Levels of DNA Methylation Vary at CpG Sites across the BRCA1 Promoter, and Differ According to Triple Negative and "BRCA-Like" Status, in Both Blood and Tumour DNA.

Triple negative breast cancer is typically an aggressive and difficult to treat subtype. It is often associated with loss of function of the BRCA1 gene, either through mutation, loss of heterozygosity or methylation. This study aimed to measure methylation of the BRCA1 gene promoter at individual CpG sites in blood, tumour and normal breast tissue, to assess whether levels were correlated between different tissues, and with triple negative receptor status, histopathological scoring for BRCA-like features and BRCA1 protein expression. Blood DNA methylation levels were significantly correlated with tumour methylation at 9 of 11 CpG sites examined (p<0.0007). The levels of tumour DNA methylation were significantly higher in triple negative tumours, and in tumours with high BRCA-like histopathological scores (10 of 11 CpG sites; p<0.01 and p<0.007 respectively). Similar results were observed in blood DNA (6 of 11 CpG sites; p<0.03 and 7 of 11 CpG sites; p<0.02 respectively). This study provides insight into the pattern of CpG methylation across the BRCA1 promoter, and supports previous studies suggesting that tumours with BRCA1 promoter methylation have similar features to those with BRCA1 mutations, and therefore may be suitable for the same targeted therapies.

Congenital long QT syndromes: prevalence, pathophysiology and management.

Long QT syndrome is a genetic disorder associated with life threatening ventricular arrhythmias and sudden death. This inherited arrhythmic disorder exhibits genetic heterogeneity, incomplete penetrance, and variable expressivity. During the past two decades there have been major advancements in understanding the genotype-phenotype correlations in LQTS. This genotype-phenotype relationship can lead to improved management of LQTS. However, development of genotype-specific or mutation-specific management strategies is very challenging. This review describes the pathophysiology of LQTS, genotype-phenotype correlations, and focuses on the management of LQTS. In general, the treatment of LQTS consists of lifestyle modifications, medical therapy with beta-blockers, device and surgical therapy. We further summarize current data on the efficacy of pharmacological treatment options for the three most prevalent LQTS variants including beta-blockers in LQT1, LQT2 and LQT3, sodium channel blockers and ranolazine for LQT3, potassium supplementation and spironolactone for LQT2, and possibly sex hormone-based therapy for LQT2.

Genotype-specific risk stratification and management of patients with long QT syndrome.

Long QT syndrome (LQTS) is an inherited disorder associated with life-threatening ventricular arrhythmias. An understanding of the relationship between the genotype and phenotype characteristics of LQTS can lead to improved risk stratification and management of this hereditary arrhythmogenic disorder. Risk stratification in LQTS relies on combined assessment of clinical, electrocardiographic, and mutations-specific factors. Studies have shown that there are genotype-specific risk factors for arrhythmic events including age, gender, resting heart rate, QT corrected for heart rate, prior syncope, the postpartum period, menopause, mutation location, type of mutation, the biophysical function of the mutation, and response to beta-blockers. Importantly, genotype-specific therapeutic options have been suggested. Lifestyle changes are recommended according to the prevalent trigger for cardiac events. Beta-blockers confer greater benefit among patients with LQT1 with the greatest benefit among those with cytoplasmic loops mutations; specific beta-blocker agents may provide greater protection than other agents in specific LQTS genotypes. Potassium supplementation and sex hormone-based therapy may protect patients with LQT2. Sodium channel blockers such as mexiletine, flecainide, and ranolazine could be treatment options in LQT3.

Cardiac resynchronization therapy for prevention of heart failure events in elderly patients with left ventricular dysfunction.

