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Myocarditis is an inflammatory condition of cardiac tissue presenting significant variability in clinical manifestations and outcomes. Its etiology is diverse, encompassing infectious agents (primarily viruses, but also bacteria, protozoa, and helminths) and non-infectious factors (autoimmune responses, toxins, and drugs), though often the specific cause remains unidentified. Recent research has highlighted the potential role of genetic susceptibility in the development of myocarditis (and in some cases the development of inflammatory dilated cardiomyopathy, i.e., the condition in which there is chronic inflammation (>3 months) and left ventricular dysfunction\dilatation), with several studies indicating a correlation between myocarditis and genetic backgrounds. Notably, pathogenic genetic variants linked to dilated or arrhythmic cardiomyopathy are found in 8–16% of myocarditis patients. Genetic predispositions can lead to recurrent myocarditis and a higher incidence of ventricular arrhythmias and heart failure. Moreover, the presence of DSP mutations has been associated with distinct pathological patterns and clinical outcomes in arrhythmogenic cardiomyopathy (hot phases). The interplay between genetic factors and environmental triggers, such as viral infections and physical stress, is crucial in understanding the pathogenesis of myocarditis. Identifying these genetic markers can improve the diagnosis, risk stratification, and management of patients with myocarditis, potentially guiding tailored therapeutic interventions. This review aims to synthesize current knowledge on the genetic underpinnings of myocarditis, with an emphasis on desmoplakin-related arrhythmogenic cardiomyopathy, to enhance clinical understanding and inform future research directions. [ABSTRACT FROM AUTHOR]

Background: Defects of mitophagy, the selective form of autophagy for mitochondria, are commonly observed in several cardiovascular diseases and represent the main cause of mitochondrial dysfunction. For this reason, mitophagy has emerged as a novel and potential therapeutic target. Methods: In this review, we discuss current evidence about the biological significance of mitophagy in relevant preclinical models of cardiac and vascular diseases, such as heart failure, ischemia/reperfusion injury, metabolic cardiomyopathy and atherosclerosis. Results: Multiple studies have shown that cardiac and vascular mitophagy is an adaptive mechanism in response to stress, contributing to cardiovascular homeostasis. Mitophagy defects lead to cell death, ultimately impairing cardiac and vascular function, whereas restoration of mitophagy by specific compounds delays disease progression. Conclusions: Despite previous efforts, the molecular mechanisms underlying mitophagy activation in response to stress are not fully characterized. A comprehensive understanding of different forms of mitophagy active in the cardiovascular system is extremely important for the development of new drugs targeting this process. Human studies evaluating mitophagy abnormalities in patients at high cardiovascular risk also represent a future challenge. [ABSTRACT FROM AUTHOR]

The role of cholesterol, mainly low-density lipoproteins (LDL-C), as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) is now established and accepted by the international scientific community. Based on this evidence, the European and American guidelines recommend early risk stratification and "rapid" achievement of the suggested target according to the risk estimation to reduce the number of major cardiovascular events. Prolonged exposure over the years to high levels of LDL-C is one of the determining factors in the development and progression of atherosclerotic plaque, on which the action of conventional risk factors (cigarette smoking, excess weight, sedentary lifestyle, arterial hypertension, diabetes mellitus) as well as non-conventional risk factors (gut microbiota, hyperuricemia, inflammation), alone or in combination, favors the destabilization of the atherosclerotic lesion with rupture/fissuration/ulceration and consequent formation of intravascular thrombosis, which leads to the acute clinical manifestations of acute coronary syndromes. In the current clinical practice, there is a growing number of cases that, although extremely common, are emblematic of the concept of long-term exposure to the risk factor (LDL hypercholesterolemia), which, not adequately controlled and in combination with other risk factors, has favored the onset of major cardiovascular events. The triple concept of "go lower, start earlier and keep longer!" should be applied in current clinical practice at any level of prevention. In the present manuscript, we will review the current evidence and documents supporting the causal role of LDL-C in determining ASCVD and whether it is time to remove it from any score. [ABSTRACT FROM AUTHOR]

