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Advances in Biomarker Discovery for Cardiovascular Disease

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (28 February 2026) | Viewed by 14173

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Special Issue Editors

Dr. Qin Fu

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Guest Editor

Proteomics and Metabolomics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY 14850, USA
Interests: proteomics; biomarkers; diseases diagnostic and therapy; pharmacokinetics
Special Issues, Collections and Topics in MDPI journals

Dr. Haijun Liu

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Guest Editor

Transplantation Research Center (TRC), Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Interests: nanomedicine; drug delivery; biomaterials
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cardiovascular disease, a disorder affecting the heart and blood vessels, is one of the leading causes of death worldwide. It includes coronary heart disease, cerebrovascular disease, rheumatic heart disease, and other conditions, causing an estimated 17.9 million deaths annually. Addressing the early detection and eventual treatment of this noncommunicable disease is crucial for maintaining public health. Multiomics, including genomics, transcriptomics, proteomics, metabolomics, etc., for biomarker discovery are unequivocally powerful tools for elucidating the molecular mechanisms underlying cardiovascular disease, which helps to unravel novel diagnostic and therapeutic biomarker candidates. Sequencing-based genomics and transcriptomics, as well as mass-spectroscopy-based proteomics and metabolomic technologies, enable the unprecedented large-scale identification and quantification of DNAs, RNAs, proteins, peptides, post-translational modifications, and metabolites, providing critical insights into cardiovascular pathophysiology. This Special Issue will focus on the latest advancements in biomarker discovery for cardiovascular disease, aiming to establish earlier detection and therapy strategies.

We cordially invite authors working on this complex and promising field to submit their original research, communications, and review articles to Biomedicines. Topics of interest include, but are not limited to, the following:

Genomics and transcriptomics studies in cardiovascular disease;
Proteome and peptidome analysis in cardiovascular disease;
Post-translational modification studies in cardiovascular disease;
Metabolomics studies in cardiovascular disease;
Novel biomarkers discovery in cardiovascular disease;
Identification of therapeutic targets for cardiovascular disease;
Mass-spectrometry-based proteomics for heart and blood vessels pathophysiology;
Development of medicines for cardiovascular disease.

Dr. Qin Fu
Dr. Haijun Liu
Guest Editors

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Keywords

cardiovascular disease
genomics
transcriptomics
proteomics
metabolomics
multiomics
gene sequencing
liquid chromatography/gas chromatography tandem mass spectrometry
diagnostic biomarkers
biomedicine

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15 pages, 1061 KB

Open AccessArticle

The Association Between Serum MOTS-c Levels and Myocardial Ischemia–Reperfusion Injury in Patients with Acute Myocardial Infarction: A Cross-Sectional Study

by Li Peng, Yanqiu Li, Xinglian Duan, Jun Long, Qin Ran, Xiaojuan Zeng, Bin Liu, Duan Wang and Jian Yang

Biomedicines 2026, 14(4), 918; https://doi.org/10.3390/biomedicines14040918 - 17 Apr 2026

Viewed by 543

Abstract

Background/Objectives: Percutaneous coronary intervention (PCI) effectively restores coronary flow in acute myocardial infarction (AMI), but myocardial ischemia–reperfusion injury (MIRI) remains a major prognostic determinant. Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) has shown cardiovascular protective effects, yet its association with MIRI is unclear. This study aimed to investigate the relationship between serum MOTS-c levels and MIRI in AMI patients. Methods: Seventy-two AMI patients undergoing PCI were enrolled and divided into MIRI (n = 34) and non-MIRI (n = 38) groups. Clinical data and MOTS-c levels in peripheral serum and intracoronary blood were compared. Multivariate logistic regression and receiver operating characteristic (ROC) analysis were performed to identify MIRI predictors. Results: The MIRI group exhibited lower systolic blood pressure, preoperative thrombolysis in myocardial infarction (TIMI) grade, and HDL-C, but higher total ischemic time, door-to-balloon time, culprit vessel stenosis severity, Killip grade and adverse event incidence (all p < 0.05). Postoperative peripheral serum MOTS-c levels were significantly lower in the MIRI group than in the non-MIRI group (p < 0.05), while preoperative peripheral and intracoronary MOTS-c levels showed no significant differences between groups. Multivariate logistic regression identified postoperative peripheral MOTS-c levels (OR = 0.986, 95%CI: 0.976–0.996) and preoperative TIMI grade ≥ 1 (OR = 0.036, 95%CI: 0.004–0.309) as independent protective factors for MIRI, whereas serum creatinine was identified as an independent risk factor. ROC analysis demonstrated that postoperative peripheral MOTS-c levels predicted MIRI with an area under the curve of 0.648. Conclusions: Postoperative peripheral serum MOTS-c levels represent an independent protective factor against MIRI in patients with acute myocardial infarction and suggest a potential predictive value for MIRI, although its clinical utility as a standalone predictor requires further validation through dynamic monitoring and larger-scale studies. This finding may offer a potential novel biomarker and therapeutic direction for MIRI. Full article

