Publications by authors named "Yasuhiro Uchida"

26 Publications

  • Page 1 of 1

Cryoballoon ablation for atrial fibrillation without the use of a contrast medium: a combination of the intracardiac echocardiography and pressure wave monitoring guided approach.

Heart Vessels 2021 Oct 12. Epub 2021 Oct 12.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.

In cryoballoon ablation (CBA), a contrast medium is commonly used to confirm balloon occlusion of the pulmonary veins (PVs). However, a contrast medium cannot always be used in patients with renal dysfunction and allergy. The present study aimed to assess the efficacy and safety of CBA without the use of a contrast medium. We retrospectively examined consecutive patients with paroxysmal atrial fibrillation (PAF) who underwent first-time CBA. We compared the procedural results and outcomes in patients for whom a contrast medium was used (contrast group) and those from whom a contrast medium was not used (non-contrast group). In the non-contrast group, we used saline injection on the intracardiac echocardiography and pressure wave monitoring for PV occlusion. Fifty patients (200 PVs) and 22 patients (88 PVs) underwent CBA with and without a contrast medium, respectively. The success rate of PV isolation with CBA alone was 93% and 90% in the non-contrast and contrast groups, respectively (p = 0.40). The fluoroscopy time and nadir temperature were significantly lower in the non-contrast group as compared to that in the contrast group. The recurrence rate 1 year after ablation did not differ between the two groups (18% vs. 18%, p > 0.99). Furthermore, the number of reconnected PVs in patients with recurrence was significantly lower in the non-contrast group than in the contrast group (6% vs. 36%, p = 0.017). In conclusion, CBA using the intracardiac echocardiography and pressure monitoring approach without the use of a contrast medium was safe and efficient.
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http://dx.doi.org/10.1007/s00380-021-01963-3DOI Listing
October 2021

Earliest pulmonary vein potential-guided cryoballoon ablation is associated with better clinical outcomes than conventional cryoballoon ablation: A result from two randomized clinical studies.

J Cardiovasc Electrophysiol 2021 Sep 17. Epub 2021 Sep 17.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.

Introduction: With regard to short-term outcome in atrial fibrillation (AF), the benefit of cryoballoon ablation (CBA) by pressing a balloon against the earliest pulmonary vein (PV) potential site during PV isolation (earliest potential [EP]-guided CBA) has been previously demonstrated. The present study aimed to evaluate the long-term outcome of the EP-guided CBA.

Methods And Results: This study included 136 patients from two randomized studies, who underwent CBA for paroxysmal AF for the first time. Patients were randomly assigned to the EP-guided and conventional CBA groups in each study. In the EP-guided CBA group, we pressed a balloon against the EP site when the time-to-isolation (TTI) after cryoapplication exceeded 60 and 45 s in the first and second studies, respectively. We compared the clinical outcomes for 1 year after the procedure between the EP-guided CBA group (68 patients) and the conventional CBA group (68 patients). The primary endpoint was the recurrence of atrial arrhythmia after ablation. No significant differences in baseline characteristics were observed between the two groups. Compared with the conventional CBA group, the EP-guided CBA group had a significantly higher success rate at TTI ≤ 90 s (98.5% vs. 90.0%, p < .001); lower touch-up rate and total cryoapplication; and shorter procedure time, and fluoroscopy time. The recurrence at 1 year after ablation was significantly lower in the EP-guided CBA group than in the conventional CBA group (6.0% vs. 19.4%; p = .019).

Conclusions: The EP-guided CBA approach can facilitate the ablation procedure and achieve low recurrence at 1 year after ablation.
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http://dx.doi.org/10.1111/jce.15246DOI Listing
September 2021

Notch1 haploinsufficiency in mice accelerates adipogenesis.

Sci Rep 2021 08 18;11(1):16761. Epub 2021 Aug 18.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Notch signaling has been recognized recently as a key regulator of metabolism. Here, we determined the role of Notch1 in adipogenesis in wild-type (WT) and Notch1 hetero-mutant (N1+/-) mice provided with 12-week normal or high-fat diet. Haploinsufficiency of Notch1 was associated with adipose tissue accumulation despite similar food intake. White adipose tissue (WAT) of N1+/- showed accumulation of adipogenic cells (CD34+CD68+ cells), crown-like structures, and upregulation of cell proliferation markers (cyclin D1 and Ki67). Notch1 expression in WAT reached peak levels in 8-week-old WT mice in parallel with fat accumulation, especially under HF/HS-feeding, whereas such increment was blunted in N1+/- mice. Downstream of Notch1 haploinsufficiency, over-expression of adipogenic factors PPARγ and C/EBPα was noted following down-regulation of downstream transcriptional factors of Notch signaling (Hes-1, Pref-1, and Sox9). Both pharmacological Notch signal inhibition and Notch1 knockdown enhanced adipogenesis of 3T3-L1 preadipocytes. N1+/- mice showed impaired glucose and insulin tolerance with downregulation of IRS-1 and GLUT4 in WAT after high-fat diet. Taken together, our results suggest that haploinsufficiency of Notch1 promotes fat accumulation and adipogenesis and provides a mechanistic link between Notch signaling and development of metabolic syndrome.
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http://dx.doi.org/10.1038/s41598-021-96017-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373919PMC
August 2021

Disappearance pattern and the last remaining earliest pulmonary vein potential during cryoballoon ablation in predicting recurrence and conduction gap site of pulmonary veins.

Heart Vessels 2021 Aug 26;36(8):1190-1200. Epub 2021 Jan 26.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.

