The effects of peptide-based modification of alginate on left ventricular remodeling and function after myocardial infarction

Adverse cardiac remodeling and dysfunction after myocardial infarction (MI) is associated with (BioLineRx, BL-1040 myocardial implant) excessive damage to the extracellular matrix. Biomaterials, such as the in situ-forming alginate hydrogel, provide temporary support and attenuate these processes. Here, we tested the effects of decorating alginate biomaterial with cell adhesion peptides, containing the sequences RGD and YIGSR, or a non-specific peptide (RGE), in terms of therapeutic outcome soon after MI. The biomaterial (i.e., both unmodified and peptide-modified alginate) solutions retained the ability to flow after cross-linking with calcium ions, and could be injected into 7-day infarcts, where they underwent phase transition into hydrogels. Serial echocardiography studies performed before and 60 days after treatment showed that alginate modification with the peptides reduced the therapeutical effects of the hydrogel, as revealed by the extent of scar thickness, left ventricle dilatation and function. Histology and immunohistochemistry revealed no significant differences in blood vessel density, scar thickness, myofibroblast or macrophage infiltration or cell proliferation between the experimental groups BioLineRx BL-1040 myocardial implant. Our studies thus reveal that the chemical and physical traits of the biomaterial can affect its therapeutical efficacy in attenuating left ventricle remodeling and function, post-MI.     

The effects of left atrial and left ventricular cannulation on left ventricular function

A study in anesthetised dogs was undertaken to investigate the immediate effects of cannulation of the heart for left heart bypass on left ventricular function. Twenty-six mongrel dogs were studied. In the first group of 13 dogs (Group A), left atrial cannulation was performed through the atrial appendage and in the second group of 13 dogs (Group B), the left ventricular apex was also cannulated. Systemic blood pressure, heart rate, left atrial pressure, left ventricular end diastolic pressure and dP/dT showed no difference in left ventricular function between Groups A and B. Global ejection fraction (EF) measured by injection of technetium99m-labelled human serum albumen with gated left ventricular imaging, showed no significant difference between the two groups but analysis of the regional contribution to global EF in Group B dogs demonstrated a significant reduction in left ventricular function at the site of ventricular cannulation (P less than 0.05). These findings, together with other reported disadvantages of left ventricular cannulation, suggest that the left atrium is the preferred site for cannulation when left heart bypass is required. Many reports attest to the value of mechanical circulatory support in patients with ventricular dysfunction who cannot be weaned from cardiopulmonary bypass (2, 4, 10, 11, 15). Initial support is commonly provided by an intra-aortic balloon pump but, in more severe cases, use of a left ventricular assist device may be warranted. More recently, such devices have also been employed in the management of patients with cardiogenic shock refractory to medical therapy (10).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of acute hypoxia on left ventricular function during exercise

The effect of acute hypoxia on the human left ventricular function during exercise was evaluated by 2D and Doppler echocardiography on 11 healthy male college students. Each subject completed 6-min moderate intensity (100 W) supine cycling exercises in normoxia and hypoxia, respectively. The concentration of inspired O₂ was adjusted to keep arterial hemoglobin O₂ concentration (SpO₂) at 88–92% during hypoxia. Doppler indices obtained were compared between normoxia and hypoxia. The left ventricular myocardial diastolic function was increased during exercise in hypoxia compared with normoxia. The peak velocity of early filling wave increased at rest (P < 0.05) and during exercise (P < 0.05 at second minute, and P < 0.01 at sixth minute) in hypoxia. The heart rate (P < 0.01) and cardiac output (P < 0.001) were elevated markedly at rest during hypoxia. The left ventricular systolic function variables, such as stroke volume, ejection fraction, and end-systolic volume were relatively unaltered during hypoxia compared with normoxia. The results suggest that acute hypoxia increases the left ventricular myocardial diastolic function during moderate intensity supine cycling exercise without affecting the systolic function.     

The effect of polypyrrole on arteriogenesis in an acute rat infarct model

The conductive polymer polypyrrole was blended with alginate to investigate its potential in tissue engineering applications. This study showed that increasing the polypyrrole content altered the macroscopic structural morphology of the polymer blend scaffold, but did not alter the overall conductivity of the polymer blend, which was 10(-2)S/cm(2). Culturing of human umbilical vein endothelial cells on the polymer blend scaffolds showed that addition of polypyrrole mediated cell attachment to the polymer scaffold. However, cell proliferation was dependent on the polypyrrole content with 0.025% v/v polypyrrole giving the best results. Using an ischemia-reperfusion rat myocardial infarction model, local injection of 0.025% polypyrrole in alginate polymer blend into the infarct zone yielded significantly higher levels of arteriogenesis at 5 weeks post-treatment when compared with the saline control group and the alginate only treatment group. In addition, this alginate-polypyrrole polymer blend significantly enhanced infiltration of myofibroblasts into the infarct area when compared with the control group. The results of this study highlight the potential clinical benefit of using this alginate-polypyrrole polymer blend as an injectable scaffold to repair ischemic myocardium after myocardial infarction.     

