Endothelial Dysfunction as an Early Sign of Atherosclerosis

The endothelium, the monolayer covering the inner surface of blood vessels, plays a pivotal role in the regulation of vascular tone and structure, as well as vascular inflammation and thrombosis, i.e., of key events of the atherosclerotic disease process and its clinical complications, such as myocardial infarction and stroke. In particular a reduced endothelial availability of nitric oxide (NO), in part due to increased vascular oxidant stress, has been shown to promote a pro-inflammatory and prothrombotic phenotype of the endothelium. More recently, it has been observed that cardiovascular risk factors reduce the number and impair the function of circulating bone marrow-derived endothelial progenitor cells (EPCs), thereby impairing the endogenous endothelial repair capacity. Importantly, endothelial dysfunction has been identified as a common link of all cardiovascular risk factors. Numerous clinical studies have further demonstrated a close association of the degree of endothelial dysfunction with the risk of future cardiovascular events. Whether endothelial dysfunction can improve cardiovascular risk prediction on top of a careful evaluation of classic cardiovascular risk factors is currently prospectively analyzed in several studies, i.e., in the PREVENT-it study. Furthermore, novel easier to use methods to assess endothelial function are currently explored, i.e., the Endo-PAT system, for their potential in improving cardiovascular risk prediction. At present, assessment of endothelial function and EPCs are highly valuable research tools to improve our understanding of mechanisms of vascular disease and to determine the impact of novel therapeutic approaches on vascular function. Before endothelial function measurements can, however, be recommended in clinical practice for cardiovascular risk assessment, the results of ongoing prospective studies assessing the additive value of these measurements for cardiovascular risk prediction should be awaite

Left atrial appendage closure: a percutaneous transcatheter approach for stroke prevention in atrial fibrillation

Atrial fibrillation is a frequent cause of stroke; in the elderly, more than 20% of strokes are attributed to this common arrhythmia. Anticoagulation with warfarin reduces the risk of stroke by ∼60%; however, a large proportion of patients with atrial fibrillation do not receive this treatment because of relative/absolute contraindications. Moreover, patients often discontinue warfarin for a variety of reasons and chronic warfarin administration rates remain suboptimal. Although the compliance with anticoagulation may improve with novel anticoagulants and bleeding risk can be somewhat reduced when compared with warfarin, there is still a progressive increase in bleeding complications over time. Accordingly, new approaches for stroke prevention in these patients are being explored and tested. In transoesophageal echocardiographic (TEE) studies, more than 90% of thrombi were found in the left atrial appendage (LAA) in non-valvular atrial fibrillation, and transcatheter LAA closure is developed and examined as a novel approach to reduce the risk of stroke in these patients. The PROTECT-AF study provides first evidence from a randomized clinical trial that a strategy of LAA occlusion using the Watchman device can be non-inferior to anticoagulation with warfarin for a combined endpoint in patients with non-valvular atrial fibrillation (mean CHADS2 score 1.8). In successfully occluded patients fulfilling TEE criteria (86%), warfarin was stopped after 45 days, followed by aspirin and clopidogrel for 6 months after randomization and subsequently aspirin. The PREVAIL trial is further evaluating this concept. Limited data are available for another LAA occlusion system, the Amplatzer Cardiac Plug (ACP) device, for which the ACP trial has been initiated. Left atrial appendage occlusion needs to be performed with meticulous care by experienced operators because periprocedural complications such as pericardial effusion or stroke have been documented. With increased operator experience and technical improvements of the device, these complications can be minimize

Adenine Nucleotide Translocase 1 Expression is Coupled to the HSP27-Mediated TLR4 Signaling in Cardiomyocytes

The cardiac-specific overexpression of the adenine nucleotide translocase 1 (ANT1) has cardioprotective effects in various experimental heart disease models. Here, we analyzed the link between ANT1 expression and heat shock protein 27 (HSP27)-mediated toll-like receptor 4 (TLR4) signaling, which represents a novel communication pathway between mitochondria and the extracellular environment. The interaction between ANT1 and HSP27 was identified by co-immunoprecipitation from neonatal rat cardiomyocytes. ANT1 transgenic (ANT1-TG) cardiomyocytes demonstrated elevated HSP27 expression levels. Increased levels of HSP27 were released from the ANT1-TG cardiomyocytes under both normoxic and hypoxic conditions. Extracellular HSP27 stimulated TLR4 signaling via protein kinase B (AKT). The HSP27-mediated activation of the TLR4 pathway was more pronounced in ANT1-TG cardiomyocytes than in wild-type (WT) cardiomyocytes. HSP27-specific antibodies inhibited TLR4 activation and the expression of HSP27. Inhibition of the HSP27-mediated TLR4 signaling pathway with the TLR4 inhibitor oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) reduced the mitochondrial membrane potential (∆ψm) and increased caspase 3/7 activity, which are both markers for cell stress. Conversely, treating cardiomyocytes with recombinant HSP27 protein stimulated TLR4 signaling, induced HSP27 and ANT1 expression, and stabilized the mitochondrial membrane potential. The activation of HSP27 signaling was verified in ischemic ANT1-TG heart tissue, where it correlated with ANT1 expression and the tightness of the inner mitochondrial membrane. Our study shows a new mechanism by which ANT1 is part of the cardioprotective HSP27-mediated TLR4 signaling

