History Of Sudden Cardiac Death Research Articles

Evolution of the ECG in idiopathic ventricular fibrillation survivors: results from a single-centre UK registry

Abstract Background Idiopathic ventricular fibrillation (VF) is a diagnosis of exclusion in subjects with an unexplained cardiac arrest and no evidence of overt structural or electrical cardiac abnormalities (1). It can be associated with an early repolarisation pattern (ERP)(2). Data on the evolution of the ECG in this population are lacking. Purpose To compare the baseline ECG characteristic of idiopathic VF survivors and age and gender matched controls, and investigate if the presence of an ERP at ECG is a predictor of risk. Methods Forty-nine subjects with idiopathic VF evaluated in our tertiary centre from 1997 to 2022, and followed-up for at least 3 months were included in this study. The first representative ECG available after cardiac arrest was evaluated and compared with that of an age and gender matched control with no symptoms, family history of sudden cardiac death and normal cardiac tests; moreover, comparison was made with a follow-up ECG off antiarrhythmic medications (quinidine, amiodarone and verapamil). Medical notes were reviewed to investigate the presence of events at f-up (SCD/appropriate ICD shock). Results The mean age at presentation was 33±7 years; 63% of patients were males, and 16% had previous syncope. Twelve cases (24%) and 6 controls (12%) showed ERP on the resting ECG (P=NS). Only resting heart rate (HR) and QRS duration differed between the two groups (Table 1). Follow-up ECGs in 46 idiopathic VF survivors indicated that resting HR, QRS axis and QTc values were significantly different compared to the baseline ECG. In addition, 4 subjects with ERP at baseline did not exhibit it on the most recent ECG, and 6 subjects without ERP at baseline showed it on the most recent ECG. Over a median follow-up of 3.3 years (IQR 6), 13 subjects experienced appropriate ICD shocks. Kaplan-Meyer survival estimates showed no differences in events between subjects showing ERP or not (log rank p=0.092). Conclusions Subjects with idiopathic VF show baseline ECGs similar to those of age and gender matched healthy controls from the general population. ECG parameters tend to change only slightly over long-term follow up. The ERP in idiopathic VF survivors is dynamic and thus its relationship with events may be underestimated.Table 1 Table 2

Clinical findings and outcomes of Brugada syndrome in women

Abstract Introduction Brugada syndrome (BrS) is a genetic disorder characterized by typical ECG changes and association with spontaneous ventricular tachyarrhythmia (VTA) and sudden death in young patients. BrS has been widely established to be particularly prevalent in men, however less information exists regarding female patients and their long-term risk. Objectives The purpose of this study was to investigate the clinical characteristics and long-term prognosis of women with BrS. Methods This study includes a retrospective analysis of a single-center cohort of patients followed and observed for relevant clinical outcomes. The data collected included demographic data, severity of symptoms (e.g. syncope, VTA), cardioverter-defibrillator logs and occurrence of sudden cardiac death. Results 317 patients were diagnosed with BrS between 1998 and 2023. Among those, 112 (36%) were female. At presentation, 5 patients (4%) were symptomatic with history of survived cardiac arrest and/or documented VTA. 29 (26%) had history of unexplained syncope and 78 (70%) were asymptomatic. The average age at diagnosis was 42.1±15.1 yrs. as opposed to 40.1±14.2 yrs. in men. Females presented less frequently with a type 1 ECG pattern (5% vs 21%; p<0.01), had a trend to a higher rate of family history of sudden cardiac death (31% vs 25%; p=n.s.), and had less sustained VTA during programmed ventricular stimulation (4% vs 19%; p<0.01). Genetic testing was performed in 89 females (79% of the sample) and pathogenic variants were present in 36 (40%) women. An implantable cardioverter defibrillator was inserted in 24 (31%) females for primary prevention. During mean follow-up of 138±72 months, 11 women had cardiovascular events (syncope, VT/VF or death). Syncope was most common and occurred in 8 cases. No VTA were documented in any female patient. In the group of ICD patients, 8 shocks have occurred. None of these were deemed appropriate by medical controls. There were 3 deaths. Two were considered non-arrhythmic due to pulmonary embolism and breast carcinoma. One ICD patient died suddenly during sleep. Unfortunately, no device interrogation data was available. Conclusion Women typically present less symptomatic and demonstrate a reduced incidence of life-threatening arrhythmias during follow-up , often experiencing a frequent occurrence of inappropriate implantable defibrillator therapy. The less frequent prevalence of the BrS ECG pattern in women adds complexity to the diagnostic process. Further studies are still needed to elucidate gender differences for risk stratification of BrS.

