The role of endothelial shear stress, shear stress gradient, and plaque topography in plaque erosion.

BACKGROUND AND AIMS: Plaque erosion is a common underlying cause of acute coronary syndromes. The role of endothelial shear stress (ESS) and endothelial shear stress gradient (ESSG) in plaque erosion remains unknown. We aimed to determine the role of ESS metrics and maximum plaque slope steepness in plaques with erosion versus stable plaques. METHODS: This analysis included 46 patients/plaques from TOTAL and COMPLETE trials and Brigham and Women's Hospital's database who underwent angiography and OCT. Plaques were divided into those with erosion (n = 24) and matched stable coronary plaques (n = 22). Angiographic views were used to generate a 3-D arterial reconstruction, with centerlines merged from angiography and OCT pullback. Local ESS metrics were assessed by computational fluid dynamics. Among plaque erosions, the up- and down-slope (Δ lumen area/frame) was calculated for each culprit plaque. RESULTS: Compared with stable plaque controls, plaques with an erosion were associated with higher max ESS (8.3 ± 4.8 vs. 5.0 ± 1.9 Pa, p = 0.02) and max ESSG any direction (9.2 ± 7.5 vs. 4.3 ± 3.11 Pa/mm, p = 0.005). Proximal erosion was associated with a steeper plaque upslope while distal erosion with a steeper plaque downslope. Max ESS and Max ESSG any direction were independent factors in the development of plaque erosion (OR 1.32, 95%CI 1.06-1.65, p = 0.014; OR 1.22, 95% CI 1.03-1.45, p = 0.009, respectively). CONCLUSIONS: In plaques with similar luminal stenosis, plaque erosion was strongly associated with higher ESS, ESS gradients, and plaque slope as compared with stable plaques. These data support that ESS and slope metrics play a key role in the development of plaque erosion and may help prognosticate individual plaques at risk for future erosion.

Endothelial shear stress computed from coronary computed tomography angiography: A direct comparison to intravascular ultrasound.

INTRODUCTION: Intravascular ultrasound (IVUS) studies have shown that biomechanical variables, particularly endothelial shear stress (ESS), add synergistic prognostic insight when combined with anatomic high-risk plaque features. Non-invasive risk assessment of coronary plaques with coronary computed tomography angiography (CCTA) would be helpful to enable broad population risk-screening. AIM: To compare the accuracy of ESS computation of local ESS metrics by CCTA vs IVUS imaging. METHODS: We analyzed 59 patients from a registry of patients who underwent both IVUS and CCTA for suspected CAD. CCTA images were acquired using either a 64- or 256-slice scanner. Lumen, vessel, and plaque areas were segmented from both IVUS and CCTA (59 arteries, 686 3-mm segments). Images were co-registered and used to generate a 3-D arterial reconstruction, and local ESS distribution was assessed by computational fluid dynamics (CFD) and reported in consecutive 3-mm segments. RESULTS: Anatomical plaque characteristics (vessel, lumen, plaque area and minimal luminal area [MLA] per artery) were correlated when measured with IVUS and CCTA: 12.7 â€‹± â€‹4.3 vs 10.7 â€‹± â€‹4.5 â€‹mm2, r â€‹= â€‹0.63; 6.8 â€‹± â€‹2.7 vs 5.6 â€‹± â€‹2.7 â€‹mm2, r â€‹= â€‹0.43; 5.9 â€‹± â€‹2.9 vs 5.1 â€‹± â€‹3.2 â€‹mm2, r â€‹= â€‹0.52; 4.5 â€‹± â€‹1.3 vs 4.1 â€‹± â€‹1.5 â€‹mm2, r â€‹= â€‹0.67 respectively. ESS metrics of local minimal, maximal, and average ESS were also moderately correlated when measured with IVUS and CCTA (2.0 â€‹± â€‹1.4 vs 2.5 â€‹± â€‹2.6 â€‹Pa, r â€‹= â€‹0.28; 3.3 â€‹± â€‹1.6 vs 4.2 â€‹± â€‹3.6 â€‹Pa, r â€‹= â€‹0.42; 2.6 â€‹± â€‹1.5 vs 3.3 â€‹± â€‹3.0 â€‹Pa, r â€‹= â€‹0.35, respectively). CCTA-based computation accurately identified the spatial localization of local ESS heterogeneity compared to IVUS, with Bland-Altman analyses indicating that the absolute ESS differences between the two CCTA methods were pathobiologically minor. CONCLUSION: Local ESS evaluation by CCTA is possible and similar to IVUS; and is useful for identifying local flow patterns that are relevant to plaque development, progression, and destabilization.

