2026· American journal of translational research· Vol 18 7, pp.
6369-6380
· 0 citations
Medicine
TL;DR
Epigenetic characteristics of cfDNA are closely associated with the severity of cardiac dysfunction in CVD patients and may serve as effective noninvasive molecular markers for cardiac function stratification and risk prediction accuracy.
Abstract
Objective
To evaluate the use of circulating free DNA (cfDNA) epigenetic characteristics in cardiac function stratification and risk prediction in patients with cardiovascular disease (CVD).
Methods
This retrospective study included 624 CVD patients diagnosed from January 2023 to January 2025. Patients were grouped according to the New York Heart Association (NYHA) classification into mild (I-II) and severe (III-IV) cardiac insufficiency groups. Genome-wide methylation level, hypermethylation proportion, and "risk-type cfDNA" (defined by hypermethylation of cardioprotective gene promoters and hypomethylation of injury-promoting gene promoters) were assessed. Logistic regression, Random Forest, and XGBoost models were constructed to identify predictors of severe cardiac dysfunction.
Results
Severe cardiac dysfunction was significantly associated with higher genome-wide methylation levels, hypermethylation proportion, and risk-type cfDNA (all P < 0.05). cfDNA concentration was an independent protective factor for endpoint events (OR = 0.946, 95% CI: 0.893-0.997, P = 0.0443). The combined model (cfDNA + left ventricular ejection fraction [LVEF] + N-terminal pro-brain natriuretic peptide [NT-proBNP] + age) achieved an area under the ROC curve (AUC) of 0.994. Machine learning models identified age, cfDNA concentration, and LVEF as the top three predictors of severe cardiac dysfunction.
Conclusion
Epigenetic characteristics of cfDNA are closely associated with the severity of cardiac dysfunction in CVD patients and may serve as effective noninvasive molecular markers for cardiac function stratification. Integrating cfDNA epigenetic features with traditional clinical indicators significantly improves risk prediction accuracy.
DNA methylation-based signatures were associated with incident ASCVD and modestly improved risk prediction beyond that of traditional risk factors, and an agnostic probe reliability-based approach was developed.
A. Barad, D. Khodasevich, P. F. Kho et al.· medRxiv· 0 citations
Diabetic Cardiomyopathy (DiabCM) develops in patients with Type-2-Diabetes Mellitus (T2D) and is characterized by cardiac dysfunction independent of ischemic heart disease or systemic hypertension. Its underlying mechanisms remain poorly defined with likely genetic and non-genetic mechanisms including epigenetic modifications. Combining T2D-derived polygenic risk scores (PRS) and methylation risk scores (MRS) with key clinical characteristics may aid risk stratification for myocardial dysfunction among patients with T2D.
We analyzed 173 deeply phenotyped participants from the CARDIATEAM discovery study, grouping them by the severity of myocardial dysfunction determined by echocardiography. Both PRS and MRS show significantly different distribution between severity groups (
p
-value = 0.02 and 1.29e-05, respectively) with significant odds ratios (ORs) at ≥ 80th and ≥ 90th percentiles: PRS (2.23 [95%CI 1.03–4.92] and 2.82 [95%CI 1.02–8.34]), and MRS (4.52 [95%CI 2.01–10.83] and 3.49 [95%CI 1.22–11.02]) respectively. Combining individuals with PRS and MRS above the 80th percentile showed a higher OR (6.48). The combined PRS + MRS model demonstrated the best discriminative ability (AUC = 0.753), while the interaction model did not enhance performance (AUC = 0.752).
Adding PRS and MRS to ten baseline covariates (age, sex and eight cardiometabolic variables) slightly increased bootstrap-validated sensitivity/specificity, from 0.819/0.878 to 0.827/0.885. MRS increased step-wise from non-diabetic low-risk to diabetic high-risk clusters, whereas PRS primarily distinguished diabetic from non-diabetic status. Exploratory pathway analysis of MRS-mapped genes identified enrichment for phosphatase signalling and oxidative-stress pathways implicated in diabetic cardiomyopathy.
