Non-Newtonian Endothelial Shear Stress Simulation: Does It Matter?

Patient-specific coronary endothelial shear stress (ESS) calculations using Newtonian and non-Newtonian rheological models were performed to assess whether the common assumption of Newtonian blood behavior offers similar results to a more realistic but computationally expensive non-Newtonian model. 16 coronary arteries (from 16 patients) were reconstructed from optical coherence tomographic (OCT) imaging. Pulsatile CFD simulations using Newtonian and the Quemada non-Newtonian model were performed. Endothelial shear stress (ESS) and other indices were compared. Exploratory indices including local blood viscosity (LBV) were calculated from non-Newtonian simulation data. Compared to the Newtonian results, the non-Newtonian model estimates significantly higher time-averaged ESS (1.69 (IQR 1.36)Pa versus 1.28 (1.16)Pa, p < 0.001) and ESS gradient (0.90 (1.20)Pa/mm versus 0.74 (1.03)Pa/mm, p < 0.001) throughout the cardiac cycle, under-estimating the low ESS (<1Pa) area (37.20 ± 13.57% versus 50.43 ± 14.16%, 95% CI 11.28-15.18, p < 0.001). Similar results were also found in the idealized artery simulations with non-Newtonian median ESS being higher than the Newtonian median ESS (healthy segments: 0.8238Pa versus 0.6618Pa, p < 0.001 proximal; 0.8179Pa versus 0.6610Pa, p < 0.001 distal; stenotic segments: 0.8196Pa versus 0.6611Pa, p < 0.001 proximal; 0.2546Pa versus 0.2245Pa, p < 0.001 distal) On average, the non-Newtonian model has a LBV of 1.45 times above the Newtonian model with an average peak LBV of 40-fold. Non-Newtonian blood model estimates higher quantitative ESS values than the Newtonian model. Incorporation of non-Newtonian blood behavior may improve the accuracy of ESS measurements. The non-Newtonian model also allows calculation of exploratory viscosity-based hemodynamic indices, such as local blood viscosity, which may offer additional information to detect underlying atherosclerosis.

Progression of ultrasound plaque attenuation and low echogenicity associates with major adverse cardiovascular events.

AIMS: Intravascular ultrasound (IVUS) imaging can visualize vulnerable plaque features including attenuation (AP) and echolucency (ELP). While IVUS-derived vulnerable plaque features associate with microvascular obstruction during percutaneous coronary intervention, the relationship between these plaque features and clinical outcomes has not been established. This analysis aimed to evaluate the association of AP/ELP with cardiovascular events. METHODS AND RESULTS: Serial IVUS imaging was reviewed in 1497 patients, followed for 18-24 months, with coronary artery disease from two clinical trials. Attenuated plaque and ELP were identified to measure each characteristics (AP arc, ELP area, and lengths), which permitted calculation of an AP index (API) and ELP volume. Attenuated plaque/ELP progression was defined as patients with any increase of API or ELP volume on serial imaging. The major cardiovascular events (MACEs) were defined as death, myocardial infarction, stroke, and coronary revascularization. AP or ELP was identified in 282 patients (18.8%) at baseline and 160 (10.7%) patients demonstrated an increase in AP or ELP at follow-up. The incidence of MACE was higher in patients with baseline AP/ELP than those without (8.2% vs. 3.9%, P = 0.002). Patients with AP/ELP progression were more likely to be acute coronary syndrome (41.9 vs. 33.2%, P = 0.03) and have greater baseline percent atheroma volume (40.0% vs. 35.8%, P < 0.001) than those without. On multivariable analysis, AP/ELP progression was more strongly associated with MACE [baseline AP/ELP: hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.05-2.97, AP/ELP progression: HR 2.19, 95% CI 1.24-3.86]. CONCLUSION: Attenuation/ELP progression was associated with a higher prevalence of cardiovascular events, supporting a potential role for the identification of high-risk vulnerable plaques in patients with coronary artery disease.

Associations of ABCG1-mediated cholesterol efflux capacity with coronary artery lipid content assessed by near-infrared spectroscopy.

