Family History Of Sudden Death Research Articles

UNPREDICTABLE IDENTIFICATION OF A TITIN MUTATION IN A YOUNG PATIENT PRESENTING WITH INFLAMMATORY CARDIOMYOPATHY

Abstract Case Presentation A 23 years old patient, affected by type 1 diabetes, presented with fever, dyspnea and bilateral peripheral edemas. In the last week he received antibiotic treatment for a persistent dry cough and sore throat, and became symptomatic for exertional dyspnea from three days. His mother died at the age of 40 for sudden cardiac death. Blood pressure and oxygen saturation were normal: the ECG showed sinus tachycardia with symmetric negative T waves in all precordial leads. High sensitivity troponin T was 0.01 mcg/L (normal value < 0.014 mcg/L). All remaining blood tests were normal, except for CRP that was slightly elevated. His echocardiogram revealed left ventricular (LV) remodelling and dilation, severely reduced LV ejection fraction (LVEF 20%) with global hypokinesia, more pronounced at the level of the anterior wall, interventricular septum and apex and a dilated right ventricle (RV) with reduced systolic function. Cardiac magnetic resonance (CMR) confirmed severe biventricular disfunction (LVEF 19%; RVEF 23%) and showed a small area of subepicardial inferior junctional late gadolinium enhancement (LGE). The patient underwent an endomyocardial biopsy that showed a lymphocytic virus–negative myocarditis. Given his known type 1 diabetes, steroid treatment was not considered and anakinra was started. The patient was discharged after two weeks with a slight amelioration of the LV function (LVEF 27%), on optimal heart failure therapy and anakinra. At six months he was in NYHA class II and CMR showed slight reduction in LV dimensions and improvement of the LV and RV function (LVEF 39%; RVEF 45%), with no changes in the LGE pattern. A genetic test was performed and revealed two titin gene mutations, both categorized as likely pathogenic (TTN c.[11831T>A]; c.[72510_72517delGACAAATG]), responsible for a genetic form of dilated cardiomyopathy. Conclusion The present case suggests that in young patients presenting with clinical or histological diagnosis of myocarditis, genetic testing for cardiomyopathies should be considered especially in presence of a positive family history for sudden death or an incomplete recovery of the LV function at follow–up. Identification of a gene mutation in these patients allows a more tailored risk stratification of the index case and a proper management of the entire family.

Clinical Application of Exercise Stress Echocardiography in an Outpatient Pediatric Population.

Background: Exercise stress echocardiography (ESE) is commonly employed in adults, but its applicability in pediatric populations remains to be clarified. Methods: A total of 309 consecutive children (C), with a mean age of 14.1 ± 2.6 years (range 6-17 years), underwent treadmill ESE starting in 2002. They were divided into two groups: Group I comprised 258 children, including 237 with symptoms related to exercise (such as chest pain, fatigue, lipothymia/syncope, or one aborted sudden death), 15 with electrocardiogram (ECG) abnormalities, and 6 with a positive ECG stress test showing ST changes. Group II consisted of 10 asymptomatic children whose parents requested routine screening, 11 with symptoms unrelated to exercise, 12 with a family history of sudden death, and 17 with known pathologies (including 10 with hypertrophic cardiomyopathy, 2 with aortic coarctation, and the remainder with various conditions, such as Cortriatriatum sinister, pulmonary stenosis, subaortic stenosis, bicuspid aortic valve, left ventricular hypertrophy related to arterial hypertension, and aortic switch operation). Regional wall motion abnormalities (RWMAs) and transvalvular or intraventricular (IVG) gradients were assessed using 2D and continuous-wave Doppler, respectively, in all cases. Results: The success rate was 100% (309/309). Stress-induced RWMAs were observed in two children. A significant IVG (>30 mmHg) was detected in 101 out of the 258 children (39%) in Group I, who presented with exercise-related symptoms, ECG abnormalities, or positive stress ECG. In Group I, the odds ratio (OR) of ESE reproducing the symptoms in children with IVG compared to those without IVG was 8.22 (95% CI: 4.84-13.99, p < 0.001). Conclusions: Treadmill ESE is both feasible and safe for pediatric populations. RWMAs demonstrated limited utility in our cohort of children, while IVG induced by exercise was frequently observed in symptomatic children.

Can we screen for heart disease in children at public health centres? A multicentre observational study of screening for heart disease with a risk of sudden death in children

