Global Medical Device Clinical Trials Involving Both the United States and Japan: Key Considerations for Development, Regulatory Approval, and Conduct.

As medical device development becomes increasingly global, the opportunities and potential advantages offered by international clinical trial and regulatory approval strategies are also growing. In particular, medical device clinical trials involving sites in both the United States and Japan and intended to support marketing in both countries may warrant particular consideration, given the similarities in their regulatory systems, patients and clinical practice patterns, and market sizes. Since 2003, the US-Japan Harmonization By Doing (HBD) initiative has been focused on identifying and addressing clinical and regulatory barriers to medical devices access in both countries via collaboration between governmental, academic, and industry stakeholders. Through the efforts of HBD participants, US-Japanese clinical trials have been conducted and the resulting data have supported regulatory approval for marketing in both countries. Based on these experiences, this paper outlines some of the key factors to consider when developing a global clinical trial involving US and Japanese participation. These considerations include the mechanisms for consultation with regulatory authorities on clinical trial strategies, the regulatory framework for clinical trial notification and approval, recruitment and conduct of clinical sites, and lessons learned from specific US-Japanese clinical trial experiences. The goal of this paper is to promote global access to promising medical technologies by assisting potential clinical trial sponsors in understanding when an international strategy may be appropriate and successful.

The associations of the national health and productivity management program with corporate profits in Japan.

OBJECTIVES: Using a dataset from a survey on national health and productivity management, we identified health and productivity factors associated with organizational profitability. METHODS: The Ministry of Economy, Trade and Industry conducted an annual survey on Health and Productivity Management between 2014 and 2021. We assessed the associations of organizational health and productivity management using survey questions collected in 2017 and 2018, with the rate of change in profits from 2017 and 2018 to 2020. We identified factors associated with organizational profitability using eXtreme Gradient Boosting, and calculated SHapley Additive exPlanation (SHAP) values for each factor. RESULTS: Among 1,593 companies (n= 4,359,834 employees), the mean age of employees at baseline was 40.3 years and the proportion of women was 25.8%. A confusion matrix for evaluating model performance had an accuracy of 0.997, precision of 0.993, recall of 0.997, and area under the precision-recall curve of 0.999. The most important factors related to an increase in corporate profits were the percentage of current smokers (SHAP value, 0.121), per-employee cost of health services (0.084) and medical services (0.050); the percentage of full-time employees working in sales departments (0.074) and distribution or customer service departments (0.054); the percentage of employees who slept well (0.055); and the percentage of employees within a company who regularly exercised (0.043). CONCLUSIONS: Employees' lifestyle-related health risk factors and organizations' management systems were associated with organizational profitability. Lifestyle medicine professionals may demonstrate a significant return on investment by creating a healthier and more productive workforce.

Japan-USA Orbital Atherectomy for Calcific Coronary Lesions: COAST Study, Harmonization by Doing Proof-of-Concept.

Effective treatment strategies and medical devices continue to be needed in Japan and the United States of America (US) to mitigate the growing burden of cardiovascular disease and coronary heart disease. Unfortunately, there can be a delay in gaining cardiovascular device approval in Japan after a device has already been approved and is in use in the US. The Harmonization by Doing (HBD) program; however, can eliminate this delay and reduce the cost of completing a clinical trial in Japan. The HBD proof-of-concept study, COAST, resulted in approval of the Diamondback 360® Coronary Orbital Atherectomy System Micro Crown simultaneously in Japan and the US on the same day. Subsequently, the Diamondback 360® Coronary OAS Classic Crown also received approval in Japan. The COAST study provides further evidence that global clinical trials via HBD for medical devices are practical and advantageous.

In Vivo Translation of the CIRPI System: Revealing Molecular Pathology of Rabbit Aortic Atherosclerotic Plaques.

