Comparison of thrombogenicity in different types of drug-eluting stents during transition from DAPT to SAPT.

BACKGROUND: During the transition from dual antiplatelet therapy (DAPT) to single antiplatelet therapy (SAPT), previous studies have raised concerns about a rebound effect. We compared platelet and inflammatory cell adhesion on different types of stents in the setting of clopidogrel presence and withdrawal. METHODS: In Experiment 1, three pigs were administered with DAPT, that is, clopidogrel and acetylsalicylic acid (ASA), for 7 days. Each animal underwent an extracorporeal carotid arteriovenous shunt model implanted with fluoropolymer-coated everolimus-eluting stent (FP-EES), biodegradable-polymer sirolimus-eluting stent (BP-SES), and biodegradable-polymer everolimus-eluting stents (BP-EES). In Experiment 2, two pigs were administered DAPT, clopidogrel was then withdrawn at day 7, and SAPT with ASA was continued for next 21 days. Then flow-loop experiments with the drawn blood from each time point were performed for FP-EES, BioLinx-polymer zotarolimus-eluting stents (BL-ZES), and BP-EES. The rebound effect was defined as the statistical increase of inflammation and platelet adhesion assessed with immunohistochemistry on the stent-strut level basis from baseline to day-14 or 28. RESULTS: Both experiments showed platelet adhesion value was highest in BP-EES, while the least in FP-EES during DAPT therapy. There was no increase in platelet or inflammatory cell adhesion above baseline values (i.e., no therapy) due to the cessation of clopidogrel on the stent-strut level. Monocyte adhesion was the least for FP-EES with the same trend observed for neutrophil adhesion. CONCLUSIONS: No evidence of rebound effect was seen after the transition from DAPT to SAPT. FP-EES demonstrated the most favorable antithrombotic and anti-inflammatory profile regardless of the different experimental designs.

Polygenic Risk Score Associates With Atherosclerotic Plaque Characteristics at Autopsy.

BACKGROUND: Polygenic risk scores (PRSs) for coronary artery disease (CAD) potentially improve cardiovascular risk prediction. However, their relationship with histopathologic features of CAD has never been examined systematically. METHODS: From 4327 subjects referred to CVPath by the State of Maryland Office Chief Medical Examiner for sudden death between 1994 and 2015, 2455 cases were randomly selected for genotyping. We generated PRS from 291 known CAD risk loci. Detailed histopathologic examination of the coronary arteries was performed in all subjects. The primary study outcome measurements were histopathologic plaque features determining severity of atherosclerosis, including %stenosis, calcification, thin-cap fibroatheromas, and thrombotic CAD. RESULTS: After exclusion of cases with insufficient DNA sample quality or with missing data, 954 cases (mean age, 48.8±14.7 years; 75.7% men) remained in the final study cohort. Subjects in the highest PRS quintile exhibited more severe atherosclerosis compared with subjects in the lowest quintile, with greater %stenosis (80.3%±27.0% versus 50.4%±38.7%; adjusted P<0.001) and a higher frequency of calcification (69.6% versus 35.8%; adjusted P=0.004) and thin-cap fibroatheroma (26.7% versus 9.5%; adjusted P=0.007). Even after adjustment for traditional CAD risk factors, subjects within the highest PRS quintile had higher odds of severe atherosclerosis (ie, ≥75% stenosis; adjusted odds ratio, 3.77 [95% CI, 2.10-6.78]; P<0.001) and plaque rupture (adjusted odds ratio, 4.05 [95% CI, 2.26-7.24]; P<0.001). Moreover, subjects within the highest quintile had higher odds of CAD-associated cause of death, especially among those aged ≤50 years (adjusted odds ratio, 4.08 [95% CI, 2.01-8.30]; P<0.001). No statistically significant associations were observed with plaque erosion after adjusting for covariates. CONCLUSIONS: This is the first autopsy study investigating associations between PRS and atherosclerosis severity at the histopathologic level in subjects with sudden death. Our pathological analysis suggests PRS correlates with plaque burden and features of advanced atherosclerosis and may be useful as a method for CAD risk stratification, especially in younger subjects.

Polygenic Risk Score Associates with Atherosclerotic Plaque Characteristics at Autopsy.

