Life-threatening Ventricular Arrhythmias Research Articles

Arrhythmogenic Right Ventricular Dysplasia Presenting with Sustained Ventricular Tachycardia: A Case Report

Arrhythmogenic right ventricular dysplasia (ARVD) is a cardiomyopathy characterized pathologically by fibrofatty tissue replacement of the myocyte of the right ventricle (RV) and clinically by life-threatening ventricular arrhythmias in young people. It is a major cause of sudden death. We present the case of a 60-year-old man with cardiovascular risk factors, was admitted for unstable ventricular tachycardia (VT) treated immediately with synchronized cardioversion. After the stabilization of the patient, Electrocardiogram demonstrated an epsilon wave in precordial leads and diffuse T-wave inversions. Transthoracic echocardiography revealed a dilated, hypokinetic right ventricle with moderately reduced function and a focal area of dyskinesia. The diagnosis of arrhythmogenic right ventricular dysplasia (ARVD) was made and an implantable cardioverter defibrillator (ICD) was indicated for secondary prevention. This case report will present the clinical presentation, diagnosis and management of this rare disease.

A novel DSP zebrafish model reveals training- and drug-induced modulation of arrhythmogenic cardiomyopathy phenotypes

Arrhythmogenic cardiomyopathy (AC) is an inherited disorder characterized by progressive loss of the ventricular myocardium causing life-threatening ventricular arrhythmias, syncope and sudden cardiac death in young and athletes. About 40% of AC cases carry one or more mutations in genes encoding for desmosomal proteins, including Desmoplakin (Dsp). We present here the first stable Dsp knock-out (KO) zebrafish line able to model cardiac alterations and cell signalling dysregulation, characteristic of the AC disease, on which environmental factors and candidate drugs can be tested. Our stable Dsp knock-out (KO) zebrafish line was characterized by cardiac alterations, oedema and bradycardia at larval stages. Histological analysis of mutated adult hearts showed reduced contractile structures and abnormal shape of the ventricle, with thinning of the myocardial layer, vessels dilation and presence of adipocytes within the myocardium. Moreover, TEM analysis revealed “pale”, disorganized and delocalized desmosomes. Intensive physical training protocol caused a global worsening of the cardiac phenotype, accelerating the progression of the disease. Of note, we detected a decrease of Wnt/β-catenin signalling, recently associated with AC pathogenesis, as well as Hippo/YAP-TAZ and TGF-β pathway dysregulation. Pharmacological treatment of mutated larvae with SB216763, a Wnt/β-catenin agonist, rescued pathway expression and cardiac abnormalities, stabilizing the heart rhythm. Overall, our Dsp KO zebrafish line recapitulates many AC features observed in human patients, pointing at zebrafish as a suitable system for in vivo analysis of environmental modulators, such as the physical exercise, and the screening of pathway-targeted drugs, especially related to the Wnt/β-catenin signalling cascade.

Amiodarone: Is it Safe in Stress Cardiomyopathy?

Amiodarone is a broad-spectrum antiarrhythmic agent used in day-to-day practice to treat ventricular tachycardia (VT) and supraventricular tachycardias like atrial flutter/atrial fibrillation. 1 It can cause QT prolongation and rarely precipitate life-threatening ventricular arrhythmias like Torsade de Pointes (TdP). 1 Torsades is characterized by prolonged ventricular repolarization with QT intervals generally exceeding 500 milliseconds. 1 , 2 Risk factors for drug-induced QT prolongation are female sex, congestive heart failure, and so on. 2 This case report describes a woman with stress cardiomyopathy 3 and atrial fibrillation who was treated with Amiodarone which precipitated Torsades. Therefore knowledge of side effects, monitoring for drug effects, and timely withdrawal of the offending drug is important. 2

Neurohormonal status is associated with long-term appropriate implantable cardioverter defibrillator therapy for life-threatening ventricular arrhythmia

Abstract Background Neurohormonal status is associated with the risk of life-threatening ventricular arrhythmia. Purpose We aimed to assess whether neurohormonal status in patients with an implantable cardioverter defibrillator (ICD) is correlated with the risk of long-term appropriate shock or overdrive delivered by the ICD for life-threatening arrhythmia. Methods A total of 331 clinically stable patients with ICD without any past history of shock or overdrive for life-threatening ventricular arrhythmia were enrolled in a two-center prospective cohort and followed up for a median time of 7.9 years. At enrolment, patients’ medical history, treatment, clinical and imaging data were recorded and, blood and, blood samples were drawn for the assessment of standard biological parameters as well as 3 neurohormones (aldosterone, A type NT-pro-Atrial natriuretic peptide (ANP) and MR-pro-Adrenomedullin (ADM). The primary endpoint of the study was the occurrence of appropriate shock or overdrive delivered by the ICD (ICD therapy). A multivariable cox model adjusted on age, gender, primary or secondary prevention ICD as well as all baseline variables unequally distributed between groups with or without ICD therapy was used for the assessment of the relationship between the 3 neurohormones and the primary endpoint. Results The population consisted of patients with a mean age of 60±15 years, among which 59(18%) women and 160(48%) with a secondary prevention indication for ICD. At baseline all data were similar between patients with or without ICD therapy with the exception of weight, systolic blood pressure, left ventricular ejection fraction (LVEF) and serum potassium and creatinine levels. No other variable, including MADIT and SHOCKED score were significantly associated with the risk of ICD therapy. Death was recorded in 114(34%) patients and a total of 78(24%), 76(23%) and 106(33%) patients had appropriate shock, overdrive and ICD therapy respectively during the follow-up. On multivariable analysis, highest levels of ANP and lowest levels of ADM but not aldosterone were independently associated with life-threatening ventricular arrhythmia requiring ICD therapy (table). Other correlates of ICD therapy were lower LVEF and, higher weight, serum potassium and creatinine concentrations. ANP and ADM had a stepwise additive impact on the risk of ICD therapy. (Figure 1) Conclusions In a stable all comer population with ICD and no history of ICD therapy, blood levels of neurohormones ANP and ADM are associated with the risk of life-threatening ventricular arrhythmia requiring ICD-delivered shock or overdrive independent of other correlates. ANP and ADM concentrations may be useful in identifying patients at high risk of such arrhythmia and who may most benefit from ICD implantation.

