The Novel Role of Noncoding RNAs in Modulating Platelet Function: Implications in Activation and Aggregation.

It is currently believed that plaque complication, with the consequent superimposed thrombosis, is a key factor in the clinical occurrence of acute coronary syndromes (ACSs). Platelets are major players in this process. Despite the considerable progress made by the new antithrombotic strategies (P2Y12 receptor inhibitors, new oral anticoagulants, thrombin direct inhibitors, etc.) in terms of a reduction in major cardiovascular events, a significant number of patients with previous ACSs treated with these drugs continue to experience events, indicating that the mechanisms of platelet remain largely unknown. In the last decade, our knowledge of platelet pathophysiology has improved. It has been reported that, in response to physiological and pathological stimuli, platelet activation is accompanied by de novo protein synthesis, through a rapid and particularly well-regulated translation of resident mRNAs of megakaryocytic derivation. Although the platelets are anucleate, they indeed contain an important fraction of mRNAs that can be quickly used for protein synthesis following their activation. A better understanding of the pathophysiology of platelet activation and the interaction with the main cellular components of the vascular wall will open up new perspectives in the treatment of the majority of thrombotic disorders, such as ACSs, stroke, and peripheral artery diseases before and after the acute event. In the present review, we will discuss the novel role of noncoding RNAs in modulating platelet function, highlighting the possible implications in activation and aggregation.

Streptozotocin-Induced Type 1 and 2 Diabetes Mellitus Mouse Models Show Different Functional, Cellular and Molecular Patterns of Diabetic Cardiomyopathy.

The main cause of morbidity and mortality in diabetes mellitus (DM) is cardiovascular complications. Diabetic cardiomyopathy (DCM) remains incompletely understood. Animal models have been crucial in exploring DCM pathophysiology while identifying potential therapeutic targets. Streptozotocin (STZ) has been widely used to produce experimental models of both type 1 and type 2 DM (T1DM and T2DM). Here, we compared these two models for their effects on cardiac structure, function and transcriptome. Different doses of STZ and diet chows were used to generate T1DM and T2DM in C57BL/6J mice. Normal euglycemic and nonobese sex- and age-matched mice served as controls (CTRL). Immunohistochemistry, RT-PCR and RNA-seq were employed to compare hearts from the three animal groups. STZ-induced T1DM and T2DM affected left ventricular function and myocardial performance differently. T1DM displayed exaggerated apoptotic cardiomyocyte (CM) death and reactive hypertrophy and fibrosis, along with increased cardiac oxidative stress, CM DNA damage and senescence, when compared to T2DM in mice. T1DM and T2DM affected the whole cardiac transcriptome differently. In conclusion, the STZ-induced T1DM and T2DM mouse models showed significant differences in cardiac remodeling, function and the whole transcriptome. These differences could be of key relevance when choosing an animal model to study specific features of DCM.

The Impact of Anesthetic Regimen on Outcomes in Adult Cardiac Surgery: A Narrative Review.

Despite improvements in surgical techniques and perioperative care, cardiac surgery still is burdened by relatively high mortality and frequent major postoperative complications, including myocardial dysfunction, pulmonary complications, neurologic injury, and acute kidney injury. Although the surgeon's skills and volume and patient- and procedure-related risk factors play a major role in the success of cardiac surgery, there is growing evidence that also optimizing perioperative care may improve outcomes significantly. The present review focuses on the aspects of perioperative care that are strictly related to the anesthesia regimen, with special reference to volatile anesthetics and neuraxial anesthesia, whose effect on outcome in adult cardiac surgery has been investigated extensively.

Atrial myxomas arise from multipotent cardiac stem cells.

