miRNA-Driven Regulation of Endothelial-to-Mesenchymal Transition Differs among Thoracic Aortic Aneurysms.

Thoracic aortic aneurysms (TAAs) represent a serious health concern, as they are associated with early aortic dissection and rupture. TAA formation is triggered by genetic conditions, in particular Marfan syndrome (MFS) and bicuspid aortic valve (BAV). During the aneurysmatic process, aortic endothelial cells can undergo endothelial-to-mesenchymal transition (End-MT) with consequent phenotypic and functional alterations. We previously documented that MFS TAA is characterized by miR-632-driven End-MT exacerbation, whereas in BAV aortopathy, the occurrence of this process remains still controversial. We investigated the End-MT process and the underlined regulatory mechanisms in BAV, TAV and MFS TAA tissues. Gene expression and immunohistochemical analysis were performed in order to analyze some important miRNAs and genes characterizing End-MT. We documented that BAV endothelium maintains the expression of the endothelial homeostasis markers, such as ERG, CD31 and miR-126-5p, while it shows lower levels of miR-632 and mesenchymal markers compared with MFS. Interestingly, we also found higher levels of miR-632 in MFS patients' blood. Our findings definitively demonstrate that the End-MT process does not characterize BAV that, among the other TAAs, better maintains the endothelial features. In addition, our results suggest miR-632 as a promising diagnostic/prognostic factor in MFS aortopathy.

miRNA Regulation of Cell Phenotype and Parietal Remodeling in Atherosclerotic and Non-Atherosclerotic Aortic Aneurysms: Differences and Similarities.

Aortic aneurysms are a serious health concern as their rupture leads to high morbidity and mortality. Abdominal aortic aneurysms (AAAs) and thoracic aortic aneurysms (TAAs) exhibit differences and similarities in their pathophysiological and pathogenetic features. AAA is a multifactorial disease, mainly associated with atherosclerosis, characterized by a relevant inflammatory response and calcification. TAA is rarely associated with atherosclerosis and in some cases is associated with genetic mutations such as Marfan syndrome (MFS) and bicuspid aortic valve (BAV). MFS-related and non-genetic or sporadic TAA share aortic degeneration with endothelial-to-mesenchymal transition (End-Mt) and fibrosis, whereas in BAV TAA, aortic degeneration with calcification prevails. microRNA (miRNAs) contribute to the regulation of aneurysmatic aortic remodeling. miRNAs are a class of non-coding RNAs, which post-transcriptionally regulate gene expression. In this review, we report the involvement of deregulated miRNAs in the different aortic remodeling characterizing AAAs and TAAs. In AAA, miRNA deregulation appears to be involved in parietal inflammatory response, smooth muscle cell (SMC) apoptosis and aortic wall calcification. In sporadic and MFS-related TAA, miRNA deregulation promotes End-Mt, SMC myofibroblastic phenotypic switching and fibrosis with glycosaminoglycan accumulation. In BAV TAA, miRNA deregulation sustains aortic calcification. Those differences may support the development of more personalized therapeutic approaches.

Early-Staged Carotid Artery Stenting Prior to Coronary Artery Bypass Grafting: Analysis of the Early and Mid-Term Results in Comparison with a Consecutive Cohort of Isolated Coronary Artery Surgery Patients.

AIM: The aim of the present study was to analyze retrospectively the results of patients who underwent early-staged, i.e., within 24-48 h, carotid artery stenting (e-s CAS) before coronary artery bypass grafting (CABG). METHODS: Between December 2014 and December 2022, 1046 consecutive patients underwent CABG; 31 of these patients (3%) were subjected to e-s CAS prior to CABG (e-s CAS + CABG group). Preoperative and intraoperative variables and early and mid-term results of the e-s CAS + CABG group were compared with those of patients who underwent isolated CABG (CABG group). RESULTS: As compared with the CABG group, the e-s CAS + CABG group showed a worse clinical risk profile due to higher Euroscore-2 values and incidence of obstructive pulmonary disease and bilateral carotid artery and peripheral artery diseases (p < 0.05, for all comparisons). The combined end point of operative mortality, periprocedural myocardial infarction, and stroke was 3.2% (0%/0%/3.2%) in the e-s CAS + CABG group vs. 5.9% (2.2%/2.8%/0.9%) in the CABG group (p > 0.5, for all measurements). At 5 years, actuarial survival was 74% ± 16% in the e-s CAS + CABG group vs. 93% ± 4.0% in the CABG group, freedom from cardiac death was 100% vs. 98% ± 1.0% (p = 0.6), and freedom from MACCEs was 85% ± 15% vs. 97% ± 2.5% (p > 0.1, for all comparisons). Independent predictors of all-causes death were advanced age at the operation (p < 0.0001), a lower value for left ventricular ejection fraction (p = 0.05), and a high Euroscore-2 (p = 0.04). CONCLUSIONS: CABG preceded by e-s CAS appears to be associated with satisfactory early outcomes while limiting the risk of myocardial infarction to a very short time interval between the two procedures. Freedom from late all-causes death, cardiac death, and MACCEs were comparable and equally satisfactory, underscoring the positive protective effects of CAS and CABG on the carotid and coronary territories over time.

