Biomarkers Of Plaque Instability Research Articles

CXCL1 as a Potential Biomarker of Plaque Instability in Carotid Stenosis. Preliminary Report.

Biomarkers of atherosclerotic plaque instability are needed. This study aimed to evaluate the level of chemokine CXCL1 (CXC motif ligand 1) in plasma and atherosclerotic plaques in patients with carotid stenosis and correlate that with plaque morphology. The study group included 82 patients (30 women and 52 men) aged 50-90 years (mean 68.1 ± 8.9) who underwent elective carotid endarterectomy. The obtained atherosclerotic plaques were macroscopically and microscopically assessed according to the American Heart Association (AHA) classification. Fifty-one (62.2%) and 31 (37.8%) of the plaques were unstable and stable, respectively. The mean concertation of CXCL1 in plaques in asymptomatic and symptomatic patients was 0.00 (±0.00) vs 88.90 (±95.19) pg/ml, respectively (P = 0.000). The mean plasma concentration of CXCL1 in the study group was 42.40 (±85.79) pg/ml, while in the control group (healthy volunteers without lesions in the carotid arteries) it was 0.00 pg/mL (±0.00) (P = 0.000). The mean plasma CXCL1 concertation in asymptomatic and symptomatic patients was 22.08 (±49.13) versus 67.72 (±107.91) pg/ml, respectively (P = 0.031). Significantly higher CXCL1 concentration in atherosclerotic plaques and plasma in symptomatic patients compared with asymptomatic patients probably resulted from unstable lesions in the carotid arteries.

YKL-40 Is Associated With Ultrasound-Determined Carotid Atherosclerotic Plaque Instability.

Background and Aims: YKL-40, an inflammatory biomarker, has been reported to be involved in the process and progression of atherosclerosis. Several studies have investigated the association between YKL-40 and plaque and suggested YKL-40 might be a potential biomarker for plaque instability. This study aimed to investigate the association between YKL-40 and carotid plaque instability.Methods: Based on a community-based study in Beijing from February 2014 to May 2016, 1,132 participants with carotid plaques were enrolled in this study. Data on demographics and medical history were collected through face-to-face interviews, and fasting blood samples were collected and stored. We used ultrasound to evaluate the presence of carotid plaque and its instability. The level of YKL-40 was measured by enzyme-linked immunosorbent assay (ELISA). Multivariate logistic regression analysis was performed to investigate the association between YKL-40 level and carotid atherosclerotic plaque instability.Results: The mean age of the 1,132 participants was 58.0 (52.0–64.0) years, and 560 (49.5%) were male. Unstable plaques were detected in 855 (75.53%) participants. YKL-40 level was classified into four groups according to its quartile: quartile 1: <25.47 ng/mL, quartile 2: 25.47–39.53 ng/mL, quartile 3: 39.53–70.55 ng/mL, quartile 4: ≥70.55 ng/mL. After adjusting for age, sex, smoking, alcohol drinking, medical history, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, homocysteine, high-sensitivity C-reactive protein, and plaque thickness, the top quartiles of YKL-40 level were significantly associated with unstable plaque (quartile 3: OR 2.10, 95% CI 1.29–3.40; quartile 4: OR 1.70, 95% CI 1.04–2.80).Conclusion: This study found that YKL-40 was associated with carotid plaque instability determined by ultrasound. Individuals with high YKL-40 may have a higher risk of unstable carotid plaque.

Identification of biomarker panels as predictors of severity in coronary artery disease.