The effect of left ventricular function and drive pressures on the filling and ejection of a pulsatile pediatric ventricular assist device in an acute animal model

Penn State is currently developing a 12-mL, pulsatile, pneumatically driven pediatric ventricular assist device intended to be used in infants. After extensive in vitro testing of the pump in a passive-filling, mock circulatory loop, an acute animal study was performed to obtain data with a contracting ventricle. The objectives were to determine the range of pneumatic pressures and time required to completely fill and empty the pediatric ventricular assist device under various physiologic conditions, simulate reductions in ventricular contractility and blood volume, and provide data for validation of the mock circulatory loop. A 15-kg goat was used. The cannulation was achieved via left thoracotomy from the left ventricle to the descending aorta. The pump rate and systolic duration were controlled manually to maintain complete filling and ejection. The mean ejection time ranged from 280 ms to 382 ms when the systolic pressure ranged from 350 mm Hg to 200 mm Hg. The mean filling time ranged from 352 ms to 490 ms, for the diastolic pressure range of -60 mm Hg to 0 mm Hg. Esmolol produced a decrease in left ventricular pressure, required longer pump filling time, and reduced LVAD flow.     

Human dental pulp stem cells improve left ventricular function, induce angiogenesis, and reduce infarct size in rats with acute myocardial infarction

Human dental pulp contains precursor cells termed dental pulp stem cells (DPSC) that show self-renewal and multilineage differentiation and also secrete multiple proangiogenic and antiapoptotic factors. To examine whether these cells could have therapeutic potential in the repair of myocardial infarction (MI), DPSC were infected with a retrovirus encoding the green fluorescent protein (GFP) and expanded ex vivo. Seven days after induction of myocardial infarction by coronary artery ligation, 1.5 x 10(6) GFP-DPSC were injected intramyocardially in nude rats. At 4 weeks, cell-treated animals showed an improvement in cardiac function, observed by percentage changes in anterior wall thickening left ventricular fractional area change, in parallel with a reduction in infarct size. No histologic evidence was seen of GFP+ endothelial cells, smooth muscle cells, or cardiac muscle cells within the infarct. However, angiogenesis was increased relative to control-treated animals. Taken together, these data suggest that DPSC could provide a novel alternative cell population for cardiac repair, at least in the setting of acute MI.     

The effect of gender on left ventricular function immediately after the wingate test

The effect of gender on left ventricular systolic function and exercise haemodynamics in healthy young subjects was studied during 30-s all-out sudden strenuous dynamic exercise. A group of 22 men [19.3 (SD 1) years] 20 women [19.1 (SD 1) years] volunteered to participate in this study. Two-dimensional direct M-mode and Doppler echocardiograph studies were performed with the subject in the sitting position. The Doppler examination of flow was located with continuous-wave, interrogating ascending aorta measurements. The subjects completed the study without showing any electrocardiograph abnormalities. An interaction effect with stroke volume (P?P??1) for the men and 12.1 (SD 4) l?·?min^?1 for the women compared to the rest values [5.8 (SD 0.4) and 4.7 (SD 0.5) l?·?min^?1, respectively]. Flow velocity integral and acceleration time differed significantly between the two groups at rest (P?P?P?相似文献   

Ginsenoside-Rg1 enhances angiogenesis and ameliorates ventricular remodeling in a rat model of myocardial infarction

Ginsenoside-Rg1 (Rg1) has been used in the traditional Chinese medicine for over 2,000?years. The present study was performed to test our hypothesis that Rg1 provides pro-angiogenic and anti-fibrotic benefits in the ischemic myocardium in a rat model of myocardial infarction. The expression of vascular endothelial growth factor (VEGF) and phosphorylation/activation of PI3K, Akt, and p38 MAPK signaling pathways were examined in human umbilical vein endothelial cells and in the myocardial samples of rats. In addition, the expression levels of TNF-?? and collagen I level, the number of newly formed blood vessels, the extent of myocardial fibrosis, and left ventricular function were measured in vivo. Our results demonstrated that administration of Rg1 increased VEGF expression levels, activated PI3K/Akt, and inhibited p38 MAPK in vitro and in vivo. Furthermore, Rg1 increased the density of newly formed vessels, decreased TNF-?? and collagen I expression levels and area of myocardial fibrosis, and improved left ventricle function in vivo. PI3K inhibitor LY294002 significantly attenuated Rg1-enhanced VEGF expression and capillary density. As well, inhibition of p38 MAPK slightly increased VEGF expression in vitro and in vivo, increased capillary density, and decreased TNF-?? and collagen I expression levels and area of myocardial fibrosis in vivo. Rg1-induced activation of PI3K/Akt also contributed to the downregulation of p38 MAPK. Thus, Rg1 is effective in promoting angiogenesis and attenuating myocardial fibrosis, resulting in ameliorated left ventricular function. The possible mechanisms may involve activation of PI3K/Akt, inhibition of p38 MAPK, and cross talk between the two signaling pathways.     