Thin-cap fibroatheroma (TCFA) are the unstable lesions in coronary artery disease that are prone to rupture, resulting in substantial morbidity and mortality worldwide. However, their small size and complex morphologic and biologic features make early detection and risk assessment difficult. We tested our newly developed catheter-based Circumferential-Intravascular-Radioluminescence-Photoacoustic-Imaging (CIRPI) system in vivo to enable detection and characterization of vulnerable plaque structure and biology in rabbit abdominal aorta. Methods: The CIRPI system includes a novel optical probe combining circumferential radioluminescence imaging and photoacoustic tomography (PAT). The probe's CaF2:Eu-based scintillating imaging window captures radioluminescence images (360° view) of plaques by detecting ß-particles during 18F-FDG decay. A tunable laser-based PAT characterizes tissue constituents of plaque at 7 different wavelengths-540 and 560 nm (calcification), 920 nm (cholesteryl ester), 1040 nm (phospholipids), 1180 nm (elastin/collagen), 1210 nm (cholesterol), and 1235 nm (triglyceride). A single B-scan is concatenated from 330 A-lines captured during a 360° rotation. The abdominal aorta was imaged in vivo in both atherosclerotic rabbits (Watanabe Heritable Hyper Lipidemic [WHHL], 13-mo-old male, n = 5) and controls (New Zealand White, n = 2). Rabbits were fasted for 6 h before 5.55 × 107 Bq (1.5 mCi) of 18F-FDG were injected 1 h before the imaging procedure. Rabbits were anesthetized, and the right or left common carotid artery was surgically exposed. An 8 French catheter sheath was inserted into the common carotid artery, and a 0.035-cm (0.014-in) guidewire was advanced to the iliac artery, guided by x-ray fluoroscopy. A bare metal stent was implanted in the dorsal abdominal aorta as a landmark, followed by the 7 French imaging catheters that were advanced up to the proximal stent edge. Our CIRPI and clinical optical coherence tomography (OCT) were performed using pullback and nonocclusive flushing techniques. After imaging with the CIRPI system, the descending aorta was flushed with contrast agent, and OCT images were obtained with a pullback speed of 20 mm/s, providing images at 100 frames/s. Results were verified with histochemical analysis. Results: Our CIRPI system successfully detected the locations and characterized both stable and vulnerable aortic plaques in vivo among all WHHL rabbits. Calcification was detected from the stable plaque (540 and 560 nm), whereas TCFA exhibited phospholipids/cholesterol (1040 nm, 1210 nm). These findings were further verified with the clinical OCT system showing an area of low attenuation filled with lipids within TCFA. PAT images illustrated broken elastic fiber/collagen that could be verified with the histochemical analysis. All WHHL rabbits exhibited sparse to severe macrophages. Only 4 rabbits showed both moderate-to-severe level of calcifications and cholesterol clefts. However, all rabbits exhibited broken elastic fibers and collagen deposition. Control rabbits showed normal wall thickness with no presence of plaque tissue compositions. These findings were verified with OCT and histochemical analysis. Conclusion: Our novel multimodality hybrid system has been successfully translated to in vivo evaluation of atherosclerotic plaque structure and biology in a preclinical rabbit model. This system proposed a paradigm shift that unites molecular and pathologic imaging technologies. Therefore, the system may enhance the clinical evaluation of TCFA, as well as expand our understanding of coronary artery disease.

The East-West late lumen loss study: Comparison of angiographic late lumen loss between Eastern and Western drug-eluting stent study cohorts.

