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BACKGROUND: Some symptomatic patients manifest pulmonary hypertension (PH), despite normal pulmonary vascular resistance and pulmonary artery wedge pressure—a condition termed unclassified PH. Although hypothesized to reflect increased flow as seen in congenital heart disease, broader clinical implications remain unknown. METHODS: The current analysis included pulmonary vascular disease phenomics participants with either no PH or unclassified PH who underwent dynamic right heart catheterization and transpulmonary metabolomics. In a validation cohort, patients with no PH or unclassified PH underwent exercise right heart catheterization. In exploratory cohorts to understand the impact of increased flow, the prevalence of unclassified PH was assessed in (1) adult congenital heart disease and (2) high output heart failure. RESULTS: The overall prevalence of unclassified PH in pulmonary vascular disease phenomics (n=1046) and the validation cohort (n=1202) was 7.8% (175/2248), which was comparable to the 6.6% (66/1005) prevalence in adult congenital heart disease (n=1005), and lower than high output heart failure (n=159, prevalence 14.5% [23/159]; P =0.006). Increased flow occurred in a minority of unclassified PH from both pulmonary vascular disease phenomics (28%; 15/53) and the validation cohort (11%; 13/122). Unclassified PH (n=53) was associated with greater adiposity, higher heart failure with preserved ejection fraction (HFpEF)–age, body mass index, atrial fibrillation score probability, and more left heart remodeling compared with those with no PH (n=216). Metabolomics revealed lower glycine metabolites in unclassified PH indicative of metabolic dysfunction. Left heart remodeling, quality of life, exercise capacity, and glycine levels were all abnormal in unclassified PH relative to healthy controls (n=96). In the validation cohort, pulmonary artery wedge pressure, pulmonary vascular resistance, and pulmonary artery compliance were subtly abnormal at rest in unclassified PH (n=122) compared with no PH (n=312). With exercise testing, 59% (72/122) with unclassified PH had exertional pulmonary artery wedge pressure elevation consistent with undiagnosed HFpEF. CONCLUSIONS: The presence of PH without obvious cause most often reflects subclinical left heart and metabolic dysfunction consistent with unrecognized early-stage HFpEF. Dynamic provocation during right heart catheterization can unmask unrecognized HFpEF in over half of unclassified PH, which may help guide appropriate initiation of proven HFpEF therapies to improve symptoms and functional status. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.

Abstract INTRODUCTION Chronic traumatic encephalopathy (CTE) is a tauopathy linked to repetitive head impacts. Factors influencing brain regional susceptibility to tau deposition and spreading remain unclear. METHODS We used three datasets: [18F]flortaucipir positron emission tomography (PET) in 157 former professional American football players and 53 controls (DIAGNOSE CTE); cortical myelin water fractions (MWF) in 50 healthy individuals (Myelin Water Atlas); and white matter (WM) tract MWF and functional connectivity (FC) in 100 healthy individuals (Human Connectome Project). We tested associations between tau‐PET uptake and covariance in football players and typical cortical gray matter (GM) MWF, WM tract MWF, and FC. RESULTS Cortical regions with lower typical GM MWF showed higher tau‐PET uptake ( β = −0.399, p = 0.001). WM tracts with lower typical MWF were associated with higher tau‐PET covariance ( β = −0.238, p < 0.001). Higher typical FC was associated with higher tau‐PET covariance ( β = 0.447, p < 0.001). DISCUSSION In former football players at risk for CTE, regional susceptibility to tau deposition may be driven by low myelin and high FC.