(This article belongs to the Special Issue Advances in Biomarker Discovery for Cardiovascular Disease)

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11 pages, 927 KB

Open AccessArticle

Homeostatic Responses to Subsystolic Arterial Occlusive Pressure in Glabrous and Non-Glabrous Skin Circulation

by Joana Caetano, Pedro de la Villa Polo, José Delgado Alves and Luis Monteiro Rodrigues

Biomedicines 2026, 14(4), 888; https://doi.org/10.3390/biomedicines14040888 - 13 Apr 2026

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Background: Reactive hyperemia (RH) is used to assess microcirculatory function in vivo and has traditionally been interpreted as a local, ischemia-driven vasodilatory response following arterial occlusion. However, perfusion changes consistently observed in contralateral, non-challenged limbs question the exclusively local nature of RH. Objective: This study aimed to characterize reactive hyperemic responses elicited by subsystolic cuff pressures, below arterial occlusion pressure (AOP), and to investigate their effects on glabrous and non-glabrous skin microcirculation and on global hemodynamics. Methods: Seven healthy women underwent a standardized protocol consisting of baseline stabilization, a 2 min subsystolic cuff inflation (70–80% of resting AOP) in one arm, and a recovery period. Microvascular perfusion was simultaneously assessed in both hands using laser Doppler flowmetry (LDF) on glabrous skin and polarized light spectroscopy (PSp) on non-glabrous dorsal skin. Hemodynamic indicators were continuously monitored using CNAP (Continuous Non-invasive Arterial Pressure) technology. Ipsilateral and contralateral responses were compared across experimental phases. Results: Subsystolic cuff inflation induced significant perfusion changes not only in the challenged limb but also in the contralateral limb, despite the absence of a complete arterial occlusion. Conclusions: These findings confirm the adaptive nature of RH emphasizing the major role for the sympathetic nervous system in glabrous skin. In glabrous (palmar) skin, a similar perfusion profile is shown in both hands but significant differences could only be found in the ipsilateral hand. In contrast, non-glabrous (dorsal) skin demonstrated region-specific increases in perfusion, again evident in the ipsilateral hand, suggesting venous stasis. No changes in global hemodynamic variables were observed throughout the protocol. Further studies in larger, more diverse populations are needed to confirm these observations and refine the mechanistic understanding of reactive hyperemia. Full article

(This article belongs to the Special Issue Advances in Biomarker Discovery for Cardiovascular Disease)

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14 pages, 3666 KB

Open AccessArticle

Assessment of Blood-Count-Derived Biomarkers, Homocysteine Levels, MTHFR Mutation, and Clinical Manifestations in Severe Peripheral Artery Disease

by Orsolya-Zsuzsa Akácsos-Szász, Zsuzsánna Simon-Szabó, Ana-Claudia Cârstea, Liliana Demian, Róbert Nemes-Nagy, Sándor Pál, Raluca-Maria Tilinca, Mónika Szilveszter, Adrian Man, Mariana Cornelia Tilinca and Enikő Nemes-Nagy

Biomedicines 2026, 14(1), 210; https://doi.org/10.3390/biomedicines14010210 - 18 Jan 2026

