Unique Antibody Responses to Malondialdehyde-Acetaldehyde (MAA)-Protein Adducts Predict Coronary Artery Disease

Malondialdehyde-acetaldehyde adducts (MAA) have been implicated in atherosclerosis. The purpose of this study was to investigate the role of MAA in atherosclerotic disease. Serum samples from controls (n = 82) and patients with; non-obstructive coronary artery disease (CAD), (n = 40), acute myocardial infarction (AMI) (n = 42), or coronary artery bypass graft (CABG) surgery due to obstructive multi-vessel CAD (n = 72), were collected and tested for antibody isotypes to MAA-modifed human serum albumin (MAA-HSA). CAD patients had elevated relative levels of IgG and IgA anti-MAA, compared to control patients (p<0.001). AMI patients had a significantly increased relative levels of circulating IgG anti-MAA-HSA antibodies as compared to stable angina (p<0.03) or CABG patients (p<0.003). CABG patients had significantly increased relative levels of circulating IgA anti-MAA-HSA antibodies as compared to non-obstructive CAD (p<0.001) and AMI patients (p<0.001). Additionally, MAA-modified proteins were detected in the tissue of human AMI lesions. In conclusion, the IgM, IgG and IgA anti-MAA-HSA antibody isotypes are differentially and significantly associated with non-obstructive CAD, AMI, or obstructive multi-vessel CAD and may serve as biomarkers of atherosclerotic disease.     

Epicardial Adipose Tissue Thickness Correlates with the Presence and Severity of Angiographic Coronary Artery Disease in Stable Patients with Chest Pain

Objective

Epicardial adipose tissue (EAT) is suggested to correlate with metabolic risk factors and to promote plaque development in the coronary arteries. We sought to determine whether EAT thickness was associated or not with the presence and extent of angiographic coronary artery disease (CAD).

Methods

We measured epicardial fat thickness by computed tomography and assessed the presence and extent of CAD by coronary angiography in participants from the prospective EVASCAN study. The association of EAT thickness with cardiovascular risk factors, coronary artery calcification scoring and angiographic CAD was assessed using multivariate regression analysis.

Results

Of 970 patients (age 60.9 years, 71% male), 75% (n = 731) had CAD. Patients with angiographic CAD had thicker EAT on the left ventricle lateral wall when compared with patients without CAD (2.74±2.4 mm vs. 2.08±2.1 mm; p = 0.0001). The adjusted odds ratio (OR) for a patient with a LVLW EAT value ≥2.8 mm to have CAD was OR = 1.46 [1.03–2.08], p = 0.0326 after adjusting for risk factors. EAT also correlated with the number of diseased vessels (p = 0.0001 for trend). By receiver operating characteristic curve analysis, an EAT value ≥2.8 mm best predicted the presence of>50% diameter coronary artery stenosis, with a sensitivity and specificity of 46.1% and 66.5% respectively (AUC:0.58). Coronary artery calcium scoring had an AUC of 0.76.

Conclusion

Although left ventricle lateral wall EAT thickness correlated with the presence and extent of angiographic CAD, it has a low performance for the diagnosis of CAD.     

The Relationship between the Severity of Coronary Artery Disease and Epicardial Adipose Tissue Depends on The Left Ventricular Function

Background

Epicardial adipose tissue (EAT) is an active metabolic and endocrine organ. Previous studies focusing mainly on patients with preserved left ventricular function (LVF) could show a correlation between increased amounts of EAT and the extent and activity of coronary artery disease (CAD). However, to date, there are no data available about the relationship between EAT and the severity of CAD with respect to the whole spectrum of LVF impairment. Therefore, we evaluated this relationship in patients with CAD.

Methods

250 patients with CAD and 50 healthy controls underwent CMR examination to assess EAT. The severity of CAD was defined using the angiographic Gensini score (GSS).

Results

The GSS ranged from 2–364. Linear regression analysis revealed a significant correlation between EAT and GSS (r = 0.177, p = 0.01). Patients with mild (GSS≤10) and moderate CAD (GSS>10−≤40) showed comparable EAT to healthy controls. However, in patients with severe CAD (GSS>40) EAT was significantly reduced (p<0.0001) compared to healthy controls. Interestingly, patients with the same GSS revealed different EAT depending on the left ventricular function (LVF). Patients with preserved LVF (LVF≥50%) showed more EAT mass compared to those with reduced LVF (LVF<50%) regardless of the GSS. In patients with preserved LVF and mild CAD, EAT was comparable to healthy controls (61.8±19.4 g vs. 62.9±14.4 g, p = 0.8). In patients with moderate CAD, EAT rose significantly to 83.1±24.9 g (p = 0.01) and started to decline to 66.4±23.6 g in patients with severe CAD (p = 0.03). Contrary, in CAD patients with reduced LVF, EAT was already significantly reduced in patients with mild CAD as compared to healthy controls (p = 0.001) and showed a stepwise decline with increasing CAD severity.