Single-nucleus RNA sequencing of TMEM43 induced arrhythmogenic cardiomyopathy reveals altered cell compositions and transcriptional states in mice

Abstract Introduction and purpose TMEM43 induced Arrhythmogenic cardiomyopathy, also referred to as arrhythmogenic cardiomyopathy type 5 or ACM5, is caused by a point mutation in TMEM43 (p.S358L). The disease is characterised by chamber dilation and a progressive dystrophy of the ventricular myocardium causing life-threatening ventricular arrhythmias and sudden cardiac death. Loss of cardiomyocytes and fibrofatty replacement of the myocardium is clearly observed in our transgenic mouse model of ACM5 overexpressing TMEM43-S358L in postnatal cardiomyocytes. However, the mechanisms underlying cardiomyocyte death and fibroblast activation remain elusive, precluding the development of effective therapeutic options. Here we applied the state-of-the-art analysis on single-nucleus RNA sequencing (snRNA-seq) to characterise the cellular compositions and molecular states in ACM5 mouse hearts. Methods Left ventricular heart tissues of severely affected ACM5 mice and their corresponding transgenic controls overexpressing wild-type TMEM43 were used for snRNA-seq analysis. We identified 10 major cell types, which aggregated into 23 distinct clusters on the basis of transcriptional similarity. Results ACM5 nuclei showed significant depletion of cardiomyocytes and expanded populations of fibroblasts and myeloid cells. Fibroblasts from mutant mice acquired an activated phenotype related to remodelling of the extracellular matrix with a large number of genes like LOX, POSTN, NOX4 or COL1A1 significantly upregulated. In addition, the mutant cardiomyocytes showed altered transcriptional states characterized by cardiac stress and heart failure markers such as NPPB or MYH7. Interestingly, we were able to identify a cluster of mutant cardiomyocytes with a highly apoptotic profile. This cluster is also enriched in genes related to the unfolding protein response (UPR) stress sensors and the DNA damage response (DDR), elucidating a new potential mechanism of myocyte death in ACM5. Furthermore, heterogeneity of the myeloid populations is also observed. The number of tissue resident macrophages is increased in mutant samples and myeloid cells show additional disease-associated transcriptional states that are almost entirely absent in control samples. Conclusion Together these data illuminated shared and distinct cell and molecular architectures of ACM5 in mouse hearts. Further confirmation on diverse gene expression profiles like the UPR and DDR pathways related to cardiomyocyte death will establish a valuable resource to explore novel therapeutic targets and personalized therapies for ACM5.

Arrhythmogenic cardiomyopathy phenotype associated with the pathogenic founder variant c.1211dup in PKP2

Abstract Background Arrhythmogenic cardiomyopathy results in life-threatening ventricular arrhythmia and heart failure. Phenotypic features vary according to genetic aetiology. Genotype-phenotype research is therefore crucial for patient counselling and treatment decisions such as implantable cardioverter defibrillator therapy. By collecting data from patient records we characterized the clinical phenotype associated with variant c.1211dup (p.Val406Serfs*4) in the plakophilin-2 gene (PKP2), common in the Dutch population. Purpose We aimed to investigate the incidence of ventricular arrhythmia and heart failure in families carrying the PKP2 c.1211dup variant. Furthermore, we aimed to determine the founder status of this variant, and compare phenotype severity with other truncating PKP2 variants. Methods Clinical data were collected retrospectively from medical records of 106 PKP2 c.1211dup heterozygous carriers (>85% of known carriers in The Netherlands) in a Castor EDC database. Using occurrence of ventricular arrhythmia and heart failure, event-free survival was compared between males and females, and probands and family members, using log-rank tests. Using data from a central curated arrhythmogenic cardiomyopathy database, c.1211dup was compared to three other truncating PKP2 variants (c.235C>T (p.Arg79*), c.397C>T (p.Gln133*) and c.2489+1G>A (p.?)) on ventricular arrhythmia-free survival by a Cox proportional hazards model, corrected for sex and proband status. Results Forty-seven carriers (44%) were diagnosed with arrhythmogenic cardiomyopathy at 41 years on average. As shown in figure 1, 29 participants (27%) experienced episodes of ventricular arrhythmia and 12 (11%) developed heart failure, with male carriers showing significantly higher risks than females on both endpoints (p<0.05). Based on available magnetic resonance imagery and echocardiographic data, 46% of carriers showed either right ventricular dilatation and/or dysfunction, and a substantial minority of 37% showed some form of left ventricular involvement. Both geographical distribution of carriers (figure 2) and haplotype analysis suggested PKP2 c.1211dup to be a founder variant originating from the South-Western coast of the Netherlands. Finally, a Cox proportional hazards model suggested significant differences in ventricular arrhythmia-free survival between four PKP2 truncating founder variants, including c.1211dup. Conclusions The PKP2 c.1211dup variant is a Dutch founder variant associated with a typical right ventricular-dominant arrhythmogenic cardiomyopathy phenotype, but also notable left ventricular involvement. Males were most susceptible to the frequent ventricular arrhythmia, and less frequent heart failure was observed in general. Finally, c.1211dup possibly leads to a more severe phenotype than other Dutch PKP2 founder variants.Phenotype onset stratified by sexGeographic distribution carriers

