Pathology of self-expanding transcatheter aortic valves: Findings from the CoreValve US pivotal trials.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has recently become an alternative to surgical aortic valve replacement for patients with severe aortic stenosis. However, paravalvular leaks, possible leaflet thrombosis, and device durability following TAVR remain unresolved issues. METHODS AND RESULTS: We conducted the first systematic microscopic and macroscopic pathologic analysis of self-expanding CoreValve transcatheter aortic valves removed at autopsy or surgically from the U.S. pivotal trial of extreme- and high-risk patients. Implants were evaluated for histopathologic changes in the valve frame and leaflets. Thrombus/neointima on the leaflets was graded depending on the leaflet thickness and the extent of leaflet involvement. Inflammation, calcification, and structural integrity were also assessed. A total of 21 cases (median age 86.0 years [IQR, 79.0-91.0]), with median duration of implant duration of 17.0 days ranged from 0 to 503 days were evaluated. No valve frame fracture was observed and severe paravalvular gaps were uncommon. Inflammation and thrombus in the valve frame was minimal, but neointimal growth increased overtime. Symptomatic valve thrombosis was observed in one case (5%) and subclinical moderate leaflet thrombus was observed in four additional cases (19%). Inflammation of the leaflets was mild, while structural changes were minimal, and one case had infective endocarditis. Pannus or leaflet calcification were not observed. CONCLUSIONS: This first systematic macroscopic and microscopic pathologic analysis of self-expanding transcatheter aortic valves demonstrates favorable short-term pathologic findings. However, our finding of subclinical leaflet thrombus formation confirms prior observations and warrants further investigation.

Rationale of cerebral protection devices in left atrial appendage occlusion.

AIMS: Aims of this case-series were to assess the feasibility of cerebral protection devices in interventional left atrial appendage occlusion (iLAAO) procedures and to yield insight into the pathomorphological correlate of early, procedural cerebral embolization during iLAAO. METHODS AND RESULTS: Five consecutive patients underwent iLLO flanked by the Sentinel CPS® (Claret Medical, Inc., Santa Rosa, CA) cerebral protection system. Placement and recapture of the Sentinel® device as well as the iLAAO were successful and safe in all cases. Histomorphometric analysis of the collected filters showed embolized debris in all patients. Acute thrombus was found in three patients, organizing thrombus in four. Interestingly, two patients had endocardial or myocardial tissue in their filters. CONCLUSIONS: Cerebral protection during iLAAO with the Sentinel CPS® device is feasible. Furthermore, this dataset identifies the formation and embolization of thrombus and cardiac tissue as emboligeneic sources and potential future targets to reduce procedural complications. © 2016 Wiley Periodicals, Inc.

Pathology of balloon-expandable transcatheter aortic valves.

BACKGROUND: The Placement of AoRtic TraNscathetER Valves trials (PARTNER) showed favorable safety and efficacy versus medical or surgical therapy in inoperable, high, and intermediate surgical risk patients with severe aortic stenosis. However, the biological responses to transcatheter aortic valves have not been well characterized. OBJECTIVES: The aim of this study was to perform pathologic assessment of Edwards SAPIEN transcatheter aortic valves removed either at autopsy or surgically during the PARTNER I and II clinical trials. METHODS: Explanted valves and frame were evaluated for pathologic responses including extent of thrombus, inflammation, neointima, and leaflet degeneration/calcification according to semiquantitative grading by implant duration (≤30 days; 31-90 days; >90 days). RESULTS: A total of 22 cases (median age 82.0 years, 45% men) were included, with a duration of implantation that ranged from 0 to 1739 days (median duration 16.5 days [interquartile range, 2.8-68.3]). Valve thrombosis resulting in severe aortic stenosis was observed in one case. Moderate leaflet thrombus was seen in 14% of cases (n = 3) and all were asymptomatic. Calcification was seen in two valves: one with severe leaflet calcification had severe aortic stenosis requiring surgical replacement, while the other showed early calcification. Mild structural leaflet changes were exclusively seen in valve implants >90 days. Valve inflammation and thrombus formation was mild in majority of the cases. CONCLUSIONS: Overall, our study demonstrates moderate thrombus formation in 14% and calcification in only 2 valves, ≥4 years duration. In this short-duration study, acceptable durability and biocompatibility of the Edwards SAPIEN transcatheter valve system was demonstrated; however, further studies are required to confirm the significance and application of our findings.

Relationship between Serum Inflammatory Biomarkers and Thrombus Characteristics in Patients with ST Segment Elevation Myocardial Infarction.

