Special Issue "Biomolecules for Translational Approaches in Cardiology"

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: 28 February 2019

Special Issue Editors

Guest Editor
Dr. Mahir Karakas

Clinic for General and Interventional Cardiology, University Heart Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Website | E-Mail
Interests: biomarkers in cardiology; clinical trials in cardiology; genomics in cardiology; genetic epidemiology; cardiology
Guest Editor
Prof. Dr. Tanja Zeller

Clinic for General and Interventional Cardiology, University Heart Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Website | E-Mail
Interests: systems medince; genomics and genetics in cardiology; biomarkers in cardiology; genetic epidemiology

Special Issue Information

Dear Colleagues, 

Over the last few years, biomarker research has improved our knowledge about the pathomechanisms and risk assessment in the cardiovascular field. Increasing our understanding of the multifactorial, complex underpinnings of cardiovascular diseases promises to have a global impact on the promotion of health. Valuable insights have already been acquired from several genomic and genetic studies and novel molecular biomarkers have been associated with cardiovascular risk. Translational approaches into a full understanding of the underlying mechanisms of biomarkers and into their clinical relevance are currently ongoing. The systematic integration of multidimensional biomarker datasets, such as genomics, transcriptomics and proteomics evolves as the next challenge, including molecular findings of interactions between biomolecules as well as knowledge from cell biology, animal experiments and human phenotypic and clinical data. We encourage scientists of diverse backgrounds (clinics, systems medicine, genetics, molecular biology, epidemiology) and working in the cardiovascular field to contribute original research or review articles covering studies on biomolecule identification or characterization and translational approaches of clinical relevance. 

Dr. Mahir Karakas
Prof. Dr. Tanja Zeller
Guest Editors

Manuscript Submission Information

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Keywords

  • cardiovascular biomarkers
  • systems medicine
  • genomics and genetics
  • epidemiology
  • cardiology
  • clinical trials
  • clinical translation

Published Papers (22 papers)

