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. 2026 Feb 19;16:6154. doi: 10.1038/s41598-026-38797-w

8-OHdG and NT-proBNP as complementary biomarkers in the postmortem diagnosis of acute ischemic heart disease

Yumi Kuninaka 1, Yuko Ishida 1,✉, Federica Grimaldi 1,2, Marco Irmici 1,2, Mizuho Nosaka 1, Momoko Munekawa 1, Susi Pelotti 2, Paolo Fais 2, Toshikazu Kondo 1,✉
PMCID: PMC12920965  PMID: 41714676

Abstract

Acute ischemic heart disease (AIHD) is a major cause of sudden cardiac death, yet postmortem diagnosis is difficult, particularly in early-phase ischemic injury or decomposed bodies. We investigated the diagnostic value of two molecular biomarkers—8-hydroxy-2′-deoxyguanosine (8-OHdG), indicating oxidative DNA damage, and N-terminal pro-brain natriuretic peptide (NT-proBNP), reflecting cardiac wall stress—in 67 human forensic autopsy cases (33 AIHD, 34 non-AIHD). Immunohistochemistry revealed significantly greater and more diffuse nuclear 8-OHdG expression in AIHD cardiomyocytes compared with controls. Postmortem blood NT-proBNP levels were also significantly higher in AIHD cases (2389.1 ± 499.6 pg/mL) than in non-AIHD cases (896.1 ± 190.1 pg/mL). No significant correlations were found between 8-OHdG expression and NT-proBNP levels, contraction band necrosis, postmortem interval, age, or sex, suggesting that these markers reflect distinct pathological processes—oxidative injury and hemodynamic stress. Both markers demonstrated postmortem stability, and their combined evaluation improved diagnostic confidence in cases with inconclusive histology. This dual-biomarker approach may enhance the accuracy of AIHD diagnosis in forensic practice and provide complementary insights into the molecular mechanisms underlying sudden cardiac death.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-026-38797-w.

Keywords: Forensic pathology, 8-OHdG, Acute ischemic heart diseases, Postmortem diagnosis, NT-proBNP

Subject terms: Biomarkers, Cardiology, Diseases, Medical research

Introduction

Acute ischemic heart disease (AIHD) is the principal cause of sudden cardiac death worldwide and presents substantial diagnostic challenges in both clinical and forensic practices. Classical histopathological markers of myocardial ischemia such as contraction band necrosis and wavy fibers provide useful postmortem evidence; however, they may be inconclusive in early-stage ischemic injury or decomposed bodies1. Hence, identifying reliable molecular biomarkers is critical for enhancing diagnostic accuracy in forensic pathology.

Oxidative stress plays a central role in ischemic cardiac injury, and results in mitochondrial dysfunction, lipid peroxidation, and DNA damage. One a notable oxidative DNA lesion, 8-hydroxy-2′-deoxyguanosine (8-OHdG), is a robust marker of oxidative DNA damage and has been linked to cardiovascular disease (CVD). Meta-analyses have confirmed the elevation of systemic 8-OHdG levels in patients with myocardial infarction and atherosclerosis compared to those in healthy controls2. In human myocardial infarction cases, increased serum and tissue 8-OHdG have been correlated with apoptotic signaling, implicating it in acute ischemic processes. However, studies specifically analyzing myocardial 8-OHdG in forensic autopsy samples remain limited, and postmortem stability remains under investigation.

N-terminal pro-brain natriuretic peptide (NT-proBNP), a neurohormone released in response to ventricular wall stress, is a valuable biomarker in both clinical and forensic cardiology. Elevated NT-proBNP levels are well-documented in heart failure and myocardial infarction, and its measurement in postmortem samples, especially pericardial and femoral blood, has demonstrated promise in diagnosing cardiac death3. However, NT-proBNP levels can also be influenced by renal dysfunction, hypertension, hemolysis, bacterial degradation, sampling sites, and agonal events4–7.