Matrix metalloproteinases (MMPs) are implicated in atherosclerotic plaque rupture and recondition. Specific tissue inhibitors (TIMPs) control MMP functions. Both MMPs and TIMPs are potential biomarkers of plaque instability. Elevated Apo‐CII and CIII and Apo‐E levels are recognized as cardiovascular disease risk factors. We aimed to establish the best blood biomarker panel to evaluate the coronary artery disease (CAD) severity. Plasma levels of MMP‐3 and MMP‐9, TIMP‐1 and TIMP‐2, Apo‐CII, Apo‐CIII and Apo‐E were measured in 472 patients with CAD evaluated by coronary angiography and electrocardiography, and in 285 healthy controls. MMP‐3 and MMP‐9 plasma levels in CAD patients were significantly increased (P < 0.001) compared to controls (3.54‐ and 3.81‐fold, respectively). Furthermore, these increments are modulated by CAD severity as well as for Apo‐CII and Apo‐CIII levels (P < 0.001). TIMPs levels were decreased in CAD versus controls (P < 0.001) and in inverse correlation to MMPs. Standard ROC curve approach showed the importance of panels of biomarkers, including MMP‐3, MMP‐9, TIMP‐1, TIMP‐2, Apo‐CII and Apo‐CIII, for disease aggravation diagnosis. A high area under curve (AUC) value (0.995) was reached for the association of MMP‐9, TIMP‐2 and Apo‐CIII. The unbalance between MMPs and TIMPs in vascular wall and dyslipidaemia creates favourable conditions for plaque disruption. Our study suggests that the combination of MMP‐9, TIMP‐2 and Apo‐CIII values (‘CAD aggravation panel’) characterizes the severity of CAD, that is electrophysiological state, number of involved vessels, stent disposal and type of stent.

Infarct Recurrence in Intracranial Atherosclerosis: Results from the MyRIAD Study

BackgroundIntracranial atherosclerotic disease (ICAD) is a common cause of ischemic stroke with a high risk of clinical stroke recurrence. Multiple mechanisms may underlie cerebral ischemia in this condition. The study's objective is to discern the mechanisms of recurrent ischemia in ICAD through imaging biomarkers of impaired antegrade flow, poor distal perfusion, abnormal vasoreactivity, and artery-to-artery embolism. MethodsThis prospective multicenter observational study enrolled patients with recent (≤21 days) ischemic stroke or transient ischemic attack (TIA) caused by ICAD with 50-99% stenosis treated medically. We obtained baseline quantitative MRA (QMRA), perfusion MRI (PWI), transcranial Doppler vasoreactivity (VMR), and emboli detection studies (EDS). The primary outcome was ischemic stroke in the territory of the stenotic artery within 1 year of follow-up; secondary outcomes were TIA at 1 year and new infarcts in the territory on MRI at 6-8 weeks. ResultsAmongst 102 of 105 participants with clinical follow-up (mean 253±131 days), the primary outcome occurred in 8.8% (12.7/100 patient-years), while 5.9% (8.5/100 patient-years) had a TIA. A new infarct in the territory of the symptomatic artery was noted in 24.7% at 6-8 weeks. A low flow state on QMRA was noted in 25.5%, poor distal perfusion on PWI in 43.5%, impaired vasoreactivity on VMR in 67.5%, and microemboli on EDS in 39.0%. No significant association was identified between these imaging biomarkers and primary or secondary outcomes. ConclusionsDespite intensive medical management in ICAD, there is a high risk of clinical cerebrovascular events at 1 year and an even higher risk of new imaging-evident infarcts in the subacute period after index stroke. Hemodynamic and plaque instability biomarkers did not identify a higher risk group. Further work is needed to identify mechanisms of ischemic stroke and infarct recurrence and their consequence on long-term physical and cognitive outcomes. Trial RegistrationClinicalTrials.gov: NCT02121028.

Diagnostic Test of Serum Pregnancy-Associated Plasma Protein-A Level as Biomarker for Early Diagnosis of Acute Myocardial Infarction

Acute coronary syndrome is the primary cause of death from heart disease worldwide. This syndrome is caused by ruptured/eroded coronary atherosclerotic plaque, resulting in partial/total occlusion of thrombosis. It is necessary to find novel cardiac biomarkers for the identification of plaque progression before ischemic and myocardial necrosis events. Pregnancy Associated Plasma Protein-A (PAPP-A) is an atherosclerotic mediator proven to be a biomarker for plaque instability. This study aimed to determine the performance of serum PAPP-A as a biomarker for the early diagnosis of AMI. This research was an analytical observational study with a cross-sectional approach. Serum PAPP-A was measured using enzyme-linked immunosorbent assay in 82 new patients. They had ACS and were admitted to the emergency installation of Dr. Moewardi Hospital in Surakarta in August-September 2019. The subjects were grouped into the AMI group (NSTEMI and STEMI) consisting of 49(59.8%) subjects and non-AMI (UAP) group composed of 33(40.2%) subjects based on ACS diagnostic criteria of PERKI 2018. Receiver Operator Characteristic (ROC) curve analysis showed that PAPP-A was a good discriminator between AMI and non-AMI patients. The area under the curve was 0.968, 95% CI (0.932–1.004), with a sensitivity of 91.8% and specificity of 90.9% (p&lt; 0.05). The cut-off value from the ROC curve was 2,526 ng/mL. Serum PAPP-A level has excellent performance as a biomarker for early diagnosis of AMI. It can also function as a screening instrument for the identification of UAP cases developing into AMI.

