of the process of myocardial repolarization, it should be taken into account not only when prescribing class III antiarrhythmic drugs to women, but also during preclinical and clinical development of drugs that have the QT interval prolonging effect.