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Background: Infection and consequent limb amputations are complications of severe peripheral artery disease, especially in diabetic patients. Risk factors and prognostic markers are of particular importance in defining patient care. Methods: This study included 99 peripheral artery disease (PAD) patients admitted for surgical intervention in the 2020–2021 time interval. The included subjects were stratified by type 2 diabetes mellitus (T2DM) diagnosis (present/absent). Protein, albumin concentrations, blood-count-derived inflammatory markers, and cultures from gangrenous wounds were assessed. In the group of severe cases, needing lower limb amputation (n = 31), homocysteine level, and related methylene tetrahydrofolate reductase (MTHFR) gene mutations were also investigated. Results: The mean age of patients was 68.36 ± 11.79 (SD) years and T2DM patients were significantly older (p = 0.0303). The measured inflammatory markers were at normal values in 20% of the subjects. In the cohort of infected patients, S. aureus, P. mirabilis, P. vulgaris, and S. agalactiae were the most commonly identified bacteria, with C. albicans prevailing as the most common fungal pathogen. The patient length of stay (LoS) was significantly longer in patients with pathological blood-count-derived biomarkers (p = 0.0283). A total of 58% of the severe cases presented hyperhomocysteinemia (mean 17.7 ± 10.6 (SD) μmol/L), and 19% of them presented homozygous mutation of the MTHFR gene (C677T), while 39% carried a heterozygous mutation. Compared to those with normal alleles, homocysteine levels were significantly higher in subjects with homozygous mutation (p = 0.0334). Discussion: Homozygous MTHFR mutation was associated with hyperhomocysteinemia. Blood-count-derived inflammatory markers may indicate an unfavorable outcome for PAD patients, guiding clinicians in identifying patients that are prone to complications. Full article

(This article belongs to the Special Issue Advances in Biomarker Discovery for Cardiovascular Disease)

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14 pages, 478 KB

Open AccessArticle

Lysyl Oxidase-like 2-Guided Benefits of Early Cardiac Rehabilitation in Acute Heart Failure: A Prospective Cohort Study in Taiwan

by Shyh-Ming Chen, Lin-Yi Wang, Hao-Yi Hsiao, Chin-Ling Wei, You-Cheng Zheng, Po-Jui Wu, Chien-Jen Chen, Chi-Ling Hang, Steve Leu and Yung-Lung Chen

Biomedicines 2025, 13(9), 2228; https://doi.org/10.3390/biomedicines13092228 - 10 Sep 2025

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Abstract

Background/Objectives: The objectives of this study were to determine whether the early initiation of cardiac rehabilitation (CR) within 6 weeks of discharge improves long-term outcomes in patients hospitalized for acute heart failure (HF) and to evaluate whether baseline lysyl oxidase-like 2 (LOXL2) levels affect the response to CR. Methods: We prospectively enrolled patients with acute HF who completed a structured Heart Failure Disease Management Program between January 2019 and July 2022. Participants were categorized into an early-CR group (initiating supervised CR within 6 weeks post-discharge and continuing a home-based program) or a non-CR group. The primary outcome was all-cause mortality. The secondary outcomes included HF rehospitalization and changes in scores on the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12) at 6 and 12 months. A post hoc analysis was conducted to stratify patients by baseline LOXL2 levels in order to assess differential CR effects in relation to the severity of cardiac fibrosis. Results: Out of 162 patients, 34 participated in early CR. After 1:1 propensity score matching, each group contained 33 patients. Over a median follow-up of 2.85 years, the early-CR group experienced lower all-cause mortality (0 vs. 87.2 events per 1000 patient-years; rate difference: −0.087). A subgroup analysis revealed the greatest benefit among patients with LOXL2 levels > 200 pg/mL (0 vs. 172.3 events per 1000 patient-years; rate difference: −0.172). Conclusions: Early post-discharge CR was associated with improved survival in patients with acute HF. The survival benefit was more pronounced in patients with an elevated level of LOXL2, suggesting its potential role as a biomarker for fibrosis-guided CR strategies. Health systems seeking scalability may consider embedding exercise-based and biomarker-guided CR programs within clinical networks early on to improve access while advancing patient-centered care. Further randomized trials are warranted to confirm these findings. Full article

(This article belongs to the Special Issue Advances in Biomarker Discovery for Cardiovascular Disease)

