Vascular remodeling in the internal mammary artery graft and association with in situ endothelin-1 and receptor expression

BACKGROUND: The vasoconstricting peptide endothelin-1 (ET-1) has been associated with atherosclerotic cardiovascular disease, vascular smooth muscle cell (VSMC) growth stimulation, and intimal thickening. ET-1 binds 2 receptor subtypes, endothelin A and B, and the ETA receptor mediates vasoconstriction and VSMC growth. This study aims to quantitatively assess arterial remodeling variables and compare them with changes in ET-1, ETA, and ETB expression in the internal mammary artery (IMA). METHODS AND RESULTS: Specimens from 55 coronary artery disease (CAD) patients (45 men, 10 women; mean age 65 years) and 14 control IMA specimens (from 7 men and 7 women; mean age 45 years) were collected. IMA cross sections were assessed by histochemical and immunohistochemical staining methods to quantify the levels of medionecrosis, fibrosis, VSMC growth, ET-1, ETA, ETB, and macrophage infiltration. The percentage area of medionecrosis in the patients was almost double that in the controls (31.85+/-14.52% versus 17.10+/-9.96%, P=0.0006). Total and type 1 collagen was significantly increased compared with controls (65.8+/-18.3% versus 33.7+/-13.7%, P=0.07, and 14.2+/-10.0% versus 4.8+/-2.8%, P=0.01, respectively). Despite ACE and/or statin therapy, ET-1 expression and cell cycling were significantly elevated in the patient IMAs relative to the controls (46.27+/-18.46 versus 8.56+/-8.42, P=0.0001, and 37.29+/-12.88 versus 11.06+/-8.18, P=0.0001, respectively). ETA and ETB staining was elevated in the patient vessels (46.88+/-11.52% versus 18.58+/-7.65%, P=0.0001, and 42.98+/-7.08% versus 34.73+/-5.20%, P=0.0067, respectively). A mild presence of macrophages was noted in all sections. CONCLUSIONS: Elevated distribution of collagen indicative of fibrosis coupled with increased cell cycling and high levels of ET-1 and ETA expression in the absence of chronic inflammation suggests altered IMA VSMC regulation is fundamental to the remodeling process.

Psychological symptoms : a review of screening practices for patients with coronary heart disease (CHD)

Background/Aims: Coronary heart disease (CHD) and coronary events have been strongly linked to psychological symptoms in patients during hospitalisation and post-discharge. Within Australia CHD average length of stay is decreasing and symptoms often do not present until discharge. Early screening and treatment of psychological symptoms has been recommended to reduce mortality and identify anxiety and depression. This literature review was undertaken to evaluate and describe current screening practices to identify psychological symptoms in these patients.

Comparison of the inflammatory burden of truly asymptomatic carotid atheroma with atherosclerotic plaques in patients with asymptomatic carotid stenosis undergoing coronary artery bypass grafting: An ultrasmall superparamagnetic iron oxide enhanced magnetic resonance study

Introduction: Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque. The aim of this study was to explore whether there is a difference in the degree of Magnetic Resonance (MR) defined inflammation using Ultra Small Super-Paramagnetic Iron Oxide (USPIO) particles, within carotid atheroma in completely asymptomatic individuals and the asymptomatic carotid stenosis in a cohort of patients undergoing coronary artery bypass grafting (CABG). Methods: 10 patients awaiting CABG with asymptomatic carotid disease and 10 completely asymptomatic individuals with no documented coronary artery disease underwent multi-sequence MR imaging before and 36 hours post USPIO infusion. Images were manually segmented into quadrants and signal change in each quadrant, normalised to adjacent muscle signal, was calculated following USPIO administration. Results: The mean percentage of quadrants showing signal loss was 94% in the CABG group, compared to 24% in the completely asymptomatic individuals (p < 0.001). The carotid plaques from the CABG patients showed a significant mean signal intensity decrease of 16.4% after USPIO infusion (95% CI 10.6% to 22.2%; p < 0.001). The truly asymptomatic plaques showed a mean signal intensity increase (i.e. enhancement) after USPIO infusion of 8.4% (95% CI 2.6% to 14.2%; p = 0.007). The mean signal difference between the two groups was 24.9% (95% CI 16.7% to 33.0%; p < 0.001). Conclusions: These findings are consistent with the hypothesis that inflammatory atheroma is a systemic disease. The carotid territory is more likely to take up USPIO if another vascular territory is symptomatic.