Background: Polygenic risk scores (PRS) for coronary artery disease (CAD) potentially improve cardiovascular risk prediction. However, their relationship with histopathologic features of CAD has never been examined systematically. Methods: From 4,327 subjects referred to CVPath by the State of Maryland Office Chief Medical Examiner (OCME) for sudden death between 1994 and 2015, 2,455 cases were randomly selected for genotyping. We generated PRS from 291 known CAD risk loci. Detailed histopathologic examination of the coronary arteries was performed in all subjects. The primary study outcome measurements were histopathologic plaque features determining severity of atherosclerosis, including %stenosis, calcification, thin-cap fibroatheromas (TCFA), and thrombotic CAD. Results: After exclusion of cases with insufficient DNA sample quality or with missing data, 954 cases (mean age 48.8±14.7; 75.7% men) remained in the final study cohort. Subjects in the highest PRS quintile exhibited more severe atherosclerosis compared to subjects in the lowest quintile, with greater %stenosis (80.3%±27.0% vs. 50.4%±38.7%; adjusted p<0.001) and a higher frequency of calcification (69.6% vs. 35.8%; adjusted p=0.004) and TCFAs (26.7% vs. 9.5%; adjusted p=0.007). Even after adjustment for traditional CAD risk factors subjects within the highest PRS quintile had higher odds of severe atherosclerosis (i.e., ≥75% stenosis; adjusted OR 3.77; 95%CI 2.10-6.78; p<0.001) and plaque rupture (adjusted OR 4.05; 95%CI 2.26-7.24; p<0.001). Moreover, subjects within the highest quintile had higher odds of CAD-associated cause of death, especially among those aged 50 years and younger (adjusted OR 4.08; 95%CI 2.01-8.30; p<0.001). No associations were observed with plaque erosion. Conclusions: This is the first autopsy study investigating associations between PRS and atherosclerosis severity at the histopathologic level in subjects with sudden death. Our pathological analysis suggests PRS correlates with plaque burden and features of advanced atherosclerosis and may be useful as a method for CAD risk stratification, especially in younger subjects. Highlights: In this autopsy study including 954 subjects within the CVPath Sudden Death Registry, high PRS correlated with plaque burden and atherosclerosis severity.The PRS showed differential associations with plaque rupture and plaque erosion, suggesting different etiologies to these two causes of thrombotic CAD.PRS may be useful for risk stratification, particularly in the young. Further examination of individual risk loci and their association with plaque morphology may help understand molecular mechanisms of atherosclerosis, potentially revealing new therapy targets of CAD. Graphic Abstract: A polygenic risk score, generated from 291 known CAD risk loci, was assessed in 954 subjects within the CVPath Sudden Death Registry. Histopathologic examination of the coronary arteries was performed in all subjects. Subjects in the highest PRS quintile exhibited more severe atherosclerosis as compared to subjects in the lowest quintile, with a greater plaque burden, more calcification, and a higher frequency of plaque rupture.

Local, Downstream, and Systemic Evaluation after Femoral Artery Angioplasty with Kanshas Drug-Coated Balloons In Vitro and in a Healthy Swine Model.

PURPOSE: To evaluate the incidence of distal embolism and local vascular responses after treatment with the Kanshas drug-coated balloon (DCB) in a preclinical model. MATERIALS AND METHODS: A total of 90 femoral arteries from 35 healthy swine were treated with a single-dose (×1) or triple-dose (×3) Kanshas DCB that applies the Unicoat technology with 3.2 µg/mm2 of paclitaxel. An uncoated Kanshas balloon was used as a control. The arterial wall, downstream skeletal muscle, and nontarget organs (kidneys, lungs, lymph nodes, liver, spleen, and heart) were histologically evaluated. For pharmacokinetic evaluation, a total of 40 healthy swine were treated with ×1 Kanshas DCB, and treated vessels were evaluated ex vivo with high-performance liquid chromatography-mass spectrometry. RESULTS: Arteries treated with the Kanshas DCB showed mild proteoglycan deposition accompanied by the loss of smooth muscle cells (SMCs). These changes increased in a dose-dependent manner (medial SMC loss at 28 days in the ×1 vs ×3 groups, in depth, 1 (0.75-1.38) vs 2 (1.63-2.44); P = .0008; in circumference, 0.83 (0.67-1) vs 1.5 (1.19-1.81); P = .0071). No evidence of distal embolization in skeletal muscles (0 of 210 histological sections) and nontarget organs (0 of 345 sections) was observed. The pharmacokinetic evaluation showed high paclitaxel concentration in the treated artery (912 ng/mg, peaking at 3 minutes), which remained detectable at up to 180 days (0.04 ng/mg). CONCLUSIONS: The Kanshas DCB showed a local drug effect in treated arteries up to 180 days with a high concentration of paclitaxel and no histological evidence of distal embolization.

