Lipid-rich Plaques Research Articles

Coronary Atherosclerosis Phenotypes in Focal and Diffuse Disease

BackgroundThe interplay between coronary hemodynamics and plaque characteristics remains poorly understood. ObjectivesThe aim of this study was to compare atherosclerotic plaque phenotypes between focal and diffuse coronary artery disease (CAD) defined by coronary hemodynamics. MethodsThis multicenter, prospective, single-arm study was conducted in 5 countries. Patients with functionally significant lesions based on an invasive fractional flow reserve ≤0.80 were included. Plaque analysis was performed by using coronary computed tomography angiography and optical coherence tomography. CAD patterns were assessed using motorized fractional flow reserve pullbacks and quantified by pullback pressure gradient (PPG). Focal and diffuse CAD was defined according to the median PPG value. ResultsA total of 117 patients (120 vessels) were included. The median PPG was 0.66 (IQR: 0.54-0.75). According to coronary computed tomography angiography analysis, plaque burden was higher in patients with focal CAD (87% ± 8% focal vs 82% ± 10% diffuse; P = 0.003). Calcifications were significantly more prevalent in patients with diffuse CAD (Agatston score per vessel: 51 [IQR: 11-204] focal vs 158 [IQR: 52-341] diffuse; P = 0.024). According to optical coherence tomography analysis, patients with focal CAD had a significantly higher prevalence of circumferential lipid-rich plaque (37% focal vs 4% diffuse; P = 0.001) and thin-cap fibroatheroma (TCFA) (47% focal vs 10% diffuse; P = 0.002). Focal disease defined by PPG predicted the presence of TCFA with an area under the curve of 0.73 (95% CI: 0.58-0.87). ConclusionsAtherosclerotic plaque phenotypes associate with intracoronary hemodynamics. Focal CAD had a higher plaque burden and was predominantly lipid-rich with a high prevalence of TCFA, whereas calcifications were more prevalent in diffuse CAD. (Precise Percutaneous Coronary Intervention Plan [P3]; NCT03782688)

Achieved low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio predicts the pathophysiological evolution of lipid-rich plaques in acute coronary syndromes: an optical coherence tomography study.

As a novel lipoprotein ratio, baseline low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (LHR) is closely related to the clinical outcomes of acute coronary syndromes (ACS) after percutaneous coronary intervention. However, the pathophysiological impact of achieved LHR (aLHR) on the evolution of non-culprit lipid-rich plaques has not been systematically explored. Between September 2013 and December 2018, ACS patients with both baseline and 1-year follow-up optical coherence tomography (OCT) examinations were included in current study. They were divided into two groups according to the median value of aLHR at 1 year. Overall, 132 patients with 215 lipid-rich plaques were enrolled, with a median aLHR: 1.62. There were thinner fibrous cap thickness (FCT) (133.3 [70.0-180.0] µm vs. 160.0 [100.0-208.3] µm, p = 0.025) and higher prevalence of thin-cap fibroatheroma (TCFA) (24 [22.4%] vs. 13 [12.0%], p = 0.044) and CLIMA-defined high-risk plaques (12 [11.2%] vs. 3[2.8%], p = 0.015) in the high aLHR group at 1 year. Compared with other serum lipid indexes, aLHR showed the best robust correlation with the evolution of plaque vulnerability in both unadjusted and adjusted analyses. Cut-off value of aLHR to predict the progression of maximal lipid arc and FCT was 1.51. In the adjusted model, aLHR ≥1.51 was an independent predictor of TCFA [odds ratio (OR): 3.008, 95% CI: 1.370 to 6.605, p = 0.006] at 1 year. aLHR correlates well with the evolution of lipid-rich plaques and vulnerable phenotypes at 1-year follow-up, which might be an important and convenient serum indicator in the secondary prevention of ACS.

Plaque burden is associated with minimal intimal coverage following drug-eluting stent implantation in an adult familial hypercholesterolemia swine model

Safety and efficacy of coronary drug-eluting stents (DES) are often preclinically tested using healthy or minimally diseased swine. These generally show significant fibrotic neointima at follow-up, while in patients, incomplete healing is often observed. The aim of this study was to investigate neointima responses to DES in swine with significant coronary atherosclerosis. Adult familial hypercholesterolemic swine (n = 6) received a high fat diet to develop atherosclerosis. Serial OCT was performed before, directly after, and 28 days after DES implantation (n = 14 stents). Lumen, stent and plaque area, uncovered struts, neointima thickness and neointima type were analyzed for each frame and averaged per stent. Histology was performed to show differences in coronary atherosclerosis. A range of plaque size and severity was found, from healthy segments to lipid-rich plaques. Accordingly, neointima responses ranged from uncovered struts, to minimal neointima, to fibrotic neointima. Lower plaque burden resulted in a fibrotic neointima at follow-up, reminiscent of minimally diseased swine coronary models. In contrast, higher plaque burden resulted in minimal neointima and more uncovered struts at follow-up, similarly to patients’ responses. The presence of lipid-rich plaques resulted in more uncovered struts, which underscores the importance of advanced disease when performing safety and efficacy testing of DES.

