Life-threatening Arrhythmic Events Research Articles

T-Wave Alternans Measured by 24-Hour Ambulatory Recordings Rather Than Exercise Stress Tests as a Risk Stratification Marker in Patients With Long QT Syndrome.

Few small-sample studies have quantified the T-wave alternans (TWA) value by 24-hour ambulatory recordings or exercise stress tests in patients with long QT syndrome (LQTS). The cutoff point of TWA ≥47 μV was based on patients with myocardial infarction. In our study, we aimed to (1) evaluate the association of TWA with life-threatening arrhythmic events (LAEs); (2) compare the predictive model of LAEs according to the TWA value measured by 24-hour ambulatory recordings and exercise stress tests; and (3) propose a cutoff point for the high risk of LAEs in patients with LQTS. The study cohort included 110 patients with LQTS referred to our hospital, and the primary outcome was LAEs. Thirty-one patients with LQTS (31/110 [28.2%]) developed LAEs during the following 24 (12-47) months. Peak TWA value quantified from 12 leads by 24-hour ambulatory recordings in patients with LQTS with LAEs (LQTS-LAEs group) was significantly higher than LQTS without LAEs (LQTS-non-LAEs group) (64.0 [42.0-86.0] μV versus 43.0 [36.0-53.0] μV; P<0.01). There was no statistical difference in TWA value measured by exercise stress tests between the 2 groups (69.0 [54.5-127.5] μV versus 68.5 [53.3-99.8] μV; P=0.871). The new cutoff point of the peak TWA value measured by 24-hour ambulatory recordings was 55.5 μV, with a sensitivity of 75.0% and a specificity of 78.6%. A univariate Cox regression analysis revealed that TWA value ≥55.5 μV was a strong predictor of LAEs (hazard ratio [HR], 4.5 [2.1-9.6]; P<0.001]. A multivariate Cox regression analysis indicated that TWA value ≥55.5 μV remained significant (HR, 2.7 [1.1-6.8]; P=0.034). Peak TWA measured by 24-hour ambulatory recordings was a more favorable risk stratification marker than exercise stress tests for patients with LQTS.

Ablation of the epicardial substrate in patients with long-QT syndrome at risk of sudden death.

Sudden cardiac death remains a critical public health concern globally, affecting millions annually. Recent advances in cardiac arrhythmia mapping have demonstrated that the ventricular epicardial region has a critical arrhythmogenic role in some inherited cardiogenetic diseases. Among these, long-QT syndrome (LQTS) exposes patients to the risk of life-threatening arrhythmic events. Despite advancements, there is a need for more effective therapeutic strategies. A recent study has uncovered a noteworthy connection between LQTS and epicardial structural abnormalities, challenging the traditional view of LQTS as purely an electrical disorder. High-density mapping revealed electroanatomic abnormalities in the right ventricular epicardium, presenting a potential target for catheter ablation, to finally suppress ventricular fibrillation recurrences in high-risk LQTS patients.

Artificial intelligence-driven echocardiographic classification identifies Brugada Syndrome patients at higher arrhythmic risk

Abstract Background Mounting evidence exists to support the hypothesis that patients with Brugada Syndrome (BrS) present morphological and structural anomalies localized to the right ventricle (RV), but this has not been investigated in a large cohort and the association with clinical outcomes are unknown. Purpose To investigate the role of echocardiography-derived RV parameters in a large, single-center cohort of patients with BrS. Methods We prospectively enrolled n=492 consecutive patients (379 males, 77%; age 46±14 years) with confirmed BrS who underwent an echocardiogram during their last visit at the outpatient clinic for inherited arrhythmogenic disorders. Comprehensive 2D and color Doppler echocardiographic evaluation was performed using the standard clinical protocol. Unsupervised clustering analysis using cluster package sorted body surface area-corrected morphological (RVOT linear dimensions and RV diastolic area) and functional measurements of RV (fractional area shortening [FAC], tricuspid annular plane systolic excursion [TAPSE]), blinded to other variables. We performed clustering with a hierarchical cluster algorithm (h-cluster) and the optimal number of clusters (k=2) was determined using fviz_nbclust-derived plots. Results All n=492 patients were classified into 2 stable clusters () with the best robustness. The Cluster 1 echocardiograms exhibited normal RV morphological and functional parameters. The Cluster 2 echocardiograms showed a dilatation of the RVOT (PLAX 17.2±2.1 vs. 15.6±2.1, p&amp;lt;0.001; PSAX 18.3±2.2 vs. 16.9±2.2, p&amp;lt;0.001) compared to Cluster 1, while the RV diastolic area was not different (9.9±1.5 vs. 9.9±1.6, p=0.801). Importantly, RV function as assessed by TAPSE was not different between the two groups, but Cluster 2 patients showed a significantly impaired radial contraction (RV FAC 40.1±3.4% vs. 48.6±3.8%, p&amp;lt;0.001). We then investigated the clinical characteristics of patients based on clusters. Patients in Cluster 1 were younger (43.2±12.8 years vs. 47.5±14.0 years, p&amp;lt;0.001) and had significantly less arrhythmic symptoms such as syncope (13% vs. 20%, p=0.046) and life-threatening arrhythmic events (2% vs. 7%, p=0.017). Importantly, no significant differences in terms of gender (77% males in both groups, p=1.000), pattern type (43% with spontaneous type 1 pattern in Cluster 1 vs. 47%, p=0.494) nor genetic status were observed. Multivariate logistic regression confirmed that at parity of age and arrhythmic syncope, Cluster 2 was independently associated with an increased incidence of life-threatening arrhythmic events (odds ratio 3.71, 95% confidence interval 1.31-10.53, p=0.039). Conclusions We constructed a novel, echocardiography-guided classification of patients with BrS using unsupervised clustering analysis. Our data suggest that RV structural abnormalities are associated with a higher incidence of life-threatening arrhythmic events in patients with BrS, independently of arrhythmic syncope or age.

