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© 2020 The Author(s). Background: Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium-glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity. Methods: This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency-to-high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT. Results: Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was - 0.57 and - 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed. Conclusions: This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events. Trial Registration: The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442.

DOI： 10.1186/s12933-020-01127-z

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<b><i>Introduction:</i></b> High-sensitive cardiac troponin reflects micro-myocardial injury in the absence of overt myocardial infarction. <b><i>Objective:</i></b> This study aimed to clarify how thyrotoxicosis affects cardiac troponin. <b><i>Methods:</i></b> This was a prospective observational study in Japan. Untreated patients with thyrotoxicosis who visited Ito Hospital were enrolled, and medical treatment was initiated for hyperthyroidism. Thyroid function, high-sensitive troponin I (hsTnI), and brain natriuretic peptide (BNP) were measured at baseline and then every 3 months for 1 year. <b><i>Results:</i></b> Data from a total of 143 patients (median age, 42 years; 32 men and 111 women) were investigated. At baseline, median hsTnI was 1.9 pg/mL and ranged from 0 to 69.6 pg/mL. Five patients (3.5%) had a high hsTnI value that exceeded 26.2 pg/mL, which is used as the cutoff for diagnosis of myocardial infarction, and 22 patients (15.4%) had an intermediate value between 5.0 and 26.2 pg/mL. Multivariable regression analysis showed that significant predictors of the hsTnI value were age (β = 0.20, <i>p</i> = 0.01) and BNP (β = 0.43, <i>p</i> < 0.0001) (<i>R</i><sup>2</sup> = 0.27, <i>F</i> = 26.0, <i>p</i> < 0.0001), and significant predictors of the BNP value were age (β = 0.23, <i>p</i> = 0.001), hemoglobin (β = −0.43, <i>p</i> < 0.0001), free T<sub>4</sub> (FT<sub>4</sub>) (β = 0.23, <i>p</i> = 0.001), and hsTnI (β = 0.27, <i>p</i> < 0.0001) (<i>R</i><sup>2</sup> = 0.49, <i>F</i> = 33.8, <i>p</i> < 0.0001). Correlations were found between a decrease in hsTnI and BNP in the first 3 months (ρ = 0.49, <i>p</i> < 0.0001). A decrease in FT<sub>4</sub> in the first 3 months was weakly correlated with decreases in hsTnI (ρ = 0.32, <i>p</i> = 0.0004) and BNP (ρ = 0.32; <i>p</i> = 0.0003). Of the 27 patients with elevated hsTnI (≥5.0 pg/mL), the hsTnI level was normalized in 20 patients within a year. <b><i>Conclusions:</i></b> In thyrotoxicosis, the myocardial biomarker hsTnI is elevated in about 20% of patients; hsTnI levels decrease as thyroid function improves and BNP decreases.

File： Watanabe-ETJ510619.pdf

DOI： 10.1159/000510619

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Platelet-rich plasma (PRP) contains numerous growth factors and promotes bone fracture healing. The aim of this study was to evaluate the effectiveness of the controlled release of PRP from biodegradable gelatin hydrogel for promoting healing in a rabbit ischemic sternal model. PRP was prepared from the whole blood of a Japanese white rabbit. Sixteen rabbits were randomized into four groups (each n = 4) and all underwent median sternotomy and bilateral internal thoracic artery removal. Before the sternum was closed, the following solutions were applied between the sternum incisions in three of the groups: 30 mg of gelatin hydrogel incorporating 300 μL of phosphate-buffered saline, 300 μL of a solution form of PRP, or 30 mg of gelatin hydrogel incorporating 300 μL of PRP (PRP + Gel). The fourth group acted as a control. Sternal healing was evaluated by histology and microcomputed tomography 7 days after the intervention. The PRP + Gel group showed a significantly higher proportion of fibrosis within the fracture area (an indicator of sternal healing) than the other groups and a significantly higher mean intensity of osteocalcin. These results indicate that the controlled release of PRP from locally applied gelatin hydrogel was markedly effective in enhancing sternal healing in the early postoperative period. This novel therapy could potentially help prevent complications, such as deep sternal wound infection and could result in early postoperative ambulation after median sternotomy.

DOI： 10.1089/ten.TEA.2017.0505

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Keloid is a cutaneous fibroproliferative disorder. It results from impaired wound healing that generates persistent inflammation and extensive deposition of collagen fibers in the wound/scar. Keloids tend to be worse in hypertensive patients. The present prospective cross-sectional study assessed whether endothelial dysfunction, which occurs in hypertension, associates with keloid formation and progression. This study included randomly selected patients with keloids who were assessed for surgical keloid treatment in 2013–2014. A series of nonkeloid patients admitted to the hospital was also recruited during this period. To measure endothelial function, all patients underwent digital reactive hyperemia peripheral arterial tonometry. Test results were expressed as reactive hyperemia index (RHI) and augmentation index (AI). In total, 57 patients with keloids and 19 nonkeloid controls were recruited. Keloid patients did not differ from the controls in terms of demographic or clinical variables, but had significantly worse RHI and AI values. Moreover, poor RHI and AI values associated with keloid development on binomial logistic regression. The keloid patients were then divided into four groups depending on whether their keloids started at age 0–12, 13–18, 19–29, or ≥30 years. Patients whose keloids arose before and well after puberty tended to have lower RHI than the controls, but these differences did not achieve statistical significance. However, these two groups did have significantly poorer AI values than the controls. Thus, endothelial dysfunction could cause keloid formation and/or aggravation. This indicates that vascular endothelial cells are important for wound healing.

DOI： 10.1111/wrr.12601

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DOI： 10.1111/dom.12871

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The purpose of this study was to estimate the severity of the participants' lower limb ischemia by calculating the lower limb muscle-to-background ratio (LMBR) using lower limb perfusion single-photon emission computed tomography-computed tomography (SPECT/CT) and to evaluate the prognostic value of LMBR in peripheral artery disease (PAD) patients.
This retrospective study consists of 38 patients with PAD (70 +/- 12 years) and observed over 1 year who were included in the analysis. All participants underwent lower limb perfusion SPECT/CT. LMBR was calculated by dividing counts/volume in lower limb muscle by mean counts/volume of background. All patients were divided into two groups based on their LMBR value and observed for the occurrence of a major adverse event (MAE).
The high and low LMBR groups consisted of 26 and 12 patients, respectively. The median LMBR in the high group was 9.59 (6.11-11.87) while that in the low group was 4.35 (3.85-4.99). A significantly higher number of patients in the low LMBR group experienced MAE than in the high LMBR group (7 of 12 vs. 1 of 26, p < 0.001).
This study demonstrated that the LMBR derived from lower limb perfusion SPECT/CT may have a high prognostic value in patients with PAD.

DOI： 10.1007/s11604-016-0602-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of highdose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79-1.19; P=0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73-1.21; P=0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72-1.2; P=0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors.

DOI： 10.1161/HYPERTENSIONAHA.116.07797

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OBJECTIVEWe evaluated the risk of cardiovascular (CV) death in all Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study participants and in those who experienced an on-study, major nonfatal CV event.RESEARCH DESIGN AND METHODSThe study randomly assigned 5,380 patients with type 2 diabetes to alogliptin or placebo within 15 to 90 days of an acute coronary syndrome (ACS). Deaths and nonfatal CV events (myocardial infarction [MI], stroke, hospitalized heart failure [HHF], and hospitalization for unstable angina [UA]) were adjudicated. Patients were monitored until censoring or death, regardless of a prior postrandomized nonfatal CV event. Time-updated multivariable Cox models were used to estimate the risk of death in the absence of or after each nonfatal event.RESULTSRates of CV death were 4.1% for alogliptin and 4.9% for placebo (hazard ratio [HR] 0.85; 95% CI 0.66, 1.10). A total of 736 patients (13.7%) experienced a first nonfatal CV event (5.9% MI, 1.1% stroke, 3.0% HHF, and 3.8% UA). Compared with patients not experiencing a nonfatal event, the adjusted HR (95% CI) for death was 3.12 after MI (2.13, 4.58; P < 0.0001) 4.96 after HHF (3.29, 7.47; P < 0.0001), 3.08 after stroke (1.29, 7.37; P = 0.011), and 1.66 after UA (0.81, 3.37; P = 0.164). Mortality rates after a nonfatal event were comparable for alogliptin and placebo.CONCLUSIONSIn patients with type 2 diabetes and a recent ACS, the risk of CV death was higher after a postrandomization, nonfatal CV event, particularly heart failure, compared with those who did not experience a CV event. The risk of CV death was similar between alogliptin and placebo.