The association between circulating lipoprotein subfractions and lipid content in coronary atheromatous plaques assessed by near-infrared spectroscopy

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Norwegian Health Association The Liaison Committee for education, research and innovation in Central Norway. Background Lipid content in coronary atheromatous plaques, measured by near-infrared spectroscopy (NIRS), can predict the risk of future coronary events. Biomarkers that reflect lipid content in coronary plaques may therefore improve coronary artery disease (CAD) risk assessment, and lipoprotein subfractions could potentially add value beyond traditional lipid measurements. Purpose We aimed to investigate the association between circulating lipoprotein subfractions and lipid content in coronary atheromatous plaques in statin-treated patients with stable CAD undergoing percutaneous coronary intervention. Methods 56 patients with stable CAD underwent three vessel imaging with NIRS when feasible. The coronary artery segment with the highest lipid content, defined as the maximum lipid core burden index within any 4mm length across the entire lesion (maxLCBI4mm), was selected as target segment. Lipoprotein subfractions were analyzed in fasting serum samples by nuclear magnetic resonance spectroscopy. Penalized linear regression analyses (lasso) were used to identify the best predictors of maxLCBI4mm. The uncertainty of the lasso estimates was assessed as the percentage of the resampled datasets by bootstrapping. Results Only modest evidence was found for an association with lipoprotein subfractions and maxLCBI4mm. The lipoprotein subfractions with strongest potential as predictors according to the percentage presence in resampled datasets were lipoprotein a (Lp(a)) (reg.coeff = 57.0; 78.1 % presence) and free cholesterol in the smallest high-density lipoprotein (HDL) subfractions (reg.coeff = 36.5; 74.3 % presence). When including established cardiovascular risk factors in the regression model, none of the lipoprotein subfractions was considered potential predictors of maxLCBI4mm. Conclusion In this study, Lp(a) and free cholesterol in the smallest HDL subfractions in serum showed the strongest potential as predictors for lipid content in coronary atheromatous plaques. Although the evidence is modest, our study suggests that measurements lipoprotein subfractions may provide additional information with respect to coronary plaque composition compared to traditional lipid measurements, but not in addition to established risk factors. Future studies are needed to verify our findings, and to investigate the clinical implication of lipoprotein subfractions as meaningful biomarkers for lipid-rich plaques and enhanced risk prediction in CAD.

Human Basilar Arterial Plaque Detected by Near-Infrared Spectroscopy: Clinical Image

A patient in their 70s presented with weakness of the left limb and aphasia. Left vertebral angiography showed acute basilar artery occlusion. After mechanical thrombectomy, basilar artery trunk stenosis was evident and catheter-based near-infrared spectroscopy (NIRS) showed lipid-rich atherosclerotic plaque extending to almost 220° of the vessel circumference in the culprit lesion. Loading doses of dual antiplatelet therapy and aggressive medical treatment were started because additional intervention might have increased risk of plaque protrusion and thrombotic reocclusion. The patient presented with minor stroke caused by restenosis of the basilar artery 4 months later; balloon angioplasty and stenting were performed without thromboembolic complications. The patient was discharged without any new neurologic deficits. NIRS visualizes the distribution of lipids in the culprit lesion and the plaque burden of residual stenosis, identifies mechanisms of in situ thrombosis, and provides suggestions for the timing of additional interventions.

Associations between circulating microRNAs and lipid-rich coronary plaques measured with near-infrared spectroscopy

Lipid-rich coronary atherosclerotic plaques often cause myocardial infarction (MI), and circulating biomarkers that reflect lipid content may predict risk of MI. We investigated the association between circulating microRNAs (miRs) are lipid-rich coronary plaques in 47 statin-treated patients (44 males) with stable coronary artery disease undergoing percutaneous coronary intervention. We assessed lipid content in non-culprit coronary artery lesions with near-infrared spectroscopy and selected the 4 mm segment with the highest measured lipid core burden index (maxLCBI4mm). Lipid-rich plaques were predefined as a lesion with maxLCBI4mm ≥ 324.7. We analyzed 177 circulating miRs with quantitative polymerase chain reaction in plasma samples. The associations between miRs and lipid-rich plaques were analyzed with elastic net. miR-133b was the miR most strongly associated with lipid-rich coronary plaques, with an estimated 18% increase in odds of lipid-rich plaques per unit increase in miR-133b. Assessing the uncertainty by bootstrapping, miR-133b was present in 82.6% of the resampled dataset. Inclusion of established cardiovascular risk factors did not attenuate the association. No evidence was found for an association between the other analyzed miRs and lipid-rich coronary plaques. Even though the evidence for an association was modest, miR-133b could be a potential biomarker of vulnerable coronary plaques and risk of future MI. However, the prognostic value and clinical relevance of miR-133b needs to be assessed in larger cohorts.

