Lack of evidence for pleiotropic effects of clopidogrel on endothelial function and inflammation in patients with stable coronary artery disease: results of the double-blind,randomized CASSANDRA study

Background  

Recently we have demonstrated a dose-dependent improvement of endothelial function after administration of a single loading dose of clopidogrel in patients with coronary artery disease (CAD). We therefore hypothesized that chronic therapy with clopidogrel may improve endothelial function in patients with CAD.     

Chronic protection against ischemia and reperfusion-induced endothelial dysfunction during therapy with different organic nitrates

Introduction

Ischemic and pharmacologic preconditioning have great clinical potential, but it remains unclear whether their effects can be maintained over time during repeated exposure.We have previously demonstrated that the acute protective effect of nitroglycerin (GTN) is attenuated during repeated daily administration. Pentaerythrityl tetranitrate (PETN) is an organic nitrate with different hemodynamic and biochemical properties. The purpose of the current experiment was to study the preconditioning-like effects of PETN and GTN during repeated daily exposure.

Methods and results

In a randomized, investigator-blind parallel trial, 30 healthy (age 25–32) volunteers were randomized to receive (1) transdermal GTN (0.6?mg/h) administered for 2?h a day for 6?days; (2) oral PETN (80?mg) once a day for 6?days; or (3) no therapy. One week later, endothelium-dependent flow-mediated dilation was assessed before and after exposure to ischemia and reperfusion (IR). IR caused a significant blunting of the endothelium-dependent relaxation in the control group (FMD before IR: 5.8?±?2.1%; after IR 1.0?±?2.1%; P?P?P?=?ns; P?P?Discussion We previously showed that upon repeated administration, the preconditioning-like effects of GTN are attenuated. The present data demonstrate a gradient in the extent of protection afforded by the two nitrates, suggesting that PETN-induced preconditioning is maintained after prolonged administration in a human in vivo model of endothelial dysfunction induced by ischemia. Using isolated human endothelial cells, we propose a mechanistic explanation for this observation based on differential effects of GTN versus PETN on the activity of mitochondrial aldehyde dehydrogenase.     

Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 levels are associated with proximal/middle segment of the LAD lesions in patients with stable coronary artery disease

Background/Objectives  

Atherosclerosis is the main underlying pathology of coronary artery disease (CAD), which is the leading cause of mortality worldwide. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved in multiple phases of vascular dysfunction, including endothelial dysfunction, atherosclerotic plaque formation, and destabilization. The purpose of the current study was to determine whether soluble LOX-1 is associated with proximal/mid and distal segment of the left anterior descending (LAD) artery lesion in patients with stable CAD.     

Effects of immunoadsorption on endothelial function,circulating endothelial progenitor cells and circulating microparticles in patients with inflammatory dilated cardiomyopathy

Background  

Immunoadsorption (IA) is used in patients with chronic inflammatory dilative cardiomyopathy (iDCM) to remove cardiotoxic autoantibodies, and to improve myocardial function. We examined the effects of IA on endothelial function, circulating endothelial progenitor cells, and circulating microparticles, including endothelial-derived microparticles, in patients with chronic iDCM.     

Coronary artery bypass surgery and longitudinal evaluation of the autonomic cardiovascular function

Introduction  

Imbalance in autonomic cardiovascular function increases the risk for sudden death in patients with coronary artery disease (CAD), but the time course of the impact of coronary artery bypass grafting (CABG) on autonomic function has been little studied. Thus, the purpose of the present study was to determine the effects of the CABG on the cardiovascular autonomic function.     

Telmisartan improves absolute walking distance and endothelial function in patients with peripheral artery disease

Background  

Peripheral artery disease (PAD) is associated with high cardiovascular mortality and a poor quality of life. The AT1-receptor blocker telmisartan has been shown to have pleiotropic effects and it may also improve endothelial function. The aim of this study was to analyze the effects of telmisartan on absolute walking distance (WD) and endothelial function in patients with PAD.     

Contribution of adiponectin polymorphisms to the risk of coronary artery disease in a North‐African Tunisian population

Background

Adiponectin, an adipocyte‐derived protein, is known to play a key role in the processes leading to atherosclerosis and coronary artery disease (CAD) through its anti‐atherogenic, anti‐inflammatory, antioxidative, and anti‐apoptotic properties. In the current study, we have studied the association of two single nucleotide polymorphisms (SNPs) +45 T>G (rs2241766) and +276 G>T (rs1501299) of the adiponectin gene with coronary artery disease (CAD) on an Arab/North‐African population from Tunisia.

