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Biological Markers of Cardiovascular Diseases: Applications and Utility in Clinical Practice

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A special issue of Applied Sciences (ISSN 2076-3417). This special issue belongs to the section "Applied Biosciences and Bioengineering".

Deadline for manuscript submissions: closed (25 April 2022) | Viewed by 24076

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Prof. Dr. Alexander E. Berezin

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Department of Internal Medicine-II, Paracelsus Medical University, 5020 Salzburg, Austria
Interests: cardiovascular disease; chronic kidney disease; metabolic comorbidities; circulating biomarkers; extracellular vesicles; progenitor cells; multiple biomarker panel; prognosis
Special Issues, Collections and Topics in MDPI journals

Dr. Michael Lichtenauer

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Department of Internal Medicine II, University Clinic Salzburg, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria
Interests: biomarkers; myocardial ischemia; heart failure; HFpEF; microRNA; vascular/endothelial stress; atherosclerosis; valvular heart disease; risk assessment; mortality prediction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over the last two decades, measures of peak levels and serial longitudinal measures of circulating cardiac biomarkers have revolutionized the clinical approaches to risk stratification, diagnosis, prediction, and individualized therapy of cardiovascular diseases. The most widely used biomarkers of biomechanical stress (natriuretic peptides) and cardiac injury (highly sensitive cardiac troponins) have been incorporated into several international clinical guidelines and statements with respect to acute coronary syndrome, myocardial infarction, and heart failure. Although these biomarkers predict cardiovascular mortality, heart failure occurrence and progression, and heart-failure-related clinical outcomes, including hospitalization, there is evidence of serious limitations to their diagnostic and predictive abilities in vulnerable populations. This stimulates the search for novel biomarkers and the development of multi-marker models to improve diagnosis and prognostication among patients at higher cardiovascular risk or those with an established cardiovascular disease.

This Special Issue focuses on the clinical application of the main groups of circulating biomarkers reflecting crucial pathological processes in the natural evolution of numerous cardiovascular diseases: myocardial damage and injury (highly sensitive cardiac troponins, heart-type fatty-acid-binding protein, cardiac myosin binding protein-C); biomechanical myocardial stress (natriuretic peptides, copeptin, mid-region pro-adrenomedullin); systemic and microvascular inflammation (highly sensitive C-reactive protein, interleukin 6, tumor necrosis factor-alpha, growth differentiation factor 15, soluble suppressor of tumorigenicity 2, galectin-3); skeletal muscle dysfunction (growth differentiation factor 11, myostatin, non-coding RNAs); platelet activation (soluble CD40 ligand, P-selectin); adipose tissue dysfunction (Klotho protein, adiponectin, leptin, resistin, visfatin), plaque instability (lipoprotein-associated phospholipase A2, matrix metalloproteinases and their tissue inhibitors); vascular remodeling and dysfunction (bone-related proteins, extracellular vesicles); calcium homeostasis (secretoneurin); and angiogenesis and cardioprotection (progenitor endothelial and mesenchymal cells).

Prof. Dr. Alexander E Berezin
Dr. Michael Lichtenauer
Guest Editors

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Keywords

cardiovascular disease
biomarkers
angiogenesis
inflammation
fibrosis
cardioprotection
progenitor cells
non-coding RNAs
extracellular exosomes

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 174 KiB

Open AccessEditorial

Editorial for the Special Issue “Biological Markers of Cardiovascular Diseases: Applications and Utility in Clinical Practice”

by Alexander E. Berezin and Michael Lichtenauer

Appl. Sci. 2023, 13(7), 4567; https://doi.org/10.3390/app13074567 - 4 Apr 2023

Viewed by 1001

Abstract

Circulating biomarkers are currently under scientific discussion as a potential tool for the diagnosis, prediction and risk stratification of cardiovascular and metabolic diseases [...] Full article

(This article belongs to the Special Issue Biological Markers of Cardiovascular Diseases: Applications and Utility in Clinical Practice)

