Familial catamenial coronary spasms.

Coronary artery spasms represent important causes of myocardial ischaemia and infarction in patients with non-obstructive coronary artery disease. They are notably seen in younger people and occur almost equally in men and women. Besides traditional risk factors (ie, smoking), female hormones might also play a role.We report of two young sisters who presented with myocardial infarction caused by catamenial coronary spasms (CS), that is, during menstruation. In one of these women, this resulted in heart failure with a severely reduced ejection fraction and ultimately a heart transplant because of intractable ventricular arrhythmias.CS might result from changing hormone levels (especially oestrogen) during menstruation. Increased awareness of the occurrence of catamenial CS is essential for diagnosis and consequent treatment with coronary vasodilators and/or specific oestrogen/progesterone regimens.

Stellate ganglion, inflammation, and arrhythmias: a new perspective on neuroimmune regulation.

Current research on the stellate ganglion (SG) has shifted from merely understanding its role as a collection of neurons to recognizing its importance in immune regulation. As part of the autonomic nervous system (ANS), the SG plays a crucial role in regulating cardiovascular function, particularly cardiac sympathetic nerve activity. Abnormal SG function can lead to disordered cardiac electrical activity, which in turn affects heart rhythm stability. Studies have shown that excessive activity of the SG is closely related to the occurrence of arrhythmias, especially in the context of inflammation. Abnormal activity of the SG may trigger excessive excitation of the sympathetic nervous system (SNS) through neuroimmune mechanisms, thereby increasing the risk of arrhythmias. Simultaneously, the inflammatory response of the SG further aggravates this process, forming a vicious cycle. However, the causal relationship between SG, inflammation, and arrhythmias has not yet been fully clarified. Therefore, this article deeply explores the key role of the SG in arrhythmias and its complex relationship with inflammation, providing relevant clinical evidence. It indicates that interventions targeting SG function and inflammatory responses have potential in preventing and treating inflammation-related arrhythmias, offering a new perspective for cardiovascular disease treatment strategies.

Assays of Variant Effect and Automated Patch Clamping Improve KCNH2-LQTS Variant Classification and Cardiac Event Risk Stratification.

BACKGROUND: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2. Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes. METHODS: We quantified cell-surface trafficking of 18 796 variants in KCNH2 using a multiplexed assay of variant effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping. We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian long QT syndrome penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events. RESULTS: Variant MAVE trafficking scores and automated patch clamping peak tail currents were highly correlated (Spearman rank-order ρ=0.69; n=433). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian long QT syndrome penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and adjusted QT interval (QTc); however, MAVE data became nonsignificant when peak tail current and penetrance estimates were also available. The area under the receiver operator characteristic curve for 20-year event outcomes based on patient-specific sex and QTc (area under the curve, 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (area under the curve, 0.86 [0.83-0.89]) or attainable automated patch clamping peak tail current data (area under the curve, 0.84 [0.81-0.88]). CONCLUSIONS: High-throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale, whereas long QT syndrome penetrance estimates and automated patch clamping peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants.

Brugada Syndrome: Anesthetic Implications in an Incidentally Diagnosed Patient.

Brugada syndrome (BS) is characterized by abnormal repolarization in cardiac cells, occurring in the absence of structural heart disease, which elevates the risk of ventricular arrhythmias and sudden cardiac death. While most BS patients are asymptomatic, a notable percentage experience syncope or sudden cardiac death. Diagnosis is primarily based on electrocardiographic (ECG) findings. A 40-year-old male with a history of syncope and a family history of sudden cardiac death was scheduled for urgent clavicle osteosynthesis. Preoperative ECG revealed type 1 BS. A multidisciplinary approach was taken, and anesthetic management involved combined general and regional anesthesia, utilizing ultrasound-guided clavipectoral and superficial cervical blocks. Postoperative pain was managed with paracetamol and ketorolac. The patient remained stable throughout the procedure, was monitored for 36 hours postoperatively, and was discharged without complications. BS poses significant perioperative risks, necessitating careful anesthetic management. This case report highlights the successful use of combined general and regional anesthesia in a BS patient, contributing to the limited evidence on safe anesthesia practices for this pathology.

Clinical Course and Treatment of Patients With Apical Aneurysms Due to Hypertrophic Cardiomyopathy.

