Heart Rhythm

Background Substrate mapping using multielectrode catheters is increasingly used for post-myocardial infarction (MI) ventricular tachycardia (VT) avoiding repeated VT induction and mapping during VT. However, these catheters may mechanically induce ventricular arrhythmias with hemodynamic compromise. This study compares pro-arrhythmogenicity between single-tip and multi-spline catheters during functional substrate mapping. Methods Thirty post-MI patients (age 68{+/-}8 years, 97% male, LVEF 40% [IQR 33-46]) referred for VT ablation at two centers (2021-2024) underwent endocardial mapping during baseline rhythm in random order with both a multi-spline catheter (Octaray, n=4; Pentaray, n=26) and a single-tip QDOT catheter. The protocol was prematurely terminated if (i) two mechanically induced VTs required ECV, (ii) recurrent ATP-treated mechanical VTs caused hemodynamic compromise, or (iii) excessive mechanically induced ectopy impaired catheter contact. Mapping time, point density, and mechanically induced arrhythmias were assessed. Results Multi-spline catheters enabled faster mapping (26{+/-}9 vs 60{+/-}16 minutes, p<0.001) with more acquired points (p<0.001). VTs were more frequently mechanically induced with multi-spline catheters (median 2 [IQR 1-4] vs 0 [0-3], p<0.05) and these VTs were faster (304ms, IQR 292-320] vs 373ms, IQR [316-405], p=0.01) and degenerated more often into VF (3 vs. 0). Overall, 17 patients (57%) experienced at least one mechanically induced VT; seven (23%) required cardioversion, and mapping was prematurely terminated in eight (27%), all while using multi-spline catheters. Conclusion Multi-spline catheters allow rapid substrate mapping but with substantial risk of mechanically induced arrhythmias, requiring premature termination of substrate mapping because of safety concerns. Their use in post-MI VT ablation warrants careful risk?benefit assessment.

Background. Durable mitral isthmus (MI) block remains challenging in persistent atrial fibrillation (PeAF) ablation. Recent epicardial vein of Marshall (VoM) recordings have shown incomplete MI transmurality and time-dependent conduction recovery after pulsed field ablation (PFA). Whether systematic VoM ethanol infusion (VoM-EI) followed by focal PFA provides stable acute MI block remains unknown. **Objectives.** To assess the incidence, timing, and procedural implications of early MI conduction recovery after systematic VoM-EI followed by focal Sphere-9 PFA. Methods.In this prospective single-center study, 55 consecutive patients undergoing first ablation for symptomatic PeAF with planned MI ablation were screened. VoM-EI was systematically attempted before left atrial access and successfully performed in 51 (92.7%), who constituted the study cohort. Pulmonary vein isolation, roof-line, and MI ablation were performed with the Sphere-9? lattice-tip catheter. After bidirectional MI block, conduction was systematically reassessed during a standardized 30-minute waiting period. Results.Mean age was 70.3 {+/-} 8.2 years, and 36 patients (70.6%) were men. Initial bidirectional MI block was achieved in 50/51 patients (98.0%). During the waiting period, conduction recovered in 9/50 (18.0%; 95% CI, 9.8%-30.8%), at a median of 16 minutes (IQR, 10-20; range, 8?23). Six of 9 patients with recovery (66.7%) required targeted coronary sinus (CS) ablation. Block was restored in all 9, yielding a final block rate of 50/51 (98.0%). Median procedure duration was 82 minutes (IQR, 73-95), with no major complications. Conclusions. Immediate bidirectional MI block was not synonymous with stable block. Despite systematic VoM-EI followed by focal Sphere-9 PFA, conduction recovered in approximately one in five patients, including beyond 20 minutes, and two thirds required targeted CS ablation. These findings support standardized 30-minute reassessment and targeted CS interrogation rather than reliance on immediate block. Chronic invasive remapping is required to determine whether this strategy improves long-term MI block durability.

