Citations

BACKGROUND: Aortic enlargement is a powerful predictor of dissection and rupture, yet it is rarely evaluated during routine myocardial perfusion imaging, despite the widespread availability of computed tomography (CT) attenuation correction scans. The aim of this study was to determine whether fully automated, opportunistically derived, artificial intelligence-based aortic measurements from myocardial perfusion imaging CT attenuation correction scans are associated with adverse outcomes in a large multicenter cohort. METHODS: CT attenuation correction scans from patients undergoing positron emission tomography/CT and single-photon emission CT/CT myocardial perfusion imaging across 10 centers were included. A deep learning model automatically segmented the thoracic aorta, and a postprocessing algorithm extracted maximum ascending and descending diameters. The aortic size index was calculated by indexing the diameter to body surface area. RESULTS: A total of 29 339 patients (56% men; median age, 66 years [interquartile range, 58–75 years]) were included. Over a median follow-up of 3.5 years (interquartile range, 1.9–5.0 years), 5083 (17.3%) patients died. Median ascending and descending aortic size index values were 1.8 cm/m 2 (interquartile range, 1.6–2.0) and 1.5 cm/m 2 (interquartile range, 1.4–1.6), respectively, with an increase with age and higher values in females. Elevated aortic size index thresholds (ascending >2.2 cm/m 2 ; descending >1.6 cm/m 2 ) were significantly associated with increased all-cause mortality (ascending: adjusted hazard ratio, 1.16 [95% CI, 1.07–1.26], P <0.001; descending: adjusted hazard ratio, 1.23 [95% CI, 1.14–1.31]; P <0.001). Notably, the prognostic value of an abnormal aortic size index persisted independent of age, sex, and perfusion abnormalities. CONCLUSIONS: Artificial intelligence can unlock previously unused information within routine myocardial perfusion imaging CT attenuation correction scans by rapidly and automatically quantifying aortic size at scale. Opportunistic aortic measurements derived from CT attenuation correction may serve as an adjunctive risk biomarker and could add prognostic value to standard myocardial perfusion imaging without additional imaging or radiation.

Abstract Background In patients with suspected amyloid cardiomyopathy (CM) and a monoclonal protein, tissue biopsy is mandatory to exclude amyloid light-chain CM (AL-CM), the subtype requiring urgent therapy. We aimed to develop a pragmatic approach to estimate the most likely final diagnosis before biopsy. Methods We studied a multicenter cohort of adults referred for biopsy because of suspected amyloid CM. Clinical, laboratory, ECG/echocardiographic and bone-tracer scintigraphy data were collected at initial suspicion. In patients with a monoclonal protein, we derived age cut-offs overall and by carpal tunnel syndrome (CTS), defined an age-based "gray zone" (74–83 years), and evaluated risk modifiers for AL-CM and transthyretin CM (ATTR-CM). We built a points-based algorithm for "gray-zone" patients. Clinical utility was assessed using decision-curve analysis. Results Among 602 patients (median age 76 years; 81% male), 524 (87%) had a monoclonal protein. In the monoclonal-protein subgroup, ATTR-CM accounted for 49%, AL-CM for 30%, and neither ATTR- nor AL-CM for 21%. Age ≤73 years was the Youden-optimal threshold favoring AL-CM (sensitivity 66%, specificity 78%), whereas age &gt;84 years made AL-CM unlikely (sensitivity 98%, negative predictive value 94%), defining a "gray zone" (n=261; ATTR-CM 63%, AL-CM 18%, no amyloid CM 20%). Within the gray zone, abnormal free light-chain ratio, positive urine immunofixation, proteinuria, and higher troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) favored AL-CM, while higher Perugini grade, male sex, greater interventricular septal thickness, and higher NT-proBNP favored ATTR-CM. Penalized models achieved cross-validated area under the curves of 0.87 (AL-CM) and 0.94 (ATTR-CM). A two-score algorithm identified small gray-zone subsets enriched for AL-CM (positive predictive value 81.5%, specificity 98%) or ATTR-CM (positive predictive value 95.2%, specificity 94%). DCA showed higher net benefit for score- and model-based strategies versus treat-all/treat-none across clinically relevant threshold probabilities, with consistent patterns across regions. Conclusions In patients with suspected amyloid CM and a monoclonal protein, age- and CTS-anchored stratification refined by a compact set of routine laboratory and imaging features provides actionable pre-biopsy probabilities and may help prioritize urgent biopsy and AL-directed work-up while definitive tissue typing is pursued.For image description, please refer to the figure legend and surrounding text.