P4442miR-200c is up-regulated in lesional skin and plasma of patients affected by psoriasis and correlates with disease severity and cardiovascular risk

Abstract Background Psoriasis is a common, chronic inflammatory disease involving skin. Psoriatic patients mostly show the plaque-type clinical form and several comorbidities, including cardiovascular (CV) diseases. We previously showed that miR-200 family members (miR-200s) is induced by reactive oxygen species (ROS). miR-200c is the most up-regulated member and is responsible for apoptosis, senescence, endothelial dysfunction, ROS increase and nitric oxide decrease. Circulating miR-200c is upregulated in Familial Hypercholesterolemia in children, a pathology associated with ROS increase and atherosclerosis. miR-200c increases also in carotid plaques and plasma of atherosclerotic pts vs healthy subjects and positively correlates with plaque instability biomarkers. Purpose Given the role of miR-200s in ROS modulation, endothelial dysfunction, cardiac remodelling and inflammation, all features associated with psoriasis, we wondered whether miR-200s were modulated in lesional skin (LS) and plasma of psoriatic patients (Pso) and whether miR-200 levels correlated with CV risk. Methods 29 Pso were compared to 29 control subjects (Ctrl) age- and sex-matched. All Pso had a severe psoriasis, defined as Psoriasis Area and Severity Index (PASI) &gt;10 and one of the following: at least two systemic psoriasis treatments, psoriasis onset &lt;40 years of age, disease duration &gt;10 years. Exclusion criteria were: diabetes, cerebrovascular events, myocardial infarction, and/or myocardial revascularization, psoriatic arthritis. Total RNA was extracted from plasma and miR-200 levels assayed by quantitative real-time PCR. The clinical parameters were similar between the two groups except for Total Cholesterol (mg/dl) (Ctrl 193.3±6.2; Pso 213.2±6.9; P&lt;0.05). Blood pressure measurement, wave reflection analysis and pulse wave velocity (PWV) were similar between groups, echocardiographic parameters were different for left ventricular (LV) mass index (g/m2) (Ctrl 84.2±5.2; Pso 102.5±4.7; P&lt;0.05) and relative wall thickness (RWT) (Ctrl 0.4±0.0; Pso 0.48±0.0; P&lt;0.01). Total RNA was extracted from biopsies of nonlesional (NLS) and LS of 6 Pso and 6 healthy subject skin (HS). Results miR-200s were increased in LS vs NLS samples. miR-200c was the most expressed and was upregulated also in LS vs HS (2.0+0.2 fold-increase; P&lt;0.01). Circulating miR-200c (2.5+0.5 fold-increase; P&lt;0.05) and miR-200a (4.8+0.7 fold; P&lt;0.0001) were up-regulated in Pso vs Ctr. Circulating miR-200c positively correlated with LV mass (Rs=0.32; P&lt;0.05), RWT (Rs=0.32; P&lt;0.05) and diastolic dysfunction assessed with E/e' parameters (Rs=0.34; P&lt;0.05). Circulating miR-200a correlated only with LV mass, although not significantly (Rs=0.30; P=0.06). miR-200c exhibited a significant positive correlation with PASI (Rs=0.43; P&lt;0.05) and with disease duration of (Rs=0.40; P&lt;0.05). Conclusion miR-200c is upregulated in skin plaques and plasma of Pso, and might be involved in inflammatory and CV risk increase in these patients. Acknowledgement/Funding Ministero della Salute RF-2016-02362708 to AM and MCC

Expression of TLR4-PTGE2 signaling genes in atherosclerotic carotid plaques and peripheral blood.

