Citations

Abstract Background Cardiogenic shock (CS) is characterized by critically low cardiac output and impaired myocardial energy transfer to cardiac work. Left-ventricular (LV) cardiac mechanical efficiency (CE), defined as the fraction of total pressure-volume area (PVA) converted to external work (EW), captures how effectively the LV converts energy into stroke work. Because CE integrates load, chamber volumes, and pump performance into a single physiologic construct, it may directly reflect the energy-work mismatch that characterizes CS. The prognostic value of transthoracic echocardiography (TTE)-derived CE for in-hospital outcomes in CS remains uncertain. Purpose To determine whether TTE-derived CE measured within 24 hours of admission predicts in-hospital mortality in patients with CS, and to compare its discriminatory performance with LV ejection fraction (LVEF). Methods Data from CS patients admitted between 2007 and 2018 were analyzed. First LV end-systolic pressure (LVESP=0.9×systolic blood pressure), stroke volume (SV), and LV end-diastolic pressure (LVEDP, estimated using the Nagueh formula) was estimated. CE was then estimated based on EW (EW=(LVESP×SV)−(SV×LVEDP)), potential energy (PE=0.5×LVESP×LV end-systolic volume) and PVA (EW+PE) as CE=EW/PVA×100. We assessed CE and LVEF by TTE performed within 24 hours of admission. Patients were separated into tertiles of CE: high (>47%), moderate (36% < CE ≤47%), and low (CE ≤36%). The primary endpoint was in-hospital mortality. A key secondary endpoint was cardiac intensive care unit (CICU) mortality. Associations were tested with multivariable logistic regression (pre-specified covariates including LVEF). Results A total of 577 patients were included. Median age was 69 (IQR: 59-78) years, 38% were females and 65% had acute coronary syndrome. CICU mortality was 20% and total in-hospital mortality was 29%. Patients with low CE had a lower LVEF compared with patients with moderate or high CE (21% (IQR:19-24%) vs 31% (IQR: 28-33%) and 45% (39-51%) respectively). Median CE was 40.5% (IQR 31.8–51.0%) and was lower for in-hospital deaths (37.1% vs 42.1%, P<0.001). Patients with lower CE exhibited significantly higher CICU (P=0.003) and in-hospital mortality (P<0.001; Figure 1). Patients with CE in the lowest tertile had significantly increased risk of CICU and in-hospital death (Figure 2) compared with moderate or high CE tertiles. In multivariate analysis, every 1% decrease in CE corresponded to an 10% increased risk of CICU death and an 8% increased risk of in-hospital death. When both CE and LVEF were included in the same multivariate model, both were significant predictors of CICU death, while only CE remained a significant predictor of in-hospital death. Conclusion In patients with CS, TTE-derived CE measured within 24 hours of admission predicts early risk of death, underscoring the prognostic importance of LV energy-work coupling as a marker of disease severity beyond LVEF measurement.Figure 1: Figure 2:

Abstract Background Diuretic resistance (DR) is the failure to achieve adequate natriuresis despite high diuretic doses, reflecting a state of low diuretic efficiency (DE). In heart failure (HF) and general intensive care cohorts, low DE and the presence of DR have been associated with adverse outcomes, including increased risk of rehospitalization and mortality (1-3). Quantitative data, however, remains limited in patients admitted to the cardiac intensive care unit (CICU) – a population characterized by cardiac critical illnesses and substantial cardiorenal interactions. Purpose The aim of this study is to investigate and characterize the association between DR and associated mortality outcomes in CICU patients. Methods This retrospective cohort study included adult CICU patients (2007-2018) who received loop diuretics on day 1 of admission. Patients with a stay <1 day or oliguria [<400mL urine output (UOP) total] were excluded. DR was defined as <500mL of UOP per 40mg oral furosemide equivalent (FSE). Acute kidney injury (AKI) was defined per KDIGO guidelines. Primary outcome was all-cause in-hospital mortality (including CICU deaths), and secondary outcome was all-cause 1-year mortality. In-hospital mortality predictors were evaluated using logistic regression and 1-year mortality predictors by Cox proportional-hazards models. 1-year survival was assessed using Kaplan-Meier curves. Multivariable models were adjusted for known confounders. Results 3,229 total patients were included. Median age was 71.2 (61.2, 80.7) years and 41.3% were female. Admission diagnoses included HF exacerbation (79.9%), acute coronary syndrome (34.5%), and respiratory failure (38.9%), among others. 1,098 (34.0%) patients met DR criterion; they had higher severity of illness scores, more comorbidities (including HF, diabetes mellitus, lung disease, and chronic kidney disease, p<0.001), and greater laboratory derangements. On admission, 23.6% patients had AKI, of which 54.3% patients met DR criterion. During hospitalization, 56.0% patients had AKI; those with DR had higher prevalence and severity of AKI (unadjusted OR 3.55 [3.02-4.17], p<0.001). Overall in-hospital mortality was 9.8% (including 5.2% in the CICU). In patients with DR, in-hospital mortality was 17.0% (9.7% in the CICU). Notably, 59.4% of all in-hospital deaths occurred in patients with DR. DR was independently associated with higher in-hospital (adjusted OR 2.00 [1.51-2.64], p<0.001) and 1-year (adjusted HR 1.64 [1.44-1.88], p<0.001) mortality. Patients with DR had higher mortality in each AKI stage (Figure 1), and patients with concomitant DR and AKI had the highest risk of 1-year mortality (Figure 2). Conclusion DR, defined by our easily applicable threshold, emerged as a powerful, independent predictor of adverse outcomes and was associated with substantially higher mortality, demonstrating potential as a valuable risk stratifying tool.

Abstract Background Hypotension is a recognized predictor of mortality in the cardiac intensive care unit (CICU) (1-3). Although prior studies link lower mean/averaged mean arterial pressure (MAP) to adverse outcomes, they highlight the need for dedicated research on the minimum MAP (mMAP), as mean data may fail to capture the clinical significance of brief, severe hypotensive episodes. Purpose This study aims to investigate the mortality outcomes associated with the mMAP within the first 24 hours of CICU admission and further stratified according to admission diagnoses. Methods This retrospective cohort study included adult CICU patients with available mMAP data (2007-2018). Patient data were extracted including admission diagnoses, critical care therapies (hemodynamic/ventilatory support, continuous renal replacement therapy), comorbidities, vital signs, lab values, and mortality outcomes. MAP was measured either invasively (arterial catheter) or non-invasively (blood pressure cuff). Primary exposure was mMAP, defined as the lowest recorded MAP in first 24 hours of CICU admission. Primary outcome was in-hospital mortality analyzed using logistic regression, before and after multivariable adjustment. Mortality outcomes were analyzed according to mMAP and stratified by admission diagnoses (not mutually exclusive). Results 11,930 patients were included. Median age was 69.4 (58.1, 79.2) years and 37.7% were female. Admission diagnoses included heart failure (48.7%), acute coronary syndrome (42.7%), shock (14.9%), and cardiac arrest (11.8%). Critical care therapies were used in 58.5%. Median mMAP was 54 (47, 62) mmHg. 1080 (9.1%) patients died during hospitalization, including 672 (5.6%) in the CICU. Median mMAP was lower in patients who died in the CICU (46 vs. 55 mmHg, p<0.001) and during the hospitalization (47 vs. 55 mmHg, p<0.001). In the overall cohort, the lowest mortality was at mMAP of 71-75 mmHg. Patients with lower mMAP had higher mortality across admission diagnosis subgroups (Fig1). The mMAP associated with the nadir mortality was slightly higher for acute coronary syndrome or cardiac arrest patients (66-70 mmHg) than for heart failure or cardiogenic shock patients (61-65 mmHg) (Fig2). Each 5 mmHg increase in mMAP was associated with lower in-hospital mortality in patients with (unadj OR 0.81 [0.79-0.84], AUC 0.64) and without (unadj OR 0.76 [0.71-0.82], AUC 0.67) critical care therapies. Conclusion Our findings re-affirm that hypotension is a significant predictor of mortality, consistent across all admission diagnoses. Notably, the mMAP range associated with the lowest in-hospital mortality was slightly lower for patients with circulatory failure (heart failure or cardiogenic shock) compared to those with acute coronary syndromes or cardiac arrest. This difference may represent an optimal balance between maintaining perfusion and preventing excessive afterload in the setting of circulatory failure, but further investigation is required.1) Mortality Per mMAP & Admission Diag 2) Nadir Mortality Point