Sudden cardiac death in children is a rare event, but of great social significance. Generally, it is related to heart disease with a risk of sudden cardiac death (SCD), which may occur with cardiovascular symptoms and/or electrocardiographic markers; thus, a primary care paediatrician (PCP) could detect them. Therefore, we proposed a study that assesses how to put into practice and conduct a cardiovascular assessment within the routine healthy-child check-ups at six and twelve years of age; that reflects cardiovascular signs and symptoms, as well as the electrocardiographic alterations that children with a risk of SCD in the selected population present; and that assesses the PCP’s skill at electrocardiogram (ECG) interpretation. In collaboration with PCPs, primary care nurses, and paediatric cardiologists, an observational, descriptive, multicentre, cross-sectional study was carried out in the Balearic Islands (Spain), from April 2021 to January 2022, inclusive. The PCPs gathered patient data through forms (medical record, electrocardiogram, and physical examination) and sent them to the investigator, together with the informed consent document and electrocardiogram. The investigator passed the electrocardiogram on to the paediatric cardiologists for reading, in an identical form to those the paediatricians had filled in. The variables were collected, and a descriptive analysis performed. Three paediatric cardiologists, twelve PCPs, and nine nurses from seven public health centres took part. They collected the data from 641 patients, but 233 patients did not participate (in 81.11% due to the PCP’s workload). Therefore, the study coverage was around 64%, representing the quotient of the total number of patients who participated, divided by the total number of patients who were eligible for the study. We detected 30 patients with electrocardiographic alterations compatible with SCD risk. Nine of these had been examined by a paediatric cardiologist at some time (functional murmur in 8/9), five had reported shortness of breath with exercise, and four had reported a family history of sudden death. The physical examination of all the patients whose ECG was compatible with a risk of SCD was normal. Upon analysing to what extent the ECG results of the PCP and the paediatric cardiologist agreed, the percentage of agreement in the final interpretation (normal/altered) was 91.9%, while Cohen’s kappa coefficient was 31.2% (CI 95%: 13.8–48.6%). The sensitivity of the ECG interpretation by the PCP to detect an ECG compatible with a risk of SCD was 29% and the positive predictive value 45%. Conclusions: This study lays the foundations for future SCD risk screening in children, performed by PCPs. However, previously, it would be important to optimise their training in reading and interpreting paediatric ECGs.What is Known:• In Spain at present, there is a programme in place to detect heart disease with a risk of sudden death [1], but it targets only children who are starting on or are doing a physical activity as a federated sport. Implementing such screening programmes has proven effective in several countries [2]. However, several studies showed that the incidence of sudden cardiac death is no higher in children competing in sport activities than in those who do not do any sport [3]. This poses an ethical conflict, because at present, children who do not do any federated sport are excluded from screening. According to the revised literature, so far, only in two studies did they screen the child population at schools, and in both, they successfully detected patients with heart disease associated to the risk of sudden death [4, 5]. We have found no studies where the screening of these features was included within the routine healthy-child check-ups by primary care paediatricians.What is New:• We did not know whether—in our setting, at present—the primary care paediatrician could perform a screening method within the routine healthy-child check-ups, in order to detect presumably healthy children at risk of sudden cardiac death, as they present one of the SCD risks. In this regard, we proposed our project: to assess how to put into practice and conduct a cardiovascular assessment via SCD risk screening in the healthy child population by primary care paediatricians and appraise primary care paediatricians’ skills in identifying the electrocardiographic alterations associated with SCD risk. The ultimate intention of this pilot study was to make it possible, in the future, to design and justify a study aimed at universalising cardiovascular screening and achieving a long-term decrease in sudden cardiac death events in children.

Characterization of the cardiac and non-cardiac phenotype associated with genetic variants in KCNJ2

Abstract Introduction Sequence variants in KCNJ2 are associated with Andersen-Tawil syndrome (ATS), a rare, multisystem disorder characterized by a triad of cardiac arrhythmia, periodic paralysis, and craniofacial-skeletal developmental anomalies. Purpose To define the cardiac and non-cardiac features of ATS associated with KCNJ2 variants. Methods Patients with KCNJ2 variants and features within the spectrum of ATS were identified from a detailed literature search between 2001 and 2020. Demographic, clinical and genetic data were collected. To avoid double counting the same proband, publications from the same authors or institutions were cross referenced and only included once unless it was evident that cases were not previously reported based on age, sex and specific KCNJ2. Minor allelic frequency was assessed in the Genome Aggregation Database (gnomAD). Results 296 patients (aged 25.5 ± 15.6 years) were identified from 66 publications. 136 (44%) were male and 162 (55%) probands. Age of symptom onset (reported in 100) was 10.7 ± 6.4 years. There were 162 probands. A family history of sudden death was reported for 23 probands. There were 69 different variants (fig 1a): missense (n=57), inframe deletion (n=5) and insertion (n=2), truncating (n=3), frameshift (n=1), copy number variant (n=1). Overall, penetrant disease was reported in 288 (96%), and only 2 (Arg312Cys, Pro415Leu) were seen in gnomAD. Variants at 2 residues (Arg67 and Arg218) were seen in 43 (26%) probands and 120 (41%) of all patients. Clinical data for all 3 major phenotypes was available for 289 individuals, with the full triad reported in 99 (34%) (fig 1b). A cardiac phenotype seen in 244 (84%), which was an isolated finding in 37 (13%). There was no difference in the phenotypic spectrum in those with variants Arg67 and Arg218 (fig 1c). An isolated cardiac phenotype was seen in 13/120 (11%) at these residues. Cardiac symptoms included palpitations (34/91; 37%), syncope (44/131; 34%). Cardiac arrest was reported in 20 (6.7%). ECG features included ventricular premature beats (VPB) (214/243; 90%), U wave (123/141; 87.2%), bidirectional (82/119; 68.9%), polymorphic (68/118; 57.6%) and monomorphic (7/35; 20.0%) ventricular tachycardia (VT). Arrhythmia-mediated cardiomyopathy was reported in 8. In 37 patients with an isolated cardiac phenotype, features included VPB (29/36; 81%), U waves (21/24; 88%), bidirectional (6/13; 43%), polymorphic (11/17; 65%) and monomorphic (2/7; 29%) VT. Cardiac arrest occurred in 5 (10%) cases. Conclusion The cardiac phenotype associated with KCNJ2 is highly varied. U-waves and VPB are prevalent features, and there is significant arrhythmic burden and morbidity. Identified KCNJ2 variants are highly penetrant and very rarely observed in the population. DIsease-associated variants are especially prevalent at the key functional residues 67 and 218. Improved recognition of this rare disorder will help further define the cardiac features and associated risk.