Introduction. Hypertrophic cardiomyopathy (HCM) is characterized by clinical and genetic heterogeneity. Age of manifestation, clinical and anatomical phenotypes of HCM vary significantly. This study discusses genetic causes and reconstructive surgery results for patients with particular intracardiac phenotype - diffused generalized HCM (DG-HCM). Methods: personal and familial medical history, general examination, 12-lead resting ECG, 24-hour ECG Holter monitoring, transthoracic and transesophageal EchoCG, cardiac MRI with gadolinium enhancement. A ten-gene panel was sequenced by IonTorrent PGM. Mutational screening in patients with suspected multisystemic diseases was performed by Sanger sequencing. Results: 170 patients with obstructive HCM (oHCM) requesting genetic counseling and surgical correction of HCM were evaluated. We distinguished particular DG-HCM subtype of oHCM (diffuse hypertrophy of IVS, LV free walls, papillary muscles displaced towards the LV apex) in 34 patients; 31 out of 34 underwent open heart reconstructive surgery. Patients with DG-HCM were younger at the time of surgery, had higher risk of SCD, and connective tissue dysplasia of the mitral valve. Hemodynamics normalization was observed in 1, 3, and 5 years after surgery. Eighteen ICDs were implanted; five patients experienced appropriate shocks. The genetic spectrum was enriched up to 30% by multisystem disorders. Mutations in "sarcomeric" genes were detected in 15%. Conclusion: Intracardiac phenotype of HCM may correlate with genetic cause and long-term prognosis. DG-HCM phenotype accounts for 20% oHCM patients and indications for open-heart surgery. Extended myectomy with parietal resection of papillary muscles and correction of mitral valve insufficiency provides long-term benefits for DG-HCM patients. Multisystem disorders in patients with DG-HCM should be of special attention. Study was supported by research project FURG-2024-0004.

Background: Obstructive hypertrophic cardiomyopathy (oHCM) causes substantial symptom burden and impaired functional capacity. Mavacamten has emerged as a targeted pharmacologic treatment, whereas alcohol septal ablation (ASA) is an established septal reduction therapy (SRT). Direct comparative real-world data remain limited. Methods: In this propensity-controlled observational study, longitudinal registry data from Heidelberg University Hospital were analyzed. Consecutive adults with oHCM, NYHA class ?II symptoms, and a maximum LVOT gradient ?50 mmHg treated with mavacamten or ASA were included. The cohort comprised 107 ASA- and 113 mavacamten-treated patients. Follow-up was performed at 6 and 12 months. The primary endpoint was a composite adverse clinical outcome including cardiovascular death, heart failure hospitalization, SRT, heart transplantation, ventricular assist device implantation, permanent pacemaker implantation for third-degree atrioventricular block, or decline in left ventricular ejection fraction to <40%. Results: Both treatments showed significant improvement in NYHA class and LVOT gradient reduction over 12 months. Mean LVOT gradient decreased from 100.3 to 44.2 mmHg after ASA and from 85.7 to 18.4 mmHg with mavacamten at 12 months (both p<0.001). Between-group differences were not significant at 6 months, whereas residual LVOT gradient was lower with mavacamten at 12 months (p=0.004). NT-proBNP declined in both groups and was lower with mavacamten at both follow-up visits (both p<0.001). Third-degree atrioventricular block occurred more frequently after ASA (6.5% vs 0%, p=0.002). The composite endpoint occurred in 13 ASA- (12.1%) and 4 mavacamten-treated patients (3.5%) (p=0.003), with higher 1-year event-free survival in the mavacamten group (HR 0.19; 95%-CI 0.06-0.60; p=0.001). Conclusions: In this real-world comparative study, both ASA and mavacamten improved symptoms and LVOT obstruction in oHCM. Mavacamten was associated with a more favorable short-term hemodynamic and safety profile at 12 months.

Background: Mitral regurgitation (MR) is a major risk factor for the development of atrial fibrillation (AF), yet the molecular mechanisms linking volume overload to arrhythmogenic remodeling remain poorly understood. Although fibrosis has long been considered the primary substrate for AF, increasing evidence suggests that fibroblast heterogeneity and cell-cell interactions may play important roles in disease progression. Methods: MR was created endovascularly by chordal avulsion in 12 dogs with 6 controls. AF inducibility was assessed by transvenous burst pacing, left atrial volume by echocardiography, and collagen content by Masson trichrome and picrosirius red staining. Single-nucleus RNA sequencing (snRNA-seq) was performed on left atrial posterior wall tissue from control, 4-week, and 6-month MR animals. Fibroblast subpopulations and fibroblast-cardiomyocyte communication were analyzed and markers validated by RNA in situ hybridization in all 18 animals. Results: MR resulted in progressive left atrial dilation, but neither the change in left atrial volume from baseline nor total collagen burden correlated with the inducibility of AF (n=6 each). SnRNA-seq resolved seven major cardiac cell populations and identified four transcriptionally distinct fibroblast populations (NOX4/GRIA4, PCOLCE2, ADRB2/HCN1, PTX3/ICAM1). Fibroblast composition shifted markedly: matrix-associated PCOLCE2 fibroblasts starkly declined by 6 months, whereas inflammatory-associated PTX3/ICAM1 fibroblasts expanded stepwise over time. Cardiomyocyte-to-fibroblast signaling, dominated by PTPRM and LAMA2, was progressively redirected toward PTX3/ICAM1 fibroblasts. RNAscope confirmed a stepwise rise in ICAM1 transcripts and higher ICAM1 in AF-inducible than non-inducible animals. Conclusions: In a canine model of MR, the inducibility of AF was associated with fibroblast state remodeling rather than with atrial dilation or collagen burden. Progressive expansion of inflammatory-associated PTX3/ICAM1 fibroblasts, together with reorganized fibroblast-cardiomyocyte signaling, defines a candidate arrhythmogenic mechanism and therapeutic target in MR.

