Maria Romero

Pathology of Human Coronary and Carotid Artery Atherosclerosis and Vascular Calcification in Diabetes Mellitus

The continuing increase in the prevalence of diabetes mellitus in the general population is predicted to result in a higher incidence of cardiovascular disease. Although the mechanisms of diabetes mellitus-associated progression of atherosclerosis are not fully understood, at clinical and pathological levels, there is an appreciation of increased disease burden and higher levels of arterial calcification in these subjects. Plaques within the coronary arteries of patients with diabetes mellitus generally exhibit larger necrotic cores and significantly greater inflammation consisting mainly of macrophages and T lymphocytes relative to patients without diabetes mellitus. Moreover, there is a higher incidence of healed plaque ruptures and positive remodeling in hearts from subjects with type 1 diabetes mellitus and type 2 diabetes mellitus, suggesting a more active atherogenic process. Lesion calcification in the coronary, carotid, and other arterial beds is also more extensive. Although the role of coronary artery calcification in identifying cardiovascular disease and predicting its outcome is undeniable, our understanding of how key hormonal and physiological alterations associated with diabetes mellitus such as insulin resistance and hyperglycemia influence the process of vascular calcification continues to grow. Important drivers of atherosclerotic calcification in diabetes mellitus include oxidative stress, endothelial dysfunction, alterations in mineral metabolism, increased inflammatory cytokine production, and release of osteoprogenitor cells from the marrow into the circulation. Our review will focus on the pathophysiology of type 1 diabetes mellitus- and type 2 diabetes mellitus-associated vascular disease with particular focus on coronary and carotid atherosclerotic calcification.

Histological Findings and Predictors of Cerebral Debris From Transcatheter Aortic Valve Replacement: The ALSTER Experience

Background Histopathological analyses of debris captured by a cerebral protection system during transcatheter aortic valve replacement have been reported, but the origin of the captured debris was not determined and risk factors were not defined. Methods and Results Embolic debris was analyzed from 322 filters used in a dual‐cerebral‐filter protection system implemented during transcatheter aortic valve replacement for 161 patients (mean age 81 years, 82 male [51%], logistic EuroSCORE 19% [interquartile range 12–31%]). The debris capture rate was high, with debris from 97% of all patients (156 of 161). No differences by filter location were found (brachiocephalic trunk 86% [139 of 161], left carotid artery 91% [147 of 161]; adjusted P=0.999). Five prevalent types of debris were identified: thrombus (91%), arterial wall tissue (68%), valve tissue (53%), calcification (46%), and foreign material (30%). Female sex (P=0.0287, odds ratio 1.364, 95% CI 1.032–1.812) and diabetes mellitus (P=0.0116, odds ratio 1.474, 95% CI 1.089–2.001) were significant risk factors for embolic debris. Additional analysis showed significantly more valve tissue in patients with predilation (P=0.0294). Stroke and transient ischemic attack rates were 0.6% each (1 of 161). Conclusion This study showed a high rate of embolic debris consisting of typical anatomic structures known to be altered in patients with aortic stenosis undergoing transcatheter aortic valve replacement. Female patients with diabetes mellitus have increased risk of embolic debris and should be protected by a cerebral protection system during transcatheter aortic valve replacement. Because valve tissue embolizes more often in patients with predilation, procedural planning should consider this finding. Both cerebral arteries (brachiocephalic trunk, left carotid artery) should be protected in the same way.

Cerebral Protection During MitraClip Implantation: Initial Experience at 2 Centers.

