Coronary Plaque Instability Research Articles

Local and Systemic Mechanisms of Plaque Rupture

Mechanisms at the basis of coronary plaque instability are still elusive. On the one hand, accumulating data, from clinical and postmortem studies, suggest the role of systemic factors, in particular inflammation, in plaque rupture. On the other hand, local factors, in particular plaque composition, such as a large lipid-rich core and a thin fibrous cap, presence of activated inflammatory cells, presence of plaque neovascularization, and specific apoptotic processes, may contribute to plaque susceptibility to rupture. In addition, other cofactors, such as platelet activation and clotting factors, are involved in the transition from stable to unstable plaque. The authors discuss the possibility that all these factors have a role in the development of acute coronary syndrome: a systemic inflammatory condition with an enhanced coagulation state may activate local hemodynamic, mechanical, and immune reactions leading to intraplaque cells activation, fibrous cap lysis, and thrombus formation.

Abnormal Glucose Regulation Is Associated With Lipid-Rich Coronary Plaque: Relationship to Insulin Resistance

This study sought to determine lipid and fibrous volume of coronary atherosclerotic plaques in subjects with abnormal glucose regulation (AGR) by integrated backscatter (IB) intravascular ultrasound (IVUS) during percutaneous coronary intervention. Abnormal glucose regulation, including impaired glucose regulation (IGR) and diabetes mellitus (DM), has emerged as an important determinant of cardiovascular risk. We hypothesized that AGR would be associated with coronary plaque instability. Conventional intravascular ultrasound and IB-IVUS using a 40-MHz (motorized pullback 1 mm/s) intravascular catheter was performed in 172 consecutive patients. The percentage of fibrous area and the percentage of lipid area were automatically calculated by IB-IVUS. Three-dimensional analysis of IB-IVUS images was performed to determine the percentage of lipid volume (%LV) and fibrous volume (%FV). Following the World Health Organization criteria, the subjects were classified into the DM group, the IGR group, and the normal glucose regulation group. The cutoff point for the lipid-rich plaque was defined as %LV >44% or %FV <52%, which was the 75th percentile of %LV or the 25th percentile of %FV in this study population. Insulin resistance (IR) was defined as the homeostasis model assessment of insulin resistance (HOMA-IR). There were no significant differences in the baseline characteristics except for glucometabolic parameters. The conventional IVUS analysis indicated that the DM group had a significantly increased plaque volume (and percent plaque volume). In the IB-IVUS analysis, as compared with the normal glucose regulation group, the DM and the IGR groups showed a significant increase in %LV (36 +/- 14% and 37 +/- 13% vs. 29 +/- 14%, p = 0.02) and a significant decrease in %FV (59 +/- 11% and 58 +/- 11% vs. 64 +/- 11%, p = 0.03). The lipid-rich plaque rate was significantly associated with an increasing HOMA-IR in the tertile (p = 0.008). On logistic regression analysis after adjusting for confounding and coronary risk factors, the DM group (odds ratio 3.52, 95% confidence interval 1.13 to 11.0, p = 0.03) and the IGR group (odds ratio 3.92, 95% confidence interval 1.13 to 13.6, p = 0.03) were significantly associated with the lipid-rich plaque. Coronary lesions in patients with AGR are associated with more lipid-rich plaque content, which may be related to the increased IR in these patients.

Role of Toll like receptor signaling pathway in ischemic coronary artery disease

Inflammatory process plays a fundamental role in ischemic coronary artery disease (CAD) in terms of both the etiology of atherosclerosis and the pathophysiology of CAD. In particular, chronic inflammation plays a key role in coronary artery plaque instability and subsequent occlusive thrombosis. It is therefore important to clarify the mechanism underlying the activation of the immune response in the pathogenesis of CAD. Currently 10 toll-like receptors (TLRs) have been reported in mammalian species, and these appear to recognize distinct pathogen-associated molecular patterns controlling innate immune responses. In recent studies, signaling of two forms of human TLR (TLR2 and TLR4) has been shown to be involved in the pathogenesis of CAD, establishing a key link between the progression of coronary atherosclerosis and immune response to both foreign pathogens and endogenously generated inflammatory ligands. A better understanding of TLR signal may provide a novel therapeutic agent for the treatment of CAD. This review summarizes the relationship between the pathogenesis of ischemic coronary artery disease and the human TLR system.