DOI： 10.2337/dc16-0303

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UNLABELLED: One problem of vascular angiogenesis therapy is the lack of reliable methods for evaluating blood flow in the microcirculation. We aimed to assess whether (99m)Tc-macroaggregated albumin perfusion scintigraphy ((99m)Tc-MAA) predicts quantitated blood flow after therapeutic angiogenesis in patients with peripheral artery disease. METHODS: Forty-six patients with peripheral artery disease were treated with bone marrow mononuclear cell implantation (BMCI). Before and 4 wk after BMCI, blood flow was evaluated via transcutaneous oxygen tension (TcPO2), ankle-brachial index, intravenous (99m)Tc-tetrofosmin perfusion scintigraphy ((99m)Tc-TF), and intraaortic (99m)Tc-MAA. RESULTS: Four weeks after BMCI, TcPO2 improved significantly (20.4 ± 14.4 to 36.0 ± 20.0 mm Hg, P < 0.01), but ankle-brachial index did not (0.65 ± 0.30 to 0.76 ± 0.24, P = 0.07). Improvement in (99m)Tc-TF count (0.60 ± 0.23 to 0.77 ± 0.29 count ratio/pixel, P < 0.01) and (99m)Tc-MAA count (5.21 ± 3.56 to 10.33 ± 7.18 count ratio/pixel, P = 0.02) was observed in the foot region but not the lower limb region, using both methods. When these data were normalized by subtracting the pixel count of the untreated side, the improvements in (99m)Tc-TF count (-0.04 ± 0.26 to 0.08 ± 0.32 count ratio/pixel, P = 0.04) and (99m)Tc-MAA count (1.49 ± 3.64 to 5.59 ± 4.84 count ratio/pixel, P = 0.03) in the foot remained significant. (99m)Tc-MAA indicated that the newly developed arteries were approximately 25 μm in diameter. CONCLUSION: BMCI induced angiogenesis in the foot, which was detected using (99m)Tc-TF and (99m)Tc-MAA. (99m)Tc-MAA is a useful method to quantitate blood flow, estimate vascular size, and evaluate flow distribution after therapeutic angiogenesis.

File： Takagi JNuclMed.pdf

DOI： 10.2967/jnumed.115.160937

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background The EXAMINE trial showed non-inferiority of the DPP-4 inhibitor alogliptin to placebo on major adverse cardiac event (MACE) rates in patients with type 2 diabetes and recent acute coronary syndromes. Concerns about excessive rates of in-hospital heart failure in another DPP-4 inhibitor trial have been reported. We therefore assessed hospital admission for heart failure in the EXAMINE trial.Methods Patients with type 2 diabetes and an acute coronary syndrome event in the previous 15-90 days were randomly assigned alogliptin or placebo plus standard treatment for diabetes and cardiovascular disease prevention. The prespecified exploratory extended MACE endpoint was all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, urgent revascularisation due to unstable angina, and hospital admission for heart failure. The post-hoc analyses were of cardiovascular death and hospital admission for heart failure, assessed by history of heart failure and brain natriuretic peptide (BNP) concentration at baseline. We also assessed changes in N-terminal pro-BNP (NT-pro-BNP) from baseline to 6 months. This study is registered with ClinicalTrials.gov,number NCT00968708.Findings 5380 patients were assigned to alogliptin (n=2701) or placebo (n=2679) and followed up for a median of 533 days (IQR 280-751). The exploratory extended MACE endpoint was seen in 433 (16.0%) patients assigned to alogliptin and in 441 (16.5%) assigned to placebo (hazard ratio [HR] 0.98, 95% CI 0.86-1.12). Hospital admission for heart failure was the first event in 85 (3.1%) patients taking alogliptin compared with 79 (2.9%) taking placebo (HR 1.07, 95% CI 0.79-1.46). Alogliptin had no effect on composite events of cardiovascular death and hospital admission for heart failure in the post hoc analysis (HR 1.00, 95% CI 0.82-1.21) and results did not differ by baseline BNP concentration. NT-pro-BNP concentrations decreased significantly and similarly in the two groups.Interpretation In patients with type 2 diabetes and recent acute coronary syndromes, alogliptin did not increase the risk of heart failure outcomes.

DOI： 10.1016/S0140-6736(14)62225-X

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BACKGROUND: Because direct application of low-energy shock waves induces angiogenesis, we investigated the safety and efficacy of this new therapy to develop a noninvasive method of repeatable therapeutic angiogenesis for treating peripheral arterial disease (PAD). SUBJECTS AND METHODS: The subjects were 10 patients who had symptomatic PAD and limited ischemia in a below-the-knee artery. Low-energy shock waves were directly applied to the calf muscles 6 times every other day. Intracorporeal changes were evaluated with ultrasonography to determine adverse effects of therapy. To assess blood flow of the microcirculation, transcutaneous oxygen tension (TcPO2), skin perfusion pressure (SPP), and (99m)technetium-tetrofosmin ((99m)Tc-TF) scintigraphy were performed before and after therapy. The TcPO2 was measured while subjects inhaled pure oxygen (maximum TcPO2). The (99m)Tc-TF perfusion index was determined as a ratio of uptake in muscle to that in the brain (control) for quantitative analysis. RESULTS: No adverse effects were noted in any patient. Maximum TcPO2 values increased significantly on the calf (57.3±28.4 to 71.0±14.5 mm Hg, p=0.044) and the dorsum of the foot (52.2±21.8 to 76.1±17.9 mm Hg, p=0.012). The SPP tended to increase after therapy on the dorsum and plantar surfaces of the foot, but the differences were not significant. The (99m)Tc-TF perfusion index in the foot significantly increased (0.48±0.09 to 0.61±0.12, p=0.0013), but that in the leg did not change. CONCLUSION: We have demonstrated that low-energy shock wave therapy is safe and can restore blood flow in the microcirculation in patients with symptomatic PAD.

DOI： 10.1272/jnms.81.19

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press  

Objective: SSc causes intractable ischaemic ulcers. To avoid major amputation, we examined the safety and efficacy of therapeutic vascular angiogenesis for digital ulcers due to SSc. Methods: A single-centre, open-label pilot study was conducted in patients with an ischaemic digital ulcer [n = 40, mean age 65 years (s.d. 8), Rutherford class III-5 or III-6) due to lcSSc (n = 11) or arteriosclerosis obliterans (ASO
n = 29). Bone marrow mononuclear cells (0.4-5.1 × 1010 cells in total) were administered into the ischaemic limbs. We evaluated short-term safety and efficacy by means of a pain scale, 99mTc-tetrofosmin scintigraphy and transcutaneous oxygen tension (TcPO2) before and 4 weeks after treatment. Also, the 2-year outcome was compared. Results: There was a case of amputation in each group within 4 weeks after therapy. The pain scale significantly decreased in both groups [lcSSc 93 mm (s.d. 9) to 11 (s.d. 16), P &lt
0.01
ASO 77 mm (s.d. 22) to 16 (s.d. 13), P &lt
0.01] and TcPO2 significantly improved [lcSSc 9.0 mmHg (s.d. 9) to 35 (s.d. 14), P &lt
0.01
ASO 18 mmHg (s.d. 10) to 29 (s.d. 21), P &lt
0.05). At the 2-year follow-up, the limb amputation rate was 9.1% in lcSSc and 20.7% in ASO (P = 0.36), while the recurrence rate was 18.2% in lcSSc and 17.2% in ASO (P = 0.95). All-cause mortality was 27.3% in lcSSc and 17.2% in ASO (P = 0.65). Conclusion: In patients with lcSSc, bone marrow mononuclear cell implantation provides clinical benefit and is safe, without major adverse reactions, and may become an effective strategy. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

File： Takagi Rheumatology-2014full.pdf

DOI： 10.1093/rheumatology/ket432

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DOI： 10.1161/CIRCULATIONAHA.112.000602

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MASSACHUSETTS MEDICAL SOC  

BackgroundTo assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome.MethodsWe randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.ResultsA total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo.ConclusionsAmong patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.)