BACKGROUND: Regulatory decisions approving new coronary drug-eluting stent (DES) require mechanistic observations of angiographic late lumen loss (LLL). Patient safety and device approval times could be enhanced if angiographic follow-up data were found to be generalizable across jurisdictions and geographies. The objectives were to assess the comparability of in-segment LLL in Eastern and Western DES populations using the world's largest compilation of follow-up quantitative coronary angiography data. METHODS: Data from 4 manufacturers involving 29 DES clinical trials in Eastern and Western hemispheres were compiled. "East" and "West" cohorts were defined by trial location. Independent core laboratories quantified in-segment LLL for all studies. East and West were compared before and after adjustment for clinical and anatomic covariates known to correlate with LLL via conditioning on propensity score quintiles. An international panel of experts and regulators prospectively established a clinically meaningful difference between East and West mean in-segment LLL of ±0.40 mm. RESULTS: The data set comprised 2,047 East and 4,456 West patients. Unadjusted mean ± SD for West and East in-segment LLL (mm) was 0.25 ± 0.46 and 0.12 ± 0.42, respectively (difference 0.13 mm; 95% CI 0.11-0.16). Propensity score-adjusted in-segment LLL East and West least squares means were 0.11 and 0.26 mm, respectively (difference 0.15 mm; 95% CI 0.13-0.18). CONCLUSIONS: In the world's largest compilation of DES protocol 8- to 13-month angiographic follow-up data, clinically meaningful comparability of in-segment LLL by independent core laboratory quantitative coronary angiography in East and West cohorts was demonstrated in both unadjusted and adjusted comparisons. These findings suggest that DES LLL, once characterized, could be generalized across regulatory jurisdictions over the course of global registration efforts.

Design Strategies for Global Clinical Trials of Endovascular Devices for Critical Limb Ischemia (CLI)　- A Joint USA-Japanese Perspective.

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 recommendations for conducting global CLI device studies are: including patients on dialysis; using a composite primary endpoint for effectiveness that includes 6-month post-procedure therapeutic success and target vessel patency; and using a 30-day primary safety endpoint of perioperative death and major adverse limb events. The proposed approach will be uniquely beneficial in facilitating both the initiation and interpretation of CLI studies and accelerating worldwide CLI device development and innovation.

Dose-Dependent Cardioprotection of Moderate (32°C) Versus Mild (35°C) Therapeutic Hypothermia in Porcine Acute Myocardial Infarction.

OBJECTIVES: The study investigated whether a dose response exists between myocardial salvage and the depth of therapeutic hypothermia. BACKGROUND: Cardiac protection from mild hypothermia during acute myocardial infarction (AMI) has yielded equivocal clinical trial results. Rapid, deeper hypothermia may improve myocardial salvage. METHODS: Swine (n = 24) undergoing AMI were assigned to 3 reperfusion groups: normothermia (38°C) and mild (35°C) and moderate (32°C) hypothermia. One-hour anterior myocardial ischemia was followed by rapid endovascular cooling to target reperfusion temperature. Cooling began 30 min before reperfusion. Target temperature was reached before reperfusion and was maintained for 60 min. Infarct size (IS) was assessed on day 6 using cardiac magnetic resonance, triphenyl tetrazolium chloride, and histopathology. RESULTS: Triphenyl tetrazolium chloride area at risk (AAR) was equivalent in all groups (p = 0.2), but 32°C exhibited 77% and 91% reductions in IS size per AAR compared with 35°C and 38°C, respectively (AAR: 38°C, 45 ± 12%; 35°C, 17 ± 10%; 32°C, 4 ± 4%; p < 0.001) and comparable reductions per LV mass (LV mass: 38°C, 14 ± 5%; 35°C, 5 ± 3%; 32°C 1 ± 1%; p < 0.001). Importantly, 32°C showed a lower IS AAR (p = 0.013) and increased immunohistochemical granulation tissue versus 35°C, indicating higher tissue salvage. Delayed-enhancement cardiac magnetic resonance IS LV also showed marked reduction at 32°C (38°C: 10 ± 4%, p < 0.001; 35°C: 8 ± 3%; 32°C: 3 ± 2%, p < 0.001). Cardiac output on day 6 was only preserved at 32°C (reduction in cardiac output: 38°C, -29 ± 19%, p = 0.041; 35°C: -17 ± 33%; 32°C: -1 ± 28%, p = 0.041). Using linear regression, the predicted IS reduction was 6.7% (AAR) and 2.1% (LV) per every 1°C reperfusion temperature decrease. CONCLUSIONS: Moderate (32°C) therapeutic hypothermia demonstrated superior and near-complete cardioprotection compared with 35°C and control, warranting further investigation into clinical applications.

