Coronary Atherosclerotic Plaque Vulnerability Research Articles

PCSK9 inhibition in atherosclerotic cardiovascular disease.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) represent a novel class of hypolipidemic drugs, providing an additional therapeutic option over conventional hypolipidemic treatments. Given the constantly lowering recommended LDL-C goals, low goal achievement rate and low compliance with treatment, new hypolipidemic drug classes may substantially contribute to residual risk reduction for atherosclerotic cardiovascular disease (ASCVD). This review aims to summarize contemporary evidence on the clinical role of PCSK9i in ASCVD prevention. PubMed and MEDLINE databases were searched for keywords in studies on PCSK9i and ASCVD. Approved PCSK9i are the monoclonal antibodies (Mabs), evolocumab and alirocumab, targeting PCSK9, and inclisiran, a small interfering RNA inhibiting PSCK9 synthesis. Overall, PCSK9i effectively reduced LDL-C and other atherogenic lipoproteins, including apolipoprotein B and lipoprotein(a) primarily. PSCK9i Mabs improved imaging markers reflecting coronary atherosclerotic plaque vulnerability and reduced ASCVD events in high-risk patients after short-term treatment ( < 3 years follow-up). They are currently indicated as a third-line treatment for secondary prevention and primary prevention in patients with familial hypercholesterolemia at high risk of not achieving their LDL-C goals. Patients with higher baseline ASCVD risk receive greater benefits from PCSK9i. Recent evidence suggests that evolocumab was effective and safe after long-term treatment. Ongoing trials investigate new therapeutic indications for PCSK9i while their cost-effectiveness is still being considered. PCSK9i is a novel hypolipidemic drug class currently indicated for reducing residual risk in secondary ASCVD prevention and high-risk patients.

Assessment of vasa vasorum on coronary plaques in patients with acute coronary syndromes using intravascular ultrasound and iMap analysis: A retrospective cohort study.

Studies have revealed that vasa vasorum (VV) neovascularization is vital for the progression and vulnerability of coronary atherosclerotic plaques. The correlation between VV, plaque constituents, and the no-reflow phenomenon (NRP) in percutaneous coronary intervention (PCI) remains elusive. We explored plaque constituents in iMap-intravascular ultrasound (iMap-IVUS) and NRP during PCI for VV lesions. We studied 166 coronary lesions in 166 patients with acute coronary syndromes (ACS) (118 lesions with VV) undergoing pre-intervention intravascular ultrasound (IVUS). We evaluated the diversity in plaque morphological status and post-PCI results based on the presence or absence of VV. The lesions with VV group had significantly higher high-sensitivity C-reactive protein (hs-CRP) levels than the lesions without VV group (8.41 ± 4.98 vs 4.19 ± 3.69 mg/L, P < .001). The frequency of after-stent deployment thrombolysis in myocardial infarction (TIMI) flow grades 0, 1, and 2 was remarkably greater in lesions with VV than in those without VV (22.9% vs 10.4%, P < .001). Plaques at the minimum lumen, necrotic core (1.26 ± 0.64 vs 0.92 ± 0.61 mm2, P < .001; 20.95 ± 7.19 vs 13.34% ± 6.54%, P < .001), and fibrous areas (4.23 ± 1.32 vs 3.92 ± 1.01 mm2, P = .006; 61.01 ± 9.41 vs 56.92% ± 11.42%, P = .001) were considerably larger in the lesions with VV than in those without VV. In addition, densely calcified plaques (0.41 ± 0.26 vs 0.81 ± 0.59 mm2, P < .001; 3.63 ± 2.19 vs 7.18% ± 2.01%, P < .001) were considerably smaller in the lesions with VV than in those without VV. Multivariate analyses revealed that VV and plaque volume were independent predictors of NRP after stent deployment (odds ratio [OR]: 5.13, 95% confidence interval [CI]: 1.19-15.32, P = .002; OR: 4.79, 95% CI: 1.08-9.01, P = .005). Lesions with VV exhibited considerable plaque vulnerability in patients with ACS, and they displayed more NRP during PCI. VV and plaque volume were independent predictors of NRP after stent deployment.