OBJECTIVES This study sought to assess the feasibility and safety of using a filter-based cerebral protection system (CPS) during MitraClip implantation and to report on the histopathologic analysis of the captured debris. BACKGROUND Stroke is one of the serious adverse events associated with MitraClip therapy. METHODS Between July 2014 and March 2015, 14 surgical high-risk patients (age 75 ± 7 years; 7 men; median logistic EuroSCORE 21%) underwent MitraClip implantation employing cerebral protection with a dual embolic filter system. All patients had severe mitral regurgitation of predominantly functional origin. RESULTS All procedures were successfully completed for both CPS deployment/retrieval and MitraClip implantation. A total of 28 filters (2 from each patient) were analyzed. Microscopically, debris was identified in all 14 patients. The most common tissue types were acute thrombus and small fragments of foreign material, which were found in 12 patients (85.7%) each. Organizing thrombus was present in 4 patients (28.6%), valve tissue and/or superficial atrial wall tissue in 9 patients (64.3%), and fragments of myocardium in 2 patients (14.3%). No transient ischemic attacks, strokes, or deaths occurred peri-procedurally or during a median follow-up interval of 8.4 months. CONCLUSIONS In this small study of patients undergoing MitraClip treatment with cerebral protection, embolic debris potentially conducive to cerebrovascular events was found in all patients. Debris was composed most often of acute thrombus, foreign material likely originating from the hydrophilic device coating, and valve/atrial wall tissue. Further studies are warranted to assess the impact of cerebral protection on the incidence of cerebrovascular events after MitraClip therapy.

Histology of debris captured by a cerebral protection system during transcatheter valve-in-valve implantation

Objective Histological analyses of debris captured by a cerebral protection system (CPS) during transcatheter valve-in-valve (VIV) procedures have not been reported. Methods Fifteen consecutive patients with stenotic aortic (n=13) or mitral (n=2) surgical or transcatheter bioprostheses were treated with implantation of a transcatheter heart valve (THV) in the presence of a dual-filter CPS. Mean patient age was 75 years; mean logistic EuroSCORE was 31%. Filters were collected and histological assessment of debris was performed. Patients were followed clinically until discharge. Results Debris captured by either or both filters was detected in all patients. Acute thrombus was the most common type of debris, found in all patients, followed in frequency by arterial wall tissue (n=12 patients (80%)), calcification (n=11 (73%)) and valve tissue (n=9 (60%)). Less frequently found were organised thrombus (n=5 (30%)), foreign material (n=4 (27%)) and myocardium (n=2 (13%)). A median of 123 debris particles per patient was detected, with a trend towards a greater median number of particles collected in proximal filters (78 vs 39, p=0.065). The average maximum particle diameter was 88 (range 56–175) µm, with a median of 20 particles ≥150 µm. No stroke or transient ischaemic attack (TIA) had occurred by the time of discharge (mean 8 days). Conclusions Transcatheter VIV procedures were associated with the release of particulate debris into the cerebral circulation in all patients. The type of debris suggests that debris originates predominantly from arterial and valvular passage of the THV.

Neoatherosclerosis From a Pathologist’s Point of View

Percutaneous coronary interventions using drug-eluting stents (DES) or bare metal stents (BMS) are the most commonly performed procedures for the management of acute coronary syndromes and stable angina.1 BMS, introduced >2 decades ago, were limited by complications of in-stent restenosis (ISR) with the need for repeat revascularization in up to one third of patients.2 DES with controlled release of antiproliferative agents developed in the past decade were specifically designed to inhibit neointimal formation and reduce restenosis within the stented coronary segment and have achieved greater success, particularly with the development of newer platforms aimed at improving the safety and efficacy. The commonly used antiproliferative drugs are highly lipophilic molecules that exert immunosuppressive effects in the case of sirolimus group of drugs by inhibiting the mammalian target of rapamycin, which prevents the degradation of p27kip1, a cyclin-dependent kinase inhibitor that plays an important role in regulating vascular smooth muscle cell (VSMC) migration and proliferation,3 whereas paclitaxel is a cytotoxic drug known to suppress VSMC and endothelial cell proliferation and migration by disrupting microtubule dynamics, thus affecting cells in the mitotic phase of the cell cycle.4 The first generation of DES (namely Cypher [Cordis Corp, Miami Lakes, FL] and Taxus [Boston Scientific, Natick, MA]) had unique disadvantages of thick metallic struts, and uneven and thick coatings of poorly biocompatible permanent polymers were used to load drugs. However, despite therapeutic efficacy and recommendations to extend dual antiplatelet therapy for at least 12 months, complications of late stent thrombosis (LST, >1 month to ≤1 year) and very late stent thrombosis (VLST, >1 year) have emerged as a significant limitation, particularly with approved first-generation DES.5 More recently, however, complications of in-stent neoatherosclerosis with associated plaque rupture have seemed to be a major contributing factor for late DES failure and as …

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.

