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

BACKGROUND: Cardioprotective drugs have not been previously shown to improve the prognosis in patients with fulminant myocarditis presentation (FMP). We aimed to investigate whether cardioprotective drugs, including angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) and β-blocker, administered during hospitalization improved the prognosis in patients with FMP. METHODS AND RESULTS: This multicenter cohort study conducted in Japan included 755 patients with clinically diagnosed FMP. Those who died within 14 days of admission were excluded, and 588 patients (median age 53 [37-65] years and 40% female) were evaluated. The primary outcome was the composite of 90-day mortality or heart transplantation. The patients were divided into 4 groups according to whether they were administered ACEI/ARB or β-blocker during hospitalization. Administration of ACEI/ARB without β-blocker improved the overall patient outcomes (log-rank test [vs. ACEI/ARB - and β-blocker -]: ACEI/ARB + and β-blocker -, P<0.001; ACEI/ARB - and β-blocker +, P=0.256). Subsequently, a matched cohort of 146 patient pairs was generated for patients with or without ACEI/ARB administration during hospitalization. The outcome-free survival at 90 days was significantly higher in the ACEI/ARB administration group than in the non-administration group (hazard ratio 0.37; 95% confidence interval 0.19-0.71). CONCLUSIONS: Administration of ACEI or ARB during hospitalization was associated with favorable outcomes in terms of 90-day mortality and heart transplantation events in patients with clinically diagnosed FMP.

DOI： 10.1253/circrep.CR-24-0059

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BACKGROUND: Guideline-directed medical therapy (GDMT) is important in heart failure management; however, polypharmacy itself may impact heart failure. Although measures against polypharmacy are needed, current discussion on unilateral drug tapering (including the drugs that should be tapered) is insufficient. In this study, we investigated the relationship between the number of prescribed GDMT drugs and prognosis in patients with heart failure. METHODS: In this single-centre retrospective study, 3,146 eligible patients with heart failure were included and divided into four groups based on the median number of prescribed GDMT drugs and the median number of drugs not included in the GDMT (ni-GDMT) at the time of hospital discharge. The definition of GDMT was based on various Japanese guidelines. The primary outcome was all-cause mortality within 3 years of hospital discharge. RESULTS: A total of 252 deaths were observed during the 3-year follow-up period. Kaplan-Meier analysis revealed that groups with GDMT drug count ≥ 5 and ni-GDMT drug count < 4 had the lowest mortality, and those with GDMT drug count < 5 and ni-GDMT drug count ≥ 4 had the highest mortality (log-rank, P < 0.001). Cox regression analysis revealed a significant association between ni-GDMT drug count and all-cause mortality, even after adjustment for number of GDMT medications, age, male, left ventricular ejection function < 40%, hemoglobin, albumin levels, and estimated glomerular filtration rate [HR = 1.06 (95% CI: 1.01-1.11), P = 0.020]. Conversely, the GDMT drug count was not associated with increased mortality rates. CONCLUSIONS: The ni-GDMT drug count was significantly associated with 3-year mortality in patients with heart failure. Conversely, the GDMT drug count did not worsen the prognosis. Polypharmacy measures should consider ni-GDMT drug quantity to improve the prognosis and outcomes in patients with heart failure.

DOI： 10.1186/s40780-024-00357-7

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Macrophages are the primary cell type orchestrating bioresorbable vascular graft (BVG) remodeling and infiltrate from three sources: the adjacent native vessel, circulating blood, and transmural migration from outer surface of the graft. To elucidate the kinetics of macrophage infiltration into the BVG, we fabricated two different bilayer arterial BVGs consisting of a macroporous sponge layer and a microporous electrospun (ES) layer. The Outer ES graft was designed to reduce transmural cell infiltration from the outer surface and the Inner ES graft was designed to reduce cell infiltration from the circulation. These BVGs were implanted in mice as infrarenal abdominal aorta grafts and extracted at 1, 4, and 8 weeks (n = 5, 10, and 10 per group, respectively) for evaluation. Cell migration into BVGs was higher in the Inner ES graft than in the Outer ES graft. For Inner ES grafts, the majority of macrophage largely expressed a pro-inflammatory M1 phenotype but gradually changed to tissue-remodeling M2 macrophages. In contrast, in Outer ES grafts macrophages primarily maintained an M1 phenotype. The luminal surface endothelialized faster in the Inner ES graft; however, the smooth muscle cell layer was thicker in the Outer ES graft. Collagen fibers were more abundant and matured faster in the Inner ES graft than that in the Outer ES graft. In conclusion, compared to macrophages infiltrating from the circulating blood, transmural macrophages from outside promote the acute inflammatory-mediated response for vascular remodeling and subsequent collagen deposition within BVGs. STATEMENT OF SIGNIFICANCE: To elucidate the kinetics of macrophage infiltration into the bioresorbable vascular graft (BVG), two different bilayer arterial BVGs were implanted in mice as infrarenal abdominal aorta grafts. Cell migration into BVGs was higher in the inner electrospun graft which cells mainly infiltrate from outer surface than in the outer electrospun graft which cells mainly infiltrate from the circulating blood. In the inner electrospun grafts, the majority of macrophages changed from the M1 phenotype to the M2 phenotype, however, outer electrospun grafts maintained the M1 phenotype. Collagen fibers matured faster in the Inner electrospun graft. Compared to macrophages infiltrating from the circulating blood, transmural macrophages from outside promote the acute inflammatory-mediated response for vascular remodeling and subsequent collagen deposition within BVGs.

DOI： 10.1016/j.actbio.2024.05.055

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AIMS: Plasma volume status (PVS), a measure of plasma volume, has been evaluated as a prognostic marker for chronic heart failure. Although the prognostic value of PVS has been reported, its significance in patients with acute decompensated heart failure (ADHF) admitted to the cardiovascular intensive care unit (CICU) remains unclear. In this study, we examined the relationship between PVS and long-term mortality in patients with ADHF admitted to the CICU. METHODS: Between January 2018 and December 2020, 363 consecutive patients with ADHF were admitted to the Nippon Medical School Hospital CICU. Of the 363 patients, 206 (mean age, 74.9 ± 12.9 years; men, 64.6%) were enrolled in this study. Patients who received red blood cell transfusions, underwent dialysis, were discharged from the CICU or died in the hospital were excluded from the study. We measured the PVS of the patients at admission, transfer to the general ward (GW) and discharge using the Kaplan-Hakim formula. The patients were assigned to four groups according to the quartiles of their PVS measured at each of the three abovementioned timepoints. We examined the association between PVS and all-cause mortality during the observation period (1134 days). The primary endpoint of this study was all-cause mortality. RESULTS: The Kaplan-Meier analysis showed that the high PVS group had a significantly higher mortality rate at admission, transfer to the GW and discharge than the other groups (log-rank test: P = 0.016, P = 0.005 and P < 0.001, respectively). Univariate Cox regression analysis showed that age, body mass index, history of heart failure, use of beta-blockers, albumin level, blood urea nitrogen level, N-terminal pro-brain natriuretic peptide level and left ventricular ejection fraction were significantly different among the PVS groups and thus were not significant prognostic factors for ADHF. Furthermore, the multivariate analysis revealed that PVS at discharge [hazard ratio (HR) = 1.06 (1.00-1.12), P = 0.048] was an independent poor prognostic factor for ADHF. CONCLUSIONS: This study highlights the effect of PVS measured at different timepoints on the prognoses of ADHF patients. Regular assessment of PVS, particularly at discharge, is crucial for optimising patient management and achieving favourable outcomes in cases of ADHF.

DOI： 10.1002/ehf2.14874

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BACKGROUND: Pimobendan reportedly improves the subjective symptoms of heart failure. However, evidence of improved prognosis is lacking. This study aimed to determine whether reinforcing guideline-directed medical therapy (GDMT) improved rehospitalization rates for worsening heart failure in patients administered pimobendan. METHODS: A total of 175 patients with heart failure who were urgently admitted to our hospital for worsening heart failure and who received pimobendan between January 2015 and February 2022 were included. Of the 175 patients, 44 were excluded because of in-hospital death at the time of pimobendan induction. The remaining 131 patients were divided into two groups, the reduced ejection fraction (rEF) (n = 93) and non-rEF (n = 38) groups, and further divided into the GDMT-reinforced and non-reinforced groups. RESULTS: In patients with rEF, the rate of rehospitalization for heart failure was significantly lower in the GDMT-reinforced group than in the non-reinforced group (log-rank test, P = .04). However, the same trend was not observed in the non-rEF group. CONCLUSIONS: Reinforcing GDMT may reduce the heart failure rehospitalization rate in patients with pimobendan administration and rEF. However, multicenter collaborative research is needed. TRIAL REGISTRATION: IRB Approval by the Nippon Medical School Hospital Ethics Committee B-2021-433 (April 10, 2023).

DOI： 10.1186/s40780-024-00346-w

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Aims

Fractional excretion of urea nitrogen (FEUN), used to differentiate the cause of acute kidney injury, has emerged as a useful fluid index in patients with heart failure (HF). We hypothesized that FEUN could be useful in identifying worsening renal function (WRF) associated with poor outcomes in patients with acute HF (AHF).

Methods and results

Overall, 1103 patients with AHF (median age, 78 years; male proportion, 60%) were categorized into six groups according to the presence of WRF and FEUN values (low, ≤32.1%; medium, &gt;32.1% and ≤38.0%; and high, &gt;38.0%) at discharge. WRF was defined as an increase of ≥0.3 mg/dL in the serum creatinine level from admission to discharge. FEUN was calculated by the following formula: (urinary urea × serum creatinine) × 100/(serum urea × urinary creatinine). The cut‐off values for low, medium, and high FEUN were based on a previous study. The primary outcome of this study was HF readmission after hospital discharge. During the 1 year follow‐up, 170 HF readmissions occurred. Kaplan–Meier analysis revealed significantly higher HF readmission rates in patients with WRF than in those without WRF (log‐rank test, P &lt; 0.001). Additionally, among patients with WRF, HF readmission rates were lowest in those with medium FEUN values, followed by those with low FEUN values and those with high FEUN values. On multivariable analysis, the presence of WRF with low or high FEUN values was independently associated with increased HF readmission, as compared with the absence of WRF with medium FEUN values. Notably, no association was noted between WRF with medium FEUN values and HF readmission.

Conclusions

The prognostic impact of WRF was significantly mediated by the FEUN values and was associated with worse outcomes only when the FEUN values were either low or high. Our study suggests that FEUN can identify prognostically relevant WRF in patients with AHF.

DOI： 10.1002/ehf2.14755

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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)日本循環器学会  

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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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Red blood cell (RBC) transfusion therapy is often performed in patients with acute heart failure (AHF) and anemia; however, its impact on subsequent cardiovascular events is unclear. We examined whether RBC transfusion influences major adverse cardiovascular events (MACE) after discharge in patients with AHF and anemia.We classified patients with AHF and anemia (nadir hemoglobin level < 10 g/dL) according to whether they received RBC transfusion during hospitalization. The endpoint was MACE (composite of all-cause death, non-fatal acute coronary syndrome/stroke, or heart failure readmission) 180 days after discharge. For survival analysis, we used propensity score matching analysis with the log-rank test. As sensitivity analysis, we performed inverse probability weighting analysis and multivariable Cox regression analysis.Among 448 patients with AHF and anemia (median age, 81 years; male, 55%), 155 received RBC transfusion and 293 did not. The transfused patients had worse clinical features than the non-transfused patients, with lower levels of nadir hemoglobin and serum albumin and a lower estimated glomerular filtration rate. In the propensity-matched cohort of 87 pairs, there was no significant difference in the MACE-free survival rate between the 2 groups (transfused, 73.8% vs. non-transfused, 65.3%; P = 0.317). This result was consistent in the inverse probability weighting analysis (transfused, 76.0% vs. non-transfused, 68.7%; P = 0.512), and RBC transfusion was not significantly associated with post-discharge MACE in the multivariable Cox regression analysis (adjusted hazard ratio: 1.468, 95% confidence interval: 0.976-2.207; P = 0.065).In conclusion, this study suggests that RBC transfusions for anemia may not improve clinical outcomes in patients with AHF.

