Citations

4235 Background: Malignant portal vein tumor thrombus (PVTT) arising from hepatic metastases is associated with poor prognosis, rapid hepatic decompensation, and limited effective local treatment options despite systemic therapy. In real-world practice, local treatment intensity is frequently adapted to disease burden and treatment response. We evaluated outcomes of a risk-adapted, step-up local treatment strategy using microwave ablation (MWA) alone or in combination with iodine-125 (I-125) seed implantation for patients with malignant PVTT. Methods: We retrospectively reviewed patients with hepatic metastases treated with MWA with or without I-125 seed implantation between 2023 and July 2025. In clinical practice, MWA alone was preferentially used for patients with relatively limited disease burden, while MWA plus I-125 was employed as an escalation strategy for patients with more advanced PVTT or disease progression following MWA alone. The primary endpoint was PVTT-directed local outcome, defined as portal vein patency and/or local control of tumor thrombus on follow-up imaging. Secondary endpoints included progression-free survival (PFS), overall survival (OS), hepatic function changes, and treatment-related toxicity. Survival analyses were considered exploratory. Results: A total of 73 patients were included, of whom 50 were treated with MWA alone and 23 with MWA plus I-125 seed implantation. Patients receiving MWA plus I-125 demonstrated more advanced disease characteristics, including universal presence of PVTT and higher disease stage, consistent with treatment escalation by disease severity. Among patients with PVTT, MWA plus I-125 achieved portal vein patency and/or local control in 65% at first follow-up imaging. Treatment-related toxicities were manageable, with no unexpected grade ≥3 adverse events attributable to I-125 implantation. Median PFS was 11.5 months in patients treated with MWA alone and 9.9 months in patients treated with MWA plus I-125, consistent with greater baseline disease burden in the latter group. Conclusions: MWA alone and MWA plus I-125 function as complementary components of a risk-adapted, step-up local treatment strategy for malignant PVTT from hepatic metastases. Escalation to MWA plus I-125 appears feasible in patients with advanced or refractory PVTT and demonstrates a potential signal for improved PVTT-directed local control and portal vein patency. Prospective studies focused on PVTT-specific endpoints are warranted.

Introduction Psychological comorbidities can negatively impact outcomes of spinal cord stimulation (SCS) for chronic pain. While psychological assessment is commonly required before SCS implantation, evidence supporting its impact on outcomes is limited, and such assessments may be unnecessary for many patients and contribute to delays in care. Our center implemented a screening tool incorporating validated questionnaires and a mental health checklist to triage the need for formal psychological evaluation. This prospective, observational cohort study compared outcomes of SCS trials and implants between patients who bypassed (fast track: FT) versus those who underwent a formal assessment by a psychologist (AP). Methods Data were collected from patients undergoing SCS trials between July 2017 and December 2021. The screening tool used thresholds on validated questionnaires assessing anxiety, depression, catastrophizing, and opioid misuse risk, along with a checklist capturing significant anxiety or depression, self-harm, substance abuse, or mental-health-related hospitalization. Patients screening positive underwent an AP; others proceeded directly to trial (FT). 1 year post implantation outcomes were collected, with successful implantation defined as ≥30% pain reduction from baseline. Results Of 171 patients (114 AP, 57 FT), trial-to-implant rates were similar (72% AP vs 70% FT, p=0.811). The proportion of responders at 1 year post implant was also comparable (53% AP vs 60% FT, p=0.927). Multivariate logistic regression identified that higher baseline pain intensity (adjusted OR (aOR) 0.70, 95% CI 0.53 to 0.92, p=0.011) and use of tricyclic antidepressants (aOR 0.15, 95% CI 0.04 to 0.56, p=0.005) were associated with implant failure, whereas pain duration >10 years was associated with implant success (aOR 3.09, 95% CI 1.06 to 9.02, p=0.039). Conclusions This screening tool effectively identifies patients who can bypass routine psychological assessment without compromising 1 year SCS outcomes. Implementation can streamline patient flow, reduce wait times, and reserve psychological resources for those who need formal evaluation.

