Carbonyl groups: Bridging the gap between sleep disordered breathing and coronary artery disease

Abstract

Sleep disordered breathing (SDB) is related to coronary artery disease (CAD), but the mechanisms are uncertain. SDB is characterized by periods of intermittent hypoxia and free radical formation. This study tested the hypothesis that carbonylation can be the link between SDB and CAD. It included 14 cases with CAD and 33 controls with <50% coronary narrowing. CAD cases have higher erythrocyte carbonyl levels than controls (p = 0.012). Positive correlation was observed between apnea-hypopnea index (AHI) and erythrocyte carbonyl concentration (ρ = 0.310; p = 0.027). To predict CAD, including as regressors: AHI, erythrocyte carbonyl, gender, age and body mass index, the significant variables in the Poisson multiple regression model were AHI and erythrocytes carbonyl. An increase of 1 pmol/gHb in erythrocyte carbonyl levels increases by 1.8% the risk of CAD and one unit of AHI increases by 3.8% the risk of CAD. The present findings represent the first evidence in humans that SDB may cause CAD through protein carbonylation.     

Blood histamine is associated with coronary artery disease,cardiac events and severity of inflammation and atherosclerosis

Background : Mast cells are prevalent in the shoulder of unstable atheromas; cardiac mast cells secrete proteases capable of activating matrix metalloproteinases. Histamine is essential in the inflammatory cascade of the unstable plaque. Ascorbate depletion has been correlated with histaminemia which has been shown to impair endothelial-dependent vasodilation. This study evaluates whether oxidative stress as measured by isoprostanes (PGF_2α) coupled with an inflammatory state characterized by histaminemia predisposes patients to acute coronary syndrome (ACS).
Methods : Whole blood histamine, serum vitamin C, and serum PGF_2α levels were drawn on 50 patients with ACS as determined by standard diagnostic criteria, 50 patients with stable coronary artery disease (SCAD), and 50 age and sex matched normal controls (C).
Results : Data were analyzed by stepwise discriminant and Spearman's rank correlation coefficient. A significant relationship exists between histamine and PGF_2α. As PGF_2α rises above 60 pg/mL, an increase in histamine occurs in both the ACS and SCAD groups. A significant inverse relationship exists between ascorbate and histamine in the ACS versus C groups (P < 0.01) and the SCAD versus C groups (P < 0.01).
Conclusion : Histamine and isoprostane levels increase in SCAD and ACS patients. Mast cell activation and lipid oxidation generated during atherosclerosis manifest this inflammatory response. Accelerated isoprostane formation and depleted ascorbate paired with histaminemia is active in CAD and predispose patients to acute coronary syndrome. Blood histamine alone may be a better risk factor for coronary events, and a better prognostic indicator than CRP even when combined with lipid indexes.     

Increased plasma HB-EGF associated with obesity and coronary artery disease

The mechanism by which the obese subjects are more associated with vascular disease remains unclear. We reported that the adipose tissues produce and secrete many bioactive molecules, conceptualized as adipocytokines. Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), produced locally by vascular macrophages and smooth muscle cells, has been suggested to induce the migration and proliferation of vascular smooth muscle cells. The current study reveals that (1) HB-EGF mRNA is abundantly expressed in human adipose tissue, (2) HB-EGF mRNA increases in the fat tissues of obese mice, (3) plasma HB-EGF levels increase in parallel with fat accumulation in human, and (4) the subjects with coronary artery disease have higher plasma HB-EGF levels, associated with fat accumulation. These results suggest that increased plasma HB-EGF derived from the accumulated fat contributes to the higher incidence of vascular disease in obesity, proposing HB-EGF as an adipocytokine directly linking adipovascular axis.     

Thioredoxin-interacting protein promotes activation and inflammation of monocytes with DNA demethylation in coronary artery disease

Numerous studies have demonstrated that thioredoxin-interacting protein (TXNIP) expression of peripheral blood leucocytes is increased in coronary artery disease (CAD). However, the molecular mechanism of this phenomenon remained unclear. DNA methylation plays important roles in the regulation of gene expression. Therefore, we speculated there might be a close association between the expression of TXNIP and methylation. In this study, we found that compared with controls, DNA methylation at cg19693031 was decreased in CAD, while mRNA expressions of TXNIP and inflammatory factors, NLRP3, IL-1β, IL-18, were increased. Methylation at cg19693031 was negatively associated with TXNIP expression in the cohort, THP-1 and macrophages/foam cells. Furthermore, Transwell assay and co-cultured adhesion assay were performed to investigate functions of TXNIP on the migration of THP-1 or the adhesion of THP-1 on the surface of endothelial cells, respectively. Notably, overexpressed TXNIP promoted the migration and adhesion of THP-1 cells and expressions of NLRP3, IL-18 and IL-1β. Oppositely, knock-down TXNIP inhibited the migration and adhesion of THP-1 and expressions of NLRP3, IL-18. In conclusion, increased TXNIP expression, related to cg19693031 demethylation orientates monocytes towards an inflammatory status through the NLRP3 inflammasome pathway involved in the development of CAD.     