Postoperative atrial fibrillation (POAF) is a frequent complication following cardiac surgery and has been associated with an increased risk of thromboembolic events. However, cardiac surgical populations are heterogeneous, and the long-term thromboembolic implications of POAF may differ according to the index surgical procedure. This systematic review and meta-analysis evaluated the procedure-specific association between POAF and long-term thromboembolic outcomes after adult cardiac surgery, with particular emphasis on coronary artery bypass grafting (CABG) and isolated valve surgery. PubMed and Scopus were searched from database inception through August 3, 2026. Studies reporting long-term thromboembolic outcomes in patients with new-onset POAF compared with patients without POAF were evaluated, with eligible evidence classified according to the index surgical procedure. Four observational studies were included in the primary quantitative synthesis, with two studies contributing to the CABG analysis and two to the isolated valve-surgery analysis. Adjusted hazard ratios (HRs) were pooled separately by procedure using inverse-variance methods, and a formal between-subgroup interaction test was performed. Following CABG, POAF was associated with an increased long-term thromboembolic hazard (pooled HR 1.147, 95% CI 1.053-1.249; I^2=0%). A stronger association was observed following isolated valve surgery (pooled HR 1.362, 95% CI 1.181-1.573; I^2=0%). The between-subgroup interaction was statistically significant ({chi}^2=4.10, P=0.043), providing exploratory evidence that the magnitude of the association may differ according to surgical procedure. These findings suggest that the long-term thromboembolic implications of POAF may not be uniform across cardiac surgical populations. However, because only two studies contributed to each procedure subgroup and the available evidence was observational, the interaction should be considered hypothesis-generating. Further adequately powered studies with standardized outcome definitions and procedure-specific reporting are required to confirm these findings and determine their implications for long-term risk stratification and anticoagulation strategies.

BACKGROUND: Atrial fibrillation (AF) remains difficult to explain using a single focal driver or rotor-centered mechanism across disease stages. We tested whether progressive atrial substrate remodeling can drive a critical transition toward turbulence-like, decentralized multi wavelet electrical activity. METHODS: We constructed a controlled two-dimensional atrial reaction-diffusion model with six graded substrate-remodeling stages. We evaluated effective wavelength, theoretical wavelet capacity, AF inducibility, vulnerable-window dynamics, spatial randomness, temporal memory, spectral dispersion, nonlinear indices, virtual ablation response and ERP-prolongation reverse mechanistic testing. RESULTS: Progressive remodeling shortened effective wavelength from 12.0 to 2.4 cm and increased theoretical wavelet capacity from 0.69 to 17.36. Inducibility rose sigmoidally as wavelength shortened, with a model-derived transition near lambda50=4.5 cm. Advanced substrates showed increased wavebreak, spatial randomness, short-memory dynamics, broad spectral dispersion, positive nonlinear indices and resistance to random local ablation. Culprit atrial premature beats within the vulnerable window efficiently triggered AF, whereas counter pacing at 20 to 35 ms reduced inducibility from 52% to 11% in stage 2. CONCLUSIONS: In this controlled model, AF initiation and maintenance were linked to substrate-dependent wavelength, wavelet capacity and vulnerable-window triggering. The model-derived transition provides a testable framework for future high-density mapping, patient30 specific modeling and device-based studies. Key Words atrial fibrillation; turbulence-like electrical activity; substrate remodeling; critical wavelength; multi-wavelet re-entry; vulnerable window; culprit premature atrial beat; counter pacing

Background Optimal timing for resuming direct oral anticoagulants (DOACs) after high-risk endoscopic procedures remains uncertain, and existing recommendations derive largely from expert opinion. The objective of this study was to characterize practice patterns and perceptions among endoscopists and outcome prioritization among patients with atrial fibrillation, in order to inform the design of the planned RESUME randomized trial. Methods We conducted parallel, cross-sectional surveys of practicing endoscopists and patients with atrial fibrillation using electronic questionnaires administered via Qualtrics. The endoscopist survey, distributed through the American Society for Gastrointestinal Endoscopy, assessed practice patterns, acceptability of early (postoperative day [POD] +1), intermediate (POD +3), and late (POD +5) resumption strategies, and perceptions of clinical equipoise. The patient survey, distributed through two advocacy organizations, assessed perceived confidence in existing guidance and prioritization of bleeding versus thromboembolic risk. Results A total of 201 endoscopists and 477 patients (92.5% taking a DOAC) provided evaluable responses. Endoscopists demonstrated wide variability in preferred timing of DOAC resumption after a standardized high-risk mucosal resection vignette, ranging from same-day resumption to delays beyond five days. POD +2 was the most commonly selected strategy, and most respondents rated more than one proposed RESUME trial arm as acceptable. Nearly all endoscopists (98.9%) rated a randomized trial to determine optimal timing as important. Patient preferences regarding bleeding versus stroke risk were heterogeneous and symmetrically distributed around the neutral response on a five-point ordinal scale. Preferences did not differ by prior stroke or transient ischemic attack, prior major bleeding, age, sex, or geographic region. More than half of patients (54.6%) reported being very or somewhat confident that clear guidance exists regarding DOAC resumption, despite the absence of high-quality randomized evidence informing this question. Conclusions Endoscopists demonstrate substantial practice variability and clinical equipoise, and patients demonstrate heterogeneous and balanced outcome preferences, regarding the timing of DOAC resumption after high-risk endoscopy. These findings support the ethical justification and relevance of the planned RESUME trial.