Electrophysiological studies have rarely evaluated the sites prone to pulmonary vein (PV) conduction gap during cryoballoon ablation (CBA) for atrial fibrillation (AF). In addition, no studies have analyzed the sequence of PV potentials just before PV isolation during CBA for AF. Of the 238 patients who underwent first-time CBA for paroxysmal AF, 115 PVs of 29 patients who underwent repeat session due to recurrence after the procedure were retrospectively evaluated in the study. We evaluated the disappearance pattern of PV potential and PV reconnection on intracardiac electrograms and investigated whether the conduction gap site of the PV was related to the last remaining earliest PV potential (EP) and sequence pattern during the first-time CBA. Time to isolation was observed in 81 PVs during the first-time CBA. At the repeat session, PV reconnection was only observed in 22 of 81 PVs. PV potentials disappeared with sequence changes in 36 PVs and without sequence changes in 38 PVs. Multivariate analysis demonstrated that disappearance of PV potentials without change in the EP site but with delay or disappearance of other PV potentials was independently associated with PV reconnection (12/22 PVs [55%] vs. 4/59 PVs [6.8%]; odds ratio 14.4; 95% confidence interval 3.75-55.5; p < 0.001). In 19 of 22 (86%) reconnected PVs, PV conduction gap sites at repeat ablation corresponded with the last remaining EP sites during first-time CBA. In conclusion, disappearance pattern of the PV potential and the last remaining EP during the CBA can predict PV reconnection and gap site.
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http://dx.doi.org/10.1007/s00380-021-01785-3DOI Listing
August 2021

Impact of the clinical frailty scale on clinical outcomes and bleeding events in patients with ST-segment elevation myocardial infarction.

Heart Vessels 2021 Jun 7;36(6):799-808. Epub 2021 Jan 7.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

The Clinical Frailty Scale (CFS) is a simple tool to assess patients' frailty and may help to predict adverse outcomes in elderly patients. The aim of the present study was to examine the impact of CFS on clinical outcomes and bleeding events after successful percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI). We enrolled 266 consecutive patients with STEMI who underwent primary PCI in between January 2015 and June 2018. Patients were categorized into two groups based on the CFS stages: CFS 1-3 and CFS ≥ 4. We collected the data and evaluated the relationship between the CFS grade and the incidence of major adverse cardiovascular events (MACE) and Bleeding Academic Research Consortium 3 or 5 bleeding events. Of these patients, CFS ≥ 4 was present in 59 (22.2%). During the follow-up, 37.3% in the CFS ≥ 4 group and 8.2% in the CFS 1-3 group experienced MACE. In Kaplan-Meier analysis, the proportion of MACE-free survival for 4 years was significantly lower in the CFS ≥ 4 group (log-rank P < 0.001). Additionally, the proportion of bleeding event-free survival was significantly lower in the CFS ≥ 4 group (log-rank P < 0.001). The CFS (per 1-grade increase) remained an independent significant predictor of MACE on multivariate Cox proportional hazard analysis [hazard ratio 1.39 (95% confidence interval: 1.08 to 1.79, P = 0.01)]. In conclusion, CFS was an independent predictor of future adverse cardiac events in patients with STEMI. Therefore, the assessment of CFS is crucial in this population.
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http://dx.doi.org/10.1007/s00380-020-01764-0DOI Listing
June 2021

Impact of skeletal muscle mass on clinical outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.

Cardiovasc Interv Ther 2021 Oct 31;36(4):514-522. Epub 2020 Oct 31.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Low skeletal muscle mass is one of the components of sarcopenia. However, the prognostic impact of skeletal muscle mass on clinical outcomes in patients after transcatheter aortic valve replacement (TAVR) remains unclear. Therefore, we assessed the impact of skeletal muscle mass on future cardiovascular events in patients undergoing TAVR. We enrolled 71 consecutive patients who underwent TAVR for symptomatic severe aortic stenosis. We applied bilateral psoas muscles as an indicator of skeletal muscle mass. Psoas muscle volumes were measured from the origin of psoas at the level of the lumbar vertebrae to its insertion in the lesser trochanter on three-dimensional computed tomography datasets. Psoas muscle mass index (PMI) was calculated as psoas muscle volume/height (cm/m). According to the median value of PMIs (79.8 and 60.0 cm/m for men and women), the enrolled patients were divided into two groups. During the follow-up, 11 (31.4%) patients in low PMI group and 4 (11.1%) in high PMI group experienced major adverse cardiovascular events (MACE) defined as a composite of death from any cause, myocardial infarction, heart failure hospitalization, and stroke. The proportion of MACE-free survival was significantly lower in low PMI group (log-rank P = 0.033), mainly due to the difference of hospital readmission for congestive heart failure. On multivariate Cox proportional hazard analysis, PMI remained an independent negative predictor of MACE [hazard ratio 0.95 (95% confidence interval 0.92-0.98, P = 0.002)]. In conclusion, low skeletal muscle mass independently predicted MACE in patients undergoing TAVR.
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http://dx.doi.org/10.1007/s12928-020-00725-8DOI Listing
October 2021

Earliest pulmonary vein potential-guided cryoballoon ablation for atrial fibrillation.

Heart Vessels 2020 Feb 11;35(2):232-238. Epub 2019 Jul 11.

Department of Cardiology, Nagoya University Hospital, Nagoya, Japan.

