Major Ventricular Arrhythmias Research Articles

The impact of comorbidities and substance use on heart failure events and major ventricular arrhythmias in phospholamban p.(Arg14del) positive individuals

Abstract Background Patients with the phospholamban (PLN) p.(Arg14del) variant can develop a severe cardiomyopathy, characterized by progressive heart failure (HF) and major ventricular arrhythmias (VA). However, there is a marked variability in disease expression among affected individuals. There is still a considerable gap of knowledge regarding the influence of comorbidities and substance use on disease progression. Purpose The aim of this study is to investigate whether specific comorbidities and substance use are associated with HF events or major VA events in PLN p.(Arg14del) positive individuals. Method Logistic regression analysis was conducted was conducted in a retrospective cohort of 880 PLN p.(Arg14del) positive individuals (N=847 without heart failure at baseline, N=810 without major arrhythmia at baseline and N=780 without both). Comorbidities and substance use at baseline were assessed in univariable and multivariable models with respect to HF events, major VA events, and a composite endpoint of these two referred to as ‘severe phenotype’. Heart failure was defined as heart failure hospitalization, left ventricle assist device implantation, heart transplantation or HF-related death. Major VA was defined as sustained VA, appropriate implantable cardioverter defibrillator intervention, or (aborted) sudden cardiac death. Results Of all tested comorbidities, only renal dysfunction defined as an eGFR (CKD-EPI) <60 ml/min per 1.73 m² was significantly and independently associated with all endpoints (p<0.001). In the substance use analysis, prior history of smoking was associated with heart failure and a severe phenotype (p<0.002 and p<0.021), however actively smoking was not associated with both endpoints. Conclusion Renal dysfunction and a history of smoking were the only factors identified to be associated with worse outcomes in PLN p.(Arg14del) positive individuals. Whether renal dysfunction signifies a risk factor or an early manifestation of disease has to be further elucidated.

Arrhythmic mitral valve prolapse with versus without prior mitral valve repair: clinical profiles, electrophysiological substrates, and long-term clinical outcomes

Abstract Background Arrhythmic mitral valve prolapse (AMVP) is characterized by an arrhythmogenic left ventricular substrate, with high prevalence of myocardial scar. Whether patients with prior mitral valve repair for mitral valve prolapse (MVP) and new-onset complex ventricular arrhythmias (VAs) after cardiac surgery have different electroanatomical substrate and arrhythmic outcomes compared with AMVP patients without prior mitral valve surgery is currently unknown. Purpose We sought to compare the electroanatomical substrate and long-term clinical outcomes of patients with new-onset complex VAs after mitral valve surgery to AMVP patients without prior surgery. Methods We conducted a multicenter, prospective, observational study, enrolling MVP patients with prior mitral valve repair and new-onset complex VAs (>1000 premature ventricular contractions [PVCs]/day, nonsustained ventricular tachycardia [NSVT], and sustained VT) after cardiac surgery (group A,n=9), and patients with MVP, complex VAs and no prior surgery (group B,n=20). Each patient underwent a comprehensive diagnostic workup, including left ventricular electroanatomical mapping. Clinical-imaging data, as well as the location and segmental extension of both low-voltage areas and late potentials were assessed and compared between the two groups. The primary outcome was the occurrence of sustained VT or ventricular fibrillation(VF) during follow-up. Results In group A, complex VAs were first diagnosed after a median of 30(8-56) months following mitral valve repair. The characteristics of patients from the two study groups are presented in the Table. Patients from group A were older, sustained VT was nonsignificantly more common at baseline, the PVC count nonsignificantly higher, and LVEF nonsignificantly lower. Mitral annular disjunction was never observed in group A, while it was found in 7 patients from group B (p=0.066). At LV electroanatomical voltage mapping, bipolar and unipolar low-voltage areas (LVAs) were equally common in the two groups overall, and typically involved basal perimitral regions. However, patients from group B had concomitant bipolar and unipolar LVAs 50% of times, with larger unipolar LVAs, while patients from group A mostly showed isolated bipolar LVAs. Over a median follow-up of 15 (12-41) months, patients from group A (n=3, 33%) had slightly higher incidence of sustained VT or VF (HR: 1.91; 95% CI, 1.06-42.65; log-rank p=0.02, Figure) than patients from group B (n=2, 10%). Conclusion Compared to patients with AMVP and no prior cardiac surgery, patients with new-onset complex VAs after mitral valve repair for MVP have a slightly different clinical profile and electroanatomical substrate, characterized by predominant bipolar LVAs in the perimitral region. The long-term risk of major ventricular arrhythmias appears slightly higher in MVP patients with prior mitral valve surgery, mandating at least an equally careful risk assessment in both groups.