Insights on Titin cardiomyopathy: from truncating variants site to phenotypic expression and outcomes

Abstract Background Titin truncating variants (TTNtv) represent the most prevalent genotype underlying dilated cardiomyopathy (DCM). Recent molecular studies provided initial evidence about distinct pathogenic mechanisms of different protein truncating sites (A-band vs non-A-band), possibly related to the presence or absence of truncated peptides. Yet, clinical studies on TTNtv-DCM failed to demonstrate any relevant clinical difference according to the band affected. We hypothesized this lack of distinction could be due to the selection bias of including only DCM patients. Thus, we studied the clinical phenotypes and outcomes of our entire population of TTNtv carriers, regardless of phenotypic expression at onset. Methods We retrospectively analysed a population of pathogenic TTNtv carriers, enrolled in our referral centre. TTNtv were classified according to their site (Z disk, I band, A band, A-M junction, M band) and further grouped for analysis in A-band and non-A band. Kaplan-Meier curves were estimated for the primary composite endpoint of all-cause mortality and heart transplant (HTx); while cumulative incidence functions were estimated for the two secondary endpoints (i) heart failure-related death, heart transplantation, or destination left ventricular assist device implantation (LVAD) and (ii) first major ventricular arrhythmia (MVA, defined as sudden death or life-threatening ventricular arrhythmia), compared by Gray’s test. Analyses were then repeated adding an independent cohort of TTVtv carriers from another tertiary centre. Results 161 TTNtv carriers were included in the study (79% A-band, 21% non-A band), 63% were probands. The most prevalent phenotype was DCM (92%). Mean age at diagnosis was 43±16 years and 68% were males. There was no difference between groups in the primary composite outcome nor in the secondary composite endpoint of heart failure-related death, HTx or destination LVAD. Instead, MVA were significantly more frequent in the non-A-band group, in which 45% (n=15) of TTNtv carriers experienced MVA as compared to 17% (n=20) of subjects in the A-band group (p=0.001). Interestingly, we observed a tendency in MVA occurring at a higher mean left ventricular ejection fraction (LVEF) in the non-A-band group as compared to the A-band group (42±13% vs 35±9%, respectively). Furthermore, there was no significant association between MVA and LVEF at the event in the non-A group, while this association was significant in A-band (p=0.03). When an external population of 22 TTNtv carriers (95% DCM, 77% A-band) was added for analysis, this secondary outcome was confirmed (p<0.001). Conclusions Among TTNtv carriers referred to two tertiary centres, those with a mutation in the non-A band seem characterized by higher arrhythmic risk, occurring independently from EF. This novel finding highlights the importance of considering the site of TTN truncating variants to guide the most appropriate clinical management for each patient.Fig 1.Secondary Outcome, arrhythmic risk

Arrhythmic form of mitral valve prolapse: presentation, risk stratification and management

Abstract Background Mitral valve prolapse (MVP) is a common finding that has been considered as benign condition for a long time. However, some anatomic forms have been recently recognized to be associated with life-threatening ventricular arrhythmia and sudden cardiac death (SCD), recently known as arrhythmic MVP (AMVP). Objectives This study is aiming to clinically characterize and risk stratify patients with malignant phenotype of MVP of high risk for ventricular arrhythmia which may lead to SCD. We aim to explore characteristics and assess potential markers for MVP induced ventricular arrhythmia that might need monitoring and follow up with medical or invasive treatment as implantable cardioverter-defibrillator, catheter ablation or even surgical repair. Methods A prospective cohort study of 45 (age 35±8, 29 females), consecutive patients with MVP and/or mitral annular disjunction (MAD) and comprehensive clinical arrhythmia on resting electrocardiography (ECG) or 48-hours Holter monitoring , Doppler echocardiography and contrast based cardiac magnetic resonance (CMR) characterization were identified. Patients were followed-up for a period of maximum one year to identify any further management needed. Results Frequent ventricular arrhythmia was evidently seen associated to MVP (69% with at least ventricular ectopy ≥5%), as well as complex ventricular arrhythmia (31% with sustained or non-sustained ventricular tachycardia ) P<0.001. AMVP was strongly associated with premature ventricular contractions (PVCs) having Right bundle branch block (RBBB) morphology on ECG and late gadolinium enhancement (LGE) on CMR (all p<0.05). Furthermore, it was shown to be associated with bileaflet prolapse and higher left ventricular volumes, however not statistically significant. On Follow-up, Out of 36 patients with ventricular arrhythmia, 64% were controlled on medical anti-arrhythmic and some others were referred either for ablation after worsening of symptoms despite of medical treatment (27.8%), implantable cardioverter-defibrillator device for secondary VT prophylaxes (5.6%) or surgery (2.8%) due to progression in mitral regurgitation severity and deterioration of symptoms. Conclusion In this small cohort study, characteristic form of MVP was found to be associated with ventricular arrhythmia more common in the form of frequent PVCs and less common in the complex form. Although majority of patients were controlled on medical treatment, few patients required further invasive management despite of medical treatment . Thus, arrhythmia associated with a special form of MVP could be life threatening and needs close monitoring, long follow-up and proper management approach to prevent SCD. Large prospective studies with comprehensive approach and long term follow up is pivotal. CMR T1 mapping and electro anatomical CARTO mapping could help in better detection and proper defining of arrhythmia substrate in future studies.AMVP illustration

