Progression of endothelial dysfunction, atherosclerosis, and arterial stiffness in stable kidney transplant patients: a pilot study.

BACKGROUND: Kidney transplant patients suffer from vascular abnormalities and high cardiovascular event rates, despite initial improvements post-transplantation. The nature of the progression of vascular abnormalities in the longer term is unknown. This pilot study investigated changes in vascular abnormalities over time in stable kidney transplant patients long after transplantation. METHODS: Brachial artery flow-mediated dilation (FMD), nitroglycerin-mediated dilation, carotid-femoral pulse wave velocity (cf-PWV), ankle-brachial pressure index, and common carotid artery intima-media thickness (CCA-IMT) were assessed in 18 kidney transplant patients and 17 controls at baseline and 3-6 months after. RESULTS: There was no difference in age (51 ± 13 vs. 46 ± 11; P = 0.19), body mass index (26 ± 5 vs. 25 ± 3; P = 0.49), serum cholesterol (4.54 ± 0.96 vs. 5.14 ± 1.13; P = 0.10), systolic blood pressure (BP) (132 ± 12 vs. 126 ± 12; P = 0.13), diastolic BP (82 ± 9 vs. 77 ± 8; P = 0.10), or diabetes status (3 vs. 0; P = 0.08) between transplant patients and controls. No difference existed in vascular markers between patients and controls at baseline. In transplant patients, FMD decreased (- 1.52 ± 2.74; P = 0.03), cf-PWV increased (0.62 ± 1.06; P = 0.03), and CCA-IMT increased (0.35 ± 0.53; P = 0.02). No changes were observed in controls. CONCLUSION: Markers of vascular structure and function worsen in the post-transplant period on long-term follow-up, which may explain the continued high cardiovascular event rates in this population.

Assessing cardiovascular risk in chronic kidney disease patients prior to kidney transplantation: clinical usefulness of a standardised cardiovascular assessment protocol.

BACKGROUND: Despite pre-kidney-transplant cardiovascular (CV) assessment being routine care to minimise perioperative risk, the utility of such assessment is not well established. The study reviewed the evaluation and outcome of a standardised CV assessment protocol. METHODS: Data were analysed for 231 patients (age 53.4 ± 12.9 years, diabetes 34.6%) referred for kidney transplantation between 1/2/2012-31/12/2014. One hundred forty-three patients were high-risk (age > 60 years, diabetes, CV disease, heart failure, peripheral vascular disease) and offered dobutamine stress echocardiography (DSE); 88 patients were low-risk and offered ECG and echocardiography with/without exercise treadmill test. RESULTS: At the end of follow-up (579 ± 289 days), 35 patients underwent kidney transplantation and 50 were active on the waitlist. There were 24 events (CV or death), none were perioperative. One hundred fifteen patients had DSE with proportionally more events in DSE-positive compared to DSE-negative patients (6/34 vs. 7/81, p = 0.164). In 42 patients who underwent coronary angiography due to a positive DSE or ischaemic heart disease symptoms, 13 (31%) had events, 6 were suspended, 11 removed from waitlist, 3 wait-listed, 1 transplanted and 17 still undergoing assessment. Patients with significant coronary artery disease requiring intervention had poorer event-free survival compared to those without intervention (56% vs. 83% at 2 years, p = 0.044). However, the association became non-significant after correction for CV risk factors (HR = 3.17, 95% CI 0.51-19.59, p = 0.215). CONCLUSIONS: The stratified CV risk assessment protocol using DSE in all high-risk patients was effective in identifying patients with coronary artery disease. The coronary angiograms identified the event-prone patients effectively but coronary interventions were not associated with improved survival.

Risk factors profile of young and older patients with myocardial infarction.