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16 pages, 388 KB

Open AccessArticle

Interferon Gamma and Tumor Necrosis Factor Alpha Are Inflammatory Biomarkers for Major Adverse Cardiovascular Events in Patients with Peripheral Artery Disease

by Ben Li, Eva Lindner, Raghad Abuhalimeh, Farah Shaikh, Houssam Younes, Batool Abuhalimeh, Abdelrahman Zamzam, Rawand Abdin and Mohammad Qadura

Biomedicines 2025, 13(7), 1586; https://doi.org/10.3390/biomedicines13071586 - 29 Jun 2025

Cited by 7 | Viewed by 1897

Abstract

Background/Objectives: Major adverse cardiovascular events (MACE)—including heart attacks and strokes—are the leading cause of death in patients with peripheral artery disease (PAD), yet biomarker research for MACE prediction in PAD patients remains limited. Inflammatory proteins play a key role in the progression of atherosclerosis and may serve as useful prognostic indicators for systemic cardiovascular risk in PAD. The objective of this study was to evaluate a broad panel of circulating inflammatory proteins to identify those independently associated with 2-year MACE in patients with PAD. Methods: We conducted a prospective cohort study involving 465 patients with PAD. Plasma concentrations of 15 inflammatory proteins were measured at baseline using validated immunoassays. Patients were followed over a two-year period for the development of MACE, defined as a composite endpoint of myocardial infarction, stroke, or mortality. Protein levels were compared between patients with and without MACE using the Mann–Whitney U test. Cox proportional hazards regression was used to determine the independent association of each protein with MACE after adjusting for baseline demographic and clinical variables, including existing coronary and cerebrovascular disease. To validate the findings, a random forest machine learning model was developed to assess the relative importance of each protein for predicting 2-year MACE. Results: The mean age of the cohort was 71 years (SD 10), and 145 participants (31.1%) were female. Over the two-year follow-up, 84 patients (18.1%) experienced MACE. Six proteins were significantly elevated in PAD patients who developed MACE: interferon gamma (IFN-γ; 42.55 [SD 15.11] vs. 33.85 [SD 12.46] pg/mL, p < 0.001), tumor necrosis factor alpha (TNF-α; 9.00 [SD 5.00] vs. 4.65 [SD 4.29] pg/mL, p < 0.001), chemokine (C-X-C motif) ligand 9 (CXCL9; 75.99 [SD 65.14] vs. 5.38 [SD 64.18] pg/mL, p = 0.002), macrophage inflammatory protein-1 beta (MIP-1β; 20.88 [SD 18.10] vs. 15.67 [SD 16.93] pg/mL, p = 0.009), MIP-1δ (25.29 [SD 4.22] vs. 17.98 [SD 4.01] pg/mL, p = 0.026), and interleukin-6 (IL-6; 12.50 [SD 40.00] vs. 6.72 [SD 38.98] pg/mL, p = 0.035). After adjusting for all baseline covariates, only two proteins—TNF-α (adjusted HR 1.66, 95% CI 1.28–2.33, p = 0.001) and IFN-γ (adjusted HR 1.25, 95% CI 1.12–2.29, p = 0.033)—remained significantly and independently associated with 2-year MACE. These findings were corroborated by the random forest model, where TNF-α and IFN-γ received the highest importance scores for predicting 2-year MACE: (TNF-α: 0.15 [95% CI 0.13–0.18], p = 0.002; IFN-γ: 0.19 [95% CI 0.17–0.21], p = 0.001). Conclusions: From a panel of 15 proteins, TNF-α and IFN-γ emerged as inflammatory biomarkers associated with 2-year MACE in PAD patients. Their measurement may aid in cardiovascular risk stratification, helping to identify high-risk individuals who could benefit from early multidisciplinary referrals to cardiology, neurology, and/or vascular medicine specialists to provide intensified medical therapy. Incorporating these biomarkers into PAD management may improve systemic cardiovascular outcomes through more personalized and targeted treatment approaches. Full article

(This article belongs to the Special Issue Advances in Biomarker Discovery for Cardiovascular Disease)

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16 pages, 820 KB

Open AccessArticle

Kynurenine as a Predictor of Long-Term Mortality: A 10-Year Follow-Up from the KORONEF Registry

by Adam Kern, Tomasz Stompór, Krystian Bojko, Ewa Sienkiewicz, Sebastian Pawlak, Krystyna Pawlak, Dariusz Pawlak, Grzegorz Poskrobko, Ewa Andrasz, Leszek Gromadziński, Rakesh Jalali, Dariusz Onichimowski, Grażyna Piwko, Artur Zalewski and Jacek Bil

