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Gene expression profiling (AlloMap®; CareDx Inc) has been used to successfully inform on immunologic risk of acute cellular rejection (ACR) in the adult heart transplant (HTx) population. However, there is a paucity of data in pediatric patients, including patients transitioning into adulthood. In this single-center analysis, we sought to characterize AlloMap scores in stable patients transitioning from pediatric to adulthood. Retrospective analysis of AlloMap scores was conducted in 13 HTx recipients from Memorial Regional Hospital in Hollywood, FL. Selected subjects were stable (defined by ISHLT 0R biopsy within 14 days of AlloMap testing), transplanted as pediatric patients, and received noninvasive AlloMap surveillance post-transplant. Patients were subdivided into 3 categories based on age at the time of AlloMap testing: 11-15 years (11 ≤ x < 15), 15-18 years (15 ≤ x < 18), and 18-21 years (18 ≤ x ≤ 21). A Spearman's correlation was conducted with statistical significance set to *p<0.05. AlloMap scores in the 3 age categories were: 11-15 years: med ± IQR= 31.5±4, n= 3 patients, 8 scores; 15-18 years: med ± IQR= 34±5, n= 9 patients, 56 scores; 18-21 years: med ± IQR= 32±6, n= 13 patients, 56 scores. Median scores in the 15-18-year age group were also higher than the other 2 groups but did not reach statistical significance. Inherent differences between the pediatric and adult immune systems may merit special attention to patients during the pediatric-to-adult transition. Our findings suggest that stable patients transitioning into adulthood may have higher baseline scores compared to what has been shown in adult patients. [ABSTRACT FROM AUTHOR]

Gene expression profiling (GEP; AlloMap®, CareDx Inc) can help stratify heart transplant (tx) patients at immunologic risk of acute cellular rejection. However, broad categorization of patients based on skin color can mask critical genetic differences between more defined ethnic groups. We hypothesized that patients of the African American (AA), Caribbean-Black (Caribbean), Latinx, and Caucasian populations possess inherent genetic differences detectable within the AlloMap gene signature. 137 stable adult heart tx patients from Memorial Regional Healthcare systems from 1/1/2018 - 8/3/2022 were analyzed for unique AlloMap gene expression. "Stable" was defined as having a negative biopsy (ISHLT=0R) within 2 weeks of AlloMap draw. Patients were categorized as AA (n=31), Caribbean (n=10), Latinx (n=32), and Caucasian (n=64). Metagene indexes are reported as a composite mean of data normalized to the Caucasian population, and statistical analysis was conducted by a Kruskal Wallis test with significance set to *p<0.05. In this single-center analysis, Latinx patients have decreased steroid responsiveness compared to AA patients, and significantly lower platelet activation compared to all subgroups. Caribbean patients also have significantly higher platelet activation than Caucasian and Latinx patients. In addition, hematopoietic proliferation is preserved across subgroups (not shown). Our work leverages molecular biology to urge integration of racial equality into post-transplant care. Of interest, the qualitative clinical observation of Warfarin-resistance in Caribbean patients can be partially explained by increased platelet activation in this population. Additionally, differences between Caribbean and Caucasian patients are not identical to differences between African American and Caucasian patients, pointing to the need to treat Caribbean and African American patients as distinct subgroups. [ABSTRACT FROM AUTHOR]