Abstract 15579: Stem Cell Modeling of a Candidate Genetic Variant in a Family With Complex Inherited Cardiomyopathy

Introduction: Inherited cardiomyopathies, such as arrhythmogenic right (or left) ventricular cardiomyopathy (ARVC; ALVC) and dilated cardiomyopathy (DCM), can lead to sudden cardiac death. Mechanisms of arrhythmogenesis in these cardiomyopathies are not fully understood, with ~ 20% of patients carrying a pathogenic variant in a validated cardiomyopathy-associated gene. Aims: Here, we investigate a family with highly variable expression of arrhythmogenic cardiomyopathy. The two affected siblings have differential ventricle involved and arrhythmia burden: with one fulfilling criteria for ARVC, and the other for ALVC. Their father has a non-ischemic cardiomyopathy with ventricular arrhythmias and a family history of sudden death. The maternal side is unaffected. The sibling with ALVC harbors a paternally inherited rare missense variant of uncertain significance (VUS) in plakoglobin ( JUP) (c.356C&gt;T; p.Pro119Leu), an ARVC-associated gene that does not segregate in the sibling with ARVC. Hypothesis: Study of patient-specific inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CM) can define an elusive genetic etiology as well molecular pathways associated with cardiomyopathy in the affected family members. Methods: We reprogrammed iPSC lines from 3 affected family members and 2 unaffected maternal controls and differentiated them into cardiomyocytes. Results: Differentiation to iPSC-CMs resulted in transcriptionally upregulated markers of cardiac stress and contractile function in affected family members ( NPPA, NPPB, MYH7 ). iPSC-CM harboring JUP c.356C&gt;T did not differ in plakoglobin RNA or protein expression. Hypertrophy was observed in the iPSC-CMs from affected family members after isoproterenol stimulation. Whole exome sequencing results revealed rare candidate variants (MAF&lt;5x10 -5 , REVEL&gt;0.7) that segregated in affected family members. Conclusions: iPSC-CMs from affected family members recapitulate cardiomyopathy phenotypes. Affected family members harbor novel candidate variants not previously associated with cardiomyopathies. Future work will utilize base editing to evaluate for compound contributions of several novel VUS on cardiomyopathy phenotypes in iPSC-CM from family members.

Clinical trial report: the electrocardiographic response to ajmaline provocation in healthy subjects

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation The Robert Lancaster Memorial Fund sponsored by McColl’s Research Group Background The electrocardiographic (ECG) response to diagnostic ajmaline provocation (AP) testing has been studied extensively in clinical cohorts. However, the healthy ECG response has not been described. We undertook a trial examining ECG changes in response to AP in a cohort of systematically recruited asymptomatic Caucasian healthy subjects with no family history of sudden death and normal baseline ECG and echocardiogram. Methods Applicants responded to a national recruitment advertisement and completed an online medical questionnaire. Those fulfilling inclusion criteria were invited to undergo further evaluation with eligible subjects undergoing a diagnostic ajmaline challenge (1mg/kg, max. 100mg over 5 minutes). A continuous ECG was recorded in the standard and high right precordial lead (HRPL) position. Automated analysis of conventional and novel ECG measurements were made at baseline and at peak drug effect, which was defined as the point of maximum QRS duration (excluding precordial leads). Results One hundred healthy Caucasian subjects underwent AP. The mean age was 26.84 years (SD ± 8.01 years) and 52% were male. A drug induced type 1 Brugada pattern (DI-T1BP) was observed in 3/100 (3%) of the cohort. We performed a paired comparison of ECG measures at baseline versus peak drug effect (Table 1). AP had a similar effect on global QRS duration and global PR interval, with both increasing by 28%, mean ∆ 25.66ms and mean ∆ 43.36ms respectively. Changes in S wave parameters in lead II were pronounced, with a 97% increase in S wave duration and a 101% increase in S wave negative amplitude. ST-J point elevation in the anterior, inferior, and lateral regions was comparable, with a 57%, 51% and 57% increase in ST-J amplitude respectively. AP had a greater effect on cardiac conduction in females compared to males (Table 2). In contrast, changes in STJ point amplitude and combined and segmented QRST segment area were greater in males. Conclusion The healthy ECG response to AP elicits a pronounced effect on cardiac conduction, more so in females compared to males, whilst changes in STJ point amplitude and QRST area were greater in male subjects. The DI-T1BP is part of the healthy response to AP.

New insights into the correlation between genotype and cardiac phenotype in laminopathies

Abstract Funding Acknowledgements Type of funding sources: None. Background Genotype-phenotype correlation and risk stratification for heart failure progression in patients with cardiolaminopathies are poorly defined. Purpose The primary aim of the present study is to characterize and correlate phenotype with genotype and sex. The secondary aim is to test the two main existing prognostic scores (the Arbustini and the Whabi score), both developed to predict ventricular arrhythmic events in cardiolaminopathies, for both major ventricular arrhythmias (MVA) and end-stage heart failure (ESHF). Methods This is a retrospective, single-center study, including patients with lamin (LMNA) and/or emerin (EMD) genetic variants. Data were collected from the first medical contact (FMC) to the last follow-up (FU). Results 28 patients (57% male, 82% probands, 68% with a family history of sudden death) were included: 96% harbored LMNA heterozygous variants, 15% had non-missense variants, 11% had variant previously never described. Functionally, 50% were variant of undetermined significance (VUS, C3), the rest were either pathogenetic or likely pathogenic (C4/C5) variants. Median age at FMC was 41 years (IQR 30-55 years), median FU was 11 years (IQR 8-18 years). At FMC, all patients had cardiac involvement, 54% had muscle involvement. By the last FU, 54% developed atrial fibrillation, 43% atrioventricular block (AVB) &amp;gt; I degree, 50% carried an implantable cardioverter defibrillator (21% with resynchronization), 50% had suffered at least one episode of MVA, 25% developed ESHF: 11% died due to refractory HF, 14% underwent heart transplantation (mean age 43.5 ± 9 years). The age of onset of the different types of cardiac phenotype was not influenced by sex. The penetrance of atrioventricular (AV) conduction defects (Figure 1 Panel A) and of atrial tachyarrhythmias (Figure 1 Panel B) was higher and earlier in subjects with non-missense variants. Subjects with VUS, compared to those with pathogenetic/likely pathogenetic variants, showed a significantly lower and later penetrance of MVA (Figure 2 Panel A) and a later penetrance of non- sustained ventricular tachycardia (NSVT, Figure 2, Panel B), but not of AV conduction disturbances, atrial arrhythmias, or contractile dysfunction. Arbustini score at FMC proved to be a predictor of both MVA and ESHF, while Whabi score only predicted MVA. Conclusions In our series, the prevalence and the age of appearance of the different cardiac phenotypes of cardiolaminopathies were not influenced by sex, while the presence of VUS correlated with a lower risk of ventricular arrhythmias, but not of the other cardiac manifestations including contractile disfunction and heart failure. Our data suggest the importance of a close cardiac monitoring and of larger prospective studies even in patients with VUS. All patients developed a sever cardiac phenotype by the age of 60.