This study provides proof-of-concept evidence that integrating T2D-derived polygenic and methylation risk scores with detailed clinical phenotyping captures distinct biological information related to subclinical myocardial dysfunction. MRS showed stronger association, including after adjustment for clinical covariates and in sensitivity analyses restricted to individuals with T2D, whereas the PRS added limited discriminatory value within the T2D population. These findings are exploratory and require validation in larger independent cohorts.
Cecilia di Primio, K. Hafeez, E. Casalone et al.· Cardiovascular Diabetology· 0 citations
Background: DNA methylation (DNAm) signatures capture cumulative lifestyle exposures and biological aging. This prospective study evaluated whether DNAm-based scores and epigenetic aging clocks are associated with clinical outcomes and mortality in a multinational cohort of patients with heart failure (HF). Methods: We studied 2,594 patients with HF from 40 countries in the Global Congestive Heart Failure (G-CHF) registry with whole-blood DNAm data. Fifteen published DNAm-based scores and epigenetic aging clocks reflecting lifestyle, environmental and physiological exposures, inflammation, frailty, mortality risk, and biological aging were derived. Associations with HF hospitalization, cardiovascular death, and all-cause death were assessed using multivariable Cox regression adjusted for age, sex, ancestry, the MAGGIC risk score, and NT-proBNP. Incremental prognostic value was compared to MAGGIC score and NT-proBNP. Extreme DNAm profiles were defined as scores or clocks exceeding {+/-}1.5 standard deviations (s.d.) from the population mean. Results: Mean age was 62.7{+/-}14.0 years, 66.2% were male, and mean left ventricular ejection fraction was 40.1{+/-}14.1%. During a median follow-up of 3.0 years, 338 patients were hospitalized for HF, 349 died from cardiovascular causes, and 565 died from any cause. Higher epigenetic age and DNAm scores for CRP, frailty, and mortality were associated with increased risk, whereas higher diet-related DNAm scores were inversely associated. For all-cause death, adjusted hazard ratios per 1-s.d. were 1.36 (95% CI, 1.24-1.50) for GrimAge, 1.27 (95% CI, 1.17-1.38) for the DNAm score for CRP, 1.44 (95% CI, 1.28-1.63) for the DNAm score for frailty, and 1.48 (95% CI, 1.32-1.65) for the DNAm score for mortality, compared with 0.81 (95% CI, 0.75-0.88) and 0.86 (95% CI, 0.79-0.94) for the DNAm scores for Alternative Healthy Eating Index and Mediterranean Diet Score. These patterns were directionally consistent for cardiovascular death and weaker for HF hospitalization and were more pronounced among patients with lower clinical risk (MAGGIC<17, Pinteraction<0.05), particularly for all-cause death. Patients with 4-5 extreme-high DNAm scores or clocks had more than twice the risk of death (HR, 2.27; 95% CI, 1.65-3.13). Conclusions: DNAm-based scores and epigenetic aging clocks reflect multiple dimensions of biological vulnerability in HF and are associated with clinical outcomes and mortality beyond clinical risk factors.
P. Meyre, M. Chong, E. Shemesh et al.· medRxiv· 0 citations
In participants with T2D and LFI, adding a metabolomic signature to SCORE2-Diabetes produced a statistically significant but moderate improvement in risk discrimination, which supports further evaluation in independent cohorts and prospective impact studies.
