Involvement of enhanced expression of classical complement C1q in atherosclerosis progression and plaque instability: C1q as an indicator of clinical outcome.

Activation of the classical complement pathway plays a major role in regulating atherosclerosis progression, and it is believed to have both proatherogenic and atheroprotective effects. This study focused on C1q, the first protein in the classical pathway, and examined its potentialities of plaque progression and instability and its relationship with clinical outcomes. To assess the localization and quantity of C1q expression in various stages of atherosclerosis, immunohistochemistry, western blotting, and real-time polymerase chain reaction (PCR) were performed using abdominal aortas from eight autopsy cases. C1q immunoreactivity in relation to plaque instability and clinical outcomes was also examined using directional coronary atherectomy (DCA) samples from 19 patients with acute coronary syndromes (ACS) and 18 patients with stable angina pectoris (SAP) and coronary aspirated specimens from 38 patients with acute myocardial infarction. C1q immunoreactivity was localized in the extracellular matrix, necrotic cores, macrophages and smooth muscle cells in atherosclerotic lesions. Western blotting and real-time PCR illustrated that C1q protein and mRNA expression was significantly higher in advanced lesions than in early lesions. Immunohistochemical analysis using DCA specimens revealed that C1q expression was significantly higher in ACS plaques than in SAP plaques. Finally, immunohistochemical analysis using thrombus aspiration specimens demonstrated that histopathological C1q in aspirated coronary materials could be an indicator of poor medical condition. Our results indicated that C1q is significantly involved in atherosclerosis progression and plaque instability, and it could be considered as one of the indicators of cardiovascular outcomes.

Association of plasma apolipoprotein CIII, high sensitivity C-reactive protein and tumor necrosis factor-α contributes to the clinical features of coronary heart disease in Li and Han ethnic groups in China.

BACKGROUND: Apolipoprotein CIII (apoCIII) is an independent risk for coronary heart disease (CHD). In this study, we investigated the associations among plasma apoCIII, hs-CRP and TNF-α levels and their roles in the clinical features of CHD in the Li and Han ethnic groups in China. METHODS: A cohort of 474 participants was recruited (238 atherosclerotic patients and 236 healthy controls) from the Li and Han ethnic groups. Blood samples were obtained to evaluate apoCIII, TNF-α, hs-CRP and lipid profiles. Chi-squared, t-tests, and Kruskal-Wallis or Wilcoxon-Mann-Whitney tests, Pearson or Spearman correlation tests and multiple unconditional logistic regression were employed to analyze lipid profiles and variations in plasma apoCIII, TNF-α, hs-CRP in subgroups of CHD and their contributions to CHD using SPSS version 20.0 software. RESULTS: Compared to healthy participants, unfavorable lipid profiles were identified in CHD patients with enhanced systolic pressure, diastolic pressure, fasting blood sugar (FBS), TG, TC, LDL-C, apoB, Lp(a) (P < 0.05, TC and Lp(a); P < 0.01, FBS, TG, LDL-C, apoB); and lower HDL-C and apoAI (P < 0.05). Plasma apoCIII, TNF-α and hs-CRP levels were higher in CHD individuals (16.77 ± 5.98 mg/dL vs. 10.91 ± 4.97 mg/dL; 17.23 ± 6.34 pg/mL vs. 9.49 ± 3.88 pg/mL; 9.55 ± 7.32 mg/L vs. 2.14 ± 1.56 mg/L; P < 0.01 vs. healthy participants). Identical patterns were obtained in the Li and Han groups (16.46 ± 6.08 mg/dL vs. 11.72 ± 5.16 mg/dL; 15.71 ± 5.52 pg/mL vs. 9.74 ± 4.31 pg/mL; 8.21 ± 7.09 mg/L vs. 2.15 ± 1.51 mg/L in Li people; 17.05 ± 5.90 mg/dL vs. 10.07 ± 4.63 mg/dL; 18.59 ± 6.73 pg/mL vs. 9.23 ± 3.38 pg/mL; 10.75 ± 7.44 mg/L vs. 2.12 ± 1.63 mg/L in Han people; P < 0.01). Paired comparisons of subgroups with stable angina, unstable angina, and acute myocardial infarction (AMI) revealed significant variation in plasma levels of apoCIII, TNF-α and hs-CRP (P < 0.01), but not among subgroups with mild, moderate and severe stenosis (P > 0.05). Plasma apoCIII, TNF-α and hs-CRP contributed to the development of CHD (OR = 2.554, 7.252, 6.035, P < 0.01) with paired correlations in CHD patients (apoCIII vs. TNF-α, r = 0.425; apoCIII vs. hs-CRP, r = 0.319; TNF-α vs. hs-CRP, r = 0.400, P < 0.01). CONCLUSIONS: Association among plasma apoCIII, hs-CRP and TNF-α interacts with unfavorable lipid profiles to contribute to the clinical features of CHD with stable angina, unstable angina, and AMI in the Li and Han ethnic groups in China.

