Effects of the factor Xa inhibitor rivaroxaban on the differentiation of endothelial progenitor cells.

BACKGROUND: We evaluated the efficacy of the factor Xa inhibitor rivaroxaban on the differentiation ability of vascular endothelial progenitor cells (EPCs), which play roles in vascular injury repair and atherogenesis. Antithrombotic treatment in patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) is challenging, and current guidelines recommend oral anticoagulant monotherapy 1 year or more after PCI. However, biological evidence of the pharmacological effects of anticoagulants is insufficient. METHODS: EPC colony-forming assays were performed using peripheral blood-derived CD34-positive cells from healthy volunteers. Adhesion and tube formation of cultured EPCs were assessed in human umbilical cord-derived CD34-positive cells. Endothelial cell surface markers were assessed using flow cytometry, and Akt and endothelial nitric oxide synthase (eNOS) phosphorylation were examined using western blot analysis of EPCs. Adhesion, tube formation and endothelial cell surface marker expression was observed in EPCs transfected with small interfering RNA (siRNA) against protease-activated receptor (PAR)-2. Finally, EPC behaviors were assessed in patients with atrial fibrillation undergoing PCI in whom warfarin was changed to rivaroxaban. RESULTS: Rivaroxaban increased the number of large EPC colonies and increased the bioactivities of EPCs, including adhesion and tube formation. Rivaroxaban also increased vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, Tie-2, and E-selectin expression as well as Akt and eNOS phosphorylation. PAR-2 knockdown increased the bioactivities of EPCs and endothelial cell surface marker expression. Patients in whom the number of large colonies increased after switching to rivaroxaban showed better vascular repair. CONCLUSIONS: Rivaroxaban increased the differentiation ability of EPCs, leading to potential advantages in the treatment of coronary artery disease.

Relationship between the serum GDF-15 concentration and muscle function in female patients receiving aortic valve replacement (TAVR, SAVR): Comparison with healthy elderly female subjects.

Purpose: Sarcopenia is closely associated with postoperative prognosis in patients undergoing cardiovascular surgery. Growth differentiation factor (GDF)-15 is involved in the pathogenesis of cardiovascular disease. We examined the relationship between the serum GDF-15 concentration and muscle function in patients receiving aortic valve replacement and healthy elderly subjects. Methods: Forty-three female patients undergoing aortic valve surgery (79.9 ± 6.4 years; transcatheter aortic valve replacement [TAVR] n = 19, conventional surgical aortic valve replacement [SAVR] n = 24) and 64 healthy elderly female subjects (75.9 ± 6.1 years) were included. Walking speed, grip strength, and skeletal muscle mass index (SMI) by a multifrequency bioelectrical impedance analyzer were measured to determine the presence of sarcopenia. Preoperative serum GDF-15 concentration was measured by enzyme-linked immunosorbent assay. Results: The GDF-15 level was higher in patients receiving aortic valve replacement than in healthy elderly subjects (aortic valve replacement: 1624 ± 1186 pg/mL vs. healthy: 955 ± 368 pg/mL, p < 0.001). Multivariate linear regression analysis showed that the serum GDF-15 level determined grip strength independently of the high-sensitivity C-reactive protein level and eGFR, even after adjusting for age (ß = -0.318, p = 0.025). Sarcopenia was found in 12.5% of healthy elderly subjects, 83.3% of patients with TAVR, and 64.3% of patients with SAVR. The GDF-15 concentration that defined sarcopenia was 1109 pg/mL in subjects including patients receiving aortic valve replacement. Conclusions: The preoperative serum GDF-15 concentration, which was higher in female patients receiving aortic valve replacement than in healthy elderly subjects, may be a serum marker of sarcopenia.

Pacemaker Treatment for Apical Hypertrophic Cardiomyopathy in the Setting of an Apical Ventricular Aneurysm.

