The "arrhythmic" presentation of peripartum cardiomyopathy: case series and critical review of the literature.

Peripartum Cardiomyopathy (PPCM) is a polymorphic myocardial disease occurring late during pregnancy or early after delivery. While reduced systolic function and heart failure (HF) symptoms have been widely described, there is still a lack of reports about the arrhythmic manifestations of the disease. Most importantly, a broad range of unidentified pre-existing conditions, which may be missed by general practitioners and gynecologists, must be considered in differential diagnosis. The issue is relevant since some arrhythmias are associated to sudden cardiac death occurring in young patients, and the overall risk does not cease during the early postpartum period. This is why multimodality diagnostic workup and multidisciplinary management are highly suggested for these patients. We reported a series of 16 patients diagnosed with PPCM following arrhythmic clinical presentation. Both inpatients and outpatients were identified retrospectively. We performed several tests to identify the arrhythmic phenomena, inflammation and fibrosis presence. Cardiomyopathies phenotypes were reclassified in compliance with the updated ESC guidelines recommendations. Arrhythmias were documented in all the patients during the first cardiological assessment. PVC were the most common recorder arrhythmias, followed by VF, NSVT, AF, CSD.

Ebstein's anomaly in children and adults: multidisciplinary insights into imaging and therapy.

Although survival has significantly improved in the last four decades, the diagnosis of Ebstein's anomaly is still associated with a 20-fold increased risk of mortality, which generally drops after neonatal period and increases subtly thereafter. With increasing age of presentation, appropriate timing of intervention is challenged by a wide spectrum of disease and paucity of data on patient-tailored interventional strategies. The present review sought to shed light on the wide grey zone of post-neonatal Ebstein's manifestations, highlighting current gaps and achievements in knowledge for adequate risk assessment and appropriate therapeutic strategy.A 'wait-and-see' approach has been adopted in many circumstances, though its efficacy is now questioned by the awareness that Ebstein's anomaly is not a benign disease, even when asymptomatic. Moreover, older age at intervention showed a negative impact on post-surgical outcome.In order to tackle the extreme heterogeneity of Ebstein's anomaly, this review displays the multimodality imaging assessment necessary for a proper anatomical classification and the multidisciplinary approach needed for a comprehensive risk stratification and monitoring strategy. Currently available predictors of clinical outcome are summarised for both operated and unoperated patients, with the aim of supporting the decisional process on the choice of appropriate therapy and optimal timing for intervention.

Challenges in Brugada Syndrome Stratification: Investigating SCN5A Mutation Localization and Clinical Phenotypes.

Brugada Syndrome (BrS) is a genetic heart condition linked to sudden cardiac death. Though the SCN5A gene is primarily associated with BrS, there is a lack of comprehensive studies exploring the connection between SCN5A mutation locations and the clinical presentations of the syndrome. This study aimed to address this gap and gain further understanding of the syndrome. The investigation classified 36 high-risk BrS patients based on SCN5A mutations within the transmembrane/structured (TD) and intra-domain loops (IDLs) lacking a 3D structure. We characterized the intrinsically disordered regions (IDRs) abundant in IDLs, using bioinformatics tools to predict IDRs and post-translational modifications (PTMs) in NaV1.5. Interestingly, it was found that current predictive tools often underestimate the impacts of mutations in IDLs and disordered regions. Moreover, patients with SCN5A mutations confined to IDL regions-previously deemed 'benign'-displayed clinical symptoms similar to those carrying 'damaging' variants. Our research illuminates the difficulty in stratifying patients based on SCN5A mutation locations, emphasizing the vital role of IDLs in the NaV1.5 channel's functioning and protein interactions. We advocate for caution when using predictive tools for mutation evaluation in these regions and call for the development of improved strategies in accurately assessing BrS risk.

Electrocardiographic temporo-spatial assessment of depolarization and repolarization changes after epicardial arrhythmogenic substrate ablation in Brugada syndrome.