BRUGADA SYNDROME: NEWEST DATA ON RISK STRATIFICATION

Abstract Background Brugada Syndrome (BrS) is a rare genetically based channelopathy responsible for malignant arrhythmias and sudden cardiac death (SCD) in young adults. Objectives The aims was to evaluate prognostic indicators useful for accurate arrhythmic risk stratification in BrS by studying genetic, clinical, anamnestic, instrumental parameters, and those derived from electrophysiological study (EPS) and intracavitary mapping. Materials and Methods 209 patients with Brugada type 1 were recruited between 01/01/2018 and 01/10/2023. Results In the first study, predictive factors related to high arrhythmic risk from the data obtained for the total population of 209 Brugada patients enrolled in our case series include a positive history of cardiogenic syncope (p value 0.000041), having had a resuscitated cardiac arrest (p value 0.00025), presenting positive EPS for inducibility of ventricular tachycardia (p value 0.00032), having a family history of sudden cardiac death (p value < 0.00001), and presenting positive cardiac mapping and MRI for pathological alterations (both with p value > 0.00001). From the data obtained for the subset of 80 Brugada patients with ICD in our case series, predictive factors related to high arrhythmic risk are different from the previously analyzed population: presenting spontaneous type 1 ECG (p value 0.0015), having had a resuscitated cardiac arrest (p value 0.014028), having a family history of sudden cardiac death (p value < 0.00001), and presenting positive mapping, genetics, and cardiac MRI for pathological alterations. Positive EPS and syncope in this subset do not appear to be risk factors, unlike the population of all 209 enrolled patients. Conclusions Multiparametric scores, including the mentioned markers, have been introduced in clinical practice for a better approach in selection. However, new markers are needed to improve risk stratification in BrS patients, especially those in the so–called "gray zone" with intermediate risk. In the future, it will be evaluated through experimental models and genotype–phenotype integration whether such electrical heterogeneity is also associated with specific genetic or structural abnormalities and may represent a new therapeutic target for etiological treatment in BrS patients. In conclusion, there is an urgent need to develop new methods for risk stratification in Brugada syndrome that are sufficiently sensitive, specific, reproducible, and easy to apply.

A WELL KNOWN CARDIOMYOPATHY BEHIND A FAMILY DRAMA: A CASE REPORT

Abstract We report a case of a 55–year–old woman who came to our regional reference center for cardiomyopathies. Her cardiovascular risk factors were systemic arterial hypertension, dyslipidemia, family history of sudden cardiac death. Her first son –20 years old– had died of sudden cardiac death during a football match, at the peak of the exertion, one year before. The autopsy had showed biventricular, diffuse fibro–fatty replacement areas diagnostic for arrhythmogenic cardiomyopathy. DNA extraction in tissue was evaluated for genetic testing. According to 2022 ESC Guidelines, familial evaluation of descendents of patients died of sudden cardiac death should include: genetic testing, gathering of medical history and performing physical examination, standard and high precordial leads ECG, echocardiography and exercise testing, CMR and ambulatory cardiac rhythm monitoring. All of these were normal, except for cardio RM which revealed: aneurysmatic bulging of the right ventricular wall, most prominent at the apex and free wall with normal contractility. Absence of both left and right ventricular dilatation. Left ventricular and right ventricular ejection fraction measured 58% and 55% respectively. According to Padua’s criteria the woman had borderline arrhythmogenic cardiomyopathy. Instead, her 18 years old little son used to practice sports and used anabolics. His cardio–RMN demonstrated: reduced function of the right ventricle with mild dilation and biventricular bulging areas. The patient met the criteria for definite Arrhythmogenic Cardiomyopathy since he had two major criteria. In the meantime of the results of genetic testing, suspension of the smoking habit and reduction of strenuous physical activity were advised. Conclusions Arrhythmogenic displasia of right ventricle is characterized histopathologically by the extensive replacement of right ventricular myocardium with fibro–fatty tissue (dysplasia triangle). Involvement of the left ventricle has been documented on a lesser frequency and has a higher mortality. Different from other conditions, in arrhythmogenic cardiomyopathy, sports practice not only conveys arrhythmic risk to that specific moment (as it happens to the little patient) but also accelerates disease progression.