Research

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21 pages, 1994 KiB

Open AccessArticle

Cytokines, Chemokines, Insulin and Haematological Indices in Type 2 Diabetic Male Sprague Dawley Rats Infected with Trichinella zimbabwensis

by Ekuyikeno Silas, Selaelo Ivy Tshilwane and Samson Mukaratirwa

Appl. Sci. 2022, 12(15), 7743; https://doi.org/10.3390/app12157743 - 1 Aug 2022

Cited by 2 | Viewed by 1872

Abstract

Diabetes mellitus is a chronic metabolic disease induced by the inability to control high blood glucose level. Helminth-induced immunomodulation has been reported to prevent or delay the onset of type 2 diabetes mellitus (T2DM), which, in turn, ameliorates insulin sensitivity. Therefore, there is a need to understand the underlying mechanisms utilized by helminths in metabolism and the induction of immuno-inflammatory responses during helminthic infection and T2DM comorbidity. This study aimed at using a laboratory animal model to determine the cytokines, chemokines and haematological indices in diabetic (T2DM) male Sprague Dawley (SD) rats infected with Trichinella zimbabwensis. One hundred and two male SD rats (160–180 g) were randomly selected into three experimental groups (i. T2DM-induced group (D) ii. T. zimbabwensis infected + T2DM group (TzD) and iii. T. zimbabwensis-infected group (Tz)). Rats selected for the D group and TzD group were injected with 40 mg/kg live weight of streptozotocin (STZ) intraperitoneally to induce T2DM, while animals in the Tz and TzD group were infected with T. zimbabwensis. Results showed that adult T. zimbabwensis worm loads and mean T. zimbabwensis larvae per gram (lpg) of rat muscle were significantly higher (p < 0.001) in the Tz group when compared to the TzD group. Blood glucose levels in the D group were significantly higher (p < 0.001) compared to the TzD group. An increase in insulin concentration was observed among the TzD group when compared to the D group. Liver and muscle glycogen decreased in the D when compared to the TzD group. A significant increase (p < 0.05) in red blood cells (RBCs) was observed in the D group when compared to the TzD and Tz groups. An increase in haematocrit, haemoglobin, white blood cells (WBCs), platelet, neutrophils and monocyte were observed in the D group when compared to the TzD group. TNF-α, IFN-γ, IL-4, IL-10 and IL-13 concentrations were elevated in the TzD group when compared to the D and Tz groups, while IL-6 concentration showed a significant reduction in the Tz when compared to the D and the TzD groups. A significant increase in CCL5 in the D and TzD groups was observed in comparison to the Tz group. CXCL10 and CCL11 concentration also showed an increase in the TzD group in comparison to the Tz and the D groups. Overall, our results confirm that T. zimbabwensis, a parasite which produces tissue-dwelling larvae in the host, regulates T2DM driven inflammation to mediate a positive protective effect against T2DM outcomes. Full article

(This article belongs to the Special Issue Biological Markers of Cardiovascular Diseases: Applications and Utility in Clinical Practice)

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16 pages, 1036 KiB

Open AccessArticle

How Do Cardiovascular Biomarkers Behave in Patients with Severe Aortic Valve Stenosis with and without Echocardiographically Proven Pulmonary Hypertension?—A Retrospective Study of Biomarker Trends before and after Transcatheter Aortic Valve Replacement

by Elke Boxhammer, Lukas Schmidbauer, Moritz Mirna, Vera Paar, Matthias Hammerer, Uta C. Hoppe and Michael Lichtenauer