Stamm- und progenitorzellbasierte Therapieansätze: Aktuelle Entwicklungen zur Behandlung des akuten Myokardinfarkts und der chronischen ischämischen Kardiomyopathie

Zusammenfassung: Die perkutane koronare Revaskularisation sowie eine optimierte medikamentöse Therapie können bei Patienten mit akutem Myokardinfarkt das linksventrikuläre (LV) Remodeling und die LV-Dysfunktion reduzieren. Trotz dieser modernen Therapiestrategien entwickelt ein nicht unerheblicher Teil dieser Patienten ein ungünstiges kardiales Remodeling, das mit einer schlechten Prognose einhergeht. Stamm- und progenitorzellbasierte Ansätze für die Behandlung des akuten Myokardinfarkts und der chronischen ischämischen Kardiomyopathie werden als potenzielle neue therapeutische Optionen intensiv untersucht. Diese Übersicht fasst die aktuellen Entwicklungen in der stamm- und progenitorzellbasierten Therapie bei ischämischer Herzerkrankung zusammen. Dabei erfolgt eine Einschätzung der Reparatur- und Regenerationsfähigkeit verschiedener Stamm- und Progenitorzellpopulationen. Darüber hinaus werden die Vor- und Nachteile der verschiedenen kardialen Applikationsformen der Zellen und mögliche neue Strategien zur Funktionsverbesserung von Stamm- und Progenitorzellen für den Einsatz der zellbasierten kardiovaskulären Therapie dargestell

Into the Wild: GWAS Exploration of Non-coding RNAs

Genome-wide association studies (GWAS) have proven a fundamental tool to identify common variants associated to complex traits, thus contributing to unveil the genetic components of human disease. Besides, the advent of GWAS contributed to expose unexpected findings that urged to redefine the framework of population genetics. First, loci identified by GWAS had small effect sizes and could only explain a fraction of the predicted heritability of the traits under study. Second, the majority of GWAS hits mapped within non-coding regions (such as intergenic or intronic regions) where new functional RNA species (such as lncRNAs or circRNAs) have started to emerge. Bigger cohorts, meta-analysis and technical improvements in genotyping allowed identification of an increased number of genetic variants associated to coronary artery disease (CAD) and cardiometabolic traits. The challenge remains to infer causal mechanisms by which these variants influence cardiovascular disease development. A tendency to assign potential causal variants preferentially to coding genes close to lead variants contributed to disregard the role of non-coding elements. In recent years, in parallel to an increased knowledge of the non-coding genome, new studies started to characterize disease-associated variants located within non-coding RNA regions. The upcoming of databases integrating single-nucleotide polymorphisms (SNPs) and non-coding RNAs together with novel technologies will hopefully facilitate the discovery of causal non-coding variants associated to disease. This review attempts to summarize the current knowledge of genetic variation within non-coding regions with a focus on long non-coding RNAs that have widespread impact in cardiometabolic diseases

High-density lipoproteins as modulators of endothelial cell functions: alterations in patients with coronary artery disease

Alteration of endothelial cell functions, including reduced endothelial nitric oxide (NO) availability, increased endothelial cell apoptosis, adhesion molecule/chemokine expression and pro-thrombotic activation are thought to contribute to the pathophysiology of atherosclerosis and coronary-artery-disease (CAD) with its clinical complications, such as acute coronary syndromes. High-density lipoproteins (HDL) from healthy subjects or reconstituted HDL have been observed to exert potential direct anti-atherogenic effects by modulating these endothelial cell functions. Importantly, endothelial effects of HDL have now been reported to be highly heterogeneous, and are modulated as part of immune responses. More recently, this has also been observed for HDL of patients with CAD, where HDL becomes potentially pro-inflammatory and endothelial-protective properties are markedly altered. Several mechanisms may lead to these altered endothelial effects of HDL in patients with CAD, including oxidative modification of HDL-associated lipids and proteins, such as apoA-I and paraoxonase-1, and alterations of HDL-proteome. These findings have to be considered with respect to interpretation of recent clinical studies failing to demonstrate reduced cardiovascular events by HDL-cholesterol raising strategies in patients with CAD. Both clinical and genetic studies suggest that HDL-cholesterol levels alone are not a sufficient therapeutic target in patients with CAD. The focus of this review is to summarize the role of HDL onto endothelial homeostasis and to describe recently characterized molecular pathways involved. We highlight how structural and functional modifications of HDL particles in patients with CAD may perturb the physiological homeostasis and lead to a loss of endothelial-protective properties of HDL in patients with CA