Increase In Vessel Area Research Articles

Abstract 418: Ready-made Microvessels Robustly Integrate Into the Infarcted Coronary Vasculature Promoting Graft Perfusion, Enhancing Cardiac Remuscularization and Function

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer an unprecedented opportunity to remuscularize infarcted hearts. However, the majority of hiPSC-CMs die post transplantation into the ischemic environment, limiting their regenerative potential. CM death occurs in the first few days post-transplantation due to ischemia. Attempts to promote intramyocardial vascularization (i.e. delivery of growth factors or cells) have not led to significant improvements due to poor cell retention and the long time required for new vessels to form and carry blood compared to the rapid death of transplanted CMs. Here, we used ready-made microvessels harvested from adipose tissue - that form a vasculature and carry blood within the first days post subcutaneous implantation - to re-vascularize ischemic rat hearts and improve hiPSC-CM survival. We performed left anterior descending artery ligation in immunocompromised rats to model MI. hiPSC-CMs (10 x10 6 ) with (CM+V) or without (CM-only, control) microvessels were delivered by intra-myocardial injection 2 weeks post MI. Cardiac function was assessed by echocardiography and pressure-volume loop. Delivery of microvessels from GFP rats allowed assessment of microvessel persistence. Compared to hiPSC-CM transplantation alone, microvessels promoted a 6-fold increase in hiPSC-CM survival, with reduction in scar size and a significantly superior functional recovery. While delivery of CM-only stabilized the heart preventing further fractional shortening decline, delivery of CM+V resulted in reversal of fractional shortening loss. This was supported by PV-loop data (ejection fraction: sham, ~20%; CM-only, ~31%; CM+V, ~39%; 4 wks). Moreover, microvessels showed unprecedented persistence and integration (>60%, 4 wks), resulting in 2-fold increase in vessel area and graft perfusion (as early as day 5 post-transplantation). This was achieved despite the very low number of cells (~2 x10 5 ) delivered in the form of microvessels. These findings provide a novel approach to cell-based therapies for MI whereby incorporation of ready-made microvessels can serve as a personalized delivery system to improve functional outcomes in cell replacement therapies.

Clinical and intravascular imaging outcomes at 1 and 2 years after implantation of absorb everolimus eluting bioresorbable vascular scaffolds in small vessels. Late lumen enlargement: does bioresorption matter with small vessel size? Insight from the ABSORB cohort B trial

BackgroundThe long-term results after second generation everolimus eluting bioresorbable vascular scaffold (Absorb BVS) placement in small vessels are unknown. Therefore, we investigated the impact of vessel size on long-term outcomes,...

Effect of different channel ushering drugs on homing of bone marrow stem cells of femoral head necrosis model rabbits

To observe the effect of Huogu II formula compatible with different channel ushering drugs on the homing of bone marrow stem cells of osteonecrosis of the femoral head (ONFH) induced by liquid nitrogen freezing in rabbits and discuss the mechanism for preventing and treating ONFH. The ONFH model was established by liquid nitrogen freezing of 84 rabbits. They were randomly assigned to the model group and the Huogu II formula group and groups of Huogu II formula combining with Achyranthis Bidentatae Radix, Asari Radix et Rhizoma, Angelicae Pubescentis Radix, Platycodonis Radix. The remaining 14 rabbits were sham-operated. During the course of ONFH modeling, all of the rabbits were subcutaneously injected with recombinant human granulocyte colony-stimulating factor (rhG-CSF)(30 microg x kg(-1) x d(-1), for consecutively 7 days). Meanwhile, normal saline and decoction of the formulae were orally administrated respectively. WBC was counted in peripheral blood before and after the injection of rhG-CSF. HE stainings at the 2nd and the 4th weeks after the modeling were adopted to observe histopathological changes, vascular morphology was observed by ink perfusion, BrdU and SDF-1 were determined by immunohistochemical assay in femoral heads of the left hind leg. Compared with the sham-operated group, the Huogu II formula group showed decrease in the ratio of empty lacuna and increase in vessel area, number of BrdU positive cells and SDF-1 level. In comparison with the model group, the Achyranthis Bidentatae Radix group displayed decreasing empty lacuna ratio and increasing vessel area at the 4th week and increasing SDF-1 at the 2nd week; the Platycodonis Radix group revealed a notably increasing empty lacuna ratio and a sharp decrease in the number of BrdU positive cells at 4th week; Asari Radix et Rhizoma and Angelicae Dubescentis Radix groups showed no remarkable change. Huogu II formula can promote the directional homing of bone marrow stem cell to the necrosis area. Channel ushering drug achyranthes can further boost above effects of Huogu II formula.