Decision-Making During Percutaneous Coronary Intervention Guided by Optical Coherence Tomography: Insights From the LightLab Initiative.

BACKGROUND: Use of intracoronary imaging is associated with improved outcomes in patients undergoing percutaneous coronary intervention (PCI). Yet, the impact of intracoronary imaging on real-time physician decision-making during PCI is not fully known. METHODS: The LightLab Initiative is a multicenter, prospective, observational study designed to characterize the use of a standardized optical coherence tomography (OCT) workflow during PCI. Participating physicians performed pre-PCI and post-PCI OCT in accordance with this workflow and operator assessments of lesion characteristics and treatment plan were recorded for each lesion based on angiography alone and following OCT. Physicians were categorized as having low (n=15), intermediate (n=13), or high (n=14) OCT use in the year preceding participation. RESULTS: Among 925 patients with 1328 lesions undergoing PCI, the prescribed OCT workflow was followed in 773 (84%) of patients with 836 lesions. Operator lesion assessment and decision-making during PCI changed with OCT use in 86% (721/836) of lesions. Pre-PCI OCT use changed operator decision-making in 80% of lesions, including lesion assessment (45%), vessel preparation strategy (27%), stent diameter (37%), and stent length (36%). Post-PCI OCT changed stent optimization decision-making in 31% of lesions. These findings were consistent across strata of physician prior OCT experience. CONCLUSIONS: A standardized OCT workflow impacted PCI decision-making in 86% of lesions, with a predominant effect on pre-PCI lesion assessment and planning of treatment strategy. This finding was consistent regardless of operator experience level and provides insight into mechanisms by which intravascular imaging might improve PCI outcomes.

A Systematic Review and Meta-Analysis of Clinical Outcomes of Patients Undergoing Chronic Total Occlusion Percutaneous Coronary Intervention.

OBJECTIVES: Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) can improve patient symptoms, but it remains controversial whether it impacts subsequent clinical outcomes. METHODS: In this systematic review and meta-analysis, we queried PubMed, ScienceDirect, Cochrane Library, Web of Science, and Embase databases (last search: September 15, 2021). We investigated the impact of CTO-PCI on clinical events including all-cause mortality, cardiovascular death, myocardial infarction (MI), major adverse cardiovascular event (MACE), stroke, subsequent coronary artery bypass surgery, target-vessel revascularization, and heart failure hospitalizations. Pooled analysis was performed using a random-effects model. RESULTS: A total of 58 publications with 54,540 patients were included in this analysis, of which 33 were observational studies of successful vs failed CTO-PCI, 19 were observational studies of CTO-PCI vs no CTO-PCI, and 6 were randomized controlled trials (RCTs). In observational studies, but not RCTs, CTO-PCI was associated with better clinical outcomes. Odds ratios (ORs) and 95% confidence intervals (CIs) for all-cause mortality, MACE, and MI were 0.52 (95% CI, 0.42-0.64), 0.46 (95% CI, 0.37-0.58), 0.66 (95% CI, 0.50-0.86), respectively for successful vs failed CTO-PCI studies; 0.38 (95% CI, 0.31-0.45), 0.57 (95% CI, 0.42-0.78), 0.65 (95% CI, 0.42-0.99), respectively, for observational studies of CTO-PCI vs no CTO-PCI; 0.72 (95% CI, 0.39-1.32), 0.69 (95% CI, 0.38-1.25), and 1.04 (95% CI, 0.46-2.37), respectively for RCTs. CONCLUSIONS: CTO-PCI is associated with better subsequent clinical outcomes in observational studies but not in RCTs. Appropriately powered RCTs are needed to conclusively determine the impact of CTO-PCI on clinical outcomes.

