Pulmonary Circulation

Background: Pulmonary arterial hypertension (PAH) manifests by pulmonary vascular remodeling, caused by hyper-proliferation and apoptosis resistance of resident PA cells, elevated right ventricular (RV) afterload, and death of RV failure. The goal of this study is to determine the role and mechanisms of action of mitotic spindle-associated microtubule regulator DLG associated protein 5 (DLGAP5) in pulmonary vascular remodeling in PAH. Methods: DLGAP5 expression was assessed in human PAH transcriptomic datasets, PAH patients' lung tissues, pulmonary artery smooth muscle cells (PASMCs), and pulmonary artery adventitial fibroblasts (PAAFs). Loss-of-function, molecular, functional, RNAseq, and network analyses were performed. Smooth muscle (SM)-specific DLGAP5 knockdown using adeno-associated virus serotype 6 (AAV6) in mice with SU5416/hypoxia-induced PH was performed. Results: DLGAP5 was overaccumulated in small muscular PAs, PASMCs, and PAAFs from PAH lungs. siRNA DLGAP5 down-regulated cyclin A2, suppressed hyper-proliferation, increased pro-apoptotic BIM, and induced apoptosis in human PAH PASMCs and PAAFs. DEP domain containing 1 (DEPDC1) was identified and validated as a downstream effector of DLGAP5 in PAH PASMCs responsible for hyper-proliferation and apoptosis resistance of human PAH PASMCs. SM-specific DLGAP5 knockdown with AAV6-enTagln-shDLGAP5 reversed DEPDC1 overaccumulation in small muscular PAs, reduced PA medial thickness, RV systolic pressure, mean PA pressure, and RV hypertrophy in mice with SuHx-induced PH. Conclusions: DLGAP5 supports proliferation and survival of human PAH PASMCs and PAAFs through up-regulation of cyclin A2, DEPDC1, and suppression of BIM, and promotes PA remodeling and PH in mice. DLGAP5 could serve as a potential molecular target to attenuate pulmonary vascular remodeling in PAH.

Pulmonary arterial hypertension (PAH) is characterized by the hyperproliferative phenotype of pulmonary arterial smooth muscle cells (PAVSMCs) and extensive extracellular matrix (ECM) remodeling. Vacuolar protein sorting 34 (VPS34), a Class III Phosphatidylinositol-3 Kinase (PI3K), regulates cell proliferation, but its specific function in pulmonary vascular remodeling remains poorly understood. We aim to determine the role of VPS34 activation and regulation in PAVSMC proliferation, matrix deposition, and the progression of PAH. First, we found a marked decrease in the inhibitory phosphorylation of VPS34 at Ser164 (P-S164-VPS34), indicative of constitutive VPS34 activation, in remodeled pulmonary arteries (PAs) from human PAH patients and male mice exposed to Sugen/Hypoxia (SuHx). In human PAH PAVSMCs, siRNA-mediated knockdown of VPS34 or pharmacological inhibition via the selective inhibitor SAR405 significantly blunted cell proliferation and reduced the production of fibronectin, a major component of the remodeled ECM. Mechanistically, we found that Akt activation in PAH PAVSMCs promotes VPS34 activation; Protein Phosphatase 1 Catalytic Subunit Alpha is a potential effector in VPS34 activation; and active VPS34 led to the activation of the mTOR/S6 signaling pathway with tuberous sclerosis complex 2 downregulation. Finally, in vivo treatment with SAR405 attenuated right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in SuHx mice, while concurrently decreasing vascular fibronectin deposition. Our study demonstrates that VPS34 activation, driven by an Akt-mediated loss of the inhibitory P-S164, is crucial in PAVSMC proliferation and fibrotic vascular remodeling in PAH. Targeting the VPS34 axis represents a promising anti-remodeling therapeutic strategy for the treatment of PAH. Keywords: Pulmonary arterial hypertension, vacuolar protein sorting 34, pulmonary vascular remodeling, pulmonary arterial vascular smooth muscle