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Open AccessArticle Electrocardiographic and Seasonal Patterns Allow Accurate Differentiation of Tako-Tsubo Cardiomyopathy from Acute Anterior Myocardial Infarction: Results of a Multicenter Study and Systematic Overview of Available Studies
Biomolecules 2019, 9(2), 51; https://doi.org/10.3390/biom9020051
Received: 31 December 2018 / Revised: 27 January 2019 / Accepted: 28 January 2019 / Published: 30 January 2019
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Abstract
Background. Though several studies about prevalence, etiology, clinical characteristics, preceding events, clinical management, and outcome of Tako-Tsubo cardiomyopathy (TTC) exist, the current knowledge of TTC remains limited. Objective. In 2006, TTC was classified among the acquired forms of cardiomyopathy. On the [...] Read more.
Background. Though several studies about prevalence, etiology, clinical characteristics, preceding events, clinical management, and outcome of Tako-Tsubo cardiomyopathy (TTC) exist, the current knowledge of TTC remains limited. Objective. In 2006, TTC was classified among the acquired forms of cardiomyopathy. On the basis of pathophysiological implications, we analyzed whether the presence of ST-segment elevation in lead -aVR (i.e., ST-segment depression in aVR) and the simultaneous absence of ST-segment elevation in lead V1 allow a reliable differentiation of TTC from acute anterior ST-segment elevation myocardial infarction (STEMI). A further investigative feature is the seasonal variation of TTC. Since acute cardiovascular events exhibit definite chronobiological patterns, various small studies have tried to evaluate whether this is also the case for TTC. Because results are conflicting, we also conducted a multicenter study and analyzed the findings in context with a systematic overview of available studies. Methods. We compared the ECG patterns of 115 patients with TTC, who were admitted to five large acute cardiac care centers associated with university hospitals in Southwestern Germany between January 2001 and June 2011, with those of 100 patients with acute anterior ST-segment elevation myocardial infarction (STEMI) treated in one of these centers. In addition, we performed a computer-assisted MEDLINE search of the literature from January 2000 to September 2011 and analyzed the chronobiological patterns of available TTC cases, including our TTC cohort. Results. Testing the predefined diagnostic criteria was superior to any other electrocardiographic finding and differentiated TTC from anterior STEMI with a sensitivity of 73%, a specificity of 84%, a positive predictive value of 63%, and a negative predictive value of 89%. Beyond that, the onset of TTC showed a clear variation as a function of season and month. While events occurred most frequently during summer (38.4%, p < 0.01), the event rate was the lowest in autumn (16.4%) and winter (21.9%). Chronobiological analyses on a monthly basis identified a significant annual rhythmic pattern in TTC, which peaked in August (11.9%; p < 0.01) and had its nadir in November (6.3%). Conclusions. Our data illustrate that the ST-segment changes in leads aVR and V1 represent a simple and accurate ECG criterion to differentiate TTC from anterior STEMI in patients who are admitted within 12 h of symptom onset. Similarly, the results of our seasonal analysis indicate a distinct chronobiological variation in TTC occurrence. TTC, thereby, differs from major acute cardiovascular diseases, especially acute myocardial infarction (AMI), which is characterized by winter peaks and troughs in summer. If these results are confirmed in large independent cohorts, they may yield diagnostic implications, changing the regular invasive AMI management in TTC patients. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessArticle Macrophage Migration Inhibitory Factor (MIF) Expression Increases during Myocardial Infarction and Supports Pro-Inflammatory Signaling in Cardiac Fibroblasts
Biomolecules 2019, 9(2), 38; https://doi.org/10.3390/biom9020038
Received: 1 December 2018 / Revised: 11 January 2019 / Accepted: 17 January 2019 / Published: 23 January 2019
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Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine known to play a major role in inflammatory diseases such as myocardial infarction (MI), where its expression increases. Cardio-protective functions of MIF during ischemia have been reported. Recently, the structurally related MIF-2 was identified [...] Read more.
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine known to play a major role in inflammatory diseases such as myocardial infarction (MI), where its expression increases. Cardio-protective functions of MIF during ischemia have been reported. Recently, the structurally related MIF-2 was identified and similar effects are assumed. We wanted to further investigate the role of MIF and MIF-2 on inflammatory processes during MI. Therefore, we subjected mice to experimentally induced MI by coronary occlusion for one and five days. During the acute phase of MI, the gene expression of Mif was upregulated in the infarct zone, whereas Mif-2 was downregulated, suggesting a minor role of MIF-2. Simulating ischemic conditions or mechanical stress in vitro, we demonstrated that Mif expression was induced in resident cardiac cells. To investigate possible auto-/paracrine effects, cardiomyocytes and cardiac fibroblasts were individually treated with recombinant murine MIF, which in turn induced Mif expression and the expression of pro-inflammatory genes in cardiac fibroblasts. Cardiomyocytes did not respond to recombinant MIF with pro-inflammatory gene expression. While MIF stimulation alone did not change the expression of pro-fibrotic genes in cardiac fibroblasts, ischemia reduced their expression. Mimicking the increased MIF levels during MI, we exposed cardiac fibroblasts to simulated ischemia in the presence of MIF, which led to further reduced expression of pro-fibrotic genes. The presented data show that MIF was expressed by resident cardiac cells during MI. In vitro, Mif expression was induced by different external stimuli in cardiomyocytes and cardiac fibroblasts. Addition of recombinant MIF protein increased the expression of pro-inflammatory genes in cardiac fibroblasts including Mif expression itself. Thereby, cardiac fibroblasts may amplify Mif expression during ischemia promoting cardiomyocyte survival. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessFeature PaperArticle Delineating the Dynamic Transcriptome Response of mRNA and microRNA during Zebrafish Heart Regeneration
