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ABSTRACT Observational studies comparing Impella and venoarterial extracorporeal membrane oxygenation (VA‐ECMO) in cardiogenic shock have reported inconsistent findings. We performed an updated systematic review and meta‐analysis, with exploratory matched‐cohort analyses where directly reportable propensity score–matched event‐level data were available. We searched PubMed, Scopus, Web of Science, and the Cochrane Library from inception through March 2026 for observational studies comparing Impella versus VA‐ECMO in adult patients with cardiogenic shock. The primary outcome was in‐hospital mortality. Secondary outcomes included all‐cause mortality, ICU outcomes, access site bleeding requiring transfusion, peripheral vascular complications, renal outcomes, and stroke. Random‐effects models using restricted maximum likelihood were applied. Fifteen observational studies including 22,618 patients were analyzed. In the primary crude analysis, Impella was not associated with a statistically significant difference in in‐hospital mortality (RR 0.84, 95% CI 0.66−1.07; p = 0.15) with substantial heterogeneity ( I ² = 92.9%). However, leave‐one‐out analysis identified an influential registry study; its exclusion markedly reduced heterogeneity and favored Impella ( p < 0.01). In exploratory propensity score‐matched analysis, Impella was also associated with lower in‐hospital mortality (RR 0.69, 95% CI 0.56−0.85, p < 0.01). Thirty‐day and 6‐month all‐cause mortality were neutral, whereas 12‐month mortality modestly favored Impella ( p = 0.048). Sensitivity analyses similarly resolved heterogeneity and favored Impella for selected secondary outcomes, including 6‐month mortality, acute kidney injury, and ischemic stroke. ICU mortality was neutral, while ICU length of stay was shorter with Impella ( p = 0.01). Impella was also associated with lower access site bleeding requiring transfusion ( p < 0.01), peripheral vascular complications ( p < 0.01), and hemorrhagic stroke ( p < 0.01). In this updated meta‐analysis of observational studies, the primary crude analysis of in‐hospital mortality was neutral overall but highly heterogeneous, whereas sensitivity and exploratory matched‐cohort analyses showed a more consistent association favoring Impella. Impella was also associated with lower bleeding and vascular complications and shorter ICU length of stay, although several outcomes remained sensitive to study‐level influence. These findings should be interpreted cautiously given the observational design, predominance of serious risk of bias, and strong potential for confounding by indication.

Introduction: Although the role of cardiometabolic risk factors (CMRF) has been characterized in steatotic liver disease, their role in the severity of alcohol-associated hepatitis (AH) remains unclear. We aimed to evaluate the impact of CMRF on mortality. Methods: Multinational prospective cohort study (2015–2024) including hospitalized patients with severe AH across 32 centers in 14 countries. Diagnosis of AH was made using the NIAAA criteria. Analyses included adjusted competing-risk models by age, sex, ethnicity, history of cirrhosis, CMRF, corticosteroid use, MELD, and ACLF grade, with liver transplantation as a competing risk. Results: 936 participants were included; mean age 48±11.2 years, and 88.9% were male. At least one CMRF was present in 46.6%; median body mass index (BMI) was 24.2 kg/m 2 [IQR: 22.8–28.2], prevalence of diabetes 17.6%, hypertension 16.5%, and dyslipidemia 5.8%. Median MELD was 24.4 [19.3–31.4], 86.7% had severe AH, and 180-day survival was 72.9%. Survival did not differ by CMRF status (log-rank p =0.453). In adjusted competing-risk models, higher age (sHR 1.02; 95%CI:1.01–1.04), greater alcohol intake (per g/day; sHR 1.001; 95%CI:1.000–1.002), MELD (sHR 1.04; 95%CI:1.01–1.06), and ACLF grade 2–3 (sHR 2.34 and 4.34) predicted mortality. However, no individual CMRF independently increased mortality. A prespecified non-linear BMI analysis showed modestly lower mortality between 25–40 kg/m², with a higher risk above 40 kg/m². Conclusion: Among patients with severe AH, metabolic dysfunction was not associated with increased mortality. Although a higher BMI was associated with slightly lower mortality in AH, this may reflect better nutritional status rather than a true protective effect.