The relationships between cholesterol crystals, NLRP3 inflammasome, and coronary atherosclerotic plaque vulnerability in acute coronary syndrome: An optical coherence tomography study.

Cholesterol crystals (CCs) in lesions are the hallmark of advanced atherosclerotic plaque. Previous studies have demonstrated that CCs could activate NLRP3 inflammasome, which played an important role in atherosclerotic lesion progression. However, the relationship between CCs, NLRP3 inflammasome pathway, and plaque vulnerability in patients with ACS is still not elucidated. Two hundred sixty-nine consecutive acute coronary syndrome (ACS) patients with 269 culprit lesions were included in this study. CCs and other plaque characteristics within the culprit lesion segment were evaluated by optical coherence tomography (OCT) before percutaneous coronary intervention (PCI). The NLRP3 mRNA expression in peripheral blood mononuclear cells (PBMCs) and the serum levels of interleukin (IL)-1β, IL-18, and other biological indices were measured. Cholesterol crystals were observed in 105 (39%) patients with 105 culprit lesions. There were no significant differences in baseline clinical characteristics between the patients with CCs (CCs group, n = 105) and the patients without CCs (non-CCs group, n = 164) within the culprit lesion segment except for lipoprotein(a) [Lp(a)]. The CCs group had a higher level of NLRP3 mRNA expression in PBMCs and higher levels of serum cytokine IL-1β and IL-18. OCT showed that the CCs group had longer lesion length, more severe diameter stenosis, and less minimum luminal area (MLA) than the non-CCs group (all p < 0.05). The frequency of thin-cap fibroatheroma (TCFA), thrombus, accumulation of macrophages, plaque rupture, micro-channel, calcification, spotty calcification, and layered plaque was higher in the CCs group than in the non-CCs groups (all p < 0.05). Multivariate logistic analysis revealed that the level of NLRP3 expression (OR = 10.204), IL-1β levels (OR = 3.523), IL-18 levels (OR = 1.006), TCFA (OR = 3.593), layered plaque (OR = 5.287), MLA (OR = 1.475), macrophage accumulation (OR = 2.881), and micro-channel (OR = 3.185) were independently associated with CCs. Acute coronary syndrome patients with CCs in culprit lesions had a higher expression of NLRP3, IL-1β, and IL-18, and had more vulnerable plaque characteristics than patients without CCs. CCs might have interacted with NLRP3 inflammasome activation in patients with ACS, which could contribute to plaque vulnerability in culprit lesions.

New Insights into the Association between Fibrinogen and Coronary Atherosclerotic Plaque Vulnerability: An Intravascular Optical Coherence Tomography Study.

Background Fibrinogen levels have been associated with coronary plaque vulnerability in experimental studies. However, it has yet to be determined if serum fibrinogen levels are independently associated with coronary plaque vulnerability as detected by optical coherence tomography (OCT) in patients with coronary heart disease. Methods Patients with coronary heart disease (CHD) who underwent coronary angiography and OCT in our department from January 2015 to August 2018 were included in this study. Coronary lesions were categorized as ruptured plaque, nonruptured with thin-cap fibroatheroma (TCFA), and nonruptured and non-TCFA. Presence of ruptured plaque and nonruptured with TCFA was considered to be vulnerable lesions. Determinants of coronary vulnerability were evaluated by multivariable logistic regression analyses. Results A total of 154 patients were included in this study; 17 patients had ruptured plaques, 15 had nonruptured plaques with TCFA, and 122 had nonruptured plaques with non-TCFA. Results of univariate analyses showed that being male, diabetes, current smoking, high body mass index (BMI), and clinical diagnosis of acute coronary syndrome (ACS) were associated with coronary vulnerability. No significant differences were detected in patient characteristics, coronary angiographic findings, and OCT results between patients with higher and normal fibrinogen. Results of multivariate logistic analyses showed that diabetes and ACS were associated with TCFA, while diabetes, higher BMI, and ACS were associated with plaque rupture. Conclusions Diabetes, higher BMI, and ACS are independently associated with coronary vulnerability as detected by OCT. Serum fibrinogen was not associated with coronary vulnerability in our cohort.

