Multisite Validation of a Functional Assay to Adjudicate SCN5A Brugada Syndrome-Associated Variants.

BACKGROUND: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in SCN5A. Interpreting the pathogenicity of SCN5A missense variants is challenging, and ≈79% of SCN5A missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification. METHODS: An in vitro SCN5A-Brugada syndrome automated patch clamp assay was generated and independently studied at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study SCN5A variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with SCN5A loss-of-function. RESULTS: Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak INa density (R2=0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values yielded 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical SCN5A variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic. CONCLUSIONS: This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future SCN5A-Brugada syndrome variants of uncertain significance.

Inpatient mortality and outcomes of COVID-19 among patients with non-ischemic cardiomyopathy: A propensity matched analysis.

BACKGROUND: Patients with chronic medical conditions, particularly cardiovascular diseases, are at a greater risk of adverse outcomes due to COVID-19. The effect of COVID-19 on patients with non-ischemic cardiomyopathy (NICM) is not known well. OBJECTIVES: To study the impact of COVID-19 infection on NICM hospital mortality and other outcomes. METHODS: This study included a cohort of patients from the 2020 and 2021 National Inpatient Sample databases. Patients hospitalized for COVID-19 with and without NICM were matched using a 1:1 propensity score-matching ratio. Outcomes analyzed were in-hospital mortality, rates of acute kidney injury (AKI), acute myocardial infarction (AMI), cardiogenic shock, cardiac arrest, mechanical ventilation, tracheal intubation, pulmonary embolism (PE), ventricular tachycardia (VT), ventricular fibrillation (VF), length of stay (LOS), and total hospitalization charges. RESULTS: A total of 2,532,652 patients met the inclusion criteria (1,199,008 females [47.3 %], predominantly white 1,456,203 (57.5 %); mean [SD] age 63 [5.4] years), including 64,155 (2.5 %) patients with a history of NICM. Following propensity matching, 10,258 COVID-19 patients with and without NICM were matched. Patients with NICM had higher rates of AMI (11.1 vs. 7.1 %, p < 0.001), cardiogenic shock (2 vs. 0.6 %, p < 0.001), cardiac arrest (4.4 vs. 3.2 %, p < 0.01), mechanical ventilation (13.7 vs 12 %, p < 0.01), VT (8.5 vs. 2.2 %, p < 0.001), and VF (1.0 vs 0.25 %, p < 0.001). The odds ratios for in-hospital mortality, AKI, and PE did not differ significantly. CONCLUSION: A History of NICM does not affect COVID-19 mortality but increases the risk of cardiovascular complications.

Life's essential 8, genetic susceptibility, and incident cardiac arrhythmias: a population-based prospective cohort study.

BACKGROUND: Ideal cardiovascular health (CVH) has been associated with reduced cardiovascular disease risk and mortality, but its association with cardiac arrhythmias were still unsettled. In this prospective cohort study, we investigated the relationship between CVH and subsequent arrhythmias risk, including atrial fibrillation/flutter (AF), ventricular arrhythmias, and bradyarrhythmias. METHODS: Data from 287,264 participants initially free of arrhythmias in the UK Biobank were included in the analysis. Cox regression models were used to examine the relationship between CVH levels calculated by the American Heart Association's Life's Essential 8 (LE8) metrics, with cardiac arrhythmias risk. RESULTS: During a median follow-up period of 12.8 years, 16,802 incident AF, 2186 incident ventricular arrhythmias, and 4128 incident bradyarrhythmias were identified. After adjustment for confounding factors, participants with high initial CVH levels had a significantly lower risk for AF (HR 0.63, 95% CI 0.59-0.68), ventricular arrhythmias (HR 0.48, 95% CI 0.40-0.59), and bradyarrhythmias (HR 0.64, 95% CI 0.55-0.74) compared to those with low CVH levels. Furthermore, each SD increase in LE8 scores was associated with a 15% lower risk of AF, 21% for ventricular arrhythmias, and 13% for bradyarrhythmias, respectively. Additionally, a significant interaction was observed between CVH levels and the genetic risk of AF (P for interaction, 0.021). The reverse correlation seemed to be more noticeable in individuals with a lower genetic susceptibility to AF. CONCLUSIONS: We concluded that higher levels of CVH, estimated by the LE8 metrics, were associated with significantly reduced risks of AF, ventricular arrhythmias, and bradyarrhythmias.