Methods

Subjects comprised 277 patients with angiographically demonstrated CAD and 269 age‐ and gender‐matched control subjects. The adiponectin genotypes were performed by polymerase chain reaction‐restriction fragment length polymorphism analysis (PCR‐RFLP). The contribution of adiponectin variants to CAD was analyzed by haplotype and regression analysis.

Results

Adiponectin +45T>G and +276G>T genotypic and allelic distributions did not show a significant difference between cases and controls. Similarly, no association with CAD was observed for the haplotype analysis. Assuming dominant model of transmission for both polymorphisms and after adjustment of a number of traditional risk factors for CAD, logistic regression analysis showed an association of SNP +45 T>G with increased risk of developing CAD [adjusted OR (95% CI) = 2.59 (1.17‐5.70); P = .01]. However, SNP + 276 G>T is associated with decreased risk of developing CAD [adjusted OR (95% CI) = 0.47 (0.22‐0.97); P = .04].

Conclusion

There is no allelic or genotypic association of +45 T>G and +276 G>T of the adiponectin gene with CAD in the Tunisian population.

     

Acute and chronic effects of exercise on inflammatory markers and B-type natriuretic peptide in patients with coronary artery disease

Background  

Few studies have prospectively addressed the effects of exercise in the inflammatory activity of patients with coronary artery disease (CAD). We sought to evaluate the consequences of an acute bout of exercise on inflammatory markers and BNP in untrained CAD patients before and after randomization to a training program.     

Real-time three-dimensional echocardiography of left atrial volume and function in patients with severe multi-vessel coronary artery disease

Purpose

To evaluate the changes in left atrial (LA) volume and function in patients with severe multi-vessel coronary artery disease (CAD) by real-time three-dimensional echocardiography (RT-3DE).

Methods

One hundred and eight subjects were stratified based on coronary angiography (CAG) imaging, comprising 48 patients with severe multi-vessel CAD, 31 patients with severe single-vessel CAD, and 29 controls. RT-3DE was performed in all groups. LA volume parameters were measured. LA ejection fractions (EF) and LA function index (LAFI) were also calculated.

Results

There were no significant differences between the single-vessel CAD group and the control group, while LA passive emptying fraction (LAVpEF) was significantly reduced in the single-vessel CAD group. In the multi-vessel CAD group, LAVpEF and LAFI were lower, while LA presystolic volume (LAVpre) was prominently higher as compared with the other groups, and LA active emptying volume (LAVa) was higher than that in the control group (p < 0.05). Receiver-operating characteristic (ROC) analysis showed that the area under the curve (AUC) of LAVpEF was the largest parameter; the optimal cut-off value, AUC, sensitivity, and specificity were 0.50, 0.864, 93.7, and 72.4 %, respectively.

Conclusion

Specifically, conduit function reflects the early changes in LA function, and CAD damage is aggravated with increasing coronary lesions, whereas the booster pump function of severe multi-vessel CAD can increase in compensation. We speculate that LAVpEF may be the most ideal threshold for detecting and differentiating severe CAD patients from controls.

     

Multimodal cardiovascular magnetic resonance quantifies regional variation in vascular structure and function in patients with coronary artery disease: Relationships with coronary disease severity

Background

Cardiovascular magnetic resonance (CMR) of the vessel wall is highly reproducible and can evaluate both changes in plaque burden and composition. It can also measure aortic compliance and endothelial function in a single integrated examination. Previous studies have focused on patients with pre-identified carotid atheroma. We define these vascular parameters in patients presenting with coronary artery disease and test their relations to its extent and severity.

