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The Role of Biomarkers in Cardiovascular Diseases

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Cardiovascular Medicine".

Deadline for manuscript submissions: closed (31 January 2026) | Viewed by 11972

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Dr. Giorgia Panichella

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Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
Interests: cardiac amyloidosis; hypertrophic cardiomyopathy; cardiomyopathies; heart failure; multimodal imaging; translational medicine; clinical cardiology

Special Issue Information

Dear Colleagues,

As is well known, cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality worldwide, underscoring the urgent need for innovative diagnostic and therapeutic strategies. Biomarkers have emerged as critical elements in addressing these challenges, offering valuable insights into disease mechanisms, risk stratification, and treatment response. The advent of omics technologies has further facilitated the identification of thousands of potential biomarkers, significantly expanding the opportunities for improving early detection and predicting outcomes across a broad range of CVDs. However, despite this promise, the journey from biomarker discovery to clinical application is often full of challenges that impede validation and implementation.

The scope of this Special Issue, "The Role of Biomarkers in Cardiovascular Diseases”, is to explore the multifaceted role of both traditional and non-traditional biomarkers in enhancing our understanding of CVDs, improving early detection, and guiding personalized treatment approaches.

We invite researchers and clinicians to submit original research and comprehensive reviews focused on novel and established cardiovascular biomarkers, their pathophysiological relevance, and their use in precision medicine for cardiovascular care. Your contributions are essential to bridge the gap between research and clinical applications, ultimately improving patient outcomes.

Thank you for your participation, and we look forward to your submissions!

Dr. Giorgia Panichella
Guest Editor

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Keywords

biomarkers
cardiovascular diseases
heart failure
ischemic heart disease
cardiomyopathy
risk stratification
diagnosis
prognosis
inflammation

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Published Papers (9 papers)

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Research

Jump to: Review

13 pages, 869 KB

Open AccessArticle

Association of Inflammatory–Hematological Biomarkers with Hypertension and Related Comorbidities

by Evelina Maria Gosav, Daniela Maria Tanase, Anca Ouatu, Cristina Gena Dascalu, Oana Nicoleta Buliga-Finis, Diana Popescu, Andreea-Iustina Enache, Nicoleta Dima, Minerva Codruta Badescu and Ciprian Rezus

J. Clin. Med. 2026, 15(6), 2279; https://doi.org/10.3390/jcm15062279 - 17 Mar 2026

Viewed by 119

Abstract

Background: According to current data, arterial hypertension (HTN) remains the leading cause of cardiovascular disease worldwide. Oftentimes, HTN is accompanied by type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), interconnected by a pro-inflammatory pattern. Our study aimed to evaluate the roles of hematological serum cells, such as neutrophils, lymphocytes, and platelets, as well as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), in subjects with HTN, CKD, and/or T2DM. Methods: This retrospective unicentric study included 6077 patients admitted between 2018 and 2023; after applying exclusion criteria, patients were divided into groups for a comparative multivariate analysis. Results: The Mann–Whitney U test and the Kruskal–Wallis test showed statistically significant differences between groups. Higher neutrophil counts, lower lymphocyte counts, and platelet fluctuations were positively associated with HTN + comorbidities (p < 0.001 **). Receiver operating characteristic (ROC) analysis identified statistically significant associations for neutrophils and NLR in HTN (AUC = 0.442, p < 0.001 **, cut-off = 1.1217), for lymphocytes in HTN + T2DM (AUC sensitivity of 64.1%, cut-off = 18.950), for NLR (AUC 0.567, sensitivity of 50.6% and a specificity of 61.9% cut-off = 4.4174) and neutrophils (cut-off = 73.550) in HTN + CKD, and for NLR and PLR in HTN + CKD + T2DM (both having reliable AUC; sensitivity 87.9% and 81.8% for cut-off = 2.6957 and 10.5194, respectively). In all groups, AUC specificities were below the acceptable threshold (which considerably diminishes the practical clinical usability potential of these markers). Conclusions: This study demonstrated an association between hematological pro-inflammatory markers and hypertension and its comorbidities. Full article

(This article belongs to the Special Issue The Role of Biomarkers in Cardiovascular Diseases)

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23 pages, 887 KB

Open AccessArticle

PAPP-A Protein Diagnostic and Prognostic Significance in Acute Coronary Syndromes Without Persistent ST-T-Segment Elevation

by Monika Różycka-Kosmalska, Rafał Frankowski, Mikołaj Grabarczyk, Kasper Sipowicz, Anna Pękala-Wojciechowska, Tadeusz Pietras, Grzegorz Opielak and Marcin Kosmalski

