Biomarkers in Coronary Artery Bypass Surgery: Ready for Prime Time and Outcome Prediction?

Coronary artery bypass surgery (CABG) is still one of the most frequently performed surgical procedures all over the world. The results of this procedure have been constantly improved over the years with low perioperative mortality rates, with relatively low complication rates. To further improve these outstanding results, the clinicians focused their attention at biomarkers as outcome predictors. Although biological testing for disease prediction has already been discussed many times, the role of biomarkers in outcome prediction after CABG is still controversial. In this article, we reviewed the current knowledge regarding the role of genetic and dynamic biomarkers and their possible association with the occurrence of adverse clinical outcomes after CABG. We also took into consideration that the molecular pathway activation and the possible imbalance may affect hard outcomes and graft patency. We analyzed biomarkers classified in two different categories depending on their possibility to change over time: genetic markers and dynamic markers. Moreover, we evaluated these markers by dividing them, into sub-categories, such as inflammation, hemostasis, renin-angiotensin, endothelial function, and other pathways. We showed that biomarkers might be associated with unfavorable outcomes after surgery, and in some cases improved outcome prediction. However, the identification of a specific panel of biomarkers or of some algorithms including biomarkers is still in an early developmental phase. Finally, larger studies are needed to analyze broad panel of biomarkers with the specific aim to evaluate the prediction of hard outcomes and graft patency

Aortic valve sclerosis as a marker of atherosclerosis: Novel insights from hepatic steatosis

Background Nowadays, aortic valve sclerosis (AVSc) might be considered an atherosclerosis-like process due to significant association with age, male gender and some major features of metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) has been recognized as a clinical expression of the metabolic syndrome and as a predictor of cardiovascular events. We aim, with this meta-analysis, to evaluate the correlation between NAFLD and AVSc; this finding might suggest new insights and interactions among NAFLD, AVSc and the atherosclerotic process. Methods and results A detailed search was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to identify all studies providing data about the association between AVSc and NAFLD. 3 studies enrolling a total of 1172 patients with NAFLD and 1467 controls without NAFLD were included in the meta-analysis. The prevalence of AVSc was 41.3% (95% CI: 32.0%, 51.4%) in NAFLD patients and 24.6% (18.4%, 32.0%) in subjects without NAFLD with a corresponding OR of 2.28 (95% CI: 1.21, 4.28, p = 0.01, I2: 77.6%, p = 0.011). A meta-regression analysis showed that age, prevalence of male gender, hypertension, body mass index, and dyslipidemia were directly and significantly associated with the difference in the prevalence of AVSc between patients with NAFLD and those without. Conclusions In conclusion, our meta-analysis shows a significant association between NAFLD and AVSc. However, further evidence is needed to validate these findings and find out if there is a real link or just a mere association

Putative Circulating MicroRNAs Are Able to Identify Patients with Mitral Valve Prolapse and Severe Regurgitation

Mitral valve prolapse (MVP) associated with severe mitral regurgitation is a debilitating disease with no pharmacological therapies available. MicroRNAs (miRNA) represent an emerging class of circulating biomarkers that have never been evaluated in MVP human plasma. Our aim was to identify a possible miRNA signature that is able to discriminate MVP patients from healthy subjects (CTRL) and to shed light on the putative altered molecular pathways in MVP. We evaluated a plasma miRNA profile using Human MicroRNA Card A followed by real-time PCR validations. In addition, to assess the discriminative power of selected miRNAs, we implemented a machine learning analysis. MiRNA profiling and validations revealed that miR-140-3p, 150-5p, 210-3p, 451a, and 487a-3p were significantly upregulated in MVP, while miR-223-3p, 323a-3p, 340-5p, and 361-5p were significantly downregulated in MVP compared to CTRL (p ≤ 0.01). Functional analysis identified several biological processes possible linked to MVP. In addition, machine learning analysis correctly classified MVP patients from CTRL with high accuracy (0.93) and an area under the receiving operator characteristic curve (AUC) of 0.97. To the best of our knowledge, this is the first study performed on human plasma, showing a strong association between miRNAs and MVP. Thus, a circulating molecular signature could be used as a first-line, fast, and cheap screening tool for MVP identification

Presence of SARS-CoV-2 Nucleoprotein in Cardiac Tissues of Donors with Negative COVID-19 Molecular Tests