CD163+ macrophages restrain vascular calcification, promoting the development of high-risk plaque.

Vascular calcification (VC) is concomitant with atherosclerosis, yet it remains uncertain why rupture-prone high-risk plaques do not typically show extensive calcification. Intraplaque hemorrhage (IPH) deposits erythrocyte-derived cholesterol, enlarging the necrotic core and promoting high-risk plaque development. Pro-atherogenic CD163+ alternative macrophages engulf hemoglobin:haptoglobin (HH) complexes at IPH sites. However, their role in VC has never been examined to our knowledge. Here we show, in human arteries, the distribution of CD163+ macrophages correlated inversely with VC. In vitro experiments using vascular smooth muscle cells (VSMCs) cultured with HH-exposed human macrophage - M(Hb) - supernatant reduced calcification, while arteries from ApoE-/- CD163-/- mice showed greater VC. M(Hb) supernatant-exposed VSMCs showed activated NF-κB, while blocking NF-κB attenuated the anticalcific effect of M(Hb) on VSMCs. CD163+ macrophages altered VC through NF-κB-induced transcription of hyaluronan synthase (HAS), an enzyme that catalyzes the formation of the extracellular matrix glycosaminoglycan, hyaluronan, within VSMCs. M(Hb) supernatants enhanced HAS production in VSMCs, while knocking down HAS attenuated its anticalcific effect. NF-κB blockade in ApoE-/- mice reduced hyaluronan and increased VC. In human arteries, hyaluronan and HAS were increased in areas of CD163+ macrophage presence. Our findings highlight an important mechanism by which CD163+ macrophages inhibit VC through NF-κB-induced HAS augmentation and thus promote the high-risk plaque development.

Relationships between neighborhood disadvantage and cardiovascular findings at autopsy in subjects with sudden death.

BACKGROUND: Neighborhood disadvantage is associated with a higher risk of sudden cardiac death. However, autopsy findings have never been investigated in this context. Here, we sought to explore associations between neighborhood disadvantage and cardiovascular findings at autopsy in cases of sudden death in the State of Maryland. METHODS: State of Maryland investigation reports from 2,278 subjects within the CVPath Sudden Death Registry were screened for street addresses and 9-digit zip codes. Area deprivation index (ADI), used as metric for neighborhood disadvantage, was available for 1,464 subjects; 650 of whom self-identified as Black and 814 as White. The primary study outcome measurements were causes of death and gross and histopathologic findings of the heart. RESULTS: Subjects from most disadvantaged neighborhoods (i.e., ADI ≥ 8; n = 607) died at younger age compared with subjects from less disadvantaged neighborhoods (i.e., ADI ≤ 7; n = 857; 46.07 ± 14.10 vs 47.78 ± 13.86 years; P = 0.02) and were more likely Black or women. They were less likely to die from cardiac causes of death (61.8% vs 67.7%; P = 0.02) and had less severe atherosclerotic plaque features, including plaque burden, calcification, intraplaque hemorrhage, and thin-cap fibroatheromas. In addition, subjects from most disadvantaged neighborhoods had lower frequencies of plaque rupture (18.8% vs 25.1%, P = 0.004). However, these associations were omitted after adjustment for traditional risk factors and race. CONCLUSION: Neighborhood disadvantage did not associate with cause of death or coronary histopathology after adjustment for cardiovascular risk factors and race, implying that social determinants of health other than neighborhood disadvantage play a more prominent role in sudden cardiac death.

Sex Differences in Coronary Atherosclerosis.

