Journal of Clinical Medicine

Editorial

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4 pages, 165 KiB

Open AccessEditorial

Assessment of Cardiac Remodeling—A Chance for Novel Cardiac Biomarkers?

by Peter Jirak, Moritz Mirna, Bernhard Wernly, Vera Paar, Uta C. Hoppe and Michael Lichtenauer

J. Clin. Med. 2020, 9(7), 2087; https://doi.org/10.3390/jcm9072087 - 3 Jul 2020

Cited by 4 | Viewed by 1964

Abstract

Biomarkers are defined as “cellular, biochemical or molecular alterations that are measurable in biological media such as human tissues, cells, or fluids”, providing “biological characteristics that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological [...] Read more.

Biomarkers are defined as “cellular, biochemical or molecular alterations that are measurable in biological media such as human tissues, cells, or fluids”, providing “biological characteristics that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention “according to Hulka et al [...] Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

Research

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12 pages, 889 KiB

Open AccessArticle

Expression of the Novel Cardiac Biomarkers sST2, GDF-15, suPAR, and H-FABP in HFpEF Patients Compared to ICM, DCM, and Controls

by Peter Jirak, Rudin Pistulli, Michael Lichtenauer, Bernhard Wernly, Vera Paar, Lukas J. Motloch, Richard Rezar, Christian Jung, Uta C. Hoppe, P. Christian Schulze, Daniel Kretzschmar, Rüdiger C. Braun-Dullaeus and Tarek Bekfani

J. Clin. Med. 2020, 9(4), 1130; https://doi.org/10.3390/jcm9041130 - 15 Apr 2020

Cited by 20 | Viewed by 4168

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) remains an ongoing therapeutic and diagnostic challenge to date. In this study we aimed for an analysis of the diagnostic potential of four novel cardiovascular biomarkers, GDF-15, H-FABP, sST2, and suPAR in HFpEF patients compared [...] Read more.

Background: Heart failure with preserved ejection fraction (HFpEF) remains an ongoing therapeutic and diagnostic challenge to date. In this study we aimed for an analysis of the diagnostic potential of four novel cardiovascular biomarkers, GDF-15, H-FABP, sST2, and suPAR in HFpEF patients compared to controls as well as ICM, and DCM. Methods: In total, we included 252 stable outpatients and controls (77 DCM, 62 ICM, 18 HFpEF, and 95 controls) in the present study. All patients were in a non-decompensated state and on a stable treatment regimen. Serum samples were obtained and analyzed for GDF-15 (inflammation, remodeling), H-FABP (ischemia and subclinical ischemia), sST2 (inflammation, remodeling) and suPAR (inflammation, remodeling) by means of ELISA. Results: A significant elevation of GDF-15 was found for all heart failure entities compared to controls (p < 0.005). Similarly, H-FABP evidenced a significant elevation in all heart failure entities compared to the control group (p < 0.0001). Levels of sST2 were significantly elevated in ICM and DCM patients compared to the control group and HFpEF patients (p < 0.0001). Regarding suPAR, a significant elevation in ICM and DCM patients compared to the control group (p < 0.0001) and HFpEF patients (p < 0.01) was observed. An AUC analysis identified H-FABP (0.792, 95% CI 0.713–0.870) and GDF-15 (0.787, 95% CI 0.696–0.878) as paramount diagnostic biomarkers for HFpEF patients. Conclusion: Based on their differences in secretion patterns, novel cardiovascular biomarkers might represent a promising diagnostic tool for HFpEF in the future. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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10 pages, 833 KiB

Open AccessArticle

Diagnosis of Non-Alcoholic Fatty Liver Disease (NAFLD) Is Independently Associated with Cardiovascular Risk in a Large Austrian Screening Cohort

by David Niederseer, Sarah Wernly, Sebastian Bachmayer, Bernhard Wernly, Adam Bakula, Ursula Huber-Schönauer, Georg Semmler, Christian Schmied, Elmar Aigner and Christian Datz

J. Clin. Med. 2020, 9(4), 1065; https://doi.org/10.3390/jcm9041065 - 9 Apr 2020

Cited by 24 | Viewed by 3675

Abstract

Background: Many patients with non-alcoholic fatty liver disease (NAFLD) simultaneously suffer from cardiovascular (CV) disease and often carry multiple CV risk factors. Several CV risk factors are known to drive the progression of fibrosis in patients with NAFLD. Objectives: To investigate whether an [...] Read more.

Background: Many patients with non-alcoholic fatty liver disease (NAFLD) simultaneously suffer from cardiovascular (CV) disease and often carry multiple CV risk factors. Several CV risk factors are known to drive the progression of fibrosis in patients with NAFLD. Objectives: To investigate whether an established CV risk score, the Framingham risk score (FRS), is associated with the diagnosis of NAFLD and the degree of fibrosis in an Austrian screening cohort for colorectal cancer. Material and Methods: In total, 1965 asymptomatic subjects (59 ± 10 years, 52% females, BMI 27.2 ± 4.9 kg/m²) were included in this study. The diagnosis of NAFLD was present if (1) significantly increased echogenicity in relation to the renal parenchyma was present in ultrasound and (2) viral, autoimmune or hereditary liver disease and excess alcohol consumption were excluded. The FRS (ten-year risk of coronary heart disease) and NAFLD Fibrosis Score (NFS) were calculated for all patients. High CV risk was defined as the highest FRS quartile (>10%). Both univariable and multivariable logistic regression models were used to calculate associations of FRS with NAFLD and NFS. Results: Compared to patients without NAFLD (n = 990), patients with NAFLD (n = 975) were older (60 ± 9 vs. 58 ± 10 years; p < 0.001), had higher BMI (29.6 ± 4.9 vs. 24.9 ± 3.6 kg/m²; p < 0.001) and suffered from metabolic syndrome more frequently (33% vs. 7%; p < 0.001). Cardiovascular risk as assessed by FRS was higher in the NAFLD-group (8.7 ± 6.4 vs. 5.4 ± 5.2%; p < 0.001). A one-percentage-point increase of FRS was independently associated with NAFLD (OR 1.04, 95%CI 1.02–1.07; p < 0.001) after correction for relevant confounders in multivariable logistic regression. In patients with NAFLD, NFS correlated with FRS (r = 0.29; p < 0.001), and FRS was highest in patients with significant fibrosis (F3-4; 11.7 ± 5.4) compared to patients with intermediate results (10.9 ± 6.3) and those in which advanced fibrosis could be ruled-out (F0-2, 7.8 ± 5.9, p < 0.001). A one-point-increase of NFS was an independent predictor of high-risk FRS after correction for sex, age, and concomitant diagnosis of metabolic syndrome (OR 1.30, 95%CI 1.09–1.54; p = 0.003). Conclusion: The presence of NAFLD might independently improve prediction of long-term risk for CV disease and the diagnosis of NAFLD might be a clinically relevant piece in the puzzle of predicting long-term CV outcomes. Due to the significant overlap of advanced NAFLD and high CV risk, aggressive treatment of established CV risk factors could improve prognosis in these patients. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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20 pages, 2421 KiB

Open AccessArticle

Circulating miR-320a as a Predictive Biomarker for Left Ventricular Remodelling in STEMI Patients Undergoing Primary Percutaneous Coronary Intervention

by Isabel Galeano-Otero, Raquel Del Toro, Agustín Guisado, Ignacio Díaz, Isabel Mayoral-González, Francisco Guerrero-Márquez, Encarnación Gutiérrez-Carretero, Sara Casquero-Domínguez, Luis Díaz-de la Llera, Gonzalo Barón-Esquivias, Manuel Jiménez-Navarro, Tarik Smani and Antonio Ordóñez-Fernández

J. Clin. Med. 2020, 9(4), 1051; https://doi.org/10.3390/jcm9041051 - 8 Apr 2020

Cited by 19 | Viewed by 4317

Abstract

Restoration of epicardial coronary blood flow, achieved by early reperfusion with primary percutaneous coronary intervention (PPCI), is the guideline recommended to treat patients with ST-segment-elevation myocardial infarction (STEMI). However, despite successful blood restoration, increasing numbers of patients develop left ventricular adverse remodelling (LVAR) [...] Read more.