Conclusion

The relationship between EAT and the severity of CAD depends on LVF. These findings emphasize the multifactorial interaction between EAT and the severity of CAD.     

The Relationship between Endothelial Progenitor Cell Populations and Epicardial and Microvascular Coronary Disease—A Cellular,Angiographic and Physiologic Study

Background

Endothelial progenitor cells (EPCs) are implicated in protection against vascular disease. However, studies using angiography alone have reported conflicting results when relating EPCs to epicardial coronary artery disease (CAD) severity. Moreover, the relationship between different EPC types and the coronary microcirculation is unknown. We therefore investigated the relationship between EPC populations and coronary epicardial and microvascular disease.

Methods

Thirty-three patients with a spectrum of isolated left anterior descending artery disease were studied. The coronary epicardial and microcirculation were physiologically interrogated by measurement of fractional flow reserve (FFR), index of microvascular resistance (IMR) and coronary flow reserve (CFR). Two distinct EPC populations (early EPC and late outgrowth endothelial cells [OECs]) were isolated from these patients and studied ex vivo.

Results

There was a significant inverse relationship between circulating OEC levels and epicardial CAD severity, as assessed by FFR and angiography (r = 0.371, p = 0.04; r = -0.358, p = 0.04; respectively). More severe epicardial CAD was associated with impaired OEC migration and tubulogenesis (r = 0.59, p = 0.005; r = 0.589, p = 0.004; respectively). Patients with significant epicardial CAD (FFR<0.75) had lower OEC levels and function compared to those without hemodynamically significant stenoses (p<0.05). In contrast, no such relationship was seen for early EPC number and function, nor was there a relationship between IMR and EPCs. There was a significant relationship between CFR and OEC function.

Conclusions

EPC populations differ in regards to their associations with CAD severity. The number and function of OECs, but not early EPCs, correlated significantly with epicardial CAD severity. There was no relationship between EPCs and severity of coronary microvascular disease.     

Coronary Collateral Circulation in Patients of Coronary Ectasia with Significant Coronary Artery Disease

Objectives

Patients with coronary ectasia (CE) usually have coexisting coronary stenosis resulting in myoischemia. Coronary collateral plays an important role in protecting myocardium from ischemia and reducing cardiovascular events. However, limited studies investigate the role of CE in coronary collaterals development.

Methods

We evaluated 1020 consecutive patients undergoing coronary angiography and 552 patients with significant coronary artery disease (SCAD), defined as diameter stenosis more than 70%, were finally analyzed. CE is defined as the ectatic diameter 1.5 times larger than adjacent reference segment. Rentrop collateral score was used to classify patients into poor (grades 0 and 1) or good (grades 2 and 3) collateral group.

Results

73 patients (13.2%) had CE lesions which were most located in the right coronary artery (53.4%). Patients with CE had a lower incidence of diabetes (43.8% vs 30.1%, p = 0.03), higher body mass index (25.4±3.5 vs 26.7±4.6, p = 0.027) and poorer coronary collateral (58.2% vs 71.2%, p = 0.040). Patients with poor collateral (n = 331) had a higher incidence of CE (15.7% vs 9.5%, p = 0.040) and fewer diseased vessels numbers (1.96±0.84 vs 2.48±0.69, p<0.001). Multivariate analysis showed diabetes (odd ratio (OR) 0.630, p = 0.026), CE (OR = 0.544, p = 0.048), and number of diseased vessels (OR = 2.488, p<0.001) were significant predictors of coronary collaterals development.

Conclusion

The presence of CE was associated with poorer coronary collateral development in patients with SCAD.     

Validation of a Novel Clinical Prediction Score for Severe Coronary Artery Diseases before Elective Coronary Angiography

Objectives

Coronary artery disease (CAD) severity is associated with patient prognosis. However, few efficient scoring systems have been developed to screen severe CAD in patients with stable angina and suspected CAD before coronary angiography. Here, we present a novel scoring system for CAD severity before elective coronary angiography.

Methods

Five hundred fifty-one patients with stable angina who were admitted for coronary angiography were enrolled in this study. Patients were divided into training (n = 347) and validation (n = 204) cohorts. Severe CAD was defined as having a Gensini score of 20 or more. All patients underwent echocardiography (ECG) to detect ejection fraction and aortic valve calcification (AVC). Multivariable analysis was applied to determine independent risk factors and develop the scoring system.