Biomolecules 2019, 9(1), 11; https://doi.org/10.3390/biom9010011
Received: 30 November 2018 / Revised: 19 December 2018 / Accepted: 21 December 2018 / Published: 28 December 2018
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Abstract
Heart diseases are the leading cause of death for the vast majority of people around the world, which is often due to the limited capability of human cardiac regeneration. In contrast, zebrafish have the capacity to fully regenerate their hearts after cardiac injury. [...] Read more.
Heart diseases are the leading cause of death for the vast majority of people around the world, which is often due to the limited capability of human cardiac regeneration. In contrast, zebrafish have the capacity to fully regenerate their hearts after cardiac injury. Understanding and activating these mechanisms would improve health in patients suffering from long-term consequences of ischemia. Therefore, we monitored the dynamic transcriptome response of both mRNA and microRNA in zebrafish at 1–160 days post cryoinjury (dpi). Using a control model of sham-operated and healthy fish, we extracted the regeneration specific response and further delineated the spatio-temporal organization of regeneration processes such as cell cycle and heart function. In addition, we identified novel (miR-148/152, miR-218b and miR-19) and previously known microRNAs among the top regulators of heart regeneration by using theoretically predicted target sites and correlation of expression profiles from both mRNA and microRNA. In a cross-species effort, we validated our findings in the dynamic process of rat myoblasts differentiating into cardiomyocytes-like cells (H9c2 cell line). Concluding, we elucidated different phases of transcriptomic responses during zebrafish heart regeneration. Furthermore, microRNAs showed to be important regulators in cardiomyocyte proliferation over time. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessArticle Association of Genetic Variation at AQP4 Locus with Vascular Depression
Biomolecules 2018, 8(4), 164; https://doi.org/10.3390/biom8040164
Received: 8 October 2018 / Revised: 27 November 2018 / Accepted: 27 November 2018 / Published: 5 December 2018
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Abstract
Despite its substantial clinical importance, specific genetic variants associated with depression have not yet been identified. We sought to identify genetic variants associated with depression by (a) focusing on a more homogenous subsample (vascular depression) and (b) applying a three-stage approach. First, we [...] Read more.
Despite its substantial clinical importance, specific genetic variants associated with depression have not yet been identified. We sought to identify genetic variants associated with depression by (a) focusing on a more homogenous subsample (vascular depression) and (b) applying a three-stage approach. First, we contacted 730 participants with a confirmed atherosclerotic disease (coronary artery disease) from a population-based study population (German Myocardial Infarction Family Study IV) for psychiatric assessment with the Mini International Neuropsychiatric Interview. Second, we genotyped these patients using genome-wide single nucleotide polymorphism (SNP) arrays. Third, we characterized the SNP via in-silico analysis. The final sample consisted of 342 patients (78.3% male, age = 63.2 ± 9.9 years), 22.8% with a severe depressive disorder. Variant rs528732638 on chromosome 18q11.2 was a genome-wide significant variant and was associated with 3.6-fold increase in the odds of lifetime depression. The locus belongs to a linkage disequilibrium block showing expression quantitative trait loci effects on three putative cis-regulated genes, including the aquaporin 4 (AQP4) locus. AQP4 is already known to mediate the formation of ischemic edema in the brain and heart, increasing the size and extent of resulting lesions. Our findings indicate that AQP4 may also play a role in the etiopathology of vascular depression. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessArticle Semantic Multi-Classifier Systems Identify Predictive Processes in Heart Failure Models across Species
Biomolecules 2018, 8(4), 158; https://doi.org/10.3390/biom8040158
Received: 20 September 2018 / Revised: 21 November 2018 / Accepted: 21 November 2018 / Published: 26 November 2018
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Abstract
Genetic model organisms have the potential of removing blind spots from the underlying gene regulatory networks of human diseases. Allowing analyses under experimental conditions they complement the insights gained from observational data. An inevitable requirement for a successful trans-species transfer is an abstract [...] Read more.
Genetic model organisms have the potential of removing blind spots from the underlying gene regulatory networks of human diseases. Allowing analyses under experimental conditions they complement the insights gained from observational data. An inevitable requirement for a successful trans-species transfer is an abstract but precise high-level characterization of experimental findings. In this work, we provide a large-scale analysis of seven weak contractility/heart failure genotypes of the model organism zebrafish which all share a weak contractility phenotype. In supervised classification experiments, we screen for discriminative patterns that distinguish between observable phenotypes (homozygous mutant individuals) as well as wild-type (homozygous wild-types) and carriers (heterozygous individuals). As the method of choice we use semantic multi-classifier systems, a knowledge-based approach which constructs hypotheses from a predefined vocabulary of high-level terms (e.g., Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways or Gene Ontology (GO) terms). Evaluating these models leads to a compact description of the underlying processes and guides the screening for new molecular markers of heart failure. Furthermore, we were able to independently corroborate the identified processes in Wistar rats. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessArticle Therapeutic Chemical Screen Identifies Phosphatase Inhibitors to Reconstitute PKB Phosphorylation and Cardiac Contractility in ILK-Deficient Zebrafish
