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Background: Thoracic aortic aneurysm (TAA) is a serious condition that affects the aorta, characterized by the dilation of its first segment. The causes of TAA (e.g., age, hypertension, genetic syndromes) are heterogeneous and contribute to the weakening of the aortic wall. This complexity makes treating this life-threatening aortopathy challenging, as there are currently no etiological therapy available, and pharmacological strategies, aimed at avoiding surgical aortic replacement, are merely palliative. Recent studies on novel therapies for TAA have focused on identifying biological targets and etiological mechanisms of the disease by using advanced -omics techniques, including epigenomics, transcriptomics, proteomics, and metabolomics approaches., Methods: This review presents the latest findings from -omics approaches and underscores the importance of integrating multi-omics data to gain more comprehensive understanding of TAA., Results: Literature suggests that the alterations in TAA mediators frequently involve members of pro-fibrotic process (i.e., TGF-β signaling pathways) or proteins associated with cell/extracellular structures (e.g., aggrecans). Further analyses often reported the importance in TAA of processes as inflammation (PCR, CD3, leukotriene compounds), oxidative stress (chromatin OXPHOS, fatty acids), mitochondrial respiration and glycolysis/gluconeogenesis (e.g., PPARs and HIF1a). Of note, more recent metabolomics studies added novel molecular markers to the list of TAA-specific detrimental mediators (proteoglycans)., Conclusion: It is increasingly clear that integrating data from different -omics branches, along with clinical data, is essential as well as complicated both to reveal hidden relevant information and to address complex diseases such as TAA. Importantly, recent progresses in metabolomics highlighted novel potential and unprecedented marks in TAA diagnosis and therapy., (© 2023. The Author(s).)

Aims: Patients with coronary heart disease (CHD) are at very high risk of recurrent events. A strategy to reduce excess risk might be to deliver structured secondary prevention programmes, but their efficacy has been mostly evaluated in the short term and in experimental settings. This is a retrospective case-control study aimed at assessing, in the real world, the efficacy of a secondary prevention programme in reducing long-term coronary event recurrences after coronary artery bypass surgery (CABG)., Methods and Results: Programme participants (henceforth 'cases') were men and women aged <75 years subjected to CABG between 2002 and 2014, living within 100 km of the hospital. Key programme actions included optimization of treatments according to the most updated European preventive guidelines, surveillance of therapy adherence, and customized lifestyle counselling. Controls were analogous patients not involved in the programme because living farther than 100 km away, matched 1:1 with cases for gender, age at CABG, and year of CABG. Both groups (n = 1248) underwent usual periodic cardiology follow-up at our centre. Data on symptomatic or silent CHD recurrences were obtained from the hospital electronic health records. Cox analysis (adjusted for baseline differences between groups) shows that programme participation was associated with a significantly lower incidence throughout 5 years post-CABG of symptomatic [hazard ratio (95% confidence interval): 0.59 (0.38-0.94)] and silent [0.53 (0.31-0.89)] coronary recurrences., Conclusion: In a real-world setting, taking part in a structured longstanding secondary prevention programme, in addition to usual cardiology care, meaningfully lowers the risk of coronary recurrences., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Coronary artery bypass graft (CABG) surgery still represents the gold standard for patients with complex multivessel coronary artery disease. However, graft occlusion still occurs in a significant proportion of CABG conduits, and oxidative stress is currently considered to be a potential contributor. Human serum albumin (HSA) represents the main antioxidant in plasma through its reduced amino acid Cys34, which can efficiently scavenge several oxidants. In a nested case-control study including 36 patients with occluded grafts and 38 age- and sex-matched patients without occlusion, we assessed the levels of the native mercaptoalbumin (HSA-SH) and oxidized thiolated form of albumin (Thio-HSA) in relation with graft occlusion within 5 years after CABG. We found that the plasma level of preoperative HSA-SH was significantly lower in patients with occluded graft at 5 years follow-up than in patients with graft patency. Furthermore, low HSA-SH remained independently associated with graft occlusion even after adjusting for preoperative D-dimer, a well-known marker of activated coagulation recently found to be associated with graft occlusion. In conclusion, the preoperative level of HSA-SH is independently associated with graft occlusion in CABG and represents a measurable and potentially druggable predictor.