Appl. Sci. 2022, 12(12), 5765; https://doi.org/10.3390/app12125765 - 7 Jun 2022

Cited by 2 | Viewed by 1375

Abstract

Background: Since right heart catheterization is rarely performed in patients with severe aortic valve stenosis (AS), echocardiography is currently the tool of choice to determine the presence or absence of pulmonary hypertension (PH). The systolic pulmonary artery pressure (sPAP) has established itself as a reliable measurement value for this purpose. The aim of our study was to evaluate the behavior of plasma-level concentrations of novel cardiovascular biomarkers (sST2, GDF-15, H-FABP, IGF-BP2, and suPAR) in patients with severe AS and an sPAP < 40 mmHg in comparison to patients with an sPAP ≥ 40 mmHg before transcatheter aortic valve replacement (TAVR) and after TAVR (24 h, 96 h, 3 months, and 12 months). Methods: We retrospectively separated 85 patients with echocardiographic evidence of severe AS before TAVR procedure into two groups based on sPAP level. An sPAP of 40 mmHg was considered the cut-off value, with the absence of PH defined by an sPAP < 40 mmH (n = 32) and the presence of PH defined by an sPAP ≥ 40 mmHg (n = 53). Blood samples were drawn from each patient one day before TAVR and 24 h, 96 h, 3 months, and 12 months after TAVR. Plasma concentrations of the cardiovascular biomarkers sST2, GDF-15, H-FABP, IGF-BP2, and suPAR were determined and analyzed with univariate and multivariate binary logistic regression and AUROC curves. Results: Patients with severe AS and an sPAP ≥ 40 mmHg had significantly higher plasma concentrations of H-FABP (baseline: p = 0.022; 24 h: p = 0.012; 96 h: p = 0.037; 3 months: p = 0.006; 12 months: p = 0.030) and IGF-BP2 (baseline: p = 0.029; 24 h: p = 0.012; 96 h: p = 0.001; 3 months: p = 0.015; 12 months: p = 0.022) before and continuously up to 12 months after TAVR than did patients with an sPAP < 40 mmHg sST2, with the exception of the 12-month follow-up. We also consistently found significantly higher plasma concentrations in the sPAP ≥ 40 mmHg group (baseline: p = 0.007; 24 h: p = 0.006; 96 h: p = 0.014; 3 months: p ≤ 0.001; 12 months: p = 0.092), whereas suPAR had significantly elevated values at baseline and after 24 h in patients with echocardiographic evidence of PH and significantly decreased values after 3 months (baseline: p = 0.003; 24 h p = 0.041; 96 h: p = 0.127; 3 months: p = 0.006; 12 months: p = 0.477). Plasma concentrations of GDF-15 were only significantly different after 24 h (baseline: p = 0.075; 24 h: p = 0.016; 96 h: p = 0.101; 3 months: p = 0.244; 12 months: p = 0.090). In a multivariate binary logistic regression, atrial fibrillation, tricuspid annular plane systolic excursion (TAPSE), and sST2 at baseline were found to have a significant p-value < 0.050. Conclusion: In this descriptive study, sST2, H-FABP, and IGF-BP2 emerged as the cardiovascular biomarkers with the greatest potential with respect to echocardiographically PH detection in long-term follow-up after TAVR, as patients with an sPAP ≥ 40 mmHg had significantly continuously higher plasma biomarker concentrations than the corresponding cohort did, with an sPAP < 40 mmHg. Full article

(This article belongs to the Special Issue Biological Markers of Cardiovascular Diseases: Applications and Utility in Clinical Practice)

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12 pages, 845 KiB

Open AccessArticle

The Association between Inflammatory Biomarkers and Cardiovascular Autonomic Dysfunction after Bacterial Infection

by Mónica Arias-Colinas, Alfredo Gea, Ahmed Khattab, Michael Vassallo, Stephen C. Allen and Joseph Kwan

