Oxidative stress and inflammation are increasingly recognized as reciprocally reinforcing components of cardiovascular disease rather than independent pathological processes. Their interaction is organized through a network that includes mitochondrial dysfunction, NADPH oxidases (NOX), redox-sensitive NF-κB signaling, NLRP3 inflammasome activation, endothelial nitric oxide synthase (eNOS) uncoupling, and loss of nitric oxide bioavailability. Within this framework, phytochemicals are more appropriately viewed as modulators of endogenous redox–inflammatory signaling than as simple radical scavengers. This review critically examines the evidence linking major phytochemical classes to the Nrf2–NOX–ROS–NF-κB/NLRP3–eNOS/NO axis and evaluates how these mechanisms translate across cardiovascular phenotypes, with emphasis on mechanistic hierarchy, as simultaneous pathway changes may reflect propagation from limited upstream targets rather than direct multi-target activity. The review addresses disease-stage dependence, context-specific roles of Nrf2 and NOX isoforms, mitochondrial–NOX crosstalk, pyroptosis, endothelial dysfunction, and the translational importance of pharmacokinetics, formulation, microbial biotransformation, and drug interactions. Current evidence supports a shift from generalized antioxidant supplementation toward mechanism-matched intervention in biologically selected patients, with the greatest credibility achieved when the active molecular species, dominant mechanism, cardiovascular phenotype, disease stage, clinically relevant exposure, molecular target engagement, functional benefit, and clinical outcomes are evaluated within an integrated framework.

Background: ELAFIN (peptidase inhibitor 3, PI3) is an endogenous inhibitor of neutrophil elastase and proteinase 3, but its circulating profile in type 2 diabetes mellitus (T2DM) and cardiovascular disease remains poorly characterized. We investigated circulating ELAFIN in patients undergoing elective coronary angiography and explored its associations with metabolic, inflammatory, renal, cardiac, and angiographic phenotypes. Methods: Forty-three consecutive clinically stable patients undergoing elective coronary angiography, including nine with T2DM, were prospectively enrolled. Plasma ELAFIN was quantified by ELISA. Associations with clinical and laboratory variables were assessed using non-parametric comparisons, correlation analyses, and parsimonious multivariable regression. Discrimination analyses were considered exploratory. Results: Median ELAFIN was 5.03-fold higher in patients with T2DM than in those without T2DM (31.2 [28.3–36.2] vs. 6.2 [5.5–7.0] ng/mL; p < 0.001; Cliff’s δ = 0.85). The association remained pronounced after adjustment for age, sex, and renal function. ELAFIN was positively correlated with REG3A and creatinine, and inversely correlated with eGFR, whereas no significant associations were observed with angiographic coronary stenosis, LVEF, or NT-proBNP. Conclusions: Circulating ELAFIN was markedly elevated in T2DM and associated predominantly with renal and inflammatory characteristics rather than anatomical coronary disease or left ventricular dysfunction. Because oxidative stress and protease activity were not directly measured, their relationship with ELAFIN remains hypothesis-generating. These findings require validation in larger prospective cohorts.

Diabetes mellitus is associated with metabolic alterations, but amino-acid differences among patients with coronary artery disease (CAD) remain incompletely characterized. We screened 45 amino acids and related metabolites by diabetes status in an exploratory retrospective disease-restricted cohort (recorded diseased-vessel count ≥ 1; n = 33). Argininosuccinic acid was available for 26 patients. Comparisons used exact Wilcoxon tests, Cliff’s delta, and Benjamini–Hochberg correction. Estimated argininosuccinic acid concentrations were higher in diabetes (0.28 [0.21–0.34] vs. 0.15 [0.13–0.19] µmol/L; Cliff’s delta = 0.765; p < 0.001; q = 0.035), the only association surviving false-discovery-rate correction. All argininosuccinic acid estimates were extrapolated below the lowest calibrator and should be interpreted as semiquantitative. The diabetes coefficient remained positive in crude and age- and sex-adjusted HC3-robust models, but renal and influence analyses were imprecise. Argininosuccinic acid correlated inversely with eGFR (rho = −0.445; p = 0.023) and positively with creatinine (rho = 0.486; p = 0.012). The diabetes-by-CAD interaction was not significant (p = 0.183). These data suggest a hypothesis-generating association requiring validation with an appropriate calibration range and careful renal phenotyping.

Background: Cardiovascular hemodynamic stress may be associated with alterations in the circulating ionome. We investigated whether a hypothesis-driven multielement composite, the congestion-associated ionomic dysregulation score (CIDS; higher copper and strontium and lower rubidium and iron), was associated with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiorenal–hematologic burden. Methods: This retrospective, single-center, cross-sectional study included 192 patients undergoing cardiovascular evaluation or treatment. Serum trace elements were quantified by inductively coupled plasma mass spectrometry, and CIDS was calculated from standardized element concentrations. Results: Higher CIDS was associated with higher NT-proBNP (ρ = 0.416, FDR-adjusted p < 0.001), worse New York Heart Association (NYHA) functional status (ρ = 0.370, p < 0.001), lower hemoglobin (ρ = −0.287, p < 0.001), lower eGFR (ρ = −0.191, p = 0.012), and higher uric acid (ρ = 0.241, p = 0.002). In the common complete-case sample, each 1-SD increase in CIDS was associated with higher log-transformed NT-proBNP after multivariable adjustment (β = 0.276, 95% CI 0.077–0.475; HC3-robust p = 0.007), and model R² increased from 0.368 to 0.407. The observed ΔR² exceeded the median from randomly weighted composites but did not clearly exceed the permutation null distribution (empirical p = 0.063). The referral-stratified estimates differed in magnitude (β = 0.179 versus 0.569), without a significant interaction (p = 0.171). Conclusions: CIDS was associated with myocardial stress and cardiorenal–hematologic burden in this cohort, but the single-center, cross-sectional findings do not establish causality, unique superiority over alternative composites, or external biomarker validity. Because CIDS was standardized internally within this cohort, no externally applicable reference values or clinical cutoffs can currently be defined.