P88 CARDIAC INVOLVEMENT IN FOUR NOVEL NESPRIN–1 GENETIC VARIANTS

Abstract Background Nesprins are proteins encoded by synaptic nuclear envelope (SYNE)–1 and –2 genes, that concur, together with lamin A/C and emerin, to nuclear envelope function. Almost 140 disease–related variants were identified, mostly resulting in central nervous system and skeletal muscle disorders; only a few were associated with cardiomyopathy, mostly with relatively late onset and no specific arrhythmic profile. Purpose To describe cardiac involvement in 4 novel SYNE1 variants. Methods 189 patients underwent genetic analysis in our center (2019–2022) for suspected genetic cardiomyopathy (TruSight Cardio panel, Illumina); 72% had a positive genetic report, including pathogenic/likely pathogenic or variants of undetermined significance (VUS). Among them, 4 (2%) males presented with a sole SYNE1 heterozygous VUS (figure). Results None had muscle or neurological involvement. Patients 1 and 2 had negative family history (FH) and underwent pacemaker implantation under 50 years old for high–grade atrioventricular block (AVB). Transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) showed a mildly impaired left ventricular ejection fraction (LVEF) without oedema or fibrosis. During 3 and 6 years of follow–up (FU), several non–sustained episodes of fast ventricular tachycardia (VT) and of atrial tachycardia occurred. Patient 3 is a 55–year–old man with negative FH and a left bundle branch block (LBBB) known since the age of 45.In 2021, while playing football, he suffered a cardiac arrest due to ventricular fibrillation treated with two DC shocks; ECG showed first–degree AVB and LBBB; TTE and CMR revealed a mildly impaired LVEF without oedema or fibrosis. A subcutaneous ICD was implanted, which recorded 3 atrial fibrillation episodes in a 1–year FU. Patient 4 is a 49–year–old man, with FH of sudden death (mother’s brothers at 40 and 50 years) and of polycystic kidney, who underwent renal transplant. He had left anterior fascicular block and suffered 2 episodes of sustained monomorphic VT from the right ventricle treated with ablation. TTE and CMR showed mild LV concentric hypertrophy with normal LVEF, segmental abnormalities in right and LV strain, no fibrosis. Conclusions SYNE1 genetic variants were found to be associated with a complex cardiac phenotype, including early onset conduction disease, atrial and ventricular arrhythmias, and cardiomyopathy. Further studies are needed to determine the functional significance of the variants.

PO-03-200 THE RESPONSE TO AJMALINE PROVOCATION IN HEALTHY SUBJECTS

The electrocardiographic (ECG) response to diagnostic ajmaline provocation (AP) testing has been studied extensively in clinical cohorts. However, the healthy ECG response has not been described. We undertook a trial examining ECG changes in response to AP in a cohort of systematically recruited asymptomatic Caucasian healthy subjects with no family history of sudden death and normal baseline ECG and echocardiogram. Applicants responded to a national recruitment advertisement and completed an online medical questionnaire. Those fulfilling inclusion criteria were invited to undergo further evaluation with eligible subjects undergoing a diagnostic ajmaline challenge (1mg/kg, max. 100mg over 5 minutes). A continuous ECG was recorded in the standard and high right precordial lead (HRPL) position. Automated analysis of conventional and novel ECG measurements were made at baseline and at peak drug effect, which was defined as the point of maximum QRS duration (excluding precordial leads). One hundred healthy Caucasian subjects underwent AP. The mean age was 26.84 years (SD ± 8.01 years) and 52% were male. A drug induced type 1 Brugada pattern (DI-T1BP) was observed in 3/100 (3%) of the cohort. We performed a paired comparison of ECG measures at baseline versus peak drug effect (Table 1). AP had a similar effect on global QRS duration and global PR interval, with both increasing by 28%, mean delta 25.66ms and mean delta 43.36ms respectively. Changes in S wave parameters in lead II were pronounced, with a 97% increase in S wave duration and a 101% increase in S wave negative amplitude. ST-J point elevation in the anterior, inferior, and lateral regions was comparable, with a 57%, 51% and 57% increase in ST-J amplitude respectively. AP had a greater effect on cardiac conduction in females compared to males (Figure 1). In contrast, changes in STJ point amplitude and combined and segmented QRST segment area were greater in males. The healthy ECG response to AP elicits a pronounced effect on cardiac conduction, more so in females compared to males, whilst changes in STJ point amplitude and QRST area were greater in male subjects. A DI-T1BP is part of the healthy response to AP.Tabled 1Table 1. Paired analysis of baseline and peak ajmaline effect ECG characteristicsECG CharacteristicsMean at baseline (SD)Mean at Peak Ajmaline Effect (SD)Mean Delta = peak - baseline (SD)% ChangeP value*Global QRS duration ms90.42 (10.59)116.06 (12.06)25.66 (11.98)28.38<0.01Global T wave duration ms210.48 (24.96)225.48 (25.53)15.00 (20.53)7.13<0.01Global PR interval ms153.14 (19.45)196.50 (25.10)43.36 (17.27)28.31<0.01Global QT interval ms408.66 (33.03)414.38 (23.70)5.72 (18.62)1.40<0.01Global RR interval ms958.39 (197.57)813.98 (130.64)-144.41 (154.18)-15.06<0.01Global P wave duration ms102.74 (10.82)121.78 (13.58)19.04 (15.38)18.53<0.01Precordial Tpeak to Tend interval ms75.39 (27.28)81.88 (29.30)6.49 (39.29)8.610.07Precordial QRS duration ms85.59 (8.89)107.69 (11.10)22.10 (8.34)25.82<0.01Precordial T wave duration ms174.48 (24.53)199.81 (26.12)25.33 (26.33)15.00<0.01Anterior STJ amplitude uV47.97 (31.20)75.55 (48.44)27.58 (27.70)57.49<0.01Inferior STJ amplitude uV24.06 (21.97)36.46 (36.96)12.40 (26.33)51.54<0.01Lateral STJ amplitude uV34.45 (21.15)54.33 (30.79)19.89 (18.84)57.74<0.01Precordial QRS area mv/ms-409.59 (242.18)-613.71 (367.56)-204.12 (183.69)48.78<0.01Precordial QRST area mv/ms1481.06 (508.03)1838.87 (681.75)357.82 (278.89)24.32<0.01Precordial T wave area mv/ms483.66 (394.14)606.11 (453.04)122.45 (225.60)25.00<0.01Precordial STJ to Tpeak area mv/ms505.59 (230.36)543.71 (228.57)38.12 (103.28)8.00<0.01Precordial Tpeak to Tend area mv/ms258.31 (110.68)311.07 (147.60)52.76 (74.02)19.23<0.01S wave duration in lead I ms21.53 (15.55)36.01 (19.35)14.48 (14.07)67.25<0.01S wave duration in lead II ms17.34 (14.50)34.24 (20.33)16.90 (14.13)97.46<0.01S wave amplitude in lead I uV-189.09 (172.35)-290.47 (234.30)-110.38 (120.50)61.29<0.01S wave amplitude lead II uV-147.23 (197.92)-298.25 (255.25)-150.02 (155.93)101.89<0.01Inferior J wave amplitude uV43.31 (92.62)25.69 (57.06)-17.62 (68.55)-40.680.01Lateral J wave amplitude uV19.65 (41.36)10.18 (30.62)-9.47 (42.11)-48.190.03Anterior J wave amplitude uV0.77 (4.41)2.31 (7.42)1.55 (6.42)201.290.02 Open table in a new tab