Aims: In Brugada syndrome (BrS), with spontaneous or ajmaline-induced coved ST elevation, epicardial electro-anatomic potential duration maps (epi-PDMs) were detected on a right ventricle (RV) outflow tract (RVOT), an arrhythmogenic substrate area (AS area), abolished by epicardial-radiofrequency ablation (EPI-AS-RFA). Novel CineECG, projecting 12-lead electrocardiogram (ECG) waveforms on a 3D heart model, previously localized depolarization forces in RV/RVOT in BrS patients. We evaluate 12-lead ECG and CineECG depolarization/repolarization changes in spontaneous type-1 BrS patients before/after EPI-AS-RFA, compared with normal controls. Methods and results: In 30 high-risk BrS patients (93% males, age 37 + 9 years), 12-lead ECGs and epi-PDMs were obtained at baseline, early after EPI-AS-RFA, and late follow-up (FU) (2.7-16.1 months). CineECG estimates temporo-spatial localization during depolarization (Early-QRS and Terminal-QRS) and repolarization (ST-Tpeak, Tpeak-Tend). Differences within BrS patients (baseline vs. early after EPI-AS-RFA vs. late FU) were analysed by Wilcoxon signed-rank test, while differences between BrS patients and 60 age-sex-matched normal controls were analysed by the Mann-Whitney test. In BrS patients, baseline QRS and QTc durations were longer and normalized after EPI-AS-ATC (151 ± 15 vs. 102 ± 13 ms, P < 0.001; 454 ± 40 vs. 421 ± 27 ms, P < 0.000). Baseline QRS amplitude was lower and increased at late FU (0.63 ± 0.26 vs. 0.84 ± 13 ms, P < 0.000), while Terminal-QRS amplitude decreased (0.24 ± 0.07 vs. 0.08 ± 0.03 ms, P < 0.000). At baseline, CineECG depolarization/repolarization wavefront prevalently localized in RV/RVOT (Terminal-QRS, 57%; ST-Tpeak, 100%; and Tpeak-Tend, 61%), congruent with the AS area on epi-PDM. Early after EPI-AS-RFA, RV/RVOT localization during depolarization disappeared, as Terminal-QRS prevalently localized in the left ventricle (LV, 76%), while repolarization still localized on RV/RVOT [ST-Tpeak (44%) and Tpeak-Tend (98%)]. At late FU, depolarization/repolarization forces prevalently localized in the LV (Terminal-QRS, 94%; ST-Tpeak, 63%; Tpeak-Tend, 86%), like normal controls. Conclusion: CineECG and 12-lead ECG showed a complex temporo-spatial perturbation of both depolarization and repolarization in BrS patients, prevalently localized in RV/RVOT, progressively normalizing after epicardial ablation.

Deep learning unmasks the ECG signature of Brugada syndrome.

One in 10 cases of sudden cardiac death strikes without warning as the result of an inherited arrhythmic cardiomyopathy, such as Brugada Syndrome (BrS). Normal physiological variations often obscure visible signs of this and related life-threatening channelopathies in conventional electrocardiograms (ECGs). Sodium channel blockers can reveal previously hidden diagnostic ECG features, however, their use carries the risk of life-threatening proarrhythmic side effects. The absence of a nonintrusive test places a grossly underestimated fraction of the population at risk of SCD. Here, we present a machine-learning algorithm that extracts, aligns, and classifies ECG waveforms for the presence of BrS. This protocol, which succeeds without the use of a sodium channel blocker (88.4% accuracy, 0.934 AUC in validation), can aid clinicians in identifying the presence of this potentially life-threatening heart disease.

Unravelling Novel SCN5A Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights.

Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the SCN5A gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel SCN5A mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions.

Atrial fibrillation recurrences during the blanking period after catheter ablation with the laser balloon technique.