Novel Three-Stent Strategy in Left Main Coronary Artery Trifurcation Disease - Combination of DK Crush and Culotte Techniques.

True trifurcation disease in left main coronary artery is an infrequent but highly complex substrate for percutaneous coronary intervention. Evidence for optimal stenting strategy for such anatomy is lacking. We describe a novel three-stent strategy using a combination of double-kissing crush (DK crush) and Culotte techniques in three patients. This approach, based on established bifurcation stenting techniques, appeared reproducible in all three cases.

International percutaneous coronary intervention complication survey.

OBJECTIVES: To investigate the perceptions of interventional cardiologists (IC) regarding the frequency, impact, and management strategies of percutaneous coronary intervention (PCI) complications. BACKGROUND: The perceptions and management strategies of ICs of PCI complications have received limited study. METHODS: Online survey on PCI complications: 46 questions were distributed via email lists and Twitter to ICs. RESULTS: Of 11,663 contacts, 821 responded (7% response rate): 60% were from the United States and the median age was 46-50 years. Annual PCI case numbers were <100 (26%), 100-199 (37%), 200-299 (21%), and ≥300 (16%); 42% do not perform structural interventions, others reported performing <40 (30%), or >100 (11%) structural cases annually. On a scale of 0-10, participating ICs were highly concerned about potential complications with a median score of 7.2 (interquartile range: 5.0-8.7). The most feared complication was death (39%), followed by coronary perforation (26%) and stroke (9%). Covered stents were never deployed by 21%, and 32% deployed at least one during the past year; 79% have never used fat to seal perforations; 64% have never used coils for perforations. Complications were attributed to higher patient/angiographic complexity by 68% and seen as opportunities for improvement by 70%; 97% of participants were interested in learning more about the management of PCI complications. The most useful learning methods were meetings (66%), webinars (48%), YouTube (32%), and Twitter (29%). CONCLUSION: ICs who participated in the survey are highly concerned about complications. Following complication management algorithms and having access to more experienced operators might alleviate stress and optimize patient outcomes.

Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee.

BACKGROUND: The phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial of ponatinib showed robust long-term benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred in ≥ 25% of patients based on investigator reporting. However, AOE rates vary depending on the definitions and reporting approach used. METHODS: To better understand clinically relevant AOEs with ponatinib, an independent cardiovascular adjudication committee reviewed 5-year AOE data from the PACE trial according to a charter-defined process and standardized event definitions. RESULTS: A total of 449 patients with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) received ponatinib (median age 59 y; 47% female; 93% ≥ 2 prior tyrosine kinase inhibitors (TKIs); median follow-up, 37.3 months). The adjudicated AOE rate (17%) was lower than the non-adjudicated rate (i.e., rate before adjudication; 25%). The only adjudicated AOE in > 2% of patients was peripheral arterial occlusive disease (4%). Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Patients with multiple baseline cardiovascular risk factors had higher adjudicated AOE rates than those without risk factors. CONCLUSIONS: This independent adjudication study identified lower AOE rates than previously reported, suggesting earlier overestimation that may inaccurately reflect AOE risk with ponatinib. This trial was registered under ClinicalTrials.gov identifier NCT01207440 on September 23, 2010 ( https://clinicaltrials.gov/ct2/show/NCT01207440 ).

Practice Patterns in the Interventional Treatment of Coronary Bifurcation Lesions: A Global Survey.

