Coronary Responses and Differential Mechanisms of Late Stent Thrombosis Attributed to First-Generation Sirolimus- and Paclitaxel-Eluting Stents

ObjectivesThe purpose of this study was to assess the mechanism(s) of late stent thrombosis (LST) and vascular healing responses in first-generation polymeric drug-eluting stents (DES).BackgroundRecent clinical trials have reported variations in late lumen loss between first-generation sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES). Little is known, however, about the vascular responses, time course of healing, and underlying mechanism(s) of complications of LST between platforms in human coronary implants.MethodsThe overall analysis included 174 cases (230 DES lesions) from the CVPath Institute's stent registry. Histomorphometry was performed on coronary stents from 127 patients (171 lesions) who died ≥30 days after receiving stent implants in which fibrin deposition, endothelial strut coverage, inflammatory response, and mechanism(s) of in-stent thrombosis were assessed.ResultsBoth platforms demonstrated increased neointimal thickness over time where values were greater in PES (mean 0.13 mm; range 0.03 to 0.20 mm) than SES (mean 0.10 mm; range 0.04 to 0.15 mm; p = 0.04). The percentage of uncovered struts was similar between SES and PES including stents with LST (SES = 21% vs. PES = 27%; p = 0.47). The underlying mechanism(s) of LST, however, was strikingly different between platforms; localized strut hypersensitivity was exclusive to SES, whereas malapposition secondary to excessive fibrin deposition was the underlying cause in PES. Moreover, although both PES and SES showed nearly complete strut coverage after 12 months for on-label use, the majority of stents placed for off-label indications remained unhealed after 12 months in both types of DES.ConclusionsDifferential mechanisms of LST involving either hypersensitivity or excessive fibrin were identified between first-generation DES in which overall stent healing was further delayed in DES placed for off-label indications

Incidence and Predictors of Drug-Eluting Stent Fracture in Human Coronary Artery A Pathologic Analysis

ObjectivesThe aim of this study was to perform pathologic assessment on stent fracture.BackgroundClinically, stent fracture has been reported in 1% to 2% of patients after drug-eluting stent (DES) implantation.MethodsHigh-contrast film-based radiographs of 177 consecutive lesions from the CVPath DES autopsy registry were reviewed. Stent fracture was graded as I (single-strut fracture), II (≥2 struts), III (≥2 struts with deformation), IV (with transection without gap), and V (with transection causing gap in stent segment). The incidence of adverse pathologic findings (thrombosis and restenosis) was assessed histologically.ResultsStent fracture was documented in 51 lesions (29%; grade I = 10, II = 14, III = 12, IV = 6, and V = 9). Lesions with stent fracture had longer duration after implantation (172 days [interquartile range (IQR) 31 to 630 days] vs. 44 days [IQR 7 to 270 days], p = 0.004), a higher rate of Cypher (Cordis Corp., Miami Lakes, Florida) stent usage (63% vs. 36%, p = 0.001), longer stent length (30.0 mm [IQR 22.0 to 40.0 mm] vs. 20.0 mm [IQR 14.0 to 27.3 mm], p < 0.0001), and a higher rate of overlapping stents (45% vs. 22%, p = 0.003). Although fracture with grade I to IV did not have significant impact on the occurrence of adverse pathologic findings such as thrombosis and restenosis, 67% of the grade V fracture lesions were associated with adverse pathologic findings at fracture sites. Longer stent length, use of Cypher, and longer duration of implant were identified as independent risk factors of stent fracture by logistic regression analysis.ConclusionsThe incidence of stent fracture was 29% lesions at autopsy, which is much higher than clinically reported. A high rate of adverse pathologic findings was observed in lesions with grade V stent fracture, whereas fracture with grade I to IV did not have a significant impact on the pathological outcome

The Pathology of Neoatherosclerosis in Human Coronary Implants Bare-Metal and Drug-Eluting Stents

ObjectivesHuman 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.BackgroundNeointimal 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.MethodsAll 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.ResultsThe 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).ConclusionsNeoatherosclerosis 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

Methodological Standardization for the Pre-Clinical Evaluation of Renal Sympathetic Denervation

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

Acute Thrombogenicity of a Durable Polymer Everolimus-Eluting Stent Relative to Contemporary Drug-Eluting Stents With Biodegradable Polymer Coatings Assessed Ex Vivo in a Swine Shunt Model