Disparities among Black and White patients in plaque burden and composition and long-term impact

BackgroundBlack patients presenting to the catheterization laboratory have more risk factors and worse long-term outcomes. This sub-analysis of the Lipid Rich Plaque (LRP) study quantifies the plaque burden and composition of Black vs White patients and associated outcomes. MethodsPatients with a singular, self-reported race presenting for cardiac catheterization were enrolled if near-infrared spectroscopy/intravascular ultrasound (NIRS-IVUS) imaging of non-stented, non-culprit (NC) vessels was performed. Lipidic content was quantified at the 4-mm region with maximum Lipid Core Burden Index (maxLCBI4mm). NC major adverse cardiac events (NC-MACE) were defined as: cardiac death, cardiac arrest, non-fatal myocardial infarction, acute coronary syndrome, revascularization, and hospital readmission for angina with >20 % disease progression through 2 years. ResultsAmong 1346 patients with a singular, self-reported race, 182 were Black. Black vs White patients were more likely to be female, had higher rates of traditional risk factors, and were more likely to present acutely. Both patients and segments were more likely to have maxLCBI4mm > 400 (46.7 % vs 30.6 %, p < 0.001, respectively; 15.5 % vs 8.9 %, p < 0.001, respectively). Vessel size and plaque burden were larger for Black vs White patients. At 2 years, maxLCBI4mm > 400 and Black race were independently predictive of NC-MACE (hazard ratio [HR] maxLCBI4mm > 400: 2.37 [95 % confidence interval (CI) 1.50–3.76, p < 0.001], Black race: 2.8 [95 % CI 1.27–3.42, p = 0.004], pinteraction = 0.137). ConclusionsCompared to White patients, Black patients had more lipid-rich plaques with greater plaque burden. Both high lipidic burden and Black race were independently predictive of NC-MACE within 2 years. Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT02033694, NCT02033694

Abstract 265: Coronavirus Infection Induced Interferon Signaling Promotes Atherosclerotic Plaque Vulnerability

Atherosclerosis is a chronic inflammatory vascular disease characterized by the formation of lipid-rich plaques inside arteries. The rupture of vulnerable plaques and consequent acute complications, such as myocardial infarction and stroke, are the leading causes of morbidity and mortality worldwide. It is known that pre-existing cardiovascular comorbidities pose a risk for severe outcomes in COVID-19, though the underlying pathophysiology is not fully understood. To investigate the role of coronavirus infection in established atherosclerotic plaques, we developed an atherosclerotic model of natural murine beta coronavirus infection with mouse hepatitis virus strain-A59 (MHV-A59). We fed Ldlr-/- mice a Western diet for three months prior to MHV-A59 intranasal inoculation and assessed plaque morphology at day post infection (dpi) 7 and dpi 30. Respiratory infection in mice recapitulated many aspects of COVID-19 pathophysiology. More strikingly, virus was detected in atherosclerotic aorta and induced multiple features of vulnerable plaques, a prerequisite for plaque rupture, characterized by thinner fibrous caps, less collagen content, and larger necrotic cores. The phenotype was persistent at dpi 30 when the mice were fully recovered. To further explore the underlying mechanism, we performed single-cell RNA sequencing (scRNA-seq) on infected aortas isolated at dpi 7. Our data revealed that interferon &amp;#947; was exclusively upregulated in activated T cells and elicited various responses across multiple cell populations within infected aortas. The drastic responses that potentially contribute to plaque instability include activation of a more proinflammatory endothelial cell phenotype, downregulation of TGF- &amp;#946; mediated fibroblast to myofibroblast transition, and enhanced degradation of extracellular matrix and smooth muscle cell senescence. Moreover, macrophages in infected plaques activate inflammasomes, release IL-18, and undergo pyroptosis, thereby further contributing to the hyperinflammatory state of the atherosclerotic plaques. Taken together, our data shed light on a molecular mechanism for coronavirus infection induced plaque instability and provide a small animal model to explore future therapeutics.

Cigarette tar mediates macrophage ferroptosis in atherosclerosis through the hepcidin/FPN/SLC7A11 signaling pathway.

