Microparticles in cardiovascular disease pathophysiology and outcomes

Microparticles (MPs) are vesicles less than one micron in diameter shed from the plasma membranes of cells that are injured, activated, or undergoing apoptosis. MPs are shed from several types of cells, and the cells of origin can be identified using combinations of antigenic markers. Platelet MPs, which play a role in coagulation and atherogenesis, are the most abundant MPs in the circulation. In vivo studies have demonstrated platelet MP levels to be higher in patients who have had acute ischemic stroke and in patients with greater degrees of retinopathy. In addition, platelet MP levels have been shown to be higher in patients with severe hypertension and in those with increased coronary heart disease risk. Endothelial MPs affect vascular tone, permeability, and hemostasis. Higher endothelial MP levels have been shown to correlate with loss of flow-mediated dilation, arterial stiffness, and severe hypertension. Most compelling are recent cohort studies that have shown endothelial MP levels to be independent predictors of cardiovascular disease events. Although more research is needed, studies suggest that MPs may have clinical applications including utility as biomarkers, use in improving cardiovascular disease risk prediction, and as potential targets of therapy.     

Molecular genetics of acute myeloid leukemia: clinical implications and opportunities for integrating genomics into clinical practice

Advances in sequencing technologies have led to the discovery of a series of mutations in a sizeable proportion of patients with acute myeloid leukemia (AML) over the last 10 years. Clinical correlative studies are now beginning to decipher the clinical importance, prevalence and potential prognostic significance of these mutations in AML but few studies have assessed the clinical implications of these mutations in a comprehensive fashion. Nonetheless, mutations in DNMT3A, TET2, and ASXL1 are emerging as important adverse prognosticators in subsets of patients with AML independent of FLT3 mutations whereas mutations in IDH2 at residue 140 are potential predictors of improved outcome in AML. Further improvements in cost, throughput, and clinical validation of second-generation sequencing technologies may allow for clinical implementation of comprehensive genetic profiling in the clinical care of AML patients.     

Renin as a biomarker of cardiovascular disease in clinical practice

The search for novel circulating blood biomarkers as predictors of cardiovascular (CV) risk and prognosis is a continuing field of interest in clinical medicine. Biomarkers from several pathophysiological pathways, including markers of organ damage, of inflammation, of the atherosclerotic process and of the coagulation pathway, have been investigated in the last decades. A particular interest has been raised for neurohormonal factors. The role of the activation of the sympathetic system and the renin-angiotensin-aldosterone system (RAAS) in the development of CV diseases has been extensively explored. Renin is the first limiting step of the RAAS and its role as a biomarker to improve CV risk stratification still remains a topic of debate. Several studies have shown that elevated plasma renin activity is associated with increased morbidity and mortality in patients with CV disease. The aim of this paper is to critically evaluate the evidence on the role of renin as a biomarker of CV risk and prognosis. With the new advances of pharmacological treatment acting on the RAAS, the effect of elevated levels of renin on the prognosis of these patients becomes even more intriguing.     

Biomarkers of pathophysiology in hypertrophic cardiomyopathy: implications for clinical management and prognosis

The study of biomarkers and their signalling pathways has allowedthe development of new therapeutic strategies in a range ofdisorders. The aim of the present systematic review is to providean overview of different biomarkers in patients with hypertrophiccardiomyopathy that could give some insight into the pathophysiologicmechanism(s) underlying the typical clinical and histologicalmanifestations of the disease. Several pathophysiological modelsare presented and discussed, including studies that have investigatedthese biomarkers for diagnostic and prognostic reasons, in relationto disease progression and/or mortality.     

Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL

Heterogeneity in the clinical behavior of patients with chronic lymphocytic leukemia (CLL) makes it difficult for physicians to accurately identify which patients may benefit from an early or more aggressive treatment strategy and to provide patients with relevant prognostic information. Given the potential efficacy of newer therapies and the desire to treat patients at "optimum" times, it is more important than ever to develop sensitive stratification parameters to identify patients with poor prognosis. The evolution of risk stratification models has advanced from clinical staging and use of basic laboratory parameters to include relevant biologic and genetic features. This article will review the dramatic progress in prognostication for CLL and will propose statistical modeling techniques to evaluate the utility of these new measures in predictive models to help determine the optimal combination of markers to improve prognostication for individual patients. This discussion will also elaborate which markers and tools should be used in current clinical practice and evaluated in ongoing clinical trials.     

Portal hypertension: from pathophysiology to clinical practice.

