Abstract Introduction Atrial fibrillation (AF) and Type 2 Diabetes Mellitus (T2DM) are two closely interconnected conditions, sharing a complex relationship within cardiac pathophysiology. Common risk factors such as obesity, hypertension, inflammation, and endothelial dysfunction contribute to their coexistence. T2DM is known to drive cardiac fibrosis and promote electrical and structural remodeling of the heart, creating a substrate conducive to AF onset, while AF in T2DM patients increases the risk of adverse cardiovascular outcomes, such as stroke. Understanding this complex relationship is pivotal for improving the therapeutic and preventive strategies for these patients. This study aims to examine the proteomic differences between AF patients with and without T2DM, providing novel insights into pathophysiological mechanisms and identifying novel therapeutic targets and biomarkers. Methods In total, 14 AF patients undergoing open-heart surgery, comprising of 6 T2DM individuals and 8 non-T2DM individuals have been included. The mean age of the T2DM patients was 69.5 ± 10 years, while the non-T2DM was 69.3 ± 8.2 and BMI was 29.2 ± 2.9 and 29.5 ± 3 respectively. Right atrial appendages (RAA) from these patients were obtained in an RNA stabilization solution during open-heart surgery and processed using the phenol-based method for protein extraction. The proteins were digested with trypsin to generate peptides, followed by an additional clean-up step using C18 pipette tips. The prepared peptide samples were analyzed by employing a label-free-based quantitative (LFQ) approach, using a C18 (75cmx75cm) column. Proteomic analysis was performed using a Nano liquid chromatography system coupled to tandem mass spectrometer (nano LC-MS/MS), followed by a comprehensive bioinformatics analysis, using appropriate software. Results A total of 1548 proteins were identified, of which 899 could be quantified using LFQ analysis. Applying strict significance criteria, including FDR <0.1 and Abundance ratio (AR)>2 or <0.5, we identified 100 differential expressed proteins, with 21 upregulated and 79 downregulated in T2DM (Fig.1). Most notably, DPP9 and ATP1A2 were overexpressed in hearts of AF patients with T2DM (AR=100), while INPPL1 and ARID5A were underexpressed (AR=0.01), thereby representing attractive therapeutic targets. In pathway enrichment analysis (Fig.2), the dysregulated proteins participate in noteworthy pathways, including Non-alcoholic fatty liver disease (NAFLD), Type II diabetes mellitus, and Insulin signaling pathway. Conclusion Given the increased morbidity associated with the coexistence of AF and T2DM, there is a pressing need for novel therapeutic strategies tailored to this patient population. While AF and T2DM share certain molecular characteristics in the heart, this study emphasizes the necessity for further evaluation and validation of the distinct proteomic signatures identified.Fig.1:Volcano PlotFig.2:Protein Enrichment Network

The involvement of the aortic arch in thoracic aortic aneurysms (TAA), or acute aortic dissections (AAD), represents a challenging clinical entity, mandating a meticulous surgical plan, tailored to each individual case. The advent of endovascular techniques and the introduction of modern arch protheses have led to the implementation of the frozen elephant trunk (FET) technique. This one-step hybrid operation consists of a total aortic arch replacement combined with an antegrade delivery of a stent–graft for the descending aorta, which acts as a proximal landing zone facilitating a potential distal endovascular reintervention. In this manner, this technique addresses acute and chronic arch disease with an acceptable morbidity and mortality. Several FET prosthetic devices are available on the global market and have exhibited favourable outcomes, although with some disadvantages in complex cases; similarly, the hybrid procedure described in this review has also been associated with complications, such as coagulopathy and neurological and graft-related events. The purpose of this review is to thus provide key insights into successful hybrid aortic arch replacements and to discuss useful tips and relevant considerations regarding its use.

