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Papers by Fumiaki Ikeno

Circulation journal : official journal of the Japanese Circulation Society, Jan 30, 2018

For more than 10 years, the Harmonization by Doing (HBD) program, a joint effort by members from ... more For more than 10 years, the Harmonization by Doing (HBD) program, a joint effort by members from academia, industry and regulators from the United States of America (USA) and Japan, has been working to increase timely regulatory approval for cardiovascular devices through the development of practical global clinical trial paradigms. Consistent with this mission and in recognition of the increasing global public health effects of critical limb ischemia (CLI), academic and government experts from the USA and Japan have developed a basic framework of global clinical trials for endovascular devices for CLI. Despite differences in medical and regulatory environments and complex patient populations in both countries, we developed a pathway for the effective design and conduct of global CLI device studies by utilizing common study design elements such as patients' characteristics and study endpoints, and minimizing the effect of important clinical differences. Some of the key recommend...

Comparative medicine, 2017

Which preclinical models are best suited for restenosis research remains uncertain. Here we compa... more Which preclinical models are best suited for restenosis research remains uncertain. Here we compared the restenotic responses after balloon or stent overstretch injury in a porcine coronary artery. A total of 30 coronary lesions in 5 pigs were treated by balloon overdilatation or oversized stent implantation at various balloon-to-artery (B:A) ratios. Four weeks later, the lesions were examined in vivo by using coronary angiography, intravascular ultrasound, and optical coherence tomography (OCT). At follow-up, the lumen area stenosis and plaque burden at the minimal lumen area site were greater in stented sites than in balloon injury site (lumen area stenosis, 21.7 ± 8.9% compared with 32.8 ± 12.1%; plaque burden, 30.1% ± 10.1% compared with 44.7% ± 10.1%, respectively). The remodeling index was significantly smaller for the balloon-injury group than the stent group (0.86 ± 0.11 compared with 1.00 ±0.04). Only the stent group that was dilated at a high B:A ratio resulted in increase...

EuroIntervention, 2016

Aims: Our aim was to evaluate stent expansion and acute recoil at deployment and post-dilatation,... more Aims: Our aim was to evaluate stent expansion and acute recoil at deployment and post-dilatation, and the impact of post-dilatation strategies on final stent dimensions. Methods and results: Optical coherence tomography (OCT) was performed on eight bare metal platforms of drug-eluting stents (3.0 mm diameter, n=6 for each) during and after balloon inflation in a silicone mock vessel. After nominal-pressure deployment, a single long (30 sec) vs. multiple short (10 sec x3) post-dilatations were performed using a non-compliant balloon (3.25 mm, 20 atm). Stent areas during deployment with original delivery systems were smaller in stainless steel stents than in cobalt-chromium and platinum-chromium stents (p<0.001), whereas subsequent acute recoil was comparable among the three materials. At post-dilatation, acute recoil was greater in cobalt-chromium and platinum-chromium stents than in stainless steel stents (p<0.001), resulting in smaller final stent areas in cobalt-chromium and platinum-chromium stents than in stainless steel stents (p<0.001). In comparison between conventional and latest-generation cobalt-chromium stents, stent areas were not significantly different after both deployment and post-dilatation. With multiple short post-dilatations, acute recoil was significantly improved from first to third short inflation (p<0.001), achieving larger final area than a single long inflation, despite stent materials/designs (p<0.001). Conclusions: Real-time OCT revealed significant acute recoil in all stent types. Both stent materials/ designs and post-dilatation strategies showed a significant impact on final stent expansion.

JACC. Cardiovascular interventions, Jan 28, 2016

This study evaluated the first clinical use of a new endovascular approach to renal denervation, ... more This study evaluated the first clinical use of a new endovascular approach to renal denervation, using chemical neurolysis, via periadventitial infusion of dehydrated alcohol (ethanol) to perform "perivascular" renal artery sympathetic denervation. Renal denervation remains a promising technology for the treatment of hypertension and other disorders. A novel 3-needle delivery device (Peregrine System Infusion Catheter, Ablative Solutions, Inc., Kalamazoo, Michigan) was introduced into the renal arteries of 18 subjects with refractory hypertension. Microdoses of alcohol were infused bilaterally via the 3 needles into to the adventitial space (0.30 ml/artery, 37 arteries). Renal artery angiography was performed at the time of the procedure and at 6 months (n = 16). The primary safety endpoints were complications associated with the catheter insertion and delivery of the neurolytic agent or any major vascular access complications. The secondary performance endpoint was a redu...