The primary purpose of this study is to establish objective molecular markers that can aid in the diagnosis of cases of early ischemia or arrhythmic death in which clear macroscopic or histological findings of infarction are absent. The AIHD group studied in this study was indeed autopsy cases with coronary arteriosclerosis and acute ischemic changes, but many of these included cases in the “pre-infarct stage” or “early ischemic phase” where morphological diagnosis is difficult. In such cases, a definitive diagnosis is difficult using conventional HE images alone, and we believe that auxiliary diagnosis using molecular markers such as 8-OHdG and NT-proBNP is useful. Therefore, this study is not intended to reconfirm typical myocardial infarction, but rather to provide molecular diagnostic support for acute ischemic sudden death (especially arrhythmic death) in which clear morphological changes are absent. We further analyzed their associations with histopathological indicators, postmortem intervals (PMI), and demographic factors to clarify their diagnostic value and limitations. By assessing both oxidative DNA damage and neurohormonal activation, we aimed to deepen our understanding of the molecular events underlying sudden cardiac death from AIHD and to enhance the forensic diagnostic framework.

Results

Histopathological analysis in autopsy samples

Histopathologically, HE staining revealed no evidence of old or extensive myocardial infarction in either the AIHD or non-AIHD groups (Fig. 1). Mild or moderate congestion was almost always observed in the hearts of both groups. Focal neutrophil infiltration, limited cardiomyocyte coagulation necrosis, and contraction band necrosis were observed in AIHD group (Fig. S1: HE and Masson’s trichrome staining). On the contrary, in non-AIHD cases, no neutrophil infiltration and coagulation necrosis were found, and only contraction band necrosis was sporadically seen in some of them. Importantly, no established or diagnostic ischemic lesions were identified in the non-AIHD group.

Fig. 1.

Fig. 1

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Histopathological analysis of the human hearts (HE staining). Representative results from non-AIHD and AIHD groups were shown. (A) Drowing case 1, (B) drowing case 2, (C) hanging case 1, (D) AIHD case 1, (E) AIHD case 2, (F) AIHD case 3. Sbars, 50 μm.

Enhanced intracardiac nuclear 8-OHdG expression in AIHD group

Immunohistochemical analysis revealed intranuclear expression of 8-OHdG in cardimomyocytes in both groups. Subsequently, semi-quantitative analyse demonstrated that a more intense and diffuses expression of 8-OHdG in the nuclei of cardiomyocytes within the AIHD group than in the non-AIHD group (Fig. 2A). Actually, the number of 8-OHdG+ cells was significantly higher in AIHD group, compared with non-AIHD groups (Fig. 2B, P = 4.96− 10).

Fig. 2.

Fig. 2

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Expression of 8-OHdG in the human heart. (A) Immunohistochemical analysis using anti-8-OHdG. Representative results from hearts of non-AIHD and AIHD groups are shown. (B) Morphometrical analysis was performed to measure the number of 8-OHdG+ cells in each group. Mean and standard error of the number of 8-OHdG+ cells per high power field (hpf) in each group. **P < 0.01 indicates a statistically significant difference.

Increased blood NT-proBNP level in AIHD group

We measured blood NT-proBNP levels in non-AIHD and AIHD groups. A comparison of the blood NT-proBNP levels in the AIHD and non-AIHD groups showed that the former group showed the significantly higher level of blood NT-proBNP than latte one (Fig. 3; P = 0.0074; non-AIHD: 896.1 ± 190.1 pg/mL, AIHD: 2389.1 ± 499.6 pg/mL).

Fig. 3.

Fig. 3

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The blood NT-proBNP levels of non-AIHD and AIHD groups. Bars indicate the mean blood NT-proBNP levels in the non-AIHD and AIHD groups, respectively. **P < 0.01 indicates a statistically significant difference.

No correlation between the 8-OHdG+ cell number and contraction bands, age, sex, post mortem intervals (PMI), or NT-proBNP

No significant differences were observed between 8-OHdG protein expression and the presence or absence of contractions (Fig. 4A), age (Fig. 4B), sex (Fig. 4C), PMI (Fig. 4D), or NT-proBNP levels (Fig. 4E). Furthermore, when the analysis was restricted to the AIHD group, no significant differences were observed between 8-OHdG protein expression and the presence or absence of contractions (Fig. 5A) or NT-proBNP levels (Fig. 5B). Similarly, when the analysis was limited to the non-AIHD group, no significant differences were observed between 8-OHdG protein expression and the presence or absence of contraction (Fig. 6A) or NT-proBNP levels (Fig. 6B).

Fig. 4.

Fig. 4

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Correlation between contraction bands, age, sex, PMI, and NT-proBNP levels and the occurrence of the occurrence of 8-OHdG+ cells in all cases (non-AIHD and AIHD cases). Pearson’s product-moment correlation coefficients were described. (A) Contraction bands, (B) Age, (C) Sex, (D) PMI, (E) NT-proBNP.

