A Clinical Diagnostic Test for Calcium Release Deficiency Syndrome.

Importance: Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective: To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants: An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention: Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures: Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results: Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS (P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases (P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance: There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

Reasons for hospitalization and risk of mortality in patients with atrial fibrillation treated with dabigatran or warfarin in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial.

AIMS: Hospitalizations are common among patients with atrial fibrillation. This article aimed to analyse the causes and consequences of hospitalizations occurring during the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial. METHODS AND RESULTS: The RE-LY database was used to evaluate predictors of hospitalization using multivariate regression modelling. The relationship between hospitalization and subsequent major adverse cardiac events was evaluated in a time dependent Cox proportional-hazard modelling. Of the 18 113 patients in RE-LY, 7200 (39.8%) were hospitalized at least once during a mean follow-up of 2 years. First hospitalization rates were 2312 (39.5%) for dabigatran etexilate (DE) 110, 2430 (41.6%) for DE 150, and 42.6% (N = 2458) for warfarin. Hospitalization was associated with post-discharge death [absolute event rate 9.1% vs. 2.2%; adjusted hazard ratio (HR) 3.6, 95% confidence interval (CI) 3.2-4.0, P < 0.0001], vascular death (adjusted HR 2.9, 95% CI 2.5-3.3, P < 0.0001), and sudden cardiac death (adjusted HR 2.3; 95% CI 1.8-2.9, P < 0.0001). Cardiovascular hospitalization was also associated with an increased risk of post-discharge death (adjusted HR 2.8, 95% CI 2.5-3.2, P < 0.0001), vascular death (adjusted HR 2.8, 95% CI 2.4-3.2, P < 0.0001), and sudden cardiac death (adjusted HR 2.1, 95% CI 1.6-2.7, P < 0.0001) compared with patients not hospitalized for any cardiovascular reason. CONCLUSION: Hospitalizations are associated an increased risk of with death and cardiovascular death in patients with atrial fibrillation.

Challenge and Impact of Quinidine Access in Sudden Death Syndromes: A National Experience.

OBJECTIVES: This study sought to determine the nature of quinidine use and accessibility in a national network of inherited arrhythmia clinics. BACKGROUND: Quinidine is an antiarrhythmic medication that has been shown to be beneficial in select patients with Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation. Because of the low prevalence of these conditions and restricted access to quinidine through a single regulatory process, quinidine use is rare in Canada. METHODS: Subjects prescribed quinidine were identified through the Hearts in Rhythm Organization that connects the network of inherited arrhythmia clinics across Canada. Cases were retrospectively reviewed for patient characteristics, indications for quinidine use, rate of recurrent ventricular arrhythmia, and issues with quinidine accessibility. RESULTS: In a population of 36 million, 46 patients are currently prescribed quinidine (0.0000013%, age 48.1 ± 16.1 years, 25 are male). Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation constituted a diagnosis in 13 subjects (28%), 6 (13%), and 21 (46%), respectively. Overall, 37 subjects (81%) had cardiac arrest as an index event. After initial presentation, subjects experienced 7.47 ± 12.3 implantable cardioverter-defibrillator shocks prior to quinidine use over 34.3 ± 45.9 months, versus 0.86 ± 1.69 implantable cardioverter-defibrillator shocks in 43.8 ± 41.8 months while on quinidine (risk ratio: 8.7, p < 0.001). Twenty-two patients access quinidine through routes external to Health Canada's Special Access Program. CONCLUSIONS: Quinidine use is rare in Canada, but it is associated with a reduction in recurrent ventricular arrhythmias in patients with Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation, with minimal toxicity necessitating discontinuation. Drug interruption is associated with frequent breakthrough events. Access to quinidine is important to deliver this potentially lifesaving therapy.

The Role of Manual Aspiration Thrombectomy in Patients Undergoing Primary Percutaneous Coronary Intervention for STEMI.

In STEMI, primary PCI restores macrovascular coronary blood flow effectively but microvascular perfusion remains a challenge. Thrombus has the potential to embolize to the microvasculature limiting effective coronary blood flow. Thrombus burden is associated with a higher mortality and manual aspiration thrombectomy has the potential to reduce thrombus burden. The first large trial of routine aspiration thrombectomy (TAPAS, N = 1071) showed an improvement in myocardial blush and an unexpected reduction in mortality. Reinforcing the enthusiasm for this finding meta-analysis of small trials also showed a reduction in mortality, which led to routine manual thrombectomy becoming a class IIa recommendation in the American and European Guidelines for STEMI. Subsequently; however, large trials such as TOTAL (N = 10,732) and TASTE (N = 7244) and meta-analysis showed an increase in the risk of stroke with routine manual thrombectomy but no improvement in mortality, myocardial infarction, stent thrombosis, or severe heart failure. As such, manual thrombectomy should not be routinely used instead saving it as a bailout procedure as indicated.