miR-632 Induces DNAJB6 Inhibition Stimulating Endothelial-to-Mesenchymal Transition and Fibrosis in Marfan Syndrome Aortopathy.

Marfan syndrome (MFS) is a connective tissue disorder caused by FBN1 gene mutations leading to TGF-ß signaling hyperactivation, vascular wall weakness, and thoracic aortic aneurysms (TAAs). The pathogenetic mechanisms are not completely understood and patients undergo early vascular surgery to prevent TAA ruptures. We previously reported miR-632 upregulation in MFS TAA tissues compared with non-genetic TAA tissues. DNAJB6 is a gene target of miR-632 in cancer and plays a critical role in blocking epithelial-to-mesenchymal transition by inhibiting the Wnt/ß catenin pathway. TGF-ß signaling also activates Wnt/ß catenin signaling and induces endothelial-to-mesenchymal transition (End-Mt) and fibrosis. We documented that miR-632 upregulation correlated with DNAJB6 expression in both the endothelium and the tunica media of MFS TAA (p < 0.01). Wnt/ß catenin signaling, End-Mt, and fibrosis markers were also upregulated in MFS TAA tissues (p < 0.05, p < 0.01 and p < 0.001). Moreover, miR-632 overexpression inhibited DNAJB6, inducing Wnt/ß catenin signaling, as well as End-Mt and fibrosis exacerbation (p < 0.05 and p < 0.01). TGF-ß1 treatment also determined miR-632 upregulation (p < 0.01 and p < 0.001), with the consequent activation of the aforementioned processes. Our study provides new insights about the pathogenetic mechanisms in MFS aortopathy. Moreover, the high disease specificity of miR-632 and DNAJB6 suggests new potential prognostic factors and/or therapeutic targets in the progression of MFS aortopathy.

A promising therapeutic peptide and preventive/diagnostic biomarker for age-related diseases: The Elabela/Apela/Toddler peptide.

Elabela (ELA), Apela or Toddler peptide is a hormone peptide belonging to the adipokine group and a component of apelinergic system, discovered in 2013-2014. Given its high homology with apelin, the first ligand of APJ receptor, ELA likely mediates similar effects. Increasing evidence shows that ELA has a critical function not only in embryonic development, but also in adulthood, contributing to physiological and pathological conditions, such as the onset of age-related diseases (ARD). However, still little is known about the mechanisms and molecular pathways of ELA, as well as its precise functions in ARD pathophysiology. Here, we report the mechanisms by which ELA/APJ signaling acts in a very complex network of pathways for the maintenance of physiological functions of human tissue and organs, as well as in the onset of some ARD, where it appears to play a central role. Therefore, we describe the possibility to use the ELA/APJ pathway, as novel biomarker (predictive and diagnostic) and target for personalized treatments of ARD. Its potentiality as an optimal peptide candidate for therapeutic ARD treatments is largely described, also detailing potential current limitations.

Cerebrovascular events after cardiovascular surgery: diagnosis, management and prevention strategies.