Divergent Biochemical Properties and Disparate Impact of Arrhythmogenic Calmodulin Mutations on Zebrafish Cardiac Function.

Calmodulin (CaM) is a ubiquitous, small cytosolic calcium (Ca2+)-binding sensor that plays a vital role in many cellular processes by binding and regulating the activity of over 300 protein targets. In cardiac muscle, CaM modulates directly or indirectly the activity of several proteins that play a key role in excitation-contraction coupling (ECC), such as ryanodine receptor type 2 (RyR2),  l-type Ca2+ (Cav1.2), sodium (NaV1.5) and potassium (KV7.1) channels. Many recent clinical and genetic studies have reported a series of CaM mutations in patients with life-threatening arrhythmogenic syndromes, such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). We recently showed that four arrhythmogenic CaM mutations (N98I, D132E, D134H, and Q136P) significantly reduce the binding of CaM to RyR2. Herein, we investigate in vivo functional effects of these CaM mutations on the normal zebrafish embryonic heart function by microinjecting complementary RNA corresponding to CaMN98I, CaMD132E, CaMD134H, and CaMQ136P mutants. Expression of CaMD132E and CaMD134H mutants results in significant reduction of the zebrafish heart rate, mimicking a severe form of human bradycardia, whereas expression of CaMQ136P results in an increased heart rate mimicking human ventricular tachycardia. Moreover, analysis of cardiac ventricular rhythm revealed that the CaMD132E and CaMN98I zebrafish groups display an irregular pattern of heart beating and increased amplitude in comparison to the control groups. Furthermore, circular dichroism spectroscopy experiments using recombinant CaM proteins reveals a decreased structural stability of the four mutants compared to the wild-type CaM protein in the presence of Ca2+. Finally, Ca2+-binding studies indicates that all CaM mutations display reduced CaM Ca2+-binding affinities, with CaMD132E exhibiting the most prominent change. Our data suggest that CaM mutations can trigger different arrhythmogenic phenotypes through multiple and complex molecular mechanisms.

Who are we missing? Language exclusivity of patient-reported outcomes in atrial fibrillation clinical trials.

INTRODUCTION: Patient-reported outcomes (PROs) are increasingly used to evaluate quality of life (QoL) in Atrial Fibrillation (AF) patients, providing crucial insights in clinical trials. This study examines the frequency of PRO use in AF trials and the linguistic accessibility of AF-specific PROs. BACKGROUND: As the United States becomes more multilingual, ensuring PROs are available in various languages is vital. The number of people speaking a language other than English at home has tripled from 23.1 million in 1980 to 67.8 million in 2019. This diversity necessitates the availability of PROs in multiple languages for inclusive clinical assessments. METHODS: We queried ClinicalTrials.gov for all US interventional AF trials up to November 28, 2023, reviewing each for PRO usage as primary or secondary outcomes. We identified the five most common AF-specific and generic PROs, extracting their available translations and original languages from published sources. RESULTS: Of 233 identified trials, 191 had associated publications, with 180 (94.2%) conducted solely in English. Only one trial (0.4%) used an AF-specific PRO as a primary outcome, compared to four (1.7%) with a generic PRO. Ten trials (4.3%) used AF-specific PROs as secondary endpoints, versus 22 (9.4%) using generic PROs. AF-specific PROs had significantly fewer translations than generic PROs (11.2 vs. 148.8; p < .001). The AF Effect on Quality-of-Life (AFEQT) was available in 24 languages, with limited translations in commonly spoken US languages like Arabic and Asian languages. CONCLUSION: The limited availability of AF-specific PRO translations highlights a barrier to inclusive AF clinical trials. Expanding translations for AF-specific PROs is crucial for equitable QoL assessments.

