Intestinal Microbiota and Derived Metabolites in Myocardial Fibrosis and Postoperative Atrial Fibrillation.

The high incidence of atrial fibrillation (AFib) following cardiac surgery (postoperative atrial fibrillation, POAF) relies on specific surgical features. However, in the setting of POAF, the role of the microbiome in the modulation of cardiac fibrosis is still not clear. This study aimed to analyze the effect of the microbiome and its main metabolic product (trimethylamine-N-oxide, TMAO) in the fibrosis of myocardial tissue, to investigate its role in POAF. Patients undergoing elective cardiac surgery with cardiopulmonary bypass, central atrio-caval cannulation and no history of AFib, were included. A fragment of the right atrium was analyzed for qualitative and mRNA-quantitative evaluation. A preoperative blood sample was analyzed with enzyme-linked immunosorbent assay (ELISA). A total of 100 patients have been included, with POAF occurring in 38%. Histologically, a higher degree of fibrosis, angiogenesis and inflammation has been observed in POAF. Quantitative evaluation showed increased mRNA expression of collagen-1, collagen-3, fibronectin, and transforming growth factor beta (TGFb) in the POAF group. ELISA analysis showed higher levels of TMAO, lipopolysaccharide and TGFb in POAF, with similar levels of sP-selectin and zonulin. TMAO ≥ 61.8 ng/mL (odds ratio, OR 2.88 [1.35-6.16], p = 0.006), preoperative hemoglobin < 13.1 g/dL (OR 2.37 [1.07-5.24], p = 0.033) and impaired right ventricular function (OR 2.38 [1.17-4.83], p = 0.017) were independent predictors of POAF. Also, TMAO was significantly associated with POAF by means of increased fibrosis. Gut microbiome product TMAO is crucial for myocardial fibrosis, which is a key factor for POAF. Patients in preoperative sinus rhythm who will develop POAF have increased genetic expression of pro-fibrotic genes and enhanced fibrosis in histological staining. Elevated TMAO level (≥61.8 ng/mL) is an independent risk factor for POAF.

External Scaffold for Venous Graft to Treat Chronic Limb-Threatening Ischemia: Results of the FRAME Vascular Support.

Background: The surgical treatment of chronic limb-threatening ischemia and optimal conduit choice are extensively debated. The presence of suboptimal autologous material, such as varicosities or venous aneurysms, might impair long-term outcomes. Therefore, kink-resistant external supports have been advocated in the recent literature to improve the conduit quality and outcomes. This study analyzes the FRAME external support in venous ectasic grafts in patients with chronic limb-threatening ischemia. Methods: From September 2017 to September 2023, a total of sixteen patients underwent CLTI surgery with FRAME external support for venous grafts. The inclusion criteria for FRAME applications were varicose or ectasic autologous material with a diameter ≥ 4.5 and ≤ 8 mm in an isolated segment or in the entire vein and a higher risk of bypass extrinsic compression (e.g., extra-anatomical venous bypass course). Results: Technical success and intraoperative patency were achieved in all cases. At 30 days, the limb salvage and survival rates were 100%. The primary bypass patency was 93.7% due to an early graft occlusion. No graft infection was registered. In one case, dehiscence of the surgical wound was treated by surgical debridement and antibiotic therapy. Minor amputation was required in four patients. Over a median follow-up of 32 months, two occlusions were observed; one was treated with reoperation and the other with major amputation. The primary patency was 68.7% and the assisted primary patency was 75%. Limb salvage rates observed during the entire follow-up period were 87.5%. No graft infections or dilatation of the reinforced veins were registered. Conclusions: For patients with CLTI undergoing infrainguinal bypass, satisfactory results in terms of patency and limb salvage rates were achieved using the autologous venous material, even if ectasic or varicose, with the vascular external support FRAME.

Panoramic on Epigenetics in Coronary Artery Disease and the Approach of Personalized Medicine.