AIMS: Cardiac myxomas usually develop in the atria and consist of an acid-mucopolysaccharide-rich myxoid matrix with polygonal stromal cells scattered throughout. These human benign tumours are a valuable research model because of the rarity of cardiac tumours, their clinical presentation and uncertain origin. Here, we assessed whether multipotent cardiac stem/progenitor cells (CSCs) give rise to atrial myxoma tissue. METHODS AND RESULTS: Twenty-three myxomas were collected and analysed for the presence of multipotent CSCs. We detected myxoma cells positive for c-kit (c-kitpos) but very rare Isl-1 positive cells. Most of the c-kitpos cells were blood lineage-committed CD45pos/CD31pos cells. However, c-kitpos/CD45neg/CD31neg cardiac myxoma cells expressed stemness and cardiac progenitor cell transcription factors. Approximately ≤10% of the c-kitpos/CD45neg/CD31neg myxoma cells also expressed calretinin, a characteristic of myxoma stromal cells. In vitro, the c-kitpos/CD45neg/CD31neg myxoma cells secrete chondroitin-6-sulfate and hyaluronic acid, which are the main components of gelatinous myxoma matrix in vivo. In vitro, c-kitpos/CD45neg/CD31neg myxoma cells have stem cell properties being clonogenic, self-renewing, and sphere forming while exhibiting an abortive cardiac differentiation potential. Myxoma-derived CSCs possess a mRNA and microRNA transcriptome overall similar to normal myocardium-derived c-kitpos/CD45neg/CD31negCSCs , yet showing a relatively small and relevant fraction of dysregulated mRNA/miRNAs (miR-126-3p and miR-335-5p, in particular). Importantly, myxoma-derived CSCs but not normal myocardium-derived CSCs, seed human myxoma tumours in xenograft's in immunodeficient NOD/SCID mice. CONCLUSION: Myxoma-derived c-kitpos/CD45neg/CD31neg CSCs fulfill the criteria expected of atrial myxoma-initiating stem cells. The transcriptome of these cells indicates that they belong to or are derived from the same lineage as the atrial multipotent c-kitpos/CD45neg/CD31neg CSCs. Taken together the data presented here suggest that human myxomas could be the first-described CSC-related human heart disease.

Unravelling the Biology of Adult Cardiac Stem Cell-Derived Exosomes to Foster Endogenous Cardiac Regeneration and Repair.

Cardiac remuscularization has been the stated goal of the field of regenerative cardiology since its inception. Along with the refreshment of lost and dysfunctional cardiac muscle cells, the field of cell therapy has expanded in scope encompassing also the potential of the injected cells as cardioprotective and cardio-reparative agents for cardiovascular diseases. The latter has been the result of the findings that cell therapies so far tested in clinical trials exert their beneficial effects through paracrine mechanisms acting on the endogenous myocardial reparative/regenerative potential. The endogenous regenerative potential of the adult heart is still highly debated. While it has been widely accepted that adult cardiomyocytes (CMs) are renewed throughout life either in response to wear and tear and after injury, the rate and origin of this phenomenon are yet to be clarified. The adult heart harbors resident cardiac/stem progenitor cells (CSCs/CPCs), whose discovery and characterization were initially sufficient to explain CM renewal in response to physiological and pathological stresses, when also considering that adult CMs are terminally differentiated cells. The role of CSCs in CM formation in the adult heart has been however questioned by some recent genetic fate map studies, which have been proved to have serious limitations. Nevertheless, uncontested evidence shows that clonal CSCs are effective transplantable regenerative agents either for their direct myogenic differentiation and for their paracrine effects in the allogeneic setting. In particular, the paracrine potential of CSCs has been the focus of the recent investigation, whereby CSC-derived exosomes appear to harbor relevant regenerative and reparative signals underlying the beneficial effects of CSC transplantation. This review focuses on recent advances in our knowledge about the biological role of exosomes in heart tissue homeostasis and repair with the idea to use them as tools for new therapeutic biotechnologies for "cell-less" effective cardiac regeneration approaches.

New imaging techniques project the cellular and molecular alterations underlying bicuspid aortic valve development.

Bicuspid aortic valve (BAV) disease is the most common congenital cardiac malformation associated with an increased lifetime risk and a high rate of surgically-relevant valve deterioration and aortic dilatation. Genomic data revealed that different genes are associated with BAV. A dominant genetic factor for the recent past was the basis to the recommendation for a more extensive aortic intervention. However very recent evidence that hemodynamic stressors and alterations of wall shear stress play an important role independent from the genetic trait led to more conservative treatment recommendations. Therefore, there is a current need to improve the ability to risk stratify BAV patients in order to obtain an early detection of valvulopathy and aortopathy while also to predict valve dysfunction and/or aortic disease development. Imaging studies based on new cutting-edge technologies, such us 4-dimensional (4D) flow magnetic resonance imaging (MRI), two-dimensional (2D) or three-dimensional (3D) speckle-tracking imaging (STI) and computation fluid dynamics, combined with studies demonstrating new gene mutations, specific signal pathways alterations, hemodynamic influences, circulating biomarkers modifications, endothelial progenitor cell impairment and immune/inflammatory response, all detected BAV valvulopathy progression and aortic wall abnormality. Overall, the main purpose of this review article is to merge the evidences of imaging and basic science studies in a coherent hypothesis that underlies and thus projects the development of both BAV during embryogenesis and BAV-associated aortopathy and its complications in the adult life, with the final goal to identifying aneurysm formation/rupture susceptibility to improve diagnosis and management of patients with BAV-related aortopathy.