INTRODUCTION: Regardless of the catheter ablation (CA) for atrial fibrillation (AF) strategy, the role of early recurrences during the blanking period (BP) is still unclear. Our aim was to evaluate atrial tachyarrhythmias (ATAs) recurrences during the BP after CA with the laser-balloon (LB) technique. METHODS: Consecutive patients undergoing LBCA were enrolled. Primary outcome of the study was the overall crude ATA recurrence rate during the BP. ATA recurrences after the BP and in-hospital readmissions during the BP were deemed secondary outcomes. RESULTS: Two hundred and twenty-four patients underwent CA with the LB. Median age was 63.0 (55.5-69.5) years and 74.1% were males. 28.6% were persistent AF patients, and 34.8% of patients were followed up with a loop recorder. 15.6% of patients experienced at least an ATA recurrence during the BP. Male sex, chronic heart failure, persistent AF, and recurrences during the BP were found to be associated with long-term ATA recurrences. Recurrences during the BP remained associated with the outcome of interest at multivariate analysis (hazard ratio [HR] = 12.393, 95% confidence interval [95% CI] = 3.699-41.865, p < .001). An association over time was found between early and late recurrences, with 73.7%, 45.5%, and 10.8% of patients presenting with recurrences at 1-, 2-, and 3-month follow-up being free from recurrences after the BP, respectively. 8.0% of patients were readmitted during the BP: 4.5% for AF electrical cardioversion, and 1.8% for CA of other atrial arrhythmias; no redo CA was performed. CONCLUSION: After adjusting for confounders, ATA recurrences during the BP represent the most significant predictor of ATA recurrences after the BP, regardless of AF pattern.

Arrhythmogenic substrate elimination for safe testosterone therapy in symptomatic Brugada syndrome patients.

BACKGROUND: Brugada Syndrome (BrS) is a cardiogenetic disease known for its association with sudden cardiac death (SCD) in individuals with structurally normal hearts. The prevalence of BrS is higher in males, who also face a greater risk of SCD. Its higher prevalence and worse outcome in male subjects may be due to testosterone effects on ion channels expression and function. The influence of testosterone on cardiac action potentials, both genomically and non-genomically, underscores its potential role in unmasking the syndrome and triggering life-threatening arrhythmias. Notably, testosterone replacement therapy (TRT), used for hypogonadism and gender reassignment, has been linked to BrS unmasking. The role of epicardial ablation in symptomatic BrS patients where hormonal therapy cannot be discontinued is unknown. METHODS AND RESULTS: In this study we describe the first two cases of substrate mapping and ablation in BrS patients experiencing arrhythmic events while on TRT. In both cases, high-density epicardial mapping revealed abnormal areas of prolonged and fragmented electrograms in the right ventricular (RV) outflow tract and anterior wall. These abnormalities were completely abolished by radiofrequency ablation (RFA). After ablation, both patients showed a persistent normalization of the ECG and were free from ventricular arrhythmias at follow-up, despite ongoing TRT. CONCLUSION: RFA can be considered as a therapeutic option in symptomatic BrS patients with a high-risk profile who cannot discontinue TRT, being essential for restoring their normal physiology or preserving their sexual identity. As testosterone use is increasing, further studies are warranted to define a standardized diagnostic and therapeutic strategy in this specific subset of BrS patients.

Ablation of ventricular arrhythmias in cardiogenetic diseases.

Sudden cardiac death is a leading cause of mortality, claiming millions of lives every year. Recent advances in cardiac arrhythmia mapping have demonstrated that the ventricular epicardial region has a critical arrhythmogenic role in some inherited cardiogenetic diseases. Historically, electroanatomic abnormalities have been identified in the ventricular epicardium of patients with arrhythmogenic right ventricular cardiomyopathy. More recently, epicardial pathological substrates have been identified also in electrical disease (Brugada syndrome, early repolarization syndrome) and currently in long QT syndrome. In light of these findings, the epicardial area has emerged as an important determinant in sudden cardiac death-related cardiomyopathies.

Analysis of the intramolecular 1,7-lactone of N-acetylneuraminic acid using HPLC-MS: relationship between detection and stability.