Biomolecules 2018, 8(4), 153; https://doi.org/10.3390/biom8040153
Received: 20 September 2018 / Revised: 24 October 2018 / Accepted: 30 October 2018 / Published: 19 November 2018
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Abstract
Patients with inherited dilated cardiomyopathy (DCM) often suffer from severe heart failure based on impaired cardiac contractility leading to increased morbidity and mortality. Integrin-linked kinase (ILK) as a part of the cardiac mechanical stretch sensor was found to be an essential genetic regulator [...] Read more.
Patients with inherited dilated cardiomyopathy (DCM) often suffer from severe heart failure based on impaired cardiac contractility leading to increased morbidity and mortality. Integrin-linked kinase (ILK) as a part of the cardiac mechanical stretch sensor was found to be an essential genetic regulator of cardiac contractility. Integrin-linked kinase localizes to z-disks and costameres in vertebrate hearts and regulates the activity of the signaling molecule protein kinase B (PKB/Akt) by controlling its phosphorylation. Despite identification of several potential drug targets in the ILK signaling pathway, pharmacological treatment strategies to restore contractile function in ILK-dependent cardiomyopathies have not been established yet. In recent years, the zebrafish has emerged as a valuable experimental system to model human cardiomyopathies as well as a powerful tool for the straightforward high-throughput in vivo small compound screening of therapeutically active substances. Using the ILK deficient zebrafish heart failure mutant main squeeze (msq), which shows reduced PKB phosphorylation and thereby impaired cardiac contractile force, we identified here, in an automated small compound screen, the protein phosphatase inhibitors calyculin A and okadaic acid significantly restoring myocardial contractile function by reconstituting PKB phosphorylation in msq ILK-deficient zebrafish embryos. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessArticle Atrial Fibrillation Predicts Long-Term Outcome after Transcatheter Edge-to-Edge Mitral Valve Repair by MitraClip Implantation
Biomolecules 2018, 8(4), 152; https://doi.org/10.3390/biom8040152
Received: 4 September 2018 / Revised: 4 November 2018 / Accepted: 8 November 2018 / Published: 19 November 2018
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Abstract
Background: Atrial fibrillation is common in patients with mitral regurgitation (MR) and has a negative impact on the clinical outcome of patients with valvular heart disease. We aimed to evaluate the impact of pre-procedural atrial fibrillation on the long-term clinical outcomes of [...] Read more.
Background: Atrial fibrillation is common in patients with mitral regurgitation (MR) and has a negative impact on the clinical outcome of patients with valvular heart disease. We aimed to evaluate the impact of pre-procedural atrial fibrillation on the long-term clinical outcomes of patients with MR undergoing transcatheter mitral valve repair by MitraClip implantation. Methods: We analysed 355 consecutive patients with and without atrial fibrillation with symptomatic, severe MR and inoperability or high surgical risk undergoing MitraClip implantation in a three-year follow-up. Results: In patients with pre-procedural atrial fibrillation undergoing MitraClip implantation, we found advanced age, higher baseline NT-pro-BNP levels, increased left atrial diameter, and higher rate of severe tricuspid regurgitation, compared to patients with sinus rhythm. In the three-year follow-up after MitraClip implantation, mortality and major adverse cardiovascular and cerebral events (MACCE) occur significantly more often in patients with atrial fibrillation, compared to patients without atrial fibrillation. Multivariate regression analysis confirmed atrial fibrillation (hazard ratio 2.39, 95%-confidence interval 1.06–5.41, p = 0.036) as an independent predictor for three-year-mortality after MitraClip implantation. Conclusions: Atrial fibrillation is an independent predictor for long-term mortality after MitraClip implantation. We demonstrate the association of atrial fibrillation with mortality and MACCE in the long-term follow-up of patients undergoing MitraClip implantation. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessArticle Add-on Immunoadsorption Shortly-after Optimal Medical Treatment Further Significantly and Persistently Improves Cardiac Function and Symptoms in Recent-Onset Heart Failure—A Single Center Experience
Biomolecules 2018, 8(4), 133; https://doi.org/10.3390/biom8040133
Received: 4 September 2018 / Revised: 17 October 2018 / Accepted: 29 October 2018 / Published: 2 November 2018
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Abstract
Background: Immunoadsorption and intravenous immunoglobulin (IVIG) administration may have beneficial effects in patients with dilated cardiomyopathy with end-stage heart failure. We investigated the effect of immunoadsorption with subsequent IVIG administration on cardiac function and symptoms in patients on optimal medical treatment (OMT) for [...] Read more.
Background: Immunoadsorption and intravenous immunoglobulin (IVIG) administration may have beneficial effects in patients with dilated cardiomyopathy with end-stage heart failure. We investigated the effect of immunoadsorption with subsequent IVIG administration on cardiac function and symptoms in patients on optimal medical treatment (OMT) for heart failure (HF) with recent-onset cardiomyopathy during long-term follow-up. Methods: Thirty-five patients with recent-onset of HF symptoms received intensive guideline-recommended medical HF therapy for 5.2 months. Subsequently, all patients received a single cycle of immunoadsorption for five days followed by IVIG administration. During the 29-month follow-up period, New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF) and N-terminal pro brain natriuretic peptide (NT-proBNP) were evaluated. Changes in quality of life (QoL) were assessed using the Minnesota Living with HF Questionnaire. Results: Three months after immunoadsorption, NYHA functional class improved from 2.0 to 1.5 (p < 0.005) and LVEF significantly increased from 27.0% to 39.0% (p < 0.0001). Long-term follow-up of 29 months showed stable NYHA functional class and a further moderate increase in LVEF from 39.0% to 42.0% (p < 0.0001) accompanied by a significant improvement in NT-proBNP and QoL scores. Conclusion: Immunoadsorption followed by IVIG administration further enhances LVEF, HF symptoms, QoL and biomarkers in patients with recent-onset HF on OMT. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessArticle Cross-Sectional Associations between Homoarginine, Intermediate Phenotypes, and Atrial Fibrillation in the Community—The Gutenberg Health Study