DOI： 10.1536/ihj.23-596

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Symptoms of lower-extremity artery disease (LEAD) emerge from impaired vascularization in distal circulation of the extremities. Calcium channel blockers (CCB) can improve distal circulation when used as adjunctive therapy with endovascular treatment (EVT), but few studies have evaluated that. We investigated the relationship between CCB therapy and post-EVT outcomes. Through a consecutive EVT registry, we evaluated those relationships in whole cohort and the following 2 subgroups; the patients suffered from intermittent claudication (IC) or chronic limb-threatening ischemia (CLTI), with adjusting baseline characteristics by propensity score matchings. The primary endpoints were major adverse cardiac and cerebrovascular events (MACCE, a composite endpoint of all death, nonfatal myocardial infarction, and nonfatal stroke), and major adverse limb event (MALE, a composite of major amputation, acute limb ischemia, and surgical reintervention). The group that received CCB had less MALE in whole cohort (HR 0.31; 95% confidence interval (CI) 0.20-0.47), and less MACCE and MALE in CLTI cohort (HR 0.67; 0.50-0.89 and 0.32; 0.20-0.52 respectively) compared to the group that did not receive CCB. The relationships were common in the cohorts with baseline adjustment. MACCE and MALE in IC (HR 1.01; 0.57-1.80 and 0.60; 0.25-1.45, respectively) showed no significant differences both with and without baseline adjustment. CCB use was related to fewer MACCE and MALE events in adjusted patients who underwent EVT, and the trend was more evident, especially in the adjusted CLTI cohort. This study highlights the necessity of future studies regarding CCB. Clinical Trial Registration: URL: https://www.umin.ac.jp ; Unique identifiers: UMIN000015100.

DOI： 10.1007/s12928-023-00925-y

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Standard non-invasive methods for diagnosing and selecting the best treatment for osteomyelitis in patients with multiple chronic conditions remain to be established. We aimed to evaluate the ability of quantitative 67 Ga-citrate single-photon emission computed tomography (Ga-SPECT/CT) to determine the indication for either non-surgical treatment or osteotomy in patients with lower-limb osteomyelitis (LLOM) associated with diabetes mellitus and lower-extremity ischemia, based on monitoring of inflammatory activity in bone tissue. This single-center prospective study conducted from January 2012 to July 2017 included 90 consecutive patients with suspected LLOM. Regions of interest were drawn on SPECT images during quantification of Ga accumulation. Subsequently, the inflammation-to-background ratio (IBR) was calculated by dividing the maximal accumulated lesion number by the mean number for the distal femur bone marrow of the unaffected side. Osteotomy was performed in 28 of 90 patients (31%). The osteotomy rate was higher for patients with IBR > 8.4 (71.4%) than for those with IBR ≤ 8.4 (5.5%) (p < 0.001, sensitivity: 0.89, specificity: 0.84). In the multivariate Cox regression analysis, IBR > 8.4 was an independent risk factor for osteotomy (hazard ratio [HR]: 19.0, 95% confident interval [CI]: 5.6-63.9, p < 0.001). Transcutaneous oxygen tension (TcPO2 ) was identified as an independent risk factor for lower-limb amputation (HR: 0.96, 95%CI: 0.92-0.99, p=0.01). The current results indicate that quantitative Ga-SPECT/CT is useful for distinguishing patients with LLOM likely to require osteotomy.

DOI： 10.1111/wrr.13075

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

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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)日本循環器学会  

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AIMS: Maintenance of euvolaemia with diuretics is critical in heart failure (HF) patients with chronic kidney disease (CKD); however, it is challenging because no reliable marker of volume status exists. Fractional excretion of urea nitrogen (FEUN) is a useful index of volume status in patients with renal failure. We aimed to examine whether FEUN is a surrogate marker of volume status for risk stratification in HF patients with CKD. METHODS AND RESULTS: We examined 516 HF patients with CKD (defined as discharge estimated glomerular filtration rate < 60 mL/min/1.73 m2 ) whose FEUN was measured at discharge (median age, 80 years; 58% male). The patients were divided into four groups according to quartile FEUN value at discharge: low-FEUN, FEUN ≤ 32.1; medium-FEUN, 32.1 < FEUN ≤ 38.0; high-FEUN, 38.0 < FEUN ≤ 43.7; and extremely-high-FEUN, FEUN > 43.7. FEUN was calculated by the following formula: (urinary urea × serum creatinine) × 100/(serum urea × urinary creatinine). During the 3 year follow-up, 131 HF readmissions occurred. Kaplan-Meier analysis showed that the HF readmission rate was significantly lower in the medium-FEUN group than in the other three groups (log-rank test, P = 0.029). Multivariate Cox regression analysis identified the low-FEUN, high-FEUN, and extremely-high-FEUN values as independent factors associated with post-discharge HF readmission. In the analysis of 130 patients who underwent right heart catheterization during hospitalization, a significant correlation between FEUN value and right atrial pressure was observed (R = 0.243, P = 0.005). Multivariate linear regression analysis revealed that FEUN value at discharge decreased in a dose-dependent manner with loop diuretics. CONCLUSIONS: In HF patients with CKD, FEUN is a potential marker of volume status for risk stratification of post-discharge HF readmission. Low FEUN value (FEUN ≤ 32.1) may represent intravascular dehydration, whereas high FEUN value (FEUN > 38.0) may represent residual congestion; both of them were independent risk factors for HF readmission. FEUN may be useful to determine euvolaemia and guide fluid management in HF patients with CKD.

DOI： 10.1002/ehf2.14327

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A 77-year-old female presented with loss of consciousness, blood pressure of 90/60 mmHg, and heart rate of 47 bpm. At admission, highly sensitive Trop-T and lactate were elevated, and an electrocardiogram revealed an infero-posterior ST elevation myocardial infarction. Echocardiography revealed a depressed left ventricular ejection fraction with abnormal wall motion in the infero-posterior region and hyperkinetic apical movement along with severe mitral regurgitation (MR). Coronary angiography showed a hypoplastic right coronary artery, 100% thrombotic occlusion of the dominant left circumflex (LCx) artery, and 75% stenosis in the left anterior descending (LAD) artery. Substantial hemodynamic improvement with the reduction of acute ischemic MR was achieved by the initiation of an Impella 2.5, which is a transvalvular axial flow pump, and successful percutaneous coronary intervention (PCI) was conducted with stents to the LCx. The patient was weaned off the Impella 2.5 in 5 days, received staged PCI to LAD, and was later discharged after completion of the staged PCI to LAD.

DOI： 10.1536/ihj.22-572

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Patients with acute myocardial infarction (AMI) triaged as life-threatening are transferred to our emergency medical care center (EMCC). However, data on these patients remain limited. We aimed to compare the characteristics and AMI prognosis of patients transferred to our EMCC with those transferred to our cardiovascular intensive care unit (CICU) using whole and propensity-matched cohorts.We analyzed the data of 256 consecutive AMI patients transferred from the scene to our hospital by ambulance between 2014 and 2017. The EMCC and CICU groups comprised 77 and 179 patients, respectively. There were no significant between-group age or sex differences. Patients in the EMCC group had more disease severity score and had the left main trunk identified as the culprit more frequently (12% versus 0.6%, P < 0.001) than those in the CICU group; however, the number of patients with multiple culprit vessels did not differ. The EMCC group had a longer door-to-reperfusion time (75 [60, 109] minutes versus 60 [40, 86] minutes, P< 0.001) and a higher in-hospital mortality (19% versus 4.5%, P < 0.001), especially from non-cardiac causes (10% versus 0.6%, P < 0.001), than the CICU group. However, peak myocardial creatine phosphokinase did not significantly differ between the groups. The EMCC group had a significantly higher 1-year post-discharge mortality than the CICU group (log-rank, P = 0.032); this trend was maintained after propensity score matching, although the difference was not statistically significant (log-rank, P = 0.094).AMI patients transferred to the EMCC exhibited more severe disease and worse overall in-hospital and non-cardiac mortality than those transferred to the CICU.

DOI： 10.1536/ihj.22-654

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

DOI： 10.1272/jnms.jnms.2024_91-106

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Although the primary percutaneous coronary intervention (PCI) is an established treatment for acute ST-elevation myocardial infarction (STEMI), relevant guidelines do not recommend it for recent-STEMI cases with a totally occluded infarcted related artery (IRA). However, PCI is allowed in Japan for recent-STEMI cases, but little is known regarding its outcomes. We aimed to examine the details and outcomes of PCI procedures in recent-STEMI cases with a totally occluded IRA and compared the findings with those in acute-STEMI cases.Among the 903 consecutive patients admitted with acute coronary syndrome, 250 were treated with PCI for type I STEMI with a totally occluded IRA. According to the time between symptom onset and diagnosis, patients were divided into the recent-STEMI (n = 32) and acute-STEMI (n = 218) groups. The background, procedure details, and short-term outcomes were analyzed. No significant differences between the groups were noted regarding patient demographics, acute myocardial infarction severity, or IRA distribution. Although the stent number and type were similar, significant differences were observed among PCI procedures, including the number of guidewires used, rate of microcatheter or double-lumen catheter use, and application rate of thrombus aspiration. The thrombolysis rate in the myocardial infarction flow 3-grade post-PCI did not differ significantly between the groups. Both groups had a low frequency of procedure-related complications. The in-hospital mortality rates were 0% and 4.6% in the recent-STEMI and acute-STEMI groups, respectively (P > 0.05).Although recent-STEMI cases required complicated PCI techniques, their safety, success rate, and in-hospital mortality were comparable to those of acute-STEMI cases.

DOI： 10.1536/ihj.22-656

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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：(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：(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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BACKGROUND: Chronic total occlusion (CTO) is a high-risk factor for stent thrombosis, but little is known about the difference in neointimal healing between CTO and non-CTO lesions regarding implanted stents. We investigated factors affecting neointimal healing after stent implantation for CTO and non-CTO lesions using angioscopy. METHODS: We retrospectively evaluated 106 stents in 85 consecutive patients between March 2016 and July 2020. Their average age was 68 ± 11 years, and participants (73 male and 12 female) underwent follow-up angiography and angioscopy 1 year after percutaneous coronary intervention (PCI). The stents (n = 106) were divided into three groups according to the lesion status at the previous PCI: CTO (n = 17), acute coronary syndrome (ACS) (n = 35), and stable coronary artery disease without CTO or non-CTO (n = 54). RESULTS: The neointimal stent coverage grade was significantly lower in the CTO and ACS groups than in the non-CTO group (0.4 ± 0.5, 0.9 ± 0.8, and 1.4 ± 0.8, respectively, p < 0.001). Thrombi were significantly more frequent in CTO and ACS than in non-CTO (71 %, 51 %, and 15 %, respectively, p < 0.001). The yellow grade in CTO was comparable to that in ACS but significantly higher in CTO than in non-CTO (CTO vs. ACS vs. non-CTO 1.5 ± 0.7, 1.4 ± 0.6, and 0.9 ± 0.7, respectively, p = 0.007). CONCLUSIONS: Delayed healing occurs in stents implanted for CTO lesions. Longer dual-antithrombotic therapy may be beneficial.