OBJECTIVES: To compare angiographic and optical coherence tomography (OCT) data pertinent to thrombi, along with the histologic characteristics of aspirated thrombi in patients presenting with ST elevation myocardial infarction (STEMI) with or without inflammation, as assessed by C-reactive protein (CRP) and myeloperoxidase (MPO). METHODS: In the OCTAVIA (Optical Coherence Tomography Assessment of Gender Diversity in Primary Angioplasty) study, 140 patients with STEMI referred for primary percutaneous intervention were enrolled. The patients underwent OCT assessment of the culprit vessel, along with blood sampling of CRP and MPO, and histologic analysis of the thrombus. RESULTS: Biomarkers were available for 129 patients, and histology and immunohistochemistry of the thrombi were available for 78 patients. Comparisons were made using the median thresholds of CRP and MPO (2.08 mg/L and 604.124 ng/mL, respectively). There was no correlation between CRP and MPO levels in the whole population (p = 0.685). Patients with high CRP levels had higher thrombus grades and more frequent TIMI flow 0/1 compared with those with low CRP levels (5 [1st quartile 3; 3rd quartile 5] vs. 3.5 mg/L [1; 5], p = 0.007, and 69.3 vs. 48.5%, p = 0.04, respectively). Patients with high MPO levels more commonly had early thrombi than had those with low MPO levels (42.5 vs. 20.0%, p = 0.04). CONCLUSIONS: CRP and MPO were not correlated in STEMI patients, possibly reflecting different pathogenic mechanisms, with CRP more related to thrombus burden and MPO to thrombus age.

Comparison of Particulate Embolization after Femoral Artery Treatment with IN.PACT Admiral versus Lutonix 035 Paclitaxel-Coated Balloons in Healthy Swine.

PURPOSE: Different carrier excipients unique to individual drug-coated balloons (DCBs) may influence embolic safety characteristics in peripheral vascular territories through embolization of released particulates. A comparator study of IN.PACT Admiral vs Lutonix 035 balloons in healthy swine was therefore performed to assess which balloon produces more downstream emboli. MATERIALS AND METHODS: Single or overlapping 80-mm IN.PACT and Lutonix 035 DCBs were assessed in the femoral arteries of 21 swine with 28- and 90-day follow-up, with standard balloon angioplasty as a control. Histologic analysis of arterial wall and downstream skeletal muscle and coronary band was performed. This analysis was supported by an analytic measurement of paclitaxel levels. RESULTS: IN.PACT DCBs demonstrated a more pronounced change in medial wall composition, characterized by a paclitaxel-induced loss of medial smooth muscle cells accompanied by increased proteoglycans. The percentage of sections with arterioles exhibiting paclitaxel-associated fibrinoid necrosis in downstream tissues was higher at 90 days with overlapping IN.PACT DBCs compared with Lutonix 035 DCBs (46.2% [interquartile range, 19.2-57.7] vs 0.0% [0.0-11.5]; P = .01), with similar trends noted for 28-day single and overlapping DCBs. Drug analysis in parallel tissues further confirmed higher paclitaxel concentrations in nontarget tissues for IN.PACT than Lutonix 035 balloons for single and overlapping configurations at both time points. Rare embolic crystalline material was observed in downstream tissues, but only for IN.PACT balloons. CONCLUSIONS: There was more fibrinoid necrosis in tissues treated with IN.PACT DCBs compared with Lutonix DCBs, suggesting increased emboli debris with higher paclitaxel levels.

Impact of Culprit Plaque and Atherothrombotic Components on Incomplete Stent Apposition in Patients With ST-Elevation Myocardial Infarction Treated With Everolimus-Eluting Stents　- An OCTAVIA Substudy.

BACKGROUND: The role of culprit plaque and related atherothrombotic components on incomplete stent apposition (ISA) occurrence after primary percutaneous coronary intervention (p-PCI) is unknown. METHODS AND RESULTS: ST-segment elevation myocardial infarction (STEMI) patients undergoing p-PCI with an everolimus-eluting stent were prospectively investigated with optical coherence tomography (OCT) of the infarct-related artery before, after stenting and at 9 months. OCT data, aspirated thrombus and serum inflammatory biomarkers were analyzed. 114 patients with 114 lesions were evaluated. Acute ISA occurred in 82 lesions (71.9%), preferentially in larger vessels with a median area of 0.2 mm(2). The presence of thrombus before stent implantation (odds ratio (OR) 5.5, 95% confidence interval (CI) [1.1-26.9], P=0.04) and the lipid content in the target segment (OR 1.3, 95% CI [1.0-1.5], P=0.04) independently predicted acute ISA. At 9-month follow-up, ISA persisted in 46 lesions (56.1%). The volume of acute ISA significantly predicted persistent ISA (OR 1.3, 95% CI [1.1-1.5], P=0.01). Late-acquired ISA occurred in 39 lesions (34.2%) with a median area of 0.3 mm(2). Red/mixed thrombus before stent implantation (OR 3.7, 95% CI [1.0-13.3], P=0.05) and length of the underlying ruptured plaque (OR 1.7, 95% CI [1.1-2.8] P=0.02) were independently associated with late-acquired ISA. CONCLUSIONS: In STEMI patients, culprit plaque and atherothrombotic components of the infarct-related artery significantly contribute to the onset of acute and late ISA. ISA persistence at follow-up depends on the initial volume of acute ISA.

Neoatherosclerosis: overview of histopathologic findings and implications for intravascular imaging assessment.

