Arrhythmic Sudden Cardiac Death Research Articles

The Role of the Immune System in Pathobiology and Therapy of Myocarditis: A Review.

The role of the immune system in myocarditis onset and progression involves a range of complex cellular and molecular pathways. Both innate and adaptive immunity contribute to myocarditis pathogenesis, regardless of its infectious or non-infectious nature and across different histological and clinical subtypes. The heterogeneity of myocarditis etiologies and molecular effectors is one of the determinants of its clinical variability, manifesting as a spectrum of disease phenotype and progression. This spectrum ranges from a fulminant presentation with spontaneous recovery to a slowly progressing, refractory heart failure with ventricular dysfunction, to arrhythmic storm and sudden cardiac death. In this review, we first examine the updated definition and classification of myocarditis at clinical, biomolecular and histopathological levels. We then discuss recent insights on the role of specific immune cell populations in myocarditis pathogenesis, with particular emphasis on established or potential therapeutic applications. Besides the well-known immunosuppressive agents, whose efficacy has been already demonstrated in human clinical trials, we discuss the immunomodulatory effects of other drugs commonly used in clinical practice for myocarditis management. The immunological complexity of myocarditis, while presenting a challenge to simplistic understanding, also represents an opportunity for the development of different therapeutic approaches with promising results.

Modulation of Cardiac Ryanodine Receptors by Chloride Intracellular Ion Channel 2

Pathogenic variants of the Chloride intracellular ion channel 2 (CLIC2) are implicated in hypertrophic cardiomyopathy (HCM), a diverse heart condition leading to arrhythmic sudden cardiac death and heart failure. CLIC2 is a unique class of metamorphic protein, related to the enzymatic glutathione s-transferase family and form functional ion channel. Artificial bilayer studies have shown that CLIC2 negatively modulates the activity of cardiac ryanodine receptor 2 (RyR2), implicating the sarcoplasmic/endoplasmic reticulum (SR/ER) Ca2+ release. However, the subsequent consequences of RyR2 and CLIC2 interaction in cardiac physiology remains unknown. Therefore, we ablated clic2 in human induced pluripotent stem cell (hiPSC) line using the CRISPR-Cas9 system and performed cardiomyocyte differentiation. clic2−/− hiPSC-derived cardiomyocytes (hiPSC-CMs) showed altered electrophysiological properties leading to impaired excitation-contraction coupling. clic2−/− hiPSC-CMs showed an increase in beat rate and field potential duration by 143.49±5.96% and 162.43±5.82%, respectively, whereas conduction velocity and spike amplitude decreased by 43.81±2.22% and 43.32±3.54%, respectively compared to WT hiPSC-CMs. Additionally, action potential duration measurements of clic2−/− hiPSC-CMs showed a decrease in APD30, APD50, and APD90 by 74.42%, 65.19%, and 66.46%, respectively compared to WT hiPSC-CMs. Moreover, clic2−/− hiPSC-CMs showed altered Ca2+ handling, with a decrease in peak amplitude (57.07±2.25%) and duration (38.29±1.30%) compared to the WT hiPSC-CMs. The caffeine induced Ca2+ release in clic2−/− hiPSC-CMs, attributed to the SR/ER Ca2+ overload which decreased by 72.19±3.51% compared to WT hiPSC-CMs. Transcriptomics analysis of clic2−/− hiPSC-CMs revealed 223 transcripts with significant changes in expression levels (89 upregulated and 134 downregulated), implicating CLIC2 in hypertrophy cardiomyopathy, dilated cardiomyopathy, and other heart diseases. Furthermore, the protein expression of CLIC2 increases in end-stage failing human heart samples compared to the non-failing heart. In conclusion, our study sheds light on the novel role of CLIC2 in the regulation of cardiac (patho)physiology. National Institutes of Health (NIH) (HL133050, and HL157453); American Heart Association-Transformational Project Award; National Center for advancing translational sciences (TR004178, understudied proteins and druggable targets) (HS). Presidential Predoctoral Fellowship; Margaret T. Nishikawara Merit Scholarship Endowment in Physiology; Graduate School’s Alumni Grants for Graduate Research and Scholarship Program, The Ohio State University (SS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Do Implantable Cardioverter-Defibrillators Prevent Sudden Cardiac Death in End-Stage Renal Disease Patients on Dialysis?

Chronic kidney disease patients appear to be predisposed to heart rhythm disorders, including atrial fibrillation/atrial flutter, ventricular arrhythmias, and supraventricular tachycardias, which increase the risk of sudden cardiac death. The pathophysiological factors underlying arrhythmia and sudden cardiac death in patients with end-stage renal disease are unique and include timing and frequency of dialysis and dialysate composition, vulnerable myocardium, and acute proarrhythmic factors triggering asystole. The high incidence of sudden cardiac deaths suggests that this population could benefit from implantable cardioverter-defibrillator therapy. The introduction of implantable cardioverter-defibrillators significantly decreased the rate of all-cause mortality; however, the benefits of this therapy among patients with chronic kidney disease remain controversial since the studies provide conflicting results. Electrolyte imbalances in haemodialysis patients may result in ineffective shock therapy or the appearance of non-shockable underlying arrhythmic sudden cardiac death. Moreover, the implantation of such devices is associated with a risk of infections and central venous stenosis. Therefore, in the population of patients with heart failure and severe renal impairment, periprocedural risk and life expectancy must be considered when deciding on potential device implantation. Harmonised management of rhythm disorders and renal disease can potentially minimise risks and improve patients' outcomes and prognosis.

