Abstract: The idea of promoting angiogenesis in ischemic tissues remains an undisputed therapeutic approach for the treatment of myocardium and skeletal muscles that lack sufficient blood supply. However, clinical experiences from several large trials indicated that delivery of proangiogenic factors to patients suffering from myocardial infarction and leg ischemia has not shown significant benefits. Despite continuous success in various animal disease models, why has this simple principle not shown proof of concept in patients? What has been missing in the trial deign? What are the differences between animal models and patients? What are the optimal components for promoting functional collateral networks? This brief review discusses molecular mechanisms underlying arteriogenesis and proposes novel approaches for improvement of therapeutic outcomes. ... Read more

Abstract: According to the World Health Organization, approximately 220 million people worldwide have type 2 diabetes mellitus. Patients with type 2 diabetes not only have a chronic disease to cope with, they are also at increased risk for coronary heart disease, peripheral vascular disease, retinopathy, nephropathy, and neuropathy. The exact causes of type 2 diabetes are still not clear. Since the 17^th century, it has been suggested that emotional stress plays a role in the etiology of type 2 diabetes mellitus. So far, review studies have mainly focused on depression as a risk factor for the development of type 2 diabetes mellitus. Yet, chronic emotional stress is an established risk factor for the development of depression. The present review provides an overview of mainly prospective epidemiological studies that have investigated the associations between different forms of emotional stress and the development of type 2 diabetes mellitus. Results of longitudinal studies suggest that not only depression but also general emotional stress and anxiety, sleeping problems, anger, and hostility are associated with an increased risk for the development of type 2 diabetes. Conflicting results were found regarding childhood neglect, life events, and work stress. It is important to emphasize that publication-bias may have occurred, resulting from "fishing-expeditions," where authors search their data for significant associations. Publication bias may also be caused by the tendency of reviewers and Editors to reject manuscripts with negative results for publication. It is therefore essential that research groups, who aim to conduct a new epidemiological cohort study, prospectively describe and publish the design of their study. Future research should focus on identifying mechanisms linking different forms of stress and incident type 2 diabetes. ... Read more

Abstract: Coronary artery calcification (CAC) has long been known to occur as a part of the atherosclerotic process; recently it has been shown to be an active process resembling bone formation within the vessel wall. There is good evidence that the extent of CAC reflects the total coronary atherosclerotic burden and this has generated interest in using CAC as a marker of risk. The current consensus is that large amounts of CAC identify a patient highly vulnerable to future events. The advent of CT angiography added the ability to non-invasively detect critical luminal stenoses that are associated with a more immediate risk of events, and to visualize the non-calcified component of the atherosclerotic plaque. ... Read more

Abstract: Anti-platelet drugs play a key role in cardiovascular medicine since the introduction of aspirin as an anti-thrombotic agent some 50 years ago. After many years of a "monopoly" of aspirin, ADP receptor P2Y12 inhibitors were introduced with a significant improvement in clinical outcome. Nowadays dual anti-platelet therapy is the common practice for both acute events and secondary prevention in selected groups of patients. The improved efficacy of multiple drug therapy is associated with an increased risk of bleeding, which raises the issue of the dosing of these drugs. Recently, numerous studies have reported a variable laboratory response to aspirin and clopidogrel, which correlates with clinical outcome. Several mechanisms for causing this variable response have been proposed, including genetic variability, disease burden, and others. A major obstacle in this field is the lack of a standardized method for testing these responses. New drugs are currently under different stages of development, including new P2Y12 receptors inhibitors, thrombaxane receptor blockers, direct thrombin inhibitors, and inhibitors for other signaling pathways including oral GPIIbIIIa inhibitors. Thus anti-platelet therapy is currently under intensive developments toward multiple drug therapy and personal dose adjustment, which may improve clinical outcome. ... Read more