Myocardial infarction (MI) among young adults (<45 years) represents a considerable proportion of the total heart attack incidents. The underlying pathophysiologic characteristics, atherosclerotic plaque features, and risk factors profile differ between young and older patients with MI. This review article discusses the main differences between the younger and elderly MI patients as well as the different pathogenic mechanisms underlying the development of MI in the younger. Young patients with MI often have eccentric atherosclerotic plaques with inflammatory features but fewer lesions, and are more likely to be smokers, obese, and have poor lifestyle, such as inactivity and alcohol intake. Compared to older MI patients, younger are more likely to be men, have familial-combined hyperlipidaemia and increased levels of lipoprotein-a. In addition, MI in younger patients may be related to use of cannabis, cocaine use, and androgenic anabolic steroids. Genomic differences especially in the pathways of coagulation and lipid metabolism have also been identified between young and older patients with MI. Better understanding of the risk factors and the anatomic and pathophysiologic processes in young adults can improve MI prevention and treatment strategies in this patient group. Awareness could help identify young subjects at increased risk and guide primary prevention strategies. Additional studies focusing on gene pathways related to lipid metabolism, inflammation, and coagulation are needed.

Finding acute coronary syndrome with serial troponin testing for rapid assessment of cardiac ischemic symptoms (FAST-TRAC): a study protocol.

OBJECTIVE: To determine the utility of a highly sensitive troponin assay when utilized in the emergency department. METHODS: The FAST-TRAC study prospectively enrolled >1,500 emergency department patients with suspected acute coronary syndrome within 6 hours of symptom onset and 2 hours of emergency department presentation. It has several unique features that are not found in the majority of studies evaluating troponin. These include a very early presenting population in whom prospective data collection of risk score parameters and the physician's clinical impression of the probability of acute coronary syndrome before any troponin data were available. Furthermore, two gold standard diagnostic definitions were determined by a pair of cardiologists reviewing two separate data sets; one that included all local troponin testing results and a second that excluded troponin testing so that diagnosis was based solely on clinical grounds. By this method, a statistically valid head-to-head comparison of contemporary and high sensitivity troponin testing is obtainable. Finally, because of a significant delay in sample processing, a unique ability to define the molecular stability of various troponin assays is possible. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00880802.

The association of air pollutants exposure with subclinical inflammation and carotid atherosclerosis.

BACKGROUND: Air pollution is a well-described environmental factor with evidence suggesting a firm association with cardiovascular diseases. The purpose of this study was to determine the association of exposure to gaseous air pollutants on atherosclerosis burden. METHODS: 1955 inhabitants of the Corinthia region, aged 40 years or older, underwent clinical and biochemical assessment as well as carotid ultrasonography to evaluate carotid intima-media thickness (cIMT) and plaque burden. Analyzers recording time series concentration of CO, NO2, and SO2 were located at 4 different open sites (Regions 1, 2, 3 and 4) based on their proximity to industries, highways or shipyards. RESULTS: A higher concentration of CO, NO2, and SO2 was observed in Region 4 compared to the other regions. Mean cIMT (Region 1: 0.93 ± 0.24 mm; Region 2: 0.96 ± 0.40 mm; Region 3: 0.94 ± 0.39 mm; Region 4: 1.14 ± 0.55 mm, p < 0.001), maximum cIMT (p < 0.001) as well as carotid plaque burden (Region 1: 13.3%; Region 2: 18.8%; Region 3: 22.4%; Region 4: 38.6%, p < 0.001) were significantly higher in individuals of Region 4. Inhabitants of Region 4 had also higher levels of C reactive protein (Region 1: 4.56 ± 4.85 mg/l; Region 2: 3.49 ± 4.46 mg/l; Region 3: 4.03 ± 3.32 mg/l, Region 4: 5.16 ± 8.26 mg/l, p < 0.001). Propensity score analysis revealed higher inter-area differences in mean cIMT of individuals with coronary artery disease (CAD) (high vs low air pollution area: 1.56 ± 0.80 mm; vs. 1.18 ± 0.54 mm, p < 0.001) while there was no difference in cIMT of the matched population without CAD (p = 0.52). CONCLUSIONS: An increased carotid atherosclerotic and inflammatory burden is observed in inhabitants of areas with the highest concentration of air pollutants.

Acute exposure to diesel affects inflammation and vascular function.