OBJECTIVES: The study aim was to assess current procedural strategies and perceptions for percutaneous coronary intervention (PCI) involving bifurcations. METHODS: We distributed an online survey via email (8050 invitations) and social media. RESULTS: Among 440 responders, median annual PCI volumes were 15 cases (interquartile range [IQR], 10-29 cases) for left main (LM) and 50 cases (IQR, 27-73 cases) for non-LM (nLM) bifurcation lesions. Radial access use was reported in 51% of LM and 82% of nLM cases. An upfront 2-stent strategy, most commonly double-kissing (DK) crush, was reported in 49% of LM and 29% of nLM lesions. Bailout stenting during provisional stenting was reported in 26% of LM-PCIs, usually using the T and protrusion technique. In provisional stenting cases, most operators (<35%) did not report predilating the side branch, but routinely postdilated after successful provisional stenting (>85%), most often using both kissing-balloon inflation and the proximal optimization technique. Intravascular imaging was used in 80% of LM and 46% of nLM cases. CONCLUSIONS: Among the survey responders, the DK crush technique was the most frequently used 2-stent strategy for bifurcation PCIs. For LM lesions, bailout stenting was performed after provisional strategy in approximately 25% of cases. For nLM lesions, use of intravascular imaging and coronary physiology was lower than for LM lesions.

OCT utilization: Summary statistics from the LightLab clinical initiative.

OBJECTIVES: The study describes the evolution of optical coherence tomography (OCT) adoption and performance during percutaneous coronary intervention (PCI) following implementation of a standardized LightLab (LL) workflow. BACKGROUND: The purpose of the LL Clinical Initiative was to evaluate the impact of a standardized workflow on physician efficiency, decision making, and image quality. METHODS: The LL Clinical Initiative is a multicenter, prospective, observational clinical program. Data were collected from 48 physicians at 17 U.S. centers from 01/21/19 to 06/08/21. The study included 401 OCT-guided PCIs during the baseline phase and 1898 during the LL workflow phases. The baseline phase consisted of physicians utilizing OCT at their discretion. After completing the baseline phase, the workflow progressed through multiple phases culminating in the expansion phase, which focused on addressing greater procedural complexity. The LL workflow utilized OCT to assess plaque Morphology, lesion Length, and vessel Diameter before PCI, and optimized results by treating Medial edge dissection, stent mal-Apposition, and stent under-eXpansion (MLD MAX). High-level summary statistics were generated to elucidate trends. RESULTS: After program implementation, there was a rise in the number of PCIs where the LL workflow was utilized compared to the baseline phase (68% during the expansion phase vs. 41% at baseline; p for trend <0.0001). Adoption of the LL workflow was associated with progressively greater procedural and lesion complexity when OCT was performed pre- and post-PCI (87% vs. 52%, p < 0.0001; 55% vs. 37%, p < 0.0001, respectively). In addition, the quality of OCT imaging obtained improved after LL workflow introduction, with over 95% of pre- and post-PCI pullback quality considered usable during the expansion phase. Finally, there was a reduction in time spent on OCT interpretation, both pre-PCI (4.6 min vs. 7.5 min, p < 0.0001) and post-PCI (2.9 min vs. 5.3 min, p < 0.0001). CONCLUSIONS: After completion of the standardized OCT-guided workflow, there was greater uptake of OCT imaging, incorporation in more complex procedures, procedural efficiency, and image quality.

The MLD MAX OCT algorithm: An imaging-based workflow for percutaneous coronary intervention.

Although extensive clinical data support the utility of intravascular imaging to guide and optimize outcomes following percutaneous coronary interventions (PCI), clinical adoption remains limited. One of the primary reasons for limited utilization may be a lack of standardization on how to best integrate the data provided by intravascular imaging practically. Optical coherence tomography (OCT) offers a high-resolution intravascular imaging modality with integrated software automation that allows for incorporation of OCT into the routine workflow of PCIs. We suggest use of an algorithm called MLD MAX to incorporate OCT for imaging-guided interventions: the baseline OCT imaging run is intended to facilitate procedural planning and strategizing, consisting of assessment for predominant lesion morphology (M), measurement for stent length (L) and determination of stent diameter (D); the post-PCI OCT imaging run is designated for assessment of need for further optimization of stent result, and consists of analysis for medial dissections (M), adequate stent apposition (A) and stent expansion (X). Incorporation of the MLD MAX algorithm into daily practice guides an efficient and easily-memorable workflow for optimized PCI procedures.