Biomedicines 2025, 13(5), 1123; https://doi.org/10.3390/biomedicines13051123 - 6 May 2025

Cited by 1 | Viewed by 1460

Abstract

Background: The kynurenine (KYN) pathway of tryptophan metabolism has been linked to inflammation and cardiovascular risk, but its long-term prognostic value remains unclear. Methods: We analyzed 492 patients from the KORONEF registry who underwent coronary and renal angiography and were followed for a median of 10.2 years. Plasma levels of tryptophan (TRP), KYN, and downstream metabolites were measured. The primary endpoint was all-cause mortality. Results: The mean age was 64.4 ± 9.9 years, and 37.2% of patients were female. Common comorbidities included hypertension (74.8%), dyslipidemia (46.0%), and diabetes (25.8%). Overall mortality reached 29.5% and increased across KYN tertiles: 17.6% (T1), 28.2% (T2), and 42.9% (T3) (p < 0.001). In a multivariable Cox analysis, KYN independently predicted mortality (HR: 1.79; 95% CI: 1.15–2.44; p < 0.001), alongside age, diabetes, prior myocardial infarction, chronic kidney disease, and left ventricular ejection fraction. Other kynurenine pathway metabolites were not independently associated with outcomes. Conclusions: Elevated kynurenine levels independently predict 10-year all-cause mortality in patients undergoing coronary angiography. KYN may represent a useful prognostic biomarker beyond traditional clinical and angiographic variables. Full article

(This article belongs to the Special Issue Advances in Biomarker Discovery for Cardiovascular Disease)

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12 pages, 517 KB

Open AccessArticle

Donor-Derived Cell-Free DNA Versus Left Ventricular Longitudinal Strain and Strain-Derived Myocardial Work Indices for Identification of Heart Transplant Injury

by Timea Teszak, Timea Barcziova, Csaba Bödör, Lajos Hegyi, Luca Levay, Beata Nagy, Attila Fintha, Adam Szijarto, Attila Kovacs, Bela Merkely and Balazs Sax

Biomedicines 2025, 13(4), 841; https://doi.org/10.3390/biomedicines13040841 - 1 Apr 2025

Cited by 1 | Viewed by 1416

Abstract

Background/Objectives: Donor-derived cell-free DNA (dd-cfDNA) is a marker of graft injury that increases in acute rejection and has excellent negative predictive value. Left ventricular global longitudinal strain (LVGLS) and strain-derived myocardial work indices are novel echocardiographic parameters with growing applications. Still, they have been poorly investigated in heart transplant (HTx) recipients so far. We sought to examine the diagnostic impact of left ventricular longitudinal strain-derived indices in diagnosing myocardial injury as assessed by dd-cfDNA after HTx. Methods: Since October 2022, HTx recipients have been shifted from our endomyocardial biopsy (EMB)-based rejection surveillance protocol to a monthly dd-cfDNA-led rejection assessment. We analysed the percentage of donor-derived to total cell-free DNA. For echocardiographic analysis, patient selection was restricted to those transplanted ≥ 6 months. We used 2D speckle-tracking echocardiography to assess LVGLS and strain-derived myocardial work parameters. Results: We analysed four hundred and forty-nine dd-cfDNA samples from seventy-one patients until November 2024. The mean dd-cfDNA fraction remained very low (0.13 ± 0.06%). Eighty-eight percent of surveillance EMBs that would have otherwise been performed were avoided. The mean LVGLS was lower than the literature reference values. We found no correlation between dd-cfDNA and LVGLS. Transplanted hearts had different myocardial work indices than the reference values reported in the literature. Conclusions: dd-cfDNA effectively rules out clinically significant acute rejection and decreases the need for invasive surveillance EMBs. LVGLS seems less sensitive than dd-cfDNA for the identification of myocardial injury in the early stages of HTx rejection in patients at low risk for rejection. Full article

(This article belongs to the Special Issue Advances in Biomarker Discovery for Cardiovascular Disease)