We describe the case of a patient with apical hypertrophic cardiomyopathy with concomitant apical aneurysm. We measured the aneurysmal cavity pressure using the pressure guidewire system. The patient underwent implantable cardioverter-defibrillator treatment successfully to reduce the pressure gradient between the aneurysmal cavity and the true left ventricle. (Level of Difficulty: Intermediate.).

Mobilization of progenitor cells and vessel healing after implantation of SYNERGY in acute coronary syndrome.

This study was aimed to compare the vascular healing process of a SYNERGY stent with that of a PROMUS PREMIER stent in patients with acute coronary syndrome (ACS). In 71 patients with ACS, undergoing coronary stent implantation using the SYNERGY stent (n = 52) or PROMUS PREMIER stent (n = 19), we measured circulating CD34+/CD133+/CD45null cells and CD34+/KDR+ cells and observed vascular healing at the stented sites using optical coherence tomography (OCT) and coronary angioscopy. On the day 7, circulating CD34+/CD133+/CD45null cells increased in SYNERGY group (P < 0.0001), while it did not change in PROMUS group. The CD34+/KDR+ cells also increased in SYNERGY group (P < 0.0001) but less significantly in the PROMUS group (P < 0.05). The OCT-based neointimal thickness (P < 0.0005) and neointimal coverage rate (P < 0.05) at 12 months were greater in SYNERGY group, compared with PROMUS group. The coronary angioscopy-based neointimal coverage grade at 12 months was also greater in SYNERGY group (P < 0.001). In overall patients, the change in CD34+/KDR+ cells on the day 7 correlated with the OCT-based neointimal thickness at 12 months (R = 0.288, P < 0.05). SYNERGY stent seems to have potential advantages over PROMUS PREMIER stent for ACS patients in terms of vascular healing process at the stented sites.

Neointimal tissue characterization after implantation of drug-eluting stents by optical coherence tomography: quantitative analysis of optical density.

Normalized optical density (NOD) measured by optical coherence tomography represents neointimal maturity after coronary stent implantation and is correlated with morphologic information provided by both light and electron microscopy. We aimed to test the hypothesis that even second generation drug-eluting stents (DESs) are problematic in terms of neointimal maturity. We implanted bare-metal stents (BMS: n = 14), everolimus-eluting stents (EESs: n = 15) or zotarolimus-eluting stents (ZESs: n = 12) at 41 sites in 32 patients with stable coronary artery disease. OCT was performed at up to 12 months of follow-up, and the average optical density of neointima covering struts was evaluated. NOD was calculated as the optical density of stent-strut covering tissue divided by the optical density of the struts. We also measured circulating CD34+ /CD133+ /CD45low cells, and serum levels of stromal cell-derived factor (SDF)-1, interleukin (IL)-8 and matrix metalloproteinase (MMP)-9 at baseline and follow-up. NOD was lower in the EES (0.70 ± 0.06) group than in the BMS (0.76 ± 0.07, P < 0.05) and ZES (0.76 ± 0.06, P < 0.05) groups. The mean neointimal area (R = 0.33, P < 0.05) and mean neointimal thickness (R = 0.37, P < 0.05) were correlated with NOD. Although NOD was not correlated with percent changes in circulating endothelial progenitor cells, and the levels of SDF-1 and IL-8, it was negatively correlated with the change in MMP-9 level (R = - 0.51, P < 0.01). Neointimal maturity might be lower at EES sites than BMS or ZES sites. This might lead to impaired neointimal tissue growth and matrix degradation. These results suggest a specific pathophysiology after DES implantation.

New Volumetric Analysis Method for Stent Expansion and its Correlation With Final Fractional Flow Reserve and Clinical Outcome: An ILUMIEN I Substudy.