Restoration of epicardial coronary blood flow, achieved by early reperfusion with primary percutaneous coronary intervention (PPCI), is the guideline recommended to treat patients with ST-segment-elevation myocardial infarction (STEMI). However, despite successful blood restoration, increasing numbers of patients develop left ventricular adverse remodelling (LVAR) and heart failure. Therefore, reliable prognostic biomarkers for LVAR in STEMI are urgently needed. Our aim was to investigate the role of circulating microRNAs (miRNAs) and their association with LVAR in STEMI patients following the PPCI procedure. We analysed the expression of circulating miRNAs in blood samples of 56 patients collected at admission and after revascularization (at 3, 6, 12 and 24 h). The associations between miRNAs and left ventricular end diastolic volumes at 6 months were estimated to detect LVAR. miRNAs were also analysed in samples isolated from peripheral blood mononuclear cells (PBMCs) and human myocardium of failing hearts. Kinetic analysis of miRNAs showed a fast time-dependent increase in miR-133a, miR-133b, miR-193b, miR-499, and miR-320a in STEMI patients compared to controls. Moreover, the expression of miR-29a, miR-29b, miR-324, miR-208, miR-423, miR-522, and miR-545 was differentially expressed even before PPCI in STEMI. Furthermore, the increase in circulating miR-320a and the decrease in its expression in PBMCs were significantly associated with LVAR and correlated with the expression of miR-320a in human failing myocardium from ischaemic origin. In conclusion, we determined the time course expression of new circulating miRNAs in patients with STEMI treated with PPCI and we showed that miR-320a was positively associated with LVAR. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
miRNAs differentially expressed in STEMI patients 3 h post PPCI. (A) Volcano plot showing miRNAs differentially expressed in STEMI patients (n = 9) relative to the control (n = 3); the x axis shows log2 (fold change), and the y-axis shows –log10 (p value). (B) Fragment of hierarchical clustered sample-centric heat-map analysis of the ΔCt value of differentially expressed miRNAs in STEMI patients 3 h post PPCI compared to the control. Scale bar: downregulated (red) and upregulated (green). Distance was measured by Pearson’s correlation. Full article ">Figure 2
Upregulation of circulating miRNAs in the serum of post-STEMI patients. (A–I) Graphs showing the kinetics of miRNAs in serum samples of STEMI patients (n = 8) before PPCI (0 h) and 3, 12, and 24 h after the PPCI procedure. Bar graphs show changes in the expression of miR-133a (A), miR-133b (B), miR-193b (C), miR-499 (D), miR-320a (E), miR-423 (F), miR-29a (G), miR-339-5p (H) and miR-324 (I) in patients after PPCI compared to control patients (n = 8). Values represent the fold changes (in logarithmic scale) for each miRNA relative to controls. Data are presented as the means ± SEM. Significance is indicated by (*) for p < 0.05, (**) for p < 0.01, (***) for p < 0.001), and (****) for p < 0.0001. Ordinary one-way ANOVA with multiples comparisons using T-test without correction (Fisher’s LSD test) was performed. Full article ">Figure 3
Downregulation of circulating miRNA levels in the serum of STEMI patients. (A–F) Graphs represent miRNA expression in the serum of STEMI patients (n = 8) compared to the control (n = 8) before PPCI (0 h) and 3, 12, and 24 h. Bar graphs show the expression of miR-29b (A), miR-208 (B), miR-522 (C), miR-545 (D), miR-1 (E) and miR-21 (F) in patients compared to control patients. Values are presented as the means ± SEM and represent the fold change in logarithmic scale for each miRNA relative to controls. Significance is indicated by (*) for p < 0.05, (**) for p < 0.01, and (***) for p < 0.001). Ordinary one-way ANOVA with multiples comparisons using T-test without correction (Fisher’s LSD test) was performed. Full article ">Figure 4
Comparison of the expression of miRNAs in patients with or without left ventricular adverse remodelling. (A–F) Bar graphs show the expression of miR-320a (A), miR-193b (B), miR-324 (C), miR-339-5p (D), miR-522 (E), and miR-545 (F) in serum samples of STEMI patients who developed left ventricular adverse remodelling (red bars, n = 4) or not (black bars, n = 4) before PPCI (0 h) and at 3, 12, and 24 h after the procedure. The values in the graphs represent the fold change in logarithmic scale for each miRNA relative to controls. Values are presented as the means ± SEM and represent the fold change in logarithmic scale for each miRNA relative to controls (n = 8). Significance is indicated by (*) for p < 0.05. Ordinary one-way ANOVA with multiples comparisons using T-test without correction (Fisher’s LSD test) was performed. Full article ">Figure 5
Comparison of the expression of miR-320a in the serum of patients with or without left ventricular adverse remodelling. (A) Bar graph shows miR-320a expression in serum samples of STEMI patients (n = 20) at 0 h, 6 h and 1 month post PPCI relative to the control (n = 8). (B) Bar graph shows the levels of miR-320a at 0 h, 6 h and 1 month after PPCI in STEMI patients who developed LVAR (red bar, n = 11) or not (black bar, n = 9). Values in the graphs represent the fold change in logarithmic scale for each miRNA relative to controls. Data are the means ± SEM. Significance is indicated by (*) for p < 0.05 and (**) for p < 0.01. Ordinary one-way ANOVA with multiples comparisons using T-test without correction (Fisher’s LSD test) was performed. Full article ">Figure 6
Correlation of serum levels of miR-320a with left ventricular adverse remodelling (LVAR) and receiver-operating characteristics (ROC) analysis. (A) Linear regression analysis using the percentage of change in left ventricular end-diastolic volume (LVEDV) as dependent variable and miR-320a expression 1 month post-PPCI as independent. (B) The area under the curve (AUC, values given on the graphs) analysis of ROC indicating sensitivity and specificity of miR-320a in predicting LVAR. Full article ">Figure 7
Expression of miR-320a in peripheral blood mononuclear cells (PBMCs) of patients with or without left ventricular adverse remodelling. (A) Bar graph shows miR-320a expression in PBMCs of STEMI patients (n = 20) at 0 h, 6 h and 1 month post PPCI relative to the control (n = 8). (B) Bar graph shows the levels of miR-320a in PBMCs at 0 h, 6 h and 1 month after PPCI in STEMI patients who developed LVAR (red bar, n = 11) or not (black bar, n = 9). Values in the graphs represent the fold change in logarithmic scale for each miRNA relative to the controls. Data are the means ± SEM. Significance is indicated by (*) for p < 0.05. Kruskal–Wallis test with multiple comparisons corrected by Dunn’s test was performed. Full article ">Figure 8
miR-320a is highly expressed in the atrium of patients with heart failure (HF) of ischaemic origin. (A) DeltaCt represents the level of Ct of different miRNAs compared to that of the endogenous control in the atrium of HF patients (n = 7). (B) Levels of expression of miR-320a related to the expression of the other miRNAs shown as fold change in logarithmic scale in the atrium of failing heart. Values are presented as the means ± SEM. Significance is indicated by (*) for p < 0.05, (**) for p < 0.01, (***) for p < 0.001), and (****) for p < 0.0001. Ordinary one-way ANOVA with multiples comparisons using T-test without correction (Fisher’s LSD test) was performed. Full article ">Figure 9
In silico analysis of miR-320a targets. PANTHER analysis showed the miR-320a predicted target genes involved in different pathways induced under ischaemia and reperfusion, such as apoptosis (dark pink), FGF (light pink) and TGF signalling (grey) pathways, inflammation (green) and oxidative stress (red). Full article ">

17 pages, 1264 KiB

Open AccessArticle

Novel Biomarkers in Patients with Chronic Kidney Disease: An Analysis of Patients Enrolled in the GCKD-Study

by Moritz Mirna, Albert Topf, Bernhard Wernly, Richard Rezar, Vera Paar, Christian Jung, Hermann Salmhofer, Kristen Kopp, Uta C. Hoppe, P. Christian Schulze, Daniel Kretzschmar, Markus P. Schneider, Ulla T. Schultheiss, Claudia Sommerer, Katharina Paul, Gunter Wolf, Michael Lichtenauer and Martin Busch

J. Clin. Med. 2020, 9(3), 886; https://doi.org/10.3390/jcm9030886 - 24 Mar 2020

Cited by 25 | Viewed by 4636

Abstract

Background: Chronic kidney disease (CKD) and cardiovascular diseases (CVD) often occur concomitantly, and CKD is a major risk factor for cardiovascular mortality. Since some of the most commonly used biomarkers in CVD are permanently elevated in patients with CKD, novel biomarkers are warranted [...] Read more.

Background: Chronic kidney disease (CKD) and cardiovascular diseases (CVD) often occur concomitantly, and CKD is a major risk factor for cardiovascular mortality. Since some of the most commonly used biomarkers in CVD are permanently elevated in patients with CKD, novel biomarkers are warranted for clinical practice. Methods: Plasma concentrations of five cardiovascular biomarkers (soluble suppression of tumorigenicity (sST2), growth differentiation factor 15 (GDF-15), heart-type fatty acid-binding protein (H-FABP), insulin-like growth factor-binding protein 2 (IGF-BP2), and soluble urokinase plasminogen activator receptor) were analyzed by means of enzyme-linked immunosorbent assay (ELISA) in 219 patients with CKD enrolled in the German Chronic Kidney Disease (GCKD) study. Results: Except for sST2, all of the investigated biomarkers were significantly elevated in patients with CKD (2.0- to 4.4-fold increase in advanced CKD (estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m² body surface area (BSA)) and showed a significant inverse correlation with eGFR. Moreover, all but H-FABP and sST2 were additionally elevated in patients with micro- and macro-albuminuria. Conclusions: Based on our findings, sST2 appears to be the biomarker whose diagnostic performance is least affected by decreased renal function, thus suggesting potential viability in the management of patients with CVD and concomitant CKD. The predictive potential of sST2 remains to be proven in endpoint studies. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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22 pages, 6973 KiB

Open AccessArticle

Salivary Oxidative Stress Increases with the Progression of Chronic Heart Failure

by Anna Klimiuk, Anna Zalewska, Robert Sawicki, Małgorzata Knapp and Mateusz Maciejczyk

J. Clin. Med. 2020, 9(3), 769; https://doi.org/10.3390/jcm9030769 - 12 Mar 2020

Cited by 47 | Viewed by 4243

Abstract

The aim of the study was to evaluate the rate of reactive oxygen species (ROS) production, antioxidant barrier, and oxidative damage in non-stimulated (NWS) and stimulated (SWS) saliva as well as plasma/erythrocytes of 50 patients with chronic heart failure (HF) divided into the [...] Read more.

The aim of the study was to evaluate the rate of reactive oxygen species (ROS) production, antioxidant barrier, and oxidative damage in non-stimulated (NWS) and stimulated (SWS) saliva as well as plasma/erythrocytes of 50 patients with chronic heart failure (HF) divided into the two subgroups: NYHA II (33 patients) and NYHA III (17 patients). The activity of superoxide dismutase and catalase was statistically increased in NWS of HF patients as compared to healthy controls. The free radical formation, total oxidant status, level of uric acid, advanced glycation end products (AGE), advanced oxidation protein products and malondialdehyde was significantly elevated in NWS, SWS, and plasma of NYHA III patients as compared to NYHA II and controls. We were the first to demonstrate that with the progression of HF, disturbances of enzymatic and non-enzymatic antioxidant defense, and oxidative damage to proteins and lipids occur at both central (plasma/erythrocytes) and local (saliva) levels. In the study group, we also observed a decrease in saliva secretion, total salivary protein and salivary amylase activity compared to age- and gender-matched control group, which indicates secretory dysfunction of salivary glands in patients with HF. Salivary AGE may be a potential biomarker in differential diagnosis of HF. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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15 pages, 1969 KiB

Open AccessArticle

Combining Novel Biomarkers for Risk Stratification of Two-Year Cardiovascular Mortality in Patients with ST-Elevation Myocardial Infarction

by Naufal Zagidullin, Lukas J. Motloch, Diana Gareeva, Aysilu Hamitova, Irina Lakman, Ilja Krioni, Denis Popov, Rustem Zulkarneev, Vera Paar, Kristen Kopp, Peter Jirak, Vladimir Ishmetov, Uta C. Hoppe, Eduard Tulbaev and Valentin Pavlov

J. Clin. Med. 2020, 9(2), 550; https://doi.org/10.3390/jcm9020550 - 18 Feb 2020

Cited by 30 | Viewed by 4116

Abstract

ST-elevation myocardial infarction (STEMI) is one of the main reasons for morbidity and mortality worldwide. In addition to the classic biomarker NT-proBNP, new biomarkers like ST2 and Pentraxin-3 (Ptx-3) have emerged as potential tools in stratifying risk in cardiac patients. Indeed, multimarker approaches [...] Read more.