Results

In the training cohort, age, male sex, AVC, abnormal ECG, diabetes, hyperlipidemia, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were identified as independent factors for severe CAD by multivariable analysis, and the Severe Prediction Scoring (SPS) system was developed. C-indices of receiver operating characteristic (ROC) curves for severe CAD were 0.744 and 0.710 in the training and validation groups, respectively. The SPS system also performed well during calibration, as demonstrated by Hosmer-Lemeshow analysis in the validation group. Compared with the Diamond-Forrester score, the SPS system performed better for severe CAD prediction before elective coronary angiography.

Conclusions

Severe CAD prediction was achieved by analyzing age, sex, AVC, ECG, diabetes status, and lipid levels. Angina patients who achieve high scores using this predicting system should undergo early coronary angiography.     

Progression of Kidney Disease in Non-Diabetic Patients with Coronary Artery Disease: Predictive Role of Circulating Matrix Metalloproteinase-2, -3, and -9

Background

Circulating matrix metalloproteinase (MMP)-2, -3 and -9 are well recognized in predicting cardiovascular outcome in coronary artery disease (CAD), but their risks for chronic kidney disease (CKD) are lacking. Therefore, the present study aimed to investigate whether circulating MMP levels could independently predict future kidney disease progression in non-diabetic CAD patients.

Methods

The prospective study enrolled 251 non-diabetic subjects referred for coronary angiography, containing normal coronary artery (n = 30) and CAD with insignificant (n = 95) and significant (n = 126) stenosis. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI formula. eGFR decline rate was calculated and the primary endpoint was a decline in eGFR over 25% from baseline.

Results

The eGFR decline rate (ml/min/1.73 m² per year) in patients with CAD (1.22 [−1.27, 1.05]) was greater than that in those with normal coronary artery (0.21 [−2.63, 0.47], P<0.01). The circulating MMP-2, -3 and -9 were independently associated with faster eGFR decline among CAD patients. The mean follow-up period was 8.5±2.4 years, and 39 patients reached the primary endpoint. In multivariate Cox regression model, the adjusted hazard ratios of MMP-2 ≥861 ng/mL, MMP-3 ≥227 ng/mL and MMP-9 ≥49 ng/mL for predicting CKD progression were 2.47 (95% CI, 1.21 to 5.07), 2.15 (1.12 to 4.18), and 4.71 (2.14 to 10.4), respectively. While added to a model of conventional risk factors and baseline eGFR, MMP-2, -3 and -9 further significantly improved the model predictability for CKD progression (c statistic, 0.817). In the sensitivity analyses, the results were similar no matter if we changed the endpoints of a decline of >20% in eGFR from baseline or final eGFR < 60 mL/min/1.73 m².

Conclusion

Circulating MMP-2, -3 and -9 are independently associated with kidney disease progression in non-diabetic CAD patients and add incremental predictive power to conventional risk factors.     

Association of Serum Uric Acid and Coronary Artery Disease in Premenopausal Women

Objective

To date, no study in the published literature has investigated the role of various serum uric acid (SUA) concentrations in the development of angiographically-proven coronary artery disease (CAD) in premenopausal women. Therefore, the aim of this study was to investigate the role SUA levels may play in the prevalence, severity, and prognosis of CAD in premenopausal women.

Methods

This cross-sectional retrospective study included 607 premenopausal women who had undergone coronary angiography. The CAD diagnosis was based upon stenosis affecting ≥50% of the luminal diameter. Association of the SUA levels with CAD prevalence, severity, and clinical outcomes were assessed by statistical analysis.

Results

In total, 369 (60.8%) of the patients were diagnosed with CAD. The CAD patients had significantly higher SUA levels than those without CAD (5.3±1.9 vs. 4.8±1.7 mg/dL, P = 0.001). The SUA levels were found to be significantly associated with CAD prevalence (P = 0.013). Patients with higher levels of SUA also showed increased rates of multivessel disease and composite end-points, such as major adverse cardiac events. Furthermore, multivariate analysis identified abnormally high levels of uric acid (hyperuricemia) as an independent risk factor for CAD (OR 1.51 (1.11–2.53), P<0.05).

Conclusions

The SUA levels are significantly associated with the prevalence of CAD. The SUA levels may be a predictor for incidence of major cardiovascular events in premenopausal women.     

Impact of Coexisting Coronary Artery Disease on the Occurrence of Cerebral Ischemic Lesions after Carotid Stenting

Background

Coronary artery disease (CAD) may coexist with extracranial carotid artery stenosis (ECAS), but the influence of CAD on procedure-related complications after carotid artery stenting (CAS) has not been well investigated. The study aimed to determine the impact of CAD on the occurrence of peri-CAS cerebral ischemic lesions on diffusion-weighted imaging (DWI) scanning.