Despite the known promotional effects of cigarette smoking on progression of atherosclerosis (AS), tar as the most dominant toxic component in cigarette smoking has been little studied. Understanding the potential role and mechanisms of tar in AS may be a prerequisite for future reductions in cardiovascular morbidity and mortality. Male ApoE-/- mice were fed with high-fat diet and injected intraperitoneally with cigarette tar (40mg/kg/day) for 16 weeks. The results showed that cigarette tar significantly promoted the formation of lipid-rich plaques with larger necrotic cores and less fibrous, and caused severe iron overload and lipid peroxidation in AS lesions. Moreover, tar significantly upregulated the expression of hepcidin and downregulated FPN and SLC7A11 of macrophages in AS plaques. Ferroptosis inhibitor (FER-1 and DFO) treatment, hepcidin-knockdown or SLC7A11-overexpression reversed above changes, thereby delaying the progression of atherosclerosis. In vitro, the use of FER-1, DFO, si-hepcidin, and ov-SLC7A11 increased cell viability and inhibited iron accumulation, lipid peroxidation and GSH depletion in tar treated macrophages. These interventions also inhibited the tar induced upregulation of hepcidin, and increased the expression of FPN, SLC7A11, and GPX4. Furthermore, NF-κB inhibitor reversed the regulatory effect of tar on hepcidin/FPN/SLC7A11 axis, and then inhibiting macrophage ferroptosis. These findings indicated that cigarette tar promotes atherosclerosis progression by inducing macrophage ferroptosis via NF-κB-activated hepcidin/FPN/SLC7A11 pathway.

Sex Differences in the Density of Lipidic Plaque Materials: Insights From the REASSURE-NIRS MultiCenter Registry.

Intravascular imaging has shown better response of coronary atheroma to statin-mediated lowering of low-density lipoprotein cholesterol in women. However, its detailed mechanism remains to be determined yet. Modifiability of coronary atheroma under lipid-lowering therapies is partly driven by lipidic plaque component. Given a smaller plaque volume in women, lipidic plaque features including their density may differ between sex. Therefore, the current study sought to characterize sex-related differences in the density of lipidic plaque. We analyzed 1429 coronary lesions (culprit/nonculprit lesions=825/604) in 758 coronary artery disease patients (men/women=608/150) from the REASSURE-NIRS multicenter registry (Revelation of Pathophysiological Phenotypes of Vulnerable Lipid-Rich Plaque on Near-Infrared Spectroscopy). Total atheroma volume at 4-mm segment, maximum 4-mm-lipid-core burden index, and lipid plaque density index (=maximum 4-mm-lipid-core burden index/total atheroma volume at 4-mm segment) on near-infrared spectroscopy/intravascular ultrasound imaging at culprit and nonculprit lesions were compared in men and women. Statin and high-intensity statin were used in 72.4 (P=0.81) and 22.9% (P=0.32) of study subjects, respectively. Women exhibited a smaller adjusted total atheroma volume at 4-mm segment (culprit lesions: 50.3±0.4 versus 54.2±0.3mm3, P<0.001, nonculprit lesions: 31.5±3.0 versus 44.4±2.1mm3, P<0.001), whereas their adjusted maximum 4-mm-lipid-core burden index did not differ between sex (culprit lesions: 544.7±29.9 versus 501.7±19.1, P=0.11, nonculprit lesions: 288.8±26.7 versus 272.7±18.9, P=0.51). Furthermore, a greater adjusted lipid plaque density index was observed in women (culprit lesions: 18.2±0.9 versus 9.8±0.6, P<0.001, nonculprit lesions: 23.0±2.0 versus 7.8±1.4, P<0.001). These adjustments of total atheroma volume at 4-mm segment, maximum 4-mm-lipid-core burden index, and lipid plaque density index included age, body mass index, hypertension, dyslipidemia, diabetes, smoking, a history of myocardial infarction and chronic kidney disease, low-density lipoprotein cholesterol level, statin and ezetimibe use, vessel volume, and hospital unit. The aforementioned plaque features consistently existed in both acute coronary syndrome and stable coronary artery disease subjects. Women harbored greater condensed lipidic plaque features, accompanied by smaller atheroma volume. These observations indicate potentially better modifiable disease in women, which underscores the need to intensify their lipid-lowering therapies for further improving their outcomes. URL: https://www. gov/; Unique identifier: NCT04864171.