BackgroundMacitentan is a dual endothelin receptor antagonist used in pulmonary arterial hypertension (PAH) and has also been studied in other forms of pulmonary hypertension (PH). Evidence across PH phenotypes has been heterogeneous. This study aims to evaluate the efficacy and safety of macitentan compared with concurrent control therapies across PH phenotypes and to explore whether treatment effects differ according to PH classification. MethodsPubMed, Embase, and the Cochrane database were searched from inception through June 2026. Randomized and non-randomized comparative studies of patients with PH receiving macitentan were eligible. Prespecified efficacy outcomes were 6-minute walk distance (6MWD), pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), and cardiac index; prespecified safety outcomes included mortality and adverse events. Random-effects meta-analyses were performed using mean differences (MDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes. ResultsFourteen studies met the eligibility criteria. Macitentan was associated with a greater reduction in PVR (MD, -134.50 dyn.s.cm; 95% CI, -226.10 to -42.86) and an increase in cardiac index (MD, 0.44 L/min/m; 95% CI, 0.22 to 0.67). No statistically significant difference was observed for 6MWD (MD, 5.04 m; 95% CI, -15.06 to 25.14) or mPAP (MD, -2.70 mmHg; 95% CI, -6.46 to 1.05). In pooled safety analyses, mortality was lower and risks of anemia, peripheral edema, and discontinuation due to adverse events were higher with macitentan. Heterogeneity and the small number of studies within several phenotype-specific analyses limited the precision of subgroup findings. ConclusionsMacitentan-containing therapy was associated with favorable changes in selected hemodynamic outcomes but not with a statistically significant improvement in 6MWD or mPAP. The safety findings were characterized by higher risks of anemia, peripheral edema, and treatment discontinuation. These results should be interpreted in the context of differences in PH phenotype, dose, comparator, study design, and outcome measurement.

Pulmonary hypertension (PH) is a progressive and fatal disease characterized by pulmonary vascular remodeling, inflammation, and immune dysregulation. Myeloid-derived suppressor cells (MDSCs) and macrophages contribute to PAH pathobiology; however, the molecular regulators of their pathological activation remain poorly defined. The triggering receptor expressed on myeloid cells 2 (TREM2) is an immunomodulatory receptor that shapes myeloid cell metabolism, survival, and immunosuppressive function, yet its role in PH has not been investigated. Methods: Single-cell RNA sequencing (scRNA-seq) data from human pulmonary artery tissue (GSE210248; n=3 PAH, n=3 donors) were analyzed to characterize TREM2 expression across cell populations. Wild-type (WT) and global TREM2 knockout (TREM2 KO) mice were exposed to chronic hypoxia (10% FiO2, 28 days). Hemodynamic, histological, flow cytometric, and ex vivo functional assessments were performed. TREM2 expression was measured by flow cytometry in circulating MDSCs from PAH patients (n=22) and healthy controls (n=13). Results: TREM2 was markedly enriched in monocyte/macrophage populations in PH pulmonary arteries and TREM2-high immune cells exhibited transcriptional downregulation of chemotaxis programs and upregulation of antigen processing and MHC II presentation pathways. TREM2 deficiency significantly attenuated hypoxia-induced RVSP increase, right ventricular dysfunction, pulmonary inflammation, and vascular remodeling. MDSCs from TREM2 KO mice exerted significantly less suppression of CD4+ and CD8+ T cell proliferation. TREM2 was significantly elevated in circulating MDSCs from PAH patients and showed a directional association with hemodynamic severity. Conclusions: TREM2 is a novel regulator of myeloid-driven immunosuppression and vascular remodeling in PAH and warrants investigation as a therapeutic target and biomarker.

Background: Genetic conditions are common in congenital heart disease (CHD) and affect care, but are often missed or diagnosed late. We asked whether routine clinical data can shortlist the most likely genetic conditions. Methods: Retrospective single-center cohort of children with CHD and an echocardiogram who had either a confirmed genetic diagnosis or negative cytogenetic testing and CHD gene sequencing. Echocardiogram images and serial medical record data were added as model inputs in the order they become clinically available. Class balanced logistic regression (LR) and a multimodal deep learning fusion network were fitted to the same inputs at each step. The primary metric was balanced top-3 accuracy (correct diagnosis among the top three, averaged across conditions), with bootstrap intervals. Results: The cohort included 1,720 children (988 with common CHD-associated genetic conditions, 231 rare diagnoses, 501 negative testing). Using only inputs generated at the echocardiogram visit, LR reached a balanced top-3 accuracy 0.758 (chance 0.429). Serial records, radiology notes and ICD-10 codes, raised this to 0.809. Multimodal fusion performed similarly at each stage. With a genetic condition withheld from training, the fusion embedding placed affected children nearest to others sharing a gene group in 0.37 of cases versus 0.10 without the embedding (+0.268 [95% CI +0.242, +0.295]). Conclusions: Routine clinical data available at first echocardiogram can help identify likely genetic diagnoses, and later coded inputs ceiling. Multimodal fusion added no accuracy over LR, but places children sharing a genetic cause near one another, making nearest-neighbor retrieval informative for undiagnosed children.