Vascular diseases: aortitis, aortic aneurysms, and vascular calcification.

Inflammatory diseases of the aorta broadly include noninfectious and infectious aortitis, periaortitis, atherosclerosis, and inflammatory atherosclerotic aneurysms. Aortitis is uncommon but is increasingly recognized as an important cause of aortic aneurysms and dissections. Abdominal (AAA) and thoracic aortic aneurysms (TAA) have different pathologies and etiologies. AAAs are the most common type of aortic aneurysm, and the vast majority of these are atherosclerotic. The causes of TAA vary depending on the site of involvement, but medial degeneration is a common pathologic substrate, regardless of etiology, and genetic influences play a prominent role in TAA expression. Standardized classification schemes for inflammatory and degenerative diseases of the aorta have only recently been added to the pathology literature. A brief overview of the new histopathologic classifications for aortic inflammatory and degenerative diseases has recently been published by the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology as a consensus document on the surgical pathology of the aorta. Vascular calcification is a highly regulated biologic process, and the mechanisms leading to vascular calcification are under investigation. Calcification may occur in the intima (atherosclerotic) or in the media secondary to metabolic disease. Rarely, vascular calcification may be associated with genetic disorders.

Embolic Myocardial Infarction as a Consequence of Atrial Fibrillation: A Prevailing Disease of the Future

Acute myocardial infarction (AMI) is a major cause of death and disability worldwide. When spontaneous AMI occurs, there is a >90% chance that the underlying etiology is primarily due to coronary events such as plaque rupture, erosion, or dissection referred to as myocardial infarction (MI) type 1.1 MI can also occur secondary to an ischemic insult in the absence of overt coronary artery disease (CAD), by an imbalance between myocardial oxygen supply and demand termed type 2 MI, which embodies a myriad of diseases (Table). In general, it is estimated that 4% to 7% of all patients diagnosed with AMI, however, do not have CAD at coronary angiography or autopsy.3 View this table: Table. List of Reported Causes of Myocardial Infarction From Coronary Embolism in the Absence of Coronary Atherosclerotic Disease Article see p 241 Another important category that falls within this realm is coronary artery embolism (CE) in which a thrombus arising from sources other than the coronary vasculature propagates into the coronary arteries causing AMI. Previous work on this subject is limited by the small numbers of patients examined, and, given the vast distribution of patients presenting with AMI worldwide, a more systematic approach would greatly improve our understanding of its diverse etiologies, in particular, the role of CE. In this issue of Circulation , Shibata et al4 report on 1776 consecutive cases of new-onset AMI between 2001 and 2013 that were screened for etiology with a focus on CE and a diagnosis based on histological, angiographic, and other diagnostic imaging modalities. Overall, 52 patients were identified with CE, with a prevalence of 2.9%, defined as probable in 20 cases, and definite in 32. The authors implicate atrial fibrillation (AF) as the most common cause of CE, 38 of 52 (73%) patients in comparison with non–AF-related CE, 116 of …

High-Risk Carotid Plaque: Lessons Learned from Histopathology

The pathophysiology and natural history of atherosclerotic carotid disease is predicated on a more extensive knowledge of lesion progression gained in the studies conducted in the coronary arteries, and these will be reviewed. While the precise sequence of lesion progression leading to carotid plaque vulnerability and cerebrovascular events remain less well understood, specific early and more advanced progressive lesion morphologies associated with stroke risk have been characterized. Of late, there has been a conscious effort for stroke prevention in symptomatic and asymptomatic patients to move beyond luminal stenosis as the only guidance to predict future cerebrovascular events. Driving this strategy are recent advances in medical imaging modalities to assess carotid atherosclerosis vulnerability particularly involving molecular imaging, which is now positioned at the forefront to provide a more detailed and mechanistic assessment of stroke risk. As such, we will spotlight the pathology of high-risk carotid plaques in patients with symptomatic and asymptomatic carotid disease with further reference into more recent mechanistic insights involving a recognized macrophage-mediated inflammatory change, intraplaque neoangiogenesis/hemorrhage, hypoxia, and microcalcification, as potential morphologic indicators of stroke risk.

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.