Procainamide-Provoked Brugada Pattern in a Patient Presenting with New-Onset Atrial Fibrillation or Flutter: When Does it Matter?

BackgroundBrugada syndrome (BrS) is an inherited disease that can lead to sudden cardiac death. Medications, such as antidysrhythmics, and fevers can unmask or induce the Brugada pattern on an electrocardiogram (ECG). This case report highlights a patient who developed drug-induced Brugada type I pattern after a procainamide infusion for the treatment of new-onset atrial fibrillation (AF) or flutter and discusses the implications for this incidental but potentially lethal finding. Case ReportWe report a case of a young man who presented to the emergency department (ED) with new-onset AF with rapid ventricular response that began within 12 h of presentation. ED treatments included a crystalloid IV fluid bolus, diltiazem pushes, synchronized electrical cardioversion, and a procainamide infusion. After the procainamide infusion, the patient developed ECG findings consistent with Brugada pattern. Both the AF and Brugada pattern resolved spontaneously within 24 h. The patient was discharged without implantable cardioverter defibrillator placement due to presumed isolated procainamide-induced Brugada pattern and lack of concerning features, such as inducible dysrhythmia during electrophysiology study, family history of sudden death, and history of syncope. The patient was counseled to follow-up with genetics and avoid BrS-inducing medications. Why Should an Emergency Physicians Be Aware of This?Procainamide, an option for the treatment of AF in the ED, can provoke Brugada pattern. If encountered, it is important to recall that some patients may not be diagnosed with BrS if determined to be low risk according to the Shanghai criteria. All patients should be referred to cardiology for further evaluation.

A multicenter, retrospective study of cardiac disease in Borzoi dogs.

Borzoi are large, relatively uncommon sighthounds anecdotally reported to suffer from sudden death. This multicenter retrospective cohort study aimed to describe the sample of Borzoi presenting to veterinary cardiologists for evaluation, with records searched from 14 centers across a study period of up to 20 years. The study sample was comprised of 152 client-owned Borzoi, with dogs most commonly presenting for pre-breed screening in 87/152 (52%), followed by evaluation of an arrhythmia in 28/152 (18%). Of the 131/152 (86%) dogs that had an echocardiogram performed, 85/131 (65%) were structurally normal, with 40/85 (47%) structurally normal dogs having trace or mild atrioventricular valve regurgitation. Tricuspid valve dysplasia was the most commonly diagnosed congenital cardiac disease (n = 6). Myxomatous mitral valve disease (n = 12) and dilated cardiomyopathy (n = 13) were diagnosed at similar frequencies, though 92% of valve disease cases were mild. Only 48/152 (32%) Borzoi had a diagnostic electrocardiogram (ECG) and/or a Holter monitor for arrhythmia screening. Despite this, ventricular arrhythmias were identified during the entirety of the available cardiac evaluation including diagnostic ECG, contemporaneous ECG monitoring during the echocardiogram, and/or Holter monitor in 25/131 (19%) dogs in which an echocardiographic diagnosis was available. Of these 25 Borzoi, 76% had minimal or no structural cardiac disease identified, and five had a family history of sudden death. A sudden death outcome was reported in 3/55 (5%) Borzoi with long-term outcome data available. In conclusion, Borzoi commonly have trace or mild atrioventricular valve insufficiencies, and may develop ventricular arrhythmias and dilated cardiomyopathy.

Factors associated with unexplained sudden deaths among adults aged 18-45 years in India - A multicentric matched case-control study.