REAL WORLD USAGE OF RANOLAZINE FOR ANTIARRHYTHMIC PURPOSES: SINGLE CENTER EXPERIENCE

Abstract Introduction Ranolazine is a late sodium current blocking drug developed as an antianginal agent, with good preliminary efficacy data even for antiarrhythmic purposes (both at atrial and at ventricular level). Objectives To evaluate patients’ clinical characteristics and antiarrhythmic efficacy of ranolazine in subjects with a history of atrial and/or ventricular arrhythmias, isolated or repetitive. Patients and methods we included patients who received a first prescription of ranolazine for antiarrhythmic purposes in our center from 1/2022 to 11/2023 and evaluated the survival free from major arrhythmic relapses/ablation. Results 93 patients were enrolled (66±13 years, 15% women): 59% with arterial hypertension, 26% diabetics, 46% with post–ischemic dilated heart disease, 32% with primary cardiomyopathy (including 11% with hypertrophic cardiomyopathy, 10% with LMNA, 14% with TTN), 46% with implantable cardioverter defibrillator, 9% with pacemaker. The mean LV ejection fraction was 42 ± 15%, the mean serum creatinine 1 ± 0.3 mg/dL. Half (50%) had a history of atrial arrhythmias in the 6 months before starting the drug, mainly paroxysmal atrial fibrillation (AF), 67% of ventricular arrhythmias (VAs), mainly isolated and repetitive premature ventricular beats (PVB, 47% of the total), but also sustained or treated VAs (n=18, 19%). Overall, 18% of patients had already undergone AF ablation, 13% ventricular tachycardia ablation, 3% cardiac sympathetic denervation. Finally, 95% of patients were on beta–blocker therapy and 28% were on amiodarone. Ranolazine was prescribed at an average initial dose of 535± 150 mg. The majority (54%) of patients (n=50) had a follow–up longer than 3 months (median 9 months, IQR 6–14); in 6% the drug was stopped due to intolerance and the average dose at the last FU was 641 ± 150 mg. Twenty–eight percent of patients with paroxysmal/persistent atrial arrhythmias had relapses, requiring ablation in 6%. Among patients with major VAs, 57% suffered recurrences, but only 19% required ablation (invasive in 2 cases, non–invasive in 1 case). Finally, among the patients with PVBs, none suffered major VAs or required PVB/VA ablation. Conclusions This is the largest available case–series reporting about the real–world usage of ranolazine for antiarrhythmic purposes. Our single center experience supports ranolazine’s good safety and tolerability and shows encouraging efficacy results in terms of clinical stabilization of complex patients.

A Comparison of the Association of Septal Scar Burden on Responses to LBBAP-CRT and BVP-CRT.

Left bundle branch area pacing (LBBAP) is an alternative to biventricular pacing (BVP) for cardiac resynchronization therapy (CRT). However, despite the presence of left bundle branch block, whether cardiac substrate may influence the effect between the 2 strategies is unclear. This study aims to assess the association of septal scar on reverse remodeling and clinical outcomes of LBBAP compared with BVP. We analyzed patients with nonischemic cardiomyopathy who had CRT indications undergoing preprocedure cardiac magnetic resonance examination. Changes in left ventricular ejection fraction (LVEF) and echocardiographic response (ER,≥5% absolute LVEF increase) were assessed at 6months. The clinical outcome was the composite of all-cause mortality, heart failure hospitalization, or major ventricular arrhythmia. There were 147 patients included (51 LBBAP and 96 BVP). Among patients with low septal scar burden (below median 5.7%, range: 0 to 5.3%), LVEF improvement was higher in the LBBAP than the BVP group (17.5% ± 10.9% vs 12.3% ± 11.8%; P=0.037), with more than 3-fold increased odds of ER (odds ratio: 4.35; P=0.033). In high sepal scar subgroups (≥5.7%, range: 5.7% to 65.9%), BVP trended towards higher LVEF improvement (9.2% ± 9.4% vs 6.4% ± 12.4%; P=0.085). Interaction between septal scar burden and pacing strategy was significant for ER (P=0.002) and LVEF improvement (P=0.011) after propensity score adjustment. During median follow-up of 33.7 (Q1-Q3: 19.8 to 42.1) months, the composite clinical outcome occurred in 34.7% (n=51) of patients. The high-burden subgroups had worse clinical outcomes independent of CRT method. Remodeling response to LBBAP and BVP among nonischemic cardiomyopathy patients is modified by septal scar burden. High septal scar burden was associated with poor clinical prognosis independent of CRT methods.

Long-term reliability of the phospholamban (PLN) p.(Arg14del) risk model in predicting major ventricular arrhythmia: a landmark study.

Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up. We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6-3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79-0.87) and calibration slope of 0.97. The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)-positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up.

