Novel electrocardiographic criteria for the diagnosis of arrhythmogenic right ventricular cardiomyopathy

Aims: In order to improve the electrocardiographic (ECG) diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC), we evaluated novel quantitative parameters of the QRS complex and the value of bipolar chest leads (CF leads) computed from the standard 12 leads. Methods and results: We analysed digital 12-lead ECGs in 44 patients with ARVC, 276 healthy subjects including 44 age and sex-matched with the patients and 36 genotyped members of ARVC families. The length and area of the terminal S wave in V1 to V3 were measured automatically using a common for all 12 leads QRS end. T wave negativity was assessed in V1 to V6 and in the bipolar CF leads computed from the standard 12 leads. The length and area of the terminal S wave were significantly shorter, whereas the S wave duration was significantly longer in ARVC patients compared with matched controls. Among members of ARVC families, those with mutations (n = 15) had shorter QRS length in V2 and V3 and smaller QRS area in lead V2 compared with those without mutations (n = 20). In ARVC patients, the CF leads were diagnostically superior to the standard unipolar precordial leads. Terminal S wave duration in V1 >48 ms or major T wave negativity in CF leads separated ARVC patients from matched controls with 90% sensitivity and 86% specificity. Conclusion: The terminal S wave length and area in the right precordial leads are diagnostically useful and suitable for automatic analysis in ARVC. The CF leads are diagnostically superior to the unipolar precordial leads

Prevalence and factors associated with musculoskeletal complaints and disability in individuals with brachial plexus injury:a cross-sectional study

Purpose (1) To determine the prevalence of musculoskeletal complaints (MSCs) in the non-affected bodily structures in individuals with brachial plexus injury (BPI) and (2) to analyse factors associated with MSCs and disability. Methods Survey among individuals with BPI and a control group. Multivariable logistic and linear regression analyses were used to identify factors associated with MSCs or disability. Results Forty-nine percent of individuals (34/70) with BPI experienced MSC, which was not significantly different from controls (35%, n = 40/113). Complaints were most often located in high back (OR = 3.6) or non-affected limb (OR = 2.2) or neck (OR = 2.1). Greater disability was associated with the presence of MSC in individuals with BPI (OR = 1.1, 95% confidence interval (95% CI) = 1.0; 1.1). Those with no or a low level of education (B = -10.2, 95% CI = -19.6; -1.4), a history of nerve surgery (B = 11.1, 95% CI = -0.2; 20.9), and moderately affected active range of motion (AROM) of the affected limb (B = 20.7, 95% CI = 8.8; 31.0) experienced most disability. Individuals with severely affected AROM showed a wide range of experienced disability. Conclusions Clinicians should be aware that almost half of individuals with BPI have MSCs in the non-affected bodily structures, which was associated with increased disability.</p

Musculoskeletal complaints in individuals with finger or partial hand amputations in the Netherlands:A cross-sectional study

PURPOSE: To compare the prevalence of musculoskeletal complaints (MSCs) in individuals with finger or partial hand amputations (FPHAs) with a control group and to explore the effect and predictors of MSCs in individuals with FPHAs. METHOD: A questionnaire-based cross-sectional study was conducted. The primary outcome measures were: prevalence of MSCs, health status, pain-related disability, physical work demands, work productivity, and hand function. RESULTS: The response rate was 61%. A comparable proportion of individuals with FPHAs (n = 99) and controls (n = 102) reported MSCs in the preceding 4 weeks (33% vs. 28%, respectively) or in the preceding year (37% vs. 33%, respectively). Individuals with FPHAs with MSCs experienced more pain than controls with MSCs. Regular occurrence of stump sensations and self-reported limited range of motion (ROM) of the wrist of the affected limb were predictors for MSCs in individuals with FPHAs. CONCLUSIONS: The prevalence of MSCs was comparable in individuals with FPHAs and controls. However, clinicians should pay special attention to the risk of developing MSCs in patients with stump sensations and limited ROM of the wrist of the affected limb. Future research should focus on the role of wrist movements and compensatory movements in the development of MSCs in individuals with FPHAs

Musculoskeletal complaints and disability in a group of young adults with major congenital upper limb differences in The Netherlands