Journal of the American College of Cardiology, 2015

BACKGROUND The efficacy of stent have been established in patients undergoing primary percutaneou... more BACKGROUND The efficacy of stent have been established in patients undergoing primary percutaneous coronary intervention (PCI) for STsegment elevation myocardial infarction (STEMI). However, early stent thrombosis in STEMI patients remains a clinical problem. We used optical coherence tomography (OCT) to assess the impact of abnormal findings after stent implantation such as tissue protrusions and stent malapposition on early stent thrombosis in patients with primary PCI for STEMI. METHODS We studied 110 patients, including 9 with early stent thrombosis after primary stenting with OCT-guidance and 101 matched control subjects without early stent thrombosis. RESULTS Although minimum stent area was similar between 2 groups (6.73 AE 1.89 mm2 vs. 6.80 AE 1.95 mm2, p ¼ 0.695), minimum lumen area within stent was significantly smaller in the early stent thrombosis group (5.35 AE 1.51 mm2 vs. 5.82 AE 1.92 mm2, p ¼ 0.037). Maximum acute stent malapposition area was similar between 2 groups (0.92 AE 1.21 mm2 vs. 0.88 AE 1.35 mm2, p ¼ 0.725). Maximum tissue protrusion area was significantly larger in the early stent thrombosis group (2.55 AE 1.37 mm2 vs. 1.04 AE 0.92 mm2, p < 0.01). CONCLUSIONS Larger tissue protrusion but not acute malapposition after stent implantation were related to early thrombosis after primary PCI for STEMI.

Journal of the American College of Cardiology, 2015

Journal of the American College of Cardiology, 2014

Cardiovascular intervention and therapeutics, Jan 14, 2015

No systematic validation study is available with optical frequency domain imaging (OFDI), directl... more No systematic validation study is available with optical frequency domain imaging (OFDI), directly compared with frequency domain optical coherence tomography (FD-OCT) and intravascular ultrasound (IVUS). Controversy also remains about the impact of different stent contour tracing methods by OFDI/FD-OCT. In vitro: coronary phantom models (1.51-5.04 mm) were imaged with OFDI, FD-OCT, and IVUS, demonstrating excellent quantitative precision with a slight overestimation of mean lumen diameter (difference 0.01-0.02 mm). In vivo: corresponding 64 OFDI/IVUS images of stented coronary segments from 20 swines were analyzed. Minimum lumen area by OFDI was larger than IVUS at baseline (P < 0.001), whereas it was smaller than IVUS at follow-up. When stent was traced at leading edges of struts by OFDI, minimum stent area was similar between OFDI and IVUS (P = 0.60). When traced at the highest intensity points of struts by OFDI, it was significantly larger in OFDI than in IVUS (P < 0.001)....

Journal of Visualized Experiments, 2009

Journal of the American College of Cardiology, Jan 10, 2015

The lack of consistent definitions and nomenclature across clinical trials of novel devices, drug... more The lack of consistent definitions and nomenclature across clinical trials of novel devices, drugs, or biologics poses a significant barrier to accrual of knowledge in and across peripheral artery disease therapies and technologies. Recognizing this problem, the Peripheral Academic Research Consortium, together with the U.S. Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, has developed a series of pragmatic consensus definitions for patients being treated for peripheral artery disease affecting the lower extremities. These consensus definitions include the clinical presentation, anatomic depiction, interventional outcomes, surrogate imaging and physiological follow-up, and clinical outcomes of patients with lower-extremity peripheral artery disease. Consistent application of these definitions in clinical trials evaluating novel revascularization technologies should result in more efficient regulatory evaluation and best practice guidelines t...