A subclass of the sialic acid family consists of intramolecular lactones that may function as key indicators of physiological and pathological states. However, the existence of these compounds in free form is highly improbable, since they are unlikely to exist in an aqueous solution due to their lability. Current analytical method used to detect them in biological fluids has not recognized their reactivity in solution and is prone to misidentification. However, recent advances in synthetic methods for 1,7-lactones have allowed the preparation of these sialic acid derivatives as authentic reference standards. We report here the development of a new HPLC-MS method for the simultaneous detection of the 1,7-lactone of N-acetylneuraminic acid, its γ-lactone derivative, and N-acetylneuraminic acid that overcomes the limitations of the previous analytical procedure for their identification.

Right ventricular epicardial arrhythmogenic substrate in long-QT syndrome patients at risk of sudden death.

AIMS: The long-QT syndrome (LQTS) represents a leading cause of sudden cardiac death (SCD). The aim of this study was to assess the presence of an underlying electroanatomical arrhythmogenic substrate in high-risk LQTS patients. METHODS AND RESULTS: The present study enrolled 11 consecutive LQTS patients who had experienced frequent implantable cardioverter-defibrillator (ICD discharges triggered by ventricular fibrillation (VF). We acquired electroanatomical biventricular maps of both endo and epicardial regions for all patients and analyzed electrograms sampled from several myocardial regions. Abnormal electrical activities were targeted and eliminated by the means of radiofrequency catheter ablation. VF episodes caused a median of four ICD discharges in eleven patients (6 male, 54.5%; mean age 44.0 ± 7.8 years, range 22-53) prior to our mapping and ablation procedures. The average QTc interval was 500.0 ± 30.2 ms. Endo-epicardial biventricular maps displayed abnormally fragmented, low-voltage (0.9 ± 0.2 mV) and prolonged electrograms (89.9 ± 24.1 ms) exclusively localized in the right ventricular epicardium. We found electrical abnormalities extending over a mean epicardial area of 15.7 ± 3.1 cm2. Catheter ablation of the abnormal epicardial area completely suppressed malignant arrhythmias over a mean 12 months of follow-up (median VF episodes before vs. after ablation, 4 vs. 0; P = 0.003). After the procedure, the QTc interval measured in a 12-lead ECG analysis shortened to a mean of 461.8 ± 23.6 ms (P = 0.004). CONCLUSION: This study reveals that, among high-risk LQTS patients, regions localized in the epicardium of the right ventricle harbour structural electrophysiological abnormalities. Elimination of these abnormal electrical activities successfully prevented malignant ventricular arrhythmia recurrences.

Clinical characteristics and electrophysiologic properties of SCN5A variants in fever-induced Brugada syndrome.

BACKGROUND: Brugada syndrome (BrS) is a severe inherited arrhythmia syndrome that can be unmasked by fever. METHODS: A multicentre clinical analysis was performed in 261 patients diagnosed with fever-induced BrS, including 198 (75.9%) and 27 (10.3%) patients who received next-generation genetic sequencing and epicardial arrhythmogenic substrate (AS) mapping, respectively. FINDINGS: In fever-induced BrS patients, pathogenic or likely pathogenic (P/LP) SCN5A variant carriers developed fever-induced BrS at a younger age, and more often in females and those of Caucasian descent. They exhibited significant electrophysical abnormalities, including a larger epicardial AS area, and more prolonged abnormal epicardial electrograms. During a median follow-up of 50.5 months (quartiles 32.5-81.5 months) after the diagnosis, major cardiac events (MCE) occurred in 27 (14.4%) patients. Patients with P/LP SCN5A variants had a higher ratio of MCE compared with the rest. Additionally, history of syncope, QRS duration, and Tpe interval could also predict an increased risk for future MCE according to univariate analysis. Multivariate analysis indicated that only P/LP SCN5A variants were independent significant predictors of MCE. Computational structural modelling showed that most variants are destabilizing, suggesting that Nav1.5 structure destabilization caused by SCN5A missense variants may contribute to fever-induced BrS. INTERPRETATION: In our cohort, P/LP SCN5A variant carriers with fever-induced BrS are more prevalent among patients of Caucasian descent, females, and younger patients. These patients exhibit aggressive electrophysiological abnormalities and worse outcome, which warrants closer monitoring and more urgent management of fever. FUNDING: The current work was supported by the National Natural Science Foundation Project of China (Nos. 82270332 & 81670304), The Fundamental Research Funds for the Central Universities of China - Independent Research Project of Wuhan University (No. 2042022kf1217) from China; the National Institutes of Health of USA [NIH R56 (HL47678), NIH R01 (HL138103), and NIH R01 (HL152201)], the W. W. Smith Charitable Trust and the Wistar and Martha Morris Fund, Sharpe-Strumia Research Foundation, the American Heart Association Postdoctoral Fellowship (20POST35220002) from United States; the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences (PREDICT2) from the Netherlands.

