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Cardiovascular responses exhibited both sex-dependent and sex-independent alterations in acute pancreatitis models of differing severity. In cerulein-induced mild acute pancreatitis, both sexes showed enhanced cardiac systolic function with only modest differences in vascular permeability. In severe acute pancreatitis, vascular permeability was similar between sexes, but compensatory cardiac systolic augmentation was preserved only in females. Angiopoietin-2 was identified as a compensatory cardiac mediator in severe disease.

Background: Alterations in cardiovascular function are key features of severe acute pancreatitis (AP) and contribute substantially to mortality. Although sex differences in cardiovascular diseases are well recognized, with males generally exhibiting higher risk and poorer outcomes, their influence on AP-associated cardiovascular responses remains poorly defined. Therefore, we hypothesized that cerulein-induced AP causes severity-dependent and sex-specific changes in vascular integrity and cardiac function. Methods: Obesity has been associated with more severe forms of AP. Thus, mild and severe AP were induced by cerulein injections (100µg/kg/h×12) in lean (n=10 males, n=13 females) and obese (n=9 males, n=12 females) C57BL/6J mice, respectively. Vascular permeability was assessed by FITC-dextran extravasation. Cardiac function was assessed by echocardiography before and after cerulein injection. Cytokines were measured with multi-plex cytokine array and the role of angiopoietin-2 (Angpt2), an endothelial-derived regulator of vascular and cardiac responses, was evaluated using a neutralizing antibody. Results: Vascular permeability did not differ significantly between sexes in either AP model. In mild AP, males and females showed comparable increases in systolic function; however, in severe AP, only female mice maintained this adaptive systolic augmentation, assessed by fractional shortening (FS; 25.78±0.27% at baseline vs. 43.44±0.57% at endpoint, n=12, p<0.0001). This impaired cardiac adaptation in males was accompanied by increased myocardial inflammatory cytokines and elevated circulating free fatty acids. Among ten circulating cytokines measured, Angpt2 levels were significantly higher in males than females (male: 63.50±1.52ng/mL, n=9 vs. female: 41.37±2.68ng/mL, n=6, p=0.013) and were negatively correlated with systolic performance (FS; R 2 =0.75, p<0.0001), while positively associated with preload (end-diastolic volume; R 2 =0.55, p=0.0015). Unexpectedly, Angpt2 neutralization did not improve the cardiac adaptations in males and instead worsened cardiac performance as reflected by reduced FS (control IgG: 32.83±1.47%, n=4 vs. Anti-Angpt2: 22.88±0.64%, n=5, p=0.013) in severe AP. Conclusions: AP elicits both sex-dependent and sex-independent cardiovascular responses, with female mice exhibiting preserved cardiac adaptation, and Angpt2 is a potential compensatory mediator of cardiac protection in severe AP.

Introduction: Endothelial cell (EC) dysfunction, driven by comorbidities of heart failure with preserved ejection fraction (HFpEF), has emerged as a potential contributor to disease progression, yet the EC specific molecular mediators in HFpEF remain poorly defined. Purpose: To identify EC-specific molecular mediators that are involved in HFpEF and determine their functional roles in disease pathogenesis. Hypothesis: Based on omics analysis of a murine HFpEF model, we hypothesized that EC plasminogen activator inhibitor-1 (PAI-1) is a key mediator of HFpEF pathogenesis. Methods: Male RiboTagEC (Cdh5CreERT2+/Rpl22HA/+) mice were used in a HFpEF model induced by hypertensive/metabolic stresses (60% calories from lard and L-NAME 0.5 g/L in water) or administrated with normal water and diet as controls. Hearts and skeletal muscle were collected for both bulk RNA sequencing (Bulk-seq) and EC-specific translatome analysis using translating ribosome affinity purification assay followed by RNA-sequencing (TRAP-seq). The functional roles of EC PAI-1 were tested using male tamoxifen-inducible, endothelial specific PAI-1 knockout (Cdh5CreERT2+/PAI-1flox/flox, PAI-1iEC KO) and control mice (PAI-1flox/flox, PAI-1iEC+/+) subjected to HFpEF induction. Cardiac function was assessed by echocardiography, pressure–volume (PV) loop analysis, and treadmill exercise testing. Student’s t-test was used (p < 0.05). Results: Bulk-seq and EC-specific TRAP-seq identified PAI-1 as one of the most upregulated genes in both heart and skeletal muscle EC in HFpEF. Bulk-seq demonstrated a 2.5-fold change (FC, log 2 FC=1.35) increases in the heart and 12.2-fold increases (log 2 FC = 3.61) in the skeletal muscle. TRAP-seq showed a 1.75-fold change (log 2 FC=0.81) increases in the heart and 4.76-fold increases (log 2 FC = 2.25) in the skeletal muscle. These consistent findings led us to investigate the functional role of EC PAI-1 in the pathogenesis of HFpEF. With similar body weight (Control: 40±4 g, n=10; KO: 38±6 g, n=11; p=0.319) and ejection fraction (Control: 54±6 %, n=10; KO: 54±5 %, n=12; p=0.686), we found that PAI-1iEC KO mice exhibited improved diastolic function after 10 weeks of HFpEF induction. Specifically, echocardiography demonstrated a significant reduction in E/e′ in KO mice (Control: 27±4, n=10; KO: 24±3, n=12; p=0.018). PV analysis confirmed this improvement with lower end-diastolic pressure (Control: 19±2 mmHg, n=8; KO: 13±5 mmHg, n=10; p=0.009), reduced Tau (Control: 9.7±1.2 ms, n=8; KO: 8.6±1.0 ms, n=10; p=0.047), and a reduced EDPVR constant β (Control: 0.20±0.05, n=6; KO: 0.10±0.03, n=6; p=0.017). KO mice also exhibited improved treadmill running distance (Control: 179±35 m, n=10; KO: 214±40 m, n=12; p=0.043). Conclusion: Endothelial PAI-1 contributes to diastolic dysfunction and reduced exercise capacity in HFpEF. These findings highlight endothelial PAI-1 as a potential therapeutic target for HFpEF. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

PURPOSE This analysis aimed to contextualize the symptoms of peripheral neuropathy (PN) experienced by patients with triple-class refractory (TCR) multiple myeloma (MM) treated with elranatamab in the MagnetisMM-3 clinical trial with those experienced by patients with TCR MM receiving a new line of physician's choice of therapy in the real-world MagnetisMM-14 study. METHODS MagnetisMM-3 included 123 patients and MagnetisMM-14 included 35 who had TCR MM and were enrolled under the same eligibility criteria. Patient-reported symptoms of PN were collected monthly using the Chemotherapy-Induced Peripheral Neuropathy-20 item (CIPN20) questionnaire and compared for clinically meaningful differences across sensory, motor, and autonomic domains. Higher scores indicated worse patient-reported PN symptoms. RESULTS Baseline demographics and clinical characteristics for patients in MagnetisMM-3 and MagnetisMM-14 were generally similar. Patients in MagnetisMM-3 had a median of five ( v four in MagnetisMM-14) prior lines of therapy. In MagnetisMM-14, common index therapies included elotuzumab + pomalidomide (23%), carfilzomib + pomalidomide (19%), or carfilzomib + cyclophosphamide (19%), all with corticosteroids. Mean scores for sensory (15.8 v 14.8) and motor (14.4 v 12.2) domains of the CIPN20 were similar between MagnetisMM-3 and MagnetisMM-14 at baseline. Mean scores for the autonomic domain were 14.0 versus 21.3 at baseline, respectively. No clinically meaningful differences for any domain were found between month 6 scores or changes in scores from baseline to month 6 between MagnetisMM-3 and MagnetisMM-14 populations. CONCLUSION These findings suggest that elranatamab treatment was not associated with a worsening of patient-reported PN symptoms across the sensory, motor, and autonomic domains of the CIPN20. Moreover, PN symptoms reported with elranatamab treatment were similar to those reported with other common therapies used in real-world clinical practice for the management of MM. MagnetisMM-3 ClinicalTrials.gov identifier: NCT04649359 .