Toll-like receptor 4 (TLR4)/prostaglandine synthetase 2 (PTGS2) signaling plays a relevant role in atherosclerotic plaque vulnerability. The purpose of this study was to check the gene expression of 6 genes participating to TLR4/PTGS2 signaling (TLR4, PTGS2, ACSL4, PTGER3, PTGER4, and EPRAP) in carotid plaques and blood samples from the same individual and to evaluate these genes as biomarker of plaque progression. We investigated differential gene expression by qRT-PCR in 62 atherosclerotic patients' carotid plaques and corresponding blood sample. A very weak or no correlation was observed in the overall population or analyzing asymptomatic patients. These analyzed genes are most likely not suitable for inclusion in the clinical routine as biomarkers of plaque instability.

Biomarkers of plaque instability.

Atherosclerosis is the proximate cause of arterial thrombosis, leading to acute occlusive cardiovascular syndromes. Thrombosis in atherosclerosis usually results from rupture of the fibrous cap of atherosclerotic plaques with a smaller proportion resulting from superficial endothelial erosion. Ruptured plaques are often associated with intimal and adventitial inflammation, increased size of lipid-rich necrotic core with thinned out collagen-depleted fibrous cap, outward remodeling, increased plaque neovascularity, intraplaque hemorrhage, and microcalcification. By inference, non-ruptured plaques with similar compositional features are considered to be at risk for rupture and hence are labeled vulnerable plaques or high-risk plaques. Identification of vulnerable plaques may help in predicting the risk of acute occlusive syndromes and may also allow targeting for aggressive systemic and possibly local therapies. Plaque rupture is believed to result from extracellular matrix (which comprises the protective fibrous cap) dysregulation due to excessive proteolysis in the context of diminished matrix synthesis. Inflammation is believed to play a key role by providing matrix-degrading metalloproteinases and also by inducing death of matrix-synthesizing smooth muscle cells. Systemic markers of inflammation are thus the most logical forms of potential biomarkers which may predict the presence of vulnerable or high-risk plaques. Several studies have suggested the potential prognostic value of a variety of systemic markers, but regrettably, their overall clinical predictive value is modestly incremental at best, especially for individual subjects compared to groups of patients. Nevertheless, continued investigation of reliable, cost-effective biomarkers that predict the presence of a high-risk plaque and future athero-thrombotic cardiovascular events with greater sensitivity and specificity is warranted.

MicroRNA-21 is a unique signature associated with coronary plaque instability in humans by regulating matrix metalloproteinase-9 via reversion-inducing cysteine-rich protein with Kazal motifs

BackgroundCoronary atherosclerotic unstable plaque is one of the leading causes of cardiovascular death. Macrophage-derived matrix metalloproteinase (MMP) 9 is considered for degrading extracellular matrix and collagen, thereby thinning the fibrous cap in plaques. miR-21 is implicated to play an important role in the progression of atherosclerosis. Nevertheless, miR-21 as the biomarker for coronary atherosclerotic unstable plaque remains unknown. We aimed to investigate the prediction role of miR-21 for unstable plaque by pathway study of miR-21 on MMPs and its inhibitor RECK in macrophages. MethodsExpression of miR-21 in macrophages and serum miR-21 as well as MMP-9 was measured in patients with coronary non-calcified plaque, calcified plaque and controls. In vitro experiment was done in human macrophages by over-expressing miR-21 or down-regulating RECK. The regulation of RECK and MMP-9 by miR-21 was evaluated by western blotting and siRNA strategy. ResultsPatients with non-calcified coronary artery lesions had significantly higher miR-21 in macrophages and lower miR-21 serum levels compared to the control and calcified plaque patients. At the same time, the serum levels of MMP-9 were significantly elevated in non-calcified patients. Experiments in vitro indicated that over-expressing miR-21 could induce the expression and secretion of pro-MMP-9 and active-MMP-9 in human macrophages via targeting gene RECK, and knocking down RECK expression by specific siRNA can resemble that of miR-21 over-expression. ConclusionsmiR-21 might be a biomarker for plaque instability by suppressing target gene RECK to promote the expression and secretion of MMP-9 in macrophages.