Purpose: To determine prevalence of musculoskeletal complaints (MSCs) in adults with major congenital upper limb differences (CoULD) compared to able-bodied controls, and to examine associations of MSCs and disability with various biopsychosocial factors. Materials and methods: Questionnaire-based cross-sectional study assessing MSCs, disability (using the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH)), general and mental health status, physical work demands, and upper extremity range of motion. Results: Seventy-one individuals with CoULD (participation rate: 41%) and 71 controls matched on age, gender, and education were included (49% female, mean age 28.9 years). Year prevalence of MSCs was significantly higher in the CoULD group (35%) than in the control group (18%). The CoULD group was less often employed and had lower scores on all measures of upper limb range of motion and hand grip. MSCs were associated with higher DASH scores and higher reported work demands. Disability was associated with female gender, more joints with limited range of motion, unemployment, and lower general and mental health. Factors associated with disability did not differ between groups.Conclusions: MSCs are a frequent problem in young adults with major CoULD. To prevent or reduce MSC and disability, clinicians and researchers should be aware of the associated factors. Implications for rehabilitation The year prevalence of musculoskeletal complaints (MSCs) in those with major congenital upper limb differences (CoULD) was approximately double to that of the control group, implying a potential relationship between CoULD and MSCs. Rehabilitation professionals should develop personalized strategies to manage work demands in those with CoULD, considering the association between MSCs and higher reported work demands. Recognizing the impact of a negatively perceived body image on mental health, clinicians should integrate psychological counseling into rehabilitation treatments to support mental well-being and improve overall quality of life in those with CoULD. Rehabilitation professionals should educate individuals with CoULD about the potential associations between upper limb work demands, MSCs, and disability.</p

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

Unique Cardiac Purkinje Fiber Transient-Outward Current Beta-Subunit Composition: A Potential Molecular Link to Idiopathic Ventricular Fibrillation.

Rationale: A chromosomal-haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial idiopathic ventricular fibrillation (IVF). The molecular basis of transient-outward current (Ito) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF Ito and that its overexpression might specifically alter PF Ito-properties and repolarization. Objective: To assess the potential role of DPP6 in PF-Ito. Methods and Results: Clinical data in 5 IVF-patients suggested arrhythmia-origin in the PF conducting-system. PF and ventricular-muscle (VM) Ito had similar density, but PF Ito differed from VM in having tetraethylammonium-sensitivity and slower recovery. DPP6-overexpression significantly increased, whereas DPP6-kockdown reduced, Ito-density and tetraethylammonium-sensitivity in canine PF, but not VM-cells. The K+-channel interacting beta-subunit KChIP2, essential for normal expression of transient outward current (Ito) in VM, was weakly-expressed in human PFs, whereas DPP6 and frequenin (NCS-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary (CHO)-cells produced very small Ito; Ito-amplitude was greatly enhanced by co-expression with KChIP2 or DPP6. Co expression of DPP6 with Kv4.3 and KChIP2 failed to alter Ito versus Kv4.3/KChIP2 alone, but DPP6 expression with Kv4.3 and NCS-1 (to mimic PF Ito-composition), greatly enhanced Ito versus Kv4.3/NCS-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that Ito-enhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously-unknown central role of DPP6 in PF Ito, with DPP6 gain-of-function selectively enhancing PF-current, and suggest that a DPP6-mediated PF early repolarization syndrome might be a novel molecular paradigm for some forms of IVF

SCN5A mutation type and topology are associated with the risk of ventricular arrhythmia by sodium channel blockers

Background: Ventricular fibrillation in patients with Brugada syndrome (BrS) is often initiated by premature ventricular contractions (PVCs). Presence of SCN5A mutation increases the risk of PVCs upon exposure to sodium channel blockers (SCB) in patients with baseline type-1 ECG. In patients without baseline type-1 ECG, however, the effect of SCN5A mutation on the risk of SCB-induced arrhythmia is unknown. We aimed to establish whether presence/absence, type, and topology of SCN5A mutation correlates with PVC occurrence during ajmaline infusion. Methods and results: We investigated 416 patients without baseline type-1 ECG who underwent ajmaline testing and SCN5A mutation analysis. A SCN5A mutation was identified in 88 patients (S+). Ajmaline-induced PVCs occurred more often in patients with non-missense mutations (Snon-missense) or missense mutations in transmembrane or pore regions of SCN5A-encoded channel protein (Smissense-TP) than patients with missense mutations in intra-/extracellular channel regions (Smissense-IE) and patients without SCN5A mutation (S−) (29%, 24%, 9%, and 3%, respectively; P < 0.001). The proportion of patients with ajmaline-induced BrS was similar in different mutation groups but lower in S− (71% Snon-missense, 63% Smissense-TP, 70% Smissense-IE, and 34% S−; P < 0.001). Logistic regression indicated Snon-missense and Smissense-TP as predictors of ajmaline-induced PVCs. Conclusions: SCN5A mutation is associated with an increased risk of drug-induced ventricular arrhythmia in patients without baseline type-1 ECG. In particular, Snon-missense and Smissense-TP are at high risk