Sodium-glucose cotransporters 2 (SGLT2) are high-capacity, low-affinity transporters, expressed mainly in the early portion of the proximal renal tube, mediating up to 90% of renal glucose uptake, while SGLT1 receptors are found mainly in the small intestine, facilitating glucose absorption. SGLT2 inhibitors (SGLT2i) originally emerged as agents for the treatment of type 2 diabetes mellitus; however, they soon demonstrated remarkable cardio- and renoprotective actions that led to their licensed use for the treatment of heart failure and chronic kidney disease, regardless of the diabetic status. Cardiovascular remodelling represents an umbrella term that encompasses changes that occur in the cardiovascular system, from the molecular and cellular level, to tissue and organs after local injury, chronic stress, or pressure. SGLT modulation has been shown to positively affect many of these molecular and cellular changes observed during pathological remodelling. Among the different pathophysiological mechanisms that contribute to adverse remodelling, various stem and progenitor cells have been shown to be involved, through alterations in their number or function. Recent studies have examined the effects of SGLT2i on stem and progenitor cell populations and more specifically on endothelial progenitor cells (EPCs). Although some found no significant effect, others showed that SGLT2i can modulate the morphology and function of EPCs. These preliminary observations of the effect of SGLT2i on EPCs may be responsible for some of the beneficial effects of gliflozins on pathological remodelling and, by extension, on cardiovascular disease. The purpose of this narrative review is to critically discuss recent evidence on the cardioprotective effects of SGLT2is, in the context of cardiac remodelling.

Despite improvements in contemporary medical and surgical therapies, cardiovascular disease (CVD) remains a significant cause of worldwide morbidity and mortality; more specifically, ischemic heart disease (IHD) may affect individuals as young as 20 years old. Typically managed with guideline-directed medical therapy, interventional or surgical methods, the incurred cardiomyocyte loss is not always completely reversible; however, recent research into various stem cell (SC) populations has highlighted their potential for the treatment and perhaps regeneration of injured cardiac tissue, either directly through cellular replacement or indirectly through local paracrine effects. Different stem cell (SC) types have been employed in studies of infarcted myocardium, both in animal models of myocardial infarction (MI) as well as in clinical studies of MI patients, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), Muse cells, multipotent stem cells such as bone marrow-derived cells, mesenchymal stem cells (MSCs) and cardiac stem and progenitor cells (CSC/CPCs). These have been delivered as is, in the form of cell therapies, or have been used to generate tissue-engineered (TE) constructs with variable results. In this text, we sought to perform a narrative review of experimental and clinical studies employing various stem cells (SC) for the treatment of infarcted myocardium within the last two decades, with an emphasis on therapies administered through thoracic incision or through percutaneous coronary interventions (PCI), to elucidate possible mechanisms of action and therapeutic effects of such cell therapies when employed in a surgical or interventional manner.

Non-A non-B aortic dissection（AAD） is an infrequently documented condition,comprising of only a small proportion of all AADs. The unique anatomy of the aortic arch and the failure of the existing classifications to adequately define individuals with non-A non-B AAD, have led to an ongoing controversy around the topic. It seems that the clinical progression of acute non-A non-B AAD diverges from the typical type A and B dissections, frequently leading to serious complications and thus mandating early intervention. Currently, the available treatment methods in the surgical armamentarium are conventional open,endovascular techniques and combined hybrid methods. The optimum approach is tailored in every individual case and may be determined by the dissection’s location, extent, the aortic diameter, the associated complications and the patient’s status. The management of non-A non-B dissections still remains challenging and a unanimous consensus defining the gold standard treatment has yet to be reached. In an attempt to provide further insight into this perplexing entity, we performed a minireview of the literature, aiming to elucidate the epidemiology,clinical course and the optimal treatment modality.

As doctors increasingly rely on technological advancements, ever-improving laboratory techniques, and imaging modalities, the importance of a thorough physical evaluation and bedside manner has been noticeably diminished. When it comes to patients scheduled for coronary artery bypass graft (CABG), the preoperative bilateral arm blood pressure (BP) measurement is often omitted; thus, sinister signs of atherosclerotic disease like the brachial gradient are neglected and the surgical plan is jeopardized. We present the case of a 72-year-old male listed for CABG, stressing the necessity of meticulous clinical examination and the routine use of color Doppler ultrasonography (CDUS), prior to surgery. This case aims to highlight the major role of thorough preoperative clinical assessment. The bilateral BP measurement and CDUS are two reliable, expeditious, noninvasive preoperative screening methods, which can detect patients with generalized atherosclerosis, altering, if necessary, the surgical plan, and aiming for the best possible outcome, without complications.

