Published papers

© 2018 Elsevier Inc. Molecular imaging provides multiple imaging techniques to identify characteristics of vulnerable plaque including I) Inflammatory cells (the presence and metabolic activity of macrophages), II) synthesis of lipid and fatty acid in the plaque, III) the presence of hypoxia in severely inflamed lesions, IV) expression of factors stimulating angiogenesis, V) expression of protease enzymes in the lesion, VI) development of microthrombi in late-phase lesions, VII) apoptosis, and VIII) microcalcification.

© 2019 S. Karger AG, Basel. Patients with chronic kidney disease (CKD) have an increased risk of adverse cardiovascular/cerebrovascular events. The aim of this study is to clarify whether stress myocardial perfusion single-photon emission computed tomography (SPECT) could predict cardiovascular/cerebrovascular events. In the Gunma-CKD SPECT Study, a multicenter prospective cohort trial, 311 patients with CKD (estimated glomerular filtration rate < 60 min/mL/1.73 m2) including 50 patients on hemodialysis underwent stress 99mTc-tetrofosmin SPECT for suspected ischemic heart disease and were followed for 2 years. The primary endpoint was the occurrence of cardiac death (CD), while the secondary endpoint was major adverse cardiovascular/cerebrovascular and renal events (MACCRE). MACCRE occurred in 91 out of 286 patients (CD in 13 and other MACCRE in 78 patients). According to a multivariate Cox analysis, hemoglobin (Hb) and end-systolic volume (ESV) were associated with CD (p < 0.05), while the summed difference score, diabetes mellitus (DM), and Hb were associated with MACCRE (p < 0.05). Kaplan-Meier analysis showed that the CD-free rate was higher in patients with ESV < 105 mL (log-rank, p = 0.0013), Hb > 12 g (log-rank, p = 0.0036), and a summed stress score < 6 (log-rank, p = 0.0058). The MACCRE-free rate was higher in patients with SDS = 0 (log-rank, p = 0.0097), without DM (log-rank, p = 0.0091), and with Hb > 12 g (log-rank, p = 0.0023). Myocardial perfusion SPECT parameters as well as renal anemia and DM can be reliable prognostic markers in patients with CKD including hemodialysis.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Purpose: Dual-energy computed tomography (DECT) can be used for visual determination of iodine distribution in the myocardium (iodine image); however, the accuracy and reproducibility of the process remains debatable. Because of the low contrast-to-noise ratio of CT, we hypothesized that quantitative measurement may be more accurate for detecting myocardial ischemia. In this study, we evaluated our quantitative method by comparing it with visual analysis using 99mTc-tetrofosmin (TF) stress-rest single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) as the reference standard. Materials and Methods: Forty-three patients who had a significant stenosis on cardiac rest DECT and had received 99mTc-TF stress-rest SPECT MPI within 1 month were retrospectively analyzed. The regions of interest were set on iodine images in accordance with the American Heart Association (AHA) 17-segment model (a total of 731 segments). The regions of interest values were divided by the amount of iodine (mg) per unit weight (kg) and defined as perfusion value (perfusion value analysis). All segments were also visually analyzed and receiver operating characteristic curve analysis performed to identify the superior analysis. Results: The receiver operating characteristic curve analysis showed that perfusion value analysis is significantly superior to visual analysis [the area under the curve: 0.921 (95% confidence interval, 0.860-0.981) versus 0.685 (95% confidence interval, 0.580-0.791), respectively, P<0.05], with 93.8% sensitivity, 99.1% specificity, 98.9% accuracy, 83.3% positive predictive value, and 99.7% negative predictive value (P<0.01). Conclusions: Quantitative analysis of the iodine image of rest DECT, called perfusion value analysis, is more accurate than visual analysis when compared with 99mTc-TF SPECT MPI as the reference standard.