Ventriculo-arterial (VA) coupling and fQRS as new selection criteria for primary prevention ICD placement.

For decades, left ventricular ejection fraction (LVEF < 35%) has been a mainstay for identifying heart failure (HF) patients most likely to benefit from an implantable cardioverter defibrillator (ICD). However, LVEF is a poor predictor of sudden cardiac death (SCD) and ignores 50% of HF patients with mildly reduced and preserved LVEF. The current international guidelines for primary prophylaxis ICD therapy are inadequate. Instead of LVEF, which is not a good measure of LV contractility or hemodynamic characterization, we hypothesize ventriculo-arterial (VA) coupling combined with fragmented QRS (fQRS) will improve risk stratification and patient suitability for an ICD. Quantifying cardiac and aortic mechanics, and predicting active arrhythmogenic substrate, from varying fQRS morphologies, may help to stratify ischemic and non-ischemic patients with different functional capacities and predisposition for lethal arrhythmias. We propose HF patients with a low physiological reserve may not benefit from ICD therapy, whereas those patients with higher reserves and extensive arrhythmogenic substrate may benefit. Our hypothesis combining VA coupling with fQRS changes has the potential to widen HF patient participation (low and high LVEF) and advance personalized medicine for HF patients at high risk of SCD.

Comparison between Remotely Supported Nurse-led Electro-Anatomic Mapping and Standard Onsite Engineer Support for Electrophysiological Procedures.

AIMS: Catheter ablations of complex cardiac arrhythmias are currently guided by electro-anatomic mapping systems. The aim of this study was to compare two different approaches: remotely supported nurse-led electro-anatomic mapping with standard onsite engineer support. METHODS AND RESULTS: In this retrospective observational study, 166 patients with complex and non-complex procedures were included. 82 patients benefited from electro-anatomic mapping with remotely supported nurse-led mapping (mean age: 62±16years), while the approach for 84 patients was with standard onsite engineer support (mean age: 56±19 years). Procedural characteristics, acute results and complication rates were compared between both groups and showed similar results.Complex and non-complex procedures were conducted in both groups, including left atrial and ventricular procedures. As ventricular tachycardia and accessory pathway ablations were more frequently conducted with standard onsite engineer support, we separately analyzed the largest subgroup, 105 patients with atrial fibrillation, left atrial flutter and left atrial tachycardia. Patients in this subgroup had comparable baseline characteristics, procedure times and procedural success. Nevertheless, there were longer ablation times and more utilization of fluoroscopy in the onsite group, most likely due to more complex procedures. CONCLUSION: Our results underline the practicality of remotely supported nurse-led electro-anatomic mapping. The latter approach proved to be a safe alternative to onsite engineer support. Due to its advantages, particularly for insular settings, it will likely play a greater role in the future.

Case Report: Sustained ventricular arrhythmia in a child supported by a Berlin heart EXCOR ventricular assist device.

Mechanical circulatory support is an established therapy to support failing hearts as a bridge to transplantation. Although tolerated overall, arrhythmias may occur after ventricular assist device implantation and can complicate patient management. We report on an infant with dilated cardiomyopathy who developed ventricular tachycardia followed by recalcitrant ventricular fibrillation, refractory to comprehensive medical therapy post Berlin Heart EXCOR® (BHE) implant.

Can Hyperthermia Unveil Brugada Pattern?

