Special Issue "Cardiovascular Disease: New Generation of Biomarkers and Future Therapeutic Concepts"

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

Deadline for manuscript submissions: 31 August 2020.

Special Issue Editors

Dr. David de Gonzalo-Calvo
Website
Guest Editor
1. Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain
2. Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
3. CIBERCV, Institute of Health Carlos III, Madrid, Spain
Interests: biomarker; cardiometabolic disease; cardiovascular disease; exercise; noncoding RNA; precision medicine
Dr. Christian Bär
Website
Co-Guest Editor
1. Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
2. REBIRTH Excellence Cluster, Hannover Medical School, Hannover, Germany
Interests: cardiovascular disease; cardiac regeneration; noncoding RNA therapy; telomere biology; aging

Special Issue Information

Dear Colleagues,

Despite the great advances in the management of cardiovascular disease, this condition persists as the most common noncommunicable disease and the leading cause of death worldwide. There is an urgent need to improve the clinical management of cardiovascular disease with regard to novel treatment concepts as well as the identification of new biomarkers. In this Special Issue, we will provide a comprehensive overview of the recent developments in cardiovascular disease, from novel tools to guide clinical decision-making, to promising next-generation therapeutic approaches.

We welcome the submission of original research and review articles on the following topics:

  1. Novel molecular mechanisms implicated in cardiovascular disease development;
  2. Recent advances in drug targets and therapeutic approaches;
  3. New biomarkers for diagnosis, prognosis and risk stratification;
  4. Prediction and monitorization of the therapeutic response;
  5. Drug repositioning;
  6. Alternative use of established clinical indicators;
  7. Advances in cardiovascular personalized medicine.

We encourage authors to include a section indicating the impact of the novel findings on the clinical management of the cardiovascular patient.

Dr. David de Gonzalo-Calvo
Dr. Christian Bär
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Biomarkers
  • Biomarker-guided therapy
  • Biomarker development and validation
  • Cardiac aging
  • Cardiac regeneration
  • Cardiovascular disease
  • Cardiovascular therapy
  • Diagnosis
  • Drug repositioning
  • Risk stratification

Published Papers (8 papers)