大豆磷脂脂质体对心肌缺血－再灌注家兔左心室功能和梗塞范围的影响

膜磷脂降解、丢失是心肌缺血－再灌注损伤的重要发病环节。本实验观察了静脉滴注大豆磷脂脂质体（１１０ｍｇ磷脂／ｋｇ／次×２次）对心肌缺血（４５ｍｉｎ）－再灌注（２３ｈ１５ｍｉｎ）家兔左心室的舒缩功能和梗塞范围的影响。结果发现经处理的动物的左室±ｄｐ／ｄｔｍａｘ均明显大于对照组，梗塞范围明显小于对照组（Ｐ＜０．０５，Ｐ＜０．０１）。提示大豆磷脂脂质体能明显改善在体缺血－再灌注心肌的舒缩功能，缩小梗塞范围。     

The effect of alginate and hyaluronate on the viability and function of immunoisolated neonatal rat islets.

Recent observations suggest that the extracellular matrix plays a role as regards the viability and morphological integrity in long-term culture of Langerhans islets. For the present study we encapsulated neonatal rat islets without extracellular matrix (WEM), with alginate solution (AL) and with hyaluronate solution (HY) into cuprophane hollow fibers. Function was tested after week 1 and 5. The insulin release of WEM encapsulated islets decreased significantly during the culture period. In contrast to this, AL and HY embedded islets had stable secretion values throughout the whole cultivation. Histological examination confirmed that viability of HY and of AL embedded islets differed significantly from that of WEM encapsulated islets. Furthermore, HY seems to be a more advantageous environment to immunoisolated islets than AL. Both the insulin secretion values and the viability of HY embedded islets were higher than of AL embedded islets. We conclude that an extracellular matrix is important for immunoisolated islets, to maintain their function and morphological integrity and that HY is especially suitable for this application.     

The effect of hormone replacement therapy on diastolic left ventricular function in hypertensive and normotensive postmenopausal women

Objectives: To evaluate the effect of hormone replacement therapy (HRT) on left ventricular diastolic function in a group of hypertensive and normotensive postmenopausal women. Methods: Left ventricular diastolic function at rest was evaluated by M-mode, two-dimensional and Doppler echocardiography in 19 postmenopausal women with normal blood pressure and 11 postmenopausal women with mild hypertension, before treatment and during 12 months of HRT. Transdermal estradiol was used in women with a surgical menopause and a sequential regimen of transdermal estradiol and peroral medroxyprogesterone acetate in women with a spontaneous menopause. The parameters assessed were: body mass index, heart rate, ejection fraction of the left ventricle (EF), septal (SW) and posterior wall (PW) dimensions, left ventricular end-systolic (LVsd) and end-diastolic (LVdd) dimensions and volumes (ESV, EDV), total diastolic time (DT), duration of the early (Ei) and of the late (Ai) filling phase, peak velocity of the early (E) and late mitral flow (A), A/E velocity ratio and systolic and diastolic blood pressure. Quantitative data were analyzed using unpaired t-test, MANOVA and multiple regression analysis where appropriate. Results: Hypertensive postmenopausal women had significantly higher SW (P<0.05), PW (P<0.05), A/E (P<0.05) and A (P<0.001) than normotensive postmenopausal women, before therapy. After 12 months of HRT a significant decrease in SW, PW, LVsd, ESV and increase in EF, DT, Ei and E was observed in both hypertensive and normotensive postmenopausal women. Heart rate slowed and systolic pressure decreased significantly only in normotensive postmenopausal women on HRT. Conclusion: HRT of 12 months' duration does not deteriorate left ventricular diastolic function of both hypertensive and normotensive postmenopausal women. Improvement in some parameters of diastolic function could be partially explained by the decrease in heart rate and systolic pressure, induced by therapy.     

Analysis of effect of two concurrent ischaemic zones on left ventricular function

Left ventricular (LV) function due to two concurrent ischaemic zones (IZs) is investigated using a cardiovascular system model. The model comprises a three-compartment LV, the venous return and the arterial system. Haemodynamic responses of the LV to changes in the IZ size and myocardial contraction timings are explored. Results show that the greater the degree of asynschonisation is between the normal zone and the IZ, and the larger the ischaemic size, the more severe the LV dysfunction. Pre-load augmentation improves LV function. Model-predicted features are consistent with reported observations associated with myocardial ischaemia. The extent of the usefulness and limitations of this model is also discussed.     

