Transplantation of cells for cardiac repair

AbstractThe inability of adult cardiomyocytes to divide to a significant extent and regenerate the myocardium after injury leads to permanent deficits in the number of functional cells, which can contribute to the development and progression of heart failure. The transplantation of skeletal myoblasts or stem cells or cardiomyocytes derived from them into the injured myocardium is a novel and promising approach in the treatment of cardiac disease and the restoration of myocardial function. In this article, skeletal myoblasts and embryonic and bone marrow stem cells are discussed in the context of their potential therapeutic use in cardiac failure. The state of the art in both laboratory and clinic is presented. We discuss current and intrinsic limitations of cardiac cellular transplantation and suggest directions for future research

Cell-Cycle-Based Strategies to Drive Myocardial Repair

Cardiomyocytes exhibit robust proliferative activity during development. After birth, cardiomyocyte proliferation is markedly reduced. Consequently, regenerative growth in the postnatal heart via cardiomyocyte proliferation (and, by inference, proliferation of stem-cell-derived cardiomyocytes) is limited and often insufficient to affect repair following injury. Here, we review studies wherein cardiomyocyte cell cycle proliferation was induced via targeted expression of cyclin D2 in postnatal hearts. Cyclin D2 expression resulted in a greater than 500-fold increase in cell cycle activity in transgenic mice as compared to their nontransgenic siblings. Induced cell cycle activity resulted in infarct regression and concomitant improvement in cardiac hemodynamics following coronary artery occlusion. These studies support the notion that cell-cycle-based strategies can be exploited to drive myocardial repair following injury

Complications in pulmonary vein isolation in the Netherlands Heart Registration differ with sex and ablation technique

Aims Pulmonary vein isolation (PVI) has become a cornerstone of the invasive treatment of atrial fibrillation. Severe complications are reported in 1-3% of patients. This study aims to compare complications and follow-up outcome of PVI in patients with atrial fibrillation. Methods and results The data were extracted from the Netherlands Heart Registration. Procedural and follow-up outcomes in patients treated with conventional radiofrequency (C-RF), multielectrode phased RF (Ph-RF), or cryoballoon (CB) ablation from 2012 to 2017 were compared. Subgroup analysis was performed to identify variables associated with complications and repeat ablations. In total, 13 823 patients (69% male) were included. The reported complication incidence was 3.6%. Patients treated with C-RF developed more cardiac tamponades (C-RF 0.8% vs. Ph-RF 0.3% vs. CB 0.3%, P Conclusion The reported complication rate during PVI was low. Patients treated with C-RF ablation were more likely to develop cardiac tamponades and vascular complications. Female sex was associated with more cardiac tamponade and bleeding complications

Outcomes in Dutch DPP6 risk haplotype for familial idiopathic ventricular fibrillation:a focused update

Background: The genetic risk haplotype DPP6 has been linked to familial idiopathic ventricular fibrillation (IVF), but the associated long-term outcomes are unknown. Methods: DPP6 risk haplotype-positive family members (DPP6 cases) and their risk haplotype-negative relatives (DPP6 controls) were included. Clinical follow-up data were collected through March 2023. Implantable cardioverter-defibrillator (ICD) indication was divided in primary or secondary prevention. Cumulative survival and event rates were calculated. Results: We included 327 DPP6 cases and 315 DPP6 controls. Median follow-up time was 9 years (interquartile range: 4–12). Of the DPP6 cases, 129 (39%) reached the composite endpoint of appropriate ICD shock, sudden cardiac arrest or death, at a median age of 45 years (range: 15–97). Median overall survival was 83 years and 87 years for DPP6 cases and DPP6 controls, respectively (p &lt; 0.001). In DPP6 cases, median overall survival was shorter for males (74 years) than females (85 years) (p &lt; 0.001). Of the DPP6 cases, 97 (30%) died, at a median age of 50 years. With a prophylactic ICD implantation advise based on risk haplotype, sex and age, 137 (42%) of DPP6 cases received an ICD, for primary prevention (n = 109) or secondary prevention (n = 28). In the primary prevention subgroup, 10 patients experienced a total of 34 appropriate ICD shocks, and there were no deaths during follow-up. DPP6 cases with a secondary prevention ICD experienced a total of 231 appropriate ICD shocks.Conclusion: Patients with the DPP6 risk haplotype, particularly males, are at an increased risk of IVF and sudden cardiac death. Using a risk stratification approach based on risk haplotype, sex and age, a substantial proportion of patients with a primary prevention ICD experienced appropriate ICD shocks, showing the benefit of prophylactic ICD implantation with this strategy.</p

Deep neural networks reveal novel sex-specific electrocardiographic features relevant for mortality risk.

AIMS: Incorporation of sex in study design can lead to discoveries in medical research. Deep neural networks (DNNs) accurately predict sex based on the electrocardiogram (ECG) and we hypothesized that misclassification of sex is an important predictor for mortality. Therefore, we first developed and validated a DNN that classified sex based on the ECG and investigated the outcome. Second, we studied ECG drivers of DNN-classified sex and mortality. METHODS AND RESULTS: A DNN was trained to classify sex based on 131 673 normal ECGs. The algorithm was validated on internal (68 500 ECGs) and external data sets (3303 and 4457 ECGs). The survival of sex (mis)classified groups was investigated using time-to-event analysis and sex-stratified mediation analysis of ECG features. The DNN successfully distinguished female from male ECGs {internal validation: area under the curve (AUC) 0.96 [95% confidence interval (CI): 0.96, 0.97]; external validations: AUC 0.89 (95% CI: 0.88, 0.90), 0.94 (95% CI: 0.93, 0.94)}. Sex-misclassified individuals (11%) had a 1.4 times higher mortality risk compared with correctly classified peers. The ventricular rate was the strongest mediating ECG variable (41%, 95% CI: 31%, 56%) in males, while the maximum amplitude of the ST segment was strongest in females (18%, 95% CI: 11%, 39%). Short QRS duration was associated with higher mortality risk. CONCLUSION: Deep neural networks accurately classify sex based on ECGs. While the proportion of ECG-based sex misclassifications is low, it is an interesting biomarker. Investigation of the causal pathway between misclassification and mortality uncovered new ECG features that might be associated with mortality. Increased emphasis on sex as a biological variable in artificial intelligence is warranted