Background Real-world data regarding mavacamten use in underserved and racially diverse populations remain limited, particularly for long-term therapy implementation. Structural barriers such as financial instability, fragmented healthcare access, and challenges adhering to REMS-related monitoring requirements may affect longitudinal therapy implementation. Methods We performed a retrospective observational study of consecutive patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) evaluated for mavacamten therapy at a tertiary HCM center in Bronx, NY, between 6/2022-10/2025. Patients were followed for up to 48 weeks after treatment initiation. Clinical characteristics, treatment interruptions, adverse events, echocardiographic and functional outcomes, and implementation barriers were assessed descriptively. Results Seventy-two patients with symptomatic oHCM were evaluated for mavacamten; sixty-seven initiated treatment. Mean age was 66.9{+/-}15.3 years, 72% were female, and 61% identified as Black or Hispanic. Median resting left ventricular outflow tract (LVOT) gradient decreased from 51mmHg (IQR30-88) at baseline to 7mmHg (IQR5-10) at 48 weeks. Median Valsalva LVOT gradient decreased from 74mmHg (IQR50-104) to 20mmHg (IQR10-29). At final follow-up, 80% of patients improved by [≥]1 NYHA functional class. LVEF declined below 50% in five patients and recovered in all cases. Approximately one-quarter experienced treatment interruption or discontinuation, nearly half related to insurance instability, non-adherence, and REMS-related monitoring barriers. Conclusions Mavacamten demonstrated efficacy and safety outcomes comparable to those reported in clinical trials and prior registries in this predominantly underserved minority urban cohort. However, structural and healthcare-access barriers substantially affected long-term treatment implementation. These findings highlight the need to address healthcare-system barriers to ensure equitable implementation of contemporary HCM therapies.

Rationale: Conventional CT-derived pulmonary vascular metrics quantify vascular pruning but do not assess the spatial heterogeneity of vascular architecture. In COPD, peripheral microvascular pruning coexists with compensatory central vessel dilation, paradoxically preserving total vessel volume while reducing effective vascular penetration into lung parenchyma. Objectives: To develop and evaluate Vascular Proximity Coverage (VPC), a distance-based CT biomarker quantifying the spatial efficiency of pulmonary vascular distribution. Methods: This retrospective analysis included 7,881 COPDGene participants [PHASE] with complete vascular segmentations. VPC was estimated by integrating the area under the cumulative lung tissue coverage curve at distances of 0-10 mm from segmented vessel voxels. Multivariable models assessed associations with lung function, six-minute walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, mMRC dyspnea score, and all-cause mortality over a median follow-up of [10.8] years, adjusting for demographics, smoking, emphysema, scanner type, and BV5. The cohort was stratified at median BV5 and VPC into concordant (high/high, low/low) and discordant (high-BV5/low-VPC, low-BV5/high-VPC) vascular phenotypes. Results: VPC declined across disease severity (5.82 {+/-} 0.50 [UNITS] in non-smokers to 5.21 {+/-} 0.64 in GOLD 4; p < 0.001). Among spirometrically normal smokers, current smokers had lower VPC than former smokers (5.31 vs. 5.68; p < 0.001). Each standard deviation decrease in VPC was independently associated with reduced 6MWD ({beta} = -16.8 m, 95% CI: -19.5 to -14.0), worse SGRQ ({beta} = 1.9, 95% CI: 1.4 to 2.4), and greater dyspnea (RR = 1.05, 95% CI: 1.03 to 1.08; all p < 0.001). The lowest VPC quartile was associated with 38% higher mortality than the reference quartile (HR = 1.38, 95% CI: 1.18 to 1.62; p < 0.001). The high-BV5/low-VPC phenotype showed 24% higher mortality than high-BV5/high-VPC (HR = 1.24, 95% CI: 1.08 to 1.42; p = 0.002) despite preserved vessel volume. Conclusions: VPC captures spatial heterogeneity of vascular architecture independent of vessel volume, is reduced in smokers without airflow obstruction, and identifies excess mortality risk among individuals whose total vessel volume appears preserved.