Biomolecules 2018, 8(3), 86; https://doi.org/10.3390/biom8030086
Received: 11 July 2018 / Revised: 26 August 2018 / Accepted: 27 August 2018 / Published: 30 August 2018
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Abstract
Homoarginine has come into the focus of interest as a biomarker for cardiovascular disease. Atrial fibrillation (AF) causes a substantial increase in morbidity and mortality. Whether circulating homoarginine is associated with occurrence or persistence of AF and may serve as a new predictive [...] Read more.
Homoarginine has come into the focus of interest as a biomarker for cardiovascular disease. Atrial fibrillation (AF) causes a substantial increase in morbidity and mortality. Whether circulating homoarginine is associated with occurrence or persistence of AF and may serve as a new predictive biomarker remains unknown. We measured plasma levels of homoarginine in the population-based Gutenberg health study (3761 patients included, of them 51.7% males), mean age 55.6 ± 10.9 years-old. Associations between homoarginine and intermediate electrocardiographic and echocardiographic phenotypes and manifest AF were examined. Patients with AF (124 patients, of them 73.4% males) had a mean age 64.8 ± 8.6 years-old compared to a mean age of 55.3 ± 10.9 in the population without AF (p-value < 0.001) and showed a less beneficial risk factor profile. The median homoarginine levels in individuals with and without AF were 1.9 μmol/L (interquartile range (IQR) 1.5–2.5) and 2.0 μmol/L (IQR 1.5–2.5), respectively, p = 0.56. In multivariable-adjusted regression analyses homoarginine was not statistically significantly related to electrocardiographic variables. Among echocardiographic variables beta per standard deviation increase was −0.12 (95% confidence interval (CI) −0.23–(−0.02); p = 0.024) for left atrial area and −0.01 (95% CI −0.02–(−0.003); p = 0.013) for E/A ratio. The odds ratio between homoarginine and AF was 0.91 (95% CI 0.70–1.16; p = 0.45). In our large, population-based cross-sectional study, we did not find statistically significant correlations between lower homoarginine levels and occurrence or persistence of AF or most standard electrocardiographic phenotypes, but some moderate inverse associations with echocardiographic left atrial size and E/A. Homoarginine may not represent a strong biomarker to identify individuals at increased risk for AF. Further investigations will be needed to elucidate the role of homoarginine and cardiac function. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessArticle Testosterone Levels and Type 2 Diabetes—No Correlation with Age, Differential Predictive Value in Men and Women
Biomolecules 2018, 8(3), 76; https://doi.org/10.3390/biom8030076
Received: 8 June 2018 / Revised: 3 August 2018 / Accepted: 13 August 2018 / Published: 20 August 2018
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Abstract
Most studies reporting on the association of circulating testosterone levels with type 2 diabetes in men are of cross-sectional design. Reports on the relevance of altered testosterone levels in women are scarce. Here, we evaluate the role of low serum testosterone levels for [...] Read more.
Most studies reporting on the association of circulating testosterone levels with type 2 diabetes in men are of cross-sectional design. Reports on the relevance of altered testosterone levels in women are scarce. Here, we evaluate the role of low serum testosterone levels for incident diabetes in men and women in a population setting of 7706 subjects (3896 females). During a mean follow up time of 13.8 years, 7.8% developed type 2 diabetes. Significant correlations of testosterone with high density lipoprotein (HDL)-cholesterol (R = 0.21, p < 0.001), body-mass-index (R = −0.23, p < 0.001), and waist-to-hip-ratio (R = −0.21, p < 0.001) were found in men. No correlation was found with age in men; in women, the correlation was negligible (R = 0.04, p = 0.012). In men, low testosterone levels predicted high risk of type 2 diabetes, while in women this relationship was opposite. Men with low testosterone levels showed increased risk of future diabetes (hazard ratio (HR) 2.66, 95% confidence interval (CI) 1.91–3.72, p < 0.001 in basic model; HR 1.56 95%, CI 1.10–2.21, p = 0.003). In women, low testosterone levels indicated lower risk with (HR 0.53, 95% CI 0.37–0.77, p = 0.003), while the association lost significance in the fully adjusted model (HR 0.72, 95% CI 0.49–1.05, p = 0.09). Low levels of testosterone predicted future diabetes in men. A borderline opposite association was found in women. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessArticle Novel DNA Methylation Sites Influence GPR15 Expression in Relation to Smoking
Biomolecules 2018, 8(3), 74; https://doi.org/10.3390/biom8030074
Received: 16 July 2018 / Revised: 6 August 2018 / Accepted: 9 August 2018 / Published: 20 August 2018
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Abstract
Smoking is a major risk factor for cardiovascular diseases and has been implicated in the regulation of the G protein-coupled receptor 15 (GPR15) by affecting CpG methylation. The G protein-coupled receptor 15 is involved in angiogenesis and inflammation. An effect on GPR15 gene [...] Read more.
