Aloke V. Finn

CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis

Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non–foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1&agr; and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1&agr; via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1&agr;/VEGF-A pathway.

Pathological mechanisms of left main stent failure

BACKGROUND Despite the increasing use of left main (LM) percutaneous coronary intervention (LM-PCI), there have been no pathological studies devoted to understanding the causes of LM stent failure. We aimed to systematically determine the pathological mechanisms of LM stent failure. METHODS AND RESULTS From the CVPath Stent registry, a total of 46 lesions were identified to have LM-PCI. Pathologic stent failure (PSF) was defined as stent thrombosis, restenosis and in-stent chronic total occlusion (CTO). Failed and patent LM stented lesions were pathologically assessed to determine predictors of PSF. Malapposition and uncovered struts were numerically greater in the LM ostium, body, and bifurcation while neointimal thickness was relatively greater in bifurcation and proximal circumflex. In this study cohort, half of the lesions (n = 23) showed PSF. Stent thrombosis (ST, n = 18) was the major mode of PSF followed by in-stent CTO (n = 4) and restenosis (n = 1). Failed lesions showed significantly greater prevalence of malapposition >20% of struts/section (65% vs. 13%, P < 0.01), stent struts crossing an ostial side branch >30% of the circumference (48% vs. 13%, P < 0.01) and uncovered struts >30% (57% vs. 18%, P = 0.03). In multivariate analysis, the prevalence of malapposition >20% was the strongest risk factor for PSF (Odds ratio 8.0, 95% confidence interval 1.8-45.4, P < 0.01) followed by struts crossing an ostial side branch >30% (Odds ratio 4.2, 95% confidence interval 0.8-24.7, P = 0.09). CONCLUSION Our data demonstrate the main pathological predictors for LM stent failure are malapposition and struts crossing an ostial side branch and suggest that imaging-guided PCI may be important.

Clinical implications of blood-material interaction and drug eluting stent polymers in review

ABSTRACT Introduction: Despite advances in drug-eluting stent (DES) technology, stent thrombosis (ST) remains the most feared complication with high morbidity and mortality. Areas covered: Stent related factors certainly play a role in the pathophysiology of ST and more recent data suggest coating technologies have the potential to favorable modify this risk though blood material interactions. Of the polymer coatings used in DES, fluorinated polymers in particular have shown significant promise in modifying the risk of ST through their preferential interactions with albumin which is believed to prevent the adhesion and aggregation of platelets to the stent surface and thus minimize thrombus formation. Preclinical data from the porcine arteriovenous fistula model and clinical data from large network meta-analysis support a role for fluorinated polymers in reducing ST. Expert commentary: The search for more biocompatible anti-thrombotic polymer coatings continues and it is likely that further modification of stent based surfaces will revolutionize the field of interventional cardiology by one day obviating the need for systemic anti-platelet therapies in patients receiving intravascular devices.

Antiproliferative Drugs for Restenosis Prevention

Cardiovascular disease is a leading cause of death and disability worldwide. Current treatment strategies aimed at treating the symptoms and consequences of obstructive vascular disease have embraced both optimal medical therapy and catheter-based percutaneous coronary intervention with drug-eluting stents. Drug-eluting stents elute antiproliferative drugs inhibiting vascular smooth muscle cell proliferation, which occurs in response to injury and thus prevents restenosis. However, all drugs currently approved for use in drug-eluting stents do not discriminate between proliferating vascular smooth muscle cells and endothelial cells, thus delaying re-endothelialization and subsequent vascular healing.

A new category stent with novel polyphosphazene surface modification

The COBRA-PzF™ (CeloNova BioSciences, Inc., TX, USA) is a new type of coronary stent composed of a cobalt chromium metallic backbone surrounded by a nanothin layer of Polyzene-F (PzF) without any added drug. Evidence from basic studies supports antithrombotic and anti-inflammatory properties for the PzF surface coating. Preclinical studies support the thromboresistance of PzF-coated surfaces and clinical studies have shown good outcomes for patients receiving this device with very low rates of stent thrombosis. COBRA-PzF may be especially useful in patients at high risk for bleeding. Ongoing clinical trials will determine whether shortening the duration of dual antiplatelet therapy to less than 1 month is feasible and these data may represent a new paradigm with regards to patients at high risk for bleeding.

