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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.

Background/Introduction Although second-generation drug eluting stent (DES) employing biodurable polymer drastically shortened the duration of dual antiplatelet therapy (DAPT), previous reports raised concerns that switching from DAPT to single antiplatelet therapy increased rates of subsequent stent thrombosis with time. Third-generation DES employing bioabsorbable polymer has been introduced so as not to hinder the healing process of the vessel wall, however, at present, both DES with bioabsorbable polymer and those with biodurable polymer are used in parallel. It means there is no conclusive evidence regarding pros and cons of these two types of polymers. Purpose This study aims to clarify how bioabsorbable polymer and biodurable polymer act on the human coronary artery by observing neointimal stent coverage (NIC) and in-stent thrombus by comparing the third-generation DES with bioabsorbable-polymer cobalt-platinum everolimus-eluting stent (BP CoPt-EES), and the second-generation DES with biodurable-polymer cobalt-chromium everolimus-eluting stent (DP CoCr-EES). Methods This is a multicenter observational study including 11 hospitals. We investigated 70 stents (BP CoPt-EES: 40, DP CoCr-EES: 30) of 60 cases, who underwent stent implantation followed by simultaneous observation by coronary angiography, IVUS and angioscopy within 6 to 12 months. For angioscopy, we used a recently available, high-resolution angioscope with a pixel count of 9,000 which realized both stent coverage analysis and planar thrombus detection precisely. Neointimal stent coverage was graded from G0: non coverage to G3: full coverage, and heterogeneity value of neointima was measured as the difference between maximum and minimum NIC grade. Results A strong relationship was observed between NIC grade and in-stent thrombus in all stents (p=0.0011), and between the heterogeneity value and stent thrombus (p=0.012). There was no statistical difference in NIC grade between BP CoPt-EES vs. DP CoCr-EES; grade 0: 0 (0.0%) vs. 2 (6.7%), grade 1: 13 (32.5%) vs. 11 (36.7%), grade 2: 6 (15.0%) vs. 6 (20.0%), grade 3: 21 (52.5%) vs. 11 (36.7%), p=0.17) and neither in the heterogeneity value of neointima (p=0.49). The ratio of stent thrombus did not reach statistical difference; 16 (40.0%) in BP CoPt-EES vs. 17 (56.7%) in DP CoCr-EES (p=0.23). Conclusion The existence of stent thrombus was associated with the neointimal stent coverage. There was no significant difference both in neointimal stent coverage and stent thrombus between bioabsorbable polymer cobalt-platinum EES and biodurable polymer cobalt-chromium EES after 6 to 12 months following stent deployment. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boston Scientific JapanOvalis ltd

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.

A 47-year-old female patient was admitted with a complaint of severe chest pain on effort. She had a history of effort angina treated using coronary artery bypass with left internal thoracic arterial bypass to the left ascending coronary artery. She also had left subclavian and vertebral arterial stenoses, which were treated with balloon-expandable stents. Exercise stress myocardial perfusion imaging revealed anterior to apex left ventricular myocardial ischemia. Cardiac ischemia due to left subclavian stenosis was diagnosed. We treated the left subclavian arterial stenosis with endovascular therapy. We observed that the vertebral Palmaz stent protruded from the ostium and the jailed subclavian artery on high-resolution angioscopy (Zemporshe with a 0.48-megapixel equivalent resolution; Taisho Biomed Instruments, Osaka, Japan) and optical frequency domain imaging (OFDI). A guide wire was successfully crossed through the Palmaz stent strut, which was confirmed using three-dimensional OFDI. The stent strut was dilated using balloon angioplasty. New imaging technologies are promising tools for improving the efficacy and safety of craniocervical intervention.

It is unclear whether arterial healing occurs beyond 1 year following paclitaxel-coated stent implantation in peripheral artery disease. An 81-year-old woman with superficial femoral artery disease underwent endovascular therapy with a paclitaxel-coated stent. An angiography 21 months later revealed peri-stent contrast staining in the superficial femoral artery, and optical frequency domain imaging demonstrated incomplete stent apposition with significant positive vascular remodeling. High-resolution angioscopy detected positive vascular wall remodeling and in-stent yellow plaque more clearly than conventional angioscopy. Refractory superficial femoral arterial wall healing was apparent more than 20 months after paclitaxel-coated stent implantation.