Methods

Coronary angiography was performed within six months before CAS. DWI scanning was repetitively done within 1 week before and after CAS. Clinical outcome measures were stroke, angina, myocardial infarction and death within 30 days.

Results

Among 126 patients (69.5±9.0 years) recruited for unilateral protected CAS, 33 (26%) patients had peri-CAS DWI-positive lesions. CAD was noted in 79% (26 in 33) and 48% (45 in 93) of patients with and without peri-CAS DWI-positive lesions (OR, 4.0; 95% CI, 1.6–10.0; P = .0018), and the number of concomitant CAD on coronary angiography was positively correlated with the risk for peri-CAS DWI-positive lesions (P = .0032). In patients with no CAD (n = 55), asymptomatic CAD (n = 41) and symptomatic CAD (n = 30), the occurrence rates of peri-CAS DWI-positive lesions were 13%, 41% and 30% (P = .0048), and the peri-CAS stroke rates were 2%, 7% and 0% (P = .2120).

Conclusions

The severity of morphological CAD and the presence of either symptomatic or asymptomatic CAD are associated with the occurrence of peri-CAS cerebral ischemic lesions.     

Neutrophil/Lymphocyte Ratio Is Associated with Non-Calcified Plaque Burden in Patients with Coronary Artery Disease

Background

Elevations in soluble markers of inflammation and changes in leukocyte subset distribution are frequently reported in patients with coronary artery disease (CAD). Lately, the neutrophil/lymphocyte ratio has emerged as a potential marker of both CAD severity and cardiovascular prognosis.

Objectives

The aim of the study was to investigate whether neutrophil/lymphocyte ratio and other immune-inflammatory markers were related to plaque burden, as assessed by coronary computed tomography angiography (CCTA), in patients with CAD.

Methods

Twenty patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) and 30 patients with stable angina (SA) underwent CCTA at two occasions, immediately prior to coronary angiography and after three months. Atherosclerotic plaques were classified as calcified, mixed and non-calcified. Blood samples were drawn at both occasions. Leukocyte subsets were analyzed by white blood cell differential counts and flow cytometry. Levels of C-reactive protein (CRP) and interleukin(IL)-6 were measured in plasma. Blood analyses were also performed in 37 healthy controls.

Results

Plaque variables did not change over 3 months, total plaque burden being similar in NSTE-ACS and SA. However, non-calcified/total plaque ratio was higher in NSTE-ACS, 0.25(0.09–0.44) vs 0.11(0.00–0.25), p<0.05. At admission, levels of monocytes, neutrophils, neutrophil/lymphocyte ratios, CD4+ T cells, CRP and IL-6 were significantly elevated, while levels of NK cells were reduced, in both patient groups as compared to controls. After 3 months, levels of monocytes, neutrophils, neutrophil/lymphocyte ratios and CD4+ T cells remained elevated in patients. Neutrophil/lymphocyte ratios and neutrophil counts correlated significantly with numbers of non-calcified plaques and also with non-calcified/total plaque ratio (r = 0.403, p = 0.010 and r = 0.382, p = 0.024, respectively), but not with total plaque burden.

Conclusions

Among immune-inflammatory markers in NSTE-ACS and SA patients, neutrophil counts and neutrophil/lymphocyte ratios were significantly correlated with non-calcified plaques. Data suggest that these easily measured biomarkers reflect the burden of vulnerable plaques in CAD.     

When Do We Really Need Coronary Calcium Scoring Prior to Contrast-Enhanced Coronary Computed Tomography Angiography? Analysis by Age,Gender and Coronary Risk Factors

Aims

To investigate the value of coronary calcium scoring (CCS) as a filter scan prior to coronary computed tomography angiography (CCTA).

Methods and Results

Between February 2008 and April 2011, 732 consecutive patients underwent clinically indicated CCTA. During this ‘control phase’, CCS was performed in all patients. In patients with CCS≥800, CCTA was not performed. During a subsequent ‘CCTA phase’ (May 2011–May 2012) another 200 consecutive patients underwent CCTA, and CCS was performed only in patients with increased probability for severe calcification according to age, gender and atherogenic risk factors. In patients where CCS was not performed, calcium scoring was performed in contrast-enhanced CCTA images. Significant associations were noted between CCS and age (r = 0.30, p<0.001) and coronary risk factors (χ² = 37.9; HR = 2.2; 95%CI = 1.7–2.9, p<0.001). Based on these associations, a ≤3% pre-test probability for CCS≥800 was observed for males <61 yrs. and females <79 yrs. According to these criteria, CCS was not performed in 106 of 200 (53%) patients during the ‘CCTA phase’, including 47 (42%) males and 59 (67%) females. This resulted in absolute radiation saving of ∼1 mSv in 75% of patients younger than 60 yrs. Of 106 patients where CCS was not performed, estimated calcium scoring was indeed <800 in 101 (95%) cases. Non-diagnostic image quality due to calcification was similar between the ‘control phase’ and the ‘CCTA’ group (0.25% versus 0.40%, p = NS).