Objectives: Human coronary bare-metal stents (BMS) and drug-eluting stents (DES) from autopsy cases with implant duration >30 days were examined for the presence of neointimal atherosclerotic disease.Background: Neointimal atherosclerotic change (neoatherosclerosis) after BMS implantation is rarely reported and usually occurs beyond 5 years. The incidence of neoatherosclerosis after DES implantation has not been reported.Methods: All available cases from the CVPath stent registry (n = 299 autopsies), which includes a total of 406 lesions-197 BMS, 209 DES (103 sirolimus-eluting stents [SES] and 106 paclitaxel-eluting stents [PES])-with implant duration >30 days were examined. Neoatherosclerosis was recognized as clusters of lipid-laden foamy macrophages within the neointima with or without necrotic core formation.Results: The incidence of neoatherosclerosis was significantly greater in DES lesions (31%) than BMS lesions (16%; p < 0.001). The median stent duration with neoatherosclerosis was shorter in DES than BMS (DES, 420 days [interquartile range [IQR]: 361 to 683 days]; BMS, 2,160 days [IQR: 1,800 to 2,880 days], p < 0.001). Unstable lesions characterized as thin-cap fibroatheromas or plaque rupture were more frequent in BMS (n = 7, 4%) than in DES (n = 3, 1%; p = 0.17), with relatively shorter implant durations for DES (1.5 ± 0.4 years) compared to BMS (6.1 ± 1.5 years). Independent determinants of neoatherosclerosis identified by multiple logistic regression included younger age (p < 0.001), longer implant durations (p < 0.001), SES usage (p < 0.001), PES usage (p = 0.001), and underlying unstable plaques (p = 0.004).Conclusions: Neoatherosclerosis is a frequent finding in DES and occurs earlier than in BMS. Unstable features of neoatherosclerosis are identified for both BMS and DES with shorter implant durations for the latter. The development of neoatherosclerosis may be yet another rare contributing factor to late thrombotic events. [ABSTRACT FROM AUTHOR]

The utility of implanting a bioscaffold mitral valve consisting of porcine small intestinal submucosa (PSIS) in a juvenile baboon model (12 to 14 months old at the time of implant; n = 3) to assess their in vivo tissue remodeling responses was investigated. Our findings demonstrated that the PSIS mitral valve exhibited the robust presence of de novo extracellular matrix (ECM) at all explantation time points (at 3-, 11-, and 20-months). Apart from a significantly lower level of proteoglycans in the implanted valve's annulus region ( p < 0.05) at 3 months compared to the 11- and 20-month explants, there were no other significant differences ( p > 0.05) found between any of the other principal valve ECM components (collagen and elastin) at the leaflet, annulus, or chordae tendinea locations, across these time points. In particular, neochordae tissue had formed, which seamlessly integrated with the native papillary muscles. However, additional processing will be required to trigger accelerated, uniform and complete valve ECM formation in the recipient. Regardless of the specific processing done to the bioscaffold valve, in this proof-of-concept study, we estimate that a 3-month window following bioscaffold valve replacement is the timeline in which complete regeneration of the valve and integration with the host needs to occur.

Objective: To evaluate the safety and the short-term function of a novel pulmonary valved conduit (Xeltis Pulmonary Valved Conduit; XPV) up to 12 months in a sheep model., Methods: XPV and Hancock bioprosthetic valved conduits (H, used as control) were implanted in adult sheep in the pulmonary artery position. Animals were killed at 2 months (n = 6 XPV), 6 months (n = 6 XPV and n = 3 H), and 12 months (n = 6 XPV) and examined histologically. During follow-up, function of the device as well as diameter of both XPV and H were assessed by transthoracic echocardiography., Results: Of 18 animals that received an XPV, 15 survived until they were killed; 3 animals that received H survived the planned observational interval. XPV showed mild neointimal thickening and degradation beginning at 2 months with an ongoing process until 12 months. Only 1 of the 18 animals with XPV had significant calcification at 6 months. Pathologic specimen did not show any significant narrowing of the conduit whereas neointimal thickness showed a peak at 6 months. Inflammatory process reached a maximum at 6 months and the degradation process at 12 months. Gel permeation chromatography analysis showed molecular weight loss beginning at 2 months with a peak at 12 months for the conduit with slower absorption for the leaflets. The wall of the H conduits showed more neointimal thickening, narrowing, and calcification compared with XPV, but the leaflets demonstrated minimal changes., Conclusions: Both conduits demonstrated an acceptable safety and functionality. Significant calcification was rarely observed in the XPV, whereas the H developed more neointimal thickness with calcification of the porcine aortic root portion of the wall., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

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., (© 2017 Wiley Periodicals, Inc.)