Brugada syndrome (BrS) is characterized by ST segment elevations in the right precordial leads, V1 - V3, with additional findings of ventricular arrhythmias and family history (FH) of sudden cardiac death (SCD) at a young age. Here, we describe a case of hyperthermia, unveiling the Brugada electrocardiography (EKG) pattern and the resolution of EKG findings with appropriate hyperthermia management. It is important to distinguish the Brugada EKG pattern from other causes of ST elevations and treat appropriately to prevent patients from developing ventricular fibrillation and SCD. It is key to identify environmental triggers in patients presenting with Brugada EKG pattern and closely monitor for ventricular fibrillation. Educating patients on prompt fever treatment with antipyretics and avoiding medications like sodium channel blockers during the febrile event is paramount to counter patients going into ventricular fibrillation. It is also crucial for close follow-up of these patients, offering them genetic testing for BrS and screening families of patients with BrS.

Cardiorespiratory motion characteristics and their dosimetric impact on cardiac stereotactic body radiotherapy.

BACKGROUND: Cardiac stereotactic body radiotherapy (CSBRT) is an emerging and promising noninvasive technique for treating refractory arrhythmias utilizing highly precise, single or limited-fraction high-dose irradiations. This method promises to revolutionize the treatment of cardiac conditions by delivering targeted therapy with minimal exposure to surrounding healthy tissues. However, the dynamic nature of cardiorespiratory motion poses significant challenges to the precise delivery of dose in CSBRT, introducing potential variabilities that can impact treatment efficacy. The complexities of the influence of cardiorespiratory motion on dose distribution are compounded by interplay and blurring effects, introducing additional layers of dose uncertainty. These effects, critical to the understanding and improvement of the accuracy of CSBRT, remain unexplored, presenting a gap in current clinical literature. PURPOSE: To investigate the cardiorespiratory motion characteristics in arrhythmia patients and the dosimetric impact of interplay and blurring effects induced by cardiorespiratory motion on CSBRT plan quality. METHODS: The position and volume variations in the substrate target and cardiac substructures were evaluated in 12 arrhythmia patients using displacement maximum (DMX) and volume metrics. Moreover, a four-dimensional (4D) dose reconstruction approach was employed to examine the dose uncertainty of the cardiorespiratory motion. RESULTS: Cardiac pulsation induced lower DMX than respiratory motion but increased the coefficient of variation and relative range in cardiac substructure volumes. The mean DMX of the substrate target was 0.52 cm (range: 0.26-0.80 cm) for cardiac pulsation and 0.82 cm (range: 0.32-2.05 cm) for respiratory motion. The mean DMX of the cardiac structure ranged from 0.15 to 1.56 cm during cardiac pulsation and from 0.35 to 1.89 cm during respiratory motion. Cardiac pulsation resulted in an average deviation of -0.73% (range: -4.01%-4.47%) in V25 between the 3D and 4D doses. The mean deviations in the homogeneity index (HI) and gradient index (GI) were 1.70% (range: -3.10%-4.36%) and 0.03 (range: -0.14-0.11), respectively. For cardiac substructures, the deviations in D50 due to cardiac pulsation ranged from -1.88% to 1.44%, whereas the deviations in Dmax ranged from -2.96% to 0.88% of the prescription dose. By contrast, the respiratory motion led to a mean deviation of -1.50% (range: -10.73%-4.23%) in V25. The mean deviations in HI and GI due to respiratory motion were 4.43% (range: -3.89%-13.98%) and 0.18 (range: -0.01-0.47) (p < 0.05), respectively. Furthermore, the deviations in D50 and Dmax in cardiac substructures for the respiratory motion ranged from -0.28% to 4.24% and -4.12% to 1.16%, respectively. CONCLUSIONS: Cardiorespiratory motion characteristics vary among patients, with the respiratory motion being more significant. The intricate cardiorespiratory motion characteristics and CSBRT plan complexity can induce substantial dose uncertainty. Therefore, assessing individual motion characteristics and 4D dose reconstruction techniques is critical for implementing CSBRT without compromising efficacy and safety.

The risk of premature cardiac contractions (PAC/PVC) related to caffeine consumption among healthcare workers: A comprehensive review.