Conclusion

The value of CCS as a filter for identification of a high calcium score is limited in younger patients with intermediate risk profile. Omitting CCS in such patients can contribute to further dose reduction with cardiac CT studies.     

The Association of Brachial-Ankle Pulse Wave Velocity with Coronary Artery Disease Evaluated by Coronary Computed Tomography Angiography

The aim of this study was to investigate whether brachial-ankle pulse wave velocity (baPWV) is associated with the severity of coronary artery disease (CAD) assessed by coronary computed tomography angiography (CCTA), and to evaluate baPWV as a predictor of obstructive CAD on CCTA. A total of 470 patients who underwent both baPWV and CCTA were included. We evaluated stenosis degree and plaque characteristics on CCTA. To estimate the severity of CAD, we calculated the number of segment with plaque (segment involvement score; SIS), stenosis degree-weighted plaque score (segment stenosis score; SSS), and coronary artery calcium score (CACS). The mean baPWV was 1,485 ± 315 cm/s (range, 935-3,175 cm/s). Non-obstructive (stenosis < 50%) and obstructive (stenosis ≥ 50%) CAD was found in 129 patients (27.4%) and 144 (30.6%), respectively. baPWV in patients with obstructive CAD was higher than that of patients with non-obstructive (1,680 ± 396 cm/s versus 1,477 ± 244 cm/s, P < 0.001) or no CAD (1,680 ± 396 cm/s versus ± 196 1,389 cm/s, P < 0.001). baPWV showed significant correlation with SSS (r = 0.429, P < 0.001), SIS (r = 0.395, P < 0.001), CACS (r 0.346, P < 0.001), and the number of segment with non-calcified plaque (r 0.092, P = 0.047), mixed plaque (r = 0.267, P < 0.001), and calcified plaque (r = 0.348, P < 0.001), respectively. The optimal baPWV cut-off value for the detection of obstructive CAD was 1,547 cm/s. baPWV ≥ 1,547 cm/s was independent predictor for the obstructive CAD. In conclusion, baPWV is well correlated with the severity of CAD evaluated by CCTA. baPWV has the potential to predict severity of coronary artery atherosclerosis.     

Effects of T-Type Calcium Channel Blockers on Renal Function and Aldosterone in Patients with Hypertension: A Systematic Review and Meta-Analysis

Background

High blood pressure can cause kidney damage, which can increase blood pressure, leading to a vicious cycle. It is not clear whether the protective effects of T-type calcium channel blockers (T-type CCBs) on renal function are better than those of L-type CCBs or renin-angiotensin system (RAS) antagonists in patients with hypertension.

Methods and Findings

PUBMED, MEDLINE, EMBASE, OVID, Web of Science, Cochrane, CNKI, MEDCH, VIP, and WANFANG databases were searched for clinical trials published in English or Chinese from January 1, 1990, to December 31, 2013. The weighted mean difference (WMD) and 95% confidence interval (CI) were calculated and reported. A total of 1494 reports were collected, of which 24 studies with 1,696 participants (including 809 reports comparing T-type CCBs versus L-type CCBs and 887 reports comparing T-type CCB versus RAS antagonists) met the inclusion criteria. Compared with L-type CCBs, T-type CCBs resulted in a significant decline in aldosterone (mean difference = −15.19, 95% CI −19.65–−10.72, p<1×10⁻⁵), proteinuria (mean difference = −0.73, 95% CI −0.88–−0.57, p<1×10⁻⁵), protein to creatinine ratio (mean difference = −0.22, 95% CI −0.41–−0.03, p = 0.02), and urinary albumin to creatinine ratio (mean difference = −55.38, 95% CI −86.67–−24.09, p = 0.0005); no significant difference was noted for systolic blood pressure (SBP) (p = 0.76) and diastolic blood pressure (DBP) (p = 0.16). The effects of T-type CCBs did not significantly differ from those of RAS antagonists for SBP (p = 0.98), DBP (p = 0.86), glomerular filtration rate (p = 0.93), albuminuria (p = 0.97), creatinine clearance rate (p = 0.24), and serum creatinine (p = 0.27) in patients with hypertension.