Arrhythmic risk stratification of filamin C truncating variants carriers

Abstract Background Truncating variants in Filamin C (FLNCtv) are a rare cause of cardiomyopathy with heterogeneous phenotypic presentation and high incidence of life-threatening ventricular arrhythmias, including sudden cardiac death (SCD). Nevertheless, there is a residual gap in the definition of solid risk markers for the stratification of arrhythmic risk and the significance of conventional predictors (i.e. left ventricular ejection fraction [LVEF]) remains extremely controversial. Purpose The aim of this study was to analyze the risk profile and to identify the factors associated with increased risk of life-threatening arrhythmias in an international multicenter cohort of FLNCtv carriers. Methods Patients were retrospectively collected from 19 international tertiary care centers for genetic cardiomyopathies. Primary endpoint was SCD/major ventricular arrhythmias (MVA, i.e. sustained ventricular tachycardia and appropriate implantable cardioverter defibrillator [ICD] shocks). Multivariate Cox regression analysis was performed to identify the predictors of SCD/MVA, taking into account non-sudden cardiac death/heart transplant/destination left ventricle assist device as competing event and including family clusters in the model as clustering factor. Results Among the 326 included carriers (median age 45 years, IQR 33-57; 51% males), 120 (37%) were probands. 100 (31%) carriers had no clinical signs of overt disease; for the others, phenotypic presentation was heterogeneous (36% dilated cardiomyopathy, 17% arrhythmogenic left dominant cardiomyopathy, 4% arrhythmogenic right or biventricular cardiomyopathy, 11% minor phenotype). Median LVEF was 51% (IQR 35%-59%, 41% had LVEF<50%), 16% had right ventricle dysfunction. During a median follow-up of 32 months (IQR 8-63), 60 carriers (18%) experienced SCD/MVA (65% probands, 97% with overt disease, median age at event 48 years, IQR 38-64, min-max 18-78). Among variables associated with the risk of SCD/MVA at univariable analysis, male sex, previous syncope and non-sustained ventricular tachycardia maintained a significant association with the primary outcome at multivariable analysis (Table), whereas there was no significant association between LVEF and the risk of SCD/MVA neither as a continuous nor categorical (i.e. LVEF<50%) variable. In the subgroup of 175 patients with available cardiac magnetic resonance, 57% had late gadolinium enhancement with no significant association with the outcome. Conclusions In the largest worldwide cohort of FLNCtv carriers the high risk of SCD/MVA was confirmed. Three important factors emerged to be associated with higher arrhythmic risk and should be considered for decisions on ICD implantation. Remarkably, LVEF was not significantly associated with SCD/MVA risk. The higher risk observed in males compared with females advocates for prompt investigations on the influence of sex-related factors on the disease expression in genetic cardiomyopathies.

Burden and causes of sudden cardiac arrest in children: implications for preparticipation screening

Abstract Introduction Competitive sports activity may increase the risk of life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in athletes with underlying cardiovascular diseases (CVD). Preparticipation screening (PPS) offers the potential to early identify CVD and reduce this risk, but the optimal age of sport PPS start is not known. Purpose The aim of this study is to assess the burden of sudden cardiac arrest (SCA) and the diagnostic yield of PPS for CVD at risk of SCA in two different age groups: 8-11 year-old and 12-15 year-old. Methods Data on the incidence and causes of SCA from 2011 to 2020 were retrieved from the sudden death registry of our region, hospital records and local press. During the same period, we assessed 25,251 young competitive athletes aged 8-15 years who underwent 58,185 annual PPS (mean 2.3/athlete) including history, physical examination, ECG and exercise testing. Further tests were required in case of abnormalities at first-line screening. Results Over 10 years, 21 sudden deaths and 5 resuscitated SCA occurred: 6 in athletes (incidence 0.7/100.000/year) versus 20 in non-athletes (0.7/100.000/year). 67% athletes versus 5% non-athletes who suffered SCA were successfully resuscitated (aborted sudden cardiac death=aSCD), (results according to the age-group in Figure 1). Idiopathic ventricular fibrillation was the most common diagnosis accounting for 14/26 (54%) cases. The incidence of SCA was 0.2/100.000/year in the age group 8-11 year-old versus 1.3/100.000/year in the age group 12-15 year-old. By PPS, 26 (0.1%) athletes received a diagnosis of at-risk CVD, significantly more often in children ≥12 year-old (0.06%/evaluation) than <12 year-old (0.02%/evaluation, p=0.02), (Figure 2). During follow-up, 2 screened athletes suffered SCA due to idiopathic ventricular fibrillation, both ≥12 year-old at the time of PPS. Conclusions The incidence of SCA was 6 times higher in the age group 12-15 years compared with the 8-11 years group. Similarly, the diagnostic yield of PPS for at-risk CVD was significantly higher after 12 years of age. This suggests that systematic PPS may not be justified before 12 year-old.Figure 1Figure 2

