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ABSTRACT: OBJECTIVE: Obstructive sleep apnoea (OSA) is characterised by reoccurring apnoeas and hypopneas, causing repetitive hypoxia and reoxygenation, and is associated with endothelial dysfunction and reduced levels of circulating progenitor cells (CPCs). The potential to improve endothelial function and CPC levels in people with OSA by preventing hypoxic episodes with Continuous Positive Airway Pressure (CPAP) was investigated in a sham-controlled CPAP study. METHODS: Men with moderate-to-severe OSA (mean±SD: age=49±12y, apnoea hypopnea index (AHI)=37.6±16.4events/h, body mass index=31.5±5.7kg/m2) who were CPAP naïve without diabetes mellitus were randomised in a 12-week double-blind sham-controlled parallel group study to receive either active (n=25) or sham (n=21) CPAP. CPCs, isolated from blood, were measured by flow cytometry and by co-staining cultured cells (7days) with acetylated low-density lipoprotein (acLDL) and lectin. Endothelial function was assessed by peripheral arterial tonometry (PAT). RESULTS: Compared to sham, CPAP significantly decreased AHI (mean between-group difference -36.0events/h; 95%CI, -49.7 to -22.3, p<0.0001) after 12weeks. Despite this improvement in AHI, CPAP had no effect on change in CPC levels (including CD34+/KDR+ (565cells/mL; -977 to 2106, p=0.45), CD34+/KDR+/CD45- (37.0cells/mL; -17.7 to 85.7, p=0.13), acLDL+/lectin+ (-43.1 cells/field, -247 to 161, p=0.67)) or change in endothelial function (0.27; -0.14 to 0.67, p=0.19) compared to sham therapy. CONCLUSIONS: Despite the improvement in OSA parameters and ablation of apnoeic events by CPAP, CPC counts and endothelial function in men with moderate-to-severe OSA were not significantly improved after 12weeks of therapeutic CPAP when compared to sham control.
International journal of cardiology 02/2013; · 7.08 Impact Factor
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ABSTRACT: Wound healing and repair are the most complex biological processes that occur in human life. After injury, multiple biological pathways become activated. Impaired wound healing, which occurs in diabetic patients for example, can lead to severe unfavorable outcomes such as amputation. There is, therefore, an increasing impetus to develop novel agents that promote wound repair. The testing of these has been limited to large animal models such as swine, which are often impractical. Mice represent the ideal preclinical model, as they are economical and amenable to genetic manipulation, which allows for mechanistic investigation. However, wound healing in a mouse is fundamentally different to that of humans as it primarily occurs via contraction. Our murine model overcomes this by incorporating a splint around the wound. By splinting the wound, the repair process is then dependent on epithelialization, cellular proliferation and angiogenesis, which closely mirror the biological processes of human wound healing. Whilst requiring consistency and care, this murine model does not involve complicated surgical techniques and allows for the robust testing of promising agents that may, for example, promote angiogenesis or inhibit inflammation. Furthermore, each mouse acts as its own control as two wounds are prepared, enabling the application of both the test compound and the vehicle control on the same animal. In conclusion, we demonstrate a practical, easy-to-learn, and robust model of wound healing, which is comparable to that of humans.
Journal of Visualized Experiments 01/2013;
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ABSTRACT: Flow recirculation zones and shear strain are associated with distinct pathogenic biological pathways relevant to thrombosis and atherogenesis. The interaction between stenosis severity and lesion eccentricity in determining the length of flow recirculation zones and peak shear strain in human coronary arteries in vivo is unclear. Computational fluid dynamics (CFD) simulations were performed under resting and hyperemic conditions on computer-generated models and the three-dimensional reconstructions (3DRs) of coronary arteriograms of 25 patients. Boundary conditions for 3DR simulations were obtained by direct measurements using a pressure-temperature sensor guidewire. In the computer-generated models, stenosis severity and lesion eccentricity were strongly associated with recirculation zone length and maximum shear strain. In the 3DRs, eccentricity increased recirculation zone length and shear strain when comparing lesions of the same stenosis severity. However, across the whole population of coronary lesions, eccentricity did not correlate with recirculation zone length or shear strain (P= ns for both), whereas stenosis severity correlated strongly with both parameters (r=0.97, P<0.001 and r=0.96, P<0.001 respectively). Non-linear regression analyses demonstrated that the relationship between stenosis severity and peak shear was exponential, whereas the relationship between stenosis severity and recirculation zone length was sigmoidal, with an apparent threshold effect, demonstrating a steep increase in recirculation zone length between 40% and 60% area stenosis. Increasing stenosis severity and lesion eccentricity can both increase flow recirculation and shear strain in human coronary arteries. Flow recirculation is much more sensitive to mild changes in the severity of intermediate stenoses than is peak shear.
