Jan 2026· International Journal of Hypertension· Vol 2026· 0 citations· 131 references
Medicine
TL;DR
This structured narrative review synthesizes RH‐specific metabolomic evidence and distinguishes it from findings extrapolated from broader hypertension populations, and discusses methodological challenges, replication gaps, pharmacometabolomic confounding, and validation standards required for clinical implementation.
Abstract
Resistant hypertension (RH), defined as uncontrolled blood pressure despite the use of at least three optimally dosed antihypertensive agents, including a diuretic, remains a major clinical challenge associated with elevated cardiovascular risk. Metabolomics offers a dynamic approach to characterize biochemical perturbations related to amino acid metabolism, lipid remodeling, mitochondrial dysfunction, oxidative stress, renal impairment, and gut microbiota–derived metabolites. However, current evidence remains limited by small sample sizes, cross‐sectional designs, heterogeneous definitions of RH, inadequate exclusion of pseudoresistance, medication confounding, and limited external validation. This structured narrative review synthesizes RH‐specific metabolomic evidence and distinguishes it from findings extrapolated from broader hypertension populations. We further discuss methodological challenges, replication gaps, pharmacometabolomic confounding, and validation standards required for clinical implementation. Integrating metabolomics with clinical phenotyping, genomics, proteomics, and microbiome profiling may eventually support RH phenotyping, treatment–response prediction, and biomarker‐guided precision medicine, but large longitudinal cohorts with confirmed true RH are needed before clinical translation.
Background Cardiovascular disease (CVD) remains a leading global health burden, with conventional risk factors lacking sufficient predictive power. Gut microbiota-derived aromatic amino acid (AAA) metabolites and oxidative tyrosine post-translational modifications (PTMs) have emerged as novel pathophysiological regulators of CVD, but their integrated mechanistic roles, clinical biomarker value, and therapeutic potential remain to be systematically elucidated. Methods A review on gut microbiota-AAA axis in CVD was conducted, synthesizing mechanistic, clinical, and translational evidence of AAA metabolites (phenylalanine, tryptophan, tyrosine derivatives) and tyrosine PTMs in the pathogenesis of CVD. We also analyzed the diagnostic potential of multi-omics identified combinatorial biomarkers and the preclinical/clinical evidence for targeted therapeutic strategies. Results Phenylacetylglutamine (PAGln) activates α2A/α2B/β2-adrenergic receptors, induces platelet hyperreactivity and myocardial injury, and is associated with increased major adverse cardiovascular events (MACE) risk. Tryptophan metabolism's pro-atherogenic kynurenine axis and gut-derived indoxyl sulfate (IS) promote endothelial dysfunction, while indole-3-propionate (IPA) exerts vasculoprotective effects. Tyrosine PTMs (sulfotyrosine, 3-nitrotyrosine) regulate leukocyte recruitment and impair endothelial enzymes, with elevated 3-nitrotyrosine predicting adverse cardiac events. The integration of combinatorial biomarkers, including PAGln, IS, Kyn/Trp ratio, 3-nitrotyrosine, and sulfotyrosine, may enhance the predictive capacity of conventional risk models, though their clinical utility requires rigorous validation across diverse populations. Gut microbiota modulation, enzymatic inhibition, and receptor antagonism show preclinical/early clinical potential for CVD intervention. Conclusions The gut microbiota-AAA axis integrates dysbiosis, inflammation, and oxidative stress to drive CVD pathogenesis, with its metabolites and PTMs providing complementary diagnostic value. If validated, interventions targeting this axis may improve CVD risk assessment and therapeutic development.
Yu-rong Wu, Rui Xu· Frontiers in Cardiovascular...· 0 citations
Recent findings from large population-based studies are described to illustrate the value of proteomics in cardiology for improved risk prediction, diagnosis and patient stratification; better understanding of disease aetiology and pathophysiology; and identification of repurposing and novel therapeutic targets.