Abstract 2600: Serum Proteomics Identifies Vitamin D-Binding Protein And Prothrombin As Novel Fingerprints of Coronary Thrombosis in Patients with STEMI

One of the intriguing possibilities offered by proteomics analysis is to define new diagnostic and prognostic biomarkers of coronary artery disease. Accordingly, the aim of the present study was to analyze modifications in the serum proteome after acute myocardial infarction. Serum samples were collected from patients (age 63.8±12.6) with ST-Elevation Myocardial Infarction (STEMI) at 2–11 hours after the onset of typical chest pain and before standard therapy was initiated. The control group included 10 age- and sex-matched normal donors. The serum samples were processed to obtain albumin- and IgG-depleted serum. Then, isotope-coded affinity tag (ICAT) method was employed to label cysteine residues and liquid chromatography-Tandem Mass Spectrometry (LC-MS/MS) analysis was performed to measure the labelled proteins. Ten out of 300 defined and analyzed proteins were identified in 100% of the samples. Interestingly, haptoglobin, alpha-1-antitrypsin and ceruloplasmin were significantly increased in the samples from patients with acute STEMI (N=10) compared to controls (N=10). These data well reproduce similar findings reported in recent studies. However, two novel proteins were identified in patients with AMI. Remarkably, we observed a significant increase of vitamin D-binding protein precursor (VDB) and heavy chain prothrombin precursor in the serum from acute STEMI patients compared to control donors. Western blot analysis confirmed the higher amount of the latter two proteins after STEMI. Interestingly, fresh thrombotic plaques, obtained during primary angioplasty, showed high expression of VDB and prothrombin by RT-PCR and immunohistochemistry, postulating a potential role of VDB and prothrombin in coronary plaque instability and thrombosis. In additional studies in ex vivo human platelets VDB, as well as prothrombin, significantly increased ADP-induced platelet aggregation. In conclusion, the serum proteomics analysis employed in this study was able to identify VDB and prothrombin protein variation as novel indicators of acute STEMI. These data could be relevant to establish specific proteomics-based serum fingerprints for diagnosis and prognosis of acute coronary syndromes.

Aortic Plaque Imaging and Monitoring Atherosclerotic Plaque Interventions

The atherosclerotic process that results in coronary artery disease (CAD) is recognized to be a generalized process that may involve the entire vasculature. The association between CAD and atherosclerotic plaques in the thoracic aorta has often been reported using transesophageal echocardiography. An autopsy study showed plaques in the abdominal aorta, but not in the thoracic aorta, to be severe in patients with cardiac events. However, studies evaluating an association between abdominal aortic plaques and CAD are scarce. Recently, magnetic resonance imaging (MRI) has become a useful tool for the noninvasive evaluation of atherosclerotic plaques in both the thoracic and abdominal aortas. Plaques in the thoracic and abdominal aortas were found to be characteristically associated with hypercholesterolemia and smoking, respectively, suggesting different susceptibilities to risk factors. Because patients have various risk factors, it seems to be preferable to evaluate atherosclerosis in multiple vascular beds than in just 1 bed. Magnetic resonance imaging can evaluate atherosclerosis in multiple vascular beds in the same examination session. Complex aortic plaques, especially in the abdominal aorta, were found to be associated with myocardial infarction and complex coronary lesions, suggesting a link between aortic and coronary plaque instability. Aortic MRI may thus be useful for identifying vulnerable patients. Moreover, MRI is a powerful tool to serially evaluate plaque progression and regression. Intensive lipid-lowering therapy can regress aortic plaques, but the susceptibility to lipid lowering and the process of plaque regression may differ between the thoracic and abdominal aortic plaques.