Aims Snaring has recently been reported as being effective in catching the retrograde guidewire (GW) in retrograde percutaneous coronary intervention (PCI) for chronic total occlusion. However, commercially available snares and previously reported homemade snares have a number of drawbacks, such as additional cost, limited size adjustability, risk of vessel injury and difficult handling. We report here a novel method to create easily an inexpensive, safe and size-adjustable snare. Methods and results Our newly developed homemade snare consists of a conventional 0.014" GW, a PCI balloon, and a guiding catheter (GC). In most cases, no extra cost is needed. As the snare is created by the soft wire tip, vascular injury is negligible. To adjust the size of the snare loop, the snare wire is simply pulled backwards and pushed forwards. Using this snare technique, we succeeded in the total revascularisation of a CTO in the left main trunk with a retrograde approach. Conclusions We report a novel method to create easily an inexpensive, safe and size-adjustable snare, and demonstrate its use in a retrograde CTO intervention. In some cases where a conventional snare is indicated, such as removal of intravascular iatrogenic foreign bodies, this novel homemade snare would be preferable because of its advantages.

Background Lipoprotein (a) (Lp(a)) is one of the risk factors for peripheral artery disease (PAD). Our previous report demonstrated that hepatocyte growth factor (HGF) gene therapy attenuated the impairment of collateral formation in Lp(a) transgenic mice. Since risk factors for atherosclerosis accelerate endothelial senescence and impair angiogenesis, we examined the role of Lp(a) in dysfunction and senescence of endothelial progenitor cells (EPC) and endothelial cells. Methods In vitro and in vivo incorporation assays were performed using ex-vivo expanded DiI-labeled human EPC. Senescence of cultured endothelial cells, production of oxidative stress and angiogenesis function were evaluated by SA-β-galactosidase staining, dihydroethidium (DHE) staining and Matrigel assay, respectively. Results EPC transplantation significantly stimulated recovery of ischemic limb perfusion, while EPC pre-treated with Lp(a) did not increase ischemic limb perfusion. Impairment of angiogenesis by EPC with Lp(a) was associated with a significant decrease in CD31-positive capillaries and DiI-labeled EPC. Importantly, Lp(a) significantly accelerated the onset of senescence and production of reactive oxygen species (ROS) in human aortic endothelial cells, accompanied by a significant increase in the protein expression of p53 and p21. On the other hand, HGF significantly attenuated EPC dysfunction, senescence, ROS production, and p53 and p21 expression induced by Lp(a). Conclusion Lp(a) might affect atherosclerosis via acceleration of senescence, ROS production, and functional impairment of the endothelial cell lineage. HGF might have inhibitory effects on these atherogenic actions of Lp(a).

Serotonin (5-hydroxytryptamine, 5-HT) plays a crucial role in peripheral artery disease (PAD) and diabetes mellitus (DM). In these conditions, the balance between the 5-HT2A receptor in smooth muscle cells and the 5-HT1B receptor in endothelial cells (ECs) regulates vascular tonus. In the present study, we focused on the role of 5-HT in endothelial dysfunction using a selective 5-HT2A receptor blocker, sarpogrelate. In human EC, 5-HT markedly stimulated eNOS expression and the phosphorylation of eNOS, Akt and ERK1/2. In addition, a dose-dependent increase in tubule-formation on Matrigel was observed after 5-HT treatment. In contrast, high glucose significantly inhibited tubule formation and eNOS expression through inactivation of Akt, while 5-HT significantly attenuated these actions of high glucose (P0.01). These results indicate that 5-HT stimulated angiogenesis through activation of Akt in ECs. However, in clinical situations, 5-HT seems to act as the "devil". To examine the role of 5-HT in diabetic PAD, a hindlimb ischemia model was created in diabetic mice. The blood flow ratio of the ischemic to non-ischemic limb was significantly lower in DM mice than in normal mice, while sarpogrelate significantly attenuated the decrease in the blood flow ratio compared to control (P0.01). Consistently, the decrease in eNOS expression and Akt activity in DM mice was significantly attenuated by sarpogrelate. Overall, the present study demonstrated that selective inhibition of 5-HT2A by sarpogrelate significantly restored ischemic limb blood perfusion in a severe diabetic mouse model through stimulation of the eNOS/Akt pathway via the endothelial 5-HT1B receptor. Enhancement of vasodilation and angiogenesis by sarpogrelate might provide a unique treatment for PAD and DM patients.