OBJECTIVES: This study sought to compare conventional methodology (CM) with a newly described optical coherence tomography (OCT)-derived volumetric stent expansion analysis in terms of fractional flow reserve (FFR)-derived physiology and device-oriented composite endpoints (DoCE). BACKGROUND: The analysis of coronary stent expansion with intracoronary imaging has used CM that relies on the analysis of selected single cross-sections for several decades. The introduction of OCT with its ability to perform semiautomated volumetric analysis opens opportunities to redefine optimal stent expansion. METHODS: A total of 291 lesions treated with post-stent OCT and FFR were enrolled. The expansion index was calculated by using a novel volumetric algorithm and was defined as: ([actual lumen area / ideal lumen area] × 100) for each frame of the stented segment. The minimum expansion index (MEI) was defined as the minimum value of expansion index along the entire stented segment. MEI and conventional lumen expansion metrics were compared for the ability to predict post-stent low FFR (<0.90) and DoCE at 1 year. RESULTS: There was a stronger correlation between MEI and final FFR, compared with CM and final FFR (r = 0.690; p < 0.001) versus (r = 0.165; p = 0.044). MEI was significantly lower in patients with DoCE than those without DoCE (72.18 ± 8.23% vs. 81.48 ± 11.03%; p < 0.001), although stent expansion by CM was similar between patients with and without DoCE (85.05 ± 22.19% and 83.73 ± 17.52%; p = 0.858), respectively. CONCLUSIONS: OCT analysis of stent expansion with a newly described volumetric method, but not with CM, yielded data that were predictive of both an acute improvement in FFR-derived physiology and DoCE.

Mobilization of progenitor cells and assessment of vessel healing after second generation drug-eluting stenting by optical coherence tomography.

BACKGROUND: Bone marrow-derived progenitor cells likely contribute to both endothelial- and smooth muscle cell-dependent healing responses in stent-injured vessel sites. This study aimed to assess mobilization of progenitor cells and vessel healing after zotarolimus-eluting (ZES) and everolimus-eluting (EES) stents. METHODS AND RESULTS: In 63 patients undergoing coronary stent implantation, we measured circulating CD34 + CD133 + CD45low cells and serum levels of biomarkers relevant to stem cell mobilization. In 31 patients of them, we assessed vessel healing within the stented segment using optical coherence tomography (OCT) imaging. The CD34 + CD133 + CD45low cells increased 68 ± 59% 7 days after bare metal stent (BMS), 10 ± 53% after ZES (P < 0.01 vs BMS), 3 ± 49% after EES (P < 0.001 vs BMS), compared with baseline. Percent change in CD34 + CD133 + CD45low cells was positively correlated with that in stromal cell-derived factor (SDF)-1α (R = 0.29, P = 0.034). Percentage of uncovered struts was higher in the EES group (14.4 ± 17.3%), compared with the BMS (0.7 ± 1.3, P < 0.01) and ZES (0.4 ± 0.5, P < 0.01) groups. The change in CD34 + CD133 + CD45low cells showed positive correlation with OCT-quantified mean neointimal area (R = 0.48, P < 0.01). Finally, circulating mononuclear cells obtained from 5 healthy volunteers were isolated to determine the effect of sirolimus, zotarolimus and everolimus on vascular cell differentiation. The differentiation of mononuclear cells into endothelial-like cells was dose-dependently suppressed by sirolimus, zotarolimus, and everolimus. CONCLUSIONS: Mobilization of progenitor cells was suppressed, and differentiation of mononuclear cells into endothelial-like cells was inhibited, in association with increased number of uncovered stent struts, even after second generation drug-eluting stenting. These data suggest that new approaches are necessary to enhance stent healing.

New insight to estimate under-expansion after stent implantation on bifurcation lesions using optical coherence tomography.