Appl. Sci. 2022, 12(7), 3484; https://doi.org/10.3390/app12073484 - 29 Mar 2022

Cited by 1 | Viewed by 3899

Abstract

Heart rate variability (HRV) is a known measure of cardiac autonomic function. A cardiovascular autonomic dysfunction (CAD), measured as changes in HRV, is usually presented after an infectious process. The aim of the present study is to assess the association between serum inflammatory markers and CAD. For this purpose, 50 volunteers (13 of them recovering from an infection) were recruited and followed-up for 6 weeks. Their serum inflammatory biomarkers (CRP, IL1, IL4, IL6, IL10, and TNFalpha) were quantified throughout those weeks, along with their HRV resting, in response to the Valsalva maneuver, metronome breathing, standing and sustained handgrip. The correlation of within-subject changes in both HRV and inflammatory biomarkers was assessed to evaluate the concurrent changes. An inverse within-subject correlation was found between CRP and HRV in response to the Valsalva maneuver (rho (95% CI): −0.517 (−0.877 to −0.001); p = 0.032) and HRV standing (rho (95% CI): −0.490 (−0.943 to −0.036); p = 0.034). At the beginning, increased values of CRP are found along with reduced levels of HRV. Then, the CRP was reduced, accompanied by an improvement (increase) in HRV. These results suggest that CRP is a potential marker of CAD. Whether it is the cause, the consequence or a risk indicator non-causally associated is still to be determined. Full article

(This article belongs to the Special Issue Biological Markers of Cardiovascular Diseases: Applications and Utility in Clinical Practice)

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12 pages, 7834 KiB

Open AccessArticle

A Comparative Analysis of Novel Biomarkers in Sepsis and Cardiovascular Disease

by Peter Jirak, Franz Haertel, Moritz Mirna, Richard Rezar, Michael Lichtenauer, Vera Paar, Lukas J. Motloch, Albert Topf, Atilla Yilmaz, Uta C. Hoppe, P. Christian Schulze, Sebastian Nuding, Karl Werdan, Daniel Kretzschmar, Rudin Pistulli and Henning Ebelt

Appl. Sci. 2022, 12(3), 1419; https://doi.org/10.3390/app12031419 - 28 Jan 2022

Cited by 3 | Viewed by 2813

Abstract

(1) Background: Sepsis still represents a major health care challenge, with mortality rates exceeding 25% in the western world. To further improve outcomes in this patient collective, new cardiovascular biomarkers present a promising opportunity as they target the paramount prognostic processes in sepsis: inflammation and ischemia. However, in contrast to cardiovascular diseases, a detailed analysis of novel biomarkers in sepsis is still lacking. (2) Objective: In this project, we aimed to perform a comparative analysis of biomarker levels in ischemic cardiovascular disease and sepsis. Analyzed markers comprised soluble suppression of tumorigenicity 2 (sST2; hemodynamics and inflammation), growth-differentiation factor 15 (GDF-15; injury, remodelling), soluble urokinase-type plasminogen activator receptor (suPAR; inflammation and remodeling) and heart-type fatty acid binding protein (H-FABP; myocardial ischemia). (3) Methods: In total, 311 patients were included in the study: 123 heart-failure (HF) patients, 60 patients with ST-segment elevation myocardial infarction (STEMI) and 53 sepsis patients. A total of 75 patients without coronary artery disease or signs of heart failure served as a control group. Plasma samples were analyzed by use of ELISA after informed consent. (4) Results: Patients with sepsis showed significantly increased plasma levels in all tested biomarkers compared to cardiovascular disease entities (sST2, suPAR, GDF-15: p < 0.001; H-FABP: compared to HF p < 0.001) and controls (sST2: 7.4-fold, suPAR: 3.4-fold, GDF-15: 6.5-fold and H-FABP: 15.3-fold increased plasma levels, p < 0.001). Moreover, in patients with sepsis, serum concentrations of sST2 and suPAR were significantly elevated in patients with HF and patients with STEMI (sST2: HF: 1.6-fold increase and STEMI: 2.5-fold increase, p < 0.001; suPAR: HF: 1.4-fold increase, p < 0.001 and STEMI: 1.4-fold increase, p < 0.01), whereas plasma levels of GDF-15 and H-FABP were markedly elevated in patients with STEMI only (GDF-15: 1.6-fold increase, H-FABP: 6.4-fold increase, p < 0.001). (5) Conclusions: All tested novel cardiac biomarkers showed significantly elevated levels in sepsis patients. Interestingly, a secretion pattern similar to STEMI was observed with regards to sST2 and HFABP. Thus, by providing an assessment tool especially covering the cardiovascular component of the disease, novel biomarkers offer a promising tool in sepsis patients. Full article