Niclosamide is a commonly used helminthicidic drug for the treatment of human parasitosis by helminths. Recently, efforts have been focusing on repurposing this drug for the treatment of other diseases, such as idiopathic pulmonary fibrosis. Subepithelial lung myofibroblasts (SELMs) isolated from tissue biopsies of patients undergoing surgery for lung cancer were stimulated with TNF-α (50 ng/mL), IL-1α (5 ng/mL), added alone or in combination, and TGF-β1 (5 ng/mL). After treatment with niclosamide at 30 nM and 100 nM concentrations, expression of collagen type I, collagen type III, and fibronectin was studied by total RNA isolation and qRT-PCR and protein collagen secretion with the use of Sircol collagen assay. The migration of SELMs was assessed by a wound-healing assay. Niclosamide had no effect on baseline SELM fibrotic factor expression. When stimulated with TGF-β1, IL-1α, and/or TNF-α, SELM expression of collagen type I, type III, and fibronectin were upregulated, as was the secretion of total collagen in the culture medium. Treatment with niclosamide attenuated the effects of cytokine stimulation leading to a notable decrease in the mRNA expression of collagen type I, type III, and fibronectin in a concentration-dependent manner. SELM collagen secretion was also reduced by niclosamide at 100 nM concentration when examined at the protein level. Migration of both TGF-β1 stimulated and unstimulated SELMs was also inhibited by niclosamide. In this study, we highlight the anti-fibrotic properties of niclosamide on SELMs under stimulation with pro-fibrotic and pro-inflammatory cytokines, thus proposing this compound as a possible new therapeutic agent against lung fibrosis.

Aortic and visceral aneurysms affect large arterial vessels, including the thoracic and abdominal aorta, as well as visceral arterial branches, such as the splenic, hepatic, and mesenteric arteries, respectively. Although these clinical entities have not been equally researched, it seems that they might share certain common pathophysiological changes and molecular mechanisms. The yet limited published data, with regard to newly designed, novel therapies, could serve as a nidus for the evaluation and potential implementation of such treatments in large artery aneurysms. In both animal models and clinical trials, various novel treatments have been employed in an attempt to not only reduce the complications of the already implemented modalities, through manufacturing of more durable materials, but also to regenerate or replace affected tissues themselves. Cellular populations like stem and differentiated vascular cell types, large diameter tissue-engineered vascular grafts (TEVGs), and various molecules and biological factors that might target aspects of the pathophysiological process, including cell-adhesion stabilizers, metalloproteinase inhibitors, and miRNAs, could potentially contribute significantly to the treatment of these types of aneurysms. In this narrative review, we sought to collect and present relevant evidence in the literature, in an effort to unveil promising biological therapies, possibly applicable to the treatment of aortic aneurysms, both thoracic and abdominal, as well as visceral aneurysms.

Kruppel-like factor 2 (KLF2) has been linked with fibrosis and neutrophil-associated thromboinflammation; however, its role in COVID-19 remains elusive. We investigated the effect of disease microenvironment on the fibrotic potential of human lung fibroblasts (LFs) and its association with KLF2 expression. LFs stimulated with plasma from severe COVID-19 patients down-regulated KLF2 expression at mRNA/protein and functional level acquiring a pre-fibrotic phenotype, as indicated by increased CCN2/collagen levels. Pre-incubation with the COMBI-treatment-agents (DNase I and JAKs/IL-6 inhibitors baricitinib/tocilizumab) restored KLF2 levels of LFs to normal abolishing their fibrotic activity. LFs stimulated with plasma from COMBI-treated patients at day-7 expressed lower CCN2 and higher KLF2 levels, compared to plasma prior-to-treatment, an effect not observed in standard-of-care treatment. In line with this, COMBI-treated patients had better outcome than standard-of-care group. These data link fibroblast KLF2 with NETosis and JAK/IL-6 signaling, suggesting the potential of combined therapeutic strategies in immunofibrotic diseases, such as COVID-19.