ST-elevation myocardial infarction (STEMI) is one of the main reasons for morbidity and mortality worldwide. In addition to the classic biomarker NT-proBNP, new biomarkers like ST2 and Pentraxin-3 (Ptx-3) have emerged as potential tools in stratifying risk in cardiac patients. Indeed, multimarker approaches to estimate prognosis of STEMI patients have been proposed and their potential clinical impact requires investigation. In our study, in 147 patients with STEMI, NT-proBNP as well as serum levels of ST2 and Ptx-3 were evaluated. During two-year follow-up (FU; 734.2 ± 61.2 d) results were correlated with risk for cardiovascular mortality (CV-mortality). NT-proBNP (HR = 1.64, 95% CI = 1.21–2.21, p = 0.001) but also ST2 (HR = 1.000022, 95% CI = 1.00–1.001, p < 0.001) were shown to be reliable predictors of CV-mortality, while the highest predictive power was observed with Ptx-3 (HR = 3.1, 95% CI = 1.63–5.39, p < 0.001). When two biomarkers were combined in a multivariate Cox regression model, relevant improvement of risk assessment was only observed with NT-proBNP+Ptx-3 (AIC = 209, BIC = 214, p = 0.001, MER = 0.75, MEV = 0.64). However, the highest accuracy was seen using a three-marker approach (NT-proBNP + ST2 + Ptx-3: AIC = 208, BIC = 214, p < 0.001, MER = 0.77, MEV = 0.66). In conclusion, after STEMI, ST2 and Ptx-3 in addition to NT-proBNP were associated with the incidence of CV-mortality, with multimarker approaches enhancing the accuracy of prediction of CV-mortality. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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12 pages, 1047 KiB

Open AccessArticle

Urinary Liver-Type Fatty-Acid-Binding Protein Predicts Long-Term Adverse Outcomes in Medical Cardiac Intensive Care Units

by Hiroyuki Naruse, Junnichi Ishii, Hiroshi Takahashi, Fumihiko Kitagawa, Hideto Nishimura, Hideki Kawai, Takashi Muramatsu, Masahide Harada, Akira Yamada, Wakaya Fujiwara, Mutsuharu Hayashi, Sadako Motoyama, Masayoshi Sarai, Eiichi Watanabe, Hideo Izawa and Yukio Ozaki

J. Clin. Med. 2020, 9(2), 482; https://doi.org/10.3390/jcm9020482 - 10 Feb 2020

Cited by 9 | Viewed by 3552

Abstract

We prospectively investigated the prognostic value of urinary liver-type fatty-acid-binding protein (L-FABP) levels on hospital admission, both independently and in combination with serum creatinine-defined acute kidney injury (AKI), to predict long-term adverse outcomes in 1119 heterogeneous patients (mean age; 68 years) treated at [...] Read more.

We prospectively investigated the prognostic value of urinary liver-type fatty-acid-binding protein (L-FABP) levels on hospital admission, both independently and in combination with serum creatinine-defined acute kidney injury (AKI), to predict long-term adverse outcomes in 1119 heterogeneous patients (mean age; 68 years) treated at medical (non-surgical) cardiac intensive care units (CICUs). Patients with stage 5 chronic kidney disease were excluded from the study. Of these patients, 47% had acute coronary syndrome and 38% had acute decompensated heart failure. The creatinine-defined AKI was diagnosed according to the “Kidney Disease: Improving Global Outcomes” criteria. The primary endpoint was a composite of all-cause death or progression to end-stage kidney disease, indicating the initiation of maintenance dialysis therapy or kidney transplantation. Creatinine-defined AKI occurred in 207 patients, with 44 patients having stage 2 or 3 disease. During a mean follow-up period of 41 months after enrollment, the primary endpoint occurred in 242 patients. Multivariate Cox regression analyses revealed L-FABP levels as independent predictors of the primary endpoint (p < 0.001). Adding L-FABP to a baseline model with established risk factors further enhanced reclassification and discrimination beyond that of the baseline model alone, for primary-endpoint prediction (both; p < 0.01). On Kaplan–Meier analyses, increased L-FABP (≥4th quintile value of 9.0 ng/mL) on admission or presence of creatinine-defined AKI, correlated with an increased risk of the primary endpoint (p < 0.001). Thus, urinary L-FABP levels on admission are potent and independent predictors of long-term adverse outcomes, and they might improve the long-term risk stratification of patients admitted at medical CICUs, when used in combination with creatinine-defined AKI. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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11 pages, 240 KiB

Open AccessArticle

Pregnancy Associated Plasma Protein-A as a Cardiovascular Risk Marker in Patients with Stable Coronary Heart Disease During 10 Years Follow-Up—A CLARICOR Trial Sub-Study

by Erik Nilsson, Jens Kastrup, Ahmad Sajadieh, Gorm Boje Jensen, Erik Kjøller, Hans Jørn Kolmos, Jonas Wuopio, Christoph Nowak, Anders Larsson, Janus Christian Jakobsen, Per Winkel, Christian Gluud, Kasper K Iversen, Johan Ärnlöv and Axel C. Carlsson

J. Clin. Med. 2020, 9(1), 265; https://doi.org/10.3390/jcm9010265 - 18 Jan 2020

Cited by 6 | Viewed by 3582

Abstract

Elevated pregnancy-associated plasma protein A (PAPP-A) is associated with mortality in acute coronary syndromes. Few studies have assessed PAPP-A in stable coronary artery disease (CAD) and results are conflicting. We assessed the 10-year prognostic relevance of PAPP-A levels in stable CAD. The CLARICOR [...] Read more.

Elevated pregnancy-associated plasma protein A (PAPP-A) is associated with mortality in acute coronary syndromes. Few studies have assessed PAPP-A in stable coronary artery disease (CAD) and results are conflicting. We assessed the 10-year prognostic relevance of PAPP-A levels in stable CAD. The CLARICOR trial was a randomized controlled clinical trial including outpatients with stable CAD, randomized to clarithromycin versus placebo. The placebo group constituted our discovery cohort (n = 1.996) and the clarithromycin group the replication cohort (n = 1.975). The composite primary outcome was first occurrence of cardiovascular event or death. In the discovery cohort, incidence rates (IR) for the composite outcome were higher in those with elevated PAPP-A (IR 12.72, 95% Confidence Interval (CI) 11.0–14.7 events/100 years) compared to lower PAPP-A (IR 8.78, 8.25–9.34), with comparable results in the replication cohort. Elevated PAPP-A was associated with increased risk of the composite outcome in both cohorts (discovery Hazard Ratio (HR) 1.45, 95% CI 1.24–1.70; replication HR 1.29, 95% CI 1.10–1.52). In models adjusted for established risk factors, these trends were attenuated. Elevated PAPP-A was associated with higher all-cause mortality in both cohorts. We conclude that elevated PAPP-A levels are associated with increased long-term mortality in stable CAD, but do not improve long-term prediction of death or cardiovascular events when added to established predictors. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

15 pages, 607 KiB

Open AccessArticle

Circulating Biomarkers of Cell Adhesion Predict Clinical Outcome in Patients with Chronic Heart Failure

by Elke Bouwens, Victor J. van den Berg, K. Martijn Akkerhuis, Sara J. Baart, Kadir Caliskan, Jasper J. Brugts, Henk Mouthaan, Jan van Ramshorst, Tjeerd Germans, Victor A. W. M. Umans, Eric Boersma and Isabella Kardys

J. Clin. Med. 2020, 9(1), 195; https://doi.org/10.3390/jcm9010195 - 10 Jan 2020

Cited by 12 | Viewed by 4110

Abstract

Cardiovascular inflammation and vascular endothelial dysfunction are involved in chronic heart failure (CHF), and cellular adhesion molecules are considered to play a key role in these mechanisms. We evaluated temporal patterns of 12 blood biomarkers of cell adhesion in patients with CHF. In [...] Read more.

Cardiovascular inflammation and vascular endothelial dysfunction are involved in chronic heart failure (CHF), and cellular adhesion molecules are considered to play a key role in these mechanisms. We evaluated temporal patterns of 12 blood biomarkers of cell adhesion in patients with CHF. In 263 ambulant patients, serial, tri-monthly blood samples were collected during a median follow-up of 2.2 (1.4–2.5) years. The primary endpoint (PE) was a composite of cardiovascular mortality, HF hospitalization, heart transplantation and implantation of a left ventricular assist device and was reached in 70 patients. We selected the baseline blood samples in all patients, the two samples closest to a PE, or, for event-free patients, the last sample available. In these 567 samples, associations between biomarkers and PE were investigated by joint modelling. The median age was 68 (59–76) years, with 72% men and 74% New York Heart Association class I–II. Repeatedly measured levels of Complement component C1q receptor (C1qR), Cadherin 5 (CDH5), Chitinase-3-like protein 1 (CHI3L1), Ephrin type-B receptor 4 (EPHB4), Intercellular adhesion molecule-2 (ICAM-2) and Junctional adhesion molecule A (JAM-A) were independently associated with the PE. Their rates of change also predicted clinical outcome. Level of CHI3L1 was numerically the strongest predictor with a hazard ratio (HR) (95% confidence interval) of 2.27 (1.66–3.16) per SD difference in level, followed by JAM-A (2.10, 1.42–3.23) and C1qR (1.90, 1.36–2.72), adjusted for clinical characteristics. In conclusion, temporal patterns of C1qR, CDH5, CHI3L1, EPHB4, ICAM2 and JAM-A are strongly and independently associated with clinical outcome in CHF patients. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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15 pages, 2021 KiB

Open AccessArticle

Left Ventricular Function and Myocardial Triglyceride Content on 3T Cardiac MR Predict Major Cardiovascular Adverse Events and Readmission in Patients Hospitalized with Acute Heart Failure

by Kuang-Fu Chang, Gigin Lin, Pei-Ching Huang, Yu-Hsiang Juan, Chao-Hung Wang, Shang-Yueh Tsai, Yu-Ching Lin, Ming-Ting Wu, Pen-An Liao, Lan-Yan Yang, Min-Hui Liu, Yu-Chun Lin, Jiun-Jie Wang, Koon-Kwan Ng and Shu-Hang Ng

J. Clin. Med. 2020, 9(1), 169; https://doi.org/10.3390/jcm9010169 - 8 Jan 2020

Cited by 10 | Viewed by 3075

Abstract

Background: This prospective study was designed to investigate whether myocardial triglyceride (TG) content from proton magnetic resonance spectroscopy (MRS) and left ventricular (LV) function parameters from cardiovascular magnetic resonance imaging (CMR) can serve as imaging biomarkers in predicting future major cardiovascular adverse events [...] Read more.

