Risk Of Ventricular Arrhythmias Research Articles

Time-varying cox model for heart failure prediction in phospholamban p.(Arg14del)-positive individuals

Abstract Background Phospholamban (PLN) p.(Arg14del)-positive individuals are at risk for developing severe heart failure (HF), yet a comprehensive risk model for this outcome is missing. Our PLN registry contains longitudinal data which enables us to capture dynamic changes in covariables over time, while prior prediction models rely on baseline clinical information which may change over time. Using this longitudinal clinical information will enhance the accuracy of HF prediction and may aid patients selection for future (gene)therapy. Purpose The aim of this study is to develop a dynamic HF risk prediction model for PLN p.(Arg14del)-positive individuals. Method Data were collected of 594 PLN p.(Arg14del)-positive individuals who had no documented history of HF or myocardial infarction at time of the first echocardiography. We incorporated two time-dependent covariates in our time-varying Cox regression model: longitudinal individual predicted left ventricular ejection fraction (LVEF) and longitudinal individual predicted relative risk for major ventricular arrhythmia (VA). Predicted LVEF values were derived using observed LVEF values in a linear mixed-effect model, while the relative risk for major VA was predicted using a Cox regression model with major VA as the outcome. These time-dependent covariates were included in the time-varying Cox regression along with baseline covariables age at inclusion and previous major VA. The results were validated using 5-fold cross-validation. Results Over a median follow-up period of 3.6 years (interquartile range 1.4-6.8), 77 (13%) individuals developed HF, defined as a composite endpoint of HF hospitalisation, implantation of left ventricular assist device, heart transplantation and HF-related mortality. Our time-varying Cox regression model demonstrated a robust 5-year mean C-statistic of 0.904 (95% CI 0.901-0.908). The hazard ratio for time-dependent LVEF predictions was 0.89 per % LVEF increase (95% CI 0.87-0.91, p <0.001) and for time-dependent relative major VA risk predictions 3.59 (95% CI 1.49-8.69, p = 0.005). Regarding baseline covariates, age at inclusion had a hazard ratio of 1.01 (95% CI 0.99-1.03, p = 0.47) and previous major VA 0.48 (95% CI 0.21-1.1, p = 0.08). Combining the hazard ratios of time-dependent predicted relative risk for major VA and major VA in history results in a hazard ratio of 1.73. Conclusion Our study introduces a novel time-varying Cox regression model for the individual prediction of heart failure events in PLN p.(Arg14del)-positive individuals which may aid patient selection for future (gene)therapy. Results demonstrate robust predictive performance (C-statistic of 0.904, 95% CI 0.901-0.908), highlighting the significance of incorporating longitudinal data for enhanced prediction accuracy.

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.

Prediction of mortality, future arrhythmia and cardiovascular disease: an artificial intelligence-enhanced electrocardiography platform

Abstract Background Artificial intelligence-enhanced electrocardiography (AI-ECG) can be used to identify existing disease, but could additionally be used to predict occurrence of future disease and death. Purpose We developed an AI-ECG platform that predicts mortality and a wide spectrum of future arrhythmia and cardiovascular disease. Methods The AI-ECG risk estimation platform (AIRE) was developed in a dataset of 1,163,401 ECGs from 189,539 patients from a secondary care setting in the USA. Uniquely, AIRE uses deep learning with a residual convolutional neural network with a discrete-time survival loss function to output subject-specific survival curves (Fig 1A). AIRE was fine-tuned to additionally predict the endpoints described below. Results AIRE accurately predicts risk of all-cause mortality (C-index 0.775 (0.773-0.776) and can differentiate prognosis in high- and low-risk subjects, even when only cardiologist-defined normal ECGs are considered (Fig 2B). Additionally, in Cox regression analyses, AIRE was superior to conventional risk factors (Fig 1B). AIRE accurately predicted future ventricular arrhythmia (c-index 0.760 (0.756-0.763)), future complete heart block (CHB) (0.809 (0.805-0.814), future atrial fibrillation (0.753 (0.751-0.756), future atherosclerotic cardiovascular disease (0.696 (0.694-0.698)) and future heart failure (0.787 (0.785-0.789)) . AIRE was superior to left ventricular ejection fraction (LVEF) in predicting risk of future ventricular arrhythmias in subjects with LVEF <50% (C-index 0.649 (0.638 – 0.660) vs 0.615 (0.603 – 0.626) p < 0.0001 ). For CHB prediction, AIRE was able to further risk stratify subjects with bifascicular block and syncope into low (1.9% 5 year CHB), intermediate (8.8%), and high risk (20.7%) groups, and could guide treatment decisions. We externally validated our findings in four diverse, transnational cohorts from Brazil and the UK, including volunteers, primary care subjects and patients with Chagas disease, and found AIRE accurately predicted all-cause mortality in all four external cohorts (Fig 2). Non-mortality endpoints were successful externally validated in the UKB. In explainability analyses, we found features of QRS morphology, low QRS voltage, poor precordial R wave progression, inverted and biphasic T waves and ST segment changes were the most significant morphological features associated with high predicted mortality (Fig 1D). Through phenome- and genome-wide association studies (GWAS), we identified candidate biological pathways including changes in cardiac structure (LV mass, LV trabeculation and left atrial size). GWAS identified variants adjacent to VGLL2, KCNQ1, CCDC91 and TBX3 which have been described in association with QT interval, biological aging and metabolic syndrome (Fig 1E). Conclusion AIRE could be used worldwide across a range of clinical contexts for risk estimation of not only mortality but a wide spectrum of future arrhythmia and cardiovascular diseases.Figure 1Figure 2