Abstract Introduction Despite regulatory mandates for advanced therapy (AT) washout periods of up to 5 drug half-lives before enrolling patients in inflammatory bowel disease (IBD) trials, the evidence base for these requirements is largely empirical, and whether shorter intervals independently increase the risk of serious infections in real-world practice remains unknown. Methods Using the OptumLabs Data Warehouse, we identified adult patients with IBD who initiated a new AT (tumor necrosis factor antagonists, vedolizumab, interleukin (IL)-12/23 or IL-23 antagonists, or Janus kinase inhibitors) between 2018 and 2023 using a class-specific new-user design. We examined whether exposure to AT within the preceding 12 months (vs no exposure to AT within that window) and timing of discontinuation (≤1 month, 1-&lt;3 months, or 3-12 months) were associated with risk of serious infections using multivariable Cox proportional hazards regression. Results Among 21 564 AT initiators (47 ± 18 years; 52% female; 57% Crohn’s disease), 7490 (34.7%) had AT exposure within the preceding 12 months. Over a mean follow-up of 1.6 ± 0.9 y, 1955 (9.1%) experienced a serious infection. Prior AT exposure was associated with higher infection risk (hazard ratio [HR]: 1.19, 95% confidence interval [CI]: 1.07-1.33), consistent in inverse probability of treatment-weighted analyses (HR, 1.20 [1.06-1.37]). Among patients with prior exposure, timing of discontinuation was not associated with infection risk (HR, 1.17 [0.95-1.43] for ≤1 month vs 3-12 months; HR, 1.01 [0.83-1.22] for 1-&lt;3 months), with no dose–response relationship on continuous modeling. Discussion AT exposure within the preceding 12 months is associated with modestly higher risk of serious infection after initiating a new AT in IBD, but timing of discontinuation does not independently influence this risk.

Background Gastro-oesophageal reflux disease (GORD) occurs in most (∼75%) patients with systemic sclerosis (SSc) and significantly impacts quality of life. Current recommendations lack depth and therefore our aim was to produce practical, consensus-based recommendations for refractory SSc-related GORD. Methods An international, multidisciplinary steering board (SB) was assembled (n=19) consisting of clinicians (rheumatologists, gastroenterologists, gastrointestinal surgeons), an expert methodologist and patient representation. After reviewing the latest definitions of GORD and refractory GORD in the published literature, the SB collectively devised a practical definition of SSc refractory-GORD. Initial recommendations were drafted/agreed on by the SB based on review of the existing guidelines, published literature and expert opinion. Two online voting rounds were conducted to determine whether items should be accepted, with >75% and >60% SB agreement required for first and second rounds, respectively. Results There was a good response/completion rate for the initial (74%) and final (84%) voting rounds. The SB agreed on all 36 draft recommendations. The majority (n=34) were approved in the first round. Recommendations were organised according to the following categories: general approach to management (n=5), assessment (n=6), non-pharmacological (n=2) and pharmacological (n=10) management, endoscopic and surgical treatment (n=3), and special circumstances including refractory GORD and SSc-interstitial lung disease (n=3), myositis and SSc connective tissue disease-overlap (n=3) and perilung transplant (n=4). Conclusion The group of experts has drafted extended and practical recommendations for the management of SSc refractory-GORD. The necessity of a structured approach and a patient assessment is highlighted in order to provide a multidisciplinary approach to the tailored choice of the treatment. Our work also has also identified significant unmet needs and has provided a research agenda to advance the field.

Abstract Aims This study aimed to identify clinical factors associated with AVC in individuals with T2D. Methods and results This cross-sectional study is a pre-specified substudy of the multicentre randomized Steno INTEN-CT trial (Clinical Trials—INTEN-CT). Participants were eligible if they had T2D without ischaemic heart disease and were aged between 55–69 years (men) or 60–74 years (women). All participants underwent non-contrast cardiac computed tomography. AVC was measured in Agatston Units and categorized as 0, 0–300, ≥ 300. Of the 4570 participants, 46% had AVC &gt; 0. With increasing AVC, patients were older, predominantly males, and with significantly more comorbidities. In multivariable ordered logistic regression age (OR per SD 1.54, 95% CI 1.43–1.66), BMI (OR per SD 1.18, 95% CI 1.11–1.25), hypertension (OR 1.21, 95% CI 1.05–1.40), and chronic kidney disease (OR 1.18, 95% CI 1.03–1.36) were associated with higher AVC. Statin use was also associated with higher AVC (OR 1.50, 95% CI 1.27–1.78). Higher LDL cholesterol showed stronger associations with AVC in men than women (OR 1.39, 95% CI 1.24–1.56 vs. OR 1.16, 95% CI 1.02–1.31, P for interaction = 0.025). T2D severity (Haemoglobin A1c, T2D duration, and number of antidiabetic drugs) was not associated with AVC. Conclusion In individuals with T2D without cardiovascular disease, AVC is prevalent in nearly half of all individuals. Higher AVC was associated with T2D-related comorbidities, but not T2D severity.