Background: Current knowledge regarding the relationship between aortic valve sclerosis (AVSc), cardiovascular risk factors, and mortality in patients with known coronary artery disease (CAD) is still unclear. The present study aimed at investigating the prevalence of AVSc as well as its association with long-term all-cause mortality in high-risk CAD patients that has never been explored in large cohorts thus far. Methods and Results: In this retrospective and observational cohort study we enrolled high-risk CAD patients, hospitalized at Centro Cardiologico Monzino (CCM), Milan, Italy, between January 2006 and December 2016. The morphology and function of the aortic valve were assessed from the recorded echocardiographic images to evaluate the presence of AVSc, defined as a non-uniform thickening of the aortic leaflets with no consequences on hemodynamics. Data on 5-year all-cause mortality was retrieved from a Regional database. Of the 5,489 patients initially screened, 4,938 (mean age 67 ± 11 years, 3,954 [80%] men) were enrolled in the study. In the overall population, AVSc was detected in 2,138 (43%) patients. Multivariable LASSO regression revealed that age, female gender, diabetes mellitus, previous MI, and left ventricular ejection fraction were independently associated with AVSc. All-cause mortality (adjusted hazard ratio: 1.29, 95%CI: 1.05-1.58) was significantly higher in AVSc than in non-AVSc patients. Conclusions: AVSc is frequently detected in high-risk CAD patients and is associated with long-term mortality. Our findings corroborate the hypothesis that AVSc is an underestimated marker of systemic cardiovascular risk. Thus, AVSc detection may be used to improve long-term risk stratification of high-risk CAD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Myasoedova, Genovese, Cavallotti, Bonomi, Chiesa, Campodonico, Rondinelli, Cosentino, Baldassarre, Veglia, Pepi, Alamanni, Colombo, Marenzi and Poggio.)

Background: A strong association between aortic valve sclerosis (AVSc), the earliest manifestation of calcific aortic valve disease, and atherosclerosis exists. The aim of the study was to evaluate the predictive capabilities of AVSc on long-term all-cause mortality, in patients requiring carotid endarterectomy (CEA). Methods and Results: 806 consecutive CEA patients were enrolled. Preoperative echocardiography was used to assess AVSc. Computed tomography angiography was applied for plaque characterization. Kaplan-Meier curves, Cox linear regression, and area under the receiving operator characteristic (AUC) curve analyses were used to evaluate the predictive capability of AVSc. Overall, 348 of 541 patients had AVSc (64%). Age, diabetes, and estimated glomerular filtration rate (eGFR) were associated with AVSc. In the 5-year follow-up, AVSc group had a mortality rate of 16.7% while in no-AVSc group was 7.8%. Independent predictors of all-cause mortality were age, sex, eGFR, left ventricular ejection fraction, and AVSc. After adjustments, AVSc was associated with a significant increase in all-cause mortality risk (hazard ratio, HR = 1.9; 95%CI: 1.04-3.54; p = 0.038). We stratify our cohort based on carotid atheromatous plaque-type: soft, calcified, and mixed-fibrotic. In patients with mixed-fibrotic plaques, the mortality rate of AVSc patients was 15.5% compared to 2.4% in no-AVSc patients. In this group, AVSc was associated with an increased long-term all-cause mortality risk with an adjusted HR of 12.8 (95%CI: 1.71-96.35; p = 0.013), and the AUC, combing eGFR and AVSc was 0.77 ( p < 0.001). Conclusions: Our findings indicate that AVSc together with eGFR may be used to improve long-term risk stratification of patients undergoing CEA surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Myasoedova, Saccu, Chiesa, Songia, Alfieri, Massaiu, Valerio, Moschetta, Gripari, Naliato, Cavallotti, Spirito, Trabattoni and Poggio.)

Background: Minimally invasive direct coronary artery bypass (MIDCAB) is a well-established, low-impact surgical procedure for revascularization of the left descending coronary artery with the left internal mammary artery. This study aimed to evaluate safety, overall survival, and freedom from major adverse cardiocerebral-related events (MACCE) after 20 years of MIDCAB., Methods: This study retrospectively collected a series of 141 patients who underwent MIDCAB between 1997 and 2017, to assess long-term outcome. A total of 133 patients who underwent revascularization of the left descending coronary artery with the left mammary artery through a full median sternotomy were analyzed., Results: Actuarial survival rates on a Kaplan-Meier curve were 100%, 95%, 90%, 83%, and 70% at 1, 5, 10, 15, and 20 years, respectively. Freedom from MACCE, defined as myocardial infarction, stroke, and cardiac death, was 97%, 90%, 79%, 75%, and 61% at 1,5,10,15, and 20 years, respectively. At Cox multivariable analysis, age, cancer, and chronic renal insufficiency were found to be independent predictors affecting long-term survival, with a hazard ratio of 1.12 (P = .007), 17.63 (P < .001), and 5.16 (P = .03), respectively. The MIDCAB group showed a significantly shorter hospital length of stay and significantly lower rates of blood transfusions, cardiac-related events, and all-cause events compared with the full sternotomy group (P = .02 and P = .001, respectively)., Conclusions: The very long-term clinical outcome of MIDCAB is satisfactory in terms of survival and freedom from MACCE. MIDCAB significantly reduces hospital length of stay and blood transfusions when compared with full sternotomy bypass surgery on the left descending coronary artery and appears to improve prognosis in terms of cardiac-related events and all-cause events effectively., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Type A aortic dissection (AAD) is a life-threatening disease with very high mortality. The gold standard treatment is surgical, as medical treatment has been proven to be ineffective. It is still unclear the role of preoperative neurological dysfunction in the prognosis of the patient. Therefore, the choice of performing surgery in patients with neurological symptoms is still left to the surgeon at the time of the diagnosis. The aim of this study is to make a narrative review of the current literature about the management of patients with neurological symptoms in AAD patients., Evidence Acquisition: A bibliographical research was performed on PubMed, looking for papers containing the words: "((preoperative neurological symptoms in type a aortic dissection) OR brain injury type A aortic dissection) AND ("2010"[Date - Publication]: "3000"[Date - Publication])". A total of 35 papers were found., Evidence Synthesis: A total of 6 papers were chosen to be reviewed. All of them concluded that even patients with severe neurological symptoms (up to comatose state) had a good chance to recover neurological functions after surgery if treated in the first hours from the onset of symptoms. Interestingly, a hemorrhagic stroke was rarely found., Conclusions: Preoperative neurological dysfunction have been long considered a contraindication to surgery. Nevertheless, several authors show neurological and survival good results in patients with preoperative neurological dysfunction. They also stress the importance of surgical timing finding in 5 to 10 hours the surgical time limit to improve neurological dysfunction. A preoperative neurological dysfunction could be considered a strong advice towards surgical intervention. It is time to change and consider prompt surgery not only for survival but also for cerebral protection.