DOI： 10.1056/NEJMoa1305889

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Background: Obesity is associated with an increased risk of heart failure (HF) but the relationship between changes in cardiac function and the specific pathological features of dilated cardiomyopathy (DCM) with obesity, remains unknown. Methods: Endomyocardial biopsies from the left ventricle (LV) were obtained from 50 patients with DCM, at the first-onset of decompensated HF. Thirty patients were obese (obese-group: body mass index &gt
30 kg/m 2) and 20 were non-obese (lean-group). Clinical data were acquired at the admission, after one month and one year. Results: The obese-group had higher systolic blood pressure (142.8 ± 33.9 vs 113.6 ± 18.7 mm Hg
p &lt
0.001) and serum troponin-T level (0.049 ± 0.07 vs 0.020 ± 0.03 ng/mL
p = 0.022) than the lean-group. LV ejection fraction (LVEF) was not significantly different between groups, but after one year the obese-group had an improved LVEF (57.0 ± 11.4 vs 44.3 ± 17.1
p = 0.003). Light microscopy revealed that the obese-group had larger cardiomyocytes (17.2 ± 1.7 vs 16.4 ± 1.4 μm
p = 0.033) and less myofilament lysis (37 vs 75%
p = 0.008) with a higher density of lipid droplets (1.93 ± 0.8 vs 0.94 ± 0.7 /μm2
p &lt
0.001). Multivariate regression analysis revealed that independent predictors of LVEF improvement after 12 months were diuretics use, nuclear diameter, and absence of myofilament lysis (p = 0.024, 0.012 and 0.028, respectively). Conclusions: Cardiac function in most patients with DCM with obesity is reversible and myocardial structural changes are trivial even at the ultrastructural level. © 2012 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ijcard.2012.09.046

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：一般社団法人 日本創傷外科学会  

マゴットセラピー（maggot debridement therapy：MDT）は医療用無菌ウジを使用した感染性創傷に対する生物学的デブリードマン治療であるが，臨床応用する際に気を付けるべき問題点や，安全な適応病変，そして治療中の副作用への対応等，初めて治療を行う場合や難治性の場合の考え方など，知っておくべきことや注意点などを紹介する。まずわれわれは，当院で治療に携わる看護師と治療を受けた患者にアンケートを行い，問題点抽出を行った。また臨床治療成績は，2008年1月～2011年12月の期間にマゴットセラピーを施行した78症例の疾患分類，臨床病態，下肢予後と生命予後に関する危険因子を解析し，Cox回帰分析とロジスティック回帰分析にて独立危険因子を推定した。マゴットセラピーは問題点と危険因子を十分に管理した集学的治療の一環として行うことにより，安全かつ苦痛を伴わず施行でき，下肢生存率，生存率ともに93％以上の成績を得られる治療法である。

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The aim of the present study was to investigate whether percutaneous coronary intervention-related periprocedural myocardial infarction (MI) can be suppressed more significantly with high- compared with low-dose rosuvastatin. A total of 232 patients scheduled to undergo elective percutaneous coronary intervention within 5 to 7 days were assigned to groups that would receive either 2.5 or 20 mg/day of rosuvastatin (n = 116 each). The incidence of periprocedural MI did not significantly differ between the high and low-dose groups (8.7% vs 18.7%, p = 0.052). In patients who were not taking statins at the time of enrollment, high-dose rosuvastatin significantly suppressed periprocedural MI compared with the low dose (10.5% vs 30.0%, p = 0.037). The difference was not significant in patients who were already taking statins (high vs low dose 7.6% vs 10.6%, p = 0.582). In conclusion, the incidence of percutaneous coronary intervention-related periprocedural MI was reduced more effectively by high-dose than by low-dose rosuvastatin in statin-naive patients. However, low-dose rosuvastatin is sufficient for patients who are already taking statins. © 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.amjcard.2013.02.018

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Heart Journal Association  

A 58-year-old male with a history of prior myocardial infarction, hypertension, and dyslipidemia was admitted due to deteriorating exertional angina. A bare metal stent (Multilink plus™, GUIDANT Corporation, Santa Clara, CA, USA) had been implanted into the proximal left anterior descending artery because of ST-elevation myocardial infarction 7 years earlier. Optical coherence tomography (OCT) showed a disruption of the atherosclerotic neointima overlying the stent. Intravascular imaging studies and pathological studies have shown that neointima within a bare-metal stent often transform into atherosclerotic tissue during an extended period of time. In the current report, OCT demonstrated that a disruption of the atherosclerotic neointima has the potential to cause the development of unstable clinical features. OCT examinations therefore help to understand the pathogenesis of acute coronary syndrome after stent implantation.

DOI： 10.1536/ihj.53.261

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The vascular endothelial function is impaired in the very early stage of atherosclerosis in diabetic patients. The goal of this study was to identify the mechanism underlying the improvementin vascular endothelial function by sitagliptin in type 2 diabetes mellitus patients. This study was an open-labeled prospective observational single arm trial. Forty patients were treated with 50 mg of sitagliptin once daily for 12-weeks. The flow-mediated dilation (FMD) and plasma adiponectin were measured at baseline and 12 weeks after initiating treatment. The %FMD was significantly increased after treatment (4.13 ± 1.59 vs 5.12 ± 1.55, P &lt
0.001), whereas the nitroglycerin-mediated dilation (NMD) did not change. The plasma adiponectin levels significantly increased (13.0 ± 11.3 vs 14.3 ± 12.8, P &lt
0.001). The changes in the FMD were significantly correlated with those of the plasma adiponectin (r = 0.322, P &lt
0.05). A multivariate linear regression analysis demonstrated that the improvement in the FMD is associated with the plasma adiponectin (P &lt
0.05). The treatment of type 2 diabetes mellitus patients with sitagliptin reverses vascular endothelial dysfunction, as evidenced by increase in the FMD, and improvement of the adiponectin levels (UMIN Clinical Trials Registry System as trial ID UMIN000004236). © 2012 The Korean Academy of Medical Sciences.

DOI： 10.3346/jkms.2012.27.11.1364

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OBJECTIVE: We examined the safety and efficacy of controlled-release basic fibroblast growth factor (b-FGF) for peripheral artery disease (PAD), compared with autologous bone marrow mononuclear cell implantation (BMCI). BACKGROUND: We recently developed a b-FGF-incorporated biodegradable hydrogel that enables slow-releasing drug delivery system. METHODS: PAD patients were divided into a b-FGF group (n=10) and BMCI group (n=15). Injection of gelatin hydrogel containing 600 μg b-FGF or BMCI (0.4-5.1×10(10) cell) was performed. Visual analog pain scale (VAS), (99m)technetium-tetrofosmin (Tc-TF) scintigraphy, transcutaneous oxygen tension (TcPO(2)), and ankle-brachial index (ABI) were evaluated before and 4 weeks after each treatment, and 2-year prognosis was determined. RESULTS: VAS (b-FGF 67±15 to 4±5, p<0.01, BMCI 67±42 to 5±9 mm, p<0.01) and TcPO(2) (b-FGF 16±14 to 47±17, p<0.01, BMCI 13±13 to 37±21 mmHg, p<0.01) were significantly improved in both groups. Tc-TF and ABI were not changed. Prognosis was similar between the groups (b-FGF 91%, BMCI 80%, NS). CONCLUSION: Controlled-release b-FGF is as safe as BMCI, and its efficacy appears to be comparable. Thus, this therapy may be an alternative to BMCI.

File： Takagi Tiss Eng_12.pdf

DOI： 10.1089/ten.tea.2010.0525

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DOI： 10.1111/j.1447-0594.2011.00695.x

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Background: Platelet-rich plasma (PRP) contains numerous growth factors that have angiogenic activities. However, the PRP-induced angiogenesis is limited by the short half-life period of growth factors. A new drug delivery system of biodegradable gelatin hydrogel was designed to achieve the controlled release of growth factors in PRP. The purpose of this study is to demonstrate the therapeutic efficacy of slow-release of PRP in the inducing of angiogenesis for critical ischemia. Methods: The PRP was prepared from the whole blood of inbred rats. Thirty-two rats underwent excision of the left femoral artery and its branches to create critical limb ischemia. The rats were randomized into four groups (n = 8 each): no treatment (control), intramuscular injection of platelet-poor plasma (PPP), PRP only, or a combination of PRP and gelatin hydrogel (PRP+Gel). Four weeks after the treatment, angiogenesis was evaluated by laser doppler, microangiogram, and immunohistology. Results: The resultant number of platelets for PRP was higher than that of PPP (p &lt
0.01). The concentrations of vascular endothelial growth factor, transforming growth factor-β1, and platelet-derived growth factor-BB were significantly higher in PRP animals than in PPP (p &lt
0.01). Although the PRP group improved tissue blood flow (82.7% ± 6.2%) compared with the control group or PPP group (69.6 ± 12.2 or 72.2 ± 11.8%, p &lt
0.05), the improvement of blood flow in the PRP+Gel group was significantly better (95.1% ± 8.0%, p &lt
0.05) than in the PRP group. Angiographic score in the PRP+Gel group was significantly higher than that in the control, PPP, and PRP groups (8.6 ± 2.1 versus 3.8 ± 0.8, 3.7 ± 0.6, and 5.6 ± 1.5, respectively
p &lt
0.01). Capillary density also increased immunohistologically in the PRP+Gel group when compared with the control, PPP, and PRP groups (p &lt
0.01). Conclusions: A controlled release system of PRP was effective in inducing angiogenesis for critical ischemia. The biodegradable gelatin hydrogel incorporating PRP as applicable could possibly be used to treat for patients with ischemic cardiomyopathy. © 2011 The Society of Thoracic Surgeons.