No studies have evaluated both the time-to-isolation (TTI) and the sequence of pulmonary vein (PV) potentials in cryoballoon ablation (CBA) for atrial fibrillation (AF). This study aimed to prospectively evaluate the acute results of pulmonary vein isolation (PVI) using a novel CBA technique-the earliest potential (EP) of PV-guided CBA-in paroxysmal AF. We pressed a balloon against the earliest PV potential site during PVI when TTI could not be achieved within 60 s (EP-guided CBA group). We compared 32 patients consecutively treated by EP-guided CBA to 32 patients treated without pressing the balloon against the EP site (conventional CBA group). The cryoapplication protocol was the same, except with regard to the pressing of the balloon. All 256 PVs (EP-guided CBA group, 128 PVs; conventional CBA group, 128 PVs) were isolated successfully. The TTI observation rate was similar in both groups. Compared with conventional CBA, EP-guided CBA was associated with a lower non-success rate of TTI ≤ 90 s (9% vs. 26%; P = 0.040) and shorter left atrial dwell time (38 ± 9 vs. 46 ± 19 min; P = 0.036), total procedure time (76 ± 15 vs. 87 ± 23 min; P = 0.043), and fluoroscopy time (23 ± 8 vs. 30 ± 11 min; P = 0.006). This novel EP-guided CBA approach may help facilitate the ablation procedure.
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http://dx.doi.org/10.1007/s00380-019-01471-5DOI Listing
February 2020

A Golgi-targeting fluorescent probe for labile Fe(ii) to reveal an abnormal cellular iron distribution induced by dysfunction of VPS35.

Chem Sci 2019 Feb 26;10(5):1514-1521. Epub 2018 Nov 26.

Laboratory of Pharmaceutical and Medicinal Chemistry , Gifu Pharmaceutical University , 1-25-4, Daigaku-Nishi , Gifu , 501-1196 , Japan . Email:

Iron is involved in numerous physiologically essential processes in our body. However, excessive iron is a pathogenic factor in neurodegenerative diseases, causing aberrant oxidative stress. Divalent metal transporter 1 (DMT1) acts as a primary transporter of Fe(ii) ions. The intracellular delivery of DMT1 toward the cellular membrane the trans-Golgi network during the endocytotic process is partially regulated by a retromer-mediated protein-sorting system comprising vacuolar protein-sorting proteins (VPSs). Thus, together with DMT1, the Golgi-apparatus acts as a hub organelle in the delivery system for intracellular Fe(ii) ions. Dysfunction of the VPS-relevant protein sorting system can induce the abnormal delivery of DMT1 toward lysosomes concomitantly with Fe(ii) ions. To explore this issue, we developed a fluorescent probe, Gol-SiRhoNox, for the Golgi-specific detection of Fe(ii) ions by integrating our original -oxide-based Fe(ii)-specific chemical switch, a new Golgi-localizable chemical motif, and polarity-sensitive fluorogenic scaffold. Our synchronous imaging study using Gol-SiRhoNox and LysoRhoNox, a previously developed fluorescent probe for lysosomal Fe(ii), revealed that the intracellular distribution balance of Fe(ii) ions between the Golgi apparatus and lysosomes is normally Golgi-dominant, whereas the lysosome-specific elevation of Fe(ii) ions was observed in cells with induced dysfunction of VPS35, a member of the retromer complex. Treatment of cells with dysfunctional VPS35 with R55, a molecular chaperone, resulted in the restoration of the subcellular distribution of Fe(ii) ions to the Golgi-dominant state. These results indicate that the impairment of the DMT1 traffic machinery affects subcellular iron homeostasis, promoting Fe(ii) leakage at the Golgi and lysosomal accumulation of Fe(ii) through missorting of DMT1.
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http://dx.doi.org/10.1039/c8sc04386hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357701PMC
February 2019

Angiotensin receptor blocker irbesartan reduces stress-induced intestinal inflammation via AT1a signaling and ACE2-dependent mechanism in mice.

Brain Behav Immun 2018 03 16;69:167-179. Epub 2017 Nov 16.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan. Electronic address:

Stress is associated with pathophysiology of both irritable bowel syndrome (IBS) and hypertension. Angiotensin receptor blockers (ARB) have anti-inflammatory properties via inhibition of angiotensin II (Ang II)/Ang II type I receptor axis (AT1). Inhibition of the classical RAS pathway is also involved in upregulation of angiotensin converting enzyme-2 (ACE2), which activates the Ang-(1-7)/Mas pathway to counteract inflammatory signaling and acts as a partner of the amino acid transporter, BAT-1, to absorb tryptophan for regulation of microbiota-gut-brain axis. In this study, we determined the effects of ARB irbesartan on stress-induced intestinal inflammation. C57BL/6J mice were subjected to 2-week intermittent restraint stress. They were orally treated during the stress with either vehicle, 3 or 10 mg/kg/day irbesartan. Restraint stress resulted in colon inflammation with higher histological damage scores, increased expression of Nox4, TLR-4 and IL1-β, accumulation of reactive oxygen species (ROS), and activation of the ACE-angiotensin II-AT1 receptor axis. Stress also downregulated intestinal amino acid transporter, ACE2/BAT-1, and activity of intestinal mammalian target of rapamycin (mTOR) and p70 S6 kinase (p70S6K), resulting in decrease in α-defensins, changes in intestinal microbial contents, and perturbation of tryptophan metabolism with activation of the kynurenine pathway. Administration of irbesartan inhibited activation of stress-induced AT1 pathway to reduce intestinal ROS accumulation and inflammation, restored expression of ACE2/BAT-1, activity of mTOR and p70S6K, dysbiosis and tryptophan metabolism. Our results suggest that AT1 is a potentially suitable therapeutic target in stress-induced intestinal inflammation, and that irbesartan could be beneficially suitable for the treatment of stressed patients with IBS.
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http://dx.doi.org/10.1016/j.bbi.2017.11.010DOI Listing
March 2018

Impact of Coronary Stent Fracture on Restenotic Neointimal Tissue Characterization After Drug-Eluting Stent Implantation.