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.

Heterogeneity of Adult Cardiac Stem Cells.

Cardiac biology and heart regeneration have been intensively investigated and debated in the last 15 years. Nowadays, the well-established and old dogma that the adult heart lacks of any myocyte-regenerative capacity has been firmly overturned by the evidence of cardiomyocyte renewal throughout the mammalian life as part of normal organ cell homeostasis, which is increased in response to injury. Concurrently, reproducible evidences from independent laboratories have convincingly shown that the adult heart possesses a pool of multipotent cardiac stem/progenitor cells (CSCs or CPCs) capable of sustaining cardiomyocyte and vascular tissue refreshment after injury. CSC transplantation in animal models displays an effective regenerative potential and may be helpful to treat chronic heart failure (CHF), obviating at the poor/modest results using non-cardiac cells in clinical trials. Nevertheless, the degree/significance of cardiomyocyte turnover in the adult heart, which is insufficient to regenerate extensive damage from ischemic and non-ischemic origin, remains strongly disputed. Concurrently, different methodologies used to detect CSCs in situ have created the paradox of the adult heart harboring more than seven different cardiac progenitor populations. The latter was likely secondary to the intrinsic heterogeneity of any regenerative cell agent in an adult tissue but also to the confusion created by the heterogeneity of the cell population identified by a single cell marker used to detect the CSCs in situ. On the other hand, some recent studies using genetic fate mapping strategies claimed that CSCs are an irrelevant endogenous source of new cardiomyocytes in the adult. On the basis of these contradictory findings, here we critically reviewed the available data on adult CSC biology and their role in myocardial cell homeostasis and repair.

The use and abuse of Cre/Lox recombination to identify adult cardiomyocyte renewal rate and origin.

The adult mammalian heart, including the human, is unable to regenerate segmental losses after myocardial infarction. This evidence has been widely and repeatedly used up-to-today to suggest that the myocardium, contrary to most adult tissues, lacks an endogenous stem cell population or more specifically a bona-fide cardiomyocyte-generating progenitor cell of biological significance. In the last 15 years, however, the field has slowly evolved from the dogma that no new cardiomyocytes were produced from shortly after birth to the present consensus that new cardiomyocytes are formed throughout lifespan. This endogenous regenerative potential increases after various forms of injury. Nevertheless, the degree/significance and more importantly the origin of adult new cardiomyocytes remains strongly disputed. Evidence from independent laboratories has shown that the adult myocardium harbours bona-fide tissue-specific cardiac stem cells (CSCs). Their transplantation and in situ activation have demonstrated the CSCs regenerative potential and have been used to develop regeneration protocols which in pre-clinical tests have shown to be effective in the prevention and treatment of heart failure. Recent reports purportedly tracking the c-kit+CSC's fate using Cre/lox recombination in the mouse have challenged the existence and regenerative potential of the CSCs and have raised scepticism about their role in myocardial homeostasis and regeneration. The validity of these reports, however, is controversial because they failed to show that the experimental approach used is capable to both identify and tract the fate of the CSCs. Despite these serious shortcomings, in contraposition to the CSCs, these publications have proposed the proliferation of existing adult fully-matured cardiomyocytes as the relevant mechanism to explain cardiomyocyte renewal in the adult. This review critically ponders the available evidence showing that the adult mammalian heart possesses a definable myocyte-generating progenitor cell of biological significance. This endogenous regenerative potential is expected to provide the bases for novel approaches of myocardial repair in the near future.

[Choosing a tailored prosthetic valve in cardiac surgery: what is the current role of mechanical prostheses?] / Il ruolo delle protesi valvolari meccaniche oggi. Dalla letteratura alla situazione italiana.