Conclusion

In a pooled analysis of data from 24 studies measuring the effects of T-type CCBs on renal function and aldosterone, the protective effects of T-type CCBs on renal function were enhanced compared with L-type CCBs but did not differ from RAS antagonists. Their protective effects on renal function were independent of blood pressure.     

Methylation of p15INK4b and Expression of ANRIL on Chromosome 9p21 Are Associated with Coronary Artery Disease

Background

Genome-wide association studies have identified that multiple single nucleiotide polymorphisms on chromosome 9p21 are tightly associated with coronary artery disease (CAD). However, the mechanism linking this risk locus to CAD remains unclear.

Methodology/Principal Findings

The methylation status of six candidate genes (BAX, BCL-2, TIMP3, p14^ARF, p15^INK4b and p16^INK4a) in 205 patients and controls who underwent coronary angiography were analyzed by quantitative MethyLight assay. Rs10757274 was genotyped and expression of INK4/ARF and antisense non-coding RNA in the INK4 locus (ANRIL) was determined by real-time RT-PCR. Compared with controls, DNA methylation levels at p15^INK4b significantly increased in CAD patients (p = 0.006). To validate and dissect the methylation percentage of each target CpG site at p15^INK4b, pyrosequencing was performed, finding CpG +314 and +332 remarkably hypermethylated in CAD patients. Further investigation determined that p15^INK4b hypermethylation prevalently emerged in lymphocytes of CAD patients (p = 0.013). The rs10757274 genotype was significantly associated with CAD (p = 0.003) and GG genotype carriers had a higher level of ANRIL exon 1–5 expression compared among three genotypes (p = 0.009). There was a stepwise increase in p15^INK4b and p16^INK4a methylation as ANRIL exon 1–5 expression elevated (r = 0.23, p = 0.001 and r = 0.24, p = 0.001, respectively), although neither of two loci methylation was directly linked to rs10757274 genotype.

Conclusions/Significance

p15^INK4b methylation is associated with CAD and ANRIL expression. The epigenetic changes in p15^INK4b methylation and ANRIL expression may involve in the mechanisms of chromosome 9p21 on CAD development.     

Basal and Ischemia-Induced Transcardiac Troponin Release into the Coronary Circulation in Patients with Suspected Coronary Artery Disease

Background

Cardiac troponin is a specific biomarker for cardiomyocyte necrosis in acute coronary syndromes. Troponin release from the coronary circulation remains to be determined because of the lower sensitivity of the conventional assay. We sought to determine basal and angina-induced troponin release using a highly sensitive troponin assay.

Methods and Results

The cardiac troponin T levels in serum sampled from the peripheral vein (PV), the aortic root (AO), and the coronary sinus (CS) were measured in 105 consecutive stable patients with coronary risk factor(s) and suspected coronary artery disease (CAD) and in 33 patients without CAD who underwent an acetylcholine provocation test. At baseline, there was a significant increase in the troponin levels from AO [9.0 (6.4, 13.1) pg/mL for median (25^th, 75^th percentiles)] to CS [10.3 (7.3, 15.5) pg/mL, p<0.001] in 96 (91.4%) patients and the difference was 1.1 (0.4, 2.1) pg/mL, which reflected basal transcardiac troponin release (TTR). TTR was positively correlated with PV levels (r = 0.22, p = 0.03). Male sex, left ventricular hypertrophy determined by echocardiography, T-wave inversion, and CAD correlated with elevated TTR defined as above: median, 1.1 pg/mL. A significant increase in TTR was noted in 17 patients with coronary spasms [0.6 (0.2, 1.2) pg/mL, p<0.01] but not in 16 patients without spasms [0.0 (−0.5, 0.9) pg/mL, p = 0.73] after the acetylcholine provocation.

Conclusion

Basal TTR in the coronary circulation was observed in most of the patients with suspected CAD and risk factor(s). This sensitive assay detected myocardial ischemia-induced increases in TTR caused by coronary spasms.     

FADS Gene Polymorphisms Confer the Risk of Coronary Artery Disease in a Chinese Han Population through the Altered Desaturase Activities: Based on High-Resolution Melting Analysis

Objective

We explored the desaturase activities and the correlation of fatty acid desaturases (FADS) gene single nucleotide polymorphisms (SNPs) with plasma fatty acid in coronary artery disease (CAD) patients in a Chinese Han population.

Methods

Plasma fatty acids were measured by gas chromatography in CAD patients (n = 505) and a control group (n = 510). Five SNPs in the FADS gene were genotyped with high-resolution melting (HRM) methods.

