Increased late sodium current (INaL) is a central mechanism underlying both inherited and acquired cardiac arrhythmias. Although Nav1.5 is the dominant cardiac sodium channel, multiple tetrodotoxin-sensitive (TTX-S) Nav isoforms are also expressed in cardiomyocytes, particularly within transverse tubules, where they influence excitation-contraction coupling. Whether these channels contribute directly to pathological INaL and arrhythmogenesis remains unresolved, in part because available pharmacological tools lack isoform selectivity. Herein, our objective was to determine the contribution of TTX-S Nav channels to pathological cardiac INaL and arrhythmia, and to establish selective pharmacological tools to dissect their role. Using automated patch-clamp and human Nav isoform profiling, we show that the reference INaL inducer ATX-II predominantly activates TTX-resistant Nav1.5 Nav channels. However, ATX-II lacks Nav isoform selectivity when inappropriately used, questioning the conclusions reached by numerous cardiac INaL studies. In contrast, AaH-II, a peptide from Androctonus australis hector scorpion venom, more selectively and potently enhances INaL through TTX-S Nav isoforms. In human iPS-derived cardiomyocytes TTX-S INaL leads to action potential prolongation. In adult ventricular cardiomyocytes, AaH-II induces abnormal Ca2+ handling and spontaneous Ca2+ release events. In isolated hearts and in vivo, selective TTX-S INaL activation produces conduction abnormalities, QT prolongation, and ventricular proarrhythmic events, which are prevented by nanomolar tetrodotoxin concentrations that spare Nav1.5. These findings demonstrate that TTX-S sodium channels are sufficient to generate arrhythmogenic late Na+ current in the heart, independently of Nav1.5. AaH-II provides a powerful new tool to selectively probe TTX-S INaL and reveals these channels as previously underappreciated contributors to cardiac electrical instability. Targeting TTX-S Nav channels may therefore represent a novel and potentially safer strategy for antiarrhythmic therapy.
BACKGROUND AND AIM:Atrial fibrillation is associated with increased risks of stroke, heart failure, and death. While stroke prevention is a key focus, heart failure is more frequent and a major contributor to mortality in atrial fibrillation. This study aimed to assess the incidence and timing of heart failure in screening-detected atrial fibrillation. METHODS:This post hoc analysis included participants without prior heart failure from the STROKESTOP and STROKESTOP II randomized screening studies, in which individuals aged 75-76 years were invited to ECG-based atrial fibrillation screening. Incident heart failure diagnoses were obtained from national registries. Incidence rates were calculated per 100 person-years, and Cox regression was used to estimate hazard ratios (HRs). RESULTS:In STROKESTOP, 23% of participants with screening-detected atrial fibrillation developed heart failure (3.76 per 100 person-years), compared with 4.43 in patients with known atrial fibrillation and 1.08 in patients without atrial fibrillation. Screening-detected atrial fibrillation was associated with a threefold higher heart failure risk vs. no atrial fibrillation (adjusted HR 3.19) and a risk comparable to known atrial fibrillation (adjusted HR 2.86). In STROKESTOP II, 20% developed heart failure (4.19 per 100 person-years), compared with 3.52 in known atrial fibrillation and 0.93 without atrial fibrillation. Screening-detected atrial fibrillation was associated with a fourfold higher heart failure risk vs. no atrial fibrillation (adjusted HR 4.73) and a higher risk than known atrial fibrillation (adjusted HR 2.59). CONCLUSION:Screening-detected atrial fibrillation is associated with a high risk of heart failure, comparable to known atrial fibrillation, and is not a benign condition.
AIMS:The appropriate antithrombotic regimen for diabetic patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) who are at high atherothrombotic risk remains uncertain. We evaluated whether the effects of different antithrombotic strategies differ according to diabetes status. METHODS AND RESULTS:The EPIC-CAD (Edoxaban versus Edoxaban with Antiplatelet Agent in Patients with Atrial Fibrillation and Chronic Stable Coronary Artery Disease) was a randomized trial comparing edoxaban monotherapy with dual antithrombotic therapy (edoxaban plus a single antiplatelet agent) in patients with AF and stable CAD. The primary outcome was a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, and major or clinically relevant nonmajor bleeding at 12 months. Among 1040 randomized patients, 421 (40.5%) had diabetes. There were no differences in the incidence of the primary outcome between diabetic and non-diabetic patients (9.7% vs. 11.6%; hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.56-1.20; P=0.30). The incidence of the primary outcome at 12 months was significantly lower with edoxaban monotherapy than with dual antithrombotic therapy in both diabetic (6.3% vs. 13.7%; HR 0.44; 95% CI 0.23-0.83; P=0.01) and non-diabetic patients (6.7% vs. 16.3%; HR 0.39; 95% CI 0.23-0.65; P=0.001), with no significant interaction between diabetic status and randomized treatment strategy (P-for-interaction=0.78). CONCLUSIONS:The risk of primary outcome was similar between diabetic and non-diabetic patients with AF and CAD. Irrespective of diabetes status, edoxaban monotherapy led to a lower risk of a primary outcome at 12 months than dual antithrombotic therapy.