The choice of the mechanical/biological heart valve prosthesis is a topic currently debated in the light of the transcatheter prosthetic models and the results obtained/expected with the new biological valve models. Consequently, it seems that increasingly younger patients would be indicated for an implantation of a biological prosthesis. This is also in order to improve the quality of life of patients who want to avoid oral anticoagulant therapy. On the other hand, the guidelines for the treatment of heart valve disease assign a central role to the use of mechanical valve prostheses, particularly for certain patient subsets and age groups. This means that mechanical prostheses are still widely used worldwide, especially in non-European or North American regions. The cardiac surgery community therefore seems to be very interested in biological prostheses and transcatheter implants and scarcely interested in mechanical prostheses, including possible strategies for self-management of anticoagulant therapy. Recently, the Italian Society of Cardiac Surgery promoted a survey among its members to stimulate interest in the cardiac surgery community. This review article aims to summarize the most current results recorded with the use of mechanical prostheses and possible strategies, especially for the management of oral anticoagulant therapy, which can improve the patient's quality of life.

Mechanical heart valves and oral anticoagulation: a survey of the Italian Society of Cardiac Surgery.

In the latest European guidelines for the management of valvular heart disease, mechanical valve prostheses maintain a strategic role, particularly for certain patient subsets and age groups. Despite the high number of devices implanted in clinical practice, particularly in non-European and North American regions, current scientific literature and debate seem to suggest a limited use of mechanical heart valves. The cardiac surgery community seems to be highly interested in biological and transcatheter valve prostheses but less interested in mechanical heart valves, including possible strategies for self-management of anticoagulation therapy. In this respect, the Italian Society of Cardiac Surgery (SICCH), in particular the Italian Group of Research for Outcome in Cardiac Surgery (GIROC), has promoted a survey among its members to stimulate the interest in this topic and express their opinion on this issue that, due to the prevalence of the affected population and the new treatment options for improving patients' quality of life, should be more appraised and debated in the cardiac surgery community. The recorded results, obtained on the answers to 111 questionnaires, seem to divide the specialists into 'pros' and 'contras' on a useful tool for the entire cardiac surgery community. For this reason, SICCH proposes in conclusion to declare its unified and institutional opinion on this topic.

Early outcomes of aortic valve replacement with Perceval PLUS sutureless valve: results of the prospective multicentric MANTRA study.

BACKGROUND: The aim of this study is to report the preliminary real-word clinical and hemodynamic performance from the MANTRA study in patients undergoing aortic valve replacement with Perceval PLUS sutureless valve. METHODS: MANTRA is an ongoing "umbrella" prospective, multi-center, international post-market study to collect real-life safety and performance data on Corcym devices (Corcym S.r.l, Saluggia, Italy). Clinical and echocardiographic outcomes were collected preoperatively, at discharge and at each follow up. KCCQ-12 and EQ-5D-5L quality of life questionnaires were collected preoperatively and at 30-days. RESULTS: A total of 328 patients underwent aortic valve replacement with Perceval PLUS in 29 International institutions. Patients were enrolled from July 2021 to October 2023 and enrollment is still ongoing. Mean age was 71.9 ± 6.4 years, mean EuroSCORE II was 2.9 ± 3.9. Minimally invasive approach was performed in 44.2% (145/328) of patients; concomitant procedures were done in 40.8% (134/328) of cases. Thirty-day mortality was 1.8% (6/328) and no re-interventions were reported. Pacemaker implant was required in 4.0% (13/328) of the patients. The assessment of the functional status demonstrated marked and stable improvement in NYHA class in most patients at 30-day follow-up, with significant increase of KCCQ-12 summary score (from 58.8 ± 23.0 to 71.8 ± 22.1, p < 0.0001) and EQ-5D-5L VAS score (from 64.5 ± 20.4 to 72.6 ± 17.5, p < 0.0001). Mean pressure gradient decreased from 46.2 ± 17.3 mmHg to 10.1 ± 4.7 mmHg at 30-day follow-up. Low or no incidence of moderate-to-severe paravalvular or central leak was reported. CONCLUSIONS: Preliminary results demonstrate good clinical outcomes and significant improvement of Quality of Life at 30-days, excellent early hemodynamic performance within patient implanted with Perceval PLUS. TRIAL REGISTRATION: The MANTRA study has been registered in ClinicalTrials.gov (NCT05002543, Initial release 26 July 2021).

