-
British Journal of Pharmacology Sep 2022HERG blocking drugs known for their propensity to trigger Torsades de Pointes (TdP) were reported to induce a sympatho-vagal coactivation and to enhance High Frequency...
BACKGROUND AND PURPOSE
HERG blocking drugs known for their propensity to trigger Torsades de Pointes (TdP) were reported to induce a sympatho-vagal coactivation and to enhance High Frequency heart rate (HFHR) and QT oscillations (HFQT) in telemetric data. The present work aimed to characterize the underlying mechanism(s) leading to these autonomic changes.
EXPERIMENTAL APPROACH
Effects of 15 torsadogenic hERG blocking drugs (astemizole, chlorpromazine, cisapride, droperidol, ibutilide, dofetilide, haloperidol, moxifloxacin, pimozide, quinidine, risperidone, sotalol, sertindole, terfenadine, and thioridazine) were assessed by telemetry in beagle dogs. Haemodynamic effects on diastolic and systolic arterial pressure were analysed from the first doses causing QTc prolongation and/or HFQT oscillations enhancement. Autonomic control changes were analysed using the high frequency autonomic modulation (HFAM) model.
KEY RESULTS
Except for moxifloxacin and quinidine, all torsadogenic hERG blockers induced parasympathetic activation or sympatho-vagal coactivation combined with enhancement of HFQT oscillations. These autonomic effects result from reflex compensatory mechanisms in response to mild haemodynamic side effects. These haemodynamic mechanisms were characterized by transient HR acceleration during HF oscillations. A phenomenon of concealed QT prolongation was unmasked for several torsadogenic hERG blockers under β-adrenoceptor blockade with atenolol. Resulting enhancement of HFQT oscillations was shown to contribute directly to triggering dofetilide-induced ventricular arrhythmias.
CONCLUSION AND IMPLICATIONS
This work supports for the first time a contribution of haemodynamic side properties to ventricular arrhythmias triggered by torsadogenic hERG blocking drugs. These haemodynamic side effects may constitute a second component of their arrhythmic profile, acting as a trigger alongside their intrinsic arrhythmogenic electrophysiological properties.
Topics: Animals; Arrhythmias, Cardiac; Dogs; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Ether-A-Go-Go Potassium Channels; Heart Rate; Long QT Syndrome; Moxifloxacin; Quinidine; Reflex; Torsades de Pointes
PubMed: 35751378
DOI: 10.1111/bph.15905 -
The Science of the Total Environment Oct 2022The removal of emerging pollutants from municipal wastewater was studied for the first time using a three-step pilot-scale system: 1) hybrid digester (HD) as first step,...
The removal of emerging pollutants from municipal wastewater was studied for the first time using a three-step pilot-scale system: 1) hybrid digester (HD) as first step, 2) subsurface vertical flow constructed wetland (VF) as second step, and 3) photodegradation (PD) unit as third step or post-treatment. The HD and VF units were built and operated in series with effluent recirculation at pilot scale. For the PD post-treatment, three alternatives were studied at lab-scale, i) UVC irradiation at 254 nm (0.5 h exposure time), ii) UVA irradiation at 365 nm using a TiO-based photocatalyst and iii) sunlight irradiation using a TiO-based photocatalyst, the last two for 1 and 2 h. Alternative iii) was also tested at pilot-scale. Degradation of nine compounds was evaluated: acetaminophen (ACE), caffeine (CAF), carbamazepine (CBZ), ketoprofen (KET), ibuprofen (IBU), diclofenac (DCL), clofibric acid (ACB), bisphenol A (BPA), and sotalol (SOT). Overall, the HD-VF-UVC system completely removed (>99.5 %) ACE, CAF, KET, IBU, DCL and ACB, and to a lesser extent SOT (98 %), BPA (83 %) and CBZ (51 %). On the other hand, the HD-VF-UVA/TiO system (at 2 h) achieved >99.5 % removal of ACE, CAF, KET, IBU and DCL while ACB, BPA, CBZ and SOT were degraded by 83 %, 81 %, 78 % and 68 %, respectively. Working also at 2 h of exposure time, in summer conditions, the HD-VF-Sol/TiO system achieved >99.5 % removal of ACE, CAF, KET, IBU, DCL and ACB, and to a minor extent BPA (80 %), SOT (74 %) and CBZ (69 %). Similar results, although slightly lower for SOT (60 %) and CBZ (59 %), were obtained in the pilot sunlight plus TiO catalyst unit. However, the use of sunlight irradiation with a TiO-based photocatalyst clearly showed lower removal efficiency in autumn conditions (i.e., 47 % SOT, 31 % CBZ).