DOI： 10.1016/j.athoracsur.2011.04.084

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PURPOSE: Despite advances in therapeutic angiogenesis by bone marrow cell implantation (BMCI), limb amputation remains a major unfavorable outcome in patients with critical limb ischemia (CLI). We sought to identify predictor(s) of limb salvage in CLI patients who received BMCI. MATERIALS AND METHODS: Nineteen patients with CLI who treated by BMCI were divided into two groups; four patients with above-the-ankle amputation by 12 weeks after BMCI (amputation group) and the remaining 15 patients without (salvage group). We performed several blood-flow examinations before BMCI. Ankle-brachial index (ABI) was measured with the standard method. Transcutaneous oxygen tension (TcPO2) was measured at the dorsum of the foot, in the absence (baseline) and presence (maximum TcPO2) of oxygen inhalation. (99m)technetium-tetrofosmin ((99m)Tc-TF) perfusion index was determined at the foot and lower leg as the ratio of brain. RESULTS: Maximum TcPO2 (p = 0.031) and (99m)Tc-TF perfusion index in the foot (p = 0.0068) was significantly higher in the salvage group than in the amputation group. Receiver operating characteristic (ROC) curve analysis identified maximum TcPO2 and (99m)Tc-TF perfusion index in the foot as having high predictive accuracy for limb salvage. CONCLUSION: Maximum TcPO2 and (99m)Tc-TF perfusion index in the foot are promising predictors of limb salvage after BMCI in CLI.

DOI： 10.3400/avd.oa.10.01049

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Plaque disruption, which may be associated with some coronary risk factors, plays a key role in the development of acute coronary syndromes and progression of atherosclerosis. However, the clinical profile of asymptomatic plaque disruption in stable ischemic heart disease has not been well evaluated. The aim of the present study was to investigate the frequency and determinants of silent plaque disruption (SPD) in patients with stable ischemic heart disease using coronary angioscopy. Forty-one patients with stable angina or old myocardial infarction (OMI) without any complaints within 3 months were included in the present study. Angioscopy was successfully performed through 49 non ischemic related coronary arteries. The presence of SPD and coronary risk factors were recorded. Silent plaque disruption was found in 12 patients with stable ischemic heart disease (12/41, 29.3%), and the frequency of SPD in non ischemic related coronary arteries was 26.5% (13/49). A significantly higher frequency of SPD was noted in yellow plaques than in white plaques (35.3% versus 6.7%, P = 0.043). Overall, the independent clinical risk factors of SPD in non ischemic related coronary arteries were diabetes mellitus (P = 0.018
OR, 18.8209
95% CI, 1.6525 to 214.3523) and hypertension (P = 0.0313
OR, 6.6485
95% CI, 1.1850 to 37.3019). These results suggest silent plaque disruption was commonly observed in non ischemic related coronary arteries in patients with stable ischemic heart disease and its determinants were diabetes mellitus and hypertension.

DOI： 10.1536/ihj.51.383

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Churg-Strauss syndrome (CSS) causes necrotizing vasculitis affecting small- to medium-sized arteries, mainly in the lungs, gastrointestinal system, heart, kidneys, and skin. Skin lesions sometimes ulcerate because of severe ischemia and become intractable when complicated by bacterial infection. We report a rare case of CSS, characterized by a nonhealing ischemic skin ulcer of the right calf with bacterial infection resistant to antibiotics. After sterile maggot debridement therapy, 2 skin autografts failed. Subsequently, a slow-release formula of basic fibroblast growth factor incorporated in biodegradable gelatin hydrogel was administered into the calf muscles to induce vascular regeneration. The ulcer eventually healed with no recurrence. This report describes the use of controlled-release basic fibroblast growth factor for an ischemic leg ulcer in a patient with CSS, suggesting a possible therapeutic role of this novel neovascularization therapy in treating severe skin lesions complicating autoimmune vasculitis syndromes.

DOI： 10.1097/MAJ.0b013e3181abbd09

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Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)   Publisher：日本医科大学医学会  

An 80-year old man with a history of abdominal aortic aneurysm was emergently admitted to our hospital with suspected ileus. The previous day he had had back pain and abdominal pain. A chest X-ray film showed widening of the aortic shadow. A computed tomography scan with contrast enhancement revealed aortic dissection (Stanford B, De Bakey IIIb). We started conservative hypotensive therapy with nicardipine, without operation or stent grafting, because of the involvement of the major branches of the aortic arch. However, the false lumen was not thrombosed during conservative therapy. Three months later a computed tomography scan with contrast enhancement revealed aortic dissection with a false lumen from the left subclavian artery through the level of the diaphragm. Petechiae were noted over the skin of the thorax and abdomen. Coagulation studies revealed a low platelet count and increased levels of fibrin degradation products and thrombin-antithrombin, indicating disseminated intravascular coagulation due to chronic consumption coagulopathy associated with aortic dissection. Because the bleeding tendency persisted in spite of the initial hypotensive therapy and blood transfusion, w

DOI： 10.1272/manms.5.167

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Coronary perforation is an undesirable complication during percutaneous coronary intervention (PCI). We reviewed the cases of overt coronary perforation in our institute and analyzed their clinical backgrounds, the characteristics of the target lesion, management, and clinical outcomes. Between 1991 and 2005, we experienced 12 cases (0.35%) of coronary perforation in a total of 3415 PCI procedures. The perforation occurred during the use of debulking devices in 3 cases, immediately after stenting in 2, immediately after postdilatation of the stent in 2, and during wiring in 3 cases. Restoration was attempted by long inflation of a balloon in 7 cases, implantation of a covered stent graft in 1, and emergency surgical repair in 1 case. Subsequent cardiac tamponade occurred in 3 patients who required pericardiocentesis, and 1 patient died due to congestive heart failure. Administration of protamine was effective in stopping the bleeding in 6 patients, whereas continuation of antiplatelet therapy resulted in no overt rebleeding. Coronary perforation during PCI is a rare complication but is associated with significant morbidity and mortality. Intravenous administration of protamine is effective when it is used in conjunction with nonsurgical devices for initial management of perforation.

DOI： 10.1536/ihj.48.1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

Since most transplanted cells rapidly die in an ischemic environment by hypoxia and hyponutrition, it is crucial to know how to protect transplanted cells for improving transplantation efficiency. We examined whether the transduction of an artificial anti-cell death protein (PTD-FNK) into bone marrow mononuclear cells (BM-MNCs) prevents cell death and improves the transplantation efficiency of BM-MNCs in ischemic regions. Rat bone marrow cells were prepared from the femur and tibia and cultured on dishes precoated with human fibronectin in the absence of serum. BM-MNCs transduced with PTD-FNK survived better than those without the protein (P&lt;0.008) and retained the potential to differentiate into endothelial progenitor cells (EPCs), as judged by the uptake of an acetylated low-density lipoprotein and the ability to bind lectin. Next, we used a co-culture system comprising human umbilical vein endothelial cells (HUVECs) and fibroblasts to examine angiogenic potential. HUVECs pretreated with PTD-FNK survived and formed a blood-vessel-like structure better than untreated cells (P&lt;0.001). When BM-MNCs expressing EGFP were transplanted into ischemic areas of a male rat ischemic hindlimb model, the cells pretreated with PTD-FNK were incorporated into blood vessel with a higher efficiency than the untreated BM-MNCs (P=0.03). BM-MNCs protected through transduction of PTD-FNK maintained their angiogenic potential. Thus, PTD-FNK improves the transplantation efficiency of BM-MNCs into ischemic regions. (c) 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yjmcc.2006.11.013

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Chronic stimulation of beta-adrenergic receptors (βARs) induces βAR downregulation. However, it is not known whether continuous activation of adenylyl cyclase without direct stimulation of βARs leads to receptor downregulation. This study investigated the effects of chronic stimulation of adenylyl cyclase with colforsin, on hemodynamic variables, and on myocardial βAR density. In all, 55 rabbits received intravenous colforsin (1.6 μg/kg/min, n = 20), isoproterenol (ISO
0.4 μg/kg/min, n = 16), or saline (n = 19) for two weeks. After chronic drug administration, responses of systolic (Δ% peak LV +dP/dt) and diastolic function (Δ% peak LV -dP/dt), and heart rate (Δ% heart rate), to acute administration of ISO (0.05 to 0.2 μg/kg/min) or colforsin (5 to 20 nmol/kg/min) were decreased compared to those before chronic administration. βAR density in the colforsin group (69.8 ± 13.8 fmol/ml protein) was less than that in the saline group (79.8 ± 15.0 fmol/ml protein, P &lt
0.05), but was greater than that in the ISO group (56.3 ± 8.4 fmol/ml protein, P &lt
0.05). Thus, chronic direct stimulation of adenylyl cyclase elicited systolic and diastolic functional desensitization to βAR stimulation or adenylyl cyclase stimulation, and myocardial βAR downregulation. © 2006 Lippincott Williams &amp
Wilkins, Inc.