The genetic architecture of exercise-induced ventricular ectopy

Abstract Background Previously, we have shown that the frequency of exercise-induced premature ventricular contractions (PVCs) during and after exercise are associated with increased risk of major adverse cardiovascular events in asymptomatic individuals from the UK Biobank study1. The underlying mechanisms are, however, unclear. Several electrocardiographic markers associated with arrhythmogenesis have a known hereditary component, but the genetic underpinnings of exercise-induced ventricular ectopy have not been investigated. Purpose Our aim was to explore the genetic basis of premature ventricular ectopy during and after exercise and unveil plausible candidate genes and biological mechanisms. Methods We conducted a genome-wide association study (GWAS) for PVC frequency during exercise and recovery in >44,000 asymptomatic individuals of European ancestry without known cardiovascular disease from the UK Biobank study. As the distribution of PVC frequency is highly skewed (e.g. absence of negative values and excess of zero values), we first applied Gaussian transformation. Simulation studies were performed to justify that this approach would lead to valid inference. In the GWAS model, we included sex, age, UK Biobank genotyping array, and the first 10 genetic principal components as covariates. Statistical power was boosted by joint analysis of exercise and recovery PVC traits using multi-trait analysis of GWAS (MTAG)2. Genetic risk scores were constructed in independent samples from UK Biobank (N=341,948) and were tested for association with heart failure and life-threatening ventricular arrhythmias. Results We identified 4 loci for PVC frequency during exercise, and 1 locus for PVC frequency during recovery (Picture 1). Candidate genes included CRIM1, FLNC, and BAG3 for which mutations have been linked in the pathogenesis of (arrhythmogenic) cardiomyopathy. Subjects in the top 10% of the genetic risk scores had a significantly higher risk of heart failure and life-threatening ventricular arrhythmias compared to the bottom 90%, (odds ratio (OR) (95% confidence interval): 1.14 (1.08 – 1.20), p < 0.001; and 1.13 (1.02 – 1.24), p < 0.001, respectively). Conclusions Ventricular ectopic burdens during exercise and recovery have a significant heritable component. Candidate genes highlight a possible shared genetic background with inherited cardiomyopathy and a genetic risk score was associated with heart failure and ventricular arrhythmias. These findings substantial advance our understanding of the genetic basis of exercise-induced ventricular ectopy in a population-based cohort without cardiovascular disease.Miami plot of ventricular ectopic burden

Comparing outcomes in cardiogenic shock patients with ischemic versus nonischemic cardiomyopathy: A nationwide retrospective observational study

Abstract Introduction Ischemic and non-ischemic cardiomyopathy are common causes of heart failure. In our study, we compare the in-hospital outcomes between these two groups of patients with cardiogenic shock. Methods Data was obtained from the Nationwide Inpatient Sample database between January 2016 to December 2020. The study included all adult patients who were in cardiogenic shock and either ischemic cardiomyopathy (ICM) or non-ischemic cardiomyopathy (NICM). The primary outcome was inpatient mortality. Secondary outcomes were cardiac arrest, arrhythmias, acute respiratory failure, and acute renal failure, as well as the need for ventilators, dialysis, and ECMO. Results Among 168,591 adult patients who had cardiogenic shock during their hospitalization, 72,538 patients had either ischemic cardiomyopathy or nonischemic cardiomyopathy. Among them, 31,854 (43.9%) had ischemic cardiomyopathy (ICM) vs 40,684 (56.1%) who had nonischemic cardiomyopathy (NICM). Patients with NICM had higher in-patient mortality (24.6% vs 26.1, aOR: 1.12; 95% CI: 1.08-1.16, p<0.001); when adjusted for age, sex, race, and Charlson comorbidity index. Furthermore, patients with NICM also had a higher risk of respiratory failure (54.1% vs 53.8%, aOR:1.11, 95% CI: 1.07-1.14, p<0.001) and required more life-saving treatments like pressors (1.6% vs 0.7%, aOR: 1.14; 95% CI: 1.10-1.20, p< 0.001) and dialysis (12.7.1% vs 11.3%, aOR:1.20, 95% CI: 1.14-1.26, p<0.001). However, these patients with NICM had a lower risk of cardiac arrest (7.2% vs 7.8%, aOR: 0.88; 95% CI: 0.84-0.94, p< 0.001) and ventricular arrhythmias (29.5% vs 32.2%, aOR: 0.82; 95% CI: 0.80-0.86, p<0.001) as well as lower ECMO utilization (2.5 vs 2.1, aOR:0.82; 95% CI: 0.73-0.92, p <0.001) and blood transfusions (9.8% vs 11.7%, aOR:0.839; 95% CI: 0.80-0.88, p< 0.001). There was no significant difference in the ventilator use between the 2 groups (40.3% vs 39.7%, aOR:1.01, 95% CI: 0.97-1.04, p=0.714). Conclusion The findings of this study underscore the higher in-patient mortality among patients with non-ischemic cardiomyopathy (NICM) presenting with cardiogenic shock. These results emphasize the need for tailored treatment approaches targeting NICM-CS, warranting dedicated diagnostic and therapeutic strategies to improve prognosis in this vulnerable patient subset.Odd's ratios for NICM-CS vs ICM-CS