Abstract Background Age and sex influence the clinical expression of transthyretin (ATTR) amyloidosis, but limited evidence exists on their real-world impact across disease phenotypes. The prospective, multi-national MaesTTRo study, currently enrolling patients from the USA, Canada, the UK, Germany and Spain, provides a uniquely comprehensive opportunity to explore age- and sex-associated differences in routine practice. The aim of this analysis was to quantify the associations between these factors and diagnostic delay and cardiac findings. Methods Baseline data from 230 consecutively enrolled patients were analysed. Cohorts were stratified by age at diagnosis (&lt;60 y, n = 45; ≥60 y, n = 185) and separately by sex (female n = 70; male n = 161). Clinical characteristics, laboratory values, echocardiographic parameters and Kansas City Cardiomyopathy Questionnaire (KCCQ-23) scores were compared descriptively. Additional data will be included in the presentation as enrollment continues. Results Younger patients exclusively expressed a hereditary genotype (100% vs 63%), and experienced a longer mean (+SD) diagnostic delay than older patients (48 ± 61.5 vs 40.9 ± 64.4 months). Cardiac involvement was markedly age-dependent: median NT-proBNP was 91.5 pg ml⁻¹ (IQR 48.5–307) in the &lt;60 yrs group versus 1,393.5 pg ml⁻¹ (457–3,065) in the ≥60 yrs group. Older patients were more likely to experience New York Health Association (NYHA) class II–IV limitation than younger patients (88% vs 44%). Nonetheless, LV ejection fraction remained preserved in both cohorts (51 ± 14.8 vs 55.6 ± 9.3%). Older patients also reported a higher burden of cardiac symptoms (52% vs 33%). Patient-reported KCCQ scores were lower in the ≥60 yrs group vs &lt;60 years (68.4 ± 22.3 vs 73.3 ± 27.4). Females were more often diagnosed with ATTRv (84% vs 63%) after longer delays (51.3 ± 80.9 vs 38.3 ± 54.6 months), despite a stronger family history (61% vs 34%), and had lower biomarkers (NT-proBNP: 589 pg ml⁻¹ [111–2,509] vs 1,220 pg ml⁻¹ [386–2,941]) and wall thickness (LV wall thickness &gt;12 mm: 58% vs 73%), although there was no difference in LV mass index. Males reported better health status (KCCQ: 70.7 ± 22.2 vs 64.7 ± 24.4). Neurologic manifestations were common in both sexes (~70%), while musculoskeletal symptoms were more commonly reported in females (33% vs 23%). Conclusions Age and sex may independently modulate the diagnostic trajectory and cardiac presentation of ATTR amyloidosis. Advanced age and male sex are associated with more pronounced structural biomarker evidence of myocardial damage, whereas younger age and female sex are linked to delayed diagnosis of primarily hereditary ATTR amyloidosis with polyneuropathy and less cardiac involvement, especially when non-indexed echo measurements are used. These results underscore the need for age- and sex-specific approaches to prompt early clinical suspicion and diagnosis in order to enable treatment to mitigate disease progression.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.

Abstract Dermatomyositis is driven by overactivation of type I and II interferons and other proinflammatory cytokines that signal via the JAK-STAT pathway. We conducted a 12-week, open-label study of brepocitinib, an oral TYK2/JAK1 inhibitor, in five adults with severe cutaneous dermatomyositis. Treatment was associated with rapid, clinically meaningful improvement in cutaneous disease activity. Single-cell and spatial transcriptomic profiling of lesional skin showed marked suppression of interferon-responsive pathways and inflammatory cell states by week 4. Together with findings from a Phase 3 randomized trial in DM patients with skin and muscle involvement (VALOR, NCT05437263 ), these data support TYK2/JAK1 inhibition as a promising therapeutic strategy for DM.