J. Clin. Med. 2026, 15(4), 1455; https://doi.org/10.3390/jcm15041455 - 12 Feb 2026

Viewed by 407

Abstract

Background: There are ongoing attempts to find a reliable, highly sensitive and specific early indicator of myocardial ischemia. Recently, a potential new function for the “non-pregnancy”-related pregnancy-associated plasma protein-A (PAPP-A) protein has been reported in many papers, including that the protein could be used in diagnosing heart conditions. Hence, our study aimed to determine the diagnostic and prognostic significance of PAPP-A protein in individuals diagnosed with non-ST-elevation acute coronary syndromes (NSTE-ACSs). Methods: The study comprised 100 consecutive patients (68 males and 32 females), aged from 42 to 83 years (mean age: 64.2 years). We assessed PAPP-A protein levels, anthropometric measurements, basic laboratory tests, ECG recordings, and coronary angiography for each patient. The participants were subsequently divided into two groups: non-ST-elevation myocardial infarction (NSTEMI, n = 74) or unstable angina (UA, n = 25). Results: The levels of PAPP-A protein in patients with NSTEMI were slightly higher than those in patients with UA, but the difference was not statistically significant (7.93 ± 6.35 mIU/L vs. 6.52 ± 5.45 mIU/L, p = 0.253). Higher PAPP-A protein levels (≥5.83 mIU/L) were associated with a numerically higher, but not statistically significant, risk of NSTEMI (OR = 1.37; 95% CI: 0.56–3.36). After 12 months, there was a significant correlation between the amount of labelled PAPP-A protein and the likelihood of experiencing acute myocardial infarction, cardiovascular death, and the necessity for unplanned coronary angiography. Conclusions: The diagnostic utility of PAPP-A protein in NSTE-ACS is limited, both in the NSTEMI and UA patient groups. However, its measurement can be used to estimate the annual risk for these groups of patients. Full article

(This article belongs to the Special Issue The Role of Biomarkers in Cardiovascular Diseases)

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18 pages, 1087 KB

Open AccessArticle

Plasma HMGB1 as a Potential Biomarker Reflecting the Clinical Outcome in Chronic Heart Failure Patients

by Marcin Mazurek, Aneta Skwarek-Dziekanowska, Grzegorz Sobieszek, Teresa Małecka-Massalska and Tomasz Powrózek

J. Clin. Med. 2026, 15(3), 1159; https://doi.org/10.3390/jcm15031159 - 2 Feb 2026

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Abstract

Background: Chronic heart failure (CHF) is a progressive cardiovascular disease that predominantly affects elderly individuals and significantly impairs quality of life. High mobility group box 1 (HMGB1) has been proposed as a key mediator in the myocardial release of proinflammatory cytokines and the progression of CHF. The primary aim of this retrospective study was to evaluate the clinical significance of plasma HMGB1 levels in patients with CHF. The secondary objective was to determine the prognostic and predictive value of plasma HMGB1. Methods: Prior to the commencement of the study, blood samples were collected from 145 patients diagnosed with CHF. Plasma HMGB1 concentrations were measured at a single baseline time point using the enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed to assess correlations between HMGB1 levels and cardiac, laboratory, and nutritional parameters. Results: Elevated HMGB1 levels were significantly associated with worse clinical status, including increased pulmonary artery systolic pressure (PASP, p = 0.011), enlarged right ventricular outflow tract (RVOT, p = 0.006), advanced New York Heart Association (NYHA) functional class III or IV (p < 0.001), and the presence of dyspnea at rest (p < 0.001). HMGB1 levels effectively distinguished between NYHA classes I–III and IV (AUC = 0.780), as well as between cachectic and non-cachectic individuals (AUC = 0.840). Importantly, higher plasma HMGB1 concentrations were significantly associated with shorter overall survival (OS) in CHF patients (HR = 2.03; p < 0.001). Conclusions: Plasma HMGB1 levels may suggest that they reflect both cardiac and nutritional status in patients with CHF and could serve as a valuable biomarker for disease severity and prognosis. Notably, elevated HMGB1 is strongly associated with reduced overall survival, supporting its potential use in risk stratification and clinical management of CHF. Full article

(This article belongs to the Special Issue The Role of Biomarkers in Cardiovascular Diseases)