Mei-Li Li, Yan-Yan Shen, You-Wei Huang et al.· Frontiers in Endocrinology· 0 citations
With the change of lifestyle and the aging of the population, the incidence of Acute coronary syndrome (ACS) is increasing and showing a trend of younger patients. Therefore, the study of risk factors for ACS has important clinical implications for the diagnosis and prognosis of patients. The purpose of this study was to explore the role of long non-coding RNA (lncRNA) SNHG9 in the diagnosis and prognosis of ACS, with a view to developing new biomarkers for the diagnosis and prognosis of ACS. A total of 130 ACS patients and 99 healthy subjects were included in this study, and their serum SNHG9 levels were measured by RT-qPCR. The diagnostic value of SNHG9 in ACS was evaluated by ROC curve and binary Logistic analysis. Risk factors for major adverse cardiovascular events (MACE) in patients with ACS were analyzed using Kaplan-Meier curves and multivariate Cox regression. Correlation of SNHG9 levels with clinical indicators was analyzed using Pearson and Spearman methods. SNHG9 was highly expressed in ACS patients compared to healthy subjects. Logistic analysis and ROC results showed high diagnostic accuracy of SNHG9 in ACS patients (OR = 7.106, P < 0.001; AUC = 0.929). Furthermore, SNHG9 expression was upregulated in the MACE events group compared to the group without MACE events. Kaplan-Meier curves indicated lower survival in ACS patients with high SNHG9 expression (P = 0.002). Cox results showed that SNHG9 is a risk factor for MACE events in ACS patients after treatment. Besides, SNHG9 was positively and significantly correlated with cTnI, NT-proBNP, hs-CRP, Gensini score, and the number of diseased vessels. SNHG9 has high predictive value for the diagnosis and prognosis of ACS patients, which may become a biomarker for clinical diagnosis and prediction of survival outcome in ACS patients.
Jinhe Chen, Yujuan Gao, Fan Liu et al.· Journal of Cardiothoracic Su...· 0 citations
Early detection of cancer therapy-related cardiotoxicity is critical to individualizing treatment and preserving long-term cardiac health, yet current biomarkers largely capture downstream injury and offer limited insight into underlying biology. Plasma cfDNA methylation profiling provides a non-invasive, integrative readout of tissue-of-origin and epigenetic state, enabling simultaneous assessment of cardiac involvement and mechanistic signals that can power biomarker discovery and risk stratification.
To evaluate whether cfDNA methylation profiling identifies tissue-of-origin shifts, epigenetic ageing signals and methylation biomarkers associated with cardiotoxicity and cardiac dysfunction.
Patients receiving anticancer therapy and suspected of cardiotoxicity were enrolled in the Cardio-Oncology outpatient care progran. Plasma cfDNA was analysed from liquid biopsy of cancer patients with proven cardiotoxicity (defined according to 2022 ESC cardio-oncology guidelines) (group Cardio-Onco, n=13) and compared to that of cancer patients without cardiotoxicity (group Onco; n=11) and age- and sex-matched healthy controls (n=12). Targeted cfDNA methylation sequencing was performed. Tissue-of-origin was inferred using UXM (methylation-based) deconvolution. Epigenetic age was estimated using DNA methylation (DNAm) GrimAge and principal component (PC) proxy clocks. Differentially methylated regions (DMRs) were identified and candidate loci prioritised using random forest-based feature selection. Associations between methylation signals and cardiac imaging and laboratory measures were evaluated using multivariable regression adjusting for age, sex and significant deconvolved cell-type proportions.
CardioOnco samples showed increased estimated contribution of cardiac fibroblast-derived cfDNA compared with Onco and healthy controls. No cohort-level acceleration of epigenetic age was detected using DNAm GrimAge or PC clocks; however, GrimAge-related proxy components linked to TIMP1, B2M and PAI1 were significantly increased in CardioOnco. Feature selection highlighted methylation loci annotated to RHOJ, MAGI1, SPON1, ANKRD2 and PALLD, implicating cell-cell adhesion and communication pathways. Fibroblast-associated DMR signals were associated with reduced left ventricular ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) and with higher troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (p<0.01).
Plasma cfDNA methylome profiling identifies a cardiac fibroblast-derived signal epigenetic changes associated with cardiotoxicity. These data support targeted cfDNA methylation as a promising non-invasive approach for monitoring and biomarker discovery in cardio-oncology and warrant validation in larger cohorts.CfDNA-epigenetic analysis CfDNA-associated methylation biomarkers
D. Lukovic, K. Hamzaraj, M. Gyongyosi et al.· European Heart Journal, Supp...· 0 citations
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