In view of anecdotal reports of sudden unexplained deaths in India's apparently healthy young adults, linking to coronavirus disease 2019 (COVID-19) infection or vaccination, we determined the factors associated with such deaths in individuals aged 18-45 years through a multicentric matched case-control study. This study was conducted through participation of 47 tertiary care hospitals across India. Cases were apparently healthy individuals aged 18-45 years without any known co-morbidity, who suddenly (<24 h of hospitalization or seen apparently healthy 24 h before death) died of unexplained causes during 1 st October 2021-31 st March 2023. Four controls were included per case matched for age, gender and neighborhood. We interviewed/perused records to collect data on COVID-19 vaccination/infection and post-COVID-19 conditions, family history of sudden death, smoking, recreational drug use, alcohol frequency and binge drinking and vigorous-intensity physical activity two days before death/interviews. We developed regression models considering COVID-19 vaccination ≤42 days before outcome, any vaccine received anytime and vaccine doses to compute an adjusted matched odds ratio (aOR) with 95 per cent confidence interval (CI). Seven hundred twenty nine cases and 2916 controls were included in the analysis. Receipt of at least one dose of COVID-19 vaccine lowered the odds [aOR (95% CI)] for unexplained sudden death [0.58 (0.37, 0.92)], whereas past COVID-19 hospitalization [3.8 (1.36, 10.61)], family history of sudden death [2.53 (1.52, 4.21)], binge drinking 48 h before death/interview [5.29 (2.57, 10.89)], use of recreational drug/substance [2.92 (1.1, 7.71)] and performing vigorous-intensity physical activity 48 h before death/interview [3.7 (1.36, 10.05)] were positively associated. Two doses lowered the odds of unexplained sudden death [0.51 (0.28, 0.91)], whereas single dose did not. COVID-19 vaccination did not increase the risk of unexplained sudden death among young adults in India. Past COVID-19 hospitalization, family history of sudden death and certain lifestyle behaviors increased the likelihood of unexplained sudden death.

Síndrome de Marfan: importância da história familiar - relato de caso

We describe a case of Marfan syndrome, referred for evaluation due to an important family history of sudden death. In the first evaluation, he presented dilation of the aortic root in addition to other clinical manifestations of the disease. Our objective is to emphasize the importance of family history as a starting point in Marfan syndrome investigation, in an effort to prevent unfavorable outcomes like aortic dissection and sudden death.

240 A PEDIATRIC CASE OF BIVENTRICULAR END-STAGE ARRHYTHMOGENIC CARDIOMYOPATHY

Abstract Background Arrhythmogenic cardiomyopathy (ACM) is a rare heart muscle disease characterized by cardiomyocyte necrosis and fibro-adipose substitution which contribute both to the genesis of malignant ventricular arrhythmias and the morpho-functional alterations of the ventricles. ACM has always been considered a right ventricular disease with secondary involvement of the left ventricle, but recently a left dominant phenotype has been also described. Case report A 14-year-old patient was admitted to our hospital after out-of-hospital cardiac arrest due to ventricular fibrillation, which occurred when she was at rest. A family history of sudden death and dilated cardiomyopathy was retrieved (her brother died at the age of 18 with a dilated heart), but other family members had never been screened to date. Cardiac magnetic resonance imaging (cMRI) appearance was consistent with biventricular dilatation along with severe systolic dysfunction (left ventricular ejection fraction 20%; right ventricular ejection fraction 25%). It showed also thinning and bulging of the basal free wall of the right ventricle proximal to the outflow tract (up to 4 mm) and multiple foci of subepicardial, mid-wall and transmural late gadolinium enhancement (LGE) in both ventricles. Signs of acute decompensated heart failure and a high arrhythmic burden were present. After cardiopulmonary stabilization, she underwent the implantation of a cardioverter-defibrillator (ICD). Conclusion We herein report an uncommon case of biventricular AC (‘definite diagnosis’ according to both Task force criteria 2010 and Padua criteria) with advanced morpho-functional dysfunction occurring already in pediatric age, without any alerting symptom until the cardiac arrest (the typical onset of the ACM in children). It shows how severe biventricular involvement may affect young patients with a rapid progression of the disease. It also stresses the need for a strict follow-up of the family members of a proband since his first diagnosis, highlighting the pivotal role of cMRI in the diagnosis of pediatric disease. This has not been thoroughly studied and lacks sensitive and specific diagnostic criteria.

641 A CONTROVERSIAL CASE OF FABRY DISEASE: ADDING ANOTHER PIECE TO THE INTERPRETATION PUZZLE OF C.376A&amp;gt;G MISSENSE MUTATION, A PATHOGENIC VARIANT

Abstract Background The association between chronic neuropathic pain in childhood, left ventricular hypertrophy(LVH), early ischemic stroke and unexplained renal failure is suggestive of FD. However, because of the heterogeneity of the genetic substrate, different and more subtle phenotypic manifestations are possible as well as single organ involvement. Diagnostic criteria require an initial measurement of both alpha-galactosidase A (α-Gal-A) activity levels in leukocytes and globotriaosylsphingosine (LysoGb3, a glycosphingolipid derivative) concentration. Genetic testing is needed to confirm the diagnosis if α-Gal-A is decreased or absent and Lyso-Gb3 is increased. Case report A 35-year-old man was referred to our outpatient cardiology clinic at the beginning of summer 2022. He had a family history of sudden death, he had no cardiovascular risk factors and a history of severe acral pain during childhood. On medical background, he had undergone renal transplantation after two years of hemodialysis therapy due to nephroangiosclerosis and tubulointerstitial nephritis, identified in renal biopsy. On physical examination were visible neither angiokeratomas nor ocular manifestations. ECG showed LV hypertrophy and a transthoracic ECO confirmed LV concentric hypertrophy, a preserved LV ejection fraction and the presence of unexplained subtle LV systolic dysfunction due to an abnormal LV global longitudinal strain. Laboratory tests revealed normal serum creatinine and elevated NT-ProBNP levels. Unfortunately, a CMR examination was not performed because of the patient's claustrophobia. Genetic and enzymatic analyses were performed on the high suspicion of a cardiac storage disorder. The enzymatic activity of α-Gal-A and lyso-Gb3 concentration was within normal values, whereas genetic analysis detected a missense mutation (c.376A&amp;gt;G) in exon 3 causing an amino acid substitution (p.S126G). The suspicion of FD was confirmed. Discussion This is an interesting case with a diagnosis of FD that is controversial for several reasons. The c.376A&amp;gt;G is a rare mutation, found mainly in female patients with normal α-Gal-A and LysoGb3 levels ​​and associated with isolated renal failure. In addition, this variant is typically responsible for the late onset of the disease, occurring after 40 years of age2,8–11. Our patient is young and presents early cardiac and severe nephrological involvement, both typical clinical features of FD. A normal activity of α-Gal-A is consistent with the missense gene mutation: enzyme activity appears to be normal up to at least 90-95% reduction of function. To date, there is little evidence in the scientific literature of similar cases and the clinical presentations associated with this mutation are contradictory. Since 2002, c.376A&amp;gt;G has been known to be a pathogenetic variant of FD12, in 2010 it was associated to late-onset disease13. However, in the International Fabry Disease Genotype-Phenotype Database, it is considered a likely benign variant of FD2. Conclusion In this case report, we emphasize that high clinical suspicion should lead to more diagnostic evaluations, including genetic testing in the daily routine. Additional studies are needed to better understand the role of the c.376 A&amp;gt;G mutation in the FD.