Myeloperoxidase gene-463G > A polymorphism and premature coronary artery disease

We investigated the association between myeloperoxidase gene -463G > A polymorphism and premature coronary artery disease (CAD) in two Chinese population samples: 229 patients and 230 controls. Genotypes were determined by ligase detection reaction-polymerase chain reaction sequencing and the grouping technique. We found lower frequencies of both the A/A genotype and the A allele in patients (p < 0.05). Multivariate logistic regression showed that the risk of premature CAD in subjects carrying the AA genotype was reduced by 83% in relation to individuals carrying the G/G genotype (OR = 0.172, 95% CI: 0.057-0.526, p = 0.002). Our results indicate that -463G > A polymorphism of the myeloperoxidase gene is associated with premature CAD in Chinese individuals, suggesting that the AA genotype is a protective factor against premature CAD.     

Clinical significance of circulating microRNAs as diagnostic biomarkers for coronary artery disease

Coronary artery disease (CAD) is one of the biggest threats to human life. Circulating microRNAs (miRNAs) have been reported to be linked to the pathogenesis of CAD, indicating the possible role in CAD diagnosis. The present study aimed to explore the expression profile of plasma miRNAs and estimate their value in diagnosis for CAD. 67 Non‐CAD control subjects and 88 CAD patients were enrolled. We conducted careful evaluation by RT‐PCR analysis, Spearman rank correlation coefficients analysis, Receiver Operating Characteristic (ROC) curves analysis and so on. The plasma levels of six miRNAs known to be related to CAD were measured and three of them showed obvious expression change. Circulating miR‐29a‐3p, miR‐574‐3p and miR‐574‐5p were all significantly increased. ROC analysis revealed the probability of the three miRNAs as biomarkers with AUCs (areas under the ROC curve) of 0.830, 0.792 and 0.789, respectively. They were significantly correlated with each other in CAD patients, suggesting the possibility of joint diagnosis. The combined AUC was 0.915, much higher than each single miRNA. Therefore, our study revealed three promising biomarkers for early diagnosis of CAD. The combination of these miRNAs may act more effectively than individual ones for CAD diagnosis.     

A potential oral microbiome signature associated with coronary artery disease in Tunisia

The coronary artery disease (CAD) is a chronic inflammatory disease involving genetic as well as environmental factors. Recent evidence suggests that the oral microbiome has a significant role in triggering atherosclerosis. The present study assessed the oral microbiome composition variation between coronary patients and healthy subjects in order to identify a potential pathogenic signature associated with CAD. We performed metagenomic profiling of salivary microbiomes by 16S ribosomal RNA (rRNA) next-generation sequencing. Oral microbiota profiling was performed for 30 individuals including 20 patients with CAD and ten healthy individuals without carotid plaques or previous stroke or myocardial infarction.We found that oral microbial communities in patients and healthy controls are represented by similar global core oral microbiome. The predominant taxa belonged to Firmicutes (genus Streptococcus, Veillonella, Granulicatella, Selenomonas), Proteobacteria (genus Neisseria, Haemophilus), Actinobacteria (genus Rothia), Bacteroidetes (genus Prevotella, Porphyromonas), and Fusobacteria (genus Fusobacterium, Leptotrichia). More than 60% relative abundance of each sample for both CAD patients and controls is represented by three major genera including Streptococcus (24.97 and 26.33%), Veillonella (21.43 and 19.91%), and Neisseria (14.23 and 15.33%).Using penalized regression analysis, the bacterial genus Eikenella was involved as the major discriminant genus for both status and Syntax score of CAD. We also reported a significant negative correlation between Syntax score and Eikenella abundance in coronary patients’ group (Spearman rho = −0.68, P=0.00094).In conclusion, the abundance of Eikenella in oral coronary patient samples compared with controls could be a prominent pathological indicator for the development of CAD.     

Association of CYBA G640A variation with coronary artery disease in Indians

Introduction: Oxidative stress induces atherosclerosis by triggering an inflammatory cascade within the vascular wall.

Objective: To investigate the role of pro-oxidant and antioxidant gene variations with CAD in Indian subjects.

Materials & methods: It’s a case-control study and genotyping for the variants MPO G-463A, CYBA G640A, SOD2 Val16Ala and CAT C-262T were performed by conventional PCR techniques.

