Cardiac Arrest Research Articles

Minimal extra-cardiac atherosclerosis in people <50 years with sudden cardiac death due to coronary disease

Abstract Background The association between severe coronary artery disease and widespread atherosclerosis in younger individuals remains uncertain. Purpose To characterise the association between severe (fatal) coronary disease and extra-cardiac atherosclerosis in a population of young and middle-aged individuals. Methods Individuals aged 1-50 years with sudden cardiac death (SCD) from 2019-23, autopsy-proven to be due to coronary artery disease, were identified using the state-wide EndUCD registry. The presence of extra-coronary atherosclerosis greater than modified American Heart Association class III was documented in five arterial beds (intra-cerebral vessels, carotid arteries, aorta, renal and femoral arteries). Results Of 3,044 individuals who experienced SCD, 372 were due to coronary artery disease and 71 of these (19.1%) had extra-coronary plaque. Plaque was identified in aorta (68/372 patients, 18.3%), carotid arteries (11/372, 3.0%), iliofemoral arteries (11/372, 3.0%), intracerebral arteries (4/157 patients who underwent examination of the brain, 2.6%) and renal arteries (7/372 patients, 1.9%). 51 patients (13.7%) had plaque in ≥2 arterial beds in addition to their coronary disease. Predictors of extra-coronary plaque were older age (median 47.7 vs 44.4 years, p<0.0001), hypertension (32.3% vs 18.9%, p=0.013), and previous percutaneous coronary intervention (9.9% vs 3.0%, p=0.01). Patients with extra-coronary plaque had higher rates of cardiomegaly (68.8% vs 51.1%, p=0.01), cardiac fibrosis indicative of previous myocardial infarction (49.3% vs 31.9%, p=0.006) and multi-vessel coronary disease (73.5% vs 55.6%, p=0.007). Conclusion Only 1 in 5 people aged 1-50 years experiencing SCD from a coronary cause exhibit extra-coronary plaque. This limits the utility of screening for carotid or aortic plaque to predict coronary atherosclerosis. Individuals with extra-coronary plaque had a higher burden of cardiovascular risk factors and more established coronary disease.

Prognostic value of synthetized right-side precordial leads in arrhythmogenic right ventricular cardiomyopathy: data from nordic, dutch, and canadian ARVC registers

Abstract Background T-wave inversion (TWI) in standard ECG leads is a proven risk marker for life-threatening ventricular arrhythmias (VA) in arrhythmogenic right ventricular cardiomyopathy (ARVC). Right-sided precordial leads (RSPL), which may be more sensitive for detection of the arrhythmogenic substrate, are rarely recorded and understudied in this context. Computerized ECG signal-processing allows synthesis of right-sided precordial ECG leads derived from standard 12-lead ECG. Objective We aimed to assess the value of TWI in RSPL, synthetized from the standard 12-lead ECG, for prediction of VA risk in ARVC patients with subtle ECG phenotypes. Methods Patients with definite ARVC by TFC2010 and no history of sustained VA prior to diagnosis from the Nordic, Canadian and Dutch ARVC registries were included. Patients with major repolarization criterion or complete right bundle branch block (RBBB) were excluded. RSPL (V3R-V6R) were derived from digitally recorded eight linearly independent leads (I, II and precordial V1 to V6) of the standard ECG using a linear ECG transformation matrix. The matrix was previously developed based on a library of body surface potential maps from a mixed group of healthy subjects and patients with cardiac diseases using multivariate linear regression and QRS-T data obtained from averaged beats of the right-sided-precordial leads and the basis leads. TWI exceeding 0.1 mV in any of the synthetized leads was tested for its ability to predict sustained VA, defined as either sustained ventricular tachycardia, appropriate ICD shock, aborted cardiac arrest, or sudden cardiac death. In a similar manner, the value of TWI in any of the inferior leads III, aVF or II was assessed. Hazard ratio was calculated using Cox regression analysis adjusted for age, sex, and proband status. Results In total, 144 patients without prior VA history were identified. After exclusion of patients with major repolarization criterion (n=37) and RBBB (n=11), 96 patients comprised the study group (mean age 40±16, 42% female, 41% probands, 48% ICD carriers). Fifty-nine patients (62%) had TWI in one or more synthetized RSPL and 33 patients (34%) had TWI in any of the inferior leads. During 10 years of follow-up, 11 patients (12%) developed VA. Kaplan-Meier curve analysis showed significant association between the presence of TWI in at least one of the RSPL and the risk of VA, which remained an independent predictor in the adjusted Cox regression analysis (HR 10.6, 95%CI 1.3-84.4, p=0.026). TWI in any of the inferior leads was not associated with the risk of VA in this cohort (HR 1.2 95%CI 0.26-5.42). Conclusions Synthetized right-sided precordial leads appear to contain information potentially useful for refining risk stratification of primary prevention ARVC patients with a subtle ECG phenotype, in whom traditional repolarization markers, such as major repolarization criterion or TWI in inferior leads, are not informative.

Causes and predictors of long-term mortality in patients referred to a cardiac rehabilitation program