Fig. 5.

Fig. 5

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Correlation between contraction bands and the occurrence of 8-OHdG+ cells and between NT-proBNP levels and the occurrence of 8-OHdG+ cells in AIHD cases only. Pearson’s product-moment correlation coefficients were described. (A) Contraction bands, (B) NT-proBNP levels.

Fig. 6.

Fig. 6

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Correlation between contraction bands and the occurrence of 8-OHdG+ cells and between NT-proBNP levels and the occurrence of 8-OHdG+ cells in non-AIHD cases only. Pearson’s product-moment correlation coefficients were described. (A) Contraction bands, (B) NT-proBNP levels.

Discussion

Our immunohistochemical analyses revealed markedly increased and diffusely distributed nuclear expression of 8-OHdG in the cardiomyocytes of the AIHD group, compared to that in the non-AIHD group. Kasai showed 8-OHdG was a well-established marker of oxidative DNA damage and served as an indicator of cumulative oxidative stress at the cellular level8. Nuclear localization of 8-OHdG in myocardial tissue supports the hypothesis that oxidative injury to the cardiomyocyte genomes is a key event in the pathogenesis of AIHD9–13. In line with previous studies, these observations demonstrated the elevation of 8-OHdG levels in myocardial infarction, heart failure, and sudden cardiac death, implicating oxidative DNA damage as a potential mechanism for cardiomyocyte dysfunction and death9,10,12,14,15. Furthermore, our previous study showed a significant increase in the number of Nrf2+ cells in the AIHD group, indicating the up-regulation of antioxidant defense mechanisms in response to increased oxidative stress. Nrf2 is a redox-sensitive transcription factor that activates the expression of cytoprotective genes and is involved in myocardial response to oxidative damage16,17.

NT-proBNP is a cardiac neurohormone released in response to ventricular wall stress and is a widely accepted biomarker of heart failure and acute cardiac injury18–21, and our present results also demonstrated significantly higher blood NT-proBNP levels in the AIHD group than in the non-AIHD one. Elevated NT-proBNP levels have also been observed in forensic autopsy cases of sudden cardiac death, highlighting its diagnostic utility even postmortem22–24. Despite the simultaneous increase in 8-OHdG and NT-proBNP levels in the AIHD group, no correlation was observed between these two markers. This lack of correlation suggests that while both markers reflect different aspects of cardiac injury, such as oxidative DNA damage versus hemodynamic stress, they may operate through largely independent pathophysiological pathways in the acute phase of ischemic cardiac injury3,25. The absence of a correlation between 8-OHdG and contraction band necrosis, sex, age, postmortem interval (PMI), and NT-proBNP levels supports the notion that 8-OHdG expression is primarily driven by acute oxidative stress rather than by secondary systemic factors or postmortem changes. This highlights its potential as a relatively stable marker of oxidative myocardial injury in forensic pathology12,25. Moreover, since NT-proBNP can remain detectable postmortem and is resistant to hemolysis and degradation5,26, the combined assessment of 8-OHdG and NT-proBNP could offer a complementary approach for evaluating acute cardiac pathology in forensic settings. While 8-OHdG reflects intracellular molecular damage, NT-proBNP serves as a surrogate for systemic cardiac stress response. Future studies should focus on combined diagnostic accuracy, especially in cases with equivocal findings on gross and histological examination3,6.

Some limitations should be considered when interpreting the findings of this study, particularly from a forensic pathology standpoint: although no significant correlation was observed between PMI and 8-OHdG expression, the effect of autolytic changes, ischemia-reperfusion delay, and tissue degradation over time cannot be entirely excluded12. Oxidative DNA lesions, such as 8-OHdG, may be influenced by both agonal processes and postmortem oxidative events, potentially confounding interpretations in cases of prolonged PMI27,28. The absence of detailed clinical information regarding cardiac function, comorbidities, or medication use before death limits our ability to correlate biochemical findings with clinical status. For example, elevated NT-proBNP levels may be affected by chronic conditions such as renal insufficiency or hypertension, which could not be fully evaluated postmortem26,29. Agonal events (e.g., hypoxia, catecholamine surge, and seizures) prior to death may independently enhance oxidative stress and neurohormonal activation, thereby elevating both 8-OHdG and NT-proBNP levels, independent of AIHD. Without detailed circumstances of death or physiological monitoring, such influences cannot be ruled out7,30,31. Although NT-proBNP is relatively stable postmortem, potential variations due to hemolysis, bacterial degradation, or redistribution from tissues may still occur. Additionally, the differences in blood sampling sites (central vs. peripheral) were not standardized and may have affected the measured concentrations3,4,26.