Results: Only CYBA G640A variant allele was found to be significantly (p?=?0.0075) associated with CAD.

Conclusion: Although CYBA G640A variation was found to be significant, a larger study is needed to validate these results and establish its role as a biomarker.     

C677T mutation of methylenetetrahydrofolate reductase gene and serum homocysteine levels in Turkish patients with coronary artery disease

Elevated levels of homocysteine is a risk factor for coronary artery disease. The C677T transition in methylenetetrahydrofolate reductase (MTHFR) is associated with increased homocysteine levels in the general population. We analysed the association between the MTHFR C677T polymorphism and serum homocysteine concentrations in patients with coronary artery disease (CAD). Allele frequencies for the 'C' (wild-type) and 'T' alleles were 0.71 and 0.29 in CAD patients and 0.70 and 0.30 in controls, respectively. There was no difference in the distribution of MTHFR genotypes between patients with CAD and control subjects (p > 0.05). In the patient group, homocysteine levels were higher than controls but not significantly (13.99 +/- 7.44 vs. 11.77 +/- 5.18 micromol l(-1); p > 0.05). Serum homocysteine concentration was significantly higher in the TT genotype with respect to CC and CT genotypes in both the control group (p < 0.01) and patient group (p < 0.01). Systolic and diastolic blood pressures in subjects with different MTHFR genotypes did not differ significantly. In conclusion, MTHFR C677T mutation was significantly related to hyperhomocysteinemia. In spite of the clear effect of the MTHFR polymorphism on elevated homocysteine levels, we did not observe any associations among the MTHFR genotypes with a the risk of CAD in the Turkish population.     

Impact of plaques in the left coronary artery on wall shear stress and pressure gradient in coronary side branches

In this study, we investigate plaques located at the left coronary bifurcation. We focus on the effect that the resulting changes in wall shear stress (WSS) and wall pressure stress gradient (WPSG) have on atherosclerotic progress in coronary artery disease. Coronary plaques were simulated and placed at the left main stem and the left anterior descending to produce >50% narrowing of the coronary lumen. Computational fluid dynamics analysis was carried out, simulating realistic physiological conditions that show the in vivo cardiac haemodynamic. WSS and WPSG in the left coronary artery were calculated and compared in the left coronary models, with and without the presence of plaques during cardiac cycles. Our results showed that WSS decreased while WPSG was increased in coronary side branches due to the presence of plaques. There is a direct correlation between coronary plaques and subsequent WSS and WPSG variations based on the bifurcation plaques simulated in the realistic coronary models.     

A review on coronary artery disease,its risk factors,and therapeutics

Coronary artery disease (CAD) is one of the major cardiovascular diseases affecting the global human population. This disease has been proved to be the major cause of death in both the developed and developing countries. Lifestyle, environmental factors, and genetic factors pose as risk factors for the development of cardiovascular disease. The prevalence of risk factors among healthy individuals elucidates the probable occurrence of CAD in near future. Genome-wide association studies have suggested the association of chromosome 9p21.3 in the premature onset of CAD. The risk factors of CAD include diabetes mellitus, hypertension, smoking, hyperlipidemia, obesity, homocystinuria, and psychosocial stress. The eradication and management of CAD has been established through extensive studies and trials. Antiplatelet agents, nitrates, β-blockers, calcium antagonists, and ranolazine are some of the few therapeutic agents used for the relief of symptomatic angina associated with CAD.     

Renin-angiotensin system genes polymorphism in Egyptians with premature coronary artery disease

Genetics polymorphism of the renin-angiotensin system (RAS) affects the pathogenesis of atherosclerosis and associated with coronary artery disease (CAD). We aimed to investigate the association between the RAS genes and premature CAD (PCAD) in Egyptians. 116 patients with PCAD, 114 patients with late onset CAD and 119 controls were included in the study. Angiotensin converting enzyme (ACE), angiotensin II receptor type 1 (ATR1) and angiotensinogen (AGT) genes polymorphisms were analyzed by polymerase chain reaction (PCR). We found that ACE DD, AGT TT and ATR1 CC increased the risk of PCAD by 2.7, 2.8 and 2.86 respectively). Smoking, hypertension, diabetes, total cholesterol, triglycerides and LDL cholesterol were independent risk factors for the development of PCAD. We conclude that the ACE DD, AGT TT and ATR1 CC genotypes may increase the susceptibility of an individual to have PCAD. The coexistence of CAD risk factors with these risky RAS genotypes may lead to the development of PCAD in Egyptian patients.     

