Endothelium plays a fundamental role in the cardiovascular system, forming an interface between blood and adjacent tissues by regulating the vascular tone through the synthesis of nitric oxide, ...prostaglandins and other relaxing factors. Endothelial dysfunction is characterized by vasoconstriction, cell proliferation and shifting toward a proinflammatory and prothrombic state. In hypertension endothelial dysfunction may be involved in the initiation and development of vascular inflammation, vascular remodeling, and atherosclerosis and is independently associated with increased cardiovascular risk. Different conditions such as impaired vascular shear stress, inflammation and oxidative stress, activation of the renin angiotensin system have been described as important pathophysiological mechanisms involved in the development of endothelial dysfunction. The release of extracellular vesicles by neighboring cells in the vascular wall has emerged as an important regulator of endothelial function and with potential antihypertensive properties and beneficial effects by counteracting the hypertension mediated organ damage. Furthermore, macrovesicles are emerging as an innovative therapeutic approach for vascular protection, allowing the delivery of bioactive molecules, such as miRNA and drugs interacting with the renin angiotensin system. In this review we summarize the available evidence about the pathophysiological implications of endothelial dysfunction in cardiovascular diseases, focusing on hypertension and its sequelae, and the potential innovative therapeutic strategies targeting the endothelium with the aim to improve vascular function and remodeling.
The endothelium is a monocellular layer covering the inner surface of blood vessels. It maintains vascular homeostasis regulating vascular tone and permeability and exerts anti-inflammatory, ...antioxidant, anti-proliferative, and anti-thrombotic functions. When the endothelium is exposed to detrimental stimuli including hyperglycemia, hyperlipidemia, and neurohormonal imbalance, different biological pathways are activated leading to oxidative stress, endothelial dysfunction, increased secretion of adipokines, cytokines, endothelin-1, and fibroblast growth factor, and reduced nitric oxide production, leading eventually to a loss of integrity. Endothelial dysfunction has emerged as a hallmark of dysmetabolic vascular impairment and contributes to detrimental effects on cardiac metabolism and diastolic dysfunction, and to the development of cardiovascular diseases including heart failure. Different biomarkers of endothelial dysfunction have been proposed to predict cardiovascular diseases in order to identify microvascular and macrovascular damage and the development of atherosclerosis, particularly in metabolic disorders. Endothelial dysfunction also plays an important role in the development of severe COVID-19 and cardiovascular complications in dysmetabolic patients after SARS-CoV-2 infection. In this review, we will discuss the biological mechanisms involved in endothelial dysregulation in the context of cardiometabolic diseases as well as the available and promising biomarkers of endothelial dysfunction in clinical practice.
Different multifactorial pathophysiological processes are involved in the development of heart failure (HF), including neurohormonal dysfunction, the hypertrophy of cardiomyocytes, interstitial ...fibrosis, microvascular endothelial inflammation, pro-thrombotic states, oxidative stress, decreased nitric oxide (NO) bioavailability, energetic dysfunction, epicardial coronary artery lesions, coronary microvascular rarefaction and, finally, cardiac remodeling. While different pharmacological strategies have shown significant cardiovascular benefits in HF with reduced ejection fraction (HFrEF), there is a residual unmet need to fill the gap in terms of knowledge of mechanisms and efficacy in the outcomes of neurohormonal agents in HF with preserved ejection fraction (HFpEF). Recently, type-2 sodium-glucose transporter inhibitors (SGLT2i) have been shown to contribute to a significant reduction in the composite outcome of HF hospitalizations and cardiovascular mortality across the entire spectrum of ejection fraction. Moreover, glucagon-like peptide-1 receptor agonists (GLP1-RA) have demonstrated significant benefits in patients with high cardiovascular risk, excess body weight or obesity and HF, in particular HFpEF. In this review, we will discuss the biological pathways potentially involved in the action of SGLT2i and GLP1-RA, which may explain their effective roles in the treatment of HF, as well as the potential implications of the use of these agents, also in combination therapies with neurohormonal agents, in the clinical practice.
