Sortilin enhances fibrosis and calcification in aortic valve disease by inducing interstitial cell heterogeneity.

AIMS: Calcific aortic valve disease (CAVD) is the most common valve disease, which consists of a chronic interplay of inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as a novel key player in the pathophysiology of CAVD, and its role in the transformation of valvular interstitial cells (VICs) into pathological phenotypes is explored. METHODS AND RESULTS: An aortic valve (AV) wire injury (AVWI) mouse model with sortilin deficiency was used to determine the effects of sortilin on AV stenosis, fibrosis, and calcification. In vitro experiments employed human primary VICs cultured in osteogenic conditions for 7, 14, and 21 days; and processed for imaging, proteomics, and transcriptomics including single-cell RNA-sequencing (scRNA-seq). The AVWI mouse model showed reduced AV fibrosis, calcification, and stenosis in sortilin-deficient mice vs. littermate controls. Protein studies identified the transition of human VICs into a myofibroblast-like phenotype mediated by sortilin. Sortilin loss-of-function decreased in vitro VIC calcification. ScRNA-seq identified 12 differentially expressed cell clusters in human VIC samples, where a novel combined inflammatory myofibroblastic-osteogenic VIC (IMO-VIC) phenotype was detected with increased expression of SORT1, COL1A1, WNT5A, IL-6, and serum amyloid A1. VICs sequenced with sortilin deficiency showed decreased IMO-VIC phenotype. CONCLUSION: Sortilin promotes CAVD by mediating valvular fibrosis and calcification, and a newly identified phenotype (IMO-VIC). This is the first study to examine the role of sortilin in valvular calcification and it may render it a therapeutic target to inhibit IMO-VIC emergence by simultaneously reducing inflammation, fibrosis, and calcification, the three key pathological processes underlying CAVD.

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.

Imaging inflammation and neovascularization in atherosclerosis: clinical and translational molecular and structural imaging targets.

PURPOSE OF REVIEW: The purpose of this study is to showcase advances in molecular imaging of atheroma biology in living individuals. RECENT FINDINGS: F-fluorodeoxyglucose (FDG) PET/computed tomography (CT) continues to be the predominant molecular imaging approach for clinical applications, particularly in the large arterial beds. Recently, there has been significant progress in imaging of neovascularization and inflammation to delineate high-risk atheroma and to evaluate drug efficacy. In addition, new hardware detection technology and imaging agents are enabling in-vivo imaging of new targets on diverse imaging platforms. SUMMARY: In this review, we present recent exciting developments in molecular and structural imaging of atherosclerotic plaque inflammation and neovascularization. Building upon prior studies, these advances develop key technology that will play an important role in propelling new diagnostic and therapeutic strategies identifying high-risk plaque phenotypes and assessing new plaque stabilization therapies in clinical trials.

Association of Preprocedural SYNTAX Score With Outcomes in Impella-Assisted High-Risk Percutaneous Coronary Intervention.

Background: Patients with complex coronary artery disease, as defined by high SYNTAX scores, undergoing percutaneous coronary intervention (PCI) have poorer outcomes when compared with patients with lower SYNTAX I scores. This study aimed to assess if mechanical circulatory support using Impella mitigates the effect of the SYNTAX I score on outcomes after high-risk percutaneous coronary intervention (HRPCI). Methods: Using data from the PROTECT III study, patients undergoing Impella-assisted HRPCI between March 2017 and March 2020 were divided into 3 cohorts based on SYNTAX I score-low (≤22), intermediate (23-32), and high (≥33). Procedural and clinical outcomes out to 90 days were compared between groups. Multivariable regression analysis was used to assess the impact of SYNTAX I score on major adverse cardiovascular and cerebrovascular events (MACCE) at 90 days. Results: A total of 850 subjects with core laboratory-adjudicated SYNTAX I scores were identified (low: n = 310; intermediate: n = 256; high: n = 284). Patients with high SYNTAX I scores were older than those with low or intermediate SYNTAX I scores (72.7 vs 69.7 vs 70.1 years, respectively; P < .01). After adjustment for covariates, high SYNTAX I score remained a significant predictor of 90-day MACCE (hazard ratio [HR], 2.14; 95% CI, 1.42-3.69; P < .01 vs low), whereas intermediate SYNTAX I score was not (HR, 0.92; 95% CI, 0.47-1.77; P = .80 vs low). These findings persisted after adjustment for post-PCI SYNTAX I score. Conclusions: A high SYNTAX I score was associated with higher rates of 90-day MACCE in patients who underwent Impella-assisted HRPCI. Further research is needed to understand the patient and procedural factors driving this finding.