Smoking is a major risk factor for cardiovascular diseases and has been implicated in the regulation of the G protein-coupled receptor 15 (GPR15) by affecting CpG methylation. The G protein-coupled receptor 15 is involved in angiogenesis and inflammation. An effect on GPR15 gene regulation has been shown for the CpG site CpG3.98251294. We aimed to analyze the effect of smoking on GPR15 expression and methylation sites spanning the GPR15 locus. DNA methylation of nine GPR15 CpG sites was measured in leukocytes from 1291 population-based individuals using the EpiTYPER. Monocytic GPR15 expression was measured by qPCR at baseline and five-years follow up. GPR15 gene expression was upregulated in smokers (beta (ß) = −2.699, p-value (p) = 1.02 × 10−77) and strongly correlated with smoking exposure (ß = −0.063, p = 2.95 × 10−34). Smoking cessation within five years reduced GPR15 expression about 19% (p = 9.65 × 10−5) with decreasing GPR15 expression over time (ß = 0.031, p = 3.81 × 10−6). Additionally, three novel CpG sites within GPR15 affected by smoking were identified. For CpG3.98251047, DNA methylation increased steadily after smoking cessation (ß = 0.123, p = 1.67 × 10−3) and strongly correlated with changes in GPR15 expression (ß = 0.036, p = 4.86 × 10−5). Three novel GPR15 CpG sites were identified in relation to smoking and GPR15 expression. Our results provide novel insights in the regulation of GPR15, which possibly linked smoking to inflammation and disease progression. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessArticle Intrinsic Iron Release Is Associated with Lower Mortality in Patients with Stable Coronary Artery Disease—First Report on the Prospective Relevance of Intrinsic Iron Release
Biomolecules 2018, 8(3), 72; https://doi.org/10.3390/biom8030072
Received: 9 July 2018 / Revised: 3 August 2018 / Accepted: 3 August 2018 / Published: 9 August 2018
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Abstract
Intrinsic iron release is discussed to have favorable effects in coronary artery disease (CAD). The aim of this study was to evaluate the prognostic relevance of intrinsic iron release in patients with CAD. Intrinsic iron release was based on a definition including hepcidin [...] Read more.
Intrinsic iron release is discussed to have favorable effects in coronary artery disease (CAD). The aim of this study was to evaluate the prognostic relevance of intrinsic iron release in patients with CAD. Intrinsic iron release was based on a definition including hepcidin and soluble transferrin receptor (sTfR). In a cohort of 811 patients with angiographically documented CAD levels of hepcidin and sTfR were measured at baseline. Systemic body iron release was defined as low levels of hepcidin (<24 ng/mL) and high levels of sTfR (≥2 mg/L). A commercially available ELISA (DRG) was used for measurements of serum hepcidin. Serum sTfR was determined by using an automated immunoassay (). Cardiovascular mortality was the main outcome measure. The criteria of intrinsic iron release were fulfilled in 32.6% of all patients. Significantly lower cardiovascular mortality rates were observed in CAD patients with systemic iron release. After adjustment for body mass index, smoking status, hypertension, diabetes, dyslipidemia, sex, and age, the hazard ratio for future cardiovascular death was 0.41. After an additional adjustment for surrogates of the size of myocardial necrosis (troponin I), anemia (hemoglobin), and cardiac function and heart failure severity (N-terminal pro B-type natriuretic peptide), this association did not change (Hazard ratio 0.37 (95% confidence interval 0.14–0.99), p = 0.047). In conclusion, significantly lower cardiovascular mortality rates were observed in CAD patients with intrinsic iron release shown during follow-up. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
Open AccessArticle Low-Circulating Homoarginine is Associated with Dilatation and Decreased Function of the Left Ventricle in the General Population
Biomolecules 2018, 8(3), 63; https://doi.org/10.3390/biom8030063
Received: 1 June 2018 / Revised: 10 July 2018 / Accepted: 19 July 2018 / Published: 30 July 2018
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Abstract
Low homoarginine is an independent marker of mortality in heart failure patients and incident cardiovascular events. Whether homoarginine is related with healthier cardiac structure and function is currently unclear. We used data of the population-based “Study of Health in Pomerania” (SHIP-Trend) to assess [...] Read more.
Low homoarginine is an independent marker of mortality in heart failure patients and incident cardiovascular events. Whether homoarginine is related with healthier cardiac structure and function is currently unclear. We used data of the population-based “Study of Health in Pomerania” (SHIP-Trend) to assess this relation. Homoarginine was measured in serum using liquid chromatography-tandem mass spectrometry. Linear regression models assessed the relation between homoarginine and several structural as well as functional parameters and N-terminal pro B-type natriuretic peptide (NTproBNP). All models were adjusted for age, sex, body mass index, and renal function. A total of 3113 subjects (median age 48 (25th percentile 37 to 75th percentile 60) years, 46% male) were included. A standard deviation decrease in homoarginine was associated with a larger left ventricular diastolic diameter (0.3; 95%-confidence interval (CI): 0.2 to 0.5 mm; p < 0.001), left ventricular systolic diameter (0.38; 95%-CI: −0.22 to 0.54 mm; p < 0.001) as well as a less relative wall thickness (–0.003 95%-CI: −0.006 to −0.0008; p = 0.01), left ventricular ejection fraction (–0.47; 95%-CI: –0.79 to −0.15%; p < 0.01) and fractional shortening (−0.35; 95%-CI: −0.62 to 0.07%; p = 0.01). Low homoarginine was also related to higher NTproBNP (−0.02 95%-CI: −0.034 to −0.009 log pg/mL; p < 0.01). Lower serum homoarginine is associated with dilatation of the heart and decreased function. Prospective clinical studies should assess if homoarginine supplementation improves cardiac health in subjects with low serum concentrations. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessArticle Adverse Outcome Prediction of Iron Deficiency in Patients with Acute Coronary Syndrome
Biomolecules 2018, 8(3), 60; https://doi.org/10.3390/biom8030060
Received: 8 June 2018 / Revised: 9 July 2018 / Accepted: 16 July 2018 / Published: 20 July 2018
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Abstract