BACKGROUND: Although high-density lipoprotein (HDL) has atheroprotective properties, the association of HDL functionality with coronary plaques remains unclear. METHODS: We investigated the association between HDL-mediated cholesterol efflux capacity (CEC) and coronary lipid burden in 74 patients who underwent near-infrared spectroscopy (NIRS) imaging for acute coronary syndrome (ACS) or stable ischemic symptoms. We measured baseline HDL-mediated CEC, distinguishing the specific pathways, and stratified patients according to their median CEC values. Coronary lipid burden was assessed as lipid core burden index (LCBI) using NIRS at baseline (n=74) and on serial imaging (n=47). RESULTS: Patients with baseline ATP-binding cassette transporter G1 (ABCG1)-mediated CEC > median had a greater baseline LCBI {74 [20, 128] vs. 32 [5, 66]; P=0.04} or change in LCBI {-30 [-89, 0] vs. -3 [-16, 0]; P=0.048}. In addition to a negative association between baseline LCBI and change in LCBI (standardized ß=-0.31; P=0.02), multivariable analysis demonstrated a significant interaction effect between clinical presentation of coronary artery disease (CAD) and baseline ABCG1-mediated CEC on change in LCBI (P=0.003), indicating that baseline ABCG1-mediated CEC was inversely associated with change in LCBI in patients with ACS (standardized ß=-0.79, P=0.003), but not in those with stable ischemic symptoms (P=0.52). CONCLUSIONS: In this study, ABCG1-mediated CEC, but not ATP-binding cassette transporter A1 and scavenger receptor B type I, was associated with regression of coronary artery lipid content, especially in patients with high-risk phenotype. Further studies are required to determine the roles of ABCG1 pathway in the development coronary plaques.

The Effect of Bromodomain and Extra-Terminal Inhibitor Apabetalone on Attenuated Coronary Atherosclerotic Plaque: Insights from the ASSURE Trial.

BACKGROUND: Apabetalone is a selective bromodomain and extra-terminal (BET) inhibitor which modulates lipid and inflammatory pathways implicated in atherosclerosis. The impact of apabetalone on attenuated coronary atherosclerotic plaque (AP), a measure of vulnerability, is unknown. METHODS: The ApoA-1 Synthesis Stimulation and intravascular Ultrasound for coronary atheroma Regression Evaluation (ASSURE; NCT01067820) study employed serial intravascular ultrasound (IVUS) measures of coronary atheroma in 281 patients treated with apabetalone or placebo for 26 weeks. AP was measured at baseline and follow-up. Factors associated with changes in AP were investigated. RESULTS: AP was observed in 31 patients (11%) [27 (13.0%) in the apabetalone group and four (5.5%) in the placebo group]. The apabetalone group demonstrated reductions in AP length by - 1 mm [interquartile range (IQR) - 4, 1] (p = 0.03), AP arc by - 37.0° (IQR - 59.2, 8.2) (p = 0.003) and the AP index by - 34.6 mm° (IQR - 52.6, 10.1) (p = 0.003) from baseline. The change in AP index correlated with on-treatment concentration of high-density lipoprotein (HDL) particles (r = - 0.52, p = 0.006), but not HDL cholesterol (r = - 0.11, p = 0.60) or apolipoprotein A-1 (r = - 0.16, p = 0.43). Multivariable analysis revealed that on-treatment concentrations of HDL particles (p = 0.03) and very low-density lipoprotein particles (p = 0.01) were independently associated with changes in AP index. CONCLUSIONS: Apabetalone favorably modulated ultrasonic measures of plaque vulnerability in the population studied, which may relate to an increase in HDL particle concentrations. The clinical implications are currently being investigated in the phase 3 major adverse cardiac event outcomes trial BETonMACE.

The Extent of Aortic Atherosclerosis Predicts the Occurrence, Severity, and Recovery of Acute Kidney Injury After Transcatheter Aortic Valve Replacement.