DILATED CARDIOMYOPATHY, GUIDELINES PERSONALIZATION OF CARE

Abstract The term Dilated cardiomyopathy (CMD) refers to a family of diseases characterized by complex interactions between environment and genetic predisposition. Diagnostic tools as cardiac magnetic resonance imaging (MRI) must be systematically implemented in clinical practice to define the etiological cause and undertake a specific therapeutic treatment. We present the case of a young man with CMD and severe left ventricular dysfunction (ejection fraction, EF: 14%; left ventricular end–diastolic volume (LVEDV): 251 ml/m2; left ventricular end–systolic volume (LVESV): 197 ml/m2. The patient has a family history of sudden cardiac death (SCD). He is affected by a psychiatric pathology (ADHD) and has a history of alcohol and drug addiction. Many diagnostic hypotheses have been considered for etiological research (viral myocarditis, genetic or alcoholic–induced cardiomyopathy, toxic substances such as narcotics and psychiatric drug–induced cardiomyopathy). MRI after 11 days in hospital confirmed FE 14%, LVEDV: 320 ml/m2, LVESV: 275 ml/m2; reduction of the wall thickness at the antero–septal wall to the middle tract; areas of altered signal, hyperintense in T2W sequences, at the left ventricular myocardial wall suspected of myocardial edema, associated with extended signal hyperintensity of periventricular tissue, which show marked enhancement immediately after intravenous contrast agent administration (Fig. 1). The underlying psychiatric pathology and the possibility of poor adherence to the maintenance of the wearable defibrillator did not facilitate the clinical follow–up which should have included the identification of the etiological cause and the appropriate treatment guaranteeing the temporary prevention of SCD. So, it was decided to make a personalized therapeutic choice, the patient underwent implantation of a subcutaneous defibrillator, pending a better diagnostic definition and the possible need of other therapies as cardiac transplantation/implantation of mechanical assistance device.

A LONG QT SYNDROME WITHOUT MANIFESTATION

Abstract A 66–year–old Caucasian woman presented for outpatient evaluation due to elevated blood pressure levels at home (approximately 220/120 mmHg) and a significant family history of long QT syndrome. The index case in the family appeared to be her sister, investigated following an ECG showing markedly prolonged QT interval and a family history of sudden cardiac death. The patient underwent genetic analysis, revealing a positive mutation in KCNQ1. She was currently on treatment with Levotiroxina for recently discovered hypothyroidism.The ECG showed sinus rhythm with a heart rate of 85 bpm, signs of left ventricular hypertrophy, particularly Sokolow (SV1 + RV6 70 mm) and Peguero Lo Presti (SD + SV4 50 mm). The QTc interval was 515 ms (Bazett). Echocardiography revealed severe left ventricular hypertrophy (SIVd 14 mm; PWd 12 mm; LVMi 128 g/m2; RWT 0.5) with normal overall systolic function (EF 60%). No significant valvular pathologies were observed, and the right ventricle appeared normal in size and function.The hypertrophy was attributed to uncontrolled severe arterial hypertension. However, the identification of a prolonged QT interval in a patient with a strong family component (Schwartz score 4, high probability) led to genetic testing, confirming a mutation in KCNQ1. As the patient was asymptomatic with a low risk of major arrhythmias over the next 5 years (1–2–3–LQTS–risk score 2.77%), she entered follow–up and received beta–blocker therapy, specifically nadolol, combined with other antihypertensive medications.This clinical case describes an entire family with LQTS1 (type 1) positive for KCNQ1 mutation, exhibiting phenotypic manifestations distinct from those reported in the literature. Notably, there was a prevalence in females, and the condition was incidentally discovered during a routine checkup conducted for unrelated reasons, without any history of major arrhythmias.Long QT syndrome (LQTS) is characterized by a prolonged QT interval, predisposing individuals to life–threatening arrhythmias leading to syncope and sudden death. Mutations in genes encoding ion channels account for 75% of LQTS cases. LQTS1, associated with a "loss–of–function" mutation in the KCNQ1 gene, represents one of the three genetic subtypes. LQTS1 typically manifests with arrhythmias in childhood, with a male predominance. Adrenergic triggers are crucial precipitants for arrhythmic events