Identification of seven loci affecting mean telomere length and their association with disease

Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 x 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.

Differences in Treatment and Management of Indigenous and Non-Indigenous Patients Presenting with Chest Pain: Results of the Heart Protection Partnership (HPP) Study

BACKGROUND: Indigenous patients with acute coronary syndromes represent a high-risk group. There are however few contemporary datasets addressing differences in the presentation and management of Indigenous and non-Indigenous patients with chest pain. METHODS: The Heart Protection Project, is a multicentre retrospective audit of consecutive medical records from patients presenting with chest pain. Patients were identified as Indigenous or non-Indigenous, and time to presentation and cardiac investigations as well as rates of cardiac investigations and procedures were compared between the two groups. RESULTS: Of the 2380 patients included, 199 (8.4%) identified as Indigenous, and 2174 (91.6%) as non-Indigenous. Indigenous patients were younger, had higher rates hyperlipidaemia, diabetes, smoking, known coronary artery disease and a lower rate of prior PCI; and were significantly less likely to have private health insurance, be admitted to an interventional facility or to have a cardiologist as primary physician. Following adjustment for difference in baseline characteristics, Indigenous patients had comparable rates of cardiac investigations and delay times to presentation and investigations. CONCLUSIONS: Although the Indigenous population was identified as a high-risk group, in this analysis of selected Australian hospitals there were no significant differences in treatment or management of Indigenous patients in comparison to non-Indigenous.

Is adiponectin implicated in venous thromboembolism?

In summary, these results imply that the relationship of adiponectin with lipoproteins is more complex than previously predicted using other methods of lipoprotein fractionation. Higher correlation of adiponectin was shown with large lipoprotein particle size, independent of the apolipoprotein content. Given the small population studied, we could not assess the influence of mild risk factors for venous thrombosis, such as obesity, on the analysis of the results. Thus, we can only state that adiponectin levels appear not to be a strong risk factor for VTE. It is possible that adiponectin deficiency may contribute indirectly to the etiology of VTE by enhancing the inflammatory state. © 2006 International Society on Thrombosis and Haemostasis.

Rates of attendance at a smoking cessation clinic within a cardiac rehabilitation service

Objectives: Smoking cessation has been shown to be an important intervention for preventing cardiovascular events and improving the health of patients with heart disease. However, unaided quit attempts in these patients often leads to high rates of failure and a return to smoking. Outpatient smoking cessation clinics using face-to-face counseling, ongoing behavioral support, advice on smoking pharmacotherapy and objective monitoring, have been found to be one of the most effective interventions for improving quit smoking rates. An outpatient smoking cessation clinic was trialed within a cardiac rehabilitation service in order to explore its effects on smoking rates for patients with or at risk of heart disease. Attendance rates to the clinic were also monitored. Methods: A descriptive exploratory design was used for this newly developed clinic. Patients who currently smoked tobacco and who had a history of either coronary artery disease, heart failure, atrial fibrillation or those seen under a chest pain assessment service were invited to an outpatient ‘Cardiac Patients Smokers Clinic’. Initially patients were offered up to 10 clinic visits over a 3 month period. Follow-up clinic visits were conducted at 3, 6 and 12 months. A portable carbon monoxide meter was used to objectively measure levels of smoking and validate smoking abstinence. Primary outcomes included rates of attendance. Results: Preliminary findings showed 24 per cent of participants (N = 6) completed all their clinic visits and remained smoke free as measured by their ongoing expired carbon monoxide readings. Clinic attendance rates appeared lowest for those with significant mental health issues such as schizophrenia or substance abuse. However, rates of attendance were improved by having an administration officer make reminder telephone calls prior to clinic visits. Conclusions: Early findings indicate the feasibility of providing a specialist smoking cessation clinic within a cardiac rehabilitation service. Further, that reminder telephone calls prior to appointments improved attendance rates in patients with heart disease to this type of clinic. However, future investigations are warranted.