BACKGROUND Several studies have highlighted the poor clinical outcomes observed among patients with relapsed/refractory multiple myeloma (MM), particularly those with triple-class refractory (TCR; refractory to at least one protease inhibitor [PI], one immunomodulatory drug [IMiD], and one anti-CD38 monoclonal antibody [mAb]) disease. The aim of this study was to describe the longitudinal changes in quality of life (QOL) and other patient-reported outcomes (PROs) among TCR MM patients who initiated a new line of therapy in real-world clinical practice. METHODS A prospective, multi-site observational study was conducted through the Mayo Clinic system. Patients with TCR MM initiating a new line of therapy (defined as the index date) were followed for a 12-month observation period. For patients initiating a CAR-T therapy, PRO survey assessments were conducted at apheresis, lymphodepletion chemotherapy, and every month after T-cell infusion until Month 6. All other patients received a survey assessment before index and every month thereafter until Month 6. PRO measures included the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30; including the Global Health Score [GHS]), the EORTC Multiple Myeloma Questionnaire (QLQ-MY20; including the Disease Symptoms [DS] domain score), the EORTC QLQ for Chemotherapy-Induced Peripheral Neuropathy (CIPN20), the EuroQoL-5 Dimensions (EQ-5D), the Patient Global Impression of Severity (PGIS), and the Patient Global Impression of Change (PGIC). PRO surveys were supplemented with retrospective chart reviews conducted at 3 months and 12 months following the index date to obtain clinical information. Descriptive data were reported at each timepoint separately for patients who received CAR-T and non-CAR-T index therapies. The study is ongoing and this abstract reflects all patient data collected as of May 2024. RESULTS This interim analysis included 77 patients (58% male, 95% White, mean age 66 years). The median time interval between becoming TCR and the index date was 5.6 months (interquartile range [IQR]: 1.8, 18.2). Most patients had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 (48% and 45%, respectively) and were Revised International Staging System (R-ISS) I or II (27% and 36%, respectively); 42% of patients had high-risk cytogenetics and 14% had extramedullary disease. The median (IQR) number of prior treatment lines was 4 (4, 5). Forty-two patients initiated a CAR-T therapy as their index therapy (12 and 30 treated with ide-cel and cilta-cel, respectively); the remaining 35 patients predominantly initiated a treatment regimen containing an IMiD (51%), a PI (54%), an anti-CD38 antibody (40%), or an alkylating agent (37%). Among these non-CAR-T patients, common regimens used were pomalidomide + elotuzumab + corticosteroids (26%), carfilzomib + cyclophosphamide + corticosteroids (20%), and pomalidomide + carfilzomib + corticosteroids (17%). Among CAR-T patients, QOL generally remained stable from apheresis (mean GHS and EQ-5D VAS were 62.3 and 66.4, respectively) to lymphodepletion (61.2 and 65.9) to Month 6 (64.2 and 68.9). Disease symptoms improved (mean DS domain scores at apheresis, lymphodepletion, and Month 6 were 25.7, 24.1, and 20.1, respectively) though pain, specifically, plateaued/worsened (mean pain domain scores were 24.5, 32.1, and 32.6). Based on the PGIC, 76% of patients reported being “a little better” or “much better” as early as Month 1, which stabilized over time (75% at Month 6). Among non-CAR-T patients, QOL largely remained stable (GHS and EQ-5D VAS was 62.9 and 68.4, respectively, at baseline and 64.9 and 67.7 at Month 6), though disease symptoms, including pain, improved over time (DS was 28.0 at baseline and 22.8 at Month 6; pain was 40.8 at baseline and 28.1 at Month 6). Based on the PGIC, 30.7% of patients reported being “a little better” or “much better” at Month 1, which improved to 52.7% by Month 6. CONCLUSIONS In this interim analysis of an ongoing prospective observational study, baseline values suggest a significant QOL burden among TCR patients. QOL generally remained stable for both CAR-T and non-CAR-T patients over the first several months post-therapy with some select improvements in disease symptoms. However, the patients (particularly CAR-T patients) directly reported some holistic improvement based on the PGIC as early as Month 1.