Abstract 17666: Impact of Myocardial Fibrosis and Female Sex on Life-Threatening Arrhythmias and Sudden Cardiac Death in MVP Patients: A Prospective CMR Study With Over 2300 Patient-Years of Follow Up

Background: Mitral valve prolapse (MVP) is a common condition that exhibits a benign course. Conversely, a small subset of patients experiences life-threatening arrhythmias and sudden cardiac death (SCD). Multiple risk factors have been proposed for arrhythmia in MVP; however, few have been validated as independent predictors of hard arrhythmic events on longitudinal follow-up. Methods: A prospective cohort of 550 consecutive patients with MVP underwent comprehensive clinical assessment and late gadolinium enhancement (LGE) cardiac magnetic resonance. Patients were longitudinally followed for a composite outcome of SCD, aborted SCD, sustained or symptomatic ventricular tachycardia (VT) requiring implantable cardiac defibrillator (ICD) placement, or ventricular ablation. In a multivariable cox regression analysis, we adjusted for female sex, LGE, MVP leaflet involvement, mitral annular disjunction (MAD), and mitral regurgitation (MR) severity. Results: The cohort median age was 62 (IQR 51-71) years, comprising 50% women. Over a mean follow-up of 4.3 years, 44 patients (mean age 62.5 years ±10) met the composite outcome, of which n=33 (75%) were women. Myocardial fibrosis (LGE) was present in 61% of the outcome group (n=27). LGE (HR 3.52 [95%CI, 1.87-6.63], P &lt;0.001) and female sex (HR 3.90 [95%CI, 1.92-7.95], P &lt;0.001) were associated with worse outcomes in univariate analysis. Kaplan Meier statistics (Figure, A) indicated patients with LGE had a higher 5-year cumulative incidence of arrhythmic composite events than those without LGE (14.8% vs 4.4%, P &lt;0.001). On multivariable analysis, female sex and myocardial fibrosis remained independent risk predictors across all models. (Figure, B). Conclusion: Female sex and myocardial fibrosis are independent predictors of life-threatening arrhythmic events and SCD in patients with MVP, suggesting that LGE should be an important component of risk stratification, especially in the female MVP population.

Artificial Intelligence ECG Analysis in Patients with Short QT Syndrome to Predict Life-Threatening Arrhythmic Events

Short QT syndrome (SQTS) is an inherited cardiac ion-channel disease related to an increased risk of sudden cardiac death (SCD) in young and otherwise healthy individuals. SCD is often the first clinical presentation in patients with SQTS. However, arrhythmia risk stratification is presently unsatisfactory in asymptomatic patients. In this context, artificial intelligence-based electrocardiogram (ECG) analysis has never been applied to refine risk stratification in patients with SQTS. The purpose of this study was to analyze ECGs from SQTS patients with the aid of different AI algorithms to evaluate their ability to discriminate between subjects with and without documented life-threatening arrhythmic events. The study group included 104 SQTS patients, 37 of whom had a documented major arrhythmic event at presentation and/or during follow-up. Thirteen ECG features were measured independently by three expert cardiologists; then, the dataset was randomly divided into three subsets (training, validation, and testing). Five shallow neural networks were trained, validated, and tested to predict subject-specific class (non-event/event) using different subsets of ECG features. Additionally, several deep learning and machine learning algorithms, such as Vision Transformer, Swin Transformer, MobileNetV3, EfficientNetV2, ConvNextTiny, Capsule Networks, and logistic regression were trained, validated, and tested directly on the scanned ECG images, without any manual feature extraction. Furthermore, a shallow neural network, a 1-D transformer classifier, and a 1-D CNN were trained, validated, and tested on ECG signals extracted from the aforementioned scanned images. Classification metrics were evaluated by means of sensitivity, specificity, positive and negative predictive values, accuracy, and area under the curve. Results prove that artificial intelligence can help clinicians in better stratifying risk of arrhythmia in patients with SQTS. In particular, shallow neural networks’ processing features showed the best performance in identifying patients that will not suffer from a potentially lethal event. This could pave the way for refined ECG-based risk stratification in this group of patients, potentially helping in saving the lives of young and otherwise healthy individuals.