Int Heart J 2017 Dec 17;58(6):861-867. Epub 2017 Nov 17.

Department of Cardiology, Nagoya University Graduate School of Medicine.

Although drug-eluting stents (DESs) reduce the rates of in-stent restenosis (ISR) and subsequent target lesion revascularization, stent fracture (SF) after DES implantation has become an important concern because of its potential association with restenosis and stent thrombosis. We aimed to assess the pathogenic impact of SF on in-stent restenotic neointimal tissue components after DES implantation. We analyzed 43 consecutive patients (14 with SF and 29 without SF) with ISR requiring revascularization after DES implantation between January 2008 and March 2014. For evaluation of in-stent tissue components, integrated backscatter intravascular ultrasound (IB-IVUS) was performed. SF was defined as complete or partial separation of stent segments observed using plain fluoroscopy or intravascular ultrasound. On volumetric IB-IVUS analyses, patients with SF had a significantly higher percentage of lipid tissue volume within the neointima and a significantly lower percentage of fibrous tissue volume than those without (37.3 ± 18.9% versus 24.9 ± 12.4%, P = 0.02, and 61.2 ± 18.3 versus 72.6 ± 12.1%, P = 0.04, respectively). Moreover, SF was positively correlated with the percentage of lipid volume on multiple linear regression analysis after adjustment for confounding factors (β = 0.36, P = 0.03). The interval from stent implantation was similar in both groups (47.0 ± 28.7 versus 37.7 ± 33.3 months; P = 0.39). In conclusion, SF is associated with larger lipid tissue volume within the neointima after DES placement, suggesting a contribution to the development of neoatherosclerosis and vulnerable neointima. Thus SF might lead to future adverse coronary events.
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http://dx.doi.org/10.1536/ihj.16-571DOI Listing
December 2017

Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice.

Sci Rep 2017 04 28;7(1):1266. Epub 2017 Apr 28.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Chronic stress is closely linked to the metabolic syndrome, diabetes, hyperuricemia and thromboembolism, but the mechanisms remain elusive. We reported recently that stress targets visceral adipose tissue (VAT), inducing lipolysis, low-grade inflammation with production of inflammatory adipokines, metabolic derangements such as insulin resistance, and prothrombotic state. In the present study, we hypothesized the involvement of VAT xanthine oxidoreductase (XOR), a source of reactive oxygen species (ROS) and uric acid (UA) in the above processes. Restraint stress in mice resulted in upregulation of XOR and xanthine oxidase activity, accumulation of ROS in VAT as well as liver and intestine, increase in serum UA levels, upregulation of NADPH oxidase subunits and downregulation of antioxidant enzymes. Immunohistochemistry and RT-PCR analysis also showed that restraint stress induced VAT monocyte accumulation and proinflammatory adipokine production, resulting in reduced insulin sensitivity and induction of plasminogen activator inhibitor-1 and tissue factor in VAT. Treatment with febuxostat, a potent XO inhibitor, suppressed stress-induced ROS production and VAT inflammation, resulting in improvement of serum UA levels, insulin sensitivity, and prothrombotic tendency. Our results suggest that stress perturbs glucose and UA metabolism, and promotes prothrombotic status, and that XO inhibition by febuxostat might be a potential therapy for stress-related disorders.
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http://dx.doi.org/10.1038/s41598-017-01366-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430858PMC
April 2017

Dipeptidyl peptidase- IV inhibitor alogliptin improves stress-induced insulin resistance and prothrombotic state in a murine model.

Psychoneuroendocrinology 2016 11 3;73:186-195. Epub 2016 Aug 3.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Stress evokes lipolytic release of free fatty acid (FFA) and low-grade inflammation in visceral adipose tissue, mediated by increased adipokine secretion, and contributes to glucose metabolism disorder and prothrombotic state. We tested the hypothesis that alogliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate the biological effects of chronic stress in mice.

Method And Results: C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle or alogliptin (dose: 15 or 45mg/kg/day). Plasma levels of lipids, proinflammatory cytokines (monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6), and 8-hydroxydeoxyguanosine were measured with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was examined by CD11b-positive cell count and mRNA expression of CD68 and F4/80 was examined by immunohistochemistry and RT-PCR, respectively. The mRNA levels of the above-mentioned proinflammatory cytokines, NADPH oxidase 4, adiponectin, and coagulation factors (plasminogen activation inhibitor-1 and tissue factor) in WAT were also assessed with RT-PCR. Glucose metabolism was assessed by glucose and insulin tolerance tests, plasma levels of DPP-4 activity, glucagon-like peptide-1, expression of DPP-4, insulin receptor substrate-1 and glucose transporter 4 in WAT and skeletal muscle. Alogliptin administration suppressed stress-induced FFA release, oxidative stress, adipose tissue inflammation, DPP-4 activation, and prothrombotic state in a dose-dependent manner, and improved insulin sensitivity in stressed mice.

Conclusions: The results indicate that alogliptin improves stress-induced prothrombotic state and insulin resistance; suggesting that alogliptin could have beneficial therapeutic effects against cardiovascular complications in diabetic patients under stress.
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http://dx.doi.org/10.1016/j.psyneuen.2016.08.004DOI Listing
November 2016

Angiotensin receptor blocker improves a stress-induced prothrombotic state in a murine model.

Blood Coagul Fibrinolysis 2016 Apr;27(3):358-60

aDepartment of Cardiology, Nagoya University Graduate School of Medicine bDepartments of Clinical Laboratory cBlood Transfusion, Nagoya University Hospital, Nagoya, Japan.

