Predictors of Optical Coherence Tomography-Defined Calcified Nodules in Patients With Acute Coronary Syndrome　- A Substudy From the TACTICS Registry.

BACKGROUND: Recent studies suggest that the presence of calcified nodules (CN) is associated with worse prognosis in patients with acute coronary syndrome (ACS). We investigated clinical predictors of optical coherence tomography (OCT)-defined CN in ACS patients in a prospective multicenter registry. METHODS AND RESULTS: We investigated 695 patients enrolled in the TACTICS registry who underwent OCT assessment of the culprit lesion during primary percutaneous coronary intervention. OCT-CN was defined as calcific nodules erupting into the lumen with disruption of the fibrous cap and an underlying calcified plate. Compared with patients without OCT-CN, patients with OCT-CN (n=28) were older (mean [±SD] age 75.0±11.3 vs. 65.7±12.7 years; P<0.001), had a higher prevalence of diabetes (50.0% vs. 29.4%; P=0.034), hemodialysis (21.4% vs. 1.6%; P<0.001), and Killip Class III/IV heart failure (21.4% vs. 5.7%; P=0.003), and a higher preprocedural SYNTAX score (median [interquartile range] score 15 [11-25] vs. 11 [7-19]; P=0.003). On multivariable analysis, age (odds ratio [OR] 1.072; P<0.001), hemodialysis (OR 16.571; P<0.001), and Killip Class III/IV (OR 4.466; P=0.004) were significantly associated with the presence of OCT-CN. In non-dialysis patients (n=678), age (OR 1.081; P<0.001), diabetes (OR 3.046; P=0.014), and Killip Class III/IV (OR 4.414; P=0.009) were significantly associated with the presence of OCT-CN. CONCLUSIONS: The TACTICS registry shows that OCT-CN is associated with lesion severity and poor clinical background, which may worsen prognosis.

Regnase-1 Prevents Pulmonary Arterial Hypertension Through mRNA Degradation of Interleukin-6 and Platelet-Derived Growth Factor in Alveolar Macrophages.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a type of pulmonary hypertension (PH) characterized by obliterative pulmonary vascular remodeling, resulting in right-sided heart failure. Although the pathogenesis of PAH is not fully understood, inflammatory responses and cytokines have been shown to be associated with PAH, in particular, with connective tissue disease-PAH. In this sense, Regnase-1, an RNase that regulates mRNAs encoding genes related to immune reactions, was investigated in relation to the pathogenesis of PH. METHODS: We first examined the expression levels of ZC3H12A (encoding Regnase-1) in peripheral blood mononuclear cells from patients with PH classified under various types of PH, searching for an association between the ZC3H12A expression and clinical features. We then generated mice lacking Regnase-1 in myeloid cells, including alveolar macrophages, and examined right ventricular systolic pressures and histological changes in the lung. We further performed a comprehensive analysis of the transcriptome of alveolar macrophages and pulmonary arteries to identify genes regulated by Regnase-1 in alveolar macrophages. RESULTS: ZC3H12A expression in peripheral blood mononuclear cells was inversely correlated with the prognosis and severity of disease in patients with PH, in particular, in connective tissue disease-PAH. The critical role of Regnase-1 in controlling PAH was also reinforced by the analysis of mice lacking Regnase-1 in alveolar macrophages. These mice spontaneously developed severe PAH, characterized by the elevated right ventricular systolic pressures and irreversible pulmonary vascular remodeling, which recapitulated the pathology of patients with PAH. Transcriptomic analysis of alveolar macrophages and pulmonary arteries of these PAH mice revealed that Il6, Il1b, and Pdgfa/b are potential targets of Regnase-1 in alveolar macrophages in the regulation of PAH. The inhibition of IL-6 (interleukin-6) by an anti-IL-6 receptor antibody or platelet-derived growth factor by imatinib but not IL-1ß (interleukin-1ß) by anakinra, ameliorated the pathogenesis of PAH. CONCLUSIONS: Regnase-1 maintains lung innate immune homeostasis through the control of IL-6 and platelet-derived growth factor in alveolar macrophages, thereby suppressing the development of PAH in mice. Furthermore, the decreased expression of Regnase-1 in various types of PH implies its involvement in PH pathogenesis and may serve as a disease biomarker, and a therapeutic target for PH as well.