A novel method for the percutaneous induction of myocardial infarction by occlusion of small coronary arteries in the rabbit.

Arrhythmic sudden cardiac death (SCD) is an important cause of mortality following myocardial infarction (MI). The rabbit has similar cardiac electrophysiology to humans and is therefore an important small animal model to study post-MI arrhythmias. The established approach of surgical coronary ligation results in thoracic adhesions that impede epicardial electrophysiological studies. Adhesions are absent following a percutaneously induced MI, which is also associated with reduced surgical morbidity and so represents a clear refinement of the approach. Percutaneous procedures have previously been described in large rabbits (3.5-5.5 kg). Here, we describe a novel method of percutaneous MI induction in smaller rabbits (2.5-3.5 kg) that are readily available commercially. New Zealand White rabbits (n = 51 males, 3.1 ± 0.3 kg) were anesthetized using isoflurane (1.5-3%) and underwent either a percutaneous MI procedure involving microcatheter tip deployment (≤1.5 Fr, 5 mm), coronary ligation surgery, or a sham procedure. Electrocardiography (ECG) recordings were used to confirm ST-segment elevation indicating coronary occlusion. Blood samples (1 and 24 h) were taken for cardiac troponin I (cTnI) levels. Ejection fraction (EF) was measured at 6-8 wk. Rabbits were then euthanized (Euthatal) and hearts were processed for magnetic resonance imaging and histology. Mortality rates were similar in both groups. Scar volume, cTnI, and EF were similar between both MI groups and significantly different from their respective sham controls. Thus, percutaneous coronary occlusion by microcatheter tip deployment is feasible in rabbits (2.5-3.5 kg) and produces an MI with similar characteristics to surgical ligation with lower procedural trauma and without epicardial adhesions.NEW & NOTEWORTHY Surgical coronary ligation is the standard technique to induce myocardial infarction (MI) in rabbits but is associated with procedural trauma and the generation of thoracic adhesions. Percutaneous coronary occlusion avoids these shortcomings and is established in pigs but has only been applicable to large rabbits because of a mismatch between the equipment used and target vessel size. Here, we describe a new scalable approach to percutaneous MI induction that is safe and effective in 2.5-3.5-kg rabbits.

Sudden sustained monomorphic ventricular tachycardia in a previously healthy adult with many causes for it, but which one is the correct? A case report

Introduction. Sustained monomorphic ventricular tachycardia (VT) ? SMVT is a rare, underdiagnosed pathology with a very poor prognosis. Along with ventricular fibrillation, SMVT is responsible for nearly all of the arrhythmic sudden cardiac deaths (SCD). The most common cause of VT is ischemic heart disease, but there are many other reasons, among which are arrhythmogenic right ventricular cardiomyopathy (ARVD) and myocardial bridging phenomenon. Treatment options include a hybrid approach consisting of antiarrhythmic drugs, catheter ablation, and implantable cardioverter defibrillators (ICD). Case report. We present a case of a 46-year-old man, a military officer, who experienced chest pain, palpitations, and nausea during regular physical activity at home. Due to the symptoms described, he was examined immediately and diagnosed with SMVT. Shortly after the diagnosis, he lost consciousness and was successfully resuscitated. A complete non-invasive and invasive cardiology examination was performed. It revealed that the patient had stable coronary disease and a muscle bridge on the left anterior descending artery. An ARVD was suspected after transthoracic echocardiography and heart magnetic resonance imaging. Genetic testing for ARVD was negative, but according to the Heart Rhythm Society expert consensus criteria, we had enough for a definitive diagnosis. The patient was hospitalized for ten days and treated with drugs without recurring VT or other disorders. We implanted an implantable loop recorder before the discharge and monitored the heart rhythm for one year. During a three-year follow-up, all of his electrocardiographic findings presented sinus rhythm without heart rhythm disorders. Conclusion. Sudden SMVT is the most common cause of SCD. It is of inestimable importance to carry out a detailed examination and determine the immediate cause of the arrhythmia and the right therapy, which, for these patients, is a life-saving form of treatment. Therapy includes medications, electrophysiology or ICD, or a combination of these treatment approaches.

Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing hearts

Sudden cardiac death (SCD) from ventricular tachycardia/fibrillation (VT/VF) is a leading cause of death, but current therapies are limited. Despite extensive research on drugs targeting sarcolemmal ion channels, none have proven sufficiently effective for preventing SCD. Sarcoplasmic ryanodine receptor 2 (RyR2) Ca2+ release channels, the downstream effectors of sarcolemmal ion channels, are underexplored in this context. Recent evidence implicates reactive oxygen species (ROS)-mediated oxidation and hyperactivity of RyR2s in the pathophysiology of SCD. We tested the hypothesis that RyR2 inhibition of failing arrhythmogenic hearts reduces sarcoplasmic Ca2+ leak and repolarization lability, mitigates VT/VF/SCD and improves contractile function. We used a guinea pig model that replicates key clinical aspects of human nonischemic HF, such as a prolonged QT interval, a high prevalence of spontaneous arrhythmic SCD, and profound Ca2+ leak via a hyperactive RyR2. HF animals were randomized to receive dantrolene (DS) or placebo in early or chronic HF. We assessed the incidence of VT/VF and SCD (primary outcome), ECG heart rate and QT variability, echocardiographic left ventricular (LV) structure and function, immunohistochemical LV fibrosis, and sarcoplasmic RyR2 oxidation. DS treatment prevented VT/VF and SCD by decreasing dispersion of repolarization and ventricular arrhythmias. Compared to placebo, DS lowered resting heart rate, preserved chronotropic competency during transient β-adrenergic challenge, and improved heart rate variability and cardiac function. Inhibition of RyR2 hyperactivity with dantrolene mitigates the vicious cycle of sarcoplasmic Ca2+ leak-induced increases in diastolic Ca2+ and ROS-mediated RyR2 oxidation, thereby reducing repolarization lability and protecting against VT/VF/SCD. Moreover, the consequent increase in sarcoplasmic Ca2+ load improves contractile function. These potentially life-saving effects of RyR2 inhibition warrant further investigation, such as clinical studies of repurposing dantrolene as a potential new therapy for heart failure and/or SCD.

Unmasking a Silent Killer and Understanding Sudden Cardiac Death in Brugada Syndrome: A Traditional Review.

Brugada syndrome (BrS) is an intricate and heterogeneous genetic disorder that engenders a formidable risk of life-threatening ventricular arrhythmias (VAs). While initially regarded as an electrophysiological aberration, emergent studies have illuminated the presence of underlying structural anomalies in select BrS cases. Although mutations in the SCN5A gene encoding the α-subunit of the cardiac sodium channel were originally identified as a primary causative factor; they account for only a fraction of the syndrome's multifaceted complexity pointing at genetic heterogeneity as a contributing factor. Remarkably, BrS has been linked to a higher incidence of fatal arrhythmic incidents and sudden cardiac death (SCD) with about 4% of SCD cases thought to be caused by BrS. Patients who spontaneously exhibit type one Brugada ECGs are more likely to experience cardiac events,emphasizing the importance of early risk stratification. To aid in risk stratification, the Shanghai score; a multifactorial risk stratification scoring system that incorporates ECG, clinical history, family history, and genetic test results; is utilized to identify those most susceptible to SCD. Beyond single ECGs, evaluation of arrhythmic findings from 24-hour Holter monitoring, ECG variables, electrophysiologic study (EPS) status in the temporal domain, and EPS data collected over time are all critical factors in risk classification. Among management options avoidance of triggers, early risk stratification, and implantation of an Implantable Cardioverter-Defibrillator (ICD) are recommended for asymptomatic patients. For symptomatic patients, pharmacotherapy and ICD implantation are available, with the latter being a highly effective choice for treating and preventing lethal arrhythmias in BrS.

#3001 PREVALENCE OF IMPLANTABLE CARDIAC DEVICES IN A COHORT OF PATIENTS WITH CHRONIC KIDNEY FAILURE: A MULTICENTER CROSS-SECTIONAL STUDY

Abstract Background and Aims Chronic kidney disease (CKD) increases the risk of arrhythmic events and sudden cardiac death. For preventive purposes, the use of cardiac implantable electronic devices (CIEDs), including pacemakers (PMs), implantable cardiac defibrillators (ICDs), pacemakers for cardiac resynchronization therapy (CRTs), and loop recorders, can be used. However, in the absence of large epidemiological studies, whether the use of CIEDs in hemodialysis patients is associated with a lower mortality benefit than in pre-dialysis patients remains controversial. In this cross-sectional study, we evaluate the prevalence of CIEDs in a cohort of patients with CKD. Method The study includes patients with CIEDs with estimated GFR <45 ml/min/1.73 m2 from two hospitals in Milan, divided into two groups based on treatment with conservative therapy (IRC stage IIIb-V) or hemodialysis. Results Of the 499 patients enrolled, 268 had CKD stage IIIb-V, and 231 were in hemodialysis (Table 1). Among CRT carriers, the prevalence in the CKD IIIb-V group is significantly higher than in the hemodialysis group (4.09% vs 0.86%; p = 0.025) (Figure 1), even if among the hemodialysis patients the prevalence of patients with previous stroke and hypertension was significantly higher (Table 1). Furthermore, in multiple logistic regressions, hemodialysis was a variable independently correlated with reduced use of CRTs (OR 0.27; 95% CI = 0.01-0.96; p 0.04), while the other devices (individually and cumulatively) correlated positively only with age and previous myocardial infarction (MI) (Table 2). Conclusion The reduced prevalence of CRT in hemodialysis patients is probably related to the shorter life expectancy and the higher rate of related complications, such as the increased risk of infectious complications and/or stenosis of the central venous vessels. Further studies are needed to evaluate the impact of these devices on the cardiac mortality of hemodialysis patients and the associated complication rate.