Objective: The maturation of an autologous arteriovenous fistula (AVF) depends on the coordinated hemodynamic adaptation of the inflow artery and the outflow vein. While venous remodeling has been extensively studied, the mechanisms of arterial adaptation are poorly understood. We addressed this knowledge gap with the first temporal single-cell atlas of the porcine AVF model. Methods: Six Yorkshire pigs underwent bilateral femoro-femoral AVF creation for tissue harvest at 2 and 21 days postoperatively or sham operation to collect native vessels after 2 days. Arteries and veins were analyzed by droplet-based single-cell RNA sequencing, histology, and immunohistochemistry. Results: All fistulas were patent, with flows reaching 1185.0 +/- 170.6 mL/min despite mild to moderate neointima formation in the veins. Arteries and veins demonstrated >60% endothelial denudation and increased neovascularization. Arterial remodeling was characterized by a progressive increase in venous-like transcriptional features. Arteries presented a venous-like endothelial cell (EC) composition at 21 days postop and a temporal increase in venous-associated phenotypes of myofibroblasts and fibroblasts. In both vessels, the latter populations were the main bearers of mechanosensitive signatures at 2 days. Despite the temporal convergence in phenotypes, arteries and veins retained vessel-selective characteristics. Arterial ECs expressed high levels of nitric oxide synthase, whereas venous ECs were largely inflammatory. Arterial myofibroblasts and fibroblasts had higher expression of Notch signaling transducers (HEY2, HEYL) and cellular communication network factors (CCN3, CCN5), while Wnt signaling regulators (DKK2, SFRP4) and complement genes (C3, C7, CFD) were upregulated in veins. Anti-inflammatory macrophages increased in both vessels during remodeling, likely contributing to the maturation of the fistulas. Conclusion: These analyses challenge the traditional paradigm of exclusive vein arterialization and support a complementary process of arterial venification after anastomosis. Recognition of this underappreciated phenomenon may reshape our understanding of AVF biology and guide the discovery of both vascular-wide and vessel-selective anti-stenotic therapies.

Introduction: Fighting the ventilator (FV) is characterized by a patients active counteraction of respiratory gas flow across multiple breaths during mechanical ventilation. An effective ventilation is prevented during such episodes. The objective of this exploratory study was to evaluate clinicians knowledge, perception and agreement regarding this condition. Methods: In a cross-sectional online survey, medical professionals with experience in intensive care medicine (mostly neonatal and pediatric patients) responded to 11 questions covering various clinical aspects of FV. Results: All respondents were familiar with the phenomenon and assessed it to be clinically relevant. Neonates were perceived to be predominantly affected. Promoting factors of FV included inadequate sedation and ventilation-associated factors. In clinical practice, the participants identified FV by clinical evaluation, analysis of ventilator waveforms and capnography and used both pharmacological and non-pharmacological intervention strategies. There was no consensus concerning the English terminology of the condition. Only few respondents were familiar with local guidelines to manage FV. Conclusion: Although there was consensus on the relevance of FV, diagnostics and management strategies were highly heterogeneous. Many participants agreed that poor patient-ventilator synchrony was an important cause of FV. Future work should focus on characterizing and generating evidence on FV.

Background: Anatomic isthmus 3 (AI 3) is defined as the myocardium between the pulmonary valve annulus and the ventricular septal defect patch that persists after tetralogy of Fallot (ToF) repair. Ventricular tachycardia (VT) propagated through slow conducting AI 3 (SCAI 3) represents a significant cause of morbidity in ToF. There is an unmet need for non-invasive identification of SCAI 3 in patients with ToF. Objectives: To assess whether the anatomic features of AI 3 as derived from cardiac computed tomography (CT) can predict slow conduction velocity during EP study. Methods: This retrospective single-center study included patients with ToF who underwent an electrophysiologic study and had AI 3 width measured from the pre-procedure cardiac CT. All patients underwent programmed ventricular stimulation, and electroanatomic. Logistic regression was performed to assess the relationship between AI 3 width and the presence of SCAI 3. Results: Of 27 consecutive patients with ToF, twelve patients were found to have SCAI 3, and ten patients were found to have SCAI 3 mediated VT. The AI 3 was significantly narrower in patients with SCAI 3 compared to those with normal AI 3 conduction (18.4 +/- 6.6 mm vs. 29.2 +/- 9.0 mm; p = 0.001). An AI 3 width above 21.5 mm carried a negative predictive value of 80.0%. Conclusion: In adults with repaired ToF referred for electrophysiology study, a narrower CT-derived AI 3 width was associated with SCAI 3 identification. AI 3 width measured on a CT obtained before PV replacement could help guide invasive risk stratification.