Introduction: Cerebrovascular events after cardiac surgery are among the most serious complications, related to a greater risk of patient mortality. This problem can occur following the formation of gas emboli during open heart surgery. Aim: To address all the mechanisms that can lead to embolic events after cardiovascular surgery, how to manage them and how to possibly prevent them. Material and methods: A search of the PubMed database was conducted. We reviewed the clinical literature and examined all aspects to identify the root causes that can lead to the formation of emboli. Results: Among the studies reviewed, it was found that the main causes include manipulation of the aorta, inadequate deaeration after cardiac surgery, and blood-component contact of extracorporeal circulation. It has been reported that gas emboli can lead to deleterious damage such as damage to the cerebral vascular endothelium, disruption of the blood-brain barrier, complement activation, leukocyte aggregation, increased platelet adhesion, and fibrin deposition in the microvascular system. Conclusions: Stroke after cardiovascular surgery is one of the most important complications, with a great impact on operative mortality and patient survival. Efforts have been made over time to understand all the pathophysiological mechanisms related to this complication, with the aim of reducing its incidence. One of the goals should be to improve both the surgical technique and the perfusion modality and minimize the formation of air bubbles or to facilitate their elimination during the cardiopulmonary bypass procedure.

Circulating Levels of Ferritin, RDW, PTLs as Predictive Biomarkers of Postoperative Atrial Fibrillation Risk after Cardiac Surgery in Extracorporeal Circulation.

Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery in conventional extracorporeal circulation (CECC), with an incidence of 15-50%. The POAF pathophysiology is not known, and no blood biomarkers exist. However, an association between increased ferritin levels and increased AF risk, has been demonstrated. Based on such evidence, here, we evaluated the effectiveness of ferritin and other haematological parameters as POAF risk biomarkers in patients subjected to cardiac surgery. We enrolled 105 patients (mean age = 70.1 ± 7.1 years; 70 men and 35 females) with diverse heart pathologies and who were subjected to cardiothoracic surgery. Their blood samples were collected and used to determine hematological parameters. Electrocardiographic and echocardiographic parameters were also evaluated. The data obtained demonstrated significantly higher levels of serum ferritin, red cell distribution width (RDW), and platelets (PLTs) in POAF patients. However, the serum ferritin resulted to be the independent factor associated with the onset POAF risk. Thus, we detected the ferritin cut-off value, which, when ≥148.5 ng/mL, identifies the subjects at the highest POAF risk, and with abnormal ECG atrial parameters, such as PW indices, and altered structural heart disease variables. Serum ferritin, RDW, and PTLs represent predictive biomarkers of POAF after cardiothoracic surgery in CECC; particularly, serum ferritin combined with anormal PW indices and structural heart disease variables can represent an optimal tool for predicting not only POAF, but also the eventual stroke onset.

The Endothelial Transcription Factor ERG Mediates a Differential Role in the Aneurysmatic Ascending Aorta with Bicuspid or Tricuspid Aorta Valve: A Preliminary Study.

The pathobiology of ascending aorta aneurysms (AAA) onset and progression is not well understood and only partially characterized. AAA are also complicated in case of bicuspid aorta valve (BAV) anatomy. There is emerging evidence about the crucial role of endothelium-related pathways, which show in AAA an altered expression and function. Here, we examined the involvement of ERG-related pathways in the differential progression of disease in aortic tissues from patients having a BAV or tricuspid aorta valve (TAV) with or without AAA. Our findings identified ERG as a novel endothelial-specific regulator of TGF-ß-SMAD, Notch, and NO pathways, by modulating a differential fibrotic or calcified AAA progression in BAV and TAV aortas. We provided evidence that calcification is correlated to different ERG expression (as gene and protein), which appears to be under control of Notch signaling. The latter, when increased, associated with an early calcification in aortas with BAV valve and aneurysmatic, was demonstrated to favor the progression versus severe complications, i.e., dissection or rupture. In TAV aneurysmatic aortas, ERG appeared to modulate fibrosis. Therefore, we proposed that ERG may represent a sensitive tissue biomarker to monitor AAA progression and a target to develop therapeutic strategies and influence surgical procedures.

Initial Surgical Strategy for the Treatment of Type A Acute Aortic Dissection: Does Proximal or Distal Extension of the Aortic Resection Influence the Outcomes?