Topics: Carbamazepine; Diclofenac; Environmental Pollutants; Photolysis; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Wetlands
PubMed: 35750172
DOI: 10.1016/j.scitotenv.2022.156750 -
Function (Oxford, England) 2022β-adrenergic receptor (β-AR) signaling in cardiac myocytes is central to cardiac function, but spatiotemporal activation within myocytes is unresolved. In rabbit...
β-adrenergic receptor (β-AR) signaling in cardiac myocytes is central to cardiac function, but spatiotemporal activation within myocytes is unresolved. In rabbit ventricular myocytes, β-AR agonists or high extracellular [Ca] were applied locally at one end, to measure β-AR signal propagation as Ca-transient (CaT) amplitude and sarcoplasmic reticulum (SR) Ca uptake. High local [Ca], increased CaT amplitude under the pipette faster than did ISO, but was also more spatially restricted. Local isoproterenol (ISO) or norepinephrine (NE) increased CaT amplitude and SR Ca uptake, that spread along the myocyte to the unexposed end. Thus, local [Ca] decline kinetics reflect spatio-temporal progression of β-AR end-effects in myocytes. To test whether intracellular β-ARs contribute to this response, we used β-AR-blockers that are membrane permeant (propranolol) or not (sotalol). Propranolol completely blocked NE-dependent CaT effects. However, blocking surface β-ARs only (sotalol) suppressed only ∼50% of the NE-induced increase in CaT peak and rate of [Ca] decline, but these changes spread more gradually than NE alone. We also tested whether A-kinase anchoring protein 7γ (AKAP7γ; that interacts with phospholamban) is mobile, such that it might contribute to intracellular spatial propagation of β-AR signaling. We found AKAP7γ to be highly mobile using fluorescence recovery after photobleach of GFP tagged AKAP7γ, and that PKA activation accelerated AKAP7γ-GFP wash-out upon myocyte saponin-permeabilization, suggesting increased AKAP7γ mobility. We conclude that local β-AR activation can activate SR Ca uptake at remote myocyte sites, and that intracellular β-AR and AKAP7γ mobility may play a role in this spread of activation.
Topics: Animals; Rabbits; Adrenergic Agents; Calcium; Calcium Signaling; Calcium, Dietary; Isoproterenol; Myocytes, Cardiac; Propranolol; Receptors, Adrenergic, beta; Sotalol; Adaptor Proteins, Signal Transducing
PubMed: 35620477
DOI: 10.1093/function/zqac020 -
Journal of Cardiology Cases May 2022A 9-year-old boy, diagnosed with double outlet right ventricle after birth, suffered sinus node dysfunction and non-sustained junctional tachycardia after an...
A 9-year-old boy, diagnosed with double outlet right ventricle after birth, suffered sinus node dysfunction and non-sustained junctional tachycardia after an extracardiac total cavopulmonary connection (TCPC). Spontaneous atrial tachycardia appeared 3 years after an extracardiac TCPC. Sotalol was administered but the bradycardia was obvious. It was difficult to increase sotalol and atrial tachycardia was uncontrollable. Atrial tachycardia continued with symptoms; direct current (DC) cardioversion was frequently required. Five years after extracardiac TCPC, we implanted a pacemaker with atrial antitachycardia pacing (ATP) using epicardial leads. On day 2 post operation, wide QRS tachycardia appeared. Due to decreased blood pressure, DC cardioversion was immediately performed, but it recurred from atrial premature contraction. We judged this was atrial tachycardia with 1:1 atrioventricular conduction based on an intracardiac electrogram and it was terminated by burst atrial pacing from the pacemaker. After changing atrial pacing rate to 150 ppm, atrial tachycardia could be suppressed. Due to atrial pacing and increasing sotalol gradually, junctional tachycardia terminated spontaneously, and atrial tachycardia was not induced after pacemaker implantation. In conclusion, implantation of a pacemaker with ATP and intensification of antiarrhythmic drugs is an effective treatment strategy for pediatric patients with bradycardia-tachycardia syndrome after extracardiac TCPC. < The treatment for bradycardia-tachycardia syndrome in children after extracardiac total cavopulmonary connection (TCPC) is challenging. The appropriate antiarrhythmic drugs for atrial tachycardia cannot be administered due to bradycardia, and it is often difficult to perform radiofrequency catheter ablation on small children. Surgical pacemaker implantation, although invasive, is the most effective treatment for bradycardia-tachycardia syndrome in small children after extracardiac TCPC.>.