DOI： 10.1016/j.jjcc.2022.08.008

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Essential thrombocythemia (ET) and polycythemia vera (PV), are common Philadelphia-negative myeloproliferative neoplasms (MPN). Patients with MPN have a high rate of cardiovascular complications and often have acquired JAK2V617F and CALR genetic mutations. In this study, we aimed to analyze vascular endothelial function in patients with MPN.We evaluated 27 outpatients, including 10 patients diagnosed with MPN, flow-mediated dilatation (FMD), and nitroglycerin-mediated dilation (NMD), between September 2014 and August 2016. We measured serum adiponectin, which protects vascular endothelial function, and serum asymmetric dimethyl arginine (ADMA), which inhibits the production of adiponectin. The presence or absence of JAK2V617F and CALR mutations was evaluated in patients with MPN.Venous thrombosis was observed more frequently in patients with MPN than in those without. Seven MPN patients were diagnosed with PV, and 3 MPN patients were diagnosed with ET. JAK2V617F and CALR mutations were found in 5 and 3 MPN patients, respectively. FMD was significantly lower in JAK2V617F-positive MPN patients than in JAK2V617F-negative MPN patients, although NMD, adiponectin, and ADMA were similar in both groups. Adiponectin levels were higher and ADMA levels were lower in CALR-positive MPN patients than in CALR-negative MPN patients. There was no difference in FMD and NMD prevalence between the 2 groups. Furthermore, we had 3 representative MPN patients who were complicated with coronary spasm, possibly caused by MPN-related endothelial dysfunction.We found that patients with MPN presented with endothelial dysfunction, which was related to the presence of genetic mutations and was sometimes associated with cardiovascular disease.

DOI： 10.1536/ihj.22-003

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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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Cyclophosphamide (CY)-induced cardiotoxicity involves rare lethal complications. We previously reported the cardiac events of 811 allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients; 12 out of 811 recipients (1.5%) developed fatal heart failure. The mortality rate was also very high (91.6%, 11/12). CY dose (200 mg/kg or more) was reported as the independent risk factor. The main disease in patients treated with 200 mg/kg or more of CY was severe aplastic anemia (AA). Therefore, we reduced the dose of CY during conditioning for AA (from 200 to 100 mg/kg), and then we analyzed the clinical features of 294 patients who received a total dose of at least 100 mg/kg of CY. We also compared the clinical features between the current study and our previous study. The proportion of patients treated with at least 200 mg/kg of CY was reduced from 4.2% to 0%. However, CY-induced heart failure occurred in four of the 294 patients (1.4%), which was similar to the finding reported in our previous study (1.5%). Two of these four patients received a post-transplant CY (PTCy) regimen (CY 100 mg/kg). All four patients were treated in the cardiac intensive care unit (C-ICU), and two patients survived. In summary, even the CY dose of 120 mg/kg or less would cause cardiotoxicity. We should also carefully monitor patients treated with PTCy, considering the possibility of CY-induced cardiotoxicity. Early diagnosis and ICU management have contributed to improved outcomes.

DOI： 10.1111/ajco.13674

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BACKGROUND: Pericardiocentesis is an essential procedure for the diagnosis and treatment of pericardial effusions. The purpose of this study was to evaluate the feasibility and safety of a subxiphoid anterior approach using fluoroscopy aided by a sagittal axis chest computed tomography (CT) view in comparison with an ultrasound-guided apical approach in patients with chronic pericardial effusion. METHODS: Among 72 consecutive patients (68.8 ± 14.4 years old, 52 males) with hemodynamically stable chronic pericardial effusions, a total of 85 procedures were retrospectively analyzed. We divided them into two groups according to the site of the approach for the pericardiocentesis. RESULTS: A subxiphoid anterior approach (n = 53) was performed guided by fluoroscopy. The sagittal axis view of the chest CT was constructed to determine the puncture angle and direction for the subxiphoid anterior approach. An apical approach (n = 32) was performed by ultrasound guidance. The success rates of the anterior and apical approaches were 98.1% and 93.8%, respectively. There were two cases with cardiac perforations in the apical approach group, while no cases developed perforations in the subxiphoid anterior approach group. CONCLUSION: The subxiphoid anterior approach for pericardiocentesis was feasible and safe for managing chronic pericardial effusions. A reconstruction of the sagittal axis view of the chest CT imaging was helpful to identify the direction and depth to access the pericardial space from the subxiphoid puncture site before the pericardiocentesis using the lateral fluoroscopic view.

DOI： 10.1002/clc.23810

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BACKGROUND: High coronary thrombus burden has been associated with unfavorable outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the optimal management of which has not yet been established. METHODS: We assessed the adjunctive catheter-directed thrombolysis (CDT) during primary percutaneous coronary intervention (PCI) in patients with STEMI and high thrombus burden. CDT was defined as intracoronary infusion of tissue plasminogen activator (t-PA; monteplase). RESULTS: Among the 1849 consecutive patients with STEMI, 263 had high thrombus burden. Moreover, 41 patients received t-PA (CDT group), whereas 222 did not receive it (non-CDT group). No significant differences in bleeding complications and in-hospital and long-term mortalities were observed (9.8% vs. 7.2%, p = 0.53; 7.3% vs. 2.3%, p = 0.11; and 12.6% vs. 17.5%, p = 0.84, CDT vs. non-CDT). In patients who underwent antecedent aspiration thrombectomy during PCI (75.6% CDT group and 87.4% non-CDT group), thrombolysis in myocardial infarction grade 2 or 3 flow rate after thrombectomy was significantly lower in the CDT group than in the non-CDT group (32.2% vs. 61.0%, p < 0.01). However, the final rates improved without significant difference (90.3% vs. 97.4%, p = 0.14). CONCLUSIONS: Adjunctive CDT appears to be tolerated and feasible for high thrombus burden. Particularly, it may be an option in cases with failed aspiration thrombectomy.

DOI： 10.3390/jcm11010262

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Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.8220-21

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Language：Japanese   Publisher：医学図書出版(株)  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Because development of acute coronary syndrome (ACS) worsens the prognosis of patients with coronary artery disease, preventing recurrent ACS is crucial. However, the degree to which secondary prevention treatment goals are achieved in patients with recurrent ACS is unknown. METHODS: 214 consecutive ACS patients were classified as having First ACS (n=182) or Recurrent ACS (n=32), and the clinical characteristics of these groups were compared. Fifteen patients died or developed cardiovascular (CV) events during hospitalization, and the remaining 199 patients were followed from the date of hospital discharge to evaluate subsequent CV events. RESULTS: Patients in the Recurrent ACS group were older than those in the First ACS group (76.8±10.8 years vs 68.8±13.4 years, p=0.002) and had a higher rate of diabetes mellitus (DM) (65.6% vs 36.8%, p=0.003). The rate of achieving a low-density lipoprotein cholesterol (LDL-C) level of <70 mg/dL in the Recurrent ACS group was only 28.1%, even though 68.8% of these patients were taking statins. An HbA1c level of <7.0% was achieved in 66.7% of patients with recurrent ACS who had been diagnosed with DM. Overall, 12.5% of patients with recurrent ACS had received optimal treatment for secondary prevention. CV events after hospital discharge were noted in 37.9% of the Recurrent ACS group and 21.2% of the First ACS group (log-rank test: p=0.004). However, recurrent ACS was not an independent risk factor for CV events (adjusted hazard ratio: 2.09, 95% confidence interval: 0.95 to 4.63, p=0.068). CONCLUSION: Optimal treatment for secondary prevention was not achieved in some patients with recurrent ACS, and achievement of the guideline-recommended LDL-C goal for secondary prevention was especially low in this population.

DOI： 10.1272/jnms.JNMS.2021_88-601

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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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Bioabsorbable arterial grafts can potentially improve patency and neovessel formation; however, their application in clinical settings has not been realized. In this study, we developed bioabsorbable gradient sheets based on silk fibroin (SF) and polyvinyl alcohol (PVA) with a core-shell nanofibrous structure. This gradient sheet was expected to promote vascular remodeling while we maintained its physical properties and a gradual degrading process from the luminal surface. ESP was conducted at various flow rates for SF and PVA to achieve the multilayer gradient structure. Furthermore, the elasticity of the gradient sheet could be increased by increasing the PVA flow rate; however, this reduced the tensile strength of the core-shell fibers. Notably, the physical properties of the gradient sheet did not degrade even after 7 days of immersion in a phosphate buffer saline solution, which indicates that the structure could maintain its structural integrity while resisting arterial pressure. In vitro experiments revealed that the number of endothelial cells attached to the SF/PVA sheet was notably higher than that on the cell-culture dish. The gradient sheets were implanted in rat abdominal aortas and explanted after 14 days to confirm acute-phase patency and vascular remodeling. The gradient sheets constructed with SF composed of polyurethane and PVA improved the ease of handling of the material, and these sheets resulted in a favorable vascular remodeling outcome. Our results strongly suggest that the SF/PVA-based gradient sheets described in this study can serve as a novel design for bioabsorbable arterial grafts upon further modifications.

DOI： 10.1002/jbm.a.37309

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本循環器学会  

BACKGROUND: Development of heart failure is associated with fluid balance, including that of extracellular water (ECW) and intracellular water (ICW). This study determined whether sodium-glucose cotransporter 2 (SGLT2) inhibitors affect fluid balance and improve heart failure in patients after acute myocardial infarction (AMI). METHODS: EMBODY was a prospective, randomized, double-blinded, placebo-controlled trial of Japanese patients with AMI and type 2 diabetes. Overall, 55 patients who underwent bioelectrical impedance analysis (BIA) were randomized to receive once daily 10 mg empagliflozin or placebo 2 weeks after AMI onset. We investigated the time course of body fluid balance measured using the BIA device, "InBody®." Primary endpoints were changes in body fluid balance from weeks 0 to 24. RESULTS: Changes between baseline and week 24 in the empagliflozin and placebo groups were -0.21 L (p=0.127) and +0.40 L (p=0.001) in ECW [p=0.001], and -0.23 L (p=0.264) and +0.74 L (p<0.001) in ICW [p<0.001], respectively. In a stratified analysis, the rise in ECW and ICW was significantly attenuated in the empagliflozin group in contrast to the placebo group in participants with body mass index ≥25 but not in those with <25 kg/m2. CONCLUSIONS: Early SGLT2 inhibitor administration may attenuate changes in ECW and ICW.

DOI： 10.1016/j.cardfail.2021.07.022

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

We herein report a case of mitochondrial disease with heart and intestinal tract involvement resulting in hemodynamic collapse. A 66-year-old woman was transferred to our hospital because of cardiogenic shock. Vasopressors were administered, and a circulatory support device was deployed. However, her hemodynamics did not improve sufficiently, and we detected abdominal compartment syndrome caused by the aggravation of chronic intestinal pseudo-obstruction as a complication. Insertion of a colorectal tube immediately decreased the intra-abdominal pressure, improving the hemodynamics. Finally, we diagnosed her with mitochondrial disease, concluding that the resulting combination of acute heart failure and abdominal compartment syndrome had aggravated the hemodynamics.