Background: This prospective study was designed to investigate whether myocardial triglyceride (TG) content from proton magnetic resonance spectroscopy (MRS) and left ventricular (LV) function parameters from cardiovascular magnetic resonance imaging (CMR) can serve as imaging biomarkers in predicting future major cardiovascular adverse events (MACE) and readmission in patients who had been hospitalized for acute heart failure (HF). Methods: Patients who were discharged after hospitalization for acute HF were prospectively enrolled. On a 3.0 T MR scanner, myocardial TG contents were measured using MRS, and LV parameters (function and mass) were evaluated using cine. The occurrence of MACE and the HF-related readmission served as the endpoints. Independent predictors were identified using univariate and multivariable Cox proportional hazard regression analyses. Results: A total of 133 patients (mean age, 52.4 years) were enrolled. The mean duration of follow-up in surviving patients was 775 days. Baseline LV functional parameters—including ejection fraction, LV end-diastolic volume, LV end-diastolic volume index (LVEDVI), and LV end-systolic volume (p < 0.0001 for all), and myocardial mass (p = 0.010)—were significantly associated with MACE. Multivariable analysis revealed that LVEDVI was the independent predictor for MACE, while myocardial mass was the independent predictor for 3- and 12-month readmission. Myocardial TG content (lipid resonances δ 1.6 ppm) was significantly associated with readmission in patients with ischemic heart disease. Conclusions: LVEDVI and myocardial mass are potential imaging biomarkers that independently predict MACE and readmission, respectively, in patients discharged after hospitalization for acute HF. Myocardial TG predicts readmission in patients with a history of ischemic heart disease. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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Figure 1
Flow diagram of the study cohort. Note.—AMI, acute myocardial infarction; CMR, cardiac magnetic resonance; HF, heart failure; MACE, major cardiovascular event; VT, ventricular tachycardia; VF, ventricular fibrillation. Full article ">Figure 2
Example myocardial CMR spectroscopy. (A) A 2 × 2 × 1 cm3 spectroscopic volume (white box) was acquired from the interventricular septum during the systolic phase to generate an input spectrum. (B) 1H-CMR spectra were fitted and analyzed using the LCModel 6.2 software package (right). We quantified the components of myocardial triglyceride resonances, i.e., fatty acids (FA, lipid resonances δ 0.9, 1.3, and 1.6 ppm) and unsaturated fatty acids (UFA, lipid resonance δ 2.1 and 2.3, 2.8, 5.3 ppm). Full article ">Figure 3
Kaplan-Meier curves for MACE-free survival in patients stratified according to the left ventricular end-diastolic volume index (LVEDVI) on CMR. Note—Kaplan-Meier survival analysis demonstrated that all patients with low LVEDVI (≤90.2 mL/m2) had a lower probability for MACE than those with high LVEDVI (>90.2 mL/m2, log-rank test, p < 0.0001). MACE, major cardiovascular event. Full article ">Figure 4
Kaplan-Meier curves for readmission-free survival in ischemic patients stratified according to the level of lipid resonances δ 1.6 ppm on 1H-MRS. Note—Kaplan-Meier survival analysis demonstrated that ischemic patients with low levels of lipid resonances δ 1.6 ppm (≤0.99) had a lower probability for heart failure-related readmission than those with high levels of lipid resonances δ 1.6 ppm (>0.99, log-rank test, p < 0.0001). Note.—Abbreviations: FA, fatty acid. Full article ">Figure 5
Kaplan-Meier curves for readmission-free survival in non-ischemic patients stratified according to LV (left ventricular) global volume on CMR. Note—Kaplan-Meier survival analysis showed that non-ischemic patients with low LV global volume (≤231 mL) had a lower probability for heart failure-related readmission than those with high LV global volume (>231 mL, log-rank test, p < 0.0001). Full article ">

16 pages, 1722 KiB

Open AccessArticle

Ceruloplasmin, NT-proBNP, and Clinical Data as Risk Factors of Death or Heart Transplantation in a 1-Year Follow-Up of Heart Failure Patients

by Ewa Romuk, Wojciech Jacheć, Ewa Zbrojkiewicz, Alina Mroczek, Jacek Niedziela, Mariusz Gąsior, Piotr Rozentryt and Celina Wojciechowska

J. Clin. Med. 2020, 9(1), 137; https://doi.org/10.3390/jcm9010137 - 3 Jan 2020

Cited by 4 | Viewed by 2726

Abstract

We investigated whether the additional determination of ceruloplasmin (Cp) levels could improve the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure (HF) patients in a 1-year follow-up. Cp and NT-proBNP levels and clinical and laboratory parameters were assessed simultaneously at [...] Read more.

We investigated whether the additional determination of ceruloplasmin (Cp) levels could improve the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure (HF) patients in a 1-year follow-up. Cp and NT-proBNP levels and clinical and laboratory parameters were assessed simultaneously at baseline in 741 HF patients considered as possible heart transplant recipients. The primary endpoint (EP) was a composite of all-cause death (non-transplant patients) or heart transplantation during one year of follow-up. Using a cut-off value of 35.9 mg/dL for Cp and 3155 pg/mL for NT-proBNP (top interquartile range), a univariate Cox regression analysis showed that Cp (hazard ratio (HR) = 2.086; 95% confidence interval (95% CI, 1.462–2.975)), NT-proBNP (HR = 3.221; 95% CI (2.277–4.556)), and the top quartile of both Cp and NT-proBNP (HR = 4.253; 95% CI (2.795–6.471)) were all risk factors of the primary EP. The prognostic value of these biomarkers was demonstrated in a multivariate Cox regression model using the top Cp and NT-proBNP concentration quartiles combined (HR = 2.120; 95% CI (1.233–3.646)). Lower left ventricular ejection fraction, VO₂max, lack of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, and nonimplantation of an implantable cardioverter-defibrillator were also independent risk factors of a poor outcome. The combined evaluation of Cp and NT-proBNP had advantages over separate NT-proBNP and Cp assessment in selecting a group with a high 1-year risk. Thus multi-biomarker assessment can improve risk stratification in HF patients. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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10 pages, 479 KiB

Open AccessArticle

Growth Differentiation Factor-8 (GDF8)/Myostatin Is a Predictor of Troponin I Peak and a Marker of Clinical Severity after Acute Myocardial Infarction

by Alexandre Meloux, Luc Rochette, Maud Maza, Florence Bichat, Laura Tribouillard, Yves Cottin, Marianne Zeller and Catherine Vergely

J. Clin. Med. 2020, 9(1), 116; https://doi.org/10.3390/jcm9010116 - 31 Dec 2019

Cited by 19 | Viewed by 3078

Abstract

Objective: Growth differentiation factor-8 (GDF8), also known as myostatin, is a member of the transforming growth factor-β superfamily that inhibits skeletal muscle growth. We aimed to investigate the association between GDF8 and peak troponin I levels after acute myocardial infarction (AMI). Methods: All [...] Read more.

Objective: Growth differentiation factor-8 (GDF8), also known as myostatin, is a member of the transforming growth factor-β superfamily that inhibits skeletal muscle growth. We aimed to investigate the association between GDF8 and peak troponin I levels after acute myocardial infarction (AMI). Methods: All consecutive patients admitted from June 2016 to February 2018 for type 1 AMI in the Coronary Care Unit of University Hospital of Dijon Bourgogne (France) were included in our prospective study. Blood samples were harvested on admission, and serum levels of GDF8 were measured using a commercially available enzyme-linked immunosorbent assay kit. Results: Among the 296 patients with type 1 AMI, median age was 68 years and 27% were women. GDF8 levels (median (IQR) = 2375 ng/L) were negatively correlated with age, sex and diabetes (p < 0.001 for all). GDF8 levels were higher in patients with in-hospital ventricular tachycardia or fibrillation (VT/VF) than those without in-hospital VT/VF. GDF8 was positively correlated with troponin I peak (r = 0.247; p < 0.001). In multivariate linear regression analysis, log GDF8 (OR: 21.59; 95% CI 34.08–119.05; p < 0.001) was an independent predictor of troponin I peak. Conclusions: These results suggest that GDF8 levels could reflect the extent of myocardial damage during AMI, similar to peak troponin I, which is currently used to estimate infarct size. Further studies are needed to elucidate the underlying mechanisms linking the GDF8 cytokine with troponin I levels. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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14 pages, 1555 KiB

Open AccessArticle

New Imaging Markers of Clinical Outcome in Asymptomatic Patients with Severe Aortic Regurgitation

by Radka Kočková, Hana Línková, Zuzana Hlubocká, Alena Pravečková, Andrea Polednová, Lucie Súkupová, Martin Bláha, Jiří Malý, Eva Honsová, David Sedmera and Martin Pěnička

J. Clin. Med. 2019, 8(10), 1654; https://doi.org/10.3390/jcm8101654 - 11 Oct 2019

Cited by 9 | Viewed by 2508

Abstract

Background: Determining the value of new imaging markers to predict aortic valve (AV) surgery in asymptomatic patients with severe aortic regurgitation (AR) in a prospective, observational, multicenter study. Methods: Consecutive patients with chronic severe AR were enrolled between 2015–2018. Baseline examination included echocardiography [...] Read more.

Background: Determining the value of new imaging markers to predict aortic valve (AV) surgery in asymptomatic patients with severe aortic regurgitation (AR) in a prospective, observational, multicenter study. Methods: Consecutive patients with chronic severe AR were enrolled between 2015–2018. Baseline examination included echocardiography (ECHO) with 2- and 3-dimensional (2D and 3D) vena contracta area (VCA), and magnetic resonance imaging (MRI) with regurgitant volume (RV) and fraction (RF) analyzed in CoreLab. Results: The mean follow-up was 587 days (interquartile range (IQR) 296–901) in a total of 104 patients. Twenty patients underwent AV surgery. Baseline clinical and laboratory data did not differ between surgically and medically treated patients. Surgically treated patients had larger left ventricular (LV) dimension, end-diastolic volume (all p < 0.05), and the LV ejection fraction was similar. The surgical group showed higher prevalence of severe AR (70% vs. 40%, p = 0.02). Out of all imaging markers 3D VCA, MRI-derived RV and RF were identified as the strongest independent predictors of AV surgery (all p < 0.001). Conclusions: Parameters related to LV morphology and function showed moderate accuracy to identify patients in need of early AV surgery at the early stage of the disease. 3D ECHO-derived VCA and MRI-derived RV and RF showed high accuracy and excellent sensitivity to identify patients in need of early surgery. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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Imaging markers. (A) Echocardiography derived three-dimensional vena contracta area; (B) echocardiography two-dimensional global longitudinal strain; (C) magnetic resonance—the left ventricular outflow tract (cine), red line—through-plane flow sequence slice position displayed on, Ao—aorta, LA—left atrium, LV—left ventricle, RV—right ventricle; (D) through-plane flow sequence at sinotubular junction level (STJ) of the aorta (displayed on (C)), the blue circle is a manually drawn region of interest where the blood flow and regurgitant volume and fraction are calculated. The exact copy of the region interest is in all four images, phantom—stationary phantom used for flow measurement correction; (E) flow-time curve based on (D)—blue line shows blood flow at STJ and red line show flow in stationary phantom; (F) native T1 mapping from modified Look–Locker Inversion recovery sequence (MOLLI) sequence, blue circle—a semi-automatically drawn region of interest within the blood pool, blue ellipsoid—a manually drawn region of interest within the myocardium at the level of the interventricular septum utilized for myocardial fibrosis calculation. Full article ">Figure 2
Receiver-operating characteristics curves of the MRI-derived: regurgitant volume (RV) and left ventricular end-diastolic volume index (LVEDVI); the 3D ECHO-derived: vena contracta area (VCA); 2D ECHO-derived: left ventricular end-systolic diameter (LVESD); RV and global longitudinal strain (GLS) to predict AV surgery. Full article ">Figure 3
(A) Kaplan–Meier curves for aortic valve surgery (AVR) in patients with 3D ECHO-derived VCA ≥30 mm2 vs. <30 mm2, (B) MRI-derived RV ≥45 mL vs. <45 mL; and (C) MRI-derived RF ≥34% vs. <34%. Full article ">