Objectives: During the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pandemic, Northern Italy had to completely reorganize its hospital activity. In Lombardy, the hub-and-spoke system was introduced to guarantee emergency and urgent cardiovascular surgery, whereas most hospitals were dedicated to patients with coronavirus disease 2019 (COVID-19). The aim of this study was to analyse the results of the hub-and-spoke organization system., Methods: Centro Cardiologico Monzino (Monzino) became one of the four hubs for cardiovascular surgery, with a total of eight spokes. SARS-CoV-2 screening became mandatory for all patients. New flow charts were designed to allow separated pathways based on infection status. A reorganization of spaces guaranteed COVID-19-free and COVID-19-dedicated areas. Patients were also classified into groups according to their pathological and clinical status: emergency, urgent and non-deferrable (ND)., Results: A total of 70 patients were referred to the Monzino hub-and-spoke network. We performed 41 operations, 28 (68.3%) of which were emergency/urgent and 13 of which were ND. The screening allowed the identification of COVID-19 (three patients, 7.3%) and non-COVID-19 patients (38 patients, 92.7%). The newly designed and shared protocols guaranteed that the cardiac patients would be divided into emergency, urgent and ND groups. The involvement of the telematic management heart team allowed constant updates and clinical discussions., Conclusions: The hub-and-spoke organization system efficiently safeguards access to heart and vascular surgical services for patients who require ND, urgent and emergency treatment. Further reorganization will be needed at the end of this pandemic when elective cases will again be scheduled, with a daily increase in the number of operations., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Postoperative atrial fibrillation (POAF) occurs in 30% to 50% of patients undergoing cardiac surgery and is associated with increased morbidity and mortality. Prospective identification of structural/molecular changes in atrial myocardium that correlate with myocardial injury and precede and predict risk of POAF may identify new molecular pathways and targets for prevention of this common morbid complication., Methods: Right atrial appendage samples were prospectively collected during cardiac surgery from 239 patients enrolled in the OPERA trial (Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation), fixed in 10% buffered formalin, and embedded in paraffin for histology. We assessed general tissue morphology, cardiomyocyte diameters, myocytolysis (perinuclear myofibril loss), accumulation of perinuclear glycogen, interstitial fibrosis, and myocardial gap junction distribution. We also assayed NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-cTnT, CRP (C-reactive protein), and circulating oxidative stress biomarkers (F2-isoprostanes, F3-isoprostanes, isofurans) in plasma collected before, during, and 48 hours after surgery. POAF was defined as occurrence of postcardiac surgery atrial fibrillation or flutter of at least 30 seconds duration confirmed by rhythm strip or 12-lead ECG. The follow-up period for all arrhythmias was from surgery until hospital discharge or postoperative day 10., Results: Thirty-five percent of patients experienced POAF. Compared with the non-POAF group, they were slightly older and more likely to have chronic obstructive pulmonary disease or heart failure. They also had a higher European System for Cardiac Operative Risk Evaluation and more often underwent valve surgery. No differences in left atrial size were observed between patients with POAF and patients without POAF. The extent of atrial interstitial fibrosis, cardiomyocyte myocytolysis, cardiomyocyte diameter, glycogen score or Cx43 distribution at the time of surgery was not significantly associated with incidence of POAF. None of these histopathologic abnormalities were correlated with levels of NT-proBNP, hs-cTnT, CRP, or oxidative stress biomarkers., Conclusions: In sinus rhythm patients undergoing cardiac surgery, histopathologic changes in the right atrial appendage do not predict POAF. They also do not correlate with biomarkers of cardiac function, inflammation, and oxidative stress. Graphic Abstract: A graphic abstract is available for this article.