PURPOSE OF REVIEW: The importance of cardiovascular disease (CVD) in women has long been underestimated. Therefore, we need to understand the impact of sex differences on CVD. RECENT FINDINGS: Traditional risk factors contribute to coronary artery disease (CAD) differently in women and men. There are female-specific risk factors and comorbid conditions that affect the risk of CAD. Plaque erosion is frequently seen in younger women who smoke, while plaque rupture is common in older women and men who have elevated blood cholesterol. Coronary artery calcification is also different in both sexes. Thus, coronary artery calcification score-based risk stratification in women is challenging. A deeper understanding of the sex differences in the risk factors and plaque morphology of coronary atherosclerosis may lead to improved outcomes of CVD in women.

Overcoming challenges in refining the current generation of coronary stents.

INTRODUCTION: Late stent thrombosis caused by delayed vascular healing and prolonged local inflammation were major drawbacks of 1st generation drug-eluting stents (DES). Strut design, biocompatibility of polymer, and drug-release profiles were improved in 2nd and 3rdgeneration DES. Accordingly, the indications for percutaneous coronary intervention with DES have been expanded to more complex patients and lesions. Despite these improvements, significant barriers such as greater flexibility in the duration of dual-antiplatelet therapy (DAPT) as well as reducing long-term stent-related events remain. To achieve ideal short- and long-term results, these existing limitations need to be overcome. AREAS COVERED: We will discuss the current limitations of coronary DES and how they might be overcome from pathological and clinical viewpoints. EXPERT OPINION: Optimizing DAPT duration after stent implantation and prevention of in-stent neoatherosclerosis are two major issues in current DES. Overcoming these drawbacks is a prerequisite toward achieving better short- and long-term clinical outcomes. New technologies including platform design, polymer types, and anti-proliferative agent itself might lead to further improvements. Although the initial experience with bioresorbable scaffold/stents (BRS) was disappointing, positive results of clinical studies regarding novel BRS are raising expectations. Overall, further device innovation is desired for overcoming the limitations of current DES.

Efficacy and safety of cerebral embolic protection systems during transcatheter aortic valve replacement: a review of current clinical findings.

INTRODUCTION: Cerebrovascular events are one of the most serious consequences after transcatheter aortic valve replacement (TAVR). More than half of the cerebrovascular events following TAVR are due to procedure-related emboli. Embolic protection devices (EPDs) have the potential to decrease cerebrovascular events during TAVR procedure. However, randomized controlled trials (RCTs) have not conclusively determined if EPDs are effective, likely because of small number of patients enrolled. However, meta-analyses and propensity-matched analyses from large registries have shown efficacy and suggest the importance of EPDs in prevention of stroke during TAVR and perhaps other structural heart procedures. AREAS COVERED: This review will focus on clinical and histopathologic studies examining the efficacy, safety, and histopathologic device capture findings in the presence and absence of EPDs during TAVR procedures. EXPERT OPINION: Clinical studies have not conclusively determined the efficacy of EPDs. Current ongoing large-scale RCT (PROTECTED TAVR [NCT04149535]) has the potential to prove their efficacy. Histopathological evaluation of debris captured by EPDs contributes to our understanding of the mechanisms of TAVR procedure-related embolic events and suggests the importance of preventing cerebral embolization of debris released during this and other structural heart procedures.

Endothelial Recovery in Bare Metal Stents and Drug-Eluting Stents on a Single-Cell Level.

OBJECTIVE: Healing processes, particularly reendothelialization, are essential for vascular homeostasis after plain old balloon angioplasty and stent implantation. Drug-eluting stents (DES) are commonly used for percutaneous coronary intervention because restenosis rates are reduced as compared with bare metal stents (BMS). However, in addition to understanding the nature of regenerated endothelial cells, concerns over incomplete stent healing persist, and the molecular effects of antiproliferative drug coatings on endothelium remain poorly understood. APPROACH AND RESULTS: We used the rabbit iliac artery model to analyze differences in stent endothelialization in BMS and DES. Histology and immunohistochemistry confirmed that stent coverage was significantly greater in BMS than in DES at 30 days after stent implantation. Single-cell RNA sequencing revealed a more immature transcriptomic signature of neointimal endothelial cell harvested from stented arteries in comparison with native and plain old balloon angioplasty­ treated arteries. Whereas the genetic signature of BMS was overall proangiogenic with enrichment of genes involved in endothelial proliferation, sprouting, and migration, as well as extracellular matrix assembly, DES-derived endothelial cell showed upregulation of genes associated with angiogenesis inhibition and endothelial activation. CONCLUSIONS: Single-cell RNA sequencing analysis identified unique transcriptional changes within regenerated endothelium after plain old balloon angioplasty and stent implantation. These data suggest unique endothelial transcriptional differences, which characterize the different response of the endothelium to vascular injury and may help explain why long-term responses in DES remain suboptimal.