Abstract Introduction Cardiac rehabilitation (CR) programs have proven to reduce short-term mortality in patients with ischemic heart disease (IHD) and hospitalization rates in patients with heart failure (HF) (1-3). However, there is insufficient evidence about long-term mortality (>24-36 months) for patients receiving treatments based on recent clinical practice recommendations. Purpose To assess the long-term prognosis and predictors of mortality in a heterogenous group of patients referred to cardiac rehabilitation, and to obtain a detailed overview of death causes. Methods An inferential analysis of consecutive patients referred for exercise-based CR at a single site between January 2016 and January 2021 was performed. Included subjects were classified attending to four indications for referral: IHD, HF, valvular heart disease (VHD) and cancer therapy-related cardiovascular toxicity (CTR-CVT). Patients who did not initiate the CR program or were referred for other indications were excluded. The primary endpoint was all cause death. The secondary endpoint was cardiovascular (CV) death. A survival analysis was performed using Kaplan Meier estimates for each referral indication and a Cox proportional hazards model was fitted to investigate mortality predictors. The initiation of the exercise program was considered the inclusion date, and patients were followed until they met the primary endpoint or censored by January 2024. Results A total of 1180 patients were included in the analysis (81% male, mean age 61 ± 11 years), with a median follow-up of 5.3 years. Most of the patients had been referred due to IHD (87%), while the proportion for HF, VHD, and CTR-CVT was 9.9%, 1.8% and 1.4%, respectively. Seventy-eight patients (6.6%) died during follow-up, with a Kaplan-Meier estimated survival of 94.5% at 5 years (95% CI 93.2%-95.9%). Nineteen patients (24.4%) died due to a cardiovascular event, mostly sudden cardiac death (47%). The predominant non-CV causes of death were infectious disease (36%) and cancer (34%). A multivariate Cox model analysis (Table 1) showed an increased risk of all cause death for patients referred due to HF (HR 2.95, 95% CI 1.33 - 6.55), VHD (HR 5.55, 95% CI 1.19 - 25.9) and CTR-CVT (22.47, 95% IC 7.32 - 68.95) when compared to IHD (Figure 1). Other significant predictors of mortality were LVEF <40%, male sex, age, diabetes, peripheral vascular disease, and multivessel coronary disease. Only LVEF <40%, VHD, CTR-CVT and peripheral vascular disease were independent predictors of CV death. Conclusion Patients who initiated an exercise-based CR program had a low risk of all cause death at 5 years. Indications for CR other than IHD were associated with higher mortality rates after adjusting for confounder variables, likely due to a selection bias of patients in advanced stages of the disease.Table 1.Cox models for all-cause deathFigure 1.KM plot for all-cause death

Ringlike late gadolinium enhancement: prevalence, association with cardiac phenotype, and patient outcome in an unselected cohort referred for cardiovascular magnetic resonance imaging

Abstract Background The identification of a non-ischemic ringlike enhancement in the left ventricular (LV) myocardium by cardiac magnetic resonance imaging (CMR) has emerged as a significant biomarker associated with arrhythmogenic cardiomyopathy (CMP) and adverse patient outcomes. Recently, the term "scarring CMP" has been also proposed to encompass various conditions characterized by a high burden of non-ischemic, often ring-like, myocardial scarring, including both genetic and acquired etiologies. Purpose To systematically evaluate CMR phenotypic traits and etiologic backgrounds in patients with ringlike enhancement and to assess the burden of adverse outcomes during follow-up (FU). Methods This is a single-center, retrospective analysis of prospectively enrolled patients undergoing CMR (from 2002 to 2024). Ringlike late gadolinium enhancement (LGE) was defined as continuous enhancement in three or more adjacent segments based on the AHA 17 segment model. Patients records were reviewed for etiologic classification and FU assessment. Results Among 23.472 patients, 19.696 (84%) underwent LGE assessment. In 152 patients (0.77%; 73% male; mean age 48.5 ± 17 years) a ringlike LGE was identified. The mean number of LV segments with LGE was 10 ± 3. Right ventricular (RV) LGE was present in 23% of subjects. LV fatty metaplasia was detected in 22%. Infero-lateral segments were most frequently affected. CMR showed the following morpho-functional features: LV dilatation (53%), LV hypokinesia (69%), LV hypertrophy (10.5%), LV non-compaction (11%), RV dilation (26%), and RV ejection fraction < 40% (21%). Phenotypic classification according to 2023 ESC guidelines identified dilated CMP phenotype (43%), non-dilated LV CMP phenotype (39%), predominant arrhythmogenic right ventricular phenotype (6%), hypertrophic phenotype (7%). 5% of cases remained unclassified, all of them showing LV dilated non-hypokinetic phenotype. Genetic analysis was performed in 101 patients (66%). Etiologic classification revealed non-desmosomal gene related CMP (24%), desmosomal gene related CMP (8%), inflammatory CMP (16%), genetic neuromuscular diseases (5%), congenital metabolic errors (3%), familiar gene elusive CMP (2%) and unknown etiology (45%). Notably, only 17% of patients classified as having inflammatory CMP and 66% of those with unknown etiology underwent genetic testing, with negative results. The median follow-up duration was 3 (IQR: 1-7) years. All-cause mortality occurred in 10.5% of patients, while 17% experienced sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator therapies, or sudden cardiac death. Heart transplantation or left ventricular assist device implantation was required in 8% of cases. Conclusion Ringlike LGE is a rare, non-disease-specific feature that can be found in different morpho-functional CMP phenotypes. It is associated with frequent genetic-determined etiology and high burden of arrhythmic and non-arrhythmic outcomes.

ECGWiz: a unified and generalizable AI model for comprehensive ECG diagnosis

Abstract Background Deep learning has demonstrated diagnostic performance in electrocardiogram (ECG) analysis comparable to that of clinicians. However, existing models primarily excel in diagnosing common conditions such as arrhythmias and heart blocks, which are easily identifiable using standard predictor variables. Conversely, models aiming to uncover novel insights, such as detecting structural changes or the presence of myocardial scar, often lack generalizability due to insufficient data, model architecture limitations, and other factors. Moreover, these models frequently encounter challenges, such as a decline in performance when applied to external datasets. To address these issues comprehensively, we propose the ECGWiz — a unified model capable of tackling diverse ECG-related problems with consistently high performance. Objective To develop a generalizable Foundation AI model for ECG diagnosis capable of detecting diverse cardiac abnormalities and diseases using few training samples. Methods We utilized publicly available datasets like PTB-XL, CPSC, etc. To build our model, totaling approximately 80,000 ECGs. These 12 lead ECGs are scaled and filtered before using them for training. The AI model is pretrained using Self Supervised Learning and Contrastive Learning strategies. Further, the model undergoes supervised training using a hierarchy of labels that increase in granularity, encompassing arrhythmias, heart blocks, other cardiac abnormalities, heart failure, sudden cardiac death and more. Lastly, the model is prepared for Few-Shot Learning — where the model learns from a minimal set of samples (5 to 10 ECGs) of the target disease. For testing the model, we are using unique datasets like PROSE which consists of non-ischemic cardiomyopathy patients with and without myocardial scaring detected using cardiac MRI imaging at the Johns Hopkins University. Results Our model, trained on a dataset of only 5 ECG recordings, demonstrated a 74% accuracy in identifying myocardial scarring as detected by LGE MRI, utilizing a standard 12-lead ECG. This performance is comparable to that of conventional deep learning methods, which necessitate datasets containing upwards of 120 ECG recordings. Conclusion Our model represents a promising stride in creating a unified and adaptable foundation AI model for comprehensive ECG-based diagnosis. Its capacity to learn from a minimal set of examples signifies a robust framework that can evolve and adapt to new challenges in ECG diagnosis. Ongoing improvements, particularly through dataset expansion, underscore its potential to enhance cardiovascular diagnostics, offering precise and efficient patient care.