Angioscopic Findings of Stenosis Versus Occlusion in Femoropopliteal Artery Disease.

BACKGROUND: Despite the increase in the number of patients with peripheral artery disease (PAD), the pathophysiology is not fully elucidated. Recently, angioscopy with a 0.48-megapixel equivalent resolution camera became available for patients with PAD. We aimed to compare the plaque component between native stenosis and occlusion in the femoropopliteal artery using this modality. MATERIALS AND METHODS: Thirty-two consecutive patients who underwent endovascular treatment for native femoropopliteal artery disease with angioscopy were studied. The major angioscopic classifications of each lesion were defined as follows: atheromatous plaque (AP) was defined as luminal narrowing without any protrusion, calcified nodule (CN) was defined as a protruding bump with surface irregularity, a mainly reddish thrombus was defined as organizing thrombus (OG), and organized thrombus (OD) was defined by more than half of the thrombus showing a whitish intima-like appearance. RESULTS: A total of 34 lesions (stenosis, n=18; occlusion, n=16) from 32 patients were included. All stenotic lesions showed AP or CN (n=8 [44%], n=10 [56%], respectively), whereas all occluded lesions showed OG or OD (n=5 [31%], n=11 [69%], respectively), which amounted to a statistically significant difference (p<0.001). In occluded lesions, stiff wires (>3 g) were required to cross all lesions classified as OD, whereas this was not always necessary for lesions classified as OG (11 [100%] of 11, 1 [25%] of 5, respectively; p=0.04). Yellow color plaques were observed to a similar degree in all angioscopic classifications. Major adverse limb events, defined as amputation and any reintervention at 12 months, were highly variable, depending on the angioscopic findings, and tended to be more frequently observed in CN and OD (13% in AP, 40% in CN, 0% in OT, and 36% in OD, p=0.25). CONCLUSION: Angioscopy revealed varying components in stenosis and occlusion with different degrees of clinical impact. This may provide new information on the pathophysiology of PAD.

Prevalence and Effects of High-Intensity Statins for Japanese Patients Presenting With Acute Coronary Syndrome　- A Post Hoc Secondary Analysis of STOPDAPT-2 ACS.

BACKGROUND: The REAL-CAD trial, reported in 2017, demonstrated a significant reduction in cardiovascular events with high-intensity statins in patients with chronic coronary syndrome. However, data are scarce on the use of high-intensity statins in Japanese patients with acute coronary syndrome (ACS).Methods and Results: In STOPDAPT-2 ACS, which exclusively enrolled ACS patients between March 2018 and June 2020, 1,321 (44.2%) patients received high-intensity statins at discharge, whereas of the remaining 1,667 patients, 96.0% were treated with low-dose statins. High-intensity statins were defined as the maximum approved doses of strong statins in Japan. The incidence of the cardiovascular composite endpoint (cardiovascular death, myocardial infarction, definite stent thrombosis, stroke) was significantly lower in patients with than without high-intensity statins (1.44% vs. 2.69% [log-rank P=0.025]; adjusted hazard ratio [aHR] 0.48, 95% confidence interval [CI] 0.24-0.94, P=0.03) and the effect was evident beyond 60 days after the index percutaneous coronary intervention (log-rank P=0.01; aHR 0.38, 95% CI 0.17-0.86, P=0.02). As for the bleeding endpoint, there was no significant difference between the 2 groups (0.99% vs. 0.73% [log-rank P=0.43]; aHR 0.96, 95% CI 0.35-2.60, P=0.93). CONCLUSIONS: The prevalence of high-intensity statins has increased substantially in Japan. The use of the higher doses of statins in ACS patients recommended in the guidelines was associated with a significantly lower risk of the primary cardiovascular composite endpoint compared with lower-dose statins.

Coronary High-Intensity Plaques at T1-weighted MRI in Stable Coronary Artery Disease: Comparison with Near-Infrared Spectroscopy Intravascular US.