DOI： 10.1097/01.fjc.0000247801.98874.a6

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本糖尿病学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本医科大学医学会  

Cholesterol crystal embolism (CCE) is a systemic disorder caused by microshowers of cholesterol crystals. It brings about decreased microcirculation and is manifested in various organs including the kidneys, skin, brain and extremities. Cholesterol microshowers are thought to occur in about 50% of invasive vascular procedures, but most cases are clinically silent. CCE has a high mortality rate, but there are as yet no established methods for managing it. We report two cases (63-year-old and 73-year-old males) of progressive renal insufficiency with eosinophilia and peripheral ischemic symptoms such as livedo reticularis and foot pain following percutaneous coronary intervention (PCI) for acute myocardial infarction. In the first case, we made a diagnosis of CCE based on clinical findings, which included deteriorating renal failure after PCI, peripheral eosinophilia, livedo reticularis, smoking history, uncontrollable hypertension, and severe atherosclerotic plaque of the aorta demonstrated by transesophageal echocardiography. In the second case, skin biopsy specimens confirmed a diagnosis of CCE. In both cases, treatment with prostaglandins and statins was unsatisfactory. However, additional treatment with LDL apheresis (LDL-A) and corticosteroids improved the eosinophillia, livedo reticularis, foot pain and renal function, suggesting that this combined treatment may have a beneficial effect on CCE.<br>

DOI： 10.1272/manms.2.115

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Recently, it has been reported that circulating oxidized low-density lipoprotein (Ox-LDL) might be a pivotal indicator for coronary artery disease and the severity of acute coronary syndromes. The purpose of this study was to investigate the effects of statins on Ox-LDL in patients with hypercholesterolemia. Sixteen patients with hypercholesterolemia were randomly assigned to 2 groups, one received 10 mg of pravastatin (n = 8) and the other received 20 mg of fluvastatin (n = 8). The plasma level of Ox-LDL was measured using a newly developed sandwich enzyme-linked immunosorbent assay (ELISA) method. There were no differences between the two groups in Ox-LDL, total cholesterol (TC), or LDL cholesterol (LDL-C) at the baseline. The reduction in Ox-LDL in the fluvastatin group was significantly higher than that in the pravastatin group (47.5% versus 25.2%, P = 0.033). The reductions in TC and LDL-C did not differ between the two groups. Conclusion: The present study has shown for the first time that the level of circulating Ox-LDL was significantly decreased by treatment with statins. In addition, the lowering effect of statins on the circulating Ox-LDL was independent of their lipid-lowering effect. Fluvastatin was more effective than pravastatin with regard to decreasing the circulating Ox-LDL.

DOI： 10.1536/jhj.45.969

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.yjmcc.2003.11.006

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We investigated efficacy and safety of implantation of autologous bone marrow mononuclear cells plus platelets, including endothelial progenitor cells (EPCs), for recovering refractory chronic peripheral arterial disease (PAD) using visual and quantitative analyses by 99mTc-tetrofosmin (TF) perfusion scintigraphy, and also investigated various quantitative assessments objectively. We performed 12 consecutive cases and 19 limbs and hands with severe chronic PAD that were almost Fontaine class IV (11/12 cases, about 92%) in this trial. This treatment was very effective in relieving severe pain of PAD, especially for Buerger's disease. We used a visual analog scale (VAS) for measurement of pain level. The maximum pain level before implantation was 66.5 ± 5.0 mm, and it decreased to 12.1 ± 2.2 mm after implantation (p &lt
0.001). Rest pain in legs and fingers was resolved in 11 cases (11/12 cases, 92%). All patients could measure pain-free walking time on a treadmill, which improved remarkably (140 ± 53 s before implantation vs. 451 ± 74 s after implantation, p = 0.034). Resting ankle brachial pressure index (ABI) in legs implanted with bone marrow mononuclear cells was also improved (0.65 ± 0.08 before implantation vs. 0.73 ± 0.07 after implantation, p = 0.055). According to 99mTc-TF perfusion scintigraphy, the proximal area (region from knee to ankle) was 1.32 ± 0.10 before implantation versus 1.56 ± 0.11 after implantation (p = 0.007). 99mTc-TF perfusion scintigraphy in the distal area (region from ankle to end of toes, or from wrist to end of fingers) was 0.79 ± 0.06 before implantation versus 0.83 ± 0.06 after implantation (p = 0.29). Ischemic legs and hands that were injected showed increased perfusion blood flow. 99mTc-TF perfusion scintigraphy was effective to estimate visual and quantitative analysis of collateral vessels in neovascularization. We were successful with this new treatment for the most severe, chronic PAD that was not curable by any of the current treatments. Thus, this therapeutic angiogenesis could be a new strategy for saving severe ischemic limbs and hands.

DOI： 10.3727/000000004783983837

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Background— Although β-adrenergic receptor (AR) blockade therapy is beneficial in the treatment of heart failure, little is known regarding the transcriptional mechanisms underlying this salutary action.

Methods and Results— In the present study, we screened mice overexpressing Gsα, β ₁ AR, β ₂ AR, or protein kinase A to test if a common genomic pathway exists in different models with enhanced β-adrenergic signaling. In mice overexpressing Gsα, differentially expressed genes were identified by mRNA profiling. In addition to well-known markers of cardiac hypertrophy (atrial natriuretic factor, CARP, and β-myosin heavy chain), uncoupling protein 2 (UCP2), a protein involved in the control of mitochondrial membrane potential, and four-and-a-half LIM domain protein-1 (FHL1), a member of the LIM protein family, were predicted to be upregulated. Upregulation of these genes was confirmed by quantitative reverse transcriptase–polymerase chain reaction at all time points tested during the development of cardiomyopathy in mice overexpressing Gsα. In mice overexpressing β ₁ AR, β ₂ AR, or protein kinase A, increased UCP2 and FHL1 expression was also observed at the onset of cardiomyopathy. βAR blockade treatment reversed the cardiomyopathy and suppressed the increased expression of UCP2 and FHL1 in mice overexpressing Gsα.

Conclusions— UCP2 and FHL1 are important candidate genes that correlate with the development of βAR-induced cardiomyopathy in different mouse models with enhanced βAR signaling. In addition to preserving cardiac function, βAR blockade treatment also prevents the genomic regulation that correlates with the onset of heart failure.

DOI： 10.1161/01.cir.0000101922.18151.7b

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Language：Japanese   Publisher：克誠堂出版  

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Other Link： http://search.jamas.or.jp/link/ui/2004080268

Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1016/s0008-6363(03)00471-1

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In a genetically engineered mouse line with disruption of type 5 adenylyl cyclase ( AC5^−/− ), a major cardiac isoform, there was no compensatory increase in other isoforms of AC in the heart. Both basal and isoproterenol (ISO)-stimulated AC activities were decreased by 30% to 40% in cardiac membranes. The reduced AC activity did not affect cardiac function (left ventricular ejection fraction [LVEF]) at baseline. However, increases in LVEF after ISO were significantly attenuated in AC5^−/− ( P &lt;0.05, n=11). Paradoxically, conscious AC5^−/− mice had a higher heart rate compared with wild-type (WT) mice (613±8 versus 523±11 bpm, P &lt;0.01, n=14 to 15). Muscarinic agonists decreased AC activity, LVEF, and heart rate more in WT than in AC5^−/− . In addition, baroreflex-mediated, ie, neuronally regulated, bradycardia after phenylephrine was also attenuated in AC5^−/− . The carbachol-activated outward potassium current (at −40 mV) normalized to cell capacitance in AC5^−/− (2.6±0.4 pA/pF, n=16) was similar to WT (2.9±0.3 pA/pF, n=27), but calcium (Ca ²⁺ )-mediated inhibition of AC activity and Ca ²⁺ channel function were diminished in AC5^−/− . Thus, AC5^−/− attenuates sympathetic responsiveness and also impairs parasympathetic and Ca ²⁺ -mediated regulation of the heart, indicating that those actions are not only regulated at the level of the receptor and G-protein but also at the level of type 5 AC.

DOI： 10.1161/01.res.0000086986.35568.63

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Proceedings of the National Academy of Sciences  

The sympathetic nervous system is designed to respond to stress. Adenylyl cyclase (AC) is the keystone of sympathetic transmission, yet its role in response to acute overload in the heart or in the pathogenesis of heart failure is controversial. We examined the effects of pressure overload, induced by thoracic aortic banding, in mice in which type 5 AC, a major cardiac AC isoform, was disrupted ( AC5^–/– ). Left ventricular weight/tibial length ratio (LVW/TL) was not different between the WT and AC5^–/– at baseline and increased progressively and similarly in both groups at 1 and 3 wk after aortic banding. However, LV ejection fraction (LVEF) fell in WT at 3 wk after banding (from 70 ± 2.8 to 57 ± 3.9%, P &lt; 0.05), and this decrease was associated with LV dilatation, indicating incipient cardiac failure. In contrast, AC5^–/– mice did not exhibit a fall in LVEF from 74 ± 2.2%. The number of apoptotic myocytes was similar at baseline, but it increased roughly 4-fold in WT at both 1 and 3 wk after banding, and significantly less, P &lt; 0.05, in AC5^–/– . Importantly, the increase in apoptosis occurred before the decline in LVEF in WT. The protective mechanism seems to involve Bcl-2, which was up-regulated significantly more in AC5^–/– mice with pressure overload. Our findings suggest that limiting type 5 AC plays a protective role in response to pressure overload and the development of heart failure, potentially through limiting the incidence of myocardial apoptosis.