Hypertension represents one of the primary and most common risk factors leading to the development of heart failure (HF) across the entire spectrum of left ventricular ejection fraction. A large body ...of evidence has demonstrated that adequate blood pressure (BP) control can reduce cardiovascular events, including the development of HF. Although the pathophysiological and epidemiological role of hypertension in the development of HF is well and largely known, some critical issues still deserve to be clarified, including BP targets, particularly in HF patients. Indeed, the management of hypertension in HF relies on the extrapolation of findings from high-risk hypertensive patients in the general population and not from specifically designed studies in HF populations. In patients with hypertension and HF with reduced ejection fraction (HFrEF), it is recommended to combine drugs with documented outcome benefits and BP-lowering effects. In patients with HF with preserved EF (HFpEF), a therapeutic strategy with all major antihypertensive drug classes is recommended. Besides commonly used antihypertensive drugs, different evidence suggests that other drugs recommended in HF for the beneficial effect on cardiovascular outcomes exert advantageous blood pressure-lowering actions. In this regard, type 2 sodium glucose transporter inhibitors (SGLT2i) have been shown to induce BP-lowering actions that favorably affect cardiac afterload, ventricular arterial coupling, cardiac efficiency, and cardiac reverse remodeling. More recently, it has been demonstrated that finerenone, a non-steroidal mineralocorticoid receptor antagonist, reduces new-onset HF and improves other HF outcomes in patients with chronic kidney disease and type 2 diabetes, irrespective of a history of HF. Other proposed agents, such as endothelin receptor antagonists, have provided contrasting results in the management of hypertension and HF. A novel, promising strategy could be represented by small interfering RNA, whose actions are under investigation in ongoing clinical trials.
Cardiorenal syndrome consists in the coexistence of acute or chronic dysfunction of heart and kidneys resulting in a cascade of feedback mechanisms and causing damage to both organs associated with ...high morbidity and mortality. In the last few years, different biomarkers have been investigated with the aim to achieve an early and accurate diagnosis of cardiorenal syndrome, to provide a prognostic role and to guide the development of targeted pharmacological and non-pharmacological therapies. In such a context, sodium-glucose cotransporter 2 (SGLT2) inhibitors, recommended as the first-line choice in the management of heart failure, might represent a promising strategy in the management of cardiorenal syndrome due to their efficacy in reducing both cardiac and renal outcomes. In this review, we will discuss the current knowledge on the pathophysiology of cardiorenal syndrome in adults, as well as the utility of biomarkers in cardiac and kidney dysfunction and potential insights into novel therapeutics.
Mitochondrial dysfunction, a feature of heart failure, leads to a progressive decline in bioenergetic reserve capacity, consisting in a shift of energy production from mitochondrial fatty acid ...oxidation to glycolytic pathways. This adaptive process of cardiomyocytes does not represent an effective strategy to increase the energy supply and to restore the energy homeostasis in heart failure, thus contributing to a vicious circle and to disease progression. The increased oxidative stress causes cardiomyocyte apoptosis, dysregulation of calcium homeostasis, damage of proteins and lipids, leakage of mitochondrial DNA, and inflammatory responses, finally stimulating different signaling pathways which lead to cardiac remodeling and failure. Furthermore, the parallel neurohormonal dysregulation with angiotensin II, endothelin-1, and sympatho-adrenergic overactivation, which occurs in heart failure, stimulates ventricular cardiomyocyte hypertrophy and aggravates the cellular damage. In this review, we will discuss the pathophysiological mechanisms related to mitochondrial dysfunction, which are mainly dependent on increased oxidative stress and perturbation of the dynamics of membrane potential and are associated with heart failure development and progression. We will also provide an overview of the potential implication of mitochondria as an attractive therapeutic target in the management and recovery process in heart failure.
Natriuretic peptides (NPs) are the principal expression products of the endocrine function of the heart. They exert several beneficial effects, mostly mediated through guanylate cyclase-A coupled ...receptors, including natriuresis, diuresis, vasorelaxation, blood volume and blood pressure reduction, and regulation of electrolyte homeostasis. As a result of their biological functions, NPs counterbalance neurohormonal dysregulation in heart failure and other cardiovascular diseases. NPs have been also validated as diagnostic and prognostic biomarkers in cardiovascular diseases such as atrial fibrillation, coronary artery disease, and valvular heart disease, as well as in the presence of left ventricular hypertrophy and severe cardiac remodeling. Serial measurements of their levels may be used to contribute to more accurate risk stratification by identifying patients who are more likely to experience death from cardiovascular causes, heart failure, and cardiac hospitalizations and to guide tailored pharmacological and non-pharmacological strategies with the aim to improve clinical outcomes. On these premises, multiple therapeutic strategies based on the biological properties of NPs have been attempted to develop new targeted cardiovascular therapies. Apart from the introduction of the class of angiotensin receptor/neprilysin inhibitors to the current management of heart failure, novel promising molecules including M-atrial natriuretic peptide (a novel atrial NP-based compound) have been tested for the treatment of human hypertension with promising results. Moreover, different therapeutic strategies based on the molecular mechanisms involved in NP regulation and function are under development for the management of heart failure, hypertension, and other cardiovascular conditions.