Myocardial sodium-glucose cotransporter 2 expression and cardiac remodelling in patients with severe aortic stenosis: The BIO-AS study.

AIM: Cardiac remodelling plays a major role in the prognosis of patients with aortic stenosis (AS) and could impact the benefits of aortic valve replacement. Our study aimed to evaluate the expression of sodium-glucose cotransporter 2 (SGLT2) gene and protein in patients with severe AS stratified in high gradient (HG) and low flow-low gradient (LF-LG) AS and its association with cardiac functional impairments. METHODS AND RESULTS: Gene expression and protein levels of main biomarkers of cardiac fibrosis (galectin-3, sST2, serpin-4, procollagen type I amino-terminal peptide, procollagen type I carboxy-terminal propeptide, collagen, transforming growth factor [TGF]-ß), inflammation (growth differentiation factor-15, interleukin-6, nuclear factor-κB [NF-κB]), oxidative stress (superoxide dismutase 1 [SOD1] and 2 [SOD2]), and cardiac metabolism (sodium-hydrogen exchanger, peroxisome proliferator-activated receptor [PPAR]-α, PPAR-γ, glucose transporter 1 [GLUT1] and 4 [GLUT4]) were evaluated in blood samples and heart biopsies of 45 patients with AS. Our study showed SGLT2 gene and protein hyper-expression in patients with LF-LG AS, compared to controls and HG AS (p < 0.05). These differences remained significant even after adjusting for age, gender, body mass index, history of diabetes mellitus, arterial hypertension, and coronary artery disease. SGLT2 gene expression was positively correlated with: (i) TGF-ß (r = 0.72, p < 0.001) and collagen (r = 0.73, p < 0.001) as markers of fibrosis; (ii) NF-κB (r = 0.36, p < 0.01) and myocardial interleukin-6 (r = 0.68, p < 0.001) as markers of inflammation: (iii) SOD2 (r = -0.38, p < 0.006) as a marker of oxidative stress; (iv) GLUT4 (r = 0.33, p < 0.02) and PPAR-α (r = 0.36, p < 0.01) as markers of cardiac metabolism. CONCLUSION: In patients with LF-LG AS, SGLT2 gene and protein were hyper-expressed in cardiomyocytes and associated with myocardial fibrosis, inflammation, and oxidative stress.

Cellular and Molecular Mechanisms Underlying Tricuspid Valve Development and Disease.

Tricuspid valve (TV) disease is highly prevalent in the general population. For ages considered "the forgotten valve" because of the predominant interest in left-side valve disease, the TV has now received significant attention in recent years, with significant improvement both in diagnosis and in management of tricuspid disease. TV is characterized by complex anatomy, physiology, and pathophysiology, in which the right ventricle plays a fundamental role. Comprehensive knowledge of molecular and cellular mechanisms underlying TV development, TV disease, and tricuspid regurgitation-related right-ventricle cardiomyopathy is necessary to enhance TV disease understanding to improve the ability to risk stratify TR patients, while also predicting valve dysfunction and/or response to tricuspid regurgitation treatment. Scientific efforts are still needed to eventually decipher the complete picture describing the etiopathogenesis of TV and TV-associated cardiomyopathy, and future advances to this aim may be achieved by combining emerging diagnostic imaging modalities with molecular and cellular studies. Overall, basic science studies could help to streamline a new coherent hypothesis underlying both the development of TV during embryogenesis and TV-associated disease and its complications in adult life, providing the conceptual basis for the ultimate and innovative field of valve repair and regeneration using tissue-engineered heart valves.

Current Views on Infective Endocarditis: Changing Epidemiology, Improving Diagnostic Tools and Centering the Patient for Up-to-Date Management.

Infective endocarditis (IE) is a rare but potentially life-threatening disease, sometimes with longstanding sequels among surviving patients. The population at high risk of IE is represented by patients with underlying structural heart disease and/or intravascular prosthetic material. Taking into account the increasing number of intravascular and intracardiac procedures associated with device implantation, the number of patients at risk is growing too. If bacteremia develops, infected vegetation on the native/prosthetic valve or any intracardiac/intravascular device may occur as the final result of invading microorganisms/host immune system interaction. In the case of IE suspicion, all efforts must be focused on the diagnosis as IE can spread to almost any organ in the body. Unfortunately, the diagnosis of IE might be difficult and require a combination of clinical examination, microbiological assessment and echocardiographic evaluation. There is a need of novel microbiological and imaging techniques, especially in cases of blood culture-negative. In the last few years, the management of IE has changed. A multidisciplinary care team, including experts in infectious diseases, cardiology and cardiac surgery, namely, the Endocarditis Team, is highly recommended by the current guidelines.