Catheterization and Cardiovascular Interventions, 2014

To report our initial animal and human experience with a new multi-lumen catheter called MultiCro... more To report our initial animal and human experience with a new multi-lumen catheter called MultiCross™ (Roxwood Medical, Inc.) in a porcine coronary model and patients with a chronic total occlusion (CTO). Preclinical safety study was done in the coronary vasculature of a porcine model. In a clinical setting, patients with a CTO of a coronary artery (n = 5) were enrolled. After an initial unsuccessful attempt using a conventional guidewire, operators could use the MultiCross system. The primary efficacy endpoint was successful recanalization (technical success) and the primary safety endpoint was serious adverse events through 30 days post-procedure. The MultiCross catheter was used for all patients after failure of the initial attempt with a guidewire. Successful recanalization was achieved in all CTOs attempted (100%). No patients reported any adverse events at 30 days post-procedure. In this first-in-man experience, the MultiCross catheter has the potential to enhance crossing of CTOs. © 2014 Wiley Periodicals, Inc.

Journal of the American College of Cardiology, 2003

OBJECTIVES We evaluated the coronary vasodilatory effects of transcutaneous low-frequency (27-kHz... more OBJECTIVES We evaluated the coronary vasodilatory effects of transcutaneous low-frequency (27-kHz) ultrasound (USD). BACKGROUND Ultrasound has been shown to affect vascular function. METHODS Ultrasound energy was administered transcutaneously to 12 dogs. Coronary arterial dimensions were assessed using intravascular coronary ultrasound (IVUS) and quantitative coronary angiography (QCA). RESULTS The IVUS mid-left anterior descending (LAD) luminal area was 6.77 Ϯ 1.27 mm 2 at baseline. After 30 s of ultrasound, this area increased by 9% (7.40 Ϯ 1.44 mm 2 , p Ͻ 0.05), after 3 min by 19% (8.05 Ϯ 1.72 mm 2 , p Ͻ 0.05) and after 5 min increased by 21% (8.16 Ϯ 1.29 mm 2 , p Ͻ 0.05). The mean coronary diameter (2.69 Ϯ 0.33 mm) at baseline (QCA of three segments of LAD and three segments of left circumflex coronary artery) increased by 19.3% (3.21 Ϯ 0.28 mm) after 5 min of USD exposure. After a 90-min observation period there was a return to baseline values (p ϭ NS). Intracoronary nitroglycerin (NTG) administered to five dogs revealed a similar magnitude of vasodilation as USD. CONCLUSIONS Noninvasive, transthoracic low-frequency USD energy results in coronary artery vasodilation within seconds of exposure. The vasodilation is reversible and is similar in magnitude to that induced by NTG. Further evaluation is needed to assess its potential applications in humans. (

Journal of the American College of Cardiology, 2012

Background: The frequency, type and extent of neoatherosclerosis within drug-eluting stents (DES)... more Background: The frequency, type and extent of neoatherosclerosis within drug-eluting stents (DES) has not been described during very long-term follow-up. Moreover, it is unknown whether DES eluting sirolimus differ from those eluting paclitaxel in the propensity for neoatherosclerosis during long-term follow-up. Methods: The SIRTAX LATE OCT population was analyzed for evidence of neoatherosclerosis within stented segments five years after DES implantation. Using OCT definitions according to the Consensus Statement of the International Working Group of OCT, we assessed the presence of fibrocalcific plaques, fibroatheromas, macrophage accumulations, microvessels, as well as surface erosions and ruptures in each single frame. Plaques were considered to be present in case of a longitudinal extension of at least 1mm, and all other findings had to be visualized in at least three consecutive frames. Results: All segments were independently assessed by two experienced observers. A total of 89 event-free patients with 41 lesions treated with SES (41 patients) and 48 lesions treated with PES (48 patients) were analysed at five years of follow-up. Neoatherosclerotic plaques were observed in 15% of lesions, and fibroatheromas (12.4%) were more common than fibrocalcific plaques (5.6%). While macrophage accumulations were frequently present (32.6%), microvessels (2.2%) and surface erosions (2.2%) were rare, and no plaque rupture was observed. Neoatherosclerotic plaques were more common among lesions treated with PES (25%) than SES (5%; P Ͻ 0.01), and differences between stent types applied to both the frequency of fibrocalcific plaques (SES 0%, PES 10.5%, pϭ0.041) as well as fibroatheromas (SES 4.9% vs. PES 18.8%, pϭ0.046). Similarly, macrophage accumulations were more frequent among lesions treated with PES (47.9%) than SES (14.6%, pϭ0.001). Conclusions: Among event-free patients, neoatherosclerotic plaques were observed in 15% of lesions five years after DES implantation. The frequency, type and extent of neoatherosclerotic changes were importantly influenced by the implanted DES type.