The ever-changing landscape of cardiology necessitates continuous education of healthcare providers. Case-based learning (CBL) provides an inquiry-based form of learning where learners apply knowledge to realistic clinical scenarios under instructor guidance. However, current case-based learning curricula are limited to representing 3-dimensional content in 2-dimensions with distinct modalities utilized for various data sources. Virtual reality (VR) shows promise for CBL given it provides an immersive and interactive 3-dimensional medium in which multi-source content can be incorporated into a unified learning experience, potentially translating to improved learning efficiency and lower cognitive load. With VR case-based learning, learners can view medical imaging in 3-dimensions or seamlessly interact with various 2-dimensional images within one unified medium. Further, additional content including simulated patients or procedures can be incorporated with a higher level of fidelity. Herein, we summarize the current literature exploring VR-CBL, demonstrate a proof-of-concept VR application, and review the implications for cardiology education. The proof-of-concept exemplifies many of the key advantages unique to VR-CBL, such as medical imaging rendered in 3-dimensions, integration of multiple imaging sources, and novel interaction methodologies. Given the importance and rapid evolution of ongoing medical education, VR-CBL, with its immersive and engaging nature, appears to be a promising form of instruction that may serve a larger role in continuing medical education initiatives.

PURPOSE In large B-cell lymphoma (LBCL), use of high-dose methotrexate (HD-MTX) to prevent CNS relapse (so-called CNS prophylaxis) remains controversial. International guidelines continue to recommend HD-MTX in patients deemed ultra high risk (UHR) because of a lack of robust data specific to these subgroups. This study was designed to examine the impact of HD-MTX specifically in UHR patients. METHODS Data from two previous retrospective analyses were combined to produce a cohort of UHR patients (≥1 of the following criteria: CNS international prognostic index score 5-6; testicular, renal/adrenal, or breast involvement; ≥3 extranodal sites), treated with or without HD-MTX. The primary outcome was CNS relapse rate (isolated or concurrent with systemic relapse) measured from diagnosis with additional landmark analysis of all responding patients with no progression event at 6 months. RESULTS Analyses were performed on 1,923 patients meeting UHR criteria. No significant difference in 3-year CNS relapse rate was observed between no HD-MTX (n = 1,051) versus HD-MTX patients (n = 872), including in multivariable analyses adjusting for baseline characteristics (3-year rate, 9.3% v 8.1%; adjusted hazard ratio [HR], 1.13 [95% CI, 0.82 to 1.57]). Analyses restricted to isolated CNS relapse also confirmed no difference (5.9% v 5.7%; adjusted HR, 1.03 [95% CI, 0.69 to 1.53]). In the landmark analysis (no HD-MTX n = 782, HD-MTX n = 773), no difference in 3-year CNS relapse was observed (6.7% v 6.6%, adjusted HR, 0.95 [95% CI, 0.62 to 1.44]). CONCLUSION To our knowledge, this is the largest international comparative data set of patients with LBCL with UHR features showing no significant reduction in CNS relapse with HD-MTX in all UHR or in any individual subgroup. Despite inherent limitations of retrospective analyses, the data strongly support previous studies in suggesting HD-MTX prophylaxis has no meaningful benefit for most patients.