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http://dx.doi.org/10.1097/MBC.0000000000000451DOI Listing
April 2016

Impact of Admission Anemia on Coronary Microcirculation and Clinical Outcomes in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

Int Heart J 2015 24;56(4):381-8. Epub 2015 Jun 24.

Department of Cardiology, Yokkaichi Municipal Hospital.

Microvascular dysfunction after primary percutaneous coronary intervention (PCI) augments myocardial damage and prognosis in acute myocardial infarction. However, the relationship between baseline anemia and coronary microcirculation in patients with ST-segment elevation myocardial infarction (STEMI) remains unclear. We performed primary PCI in 337 consecutive patients with STEMI. Anemia was defined as a hemoglobin level < 13 g/dL in men and < 12 g/dL in women. Admission anemia was present in 17.5% of the patients enrolled. Data on epicardial coronary flow, STsegment resolution (STR) on electrocardiography, myocardial injury, and the incidence of adverse cardiac events defined as cardiac death or hospitalization for congestive heart failure were analyzed. The median follow-up period was 54.8 months. Despite comparable epicardial coronary flow, the rate of STR ≥ 50% was lower in anemic patients compared with non-anemic patients (55.9% versus 71.2%, P = 0.02). On multivariate logistic regression analysis, baseline anemia was an independent negative predictor of STR ≥ 50% (odds ratio, 0.53; 95% confidence interval: 0.31-0.92, P = 0.03). Moreover, anemic patients had higher maximum creatine kinase levels normalized for body surface area (2,215 ± 1,318 IU/L/m(2) versus 1,797 ± 1,199 IU/L/m(2), P = 0.047). Anemia remained an independent significant predictor of adverse events on multivariate Cox proportional hazard analysis (hazard ratio, 2.34; 95% confidence interval: 1.01-5.64, P = 0.048). In conclusion, admission anemia was related to microcirculatory dysfunction and poor prognosis in patients with STEMI. The decreased oxygen delivery might exacerbate microvascular function.
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http://dx.doi.org/10.1536/ihj.15-006DOI Listing
September 2015

Microvascular obstruction on delayed enhancement cardiac magnetic resonance imaging after acute myocardial infarction, compared with myocardial (201)Tl and (123)I-BMIPP dual SPECT findings.

Eur J Radiol 2015 Aug 15;84(8):1516-1524. Epub 2015 May 15.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: The hypo-enhanced regions within the hyper-enhanced infarct areas detected by cardiac magnetic resonance (CMR) imaging reflect microvascular obstruction (MO) after acute myocardial infarction (AMI). The combined myocardial thallium-201 ((201)Tl)/iodine-123-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid ((123)I-BMIPP) dual single-photon emission computed tomography (SPECT) is a useful tool for detecting myocardial reversibility after AMI. We evaluated whether MO could be an early predictor of irreversible myocardial damage in comparison with (201)Tl and (123)I-BMIPP dual SPECT findings in AMI patients.

Methods: Sixty-two patients with initial AMI who successfully underwent coronary revascularization were enrolled. MO was defined by CMR imaging. Patients were divided into 2 groups as follows: MO group (n=32) and non-MO group (n=30). Scintigraphic defect scores were calculated using a 17-segment model with a 5-point scoring system. The mismatch score (MMS) was calculated as follows: the total sum of (Σ) (123)I-BMIPP defect score minus Σ(201)Tl defect score. The percentage mismatch score (%MMS) was calculated as follows: MMS/(Σ(123)I-BMIPP score)×100 (%).

Results: The percentage infarct size (%IS) was significantly greater in the MO group than in the non-MO group (32.2±13.8% vs. 18.3±12.1%, p<0.001). The %MMS significantly correlated with the %IS and the percentage MO (r=-0.26, p=0.03; r=-0.45, p<0.001, respectively). The %MMS was significantly greater in the non-MO group than in the MO group (45.4±42.4% vs. 13.3±28.0%, p=0.001), and was an independent predictor for MO (OR 0.97, 95%CI 0.94-0.99, p=0.02).

Conclusions: Our results reconfirm that, in comparison with myocardial dual scintigraphy, MO is an important structural abnormality. CMR imaging is useful for the early detection of irreversible myocardial damage after AMI.
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http://dx.doi.org/10.1016/j.ejrad.2015.05.002DOI Listing
August 2015

Angiotensin II receptor blocker ameliorates stress-induced adipose tissue inflammation and insulin resistance.

PLoS One 2014 31;9(12):e116163. Epub 2014 Dec 31.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

A strong causal link exists between psychological stress and insulin resistance as well with hypertension. Meanwhile, stress-related responses play critical roles in glucose metabolism in hypertensive patients. As clinical trials suggest that angiotensin-receptor blocker delays the onset of diabetes in hypertensive patients, we investigated the effects of irbesartan on stress-induced adipose tissue inflammation and insulin resistance. C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle, 3 and 10 mg/kg/day irbesartan. The plasma concentrations of lipid and proinflammatory cytokines [Monocyte Chemoattractant Protein-1 (MCP-1), tumor necrosis factor-α, and interleukin-6] were assessed with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was observed with CD11b-positive cell counts and mRNA expressions of CD68 and F4/80 using immunohistochemistry and RT-PCR methods respectively. The mRNA levels of angiotensinogen, proinflammatory cytokines shown above, and adiponectin in WAT were also assessed with RT-PCR method. Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests, and mRNA expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT. Restraint stress increased monocyte accumulation, plasma free fatty acids, expression of angiotensinogen and proinflammatory cytokines including MCP-1, and reduced adiponectin. Irbesartan reduced stress-induced monocyte accumulation in WAT in a dose dependent manner. Irbesartan treatment also suppressed induction of adipose angiotensinogen and proinflammatory cytokines in WAT and blood, and reversed changes in adiponectin expression. Notably, irbesartan suppressed stress-induced reduction in adipose tissue weight and free fatty acid release, and improved insulin tolerance with restoration of IRS-1 and GLUT4 mRNA expressions in WAT. The results indicate that irbesartan improves stress-induced adipose tissue inflammation and insulin resistance. Our results suggests that irbesartan treatment exerts additive benefits for glucose metabolism in hypertensive patients with mental stress.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116163PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281136PMC
May 2016

Recovery of flow-mediated vasodilatation after repetitive measurements is involved in early vascular impairment: comparison with indices of vascular tone.