AJP Heart and Circulatory Physiology 12/2012; · 3.71 Impact Factor
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Jamie Morton,
Sophia Zoungas,
Qiang Li,
Anushka A Patel,
John Chalmers,
Mark Woodward,
David S Celermajer,
Joline W J Beulens,
Ronald P Stolk,
Paul Glasziou, Martin K C Ng
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ABSTRACT: OBJECTIVE Although low HDL cholesterol (HDL-C) is an established risk factor for atherosclerosis, data on HDL-C and the risk of microvascular disease are limited. We tested the association between HDL-C and microvascular disease in a cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 11,140 patients with type 2 diabetes and at least one additional vascular risk factor were followed a median of 5 years. Cox proportional hazards models were used to assess the association between baseline HDL-C and the development of new or worsening microvascular disease, defined prospectively as a composite of renal and retinal events. RESULTS The mean baseline HDL-C level was 1.3 mmol/L (SD 0.45 mmol/L [range 0.1-4.0]). During follow-up, 32% of patients developed new or worsening microvascular disease, with 28% experiencing a renal event and 6% a retinal event. Compared with patients in the highest third, those in the lowest third had a 17% higher risk of microvascular disease (adjusted hazard ratio 1.17 [95% CI 1.06-1.28], P = 0.001) after adjustment for potential confounders and regression dilution. This was driven by a 19% higher risk of renal events (1.19 [1.08-1.32], P = 0.0005). There was no association between thirds of HDL-C and retinal events (1.01 [0.82-1.25], P = 0.9). CONCLUSIONS In patients with type 2 diabetes, HDL-C level is an independent risk factor for the development of microvascular disease affecting the kidney but not the retina.
Diabetes care 08/2012; 35(11):2201-2206. · 8.09 Impact Factor
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Anna Waterhouse,
Steven G Wise,
Yongbai Yin,
Buchu Wu,
Barbara James,
Hala Zreiqat,
David R McKenzie,
Shisan Bao,
Anthony S Weiss, Martin K C Ng,
Marcela M M Bilek
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ABSTRACT: Bare metal and drug-eluting coronary stents suffer an inherent lack of vascular cell and blood compatibility resulting in adverse patient responses. We have developed a plasma-activated coating (PAC) for metallic coronary stents that is durable, withstands crimping and expansion, has low thrombogenicity and can covalently bind proteins, linker-free. This has been shown to enhance endothelial cell interactions in vitro and has the potential to promote biointegration of stents. Using the rabbit denuded iliac artery model, we show for the first time that PAC is a feasible coating for coronary stents in vivo. The coating integrity of PAC was maintained following implantation and expansion. The rate of endothelialization, strut coverage, neointimal response and the initial immune response were equivalent to bare metal stents. Furthermore, the initial thrombogenicity caused by the PAC stents showed a reduced trend compared to bare metal stents. This work demonstrates a robust, durable, non-cytotoxic plasma-based coating technology that has the ability to covalently immobilize bioactive molecules for surface modification of coronary stents. Improvements in the clinical performance of implantable cardiovascular devices could be achieved by the immobilization of proteins or peptides that trigger desirable cellular responses.
Biomaterials 08/2012; 33(32):7984-92. · 7.40 Impact Factor
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ABSTRACT: Periprocedural myocardial infarction (MI) occurs in a significant proportion of patients undergoing percutaneous coronary intervention (PCI) and portends poor outcomes. Currently, no clinically applicable method predicts periprocedural MI in the cardiac catheterization laboratory before it occurs. We hypothesized that impaired baseline coronary microcirculatory reserve, which reduces the ability to tolerate ischemic insults, is a risk for periprocedural MI and that the index of microcirculatory resistance (IMR) measured during PCI can predict occurrence of periprocedural MI.