Portal hypertension (PHT) is responsible for the more severe and often lethal complications of cirrhosis such as bleeding oesophageal varices, ascites, renal dysfunction and hepatic encephalopathy. Because of the combined impact of these complications, PHT remains the most important cause of morbidity and mortality in patients with cirrhosis. Over the years, it has become clear that a decrease in portal pressure is not only protective against the risk of variceal (re)bleeding but is also associated with a lower long-term risk of developing complications and an improved long-term survival. A milestone in therapy was the introduction of non-selective beta-blockers for the prevention of bleeding and rebleeding of gastro-esophageal varices. However, in practice, less than half the patients under beta-blockade are protected from these risks, supporting the overall demand for innovation and expansion of our therapeutic armamentarium. Recent advances in the knowledge of the pathophysiology of cirrhotic PHT have directed future therapy towards the increased intrahepatic vascular resistance, which, in part, is determined by an increased hepatic vascular tone. This increased vasculogenic component provides the rationale for the potential use of therapies aimed at increasing intrahepatic vasorelaxing capacity via gene therapy, liver-selective nitric oxide donors and statines on the one hand, and at antagonizing excessive intrahepatic vasoconstrictor force through the use of endothelin antagonists, angiotensin blockers, alpha(1) adrenergic antagonists or combined alpha(1)- and non-selective beta-blockers or somatostatin analogues on the other. The focus of this review is to give an update on the pathophysiology of PHT in order to elucidate these potential novel strategies subsequently.     

The challenges of integrating ultrasonography into routine rheumatology practice: addressing the needs of clinical rheumatologists

OBJECTIVES: The practice of musculoskeletal ultrasonography (MSKUS) by UK rheumatologists remains limited, despite their reported enthusiasm. This study aimed to investigate factors that may encourage or limit future dissemination of rheumatologist-performed MSKUS and provide insights into perceived clinical importance and learning motivation relating to published recommendations by MSKUS experts. METHODS: A written questionnaire study was conducted, involving 48 rheumatologists. Questions included the potential role of self-performed MSKUS, skills that they would be willing to learn and factors that may encourage or limit learning and practice. Competency recommendations proposed by imaging experts (142 skills in 7 anatomical areas) were reviewed, and quantitative and qualitative data collected regarding 'value to their practice' and 'learning motivation'. RESULTS: Eighty-nine percent wished to learn MSKUS. Factors influencing learning and practice included time to achieve competency; relative-added clinical value of MSKUS examination; limited training infrastructure; access to existing imaging service; equipment funding. Skills offering greatest clinical utility were inflammatory arthritis assessment and guided procedures; least useful were evaluation of ligament/muscle lesions and soft tissue masses. There was a close correlation between clinical utility, learning motivation and competency standard. CONCLUSIONS: A trade-off between added clinical value and time to achieve competency is the major factor influencing practice and training in MSKUS. Most rheumatologists report limited time to devote to training and therefore need to prioritize areas of importance for dedicated learning. Educational programmes need to be highly focused and relevant to clinical and job-plan requirements in order to encourage future dissemination of MSKUS practice by rheumatologists.     

Ventricular arterial stiffening: integrating the pathophysiology

Vascular stiffening of the large arteries is a common feature of aging and is exacerbated by many common disorders such as hypertension, diabetes, and renal disease. This change influences the phasic mechanical stresses imposed on the blood vessels that in turn is important to regulating smooth muscle tone, endothelial function, and vascular health. In addition, the heart typically adapts to confront higher and later systolic loads by both hypertrophy and ventricular systolic stiffening. This creates altered coupling between heart and vessel that importantly affects cardiovascular reserve function. In this overview, I discuss the notion of a coupling disease in which stiffness of both heart and arteries interact to limit performance and generate clinical symptoms. This involves changes in the mechanical interaction of both systems, changes in signaling within the arteries themselves, and alterations in coronary flow regulation. Lastly, I briefly review recent development in de-stiffening strategies that may pave the way to treat this syndrome and its clinical manifestations.     

On the value of doing nothing: anger and cardiovascular disease in clinical practice

Type A behavior, anger, and hostility have all been described as psychosocial risk factors or potential risk factors for cardiovascular disease (CVD). However, in the populations evaluated, the methods used to measure these traits and the endpoints used to determine outcomes have varied widely. The results of these studies have also been quite disparate. The present article reviews data from all the existing quantitative (meta-analytic) and qualitative systematic review articles that cover this topic, using the Database of Abstracts of Reviews of Effects (DARE) criteria. We conclude that the existing data do not support a meaningful clinical relationship between current measurements of these traits and the development of CVD.     

Colonic diverticular disease: pathophysiology and clinical picture

Colonic diverticulosis is the most frequent structural abnormality of the large bowel, although it was a rarity before the 20th century. Lifestyle changes in westernized societies with reduced fiber diet are supposed to be the main cause for its high prevalence nowadays. In African countries, where staple diet is rich in fiber, diverticulosis remains very infrequent. Prevalence increases with ageing too. A fiber-deficient diet and subsequent reduction in bowel content volume would lead to increased intraluminal pressures and colonic segmentation, thus promoting diverticula formation. Animal and human studies have shown increased intracolonic pressures in patients with diverticulosis. Alterations in colonic muscle properties, collagen metabolism and in the interactions of the extracellular matrix components may play a role in remodelling the gut wall in diverticular disease. At least one fourth of patients with diverticulosis will develop symptoms, sometimes overlapping with irritable bowel syndrome, but 10-25% will suffer diverticulitis and 3-5% diverticular bleeding. Conservative medical management is usually sufficient in the first episode of diverticulitis, but surgical treatment is generally advocated in recurrences. Diverticular bleeding is a major cause of lower digestive haemorrhage, but generally self-limited. With the application of therapeutic endoscopic and angiographic methods, emergency surgery can often be avoided.