Abstract Objectives This study aimed to investigate the procedural characteristics, efficacy, and safety of atrioventricular junction (AVJ) ablation for atrial tachyarrythmia (AT) in patients with congenital heart disease (CHD). Background Although AVJ ablation is an established treatment option for intractable AT in the general population, there is no existing data on this treatment in patients with CHD. Methods Data were analyzed from an observational, retrospective, multicenter cohort, initiated jointly by the Pediatric and Congenital Electrophysiology Society and the International Society of Adult Congenital Heart Disease. Eleven centers contributed baseline, procedural and longitudinal data, including vital status, echocardiographic data, QRS duration, and NYHA class. Outcomes were assessed at early (3 months-1 year), and late follow-up (≥2 years) after AVJ ablation. Results A total of 66 patients (46.7 ± 20.2 years) underwent 71 AVJ ablations. In total, 58.5% had moderate or complex CHD, including 17.1% patients with a systemic RV or single ventricular circulation. The cumulative AVJ ablation success rate was 98.5%. An abnormal location of the atrioventricular conduction pathway was successfully targeted in 20.0% of the patients, which was significantly more common in patients with complex CHD compared to moderate or mild CHD (44.4%, 15.8%, and 3.6%, respectively; both P&lt;0.05). Thirty-six patients (54.5%) underwent primary pacemaker implantation as part of the ‘pace and ablate’ strategy; final pacing modes were VVI pacing in 60.9%, and CRT/CSP in 39.1%. The transplant-free survival rates at 2, 5 and 10 years after AVJ ablation were 91.5%, 84.3%, and 69.0%, respectively. The acute and long-term complication rates were 3.0% and 13.6%, respectively. Conclusions AVJ ablation can be successfully performed in CHD patients with a high acute success rate and low complication rate. Anatomical challenges were common, which underscores the need for careful planning and operator experience. Given the acceptable long-term survival, these findings support the consideration of a ‘pace and ablate’ strategy in CHD patients with intractable AT.

Abstract Embryonal tumors with multilayered rosettes (ETMR) are rare, highly aggressive tumors of infancy with extremely poor outcomes and no established standard of care therapy. ETMRs were recognized as a distinct molecular entity in 2016, however, the absence of prospective, biology-driven clinical trials has limited translation of these insights into standardized, risk-adapted treatment approaches for this vulnerable population. To address this gap, the Collaborative Network for Neuro-oncology Clinical Trials (CONNECT) developed CURE(Clinical trial advancing Understanding of Rare Embryonal Brain Tumors), an international, multi-institutional, molecularly guided umbrella trial. All patients enroll through the centralized CURE-Screening protocol, which provides rapid comprehensive molecular profiling with real-time central pathology, molecular, and radiographic review to confirm diagnosis, define molecular subtype, and determine eligibility and assignment to disease-specific treatment arms. CURE-ETMR represents the first disease-specific arm to open within this platform. Following centralized screening, children with newly diagnosed ETMR are assigned to clinically defined risk strata using integrated molecular, radiographic, and clinical criteria. Patients will be treated using a risk-adapted multimodal approach in which we prioritize maximal safe surgical resection with consideration of second-look surgery based on centralized imaging review; administer induction chemotherapy followed by consolidation with high-dose chemotherapy and autologous hematopoietic cell rescue or dose-intensified chemotherapy, selectively incorporate radiation sparing approach or early focal radiotherapy for patients with unresectable residual disease or brainstem involvement; deliver intrathecal chemotherapy for leptomeningeal prophylaxis; and include biologically informed maintenance therapy. In parallel, protocol-required longitudinal collection of tumor tissue, cerebrospinal fluid, blood, and advanced neuroimaging supports integrated molecular, liquid biopsy, and imaging biomarker analyses to identify predictors of treatment response, resistance, and relapse. Primary objectives include evaluation of feasibility, safety, progression-free survival, and overall survival compared with molecularly annotated historical cohorts. This centralized screening to assignment framework establishes a scalable model for prospective, biology-driven trials in rare embryonal brain tumors.