Purpose of Review: Left ventricular arrhythmogenic cardiomyopathy (ALVC) is a rare and poorly characterized cardiomyopathy that has recently been reclassified in the group of non-dilated left ventricular cardiomyopathies. This review aims to summarize the background, diagnosis, and sudden cardiac death risk in patients presenting this cardiomyopathy. Recent Findings: Although there is currently a lack of data on this condition, arrhythmogenic left ventricular dysplasia can be considered a specific disease of the left ventricle (LV). We have collected the latest evidence about the management and the risks associated with this cardiomyopathy. Summary: Left ventricular arrhythmogenic cardiomyopathy is still poorly characterized. ALVC is characterized by fibrofatty replacement in the left ventricular myocardium, with variable phenotypic expression. Diagnosis is based on a multiparametric approach, including cardiac magnetic resonance (CMR) and genetic testing, and is important for sudden cardiac death (SCD) risk stratification and management. Recent guidelines have improved the management of left ventricular arrhythmogenic cardiomyopathy. Further studies are necessary to improve knowledge of this cardiomyopathy. [ABSTRACT FROM AUTHOR]

The cellular and molecular mechanisms that are responsible for the poor regenerative capacity of the adult heart after myocardial infarction (MI) are still unclear and their understanding is crucial to develop novel regenerative therapies. Considering the lack of reliable in vitro tissue-like models to evaluate the molecular mechanisms of cardiac regeneration, we used cryoinjury on rat Engineered Heart Tissues (rEHTs) as a new model which recapitulates in part the in vivo response after myocardial injury of neonatal and adult heart. When we subjected to cryoinjury immature and mature rEHTs, we observed a significant increase in cardiomyocyte (CM) DNA synthesis when compared to the controls. As expected, the number of mitotic CMs significantly increases in immature rEHTs when compared to mature rEHTs, suggesting that the extent of CM maturation plays a crucial role in their proliferative response after cryoinjury. Moreover, we show that cryoinjury induces a temporary activation of fibroblast response in mature EHTs, similar to the early response after MI, that is however incomplete in immature EHTs. Our results support the hypothesis that the endogenous maturation program in cardiac myocytes plays a major role in determining the proliferative response to injury. Therefore, we propose rEHTs as a robust, novel tool to in vitro investigate critical aspects of cardiac regeneration in a tissue-like asset free from confounding factors in response to injury, such as the immune system response or circulating inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs), such as arterial hypertension, myocardial infarction, stroke, heart failure, atrial fibrillation, etc., still represent the main cause of morbidity and mortality worldwide. They significantly modify the patients' quality of life with a tremendous economic impact. It is well established that cardiovascular risk factors increase the probability of fatal and non-fatal cardiac events. These risk factors are classified into modifiable (smoking, arterial hypertension, hypercholesterolemia, low HDL cholesterol, diabetes, excessive alcohol consumption, high-fat and high-calorie diet, reduced physical activity) and non-modifiable (sex, age, family history, of previous cardiovascular disease). Hence, CVD prevention is based on early identification and management of modifiable risk factors whose impact on the CV outcome is now performed by the use of CV risk assessment models, such as the Framingham Risk Score, Pooled Cohort Equations, or the SCORE2. However, in recent years, emerging, non-traditional factors (metabolic and non-metabolic) seem to significantly affect this assessment. In this article, we aim at defining these emerging factors and describe the potential mechanisms by which they might contribute to the development of CVD. [ABSTRACT FROM AUTHOR]

Several lines of evidence have clearly indicated that inflammation plays a pivotal role in the development of atherosclerosis and of its thrombotic complications such as acute coronary syndromes or ischemic stroke. Thus, it has been postulated that the use of anti-inflammatory agents might be extremely useful to improve cardiovascular outcome. Recently, increasing attention has been reserved to one of the oldest plant-derived drugs still in use in clinical practice, colchicine that has been used as drug to treat inflammatory diseases such gout or Mediterranean fever. To date, current guidelines of the European Society of Cardiology have included colchicine as first line choice for treatment of acute and recurrent pericarditis. Moreover, several studies have investigated its role in the clinical scenarios of cardiovascular disease including chronic and acute coronary syndromes with promising results. In this review, starting from a description of the mechanism(s) involved behind its anti-inflammatory effects, we give an overview on its potential effects in atherothrombosis and finally present an updated overview of clinical evidence on the role of this drug in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background and Objectives: It is well established that patients with peripheral artery disease (PAD) as well abdominal aortic aneurysm (AAA) have an increased cardiovascular (CV) mortality. Despite this higher risk, PAD and AAA patients are often suboptimality treated. This study assessed the CV profile of PAD and AAA patients, quantifying the survival benefits of target-based risk-factors modification even in light of the COVID-19 pandemic. Materials and Methods: PAD and AAA patients admitted for any reason to the Vascular Unit from January 2019 to February 2020 were retrospectively analyzed. Biochemical and CV profiles as well as ongoing medical therapies were recorded. Benefits of CV risk-factors control were estimated using the SMART-REACH model. A follow-up visit during the year 2020 was scheduled. Results: A total of 669 patients were included. Of these, 190 showed AAA and 479 PAD at any stage. Only 54% of PAD and 41% of AAA patients were on lipid-lowering drugs with non-optimal low-density lipoprotein (LDL) levels for most of them. A better control of all modifiable CV risk-factors based on the current guidelines would offer an absolute risk reduction of the mean 10-year CV risk by 9% in PAD and 14% in AAA. Unfortunately, the follow-up visit was lost because of COVID-19 limitations. Conclusions: Lipid profiles of PAD and AAA patients were far from guideline-based targets, and medical management was suboptimal. In our center, the COVID-19 pandemic impacted on the strict surveillance required in these very high-risk patients. The achievement of guideline-based therapeutic targets would definitively confer additional significant benefits in reducing the CV risk in these patients. [ABSTRACT FROM AUTHOR]