© 2020, The International Urogynecological Association. Introduction and hypothesis: This study was aimed at comparing pelvic floor parameters between the standing and supine positions using upright computed tomography (CT) and evaluating the effects of sex and age in normal healthy volunteers. Methods: In total, 139 volunteers (70 men, mean 46.7 years; 69 women, mean 47.3 years) underwent both upright CT in the standing position and conventional CT in the supine position. The distances from the bladder neck to the pubococcygeal line (PCL) and anorectal junction (ARJ), defined as the posterior aspect of the puborectalis muscle, to PCL were measured. The length, width, and area of the levator hiatus (LH) were measured on oblique axial images. Results: The bladder neck (men, 22.2 ± 4.9 mm vs 28.3 ± 5.3 mm; women, 9.0 ± 5.1 mm vs 19.0 ± 4.0 mm) and ARJ (men, −18.8 ± 5.5 mm vs −12.1 ± 5.1 mm; women, −20.0 ± 4.7 mm vs −11.2 ± 4.3 mm) were significantly lower in the standing position than in the supine position (all p < 0.0001). The LH area (men, 1,990 ± 380 mm2 vs 1,697 ± 329 mm2; women, 2,284 ± 344 mm2 vs 1,811 ± 261 mm2) was significantly larger in the standing position (both p < 0.0001). Differences in all parameters between the standing and supine positions were larger in women than in men. ARJ in women showed a significant tendency to descend with age only in the standing position (r = −0.29, p = 0.017). Conclusions: The bladder neck and ARJ descend and the LH area enlarges in the standing position. Pelvic floor mobility is greater in women than in men. Descent of the ARJ in the standing position is associated with aging in women.

Expression of bone-associated proteins and osteoblastic transcription factor Runx2 in arterial cells has been implicated in the development of vascular calcification. However, the signaling upstream of the Runx2-mediated activation of osteoblastic program in vascular smooth muscle cells (VSMC) is poorly understood. We examined the effects of fibroblast growth factor-2 (FGF-2), an important regulator of bone formation, on osteoblastic differentiation of VSMC. Stimulation of cultured rat aortic SMC (RASMC) with FGF-2 induced the expression of the osteoblastic markers osteopontin (OPN) and osteocalcin. Luciferase assays showed that FGF-2 induced osteocyte-specific element (OSE)-dependent transcription. Downregulation of Runx2 by siRNA repressed the basal and FGF-2-stimulated expression of the OPN gene in RASMC. FGF-2 produced hydrogen peroxide in RASMC, as evaluated by fluorescent probe. Induction of OPN expression by FGF-2 was inhibited not only by PD98059 (MEK1 inhibitor) and PP1 (c-Src inhibitor), but also by an antioxidant, N-acetyl cysteine. Nuclear extracts from FGF-2-treated RASMC exhibited increased DNA-binding of Runx2 to its target sequence. Immunohistochemistry of human coronary atherectomy specimens and calcified aortic tissues showed that expression of FGF receptor-1 and Runx2 was colocalized. In conclusion, these results suggest that FGF-2 plays a role in inducing osteoblastic differentiation of VSMC by activating Runx2 through mitogen-activated protein kinase (MAPK)-dependent- and oxidative stress-sensitive-signaling pathways. © 2009 Elsevier Inc. All rights reserved.

© 2015, Springer-Verlag Berlin Heidelberg. Purpose: Patients with chronic kidney disease (CKD) have an increased risk of adverse cardio-cerebrovascular events. We examined whether stress myocardial perfusion single photon emission computed tomography (SPECT) provides reliable prognostic markers for these patients. Methods: In this multicenter, prospective cohort trial from the Gunma-CKD SPECT study protocol, patients with CKD [estimated glomerular filtration rate (eGFR) < 60 min/ml per 1.73 m2] undergoing stress 99mTc-tetrofosmin SPECT for suspected or possible ischemic heart disease were initially followed for 1 year, with the following study endpoints: primary, the occurrence of cardiac deaths (CDs), and secondary, major adverse cardiac, cerebrovascular, and renal events (MACCREs). The summed stress score (SSS), summed rest score, and summed difference score (SDS) were estimated with the standard 17-segment, 5-point scoring model. Left ventricular end-diastolic volume, end-systolic volume (ESV), and ejection fraction were measured using electrocardiogram-gated SPECT. Results: During the first year of follow-up, 69 of 299 patients experienced MACCREs (CD, n = 7; non-fatal myocardial infarction, n = 3; hospitalization for heart failure, n = 13; cerebrovascular accident, n = 1; need for revascularization, n = 38; and renal failure, i.e., hemodialysis initiation, n = 7). ESV and SSS were associated with CDs (p < 0.05), and eGFR and SDS were associated with MACCREs (p < 0.05), in multivariate logistic analysis. Patients with high ESV and high SSS had a significantly higher CD rate during the first year than the other CKD patient subgroups (p < 0.05). Patients with low eGFR and high SDS had a significantly higher MACCRE rate than the other subgroups (p < 0.05). Conclusion: Myocardial perfusion SPECT can provide reliable prognostic markers for patients with CKD.