Background: There is controversy about risk of malignant arrhythmias and stroke in patients with apical aneurysms in hypertrophic cardiomyopathy (HCM). Objectives: The aim of this study was to estimate the associations of aneurysm size and major HCM risk factors with the incidence of lethal and potentially lethal arrhythmias and to estimate incidence of unexplained stroke. Methods: In 108 patients (age 57.4 ± 13.5 years, 37% female) from 3 HCM centers, we assessed American Heart Association/American College of Cardiology guidelines risk factors and initial aneurysm size by echocardiography and cardiac magnetic resonance imaging and assessed outcomes after median 5.9 (IQR: 3.7-10.0) years. Results: Implantable cardioverter defibrillator discharges or sudden cardiac death (SCD) occurred in 21 (19.4%) patients. Of patients with a risk factor, 55% subsequently had ventricular tachycardia (VT), ventricular fibrillation (VF), or SCD at follow-up, compared with 10% in those who did not (P < 0.001). The upper tercile of size had a 5-year cumulative risk of 35%, while the lower tercile had 5-year risk of 6% (P = 0.0046). In those with the smallest aneurysms <2 cm2 and also without risk factors VT, VF, or SCD occurred in only 2.5%. Clinical atrial fibrillation (AF) was prevalent, occurring in 49 (45%). Stroke was commonly associated with AF. Stroke without conventional cause had an incidence of 0.5%/year. Surgery in 19% was effective in reducing symptoms. VT ablation and surgery were moderately effective in preventing recurrent VT. Conclusions: Risk factors and aneurysm size were associated with subsequent VT, VF, or SCD. Patients with aneurysms in the lowest tercile of size have a low cumulative 5-year risk. Clinical AF occurred frequently. Stroke prevalence in absence of known stroke etiologies is uncommon and comparable to risk of severe bleeding.

Cardiac implications in myasthenia gravis.

This editorial aimed to consolidate the current evidence in literature on the association between myasthenia gravis (MG) and cardiac involvement, focusing on the impact of thymoma, antistriational antibodies, and late-onset MG. Additionally, the study aimed to explore the influence of genetic differences among populations on the association with cardiac disease. We conducted a review of existing literature in PubMed and Google Scholar to find relevant studies on cardiac involvement in MG. We created search criteria using a combination of free text words, including MG, antistriational antibodies, thymectomy, cardiomyopathy, myocarditis, arrhythmias, autonomic dysfunction. Relevant articles published in English language were analyzed and incorporated. The findings indicate a strong association between thymoma, myasthenic crisis, antistriational antibodies, and late-onset MG with cardiac involvement. The study also revealed that genetic differences among populations influence the risk of cardiac disease and electrocardiography (ECG) abnormalities in MG patients. Autonomic dysfunctions altered cardiac autonomic response and increased susceptibility to arrhythmias and sudden cardiac death in MG patients. The study supports the significance of thymoma, antistriational antibodies, and late-onset MG as key factors associated with cardiac involvement in MG patients. It emphasizes the importance of ECG as the initial test in managing MG patients, particularly in the perioperative period, to identify and genetic testing if needed to address their cardiac risk effectively.

Atomistic mechanisms of the regulation of small-conductance Ca2+-activated K+ channel (SK2) by PIP2.

Small-conductance Ca2+-activated K+ channels (SK, KCa2) are gated solely by intracellular microdomain Ca2+. The channel has emerged as a therapeutic target for cardiac arrhythmias. Calmodulin (CaM) interacts with the CaM binding domain (CaMBD) of the SK channels, serving as the obligatory Ca2+ sensor to gate the channels. In heterologous expression systems, phosphatidylinositol 4,5-bisphosphate (PIP2) coordinates with CaM in regulating SK channels. However, the roles and mechanisms of PIP2 in regulating SK channels in cardiomyocytes remain unknown. Here, optogenetics, magnetic nanoparticles, combined with Rosetta structural modeling, and molecular dynamics (MD) simulations revealed the atomistic mechanisms of how PIP2 works in concert with Ca2+-CaM in the SK channel activation. Our computational study affords evidence for the critical role of the amino acid residue R395 in the S6 transmembrane segment, which is localized in propinquity to the intracellular hydrophobic gate. This residue forms a salt bridge with residue E398 in the S6 transmembrane segment from the adjacent subunit. Both R395 and E398 are conserved in all known isoforms of SK channels. Our findings suggest that the binding of PIP2 to R395 residue disrupts the R395:E398 salt bridge, increasing the flexibility of the transmembrane segment S6 and the activation of the channel. Importantly, our findings serve as a platform for testing of structural-based drug designs for therapeutic inhibitors and activators of the SK channel family. The study is timely since inhibitors of SK channels are currently in clinical trials to treat atrial arrhythmias.