Abstract The impact of microglia antigen presentation on CNS infiltrating CD8 T cells responses during neurotropic virus infection has been difficult to define. Using Theiler’s murine encephalomyelitis virus (TMEV) infection of neurons as a model system, our laboratory has previously determined that H-2D b restricted, but not H-2K b restricted CD8 T cells are required for viral clearance, demonstrating the role of discrete MHC class I alleles. To determine the extent microglia antigen presentation impacts brain-infiltrating CD8 T cells, our laboratory generated novel single MHC class I conditional knockout mice in which H-2K b or H-2D b can be specifically deactivated in TMEM119+ microglia with tamoxifen administration. During TMEV infection, conditional knockout of H-2K b in microglia reduced antigen-specific CD8 T cell proliferation in the brain. Meanwhile, mice with deletion of D b in microglia had reduced levels of perforin in antigen-specific CD8 T cells. Furthermore, microglia specific deletion of H-2D b reduced CD8 T cell numbers in the brain and preserved blood-brain barrier (BBB) integrity. Microglial D b restricted antigen presentation was also essential for the reactivation of CD8 tissue resident memory (TRM) cells and BBB integrity during memory recall responses. These findings further our understanding of how brain infiltrating antiviral CD8 T cell responses are impacted by microglia, as well as define how this cellular interaction contributes to BBB disruption during neuroinflammation. These findings also have high significance to our understanding of how microglia impact CD8 TRM cell populations that reside in the brain long after virus infection is cleared. Graphical abstract

PURPOSE The Lynch syndrome (LS) genes, MLH1 , MSH2 , MSH6 , and PMS2 , are considered to be some of the highest-priority genes to be tested for population genomic screening, with the aim to prevent and detect cancers early in those with a higher risk for such diagnoses. The objective of this study was to determine the risk of cancer associated with pathogenic variants in MLH1 , MSH2 , MSH6 , or PMS2 in the general population to build evidence-based guidelines for population genomic screening METHODS This retrospective case-control study uses Helix Research Network data from 230,159 participants across nine US health systems. Variant interpretation was performed following the American College of Medical Genetics and Association for Molecular Pathology guidelines. Clinical diagnoses were identified from electronic health records and claims data for 11 cancer types associated with LS, including colorectal and endometrial cancers. RESULTS Individuals with pathogenic variants in MLH1 , MSH2 , and MSH6 showed substantial risk for LS-related cancers compared with those without pathogenic variants. Conversely, individuals with pathogenic variants in PMS2 had no increase in risk for all 11 LS-associated cancers with hazard ratio (HR) of 1.0 (95% CI, 0.6 to 1.8) compared with those without a pathogenic variant. There was a small increase in risk when restricting the analysis to colorectal cancer with an HR of 3.5 (1.7-7.4). This increase in colorectal cancer risk was predominantly observed after age 60 years, 10 years after US Preventive Services Task Force guidelines recommend starting colonoscopies for the average population. Up to age 60 years, 2.6% of individuals with PMS2 pathogenic variants were diagnosed with colorectal cancer, closer to the general population (0.7%) than those with MLH1 (37.3%), MSH2 (28.9%), or MSH6 (6.7%) pathogenic variants. For 100,000 individuals screened for PMS2 , 854 additional colonoscopies would be performed, which would prevent or detect early 3.2 colorectal cancers. CONCLUSION This analysis across nine health systems highlights the clinical phenotypes of PMS2 pathogenic germline variants in the entire population.