Journal of the American College of Cardiology, 2013

Background: Previous EBCT studies showed that coronary artery calcification (CAC) predicts athero... more Background: Previous EBCT studies showed that coronary artery calcification (CAC) predicts atherosclerotic burden and future cardiac events. However, the mechanism underlying this relationship has not been well studied. Methods: In PROSPECT, following PCI in 697 acute coronary syndrome patients, 3-vessel grayscale and virtual histology (VH) intravascular ultrasound (IVUS) was performed. Untreated non-culprit lesions (NLCs) which were vulnerable (resulting in future events) were found to have large plaque burden, small minimal luminal area (MLA), or be a VH thin-cap fibroatheroma (TCFA). In this analysis, total VH-IVUS dense calcium volume was calculated at the patient level based on the sum of the calcium volumes among the NCLs imaged in each patient (defined as >40% plaque burden for !3 frames). Results: Overall, 609 patients comprised the present analysis. Increasing quartiles of total per patient NCL calcium volume were significantly associated with a smaller per patient MLA among the NCLs identified. Furthermore, the total per patient plaque volume and necrotic core (NC) volume, which were also calculated as the sum of NCL plaque and NC volumes in each patient, were highest in the 4th quartile. Finally, the number of lesions identified as fibroatheroma (FA), a TCFA, or thick-cap fibroatheroma (ThCFA) all increased significantly across quartiles of total calcium volume per-patient (Table). Conclusions: Total NCL calcium volume per patient was significantly associated with high-risk "vulnerable" characteristics including a larger overall plaque burden, a smaller MLA, and greater number of FAs and VH-TCFAs. These findings may explain why CAC score is useful to predict future cardiac events.

Journal of the American College of Cardiology, 2010

The purpose of this study was to investigate the 2-year outcome of percutaneous coronary interven... more The purpose of this study was to investigate the 2-year outcome of percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) in patients with multivessel coronary artery disease (CAD). Background In patients with multivessel CAD undergoing PCI, coronary angiography is the standard method for guiding stent placement. The FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study showed that routine FFR in addition to angiography improves outcomes of PCI at 1 year. It is unknown if these favorable results are maintained at 2 years of follow-up. Methods At 20 U.S. and European medical centers, 1,005 patients with multivessel CAD were randomly assigned to PCI with drug-eluting stents guided by angiography alone or guided by FFR measurements. Before randomization, lesions requiring PCI were identified based on their angiographic appearance. Patients randomized to angiography-guided PCI underwent stenting of all indicated lesions, whereas those randomized to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was Յ0.80. Results The number of indicated lesions was 2.7 Ϯ 0.9 in the angiography-guided group and 2.8 Ϯ 1.0 in the FFRguided group (p ϭ 0.34). The number of stents used was 2.7 Ϯ 1.2 and 1.9 Ϯ 1.3, respectively (p Ͻ 0.001). The 2-year rates of mortality or myocardial infarction were 12.9% in the angiography-guided group and 8.4% in the FFR-guided group (p ϭ 0.02). Rates of PCI or coronary artery bypass surgery were 12.7% and 10.6%, respectively (p ϭ 0.30). Combined rates of death, nonfatal myocardial infarction, and revascularization were 22.4% and 17.9%, respectively (p ϭ 0.08). For lesions deferred on the basis of FFR Ͼ0.80, the rate of myocardial infarction was 0.2 % and the rate of revascularization was 3.2 % after 2 years. Conclusions Routine measurement of FFR in patients with multivessel CAD undergoing PCI with drug-eluting stents significantly reduces mortality and myocardial infarction at 2 years when compared with standard angiography-guided PCI.