We previously reported that overexpression of full-length periostin, Pn-1, resulted in ventricular dilation with enhanced interstitial collagen deposition in a rat model. However, other reports have documented that the short-form splice variants Pn-2 (lacking exon 17) and Pn-4 (lacking exons 17 and 21) promoted cardiac repair by angiogenesis and prevented cardiac rupture after acute myocardial infarction. The apparently differing findings from those reports prompted us to use a neutralizing antibody to selectively inhibit Pn-1 by blockade of exon 17 in a rat acute myocardial infarction model. Administration of Pn neutralizing antibody resulted in a significant decrease in the infarcted and fibrotic areas of the myocardium, which prevented ventricular wall thinning and dilatation. The inhibition of fibrosis by Pn neutralizing antibody was associated with a significant decrease in gene expression of fibrotic markers, including collagen I, collagen III, and transforming growth factor-β1. Importantly, the number of α-smooth muscle actin–positive myofibroblasts was significantly reduced in the hearts of animals treated with Pn neutralizing antibody, whereas cardiomyocyte proliferation and angiogenesis were comparable in the IgG and neutralizing antibody groups. Moreover, the level of Pn-1 expression was significantly correlated with the severity of myocardial infarction. In addition, Pn-1, but not Pn-2 or Pn-4, inhibited fibroblast and myocyte attachment, which might account for the cell slippage observed during cardiac remodeling. Collectively, these results indicate that therapeutics that specifically inhibit Pn exon-17, via a neutralizing antibody or drug, without suppressing other perisotin variants might offer a new class of medication for the treatment of acute myocardial infarction patients.

Background: Periostin (PN) is a matricellular protein that is induced by mechanostress and regulates organ remodeling. We previously documented that over-expression of full-length periostin (periostin1:Pn1) resulted in ventricular dilation with enhanced interstitial collagen deposition. Controversially, supplement of PN splicing variant lacking exon 17 (periostin2:Pn2) was reported to accelerate cardiac repair with the induction of cardiomyocyte proliferation and angiogenesis. The aim of this study was to investigate the different roles of PN splicing isoforms in cardiac remodeling. Methods: Coronary ligation was employed to induce cardiac remodeling in rat. A neutralizing antibody against exon17 (Pn1Ab) was injected intravenously every 6 days until day 21. Mice were followed ultrasonographically and then euthanized for histological analysis at day 56. In vitro study, the effect of each PN splicing isoform was assessed in rat cardiac fibroblast and HUVEC. Results: Administration of Pn1Ab resulted in 24.1 % decrease in infarct size and 38.2 % decrease in fibrotic area at day 56 post-operation (n=21, P Conclusions: Pn1Ab preserved cardiac function through anti-fibrotic effect without cardiomyocyte proliferation and angiogenesis. Specific blockade of Pn1 without Pn2 will potentially lead to new therapeutic targets on a molecular basis to limit cardiac remodeling.