Histopathologic and physiologic effect of overlapping vs single coronary stents: impact of stent evolution

ABSTRACT Introduction: Bare metal stents (BMS) and drug eluting stents (DES) have been deployed in single and overlap configurations, the latter mostly to cover long-lesions. Both type of stents in overlap configuration increases the risk of adverse events. Areas covered: We present the rationale for either BMS or DES usage utilizing both preclinical and clinical studies for the use of single vs. overlapped stents. Further, employing experimental and pathological studies, we discuss the disadvantages of stent overlapping vs. single stenting and propose that vessel injury, local blood flow disturbance, higher drug/polymer dose are mechanisms leading to poor clinical outcomes including in-stent restenosis (ISR), delayed arterial healing, thrombosis, and hypersensitivity reactions. We also explore whether newer generation (2nd generation) DES with reduced strut thickness, optimized drug release profiles, better polymer biocompatibility minimize the disadvantages of stent overlap seen in 1st generation DES. Finally, we examine the reasons why fully bioabsorbable scaffolds resulted in increased adverse events. Expert commentary: DES innovations have minimized the risk of ISR and repeat revascularization. In contradistinction to 1st generation DES, major adverse cardiac events (MACE) is similar between single and overlapped stents in 2nd generation DES, suggestion stent design play an important role in clinical outcomes.

Is there an effect of antithrombotics on carotid intraplaque haemorrhage

Thrombotic occlusion or thrombus embolization plays a major role in the pathogenesis of vascular events including ischaemic or embolic stroke and myocardial infarction. Patients with acute coronary syndromes (ACSs) or ischaemic stroke are routinely treated with aspirin and a P2Y12 receptor blocker such as clopidogrel [dual anti platelet therapy (DAPT)], while those with atrial fibrillation are treated with anticoagulants such as coumadin or, more recently, novel oral anticoagulants (NOACs) such as dabigatran, apixaban, or rivaroxiban. Such therapies are considered essential for primary and secondary prevention of ischaemic events. Bleeding is a well-known side effect of these therapies, and major or minor bleeds are clinically what are most commonly noted by physicians as side effects. However, as atherosclerotic plaques progress, it is well known that microbleeds or intraplaque haemorrhages (IPHs) inside of advanced atherosclerotic plaques are an important risk factor for plaque progression (Take home figure). Red cell membranes are rich in free cholesterol and their presence inside atherosclerotic lesions is thought to increase plaque bulk and necrotic core size, leading to plaque progression. Despite their widespread use, the effect and duration of antiplatelet and anticoagulant therapies on plaque composition remains relatively unknown. Yet, it seems logical to be concerned that anticoagulants may increase IPH and plaque progression, thereby causing an increase in events, especially in individuals who require long-term treatment. Technological advances in non-invasive imaging, especially magnetic resonance imaging (MRI), have allowed a more detailed characterization of plaque components, especially for the examination of carotid artery plaques. Although limited by methodological concerns, previous work has suggested a potential link between the use of both antiplatelet and anticoagulant therapies and the occurrence of IPH. Liem et al. performed a carotid MRI study in 100 patients with recently symptomatic carotid stenosis. Prior use of antiplatelet agents was associated with the presence of IPH on MRI imaging. Pathological studies conducted in post-mortem coronary arteries or endarterectomy samples have also been conducted. Vink et al. performed a small study in 30 autopsy cases and found that coronary segments with IPH were more frequently found in patients on oral anticoagulants (61%) and antiplatelet therapies (53%) compared with patients on none of these therapies (46%). Derksen et al. showed that coumadin-type anticoagulation was associated with the presence of carotid but not femoral IPH in endarterectomies, while statin use was associated with less IPH. Of course, such studies are confounded by the fact that those with more advanced atherosclerosis tend to be sicker patients requiring antithrombotic medications, and would also be more likely to have IPH. In this issue of the European Heart Journal, Mujaj et al. present data from a substudy of the population-based Rotterdam Study. On the basis of pre-screening with carotid ultrasound, 1740 patients with carotid atherosclerosis (intima media thickness >2.5 mm) on ultrasound underwent carotid MRI. The investigators found that carotid IPH was more frequently found in users of antithrombotic therapies compared with never-users. Current and past use of both vitamin K antagonists (VKAs) and antiplatelet agents was associated with a nonstatistically significant trend towards higher presence of IPH. No associations were found between use of either VKAs or antiplatelet agents and the higher presence of lipid core or calcification. While use of VKA for 3 months or less was not associated with the presence of IPH, a longer duration of use (i.e. >3 months) was associated with IPH, and this relationship became more prominent when adjusted for international normalized ratio (INR) >2.97. Overall, the use of antiplatelet agents for less than or greater than 30 months was not related to the presence of IPH. However, daily dosages >1.0 for antiplatelet agents were significantly associated with the presence of IPH. While the results of this population-based study seem to suggest a potential harmful effect of antithrombotic treatment on carotid atherosclerotic plaque composition, a closer analysis is warranted.