16 pages, 3247 KiB

Open AccessArticle

Tissue-Specific miRNAs Regulate the Development of Thoracic Aortic Aneurysm: The Emerging Role of KLF4 Network

by Stasė Gasiulė, Vaidotas Stankevičius, Vaiva Patamsytė, Raimundas Ražanskas, Giedrius Žukovas, Žana Kapustina, Diana Žaliaduonytė, Rimantas Benetis, Vaiva Lesauskaitė and Giedrius Vilkaitis

J. Clin. Med. 2019, 8(10), 1609; https://doi.org/10.3390/jcm8101609 - 3 Oct 2019

Cited by 20 | Viewed by 4175

Abstract

MicroRNAs (miRNAs) are critical regulators of the functional pathways involved in the pathogenesis of cardiovascular diseases. Understanding of the disease-associated alterations in tissue and plasma will elucidate the roles of miRNA in modulation of gene expression throughout development of sporadic non-syndromic ascending thoracic [...] Read more.

MicroRNAs (miRNAs) are critical regulators of the functional pathways involved in the pathogenesis of cardiovascular diseases. Understanding of the disease-associated alterations in tissue and plasma will elucidate the roles of miRNA in modulation of gene expression throughout development of sporadic non-syndromic ascending thoracic aortic aneurysm (TAA). This will allow one to propose relevant biomarkers for diagnosis or new therapeutic targets for the treatment. The high-throughput sequencing revealed 20 and 17 TAA-specific miRNAs in tissue and plasma samples, respectively. qRT-PCR analysis in extended cohort revealed sex-related differences in miR-10a-5p, miR-126-3p, miR-155-5p and miR-148a-3p expression, which were the most significantly dysregulated in TAA tissues of male patients. Unexpectedly, the set of aneurysm-related miRNAs in TAA plasma did not resemble the tissue signature suggesting more complex organism response to the disease. Three of TAA-specific plasma miRNAs were found to be restored to normal level after aortic surgery, further signifying their relationship to the pathology. The panel of two plasma miRNAs, miR-122-3p, and miR-483-3p, could serve as a potential biomarker set (AUC = 0.84) for the ascending TAA. The miRNA-target enrichment analysis exposed TGF-β signaling pathway as sturdily affected by abnormally expressed miRNAs in the TAA tissue. Nearly half of TAA-specific miRNAs potentially regulate a key component in TGF-β signaling: TGF-β receptors, SMADs and KLF4. Indeed, using immunohistochemistry analysis we detected increased KLF4 expression in 27% of TAA cells compared to 10% of non-TAA cells. In addition, qRT-PCR demonstrated a significant upregulation of ALK1 mRNA expression in TAA tissues. Overall, these observations indicate that the alterations in miRNA expression are sex-dependent and play an essential role in TAA via TGF-β signaling. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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Differential miRNA expression analysis in TAA tissue and plasma samples using high-throughput RNA sequencing. (A) Schematic diagram of miRNA-Seq experiment. (B) Heat map showing a total of 20 miRNAs differentially expressed (fold change, FC > 1.5, p < 0.05, normalized read count average, RC > 10) in TAA tissue samples (n = 8) compared to normal aorta tissue (n = 6). Red color indicates upregulated log-transformed expression level ratios of corresponding miRNAs, blue – downregulated; (C) Venn’s diagram showing the number of differentially expressed miRNAs (FC > 1.5, p ≤ 0.05 and RC > 20) in TAA plasma samples (n = 7) compared to non-aneurysmal group (n = 7) and plasma samples obtained 3 months after aortic reconstructive surgery (n = 4); (D) Venn’s diagram demonstrating the number of differentially expressed miRNAs in TAA tissue and plasma samples; (E) Heat map demonstrating the expression of six miRNAs, which were significantly deregulated in TAA plasma samples, but were almost absent in TAA tissue samples. Color intensity indicates log-transformed normalized read counts of corresponding miRNA. Full article ">Figure 2
Validation of differentially expressed miRNAs in TAA tissue and plasma samples by qRT-PCR. qRT-PCR analysis was used for the comparison of relative miRNA expression levels between non-TAA and TAA groups in tissue (A) and plasma (B) both types (C) of samples. The cycle threshold (Ct) values of observed miRNAs were normalized to miR-152-3p and miR-185-5p for tissue and plasma samples, respectively, which were revealed as the most reliable endogenous controls according to miRNA-Seq data. Lines within boxes indicate relative miRNA expression median values; whiskers—5–95 percentile of the relative miRNA expression values. Significance between each group was evaluated using Student’s t test and is shown as follows: n.s.—not significant; * p < 0.05; ** p < 0.01 and *** p < 0.001. (D) Diagnostic ROC curve analysis showing sensitivity and specificity of mir-122-3p, mir-483-3p, mir-4732-3p and mir-143-3p selected circulating miRNAs or the combination of mir-122-3p and mir-483-3p together. AUC denotes area under the ROC curve. Full article ">Figure 3
Functional analysis of target genes of miRNAs dysregulated in TAA. (A) Network analysis of 48 KEGG categories specified three clusters of closely related categories including immune response, cancer, kinase signaling pathways and ten separate groups that were not significantly associated with any other category. TGF-β signaling pathway is included in a grey box. The size of node represents gene number in particular, KEGG category, the node color – the significance level value of particular KEGG category. Edges indicate a statistically significant association between categories. (B) Expanded molecular network of miRNAs and their potential target genes involved in TGF-β signaling pathway. Grey nodes denote target genes, red and blue – upregulated and downregulated miRNAs, respectively. Dark orange area covers TGF-β ligands and receptors; light orange – regulatory SMADs (rSMADs). (C) Simplified hypothetical schema of TGF-β signal transduction in TAA tissue cells. miRNAs, which were differentially expressed in TAA tissue (grey boxes), could potentially disturb TGF-β signaling by targeting TGF-β ligands, receptors or rSMADs leading to dysregulation of MyoCD–KLF4 transcription regulator axis and further TAA progression. Full article ">Figure 4
Immunohistochemical (IHC) analysis of KLF4, MyoCD, and osteopontin expression in non-TAA and TAA tissue samples. The abundance of proteins was examined by immunostaining and visualized with diaminobenzidine (brown). The sections were counterstained with hematoxylin (blue). Histological quantification of KLF4 was performed by counting KLF4 positive cell nucleus (black arrows; n = 43), whereas osteopontin (n = 46) and MyoCD (n = 20) by IHC score (graphs in right panel). Lines within boxes indicate KLF4 positive nucleus mean or MyoCD and osteopontin IHC score median values, whiskers – 5-95 percentile of KLF4 positive nucleus or MyoCD and osteopontin IHC score values. The histological data were assessed using Student’s t test (for KLF4) or non-parametric Mann-Whitney U test (for MyoCD and osteopontin). The significance between each group is shown as follows: n.s.—not significant; * p < 0.05; ** p < 0.01, *** p < 0.001. Full article ">

16 pages, 2138 KiB

Open AccessArticle

Growth Differentiation Factor-15 (GDF-15) Is a Biomarker of Muscle Wasting and Renal Dysfunction in Preoperative Cardiovascular Surgery Patients

by Toshiaki Nakajima, Ikuko Shibasaki, Tatsuya Sawaguchi, Akiko Haruyama, Hiroyuki Kaneda, Takafumi Nakajima, Takaaki Hasegawa, Takuo Arikawa, Syotaro Obi, Masashi Sakuma, Hironaga Ogawa, Shigeru Toyoda, Fumitaka Nakamura, Shichiro Abe, Hirotsugu Fukuda and Teruo Inoue

J. Clin. Med. 2019, 8(10), 1576; https://doi.org/10.3390/jcm8101576 - 1 Oct 2019

Cited by 39 | Viewed by 6016

Abstract

Frailty and sarcopenia increase the risk of complications and mortality when invasive treatment such as cardiac surgery is performed. Growth differentiation factor-15 (GDF-15) involves various pathophysiological conditions including renal dysfunction, heart failure and cachexia. We investigated the pathophysiological roles of preoperative GDF-15 levels [...] Read more.

Frailty and sarcopenia increase the risk of complications and mortality when invasive treatment such as cardiac surgery is performed. Growth differentiation factor-15 (GDF-15) involves various pathophysiological conditions including renal dysfunction, heart failure and cachexia. We investigated the pathophysiological roles of preoperative GDF-15 levels in cardiovascular surgery patients. Preoperative skeletal muscle index (SMI) determined by bioelectrical impedance analysis, hand-grip strength, 4 m gait speed, and anterior thigh muscle thickness (TMth) measured by echocardiography were assessed in 72 patients (average age 69.9 years) who underwent cardiovascular surgery. The preoperative serum GDF-15 concentration was determined by enzyme-linked immunosorbent assay. Circulating GDF-15 level was correlated with age, brain natriuretic peptide, and estimated glomerular filtration rate (eGFR). It was also negatively correlated with SMI, hand-grip strength, and anterior TMth. In multivariate analysis, eGFR and anterior TMth were the independent determinants of GDF-15 concentration even after adjusting for age, sex, and body mass index. Alternatively, the GDF-15 level was an independent determinant of eGFR and anterior TMth. We concluded that preoperative GDF-15 levels reflect muscle wasting as well as renal dysfunction in preoperative cardiovascular surgery patients. GDF-15 may be a novel biomarker for identify high-risk patients with muscle wasting and renal dysfunction before cardiovascular surgery. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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18 pages, 961 KiB

Open AccessArticle

Catestatin in Acutely Decompensated Heart Failure Patients: Insights from the CATSTAT-HF Study

by Josip A. Borovac, Duska Glavas, Zora Susilovic Grabovac, Daniela Supe Domic, Domenico D’Amario and Josko Bozic

J. Clin. Med. 2019, 8(8), 1132; https://doi.org/10.3390/jcm8081132 - 30 Jul 2019

Cited by 25 | Viewed by 9240

Abstract

The role of catestatin (CST) in acutely decompensated heart failure (ADHF) and myocardial infarction (MI) is poorly elucidated. Due to the implicated role of CST in the regulation of neurohumoral activity, the goals of the study were to determine CST serum levels among [...] Read more.