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13 pages, 625 KB

Open AccessArticle

Revisiting High-Sensitivity Cardiac Troponin Abnormal Baseline Cutoffs: Implications for AMI Diagnosis in the Emergency Department

by Kavithalakshmi Sataranatarajan, Madhusudhanan Narasimhan, Ishwar Daniel Chuckaree, Jyoti Balani, Ray Zhang, Rebecca Vigen and Alagarraju Muthukumar

J. Clin. Med. 2025, 14(20), 7308; https://doi.org/10.3390/jcm14207308 - 16 Oct 2025

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Abstract

Background: Current clinical guidelines recommend 52 ng/L as the abnormal baseline cutoff in high-sensitivity cardiac troponin (hs-cTn) algorithms for the rapid diagnosis of acute myocardial infarction (AMI). Though abnormal, this threshold is not AMI-specific, leading to extensive workups for many non-AMI chest pain patients, overutilization of resources, and emergency department (ED) overcrowding. Hence, the performance of this baseline abnormal cutoff was compared against the refined new thresholds for rapid AMI diagnosis in ED chest pain patients. Methods: We included ED chest pain patients with hs-cTnT and hs-cTnI levels simultaneously measured and clinical outcomes adjudicated by cardiologists. We performed receiver operating characteristics (ROC) analyses across various thresholds for diagnostic performance, including sensitivity, specificity, negative and positive likelihood ratios, and predictive values. Statistical analysis was carried out using Graphpad Prism 10, with p < 0.05 considered as significant. Results: In our study, 17 patients were adjudicated as AMI, and 682 patients were ruled out for AMI. In 15/17 AMI cases, baseline hs-cTn values far exceeded 52 ng/L. Notably, among non-AMI individuals, 140 (hs-cTnT) and 91 (hs-cTnI) also exceeded this cutoff. ROC analyses identified optimal abnormal cutoffs of 82 ng/L for hs-cTnT and 122 ng/L for hs-cTnI, which improved specificity without compromising sensitivity. Post-discharge follow-up at 1, 3, and 12 months for cardiovascular events supported these revised thresholds. Conclusions: Increasing the baseline abnormal value from 52 ng/L to 82 ng/L for hs-cTnT and to 122 ng/L for hs-cTnI in care pathways could reduce false positives with the potential to decrease unnecessary testing and alleviate long stays in the ED and resource management. Larger, diverse cohort studies are warranted to validate these findings. Full article

(This article belongs to the Special Issue The Role of Biomarkers in Cardiovascular Diseases)

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13 pages, 434 KB

Open AccessArticle

Association of TNF-R1 with Exercise Capacity in Asymptomatic Hypertensive Heart Disease—Mediating Role of Left Ventricular Diastolic Function Deterioration

by Anna Teresa Gozdzik and Marta Obremska

J. Clin. Med. 2025, 14(15), 5391; https://doi.org/10.3390/jcm14155391 - 31 Jul 2025

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Abstract

Background: TNF receptor 1 (TNF-R1) mediates the proinflammatory and proapoptotic effects of TNF-alpha, with its soluble form predicting incident heart failure (HF). While there is evidence linking TNF pathway activation to cardiac dysfunction, the mechanisms involved remain unclear. This study aimed to investigate the association between TNF-R1, exercise capacity, and cardiac function in asymptomatic patients with hypertensive heart disease (HHD). Methods: We enrolled 80 patients (mean age 55 ± 12 years) with HHD and no clinical symptoms of HF (stages A and B). Echocardiography, including tissue Doppler and left atrial and left ventricular (LV) strain assessment, was performed at rest. Peripheral venous blood samples were collected to measure serum TNF-R1 concentration. Results: The study population was divided into two subsets based on the median exercise capacity (peak VO₂) value. Patients with higher VO₂ had lower serum TNF-R1 concentration and higher early peak mitral annular velocity (e’) and peak atrial longitudinal strain (PALS). After adjusting for other covariates, multivariable regression analysis identified TNF-R1 as an independent determinant of peak VO₂. Mediation analysis revealed that the relationship between TNF-R1 and peak VO₂ was mediated by LV diastolic function (PALS or e’), with a decrease in the beta coefficient after including mediator variables from 0.37 (p < 0.001) to 0.30 (p < 0.006) and 0.31 (p = 0.004), respectively. Conclusions: In patients with HHD, higher TNF-R1 levels are associated with lower exercise capacity, which may be mediated by impaired LV diastolic function. These findings might suggest a role of TNF signalling in early HF development, justifying further studies to evaluate TNF-R1 as a biomarker for risk of HF progression. Full article