PLoS One 2014 2;9(1):e83977. Epub 2014 Jan 2.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

In repetitive measurements of flow-mediated dilatation (FMD), the duration of the interval between measurements remains controversial. In this pilot study, we conducted three sequential measurements of low-flow-mediated constriction (L-FMC), FMD and flow-mediated total dilation (FMTD; L-FMC+ FMD) at baseline and intervals of 15 and 60 min in 30 healthy males. FMD15, L-FMC15, and FMTD15 were significantly lower than the respective first measurements, but all indices showed full recovery at 60 min in all subjects. The baseline diameter was slightly increased at 15 min and restored at 60 min, but the maximum diameter, and the baseline and reactive flow velocity unchanged. We examined the relationship between recovery rate of FMTD at 15 min (FMTD-R) and cardio-ankle vascular index (CAVI). Univariate analysis showed moderate correlation between FMTD-R, and CAVI and L-FMC0. Patients were divided according to FMTD-R value; the low-FMTD-R group [below the median value (-26.2%)] included a significantly higher proportion of smokers and higher CAVI values than the high-FMTD-R group. The reproducibility of FMTD and FMTD-R was evaluated in another group of 25 healthy subjects. The range of variation across measurements was 1.1% for FMTD and 4.6% for FMTD-R; with intraclass correlation coefficients of 0.93 and 0.95, respectively. The present study demonstrated blunted recovery of FMD within 15 min, suggesting the need for selection of a more adequate interval between measurements to avoid underestimation of FMD in subsequent measurements. The findings demonstrated the reproducibility of FMTD-R and FMTD measurements, and that FMTD-R might be involved in arterial stiffness and early vascular impairment in the healthy subjects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083977PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879271PMC
November 2014

Impact of the circadian rhythm on microvascular function in patients with ST-elevation myocardial infarction.

Int J Cardiol 2013 Oct 23;168(5):4948-9. Epub 2013 Jul 23.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Cardiology, Yokkaichi Municipal Hospital, Yokkaichi, Japan.

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http://dx.doi.org/10.1016/j.ijcard.2013.07.106DOI Listing
October 2013

Impact of metabolic syndrome on various aspects of microcirculation and major adverse cardiac events in patients with ST-segment elevation myocardial infarction.

Circ J 2012 23;76(8):1972-9. Epub 2012 May 23.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Microvascular impairment is associated with a poor prognosis even after successful percutaneous coronary intervention (PCI) in acute myocardial infarction. The aim of the present study was to examine the impact of metabolic syndrome (MetS) on various aspects of microvascular function and clinical outcomes.

Methods And Results: In 216 consecutive patients with ST-segment elevation myocardial infarction (STEMI) after successful primary PCI, data were collected and analyzed on epicardial coronary flow, ST-segment resolution (STR) on electrocardiography, maximum serum creatine kinase levels, and the incidence of major adverse cardiac events (MACE). The prevalence of MetS was 40.7% (88 patients). Corrected Thrombolysis In Myocardial Infarction frame count was significantly higher in the MetS group than in the non-MetS group (28.1±9.4 vs. 24.7±7.9, P=0.04). STR ≥50% was observed in 51.1% and 69.5%, respectively (P=0.01). Patients with MetS also had higher maximum creatine kinase levels (3,470±2,320IU/L vs. 2,664±1,850IU/L, P=0.01). On logistic regression analysis after adjustment for confounders, MetS was an independent negative predictor of complete STR (odds ratio, 0.49; 95% confidence interval [CI]: 0.25-0.95, P=0.03). On Cox multivariate analysis, MetS was an independent predictor for MACE (hazard ratio, 4.85; 95% CI: 1.28-18.3, P=0.02).

Conclusions: MetS may damage microcirculation after direct PCI in patients with STEMI and lead to poor prognosis.
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http://dx.doi.org/10.1253/circj.cj-11-1299DOI Listing
December 2012

Stress augments insulin resistance and prothrombotic state: role of visceral adipose-derived monocyte chemoattractant protein-1.

Diabetes 2012 Jun 6;61(6):1552-61. Epub 2012 Mar 6.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Stressors contribute to thrombosis and insulin resistance. Since obesity-related adipose inflammation is also involved in these pathological states, we assumed that stress correlates with adipose inflammation. Male mice were subjected to 2-week intermittent restraint stress. Expression of plasma lipids, monocyte/macrophage markers (CD11b, CD68, and F4/80), proinflammatory cytokines (monocyte chemoattractant protein-1 [MCP-1], tumor necrosis factor-α, and interleukin-6), adiponectin, heat shock protein 70.1 (HSP70.1), and coagulation factors (plasminogen activation inhibitor-1 [PAI-1] and tissue factor [TF]) in blood and inguinal white adipose tissue (WAT) was determined using immunohistochemistry, enzyme-linked immunosorbent assay, and RT-PCR, respectively. Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests, and expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT. To examine effects of MCP-1 blockade, animals were treated with control or neutralizing antibody, or transplanted with control or 7ND (dominant-negative form of MCP-1)-overexpressing adipose-derived stromal cells (ADSCs). Stress increased monocyte accumulation, free fatty acids, proinflammatory cytokine, and HSP70.1 and reduced adiponectin. Adipose stromal cells highly expressed MCP-1. The stress-induced adipose inflammation increased PAI-1 and TF but did not give rise to thrombus formation. Without any changes in GTT, stress worsened insulin sensitivity and decreased IRS-1 and GLUT4 in WAT. Neutralizing antibody and 7ND-ADSCs reversed stress-induced adipose inflammation, procoagulant state, and insulin resistance. Stress evoked adipose inflammation to increase coagulation factors and impair insulin sensitivity through adipose-derived MCP-1.
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http://dx.doi.org/10.2337/db11-0828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3357288PMC
June 2012