Heart failure (HF) due to left ventricular (LV) systolic dysfunction contributes significantly to cardiovascular morbidity and is a major cause of mortality throughout the world. Its prevalence is increasing as the population ages. Age-related structural and functional changes of the heart in combination with multiple coexisting comorbid conditions significantly reduce cardiovascular reserve capacity and increase the risks of developing symptomatic HF in the elderly. Cardiac resynchronization therapy (CRT) has been demonstrated to reduce HF-related hospitalization as well as mortality and has become an important part of treatment for qualified patients with advanced HF. More recent studies showed a significant reduction in the risk of HF and mortality among CRT recipients with asymptomatic and mildly symptomatic HF (New York Heart Association functional class I­II), LV systolic dysfunction and widened QRS complex, supporting the notion that CRT may prevent or delay disease progression. Although data on the benefit of preventive CRT in the elderly are limited to retrospective subgroup analyses with relatively small numbers of elderly patients, accumulating data suggest that CRT confers similar or greater clinical benefit among elderly patients compared with their younger counterparts. As the proportion of elderly patient with LV systolic dysfunction is increasing dramatically, further research is warranted to confirm these possible clinically beneficial effects of CRT in this population.

Bone marrow resident and circulating progenitor cells in patients undergoing cardiac surgery.

BACKGROUND: Vascular trauma induced by surgical revascularization stimulates mobilization of hematopoietic and nonhematopoietic progenitor cells. However, it is not clear whether mobilized progenitors are functionally active and participate in peripheral homing. We have found no clinical studies available regarding the reaction of bone marrow to surgical revascularization. METHODS: This was an observational prospective study of 76 patients undergoing elective coronary artery bypass graft surgery. Bone marrow aspirates and blood samples were collected at baseline, at the end of surgery, and 24 hours postoperatively (blood samples only). The CD34+, CD34+CD133+, and CD34+CXCR4+ progenitor cell counts, CXCR4+ mononuclear cell counts, and CXCR4 expression on CD34+ cells were measured by flow cytometry. Progenitor cell functions were studied in vitro by clonogenic and migration assays. RESULTS: In response to coronary revascularization there was mobilization of CD34+ progenitors, having increased migratory and clonogenic function. The CD34+CXCR4+ subsets and CXCR4 expression on CD34+ cells in peripheral blood increased significantly 24 hours postoperatively. The CXCR4 expression on mobilized progenitors at the end of surgery was independently related to baseline CXCR4 expression on bone marrow resident CD34+ cells and duration of cardiopulmonary bypass in a multivariate model. At the end of surgery there was a significant fall in the expression of CXCR4 on CD34+ bone marrow cells, suggesting egress into peripheral circulation of the most active CXCR4-expressing progenitors. CONCLUSIONS: Coronary artery bypass graft surgery is associated with bone marrow release of functionally active progenitor cells. Further studies are needed to verify whether mobilized progenitors participate in regeneration of injured tissues.

Stem/Progenitor cells, atherosclerosis and cardiovascular regeneration.

Regenerative cell based therapy has potential to become effective adjuvant treatment for patients with atherosclerotic disease. Although data from animal studies support this notion, clinical studies undertaken in patients with acute and chronic coronary artery disease do not conclusively demonstrate benefits of such therapy. There are many questions on the stem cell translational roadmap. The basic mechanisms of stem cell-dependent tissue regeneration are not well understood. There is a debate regarding characterization of specific cell types conferring therapeutic effects. In particular, the role of endothelial progenitor cells as a specific reparative cell subtype is questioned, and the role of myeloid cell linage in fostering of vasculo- and angiogenesis is being increasingly appreciated. Intense discussions surround the place of stem/progenitor cells in atherosclerosis progression, plaque destabilization and vessel remodeling. This paper summarizes the current knowledge on the regenerative stem/progenitor cell definitions, mechanisms of stem cell trafficking, homing and their involvement in atherosclerosis progression.

Endogenous stem cells in patients undergoing coronary artery bypass graft surgery.

Considerable research efforts have recently been made towards the application of autologous stem cell therapy for cardiovascular regeneration. Patients with coronary artery disease undergoing surgery represent a potential target. As yet, this approach has failed to obtain satisfactory evidence in clinical studies. However, several observational studies have described mobilising effect of cardiac surgery on endogenous stem cells, although the mechanisms of this phenomenon and its clinical relevance are not defined. This article reviews available clinical data on the effect of cardiac surgery on endogenous stem cells and outlines some of the controversies in this area.

Candidate circulating biomarkers for the cardiovascular disease continuum.