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Research

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Open AccessArticle
Upstroke Time Per Cardiac Cycle as A Novel Parameter for Mortality Prediction in Patients with Acute Myocardial Infarction
J. Clin. Med. 2020, 9(4), 904; https://doi.org/10.3390/jcm9040904 (registering DOI) - 25 Mar 2020
Abstract
Background: Acute myocardial infarction (AMI) is one of the leading causes of death in the world. How to simply predict mortality for AMI patients is important because the appropriate treatment should be done for the patients with higher risk. Recently, a novel parameter [...] Read more.
Background: Acute myocardial infarction (AMI) is one of the leading causes of death in the world. How to simply predict mortality for AMI patients is important because the appropriate treatment should be done for the patients with higher risk. Recently, a novel parameter of upstroke time per cardiac cycle (UTCC) in lower extremities was reported to be a good predictor of peripheral artery disease and mortality in elderly. However, there was no literature discussing the usefulness of UTCC for prediction of cardiovascular (CV) and overall mortality in AMI patients. Methods: 184 AMI patients admitted to the cardiac care unit were enrolled. Ankle-brachial index (ABI) and UTCC were measured by an ABI-form device in the same day of admission. Results: The median follow-up to mortality was 71 months. There were 36 CV and 124 overall mortality. Higher UTCC was associated with increased CV and overall mortality after multivariable analysis (P = 0.033 and P < 0.001, respectively). However, ABI was only associated with CV mortality and overall mortality in the univariable analysis but became insignificant after the multivariable analysis. In addition, after adding UTCC into a basic model including important clinical parameters, left ventricular ejection fraction, Charlson comorbidity index, and ABI, we found the basic model + UTCC had a better predictive value for overall mortality than the basic model itself (P < 0.001). Conclusions: Our study is the first one to evaluate the usefulness of UTCC in AMI patients for prediction of long-term mortality. Our study showed UTCC was an independent predictor of long-term CV and overall mortality and had an additive predictive value for overall mortality beyond conventional parameters. Therefore, screening AMI patients by UTCC might help physicians to identify the high-risk group with increased mortality. Full article
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Open AccessArticle
A Case-Control Study of Salivary Redox Homeostasis in Hypertensive Children. Can Salivary Uric Acid be a Marker of Hypertension?
J. Clin. Med. 2020, 9(3), 837; https://doi.org/10.3390/jcm9030837 (registering DOI) - 19 Mar 2020
Abstract
Oxidative stress plays a critical role in the pathogenesis of hypertension; however, there are no data on salivary redox homeostasis and salivary gland function in children with hypertension. A total of 53 children with hypertension and age- and sex-matched controls were classified for [...] Read more.
Oxidative stress plays a critical role in the pathogenesis of hypertension; however, there are no data on salivary redox homeostasis and salivary gland function in children with hypertension. A total of 53 children with hypertension and age- and sex-matched controls were classified for the study. The antioxidant barrier and oxidative/nitrosative stress were evaluated in non-stimulated (NWS) and stimulated (SWS) whole saliva, plasma, and erythrocytes, with Student’s t-test and Mann–Whitney U-test used for statistical analysis. We demonstrated that the activities of superoxide dismutase, catalase, and peroxidase were significantly higher in NWS, SWS, and erythrocytes of children with hypertension, similar to oxidative damage in proteins (advanced glycation end products) and lipids (malondialdehyde) as well as nitrosative stress markers (peroxynitrite and nitrotyrosine). The level of uric acid (UA) was significantly higher in NWS, SWS, and plasma of children with hypertension. UA concentration in SWS correlated positively with systolic and diastolic blood pressure and UA content in plasma. This parameter differentiates children with hypertension from healthy controls (AUC = 0.98) with a high degree of sensitivity (94%) and specificity (94%). Stimulated salivary flow was significantly lower in the hypertension group, similar to total protein content and salivary amylase activity. In summary, childhood hypertension is associated with hyposalivation as well as disturbances in antioxidant defense and enhanced oxidative/nitrosative damage both in the plasma/erythrocytes as well as saliva. Salivary UA may be a potential biomarker of hypertension in children. Full article
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Open AccessArticle
Modulation of SERCA in Patients with Persistent Atrial Fibrillation Treated by Epicardial Thoracoscopic Ablation: The CAMAF Study
J. Clin. Med. 2020, 9(2), 544; https://doi.org/10.3390/jcm9020544 - 17 Feb 2020
Abstract
Objectives: To evaluate atrial fibrillation (AF) recurrence and Sarcoplasmic Endoplasmic Reticulum Calcium ATPase (SERCA) levels in patients treated by epicardial thoracoscopic ablation for persistent AF. Background: Reduced levels of SERCA have been reported in the peripheral blood cells of patients with AF. We [...] Read more.
Objectives: To evaluate atrial fibrillation (AF) recurrence and Sarcoplasmic Endoplasmic Reticulum Calcium ATPase (SERCA) levels in patients treated by epicardial thoracoscopic ablation for persistent AF. Background: Reduced levels of SERCA have been reported in the peripheral blood cells of patients with AF. We hypothesize that SERCA levels can predict the response to epicardial ablation. Methods: We designed a prospective, multicenter, observational study to recruit, from October 2014 to June 2016, patients with persistent AF receiving an epicardial thoracoscopic pulmonary vein isolation. Results: We enrolled 27 patients. Responders (n = 15) did not present AF recurrence after epicardial ablation at one-year follow-up; these patients displayed a marked remodeling of the left atrium, with a significant reduction of inflammatory cytokines, B type natriuretic peptide (BNP), and increased levels of SERCA compared to baseline and to nonresponders (p < 0.05). Furthermore, mean AF duration (Heart rate (HR) 1.235 (1.037–1.471), p < 0.05), Left atrium volume (LAV) (HR 1.755 (1.126–2.738), p < 0.05), BNP (HR 1.945 (1.895–1.999), p < 0.05), and SERCA (HR 1.763 (1.167–2.663), p < 0.05) were predictive of AF recurrence. Conclusions: Our data indicate for the first time that baseline values of SERCA in patients with persistent AF might be predictive of failure to epicardial ablative approach. Intriguingly, epicardial ablation was associated with increased levels of SERCA in responders. Therefore, SERCA might be an innovative therapeutic target to improve the response to epicardial ablative treatments. Full article
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Open AccessArticle
Soluble ST2 is a Useful Biomarker for Grading Cerebral–Cardiac Syndrome in Patients after Acute Ischemic Stroke
J. Clin. Med. 2020, 9(2), 489; https://doi.org/10.3390/jcm9020489 - 11 Feb 2020
Abstract
This study tested whether the soluble (s)ST2 is a superb biomarker predictive of moderate to severe cerebral–cardiac syndrome (CCS) (defined as coexisting National Institute of Health Stroke Scale (NIHSS) >8 and left-ventricular ejection fraction (LVEF) <60%) in patients after acute ischemic stroke (IS). [...] Read more.