Optical coherence tomography (OCT) allows full volumetric segmentation of the lumen. However, for the estimation of stent under-expansion we still rely on the conventional method (CM) of single cross-sectional narrowing compared with reference vessel, likely masking true lesion significance, especially for bifurcations and tapered vessels. We, therefore, suggest a novel concept of volumetric metrics that take into account vessel tapering and major side branches and is capable of obtaining ideal lumen area for every frame of the stent by OCT. Forty-four patients with bifurcation lesions were enrolled. In volumetric metrics, expansion index was calculated as [(actual lumen area/ideal lumen area) × 100] in all frames. While minimum expansion index (MEI) was often located in the proximal segment to the major side branch, minimum stent area (MSA) by CM was frequently located in the distal segment (p < 0.001). Furthermore, the frequency of the under-expansion was significantly greater in newly metrics compared with CM [21 (47.7%) and 11 (25.0%), p = 0.045]. New metrics changed the presence of the under-expansion in 40.9% (18/44) of patients and the locations of MEI and MSA were different in 72.7% (32/44) of cases. Volumetric assessment enables to more accurately assess stent under-expansion.

Failure Mechanisms and Neoatherosclerosis Patterns in Very Late Drug-Eluting and Bare-Metal Stent Thrombosis.

BACKGROUND: There are few clinical studies on the pathophysiological mechanisms of very late stent thrombosis (VLST). We report optical coherence tomography findings in patients with VLST and compare the findings between bare-metal stents (BMS) and drug-eluting stents (DES). METHODS AND RESULTS: We conducted a registry of stent thrombosis at 4 North American centers with optical coherence tomography imaging programs SAFE registry (The Study of Late Stent Failure Evaluated by OCT). Images were acquired in 61 patients (42 DES and 19 BMS) presenting with definite VLST. The median duration from implantation to VLST presentation was 51.4 months in the DES and 69.9 months in the BMS group (P=0.011). Uncovered and malapposed struts were observed in 70.5% (43/61) and 62.3% (38/61) of patients, respectively, whereas neoatherosclerosis was revealed in 49.2% (30/61). Stent underexpansion was observed in 42.4% of patients. Malapposed struts and stent underexpansion were more frequently demonstrated in DES than in BMS patients, whereas neoatherosclerosis was frequently observed in BMS (40.5% in DES and 68.4% in BMS; P=0.056). The percentage of frames with neoatherosclerosis was lower in DES than in BMS (15.56% [12.24-28.57] versus, 56.41% [40.74-70.00], respectively; P<0.001). Maximum consecutive lipid neointima length was shorter in DES than in BMS (2.4 [1.2-3.6] and 5.3 [3.0-7.0] mm; P=0.011). CONCLUSIONS: Optical coherence tomography imaging demonstrated that VLST in DES and BMS had a wide variety of abnormal findings, such as neoatherosclerosis, uncovered strut, and malapposed strut. Neoatherosclerosis and lipid neointima were more frequently observed and had more longitudinal extension in BMS compared with DES.

Dextran or Saline Can Replace Contrast for Intravascular Optical Coherence Tomography in Lower Extremity Arteries.

PURPOSE: To examine the hypothesis that alternative flush media could be used for lower extremity optical coherence tomography (OCT) imaging in long lesions that would normally require excessive use of contrast. METHODS: The OPTical Imaging Measurement of Intravascular Solution Efficacy (OPTIMISE) trial was a single-center, prospective study (ClinicalTrials.gov identifier NCT01743872) that enrolled 23 patients (mean age 68±11 years; 14 men) undergoing endovascular intervention involving the superficial femoral artery. Four flush media (heparinized saline, dextran, carbon dioxide, and contrast) were used in succession in random order for each image pullback. Quality was defined as ≥270° visualization of vessel wall layers from each axial image. Mean proportions (± standard deviation) of image quality for each flush medium were assessed using 1-way analysis of variance and are reported with the 95% confidence intervals (CI). RESULTS: Four OCT catheters failed, leaving 19 patients who completed the OCT imaging protocol; from this cohort, 51 highest quality runs were selected for analysis. Average vessel diameter was 3.99±1.01 mm. OCT imaging allowed 10- to 15-µm resolution of the lumen border, with diminishing quality as vessel diameter increased. Plaque characterization revealed fibrotic lesions. Mean proportions of image quality were dextran 87.2%±12% (95% CI 0.81 to 0.94), heparinized saline 74.3%±24.8% (95% CI 0.66 to 0.93), contrast 70.1%±30.5% (95% CI 0.52 to 0.88), and carbon dioxide 10.0%±10.4% (95% CI 0.00 to 0.26). Dextran, saline, and contrast provided better quality than carbon dioxide (p<0.001). CONCLUSION: OCT is feasible in peripheral vessels <5 mm in diameter. Dextran or saline flush media can allow lesion characterization, avoiding iodinated contrast. Carbon dioxide is inadequate for peripheral OCT imaging. Axial imaging may aid in enhancing durability of peripheral endovascular interventions.