Pulmonary lymphatic vessels are essential for interstitial fluid balance and macromolecular clearance, yet the endothelial mechanisms regulating lymphatic vessel function during chronic fibroproliferative lung injury remain undefined. Here, we demonstrate that the lineage-defining transcription factor ERG in lymphatic endothelial cells (LECs) governs junctional plasticity and fluid drainage in pulmonary fibrosis. In human idiopathic pulmonary fibrosis (IPF) lungs, lymphatic ERG expression is markedly downregulated. Lineage-specific inducible deletion of Erg in murine LECs (Erg-CKO) unexpectedly conferred robust protection against bleomycin-induced pulmonary fibrosis, significantly dampening acute inflammation, reducing edema, and preserving pulmonary compliance. Mechanistically, loss of ERG enhanced lymphatic drainage capacity in vivo. Transcriptomic profiling of isolated LECs revealed that ERG deficiency activates actomyosin contractile pathways and selectively upregulates Endothelin Receptor Type B (Ednrb), driving junctional remodeling from continuous zippers into discontinuous button-like configurations that facilitate interstitial fluid entry. Pharmacological blockade of EDNRB with BQ-788 abolished junctional reorganization, eliminated the enhanced lymphatic drainage, and completely reversed the anti-fibrotic protection in Erg-CKO mice. Together, our findings identify an endothelial ERG-EDNRB regulatory axis that controls lymphatic junctional architecture and demonstrate that promoting lymphatic clearance via endothelial junctional remodeling represents a viable therapeutic strategy for fibrotic vascular remodeling.

Rural patients with heart failure (HF) have poor access to care, worse outcomes, and may benefit from at-home monitoring. We evaluated whether foot temperature measured using a thermographic floor mat was associated with invasively measured cardiac output and whether longitudinal temperature changes preceded HF events. We conducted a two-part prospective, observational single-center study using the SmartMat (Podimetrics, Somerville, MA), which acquires plantar thermograms and ambient temperature. In the acute study, patients undergoing clinically indicated right heart catheterization completed 4 scans on the same day. In the chronic study, patients with a HF hospitalization in the past year and New York Heart Association Class II-III symptoms were instructed to use the device and a scale daily for 6 months. A HF event was defined as receiving at least one dose of intravenous or subcutaneous diuretic. Thirty patients were enrolled in the acute study. Mean right hallux temperature positively correlated with thermodilution cardiac output (r=0.63, p<0.001). 42 patients were enrolled in the chronic study. Among patients experiencing an HF event, ambient-adjusted hallux temperature declined in the 15 days immediately preceding the event compared with days 15-30 before the event. Plantar thermograms are associated with invasively measured cardiac output and may detect subclinical worsening before HF events. Foot temperature may provide complementary information regarding HF decompensation, supporting further evaluation of plantar thermography for remote HF monitoring.

Aims: Mature, contractile vascular smooth muscle cells (vSMC) in muscular blood vessels can de-differentiate into synthetic vSMC, while human pluripotent stem cells (hPSC) differentiate into proliferating, fetal-like vSMC that can be induced to form contractile vSMC. Given the complicated embryonic origins and conflicting views on vSMC heterogeneity, our aim was to establish how closely hPSC-vSMC of a known germ layer lineage and defined phenotype are representative of vSMC obtained from aorta (AoSMC). Methods and Results: We generated paraxial mesoderm (PM)-derived synthetic and contractile vSMC from hPSC lines and performed phenotypic and mechanical comparisons with AoSMC. Synthetic hPSC-vSMC and cultured AoSMC are proliferative, sensitive to contact inhibition and exhibit phenotype switching. Contractile hPSC-vSMC are non-proliferative, capable of phenotype switching and have elevated levels of contractile proteins (CNN1, TAGLN, ACTA2). These contractile proteins also displayed density-dependent, cell-to-cell heterogeneity in both AoSMC and hPSC-vSMC. Single-cell traction force measurements on micropost array detectors (mPADs) yielded comparable forces per micropost in the nN range across cell types. Quantitative 3D force measurements on humanized smooth muscle cell microtissues (SMTs) developed similar forces per cell. Larger forces were generated by MEKi-treated hPSC-vSMC and AoSMC versus controls. Conclusions: We have systematically studied the properties of hPSC-vSMC and performed comprehensive phenotypic and mechanical comparisons with AoSMC. These results demonstrate that synthetic hPSC-vSMC generated in vitro and cultured AoSMC derived from tissues are comparable and mechanically similar, but results with hPSC-vSMC are more reproducible.

