Alexander H Jan Danser

Background: Patients with chronic heart failure (HF) are at increased risk of vasoplegia after cardiac surgery, potentially because neurohormonal activation in the context of HF alters vascular regulation. Methods: We compared perioperative vasoresponsiveness in patients with and without HF undergoing cardiac surgery with cardiopulmonary bypass (CPB). Patients were prospectively enrolled, and changes in systemic vascular resistance (ΔSVR) after phenylephrine and nitroglycerin were measured perioperatively (in vivo). Ex vivo vasoreactivity to phenylephrine and vasopressin was tested in 40 biopsies. Results: In vivo and ex vivo analyses included 36 and 13 patients (10 controls and 3 HF patients), respectively. At baseline, phenylephrine increased SVR by 26% in HF patients (estimated marginal mean, 95% CI 16–35%) versus 51% in controls (95% CI 38–64%; p = 0.002). This attenuated response persisted during CPB, and ex vivo observations suggested a similar pattern. Responsiveness to nitroglycerin was unchanged. Lower post-CPB ΔSVR was associated with greater norepinephrine use during the first postoperative day (β = −346.6, 95% CI −541.2 to −151.9; R² = 0.291). Conversely, HF patients showed greater ex vivo responsiveness to vasopressin. Conclusions: HF is associated with marked impairment of α₁-adrenergic vasoresponsiveness, indicating impaired α₁-adrenergic signaling. Preserved vasopressin responsiveness may support its earlier use for postoperative hypotension in these patients.

Chronic inhibition of the renin–angiotensin–aldosterone system (RAAS) causes progressive renal vascular disease characterized by concentric arterial and arteriolar hypertrophy (CAAH), driven by sustained activation of renin-producing cells. However, the mechanisms linking impaired RAAS signaling to vascular remodeling remain unclear. Using a Ren1c-T2A knock-in mouse, we identified a mechanistic link between defective renin function and progressive vascular disease. The T2A insertion generates a hypomorphic renin allele, and homozygous mice develop progressive CAAH accompanied by markedly reduced levels of enzymatically active renin in the circulation. In response to reduced renin activity, mice activate a robust compensatory program characterized by increased Ren1 mRNA expression, depletion of renal renin stores, accumulation of catalytically impaired renin in the circulation, and extensive recruitment of renin-lineage cells along the renal arteriolar tree. Despite this response, RAAS activity remains insufficient, and homozygous mice develop progressive hypotension and renal dysfunction following the onset of CAAH. To define the basis of impaired renin function, molecular dynamics simulations revealed that the C-terminal T2A peptide alters the renin catalytic pocket, disrupting key aspartate residues and electrostatic interactions required for efficient angiotensinogen cleavage. These findings demonstrate that chronic renin deficiency is sufficient to drive renal arteriolar remodeling and functional decline in the absence of overt glomerular injury. Our results provide a mechanistic framework linking chronic RAAS suppression to progressive renal vascular disease and establish the present model as a platform for investigating the long-term consequences of RAAS inhibition and pathogenic renin variants.

