The Combination of Hyperuricemia and Elevated High-Sensitivity C-Reactive Protein Increased the Risk of Cardiac Conduction Block.

Objective: This study aimed to explore the impact of a combination of hyperuricemia (HUA) and excessive high-sensitivity C-reactive protein (hs-CRP) levels on the likelihood of developing cardiac conduction block (CCB). Additionally, it sought to assess whether the influence of uric acid (UA) on CCB is mediated by hs-CRP. Methods: A prospective study was executed utilizing data from the Kailuan cohort, including 81,896 individuals initially free from CCB. The participants were categorized into four groups depending on the existence of HUA and low-grade inflammation (hs-CRP>3 mg/L). Cox regression analysis was employed to ascertain hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of incident CCB. A mediation analysis was performed to determine if hs-CRP functioned as a mediator in the connection between UA levels and the incidence of CCB. Results: During a median observation period of 11.8 years, we identified 3160 cases of newly occurring CCB. Compared with the low UA/low CRP group, the combination of HUA and low-grade inflammation elevated the CCB risks (HR:1.56, 95% CI:1.22-1.99), atrioventricular block (AVB) (HR:1.88, 95% CI:1.27-2.77), and right bundle branch block (HR:1.47, 95% CI:1.02-2.12), respectively. Mediation analysis revealed that in the HUA group, compared with the non-HUA group, the risk of CCB elevated by 14.0%, with 10.3% of the increase mediated through hs-CRP. Conclusion: HUA combined with elevated hs-CRP increased the risk of CCB, especially AVB. The connection between UA and the CCB risk was partly mediated by hs-CRP.

Electrophysiological Changes in the Rabbit Ventricular Wedge and Human-Induced Pluripotent Stem-Cell Derived (IPSC) Cardiomyocytes Translate to Severe Arrhythmia Observed in a Canine Toxicology Study, Not Predicted by Standard In Vitro Ion Channel Assays.

During drug discovery, small molecules are typically assayed in vitro for secondary pharmacology effects, which include ion channels relevant to cardiac electrophysiology. Compound A was an irreversible inhibitor of myeloperoxidase investigated for the treatment of peripheral artery disease. Oral doses in dogs at ≥5 mg/kg resulted in cardiac arrhythmias in a dose-dependent manner (at Cmax, free ≥1.53 µM) that progressed in severity with time. Nevertheless, a panel of 13 different cardiac ion channel (K, Na, and Ca) assays, including hERG, failed to identify pharmacologic risks of the molecule. Compound A and a related Compound B were evaluated for electrophysiological effects in the isolated rabbit ventricular wedge assay. Compounds A and B prolonged QT and Tp-e intervals at ≥1 and ≥.3 µM, respectively, and both prolonged QRS at ≥5 µM. Compound A produced early after depolarizations and premature ventricular complexes at ≥5 µM. These data indicate both compounds may be modulating hERG (Ikr) and Nav1.5 ion channels. In human IPSC cardiomyocytes, Compounds A and B prolonged field potential duration at ≥3 µM and induced cellular dysrhythmia at ≥10 and ≥3 µM, respectively. In a rat toxicology study, heart tissue: plasma concentration ratios for Compound A were ≥19X at 24 hours post-dose, indicating significant tissue distribution. In conclusion, in vitro ion channel assays may not always identify cardiovascular electrophysiological risks observed in vivo, which can be affected by tissue drug distribution. Risk for arrhythmia may increase with a "trappable" ion channel inhibitor, particularly if cardiac tissue drug levels achieve a critical threshold for pharmacologic effects.

Mexiletine: Antiarrhythmic mechanisms, emerging clinical applications and mortality.

Mexiletine, a class Ib antiarrhythmic drug, exhibits its major antiarrhythmic effect via inhibition of the fast and late Na+ currents in myocardial tissues that are dependent on the opening of Na+ channels for their excitation. Through a comprehensive examination of mexiletine's therapeutic benefits and potential risks, we aim to provide valuable insights that reinforce its role as a vital therapeutic option for patients with ventricular arrhythmias, long QT syndrome, and other heart rhythm disorders. This review will highlight the current understandings of the antiarrhythmic effects and rationales for recent off-label use and address the mortality and proarrhythmic effects of mexiletine utilizing published basic and clinical studies over the past five decades.

Spiked Helmet Sign in the Inferior Leads.

This case report describes a patient in their 80s who was admitted to the critical care unit with pulseless electrical activity cardiac arrest.

Wandering Bundles With Sinus Arrhythmia.

A 3-year-old boy with congenital ventricular septal defect underwent a closure procedure. Telemetry after the procedure reveals sinus arrhythmia with varying types of bundle branch blocks. Inverse decremental conduction in left posterior fascicle, related to preceding RP interval during sinus arrhythmia, underlies changes between right and left bundle branch blocks. (Level of Difficulty: Advanced.).

Pseudotachycardia in a Teenager With Recurrent Syncope.

This case report describes a teenager with a history of cardiomyopathy and recurrent syncope who was admitted to the pediatric unit with a urinary tract infection.