Abstract LB-311: Inhibition of angiopoietin and Dll4 signaling in the tumor vasculature leads to increased efficacy in mouse tumor xenograft models

Abstract Inhibition of angiogenesis is a proven cancer treatment strategy as an adequate blood supply is critical for tumor growth. Two of the key pathways regulating tumor angiogenesis are angiopoietin/Tie2 and Dll4/Notch. Inhibition of the angiopoietin/Tie2 pathway has been shown to reduce blood vessel density and inhibit tumor growth in mouse xenograft models. Inhibition of Dll4 also prevents tumor xenograft growth but does so by promoting a non-productive vascular network via excessive endothelial branching and sprouting. In this study, we examined the effects of combined inhibition of these pathways in models of angiogenesis and tumor growth. To inhibit the angiopoietin pathway we used AMG 386, a selective angiopoietin 1/2-neutralizing peptibody that prevents the interaction between these two angiopoietins and the Tie2 receptor. To inhibit Dll4 we used a neutralizing monoclonal antibody. The combination of AMG 386 and anti-Dll4 led to enhanced antitumor activity compared with either agent alone in four xenograft models (U-87 glioma, Calu-6 lung, Colo205 colorectal and MiaPaca pancreatic tumors). All treatments were well tolerated and no weight loss was observed. Histological analysis of U-87 tumors following one week of treatment revealed an increase in vessel area with anti-Dll4 alone and the combined treatment with AMG 386 showed a similar increase. At these same doses, AMG 386 reduced anti-Dll4-induced tumor associated endothelial cell proliferation following 24 hours of treatment. We also examined AMG 386/anti-Dll4 treatment in models of angiogenesis. In the rat cornea, individual anti-Dll4 and AMG 386 treatment had distinct morphological effects on VEGF-induced vessel formation. Vessel number and area were decreased following AMG 386 treatment, whereas vessel cross-branching and terminal tufting were observed following anti-Dll4 treatment. After combined treatment, vessels were truncated but the branching/tufting phenotype was preserved. Similar effects were seen in the mouse neonatal retina, where AMG 386 and anti-Dll4 treatment alone resulted in the expected distinct vascular phenotypes; AMG 386 treatment reduced vessel density and inhibited radial expansion, while anti-Dll4 treatment resulted in marked branching and thickening, and showed full radial expansion. In this model, combined treatment led to clear evidence of both mechanisms of action: increased branching and reduced radial expansion were observed in all retinas examined. Taken together, these data suggest that combined inhibition of the angiopoietin/Tie2 and Dll4/Notch pathways does not interfere with their individual mechanisms of action and furthermore, leads to enhanced efficacy in preclinical models. Therefore, the combination of these agents may have the potential to provide an expanded therapeutic opportunity to inhibit tumor angiogenesis beyond either individual agent alone. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-311. doi:1538-7445.AM2012-LB-311

Mechanisms of Late Stent Malapposition After Primary Stenting in ST‐Elevation Myocardial Infarction: A Subanalysis of the Selection Trial