(This article belongs to the Special Issue Biological Markers of Cardiovascular Diseases: Applications and Utility in Clinical Practice)

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11 pages, 1123 KiB

Open AccessArticle

sST2 Predicts Short Term Therapy Success in Patients with Therapy Resistant Hypertension after Renal Sympathetic Denervation

by Albert Topf, Vera Paar, Janine Grueninger, Bernhard Wernly, Kristen Kopp, Thomas Weber, Christiana Schernthaner, Moritz Mirna, Sarah X. Gharibeh, Robert Larbig, Rudin Pistulli, Uta C. Hoppe, Michael Lichtenauer, Lukas J. Motloch and Mathias C. Brandt

Appl. Sci. 2021, 11(23), 11130; https://doi.org/10.3390/app112311130 - 24 Nov 2021

Cited by 1 | Viewed by 1654

Abstract

Background: Renal sympathetic denervation (RSD) has provided promising data in its ability to treat therapy resistant arterial hypertension. The effect of RSD on sST-2, a promising biomarker for risk stratification in cardiovascular diseases, has so far not been systematically studied. Methods: We evaluated serum levels of sST-2 and clinical parameter including left ventricular mass (LVM) in 54 patients with resistant hypertension (RH) undergoing bilateral RSD at baseline as well as at one and/or three months. Results: After RSD, mean office blood pressure showed a significant decrease after one month (p < 0.001). On echocardiography a reduction of LVM was observed at three months (p < 0.01). This was accompanied by a significant decrease of sST-2 levels at three months (sST-2 baseline: 6310.1 ± 3246.0 pg/mL vs. sST-2 three months: 4703.8 ± 1585.9 pg/mL, p = 0.048). Furthermore, baseline sST-2 levels were positively correlated with systolic blood pressure at one month (r = 0.514, p < 0.01) but not three months, indicating a potential predictive value of sST-2 for early intervention success. Conclusion: In patients with RH, RSD is associated with a significant decrease of sST-2 levels after three months, indicating sST-2 to be involved in remodeling processes after RSD. Furthermore, lower sST-2 levels at baseline might be a potential predictor of early intervention success of RSD. Full article

(This article belongs to the Special Issue Biological Markers of Cardiovascular Diseases: Applications and Utility in Clinical Practice)

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13 pages, 964 KiB

Open AccessFeature PaperArticle

The Effect of Rivaroxaban on CYP4F2 and Transcription Factors’ Activity in HUVECs

by Ieva Ciapiene, Vacis Tatarunas, Agne Giedraitiene, Vaidotas Zvikas, Valdas Jakstas, Audrone Veikutiene, Ugne Meskauskaite, Ugne Venckyte, Audrius Pukalskas and Vaiva Lesauskaite

Appl. Sci. 2021, 11(22), 10851; https://doi.org/10.3390/app112210851 - 17 Nov 2021

Cited by 1 | Viewed by 2174

Abstract

Interindividual variabilities between patients taking the anticoagulant rivaroxaban are a result of hepatic metabolism by CYP 450 enzymes. The objective of this study was to evaluate the impact of rivaroxaban on CYP4F2 and transcription factors’ activity in HUVECs. Rivaroxaban and its metabolites were detected by UPLC-ESI-MS and UPLC-QTOF-MS. CYP4F2, HNF4α, PXR and CAR expressions were determined in HUVECs by qPCR; CYP4F2 protein concentration was determined by ELISA. Rivaroxaban metabolites (M-1, M-2, M-5, M-8, M-10, M-11 and M-18) were detected in endothelial cells’ culture medium. Increasing concentrations of rivaroxaban determined lower 13-docosenamide concentrations. Rivaroxaban and dexamethasone reduced the expression of CYP4F2 when hsa-miR-24-3p—both CYP4F2 expression and CYP4F2 protein levels in HUVECs. The expression of the transcription factors HNF4α, PXR and CAR was not detected in HUVECs. Full article