DOI： 10.2169/internalmedicine.7729-21

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INTRODUCTION: Plasma volume status (PVS), a parameter of the discrepancy between actual plasma volume (PV) and ideal PV, has been recently evaluated as a prognostic marker in patients with heart failure. This subgroup analysis of the EMBODY trial was designed to determine whether a sodium-glucose cotransporter 2 (SGLT2) inhibitor affects the alleviation of heart failure and improvement of PVS in patients after acute myocardial infarction (AMI) with congestive heart failure (CHF). METHODS: The EMBODY trial was a prospective, multicenter, randomized, double-blind, placebo-controlled trial to identify the effect of an SGLT2 inhibitor on cardiac sympathetic hyperactivity in patients with AMI and type 2 diabetes mellitus (T2DM) in Japan. In total, 105 patients were randomized (1:1) to receive 10 mg empagliflozin or a placebo (once daily), 2 weeks after the onset of AMI. In this subanalysis, we investigated the time-course of PVS at baseline and weeks 4, 12, and 24. RESULTS: Overall, 96 patients were included in the subgroup analysis set (age 64.3 ± 10.9 years, 80.2% men; 46 in the empagliflozin group and 50 in the placebo group). Body weight and PVS decreased in the empagliflozin group compared with the placebo group at 24 weeks (- 2.2 vs. + 0.1 kg, P < 0.001, and - 5.1 vs. - 0.3%, P < 0.001, respectively). Decreased PVS, defined as a change in PVS of < - 4.5%, was associated with the administration of empagliflozin (odds ratio 2.61, 95% confidence interval 1.11-6.15, P = 0.028). N-terminal pro b-type natriuretic peptide levels decreased in both the empagliflozin and placebo groups (1028.7-370.3 pg/mL, P < 0.001, and 1270.6-673.7 pg/mL, P < 0.01, respectively). CONCLUSION: Empagliflozin reduced the body weight and PVS. Early SGLT2 inhibitor administration in patients with AMI, CHF, and T2DM can therefore be effective in reducing the body weight and PVS. TRIAL REGISTRATION: UMIN 000030158.

DOI： 10.1007/s13300-021-01103-0

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AIMS: Although the reno-protective effects of sodium-glucose cotransporter 2 inhibitors are known in patients with heart failure or type 2 diabetes mellitus (T2DM), this effect has not been confirmed in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: The prospective, multicentre, randomized, double-blind, placebo-controlled EMBODY trial investigated patients with AMI and T2DM in Japan. The eligible patients included adults aged 20 years or older, diagnosed with AMI and T2DM, and who could be discharged within 2-12 weeks after the onset of AMI. One hundred and five patients were randomized (1:1) to receive once daily 10 mg empagliflozin or placebo within 2 weeks of AMI onset. In this sub-analysis, we investigated the time course of renal functional parameters such as serum creatinine levels and estimated glomerular filtration rate (eGFR) from baseline to Weeks 4, 12, and 24. Ninety-six patients (64 ± 11 years, 78 male) were included in the full analysis (n = 46 and 50 in the empagliflozin and placebo groups, respectively). We used serum creatinine and eGFR as indicators of renal function. In the placebo group, eGFR decreased from 66.14 mL/min/1.73 m2 at baseline to 62.77 mL/min/1.73 m2 by Week 24 (P = 0.023) but remained unchanged in the empagliflozin group (from 64.60 to 64.36 mL/min/1.73 m2 , P = 0.843). In the latter group, uric acid improved from 5.8 mg/dL at baseline to 4.9 mg/dL at Week 24 (P < 0.001). In the earlier analysis of 56 patients with eGFR ≥ 60 mL/min/1.73 m2 , the eGFR decreased and the serum creatinine increased from baseline to 24 weeks in the placebo group, significantly different to the empagliflozin group (-6.61 vs. +0.22 mL/min/1.73 m2 , P = 0.008 and +0.063 vs. -0.001 mg/dL, P = 0.030, respectively). The changes in serum creatinine and eGFR from baseline to Week 24 were significantly correlated with those in uric acid in the placebo group (r = 0.664, P < 0.001 and r = -0.675, P < 0.001, respectively) but not in the empagliflozin group. CONCLUSIONS: Empagliflozin prevented the kidney functional decline in patients with AMI and T2DM, especially those with baseline eGFR ≥ 60 mL/min/1.73 m2 . Early administration of sodium-glucose cotransporter 2 inhibitors in these patients is considered desirable for renal protection.

DOI： 10.1002/ehf2.13509

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BACKGROUND: Alcohol septal ablation (ASA) is a treatment option in patients with drug-refractory symptomatic hypertrophic obstructive cardiomyopathy (HOCM). In many patients, right bundle branch block (RBBB) develops during ASA because septal branches supply the right bundle branch. However, the clinical significance of procedural RBBB is uncertain.Methods and Results:We retrospectively reviewed 184 consecutive patients with HOCM who underwent ASA. We excluded 40 patients with pre-existing RBBB (n=10), prior pacemaker implantation (n=15), mid-ventricular obstruction type (n=10), and those lost to follow-up (n=5), leaving 144 patients for analysis. Patients were divided into 2 groups according to the development (n=95) or not (n=49) of procedural RBBB. ASA conferred significant decreases in the left ventricular pressure gradient (LVPG) in both the RBBB and no-RBBB group (from 74±48 to 27±27 mmHg [P<0.001] and from 75±45 to 31±33 mmHg [P<0.001], respectively). None of the RBBB patients developed further conduction system disturbances. The percentage reduction in LVPG at 1 year after the procedure was significantly greater in the RBBB than no-RBBB group (66±24% vs. 49±45%; P=0.035). Procedural RBBB was not associated with pacemaker implantation after ASA, but was associated with reduction in repeat ASA (odds ratio 0.34; 95% confidence interval 0.13-0.92; P=0.045). CONCLUSIONS: Although RBBB frequently occurs during the ASA procedure, it does not adversely affect clinical outcomes.

DOI： 10.1253/circj.CJ-20-1191

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BACKGROUND: In the modern US cardiovascular intensive care unit (CICU), the incidence of non-cardiovascular disorders has increased and non-cardiovascular disorders are associated with an increase in morbidity and mortality. In Japan, however, data regarding the association between non-cardiovascular disorders and outcomes in the CICU are limited. METHODS: This study examined 490 consecutive admissions to a closed CICU at the Nippon Medical School Hospital from January to December 2017. Characteristics, diagnoses, treatments, and outcomes of admitted patients were identified. RESULTS: The most common primary diagnosis was acute coronary syndrome (50.4%), followed by acute heart failure (20.0%), arrhythmia (6.7%), and non-cardiovascular diseases (3.7%). The mortality rate and median length of stay (LOS) in the CICU were 4.7% and 4 (interquartile range, 2-8) days, respectively. Of all patients, 42.2% (n = 207) developed non-cardiovascular complications such as acute respiratory failure, acute kidney injury, or sepsis during CICU stay. Multivariate logistic regression analysis revealed that acute respiratory failure and sepsis were significantly associated with mortality in the CICU (odds ratio, 11.014 and 25.678, respectively; both p<0.05). The multiple linear regression analysis showed that acute kidney injury was significantly associated with LOS in the CICU (β=0.144, p = 0.002). CONCLUSIONS: Approximately half of patients admitted to the CICU had non-cardiovascular disorders including non-cardiovascular disease and non-cardiovascular complications, which were significantly associated with mortality and LOS in the CICU.

DOI： 10.1016/j.jjcc.2021.03.002

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BACKGROUND: An inter-arm difference in blood pressure (IADBP) is characteristic of acute aortic dissection (AAD), but which arm shows lower blood pressure (BP) and the mechanism of IADBP has not been fully elucidatedMethods: We identified consecutive patients with chest and/or back pain and suspected acute cardiovascular disease whose BP had been measured in both arms. We retrospectively compared the characteristics of such patients with AAD (n=93) to those without (non-AAD group, n=122). Additionally, we separately compared patients with type A AAD (TAAD group, n=58) or type B AAD (TBAD group, n=35) to non-AAD group. Characteristics included in these comparisons were patients' backgrounds and IADBP-related factors such as systolic BP (SBP) in the right arm (R) and left arm (L), R-L or L-R as the IADBP. Computed tomography (CT) findings of AD extending to the brachiocephalic artery (BCA) and/or left subclavian artery (LSCA) were examined in patients having IADBP. RESULTS: In the TAAD group, the prevalence of R<130mmHg (38%-vs.-19%, p=0.009), L-R>15mmHg (19%-vs.-8%, p=0.047), L-R>20mmHg (14%-vs.-4%, p=0.029) was higher than in the non-AAD group. Multivariate analysis showed L-R>15mmHg with R<130mmHg was independently associated with TAAD (OR 25.97, 95% CI 2.45-275.67, p=0.007). However, IADBP-related factors were not associated with TBAD. AAD patients with L-R>20mmHg were all TAAD, and all aortic dissection extended to BCA just before the right common carotid artery on CT. CONCLUSIONS: IADBP was characterized by R<L with low R in TAAD, but was not associated with TBAD.

DOI： 10.1272/jnms.JNMS.2021_88-605

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Gastrointestinal (GI) bleeding worsens the outcomes of critically ill patients in the intensive care unit (ICU). Owing to a lack of corresponding data, we aimed to investigate whether GI bleeding during cardiovascular-ICU (C-ICU) admission in acute cardiovascular (CV) disease patients is a risk factor for subsequent CV events. Totally, 492 consecutive C-ICU patients (40.9% acute coronary syndrome, 22.8% heart failure) were grouped into GI bleeding (n = 27; 12 upper GI and 15 lower GI) and non-GI bleeding (n = 465) groups. Thirty-nine patients died or developed CV events during hospitalization, and 453 were followed up from the date of C-ICU discharge to evaluate subsequent major adverse CV events. The GI bleeding group had a higher Acute Physiology and Chronic Health Evaluation II score (20.2 ± 8.2 vs. 15.1 ± 6.8, p < 0.001), higher frequency of mechanical ventilator use (29.6% vs. 13.1%, p = 0.039), and longer C-ICU admission duration (8 [5-16] days vs. 5 [3-8] days, p < 0.001) than the non-GI bleeding group. The in-hospital mortality rate did not differ between the groups. Of those who were followed-up, CV events after C-ICU discharge were identified in 34.6% and 14.3% of patients in the GI and non-GI bleeding groups, respectively, during a median follow-up period of 228 days (log rank, p < 0.001). GI bleeding was an independent risk factor for subsequent CV events (adjusted hazard ratio: 2.23, 95% confidence interval: 1.06-4.71; p = 0.035). GI bleeding during C-ICU admission was independently associated with subsequent CV events in such settings.