The Uncertain Benefit from Implantable Cardioverter-Defibrillators in Nonischemic Cardiomyopathy: How to Guide Clinical Decision-Making?

Life-threatening dysrhythmias remain a significant cause of mortality in patients with nonischemic cardiomyopathy (NICM). Implantable cardioverter-defibrillators (ICD) effectively reduce mortality in patients who have survived a life-threatening arrhythmic event. The evidence for survival benefit of primary prevention ICD for patients with high-risk NICM on guideline-directed medical therapy is not as robust, with efficacy questioned by recent studies. In this review, we summarize the data on the risk of life-threatening arrhythmias in NICM, the recommendations, and the evidence supporting the efficacy of primary prevention ICD, and highlight tools that may improve the identification of patients who could benefit from primary prevention ICD implantation.

High-risk imaging characteristics in left ventricular apex for the life-threatening arrhythmic events in Japanese hypertrophic cardiomyopathy patients.

Left ventricular (LV) apical aneurysm is known to be associated with the life-threatening arrhythmic events in hypertrophic cardiomyopathy (HCM). However, the current 2014 ESC guideline has not included apical aneurysm as a major risk factor for sudden cardiac death and 2018 JCS guideline includes it only as a modulator, while it has been included as a new major risk marker in 2020 AHA/ACC guideline. Therefore, we sought to identify high-risk imaging characteristics in LV apex which is associated with a higher occurrence of ventricular tachycardia/fibrillation (VT/VF). In 99 consecutive Japanese HCM patients (median age, 65years; 59 males) undergoing implantable cardioverter-defibrillator (ICD) implantation for primary prevention following cardiac magnetic resonance including late gadolinium enhancement (LGE), the occurrence of appropriate ICD interventions for VT/VF was evaluated for 6.2 (median) years after ICD implantation. Overall, appropriate ICD interventions occurred in 43% with annual rates of 7.0% for appropriate interventions. Kaplan-Meier analysis demonstrated that the presence of LV apical aneurysm was significantly associated with a higher occurrence of appropriate interventions (annual rates 18.9% vs. 6.4%, P = 0.013). Similarly, patients with high LV mid-to-apex pressure gradient (annual rates 14.9% vs. 6.2%, P = 0.022) and presence of apical LGE (annual rates 10.9% vs. 4.0%, P = 0.001) experienced appropriate interventions more frequently. An aneurysm, high-pressure gradient, and LGE in an apex are associated with VT/VF. These characteristics in apex should be kept in mind when implanting ICD in Japanese HCM patients as a primary prevention.

Store-Operated Ca2+ Entry as a Putative Target of Flecainide for the Treatment of Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder that may lead patients to sudden cell death through the occurrence of ventricular arrhythmias. ACM is characterised by the progressive substitution of cardiomyocytes with fibrofatty scar tissue that predisposes the heart to life-threatening arrhythmic events. Cardiac mesenchymal stromal cells (C-MSCs) contribute to the ACM by differentiating into fibroblasts and adipocytes, thereby supporting aberrant remodelling of the cardiac structure. Flecainide is an Ic antiarrhythmic drug that can be administered in combination with β-adrenergic blockers to treat ACM due to its ability to target both Nav1.5 and type 2 ryanodine receptors (RyR2). However, a recent study showed that flecainide may also prevent fibro-adipogenic differentiation by inhibiting store-operated Ca2+ entry (SOCE) and thereby suppressing spontaneous Ca2+ oscillations in C-MSCs isolated from human ACM patients (ACM C-hMSCs). Herein, we briefly survey ACM pathogenesis and therapies and then recapitulate the main molecular mechanisms targeted by flecainide to mitigate arrhythmic events, including Nav1.5 and RyR2. Subsequently, we describe the role of spontaneous Ca2+ oscillations in determining MSC fate. Next, we discuss recent work showing that spontaneous Ca2+ oscillations in ACM C-hMSCs are accelerated to stimulate their fibro-adipogenic differentiation. Finally, we describe the evidence that flecainide suppresses spontaneous Ca2+ oscillations and fibro-adipogenic differentiation in ACM C-hMSCs by inhibiting constitutive SOCE.

Long QT syndrome-associated calmodulin variants disrupt the activity of the slowly activating delayed rectifier potassium channel.