Using the 3D architecture of scar to predict life-threatening ventricular arrhythmias, still a long way to go

Abstract Background Late gadolinium enhancement (LGE) has been proposed as an independent predictor of ventricular arrhythmias. Purpose The purpose of this study was to assess if myocardial scar characterization could enhance the risk stratification for life-threatening arrhythmias and sudden cardiac death (SCD). Methods We included patients with an indication for ICD or CRT-D implantation who underwent cardiac magnetic resonance for clinical proposes since February/2018 and in whom a 3D-LGE dataset was obtained. Patients with channelopathies (n=2) or inappropriate imaging quality (imaging artifacts; n=7) were excluded. Scar characterization using ADAS software was performed in 3D-LGE datasets in all but 16 patients, where 2D datasets were used. The primary endpoint was the composite of appropriate ICD therapy (classified as ATP or shock), sustained ventricular tachycardia or SCD. Results A total of 116 patients were analysed (mean age 66 ± 14 years; 81% male; mean LVEF 34 ± 14%; 74 patients with ischemic and 42 with non-ischemic cardiomyopathy; 40 patients received a device in the setting of secondary prevention). During a median follow-up of 2.3 years (IQR 1.3 – 3.3 years) there were 23 events (18 appropriate ICD therapies [9 shocks and 9 ATP], 3 episodes of VT under the threshold for ICD therapy and 2 SCD). No statistically significant differences were found between patients with or without events in terms of scar mass, border zone (BZ) mass, BZ channels (BZC), BZC mass, number of channels detected, and scar heterogeneity (BZ mass / scar mass ratio) - all p values > 0.2 – Figure. Restricting the analysis to only primary prevention cases yielded similar results. Overall, 26 patients did not show any channel. Four of these (all with non-ischemic LGE) experienced an arrhythmic event, yielding a negative predictive value of 83% (95% CI 64-93%) for the absence of channels. Conclusion In this cohort with still relatively limited follow-up duration, no single parameter reflecting scar tissue characterization was able to predict appropriate device therapies or sudden cardiac death.

Does scar burden predict sudden cardiac death in patients with cardiac resynchronization therapy? - A Systematic Review and Meta-Analysis

Abstract Background Based on latest guidelines, scar burden assessment may have a crucial role in appropriate device choice in cardiac resynchronization therapy (CRT), but no randomized controlled trials have been made yet.1 Scar burden is associated with a higher prevalence of ventricular arrhythmias (VA) and sudden cardiac death (SCD).2 Late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) can accurately evaluate the extent of myocardial scar.3. Purpose Our aim is to investigate the association between scar burden and SCD risk in cardiac resynchronization therapy patients. Methods We performed a systematic literature search on MEDLINE using the PubMed, Embase, Scopus, and CENTRAL databases. Heart failure patients with reduced ejection fraction and CRT therapy were collected. The primary endpoint was sudden cardiac death events. Meta-analyses were performed using the META and DMETAR packages in R, using a random-effects model. The risk of bias was assessed using Quips tool and the quality of evidence was evaluated using the GRADE assessment. Results 18 eligible articles have been included in our study, with a total of 2917 patients, of whom 830, 1324, and 391 have been implanted with an ICD, CRT-D, CRT-P respectively. Altogether 59,05 % of the total population were LGE-CMR positive. The average proportion of appropriate ICD shock was 15,65 % per the total population during the median follow-up time of 39,45 months. Based on the univariant analysis of 14 articles, the cumulative hazard ratio of developing sudden cardiac death events, in the scar burden positive population compared to scar burden negative was 1,95 with CI: 1,29- 2,96 p<0,001. The multivariant analysis shows the HR of 1,88 with CI: 1,20- 2,93 p<0,001. There were 4 articles using the competing risk model which is considered to be the highest evidence level. Based on that analysis we found only a trend with a HR of 1,55 CI: 0,75-2,92. Calculating from the event numbers based on 8 eligible articles, the high scar burden group had 5.55 higher odds of getting SCD events. (OR: 5.55. CI 2,52-12,22 p<0,001). Conclusion In our meta-analysis, LGE-CMR was associated with a trend toward appropriate device therapy and can identify a subgroup of patients with an increased risk of life-threatening VA. Based on our results performing an MRI before device implantation might be important to select high-risk patients for SCD.Forest plot O.R.Forest plot uni. H.R.

