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Europace : European Pacing,... Jun 2024Patients with persistent atrial fibrillation (AF) experience 50% recurrence despite pulmonary vein isolation (PVI), and no consensus is established for secondary...
AIMS
Patients with persistent atrial fibrillation (AF) experience 50% recurrence despite pulmonary vein isolation (PVI), and no consensus is established for secondary treatments. The aim of our i-STRATIFICATION study is to provide evidence for stratifying patients with AF recurrence after PVI to optimal pharmacological and ablation therapies, through in silico trials.
METHODS AND RESULTS
A cohort of 800 virtual patients, with variability in atrial anatomy, electrophysiology, and tissue structure (low-voltage areas, LVAs), was developed and validated against clinical data from ionic currents to electrocardiogram. Virtual patients presenting AF post-PVI underwent 12 secondary treatments. Sustained AF developed in 522 virtual patients after PVI. Second ablation procedures involving left atrial ablation alone showed 55% efficacy, only succeeding in the small right atria (<60 mL). When additional cavo-tricuspid isthmus ablation was considered, Marshall-PLAN sufficed (66% efficacy) for the small left atria (<90 mL). For the bigger left atria, a more aggressive ablation approach was required, such as anterior mitral line (75% efficacy) or posterior wall isolation plus mitral isthmus ablation (77% efficacy). Virtual patients with LVAs greatly benefited from LVA ablation in the left and right atria (100% efficacy). Conversely, in the absence of LVAs, synergistic ablation and pharmacotherapy could terminate AF. In the absence of ablation, the patient's ionic current substrate modulated the response to antiarrhythmic drugs, being the inward currents critical for optimal stratification to amiodarone or vernakalant.
CONCLUSION
In silico trials identify optimal strategies for AF treatment based on virtual patient characteristics, evidencing the power of human modelling and simulation as a clinical assisting tool.
Topics: Atrial Fibrillation; Humans; Catheter Ablation; Pulmonary Veins; Anti-Arrhythmia Agents; Recurrence; Treatment Outcome; Models, Cardiovascular; Computer Simulation; Action Potentials; Risk Assessment; Heart Atria; Male; Anisoles; Patient Selection; Female; Patient-Specific Modeling; Middle Aged; Pyrrolidines; Electrocardiography; Clinical Decision-Making
PubMed: 38870348
DOI: 10.1093/europace/euae150 -
Endocrine Reviews Jun 2024Iodine is a micronutrient that is required for thyroid hormone synthesis. The iodide cycle in thyroid hormone synthesis consists of a series of transport, oxidation,...
Iodine is a micronutrient that is required for thyroid hormone synthesis. The iodide cycle in thyroid hormone synthesis consists of a series of transport, oxidation, organification, and binding/coupling steps in thyroid follicular cells. Common sources of iodine include the consumption of an iodine-rich diet or iodine fortified foods, the administration of amiodarone, iodine-containing supplements, or iodinated contrast media, and other miscellaneous sources. Methods to assess population iodine status include the measurement of urinary iodine concentrations, blood thyroglobulin levels, prevalence of elevated neonatal TSH levels, and thyroid volume. Although excessive iodine intake or exposure is generally well tolerated, an acute iodine load may result in thyroid dysfunction (hypothyroidism or hyperthyroidism) in certain susceptible individuals due to the failure to escape from the Wolff-Chaikoff effect and to the Jod-Basedow phenomenon, respectively. In this review, we discuss the associations between excessive iodine intake or exposure, with particular focus on iodinated contrast media as a common source of excess iodine in healthcare settings, and risks of incident thyroid dysfunction. We also summarize the risks of iodine excess in vulnerable populations and review current guidelines regarding the screening and monitoring of iodinated contrast-induced thyroid dysfunction. Finally, we discuss the long-term potential nonthyroidal health risks associated with iodine excess and suggest the need for more data to define safe upper limits for iodine intake, particularly in high-risk populations.
PubMed: 38870258
DOI: 10.1210/endrev/bnae019 -
Cardiology in Review Jun 2024Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice projected to affect 12.1 million individuals by the year 2030. Patients...
Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice projected to affect 12.1 million individuals by the year 2030. Patients who are diagnosed with AF have an increased risk of morbidity and mortality. Although catheter ablation is a class I treatment recommendation in patients with symptomatic paroxysmal AF, antiarrhythmic medications (AAM) continue to be the mainstay of treatment in limited resource settings not offering ablation procedures. Currently, the most used AAMs are those which block either the sodium or potassium channels. We hypothesized that the use of selective dual AAM (sodium and potassium channel blockers) (DAAM) improves the chance of maintaining sinus rhythm and decreases the need for catheter ablation when compared with single AAM (SAAM). This retrospective observational study was conducted in 150 patients with paroxysmal AF over 5 years at Richmond University Medical Center in Staten Island, New York. The following data were collected: age, sex, comorbidities, electrocardiogram findings, ejection fraction by echocardiography, classes of AAM, duration, and response to treatments. The primary endpoint included the absence of symptoms and maintenance of sinus rhythm. The secondary endpoint included the requirement of electrical cardioversion or catheter ablation. A total of 86 patients met the inclusion criteria in our analysis. The average age of the patients was 71.06 years (SD = 7.66). About 45 patients were given DAAM of either amiodarone + flecainide or dronedarone + flecainide and were treated for an average of 15.4 months, followed by catheter ablation, if needed. Also, 41 patients received a SAAM followed by catheter ablation, if needed. A Mann-Whitney test indicated that electrical cardioversion and catheter ablation were greater for the SAAM group (Md = 1) than for the DAAM group (Md = 0) (U = 294.00, P value <0.001; U = 507.00, P value <0.001, respectively). No pro-arrhythmic side effects or death were encountered in either group. Treatment of paroxysmal AF with DAAM is effective compared with SAAM and is less likely to need catheter ablation or electrical cardioversion. Well-designed prospective studies are needed to further explore the use of DAAM in the management of paroxysmal AF and its clinical impact in limited resource settings.
PubMed: 38869272
DOI: 10.1097/CRD.0000000000000738 -
European Heart Journal Supplements :... Apr 2024Arrhythmic storm is a clinical emergency associated with high mortality, which requires multi-disciplinary management. Reprogramming of the implantable cardiac...
Arrhythmic storm is a clinical emergency associated with high mortality, which requires multi-disciplinary management. Reprogramming of the implantable cardiac defibrillator (ICD) aimed at reducing shocks, adrenergic blockade using beta-blockers, sedation/anxiolysis, and blockade of the stellate ganglion represent the first simple and effective manoeuvres, but further suppression of arrhythmias with antiarrhythmics is often required. A low-risk patient (e.g. monomorphic ventricular tachycardia, functioning ICD, and haemodynamically stable) should be managed with a beta-blocker (possibly non-selective) plus amiodarone, in addition to sedation with a benzodiazepine or dexmedetomidine; in patients at greater risk (high burden and haemodynamic instability), autonomic modulation with blockade of the stellate ganglion and the addition of a second antiarrhythmic (lidocaine) should be considered. In patients refractory to these measures, with advanced heart failure, general anaesthesia with intubation and the establishment of a haemodynamic circulatory support should be considered. Ablation, performed early, appears to be superior in terms of mortality and reduction of future shocks compared with titration of antiarrhythmics.
PubMed: 38867867
DOI: 10.1093/eurheartjsupp/suae016 -
Resuscitation Jun 2024Out-of-hospital cardiac arrest (OHCA) complicated by refractory ventricular fibrillation (VF) is associated with poor outcome. Beta-1-receptor selective blockade might...
BACKGROUND
Out-of-hospital cardiac arrest (OHCA) complicated by refractory ventricular fibrillation (VF) is associated with poor outcome. Beta-1-receptor selective blockade might overcome refractory VF and improve survival. This trial investigates the efficacy and safety of prehospital landiolol in OHCA and refractory VF.
METHODS
In this randomized, double-blind, placebo-controlled pilot trial, patients with OHCA and recurrent or refractory VF (at least 3 defibrillation attempts and last rhythm shockable), pretreated with epinephrine and amiodarone, were allocated to receive add-on treatment with landiolol or placebo. Landiolol was given as a 20 mg bolus infusion. The primary efficacy outcome was time from trial drug infusion to sustained return of spontaneous circulation (ROSC). Safety outcomes included the onset of bradycardia and asystole.
RESULTS
A total of 36 patients were enrolled, 19 were allocated to the landiolol group and 17 to the placebo group. Time from trial drug infusion to sustained ROSC was similar between treatment groups (39 min [landiolol] versus 41 min [placebo]). Sustained ROSC was numerically lower in the landiolol group compared with the placebo group (7 patients [36.8%] versus 11 patients [64.7%], respectively). Asystole within 15 min of trial drug infusion occurred significantly more often in the landiolol group than in the placebo group (7 patients [36.8%] and 0 patients [0.0%], respectively).