Coronary Atherosclerotic Plaque Vulnerability Rather than Stenosis Predisposes to Non-ST Elevation Acute Coronary Syndromes.

Background Non-ST elevation acute coronary syndromes (NSTE-ACS) may arise from moderately stenosed atherosclerotic lesions that suddenly undergo transformation to vulnerable plaques complicated by rupture and thrombosis. Objective Assessment and tissue characterization of the coronary atherosclerotic lesions among NSTE-ACS patients compared to those with stable angina. Methodology Evaluation of IVUS studies of 312 coronary lesions was done by 2 different experienced IVUS readers, 216 lesions in 66 patients with NSTE-ACS (group I) versus 96 lesions in 50 patients with stable angina (group II). Characterization of coronary plaques structure was done using colored-coded iMap technique. Results The Syntax score was significantly higher in group I compared to group II (18.7 ± 7.8 vs. 8.07 ± 2.5, p=0.001). Body mass index (BMI) was significantly higher in group II while triglycerides levels were higher in group I (P=0.01 & P=0.04, respectively). History of previous MI and PCI was significantly higher in group I (P=0.016 & P=0.001, respectively). The coronary lesions of NSTE-ACS patients had less vessel area (9.86 ± 3.8 vs 11.36 ± 2.9, p=0.001), stenosis percentage (54.7 ± 14.9% vs 68.6 ± 8.7%, p=0.001), and plaque burden (54.4 ± 14.7 vs 67.8 ± 9.8, p=0.001) with negative remodeling index (0.95 ± 20 vs 1.02 ± 0.14, p=0.008) compared to the stable angina group. On the other hand, they had more lipid content (21.8 ± 7.03% vs 7.26 ± 3.47%, p=0.001), necrotic core (18.08 ± 10.19% vs 15.83 ± 4.9%, p=0.02), and calcifications (10.4 ± 5.2% vs 4.19 ± 3.29%, p=0.001) while less fibrosis (51.67 ± 7.07% vs 70.37 ± 11.7%, p=0.001) compared to the stable angina patients. Syntax score and core composition especially calcification and lipid content were significant predictors to NSTE-ACS. Conclusions The vulnerability rather than the stenotic severity is the most important factor that predisposes to non-ST segment elevation acute coronary syndromes. The vulnerability is related to the lesion characteristics especially lipidic core and calcification while lesion fibrosis favours lesion stability.

Association between Gamma-Glutamyl Transferase and Coronary Atherosclerotic Plaque Vulnerability: An Optical Coherence Tomography Study.

Background Gamma-glutamyl transferase (GGT) has been detected in coronary plaques. However, the association between serum GGT levels and coronary atherosclerotic plaque vulnerability in patients with coronary artery disease (CAD) as detected by optical coherence tomography (OCT) has not been investigated. Methods We performed a retrospective study of consecutively enrolled CAD patients undergoing preintervention OCT examination during coronary angiography. Plaque vulnerability was defined as the presence of ruptured plaques or thin-cap fibroatheroma (TCFA) upon OCT. The association between serum GGT levels and coronary plaque vulnerability was evaluated using multivariate logistic regression analysis. Results A total of 142 patients were included in our analysis. OCT examination detected ruptured plaques in 16 patients, nonruptured plaques with TCFA in 17 patients, and nonruptured plaques and non-TCFA in 109 patients. Univariate analyses showed that gender, diabetes, Apolipoprotein A1 (ApoA1) and high-density lipoprotein cholesterol (HDL-c), and diagnosis of acute coronary syndrome (ACS) were associated with plaque vulnerability (P all < 0.05). Patients grouped according to serum GGT tertiles did not differ statistically in baseline characteristics or OCT findings. Results of multivariate logistic analyses showed that diabetes and diagnosis of ACS were associated with plaque rupture and TCFA (P < 0.05). Conclusions GGT serum levels were not associated with OCT detected coronary vulnerability in our cohort of CAD patient.