Environmental impact analysis of ajmaline challenge protocols: a comparative assessment of carbon footprint reduction in Brugada Syndrome diagnosis

Abstract Background Climate change is an urgent public health crisis that significantly impacts disease development and health outcomes. The 2022 Lancet Countdown Report revealed that healthcare contributes with 5.2% of global emissions, prompting a call for environmentally conscious approaches. In this context, we explored the environmental impact of different ajmaline challenge protocols, aiming to contribute to a more sustainable medical landscape. Purpose This study aims to compare the carbon footprint of two ajmaline challenge protocols commonly used in diagnosing Brugada syndrome, an inherited cardiac disorder associated with sudden cardiac death. Methods We performed a retrospective and observational analysis of adult patients (pts) who underwent ajmaline testing between March 2020 and June 2023 in two hospitals. In Group A (infusion protocol), 1mg/kg of ajmaline diluted in 50 mL of 5% glucose solution was infused in 10 minutes, up to the target dose, until a positive result or termination criteria ensued. In Group B (bolus protocol), 10 mg of ajmaline were administered every 2 minutes, again up to the target dose of 1mg/kg (maximum of 100 mg) or test interruption was indicated. Greenhouse gas emissions resulting from material processing were estimated based on life cycle analyses of each product's composition. Material consumption, waste production, and direct measurement of weights were considered. Results A total of 101 pts were included, 49 pts in group A with a mean age of 47.3±14.3 years old and 52 patients in group B with a mean age of 43.9±16.6 years-old. No complications were observed in either group. Test performance was not evaluated, since both protocols have been previously validated. Group A, utilizing the infusion method, exhibited a higher environmental impact, producing 18.19 kg CO2eq, compared to 6.23 kg CO2eq (p<0.001) in Group B (bolus protocol). Group B not only demonstrated a 66% reduction in CO2eq emissions but also used significantly less plastic (16g vs 102g per test) and glass (1.58 kg vs 1,79Kg), emphasizing its environmental superiority. Conclusions Shifting from infusion to bolus in ajmaline challenge protocols results in a substantial reduction in carbon footprint. Our findings emphasize the potential impact of adopting more dematerialized approaches in cardiac testing, urging healthcare professionals to embrace sustainable practices. Despite the study's limited sample size, the global adoption of such environmentally friendly strategies promises significant positive effects on healthcare's environmental footprint.

Substantial morbidity and mortality due to cardiovascular diseases in hospitalized vaccinated and un-vaccinated patients with COVID-19 from 16 countries: the WHF COVID-19 Long-term study

Abstract Background Long-term adverse consequences of the COVID-19 affect many organ systems, and this requires the identification and appropriate care of diverse symptoms. Purpose The World Heart Federation (WHF) international study describes the burden of clinical sequelae of COVID-19 up to 1 year after hospitalization, including patients from low- middle-and high-income countries. Methods We prospectively recruited patients hospitalized due to COVID-19 from 16 countries between January 2022 and June 2023. Patients were followed up at 1, 3, 6, and 9-12 months after hospital discharge. A standardized questionnaire administered by telephone collected data on long COVID symptoms, quality of life using the EuroQol 5 Dimension scale (EQ-5D), and disease outcomes including new onset diabetes and hypertension, major adverse cardiovascular events (MACE), and mortality. We report a descriptive analysis including demographic characteristics and outcomes up to one year after initial hospitalization. Results Of 2504 patients, the majority were Asian (78%), and male (56%). Mean age was 59.2 years (SD 19.9). Low- and lower-middle-income country participants constituted 65% of the cohort, with upper middle-income and high-income representing 20% and 15%, respectively. Follow-up rate was complete for 86%. 55% had received at least two doses of COVID-19 vaccination. At 1 month, 63% reported at least one persistent symptom, which decreased to 28% at 9-12 months. Fatigue was reported by 45% at 1-month and 17% at final follow-up. Anxiety occurred in 20% and 9% at these respective timepoints, and breathlessness in 12% and 6%. At 9-12 months, moderate to severe impairment of usual activities as measured by EQ-5D occurred in 19%, anxiety/depression in 10%, and mobility problems in 10%. The most frequent post-discharge new-onset illnesses were pulmonary embolism (7%), kidney problems (4%), and hypertension (3%). In-hospital mortality was 4% (n=102), and a further 12% (265 patients) died by one-year. The most common cause was sudden cardiac death (59%), respiratory disease including pulmonary embolism (13%), and stroke (6%). Conclusions We observed a significant burden of post-COVID-19 complications with one fifth of patients with persistent difficulties in usual activities at one year. This underscores the urgent need to understand the underlying mechanisms for organ damage and death, and for targeted preventive strategies and proactive management approaches to reduce them.

Empagliflozin's role in reducing ventricular repolarization heterogeneity: insights into cardiovascular mortality decline from the EMPATHY-HEART trial

