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.

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.

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.

Roles of PAD4 and NETosis in Experimental Atherosclerosis and Arterial Injury: Implications for Superficial Erosion.

RATIONALE: Neutrophils likely contribute to the thrombotic complications of human atheromata. In particular, neutrophil extracellular traps (NETs) could exacerbate local inflammation and amplify and propagate arterial intimal injury and thrombosis. PAD4 (peptidyl arginine deiminase 4) participates in NET formation, but an understanding of this enzyme's role in atherothrombosis remains scant. OBJECTIVE: This study tested the hypothesis that PAD4 and NETs influence experimental atherogenesis and in processes implicated in superficial erosion, a form of plaque complication we previously associated with NETs. METHODS AND RESULTS: Bone marrow chimeric Ldlr deficient mice reconstituted with either wild-type or PAD4-deficient cells underwent studies that assessed atheroma formation or procedures designed to probe mechanisms related to superficial erosion. PAD4 deficiency neither retarded fatty streak formation nor reduced plaque size or inflammation in bone marrow chimeric mice that consumed an atherogenic diet. In contrast, either a PAD4 deficiency in bone marrow-derived cells or administration of DNaseI to disrupt NETs decreased the extent of arterial intimal injury in mice with arterial lesions tailored to recapitulate characteristics of human atheroma complicated by erosion. CONCLUSIONS: These results indicate that PAD4 from bone marrow-derived cells and NETs do not influence chronic experimental atherogenesis, but participate causally in acute thrombotic complications of intimal lesions that recapitulate features of superficial erosion.

Lesion Complexity and Outcomes of Extended Dual Antiplatelet Therapy After Percutaneous Coronary Intervention.

BACKGROUND: Subjects undergoing coronary stenting with complex lesion anatomy may experience different risks and benefits with prolonged dual antiplatelet therapy. OBJECTIVES: The authors assessed the effect of 30 months versus 12 months of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) based on the presence or absence of anatomically-complex target lesions. METHODS: In the DAPT Study, combined myocardial infarction (MI) or stent thrombosis and moderate/severe bleeding were assessed in enrolled (n = 25,416) and randomized (n = 11,554) subjects. Complex lesions had any of the following characteristics: unprotected left main, >2 lesions/vessel, length ≥30 mm, bifurcation with side branch ≥2.5 mm, vein bypass graft, or thrombus-containing lesion. Events were evaluated according to increasing number of complexity characteristics and compared according to DAPT score. RESULTS: Enrolled subjects with more complex target lesions had higher rates of MI or stent thrombosis in the first 12 months after PCI (3.9% vs. 2.4%; p < 0.001). Among those who were event-free at 12 months, rates of MI or stent thrombosis between 12 and 30 months were similar between those with versus without complex anatomy (3.5% vs. 2.9%; p = 0.07). Reduction of MI or stent thrombosis with continued thienopyridine beyond 12 months versus placebo was similar for subjects with (2.5% vs. 4.5%; hazard ratio: 0.55; 95% confidence interval: 0.38 to 0.79; p = 0.001) and without (2.0% vs. 3.8%; hazard ratio: 0.52; 95% confidence interval: 0.39 to 0.69; p < 0.001) anatomic complexity (pinteraction = 0.81), as was increase in moderate/severe bleeding (pinteraction = 0.44). Among subjects with anatomic complexity, those with DAPT scores ≥2 randomized to continued thienopyridine had greater reductions in MI or stent thrombosis (3.0% vs. 6.1%; p < 0.001) compared with subjects with scores <2 (1.7% vs. 2.3%; p = 0.42; p value comparing risk differences = 0.03). CONCLUSIONS: Complex target-lesion anatomy is associated with increased ischemic events, particularly within the first year after PCI. Among those without events in the first 12 months, the benefits of extending DAPT were similar in subjects with and without complex lesions. A high DAPT score identified those experiencing the most benefit from extended treatment among patients with and without complex anatomy. (The Dual Antiplatelet Therapy Study [DAPT Study]; NCT00977938).

Usefulness of Intracoronary Brachytherapy for Patients With Resistant Drug-Eluting Stent Restenosis.