Background: Apoptosis in atherosclerotic lesions contributes to plaque vulnerability by lipid core enlargement and fibrous cap attenuation. Apoptosis is associated with exteriorization of phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the cell membrane. Although PS-avid radiolabeled annexin-V has been employed for molecular imaging of high-risk plaques, PE-targeted imaging in atherosclerosis has not been studied. Objectives: This study sought to evaluate the feasibility of molecular imaging with PE-avid radiolabeled duramycin in experimental atherosclerotic lesions in a rabbit model and compare duramycin targeting with radiolabeled annexin-V. Methods: Of the 27 rabbits, 21 were fed high-cholesterol, high-fat diet for 16 weeks. Nine of the 21 rabbits received Tc-duramycin (test group), 6 received Tc-linear duramycin (duramycin without PE-binding capability, negative radiotracer control group), and 6 received Tc-annexin-V for radionuclide imaging. The remaining normal chow-fed 6 animals (disease control group) received Tc-duramycin. In vivo microSPECT/microCT imaging was performed, and the aortas were explanted for ex vivo imaging and for histological characterization of atherosclerosis. Results: A significantly higher duramycin uptake was observed in the test group compared with that of disease control and negative radiotracer control animals; duramycin uptake was also significantly higher than the annexin-V uptake. Quantitative duramycin uptake, represented as the square root of percent injected dose per cm (√ID/cm) of abdominal aorta was >2-fold higher in atherosclerotic lesions in test group (0.08 ± 0.01%) than in comparable regions of disease control animals (0.039 ± 0.0061%, p = 3.70·10 ). Mean annexin uptake (0.060 ± 0.010%) was significantly lower than duramycin (p = 0.001). Duramycin uptake corresponded to the lesion severity and macrophage burden. The radiation burden to the kidneys was substantially lower with duramycin (0.49% ID/g) than annexin (5.48% ID/g; p = 4.00·10 ). Conclusions: Radiolabeled duramycin localizes in lipid-rich areas with high concentration of apoptotic macrophages in the experimental atherosclerosis model. Duramycin uptake in atherosclerotic lesions was significantly greater than annexin-V uptake and produced significantly lower radiation burden to nontarget organs. 99m 99m 99m 99m –8 –4