Coronary microvascular dysfunction (CMD) has emerged as a crucial contributor to cardiovascular morbidity and mortality, particularly in patients with ischemia and non-obstructive coronary arteries (INOCA). The condition arises from a complex interplay of structural and functional abnormalities within the small coronary vessels, driven by underlying molecular mechanisms including endothelial nitric oxide synthase (eNOS) uncoupling, oxidative stress, and chronic inflammation. Lipid metabolism plays a central role in this pathology, especially in the setting of elevated low-density lipoprotein cholesterol (LDL-C). Furthermore, the protective capacity of high-density lipoprotein (HDL) is increasingly understood to depend on its functionality rather than absolute levels, as it can become dysfunctional and pro-inflammatory in pathological states. Emerging evidence has identified lipoprotein(a) [Lp(a)] and triglyceride-rich lipoproteins as significant, independent contributors to microvascular injury. Comprehensive clinical assessment of microvascular dysfunction therefore requires integration of advanced lipid profiling, including apolipoprotein B (ApoB), [Lp(a)], and the triglyceride-glucose (TyG) index with invasive and non-invasive measures of coronary flow reserve to more precisely stratify risk. In this narrative review, we synthesize current observational, mechanistic, and early interventional data linking diverse lipid phenotypes to coronary microvascular dysfunction. We propose a concept of lipid-driven CMD endotypes, such as ApoB-/particle overload, dysfunctional HDL, Lp(a)-mediated risk, and metabolic/TyG-high states, and map these to a practical, mechanism-informed management framework. While intensive LDL-C lowering with high-intensity statins and combination therapy remains guideline-directed care for high-risk patients, evidence for dedicated microvascular benefit from newer lipid and cardiometabolic agents is still largely hypothesis-generating. A personalized approach that aligns lipid phenotyping, CMD endotyping, and existing guideline-based therapies may help refine risk assessment and inform future trials.

In metabolic dysfunction–associated steatohepatitis (MASH), liver sinusoidal endothelial cells (LSECs) acquire a proinflammatory phenotype termed lipotoxic endotheliopathy. We previously identified glycogen synthase kinase 3β (GSK3β) as a central signaling hub in LSECs during MASH. To elucidate the molecular mechanisms and functional outcome of lipotoxicity-induced GSK3β activation in LSECs, we utilized endothelial cell–specific Gsk3 β -KO ( Gsk3 β ΔEnd ) mice fed MASH-inducing diets. Endothelial Gsk3 β deletion significantly reduced markers of lipotoxic endotheliopathy, including adhesion molecules and chemokines, alongside liver injury, inflammation, and fibrosis. Immune profiling via flow cytometry and mass cytometry by time of flight (CyTOF) identified decreased hepatic infiltration of proinflammatory myeloid populations, particularly mature DCs in Gsk3 β ΔEnd mice. In a coculture system, GSK3β in lipotoxic LSECs promoted DCs maturation. Mechanistically, GSK3 inhibition restored lipotoxicity-induced alterations in LSEC mitochondrial morphology and respiration by regulating AMP-activated protein kinase and dynamin-related protein 1. This rescue suppressed chemokine and adhesion molecule expression, thereby limiting immune cell recruitment. Collectively, under lipotoxic stress, GSK3β amplifies mitochondrial dysfunction and inflammatory signaling in LSECs, enhancing myeloid cell homing and DC maturation. Targeting LSEC GSK3β may, therefore, represent a promising therapeutic strategy to mitigate LSEC-driven fibroinflammatory response in human MASH.