Consecutive patients undergoing elective PCI of a single lesion in the left anterior descending coronary artery were recruited. A pressure-temperature sensor wire was used to measure IMR before PCI. Of the 50 patients studied, 10 had periprocedural MI. From binary logistic regression analyses of all clinical, procedural, and physiological parameters, univariable predictors of periprocedural MI were pre-PCI IMR (P=0.003) and the number of stents used (P=0.039). Pre-PCI IMR was the only independent predictor in bivariable regression analyses performed by adjusting for each available covariate one at a time (all P≤0.02). Pre-PCI IMR ≥27 U had 80.0% sensitivity and 85.0% specificity for predicting periprocedural MI (C statistic, 0.80; P=0.003). Pre-PCI IMR ≥27 U was independently associated with a 23-fold risk of developing periprocedural MI (odds ratio, 22.7; 95% CI, 3.8-133.9).
These data suggest that the status of the coronary microcirculation plays a role in determining susceptibility toward periprocedural MI at the time of elective PCI. The IMR can predict subsequent risk of developing myocardial necrosis and may guide adjunctive prevention strategies.
Circulation Cardiovascular Interventions 08/2012; 5(4):515-22. · 6.06 Impact Factor
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ABSTRACT: Recent studies show that coronary microcirculatory impairment is an independent predictor of poor outcomes in patients with cardiovascular disease. However, controversy exists over whether microcirculatory resistance, a measure of coronary microcirculatory status, is dependent on epicardial stenosis severity. Previous studies demonstrating that microcirculatory resistance is dependent on epicardial stenosis severity have not accounted for collateral flow in their measurement of microcirculatory resistance. We investigated whether the index of microcirculatory resistance is independent of epicardial stenosis by comparing the index of microcirculatory resistance (IMR) levels in patients before and after percutaneous coronary intervention (PCI).
Consecutive patients undergoing elective PCI of the left anterior descending artery were recruited. Patients who developed periprocedural myocardial infarction were excluded. A pressure-temperature sensor wire was used to measure the apparent IMR (IMR(app)), which does not adjust for collateral flow, and the true IMR (IMR(true)), which incorporates wedge pressure measurement to account for collateral flow, before and after PCI. In 43 patients, there was no difference between pre- and post-PCI IMR(true) (mean difference=0.8±11.7, P=0.675). IMR(app) was higher pre-PCI compared with post-PCI (mean difference=10.0±14.5, P<0.001). IMR(app) was higher than IMR(true) (mean difference=9.3±14.2, P<0.001), and the difference between the IMR(app) and IMR(true) became greater with decreasing fractional flow reserve and increasing coronary wedge pressure. Pre-PCI fractional flow reserve correlated modestly with IMR(app) (r=-0.33, P=0.03), but not IMR(true) (r=0.26, P=0.10).
Coronary microcirculatory resistance is independent of functional epicardial stenosis severity when collateral flow is taken into account.
Circulation Cardiovascular Interventions 02/2012; 5(1):103-8, S1-2. · 6.06 Impact Factor
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ABSTRACT: Although not a definitive treatment, percutaneous coronary intervention offers a palliative benefit to patients with cardiac allograft vasculopathy. Given the superior outcomes with drug-eluting stents (DESs) over bare metal stents (BMSs) in native coronary artery disease, similar improvements might be expected in transplant patients; however, the results have been mixed. Consecutive cardiac transplantation recipients at a single center receiving a stent for de novo cardiac allograft vasculopathy from 1997 to 2009 were retrospectively analyzed according to receipt of a DES versus a BMS. The angiographic and clinical outcomes were subsequently evaluated at 1 year. The baseline clinical and procedural characteristics were similar among those receiving DESs (n = 18) and BMSs (n = 16). Quantitative coronary angiography revealed no difference in the reference diameter, lesion length, or pre-/postprocedural minimal luminal diameter. At the 12-month angiographic follow-up visit, the mean lumen loss was significantly lower in the DES group than in the BMS group (0.19 ± 0.73 mm vs 0.76 ± 0.97 mm, p = 0.02). The DES group also had a lower rate of in-stent restenosis (12.5% vs 33%, p = 0.18), as well as a significantly lower rate of target lesion revascularization (0% vs 19%, p = 0.03). At 1 year, DESs were associated with a lower composite rate of cardiac death and nonfatal myocardial infarction (12% vs 38%, p = 0.04). In conclusion, DESs are safe and effective in the suppression of neointimal hyperplasia after percutaneous coronary intervention for cardiac allograft vasculopathy, resulting in significantly lower rates of late lumen loss and target lesion revascularization, as well as a reduced combined rate of cardiac death and nonfatal myocardial infarction.