(This article belongs to the Special Issue The Role of Biomarkers in Cardiovascular Diseases)

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14 pages, 1209 KB

Open AccessArticle

Investigation of Growth Differentiation Factor 15 as a Prognostic Biomarker for Major Adverse Limb Events in Peripheral Artery Disease

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

J. Clin. Med. 2025, 14(15), 5239; https://doi.org/10.3390/jcm14155239 - 24 Jul 2025

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Abstract

Background/Objectives: Peripheral artery disease (PAD) impacts more than 200 million individuals globally and leads to mortality and morbidity secondary to progressive limb dysfunction and amputation. However, clinical management of PAD remains suboptimal, in part because of the lack of standardized biomarkers to predict patient outcomes. Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine that has been studied extensively in cardiovascular disease, but its investigation in PAD remains limited. This study aimed to use explainable statistical and machine learning methods to assess the prognostic value of GDF15 for limb outcomes in patients with PAD. Methods: This prognostic investigation was carried out using a prospectively enrolled cohort comprising 454 patients diagnosed with PAD. At baseline, plasma GDF15 levels were measured using a validated multiplex immunoassay. Participants were monitored over a two-year period to assess the occurrence of major adverse limb events (MALE), a composite outcome encompassing major lower extremity amputation, need for open/endovascular revascularization, or acute limb ischemia. An Extreme Gradient Boosting (XGBoost) model was trained to predict 2-year MALE using 10-fold cross-validation, incorporating GDF15 levels along with baseline variables. Model performance was primarily evaluated using the area under the receiver operating characteristic curve (AUROC). Secondary model evaluation metrics were accuracy, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). Prediction histogram plots were generated to assess the ability of the model to discriminate between patients who develop vs. do not develop 2-year MALE. For model interpretability, SHapley Additive exPlanations (SHAP) analysis was performed to evaluate the relative contribution of each predictor to model outputs. Results: The mean age of the cohort was 71 (SD 10) years, with 31% (n = 139) being female. Over the two-year follow-up period, 157 patients (34.6%) experienced MALE. The XGBoost model incorporating plasma GDF15 levels and demographic/clinical features achieved excellent performance for predicting 2-year MALE in PAD patients: AUROC 0.84, accuracy 83.5%, sensitivity 83.6%, specificity 83.7%, PPV 87.3%, and NPV 86.2%. The prediction probability histogram for the XGBoost model demonstrated clear separation for patients who developed vs. did not develop 2-year MALE, indicating strong discrimination ability. SHAP analysis showed that GDF15 was the strongest predictive feature for 2-year MALE, followed by age, smoking status, and other cardiovascular comorbidities, highlighting its clinical relevance. Conclusions: Using explainable statistical and machine learning methods, we demonstrated that plasma GDF15 levels have important prognostic value for 2-year MALE in patients with PAD. By integrating clinical variables with GDF15 levels, our machine learning model can support early identification of PAD patients at elevated risk for adverse limb events, facilitating timely referral to vascular specialists and aiding in decisions regarding the aggressiveness of medical/surgical treatment. This precision medicine approach based on a biomarker-guided prognostication algorithm offers a promising strategy for improving limb outcomes in individuals with PAD. Full article

(This article belongs to the Special Issue The Role of Biomarkers in Cardiovascular Diseases)

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16 pages, 1700 KB

Open AccessArticle

Association Between Plasma Homocysteine, Folate, Vitamin B12 Levels, and Metabolic Dysfunction Indices in Elderly with Arterial Stiffness

by Jintana Sirivarasai, Prapimporn Chattranukulchai Shantavasinkul, Manasid Thitiwiwatkul, Wutarak Monsuwan, Pachara Panpunuan and Piyamitr Sritara