Revisiting the role of durable polymers in cardiovascular devices

ABSTRACT Introduction: Polymers are an essential component of drug-eluting stents (DES) used to control drug release but remain the most controversial component of DES technology. There are two types of polymers employed in DES: durable polymer based DES (DP-DES) and biodegradable polymer DES (BP-DES). First-generation DES were exclusively composed of DP and demonstrated increased rates of late stent failure due in part to poor polymer biocompatibility. Newer generations DES use more biocompatible durable polymers or biodegradable polymers. Areas covered: We will cover issues identified with 1st-generation DP-DES, areas of success and failure in 2nd-generation DP-DES and examine the promise and shortcomings of BP-DES. Briefly, fluorinated polymers used in 2nd-generation DP-DES have excellent anti-thrombogenicity and better biocompatibility than 1st-generation DES polymers. However, these devices lead to persistent drug exposure to the endothelium which impairs endothelial function and predisposes towards neoatherosclerosis. Meanwhile, BP-DES has shortened the duration of drug exposure which might be beneficial for endothelial functional recovery leading to less neoatherosclerosis. However, it remains uncertain whether the long-term biocompatibility of bare metal surfaces is better than that of polymer-coated metals. Expert commentary: Each technology has distinct advantages, which can be optimized depending upon the particular characteristics of the patient being treated.

TCT-836 Endothelial Cell Coverage and Inflammation Comparing COBRA Polyzene-F (PzF) Coated Stent to Durable Fluoropolymer and Biodegradable Polymer Drug-Eluting Stents in a Rabbit Model

TCT-836 Endothelial Cell Coverage and Inflammation Comparing COBRA Polyzene-F (PzF) Coated Stent to Durable Fluoropolymer and Biodegradable Polymer Drug-Eluting Stents in a Rabbit Model Kazuyuki Yahagi, Frank Kolodgie, Daivid Cheng, Eduardo Acampado, Hiroyoshi Mori, Khaja Chinnakondepali, Maria Romero, Aloke Finn, Renu Virmani CVPath Institute, Inc., Geithersburg, Maryland, United States; CVPath Institute, Gaithersburg, Maryland, United States; Unknown, Bethesda, Maryland, United States; University Hospital La Timone; Division of cardiovascular surgery, Saiseikai Kumamoto Hospital Cardiovascular center; St. Luke’s Mid America Institute; Duke Clinical Research Institute; CVPath Institute Inc. and University of Maryland, Baltimore, Gaithersburg, Maryland, United States; CVPath Institute, Inc., Gaithersburg, Maryland, United States

TCT-835 Endothelial Function Assessed by Expression of Adherens Junctions and Inflammation between Durable and Biodegradable Polymer Drug-Eluting Stents in the Rabbit Iliofemoral Model

TCT-833 Late Lumen Gain with Bioresorbable Vascular Scaffold in the Porcine Model of Spontaneous Untreated Atherosclerosis: a 3-year IVUS and OCT Study Yanping Cheng, Gaoke Feng, Jinggang Xia, Pawel Gasior, Qing Wang, Laura Perkins, Richard Rapoza, Jenn McGregor, Gerard Conditt, Greg Kaluza, Juan Granada Cardiovascular Research Foundation, ORANGEBURG, New York, United States; Cardiovascular Research Foundation, Orangeburg, New York, United States; MedStar Washington Hospital Center; CRF Skirball Center for Innovation, Fort Lee, New Jersey, United States; abbott vascular, Santa Clara, California, United States; Abbott Vascular, Mattaponi, Virginia, United States; Abbott Vascular, Santa Clara, California, United States; Cardiovascular Research Foundation, Orangeburg, New York, United States; CRF-Skirball Center for Innovation, Nyack, New York, United States; CRF Skirball Center for Innovation, Orangeburg, New York, United States; CRF Skirball Center for Innovation, Orangeburg, New York, United States