Theworld population is aging, and by 2017, there will bemore people over the age of 65 than under age 5, and by 2050, two billion of the estimated nine billion people on Earth will be older than 60. Aging itself is a major cardiovascular risk factor, affecting morbidity and mortality of the aging population. At the same time, aging increases the likelihood of the presence of other risk factors. The aged myocardium is characterized by several structural and functional progressive changes that impair its ability to respond appropriately to stressful conditions. Although some progress to understand the complex mechanisms that underlie these phenotypic changes, the molecular pathways that determine the balance between aging and rejuvenation in the aged myocardium still remain elusive. In this article, we review molecular mechanisms responsible for the phenotypic changes observed with aging in the heart, providing insight into molecular pathways and pharmacological interventions that may rejuvenate the aged myocardium. A better understanding of these pathways is essential for determining their therapeutic potential in humans, improving the possibility that the increase in life expectancy that we are observing will be accompanied by a parallel increase in healthspan. [ABSTRACT FROM AUTHOR]

Abstract Introduction Platelets activation/aggregation with subsequent thrombus formation is the main event in the pathophysiology of acute coronary syndrome. Once activated, platelets show an extensive cytoskeleton rearrangement that leads to recruitment of additional platelets to finally cause haemostatic plug formation. Thus, the cytoskeleton plays a pivotal role in this phenomenon. Colchicine (COLC) is an anti-inflammatory drug proven to reduce major cardiovascular events in patients with coronary artery disease. The molecular mechanisms by which COLC exerts these protective effects remain partially still unknown. Since COLC causes disruption of tubulin, a component of cell cytoskeleton, we investigated whether this drug might interfere with platelet aggregation by acting on cytoskeleton rearrangement. Methods and results Platelets isolated from healthy volunteers were activated with Adenosine Diphosphate (ADP, 20 μM) Collagen (COLL, 60 μg/ml) and Thrombin Activating Receptor Peptide (TRAP 25 μM) with/without COLC 10 μM pretreatment. After stimulus, aggregation was measured by light aggregometry overtime. Microtubules structure was assessed by immunohistochemistry and key proteins involved in regulation of actin-filament assembly and contractility such as Myosin Phosphatase Targeting subunit (MYPT), LIM domain kinase 1(LIMK1) and cofilin were evaluated by Western Blot analysis. Colchicine pretreatment significantly blunted ADP/COLL/TRAP-induced platelet aggregation (up to 40%). COLC effects appeared mediated by microtubules depolymerization and cytoskeleton disarrangement associated to inactivation of MYPT and LIMK1 that finally interfered with cofilin activity. Conclusions Our data indicate that colchicine exerts anti-platelet effects in vitro via inhibition of key proteins involved in cytoskeleton rearrangement, suggesting that its beneficial cardiovascular properties may be due, at least in part, to an inhibitory effect of platelet activity. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Background/Aims: CD117+ stem cell (SC) based therapy is considered an alternative therapeutic option for terminal heart disease. However, controversies exist on the effects of CD117+ SC implantation. In particular, the link between CD117+ SC function and angiotensin-II-type-2 receptor (AT2R) after MI is continuously discussed. We therefore asked whether 1) AT2R stimulation influences CD117+ SC properties in vitro and, 2) which effects can be ascribed to AT2R stimulation in vivo. Methods: We approached AT2R stimulation with Angiotensin II while simultaneously blocking its opponent receptor AT1 with Losartan. CD117 effects were dissected using a 2D-Matrigel assay and HL-1 co-culture in vitro. A model of myocardial infarction, in which we implanted EGFP+ CD117 SC, was further applied. Results: While we found indications for AT2R driven vasculogenesis in vitro, co-culture experiments revealed that CD117+ SC improve vitality of cardiomyocytes independently of AT2R function. Likewise, untreated CD117+ SC had a positive effect on cardiac function and acted cardioprotective in vivo. Conclusions: Therefore, our data show that transient AT2R stimulation does not significantly add to the beneficial actions of CD117+ SC in vivo. Yet, exploiting AT2R driven vasculogenis via an optimized AT2R stimulation protocol may become a promising tool for cardiac SC therapy. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Parabiosis experiments indicate that impaired regeneration in aged mice is reversible by exposure to a young circulation, suggesting that young blood contains humoral "rejuvenating" factors that can restore regenerative function. Here, we demonstrate that the circulating protein growth differentiation factor 11 (GDF11) is a rejuvenating factor for skeletal muscle. Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity. These data indicate that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction. [ABSTRACT FROM AUTHOR]