Abstract Introduction The incidence of myocardial infarction (MI) and sudden cardiac death (SCD) is significantly higher in individuals with Type 2 Diabetes Mellitus (T2DM). Predictive measures for fatal arrhythmias are often inadequate, highlighting the need for novel non-invasive diagnostic tools. The T-wave heterogeneity (TWH) index, which measures variations in ventricular repolarization, has emerged as a promising predictor for severe ventricular arrhythmias. Although the EMPA-REG trial reported reduced cardiovascular mortality with empagliflozin, the underlying mechanisms remain unclear. This study investigates the potential of empagliflozin in mitigating electrical instability in patients with T2DM and coronary heart disease (CHD) by examining changes in TWH. Methods Participants were adult outpatients with T2DM and CHD, exhibiting a baseline TWH of at least 80 µV. They received a 25mg daily dose of empagliflozin and were evaluated clinically, including ECG measurements at baseline and after 4 weeks. TWH was computed from leads V4, V5, and V6 using a validated technique. The primary study outcome was the alteration in TWH following empagliflozin administration, assessed via the Wilcoxon test, with a significance threshold of p<0.05. Results An initial review of 6,000 medical records pinpointed 800 patients for TWH evaluation. Of these, 412 exhibited TWH above 80 µV, with 144 completing clinical assessments and 90 meeting the criteria for high cardiovascular risk enrollment. Empagliflozin adherence exceeded 80%, resulting in notable reductions in blood pressure without affecting heart rate. Side effects were generally mild, with 13.3% experiencing mostly Level 1 hypoglycemia, alongside infrequent urinary and genital infections. The treatment consistently reduced median TWH from 116 to 103 µV (p=0.01), as detailed in Figure 1. Conclusion The EMPATHY-HEART trial preliminarily suggests that empagliflozin decreases heterogeneity in ventricular repolarization among patients with T2DM and CHD. This reduction in TWH may provide insight into the mechanism behind the decreased cardiovascular mortality observed in previous trials, potentially offering a therapeutic pathway to mitigate the risk of severe arrhythmias in this population.Table 1 Figure 1

Impact of measured or calculated small dense LDL cholesterol compared with apolipoprotein B or non-HDL cholesterol for long-term secondary prevention in patients with stable coronary artery disease

Abstract Background This study was aimed to investigate whether directly measured small dense low-density lipoprotein cholesterol (D-sdLDL-C) can predict long-term coronary artery disease (CAD) events compared with LDL-C, non–high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apoB), and estimated sdLDL-C (E-sdLDL-C) determined by Sampson’s equation in patients with stable CAD. Methods D-sdLDL-C measured at Showa University, and E-sdLDL-C were evaluated in 790 male and 244 female patients with stable CAD. CAD events defined as sudden cardiac death, onset of acute coronary syndrome, and/or need for coronary revascularization were monitored for 12 years. Cut-points of D-sdLDL-C, E-sdLDL-C, LDL-C, non-HDL-C, and apoB were determined by receiver operating characteristic curves. Results CAD events were observed in 238 male and 67 female patients. The Kaplan–Meier event-free survival curves showed that patients with D-sdLDL-C ≥32.1 mg/dL had an increased risk for CAD events (chi-square from log-rank test = 7.23), whereas risk in patients with E-sdLDL-C ≥36.2 mg/dL was not. In the group with high D-sdLDL-C, the multivariable-adjusted hazard ratio (HR) was 1.47, 95% confidence interval (CI) 1.15-1.89, and it remained significant after adjustment for LDL-C, non-HDL-C, or apoB. These results remained significant in the patients treated with statin. HRs for high LDL-C, non-HDL-C, or apoB were not statistically significant after adjustment for high D-sdLDL-C. The high D-sdLDL-C enhanced risk of high LDL-C, non-HDL-C, and apoB (HR 1.73, 95%CI 1.27-2.37). Conclusions: High D-sdLDL-C can predict long-term recurrence of CAD in stable CAD patients independently of apoB and non-HDL-C by distinguishing the patients at high risk. D-sdLDL-C is an independent risk-enhancer for secondary CAD prevention whereas E-sdLDL-C is not.Figure

Outcomes and management of Haemoptysis in the Fontan population

Abstract Background Patients with a Fontan circulation for palliation of a univentricular congenital heart defect commonly possess pulmonary vascular abnormalities including arteriovenous malformations (AVM), aortopulmonary and venous-venous collaterals (1). These vessels are prone to haemorrhage which may result in life-threatening haemoptysis (2). This risk is increased with oral anticoagulant medication, given to reduce the risk of thromboembolism in Fontan patients (3). Management of these patients is difficult, and strategies vary across institutions. Purpose We aim to describe our experience with managing adult Fontan patients presenting with haemoptysis in a tertiary centre with a large Fontan cohort. Methods We retrospectively reviewed the records of 410 adult Fontan patients. Individuals admitted to our institution with an episode of haemoptysis were included. Details relating to anticoagulation regimens, interventions and mortality of patients were captured. Results From a cohort of 410 Fontan patients, 35 haemorrhagic events were observed in 11 patients (2.68%). The median age at initial haemoptysis was 24.5 years (range 19 to 43 years). 6 of the 11 patients were female (54.5%). Haemoptysis recurred in 8 of the 11 patients (72.7%). 2 out of 11 had a prior history of haemoptysis in childhood. All patients were administered with oral vitamin K antagonists at presentation. 24 of the 35 events were managed conservatively with IV fluids, anticoagulation reversal and tranexamic acid (66.7%). 11 events required catheter-based interventions, with coil and/or plug embolization of bleeding vessels. Prior to intervention, CT successfully identified potential bleeding sites in 10 of the 11 events (90.9%) but could not visualise all vessels that were subsequently embolized. The most common culprits for haemoptysis were aortopulmonary collaterals, followed by AVMs and venous-venous collaterals. In severe cases, more extensive management was required including transfusions, bronchoscopy, intubation, surgical exploration (1 patient) and pneumonectomy (1 patient). 3 patients died following recurrent severe haemoptysis (27.3%), and 2 patients died of subsequent Fontan failure and sudden cardiac death respectively. Total mortality of the cohort is 5 out of 11 (45.5%) with a median follow up of 10.75 years (range 3 days to 27 years). Conclusions Haemoptysis is a rare but potentially fatal complication in patients who have undergone a Fontan procedure. The variability in presentation of this condition mandates an individualised approach to management with involvement of a multidisciplinary team. There is a high rate of recurrence following haemoptysis and a comprehensive assessment of all potential bleeding sites is necessary. CT is a useful tool to help facilitate this and guide further management. Our policy is to close all potential sources of bleeding as CT and invasive angiography rarely identifies an active point of bleeding.