PubMed: 35582084
DOI: 10.1016/j.jccase.2021.10.008 -
Journal of the American Heart... May 2022Background There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease,...
Background There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease, including those with severe myocardial dysfunction. A multicenter registry study was designed to evaluate the safety, efficacy, and dosing of IV sotalol. Methods and Results A total of 85 patients (age 1 day-36 years) received IV sotalol, of whom 45 (53%) had additional congenital cardiac diagnoses and 4 (5%) were greater than 18 years of age. In 79 patients (93%), IV sotalol was used to treat supraventricular tachycardia and 4 (5%) received it to treat ventricular arrhythmias. Severely decreased cardiac function by echocardiography was seen before IV sotalol in 7 (9%). The average dose was 1 mg/kg (range 0.5-1.8 mg/kg/dose) over a median of 60 minutes (range 30-300 minutes). Successful arrhythmia termination occurred in 31 patients (49%, 95% CI [37%-62%]) with improvement in rhythm control defined as rate reduction permitting overdrive pacing in an additional 18 patients (30%, 95% CI [19%-41%]). Eleven patients (16%) had significant QTc prolongation to >465 milliseconds after the infusion, with 3 (4%) to >500 milliseconds. There were 2 patients (2%) for whom the infusion was terminated early. Conclusions IV sotalol was safe and effective for termination or improvement of tachyarrhythmias in 79% of pediatric patients and patients with congenital heart disease, including those with severely depressed cardiac function. The most common dose, for both acute and maintenance dosing, was 1 mg/kg over ~60 minutes with rare serious complications.
Topics: Arrhythmias, Cardiac; Child; Heart Defects, Congenital; Humans; Infant; Registries; Sotalol; Tachycardia, Supraventricular
PubMed: 35491986
DOI: 10.1161/JAHA.121.024375 -
Frontiers in Cardiovascular Medicine 2022Whether early pharmacologic cardioversion is necessary for recent-onset atrial fibrillation is still controversial. Current meta-analyses were limited to evaluating the...
Effect of Early Pharmacologic Cardioversion vs. Non-early Cardioversion in the Patients With Recent-Onset Atrial Fibrillation Within 4-Week Follow-Up Period: A Systematic Review and Network Meta-Analysis.
BACKGROUND
Whether early pharmacologic cardioversion is necessary for recent-onset atrial fibrillation is still controversial. Current meta-analyses were limited to evaluating the effects within 24 h without sufficient considering longer follow-up outcomes. We aimed to compare the effect of early pharmacologic cardioversion and non-early cardioversion in patients with recent-onset atrial fibrillation within 4-weeks of follow-up.
METHODS
We searched the Cochrane Library, EMBASE, MEDLINE, PubMed, Web of Science, ClinicalTrials.gov, and Clinicaltrialsregister. eu for randomized controlled trials (RCTs) published before November 2021 comparing early pharmacologic cardioversion and non-early cardioversion in recent-onset atrial fibrillation and synthesized data in accordance with PRISMA-Systematic Reviews and Network Meta-Analysis (NMA). Early pharmacological cardioversion referred to immediate cardioversion with antiarrhythmic drugs (i.e., amiodarone, propafenone, flecainide, tedisamil, vernakalant, vanoxerine, and sotalol) upon admission, while non-early cardioversion involved the administration of rate-control or placebo medication without immediate cardioversion.
RESULTS
16 RCTs with 2,395 patients were included. Compared to non-early cardioversion, a systematic review showed that early pharmacologic cardioversion resulted in a higher probability of sinus rhythm maintenance within 24 h (odds ratios [OR] 2.50, 95% credible interval [CrI] 1.76 to 3.54) and 1-week (2.50, 1.76 to 3.54), however, there was no significant difference in sinus rhythm maintenance within 4-weeks (1.37, 0.90 to 2.09). In subgroup analysis, the Bayesian NMA revealed that vernakalant may be successful in sinus rhythm maintenance within both 24 h (3.55, 2.28 to 5.55) and 1-week (2.72, 1.72 to 4.31). The results were consistent with the frequentist NMA.