The early identification of susceptibility to adverse cardiovascular outcomes and risk stratification amongst asymptomatic individuals, as well as amongst those with overt disease continues to be one of the major priorities of clinically-orientated research in the field of atherothrombosis. Available data from epidemiological studies indicate that traditional risk factors do not fully explain the predisposition to cardiovascular disease, its dynamics in different population groups and treatment responses. The pressing need for the development and clinical implementation of new markers of atherothrombotic disease has fuelled rapidly expanding research into cardiac biomarkers. This review outlines the main principles of biomarker qualification that have entered clinical practice, as well as an overview of the development of targeted biomarkers across the cardiovascular "continuum". We discuss in detail the evidence from epidemiological and clinical studies advocating the potential clinical use of the most promising candidate plasma biomarkers (more specifically, C-reactive protein, coagulation and inflammatory mediators and natriuretic peptides). Such an application of biomarkers to aid clinical risk assessment would be important in our efforts to improve risk stratification of subjects at risk of cardiovascular events.

Hypertension in people with diabetes and the metabolic syndrome: pathophysiologic insights and therapeutic update.

Hypertension (HTN) and type 2 diabetes mellitus (T2DM) are emerging as epidemics of the 21st century and are important components of the metabolic syndrome (MS). Evidence demonstrates a relationship between HTN, T2DM, and several vascular and metabolic abnormalities that are components of the MS. HTN affects nearly 70 million Americans and over one billion worldwide; likewise, the MS affects 44% of the US population above the age of 60 years and is rapidly increasing. HTN associated with the MS has certain pathophysiologic characteristics that provide clinical challenges. There is growing evidence that tissue activation of the renin-angiotensin system contributes to endothelial dysfunction, microalbuminuria, insulin resistance, and subsequent increased risk for cardiovascular and chronic kidney disease. The notion that HTN is a metabolic as well as a vascular disease provides a new treatment paradigm.

Statin therapy-evidence beyond lipid lowering contributing to plaque stability.

Primarily statin drugs inhibit hepatic 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is responsible for the reduction in circulating low-density lipoprotein (LDL) cholesterol. Several findings from recent research studies indicate that statins have multiple actions that favorably influence key factors involved in the atherogenic process. These so-called pleiotropic properties affect various aspects of cell function, inflammation, coagulation, and vasomotor activity. These effects are mediated either indirectly through LDL cholesterol reduction or via a direct effect on cellular functions. Such actions may contribute to the early cardiovascular benefit observed in several outcome trials with statin drugs therapy. Although many of the pleiotropic properties of statins may be a class effect, some may be unique to certain agents and account for differences in their pharmacological activity. This review summarise the results of the major outcome trials of statins and non-statins therapy and the possible mechanisms beyond lipid lowering contributing to plaque stability.

The role of anticoagulation in cancer patients: facts and figures.

Thromboembolic events contribute significantly to the morbidity and mortality in cancer. Effective and safe anticoagulation - mainstay in prevention and treatment of thrombosis - remains very challenging clinical task in oncology patients - population of high rate of treatment failure, bleeding complications and thromboembolic events recurrences. Prospective randomized clinical studies have documented that with advent of low molecular weight heparins new possibilities for thrombosis treatment and long-term prevention with more convenient and safe anticoagulation have emerged. Considerable advances have been achieved at present time in our understanding of the pathobiology of thrombogenesis in human malignancies, particularly of the interactions between coagulation cascade reactions and processes of tumor growth and dissemination. This builds up a new challenge for modern oncology - appreciation of the hypothesis of anti-malignant effects of anticoagulants, which could influence the outcome of human cancer. Antineoplastic effects of antithrombotic drugs have been reported in various experimental models. Heparins have been the most extensively studied and have been shown to reduce the primary tumour growth and its metastatic spread. Joint evidence from fundamental research and from several randomized clinical trials, observing beneficial impact of low molecular weight heparins therapy on cancer patients survival, dictate the need for further scientific steps to confirm biological effects of heparins in human malignancies. The evidence is started to accumulate, that clinically approved heparins have different abilities to influence some processes of metastasis spread. The experimental work towards development of heparin derivates with low anticoagulant activity, but with potential inhibitory effects on tumor cells migration is in progress.