Background The histologic nature of coronary high-intensity plaques (HIPs) at T1-weighted MRI in patients with stable coronary artery disease remains to be fully understood. Coronary atherosclerosis T1-weighted characterization (CATCH) enables HIP detection by simultaneously acquiring dark-blood plaque and bright-blood anatomic reference images. Purpose To determine if intraplaque hemorrhage (IPH) or lipid is the predominant substrate of HIPs on T1-weighted images by comparing CATCH MRI scans with findings on near-infrared spectroscopy (NIRS) intravascular US (IVUS) images. Materials and Methods This study retrospectively included consecutive patients who underwent CATCH MRI before NIRS IVUS between December 2019 and February 2021 at two facilities. At MRI, HIP was defined as plaque-to-myocardium signal intensity ratio of at least 1.4. The presence of an echolucent zone at IVUS (reported to represent IPH) was recorded. NIRS was used to determine the lipid component of atherosclerotic plaque. Lipid core burden index (LCBI) was calculated as the fraction of pixels with a probability of lipid-core plaque greater than 0.6 within a region of interest. Plaque with maximum LCBI within any 4-mm-long segment (maxLCBI4 mm) greater than 400 was regarded as lipid rich. Multivariable analysis was performed to evaluate NIRS IVUS-derived parameters associated with HIPs. Results There were 205 plaques analyzed in 95 patients (median age, 74 years; interquartile range [IQR], 67-78 years; 75 men). HIPs (n = 42) at MRI were predominantly associated with an echolucent zone at IVUS (79% [33 of 42] vs 8.0% [13 of 163], respectively; P < .001) and a higher maxLCBI4 mm at NIRS (477 [IQR, 258-738] vs 232 [IQR, 59-422], respectively; P < .001) than non-HIPs. In the multivariable model, HIPs were independently associated with an echolucent zone (odds ratio, 24.5; 95% CI: 9.3, 64.7; P < .001), but not with lipid-rich plaque (odds ratio, 2.0; 95% CI: 0.7, 5.4; P = .20). Conclusion The predominant substrate of T1-weighed MRI-defined high-intensity plaques in stable coronary artery disease was intraplaque hemorrhage, not lipid. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Stuber in this issue.

Vascular responses to coronary calcification following implantation of newer-generation drug-eluting stents in humans: impact on healing.

AIMS: Vascular calcification is routinely encountered in percutaneous coronary intervention (PCI) and severe coronary calcification is a known predictor of in-stent restenosis and stent thrombosis. However, the histopathologic mechanisms behind such events have not been systematically described. METHODS AND RESULTS: From our registry of 1211 stents, a total of 134 newer-generation drug-eluting stents (DES) (Xience, Resolute-Integrity, PROMUS-Element, and Synergy) with duration of implant ≥30 days were histologically analysed. The extent of calcification of the stented lesions was evaluated radiographically and divided into severe (SC, n = 46) and non-severely calcified lesions (NC, n = 88). The percent-uncovered struts per section {SC vs. NC; median 2.4 [interquartile range (IQR) 0.0-19.0] % vs. 0.0 (IQR 0.0-4.6) %, P = 0.02} and the presence of severe medial tears (MTs) (59% vs. 44%, respectively, P = 0.03) were greater in SC than NC. In addition, SC had a higher prevalence of ≥3 consecutive struts lying directly in contact with surface calcified area (3SC) (52% vs. 8%, respectively, P < 0.0001). Multivariate analysis demonstrated that sections with duration of implantation ≤6 months [odds ratio (OR): 7.7, P < 0.0001], 3SC (OR: 6.5, P < 0.0001), strut malapposition (OR: 5.0, P < 0.0001), and lack of MTs (OR: 2.5, P = 0.0005) were independent predictors of uncovered struts. Prevalence of neoatherosclerosis was significantly lower in SC than that of NC (24% vs. 44%, P = 0.02). CONCLUSION: Severe calcification, especially surface calcified area is an independent predictor of uncovered struts and delayed healing after newer-generation DES implantation. These data expand of knowledge of the vascular responses of stenting of calcified arteries and suggests further understand of how best to deal with calcification in patients undergoing PCI.

Early Vascular Response to Ultrathin Biodegradable Polymer Sirolimus-Eluting Stents for the Treatment of ST-Elevation Myocardial Infarction After Plaque Rupture.