Bilateral Cardiac Sympathetic Denervation for Refractory Multifocal Premature Ventricular Contractions in Patients With Nonischemic Cardiomyopathy

BackgroundBilateral cardiac sympathetic denervation (BCSD) for refractory life-threatening ventricular arrhythmias is a neuromodulatory intervention targeting sympathetically driven focal or re-entrant ventricular arrhythmias. ObjectivesThis study sought to provide a more complete and successful option for intervention in patients in whom premature ventricular contraction (PVC) ablation is not feasible or has been unsuccessful. MethodsA total of 43 patients with >5% PVC burden and concomitant nonischemic cardiomyopathy (NICM) who previously failed medical and ablation therapies were referred for BCSD. All patients underwent bilateral video-assisted thoracoscopic surgical approach with T1-T4 sympathectomy. Primary effectiveness endpoints were postprocedural PVC burden resolution, improvement in left ventricular ejection fraction (LVEF), and cessation of antiarrhythmic drugs (AADs). Safety endpoints included peri- and postprocedural complications. Outcomes were assessed over a 1-year follow-up period. ResultsAmong the 43 patients who underwent BCSD, the mean age was 52.3 ± 14.7 years, 69.8% of whom were male patients. Presenting mean LVEF was 38.7% ± 7.8%, and PVC burden was 23.7% ± 9.9%. There were significant reductions in PVC burden postprocedurally (1.3% ± 1.1% post-BCSD, compared with 23.7% ± 9.9% pre-BCSD, P < 0.001) and improvements in LVEF (46.3% ± 9.5% post-BCSD, compared with 38.7% ± 7.8% pre-BCSD, P < 0.001). The rate of ICD therapies decreased from 81.4% (n = 35) to 11.6% (n = 5) (P < 0.001), leading to a significant reduction in use of AADs (100.0% to 11.6%, P < 0.001) and improvement in mean NYHA functional class (2.5 ± 0.5 to 1.4 ± 0.2, P < 0.001). Major intraoperative complications were seen in 4.7% of patients (hemothorax and chylothorax). Of the patients, 81.4% (n = 35) experienced no mortality or major complications over a 1-year follow-up period, with the remaining still within their first year postprocedure. ConclusionsBCSD is effective for the management of refractory PVCs and ventricular tachycardia who have failed previous ablation therapy.

Abstract 15511: Predictors of Polymorphic Ventricular Tachycardia and Ventricular Fibrillation in Patients With Stress Cardiomyopathy

Introduction: Polymorphic ventricular tachycardia (PVT) and ventricular fibrillation (VF) are life-threatening complications of stress cardiomyopathy (SCM) that occur in 2-10% of patients with SCM. Hypothesis: To identify which social and medical factors are associated with an increased risk of PVT and VF in patients with SCM. Methods: All consecutive patients meeting the InterTAK (international takotsubo) diagnostic criteria for stress cardiomyopathy at the Hennepin County Medical Center between January 1 st , 2010, and December 31 st , 2022, were identified from electronic medical records. Logistic regression was used to estimate the odds ratios (OR). The receiver operating characteristic curve (ROC) was plotted to identify the best QTc cutoff at admission to predict ventricular arrhythmia. Results: A total of 296 patients were included in the study, of which 27 (9.1%) experienced PVT/VF. Baseline demographics, including gender, race, and age at diagnosis, were similar to patients without PVT/VF (median age 61 years, and 66.7% were females). Patients with PVT/VF were more likely to have a history of stimulant use (22.2% vs. 8.2%, OR =3.20 p =0.023), apical (Takotsubo) variant stress cardiomyopathy (78% vs.56%, OR=2.69 p=0.038), and an ejection fraction (EF) of less than 30% on admission (63% vs. 41.5%, OR=2.39 p=0.032) ( Table 1 ). Admission QTc interval cut-off value of 490 msec had the highest sensitivity and specificity in predicting the risk of ventricular arrhythmia (AUC=0.687). Notably, all PVT/VF events occurred within 17 hours of hospital admission. Conclusion: Nealy 1 in 10 patients with SCM had life-threatening ventricular arrhythmia. The presence of severe LV systolic dysfunction, recent stimulant use, apical variant SCM, or prolonged QTc &gt; 490 msec is associated with the occurrence of PVT/VF, with the first day of hospital admission being an especially high-risk period.

Abstract 15846: Impaired Contraction and High Susceptibility to Arrhythmias in a Mouse Model of Desmoplakin-Mediated Arrhythmogenic Cardiomyopathy