BACKGROUND: Placenta-related complications are major contributors to maternal and neonatal morbidity. Glycosylation modulates immunoglobulin function by altering molecular structure and receptor affinity. During pregnancy, IgG (immunoglobulin G) and IgA (immunoglobulin A) glycosylation normally shift toward a more anti-inflammatory profile. We hypothesized that this adaptation is attenuated in complicated pregnancies, resulting in altered glycosylation trajectories. METHODS: Women with singleton pregnancies were enrolled in the prospective Rotterdam Periconception Cohort (2017–2018). Serum samples were collected at 9, 11, 13, 22, and 32 weeks of gestational age. IgG and IgA glycosylation was measured using liquid chromatography-mass spectrometry, and summarized into glycosylation traits (galactosylation, sialylation, fucosylation, bisection). Placenta-related complications (preeclampsia, pregnancy-induced hypertension, preterm birth, or small-for-gestational-age) were identified from medical records. Longitudinal changes and group differences in Ig glycosylation were analyzed using linear mixed-effects models with false discovery rate correction. RESULTS: Among the included 193 pregnancies, 54 were complicated by at least 1 placenta-related disorder. In complicated pregnancies, galactosylation and sialylation were consistently lower, whereas fucosylation and bisection were higher. From 9 weeks of gestational age onwards, fucosylation was significantly elevated at IgA Asn327/Asn340 and Asn205 ( Z -score difference: 0.45–0.52; q =0.002–0.004 and 0.33–0.37; q =0.038). Bisection increased more steeply at IgG1, IgA Asn144/Asn131, and IgA Asn327/Asn340 ( q =0.021–0.027). IgG galactosylation rose less across gestation ( q =0.021–0.024), and IgA galactosylation and sialylation declined more sharply at Asn144/Asn131, Asn205, and Asn327/Asn340 (q=0.000–0.026). CONCLUSIONS: Pregnancies with placenta-related complications exhibit more proinflammatory glycosylation profiles. These findings suggest a potential mechanistic link between immunoglobulin glycosylation and placental dysfunction, with specific glycopeptides as possible biomarkers. REGISTRATION: URL: https://onderzoekmetmensen.nl/en/trial/57880 ; Unique identifier: NL-OMON57880.

Background and Purpose: Metformin is increasingly recognised for its vasculoprotective effects, primarily through activation of AMP‐activated protein kinase (AMPK). We combined population‐based genetic epidemiology, with an ex vivo vascular model, to investigate the beneficial vascular effects of AMPK activation by metformin. Experimental Approach: We used genetically proxied AMPK activation (GP‐AMPK), based on 20 genome‐wide significant single‐nucleotide polymorphisms (SNPs), to assess associations with pulse wave velocity (PWV) and carotid intima‐media thickness (cIMT). A two‐sample Mendelian randomisation (MR) was performed to test the effect of GP‐AMPK on a panel of inflammatory markers. We also developed a porcine coronary artery model of endothelial dysfunction to test the restorative effects of metformin on vascular function and related molecular signalling pathways. Key Results: Higher GP‐AMPK activation was associated with lower PWV, but not cIMT, in our epidemiological analysis (mean age 64.3 years, 43.8% female). Ex vivo, metformin restored endothelial relaxation in Angiotensin (Ang) II–treated vessels via endothelium‐dependent hyperpolarisation (EDH) mechanisms, an effect abolished by AMPK inhibition. Western blotting confirmed the activation of AMPK (alpha 1 subunit) with metformin treatment. Inhibitor studies demonstrated a shift from NO‐mediated to EDH‐mediated relaxation with metformin. Molecular analyses showed reduced Ang II–induced expression of matrix remodelling (MMP1, MMP2) and senescence (P21) markers, as well as suppression of pro‐inflammatory cytokines (Il‐1β, Il‐6, TNF‐α), consistent with MR results. Conclusion and Implications: Metformin restored endothelial function and reduced vascular stiffness through an AMPK–EDH axis, highlighting a novel, potential therapeutic mechanism for early vascular dysfunction independent of glycaemic effects.

The use of cannabis during pregnancy is increasing, in line with its growing societal acceptance and legalization. Cannabis use mainly concerns its active components Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). While cannabis has therapeutic effects on pain, nausea, and vomiting, its impact on fetal development remains a significant public health concern. Given the existence of a local endocannabinoid system (ECS) in the placenta, with proven effects on placental development and blood flow, it is likely that THC and CBD exert effects via interference with the placental ECS. This review summarizes how cannabis use affects the placental ECS and describes the consequences of such use on placental function and fetal development. It starts with discussing the placental ECS, the effects of THC and CBD on placental function, and the pharmacokinetics of cannabinoids during pregnancy. It then describes the effects of both paternal and maternal cannabis use and provides epidemiological data linking placental insufficiency, impaired fetal growth, and preeclampsia to cannabis use. It also raises awareness for the possibility that cannabis use, by altering DNA methylation, might result in transgenerational effects. It is concluded that current evidence supports abstaining from cannabis use during preconception, pregnancy, and lactation to optimize maternal, fetal, and intergenerational health outcomes.