Background: Dysfunction of systemic vascular endothelial cells (ECs) is common in heart failure with preserved ejection fraction (HFpEF). We sought to determine if organ-specific EC translational heterogeneity is present in HFpEF. Using a transgenic mouse model (RiboTag EC ), we analyzed the translatome (the mRNAs bound with ribosomes) of organ-specific ECs in a mouse HFpEF model induced by hypertensive/metabolic stresses. Methods: Six-month-old male RiboTag EC ( Cdh5 CreERT2+ / Rpl22 HA/+ ) mice, expressing a hemagglutinin tag in EC ribosomal protein Rpl22, were fed a high-fat diet and L-NAME water (N=4) or a normal diet and water (N=5) for 7 weeks. Organs were collected for Translating Ribosome Affinity Purification, RNA isolation, and RNA-seq. RNA-seq data were visualized using uniform manifold approximation and projection (UMAP). Differentially expressed genes (DEGs; absolute fold change ≥ 2 and false discovery rate (FDR) adjusted p-value ≤ 0.05). Pathway enrichment analyses were conducted (Ingenuity Pathways Analysis (IPA)). Results: In UMAP, the EC translatome clustered by organ (heart, lung, skeletal muscle, and liver) highlighting organ-specific EC heterogeneity and by disease (HFpEF) status with cardiac ECs showing the most dramatic changes with HFpEF (Fig A). Cardiac ECs in HFpEF (vs Control) had 283 downregulated and 23 upregulated DEG (Fig B) out of 14,923 genes identified. There were significant differences in 142 canonical pathways (16 upregulated, 126 downregulated), including LXR/RXR activation, DHCR 24 signaling, regulation of insulin-like growth factors, eNOS signaling, acute phrase response (all down regulated) and IL-1b-mediated inhibition of RXR and unfolded protein response (both up regulated) (Fig C). Conclusion: HFpEF induction caused extensive translational changes in EC but particularly cardiac ECs. In cardiac ECs, metabolism, anti-inflammatory, vasodilation, tissue repair, and angiogenesis pathways were inhibited, while pro-inflammatory response, insulin resistance, and proteostasis pathways were activated.

Background and Objective: Decline of cardiovascular (CV) function is commonly observed in patients with severe acute pancreatitis (AP), which is associated with high mortality and morbidity. While the pathological changes in the pancreas during severe AP have been extensively studied, the impact on the CV system has not been well characterized. Furthermore, obesity is a major risk factor for severe AP. Hereby we utilized an obesity-associated mouse AP model to assess potential alterations in vascular integrity and cardiac function, two major components of circulatory failure. Methods: Wild-type male C57BL6J mice were fed a normal or a high fat (to induce obesity) diet. Both groups received intraperitoneal injection of cerulein (100 mg/kg/h x12) to induce AP. H&E and TUNEL staining of pancreas were performed to assess histology and cell death. To measure vascular integrity, we measured the leakiness of a fluorescein-conjugated dextran (70 kDa) in tissue parenchyma and serum levels of soluble vascular endothelial (VE)-cadherin, which has recently shown to be shed from endothelial cells with disrupted adherens junctions. Cardiac systolic and diastolic function were assessed by echocardiography at baseline and post-AP induction. Results: Compared to lean mice, obese mice developed more severe pancreatic edema, cell death and inflammatory cell infiltration, along with significantly increased accumulation of fluorescent dextran in multiple organs including pancreas, heart, lung, and kidney, suggesting systemic disruption of vascular integrity. Increased serum levels of soluble VE-cadherin in obese mice (vs. lean) after AP induction further supported compromised endothelial cell barrier function. At baseline, obese mice exhibited similar cardiac function to lean mice. However, obese mice, but not lean mice, developed impaired systolic and diastolic function post-AP induction, as supported by decreased ejection fraction and e’ velocity respectively. Conclusion: In this obesity-associated severe AP mouse model, systemic vascular permeability is increased, and cardiac function is substantially compromised. Systemic vascular hyperpermeability and cardiac dysfunction may represent therapeutic targets to enhance the outcomes in severe AP.