Introduction: Desmoplakin (DSP) is a key protein for cardiac myocyte cell-to-cell adhesion that connects the desmosomes present in intercalated discs to the cytoplasmic network of desmin intermediate filaments. Pathogenic variants of the human DSP gene often lead to left ventricular (LV)-dominant and biventricular forms of arrhythmogenic cardiomyopathy characterized by a dilated LV, arrhythmias, and an elevated risk of sudden cardiac death. Nonetheless, the pathophysiological pathways triggered by DSP variants remain unknown. Hypothesis: We hypothesized that DSP pathogenic variants modify cardiomyocyte excitation-contraction coupling leading to life-threatening ventricular arrhythmias. Methods: We created a novel knock-in mouse model based on the human DSP p.S2859LfsX5 variant that leads to a murine protein truncated from its last 9 amino-acids. We compared one-year-old sedentary heterozygous (Dsp +/- ) animals to WT littermates and defined histologic, cellular, and molecular outcomes of the variant. Results: Western blotting revealed 50% Dsp reduction (N= 5 hearts/group; P &lt; 0.05) in mutant right ventricle (RV) indicating mutant protein instability. Histologic assessments of Dsp +/- hearts revealed LV chamber enlargement and RV wall thinning in the absence of fibrosis and lipid infiltration. Dsp +/- myocytes isolated from LV and RV free walls and field stimulated at 3 Hz exhibited 30-40% reduction in sarcomere shortening (n= 17-25 myocytes/ventricle/3-4 hearts/group; P &lt; 0.05), while their Ca 2+ handling properties remained normal. Pacing of Dsp +/- isolated myocytes (LV and RV) in the presence of (100 nmol/L) isoproterenol provoked a 20-30% increase in Ca 2+ release due to sarcoplasmic reticulum Ca 2+ overload (n= 15-20 myocytes/ventricle/3-4 hearts/group; P &lt; 0.05). Finally, surface ECGs showed that activation of the sympathetic pathway (isoproterenol + caffeine) in 6-month-old Dsp +/- mice increased mutant heart susceptibility to ventricular arrhythmias. Conclusions: The pathogenic variant p.S2859LfsX5 promotes biventricular dysfunction due to the loss in myocyte contraction capacity and catecholaminergic-mediated ventricular arrhythmias from cardiomyocyte Ca 2+ overload.

Abstract 11956: Arumenamide-787 Suppresses Arrhythmogenesis Associated With the J Wave Syndrome as Well as Hypothermia

Background: The J-wave syndromes (JWS), comprised of Brugada (BrS) and early repolarization syndromes (ERS), increase the risk of life-threatening ventricular arrhythmias in patients resulting in sudden cardiac death. There are limited therapeutic strategies to treat these life-threatening conditions. Present management is via an implantable cardioverter defibrillator and/or medication, including quinidine. However, these treatments may have serious side-effects. Thus, novel therapies are needed to treat JWS. In this study, we investigate the effects of ARumenamide-787 (AR-787) in suppressing the electrocardiographic and arrhythmic manifestations of JWS and hypothermia. Methods: We studied the effects of AR-787 on sodium current (I Na ) and the delayed-rectifier potassium current (I Kr ) in HEK-293 cells stably expressing the α- and β1-subunits of the cardiac (Na V 1.5) sodium channel or the hERG channel. In addition, we studied its effect on the transient outward potassium current (I to ) and calcium current (I Ca ) from dissociated canine ventricular myocytes, along with action potentials and ECG from coronary-perfused right (RV) and left (LV) ventricular wedge preparations. The I to agonist, NS5806, I Ca blocker, verapamil, and sodium current (I Na ) blocker, ajmaline, to induce the electrocardiographic and arrhythmic manifestations of JWS (prominent J waves/ST segment elevation, phase 2 reentry, and polymorphic VT/VF) in right and left canine ventricular wedge preparations. Results: AR-787 exerted pleiotropic effects on the cardiac ion channels. The predominant effect was an inhibition of I to and enhancement of I Na , with subtle effects to inhibit the I Kr and augment I Ca . AR-787 diminished the electrocardiographic J wave and prevented and/or suppressed all arrhythmic activity in canine RV and LV experimental models of BrS, ERS and hypothermia. We observed no arrhythmogenic effects of AR-787 on I Kr . Conclusions: Our findings point to AR-787 as a promising candidate for the pharmacologic treatment of JWS and hypothermia. AR-787 suppresses the electrocardiographic and arrhythmic manifestations of JWS and hypothermia without significant prolongation of the QT interval, as with the classic BrS drug, quinidine.

Abstract 16616: Automatic Measurement of Short-Term Variability of Repolarization Captures Modulation by Pacing on Human Intracardiac Electrograms

Introduction: Short-term variability of repolarization (STV) increases prior to ventricular arrhythmias (VA) both in humans and in animal models of VA, and is therefore a promising tool for real-time monitoring of arrhythmic risk. To integrate this concept in cardiac devices, a method to automatically determine STV on intracardiac electrograms (EGM) was developed. This STV algorithm demonstrated high efficacy in predicting life-threatening VA in animal studies, but still needs to be evaluated on human signals. Objective: To assess the performance of the novel automatic method of STV measurement on human EGMs during sinus rhythm (SR) and pacing. Methods: ECG and EGM signals with a 1 kHz sampling frequency were recorded in 14 dual chamber implantable cardioverter-defibrillator (ICD) patients during implantation (n=4) or replacement (n=10) procedures. Recordings were obtained in SR, atrial pacing at 80 beats per minute (AAI80) and atrioventricular pacing at the same frequency (DDD80). STV was calculated over 31 consecutive beats as Σ

Combined subcutaneous implantable cardioverter defibrillator and pacemaker devices in complex congenital heart disease: a single-center experienced based study.