HYPERTROPHIC CARDIOMYOPATHY AND MYBPC3 VARIANT - A CLINICAL CASE

Abstract Introduction Hypertrophic cardiomyopathy is a primary pathology of the cardiac muscle. Sarcomeric forms of hypertrophic cardiomyopathy (HCM) often have autosomal dominant transmission. A pathogenetic or likely pathogenetic mutation affecting genes encoding sarcomeric proteins is present in 30-60% of cases. In this study, we present a case of a family affected by hypertrophic cardiomyopathy with a mutation classified as of uncertain significance in the MYBPC3 gene. Clinical Case Mr. AA, 74 years old, attended the cardiomyopathy outpatient clinic of our hospital in June 2021 due to worsening heart failure with an hypertrophic phenotype. His medical history reported an increase in the thickness of the interventricular septum (IVS) since 1985. In 2015, the patient underwent pacemaker implantation for symptomatic 2:1 atrioventricular block associated with syncope and complete left bundle branch block. Since 2016, he had paroxysmal atrial fibrillation complicated by an ischemic stroke in 2019 with subtherapeutic INR. Cardiac magnetic resonance imaging (MRI) or genetic evaluation had never been performed. During the visit, the patient reported that his sister (AG, 73 years old) had undergone tests due to diffuse negative T waves findings in a previous ECG, revealing the presence of a long myocardial bridge of the left anterior descending artery (LAD). No family history of sudden cardiac death was reported. The echocardiogram of AA showed LV hypertrophy (septal wall thickness/posterior wall thickness 18/15 mm, respectively) with an ejection fraction of 36%. Suspecting sarcomeric HCM, a genetic test (TruSight One Expanded Illumina) was performed, revealing two variants of uncertain significance in heterozygosity in the CACNA1C - Calcium Voltage-Gated Channel Subunit Alpha1 C gene (c.2460G>C p.(Lys820Asn)) and MYBPC3 gene (c.2030C>T p.(Pro677Leu)). After a few months, AG presented MRI results suggestive of HCM apical variant (Figure 1). The genetic consultant recommended family screening, and the pedigree is shown in Figure 2. All carriers of the CACNA1C mutation had a negative phenotype. AG's son, IF, 56 years old, carriers of MYBPC3 mutation, presented an MRI compatible with early-stage HCM (Figure 3). His son, carriers of MYBPC3 mutation as well, is now awaiting a cardiac MRI. Conclusions In the family presented here, the MYBPC3 variant (c.2030C>T p.(Pro677Leu)) appears to be correlated with the development of sarcomeric hypertrophic cardiomyopathy. Registry studies with a large sample size are desirable to accurately classify variants of uncertain significance, which are becoming more common due to the widespread use of genetic tests.

Sudden Cardiac Death in Young Age, What Should We Know?

While young sudden cardiac death (SCD) is statistically uncommon, its dramatic presentation and impact on families and communities make it a newsworthy issue. Nonetheless, it is important to view SCD in children and adolescents as a public health concern and devise strategies based on research and consensus to address it. Both individuals with and without a history of cardiovascular illness are susceptible to sudden cardiac death. Employing cardiovascular disease risk screening for healthy individuals and those with a family history of sudden cardiac death can serve as a preventive approach against sudden cardiac death. Assessing the severity of cardiovascular disease in people becomes essential to prevent disease progression and minimize the risk of mortality from cardiovascular conditions. Keyword: Young, Sudden Cardiac Death, Preventive.

Family history of sudden cardiac death among vctims of sudden death in yazd, iran

Objectives: A positive family history of Sudden Cardiac Death (SCD) is an independent risk factor for mortality. This study aimed to determine the prevalence of a positive family history of SCD and its associated risk factors among victims of sudden death in Yazd.
 Methods: This cross-sectional study investigated SCD cases in Yazd, Iran, in 2011. The study included victims who were aged 20 years or older, and the cause of death was the cardiac arrest within one hour of symptom onset. The data obtained from families of SCD victims through verbal autopsy interviews.
 Results: A total of 317 cases of SCD occurred among victims, resulting in an incidence rate of 139.4 per 100,000 population 26.2% had a positive family history of SCD, with a mean age of 60.4 ± 12.3 years. Individuals with a positive family history of SCD had a significantly younger mean age at the time of death (60.9 ± 12.3 vs. 66.9 ± 16.5 years, P = 0.018). The prevalence of diabetes mellitus (odds ratio 1.43, CI 95% = 1.03–1.99, P = 0.042), dyslipidemia (odds ratio 1.47, CI 95% = 1.07–2.1, P = 0.038), chronic coronary artery disease (P =0.027), and revascularization (P = 0.049) had a significant association with positive family history of SCD.
 Conclusions: This study highlights the importance of assessing family history as a risk factor for SCD, along with other risk factors such as diabetes, dyslipidemia, and chronic coronary artery disease.

A MYH7 variant in a five-generation-family with hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is a genetic condition with a prevalence of 1:500-1:3 000. Variants in genes encoding sarcomeric proteins are mainly responsible for the disease. MYH7 gene encoding a myosin heavy chain beta, together with MYPBC3 gene are the two most commonly affected genes. The clinical presentation of this disease varies widely between individuals. This study aims to report a variant of MYH7 responsible for HCM in a five-generation family with a history of cardiac problems. Methods: The diagnosis was established according to the European Society of Cardiology HCM criteria based on two-dimensional Doppler echocardiography or cardiovascular magnetic resonance. Genetic analysis was performed using next-generation-sequencing and Sanger method. Results: The medical history of the presented family began with a prenatal diagnosis of HCM in the first child of a family with previously healthy parents. Five generations of the family had a long history of sudden cardiac death and cardiac problems. A NM_000257.4:c.2342T>A (p.Leu781Gln) variant was detected in the MYH7 gene. It was heterozygous in the proband and in all affected individuals in a large family. The variant was present in 10 affected members of the family, and was absent in 7 members. The clinical course of the disease was severe in several members of the family: three family members died of sudden cardiac death, one patient required heart transplantation, three underwent septal myectomy, and three required implantable cardioverter defibrillator (ICD) implantation. Conclusion: Herein, we report a MYH7 variant responsible for HCM. Familial HCM is inherited primarily in autosomal dominant mode, which is in accordance with our study. However, the presented family showed a broad clinical spectrum of HCM. Out of 10 family members with positive genetic testing 8 had severe presentation of the disease and 2 had a mild phenotype. This suggests that the severity of the disease may depend on other factors, most likely genetic.