AbstractObjectivesThis study sought to evaluate whether the permanent fluoropolymer-coated Xience Xpedition everolimus-eluting stent (Xience-EES) exhibits lower acute thrombogenicity compared with contemporary drug-eluting stents (DES) with biodegradable polymer coatings in an acute swine shunt model.BackgroundPrevious pre-clinical and clinical experience suggests that several factors may influence the predisposition for acute thrombus formation of polymer-coated DES, including stent design and the polymer coating technology. It remains unclear whether relevant differences exist with respect to acute thrombogenicity, particularly between current commercial stent designs using permanent polymers and those using biodegradable polymers.MethodsAn ex vivo carotid to jugular arteriovenous porcine shunt model involving a test circuit of 3 in-line stents, was used to test acute thrombogenicity, where Xience-EES (n = 24) was compared with 4 CE-marked DES with biodegradable polymer coatings (BioMatrix Flex, Synergy, Nobori, and Orsiro [n = 6 each]). After 1 h of circulation, platelet aggregation in whole mount stents was evaluated by confocal microscopy with immunofluorescent staining against dual platelet markers (CD61/CD42b) along with scanning electron microscopy.ResultsXience-EES showed the least percentage of thrombus-occupied area as compared with the biodegradable polymer-coated DES, with a significant difference compared with BioMatrix Flex and Synergy (mean differences: [BioMatrix Flex: 15.54, 95% confidence interval [CI]: 11.34 to 19.75, p < 0.001; Synergy: 8.64, 95% CI: 4.43 to 12.84, p < 0.001; Nobori: 4.22, 95% CI: -0.06 to 8.49, p = 0.055; Orsiro: 2.95, 95% CI: -1.26 to 7.15, p = 0.286). The number of cell nuclei on strut surfaces was also the least in Xience-EES, with a significant difference relative to BioMatrix Flex, Nobori, and Orsiro (mean ratios: BioMatrix Flex: 4.73, 95% CI: 2.46 to 9.08, p < 0.001; Synergy: 1.44, 95% CI: 0.75 to 2.76, p = 0.51; Nobori: 5.97, 95% CI: 3.11 to 11.44, p < 0.001; Orsiro: 5.16, 95% CI: 2.69 to 9.91, p < 0.001).ConclusionsXience-EES’s overall design confers acute thromboresistance relative to contemporary DES with biodegradable coatings, with less platelet aggregation versus BioMatrix Flex and Synergy, and less inflammatory cell attachment versus BioMatrix Flex, Nobori, and Orsiro, in an ex vivo swine shunt model, which lends support to reported clinical findings of lower early stent thrombosis

Dual molecular imaging for targeting metalloproteinase activity and apoptosis in atherosclerosis: molecular imaging facilitates understanding of pathogenesis

Macrophage apoptosis and MMP activity contribute to vulnerability of atherosclerotic plaques to rupture. By employing molecular imaging techniques, we investigated if apoptosis and MMP release are interlinked. Atherosclerosis was produced in rabbits receiving high-cholesterol diet (HC), who underwent dual radionuclide imaging with 99mTc-labeled matrix metalloproteinase inhibitor (MPI) and 111In-labeled annexin A5 (AA5) using micro-SPECT/CT. %ID/g MPI and AA5 uptake was measured, followed by histological characterization. Unmanipulated animals were used as disease controls. Correlation between MPI and AA5 uptake was undertaken and relationship confirmed in culture study of activated THP-1 monocytes. MPI and AA5 uptake was best visualized in HC diet animals (n = 6) and reduced significantly after fluvastatin treatment (n = 4) or diet withdrawal (n = 3). %ID/g MPI (.087 ± .018%) and AA5 (.03 ± .01%) uptake was higher in HC than control (n = 6) animals (.014 ± .004%, P &lt; .0001; .0007 ± .0002%, P &lt; .0001), and reduced substantially after diet or statin intervention. There was a significant correlation between MPI and AA5 uptake (r = .62, P &lt; .0001), both correlated with pathologically verified MMP-9 activity, macrophage content, and TUNEL staining. In vitro studies demonstrated MMP-9 release in culture medium from apoptotic THP-1 monocytes. The present study suggests that apoptosis and MMP are interrelated in atherosclerotic lesions and the targeting of more than one molecular candidate is feasible by molecular imaging

Vulnerable Plaque in Patients with Acute Coronary Syndrome: Identification, Importance, and Management

MI is a leading cause of morbidity and mortality worldwide. Coronary artery thrombosis is the final pathologic feature of the most cases of acute MI primarily caused by atherosclerotic coronary artery disease. The concept of vulnerable plaque has evolved over the years but originated from early pioneering work unveiling the crucial role of plaque rupture and subsequent coronary thrombosis as the dominant cause of MI. Along with systemic cardiovascular risk factors, developments of intravascular and non-invasive imaging modalities have allowed us to identify coronary plaques thought to be at high risk for rupture. However, morphological features alone may only be one of many factors which promote plaque progression. The current vulnerable-plaque-oriented approaches to accomplish personalized risk assessment and treatment have significant room for improvement. In this review, the authors discuss recent advances in the understanding of vulnerable plaque and its management strategy from pathology and clinical perspectives

Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006)

Crosstalk between reactive oxygen species and pro-inflammatory markers in developing various chronic diseases: a review

The inflammation process in the human body plays a central role in the pathogenesis of many chronic diseases. In addition, reactive oxygen species (ROS) exert potentially a decisive role in human body, particularly in physiological and pathological process. The chronic inflammation state could generate several types of diseases such as cancer, atherosclerosis, diabetes mellitus and arthritis, especially if it is concomitant with high levels of pro-inflammatory markers and ROS. The respiratory burst of inflammatory cells during inflammation increases the production and accumulation of ROS. However, ROS regulate various types of kinases and transcription factors such nuclear factor-kappa B which is related to the activation of pro-inflammatory genes. The exact crosstalk between pro-inflammatory markers and ROS in terms of pathogenesis and development of serious diseases is still ambitious. Many studies have been attempting to determine the mechanistic mutual relationship between ROS and pro-inflammatory markers. Therefore hereby, we review the hypothetical relationship between ROS and pro-inflammatory markers in which they have been proposed to initiate cancer, atherosclerosis, diabetes mellitus and arthritis