BackgroundInsular damage leads to marked cardiovascular alterations and the mechanisms need to be understood. Mouse models provide unique opportunities to gain insights into pathophysiological mechanisms. Here, we evaluated the effects of rilmenidine, a centrally acting antihypertensive drug, on the cardiac functional parameters and cardiac inflammatory cell infiltration in a newly developed mice model of insular hemorrhagic stroke. MethodsC57BL/6J mice were instrumented for injection of blood or vehicle into the insular cortex (IC). Immediately after IC stroke induction, separate groups received intraperitoneal treatment with vehicle (0.9% NaCl, 0.1 mL/100 g) or rilmenidine (10 g/kg) for three days. Electrocardiogram recording,cardiac catecholamine levels and myocardial accumulation of immune cells were evaluated. ResultsMice subjected to hemorrhagic stroke exhibited higher baseline heart rate (HR) (control: 296 {+/-} 33 bpm vs. stroke: 349 {+/-} 38 bpm; P < 0.01) and prolonged QTc interval (control: 89 {+/-} 11 ms vs. stroke: 100 {+/-} 7 ms; P < 0.01). Stroke also increased cardiac norepinephrine levels (control: 9 {+/-} 4 ng/mg vs. stroke: 25 {+/-} 14 ng/mg; P < 0.05), as well as the number of myocardial CD68+ macrophages (control: 7 {+/-} 4 vs. stroke: 16 {+/-} 6 cells/field; P < 0.0001) and Ly6G+ neutrophils (control: 0.5 {+/-} 0.7 vs. stroke: 1.5 {+/-} 1 cells/field; P < 0.001). Rilmenidine treatment markedly prevented all major stroke- induced myocardial functional and inflammatory changes ConclusionsInsular hemorrhagic stroke in mice induces centrally mediated cardiac noradrenergic hyperactivation accompanied by myocardial accumulation of immune cells. These findings support the relevance of this murine model for investigating mechanisms associated with insular stroke.

Background Adults with a systemic right ventricle (sRV) due to congenitally corrected transposition of the great arteries (ccTGA) or atrial switch repair for d-transposition of the great arteries (d-TGA) experience substantial physiologic and psychosocial morbidity. Relationships among exercise capacity, sRV function, and mental health remain incompletely characterized. Objectives To characterize relationships among anatomic subtype, exercise capacity, sRV function, and mental health in adults with sRV physiology. Methods We performed a retrospective cohort study of adults with ccTGA or d-TGA (Mustard/Senning) followed at a tertiary Adult Congenital Heart Disease program from 2000 to 2025. Clinical, imaging, cardiopulmonary exercise testing, and patient-reported data were obtained from electronic health records. Mental health diagnoses were identified from clinical documentation. Functional status was assessed using NYHA class and the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Results Among 137 adults (ccTGA, n = 51; d-TGA, n = 86), percent-predicted peak VO2 was lower in d-TGA than ccTGA (60% vs 74%, p < 0.001), as was sRV systolic function (41 +/- 11% vs 47 +/- 10%, p < 0.01). Anxiety or depression was more common in d-TGA (46% vs 25%, p < 0.05). Across the cohort, anxiety or depression was associated with lower exercise capacity, worse NYHA functional class, and lower KCCQ scores. Conclusions Adults with d-TGA following atrial switch have lower exercise capacity, reduced sRV systolic function, and greater mental health burden than adults with ccTGA. These findings support integrated assessment of physiologic performance, functional status, and mental health in adults with sRV physiology.