DOI： 10.1073/pnas.1733772100

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Physiological Society  

We examined the effects of gender and aging on cardiac and peripheral hemodynamic responses to β-adrenergic receptor (β-AR) stimulation in young (male = 5.9 ± 0.4 yr old and female = 6.5 ± 0.7 yr old) and old (male = 19.8 ± 0.7 yr old and female = 21.2 ± 0.2 yr old) conscious monkeys ( Macaca fascicularis), chronically instrumented for measurements of left ventricular (LV) and arterial pressures as well as cardiac output. Baseline LV pressure, the first derivative of LV pressure (LV dP/d t), cardiac index, mean arterial pressure, total peripheral resistance (TPR), and heart rate in conscious monkeys were not different among the four groups. Increases in LV dP/d t in response to 0.1 μg/kg isoproterenol (Iso) were diminished ( P &lt; 0.05) in old males (+99 ± 11%) compared with young males (+194 ± 18%). In addition, the inotropic responses to norepinephrine (NE) and forskolin (FSK) were significantly depressed ( P &lt; 0.05) in old males. Iso-induced reductions of TPR were less ( P &lt; 0.05) in old males (–28 ± 2%) than in young males (–49 ± 2%). The changes of TPR in response to NE and FSK were also significantly attenuated ( P &lt; 0.05) in old males. However, the LV dP/d t responses to BAY y 5959 (15 μg · kg^–1 · min^–1), a Ca²⁺ channel promotor independent of β-AR signaling, were not significantly different between old and young males. In contrast to results in male monkeys, LV dP/d t and TPR responses to Iso, NE, and FSK in old females were similar to those observed in young females. Thus both cardiac contractile and peripheral vascular dynamic responses to β-AR stimulation are preserved in old female but not old male monkeys. This may explain, in part, the reduced cardiovascular risk in the older female population.

DOI： 10.1152/ajpheart.01034.2002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

To seek evidence that the nonhuman primate arterial wall, as it ages in the absence of atherosclerosis, exhibits alterations in pathways that are involved in the pathogenesis of experimental atherosclerosis, we assessed aortic matrix metalloproteinase-2 (MMP-2) and its regulators, ie, membrane type-1 of matrix metalloproteinase (MT1-MMP) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), and the expression of angiotensin II (Ang II), angiotensin-converting enzyme (ACE), and chymase in young (6.4±0.7 years) and old (20.0±1.9 years) male monkeys. With advancing age, (1) the intimal thickness increased 3-fold and contained numerous vascular smooth muscle cells and matrix, but no inflammatory cells; (2) the intimal MMP-2 antibody–staining fraction increased by 80% ( P &lt;0.01); (3) in situ zymography showed that MMP-2 activity, mainly confined to the intima, increased 3-fold ( P &lt;0.01); (4) the MT1-MMP antibody–staining fraction increased by 150% ( P &lt;0.001), but the TIMP-2 antibody–staining fraction did not significantly change; (5) steady levels of the mRNA-staining fraction (via in situ hybridization) for MMP-2 increased 7-fold, for MT1-MMP increased 9-fold, and for TIMP-2 increased 2-fold (all P &lt;0.001); and (6) intimal Ang II and ACE immunofluorescence were increased 5-fold and 5.6-fold, respectively, and colocalized with MMP-2. Thus, age-associated arterial remodeling and the development and progression of experimental atherosclerosis in young animals share common mechanisms, ie, MMP-2 activation and increased Ang II signaling. This might explain, in part, the dramatically exaggerated prevalence and severity of vascular diseases with aging.

DOI： 10.1161/01.hyp.0000073843.56046.45

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1054/jcaf.2003.32

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Clinical Investigation  

DOI： 10.1172/jci14938

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Physiological Society  

There is increasing evidence that nitric oxide (NO) produced by inducible NO synthase (iNOS) plays a key role in cadioprotection during the “second window of protection” (SWOP). The goals of this study were to determine 1) whether a transient ischemic episode [10-min coronary artery occlusion (CAO), followed by full reperfusion] enhances NOS function in cardiac myocytes, 2) which specific NOS isoform is responsible for the enhanced NOS function in myocytes, and 3) to localize iNOS expression during SWOP. To address these questions, 10 dogs were instrumented to measure aortic and left ventricular pressures and wall thickness. At 1–2 wk after recovery, myocardial ischemia was induced regionally by a 10-min left circumflex CAO. After 24-h reperfusion, cardiac myocytes were isolated from the previously ischemic and nonischemic regions ( n = 6). Myocyte contractile function was assessed using a video motion detector at 1 Hz (35 ± 2°C). At baseline, myocyte contractile function (% contraction) was similar in the two regions (ischemic 7.8 ± 0.5% vs. nonischemic 7.8 ± 0.2%).l-Arginine (1 mM) significantly reduced ( P &lt; 0.05) myocyte contraction in the ischemic (−34 ± 3%, P &lt; 0.05) but not (−7 ± 4%) nonischemic regions; these responses were abolished by N^G-nitro-l-arginine (1 mM), a nonspecific NOS inhibitor, as well as 2-amino-5,6-dihydro-6-methy-4H-1,3,thiazine (1 mM), a specific iNOS inhibitor. Immunohistochemistry also revealed enhanced iNOS expression in the myocardium and in particular the interstitial spaces in the ischemic zone. These results indicate that a brief ischemic episode upregulates iNOS function in myocytes as well as in the interstitial space between blood vessels and myocytes, strategically where it can regulate both vascular and myocyte function during the SWOP.

DOI： 10.1152/ajpheart.00609.2001

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DOI： 10.1006/jmcc.2001.1490

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

The mechanism of myocardial stunning has been studied extensively in rodents and is thought to involve a decrease in Ca ²⁺ responsiveness of the myofilaments, degradation of Troponin I (TnI), and no change in Ca ²⁺ handling. We studied the mechanism of stunning in isolated myocytes from chronically instrumented pigs. Myocytes were isolated from the ischemic (stunned) and nonischemic (normal) regions after 90-minute coronary stenosis followed by 60-minute reperfusion. Baseline myocyte contraction was reduced, P &lt;0.01, in stunned myocytes (6.3±0.4%) compared with normal myocytes (8.8±0.4%). The time for 70% relaxation was prolonged, P &lt;0.01, in stunned myocytes (131±8 ms) compared with normal myocytes (105±5 ms). The impaired contractile function was associated with decreased Ca ²⁺ transients (stunned, 0.33±0.04 versus normal, 0.49±0.05, P &lt;0.01). Action potential measurements in stunned myocytes demonstrated a decrease in plateau potential without a change in resting membrane potential. These changes were associated with decreased L-type Ca ²⁺ -current density (stunned, −4.8±0.4 versus normal, −6.6±0.4 pA/pF, P &lt;0.01). There were no differences in TnI, sarcoplasmic reticulum Ca ²⁺ ATPase (SERCA2a), and phospholamban protein quantities. However, the fraction of phosphorylated phospholamban monomer was reduced in stunned myocardium. In rats, stunned myocytes demonstrated reduced systolic contraction but actually accelerated relaxation and no change in Ca ²⁺ transients. Thus, mechanisms of stunning in the pig are radically different from the widely held concepts derived from studies in rodents and involve impaired Ca ²⁺ handling and dephosphorylation of phospholamban, but not TnI degradation.

DOI： 10.1161/hh2101.098547

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1006/jmcc.2001.1413

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Background —We investigated the effects of aging on the responses to endothelin (ET) in conscious old (19.8±0.6 years) and young adult (6.8±0.3 years) monkeys and compared these results with those of other vasoconstrictors, eg, phenylephrine (PE) and angiotensin II (Ang II).

Methods and Results —The monkeys ( Macaca fascicularis ) were chronically instrumented. Baseline total peripheral resistance (TPR) was not different between the 2 groups. As expected, TPR rose less ( P &lt;0.05) with PE (5 μg/kg) in old monkeys (34±3%) than in young monkeys (57±6%); TPR also rose less with Ang II. Surprisingly, TPR rose more ( P &lt;0.05) with endothelin-1 (ET-1, 25 ng · kg ⁻¹ · min ⁻¹ ) in old monkeys (36±6%) than in young monkeys (10±2%). An ET _B receptor agonist, sarafotoxin (S6c, 30 ng · kg ⁻¹ · min ⁻¹ ) was administered in the presence of an ET _A receptor antagonist, BQ-123 (1 mg/kg). Under these conditions, TPR increased more ( P &lt;0.05) in old monkeys (59±10%) than in young monkeys (31±4%). In the presence of nitric oxide synthase (NOS) inhibition with N^W -nitro- l -arginine methyl ester (60 mg/kg), vasoconstriction induced by S6c no longer differed with age, because it was enhanced in young monkeys ( P &lt;0.05) (68±9% versus 31±4%) but not in old monkeys (58±6% versus 59±10%). Thus, after NOS inhibition, vasoconstrictor responses to ET were no longer enhanced in old monkeys.