Imaging atherosclerosis and risk of plaque rupture.

Atherosclerosis imaging strategies can delineate characteristics of plaques at risk of rupture and thrombosis. Structural plaque imaging identifies high-risk plaque features, including lipid pools, thin fibrous caps, and intraplaque hemorrhage. New molecular imaging techniques complement structural imaging approaches by illuminating important features of plaque biology, with a prominent focus on detecting inflammation as a high-risk phenotype. As we unravel the molecular and structural characteristics underlying thrombosis-prone plaques, there is significant promise for eventual early identification and prediction of atherosclerotic plaque complications before they occur. Here we focus on recent imaging insights into high-risk arterial plaques, the etiologic agent of acute myocardial infarction, stroke, and sudden cardiac death.

Safety and efficiency of percutaneous coronary intervention using a standardised optical coherence tomography workflow.

BACKGROUND: While intravascular imaging guidance during percutaneous coronary intervention (PCI) improves outcomes, routine intravascular imaging usage remains low, in part due to perceived inefficiency and safety concerns.  Aims: The LightLab (LL) Initiative was designed to evaluate whether implementing a standardised optical coherence tomography (OCT) workflow impacts PCI safety metrics and procedural efficiency. METHODS: In this multicentre, prospective, observational study, PCI procedural data were collected over 2 years from 45 physicians at 17 US centres. OCT-guided PCI incorporating the LL workflow (N=264), a structured algorithm using routine pre- and post-PCI OCT imaging, was compared with baseline angiography-only PCI (angio) (N=428). Propensity score analysis identified 207 matched procedures. Outcomes included procedure time, radiation exposure, contrast volume, device utilisation, and treatment strategy. RESULTS: Compared with angiography alone, LL workflow OCT-guided PCI increased the median procedural time by 9 minutes but reduced vessel preparation time (2 min LL workflow vs 3 min angio; p<0.001) and resulted in less unplanned additional treatment (4% LL workflow vs 10% angio; p=0.01). With LL workflow OCT guidance, fewer cineangiography views were needed compared to angiography guidance, leading to decreased radiation exposure (1,133 mGy LL workflow vs 1,269 mGy angio; p=0.02), with no difference in contrast utilisation between groups (p=0.28). Furthermore, LL workflow OCT guidance resulted in fewer predilatation balloons and stents being used, more direct stent placement, and greater stent post-dilatation than angiography-guided PCI. CONCLUSIONS: The incorporation of a standardised pre- and post-PCI OCT imaging workflow improves procedural efficiency and safety metrics, at a cost of a modestly longer procedure time.

Association Between Intracoronary Imaging During PCI and Clinical Outcomes in a Real-World US Medicare Population.

Background: Use of intravascular ultrasound (IVUS) or optical coherence tomography (OCT) during percutaneous coronary intervention (PCI) is endorsed by society guidelines, but US data on real-world outcomes are lacking. Methods: Medicare claims data were identified for inpatient PCIs performed October 2015 to March 2020, with IVUS/OCT captured by ICD-10-PCS codes. Three-way propensity score matching (angio vs IVUS vs OCT) on baseline and procedural characteristics was performed. Major adverse cardiovascular events (MACE), a composite of death, myocardial infarction (MI), or repeat revascularization, was evaluated through 3 years, with a 30-day blanking window after index PCI to exclude staged procedures. Results: Of the 502,821 PCI procedures, 463,201 (92%) were guided by angiography alone, with IVUS or OCT used in 37,908 (7.5%) and 1712 (0.3%), respectively. After propensity matching, compared with angiography, the risk of major adverse cardiovascular event was similar for IVUS (hazard ratio [HR], 0.97; 95% CI, 0.91-1.03; P = .285) but lower for OCT (HR, 0.85; 95% CI, 0.77-0.94; P = .001). A similar trend was observed in clinically relevant subgroups. Compared with angiography alone, the risk of MI or repeat revascularization was lower with OCT (HR, 0.86; 95% CI, 0.76-0.97; P = .015), and the risk of MI alone was lower with IVUS (HR, 0.90; 95% CI, 0.82-0.99; P = .038). Conclusions: In a real-world US cohort, IVUS and OCT were used infrequently during PCI. Compared with angiography alone, use of intracoronary imaging during index PCI was associated with lower rates of clinical events through 3 years.