Results

After adjustment, D6D activity, assessed as arachidonic acid (AA, C20:4n-6)/linoleic acid (LA, C18:2n-6), was higher in CAD patients (p<0.001). D9D activity, which was estimated as the ratio of palmitoleic acid (C16:1)/palmitic acid (C16:0) or oleic acid (C18:1n-9) to stearic acid (C18:0), was also increased (p<0.001). The genotype distributions of rs174537 G>T and rs174460 C>T were different between the two groups. The rs174537 T allele was associated with a lower risk of CAD [OR 0.743, 95% CI (0.624, 0.884), p = 0.001]. Carriers of the rs174460 C allele were associated with a higher risk of CAD [OR 1.357, 95% CI (1.106, 1.665), p = 0.003].

Conclusions

We firstly report that the rs174460 C allele is associated with a higher risk of CAD, and confirm that the rs174537 T allele is associated with a lower risk of CAD. Our results indicate that FADS gene polymorphisms are likely to influence plasma fatty acid concentrations and desaturase activities.     

Non-Invasive Detection of Coronary Endothelial Response to Sequential Handgrip Exercise in Coronary Artery Disease Patients and Healthy Adults

Objectives

Our objective is to test the hypothesis that coronary endothelial function (CorEndoFx) does not change with repeated isometric handgrip (IHG) stress in CAD patients or healthy subjects.

Background

Coronary responses to endothelial-dependent stressors are important measures of vascular risk that can change in response to environmental stimuli or pharmacologic interventions. The evaluation of the effect of an acute intervention on endothelial response is only valid if the measurement does not change significantly in the short term under normal conditions. Using 3.0 Tesla (T) MRI, we non-invasively compared two coronary artery endothelial function measurements separated by a ten minute interval in healthy subjects and patients with coronary artery disease (CAD).

Methods

Twenty healthy adult subjects and 12 CAD patients were studied on a commercial 3.0 T whole-body MR imaging system. Coronary cross-sectional area (CSA), peak diastolic coronary flow velocity (PDFV) and blood-flow were quantified before and during continuous IHG stress, an endothelial-dependent stressor. The IHG exercise with imaging was repeated after a 10 minute recovery period.

Results

In healthy adults, coronary artery CSA changes and blood-flow increases did not differ between the first and second stresses (mean % change ±SEM, first vs. second stress CSA: 14.8%±3.3% vs. 17.8%±3.6%, p = 0.24; PDFV: 27.5%±4.9% vs. 24.2%±4.5%, p = 0.54; blood-flow: 44.3%±8.3 vs. 44.8%±8.1, p = 0.84). The coronary vasoreactive responses in the CAD patients also did not differ between the first and second stresses (mean % change ±SEM, first stress vs. second stress: CSA: −6.4%±2.0% vs. −5.0%±2.4%, p = 0.22; PDFV: −4.0%±4.6% vs. −4.2%±5.3%, p = 0.83; blood-flow: −9.7%±5.1% vs. −8.7%±6.3%, p = 0.38).

Conclusion

MRI measures of CorEndoFx are unchanged during repeated isometric handgrip exercise tests in CAD patients and healthy adults. These findings demonstrate the repeatability of noninvasive 3T MRI assessment of CorEndoFx and support its use in future studies designed to determine the effects of acute interventions on coronary vasoreactivity.     

Association of Four Genetic Polymorphisms of AGER and Its Circulating Forms with Coronary Artery Disease: A Meta-Analysis

Background

Considerable efforts have been devoted to evaluating the association of the receptor for advanced glycation end-products (gene AGER and protein: RAGE) genetic variants to coronary artery disease (CAD); the results, however, are often irreproducible. To generate more information, we sought to explore four common polymorphisms of AGER and its circulating forms associated with the risk of CAD via a meta-analysis.

Methodology/Principal Findings

Articles were identified by searching PubMed, EMBASE, Wanfang and CNKI databases before March 2013. Qualified articles had case-control designs and investigated AGER four polymorphisms (T-429C, T-374A, Gly82Ser, G1704A) or circulating soluble RAGE (sRAGE) or endogenous secretory RAGE (esRAGE) levels associated with CAD. Twenty-seven articles involving 39 independent groups fulfilled the predefined criteria. Overall, no significance was observed for all examined polymorphisms under allelic and dominant models. When restricting groups to CAD patients with diabetes mellitus or renal disease, deviations of risk estimates from the unity were stronger than overall estimates for all polymorphisms except for G1704A due to limited available studies. For example, under dominant model, having -429C allele increased the odds of developing CAD in diabetic patients by 1.22-fold (95% confidence interval (95% CI) 0.99–1.51; P = 0.06; I ² = 6.7%) compared with that of overall estimate of 1.15-fold (95% CI: 0.97–1.36; P = 0.111; I ² = 18.0%). Circulating sRAGE levels were non-significantly lower in CAD patients than in controls, whereas this reduction was totally and significantly reversed in CAD patients with diabetes mellitus (weighted mean difference: 185.71 pg/ml; 95% CI: 106.82 to 264.61 pg/ml). Circulating esRAGE levels were remarkably lower in CAD patients, as well as in subgroups with or without diabetes mellitus and without renal disease.