Methods and Results

100 patients with CAD [single-vessel (16%); two-vessel (39%); and three-vessel (42%) non-obstructed coronary arteries (3%)] were studied. CAD severity and extent was expressed as modified Gensini score (mean modified score 12.38 ± 5.3). A majority of carotid plaque was located in the carotid bulb (CB). Atherosclerosis in this most diseased segment correlated modestly with the severity and extent of CAD, as expressed by the modified Gensini score (R = 0.251, P < 0.05). Using the AHA plaque classification, atheroma class also associated with CAD severity (rho = 0.26, P < 0.05). The distal descending aorta contained the greatest plaque, which correlated with the degree of CAD (R = 0.222; P < 0.05), but with no correlation with the proximal descending aorta, which was relatively spared (R = 0.106; P = n. s.). Aortic distensibility varied along its length with the ascending aorta the least distensible segment. Brachial artery FMD was inversely correlated with modified Gensini score (R = -0.278; P < 0.05). In multivariate analysis, distal descending aorta atheroma burden, distensibility of the ascending aorta, carotid atheroma class and FMD were independent predictors of modified Gensini score.

Conclusions

Multimodal vascular CMR shows regional abnormalities of vascular structure and function that correlate modestly with the degree and extent of CAD.     

Impact of glucose and lipid markers on the correlation of calculated and enzymatic measured low‐density lipoprotein cholesterol in diabetic patients with coronary artery disease

Background and Aims

Low‐density lipoprotein cholesterol (LDL‐C) is widely estimated by Friedewald equation (FE) and Enzymatic test (ET), which are affected by several factors. The aim of this study was to observe the impact of diabetic lipid and glucose patterns on the correlation between FE LDL‐C (F‐LDL) and ET LDL‐C (E‐LDL) in patients with coronary artery disease (CAD).

Methods and Results

A total of 8155 CAD patients were consecutively enrolled and their lipid profiles were measured. The impacts of triglyceride (TG), glycosylated hemoglobin A1c (HbA1c), and high‐density lipoprotein cholesterol (HDL‐C) on the correlation of F‐LDL and E‐LDL were examined. The difference value (DV) between F‐LDL and E‐LDL was compared using ANOVA test. The CAD patients with DM were elder and had higher body mass index, plasma TG compared with those without DM (P < .05 separately). In the whole population, F‐LDL was lower than E‐LDL but showed a high correlation with E‐LDL (r = .970, P = .000). Moreover, as the TG concentrations increased, the DV increased accordingly but the correlation between F‐LDL and E‐LDL decreased (P < .01). The similar trend was also found in both DM and non‐DM patients comparing with different TG groups. However, in patients with DM, there was no significant difference of DV in different HbA1c groups or HDL‐C concentrations (P > .05).

Conclusion

Although F‐LDL might underestimate the value of LDL‐C, the correlation between F‐LDL and E‐LDL was clinically acceptable (r = .97), suggesting the LDL‐C values measured by two methods were similarly reliable in CAD patients with or without DM.

     

Impact of therapy with statins,beta-blockers and angiotensin-converting enzyme inhibitors on plasma myeloperoxidase in patients with coronary artery disease

Purpose  

The present study investigated whether therapy with statins, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors on admission affects the plasma level of myeloperoxidase (MPO) in patients with coronary artery disease (CAD).     

Carotid and brachial artery intima-media thickness is related to coronary atherosclerotic burden and may also represent high cardiovascular risk in patients with normal coronary angiograms

Background  

Carotid and brachial artery intima-media thicknesses (IMT) determined using B-mode ultrasonography are validated surrogate markers of the severity and extent of coronary artery disease (CAD). The markers may also reflect the general vascular atherosclerotic involvement and cardiovascular risk in patients with normal coronary arteries (NCA). We aimed to investigate the relationship of carotid artery IMT (CIMT) and brachial artery IMT (BIMT) with CAD simultaneously, and also examined whether both markers represent cardiovascular risk determined by cardiovascular risk factors in patients with NCA.     

Impact of pioglitazone on coronary endothelial function in non-diabetic patients with coronary artery disease