Timing of oral anticoagulation in atrial fibrillation patients after acute ischaemic stroke and outcome after 3 months: results of the multicentre Berlin Atrial Fibrillation Registry.

BACKGROUND: Oral anticoagulation (OAC) is key in stroke prevention in patients with atrial fibrillation (AF) but there is uncertainty regarding the optimal timing of OAC (re)initiation after stroke, as recent large randomised controlled trials have methodological weaknesses and excluded stroke patients on therapeutic anticoagulation at stroke onset as well as patients started on a vitamin K antagonist after stroke. The '1-3-6-12 days rule', based on expert consensus and referring to stroke severity, was used in clinical practice to initiate OAC after acute ischaemic stroke or transient ischaemic attack (TIA) since publication in 2013. METHODS: We retrospectively assessed whether compliance to the '1-3-6-12 days rule' was associated with the composite endpoint (recurrent stroke, systemic embolism, myocardial infarction, major bleeding or all-cause death). RESULTS: Among 708 registry patients with known AF before stroke and hospitalisation within 72 hours after stroke, 432 were anticoagulated at stroke onset. OAC was started according to the '1-3-6-12 days rule' in 255 (39.2%) patients. Non-adherence to the '1-3-6-12 days rule' was not associated with the composite endpoint within 3 months in 661 patients who (re-)started on OAC (log-rank test: p=0.74).Results were similar for 521 patients (re)started on a non-vitamin K-dependent OAC. CONCLUSION: (Re)starting OAC after stroke followed the '1-3-6-12 days rule' in about 40% of all patients with AF, and more often in those anticoagulated at stroke onset. Adherence to the '1-3-6-12 days rule' did not reduce the composite clinical endpoint, if OAC was restarted within 3 months of stroke/TIA. TRIAL REGISTRATION NUMBER: NCT02306824.

Prostate Cancer Therapy Cardiotoxicity Map (PROXMAP) for Advanced Disease States: A Systematic Review and Network Meta-analysis with Bayesian Modeling of Treatment Histories.

BACKGROUND AND OBJECTIVE: Recommendations of first-line therapies for metastatic hormone-sensitive (mHSPC), nonmetastatic castrate-resistant (M0CRPC), and metastatic castrate-resistant (mCRPC) prostate cancer do not account for cardiotoxicity due to a lack of clear prior evidence. This manuscript assesses cardiotoxicity of these therapies. METHODS: We searched Ovid Medline, Elsevier Embase, and the Cochrane Library for randomized clinical trials (RCTs) from database inception to January 14, 2024. Network meta-analyses of first-line mHSPC, M0CRPC, and mCRPC therapies were constructed for the five cardiotoxicity metrics defined by the International Cardio-Oncology Society: heart failure, myocarditis, vascular toxicity, hypertension, and arrhythmias. Additional Bayesian network meta-analyses also accounted for prior treatment history. KEY FINDINGS AND LIMITATIONS: Thirteen RCTs (16 292 patients) were included. For mHSPC, androgen deprivation therapy (ADT) plus docetaxel (DTX) plus abiraterone acetate (AA) with prednisone (P) demonstrated a significant increase in hypertension and arrhythmias versus ADT + DTX (risk ratio [RR] 2.85, 95% confidence interval [CI] 1.67-4.89, and RR 2.01, 95% CI 1.17-3.44, respectively); however, no corresponding differences were observed between ADT + DTX plus darolutamide (DAR) and ADT + DTX (RR 1.55, 95% CI 0.73-3.30, and RR 0.94, 95% CI 0.63-1.40, respectively). For mCRPC assuming a history of mHSPC treatment, ADT + AA + P plus olaparib (OLA) demonstrated a statistically significant decrease in hypertension versus ADT + AA + P (RR 0.20, 95% CI 0.16-0.26). M0CRPC results were unremarkable. CONCLUSIONS AND CLINICAL IMPLICATIONS: For mHSPC, ADT + DTX + DAR demonstrates less cardiotoxicity than ADT + DTX + AA + P due to a lower risk of hypertension and arrhythmias from decreased mineralocorticoid excess. In addition, OLA counterintuitively offers decreased hypertension when superimposed on ADT + AA + P for mCRPC treatment after prior androgen deprivation from mHSPC therapy.