Background: Calcific aortic valve disease (CAVD) is the most common valvular heart disease in older adults and currently has no approved pharmacological therapy to prevent or slow disease progression. Aortic valve replacement, either surgically or by transcatheter aortic valve implantation (TAVI), therefore remains the only effective treatment for severe CAVD. Monocytes play an important role in driving inflammation and disease progression in CAVD. As the disease progresses and the aortic valve becomes increasingly stenotic, circulating monocytes passing through the narrowed valve are repeatedly exposed to pathological haemodynamic forces, including markedly elevated shear stress, before their recruitment into the valve tissue. However, how exposure to these mechanical forces reprograms circulating monocytes influences their subsequent responses within the valve remain poorly understood. Methods and Results: In this study, we used an engineered model of aortic valve stenosis combined with phosphoproteomic profiling to investigate how prolonged exposure to pathological shear stress reprograms circulating monocytes and influences their subsequent phenotype and function following recruitment into the valve matrix. We further used TAVI as a unique clinical model to determine whether restoration of physiological haemodynamics in patients with severe aortic stenosis reverses the shear-induced monocyte phenotype observed in our experimental model. We found that prolonged exposure of monocytes to pathological shear stress induced extensive remodelling of the proteomic and phosphoproteomic landscape, with enrichment of pathways associated with cellular metabolism, cytoskeletal organisation, and inflammatory signalling. Kinase activity analysis further identified increased protein kinase C (PKC) activity accompanied by suppression of AKT signalling. Consistent with these molecular changes, pathological shear stress increased actin polymerisation, mitochondrial membrane potential, intracellular calcium signalling, and PKC activity. Using a bioengineered extracellular matrix model that recapitulates the glycosaminoglycan-rich microenvironment of the stenotic aortic valve we found that prior exposure to pathological shear stress altered monocyte-to-macrophage differentiation, reducing oxidised LDL uptake and foam-cell formation while promoting co-expression of CD80 and CD163, indicative of a mixed macrophage phenotype. Finally, using a myeloid-specific Piezo1 knockout mouse model, we identified Piezo1 as a key mechanosensor linking pathological shear stress to PKC activation, mitochondrial responses, and persistent changes in monocyte phenotype following migration into the extracellular matrix. Conclusions: These findings establish a mechanistic link between abnormal valve haemodynamics, metabolic and inflammatory reprogramming of circulating monocytes, extracellular matrix remodelling, and immune dysregulation during CAVD progression, highlighting monocyte mechanotransduction and downstream PKC/Piezo1 signalling as potential therapeutic targets.

Background: Atrial fibrillation (AF) has been observed in adults with anomalous pulmonary venous return (APVR), but data on catheter ablation outcomes in this population remain limited to case reports and small series. Methods: We retrospectively reviewed 14 adult patients with confirmed APVR who underwent catheter ablation for AF at three tertiary academic centers in the United States between July 2003 and May 2025. Baseline, procedural, electroanatomic mapping, and outcome data were collected. Freedom from atrial arrhythmia recurrence was estimated by Kaplan-Meier analysis. Results: Mean age was 56 +/- 13 years and 79% were male. Heart failure was present in 64%, and hypertension and coronary artery disease in 43% each. Most had partial APVR (86%), and 57% had prior surgical correction. Radiofrequency ablation was used in all patients, combined with pulsed-field ablation in one. Acute success was achieved in all patients, although areas with residual pulmonary vein or SVC electrical activity were left untreated in 3 (21%). Non-pulmonary-vein electrical activity was more common in patients with prior surgical correction than in those without (43% vs 17%). Median follow-up was 3.4 years (IQR, 2.0-9.6). Freedom from arrhythmia recurrence was 78.6% at 1 year and 53.9% at 5 years. Two patients (14%) required reablation; complications occurred in 3 (21%) without long-term sequelae. Conclusions: Catheter ablation was acutely successful in all patients in this largest reported APVR cohort, despite substantial comorbidity burden and anatomic complexity. The arrhythmogenic substrate often extended beyond the anomalous vein, particularly in surgically corrected patients, supporting individualized, substrate-guided ablation in this population.