Abstract: Vitamin K antagonists (VKA), such as warfarin, have been the only available oral anticoagulants despite their many limitations. The greatest medical need is to find a replacement for warfarin for long-term therapy, particularly for stroke prevention in atrial fibrillation (AF) patients. Emerging oral anticoagulants are free from many of warfarin's drawbacks and may offer a convenient alternative. Drugs in advanced development target factor Xa (rivaroxaban, apixaban) or thrombin (dabigatran etexilate). Recently, the RE-LY phase III study found dabigatran etexilate was an effective and convenient alternative to warfarin in stroke prevention for AF patients. Within the next two years, similar studies comparing rivaroxaban and apixaban versus warfarin in AF patients will become available. This paper reviews warfarin's limitations, discusses the pharmacokinetics of emerging anticoagulants in advanced development, and summarizes trials with an emphasis on head-to-head studies comparing novel anticoagulants to warfarin. ... Read more

Abstract: The evolution of the immune system has provided a multilevel system that interconnects the innate and adaptive immune systems to serve at least three central purposes: the defense from microbial pathogens, the capacity for discrimination of self- from non-self necessary for the prevention of autoimmune disease, and essential effector roles in wound repair and tissue remodeling. In recent studies, we have elucidated an unsuspected role for a class of naturally occurring autoreactive antibodies from the most primitive tier of B lymphocytes, which regulates fundamental functions of the innate immune system. Our findings also throw light onto long unresolved mysteries regarding the origins of the earliest waves of B lymphocyte development. ... Read more

Abstract: Metabolic syndrome is a major risk factor for cardiovascular and metabolic diseases. Playing a central role in the development of metabolic syndrome and in its clinical consequences is visceral obesity. Adipose tissue is now considered to be an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that is seen in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Recent studies have shown that obesity induces chronic local inflammation in adipose tissue, and that cells of the innate immune system, particularly macrophages, are crucially involved in adipose inflammation and systemic metabolic abnormalities. Moreover, we and others recently revealed that T cells are key regulators of adipose inflammation, and that the adaptive immune system is also crucially important. In mouse models modulation of T cell function ameliorated not only adipose inflammation but also systemic insulin resistance induced by obesity. Thus clarification of the inflammatory processes ongoing in obese adipose tissue would seem essential for the understanding of metabolic syndrome and for developing novel therapeutic strategies to treat it. ... Read more

Abstract: Historically atherosclerosis has been viewed as a disease associated with dyslipidemia because many studies (e.g., Framingham study) have demonstrated that dyslipidemia is clearly a risk factor for the disease and lipid-lowering statin therapies have proven to be highly effective in reducing the cardiovascular events and improving the quality of life for patients with coronary heart disease all over the world. Over the last decade, both preclinical and clinical research has provided multiple lines of unequivocal evidence that inflammation and immune response are integral components of the pathogenesis for atherosclerosis. In this article, both clinical and preclinical evidence in support of atherosclerosis as an inflammatory disease will be reviewed. Evidence in support of atherosclerosis as an autoimmune disease will also be presented. Furthermore, opportunities for translating the newly gained knowledge of atherosclerosis as an inflammatory/autoimmune disease into novel diagnostic and therapeutic modalities will be discussed along with challenges in developing these modalities. ... Read more

Abstract: Neutrophils are important, expedient front-line "soldiers" in fighting against bacterial infection. In sepsis, the overwhelming immune response to bacterial infection precipitates systemic inflammation and organ dysfunction. Neutrophils release many lysis-inducing factors and cause local tissue damage, and neutrophils themselves became a target in controlling sepsis. ... Read more

Abstract: It is commonly thought that bacterial endotoxin such as lipopolysaccharide (LPS) causes sepsis. Authors argue that LPS is merely a disease marker. The real mechanism of sepsis lies in the Toll-like receptors that suppress sepsis caused by tissue injury or endotoxin. When Toll-like receptors' initial suppression role is overwhelmed, sepsis ensues. ... Read more