Whole blood choline and plasma choline in acute coronary syndromes: Prognostic and pathophysiological implications

BackgroundWhole blood choline (WBCHO) and plasma choline (PLCHO) concentrations increase rapidly after stimulation of phospholipase D in acute coronary syndromes (ACS). Early risk-stratification was analyzed in 217 patients with suspected ACS and a negative admission troponin T (<0.03 μg/L). MethodsWBCHO and PLCHO were measured using high-performance-liquid-chromatography mass spectrometry. Major cardiac events (MACE) were defined as cardiac death/arrest, coronary intervention or myocardial infarction (MI). ResultsWBCHO (≥28.2 μmol/L) was predictive for MACE (hazard ratio [HR] 2.7; p<0.001), cardiac death/arrest (HR 4.2; p=0.015), heart failure (HR 2.8; p=0.003), coronary intervention (HR 2.1; p=0.01) and MI (HR 8.4; p=0.002) after 30 days. PLCHO (≥25.0 μmol/L) was predictive for MACE (HR 2.6; p=0.005), cardiac death/arrest (HR 15.7; p<0.001), heart failure (HR 6.0; p<0.001) but not for coronary intervention and MI. WBCHO and PLCHO were predictive for MACE in multivariate analysis (Odds ratio [OR] 2.7, p=0.009 and OR 3.3, p=0.03) independently of age, gender, prior MI, coronary risk factors and ECG. ConclusionsWBCHO and PLCHO are significant and independent predictors of major cardiac events in admission troponin T negative acute coronary syndromes. Both are predictive for events related to tissue ischemia and WBCHO is capable of detecting risks associated with coronary plaque instability.

The complex link between oxidised low-density lipoprotein and unstable angina

The role of oxidised low-density lipoprotein (ox-LDL) in plaque destabilisation is controversial; therefore we aimed at comparing plaque and plasma ox-LDL content in stable and unstable ischaemic syndromes. We also assessed the correlation between plaque or plasma ox-LDL and angiographic complex stenosis morphology. Ten consecutive patients with chronic stable angina (SA) and 10 consecutive patients with unstable angina (UA) were studied. Plaque sections obtained by directional coronary atherectomy were immunostained with the monoclonal antibody mAb-4E6, which recognises several oxidation epitopes on LDL (mAb-4E6 ox-LDL), and with the monoclonal antibody mAb-1H11 (mAb-1H11 ox-LDL), which recognises malondialdehyde-modified LDL. An mAb-4E6-based competition ELISA was used for quantification of ox-LDL in plasma. C-reactive protein serum levels were measured by a high-sensitivity nephelometric assay. An angiographic analysis was performed to assess severity and extent of coronary atherosclerotic disease and stenosis morphology. Percent plaque area occupied by mAb-4E6 ox-LDL or mAb-1H11 ox-LDL was similar in patients with SA or UA (22.4 +/- 13.1 vs. 21.1 +/- 19.7%, P = 0.8 and 19.3 +/- 10.4 vs. 16.8 +/- 16.9%, P = 0.6, respectively), whereas ox-LDL plasma levels were significantly higher in patients with UA than in patients with SA (2.4 +/- 1.1 vs. 0.9 +/- 0.6 mg/dl; P = 0.03). Furthermore, a significant correlation was found between plasma levels of ox-LDL and the number of angiographically complex lesions (P = 0.03) or C-reactive protein serum levels (P = 0.04). Neither plaque mAb-4E6 ox-LDL nor plaque mAb-1H11 ox-LDL seem to be a major trigger of coronary plaque instability. However, circulating ox-LDL might be involved in plaque vulnerability and coronary artery disease activity.

Determinants of Arterial Wall Remodeling During Lipid-Lowering Therapy

Coronary plaque progression and instability are associated with expansive remodeling of the arterial wall. However, the remodeling response during plaque-stabilizing therapy and its relationship to markers of lipid metabolism and inflammation are incompletely understood. Serial intravascular ultrasound (IVUS) data from the Reversal of Atherosclerosis with Aggressive Lipid Lowering Therapy (REVERSAL) trial were obtained during 18 months of intensive versus moderate lipid-lowering therapy. In a subgroup of 210 patients, focal coronary lesions with mild luminal narrowing were identified. Lumen area, external elastic membrane (EEM) area, and plaque area were determined at the lesion and proximal reference sites at baseline and during follow-up. The remodeling ratio (RR) was calculated by dividing the lesion EEM area by the reference EEM area. The relationship between the change in remodeling, change in plaque area, lipid profile, and inflammatory markers was examined. At the lesion site, a progression in plaque area (8.9+/-25.7%) and a decrease in the RR (-3.0+/-11.2%) occurred during follow-up. In multivariable analyses, the percentage change in plaque area (P<0.0001), baseline RR (P<0.0001), baseline lesion lumen area (0.019), logarithmic value of the change in high-sensitivity C-reactive protein (P=0.027), and hypertension at baseline (P=0.014) showed a significant, direct relation with the RR at follow-up. Lesion location in the right coronary artery (P=0.006), percentage change in triglyceride levels (P=0.049), and age (P=0.037) demonstrated a significant, inverse relation with the RR at follow-up. Changes in LDL cholesterol, HDL cholesterol, and treatment group demonstrated no significant associations. Constrictive remodeling of the arterial wall was observed during plaque-stabilizing therapy with statin medications and appears related to their antiinflammatory effects.