Effect of a single session of exercise on lipoprotein(a)

Lipoprotein(a) (Lp(a)) is bound to apolipoprotein B-100 by disulfide linkage and is associated in the upper density range of low density lipoprotein cholesterol. Persons with elevated concentrations of Lp(a) are regarded as having an increased risk for premature coronary artery disease. Although many studies exist evaluating the effects of a single session of exercise on lipids and lipoproteins, little information is available concerning the effects of exercise on Lp(a). Therefore, the purpose of this study was to determine the effects of a single exercise session on plasma Lp(a). Twelve physically active men completed two 30-min submaximal treadmill exercise sessions: low intensity (LI, 50% VO2max) and high intensity (HI, 80% VO2max). Blood samples were obtained immediately before and after exercise. Total cholesterol (LI: before 4.22 +/- 0.26, after 4.24 +/- 0.28; HI: before 4.24 +/- 0.31, after 4.11 +/- 0.28 mmol . l(-1), mean +/- SE) and triglyceride (LI: before 1.14 +/- 0.16, after 1.06 +/- 0.16; HI: before 1.12 +/- 0.19, after 1.21 +/- 0.19 mmol . l(-1)) concentrations did not differ immediately after either exercise session, nor did Lp(a) concentrations differ immediately after either exercise session (LI: before 4.1 +/- 2.2, after 4.0 +/- 2.1; HI: before 3.9 +/- 2.2, after 3.7 +/- 2.0 mg . dl(-1)). These results suggest that neither a low nor a high intensity exercise session lasting 30 min in duration has an immediate effect on plasma Lp(a).

Ramipril - improving exercise tolerance in intermittent claudication?

Peripheral artery disease (PAD) is one of the most common manifestations of systemic atherosclerosis. It is estimated that 10-15% of the general population is affected by PAD, whereby the narrowed arteries lead to reduced blood flow to the extremeties - particularly the legs. While many people have mild or no systems with PAD, approximately one-third of people experience intermittent claudication (IC).

Bayesian refinement of association signals for 14 loci in 3 common diseases

To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies. © 2012 Nature America, Inc. All rights reserved.

The new Vancouver Chest Pain Rule using troponin as the only biomarker: An external validation study

Objectives To externally evaluate the accuracy of the new Vancouver Chest Pain Rule and to assess the diagnostic accuracy using either sensitive or highly sensitive troponin assays. Methods Prospectively collected data from 2 emergency departments (EDs) in Australia and New Zealand were analysed. Based on the new Vancouver Chest Pain Rule, low-risk patients were identified using electrocardiogram results, cardiac history, nitrate use, age, pain characteristics and troponin results at 2 hours after presentation. The primary outcome was 30-day diagnosis of acute coronary syndrome (ACS), including acute myocardial infarction, and unstable angina. Sensitivity, specificity, positive predictive values and negative predictive values were calculated to assess the accuracy of the new Vancouver Chest Pain Rule using either sensitive or highly sensitive troponin assay results. Results Of the 1635 patients, 20.4% had an ACS diagnosis at 30 days. Using the highly sensitive troponin assay, 212 (13.0%) patients were eligible for early discharge with 3 patients (1.4%) diagnosed with ACS. Sensitivity was 99.1% (95% CI 97.4-99.7), specificity was 16.1 (95% CI 14.2-18.2), positive predictive values was 23.3 (95% CI 21.1-25.5) and negative predictive values was 98.6 (95% CI 95.9-99.5). The diagnostic accuracy of the rule was similar using the sensitive troponin assay. Conclusions The new Vancouver Chest Pain Rule should be used for the identification of low risk patients presenting to EDs with symptoms of possible ACS, and will reduce the proportion of patients requiring lengthy assessment; however we recommend further outpatient investigation for coronary artery disease in patients identified as low risk.