Aims: Arrhythmogenic cardiomyopathy (ACM) is a genetic disease defined by arrhythmias and myocardial fibrosis with impaired cardiac function and increased risk of sudden cardiac death. Pathogenic variants are mostly identified in desmosomal genes such as desmoglein-2 (DSG2). We identified a novel disease phenotype in patients homozygous for the DSG2 variant c.523+2T>C (splice site of exon 5/intron 5), characterized by cardioembolic events in addition to classical ACM features. Here, we evaluate this new thromboembolic phenotype by comparing the clinical data to specific murine disease models. Methods and Results: We describe three unrelated patients presenting with an embolic event and/or left ventricular thrombus. Clinical evaluation revealed a shared right ventricular ACM phenotype characterized by arrhythmias, impaired function, and fibrotic remodeling. In addition, patients exhibited localized fibrotic changes of the left ventricular apex with formation of an aneurysm and predisposition to thrombus formation. Genetic analysis identified the DSG2 variant c.523+2T>C as a founder variant from the "Bernese Oberland". To elucidate the variant's functional impact, a mouse model deficient for Dsg2 exon 5 (Dsg2{Delta}ex5) was established and compared to a model carrying the adhesion-deficient Dsg2-W2A variant. Echocardiography, ECG, and histology in Dsg2{Delta}ex5 mice revealed similar disease patterns to patients and a loss of DSG2 expression. Importantly, these animals exhibited left apical fibrosis with aneurysm formation and left ventricular thrombus formation. In contrast, the Dsg2-W2A model presented with a biventricular ACM-phenotype but without left ventricular thrombi. Conclusions: We identified a novel ACM phenotype in patients homozygous for the DSG2 founder variant c.523+2T>C characterized by left ventricular apical fibrosis. Dsg2{Delta}ex5 mice recapitulate the patients' phenotype suggesting a causative link between left ventricular aneurysm due to DSG2 deficiency and thrombus formation with subsequent embolism. This highlights a novel pathological feature of ACM and the need for variant and phenotype-specific therapy.

Background: A dose finding trial evaluated safety and adherence for pre-cardiac surgery administration of sodium valproate. Integrated multi-omics analyses of myocardium were used to characterise mechanisms underlying the treatment effects. Methods: Adults undergoing cardiac surgery were randomised 1:1:1:1 with concealed allocation to no treatment (Controls), sodium valproate 15mg/kg/day for 1-2 weeks, 15mg/kg/day for 4-6 weeks, or 25mg/kg/day for 4-6 weeks pre-surgery. The primary analysis evaluated adherence and toxicity. Myocardial injury was defined by high sensitivity serum troponin at 24 hours post-surgery. Single-nucleus Assay for Transposase-Accessible Chromatin with sequencing (snATACseq) and single nuclei RNA sequencing (snRNAseq) of myocardial biopsies collected at surgery assessed treatment effects on chromatin accessibility and gene expression. Candidate mechanisms were validated in in vitro. Results: The analysis cohort included 42 participants enrolled between January 2020 and August 2024. Non-compliance (38%) was highest with longer and higher dosing. Sodium valproate 15mg/kg/day for 1-2 weeks had the highest levels of complete treatment adherence (70%), with 20% experiencing moderate/severe drug related adverse effects. An as-treated analyses demonstrated reductions in troponin release in participants receiving Valproate[&le;]14 days. Myocardial biopsies from trial participants demonstrated activation of hormetic p53 and Akt-GSK-3{beta} ferroptosis protection pathways. Treatment effects were not attributable to chromatin accessibility. Treatment >14 days resulted in a heart failure phenotype with suppression of ferroptosis protection pathways, endothelial mesenchymal transition, and increased myocardial injury. Conclusions: Sodium valproate 15mg/kg/day for [&le;]14 days pre-surgery is well tolerated in adults awaiting cardiac surgery. This treatment was associated with upregulation of ferroptosis protection pathways and reductions in myocardial injury.

Mitofusin 2 (MFN2), a key outer mitochondrial membrane GTPase, regulates mitochondrial fusion, mitophagy, calcium homeostasis, and cellular bioenergetics. This study investigated the role of MFN2 variants in patients with Dilated Cardiomyopathy (DCM) using whole-exome sequencing (WES) of 5 familial and 10 sporadic DCM cases. A rare de-novo MFN2 variant, c.932A>G (p. N311S), was identified in a DCM patient, which is absent in 100 healthy controls as well as in the 1000 Genomes, IndiGenomes, databases while it shows very low MAF (0.0000081) in gnomAD. Structural modelling predicted the variant to be highly deleterious and revealed marked conformational distortion of the mutant protein (RMSD = 8.95 A). Molecular docking further showed a weakened interaction between MFN2-N311S and PRKN (Parkin), indicating impaired mitophagy and defective mitochondrial quality control. Moreover, functional analysis in stable H9c2 cardiomyoblast cell lines demonstrated significantly reduced MFN2 mutant protein expression, extensive mitochondrial clustering and fragmentation. The mutant protein also indicated significant reduction in mitochondrial membrane potential, ATP production, and oxygen consumption rate (OCR), together with elevated cytosolic Ca2+ and reactive oxygen species (ROS) levels. qRT-PCR analysis further revealed activation of the PI3K/AKT/mTOR signalling pathway and increased expression of hypertrophic markers Myh6, Nppa, Nfatc1, and Nfatc2. The above findings collectively highlight the significant impact of the MFN2 mutation on mitochondrial dynamics and cellular health, suggesting a significant correlation with the pathogenesis of DCM. This finding could further open a door to develop a potential therapeutic target for DCM.