Learning and innovation among interventional cardiologists: Insights from an international survey.

BACKGROUND: The willingness of interventional cardiologists to adopt innovation and implement changes in day-to-day practice has received limited study. METHODS: Online-based survey on learning and innovation: 38 questions were distributed via email list to interventional cardiologists. RESULTS: The survey was distributed to 8,110 e-mails and completed by 621 (7.7%, 91.8% men, 60% in the 35 to 54-year-old age group). Of the respondents who perform coronary interventions, 45% perform >100 cases of noncomplex percutaneous coronary interventions per year and of the respondents who perform structural interventions, 15% perform more than >100 transcatheter aortic valve replacements per year. Most respondents (86.7%) rate themselves as highly likely/likely to introduce recently approved equipment in everyday practice and 47.5% have tried a new coronary guidewire in the past 6 months. The most common reasons for reluctance to use new equipment were high cost (64%) and uncertainty about whether it provides additional benefits compared with existing equipment (48.5%). Radial access in STEMI cases is always used by 43.6% of the respondents and 55% always use radial access for coronary angiography. Of those who use femoral access, 32% always use ultrasound guidance and 91% have used a closure device in the last 6 months. Most respondents (80%) read journals to keep up with current practice and believe that the most effective way to learn is through attendance of workshops/short courses (77.5%). Most respondents (69%) are involved in research. CONCLUSION: Interventional cardiologists who participated in the survey are highly likely to adopt innovation in daily clinical practice.

Safety and efficacy of dedicated guidewire, microcatheter, and guide catheter extension technologies for chronic total coronary occlusion revascularization: Primary results of the Teleflex Chronic Total Occlusion Study.

BACKGROUND: Description of procedural outcomes using contemporary techniques that apply specialized coronary guidewires, microcatheters, and guide catheter extensions designed for chronic total occlusion (CTO) percutaneous revascularization is limited. METHODS: A prospective, multicenter, single-arm study was conducted to evaluate procedural and in-hospital outcomes among 150 patients undergoing attempted CTO revascularization utilizing specialized guidewires, microcatheters and guide extensions. The primary endpoint was defined as successful guidewire recanalization and absence of in-hospital cardiac death, myocardial infarction (MI), or repeat target lesion revascularization (major adverse cardiac events, MACE). RESULTS: The prevalence of diabetes was 32.7%; prior MI, 48.0%; and previous bypass surgery, 32.7%. Average (mean ± standard deviation) CTO length was 46.9 ± 20.5 mm, and mean J-CTO score was 1.9 ± 0.9. Combined radial and femoral arterial access was performed in 50.0% of cases. Device utilization included: support microcatheter, 100%; guide catheter extension, 64.0%; and mean number of study guidewires/procedure was 4.8 ± 2.6. Overall, procedural success was achieved in 75.3% of patients. The rate of successful guidewire recanalization was 94.7%, and in-hospital MACE was 19.3%. Achievement of TIMI grade 2 or 3 flow was observed in 93.3% of patients. Crossing strategies included antegrade (54.0%), retrograde (1.3%) and combined antegrade/retrograde techniques (44.7%). Clinically significant perforation resulting in hemodynamic instability and/or requiring intervention occurred in 16 (10.7%) patients. CONCLUSIONS: In a multicenter, prospective registration study, favorable procedural success was achieved despite high lesion complexity using antegrade and retrograde guidewire maneuvers and with acceptable safety, yet with comparably higher risk than conventional non-CTO PCI.

Adverse Events With Intravascular Lithotripsy After Peripheral and Off-Label Coronary Use: A Report From the FDA MAUDE Database.