Idiopathic pulmonary fibrosis (IPF) is caused by progressive lung tissue impairment due to extended chronic fibrosis, and it has no known effective treatment. The use of conditioned media (CM) from an immortalized human adipose mesenchymal stem cell line could be a promising therapeutic strategy, as it can reduce both fibrotic and inflammatory responses. We aimed to investigate the anti-inflammatory and anti-fibrotic effect of CM on human pulmonary subepithelial myofibroblasts (hPSM) and on A549 pulmonary epithelial cells, treated with pro-inflammatory or pro-fibrotic mediators. CM inhibited the proinflammatory cytokine-induced mRNA and protein production of various chemokines in both hPSMs and A549 cells. It also downregulated the mRNA expression of IL-1α, but upregulated IL-1β and IL-6 mRNA production in both cell types. CM downregulated the pro-fibrotic-induced mRNA expression of collagen Type III and the migration rate of hPSMs, but upregulated fibronectin mRNA production and the total protein collagen secretion. CM’s direct effect on the chemotaxis and cell recruitment of immune-associated cells, and its indirect effect on fibrosis through the significant decrease in the migration capacity of hPSMs, makes it a plausible candidate for further development towards a therapeutic treatment for IPF.

In this paper, we describe a rare case of a giant aneurysm of the circumflex artery that we managed. A 59-year-old female patient presented in cardiogenic shock after partial aneurysm rupture. Giant aneurysms of the circumflex artery are extremely rare entities. The optimal surgical management dictates meticulous preoperative planning and the operation should be carried out on an elective basis.

During fetal development, shear stress regulates several aspects of vascular development. Alterations in signaling pathways due to disturbed flow in atheroprone regions closely mirror phenomena seen during embryogenesis. This flow‐dependent dysregulation of developmental genes appears to promote atherogenesis by mediating inflammatory phenomena, cell cycle progression, apoptosis, cell migration, and oxidative stress. Indeed, several stem cell genes have been implicated in vascular health and atheromatosis. Klotho is key in maintaining endothelial integrity, reducing oxidative stress, and sustaining endothelial nitric oxide production. In atherosclerotic lesions, OCT4 mediates the conversion of vascular smooth muscle cells from contractile to a de‐dedifferentiated proliferative phenotype with phagocytic ability. HIF1α drives atherosclerotic plaque progression by promoting intraplaque angiogenesis. BMP4 promotes osteochondrogenic development and arterial calcification. Strategic extracellular matrix changes are also seen during the various phases of atherosclerosis. The aforementioned conceptual framework explains how proatherogenic inflammation develops in response to low shear stress. In the present review, we explored the effect of cardinal atheroprotective ( Klotho, OCT4 ) and proatherogenic ( HIF1α, BMP4 ) genes in mediating proatherogenic inflammation.

In this paper, we describe a rare case of a giant aneurysm of the circumflex artery that we managed. A 59-year-old female patient presented in cardiogenic shock after partial aneurysm rupture. Giant aneurysms of the circumflex artery are extremely rare entities. The optimal surgical management dictates meticulous preoperative planning and the operation should be carried out on an elective basis.

Aiming to reduce mortality in COVID-19 with severe respiratory failure we administered a combined rescue treatment (COMBI) on top of standard-of-care (SOC: dexamethasone/heparin) consisted of inhaled DNase to dissolve thrombogenic neutrophil extracellular traps, plus agents against cytokine-mediated hyperinflammation, namely anti-IL-6-receptor tocilizumab and JAK1/2 inhibitor baricitinib. Patients with PaO2/FiO(2) < 100 mmHg were analysed. COMBI group (n = 22) was compared with similar groups that had received SOC alone (n = 26) or SOC plus monotherapy with either IL-1-receptor antagonist anakinra (n = 19) or tocilizumab (n = 11). COMBI was significantly associated with lower in-hospital mortality and intubation rate, shorter duration of hospitalization, and prolonged overall survival after a median follow-up of 110 days. In vitro, COVID-19 plasma induced tissue factor/thrombin pathway in primary lung fibroblasts. This effect was inhibited by the immunomodulatory agents of COMBI providing a mechanistic explanation for the clinical observations. These results support the conduct of randomized trials using combined immunomodulation in COVID-19 to target multiple interconnected pathways of immunothrombosis.