Role of arrhythmic phenotype in prognostic stratification and management of dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) with arrhythmic phenotype combines phenotypical aspects of DCM and predisposition to ventricular arrhythmias, typical of arrhythmogenic cardiomyopathy. The definition of DCM with arrhythmic phenotype is not universally accepted, leading to uncertainty in the identification of high-risk patients. This study aimed to assess the prognostic impact of arrhythmic phenotype in risk stratification and the correlation of arrhythmic markers with high-risk arrhythmogenic gene variants in DCM patients. In this multicentre study, DCM patients with available genetic testing were analysed. The following arrhythmic markers, present at baseline or within 1 year of enrolment, were tested: unexplained syncope, rapid non-sustained ventricular tachycardia (NSVT), ≥1000 premature ventricular contractions/24 h or ≥50 ventricular couplets/24 h. LMNA, FLNC, RBM20, and desmosomal pathogenic or likely pathogenic gene variants were considered high-risk arrhythmogenic genes. The study endpoint was a composite of sudden cardiac death and major ventricular arrhythmias (SCD/MVA). We studied 742 DCM patients (45 ± 14 years, 34% female, 410 [55%] with left ventricular ejection fraction [LVEF]<35%). During a median follow-up of 6 years (interquartile range 1.6-12.1), unexplained syncope and NSVT were the only arrhythmic markers associated with SCD/MVA, and the combination of the two markers carried a significant additive risk of SCD/MVA, incremental to LVEF and New York Heart Association class. The probability of identifying an arrhythmogenic genotype rose from 8% to 30% if both early syncope and NSVT were present. In DCM patients, the combination of early detected NSVT and unexplained syncope increases the risk of life-threatening arrhythmic outcomes and can aid the identification of carriers of malignant arrhythmogenic genotypes.

Prognostic implications of family screening in Dilated and Arrhythmogenic Cardiomyopathies

Abstract Introduction Dilated cardiomyopathy (DCM) and arrhythmogenic left dominant cardiomyopathy (ALVC) are overlapping phenotypes of inherited cardiomyopathies characterized by left ventricular systolic dysfunction (LVSD), sharing the same genetic background. The risk of disease development in relatives is relevant and influenced by multiple factors. The purpose of familial screening (FS) is to early detect cardiac manifestations by ECG and echocardiogram every 2-5 years. Recent studies suggested a possible role of Holter-ECG and Global Longitudinal Strain (GLS) for disease prediction. However, these are not strongly recommended in the current FS guidelines. Moreover, it is unclear if FS represents a useful tool to prevent cardiac events in family members. Purpose Our study aims to 1) elucidate the role of genetic and environmental factors for cardiac disease development in relatives of probands affected by DCM/ALVC, 2) quantify the predictive role of FS for LVSD, and 3) assess the prognostic impact of FS on relatives. Methods Reasons for first medical contact, genetic data, baseline and follow-up (FU) clinical, ECG, echocardiogram, GLS, Holter-ECG data and outcomes were compiled. LVSD was defined as ejection fraction &amp;lt; 50%. Moreover, a primary outcome including all-cause death (D) and heart transplantation (HT) and an arrhythmic secondary outcome including sudden cardiac death (SCD) and major ventricular arrhythmias (MVA) were evaluated in affected relatives. Results A total of 385 relatives (85% with a proband affected by DCM) were enrolled. Among these, 223 (58%) were unaffected at baseline. During a median follow-up of 60 (IQR 30-110) months, 81 (36%) developed LVSD. Being carrier of pathogenic variants and having a family history of SCD were the main clinical factors significantly associated with LVSD development in the multivariable model, whereas environmental factors were not. Moreover, the GLS value at baseline was significantly lower in relatives developing LVSD compared to persistent unaffected relatives (-14.9 ±3.2 vs -19.8 ±3.2, p&amp;lt;0.001), and its value was an independent predictor of LVSD. Furthermore, in comparison to previously published predictive models which included age, ECG and echocardiographic abnormalities (C-index 0.64), adding Holter-ECG offers a better fit and increases the concordance by 20% (C-index 0.77). In conclusion, in the total population of 243 relatives (63%) with LVSD (at the baseline or at FU), cardiac events were less frequent among relatives detected by FS. Conclusions Genetic background plays a major role in the development of LVSD in relatives of DCM/ALVC probands. GLS and Holter-ECG could be useful tools to improve the efficiency of FS to predict LVSD, suggesting early FU visits. FS shows a significant prognostic protective impact in this study population.