BACKGROUND:Data on long-term durability of pulmonary vein isolation (PVI) with newer pulsed field ablation (PFA) platforms and incremental value of electroanatomic mapping (EAM) guidance remain limited. This study evaluated chronic PVI durability following ablation with a balloon-in-basket PFA catheter and compared outcomes of fluoroscopy-only versus fluoroscopy plus EAM workflows. METHODS:In this prospective, single-center trial, consecutive patients with paroxysmal or persistent atrial fibrillation (AF) underwent de novo PVI with a balloon-in-basket PFA catheter. Patients were randomized 1:1 to fluoroscopy-only or fluoroscopy plus EAM workflow. Systematic invasive remapping was planned >30 days after the index procedure. The dual primary efficacy endpoint was the proportion of pulmonary veins (PVs) and of patients with all PVs durably isolated. The prespecified secondary endpoint was the comparison of procedural characteristics and PVI durability between workflows. Safety outcomes included major adverse events within 30 days of index or remapping procedures. RESULTS:Ninety-six patients (67.4 ± 9.2 years, 44.8% female, 57.3% with paroxysmal AF) underwent index ablation. Fluoroscopy time and number of applications were 3.4 [2.4-4.6] minutes and 15 [13-16], respectively. Systematic remapping was performed in 86 patients at a median of 41 days, with per-vein and per-patient durability of 341/350 (97.4%), and 79/86 (91.9%) respectively. PVI durability and chronic remapping parameters were comparable between guidance strategies. No major adverse events occurred. CONCLUSION:A standardized balloon-in-basket PFA workflow for PVI achieved high PVI durability. EAM guidance did not confer additional procedural or durability benefit over fluoroscopy-only guidance.
BACKGROUND AND AIMS:Antiarrhythmic drugs (AADs) are essential for preventing symptoms, morbidity, and mortality associated with cardiac arrhythmias. However, concerns are increasing about their accessibility. We aimed to assess insights into current access to AADs. METHODS:Online surveys were distributed to members of the European Heart Rhythm Association (EHRA), the Association for European Paediatric and Congenital Cardiology, the European Reference Network GUARD-Heart, and national heart rhythm societies. RESULTS:Responses were obtained from 558 respondents across 80 countries. Among countries included in the main analysis (≥5 respondents; 16 countries within and 7 outside the European Union, n=298 respondents), only 16-59% of surveyed AADs were considered readily accessible. Accessibility varied substantially by drug: oral flecainide and propranolol were available in 88% of countries, whereas mexiletine solution was available in only 10%. Marked differences in accessibility were reported both between and within countries, with availability also changing over time. Higher-income countries generally reported better access and a greater number of market authorization holders than lower-income countries. National societies' perception was that limited access negatively affected patients' quality of life (72%) and life expectancy (35%), while 73% expected these challenges to persist or worsen in the coming years. CONCLUSION:Physicians worldwide frequently encounter problems accessing guideline recommended antiarrhythmic drugs for their patients, which putatively impacts on their patients' quality of life and life expectancy. This highlights systemic vulnerabilities that extend across national and institutional boundaries, urging close collaboration among clinicians, policymakers, manufacturers, and institutions to guarantee timely and equitable treatment for all patients.