Conclusions

Our findings demonstrated that association of AGER genetic polymorphisms with CAD was potentiated in patients with diabetes mellitus or renal disease. Practically, circulating esRAGE might be a powerful negative predictor for the development of CAD.     

Hospital Admissions for Hypertensive Crisis in the Emergency Departments: A Large Multicenter Italian Study

Epidemiological data on the impact of hypertensive crises (emergencies and urgencies) on referral to the Emergency Departments (EDs) are lacking, in spite of the evidence that they may be life-threatening conditions. We performed a multicenter study to identify all patients aged 18 years and over who were admitted to 10 Italian EDs during 2009 for hypertensive crises (systolic blood pressure ≥220 mmHg and/or diastolic blood pressure ≥120 mmHg). We classified patients as affected by either hypertensive emergencies or hypertensive urgencies depending on the presence or the absence of progressive target organ damage, respectively. Logistic regression analysis was then performed to assess variables independently associated with hypertensive emergencies with respect to hypertensive urgencies. Of 333,407 patients admitted to the EDs over the one-year period, 1,546 had hypertensive crises (4.6/1,000, 95% CI 4.4–4.9), and 23% of them had unknown hypertension. Hypertensive emergencies (n = 391, 25.3% of hypertensive crises) were acute pulmonary edema (30.9%), stroke (22.0%,), myocardial infarction (17.9%), acute aortic dissection (7.9%), acute renal failure (5.9%) and hypertensive encephalopathy (4.9%). Men had higher frequency than women of unknown hypertension (27.9% vs 18.5%, p<0.001). Even among known hypertensive patients, a larger proportion of men than women reported not taking anti-hypertensive drug (12.6% among men and 9.4% among women (p<0.001). Compared to women of similar age, men had higher likelihood of having hypertensive emergencies than urgencies (OR = 1.34, 95% CI 1.06–1.70), independently of presenting symptoms, creatinine, smoking habit and known hypertension. This study shows that hypertensive crises involved almost 5 out of 1,000 patients-year admitted to EDs. Sex differences in frequencies of unknown hypertension, compliance to treatment and risk of hypertensive emergencies might have implications for public health programs.     

Effects of Cytochrome P450 2C19 and Paraoxonase 1 Polymorphisms on Antiplatelet Response to Clopidogrel Therapy in Patients with Coronary Artery Disease

Clopidogrel is an antiplatelet prodrug that is recommended to reduce the risk of recurrent thrombosis in coronary artery disease (CAD) patients. Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results. Here, we sought to determine the associations of CYP2C19 and PON1 gene polymorphisms with clopidogrel response and their role in ADP-induced platelet aggregation. Clopidogrel response and platelet aggregation were determined using Multiplate aggregometer in 211 patients with established CAD who received 75 mg clopidogrel and 75–325 mg aspirin daily for at least 14 days. Polymorphisms in CYP2C19 and PON1 were genotyped and tested for association with clopidogrel resistance. Linkage disequilibrium (LD) and their epistatic interaction effects on ADP-induced platelet aggregation were analysed. The prevalence of clopidogrel resistance in this population was approximately 33.2% (n = 70). The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders. After adjusting for established risk factors, CYP2C19*2 and *3 alleles independently increased the risk of clopidogrel resistance with adjusted ORs 2.94 (95%CI, 1.65–5.26; p<0.001) and 11.26 (95%CI, 2.47–51.41; p = 0.002, respectively). Patients with *2 or *3 allele and combined with smoking, diabetes and increased platelet count had markedly increased risk of clopidogrel resistance. No association was observed between PON1 Q192R and clopidogrel resistance (adjusted OR = 1.13, 95%CI, 0.70–1.82; p = 0.622). Significantly higher platelet aggregation values were found in CYP2C19*2 and *3 patients when compared with *1/*1 allele carriers (p = 1.98×10⁻⁶). For PON1 Q192R genotypes, aggregation values were similar across all genotype groups (p = 0.359). There was no evidence of gene-gene interaction or LD between CYP2C19 and PON1 polymorphisms on ADP-induced platelet aggregation. Our findings indicated that only CYP2C19*2 and *3 alleles had an influence on clopidogrel resistance. The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.