One of the major predictors of late stent malapposition (LSM) is primary stenting in acute myocardial infarction. However, mechanisms of LSM are still under debate. Patients with ST-elevation myocardial infarction (STEMI) and enrolled in the SELECTION trial (38 patients in the paclitaxel-eluting stent, PES, and 35 in the bare metal stent, BMS, cohort) were retrospectively analyzed to evaluate LSM, by means of intravascular ultrasound (IVUS) data recorded at the index and 7-month follow-up procedures. Stent malapposition was documented in 21 lesions in 21 patients (28.8%): in 8 of these 21 patients (38.1%) it was LSM. Although statistical significance was not reached, LSM was more frequent after PES than BMS implantation (15.8% vs. 5.7%). LSM was mainly located within the body of the stent (62.5% of the cases). At the LSM segment, a significant increase of vessel area (19.2 +/- 3.3 mm(2) vs. 21.9 +/- 5.3 mm(2), P = 0.04) and a reduction of plaque area (12.6 +/- 4.6 mm(2) vs. 9.1 +/- 3.9 mm(2), P = 0.04) were observed at IVUS between the index and follow-up procedure. After primary stenting for STEMI, LSM seems to be more frequent after PES rather than BMS implantation. In the STEMI setting, possible mechanisms leading to LSM include positive remodeling and plaque mass decrease.

Incomplete Stent Apposition After Implantation of Paclitaxel-Eluting Stents or Bare Metal Stents

The clinical impact of late incomplete stent apposition (ISA) for drug-eluting stents is unknown. We sought to prospectively investigate the incidence and extent of ISA after the procedure and at 6-month follow-up of paclitaxel-eluting stents in comparison with bare metal stents (BMS) and survey the clinical significance of ISA over a period of 12 months. TAXUS II was a randomized, double-blind study with 536 patients in 2 consecutive cohorts comparing slow-release (SR; 131 patients) and moderate-release (MR; 135 patients) paclitaxel-eluting stents with BMS (270 patients). This intravascular ultrasound (IVUS) substudy included patients who underwent serial IVUS examination after the procedure and at 6 months (BMS, 240 patients; SR, 113; MR, 116). The qualitative and quantitative analyses of ISA were performed by an independent, blinded core laboratory. More than half of the instances of ISA observed after the procedure resolved at 6 months in all groups. No difference in the incidence of late-acquired ISA was observed among the 3 groups (BMS, 5.4%; SR, 8.0%; MR, 9.5%; P=0.306), with a similar ISA volume (BMS, 11.4 mm3; SR, 21.7 mm3; MR, 8.5 mm3; P=0.18). Late-acquired ISA was the result of an increase of vessel area without change in plaque behind the stent. Predictive factors of late-acquired ISA were lesion length, unstable angina, and absence of diabetes. No stent thrombosis occurred in the patients diagnosed with ISA over a period of 12 months. The incidence and extent of late-acquired ISA are comparable in paclitaxel-eluting stents and BMS. ISA is a pure IVUS finding without clinical repercussions.

Impact of moderate lesion calcium on mechanisms of coronary stenting as assessed with three-dimensional intravascular ultrasound in vivo

Axial plaque redistribution is an important mechanism of lumen enlargement after stenting of noncalcified lesions. To assess effects of lesion calcification on mechanisms of coronary stenting, we analyzed 55 lesions with noncircumferential calcification with 3-dimensional intravascular ultrasound (IVUS) (standard qualitative and quantitative analyses) before and after implantation of balloon-expandable stents. Thirty-two plaques (58%) showed arcs of calcium <120° of vessel circumference (group A), whereas 23 lesions (42%) contained arcs of calcium ≥120° of vessel circumference (group B). In the entire cohort of 55 lesions, as well as groups A and B, which were studied separately, both single-slice IVUS analysis (performed at minimum lumen site before intervention) and mean stented segment IVUS analysis showed an increase in lumen and vessel area and a decrease in plaque area (p <0.001). The magnitude of lumen and vessel increase and of plaque decrease was similar in both groups. Group A lesions showed significant plaque extrusion into the distal reference segment that was not observed in group B (increase in plaque area of 1.3 ± 1.9 vs 0.1 ± 2.0 mm 2, p <0.04). Stenting did not alter plaque area of the proximal reference segment in either group. In addition, there was an increase in vessel area of the distal reference of both groups, indicating that stent-induced vessel expansion observed within the lesion also affected the distal reference. Thus, longitudinal plaque redistribution and vessel expansion contribute to increased lumen dimensions during stenting of lesions with varying amounts of calcium; however, marked plaque extrusion was found only in lesions with a calcium arc of <120°.

Pulmonary Arterial Wall Distensibility Assessed by Intravascular Ultrasound in Children With Congenital Heart Disease: An Indicator for Pulmonary Vascular Disease?