CONCLUSIONS
Non-early pharmacologic cardioversion may not be inferior to early cardioversion within a 4-week follow-up period in patients with recent-onset atrial fibrillation. The evidence remains insufficient to determine which antiarrhythmic agent is optimal in the longer run. Further high-quality relevant RCTs are necessary.
CLINICAL TRIAL REGISTRATION
PROSPERO CRD42020166862.
PubMed: 35479281
DOI: 10.3389/fcvm.2022.843939 -
Journal of the American College of... Apr 2022In patients with ischemic cardiomyopathy and an implantable cardioverter-defibrillator (ICD), catheter ablation and antiarrhythmic drugs (AADs) reduce ICD shocks, but... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In patients with ischemic cardiomyopathy and an implantable cardioverter-defibrillator (ICD), catheter ablation and antiarrhythmic drugs (AADs) reduce ICD shocks, but the most effective approach remains uncertain.
OBJECTIVES
This trial compares the efficacy and safety of catheter ablation vs AAD as first-line therapy in ICD patients with symptomatic ventricular tachycardias (VTs).
METHODS
The SURVIVE-VT (Substrate Ablation vs Antiarrhythmic Drug Therapy for Symptomatic Ventricular Tachycardia) is a prospective, multicenter, randomized trial including patients with ischemic cardiomyopathy and appropriated ICD shock. Patients were 1:1 randomized to complete endocardial substrate-based catheter ablation or antiarrhythmic therapy (amiodarone + beta-blockers, amiodarone alone, or sotalol ± beta-blockers). The primary outcome was a composite of cardiovascular death, appropriate ICD shock, unplanned hospitalization for worsening heart failure, or severe treatment-related complications.
RESULTS
In this trial, 144 patients (median age, 70 years; 96% male) were randomized to catheter ablation (71 patients) or AAD (73 patients). After 24 months, the primary outcome occurred in 28.2% of patients in the ablation group and 46.6% of those in the AAD group (hazard ratio [HR]: 0.52; 95% CI: 0.30-0.90; P = 0.021). This difference was driven by a significant reduction in severe treatment-related complications (9.9% vs 28.8%, HR: 0.30; 95% CI: 0.13-0.71; P = 0.006). Eight patients were hospitalized for heart failure in the ablation group and 13 in the AAD group (HR: 0.56; 95% CI: 0.23-1.35; P = 0.198). There was no difference in cardiac mortality (HR: 0.93; 95% CI: 0.19-4.61; P = 0.929).
CONCLUSIONS
In ICD patients with ischemic cardiomyopathy and symptomatic VT, catheter ablation reduced the composite endpoint of cardiovascular death, appropriate ICD shock, hospitalization due to heart failure, or severe treatment-related complications compared to AAD. (Substrate Ablation vs Antiarrhythmic Drug Therapy for Symptomatic Ventricular Tachycardia [SURVIVE-VT]: NCT03734562).
Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Cardiomyopathies; Catheter Ablation; Defibrillators, Implantable; Female; Heart Failure; Humans; Male; Myocardial Ischemia; Prospective Studies; Tachycardia, Ventricular; Treatment Outcome
PubMed: 35422240
DOI: 10.1016/j.jacc.2022.01.050 -
The Egyptian Heart Journal : (EHJ) :... Apr 2022Accessory mitral valve tissue (AMVT) is a rare congenital cardiac anomaly that mainly diagnosed in the first decade of life. However, asymptomatic cases may not be...
BACKGROUND
Accessory mitral valve tissue (AMVT) is a rare congenital cardiac anomaly that mainly diagnosed in the first decade of life. However, asymptomatic cases may not be diagnosed even up to adulthood. We report a fetus with AMVT to show the diagnostic ability of the fetal echocardiography for detection of this pathology in the prenatal period.
CASE PRESENTATION
AMVT was diagnosed in a 26-week-old male fetus with persistent dysrhythmia. Dysrhythmia could not be aborted and controlled by sotalol till the third trimester evaluation. Apical left ventricular (LV) diverticulum was the additional finding in his fetal echocardiogram. After birth, he was in sinus rhythm and echocardiography confirmed the presence of AMVT, however, without any evidence of LV apical diverticulum.
CONCLUSIONS
The diagnosis of AMVT in the prenatal period is possible by fetal echocardiography.