冠心病患者运动致QRS延长的临床意义

为探讨冠心病病人由于急性心肌缺血对ＱＲＳ持续时间变化的影响及其意义。本文收集了５３例病人,均进行运动试验和冠脉造影,其中２０例经冠脉造影排除心病,其他３３例经冠脉造影确定为冠心病。结果运动使冠脉正常者ＱＲＳ持续时间缩短,而使冠心病者ＱＲＳ持续时间延长。     

Diagnostic and prognostic value of absence of coronary artery calcification in patients with stable chest symptoms

The aim of this study was to determine the prognostic value of a coronary artery calcium score (CACS) of 0 in patients with stable chest symptoms and to compare it as a first-line test with bicycle exercise testing (X-ECG). Altogether, 315 consecutive patients over 44 years of age, with stable chest symptoms and no previous diagnosis of coronary artery disease (CAD) visited the outpatient clinic of our community hospital and underwent both CACS and X-ECG. The mean age was 60.54 years (SD 9.7; range 45–88 years). Of these patients, 141 had no detectable coronary calcium (44.8%) We excluded patients who did not sign informed consent (n = 4). Three patients were lost to follow-up. The follow-up group therefore consisted of 134 patients. The mean follow-up period was 44.6 months (25th–75th percentile: 35.5–54.3 months), during which no major adverse cardiac events (MACE) occurred. The negative predictive value (NPV) was 100%. X-ECG was negative in only 89 patients, equivocal in 39 patients and false-positive in 6 patients requiring additional stress myocardial imaging in 45 patients. NPV as a first-line test was therefore 66.4%. In conclusion: patients over 44 years with stable chest symptoms and no detectable coronary calcium have an excellent prognosis. CACS performs better compared with X-ECG as an initial test in patients with stable chest symptoms.     

Oxidative stress status of highly prolific sows during gestation and lactation

Elevated oxidative stress is reported to be associated with pregnancy complications in highly prolific sows. Oxidative DNA damage and the antioxidant status were determined in blood samples collected during the course of gestation and lactation in multiparous sows. Blood samples were drawn from sows (n = 5) on days 30, 60, 90 and 110 of gestation (G30, G60, G90 and G110, respectively), on day 3, 10 and 18 of lactation (L3, L10 and L18, respectively) and on day 5 of postweaning (W5). Lymphocytes were isolated from the fresh blood and cryopreserved in each time point. Lymphocyte DNA damage was analyzed by alkaline single-cell gel electrophoresis (comet assay) to determine the single- and double-strand brakes and endogenous antioxidant concentrations using an HPLC system with UV detection. The comet assay showed elevated (P < 0.05) DNA damage (between 38% and 47%) throughout the gestational and lactational periods than during early gestation (G30; 21%). Plasma retinol concentration was reduced (P < 0.05) at the end of gestation (G110) compared with G30. Plasma α-tocopherol concentrations also showed a similar trend as to retinol. This study indicates that there is an increased systemic oxidative stress during late gestation and lactation, which are not fully recovered until the weaning compared with the G30, and that antioxidant nutrients in circulation substantially reduced in the mother pig at G110.     

Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease

Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease‐modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady‐state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.     

Serum Metrnl is associated with the presence and severity of coronary artery disease

Meteorin‐like (Metrnl) is a novel adipokine that is highly expressed in white adipose tissue. Metrnl stimulates energy expenditure and improves glucose tolerance in rodents. However, whether Metrnl plays a role in coronary artery disease (CAD) remains to be elucidated. The present study aimed to investigate the association of serum Metrnl with CAD in Chinese patients. A total of 193 patients with CAD and 156 control subjects were enrolled in this study. Serum Metrnl concentration was measured by enzyme‐linked immunosorbent assay. Anthropometric phenotypes, fasting glucose, serum lipids, and inflammatory cytokines were measured. Serum Metrnl was lower in CAD patients when compared to those controls (132.41 vs 173.17 pg/mL, P < 0.001). Serum Metrnl was negatively correlated with metabolic parameters, including body mass index, total cholesterol, and low‐density lipoprotein cholesterol as well as inflammatory markers including high‐sensitivity C‐reactive protein, IL‐1β, and IL‐11 even after adjustment for potential confounding variables (P < 0.05). In multivariable logistic regression analyses, compared to those in the highest tertile of serum Metrnl levels, subjects in the lowest tertile had the highest risks for CAD (adjusted OR = 2.63, 95% CI = 1.46‐4.27, P = 0.001). After adjustment for potential confounding variables, serum Metrnl was also decreased as the number of stenosed vessels increased (P < 0.001). Furthermore, decreased Metrnl level was negatively correlated with the severity of CAD quantified by the Gensini score. This first case‐control study shows significant associations of serum Metrnl with the presence and severity of CAD, suggesting Metrnl might be a new promising therapeutic target for CAD.