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., (© 2017 Wiley Periodicals, Inc.)

Tropoelastin (TE), the soluble precursor of insoluble elastin fibers, is produced in minimal amounts in adults. Burn injuries result in inflexible collagen-rich scars because of lack of elastin fiber formation. We studied the feasibility of using recombinant human tropoelastin to enable elastin fiber production in burn and surgical scars to improve skin flexibility. In a swine hypertrophic burn scar model, normal skin and 3 × 3-cm partial thickness thermal burns underwent dermatome resection at 1 week post burn and randomized to four subcutaneous injections of saline or TE (either 0.5, 5, or 10 mg/ml) spaced 3 days apart. Two burn sites received TE injections after wound closure (0.5 or 10 mg/ml). At 90 days, skin hardness, flexibility, and histology were evaluated. All injury sites developed hypertrophic scars. New elastin fibers were found in burn scars in all injuries injected after skin closure with low (5/5) and high (6/6) TE doses (P < .05). No elastin fibers were observed without TE treatment. No significant differences in skin hardness, flexibility, or inflammation were observed. This is the first report demonstrating that subcutaneous injections of TE into surgical and burn injuries can safely produce new elastin fibers in scars. Despite the development of new elastin fibers, skin flexibility was not improved, possibly because of insufficient elastin fiber maturation or the hypertrophic model used. The ability to restore elastin fiber formation in adult skin after burns, trauma, and surgery may improve skin regeneration and reduce disabling complications of scar formation.

Objectives: The aim of this study was to explore the pathology of in-stent chronic total occlusion (IS-CTO) in bare-metal (BMS) versus drug-eluting stents (DES)., Background: Despite a relatively high prevalence of IS-CTO, little is known about the underlying etiology and histopathologic characteristics of the occlusion., Methods: From CVPath Institute's stent registry of human native coronary arteries, the authors identified 56 lesions (32 BMS and 24 DES) from 54 patients with IS-CTO. Sections of stented coronary arteries were examined for histological features of IS-CTO. The underlying mechanisms of IS-CTO were determined along with the histopathological characteristics., Results: The pathological prevalence of IS-CTO was significantly higher in BMS versus DES cases at autopsy (11.7% vs. 5.9%; p = 0.01). The most frequent etiology of IS-CTO was acute thrombotic occlusion (51% in BMS vs. 67% in DES), followed by restenosis (31% vs. 8%) and neoatherosclerotic rupture (9% vs. 4%). The proximal lumen pattern was abrupt in 67% of BMS and in 57% of DES, whereas the distal lumen was tapered in 68% of BMS and in 74% of DES. BMS showed longer fibrous cap of IS-CTO than DES in both proximal (4.6 mm vs. 1.6 mm; p = 0.06) and distal (5.3 mm vs. 2.0 mm; p = 0.06)., Conclusions: At autopsy, IS-CTO was observed more frequently in BMS versus DES, with acute thrombotic occlusion being the most frequent cause, followed by restenosis (especially in BMS) and neoatherosclerotic rupture. Our findings shed new light upon the frequency, mechanisms, and pathology of IS-CTO., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Hypertension is strongly associated with cardiovascular diseases such as heart failure, stroke, kidney disease, and has been correlated with an increased risk for heart attack. Current treatment regimens for hypertension are highly inadequate, with reports indicating that only 50.1% of the clinical population with the disease has their blood pressure under control., Objective: To study the feasibility of using minimally invasive radiosurgery to ablate the renal nerves as a novel treatment for refractory hypertension, and to assess the safety and efficacy of such an approach., Methods: A Hanford porcine (miniswine) model (N = 6) was used to investigate the feasibility of using the CyberHeart radiosurgical platform (CyberHeart Inc., Mountain View, CA, USA) to create safe renal nerve ablations. Norepinephrine (NE) levels were measured pre and post treatment. Additionally, renal nerve and arterial histology were studied to examine effect., Results: Plasma norepinephrine levels showed a decrease over the six-month time point. Urea, nitrogen, and creatinine levels showed no changes post procedure. Histology documented no significant arterial injury in targeted areas. Renal nerves documented histologic change consistent with nerve ablation., Conclusion: CyberHeart radiosurgery of the renal nerve is feasible and resulted in norepinephrine reduction and renal nerve injury consistent with radiosurgical targeted ablation., Competing Interests: US 2012/0323233 A1