Long-term time-to-ventricular arrhythmic event prediction using a deep learning based model on the electrocardiogram signal

Abstract Background Ventricular arrhythmias (VA) risk stratification tools in individuals without known cardiovascular disease are still insufficient. Previous studies have used convolutional neural networks (CNN) to classify VA by the end of an established follow-up period using the electrocardiogram (ECG), showing a moderate performance (area under the curve [AUC] of 0.610). We hypothesised that the appearance of the VA substrate on the ECG signal depends on the proximity of the ECG acquisition to the VA event. Thus, the performance could improve if the CNN was trained to predict time-to-VA event instead, and if the presence of censored data was considered. Purpose We developed and tested a CNN to predict time-to-VA event in middle-aged individuals without known cardiovascular disease, and we compared its performance with that from ECG indices, such as QRS duration, QT interval and T-wave morphology variations (TMV), as well as sex and age. Methods A total of 69,283 individuals without known cardiovascular disease from the UK Biobank were used as the training set. We applied 10-fold cross validation to train a CNN, where the input was a 15-second ECG at rest (lead I), and the output was ‘occurrence of VA’, ‘censored’, or ‘survival’, up to 1, 2, 3, 4, 6, 8, 10 and 12 years after the ECG acquisition. We used 15-second ECG (lead I) from an independent cohort of 17,320 individuals without cardiovascular disease also from UK Biobank as a test set, where we set a follow-up of 10 years. The above ECG indices were derived from the median heartbeat from the ECG using in-house algorithms. We derived optimal cut-off thresholds from the training test, and we evaluated the AUC, sensitivity, specificity and Cox regression hazard ratios (HR) in the test set. Results In the test set, 9,206 individuals (53%) reached the 10-year follow-up, during which 60 (0.7%) had a VA event. The AUC, sensitivity and specificity values of the CNN were 0.715, 0.881 and 0.400, respectively. These values were 0.592, 0.686 and 0.383 for the QRS duration, 0.569, 0.156 and 0.717 for the QT interval and 0.552, 0.712 and 0.350 for TMV. The combination of sex and age alone showed performance values of 0.760, 0.694 and 0.683, respectively. Survival analyses showed a HR of 3.883 (P = 3.0 x 10-7) for individuals with a CNN prediction greater than the threshold derived in the training set after adjusting for age and gender. Conclusions A CNN that is trained to predict time-to-VA event and accounts for censored data outperforms previous classification proposed models and the predictive value of individual ECG indices of risk. Although the predictive value of the CNN does not show a better long-term VA predictive value than sex and age alone, it provides a significant contribution independently from these two risk factors. Our findings support the use of the ECG to improve long-term VA risk stratification, which might be particularly useful in age- and sex-stratified analyses.

Smaller intrinsic QRS area and smaller reduction of QRS area during cardiac resynchronisation therapy are associated with higher risk of ventricular arrhythmias and appropriate ICD therapy