In-stent restenosis (ISR) remains a concern even in the drug-eluting stent (DES) era and carries a high risk of recurrence. Brachytherapy is being used as an alternative treatment for resistant ISR, yet the safety and efficacy of this approach has not been well studied. We analyzed the outcomes of 101 patients who underwent coronary brachytherapy for resistant DES ISR. Baseline demographic, clinical, procedural, and outcome data were collected by phone and from electronic records. Comorbidities and overt cardiovascular disease were highly prevalent. Median previous stent layers were 2 with a maximum of 5 layers. Procedural angiographic success rate was 97% and median time to discharge was 1 day after brachytherapy. The primary outcome of target vessel revascularization was 24% at 1 year, 32% at 2 years, and 42% at 3 years. The rate of nonfatal myocardial infarction was 0% at 1 year, 3.5% at 2 years, and 6% at 3 years. The rate of all-cause mortality was 8.5% at 1 year, 12% at 2 years, and 16% at 3 years. We observed only 1 case of late stent thrombosis. After multivariable adjustment, female gender (hazard ratio 2.37, 95% confidence interval 1.02 to 5.52, p = 0.04) and diffuse ISR pattern (hazard ratio 2.95, 95% confidence interval 1.21 to 7.17, p = 0.01) were independently associated with the primary outcome. In conclusion, brachytherapy is feasible for the treatment of resistant DES ISR and is associated with high immediate procedural success and reasonable efficacy in a complex patient population. This approach might be used as an alternative for these patients.

Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion.

RATIONALE: Superficial erosion currently causes up to a third of acute coronary syndromes; yet, we lack understanding of its mechanisms. Thrombi because of superficial intimal erosion characteristically complicate matrix-rich atheromata in regions of flow perturbation. OBJECTIVE: This study tested in vivo the involvement of disturbed flow and of neutrophils, hyaluronan, and Toll-like receptor 2 ligation in superficial intimal injury, a process implicated in superficial erosion. METHODS AND RESULTS: In mouse carotid arteries with established intimal lesions tailored to resemble the substrate of human eroded plaques, acute flow perturbation promoted downstream endothelial cell activation, neutrophil accumulation, endothelial cell death and desquamation, and mural thrombosis. Neutrophil loss-of-function limited these findings. Toll-like receptor 2 agonism activated luminal endothelial cells, and deficiency of this innate immune receptor decreased intimal neutrophil adherence in regions of local flow disturbance, reducing endothelial cell injury and local thrombosis (P<0.05). CONCLUSIONS: These results implicate flow disturbance, neutrophils, and Toll-like receptor 2 signaling as mechanisms that contribute to superficial erosion, a cause of acute coronary syndrome of likely growing importance in the statin era.

Upstream clopidogrel, prasugrel, or ticagrelor for patients treated with primary angioplasty: Results of an angiographic randomized pilot study.

OBJETIVES: The main objective of the present randomized pilot study was to explore the effects of upstream prasugrel or ticagrelor or clopidogrel for patients with ST-segment-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). BACKGROUND: Administration of clopidogrel "as soon as possible" has been advocated for STEMI. Pretreatment with prasugrel and ticagrelor may improve reperfusion. Currently, the angiographic effects of upstream administration of these agents are poorly understood. METHODS: A total of 132 patients with STEMI within the first 12 hr of chest pain referred to primary angioplasty were randomized to upstream clopidogrel (600 mg), prasugrel (60 mg), or ticagrelor (180 mg) while still in the emergency room. All patients underwent protocol-mandated thrombus aspiration. RESULTS: Macroscopic thrombus material was retrieved in 79.5% of the clopidogrel group, 65.9% of the prasugrel group, and 54.3% of the ticagrelor group (P = 0.041). At baseline angiography, large thrombus burden was 97.7% vs. 87.8% vs. 80.4% in the clopidogrel, prasugrel, and ticagrelor groups, respectively (P = 0.036). Also, at baseline, 97.7% presented with an occluded target vessel in the clopidogrel group, 87.8% in the prasugrel group and 78.3% in the ticagrelor group (P = 0.019). At the end of the procedure, the percentages of patients with combined TIMI grade III flow and myocardial blush grade III were 52.3% for clopidogrel, 80.5% for prasugrel, and 67.4% for ticagrelor (P = 0.022). CONCLUSIONS: In patients with STEMI undergoing primary PCI within 12 hr, upstream clopidogrel, prasugrel or ticagrelor have varying angiographic findings, with a trend toward better results for the latter two agents. © 2015 Wiley Periodicals, Inc.

Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis.

Despite the well-documented association between insulin resistance and cardiovascular disease, the key targets of insulin relevant to the development of cardiovascular disease are not known. Here, using non-biased profiling methods, we identify the enzyme flavin-containing monooxygenase 3 (Fmo3) to be a target of insulin. FMO3 produces trimethylamine N-oxide (TMAO), which has recently been suggested to promote atherosclerosis in mice and humans. We show that FMO3 is suppressed by insulin in vitro, increased in obese/insulin resistant male mice and increased in obese/insulin-resistant humans. Knockdown of FMO3 in insulin-resistant mice suppresses FoxO1, a central node for metabolic control, and entirely prevents the development of hyperglycaemia, hyperlipidemia and atherosclerosis. Taken together, these data indicate that FMO3 is required for FoxO1 expression and the development of metabolic dysfunction.

S-nitrosothiol signaling regulates liver development and improves outcome following toxic liver injury.

Toxic liver injury is a leading cause of liver failure and death because of the organ's inability to regenerate amidst massive cell death, and few therapeutic options exist. The mechanisms coordinating damage protection and repair are poorly understood. Here, we show that S-nitrosothiols regulate liver growth during development and after injury in vivo; in zebrafish, nitric-oxide (NO) enhanced liver formation independently of cGMP-mediated vasoactive effects. After acetaminophen (APAP) exposure, inhibition of the enzymatic regulator S-nitrosoglutathione reductase (GSNOR) minimized toxic liver damage, increased cell proliferation, and improved survival through sustained activation of the cytoprotective Nrf2 pathway. Preclinical studies of APAP injury in GSNOR-deficient mice confirmed conservation of hepatoprotective properties of S-nitrosothiol signaling across vertebrates; a GSNOR-specific inhibitor improved liver histology and acted with the approved therapy N-acetylcysteine to expand the therapeutic time window and improve outcome. These studies demonstrate that GSNOR inhibitors will be beneficial therapeutic candidates for treating liver injury.

CD47 plays a critical role in T-cell recruitment by regulation of LFA-1 and VLA-4 integrin adhesive functions.

CD47 plays an important but incompletely understood role in the innate and adaptive immune responses. CD47, also called integrin-associated protein, has been demonstrated to associate in cis with ß1 and ß3 integrins. Here we test the hypothesis that CD47 regulates adhesive functions of T-cell α4ß1 (VLA-4) and αLß2 (LFA-1) in in vivo and in vitro models of inflammation. Intravital microscopy studies reveal that CD47(-/-) Th1 cells exhibit reduced interactions with wild-type (WT) inflamed cremaster muscle microvessels. Similarly, murine CD47(-/-) Th1 cells, as compared with WT, showed defects in adhesion and transmigration across tumor necrosis factor-α (TNF-α)-activated murine endothelium and in adhesion to immobilized intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion protein 1 (VCAM-1) under flow conditions. Human Jurkat T-cells lacking CD47 also showed reduced adhesion to TNF-α-activated endothelium and ICAM-1 and VCAM-1. In cis interactions between Jurkat T-cell ß2 integrins and CD47 were detected by fluorescence lifetime imaging microscopy. Unexpectedly, Jurkat CD47 null cells exhibited a striking defect in ß1 and ß2 integrin activation in response to Mn(2+) or Mg(2+)/ethylene glycol tetraacetic acid treatment. Our results demonstrate that CD47 associates with ß2 integrins and is necessary to induce high-affinity conformations of LFA-1 and VLA-4 that recognize their endothelial cell ligands and support leukocyte adhesion and transendothelial migration.

Recommendations for management of antiplatelet therapy in patients undergoing elective noncardiac surgery after coronary stent implantation.

Patients commonly undergo noncardiac surgical procedures after implantation of a coronary stent. In the case where surgery cannot be deferred until completing the minimum duration of dual antiplatelet therapy, the Brigham and Women's Hospital Cardiac Catheterization Laboratory recommends using a glycoprotein IIb/IIIa bridging protocol to minimize the risk of perioperative ischemic events. We discuss our algorithm for managing antiplatelet agents, including the newer agents, prasugrel and ticagrelor, in patients undergoing noncardiac surgery after coronary stenting and present our glycoprotein IIb/IIIa bridging strategy along with a review of the relevant pharmacodynamic and clinical evidence.