Prophylactic rivaroxaban in the early post-discharge period reduces the rates of hospitalization for atrial fibrillation and incidence of sudden cardiac death during long-term follow-up in hospitalized COVID-19 survivors.

Introduction: While acute Coronavirus disease 2019 (COVID-19) affects the cardiovascular (CV) system according to recent data, an increased CV risk has been reported also during long-term follow-up (FU). In addition to other CV pathologies in COVID-19 survivors, an enhanced risk for arrhythmic events and sudden cardiac death (SCD) has been observed. While recommendations on post-discharge thromboprophylaxis are conflicting in this population, prophylactic short-term rivaroxaban therapy after hospital discharge showed promising results. However, the impact of this regimen on the incidence of cardiac arrhythmias has not been evaluated to date. Methods: To investigate the efficacy of this therapy, we conducted a single center, retrospective analysis of 1804 consecutive, hospitalized COVID-19 survivors between April and December 2020. Patients received either a 30-day post-discharge thromboprophylaxis treatment regimen using rivaroxaban 10mg every day (QD) (Rivaroxaban group (Riva); n = 996) or no thromboprophylaxis (Control group (Ctrl); n = 808). Hospitalization for new atrial fibrillation (AF), new higher-degree Atrioventricular-block (AVB) as well as incidence of SCD were investigated in 12-month FU [FU: 347 (310/449) days]. Results: No differences in baseline characteristics (Ctrl vs Riva: age: 59.0 (48.9/66.8) vs 57 (46.5/64.9) years, p = n.s.; male: 41.5% vs 43.7%, p = n.s.) and in the history of relevant CV-disease were observed between the two groups. While hospitalizations for AVB were not reported in either group, relevant rates of hospitalizations for new AF (0.99%, n = 8/808) as well as a high rate of SCD events (2.35%, n = 19/808) were seen in the Ctrl. These cardiac events were attenuated by early post-discharge prophylactic rivaroxaban therapy (AF: n = 2/996, 0.20%, p = 0.026 and SCD: n = 3/996, 0.30%, p < 0.001) which was also observed after applying a logistic regression model for propensity score matching (AF: χ 2-statistics = 6.45, p = 0.013 and SCD: χ 2-statistics = 9.33, p = 0.002). Of note, no major bleeding complications were observed in either group. Conclusion: Atrial arrhythmic and SCD events are present during the first 12months after hospitalization for COVID-19. Extended prophylactic Rivaroxaban therapy after hospital discharge could reduce new onset of AF and SCD in hospitalized COVID-19 survivors.

Tachyarrhythmias after extracardiac conduit Fontan procedure in the long-term follow-up: may native anatomy of single ventricle predict their occurrence?

Abstract Funding Acknowledgements Type of funding sources: None. Background Arrhythmic complications, especially tachycardias, represent a common and important comorbidity during long-term follow up (FU) in patients with Fontan palliation for complexes congenital heart diseases (CHDs) with univentricular hearts. Surgical Fontan technique has evolved from direct atrio-pulmonary connection via the intracardiac lateral tunnel to the latest extracardiac conduit (ECC) procedure. Despite its shorter FU compared to previous techniques, the ECC variation is nowadays the main approach for many improvements, including lower incidence of arrhythmic complications (especially atrial arrhythmias). Purpose The aim of this study was to evaluate, during a long-term FU, the incidence of tachyarrhythmias and their correlation with the morphology of CHDs’ single ventricle native anatomy in a large cohort of patients with previous ECC Fontan procedure. Methods In this single centre observational cohort study, we retrospectively evaluated 351 patients treated with ECC Fontan palliation in our Institution between January 1987 and October 2017. Exclusion criteria were ECC Fontan take-down and a FU less than 5 years. CHD diagnosis, single ventricle native anatomy and surgical history were reviewed. Patients had cardiac examination once a year. We divided the overall study population in 2 groups based on unique ventricle's morphology: left-type (LV group) or right-type (RV group). Results A total of 303 patients [56% males; mean age at last FU 20 (IQR 15-28) years; 64.7% LV group] with ECC Fontan were enrolled. The mean FU was 16 (IQR 11-20, the longest 33) years. No sudden arrhythmic cardiac death occurred. Ten patients (6 of the LV group) underwent cardiac transplantation for Fontan failure. During FU, 34 patients of the LV (17.3%) and 22 of the RV group (20.2%) showed at least one tachyarrhythmia after a mean time of 12.1 and 12.9 years from ECC procedure, respectively. One patient (LV group) had one tachyarrhythmia in the early time period, &amp;lt;30 days from procedure. LV group showed a higher incidence of supraventricular tachyarrhythmias (SVTs) than RV group (68% vs 41% of total arrhythmias, p=0.08); in contrast, in RV group we found a higher number of ventricular tachyarrhythmias (VTs) compared to the other group (73% vs 41%, p=0.04). We observed both types of tachyarrhythmias (SVT and VT) in 3 patients of LV and 2 of RV group. Conclusions This study, with one of the largest cohort and longest FU after ECC Fontan, shows that ECC is associated with higher arrhythmic complications than previously reported, even though with longer latency period than other Fontan procedures. Moreover, our results suggest that patients with right-type single ventricle native anatomy are significantly more prone to develop VTs compared to those with left-type ventricle. This may reflect the drawbacks of the right ventricle physiology within Fontan circulation where the right ventricle acts for long time as the main pump of the circulatory system.