High-risk Brugada syndrome: factors associated with arrhythmia recurrence and benefits of epicardial ablation in addition to implantable cardioverter defibrillator implantation.

AIMS: This study aims to evaluate the prognostic impact of the arrhythmogenic substrate size in symptomatic Brugada syndrome (BrS) as well as to validate the long-term safety and effectiveness of epicardial radiofrequency ablation (RFA) compared with no-RFA group. METHODS AND RESULTS: In this prospective investigational long-term registry study, 257 selected symptomatic BrS patients with implantable cardioverter defibrillator (ICD) implantation were included. Among them, 206 patients underwent epicardial RFA and were monitored for over 5 years post-ablation (RFA group), while 51 patients received only ICD implantation declining RFA. Primary endpoints included risk factors for ventricular fibrillation (VF) events pre-ablation and freedom from VF events post-ablation. In the RFA group, BrS substrates were identified in the epicardial surface of the right ventricle. During the pre-RFA follow-up period (median 27 months), VF episodes and VF storms were experienced by 53 patients. Independent risk factors included substrate size [hazard ratio (HR), 1.13; 95% confidence interval (CI), 1.08-1.18; P < 0.001], aborted cardiac arrest (HR, 2.98; 95% CI, 1.68-5.28; P < 0.001), and SCN5A variants (HR, 2.22; 95% CI, 1.15-4.27; P = 0.017). In the post-RFA follow-up (median 40 months), the RFA group demonstrated superior outcomes compared with no-RFA (P < 0.001) without major procedure-related complications. CONCLUSION: Our study underscores the role of BrS substrate extent as a crucial prognostic factor for recurrent VF and validates the safety and efficacy of RFA when compared with a no-RFA group. Our findings highlight the importance of ajmaline in guiding epicardial mapping/ablation in symptomatic BrS patients, laying the groundwork for further exploration of non-invasive methods to guide informed clinical decision-making.

Alterations of the Sialylation Machinery in Brugada Syndrome.

Brugada Syndrome (BrS) is an inherited arrhythmogenic disorder with an increased risk of sudden cardiac death. Recent evidence suggests that BrS should be considered as an oligogenic or polygenic condition. Mutations in genes associated with BrS are found in about one-third of patients and they mainly disrupt the cardiac sodium channel NaV1.5, which is considered the main cause of the disease. However, voltage-gated channel's activity could be impacted by post-translational modifications such as sialylation, but their role in BrS remains unknown. Thus, we analyzed high risk BrS patients (n = 42) and healthy controls (n = 42) to assess an involvement of sialylation in BrS. Significant alterations in gene expression and protein sialylation were detected in Peripheral Blood Mononuclear Cells (PBMCs) from BrS patients. These changes were significantly associated with the phenotypic expression of the disease, as the size of the arrhythmogenic substrate and the duration of epicardial electrical abnormalities. Moreover, protein desialylation caused a reduction in the sodium current in an in vitro NaV1.5-overexpressing model. Dysregulation of the sialylation machinery provides definitive evidence that BrS affects extracardiac tissues, suggesting an underlying cause of the disease. Moreover, detection of these changes at the systemic level and their correlation with the clinical phenotype hint at the existence of a biomarker signature for BrS.

