Emanuel Harari

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.

Linking Hemorrhage, Angiogenesis, Macrophages, and Iron Metabolism in Atherosclerotic Vascular Diseases

Intraplaque hemorrhage (IPH) is a phenomenon observed in advanced atherosclerotic plaques. Paterson1 was the first to propose vasa vasorum as the source of IPH. Barger et al2 described an abundance of plaque microvessels found in diseased coronary arteries compared with healthy ones and proposed that plaque neovascularization plays an important role in the pathogenesis of atherosclerosis. A postmortem study from our group established a critical relationship between erythrocyte extravasation in coronary atherosclerotic plaques (measured by the red blood cell membrane sialoglycoprotein glycophorin A) and necrotic core enlargement and plaque progression.3 In a different postmortem study, plaque macrophages were found to be 2- to 4-fold more abundant in patients with symptomatic cardiovascular disease, and the adjacent microvessel network was found to be denser.4 Kockx et al5 showed that perivascular foam cells in areas of high microvascular density within carotid plaques frequently contained platelets and erythrocytes. Phagocytosis of red blood cells was shown to be a trigger for macrophage activation in both in vitro and in vivo. It was also shown that macrophages were particularly abundant around newly formed leaky microvessels.5–7 This and other emerging data support the notion that IPH plays a causal role in promoting plaque progression via deposition of free cholesterol from red blood cells.8–10 The effect of plaque hemorrhage translates into higher plaque burden and vulnerability, which are demonstrable in imaging modalities such as magnetic resonance imaging, intravascular ultrasound, and near infrared spectroscopy.11,12 Here, we summarize recent progress made in our understanding of the collective role of IPH, angiogenesis, macrophages, and iron metabolism in atherosclerotic plaque progression. In a recent article, Sun et al13 examined the effect of the blood pressure on carotid plaque IPH diagnosed by magnetic resonance imaging in an asymptomatic …

Very Late Pathological Responses to Cobalt–Chromium Everolimus‐Eluting, Stainless Steel Sirolimus‐Eluting, and Cobalt–Chromium Bare Metal Stents in Humans

Background The “very late” clinical outcomes for durable polymer drug‐eluting stents and bare metal stents (BMSs) have been shown to be dissimilar in clinical studies. Conceptually, the long‐term vascular compatibility of BMSs is still regarded to be superior to drug‐eluting stents; however, no pathologic study to date has specifically addressed this issue. We evaluated the very late (≥1 year) pathologic responses to durable polymer drug‐eluting stents (cobalt–chromium [CoCr] everolimus‐eluting stents [EESs] and stainless steel sirolimus‐eluting stents [SS‐SESs]) versus BMSs (CoCr‐BMSs). Methods and Results From the CVPath stent registry, we studied a total of 119 lesions (40 CoCr‐EESs, 44 SS‐SESs, 35 CoCr‐BMSs) from 92 autopsy cases with a duration ranging from 1 to 5 years. Sections of stented coronary segments were pathologically analyzed. Inflammation score and the percentage of struts with giant cells were lowest in CoCr‐EESs (median inflammation score: 0.6; median percentage of struts with giant cells: 3.8%) followed by CoCr‐BMSs (median inflammation score: 1.3 [P<0.01]; median percentage of struts with giant cells: 8.9% [P=0.02]) and SS‐SESs (median inflammation score: 1.7 [P<0.01]; median percentage of struts with giant cells: 15.3% [P<0.01]). Polymer delamination was observed exclusively in SS‐SESs and was associated with increased inflammatory and giant cell reactions. The prevalence of neoatherosclerosis with CoCr‐EESs (50%) was significantly less than with SS‐SESs (77%, P=0.02) but significantly greater than with CoCr‐BMSs (20%, P<0.01). Conclusions CoCr‐EESs, SS‐SESs, and BMSs each demonstrated distinct vascular responses. CoCr‐EESs demonstrated the least inflammation, near‐equivalent healing to BMSs, and lower neointimal formation. These results challenge the belief that BMSs have superior biocompatibility compared with some polymeric coated drug‐eluting stents and may have implications for future stent design.

Safety of Zilver PTX Drug-Eluting Stent Implantation Following Drug-Coated Balloon Dilation in a Healthy Swine Model:

Purpose: To compare the safety of Zilver PTX drug-eluting stents (DES) following drug-coated balloon (DCB) angioplasty or conventional balloon angioplasty (BA) in a healthy porcine iliofemoral artery model. Methods: DES implantation following DCB (DCB+DES) or BA (BA+DES) was assessed by angiography and histology in the nondiseased iliofemoral arteries of 20 animals, with sacrifice at 1, 3, and 6 months. Safety assessment compared quantitative measures of vessel integrity (eg, preservation of artery geometry, structure, and lumen dimensions; absence of aneurysm; malapposition) and histological parameters (eg, excessive inflammation). The percentage of uncovered struts could not be >30% per section and the endothelial cell loss had to be <50%. The vascular and skeletal muscle changes in the downstream regions were also assessed histologically for evidence of emboli. Results: No significant differences in safety parameters, including inflammation and endothelial cell loss, were observed between the 2 groups at all time points. Percentage of fibrin was significantly higher in DCB+DES at 3 months [20.0% (IQR 11.6, 28.4) vs BA+DES 4.2% (IQR 1.4, 9.6), respectively; p=0.04], with consistent trends between groups at all time points. Medial smooth muscle cell loss peaked at 1 month and was not statistically different between groups at any time point, although the loss was greater in the DCB+DES group. Sections with arterioles exhibiting paclitaxel-associated fibrinoid necrosis in downstream tissues were observed exclusively in the DCB group at 1 month (14.3% of sections) and 3 months (11.5%). Conclusion: This preclinical study suggests that Zilver PTX stent implantation is a safe strategy after DCB angioplasty and might be considered for patients who require stenting after DCB treatment.

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.

Heart-resident macrophages: are they involved in the rhythm of every beat?

Macrophages are one of the main components of the innate immune system and play a major role in cardiovascular disease (1,2). These cells are derived from blood monocytes and differentiate into tissue macrophages. They are well known for their immunologic roles including phagocytosis and antigen presentation. The role of macrophages in normal and disease physiology, however, is much more complex as illustrated by the fact that they can develop into distinct functional phenotypes depending upon their microenvironment. Different sub-populations of macrophages have been characterized, of which M1 “inflammatory” macrophages and “pro-healing” M2 macrophages are the most studied (3).

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.

Early treatment with high-potency statins in patients with acute coronary syndrome—an example of personalized medicine

Statins, together with aspirin, are the cornerstone of secondary prevention treatment in stable coronary artery disease (CAD) and acute coronary syndrome (ACS). The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study was one of the first randomized controlled trials which demonstrated a benefit of high-potency statin therapy in the setting of ACS (1).

PATHOLOGICAL FEATURES OF LEFT MAIN STENT THROMBOSIS

Background: Left main stenting using drug eluting stents is considered a acceptable treatment in patients with isolated left main disease or those at high risk for surgery. Stent thrombosis (ST) is a known and catastrophic complication associated with left main stenting yet the pathologic risk

RACIAL DIFFERENCE IN GENETIC VARIANTS ASSOCIATED WITH HYPERTROPHIC CARDIOMYOPATHY

Background: Hypertrophic cardiomyopathy (HCM) is a fairly common heart disease with estimated prevalence of 1 in 500 people. In more than 1/3 of patients, casual genetic variants have been identified and genotyping may be used to assess risk among families of affected patients. Manrai et al.