(1) Background: We sought to analyze and compare the outcomes in terms of early and late mortality and freedom from a redo operation in patients undergoing surgical treatment for a type A acute aortic dissection in relation to the initial surgical treatment strategy, i.e., proximal or distal extension of the aortic segment resection, compared with isolated resection of the supracoronary ascending aorta. (2) Methods: This is a retrospective study in which we included 269 patients who underwent operations for a type A acute aortic dissection in the Department of Cardiac Surgery of Tor Vergata University from May 2006 to May 2016. The patients were grouped according to the extent of the performed surgical treatment: isolated replacement of the supracoronary ascending aorta (NE, no extension), replacement of the aortic root (PE, proximal extension), replacement of the aortic arch (DE, distal extension), and both (BE, bilateral extension). The analyzed variables were in-hospital mortality, postoperative complications (incidence of neurological damage, renal failure and need for prolonged intubation), late mortality and need for a redo operation. (3) Results: Unilateral cerebral perfusion was performed in 49.3% of the patients, and bilateral perfusion-in 50.6%. The overall in-hospital mortality was 31.97%. In the multivariate analysis, advanced age, cardiopulmonary bypass time and preoperative orotracheal intubation were independent predictors of in-hospital mortality. In the population of patients who survived the surgery, the probability of survival at 92 months was 70 ± 5%, the probability of freedom from a redo operation was 71.5 ± 5%, the probability of freedom from the combined end-point death and a redo operation was 50 ± 5%. The re-intervention rate in the general population was 16.9%. The overall probability of freedom from re-intervention was higher in patients undergoing aortic root replacement, although not reaching a level of statistical significance. Patients who underwent aortic arch treatment showed reduced survival. (4) Conclusions: In the treatment of type A acute aortic dissection, all the surgical strategies adopted were associated with satisfactory long-term survival. In the group of patients in which the aortic root had not been replaced, we observed reduced event-free survival.

Bentall Operation: Early Surgical Results, Seven-Year Outcomes, and Risk Factors Analysis.

Aim: To analyze early and mid-term outcomes of the Bentall operation. Methods: Two hundred and seventeen patients (mean age 65.6 ± 15.9 years, males/females 172/45) underwent Bentall operation in a 7-year period (January 2015−December 2021), on average, 30 Bentall operations occurred per year, using biological (n = 104) or mechanical (n = 113) valved conduits for the treatment of ascending aorta−aortic root aneurysms. Associate procedures were performed in 58 patients (26.7%); coronary artery bypass grafting (CABG) in 35 (16%). Mean follow-up was 55.2 ± 24 (median 60.2) months. Cox model analysis was used to assess risk factors, Kaplan−Meier and log-rank tests were used to assess different survival rates. Results: Operative mortality was 1.38%. At 7 years, survival, freedom from cardiac death, and event-free survival were 93% ± 2%, 99% ± 1%, and 81% ± 5%. NYHA class (p < 0.0001), trans-aortic valve mean (p < 0.0001) and maximum (p < 0.000) gradients, left ventricular hypertrophy (p < 0.05), and pulmonary arterial pressure (p = 0.002) significantly improved vs. preoperative values. Concomitant CABG during Bentall operation independently affected late outcomes (HR 1.9−2.3; p-values < 0.05). Late survival was affected by concomitant CABG (84% ± 8% vs. 95% ± 2%, p = 0.04), preoperative myocardial infarction (91% ± 9% vs. 97% ± 2%, p = 0.02), and biological vs. mechanical prostheses valved conduits (91% ± 9% vs. 95% ± 3%, p = 0.02). Event-free survival also was affected by concomitant CABG (62% ± 14% vs. 85% ± 5%, p = 0.005) and biological prostheses (78% ± 8% vs. 84% ± 6%, p = 0.06). Freedom from endocarditis−redo operation was 83% ± 9% for biological prostheses vs. 89% ± 6% for mechanical prostheses (p = 0.49). Conclusions: Low rates of operative mortality and late complications make Bentall operation the gold standard for the treatment of ascending aorta−aortic root aneurysms. Coronary ischemic disease affects late outcomes. Biological prostheses should be preferred for the elderly.

The impact of dual antiplatelet therapy administration on the risk of bleeding complications during coronary artery bypass surgery.