The role of catestatin (CST) in acutely decompensated heart failure (ADHF) and myocardial infarction (MI) is poorly elucidated. Due to the implicated role of CST in the regulation of neurohumoral activity, the goals of the study were to determine CST serum levels among ninety consecutively enrolled ADHF patients, with respect to the MI history and left ventricular ejection fraction (LVEF) and to examine its association with clinical, echocardiographic, and laboratory parameters. CST levels were higher among ADHF patients with MI history, compared to those without (8.94 ± 6.39 vs. 4.90 ± 2.74 ng/mL, p = 0.001). CST serum levels did not differ among patients with reduced, midrange, and preserved LVEF (7.74 ± 5.64 vs. 5.75 ± 4.19 vs. 5.35 ± 2.77 ng/mL, p = 0.143, respectively). In the multivariable linear regression analysis, CST independently correlated with the NYHA class (? = 0.491, p < 0.001), waist-to-hip ratio (WHR) (? = ?0.237, p = 0.026), HbA1c (? = ?0.235, p = 0.027), LDL (? = ?0.231, p = 0.029), non-HDL cholesterol (? = ?0.237, p = 0.026), hs-cTnI (? = ?0.221, p = 0.030), and the admission and resting heart rate (? = ?0.201, p = 0.036 and ? = ?0.242, p = 0.030), and was in positive association with most echocardiographic parameters. In conclusion, CST levels were increased in ADHF patients with MI and were overall associated with a favorable cardiometabolic profile but at the same time reflected advanced symptomatic burden (CATSTAT-HF ClinicalTrials.gov number, NCT03389386). Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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11 pages, 1703 KiB

Open AccessArticle

New Cardiovascular Biomarkers in Ischemic Heart Disease—GDF-15, A Probable Predictor for Ejection Fraction

by Daniel Dalos, Georg Spinka, Matthias Schneider, Bernhard Wernly, Vera Paar, Uta Hoppe, Brigitte Litschauer, Jeanette Strametz-Juranek and Michael Sponder

J. Clin. Med. 2019, 8(7), 924; https://doi.org/10.3390/jcm8070924 - 27 Jun 2019

Cited by 20 | Viewed by 4407

Abstract

Background: Various biomarkers have been associated with coronary artery disease (CAD) and ischemic heart failure. The aim of this study was to investigate the correlation of serum levels of soluble urokinase-type plasminogen activator receptor (suPAR), growth differentiation factor 15 (GDF-15), heart-type fatty acid-binding [...] Read more.

Background: Various biomarkers have been associated with coronary artery disease (CAD) and ischemic heart failure. The aim of this study was to investigate the correlation of serum levels of soluble urokinase-type plasminogen activator receptor (suPAR), growth differentiation factor 15 (GDF-15), heart-type fatty acid-binding protein (H-FABP), and soluble suppression of tumorigenicity 2 (sST2) with left ventricular ejection fraction (EF) in CAD patients and controls. Methods and Results: CAD patients were divided into three groups according to their EF as measured by the biplane Simpson method (53–84%, 31–52%, ≤30%). Overall, 361 subjects were analyzed. In total, 155 CAD patients had an EF of 53–84%, 71 patients had an EF of 31–52%, and 23 patients had an EF of ≤30% as compared to 112 healthy controls (age 51.3 ± 9.0 years, 44.6% female). Mean ages according to EF were 62.1 ± 10.9, 65.2 ± 10.1, and 66.6 ± 8.2 years, respectively, with females representing 29.0, 29.6, and 13.0%. suPAR, GDF-15, H-FABP, and sST2 values were significantly higher in CAD patients and showed an exponential increase with decreasing EF. In a multiple logistic regression model, GDF-15 (p = 0.009), and NT-brain natriuretic peptide (p = 0.003) were independently associated with EF. Conclusion: Biomarkers such as suPAR, GDF-15, H-FABP, and sST2 are increased in CAD patients, especially in highly impaired EF. Besides NT-proBNP as a well-known marker for risk prediction, GDF-15 may be an additional tool for diagnosis and clinical follow-up. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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15 pages, 2343 KiB

Open AccessArticle

Very Low-Density Lipoproteins of Metabolic Syndrome Modulates STIM1, Suppresses Store-Operated Calcium Entry, and Deranges Myofilament Proteins in Atrial Myocytes

by Yi-Lin Shiou, Hsin-Ting Lin, Liang-Yin Ke, Bin-Nan Wu, Shyi-Jang Shin, Chu-Huang Chen, Wei-Chung Tsai, Chih-Sheng Chu and Hsiang-Chun Lee

J. Clin. Med. 2019, 8(6), 881; https://doi.org/10.3390/jcm8060881 - 20 Jun 2019

Cited by 15 | Viewed by 4010

Abstract

Individuals with metabolic syndrome (MetS) are at high risk for atrial myopathy and atrial fibrillation. Very low-density lipoproteins (VLDLs) of MetS (MetS-VLDLs) are cytotoxic to atrial myocytes in vivo and in vitro. The calcineurin–nuclear factor of activated T-cells (NFAT) pathway, which is regulated [...] Read more.

Individuals with metabolic syndrome (MetS) are at high risk for atrial myopathy and atrial fibrillation. Very low-density lipoproteins (VLDLs) of MetS (MetS-VLDLs) are cytotoxic to atrial myocytes in vivo and in vitro. The calcineurin–nuclear factor of activated T-cells (NFAT) pathway, which is regulated by stromal interaction molecule 1 (STIM1)/ calcium release-activated calcium channel protein 1 (Orai1)–mediated store-operated Ca²⁺ entry (SOCE), is a pivotal mediator of adaptive cardiac hypertrophy. We hypothesized that MetS-VLDLs could affect SOCE and the calcineurin–NFAT pathway. Normal-VLDL and MetS-VLDL samples were isolated from the peripheral blood of healthy volunteers and individuals with MetS. VLDLs were applied to HL-1 atrial myocytes for 18 h and were also injected into wild-type C57BL/6 male mouse tails three times per week for six weeks. After the sarcoplasmic reticulum (SR) Ca²⁺ store was depleted, SOCE was triggered upon reperfusion with 1.8 mM of Ca²⁺. SOCE was attenuated by MetS-VLDLs, along with reduced transcriptional and membranous expression of STIM1 (P = 0.025), and enhanced modification of O-GlcNAcylation on STIM1 protein, while Orai1 was unaltered. The nuclear translocation and activity of calcineurin were both reduced (P < 0.05), along with the alteration of myofilament proteins in atrial tissues. These changes were absent in normal-VLDL-treated cells. Our results demonstrated that MetS-VLDLs suppressed SOCE by modulating STIM1 at the transcriptional, translational, and post-translational levels, resulting in the inhibition of the calcineurin–NFAT pathway, which resulted in the alteration of myofilament protein expression and sarcomere derangement in atrial tissues. These findings may help explain atrial myopathy in MetS. We suggest a therapeutic target on VLDLs to prevent atrial fibrillation, especially for individuals with MetS. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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Figure 1
Effects of metabolic syndrome (MetS)-very low-density lipoproteins (VLDLs) on the expression of stromal interaction molecule 1 (STIM1) and calcium release-activated calcium channel protein 1 (Orai1) and the O-GlcNAcylation of STIM1. (a) Quantitative RT-PCR of STIM1 (n = 4 for each group). Reduced STIM1 mRNA in the MetS-VLDL-treated group (MetS) ($ P = 0.012, # P = 0.005). (b) Representative bands of western blots for STIM1 and Orai1 channel proteins. (c) Reduced STIM1 membrane protein expression in the MetS-VLDL group (n = 4 for each group; $ P = 0.025, # P = 0.021). (d) Orai1 channel membrane protein expression among groups (n = 4 for each group; P = 0.5223). (e,f) Representative immunoblots and densitometry analysis (n = 4 for each group). Although STIM1 protein expression was reduced, the O-GlcNAcylation (85 kDa, indicated by the arrow) was larger in the MetS group. $ P = 0.038 for the MetS group versus the control. All of the changes in the MetS group were absent in the normal-VLDL group (Normal). (g) Whole-cell O-GlcNAcylation immunoblotting showed enhanced O-GlcNAcylation of the nuclear, cytosol, and membranous protein fractions in the MetS groups. (g,h) The inhibition (with 5 μM deoxynorleucine (DON)) and enhancement (with 10 nM Thiamet G (ThmG)) of O-GlcNAcylation did not affect the expression of STIM1. Full article ">Figure 2
Suppressed store-operated Ca2+ entry (SOCE) following sarcoplasmic reticulum (SR) Ca2+ depletion in MetS-VLDL-treated HL-1 cardiomyocytes. (a–c) Representative ratiometric tracings in fluorescence measurements in control, normal-VLDL, and MetS-VLDL-treated HL-1 cells during SOCE testing. (d–e) Representative ratiometric tracings from STIM-1 inhibited HL-1 cells. SKF 96365, a STIM1 inhibitor. (f) Analysis of data from the ratiometric fluorescence 340:380 ratio for the peak response to thapsigargin/caffeine (TG/Caff) (n = 5 experiments; $ P = 0.024, # P < 0.001, * P < 0.01, all vs. control) and the peak of SOCE (n = 5 experiments; all # P < 0.001 vs. control; all * P < 0.001 vs. normal-VLDLs). Full article ">Figure 3
MetS-VLDLs suppressed calcineurin–nuclear factor of activated T-cells (NFAT) signaling pathways. (a) Representative bands of western blots (n = 4 for each group) for nuclear and cytosolic fractions of calcineurin, NFAT, and phosphorylated NFAT in proteins. (b) Reduced nuclear calcineurin in the MetS-VLDL group (MetS) (n = 4; $ P = 0.037 vs. control, # P = 0.04 vs. normal-VLDL group (Normal)). (c) Unchanged cytosolic expression of calcineurin protein (n = 4, P = 0.9377). (d) Reduced nuclear NFAT in the MetS group (n = 4; $ P = 0.007, # P = 0.009). (e) Increased phosphorylated NFAT in the cytoplasm of the MetS group (n = 4, $ P = 0.04). (f) Reduced calcineurin activity in the MetS group (n = 6; $ P = 0.0001, # P = 0.0001). Full article ">Figure 4
MetS-VLDLs altered myofilament protein expression and induced sarcomere derangement. (a) Phosphorylated cardiac myosin-binding protein C (cMyBPC), cardiac troponin I (TnI) and T (TnT), and myosin light chain 2 (MLC2) on 1D-gradient gels stained with ProQ Diamond reagent (left) and total protein expression shown on the gel subsequently stained with SYPRO Ruby (right). SKF 96365, a STIM1-inhibtor; FK-506, a calcineurin-inhibitor; n = 4 for each group. (b). Densitometry analyses from gels with ProQ and SYPRO staining. (c) ProQ Diamond staining gels of mouse atrial proteins (n = 3 for each group: Control; Normal-VLDL-injected mice, nVLDL; and MetS-VLDL-injected mice, msVLDL). (d) Densitometry analyses for phosphorylated cMyBPC, desmin, TnT, TnI, and MLC2. $ P < 0.05 msVLDL versus control; # P < 0.05 msVLDL versus nVLDL. (e,f) Western blot and densitometry analysis for desmin in atrial tissues. (g) Representative transmission electron microscopy (TEM) pictures (at 5000× magnification) showing disorganized Z lines (Z, highlighted with dashed lines) in the atrial tissue of mice receiving a MetS-VLDL injection (msVLDL) compared to normal Z lines in the controls and in mice receiving normal-VLDLs (nVLDL) (n = 3 for each group). Atrial sarcomeres are aligned with mitochondria (m). Full article ">Figure 5
Lipotoxicity of VLDLs on mediating maladaptation of calcium regulation to derangement of sarcomere proteins in atrial myopathy. In metabolic syndrome (MetS), VLDLs undergo biochemical property changes and become different from VLDLs of normal conditions [<a href="#B23-jcm-08-00881" class="html-bibr">23</a>]. MetS-VLDLs reduce STIM1 expression and enhance O-GlcNAcylation on STIM1 protein. These changes in concert suppress SOCE and the downstream calcineurin–NFAT pathway, resulting in alteration of myofilament protein expression, disruption of sarcomere organization, and atrial myopathy [<a href="#B35-jcm-08-00881" class="html-bibr">35</a>]. The progression of atrial myopathy ultimately leads to atrial fibrillation. Full article ">