In summary, our findings underscore the potential forensic utility of combining 8-OHdG and NT-proBNP levels as complementary biomarkers for assessing acute ischemic cardiac injury. While each reflects distinct pathological processes, oxidative DNA damage and cardiac wall stress, their simultaneous evaluation may enhance diagnostic accuracy, particularly in cases with ambiguous morphological evidence. Despite the inherent limitations of postmortem analysis, these markers offer promising avenues for improving the postmortem diagnosis of AIHD and warrant further validation in larger, clinically characterized cohorts.

Limitations

A further limitation of this study is that we did not include non-cardiac death cases with severe coronary atherosclerosis as a control group. Therefore, although elevated 8-OHdG expression was observed in AIHD cases, we cannot completely exclude the possibility that chronic ischemic changes related to advanced coronary artery disease may have contributed to the observed oxidative DNA damage. Future studies comparing AIHD with non-cardiac deaths with comparable coronary pathology are warranted.

Methods

Antibody

In this study, following monoclonal antibody (mAbs) were used for immunohistochemical analyses: mouse anti-human 8-OHdG mAb (clone N45.1; MOG-100P; Japan Institute for the Control of Aging, Shizuoka, Japan).

Measurement of blood NT-proBNP

NT-proBNP levels were measured using an electrochemiluminescence immunoassay (ECLIA) using blood samples obtained from forensic autopsy cases (Medic Co., Ltd., Shiga, Japan).

Human heart tissue samples

A total of 67 human forensic autopsy cases were included in this study (43 males; 24 females) with a PMI of less than 72 h, selected based on autopsy documents. The individual ages ranged from 29 to 100 years (mean age, 65.1 ± 17.7). In each case, the cause of death was carefully determined through a comprehensive examination, including complete autopsy, histology, toxicology, and diatom tests. The cases were divided into two groups: 33 AIHD cases with advanced sclerosis and/or stenosis in the coronary artery and 34 others, including drowning (17 cases), fire death (4 cases), hanging (3 cases), traumatic shock (3 cases), asphyxia (2 cases), severe head injury (2 cases), drug and poisoning (2 cases), and peritonitis (one case). Detailed profiles of all cases (sex, age, and PMI) are shown in Table 1. The following study groups were selected: The AIHD group consisted of 33 patients with sudden death who met the following criteria: severe coronary artery atherosclerosis, stenosis, or atherosclerosis, and histological findings of acute myocardial ischemia (e.g., contraction band necrosis, wavy fibers, etc.). Patients who underwent percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), or those with significant decay, were excluded. The control group (non-AIHD group) consisted of 34 patients with no history of cardiac disease or morphological abnormalities, and whose cause of death was noncardiac. Causes of death included drowning, trauma, asphyxiation, drug poisoning, and peritonitis, but none of these non-AIHD cases demonstrated characteristic changes of myocardial infarction such as neutrophil infiltration and coagulation necrosis in the heart. Furthermore, randomization was not statistical sampling, but rather purposive selection based on clear pathological and clinical criteria. The sample size (n = 33, 34) was determined based on the standard scale required to detect significant differences in previous forensic molecular studies16,32. Therefore, although the control group includes a variety of causes of death, it is homogenized in that it is “non-cardiac and lacks morphological cardiac lesions,” ensuring the validity of the comparison.

Table 1.

Forensic autopsy cases.