Calmodulin (CaM) is a highly conserved mediator of calcium (Ca2+ )-dependent signalling and modulates various cardiac ion channels. Genotyping has revealed several CaM mutations associated with long QT syndrome (LQTS). LQTS patients display prolonged ventricular recovery times (QT interval), increasing their risk of incurring life-threatening arrhythmic events. Loss-of-function mutations to Kv7.1 (which drives the slow delayed rectifier potassium current, IKs, a key ventricular repolarising current) are the largest contributor to congenital LQTS (>50% of cases). CaM modulates Kv7.1 to produce a Ca2+ -sensitive IKs, but little is known about the consequences of LQTS-associated CaM mutations on Kv7.1 function. Here, we present novel data characterising the biophysical and modulatory properties of three LQTS-associated CaM variants (D95V, N97I and D131H). We showed that mutations induced structural alterations in CaM and reduced affinity for Kv7.1, when compared with wild-type (WT). Using HEK293T cells expressing Kv7.1 channel subunits (KCNQ1/KCNE1) and patch-clamp electrophysiology, we demonstrated that LQTS-associated CaM variants reduced current density at systolic Ca2+ concentrations (1μm), revealing a direct QT-prolonging modulatory effect. Our data highlight for the first time that LQTS-associated perturbations to CaM's structure impede complex formation with Kv7.1 and subsequently result in reduced IKs. This provides a novel mechanistic insight into how the perturbed structure-function relationship of CaM variants contributes to the LQTS phenotype. KEY POINTS: Calmodulin (CaM) is a ubiquitous, highly conserved calcium (Ca2+ ) sensor playing a key role in cardiac muscle contraction. Genotyping has revealed several CaM mutations associated with long QT syndrome (LQTS), a life-threatening cardiac arrhythmia syndrome. LQTS-associated CaM variants (D95V, N97I and D131H) induced structural alterations, altered binding to Kv7.1 and reduced IKs. Our data provide a novel mechanistic insight into how the perturbed structure-function relationship of CaM variants contributes to the LQTS phenotype.

3D substrate complexity analysis using cardiac MRI predicts ICD therapy in post-infarct ventricular tachycardia

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): EACVI, Netherlands Heart Institute. Background Implantable cardiac defibrillator (ICD) implantation can protect against sudden cardiac death (SCD) after a myocardial infarction. However, relatively few patients with an ICD experience a life-threatening arrhythmic event. Imaging studies have proposed metrics based on 2D analysis of late gadolinium enhancement (LGE) characteristics to predict post-infarct malignant arrhythmias and improve SCD risk assessment. However, given the intrinsic 3D nature of the electrical pathways through the infarcted regions, 3D reconstructions of the scar substrate from LGE imaging may be required to fully characterize the pro-arrhythmic nature of the scar substrate. Aim To evaluate the accuracy of LGE based 3D metrics such as conduction corridors (regions of borderzone (BZ) surrounded by scar core) and 3D interface surfaces (boundaries between scar and myocardium) towards predicting ICD therapy. Methods ADAS LV and custom-made software was used to generate 3D patient-specific ventricular models in a prospective cohort of post-infarct patients (n=40) having undergone LGE imaging pre-ICD implantation. The extent of variation in scar-characteristics was evaluated in ADAS by quantifying the BZ, scar core, the number and weight of conduction corridors i.e. BZ surrounded by scar core. Custom-written scripts were used to calculate metrics describing the 3D topology of the scar substrate, specifically the interface area between myocardium and total enhancement (BZ+core), and the interface between BZ and core. These metrics were compared with ICD therapy during follow-up. Results Total corridors were comparable between both groups (6.53 ± 7.9 vs. 4.6 ± 4, p = .38). Corridor weight demonstrated a trend towards higher mass in the event group (2.7 ± 2.1g vs. 1.6 ± 1.4g, p = .06). Patients with an event (n=17) had higher myocardium-total enhancement interface (103.8±35.1cm2 vs. 77.4±33.7cm2, p = .021) and BZ-core interface (76±27.5cm2 vs. 55.2±27.6cm2, p = .024). Cox-regression demonstrated a significant independent association of myocardium-total enhancement interface with an event (HR 2.79; 1.44–5.44, p &amp;lt; .01). Kaplan-Meier analysis (Figure 1) showed a significantly higher event rate in patients with an interface area between myocardium-total enhancement of more than 72cm2 and BZ-core more than 42.3cm2. Conclusion These results demonstrate that patients with appropriate device therapy had larger myocardium-total enhancement and BZ-core surface interface areas. Conceptually, the BZ-core interface could be considered to be related to the reentrant circuit path-length whilst the myocardium-total enhancement interface reflects the surfaces most-likely to initiate unidirectional block, both of which can be consider pro-arrhythmic substrates. These findings emphasize the importance of visualizing and thereby characterizing substrate as a 3D entity instead of the currently applied 2D approach to facilitate early identification of high-risk patients.