Multiple Xanthoma Tuberosum

A 43-year-old unmarried healthy woman presented at the dermatology clinic with xanthelasma (Panel A) and asymptomatic multiple rounded, grouped, and yellow to orange colored nodules, located on the hands and feet for 16 years (Panels B and C). The lesions were 15 mm in size; and were indurated, coalesced, and gradually grown. The patient had no history of diabetes mellitus, hypertension, heart problems, or any history of thyroid disease. On the other hand, she had a family history of sudden death when her brother died at the age of 28 years after a cardiac attack. The vital signs were normal. Full blood counts were normal. Fasting blood glucose was 98 mg/dl (reference range 70 to 99 mg/dl), triglycerides 174 mg/dl (reference range < 150 mg/dl), serum total cholesterol 216 mg/dl (reference range < 200 mg/dl), low density lipoprotein 259 mg/dl (reference range < 116 mg/dl), and high density lipoprotein 29.5 mg/dl (reference range > 55 mg/dl for females). Serum uric acid, liver enzymes, and thyroid function tests were within normal limits. The patient had no evidence of ischemic heart disease or pancreatitis. Treatment started with Rosuvastatin at 40 mg/day. The diagnosis is multiple xanthoma tuberosum (MXT). It is characterized by deposition of lipid at the subcutaneous tissue, particularly on the elbows, knees, face, knuckles, and toe joints. Equal prevalence is reported in males and females. The biopsy is not performed owing to the missing of the patient. This case shed light on MXT associated with abnormal serum lipoprotein levels and a family history of sudden cardiac death. The affected subjects with MXT need long-life follow-up to catch its serious cardiovascular complications as early as possible and treated them promptly.

Association between obesity and hypertrophic cardiomyopathy phenotype, validation in a latin american cohort

Abstract Objectives Hypertrophic Cardiomyopathy (HCM) is the most common genetic cardiomyopathy. The influence of obesity on the disease phenotype is not well established. A recent publication sought to answer this gap. Our objective is to assess the relationship of a obesity on the phenotype of our cohort and compare it to the published literature. Methods We performed a retrospective observational study of consecutive patients diagnosed with HCM at a single center in Argentina. We included 1331 patients between March 1993 and December 2021. We excluded patients &amp;lt;18 years of age, metabolic diseases &amp; syndromes and patients who were lost on follow up. We defined Obesity as a body mass index ≥30 kg/m2. Results 1168 patients had available data for analysis. 54 (10.4%) patients were obese. Mean age was 54±28 years and 33 (61%) were male. Average maximal left ventricular wall thickness (LVWT) in this group was 20 mm ± 5 mm. When comparing obese vs non-obese patients we found no statistically significant differences for gender, age, family history of HCM, family history of sudden death (SD), previous VF/VT/NSVT, ESC low, intermediate or high risk for SD groups, fibrosis, apical aneurism, LV diameter, maximum LVWT, high risk genetic mutation, abnormal BP response to exercise, device implant, septal alcohol ablation, reduced EF on follow up, nor death/HF/Stroke/AICD appropriate therapy/AF development. We did find that obese patients had less unexplained syncope (6% vs 13%, OR 0.43, p=0.03), had more frequently an NYHA &amp;gt; III/IV (15.3% vs 8.9%, OR 1.8, p=0,03), a trend to having less frequently a LVWT &amp;gt;30 mm (3.5% vs 8.1%, OR 0.41, p=0.07) but more frequently had systolic anterior motion of the mitral valve on echocardiography (45% vs 34%, OR 1.58, p=0.04). We noted a trend to being more frequently indicated LV myectomy (9.2% vs 5%, OR 1.9, p=0,07) and significantly having elevated ultrasensitive troponin I (7.8% vs 3.7%, OR 2.2, p=0,04). Conclusions We found that obese patients from our cohort, as described in other series, had more advanced symptoms. In our set of obese patients they were more frequently sent to myectomy rather than alcohol septal ablation as described in other series. AF was not more prevalent among our obese patients and maximum wall thickness and fibrosis were not higher either. We did find that obese patients had more frequently elevated biomarkers. As HCM is so frequent it is important to characterize cohorts and compare data. Funding Acknowledgement Type of funding sources: None.