(This article belongs to the Special Issue Biological Markers of Cardiovascular Diseases: Applications and Utility in Clinical Practice)

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Review

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24 pages, 902 KiB

Open AccessReview

Heart Failure and Diabetes Mellitus: Biomarkers in Risk Stratification and Prognostication

by Michael Lichtenauer, Peter Jirak, Vera Paar, Brigitte Sipos, Kristen Kopp and Alexander E. Berezin

Appl. Sci. 2021, 11(10), 4397; https://doi.org/10.3390/app11104397 - 12 May 2021

Cited by 5 | Viewed by 4131

Abstract

Heart failure (HF) and type 2 diabetes mellitus (T2DM) have a synergistic effect on cardiovascular (CV) morbidity and mortality in patients with established CV disease (CVD). The aim of this review is to summarize the knowledge regarding the discriminative abilities of conventional and novel biomarkers in T2DM patients with established HF or at higher risk of developing HF. While conventional biomarkers, such as natriuretic peptides and high-sensitivity troponins demonstrate high predictive ability in HF with reduced ejection fraction (HFrEF), this is not the case for HF with preserved ejection fraction (HFpEF). HFpEF is a heterogeneous disease with a high variability of CVD and conventional risk factors including T2DM, hypertension, renal disease, older age, and female sex; therefore, the extrapolation of predictive abilities of traditional biomarkers on this population is constrained. New biomarker-based approaches are disputed to be sufficient for improving risk stratification and the prediction of poor clinical outcomes in patients with HFpEF. Novel biomarkers of biomechanical stress, fibrosis, inflammation, oxidative stress, and collagen turn-over have shown potential benefits in determining prognosis in T2DM patients with HF regardless of natriuretic peptides, but their role in point-to-care and in routine practice requires elucidation in large clinical trials. Full article

(This article belongs to the Special Issue Biological Markers of Cardiovascular Diseases: Applications and Utility in Clinical Practice)

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13 pages, 890 KiB

Open AccessFeature PaperReview

Promising Novel Biomarkers in Cardiovascular Diseases

by Brigitte Sipos, Peter Jirak, Vera Paar, Richard Rezar, Moritz Mirna, Kristen Kopp, Uta C. Hoppe, Alexander E. Berezin and Michael Lichtenauer

Appl. Sci. 2021, 11(8), 3654; https://doi.org/10.3390/app11083654 - 19 Apr 2021

Cited by 5 | Viewed by 3697

Abstract

Cardiovascular diseases remain the most common causes of death globally, according to the World Health Organization. In recent years, a great number of biomarkers have been investigated, whereas only some have gained value in the diagnosis, prognosis, and risk stratification of different cardiovascular illnesses. As numerous studies have investigated the diagnostic yield of novel biomarkers in various disease entities every year, this review aims to provide an overview of the current status of four promising representatives. In particular, this manuscript refers to soluble suppression of tumorigenicity 2 (sST2), heart-type fatty acid binding protein (H-FABP), growth differentiation factor (GDF-15) and soluble urokinase-type plasminogen activator receptor (suPAR). These markers are of special interest as they are thought to provide an accurate estimate of cardiovascular risk in certain patient populations, especially those with pre-existing diseases, such as obesity or diabetes mellitus. We sought to give an overview of their function, individual diagnostic and predictive value and determination in the laboratory. A review of the literature regarding the aforementioned cardiovascular biomarkers yielded manifold results with respect to their individual diagnostic and prognostic value. Yet, the clinical relevance of these findings remains unclear, warranting further studies to identify their optimal use in clinical routine. Full article

(This article belongs to the Special Issue Biological Markers of Cardiovascular Diseases: Applications and Utility in Clinical Practice)

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