Clinical and genetic characterization of patients with catecholaminergic polymorphic ventricular tachycardia: a case series

AIM: of the study was to evaluate the clinical and genetic characteristics, including the development of adverse events and outcomes in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT).
 MATERIALS AND METHODS: The clinical phenotype of eight patients with CPVT, two of whom were relatives of probands, was observed over 4 years. The clinical and instrumental study included ECG-12, 24-hour Holter ECG monitoring, genealogical history collection and family history of sudden cardiac death (SCD), transthoracic echocardiography and cardiac magnetic resonance imaging to detect structural myocardial changes, electrophysiologic study according to indications, and ICD monitoring. High-throughput sequencing (NGS) was utilized to search for mutations in genes linked to the onset of channelopathies and other inherited rhythm disorders.
 RESULTS: In 8 patients, nucleotide variants of pathogenicity classes III-V were identified according to the ACMG (2015) criteria in the RYR2 gene associated with CPVT. Pathogenic (IV-V class) and likely pathogenic (IV class) mutations in the RYR2 gene were found in 6 (75%) probands, variants with uncertain clinical significance (VUS, class III) were found in 2 patients. At the time of diagnosis, transient QTc interval prolongation of more than 480 ms was detected in 4 (50%) patients; bradycardia less than 54 beats/min — in 2 (25%) patients, sequences of supraventricular tachycardia and ventricular tachyarrhythmia — in 2 (25%) patients. The most severe form of the disease with marked clinical manifestations and an episode of clinical death with subsequent resuscitation, as well as a transient QTc interval prolongation exceeding 500 ms was observed in patients with mutations c.11814C A (p.Ser3938Arg, rs794728704); c.463G A (p.Gly155Arg) and c.14876G A (p.Arg4959Gln, rs794728811) in the RYR2 gene. Three (37.5%) patients underwent ICD implantation; one for primary SCD prevention and two for secondary prevention.
 CONCLUSION: In this study, the spectrum of clinical manifestations in patients with genetically confirmed CPVT was examined. The findings highlight transient QTc interval extensions, significant sinus bradycardia, and sequences of supraventricular tachyarrhythmias, which can escalate into life-threatening ventricular tachyarrhythmias in CPVT patients.

Idiopathic Dilated Cardiomyopathy Associated with Bicavitary Thrombi: Case Report, Diagnostic Approach and Literature Review

Dilated cardiomyopathy is considered as a dysfunction of the left ventricle systolic function or even both ventricles associated with myocardial dilation. Approximately 50% of cases have an identifiable cause such as genetic mutations, infectious, autoimmune or metabolic diseases, among others. When the origin of dilated cardiomyopathy is not identified, it is considered idiopathic, which constitutes the other 50% of cardiomyopathies. The diagnostic approach is based on laboratory and image studies trying to identify the known causes of dilated cardiomyopathy, the treatment consists in those cases of known etiology cardiomyopathy in the treatment of the underlying disease as well as the heart failure if it presents, if the etiology is unknown we only focus in improve the symptoms caused by cardiomyopathy. We present a case of a 27-year-old man with history of sudden cardiac death in a second degree relative, who initially presented signs of heart failure with later pulmonary thromboembolism secondary to biventricular intracardiac thrombi. A complete diagnostic approach was performed, ruling out genetic and non-genetic causes of dilated cardiomyopathy, without being perform an endomyocardial biopsy to complete the diagnostic approach due to the risk that the procedure involved and the patient's refusal.