J. Clin. Med. 2025, 14(9), 2998; https://doi.org/10.3390/jcm14092998 - 26 Apr 2025

Cited by 5 | Viewed by 3071

Abstract

Background/Objectives: Arterial stiffness is a prevalent age-related condition that can significantly increase the risk of cardiovascular disease and mortality in older adults. Understanding the factors that contribute to vascular health, including metabolic dysfunction and hyperhomocysteinemia, alongside vitamin B status, is essential for developing effective interventions. This study aimed to explore the relationship between plasma levels of homocysteine, folate, and vitamin B12, as well as various indices of metabolic dysfunction, in elderly individuals with arterial stiffness. Methods: We conducted a cross-sectional analysis involving 884 participants aged 65 and older, assessing arterial stiffness using the cardio/ankle vascular index method. Additionally, we collected fasting blood samples to evaluate plasma homocysteine, folate, vitamin B12 levels, and other relevant biochemical markers. Results: Higher plasma homocysteine levels are significantly correlated with elevated CAVI scores and increased indices of metabolic dysfunction (p < 0.05). Furthermore, a multivariate logistic regression analysis demonstrated that elevated plasma homocysteine levels, along with higher levels of lipid accumulation product (LAP), triglyceride/glucose index (TyG), and visceral adiposity index (VAI), are associated with increased arterial stiffness. Conclusions: These findings suggest that monitoring and optimizing homocysteine, folate, and vitamin B12 levels may be beneficial for preventing or managing arterial stiffness and related metabolic disorders in the elderly population. Full article

(This article belongs to the Special Issue The Role of Biomarkers in Cardiovascular Diseases)

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17 pages, 1732 KB

Open AccessReview

Noninvasive Biomarkers for Cardiac Allograft Rejection Monitoring: Advances, Challenges, and Future Directions

by Yijie Luo, Junlin Lai, Chenghao Li and Guohua Wang

J. Clin. Med. 2026, 15(3), 986; https://doi.org/10.3390/jcm15030986 - 26 Jan 2026

Viewed by 339

Abstract

Cardiac transplantation remains an important therapy for end-stage heart failure, although allograft rejection continues to pose significant clinical challenges. This review evaluates both established and emerging blood-based biomarkers for noninvasive monitoring of rejection in heart transplant recipients. Donor-derived cell-free DNA (ddcfDNA) and gene expression profiling (GEP) represent well-validated, commercially available molecular tools that demonstrate strong discriminative capacity for acute rejection episodes. Additionally, microRNAs (miRs) and extracellular vesicles (EVs) show considerable potential as novel biomarkers, although further validation is required. In contrast, conventional biomarkers such as B-type natriuretic peptide (BNP), cardiac troponins, and creatine kinase-MB (CK-MB) offer limited specificity in the context of rejection. This review synthesizes current evidence on the clinical utility, methodological challenges, and integration strategies of these biomarkers, highlighting a shift toward molecular-based approaches for improving post-transplant surveillance and patient outcomes. Full article

(This article belongs to the Special Issue The Role of Biomarkers in Cardiovascular Diseases)

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22 pages, 1189 KB

Open AccessReview

Arrhythmogenic Cardiomyopathy and Biomarkers: A Promising Perspective?

by Federico Barocelli, Nicolò Pasini, Alberto Bettella, Antonio Crocamo, Enrico Ambrosini, Filippo Luca Gurgoglione, Eleonora Canu, Laura Torlai Triglia, Francesca Russo, Angela Guidorossi, Francesca Maria Notarangelo, Domenico Corradi, Antonio Percesepe and Giampaolo Niccoli

J. Clin. Med. 2025, 14(19), 7046; https://doi.org/10.3390/jcm14197046 - 5 Oct 2025

Viewed by 1377

Abstract

Arrhythmogenic cardiomyopathy (ACM; MIM #107970) is a primitive heart muscle disease characterized by progressive myocardial loss and fibrosis or fibrofatty replacement, predisposing patients to ventricular arrhythmias, sudden cardiac death, and heart failure. Despite advances in imaging and genetics, early diagnosis remains challenging due to incomplete penetrance, variable phenotypic expressivity, and the fact that fatal arrhythmic events may often occur in the early stages of the disease. In this context, the identification of reliable biomarkers could enhance diagnostic accuracy, support risk stratification, and guide clinical management. This narrative review examines the current landscape of potential and emerging biomarkers in ACM, including troponins, natriuretic peptides, inflammatory proteins, microRNAs, fibrosis-related markers, and other molecules. Several of these biomarkers have demonstrated associations with disease severity, arrhythmic burden, or structural progression, although their routine clinical utility remains limited. The increasing relevance of genetic testing and non-invasive tissue characterization—particularly through cardiac imaging techniques—should also be emphasized as part of a multimodal diagnostic strategy in which biomarkers may play a complementary role. Although no single biomarker currently meets the criteria for a standalone diagnostic application, ongoing research into multi-marker panels and novel molecular targets offers promising perspectives. In conclusion, the integration of circulating biomarkers with imaging findings, genetic data, and clinical parameters may open new avenues for improving early detection and supporting personalized therapeutic strategies in patients with suspected ACM. Full article

(This article belongs to the Special Issue The Role of Biomarkers in Cardiovascular Diseases)

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