© Wolters Kluwer Health, Inc. All rights reserved. Objectives Multiple human systems are greatly affected by gravity, and many disease symptoms are altered by posture. However, the overall anatomical structure and pathophysiology of the human body while standing has not been thoroughly analyzed due to the limitations of various upright imaging modalities, such as low spatial resolution, low contrast resolution, limited scan range, or long examination time. Recently, we developed an upright computed tomography (CT), which enables whole-torso cross-sectional scanning with 3-dimensional acquisition within 15 seconds. The purpose of this study was to evaluate the performance, workflow efficacy, effects of gravity on a large circulation system and the pelvic floor, and potential clinical impact of upright CT. Materials and Methods We compared noise characteristics, spatial resolution, and CT numbers in a phantom between supine and upright CT. Thirty-two asymptomatic volunteers (48.4 ± 11.5 years) prospectively underwent both CT examinations with the same scanning protocols on the same day. We conducted a questionnaire survey among these volunteers who underwent the upright CT examination to determine their opinions regarding the stability of using the pole throughout the acquisition (closed question), as well as safety and comfortability throughout each examination (both used 5-point scales). The total access time (sum of entry time and exit time) and gravity effects on a large circulation system and the pelvic floor were evaluated using the Wilcoxon signed-rank test and the Mann-Whitney U test. For a large circulation system, the areas of the vena cava and aorta were evaluated at 3 points (superior vena cava or ascending aorta, at the level of the diaphragm, and inferior vena cava or abdominal aorta). For the pelvic floor, distances were evaluated from the bladder neck to the pubococcygeal line and the anorectal junction to the pubococcygeal line. We also examined the usefulness of the upright CT in patients with functional diseases of spondylolisthesis, pelvic floor prolapse, and inguinal hernia. Results Noise characteristics, spatial resolution, and CT numbers on upright CT were comparable to those of supine CT. In the volunteer study, all volunteers answered yes regarding the stability of using the pole, and most reported feeling safe (average rating of 4.2) and comfortable (average rating of 3.8) throughout the upright CT examination. The total access time for the upright CT was significantly reduced by 56% in comparison with that of supine CT (upright: 41 ± 9 seconds vs supine: 91 ± 15 seconds, P < 0.001). In the upright position, the area of superior vena cava was 80% smaller than that of the supine position (upright: 39.9 ± 17.4 mm2 vs supine: 195.4 ± 52.2 mm2, P < 0.001), the area at the level of the diaphragm was similar (upright: 428.3 ± 87.9 mm2 vs supine: 426.1 ± 82.0 mm2, P = 0.866), and the area of inferior vena cava was 37% larger (upright: 346.6 ± 96.9 mm2 vs supine: 252.5 ± 93.1 mm2, P < 0.001), whereas the areas of aortas did not significantly differ among the 3 levels. The bladder neck and anorectal junction significantly descended (9.4 ± 6.0 mm and 8.0 ± 5.6 mm, respectively, both P < 0.001) in the standing position, relative to their levels in the supine position. This tendency of the bladder neck to descend was more prominent in women than in men (12.2 ± 5.2 mm in women vs 6.7 ± 5.6 mm in men, P = 0.006). In 3 patients, upright CT revealed lumbar foraminal stenosis, bladder prolapse, and inguinal hernia; moreover, it clarified the grade or clinical significance of the disease in a manner that was not apparent on conventional CT. Conclusions Upright CT was comparable to supine CT in physical characteristics, and it significantly reduced the access time for examination. Upright CT was useful in clarifying the effect of gravity on the human body: Gravity differentially affected the volume and shape of the vena cava, depending on body position. The pelvic floor descended significantly in the standing position, compared with its location in the supine position, and the descent of the bladder neck was more prominent in women than in men. Upright CT could potentially aid in objective diagnosis and determination of the grade or clinical significance of common functional diseases.

© 2020 Background: No clinical studies to date have compared unilateral lung or lobe volumes between the supine and standing positions. Objectives: To compare lung/lobe volumes on computed tomography (CT) between these two positions and evaluate the correlation between the total lung volume and total lung capacity (TLC) on pulmonary function tests (PFTs). Methods: Thirty-two asymptomatic volunteers underwent both conventional CT (supine position) and upright CT (standing position), during deep inspiration breath-hold, and PFTs on the same day. We measured lung/lobe volumes on CT in each position. Paired t tests were used for statistical analysis. Results: The volumes of the total lung (10.9% increase), right lung (10.3% increase), right upper lobe (8.6% increase), right lower lobe (14.6% increase), left lung (11.6% increase), left upper lobe (7.1% increase), and left lower lobe (16.0% increase) were significantly greater in the standing position than in the supine position (all p < 0.0001). The right middle lobe volume was similar between the two positions (p = 0.16). Intraclass correlation coefficients for agreement between total lung volumes on CT in the supine/standing positions and the TLC on PFT were 0.891/0.938, respectively. Conclusions: While the volumes of the bilateral upper and lower lobes and bilateral lungs were significantly greater in the standing than in the supine position, with lower lobes showing larger changes, the right middle lobe volume did not change significantly between positions. The total lung volume on upright CT in the standing position was more similar to TLC on PFT than that in the supine position.