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&amp;lt;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

Prognostic value of cardiac magnetic resonance - LGE distribution in non-ischemic dilated cardiomyopathy for prophylactic implantable-cardioverter defibrillator therapy

Abstract Background/Introduction International guidelines recommend implantable cardioverter-defibrillator (ICD) implantation when patients with nonischemic dilated cardiomyopathy (NICM) have left ventricular ejection fraction (LVEF) of 35% or less. Tissue characterization obtained by cardiac magnetic resonance (CMR) has emerged as a promising tool for better identification of patients at high arrhythmic risk and thus worthy of prophylactic ICD therapy. Purpose Current analysis has the scope to assess the prognostic value of fibrosis as evaluated by late gadolinium enhancement sequences (LGE) specifically regarding its LV wall distribution. The primary endpoint was all-cause mortality. The secondary end-point consisted of major adverse arrhythmic cardiac events (MAACE), defined as combination of SCD, aborted SCD, and sustained ventricular tachycardia. Methods Study population is part of DERIVATE Study, an international, multicenter, prospective, observational registry including consecutive patients from 21 sites across Europe and US referred for heart failure (HF) work-up including transthoracic echocardiography (TTE) and CMR without a history of previous major ventricular arrhythmias. Inclusion criteria were: (i) aged 18 or older, (ii) chronic HF according to the ESC Task force definition, and (iii) LV-EF&amp;lt;50% at initial TTE. All patients underwent TTE and CMR within 3 months. Patients with (i) decompensated within 3 months of enrollment, (ii) recent myocardial infarction (&amp;lt;40 days), (iii) unstable angina, (iv) severe valvular disease, (v) primary or secondary cardiomyopathies other than NICM, (vi) cardiac amyloidosis, and (vii) congenital heart disease were excluded. Results The entire cohort consisted of 1384 subjects [mean age: 56±14 years, male: 948 (68.4%)]. The median follow-up time was 959 days. Mortality and MAACE occurred in 92 (6.6%) and 125 (9%) patients, respectively. SCD, aborted SCD, and sustained VT occurred in 15 (1.1%), 80 (5.8%), and 104 (7.5%), respectively. In the multivariate analyses for all-cause mortality, only the number of segments with LGE at the level of the septum was an independent predictor (p=0.002), while in the analyses for MAACE the only independent predictors were male gender, LVEDVi by CMR, and the number of segments with LGE at the level of septum inferior. Based on the multivariate analysis, the DERIVATE score (including all 1384 patients) ranging from 0 to 8 (Cox regression analysis HR=1.35, 95%CI 1.24-1.46, p&amp;lt; 0.001) was built up. The redistribution of patients according to the CMR composite DERIVATE risk/year MAACE was of 44%, 37% and 32% for the low, intermediate and high risk groups, respectively. Conclusions The arrhythmic risk of patients with NICM is also dependent on the different distribution of fibrosis in the LV. The redistribution of the event rate according to the CMR composite risk score indicates the potential to alter the decision on ICD implantation in a relevant portion of NICM patients.

Abstract 17084: Impact of Hereditary Gene Mutations on Outcomes in an Ethnically Diverse Patient Cohort With Nonischemic Dilated Cardiomyopathy

Introduction: Nonischemic cardiomyopathy (NICM) is a leading cause of heart failure (HF). Heritable gene mutations are found in a subset of these cases and help to identify at risk individuals. The purpose of this study is to characterize the impact of genotype on clinical outcomes. Methods: Data from a single center registry of patients who underwent cardiomyopathy and arrhythmias gene panel testing between 2018 and 2022 was used. Patients with an LVEF &lt; 50% without a history of hypertrophic, infiltrative or ischemic cardiomyopathy were included. Genotyping, demographics, and clinical data including HF and major ventricular arrhythmia (MVA) outcomes were collected. Patients were stratified by genotype ((+): Pathogenic/Likely Pathogenic; (-): VUS/Likely Benign/Benign/no variant). Genotype (+) patients were also grouped by functional gene class. Chi Square and Wilcoxon testing were used for between group comparisons. Kaplan Meier with log-rank testing was used for time to event analyses. Results: This study included 350 patients with a median age of 54 years (IQR: 42-65 years) at last follow up. Table 1 shows demographics and outcomes. Genotype (+) patients had more HF and MVA events. There was a trend towards genotype predicting HF and MVA at all ages, with curves separating after age 26 (p = 0.0475) Figure 1. Genotype (+) LMNA patients had HF and MVA events at earlier ages compared to Genotype (-) (n=6, 85.7 %, p = 0.005). Conclusion: NICM patients with a hereditary gene identified have worse outcomes than those without, suggesting an opportunity to improve risk stratification and guide patient management decisions with genetic testing.

Clinical profiling and outcomes of viral myocarditis manifesting with ventricular arrhythmias.