Computational Medicine: What Electrophysiologists Should Know to Stay Ahead of the Curve.

PURPOSE OF REVIEW: Technology drives the field of cardiac electrophysiology. Recent computational advances will bring exciting changes. To stay ahead of the curve, we recommend electrophysiologists develop a robust appreciation for novel computational techniques, including deterministic, statistical, and hybrid models. RECENT FINDINGS: In clinical applications, deterministic models use biophysically detailed simulations to offer patient-specific insights. Statistical techniques like machine learning and artificial intelligence recognize patterns in data. Emerging clinical tools are exploring avenues to combine all the above methodologies. We review three ways that computational medicine will aid electrophysiologists by: (1) improving personalized risk assessments, (2) weighing treatment options, and (3) guiding ablation procedures. Leveraging clinical data that are often readily available, computational models will offer valuable insights to improve arrhythmia patient care. As emerging tools promote personalized medicine, physicians must continue to critically evaluate technology-driven tools they consider using to ensure their appropriate implementation.

Type and dimensions can predict ventricular arrhythmias and cardiac death in primary benign cardiac tumors in children.

Despite being extremely rare in children, primary benign cardiac tumors can cause malignant ventricular arrhythmias (VA) or even sudden cardiac death. To assess the predictors of cardiovascular death and malignant VAs, we designed a retrospective single-center study enrolling paediatric patients. We defined as primary outcome a composite of cardiovascular death, sustained VT, ventricular fibrillation and rapid, symptomatic non-sustained VT. Our secondary endpoint was to assess the prevalence of clinically significant arrhythmias in our population. METHODS AND RESULTS: We fitted a multivariate Cox regression model to assess the predictors of the primary outcome. Over a period of 38 years, a total of 97 children were enrolled in the study. Among them, there were 73 rhabdomyomas, 13 fibromas, 3 myxomas, 3 teratomas, 1 lipoma, 2 haemangiomas and 2 fibroelastomas. Over a median follow up of 10.53 years, 16 patients met the primary outcome. Kaplan Meier unadjusted survival estimates showed that tumor dimensions larger than 2.3 cm and diagnosis of fibroma predicted worse outcomes compared with smaller tumors or other histotypes, (log rank p < 0.0002 and < 0.0001 respectively). In multivariate Cox proportional hazards analysis, diagnosis of fibroma and tumor dimensions were independently associated to the primary endpoint (HR: 5.06, 95 %CI (1.3-19); and 1.26 • (1.05-11), respectively). Clinically significant arrhythmias were reported in 24.5 % of the study population. CONCLUSIONS: Among paediatric primary cardiac tumors, type and dimensions may predict the hazard of malignant VAs and cardiac death.

Achieving Real-Time Prediction of Paroxysmal Atrial Fibrillation Onset by Convolutional Neural Network and Sliding Window on R-R Interval Sequences.

Early diagnosis of paroxysmal atrial fibrillation (PAF) could prompt patients to receive timely interventions in clinical practice. Various PAF onset prediction algorithms might benefit from accurate heart rate variability (HRV) analysis and machine learning classification but are challenged by real-time monitoring scenarios. The aim of this study is to present an end-to-end deep learning-based PAFNet model that integrates a sliding window technique on raw R-R intervals of electrocardiogram (ECG) segments to achieve a real-time prediction of PAF onset. This integration enables the deep convolutional neural network (CNN) to be customized as a light-weight architecture that accommodates the size of sliding windows simply by altering the input layer, and specifically its effectiveness in making a new prediction with each new heartbeat. Catering to the potential influence of input sizes, three CNN models were trained using 50, 100, and 200 R-R intervals, respectively. For each model, the performance of the automated algorithms was evaluated for PAF prediction using a ten-fold cross-validation. As a results, a total of 56,381 PAFN-type and 56,900 N-type R-R interval segments were collected from publicly accessible ECG databases, and a promising prediction performance of the automated algorithm with 100 R-R intervals was achieved, with a sensitivity of 97.12%, a specificity of 97.77%, and an accuracy of 97.45%, respectively. Importantly, the automated algorithm with a sliding window step of 1 could process one sample in only 23.1 milliseconds and identify the onset of PAF at least 45 min in advance. The present results suggest that the sliding window technique on raw R-R interval sequences, along with deep learning-based algorithms, may offer the possibility of providing an accurate, real-time, end-to-end clinical tool for mass monitoring of PAF.