BACKGROUND: Currently only the peripheral intravascular lithotripsy (IVL) device is approved for use in the United States. We queried the United States Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database from January 1, 2016 to December 14, 2020 for all reports of adverse events and modes of failure related to the peripheral IVL device, when used for on- and off-label indications. There were 20 reports of use in peripheral artery disease interventions and 3 reports of off-label use in coronary interventions. Device malfunction in 13 of 23 patients (56.5%) was the most common adverse event reported. Partial balloon or catheter dislodgment was the most common mode of IVL device failure in 12 of 20 patients (60%), followed by balloon rupture in 3 of 20 patients (15%). Coronary use was rare, and associated with balloon perforation in 1 of 3 patients, bradycardia in 1 of 3 patients, and aortocoronary dissection in 1 of 3 patients. In summary, IVL use carries risk of complications; hence, continued vigilance and postmarketing monitoring are warranted.

Global Chronic Total Occlusion Crossing Algorithm: JACC State-of-the-Art Review.

The authors developed a global chronic total occlusion crossing algorithm following 10 steps: 1) dual angiography; 2) careful angiographic review focusing on proximal cap morphology, occlusion segment, distal vessel quality, and collateral circulation; 3) approaching proximal cap ambiguity using intravascular ultrasound, retrograde, and move-the-cap techniques; 4) approaching poor distal vessel quality using the retrograde approach and bifurcation at the distal cap by use of a dual-lumen catheter and intravascular ultrasound; 5) feasibility of retrograde crossing through grafts and septal and epicardial collateral vessels; 6) antegrade wiring strategies; 7) retrograde approach; 8) changing strategy when failing to achieve progress; 9) considering performing an investment procedure if crossing attempts fail; and 10) stopping when reaching high radiation or contrast dose or in case of long procedural time, occurrence of a serious complication, operator and patient fatigue, or lack of expertise or equipment. This algorithm can improve outcomes and expand discussion, research, and collaboration.

Targeted delivery of protein arginine deiminase-4 inhibitors to limit arterial intimal NETosis and preserve endothelial integrity.

AIMS: Recent evidence suggests that 'vulnerable plaques', which have received intense attention as underlying mechanism of acute coronary syndromes over the decades, actually rarely rupture and cause clinical events. Superficial plaque erosion has emerged as a growing cause of residual thrombotic complications of atherosclerosis in an era of increased preventive measures including lipid lowering, antihypertensive therapy, and smoking cessation. The mechanisms of plaque erosion remain poorly understood, and we currently lack validated effective diagnostics or therapeutics for superficial erosion. Eroded plaques have a rich extracellular matrix, an intact fibrous cap, sparse lipid, and few mononuclear cells, but do harbour neutrophil extracellular traps (NETs). We recently reported that NETs amplify and propagate the endothelial damage at the site of arterial lesions that recapitulate superficial erosion in mice. We showed that genetic loss of protein arginine deiminase (PAD)-4 function inhibited NETosis and preserved endothelial integrity. The current study used systemic administration of targeted nanoparticles to deliver an agent that limits NETs formation to probe mechanisms of and demonstrate a novel therapeutic approach to plaque erosion that limits endothelial damage. METHODS AND RESULTS: We developed Collagen IV-targeted nanoparticles (Col IV NP) to deliver PAD4 inhibitors selectively to regions of endothelial cell sloughing and collagen IV-rich basement membrane exposure. We assessed the binding capability of the targeting ligand in vitro and evaluated Col IV NP targeting to areas of denuded endothelium in vivo in a mouse preparation that recapitulates features of superficial erosion. Delivery of the PAD4 inhibitor GSK484 reduced NET accumulation at sites of intimal injury and preserved endothelial continuity. CONCLUSIONS: NPs directed to Col IV show selective uptake and delivery of their payload to experimentally eroded regions, illustrating their translational potential. Our results further support the role of PAD4 and NETs in superficial erosion.

Spatial relationships among hemodynamic, anatomic, and biochemical plaque characteristics in patients with coronary artery disease.