ABSTRACT Background Pulmonary arterial hypertension (PAH) is characterized by circulating metabolic alterations, but whether these reflect disease-specific metabolic programs or reorganization of normal metabolic architecture, and how they relate to right ventricular-pulmonary vascular function (RV-PV), remains unclear. We hypothesized that the PAH metabolome is organized into biologically coherent, co-regulated metabolic modules whose relationships to RV-PV function would provide insight into known and novel metabolic pathways. Methods We applied weighted gene co-expression network analysis (WGCNA) to untargeted metabolomic data from 412 PAH patients enrolled in the multicenter PVDOMICS study. Module preservation analysis was performed in 85 healthy controls, with external replication in an independent single-center pulmonary hypertension cohort of 89 patients. Results WGCNA identified 16 distinct metabolic modules organized around biologically coherent programs. A coherent fatty acid axis, spanning substrate pools, β-oxidation intermediates, and conjugated fatty acid disposal products, formed a central organizing structure, with downstream fatty acid oxidation modules strongly associated with adverse hemodynamics and worse RV-pulmonary artery (PA) coupling. Acylcholine-enriched and 5α-reduced androgen metabolite modules were associated with favorable hemodynamic indices. Module architecture was largely preserved in healthy controls, with subtle disease-associated modular reorganization, rather than emergence of novel modules, observed in PAH. Core modules were recovered in the replication cohort with conserved hub metabolites. Conclusions These findings establish a systems-level framework demonstrating that PAH involves structured intensification and reorganization of interconnected metabolic programs associated with favorable and adverse RV-PV phenotypes. This work provides new insight into the metabolic architecture underlying PAH and identifies coordinated metabolic pathways linked to pulmonary vascular and right ventricular function.

Abstract Rationale The impacts of COVID-19 vaccination and SAR-CoV-2 infection on brain tissues and structures remain controversial. This study examines whether COVID-19-related exposures are associated with measurable changes in structural magnetic resonance imaging (MRI) using data from the US general population-based Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study. Methods The C4R study is an observational meta-cohort study of 14 NIH-funded population-based cohorts, with directly measured data on COVID-19-related exposures, including vaccination and infection. For this analysis, we included participants with C4R data and paired brain MRI scans from both before and after the onset of the COVID-19 pandemic (defined as March 1, 2020) from two cohorts: the Atherosclerosis Risk in Communities study (ARIC) and Framingham Heart Study (FHS). MRI features examined as outcomes were white matter volume (WMV), gray matter volume (GMV), total brain volume (BV), hippocampal volume (HV), and white matter hyperintensity volume (WMH), a marker of microvascular disease. Exposures included SARS-CoV-2 infections identified via questionnaires, serosurveys, and medical record reviews from 2020-2025. Infections resulting in hospitalization were classified as severe. Time-to-recovery, symptoms of long COVID, and vaccination status were self-reported by questionnaire. Analysis of covariance (ANCOVA) estimated associations between COVID-19-related exposures and pandemic MRI-measured outcomes, with adjustment for: the corresponding pre-pandemic MRI measure, the time between the two MRI scans, age, sex, systolic blood pressure, diabetes, and cardiovascular disease. Results Of 270 participants with available data, mean (SD) age was 80.6 years (10.6); 43.0% were male; and the mean (SD) interval between paired MRI scans was 4.2 (2.0) years. Most (90%) were vaccinated (of whom 6.7% vaccinated before infection) and 7.9% reported SARS-CoV-2 infection (of which 13.6% were severe infections) prior to their pandemic MRI (conducted March 2020 - June 2022). In fully adjusted models, there was no statistically significant association for change in WMV, GMV, BV, HV, or WMH with SAR-CoV2 infection status, infection severity, vaccination status, or vaccination timing (Table, P &gt; 0.05 for all comparisons). Self-reported symptoms of long COVID and vaccine manufacturer were also not associated with MRI outcomes. Conclusions Based on repeated (pre-pandemic and pandemic era) structural MRI scans, we found no evidence that SARS-CoV-2 infection or COVID-19 vaccination were associated with changes in brain structure or brain microvascular disease. These findings are consistent with prior data supporting COVID-19 vaccine safety and suggest resilience of brain structures following SARS-CoV-2 exposures. Nonetheless, further research is warranted using more sensitive measures and assessing longer term effects. This abstract is funded by: OT2HL156812

Abstract The Tau Global Conference 2025, hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation, convened international experts from academia, industry, government, and philanthropy to explore advances and challenges in tauopathy research. The meeting highlighted progress across tau biology, including emerging models of tau regulation, degradation, and propagation; advances in biomarker development for the diagnosis and staging of tauopathies; and evolving therapeutic strategies targeting diverse aspects of tau pathophysiology. Discussions also emphasized the importance of cross‐sector collaboration, and global initiatives to address disparities in tau research. This report synthesizes key insights from the conference and underscores the critical role of interdisciplinary, biomarker‐driven, and globally inclusive approaches in accelerating the translation of tau research into effective clinical applications.