Recent clinical studies suggest that newer-generation drug-eluting stents that combine ultrathin struts and nanocoating (biodegradable polymer sirolimus-eluting stents, BP-SES) could improve long-term clinical outcomes in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). However, the early vascular response to BP-SES in these patients has not been investigated so far.We examined this response in 20 patients with STEMI caused by plaque rupture using frequency-domain optical coherence tomography (OCT) to understand the underlying mechanisms. Plaque rupture was diagnosed by OCT before PCI with BP-SES implantation was performed. OCT was again performed before the final angiography (post-PCI) and after 2 weeks (2W-OCT).BP-SES placement caused protrusion of atherothrombotic material into the stent lumen and incomplete stent apposition in all patients. After 2 weeks, incomplete stent apposition was significantly reduced (% malapposed struts: post-PCI 4.7 ± 3.3%; 2W-OCT 0.9 ± 1.2%; P < 0.0001), and the percentage of uncovered struts also significantly decreased (% uncovered struts: post-PCI; 69.8 ± 18.3%: 2W-OCT; 29.6 ± 11.0%, P < 0.0001). The maximum protrusion area of the atherothrombotic burden was significantly reduced (post-PCI 1.36 ± 0.70 mm2; 2W-OCT 0.98 ± 0.55 mm2; P = 0.004).This study on the early vascular responses following BP-SES implantation showed rapid resolution of atherothrombotic material and progression of strut apposition and coverage. (UMIN000041324).

Early Vascular Healing Following Bioresorbable-Polymer Sirolimus-Eluting Stent Placement Compared to That with Durable-Polymer Everolimus-Eluting Stent.

A recent thinner strut drug-eluting stent might facilitate early strut coverage after its placement. We aimed to investigate early vascular healing responses after the placement of an ultrathin-strut bioresorbable-polymer sirolimus-eluting stent (BP-SES) compared to those with a durable-polymer everolimus-eluting stent (DP-EES) using optical coherence tomography (OCT) imaging.This study included 40 patients with chronic coronary syndrome (CCS) who underwent OCT-guided percutaneous coronary intervention (PCI). Twenty patients each received either BP-SES or DP-EES implantation. OCT was performed immediately after stent placement (baseline) and at 1-month follow-up.At one month, the percentage of uncovered struts reduced significantly in both the BP-SES (80.9 ± 10.3% to 2.9 ± 1.7%; P < 0.001) and DP-EES (81.9 ± 13.0% to 5.7 ± 1.8%; P < 0.001) groups, and the percentage was lower in the BP-SES group than in the DP-EES group (P < 0.001). In the BP-SES group, the percentage of malapposed struts also decreased significantly at 1 month (4.9 ± 3.7% to 2.6 ± 3.0%; P = 0.025), which was comparable to that of the DP-EES group (2.5 ± 2.2%; P = 0.860). The optimal cut-off value of the distance between the strut and vessel surface immediately after the placement to predict resolved malapposed struts was ≤ 160 µm for BP-SES and ≤ 190 µm for DP-EES.Compared to DP-EES, ultrathin-strut BP-SES demonstrated favorable vascular responses at one month, with a lower rate of uncovered struts and a comparable rate of malapposed struts.

Pristane/Hypoxia (PriHx) Mouse as a Novel Model of Pulmonary Hypertension Reflecting Inflammation and Fibrosis.