Abstract Background Cardiac resynchronisation therapy (CRT) patients are at high risk for ventricular arrhythmias (VAs), and little is known about which characteristics are associated with an increased risk for arrhythmic events. Purpose To investigate the association between QRS area parameters and the risk for VAs in patients with heart failure undergoing primary preventive CRT with defibrillator (CRT-D) implantation. Methods All patients receiving CRT-D between 2015 and 2020 at a large-volume tertiary care center were retrospectively evaluated. Digital 12-lead electrocardiograms (ECGs) were collected before and after CRT implantation. Patients were included if they had native LBBB and were implanted with a primary preventive CRT-D. Kors’ regression transformation was used to derive vectorcardiographic QRS area from the 12-lead ECGs. QRS area parameters were analysed in relation to a primary endpoint of first appropriate ICD therapy, i.e., ATP or shock therapy. Results 177 patients with LBBB (68.9 years [60.7–73.8]; 21.5% female; 52.9% New York Heart Association (NYHA) class III-IV; LVEF 25.9±6.3%) were followed over a median follow-up time of 2.5 years [1.6–3.0] after CRT-D implantation. 27 patients reached the primary endpoint. The median pre-CRT QRS area was 134.5 μVs [102.3–163.8]. Multivariable Cox regression identified a small pre-CRT QRS area (HR, per 10 μVs decrease, 1.30; [1.12–1.51]; p=<.001) and a small post-CRT reduction in QRS area (HR, per 10 μVs decrease, 1.30; [1.13–1.49]; p=<.001) as independent predictors of an increased risk of appropriate ICD therapy. In analyses with a scoring variable combining pre-CRT QRS area and QRS area reduction both above or below median, the combination of a small pre-CRT QRS area and a small QRS area reduction was strongly associated with an increased risk of reaching the endpoint (HR, per point increase, 2.47; [1.2–4.9]; p=0.01). Conclusion A small intrinsic QRS area, by itself or in combination with a small reduction of post-CRT QRS area, was strongly associated with a higher risk of ventricular arrhythmias in this cohort of CRT-D treated patients. In conjunction with other parameters, further risk stratification for arrhythmic events could be achieved by assessing QRS area data pre- and post-CRT.Figure 1.K-M pre-CRT QRS area quartilesFigure 2.K-M QRS area score

Comparison of ventricular tachyarrhythmias in HF patients on dapagliflozin versus empagliflozin

Abstract Background Ventricular tachycardia (VT) and ventricular fibrillation (VF) are devastating tachyarrhythmias that can cause sudden cardiac death in patients with heart failure (HF) if not anticipated or treated promptly. Although post-hoc analysis in DAPA-HF showed promise in their benefit, Sodium-glucose transport protein 2 inhibitors (SGLT2i) have not yet been evaluated for their effect on these tachyarrhythmias. This retrospective analysis aims to compare the 2 most commonly used SGLT2i agents, dapagliflozin and empagliflozin, and the incidence of VT in patients with HF. Methods The TriNetX Research network was used for this study. The two initial patient cohorts were created using ICD-10 codes and medication codes from the TriNetX platform. Both cohorts consisted of patients over age 60 with a history of heart failure and either VF or VT. One cohort was on treatment with dapagliflozin and the other with empagliflozin. The cohorts were balanced by propensity score matching and the greedy nearest neighbor algorithm for age, gender, race, ethnicity, hyperkalemia, and the current use of spironolactone, amiodarone, metoprolol, and carvedilol, resulting in 9,841 patients in each arm. The cohorts were then evaluated for the development of VF or VT over the subsequent five years as well as all-cause mortality. Additional cohorts were created to evaluate dapagliflozin vs empagliflozin in diabetics, nondiabetics, and patients with ejection fractions less than 35% Results Dapagliflozin was associated with an increased risk of ventricular arrhythmia in heart failure patients compared to empagliflozin (46.0% vs. 40.8%, RR 1.13, 95% CI (1.09,1.16), P value < 0.0001). It was also associated with higher mortality at five years (RR 1.10, 95% CI (1.03,1.18), P value 0.0034). Conclusions In comparisons between dapagliflozin and empagliflozin in heart failure patients with previously documented ventricular arrhythmias, empagliflozin had 13% less risk of recurrence of ventricular arrhythmias. Secondarily, the empagliflozin cohort also exhibited lower all-cause mortality (14.8% vs 16.3%) at five years from starting the drug. Our analysis does not disprove findings in DAPA-HF, but rather may support the potential class effect of SGLT2 inhibitors in their ability to suppress VT.(1) Importantly, the overall incidence of ventricular tachyarrhythmias is high in both cohort, given we selected a high-risk population. Notably, our documented recurrence rate is similar to past reports of recurrence after VT ablation, the gold standard for treatment of VT. (2) SGLT2 inhibitors have shown clear benefit in multiple placebo-controlled studies in terms of heart failure outcomes like mortality and readmission, but their effect on arrhythmias is one more additional benefit this class may have. (3) Given these associations, empagliflozin may be a more favorable options for HF patients who have already had VT or VF.

The cardiac sympathetic co-transmitter neuropeptide-Y is pro-arrhythmic in human cardiomyocytes by lengthening activation-recovery interval