Abstract Aims Calcium release channel deficiency syndrome (CRCDS) results from loss-of-function (LOF) variants in the RYR2-encoded type 2 ryanodine receptor (RyR2), predisposing patients to sudden cardiac arrest/death (SCA/SCD) without abnormalities on a stress electrocardiogram (ECG). Undetected CRCDS may underlie idiopathic ventricular fibrillation (IVF) and sudden unexplained death in the young (SUDY). We aimed to determine the prevalence of potential CRCDS-causative RYR2 variants in IVF and SUDY. Methods and results We reviewed clinical evaluation and RYR2 genetic analysis of 169 IVF patients and 279 SUDY victims. Only ultra-rare (<0.005% in gnomAD) nonsynonymous RYR2 variants were considered potentially pathogenic. Among IVF patients, 6/169 (3%) overall—and 6/67 (9%) with exertion-related SCA—harboured an RYR2 variant and represent potential CRCDS cases. All exhibited normal resting and stress ECGs. Genetic analysis revealed six distinct RYR2 variants, two previously characterized as LOF. In SUDY, 31/279 victims (11%) had a RYR2 variant (30 unique variants), predominantly observed in exertion-related SCD 20/83 (24%) vs. rest-related 11/196 (6%). Of the 14 SUDY victims with functionally characterized RYR2 variants, five (2% of total cohort) had a LOF variant; among the 56 exertion-related SUDY cases, four (7%) had a LOF variant. Conclusion CRCDS may account for 3% of IVF overall and 9% of exertion-related SCA in IVF. Ultra-rare RYR2 variants may underlie up to 11% of SUDY, with 65% of RYR2-positive cases occurring during exertion. LOF-RYR2 variants may contribute to ≥7% of exercise-associated SUDY. Accurate identification of the underlying ryanodinopathy is essential for clinical management of affected patients.

Abstract Background Short QT syndrome type 1 (SQT1) is a genetic channelopathy caused by gain-of-function variants in the KCNH2-encoded Kv11.1 potassium channel, responsible for the repolarising IKr current. These variants lead to pathologically shortened cardiac repolarisation and QT intervals on 12-lead ECG, predisposing patients to life-threatening ventricular arrhythmias and sudden cardiac death. Purpose To investigate the therapeutic efficacy of our KCNH2-specific suppression-replacement gene therapy (KCNH2-SupRep) in transgenic SQT1 rabbits generated by cardiac-specific overexpression of KCNH2-N588K. Methods KCNH2-SupRep was developed by combining a custom-designed KCNH2 shRNA with its corresponding shRNA-immune KCNH2 cDNA, packaged into a single AAV9 vector and delivered directly into the aortic root via a Swan Ganz catheter (1E10 vg/kg). Therapeutic efficacy was evaluated in vivo by 12-lead ECG recordings pre- and three weeks post-therapy, ex vivo by optical voltage mapping, and at the cellular level by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs) isolated from adult transgenic SQT1 and wild-type (WT) rabbits. Results In vivo, KCNH2-SupRep normalized the heart-rate corrected QT interval (QTc) in transgenic SQT1 rabbits towards WT levels (baseline-SQT1: 153±4ms vs SupRep-SQT1: 167±5ms, p=0.0002; Fig. 1A), without adversely impacting repolarisation heterogeneity. No such QTc changes were observed in sham-treated SQT1 rabbits (sham-SQT1) (baseline-SQT1: 155±4ms vs sham-SQT1: 146±5ms, p=0.1422). Ex vivo, at a 2.5Hz stimulation frequency, KCNH2-SupRep therapeutically prolonged the APD90 in SupRep-SQT1 hearts (176±4ms) near WT levels (179±4ms), compared to untreated (UT)-SQT1 (154±4), and resolved the pathologically increased apicobasal APD90 heterogeneity observed in UT-SQT1 hearts, supporting an anti-arrhythmic effect of KCNH2-SupRep (Fig. 1B). At the cellular level, at a 1Hz stimulation frequency, KCNH2-SupRep prolonged the APD90 in VCMs isolated from SupRep-SQT1 rabbits (363±11ms) closer to WT levels (404±14ms) as compared to UT- (314±12ms) and sham-SQT1 (322±11ms; Fig. 1C). Moreover, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window (cEMW, Ca2+ transient duration – APD) and normalized IKr in nearly 50% of VCMs (Fig. 1D), in line with a 50-60% suppression of the mutant KCNH2 transcript. This partial therapeutic effect on IKr may explain the incomplete APD90 normalization in individual VCMs. Nonetheless, both in vivo and ex vivo, this partial therapeutic effect was sufficient to completely restore the electrical properties. Conclusion This proof-of-concept study is the first to demonstrate the efficacy of gene therapy in treating SQT1 in a medium-sized animal model. KCNH2-SupRep rescued the disease phenotype in vivo, ex vivo and at cellular levels in transgenic SQT1 rabbits.Therapeutic efficacy of KCNH2-SupRep