Introduction: Shared medical appointments (SMAs) are medical visits where multiple individuals are seen together in a group setting. For patients with inherited cardiovascular disease, where multiple family members often require ongoing cardiac care and screening, family SMAs may be particularly valuable as a tool to facilitate family communication and comprehension of their condition. This research aimed to identify patient perspectives on the potential benefits and challenges of family SMAs in comparison to an existing individual clinic model. Methods: Qualitative semi-structured interviews were conducted with adult family representatives. Each family had at least one family member seen at the adult and pediatric inherited cardiovascular disease clinics. Interview recordings were transcribed verbatim and inductively coded using a content analysis approach. Results: Sixteen families were interviewed in this study. The mean age of the family representative interviewed was 43.4 years ({+/-} 9.3 SD), and they were followed at Stanford Health Care for a mean of 7.3 years ({+/-} 4.2 SD). 81.2% (13/16) of families said they would find family SMAs beneficial. For interested families who consented to recorded interviews (n=12), benefits and challenges fell into two major categories: care quality and access and logistics. Interested families thought family SMAs would provide an added care quality benefit by increasing understanding among adults, children, and providers (83.3%, 10/12). Six of twelve participants interested in having family SMA visits felt there would be logistical/access-based benefits to this new model (50%, 6/12). Families also identified possible challenges with this model, such as less individualized care, potential privacy concerns, and concerns regarding the smoothness of the clinic process in coordinating a family SMA. Conclusion: The majority of families believed a family SMA model would provide added benefit to families with inherited cardiovascular disease, but requires thoughtful implementation and should be tailored to families? unique needs.

Background: Atrial fibrillation (AF) burden is increasingly recognized as a determinant of clinical risk. Currently, AF burden can only be estimated using long-term rhythm monitoring. Bone morphogenetic protein 10 (BMP10) is a protein secreted from cardiac atria associated with AF and AF-related complications. This study evaluated whether BMP10 concentrations are associated with AF burden in a human atrial model: atrial engineered heart tissue (aEHT). Methods: Human induced pluripotent stem cell-derived atrial cardiomyocytes were cast into atrial engineered heart tissues (aEHTs). To mimic AF burden, mature aEHTs were optogenetically-paced at a high rate of 4 Hz, either intermittently for 4 hours every 2 days (~10% burden) or continuously for 24 hours per day (100% burden). After 18 days of high-rate pacing intervention, 7 days of recovery without pacing followed. BMP10 release was quantified by ELISA and contractile function was assessed by video analysis. EHT transcriptional remodeling in response to mimicked AF burden was assessed by RNA sequencing and the effect of recovery was analyzed by qPCR. Results: High-rate optogenetic pacing mimicking AF lead to a dynamic, burden-dependent BMP10 release: BMP10 concentrations in the medium were increased by intermittent optogenetic pacing (~10% burden) and highest under continuous optogenetic pacing (100% burden). BMP10 release declined toward control levels during recovery. Contractile dysfunction was most impaired after continuous pacing and showed only partial recovery within 7 days after pacing cessation. RNA sequencing revealed distinct burden-dependent transcriptional states. Pacing-regulated transcripts were related to BMP/TGF{beta} signaling, atrial identity, calcium handling, contractile phenotype, and electrophysiological remodeling. After recovery, BMP10 mRNA expression remained elevated despite normalization of BMP10 protein release. Conclusions: AF burden dynamically regulates BMP10 release and functional and molecular remodeling in human aEHTs. BMP10 release depicts a secreted protein-based readout of current or recent atrial high-rate stress, whereas persistent transcriptional changes indicate molecular memory of prior AF burden. These findings support BMP10 release as a burden-sensitive AF biomarker