Patients With Acute Coronary Syndrome Show Oligoclonal T-Cell Recruitment Within Unstable Plaque

Recent studies indicate that T-cell activation may play an important role in the pathophysiology of acute coronary syndromes (ACS). However, although those studies detected T-cell expansion in peripheral blood cells, demonstration of specific T-cell expansion within the plaque of patients with ACS is lacking. The present study aims to address whether a specific, immune-driven T-lymphocyte recruitment occurs within the unstable plaque of patients with ACS. We simultaneously examined the T-cell repertoire using CDR3 size analysis both in coronary plaques (obtained by directional atherectomy) and in peripheral blood of patients with either ACS (n=11) or chronic stable angina (n=10). Unstable plaques showed a 10-fold increase in T-cell content by quantitative PCR. Using spectratyping analysis, we found several specific T-cell clonotype expansions only in unstable plaque from each patient with ACS, indicating a specific, antigen-driven recruitment of T cells within unstable lesions. For the first time, T-cell repertoire was investigated directly into coronary plaques; using this approach, we demonstrate that coronary plaque instability in the setting of ACS is associated with immune-driven T-cell recruitment, specifically within the plaque.

A Possible Association Between Coronary Plaque Instability and Complex Plaques in Abdominal Aorta

Coronary plaque instability causes myocardial infarction (MI). Angiographic lesions with such instability are complex lesions. Complex carotid plaques were reported to be prevalent in unstable angina. We investigated associations between coronary plaque instability, such as MI and angiographic complex coronary lesions, and aortic plaques. Aortic MRI was performed in 146 patients undergoing coronary angiography, of whom 108 had coronary artery disease (CAD) and 44 also had MI. Prevalence of plaques in thoracic and abdominal aortas was higher in patients with than without CAD (73% and 94% versus 32% and 79%), but it was similar in CAD patients with and without MI. Notably, complex plaques in abdominal aorta were more prevalent in CAD patients with than without MI (36% versus 14%; P<0.025). In multivariate analysis, abdominal complex plaques were associated with MI (odds ratio [OR], 4.5; 95% CI, 1.5 to 13.8). Among patients without MI, thoracic and abdominal complex plaques were more prevalent in patients with than without complex coronary lesions (22% and 33% versus 2% and 7%; P<0.05). Abdominal complex plaques were also associated with complex coronary lesions (OR, 9.8; 95% CI, 1.1 to 85.9). Complex plaques in abdominal aorta were associated with MI and complex coronary lesions, suggesting a link between coronary and aortic plaque instability.

Stabilization of Carotid Atheroma Assessed by Quantitative Ultrasound Analysis in Nonhypercholesterolemic Patients With Coronary Artery Disease