Comparing E-Cigarettes and Traditional Cigarettes in Relation to Myocardial Infarction, Arrhythmias, and Sudden Cardiac Death: A Systematic Review and Meta-Analysis.

BACKGROUND: The use of electronic cigarettes (e-cigarettes) as a perceived safer alternative to traditional cigarettes has grown rapidly. However, the cardiovascular risks associated with e-cigarettes compared to regular cigarettes remain unclear. OBJECTIVE: To systematically review and compare the cardiovascular outcomes of e-cigarette use versus traditional cigarette use, focusing on the risks of myocardial infarction, arrhythmias, and sudden death. METHODS: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Peer-reviewed studies published in English were included if they reported cardiovascular outcomes related to e-cigarette or traditional cigarette use. A total of 20 studies were included, covering observational and interventional studies focusing on heart rate variability, myocardial infarction, arrhythmias, and sudden cardiac events. The quality of the evidence was assessed using the GRADE criteria, and data were extracted and analyzed based on the PICOS (Population, Interventions, Comparisons, Outcomes, and Study designs) framework. RESULTS: The systematic review found that both e-cigarettes and traditional cigarettes pose significant cardiovascular risks, with traditional cigarettes linked to a higher incidence of myocardial infarction, arrhythmias, and sudden cardiac death. E-cigarette users also face increased risks of arrhythmias and myocardial infarction compared to non-smokers, primarily due to the constituents of aerosolized e-liquid, including nicotine and flavorings, which contribute to adverse cardiac effects. Regular e-cigarette use, particularly in combination with traditional cigarette use, was associated with a heightened risk of myocardial infarction. Studies also reported heart function abnormalities, such as systolic and diastolic dysfunction, and reduced ejection fractions. Additionally, changes in heart rate variability, heart rate, and blood pressure were observed, indicating both acute and chronic effects of e-cigarettes on cardiovascular autonomic regulation. CONCLUSIONS: While e-cigarettes may present a lower cardiovascular risk compared to traditional cigarettes, they are not without harm. Both products are linked to increased risks of myocardial infarction and arrhythmias, though traditional cigarettes pose a higher overall threat. Given the limitations in the current evidence base, particularly concerning the long-term effects of e-cigarette use, further research is needed to clarify these cardiovascular risks and inform public health guidelines.

Cardiac resynchronization therapy in heart failure based on Strauss criteria for left bundle branch block.

AIMS: The left bundle branch block (LBBB) is a strong predictor of response to cardiac resynchronization therapy (CRT). However, a significant number of patients do not respond to the treatment. The study sought to evaluate the impact of the stricter Strauss criteria for left bundle branch block (St-LBBB) on CRT response, hospitalizations, ventricular arrhythmia (VA) events and mortality. METHODS: This study is a retrospective analysis of prospectively collected data on heart failure (HF) patients with LBBB admitted for CRT implantation. Patients were divided into two groups according to the fulfilment or not of St-LBBB criteria. RESULTS: The study included 82 patients with ischaemic (ICM) and non-ischaemic (NICM) cardiomyopathy [46 (56%) with St-LBBB and 36 (44%) with non-St-LBBB]. Patients with St-LBBB showed higher CRT response rates compared with those with non-St-LBBB (P < 0.01), while the group with NICM exhibited the greatest benefit (P < 0.01). St-LBBB CRT responders displayed significantly lower rates of HF hospitalization (P < 0.0001) compared with the non-St-LBBB group. According to Kaplan-Meier time curves, this was primarily evident in patients with NICM (P < 0.0001). CRT responders displayed significantly fewer VA events (P < 0.001) and lower mortality rates (P < 0.0001) than non-responders. Kaplan-Meier estimates demonstrated a significantly lower incidence of VAs in NICM patients with St-LBBB (P = 0.049) compared with ICM patients with St-LBBB (P = 0.25). Lower mortality rates were observed in CRT responders than non-responders (P < 0.0001), with the group of NICM with St-LBBB criteria exhibiting the greatest benefit (P = 0.0238). CONCLUSIONS: Patients with NICM and St-LBBB present the greatest benefit concerning CRT response, HF hospitalizations, VA events and mortality. Although St-LBBB criteria seem to improve patient selection for CRT, more data are needed to elucidate the role of St-LBBB criteria in this setting.