Optoacoustic and optical coherence tomography guided lipid-selective ablation for atherosclerotic plaque

Atherosclerosis is a life-threatening disease of utmost clinical importance, which, despite recent progress in cardiovascular field, is still related to high morbidity and mortality. It is characterized by the accumulation of lipids within the arterial wall that is vulnerable and prone to rupture in pathological cardiovascular changes and acute events. In this paper, for the first time, we proposed a conceptually theranostics method to stabilize the atherosclerosis: Optoacoustic tomography (OAT)/optical coherence tomography (OCT) guided lipid-selective ablation for atherosclerotic plaque. To achieve this theranostics goal, the underlying pulsed laser-tissue interaction mechanisms of OA/OCT theranostics models was investigated for both OAT localization of lipid core as well as pulsed laser power titration for ablation. OCT was used to observe pre- and post-ablation result of fibrous caps and vessel wall, followed by histology validation. The feasibility of OA/OCT was first verified by plaque composition mimicking experiment. Furthermore, ex-vivo mouse aortas containing lipid-rich plaque were imaged and selectively ablated to show the intrinsically registered OA/OCT for targeting lipid core without causing adjacent tissue damage. Our results demonstrated the superiority of this theranostics technique for effective and precise removal of atherosclerotic plaque, which brings new capabilities and photonics insights to cardiovascular medicine.

Multimodality imaging to identify lipid-rich coronary plaques and predict periprocedural myocardial injury: Association between near-infrared spectroscopy and coronary computed tomography angiography.

This study compares the efficacy of coronary computed tomography angiography (CCTA) and near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) in patients with significant coronary stenosis for predicting periprocedural myocardial injury during percutaneous coronary intervention (PCI). We prospectively enrolled 107 patients who underwent CCTA before PCI and performed NIRS-IVUS during PCI. Based on the maximal lipid core burden index for any 4-mm longitudinal segments (maxLCBI4mm) in the culprit lesion, we divided the patients into two groups: lipid-rich plaque (LRP) group (maxLCBI4mm ≥ 400; n = 48) and no-LRP group (maxLCBI4mm < 400; n = 59). Periprocedural myocardial injury was a postprocedural cardiac troponin T (cTnT) elevation of ≥5 times the upper limit of normal. The LRP group had a significantly higher cTnT (p = 0.026), lower CT density (p < 0.001), larger percentage atheroma volume (PAV) by NIRS-IVUS (p = 0.036), and larger remodeling index measured by both CCTA (p = 0.020) and NIRS-IVUS (p < 0.001). A significant negative linear correlation was found between maxLCBI4mm and CT density (rho = -0.552, p < 0.001). Multivariable logistic regression analysis identified maxLCBI4mm [odds ratio (OR): 1.006, p = 0.003] and PAV (OR: 1.125, p = 0.014) as independent predictors of periprocedural myocardial injury, while CT density was not an independent predictor (OR: 0.991, p = 0.22). CCTA and NIRS-IVUS correlated well to identify LRP in culprit lesions. However, NIRS-IVUS was more competent in predicting the risk of periprocedural myocardial injury.

Relation of GRACE Risk Score to Coronary Lipid Core Plaques in Patients with Acute Coronary Syndrome.

The GRACE risk score is established to predict thrombotic events in patients with acute coronary syndrome (ACS). Although thrombotic events including myocardial infarction after ACS are mainly attributable to vulnerable plaque formation, whether the GRACE score correlates with coronary lipid-rich plaque is unclear. A total of 54 patients with ACS undergoing primary percutaneous coronary intervention under near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) guidance were included in a prospective manner. Patients were divided into two groups according to the median of the GRACE risk score. Coronary lipid plaques in the target vessel were assessed by NIRS-IVUS with lipid core burden index (LCBI) and a maximum LCBI in 4 mm (maxLCBI4mm). The receiver operating characteristics (ROC) curve analysis was performed based on the major adverse cardiovascular events as an exploratory analysis. The GRACE risk score was significantly and positively correlated with LCBI (r = 0.31, p = 0.03) and maxLCBI4mm (r = 0.38, p = 0.006). LCBI (111.7 ± 85.7 vs. 169.0 ± 83.5, p = 0.02) and maxLCBI4mm (428.5 ± 227.1 vs. 600.6 ± 227.7, p = 0.009) in the target vessel were significantly higher in the high GRACE risk score group than their counterpart. In the ROC curve analysis, LCBI and maxLCBI4mm were predictive for clinical events. In conclusion, the higher GRACE risk score may serve as a discriminator of risk comprising more lipid-rich plaques as an underlying mechanism of an increased risk of thrombotic events after ACS. In patients with ACS, the higher GRACE risk score was significantly and modestly associated with greater coronary lipid plaques in the target vessel.

Walnut inclusion in a palm oil-based atherogenic diet promotes traits predicting stable atheroma plaque in Apoe-deficient mice.