CONCLUSION
In patients with OHCA and refractory VF who are pretreated with epinephrine and amiodarone, add-on bolus infusion of landiolol 20 mg did not lead to a shorter time to sustained ROSC compared with placebo. Landiolol might be associated with bradycardia and asystole.
PubMed: 38866231
DOI: 10.1016/j.resuscitation.2024.110273 -
Netherlands Heart Journal : Monthly... Jun 2024When electrical storm (ES) is amenable to neither antiarrhythmic drugs, nor deep sedation or catheter ablation, autonomic modulation may be considered. We report our...
INTRODUCTION
When electrical storm (ES) is amenable to neither antiarrhythmic drugs, nor deep sedation or catheter ablation, autonomic modulation may be considered. We report our experience with percutaneous left stellate ganglion block (PSGB) to temporarily suppress refractory ventricular arrhythmia (VA) in patients with structural heart disease.
METHODS
A retrospective analysis was performed at our institution of patients with structural heart disease and an implantable cardioverter defibrillator (ICD) who had undergone PSGB for refractory VA between January 2018 and October 2021. The number of times antitachycardia pacing (ATP) was delivered and the number of ICD shocks/external cardioversions performed in the week before and after PSGB were evaluated. Charts were checked for potential complications.
RESULTS
Twelve patients were identified who underwent a combined total of 15 PSGB and 5 surgical left cardiac sympathetic denervation procedures. Mean age was 73 ± 5.8 years and all patients were male. Nine of 12 (75%) had ischaemic cardiomyopathy, with the remainder having non-ischaemic dilated cardiomyopathy. Mean left ventricular ejection fraction was 35% (± 12.2%). Eight of 12 (66.7%) patients were already being treated with both amiodarone and beta-blockers. The reduction in ATP did not reach statistical significance (p = 0.066); however, ICD shocks (p = 0.028) and ATP/shocks combined were significantly reduced (p = 0.04). At our follow-up electrophysiology meetings PSGB was deemed ineffective in 4 of 12 patients (33%). Temporary anisocoria was seen in 2 of 12 (17%) patients, and temporary hypotension and hoarseness were reported in a single patient.
DISCUSSION
In this limited series, PSGB showed promise as a method for temporarily stabilising refractory VA and ES in a cohort of male patients with structural heart disease. The side effects observed were mild and temporary.
PubMed: 38865067
DOI: 10.1007/s12471-024-01880-w -
Journal of Lipid Research Jun 2024Bis(monoacylglycerol)phosphate (BMP) is an acidic glycerophospholipid localized to late endosomes and lysosomes. However, the metabolism of BMP is poorly understood....
Bis(monoacylglycerol)phosphate (BMP) is an acidic glycerophospholipid localized to late endosomes and lysosomes. However, the metabolism of BMP is poorly understood. Because many drugs that cause phospholipidosis inhibit lysosomal phospholipase A2 (LPLA2, PLA2G15, LYPLA3) activity, we investigated whether this enzyme has a role in BMP catabolism. The incubation of recombinant human LPLA2 (hLPLA2) and liposomes containing the naturally occurring BMP (sn-(2-oleoyl-3-hydroxy)-glycerol-1-phospho-sn-1'-(2'-oleoyl-3'-hydroxy)-glycerol (S,S-(2,2',C)-BMP) resulted in the deacylation of this BMP isomer. The deacylation rate was 70 times lower than that of dioleoyl phosphatidylglycerol (DOPG), an isomer and precursor of BMP. The release rates of oleic acid from DOPG and four BMP stereoisomers by LPLA2 differed. The rank order of the rates of hydrolysis were DOPG>S,S-(3,3',C)-BMP>R,S-(3,1',C)-BMP>R,R-(1,1',C)>S,S-(2,2')-BMP. The cationic amphiphilic drug amiodarone (AMD) inhibited the deacylation of DOPG and BMP isomers by hLPLA2 in a concentration dependent manner. Under these experimental conditions, the ICs of amiodarone-induced inhibition of the four BMP isomers and DOPG were less than 20 μM and approximately 30 μM, respectively. BMP accumulation was observed in AMD-treated RAW 264.7 cells. The accumulated BMP was significantly reduced by exogenous treatment of cells with active recombinant hLPLA2 but not with diisopropylfluorophosphate-inactivated recombinant hLPLA2. Finally, a series of cationic amphiphilic drugs known to cause phospholipidosis were screened for inhibition of LPLA2 activity as measured by either the transacylation or fatty acid hydrolysis of BMP or phosphatidylcholine as substrates. Fifteen compounds demonstrated significant inhibition with ICs ranging from 6.8 to 63.3 μM. These results indicate that LPLA2 degrades BMP isomers with different substrate specificities under acidic conditions and may be the key enzyme associated with BMP accumulation in drug-induced phospholipidosis.