Epigenetic modifications play a fundamental role in the progression of coronary artery disease (CAD). This panoramic review aims to provide an overview of the current understanding of the epigenetic mechanisms involved in CAD pathogenesis and highlights the potential implications for personalized medicine approaches. Epigenetics is the study of heritable changes that do not influence alterations in the DNA sequence of the genome. It has been shown that epigenetic processes, including DNA/histone methylation, acetylation, and phosphorylation, play an important role. Additionally, miRNAs, lncRNAs, and circRNAs are also involved in epigenetics, regulating gene expression patterns in response to various environmental factors and lifestyle choices. In the context of CAD, epigenetic alterations contribute to the dysregulation of genes involved in inflammation, oxidative stress, lipid metabolism, and vascular function. These epigenetic changes can occur during early developmental stages and persist throughout life, predisposing individuals to an increased risk of CAD. Furthermore, in recent years, the concept of personalized medicine has gained significant attention. Personalized medicine aims to tailor medical interventions based on an individual's unique genetic, epigenetic, environmental, and lifestyle factors. In the context of CAD, understanding the interplay between genetic variants and epigenetic modifications holds promise for the development of more precise diagnostic tools, risk stratification models, and targeted therapies. This review summarizes the current knowledge of epigenetic mechanisms in CAD and discusses the fundamental principles of personalized medicine.

Tissue Engineering and Targeted Drug Delivery in Cardiovascular Disease: The Role of Polymer Nanocarrier for Statin Therapy.

Atherosclerosis-related coronary artery disease (CAD) is the leading cause of mortality and morbidity worldwide. This requires effective primary and secondary prevention in reducing the complications related to CAD; the regression or stabilization of the pathology remains the mainstay of treatment. Statins have proved to be the most effective treatment in reducing adverse effects, but there are limitations related to the administration and achievement of effective doses as well as side effects due to the lack of target-related molecular specificity. The implemented technological steps are polymers and nanoparticles for the administration of statins, as it has been seen how the conjugation of drug delivery systems (DDSs) with statins increases bioavailability by circumventing the hepatic-renal filter and increases the related target specificity, enhancing their action and decreasing side effects. Reduction of endothelial dysfunction, reduced intimal hyperplasia, reduced ischemia-reperfusion injury, cardiac regeneration, positive remodeling in the extracellular matrix, reduced neointimal growth, and increased reendothelialization are all drug-related effects of statins enhanced by binding with DDSs. Recent preclinical studies demonstrate how the effect of statins stimulates the differentiation of endogenous cardiac stem cells. Poly-lactic-co-glycolic acid (PLGA) seems to be the most promising DDS as it succeeds more than the others in enhancing the effect of the bound drug. This review intends to summarize the current evidence on polymers and nanoparticles for statin delivery in the field of cardiovascular disease, trying to shed light on this topic and identify new avenues for future studies.

The Diagnostic Value of Circulating Biomarkers and Role of Drug-Coated Balloons for In-Stent Restenosis in Patients with Peripheral Arterial Disease.

Peripheral arterial disease (PAD) is an increasingly pathological condition that commonly affects the femoropopliteal arteries. The current fashionable treatment is percutaneous transluminal angioplasty (PTA), often with stenting. However, the in-stent restenosis (ISR) rate after the stenting of the femoropopliteal (FP) district remains high. Many techniques have been proposed for the treatment of femoropopliteal ISR, such as intravascular brachytherapy, laser atherectomy, second stenting and drug-coated balloons angioplasty (DCB). DCB showed a significantly lower rate of restenosis and target lesions revascularization (TLR) compared to conventional PTA. However, further studies and multi-center RCTs with dedicated long-term follow-up are needed to verify the true efficiency of this approach. Nowadays, the correlation between PAD and inflammation biomarkers is well known. Multiple studies have shown that proinflammatory markers (such as C-reactive proteins) and the high plasma levels of microRNA could predict the outcomes after stent placement. In particular, circulating microRNA-320a, microRNA-3937, microRNA-642a-3p and microRNA-572 appear to hold promise in diagnosing ISR in patients with PAD, but also as predictors of stent patency. This narrative review intends to summarize the current knowledge on the value of circulating biomarkers as predictors of ISR and to foster the scientific debate on the advantages of using DCB in the treatment of ISR in the FP district.

miRNAs in Cardiac Myxoma: New Pathologic Findings for Potential Therapeutic Opportunities.

MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, contributing to all major cellular processes. The importance of miRNAs in cardiac development, heart function, and valvular heart disease has been shown in recent years, and aberrant expression of miRNA has been reported in various malignancies, such as gastric cancer and breast cancer. Different from other fields of investigation, the role of miRNAs in cardiac tumors still remains difficult to interpret due to the scarcity publications and a lack of narrative focus on this topic. In this article, we summarize the available evidence on miRNAs and cardiac myxomas and propose new pathways for future research. miRNAs play a part in modifying the expression of cardiac transcription factors (miR-335-5p), increasing cell cycle trigger factors (miR-126-3p), interfering with ceramide synthesis (miR-320a), inducing apoptosis (miR-634 and miR-122), suppressing production of interleukins (miR-217), and reducing cell proliferation (miR-218). As such, they have complex and interconnected roles. At present, the study of the complete mechanistic control of miRNA remains a crucial issue, as proper understanding of signaling pathways is essential for the forecasting of therapeutic implications. Other types of cardiac tumors still lack adequate investigation with regard to miRNA. Further research should aim at investigating the causal relationship between different miRNAs and cell overgrowth, considering both myxoma and other histological types of cardiac tumors. We hope that this review will help in understanding this fascinating molecular approach.

Metformin Therapy Effects on the Expression of Sodium-Glucose Cotransporter 2, Leptin, and SIRT6 Levels in Pericoronary Fat Excised from Pre-Diabetic Patients with Acute Myocardial Infarction.

BACKGROUND AND PURPOSE: pericoronary fat over-inflammation might lead to the development and destabilization of coronary plaque in patients with pre-diabetes (PDM). Notably, pericoronary fat could over-express the sodium-glucose cotransporter 2 (SGLT2) and leptin, along with decreased sirtuin 6 (SIRT6) expression in PDM vs. normoglycemic (NG) patients undergoing coronary artery bypass grafting (CABG) for acute myocardial infarction (AMI). However, in the current study, we evaluated inflammatory markers, SGLT2, SIRT6, and leptin levels in pericoronary fat and, subsequently, 12-month prognosis comparing PDM to NG subjected to CABG for AMI. In addition, we evaluated in PDM patients the effects of metformin therapy on SIRT6 expression, leptin, and SGLT2 levels, and assessed its beneficial effect on nitrotyrosine and inflammatory cytokine levels. METHODS: we studied AMI patients referred for CABG, divided into PDM and NG-patients. PDM patients were divided into never-metformin users and metformin users. Finally, we evaluated major adverse cardiac events (MACE) at a 12-month follow-up. RESULTS: the MACE was 9.1% in all PDM and 3% in NG patients (p < 0.05). Metformin users presented a significantly lower MACE rate in PDM than never-metformin users (p < 0.05). PDM showed higher inflammatory cytokines, 3-nitrotyrosine levels, SGLT2, and leptin content, and decreased SIRT6 protein levels in pericoronary fat compared to NG-patients (p < 0.05). PDM never-metformin-users showed higher SGLT2 and leptin levels in pericoronary fat than current-metformin-users (p < 0.05). CONCLUSIONS: metformin therapy might ameliorate cardiovascular outcomes by reducing inflammatory parameters, SGLT2, and leptin levels, and finally improving SIRT6 levels in AMI-PDM patients treated with CABG.

Microbiota thrombus colonization may influence athero-thrombosis in hyperglycemic patients with ST segment elevation myocardialinfarction (STEMI). Marianella study.