Abstract Background Myocardial infarction (MI) is associated with sympathetic overactivity, during which the co-release of neuropeptide-Y (NPY) is prominent. NPY is associated with arrhythmia risk and mortality following ST-elevation MI, although the exact mechanisms for this in human cardiomyocytes remains unclear. Purpose We therefore tested the hypothesis that NPY signalling would alter the electrophysiology of human induced-pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in a way that would promote arrhythmia, and that in patients being treated for MI, high NPY concentrations previously associated with ventricular arrhythmia (>27.3 pg.mL-1) would be associated with comparable ECG changes. Methods Immunohistochemistry and western blot were performed on hiPSC-CMs and ventricular biopsies from human patients undergoing valve surgery. The FRET-based sensor Epac-SH187 was expressed in hiPSC-CMs to monitor the cyclic adenosine 3’,5’-monophosphate (cAMP) response to NPY. A micro-electrode array was used to investigate the effects of NPY on a confluent layer of iPSC-CMs, measuring changes in activation, recovery, conduction velocity and spontaneous automaticity. Additionally, patients presenting with ST-elevation MI had peripheral venous [NPY] measured and compared to 12-lead ECGs recorded following stenting. Results hiPSC-CMs expressed Y1 and Y5 receptor mRNA and protein, which are also expressed in ventricular biopsies from human patients. NPY (1-100 nM) significantly reduced intracellular cAMP levels (n=65), most effectively prevented by Y5 receptor inhibition (1µM CGP71683A, n=40). In a confluent layer of hiPSC-CM, NPY (100 nM) slowed late-repolarisation represented by T-wave peak-end duration (p=0.04), which could be prevented by Y1-receptor inhibition (1 μM BIBO 3304, n=6), and caused prolongation of rate corrected activation-recovery interval (ARIc) (p=0.009, n=6) which could be abolished by Y5-receptor inhibition (n=7). NPY significantly increased automaticity to more than one site of initiation in 4/6 (66.7%) compared to 2/14 (14.3%) control plates (p=0.037), despite no change in conduction velocity. Moreover, in 65 patients being treated for ST elevation MI, those with high peripheral venous NPY concentrations were well matched in terms of cardiovascular risk factors, medications on admission, and pain to balloon times, but had significantly longer corrected QT interval (QTc) on the 12 lead ECG (p=0.04) despite no differences in PR interval, heart rate or electrolyte concentrations. Conclusions NPY slowed late repolarisation and caused ARIc prolongation, which was associated with increased automaticity in human iPSC-CMs. NPY also correlated with QTc-prolongation in patients being treated for MI and may contribute to the increased incidence of ventricular arrhythmia observed in these patients. Antagonists of Y1 and Y5 receptors may therefore offer an adjunct to β-blockade therapy to reduce the risk of ventricular arrhythmia.

Diabetes and sudden cardiac death in a nationwide, unselected population

Abstract Background and purpose Sudden cardiac death (SCD) remains a prominent cause of mortality, with individuals afflicted by diabetes mellitus (DM) bearing a heightened risk of ventricular arrhythmias and SCD. However, comprehensive investigations in a nationwide, unselected context are lacking. Therefore, this study aimed to compare the incidence rates (IR) of SCD among individuals with Type 1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus (T2DM) to the general population. Methods The study included the entire Danish population (approximately 5.5 million individuals) in 2010. SCD cases were identified through the detailed Danish death certificates and discharge summaries, yielding 6851 cases of SCD. The Danish Register of Medicinal Product Statistics, containing comprehensive prescription data from Danish pharmacies, facilitated the identification of individuals with T1DM and T2DM. Loss of life years was estimated for both T1DM and T2DM patients. Results Among the identified 6851 SCD cases, 272 (4%) were diagnosed with T1DM, and 833 (12%) with T2DM. Incidence rates of SCD were consistently elevated across all age groups for individuals with diabetes, compared to the general population (Figure 1). Patients with T1DM exhibited higher incidence rates than patients with T2DM (Figure 1). Notably, individuals aged 30-40 years with DM showed the greatest differences in incidence rates of SCD compared to the general population, with incidence rate ratios of 20.0 (95% confidence interval: 11.8-80.0) and 5.6 (95% confidence interval: 2.7-14.0) for T1DM and T2DM, respectively. On average, each 30-year-old patient with either T1DM or T2DM experiences a reduction of 3.7 and 3 life-years, respectively, due to the increased risk of SCD in these groups (Figure 2). Conclusion This nationwide study examines the incidence rates of SCD among individuals with and without a history of DM across all age brackets. Notably, patients with DM display consistently elevated incidence rates across age groups, with a particularly pronounced risk observed in those with T1DM. For both T1DM and T2DM, SCD is an important contributing factor to their shorter life expectancy compared to the general population. The heightened risk among individuals with DM underscores the importance of improved risk stratification for these patients.Incidence rates of SCDStacked cumulative incidence curves

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.

Atrial cardiomyopathy resulting from loss of plakophilin-2 expression: Response to adrenergic stimulation and implications for the exercise response.