The prevalence of obesity worldwide has increased in recent decades not only among adults, but also in children and adolescents. This phenomenon contributes to an increased risk of cardiovascular ...diseases (CVD), also after the adjustment for conventional risk factors such as hypertension, diabetes and dyslipidemia. Indeed, obesity contributes to the development of insulin resistance, endothelial dysfunction, sympathetic nervous system activation, increased vascular resistance and inflammatory and prothrombotic state which promote the incidence of major cardiovascular events. On the basis of this evidence, in 2021 obesity has been acknowledged as a definite pathological identity and identified as a recurrent, chronic non-communicable disease. Therapeutic strategies for the pharmacological treatment of obesity include the combination of naltrexone and bupropione and the lipase inhibitor orlistat and they have been recently implemented with the glucagon like peptide-1 receptor agonists semaglutide and liraglutide, which have produced positive and sustained effects on body weight reduction. If drug interventions are not effective, bariatric surgery may be considered, representing an efficacious treatment option for extreme obesity or obesity with comorbidities. The present executive paper is aimed to increase knowledge on the relationships between obesity and CVD, to raise the perception of this condition which is currently insufficient and to support the clinical practice management.
Tacaribe virus (TCRV) is the prototype of New World mammarenaviruses, a group that includes several members that cause hemorrhagic fevers in humans. The TCRV genome comprises two RNA segments, named ...S (small) and L (large). Both genomic segments contain noncoding regions (NCRs) at their 5' and 3' ends. While the 5'- and 3'-terminal 19-nucleotide sequences are known to be essential for promoter function, the role of their neighboring internal noncoding region (iNCR) sequences remains poorly understood. To analyze the relevance of the 5' and 3' iNCRs in TCRV S RNA synthesis, mutant S-like minigenomes and miniantigenomes were generated. Using a minireplicon assay, Northern blotting, and reverse transcription-quantitative PCR, we demonstrated that the genomic 5' iNCR is specifically engaged in minigenome replication yet is not directly involved in minigenome transcription, and we showed that the S genome 3' iNCR is barely engaged in this process. Analysis of partial deletions and point mutations, as well as total or partial substitution of the 5' iNCR sequence, led us to conclude that the integrity of the whole genomic 5' iNCR is essential and that a local predicted secondary structure or RNA-RNA interactions between the 5' and 3' iNCRs are not strictly required for viral S RNA synthesis. Furthermore, we employed a TCRV reverse genetic approach to ask whether manipulation of the S genomic 5' iNCR sequence may be suitable for viral attenuation. We found that mutagenesis of the 5' promoter-proximal subregion slightly impacted recombinant TCRV virulence
.
The
genus of the
family includes several members that cause severe hemorrhagic fevers associated with high morbidity and mortality rates, for which no FDA-approved vaccines and limited therapeutic resources are available. We provide evidence demonstrating the specific involvement of the TCRV S 5' noncoding sequence adjacent to the viral promoter in replication. In addition, we examined the relevance of this region in the context of an
infection. Our findings provide insight into the mechanism through which this 5' viral RNA noncoding region assists the L polymerase for efficient viral S RNA synthesis. Also, these findings expand our understanding of the effect of genetic manipulation of New World mammarenavirus sequences aimed at the rational design of attenuated recombinant virus vaccine platforms.
This study aimed to investigate the effects of Mindfulness-Based Relapse Prevention (MBRP) in decision-making, inhibitory control and impulsivity compared to Treatment as Usual (TAU) for individuals ...with Substance Use Disorders (SUD's) in Brazil. A randomized clinical trial was conducted with participants from a therapeutic community (n = 122). Decision-making (Iowa Gambling Task), impulsivity dimensions (UPPS-P Scale), and inhibitory control (Stroop Color-Word Test) were assessed before and after the MBRP 8-week intervention. GLM Multivariate analysis was used to evaluate the effects of MBRP on different impulsivity measures. The results showed that MBRP+TAU improved the general decision-making score (p = 0,008) compared to TAU. However, no significant effects were found in impulsivity dimensions and inhibitory control in individuals with SUDs in the therapeutic community. This study found improvement in decision-making in the total IGT score; however, no effect for self-reported impulsivity and inhibitory control among middle-aged patients after an 8-weeks intervention of MBRP protocol in an inpatient setting. It adds information to the subject, with implications and possible directions to be followed by the next clinical trials with patients with SUDs in treatment. Trial registration: EnsaiosClinicos.gov.br: RBR-6c9njc.
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