Acute thrombogenicity of fluoropolymer coated stents versus competitive drug-eluting stents under single antiplatelet therapy.

BACKGROUND: Recent clinical studies have suggested the feasibility of 1-month dual antiplatelet therapy (DAPT) for patients receiving drug-eluting stent (DES). Although our previous ex-vivo swine arteriovenous (AV) shunt studies under low dose heparin treatment suggested superior thromboresistance of fluoropolymer-coated everolimus-eluting stent (FP-EES) when compared to other polymer-based DESs, the relative thromboresistance of different DESs under single antiplatelet therapy (SAPT) has never been examined. This study aimed to evaluate platelet adhesion under SAPT in competitive DESs in the in vitro flow loop model and ex vivo swine AV shunt model. METHODS: The thrombogenicity of FP-EES, BioLinx polymer zotarolimus-eluting stent (BL-ZES), and biodegradable polymer everolimus-eluting stent (BP-EES) was assessed acutely using the swine AV shunt model under aspirin or clopidogrel SAPT. Stents were immunostained using antibodies against platelets and inflammatory markers and evaluated by confocal microscopy. Also, the adhesion of platelet and albumin on the three DESs was assessed by an in-vitro flow loop model using human platelets under aspirin SAPT and fluorescent albumin, respectively. RESULTS: In the shunt model, FP-EES showed significantly less platelet and inflammatory cell adhesion than BL-ZES and BP-EES. In the flow loop model, FP-EES showed significantly less platelet coverage and more albumin adsorption than BL-ZES and BP-EES. CONCLUSIONS: These results suggest FP-EES may have particular advantage for short-term DAPT compared to other DESs.

Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals.

Importance: Unexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined. Objective: To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes. Design, Setting, and Participants: This genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021. Main Outcomes and Measures: The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD. Results: The median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants. Conclusions and Relevance: In this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

APOL1 Genetic Variants Are Associated With Increased Risk of Coronary Atherosclerotic Plaque Rupture in the Black Population.

[Figure: see text].

Intravascular imaging and histological correlates of medial and intimal calcification in peripheral artery disease.

BACKGROUND: In peripheral artery disease, two different types of calcification are frequently observed, i.e., medial and intimal calcification. AIMS: The aim of this study was to determine the ability of intravascular ultrasound (IVUS) imaging and optical frequency domain imaging (OFDI) to detect medial and intimal calcification in human peripheral arteries. METHODS: We performed ex vivo intravascular imaging of cadaveric human peripheral arteries with calcifications. IVUS and OFDI images were co-registered with histology. A total of 12 legs from nine patients were examined, and 438 cross-sectional images were co-registered with histology. RESULTS: OFDI could detect 183 of 231 intimal calcifications by histology, whereas IVUS could detect 194 (OFDI: sensitivity 79%, specificity 86%, area under the curve [AUC] 0.83; IVUS: sensitivity 84%, specificity 85%, AUC 0.85). Of 245 medial calcifications by histology, 160 and 164 were detected by OFDI and IVUS, respectively (OFDI: sensitivity 65%, specificity 85%, AUC 0.75; IVUS: sensitivity 67%, specificity 80%, AUC 0.74). Medial calcification with overlying intimal calcification (overlapped calcification) and an unclear border between intima and media were the main reasons for misdiagnosis. Without those 89 overlapped calcifications, sensitivity in both OFDI and IVUS was improved (OFDI: sensitivity 81%, specificity 85%, AUC 0.83; IVUS: sensitivity 88%, specificity 80%, AUC 0.84). CONCLUSIONS: There are limitations in detecting medial calcification in overlapped intimal calcification and with an unclear border between intima and media by both IVUS and OFDI. It is important to distinguish medial calcification from intimal calcification before proceeding with endovascular therapy since different approaches will be required.

Paradise™ Ultrasound Renal Denervation System for the treatment of hypertension.