Correction to: Cost-effectiveness of orbital atherectomy compared to rotational atherectomy in treating patients with severely calcified coronary artery lesions in Japan.

In the original publication of this article, in Abstract the 1-year mortality of OAS should be stated as 4.7 and not 5.5%.

Cost-effectiveness of orbital atherectomy compared to rotational atherectomy in treating patients with severely calcified coronary artery lesions in Japan.

Compared to rotational atherectomy (RA), orbital atherectomy (OA) has been shown to decrease procedure failure and reintervention rates in the treatment of severely calcified coronary artery lesions. Our objective was to explore the cost-effectiveness 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-effectiveness in Japanese Yen (JPY) per life year (LY) gained based on differences 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-effective across the tested range, at ICERs substantially below the willingness-to-pay threshold. In conclusion, orbital atherectomy for the treatment of severely calcified coronary artery lesions, compared to rotational atherectomy, is a cost-effective treatment approach in the Japanese healthcare system due to improved clinical performance.

Assessment of bioresorbable scaffold with a novel high-definition 60 MHz IVUS imaging system: Comparison with 40-MHz IVUS referenced to optical coherence tomography.

BACKGROUND: In vivo assessment of bioresorbable scaffold (BRS) is of growing clinical interest. The novel 60MHz high-definition intravascular ultrasound (HD-IVUS) has been developed to overcome the limitations of conventional 40 MHz IVUS. This study aimed to evaluate the performance and limitations of 60 MHz HD-IVUS compared with 40 MHz IVUS with respect to polymeric-strut visualization, quantitative and qualitative analysis, and feasibility of high-speed pullback in the assessment of BRS. METHODS AND RESULTS: In a bench-test model, 361 struts were analyzed to evaluate the influence of ultrasound-beam angles and proximity of adjacent struts on IVUS visualization of BRS struts. Various settings were created by deforming the BRS and positioning the transducer offcenter. In an in vivo swine coronary model, scaffold and lumen areas, degree of visible external elastic membrane, incomplete strut apposition, and strut fracture were evaluated in 59 matched cross-sections obtained at conventional (0.5 mm/sec) and high speed (10 mm/sec) pullbacks. Both studies utilized optical coherence tomography (OCT) as reference. Overall, 60 MHz HD-IVUS demonstrated significantly improved visualization of polymeric struts compared with 40 MHz IVUS (well-visualized: 84.5% vs 62.3%, not visible: 4.4% vs 13.9%, respectively. P < 0.001), which was less affected by the beam angle and adjacent strut proximity. In the in vivo model, 60-MHz HD-IVUS showed better agreement of area measurements and strut abnormalities with OCT than 40 MHz IVUS. These findings were also confirmed on high-speed pullback images of 60 MHz HD-IVUS. CONCLUSION: As referenced to OCT, this study showed superiority of 60 MHz HD-IVUS over 40 MHz IVUS in the assessment of BRS with feasibility of high-speed pullback imaging.

Differences in Vascular Response between Balloon Overstretch and Stent Overexpansion in Nonatherosclerotic Porcine Coronary Arteries.

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 increased plaque burden. In the balloon-injury sites, high B:A ratios were significantly associated with greater negative remodeling. Tissue morphology assessment by OCT revealed that the predominant pattern in balloon injury sites was homogeneous, whereas that in stented sites was a layered to heterogeneous pattern. Neointimal proliferation was significantly greater after oversized stenting than after balloon overstretch injury. Together these findings suggest that stent overexpansion of porcine coronary arteries might be appropriate for researching restenosis than is the balloon overstretch injury model.