Background: Congenital long QT syndrome (LQTS) is characterized by a prolongation of the heart rate-corrected QT interval (QTc) and an increased risk of syncope, seizure and sudden cardiac arrest/death (SCA/SCD). Genome-wide association studies have identified numerous QT interval-influencing loci of small effect sizes. Herein, we sought to investigate whether a polygenic background for the QT interval contributes to the phenotypic heterogeneity in patients with genotype-positive LQTS. Methods: We used summary statistics from a recent genome-wide meta-analysis for QT interval (n = 117,532) to derive 160 different polygenic scores for QT interval (PGS QT ) using LDpred2-grid, each comprising ~1.4 million common variants with varying assumptions of the underlying genetic architecture. Next, we applied these PGS QT to predict the QTc value in a genetically unrelated, European ancestry subset of the ‘All of Us’ cohort with available electrocardiogram and genetic data (n=6,404), where the best performing PGS QT was determined based on explained variance. Next, using 225 patients with genetically confirmed LQTS who were evaluated in the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic, we tested the effect of the best performing PGS QT on QTc duration and LQTS-associated cardiac events (defined as a composite of syncope, seizures, sustained ventricular arrhythmia, appropriate ICD shocks, and SCA/SCD) using Bayesian regression models. Results: Overall, the best performing PGS QT explained 11.8% of the variance in the QTc in the ‘All of Us’ cohort. Among patients with genotype-positive LQTS (n [%]; KCNQ1 125 [55.6], KCHN2 76 [33.8], SCN5A 21 [9.3], Other 3 [1.3]), those with higher PGS QT had a higher QTc (predicted mean QTc [95% uncertainty interval], 95 th percentile vs 50 th percentile for PGS QT , 478 ms [464-491] vs 459 ms [449-468]). In comparison to the median PGS, those LQTS patients with a PGS QT >95 th percentile were more than twice as likely to have experienced a LQTS-associated cardiac event (Odds ratio [95% UI], 95 th percentile vs 50 th percentile for PGS QT ; 2.16 [1.02-5.41]), ( Figure ). Conclusions: Individuals with genotype-positive LQTS who have high polygenic susceptibility for QTc prolongation are more likely to phenotypically exhibit a higher QTc value and experience potentially life-threatening LQTS-associated cardiac events. Accounting for polygenic background may refine risk stratification strategies for patients with genotype-positive LQTS

Spinal cord stimulation (SCS) is effective for some pain syndromes, but inappropriate referrals can frustrate patients and misuse resources. This retrospective study reviewed 370 patients referred to a Neuromodulation for Pain Program (NPP) from July 2022 to June 2024. Of these, 241 were deemed appropriate for SCS. The SCS-appropriate group had higher pain intensity, more neuropathic pain, and lower opioid use. Inappropriate referrals were often from family physicians. Key factors associated with inappropriateness included low pain intensity, lack of neuropathic features, and high opioid use. Enhancing referral quality through targeted education may improve care and system efficiency.

Abstract Background and Aims Type 1 short QT syndrome (SQT1) is a genetic channelopathy caused by gain-of-function variants in KCNH2, resulting in shortened cardiac repolarization and QT intervals, which predispose patients to ventricular arrhythmias and sudden cardiac death. This study aimed to investigate the therapeutic efficacy of KCNH2-specific suppression-and-replacement (KCNH2-SupRep) gene therapy in a transgenic rabbit model of SQT1. Methods KCNH2-SupRep was developed by combining a KCNH2-shRNA with its corresponding shRNA-immune KCNH2-cDNA into an AAV9 vector, delivered directly into the aortic root (1 × 1010 vg/kg). Therapeutic efficacy was evaluated in vivo by electrocardiogram, ex vivo by optical mapping, and at cellular levels by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs). Results In vivo, KCNH2-SupRep normalized the heart rate-corrected QT interval (QTc) in SQT1 rabbits, without affecting repolarization heterogeneity. Ex vivo, KCNH2-SupRep corrected the action potential duration (APD90) and resolved the increased apicobasal APD90 heterogeneity observed in untreated (UT)-SQT1 hearts, supporting an antiarrhythmic effect, which was further validated by reduced re-entry formation in silico. At cellular levels, KCNH2-SupRep prolonged APD90 in VCMs from SupRep-SQT1 rabbits closer to wildtype levels compared with UT- and sham-SQT1. Additionally, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window and normalized IKr in nearly 50% of VCMs, in line with a 50%–60% suppression of the mutant KCNH2 transcript. Conclusions This proof-of-concept study is the first to demonstrate the efficacy of gene therapy for SQT1 in a medium-sized animal model. KCNH2-SupRep gene therapy successfully corrected the pathologic phenotype in vivo, ex vivo, and at cellular levels in transgenic SQT1 rabbits.