3D substrate complexity analysis using cardiac MRI predicts ICD therapy in post-infarct ventricular tachycardia

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): EACVI Research Grant Academy Van Leersum grant of the Academy Medical Sciences Fund (Royal Netherlands Academy of Arts &amp; Sciences). Background Implantable cardiac defibrillator (ICD) implantation can protect against sudden cardiac death (SCD) after a myocardial infarction. However, relatively few patients with an ICD experience a life-threatening arrhythmic event. Imaging studies have proposed metrics based on 2D analysis of late gadolinium enhancement (LGE) characteristics to predict post-infarct malignant arrhythmias and improve SCD risk assessment. However, given the intrinsic 3D nature of the electrical pathways through the infarcted regions, 3D reconstructions of the scar substrate from LGE imaging may be required to fully characterize the pro-arrhythmic nature of the scar substrate. Aim To evaluate the accuracy of LGE based 3D metrics such as conduction corridors (regions of borderzone (BZ) surrounded by scar core) and 3D interface surfaces (boundaries between scar and myocardium) towards predicting ICD therapy. Methods ADAS LV and custom-made software was used to generate 3D patient-specific ventricular models in a prospective cohort of post-infarct patients (n=40) having undergone LGE imaging pre-ICD implantation. The extent of variation in scar-characteristics was evaluated in ADAS by quantifying the BZ, scar core, the number and weight of conduction corridors i.e. BZ surrounded by scar core. Custom-written scripts were used to calculate metrics describing the 3D topology of the scar substrate, specifically the interface area between myocardium and total enhancement (BZ+core), and the interface between BZ and core. These metrics were compared with ICD therapy during follow-up. Results Total corridors were comparable between both groups (6.53 ± 7.9 vs. 4.6 ± 4, p = .38). Corridor weight demonstrated a trend towards higher mass in the event group (2.7 ± 2.1g vs. 1.6 ± 1.4g, p = .06). Patients with an event (n=17) had higher myocardium-total enhancement interface (103.8±35.1cm2 vs. 77.4±33.7cm2, p=.021) and BZ-core interface (76±27.5cm2 vs. 55.2±27.6cm2, p=.024). Cox-regression demonstrated a significant independent association of myocardium-total enhancement interface with an event (HR 2.79; 1.44-5.44, p &amp;lt; .01). Kaplan-Meier analysis showed a significantly higher event rate in patients with an interface area between myocardium-total enhancement of more than 72cm2 (Figure 1A) and BZ-core more than 42.3cm2 (Figure 1B). Conclusion These results demonstrate that patients with appropriate device therapy had larger myocardium-total enhancement and BZ-core surface interface areas. Conceptually, the BZ-core interface could be considered to be related to the reentrant circuit path-length whilst the myocardium-total enhancement interface reflects the surfaces most-likely to initiate unidirectional block, both of which can be consider pro-arrhythmic substrates. These findings emphasize the importance of visualizing and thereby characterizing substrate as a 3D entity instead of the currently applied 2D approach to facilitate early identification of high-risk patients.

Arrhythmic risk stratification in non-ischaemic dilated cardiomyopathy.

Dilated cardiomyopathy is a primary disease of the heart muscle, which affects relatively young patients with a low comorbidity profile. It is characterized by structural and/or functional abnormalities leading to systolic dysfunction of the left ventricle or of both ventricles, often associated with dilatation, in the absence of an ischaemic, valvular, or pressure overload cause sufficient to explain the phenotype. Although the prognosis of the disease has greatly improved over the last few decades, prognostic stratification remains a fundamental objective, especially about the prediction of potentially life-threatening arrhythmic events. An accurate diagnostic work-up and an appropriate aetiopathogenetic characterization affect the patients' outcome and represent the essential basis of an adequate prognostic stratification. It is necessary to adopt a multiparametric approach, especially when the aim is the prediction of arrhythmic risk; it includes an integration of medical history and physical examination with cardiac imaging and genetic testing, in order to obtain a personalized diagnosis and therapeutic strategies. Furthermore, the evaluation should be repeated at every clinical check-up, considering the dynamic trend of the pathology and the arrhythmic risk changes over time. This article aims to illustrate how, starting from an exhaustive aetiological and clinical-instrumental characterization, including all diagnostic methods available at present time, it is possible to obtain a tailored diagnostic evaluation and stratification of the arrhythmic risk as accurate as possible.

Real-World Use and Predictors of Response to Disopyramide in Patients with Obstructive Hypertrophic Cardiomyopathy