Marked QTc Reduction Immediately Following Direct Current Cardioversion of Atrial Fibrillation: Clinical Implications and Mechanisms.

BACKGROUND: The QTc in sinus rhythm (SR) following direct current cardioversion (DCCV) of atrial fibrillation (AF) is commonly used as a baseline QTc for patients who require initiation of antiarrhythmic drugs for rhythm control. Inaccurate baseline QTc may cause drug-induced torsades de pointes. OBJECTIVES: This study sought to assess time-dependent QTc changes following DCCV. METHODS: We prospectively assessed QTc changes with Bazett's QTc and Fridericia's QTc formulas in 65 patients following conversion of AF to SR. Among these 65 patients, 48 underwent DCCV and 17 spontaneously converted to SR. RESULTS: There was a large and statistically significant decrease in QTc in SR immediately following DCCV in 40 patients, which occurred with an abrupt reduction in heart rate postcardioversion. This finding excluded 8 patients with ventricular-paced QRS. The mean decrease from QTc in AF was 70.7 ± 37.2 milliseconds in the QTc interval for heart rate using Bazett's formula and 33.8 ± 17.9 milliseconds in the QTc interval for heart rate using Fridericia's formula at 1-minute post-DCCV. In 17 patients with spontaneous conversion from AF to SR, the QTc reduction was comparable to those in patients with DCCV. The QTc increased with time and reached a steady state at 5 minutes following conversion. Initiation of Class III drugs based on the "shortened" baseline QTc following DCCV was associated with drug-induced torsades de pointes. CONCLUSIONS: In patients with AF following conversion, regardless spontaneous or DCCV, the QTc shortened significantly with decreases in heart rate, likely via the mechanism of time-dependent rate adaption of ventricular repolarization. A steady-state QTc at 5-minutes following DCCV should be used as real baseline for guidance of pharmacotherapy in patients with AF.

One Beat Is All It Takes-Wide Complex Tachycardia in a Middle-aged Man.

A man in his mid-50s with a medical history of nonspecific T-wave abnormalities on electrocardiogram reported new-onset chest discomfort, diaphoresis, and shortness of breath that woke him from sleep. Emergency medical services found him to be in a wide complex tachycardia. What would you do next?

Alternating Early Afterdepolarizations Underlying Bradycardia-Dependent Macroscopic T Wave and Discordant Mechanical Alternans.

BACKGROUND: Macroscopic T wave alternans (macro-TWA) often heralds the onset of Torsades de Pointes in patients with QT prolongation. However, the mechanisms underlying macro-TWA remain unclear. We examined the cellular and ionic basis for macro-TWA in rabbits with left ventricular hypertrophy (LVH). METHODS: The renovascular hypertension model was used to induce LVH in rabbits. Action potentials were simultaneously recorded from epicardium and endocardium together with a transmural ECG and isometric contractility in arterially perfused left ventricular wedges. Late sodium current (INa-L) was recorded in single-isolated left ventricular myocytes with the whole cell patch-clamp technique. RESULTS: Macro-TWA and accompanied mechanical alternans occurred spontaneously in 8 of 33 LVH rabbits (P<0.05, versus 0/15 in controls) and were induced by an INa-L enhancer ATX-II at 1 to 3 nM in additional 7. Macro-TWA and mechanical alternans occurred discordantly, that is, that longer QT interval and larger T wave were associated with weaker isometric contvractility. Alternating early afterdepolarizations in the endocardium caused macro-TWA in 12 of 15 LVH rabbits and, therefore, early afterdepolarization-dependent R-from-T extrasystoles and Torsades de Pointes always originated from the beats with longer QT and larger T wave during macro-TWA. INa-L density was significantly larger in LVH myocytes than that of control myocytes. Macro-TWA, mechanical alternans, R-from-T extrasystoles, and Torsades de Pointes were all abolished by INa-L blocker ranolazine or mexiletine. CONCLUSIONS: LVH enhances INa-L density and promotes alternating early afterdepolarizations in the left ventricular endocardium that manifest as macro-TWA with discordant mechanical alternans. INa-L blockade abolishes macro-TWA, mechanical alternans, early afterdepolarization-dependent R-from-T extrasystoles, and Torsades de Pointes.

Dual atrial rhythms: a case report of an unusual cause of pacemaker syndrome.

BACKGROUND: Atrial dissociation (AD) is described as the existence of two simultaneous electrically isolated atrial rhythms. Theoretically, detection of dual atrial rhythms with a sufficiently high rate by pacemaker can lead to automatic mode switching and associated pacemaker syndrome. Such a clinical observation has not been reported before in the literature. CASE SUMMARY: An 87-year-old female with Ebstein's anomaly status post-tricuspid valve annuloplasty and tricuspid valve replacement and a dual-chamber pacemaker presented with congestive heart failure 1 week after undergoing atrial lead revision. Interrogation of her dual-chamber pacemaker revealed two atrial rhythms: sinus or atrial-paced rhythm and electrically isolated atrial tachycardia (AT). Sensing of both atrial rhythms by the pacemaker led to automatic mode switching, which manifested as ventricular paced rhythm with retrograde P waves on electrocardiogram. Adjusting the atrial lead sensitivity to a level higher than the sensing amplitude of AT restored atrial paced and ventricular sensed rhythm, which resulted in resolution of heart failure symptoms. DISCUSSION: Regardless of the cause of AD, there must be electrical insulation between the two rhythms for their independent coexistence in the atria. Atrial dissociation can lead to pacemaker syndrome from automatic mode switching. If the sensing amplitude during sinus rhythm is significantly larger than that of AT, adjusting the atrial lead sensitivity would solve the issue, as in the present case. Otherwise, atrial lead revision, pharmacotherapy, or AT ablation should be considered.

