Naoki Itaya

Coronary Endothelial Dysfunction Distal to Stent of First-Generation Drug-Eluting Stents

OBJECTIVES This study sought to evaluate the relationship between coronary endothelial function and neointimal coverage after drug-eluting stent (DES) implantation. BACKGROUND The mechanisms of endothelial dysfunction after DES implantation remain to be fully elucidated. We hypothesized that poor neointimal coverage after DES implantation may be associated with endothelial dysfunction distal to the stent site. METHODS Sixty-six stable angina patients treated with a first-generation DES were enrolled. At 9-month follow-up, coronary endothelial function was evaluated with intracoronary infusion of incremental doses of acetylcholine (10(-8), 10(-7), and 10(-6) mol/l) and nitroglycerin (200 μg). Vascular responses at the segments proximal and distal to the stent site were angiographically and quantitatively measured. At the same time, the degree of neointimal coverage was evaluated using coronary angioscopy and classified into 4 grades: 0 (no coverage) to 3 (full coverage). RESULTS We divided the subjects into poor-coverage (grades 0 to 1, n = 33) and good-coverage (grades 2 to 3, n = 33) groups. Acetylcholine induced dose-dependent coronary vasoconstrictions in both groups. At the segment distal to the stent, the magnitude of vasoconstriction to acetylcholine in the poor-coverage group was significantly greater than in the good-coverage group (p < 0.001), whereas vasomotor responses proximal to the stent and vasodilation by nitroglycerine were similar between the 2 groups. CONCLUSIONS Coronary endothelial dysfunction distal to the stent was associated with poor neointimal coverage after DES implantation.

Platelet-derived microparticles augment the adhesion and neovascularization capacities of circulating angiogenic cells obtained from atherosclerotic patients

OBJECTIVE The neovascularization-related capacities of circulating angiogenic cells (CACs) are impaired in atherosclerotic patients, which may explain the unsatisfactory effects of therapeutic angiogenesis with atherosclerotic patient-derived CACs. Platelet-derived microparticles (PMPs) were reported to augment the re-endothelialization capacity of CACs. Accordingly, we investigated whether PMPs could augment the neovascularization-related capacities of atherosclerotic patient-derived CACs in vitro and in vivo and if so, the associated mechanisms. METHODS AND RESULTS We isolated mononuclear cells and PMPs from atherosclerotic patient-derived peripheral blood and generated PMP-pretreated CACs (PMP-CACs) by co-culture of the mononuclear cells and PMPs. Although the migration capacity of PMP-CACs was similar to that of CACs, the adhesion capacity of PMP-CACs was greater. PMPs released RANTES into the culture medium, and the receptors were similarly expressed on the surfaces of CACs and PMP-CACs. Intravenous injection of PMP-CACs to rats with hindlimb ischemia augmented neovascularization of the ischemic limbs more than the injection of CACs. The number of PMP-CACs incorporated into the capillaries of the ischemic limbs was greater than that of incorporated CACs. The augmented adhesion and neovascularization capacities by PMP-CACs were canceled out by a RANTES neutralizing antibody. CONCLUSIONS PMP-secreted RANTES may play a role in the augmenting adhesion and neovascularization capacities of CACs. Injection of PMP-CACs may be a new strategy to augment the effects of therapeutic angiogenesis for limb ischemia in atherosclerotic patients.

Differential angioscopic findings of neointimal coverage among first-, second-, and next generation drug-eluting stents.

Article history: Received 21 July 2016 Accepted 7 August 2016 Available online 9 August 2016 markedly yellow plaques (45%) were observed by angioscopy (N = 24 patients; Panel 1A and B). In the second generation DES, white but thin neointimal coverage of stent struts was observed as a transparent and homogeneous layer with less thrombi (20% of patients) or yellow plaques (20%) (N = 24 patients; Panel 2A–C), an indication of better neointimal coverage than first-generation DES.

Optical frequency-domain imaging and pulmonary angioscopy in chronic thromboembolic pulmonary hypertension.

Unresolved thromboemboli in the pulmonary arteries (PAs) cause chronic thromboembolic pulmonary hypertension (CTEPH), which is usually diagnosed by mismatched perfusion defects on ventilation-perfusion lung scintigraphy and chronic thromboembolic signs on computed tomography (CT) scan and/or conventional pulmonary angiography. In our recent three cases of CTEPH (Case 1; …

FOXO4-knockdown suppresses oxidative stress-induced apoptosis of early pro-angiogenic cells and augments their neovascularization capacities in ischemic limbs.

The effects of therapeutic angiogenesis by intramuscular injection of early pro-angiogenic cells (EPCs) to ischemic limbs are unsatisfactory. Oxidative stress in the ischemic limbs may accelerate apoptosis of injected EPCs, leading to less neovascularization. Forkhead transcription factor 4 (FOXO4) was reported to play a pivotal role in apoptosis signaling of EPCs in response to oxidative stress. Accordingly, we assessed whether FOXO4-knockdown EPCs (FOXO4KD-EPCs) could suppress the oxidative stress-induced apoptosis and augment the neovascularization capacity in ischemic limbs. We transfected small interfering RNA targeted against FOXO4 of human EPCs to generate FOXO4KD-EPCs and confirmed a successful knockdown. FOXO4KD-EPCs gained resistance to apoptosis in response to hydrogen peroxide in vitro. Oxidative stress stained by dihydroethidium was stronger for the immunodeficient rat ischemic limb tissue than for the rat non-ischemic one. Although the number of apoptotic EPCs injected into the rat ischemic limb was greater than that of apoptotic EPCs injected into the rat non-ischemic limb, FOXO4KD-EPCs injected into the rat ischemic limb brought less apoptosis and more neovascularization than EPCs. Taken together, the use of FOXO4KD-EPCs with resistance to oxidative stress-induced apoptosis may be a new strategy to augment the effects of therapeutic angiogenesis by intramuscular injection of EPCs.