Phase I gene therapy clinical trial design of RP-A601 in adult patients with PKP2-arrhythmogenic cardiomyopathy (PKP2-ACM)

Abstract Background Arrhythmogenic cardiomyopathy (ACM) is a rare, progressive, autosomal dominant disorder characterized by increased risk of ventricular arrhythmias and sudden cardiac death. Up to 45% of all ACM cases are caused by pathogenic variants in the PKP2 gene, which encodes for the desmosomal protein Plakophilin-2. This genetic cardiomyopathy is referred to as PKP2-ACM. AAVrh.74-PKP2a is a recombinant adeno-associated viral (AAV) vector containing the coding sequence of human PKP2 isoform A (PKP2a) and delivers the functional PKP2 gene to cardiomyocytes. Preclinical testing conducted in a clinically relevant mouse model of PKP2-ACM (with survival ≤50 days post disease onset) demonstrated that administration of a single AAVrh.74-PKP2a dose after disease onset extended survival through 5 months with improved right ventricular (RV) function, and decreased cardiac dilation, myocardial fibrosis, and arrhythmias. Additional studies in rodents and nonhuman primates demonstrated AAVrh.74-PKP2a safety. These preclinical findings support clinical initiation. Purpose We describe the design of a phase I trial to assess safety and preliminary efficacy of AAVrh.74-PKP2a (RP-A601) in high-risk adult patients with PKP2-ACM. Methods This study (NCT05885412) is a multi-center, open-label, dose escalation trial evaluating the safety and preliminary efficacy of a single intravenous infusion of RP-A601 in adult patients (age ≥18 yrs) with clinical and genetic PKP2-ACM diagnosis and an implanted ICD. Patients with severe right ventricular dysfunction, LV ejection fraction ≤50% (echocardiogram or cardiac MRI) and/or NYHA Class IV heart failure are excluded. Preliminary efficacy will be assessed at 12 months after RP-A601 infusion and includes evaluation of change in PKP2 myocardial tissue expression and clinical markers of arrhythmia burden. Conclusions PKP2-ACM is a devastating disease associated with high morbidity and mortality. This Phase I trial will evaluate the safety and preliminary efficacy of RP-A601 and was initiated based on robust preclinical efficacy and safety data.

Semaglutide and atrial fibrillation: a systematic review and meta-analysis of randomized clinical trials

Abstract Introduction Semaglutide is a glucagon-like peptide-1 receptor agonist that has been highly recommended for glycemic controland weight reduction. Obesity can also increase the risk of developing atrial fibrillation (AF). Aims To assess the association of semaglutide with cardiac arrhythmias, primarily AF. Methods We performed a systematic searched Pubmed, Embase and Cochrane database, between November and December 2023, to identify semaglutide’s randomized controlled trials (RCTs) with or without diabetic patients that reported new-onset cardiac arrythmias. A Mantel-Haenszel method and a random-effects model was used to calculate the odds ratio (OR) and 95% confidence interval (CI). Results 16 RCTs were included, 6 with oral semaglutide and 11 with subcutaneous semaglutide. A total of 19892 patients were included, providing 137 new-onset AF. Our meta-analysis revealed a lower incidence of new-onset AF in semaglutide patients (pooled odds ratio [OR], 0.54; 95% confidence interval [CI] 0.39, 0.77, P < 0.01; I2 = 0%). Sub-analysis of oral and subcutaneous showed similar significant reduction (pooled OR 0.44; 95% CI [0.22, 0.87], P = 0.02, I2 = 0% and pooled OR 0.59; 95% CI [0.39, 0.88], P < 0.01, I2 = 0%, respectively). Significant reduction was also observed, regardless diabetic status. However, semaglutide revealed similar atrial flutter incidence (pooled OR 0.78; 95% CI [0.30, 2.05], P = 0.62, I2 = 0%), ventricular arrhythmias (pooled OR 1.68; 95% CI [0.77, 3.6], P = 0.19, I2 = 0%) and sudden cardiac death (pooled OR 1.68; 95% CI [0.77, 3.66], P = 0.19, I2 = 0%). Conclusion Our study suggests that in patients with or without diabetes, semaglutide reduces the risk of new-onset atrial fibrillation. This analysis provides an additionalcardiovascular benefit of this drug besides the major adverse cardiovascular events.

Diagnostic yield of clinical cardiac screening in first-degree relatives of SADS and unexplained cardiac arrest probands: a systematic review of the literature

Abstract Background First-degree relatives of SADS victims (defined as a sudden death of a previously healthy individual where no cause can be found despite post-mortem examination) or individuals suffering an Unexplained Cardiac Arrest (defined as a sudden cardiac arrest with successful resuscitation where no cause can be found despite thorough investigation) are recommended to undergo clinical cardiac evaluation for potential inherited cardiac conditions (ICC). However, data on the yield of family screening in these populations remains scarce. Aim This study aimed to perform the first systematic review of the diagnostic yield of clinical screening of first-degree relatives of SADS or UCA probands. A secondary aim was to compare the diagnostic yield of adult-aged and paediatric-aged relatives. Methods The systematic review was prospectively registered on PROSPERO and was undertaken utilising PRISMA guidelines. The online databases Embase, Medline and Web of Science were searched for original articles published in English from 1946 to June 2023. Included studies described the clinical cardiac screening and diagnostic yield of first-degree relatives of SADS and UCA probands. Quality of selected studies were assessed using a modified Joanna Briggs Institute (JBI) checklist. Results 14 studies met the inclusion criteria, which together included 1646 first-degree relatives of SADS probands and 656 first-degree relatives of UCA probands. 11 out of the 14 studies were retrospective cohort studies and cohort size varied from 56 – 398 (median 108, IQR 82-215). Of those studies that reported follow up length (n=8), screening ranged from one-off clinical evaluation to serial clinical screening. Overall diagnostic yield described by included studies ranged from 0 – 25%. The combined mean diagnostic yield of SADS relatives was 11.7% ± 7.5. This did not differ significantly from that of relatives of UCA probands (6.9% ± 7.4) [p=0.246]. Three studies described outcomes of clinical screening in 235 paediatric relatives, with an overall reported yield of 9.4% ± 3.4, which is not significantly different to adult populations (10.4% ± 8.4 [p=0.849]). The most common diagnosis in relatives was Long QT Syndrome followed by Brugada Syndrome. Despite probands having no heart muscle phenotype on post-mortem or clinical evaluation, 22 relatives were diagnosed with a cardiomyopathy (9.3% of all diagnoses). Conclusion Whilst there is a clear indication for clinical screening of first-degree relatives for ICCs following a SADS death or an Unexplained Cardiac Arrest, a lack of well-designed large population-based studies means that the evidence base supporting when or how relatives should be screened is not robust. The diagnostic yield in reported literature varies considerably with no difference between SADS and UCA cohorts and a similar yield in paediatric and adult relatives. This supports systematic screening for all first-degree relatives regardless of age.PRISMA Flow Diagram