Background: Graft patency is one of the major determinants of long-term outcome following coronary artery bypass graft surgery (CABG). Biomarkers, if indicative of the underlying pathophysiological mechanisms, would suggest strategies to limit graft failure. The prognostic value of microvesicles (MVs) for midterm graft patency has never been tested., Objectives: The aim of this study was to evaluate whether MV pre-operative signature (number, cellular origin, procoagulant phenotype) could predict midterm graft failure and to investigate potential functional role of MVs in graft occlusion., Methods: This was a nested case-control substudy of the CAGE (CoronAry bypass grafting: factors related to late events and Graft patency) study that enrolled 330 patients undergoing elective CABG. Of these, 179 underwent coronary computed tomography angiography 18 months post-surgery showing 24% graft occlusion. Flow cytometry MV analysis was performed in 60 patients (30 per group with occluded [cases] and patent [control subjects] grafts) on plasma samples collected the day before surgery and at follow-up., Results: Before surgery, cases had 2- and 4-fold more activated platelet-derived and tissue-factor positive MVs respectively than control subjects. The MV procoagulant capacity was also significantly greater. Altogether this MV signature properly classified graft occlusion (area under the curve 0.897 [95% confidence interval: 0.81 to 0.98]; p < 0.0001). By using an MV score (0 to 6), the odds ratio for occlusion for a score above 3 was 16.3 (95% confidence interval: 4.1 to 65.3; p < 0.0001)., Conclusions: The pre-operative signature of MVs is independently associated with midterm graft occlusion in CABG patients and a cumulative MV score stratifies patients' risk. Because the MV signature mirrors platelet activation, patients with a high MV score could benefit from a personalized antiplatelet therapy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fractional flow reserve (FFR) is a reliable tool for the functional assessment of coronary stenoses. FFR computed tomography (CT) derived (FFR CT ) has shown to be accurate, but its clinical usefulness in patients with complex coronary artery disease remains to be investigated. The present study sought to determine the impact of FFR CT on heart team's treatment decision-making and selection of vessels for revascularization in patients with 3-vessel coronary artery disease., Methods: The trial was an international, multicenter study randomizing 2 heart teams to make a treatment decision between percutaneous coronary interventions and coronary artery bypass grafting using either coronary computed tomography angiography or conventional angiography. The heart teams received the FFR CT and had to make a treatment decision and planning integrating the functional component of the stenoses. Each heart team calculated the anatomic SYNTAX score, the noninvasive functional SYNTAX score and subsequently integrated the clinical information to compute the SYNTAX score III providing a treatment recommendation, that is, coronary artery bypass grafting, percutaneous coronary intervention, or equipoise coronary artery bypass grafting-percutaneous coronary intervention. The primary objective was to determine the proportion of patients in whom FFR CT changed the treatment decision and planning., Results: Overall, 223 patients were included. Coronary computed tomography angiography assessment was feasible in 99% of the patients and FFR CT analysis in 88%. FFR CT was available for 1030 lesions (mean FFR CT value 0.64±13). A treatment recommendation of coronary artery bypass grafting was made in 24% of the patients with coronary computed tomography angiography with FFR CT . The addition of FFR CT changed the treatment decision in 7% of the patients and modified selection of vessels for revascularization in 12%. With conventional angiography as reference, FFR CT assessment resulted in reclassification of 14% of patients from intermediate and high to low SYNTAX score tertile., Conclusions: In patients with 3-vessel coronary artery disease, a noninvasive physiology assessment using FFR CT changed heart team's treatment decision-making and procedural planning in one-fifth of the patients., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02813473.

Aims: Aortic valve sclerosis (AVSc), a non-uniform thickening of leaflets with an unrestricted opening, is characterized by inflammation, lipoprotein deposition, and matrix degradation. In the general population, AVSc predicts long-term cardiovascular mortality (+50%) even after adjustment for vascular risk factors and clinical atherosclerosis. We have hypothesized that AVSc is a risk-multiplier able to predict even short-term mortality. To address this issue, we retrospectively analyzed 90-day mortality of all patients who underwent isolated coronary artery bypass grafting (CABG) at Centro Cardiologico Monzino over a ten-year period (2006-2016)., Methods: We analyzed 2246 patients and 90-day all-cause mortality was 1.5% (31 deaths). We selected only patients deceased from cardiac causes ( n = 29) and compared to alive patients ( n = 2215). A cardiologist classified the aortic valve as no-AVSc ( n = 1352) or AVSc ( n = 892). Cox linear regression and integrated discrimination improvement (IDI) analyses were used to evaluate AVSc in predicting 90-day mortality., Results: AVSc 90-day survival (97.6%) was lower than in no-AVSc (99.4%; p < 0.0001) with a hazard ratio (HR) of 4.0 (95%CI: 1.78, 9.05; p < 0.0001). The HR for AVSc, adjusted for propensity score, was 2.7 (95%CI: 1.17, 6.23; p = 0.02) and IDI statistics confirmed that AVSc significantly adds ( p < 0.001) to the identification of high-risk patients than EuroSCORE II alone., Conclusion: Our data supports the hypothesis that a risk stratification strategy based on AVSc, added to ESII, may allow better recognition of patients at high-risk of short-term mortality after isolated surgical myocardial revascularization. Results from this study warrant further confirmation.