Although self-renewal ability of adult mammalian heart has been reported, few pharmacological treatments are known to promote cardiomyocyte regeneration after injury. In this study, we demonstrate that the critical period of stem/progenitor cell-mediated cardiomyocyte replenishment is initiated within 7 days and saturates on day 10 post-infarction. Moreover, blocking the inflammatory reaction with COX-2 inhibitors may also reduce the capability of endogenous stem/progenitor cells to repopulate lost cells. Injection of the COX-2 product PGE2 enhances cardiomyocyte replenishment in young mice and recovers cell renewal through attenuating TGF-β1 signaling in aged mice. Further analyses suggest that cardiac stem cells are PGE2-responsive and that PGE2 may regulate stem cell activity directly through the EP2 receptor or indirectly by modulating its micro-environment in vivo. Our findings provide evidence that PGE2 holds great potential for cardiac regeneration. [ABSTRACT FROM AUTHOR]

Human endometrial stem cells (En SCs) have the potential to be 'off the shelf' clinical reagents for the treatment of heart failure. Here, using an immunocompetent rat model of myocardial infarction ( MI), we provide evidence that the functional benefits of En SC transplantation are principally and possibly exclusively through a paracrine effect. Human En SCs were delivered by intramyocardial injection into rats 30 min. after coronary ligation. En SC therapy significantly preserved viable myocardium in the infarct zone and improved cardiac function at 28 days. Despite increased viable myocardium and vascular density, there was scant evidence of differentiation of En SCs into any cardiovascular cell type. Cultured human En SCs expressed a distinctive profile of cytokines that enhanced the survival, proliferation and function of endothelial cells in vitro. When injected into the peri-infarct zone, human En SCs activated AKT, ERK1/2 and STAT3 and inhibited the p38 signalling pathway. En SC therapy decreased apoptosis and promoted cell proliferation and c-kit+ cell recruitment in vivo. Myocardial protection and enhanced post-infarction regeneration by En SCs is mediated primarily by paracrine effects conferred by secreted cytokines that activate survival pathways and recruit endogenous progenitor stem cells. Menstrual blood provides a potentially limitless source of biologically competent 'off the shelf' En SCs for allogeneic myocardial regenerative medicine. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) have important research value and broad application prospects in the cardiovascular disease. This study provides information on the latest progress, evolutionary path, frontier research hotspots, and future research developmental trends in this field. Methods: A knowledge map was generated by CiteSpace and VOSviewer analysis software based on data obtained from the literature on MSCs in the cardiovascular field. Results: The USA and China ranked at the top in terms of the percentage of articles, accounting for 34.306% and 28.550%, respectively. The institution with the highest number of research publications in this field was the University of Miami, followed by the Chinese Academy of Medical Sciences and Harvard University. The research institution with the highest ACI value was Harvard University, followed by the Mayo Clinic and the University of Cincinnati. The top three subjects in terms of the number of published articles were cell biology, cardiovascular system cardiology, and research experimental medicine. The journal with the most publications in this field was Circulation Research, followed by Scientific Reports and Biomaterials. The direction of research on MSCs in the cardiovascular system was divided into four parts: (1) tissue engineering, scaffolds, and extracellular matrix research; (2) cell transplantation, differentiation, proliferation, and signal transduction pathway research; (3) assessment of the efficacy of stem cells from different sources and administration methods in the treatment of acute myocardial infarction, myocardial hypertrophy, and heart failure; and (4) exosomes and extracellular vesicles research. Tissue research is the hotspot and frontier in this field. Conclusion: MSC research has presented a gradual upward trend in the cardiovascular field. Multidisciplinary intersection is a characteristic of this field. Engineering and materials disciplines are particularly valued and have received attention from researchers. The progress in multidisciplinary research will provide motivation and technical support for the development of this field. [ABSTRACT FROM AUTHOR]