BACKGROUND AND AIMS: We aimed to characterize the spatial proximity of plaque destabilizing features local endothelial shear stress (ESS), minimal luminal area (MLA), plaque burden (PB), and near-infrared spectroscopy (NIRS) lipid signal in high- vs. low-risk plaques. METHODS: Coronary arteries imaged with angiography and NIRS-intravascular ultrasound (IVUS) underwent 3D reconstruction and computational fluid dynamics calculations of local ESS. ESS, PB, MLA, and lipid core burden index (LCBI), for each 3-mm arterial segment were obtained in arteries with large lipid-rich plaque (LRP) vs. arteries with smaller LRP. The locations of the MLA, minimum ESS (minESS), maximum ESS (maxESS), maximum PB (maxPB), and maximum LCBI in a 4-mm segment (maxLCBI4mm) were determined along the length of each plaque. RESULTS: The spatial distributions of minESS, maxESS, maxPB, and maxLCBI4mm, in reference to the MLA, were significantly heterogeneous within and between each variable. The location of maxLCBI4mm was spatially discordant from sites of the MLA (p<0.0001), minESS (p = 0.003), and maxESS (p = 0.003) in arteries with large LRP (maxLCBI4mm ≥ 400) and non-large LRP. Large LRP arteries had higher maxESS (9.31 ± 4.78 vs. 6.32 ± 5.54 Pa; p = 0.023), lower minESS (0.41 ± 0.16 vs. 0.61 ± 0.26 Pa; p = 0.007), smaller MLA (3.54 ± 1.22 vs. 5.14 ± 2.65 mm2; p = 0.002), and larger maxPB (70.64 ± 9.95% vs. 56.70 ± 13.34%, p<0.001) compared with non-large LRP arteries. CONCLUSIONS: There is significant spatial heterogeneity of destabilizing plaque features along the course of both large and non-large LRPs. Large LRPs exhibit significantly more abnormal destabilizing plaque features than non-large LRPs. Prospective, longitudinal studies are required to determine which patterns of heterogeneous destabilizing features act synergistically to cause plaque destabilization.

Oxidized Low-Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles.

Background Activated vascular cells produce submicron prothrombotic and proinflammatory microparticle vesicles. Atherosclerotic plaques contain high levels of microparticles. Plasma microparticle levels increase during acute coronary syndromes and the thrombotic consequences of plaque rupture likely involve macrophage-derived microparticles (MΦMPs). The activation pathways that promote MΦMP production remain poorly defined. This study tested the hypothesis that signals implicated in atherogenesis also stimulate MΦMP production. Methods and Results We stimulated human primary MΦs with proinflammatory cytokines and atherogenic lipids, and measured MΦMP production by flow cytometry. Oxidized low-density lipoprotein (oxLDL; 25 µg/mL) induced MΦMP production in a concentration-dependent manner (293% increase; P<0.001), and these oxLDL MΦMP stimulatory effects were mediated by CD36. OxLDL stimulation increased MΦMP tissue factor content by 78% (P<0.05), and oxLDL-induced MΦMP production correlated with activation of caspase 3/7 signaling pathways. Salvionolic acid B, a CD36 inhibitor and a CD36 inhibitor antibody reduced oxLDL-induced MΦMP by 67% and 60%, respectively. Caspase 3/7 inhibition reduced MΦMP release by 52% (P<0.01) and caspase 3/7 activation increased MΦMP production by 208% (P<0.01). Mevastatin pretreatment (10 µM) decreased oxLDL-induced caspase 3/7 activation and attenuated oxLDL-stimulated MΦMP production and tissue factor content by 60% (P<0.01) and 43% (P<0.05), respectively. Conclusions OxLDL induces the production of prothrombotic microparticles in macrophages. This process depends on caspases 3 and 7 and CD36 and is inhibited by mevastatin pretreatment. These findings link atherogenic signaling pathways, inflammation, and plaque thrombogenicity and identify a novel potential mechanism for antithrombotic effects of statins independent of LDL lowering.

Preemptive percutaneous coronary intervention for coronary artery disease: identification of the appropriate high-risk lesion.