This study examined whether intensive cholesterol-lowering therapy with statins in nonhypercholesterolemic patients is effective in improving echolucency of vulnerable plaques assessed by ultrasound with integrated backscatter (IBS) analysis. Atherosclerotic plaque stabilization is a promising clinical strategy to prevent cardiovascular events in patients with coronary artery disease (CAD). There is a correlation between coronary and carotid plaque instability, and echolucent plaques are recognized as vulnerable plaques. Consecutive nonhypercholesterolemic patients with CAD were randomly assigned Adult Treatment Panel-III diet therapy (diet group; n = 30) or pravastatin (statin group; n = 30). Echolucent carotid plaques were monitored by measuring intima-media thickness (IMT) and echogenicity by IBS for six months. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-sensitivity C-reactive protein were significantly decreased in the statin group (from 197 +/- 15 mg/dl to 170 +/- 18 mg/dl [p < 0.001]; from 131 +/- 14 mg/dl to 99 +/- 14 mg/dl [p < 0.001]; and from 0.11 [0.04 to 0.22] mg/dl to 0.06 [0.04 to 0.11] mg/dl [p < 0.05]; respectively), whereas only total cholesterol was moderately reduced (from 193 +/- 24 mg/dl to 185 +/- 22 mg/dl [p < 0.05]) and LDL-C and triglycerides insignificantly reduced in the diet group. Significant increases of echogenicity of carotid plaques were noted in the statin group but not in the diet group (from -18.5 +/- 4.1 dB to -15.9 +/- 3.7 dB [p < 0.001] and from -18.2 +/- 4.0 dB to -18.9 +/- 3.5 dB [p = 0.13]; respectively) without significant regression of plaque-IMT values in both groups. Statin therapy is rapidly effective in increasing echogenicity of vulnerable plaques without regression of plaque size in nonhypercholesterolemic patients with CAD. Quantitative assessment of carotid plaque quality by ultrasound with IBS is clinically useful for monitoring atherosclerotic lesions by evaluating vulnerability of atheroma.

Monocyte matrix and ADAM metalloproteinase expression in type 2 diabetes after aspirin therapy

The matrix metalloproteinase system (MMP and the TIMP inhibitors), and the ADAM metalloproteinases, have roles in maintaining vascular plaque stability and the shedding of cell surface molecules, such as TNF-α and adhesion molecules; aspirin suppresses MMP expression and ADAM activity from some cell lines in vitro. In a randomised prospective controlled study, we examined peripheral venous monocyte MMP-9, TIMP-1 and ADAM mRNA levels, and protein expression, in subjects with type 2 diabetes ( n = 10) and controls ( n = 14) before and after oral aspirin therapy (150 mg daily for 14 days) or no active intervention. Baseline monocyte TIMP-1 mRNA levels were significantly lower in the diabetes group ( p = 0.0014), although monocyte MMP-9 mRNA, and MMP-9 and TIMP-1 protein expression after culture did not differ significantly between groups. Plasma MMP-9 ( p = 0.027) and TIMP-1 ( p = 0.016) concentrations were significantly greater, and the ratio of plasma TIMP-1:MMP-9 concentrations significantly lower, in the diabetes group ( p = 0.023). ADAM mRNA levels did not differ significantly between groups and oral aspirin therapy had no significant effect on any variable. Type 2 diabetes is characterised by reduced monocyte TIMP-1 mRNA levels, and a lower plasma MMP-9 to TIMP-1 protein ratio compared to controls, a pattern that would promote coronary plaque instability if reproduced within vascular plaque. Monocyte ADAM mRNA levels do not differ between group and oral aspirin has no significant effect on these variables.

Fluvastatin in the therapy of acute coronary syndrome: Rationale and design of a multicenter, randomized, double-blind, placebo-controlled trial (The FACS Trial)[ISRCTN81331696

BackgroundActivation of inflammatory pathways plays an important contributory role in coronary plaque instability and subsequent rupture, which can lead to the development of acute coronary syndrome (ACS). Elevated levels of serum inflammatory markers such as C-reactive protein (CRP) represent independent risk factors for further cardiovascular events. Recent evidence indicates that in addition to lowering cholesterol levels, statins also decrease levels of inflammatory markers. Previous controlled clinical trials reporting the positive effects of statins in participants with ACS were designed for very early secondary prevention. To our knowledge, no controlled trials have evaluated the potential benefits of statin therapy, beginning immediately at the time of hospital admission. A previous pilot study performed by our group focused on early initiation of cerivastatin therapy. We demonstrated a highly significant reduction in levels of inflammatory markers (CRP and interleukin-6). Based on these preliminary findings, we are conducting a clinical trial to evaluate the efficacy of another statin, fluvastatin, as an early intervention in patients with ACS.MethodsThe FACS-trial (Fluvastatin in the therapy of Acute Coronary Syndrome) is a multicenter, randomized, double-blind, placebo-controlled study evaluating the effects of fluvastatin therapy initiated at the time of hospital admission. The study will enroll 1,000 participants admitted to hospital for ACS (both with and without ST elevation). The primary endpoint for the study is the influence of fluvastatin therapy on levels of inflammatory markers (CRP and interleukin-6) and on pregnancy associated plasma protein A (PAPP-A). A combined secondary endpoint is 30-day and one-year occurrence of death, nonfatal myocardial infarction, recurrent symptomatic ischemia, urgent revascularization, and cardiac arrest.ConclusionThe primary objective of the FACS trial is to demonstrate that statin therapy, when started immediately after hospital admission for ACS, results in reduction of inflammation and improvement of prognosis. This study may contribute to new knowledge regarding therapeutic strategies for patients suffering from ACS and may offer additional clinical indications for the use of statins.