Background: Although disopyramide has been widely used to reduce left ventricular outflow obstruction (LVOTO) and to improve symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM), its use in real world as well as patient characteristics associated with a positive treatment response are still unclear. Methods: From 1980 to 2021, 1527 patients with HCM were evaluated and 372 (23%) had a LVOTO with active follow-up. The efficacy and safety of disopyramide were assessed systematically during 12 months (2-, 6-, and 12-month visits). Responders were patients with a final NYHA = I and a LVOTO < 30 mmHg; incomplete responders were those patients with NYHA > I and a LVOTO < 30 mmHg; and non-responders were symptomatic patients with no change in functional class NYHA and a LVOT gradient > 30 mmHg. Results: Two-hundred-fifty-four (66%) patients were in functional class NYHA I/II and 118 (34%) in NYHA III/IV. A total of 118/372 (32%, 55 ± 16 years) underwent disopyramide therapy. Twenty-eight (24%) patients responded to therapy, 39 (33%) were incomplete responders, and 51 (43%) did not respond. Responder were mainly patients in functional NYHA class I/II (24/28, 86%), whereas incomplete responders and non-responders were more often in functional NYHA class III/IV (50/54 (93%)). An independent predictor of response to disopyramide treatment was the presence of NYHA I/II at the initiation of therapy (HR 1.5 (95% CI 1.1-4.5), p = 0.03). No major life-threatening arrhythmic events or syncope occurred, despite 19 (16%) patients showing reduced QTc from baseline, 19 (16%) having no difference, while 80 (69%) patients had prolonged QTc interval. Thirty-one (26%) patients experienced side effects, in particular, 29 of the anticholinergic type. Conclusions: Disopyramide was underused in oHCM but effective in reducing LVOTO gradients and symptoms in slightly symptomatic patients with less severe disease phenotype with a safe pro-arrhythmic profile.

Arrhythmic Manifestations of Cardiac Amyloidosis: Challenges in Risk Stratification and Clinical Management

Amyloidosis is a systemic disease characterized by extracellular deposits of insoluble amyloid in various tissues and organs. Cardiac amyloidosis is a frequent feature of the disease, causing a progressive, restrictive type of cardiomyopathy, and is associated with adverse clinical outcomes and increased mortality. The typical clinical presentation in patients with cardiac amyloidosis is heart failure (HF) with preserved ejection fraction. Most patients present with typical symptoms and signs of HF, such as exertional dyspnea, pretibial edema, pleural effusions and angina pectoris due to microcirculatory dysfunction. However, patients may also frequently encounter various arrhythmias, such as atrioventricular nodal block, atrial fibrillation and ventricular tachyarrhythmias. The management of arrhythmias in cardiac amyloidosis patients with drugs and devices is often a clinical challenge. Moreover, predictors of life-threatening arrhythmic events are not well defined. This review intends to give a deepened insight into the arrhythmic features of cardiac amyloidosis by discussing the pathogenesis of these arrhythmias, addressing the challenges in risk stratification and strategies for management in these patients.

Clinical Features, Genetic Findings, and Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy: Data From a Brazilian Cohort.

Arrhythmogenic right ventricular cardiomyopathy (ARVC), a rare inherited disease, causes ventricular tachycardia, sudden cardiac death, and heart failure (HF). We investigated ARVC clinical features, genetic findings, natural history, and the occurrence of life-threatening arrhythmic events (LTAEs), HF death, or heart transplantation (HF-death/HTx) to identify risk factors. The clinical course of 111 consecutive patients with definite ARVC, predictors of LTAE, HF-death/HTx, and combined events were analyzed in the entire cohort and in a subgroup of 40 patients without sustained ventricular arrhythmia before diagnosis. The 5-year cumulative probability of LTAE was 30% and HF-death/HTx was 10%. Predictors of HF-death/HTx were reduced right ventricle ejection fraction (HR: 0.93; P=0.010), HF symptoms (HR: 4.37; P=0.010), epsilon wave (HR: 4.99; P=0.015), and number of leads with low QRS voltage (HR: 1.28; P=0.001). Each additional lead with low QRS voltage increased the risk of HF-death/HTx by 28%. Predictors of LTAE were prior syncope (HR: 1.81; P=0.040), number of leads with T wave inversion (HR: 1.17; P=0.039), low QRS voltage (HR: 1.12; P=0.021), younger age (HR: 0.97; P=0.006), and prior ventricular arrhythmia/ventricular fibrillation (HR: 2.45; P=0.012). Each additional lead with low QRS voltage increased the risk of LTAE by 17%. In patients without ventricular arrhythmia before clinical diagnosis of ARVC, the number of leads with low QRS voltage (HR: 1.68; P=0.023) was independently associated with HF-death/HTx. Our study demonstrated the characteristics of a specific cohort with a high prevalence of arrhythmic burden at presentation, male predominance, younger age and HF severe outcomes. Our main results suggest that the presence and extension of low QRS voltage can be a risk predictor for HF-death/HTx in ARVC patients, regardless of the arrhythmic risk. This study can contribute to the global ARVC risk stratification, adding new insights to the international current scientific knowledge.