Highly Selective PPARα (Peroxisome Proliferator-Activated Receptor α) Agonist Pemafibrate Inhibits Stent Inflammation and Restenosis Assessed by Multimodality Molecular-Microstructural Imaging.

BACKGROUND New pharmacological approaches are needed to prevent stent restenosis. This study tested the hypothesis that pemafibrate, a novel clinical selective PPARα (peroxisome proliferator-activated receptor α) agonist, suppresses coronary stent-induced arterial inflammation and neointimal hyperplasia. METHODS AND RESULTS Yorkshire pigs randomly received either oral pemafibrate (30 mg/day; n=6) or control vehicle (n=7) for 7 days, followed by coronary arterial implantation of 3.5 × 12 mm bare metal stents (2-4 per animal; 44 stents total). On day 7, intracoronary molecular-structural near-infrared fluorescence and optical coherence tomography imaging was performed to assess the arterial inflammatory response, demonstrating that pemafibrate reduced stent-induced inflammatory protease activity (near-infrared fluorescence target-to-background ratio: pemafibrate, median [25th-75th percentile]: 2.8 [2.5-3.3] versus control, 4.1 [3.3-4.3], P=0.02). At day 28, animals underwent repeat near-infrared fluorescence-optical coherence tomography imaging and were euthanized, and coronary stent tissue molecular and histological analyses. Day 28 optical coherence tomography imaging showed that pemafibrate significantly reduced stent neointima volume (pemafibrate, 43.1 [33.7-54.1] mm3 versus control, 54.2 [41.2-81.1] mm3; P=0.03). In addition, pemafibrate suppressed day 28 stent-induced cellular inflammation and neointima expression of the inflammatory mediators TNF-α (tumor necrosis factor-α) and MMP-9 (matrix metalloproteinase 9) and enhanced the smooth muscle differentiation markers calponin and smoothelin. In vitro assays indicated that the STAT3 (signal transducer and activator of transcription 3)-myocardin axes mediated the inhibitory effects of pemafibrate on smooth muscle cell proliferation. CONCLUSIONS Pemafibrate reduces preclinical coronary stent inflammation and neointimal hyperplasia following bare metal stent deployment. These results motivate further trials evaluating pemafibrate as a new strategy to prevent clinical stent restenosis.

Physiological Assessment of Coronary Lesions in 2020.

PURPOSE OF REVIEW: Physiological assessment of coronary artery disease (CAD) is an essential component of the interventional cardiology toolbox. However, despite long-term data demonstrating improved outcomes, physiology-guided percutaneous coronary intervention (PCI) remains underutilized in current practice. This review outlines the indications and technical aspects involved in evaluating coronary stenosis physiology, focusing on the latest developments in the field. RECENT FINDINGS: Beyond fractional flow reserve (FFR), non-hyperemic pressure ratios (NHPR) that assess coronary physiology at rest without hyperemia now abound. Additional advances in other alternative FFR approaches, including non-invasive coronary CT (FFRCT), invasive angiography (FFRangio), and optical coherence tomography (FFROCT), are being realized. Artificial intelligence algorithms and robust tools that enable detailed pre-procedure "virtual" intervention are also emerging. The benefits of coronary physiological assessment to determine lesion functional significance are well established. In addition to stable CAD, coronary physiology can be especially helpful in clinical scenarios such as left main and multivessel CAD, serial lesions, non-infarct-related arteries in acute coronary syndromes, and residual ischemia post-PCI. Today, coronary physiological assessment remains an indispensable tool in the catheterization laboratory, with an exciting technological future that will further refine clinical practice and improve patient care.