Oxidized low-density lipoprotein levels circulating in plasma and deposited in the tissues: Comparison between Helicobacter pylori-associated gastritis and acute myocardial infarction

Background Oxidized low-density lipoprotein (ox-LDL) is a key factor in the progression of atherosclerosis. We developed a sensitive method for measuring plasma ox-LDL levels using a novel anti-ox-LDL antibody. Recently, several studies have shown positive associations between Helicobacter pylori ( H pylori) infection and coronary heart disease. Thus the question arises whether an increase in the plasma levels of ox-LDL occurs in patients with H pylori gastritis. Methods We measured plasma ox-LDL levels in patients with H pylori gastritis (n = 27) and compared them with those in patients with acute myocardial infarction (AMI) (n = 62) and stable angina pectoris (SAP; n = 63) and those in control subjects (n = 64). In addition, ox-LDL localization and the presence of macrophages and neutrophils were studied immunohistochemically in gastritis specimens and in coronary culprit lesions obtained from patients with AMI. Results Plasma ox-LDL levels in patients with AMI were significantly higher than those in patients with SAP ( P <.0001), patients with H pylori gastritis ( P <.0001), or in control subjects ( P <.0001; AMI, 1.34 ± 0.95; SAP, 0.61 ± 0.29; Gastritis, 0.53 ± 0.17; control, 0.57 ± 0.23 ng/5μg LDL protein). Immunohistochemically, H pylori gastritis specimens showed distinct infiltration of macrophages and myeloperoxidase-positive neutrophils; however, ox-LDL localization was not detected. In contrast, coronary culprit plaques revealed strong positivity for ox-LDL in ruptured lipid cores with abundant macrophage-derived foam cells, and these plaques also contained myeloperoxidase-positive neutrophils. Conclusion Our results suggest that plasma ox-LDL levels do not seem to be associated with H pylori infection, but do relate to coronary plaque instability in AMI.

Inflammation as a possible link between coronary and carotid plaque instability

Inflammation as a possible link between coronary and carotid plaque instability

Coronary plague instability in severe acute respiratory syndrome

In his second week of severe acute respiratory syndrome (SARS) illness, a patient developed an unusually complicated course of acute coronary syndrome. One day after initial stabilization of a non-ST-elevated anterior myocardial infarction (MI), he sustained an ST-elevated anterior MI. Eight hours after emergency coronary intervention to the culprit lesion, he developed another ST-elevated MI in the inferior territory. Acute inflammation and cytokine storm in the immunopathological phase of SARS may play a role in coronary plague instability. Physicians should be alert to this potentially fatal complication and adopt appropriate vigilant and aggressive management strategies.

Role and importance of biochemical markers in clinical cardiology.

This paper reviews the current contribution of the biochemical marker determination to clinical cardiology and discusses some important developments in this field. Biochemical markers play a pivotal role in the diagnosis and management of patients with acute coronary syndrome (ACS), as witnessed by the incorporation of cardiac troponins into new international guidelines for patients with ACS and in the re-definition of myocardial infarction. Despite the success of cardiac troponins, there is still a need for the development of early markers that can reliably rule out ACS from the emergency room at presentation and also detect myocardial ischaemia in the absence of irreversible myocyte injury. Under investigation are two classes of indicators: markers of early injury/ischaemia and markers of inflammation and coronary plaque instability and disruption. Finally, with the characterisation of the cardiac natriuretic peptides, Laboratory Medicine is also assuming a role in the assessment of cardiac function.

Inflammation as a possible link between coronary and carotid plaque instability.