Clinical features and risk stratification of patients with viral myocarditis (VM) complicated by ventricular arrhythmias (VA) are incompletely understood. We aim to describe arrhythmia patterns and outcomes in patients with VM and early-onset VA. We present a single-centre study, enrolling patients with VM proven by endomyocardial biopsy, and evidence of VA within 24 h of hospitalization. The incidence of major adverse events (MAE), including all-cause death, severe heart failure, advanced atrioventricular blocks, or major VA, was evaluated during a 24-month follow-up (FU) and compared with a matched group of virus-negative myocarditis. Of patients with VM (n = 74, mean age 47 ± 16 years, 66% males, and left ventricular ejection fraction 51 ± 13%), 20 (27%) presented with major VA [ventricular tachycardia/ventricular fibrillation (VT/VF)], and 32 (44%) had polymorphic VA. Patients with polymorphic VA more commonly had evidence of ongoing systemic infection (24/32 vs. 10/42, P = 0.004) and experienced greater occurrence of MAE at discharge (15/32 vs. 2/42, P < 0.001). However, the incidence of MAE during FU was higher in patients with monomorphic VA compared to those with polymorphic VA (17/42 vs. 2/28, P = 0.002). Patients with monomorphic VA displayed frequently signs of chronic cardiomyopathy and had outcomes comparable with virus-negative myocarditis (log rank P = 0.929). Presentation with VT/VF was independently associated with MAE [at discharge: hazard ratio (HR) 4.7, 95% confidence interval (CI) 1.6-14.0, P = 0.005; during FU: HR 6.3, 95% CI 2.3-17.6, P < 0.001]. In patients with VM, polymorphic VA point to ongoing systemic infection and early adverse outcomes, whereas monomorphic VA suggest chronic cardiomyopathy and greater incidence of MAE during FU. Presentation with VT/VF is independently associated with MAE.

Acute Cardiovascular Events After COVID-19 in England in 2020: A Self-Controlled Case Series Study.

To assess the risk of incident cardiovascular outcomes after COVID-19 by level of cardiovascular risk in waves one and two of the pandemic in England in 2020. We conducted a self-controlled case-series study among adults aged 40-84 years with no pre-existing cardiovascular disease using linked data from the Clinical Practice Research Datalink. We generated season-adjusted incidence ratios (IRs) for first acute cardiovascular event after SARS-CoV-2 infection compared with baseline time before and >91 days after infection. We used composite and individual acute cardiovascular event outcomes including myocardial infarction, major ventricular arrhythmia, left ventricular heart failure, and ischemic stroke. We stratified by cardiovascular risk, using diagnosed hypertension and QRISK3 predicted risk, and by wave one and two of the pandemic. We included 1762 individuals, 76.6% had a QRISK3 score ≥10% and 59.4% had hypertension. The risk of any cardiovascular event was elevated in the 1-7 days after infection (IR 7.14 [95% CI 6.06-8.41]) and, while the effect size tapered, the risk remained for 15-28 days after infection (1.74 [1.33-2.26]). Risks were similar for individual event type, differing by level of cardiovascular risk, and in wave one and two of the pandemic. . SARS-CoV-2 infection is associated with early elevations in the risk of first acute cardiovascular event, across cardiovascular risk levels and in both wave one and two of the pandemic. Prevention of COVID-19 is important to avert cardiovascular complications.

Late gadolinium enhancement distribution patterns in non-ischaemic dilated cardiomyopathy: genotype-phenotype correlation.

Late gadolinium enhancement (LGE) is frequently found in patients with dilated cardiomyopathy (DCM); there is little information about its frequency and distribution pattern according to the underlying genetic substrate. We sought to describe LGE patterns according to genotypes and to analyse the risk of major ventricular arrhythmias (MVA) according to patterns. Cardiac magnetic resonance findings and LGE distribution according to genetics were performed in a cohort of 600 DCM patients followed at 20 Spanish centres. After exclusion of individuals with multiple causative gene variants or with variants in infrequent DCM-causing genes, 577 patients (34% females, mean age 53.5 years, left ventricular ejection fraction 36.9 ± 13.9%) conformed to the final cohort. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. Significant differences were found comparing LGE patterns between genes (P < 0.001). LGE was absent or rare in patients with variants in TNNT2, RBM20, and MYH7 (0, 5, and 20%, respectively). Patients with variants in DMD, DSP, and FLNC showed a predominance of LGE subepicardial patterns (50, 41, and 18%, respectively), whereas patients with variants in TTN, BAG3, LMNA, and MYBPC3 showed unspecific LGE patterns. The genetic yield differed according to LGE patterns. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE. LGE patterns in DCM have a specific distribution according to the affected gene. Certain LGE patterns are associated with an increased risk of MVA and with an increased yield of genetic testing.

Efficacy and safety of a bolus of half-dose r-SAK prior to primary PCI in ST-elevation myocardial infarction: Rationale and design of the OPTIMA-6 trial