Abstract 15723: Risk Factors for Beta-Blockers Failure in Catecholaminergic Polymorphic Ventricular Tachycardia

Introduction: Patients with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) may experience life-threatening arrhythmic events (LAE) despite standard-of-care treatment with beta-blockers (BB), but risk stratification is not well defined. Hypothesis: Both clinical and genetic risk factors predispose to BB failure, including the class of BBs (β1-selective vs. non-selective). Methods: LAE was defined as the composite of sudden cardiac death, aborted cardiac arrest, or hemodynamically non-tolerated ventricular tachycardia. We fitted a Cox proportional hazards regression model with multiple events during BB treatment only with the following explanatory covariates: 1) LAE before diagnosis, 2) unexplained syncope before diagnosis, 3) genotype, and 4) type of BB (as time-dependent variable). Results: We included n=238 CPVT patients: n=135 (57%) probands, n=134 (56%) females, n=216 (91%) RYR2, n=10 (4%) CASQ2, n=5 (2%) RYR2-Loss-of-Function, n=4 (2%) TRDN and n=3 (1%) TECRL. Before the diagnosis, 48/238 (20%) patients experienced an LAE, while 110/238 (46%) patients experienced an unexplained syncope. During a mean follow-up of 9.7±7.6 years of treatment with BB only, 35/238 (15%) patients experienced one or more LAEs (annual rate 4.0%, 95% CI: 3.1%-5.0%), with a mean of 2.1±2.4 LAEs per patient. Multivariable analysis with multiple events at follow-up showed that LAE before diagnosis (HR 3.9; 95%CI: 2.3-6.8; p&lt;0.001), syncope before diagnosis (HR 2.7; 95%CI: 1.5-5.0; p=0.001), TRDN mutations (HR 10.9; 95%CI: 4.2-28.0; p&lt;0.001) and use of β1-selective BBs (HR 3.0; 95%CI: 1.7-5.3; p&lt;0.001) were significantly associated with the occurrence of LAE (Figure). Conclusions: In patients with CPVT, history of LAE and/or unexplained syncope before diagnosis, TRDN mutations and the use of selective BBs are independent risk factors for the occurrence of multiple LAEs at follow-up during BB treatment.

Abstract 15666: Survival Benefit of Implantable Cardioverter Defibrillators in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

Introduction: The effectiveness of implantable cardioverter-defibrillators (ICDs) in reducing mortality in patients with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is debated.Hypothesis. The ICD confers survival benefit in patients with CPVT. Methods: We included n=238 genotype-proven CPVT patients, of whom 91 (38%) had an ICD implanted. All patients were treated with beta-blocker (BB) monotherapy. Survival probability at the occurrence of a first Life-threatening Arrhythmic Event (LAE, defined as: sudden cardiac death, aborted cardiac arrest or hemodynamically non-tolerated ventricular tachycardia) was compared between ICD carriers and non-ICD carriers. In ICD carriers, the benefit-to-harm ratio (rate of appropriate shocks on LAE over rate of major complications) was investigated. Results: During 1,643 person-years of follow-up, 35/238 (15%) patients experienced a first LAE on BB monotherapy (annual LAE rate 2.1%, 95%CI: 1.5-3.0%). Of the 35 individuals who experienced an LAE, 23 patients had an ICD when the LAE occurred, and all survived after ICD shock. Of the remaining 12 patients who were not carriers of an ICD, 4/12 (33%) died suddenly, 2/12 (17%) survived but suffered anoxic brain injury, while 6/12 (50%) survived without consequences. The probability of dying at the occurrence of a first LAE was 25-fold higher (OR: 24.9, 95% CI: 1.2-513.0; p=0.037) in patients without an ICD, as compared to patients with an ICD. Major complications occurred in 17/91 (19%) patients with an ICD (2.6% per year, 95%CI: 1.5%-4.1%). Comparing the rate of major complication to the rate of appropriate ICD shocks on LAE (LAE rate 5.2% per year, 95%CI: 3.5-7.4%), the benefit-to-harm ratio was 2, favoring the benefit of ICD therapy. Conclusion: The ICD conferred a significant survival benefit in terms of arrhythmic mortality at the occurrence of the first LAE in BB monotherapy.

Abstract 15656: Genotype-Specific Natural History of Catecholaminergic Polymorphic Ventricular Tachycardia

Background: Based on the genetic background, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) has been recently classified in “typical” (RYR2 and CASQ2) and “atypical” (TRDN, TECRL, CALM1-3, RYR2 loss-of-function [RYR2-LoF]), but genotype-specific outcome is unknown.Hypothesis. We aimed to describe genotype-specific outcomes of patients with “typical” and “atypical” CPVT before treatment. Methods: Patients were classified in: 1) “Typical” CPVT (RYR2, CASQ2); 2) “Atypical” CPVT (TRDN, TECRL, CALM1-3 and RYR2-LoF). We assessed the occurrence of a first life-threatening arrhythmic event (LAE; sudden cardiac death, aborted cardiac arrest or hemodynamically non-tolerated ventricular tachycardia) before the initiation of therapy. We used the Kaplan-Meier life-table method and the log-rank test to compare the cumulative probability of experiencing a first LAE by the age of 40 years in the absence of treatment. Results: We included 238 patients (56% females, median age 14 years [IQR: 9-28 years]): 226/238 (95%) patients with “typical” CPVT (216 RYR2, 10 CASQ2), and 12/238 (5%) patients with “atypical” CPVT (5 RYR2-LoF, 4 TRDN, 3 TECRL). Interestingly, in 47% of probands the RYR2 variant was likely de novo. No patients experienced an LAE in the first year of age, but patients with atypical CPVT had an increased probability to experience a LAE by the age of 5 years (3/5, 60%), as compared with patients with typical CPVT (2/43, 5%; OR 30.8; p=0.003). In half of patients with LAE (23/48; 48%), the occurrence of LAE was the first clinical manifestation of CPVT. Overall, the probability to experience an LAE by the age of 40 years in the absence of treatment was higher in patients with atypical CPVT (100%), as compared to patients with typical CPVT (39%; p=0.003, Figure). Conclusions: Patients with atypical variants of CPVT are at increased risk to experience an LAE before treatment, especially during early childhood.

Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance.

Variants in KCNH2, encoding the human ether a-go-go (hERG) channel that is responsible for the rapid component of the cardiac delayed rectifier K+ current (IKr), are causal to long QT syndrome type 2 (LQTS2). We identified eight index patients with a new variant of unknown significance (VUS), KCNH2:c.2717C > T:p.(Ser906Leu). We aimed to elucidate the biophysiological effect of this variant, to enable reclassification and consequent clinical decision-making. A genotype-phenotype overview of the patients and relatives was created. The biophysiological effects were assessed independently by manual-, and automated calibrated patch clamp. HEK293a cells expressing (i) wild-type (WT) KCNH2, (ii) KCNH2-p.S906L alone (homozygous, Hm) or (iii) KCNH2-p.S906L in combination with WT (1:1) (heterozygous, Hz) were used for manual patching. Automated patch clamp measured the variants function against known benign and pathogenic variants, using Flp-In T-rex HEK293 KCNH2-variant cell lines. Incomplete penetrance of LQTS2 in KCNH2:p.(Ser906Leu) carriers was observed. In addition, some patients were heterozygous for other VUSs in CACNA1C, PKP2, RYR2 or AKAP9. The phenotype of carriers of KCNH2:p.(Ser906Leu) ranged from asymptomatic to life-threatening arrhythmic events. Manual patch clamp showed a reduced current density by 69.8 and 60.4% in KCNH2-p.S906L-Hm and KCNH2-p.S906L-Hz, respectively. The time constant of activation was significantly increased with 80.1% in KCNH2-p.S906L-Hm compared with KCNH2-WT. Assessment of KCNH2-p.S906L-Hz by calibrated automatic patch clamp assay showed a reduction in current density by 35.6%. The reduced current density in the KCNH2-p.S906L-Hz indicates a moderate loss-of-function. Combined with the reduced penetrance and variable phenotype, we conclude that KCNH2:p.(Ser906Leu) is a low penetrant likely pathogenic variant for LQTS2.

Assessment of absolute risk of life-threatening cardiac events in long QT syndrome patients.

BackgroundRisk stratification in long QT syndrome (LQTS) patients is important for optimizing patient care and informing clinical decision making. We developed a risk prediction algorithm with prediction of 5-year absolute risk of the first life-threatening arrhythmic event [defined as aborted cardiac arrest, sudden cardiac death, or appropriate implantable cardioverter defibrillator (ICD) shock] in LQTS patients, accounting for individual risk factors and their changes over time.MethodsRochester-based LQTS Registry included the phenotypic cohort consisting of 1,509 LQTS patients with a QTc ≥ 470 ms, and the genotypic cohort including 1,288 patients with single LQT1, LQT2, or LQT3 mutation. We developed two separate risk prediction models which included pre-specified time-dependent covariates of beta-blocker use, syncope (never, syncope while off beta blockers, and syncope while on beta blockers), and sex by age < and ≥13 years, baseline QTc, and genotype (for the genotypic cohort only). Follow-up started from enrollment in the registry and was censored at patients’ 50s birthday, date of death due to reasons other than sudden cardiac death, or last contact, whichever occurred first. The predictive models were externally validated in an independent cohort of 1,481 LQTS patients from Pavia, Italy.ResultsIn Rochester dataset, there were 77 endpoints in the phenotypic cohort during a median follow-up of 9.0 years, and 47 endpoints in the genotypic cohort during a median follow-up of 9.8 years. The time-dependent extension of Harrell’s generalized C-statistics for the phenotypic model and genotypic model were 0.784 (95% CI: 0.740–0.827) and 0.785 (95% CI: 0.721–0.849), respectively, in the Rochester cohort. The C-statistics obtained from external validation in the Pavia cohort were 0.700 (95% CI: 0.610–0.790) and 0.711 (95% CI: 0.631–0.792) for the two models, respectively. Based on the above models, an online risk calculator estimating a 5-year risk of life-threatening arrhythmic events was developed.ConclusionThis study developed two risk prediction algorithms for phenotype and genotype positive LQTS patients separately. The estimated 5-year absolute risk can be used to quantify a LQTS patient’s risk of developing life-threatening arrhythmic events and thus assisting in clinical decision making regarding prophylactic ICD therapy.