Stroke in the TOTAL trial: a randomized trial of routine thrombectomy vs. percutaneous coronary intervention alone in ST elevation myocardial infarction.

AIMS: TOTAL (N = 10 732), a randomized trial of routine manual thrombectomy vs. percutaneous coronary intervention alone in ST elevation myocardial infarction, showed no difference in the primary efficacy outcome but a significant increase in stroke. We sought to understand these findings. METHODS AND RESULTS: A detailed analysis of stroke timing, stroke severity, and stroke subtype was performed. Strokes were adjudicated by neurologists blinded to treatment assignment. Stroke within 30 days, the primary safety outcome, was increased [33 (0.7%) vs. 16 (0.3%), hazard ratio (HR) 2.06; 95% confidence interval (CI) 1.13-3.75]. The difference in stroke was apparent within 48 h [15 (0.3%) vs. 5 (0.1%), HR 3.00; 95% CI 1.09-8.25]. There was an increase in strokes within 180 days with minor or no disability (Rankin 0-2) [18 (0.4%) vs. 13 (0.3%) HR 1.38; 95% CI 0.68-2.82] and in strokes with major disability or fatal (Rankin 3-6) [35 (0.7%) vs. 13 (0.3%), HR 2.69; 95% CI 1.42-5.08]. Most of the absolute difference was due to an increase in ischaemic strokes within 180 days [37 (0.7%) vs. 21 (0.4%), HR 1.71; 95% CI 1.03-3.00], but there was also an increase in haemorrhagic strokes [10 (0.2%) vs. 2 (0.04%), HR 4.98; 95% CI 1.09-22.7]. Patients that had a stroke had a mortality of 30.8% within 180 days vs. 3.4% without a stroke (P < 0.001). A meta-analysis of randomized trials (N = 21 173) showed an increase in risk of stroke (odds ratio 1.59; 95% CI 1.11-2.27) but a trend towards reduction in mortality odds ratio (odds ratio 0.87; 95% CI 0.76-1.00). CONCLUSION: Thrombectomy was associated with a significant increase in stroke. Based on these findings, future trials must carefully collect stroke to determine safety in addition to efficacy.

A Meta-Analysis of Randomized Controlled Trials of Conventional Stenting Versus Direct Stenting in Patients With Acute Myocardial Infarction.

BACKGROUND: Direct stenting (DS) is commonly used during percutaneous coronary intervention for acute myocardial infarction (AMI) to prevent distal embolization; however, no guideline recommendations exist regarding DS. We sought to compare DS with conventional stenting (CS) in patients presenting with AMI in a meta-analysis of randomized controlled trials. METHODS: Studies were identified from EMBASE, MEDLINE, and Cochrane databases. To be included, randomized controlled trials must have compared DS with CS in patients with AMI. Data were extracted and articles were critically appraised by two authors. A fixed effects model was used, with Peto odds ratios (ORs). The primary endpoint was death from cardiovascular causes. RESULTS: Five trials (n = 754) met the eligibility criteria. ST-segment resolution occurred in 68.9% (146/212) in the DS group vs 60.2% (127/211) in the CS group (OR, 1.51; 95% CI, 1.00-2.27; P=.05; I²=52%). No-reflow occurred in 6.6% in the DS group compared with 6.9% in the CS group (OR, 0.78; 95% CI, 0.39-1.55; P=.48; I²=0%). DS was associated with a significant reduction in the risk of in-hospital cardiovascular death (OR, 0.21; 95% CI, 0.06-0.77; P=.02; I²=0%). No significant differences were observed in myocardial infarction (OR, 0.38; 95% CI, 0.09-1.51; P=.17; I²=7%) or target lesion revascularization (OR, 1.20; 95% CI, 0.36-3.97; P=.76; I²=0%). CONCLUSION: Small trials suggest a potential benefit to DS in AMI. Further large-scale randomized trials are warranted to confirm the benefit of this approach.

How to succeed in research during medical training: a qualitative study.

PURPOSE: The objective of this study was to examine the characteristics of the medical trainee (resident), the supervisor and the project that contribute to successful completion of resident-led research and publication in a peer-reviewed scientific journal. METHODS: Qualitative, interview-based study of Internal Medicine trainees and their supervisors. All interviewed trainees published at least one first-author research paper based on a project they completed during residency. Thematic analysis was used to explore key themes from interview transcripts. An iterative, team-based approach was used to develop a coding framework, which was then applied to the data and summarized. Six investigators independently reviewed and coded transcripts, discussed the data collectively and developed key themes by consensus. RESULTS: Thirty participants (15 residents and 15 supervisors) were interviewed. Three major themes for successful resident research projects emerged: 1) the resident is the project champion; 2) supervisors ensure feasibility and timeliness of the project; and, 3) limited time is a challenge that can be overcome. Residents were motivated by fellowship aspirations, prioritized the project and were genuinely interested in the content area. Supervisors were responsible for setting deadlines, limiting the scope of the project and ensuring feasibility of the study design. Existing research funds and infrastructure from other projects were frequently used by supervisors to support research done by trainees. CONCLUSIONS: Successful resident-led research projects require leadership and motivation by the resident and engagement, reality-checking and deadline-setting by the supervisor. Responsibilities and expectations in the resident-supervisor relationship should be set early and adequate program resources and funding are required.