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20 pages, 2893 KB

Open AccessArticle

Early Myocardial Strain Reduction and miR-122-5p Elevation Associated with Interstitial Fibrosis in Anthracycline-Induced Cardiotoxicity

by María de Regla Caballero-Valderrama, Elisa Bevilacqua, Miriam Echevarría, Francisco Javier Salvador-Bofill, Antonio Ordóñez, José Eduardo López-Haldón, Tarik Smani and Eva M. Calderón-Sánchez

Biomedicines 2025, 13(1), 45; https://doi.org/10.3390/biomedicines13010045 - 27 Dec 2024

Cited by 2 | Viewed by 1918

Abstract

Echocardiographic myocardial strain is crucial for early detection of anthracycline-induced cardiotoxicity, particularly in patients at moderate or high risk. Background/Objectives: This study investigates changes in global longitudinal strain (GLS) in breast cancer patients with low baseline risk for cardiotoxicity during cancer therapy. We also examined the relationship between echocardiographic strain, structural myocardial changes, and microRNA (miRNA) dysregulation associated with cancer treatment using an animal model. Methods: Echocardiography and blood tests were examined in 33 breast cancer patients with low baseline risk for cardiotoxicity during anthracycline treatment, with a follow-up at 12 months. Additionally, 16 Wistar rats received epirubicin (20 mg/kg over 4 weeks) to examine cardiac strain and structural changes. Moreover, circulating miRNA levels were assessed in patients’ serum using microarray at the end of the treatment and further analyzed in peripheral blood from the animal model. Results: Pathological GLS values were observed in 27.27% of patients after four cycles, with 15.15% showing reduced left ventricular ejection fraction (LVEF) after 12 months. In the animal model, epirubicin-induced circumferential strain (CS) decrease correlates with myocardial fibrosis assessed histologically and by a significant increase in COL1 and TGFB2 expression. Furthermore, we found a significant decrease in aquaporin1 expression associated with the presence of vacuoles in treated rats. Furthermore, dysregulation in the expression of miRNAs was observed in patients with cardiotoxicity. Among them, hsa-miR-122-5p is increased in both patient and rat serum post-treatment. Conclusions: A notable percentage of low-risk patients exhibited cardiac strain reduction due to cardiotoxicity. Epirubicin treatment caused structural heart changes in rats, highlighting miR-122-5p as a potential fibrosis marker that correlated with echocardiographic parameters. Full article

(This article belongs to the Special Issue Advances in Biomarker Discovery for Cardiovascular Disease)

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15 pages, 767 KB

Open AccessArticle

Prediction of Major Adverse Cardiovascular Events in Patients with Peripheral Artery Disease Using Circulating Immunomodulatory Proteins

by Ben Li, Farah Shaikh, Houssam Younes, Batool Abuhalimeh, Jason Chin, Khurram Rasheed, Abdelrahman Zamzam, Rawand Abdin and Mohammad Qadura

Biomedicines 2024, 12(12), 2842; https://doi.org/10.3390/biomedicines12122842 - 13 Dec 2024