BACKGROUND: Pulmonary arterial hypertension (PAH), particularly connective tissue disease-associated PAH (CTD-PAH), is a progressive disease and novel therapeutic agents based on the specific molecular pathogenesis are desired. In the pathogenesis of CTD-PAH, inflammation, immune cell abnormality, and fibrosis play important roles. However, the existing mouse pulmonary hypertension (PH) models do not reflect these features enough. The relationship between inflammation and hypoxia is still unclear.Methods and Results:Intraperitoneal administration of pristane, a kind of mineral oil, and exposure to chronic hypoxia were combined, and this model is referred to as pristane/hypoxia (PriHx) mice. Hemodynamic and histological analyses showed that the PriHx mice showed a more severe phenotype of PH than pristane or hypoxia alone. Immunohistological and flow cytometric analyses revealed infiltration of immune cells, including hemosiderin-laden macrophages and activated CD4+helper T lymphocytes in the lungs of PriHx mice. Pristane administration exacerbated lung fibrosis and elevated the expression of fibrosis-related genes. Inflammation-related genes such asIl6andCxcl2were also upregulated in the lungs of PriHx mice, and interleukin (IL)-6 blockade by monoclonal anti-IL-6 receptor antibody MR16-1 ameliorated PH of PriHx mice. CONCLUSIONS: A PriHx model, a novel mouse model of PH reflecting the pathological features of CTD-PAH, was developed through a combination of pristane administration and exposure to chronic hypoxia.

Direct Targeting of the mTOR (Mammalian Target of Rapamycin) Kinase Improves Endothelial Permeability in Drug-Eluting Stents-Brief Report.

Objective- Drug-eluting stents eluting canonical mTOR (mammalian target of rapamycin) inhibitors are widely used to treat coronary artery disease but accelerate the development of atherosclerosis within the stent (neoatherosclerosis)-a leading cause of late stent failure. We recently showed that canonical mTOR inhibitors bind FKBP12.6 (12.6-kDa FK506-binding protein 12), displace it from calcium release channels, resulting in activation of PKCα (protein kinase Cα) and dissociation of p-120-catenin (p120) from VE-CAD (vascular endothelial cadherin; promoting endothelial barrier dysfunction [EBD]). However, the relevance of these findings to drug-eluting stents remains unknown. Newer generation direct mTOR kinase inhibitors do not bind FKBP12.6 and offer the potential of improving endothelial barrier function while maintaining antirestenotic efficacy, but their actual effects are unknown. We examined the effects of 2 different pharmacological targeting strategies-canonical mTOR inhibitor everolimus and mTOR kinase inhibitors Torin-2-on EBD after stenting. Approach and Results- Using the rabbit model of stenting and a combination of Evans blue dye, confocal and scanning electron microscopy studies, everolimus-eluting stents resulted in long-term EBD compared with bare metal stents. EBD was mitigated by using stents that eluted mTOR kinase inhibitors (Torin-2-eluting stent). At 60 days after stent placement, everolimus-eluting stents demonstrated large areas of Evans blue dye staining and evidence of p120 VE-CAD dissociation consistent with EBD. These findings were absent in bare metal stents and significantly attenuated in Torin-2-eluting stent. As proof of concept of the role of EBD in neoatherosclerosis, 100 days after stenting, animals were fed an enriched cholesterol diet for an additional 30 days. Everolimus-eluting stents demonstrated significantly more macrophage infiltration (consistent with neoatherosclerosis) compared with both bare metal stents and Torin-2-eluting stent. Conclusions- Our results pinpoint interactions between FKBP12.6 and canonical mTOR inhibitors as a major cause of vascular permeability and neoatherosclerosis, which can be overcome by using mTOR kinase inhibitors. Our study suggests further refinement of molecular targeting of the mTOR complex may be a promising strategy (Graphic Abstract).

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.

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

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

Biologic Drug Effect and Particulate Embolization of Drug-Eluting Stents versus Drug-Coated Balloons in Healthy Swine Femoropopliteal Arteries.