Aims: The blood pressure-lowering effect of percutaneous renal denervation (RDN) is controversial. The success of RDN may be device-dependent. We sought to compare the efficacy of RDN by chemical neurolysis using alcohol (Peregrine System Infusion Catheter; Ablative Solutions, Inc., Menlo Park, CA, USA) to RDN by radiofrequency (RF) ablation with the single-electrode RF catheter (Symplicity Flex; Medtronic, Minneapolis, MN, USA) in a porcine model., Methods and Results: This was a prospective, randomised, blinded study. Pigs were assigned to undergo bilateral RF ablation or chemical neurolysis. Primary endpoints were ablation depth and renal tissue norepinephrine (NE) concentrations at three-month follow-up. Twelve pigs underwent RF ablation (n=4) or chemical neurolysis by infusion of 0.3 mL (n=4) or 0.6 mL (n=4) alcohol. Ninety days after RF ablation and chemical neurolysis with 0.3 mL and 0.6 mL of alcohol, mean maximal tissue injury depth was 3.9±1.2 mm, 6.6±1.7 mm and 8.2±2.2 mm, respectively (p<0.001 for either dose of alcohol vs. RF ablation). Compared with historical controls, median renal tissue NE concentration reductions were 66%, 78% and 83% after RF ablation and chemical neurolysis using 0.3 mL and 0.6 mL alcohol, respectively (p=0.107 for chemical neurolysis vs. RF ablation). Mean total ablation area was significantly greater in both (0.3 mL and 0.6 mL) alcohol groups (p=0.0001 for both) than the RF ablation group (30.8±13.7 mm2, 41.6±12.4 mm2 and 11.0±7.5 mm2, respectively)., Conclusions: RDN is more effective using chemical neurolysis than single-electrode RF ablation. Our findings suggest that the efficacy of RDN may be device-dependent.

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., (© 2016 Wiley Periodicals, Inc.)

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., (© 2016 S. Karger AG, Basel.)

Objectives: The aim of this study was to identify histological features that correlate with terms commonly used to describe optical coherence tomographic (OCT) and optical frequency-domain imaging (OFDI) images of stented vessels, by means of a histopathological validation study using stented human coronary arteries., Background: OCT imaging and OFDI are used to evaluate vascular responses to stent implantation. Descriptive terms such as "peristrut low attenuation" and "heterogeneous" have been used to describe neointimal characteristics that may have clinical relevance. However, only limited histopathological correlations are available., Methods: Using the CVPath stent registry, 19 cases were identified in whom implantation duration was >30 days and OCT imaging or OFDI and histological findings were available. Consecutive OCT or OFDI frames (n = 1,063) of stented coronary arteries were categorized according to their predominant imaging features in 1-mm intervals. Coregistration of OCT or OFDI frames and histopathological cross sections was performed in 111 frames., Results: Seven distinct OCT or OFDI patterns were found: homogenous (45%), layered (15%), high intensity with high attenuation (14%), intraluminal protruding masses (8%), peristrut low attenuation (7%), heterogeneous (2%), and honeycomb (1%). Histopathologically, the homogenous pattern correlated most often with smooth muscle cells within collagenous/proteoglycan matrix and less often with organized thrombus. The layered pattern correlated with healed neointimal rupture or erosion, peristrut neovascularization, or smooth muscle cells within collagen/proteoglycan matrix. High intensity with high attenuation correlated with superficial macrophage accumulation in the majority of cases, but with other histological findings in 30% of cases. The diagnostic accuracy was greater in restenotic lesions. The only OCT or OFDI finding that had a single histological feature was the honeycomb pattern., Conclusions: This study suggests a lack of correlation between OCT image patterns and distinct histological tissue characteristics., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

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., (Copyright © 2016 SIR. Published by Elsevier Inc. All rights reserved.)