BACKGROUND AND AIMS:Evidence supporting first-line cryoballoon ablation (CBA) in treatment-naive persistent atrial fibrillation (PersAF) is limited. Consequently, we compared CBA with guideline-directed antiarrhythmic drug (AAD) therapy in this advanced form of disease. METHODS:This multicenter, prospective, randomized, open-label trial assigned 320 symptomatic, treatment-naive patients with PersAF (1:1) to CBA or AAD therapy. The primary endpoint was the first documented atrial tachyarrhythmia recurrence lasting at least 30 seconds during days 91-365. Secondary endpoints included recurrence during days 1-90 and 1-365, time-to-first recurrence, quality of life, and safety. RESULTS:In the intention-to-treat population, recurrence during days 91-365 occurred in 30/160 (18.8%) patients assigned to CBA and 71/160 (44.4%) assigned to AAD therapy (absolute difference, -25.6 percentage points; 95% confidence interval, -35.4 to -15.8; P<0.001). Supportive time-to-event analysis favored CBA (hazard ratio for AAD vs. CBA, 2.29; 95% confidence interval, 1.48-3.56; log-rank P<0.001). In CBA vs AAD comparisons, overall recurrence during days 1-365 was 23.8% vs. 55.6%, and early recurrence was 11.2% vs. 28.1% (both P<0.001; respectively). Improvement in AFEQT score was greater with CBA (17.3 vs. 6.6 points; P<0.001); whereas SF-12 component scores did not differ significantly. Adverse events recorded on event forms were infrequent in both cohorts. CONCLUSION:In selected treatment-naive patients with PersAF, first-line CBA reduced atrial tachyarrhythmia recurrence and improved disease-specific quality of life compared with AAD therapy.
AIMS:Conventional screening modalities for atrial fibrillation (AF) are often constrained by considerable resource and logistical demands. The randomized controlled NORwegian atrial fibrillation self-SCREENing (NORSCREEN) trial employs a fully digital approach to recruitment and implementation. The aim of this pre-specified analysis was to evaluate the effectiveness of the fully digital recruitment and screening strategy, determine the prevalence of screen-detected AF, and assess initial adherence to therapeutic recommendations. METHODS AND RESULTS:Individuals aged ≥65 years with ≥1 additional risk factor for stroke were digitally recruited from the general Norwegian population and randomized 1:1 to screening or usual care. Exclusion criteria included prior AF, anticoagulation, implantable cardiac electronic devices, or lack of smartphone access. Participants allocated to screening were mailed a patch-based electrocardiogram sensor for site-less continuous monitoring over 7 days. Those with diagnosed AF were advised to contact their general practitioner to initiate appropriate therapy. A total of 551 555 Norwegian residents were digitally invited; of these, 139 596 (25.3%) completed the digital eligibility assessment, 74 956 (53.7%) were eligible, and 50 549 (67.4%) were randomized to screening or usual care. The median age was 75 years (inter-quartile range: 69-78), 23 445 (46.4%) were female, and the mean CHA2DS2-VA risk score was 2.6 ± 0.9. In the screening group, 19 723 (78.1%) completed the study procedures. Previously undiagnosed AF was identified in 382 (1.9%) screened participants, of whom 366 (95.8%) initiated anticoagulation therapy. CONCLUSION:The NORSCREEN trial demonstrates that fully digital, large-scale, site-less AF screening is feasible and effective in an at-risk population, identifying previously undiagnosed AF in 1.9% of screened individuals and showing high adherence to therapeutic recommendations. CLINICAL TRIAL REGISTRATION:NCT05914883.
AIMS:Population-based screening for atrial fibrillation (AF) should be considered in elderly individuals to enable AF detection. However, participation in systematic screening programmes is often suboptimal. STROKESTOP III evaluated whether opportunistic screening could improve participation compared with systematic screening. METHODS AND RESULTS:STROKESTOP III is a cluster-randomized trial including individuals aged 75-76 years from 16 primary care centres in Region Värmland, Sweden. Centres were randomized to systematic screening, using mailed invitations, or opportunistic screening, using invitations during visits.In the systematic arm, 1312 individuals were eligible and invited, of whom 607 participated (46.3%). In the opportunistic arm, 1390 individuals attended participating primary care centres and were potentially eligible for invitation. However, 641 individuals (46.1%) were not assessed for eligibility. Among the 749 assessed individuals, 609 were eligible and 374 participated.Participation among invited eligible individuals was significantly higher with opportunistic than systematic screening (374/609, 61.4% vs. 607/1,312, 46.3%; P < 0.005). However, overall reach was lower in the opportunistic arm because of incomplete assessment for invitation (374/1,479, 25.3% vs. 607/1,437, 42.2%; P < 0.005). Participants in the opportunistic arm had a higher cardiovascular risk burden, including more hypertension, diabetes, and a higher CHA2DS2-VASc-score (3.99 vs. 3.60; P < 0.005). Exclusion rates were higher (18.7% vs. 8.7%; P < 0.005), mainly due to previously diagnosed AF and cognitive impairment. CONCLUSION:Opportunistic screening increased participation among invited individuals and identified a higher-risk population, but its overall population reach was limited by incomplete eligibility assessment. Combining opportunistic and systematic strategies may optimize reach and participation in AF screening programmes.