Background: The timing of coronary artery bypass grafting (CABG) in patients with non-ST-elevation myocardial infarction (NSTEMI) may critically impact clinical outcomes, yet the ideal surgical window remains unclear. We aimed to evaluate the association between time-to-CABG and in-hospital outcomes among NSTEMI admissions undergoing CABG. Methods: This retrospective cohort study utilized the US National Inpatient Sample database from 2017 to 2021 to evaluate the association between time-to-CABG and key in-hospital outcomes, including mortality, cardiac arrest, cardiogenic shock, ischemic stroke, acute kidney injury, and blood transfusion rates, while assessing length of stay (LOS) and hospital charges exclusively among survivors. Adult admissions with principal diagnosis of NSTEMI who underwent CABG without prior interhospital transfer were grouped by the calendar day of CABG from admission (0, 1, 2, 3, 4, 5, 6, and ≥7). Multivariate regression models were used to assess the outcomes across these eight groups. Results: Of 142,200 included admissions, same-day CABG (hospital day 0) was associated with the highest rates of in-hospital mortality, cardiac arrest, cardiogenic shock, and ischemic stroke. The adjusted odds of mortality, cardiac arrest, and cardiogenic shock were lower among admissions undergoing CABG between days 2 and 5. Likewise, the adjusted odds of ischemic stroke were lowest when CABG occurred on days 2 to 4. The odds of AKI increased when CABG was delayed beyond day 6, whereas blood transfusion rates showed no statistically significant association with time-to-CABG. Among survivors, LOS and hospital charges progressively increased with delayed CABGs. Conclusions: Among NSTEMI admissions undergoing CABG, CABG performed on hospital days 2 to 4 was associated with lower adjusted odds of several adverse in-hospital outcomes compared with same-day CABG. Further prospective studies are needed to validate these results and guide clinical decision-making.

Background and Aims: Unresolved inflammation and fibrosis are defining features of metabolic dysfunction–associated steatohepatitis (MASH), a progressive form of steatotic liver disease that can advance to cirrhosis and hepatocellular carcinoma. While innate immune mechanisms in MASH have been extensively characterized, the role of CD4 + T cells remains poorly understood despite their central function in orchestrating immune responses through effector and regulatory mechanisms. Approach and Results: Integrated single-cell proteomic, transcriptomic, and functional analyses were used to investigate the CD4 + T-cell landscape in murine and human MASH. We delineated a profound shift in the differentiation of intrahepatic and peripheral CD4 + T cells toward Th1, regulatory, and cytotoxic phenotypes in murine and human MASH. Notably, hepatic CD4 + T cells exhibited heightened effector activity and elevated secretion of proinflammatory cytokines, thus amplifying inflammatory signaling cascades. The CD4 + T-cell reprogramming in MASH also included the induction of the co-stimulatory receptor OX40. In parallel, OX40 ligand (OX40L)-expressing monocyte-derived macrophages and dendritic cells accumulated in MASH livers, establishing a feed-forward CD4 + T cell-myeloid activation loop. Therapeutic blockade of the OX40–OX40L axis, in turn, reversed liver pathology in mice with established MASH and reduced disease markers in an ex vivo human liver model. Furthermore, genetic depletion or functional inhibition of CD4 + T cells attenuated fibrosis, accompanied by decreased infiltration of monocyte-derived macrophages. Conclusions: These studies provide a comprehensive single-cell proteogenomic atlas of CD4 + T cells in MASH and identify an OX40-dependent CD4 + T cell-macrophage axis as a promising therapeutic target for the treatment of MASH and liver fibrosis.