Time to reperfusion is the key to the treatment of patients with ST-elevation myocardial infarction (STEMI). It is uncertain whether adjunctive thrombolytic therapy combined with contemporary antiplatelet agent ticagrelor improves outcomes as administered prior to primary percutaneous coronary intervention (PCI) expected to be performed within 120 minutes. OPTIMA-6 is a multicenter, randomized, double-blind, placebo-controlled, and superiority trial to evaluate the efficacy of a bolus of half-dose recombinant staphylokinase (r-SAK) vs placebo prior to timely primary PCI in patients with STEMI. Enrollment began in April 2023 and is expected to enroll 2,260 patients at approximately 50 centers. Patients with acute STEMI presenting ≤12 hours of symptom onset and expected to undergo primary PCI within 120 minutes but more than 30 minutes are to be randomized to a bolus of half-dose r-SAK or placebo. All recruited patients will be mandatory to take aspirin and ticagrelor and receive a bolus of loading dose heparin before the thrombolytic therapy. The primary efficacy endpoint is major adverse cardiovascular events (MACE) within 90 days, and the MACE is defined as a composite of all-cause death, reinfarction, unplanned target vessel revascularization, heart failure or cardiogenic shock, and major ventricular arrhythmia. The primary safety endpoints are major bleeding events (BARC 3, 5) within 90 days. OPTIMA-6 will reveal the efficacy and safety of a contemporary facilitated PCI with a bolus of half-dose r-SAK in combination with ticagrelor in patients with STEMI.

Cardiac magnetic resonance for prophylactic implantable-cardioverter defibrillator therapy international registry: prognostic value of LGE distribution in non-ischemic dilated cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): This work was supported by Italian Ministry of Health, Rome, Italy (RC 2017 R659/17-CCM698). Background/Introduction Tissue characterization obtained by cardiac magnetic resonance (CMR) has emerged as a promising tool for better identification of non ischemic cardiomyopathy patients at high arrhythmic risk and thus worthy of prophylactic ICD therapy. Purpose Current analysis has the scope to assess the prognostic value of fibrosis, as evaluated by late gadolinium enhancement sequences (LGE) specifically regarding its LV wall distribution, and a CMR-derived risk score. The primary endpoint was all-cause mortality. The secondary end-point consisted of major adverse arrhythmic cardiac events (MAACE), defined as combination of SCD, aborted SCD, and sustained ventricular tachycardia Methods DERIVATE Study is an international, multicenter, prospective, observational registry including consecutive patients from 21 sites referred for heart failure (HF) work-up including transthoracic echocardiography (TTE) and CMR without a history of previous major ventricular arrhythmias. Inclusion criteria were: (i) aged 18 or older, (ii) chronic HF, and (iii) LV-EF&amp;lt;50% at initial TTE. All patients underwent TTE and CMR within 3 months. Patients with (i) decompensated within 3 months of enrollment, (ii) recent myocardial infarction (&amp;lt;40 days), (iii) unstable angina, (iv) severe valvular disease, (v) primary or secondary cardiomyopathies other than NICM, (vi) cardiac amyloidosis, and (vii) congenital heart disease were excluded. Results The entire cohort consisted of 1384 subjects [mean age: 56±14 years, male: 948 (68.4%)]. The median follow-up time was 959 days. Mortality and MAACE occurred in 92 (6.6%) and 125 (9%) patients, respectively. SCD, aborted SCD, and sustained VT occurred in 15 (1.1%), 80 (5.8%), and 104 (7.5%), respectively. The sum of events exceeds the overall number of MAACE because several events could occur in the same patients but just the first event was counted. In the multivariate analyses for all-cause mortality, only the number of segments with LGE at the level of the septum was an independent predictor (p = 0.002), while in the analyses for MAACE the only independent predictors were male gender, LVEDVi by CMR, and the number of segments with LGE at the level of septum inferior. Based on the multivariate analysis, the DERIVATE score (including all 1384 patients) ranging from 0 to 8 (Cox regression analysis HR=1.35, 95%CI 1.24–1.46, p&amp;lt; 0.001) was realized. The redistribution of patients according to the CMR composite DERIVATE risk/year MAACE was of 44%, 37% and 32% for the low, intermediate and high risk groups, respectively. Conclusions The arrhythmic risk of patients with NICM is also dependent on the different distribution of fibrosis in the LV. The redistribution of the event rate according to the CMR composite risk score indicates the potential to alter the decision on ICD implantation in a relevant portion of NICM patients. These results warrant further confirmation in prospective randomized controlled trials.

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

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

P287 RELATIONSHIP OF HYPOVITAMINOSIS D WITH HEART FAILURE DEVELOPMENT, HEART TRANSPLANTATION NECESSITY AND MORTALITY AMONG INDIVIDUALS WITH DILATED CARDIOMYOPATHY