Quantitative Extent of Atherosclerotic Plaque in the Major Epicardial Coronary Arteries in Patients with Fatal Coronary Heart Disease, in Coronary Endarterectomy Specimens, in Aorta-Coronary Saphenous Venous Conduits, and Means to Prevent the Plaques: A Review after Studying the Coronary Arteries for 50 Years.

This review tries to answer the following 15 questions: Is atherosclerosis a systemic or a regional disease? Is atherosclerosis in any particular region focal or diffuse? What is the quantity of atherosclerotic plaques in endarterectomy specimens of the right coronary artery in patients undergoing coronary artery bypass grafting (CABG) compared to that in the right coronary artery in patients with fatal coronary artery disease? How do the units used for measuring arterial narrowing by angiography compare to the units used for measuring arterial narrowing at necropsy? What do atherosclerotic plaques consist of in coronary arteries in patients with fatal coronary disease? What is the quantity of atherosclerotic plaque in bypassed -vs- non-bypassed native coronary arteries in patients dying early (<60 days) or late (>60 days) after coronary artery bypass grafting? What is the frequency of acute coronary lesions and multi-luminal channels at necropsy in patients with unstable angina pectoris, sudden coronary death, and acute myocardial infarction? What is the mechanism of luminal widening by angioplasty in the coronary arteries? What observations suggest that atherosclerotic plaques are the result at least in part of organization of thrombi? Is atherosclerosis a multifactoral or a unifactoral disease? What characteristics distinguish carnivores and herbivores? What are reasonable guidelines for whom to treat with lipid-altering agents? What is the rule of 5 and the rule of 7 in statin therapy? What is the effect of lipid lowering drug therapy on coronary luminal narrowing? What are some requisites for a healthy life?

Evaluation of the endothelial glycocalyx damage in patients with acute coronary syndrome.

BACKGROUND: Endothelial glycocalyx (EG) is sugar-based cell-bound surface molecules linked to transmembrane proteins observed on the endothelial surface of the vessels. Damage to this structure causes an increase in platelet and leucocyte adhesion and shear stress in the vessel. We hypothesized a possible link between EG damage and acute coronary syndrome (ACS). METHODS: We measured the syndecan-1 levels (a biomarker of EG damage) in 141 patients (99 men) with ACS and compared to those of 45 patients (24 men) with non-coronary chest pain (NCCP) and of 24 (14 men) healthy individuals (CONTROL). RESULTS: The baseline characteristics of the ACS and NCCP groups were similar. Syndecan-1 levels were significantly higher in the ACS group than in the NCCP (p = 0.01) and CONTROL (p = 0.001) groups but did not differ between the NCCP and CONTROL groups (p = 0.83). In analysis according to gender category, the difference among the groups remained significant only for men (p = 0.0009). A syndecan-1 level higher than 148 ng/ml was associated with ACS diagnosis with an odds ratio of 14 (95% confidence interval (CI): 1.8 to 102), p = 0.011. After adjusting for gender, age and current or past tobacco use, this syndecan-1 level remained positively associated with ACS diagnosis with an odds ratio of 12 (95% CI: 1.6 to 93), p = 0.016. CONCLUSION: Higher syndecan-1 levels were observed during ACS, mostly in men, suggesting that EG damage could participate in the atherosclerotic plaque vulnerability process in these patients.

Resting angina due to papillary fibroelastoma of the right coronary cusp.