The American journal of cardiology 06/2011; 108(5):665-8. · 3.58 Impact Factor
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ABSTRACT: Cardiovascular disease remains the leading cause of death worldwide. Despite progress in management, there remain a significant number of patients who are not eligible for current treatment options. Traditionally, HO-1 (haem oxygenase-1), one of two isoenzymes that initiate haem catabolism, was thought to only play a metabolic role. However, HO-1 is now recognized to have additional protective activities in states of heightened noxious stimuli or stress such as acute coronary syndromes. The present review article provides an overview of the mode of action of HO-1 in vascular protection, with particular emphasis on its atheroprotective, anti-inflammatory and antioxidative properties, as well as its role in vascular repair. Furthermore, we present evidence for the protective effects of HO-1 in CVD (cardiovascular disease) in both animal and human studies. Given its potential in vascular protection and repair, strategies aimed at inducing HO-1 emerge as a novel and alternative therapeutic target in the management of CVD.
Clinical Science 03/2011; 120(12):493-504. · 4.61 Impact Factor
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ABSTRACT: We investigated whether three-dimensional (3D) and two-dimensional quantitative coronary angiography (2D-QCA) measurements differed in their accuracy in predicting reduced fractional flow reserve (FFR), and how this varied with stenosis severity and the FFR cut-off used.
Three-dimensional and 2D-QCA were compared in their measurements of minimum luminal area (MLA), percentage area stenosis, lesion length, minimum luminal diameter (MLD) and percentage diameter stenosis, and in their prediction of functionally significant FFR. In total, 63 target lesions were interrogated in 63 patients undergoing elective percutaneous coronary intervention. Of all measurements of lesion severity obtained by 3D-QCA, MLA best correlated with FFR (R = 0.63, P < 0.001), and was the most accurate predictor of FFR < 0.75 (C statistic 0.86, P < 0.001). Of 2D-QCA measurements, MLD correlated best with FFR (R = 0.58, P < 0.001), and best predicted FFR < 0.75 (C statistic 0.80, P < 0.001). Overall, 3D-QCA showed a non-significant trend towards more accurate prediction of FFR than 2D-QCA, especially in intermediate lesions. The relationship between FFR and apparent stenosis severity was found to be curvilinear. Both 3D- and 2D-QCA were less accurate in intermediate lesions, and in predicting FFR ≤ 0.80 than in predicting FFR <0.75.
The accuracy of QCA in predicting functionally significant FFR is limited and is dependent on FFR cut-off used and lesion severity. Where FFR is not available or contraindicated, 3D-QCA may assist in the evaluation of coronary lesions of intermediate severity.
European Heart Journal 02/2011; 32(3):345-53. · 10.48 Impact Factor
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ABSTRACT: Small-diameter synthetic vascular graft materials fail to match the patency of human tissue conduits used in vascular bypass surgery. The foreign surface retards endothelialization and is highly thrombogenic, while the mismatch in mechanical properties induces intimal hyperplasia. Using recombinant human tropoelastin, we have developed a synthetic vascular conduit for small-diameter applications. We show that tropoelastin enhances endothelial cell attachment (threefold vs. control) and proliferation by 54.7 ± 1.1% (3 days vs. control). Tropoelastin, when presented as a monomer and when cross-linked into synthetic elastin for biomaterials applications, had low thrombogenicity. Activation of the intrinsic pathway of coagulation, measured by plasma clotting time, was reduced for tropoelastin (60.4 ± 8.2% vs. control). Platelet attachment was also reduced compared to collagen. Reductions in platelet interactions were mirrored on cross-linked synthetic elastin scaffolds. Tropoelastin was subsequently incorporated into a synthetic elastin/polycaprolactone conduit with mechanical properties optimized to mimic the human internal mammary artery, including permeability, compliance, elastic modulus and burst pressure. Further, this multilayered conduit presented a synthetic elastin internal lamina to circulating blood and demonstrated suturability and mechanical durability in a small scale rabbit carotid interposition model.