Catheter-based renal denervation is a novel treatment approach for patients with hypertension and initial unblinded trials have shown promising results. The Paradise™ Ultrasound Renal Denervation System (ReCor Medical, CA, USA) is an ultrasound-based catheter with a distal balloon that acts as a coolant to protect the renal arterial wall. This device received CE-mark in 2012. Randomized, sham-controlled trials and postmarket studies have shown promising efficacy and safety results. Currently, three additional ongoing randomized, sham-controlled trials are underway in the USA, Europe, Japan and Korea, and the results will be pivotal in device approval in some of these countries. These studies with larger numbers of patients and longer duration of follow-up are needed to further confirm the safety and efficacy of this device.

Eruptive Calcified Nodules as a Potential Mechanism of Acute Coronary Thrombosis and Sudden Death.

BACKGROUND: Calcified nodule (CN) has a unique plaque morphology, in which an area of nodular calcification causes disruption of the fibrous cap with overlying luminal thrombus. CN is reported to be the least frequent cause of acute coronary thrombosis, and the pathogenesis of CN has not been well studied. OBJECTIVES: The purpose of this study is to provide a comprehensive morphologic assessment of the CN in addition to providing an evolutionary perspective as to how CN causes acute coronary thrombosis in patients with acute coronary syndromes. METHODS: A total of 26 consecutive CN lesions from 25 subjects from our autopsy registry were evaluated. Detailed morphometric analysis was performed to understand the plaque characteristics of CN and nodular calcification. RESULTS: The mean age was 70 years, with a high prevalence of diabetes and chronic kidney disease. CNs were equally distributed between men and women, with 61.5% of CNs found in the right coronary artery (n = 16), mainly within its mid-portion (56%). All CNs demonstrated surface nonocclusive luminal thrombus, consisting of multiple nodular fragments of calcification, protruding and disrupting the overlying fibrous cap, with evidence of endothelial cell loss. The degree of circumferential sheet calcification was significantly less in the culprit section (89° [interquartile range: 54° to 177°]) than in the adjacent proximal (206° [interquartile range: 157° to 269°], p = 0.0034) and distal (240° [interquartile range: 178° to 333°], p = 0.0004) sections. Polarized picrosirius red staining showed the presence of necrotic core calcium at culprit sites of CNs, whereas collagen calcium was more prevalent at the proximal and distal regions of CNs. CONCLUSIONS: Our study suggests that fibrous cap disruption in CN with overlying thrombosis is initiated through the fragmentation of necrotic core calcifications, which is flanked-proximally and distally-by hard, collagen-rich calcification in coronary arteries, which are susceptible to mechanical stress.

Vascular Response of a Polymer-Free Paclitaxel-Coated Stent (Zilver PTX) versus a Polymer-Coated Paclitaxel-Eluting Stent (Eluvia) in Healthy Swine Femoropopliteal Arteries.

PURPOSE: To compare the long-term vascular healing responses of healthy swine iliofemoral arteries treated with a polymer-free paclitaxel-eluting stent (Z-PES, Zilver PTX) or a fluoropolymer-based paclitaxel-eluting stent (FP-PES, Eluvia). MATERIALS AND METHODS: Bilateral iliofemoral arteries in 20 swine were treated with a Z-PES (n = 16) or a FP-PES (n = 24) and were examined histologically at 1, 3, 6, and 12 months. RESULTS: Morphometric analysis revealed larger external and internal elastic lamina, stent expansion, and lumen area in the FP-PES than in the Z-PES at all timepoints. Luminal narrowing was similar in the 2 groups at 1 month; however, greater stenosis was observed in the Z-PES group at 3 months, with significant regression thereafter, resulting in equivalent stenosis at 6 and 12 months. Greater drug effect and less complete vessel healing were found in the FP-PES group at all timepoints, including greater numbers of malapposed struts with excessive fibrin deposition at 1 and 3 months, than in the Z-PES group. Three of 12 FP-PESs from the 6- and 12-month cohorts also showed circumferential medial disruption with peri-strut inflammation, whereas no abnormal findings were observed in contralateral Z-PESs. CONCLUSIONS: Prolonged paclitaxel release with the presence of a permanent polymer may contribute to the differential vascular responses seen for the Z-PES and FP-PES groups, including medial layer disruption and aneurysmal vessel degeneration that was sometimes observed in the FP-PES group. These distinct features should be confirmed by pathology and in vivo imaging of human superficial femoral arteries to determine their clinical significance.