A Mouse Model of Dilated Cardiomyopathy Produced by Isoproterenol Acute Exposure Followed by 5-Fluorouracil Administration.

Appropriate dilated cardiomyopathy (DCM) animal models are highly desirable considering the pathophysiological and clinical heterogeneity of DCM. Genetically modified mice are the most widely and intensively utilized research animals for DCM. However, to translate discoveries from basic science into new and personalized medical applications, research in non-genetically based DCM models remains a key issue. Here, we characterized a mouse model of non-ischemic DCM induced by a stepwise pharmacologic regime of Isoproterenol (ISO) high dose bolus followed by a low dose systemic injection of the chemotherapy agent, 5-Fluorouracil (5-FU). C57BL/6J mice were injected with ISO and, 3 days after, were randomly assigned to saline or 5-FU. Echocardiography and a strain analysis show that ISO + 5FU in mice induces progressive left ventricular (LV) dilation and reduced systolic function, along with diastolic dysfunction and a persistent global cardiac contractility depression through 56 days. While mice treated with ISO alone recover anatomically and functionally, ISO + 5-FU causes persistent cardiomyocyte death, ensuing in cardiomyocyte hypertrophy through 56 days. ISO + 5-FU-dependent damage was accompanied by significant myocardial disarray and fibrosis along with exaggerated oxidative stress, tissue inflammation and premature cell senescence accumulation. In conclusions, a combination of ISO + 5FU produces anatomical, histological and functional cardiac alterations typical of DCM, representing a widely available, affordable, and reproducible mouse model of this cardiomyopathy.

An Unusual Case of a Double Tricuspid and Mitral Valves Infective Endocarditis Complicated by Multiple Septic Embolisms Secondary to an Atrial Septal Defect: A Case Report and Review of Literature.

Multivalvular endocarditis (MVE) is an uncommon infection that mostly involves mitral and aortic valves, and it is related to a higher risk of congestive heart failure and a higher mortality. We described a case of a bilateral MVE and performed a review of the literature on similar clinical cases. We reported an unusual case of a 68-year-old male patient with a tricuspid and mitral infective endocarditis due to a methicillin-resistant Staphylococcus aureus complicated by multiple right- and left-sided septic embolization (lungs, brain, spleen, L2-L3 vertebral bones) due to an unknown atrial septal defect identified and repaired during cardiac surgery. Despite the severity of the clinical case, the patient experienced a good clinical outcome also thanks to a multidisciplinary approach. We identified 21 case reports describing bilateral MVE. A multidisciplinary approach is essential in the management of valve diseases to improve the prognosis of patients, especially in bilateral MVE.

Long-Term Outcome of Infective Endocarditis Involving Cardiac Implantable Electronic Devices: Impact of Comorbidities and Lead Extraction.

(1) Background: Management of cardiac implantable electronic device-related infective endocarditis (CIED-IE) hinges on complete hardware removal. We assessed whether long-term prognosis is affected by device removal, considering baseline patient comorbid conditions; (2) Methods: A total of 125 consecutive patients hospitalized for CIED-IE were included in this retrospective analysis. Outcomes were in-hospital, one-year, and long-term mortality. There were 109 patients who underwent device removal, 91 by transvenous lead extraction (TLE) and 18 by open heart surgery (OHS); (3) Results: TLE translated into lower hospital mortality (4.4% vs. 22.5% with OHS; p = 0.03). Septic pulmonary embolism was the only independent predictor of in-hospital mortality (OR:7.38 [1.49-36.6], p = 0.013). One-year mortality was in contrast independently associated to tricuspid valve involvement (p = 0.01) and Charlson comorbidity index (CCI, p = 0.039), but not the hardware removal modality. After a median follow-up of 41 months, mortality rose to 24%, and was significantly influenced only by CCI. Specifically, patients with a higher CCI who were also treated with TLE showed a survival rate not significantly different from those managed with medical therapy only; (4) Conclusions: In CIED-IE, TLE is the strategy of choice for hardware removal, improving early outcomes. Long-term benefits of TLE are lessened by comorbidities. In cases of CIED-IE with high CCI, a more conservative approach might be an option.