Apparent anti-Woodward-Hoffmann addition to a nickel bis(dithiolene) complex: the reaction mechanism involves reduced, dimetallic intermediates.

Nickel dithiolene complexes have been proposed as electrocatalysts for alkene purification. Recent studies of the ligand-based reactions of Ni(tfd)2 (tfd = S2C2(CF3)2) and its anion [Ni(tfd)2](-) with alkenes (ethylene and 1-hexene) showed that in the absence of the anion, the reaction proceeds most rapidly to form the intraligand adduct, which decomposes by releasing a substituted dihydrodithiin. However, the presence of the anion increases the rate of formation of the stable cis-interligand adduct, and decreases the rate of dihydrodithiin formation and decomposition. In spite of both computational and experimental studies, the mechanism, especially the role of the anion, remained somewhat elusive. We are now providing a combined experimental and computational study that addresses the mechanism and explains the role of the anion. A kinetic study (global analysis) for the reaction of 1-hexene is reported, which supports the following mechanism: (1) reversible intraligand addition, (2) oxidation of the intraligand addition product prior to decomposition, and (3) interligand adduct formation catalyzed by Ni(tfd)2(-). Density functional theory (DFT) calculations were performed on the Ni(tfd)2/Ni(tfd)2(-)/ethylene system to shed light on the selectivity of adduct formation in the absence of anion and on the mechanism in which Ni(tfd)2(-) shifts the reaction from intraligand addition to interligand addition. Computational results show that in the neutral system the free energy of activation for intraligand addition is lower than that for interligand addition, in agreement with the experimental results. The computations predict that the anion enhances the rate of the cis-interligand adduct formation by forming a dimetallic complex with the neutral complex. The [(Ni(tfd)2)2](-) dimetallic complex then coordinates ethylene and isomerizes to form a Ni,S-bound ethylene complex, which then rapidly isomerizes to the stable interligand adduct but not to the intraligand adduct. Thus, the anion catalyzes the formation of the interligand adduct. Significant experimental evidence for dimetallic species derived from nickel bis(dithiolene) complexes has been found. ESI-MS data indicate the presence of a [(Ni(tfd)2)2](-) dimetallic complex as the acetonitrile adduct. A charge-neutral association complex of Ni(tfd)2 with the ethylene adduct of Ni(tfd)2 has been crystallographically characterized. Despite the small driving force for the reversible association, very major structural reorganization (square-planar → octahedral) occurs.

The mechanism of alkene addition to a nickel bis(dithiolene) complex: the role of the reduced metal complex.

The binding of an alkene by Ni(tfd)(2) [tfd = S(2)C(2)(CF(3))(2)] is one of the most intriguing ligand-based reactions. In the presence of the anionic, reduced metal complex, the primary product is an interligand adduct, while in the absence of the anion, dihydrodithiins and metal complex decomposition products are preferred. New kinetic (global analysis) and computational (DFT) data explain the crucial role of the anion in suppressing decomposition and catalyzing the formation of the interligand product through a dimetallic complex that appears to catalyze alkene addition across the Ni-S bond, leading to a lower barrier for the interligand adduct.

Variations in the management of pneumonia in pediatric emergency departments: compliance with the guidelines.

OBJECTIVE: We sought to assess compliance with evidence-based guidelines for the management of pediatric pneumonia, including the variations in tests ordered and antimicrobials prescribed. Our primary hypothesis was that compliance with the treatment recommendations from the most current guidelines would be low for antimicrobial prescriptions. METHODS: We conducted a chart review at the Children's Hospital in London, Ont., to assess variation in the management of pediatric pneumonia. All patients aged 3 months to 18 years seen at the pediatric emergency department between Apr. 1, 2006, and Mar. 31, 2007, with a diagnosis of pneumonia were eligible for inclusion in the study. RESULTS: Compliance with management guidelines was 59.7% (95% confidence interval [CI] 53%-66%, n = 211) in children 5-18 years old and 83.0% (95% CI 80%-86%, n = 605) in children 3 months to 5 years old. Significant variation existed in the choice of antimicrobial agent for children with pneumonia, with nonrecommended agents frequently prescribed. CONCLUSION: Significant variation existed in the management of pediatric pneumonia, and adherence to guidelines was low for the group of patients aged 5-18 years. Future studies should attempt to provide guidance to distinguish between viral and bacterial etiology to allow judicious use of antimicrobials.