Genotype-phenotype correlations in patients with titin variants and cardiomyopathy from a Swiss cohort

Abstract Background Alterations in titin (TTN) are mostly described with dilated cardiomyopathy (DCM). Few studies identified TTN variants in arrhythmogenic cardiomyopathy (ACM), but the overlap of dilated and arrhythmogenic phenotypes in TTN variants is scarcely studied. Most pathogenic TTN variants are located on the A-band, but there is few knowledge about the phenotypic presentation of I-band and Z-disc (non-A-band) variants. Purpose The aim of this study is to characterize and investigate the outcome of patients with cardiomyopathy and pathogenic (P) or likely pathogenic (LP) TTN variants with a particular focus on the cardiomyopathy phenotype (DCM vs. ACM) at initial presentation and follow-up. Further, we studied the association of the TTN variant (A-band vs. non-A-band regions) and a unique phenotype. Methods This is a retrospective multicenter study from a Swiss cohort including 34 patients with P/LP TTN variants and cardiomyopathy. The variables of the secured anonymized database include patient characteristics, genetic, ECG, echocardiographic, and cardiac magnetic resonance (CMR) data. Ventricular arrhythmia (VA) events were divided into non-sustained ventricular tachycardia (nsVT), sustained ventricular tachycardia (sVT) and sudden cardiac arrest (SCA +/- ventricular fibrillation). Results Of 34 included patients, 68% were male. Median age at presentation was 43.5 years. 29 (85%) patients presented with DCM, 7 (21%) left dominant ACM (2020 Padua criteria) and none ARVC (2010 ARVC Task Force criteria). At median follow-up of 48.5 months, 17 (50%) patients had VA events (15 nsVT, 5 sVT and 3 SCA events). VA events significantly increased over time (p=0.008) and were not associated with gender or left ventricular ejection fraction (LVEF) <35%. Under optimal guideline-directed medical therapy (GDMT) mean LVEF and right ventricular function increased significantly (LVEF: 28.3±14.4% vs. 41.9±9.8% and right ventricular fractional area change (RV FAC): 24.7±7.5% vs. 35.8±4.8%, p<0.05). Late gadolinium enhancement (LGE) on CMR was commonest in the basal septum, but no patient had higher degree atrioventricular block (AVB) at baseline and follow-up. At last follow-up, 8 (24%) patients fulfilled ACM and 13 (38%) DCM criteria (Figure 1). Most TTN variants were located on the A-band (21, 62%), 10 (29%) on the non-A-band regions. Latter had higher rates of sVT (log-rank p=0.041) during follow-up (Figure 2). 20 (59%) had LP and 11 (32%) P variants. P variant carriers were younger at disease presentation compared to LP variant carriers. Conclusion Patients with TTN variants frequently present as DCM, whereas presentation as left dominant ACM is less common. TTN does not seem to be a classical ARVC causing gene. Despite favourable biventricular remodelling under GDMT, ventricular arrhythmic events increase during follow-up. I-band and Z-disk variants are associated with a higher risk of sVT, which may help in the risk stratification process.

Atrial and ventricular arrhythmias in young, lifelong and retired elite endurance athletes

Abstract Background Whilst endurance athletes are known to have an overall higher prevalence of atrial fibrillation (AF), the prevalence of other non-sustained and sustained atrial arrhythmias (AAs) and ventricular arrhythmias (VAs) remains poorly defined. Purpose We aimed to define the prevalence of non-sustained and sustained AAs (including AF) and VAs in a healthy cohort of young, lifelong and retired elite endurance athletes. We also sought to assess associations between arrhythmias, fitness and measures of cardiac structure. Methods Holter monitors in healthy endurance athletes (n=288) from an international cohort of elite endurance athletes (the Pro@Heart consortium) were analysed for the presence of sustained and non-sustained AAs and VAs. Athletes were sub-divided into young elite athletes (n=176) and former elite athletes (n=112) of which 60 were lifelong (≥2.5 hours/week) and 52 retired (<2.5 hours/week) athletes (determined by current high-intensity exercise activity). Each athlete underwent cardio-pulmonary exercise testing, echocardiography and contrast-enhanced cardiac MRI. Participants with known structural or electrical cardiac disease were excluded. Independent T-test / One-Way ANOVA (parametric data) or Mann-Whitney U / Kruskal-Wallis Tests (non-parametric data) assessed for differences between the groups. Results Young athletes (n=176, 70.5% male) were significantly fitter with a greater degree of cardiac remodelling as compared with lifelong (n=60, 63.3% male) and retired (n=52, 82.7% male) athletes (Figure 1). The prevalence of non-sustained AAs (young: 4.0% vs lifelong: 66.7% vs retired: 61.5%, p<0.001), sustained AAs (young: 0.6% vs lifelong: 8.3% vs retired: 15.4%, p<0.001) and non-sustained VAs (young: 1.7% vs lifelong: 18.3% vs retired: 23.1%, p<0.001) was higher in lifelong and retired athletes compared with young athletes (Figure 2). Non-sustained VAs were predominately monomorphic (85%), short and moderate rate (median duration 2.8 seconds and heart rate 154 beats per minute). No athletes developed sustained VAs and/or sudden cardiac arrest. Young athletes had less VAs that were multifocal in origin compared with lifelong and retired athletes (young: 29.5%, lifelong: 37.3%, retired: 53.5%, p=0.027). There was no difference in prevalence of any arrhythmia between lifelong and retired athletes. There were no significant correlations between arrhythmias and fitness or cardiac imaging parameters. Conclusion Healthy athletes have a significant prevalence of non-sustained atrial and ventricular arrhythmias and sustained atrial arrhythmias that is more prevalent in older athletes. In older athletes, the prevalence of arrhythmias is similar regardless of whether athletes are actively engaged in training or retired suggesting that pro-arrhythmic remodelling in athletes is sustained, not immediately reversible and may be minimally responsive to detraining.Arrhythmias and cardiac imagingArrhythmias amongst athlete groups

Low levels of apolipoprotein M are associated with increased risk of ventricular arrhythmias