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor that regulates cell growth, cell motility, and morphogenesis of various types of cells and is, thus, considered a humoral mediator of epithelial-mesenchymal interactions. Although HGF was originally identified as a potent mitogen for hepatocytes, HGF is now well known as an angiogenic growth factor. Because the presence of its specific receptor, c-met, is observed in vascular cells and cardiac myocytes, the cardiovascular HGF-met system has been a center of interest. Malatino et al1 suggested that an increase in circulating HGF might be compensated to myocardial damage in dialysis patients, because our recent report demonstrated that HGF reduced cardiac fibrosis through the inhibition of endothelial mesenchymal transition and the transformation of fibroblasts to myofibroblasts.2 We agree with their hypothesis that circulating HGF might be increased to attenuate the cardiovascular damage. In various pathophysiological conditions, such as hypertension, peripheral …

The purpose of this study was to investigate the effect of hepatocyte growth factor (HGF) on the pathogenesis of cardiac fibrosis induced by pressure overload in mice. Although cardiac fibrosis is attributed to excess pathological deposition of extracellular matrix components, the mechanism remains unclear. Recent reports revealed that α-smooth muscle actin–expressing myofibroblasts are primarily responsible for fibrosis. It is believed that myofibroblasts are differentiated from resident fibroblasts, whereas the transformation of vascular endothelial cells into myofibroblasts, known as endothelial-mesenchymal transition, has been suggested to be intimately associated with perivascular fibrosis. Thus, we hypothesized that HGF prevents cardiac fibrosis by blocking these pathways. We analyzed the pressure-overloaded HGF-transgenic mouse model made by transverse aortic constriction. Human coronary artery endothelial cells and human cardiac fibroblasts were examined in vitro after being treated with transforming growth factor-β1 or angiotensin II with or without HGF. The amount of cardiac fibrosis significantly decreased in pressure-overloaded HGF-transgenic mice compared with pressure-overloaded nontransgenic controls, particularly in the perivascular region. This was accompanied by a reduction in the expression levels of fibrosis-related genes and by significant preservation of echocardiographic measurements of cardiac function in the HGF-transgenic mice ( P P

Angiotensin (Ang) II type 1 receptor blockers have demonstrated beneficial effects beyond blood pressure control in the treatment of chronic kidney disease. There is clinical evidence that telmisartan is more effective than losartan in reducing proteinuria in hypertensive patients with diabetic nephropathy, because it is a partial agonist of peroxisome-proliferator activated receptor-γ (PPARγ), as well as an Ang II type 1 receptor blocker (AMADEO Study [A comparison of telMisartan versus losArtan in hypertensive type 2 DiabEtic patients with Overt nephropathy]). In this study, we examined the role of PPARγ activation in the renal protective actions of telmisartan using Ang II type 1 receptor–deficient mice. Renal injury was induced in Ang II type 1 receptor–deficient mice by producing unilateral ureteral obstruction, which exhibited severe renal interstitial fibrosis and inflammation. In these mice, telmisartan prevented hydronephrosis induced by unilateral ureteral obstruction more strongly than did losartan. Importantly, the prevention of renal atrophy and fibrosis by telmisartan was significantly attenuated by GW9662, a PPARγ antagonist. Interestingly, the downstream effector of PPARγ activation by telmisartan is hepatocyte growth factor (HGF), a well-known antifibrotic factor, because renal HGF expression was significantly increased by telmisartan, and a neutralizing antibody against HGF diminished the renal protective action of telmisartan. These beneficial changes by telmisartan were associated with a decrease in the expression of transforming growth factor-β1 and other proinflammatory and profibrotic cytokine genes through PPARγ/HGF activation. Our findings provide evidence of organ protective actions of telmisartan through the PPARγ/HGF pathway, independent of Ang II type 1 receptor blockade. Further development of the next generation of Ang II type 1 receptor blockers with added organ protective actions, such as PPARγ activation, might provide new beneficial drugs to treat renal and cardiovascular diseases.