Background and Aims: Premature atrial contractions (PACs) and premature ventricular contractions (PVCs) are ectopic heart rhythm disorders with implications for cardiovascular health. This study explores the relationship between caffeine consumption and the risk of PACs and PVCs, with a focus on healthcare workers, such as doctors, nurses, pharmacists, and midwives, who often rely on caffeine to combat fatigue, especially during night shifts. Methods: A thorough review was conducted through PubMed, Scopus, Google Scholar, and Web of Science, utilizing a combination of MeSH terms and keywords. Studies examining the link between caffeine consumption and PACs and PVCs, particularly in healthcare workers, were included. Results: We found that caffeine shows various effects based on dosage and can impact arrhythmia risk. Individuals working long shifts, including healthcare professionals, are prone to increased caffeine intake, leading to higher cardiovascular risk. To mitigate these risks, tailored guidelines for caffeine consumption, flexible shift scheduling, and mental health support services are recommended. Promoting caffeine alternatives within healthcare institutions can be beneficial. Conclusion: Although caffeine may have potential benefits, its drawbacks, particularly concerning cardiovascular health, may surpass its advantages, especially when consumed in high doses. A multidisciplinary approach is crucial for healthcare workers' well-being and quality of patient care. Further research is required to refine and support these recommendations.

When annuloplasty is not enough: a case report of ventricular arrhythmias stepwise abolition after mitral valve re-repair.

Background: Some patients affected by mitral valve (MV) prolapse (MVP) are at higher risk of ventricular arrhythmias (VAs), but the underlying pathogenesis, as well as the effects of surgery on VA, remain not fully understood. Mitral valve repair, however, represents a privileged point of view to deepen the understanding of arrhythmogenesis in this context. Hence, we report an interesting case of MV re-repair. Case summary: A 52-year-old man was referred to our institution for severe mitral regurgitation (MR) due to P2 prolapse in the context of myxomatous MV degeneration. Pre-operative imaging showed systolic mitral annular disjunction, left ventricular (LV) wall curling, Pickelhaube's sign, and a prolapsing tricuspid valve (TV) with only mild regurgitation. Twenty-four-hour electrocardiogram (ECG) Holter revealed a significant burden of premature ventricular contractions (PVCs), most of them originating from anterior papillary muscle (APM), posterior papillary muscle (PPM), and mitral annulus (MA). Quadrangular resection of P2 and mitral annuloplasty were performed. One year later, relapse of severe MR due to a residual P2M1 prolapse occurred. Twenty-four-hour ECG Holter showed no PVCs from PPM and MA, while those from APM persisted. A central edge-to-edge repair was effectively used to fix the residual prolapse. After 1 year from REDO surgery, a third ECG Holter confirmed the absence of any remaining LV PVCs, but still few ectopic beats originating from TV were recorded. Discussion: Here, we report a case of VA resolution after specific, anatomical triggers addressing surgical gestures. Our experience confirms that MV surgery may have a role in MVP patients' arrhythmias correction.

Early Impressions and Adoption of the AtriAmp for Managing Arrhythmias Following Congenital Heart Surgery.

AtriAmp is a new medical device that displays a continuous real-time atrial electrogram on telemetry using temporary atrial pacing leads. Our objective was to evaluate early adoption of this device into patient care within our pediatric intensive care unit (PICU). This is a qualitative study using inductive analysis of semi-structured interviews to identify dominant themes. The study was conducted in a single-center, tertiary, academic 21-bed mixed PICU. The subjects were PICU multidisciplinary team members (Pediatric Cardiac Intensivists, PICU Nurse Practitioners, PICU nurses and Pediatric Cardiologists) who were early adopters of the AtriAmp (n = 14). Three prominent themes emerged: (1) Accelerated time from arrhythmia event to diagnosis and treatment; (2) Increased confidence in the accuracy of providers' arrhythmia diagnosis; and (3) Improvement in the ability to educate providers about post-operative arrhythmias. Providers also noted some learning curves, but none compromised medical care or clinical workflow. Insights from early adopters of AtriAmp signal the need for simplicity and fidelity in new PICU technologies. Our research suggests that such technologies can be pivotal to the support and growth of multi-disciplinary teams, even among those who do not participate in early implementation. Further research is needed to understand when and why novel technology adoption becomes widespread in high-stakes settings.