Mitral annular disjunction (MAD) is a structural abnormality defined by a distinct separation of the mitral valve annulus—left atrial wall continuum and the basal aspect of the posterolateral left ventricle. This anomaly is often observed in patients with myxomatous mitral valve prolapse. Importantly, MAD has been strongly associated with serious ventricular arrhythmias and predisposes to sudden cardiac death. Therefore, we have to emphasize the need to diagnose this morphologic and functional abnormality in routine practice in order to facilitate optimal mitral valve repair and minimize patient risks. Nevertheless, clinical knowledge regarding MAD still remains limited. In the present review, we aim to shed light on several aspects of MAD, including distinct anatomical and pathophysiological characteristics, imaging modalities, association with ventricular arrhythmias, and current methods of treatment.

Background Intimal calcification typically develops in advanced atherosclerosis, and microcalcification may promote plaque progression and instability. Conversely, intraplaque hemorrhage and erythrocyte extravasation may stimulate osteoblastic differentiation and intralesional calcium phosphate deposition. The presence of erythrocytes and their main cellular components (membranes, hemoglobin, and iron) and colocalization with calcification has never been systematically studied. Methods and Results We examined three types of diseased vascular tissue specimens, namely, degenerative aortic valve stenosis (n = 46), atherosclerotic carotid artery plaques (n = 9), and abdominal aortic aneurysms (n = 14). Biomaterial was obtained from symptomatic patients undergoing elective aortic valve replacement, carotid artery endatherectomy, or aortic aneurysm repair, respectively. Serial sections were stained using Masson–Goldner trichrome, Alizarin red S, and Perl's iron stain to visualize erythrocytes, extracelluar matrix and osteoid, calcium phosphate deposition, or the presence of iron and hemosiderin, respectively. Immunohistochemistry was employed to detect erythrocyte membranes (CD235a), hemoglobin or the hemoglobin scavenger receptor (CD163), endothelial cells (CD31), myofibroblasts (SMA), mesenchymal cells (osteopontin), or osteoblasts (periostin). Our analyses revealed a varying degree of intraplaque hemorrhage and that the majority of extravasated erythrocytes were lysed. Osteoid and calcifications also were frequently present, and erythrocyte membranes were significantly more prevalent in areas with calcification. Areas with extravasated erythrocytes frequently contained CD163-positive cells, although calcification also occurred in areas without CD163 immunosignals. Conclusion Our findings underline the presence of extravasated erythrocytes and their membranes in different types of vascular lesions, and their association with areas of calcification suggests an active role of erythrocytes in vascular disease processes.

Dimos Karangelis, Vasiliki Androutsopoulou, Aphrodite Tzifa, George Chalikias, Dimitrios Tziakas, Fotis Mitropoulos, Dimitrios Mikroulis

The coronary-subclavian steal syndrome is a hemodynamic phenomenon in which a subclavian artery stenosis or occlusion impairs blood flow at the origin of the left internal mammary artery used for coronary artery bypass grafting (CABG), causing retrograde blood flow and thus provoking symptoms of cardiac ischemia and its complications. Once considered the gold-standard operation of choice, open revascularization has now been abandoned as a first line treatment and replaced by endovascular techniques. In all cases, detailed and oriented physical examination in combination with further imaging in high clinical suspicion for coronary-subclavian steal syndrome remains the sine qua non of the preoperative examination of the patient. We report the case of a 50-year-old male patient suffering from acute onset angina post- coronary artery bypass grafting and managed by endovascular means.