Comprehensive Assessment of Human Accessory Renal Artery Periarterial Renal Sympathetic Nerve Distribution.

OBJECTIVES: The aim of this study was to understand the anatomy of periarterial nerve distribution in human accessory renal arteries (ARAs). BACKGROUND: Renal denervation is a promising technique for blood pressure control. Despite the high prevalence of ARAs, the anatomic distribution of periarterial nerves around ARAs remains unknown. METHODS: Kidneys with surrounding tissues were collected from human autopsy subjects, and histological evaluation was performed using morphometric software. An ARA was defined as an artery arising from the aorta above or below the dominant renal artery (DRA) or an artery that bifurcated within 20 mm of the takeoff of the DRA from the aorta. The DRA was defined as an artery that perfused >50% of the kidney. RESULTS: A total of 7,287 nerves from 14 ARAs and 9 DRAs were evaluated. The number of nerves was smaller in the ARA than DRA (median: 30 [interquartile range: 17.5 to 48.5] vs. 49 [interquartile range: 36 to 76]; p < 0.0001). In both ARAs and DRAs, the distance from the arterial lumen to nerve was shortest in the distal, followed by the middle and proximal segments. On the basis of the post-mortem angiography, ARAs were divided into large (≥3 mm diameter) and small (<3 mm) groups. The number of nerves was greatest in the DRA, followed by the large and small ARA groups (53 [41 to 97], 38 [25 to 53], and 24.5 [10.5 to 36.3], respectively; p = 0.001). CONCLUSIONS: ARAs showed a smaller number of nerves than DRAs, but these results were dependent on the size of the ARA. Ablation, especially in large ARAs, may allow more complete denervation with the potential to further reduce blood pressure.

Risk prediction of in-stent restenosis among patients with coronary drug-eluting stents: current clinical approaches and challenges.

Introduction: In-stent restenosis (ISR) has been one of the biggest limitations to the success of percutaneous coronary intervention for the treatment of coronary artery disease (CAD). The introduction of drug-eluting stent (DES) was a revolution in the treatment of CAD because these devices drastically reduced ISR to very low levels (<5%). Subsequently, newer generation DES treatments have overcome the drawbacks of first-generation DES, i.e. delayed endothelialization, and late stent thrombosis. However, the issue of late ISR, including neoatherosclerosis after DES implantation especially in high-risk patients and complex lesions, still exists as a challenge to be overcome.Areas covered: We discuss the mechanisms of ISR development including neoatherosclerosis, past and current clinical status of ISR, and methods to predict and overcome this issue from pathological and clinical points of view.Expert opinion: The initial drawbacks of first-generation DES, such as delayed endothelial healing and subsequent risk of late stent thrombosis, have been improved upon by the current generation DES. To achieve better long-term clinical outcomes, further titration of drug-release and polymer degradation profile, strut thickness as well as material innovation are needed.

Comparison of acute thrombogenicity and albumin adsorption in three different durable polymer coronary drug-eluting stents.

BACKGROUND: The relative thrombogenicity and albumin adsorption and retention of different durable polymers used in coronary stents has not been tested. AIMS: This study sought to compare the thromboresistance and albumin binding capacity of different durable polymer drug-eluting stents (DES) using dedicated preclinical and in vitro models. METHODS: In an ex vivo swine arteriovenous shunt model, a fluoropolymer everolimus-eluting stent (FP-EES) (n=14) was compared with two durable polymer DES, the BioLinx polymer-coated zotarolimus-eluting stent (BL-ZES) (n=9) and a CarboSil elastomer polymer-coated ridaforolimus-eluting stent (EP-RES) (n=6), and bare metal stents (BMS) (n=10). Stents underwent immunostaining using a cocktail of antiplatelet antibodies and a marker for inflammation and were then evaluated by confocal microscopy (CM). Albumin retention was assessed using a flow loop model with labelled human serum albumin (FP-EES [n=8], BL-ZES [n=4], EP-RES [n=4], and BMS [n=7]), and scanned by CM. RESULTS: The area of platelet adherence (normalised to total stent surface area) was lower in the order FP-EES (9.8%), BL-ZES (32.7%), EP-RES (87.6%) and BMS (202.0%), and inflammatory cell density was least for FP-EES