A randomized comparison of sirolimus- vs. paclitaxel-eluting stents for treatment of bifurcation lesions by single stent and kissing balloon: results of the SINGLE KISS trial.

Int J Cardiol 2013 Jun 8;166(1):187-92. Epub 2011 Nov 8.

Department of Cardiology, Toyohashi Heart Center, 21-1 Gobutori, Oyamacho, Toyohashi, 441-8530, Aichi, Japan.

Background: In the treatment of bifurcation lesions, routine stenting of both branches has thus far failed to demonstrate a clear clinical advantage over a provisional one-stent strategy. On the other hand, large scale data evaluating different stent types for clinical outcomes after one-stent treatment with final kissing inflation (FKI) of bifurcation lesions is also limited. This prospective study evaluated the clinical and angiographic outcomes of paclitaxel-eluting stents (PES) vs. sirolimus-eluting stents (SES) in single crossover main branch stenting followed by FKI in patients with bifurcation lesions.

Methods: We randomized 800 patients with single bifurcation lesions to PES (n=400) and SES (n=400) groups.

Results: Crossover rates to the two-stent strategy were low in both groups (PES 1.5%, SES 2.8%; p=0.23). At 1 year, there was no significant difference in the primary endpoint of this study, target lesion revascularization rate (PES 3.8%, SES 3.2%, hazard ratio 0.83; 95% confidence interval 0.39 to 1.76; p=0.62). Stent thrombosis occurred in only 1 case in the SES group after 282 days. At 9 months, a total of 593 patients underwent quantitative coronary measurement. The main branch restenosis rate in the PES group was significantly higher than that of the SES group (PES 12.2%, SES 5.5%; p=0.004), however both groups exhibited similar high side branch restenosis rates (PES 17.2%, SES 19.3%; p=0.6).

Conclusions: In patients with bifurcation lesions, a single stent strategy using PES and SES with FKI indicated similar 1 year clinical outcomes and safety profiles.
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http://dx.doi.org/10.1016/j.ijcard.2011.10.101DOI Listing
June 2013

Impact of plaque burden in the left main coronary artery determined by intravascular ultrasound on cardiovascular events in a Japanese population undergoing percutaneous coronary intervention.

Am J Cardiol 2012 Feb 8;109(3):352-8. Epub 2011 Nov 8.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

The left main coronary artery (LMCA) is a particularly important target of atherosclerotic plaque accumulation. The aim of this study was to investigate the connection between subclinical plaque burden in the LMCA measured by intravascular ultrasound and future cardiovascular events. Two hundred eighteen consecutive patients underwent percutaneous coronary intervention for the left anterior descending coronary artery or the left circumflex coronary artery under intravascular ultrasound guidance. Plaque burden in the LMCA was analyzed for these patients, and major adverse cardiac events were also evaluated. Data were analyzed by grouping the patients into tertiles according to plaque burden values; tertile 1, <32% area stenosis; tertile 2, 32% to 45% area stenosis; and tertile 3, >45% area stenosis. During a 3-year follow-up period (average 16.1 months), 12% of tertile 1, 18% of tertile 2, and 40% of tertile 3 experienced major adverse cardiac events, mostly due to repeat revascularization (p <0.001). On Cox multivariate analysis, plaque burden in the LMCA (per percentage) detected by intravascular ultrasound remained an independent significant predictor of major adverse cardiac events (hazard ratio 1.04, 95% confidence interval 1.02 to 1.07) and future revascularization (hazard ratio 1.05, 95% confidence interval 1.02 to 1.07) (p <0.001). In conclusion, plaque burden in the LMCA is useful as an indicator of coronary atherosclerosis and may be a significant predictor of cardiovascular events, especially revascularization.
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http://dx.doi.org/10.1016/j.amjcard.2011.09.021DOI Listing
February 2012

Pitavastatin-induced angiogenesis and arteriogenesis is mediated by Notch1 in a murine hindlimb ischemia model without induction of VEGF.

Lab Invest 2011 May 7;91(5):691-703. Epub 2011 Feb 7.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Notch signaling is reported to regulate angiogenesis, interacting with vascular endothelial growth factor (VEGF) signaling. HMG CoA reductase inhibitors (statins) also alter Notch signaling in vascular cells, but the mechanism and involvement of Notch and VEGF signaling in statin-mediated angiogenesis remain unclear. Here, we examined how statins activate the endothelial Notch1, and promote angiogenesis and arteriogenesis. We examined blood flow recovery after hindlimb ischemia in wild-type (WT) and Notch1 mutant mice treated with or without pitavastatin (3 mg/kg/day, p.o.). Although VEGF induction was not altered in ischemic limbs, pitavastatin promoted blood flow recovery in ischemic limbs in control mice but not in Notch1 mutant mice. Furthermore, pitavastatin induced endothelial ephrinB2 downstream of Notch1 and increased the density of both capillaries and arterioles in the ischemic limbs of WT but not of Notch1 mutant mice. Pitavastatin (100 nmol/l) rapidly activated γ-secretase and Notch1 in human umbilical vein endothelial cells without VEGF induction, which was suppressed by pharmacological inhibition and knockdown of Akt. Pitavastatin also augmented endothelial proliferation and tube formation on Matrigel, which were suppressed by either γ-secretase inhibition or knockdown of Notch1. Pitavastatin-induced microvascular sprouting was also impaired in Notch1 mutant aortic explants. Taken together, pitavastatin activates Notch1 through Akt-dependent stimulation of γ-secretase in endothelial cells, and thereby increases vasculogenesis without VEGF induction.
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http://dx.doi.org/10.1038/labinvest.2011.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807100PMC
May 2011