Introduction. Whether the arterial pressure waveform carries structural vascular information that brachial pressure does not, and whether its shape can be read from facial video, are both uncertain, and recording a continuous pressure reference with synchronised video in a hypertension clinic has not been reported. We sought to determine whether continuous finger arterial pressure recording with synchronised facial video, linked to existing coronary calcium imaging, is feasible in adults attending a hypertension clinic, whether a consumer camera recovers heart rate and pulse shape in that setting, and to generate exploratory estimates of association between waveform morphology and coronary calcium. Methods. BP-WAVE is a single-site prospective observational pilot study. The primary outcome was feasibility, pre-specified as recruitment, consent, completeness of waveform recording, imaging availability and data completeness. Secondary outcomes were waveform quality, device agreement, feature extraction, and recovery of heart rate and pulse shape from video. The exploratory outcome was the Spearman correlation of 14 waveform features with the Agatston calcium score, with exact permutation p values adjusted within each family of tests. Results. Nine of ten planned participants were recorded over 12 days (median age 55 years, range 40 to 74; five women); all nine completed the recording with video and had a calcium score (median 351, range 33 to 1816). Of 4,178 detected beats, 2,965 (71%) passed quality control. Video recovered heart rate within 0.4 to 4.1 beats per minute in eight of nine participants and pulse shape above a phase-randomised noise bound in six of nine (held-out r 0.48 to 0.76). Form factor had the strongest correlation with calcium (rho -0.68, exact p 0.050, q 0.68); no feature was associated with calcium after Benjamini-Hochberg adjustment within any of the nine families of 14 tests (126 tests in all; smallest q 0.17). Conclusion. In this single-site pilot of nine adults from a hypertension clinic, continuous finger arterial pressure recording with synchronised facial video and linkage to coronary calcium was feasible, a consumer camera recovered heart rate in eight and pulse shape in six participants, and no waveform feature was associated with coronary calcium after correction for multiple testing.

Background: Localized or segmental overgrowth is a rare condition that may co-occur with vascular malformations. These diseases generally are caused by somatic mutations in the PI3K/AKT/mTOR pathway. Most lesions are progressive and may cause symptoms including pain, functional impairment, and disfigurement. Treatment options are limited, especially for the overgrowth component. Objective: To evaluate the efficacy and safety of the mTOR inhibitor sirolimus in patients with overgrowth with or without a vascular malformation over a 6-months treatment period. Methods: We conducted a single-arm, open-label, phase II study including 18 patients (12 pediatric, six adult) with overgrowth, all of whom initiated oral sirolimus. 16/18 (88.9%) participants received oral sirolimus for 6 months, with dosing adjusted to achieve target blood trough levels of 3-8 ng/mL. Primary outcome was radiological response at six months assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary outcome parameters were evaluated at three, six and nine months and included size and visual appearance of the overgrowth, quality of life (QoL), pain intensity, performance status, and safety. Results: No patient achieved complete or partial radiological response. 17 of 18 patients (94.4%) maintained stable disease at month six; one was not evaluable. QoL measured with WHOQOL-BREF improved modestly in patients aged >= 18 years (n=5, mean difference to baseline +9.3 (95%-CI: -0.9 to 19.5) in physical and +9.2 (95%-CI: 0.7 to 17.7) in psychological domains at month 6). In pediatric participants, no relevant improvement in KINDL total scores was observed over the study period. No significant changes occurred in pain scores. Performance status measured by the Lansky/Karnofsky scales showed minor improvement (mean +3.5 points (95%-CI: 1.0 to 6.1)). All patients experienced at least one adverse event, but no serious adverse events or CTCAE v5.0 grade [&ge;]3 toxicities occurred. Sirolimus was well tolerated. Six patients decided to resume sirolimus after study completion. Conclusions: Sirolimus induced minor lesion shrinkage in a subset of patients, although this did not meet the predefined radiological RECIST endpoint. However, sirolimus can lead to functional improvement in some adults, which may indicate that the primary radiological outcome did not capture patient-perceived benefit.

Introduction: The inability to measure renal sympathetic outflow clinically poses a significant problem for patient identification and intraprocedural feedback for renal denervation. Sympathetic vasomotion is a novel physiologic measure of rhythmic vascular control that reflects renal sympathetic nervous system activity, but previous measurements of sympathetic vasomotion relied on 15-minute data recordings, which may be impractical in many clinical settings. We therefore tested whether shorter data segments can provide reliable sympathetic vasomotion assessment to enhance decision making for renal denervation. Methods: Ten swine that had previously undergone unilateral surgical renal denervation underwent four rounds of catheter-based denervation of the contralateral kidney. Sympathetic vasomotion was quantified from the time-varying arterial pressure-resistive renal blood flow transfer function of recordings obtained before and after each round of ablation. Randomly placed 1- to 14-minute data segments were scored and compared with the corresponding 15-minute sympathetic vasomotion scores across 100 passes using correlation, intraclass correlation, error, and Bland-Altman agreement metrics, and by whether they reproduced the denervation decisions made from the full recordings. Results: Agreement with the 15-minute reference score improved steeply with recording length up to approximately four minutes and slowly thereafter, with the point of diminishing returns at four minutes for every group-level measure. Four-minute data segments showed an intraclass correlation coefficient of 0.94, reproduced the group-level statistical results across ablations, and preserved intraprocedural denervation decisions. Bland-Altman analysis revealed that individual-level precision continued to improve with recording length; the proportion of scores falling within a quarter of the average difference between innervated and denervated kidneys at baseline was 65 percent at four minutes and 96 percent at ten minutes. Discussion: Four-minute data segments provide a feasible minimum recording duration when the question is a group comparison or a paired, within-individual decision, such as intraprocedural confirmation that an innervated kidney has shifted toward a denervated state. When a single score must be interpreted on its own, as in preprocedural patient selection, ten-minute recordings provide greater precision. Further studies are needed to prospectively evaluate sympathetic vasomotion in clinical settings and determine whether this technology can support procedural feedback and inform patient selection.