Subcutaneous implantable cardioverter defibrillators (S-ICD) are widely accepted therapy in congenital heart disease (CHD) patients at risk of life-threatening ventricular arrhythmias or sudden cardiac death (SCD) when pacing is not required. Occasionally, pacemaker (PM)-dependent CHD patients will subsequently develop an indication for a cardioverter defibrillator. The use of S-ICD in complex CHD patients who have had already PM devices implanted implies some specific considerations, as the safety for these patients in unknown and recommendations among physicians may vary widely. We review the data and studied the indications for S-ICD in complex CHD with previous PM and discuss its usefulness in clinical practice. From a large cohort of 345 patients enrolled in the S-ICD Monaldi care registry, which encompass all the patients implanted in the Monaldi Hospital of Naples, we considered 11 consecutive complex CHD patients (10M/1F aged 40.4 ±18.4 years) who underwent S-ICD implant after a previous PM implant, from February 2015 to October 2022. Mean follow-up was 25.5 ± 22 months. All the patients showed a good compliance to the device system with no complications (infections or skin erosions). In complex CHD with already implanted PM devices, S-ICD implant appears to be a safe alternative to PM upgrading to transvenous ICD system, avoiding abandoned leads or life-threatening lead extraction. However, there are important issues with regard to testing and programming that need to be addressed at the time of implantation.

Prognostic Significance of Different Ventricular Ectopic Burdens During Submaximal Exercise in Asymptomatic UK Biobank Subjects.

The consequences of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals remain unclear. This study aimed to assess the association between PVC burdens during submaximal exercise and major adverse cardiovascular events (MI/HF/LTVA: myocardial infarction [MI], heart failure [HF], and life-threatening ventricular arrhythmia [LTVA]), and all-cause mortality. Additional end points were MI, LTVA, HF, and cardiovascular mortality. A neural network was developed to count PVCs from ECGs recorded during exercise (6 minutes) and recovery (1 minute) in 48 315 asymptomatic participants from UK Biobank. Associations were estimated using multivariable Cox proportional hazard models. Explorative studies were conducted in subgroups with cardiovascular magnetic resonance imaging data (n=6290) and NT-proBNP (N-terminal Pro-B-type natriuretic peptide) levels (n=4607) to examine whether PVC burden was associated with subclinical cardiomyopathy. Mean age was 56.8±8.2 years; 51.1% of the participants were female; and median follow-up was 12.6 years. Low PVC counts during exercise and recovery were both associated with MI/HF/LTVA risk, independently of clinical factors: adjusted hazard ratio (HR), 1.2 (1-5 exercise PVCs, P<0.001) and HR, 1.3 (1-5 recovery PVCs, P<0.001). Risks were higher with increasing PVC count: HR, 1.8 (>20 exercise PVCs, P<0.001) and HR, 1.6 (>5 recovery PVCs, P<0.001). A similar trend was observed for all-cause mortality, although associations were only significant for high PVC burdens: HRs, 1.6 (>20 exercise PVCs, P<0.001) and 1.5 (>5 recovery PVCs, P<0.001). Complex PVC rhythms were associated with higher risk compared with PVC count alone. PVCs were also associated with incident HF, LTVA, and cardiovascular mortality, but not MI. In the explorative studies, high PVC burden was associated with larger left ventricular volumes, lower ejection fraction, and higher levels of NT-proBNP compared with participants without PVCs. In this cohort of middle-aged and older adults, PVC count during submaximal exercise and recovery were both associated with MI/HF/LTVA, all-cause mortality, HF, LTVAs, and cardiovascular mortality, independent of clinical and exercise test factors, indicating an incremental increase in risk as PVC count rises. Complex PVC rhythms were associated with higher risk compared with PVC count alone. Underlying mechanisms may include the presence of subclinical cardiomyopathy.

Lifetime exercise dose and ventricular arrhythmias in patients with mitral valve prolapse.

Patients with mitral valve prolapse (MVP) have high risk of life-threatening ventricular arrhythmias (VAs). Data on the impact of exercise on arrhythmic risk in these patients are lacking. We explored whether lifetime exercise dose was associated with severe VA and with established risk factors in patients with MVP. Furthermore, we explored the circumstances at the VA event. In this retrospective cohort study, we included patients with MVP and assessed lifetime exercise dose as metabolic equivalents of task (MET) hours/week. Severe VA was defined as sustained ventricular tachycardia or fibrillation, aborted cardiac arrest, and appropriate shock by a primary preventive implantable cardioverter defibrillator. We included 136 MVP patients (48 years [interquartile range (IQR) 35-59], 61% female), and 17 (13%) had previous severe VA. The lifetime exercise dose did not differ in patients with and without severe VA (17 MET h/week [IQR 9-27] vs. 14 MET h/week [IQR 6-31], P = 0.34). Lifetime exercise dose > 9.6 MET h/week was a borderline significant marker for severe VA (OR 3.38, 95% CI 0.92-12.40, P = 0.07), while not when adjusted for age (OR 2.63, 95% CI 0.66-10.56, P = 0.17). Ventricular arrhythmia events occurred most frequently during wakeful rest (53%), followed by exercise (29%) and sleep (12%). We found no clear association between moderate lifetime exercise dose and severe VA in patients with MVP. We cannot exclude an upper threshold for safe levels of exercise. Further studies are needed to explore exercise and risk of severe VA.