This study tested whether the soluble (s)ST2 is a superb biomarker predictive of moderate to severe cerebral–cardiac syndrome (CCS) (defined as coexisting National Institute of Health Stroke Scale (NIHSS) >8 and left-ventricular ejection fraction (LVEF) <60%) in patients after acute ischemic stroke (IS). Between November 2015 and October 2017, a total of 99 IS patients were prospectively enrolled and categorized into three groups based on NIHSS, i.e., group 1 (NIHSS ≤ 8, n = 66), group 2 (NIHSS = 9-15, n = 14) and group 3 (NIHSS ≥ 16, n = 19), respectively. Blood samples were collected immediately after hospitalization, followed by transthoracic echocardiographic examination. The results showed that the flow cytometric analysis for assessment of inflammatory biomarkers of TLR2+/CD14+cells, TLR4+/CD14+cells, Ly6g+/CD14+cells, and MPO+/CD14+cells, and ELISA assessment for circulatory level of sST2 were significantly higher in groups 2/3 than in group 1 (all p < 0.01). However, these parameters did not show significant differences between groups 2 and 3 (all p > 0.05). The LVEF was significantly lower in group 3 than in group 1 (p < 0.001), but it displayed no difference between groups 1/2 or between groups 2/3. These inflammatory biomarkers ((TLR2+/CD14+cells// TLR4+/CD14+cells// MPO+/CD14+cells) and sST2)) were significantly positively correlated to NIHSS and strongly negatively correlated to LVEF (all p < 0.05). Multivariate analysis demonstrated that both MPO/CD14+cells >20% (p = 0.027) and sST2 ≥ 17,600 (p = 0.004) were significantly and independently predictive of moderate-severe CCS after acute IS. Receiver operating characteristic curve analysis demonstrated that sST2 was the most powerful predictor of CCS with a sensitivity of 0.929 and a specificity of 0.731 (p < 0.001). In conclusion, sST2 is a useful biomarker for prediction of CCS severity in patients after acute IS. Full article
Open AccessArticle
Does Chronic Kidney Disease Facilitate Malignant Myocardial Fibrosis in Heart Failure with Preserved Ejection Fraction of Hypertensive Origin?
J. Clin. Med. 2020, 9(2), 404; https://doi.org/10.3390/jcm9020404 - 03 Feb 2020
Abstract
In hypertensive patients with heart failure (HF) a serum biomarker combination of high carboxy-terminal propeptide of procollagen type-I (PICP) and low carboxy-terminal telopeptide of collagen type-I to matrix metalloproteinase-1 (CITP:MMP-1) ratio identifies a histomolecular phenotype of malignant myocardial fibrosis (mMF) associated with severe [...] Read more.
In hypertensive patients with heart failure (HF) a serum biomarker combination of high carboxy-terminal propeptide of procollagen type-I (PICP) and low carboxy-terminal telopeptide of collagen type-I to matrix metalloproteinase-1 (CITP:MMP-1) ratio identifies a histomolecular phenotype of malignant myocardial fibrosis (mMF) associated with severe diastolic dysfunction (DD) and poor outcomes. As chronic kidney disease (CKD) facilitates MF and DD, we investigated the influence of CKD on the mMF biomarker combination in HF patients with preserved ejection fraction (HFpEF). Hypertensives (n = 365), 232 non-HF and 133 HFpEF, were studied, and 35% non-HF and 46% HFpEF patients had CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2 or urine albumin-to-creatinine ratio ≥ 30 mg/g). Specific immunoassays were performed to determine biomarkers. Medians were used to establish the high PICP and low CITP:MMP-1 combination. A comparison with non-HF showed that the biomarker combination presence was increased in HFpEF patients, being associated with CKD in all patients. CKD influenced the association of the biomarker combination and HFpEF (p for interaction ≤ 0.019). The E:e’ ratio was associated with the biomarker combination in CKD patients. Among CKD patients with HFpEF, those with the biomarker combination exhibited higher (p = 0.016) E:e’ ratio than those without the pattern. These findings suggest that CKD facilitates the development of biomarker-assessed mMF and DD in hypertensive HFpEF patients. Full article
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Open AccessArticle
Circulating PCSK9 Level and Risk of Cardiovascular Events and Death in Hemodialysis Patients
J. Clin. Med. 2020, 9(1), 244; https://doi.org/10.3390/jcm9010244 - 17 Jan 2020
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for the prevention of cardiovascular (CV) events. However, the clinical significance of circulating PCSK9 is unclear in hemodialysis (HD) patients. A total of 353 HD patients were prospectively enrolled from June 2016 [...] Read more.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for the prevention of cardiovascular (CV) events. However, the clinical significance of circulating PCSK9 is unclear in hemodialysis (HD) patients. A total of 353 HD patients were prospectively enrolled from June 2016 to August 2019 in a K-cohort. Plasma PCSK9 level was measured at the time of study enrollment. The primary endpoint was defined as a composite of CV event and death. Plasma PCSK9 level was positively correlated with total cholesterol level in patients with statin treatment. Multivariate linear regression analysis revealed that baseline serum glucose, albumin, total cholesterol, and statin treatment were independent determinants of circulating PCSK9 levels. Cumulative rates of composite and CV events were significantly higher in patients with tertile 3 PCSK9 (p = 0.017 and p = 0.010, respectively). In multivariate Cox-regression analysis, PCSK9 tertile 3 was associated with a 1.97-fold risk of composite events (95% CI, 1.13–3.45), and it was associated with a 2.31-fold risk of CV events (95% CI, 1.17–4.59). In conclusion, a higher circulating PCSK9 level was independently associated with incident CV events and death in HD patients. These results suggest the importance of future studies regarding the effect of PCSK9 inhibition. Full article
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Open AccessArticle
IgG Anti-High Density Lipoprotein Antibodies Are Elevated in Abdominal Aortic Aneurysm and Associated with Lipid Profile and Clinical Features
J. Clin. Med. 2020, 9(1), 67; https://doi.org/10.3390/jcm9010067 - 26 Dec 2019
Abstract
High-density lipoproteins cholesterol (HDLc) levels are decreased in abdominal aortic aneurysm (AAA), which is hallmarked by autoimmunity and lipid aortic deposits. To investigate whether IgG anti-HDL antibodies were present in AAA and their potential association with clinical features, IgG anti-HDL and total IgG [...] Read more.
High-density lipoproteins cholesterol (HDLc) levels are decreased in abdominal aortic aneurysm (AAA), which is hallmarked by autoimmunity and lipid aortic deposits. To investigate whether IgG anti-HDL antibodies were present in AAA and their potential association with clinical features, IgG anti-HDL and total IgG along with HDLc plasma levels were measured in 488 AAA patients and 184 controls from the Viborg Vascular (VIVA) study, and in tissue-conditioned media from AAA intraluminal thrombus and media layer samples compared to control aortas. Higher IgG anti-HDL levels were found in AAA compared to controls, even after correcting for total IgG, and after adjusting for potential confounders. IgG anti-HDL levels were correlated with aortic diameter in univariate and adjusted multivariate analyses. IgG anti-HDL antibodies were negatively associated with HDLc levels before and after correcting for potential confounders. Increased anti-HDL antibodies were identified in tissue-conditioned media from AAA samples compared to healthy aortas, with higher levels being observed in the media layer. In conclusion, increased IgG anti-HDL levels (both in plasma and in tissue) are linked to AAA, associated with aortic diameter and HDLc levels. These data suggest a potential immune response against HDL in AAA and support an emerging role of anti-HDL antibodies in AAA. Full article
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Review