Background: Atherosclerotic cardiovascular disease (ASCVD) leaves substantial residual risk despite intensive low-density lipoprotein-cholesterol lowering and anti-inflammatory therapy. Reactive oxygen species (ROS) have long been implicated, yet neutral broad-antioxidant trials left unclear which dimensions of ROS imbalance are causal, clinically informative, and therapeutically tractable. Aim: To critically appraise ROS imbalance in atherosclerosis through a plausibility–association–utility hierarchy and to propose a staged framework for precision cardiovascular prevention. Methods: We synthesized mechanistic, biomarker, and translational evidence from targeted PubMed/MEDLINE, Embase, and Cochrane searches (January 2000–February 2026), combining terms for ROS, oxidative stress, atherosclerosis, oxidative biomarkers, and residual cardiovascular risk, with citation chaining. Mass-spectrometry biomarker work, prospective cohorts, and randomized trials received greater interpretive weight. Systematic-review procedures were not applied. Results: Compartmentalized, source-specific ROS imbalance contributes to endothelial dysfunction, lipoprotein oxidation, inflammatory amplification, and plaque progression, particularly in high-risk cardiometabolic phenotypes. Human biomarker data are predominantly observational, assay standardization is incomplete, and risk-reclassification evidence is limited. F2-isoprostanes are a relatively mature lipid-peroxidation marker better suited to trial enrichment than treatment selection. Conclusion: Oxidative biomarkers are defensibly used for trial enrichment but not individual treatment selection. A staged precision-prevention agenda should test source-selective interventions in biomarker-enriched cohorts using vascular and mechanistic endpoints before large outcome trials. Relevance for Patients: Adults whose cardiovascular risk remains high despite cholesterol-lowering and anti-inflammatory treatment—including those with diabetes, kidney disease, smoking, obesity, or recurrent events—may eventually benefit if oxidative stress tests can identify who remains vulnerable and guide targeted prevention.
Yasser M. Esmaeil, Marjona Nurillaeva, Aamir Khan et al.· Journal of Clinical and Tran...· 0 citations
ARTICLE HIGHLIGHTS
Previous studies have identified heterogeneity among prediabetes subgroups using clinical characteristics; however, biological and metabolic heterogeneity remains insufficiently captured. This study examined whether data-driven clustering based on metabolomic biomarkers could define distinct prediabetes subtypes with differential type 2 diabetes, cardiovascular disease, and chronic kidney disease risk. Using 16 metabolomic biomarkers, we identify three metabolically distinct clusters showing progressively higher risks of incident type 2 diabetes, cardiovascular disease, and chronic kidney disease. Differential diet-cluster associations across clusters were obtained, and Mendelian randomization supported potential causal roles for several metabolomic biomarkers. Metabolomics-based stratification may improve risk prevention and enable cluster-specific dietary interventions in prediabetes.
Fei Chen, Yang Zhang, Weihao Wang et al.· Diabetes· 0 citations
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide, driven by complex interactions among dyslipidemia, chronic inflammation, insulin resistance, endothelial dysfunction, and gut microbiome-derived metabolites. This review synthesizes mechanistic and clinical evidence on non-pharmacological strategies that modulate these pathways and contribute to ASCVD risk reduction. Dietary patterns such as Mediterranean, DASH, and plant-based diets improve lipid metabolism, attenuate inflammation, and enhance endothelial function. Chrononutrition approaches, including time-restricted feeding and structured fasting protocols, influence circadian regulation of glucose and lipid homeostasis. Circadian misalignment—including irregular sleep timing, shift work, and disrupted feeding–fasting cycles—independently contributes to ASCVD through impaired glucose tolerance, dyslipidemia, endothelial dysfunction, and systemic inflammation. Modulation of the gut microbiome, particularly through increased short-chain fatty acid production and reduced TMAO formation, provides additional cardiometabolic benefits. Key nutraceuticals—phytosterols, omega-3 fatty acids, and berberine—demonstrate clinically meaningful effects through micellar competition, inflammation-resolving lipid mediators, and AMPK activation, respectively. When combined with evidence-based pharmacotherapy, these interventions exert synergistic effects on cardiometabolic risk factors. This integrative biomedical framework highlights the importance of combining lifestyle, metabolic, microbiome-targeted, and nutraceutical strategies for comprehensive ASCVD prevention.
Tatyana I. Kovyanova, M. Nerush, Vasily P. Karagodin et al.· Biomedicines· 0 citations
Urinary 1H Nuclear Magnetic Resonance (NMR)-based metabolomics has emerged as a robust, non-invasive approach for profiling systemic and renal metabolic alterations. This review summarizes recent clinical applications across kidney disease, cardiometabolic disorders, cancer, immune-mediated and infectious diseases, pediatric disorders, and lifestyle or environmental exposures. We first outline methodological aspects specific to urine, including sampling strategies, osmolarity variation, normalization approaches, and spectral analysis. We then discuss disease-focused applications, emphasizing key metabolites, study designs, and diagnostic performance, and we highlight areas of concordance and inconsistency cross-studies. Shared advantages and limitations of 1H NMR-based urine metabolomics are consolidated in a dedicated section on challenges, and future directions are explored with particular attention to standardization, automation, artificial intelligence–assisted spectral interpretation, multi-omics integration, and large-scale validation. A brief comparison with mass spectrometry (MS) illustrates the complementary roles of NMR and MS in clinical metabolomics. Overall, 1H NMR-based urine metabolomics has potential as a scalable platform for non-invasive phenotyping and holds considerable promise for personalized medicine once technical and translational barriers are addressed.
Qiong Yang, Zhou Zhou, Ya-hui Lin· Health and Metabolism· 0 citations
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