A 63-year-old man with chest pain at rest was referred to our hospital. Transthoracic echocardiography showed a mobile ball-like mass at the top of the right coronary cusp. Subsequently, transesophageal echocardiography also showed a mobile mass at the right coronary cusp. Aortic valve replacement with a mechanical valve was performed under general anesthesia. We diagnosed this condition as papillary fibroelastoma based upon the pathological findings with hematoxylin and eosin staining, and Elastica van Gieson staining. Coronary angiography revealed no organic lesions. The operation was successful, and the patient remains asymptomatic. We speculate that the resting chest pain was induced by transient occlusion of the right coronary orifice by the tumor. We describe this rare case in detail including a review of the literature.

Platelet-bound cyclophilin A in patients with stable coronary artery disease and acute myocardial infarction.

OBJECTIVE: Recently, we reported that extracellular cyclophilin A (CyPA) is an important agonist for platelets. Whereas soluble CyPA-levels have been associated with cardiovascular risk factors, cell-bound CyPA has not been investigated yet. In this study, we analyzed for the first time platelet-bound CyPA in patients with symptomatic coronary artery disease (CAD). METHODS AND RESULTS: blood was obtained from 388 consecutive patients: 204 with stable CAD and 184 with acute coronary syndrome (76 with unstable angina, 78 with non ST-elevation myocardial infarction (NSTEMI), and 30 with STEMI). In vitro stimulation of platelets with classical agonists revealed an enhanced expression of CyPA on the platelet surface. In patients with stable CAD, platelet-bound CyPA correlated excellently with platelet activity measured by P-selectin exposure in flow cytometry. The analysis of classical risk factors for atherosclerosis revealed that patients with hypertension and hypercholesterolemia had significantly enhanced platelet-bound CyPA, whereas diabetes and smoking were not associated with enhanced CyPA-binding to the platelet surface. In multivariate analysis, hypercholesterolemia was the only significant predictor of enhanced platelet-bound CyPA. Interestingly, in patients with acute myocardial infarction (AMI) platelet-bound CyPA was significantly decreased compared with patients with stable CAD. CONCLUSIONS: Enhanced platelet-bound CyPA is associated with hypertension and hypercholesterolemia in stable CAD patients. In patients with AMI platelet-bound CyPA is significantly decreased.

Anatomical criteria of malignancy by computed tomography angiography in patients with anomalous coronary arteries with an interarterial course.

PURPOSE: We sought to determine the relation between major adverse cardiac events (MACE) and anatomical criteria assessed by coronary computed tomography angiography (CCTA) in patients with an anomalous coronary artery with an interarterial course (ACAIAC). MATERIAL AND METHODS: We selected CCTA studies of patients with an ACAIAC from a database of 4,160 examinations and studied anatomical criteria according to the presence of prior MACE, defined as syncope, unstable angina, myocardial infarction and resuscitated sudden cardiac death. RESULTS: There were 19 patients (18 males) with an ACAIAC during the study period (incidence 0.46 %). Seven patients with prior MACE were younger (26 years vs 59 years, p < 0.001), had a smaller minimal lumen area (3.6 mm(2) vs 9.0 mm(2), p = 0.001), a higher degree of area stenosis (57 % vs 24 %, p = 0.001), a longer interarterial course (14.7 vs 8.6 mm, p = 0.003) and a smaller proximal segment width (1.6 mm vs 2.5 mm, p = 0.02) compared with the 12 patients without prior MACE. All patients with MACE had the following concomitant anatomical characteristics: minimum lumen area ≤4 mm(2), an area stenosis ≥50 % and intra-arterial length >10 mm CONCLUSIONS: Prior MACE is associated with specific anatomical CCTA characteristics among patients with ACAIAC. CCTA may therefore contribute to distinguish patients at risk of adverse events.

[Antioxidant status and glutathione redox potential of erythrocytes in patients with acute coronary syndrome].

Indicators of oxidative stress (OS), systemic inflammation, metabolism and redox status of glutathione (GSH) were investigated and compared in patients with ST-segment elevation myocardial infarction on electrocardiograms (STEMI), and patients with unstable angina (UA). The elevated and decreased myeloperoxidase level, superoxide dismutase activity, and moderate increased plasma levels of interleukin-6, while maintaining the antioxidant potential, were found in Group 1. Disorders in pro-/antioxidant balance and systemic inflammatory response were manifested in UA. Increased GSH concentration (and total GSH) in erythrocytes has been established for STEMI patients and the decreased GSH for UA patients. Thus, a significant shift of erythrocytes redox to oxidization and increase (unlike STEMI patients) of glutathione peroxidase activity were recorded. Mechanisms of the pro- and antioxidant functions of red blood cells in acute coronary syndrome are considered. The role of red blood cell glutathione to provide more oxidized intravascular environment for S-glutathionylation and optimization of redox signaling in target cells is pronounced.