Abstract Background Non–ischemic dilated cardiomyopathy (DCM) is a progressive heart disease often affecting young individuals leading to heart failure (HF) development, heart transplantation (HT) and adverse outcome. We aimed to evaluate the prevalence of hypovitaminosis D among Italian patients with DCM and its prognostic value during follow–up. Methods Plasma vitamin D levels were measured in 204 patients with DCM enlisted from The Trieste Registry of Cardiomyopathies. The endpoints during follow–up were defined as the incidence of major ventricular arrhythmias (MVAs), HT, hospitalization for HF and all–cause mortality. Results The median concentration of vitamin D in our cohort was 20.7 (15.53–29.3) ng/ml) and the majority of enrolled individuals were vitamin D deficient (54.4%). Vitamin D levels positively correlated with left ventricular ejection fraction (LVEF) (R=0.216, p=0.002) and patients with LVEF &amp;gt; 35 have significantly higher plasma vitamin D concentration compared to patients with LVEF &amp;lt;= 35 (respectively, 22.7 (17.35 – 30.5) ng/ml vs 19.2 (13.0 – 26.35) ng/ml, p=0.009). During a median follow–up of 58.47 (38.05 – 74.97) months, 7.8% of patients died, 3.9% had HT, 12.3% of individuals were hospitalized for HF, and 12.7% suffered from MVAs. Deceased individuals, patients requiring HT and hospitalized for HF during follow–up were observed to have significantly lower plasma vitamin D values compared to living and event–free individuals at the end of follow–up (respectively, 18.65 (9.49 – 20.7) ng/ml vs 21.3 (15.75 – 29.58) ng/ml, p=0.046, 14.35 (7.03 – 17.85 ng/ml vs 20.9 (15.9 – 29.48) ng/ml, p=0.021, 15.5 (9.56 – 21.35) ng/ml vs 21.7 (16.2 – 29.5) ng/ml, p= 0.012). In addition, patients suffering from MVAs had lower vitamin D values compared to individuals without events, although not significant (18.8 (14.48 – 24.48) ng/ml 21.56 (15.6 – 29.53) ng/ml, p=0.219). Unfortunately, Kaplan–Meier analysis and multivariate Cox regression analysis did not show an association and prognostic feature of vitamin D levels with events as expected probably due to the limited number of samples. Conclusions Hypovitaminosis D is common in patients with DCM. Given that lower levels of vitamin D are noted among patients with MVA, HT, HF hospitalization and poor outcome, future studies with a larger cohort are needed to confirm its predictive value. Vitamin D supplementation should be highly recommended as part of preventive therapies in patients with DCM.

207 RE-DEFINING ARRHYTHMOGENIC CARDIOMYOPATHY: CHARACTERIZATION AND LONG-TERM PROGNOSTIC IMPLICATIONS

Abstract Background Arrhythmogenic dilated cardiomyopathy (AR-DCM) combines phenotypical aspects of dilated cardiomyopathy (DCM) and risk of sudden cardiac death (SCD), typical of the arrhythmogenic form (ACM). However, AR-DCM is often ambiguously defined leaving clinicians uncertain on how to identify these high-risk patients. The aims of the study were to re-define AR-DCM based on outcome related arrhythmic markers and to test the usefulness of the novel AR-DCM definition in identifying arrhythmogenic genotypes (i.e., LMNA, FLNC, RBM20, and desmosomal genes). Materials and methods Consecutive DCM patients with genetic evaluation and Holter ECG monitoring or telemetry in two referral institution were analyzed. The arrhythmic markers tested to define AR-DCM were: SCD or major ventricular arrhythmias (MVA), unexplained syncope, rapid nonsustained ventricular tachycardia (nsTV), ≥1000 premature ventricular contractions/24 hours, or ≥50 ventricular couplets/24 hours. Patients were labeled as Early AR-DCM if criteria were met within 12 months from enrolment. The primary endpoint was a composite of SCD/MVA; the secondary endpoint was a composite of all-cause mortality/heart transplant/LVAD implantation (D/HTx/LVAD). Results Among the 743 DCM patients included, 290 had disease-related variants (39%), 94 (30%) of these carried arrhythmogenic genotype. Early AR-DCM was identified in 429 (58%) patients. During a median follow-up of 7.0 [2.2-13.8] years, among arrhythmic markers the occurrence of syncope and/or nsVT within 12 months from enrolment were the only arrhythmic markers independently associated with SCD/MVA (Figure), while the occurrence of early MVA and/or nsTV emerged as the strongest long-term predictors of D/ HTx/LVAD. Family history of MVA was also independently associated with primary and secondary endpoints, and together with MVA, nsTV or unexplained syncope increased the agreement between AR-DCM and arrhythmogenic genotypes in 1 out 2 patients. Conclusions A combination of early (i.e., within 1 year from diagnosis) MVA or nsVT or unexplained syncope might be proposed as a clinically useful new definition of AR-DCM, especially if associated to family history of MVA. This definition in fact allows clinicians to anticipates worse long-term arrhythmic and global outcomes, and to accurately identify malignant arrhythmogenic genotypes.