Abstract Background Ventricular arrhythmia (VA) is a frequent cause of sudden cardiac death (SCD). Treatment to prevent SCD includes device therapy with implantable cardioverter defibrillator (ICD). Although the electrophysiology underlying VA have been described, the molecular understanding of VA risk remains unclear. Purpose To identify proteins that are associated with higher and lower risk of VA. Methods SMASH 1 Study was a prospective observational study of 490 patients treated with ICD. The plasma proteome was analyzed with the Olink Explore 384 Cardiometabolic platform at study inclusion, and patients were followed for mean 3.1± 0.7 years. VA events were defined as adjudicated ventricular fibrillation or sustained ventricular tachycardia registered from ICD recordings and clinical events were recorded from electronic health records. Protein concentrations were quantified relatively as normalized protein expression on a log2-transformed concentrations where a large number represents higher protein level in the sample. Results The mean age was 66±12 years, 83% were male and 51% had a primary prevention ICD-indication. Episode(s) of VA occurred in 137 patients (28%) during follow-up. In total, 353 distinct proteins were successfully analyzed in all patients. Among these, high B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels were associated with a higher risk of VA, while Apolipoprotein M (APOM) was the only protein significantly associated with a lower risk of VA after multiple testing using Benjamini-Hochberg correction (Figure, Panel A). After adjusting for age, sex, body mass index, coronary artery disease, heart failure, renal function, left ventricular ejection fraction and antiarrhythmic medication, only low APOM levels remained significantly associated with VA: HR 0.51 (95%CI 0.32-0.79] per log unit increase, p=0.003. Patients in the lowest quartile of APOM had a particularly high risk of incident VA: HR 2.26 (95%CI 1.60-3.19), p=3.61x10-6, compared to quartile 2-4 (Figure, Panel B). High APOM levels were also associated with a lower risk of HF hospitalizations (HR 0.25 [95%CI 0.16-0.40], p<0.001) and all-cause mortality (HR 0.36 [95%CI 0.22-0.60], p<0.001), and these associations remained significant in adjusted models. Conclusions Low levels of APOM are associated with a greater risk of incident VA, independently of established risk factors. Low APOM also predicted risk of HF hospitalizations and mortality in our cohort, which suggest protective cardiovascular effects of APOM. Figure: Association of individual proteomic measures with risk of ventricular arrhythmias (VA).A:Volcano plots of the associations of individual plasma proteins with incident VA. The dotted line represents the significance level at false discovery rate <0.05 and the red dots are significant proteins after multiple testing using Benjamini-Hochberg correction.B: Risk of VA by quartile of Apolipoprotein M.

Changes in practice of exercise advice provision following the publication of ESC 2020 guidelines on sports cardiology and exercise at a central London inherited cardiac conditions outpatient service

Abstract ESC 2005 and AHA guidelines 2015 in sports cardiology restricted individuals with hypertrophic cardiomyopathy (HCM) from moderate and high intensity exercise and limited them to low intensity sport.1,2 Perceived increased risk of sudden cardiac death (SCD) with vigorous exercise in individuals with HCM was based on early registry data from the United States.3 This enforced sedentary lifestyle has led to an increasing trend towards obesity, atrial fibrillation and atherosclerotic coronary artery disease in patients with HCM.4 Recent ESC 2020 guidelines on exercise5 has enabled clinicians to recommend safe levels of exercise for these patients. We audited how well our outpatient practice reflected the guidance set out in 2020 ESC guidelines on exercise for patients with cardiovascular disease. Electronic records of 731 patients with a clinical diagnosis of HCM seen in our outpatient service between 2008-2023 were audited to determine whether written advice on exercise was given and if this was in line with the current ESC guidelines at any encounter. 731 patients with a mean age of 62±14.5 (range 17-91 years) were seen in our specialist outpatient service. 68% were male. 51% of patients received exercise advice either at their initial visit ± a follow-up visit. A significant proportional increase (16%,P<0.001) was seen in the number of patients receiving exercise advice at their initial visit after publication of the ESC 2020 guidelines (Table 1). 43% (270/634) of those who had their initial visit pre-guidelines received updated exercise advice as per 2020 ESC guidelines during follow-up. There was an increase in the proportion of patients receiving exercise advice each year after publication of ESC guidelines (Graph 1). Immediately following the publication, a high proportion received specific advice pertaining to intensity and duration of exercise (68% in 2020) with a slight decline subsequently (43%, 36% and 47% in 2021, 2022 and 2023 respectively). 27 patients had an implantable cardioverter defibrillator (ICD) in situ at the time of initial review with a further 127 undergoing ICD insertion under our care. SCD risk was documented for 66% (468/704) of patients according to the 2014 ESC Risk-SCD Model. 63% (214/338) of low-risk patients received exercise advice, whilst 77% (40/52) and 54% (42/78) of intermediate and high-risk patients received exercise advice respectively. 22 deaths (3%) were recorded during the follow-up period with none occurring during exercise. All cases except 2 were non-cardiac related. An overall improvement was seen in our practice with a significant increase in the number of patients receiving exercise advice after publication of the new guidelines. Despite this, only 51% of our patients received any written guidance on exercise demonstrating a need for further improvement in our outpatient practice to reflect the paradigm shift in the approach to exercise in individual with HCM as set out by the ESC 2020 guidance.

Novel electric predictors of lethal arrhythmic event in patients with hypertrophic cardiomyopathy

Abstract Background Little is known regarding the association between electrical markers and lethal arrhythmic events (LAE) in patients with hypertrophic cardiomyopathy (HCM). This study aimed to identify the electrical predictors of LAE in adult patients with HCM. Methods This study was a retrospective analysis of patients with HCM at a single center from 1998 to 2021. LAE was defined as a composite outcome of (1) sustained ventricular arrhythmia, (2) aborted sudden cardiac death (SCD), (3) implantable cardioverter defibrillator (ICD) implantation, and (4) appropriate ICD shock. A 12-lead electrocardiography was performed at the time of diagnosis. Results A total of 611 patients with HCM were analyzed, and 48 (7.8%) experienced LAE. Patients who experienced LAE were diagnosed at a younger age and more frequently had history of ventricular arrhythmia, new-onset atrial fibrillation (AF) or non-sustained ventricular tachycardia. New-onset AF, an increase in the QTc interval, and the absence of massive LVH were associated with LAE risk. In addition to conventional markers of HCM Risk-SCD, consideration of the QTc interval and massive LVH on electrocardiography improved the prediction of LAE (area under curve 0.682 to 0.740). Further inclusion of new-onset AF, history of ventricular arrhythmia, HCM type, and left ventricular mass index improved the predictability to 0.867. Conclusion An increase in the QTc interval, the absence of a massive LVH pattern on electrocardiography (ECG), and new-onset AF were independently associated with an increased risk of LAE. Comprehensive stratification using electrical markers improves the prediction of LAE when combined with conventional markers.