Background: Patients with heart failure (HF) experience high mortality, yet survival estimates remain challenging. Available prognostic tools commonly predict survival beyond 1-year, limiting goals of care discussions and enrollment on palliative care programs. The objective of this project was to develop a novel prognostic score to better predict 6-month mortality. Methods: Patients with HF admitted to the St. Boniface Hospital (Winnipeg, Canada) between January 1, 2019 and January 1, 2024 were identified. Patient characteristics, imaging parameters, laboratory values, and functional assessments (Palliative Performance Scale; PPSv2) were collected. Patients were randomly divided into development (80%) and validation (20%) cohorts. Penalized LASSO regression was used to select variables most predictive of 6-month mortality in the development cohort. Retained variables were incorporated into a multivariable logistic regression model to derive the CARDIO-PAL score, the performance of which was assessed in the holdout validation cohort. Results: Characteristics were similar between the development (n = 2036) and validation (n = 508) cohorts, with 6-month mortality rates of 29% and 31%, respectively. 8 candidate variables were retained: age (adjusted odds ratio [aOR] 1.01), PPSv2 (aOR 2.08), systolic blood pressure (aOR 1.14), discontinued use of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (aOR 2.58), beta-blocker (aOR 1.59), and mineralocorticoid receptor antagonist (aOR 2.67), right ventricular systolic pressure (aOR 2.06), and urea (aOR 2.13). The CARDIO-PAL score demonstrated good discrimination, with an area under the curve of 0.80 (95% confidence interval 0.75 - 0.84) and good calibration (slope 0.84, intercept -0.04). 6-month mortality across low, intermediate, and high-risk groups was 2%, 15%, and 54%, respectively. Conclusion: The CARDIO-PAL score is a novel tool to predict 6-month mortality in HF inpatients. A collaborative approach integrating CARDIO-PAL with other prognostic scores and serial clinical assessments has the potential to promote patient-centered care and improve referral to palliative care programs.

Background Several disease-modifying agents for transthyretin amyloid cardiomyopathy (ATTR-CM) have been investigated, but differences in trial design and background stabilizer use complicate interpretation of their efficacy. This meta-analysis assessed their efficacy overall and by background stabilizer use. Methods PubMed, Embase, and the Cochrane Library were searched through September 2026 for phase III randomized, placebo-controlled trials of disease-modifying therapy in ATTR-CM. Primary endpoints were all-cause mortality, 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP), pooled with a random-effects model. Treatment effects were compared between the monotherapy and baseline stabilizer strata using a mixed-effects model. Results Five trials (ATTR-ACT, APOLLO-B, ATTRibute-CM, HELIOS-B, CARDIO-TTRansform; N=3497) were included. Disease-modifying therapy reduced all-cause mortality (risk ratio, 0.76; 95% confidence interval [CI], 0.66-0.87; I2=0%) and improved 6MWD (pooled standardized mean difference [SMD], 0.43; 95% CI, 0.20-0.67), KCCQ-OS score (SMD, 0.37; 95% CI, 0.19-0.55), and NT-proBNP (SMD, -0.53; 95% CI, -0.89 to -0.18). The mortality benefit was similar whether therapy was given alone or added to a background stabilizer (pooled risk ratio, 0.77 vs. 0.71; P for interaction = 0.59), but treatment effects on 6MWD (pooled SMD, 0.49 vs. 0.14), KCCQ-OS score (0.44 vs. 0.07), and NT-proBNP (-0.65 vs. -0.13) were smaller among patients receiving a background stabilizer (P for interaction = 0.012, <0.001, and 0.029, respectively). Conclusion Disease-modifying treatments reduced all-cause mortality and favored functional capacity, health status, and NT-proBNP outcomes in patients with ATTR-CM. Exploratory subgroup analyses showed smaller treatment effects on 6MWD, KCCQ-OS score, and NT-proBNP among patients receiving a background stabilizer, with no statistically significant difference in the mortality effect according to baseline stabilizer use.