Atrial arrhythmias occur in 20-40% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and are associated with an increased risk of sustained ventricular arrhythmias and inappropriate implantable cardioverter-defibrillator shocks. The pathophysiology of atrial arrhythmias in ARVC remains unclear. Most cases of gene-positive ARVC are linked to pathogenic variants in the desmosomal gene plakophilin-2 (PKP2). Here, we test the hypothesis that loss of PKP2 expression leads to pro-arrhythmic changes in atrial cardiomyocytes. Atrial cells/tissue were obtained from a cardiac-specific, tamoxifen-activated model of PKP2 deficiency (PKP2cKO). By contrast to PKP2cKO ventricular myocytes, PKP2cKO atrial cardiomyocytes presented no significant differences in intracellular calcium (Ca2+ i) transient dynamics, sarcoplasmic reticulum load or action potential morphology. PKP2cKO atrial cardiomyocytes showed elevated reactive oxygen species levels, increased frequency and amplitude of Ca2+ sparks, and increased diastolic [Ca2+]i compared to control; the latter two parameters were further increased by isoproterenol exposure and reversed by exposure to ryanodine receptor blocker dantrolene. We speculate that these isoproterenol-dependent effects may impact on the exercise-related atrial arrhythmia risk in ARVC patients. Despite absence of changes in Ca2+ i transient dynamics, PKP2cKO atrial cardiomyocytes showed enhanced sarcomere shortening and impaired sarcomere relaxation. Orthogonal transcriptomic analysis of human(GTEx) and PKP2cKO atrial tissue led to identification of 41 transcripts depending on PKP2 expression. Biochemical follow-up confirmed reduced abundance of sarcomeric protein myosin binding protein C, potentially playing a role in cellular shortening and relaxation changes observed. Our findings provide novel insights into the role of PKP2 in atrial myocardium with potential implications to therapeutic management of atrial fibrillation in patients with PKP2-related ARVC. KEY POINTS: Atrial arrhythmias occur in a large group of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a cardiac disease mostly caused by pathogenic variants in the desmosomal gene plakophilin-2 (PKP2). Exercise is considered to be an independent risk factor for arrhythmias consequent to PKP2 deficiency. Weshow that loss of PKP2 expression affects cellular calcium handling and electrophysiology differently in left atrial vs. ventricular myocardium and causes extensive atrial fibrosis. PKP2-deficient atrial cardiomyocytes present increased spontaneous sarcoplasmic reticulum calcium release events, furtherenhancedby isoproterenol exposure and reversiblebya ryanodine receptor blocker(dantrolene). In addition, PKP2-deficient atrial myocytes exhibit impaired relaxation and enhanced sarcomere shortening, most probably related to reduced abundance of myosin binding protein C. We speculate that cellular effects reported upon isoproterenol impact on the exercise-related atrial arrhythmia risk in ARVC patients. We further propose that therapeutic approaches aimed at mitigating ventricular damage may be effective to treat the atrial disease in ARVC.

Novel <i>FLNC</i> Gene Variant Associated with Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, affecting approximately 1 in 500 people. It is the most common genetic cardiomyopathy inherited as a Mendelian trait in approximately 50% of patients, mainly due to pathogenic variants in genes encoding sarcomeric proteins. Mutations in the sarcomeric protein filamin C (<em>FLNC</em>) gene, with a cytogenetic localization on 7q32.1, have been linked to hypertrophic cardiomyopathy, as they have been determined to increase the risk of ventricular arrhythmia and sudden death. We present the case of a patient with HCM recognized by magnetic resonance imaging and echocardiography with a family history of cardiopathies. The molecular study in this patient was performed by next-generation sequencing on the Illumina MiniSeq instrument, comparing the results with international databases. In genetic studies, a novel mutation in the protein <em>FLNC</em> was detected. It is heterozygous, missence type. It is a variant where Cytosine is changed by timina at position 6305 of the <em>FLNC</em> gene. This produces the change of the amino acid proline by leucine at position 2102 of the Filamin C protein. The rare variant is located in Ig-like domain 19 within the ROD2 domain. This variant report suggests that there may indeed be a direct relationship between <em>FLNC</em> variants, mainly the ROD2 domain, and HCM. We think this new result should be considered for future genetic counseling of families affected by this type of cardiomyopathy.

Elevated B-Type Natriuretic Peptide Level as a Residual Risk Factor for Ventricular Arrhythmias Among Patients Undergoing Cardiac Resynchronization Therapy With Improved Left Ventricular Ejection Fraction.

Patients who achieve improved left ventricular ejection fraction (LVEF >35%) with cardiac resynchronization therapy (CRT) are at a lower risk of ventricular arrhythmia (VA). Little is known about the significance of the B-type natriuretic peptide (BNP) level for the risk of VA. This study investigated the risk factors for VA in CRT and the risk stratification of VA with BNP in CRT with improved LVEF. This study evaluated 352 CRT patients from 2012 to 2020. Patients were categorized into 2 groups: improved LVEF (impEF; LVEF >35%), and low LVEF (lowEF; LVEF ≤35%). The serum BNP levels 6 months after CRT device implantation were measured. The primary endpoint was defined as VA requiring treatment with anti-tachycardia pacing or shock or persisting for ≥30 s. Overall, 102 patients had improved LVEF. The impEF group had a significantly lower VA risk than the lowEF group. Patients with low BNP had a lower VA risk than those with high BNP; however, no significant difference was observed between patients with high BNP and those in the lowEF group. Univariate analysis revealed that high BNP was a predictor of VA in the impEF group. The VA risk is reduced with improved LVEF after CRT but not with high BNP levels. The post-BNP level after CRT implantation is a useful marker for predicting VA in patients with improved LVEF.