Impact of Neointimal Calcifications on Acute Stent Performance during the Treatment of In-Stent Restenosis.

Optical coherence tomography (OCT) has become the invasive imaging modality of choice for coronary stent assessment due to its unmatched spatial resolution. Neointimal calcification (NC) is a rare finding, observed in 5-10% of in-stent restenosis (ISR) neointima. The impact of NC on percutaneous coronary intervention of ISR is unknown. We therefore present the outcome of six unique cases of ISR and NC in which OCT was used to evaluate the impact of NC on the quality of stent-in-stent deployment for the treatment of ISR. This series demonstrates for the first time the impact of NC on stent expansion, a finding which might help guiding percutaneous coronary intervention for ISR with NC.

The late-phase inflammatory response after drug-eluting stent implantation.

Recent advances in drug-eluting stent (DES) technology have succeeded in preventing restenosis. In addition to inhibiting smooth muscle cell proliferation, DES greatly inhibits the local inflammatory response in the acute phase after implantation, leading to prevention of restenosis. However, a unique issue in DES implantation is an impairment of reendothelialization, which may result in abnormal wound healing. Consequently, a late-phase inflammatory relapse could appear in the long term after DES implantation. In this study, we measured serum levels of inflammatory markers, including interleukin (IL)-6, IL-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, matrix metalloproteinase-9, and myeloperoxidase, as well as high-sensitivity C-reactive protein at follow-up coronary angiography (mean 9 months) in 54 patients who received DES stenting who did not experience restenosis, and compared them with 51 patients receiving bare-metal stents (BMS) without restenosis. The level of IL-6 was over the measurement threshold (≥2.22 pg/ml) in 12 patients (21 %) in the DES group, but in only 2 patients (4 %) in the BMS group (P = 0.003). IL-8 was significantly higher in the DES group than in the BMS group (4.51 ± 2.40 vs 3.84 ± 1.34 pg/ml, P = 0.015). The levels of other biomarkers were similar between the two groups. DES showed an increase in inflammatory cytokines in the late phase after implantation in comparison with patients who received BMS, suggesting late-stage inflammation. Therefore, the wound-healing response after DES implantation might be different from that after BMS.

Late-phase inflammatory response as a feature of in-stent restenosis after drug-eluting stent implantation.

OBJECTIVES: The aim of this study was to compare pathological features among in-stent restenosis lesions after drug-eluting stent (DES) placement, those after bare metal stent (BMS) placement, and de-novo atherosclerotic lesions. BACKGROUND: Restenosis after stenting is an over-reaction of the wound-healing response after vascular injury, which is characterized by a sequence of inflammation, granulation, extracellular matrix remodeling, and smooth muscle cell proliferation and migration. Recent advances in DES technology could considerably succeed in inhibiting this sequence of events. Thus, we hypothesized that the mechanism of in-stent restenosis after DES stenting might be different from that after BMS stenting as well as atherosclerosis. METHODS: Tissues obtained by directional atherectomy (DES: seven specimens, BMS: 17 specimens, and de-novo: 15 specimens) were immunostained for T lymphocytes (CD45), macrophages (CD68), smooth muscle cells (α-smooth muscle actin), endothelial cells (von Willebrand factor), and activated platelets (P-selectin). RESULTS: The accumulation of T lymphocytes tended to increase and that of macrophages increased significantly in the DES lesions compared with BMS lesions. No significant differences were observed for the other parameters evaluated. CONCLUSION: Pathological features of restenotic tissues after DES implantation showed a stronger inflammatory response compared with those after BMS implantation. Thus, the mechanism of restenosis after DES implantation may be different from that observed after BMS implantation.