BACKGROUND: Acute kidney injury (AKI) can be a major complication of transcatheter aortic valve replacement (TAVR). Atheroembolization of debris during catheter manipulation has been considered as a potential factor causing AKI. This study investigates the impact of aortic atheroma burden on AKI post-TAVR and evaluates the potential of preoperative multislice computed tomographic (MSCT) imaging for the assessment of AKI in these patients. METHODS AND RESULTS: Preoperative multislice computed tomographic images were analyzed in 278 patients with symptomatic severe aortic stenosis who underwent TAVR. AKI was defined as an absolute increase in serum creatinine ≥0.3 mg/dL. Aorta vessel and lumen areas in each 1-mm cross-sectional image were measured. Percent atheroma volume above (PAVabove renal arteries) and below (PAVbelow renal arteries) renal arteries were calculated by the following formula: PAV={Σ (vessel area-lumen area)/Σ(vessel area)}×100. AKI occurred in 92 patients (33.1%) after TAVR. AKI was associated with a greater PAV above (30.4±8.2 versus 21.3±5.8%; P=0.02) but not below (28.9±7.7 versus 25.8±6.1%; P=0.41) the renal arteries. Greater PAVabove renal arteries was associated directly with AKI severity ( P=0.008) and inversely with recovery in serum creatinine level from peak to discharge ( r=0.78; P=0.002). Multivariate analysis demonstrated that PAVabove renal arteries was a significant predictor of AKI ( P=0.02). Receiver-operating curve analysis identified PAVabove renal arteries >29.5% as an optimal threshold to predict AKI. CONCLUSIONS: Suprarenal aortic atheroma burden is associated with the occurrence, severity, and recovery of AKI after TAVR. This highlights the utility of preoperative assessment of aortic atherosclerosis on multislice computed tomography to identify patients at high-risk for AKI.

Effect of Evolocumab on Coronary Plaque Composition.

BACKGROUND: Incremental low-density lipoprotein (LDL) cholesterol lowering with the proprotein convertase subtilisin kexin type 9 inhibitor evolocumab regresses coronary atherosclerosis in statin-treated patients. OBJECTIVES: The purpose of this study was to evaluate the effect of adding evolocumab to statin therapy on coronary plaque composition. METHODS: A total of 968 statin-treated coronary artery disease patients underwent serial coronary intravascular ultrasound imaging at baseline and following 76 weeks of treatment with placebo or evolocumab 420 mg monthly. Plaque composition changes were determined in 331 patients with evaluable radiofrequency analysis of the ultrasound backscatter signal. RESULTS: Compared with statin monotherapy, evolocumab further reduced LDL cholesterol (33.5 mg/dl vs. 89.9 mg/dl; p < 0.0001) and induced regression of percent atheroma volume (-1.2% vs. +0.17%; p < 0.0001) and total atheroma volume (-3.6 mm3 vs. -0.8 mm3; p = 0.04). No difference was observed between the evolocumab and placebo groups in changes in calcium (1.0 ± 0.3 mm3 vs. 0.6 ± 0.3 mm3; p = 0.49), fibrous (-3.0 ± 0.6 mm3 vs. -2.4 ± 0.6 mm3; p = 0.49), fibrofatty (-5.0 ± 1.0 mm3 vs. -3.0 ± 1.0 mm3; p = 0.49), and necrotic (-0.6 ± 0.5 mm3 vs. -0.1 ± 0.5 mm3; p = 0.49) volumes. An inverse correlation was observed between changes in LDL cholesterol and plaque calcification (r = -0.15; p < 0.001). CONCLUSIONS: The addition of evolocumab to a statin did not produce differential changes in plaque composition compared with statin monotherapy. This suggests that evaluation of plaque morphology using virtual histology imaging may provide no incremental information about the plaque effects of evolocumab beyond measurement of plaque burden. (GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound [GLAGOV]; NCT01813422).

The relationship between segmental wall shear stress and lipid core plaque derived from near-infrared spectroscopy.

BACKGROUND AND AIMS: Wall shear stress (WSS) has an important role in the natural history of coronary atherosclerosis. The aim of this study is to investigate the relationship between WSS and the lipid content of atherosclerotic plaques as assessed by near-infrared spectroscopy (NIRS). METHODS: We performed serial NIRS and intravascular ultrasound (IVUS) upon Doppler coronary flow guidewire of coronary plaques at baseline and after 12-18 months in 28 patients with <30% angiographic stenosis, who presented with coronary artery disease. Segmental WSS, plaque burden and NIRS-derived lipid rich plaque (LRP) were evaluated at both time-points in 482 consecutive 2-mm coronary segments. RESULTS: Segments with LRP at baseline (n = 106) had a higher average WSS (1.4 ±â€¯0.6 N/m2), compared to those without LRP (n = 376) (1.2 ±â€¯0.6 N/m2, p<0.001). In segments without baseline LRP, WSS was higher in those who subsequently developed new LRP (n = 35) than those who did not (n = 341) (1.4 ±â€¯0.8 vs. 1.1 ±â€¯0.6 N/m2, p=0.002). Conversely, in segments with baseline LRP, WSS was lower in those who had regression of lipid content (n = 41) than those who did not (n = 65) (1.2 ±â€¯0.4 vs. 1.6 ±â€¯0.7 N/m2, p=0.007). Segments with the highest tertile of WSS displayed greater progression of LCBI irrespective of baseline lipid content (p<0.001). Multivariate analysis revealed that baseline WSS (p=0.017), PAV (p<0.001) and LCBI (p<0.001) were all independent predictors of change in LCBI over time. CONCLUSIONS: Coronary segments with high WSS associate with progression of lipid content over time, which may indicate transformation to a more vulnerable phenotype.