Life-threatening ventricular arrhythmia prediction in patients with dilated cardiomyopathy using explainable electrocardiogram-based deep neural networks

AIMS: While electrocardiogram (ECG) characteristics have been associated with life-threatening ventricular arrhythmias (LTVA) in dilated cardiomyopathy (DCM), they typically rely on human-derived parameters. Deep neural networks (DNNs) can discover complex ECG patterns, but the interpretation is hampered by their 'black-box' characteristics. We aimed to detect DCM patients at risk of LTVA using an inherently explainable DNN. METHODS AND RESULTS: In this two-phase study, we first developed a variational autoencoder DNN on more than 1 million 12-lead median beat ECGs, compressing the ECG into 21 different factors (F): FactorECG. Next, we used two cohorts with a combined total of 695 DCM patients and entered these factors in a Cox regression for the composite LTVA outcome, which was defined as sudden cardiac arrest, spontaneous sustained ventricular tachycardia, or implantable cardioverter-defibrillator treated ventricular arrhythmia. Most patients were male (n = 442, 64%) with a median age of 54 years [interquartile range (IQR) 44-62], and median left ventricular ejection fraction of 30% (IQR 23-39). A total of 115 patients (16.5%) reached the study outcome. Factors F8 (prolonged PR-interval and P-wave duration, P < 0.005), F15 (reduced P-wave height, P = 0.04), F25 (increased right bundle branch delay, P = 0.02), F27 (P-wave axis P < 0.005), and F32 (reduced QRS-T voltages P = 0.03) were significantly associated with LTVA. CONCLUSION: Inherently explainable DNNs can detect patients at risk of LTVA which is mainly driven by P-wave abnormalities

The genetic basis of apparently idiopathic ventricular fibrillation:A retrospective overview

Aims: During the diagnostic work-up of patients with idiopathic ventricular fibrillation (VF), next-generation sequencing panels can be considered to identify genotypes associated with arrhythmias. However, consensus for gene panel testing is still lacking, and variants of uncertain significance (VUS) are often identified. The aim of this study was to evaluate genetic testing and its results in idiopathic VF patients. Methods and results: We investigated 419 patients with available medical records from the Dutch Idiopathic VF Registry. Genetic testing was performed in 379 (91%) patients [median age at event 39 years (27-51), 60% male]. Single-gene testing was performed in 87 patients (23%) and was initiated more often in patients with idiopathic VF before 2010. Panel testing was performed in 292 patients (77%). The majority of causal (likely) pathogenic variants (LP/P, n = 56, 15%) entailed the DPP6 risk haplotype (n = 39, 70%). Moreover, 10 LP/P variants were found in cardiomyopathy genes (FLNC, MYL2, MYH7, PLN (two), TTN (four), RBM20), and 7 LP/P variants were identified in genes associated with cardiac arrhythmias (KCNQ1, SCN5A (2), RYR2 (four)). For eight patients (2%), identification of an LP/P variant resulted in a change of diagnosis. In 113 patients (30%), a VUS was identified. Broad panel testing resulted in a higher incidence of VUS in comparison to single-gene testing (38% vs. 3%, P &lt; 0.001). Conclusion: Almost all patients from the registry underwent, albeit not broad, genetic testing. The genetic yield of causal LP/P variants in idiopathic VF patients is 5%, increasing to 15% when including DPP6. In specific cases, the LP/P variant is the underlying diagnosis. A gene panel specifically for idiopathic VF patients is proposed.</p

STereotactic Arrhythmia Radioablation (STAR): the Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary consortium (STOPSTORM.eu) and review of current patterns of STAR practice in Europe

The EU Horizon 2020 Framework-funded Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary (STOPSTORM) consortium has been established as a large research network for investigating STereotactic Arrhythmia Radioablation (STAR) for ventricular tachycardia (VT). The aim is to provide a pooled treatment database to evaluate patterns of practice and outcomes of STAR and finally to harmonize STAR within Europe. The consortium comprises 31 clinical and research institutions. The project is divided into nine work packages (WPs): (i) observational cohort; (ii) standardization and harmonization of target delineation; (iii) harmonized prospective cohort; (iv) quality assurance (QA); (v) analysis and evaluation; (vi, ix) ethics and regulations; and (vii, viii) project coordination and dissemination. To provide a review of current clinical STAR practice in Europe, a comprehensive questionnaire was performed at project start. The STOPSTORM Institutions' experience in VT catheter ablation (83% ≥ 20 ann.) and stereotactic body radiotherapy (59% > 200 ann.) was adequate, and 84 STAR treatments were performed until project launch, while 8/22 centres already recruited VT patients in national clinical trials. The majority currently base their target definition on mapping during VT (96%) and/or pace mapping (75%), reduced voltage areas (63%), or late ventricular potentials (75%) during sinus rhythm. The majority currently apply a single-fraction dose of 25 Gy while planning techniques and dose prescription methods vary greatly. The current clinical STAR practice in the STOPSTORM consortium highlights potential areas of optimization and harmonization for substrate mapping, target delineation, motion management, dosimetry, and QA, which will be addressed in the various WPs