The 2019 Coronavirus disease (COVID-19) outbreak had detrimental effects on essential medical services such as organ and tissue donation. Lombardy, one of the most active Italian regions in organ/tissue procurement, has been strongly affected by the COVID-19 pandemic. To date, data concerning the risk of SARS-CoV-2 transmission after tissue transplantation are controversial. Here, we aimed to evaluate the presence/absence of SARS-CoV-2 in different cardiac tissues eligible for transplantation obtained from Lombard donors. We used cardiovascular tissues from eight donors potentially suitable for pulmonary valve transplantation. All donor subjects involved in the study returned negative results for the SARS-CoV-2 RNA molecular tests (quantitative real-time reverse-transcription PCR, qRT-PCR, and chip-based digital PCR) in nasopharyngeal swabs (NPS) or bronchoalveolar lavage (BAL). None of the eight donors included in this study revealed the presence of the SARS-CoV-2 viral genome. However, evaluation of the protein content of pulmonary vein wall (PVW) tissue revealed variable levels of SARS-CoV-2 nucleoprotein signal in all donors. Our study demonstrated for the first time, to the best of our knowledge, that viral nucleoprotein but not viral RNA was present in the examined tissue bank specimens, suggesting the need for caution and in-depth investigations on implantable tissue specimens collected during the COVID-19 pandemic period

Purinergic Receptor P2Y2 Stimulation Averts Aortic Valve Interstitial Cell Calcification and Myofibroblastic Activation

Rationale—Calcific aortic valve stenosis (CAVS) is a pathological condition of the aortic valve with a prevalence of 3% in the general population. It is characterized by massive rearrangement of the extracellular matrix, mostly due to the accumulation of fibro-calcific deposits driven by valve interstitial cells (VIC), and no pharmacological treatment is currently available. The aim of this study was to evaluate the effects of P2Y2 receptor (P2RY2) activation on fibro-calcific remodeling of CAVS. Methods—We employed human primary VICs isolated from CAVS leaflets treated with 2-thiouridine-5′-triphosphate (2ThioUTP, 10 µM), an agonist of P2RY2. The calcification was induced by inorganic phosphate (2 mM) and ascorbic acid (50 µg/mL) for 7 or 14 days, while the 2ThioUTP was administered starting from the seventh day. 2ThioUTP was chronically administered for 5 days to evaluate myofibroblastic activation. Results—P2RY2 activation, under continuous or interrupted pro-calcific stimuli, led to a significant inhibition of VIC calcification potential (p < 0.01). Moreover, 2ThioUTP treatment was able to significantly reduce pro-fibrotic gene expression (p < 0.05), as well as that of protein α-smooth muscle actin (p = 0.004). Conclusions—Our data suggest that P2RY2 activation should be further investigated as a pharmacological target for the prevention of CAVS progression, acting on both calcification and myofibroblastic activation

Impact of Oxidative Stress and Protein S-Glutathionylation in Aortic Valve Sclerosis Patients with Overt Atherosclerosis

Aortic valve sclerosis (AVSc) is characterized by non-uniform thickening of the leaflets without hemodynamic changes. Endothelial dysfunction, also caused by dysregulation of glutathione homeostasis expressed as ratio between its reduced (GSH) and its oxidised form (GSSG), could represent one of the pathogenic triggers of AVSc. We prospectively enrolled 58 patients with overt atherosclerosis and requiring coronary artery bypass grafting (CABG). The incidence of AVSc in the studied population was 50%. The two groups (No-AVSc and AVSc) had similar clinical characteristics. Pre-operatively, AVSc group showed significantly lower GSH/GSSG ratio than No-AVSc group (p = 0.02). Asymmetric dimethylarginine (ADMA) concentration was significantly higher in AVSc patients compared to No-AVSc patients (p < 0.0001). Explanted sclerotic aortic valves presented a significantly increased protein glutathionylation (Pr-SSG) than No-AVSc ones (p = 0.01). In vitro, inhibition of glutathione reductase caused β-actin glutathionylation, activation of histone 2AX, upregulation of α2 smooth muscle actin (ACTA2), downregulation of platelet and endothelial cell adhesion molecule 1 (PECAM1) and cadherin 5 (CDH5). In this study, we showed for the first time that the dysregulation of glutathione homeostasis is associated with AVSc. We found that Pr-SSG is increased in AVSc leaflets and it could lead to EndMT via DNA damage. Further studies are warranted to elucidate the causal role of Pr-SSG in aortic valve degeneration