Diabetes-Induced Cellular Senescence and Senescence-Associated Secretory Phenotype Impair Cardiac Regeneration and Function Independently of Age.

Diabetes mellitus (DM) affects the biology of multipotent cardiac stem/progenitor cells (CSCs) and adult myocardial regeneration. We assessed the hypothesis that senescence and senescence-associated secretory phenotype (SASP) are main mechanisms of cardiac degenerative defect in DM. Accordingly, we tested whether ablation of senescent CSCs would rescue the cardiac regenerative/reparative defect imposed by DM. We obtained cardiac tissue from nonaged (50- to 64-year-old) patients with type 2 diabetes mellitus (T2DM) and without DM (NDM) and postinfarct cardiomyopathy undergoing cardiac surgery. A higher reactive oxygen species production in T2DM was associated with an increased number of senescent/dysfunctional T2DM-human CSCs (hCSCs) with reduced proliferation, clonogenesis/spherogenesis, and myogenic differentiation versus NDM-hCSCs in vitro. T2DM-hCSCs showed a defined pathologic SASP. A combination of two senolytics, dasatinib (D) and quercetin (Q), cleared senescent T2DM-hCSCs in vitro, restoring their expansion and myogenic differentiation capacities. In a T2DM model in young mice, diabetic status per se (independently of ischemia and age) caused CSC senescence coupled with myocardial pathologic remodeling and cardiac dysfunction. D + Q treatment efficiently eliminated senescent cells, rescuing CSC function, which resulted in functional myocardial repair/regeneration, improving cardiac function in murine DM. In conclusion, DM hampers CSC biology, inhibiting CSCs' regenerative potential through the induction of cellular senescence and SASP independently from aging. Senolytics clear senescence, abrogating the SASP and restoring a fully proliferative/differentiation-competent hCSC pool in T2DM with normalization of cardiac function.

Effects of Sodium-Glucose Transporter 2 Inhibitors (SGLT2-I) in Patients With Ischemic Heart Disease (IHD) Treated by Coronary Artery Bypass Grafting via MiECC: Inflammatory Burden, and Clinical Outcomes at 5 Years of Follow-Up.

Introduction: Minimally invasive extracorporeal circulation (MiECC) reduced inflammatory burden, leading to best clinical outcomes in patients treated with coronary artery bypass grafting (CABG). Despite this, the patients with type 2 diabetes mellitus (T2DM) vs those without T2DM (non-T2DM) have a worse prognosis, caused by over-inflammation and modulated by sodium-glucose transporter 2 receptors. However, we evaluated the inflammatory burden and clinical outcomes in non-T2DM vs T2DM patients under sodium-glucose transporter 2 inhibitors (SGLT2-I users) vs non-SGLT2-I users at 5 years of follow-up post-CABG via MiECC. Materials and methods: In a multicenter study, we screened consecutive patients with indications to receive CABG. The study endpoints were the inflammatory burden (circulating serum levels of tumor necrosis factor-alpha (TNF-α), interleukin 1 and 6 (IL-1 and IL-6), C-reactive protein (CRP), and leucocytes count) and the clinical outcomes at follow-up of 5 years in non-T2DM vs SGLT2-I users, in non-T2DM vs non-SGLT2-I users, and SGLT2-I users vs non-SGLT2-I users. Results: At baseline, and at one year and 5 years of follow-up, the non-T2DM vs SGLT2-I users, non-T2DM vs non-SGLT2-I users, and SGLT2-I users vs non-SGLT2-I users had the lowest values of IL-1, IL-6, and TNF-α (p < 0.05). At one year of follow-up, SGLT2-I users vs non-T2DM and non-SGLT2-I users vs non-T2DM users had a higher rate of all deaths, cardiac deaths, re-myocardial infarction, repeat revascularization, and stroke, and of the composite endpoint (p < 0.05). In a multivariate Cox regression analysis, the composite endpoint was predicted by IL-1 [2.068 (1.367-3.129)], TNF-α [1.989 (1.081-2.998)], and SGLT2-I [0.504 (0.078-0.861)]. Conclusion: In T2DM patients, the SGLT2-I significantly reduced the inflammatory burden and ameliorated clinical outcomes at 5 years of follow-up post-CABG via MiECC.