Intravascular Ultrasound Studies of Plaque Progression and Regression: Impact of Lipid-Modifying Therapies.

Application of serial intravascular ultrasound imaging within the coronary arteries enables characterization of the factors associated with progression of atherosclerotic plaque. Integration into clinical trials has enabled determination of the impact of medical therapies on coronary disease. These trials have provided important insights into the effects of lipid-modifying agents currently used in clinical practice and of experimental agents at early stages of clinical development. The results of these trials are reviewed.

Evaluation of human coronary vasodilator function predicts future coronary atheroma progression.

OBJECTIVE: Coronary vasodilator function and atherosclerotic plaque progression have both been shown to be associated with adverse cardiovascular events. However, the relationship between these factors and the lipid burden of coronary plaque remains unknown. These experiments focus on investigating the relationship between impaired coronary vasodilator function (endothelium dependent (salbutamol) and endothelium independent (glyceryl trinitrate)) and the natural history of atheroma plaque progression and lipid burden using dual modality intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) imaging. METHODS: 33 patients with stable chest pain or acute coronary syndrome underwent serial assessment of coronary vasodilator function and intracoronary plaque IVUS and NIRS imaging. Coronary segmental macrovascular response (% change segmental lumen volume (ΔSLV)), plaque burden (per cent atheroma volume (PAV)), lipid core (lipid-rich plaque (LRP) and lipid core burden index (LCBI)) were measured at baseline and after an interval of 12-18 months (n=520 segments). RESULTS: Lipid-negative coronary segments which develop into LRP over the study time period demonstrated impaired endothelial-dependent function (-0.24±2.96 vs 5.60±1.47%, P=0.04) and endothelial-independent function (13.91±4.45 vs 21.19±3.19%, P=0.036), at baseline. By multivariate analysis, endothelial-dependent function predicted ∆LCBI (ß coefficient: -3.03, 95% CI (-5.81 to -0.25), P=0.033) whereas endothelial-independent function predicted ∆PAV (ß coefficient: 0.07, 95% CI (0.04 to 0.10), P<0.0001). CONCLUSIONS: Epicardial coronary vasodilator function is a determinant of future atheroma progression and composition irrespective of the nature of clinical presentation. TRIAL REGISTRATION NUMBER: ACTRN12612000594820, Post-results.

High-density lipoprotein cholesterol associated with change in coronary plaque lipid burden assessed by near infrared spectroscopy.

BACKGROUND AND AIMS: Little is known about the relation between serum lipid parameters and serial change in plaque composition using in vivo coronary imaging. The aim of this study was to examine the association between serum lipids and change in coronary plaque lipid burden assessed by near-infrared spectroscopy (NIRS). METHODS: We performed serial NIRS-intravascular ultrasound studies in 49 patients who underwent coronary angiography for an acute coronary syndrome (ACS) or stable ischemic symptoms. Univariable and multivariable linear regression analyses were applied to evaluate the relationship between serum lipid parameters and change in lipid core burden index at the 4-mm maximal segment (max LCBI4mm). RESULTS: Mean patient age was 61 ± 9 y, 29% were women, 35% had an ACS clinical presentation, 78% received statin therapy at baseline, and median low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), total cholesterol and triglyceride levels were 101, 43, 174 and 133 mg/dL, respectively. During a median follow-up period of 13 months, max LCBI4mm significantly decreased from 277 to 194 (p = 0.001). On univariable analysis, the percent change in HDL-C negatively associated with the change in max LCBI4mm (ß = -3.19, p = 0.004). There were no significant associations between the other lipid parameters and change in max LCBI4mm. On multivariable analysis, percent change in HDL-C remained significantly associated with the change in max LCBI4mm (p = 0.002). CONCLUSIONS: Change in HDL-C, but not other lipids parameters, associated with changes in coronary plaque lipid burden assessed by NIRS. These findings highlight the potential therapeutic importance of high-density lipoprotein on serial change in plaque composition.