Background: Aortic valve calcification (AVC) is an active process that involves inflammation, disorganization of matrix disposition, lipid accumulation and lamellar bone formation. AVC without hemodynamic changes has been associated with cardiovascular (CV) risk factors and increased risk of coronary and CV events. Nowadays, echocardiography is the standard imaging technique to evaluate aortic valve pathologies. However, cardiac computed tomography (CT) allows high accuracy and reproducible measurement of AVC, without exposing the patients to excessive radiation or contrast administration., Aims: To better understand if AVC assessment may improve CV risk-prediction, we performed a systematic search and meta-analysis of literature studies, evaluating the relationship among AVC, coronary artery disease (CAD), and overall mortality., Methods and Results: A detailed search, according to PRISMA guidelines, was performed to identify all available studies investigating AVC, measured by CT scan, and CV events. Thirteen studies on 3,782 AVC patients and 32,890 controls were included in the final analysis. Patients with AVC have a higher risk of CAD (OR 1.7, 95%CI: 1.04-2.87; p = 0.04) when compared to controls. We also found an association between AVC and coronary artery calcification (OR 3.8; 95%CI: 2.4-6.0; p < 0.001.) Finally, AVC had 93.2% specificity for overall mortality (95%CI: 92.8-93.6) with a negative predictive value of 98.8% (95%CI: 98.7-98.8)., Conclusion: AVC is associated with coronary artery calcification and overall mortality. The present data cannot support the use of cardiac CT over echocardiography for AVC assessment in all patients, but when cardiac CT is performed for suspected CAD, AVC evaluation may contribute to risk stratification and patient management. Ad hoc designed studies should address this issue in the next future., (Copyright © 2019 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Mitral valve prolapse (MVP) is the most common cause of severe mitral regurgitation. It has been reported that MVP patients-candidates for mitral valve repair (MVRep)-showed an alteration in the antioxidant defense systems as well as in the L-arginine metabolic pathway. In this study, we investigate if oxidative stress and endothelial dysfunction are an MVP consequence or driving factors. Forty-five patients undergoing MVRep were evaluated before and 6 months post surgery and compared to 29 controls. Oxidized (GSSG) and reduced (GSH) forms of glutathione, and L-arginine metabolic pathway were analyzed using liquid chromatography-tandem mass spectrometry methods while osteoprotegerin (OPG) through the ELISA kit and circulating endothelial microparticles (EMP) by flow cytometry. Six-month post surgery, in MVP patients, the GSSG/GSH ratio decreased while symmetric and asymmetric dimethylarginines levels remained comparable to the baseline. Conversely, OPG levels significantly increased when compared to their baseline. Finally, pre-MVRep EMP levels were significantly higher in patients than in controls and did not change post surgery. Overall, these results highlight that MVRep completely restores the increased oxidative stress levels, as evidenced in MVP patients. Conversely, no amelioration of endothelial dysfunction was evidenced after surgery. Thus, therapies aimed to restore a proper endothelial function before and after surgical repair could benefit MVP patients.

Background CD 34 + stem/progenitor cells are involved in vascular homeostasis and in neovascularization of ischemic tissues. The number of circulating CD 34 + stem cells is a predictive biomarker of adverse cardiovascular outcomes in diabetic patients. Here, we provide evidence that hyperglycemia can be "memorized" by the stem cells through epigenetic changes that contribute to onset and maintenance of their dysfunction in diabetes mellitus. Methods and Results Cord-blood-derived CD 34 + stem cells exposed to high glucose displayed increased reactive oxygen species production, overexpression of p66 shc gene, and downregulation of antioxidant genes catalase and manganese superoxide dismutase when compared with normoglycemic cells. This altered oxidative state was associated with impaired migration ability toward stromal-cell-derived factor 1 alpha and reduced protein and mRNA expression of the C-X-C chemokine receptor type 4 ( CXCR 4) receptor. The methylation analysis by bisulfite Sanger sequencing of the CXCR 4 promoter revealed a significant increase in DNA methylation density in high-glucose CD 34 + stem cells that negatively correlated with mRNA expression (Pearson r=-0.76; P=0.004). Consistently, we found, by chromatin immunoprecipitation assay, a more transcriptionally inactive chromatin conformation and reduced RNA polymerase II engagement on the CXCR 4 promoter. Notably, alteration of CXCR 4 DNA methylation, as well as transcriptional and functional defects, persisted in high-glucose CD 34 + stem cells despite recovery in normoglycemic conditions. Importantly, such an epigenetic modification was thoroughly confirmed in bone marrow CD 34 + stem cells isolated from sternal biopsies of diabetic patients undergoing coronary bypass surgery. Conclusions CD 34 + stem cells "memorize" the hyperglycemic environment in the form of epigenetic modifications that collude to alter CXCR 4 receptor expression and migration.

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.