© 2017 American College of Cardiology Foundation Background Although early reperfusion is the most desirable intervention after ischemic myocardial insult, it may add to damage through oxidative stress. Objectives This study investigated the cardioprotective effects of a single intravenous dose of heat shock protein-72 (HSP72) coupled to a single-chain variable fragment (Fv) of monoclonal antibody 3E10 (3E10Fv) in a rabbit ischemia-reperfusion model. The Fv facilitates rapid transport of HSP72 into cells, even with intact membranes. Methods A left coronary artery occlusion (40 min) reperfusion (3 h) model was used in 31 rabbits. Of these, 12 rabbits received the fusion protein (Fv-HSP72) intravenously. The remaining 19 control rabbits received a molar equivalent of 3E10Fv alone (n = 6), HSP72 alone (n = 6), or phosphate-buffered saline (n = 7). Serial echocardiographic examinations were performed to assess left ventricular function before and after reperfusion. Micro–single-photon emission computed tomography imaging of 99mTc-labeled annexin-V was performed with micro–computed tomography scanning to characterize apoptotic damage in vivo, followed by gamma counting of the excised myocardial specimens to quantify cell death. Histopathological characterization of the myocardial tissue and sequential cardiac troponin I measurements were also undertaken. Results Myocardial annexin-V uptake was 43% lower in the area at risk (p = 0.0003) in Fv-HSP72–treated rabbits compared with control animals receiving HSP72 or 3E10Fv alone. During reperfusion, troponin I release was 42% lower and the echocardiographic left ventricular ejection fraction 27% higher in the Fv-HSP72–treated group compared with control animals. Histopathological analyses confirmed penetration of 3E10Fv-containing molecules into cardiomyocytes in vivo, and treatment with Fv-HSP72 showed fewer apoptotic nuclei compared with control rabbits. Conclusions Single-dose administration of Fv-HSP72 fusion protein at the time of reperfusion reduced myocardial apoptosis by almost one-half and improved left ventricular functional recovery after myocardial ischemia-reperfusion injury in rabbits. It might have potential to serve as an adjunct to early reperfusion in the management of myocardial infarction.

© 2017 American College of Cardiology Foundation Vascular calcification is a hallmark of atherosclerosis. The location, density, and confluence of calcification may change portions of the arterial conduit to a noncompliant structure. Calcifications may also seed the cap of a thin cap fibroatheroma, altering tensile forces on the cap and rendering the lesion prone to rupture. Many local and systemic factors participate in this process, including hyperlipidemia, ongoing inflammation, large necrotic cores, and diabetes. Vascular cells can undergo chondrogenic or osteogenic differentiation, causing mineralization of membranous bone and formation of endochondral bone. Calcifying vascular cells are derived from local smooth muscle cells and circulating hematopoietic stem cells (especially in intimal calcification). Matrix vesicles in the extracellular space of the necrotic core serve as a nidus for calcification. Although coronary calcification is a marker of coronary atheroma, dense calcification (>400 HU) is usually associated with stable plaques. Conversely, microcalcification (often also referred to as spotty calcification) is more commonly an accompaniment of vulnerable plaques. Recent studies have suggested that microcalcification in the fibrous cap may increase local tissue stress (depending on the proximity of one microcalcific locus to another, and the orientation of the microcalcification in reference to blood flow), resulting in plaque instability. It has been proposed that positron emission tomography imaging with sodium fluoride may identify early calcific deposits and hence high-risk plaques.

A 71-year-old man, a heavy smoker, was admitted for evaluation of "chest oppression" after every dinner. Cardiac CT with a beta-blocker showed coronary stenosis in the left circumflex. Although adenosine triphosphate-stress perfusion single-photon emission CT revealed no ischemia, Holter electrocardiography belatedly indicated an ST elevation associated with his symptoms while smoking. He was diagnosed to have vasospastic angina. Cardiac CT without a beta-blocker showed thin diffuse plaque and negative remolding without any significant stenosis at the same site. Asian patients have a tendency to develop vasospastic angina. Although beta-blockers are recommended for cardiac CT, the routine administration of beta-blockers in cardiac CT may have some risk for suchcases. © 2014 Society of Cardiovascular Computed Tomography.