Hiroshi Koiwaya

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.

Augmented neovascularization with magnetized endothelial progenitor cells in rats with hind-limb ischemia

Augmenting neovascularization with the use of endothelial progenitor cells (EPCs) is a therapeutic option to rescue critical limb ischemia (CLI). However, the outcomes have been not so satisfactory. The detectable number of injected EPCs at the ischemic site is rather small. If EPCs accumulate more and stay longer there, neovascularization will be augmented. In this study, we tested whether external magnetic forces (EMFs) accumulated magnetized EPCs (Mag-EPCs) at the ischemic site and thereby augmented neovascularization. We cultured peripheral blood-derived mononuclear cells to obtain EPCs and generated Mag-EPCs by a magnetofection method with nanoparticles. Prussian-blue staining revealed magnetic nanoparticles incorporated into the cytoplasms and nuclei of Mag-EPCs. The survival rate of Mag-EPCs at day 9 of culture was 98.7%, indicating no cell toxicity of magnetic nanoparticles. EMFs augmented adhesion capacity of Mag-EPCs not only in the static but also in the flow condition in vitro, compared to without EMFs. The migration capacity of Mag-EPCs with EMFs was 160% more than EPCs or Mag-EPCs without them. After an intravenous injection of Mag-EPCs into the rat with hind-limb ischemia, the recovery of blood flow and capillary density in the ischemic limb were significantly more (p<0.01) with EMFs than without them. EMFs augmented neovascularization capacity of Mag-EPCs compared to EPCs alone. This method could be a new therapeutic strategy for patients with CLI.

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.

Autologous transplantation of bone marrow mononuclear cells improved ischemic peripheral neuropathy in humans.

To the Editor: Ischemic peripheral neuropathy is a term used to describe the neurological deficits of peripheral nerves in patients with peripheral artery obstructive disease ([1][1]). Although ischemic peripheral neuropathy is a major complication of critical limb ischemia resulting in impaired

Predictors of Recurrent In-Stent Restenosis After Paclitaxel-Coated Balloon Angioplasty

BACKGROUND Although paclitaxel-coated balloon (PCB) angioplasty is an effective procedure for in-stent restenosis (ISR) after coronary stenting, recurrent ISR after PCB angioplasty still occurs. The aim of this study was to evaluate the predictors of recurrent ISR after PCB angioplasty for ISR.Methods and Results:A total of 157 ISR lesions treated with PCB angioplasty from January 2014 to May 2015 were retrospectively examined. Recurrent ISR was judged on 6-month follow-up angiography. Clinical, angiographic and procedural parameters were evaluated as possible predictors of recurrent ISR. Recurrent ISR occurred in 13.9% of lesions after PCB angioplasty. On multivariate analysis the following independent predictors of recurrent ISR were identified: (1) smaller acute gain after initial ballooning (OR, 3.06; 95% CI: 1.08-8.71; P=0.04); (2) geographic mismatch between PCB position and initial ballooning (OR, 5.59; 95% CI: 1.64-19.1; P=0.006); and (3) use of percutaneous transluminal coronary rotational atherectomy (PTCRA) at primary percutaneous coronary intervention (PCI; OR, 5.53; 95% CI: 1.89-16.2; P=0.002). CONCLUSIONS Optimal expansion at initial ballooning before PCB angioplasty and careful positioning of PCB are important technical tips to prevent recurrent ISR after PCB angioplasty. Recurrent ISR occurred more frequently in severely calcified lesions that required PTCRA at primary PCI.

The impact of three-dimensional optical coherence tomography and kissing-balloon inflation for stent implantation to bifurcation lesions

The rates of restenosis and stent thrombosis after the therapeutic stent deployment for bifurcation lesions are still comparably high after the introduction of the new-generation drug-eluting stents (DESs), because of the various factors including their morphology. We experienced a case of a successful percutaneous coronary intervention using three-dimensional optical coherence tomography (3D OCT) with a single stent deployment to a bifurcation lesion of the left anterior descending artery (LAD) and left circumflex artery (LCx) with a following kissing-balloon inflation (KBI). The 3D OCT, after the inflation of the jailed ostium of the LCx following the stent deployment to the LAD crossing the LCx, could clearly demonstrate a stent deformation and incomplete apposition at an opposite site of the LCx, which may cause high rates of restenosis and stent thrombosis. These stent abnormalities were steadily corrected by a subsequent KBI of the LAD and LCx. Furthermore, the 3D OCT images were the same findings as those of the experiments from both an in vitro phantom coronary bifurcation model and macroscopic images of the stent. <Learning objective: In view of this case report, these modalities with three-dimensional optical coherence tomography and the techniques for the following kissing-balloon inflation may be one of the useful and effective therapeutic strategies to reduce the rates of restenosis and stent thrombosis of the percutaneous coronary intervention for bifurcation lesions.>.

BLOOD LACTATE LEVEL AT CORONARY CARE UNIT CAN PREDICT SHORT-TERM PROGNOSIS AFTER PRIMARY PERCUTANEOUS CORONARY INTERVENTION FOR ACUTE MYOCARDIAL INFARCTION

Hyperlactatemia has been known as a simple marker of poor prognosis in various acutely ill patients. Little is known regarding the prognostic implication of blood lactate level at coronary care unit in patients with acute myocardial infarction (AMI). We investigated the relationship among blood

The Course of Ischemic Mitral Regurgitation in Acute Myocardial Infarction After Primary Percutaneous Coronary InterventionCLINICAL PERSPECTIVE: From Emergency Room to Long-Term Follow-Up

Background—Previously published evidence on ischemic mitral regurgitation (IMR) and its adverse prognosis after myocardial infarction has been based on the severity of IMR in the subacute or chronic period of myocardial infarction. However, the state of IMR can vary from the early stage to the chronic stage as a result of various responses of myocardium after primary percutaneous coronary intervention (PCI). Methods and Results—Standard echocardiography was serially performed in 546 consecutive patients with first-onset acute myocardial infarction (1) immediately after their arrival (pre-PCI), (2) before discharge (early post-PCI), and (3) 6 to 8 months after PCI (late post-PCI). The course of IMR after primary PCI and the prognostic impact of the IMR in each phase were investigated. IMR was found in 193/546 (35%) patients at the emergency room. In the acute phase after PCI, IMR improved in 63 patients. IMR worsened in 78 patients despite successful PCI. Shorter onset-to-reperfusion time and nontotal occlusion before PCI were the independent predictors of early improvement of IMR. In the chronic phase, IMR improved in 79 patients and worsened in 36 patients. Lower peak creatine kinase–myocardial band was an independent predictor of late improvement of IMR. IMR before PCI worsened 30-day prognosis (P=0.02), and persistent IMR in the chronic phase worsened long-term prognosis (P=0.04) after primary PCI. Conclusions—Degrees of IMR changed in the early and chronic phase after primary PCI for acute myocardial infarction. IMR on arrival and persistent IMR in the chronic phase worsened short-term and long-term prognosis after acute myocardial infarction, respectively.