Clinical risk factors associated with ventricular fibrillation during first ST-elevation myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union’s Horizon 2020 research and innovation programme under acronym ESCAPE-NET, registered under grant agreement No 733381 Introduction Sudden cardiac death (SCD) remains a major public health issue. Most cases in the general population are caused by ischemic heart disease, and often occur in patients without known ischemic heart disease. The assessment of risk factors may point to novel causal pathways or new targets for intervention and risk prediction of SCD. Objective The aim of this study was to evaluate the effect of family history of sudden death, prior history of atrial fibrillation (AF), and anterior infarct location on ECG on the development of ventricular fibrillation (VF) during first ST-elevation myocardial infarction (STEMI). Methods We performed individual participant data meta-analyses of three European case-control studies including first STEMI patients (aged 18-80 years) with VF (cases) and without VF (controls) before revascularization (GEVAMI, AGNES, and PREDESTINATION). Analyses were done using fixed-effect, inverse variance weighted meta-analysis and multivariable logistic regression. Potential confounding variables were identified using causal diagrams and missing data were handled with multiple imputation for each cohort separately. Results We included 1664 cases and 2497 controls (median age (IQR) = 59 (51-67) years, 20% females) in the analyses. After adjusting for potential confounding, we found an independent and additive association between the three exposures and VF (see picture): for family history of sudden death odds ratio (OR) 1.59 (95% confidence interval: 1.37-1.85), for AF OR 2.41 (1.49-3.89), and for anterior myocardial infarction OR 1.50 (1.32-1.71). Further investigation indicated increased effect of family history with multiple sudden deaths in the family, a stronger effect of AF on VF developing within the first minutes of symptoms, and the effect of anterior infarctions being modified by enzymatically determined infarct size. The three risk factors showed an additive effect: with one factor present OR 1.59 (1.38-1.84), two factors OR 2.41 (1.95-2.99), and all three factors OR 5.49 (1.43-21.1). Complete case analysis gave similar results for all analyses. Conclusions Family history of sudden death, history of AF, and anterior infarct location with significant interaction with enzymatic infarct size were all independently and additively associated with an increased risk of VF in patients with a first STEMI.

P28 AN OMINOUS FINDING OF BRUGADA PATTERN: FROM PAROXYSMAL ATRIAL FIBRILLATION TO SEVERE TRICUSPID VALVE REGURGITATION

Abstract 49 years old male, without family history of sudden cardiac death, subjected in 2010 to effective electrical cardioversion for a first episode of paroxysmal atrial fibrillation. In 2013, a new episode of atrial fibrillation subjected to effective pharmacological cardioversion with flecainide and contextual finding of intermittent Brugada type I pattern, confirmed by ajmaline provocation test. Considering the asymptomaticity of the patient and the negative family history of sudden cardiac death, no indication was given to defibrillator implantation. In 2015 the patient performed an Electrophysiological Study, positive for induction of ventricular fibrillation, in the light of which an ICD was implanted. In the following years regular checks of the device were performed, in absence of activations. In 2021, at the annual checkup, rupture of the leads was documented, resulting in a complete extraction and reimplantation of the device. A few days later the patient was admitted to the Emergency Room for chest pain and worsening dyspnea, signs of initial right heart failure and increased inflammatory markers. In consideration of the anamnestic history, the presence of infective endocarditis was suspected, for which the patient was admitted to the Cardiology ward. The echocardiogram showed severe tricuspid valve regurgitation due to complete flail of the septal flap and rupture of first order tendon cord, probably iatrogenic and consequent to the extraction of the leads. FDG–PET was performed, which ruled out the presence of infective endocarditis, and surgical correction of the valvulopathy and definitive ICD explant was indicated. The surgery consisted of plastic repair of the tricuspid valve, implantation of definitive epicardial bipolar electrodes, isolation of the pulmonary veins for atrial fibrillation ablation and removal of the ICD. Brugada syndrome, starting from the 2013 consensus, can be diagnosed in patients who only feature the type 1 pattern, spontaneous or pharmacologically induced, even in the absence of malignant arrhythmias or family history of sudden death. This leads as a consequence to an increase in the number of patients undergoing invasive procedures and interventions even with low arrhythmic risk, being instead susceptible to the complications that such procedures can fatally provoke.

P406 UNMASKING A PATTERN OF BRUGADA: FLECAINIDE VS AJMALINA

Abstract Brugada syndrome mainly affects men in the third and fourth decade of life. It presents with a typical electrocardiographic pattern, unmasked by sodium channel blocking drugs or hyperpyrexia. A 36–year–old young man, with no reported cardiovascular risk factors or family history of sudden death, had convulsions and loss of consciousness during hyperpyrexia, for which family members alerted the local emergency service. During transport to the hospital, the vital parameters and heart rhythm were normal, but, due to the onset of seizures, the patient was sedated, intubated and hospitalized in intensive care unit (ICU). The ECG performed at the entrance (in the course of hyperpyrexia) showed a dubious type 1 Brugada pattern (Figure 1). The echocardiogram (as well as the subsequent cardiac resonance) showed the absence of cardiac structural alterations. Prompt treatment of hyperpyrexia was recommended, the use of drugs listed on brugadadrugs.org was contraindicated and careful ECG monitoring was recommended. Non–sustained ventricular tachycardia was documented during the hospitalization in ICU. When the clinical picture stabilized with resumption of spontaneous breathing, the patient was transferred to our ICU for continuation of the diagnostic and therapeutic process (Figure 2). From the interview with the patient, a previous paroxysmal tachycardia from atrio–ventricular reentry emerged in antiarrhythmic prophylaxis for several years with Propafenone and subsequently treated with catheter ablation of the right lateral accessory path. Considering the lack of documentation of complex ventricular arrhythmias by the 118 during transport to the hospital and during the stay in the UTIC, the long antiarrhythmic therapy with sodium channel inhibitors, as well as the absence of a typical Brugada pattern during fever, we decide to perform a Flecainide test (2 mg / Kg in 10 ‘), negative result for Brugada type 1 pattern (Figure 2) In the following days, considering the absolute negativity of all the neuroradiological and EEG investigations, not having found the cause of the loss of consciousness during hyperpyrexia, we performed ajmaline test (1 mg / kg in 100 cc of SG5% in 10 ‘) with the identification of the diagnostic pattern type 1 (Figure 3). Finally, the implantation of a subcutaneous cardioverting defibrillator (S–ICD) was performed.