Abstract Background Climate-related stressors such as heat, wildfires, and extreme weather are increasingly recognized as determinants of cardiovascular and oncologic health. However, their joint impact on overlapping cancer–cardiovascular disease (CVD) burdens remains unknown. We developed a Cardio-Oncology Burden Index (COBI) to quantify the co-prevalence of cancer and CVD at the community level and examined its association with climate vulnerability across U.S. census tracts. Methods We conducted a cross-sectional ecological analysis of 82,679 census tracts (328,683,841 residents) using the CDC PLACES database. COBI was derived using principal component analysis of age-adjusted prevalence of cancer, coronary artery disease, and stroke. The Climate Burden Index (CBI, 0–1 percentile) integrates multiple climate-related exposures, including extreme temperature, wildfire frequency, and severe weather events. Population-weighted mixed-effects regression models with county-level random effects estimated associations between CBI and COBI, adjusting for region, rurality, and environmental justice indicators. β coefficients represent percentage-point differences in COBI per unit (or category) increase in climate burden. Exposure–response relationships were examined using restricted cubic splines (RCS). Robustness was assessed via geographically matched (&lt;50 km) and fully matched (region, rural–urban commuting area, and environmental justice) analyses. Results Marked spatial heterogeneity was observed in both CBI and COBI across the U.S. (Fig. A–B). Higher climate burden was consistently associated with greater cardio-oncology burden (Fig. C), demonstrating a dose–response relationship: second vs lowest quartile β=0.92 (95% CI, 0.61–1.24); third vs lowest quartile β=1.61 (95% CI, 1.30–1.92); highest vs lowest quartile β=3.44 (95% CI, 3.11–3.76). The RCS model revealed a significant non-linear association (p_non-linear&lt;0.001), with a plateau at moderate exposures and a steep rise at the highest CBI levels (Fig. D). Results remained robust in sensitivity analyses (β=4.17 [95% CI, 3.62–4.71] for geographically matched; β=4.39 [95% CI, 4.10–4.69] for fully matched tracts; Table). Conclusions Greater climate burden is independently associated with higher cardio-oncology burden across U.S. communities, with disproportionate effects in the most climate-vulnerable areas. This novel, population-level linkage between climate stress and onco-cardiovascular disease burden, highlights an emerging syndemic at the intersection of environment, cancer, and CVD. Targeted mitigation and prevention strategies integrating environmental resilience into chronic disease prevention are urgently needed.For image description, please refer to the figure legend and surrounding text.

Abstract Background World Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype–hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing. Methods We studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield. Results Adjudicated Group 2 PH was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype–hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non–Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post/NonG2 participants, consistent with ventricular interdependence. RV/LV ratio ≥0.94 reduced discordant Post/NonG2 classification by 70.5%, and incorporation of PCWP/cardiac output slope improved physiologic specificity during exercise. Conclusions Group 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment. Clinical Perspective What Is New? In the deeply phenotyped PVDOMICS cohort, resting pulmonary capillary wedge pressure demonstrated good overall discrimination for adjudicated Group 2 (left heart disease) pulmonary hypertension, yet intermediate values frequently either concealed latent left-heart disease or overclassified patients without intrinsic left-heart disease Resting pulmonary capillary wedge pressure should be viewed as a continuous probability signal rather than a binary threshold, allowing additional physiologic testing to be targeted according to the degree of diagnostic uncertainty a clinician is willing to accept. A staged physiology-guided approach incorporating inhaled nitric oxide, ventricular geometry, and provocative testing improved concordance with adjudicated PH category and pre or post-capillary classification. What Are the Clinical Implications? Pre- versus post-capillary classification should be interpreted within the broader clinical and physiologic context rather than relying on a single resting pulmonary capillary wedge pressure threshold. Intermediate pulmonary capillary wedge pressure values should prompt consideration of additional physiologic evaluation, with inhaled nitric oxide providing a practical intermediate step and provocative testing providing the greatest incremental diagnostic yield. Exercise pulmonary capillary wedge pressure/cardiac output slope and markers of ventricular interdependence may provide complementary information for resolving uncertainty when resting and dynamic hemodynamics are discordant.