INTRODUCTION: Dual antiplatelet therapy reduces the risk of cardiovascular death, myocardial infarction and recurrence of adverse ischemic events in patients affected by acute coronary syndromes, but in patients urgently needing coronary artery surgery it can increase the risk of severe perioperative bleeding complications. AIM: We evaluated the impact of dual antiplatelet therapy (DAPT) based on acetylsalicylic acid plus clopidogrel or ticagrelor in patients undergoing coronary artery bypass grafting (CABG). MATERIAL AND METHODS: Three hundred and thirty-three patients underwent coronary artery bypass grafting with DAPT discontinuation > 72 hours or 3-4 days (group A, n = 159), 48-72 hours or 2-3 days (group B, n = 126), < 24 hours or 0-1 day (group C, n = 24) prior to CABG. RESULTS: Operative mortality was 1.87% (group A), 0.79% (group B), absent (group C). The incidence of mediastinal re-exploration was 1.25% or 2 patients (group A), 1.59% or 2 patients (group B), 8.33% or 4 patients (group C) (p = 0.01). Group C showed postoperatively a greater incidence of a blood loss greater than 500 ml at 6 hours and a blood loss from chest tube drainages significantly higher at 6 and 24 hours (p < 0.01). Multivariate analysis showed that ongoing ticagrelor intake in group C (HR = 42.4; p = 0.02) and group C (HR = 6.9; p = 0.04) were the only independent predictors of surgical re-exploration. In group C, surgical re-exploration was 2.56% or 1/39 patients taking clopidogrel, 33.3% or 3/9 patients taking ticagrelor (p = 0.002). CONCLUSIONS: Dual antiplatelet therapy ongoing until 1 day or 24 hours before CABG showed a significantly increased risk of bleeding complications in comparison with its discontinuation at 2-3 and > 3-4 days before, respectively. Major blood loss and surgical re-exploration were not associated with increased risk of operative all-cause or bleeding-related mortality. As expected, taking ticagrelor compared with clopidogrel in the short interval confers a higher risk of bleeding complications.

The effects of DeBakey type acute aortic dissection and preoperative peripheral and cardiac malperfusion on the outcomes after surgical repair.

INTRODUCTION: Emergent surgical repair of DeBakey type I and II acute aortic dissection represents the standard of care to prevent lethal complications. AIM: Evaluation of the effect of extension of aortic dissection (AAD) according to DeBakey classification, type I and II AAD, and the relationship with preoperative peripheral and myocardial malperfusion on early outcome and the mid-term follow-up period. MATERIAL AND METHODS: A total of 135 patients who underwent AAD surgery between January 2015 and October 2019 were analysed. RESULTS: In total 103 patients were affected by DeBakey type I AAD and 32 by DeBakey type II; 56 patients preoperatively showed peripheral, cardiac malperfusion, or both. Intra-operative mortality was 11%. Postoperative peripheral, cardiac malperfusion, and intraoperative and postoperative mortality were lower for type II AAD. The protective factor for intra- and postoperative 60-day mortality was type II AAD (RR = 0.03, p = 0.001); independent predictors were hypertension, and preoperative cardiac and renal-visceral malperfusion. At 5 years the overall survival was 74 ±6.9%. Independent predictors of reduced survival were major extension of type I AAD (RR = 5.37, p < 0.05) and preoperative cardiac malperfusion (RR = 5.78, p < 0.05). Five-year freedom from cardiac death, redo surgical operation, and new vascular procedures on the thoracic and abdominal aorta was 92 ±5.7%, 99 ±1.2%, and 81 ±7.2%, respectively. Extension of DeBakey type I AAD into the thoracic-abdominal aorta segment was also a predictor of the need for new vascular procedures (RR = 1.66, p = 0.05). CONCLUSIONS: A more favourable anatomy of DeBakey type II AAD is associated with better early and late outcomes after aortic repair. This is due to a lower incidence of peripheral and cardiac malperfusion.

Surgical "elephant trunk" arch replacement with a branched arch prosthesis: two alternative operative techniques.

