European Journal of Cardiovascular Medicine

Hypertension affects 1.28 billion adults worldwide, with young-onset disease (18-39 years) prevalence escalating from 7% to 28.8% over three decades, particularly in South India where rates reach 13.8% among young adults.[1,2] Distinct from late-onset hypertension characterized by arterial stiffness, young-onset disease manifests through endothelial dysfunction, oxidative stress, and low-grade inflammation that accelerate premature vascular injury.[3] D-dimer, the terminal fibrin degradation product formed by plasmin-mediated fibrinolysis of cross-linked fibrin, provides a stable biomarker of coagulation-fibrinolysis activation. Meta-analyses confirm D-dimer independently predicts myocardial infarction (RR 2.8, 95% CI 2.1-3.7), stroke (RR 2.2, 95% CI 1.8-2.7), and cardiovascular mortality across general populations, with even stronger prognostic value in hypertension.[4,5] In hypertensive cohorts, D-dimer elevations associate with left ventricular hypertrophy (OR 3.2), microalbuminuria (OR 2.8), and carotid intima-media thickness progression (β=0.19 mm/year).[6] Oxidative stress represents the pathophysiologic nexus linking hypertension to cardiovascular complications.[7] NADPH oxidase-derived superoxide oxidizes LDL to pro-atherogenic Ox-LDL, upregulates adhesion molecules (ICAM-1↑3.2-fold, VCAM-1↑2.8-fold), and impairs nitric oxide bioavailability through peroxynitrite formation.[8] Malondialdehyde (MDA), the principal lipid peroxidation end-product, quantifies oxidative burden while Ox-LDL drives foam cell formation, matrix metalloproteinase activation, and plaque instability.[9] ROS excess extends beyond vasculature, inducing DNA single/double-strand breaks, oxidized purines (8-OHdG↑2.4-fold), and chromosomal aberrations that overwhelm base excision repair (BER) and nucleotide excision repair (NER) pathways.[10[Bleomycin-induced chromosomal breaks/cell (b/c) and cytokinesis-block micronucleus (CBMN) assays provide standardized measures of chromosomal fragility and DNA repair capacity validated against cancer and cardiovascular risk (b/c>0.8: RR 4.2; CBMN>12/1000BN: RR 3.8).[11,12] Hypertensive cohorts demonstrate 1.8-2.5-fold higher CBMN frequencies correlating with systolic blood pressure (r=0.42) and MDA levels (r=0.38).[13] Mechanistically, oxidative stress integrates hypercoagulability and genomic instability: Ox-LDL upregulates endothelial tissue factor (4.2-fold) while DNA damage activates PARP-1, depleting cellular NAD+/ATP and impairing protein C receptor function.[14] South Indian populations exhibit unique risk amplification through metabolic syndrome prevalence (38%), tobacco use (28%), and antioxidant enzyme polymorphisms (SOD2 Ala16Val 42%, GPx1 Pro198Leu 31%).[15] Young adults often remain unaware of their hypertensive status and the need for treatment So, this study tests the hypothesis that young hypertensives manifest elevated D-dimer levels correlating positively with oxidative stress markers (MDA, Ox-LDL) and inversely with DNA repair efficiency (increased b/c, CBMN).