Improvement of Local Cell Delivery Using Helix Transendocardial Delivery Catheter in a Porcine Heart.

Cardiac regeneration strategies using stem cells have shown variable and inconsistent results with respect to patient cardiac function and clinical outcomes. There has been increasing consensus that improving the efficiency of delivery may improve results. The Helix transendocardial delivery system (BioCardia Inc.) has been developed to enable percutaneous transendocardial biotherapeutic delivery. Therefore, we evaluated cell retention using this unique system compared with direct transepicardial injection and intracoronary infusion in an animal model.Twelve healthy swine were used in this study. 18Fluorodeoxyglucose (FDG)-labeled bone marrow mononuclear cells were delivered via percutaneous transendocardial route using the Helix system (TE group, n = 5), via direct transepicardial injection using a straight 27-gauge needle in an open chest procedure (TP group, n = 4), or via percutaneous intracoronary (IC) infusion (IC group, n = 3). One hour after cell delivery, the distribution of injected cells within the myocardium was assessed by PET-CT. Regions of interest were defined and their signals were compared in each group. Retention rates were calculated as a percentage of the comparing signal.The distribution of injected cells in the myocardium was higher in the TE group (17.9%) than in the TP group (6.0%, versus TE, P < 0.001) and the IC group (1.0%, versus TE, P < 0.001). Consistent with previous reports, there were signal distributions in the lungs, liver, and kidneys in qualitative whole body PET assessment.TE cell delivery using a helical infusion catheter is more efficient in cell retention than either TP delivery or IC delivery using PET-CT analysis.

SYNTAX Score and Long-Term Outcomes: The BARI-2D Trial.

BACKGROUND: The extent of coronary disease affects clinical outcomes and may predict the effectiveness of coronary revascularization with either coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score quantifies the extent of coronary disease. OBJECTIVES: This study sought to determine whether SYNTAX scores predicted outcomes and the effectiveness of coronary revascularization compared with medical therapy in the BARI-2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. METHODS: Baseline SYNTAX scores were retrospectively calculated for BARI-2D patients without prior revascularization (N = 1,550) by angiographic laboratory investigators masked to patient characteristics and outcomes. The primary outcome was major cardiovascular events (a composite of death, myocardial infarction, and stroke) over 5 years. RESULTS: A mid/high SYNTAX score (≥23) was associated with a higher risk of major cardiovascular events (hazard ratio: 1.36, confidence interval: 1.07 to 1.75, p = 0.01). Patients in the CABG stratum had significantly higher SYNTAX scores: 36% had mid/high SYNTAX scores compared with 13% in the PCI stratum (p < 0.001). Among patients with low SYNTAX scores (≤22), major cardiovascular events did not differ significantly between revascularization and medical therapy, either in the CABG stratum (26.1% vs. 29.9%, p = 0.41) or in the PCI stratum (17.8% vs. 19.2%, p = 0.84). Among patients with mid/high SYNTAX scores, however, major cardiovascular events were lower after revascularization than with medical therapy in the CABG stratum (15.3% vs. 30.3%, p = 0.02), but not in the PCI stratum (35.6% vs. 26.5%, p = 0.12). CONCLUSIONS: Among patients with diabetes and stable ischemic heart disease, higher SYNTAX scores predict higher rates of major cardiovascular events and were associated with more favorable outcomes of revascularization compared with medical therapy among patients suitable for CABG. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes; NCT00006305).

Clinical value of post-percutaneous coronary intervention fractional flow reserve value: A systematic review and meta-analysis.