Objective  Pioglitazone has been shown to exert multiple antiatherosclerotic actions independent from its glycemic effects. We studied the hypothesis that pioglitazone improves coronary endothelial dysfunction in non-diabetic patients with coronary artery disease (CAD) in a randomized, placebo-controlled, double-blind trial. Methods  Fifty non-diabetic patients with CAD were randomized to 6 months treatment with pioglitazone 30 mg daily or placebo. Coronary endothelial function was tested at baseline and after 6 months with intracoronary infusion of adenosine, acetylcholine (0.072; 0.72; 7.2, and 36 μg/min), glyceroltrinitrate, and cold pressor test (CPT). The primary endpoint was the mean effect of treatment compared with placebo on acetylcholine-induced coronary vascular response for all acetylcholine dosages, based on percent change in luminal area measured by quantitative coronary angiography. Results  There was no difference in baseline coronary endothelial function. The primary endpoint was significantly different between the groups with a 1.8% ± 2.0% increase in luminal area between baseline and follow-up with pioglitazone and a 7.6% ± 2.4% decrease in the placebo group (P < 0.008). At follow-up, there was a trend for a difference in CPT (P = 0.057). No difference was observed regarding intracoronary glyceroltrinitrate or adenosine. Conclusions  Pioglitazone treatment in non-diabetic patients with CAD was associated with a significantly better coronary endothelial function compared to placebo.     

Circulating lncRNA IFNG‐AS1 expression correlates with increased disease risk,higher disease severity and elevated inflammation in patients with coronary artery disease

Background

This study aimed to investigate the associations of circulating long, non‐coding (lncRNA) IFNG‐AS1, lncRNA ANRIL and lncRNA ITSN1 relative expressions with disease risk, severity and inflammatory cytokines levels in coronary artery disease (CAD) patients.

Methods

One hundred and ninety‐one patients suspected of CAD who underwent coronary angiography were consecutively enrolled in this casecontrol study, and divided into CAD patients (N = 102) and controls (N = 89) according to coronary angiographic results. Blood samples of all participants were collected. Plasma lncRNA IFNG‐AS1, lncRNA ANRIL and lncRNA ITSN1 expressions were detected using quantitative polymerase chain reaction (qPCR). Serum tumor necrosis factor‐α (TNF‐α), interleukin (IL)‐1β (IL‐1β), IL‐6, IL‐8, IL‐10, and IL‐17 were assessed using enzyme‐linked immunosorbent assay (ELISA). Gensini Score was used to evaluate the disease severity of CAD patients.

Results

LncRNA IFNG‐AS1 relative expression in CAD patients was upregulated compared with that in controls (P < .001), and the receiver operating characteristic (ROC) curve showed that the area under curve (AUC) of lncRNA‐IFNG‐AS1 for predicting the risk of CAD was 0.755 (95% CI: 0.688‐0.821). lncRNA IFNG‐AS1 relative expression was remarkably associated with Gensini Score (r = .259, P = .009). Additionally, lncRNA IFNG‐AS1 relative expression was positively associated with high‐sensitivity C‐reactive protein (hs‐CRP) (r = .283, P = .004), TNF‐α (r = .269, P = .006), and IL‐6 levels (r = .425, P < .001), while it was negatively correlated with IL‐10 level (r = −.263, P = .008). lncRNA ANRIL or lncRNA ITSN1 was not correlated with CA D risk, Gensini Score, hs‐CRP, ESR, TNF‐α, IL‐1β, IL‐6, IL‐8, IL‐10, or IL‐17 levels (all P > .05).

Conclusion

Circulating lncRNA IFNG‐AS1 expression correlates with increased disease risk, higher disease severity and elevated inflammation in CAD patients.

     

Severe endothelial injury and subsequent repair in patients after successful cardiopulmonary resuscitation

Introduction  

Ischemia and reperfusion after cardiopulmonary resuscitation (CPR) induce endothelial activation and systemic inflammatory response, resulting in post-resuscitation disease. In this study we analyzed direct markers of endothelial injury, circulating endothelial cells (CECs) and endothelial microparticles (EMPs), and endothelial progenitor cells (EPCs) as a marker of endothelial repair in patients after CPR.     

E‐selectin gene in essential hypertension: a case‐control study

Background

Hypertension is associated with endothelial cell dysfunction. E‐selectin, an endothelial cell adhesion molecule, is specific for endothelial cell activation. Polymorphism in E‐selectin gene has recently been identified among which Leu554Phe E‐selectin gene polymorphism is least investigated in essential hypertension. This study reports the association of E‐selectin gene Leu554Phe polymorphism and the expression of E‐selectin gene in patients with essential hypertension.

Materials and methods

We analysed the Leu554Phe polymorphism and expression of E‐selectin gene in 250 patients with essential hypertension and 250 normal healthy controls. Genotyping of Leu554Phe polymorphism was performed by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP), and the expression of E‐selectin gene at mRNA and protein levels were carried out by real‐time PCR and Western blot, respectively.

