Inhibition of P110α and P110δ catalytic subunits of PI3 kinase reverses impaired arterial healing after injury in hypercholesterolemic male mice.

Endothelial cell (EC) migration is critical for healing arterial injuries, such as those that occur with angioplasty. Impaired re-endothelialization following arterial injury contributes to vessel thrombogenicity, intimal hyperplasia, and restenosis. Oxidized lipid products, including lysophosphatidylcholine (lysoPC), induce canonical transient receptor potential 6 (TRPC6) externalization leading to increased [Ca2+]i, activation of calpains, and alterations of the EC cytoskeletal structure that inhibit migration. The p110α and p110δ catalytic subunit isoforms of phosphatidylinositol 3-kinase (PI3K) regulate lysoPC-induced TRPC6 externalization in vitro. The goal of this study was to assess the in vivo relevance of those in vitro findings to arterial healing following a denuding injury in hypercholesterolemic mice treated with pharmacologic inhibitors of the p110α and p110δ isoforms of PI3K and a general PI3K inhibitor. Pharmacologic inhibition of the p110α or the p110δ isoform of PI3K partially preserves healing in hypercholesterolemic male mice, similar to a general PI3K inhibitor. Interestingly, the p110α, p110δ, and the general PI3K inhibitor do not improve arterial healing after injury in hypercholesterolemic female mice. These results indicate a potential new role for isoform-specific PI3K inhibitors in male patients following arterial injury/intervention. The results also identify significant sex differences in the response to PI3K inhibition in the cardiovascular system, where female sex generally has a cardioprotective effect. This study provides a foundation to investigate the mechanism for the sex differences in response to PI3K inhibition to develop a more generally applicable treatment option.

Comparison of neointimal coverage between durable-polymer everolimus-eluting stents and bioresorbable-polymer everolimus-eluting stents 1 year after implantation using high-resolution coronary angioscopy.

OBJECTIVES: We aimed to compare the coronary angioscopic appearance of neointimal coverage (NIC) over durable-polymer everolimus-eluting stents (XIENCE-EES) and bioresorbable-polymer everolimus-eluting stents (SYNERGY-EES) 1 year after implantation. BACKGROUND: XIENCE-EES and SYNERGY-EES have been developed to prevent delayed arterial healing associated with first generation drug-eluting stents. However, the process of arterial healing after XIENCE-EES and SYNERGY-EES implantation has not been clarified. METHODS: Patients who underwent implantation of XIENCE-EES (n = 20) or SYNERGY-EES (n = 20) were enrolled in this study. Coronary angiography and coronary angioscopy were performed 12 ± 1 months after stent implantation. The NIC over the stent was classified into four grades: grade 0, stent struts fully exposed; grade 1, stent struts bulging into the lumen and, still visible; grade 2, stent struts embedded in neointima but still visible; and grade 3, stent struts fully embedded and invisible. Stents exhibiting more than one NIC grade was defined as heterogeneous. Moreover, presence of thrombi was investigated. RESULTS: The distribution of dominant NIC grade (XIENCE-EES: grade 0, 0%; grade 1, 25%; grade 2, 50%; grade 3, 25%; SYNERGY-EES: grade 0, 0%; grade 1, 5%; grade 2, 15%; grade 3, 80%; P = 0.002) and NIC heterogeneity was significantly different (P = 0.004). Thrombi were more frequent in XIENCE-EES than in SYNERGY-EES (40 versus 10%, respectively; P = 0.03). CONCLUSION: Compared with XIENCE-EES, SYNERGY-EES were well covered by neointima and accompanied by fewer thrombi. These findings implied arterial healing of SYNERGY-EES was better than that of XIENCE-EES.

Early- and Middle-Phase Angioscopic Assessment of Arterial Healing Following Current Drug-Eluting Stent Implantation in Patients With Acute Coronary Syndrome.

Background: Drug-eluting stents (DESs) have been widely used for the treatment of acute coronary syndrome (ACS). However, there are few reports on early- and middle-phase arterial repair after DES implantation in ACS patients. Methods and Results: Coronary angioscopy (CAS) findings covering the early and middle phases (mean [±SD] 4±1 and 10±2 months, respectively) of arterial healing after second- and later-generation DES placement between May 2009 and January 2020 were extracted from the Kansai Rosai Hospital Cardiovascular Center database. Neointimal coverage (NIC), yellow color intensity, and the incidence of thrombus adhesion were compared between ACS and chronic coronary syndrome (CCS) in the early (54 stents of 47 lesions, 38 ACS patients; 86 stents of 70 lesions, 52 CCS patients) and middle (179 stents of 154 lesions from 136 ACS patients; 459 stents of 374 lesions from 287 CCS patients) phases. In the early phase, NIC, the incidence of thrombus adhesion (ACS, 39.1%; CCS, 38.0%), and maximum yellow color grade were similar between the 2 groups. In the middle phase, although the maximum yellow color grade was significantly higher in the ACS group (P=0.013), NIC and the incidence of thrombus adhesion (ACS, 24.6%; CCS, 23.4%) were similar in the 2 groups. Conclusions: Arterial healing assessment with CAS showed that NIC and the incidence of thrombus adhesion after DES implantation were similar between ACS and CCS patients.