Acute myocardial infarction remains a leading cause of morbidity and mortality. While iron deficient heart failure patients are at increased risk of future cardiovascular events and see improvement with intravenous supplementation, the clinical relevance of iron deficiency in acute coronary syndrome remains unclear. [...] Read more.
Acute myocardial infarction remains a leading cause of morbidity and mortality. While iron deficient heart failure patients are at increased risk of future cardiovascular events and see improvement with intravenous supplementation, the clinical relevance of iron deficiency in acute coronary syndrome remains unclear. We aimed to evaluate the prognostic value of iron deficiency in the acute coronary syndrome (ACS). Levels of ferritin, iron, and transferrin were measured at baseline in 836 patients with ACS. A total of 29.1% was categorized as iron deficient. The prevalence of iron deficiency was clearly higher in women (42.8%), and in patients with anemia (42.5%). During a median follow-up of 4.0 years, 111 subjects (13.3%) experienced non-fatal myocardial infarction (MI) and cardiovascular mortality as combined endpoint. Iron deficiency strongly predicted non-fatal MI and cardiovascular mortality with a hazard ratio (HR) of 1.52 (95% confidence interval (CI) 1.03-2.26; p = 0.037) adjusted for age, sex, hypertension, smoking status, diabetes, hyperlipidemia, body-mass-index (BMI) This association remained significant (HR 1.73 (95% CI 1.07–2.81; p = 0.026)) after an additional adjustment for surrogates of cardiac function and heart failure severity (N-terminal pro B-type natriuretic peptide, NT-proBNP), for the size of myocardial necrosis (troponin), and for anemia (hemoglobin). Survival analyses for cardiovascular mortality and MI provided further evidence for the prognostic relevance of iron deficiency (HR 1.50 (95% CI 1.02–2.20)). Our data showed that iron deficiency is strongly associated with adverse outcome in acute coronary syndrome. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessCommunication A Novel Class of tRNA-Derived Small Non-Coding RNAs Respond to Myocardial Hypertrophy and Contribute to Intergenerational Inheritance
Biomolecules 2018, 8(3), 54; https://doi.org/10.3390/biom8030054
Received: 14 April 2018 / Revised: 12 June 2018 / Accepted: 9 July 2018 / Published: 16 July 2018
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Abstract
tRNA-derived fragments (tRFs) are a new class of non-coding RNA that play an important role in regulating cellular RNA processing and protein translation. However, there is currently no study reporting the influence of tRFs on myocardial hypertrophy. In this study, we used an [...] Read more.
tRNA-derived fragments (tRFs) are a new class of non-coding RNA that play an important role in regulating cellular RNA processing and protein translation. However, there is currently no study reporting the influence of tRFs on myocardial hypertrophy. In this study, we used an isoproterenol (ISO)-induced myocardial hypertrophy rat model. Small RNA (<40 nts) transcriptome sequencing was used to select differentially expressed tRFs. We also compared the tRFs expression pattern in F0 sperm and the hearts of F1 offspring between the myocardial hypertrophy group (Hyp) and the control group (Con). Isoproterenol successfully induced a typical cardiac hypertrophy model in our study. Small RNA-seq revealed that tRFs were extremely enriched (84%) in the Hyp heart. Overexpression of tRFs1 and tRFs2 both enlarged the surface area of cardiac cells and increased expression of hypertrophic markers (ANF, BNP, and β-MHC). Luciferase reporter assay identified that tRFs1 directly target 3′UTR of Timp3. tRFs1, tRFs2, tRFs3, and tRFs4 were also highly expressed in Hyp F0 sperm and in Hyp F1 offspring hearts, but there was no differential expression of tRFs7, tRFs9, and tRFs10. Compared to Con F1 offspring, Hyp F1 offspring had elevated expression levels of β-MHC and ANP genes, and they had increased fibrosis and apoptosis in their hearts. These results demonstrated that tRFs are involved in regulating the response of myocardial hypertrophy. Besides, tRFs might serve as novel epigenetic factors that contribute to the intergenerational inheritance of cardiac hypertrophy. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessArticle Prognostic Value of Iron-Homeostasis Regulating Peptide Hepcidin in Coronary Heart Disease—Evidence from the Large AtheroGene Study
Biomolecules 2018, 8(3), 43; https://doi.org/10.3390/biom8030043
Received: 8 June 2018 / Revised: 25 June 2018 / Accepted: 26 June 2018 / Published: 28 June 2018
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Abstract
Iron is essential in terms of oxygen utilization and mitochondrial function. The liver-derived peptide hepcidin has been recognized as a key regulator of iron homeostasis. Since iron metabolism is crucially linked to cardiovascular health, and low hepcidin was proposed as potential new marker [...] Read more.
Iron is essential in terms of oxygen utilization and mitochondrial function. The liver-derived peptide hepcidin has been recognized as a key regulator of iron homeostasis. Since iron metabolism is crucially linked to cardiovascular health, and low hepcidin was proposed as potential new marker of iron metabolism, we aimed to evaluate the prognostic value of hepcidin in a large cohort of patients with coronary heart disease (CHD). Serum levels of hepcidin were determined at baseline in patients with angiographically documented CHD. The main outcome measure was non-fatal myocardial infarction (MI) or cardiovascular death. During a median follow-up of 4.1 years, 10.3% experienced an endpoint. In Cox regression analyses for hepcidin the hazard ratio for future cardiovascular death or MI was 1.03 (95% confidence interval (CI) 0.91–1.18, p = 0.63) after adjustment for sex and age. This association virtually did not change after additional adjustment for body mass index (BMI), smoking status, hypertension, diabetes, dyslipidemia, and surrogates of cardiac function (NT-proBNP), size of myocardial necrosis (troponin I), and anemia (hemoglobin). In this study, by far the largest evaluating the predictive value of hepcidin, hepcidin levels were not associated with future MI or cardiovascular death. This implicates a limited, if any, role for hepcidin in secondary cardiovascular risk prediction. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Review