Results

A significant association of E‐selectin genotypes (CT + TT) with essential hypertension (P < .0001, Odds ratio = 2.2 [1.58‐3.24] at 95% CI) was observed. The expression of mRNA for E‐selectin gene in patients with essential hypertension was ~12‐fold higher as compared to control. We observed an elevated level of E‐selectin protein expression (up to 1.9 times) in patients as compared to controls.

Conclusions

A significant association of E‐selectin (Leu554Phe) gene and increased expression of E‐selectin gene at mRNA and protein levels in patients might be related to the genetic predisposition to develop essential hypertension.     

Lipoprotein(a) level associates with coronary artery disease rather than carotid lesions in patients with familial hypercholesterolemia

Background

Lipoprotein(a) [Lp(a)] level is a novel risk factor for atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia (FH), while its impact on the different sites of arteries remains undetermined. We aim to examine the associations of Lp(a) levels with coronary and carotid atherosclerosis in patients with heterozygous FH (HeFH).

Methods

A total of 148 patients with HeFH who have received carotid ultrasonography and coronary angiography due to chest pain were enrolled. Plasma Lp(a) was measured using immunoturbidimetric method. Finally, the associations between Lp(a) and coronary as well as carotid lesions were evaluated.

Results

Patients with Lp(a) ≥ 300 mg/L had similar carotid intima‐media thickness (IMT, 0.782 ± 0.16 mm vs 0.798 ± 0.18 mm, P = .579) and plaque prevalence (66.7% vs 65%, P = .833) compared to those with Lp(a) < 300 mg/L, but had a higher prevalence of coronary artery disease (CAD, 69.7% vs 50.0%, P = .016) and higher Gensini score (GS, median 27 vs 3, P = .006). Moreover, no correlations were found between carotid mean IMT with either Lp(a) level or Lp(a) year score, while positive relation of Lp(a) with GS did. Multivariate regression analysis revealed that Lp(a), Lp(a) year score, and Lp(a) ≥ 300 g/L were all independent predictors for the presence of CAD (OR = 4.99, P = .007; OR = 4.73, P = .009; OR = 4.46, P = .006, respectively) but not for carotid plaques.

Conclusions

This study suggested that Lp(a) level was associated with the presence and severity of CAD but not with carotid atherosclerosis in patients with HeFH.

     

Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis

Background  

We conducted a meta-analysis of observational studies which examined the association between flow-mediated dilatation (FMD) of brachial artery, a noninvasive measure of endothelial function, and future cardiovascular events.     

Emergency endoscopy for upper gastrointestinal bleeding in patients with coronary artery disease

Background

Endoscopy is useful for diagnosis and treatment of upper gastrointestinal bleeding (UGIB). However, both endoscopy and UGIB may compromise the cardiovascular function. The present study is to investigate the cardiovascular responses of emergency endoscopy for patients with UGIB and stable coronary artery disease (CAD).

Methods

Consecutive 50 patients with known CAD and 50 patients without CAD history (non-CAD group) in whom emergency endoscopy was requested for UGIB were prospectively enrolled. All patients received ambulatory electrocardiographic monitoring before, during, and after endoscopies. Cardiac indices including supraventricular and ventricular arrhythmia, ST ischemic change, and autonomic nervous function evaluated by heart rate variability were compared.

Results

All patients in both groups had successful primary hemostasis, and peptic ulcer bleeding was the main etiology (82%). Compared with the non-CAD group, patients with CAD had a significantly higher incidence (42% vs 16%, P = .004) and frequency (1.19 vs 0.12 events per minute, P = .003) of ventricular arrhythmias during endoscopy. Nine patients with CAD and 1 patient without CAD had ischemic ST changes (P = .016). Comorbidity with congestive heart failure was not only associated with a higher frequency (P = .02) but also a more severe fluctuation (P = .002) of ventricular arrhythmia. None in both groups had angina or MI before, during, or after endoscopy. Heart rate variability did not show a difference.

Conclusions

Ventricular arrhythmias and myocardial ischemia, although mostly subclinical, were common in patients with stable CAD undergoing emergent endoscopy for UGIB, especially in those with concomitant congestive heart failure.