15 pages, 1688 KiB

Open AccessArticle

High TSH Level within Normal Range Is Associated with Obesity, Dyslipidemia, Hypertension, Inflammation, Hypercoagulability, and the Metabolic Syndrome: A Novel Cardiometabolic Marker

by Yi-Cheng Chang, Shih-Che Hua, Chia-Hsuin Chang, Wei-Yi Kao, Hsiao-Lin Lee, Lee-Ming Chuang, Yen-Tsung Huang and Mei-Shu Lai

J. Clin. Med. 2019, 8(6), 817; https://doi.org/10.3390/jcm8060817 - 7 Jun 2019

Cited by 54 | Viewed by 8980

Abstract

(1) Background: Overt and subclinical hypothyroidism has been associated with increased cardiometabolic risks. Here we further explore whether thyroid function within normal range is associated with cardiometabolic risk factors in a large population-based study. (2) Methods: We screened 24,765 adults participating in health [...] Read more.

(1) Background: Overt and subclinical hypothyroidism has been associated with increased cardiometabolic risks. Here we further explore whether thyroid function within normal range is associated with cardiometabolic risk factors in a large population-based study. (2) Methods: We screened 24,765 adults participating in health examinations in Taiwan. Participants were grouped according to high-sensitive thyroid-stimulating hormone (hsTSH) level as: <50th percentile (0.47–1.48 mIU/L, the reference group), 50–60th percentile (1.49–1.68 mIU/L), 60–70th percentile (1.69–1.94 mIU/L), 70–80th percentile (1.95–2.3 mIU/L), 80–90th percentile (2.31–2.93 mIU/L), and >90th percentile (>2.93 mIU/L). Cardiometabolic traits of each percentile were compared with the reference group. (3) Results: Elevated hsTSH levels within normal range were dose-dependently associated with increased body mass index, body fat percentage, waist circumferences, blood pressure, hemoglobin A1c (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), high homeostasis model of assessment of beta-cell (HOMA-?), triglycerides, total cholesterols, fibrinogen, and uric acids (p-for-trend <0.001), but not with fasting glucose levels. The association remained significant after adjustment of age, sex, and lifestyle. As compared to the reference group, subjects with the highest hsTSH percentile had significantly increased risk of being overweight (adjusted odds ratio (adjOR): 1.35), increased body fat (adjOR: 1.29), central obesity (adjOR: 1.36), elevated blood pressure (adjOR: 1.26), high HbA1c (adjOR: 1.20), hyperinsulinemia (adjOR: 1.75), increased HOMA-IR (adjOR: 1.45), increased HOMA-? (adjOR: 1.40), hypertriglyceridemia (adjOR: 1.60), hypercholesterolemia (adjOR: 1.25), elevated hsCRP (adjOR: 1.34), increased fibrinogen (adjOR: 1.45), hyperuricemia (adjOR: 1.47), and metabolic syndrome (adjOR: 1.42), but significant risk of low fasting glucose (adjOR: 0.89). Mediation analysis indicates that insulin resistance mediates the majority of the association between thyroid hormone status and the metabolic syndrome. (4) Conclusion: Elevated hsTSH within the normal range is a cardiometabolic risk marker associated with central obesity, insulin resistance, elevated blood pressure, dyslipidemia, hyperuricemia, inflammation, and hypercoagulability. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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19 pages, 2116 KiB

Open AccessArticle

Plasma microRNA Profiling Reveals Novel Biomarkers of Epicardial Adipose Tissue: A Multidetector Computed Tomography Study

by David de Gonzalo-Calvo, David Vilades, Pablo Martínez-Camblor, Àngela Vea, Andreu Ferrero-Gregori, Laura Nasarre, Olga Bornachea, Jesus Sanchez Vega, Rubén Leta, Núria Puig, Sonia Benítez, Jose Luis Sanchez-Quesada, Francesc Carreras and Vicenta Llorente-Cortés

J. Clin. Med. 2019, 8(6), 780; https://doi.org/10.3390/jcm8060780 - 1 Jun 2019

Cited by 16 | Viewed by 3506

Abstract

Epicardial adipose tissue (EAT) constitutes a novel parameter for cardiometabolic risk assessment and a target for therapy. Here, we evaluated for the first time the plasma microRNA (miRNA) profile as a source of biomarkers for epicardial fat volume (EFV). miRNAs were profiled in [...] Read more.

Epicardial adipose tissue (EAT) constitutes a novel parameter for cardiometabolic risk assessment and a target for therapy. Here, we evaluated for the first time the plasma microRNA (miRNA) profile as a source of biomarkers for epicardial fat volume (EFV). miRNAs were profiled in plasma samples from 180 patients whose EFV was quantified using multidetector computed tomography. In the screening study, 54 deregulated miRNAs were identified in patients with high EFV levels (highest tertile) compared with matched patients with low EFV levels (lowest tertile). After filtering, 12 miRNAs were selected for subsequent validation. In the validation study, miR-15b-3p, miR-22-3p, miR-148a-3p miR-148b-3p and miR-590-5p were directly associated with EFV, even after adjustment for confounding factors (p value < 0.05 for all models). The addition of miRNA combinations to a model based on clinical variables improved the discrimination (area under the receiver-operating-characteristic curve (AUC) from 0.721 to 0.787). miRNAs correctly reclassified a significant proportion of patients with an integrated discrimination improvement (IDI) index of 0.101 and a net reclassification improvement (NRI) index of 0.650. Decision tree models used miRNA combinations to improve their classification accuracy. These results were reproduced using two proposed clinical cutoffs for epicardial fat burden. Internal validation corroborated the robustness of the models. In conclusion, plasma miRNAs constitute novel biomarkers of epicardial fat burden. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

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Full article ">Figure 1
Plasma microRNA (miRNA) profiling. (A) Unsupervised hierarchical clustering. The heat map diagram shows the result of a two-way hierarchical clustering of patients and miRNAs. Each column represents a patient (Tertile 1 of epicardial fat volume vs. Tertile 3 of epicardial fat volume). Each row represents a miRNA. The patient clustering tree is shown on top. The miRNA clustering tree is shown on the left. The color scale illustrates the relative expression level of miRNAs. The expression intensity of each miRNA in each sample varies from red to blue, which indicates relatively high or low expression, respectively. (B) p value for the comparison between study groups. Each point represents a miRNA. Red dots represent the selected candidates. (C) Plasma expression levels of miRNAs in study groups. (D) Expression levels of miRNAs in epicardial adipose tissue explants. Each point represents a sample. (E) Expression levels of miRNAs in conditioned media exposed to epicardial adipose tissue explants. Each point represents a sample. Relative quantification was performed using cel-miR-39-3p as the external standard for extracellular miRNAs and SNORD48 as the internal standard for tissue miRNAs. MicroRNA levels were log2-transformed. MicroRNA expression levels are expressed as arbitrary units. Differences between groups were analyzed using the Mann–Whitney U test. p values describe the significance level of differences for each comparison. Full article ">Figure 2
Plasma microRNA (miRNA) validation. (A–B) Examples of multidetector computed tomography scans and the corresponding epicardial fat volume of patients in the first-second and third tertiles of epicardial fat volume. (C) Plasma expression levels of miRNAs in study groups. MicroRNA levels were log2-transformed. MicroRNA expression levels are expressed as arbitrary units. Differences between groups were analyzed using Student’s t-test for independent samples. p values describe the significance level of differences for each comparison. EFV: epicardial fat volume. Full article ">Figure 3
Plasma microRNAs (miRNAs) as biomarkers of epicardial fat volume, according to EFV tertiles. (A) Area under the ROC curve (AUC) for each individual miRNAs and for combinations of miRNAs in pairs or families. (B) Performance of plasma miRNAs as biomarkers. (C,D) Decision trees calculated by chi-squared automatic interaction detector (CHAID) algorithm. The following variables were included in the clinical model: age, sex, body mass index and diabetes mellitus. MicroRNA levels were log2-transformed. For logistic regression models, data are presented as an odds ratio (OR) and 95% confidence intervals (CI). For discrimination analysis, data are presented as the AUC and 95% CI. For reclassification analysis, data are presented as the Integrated Discrimination Improvement (IDI) index and Net Reclassification Improvement (NRI) index and their respective and 95% CI. For decision trees, data are shown as frequency (percentage) of patients in each study group. Full article ">Figure 4
Plasma microRNAs (miRNAs) as biomarkers of epicardial fat volume, according to the cutoff values proposed by Spearman et al. [<a href="#B15-jcm-08-00780" class="html-bibr">15</a>]. (A) Area under the ROC curve (AUC) for each individual miRNAs and for combinations of miRNAs in pairs or families. (B) Performance of plasma miRNAs as biomarkers. (C,D) Decision trees calculated by Chi-squared Automatic Interaction Detector (CHAID) algorithm. The following variables were included in the clinical model: age, sex, body mass index and diabetes mellitus. MicroRNA levels were log2-transformed. For logistic regression models, data are presented as an odds ratio (OR) and 95% confidence intervals (CI). For discrimination analysis, data are presented as the AUC and 95% CI. For reclassification analysis, data are presented as the Integrated Discrimination Improvement (IDI) index and Net Reclassification Improvement (NRI) index and their respective 95% CI. For decision trees, data are shown as frequency (percentage) of patients in each study group. Full article ">

12 pages, 1188 KiB

Open AccessArticle

CA125 as a Marker of Heart Failure in the Older Women: A Population-Based Analysis

by Weronika Bulska-Będkowska, Elżbieta Chełmecka, Aleksander J. Owczarek, Katarzyna Mizia-Stec, Andrzej Witek, Aleksandra Szybalska, Tomasz Grodzicki, Magdalena Olszanecka-Glinianowicz and Jerzy Chudek

J. Clin. Med. 2019, 8(5), 607; https://doi.org/10.3390/jcm8050607 - 3 May 2019

Cited by 10 | Viewed by 6050

Abstract

(1) Background: Cancer antigen 125 (CA125) is a glycoprotein that is expressed by tissue derived from coelomic epithelium in the pleura, peritoneum, pericardium. It has been shown that CA125 concentrations are correlated with NT-proBNP in older people with congestive heart failure (HF). We [...] Read more.