The lower rates of cardiovascular disease in Southern Europe could be partially explained by the low prevalence of lipid-rich atheroma plaques. Consumption of certain foods affects the progression and severity of atherosclerosis. We investigated whether the isocaloric inclusion of walnuts within an atherogenic diet prevents phenotypes predicting unstable atheroma plaque in a mouse model of accelerated atherosclerosis. Apolipoprotein E-deficient male mice (10-week-old) were randomized to receive a control diet (9.6% of energy as fat, n = 14), a palm oil-based high-fat diet (43% of energy as fat, n = 15), or an isocaloric diet in which part of palm oil was replaced by walnuts in a dose equivalent to 30 g/day in humans (n = 14). All diets contained 0.2% cholesterol. After 15 weeks of intervention, there were no differences in size and extension in aortic atherosclerosis among groups. Compared to control diet, palm oil-diet induced features predicting unstable atheroma plaque (higher lipid content, necrosis, and calcification), and more advanced lesions (Stary score). Walnut inclusion attenuated these features. Palm oil-based diet also boosted inflammatory aortic storm (increased expression of chemokines, cytokines, inflammasome components, and M1 macrophage phenotype markers) and promoted defective efferocytosis. Such response was not observed in the walnut group. The walnut group's differential activation of nuclear factor kappa B (NF-κB; downregulated) and Nrf2 (upregulated) in the atherosclerotic lesion could explain these findings. The isocaloric inclusion of walnuts in an unhealthy high-fat diet promotes traits predicting stable advanced atheroma plaque in mid-life mice. This contributes novel evidence for the benefits of walnuts, even in an unhealthy dietary environment.

Efficacy of a new generation intracoronary optical coherence tomography imaging system with fast pullback.

We sought to investigate whether a novel, fast-pullback, high-frequency optical coherence tomography (HF-OCT) imaging system enables data acquisition with a reduced amount of contrast agents while retaining the same qualitative and quantitative lesion assessment to conventional OCT. The increased amount of administered contrast agents is a major concern when performing intracoronary OCT. The present study is a single-center, prospective, observational study including 10 patients with stable coronary artery disease. A total of 28 individual coronary arteries were assessed by both fast-pullback HF-OCT and by conventional OCT. The contrast volume used in each OCT run for the HF-OCT system was significantly lower than for the conventional OCT system (5.0 ± 0.0 mL vs. 7.8 ± 0.7 mL, respectively, with a mean difference of -2.84 [95% confidence interval [CI]: -3.10 to -2.58]). No significant difference was found in the median value of the clear image length between the two OCT systems (74 mm [interquartile range[IQR]; 63, 81], 74 mm [IQR; 71, 75], p = 0.89). Fast-pullback HF-OCT showed comparable measurements to conventional OCT, including minimum lumen area (3.27 ± 1.53 mm2 vs. 3.21 ± 1.53 mm2 , p = 0.27), proximal reference area (7.03 ± 2.28 mm2 vs. 7.03 ± 2.34 mm2 , p = 0.96), and distal reference area (5.93 ± 1.96 mm2 vs. 6.03 ± 2.02 mm2 , p = 0.23). Qualitative OCT findings were comparable between the fast-pullback HF-OCT runs and conventional OCT with respect to identifying lipid-rich plaques, calcifications, layered plaques, macrophages, and cholesterol crystals. With the fast pullback function of a novel HF-OCT imaging system, we acquired OCT images using a significantly lower amount of contrast volume while retaining a comparable qualitative and quantitative lesion assessment to conventional OCT.

Relationship between coronary high-intensity plaques on T1-weighted imaging by cardiovascular magnetic resonance and vulnerable plaque features by near-infrared spectroscopy and intravascular ultrasound: a prospective cohort study