BACKGROUND: Diesel exhaust fumes represent one of the most common toxic pollutants. The prolonged effects of acute exposure to this pollutant on inflammatory status and vascular properties are unknown. METHODS: During a 2-h session, 40 healthy subjects were exposed to diesel exhaust fumes and/or filtered air. Endothelial function was assessed with flow mediated dilation, arterial stiffness with pulse wave velocity and reflected waves with augmentation index. C-reactive protein, fibrinogen, protein C levels and protein S activity were also measured. Standard deviation of normal to normal R-R intervals (SDNN) was used to assess heart rate variability. Measurements were assessed before exposure and 2 and 24 h after diesel exposure. RESULTS: Compared with filtered air, exposure to diesel exhaust fumes decreased flow mediated dilation and increased pulse wave velocity and augmentation index up to 24 h after the exposure (p < 0.001 for all). Similarly, compared with filtered air, diesel exhaust exposure impaired SDNN during the 24-h study period (p = 0.007). C-reactive protein and fibrinogen levels were significantly increased after diesel exhaust exposure while protein C levels and protein S activity decreased (p < 0.01 for all). Exposure to diesel exhaust fumes resulted in higher C-reactive protein concentration in smokers compared with non-smokers (p < 0.001). CONCLUSION: Short-term exposure to diesel exhaust fumes has a prolonged adverse impact on endothelial function and vascular wall properties, along with impaired heart rate variability, abnormal fibrinolytic activity and increased markers of inflammation. These findings give insights into the mechanisms underlining the increased cardiovascular risk of subjects regularly exposed to diesel exhaust fumes.

Melatonin and circadian biology in human cardiovascular disease.

Diurnal rhythms influence cardiovascular physiology, i.e. heart rate and blood pressure, and they appear to also modulate the incidence of serious adverse cardiac events. Diurnal variations occur also at the molecular level including changes in gene expression in the heart and blood vessels. Moreover, the risk/benefit ratio of some therapeutic strategies and the concentration of circulating cardiovascular system biomarkers may also vary across the 24-hr light/dark cycle. Synchrony between external and internal diurnal rhythms and harmony among molecular rhythms within the cell are essential for normal organ biology. Diurnal variations in the responsiveness of the cardiovascular system to environmental stimuli are mediated by a complex interplay between extracellular (i.e. neurohumoral factors) and intracellular (i.e. specific genes that are differentially light/dark regulated) mechanisms. Neurohormones, which are particularly relevant to the cardiovascular system, such as melatonin, exhibit a diurnal variation and may play a role in the synchronization of molecular circadian clocks in the peripheral tissue and the suprachiasmatic nucleus. Moreover, mounting evidence reveals that the blood melatonin rhythm has a crucial role in several cardiovascular functions, including daily variations in blood pressure. Melatonin has antioxidant, anti-inflammatory, chronobiotic and, possibly, epigenetic regulatory functions. This article reviews current knowledge related to the biological role of melatonin and its circadian rhythm in cardiovascular disease.

Differential pathways govern CD4+ CD28- T cell proinflammatory and effector responses in patients with coronary artery disease.

Patients with acute coronary syndromes experience circulatory and intraplaque expansion of an aggressive and unusual CD4(+) lymphocyte subpopulation lacking the CD28 receptor. These CD4(+)CD28(-) cells produce IFN-gamma and perforin, and are thought to play an important role in coronary atheromatous plaque destabilization. Aberrant expression of killer Ig-like receptors (KIRs) in CD4(+)CD28(-) cells is broadly thought to be responsible for their cytotoxicity, but the mechanisms involved remain poorly defined. We therefore sought to investigate the mechanism and regulation of CD4(+)CD28(-) cell functionality using T cell clones (n = 536) established from patients with coronary artery disease (n = 12) and healthy volunteers (n = 3). Our functional studies demonstrated that KIR2DS2 specifically interacted with MHC class I-presenting human heat shock protein 60 (hHSP60) inducing cytotoxicity. Further investigations revealed the novel finding that hHSP60 stimulation of TCR alone could not induce a cytotoxic response, and that this response was specific and KIR dependent. Analysis of CD4(+)CD28(-)2DS2(+) clones (n = 162) showed that not all were hHSP60 cytotoxic; albeit, their prevalence correlated with coronary disease status (p = 0.017). A higher proportion of clones responded to hHSP60 by IFN-gamma compared with perforin (p = 0.008). In this study, for the first time, we define the differential regulatory pathways involved in CD4(+)CD28(-) cell proinflammatory and effector responses. We describe in this study that, contrary to previous reports, CD4(+)CD28(-) cell recognition and killing can be specific and discriminate. These results, in addition to contributing to the understanding of CD4(+)CD28(-) cell functionality, may have implications for the monitoring and management of coronary artery disease progression.

Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease.

AIMS: To demonstrate that exposure to chronic inflammation results in coronary microvascular dysfunction (CMD). METHODS AND RESULTS: Using positron emission tomography, resting and hyperaemic (adenosine, 140 microg/kg/min) myocardial blood flow (MBF) was measured in 25 patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). Coronary flow reserve (CFR) was calculated as adenosine/resting MBF. Patients had normal or minimally diseased (i.e.

Assessment of carotid compliance using real time vascular ultrasound image analysis in Marfan syndrome.

BACKGROUND: Fibrillin-1 deficiency, dysregulated cytokine transforming growth factor-beta, and increased collagen deposition related to fibrillin-1 gene mutations could predispose to impaired carotid compliance (CC) in Marfan syndrome (MFS). We sought to detect any alterations in CC using the vascular image analysis system (VIA). METHODS AND RESULTS: Thirty-two MFS patients, 20 men and 12 women (mean age 34.2 +/- 12.05 years), and 29 controls matched for age, sex, and body surface area (BSA) were recruited. The entire length of each carotid system was initially scanned longitudinally using a 14 MHz linear transducer. Then, a stereotactic clamp held the transducer in contact with the carotid artery. Arterial diameter changes during the cardiac cycle were recorded for 1 minute from both right (RCCA) and left common carotid arteries (LCCA) separately using the VIA system. RCCA and LCCA compliance and distensibility measurements were significantly reduced in MFS patients when compared to controls, P < 0.05. RCCA and LCCA intima-media thickness did not differ between patients and controls, P > 0.05. MFS diagnosis and age were associated with reduced CC in both carotid arteries after adjusting for variables such as, sex, BSA, heart rate, beta-blockade, intima-media thickness, and aortic root size. CONCLUSIONS: Our findings showed a reduction in CC in adult patients with MFS. This could be attributed to fibrillin-1 deficiency resulting in structural abnormalities in the carotid arterial wall.

An improved synthesis of a cyclopropene-based molecule for the fabrication of bioengineered tissues via copper-free click chemistry.

BACKGROUND: Since its introduction in the field of biological imaging, the use of copper-free click chemistry has been extended to produce improved materials for vascular surgery, ophthalmology, environmental, and automotive applications. This wide applicability suggests that larger quantities of the chemical reagents for copper-free click chemistry will be required in the future. However, the large-scale synthesis of such chemicals has been barely investigated. A possible reason is the shortage of reliable synthetic protocols to obtain large quantities of these building blocks. We therefore present in this paper an improved synthetic protocol to obtain a cyclopropene-based carbonate, a key building block for the well-known copper-free click chemistry. METHOD: Our protocol builds upon an already available method to obtain a cyclopropene-based carbonate. When scaled up, several parameters of this method were changed in order to obtain an improved yield. First, the use of lower temperatures and slower addition rates of the chemicals avoided the formation of detrimental hotspots in the reaction system. Second, the use of less hygroscopic solvents minimized the decomposition of the cyclopropene carbonate. Finally, chromatographic purifications were minimized and improved by using deactivated silica. RESULTS: We obtained the compound (2-methylcycloprop-2-en-1-yl)methyl (4-nitrophenyl) carbonate, a key building block for copper-free click chemistry, in an unprecedented 60% overall yield on a six-gram scale. CONCLUSIONS: Our improved synthetic protocol demonstrates the potential of large-scale production of improved materials using click chemistry, with potential future applications in the fields of molecular imaging, vascular surgery, ophthalmology, and theranostics.