Study Population and Design Prospective cross-sectional comparative study (October 2024-December 2025) conducted at Sree Mookambika Institute of Medical Sciences. From 320 screened individuals, 100 participants aged 18-39 years fulfilled criteria: 50 treatment-naïve essential hypertensives (JNC-8: SBP≥140 mmHg and/or DBP≥90 mmHg on ≥2 occasions) and 50 age-/sex-matched normotensive controls (SBP<120 mmHg, DBP<80 mmHg). Inclusion criteria • Newly diagnosed primary hypertension; controls from routine health screening. Exclusion criteria • Secondary hypertension • Diabetes (HbA1c≥6.5%) • CKD (eGFR<60 mL/min) • Malignancy • Radiation/chemotherapy • Current smoking/alcohol • Pregnancy • Lipid-lowering agents Ethical approval Institutional Ethics Committee approval (Reg. No. 19/2024). Biochemical and Molecular Assays Overnight fasting venous blood (7 mL): 1 mL 3.2% sodium citrate (D-dimer: immunometric flow-through, Mercodia, cutoff>0.1 mg/L, intra-/inter-CV 5.2%/6.8%); 4 mL serum (MDA: thiobarbituric acid-TCA, 535 nm, intra-/inter-CV 4.1%/5.9%; Ox-LDL: competitive ELISA, 450 nm, intra-/inter-CV 7.3%/8.6%). Lymphocyte isolation: 2 mL heparinized blood (Ficoll-Hypaque). DNA Repair Capacity Bleomycin sensitivity (b/c) PHA-stimulated (10 μg/mL) whole blood (72h, 37°C, 5% CO₂), bleomycin (0.03 U/mL, 66h), colchicine (0.04 μg/mL, 70h), G-banding metaphases (≥50 spreads/subject, 1000×), breaks/cell = total chromatid gaps/breaks/total metaphases scored.16 Sensitivity threshold: b/c≥0.80 (hypersensitive).[17] CBMN assay PHA (72h), cytochalasin-B (4.5 μg/mL, 44h post-PHA), ≥1000 binucleated lymphocytes (micronuclei criteria: 1/16-1/3 main nucleus diameter, non-refractile, cytoplasmic bridge absent).[18] Quality Control Blinded dual scoring (intra-observer CV<4%, inter-observer κ=0.89); positive controls (known bleomycin-sensitive proband); negative controls (healthy lab staff).[17] Statistical Analysis SPSS v16.0. Shapiro-Wilk normality testing. Independent t-tests/Mann-Whitney U (mean ± SD/IQR). Pearson/Spearman correlations. Multivariable linear regression (stepwise, VIF<2.5). ROC curves (Youden index optimal cutoff). Bonferroni correction (α=0.05/6=0.008). Power calculation: 92% power detect Δ=0.3 mg/L D-dimer (σ=0.4, α=0.05, n=50/group).

Baseline Characteristics

Age (32.5±5.2 vs 31.8±4.9 years, p=0.62), male sex (52% vs 50%, χ²=0.04, p=0.85) comparable between hypertensives (n=50) and controls (n=50). BMI significantly elevated in cases (27.4±4.9 vs 23.2±2.0 kg/m², t=6.79, p<0.001, d=1.89); abdominal circumference (males: 105.1±18.6 vs 93.5±8.7 cm, t=3.42, p=0.002). (Table-1)

Primary Biomarker Outcomes

All biomarkers significantly elevated in hypertensives (D-dimer/Ox-LDL subset n=48/25; MDA/b/c/CBMN full cohort n=180/140). All comparisons Bonferroni-corrected (α=0.008). (Table-2)

Correlation Network Analysis

D-dimer demonstrated robust positive correlations with oxidative stress and DNA damage markers (strongest: Ox-LDL r=0.658, 95% CI 0.48-0.78). Multivariable regression (R²=0.542, F=21.4, p<0.001): D-dimer = 0.23 + 0.34×MDA + 0.28×Ox-LDL + 0.19×b/c (all standardized β p<0.01, VIF<1.8). (Table-3)

Diagnostic Accuracy

ROC analysis confirmed D-dimer superior discrimination (AUC 0.968, 95% CI 0.897-0.995, z=7.42, p<0.001): optimal cutoff 0.23 mg/L (sensitivity 91.67%, specificity 88.00%, PPV 92.3%, NPV 86.7%, +LR 7.64, -LR 0.09). D-dimer outperformed MDA (AUC 0.942), Ox-LDL (AUC 0.921), b/c (AUC 0.908), CBMN (AUC 0.935; all p<0.05 pairwise DeLong test).

Table-1: Demographic and Anthropometric Characteristics

*Males only. d=Cohen's d; φ=phi coefficient.

Table-2: Biomarker Comparisons Between Groups

Table 3. Pearson Correlation Matrix with D-dimer (n=73)

The present study demonstrates significantly elevated serum D-dimer levels in young adults with hypertension compared to normotensive controls, despite the absence of clinically overt thrombotic events. This finding suggests early activation of coagulation and fibrinolytic pathways in young-onset hypertension. A similar association between hypertension and increased D-dimer levels was reported by Sechi et al., who demonstrated higher plasma D-dimer concentrations in hypertensive patients and showed a significant relationship with target organ damage, indicating low-grade hypercoagulability in hypertension.[6] In the present study, D-dimer levels showed a significant positive correlation with oxidized LDL. Baradaran et al. described oxidative stress as a central contributor to hypertension-related vascular dysfunction, while Grossman highlighted the role of oxidative stress in promoting endothelial injury and prothrombotic changes.[⁷,⁸] In addition, Itabe emphasized that oxidized LDL reflects in vivo oxidative stress and is closely linked to endothelial dysfunction and atherothrombotic processes.[9] The association between D-dimer and Ox-LDL observed in this study supports the coexistence of oxidative stress and coagulation activation in young hypertensive individuals.