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Open AccessReview
Title: Human Serum/Plasma Glycoprotein Analysis by 1H-NMR, an Emerging Method of Inflammatory Assessment
J. Clin. Med. 2020, 9(2), 354; https://doi.org/10.3390/jcm9020354 - 27 Jan 2020
Abstract
Several studies suggest that variations in the concentration of plasma glycoproteins can influence cellular changes in a large number of diseases. In recent years, proton nuclear magnetic resonance (1H-NMR) has played a major role as an analytical tool for serum and [...] Read more.
Several studies suggest that variations in the concentration of plasma glycoproteins can influence cellular changes in a large number of diseases. In recent years, proton nuclear magnetic resonance (1H-NMR) has played a major role as an analytical tool for serum and plasma samples. In recent years, there is an increasing interest in the characterization of glycoproteins through 1H-NMR in order to search for reliable and robust biomarkers of disease. The objective of this review was to examine the existing studies in the literature related to the study of glycoproteins from an analytical and clinical point of view. There are currently several techniques to characterize circulating glycoproteins in serum or plasma, but in this review, we focus on 1H-NMR due to its great robustness and recent interest in its translation to the clinical setting. In fact, there is already a marker in H-NMR representing the acetyl groups of the glycoproteins, GlycA, which has been increasingly studied in clinical studies. A broad search of the literature was performed showing a general consensus that GlycA is a robust marker of systemic inflammation. The results also suggested that GlycA better captures systemic inflammation even more than C-reactive protein (CRP), a widely used classical inflammatory marker. The applications reviewed here demonstrated that GlycA was potentially a key biomarker in a wide range of diseases such as cancer, metabolic diseases, cardiovascular risk, and chronic inflammatory diseases among others. The profiling of glycoproteins through 1H-NMR launches an encouraging new paradigm for its future incorporation in clinical diagnosis. Full article
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