Brugada syndrome: variability of clinical and genetic characteristics

AIM: To evaluate the clinical characteristics of patients with diverse genetic variants of Brugada syndrome.
 MATERIALS AND METHODS: 24 patients (17 male and 7 female) aged 18 to 55 years (median age 32.5 [20; 42] years) with a pattern of Brugada syndrome on electrocardiogram were observed for 3 years. From their ECGs, a type 1 pattern was found in 9 (37.5%) of these patients, type 2 pattern in 14 (58.3%) and type 3 pattern only in 1 patient. The clinical and instrumental study included 12-lead electrocardiogram, 24-hour Holter electrocardiogram monitoring, provocative drug test with intravenous administration of sodium channel blockers (novocainamide), electrophysiologic study according to indications, genealogical history collection and family history of sudden cardiac death, transthoracic echocardiography and cardiac magnetic resonance imaging to detect structural myocardial changes. High-throughput sequencing was utilized to search for mutations in genes linked to the onset of channelopathies and other inherited rhythm disorders.
 RESULTS: In 15 (62.5%) of the 24 probands included in the study, variants of the nucleotide sequence of pathogenicity classes III–V according to The American College of Medical Genetics and Genomics criteria (2015) were found in genes encoding sodium (SCN5A, SCN10A) and potassium (KCNE3, KCNJ2, KCNJ8, KCNA5) channels, as well as in HCN4 and SNTA1 genes linked with these channels. Moreover, 3 variants were identified in ANK2 gene associated with ankyrinopathies, and 3 variants in DSP and DES genes connected with arrhythmogenic right ventricular cardiomyopathy. Four genetic variants in SCN5A gene were of pathogenicity classes IV and V, the rest were variants of uncertain clinical significance (class III). Six (40.0%) of the 15 genotype-positive patients had several genetic variants. The most severe form of the disease, manifested by the development of ventricular fibrillation with successful resuscitation and subsequent cardioverter-defibrillator implantation, was observed in patients with mutations in SCN5A, SCN10A genes. Recurrent syncope, polymorphic ventricular tachycardia induced by programmed ventricular stimulation during electrophysiologic study, followed by cardioverter-defibrillator implantation were observed in patients with variants KCNJ8 and HCN4, DES and MYH11. In 2 patients with clinical manifestations, no mutations were identified. 13 (54.2%) patients were asymptomatic, while 3 of them had pathogenic and likely pathogenic mutations in SCN5A gene, as well as variants of uncertain clinical significance.
 CONCLUSION: Thus, this study examined various genetic variants in patients with Brugada syndrome based on their clinical manifestation. The impact of the genotype on the Brugada syndrome phenotype is not unambiguous. The most severe form of the disease with the development of ventricular fibrillation and successful resuscitation with subsequent cardioverter-defibrillator implantation was observed mainly in patients with variants in several genes (SCN5A and JUP, KCNJ8 and HCN4, DES and MYH11). This substantiate the idea that Brugada syndrome, along with monogenic, may also have a polygenic nature of the disease, in which the clinical phenotype is determined by variants in respective genes linked to the onset of cardiovascular disorders.

Sudden Cardiac Death in Biventricular Arrhythmogenic Cardiomyopathy: A New Undescribed Variant of the MYH6 Gene

Arrhythmogenic cardiomyopathy (ACM) may present with sudden cardiac arrest (SCA), and demonstration of a pathogenic variant in ACM-related genes is crucial for its definitive diagnosis. A 42-year-old female patient with family history of sudden cardiac death (SCD) was referred to the cardiomyopathy clinic after two episodes of aborted SCA. In the second episode, the patient was transported under cardiopulmonary resuscitation (downtime of 57 min) until extracorporeal membrane oxygenation was implanted. A thorough diagnostic work-up led to a diagnosis of biventricular ACM. Genetic testing revealed a previously undescribed variant in ACM patients in the MYH6 gene, c.3673G>T p.(Glu 1225*), which inserts a premature stop codon. This was considered a possible pathogenic variant originating a truncated protein, previously undescribed in ACM. The patient’s 23-year-old daughter was positive for the MYH6 variant and had ECG abnormalities suggestive of ACM. This case details the complex differential diagnosis of SCA and explores the current recommendations for the diagnosis of biventricular ACM. The identification of a MYH6 variant in a patient with ACM, recurrent SCA, and family history of SCD appears to support the hypothesis of the pathogenicity of MYH6 variants in ACM, in which the association of phenotype with sarcomere variants is still unclear.

RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome.

Hypertrophic cardiomyopathy (HCM) is predominantly caused by mutations in sarcomeric genes. However, a subset of cases is attributed to genetic disorders unrelated to sarcomeric genes, such as Noonan syndrome (NS) and other RASopathies. In this study, we present a family with a history of sudden cardiac death (SCD) and focus on two adults with syndromic left ventricular hypertrophy (LVH). Clinical evaluations, including echocardiography, were conducted to assess cardiac manifestations. Whole-exome sequencing was performed to identify potential genetic variants underlying syndromic LVH in the study participants. Whole-exome sequencing revealed a missense variant in the RAF1 gene, c.782C>T (p.Pro261Leu). This variant confirmed the diagnosis of NS in the affected individuals. The findings of this study underscore the importance of family history investigation and genetic testing in diagnosing syndromic LVH. By identifying the underlying genetic cause, clinicians can better understand the etiology of RAS-HCM and its association with SCD in young adults.