Characteristics of images from an in-stent restenosis lesion of a saphenous vein graft after bare-metal stent implantation: Assessment using optical coherence tomography.

J Cardiol Cases 2010 Jun 12;1(3):e151-e153. Epub 2010 Jan 12.

Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Shouwa-ku, Nagoya 466-8550, Japan.

Restenosis of saphenous vein grafts (SVG) after bare-metal stent (BMS) implantation remains a clinical problem. Recently, intravascular optical coherence tomography (OCT) has been proposed as a high resolution intravascular imaging modality, and is able to distinguish several components of intracoronary structures. images of in-stent restenosis (ISR) lesions in an SVG using OCT have not been reported. In this case report, we present the characteristics of OCT images from an ISR lesion of an SVG after BMS implantation.
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http://dx.doi.org/10.1016/j.jccase.2009.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264951PMC
June 2010

Roles of leukocytosis and cysteinyl leukotriene in polymorphonuclear leukocyte-dependent plasma extravasation.

J Leukoc Biol 2006 Dec 29;80(6):1308-19. Epub 2006 Aug 29.

Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.

The PMN-dependent plasma extravasation is a major mechanism of permeability enhancement in acute inflammation. To reveal the pathophysiological significance of the PMN-dependent plasma extravasation, we prepared a systemic leukocytotic guinea pig model by a daily injection of recombinant human (rh)G-CSF. The extent of the PMN-dependent plasma extravasation, regarded as the late-phase permeability induced by an intradermal injection of zymosan-activated guinea pig plasma (ZAP) or of rhC5a, clearly correlated to the circulating PMN number. The augmentation of local response following the systemic response seemed to be the characteristic feature of the PMN-dependent plasma extravasation. We then revealed the molecular mechanism of the PMN-dependent plasma extravasation. Neither the antihistaminic agent diphenhydramine, nor the bradykinin B2 receptor antagonist, HOE140, affected the ZAP-induced, late-phase extravasation. In contrast to this, pretreatment with an antagonist of cysteinyl leukotriene (cys-LT) 1 receptor, pranlukast, significantly reduced the late-phase extravasation. Similarly, it was reduced by pretreatment with a 5-lipoxygenase inhibitor, MK-886, indicating the participation of cys-LTs in the PMN-dependent plasma extravasation. Histologically, pretreatment with pranlukast or MK-886 did not affect the ZAP-induced PMN infiltration. Consistently, a combined treatment with pranlukast and diphenhydramine completely suppressed the early-phase extravasation. As pranlukast pretreatment did not affect plasma extravasation induced by mast cell degranulation, and depletion of platelets did not influence the pranlukast-inhibitable plasma extravasation induced by rhC5a injection, cys-LTs are most likely produced by transcellular biosynthesis involving PMNs and vascular wall cells.
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http://dx.doi.org/10.1189/jlb.0805488DOI Listing
December 2006

Vitamin D hormone inhibits osteoclastogenesis in vivo by decreasing the pool of osteoclast precursors in bone marrow.

J Bone Miner Res 2002 Apr;17(4):622-9

Department of Geriatric Research, National Institute for Longevity Sciences, Aichi, Japan.

Previous observations that vitamin D hormone induces the expression of the receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL), thereby stimulating osteoclastogenesis in vitro, led to the widespread belief that 1alpha,25-dihydroxyvitamin D3 [1a,25(OH)2D3] is a bone-resorbing hormone. Here, we show that alfacalcidol, a prodrug metabolized to 1alpha,25(OH)2D3, suppresses bone resorption at pharmacologic doses that maintain normocalcemia in an ovariectomized (OVX) mouse model of osteoporosis. Treatment of OVX mice with pharmacologic doses of alfacalcidol does not increase RANKL expression, whereas toxic doses that cause hypercalcemia markedly reduce the expression of RANKL. When bone marrow (BM) cells from OVX mice were cultured with sufficient amounts of macrophage colony-stimulating factor (M-CSF) and RANKL, osteoclastogenic activity was higher than in sham mice. Marrow cultures from alfacalcidol- or estrogen-treated OVX mice showed significantly less osteoclastogenic potential compared with those from vehicle-treated OVX mice, suggesting that the pool of osteoclast progenitors in the marrow of vitamin D-treated mice as well as estrogen-treated mice was decreased. Frequency analysis showed that the number of osteoclast progenitors in bone marrow was increased by OVX and decreased by in vivo treatment with alfacalcidol or estrogen. We conclude that the pharmacologic action of active vitamin D in vivo is to decrease the pool of osteoclast progenitors in BM, thereby inhibiting bone resorption. Because of its unusual activity of maintaining bone formation while suppressing bone resorption, in contrast to estrogens that depress both processes, vitamin D hormone and its bone-selective analogs may be useful for the management of osteoporosis.
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http://dx.doi.org/10.1359/jbmr.2002.17.4.622DOI Listing
April 2002
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