Interleukin-1β is associated with coronary endothelial dysfunction in patients with mTOR-inhibitor-eluting stent implantation

Implantation of mammalian target of rapamycin (mTOR)-inhibitor drug-eluting stents (DESs) impairs coronary endothelial function. There are no known non-invasive biomarkers of coronary endothelial dysfunction. We aimed to assess the association between serum interleukin-1beta (IL-1β) and coronary endothelial dysfunction in patients with mTOR-inhibitor DES implantation and to investigate the association between the mTOR pathway and IL-1β. We enrolled 35 patients who had implanted DESs for coronary artery disease. At a 10-month follow-up, peripheral venous blood samples were collected to measure IL-1β levels. Coronary endothelial dysfunction was evaluated by intracoronary infusion of incremental doses of acetylcholine. Serum IL-1β levels were significantly associated with the magnitude of vasoconstriction to acetylcholine at the segment distal (P < 0.05) but not proximal to the stent. Serum IL-1β levels were positively correlated with stent length (P < 0.05). To examine the direct effects of mTOR inhibition on IL-1β release, sirolimus was incubated in cultured human umbilical vein endothelial cells (HUVECs) or coronary artery smooth muscle cells (CASMCs). Sirolimus directly increased IL-1β mRNA expression (P < 0.01) and enhanced IL-1β release into the culture media (P < 0.01) in CASMCs, but not in HUVECs. Inhibition of mTOR triggers IL-1β release through transcriptional activation in CASMCs. Serum IL-1β levels are a potential biomarker for mTOR-inhibitor DES-associated coronary endothelial dysfunction.

Pulmonary artery dysfunction in chronic thromboembolic pulmonary hypertension

Background Unresolved thromboemboli in the pulmonary arteries (PA) is known to cause chronic thromboembolic pulmonary hypertension (CTEPH). However, it remains unknown if vascular dysfunction in pulmonary arteries exists in patients with CTEPH. Methods and results We enrolled 7 female patients with CTEPH in this study, who have stable pulmonary hemodynamics after balloon pulmonary angioplasty (age; 73.6 ± 3.0 years old, mean right atrial pressure; 4.1 ± 0.4 mm Hg, mean pulmonary arterial pressure; 29.4 ± 2.7, mean pulmonary artery wedge pressure; 8.1 ± 1.2, pulmonary vascular resistance; 397.3 ± 51.7 dynes, cardiac index; 3.1 ± 0.2 L/min/m2). Pulmonary artery vascular function was evaluated by measuring pulmonary artery vasomotion in response to acetylcholine (Ach) at 10-month follow-up after balloon pulmonary angioplasty. All pulmonary vasoactive drugs were discontinued on the day of the procedures. The endothelium-dependent vasomotor response was evaluated by intra-pulmonary artery infusion of Ach at the dose of 10− 8 mol/l, and the vaso-spastic response was at 10− 6 mol/l. We evaluated vasomotor responses at the same segment in each patient, by measuring % changes of luminal area detected by quantitative pulmonary arterial optical frequency-domain imaging (OFDI), where OFDI catheter was fixed during the procedure. Endothelial dysfunction was observed at the dose of Ach at 10− 8 mol/l and vasoconstriction was also confirmed at the dose of Ach at 10− 6 mol/l in the diseased pulmonary arteries in CTEPH. Conclusions These results indicated that the pulmonary artery dysfunction exists in patients with CTEPH, which may be involved in the pathogenesis and progression of CTEPH.

Unstable Angina Pectoris in a 22-year-old Female Patient

Because of the protective effect of estrogen for atherosclerosis, the prevalence of acute coronary syndrome in women before menopause is low. We report a rare case of unstable angina in a young Japanese female who had a history of cigarette smoking and contraceptive use. Her coronary stenosis was successfully treated by percutaneous coronary intervention.

Successful Endovascular Treatment of Aortoiliac Bifurcation Stenosis Using an Empirically Based T and Protrude-Stenting with Self- and Balloon-Expandable Stents

A 73-year-old woman with arteriosclerosis obliterans (ASO) was underwent a crossover stenting for an aortoiliac bifurcation from the right common iliac artery (CIA) with a self-expandable bare-metal stent (SE-BMS); however, a new stenosis later occurred just behind the bifurcation of the left CIA. An ex vivo experiment demonstrated that culotte-stenting by additional implantation of a balloon-expandable bare-metal stent (BE-BMS) through stent struts of the SE-BMS would be empirically infeasible. Although we had initially planned a T-stenting for the additional implantation of a BE-BMS in the left CIA, we finally deployed the stent in the CIA with the proximal end protruding into the previously-implanted SE-BMS through the stent struts to avoid incomplete coverage of the stenosis by reference to the ex vivo experiments. The patient has had no recurrence for 36 months.