Ventricular arrhythmias in patients with hypertrophic cardiomyopathy: Prevalence, distribution, predictors, and outcome

Hypertrophic cardiomyopathy (HCM) carries an increased risk of sudden cardiac death. Ventricular fibrillation (VF) is thought to be the common culprit arrhythmia. The purpose of this study was to describe the incidence and predictors of sustained ventricular arrhythmias (VTAs) in HCM patients. We retrospectively analyzed all patients with HCM and an implantable cardioverter-defibrillator (ICD) from a prospectively derived registry in 2 tertiary medical centers. Clinical, electrocardiographic, echocardiographic, ICD interrogation, and genetic data were collected and compared, first between patients with and without VTAs and then between patients with only VF and those with ventricular tachycardia (VT) with or without VF. Of the 1328 HCM patients, 207 (145 [70%] male; mean age 33 ± 16 years) were implanted with ICDs. Over a mean follow-up of 10 ± 6 years, 37 patients with ICDs (18%) developed sustained VTAs. These were associated with a family history of sudden cardiac death and a personal history of VTAs (P = .036 and P = .001, respectively). Sustained monomorphic VT was the most common arrhythmia (n = 26, 70%) and was linked to decreased left ventricular (LV) ejection fraction and increased LV end-systolic and end-diastolic diameters. Antitachycardia pacing (ATP) successfully terminated 258 (79%) of the 326 VT events. Mortality rates were comparable between patients with and without VTAs (4 [11%] vs 29 [17%]; P = .42) and between those with and without ICDs (24 [16%] vs 85 [20%]; P = .367). VT rather than VF is the most common arrhythmia in patients with HCM; it is amenable to ATP and is associated with lower LV ejection fraction and higher LV diameters. Therefore, ATP-capable devices may be considered in HCM patients with these LV features.

The Case Files

The Case Files

Family screening in inherited cardiac conditions: predicting likelihood of a diagnosis

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Cardiovascular Research Scholarship awarded by 'Research, Innovation and Development Trust (University of Malta)', kindly donated by Beating Hearts Malta. Scholarship awarded by Tertiary Education Scholarship Scheme. Introduction Family screening is an important pillar in inherited cardiac conditions (ICC), yet the likelihood of disease in screened relatives is difficult to predict. The objective of this study was to create a clinical score to help predict the likelihood of a diagnosis in relatives undergoing screening. Methodology The BEAT-IT national cardiac screening program enrolled 2708 adolescents (14-16 years). Families of probands with a preclinical or clinical diagnosis were offered cardiac screening. Those with an abnormal preliminary screen were further evaluated. Data was analyzed with SPSS v23 using chi squared. P<0.05 was considered statistically significant. Results A total of 19 families were evaluated, 81 family members (60.5% female, mean age 41.1±16.7 at evaluation) underwent cardiac screening because of a preclinical (n=17, 89.4%) or clinical (n=1 HCM, n=1 LQTS) phenotype in the index case. Some (n=8, 9.9%) were labelled with a clinical phenotype (n=5 LQTS, n=2 HCM, n=1 DCM). The highest diagnostic yield was in long QT (55.6%) and HCM (50.0%) probands. All relatives were asymptomatic. Several factors increased the likelihood of a relative being given a diagnosis at screening. The i) presence of a proband phenotype (p<0.001), ii) abnormal screening ECG (p<0.001), iii) abnormal echocardiography suggestive of an ICC (p<0.001), iv) low ejection fraction (p=0.043), v) fibrosis on MRI (p=0.035), vi) likely or definite pathogenic mutation in the proband (p<0.001) and vii) a gene positive relative (p<0.001) were all significantly predictive. Age at evaluation, gender, family history of sudden cardiac death and arrhythmias at screening were not predictive. A relative with ≥3 variables had a higher probability of a clinical diagnosis (72.7% vs 0%, p<0.001). Conclusion A combined clinical and genetic evaluation was able to identify an ICC in 9.9% of screened family members. The presence of ≥3 clinical variables at screening was linked to a higher probability of a diagnosis in relatives. A comprehensive evaluation in relatives with a suspicion of an ICC is necessary useful for diagnostic purposes.