Abstract Aims Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular events. However, the effect of Lp(a) on coronary plaque composition and high-risk plaque features has not been fully characterized. This study aimed to investigate the association between Lp(a) and coronary atherosclerotic plaque phenotype at the plaque level. Methods and results This study included 710 patients who underwent coronary computed tomography angiography (CCTA) and had Lp(a) measured between 2008 and 2024. CCTA scans were analysed with a previously validated artificial intelligence-based algorithm (AI-QCT, Cleerly Inc.). The association of Lp(a) with non-calcified and calcified plaque volumes and HRP features was evaluated at the plaque level using generalized estimating equation models adjusted for traditional cardiovascular risk factors. Among the 710 patients, the mean age was 56 ± 10 years and 379 (53%) were male. In total, 3642 plaques were identified. In the adjusted plaque-level analysis, elevated Lp(a) (≥150 nmol/L) was associated with an increase in non-calcified plaque volume per plaque (P = 0.009), but not with an increase in calcified plaque volume (P = 0.81). Furthermore, elevated Lp(a) (≥150 nmol/L) was strongly associated with the presence of high-risk plaque at the plaque level (adjusted odds ratio: 1.78, 95% CI: 1.25–2.54, P = 0.001), whereas low-density lipoprotein-cholesterol and high-sensitivity C-reactive protein were not (P &gt; 0.05). Conclusion In this plaque-level CCTA study of 3642 individual plaques, elevated Lp(a) levels were independently associated with increased non-calcified plaque volume and with the presence of high-risk plaque, but not with calcified plaque volume. These findings elucidate the impact of Lp(a) on unstable plaque phenotypes, even in patients without prior cardiovascular events.

Microplastics may pose health risks, particularly for chronic lung diseases. Clarifying the link between circulating microplastics and pulmonary disease is vital for shaping research and interventions. The objective of this study was to evaluate whether microplastics in peripheral blood are associated with COPD or IPF vs. no lung disease. In this pilot prospective case-control study, participants were grouped as control (n = 10), COPD (n = 9), or IPF (n = 10). Relevant comorbidities and exposures were obtained from records and questionnaires. All underwent standardized blood collection (PlasticTox©). Samples were analyzed for total microplastic concentration, stratified by size (<10 µm, 10–30 µm, 30–70 µm). The primary outcome was to show a difference in total microplastic burden between lung disease and controls. Secondary measures were to determine size-specific concentrations and associations with demographic variables and smoking history. Among 29 participants (median age 70 (IQR 64–80); 14 women (48.3%)), COPD/IPF groups had significantly higher total microplastic concentrations vs. controls (median 26.0 vs. 3.5 particles/100 µL; p < 0.01). Particle burdens <10 µm and 10–30 µm were particularly elevated (both p < 0.01). After adjusting for smoking, only the <10 µm fraction remained independently associated with lung disease (adjusted odds ratio 1.94 (95% CI, 1.23–7.04)). In this pilot exploratory study, individuals with COPD or IPF showed greater circulating microplastic levels than controls. These findings should be interpreted as hypothesis-generating, and larger analytically validated studies are needed to clarify directionality, causal mechanisms, contamination control, and the clinical relevance of circulating microplastic burden.

Abstract Objective To evaluate the short- and long-term clinical outcomes of transcatheter aortic valve replacement (TAVR) among participants with RA and aortic stenosis compared with those without RA, using real-world data from a large multicentre registry. Methods Using the TriNetX Research Network, participants with aortic stenosis undergoing TAVR with (RA+) vs without (RA−) RA were identified. Odds ratios (ORs) with 95% CIs estimated 30-day all-cause mortality, permanent pacemaker implantation, ischaemic stroke, acute kidney injury, myocardial infarction, cardiogenic shock, major vascular complications, and major or life-threatening bleeding were evaluated. Five-year outcomes included all-cause mortality, ischaemic stroke, myocardial infarction and all-cause hospitalization. Cox regression was used to estimate hazard ratios (HRs) with 95% CIs. Results A total of 1414 RA+ (4.3%) and 39 004 RA− participants were eligible. After matching, 1374 were included in each cohort. At 30 days, outcomes did not differ between RA+ and RA− groups; mortality was 2.0% vs 1.5% (OR 1.29; 95% CI 0.73–2.29), with no significant differences in other endpoints. Over 5 years, mortality was 23.8% vs 20.5% (OR 1.12; 95% CI 0.97–1.31), and stroke, myocardial infarction and hospitalization were similar; HRs were concordant with OR estimates. In sex-based analyses of RA patients, outcomes did not differ by sex. Conclusion In this large observational study, TAVR was not associated with excess short- or long-term risk in patients with RA. These findings support TAVR as a safe therapeutic option in RA patients with aortic stenosis.