Multiple Biomarkers for the prediction of ischemic stroke: the PRIME study

Objective: To simultaneously evaluate 14 biomarkers from distinct biological pathways for risk prediction of ischemic stroke, including biomarkers of hemostasis, inflammation, and endothelial activation as well as chemokines and adipocytokines.
Methods and Results: The Prospective Epidemiological Study on Myocardial Infarction (PRIME) is a cohort of 9771 healthy men 50 to 59 years of age who were followed up over 10 years. In a nested case–control study, 95 ischemic stroke cases were matched with 190 controls. After multivariable adjustment for traditional risk factors, fibrinogen (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.03–2.28), E-selectin (OR, 1.76; 95% CI, 1.06–2.93), interferon-γ-inducible-protein-10 (OR, 1.72; 95% CI, 1.06–2.78), resistin (OR, 2.86; 95% CI, 1.30–6.27), and total adiponectin (OR, 1.82; 95% CI, 1.04–3.19) were significantly associated with ischemic stroke. Adding E-selectin and resistin to a traditional risk factor model significantly increased the area under the receiver-operating characteristic curve from 0.679 (95% CI, 0.612–0.745) to 0.785 and 0.788, respectively, and yielded a categorical net reclassification improvement of 29.9% (P=0.001) and 28.4% (P=0.002), respectively. Their simultaneous inclusion in the traditional risk factor model increased the area under the receiver-operating characteristic curve to 0.824 (95% CI, 0.770–0.877) and resulted in an net reclassification improvement of 41.4% (P<0.001). Results were confirmed when using continuous net reclassification improvement.
Conclusion: Among multiple biomarkers from distinct biological pathways, E-selectin and resistin provided incremental and additive value to traditional risk factors in predicting ischemic stroke.

The role of immune-related myeloid cells in angiogenesis

Macrophage function is not restricted to the innate and adaptive immune responses, but also includes host defence, wound healing, angiogenesis and homeostatic processes. Within the spectrum of macrophage activation there are two extremes: M1 classically activated macrophages which have a pro-inflammatory phenotype, and M2 alternatively activated macrophages which are pro-angiogenic and anti-inflammatory. An important property of macrophages is their plasticity to switch from one phenotype to the other and they can be defined in their polarisation state at any point between the two extremes. In order to determine what stage of activation macrophages are in, it is essential to profile various phenotypic markers for their identification. This review describes the angiogenic role for myeloid cells: circulating monocytes, Tie-2 expressing monocytes (TEMs), myeloid-derived suppressor cells (MDSCs), tumour associated macrophages (TAMs), and neutrophils. Each cell type is discussed by phenotype, roles within angiogenesis and possible targets as a cell therapy. In addition, we also refer to our own research on myeloid angiogenic cells (MACs), outlining their ability to induce angiogenesis and their similarities to alternatively activated M2 macrophages. MACs significantly contribute to vascular repair through paracrine mechanisms as they lack the capacity to differentiate into endothelial cells. Since MACs also retain plasticity, phenotypic changes can occur according to disease states and the surrounding microenvironment. This pro-angiogenic potential of MACs could be harnessed as a novel cellular therapy for the treatment of ischaemic diseases, such as diabetic retinopathy, hind limb ischaemia and myocardial infarction; however, caution needs to be taken when MACs are delivered into an inflammatory milieu.

A review of patents relating to therapeutic angiogenesis using endothelial progenitors and other vasculogenesis-related cell types

Stem and progenitor cells have generated considerable scientific and commercial interest in recent years due to their potential for novel cell therapy for a variety of medical conditions. A highly active research area in the field of regenerative medicine is vascular biology. Blood vessel repair and angiogenesis are key processes with endothelial progenitor cells (EPCs) playing a central role. Clinical trials for ischemic conditions, such as myocardial infarction and peripheral arterial disease, have suggested cell therapies to be feasible, safe, and potentially beneficial. Development of efficient methodologies to deliver EPC-based cytotherapies offers new hope for millions of patients with ischemic conditions. Evidence indicates that EPCs, depending on the subtype, mediate angiogenesis through different mechanisms. Differentiation into endothelium and complete integration into damaged vasculature was the first EPC mechanism to be proposed. However, many studies have demonstrated that vasoregulatory paracrine factor secretion by transplanted cells is also important. Many EPC subsets enhance angiogenesis and promote tissue repair by cytokine release without incorporating into the damaged vasculature. Whatever the mechanism, vascular repair and therapeutic angiogenesis using EPCs represent a realistic treatment option and also provides many commercialization opportunities. This review discusses recent advances in the EPC field whilst recounting relevant patents.