Aging aggravates nitrate-mediated ROS/RNS changes.

Nitrates are the most frequently prescribed and utilized drugs worldwide. The elderly are a major population receiving nitrate therapy. Both nitrates and aging can increase in vivo reactive oxygen species (ROS) and reactive nitrogen species (RNS). To date, the effects of aging upon nitrate-induced ROS/RNS alteration are unknown. The present study tested the effects of aging upon nitrate-induced ROS/RNS alteration in vivo. 32 adults and 43 elderly unstable angina (UA) patients were subjected to 48 hours of isosorbide dinitrate intravenous injection (50 µg/minutes) in this clinical study. Blood samples were obtained at baseline and conclusion. Outcome measures of oxidative stress included plasma malondialdehyde (MDA), myeloperoxidase (MPO), and reduced glutathione (GSH). Plasma concentrations of NOx and nitrotyrosine served as markers of RNS. Because of the significant differences in basic clinical characters between adults and the elderly, we designed an additional experiment determining ROS/RNS stress in rat cardiac tissue. Additionally, rat thoracic aortic NOS activity served as a marker indicating endothelial function. Our study demonstrated that nitrate therapy significantly increased in vivo ROS/RNS stress in the elderly compared to adult patients, confirmed by animal data. Decreased NOS activity was observed in old rats. Taken together, the present study's data suggests a synergism between nitrate treatment and the aging process.

Remote ischemic preconditioning immediately before percutaneous coronary intervention does not impact myocardial necrosis, inflammatory response, and circulating endothelial progenitor cell counts: a single center randomized sham controlled trial.

AIMS: Percutaneous coronary intervention (PCI) is frequently accompanied by myocardial injury. The present study was performed to determine whether remote ischemic preconditioning (IP) induces cardioprotection during PCI. METHODS: We enrolled 95 patients requiring nonemergency PCI for stable disease or unstable angina into this prospective clinical trial. Patients were randomized to either remote IP (induced by three 3-min cycles of blood pressure cuff inflations to 200 mm Hg around the upper arm, followed by 3-min of reperfusion n = 47) or sham control (n = 48) immediately preceding PCI. The primary outcome measure was the frequency of post-PCI myonecrosis, defined as a peak postprocedural cTnT T ≥ 0.03 ng/dL. Secondary outcome measures were the change in plasma high-sensitivity C-reactive protein (hsCRP) levels following PCI and in endothelial progenitor cells (EPC) counts following IP. RESULTS: There was no difference in the primary endpoint of the frequency of PCI related myonecrosis which occurred in 22 (47%) and 19 (40%) patients in the remote IP and control groups, respectively, P = 0.42. There was significant increase in hsCRP post-PCI in both groups (P < 0.001), but there was no difference between the groups (median %change in hsCRP 46% vs. 54%, P = 0.73). There was no significant change in circulating early (CD34 -/CD133+/KDR+), intermediate (CD34+/CD133+/KDR+), or late (CD34+/CD133-/KDR+) EPC in the two groups immediately following IP. The composite rate of death, myocardial infarction, and target lesion revascularization at 1 year was 14.1% versus 13.7% (P = 0.90). CONCLUSIONS: Our study indicates that remote IP immediately before PCI does not induce cardioprotection in low to moderate risk patients.

[Effectiveness of early invasive strategy of treatment of angina of new onset].