Interobserver variability in target definition for stereotactic arrhythmia radioablation

BackgroundStereotactic arrhythmia radioablation (STAR) is a potential new therapy for patients with refractory ventricular tachycardia (VT). The arrhythmogenic substrate (target) is synthesized from clinical and electro-anatomical information. This study was designed to evaluate the baseline interobserver variability in target delineation for STAR.MethodsDelineation software designed for research purposes was used. The study was split into three phases. Firstly, electrophysiologists delineated a well-defined structure in three patients (spinal canal). Secondly, observers delineated the VT-target in three patients based on case descriptions. To evaluate baseline performance, a basic workflow approach was used, no advanced techniques were allowed. Thirdly, observers delineated three predefined segments from the 17-segment model. Interobserver variability was evaluated by assessing volumes, variation in distance to the median volume expressed by the root-mean-square of the standard deviation (RMS-SD) over the target volume, and the Dice-coefficient.ResultsTen electrophysiologists completed the study. For the first phase interobserver variability was low as indicated by low variation in distance to the median volume (RMS-SD range: 0.02–0.02 cm) and high Dice-coefficients (mean: 0.97 ± 0.01). In the second phase distance to the median volume was large (RMS-SD range: 0.52–1.02 cm) and the Dice-coefficients low (mean: 0.40 ± 0.15). In the third phase, similar results were observed (RMS-SD range: 0.51–1.55 cm, Dice-coefficient mean: 0.31 ± 0.21).ConclusionsInterobserver variability is high for manual delineation of the VT-target and ventricular segments. This evaluation of the baseline observer variation shows that there is a need for methods and tools to improve variability and allows for future comparison of interventions aiming to reduce observer variation, for STAR but possibly also for catheter ablation

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

Refining Critical Structure Contouring in STereotactic Arrhythmia Radioablation (STAR): Benchmark Results and Consensus Guidelines from the STOPSTORM.eu Consortium.

BACKGROUND AND PURPOSE In patients with recurrent ventricular tachycardia (VT), STereotactic Arrhythmia Radioablation (STAR) shows promising results. The STOPSTORM consortium was established to investigate and harmonise STAR treatment in Europe. The primary goals of this benchmark study were to standardise contouring of organs at risk (OAR) for STAR, including detailed substructures of the heart, and accredit each participating centre. MATERIALS AND METHODS Centres within the STOPSTORM consortium were asked to delineate 31 OAR in three STAR cases. Delineation was reviewed by the consortium expert panel and after a dedicated workshop feedback and accreditation was provided to all participants. Further quantitative analysis was performed by calculating DICE similarity coefficients (DSC), median distance to agreement (MDA), and 95th percentile distance to agreement (HD95). RESULTS Twenty centres participated in this study. Based on DSC, MDA and HD95, the delineations of well-known OAR in radiotherapy were similar, such as lungs (median DSC=0.96, median MDA=0.1mm and median HD95=1.1mm) and aorta (median DSC=0.90, median MDA=0.1mm and median HD95=1.5mm). Some centres did not include the gastro-oesophageal junction, leading to differences in stomach and oesophagus delineations. For cardiac substructures, such as chambers (median DSC=0.83, median MDA=0.2mm and median HD95=0.5mm), valves (median DSC=0.16, median MDA=4.6mm and median HD95=16.0mm), coronary arteries (median DSC=0.4, median MDA=0.7mm and median HD95=8.3mm) and the sinoatrial and atrioventricular nodes (median DSC=0.29, median MDA=4.4mm and median HD95=11.4mm), deviations between centres occurred more frequently. After the dedicated workshop all centres were accredited and contouring consensus guidelines for STAR were established. CONCLUSION This STOPSTORM multi-centre critical structure contouring benchmark study showed high agreement for standard radiotherapy OAR. However, for cardiac substructures larger disagreement in contouring occurred, which may have significant impact on STAR treatment planning and dosimetry evaluation. To standardize OAR contouring, consensus guidelines for critical structure contouring in STAR were established