Angioscopic assessments and clinical outcomes one year after polymer-free biolimus A9-coated coronary stent implantation.

BACKGROUND: Polymer-free biolimus A9-coated coronary stent (DCS) has novel features which lead to the expectation of better arterial healing. However, comparisons of intravascular status between DCS and drug-eluting stents (DES), and robust real-word clinical assessments of DCS have been lacking to date. METHODS: From September 2017 to September 2018, we evaluated the intra-vascular status of 74 DCS implanted in 55 lesions from 43 patients using coronary angioscopy (CAS) approximately one year after implantation from a cohort of 219 lesions in 158 patients. We set 239 second-generation durable-polymer DES (DP-DES) implanted in 211 lesions from 180 patients from a cohort of 2652 lesions in 1914 patients as the control. Angioscopic images were analyzed to determine (1) the dominant degree of neointimal coverage (NIC) over the stent; (2) the heterogeneity of NIC; (3) yellow color grade of the stented segment; and (4) the presence of intra-stent thrombus. The primary outcome was the incidence of thrombus and secondary outcomes were the other CAS findings, and the 1-year clinical outcomes which included target lesion revascularization (TLR) and major adverse cardiac events (MACE). To minimize inter-group differences in baseline characteristics, propensity score matching was performed for clinical outcomes. RESULTS: Incidence of thrombus adhesion was similar in DCS and DP-DES groups (28.4% versus 22.6%, p=0.31). However, the dominant NIC grade was significantly higher in DCS (p<0.001), while NIC was more heterogeneous in DCS than in DP-DES (p=0.001). Maximum yellow color grade was similar (p=0.22). After propensity score matching, 202 lesion pairs from 146 patient pairs were retained for analysis. The cumulative incidence of TLR (4.6% versus 3.8%, p=0.38) and MACE (11.6% versus 11.7%, p=0.84) was similar for DCS and DP-DES. CONCLUSIONS: DCS showed thrombus adhesion and clinical outcomes at 1 year similar to DP-DES. DCS can thus be used with similar safety and efficacy as DP-DES.

Impact of different coronary angioscopic findings on arterial healing one year after bioresorbable-polymer and second-generation durable-polymer drug-eluting stent implantation.

BACKGROUND: The advantage of using bioresorbable-polymer drug-eluting stent (BP-DES) compared with second-generation durable-polymer drug-eluting stent (2G DP-DES) still remains controversial in clinical situations. The purpose of this study to evaluate the degree of re-endothelialization and the prevalence of high-grade yellow-colored plaque (YCP), which might concern arterial healing after BP-DES and 2G DP-DES implantation using a high-resolution coronary angioscopy (CAS). METHODS: In total, 104 DESs (52: 2G DP-DES and 52: BP-DES) were prospectively observed using CAS 12±1 months after coronary intervention. The grade of neointimal coverage (NIC) over the stent was scored on a 4-point scale from 0 (no coverage) to 3 (complete coverage). YCP grade was also scored on a 4-point scale as 0 (white) to 3 (intensive yellow). High-grade YCP was defined as maximum grade ≥2. Moreover, the prevalence of high-grade YCP and the incidence of thrombus were investigated. RESULTS: BP-DES revealed better dominant NIC grade and less NIC heterogeneity than 2G DP-DES (p=0.0001 and p=0.015, respectively). The prevalence of high-grade YCP was lower for BP-DES than for 2G DP-DES (p=0.05). However, the incidence of thrombus was not significantly different (p=0.41). Multivariate analysis identified that low-density lipoprotein cholesterol levels [odds ratio (OR), 1.03; 95% Confidence Interval (CI): 1.01-1.06, p=0.01] and the usage of BP-DES [OR, 0.36; 95% CI: 0.14-0.91, p=0.03] as independent predictors of high-grade YCP. CONCLUSIONS: Compared with 2G DP-DES, BP-DES was less heterogeneous and well-covered NIC and less prevalence of the high-grade YCP implying optimal arterial healing.

Optical coherence tomography study of chronic-phase vessel healing after implantation of bare metal and paclitaxel-eluting self-expanding nitinol stents in the superficial femoral artery.