Vitamin D deficiency, endothelial function and bone biomarkers in post-kidney transplantation patients from North India.

PURPOSE: CKD patients after kidney transplantation continue to suffer from elevated CV events which may be related to low vitamin D and its adverse impact on vascular function. The prevalence of vitamin D deficiency in North Indian kidney transplantation patients and its impact on vascular and bone biomarkers is unknown which this study investigated. METHODS: Non-diabetic, stable, > 6 months post-kidney transplantation patients, not on vitamin D supplementation, were recruited after informed consent. Data on demographics, anthropometrics and treatment were collected. Blood samples were stored at - 80 °C until analysis for bone and endothelial cell biomarkers using standard ELISA techniques. RESULTS: The clinical characteristics were: age 37.4 ± 9.9 years, 80% men, 27% ex-smokers, BP 125.5 ± 15.7/78.6 ± 9.7 mmHg, cholesterol 172.0 ± 47.8 mg/dL, hemoglobin 12.6 ± 2.3 g/dL, calcium 9.5 ± 0.6 mg/d and iPTH 58.4 ± 32.9 ng/mL and vitamin D 36.5 ± 39.8 nmol/L. Patients with vitamin D < 37.5 nmol/L (66%) had similar age, serum creatinine, serum phosphate, iPTH, blood pressure but lower calcium (9.3 ± 0.7 vs. 9.6 ± 0.5 mg/dL; p = 0.024), lower FGF23 (median 18.8 vs. 80.0 pg/mL; p = 0.013) and higher E-selectin (15.8 ± 7.9 vs. 13.0 ± 5.5 ng/mL; p = 0.047). On Univariate analysis, E-selectin (r = - 0.292; p = 0.005), FGF23 (r = 0.217; p = 0.036) and calcium (r = 0.238; p = 0.022) were significantly correlated with vitamin D levels. On stepwise multiple regression analysis, only E-selectin was associated with vitamin D levels (ß = - 0.324; p = 0.002). CONCLUSION: Vitamin D deficiency was common in kidney transplant recipients in North India, associated with low FGF23 and high E-selectin. These findings suggest further investigations to assess the role of vitamin D deficiency-associated endothelial dysfunction, its implications and reversibility in kidney transplantation recipients.

Management of Tako-tsubo syndrome.

INTRODUCTION: This manuscript reviews the current evidence for proposed pathophysiological mechanisms of Tako-tsubo syndrome and its management. DISCUSSION: The Tako-tsubo syndrome is defined by the presence of transient left ventricular apical ballooning after an acute coronary syndrome in patients with angiographically normal coronary arteries. Intriguingly, only the apex is affected and compensatory basal hypercontractility is seen. Several mechanisms have been offered as explanations for the characteristic clinical presentation and echocardiographic appearance of this syndrome. CONCLUSION: Tako-tsubo syndrome encompasses heterogeneous patient populations and it is likely that different pathogenic mechanisms may operate in different patients. Treatment of the condition is at present empirical and aimed at preserving ventricular function.

Nordic walking for individuals with cardiovascular disease: A systematic review and meta-analysis of randomized controlled trials.