915 PHENOTYPIC EXPRESSION AND OUTCOMES OF CARDIOMYOPATHY CAUSED BY TITIN TRUNCATING VARIANTS: TRANSLATIONAL INSIGHTS

Abstract Background Titin truncating variants (TTNtv) represent the most prevalent genotype underlying dilated cardiomyopathy (DCM). Recent molecular studies provided initial evidence about different pathogenic mechanisms produced by different mutation sites of the truncating variant (A-Band vs non-A-band), possibly related to the presence or absence of truncated titin (TTN) peptides. However, to date, clinical studies on DCM patients carrying TTNtv failed to demonstrate any relevant clinical difference according to the titin band affected. We hypothesized this lack of variation could be partially explained by the selection bias of including only DCM phenotype patients. Thus, we studied the clinical phenotypes and outcomes of our entire population of subjects with pathogenic TTNtv regardless of phenotypic expression at the onset. Methods We retrospectively analyzed a population of pathogenic TTNtv carriers, enrolled in the Trieste Heart Muscle Disease Registry. 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. Variables were expressed as mean±SD, median and interquartile range, or counts and percentage, as appropriate. Kaplan-Meier curves were estimated for the composite endpoints of (i) heart failure-related death, heart transplant, and destination left ventricular assist device implantation and (ii) first major ventricular arrhythmia (MVA, defined as SCD or life-threatening ventricular arrhythmia) and compared by the log-rank test. Results 154 TTNtv carriers were included in the study, of whom 66% were probands. The most prevalent phenotype was DCM (92%). The mean age of subjects at diagnosis was 43±16 years and 70% were males. There was no difference between groups in the first composite outcome of heart failure-related death, heart transplant, and destination left ventricular assist device implantation. Instead, major ventricular arrhythmias were significantly more frequent in the non-A-band group, in which 47% (n=14) of TTNtv carriers experienced MVA as compared to 19% (n=20) of subjects in the A-band group (p=0.001). Interestingly, we observed a tendency in MVA occurrence 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). Conclusions Among TTNtv carriers referred to a tertiary center, those with a mutation in the non-A band seem characterized by higher arrhythmic risk. This novel finding highlights the importance of considering the site of TTN truncating variants to guide the most appropriate clinical management for each patient.

1117 FAMILY SCREENING IN DILATED CARDIOMYOPATHY: CLINICAL CHARACTERIZATION AND FOLLOW UP OF RELATIVES

Abstract Background Familial patterns of inheritance and genetic mutations have been identified as pathogenic in nearly 40-50% of previously defined “idiopathic” Dilated Cardiomyopathy (DCM). Genetic testing in the proband allows cascade genetic screening in relatives, in order to promote an early diagnosis even in a pre-clinical stage of the disease, as recommended by international guidelines. This study aims to describe the clinical characteristics of screened relatives of Dilated Cardiomyopathy (DCM) patients, at baseline and during follow-up. Methods Screened relatives of patients affected by DCM were enrolled retrospectively and followed from January 2000 to August 2021. At baseline, the family screening included a clinical evaluation, ECG and echocardiogram. If likely pathogenetic (LP) or pathogenetic (P) variant was identified in the proband Genetic testing was offered and performed on relatives according to available consensus documents from the age of 10-12 years. The onset of disease was defined as left ventricular (LV) dilation and/or LV systolic dysfunction. The following information was obtained during the follow-up: all-cause death, cardiovascular death, sudden cardiac death (SCD), hospitalization for heart failure (HF), heart transplantation, ventricular assist device (VAD) implantation, ICD or CRT-D implantation and major ventricular arrhythmias (MVA). Results We enrolled 203 relatives from 32 families with DCM. The median follow-up was 94 months. At baseline, symptomatic relatives for dyspnea (NYHA II-III class) were 29 (14%), versus 174 (86%) of asymptomatic (NYHA I). All these subjects showed initial signs of DCM and experienced more frequently adverse outcomes, such as hospitalization for HF (p&amp;lt;0,001) and MVA (p&amp;lt;0,001) during follow-up. Among asymptomatic relatives, patients with initial signs of disease were 46 (26%), 20 (43%) with LV dilation and dysfunction, 18 (39%) with LV dysfunction and 7 (15%) with LV dilatation. During follow-up, 5 of them (11%) died and 2 (4%) experienced SCD (one carrier of FLNC variant). Globally, affected relatives at baseline carried a LP/P variant in more than half of the cases (57%), the remaining part being relative of proband with no or negative genetic testing. Non-affected relatives were 128 (74%) at baseline. 15 relatives (12%) developed initial signs of DCM (5 with LV dilation, 5 with LV dysfunction, 5 with LV dilation and dysfunction) during follow-up. Of those, 13 patients (87%) carried a LP/P variant. The genes mostly involved were TTN (9 cases,69%), followed by DSP and FLNC. Conclusions Familial screening allows an early diagnosis of DCM-affected patients. Asymptomatic relatives at the baseline showed a better outcome compared with symptomatic ones. However, SCD events were only detected in the asymptomatic group. Moreover, subjects who develop the disease during follow-up were carriers of a LP/P variant. Seriate follow-up is mandatory in relatives independently by symptoms at the baseline: genetic testing supports a focused clinical screening of high-risk relatives.