Conclusions —Peripheral vasoconstriction (PE and Ang II) is reduced in old monkeys, as expected. Paradoxically, vasoconstriction induced by ET-1 was actually enhanced in old monkeys, which appears to be a result of impaired endothelium-dependent vasodilation, which with ET-1 should involve the ET _B receptor.

DOI： 10.1161/01.cir.103.19.2382

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/00005344-200007000-00003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Abstract —To determine the effects of aging on vasoactivity in a primate model ( Macaca fascicularis ), 13 young male monkeys (aged 7.1±0.4 years) and 9 old male monkeys (aged 19.8±0.6 years) were chronically instrumented for measurement of left ventricular and aortic pressures and cardiac output. Total cholesterol, triglyceride, and fasting blood sugar levels were not different between the 2 groups. There were no significant differences in baseline mean aortic pressure and total peripheral resistance (TPR) in the young monkeys versus the old monkeys. TPR fell less ( P &lt;0.05) with acetylcholine (1 μg/kg) in old monkeys (−25±1%) than in young monkeys (−34±2%), whereas decreases in TPR with sodium nitroprusside were similar in old and young monkeys. There was no evidence of atherosclerosis, but apoptosis of endothelial cells was enhanced ( P &lt;0.05) in the aortas and femoral arteries, but not in the media, of the old monkeys. There was a relationship ( r =0.62, P =0.013) between the incidence of terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling (TUNEL)-positive endothelial cells and endothelial cell density in the femoral artery. The reduced endothelial cell density was also correlated ( r =0.82, P &lt;0.01) with depressed TPR responses to acetylcholine. Thus, vascular endothelial dysfunction was present in old monkeys without evidence of atherosclerosis, which may be due to endothelial apoptosis and reduced endothelial cell density.

DOI： 10.1161/01.atv.20.6.1493

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Clinical Investigation  

DOI： 10.1172/jci7418

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Physiological Society  

The goal of this study was to determine the extent to which the effects of milrinone were desensitized in heart failure (HF) and to determine the mechanisms, i.e., whether these effects could be ascribed to changes in cAMP or phosphodiesterase (PDE) activity in HF. Accordingly, we examined the effects of milrinone in seven conscious dogs before and after HF was induced by rapid ventricular pacing at 240 beats/min. The dogs were chronically instrumented for measurements of left ventricular (LV) pressure and first derivative of LV pressure (dP/d t), arterial pressure, LV internal diameter, and wall thickness. Milrinone (10 μg ⋅ kg⁻¹ ⋅ min⁻¹iv) increased LV dP/d t by 1,854 ± 157 from 2,701 ± 105 mmHg/s ( P &lt; 0.05) before HF. After HF the increase in LV dP/d t in response to milrinone was attenuated significantly ( P &lt; 0.05); it increased by 615 ± 67 from 1,550 ± 107 mmHg/s, indicating marked desensitization. In the presence of ganglionic blockade the increases in LV dP/d t (+445 ± 65 mmHg/s) in response to milrinone were markedly less ( P &lt; 0.01), and milrinone increased LV dP/d t even less in HF (+240 ± 65 mmHg/s). cAMP and PDE activity were measured in endocardial and epicardial layers in normal and failing myocardium. cAMP was decreased significantly ( P &lt; 0.05) in LV endocardium (−26%) but not significantly in LV epicardium (−14%). PDE activity was also decreased significantly ( P &lt; 0.05) in LV endocardium (−18%) but not in LV epicardium (−4%). Thus significant desensitization to milrinone was observed in conscious dogs with HF. The major effect was autonomically mediated. The biochemical mechanism appears to be due in part to the modest reductions in PDE activity in failing myocardium, which, in turn, may be a compensatory mechanism to maintain cAMP levels in HF. Reductions in cAMP and PDE levels were restricted to the subendocardium, suggesting that the increased wall stress and reduced coronary reserve play a role in mediating these changes.

DOI： 10.1152/ajpheart.1999.276.5.h1699

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Abstract —Left ventricular hypertrophy (LVH) is a compensatory mechanism to cope with pressure overload. Recently, a calcineurin pathway mediating LVH and its prevention by cyclosporine was reported. We examined whether calcineurin mediates LVH due to pressure overload in mice. Pressure overload was induced by aortic banding in 53 mice (32 treated with cyclosporine [25 mg · kg ⁻¹ · d ⁻¹ ], 21 treated with vehicle). There were 17 sham-operated mice (9 treated with vehicle, 8 treated with cyclosporine). At 3 weeks after surgery, LV weight to body weight was greater in the nontreatment banded group (4.39±0.16 mg/g) than in the cyclosporine-treated banded group (3.95±0.14 mg/g, P &lt;0.05), with both groups being greater compared with the entire group of sham-operated mice (3.02±0.04 mg/g). The pressure gradient between the ascending and abdominal aorta was not different between the cyclosporine-treated (49.6±6.1 mm Hg) and nontreatment groups (48.7±4.6 mm Hg). Although LV systolic pressure was lower in the cyclosporine-treated banded animals, LV systolic wall stress was similar in the nontreatment banded group and in the cyclosporine-treated group. However, LV dP/dt was lower ( P =0.05) in the cyclosporine-treated banded group (4774±656 mm Hg/s) than in the nontreatment banded group (6604±516 mm Hg/s). During the protocol, 23 of 32 mice in the cyclosporine-treated group and 9 of 21 mice in the nontreatment group died. All deaths occurred within 10 days after surgery. Deaths caused by heart failure were 7.2-fold higher ( P &lt;0.05) in the cyclosporine-treated group, whereas deaths due to other causes were not different between the 2 groups. In addition, LV function of mice was assessed at 48 hours after banding; LV ejection fraction measured with echocardiography was lower ( P &lt;0.05) in the cyclosporine-treated banded group (66±3.0%) than in the nontreatment banded group (79±1.5%), whereas LV systolic wall stresses were similar. Calcineurin phosphatase activity was depressed similarly in both cyclosporine-treated groups compared with both nontreatment groups. Thus, cyclosporine could attenuate, but not prevent, LVH at the expense of inhibiting an important compensatory mechanism in response to pressure overload, resulting in reduced LV wall stress and function and increased susceptibility to decompensation and heart failure.

DOI： 10.1161/01.res.84.6.735

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Clinical Investigation  

DOI： 10.1172/jci4848

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Medical Association of Nippon Medical School  

DOI： 10.1272/jnms1923.63.154

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Language：Japanese   Publisher：(一社)日本病院総合診療医学会  

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Language：Japanese   Publisher：(一社)日本脈管学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(公社)日本臨床工学技士会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本循環器学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.amjcard.2018.10.035

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Language：Japanese   Publisher：(一社)日本フットケア学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本脈管学会  

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Language：English   Publisher：(一社)日本心血管インターベンション治療学会  

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Language：English   Publisher：(一社)日本心血管インターベンション治療学会  

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DOI： 10.1016/j.amjmed.2018.02.023

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Language：Japanese   Publisher：日本下肢救済・足病学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本創傷治癒学会  

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Language：Japanese   Publisher：(一社)日本創傷治癒学会  

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Language：Japanese   Publisher：(一社)日本脈管学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本脈管学会  

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Language：English   Publisher：(一社)日本心血管インターベンション治療学会  

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Language：English   Publisher：(一社)日本心血管インターベンション治療学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

Background Concerns raised regarding adverse cardiovascular (CV) outcomes with new therapies for type 2 diabetes mellitus (T2DM) have led to several large-scale CV outcome trials. The EXAMINE trial confirmed noninferiority of the dipeptidyl dipeptidase 4 inhibitor alogliptin to placebo on major adverse cardiac event rates in a post-acute coronary syndrome (ACS) T2DM population. We present data on additional ischemic cardiac events and CV hospitalizations in EXAMINE.
Methods Patients with T2DM and an ACS event in the previous 15 to 90 days were randomly assigned to alogliptin or placebo on a background of standard treatment for diabetes. The incident rates of a 5-component composite end point of CV death, stroke, myocardial infarction, unstable angina, and coronary revascularization as well as CV hospitalization were calculated in all participants and according to macrovascular disease at baseline.
Results There were no significant differences between alogliptin (n = 2,701) and placebo (n = 2,679) in the event rate of the 5-component composite endpoint with median follow-up 533 days (21.0% vs 21.5%, hazard ratio [HR] 0.98 [0.87-1.10], P = .72). No differences were observed in terms of CV hospitalization (25.0% vs 25.4%, HR 0.98 [0.88-1.09], P = .70) or coronary revascularization (10.6% vs 10.2%, HR 1.05 [0.88-1.09], P = .60). No interactions were observed for treatment and prior macrovascular disease.
Conclusions EXAMINE demonstrates that there was no increase in the risk of cardiac ischemic events and CV hospitalizations with alogliptin in a high-risk post-ACS patient population. Because these are major driver of overall health care costs, these data suggest that there would be no adverse impact on health care resource utilization.