Human Sarcopenic Myoblasts Can Be Rescued by Pharmacological Reactivation of HIF-1α.

Sarcopenia, an age-related decline in muscle mass and strength, is associated with metabolic disease and increased risk of cardiovascular morbidity and mortality. It is associated with decreased tissue vascularization and muscle atrophy. In this work, we investigated the role of the hypoxia inducible factor HIF-1α in sarcopenia. To this end, we obtained skeletal muscle biopsies from elderly sarcopenic patients and compared them with those from young individuals. We found a decrease in the expression of HIF-1α and its target genes in sarcopenia, as well as of PAX7, the major stem cell marker of satellite cells, whereas the atrophy marker MURF1 was increased. We also isolated satellite cells from muscle biopsies and cultured them in vitro. We found that a pharmacological activation of HIF-1α and its target genes caused a reduction in skeletal muscle atrophy and activation of PAX7 gene expression. In conclusion, in this work we found that HIF-1α plays a role in sarcopenia and is involved in satellite cell homeostasis. These results support further studies to test whether pharmacological reactivation of HIF-1α could prevent and counteract sarcopenia.

Neu3 Sialidase Activates the RISK Cardioprotective Signaling Pathway during Ischemia and Reperfusion Injury (IRI).

Coronary reperfusion strategies are life-saving approaches to restore blood flow to cardiac tissue after acute myocardial infarction (AMI). However, the sudden restoration of normal blood flow leads to ischemia and reperfusion injury (IRI), which results in cardiomyoblast death, irreversible tissue degeneration, and heart failure. The molecular mechanism of IRI is not fully understood, and there are no effective cardioprotective strategies to prevent it. In this study, we show that activation of sialidase-3, a glycohydrolytic enzyme that cleaves sialic acid residues from glycoconjugates, is cardioprotective by triggering RISK pro-survival signaling pathways. We found that overexpression of Neu3 significantly increased cardiomyoblast resistance to IRI through activation of HIF-1α and Akt/Erk signaling pathways. This raises the possibility of using Sialidase-3 activation as a cardioprotective reperfusion strategy after myocardial infarction.

Brugada Syndrome: Warning of a Systemic Condition?

Brugada syndrome (BrS) is a hereditary disorder, characterized by a specific electrocardiogram pattern and highly related to an increased risk of sudden cardiac death. BrS has been associated with other cardiac and non-cardiac pathologies, probably because of protein expression shared by the heart and other tissue types. In fact, the most commonly found mutated gene in BrS, SCN5A, is expressed throughout nearly the entire body. Consistent with this, large meals and alcohol consumption can trigger arrhythmic events in patients with BrS, suggesting a role for organs involved in the digestive and metabolic pathways. Ajmaline, a drug used to diagnose BrS, can have side effects on non-cardiac tissues, such as the liver, further supporting the idea of a role for organs involved in the digestive and metabolic pathways in BrS. The BrS electrocardiogram (ECG) sign has been associated with neural, digestive, and metabolic pathways, and potential biomarkers for BrS have been found in the serum or plasma. Here, we review the known associations between BrS and various organ systems, and demonstrate support for the hypothesis that BrS is not only a cardiac disorder, but rather a systemic one that affects virtually the whole body. Any time that the BrS ECG sign is found, it should be considered not a single disease, but rather the final step in any number of pathways that ultimately threaten the patient's life. A multi-omics approach would be appropriate to study this syndrome, including genetics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and glycomics, resulting eventually in a biomarker for BrS and the ability to diagnose this syndrome using a minimally invasive blood test, avoiding the risk associated with ajmaline testing.