The Role of Nuclear Medicine in the Diagnostic Work-Up of Athletes: An Essential Guide for the Sports Cardiologist.

Athletes with heart disease are at increased risk of malignant ventricular arrhythmias and sudden cardiac death compared to their sedentary counterparts. When athletes have symptoms or abnormal findings at preparticipation screenings, a precise diagnosis by differentiating physiological features of the athlete's heart from pathological signs of cardiac disease is as important as it is challenging. While traditional imaging methods such as echocardiography, cardiac magnetic resonance, and computed tomography are commonly employed, nuclear medicine offers unique advantages, especially in scenarios requiring stress-based functional evaluation. This article reviews the use of nuclear medicine techniques in the diagnostic work-up of athletes with suspected cardiac diseases by highlighting their ability to investigate myocardial perfusion, metabolism, and innervation. The article discusses the application of single photon emission computed tomography (SPECT) and positron emission tomography (PET) using radiotracers such as [99mTc]MIBI, [99mTc]HDP, [18F]FDG, and [123I]MIBG. Several clinical scenarios are explored, including athletes with coronary atherosclerosis, congenital coronary anomalies, ventricular arrhythmias, and non-ischemic myocardial scars. Radiation concerns are addressed, highlighting that modern SPECT and PET equipment significantly reduces radiation doses, making these techniques safer for young athletes. We conclude that, despite being underutilized, nuclear medicine provides unique opportunities for accurate diagnosis and effective management of cardiac diseases in athletes.

Lifetime cumulative activity burden is associated with symptomatic heart failure and arrhythmic risk in patients with arrhythmogenic right ventricular cardiomyopathy: a retrospective cohort study.

Sports-related physical activity is associated with an increased risk of ventricular dysfunction and arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). However, there are currently no standardized strategies for activity assessment. Thresholds for harmful levels of physical activity suggested by previous studies vary substantially and neither lifetime activity burden nor continuous modelling approaches were considered. For this single-centre retrospective study, ARVC patients were interviewed to assess sports-related and non-sports-related physical activity between the age of 10 years and the last follow-up. Activity data were aggregated to the median metabolic equivalent of task-hours (METh) per week for each year. The association between cumulative physical activity burden and clinical study endpoints was investigated using Cox regression models. A total of 124 patients (median age: 39.5 years, 48% male) were included in the analysis, of whom 93 had been diagnosed with definite ARVC. Study participants reported a median overall activity of 202.3 METh/week, with 38.7 METh/week attributed to sports-related activity. In the continuous model, cumulative overall activity burden was associated with the occurrence of symptomatic heart failure [hazard ratio (HR) per 100 METh/week: 1.017, 95% CI (1.003, 1.032), P = 0.015], sustained ventricular tachycardia [HR: 1.021, 95% CI (1.006, 1.037), P = 0.007], and implantable cardioverter defibrillator interventions [HR: 1.017, 95%CI (1.000, 1.034), P = 0.048]. This finding was consistent when considering sports-related activity separately as a predictor variable, whereas the resulting hazard ratios did not show a significant association for non-sports-related physical activity. This study demonstrates for the first time that cumulative physical activity as a continuous predictor variable is associated with symptomatic heart failure and arrhythmic risk in ARVC patients. Collaborative research is required in larger cohorts to investigate the influence of potential confounders on event occurrence and to develop threshold recommendations for clinical practice.

Deep behavioural representation learning reveals risk profiles for malignant ventricular arrhythmias

We aimed to identify and characterise behavioural profiles in patients at high risk of SCD, by using deep representation learning of day-to-day behavioural recordings. We present a pipeline that employed unsupervised clustering on low-dimensional representations of behavioural time-series data learned by a convolutional residual variational neural network (ResNet-VAE). Data from the prospective, observational SafeHeart study conducted at two large tertiary university centers in the Netherlands and Denmark were used. Patients received an implantable cardioverter-defibrillator (ICD) between May 2021 and September 2022 and wore wearable devices using accelerometer technology during 180 consecutive days. A total of 272 patients (mean age of 63.1 ± 10.2 years, 81% male) were eligible with a total sampling of 37,478 days of behavioural data (138 ± 47 days per patient). Deep representation learning identified five distinct behavioural profiles: Cluster A (n = 46) had very low physical activity levels and a disturbed sleep pattern. Cluster B (n = 70) had high activity levels, mainly at light-to-moderate intensity. Cluster C (n = 63) exhibited a high-intensity activity profile. Cluster D (n = 51) showed above-average sleep efficiency. Cluster E (n = 42) had frequent waking episodes and poor sleep. Annual risks of malignant ventricular arrhythmias ranged from 30.4% in Cluster A to 9.8% and 9.5% for Clusters D-E, respectively. Compared to low-risk profiles (D-E), Cluster A demonstrated a three-to-four fold increased risk of malignant ventricular arrhythmias adjusted for clinical covariates (adjusted HR 3.63, 95% CI 1.54–8.53, p < 0.001). These behavioural profiles may guide more personalised approaches to ventricular arrhythmia and SCD prevention.