Multiple complex stenoses, plaque fissures, and widespread coronary inflammation are common in acute coronary syndromes. A systemic cause of atherosclerotic plaque instability is also suggested by studies of ischemic cerebrovascular disease. We investigated the association between coronary and carotid plaque instability and the potential common causal role of inflammation. The ultrasound characteristics of carotid plaques were evaluated retrospectively in patients scheduled for coronary bypass surgery, 181 with unstable and 92 with stable angina, and prospectively in a similar group of patients, 67 with unstable and 25 with stable angina, in whom serum C-reactive protein levels were also measured. The prevalence of carotid plaques was similar in the retrospective and prospective studies and >64% in both unstable and stable coronary patients. The prevalence of complex, presumably unstable carotid plaques was 23.2% in unstable versus 3.2% in stable patients (P<0.001) in the retrospective study and 41.8% versus 8.0% (P=0.002) in the prospective study. C-reactive protein levels were higher in patients with complex (7.55 mg/L) than in those with simple (3.94 mg/L; P<0.05) plaques or without plaques (2.45 mg/L; P<0.05). On multivariate analysis, unstable angina and C-reactive protein levels >3 mg/L were independently associated with complex carotid plaques (OR, 6.09; 95% CI, 1.01 to 33.72; P=0.039, and OR, 5.80; 95% CI, 1.55 to 21.69; P=0.009, respectively). In unstable angina, plaque instability may not be confined to coronary arteries, and inflammation may be the common link with carotid plaque instability. These observations may have relevant implications for understanding the mechanisms of acute widespread atherothrombotic plaque inflammation.

Tenascin-C is associated with coronary plaque instability in patients with acute coronary syndromes.

Tenascin-C (TNC) is an extracellular matrix glycoprotein that increases after inflammation and injury. In cultured cells TNC has been reported to markedly induce the expression of matrix metalloproteinase-9, which stimulates collagen degradation in the fibrous cap of human atherosclerotic plaque. Immunohistochemical techniques were used to analyze the expression of TNC protein in 51 coronary atherectomy specimens obtained from patients with stable angina pectoris (SAP, n=23) or acute coronary syndromes (ACS) (n=28; unstable angina pectoris, n=20, acute myocardial infarction, n=8). Immunostaining for alpha-smooth muscle actin, CD68, CD45, and CD31 was also performed in serial sections to identify the cell types that express TNC protein. The %TNC + area (percentage of the area of immunostaining for TNC protein in the total surface area of the plaque) was larger in coronary samples with the plaque characteristics of thrombus, angiogenesis, intraplaque hemorrhage, and macrophage (CD68(+)), and lymphocyte (CD45 (+)) clusters than in coronary samples without them (52+/-3.4 vs 39+/-4.8, p<0.05; 57+/-3.7 vs 36+/-3.7, p<0.01; 51+/-3.6 vs 39+/-4.8, p<0.05; 53+/-3.4 vs 33+/-4.5, p<0.01; 56+/-4.1 vs 37+/-3.6, p<0.01, respectively). The presence of other components, such as dense fibrous tissue, neointimal hyperplasia, atheromatous gruel and calcification, was not significantly correlated with the %TNC + area. The %TNC + area was larger in coronary samples from patients with ACS than in samples from patients with SAP (56+/-3.2% vs 34+/-4.3%, p<0.01). The results suggest that TNC may have specific functions in coronary plaque formation and may be involved in the pathogenesis of coronary lesions in ACS.

Biochemical markers of cardiac diseases

This article reviews the current contribution of the determination of biochemical markers to clinical cardiology and discusses some important developments in this field. Biochemical markers play a pivotal role in the diagnosis and management of patients with acute coronary syndrome (ACS), as witnessed by the incorporation of cardiac troponins into new international guidelines for patients with ACS and in the redefinition of myocardial infarction. Despite the success of cardiac troponins, there is still a need for development of early markers that can reliably rule out ACS from the emergency room at presentation and detect myocardial ischemia also in the absence of irreversible myocyte injury. Under investigation are two classes of indicators: markers of early injury/ischemia and markers of coronary plaque instability and disruption. Finally, with the characterization of the cardiac natriuretic peptides, Laboratory Medicine is also assuming part in the assessment of cardiac function.