PO-04-139 THE CLINICAL COURSE OF GENOTYPE-POSITIVE PHENOTYPE-NEGATIVE PATIENTS WITH RYR2-MEDIATED CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but potentially lethal inherited cardiac arrhythmia, mostly associated with RYR2 variants. Data on phenotype-negative patients with a RYR2 variant, a growing population due to cascade screening, are lacking. We aimed to assess the clinical course of phenotype-negative patients with a RYR2 variant. All patients from the International CPVT Registry with a (likely) pathogenic RYR2 variant who were asymptomatic (defined as absence of syncope or sudden cardiac arrest [SCA]) were included if they had a negative phenotype (defined as absence of any ventricular ectopy) on baseline exercise stress test (EST) off anti-arrhythmic drugs. All ESTs during follow-up were assessed for the development of a phenotype, and data on arrhythmic events (defined as syncope, appropriate implantable cardioverter defibrillator (ICD) shock, SCA, and sudden cardiac death) during follow-up were collected. One-hundred-four patients were included (median age at first cardiologic examination 17.9 [IQR 10.4-39.2] years, 55 (52.9%) females, from 35 families with 30 different RYR2 variants). During a median follow-up duration of 6.1 [IQR 3.0-9.1] years, 449 ESTs of 79 patients were collected. When censoring at the last EST, 50.2% (95% CI 38.7-62.9) of the patients developed a phenotype at 5 years follow-up (Figure), including 25 on beta-blocker therapy. During follow-up, the overall arrhythmic event-rate was 0.010 per person year. Four (3.8%) patients experienced a syncope, of whom one was untreated and three were treated with a β1-selective beta-blocker, including one with confirmed non-adherence. Two of 3 patients with ESTs during follow-up prior to syncope had developed a phenotype. One showed a phenotype immediately after the event. One patient who had become phenotype-positive experienced a recurrent event (appropriate ICD shock). One (1.0%) patient had a SCA while being phenotype-positive and non-adherent to beta-blocker and flecainide. Twenty-nine patients never received medical therapy and were event-free during a median follow-up duration of 3.9 [IQR: 0.2-9.7] years. Following the initial phenotype-negative screening, approximately half of the patients with a RYR2 variant developed a phenotype during 5 years of follow-up. The event rate was low and only two patients had a near-fatal arrhythmic event, both after developing a phenotype. This information could guide management of phenotype-negative patients with CPVT.

Should lethal arrhythmias in hypertrophic cardiomyopathy be predicted using non-electrophysiological methods?

While sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) is due to arrhythmias, the guidelines for prediction of SCD are based solely on non-electrophysiological methods. This study aims to stimulate thinking about whether the interests of patients with HCM are better served by using current, 'risk factor', methods of prediction or by further development of electrophysiological methods to determine arrhythmic risk. Five published predictive studies of SCD in HCM, which contain sufficient data to permit analysis, were analysed to compute receiver operating characteristics together with their confidence bounds to compare their formal prediction either by bootstrapping or Monte Carlo analysis. Four are based on clinical risk factors, one with additional MRI analysis, and were regarded as exemplars of the risk factor approach. The other used an electrophysiological method and directly compared this method to risk factors in the same patients. Prediction methods that use conventional clinical risk factors and MRI have low predictive capacities that will only detect 50-60% of patients at risk with a 15-30% false positive rate [area under the curve (AUC) = ∼0.7], while the electrophysiological method detects 90% of events with a 20% false positive rate (AUC = ∼0.89). Given improved understanding of complex arrhythmogenesis, arrhythmic SCD is likely to be more accurately predictable using electrophysiologically based approaches as opposed to current guidelines and should drive further development of electrophysiologically based methods.

Declining Risk of Sudden Cardiac Death in Heart Failure: Fact or Myth?

The notion that the risk of sudden cardiac death (SCD) in patients with heart failure (HF) is declining seems to be gaining traction. Numerous editorials and commentaries have suggested that SCD, specifically arrhythmic SCD, is no longer a significant risk for patients with HF on guideline-directed medical therapy. In this review, we question whether the risk of SCD has indeed declined in HF trials and in the real world. We also explore whether, despite relative risk reductions, the residual SCD risk after guideline-directed medical therapy still suggests a need for implantable cardioverter defibrillator therapy. Among our arguments is that SCD has not decreased in HF trials, nor in the real world. Moreover, we argue that data from HF trials, which have not adhered to guideline-directed device therapy, do not obviate or justify delays to implantable cardioverter defibrillator therapy. In this context, we underline the challenges of translating the findings of HF randomized, controlled trials of guideline-directed medical therapy to the real world. We also make the case for HF trials that adhere to current guideline-directed device therapy so that we can better understand the role of implantable cardioverter defibrillators in chronic HF.