Journal of Biomedicine and Biotechnology, 2011

To improve human health, scientific discoveries must be translated into practical applications. I... more To improve human health, scientific discoveries must be translated into practical applications. Inherent in the development of these technologies is the role of preclinical testing using animal models. Although significant insight into the molecular and cellular basis has come from small animal models, significant differences exist with regard to cardiovascular characteristics between these models and humans. Therefore, large animal models are essential to develop the discoveries from murine models into clinical therapies and interventions. This paper will provide an overview of the more frequently used large animal models, especially porcine models for preclinical studies.

Journal of the American College of Cardiology, Jan 20, 2012

The purpose of this document is to make the output of the International Working Group for Intrava... more The purpose of this document is to make the output of the International Working Group for Intravascular Optical Coherence Tomography (IWG-IVOCT) Standardization and Validation available to medical and scientific communities, through a peer-reviewed publication, in the interest of improving the diagnosis and treatment of patients with atherosclerosis, including coronary artery disease.

JACC: Cardiovascular Interventions, 2008

Objectives The purpose of this study was to evaluate optical coherence tomography (OCT) for detec... more Objectives The purpose of this study was to evaluate optical coherence tomography (OCT) for detecting small degrees of in-stent neointima (ISN) after stent implantation compared with intravascular ultrasound (IVUS). Background The importance of detecting neointimal coverage of stent struts has grown with the appreciation of the increased risk for late stent thrombosis after drug-eluting stent (DES) implantation. Intravascular ultrasound, the current standard for evaluating the status of DES, lacks the resolution to detect the initial neointimal coverage. Optical coherence tomography has greater resolution but has not yet been compared with IVUS in vivo with histological correlation for validation. Methods Intravascular ultrasound and OCT were performed with motorized pullback imaging in 6 pigs across 33 stents, 1 month after implantation. Each pig was euthanized, and histological measurements of vessel, stent, and lumen dimensions were performed in 3 sections of each stent. A small degree of ISN was defined as occupying Ͻ30% of the stent area measured with histology. The IVUS, OCT, and histological assessment of ISN were compared in matched cross-sections of the stents with a small degree of ISN. Results Eleven stents had a small degree of ISN (average ISN area: 1.26 Ϯ 0.46 mm 2 , and percent area obstruction: 21.4 Ϯ 5.2%). Compared with histology, the diagnostic accuracy of OCT (area under the receiver operating characteristic curve [AUC] ϭ 0.967, 95% confidence interval [CI] 0.914 to 1.019) was higher than that of IVUS (AUC ϭ 0.781, 95% CI 0.621 to 0.838). Conclusions Optical coherence tomography detects smaller degrees of ISN more accurately than IVUS and might be a useful method for identifying neointimal coverage of stent struts after DES implantation.

JACC: Cardiovascular Interventions, 2009

Objectives The aim of this study was to clarify whether pioglitazone suppresses in-stent neointim... more Objectives The aim of this study was to clarify whether pioglitazone suppresses in-stent neointimal proliferation and reduces restenosis and target lesion revascularization (TLR) after percutaneous coronary intervention (PCI). Background Previous single-center studies have demonstrated the anti-restenotic effect of a peroxisome proliferator-activated receptor gamma agonist, pioglitazone, after PCI. Methods A total of 97 patients with type 2 diabetes mellitus (T2DM) undergoing PCI (bare-metal stents only) were enrolled. After PCI, patients were randomly assigned to either the pioglitazone group (n ϭ 48) or the control group (n ϭ 49). Angiographical and intravascular ultrasound (IVUS) imaging were performed at baseline and repeated at 6-month follow-up. Primary end points included angiographical restenosis and TLR at 6 months follow-up. Secondary end point was in-stent neointimal volume by IVUS. Results Baseline glucose level and glycosylated hemoglobin (HbA1c) level were similar between the pioglitazone group and the control group. Angiographical restenosis rate was 17% in the pioglitazone group and 35% in control group (p ϭ 0.06). The TLR was significantly lower in pioglitazone group than in control group (12.5% vs. 29.8%, p ϭ 0.04). By IVUS (n ϭ 56), in-stent neointimal volume at 6 months showed a trend toward smaller in the pioglitazone group than in the control group (48.0 Ϯ 30.2 mm 3 vs. 62.7 Ϯ 29.0 mm 3 , p ϭ 0.07). Neointimal index (neointimal volume/stent volume ϫ 100) was significantly smaller in the pioglitazone group than in the control group (31.1 Ϯ 14.3% vs. 40.5 Ϯ 12.9%, p ϭ 0.01).