BackgroundThis study aimed to compare the coronary plaque characterization by cardiovascular magnetic resonance (CMR) and near-infrared spectroscopy (NIRS)-intravascular ultrasound (IVUS) (NIRS-IVUS), and to determine whether pre–percutaneous coronary intervention (PCI) evaluation using CMR identifies high-intensity plaques (HIPs) at risk of peri-procedural myocardial infarction (pMI). Although there is little evidence in comparison with NIRS-IVUS findings, which have recently been shown to identify vulnerable plaques, we inferred that CMR-derived HIPs would be associated with vulnerable plaque features identified on NIRS-IVUS. Methods52 patients with stable coronary artery disease who underwent CMR with non-contrast T1-weighted imaging and PCI using NIRS-IVUS were studied. HIP was defined as a signal intensity of the coronary plaque-to-myocardial signal intensity ratio (PMR) ≥ 1.4, which was measured from the data of CMR images. We evaluated whether HIPs were associated with the NIRS-derived maximum 4-mm lipid-core burden index (maxLCBI4mm) and plaque morphology on IVUS, and assessed the incidence and predictor of pMI defined by the current Universal Definition using high-sensitive cardiac troponin-T. ResultsOf 62 lesions, HIPs were observed in 30 lesions (48%). The HIP group had a significantly higher remodeling index, plaque burden, and proportion of echo-lucent plaque and maxLCBI4mm ≥ 400 (known as large lipid-rich plaque [LRP]) than the non-HIP group. The correlation between the maxLCBI4mm and PMR was significantly positive (r = 0.51). In multivariable logistic regression analysis for prediction of HIP, NIRS-derived large LRP (odds ratio [OR] = 5.41; 95% confidence intervals [CIs] 1.65–17.8, p = 0.005) and IVUS-derived echo-lucent plaque (OR = 5.12; 95% CIs 1.11–23.6, p = 0.036) were strong independent predictors. Furthermore, pMI occurred in 14 of 30 lesions (47%) with HIP, compared to only 5 of 32 lesions (16%) without HIP (p = 0.005). In multivariable logistic regression analysis for prediction of incidence of pMI, CMR-derived HIP (OR = 5.68; 95% CIs 1.53–21.1, p = 0.009) was a strong independent predictor, but not NIRS-derived large LRP and IVUS-derived echo-lucent plaque. ConclusionsThere is an important relationship between CMR-derived HIP and NIRS-derived large LRP. We also confirmed that non-contrast T1-weighted CMR imaging is useful for characterization of vulnerable plaque features as well as for pre-PCI risk stratification.Trial registration The ethics committee of Juntendo Clinical Research and Trial Center approved this study on January 26, 2021 (Reference Number 20-313).

Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Phosphate Accelerates Cellular Cholesterol Efflux in THP-1 Cells.

Cholesterol efflux is a major atheroprotective function of high-density lipoproteins (HDLs) which removes cholesterol from the foam cells of lipid-rich plaques in Type 2 diabetes. The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin phosphate increases plasma glucagon-like peptide-1 (GLP-1) concentrations and is used to treat Type 2 diabetes. GLP-1 plays an important role in regulating insulin secretion and expression via the GLP-1 receptor (GLP-1R), which is expressed in pancreatic islets as well as freshly isolated human monocytes and THP-1 cells. Here, we identified a direct role of GLP-1 and DPP-4 inhibition in HDL function. Cholesterol efflux was measured in cultivated phorbol 12-myristate 13-acetate-treated THP-1 cells radiolabeled with 3H-cholesterol and stimulated with liver X receptor/retinoid X receptor agonists. Contrary to vildagliptin, sitagliptin phosphate together with GLP-1 significantly (p < 0.01) elevated apolipoprotein (apo)A1-mediated cholesterol efflux in a dose-dependent manner. The sitagliptin-induced increase in cholesterol efflux did not occur in the absence of GLP-1. In contrast, adenosine triphosphate-binding cassette transporter A1 (ABCA1) mRNA and protein expressions in the whole cell fraction were not changed by sitagliptin in the presence of GLP-1, although sitagliptin treatment significantly increased ABCA1 protein expression in the membrane fraction. Furthermore, the sitagliptin-induced, elevated efflux in the presence of GLP-1 was significantly decreased by a GLP-1R antagonist, an effect that was not observed with a protein kinase A inhibitor. To our knowledge, the present study reports for the first time that sitagliptin elevates cholesterol efflux in cultivated macrophages and may exert anti-atherosclerotic actions that are independent of improvements in glucose metabolism. Our results suggest that sitagliptin enhances HDL function by inducing a de novo HDL synthesis via cholesterol efflux.

Wall shear stress-related plaque growth of lipid-rich plaques in human coronary arteries: an near-infrared spectroscopy and optical coherence tomography study.

Low wall shear stress (WSS) is acknowledged to play a role in plaque development through its influence on local endothelial function. Also, lipid-rich plaques (LRPs) are associated with endothelial dysfunction. However, little is known about the interplay between WSS and the presence of lipids with respect to plaque progression. Therefore, we aimed to study the differences in WSS-related plaque progression between LRPs, non-LRPs, or plaque-free regions in human coronary arteries. In the present single-centre, prospective study, 40 patients who presented with an acute coronary syndrome successfully underwent near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) and optical coherence tomography (OCT) of at least one non-culprit vessel at baseline and completed a 1-year follow-up. WSS was computed applying computational fluid dynamics to a three-dimensional reconstruction of the coronary artery based on the fusion of the IVUS-segmented lumen with a CT-derived centreline, using invasive flow measurements as boundary conditions. For data analysis, each artery was divided into 1.5 mm/45° sectors. Plaque growth based on IVUS-derived percentage atheroma volume change was compared between LRPs, non-LRPs, and plaque-free wall segments, as assessed by both OCT and NIRS. Both NIRS- and OCT-detected lipid-rich sectors showed a significantly higher plaque progression than non-LRPs or plaque-free regions. Exposure to low WSS was associated with a higher plaque progression than exposure to mid or high WSS, even in the regions classified as a plaque-free wall. Furthermore, low WSS and the presence of lipids had a synergistic effect on plaque growth, resulting in the highest plaque progression in lipid-rich regions exposed to low shear stress. This study demonstrates that NIRS- and OCT-detected lipid-rich regions exposed to low WSS are subject to enhanced plaque growth over a 1-year follow-up. The presence of lipids and low WSS proves to have a synergistic effect on plaque growth.