OBJECTIVES: We examined the association of the coronary thrombus microbiota and relative metabolites with major adverse cardiovascular events (MACE) in hyperglycemic patients with ST segment elevation myocardial infarction (STEMI). BACKGROUND: Hyperglycemia during STEMI may affect both development and progression of coronary thrombus via gut and thrombus microbiota modifications. METHODS: We undertook an observational cohort study of 146 first STEMI patients treated with primary percutaneous coronary intervention (PPCI) and thrombus-aspiration (TA). Patients were clustered, based on admission blood glucose levels, in hyperglycemic (≥140 mg/dl) and normoglycemic (<140 mg/dl). We analyzed gut and thrombus microbiota in all patients. Moreover, we assessed TMAO, CD40L and von Willebrand Factor (vWF) in coronary thrombi. Cox regressions were used for the association between Prevotellaspp. and TMAO terziles and MACE. MACE endpoint at 1 year included death, re-infarction, unstable angina. RESULTS: In fecal and thrombus samples, we observed a significantly different prevalence of both Prevotellaspp. and Alistipesspp. between patients with hyperglycemia (n = 56) and those with normal glucose levels (n = 90). The abundance of Prevotella increased in hyperglycemic vs normoglycemic patients whereas the contrary was observed for Alistipes. Interestingly, in coronary thrombus, the content of Prevotella was associated with admission blood glucose levels (p < 0.01), thrombus dimensions (p < 0.01), TMAO, CDL40 (p < 0.01) and vWF (p < 0.01) coronary thrombus contents. Multivariate Cox-analysis disclosed a reduced survival in patients with high levels of Prevotella and TMAO in coronary thrombus as compared to patients with low levels of Prevotella and TMAO, after 1-year follow up. CONCLUSIONS: Hyperglycemia during STEMI may increase coronary thrombus burden via gut and thrombus microbiota dysbiosis characterized by an increase of Prevotella and TMAO content in thrombi. CLINICAL TRIAL REGISTRATION: NCT03439592. September 30, 2016. Ethic Committee Vanvitelli University: 268/2016.

Pericoronary fat inflammation and Major Adverse Cardiac Events (MACE) in prediabetic patients with acute myocardial infarction: effects of metformin.

BACKGROUND/OBJECTIVES: Pericoronary adipose tissue inflammation might lead to the development and destabilization of coronary plaques in prediabetic patients. Here, we evaluated inflammation and leptin to adiponectin ratio in pericoronary fat from patients subjected to coronary artery bypass grafting (CABG) for acute myocardial infarction (AMI). Furthermore, we compared the 12-month prognosis of prediabetic patients compared to normoglycemic patients (NG). Finally, the effect of metformin therapy on pericoronary fat inflammation and 12-months prognosis in AMI-prediabetic patients was also evaluated. METHODS: An observational prospective study was conducted on patients with first AMI referred for CABG. Participants were divided in prediabetic and NG-patients. Prediabetic patients were divided in two groups; never-metformin-users and current-metformin-users receiving metformin therapy for almost 6 months before CABG. During the by-pass procedure on epicardial coronary portion, the pericoronary fat was removed from the surrounding stenosis area. The primary endpoints were the assessments of Major-Adverse-Cardiac-Events (MACE) at 12-month follow-up. Moreover, inflammatory tone was evaluated by measuring pericoronary fat levels of tumor necrosis factor-α (TNF-α), sirtuin 6 (SIRT6), and leptin to adiponectin ratio. Finally, inflammatory tone was correlated to the MACE during the 12-months follow-up. RESULTS: The MACE was 9.1% in all prediabetic patients and 3% in NG-patients. In prediabetic patients, current-metformin-users presented a significantly lower rate of MACE compared to prediabetic patients never-metformin-users. In addition, prediabetic patients showed higher inflammatory tone and leptin to adiponectin ratio in pericoronary fat compared to NG-patients (P < 0.001). Prediabetic never-metformin-users showed higher inflammatory tone and leptin to adiponectin ratio in pericoronary fat compared to current-metformin-users (P < 0.001). Remarkably, inflammatory tone and leptin to adiponectin ratio was significantly related to the MACE during the 12-months follow-up. CONCLUSION: Prediabetes increase inflammatory burden in pericoronary adipose tissue. Metformin by reducing inflammatory tone and leptin to adiponectin ratio in pericoronary fat may improve prognosis in prediabetic patients with AMI. Trial registration Clinical Trial NCT03360981, Retrospectively Registered 7 January 2018.