DOI： 10.1016/j.ahj.2016.01.011

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Language：Japanese   Publisher：(株)日本臨床社  

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Language：Japanese   Publisher：日本衛生動物学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本脈管学会  

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Language：Japanese   Publisher：日本下肢救済・足病学会  

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Language：Japanese   Publisher：日本下肢救済・足病学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Medical Association of Nippon Medical School  

Background: Inhibition of the renin-angiotensin system (RAS) has been used to treat diabetic nephropathy. However, RAS inhibition increases the risk of renal complications. In this study, we evaluated the effect of combining RAS inhibitor treatment with beraprost sodium (BPS), a prostaglandin I2 analog, in diabetic nephropathy with arteriosclerosis obliterans. Methods: This study was a prospective, randomized, open-label study. Twenty-six Japanese patients (age &gt
30 years) with diabetic nephropathy and arteriosclerosis obliterans were randomly assigned to the BPS group (n=13), which received the combination of an RAS inhibitor and BPS (120 μg/day) therapy, or the control group (n=13), which received only an RAS inhibitor. Patients were followed up for 1 year. The primary endpoint was the effect of BPS on renal function. Results: In the control group, serum creatinine (1.64±0.87 to 2.34±1.53 mg/dL, p&lt
0.001), 1/creatinine (0.82±0.47 to 0.65±0.47, p=0.003) cystatin C (1.77±0.61 to 2.18±0.86 mg/L, p&lt
0.001), and the estimated glomerular filtration rate (43.9±26.1 to 34.0±24.6 mL/min/1.73 m2 , p=0.004) were significantly worsened 48 weeks after the start of treatment. Conversely, in the BPS group, serum creatinine (1.71±0.75 to 1.66± 0.81 mg/dL, p=0.850), 1/creatinine (0.66±0.19 to 0.71±0.25, p=0.577), cystatin C (1.79±0.55 to 1.80±0.57 mg/L, p=0.999), and the estimated glomerular filtration rate (35.8±10.8 to 38.7±14.4 mL/min/1.73 m2 , p= 0.613) were unchanged. Conclusions: Combination treatment with BPS and an RAS inhibitor prevented the progression of diabetic nephropathy. These observations should be confirmed in large-scale studies with long-term followup.

DOI： 10.1272/jnms.82.84

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Language：Japanese   Publisher：(一社)日本創傷治癒学会  

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：(一社)日本脈管学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本フットケア学会  

自己骨髄細胞を用いた血管再生医療は、難病指定疾患であるバージャー病と閉塞性動脈硬化症(ASO)の治療抵抗性症例に対して、安全性に優れ有効性も証明され、わが国再生医療初の高度先進医療(当時)として承認され、現在も第2項先進医療技術に承認されている。さらに末梢血単核球細胞、末梢血幹細胞を使用した血管再生治療も第2項先進医療技術に追加承認された。血管再生治療(先進医療承認)は、末梢動脈疾患(PAD)に対する経皮的血管形成術(PTA)、末梢血管バイパス手術に次ぐ第3の治療法として認識されつつあり(Beyond TASC II)、さらに厚生労働省難治性疾患克服研究事業の一つとして、膠原病の中でも難治性潰瘍・壊疽を合併することが最も多い全身性強皮症(PSS)に対して研究班で多施設共同研究を実施し、安全性と有効性を証明した。さらに進化させた次世代型血管再生療法として、血管形成に不可欠な塩基性線維芽細胞増殖因子(b-FGF)をゼラチンハイドロゲルと混入し、患肢筋肉内に注射するだけで血管再生可能な「DDS(薬物伝送システム)徐放化b-FGFハイドロゲルによる血管再生療法(2008年内閣府スーパー医療特区分担研究課題)」の臨床研究を実施して安全性と有効性を報告した。また最近では、現在泌尿器科、消化器外科等で実施されている結石破砕術の約10分1の低出力(約0.09mJ/mm2)の衝撃波(shock wave)を虚血患肢に当てるだけで血流増加を可能にする新治療法である低出力体外衝撃波治療による血管再生治療を臨床応用し、これも安全性および有意な下肢血流増加効果を証明した。このように血管再生治療は治療抵抗性PADに対して、各種の臨床研究を通じて徐々に安全性と有効性が一般に認識され、PTAやバイパス術が不可能な難治性症例の最後に考慮されうるべき最新治療となりつつある。(著者抄録)

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Language：Japanese   Publisher：日本下肢救済・足病学会  

わが国において難治性創傷に対する医療用無菌ウジを用いるマゴットセラピーを臨床応用し，さらに発展・普及させるために大学発バイオベンチャーを起業した．マゴットセラピーは，debridement 効果に優れ，抗菌ペプチド等により感染症例に対して極めて有効であり，その驚くべき短時間での健康肉芽増殖効果により創傷治療期間の大幅な短縮をもたらしている．さらに医療用無菌ウジが，①逃げない，②外から見えない，さらに③痛みが少ない，④着脱が簡単，という特徴を有し，高分子バッグに医療用無菌ウジを封入し，静置するだけの"マゴットバッグ"を開発し，その臨床応用を開始している．当科でのマゴットセラピー実施159 症例の予後に関しては，平均追跡期間7.1±0.2 年において，下肢温存率91.8％，生存率91.2％と極めて良好であった．特に血流不全のない糖尿病足壊疽症例ではいかなるイベントも認めず，安全・有効に施行可能であった．自費診療という欠点を克服すれば大い

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Language：Japanese   Publisher：(公社)日本臨床工学技士会  

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Language：Japanese   Publisher：(一社)日本創傷治癒学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(株)医事出版社  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本創傷治癒学会  

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Language：Japanese   Publisher：(一社)日本創傷治癒学会  

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Language：Japanese   Publisher：(一社)日本創傷治癒学会  

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Language：Japanese   Publisher：日本外科系連合学会  

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Language：Japanese   Publisher：(NPO)日本血管外科学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(NPO)日本冠疾患学会  

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Language：Japanese   Publisher：(NPO)日本冠疾患学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(株)医事出版社  

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Language：Japanese   Publisher：(NPO)日本冠疾患学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Authorship：Corresponding author   Language：Japanese   Publisher：学習研究社  

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Language：Japanese   Publisher：(株)医事出版社  

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Language：Japanese   Publisher：(一社)日本循環器学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本脈管学会  

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Language：Japanese   Publisher：日本外科系連合学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(株)医事出版社  

53歳男.2型糖尿病,左足背,左足底部糖尿病性壊疽の診断でインスリン治療を開始した.左足壊疽部は感染を合併し,膿汁の排出を認め,多剤耐性菌が複数出現した.創部感染コントロール不可能となり,増悪傾向にあったため患肢切断と診断した.患者は患肢切断に同意せず,入院となった.感受性陰性多剤耐性緑膿菌(MDRP)の検出のため抗生剤は使用しなかった.左足壊疽部の感染は改善せず,Maggot Debridement Therapy(MDT)を決定した.医療用ウジ約500匹を壊疽部へ付着,生理食塩水含有ガーゼを置き包帯で被覆した.5日目に医療用ウジを除去し屠殺した.16日目では良好健康肉芽増生を確認し,感染もなく生着した.経過良好のため医療用ウジ治療開始後28病日で自立歩行にて退院した

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Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：一般社団法人 日本耳鼻咽喉科学会  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：日本下肢救済・足病学会  

マゴットセラピー(maggot debridement therapy: MDT)はデブリードマンの一手法であり，慢性創傷に対する集学的治療の一つとして本邦においても2004年より本格的に臨床導入され，その有効性が認知されるようになってきた．治療の実施には適切な適応疾患の選択，治療中の脱走を防ぐための正しいドレッシング法の選択，副作用を最小限にするための対策などを知っておく必要がある．本稿では臨床の実際を詳細に解説すると共に，海外の報告を中心に既出の臨床エビデンスを紹介する．

DOI： 10.7792/jlspm.5.55

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Other Link： http://search.jamas.or.jp/link/ui/2017373441

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Language：Japanese   Publisher：(一社)日本高気圧環境・潜水医学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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DOI： 10.1016/j.yjmcc.2007.03.223

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