(1) Background: Cancer antigen 125 (CA125) is a glycoprotein that is expressed by tissue derived from coelomic epithelium in the pleura, peritoneum, pericardium. It has been shown that CA125 concentrations are correlated with NT-proBNP in older people with congestive heart failure (HF). We conducted a study on the association between concentrations of CA125 and NT-proBNP in a population-based cohort of older Polish women. (2) Methods: The current research is sub-study of a large, cross-sectional research project (PolSenior). The study group consisted of 1565 Caucasian women aged 65–102 years. To assess the relationship between CA125 and other variables a stepwise backward multivariate normal and skew-t regression analyses were performed. (3) Results: The median of CA125 concentration was 13.0 U/mL and values over the upper normal range limit (35 U/mL) were observed in 5.1% (n = 79) of the study cohort. The concentration of CA125 was positively related to age, hospitalization for HF and history of atrial fibrillation and chronic obstructive pulmonary disease, levels of NT-proBNP, IL-6, hs-CRP and triglycerides. We found in the multivariate analyses, that increased CA125 levels were independently associated with log₁₀ (IL-6) (β = 11.022), history of hospitalization for HF (β = 4.619), log₁₀ (NT-proBNP) (β = 4.416) and age (β = 3.93 for 10 years). (4) Conclusions: Despite the association between CA125 and NT-proBNP, the usefulness of CA125 for the detection of HF in older women is limited by factors such as inflammatory status and age. Full article

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14 pages, 770 KiB

Open AccessArticle

Associations of Adiposity and Diet Quality with Serum Ceramides in Middle-Aged Adults with Cardiovascular Risk Factors

by Margaret A. Drazba, Ida Holásková, Nadine R. Sahyoun and Melissa Ventura Marra

J. Clin. Med. 2019, 8(4), 527; https://doi.org/10.3390/jcm8040527 - 17 Apr 2019

Cited by 10 | Viewed by 3644

Abstract

Rates of adverse cardiovascular events have increased among middle-aged adults. Elevated ceramides have been proposed as a risk factor for cardiovascular events. Diet quality and weight status are inversely associated with several traditional risk factors; however, the relationship to ceramides is less clear. [...] Read more.

Rates of adverse cardiovascular events have increased among middle-aged adults. Elevated ceramides have been proposed as a risk factor for cardiovascular events. Diet quality and weight status are inversely associated with several traditional risk factors; however, the relationship to ceramides is less clear. This study aimed to determine associations of adiposity and diet quality with circulating ceramides in middle-aged adults (n = 96). Diet quality was estimated using the Healthy Eating Index 2015 (HEI-2015). Serum ceramide concentrations were determined by liquid chromatography–mass spectrometry. A ceramide risk score was determined based on ceramides C16:0, C18:0, and C24:1 and their ratios to C24:0. Participants who were classified as at ‘moderate risk’ compared to ‘lower-risk’ based on a ceramide risk score had significantly higher body mass index (BMI) values, as well as higher rates of elevated fibrinogen levels, metabolic syndrome, and former smoking status. BMI was positively associated with the ceramide C18:0 (R² = 0.31, p < 0.0001), the ratio between C18:0/C24:0 ceramides (R² = 0.30, p < 0.0001), and the ceramide risk score (R² = 0.11, p < 0.009). Total HEI-2015 scores (R² = 0.42, p = 0.02), higher intakes of vegetables (R² = 0.44, p = 0.02) and whole grains (R² = 0.43, p = 0.03), and lower intakes of saturated fats (R² = 0.43, p = 0.04) and added sugar (R² = 0.44, p = 0.01) were associated with lower C22:0 values. These findings suggest that circulating ceramides are more strongly related to adiposity than overall diet quality. Studies are needed to determine if improvements in weight status result in lower ceramides and ceramide risk scores. Full article

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29 pages, 392 KiB

Open AccessReview

Classic and Novel Biomarkers as Potential Predictors of Ventricular Arrhythmias and Sudden Cardiac Death

by Zornitsa Shomanova, Bernhard Ohnewein, Christiane Schernthaner, Killian Höfer, Christian A. Pogoda, Gerrit Frommeyer, Bernhard Wernly, Mathias C. Brandt, Anna-Maria Dieplinger, Holger Reinecke, Uta C. Hoppe, Bernhard Strohmer, Rudin Pistulli and Lukas J. Motloch

J. Clin. Med. 2020, 9(2), 578; https://doi.org/10.3390/jcm9020578 - 20 Feb 2020

Cited by 20 | Viewed by 4737

Abstract

Sudden cardiac death (SCD), most often induced by ventricular arrhythmias, is one of the main reasons for cardiovascular-related mortality. While coronary artery disease remains the leading cause of SCD, other pathologies like cardiomyopathies and, especially in the younger population, genetic disorders, are linked [...] Read more.

Sudden cardiac death (SCD), most often induced by ventricular arrhythmias, is one of the main reasons for cardiovascular-related mortality. While coronary artery disease remains the leading cause of SCD, other pathologies like cardiomyopathies and, especially in the younger population, genetic disorders, are linked to arrhythmia-related mortality. Despite many efforts to enhance the efficiency of risk-stratification strategies, effective tools for risk assessment are still missing. Biomarkers have a major impact on clinical practice in various cardiac pathologies. While classic biomarkers like brain natriuretic peptide (BNP) and troponins are integrated into daily clinical practice, inflammatory biomarkers may also be helpful for risk assessment. Indeed, several trials investigated their application for the prediction of arrhythmic events indicating promising results. Furthermore, in recent years, active research efforts have brought forward an increasingly large number of “novel and alternative” candidate markers of various pathophysiological origins. Investigations of these promising biological compounds have revealed encouraging results when evaluating the prediction of arrhythmic events. To elucidate this issue, we review current literature dealing with this topic. We highlight the potential of “classic” but also “novel” biomarkers as promising tools for arrhythmia prediction, which in the future might be integrated into clinical practice. Full article

(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)

24 pages, 1134 KiB

Open AccessReview

Peripheral Blood Mononuclear Cells and Platelets Mitochondrial Dysfunction, Oxidative Stress, and Circulating mtDNA in Cardiovascular Diseases

by Abrar Alfatni, Marianne Riou, Anne-Laure Charles, Alain Meyer, Cindy Barnig, Emmanuel Andres, Anne Lejay, Samy Talha and Bernard Geny

J. Clin. Med. 2020, 9(2), 311; https://doi.org/10.3390/jcm9020311 - 22 Jan 2020

Cited by 37 | Viewed by 6473

Abstract

Cardiovascular diseases (CVDs) are devastating disorders and the leading cause of mortality worldwide. The pathophysiology of cardiovascular diseases is complex and multifactorial and, in the past years, mitochondrial dysfunction and excessive production of reactive oxygen species (ROS) have gained growing attention. Indeed, CVDs [...] Read more.

Cardiovascular diseases (CVDs) are devastating disorders and the leading cause of mortality worldwide. The pathophysiology of cardiovascular diseases is complex and multifactorial and, in the past years, mitochondrial dysfunction and excessive production of reactive oxygen species (ROS) have gained growing attention. Indeed, CVDs can be considered as a systemic alteration, and understanding the eventual implication of circulating blood cells peripheral blood mononuclear cells (PBMCs) and or platelets, and particularly their mitochondrial function, ROS production, and mitochondrial DNA (mtDNA) releases in patients with cardiac impairments, appears worthwhile. Interestingly, reports consistently demonstrate a reduced mitochondrial respiratory chain oxidative capacity related to the degree of CVD severity and to an increased ROS production by PBMCs. Further, circulating mtDNA level was generally modified in such patients. These data are critical steps in term of cardiac disease comprehension and further studies are warranted to challenge the possible adjunct of PBMCs’ and platelets’ mitochondrial dysfunction, oxidative stress, and circulating mtDNA as biomarkers of CVD diagnosis and prognosis. This new approach might also allow further interesting therapeutic developments. Full article

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14 pages, 1463 KiB

Open AccessReview

Heart-Type Fatty Acid-Binding Protein (H-FABP) and Its Role as a Biomarker in Heart Failure: What Do We Know So Far?

by Richard Rezar, Peter Jirak, Martha Gschwandtner, Rupert Derler, Thomas K. Felder, Michael Haslinger, Kristen Kopp, Clemens Seelmaier, Christina Granitz, Uta C. Hoppe and Michael Lichtenauer

J. Clin. Med. 2020, 9(1), 164; https://doi.org/10.3390/jcm9010164 - 7 Jan 2020

Cited by 71 | Viewed by 10553

Abstract

Background: Heart failure (HF) remains one of the leading causes of death to date despite extensive research funding. Various studies are conducted every year in an attempt to improve diagnostic accuracy and therapy monitoring. The small cytoplasmic heart-type fatty acid-binding protein (H-FABP) has [...] Read more.

Background: Heart failure (HF) remains one of the leading causes of death to date despite extensive research funding. Various studies are conducted every year in an attempt to improve diagnostic accuracy and therapy monitoring. The small cytoplasmic heart-type fatty acid-binding protein (H-FABP) has been studied in a variety of disease entities. Here, we provide a review of the available literature on H-FABP and its possible applications in HF. Methods: Literature research using PubMed Central was conducted. To select possible studies for inclusion, the authors screened all available studies by title and, if suitable, by abstract. Relevant manuscripts were read in full text. Results: In total, 23 studies regarding H-FABP in HF were included in this review. Conclusion: While, algorithms already exist in the area of risk stratification for acute pulmonary embolism, there is still no consensus for the routine use of H-FABP in daily clinical practice in HF. At present, the strongest evidence exists for risk evaluation of adverse cardiac events. Other future applications of H-FABP may include early detection of ischemia, worsening of renal failure, and long-term treatment planning. Full article

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