Echocardiographic Parameters to Predict Malignant Events in Arrhythmic Mitral Valve Prolapse Population.

Bileaflet Mitral Valve Prolapse (bMVP) has been linked to major arrhythmic events and sudden cardiac death (SCD). Consistent predictors in this field are still lacking. Echocardiography is the best tool for the analysis of the prolapse and its impact on the ventricular mechanics. The aim of this study was to find new echocardiographic predictors of malignant events within an arrhythmic MVP population. We evaluated 22 patients with arrhythmic bMVP with a transthoracic echocardiogram focused on mitral valve anatomy and ventricular contraction. Six of them had major arrhythmic events that required ICD implantation (ICD-MVP group), while sixteen presented with a high arrhythmic burden without major events (A-MVP group). The best predictors of malignant events were the Anterior Mitral Leaflet (AML) greater length and greater Mechanical Dispersion (MD) of basal and mid-ventricular segments, while other significant predictors were the larger mitral valve annulus (MVA) indexed area, lower MVA anteroposterior diameter/AML length ratio, higher inferolateral basal segment S3 velocity.

630 CARDIAC AMYLOIDOSIS: THE IMPORTANCE OF THE RIGHT DIAGNOSTIC TOOLS

Abstract Introduction Amyloidosis (a.) consists of the build-up of misfolded proteins in the whole body leading to life threatening organ disfunction. The most common form is the AL a., that is the result of kappa or lambda monoclonal light chains deposition as amyloid fibril. Cardiac involvement in AL a. has a high mortality. Once cardiac symptoms reveal, early diagnosis is important in order of the inverse relationship between time after the onset of cardiac symptoms and survival. Case Report A 80-y/o male was admitted in our department. Four months before he had an hospitalization in whom a coronarography was performed, showing no emodinamically signifiant lesions, leading to diagnosis of acute coronary syndrome with non occlusive coronary disease. For two months, he experienced progressive dyspnea, edema of the lower limbs and bilateral pleural effusions. On arrival, he was hemodynamically stable, his laboratory results were significant for a pro-BNP of 26,568 pg/ml and high sensitivity troponin T of 359 ng/L but without movement, the electrocardiogram showed sinus rhythm with heart rate of 72 bpm, right bundle block, non specific alterations of repolarization and low voltages. The chest X-ray showed bilateral pleural effusion. A first echocardiogram was performed and showed normal left ventricular systolic function with an ejection fraction of 60%, without wall motion abnormalities, severe concentric hypertrophy, with a left ventricular posterior wall thickness of 16 mm that is over the cutoff proposed by Marume et al., a LV septal WT of 17 mm, over the cutoff of Arvidsson at al., and a granular appearance of the myocardium, seen as hyperrefractile myocardial echoes. There was a moderate-severe diastolic dysfunction (E/E’ ratio of 22). A small pericardial effusion (8 mm) and a right ventricular dilatation (30mm) were present, too. The last parameter is a poor prognostic marker of right heart failure (in our patient there was also a tricuspid insufficiency) and a median survival of four month, as Patel et al. demonstrate. All these parameters are suspicious for storage disease, in particular amyloid deposition. M spike was not shown at serum and urine electrophoresis, and no paraproteins were found in immunofixation. However, increased kappa and lambda free light chains (248 mg/L and 31 mg/L respectively) with an increased serum and urinary kappa/lambda ratio (8.00 and 105.19) were found. Thus, a fine needle aspiration was performed, showing a bone marrow localization of Multiple myeloma (MM). A bone marrow biopsy was done but the result was still unknown at the time of discharge. A negative scintigraphy was performed. The patient was discharged from our department with a diagnosis of chronic heart failure and ongoing investigation about the link between MM and CA. One month later we have seen the result of the bone marrow biopsy that was negative for Congo red staining. During the same month the patient died, so there was no possibility to practice a cardiac biopsy. Discussion The purpose of this abstract is to emphasize the importance of fast diagnosis and cardiac biopsy in a characteristic case of clinical and echocardiogram suspicious of CA and a negative scintigraphy. Therefore the cardiac biopsy is preferable to extracardiac biopsy, as fat pad or bone marrow ones, because the cardiac one is more specific and sensitive. The heart of the matter is that it is not possible for all the departments to carry out this procedure in short-term, as in our case, and a non rapid diagnosis is linked with arrhythmic sudden cardiac death but also a rapidly worsening heart failure, as in our patient.