PURPOSE: To compare the drug effect in treated vessels and downstream effects in distal skeletal muscle of drug-coated balloons (DCBs) and drug-eluting stents (DESs) in a healthy preclinical swine model. MATERIALS AND METHODS: Four groups of treated iliofemoral arteries (percutaneous transluminal angioplasty [PTA]+DES, DCB+DES, DCB+bare metal stent [BMS], and DCB alone) of 12 healthy swine were assessed, with euthanasia at 30 days. Biological drug effect was evaluated using smooth muscle cell (SMC) loss score according to both depth and circumference as well as a neointimal fibrin and medial proteoglycan scores which were compared between the 4 groups. Vascular and skeletal muscle changes in regions downstream from the treated site were also assessed histologically for evidence of emboli. RESULTS: DESs showed greater medial SMC loss in the treated arteries irrespective of preceding DCB or PTA treatment in terms of depth (DCB+DES vs PTA+DES vs DCB+BMS vs DCB alone; median, 4.0 mm vs 3.8 mm vs 3.0 mm vs 2.2 mm; P = .009) and circumference (4.0 mm vs 3.5 mm vs 2.0 mm vs 1.2 mm, respectively; P = .007). Sections of skeletal muscles downstream from the treated arteries showed arteriolar changes of fibrinoid necrosis consistent with paclitaxel effect exclusively in the DCB groups (DCB+BMS, 26.9% of sections; DCB+DES, 14.3%; DCB alone, 19.2%; PTA+DES, 0%; P = .02). CONCLUSIONS: In the treated arteries, irrespective of preceding DCB treatment or PTA, DES treatment showed maximum drug effects vs DCB alone or in combination with BMS placement, and there was no detrimental toxic effect in DCB-treated iliofemoral arteries before DES treatment compared with PTA before DES treatment. Downstream vascular changes were exclusively seen in groups treated with DCBs.

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

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

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.

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.

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.

Kisspeptin-10 induces endothelial cellular senescence and impaired endothelial cell growth.

The KPs (kisspeptins) are a family of multifunctional peptides with established roles in cancer metastasis, puberty and vasoconstriction. The effects of KPs on endothelial cells have yet to be determined. The aim of the present study was to investigate the effects of KP-10 on endothelial cell growth and the mechanisms underlying those effects. The administration of recombinant KP-10 into the hindlimbs of rats with ischaemia significantly impaired blood flow recovery, as shown by laser Doppler, and capillary growth, as shown using histology, compared with the controls. HUVECs (human umbilical vein endothelial cells) express the KP receptor and were treated with KP-10 in culture studies. KP-10 inhibited endothelial cell tube formation and proliferation in a significant and dose-dependent manner. The HUVECs treated with KP exhibited the senescent phenotype, as determined using a senescence-associated ß-galactosidase assay, cell morphology analysis, and decreased Sirt1 (sirtuin 1) expression and increased p53 expression shown by Western blot analysis. Intriguingly, a pharmacological Rho kinase inhibitor, Y-27632, was found to increase the proliferation of HUVECs and to reduce the number of senescent phenotype cells affected by KP-10. In conclusion, KP-10 suppressed endothelial cells growth both in vivo and in vitro in the present study. The adverse effect of KP on endothelial cells was attributable, at least in part, to the induction of cellular senescence.

Mechanisms of Very Late Stent Thrombosis in Japanese Patients as Assessed by Optical Coherence Tomography.

BACKGROUND: Although very late stent thrombosis (VLST) remains an important concern, the underlying etiology and clinical characteristics are not fully elucidated in Japanese patients who undergo intravascular imaging-guided percutaneous coronary intervention (PCI) regularly. METHODS: We identified 50 VLST lesions (bare-metal stent [BMS] [n = 16], first-generation drug-eluting stent [DES] [n = 14] and newer-generation DES [n = 20]) in patients managed in our institutes. The underlying mechanism of VLST was assessed by optical coherence tomography (OCT), and the major etiology of each lesion was determined. The aim of this study was to explore the mechanisms of VLST of BMSs and DESs in Japanese patients. RESULTS: The median duration since stent implantation was 10 years (range: 1-20). The most frequent etiology of VLST was neoatherosclerotic rupture (44%), followed by neointimal erosion (24%). Edge disease (10%) and evagination (10%) were similarly observed. Malapposition (8%) was deemed to be acquired late by looking at intravascular imaging from the index procedure. Uncovered struts (2%) and in-stent calcified nodule (2%) were the least frequent etiologies. Regardless of etiology, signs of neoatherosclerosis were present in most lesions (82%). Most patients received single (68%) or dual (8%) antiplatelet therapy or oral anticoagulation alone (4%), whereas a considerable proportion of patients discontinued medication (20%). Regarding the treatment strategy, drug-coated balloon was the most frequent strategy (56%), followed by implantation of newer DESs (34%). CONCLUSIONS: Various mechanisms have been identified in Japanese patients with VLST. In these patients, biological responses seemed to be more relevant than the index procedure-related factors.