Over the past two decades cardiac cell therapy (CCT) has emerged as a promising new strategy to cure heart diseases at high unmet need. Thousands of patients have entered clinical trials for acute or chronic heart conditions testing different cell types, including autologous or allogeneic bone marrow (BM)-derived mononuclear or selected cells, BM- or adipose tissue-derived mesenchymal cells, or cardiac resident progenitors based on their potential ability to regenerate scarred or dysfunctional myocardium. Nowadays, the original enthusiasm surrounding the regenerative medicine field has been cushioned by a cumulative body of evidence indicating an inefficient or modest efficacy of CCT in improving cardiac function, along with the continued lack of indisputable proof for long-term prognostic benefit. In this review, we have firstly comprehensively outlined the positive and negative results of cell therapy studies in patients with acute myocardial infarction, refractory angina and chronic heart failure. Next, we have discussed cell therapy- and patient-related variables (e.g. cell intrinsic and extrinsic characteristics as well as criteria of patient selection and proposed methodologies) that might have dampened the efficacy of past cell therapy trials. Finally, we have addressed critical factors to be considered before embarking on further clinical trials., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: In this observational prospective study, we assessed the role of clinical variables and circulating biomarkers in graft occlusion at 18 months to identify a signature for graft occlusion., Methods: A total of 330 patients undergoing primary elective coronary artery bypass grafting were enrolled. Blood collection for biomarker assessment was performed before surgery and discharge. Patients were then scheduled to undergo coronary computed tomography angiography at 18 months follow-up, and 179 patients underwent coronary computed tomography angiography 18 ± 2 months postoperatively., Results: There were 46 of 503 (9.1%) occluded grafts; of these, 29 (63%) were venous and 17 (37%) were arterial grafts; overall, 43 of 179 patients (24%) had at least 1 occluded graft. Logistic mixed effects model assessing independent factors associated with graft occlusion identified that lower D-dimer levels at baseline (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.36-4.89; P = .00) and total protein content at discharge (OR, 1.09; 95% CI, 1.01-1.19; P = .028) were related to overall graft occlusion at follow-up, along with an arterial graft other than the left internal thoracic artery (OR, 2.92; 95% CI, 1.24-6.9; P = .078); moreover, a venous graft emerged was possibly associated with graft occlusion (OR, 1.51; 95% CI, 0.95-2.39; P = .078). By separately analyzing saphenous vein and arterial grafts, D-dimer levels (OR, 2.67; 95% CI, 1.15-6.2; P = .022 and OR, 2.5; 95% CI, 1.01-7.0; P = .05 for venous and arterial graft, respectively) were still associated with arterial and venous graft occlusion at follow-up., Conclusions: We identified D-dimer as a biomarker associated with arterial and venous grafts occlusion. This may help stratify patients at risk of graft failure and identify new molecular targets to prevent this complication., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

On-pump cardiac surgery may trigger inflammation and accelerate platelet cyclooxygenase-1 renewal, thereby modifying low-dose aspirin pharmacodynamics. Thirty-seven patients on standard aspirin 100 mg once-daily were studied before surgery and randomized within 36 hours postsurgery to 100 mg once-daily, 100 mg twice-daily, or 200 mg once-daily for 90 days. On day 7 postsurgery, immature and mature platelets, platelet mass, thrombopoietin, glycocalicin, leukocytes, C-reactive protein, and interleukin-6 significantly increased. Interleukin-6 significantly correlated with immature platelets. At day 7, patients randomized to 100 mg once-daily showed a significant increase in serum thromboxane (TX)B 2 within the 24-hour dosing interval and urinary TXA 2 metabolite (TXM) excretion. Aspirin 100 mg twice-daily lowered serum TXB 2 and prevented postsurgery TXM increase (P < 0.01), without affecting prostacyclin metabolite excretion. After cardiac surgery, shortening the dosing interval, but not doubling the once-daily dose, rescues the impaired antiplatelet effect of low-dose aspirin and prevents platelet activation associated with acute inflammation and enhanced platelet turnover., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Background: Leaflet resection represents the reference standard for surgical treatment of mitral valve (MV) regurgitation. New approaches recently proposed place emphasis on respecting, rather than resecting, the leaflet tissue to avoid the drawbacks of the 'resection' approach., Objectives: The lateral dislocation of mid portion of mitral posterior leaflet (P2) technique for MV repair is a nonresectional technique in which the prolapsed P2 segment is sutured to normal P1 segment. Our study evaluates the effectiveness of this technique., Patients and Methods: We performed the procedure on seven patients. Once ring annular sutures were placed, the prolapsed P2 segment was dislocated toward the normal P1 segment with a rotation of 90° and without any resection. If present, residual clefts between P2 and P3 segments were closed. Once the absence of residual mitral regurgitation is confirmed by saline pressure test, ring annuloplasty was completed. The valve was evaluated using transesophageal echocardiography in the operating room and by transthoracic echocardiography before discharge., Results: At the last follow-up visit, transthoracic echocardiography revealed no mitral regurgitation and normal TRANSVALVULAR gradients., Conclusion: The lateral dislocation of P2 is an easily fine-tuned technique for isolated P2 prolapse, with the advantage of short aortic cross-clamp and cardiopulmonary bypass times. We think it might be very favorable in older and frail patients. Long-term follow-up is necessary to assess the durability of this technique.