PubMed: 38857781
DOI: 10.1016/j.jlr.2024.100574 -
Frontiers in Cardiovascular Medicine 2024Restrictive cardiomyopathy (RCM) represents a rare cardiovascular disorder stemming from filament-associated genes. Nonetheless, treating RCM presents considerable...
BACKGROUND
Restrictive cardiomyopathy (RCM) represents a rare cardiovascular disorder stemming from filament-associated genes. Nonetheless, treating RCM presents considerable challenges, particularly concerning device implantation and mechanical support. Furthermore, elucidating the molecular function of specific variants holds promise in benefiting patients and enhancing prognosis, given the significant heterogeneity among RCM variants.
CASE PRESENTATION
The proband, an eight-year-old female, was admitted to our hospital post cardiopulmonary resuscitation due to sudden cardiac arrest. Echocardiography revealed bilateral atrial enlargement. Whole-exome sequencing uncovered a novel heterozygous mutation (c.509G>A, p.R170Q) in TNNI3. Evaluation using the MutationTaster application deemed c.509G>A pathogenic (probability = 0.99). Following clinical manifestations, imaging assessments, and genetic screening, the proband received an RCM diagnosis. ECMO was recommended along with continuous renal replacement therapy. However, persistent atrial flutter ensued post-ECMO withdrawal. Attempts to restore cardiac rhythm with cardioversion, metoprolol, and amiodarone proved futile. Subsequent heart failure led to the patient's demise due to cardiac shock. Based on crystal protein structural analysis, we observed that cTnI-R170Q and R170W exerted similar impacts on protein structural stability and formation. However, both differed significantly from cTnI-R170G, primarily influencing amino acid regions 32-79 and 129-149, involved in TnC and actin binding. Therefore, cTnI-R170Q was revealed to induce RCM via the same molecular mechanism as cTnI-R170W.
CONCLUSION
Managing RCM remains a critical challenge. This study underscores the discouragement of device implantations for cardiac pump functional support in RCM, particularly for non-short-term scheduled HTx. Additionally, considering catheter ablation for atrial fibrosis-induced AFs is recommended. Mechanistically, cTnI-R170Q primarily diminishes troponin-actin interactions and destabilizes thin filaments.
PubMed: 38854656
DOI: 10.3389/fcvm.2024.1365209 -
Journal of Pharmacological and... Jun 2024Cardiovascular safety and the risk of developing the potentially fatal ventricular tachyarrhythmia, Torsades de Pointes (TdP), have long been major concerns of drug...
INTRODUCTION
Cardiovascular safety and the risk of developing the potentially fatal ventricular tachyarrhythmia, Torsades de Pointes (TdP), have long been major concerns of drug development. TdP is associated with a delayed ventricular repolarization represented by QT interval prolongation in the electrocardiogram (ECG), typically due to block of the potassium channel encoded by the human ether-a-go-go related gene (hERG). Importantly however, not all drugs that prolong the QT interval are torsadagenic and not all hERG blockers prolong the QT interval. Recent clinical reports suggest that partitioning the QT interval into early (J to T peak; JTp) and late repolarization (T peak to T end; TpTe) components may be valuable for distinguishing low-risk mixed ion channel blockers (hERG plus calcium and/or late sodium currents) from high-risk pure hERG channel blockers. This strategy, if true for nonclinical animal models, could be used to de-risk QT prolonging compounds earlier in the drug development process.
METHODS
To explore this, we investigated JTp and TpTe in ECG data collected from telemetered dogs and/or monkeys administered moxifloxacin or amiodarone at doses targeting relevant clinical exposures. An optimized placement of the Tpeak fiducial mark was utilized, and all intervals were corrected for heart rate (QTc, JTpc, TpTec).
RESULTS
Increases in QTc and JTpc intervals with administration of the pure hERG blocker moxifloxacin and an initial QTc and JTpc shortening followed by prolongation with the mixed ion channel blocker amiodarone were detected as expected, aligning with clinical data. However, anticipated increases in TpTec by both standard agents were not detected.
DISCUSSION
The inability to detect changes in TpTec reduces the utility of these subintervals for prediction of arrhythmias using continuous single‑lead ECGs collected from freely moving dogs and monkeys.
PubMed: 38852685
DOI: 10.1016/j.vascn.2024.107527 -
Journal of the Academy of... Jun 2024
PubMed: 38852623
DOI: 10.1016/j.jaclp.2024.06.001