Aim of the study was to assess effectiveness of early invasive strategy of treatment of angina of new onset (ANO). We conducted comparative assessment on invasive and noninvasive risk estimation in 106 patients admitted to N.V.Sklifosofsky Institute of Urgent Aid in 2003-2007. Percutaneous coronary interventions (PCI) on symptom related artery (SRA) within single procedure were carried out in 74 cases (70%), indications to coronary artery bypass surgery were detected in 16 cases (15%), in 16 more cases conservative treatment was used. The data obtained showed that it is rational to consider ANO as unstable angina in all cases including those without progression. Visualization of coronary arteries gives possibility to define significance of SRA and zone at risk of injury, determine indications to myocardial revascularization, and avoid inadequacy of noninvasive assessment of risk and choice of treatment tactics. The method of choice in the treatment of patients with ANO is PCI performed during single procedure. Detection of indications to coronary artery bypass surgery in low risk patients and in absence of progression confirm necessity of routine use of invasive strategy which provides timely pathogenetic treatment. Absence of indications to myocardial revascularization detected in sporadic cases provides possibility to avoid groundless hospitalizations.

Beneficial effect of ischemic preconditioning on post-infarction left ventricular remodeling and global left ventricular function.

BACKGROUND: Preinfarction angina (PA) is a clinical analogue of ischemic preconditioning that improves postinfarct prognosis. Data concerning the association of PA with post infarction left ventricular (LV) remodeling and LV diastolic function are limited. We aimed to evaluate this association in patients with acute myocardial infarction (AMI) in the modern clinical era of widespread use of revascularization and antiremodeling medical treatment. METHODS: We studied 53 patients with anterior AMI who underwent complete reperfusion and received up to date antiremodeling medical treatment. LV remodeling, systolic and diastolic function were assessed using 2D echocardiography at baseline and 6 at months follow-up. Patients were divided into two groups regarding the presence or absence of PA. RESULTS: LV remodeling at follow-up was less frequent in the PA group (25 vs. 55 %, P<.05). Patients with PA had lower end-systolic volume index at baseline and follow up (24.1±6 vs. 30.1±14 ml/m(2), P<.001 and 25.3±8 vs. 35.6±2 ml/m(2), P=.001 respectively). Additionally at 6 months, they had better LV ejection fraction (52.1±9 vs. 42.9±10 %, P=.002) and exhibited improved diastolic filling as reflected by mitral E/e' (14.6±5 vs. 18.8±8, P=.05). CONCLUSIONS: Ischemic preconditioning in the form of PA promotes better LV systolic and diastolic function in the mid-term and is associated with less postinfarct LV remodeling in this specific study population. The results of the study underline the possible need for further risk stratification of AMI patients regarding the absence of PA.

Comparison of tissue characteristics between acute coronary syndrome and stable angina pectoris. An integrated backscatter intravascular ultrasound analysis of culprit and non-culprit lesions.

BACKGROUND: Patients with acute coronary syndrome (ACS) have multiple complex coronary plaques associated with plaque vulnerability. The present study assessed the tissue characteristics of coronary plaques between ACS and stable angina pectoris (SAP) of culprit and non-culprit lesions using integrated backscatter intravascular ultrasound (IB-IVUS). METHODS AND RESULTS: IVUS was performed in 165 patients (40 patients with ACS) with 225 culprit (65 lesions in ACS) and 171 non-culprit lesions (42 lesions in ACS). The percentage of fibrous area (fibrous area/plaque area, %FIB) and the percentage of lipid area (lipid area/plaque area, %LIP) at the segment with minimal luminal area were calculated using IB-IVUS system. Culprit and non-culprit lesions with ACS showed a significant increase in %LIP (38±18 vs. 30±15%, P=0.002, and 38±21 vs. 32±17%, P=0.03, respectively) and a significant decrease in %FIB (59±15 vs. 63±12 %, P=0.04, and 57±18 vs. 62±14%, P=0.04, respectively) compared to those with SAP. On logistic regression analysis, not only culprit lesions but also non-culprit lesions with ACS patients were significantly associated with the lipid-rich plaque. CONCLUSIONS: Non-culprit coronary lesions with ACS patients are associated with the lipid-rich plaque, suggesting the extensive development of plaques instability in these patients.

A comparative study of biomarkers for risk prediction in acute coronary syndrome-Results of the SIESTA (Systemic Inflammation Evaluation in non-ST-elevation Acute coronary syndrome) study.