Background Exercise is the cornerstone of rehabilitation programmes for individuals with cardiovascular disease (IwCVD). Although conventional cardiovascular rehabilitation (CCVR) programmes have significant advantages, non-conventional activities such as Nordic walking (NW) may offer additional health benefits. Our aim was to appraise research evidence on the effects of Nordic walking for individuals with cardiovascular disease. Design Systematic review and meta-analysis. Methods A literature search of clinical databases (PubMed, MEDLINE, Scopus, Web of Science, Cochrane) was conducted to identify any randomized controlled trials, including: (i) individuals with cardiovascular disease, (ii) analyses of the main outcomes arising from Nordic walking (NW) programmes. Data from the common outcomes were extracted and pooled in the meta-analysis. Standardized mean differences (SMDs) were calculated and pooled by random effects models. Results Fifteen randomized controlled trials were included and eight trials entered this meta-analysis. Studies focused on coronary artery disease, peripheral arterial disease, heart failure and stroke. In coronary artery disease, significant differences between NW+CCVR and CCVR were found in exercise capacity (SMD: 0.49; p = 0.03) and dynamic balance (SMD: 0.55; p = 0.01) favouring NW+CCVR. In peripheral artery disease, larger changes in exercise duration (SMD: 0.93; p < 0.0001) and oxygen uptake (SMD: 0.64; p = 0.002) were observed following NW compared with controls. In heart failure, no significant differences were found between NW and CCVR or usual care for peak VO2 and functional mobility. In post-stroke survivors, functional mobility was significantly higher following treadmill programmes with poles rather than without (SMD: 0.80; p = 0.03). Conclusions These data portray NW as a feasible and promising activity for individuals with cardiovascular disease. Further studies are necessary to verify whether NW may be incorporated within CCVR for individuals with cardiovascular disease.

Contrast agents for cardiovascular magnetic resonance imaging: an overview.

Cardiovascular Magnetic Resonance (CMR), a non-invasive and nonionizing imaging technique, plays a major role in research and clinical cardiology. The strength of CMR lies in its high temporal resolution, superior contrast, and unique tissue characterization capabilities. Contrast agents have been used to improve sensitivity and specificity of CMR in detecting and evaluating various pathologies. Much effort has been made to develop more efficient contrast reagents to detect cardiovascular diseases at an asymptomatic stage, which has led to a plethora of products in animal studies. However, very few of the developed contrast agents are currently approved for human use. Major obstacles are high dosages, toxicity, body clearance rate and long-term immunogenicity. In this review, we critically assess recent developments in the field of the contrast agents for CMR, highlighting both benefits and current drawbacks. A clearer insight regarding the challenges facing the development of improved contrast agents may help collaborative work to enhance images contrast, decrease toxicity and accelerate their translation into clinical use.

Meta-analysis of ischemia-modified albumin to rule out acute coronary syndromes in the emergency department.

BACKGROUND: Because of possible adverse outcomes, many of the >6 million annual emergency department (ED) patients with suspected acute coronary syndromes (ACS) undergo extensive evaluations. To minimize medical errors, chest pain evaluations are structured to identify accurately nearly 100% of patients with ACS. This is at a cost of negative evaluation rates that can exceed 90%. Ischemia-modified albumin (IMA), a serum biomarker with a high negative predictive value (NPV) at ED presentation, may exclude ACS. Our objective was to perform a meta-analysis of IMA use for ACS risk stratification. METHODS: By computer literature search and communication with authors of unpublished information, all IMA data were considered. This analysis included studies if they reported IMA results from an ED presentation for suspected ACS. We defined a negative triple prediction test (TPT) as a nondiagnostic electrocardiogram, negative troponin, and negative IMA. RESULTS: Eight studies of >1800 patients met the entry criteria. The TPT sensitivity and NPV for acute ACS were 94.4% and 97.1% and, for longer-term outcomes, were 89.2% and 94.5%, respectively. CONCLUSIONS: A negative TPT of a nondiagnostic electrocardiogram, negative troponin, and negative IMA has a high NPV for excluding ACS in the ED.

Plaque stability and the southern European paradox.

Differences between European countries in coronary heart disease mortality were initially described in the 20th century, and albeit less dramatic than first reported, these differences remain substantial. Three main hypotheses have been proposed to explain the so-called "Mediterranean paradox": a) underestimation of coronary heart disease mortality due to methodological flaws; b) the "lag time" hypothesis, and c) the traditional Mediterranean diet and lifestyle. In this manuscript we present and discuss another possible explanation for the Mediterranean paradox related to the higher prevalence and and incidence of stable atheromatous plaques in this area.