Methadone: increased risk of ventricular arrhythmias

Methadone: increased risk of ventricular arrhythmias

Children and Adolescent Patients with Variants in the ATP1A3 -encoded Sodium-Potassium ATPase Alpha-3 Subunit Demonstrate an Impaired QT Response to Bradycardia and Predisposition to Sinus Node Dysfunction.

Alternating hemiplegia of childhood (AHC) is a rare disorder with both neurologic and cardiac manifestations. The ATP1A3-D801N variant is associated with a pathologically short QT interval and risk of ventricular arrhythmia following bradycardia; however, the mechanism of this remains unknown. We investigated the relationship between heart rate (HR), QT, and QTc, hypothesizing that individuals with ATP1A3-D801N have abnormal, impaired shortening of QT and QTc at lower HR leading to arrhythmia predisposition. We performed a retrospective observational study of individuals who underwent clinical evaluation, Holter monitoring, and genetic testing for AHC at Duke University Hospitals. We also compiled a group of healthy individuals as a control cohort. A larger, worldwide cohort of individuals with ATP1A3 - related phenotypes was compiled to investigate sinus node dysfunction. Linear regression analysis was then performed. The cohort consisted of 44 individuals with ATP1A3 -related phenotypes with 81 Holter recordings (52.27% female; mean age at first Holter 8.04 years, range 0.58 - 33 years), compared to 36 healthy individuals with 57 Holter recordings (52.78% female; mean age at first Holter 9.84 years, range 0.08 - 38 years). Individuals with ATP1A3-D801N had reduced prolongation of QT at lower HR, manifest as a significantly lower slope for HR vs QT compared to healthy (P<0.0001). This resulted in a significantly higher slope of the relationship for HR vs QTc compared to healthy (P<0.0001). Individuals with ATP1A3 - related phenotypes and baseline QTc <350 milliseconds (ms) had increased shortening of QT and QTc at lower HR compared to those with normal QTc (P=0.003; P=0.001). Among worldwide cases, 3 out of 131 individuals with ATP1A3 -related phenotypes required device implantation and/or had sinus pauses >4 seconds. Individuals with the ATP1A3-D801N variant exhibit paradoxical shortening of QT and QTc at lower HR, which contribute to an increased risk of arrhythmias during bradycardia. This is exacerbated by an underlying risk of sinus node dysfunction. What is Known: Individuals with ATP1A3-D801N have a short baseline QTc.Two individuals with AHC experienced ventricular fibrillation following bradycardia. What the Study Adds: The QT and QTc shorten to a greater extent at lower heart rate in individuals with ATP1A3-D801N than in healthy individuals. Individuals with ATP1A3 -related phenotypes and QTc <350ms show greater impairment of QT and QTc dynamics than those with normal QTc. There is low prevalence of device implantation and significant sinus pauses in individuals with ATP1A3 -related phenotypes, with a relatively greater prevalence in those with ATP1A3-D801N.

Incidentally Induced Atrial Fibrillation During Programmed Electrical Stimulation in Patients With Depressed Left Ventricular Systolic Function After an Acute Myocardial Infarction.

The aim of this study was to investigate the clinical implication of incidentally induced atrial fibrillation (AF) during programmed electrical stimulation (PES) in patients with left ventricular systolic dysfunction (≤40%) after an acute myocardial infarction (MI). In this study, we included 231 patients from the Cardiac Arrhythmias and RIsk Stratification after Myocardial InfArction (CARISMA) study with left ventricular ejection fraction ≤40% and no prior history of AF. These patients underwent PES 6 weeks post-MI as part of the study protocol. Patients all received an implantable cardiac monitor (ICM) 3-21 days post-MI and were continuously monitored for cardiac arrhythmias for 2 years. Induction of AF was unwanted but reported if this incidentally occurred. A total of 61 patients (26%) developed AF within 2 years of follow-up, in which n = 10 (29%) had incidental AF during PES at baseline. The overall risk of AF was not significantly increased in patients with incidental AF (n = 34) during PES compared to patients without incidental AF (n = 197) (HR 1.6 [0.9-3.0], p = 0.14). The risk of bradyarrhythmia (HR = 0.2 [0.0-1.2], p = 0.07), ventricular arrhythmias (HR = 0.7 [0.1-5.8], p = 0.77), and major cardiovascular events (MACE) (HR 0.5 [0.2-1.7], p = 0.28) was not significantly different in patients with versus without incidental AF. Incidentally induced AF during PES in post-MI patients with reduced LVEF was not significantly associated with a higher risk of long-term atrial fibrillation, other cardiac arrhythmias, or major cardiac events. NCT00145119.