Background/Objectives : Although systematic reviews and meta-analyses have examined immune-inflammatory indices in cardiovascular disease (CVD), the evidence remains scattered and inconsistent. This umbrella review aims to synthesize findings and evaluate the overall predictive value of these indices for clinical outcomes. Methods: We systematically searched PubMed, Cochrane Library, Web of Science, Embase, Scopus, and Medline for systematic reviews with meta-analyses assessing neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), platelet-to-lymphocyte ratio (PLR), and systemic inflammation response index (SIRI) in patients with CVD. Study quality and certainty of evidence were appraised using AMSTAR-2 and GRADE, respectively. Results: A total of 35 meta-analyses covering 106 unique outcomes were included, of which 87 showed significant associations. Elevated NLR and SII were consistently linked to higher risks of CVD mortality, major adverse cardiovascular events, myocardial infarction, heart failure, and stroke. PLR and SIRI were primarily associated with poor recovery from stroke and increased mortality in ST-elevation myocardial infarction. Specifically, the methodological quality of the included reviews was generally moderate to high according to AMSTAR-2, whereas none of the associations reached high certainty based on GRADE, with most rated as low or very low and about one-quarter as moderate certainty. Conclusions: The overall certainty of evidence remains limited according to GRADE, alongside methodological heterogeneity, population variability, and inconsistent thresholds that further restrict the direct applicability of these findings in clinical practice. Nevertheless, available evidence indicates that elevated immune-inflammatory indices are likely associated with worse clinical outcomes in patients with CVD. Future research should prioritize establishing standardized cutoffs, improving methodological consistency, and validating these indices across diverse populations to support their integration into clinical risk-stratification frameworks.

Bile acids are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a bile acid synthesis enzyme. In these Cyp8b1^-/-, and in Wt mice administered CDCA, stroke infarct area was reduced. Elevated glutamate-induced excitotoxicity mediated by aberrant N-methyl-D-aspartate receptor (NMDAR) overactivation contributes to neuronal death in ischemic stroke. We found reduced glutamate-induced excitotoxicity in neurons from Cyp8b1^-/- and CDCA-treated Wt mice. CDCA decreased NMDAR-mediated excitatory post-synaptic currents by reducing over-activation of NMDAR subunit GluN2B in Wt brains. Synaptic NMDAR activity was also decreased in Cyp8b1^-/- brains. Expression and synaptic distribution of GluN2B were unaltered in Cyp8b1^-/- mice, suggesting CDCA may directly antagonize GluN2B-containing NMDARs. Supporting our findings, in a case-control cohort of acute ischemic stroke patients, we found lower circulatory CDCA. Together, our data suggest that CDCA, acting in the liver-brain axis, decreases GluN2B-containing NMDAR overactivation, contributing to neuroprotection in stroke.

This study identifies a coexpression network module connecting birth weight with cord blood indole metabolites, highlighting an integrated neonatal growth-metabolism signature. Maternal lipid status tracks with this signature, adding molecular resolution to the developmental origins of health and disease (DOHaD) paradigm by implicating growth-linked biochemical perturbations in gut-derived indole metabolites. Given the established relevance of indole metabolites to cardiovascular health, our preliminary results motivate future studies aimed at targeting neonatal metabolism as an early window for cardiovascular health intervention.

High circulating levels of trimethylamine-N-oxide (TMAO), largely produced by hepatic oxidation of gut-microbiota-derived trimethylamine (TMA), are associated with increased risk of cardiometabolic and neurodegenerative diseases. In contrast, the diet-derived compound ergothioneine (ET) possesses cytoprotective and neuroprotective properties, and higher circulating ET levels have been linked to a lower risk of cardiovascular, neurodegenerative, and other age-related disorders. However, concerns have been raised that microbial degradation of ET may also contribute to the TMAO pool. In this study, we examined the relationship between ET and TMAO. Bioinformatic analyses indicated that ergothionase, the enzyme responsible for ET degradation to trimethylamine (TMA), is restricted to a limited number of bacterial genera and is far less prevalent than choline trimethylamine lyase, which generates TMA from choline. In a randomised, placebo-controlled human study, ET supplementation (25 mg/day for 7 days) significantly increased plasma ET levels but did not increase TMAO concentrations. Similarly, in a heart failure cohort, plasma ET showed no correlation with TMA or TMAO levels, whereas TMAO was clearly correlated with TMA. Collectively, these findings suggest that ET is unlikely to contribute significantly to systemic TMAO levels.

Aims: Metabolic dysregulation accompanies heart failure (HF), yet coordinated biochemical shifts are rarely quantified for prognostication. We investigated whether early metabolic profiles predict morbidity and mortality in HF with preserved (HFpEF) or reduced ejection fraction (HFrEF). Methods and results: In the PEOPLE and SHOP cohorts (n = 1520), 288 plasma metabolites were quantified by tandem mass spectrometry. Weighted co-expression network analysis produced metabolic indices that were regressed against all-cause mortality and composite outcomes (death or readmission) using multivariable proportional hazards and win-ratio models. In HFpEF, metabolic indices of nitric oxide signalling and glycaemic control (netNO-pEF) and purine metabolism (netPurine-pEF) predicted outcomes. In HFrEF, indices of acylcarnitine (netACa-rEF) and amino acids (netAA-rEF) predicted outcomes. Every 20% higher netNO-pEF was associated with adjusted hazard ratios (HR20%higher) of 0.64 [95% CI 0.49–0.84] in PEOPLE-HFpEF and 0.40 [0.20–0.83] in SHOP-HFpEF; HR20%higher for netPurine-pEF were 1.71 [1.30–2.24] in PEOPLE-HFpEF and 1.96 [1.08–3.55] in SHOP-HFpEF; HR20%higher for netACa-rEF were 1.48 [1.23–1.79] in PEOPLE-HFrEF and 1.39 [1.15–1.68] in SHOP-HFrEF; HR20%higher for netAA-rEF were 0.75 [0.62–0.91] in PEOPLE-HFrEF and 0.51 [0.39–0.67] in SHOP-HFrEF. Adjusted inverse win-ratios were concordant: 1/WR20%higher for netACa-rEF were 1.40 [1.19–1.64] in PEOPLE-HFrEF and 1.17 [1.02–1.34] in SHOP-HFrEF; 1/WR20%higher for netNO-pEF were 0.74 [0.54–1.00] in PEOPLE-HFrEF and 0.55 [0.33–0.89] in SHOP-HFrEF. netNO-pEF was negatively associated with body surface area among HFpEF with concomitant hypertension and diabetes, but only in SHOP-HFpEF. Adding orotic acid, a constituent metabolite of netNO-pEF, to a base model containing five risk indices (MAGGIC score, NT-proBNP, hsTnT, GDF15, and E/e′ ratio) incrementally improved 2-year mortality prediction (AUROC: 0.82→0.83 in PEOPLE; 0.74→0.79 in SHOP). Conclusion: Differential metabolic signatures tied to metabolic inflammation in HFpEF and impaired energy metabolism in HFrEF enhance risk stratification and point to therapeutic targets.