Type D personality and coronary atherosclerotic plaque vulnerability: The potential mediating effect of health behavior

ObjectiveThe association between type D personality and coronary plaque vulnerability has been suggested. The objective of the study was to evaluate the potential mediating effects of health behavior on the association between type D personality and plaque vulnerability in coronary artery disease (CAD) patients. MethodsA total of 319 CAD patients were assessed for type D personality and health behavior via self-administered questionnaires. The plaque vulnerability, evaluated according to characteristics, accompaniment, and outcomes of plaque, was assessed by optical coherence tomography. ResultsRegression analysis showed that type D personality was independently associated with lipid plaque (odds ratio [OR] = 2.387, p = 0.001), thin cap fibroatheroma (TCFA) (OR = 2.366, p = 0.001), rupture (OR = 2.153, p = 0.002), and lipid arc (β = −0.291, p < 0.001). Mediation analyses showed that aspects of health behavior were significant mediators of the relationship between type D personality and plaque vulnerability. Psychological stress mediated the relationship between type D and lipid plaque (p = 0.030), TCFA (p = 0.034), and rupture (p = 0.013). Living habits significantly mediated the relationship between type D and lipid plaque (p = 0.028), TCFA (p = 0.036), but not rupture (p = 0.066). Participating in activities was not a significant mediator of the relationship between type D personality and lipid plaque (p = 0.115), TCFA (p = 0.115), or rupture (p = 0.077). ConclusionsHealth behaviors (psychological stress and living habits) may be mediators of the association between type D personality and plaque vulnerability.

Lower AMP-activated protein kinase level is associated with the vulnerability of coronary atherosclerotic plaques by attenuating the expression of monocyte autophagy.

Coronary atherosclerotic plaque formation is driven by macrophage infiltration. Monocytes and macrophages contribute to the progression of atherosclerosis. However, research on the relationship between AMP-activated protein kinase (AMPK) and vulnerable atherosclerotic plaques is still insufficient. In the present study, we aimed to elucidate the adaptive mechanism between autophagy of peripheral blood monocytes (PBMs) and the rupture of atherosclerotic plaques. We investigated whether AMPK and autophagy of monocytes can enhance the stability of coronary atherosclerotic plaques in the human body. Samples of PBMs were collected and isolated from all patients with stable angina pectoris (SAP), non-ST-segment elevation acute coronary syndrome, ST-segment elevation acute myocardial infarction, and without coronary artery disease (control). Then, western blot was used to detect the expression levels of AMPK and autophagy-related protein. The expression levels of beclin-1 and ATG7 were all significantly lower in the acute coronary syndrome groups than those in the SAP and control groups (all P<0.01). The level of phosphorylated AMPK was significantly decreased in patients with acute coronary syndrome compared with those in the SAP and control groups (P<0.01). However, there was no statistical difference between the SAP group and the control group. The activation of mTOR was distinctly increased in the STEMI group (P<0.05). Therefore, our work is novel in showing that AMPK of PBMs may decrease plaque vulnerability and subsequent plaque rupture through activation of autophagy.

Update on the role of angiotensin in the pathophysiology of coronary atherothrombosis.