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Perinatal nutrition and gastrointestinal disorders : Working Group Report of the Second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

Metabolic programming during the perinatal period as a consequence of early nutrition is an emerging area of great interest. This concept is known as the "fetal origins of adult disease" theory (1). Numerous epidemiological studies published over the past 20 years or so have suggested that small body size at birth and during infancy and, more specifically, intrauterine growth retardation are associated later in life with lowered cognitive performance and increased rates of coronary heart disease and its major biological risk factors, ie, raised blood pressure, insulin resistance, coronary artery disease, and abnormalities in lipid metabolism. The molecular mechanisms that govern this phenomenon in humans, however, are unknown and need to be elucidated.

Utility of magnetic resonance imaging-based finite element analysis for the biomechanical stress analysis of hemorrhagic and non-hemorrhagic carotid plaques

Background: Biomechanical stress analysis has been used for plaque vulnerability assessment. The presence of plaque hemorrhage (PH) is a feature of plaque vulnerability and is associated with thromboembolic ischemic events. The purpose of the present study was to use finite element analysis (FEA) to compare the stress profiles of hemorrhagic and non-hemorrhagic profiles. Methods and Results: Forty-five consecutive patients who had suffered a cerebrovascular ischemic event with an underlying carotid artery disease underwent high-resolution magnetic resonance imaging (MRI) of their symptomatic carotid artery in a 1.5-T MRI system. Axial images were manually segmented for various plaque components and used for FEA. Maximum critical stress (M-CstressSL) for each slice was determined. Within a plaque, the maximum M-CstressSL for each slice of a plaque was selected to represent the maximum critical stress of that plaque (M-CstressPL) and used to compare hemorrhagic and non-hemorrhagic plaques. A total of 62% of plaques had hemorrhage. It was observed that plaques with hemorrhage had significantly higher stress (M-CstressPL) than plaques without PH (median [interquartile range]: 315 kPa [247-434] vs. 200 kPa [171-282], P=0.003). Conclusions: Hemorrhagic plaques have higher biomechanical stresses than non-hemorrhagic plaques. MRI-based FEA seems to have the potential to assess plaque vulnerability.

Association between biomechanical structural stresses of atherosclerotic carotid plaques and subsequent ischaemic cerebrovascular events - A longitudinal in vivo magnetic resonance imaging-based finite element study

Background: High-resolution magnetic resonance (MR) imaging has been used for MR imaging-based structural stress analysis of atherosclerotic plaques. The biomechanical stress profile of stable plaques has been observed to differ from that of unstable plaques; however, the role that structural stresses play in determining plaque vulnerability remains speculative. Methods: A total of 61 patients with previous history of symptomatic carotid artery disease underwent carotid plaque MR imaging. Plaque components of the index artery such as fibrous tissue, lipid content and plaque haemorrhage (PH) were delineated and used for finite element analysis-based maximum structural stress (M-C Stress) quantification. These patients were followed up for 2 years. The clinical end point was occurrence of an ischaemic cerebrovascular event. The association of the time to the clinical end point with plaque morphology and M-C Stress was analysed. Results: During a median follow-up duration of 514 days, 20% of patients (n=12) experienced an ischaemic event in the territory of the index carotid artery. Cox regression analysis indicated that M-C Stress (hazard ratio (HR): 12.98 (95% confidence interval (CI): 1.32-26.67, pZ0.02), fibrous cap (FC) disruption (HR: 7.39 (95% CI: 1.61e33.82), p Z 0.009) and PH (HR: 5.85 (95% CI: 1.27e26.77), p Z 0.02) are associated with the development of subsequent cerebrovascular events. Plaques associated with future events had higher M-C Stress than those which had remained asymptomatic (median (interquartile range, IQR): 330 kPa (229e494) vs. 254 kPa (166-290), p Z0.04). Conclusions: High biomechanical structural stresses, in addition to FC rupture and PH, are associated with subsequent cerebrovascular events.