Biological niches within human calcified aortic valves. Towards understanding of the pathological biomineralization process

Despite recent advances, mineralization site, its microarchitecture, and composition in calcific heart valve remain poorly understood. A multiscale investigation, using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and energy dispersive X-ray spectrometry (EDS), from micrometre up to nanometre, was conducted on human severely calcified aortic and mitral valves, to provide new insights into calcificationp rocess. Our aim was to evaluate the spatial relationship existing between bioapatite crystals, their local growing microenvironment, and the presence of a hierarchical architecture. Here we detected the presence of bioapatite crystals in two different mineralization sites that suggest the action of two different growth processes:a pathological crystallization process that occurs in biological niches and is ascribed to a purely physicochemical process and a matrix- mediated mineralized process in which the extracellular matrix acts as the template for a site-directed nanocrystals nucleation. Different shapes of bioapatite crystallization were observed at micrometer scale in each microenvironment but at the nanoscale level crystals appear to be made up by the same subunit

Oral plaque from Type 2 diabetic patients reduces the clonogenic capacity of dental pulp-derived mesenchymal stem cells

Type 2 diabetes (T2D) is a major metabolic disease and a key epigenetic risk factor for the development of additional clinical complications. Among them, periodontitis (PD), a severe inflammatory disease ascribable to a dysregulated physiology and composition of the oral microbiota, represents one of the most relevant complications. Periodontitis can impact the structure of the tooth and likely the stem and progenitor cell pool, which actively contributes to the periodontal microenvironment and homeostasis. Modifications of the oral plaque play a key role in the etiopathogenesis of PD caused by T2D. However, to what extent the biology of the progenitor pool is affected has still to be elucidated. In this short report, we aimed to explore the biological effects of oral plaque derived from T2D patients with PD in comparison to non-diabetic patients with PD. Oral plaque samples were isolated from T2D and non-diabetic subjects with PD. Dental pulp stem cells (DPSCs), derived from the premolar tooth, were conditioned for 21 days with oral plaque samples and tested for their clonogenic ability. Cultures were also induced to differentiate towards the osteogenic lineage, and ALP and osteocalcin gene expression levels were evaluated by real-time qPCR. Results have shown that the number of clones generated by DPSCs exposed to T2D oral plaque was significantly lower compared to controls (ctl). The multivariate analysis confirmed that the decreased clonogenesis was significantly correlated only with T2D diagnosis. Moreover, the effect of T2D oral plaque was specific to DPSCs. Indicators of osteogenic differentiation were not significantly affected. This study provides a new biological insight into the effects ascribable to T2D in PD

Β-blockers treatment of cardiac surgery patients enhances isolation and improves phenotype of cardiosphere-derived cells

Β-blockers (BB) are a primary treatment for chronic heart disease (CHD), resulting in prognostic and symptomatic benefits. Cardiac cell therapy represents a promising regenerative treatment and, for autologous cell therapy, the patients clinical history may correlate with the biology of resident progenitors and the quality of the final cell product. This study aimed at uncovering correlations between clinical records of biopsy-donor CHD patients undergoing cardiac surgery and the corresponding yield and phenotype of cardiospheres (CSs) and CS-derived cells (CDCs), which are a clinically relevant population for cell therapy, containing progenitors. We describe a statistically significant association between BB therapy and improved CSs yield and CDCs phenotype. We show that BB-CDCs have a reduced fibrotic-like CD90 + subpopulation, with reduced expression of collagen-I and increased expression of cardiac genes, compared to CDCs from non-BB donors. Moreover BB-CDCs had a distinctive microRNA expression profile, consistent with reduced fibrotic features (miR-21, miR-29a/b/c downregulation), and enhanced regenerative potential (miR-1, miR-133, miR-101 upregulation) compared to non-BB. In vitro adrenergic pharmacological treatments confirmed cytoprotective and anti-fibrotic effects of β1-blocker on CDCs. This study shows anti-fibrotic and pro-commitment effects of BB treatment on endogenous cardiac reparative cells, and suggests adjuvant roles of β-blockers in cell therapy applications

The light and shadow of senescence and inflammation in cardiovascular pathology and regenerative medicine

Recent epidemiologic studies evidence a dramatic increase of cardiovascular diseases, especially associated with the aging of the world population. During aging, the progressive impairment of the cardiovascular functions results from the compromised tissue abilities to protect the heart against stress. At the molecular level, in fact, a gradual weakening of the cellular processes regulating cardiovascular homeostasis occurs in aging cells. Atherosclerosis and heart failure are particularly correlated with aging-related cardiovascular senescence, that is, the inability of cells to progress in the mitotic program until completion of cytokinesis. In this review, we explore the intrinsic and extrinsic causes of cellular senescence and their role in the onset of these cardiovascular pathologies. Additionally, we dissect the effects of aging on the cardiac endogenous and exogenous reservoirs of stem cells. Finally, we offer an overview on the strategies of regenerative medicine that have been advanced in the quest for heart rejuvenation

from big data to bedside decision making the case for adverseevents

Evidence-based medicine has gained mainstream popularity, but it requires a delicate balance between clinical evidence, physician skills, patient preferences, and costs. Facing the individual patient, even a simple decision such as which antithrombotic agent should be prescribed becomes complex. There are several reasons for this conundrum, but one of the foremost is the limited external validity of pivotal randomized trials, with their extremely restrictive selection criteria. Post-marketing reporting of adverse events is a very useful and democratic means to appraise the risk-benefit profile, but to date such reports were not organized or available. The development of the Food and Drug Administration (FDA) venue for such task, the FDA Adverse Event Reporting System (FAERS) has substantially improved data collection. However, analysis of this extensive relational database remains complex for most but few companies or agencies. AdverseEvents is a novel online platform enabling updated and user-friendly inquiry of FAERS. Given its ease of use, flexibility and comprehensiveness, it is likely going to improve decision making for healthcare authorities and practitioners, as well as patients. This is clearly testified by the precise and informative comparative analysis that can be performed with AdverseEvents on novel antithrombotic agents.</p