Coronary atherothrombosis due to atherosclerotic plaque rupture or erosion is frequently associated with acute coronary syndromes (ACS). Significant efforts have been made to elucidate the pathophysiological mechanisms underlying acute coronary events. This narrative review is based on the material searched for and obtained via PubMed up to August 2014. The search terms we used were as follows: 'angiotensin, acute coronary syndromes, acute myocardial infarction' in combination with 'atherosclerosis, vulnerability, clinical trial, ACE inhibitors, inflammation'. Among several regulatory components, the renin-angiotensin system (RAS) was shown as a key pathway modulating coronary atherosclerotic plaque vulnerability. Indeed, these molecules are involved in all stages of atherogenesis. Classically, the RAS is composed by a series of enzymatic reactions leading to the angiotensin (Ang) II generation and activity. However, the knowledge of RAS has expanded and become more complex. The discovery of novel components and their functions has revealed additional pathways that contribute to or counterbalance the actions of Ang II. In this review, we discussed on recent findings concerning the role of different angiotensin peptides in the pathophysiology of ACS and coronary atherothrombosis, exploring the link between these molecules and atherosclerotic plaque vulnerability. Treatments selectively targeting angiotensins (including Mas and AT2 agonists, ACE2 recombinant, or Ang-(1-7) and almandine in oral formulations) have been tested in animal studies or in small human subgroups, expanding the perspective in the ACS prevention. These novel strategies, especially in the counter-regulatory axis ACE2/Ang-(1-7)/Mas, might be promising to reduce plaque vulnerability and inflammation.

Circulating CD36 and fractalkine levels are associated with vulnerable plaque progression in patients with unstable angina pectoris.

The chemokine, fractalkine, independently enhances the vulnerability of coronary atherosclerotic plaques. The present study investigated the combined effects of CD36 and fractalkine on coronary plaque progression in patients with unstable angina pectoris. In the present study, 120 unstable angina pectoris patients undergoing coronary angiography and intravascular ultrasound were divided into two groups: an intermediate lesion group (lumen diameter stenosis 50-70%, 80 patients) and a severe lesion group (at least one lesion with lumen diameter stenosis > 70%, 40 patients). The control group consisted of 40 healthy age- and sex-matched subjects. Concentrations of CD36 and fractalkine were measured by enzyme-linked immunosorbent assay. Major adverse cardiovascular events were monitored over a 2-year follow up. Intravascular ultrasound showed that patients with severe lesions had more calcified and mixed plaques, and a larger plaque area and plaque burden than patients with intermediate lesions (P < 0.05-0.01). More patients with severe lesions underwent stent deployment (P < 0.05) than those with intermediate lesions. CD36 and fractalkine concentrations were significantly higher in the severe lesion patients (P < 0.05), and both had significant positive correlations (P < 0.05) with the plaque burden of atherosclerotic lesions. Using the matched nested case-control study, we found that CD36 and fractalkine levels were higher in patients with recurrent major adverse cardiovascular events than controls (P < 0.05). In conclusion, CD36 and fractalkine both promote, and might synergistically enhance, the progression of coronary atherosclerotic plaques.

Mapping Intravascular Ultrasound Controversies in Interventional Cardiology Practice

Intravascular ultrasound is a catheter-based imaging modality that was developed to investigate the condition of coronary arteries and assess the vulnerability of coronary atherosclerotic plaques in particular. Since its introduction in the clinic 20 years ago, use of intravascular ultrasound innovation has been relatively limited. Intravascular ultrasound remains a niche technology; its clinical practice did not vastly expand, except in Japan, where intravascular ultrasound is an appraised tool for guiding percutaneous coronary interventions. In this qualitative research study, we follow scholarship on the sociology of innovation in exploring both the current adoption practices and perspectives on the future of intravascular ultrasound. We conducted a survey of biomedical experts with experience in the technology, the practice, and the commercialization of intravascular ultrasound. The collected information enabled us to map intravascular ultrasound controversies as well as to outline the dynamics of the international network of experts that generates intravascular ultrasound innovations and uses intravascular ultrasound technologies. While the technology is praised for its capacity to measure coronary atherosclerotic plaque morphology and is steadily used in clinical research, the lack of demonstrated benefits of intravascular ultrasound guided coronary interventions emerges as the strongest factor that prevents its expansion. Furthermore, most of the controversies identified were external to intravascular ultrasound technology itself, meaning that decision making at the industrial, financial and regulatory levels are likely to determine the future of intravascular ultrasound. In light of opinions from the responding experts', a wider adoption of intravascular ultrasound as a stand-alone imaging modality seems rather uncertain, but the appeal for this technology may be renewed by improving image quality and through combination with complementary imaging modalities.