DOI： 10.1007/s00380-021-01822-1

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

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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：Japanese   Publisher：(一社)日本脈管学会  

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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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BACKGROUND: Bioresorbable vascular grafts (BVGs) can transform biologically into active blood vessels and represent an alternative to traditional synthetic conduits, which are prone to complications such as infection and thrombosis. Although platelet-derived growth factors and c-Kit positive cells play an important role in smooth muscle cell (SMC) migration and proliferation in vascular injury, atherosclerosis, or allograft, their roles in the vascular remodeling process of an arterial BVG remains unknown. Thus, we assessed the neottisue formation on arterial BVG remodeling by administrating imatinib, which is both a platelet-derived growth factor receptor kinase inhibitor and c-Kit receptor kinase inhibitor, in a murine model. METHODS: BVGs were composed of an inner poly(L-lactic-co-ε-caprolactone) copolymer sponge layer and an outer electrospun poly(L-lactic acid) nanofiber layer, which were implanted into the infrarenal abdominal aortas of C57BL/6 mice. After graft implantation, saline or 100 mg/kg of imatinib was administrated intraperitoneally daily for 2 weeks (n = 20 per group). Five mice in each group were scheduled to be humanely killed at 3 weeks and 15 at 8 weeks, and BVGs were explanted for histologic assessments. RESULTS: Graft patency during the 8-week observational period was not significantly different between groups (control, 86.7% vs imatinib, 80.0%; P > .999). Neotissue formation consisting of endothelialization, smooth muscle proliferation, and deposition of collagen and elastin was not observed in either group at 3 weeks. Similar endothelialization was achieved in both groups at 8 weeks, but thickness and percent area of neotissue formation were significantly higher in the control group than in the imatinib group, (thickness, 30. 1 ± 7.2 μm vs 19.6 ± 4.5 μm [P = .001]; percent area, 9.8 ± 2.7% vs 6.8 ± 1.8% [P = .005]). Furthermore, SMC layer and deposition of collagen and elastin were better organized at 8 weeks in the control group compared with the imatinib group. The thickness of SMC layer and collagen fiber area were significantly greater at 8 weeks in the control group than in the imatinib group (P < .001 and P = .026, respectively). Because there was no difference in the inner diameter of explanted BVGs (831.7 ± 63.4 μm vs 841.8 ± 41.9 μm; P = .689), neotissue formation was thought to advance toward the outer portion of the BVG with degradation of the polymer scaffold. CONCLUSIONS: Imatinib attenuates neotissue formation during vascular remodeling in arterial bioresorbable vascular grafts (BVGs) by inhibiting SMC layer formation and extracellular matrix deposition. CLINICAL RELEVANCE: This study demonstrated that imatinib attenuated neotissue formation during vascular remodeling in arterial Bioresorbable vascular graft (BVG) by inhibiting smooth muscle cell formation and extracellular matrix deposition. In addition, as imatinib did not modify the inner diameter of BVG, neotissue advanced circumferentially toward the outer portion of the neovessel. Currently, BVGs have not yet been clinically applied to the arterial circulation. The results of this study are helpful for the design of BVG that can achieve an optimal balance between polymer degradation and neotissue formation.

DOI： 10.1016/j.jvssci.2020.03.002

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Electrospinning is commonly used to generate polymeric scaffolds for tissue engineering. Using this approach, we developed a small-diameter tissue engineered vascular graft (TEVG) composed of poly-ε-caprolactone-co-l-lactic acid (PCLA) fibers and longitudinally assessed its performance within both the venous and arterial circulations of immunodeficient (SCID/bg) mice. Based on in vitro analysis demonstrating complete loss of graft strength by 12 weeks, we evaluated neovessel formation in vivo over 6-, 12- and 24-week periods. Mid-term observations indicated physiologic graft function, characterized by 100% patency and luminal matching with adjoining native vessel in both the venous and arterial circulations. An active and robust remodeling process was characterized by a confluent endothelial cell monolayer, macrophage infiltrate, and extracellular matrix deposition and remodeling. Long-term follow-up of venous TEVGs at 24 weeks revealed viable neovessel formation beyond graft degradation when implanted in this high flow, low-pressure environment. Arterial TEVGs experienced catastrophic graft failure due to aneurysmal dilatation and rupture after 14 weeks. Scaffold parameters such as porosity, fiber diameter, and degradation rate informed a previously described computational model of vascular growth and remodeling, and simulations predicted the gross differential performance of the venous and arterial TEVGs over the 24-week time course. Taken together, these results highlight the requirement for in vivo implantation studies to extend past the critical time period of polymer degradation, the importance of differential neotissue deposition relative to the mechanical (pressure) environment, and further support the utility of predictive modeling in the design, use, and evaluation of TEVGs in vivo. STATEMENT OF SIGNIFICANCE: Herein, we apply a biodegradable electrospun vascular graft to the arterial and venous circulations of the mouse and follow recipients beyond the point of polymer degradation. While venous implants formed viable neovessels, arterial grafts experienced catastrophic rupture due to aneurysmal dilation. We then inform a previously developed computational model of tissue engineered vascular graft growth and remodeling with parameters specific to the electrospun scaffolds utilized in this study. Remarkably, model simulations predict the differential performance of the venous and arterial constructs over 24 weeks. We conclude that computational simulations should inform the rational selection of scaffold parameters to fabricate tissue engineered vascular grafts that must be followed in vivo over time courses extending beyond polymer degradation.

DOI： 10.1016/j.actbio.2019.05.063

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

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INTRODUCTION: Protection from lethal ventricular arrhythmias leading to sudden cardiac death is one of the most important problems after myocardial infarction. Cardiac sympathetic hyperactivity is related to poor prognosis and fatal arrhythmias and can be non-invasively assessed with heart rate variability, heart rate turbulence, T-wave alternans, late potentials, and 123I-meta-iodobenzylguanide (123I-MIBG) scintigraphy. Sodium glucose cotransporter 2 (SGLT2) inhibitors potentially reduce sympathetic nervous system activity that is augmented in part due to the stimulatory effect of hyperglycemia. The EMBODY trial is designed to determine whether the suppression of cardiac sympathetic activity induced by the SGLT2 inhibitor is accompanied by protection against adverse cardiovascular outcomes. METHODS: The EMBODY trial is a prospective, multicenter, randomized, double-blind, placebo-controlled trial in patients with acute MI and type 2 diabetes in Japan. A total of 98 patients will be randomized (1:1) to receive once-daily placebo or empagliflozin, an SGLT2 inhibitor, 10 mg. The primary end point is the change from baseline to 24 weeks in heart rate variability. Secondary end points include the change from baseline for other sudden cardiac death surrogate-markers such as heart rate turbulence, T-wave alternans, late potentials, and 123I-MIBG scintigraphy imaging. Adverse effects will be evaluated throughout the trial period. PLANNED OUTCOMES: The EMBODY trial will evaluate the potential cardioprotective effect of empagliflozin and will provide additional important new data regarding its preventative effects on sudden cardiac death. TRIAL REGISTRATION: Unique Trial Number, UMIN000030158 ( https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000034442 ). FUNDING: Nippon Boehringer Ingelheim and Eli Lilly and Company.

DOI： 10.1007/s13300-018-0480-7

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BACKGROUND: Acute thrombosis is a crucial cause of bioresorbable vascular graft (BVG) failure. Bone marrow-derived mononuclear cell (BM-MNC)-seeded BVGs demonstrated high graft patency, however, the effect of seeded BM-MNCs against thrombosis remains to be elucidated. Thus, we evaluated an antithrombotic effect of BM-MNC-seeding and utilized platelet-depletion mouse models to evaluate the contribution of platelets to acute thrombosis of BVGs. METHODS AND RESULTS: BVGs were composed of poly(glycolic acid) mesh sealed with poly(l-lactideco-ε-caprolactone). BM-MNC-seeded BVGs and unseeded BVGs were implanted to wild type C57BL/6 mice (n = 10/group) as inferior vena cava interposition conduits. To evaluate platelet effect on acute thrombosis, c-Mpl-/- mice and Pf4-Cre+; iDTR mice with decreased platelet number were also implanted with unseeded BVGs (n = 10/group). BVG patency was evaluated at 2, 4, and 8 weeks by ultrasound. BM-MNC-seeded BVGs demonstrated a significantly higher patency rate than unseeded BVGs during the acute phase (2-week, 90% vs 30%, p = .020), and patency rates of these grafts were sustained until week 8. Similar to BM-MNC-seeded BVGs, C-Mpl-/- and Pf4-Cre+; iDTR mice also showed favorable graft patency (2-week, 90% and 80%, respectively) during the acute phase. However, the patency rate of Pf4-Cre+; iDTR mice decreased gradually after DTR treatment as platelet number recovered to baseline. An in vitro study revealed BM-MNC-seeding significantly inhibited platelet adhesion to BVGs compared to unseeded BVGs, (1.75 ± 0.45 vs 8.69 ± 0.68 × 103 platelets/mm2, p < .001). CONCLUSIONS: BM-MNC-seeding and the reduction in platelet number prevented BVG thrombosis and improved BVG patency, and those results might be caused by inhibiting platelet adhesion to the BVG.

DOI： 10.1016/j.ijcard.2018.01.059

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DOI： 10.1093/eurheartj/ehx812

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Society of Polymer Science  

Silk fibroin (SF) is a fibrous protein containing crystalline ¢-sheets with biocompatible and biodegradable properties. However, cell response and elasticity of SF is not sufficient for cardiovascular applications. In order to improve this property, we used elastin (EL) with SF by cross-linking with genipin. EL shows smooth muscle cells (SMCs) contractile phenotype and prevents intimal hyperplasia. Genipin is a cross linker agent which reacts on amino groups of proteins. Because SF exposes basic amino acid only at the terminal region, we expected to promote cell response by elastin content and maintain the structure of the SF. Contact angle observation showed that the hydrophobic surface character increased with increasing EL ratio. Also underwater tension testing showed that EL adds flexibility to films. In addition, higher attachment and lower proliferation of SMCs was observed by increasing the EL ratio. This phenomenon suggests that elastin in the film promotes contractile phenotype of SMCs which results in suppressing cell proliferation.

DOI： 10.1295/koron.2017-0068

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：SOC POLYMER SCIENCE JAPAN  

Non-woven fabrics made of two kinds of silk fibroin, one extracted directly from silk glands of living silkworms (silk grand fibroin; SGF) and the other regenerated from degummed silk fibroin (regenerated silk fibroin; RSF), were prepared. The secondary structure, mechanical properties and histological characters of these two kinds of fabrics were investigated and compared for biomaterial use. Although the a-sheet crystal contents of these two kinds of fabrics were the same, the breaking strength and the Young's modulus values of SGF fabric were significantly higher than those of RSF fabric. The difference of the physical properties is considered to be derived from the difference of the molecular weights of the silk fibroins because RSF degrades during the degumming process. In the histological test, SGF fabrics didn't show calcification, but phagocytosis by multinucleated giant cells was partly observed 4weeks after the implantation into subcutaneous mouse tissue. Expression level of cytokines from in vitro tests revealed that inflammation by macrophages is the same in SGF and RSF films.

DOI： 10.1295/koron.2017-0069

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

AIM: Surgical management of pediatric extrahepatic portal vein obstruction requires meso-Rex bypass using autologous or synthetic grafts. Tissue-engineered vascular grafts (TEVGs) provide an alternative, but no validated animal models using portal TEVGs exist. Herein, we preclinically assess TEVGs as portal vein bypass grafts. MATERIALS & METHODS: TEVGs were implanted as portal vein interposition conduits in SCID-beige mice, monitored by ultrasound and micro-computed tomography, and histologically assessed postmortem at 12 months. RESULTS: TEVGs remained patent for 12 months. Histologic analysis demonstrated formation of neovessels that resembled native portal veins, with similar content of smooth muscle cells, collagen type III and elastin. CONCLUSION: TEVGs are feasible portal vein conduits in a murine model. Further preclinical evaluation of TEVGs may facilitate pediatric clinical translation.