Electric storm triggered by short-coupled premature ventricular complexes in a young patient with non-obstructive hypertrophic cardiomyopathy.

Ventricular arrhythmias are commonly associated with hypertrophic cardiomyopathy with and without midventricular obstruction. Although the overall prognosis is relatively good with an annual mortality rate <1%, the propensity to potentially fatal ventricular arrhythmias (ventricular tachycardia) is the most feared complication. Electrical storms are a severe manifestation of ventricular arrhythmias, with poor outcomes. In this report, we present a case of a young patient with non-obstructive hypertrophic cardiomyopathy who presents after a syncopal episode and is found to have an electric storm that is refractory to medical therapy.

Impact on ventricular arrhythmic burden of SGLT2 inhibitors in patients with chronic heart failure evaluated with cardiac implantable electronic device monitoring.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have revolutionized the therapeutic scenario of heart failure, demonstrating favorable effects on mortality and quality of life. Previous studies have yielded conflicting data regarding the effects on ventricular arrhythmias. METHODS: A prospective observational study was conducted to investigate the anti-arrhythmic properties of SGLT2 inhibitors evaluating the intra-patient difference in major adverse arrhythmic cardiac events (MAACE) over a six-month period in patients with chronic heart failure who were undergoing continuous monitoring using a cardiac implantable electronic device. RESULTS: From January 2022 to January 2023, 82 patients [median age 63 years (IQR 15), male 87 %] were enrolled in the study, with a median follow-up of 28 weeks (IQR 5). The rate of MAACE at baseline was 11 %, without relevant differences in the follow up in terms of major and minor arrhythmic events. In patients with an arrhythmic phenotype at baseline, a mild but non statistically significant reduction of MAACE (from 36 % to 28 %, p = 0.727) was observed and a significant decrease of non-sustained ventricular tachycardia (from 68 % to 32 %, p = 0.022). CONCLUSIONS: Our findings suggest potential anti-arrhythmic properties of SGLT2 inhibitors, evident in patients with arrhythmic events before the initiation of the drug.

Cardiac channelopathies in pediatrics: a genetic update.

Cardiac channelopathies are a group of inherited syndromes that can cause malignant arrhythmias and sudden cardiac death, particularly in the pediatric population. Today, a 12-lead electrocardiogram is the most effective tool to diagnose these diseases. Incomplete penetrance and variable expressivity are hallmarks of these syndromes. Some of these malignant entities may remain hidden and only a trigger such as exercise, emotions or fever can unmask the electrical pattern to diagnose the disease. Sudden cardiac death may be the first manifestation of any of these syndromes. The use of complementary tests that allow early diagnosis is strongly recommended, among which we find: pharmacological provocations, exercise tests, and genetic analysis. Genetic testing makes it possible to unravel the origin of the disease, and also identify family members who carry the harmful genetic defect and are therefore at risk. One of the main challenges in this area is the large number of genetic variants of uncertain significance, which prevent effective translation into clinical practice. Early identification of the pediatric population at risk and adequate risk stratification are crucial to adopting personalized preventive measures that reduce the risk of lethal episodes in this population. What is Known: • In the pediatric population, malignant arrhythmias leading to sudden cardiac death are mainly caused by inherited syndromes. • A conclusive genetic diagnosis unravels the origin of the syndrome and allows cascade screening to identify relatives carrying the genetic alteration. What is New: • The use of sequencing technologies allows a broad genetic analysis, helping to unravel new genetic alterations causing inherited arrhythmogenic syndromes. • A periodic reanalysis of genetic variants that currently have an ambiguous role will help discern those that are truly pathogenic.