JACC: Cardiovascular Interventions, 2009

Scientific discoveries for improvement of human health must be translated into practical applicat... more Scientific discoveries for improvement of human health must be translated into practical applications. Such discoveries typically begin at "the bench" with basic research, then progress to the clinical level. In particular, in the field of interventional cardiology, percutaneous cardiovascular intervention has rapidly evolved from an experimental procedure to a therapeutic clinical setting. Pre-clinical studies using animal models play a very important role in the evaluation of efficacy and safety of new medical devices before their use in human clinical studies. This review provides an overview of the emerging role, results of pre-clinical studies and development, and evaluation of animal models for percutaneous cardiovascular intervention technologies for patients with symptomatic cardiovascular disease. (J Am

Circulation journal : official journal of the Japanese Circulation Society, Jan 30, 2018

Comparative medicine, 2017

EuroIntervention, 2016

JACC. Cardiovascular interventions, Jan 28, 2016

Journal of the American College of Cardiology, 2015

Journal of the American College of Cardiology, 2014

Cardiovascular intervention and therapeutics, Jan 14, 2015

Journal of Visualized Experiments, 2009

Journal of the American College of Cardiology, Jan 10, 2015

Catheterization and Cardiovascular Interventions, 2014

Journal of the American College of Cardiology, 2003

Journal of the American College of Cardiology, 2012

Journal of the American College of Cardiology, 2013

Journal of the American College of Cardiology, 2010

Journal of Biomedicine and Biotechnology, 2011

Journal of the American College of Cardiology, Jan 20, 2012

JACC: Cardiovascular Interventions, 2008

JACC: Cardiovascular Interventions, 2009

Compared to rotational atherectomy (RA), orbital atherectomy (OA) has been shown to decrease proc... more Compared to rotational atherectomy (RA),
orbital atherectomy (OA) has been shown to decrease procedure
failure and reintervention rates in the treatment of
severely calcifed coronary artery lesions. Our objective was
to explore the cost-efectiveness of OA compared to RA in
the Japanese healthcare system. A decision-analytic model
calculated reintervention rates and consequent total 1-year
costs. Effectiveness inputs were therapy-specific target
lesion revascularization (TLR) rates and all-cause mortality,
pooled from clinical studies. Index and reintervention costs
were determined based on claims data analysis of n = 33,628
subjects treated in 2014–2016. We computed incremental
cost-efectiveness in Japanese Yen (JPY) per life year (LY)
gained based on diferences in 1-year cost and projected
long-term survival, assuming OA device cost between JPY
350,000 and JPY 550,000. OA was found to be associated
with improved clinical outcomes (12-month TLR rate 5.0
vs. 15.7%) and projected survival gain (8.34 vs. 8.16 LYs
(+0.17), based on 1-year mortality of 5.5 vs. 6.8%). Total
1-year costs were lower for device cost of JPY 430,000 or
less, and reached a maximum ICER of JPY 753,445 per LY
at the highest assumed device cost, making OA dominant
or cost-efective across the tested range, at ICERs substantially
below the willingness-to-pay threshold. In conclusion,
orbital atherectomy for the treatment of severely calcifed
coronary artery lesions, compared to rotational atherectomy,
is a cost-efective treatment approach in the Japanese healthcare
system due to improved clinical performance.