All-Cause Mortality up to and After Coronary Heart Disease and Stroke Events in European Middle-Aged Men The PRIME Study

Background and Purpose-The aim was to investigate prospectively the all-cause mortality risk up to and after coronary heart disease (CHD) and stroke events in European middle-aged men.

Methods-The study population comprised 10 424 men 50 to 59 years of age recruited between 1991 and 1994 in France (N=7855) and Northern Ireland (N=2747) within the Prospective Epidemiological Study of Myocardial Infarction. Incident CHD and stroke events and deaths from all causes were prospectively registered during the 10-year follow-up. In Cox's proportional hazards regression analysis, CHD and stroke events during follow-up were used as time-dependent covariates.

Results-A total of 769 CHD and 132 stroke events were adjudicated, and 569 deaths up to and 66 after CHD or stroke occurred during follow-up. After adjustment for study country and cardiovascular risk factors, the hazard ratios of all-cause mortality were 1.58 (95% confidence interval 1.18-2.12) after CHD and 3.13 (95% confidence interval 1.98-4.92) after stroke.

Conclusions-These findings support continuous efforts to promote both primary and secondary prevention of cardiovascular disease.

Accumulating research: a systematic account of how cumulative meta-analyses would have provided knowledge, improved health, reduced harm and saved resources

BACKGROUND: "Cumulative meta-analysis" describes a statistical procedure to calculate, retrospectively, summary estimates from the results of similar trials every time the results of a further trial in the series had become available. In the early 1990 s, comparisons of cumulative meta-analyses of treatments for myocardial infarction with advice promulgated through medical textbooks showed that research had continued long after robust estimates of treatment effects had accumulated, and that medical textbooks had overlooked strong, existing evidence from trials. Cumulative meta-analyses have subsequently been used to assess what could have been known had new studies been informed by systematic reviews of relevant existing evidence and how waste might have been reduced.

METHODS AND FINDINGS: We used a systematic approach to identify and summarise the findings of cumulative meta-analyses of studies of the effects of clinical interventions, published from 1992 to 2012. Searches were done of PubMed, MEDLINE, EMBASE, the Cochrane Methodology Register and Science Citation Index. A total of 50 eligible reports were identified, including more than 1,500 cumulative meta-analyses. A variety of themes are illustrated with specific examples. The studies showed that initially positive results became null or negative in meta-analyses as more trials were done; that early null or negative results were over-turned; that stable results (beneficial, harmful and neutral) would have been seen had a meta-analysis been done before the new trial; and that additional trials had been much too small to resolve the remaining uncertainties.

CONCLUSIONS: This large, unique collection of cumulative meta-analyses highlights how a review of the existing evidence might have helped researchers, practitioners, patients and funders make more informed decisions and choices about new trials over decades of research. This would have led to earlier uptake of effective interventions in practice, less exposure of trial participants to less effective treatments, and reduced waste resulting from unjustified research.

Low alanine aminotransferase levels and higher number of cardiovascular events in people with Type 2 diabetes: analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

AIMS: To determine whether alanine aminotransferase or gamma-glutamyltransferase levels, as markers of liver health and non-alcoholic fatty liver disease, might predict cardiovascular events in people with Type 2 diabetes.

METHODS: Data from the Fenofibrate Intervention and Event Lowering in Diabetes study were analysed to examine the relationship between liver enzymes and incident cardiovascular events (non-fatal myocardial infarction, stroke, coronary and other cardiovascular death, coronary or carotid revascularization) over 5 years.

RESULTS: Alanine aminotransferase level had a linear inverse relationship with the first cardiovascular event occurring in participants during the study period. After adjustment, for every 1 sd higher baseline alanine aminotransferase value (13.2 U/l), the risk of a cardiovascular event was 7% lower (95% CI 4-13; P=0.02). Participants with alanine aminotransferase levels below and above the reference range 8-41 U/l for women and 9-59 U/l for men, had hazard ratios for a cardiovascular event of 1.86 (95% CI 1.12-3.09) and 0.65 (95% CI 0.49-0.87), respectively (P=0.001). No relationship was found for gamma-glutamyltransferase.