Background: Blood volume (BV) in patients with chronic heart failure (HF) is characterized by heterogeneity in volume profiles; one profile being "normal BV". While overall intravascular volume may be considered normal clinically, the relative contributions of red blood cell (RBC) mass and plasma volume (PV) may not be. Objective: Assess how normal is a "normal BV" based on quantitative measures of RBC mass and PV. Methods: Retrospective analysis was undertaken in 395 patients with Class II-III HF. BV was quantitated using indicator-dilution methodology. Cohort was stratified by normal and hypervolemic BV. Results: Of the cohort, 31% (123/395) demonstrated normal total BV and 62% (244/395) hypervolemic BV. Of patients with "normal BV", 36% (44/123) demonstrated normal RBC mass and 60% normal PV (74/123). Importantly, 60% (74/123) demonstrated a deficit in RBC mass (true anemia), while a low hemoglobin (<12 g/dL) was present in just 29% (36/123). An excess in RBC mass (erythrocytosis) in 4% (5/123). Notably, true normal BV (i.e., normal RBC mass and normal PV) was observed in only 30% (37/123) of patients with an overall "normal" intravascular volume. Conclusions: Findings reveal that "normal BV" can be misleading by concealing substantial variability in RBC mass (including unrecognized anemia and erythrocytosis) as well as different degrees of PV expansion and contraction. An actual normal BV was identified in a minority of "normal BV" patients. This underscores the importance of looking beyond overall "normal BV" to the contributing elements of RBC mass and PV with significant implications for patient management and outcomes.

Background: Bailout cardiac surgery during transcatheter aortic valve replacement (TAVR) is uncommon but remains associated with substantial morbidity and mortality. Although registries have described its incidence and major causes, they often provide limited detail regarding device-related failure mechanisms, attempted transcatheter rescue, and the clinical pathway leading to surgical conversion. We aimed at analyzing post-marketing safety reports from the U.S. Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database to characterize the mechanisms, management strategies, and reported outcomes of bailout surgery during or shortly after TAVR. Methods: We retrospectively analyzed FDA MAUDE reports received from July 1, 2016, through June 30, 2026. Eligible reports described unplanned urgent or emergent open cardiac surgery during or immediately after TAVR. Candidate reports were screened, adjudicated, and deduplicated at the clinical-event level. Events were classified by precipitating complication, transcatheter rescue, operative pathway, and reported outcome. Associations were evaluated using permutation tests, Fisher exact tests with Benjamini?Hochberg correction, adjusted regression models, and sensitivity analyses. Results: After screening 43,239 initial reports, we identified 376 bailout-surgery events, with survival status was documented in 254, including 104 deaths and 150 survivors, corresponding to 40.9% reported mortality. Valve embolization, migration, or malposition was the most frequent complication phenotype (32.4%), whereas ventricular perforation or laceration was associated with the highest mortality (74.1%; OR, 4.86; 95% CI, 1.97?11.99). Mortality differed across complication phenotypes (p<0.001) and operative pathways (p<0.001), but not across transcatheter rescue pathways (p=0.355). Valve explantation with SAVR was associated with lower reported mortality (18.9%; OR, 0.29; 95% CI, 0.12?0.69), whereas unspecified surgery or access/support alone was associated with higher mortality (56.9%; OR, 3.04; 95% CI, 1.80?5.12). Ancillary analyses identified potential platform-specific differences in complication and management patterns, while bailout timing was not independently associated with mortality after adjustment. Conclusions: In this MAUDE analysis, bailout cardiac surgery after TAVR was most commonly precipitated by valve embolization, migration, or malposition, whereas ventricular perforation or laceration was associated with the highest reported mortality. Outcomes differed across complication and operative pathways but not across transcatheter rescue strategies or bailout timing after adjustment. These findings identify clinically relevant post-marketing safety signals but should not be interpreted as incidence estimates, comparative device risks, or causal treatment effects.

Background: Heart failure (HF) is classified by ejection fraction: reduced EF (<40%) is HFrEF and preserved EF (>50%) is HFpEF. Unlike HFrEF, no therapeutic agent improves mortality in HFpEF. The molecular mechanism that produces HFpEF is not completely understood, but the cascade of pathology that produces HFpEF is thought to begin with changes in vascular reactivity, including a decrease in NO mediated vasodilatation, which coupled with subsequent changes in contractility, energetics and coronary blood flow produce HFpEF. If abnormal vascular reactivity is the initial step in the pathological cascade that produces HFpEF, restoring and/or improving vascular reactivity could represent a novel treatment strategy. Vascular reactivity is primarily regulated by myosin light chain phosphatase, which has catalytic, myosin targeting (MYPT1) and 20kDa subunits. Alternative mRNA splicing of exon24 (E24) of the MYPT1 transcript produces MYPT1 isoforms that differ by the presence or absence of a COOH-terminal leucine zipper (LZ+/LZ-); E24 exclusion produces an NO responsive LZ+ MYPT1, while E24 inclusion produces an NO unresponsive LZ- MYPT. Methods: We used the mouse two-hit model of HFpEF (high fat diet and L-NAME) and treated mice with an antisense octo-guanidine targeting the 5' splice site of E24 (ASO-E24) to increase the expression of the NO responsive, LZ+ MYPT1 isoform in vascular smooth muscle. Invasive and noninvasive hemodynamics were used to determine LV function. Results: Compared to mice with HFpEF, ASO-E24 treatment maintains LZ+ MYPT1 expression (4.7{+/-}0.7au v 1.0{+/-}0.4au v 2.0{+/-}0.4au, control v HFpEF v ASO-E24 Rx, p<0.05), improves diastolic function; LVEDP (10{+/-}1mmHg v 20{+/-}4mmHg v 14{+/-}3mmHg, p<0.05), dP/dtmin (-8000{+/-}300mmHg/s v 6000{+/-}500mmHg/s v 8500{+/-}700mmHg/s, p<0.05), both early (E; 0.60{+/-}0.05m/s v 0.42{+/-}0.06m/s v 0.64{+/-}0.06m/s, p<0.05) and late diastolic filling (A; 0.38{+/-}0.03m/s v 0.24{+/-}0.02m/s v 0.47{+/-}0.04m/s, p<0.050 and also prevents the increase in lung weight (167{+/-}5g v 175{+/-}7g v 166{+/-}5g, p<0.05). Further, mice treated with ASO-E24 maintained normal relaxation to 8Br-cGMP (65{+/-}5% v 44{+/-}9% v 72{+/-}9%, p=0.05). Conclusion: These data demonstrate that maintaining normal LZ+ MYPT1 expression and vascular reactivity prevent the development of HFpEF. These results are consistent with the hypothesis that abnormal vascular reactivity is the initial and primary step in the pathological cascade that produces HFpEF and ASO-E24, which is designed to preserve normal LZ+ MYPT1 expression and vascular reactivity, could represent a novel and effective treatment strategy for HFpEF.