BACKGROUND Several studies have highlighted the poor outcomes observed among patients with relapsed/refractory multiple myeloma (MM), particularly those with triple-class refractory (TCR; refractory to at least one PI, one IMiD, and one anti-CD38 mAb) disease. The aim of this study was to describe the longitudinal changes in quality of life (QOL) and other patient-reported outcomes (PROs) among TCR MM patients in real-world clinical practice who initiate a new line-of-therapy. METHODS A prospective, multi-site observational study of patients with TCR MM was conducted through the Mayo Clinic system. Patients initiating a new post-TCR therapy (defined as the index date) were followed for a 12-month observation period during which PRO surveys were administered for the first 6 months. For patients initiating a CAR-T therapy, a survey assessment was conducted at apheresis, lymphodepletion chemotherapy, and every month after T-cell infusion until Month 6. All other patients received a survey assessment before index and then every month thereafter until Month 6. PRO measures included the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30; including the Global Health Score [GHS]), the EORTC Multiple Myeloma Questionnaire (QLQ-MY20; including the Disease Symptoms [DS] domain score), the EORTC QLQ for Chemotherapy-Induced Peripheral Neuropathy (CIPN20), the EuroQoL-5 Dimensions (EQ-5D), the Patient Global Impression of Severity (PGIS), and the Patient Global Impression of Change (PGIC). Patient surveys were supplemented with retrospective chart reviews conducted 3 months and 12 months following the index date to obtain clinical information. Descriptive data were reported at each timepoint separately for patients who received CAR-T and non-CAR-T index therapies. The study is ongoing and this abstract reflects all patient visit data as of April 2023. RESULTS N=55 patients (60% male, 96% White, mean age 66 years) were included in this interim analysis. The median time interval between becoming TCR and the index date was 3.9 months (interquartile range [IQR]: 1.7, 15.5). Most patients had an ECOG score of 0 or 1 (53% and 38%, respectively) and were R-ISS I or II (36% and 54%, respectively); 53% of patients had high-risk cytogenetics and 20% had extramedullary disease. The median (IQR) number of prior treatment lines was 4 (4.0, 5.5). N=24 patients initiated a CAR-T therapy as their index therapy (equally split between ide-cel and cilta-cel); the remaining N=31 patients predominantly initiated a treatment regimen containing an IMiD (52%), a PI (55%), an anti-CD38 antibody (13%), or an alkylating agent (36%). Among CAR-T patients, QOL and disease-related symptoms worsened from baseline through Month 2-3 (eg, mean GHS was 65.9 at apheresis, 64.9 at lymphodepletion, and 53.3 at Month 2 [higher scores indicate better QOL]; mean DS domain score from the QLQ-MY20 was 24.1 at apheresis, 23.4 at lymphodepletion, and 33.7 at Month 2 [higher scores indicate more symptoms]; see Table 1). These decrements were followed by improvement back to baseline levels and, in some cases, improvement above baseline levels (eg, GHS was 67.9 and 65.0 at Months 4 and 5, respectively; DS was 18.3 and 17.8 at Months 4 and 5), though few patients had sufficient follow up to analyze QOL at later timepoints. Based on the PGIC, 77.8% of patients reported being “a little better” or “much better” as early as Month 1, though this number declined over time. Among non-CAR-T patients, QOL largely plateaued (GHS was 62.2 at baseline and 58.3 at Month 6), though disease symptoms improved over time (DS was 28.6 at baseline and 24.5 at Month 6; pain was 42.3 at baseline and 29.2 at Month 6). Based on the PGIC, 34.7% of patients reported being “a little better” or “much better” at Month 1, which improved to 50% by Month 6. CONCLUSIONS In this interim analysis of an ongoing prospective observational study, QOL and symptom measures generally worsened over the first few months for CAR-T patients in the real-world though improved to baseline levels and beyond at later time points. Patients did, however, directly report improvement in their disease state as early as Month 1 based on the PGIC. Non-CART patients generally showed a QOL plateau with some modest improvement in disease symptoms which was also reflected in their self-reported assessment of disease state improvement based on the PGIC.