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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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.

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Objective: Smooth muscle cells, macrophage infiltration and accumulation of lipids, proteoglycans, collagen matrix and calcification play a central role in atherosclerosis. The early histologic changes of plaque progression from pathologic intimal thickenings (PIT) to late fibroatheroma lesions have not been fully characterized., Methods: A total of 151 atherosclerotic coronary lesions were collected from 67 sudden death victims. Atherosclerotic plaques were classified as PIT without macrophage infiltration, PIT with macrophages, and early and late fibroatheromas. Presence of macrophages and proteoglycans (versican, decorin and biglycan) were recognized by specific antibodies while hyaluronan was detected by affinity histochemistry. Lipid deposition was identified by oil-red-O, and calcification was assessed following von Kossa and alizarin red staining., Results: Lesion progression from PIT to late fibroatheroma was associated with increase in macrophage accumulation (p < 0.001) and decreasing apoptotic body clearance by macrophages (ratio of engulfed-to-total apoptotic bodies) (p < 0.001). Lipid deposition in lipid pool of PIT had a microvesicular appearance whereas those in the necrotic core were globular in nature. Overall, the accumulation of hyaluronan (p < 0.001), and proteoglycan versican (p < 0.001) and biglycan (p = 0.013) declined along with lesion progression from PIT to fibroatheromas. Microcalcification was first observed only within areas of lipid pools and its presence and size increased in lesions with necrotic core., Conclusions: PIT to fibroatheroma lesions are accompanied by early lipid accumulation, followed by macrophage infiltration with defective clearance of apoptotic bodies along with decrease in proteoglycan and hyaluronan in lipid pools that convert to necrotic cores. Calcification starts in PIT and increases with plaque progression., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This paper reviews the published data and reports 3 cases of thrombosis involving CoreValve (Medtronic, Minneapolis, Minnesota) and 1 involving Edward Sapien (Edwards Lifesciences, Irvine, California) devices. Three of these cases had pathological findings at autopsy., Background: Only a limited number of cases of valve dysfunction with rapid increase of transvalvular aortic gradients or aortic insufficiency post-transcatheter aortic valve replacement (TAVR) have been described. This nonstructural valvular dysfunction has been presumed to be because of early pannus formation or thrombosis., Methods: Through reviews of the published reports and 4 clinical cases, pathological and clinical findings of early valve thrombosis are examined to elucidate methods for recognition and identifying potential causes and treatments., Results: This paper presents 4 cases, 2 of which had increasing gradients post-TAVR. All 3 pathology cases showed presence of a valve thrombosis in at least 2 TAV leaflets on autopsy, but were not visualized by transthoracic echocardiogram or transesophageal echocardiogram. One case was medically treated with oral anti coagulation with normalization of gradients. The consequence of valve thrombosis in all 3 pathology patients either directly or indirectly played a role in their early demise. At least 18 case reports of early valve thrombosis have been published. In 12 of these cases, the early treatment with anticoagulation therapy resolved the thrombus formation and normalized aortic pressures gradients successfully., Conclusions: These 4 cases elucidate the occurrence of valve thrombosis post-TAVR. Consideration should be given to treatment with dual antiplatelet therapy and oral anticoagulation in patients post-TAVR with increasing mean pressure gradients and maximum aortic valve velocity. Further research should be conducted to create guidelines for antithrombotic therapy following TAVR procedure., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The Paradise Ultrasound Renal Denervation System is a next-generation catheter-based device which was used to investigate whether the target ablation area can be controlled by changing ultrasound energy and duration to optimise nerve injury while preventing damage to the arterial wall., Methods and Results: Five ultrasound doses were tested in a thermal gel model. Catheter-based ultrasound denervation was performed in 15 swine (29 renal arteries) to evaluate five different doses in vivo, and animals were euthanised at seven days for histopathologic assessment. In the gel model, the peak temperature was highest in the low power-long duration (LP-LD) dose, followed by the mid-low power-mid duration (MLP-MD) dose and the mid-high power-short duration (MHP-SD) dose, and lowest in the mid power-short duration (MP-SD) dose and the high power-ultra short duration (HP-USD) dose. In the animal study, total ablation area was significantly greater in the LP-LD group, followed by the MLP-MD group, and it was least in the HP-USD, MP-SD and MHP-SD groups (p=0.02). Maximum distance was significantly greater in the LP-LD group, followed by the MLP-MD group, the MHP-SD group, and the HP-USD group, and shortest in the MP-SD group (p=0.007). The short spare distance was not different among the five groups (p=0.38). Renal artery damage was minimal, while preserving significant nerve damage in all groups., Conclusions: The Paradise Ultrasound Renal Denervation System is a controllable system where total ablation area and depth of ablation can be optimised by changing ultrasound power and duration while sparing renal arterial tissue damage but allowing sufficient peri-arterial nerve damage.