Diagnostic and Prognostic Value of Right Ventricular Fat Quantification from Computed Tomography in Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: In arrhythmogenic right ventricular cardiomyopathy (ARVC) non-invasive scar evaluation is not included among the diagnostic criteria or the predictors of ventricular arrhythmias (VA) and sudden death (SD). Computed tomography (CT) has excellent spatial resolution and allows a clear distinction between myocardium and fat; thus, it has great potential for the evaluation of myocardial scar in ARVC. Objective: The objective of this study is to evaluate the feasibility, and the diagnostic and prognostic value of semi-automated quantification of right ventricular (RV) fat replacement from CT images. Methods: An observational case-control study was carried out including 23 patients with a definite (19) or borderline (4) ARVC diagnosis and 23 age- and sex-matched controls without structural heart disease. All patients underwent contrast-enhanced cardiac CT. RV images were semi-automatically reconstructed with the ADAS-3D software (ADAS3D Medical, Barcelona, Spain). A fibrofatty scar was defined as values of Hounsfield Units (HU) <-10. Within the scar, a border zone (between -10 HU and -50 HU) and dense scar (<-50 HU) were distinguished. Results: All ARVC patients had an RV scar and all scar-related measurements were significantly higher in ARVC cases than in controls (p < 0.001). The total scar area and dense scar area showed no overlapping values between cases and controls, achieving perfect diagnostic performance (sensitivity and specificity of 100%). Among ARVC patients, 16 (70%) had experienced sustained VA or aborted SD. Among all clinical, ECG and imaging parameters, the dense scar area was the only one with a statistically significant association with VA and SD (p = 0.003). Conclusions: In ARVC, RV myocardial fat quantification from CT is feasible and may have considerable diagnostic and prognostic value.

The potential anti-arrhythmic effect of SGLT2 inhibitors.

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) were initially recommended as oral anti-diabetic drugs to treat type 2 diabetes (T2D), by inhibiting SGLT2 in proximal tubule and reduce renal reabsorption of sodium and glucose. While many clinical trials demonstrated the tremendous potential of SGLT2i for cardiovascular diseases. 2022 AHA/ACC/HFSA guideline first emphasized that SGLT2i were the only drug class that can cover the entire management of heart failure (HF) from prevention to treatment. Subsequently, the antiarrhythmic properties of SGLT2i have also attracted attention. Although there are currently no prospective studies specifically on the anti-arrhythmic effects of SGLT2i. We provide clues from clinical and fundamental researches to identify its antiarrhythmic effects, reviewing the evidences and mechanism for the SGLT2i antiarrhythmic effects and establishing a novel paradigm involving intracellular sodium, metabolism and autophagy to investigate the potential mechanisms of SGLT2i in mitigating arrhythmias.

CaMKIIδ-dependent dysregulation of atrial Na+ homeostasis promotes pro-arrhythmic activity in an obstructive sleep apnea mouse model.