879 STUDY OF ATRIOVENTRICULAR CONDUCTION DEFECTS AND ARRHYTHMIAS IN PATIENTS WITH DILATATIVE CARDIOMIOPATHY CLINICAL PROGNOSTIC VALUE OF THE GENETIC ANALYSIS USING NEXT GENERATION SEQUENCING AT THREE YEARS

Abstract Background Dilated cardiomyopathy is one of the most common cardiomyopathies that at the onset shows a with dysfunction, commonly expressed by the reduced ejection fraction (EF) and which can lead to heart transplantation. Cardiac "laminopathies" are part of the complex set of CMD. In many cases they show a defect in myocardial electrical conduction. Mutations in the Lamina A / C genes have been associated with high arrhythmic risk and sudden cardiac death. In addition to these, there are others concerning the MYH7, TTN, MYBPC3 genes, related to the CMD phenotype and whose meaning is being defined. Objectives The project has the goal of evaluating the association of arrhythmic disorders with possible CMD phenotypes and the genetic mutations described above. Materials and Methods We studied 33 out of 100 patients screened for CMD on voluntary availability, suffering from different forms without significant coronary lesions. All of them underwent diagnostic-instrumental checks (ECG, Holter Ecg, echocardiogram and enzymatic profile) and followed for a minimum period of 18 months. At the same time at the ordinary check -up, genetic analyses were carried out through the NGS study of a panel of genes related to CMD in collaboration between the AOU G. Martino di Messina and the Bambino Gesu’ Hospital in Rome. Results On 33 patients undergoing a genetic study, variants of uncertain significance (VUS) were identified: variant c.2359 C&amp;gt; T (p.Arg787Cys) in the MYH7 gene reported in VarSome as probably pathogenetic in a symptomatic patient with endomyocardial biopsy CMD +; the variant c.54016G&amp;gt; T in heterozygosity in the TTN gene, in another case, which at the protein level determines the introduction of the premature stop codon not described in scientific literature and classified according to the ACMG guidelines as a probably pathogenic variant; finally pathogenic variant c.949G&amp;gt; A in heterozygosity in the LMNA gene, in a family with a history of sudden cardiac death with manifest CMD in some members with arrhythmias at follow up (ICD). and the presence of a second mutation; c.836G&amp;gt; C in heterozygosity in the MYBPC3 gene, in other members of the same family with better clinical course. Conclusions Our study shows that there are VUS associated with cases of CMD. Within these, the presence of mutations in the lamina gene seem to be more closely related to the incidence of arrhythmias. Therefore, further studies are necessary for a better definition of all possible VUS also to carry out a differential diagnosis in the broad spectrum of cardiomyopathies.

Abstract 14888: Arrhythmogenic Right Ventricular Cardiomyopathy-Brugada Syndrome Overlap: A Rare Clinical Entity

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) and Brugada syndrome (BS) are inherited disorders that predispose individuals to arrhythmic sudden cardiac death. ARVC is a heart muscle disorder of intercellular junctions resulting from mutations of desmosomal (DS) genes, often leading to heart failure, and monomorphic ventricular tachycardia (VT). BS is a channelopathy due to sodium channel mutations, usually presenting as polymorphic VT without cardiomyopathy. Case presentation: A 35-year-old male with history of migraines presented with syncope resulting in a fall. No family history of arrhythmias or sudden cardiac death. Initial EKG showed wide complex monomorphic VT. Repeat EKG (figure 1), revealed coved ST-segment elevations in V1, V2 consistent with Brugada type 1 pattern. Emergent coronary angiography was unremarkable, and echocardiogram showed left ventricular ejection fraction of 55-60%, right ventricle (RV) outflow tract proximal diameter measured 3.5cm and normal RV function. An implantable cardioverter-defibrillator (ICD) was implanted for secondary prevention. Device interrogation on follow-up showed 11 shocks for recurrent episodes of monomorphic VT and patient was started on quinidine maintenance therapy. He remained symptom-free on subsequent visits. Genetic testing was positive for DSC2, DSP, and TMEM43 mutations associated with ARVC, but negative for genes associated with BS. Cardiac MRI results are pending. Discussion: Our patient has overlapping features of ARVC (genotype and monomorphic VT) and BS (EKG with coved ST elevations in V1, V2). Emerging evidence supports the theory that defects in DS proteins may affect the integrity of voltage-gated sodium channels in cardiac intercalated discs, leading to BS like phenotype. Conclusion: ARVC and BS could be related to the same disease spectrum, but further studies are required to understand pathophysiology, to guide treatment decisions.

Late gadolinium enhancement is a strong predictor of life threatening arrhythmias in patients with dilated cardiomyopathy undergoing ICD implantation for primary prevention of sudden cardiac death