PURPOSE Remote symptom monitoring using patient-reported outcomes (PROs) has been shown to improve symptom control and physical function among patients with advanced cancer. However, it is unclear whether these benefits are similar across demographic groups. This exploratory analysis of the PRO-TECT trial examined whether the effects of electronic symptom monitoring varied by race, age, sex, and educational attainment. METHODS PRO-TECT was a cluster randomized trial conducted across 52 US community oncology practices comparing weekly electronic symptom monitoring with usual care (UC). Adult patients with metastatic solid tumors receiving systemic therapy were enrolled (N = 1,191). Participants in the PRO arm completed weekly symptom surveys including the PRO-CTCAE, triggering alerts to the care team for severe or worsening symptoms. Patients chose whether to complete weekly PROs online or via telephone-based interactive voice response not requiring Internet access. Outcomes were measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 symptom control and physical function scales. Subgroup analyses were performed by race (Black v White), age (<65 v ≥65 years), sex (male v female), and educational attainment (≤high school v >high school). RESULTS From baseline to 3 months, PRO participants showed greater improvements in symptom control (+2.37 v −0.20, P = .002) and physical function (+1.54 v −0.93, P = .02) versus UC. Benefits were most pronounced among younger, female, Black, and less educated participants. Black participants in the PRO arm were more likely to report that symptom reporting made them feel more in control of their care compared with White participants. CONCLUSION Electronic symptom monitoring improved quality-of-life outcomes overall, including among groups who have historically experienced higher symptom burden or barriers to communication. Remote PRO systems may represent an equitable strategy to enhance cancer care delivery.

Rationale: Pulmonary hypertension (PH) is a fatal disease characterized by a sustained elevated pulmonary vascular resistance that results in right heart failure. Despite therapeutic advances, no treatment provides disease progression reversion, resulting in poor long-term survival. Identifying new therapeutic targets for PH therefore requires a deeper understanding of its mechanisms. A defining feature of PH is pulmonary vascular remodeling, a result from excessive proliferation, migration, and apoptosis resistance of pulmonary artery smooth muscle cells (PASMC). SNAI1, a transcription factor regulating cell proliferation and differentiation during development and disease, has recently been implicated in endothelial dysfunction and endothelial-to-mesenchymal transition in PH. However, its role within PASMC remains unknown. Here, we aimed to define the contribution of SNAI1 in PASMC to the pathogenesis of PH. Methods: Normal human PASMC were exposed to normoxia (21% O 2 ) or hypoxia (3% O 2 ) for 72 hours. PASMC were also isolated from patients with or without PH. Cell proliferation and migration were assessed by EdU incorporation and wound scratch assays respectively. Mice were exposed to hypoxia (10% O 2 ) or Sugen5416/hypoxia (10% O 2 plus Sugen5416 20mg/kg, i.p., weekly) for 6 weeks. PH phenotype was characterized by right heart catheterization, right ventricle (RV) hypertrophy by Fulton index and pulmonary artery (PA) remodeling by H&E staining of lung tissues. Pharmacological blocker GN-25 was used to inhibit SNAI1 in vitro and in vivo. Results: SNAI1 expression was markedly increased in hypoxic PASMC and in PASMC from patients with PH. Hypoxia also upregulated HIF-1alpha, Vimentin, p-AKT, PCNA at the protein level in PASMC. EdU incorporation and migration rates were significantly higher in hypoxic cells as well as in PASMC isolated from PH patients compared with controls. In vitro, GN-25 (100 nM) abolished hypoxia-induced PASMC proliferation and migration. Right ventricular systolic pressure (RVSP), a surrogate measurement of PA systolic pressure, estimated mean PAP (mPAP), and RV contractility (RV-±dP/dtmax) were significantly increased in both PH models compared with controls. Additionally, Sugen5416/hypoxia-treated mice exhibited higher RVSP, mPAP and RV-±dP/dtmax compared to hypoxia-treated animals. The Fulton index (weight of RV vs. left ventricle and septum), was increased in both PH groups indicating development of RV hypertrophy in PH compared to control. PH mice lost body weight by 5-10%. Additionally, when Fulton index was normalized by body weight, RV hypertrophy was significantly higher in Sugen5416/hypoxia-treated mice compared with hypoxic animals. Lung tissues from PH mice exhibit PA hypertrophy (media remodeling) with some PA partially or completely occluded. Additionally, we detected protein upregulation of Snai1 and Vimentin in lung tissues of PH mice in both groups. Treatment of PH mice with GN-25 (20 mg/kg, daily, for the last 3 weeks under PH stimuli) in reversal experiments attenuated PH phenotype in both animal models by decreasing hemodynamic parameters, right ventricle hypertrophy and pulmonary vascular remodeling. Conclusions: Our findings identify a key role for SMC SNAI1 in the pathogenesis of lung vascular remodeling during hypoxia-induced PH. Inhibition of SNAI1 in PASMC may constitute a new therapeutic strategy for the treatment of PH. 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.