BACKGROUND: Fractional flow reserve (FFR) prior to percutaneous coronary intervention (PCI) is useful to guide treatment. Whether post-PCI FFR assessment might have clinical impact is controversial. The aim of this study is to evaluate the range of post-PCI FFR values and analyze the relationship between post-PCI FFR and clinical outcomes. METHODS: We systematically searched the PubMed, EMBASE, and Cochrane Library databases with cross-referencing of articles reporting post-PCI FFR and correlating post-PCI FFR values and clinical outcomes. The outcomes of interest were the immediate post-PCI FFR values and the correlations between post-PCI FFR and the incidence of repeat intervention and major adverse cardiac events (MACE). RESULTS: From 1995 to 2015, a total of 105 studies (n = 7470) were included, with 46 studies reporting post-PCI FFR and 59 studies evaluating relationship between post-PCI and clinical outcomes up to 30 months after PCI. Overall, post-PCI FFR values demonstrated a normal distribution with a mean value of 0.90 ± 0.04. There was a positive correlation between the percentage of stent use and post-PCI FFR (P < .0001). Meta-regression analysis indicated that higher post-PCI FFR values were associated with reduced rates of repeat intervention (P < .0001) and MACE (P = .0013). A post-PCI FFR ≥0.90 was associated with significantly lower risk of repeat PCI (odds ratio 0.43, 95% CI 0.34-0.56, P < .0001) and MACE (odds ratio 0.71, 95% CI 0.59-0.85, P = .0003). CONCLUSIONS: FFR measurement after PCI was associated with prognostic significance. Further investigation is required to assess the role of post-PCI FFR and validate cutoff values in contemporary clinical practice.

Rationale and design of the East-West late lumen loss study: Comparison of late lumen loss between Eastern and Western drug-eluting stent study cohorts.

BACKGROUND: The contemporary evaluation of novel drug-eluting stents (DES) includes mechanistic observations that characterize postdeployment stent behavior. Quantification of late lumen loss due to neointimal hyperplasia 8-13 months after stent implantation, via quantitative coronary angiography (QCA), constitutes such an observation and is required by most regulatory authorities. Late lumen loss, as determined by QCA, has been validated as a surrogate for clinical endpoints such as target vessel revascularization. The mechanistic response to DES has not been directly compared across predominantly Asian or Western populations, whereas understanding their comparability across geographic populations could enhance global DES evaluation. OBJECTIVE: The East-West late lumen loss study is designed to demonstrate whether the residual differences in late lumen loss, as assessed by QCA, is different between Eastern and Western DES recipients from studies with protocol angiography at 8-13 months of follow-up. METHODS: Data from independent core laboratories that have characterized angiographic late lumen loss in DES clinical trials with protocol follow-up angiography will be compiled and dichotomized into Eastern and Western populations. A prospectively developed propensity score model incorporating clinical and anatomic variables affecting late lumen loss will be used to adjust comparisons of QCA measurements. CONCLUSION: Documentation of whether there are clinically meaningful differences in mechanistic response to DES implantation across genetically unique geographies could facilitate both the quality and efficiency of global device evaluation requiring invasive follow-up for novel stent designs.

Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part II. In Vivo Imaging of Bone Marrow Stromal Cells in Swine with PET/CT and MR Imaging.

Purpose To quantitatively determine the limit of detection of marrow stromal cells (MSC) after cardiac cell therapy (CCT) in swine by using clinical positron emission tomography (PET) reporter gene imaging and magnetic resonance (MR) imaging with cell prelabeling. Materials and Methods Animal studies were approved by the institutional administrative panel on laboratory animal care. Seven swine received 23 intracardiac cell injections that contained control MSC and cell mixtures of MSC expressing a multimodality triple fusion (TF) reporter gene (MSC-TF) and bearing superparamagnetic iron oxide nanoparticles (NP) (MSC-TF-NP) or NP alone. Clinical MR imaging and PET reporter gene molecular imaging were performed after intravenous injection of the radiotracer fluorine 18-radiolabeled 9-[4-fluoro-3-(hydroxyl methyl) butyl] guanine ((18)F-FHBG). Linear regression analysis of both MR imaging and PET data and nonlinear regression analysis of PET data were performed, accounting for multiple injections per animal. Results MR imaging showed a positive correlation between MSC-TF-NP cell number and dephasing (dark) signal (R(2) = 0.72, P = .0001) and a lower detection limit of at least approximately 1.5 × 10(7) cells. PET reporter gene imaging demonstrated a significant positive correlation between MSC-TF and target-to-background ratio with the linear model (R(2) = 0.88, P = .0001, root mean square error = 0.523) and the nonlinear model (R(2) = 0.99, P = .0001, root mean square error = 0.273) and a lower detection limit of 2.5 × 10(8) cells. Conclusion The authors quantitatively determined the limit of detection of MSC after CCT in swine by using clinical PET reporter gene imaging and clinical MR imaging with cell prelabeling. (©) RSNA, 2016 Online supplemental material is available for this article.

Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part I. Reporter Gene Design, Characterization, and Optical in Vivo Imaging of Bone Marrow Stromal Cells after Myocardial Infarction.

Purpose To use multimodality reporter-gene imaging to assess the serial survival of marrow stromal cells (MSC) after therapy for myocardial infarction (MI) and to determine if the requisite preclinical imaging end point was met prior to a follow-up large-animal MSC imaging study. Materials and Methods Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice (n = 19) that had experienced MI were injected with bone marrow-derived MSC that expressed a multimodality triple fusion (TF) reporter gene. The TF reporter gene (fluc2-egfp-sr39ttk) consisted of a human promoter, ubiquitin, driving firefly luciferase 2 (fluc2), enhanced green fluorescent protein (egfp), and the sr39tk positron emission tomography reporter gene. Serial bioluminescence imaging of MSC-TF and ex vivo luciferase assays were performed. Correlations were analyzed with the Pearson product-moment correlation, and serial imaging results were analyzed with a mixed-effects regression model. Results Analysis of the MSC-TF after cardiac cell therapy showed significantly lower signal on days 8 and 14 than on day 2 (P = .011 and P = .001, respectively). MSC-TF with MI demonstrated significantly higher signal than MSC-TF without MI at days 4, 8, and 14 (P = .016). Ex vivo luciferase activity assay confirmed the presence of MSC-TF on days 8 and 14 after MI. Conclusion Multimodality reporter-gene imaging was successfully used to assess serial MSC survival after therapy for MI, and it was determined that the requisite preclinical imaging end point, 14 days of MSC survival, was met prior to a follow-up large-animal MSC study. (©) RSNA, 2016 Online supplemental material is available for this article.

Acute stent recoil and optimal balloon inflation strategy: an experimental study using real-time optical coherence tomography.

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.

Transcatheter Alcohol-Mediated Perivascular Renal Denervation With the Peregrine System: First-in-Human Experience.

OBJECTIVES: 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. BACKGROUND: Renal denervation remains a promising technology for the treatment of hypertension and other disorders. METHODS: 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 reduction in office-based systolic blood pressure at 6 months compared with baseline. RESULTS: Procedural success was achieved in 100% of subjects (N = 18) and arteries (N = 37). There were no study-related adverse clinical events at follow-up. One death of a subject was recorded but determined by the investigator and an independent medical monitor to be non-study related. There were no angiographic observations of renal artery stenosis, aneurysms, or other renal artery abnormalities at 6 months (32 renal arteries). Sixteen of the 18 subjects had a 6-month follow-up. The mean office systolic blood pressure decreased from 175 ± 17 mm Hg to 151 ± 26 mm Hg (-24 mm Hg). There was an average reduction of antihypertensive medications from 3.4 (baseline) to 2.0 per subject at 6 months. CONCLUSIONS: Chemical renal denervation using the infusion of very low doses of alcohol directly into the adventitial space appears to be feasible and safe. This approach may be a promising alternative approach to perform catheter-based renal denervation. These results need to be confirmed in larger scale clinical studies.