Indications and outcomes of excimer laser coronary atherectomy: Efficacy and safety for thrombotic lesions-The ULTRAMAN registry.

BACKGROUND: Excimer laser coronary atherectomy (ELCA) recently became available in Japan, but ELCA's effectiveness and safety are not clear. METHODS AND RESULTS: We enrolled consecutive patients who underwent ELCA and were registered in the Utility of Laser for Transcatheter Atherectomy-Multicenter Analysis around Naniwa (ULTRAMAN) registry comprising six Japanese medical centers around Naniwa in Japan with patients registered from April 2006 to June 2015. We evaluated the catheter sizes used and compared the success rate, thrombolysis in myocardial infarction (TIMI) flow, blush score, and complications between the rich-thrombus (RT) group [acute coronary syndrome (ACS) and saphenous vein graft (SVG)] and the poor-thrombus (PT) group [in-stent restenosis (ISR), chronic total occlusion (CTO), calcification, and long or bifurcation (L&B) lesions]. Of the 328 patients, 6 (1.8%) were treated for an SVG, 175 (53.4%) were treated for ACS, 18 (5.5%) for CTO, 106 (32.4%) for ISR, 8 (2.4%) for calcification, and 15 for L&B lesions (4.6%). A 1.7-mm (concentric)-diameter ELCA catheter was used most frequently (59.4%). High success rates were achieved in both the RT and PT groups, but the TIMI flow grade and blush score were significantly lower and the complications rate was significantly higher in the RT group (n=181). CONCLUSIONS: In Japan, the major indications for ELCA have been ACS and ISR. ELCA can provide a safe and effective treatment even for RT lesions.

Noninvasive imaging modalities to visualize atherosclerotic plaques.

Atherosclerotic cardiovascular disease is becoming a major cause of death in the world due to global epidemic of diabetes and obesity. For the prevention of atherosclerotic cardiovascular disease, it is necessary to detect high-risk atherosclerotic plaques prior to events. Recent technological advances enable to visualize atherosclerotic plaques noninvasively. This ability of noninvasive imaging helps to refine cardiovascular risk assessment in various individuals, select optimal therapeutic strategy and evaluate the efficacy of medical therapies. In this review, we discuss the role of the currently available imaging modalities including computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography. Advantages and disadvantages of each noninvasive imaging modality will be also summarized.

Vaporizing thrombus with excimer laser before coronary stenting improves myocardial reperfusion in acute coronary syndrome.

BACKGROUND: Mechanical reperfusion has proven to be an unquestionably superior treatment strategy over that of thrombolytic therapy in patients with acute coronary syndrome (ACS). Excimer laser coronary angioplasty (ELCA) is a unique revascularization device that has a lytic effect on thrombus, in addition to its debulking effect on the atherosclerotic plaque beneath the thrombus. METHODS AND RESULTS: This single-center retrospective analysis consisted of consecutive ACS patients treated with ELCA (n=50) and age- and sex-matched ACS patients treated with manual aspiration (n=48) without use of a distal protection device. Success rate was judged by lesion crossability, procedure complications, and significant reduction of stenosis. Tissue-level perfusion was assessed on antegrade Thrombolysis In Myocardial Infarction (TIMI) flow grade, myocardial blush grade (MBG), and ST-segment elevation resolution (STR). Short-term outcome was evaluated according to occurrence of in-hospital major adverse cardiac events (MACE; myocardial infarction, target lesion revascularization, coronary artery bypass graft, and death). Lesion crossability was higher in the ELCA group than in the aspiration group (96.2% vs. 82.6%, P=0.04). Attainment of TIMI 3 flow (86.0% vs. 68.8%, P=0.04) and MBG 3 (76.0% vs. 54.2%, P=0.02) was also higher in the ELCA group than in the aspiration group. Complete STR was similar between the 2 groups. In-hospital MACE were significantly more frequent in the aspiration group. CONCLUSIONS: ELCA is feasible, safe, and effective for the treatment of patients with ACS and appears to be useful as an adjunctive lesion preparation device.