Cause of death n Male/female Age (years) PMI (hours)
Range Mean ± SD Range Mean ± SD
AIHD 33 23/10 29–100 66.3 ± 17.9 3–72 25.5 ± 14.6
Non-AIHD 34 20/14 34–97 63.9 ± 17.6 10–72 29.9 ± 15.3
Drowning 17
Fire death 4
Hanging 3
Traumatic shock 3
Asphyxia 2
Severe head injury 2
Drug and poisoning 2
Peritonitis 1
Total 67 43/24 29–100 65.1 ± 17.7 3–72 27.7 ± 15.0
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Histopathological analyses

For immunohistochemical analysis of 8-OHdG, myocardial tissue samples were consistently obtained from the central region of the left ventricular anterior wall, corresponding to the territory supplied by the left anterior descending coronary artery (LAD) in both non-AIHD and AIHD group. This region was selected to standardize sampling and to reflect a myocardial area commonly affected in acute ischemic heart disease. The heart samples were fixed in 4% formaldehyde buffered with PBS and embedded in paraffin. Sections were stained with hematoxylin-eosin (HE) for histological analysis. Immunohistochemical analysis was performed using an anti-8-OHdG mAb. The deparaffinized sections were immersed in 0.3% H2O2 in methanol for 30 min to eliminate endogenous peroxidase activity. The sections were further incubated with PBS containing 1% normal goat serum and 1% BSA to reduce nonspecific reactions. Subsequently, the sections were incubated with primary antibodies at 4°C overnight. After incubation with Envision+ System-HRP Labelled Polymer (Dako Denmark A/S, Glostrup, Denmark), the immune complexes were visualized using 3,3’-Diaminobenzidine (DAB) solution (FUJIFILM Wako, Osaka, Japan) according to the manufacturer’s instructions. As a negative control, the sections were incubated with normal mouse IgG instead of primary antibodies, and no positive signal was detected, indicating the specificity of the primary antibody.

Morphometrical analysis

Morphometry was performed for semiquantitative evaluation, as previously reported16. For 8-OHdG, five high-power microscopic fields (× 400, 0.2 × 0.2 mm each) were randomly chosen in each section. The number of 8-OHdG+ cells was counted, and the average number was evaluated for each heart specimen.

Statistical analysis

The AIHD and control groups were examined using nonparametric tests (Mann–Whitney U test) to identify significant differences (P < 0.01 was considered significant). Pearson’s product-moment correlation coefficient was used for statistical analysis of each correlation. All statistical analyses were performed using Statcel3 software under the supervision of a medical statistician as previously described16.

Ethical approval

This study was approved by the Research Ethics Committee of Wakayama Medical University (No. 3176). All the procedures were performed in accordance with the principles of the Declaration of Helsinki. Moreover, this study was conducted using past autopsy records, and informed consent was not obtained from bereaved family members for the use of these records. Therefore, we conducted this study in accordance with the “Ethical Guidelines for Medical Research Involving Human Subjects (enacted by the Ministry of Health, Labor, and Welfare in Japan), Sects. 12–12 (a) (c).” This was a de-identified study using archived tissue obtained from judicial autopsy cases, and information on the implementation of the study was posted on our website (https://www.wakayama-med.ac.jp/dept/igakubu/160420/index.html). If they were requested to refuse the use of the samples for research, they were excluded from the study. In addition, the review board of the Research Ethics Committee of Wakayama Medical University waived the need for written informed consent from relatives of the individuals studied in accordance with national legislation and institutional requirements.

Supplementary Information

Supplementary Information. (673.6KB, docx)

Acknowledgements

We sincerely thank Ms. Mariko Kawaguchi for her technical assistance.

Author contributions

Conceptualization: Y. I. and T. K.; Formal Analysis: F. G., M. I., and M. M.; Funding Acquisition:　Y. I.,  Y. K., M. N., and T. K.; Investigation: F. G., M. I. and Y. I.; Project Administration: T. K.; Validation: P. F. and S. P.; Writing—Original Draft Preparation: Y. I.; Writing—Review and Editing: T. K.

Funding

This work was supported by Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Pioneering) 25K21796 and (Exploratory) 22K19676 (Y. I.), Grant-in-Aid for Challenging Research (Pioneering) 23K17445 and Grant-in-Aid Scientific Research (B) 23K24624 (T. K.), Grant-in-Aid Scientific Research (C) 23K09770 (Y. K.), and Grant-in-Aid Scientific Research (C) 25K13658 (M. N.).

Data availability

The authors declare that all data are available in the article file, or available from the corresponding author (Toshikazu Kondo) upon reasonable request.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Yuko Ishida, Email: iyuko@wakayama-med.ac.jp.

Toshikazu Kondo, Email: kondot@wakayama-med.ac.jp.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Information. (673.6KB, docx)

Data Availability Statement

The authors declare that all data are available in the article file, or available from the corresponding author (Toshikazu Kondo) upon reasonable request.

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