PubMed: 35403983
DOI: 10.1186/s43044-022-00263-z -
Journal of Veterinary Internal Medicine Mar 2022Transvenous electrical cardioversion (TVEC) is 1 of the main treatment options for atrial fibrillation (AF) in horses. Large-scale studies on factors affecting success...
BACKGROUND
Transvenous electrical cardioversion (TVEC) is 1 of the main treatment options for atrial fibrillation (AF) in horses. Large-scale studies on factors affecting success and prognosis have primarily been performed in Standardbred populations.
HYPOTHESIS/OBJECTIVES
To determine factors affecting cardioversion success, cardioversion difficulty and recurrence in a predominant Warmblood study sample.
ANIMALS
TVEC records of 199 horses.
METHODS
Retrospective study of TVEC procedures of horses admitted for AF without severe echocardiographic abnormalities. Horse and procedural factors for success and cumulative amount of energy (≤ 600 J vs > 600 J) were determined using multivariable logistic regression. A survival analysis was performed to determine risk factors for recurrence.
RESULTS
Two hundred and thirty-one TVEC procedures were included, with a 94.4% success rate and 31.9% recurrence rate (51/160). Mitral regurgitation (OR 0.151, 95% CI 0.032-0.715, P = .02) and AF cycle length (OR 1.05, 95% CI 1.01-1.09, P = .02) were independent determinants for success. Catheter type (OR 0.154, 95% CI 0.074-0.322, P < .001), previous AF episode (OR 3.10, 95% CI 1.20-8.01, P = .02), tricuspid regurgitation (OR 2.54, 95% CI 1.25-5.13, P = .01), and body weight (OR 1.009, 95% CI 1.003-1.015, P = .004) were significantly correlated with cumulative amount of energy delivered. Significant risk factors for recurrence after a first AF episode were sex (stallion; HR 3.05, 95% CI 1.34-6.95, P = .008), mitral regurgitation (HR 1.91, 95% CI 1.08-3.38, P = .03), and AF duration (HR 1.001, 95% CI 1.0001-1.0026, P = .04).
CONCLUSIONS AND CLINICAL IMPORTANCE
Both horse and procedural factors should be considered when assessing treatment options and prognosis in horses with AF.
Topics: Animals; Atrial Fibrillation; Echocardiography; Electric Countershock; Horse Diseases; Horses; Male; Recurrence; Retrospective Studies
PubMed: 35246994
DOI: 10.1111/jvim.16395 -
Journal of the American Heart... Mar 2022Background Guideline recommendations are the accepted reference for selection of therapies for rhythm control of atrial fibrillation (AF). This study was designed to...
Background Guideline recommendations are the accepted reference for selection of therapies for rhythm control of atrial fibrillation (AF). This study was designed to understand physicians' treatment practices and adherence to guidelines. Methods and Results The AIM-AF (Antiarrhythmic Medication for Atrial Fibrillation) study was an online survey of clinical cardiologists and electrophysiologists that was conducted in the United States and Europe (N=629). Respondents actively treated ≥30 patients with AF who received drug therapy, and had received or were referred for ablation every 3 months. The survey comprised 96 questions on physician demographics, AF types, and treatment practices. Overall, 54% of respondents considered guidelines to be the most important nonpatient factor influencing treatment choice. Across most queried comorbidities, amiodarone was selected by 60% to 80% of respondents. Other nonadherent usage included sotalol by 21% in patients with renal impairment; dofetilide initiation (16%, United States only) outside of hospital; class Ic agents by 6% in coronary artery disease; and dronedarone by 8% in patients with heart failure with reduced ejection fraction. Additionally, rhythm control strategies were frequently chosen in asymptomatic AF (antiarrhythmic drugs [AADs], 35%; ablation, 8%) and subclinical AF (AADs, 38%; ablation, 13%). Despite guideline algorithms emphasizing safety first, efficacy (48%) was selected as the most important consideration for AAD choice, followed by safety (34%). Conclusions Despite surveyed clinicians recognizing the importance of guidelines, nonadherence was frequently observed. While deviation may be reasonable in selected patients, in general, nonadherence has the potential to compromise patient safety. These findings highlight an underappreciation of the safe use of AADs, emphasizing the need for interventions to support optimal AAD selection.
Topics: Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Physicians; Surveys and Questionnaires; Treatment Outcome; United States
PubMed: 35243874
DOI: 10.1161/JAHA.121.023838