Both angiotensin II (Ang II) and transforming growth factor (TGF)-β1 are thought to be involved in the progression of chronic kidney disease. In contrast, hepatocyte growth factor (HGF) counteracts the actions of Ang II and TGF-β1. Therefore, in this study, we investigated the molecular mechanisms of how HGF antagonizes the Ang II-TGF-β axis in renal cells. In cultured human mesangial cells, TGF-β1 increased angiotensin type 1 receptor (AT 1 R) mRNA, mainly dependent on the Akt/phosphatidylinositol 3-kinase signaling pathway. Furthermore, TGF-β1 decreased the expression and phosphatase activity of phosphatase and tensin homolog, deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/Akt pathway. These data revealed positive feedback of the Ang II-TGF-β pathway, because Ang II increased TGF-β expression. In contrast, HGF significantly attenuated the increase in AT 1 R gene expression, and inhibited the decrease in PTEN induced by TGF-β1. Of importance, a PTEN-specific inhibitor significantly attenuated the reduction in TGF-β1–induced AT 1 R expression by HGF. These data suggest that HGF attenuated TGF-β1–induced AT 1 R expression through the PTEN/Akt pathway. To investigate this hypothesis, we performed in vivo experiments in mice with increased circulating levels of HGF produced by transgenically expressing HGF under control of a cardiac-specific transgene (HGF-Tg). In HGF-Tg mice, renal injury and fibrosis were significantly decreased, associated with reduction in AT 1 R expression and increase in PTEN after Ang II infusion, as compared with control mice. Moreover, these renal protective effects were abrogated by a neutralizing antibody against HGF. Thus, the present study demonstrated that HGF counteracts the vicious cycle of Ang II-TGF-β1-AT 1 R, mediating the inhibition of PTEN.

Objective The progression of chronic kidney disease (CKD) is characterized by the persistent accumulation of extracellular matrix. Especially, α-SMA-positive myofibroblasts producing large amounts of TGF-β1 are considered to play a key role in interstitial fibrosis. Although hepatocyte growth factor (HGF) improved renal fibrosis in various models, the molecular mechanisms involved are not yet fully understood. Methods and results In this study, the molecular mechanisms of the inhibition of fibrosis by HGF was examined using HGF transgenic mice (HGF-Tg) with angiotensin II (Ang II) infusion in 4 weeks models. HGF-Tg mice showed significantly decreased Ang II-induced renal fibrosis and lesser numbers of interstitial myofibroblasts, whereas the antifibrotic effect of HGF was abrogated using HGF-neutralizing antibody. The antifibrotic action in HGF-Tg mice was concordant with a decrease in TGF- β1, collagen type I and IV mRNA expression and an increase in MMP-2 and MMP-9 expression. Furthermore, HGF-Tg mice treated with Ang II showed apoptosis of myofibroblasts. To further investigate the antifibrotic effect of HGF, cultured human mesangial cells were used. HGF induced apoptosis of myofibroblast. Inhibition of the FAK-ERK-MMP signaling cascade by specific inhibitor or siRNA significantly decreased HGF-induced myofibroblast apoptosis. Conclusion The present study demonstrates that the increase in metalloproteinases through FAK-ERK signaling by HGF promotes myofibroblast apoptosis. Activation of metalloproteinases by HGF in the fibrotic kidney might be considered to attenuate the progression of CKD.

Rationale: Neointimal hyperplasia contributes to atherosclerosis and restenosis after percutaneous coronary intervention. Vascular injury in each of these conditions results in the release of mitogenic growth factors and hormones that contribute to pathological vascular smooth muscle cell growth and inflammation. Hepatocyte growth factor (HGF) is known as an antiinflammatory growth factor, although it is downregulated in injured tissue. However, the precise mechanism how HGF reduces inflammation is unclear. Objective: To elucidate the mechanism how HGF and its receptor c-Met reduces angiotensin II (Ang II)–induced inflammation. Methods and Results: HGF reduced Ang II–induced vascular smooth muscle cell growth and inflammation by controlling translocation of SHIP2 (Src homology domain 2–containing inositol 5′-phosphatase 2), which led to Ang II–dependent degradation of epithelial growth factor receptor. Moreover, the present study also revealed a preventive effect of HGF on atherosclerotic change in an Ang II infusion and cuff HGF transgenic mouse model. Conclusions: These data suggest that the HGF/c-Met system might regulate extrinsic factor signaling that maintains the homeostasis of organs.