DOI： 10.2217/rme-2017-0021

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Implanting a self-expandable stent at the ostium of the common iliac artery (CIA) may lead to coverage of the orifice of the contralateral CIA. Here, we describe a novel application of the culotte stent technique using a balloon-expandable stent to bail out an ostial stenotic legion of a jailed CIA due to prior self-expandable stent placement. The bilateral CIAs were revascularized by culotte stenting, and patency of the stents was confirmed 3 years after the procedure. The culotte stent technique was successfully applied to an ostial stenotic lesion of a jailed CIA.

DOI： 10.1016/j.jvscit.2017.09.005

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

OBJECTIVE: Bioresorbable vascular grafts are biologically active grafts that are entirely reconstituted by host-derived cells through an inflammation-mediated degradation process. Calcification is a detrimental condition that can severely affect graft performance. Therefore, prevention of calcification is of great importance to the success of bioresorbable arterial vascular grafts. The objective of this study was to test whether fast-degrading (FD) bioresorbable arterial grafts with high cellular infiltration will inhibit calcification of grafts. METHODS: We created two versions of bioresorbable arterial vascular grafts, slow-degrading (SD) grafts and FD grafts. Both grafts had the same inner layer composed of a 50:50 poly(l-lactic-co-ε-caprolactone) copolymer scaffold. However, the outer layer of SD grafts was composed of poly(l-lactic acid) nanofiber, whereas the outer layer of FD grafts was composed of a combination of poly(l-lactic acid) and polyglycolic acid nanofiber. Both grafts were implanted in 8- to 10-week-old female mice (n = 15 in the SD group, n = 10 in the FD group) as infrarenal aortic interposition conduits. Animals were observed for 8 weeks. RESULTS: von Kossa staining showed calcification in 7 of 12 grafts in the SD group but zero in the FD group (P < .01, χ2 test). The cell number in the outer layer of FD grafts was significantly higher than in the SD grafts (SD, 0.87 ± 0.65 × 103/mm2; FD, 2.65 ± 1.91 × 103/mm2; P = .02). CONCLUSIONS: The FD bioresorbable arterial vascular graft with high cellular infiltration into the scaffold inhibited calcification of grafts.

DOI： 10.1016/j.jvs.2016.05.096

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Neointimal hyperplasia, which results from the activation, proliferation and migration of vascular smooth muscle cells (SMCs), is a detrimental condition for vascular stents or vascular grafts that leads to stenosis. Preventing neointimal hyperplasia of vascular grafts is critically important for the success of arterial vascular grafts. We hypothesized that tropoelastin seeding onto the luminal surface of the graft would prevent neointimal hyperplasia through suppressing neointimal smooth muscle cell proliferation. In this study, we investigated the efficacy of tropoelastin seeding in preventing neointimal hyperplasia of bioresorbable arterial vascular grafts. Poly (glycolic acid) (PGA) fiber mesh coated with poly (l-lactic-co-ε-caprolactone) (PLCL) scaffolds reinforced by poly (l-lactic acid) (PLA) nano-fibers were prepared as bioresorbable arterial grafts. Tropoelastin was then seeded onto the luminal surface of the grafts. Tropoelastin significantly reduced the thickness of the intimal layer. This effect was mainly due to a substantial reduction the number of cells that stained positive for SMC (α-SMA) and PCNA in the vessel walls. Mature elastin and collagen type I and III were unchanged with tropoelastin treatment. This study demonstrates that tropoelastin seeding is beneficial in preventing SMC proliferation and neointimal hyperplasia in bioresorbable arterial vascular grafts. STATEMENT OF SIGNIFICANCE: Small resorbable vascular grafts can block due to the over-proliferation of smooth muscle cells in neointimal hyperplasia. We show here that the proliferation of these cells is restricted in this type of graft. This is achieved with a simple dip, non-covalent coating of tropoelastin. It is in principle amendable to other grafts and is therefore an attractive process. This study is particularly significant because: (1) it shows that smooth muscle cell proliferation can be reduced while still accommodating the growth of endothelial cells, (2) small vascular grafts with an internal diameter of less than 1mm are amenable to this process, and (3) this process works for resorbable grafts.

DOI： 10.1016/j.actbio.2016.12.044

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Stenosis limits widespread use of tissue-engineered vascular grafts (TEVGs), and bone marrow mononuclear cell (BM-MNC) seeding attenuates this complication. Yet seeding is a multistep process, and the singular effects of each component are unknown. We investigated which components of the clinical seeding protocol confer graft patency and sought to identify the optimal MNC source. Scaffolds composed of polyglycolic acid and ε-caprolactone/ι-lactic acid underwent conditioned media (CM) incubation (n = 25) and syngeneic BM-MNC (n = 9) or peripheral blood (PB)-MNC (n = 20) seeding. TEVGs were implanted for 2 weeks in the mouse IVC. CM incubation and PB-MNC seeding did not increase graft patency compared to control scaffolds prewet with PBS (n = 10), while BM-MNC seeding reduced stenosis by suppressing inflammation and smooth muscle cell, myofibroblast, and pericyte proliferation. IL-1β, IL-6, and TNFα were elevated in the seeded BM-MNC supernatant. Further, BM-MNC seeding reduced platelet activation in a dose-dependent manner, possibly contributing to TEVG patency.

DOI： 10.1021/acsbiomaterials.6b00123

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

BACKGROUND: Current commercialized small-diameter arterial grafts have not shown clinical effectiveness due to their poor patency rates. The present study evaluated the feasibility of an arterial bioresorbable vascular graft, which has a porous sponge-type scaffold, as a small-diameter arterial conduit. METHODS: The grafts were constructed by a 50:50 poly (1-lactic-co-ε-caprolactone) copolymer (PLCL) scaffold reinforced by a poly (1-lactic acid) (PLA) nanofiber. The pore size of the PLCL scaffold was adjusted to a small size (12.8 ± 1.85 μm) or a large size (28.5 ± 5.25 μm). We compared the difference in cellular infiltration, followed by tissue remodeling, between the groups. The grafts were implanted in 8- to 10-week-old female mice (n = 15 in each group) as infrarenal aortic interposition conduits. Animals were monitored for 8 weeks and euthanized to evaluate neotissue formation. RESULTS: No aneurysmal change or graft rupture was observed in either group. Histologic assessment demonstrated favorable cell infiltration into scaffolds, neointimal formation with endothelialization, smooth muscle cell proliferation, and elastin deposition in both groups. No significant difference was observed between the groups. Immunohistochemical characterization with anti-F4/80 antibody demonstrated that macrophage infiltration into the grafts occurred in both groups. Staining for M1 and M2, which are the two major macrophage phenotypes, showed no significant difference between groups. CONCLUSIONS: Our novel bioresorbable vascular grafts showed well-organized neointimal formation in the high-pressure arterial circulation environment. The large-pore scaffold did not improve cellular infiltration and neotissue formation compared with the small-pore scaffold.

DOI： 10.1016/j.athoracsur.2016.01.110

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FEDERATION AMER SOC EXP BIOL  

Stenosis is a critical problem in the long-term efficacy of tissue-engineered vascular grafts (TEVGs). We previously showed that host monocyte infiltration and activation within the graft drives stenosis and that TGF-β receptor 1 (TGF-βR1) inhibition can prevent it, but the latter effect was attributed primarily to inhibition of mesenchymal cell expansion. In this study, we assessed the effects of TGF-βR1 inhibition on the host monocytes. Biodegradable TEVGs were implanted as inferior vena cava interposition conduits in 2 groups of C57BL/6 mice (n = 25/group): unseeded grafts and unseeded grafts with TGF-βR1 inhibitor systemic treatment for the first 2 wk. The TGF-βR1 inhibitor treatment effectively improved TEVG patency at 6 mo compared to the untreated control group (91.7 vs. 48%, P < 0.001), which is associated with a reduction in classic activation of mononuclear phagocytes. Consistent with these findings, the addition of rTGF-β to LPS/IFN-γ-stimulated monocytes enhanced secretion of inflammatory cytokines TNF-α, IL-12, and IL-6; this effect was blocked by TGF-βR1 inhibition (P < 0.0001). These findings suggest that the TGF-β signaling pathway contributes to TEVG stenosis by inducing classic activation of host monocytes. Furthermore, blocking monocyte activation by TGF-βR1 inhibition provides a viable strategy for preventing TEVG stenosis while maintaining neotissue formation.-Lee, Y.-U., de Dios Ruiz-Rosado, J., Mahler, N., Best, C. A., Tara, S., Yi, T., Shoji, T., Sugiura, T., Lee, A. Y., Robledo-Avila, F., Hibino, N., Pober, J. S., Shinoka, T., Partida-Sanchez, S., Breuer, C. K. TGF-β receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation.

DOI： 10.1096/fj.201500179R

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

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FUTURE MEDICINE LTD  

AIM: We investigated the effect of cell seeding dose and incubation time on tissue-engineered vascular graft (TEVG) patency. MATERIALS & METHODS: Various doses of bone marrow-derived mononuclear cells (BM-MNCs) were seeded onto TEVGs, incubated for 0 or 12 h, and implanted in C57BL/6 mice. Different doses of human BM-MNCs were seeded onto TEVGs and measured for cell attachment. RESULTS: The incubation time showed no significant effect on TEVG patency. However, TEVG patency was significantly increased in a dose-dependent manner. In the human graft, more bone marrow used for seeding resulted in increased cell attachment in a dose-dependent manner. CONCLUSION: Increasing the BM-MNC dose and reducing incubation time is a viable strategy for improving the performance and utility of the graft.

DOI： 10.2217/rme.15.85

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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.

DOI： 10.2967/jnumed.115.160937

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NUCLEAR MEDICINE INC  

One problem of vascular angiogenesis therapy is the lack of reliable methods for evaluating blood flow in the microcirculation. We aimed to assess whether (99)mTc-macroaggregated albumin perfusion scintigraphy ((99)mTc-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 (BMCl). Before and 4 wk after BMCI, blood flow was evaluated via transcutaneous oxygen tension (TcPO2), ankle -brachial index, intravenous (99)mTc-tetrofosmin perfusion scintigraphy ((99)mTc-TF), and intraaortic (99)mTc-MAA. Results: Four weeks after BMCI, TcPO2 improved significantly (20.4 +/- 14.4 to 36.0 +/- 20.0 mm Hg, P &lt; 0.01), but ankle-brachial index did not (0.65 +/- 0.30 to 0.76 +/- 0.24, P = 0.07). Improvement in Tc-99m-TF count (0.60 +/- 0.23 to 0.77 +/- 0.29 count ratio/pixel, P &lt; 0.01) and (99)mTc-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 (99)mTc-TF count (-0.04 +/- 0.26 to 0.08 +/- 0.32 count ratio/pixel, P = 0.04) and (99)mTc-MAA count (1.49 +/- 3.64 to 5.59 +/- 4.84 count ratio/pixel, P = 0.03) in the foot remained significant. (99)mTc-MAA indicated that the newly developed arteries were approximately 25 pm in diameter. Conclusion: BMCI induced angiogenesis in the foot, which was detected using (99)mTc-TF and (99)mTc-MAA. (99)mTc-MAA is a useful method to quantitate blood flow, estimate vascular size, and evaluate flow distribution after therapeutic angiogenesis.