CONCLUSIONS: The data may indicate that in people with Type 2 diabetes, which is associated with higher alanine aminotransferase levels because of prevalent non-alcoholic fatty liver disease, a low alanine aminotransferase level is a marker of hepatic or systemic frailty rather than health. This article is protected by copyright. All rights reserved.

Systematic review of the use of behaviour change techniques (BCTs) in home-based cardiac rehabilitation programmes for patients with cardiovascular disease-protocol

BACKGROUND: Cardiovascular diseases (CVDs), including myocardial infarction, heart failure, peripheral arterial disease and strokes, are highly prevalent conditions and are associated with high morbidity and mortality. Cardiac rehabilitation (CR) is an effective form of secondary prevention for CVD but there is a lack of information regarding which specific behaviour change techniques (BCTs) are included in programmes that are associated with improvements in cardiovascular risk factors. This systematic review will describe the BCTs which are utilised within home-based CR programmes that are effective at reducing a spectrum of CVD risk factors.

METHODS/DESIGN: The review will be reported in line with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidance. Randomised and quasi-randomised controlled trials of home-based CR initiated following a vascular event (myocardial infarction, heart failure, peripheral arterial disease and stroke patients) will be included. Articles will be identified through a comprehensive search of MEDLINE, Embase, PsycINFO, Web of Science and Cochrane Database guided by a medical librarian. Two review authors will independently screen articles retrieved from the search for eligibility and extract relevant data, identifying which specific BCTs are included in programmes that are associated with improvements in particular modifiable vascular risk factors.

DISCUSSION: This review will be of value to clinicians and healthcare professionals working with cardiovascular patients by identifying specific BCTs which are used within effective home-based CR. It will also inform the future design and evaluation of complex health service interventions aimed at secondary prevention in CVD.

Glucagon-like peptide-1 based therapies as a novel approach for chronic heart failure

Glucagon-like peptide-1 (GLP-1) is an endogenous peptide hormone whose metabolic effects have been exploited for glycaemic control in diabetes, but which also exerts important cardiovascular actions. We have recently reported that the GLP-1 mimetic, exendin-4, exerts clear benefits post-myocardial infarction via specific effects on extracellular matrix remodelling which is dysregulated in the diabetic heart (Robinson E et al, Basic Res Cardiol 2015; 110: 20), and have now shown similar cardioprotective actions in experimental diabetes, which are mediated via direct effects on infiltrating macrophages (Tate M et al, Basic Res Cardiol 2015; in press). Taken together with the apparent complexity of GLP-1 signalling and disappointing results of recent cardiovascular trials, our work strongly suggests that selective targeting of GLP-1 may be required in order to realise therapeutic benefit for both diabetic and non-diabetic heart failure patients. This is particularly important given the epidemic increase in the incidence of diabetes which is associated with a markedly enhanced susceptibility to cardiovascular stress.

Glucagon-like peptide-1 based therapies as a novel approach for chronic heart failure

Glucagon-like peptide-1 (GLP-1) is an endogenous peptide hormone whose metabolic effects have been exploited for glycaemic control in diabetes, but which also exerts important cardiovascular actions. We have recently reported that the GLP-1 mimetic, exendin-4, exerts clear benefits post-myocardial infarction via specific effects on extracellular matrix remodelling which is dysregulated in the diabetic heart (Robinson E et al, Basic Res Cardiol 2015; 110: 20), and have now shown similar cardioprotective actions in experimental diabetes, which are mediated via direct effects on infiltrating macrophages (Tate M et al, Basic Res Cardiol 2016; 111: 1). Taken together with the apparent complexity of GLP-1 signalling and disappointing results of recent cardiovascular trials, our work strongly suggests that selective targeting of GLP-1 may be required in order to realise therapeutic benefit for both diabetic and non-diabetic heart failure patients. This is particularly important given the epidemic increase in the incidence of diabetes which is associated with a markedly enhanced susceptibility to cardiovascular stress.