Mercaptoalbumin Is Associated with Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting.

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.

Long-term secondary cardiovascular prevention programme in patients subjected to coronary artery bypass surgery.

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.

Aortic Valve Sclerosis as an Important Predictor of Long-Term Mortality in Patients With Carotid Atheromatous Plaque Requiring Carotid Endarterectomy.

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.

Very Long-term Outcome of Minimally Invasive Direct Coronary Artery Bypass.

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.

Prospective Evaluation of Clinico-Pathological Predictors of Postoperative Atrial Fibrillation: An Ancillary Study From the OPERA Trial.

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.

Preoperative neurological dysfunctions: what is their meaning in patients presenting with acute type A aortic dissection?

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.

A call to action becomes practice: cardiac and vascular surgery during the COVID-19 pandemic based on the Lombardy emergency guidelines.

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.

Association of Microvesicles With Graft Patency in Patients Undergoing CABG Surgery.

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.

Impact of Fractional Flow Reserve Derived From Coronary Computed Tomography Angiography on Heart Team Treatment Decision-Making in Patients With Multivessel Coronary Artery Disease: Insights From the SYNTAX III REVOLUTION Trial.

BACKGROUND: Fractional flow reserve (FFR) is a reliable tool for the functional assessment of coronary stenoses. FFR computed tomography (CT) derived (FFRCT) 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 FFRCT 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 FFRCT 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 FFRCT 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 FFRCT analysis in 88%. FFRCT was available for 1030 lesions (mean FFRCT 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 FFRCT. The addition of FFRCT changed the treatment decision in 7% of the patients and modified selection of vessels for revascularization in 12%. With conventional angiography as reference, FFRCT 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 FFRCT 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.

Endothelial Dysfunction in Patients with Severe Mitral Regurgitation.

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.

Cardiovascular morbidity and mortality in patients with aortic valve calcification: A systematic review and meta-analysis.

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.

Abnormal DNA Methylation Induced by Hyperglycemia Reduces CXCR 4 Gene Expression in CD 34+ Stem Cells.

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 p66shc 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.

D-dimer is associated with arterial and venous coronary artery bypass graft occlusion.

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.

Impact of Valve Morphology on the Prevalence of Coronary Artery Disease: A Systematic Review and Meta-Analysis.

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.

Full GMP-compliant validation of bone marrow-derived human CD133(+) cells as advanced therapy medicinal product for refractory ischemic cardiomyopathy.

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).

Do statins improve outcomes and delay the progression of non-rheumatic calcific aortic stenosis?

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.

Biology of mitral valve prolapse: the harvest is big, but the workers are few.

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.