OBJECTIVE: We compared the 1-year predictive value of several inflammatory and non-inflammatory biomarkers in ACS patients. METHODS: In 610 patients (73.0% male)--36.0% unstable angina (UA) and 64.0% NSTEMI--we assessed high-sensitivity C-reactive protein (hs-CRP), interleukins 6, 10 and 18, soluble CD40 ligand, P- and E-selectin, NT-proBNP, fibrinogen and cystatin C at hospital admission. Two outcomes at 1-year follow up were selected for analysis: (1) all-cause death, MI, UA, or coronary revascularization, and (2) all-cause death, and non-fatal MI. The effect of biomarker levels on endpoints was examined by the Cox proportional hazards model, and their discrimination ability with the C statistic (AUC). RESULTS: Of 549 patients (90.0%) who completed the 1-year follow up, 206 (37.5%) and 54 (8.9%) reached the first and second composite endpoints, respectively. None of the biomarkers studied improved prediction of the first endpoint. However, considered as continuous variables, and in combination, NT-proBNP and fibrinogen, increased the AUC from 0.64 (95% CI 0.55-0.72) to 0.73 (95% CI 0.64-0.81; p=0.02) for prediction of the second endpoint. Cut-off values for NT-proBNP and fibrinogen, regarding best sensitivity and specificity for prediction of the secondary endpoint were 1043.9 ng/L and 4.47 mg/dL, respectively. For these cut-off points, sensitivity, specificity, positive predictive value and negative predictive value were 40.5% vs 59.5%, 83.3% vs 67.1%, 18.8% vs 14.9% and 93.5% vs 94.4% for NT-proBNP and fibrinogen, respectively. CONCLUSION: In ACS patients, inflammatory biomarkers offer modest incremental information to that provided by clinical risk markers. Fibrinogen and NT-proBNP measurements, however, improve cardiovascular risk prediction.

Role of a streamer-like coronary thrombus in the genesis of unstable angina.

INTRODUCTION: It is generally believed that the coronary occlusion occurs at the site of plaque disruption in acute coronary syndromes. An exceptional mechanism of coronary occlusion, namely a streamer-like thrombus (SLT) originating in a nonstenotic lesion extended distally to obstruct a just distal nondisrupted stenotic segment, was found by angioscopy in patients with unstable angina (UA). This study was carried out to examine the incidence of this phenomenon and its relationship to the subtypes of UA. METHODS: The culprit coronary artery was investigated by angioscopy in successive 48 patients (mean +/- SE age, 61.0 +/- 2.3 years; 10 females and 38 males) with UA. RESULTS: SLT originating in a nonstenotic lesion extended distally, and obstructed the just distal most stenotic segment (DMSS) by its tail in 11 patients (eight with class III and three with class II according to Braunwald's classification). Recurrent anginal attacks were observed in all. The nonstenotic lesion in which the SLT originated was a disrupted yellow plaque in most cases. The SLT was frequently red and yellow in a mosaic pattern, indicating a mixture of fresh thrombus and plaque debris. The plaques that constructed the DMSS were not disrupted. Angiographically, the SLT was not detectable and the entry of the DMSS showed a "tapering" configuration. CONCLUSIONS: Obstruction of the DMSS by the tail of SLT originating in a nonstenotic lesion is another mechanism of UA. Therefore, treatment of both the nonstenotic lesion and DMSS is needed to prevent recurrent thrombus formation and consequent reattacks.

A pilot study of the clinical relevance of the relationship between the serum level of pregnancy-associated plasma protein A and the degree of acute coronary syndrome.

Serum levels of pregnancy-associated plasma protein-A (PAPP-A), high-sensitivity C-reactive protein (hs-CRP) and tumour necrosis factor-alpha (TNF-alpha) were measured in 70 patients with acute coronary syndrome (ACS), comprising 18 with unstable angina (UA), 37 with acute myocardial infarction (AMI) and 15 with stable angina (SA); 15 healthy controls were also included. Levels of PAPP-A were significantly higher in the UA and AMI groups than in the SA and control groups. Levels of PAPP-A were similar in the SA and control groups, and higher in the ACS patients who were cardiac troponin T-negative (comprising UA and AMI patients) than in the control and SA groups. Levels of hs-CRP and TNF-alpha were significantly higher in the SA group than in the control group, significantly higher in the UA group than in the SA and control groups, and significantly higher in the AMI group than in all other groups. Levels of PAPP-A in ACS patients were positively correlated with levels of hs-CRP and TNF-alpha. It would seem, therefore, that PAPP-A is associated with inflammation and might be used to detect plaque instability and rupture before an increase in cardiac troponin T is detectable.