Background: Obstructive sleep apnea (OSA) has been linked to various pathologies, including arrhythmias such as atrial fibrillation. Specific treatment options for OSA are mainly limited to symptomatic approaches. We previously showed that increased production of reactive oxygen species (ROS) stimulates late sodium current through the voltage-dependent Na+ channels via Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ), thereby increasing the propensity for arrhythmias. However, the impact on atrial intracellular Na+ homeostasis has never been demonstrated. Moreover, the patients often exhibit a broad range of comorbidities, making it difficult to ascertain the effects of OSA alone. Objective: We analyzed the effects of OSA on ROS production, cytosolic Na+ level, and rate of spontaneous arrhythmia in atrial cardiomyocytes isolated from an OSA mouse model free from comorbidities. Methods: OSA was induced in C57BL/6 wild-type and CaMKIIδ-knockout mice by polytetrafluorethylene (PTFE) injection into the tongue. After 8 weeks, their atrial cardiomyocytes were analyzed for cytosolic and mitochondrial ROS production via laser-scanning confocal microscopy. Quantifications of the cytosolic Na+ concentration and arrhythmia were performed by epifluorescence microscopy. Results: PTFE treatment resulted in increased cytosolic and mitochondrial ROS production. Importantly, the cytosolic Na+ concentration was dramatically increased at various stimulation frequencies in the PTFE-treated mice, while the CaMKIIδ-knockout mice were protected. Accordingly, the rate of spontaneous Ca2+ release events increased in the wild-type PTFE mice while being impeded in the CaMKIIδ-knockout mice. Conclusion: Atrial Na+ concentration and propensity for spontaneous Ca2+ release events were higher in an OSA mouse model in a CaMKIIδ-dependent manner, which could have therapeutic implications.

Structural phenotyping in atrial fibrillation with combined cardiac CT and atrial MRI: Identifying and differentiating individual structural remodelling types in AF.

INTRODUCTION: Atrial remodelling (AR) is the persistent change in atrial structure and/or function and contributes to the initiation, maintenance and progression of atrial fibrillation (AF) in a reciprocal self-perpetuating relationship. Left atrial (LA) size, geometry, fibrosis, wall thickness (LAWT) and ejection fraction (LAEF) have all been shown to vary with pathological atrial remodelling. The association of these global remodelling markers with each other for differentiating structural phenotypes in AF is not well investigated. METHOD: Patients referred for first-time AF ablation and controls without AF were prospectively recruited to undergo cardiac computed tomographic angiography (CCTA) and magnetic resonance imaging (MRI) with 3D atrial late-gadolinium enhanced (LGE) sequences. LAWT, atrial myocardial mass, LA volume and sphericity were calculated from CT. Biplane LA EF and LA fibrosis burden were derived from atrial MRI. Results were compared between patients with AF and controls. RESULTS: Forty two AF patients (64.3% male, age 64.6 ± 10.2 years, CHA2DS2-VASc 2.48 ± 1.5, 69.0% paroxysmal AF, 31% persistent AF, LVEF 57.9 ± 10.5%) and 37 controls (64.9% male, age 56.6 ± 7.2, CHA2DS2-VASc 1.54 ± 1.1, LVEF 60.4 ± 4.9%) were recruited. Patients with AF had a significantly higher LAWT (1.45 ± 0.52 mm vs 1.12 ± 0.42 mm, p = 0.003), tissue mass (15.81 ± 6.53 g vs. 12.18 ± 5.01 g, p = 0.011), fibrosis burden (9.33 ± 8.35% vs 2.41 ± 3.60%, p = 0.013), left atrial size/volume (95.68 ± 26.63 mL vs 81.22 ± 20.64 mL, p = 0.011) and lower LAEF (50.3 ± 15.3% vs 65.2 ± 8.6%, p < 0.001) compared to controls. There was no significant correlation between % fibrosis with LAWT (p = 0.29), mass (p = 0.89), volume (p = 0.49) or sphericity (p = 0.79). LAWT had a statistically significant weak positive correlation with LA volume (r = 0.25, p = .041), but not with sphericity (p = 0.86). LAEF had a statistically significant but weak negative correlation with fibrosis (r = -0.33, p = 0.008) and LAWT (r = -0.24, p = 0.07). CONCLUSION: AF is associated with significant quantifiable structural changes that are evident in LA size, tissue thickness, total LA tissue mass and fibrosis. These individual remodelling markers do not or only weakly correlate with each other suggesting different remodelling subtypes exist (e.g. fibrotic vs hypertrophic vs dilated). If confirmed, such a detailed understanding of the structural changes observed has the potential to inform clinical management strategies targeting individual mechanisms underlying the disease process.