Background: The pathology of radiofrequency-derived sympathetic renal denervation has not been studied over time and may provide important understanding of the mechanisms resulting in sustained blood pressure reduction. The purpose of this study was to investigate chronological changes after radiofrequency-renal denervation in the swine model., Methods and Results: A total of 49 renal arteries from 28 animals with 4 different time points (7, 30, 60, and 180 days) were examined. Semiquantitative histological assessment of arteries and associated tissue was performed to characterize the chronological progression of the radiofrequency lesions. Arterial medial circumferential injury (%) was greatest at 7 days (38±13%), followed by 30 days (31±6%) and 60 days (31±15%), and least at 180 days (21±12%) (P=0.046). Nerve injury score was significantly greater (P<0.001) at 7 days (3.9±0.4) compared with 30 days (2.5±0.5), 60 days (2.6±0.5), and 180 days (1.9±0.9). Tyrosine hydroxylase score, which assesses functional nerve damage, was significantly less after 7 (1±1) and 30 days (0.7±0.6) compared with 60 (2.7±0.6) and 180 days (2.7±0.6; P=0.01). Focal nerve regeneration at the sites of radiofrequency ablation was observed in 17% of renal arteries at 60 days and 71% of 180 days., Conclusions: Nerve injury after radiofrequency ablation was greatest at 7 days, with maximum functional nerve damage sustained ≤30 days. Focal terminal nerve regeneration was observed only at the sites of ablation as early as 60 days and continued to 180 days. Renal artery and peri-arterial soft tissue injury is greatest in the subacute phase, and least in the chronic phase, suggesting gradual recovery of the renal arterial wall and surrounding tissue., (© 2015 American Heart Association, Inc.)

Background: The long-term efficacy of radiofrequency ablation of renal autonomic nerves has been proven in nonrandomized studies. However, long-term safety of the renal artery (RA) is of concern. The aim of our study was to determine if cooling during radiofrequency ablation preserved the RA while allowing equivalent nerve damage., Methods and Results: A total of 9 swine (18 RAs) were included, and allocated to irrigated radiofrequency (n=6 RAs, temperature setting: 50°C), conventional radiofrequency (n=6 RAs, nonirrigated, temperature setting: 65°C), and high-temperature radiofrequency (n=6 RAs, nonirrigated, temperature setting: 90°C) groups. RAs were harvested at 10 days, serially sectioned from proximal to distal including perirenal tissues and examined after paraffin embedding, and staining with hematoxylin-eosin and Movat pentachrome. RAs and periarterial tissue including nerves were semiquantitatively assessed and scored. A total of 660 histological sections from 18 RAs were histologically examined by light microscopy. Arterial medial injury was significantly less in the irrigated radiofrequency group (depth of medial injury, circumferential involvement, and thinning) than that in the conventional radiofrequency group (P<0.001 for circumference; P=0.003 for thinning). Severe collagen damage such as denatured collagen was also significantly less in the irrigated compared with the conventional radiofrequency group (P<0.001). Nerve damage although not statistically different between the irrigated radiofrequency group and conventional radiofrequency group (P=0.36), there was a trend toward less nerve damage in the irrigated compared with conventional. Compared to conventional radiofrequency, circumferential medial damage in highest-temperature nonirrigated radiofrequency group was significantly greater (P<0.001)., Conclusions: Saline irrigation significantly reduces arterial and periarterial tissue damage during radiofrequency ablation, and there is a trend toward less nerve damage., (© 2014 American Heart Association, Inc.)