Abstract Background The usefulness of implantable cardioverter defibrillators (ICD) for primary prevention of arrhythmic sudden cardiac death (SCD) in patients with non-ischemic dilated cardiomyopathy (DCM) has been questioned. Efforts to improve risk stratification have included scores such as the “MADIT-ICD benefit score”, and the use of late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR). The purpose of this study was to evaluate the potential usefulness of these two tools to assess the risk of life-threatening arrhythmias in patients with non-ischemic DCM undergoing ICD implantation for primary prevention of SCD. Methods We conducted a single-center retrospective study of consecutive patients who underwent contrast-enhanced CMR before ICD implantation for primary prevention of SCD. Patients with ischemic cardiomyopathy were used as reference. Patients with non-dilated cardiomyopathies were excluded. The arrhythmic component of the MADIT-ICD benefit score (VT/VF score) was calculated for each patient, and considered high if ≥7, as recommended. The primary endpoint was the occurrence of SCD or life-threatening arrhythmias (VF or VT &amp;gt;200 bpm). Follow-up was performed by device interrogation in all patients except those who suffered SCD. Results A total of 151 patients (93 ischemic, mean age 62±13 years, 75% male) with mean left ventricular ejection fraction (LVEF) of 27±8% were included. Overall, 72% (n=67) ischemic and 45% (n=26) non-ischemic patients had scores ≥7 and were considered high-risk. LGE was present in all patients with ischemic cardiomyopathy, and in 76% (n=44) of patients with non-ischemic DCM. During a median follow-up of 21 (8–38) months, 21 patients (13.9%, 11 ischemic and 10 non-ischemic) met the primary endpoint. Overall, the event-free survival of non-ischemic patients was similar to that of ischemic patients (log rank p=0.269). In patients with non-ischemic DCM, there were 7 arrhythmic events (26.9%) in those with MADIT-ICD VT/VF scores ≥7, and 3 events (9.4%) in those with scores &amp;lt;7 (log rank p=0.104). In the same population, there were 10 arrhythmic events (23%) in patients with LGE, but no events in patients without LGE (log rank p=0.036). LVEF was similar in patients with and without arrhythmic events (26±8% vs. 27±7%, p=0.717), and in those with and without LGE (26±7% vs. 28±9%, p=0.342). Conclusion The presence of LGE is a strong predictor of life threatening arrhythmias in patients in non-ischemic DCM undergoing ICD implantation for primary prevention, seemingly outperforming the clinical MADIT-ICD benefit score. Funding Acknowledgement Type of funding sources: None.

A review on role of autopsy in the diagnosis of sudden arrhythmic deaths

Sudden death (SD) is described as “death within 24 hours from the earliest manifestation, without any proof of violence and with no pre-existing disease, where no cause of death can be identified clinically”. In about 5%–10% of cases of sudden cardiac death (SCD), no underlying heart disease can be found at autopsy. Mostly these are the arrhythmic SCD and have a morphologically normal heart. There is a scope for uncertainty among relatives and/or investigating authorities regarding the cause &amp; manner of death specifically in unattended sudden cardiac death. The postmortem examination must include detailed history or clinically relevant information of the deceased, his/her family members, macroscopic, microscopic, toxicological &amp; molecular examination.

Late gadolinium enhancement is a strong predictor of life threatening arrhythmias in patients with non-ischemic dilated cardiomyopathy undergoing ICD implantation for primary prevention of sudden card

Abstract Funding Acknowledgements Type of funding sources: None. Background The usefulness of implantable cardioverter defibrillators (ICD) for primary prevention of arrhythmic sudden cardiac death (SCD) in patients with non-ischemic dilated cardiomyopathy (DCM) has been questioned. Efforts to improve risk stratification have included scores such as the ‘MADIT-ICD benefit score’, and the use of late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR). The purpose of this study was to evaluate the potential usefulness of these two tools to assess the risk of life-threatening arrhythmias in patients with non-ischemic DCM undergoing ICD implantation for primary prevention of SCD. Methods We conducted a single-center retrospective study of consecutive patients who underwent contrast-enhanced CMR before ICD implantation for primary prevention of SCD. Patients with ischemic cardiomyopathy were used as reference. Patients with non-dilated cardiomyopathies were excluded. The arrhythmic component of the MADIT-ICD benefit score (VT/VF score) was calculated for each patient, and considered high if ≥ 7, as recommended. The primary endpoint was the occurrence of SCD or life-threatening arrhythmias (VF or VT &amp;gt;200 bpm). Follow-up was performed by device interrogation in all patients except those who suffered SCD. Results A total of 151 patients (93 ischemic, mean age 62±13 years, 75% male) with mean left ventricular ejection fraction (LVEF) of 27±8% were included. Overall, 72% (n=67) ischemic and 45% (n=26) non-ischemic patients had scores ≥ 7 and were considered high-risk. LGE was present in all patients with ischemic cardiomyopathy, and in 76% (n=44) of patients with non-ischemic DCM. During a median follow-up of 21 (8-38) months, 21 patients (13.9%, 11 ischemic and 10 non-ischemic) met the primary endpoint. Overall, the event-free survival of non-ischemic patients was similar to that of ischemic patients (log rank p=0.269) – Fig 1A. In patients with non-ischemic DCM, there were 7 arrhythmic events (26.9%) in those with MADIT-ICD VT/VF scores ≥7, and 3 events (9.4%) in those with scores &amp;lt;7 (log rank p= 0.104) – Fig 1B. In the same population, there were 10 arrhythmic events (23%) in patients with LGE, but no events in patients without LGE (log rank p=0.036) – Fig 1C. LVEF was similar in patients with and without arrhythmic events (26±8% vs. 27±7%, p=0.717), and in those with and without LGE (26±7% vs. 28±9%, p=0.342). Conclusion The presence of LGE is a strong predictor of life threatening arrhythmias in patients in non-ischemic DCM undergoing ICD implantation for primary prevention, seemingly outperforming the clinical MADIT-ICD benefit score.