Increased coronary atherosclerotic plaque vulnerability by coronary computed tomography angiography in HIV-infected men

Among HIV-infected patients, high rates of myocardial infarction (MI) and sudden cardiac death have been observed. Exploring potential underlying mechanisms, we used multidetector spiral coronary computed tomography angiography (coronary CTA) to compare atherosclerotic plaque morphology in HIV-infected patients and non-HIV-infected controls. Coronary atherosclerotic plaques visualized by CTA in HIV-infected (101) and non-HIV-infected (41) men without clinically apparent heart disease matched on cardiovascular risk factors were analyzed for three vulnerability features: low attenuation, positive remodeling, and spotty calcification. Ninety-five percent of HIV-infected patients were receiving ART (median duration 7.9 years) and had well controlled disease (median CD4 cell count, 473 cells/μl; median HIV RNA <50 copies/ml). Age and traditional cardiovascular risk factors were similar in HIV-infected patients and controls. Among the HIV-infected (versus control) group, there was a higher prevalence of patients with at least one: low attenuation plaque (22.8 versus 7.3%, P = 0.02), positively remodeled plaque (49.5 versus 31.7%, P = 0.05) and high-risk 3-feature plaque (7.9 versus 0%, P = 0.02). Moreover, patients in the HIV-infected (versus control) group demonstrated a higher number of low attenuation plaques (P = 0.01) and positively remodeled plaques (P = 0.03) per patient. Our data demonstrate an increased prevalence of vulnerable plaque features among relatively young HIV-infected patients. Differences in coronary atherosclerotic plaque morphology - namely, increased vulnerable plaque among HIV-infected patients - are here for the first time reported and may contribute to increased rates of MI and sudden cardiac death in this population.

Independent Roles of Monocyte Chemoattractant Protein-1, Regulated on Activation, Normal T-Cell Expressed and Secreted and Fractalkine in the Vulnerability of Coronary Atherosclerotic Plaques

Monocyte chemotactic factors contribute to the formation of atherosclerotic plaques. The present study aimed to elucidate the roles of monocyte chemoattractant protein-1 (MCP-1), Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES) and fractalkine on the vulnerability of atherosclerotic plaques in patients with acute myocardial infarction (AMI) or unstable angina pectoris (UAP). Sixty patients with AMI, 60 patients with UAP, 60 patients with stable angina pectoris (SAP) and 40 patients without coronary heart disease comprised the study group. Quantitative coronary angiography and intravascular ultrasound (IVUS) were performed. Concentrations and mRNA expression levels of high-sensitivity C-reactive protein, MCP-1, RANTES and fractalkine were measured by ELISA and RT-PCR, respectively. IVUS found that 51.3% of the AMI patients and 47.7% of the UAP patients had soft lipid plaques. Among the SAP patients, 52.4% had fibrous plaques and only 17.1% had soft plaques. AMI and UAP patients had larger plaque burden and vascular remodeling index than did the SAP patients (P<0.01). The averaged number of migrated monocytes was higher in AMI and UAP patients. Concentrations and mRNA expression levels of MCP-1, RANTES and fractalkine were significantly higher in AMI and UAP patients than in SAP patients (P<0.05-0.01). The plaque burden in UAP patients as measured with IVUS correlated well with monocytes chemotaxis (r=0.56, P<0.01). MCP-1, RANTES and fractalkine independently participate in the pathogenesis of plaque vulnerability and subsequent plaque rupture.