Obesity and cardiovascular risk. Systematic intervention is the key for prevention

Obesity is a serious public health issue and associated with an increased risk of cardiovascular disease events and mortality. The risk of cardiovascular complications is directly related to excess body fat mass and ectopic fat deposition, but also other obesity-related complications such as pre-type 2 diabetes, obstructive sleep apnoea, and non-alcoholic fatty liver diseases. Body mass index and waist circumference are used to classify a patient as overweight or obese and to stratify cardiovascular risk. Physical activity and diet, despite being key points in preventing adverse events and reducing cardiovascular risk, are not always successful strategies. Pharmacological treatments for weight reduction are promising strategies, but are restricted by possible safety issues and cost. Nonetheless, these treatments are associated with improvements in cardiovascular risk factors, and studies are ongoing to better evaluate cardiovascular outcomes. Bariatric surgery is effective in reducing the incidence of death and cardiovascular events such as myocardial infarction and stroke. Cardiac rehabilitation programs in obese patients improve cardiovascular disease risk factors, quality of life, and exercise capacity. The aim of this review was to critically analyze the current role and future aspects of lifestyle changes, medical and surgical treatments, and cardiac rehabilitation in obese patients, to reduce cardiovascular disease risk and mortality, and to highlight the need for a multidisciplinary approach to improving cardiovascular outcomes

An overview of sport participation and exercise prescription in mitral valve disease

The incidence of heart valve disease (HVD) has been rising over the last few decades, mainly due to the increasing average age of the general population, and mitral valve (MV) disease is the second most prevalent HVD after calcific aortic stenosis, but MV disease is a heterogeneous group of different pathophysiological diseases. It is widely proven that regular physical activity reduces all-cause mortality rates, and exercise prescription is part of the medical recommendations for patients affected by cardiovascular diseases. However, changes in hemodynamic balance during physical exercise (including the increase in heart rate, preload, or afterload) could favor the progression of the MV disease and potentially trigger major cardiac events. In young patients with HVD, it is therefore important to define criteria for allowing competitive sport or exercise prescription, balancing the positive effects as well as the potential risks. This review focuses on mitral valve disease pathophysiology, diagnosis, risk stratification, exercise prescription, and competitive sport participation selection, and offers an overview of the principal mitral valve diseases with the aim of encouraging physicians to embody exercise in their daily practice when appropriate

A novel closed-chest porcine model of chronic ischemic heart failure suitable for experimental research in cardiovascular disease

Cardiac pathologies are among the leading causes of mortality and morbidity in industrialized countries, with myocardial infarction (MI) representing one of the major conditions leading to heart failure (HF). Hitherto, the development of consistent, stable, and reproducible models of closed-chest MI in large animals, meeting the clinical realism of a patient with HF subsequent to chronic ischemic necrosis, has not been successful. We hereby report the design and ensuing application of a novel porcine experimental model of closed-chest chronic ischemia suitable for biomedical research, mimicking post-MI HF. We also emphasize the key procedural steps involved in replicating this unprecedented model, from femoral artery and vein catheterization to MI induction by permanent occlusion of the left anterior descending coronary artery through superselective deployment of platinum-nylon coils, as well as endomyocardial biopsy sampling for histologic analysis and cell harvesting. Our model could indeed represent a valuable contribution and tool for translational research, providing precious insights to understand and overcome the many hurdles concerning, and currently quenching, the preclinical steps mandatory for the clinical translation of new cardiovascular technologies for personalized HF treatments

Dark Chocolate Intake Positively Modulates Redox Status and Markers of Muscular Damage in Elite Football Athletes: A Randomized Controlled Study

Intensive physical exercise may cause increase oxidative stress and muscular injury in elite football athletes. The aim of this study was to exploit the effect of cocoa polyphenols on oxidative stress and muscular injuries induced by intensive physical exercise in elite football players. Oxidant/antioxidant status and markers of muscle damage were evaluated in 24 elite football players and 15 controls. Furthermore, the 24 elite football players were randomly assigned to either a dark chocolate (>85% cocoa) intake (n = 12) or a control group (n = 12) for 30 days in a randomized controlled trial. Oxidative stress, antioxidant status, and muscle damage were assessed at baseline and after 30 days of chocolate intake. Compared to controls, elite football players showed lower antioxidant power and higher oxidative stress paralleled by an increase in muscle damage markers. After 30 days of dark chocolate intake, an increased antioxidant power was found in elite athletes assuming dark chocolate. Moreover, a significant reduction in muscle damage markers (CK and LDH, p < 0.001) was observed. In the control group, no changes were observed with the exception of an increase of sNox2-dp, H2O2, and myoglobin. A simple linear regression analysis showed that sNox2-dp was associated with a significant increase in muscle damage biomarker release (p = 0.001). An in vitro study also confirmed that polyphenol extracts significantly decreased oxidative stress in murine myoblast cell line C2C12-derived. These results indicate that polyphenol-rich nutrient supplementation by means of dark chocolate positively modulates redox status and reduced exercise-induced muscular injury biomarkers in elite football athletes. This trial is registered with NCT03288623