Citations

Background: Heart failure with preserved ejection fraction (HFpEF) involves myocardial aging, inflammation, and diastolic dysfunction. Monoamine oxidase-A (MAO-A), a mitochondrial enzyme generating reactive oxygen species (ROS), may contribute to cardiac injury, but its role in HFpEF-associated cardiomyocyte senescence is unclear. Hypothesis: Cardiac MAO-A promotes cardiomyocyte senescence via ROS-induced mitochondrial DNA (mtDNA) release and cGAS-STING signaling, exacerbating HFpEF. Methods: Plasma MAO-A activity, circulating mtDNA, and inflammatory cytokines were measured in HFpEF patients and controls. In mice, HFpEF was induced (high-fat diet+l-NAME, 15 wk) in cardiac-specific MAO-A knockout (Maoa^fl/fl; αMHC-Cre) and control littermates, with additional groups receiving MAO-A inhibitor (clorgyline) or STING inhibitor (H-151). Cardiac function, histology, ROS, mtDNA leakage, cGAS-STING activation, and senescence markers were evaluated. In vitro, H9c2 cardiomyoblasts were treated with angiotensin II+high glucose ± MAO-A siRNA. Mitochondrial ROS, cGAS-STING, senescence markers (SA-β-gal, Cdkn2a/Cdkn1a), and senescence-associated secretory phenotype (SASP) secretion were assessed. Conditioned media were used to evaluate fibroblast activation, macrophage polarization, and endothelial inflammation. Results: HFpEF patients had increased MAO-A activity and circulating mtDNA correlating with worse diastolic dysfunction. In mice, cardiomyocyte-specific MAO-A deletion or MAO-A/STING inhibition reduced ROS, mtDNA leakage, cGAS-STING activation, senescence markers, and improved diastolic function . In vitro, dual stimulation activated cGAS-STING, induced senescence and SASP secretion, effects attenuated by MAO-A silencing. Conditioned media from senescent H9c2 cells significantly induced cardiac fibroblast activation, as evidenced by increased α-smooth muscle actin; promoted macrophage M1 polarization, indicated by elevated inducible nitric oxide synthase; and triggered an endothelial inflammatory phenotype, characterized by higher vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression together with enhanced monocyte adhesion. These effects were partially reversed when MAO-A was silenced in the donor H9c2 cells. Conclusions: MAO-A promotes ROS-dependent cardiomyocyte senescence and diastolic dysfunction in HFpEF via cGAS-STING signaling. Targeting this axis may offer therapeutic benefit in HFpEF.

Abstract Background and Aims Patient-reported outcomes are recommended endpoints in Crohn’s disease [CD] trials. The association between patient-reported general well-being relative to symptoms of diarrhoea and abdominal pain [AP] in patients with moderate to severe CD was explored. Methods Patients from three randomized, placebo-controlled, double-blind adalimumab or upadacitinib studies with average daily very soft/liquid stool frequency [SF] ≥4 and/or AP score ≥2 at baseline were included. Using electronic diaries, patients reported general well-being [seven-point Likert scale; 1 = worst; 7 = best] in item 10 of the Inflammatory Bowel Disease Questionnaire [IBDQ]. Changes in well-being and clinical outcomes of SF and AP from baseline to week 12 or 16, and the relationship between well-being and clinical outcomes were evaluated using cumulative distribution function and probability density function curves. Results In total, 858 patients with CD were included [adalimumab, n = 695; upadacitinib, n = 163]. Patients who achieved clinical remission [SF ≤2.8, AP score ≤1.0, neither worse than baseline] were more likely than those not in clinical remission to report IBDQ item 10 response in the 6–7 group category but not IBDQ categories ≤5. Higher IBDQ score for item 10 [6–7] was associated with lower SF and AP score. Greater point increases in IBDQ item 10 were associated with a greater percentage decrease in clinical parameters; a ≥25–30% decrease in SF or AP was associated with a ≥1-point improvement in IBDQ. Conclusions An association between improvements in patient-reported general well-being and clinical remission/response was observed using outcomes of SF and AP, supporting the clinical remission/response endpoint definitions used in clinical studies of CD. Clinical Trial Registrations [ClinicalTrials.gov]: NCT00077779 [CHARM]; NCT00348283 [EXTEND]; NCT02365649 [CELEST].