Protective effect of K201 on isoproterenol-induced and ischemic-reperfusion-induced ventricular arrhythmias in the rat: comparison with diltiazem.

AIM: Ventricular arrhythmia (VA) is a risk for sudden death. Polymorphic ventricular tachycardia (VT) degenerating to ventricular fibrillation occurs subsequent to the prolongation of the QT interval following administration of catecholamines under Ca(2+) loading. Fatal VA also occurs in ischemia and ischemic-reperfusion. We compared the suppressive effect of K201 (JTV519), a multiple-channel blocker and cardiac ryanodine receptor-calcium release channel (RyR2) stabilizer, with that of diltiazem, a Ca(2+ )channel blocker, in 2 studies of isoproterenol-induced (n = 30) and ischemic-reperfusion-induced VAs (n = 38) in rats. METHODS: Adult male Wistar rats were administered 12 mg/kg/min calcium chloride (CaCl(2)) for 20 minutes and then 6 µg/kg/min isoproterenol was infused with CaCl(2) for a further 20 minutes. In other rats, the left coronary artery was ligated for 5 minutes followed by reperfusion for 20 minutes. K201 or diltiazem (both 1 mg/kg) was administered before infusion of the isoproterenol or induction of ischemia. RESULTS: After administration of isoproterenol under Ca(2+) loading, fatal VA frequently occurred in the vehicle (9 of 10 animals, 90%) and diltiazem (8 of 10, 80%) groups, and K201 significantly suppressed the incidences of arrhythmia and mortality (2 of 10, 20%). In the reperfusion study, the incidence and the time until occurrence of reperfusion-induced VA and mortality were significantly suppressed in the K201 (2 of 15 animals, 13%) and diltiazem (1 of 9 animals, 11%) groups compared to the vehicle group (8 of 14 animals, 57%). SIGNIFICANCE: Induction of VA in an experimental model was achieved with a low dose of isoproterenol under Ca(2+) loading. K201 markedly suppressed both the isoproterenol-induced and the reperfusion-induced VAs, whereas diltiazem did not suppress the isoproterenol-induced VA. The results suggest that both VAs are related to early after depolarization (EAD) and indicate that K201 has the potential to suppress EAD by stabilizing RyR2 to mediate Ca(2+) release from the sarcoplasmic reticulum and acting as a multiple-channel blocker.

Pathological features of in-stent restenosis after sirolimus-eluting stent versus bare metal stent placement.

A 70-year-old man developed diffuse restenosis in the right coronary artery, in which a bare metal stent (BMS) and two sirolimus-eluting stents (SES) were deployed sequentially. He underwent directional coronary atherectomy (DCA) for in-stent restenosis (ISR) lesions 13 months after both BMS and SES stenting. Further 4 months later, that is, 17 months after stent implantation, however, ISR recurred just at the SES site alone. Then we performed second DCA for the ISR lesion at SES site. The tissue materials obtained from debulking were compared histologically. In the first DCA specimen, accumulation of inflammatory cells such as T lymphocytes and macrophages was observed densely in ISR lesions at SES site but not in those at BMS site, and endothelial coverage was absent in ISR lesions at SES site but present in those at BMS site. In the second DCA specimen, ISR lesions at SES site showed less inflammatory cells, compared with first DCA specimen. ISR lesions after drug-eluting stenting showed persistent signs of delayed or incomplete wound healing and relapsed inflammation, compared with BMS. Thus, the mechanism of restenosis after drug-eluting stenting may be different from that after BMS placement.