Transcatheter ablation of renal autonomic nerves is a viable option for the treatment of resistant arterial hypertension; however, structured pre-clinical evaluation with standardization of analytical procedures remains a clear gap in this field. Here we discuss the topics relevant to the pre-clinical model for the evaluation of renal denervation (RDN) devices and report methodologies and criteria toward standardization of the safety and efficacy assessment, including histopathological evaluations of the renal artery, periarterial nerves, and associated periadventitial tissues. The pre-clinical swine renal artery model can be used effectively to assess both the safety and efficacy of RDN technologies. Assessment of the efficacy of RDN modalities primarily focuses on the determination of the depth of penetration of treatment-related injury (e.g., necrosis) of the periarterial tissues and its relationship (i.e., location and distance) and the effect on the associated renal nerves and the correlation thereof with proxy biomarkers including renal norepinephrine concentrations and nerve-specific immunohistochemical stains (e.g., tyrosine hydroxylase). The safety evaluation of RDN technologies involves assessing for adverse effects on tissues local to the site of treatment (i.e., on the arterial wall) as well as tissues at a distance (e.g., soft tissue, veins, arterial branches, skeletal muscle, adrenal gland, ureters). Increasing experience will help to create a standardized means of examining all arterial beds subject to ablative energy and in doing so enable us to proceed to optimize the development and assessment of these emerging technologies., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Although renal sympathetic denervation therapy has shown promising results in patients with resistant hypertension, the human anatomy of peri-arterial renal nerves is poorly understood., Objectives: The aim of our study was to investigate the anatomic distribution of peri-arterial sympathetic nerves around human renal arteries., Methods: Bilateral renal arteries were collected from human autopsy subjects, and peri-arterial renal nerve anatomy was examined by using morphometric software. The ratio of afferent to efferent nerve fibers was investigated by dual immunofluorescence staining using antibodies targeted for anti-tyrosine hydroxylase and anti-calcitonin gene-related peptide., Results: A total of 10,329 nerves were identified from 20 (12 hypertensive and 8 nonhypertensive) patients. The mean individual number of nerves in the proximal and middle segments was similar (39.6 ± 16.7 per section and 39.9 ± 1 3.9 per section), whereas the distal segment showed fewer nerves (33.6 ± 13.1 per section) (p = 0.01). Mean subject-specific nerve distance to arterial lumen was greatest in proximal segments (3.40 ± 0.78 mm), followed by middle segments (3.10 ± 0.69 mm), and least in distal segments (2.60 ± 0.77 mm) (p < 0.001). The mean number of nerves in the ventral region (11.0 ± 3.5 per section) was greater compared with the dorsal region (6.2 ± 3.0 per section) (p < 0.001). Efferent nerve fibers were predominant (tyrosine hydroxylase/calcitonin gene-related peptide ratio 25.1 ± 33.4; p < 0.0001). Nerve anatomy in hypertensive patients was not considerably different compared with nonhypertensive patients., Conclusions: The density of peri-arterial renal sympathetic nerve fibers is lower in distal segments and dorsal locations. There is a clear predominance of efferent nerve fibers, with decreasing prevalence of afferent nerves from proximal to distal peri-arterial and renal parenchyma. Understanding these anatomic patterns is important for refinement of renal denervation procedures., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)