The role of the arrhythmologist in a sports cardiology centre: the devil is in the detail

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The role of the arrhythmologist in a sports cardiology centre (SCC) is to provide comprehensive care to athletes with cardiac arrhythmias. Objective To determine the proportion of athletes with arrhythmias examined at a SCC. To define the differences in care between an athlete with and without arrhythmia. Methods Retrospective analysis of the registry of all athletes of one SCC. Identification of patients=athletes with arrhythmias, description of key differences in access to arrhythmology subunits. Cohort: Between 1/2020-6/2022, a total of 115 cases of athletes, 100 males and 15 females (13%), aged 26 (+/-11 years), were examined and definitively closed at SCC. Twenty-two athletes (19%) received care for cardiac rhythm disorders. Duration of sports activity was at the borderline of statistical significance in demographic parameters (see Table No. 1), with 15 (+/-11) vs 12 (+/-8) years for athletes with non-arrhythmic diagnoses (p=0.085). Results In the statistical comparison of the groups without and with arrhythmias (Table No. 2), we see a statistically significantly higher proportion of athletes presenting because of symptoms and with pathological findings of the pre-participation screening, with a higher proportion of family history of sudden cardiac death, with a higher proportion of coronary CT use and an extraordinary statistical significance of cardiac MRI use. Conversely, there is no statistically significant difference in diagnosis and impact on sports eligibility. The sports cardiologist must be particularly cautious in the diagnosis and treatment of ventricular extrasystoles, which have a different "diagnostic-eligibility" pathway for athletes. Similarly, they must listen to the medical history more than non-athletes and be willing and able to use various sports monitor records. In invasive methods of diagnosing and treating arrhythmias, it is necessary to understand when arrhythmias occur in real life and try to mimic the diagnostic conditions of this situation (e.g., when inducing clinical arrhythmias that an athlete has in real life during the peak moments of a match or race). Last but not least, the sports cardiologist must communicate the potential changes that may occur by ablative treatment of the arrhythmia (e.g., a decrease in maximal heart rate after AVNRT ablation on the so-called slow pathway, or, e.g. a possible increase in resting heart rate after pulmonary vein isolation with radiofrequency or laser energy). Conclusion Athletes with arrhythmias are different in many aspects, and the role of the arrhythmologist in the sports cardiology team is to be prepared to respect these differences in an effort to provide the best possible care for the athlete.

Added value of 12-lead 24-hour ambulatory ECG monitoring in the identification of a spontaneous type 1 Brugada pattern and its prognostic role. A sub-study of the BHF RASE Brugada project

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background A spontaneous type 1 Brugada (spT1-BrS) pattern is a recognised marker of arrhythmic risk. However, its fluctuations may underestimate the risk in subjects with concealed T1-BrS at presentation. Aim To investigate the yield of repeat resting and high-lead 12-lead ECG and the additional role of 12-lead 24-hour Holter monitoring with leads V1 and V2 in standard and high precordial ECG positions (12-HPL Holter), and evaluate the prognostic role of spT1-BrS in a large, single-centre, cohort of BrS patients. Methods Three-hundred and eighty-one subjects with BrS enrolled in our Registry from 2008 to December 2021 and with at least 3 months follow-up data were included in this study. Seventy-seven had spT1-BrS pattern at presentation (Group 1), and 304 did not (Group 2). All received lifestyle recommendations and had regular follow-up appointments with 12-lead ECG; the majority of them were also screened with 12-HPL Holter. Medical notes and tracings were reviewed to identify a dynamic spT1-BrS and events at f-up (SCD/appropriate ICD shock). Results The mean age at presentation was 44±15 years; 52% of participants were males. All had at least 2 resting ECGs recorded; in 281 subjects at least one 12-HPL Holter was available (total 643, median 2, range 1-8). Over a median follow-up of 66 months (IQR 75), 37 subjects in Group 2 showed a spT1-BrS at least once: 10 during a repeat resting ECG, 2 during/after exercise tolerance test, 25 at 12-HPL Holter. The average time at spT1 appearance during follow-up was 23 months (range 1- 225). Those with a newly detected spT1-BrS were more frequently males and less likely to have a familial history of sudden cardiac death (Table 1). Excluding subjects with previous aCA/documented VT, 6 events occurred at f-up, all in subjects with spT1 (Figure 1). Univariate models showed that the presence of a spT1-BrS pattern was consistently associated with increased risk of events (at presentation: HR 10, 95% C.I. 1.8-54; at follow-up: HR 5.3, 95% C.I. 1.6-17). Conclusions A spontaneous T1-BrS can be detected in up to 12% of subjects with concealed BrS at presentation using 12-HPL Holter monitoring. Its presence is consistently associated with arrhythmic risk at f-up up, regardless of the time at detection. Prolonged ambulatory ECG monitoring is fundamental for risk stratification in this population.