Delta QRS distinguishes Ito -mediated J waves from pseudo J waves produced by conduction delay on body surface electrocardiographic.

BACKGROUND: On surface electrocardiographic (ECGs), it is difficult to differentiate Ito -mediated J waves, a repolarization phenomenon seen in J wave syndromes (JWS) from terminal QRS deflections that mimic J waves (pseudo J waves) in intraventricular conduction delay (IVCD), an abnormality in depolarization. We hypothesize that the difference between the "maximum QRS duration" inclusive of J point or terminal QRS deflections and the minimum QRS duration identified across a 12-lead ECG is significantly larger in Ito -mediated J waves, and can serve as a marker to make this distinction. METHODS: A retrospective analysis was performed on adults with ECGs consisting of one of the four following manifestations: J waves associated with hypothermia and early repolarization, and pseudo J waves associated with right bundle branch block (RBBB) and non-specific intraventricular conduction delay (NS-IVCD). All ECGs were assessed individually and the maximum and minimum discrete QRS deflections on 12-lead tracings, defined as "QRSmax " and QRSmin , were identified. The difference between "QRSmax " and QRSmin , designated as ∆QRS, was calculated and compared across the studied populations. RESULTS: A total of 60 patients consisting of 15 patients in each arm were included in the study. ΔQRS was significantly larger in the hypothermia and early repolarization groups, compared to RBBB and NS-IVCD (p < .0001), with the following mean ∆QRS: hypothermia 54.3 ± 13.7 ms, early repolarization pattern 47.3 ± 15.3 ms, RBBB 19.3 ± 6.5 ms, and NS-IVCD 16.0 ± 6.6 ms. CONCLUSION: ∆QRS may serve as a reliable ECG parameter for distinguishing Ito -mediated J waves from pseudo J waves produced by delayed intraventricular conduction.

Genotype-Phenotype Correlation of SCN5A Genotype in Patients With Brugada Syndrome and Arrhythmic Events: Insights From the SABRUS in 392 Probands.

BACKGROUND: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event. METHODS: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and SCN5A genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed. RESULTS: The study group comprised 392 probands: 92 (23.5%) SCN5A+(44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) SCN5A-.SCN5A missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (<16 years) compared with SCN5A- (11.4% versus 3%, P=0.023). The proportion of females was higher among patients with P/LP compared with SCN5A- (18.2% versus 6.3%, P=0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with SCN5A- (41.9% versus 16.8%, P<0.001). A higher proportion of patients with P/LP were White compared with SCN5A- (87.5% versus 47%, P<0.001). Ethnicity (odds ratio, 5.41 [2.8-11.19], P<0.001) and family history of sudden cardiac death (odds ratio, 2.73 [1.28-5.82], P=0.009) were independent variables associated with P/LP genotype following logistic regression. CONCLUSIONS: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with SCN5A-. In addition, they were more likely to be White and to have family history of sudden cardiac death. Among females, a P/LP variant suggests an increased risk of being symptomatic. This association should be further studied on an ethnically specific basis in large prospectively collected international cohorts.

Arrhythmogenic Mechanisms in Hypokalaemia: Insights From Pre-clinical Models.

Potassium is the predominant intracellular cation, with its extracellular concentrations maintained between 3. 5 and 5 mM. Among the different potassium disorders, hypokalaemia is a common clinical condition that increases the risk of life-threatening ventricular arrhythmias. This review aims to consolidate pre-clinical findings on the electrophysiological mechanisms underlying hypokalaemia-induced arrhythmogenicity. Both triggers and substrates are required for the induction and maintenance of ventricular arrhythmias. Triggered activity can arise from either early afterdepolarizations (EADs) or delayed afterdepolarizations (DADs). Action potential duration (APD) prolongation can predispose to EADs, whereas intracellular Ca2+ overload can cause both EADs and DADs. Substrates on the other hand can either be static or dynamic. Static substrates include action potential triangulation, non-uniform APD prolongation, abnormal transmural repolarization gradients, reduced conduction velocity (CV), shortened effective refractory period (ERP), reduced excitation wavelength (CV × ERP) and increased critical intervals for re-excitation (APD-ERP). In contrast, dynamic substrates comprise increased amplitude of APD alternans, steeper APD restitution gradients, transient reversal of transmural repolarization gradients and impaired depolarization-repolarization coupling. The following review article will summarize the molecular mechanisms that generate these electrophysiological abnormalities and subsequent arrhythmogenesis.