Cited by 2 | Viewed by 1978

Abstract

Background/Objectives: The leading cause of death for people with peripheral artery disease (PAD) is major adverse cardiovascular events (MACE), including heart attacks and strokes. However, research into biomarkers that could help predict MACE in patients with PAD has been limited. Immunomodulatory proteins are known to significantly influence systemic atherosclerosis, suggesting they could be useful prognostic indicators for MACE in patients with PAD. In this study, we evaluated a broad panel of immunomodulatory proteins to identify those linked to MACE in individuals with PAD. Methods: We conducted a prognostic study involving a prospectively recruited cohort of 406 patients consisting of 254 with PAD and 152 without PAD. At the baseline, we measured the plasma concentrations of 17 circulating immunomodulatory proteins and followed the cohort for two years. The primary outcome was 2-year MACE, a composite of myocardial infarction, stroke, or death. Plasma protein concentrations were compared between patients with PAD with and without 2-year MACE using Mann–Whitney U tests. We further examined the prognostic potential of differentially expressed proteins through a Cox proportional hazards analysis, determining their independent associations with 2-year MACE while controlling for all the baseline demographic and clinical characteristics, including the existing coronary artery and cerebrovascular diseases. Additionally, A Kaplan–Meier analysis was performed to evaluate the 2-year freedom from MACE in patients with low versus high levels of the differentially expressed proteins based on the median plasma concentrations. Results: The mean age of the cohort was 68.8 years (SD 11.1), with 134 patients (33%) being female. During the two-year follow-up, 63 individuals (16%) developed MACE. The following proteins were significantly elevated in patients with PAD who experienced 2-year MACE compared to those who did not: galectin-1 (0.17 [SD 0.06] vs. 0.10 [SD 0.07] pg/mL, p = 0.012), alpha-1-microglobulin (16.68 [SD 7.48] vs. 14.74 [SD 6.71] pg/mL, p = 0.019), and galectin-9 (0.14 [SD 0.09] vs. 0.09 [SD 0.05] pg/mL, p = 0.033). The Cox proportional hazards analysis indicated that these three proteins were independently associated with 2-year MACE after adjusting for all the baseline demographic and clinical factors: galectin-1 (HR 1.45 [95% CI 1.09–1.92], p = 0.019), alpha-1-microglobulin (HR 1.31 [95% CI 1.06–1.63], p = 0.013), and galectin-9 (HR 1.35 [95% CI 1.02–1.78], p = 0.028). Over the two-year follow-up, patients with higher levels of galectin-1, galectin-9, and alpha-1-microglobulin had a lower freedom from MACE. Additional analysis showed that these three proteins were not significantly associated with 2-year MACE in patients without PAD. Conclusions: Among the 17 immunomodulatory proteins evaluated, galectin-1, galectin-9, and alpha-1-microglobulin were found to be independently and specifically associated with 2-year MACE in patients with PAD. Assessing the plasma concentrations of these proteins can aid in risk stratification for MACE in patients with PAD, helping to inform clinical decisions regarding multidisciplinary referrals to cardiologists, neurologists, and vascular medicine specialists. This information can also guide the aggressiveness of medical management, ultimately improving cardiovascular outcomes for patients with PAD. Full article

(This article belongs to the Special Issue Advances in Biomarker Discovery for Cardiovascular Disease)

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Open AccessReview

Maternal Blood as a Window to the Fetal Heart: Novel Biomarkers for Early Detection of Septal Defects

by Alexandru Carauleanu, Catalin M. Buzduga, Razvan I. Tudosa, Claudia Florida Costea, Anca Petruta Morosan, Alexandru Nemtoi, Emilia Patrascanu, Gina Madalina Toma, Camelia Tamas, Anca Haisan, Roxana Covali, Andrei I. Cucu and Amelian M. Bobu

Biomedicines 2026, 14(3), 586; https://doi.org/10.3390/biomedicines14030586 - 5 Mar 2026

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Abstract

Congenital heart defects (CHDs) represent the most common category of congenital malformations and constitute a significant cause of infant morbidity and mortality. Despite advances in prenatal imaging, such as fetal echocardiography, early detection remains challenging, particularly in pregnancies without identified risk factors. Recent studies suggest that maternal circulating non-coding RNAs, including microRNAs and long non-coding RNAs (lncRNAs), may serve as promising non-invasive biomarkers for the prenatal diagnosis of CHDs. Following a review of the most relevant clinical and preclinical studies, it was found that maternal circulating RNA, particularly microRNAs and lncRNAs, shows potential as non-invasive biomarkers for detecting fetal congenital heart defects. Among microRNAs, miR-146a-5p demonstrated the highest diagnostic accuracy for ventricular septal defects (VSDs), while panels of lncRNAs, such as LINC00598, LINC01551, and GATA3-AS1, exhibited high performance for atrial septal defects (ASDs). In addition, miR-19b, miR-29c, and miR-375 were associated with both VSDs and ASDs, suggesting a shared role in septal development. However, the studies displayed variability in biomarker selection and analytical methodologies. The findings indicate that maternal circulating microRNAs and lncRNAs hold significant potential as non-invasive biomarkers for the early detection of CHDs. Nonetheless, methodological heterogeneity and small sample sizes highlight the need for standardized protocols and larger multicenter studies prior to clinical implementation. These observations support the future integration of RNA biomarkers with fetal echocardiography to enhance early CHD screening and to inform prenatal counseling. Full article

(This article belongs to the Special Issue Advances in Biomarker Discovery for Cardiovascular Disease)

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