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Open AccessReview Overview of Bile Acids Signaling and Perspective on the Signal of Ursodeoxycholic Acid, the Most Hydrophilic Bile Acid, in the Heart
Biomolecules 2018, 8(4), 159; https://doi.org/10.3390/biom8040159
Received: 11 October 2018 / Revised: 15 November 2018 / Accepted: 15 November 2018 / Published: 27 November 2018
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Abstract
Bile acids (BA) are classically known as an important agent in lipid absorption and cholesterol metabolism. Nowadays, their role in glucose regulation and energy homeostasis are widely reported. BAs are involved in various cellular signaling pathways, such as protein kinase cascades, cyclic AMP [...] Read more.
Bile acids (BA) are classically known as an important agent in lipid absorption and cholesterol metabolism. Nowadays, their role in glucose regulation and energy homeostasis are widely reported. BAs are involved in various cellular signaling pathways, such as protein kinase cascades, cyclic AMP (cAMP) synthesis, and calcium mobilization. They are ligands for several nuclear hormone receptors, including farnesoid X-receptor (FXR). Recently, BAs have been shown to bind to muscarinic receptor and Takeda G-protein-coupled receptor 5 (TGR5), both G-protein-coupled receptor (GPCR), independent of the nuclear hormone receptors. Moreover, BA signals have also been elucidated in other nonclassical BA pathways, such as sphingosine-1-posphate and BK (large conductance calcium- and voltage activated potassium) channels. Hydrophobic BAs have been proven to affect heart rate and its contraction. Elevated BAs are associated with arrhythmias in adults and fetal heart, and altered ratios of primary and secondary bile acid are reported in chronic heart failure patients. Meanwhile, in patients with liver cirrhosis, cardiac dysfunction has been strongly linked to the increase in serum bile acid concentrations. In contrast, the most hydrophilic BA, known as ursodeoxycholic acid (UDCA), has been found to be beneficial in improving peripheral blood flow in chronic heart failure patients and in protecting the heart against reperfusion injury. This review provides an overview of BA signaling, with the main emphasis on past and present perspectives on UDCA signals in the heart. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessReview Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease
Biomolecules 2018, 8(3), 96; https://doi.org/10.3390/biom8030096
Received: 3 August 2018 / Revised: 10 September 2018 / Accepted: 12 September 2018 / Published: 18 September 2018
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Abstract
The mineralocorticoid receptor (MR) was first identified as a blood pressure regulator, modulating renal sodium handling in response to its principal ligand aldosterone. The mineralocorticoid receptor is also expressed in many tissues other than the kidney, such as adipose tissue, heart and vasculature. [...] Read more.
The mineralocorticoid receptor (MR) was first identified as a blood pressure regulator, modulating renal sodium handling in response to its principal ligand aldosterone. The mineralocorticoid receptor is also expressed in many tissues other than the kidney, such as adipose tissue, heart and vasculature. Recent studies have shown that MR plays a relevant role in the control of cardiovascular and metabolic function, as well as in adipogenesis. Dysregulation of aldosterone/MR signaling represents an important cause of disease as high plasma levels of aldosterone are associated with hypertension, obesity and increased cardiovascular risk. Aldosterone displays powerful vascular effects and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Mineralocorticoid receptor activation regulates genes involved in vascular and cardiac fibrosis, calcification and inflammation. This review focuses on the role of novel potential biomarkers related to aldosterone/MR system that could help identify cardiovascular and metabolic detrimental conditions, as a result of altered MR activation. Specifically, we discuss: (1) how MR signaling regulates the number and function of different subpopulations of circulating and intra-tissue immune cells; (2) the role of aldosterone/MR system in mediating cardiometabolic diseases induced by obesity; and (3) the role of several MR downstream molecules as novel potential biomarkers of cardiometabolic diseases, end-organ damage and rehabilitation outcome. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessReview Potential Impact of Oral Inflammations on Cardiac Functions and Atrial Fibrillation
Biomolecules 2018, 8(3), 66; https://doi.org/10.3390/biom8030066
Received: 21 June 2018 / Revised: 14 July 2018 / Accepted: 26 July 2018 / Published: 1 August 2018
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Abstract
Inflammation may be a risk factor for atrial fibrillation (AF). Oral infections frequently lead to chronic inflammation, such as gingivitis, periodontitis, and endodontic lesions. In this narrative review, we consider five basic pathogenic mechanisms that involve oral infections and inflammations in the pathogenesis [...] Read more.
Inflammation may be a risk factor for atrial fibrillation (AF). Oral infections frequently lead to chronic inflammation, such as gingivitis, periodontitis, and endodontic lesions. In this narrative review, we consider five basic pathogenic mechanisms that involve oral infections and inflammations in the pathogenesis of AF: (1) low level bacteremia by which oral bacteria enter the blood stream at inflamed sites of the oral cavity and invade the heart; (2) Systemic inflammation induced by inflammatory mediators, which are released from the sites of oral inflammation into the blood stream, affecting cardiac remodeling; (3) autoimmunity against molecular structures expressed in the heart caused by the host immune response to specific components of oral pathogens; (4) potentially arrhythmic effects mediated by activation of the autonomous nervous system triggered by oral inflammations; and (5) arrhythmic effects resulting from specific bacterial toxins that are produced by oral pathogenic bacteria. A number of studies support the involvement of all five mechanisms, suggesting a potentially complex contribution of oral inflammations to the pathogenesis of AF. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessFeature PaperReview Novel Approaches for BAV Aortopathy Prediction—Is There a Need for Cohort Studies and Biomarkers?
Biomolecules 2018, 8(3), 58; https://doi.org/10.3390/biom8030058
Received: 30 May 2018 / Revised: 9 July 2018 / Accepted: 13 July 2018 / Published: 19 July 2018
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Abstract
Bicuspid aortic valve (BAV) disease is the most common congenital malformation of the human heart with a prevalence of 1–2% in the general population. More than half of patients with a BAV present with a dilated proximal aorta (so-called bicuspid aortopathy) which is [...] Read more.
Bicuspid aortic valve (BAV) disease is the most common congenital malformation of the human heart with a prevalence of 1–2% in the general population. More than half of patients with a BAV present with a dilated proximal aorta (so-called bicuspid aortopathy) which is associated with an enhanced risk of life-threatening aortic complications. Up to now, the pathogenesis of bicuspid aortopathy as well as the risk stratification of aortic complications has not yet been sufficiently clarified. Recent findings have shown that bicuspid aortopathy features phenotypic heterogeneity. Two distinct valvulo-aortic phenotypes, the so-called root phenotype, as well as a dilation of the tubular ascending aorta, coincide with a significantly different risk for aortal complications. However, the phenotype-based classification that is only based on these two clinical forms is not sufficient to estimate the risk of aortal complications in a prognostically relevant way. Therefore, there is growing clinical interest to assess novel approaches in BAV research and to introduce circulating biomarkers as an elegant diagnostic tool to improve risk stratification in BAV aortopathy. A large scale epidemiological cohort study, ranking from apparently healthy individuals to disease patients, and comprehensive biobanks provide the opportunity to study BAV disease and its complications and to identify novel biomarkers for BAV aortopathy surveillance and prognosis. Firstly, the data indicate that several protein-based biomarkers and non-coding RNA molecules, in particular circulating microRNAs, can serve as relevant molecular biomarkers to predict the course of BAV-associated aortopathy. Here, we review the current literature and knowledge about BAV from a clinical point of view, and report about novel approaches in BAV biomarker research. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessFeature PaperReview Nontraditional Cardiovascular Biomarkers and Risk Factors: Rationale and Future Perspectives
Biomolecules 2018, 8(2), 40; https://doi.org/10.3390/biom8020040
Received: 15 May 2018 / Revised: 11 June 2018 / Accepted: 13 June 2018 / Published: 15 June 2018
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Abstract
The primary prevention of cardiovascular (CV) disease depends on the capacity to identify subjects at higher risk long before the occurrence of CV clinical manifestations. Traditional risk factors do not cover fully prediction of individual risk. Moreover, there is an area of gray [...] Read more.
The primary prevention of cardiovascular (CV) disease depends on the capacity to identify subjects at higher risk long before the occurrence of CV clinical manifestations. Traditional risk factors do not cover fully prediction of individual risk. Moreover, there is an area of gray for patients at intermediate CV risk, which offers wide margins of improvement. These observations highlight the need for new additive tools for a more accurate risk stratification. An increasing number of candidate biomarkers have been identified to predict CV risk and events, although they generally give only a moderate increase when added to currently available predictive scores. The approach utilizing a relative small number of biomarkers in multiple combinations, but only weakly related to each other or unrelated, thus belonging to independent-pathways, and so able to catch the multidimensional characteristic of atherosclerosis, appears promising. We discuss vitamin D and bone turnover biomarkers, hepatitis C virus, and psycho-emotional factors that may reflect alternative pathways over those generally considered for atherosclerosis (e.g., aspects directly related to inflammation and thrombosis). These new biomarkers could facilitate a more accurate assessment of CV risk stratification if incorporated in the current risk assessment algorithms. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)

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Open AccessErratum Erratum: Traghella, I.; et al. Nontraditional Cardiovascular Biomarkers and Risk Factors: Rationale and Future Perspectives. Biomolecules 2018, 8, 40
Biomolecules 2018, 8(4), 168; https://doi.org/10.3390/biom8040168
Received: 28 November 2018 / Accepted: 28 November 2018 / Published: 10 December 2018
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Abstract
The authors wish to make the following change in their paper [...] Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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