BACKGROUND: This study aimed to assess chronic-phase suppression of neointimal proliferation and arterial healing following paclitaxel-coated (PTX) and bare metal stent (BMS) implantation in the superficial femoral artery using optical coherence tomography (OCT). METHODS: Twenty-five patients with 68 stents underwent an 8-month OCT follow-up. Besides standard OCT variables, neointimal characterization and frequencies of peri-strut low-intensity area (PLIA), macrophage accumulation, and in-stent thrombi were evaluated. RESULTS: The mean neointimal thickness was significantly less with PTX stents (544.9±202.2 µm vs. 865.0±230.6 µm, p<0.0001). The covered and uncovered strut frequencies were significantly smaller and larger, respectively, in the PTX stent group vs. the BMS group (93.7% vs. 99.4%; p<0.0001, 4.0% vs. 0.4%; p<0.0001, respectively). Heterogeneous neointima was only observed in the PTX stent group (12.5% vs. 0%, p=0.017). The frequencies of PLIA and macrophage accumulation were significantly greater in the PTX stent group (87.2% vs. 67.6%, p=0.001 and 46% vs. 9.1%, p=0.003, respectively). CONCLUSION: After 8 months, reduced neointimal proliferation was observed with PTX stent implantation. On the other hand, delayed arterial healing was observed compared with BMS.

Apolipoprotein A-I mimetic peptide reverses impaired arterial healing after injury by reducing oxidative stress.

OBJECTIVE: Endothelial cell (EC) migration is essential for healing of arterial injuries caused by angioplasty, but a high cholesterol diet inhibits endothelial repair. In vivo studies suggest that apolipoprotein A-I (apoA-I), the major protein constituent of HDL, is essential for normal healing of arterial injuries. ApoA-I mimetics, including 4F, have been designed to mimic the amphipathic portion of the apoA-I molecule. This study was undertaken to determine if 4F improves endothelial migration and healing. METHODS: A razor scrape assay was used to analyze the effect of 4F on EC migration in vitro. Endothelial healing in vivo was assessed following electrical injury of carotid arteries in mice. Markers of oxidative stress were also examined. RESULTS: Lipid oxidation products inhibited EC migration in vitro, but preincubation with L-4F preserved EC migration. Endothelial healing of carotid arterial injuries in mice on a high cholesterol diet was delayed compared with mice on a chow diet with 27.8% vs. 48.2% healing, respectively, at 5 days. Administration of D-4F improved endothelial healing in mice on a high cholesterol diet to 43.4%. D-4F administration had no effect on lipid levels but decreased markers of oxidation. In vivo, there was a significant inverse correlation between endothelial healing and plasma markers of oxidative stress. CONCLUSION: These studies suggested that an apoA-I mimetic can improve endothelial healing of arterial injuries by decreasing oxidative stress.

Differential healing response attributed to culprit lesions of patients with acute coronary syndromes and stable coronary artery after implantation of drug-eluting stents: an optical coherence tomography study.

BACKGROUND: Pathology studies have shown delayed arterial healing in culprit lesions of patients with acute coronary syndrome (ACS) compared with stable coronary artery disease (CAD) after placement of drug-eluting stents (DES). It is unknown whether similar differences exist in-vivo during long-term follow-up. Using optical coherence tomography (OCT), we assessed differences in arterial healing between patients with ACS and stable CAD five years after DES implantation. METHODS AND RESULTS: A total of 88 patients comprised of 53 ACS lesions with 7864 struts and 35 stable lesions with 5298 struts were suitable for final OCT analysis five years after DES implantation. The analytical approach was based on a hierarchical Bayesian random-effects model. OCT endpoints were strut coverage, malapposition, protrusion, evaginations and cluster formation. Uncovered (1.7% vs. 0.7%, adjusted p=0.041) or protruding struts (0.50% vs. 0.13%, adjusted p=0.038) were more frequent among ACS compared with stable CAD lesions. A similar trend was observed for malapposed struts (1.33% vs. 0.45%, adj. p=0.072). Clusters of uncovered or malapposed/protruding struts were present in 34.0% of ACS and 14.1% of stable patients (adj. p=0.041). Coronary evaginations were more frequent in patients with ST-elevation myocardial infarction compared with stable CAD patients (0.16 vs. 0.13 per cross section, p=0.027). CONCLUSION: Uncovered, malapposed, and protruding stent struts as well as clusters of delayed healing may be more frequent in culprit lesions of ACS compared with stable CAD patients late after DES implantation. Our observational findings suggest a differential healing response attributable to lesion characteristics of patients with ACS compared with stable CAD in-vivo.