Objective: To identify patient- and clinician-reported barriers, facilitators, and design requirements for a centralized cascade-screening program for familial hypercholesterolemia (FH) in the United States. Methods: From June through November 2023, we conducted individual telephone interviews with 20 patients with FH and 10 clinicians recruited from UT Southwestern Medical Center, Parkland Health, the North Texas Veterans Affairs, and other clinical settings. Interview guides were informed by the Consolidated Framework for Implementation Research. Transcripts were coded in Dedoose using a piloted codebook, with discrepancies and emergent themes resolved through consensus. An advisory panel then helped translate interview findings into program design requirements and implementation strategies. Results: Five themes characterized barriers and facilitators to centralized cascade screening: (1) health-system access and fragmentation, including screening and treatment costs, transportation, and cross-system coordination; (2) privacy and trust, including concerns about genetic information and unsolicited outreach; (3) family relationships and practical burden, including competing demands, language barriers, limited contact, fear, and denial; (4) clinician capacity and workflow, including limited time, knowledge, and genetic-counseling capacity; and (5) communication and care continuity. Participants recommended proband pre-notification of relatives, culturally and linguistically responsive materials, secure data exchange, standardized scripts, flexible testing pathways, and centralized coordination. These findings informed a program model incorporating a secure pedigree platform, educational and communication resources, testing coordination, and linkage to follow-up care. Conclusions: Patients and clinicians identified multilevel determinants that a centralized FH cascade-screening program must address. The findings support specific design requirements but do not establish program feasibility or effectiveness, which require prospective evaluation.

Background Exercise intolerance is common in adults with repaired tetralogy of Fallot (rTOF) despite preserved left ventricular ejection fraction (LVEF [&ge;]50%). Whether reduced exercise capacity is associated with early cardiac remodeling remains unclear. Objectives To determine whether reduced exercise capacity in rTOF with preserved LVEF is associated with diastolic dysfunction, atrial remodeling, right ventricular (RV) dysfunction, and myocardial fibrosis. Methods We retrospectively studied adults with rTOF and preserved LVEF who underwent cardiopulmonary exercise testing (CPET) and transthoracic echocardiography (TTE) and/or cardiac MRI (CMR) within 18 months. Exercise capacity was assessed by percent-predicted peak VO2 (ppVO2). Diastolic function and atrial remodeling were evaluated by TTE, and CMR assessed RV function and myocardial fibrosis. Results Reduced exercise capacity was associated with larger left atrial volume index (LAVI; p < 0.001), elevated E/e' and reduced e' velocity (both p < 0.05), and reduced RV systolic function (p < 0.001). LAVI correlated inversely with ppVO2 ({rho} = -0.27, p = 0.003). A composite diastolic dysfunction score showed a graded relationship with exercise capacity, with patients exhibiting [&ge;]2 abnormalities having lower ppVO2 than those with [&le;]1 abnormality (both p < 0.01). In contrast, pulmonary regurgitation (PR) severity and myocardial fibrosis by late gadolinium enhancement (LGE) were not associated with exercise capacity. Conclusions In adults with rTOF and preserved LVEF, reduced exercise capacity is associated with atrial remodeling, diastolic dysfunction, and RV dysfunction despite the absence of overt myocardial fibrosis. This suggests that multimodal imaging identifies an imaging-defined cardiac remodeling phenotype associated with early functional impairment.