Despite the reduction in late thrombotic events with newer-generation drug-eluting stents (DES), late stent failure remains a concern following stent placement. In-stent neoatherosclerosis has emerged as an important contributing factor to late vascular complications including very late stent thrombosis and late in-stent restenosis. Histologically, neoatherosclerosis is characterized by accumulation of lipid-laden foamy macrophages within the neointima with or without necrotic core formation and/or calcification. The development of neoatherosclerosis may occur in months to years following stent placement, whereas atherosclerosis in native coronary arteries develops over decades. Pathologic and clinical imaging studies have demonstrated that neoatherosclerosis occurs more frequently and at an earlier time point in DES when compared with bare metal stents, and increases with time in both types of implant. Early development of neoatherosclerosis has been identified not only in first-generation DES but also in second-generation DES. The mechanisms underlying the rapid development of neoatherosclerosis remain unknown; however, either absence or abnormal endothelial functional integrity following stent implantation may contribute to this process. In-stent plaque rupture likely accounts for most thrombotic events associated with neoatherosclerosis, while it may also be a substrate of in-stent restenosis as thrombosis may occur either symptomatically or asymptomatically. Intravascular optical coherence tomography is capable of detecting neoatherosclerosis; however, the shortcomings of this modality must be recognized. Future studies should assess the impact of iterations in stent technology and risk factor modification on disease progression. Similarly, refinements in imaging techniques are also warranted that will permit more reliable detection of neoatherosclerosis.

Pathology of second-generation everolimus-eluting stents versus first-generation sirolimus- and paclitaxel-eluting stents in humans.

BACKGROUND: Clinical trials have demonstrated that the second-generation cobalt-chromium everolimus-eluting stent (CoCr-EES) is superior to the first-generation paclitaxel-eluting stent (PES) and is noninferior or superior to the sirolimus-eluting stent (SES) in terms of safety and efficacy. It remains unclear whether vascular responses to CoCr-EES are different from those to SES and PES because the pathology of CoCr-EES has not been described in humans. METHODS AND RESULTS: A total of 204 lesions (SES=73; PES=85; CoCr-EES=46) from 149 autopsy cases with duration of implantation >30 days and ≤3 years were pathologically analyzed, and comparison of vascular responses was corrected for duration of implantation. The observed frequency of late and very late stent thrombosis was less in CoCr-EES (4%) versus SES (21%; P=0.029) and PES (26%; P=0.008). Neointimal thickness was comparable among the groups, whereas the percentage of uncovered struts was strikingly lower in CoCr-EES (median=2.6%) versus SES (18.0%; P<0.0005) and PES (18.7%; P<0.0005). CoCr-EES showed a lower inflammation score (with no hypersensitivity) and less fibrin deposition versus SES and PES. The observed frequency of neoatherosclerosis, however, did not differ significantly among the groups (CoCr-EES=29%; SES=35%; PES=19%). CoCr-EES had the least frequency of stent fracture (CoCr-EES=13%; SES=40%; PES=19%; P=0.007 for CoCr-EES versus SES), whereas fracture-related restenosis or thrombosis was comparable among the groups (CoCr-EES=6.5%; SES=5.5%; PES=1.2%). CONCLUSIONS: CoCr-EES demonstrated greater strut coverage with less inflammation, less fibrin deposition, and less late and very late stent thrombosis compared with SES and PES in human autopsy analysis. Nevertheless, the observed frequencies of neoatherosclerosis and fracture-related adverse pathological events were comparable in these devices, indicating that careful long-term follow-up remains important even after CoCr-EES placement.

Comparison of pathology of chronic total occlusion with and without coronary artery bypass graft.

AIMS: The aim of our study was to investigate chronic total occlusion (CTO) in human coronary arteries to clarify the difference between CTO with prior coronary artery bypass graft (CABG) and those without prior CABG. METHODS AND RESULTS: A total of 95 CTO lesions from 82 patients (61.6 ± 14.0 years, male 87.8%) were divided into the following three groups: CTO with CABG (n = 34) (CTO+CABG), CTO without CABG--of long-duration (n = 49) (LD-CTO) and short-duration (n = 12) (SD-CTO). A histopathological comparison of the plaque characteristics of CTO, proximal and distal lumen morphology, and negative remodelling between groups was performed. A total of 1127 sections were evaluated. Differences in plaque characteristics were observed between groups as follows: necrotic core area was highest in SD-CTO (18.6%) (LD-CTO: 7.8%; CTO+CABG: 4.5%; P = 0.02); calcified area was greatest in CTO+CABG (29.2%) (LD-CTO: 16.8%; SD-CTO: 12.1%; P = 0.009); and negative remodelling was least in SD-CTO [remodelling index (RI) 0.86] [CTO+CABG (RI): 0.72 and LD-CTO (RI): 0.68; P < 0.001]. Approximately 50% of proximal lumens showed characteristics of abrupt closure, whereas the majority of distal lumen patterns were tapered (79%) (P < 0.0001). CONCLUSION: These pathological differences in calcification, negative remodelling, and presence of necrotic core along with proximal and distal tapering, which has been associated with greater success, help explain the differences in success rates of percutaneous coronary intervention in CTO patients with and without CABG.