Cardiac cell-based therapy has emerged as a novel therapeutic option for patients dealing with untreatable refractory angina (RA). However, after more than a decade of controlled studies, no definitive consensus has been reached regarding clinical efficacy. Although positive results in terms of surrogate endpoints have been suggested by early and phase II clinical studies as well as by meta-analyses, the more recent reports lacked the provision of definitive response in terms of hard clinical endpoints. Regrettably, pivotal trials designed to conclusively determine the efficacy of cell-based therapeutics in such a challenging clinical condition are therefore still missing. Considering this, a comprehensive reappraisal of cardiac cell-based therapy role in RA seems warranted and timely, since a number of crucial cell- and patient-related aspects need to be systematically analysed. As an example, the large variability in efficacy endpoint selection appears to be a limiting factor for the advancement of cardiac cell-based therapy in the field. This review will provide an overview of the key elements that may have influenced the results of cell-based trials in the context of RA, focusing in particular on the understanding at which the extent of angina-related endpoints may predict cell-based therapeutic efficacy.

Background: Literature studies suggested a lower prevalence of coronary artery disease (CAD) in bicuspid aortic valve (BAV) than in tricuspid aortic valve (TAV) patients. However, this finding has been challenged. We performed a meta-analysis to assess whether aortic valve morphology has a different association with CAD, concomitant coronary artery bypass grafting (CABG), and postoperative mortality., Methods and Results: Detailed search was conducted according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guideline to identify all patients with BAV or TAV and presence of CAD, concomitant myocardial surgical revascularization, and the postoperative mortality. Thirty-one studies on 3017 BAV and 4586 TAV patients undergoing aortic valve surgery were included. BAV patients showed a lower prevalence of CAD (odds ratio [OR]: 0.33; 95% CI: 0.17, 0.65), concomitant CABG (OR, 0.45; 95% CI: 0.35, 0.59), and postoperative mortality (OR, 0.62; 95% CI: 0.40, 0.97) than TAV. However, BAV subjects were significantly younger than TAV (mean difference: -7.29; 95% CI: -11.17, -3.41) were more frequently males (OR, 1.61; 95% CI: 1.33, 1.94) and exhibited a lower prevalence of hypertension (OR, 0.58; 95% CI: 0.39, 0.87) and diabetes (OR, 0.71; 95% CI: 0.54, 0.93). Interestingly, a metaregression analysis showed that younger age and lower prevalence of diabetes were associated with lower prevalence of CAD (Z value: -3.03; P=0.002 and Z value: -3.10; P=0.002, respectively) and CABG (Z value: -2.69; P=0.007 and Z value: -3.36; P=0.001, respectively) documented in BAV patients., Conclusions: Analysis of raw data suggested an association of aortic valve morphology with prevalence of CAD, concomitant CABG, and postoperative mortality. Interestingly, the differences in age and diabetes have a profound impact on prevalence of CAD between BAV and TAV. In conclusion, our meta-analysis suggests that the presence of CAD is independent of aortic valve morphology., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

According to the European Medicine Agency (EMA) regulatory frameworks, Advanced Therapy Medicinal Products (ATMP) represent a new category of drugs in which the active ingredient consists of cells, genes, or tissues. ATMP-CD133 has been widely investigated in controlled clinical trials for cardiovascular diseases, making CD133(+) cells one of the most well characterized cell-derived drugs in this field. To ensure high quality and safety standards for clinical use, the manufacturing process must be accomplished in certified facilities following standard operative procedures (SOPs). In the present work, we report the fully compliant GMP-grade production of ATMP-CD133 which aims to address the treatment of chronic refractory ischemic heart failure. Starting from bone marrow (BM), ATMP-CD133 manufacturing output yielded a median of 6.66 × 10(6) of CD133(+) cells (range 2.85 × 10(6)-30.84 × 10(6)), with a viability ranged between 96,03% and 99,97% (median 99,87%) and a median purity of CD133(+) cells of 90,60% (range 81,40%-96,20%). Based on these results we defined our final release criteria for ATMP-CD133: purity ≥ 70%, viability ≥ 80%, cellularity between 1 and 12 × 10(6) cells, sterile, and endotoxin-free. The abovementioned criteria are currently applied in our Phase I clinical trial (RECARDIO Trial).