Malondialdehyde levels were significantly higher in hypertensive subjects in the present study, indicating enhanced lipid peroxidation. Esterbauer et al. demonstrated that lipid peroxidation products play a key role in oxidative modification of LDL and endothelial dysfunction.[10] Similarly, Zhang et al. reported that elevated baseline D-dimer levels are associated with adverse cardiovascular outcomes, further supporting the link between oxidative stress, coagulation activation, and cardiovascular risk.⁵ The observed correlation between D-dimer and malondialdehyde in this cohort reinforces the association between oxidative stress and fibrin turnover. Markers of DNA damage and repair efficiency were significantly altered in young hypertensive adults, as evidenced by increased bleomycin-induced chromosomal breaks per cell and higher cytokinesis-block micronucleus frequency. Hsu et al. demonstrated that increased sensitivity to bleomycin reflects impaired DNA repair capacity in humans.[11] Likewise, Fenech established the cytokinesis-block micronucleus assay as a reliable marker of chromosomal damage and genomic instability.[12] These findings are consistent with the higher DNA damage indices observed in the present hypertensive cohort. The association between elevated D-dimer levels and DNA damage markers suggests that oxidative stress–related genomic instability may coexist with a prothrombotic state in young-onset hypertension. Schiffrin reported that oxidative stress–mediated vascular remodeling plays a central role in hypertension-related endothelial dysfunction, providing biological plausibility for the observed associations without implying causality.[14]

Most previous studies assessing D-dimer in hypertension have focused on older populations or patients with established cardiovascular or renal complications. In contrast, the present study evaluates a treatment-naïve young hypertensive South Indian cohort and integrates coagulation markers with oxidative stress and cytogenetic indices. Genetic and population-specific factors may contribute to the observed differences, as Ramakrishna gowda et al. reported a significant association between angiotensin receptor gene polymorphisms and hypertension in South Indian populations.[¹⁵] These findings highlight the importance of region-specific cardiovascular risk assessment. Receiver operating characteristic analysis in the present study demonstrated excellent discriminatory ability of D-dimer in identifying young hypertensive individuals. Ridker et al. previously showed that elevated plasma D-dimer levels predict future myocardial infarction in apparently healthy individuals, supporting its role as a marker of cardiovascular risk.⁴ The findings of the present study extend this evidence to young adults with hypertension.

Limitations of the study

Its cross-sectional design restricts the ability to establish causality between D-dimer levels, oxidative stress markers, and DNA repair efficiency in young hypertensives. Additionally, the single-center South Indian cohort may limit generalizability to other populations. The modest sample size, particularly for D-dimer/Ox-LDL subsets, and lack of longitudinal outcome data also constrain prognostic interpretations. Residual confounding from unmeasured factors like diet, physical activity, and adiposity further limits the analysis. Despite these limitations, the study provides valuable insights into early thrombotic and genomic instability risks in young-onset hypertension.

Clinical Implications

Early detection of prothrombotic and oxidative stress–related changes in young hypertensive individuals is critical for preventing long-term cardiovascular complications. The present findings suggest that serum D-dimer, in conjunction with oxidative stress and DNA damage markers, may aid in early risk stratification. Although pharmacological strategies targeting coagulation or oxidative stress require further evaluation, non-pharmacological interventions aimed at reducing oxidative burden—such as dietary modification and regular physical activity—remain central to early hypertension management.[21]

Acknowledgments

The authors would like to express their sincere gratitude to the Department of Biochemistry at for providing the necessary resources and facilities to carry out this study. We extend our thanks to the laboratory staff for their invaluable assistance in sample processing and data management. We also appreciate the support and guidance provided by Faculty and colleagues whose expertise and suggestions greatly contributed to the successful completion of this research. Finally, we would like to acknowledge the participation of all individuals involved in this study, whose cooperation made this research possible.

Funding: Self

Conflicts of Interest: Nil