DOI： 10.2967/jnumed.115.160937

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

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

Background: Endocardial fibroelastosis (EFE) is a pathologic condition of abnormal deposition of collagen and elastin within the endocardium of the heart. It is seen in conjunction with a variety of diseases including hypoplastic left heart syndrome and viral endocarditis. While an experimental model using heterotopic heart transplant in rats has been described, we sought to fully describe a mouse model that can be used to further elucidate the potential mechanisms of and treatments for EFE.
Materials and methods: The hearts of 2-day-old C57BL/6 mice were transplanted into the abdomen of 7-week-old C57BL/6 mice. At 2 weeks, the hearts were harvested and histologic analysis was performed using hematoxylin and eosin, Masson's trichrome, Russell-Movat's pentachrome, Picrosirius red, Hart's, Verhoeff-Van Gieson, and Weigert's Resorcin-Fuchsin stains. Additionally, one heart was analyzed using transmission electron microscopy (TEM). Results: Specimens demonstrated abnormal accumulation of both collagen and elastin within the endocardium with occasional expansion into the myocardium. Heterogeneity in extracellular matrix deposition was noted in the histologic specimens. In addition, TEM demonstrated the presence of excess collagen within the endocardium.
Conclusions: The heterotopic transplantation of an immature heart into a mouse results in changes consistent with EFE. This model is appropriate to investigate the etiology and treatment of EFE. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.carpath.2015.08.002

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

OBJECTIVE: Autologous grafts are used to repair atherosclerotic cardiovascular diseases; however, many patients lack suitable donor graft tissue. Recently, tissue engineering techniques have emerged to make biologically active blood vessels. We applied this technique to produce arterial grafts using established biodegradable materials without cell seeding. The grafts were evaluated in vivo for vessel remodeling during 12 months. METHODS: Poly(L-lactide-co-ε-caprolactone) scaffolds reinforced by poly(lactic acid) (PLA) fiber were prepared as arterial grafts. Twenty-eight cell-free grafts were implanted as infrarenal aortic interposition grafts in 8-week-old female SCID/Bg mice. Serial ultrasound and micro computed tomography angiography were used to monitor grafts after implantation. Five grafts were harvested for histologic assessments and reverse transcription-quantitative polymerase chain reaction analysis at time points ranging from 4 months to 1 year after implantation. RESULTS: Micro computed tomography indicated that most implanted mice displayed aneurysmal changes (three of five mice at 4 months, four of five mice at 8 months, and two of five mice at 12 months). Histologic assessments demonstrated extensive tissue remodeling leading to the development of well-circumscribed neovessels with an endothelial inner lining, a neointima containing smooth muscle cells and elastin, and a collagen-rich extracellular matrix. There were a few observed calcified deposits, located around residual PLA fibers at 12 months after implantation. Macrophage infiltration into the scaffold, as evaluated by F4/80 immunohistochemical staining, remained after 12 months and was focused mostly around residual PLA fibers. Reverse transcription-quantitative polymerase chain reaction analysis revealed that gene expression of Itgam, a marker for macrophages, and of matrix metalloproteinase 9 was higher than in native aorta during the course of 12 months, indicating prolonged inflammation (Itgam at 8 months: 11.75 ± 0.99 vs native aorta, P < .01; matrix metalloproteinase 9 at 4 months: 4.35 ± 3.05 vs native aorta, P < .05). CONCLUSIONS: In this study, we demonstrated well-organized neotissue of cell-free biodegradable arterial grafts. Although most grafts experienced aneurysmal change, such findings provide insight into the process of tissue-engineered vascular graft remodeling and should allow informed rational design of the next generation of arterial grafts.

DOI： 10.1016/j.jvs.2014.03.011

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

OBJECTIVE: Despite successful translation of bioresorbable vascular grafts for the repair of congenital heart disease, stenosis remains the primary cause of graft failure. In this study, we investigated the efficacy of long-term treatment with the antiplatelet drugs, aspirin and cilostazol, in preventing stenosis and evaluated the effect of these drugs on the acute phase of inflammation and tissue remodeling. APPROACH AND RESULTS: C57BL/6 mice were fed a drug-mixed diet of aspirin, cilostazol, or normal chow during the course of follow-up. Bioresorbable vascular grafts, composed of poly(glycolic acid) mesh sealed with poly(l-lactide-co-ε-caprolactone), were implanted as inferior vena cava interposition conduits and followed up for 2 weeks (n=10 per group) or 24 weeks (n=15 per group). Both aspirin and cilostazol suppressed platelet activation and attachment onto the grafts. On explant at 24 weeks, well-organized neotissue had developed, and cilostazol treatment resulted in 100% graft patency followed by the aspirin (67%) and no-treatment (60%) groups (P<0.05). Wall thickness and smooth muscle cell proliferation in the neotissue of the cilostazol group were decreased when compared with that of the no-treatment group at 24 weeks. In addition, cilostazol was shown to have an anti-inflammatory effect on neotissue at 2 weeks by regulating the recruitment and activation of monocytes. CONCLUSIONS: Cilostazol prevents stenosis of bioresorbable vascular graft in a mouse inferior vena cava implantation model up to 24 weeks and is accompanied by reduction of smooth muscle cell proliferation and acute inflammation.

DOI： 10.1161/ATVBAHA.115.306027

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

Decellularized allograft heart valves have been used as tissue-engineered heart valve (TEHV) scaffolds with promising results; however, little is known about the cellular mechanisms underlying TEHV neotissue formation. To better understand this phenomenon, we developed a murine model of decellularized pulmonary heart valve transplantation using a hemodynamically unloaded heart transplant model. Furthermore, because the hemodynamics of blood flow through a heart valve may influence morphology and subsequent function, we describe a modified loaded heterotopic heart transplant model that led to an increase in blood flow through the pulmonary valve. We report host cell infiltration and endothelialization of implanted decellularized pulmonary valves (dPV) and provide an experimental approach for the study of TEHVs using mouse models.

DOI： 10.1089/ten.TEC.2015.0011

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

Our approach for fabricating tissue-engineered vascular grafts (TEVG), applied in the surgical management of congenital heart disease, is accomplished by seeding isolated bone marrow-derived mononuclear cells (BM-MNCs) onto biodegradable scaffolds. The current method used for isolation of BM-MNCs is density centrifugation in Ficoll. This is a time-consuming, labor-intensive, and operator-dependent method. We previously demonstrated that a simpler, faster, and operator-independent method for isolating BM-MNCs using a filter elution technique was feasible. In this study, we compare the use of each technique to determine if the BM-MNCs isolated by the filtration elution method are biologically equivalent to BM-MNCs isolated using density centrifugation. Scaffolds were constructed from a nonwoven poly(glycolic acid) fiber mesh coated with 50:50 poly(l-lactide-co-ɛ-caprolactone) sealant. BM-MNCs were isolated from the bone marrow of syngeneic C57BL/6 mice by either density centrifugation with Ficoll or filtration (Ficoll vs. Filter), then statically seeded onto scaffolds, and incubated overnight. The TEVG were implanted in 10-week-old C57BL/6 mice (n=23 for each group) as inferior vena cava interposition grafts and explanted at 14 days for analysis. At 14 days after implantation, there were no significant differences in graft patency between groups (Ficoll: 87% vs. Filter: 78%, p=0.45). Morphometric analysis by hematoxylin and eosin staining showed no difference of graft luminal diameter or neointimal thickness between groups (luminal diameter, Ficoll: 620.3±82.9 μm vs. Filter: 633.3±131.0 μm, p=0.72; neointimal thickness, Ficoll: 37.9±7.8 μm vs. Filter: 37.9±11.2 μm, p=0.99). Histologic examination demonstrated similar degrees of cellular infiltration and extracellular matrix deposition, and endothelial cell coverage on the luminal surface, in either group. Macrophage infiltration showed no difference in the number of F4/80-positive cells or macrophage phenotypes between the two experimental groups (Ficoll: 2041±1048 cells/mm(2) vs. Filter: 1887±907.7 cells/mm(2), p=0.18). We confirmed the biological equivalence of BM-MNCs, isolated using either density centrifugation or filtration, for making TEVG.

DOI： 10.1089/ten.TEC.2014.0442

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

We developed a prototype for a closed apparatus for assembling tissue-engineered vascular grafts (TEVGs) with the goal of creating a simple operator-independent method for making TEVGs to optimize safety and enable widespread application of this technology. The TEVG is made by seeding autologous bone marrow-derived mononuclear cells onto a biodegradable tubular scaffold and is the first man-made vascular graft to be successfully used in humans. A critical barrier, which has prevented the widespread clinical adoption of the TEVG, is that cell isolation, scaffold seeding, and incubation are performed using an open method. To reduce the risk of contamination, the TEVG is assembled in a clean room. Clean rooms are expensive to build, complex to operate, and are not available in most hospitals. In this investigation, we used an ovine model to compare the safety and efficacy of TEVGs created using either a standard density centrifugation-based open method or the new filter-based closed system. We demonstrated no graft-related complications and maintenance of growth capacity in TEVGs created using the closed apparatus. In addition, the use of the closed system reduced the amount of time needed to assemble the TEVG by ∼ 50%. Adaptation of similar methodologies may facilitate the safe translation and the widespread use of other tissue engineering technologies.

DOI： 10.1089/ten.TEC.2014.0160

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

The surgical repair of heart and vascular disease often requires implanting synthetic grafts. While synthetic grafts have been successfully used for medium-to-large sized arteries, applications for small diameter arteries (<6 mm) is limited due to high rates of occlusion by thrombosis. Our objective was to develop a tissue engineered vascular graft (TEVG) for small diameter arteries. TEVGs composed of polylactic acid nanofibers with inner luminal diameter between 0.5 and 0.6 mm were surgically implanted as infra-renal aortic interposition conduits in 25 female C17SCID/bg mice. Twelve mice were given sham operations. Survival of mice with TEVG grafts was 91.6% at 12 months post-implantation (sham group: 83.3%). No instances of graft stenosis or aneurysmal dilatation were observed over 12 months post-implantation, assessed by Doppler ultrasound and microCT. Histologic analysis of explanted TEVG grafts showed presence of CD31-positive endothelial monolayer and F4/80-positive macrophages after 4, 8, and 12 months in vivo. Cells positive for α-smooth muscle actin were observed within TEVG, demonstrating presence of smooth muscle cells (SMCs). Neo-extracellular matrix consisting mostly of collagen types I and III were observed at 12 months post-implantation. PCR analysis supports histological observations. TEVG group showed significant increases in expressions of SMC marker, collagen-I and III, matrix metalloproteinases-2 and 9, and itgam (a macrophage marker), when compared to sham group. Overall, patency rates were excellent at 12 months after implantation, as structural integrity of these TEVG. Tissue analysis also demonstrated vessel remodeling by autologous cell.

DOI： 10.1371/journal.pone.0120328

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Language：Japanese   Publisher：The Oto-Rhino-Laryngological Society of Japan, Inc.  

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 Buerger 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 【先進医療 A】 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先進医療技術Aに追加承認された.<br> 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.<br> 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 蛋白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.<br> 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分の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.<br> 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得るべき最新治療となりつつある.