Both pulmonary hypertension and pulmonary overflow are associated with functional and structural changes of the pulmonary arterial wall. Current techniques to evaluate the pulmonary vasculature neglect the pulsatile nature of pulmonary flow. To determine whether the dynamic properties of the pulmonary arterial wall are altered in patients with abnormal pulmonary hemodynamics due to congenital heart defects, and whether these changes are associated with the progression of pulmonary vascular disease (PVD). In 43 children with PVD due to congenital heart defects and 12 control subjects, pulmonary arterial pulsatility (the relative increase in vessel area during the cardiac cycle) and distensibility (the inverse of the stress/strain elastic modulus) were determined with intravascular ultrasound. Results were correlated with clinical and hemodynamic parameters. Pulsatility correlated with pulmonary pulse pressure (p < 0.001), pulmonary-to-systemic vascular resistance ratio (PVR/SVR) [p = 0.001], and hemoglobin concentration (p = 0.01). However, when corrected for these variables, pulsatility did not differ between patients and control subjects. In contrast, arterial wall distensibility decreased with the severity of PVD and correlated independently with pulmonary-to-systemic arterial pressure ratio (p < 0.001) and PVR/SVR (p = 0.03), and with hemoglobin concentration (p < 0.01). Adjusted for hemodynamic variables, distensibility was still decreased in patients with PVD compared to control subjects. These results demonstrate that pulmonary arterial wall distensibility is progressively decreased in PVD; moreover, this decreased distensibility is, in part, related to increased distending pressure as a result of pulmonary hypertension but also, in part, to stiffening of the arterial wall during the disease process. Arterial wall distensibility may be of additional value in the evaluation of pulmonary vasculature and ventricular workload.

Qualitative and quantitative contrasts in the mechanisms of lumen enlargement by coronary balloon angioplasty and directional coronary atherectomy

Objectives. This study was designed to define and contrast the mechanisms of lumen enlargement from coronary balloon angioplasty and directional coronary atherectomy using intracoronary ultrasound imaging in vivo.Background. The mechanisms of lumen enlargement produced by percutaneous transluminal coronary balloon angioplasty and directional coronary atherectomy are not known because the coronary artery wall has not previously been studied both before and after dilation.Methods. We used intracoronary ultrasound to quantitate coronary lumen, vessel and plaque area both before and immediately after successful coronary angioplasty (n =30) and directional coronary atherectomy (n = 25) at the site of most severe stenosis.Results. Angioplasty increased lumen area by 2.80 ± 0.25 mm2(mean ± SE, p < 0.0001). Eighty-one percent of this lumen gain resulted from an increase in vessel area and the remaining 19% from a reduction in plaque area. Lumen gain of individual lesions was separated into three groups: 67% had an increase in vessel area (vessel expansion), 13% had a decrease in plaque area and 20% had a combination of both. In contrast, vessel expansion contributed only 22% of the lumen gain with directional coronary atherectomy, with the majority (78%) of increase in lumen size coming from a reduction in plaque area. Directional coronary atherectomy increased from 2.36 ± 0.05 to 7.00 ± 0.28 mm2(p < 0.0001). Plaque reduction was the sole mechanism in 60% of lesions, vessel expansion was the sole mechanism in 12% and a combination of both mechanisms occurred in 28%. Lumen enlargement of eccentric lesions treated with directional coronary atherectomy was more commonly associated with plaque reduction (p < 0.02), whereas eccentricity did not affect the mechanism of lumen enlargement with coronary angioplasty.Conclusions. This is the first study to systematically examine the coronary artery wall in vivo at the site of a severe stenosis both before and after catheter-based interventions in humans. Lumen enlargement from coronary asgioptasty occurs predominantly from vessel expansion or stretching, although a reduction in plaque area contributes to the lumen gain in many patients and is the sole mechanism in a few. Lumen gain from directional coronary atherectomy is predominantly from reduction in plaque area (probably owing to tissue removal), although vessel stretching (balloon effect) occurs and is the sole mechanism in a small minority of vessels. Plaque reduction is more common in directional coronary atherectomy of eccentric lesions.