Degradation of Troponin I in Serum or Plasma: Mechanisms, and Analytical and Clinical Implications

A prolonged myocardial ischemia, which results from a total deprivation of blood supply to an area of cardiac muscle for an appreciable period of time, is the leading mechanism responsible for acute myocardial infarction (AMI). The irreversible injury of myocardiocytes and the subsequent release of a variety of intracellular components into blood is the cornerstone of the diagnosis of AMI. Cardiac troponins are advocated as the biochemical gold standards among the various biomarkers of plaque instability, plaque rupture, ischemia, reversible cellular injury, and early and late necrosis (i.e., irreversible injury). The assessment of cardiac troponins in the diagnostic approach of patients with chest pain presents, however, some specific challenges due to the complex mechanisms of release from the injured myocardium, as well as to the enzymatic degradation by cardiac and extracardiac proteases (i.e., calpains, caspases, cathepsin L, and gelatinase A) that might alter the immunoreactivity (and thus laboratory detection) of the molecules. These two aspects will be discussed in this article, with specific focus on cardiac troponin I, as a variety of immunoassays based on antibodies which recognize different epitopes on the molecule is available for the measurement of this important cardiac biomarker.

Markers of Plaque Instability in the Early Diagnosis and Risk Stratification of Acute Myocardial Infarction

Plaque erosion and plaque rupture occur early in the pathophysiology of acute myocardial infarction (AMI). We hypothesized that markers of plaque instability might be useful in the early diagnosis and risk stratification of AMI. In this multicenter study, we examined 4 markers of plaque instability, myeloperoxidase (MPO), myeloid-related protein 8/14 (MRP-8/14), pregnancy-associated plasma protein-A (PAPP-A), and C-reactive protein (CRP) in 398 consecutive patients presenting to the emergency department with acute chest pain and compared them to normal and high-sensitivity cardiac troponin T (cTnT and hs-cTnT). The final diagnosis was adjudicated by 2 independent cardiologists. Primary prognostic end point was death during a median follow-up of 27 months. The adjudicated final diagnosis was AMI in 76 patients (19%). At emergency department presentation, concentrations of all 4 biomarkers of plaque instability were significantly higher in patients with AMI than in patients with other diagnoses. However, their diagnostic accuracy as quantified by the area under the ROC curve (AUC) was low (MPO 0.63, MRP-8/14 0.65, PAPP-A 0.62, CRP 0.59) and inferior to both normal and high-sensitivity cardiac troponin T (cTnT 0.88, hs-cTnT 0.96; P<0.001 for all comparisons). Thirty-nine patients (10%) died during follow-up. Concentrations of MPO, MRP-8/14, and CRP were higher in nonsurvivors than in survivors and predicted all-cause mortality with moderate accuracy. Biomarkers of plaque instability do not seem helpful in the early diagnosis of AMI but may provide some incremental value in the risk stratification of patients with acute chest pain.

PET imaging of aortic atherosclerosis: Is combined imaging of plaque anatomy and function an amaranthine quest or conceivable reality?

Traditionally, blood vessels have been studied using contrast luminography to determine the site, extent and severity of luminal compromise by atherosclerotic deposits. Similar anatomical data can now be acquired non-invasively using ultrasound, computed tomography or magnetic resonance imaging. Plaque stability is an important determinant of subsequent vascular events and currently functional data on the stability of plaque is less well provided by these methods. The search for non-invasive techniques to image combined plaque anatomy and function has been pursued with visionary anticipation. This expectation may soon be realised as imaging with radionuclide-labelled atheroma-targeted contrast agents has demonstrated that plaque functional characteristics can now be shown. Increasingly positron emission tomography/computed tomography (PET/CT) imaging with 18F fluorodexoyglucose (FDG) and other radionuclides is being used to determine culprit plaques in complex clinically scenarios. Clinically, this information may prove extremely valuable in the assessment of stable and unstable patients and its use in prime time medical practice is eagerly awaited. We will discuss the current clinical applications of functional atheroma imaging in the aorta and highlight the promising preclinical data on novel image biomarkers of plaque instability. If clinical science is able to successfully translate these advances in vascular imaging from the bench to the bedside, a new paradigm will be achieved in cardiovascular diagnostics.