Association of Statins With Nonculprit Coronary Lesions and Adverse Events (from the LRP Study)

Intravascular ultrasound and near-infrared spectroscopy can identify vulnerable coronary atherosclerotic plaques. In this LRP (Lipid-Rich Plaque) substudy, we evaluated the association of statins with nonculprit lesion arterial wall lipidic content and subsequent nonculprit major adverse cardiac events. Patients from the LRP study with known statin use were included. We divided the patients into 2 cohorts-"statin therapy" and "statin-naïve"-upon presentation and then described the intravascular ultrasound and near-infrared spectroscopy analysis based on maximum 4-mm lipid core burden index (maxLCBI4mm). At 2-year follow-up, the patients' clinical events were assessed based on their statin regimen change upon discharge. Finally, patients were stratified by statin intensity based on discharge regimen. Among the 1,526 patients, 1,120 were on a statin versus 396 who were statin-naive upon presentation. Patients on a statin at baseline had a statistically higher rate of cardiovascular risk factors, patients who were statin-naive were more likely to present with an acute coronary syndrome, and the maxLCBI4mm did not differ between the 2 groups (315.67 ± 181.36 vs 325.55 ± 192.16; p=0.359). These findings were consistent in a secondary analysis evaluating statin intensity. Patients who were switched from no statin to a statin had improved outcomes (nonculprit major adverse cardiac events) compared with patients who were on a statin at baseline without change. In conclusion, despite having a higher burden of nonlipid-related cardiac co-morbidities, patients on a statin at baseline had similar maxLCBI4mm with patients who were statin-naive, regardless of intensity. Initiating a statin at discharge provides the most benefit for events related to nonculprit lesions.

483 CORONARY ATHEROSCLEROSIS PHENOTYPES IN FOCAL AND DIFFUSE DISEASE

Abstract Introduction The pathophysiological interplay between coronary physiology and plaque characteristics remains poorly understood. Pullback pressure gradient (PPG) is a novel physiological index that discriminates focal from diffuse coronary artery disease (CAD) based on coronary physiology. We aimed to compare plaque characteristics using between atherosclerotic patterns defined by coronary physiology. Methods Multicenter, prospective, controlled, single-arm study conducted in five countries (NCT03782688). Patients with functionally significant lesions based on invasive fractional flow reserve (FFR&amp;lt;0.80) were included. Subjects underwent coronary computed tomography angiography (CCTA) with quantitative plaque analysis followed by an invasive procedure with optical coherence tomography (OCT) and motorized intracoronary pressure recordings. Fractional flow reserve (FFR) pullback curves were processed to calculate the PPG. The PPG ranges from 0, indicating diffuse disease, to 1, pointing to focal CAD. Focal and diffuse CAD were defined according to the median PPG value. Results Overall, 117 patients (120 vessels) were included. The mean age was 64±9, 80% were male, and 22% had diabetes (no difference between focal vs. diffuse). Median PPG was 0.66 [0.54, 0.75]. In CCTA analysis, the plaque burden at minimum lumen area was higher in patients with focal CAD (87±8% focal vs. 82±10% diffuse, p=0.003). Calcifications were significantly more prevalent in patients with diffuse CAD (Agatston score per vessel 50 [9, 166] focal vs. 151 [46, 360] diffuse, p=0.019). In OCT plaque analysis, patients with focal CAD had a significantly higher prevalence of circumferential lipid-rich plaque (37% focal vs. 4% diffuse, p=0.001) and thin-cap fibroatheroma (TCFA 47% focal vs. 10% diffuse, p=0.002). High PPG predicted the presence of TCFA with an AUC of 0.73 (95% CI 0.58 to 0.87). PPG and fibrous cap thickness were negatively correlated (r=-0.55, 95% CI -0.74 to -0.28) independently of FFR. Conclusions Atherosclerotic plaque phenotypes associate with intracoronary hemodynamics. Vessels with focal disease (high PPG) had a higher plaque burden and predominantly lipid-rich plaque with a high prevalence of TCFA, whereas calcifications were the hallmark of vessels with diffuse pressure loss.