Genotype-phenotype relationship in hypertrophic cardiomyopathy

Abstract Background/Introduction Hypertrophic cardiomyopathy (HCM) is an inherited highly heterogeneous disease with variable penetrance and expression, but the exact relationship between the underlying genetic cause and the clinical course remains elusive. Purpose The aim of our study was to analyse the phenotypic and molecular characteristics of individuals with HCM examined and treated at our University Hospital. Methods Clinical data from adult HCM patients treated at our hospital between 2005 and 2023 were analysed. Informed consents to participate in the study were obtained from all participants. Clinical manifestation, instrumental examination and next generation sequencing (NGS) data of HCM related genes were collected. The Mann–Whitney U for two groups and Kruskal–Wallis tests for more than two groups were used to compare continuous variables. Univariate logistic regression was used to analyze categorical variables. Results The study involved 191 unrelated individuals, 58.6% males, the median age at HCM diagnosis was 50, interquartile range 37 – 60 years. A median follow-up was 3.9 [1.6-6.4] years. Pathogenic and likely pathogenic (P/LP) variants were identified in 45.5% (N=87) of affected individuals. Truncating variants were observed in 31 individuals. MYBPC3 P/LP variants were the most common (N=47), following by MYH7 (N=22) and other (N=18). Individuals with MYBPC3 P/LP truncating variants had higher HCM estimated 5-year risk of sudden cardiac death (SCD) during primary evaluation (3.1 [2.5-4.6]) compared to individuals with P/LP variants in other genes (2.4 [1.9-3.7]) and individuals with negative NGS results (1.8 [1.5-2.7], p<0,001). Patients with MYBPC3 P/LP variants experienced the earliest onset of symptoms (median age 37.0 [30.5-50.0] years) and HCM diagnosis (median age 38.0 [31.0-51.5] years) compared to individuals with other genes P/LP variants (median age 46.0 [31.0-56.2] years and 47.5 [31.5 – 59.5] years, respectively) and genotype negative individuals (median age 51.5 [44.0-61.0] years and 52.0 [45.0-63.2] years, respectively), p>0,001). The presence of P/LP variant was associated with significantly thicker left ventricular wall (maximal thickness) on cardiac imaging in comparison with negative NGS results (18.0 [15.0-21.0] mm vs. 16.0 [14.0-18.0] mm, p=0.002 on transthoracic echocardiography and 20.0 [17.0-22.5] mm vs. 18.0 [16.0-20.0] mm, p<0,001 on cardiac magnetic resonance). The presence of MYBPC3 truncating variants were associated with the greatest risk of ventricular tachycardia in comparison with negative NGS results (OR 3.05, 95% CI:1.3, 8.0, p=0.025). Conclusion More severe HCM phenotype is associated with detection of P/LP variants in HCM related genes. The presence of the MYBPC3 P/LP variant is associated with an earlier onset of the disease and truncating variants of this gene are related to a higher risk for ventricular tachycardia and an estimated 5-year risk of SCD.

Changes in mental health and illness perception in patients with hypertrophic cardiomyopathy referred to hybrid cardiac telerehabilitation in comparison to usual care - a randomised-control trial

Abstract Purpose Hypertrophic cardiomyopathy (HCM) is a complex cardiac disorder, that influences patients' physical capacity and quality of life, as well as the risk of sudden cardiac death (SCD). Patients with HCM often experience emotional distress due to the uncertainty of their condition and have a threatening illness perception (the way individuals make sense of their illness, which can have a significant impact on adherence to treatment). Current studies suggest that some HCM patients could benefit from hybrid cardiac telerehabilitation (HCTR) in terms of somatic and psychological status. This study is part of a research project investigating the safety and effectiveness of hybrid cardiac telerehabilitation for HCM patients. The specific focus of this part is to evaluate the changes in mental health status and illness perception of HCM patients who have been referred for cardiac telerehabilitation compared to those receiving usual care. Methods An RCT study was conducted, with the inclusion criteria for the study of being above 18 y.o., HCM without LVOT obstruction, NYHA Class II or III, LVEF ≥ 50%, and having CIED. The study involved telerehabilitation (HCTR) and control (CG) groups. Both groups were completing questionnaires assessing illness perception (Brief IPQ) and overall psychosocial distress (GHQ-28) with its 4 domains: somatic symptoms, anxiety, social impairment, and depression. Psychological assessment was performed at the beginning and at the end of telerehabilitation/outpatient care, and at 3, 6 and 12 months after the end of care (T1/T2/T3/T4/T5). Results There was a significant improvement in the overall distress level in the HCTR group (p=0.003) but not in the CG (p=0.559). It remained significant in the HCTR group for the T2 (p<0.001), T3 (p=0.008), and T4 (p<0.001). The positive change was observed in somatic symptoms only in the HCTR group: for T2 (p=0.025) and T3 (p=0.032) compared to the T1. The gradual decrease in anxiety level was observed in the HCTR group, but not in the CG, with a significant difference for T4 (p=0.013) compared to T1. Although there was an improvement in social impairment in both groups (p=0.049 for the CG, and p=0<0.001 for the HCTR group), only in the HCTR group it held a stable pattern after the intervention (p<0.001 for T2; p=0.013 for T3; p=0.032 for T4). There were no changes in the level of depressive symptoms in either of the compared groups. There were also no significant differences in the illness perception (p=0.200 for the HCTR group and p=0.090 for the CG), although the HCTR group showed short-term improvement after three months of HCTR (T2) (p=0.032). Conclusions There are significant benefits of hybrid cardiac telerehabilitation for mental health, level of distress, and illness perception in HCM patients. It is worth noticing that this improvement is short-term, and prolonged effects might require providing additional support during extended care.overall distress in HCTR vs CGsubscales of GHQ_28 in HCTR vs CG