Mitral valve prolapse (MVP) represents a common degenerative disease, often requiring surgery. If untreated, MVP with considerable valve incompetence can lead to cardiovascular and systemic complications causing substantial morbidity and mortality. In contrast with the wide knowledge concerning clinical and physiological features, currently available data regarding its molecular bases are very limited. We review current knowledge concerning MVP biological mechanisms, focusing on specific aspects of haemostasis, platelet function, oxidative stress, extracellular matrix remodeling and genomics. In particular, available evidence supports the role played by tissue remodeling processes in determining MVP onset and progression. Moreover, even if a consistent although controversial perturbation of haemostatic system and alterations of the oxidative stress equilibrium have been proposed to influence disease development, it is unknown whether these changes precede or follow MVP occurrence. Consequently, the complete knowledge of all the biochemical pathways involved are far from complete. In addition, changes in the regulation pattern of adrenergic and renin-angiotensin-aldosterone systems have been described in MVP syndrome, a condition characterized by the association of MVP with other peculiar neurological and general symptoms, but it is unknown whether these abnormalities are shared by "traditional" MVP. In conclusion, MVP is probably a multi-factorial process, and many aspects still need to be clarified. As surgery can only correct the damaged valve but not the underlying mechanisms, a more complete knowledge of the involved molecular pathways is necessary, as it may allow the discovery of targeted therapeutic strategies aimed at modifying or slackening MVP natural course in the early phases., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Context: It is not known whether statin treatment improves clinical outcomes and reduces aortic stenosis progression in non-rheumatic calcific aortic stenosis., Objective: A meta-analysis of studies was performed comparing statin therapy with placebo or no treatment on outcomes and on aortic stenosis progression echocardiographic parameters., Data Sources: The authors searched Medline and Pubmed up to January 2010., Data Extraction: Two independent reviewers independently abstracted information on study design (prospective vs retrospective or randomised vs non-randomised), study and participant characteristics. Fixed and random effects models were used. A-priori subanalyses assessed the effect of statins on low-quality (retrospective or non-randomised) and on high-quality (prospective or randomised) studies separately., Results: Meta-analysis identified 10 studies with a total of 3822 participants (2214 non-statin-treated and 1608 statin-treated); five studies were classified as prospective and five as retrospective; concerning randomisation, three trials were randomised whereas seven were not. No significant differences were found in all-cause mortality, cardiovascular mortality or in the need for aortic valve surgery. Lower-quality (retrospective or non-randomised) studies showed that, in statin-treated patients, the annual increase in peak aortic jet velocity and the annual decrease in aortic valve area were lower, but this was not confirmed by the analysis in high-quality (prospective or randomised) studies. Statins did not significantly affect the progression over time of peak and mean aortic gradient., Conclusions: Currently available data do not support the use of statins to improve outcomes and to reduce disease progression in non-rheumatic calcific aortic valve stenosis.

Background: The European System for Cardiac Operative Risk Evaluation (EuroSCORE) was developed to predict immediate outcomes after adult cardiac operations, but less than 30% of the cases used to develop this score were valve procedures. We studied EuroSCORE performance in valve procedures., Methods: We performed a meta-analysis of published studies reporting the assessment of discriminatory power of the EuroSCORE by receiver operating characteristics (ROC) curve analysis in adult valve operations. A comparison of observed and predicted mortality rates was also performed., Results: A literature search identified 37 potentially eligible studies, and 12 were selected for meta-analysis comprising 26,621 patients with 1250 events (mortality rate, 4.7%). Meta-analysis of these studies provided an average area under the curve (AUC) value of 0.730 (95% confidence interval [CI], 0.717 to 0.743). The same results were obtained when meta-analyses were performed separately in studies categorized on reliability of uncertainty estimation: in the seven studies reporting reliable uncertainty estimation (8175 patients with 358 events; mortality rate, 4.4%), the ROC curve provided an average AUC value of 0.724 (95% CI, 0.699 to 0.749). The five studies not reporting reliable uncertainty estimation (18,446 patients with 892 events; mortality rate, 4.8%) had an average AUC of 0.732 (95% CI, 0.717 to 0.747). We documented a constant trend to overpredict mortality by EuroSCORE, both in the additive and especially in the logistic form., Conclusions: The EuroSCORE has low discrimination ability for valve surgery, and it sensibly overpredicts risk. Alternative risk scoring algorithms should be seriously considered., (2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Calcific aortic stenosis is a frequent degenerative disease, which represents the most common indication for adult heart valve surgery, and carries substantial morbidity and mortality. Due to ageing populations in western countries, its prevalence is expected to increase in the coming years. Basic science studies suggest that the progression of aortic valve stenosis involves an active biological process, and that the molecular mechanisms promoting this development resemble those of atherosclerosis, as stenotic aortic valves are characterized by complex histological lesions, consisting of activated inflammatory cells, lipid deposits, extracellular matrix remodeling, calcific nodules, and bone tissue. This has led to the hypothesis that drugs effective in delaying atherosclerosis progression (e.g. statins) might also be able to prevent the progression of calcific aortic valve stenosis. The potential benefit of statin therapy, however, is controversial and widely debated, as recent randomized studies done in patients with moderate to severe degrees of aortic stenosis failed to consistently show substantial benefits of this class of drugs. This review focuses on various aspects of molecular mechanisms underlying calcific aortic valve stenosis and discusses recent experimental and clinical studies that address the potential benefit of targeted drug therapies. Taken together, current evidence suggests that the progression of calcific aortic stenosis is a multi-factorial process; the multitude of the mechanisms potentially involved in aortic valve stenosis indicates that drug therapy aimed at reducing its progression is necessarily multi-factorial and should address the earliest stages of the disease, as it is now evident that pharmacological treatment administered in more advanced stages of the disease may be ineffective or, at best, much less effective.