Abstract Aims Pronounced sex-differences are known in the incidence of atrial fibrillation (AF). In this study, we aimed to investigate the atrial electrophysiological properties that may underlie sex-differences in AF incidence in the younger population, focusing on IK1, a cardiac ion current important for action potential (AP) stability and triggered activity. Methods and results We assessed sex-differences in P-wave morphology in 12-lead ECG in healthy young New Zealand White rabbits. Males presented longer PWD and larger P-wave area compared to females. Patch-clamp experiments were performed in isolated rabbit atrial cardiomyocytes (CMs). Male atrial CMs presented higher delayed after depolarizations (DAD) incidence, amplitude, and area under the curve (AUC) than females, potentially facilitating the presence of atrial triggered activity in males. Male atrial CMs showed a less hyperpolarized resting membrane potential (RMP), a 50% smaller IK1, and a 26% reduction in Kir2.1 protein expression, a pore forming subunit of IK1, than females. Dihydrotestosterone (DHT) effects were investigated acutely and semi-chronically ex vivo. Experiments showed that the sex-difference in IK1 could be mimicked by DHT. In female atrial CMs, acute and semi-chronic (24 h) DHT administration reduced IK1. In the presence of a PKC-inhibitor, DHT-mediated IK1 reduction was not observed in atrial female CMs, suggesting it to be PKC-mediated. Chronic DHT-effects were investigated in vivo in female rabbits after hormone-releasing pellet implantation. After 2 weeks, animals showed a significantly prolonged and larger P-wave, a smaller atrial IK1 and a trend towards an increased DAD amplitude and AUC. Conclusion Sex impacts on atrial electrophysiology, leading to sex-differences in P-wave morphology, triggered activity, RMP, and IK1. These sex-differences can be mimicked by sex hormone-treatment, suggesting that sex hormones—particularly DHT—play a pivotal role in mediating sex-differences in atrial electrophysiology. Such sex-differences might impact on the propensity to develop AF, particularly in the younger population.

Background: LQTS is a genetic heart disease associated with an increased risk of sudden death. Despite advances in genetic testing, a small subset of patients still lacks identifiable genetic markers. Consequently, the true prevalence and clinical phenotype of genotype negative remains to be determined. Objective: To determine the prevalence and clinical characteristics of patients with a clinical diagnosis of LQTS but a negative genetic test. Methods: A retrospective review was conducted on patients evaluated and treated at a tertiary hospital between 2000 and 2024, focusing on those with a clinical diagnosis of LQTS, but a negative genetic test for all LQTS-associated genes, with available follow-up of at least 1 year. Results: After exclusion for follow-up and lack of genetic testing, the study cohort consisted of 1834 patients with LQTS including 1708 (93%) with a (likely) pathogenic (LP/P), LQTS-causative variant. Also, in 95 patients (5%), their variant of uncertain significance was clinically upgraded to a LP/P-variant, leaving only 31 patients classified as phenotype positive but genotype negative (1.6%). Of these, 16/31 underwent next-generation genetic sequencing, revealing the genetic cause in 6/16 cases (37%; 0.3% of all patients). For the remaining 25 genotype negative LQTS patients (1.3%), the mean age at diagnosis was 26 ± 15 years, with 19 (76%) being female, and an average initial QTc of 497 ± 41 ms. In total, 11 patients (44%) experienced a cardiac event before diagnosis [1 sudden cardiac arrest (SCA), 1 Torsades, 1 VT, 8 syncopes] and 1 patient had his first cardiac event during follow-up; 7/12 patients had more than one subsequent event. Twenty patients were proband (80%) and 6 had a family history of SCA. Eleven patients received an ICD (44%), left cardiac sympathetic denervation was performed in 4 (16%), and 2 patients experienced arrhythmia-related deaths (8%). The mean follow-up since diagnosis was 7 ± 5 years. Conclusion: With a prevalence of genotype-negative LQTS of 2%, the number of these patients is much lower than previously suggested, underscoring the advancements in identifying new genetic markers and the role of phenotype-enhanced variant adjudication and next-generation sequencing. Additionally, significant disease severity was observed in the remaining patients, emphasizing the pivotal role of genotype-phenotype correlations and risk stratification in managing and counseling patients lacking identified LQTS-causing mutations.