PURPOSE OF REVIEW: Management of patients with coronary artery disease (CAD) has been based on identification of a coronary obstruction causing ischemia and performing a revascularization procedure to reduce that ischemia, with the goal of thereby preventing subsequent major adverse cardiac events (MACEs) in that vascular territory. Recent investigations demonstrate that preemptive percutaneous coronary intervention (PCI) of nonculprit coronary lesions (NCLs) that may not cause ischemia in patients with ST-segment elevation myocardial infarction (STEMI) reduces MACE. In this review, we focus on preemptive PCI, discuss its mechanistic benefits and speculate on its potential value for other coronary syndromes. RECENT FINDINGS: The COMPLETE trial in STEMI patients treated with primary PCI demonstrated that preemptive PCI of NCL obstructions, which may not cause ischemia, but often exhibit high-risk OCT plaque characteristics, reduced cardiovascular death or nonfatal myocardial infarction. Reduction in MACE from preemptive PCI of NCL was similar for lesions confirmed to cause ischemia (fractional flow reserve <0.80) and for lesions that were only visually assessed to have luminal obstruction at least 70%.The ISCHEMIA trial in patients with stable CAD and moderate/severe ischemia demonstrated that MACE risk increased progressively with more extensive atherosclerosis, but that performing PCI of ischemia-producing lesions did not reduce MACE. Adverse cardiac events likely originated in high-risk plaque areas not treated with PCI. SUMMARY: In STEMI patients, preemptive PCI of high-risk NCL that may not cause ischemia improves long-term MACE. In stable CAD patients, MACE increases as the atherosclerotic burden increases, but PCI of the ischemia-producing lesion itself does not improve outcomes compared with optimal medical therapy. Adverse events likely originate in high-risk plaque areas that are distinct from ischemia-producing obstructions. Identification of highest-risk atherosclerotic lesions responsible for future MACE may provide an opportunity for preemptive PCI in patients with a variety of coronary syndromes.

S100A9-RAGE Axis Accelerates Formation of Macrophage-Mediated Extracellular Vesicle Microcalcification in Diabetes Mellitus.

OBJECTIVE: Vascular calcification is a cardiovascular risk factor and accelerated in diabetes mellitus. Previous work has established a role for calcification-prone extracellular vesicles in promoting vascular calcification. However, the mechanisms by which diabetes mellitus provokes cardiovascular events remain incompletely understood. Our goal was to identify that increased S100A9 promotes the release of calcification-prone extracellular vesicles from human macrophages in diabetes mellitus. Approach and Results: Human primary macrophages exposed to high glucose (25 mmol/L) increased S100A9 secretion and the expression of receptor for advanced glycation end products (RAGE) protein. Recombinant S100A9 induced the expression of proinflammatory and osteogenic factors, as well as the number of extracellular vesicles with high calcific potential (alkaline phosphatase activity, P<0.001) in macrophages. Treatment with a RAGE antagonist or silencing with S100A9 siRNA in macrophages abolished these responses, suggesting that stimulation of the S100A9-RAGE axis by hyperglycemia favors a procalcific environment. We further showed that an imbalance between Nrf-2 (nuclear factor 2 erythroid related factor 2) and NF-κB (nuclear factor-κB) pathways contributes to macrophage activation and promotes a procalcific environment. In addition, streptozotocin-induced diabetic Apoe-/-S100a9-/- mice and mice treated with S100a9 siRNA encapsulated in macrophage-targeted lipid nanoparticles showed decreased inflammation and microcalcification in atherosclerotic plaques, as gauged by molecular imaging and comprehensive histological analysis. In human carotid plaques, comparative proteomics in patients with diabetes mellitus and histological analysis showed that the S100A9-RAGE axis associates with osteogenic activity and the formation of microcalcification. CONCLUSIONS: Under hyperglycemic conditions, macrophages release calcific extracellular vesicles through mechanisms involving the S100A9-RAGE axis, thus contributing to the formation of microcalcification within atherosclerotic plaques.