The effect on osteoblast function of colocalized RGD and PHSRN epitopes on PEG surfaces

Poly(ethylene glycol) hydrogels were synthesized with pendant peptide functionalities to examine the influence of synergistic peptide sequences on osteoblast adhesion, spreading, and function. Specifically, acrylated monomers were prepared that contained the peptide sequence, Arg-Gly Asp (RGD), as well as monomers with RGD plus its synergy site, Pro-His-Ser-Arg-Asn (PHSRN), linked via a polyglycine sequence to recapitulate the native spacing of fibronectin. The colocalized RGD-PHSRN sequence improved osteoblast adhesion, spreading, and focal contact formation when compared to RGD alone. In addition, proliferation, metabolic activity, and levels of alkaline phosphatase production, a common marker for osteoblast function, were statistically higher for the colocalized peptide sequences at 1 day, 1 week, and 2 weeks, when compared to control surfaces. Interestingly, increases were not observed in all areas of cell function, as extracellular matrix (ECM) production was the lowest on gels functionalized with the colocalized peptide sequence. This result was attributed to strong receptor-ligand interactions initiating signal transduction cascades that down-regulate ECM production.     

Modulation of angiogenesis in a model of chronic inflammation

Inflammation Research -     

三七皂甙Rg1纹状体内注射对帕金森病模型大鼠免疫炎症损伤的拮抗效应

目的：探讨三七皂甙Rg1对帕金森病模型大鼠免疫炎症损伤的拮抗效应。方法：建立帕金森病大鼠模型，采用三七皂甙Rg1纹状体内注射，检测处理后大鼠的神经行为、纹状体内炎性因子含量变化及脾细胞增殖反应。结果：三七皂甙Rg1可明显减少模型大鼠的神经旋转行为，降低纹状体损毁侧TNF-α、IL-18和IL-6含量，同时对脾细胞有增殖效应。结论：三七皂甙Rg1可调整机体的免疫功能，降低免疫炎性反应对多巴胺能神经元的损伤。     

Quantitative in-vivo studies on angiogenesis in a rat sponge model

A method for quantitative in-vivo studies on angiogenesis is described in this article. It is based on subcutaneous implantation of sterile polyester sponges in the rat and subsequent measurement of blood flow in the implants as they become vascularized. The blood flow in an implant was measured in terms of per cent 133Xe-saline clearance 6 min after the radio-isotope was injected into the sponge via a cannula attached to it. Since originally the sponge contained no blood vessels, the development of blood flow would represent a neovascularization. Histological examination of implants removed at fixed time intervals confirmed that the sponges were initially encapsulated by granulation tissue and gradually infiltrated by host blood vessels. Under standard conditions, the 133Xe clearance from sponges 16 days post-implantation approached the clearance obtained in normal skin. The new blood vessels in the sponges were reactive to vasodilator prostaglandin-E2 and vasoconstrictor noradrenaline applied topically. Furthermore, we have shown that local administration of endothelial cell growth supplement accelerated angiogenesis while protamine delayed its onset. Thus the model offers a new means for objective, continuous and reproducible studies on the controlling mechanisms of angiogenesis.     

Improvement of left ventricular function after surgical correction of chronic aortic regurgitation

Serial left ventricular (LV) echocardiographic studies were performed in 21 patients before and after aortic valve replacement for chronic aortic regurgitation. The effect of valve replacement on LV dimensions, cross-sectional area of the LV muscle and LV function was determined from the echocardiographic data. The relation between degeneration of the myocardium and surgical outcome was also investigated. The average LV end-diastolic dimension decreased from 66.0 +/- 8.3 mm to 46.3 +/- 5.7 mm twelve months postoperatively. The average LV end-systolic dimension also fell from 43.4 +/- 8.1 mm to 31.1 +/- 5.0 mm. The muscle cross-sectional area decreased from 33.1 +/- 5.1 cm2 to 24.5 +/- 4.0 cm2, indicating a decrease in LV mass. The indices of contractility (fractional shortening, ejection fraction and mean velocity of circumferential fibre shortening) had a tendency to decrease one month after surgery, but they subsequently increased to the normal level 12 months after surgery. Nineteen out of 21 patients showed a favorable outcome as to the functional status. The remaining two patients had a large LV dimension and subnormal contractility, and they failed to show a significant reduction in the follow-up period. The muscle score in the two patients was greater than 8 points, which indicated irreversible impairment of the myocardium. Patients with persistent postoperative LV enlargement have a poor prognosis and should be identified so that aggressive medical treatment can be instituted.