DOI： 10.3950/jibiinkoka.118.1281

CiNii Books

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Other Link： https://jlc.jst.go.jp/DN/JLC/20018517994?from=CiNii

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

OBJECTIVE: Tissue engineering techniques have emerged that allow bioresorbable grafts to be implanted that restore function and transform into biologically active arteries. However, these implants are susceptible to calcification during the remodeling process. The objective of this study was to evaluate the role of pore size of bioabsorbable grafts in the development of calcification. METHODS: Two types of grafts were prepared: a large-pore graft constructed of poly(L-lactic acid) (PLA) fibers coated with poly(L-lactide-co-ε-caprolactone) (PLCL) (PLA-PLCL), and a small-pore graft made of electrospun PLA nanofibers (PLA-nano). Twenty-eight PLA-PLCL grafts and twenty-five PLA-nano grafts were implanted as infra-renal aortic interposition conduits in 8-week-old female SCID/Bg mice, and followed for 12 months after implantation. RESULTS: Large-pore PLA-PLCL grafts induced a well-organized neointima after 12 months, and Alizarin Red S staining showed neointimal calcification only in the thin neointima of small-pore PLA-nano grafts. At 12 months, macrophage infiltration, evaluated by F4/80 staining, was observed in the thin neointima of the PLA-nano graft, and there were few vascular smooth muscle cells (VSMCs) in this layer. On the other hand, the neointima of the PLA-PLCL graft was composed of abundant VSMCs, and a lower density of macrophages (F4/80 positive cells, PLA-PLCL; 68.1 ± 41.4/mm(2) vs PLA-nano; 188.3 ± 41.9/mm(2), p = 0.007). The VSMCs of PLA-PLCL graft expressed transcription factors of both osteoblasts and osteoclasts. CONCLUSION: These findings demonstrate that in mouse arterial circulation, large-pore PLA-PLCL grafts created a well-organized neointima and prevented calcific deposition compared to small-pore, electrospun PLA-nano grafts.

DOI： 10.1016/j.atherosclerosis.2014.09.030

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

OBJECTIVES: The clinical translation of tissue-engineered vascular grafts has been demonstrated in children. The remodeling of biodegradable, cell-seeded scaffolds to functional neovessels has been partially attributed to matrix metalloproteinases. Noninvasive assessment of matrix metalloproteinase activity can indicate graft remodeling and elucidate the progression of neovessel formation. Therefore, matrix metalloproteinase activity was evaluated in grafts implanted in lambs using in vivo and ex vivo hybrid imaging. Graft growth and remodeling was quantified using in vivo x-ray computed tomography angiography. METHODS: Cell-seeded and unseeded scaffolds were implanted in 5 lambs as inferior vena cava interposition grafts. At 2 and 6 months after implantation, in vivo angiography was used to assess graft morphology. In vivo and ex vivo single photon emission tomography/computed tomography imaging was performed with a radiolabeled compound targeting matrix metalloproteinase activity at 6 months. The neotissue was examined at 6 months using qualitative histologic and immunohistochemical staining and quantitative biochemical analysis. RESULTS: The seeded grafts demonstrated significant luminal and longitudinal growth from 2 to 6 months. In vivo imaging revealed subjectively greater matrix metalloproteinase activity in grafts versus native tissue. Ex vivo imaging confirmed a quantitative increase in matrix metalloproteinase activity and demonstrated greater activity in unseeded versus seeded grafts. The glycosaminoglycan content was increased in seeded grafts versus unseeded grafts, without significant differences in collagen content. CONCLUSIONS: Matrix metalloproteinase activity remained elevated in tissue-engineered grafts 6 months after implantation and could indicate remodeling. Optimization of in vivo imaging to noninvasively evaluate matrix metalloproteinase activity could assist in the serial assessment of vascular graft remodeling.

DOI： 10.1016/j.jtcvs.2014.05.037

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOURNAL OF VISUALIZED EXPERIMENTS  

Tissue engineered heart valves, especially decellularized valves, are starting to gain momentum in clinical use of reconstructive surgery with mixed results. However, the cellular and molecular mechanisms of the neotissue development, valve thickening, and stenosis development are not researched extensively. To answer the above questions, we developed a murine heterotopic heart valve transplantation model. A heart valve was harvested from a valve donor mouse and transplanted to a heart donor mouse. The heart with a new valve was transplanted heterotopically to a recipient mouse. The transplanted heart showed its own heartbeat, independent of the recipient's heartbeat. The blood flow was quantified using a high frequency ultrasound system with a pulsed wave Doppler. The flow through the implanted pulmonary valve showed forward flow with minimal regurgitation and the peak flow was close to 100 mm/sec. This murine model of heart valve transplantation is highly versatile, so it can be modified and adapted to provide different hemodynamic environments and/or can be used with various transgenic mice to study neotissue development in a tissue engineered heart valve.

DOI： 10.3791/51695

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOURNAL OF VISUALIZED EXPERIMENTS  

Biodegradable scaffolds seeded with bone marrow mononuclear cells (BMCs) are often used for reconstructive surgery to treat congenital cardiac anomalies. The long-term clinical results showed excellent patency rates, however, with significant incidence of stenosis. To investigate the cellular and molecular mechanisms of vascular neotissue formation and prevent stenosis development in tissue engineered vascular grafts (TEVGs), we developed a mouse model of the graft with approximately 1 mm internal diameter. First, the TEVGs were assembled from biodegradable tubular scaffolds fabricated from a polyglycolic acid nonwoven felt mesh coated with ε-caprolactone and L-lactide copolymer. The scaffolds were then placed in a lyophilizer, vacuumed for 24 hr, and stored in a desiccator until cell seeding. Second, bone marrow was collected from donor mice and mononuclear cells were isolated by density gradient centrifugation. Third, approximately one million cells were seeded on a scaffold and incubated O/N. Finally, the seeded scaffolds were then implanted as infrarenal vena cava interposition grafts in C57BL/6 mice. The implanted grafts demonstrated excellent patency (>90%) without evidence of thromboembolic complications or aneurysmal formation. This murine model will aid us in understanding and quantifying the cellular and molecular mechanisms of neotissue formation in the TEVG.

DOI： 10.3791/51632

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV 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 x 10(10) cells in total) were administered into the ischaemic limbs. We evaluated short-term safety and efficacy by means of a pain scale, Tc-99m-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.

DOI： 10.1093/rheumatology/ket432

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

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 × 10(10) cells in total) were administered into the ischaemic limbs. We evaluated short-term safety and efficacy by means of a pain scale, (99m)Tc-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 < 0.01; ASO 77 mm (s.d. 22) to 16 (s.d. 13), P < 0.01] and TcPO2 significantly improved [lcSSc 9.0 mmHg (s.d. 9) to 35 (s.d. 14), P < 0.01; ASO 18 mmHg (s.d. 10) to 29 (s.d. 21), P < 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. TRIAL REGISTRATION: UMIN-CTR, http://www.umin.ac.jp/ctr/index-j.htm, no. UMIN000004112.

DOI： 10.1093/rheumatology/ket432

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

The development of vascular bioengineering has led to a variety of novel treatment strategies for patients with cardiovascular disease. Notably, combining biodegradable scaffolds with autologous cell seeding to create tissue-engineered vascular grafts (TEVG) allows for in situ formation of organized neovascular tissue and we have demonstrated the clinical viability of this technique in patients with congenital heart defects. The role of the scaffold is to provide a temporary 3-dimensional structure for cells, but applying TEVG strategy to the arterial system requires scaffolds that can also endure arterial pressure. Both biodegradable synthetic polymers and extracellular matrix-based natural materials can be used to generate arterial scaffolds that satisfy these requirements. Furthermore, the role of specific cell types in tissue remodeling is crucial and as a result many different cell sources, from matured somatic cells to stem cells, are now used in a variety of arterial TEVG techniques. However, despite great progress in the field over the past decade, clinical effectiveness of small-diameter arterial TEVG (<6mm) has remained elusive. To achieve successful translation of this complex multidisciplinary technology to the clinic, active participation of biologists, engineers, and clinicians is required.

DOI： 10.1253/circj.CJ-13-1440

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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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Publishing type：Part of collection (book)  

Over the last decade, advancements in the field of vascular tissue engineering have generated a variety of novel treatment strategies for patients with cardiac defects and vascular disease. Notably, the technique of seeding cells onto biodegradable polymeric scaffolds to create tissue-engineered vascular grafts (TEVGs) allows for the formation of organized neovascular tissue and enables the implanted construct to grow with the patient. Studies in animal models have resulted in a greater understanding of the complex and dynamic processes behind neovessel development and enabled the creation of a TEVG seeded with bone marrow-derived mononuclear cells for use in a pilot clinical trial. Current research indicates that this tissue engineering approach is safe and effective, and the ongoing translation of this technology holds great promise. In this text, we review the scaffold materials, cell types, and seeding methods for TEVG creation, and we introduce our clinical application of TEVGs. © 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/B978-0-12-398523-1.00058-6

Scopus

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

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.

DOI： 10.1089/ten.tea.2010.0525

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1447-0594.2011.00695.x

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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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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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

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   Publisher：学習研究社  

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Authorship：Lead author   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<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<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.

DOI： 10.1016/j.yjmcc.2006.11.013

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

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Language：Japanese   Publisher：医学図書出版(株)  

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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：日本循環制御医学会  

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Language：Japanese   Publisher：医学図書出版(株)  

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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：(一社)日本心臓病学会  

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

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：English   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   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：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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

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

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Language：Japanese   Publisher：医学図書出版(株)  

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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：日本心臓血管内視鏡学会  

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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：(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)日本心臓病学会  

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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：(公財)日本心臓財団  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00679&link_issn=&doc_id=20170720210029&doc_link_id=10.11281%2Fshinzo.49.754&url=https%3A%2F%2Fdoi.org%2F10.11281%2Fshinzo.49.754&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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   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：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：日本静脈学会  

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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, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

Web of Science

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

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：Japanese   Publisher：(NPO)日本心臓血管外科学会  

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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J-GLOBAL

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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：(NPO)日本冠疾患学会  

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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：日本バイオマテリアル学会  

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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：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：医学書院  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

Web of Science

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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：日本心臓血管内視鏡学会  

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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   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   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：Japanese   Publisher：日本衛生動物学会  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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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：日本心脈管作動物質学会  

組織工学(TE)を用いた生体分解性人工血管(TEVG)の利点には、再生後に血管としての生理学的特性が期待できる、小児患児では身体的な成長に伴い生物学的成長が期待できる、傷害時の自己修復機転が期待できるなどがある。心臓・血管外科領域における生体分解性素材を用いた血管再生医療の現況について、以下の項目に分けて述べた。1)TEを用いた血管再生医療の構成、2)TEVGの臨床応用、3)再生血管における組織形成のメカニズム、4)小口径動脈でのTEVG、とした。

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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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：日本下肢救済・足病学会  

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Language：Japanese   Publisher：(NPO)日本心臓血管外科学会  

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Language：Japanese   Publisher：(一社)日本美容外科学会  

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

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

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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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：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：Japanese   Publisher：(株)医学出版  

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

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Language：Japanese   Publisher：日本血管内治療学会  

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

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

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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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：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本老年医学会  

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J-GLOBAL

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

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：全日本病院出版会  

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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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J-GLOBAL

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J-GLOBAL

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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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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese  

J-GLOBAL

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：日本医科大学医学会  

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J-GLOBAL

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J-GLOBAL

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

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

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Language：Japanese   Publisher：(株)ライフ・サイエンス  

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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：(一社)日本循環器学会  

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Web of Science

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：Japanese   Publisher：(株)メヂカルフレンド社  

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Language：Japanese   Publisher：(株)メディカ出版  

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Language：Japanese  

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

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Web of Science

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

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DOI： 10.1016/j.yjmcc.2007.03.223

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：Japanese  

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Language：Japanese   Publisher：日本獣医生命科学大学  

CiNii Books

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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