INTRODUCTION: Elephant trunk repair of the aortic arch cannot be performed with a branched prosthesis. AIM: We conceived two different modifications of the original technique to perform an arch replacement with a branched graft, while arranging an adequate landing zone for a subsequent thoracic endovascular aortic repair, without the need of dedicated material. MATERIAL AND METHODS: Eight consecutive patients underwent arch replacement with one of our techniques. Five were emergency patients with acute aortic dissection, and 3 suffered chronic expansive disease. The "modified elephant trunk" includes a separate anastomosis of an endo-luminal prosthetic segment in the descending aorta. Subsequently, the branched arch prosthesis is anastomosed to the distal aortic stump with the attached trunk. In the "prophylactic debranching", a tail is left on the distal end of the arch prosthesis, so that the branches for the supra-aortic vessels will remain displaced proximally, allowing a "zone 1" available for landing. RESULTS: Three patients experienced transient cerebral deficits (1 transient ischemic attack and post-operative delirium in 2 cases), 1 required re-operation for bleeding and 2 needed prolonged intubation. One died of multi-organ failure. CONCLUSIONS: Both techniques proved to be easily reproducible, and allow an adequate landing zone for a subsequent endovascular procedure, while retaining the advantages of using a tetra-furcated prosthesis. They are a viable alternative when a hybrid prosthesis cannot be implanted.

Polymorphisms of Pro-Inflammatory IL-6 and IL-1ß Cytokines in Ascending Aortic Aneurysms as Genetic Modifiers and Predictive and Prognostic Biomarkers.

BACKGROUND: Previous studies have demonstrated that polymorphisms involved in immune genes can affect the risk, pathogenesis, and outcome of thoracic ascending aortic aneurysms (TAAA). Here, we explored the potential associations of five functional promoter polymorphisms in interleukin-6 (IL-6), IL-1B, IL-1A, IL-18, and Tumor necrosis factor (TNF)A genes with TAAA. METHODS: 144 TAAA patients and 150 age/gender matched controls were typed using KASPar assays. Effects on telomere length and levels of TAAA related histopathological and serological markers were analyzed. RESULTS: Significant associations with TAAA risk were obtained for IL-6 rs1800795G>C and IL-1B rs16944C>T SNPs. In addition, the combined rs1800795C/rs16944T genotype showed a synergic effect on TAAA pathogenesis and outcome. The combined rs1800795C/rs16944T genotype was significantly associated with: (a) higher serum levels of both cytokines and MMP-9 and -2; (b) a significant CD3+CD4+CD8+ CD68+CD20+ cell infiltration in aorta aneurysm tissues; (c) a significant shorter telomere length and alterations in telomerase activity. Finally, it significantly correlated with TAAA aorta tissue alterations, including elastic fragmentation, medial cell apoptosis, cystic medial changes, and MMP-9 levels. CONCLUSIONS: the combined rs1800795C/rs16944T genotype appears to modulate TAAA risk, pathogenesis, and outcome, and consequently can represent a potential predictive and prognostic TAAA biomarker for individual management, implementation of innovative treatments, and selection of the more proper surgical timing and approaches.

Imaging and monitoring in minimally invasive valve surgery using an intra-aortic occlusion device: a single center experience.

BACKGROUND: Minimally invasive approach through a right mini-thoracotomy is a world-wide used procedure for mitral valve surgery. We performed a retrospective analysis based on our center experience in order to propose an effective, safe and reproducible method using an intra-aortic occlusion device. METHODS: This is a retrospective analysis on 48 consecutive patients undergoing mitral valve surgery through a right anterolateral mini-thoracotomy in our center. An intra-aortic occlusion device was used for aortic clamping and cardioplegia delivery. Simultaneous multi-plane three-dimensional echocardiography imaging was acquired to detect the venous cannulas position, the intra-aortic device location in the ascending aorta, the balloon inflation, the complete occlusion of the aorta, the cardioplegia delivery, the origin and the blood flow in the right coronary artery. Aortic root pressure was measured by the tip of the intra-aortic occlusion device. A bilateral upper extremity invasive arterial pressure monitoring was detected. Neuromonitoring was performed through bilateral cerebral oximetry. RESULTS: The analysis has shown no aortic dissection, neurological damage type 1 and myocardial ischemia in the study population. In 3 cases a distal displacement of the intra-aortic occlusion device was promptly detected by the combined use of echocardiographic imaging and by a drop of the right cerebral oximetry saturation and of the right radial artery pressure. CONCLUSIONS: The combined use of transesophageal simultaneous multi-plane three- dimensional echocardiography imaging, bilateral upper extremity invasive arterial pressure monitoring, aortic root pressure and cerebral oximetry is an effective, safe and reproducible method in patients undergoing minimally invasive valve surgery using an intra-aortic occlusion device.