Acta biomaterialia 01/2011; 7(1):295-303. · 3.98 Impact Factor
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ABSTRACT: Surface-induced thrombosis is a significant issue for artificial blood-contacting materials used in the treatment of cardiovascular diseases. The development of biomaterials and tissue-engineered constructs that mimic the vasculature represents a way to overcome this problem. Elastin is an extracellular matrix macromolecule that imparts arterial elasticity where it comprises up to 50% of the nonhydrated mass of the vessel. In addition to its critical role in maintaining vessel integrity and elastic properties under pulsatile flow, elastin plays an important role in signaling and regulating luminal endothelial cells and smooth muscle cells in the arterial wall. Despite its well-established significance in the vasculature and its growing use as a biomaterial in tissue engineering, the hemocompatibility of elastin is often overlooked. Past studies pointing to the potential of arterial elastin and decellularized elastin as nonthrombogenic materials have begun to be realized, with elastin scaffolds and coatings displaying increased hemocomptibility. This review explores the mechanisms of elastin's nonthrombogenicity and highlights the current problems limiting its wider application as a biomaterial. We discuss the benefits of constructing biomaterials encompassing the relevant mechanical and biological features of elastin to provide enhanced hemocompatibility to biomaterials.
Tissue Engineering Part B Reviews 01/2011; 17(2):93-9. · 4.64 Impact Factor
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ABSTRACT: Aims We investigated whether three-dimensional (3D) and two-dimensional quantitative coronary angiography (2D-QCA) measurements differed in their accuracy in predicting reduced fractional flow reserve (FFR), and how this varied with stenosis severity and the FFR cut-off used.Methods and results Three-dimensional and 2D-QCA were compared in their measurements of minimum luminal area (MLA), percentage area stenosis, lesion length, minimum luminal diameter (MLD) and percentage diameter stenosis, and in their prediction of functionally significant FFR. In total, 63 target lesions were interrogated in 63 patients undergoing elective percutaneous coronary intervention. Of all measurements of lesion severity obtained by 3D-QCA, MLA best correlated with FFR (R = 0.63, P< 0.001), and was the most accurate predictor of FFR <0.75 (C statistic 0.86, P< 0.001). Of 2D-QCA measurements, MLD correlated best with FFR (R = 0.58, P< 0.001), and best predicted FFR <0.75 (C statistic 0.80, P<0.001). Overall, 3D-QCA showed a non-significant trend towards more accurate prediction of FFR than 2D-QCA, especially in intermediate lesions. The relationship between FFR and apparent stenosis severity was found to be curvilinear. Both 3D- and 2D-QCA were less accurate in intermediate lesions, and in predicting FFR ≤0.80 than in predicting FFR <0.75.Conclusions The accuracy of QCA in predicting functionally significant FFR is limited and is dependent on FFR cut-off used and lesion severity. Where FFR is not available or contraindicated, 3D-QCA may assist in the evaluation of coronary lesions of intermediate severity.
European Heart Journal. 01/2011; 32(3):345-353.
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Journal of The American College of Cardiology - J AMER COLL CARDIOL. 01/2011; 57(14).
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ABSTRACT: Current endovascular stents have sub-optimal biocompatibility reducing their clinical efficacy. We previously demonstrated a plasma-activated coating (PAC) that covalently bound recombinant human tropoelastin (TE), a major regulator of vascular cells in vivo, to enhance endothelial cell interactions. We sought to develop this coating to enhance its mechanical properties and hemocompatibility for application onto coronary stents. The plasma vapor composition was altered by incorporating argon, nitrogen, hydrogen or oxygen to modulate coating properties. Coatings were characterized for 1) surface properties, 2) mechanical durability, 3) covalent protein binding, 4) endothelial cell interactions and 5) thrombogenicity. The N(2)/Ar PAC had optimal mechanical properties and did not delaminate after stent expansion. The N(2)/Ar PAC was mildly hydrophilic and covalently bound the highest proportion of TE, which enhanced endothelial cell proliferation. Acute thrombogenicity was assessed in a modified Chandler loop using human blood. Strikingly, the N(2)/Ar PAC alone reduced thrombus weight by ten-fold compared to 316L SS, a finding unaltered with immobilized TE. Serum soluble P-selectin was reduced on N(2)/Ar PAC and N(2)/Ar PAC + TE (p < 0.05), consistent with reduced platelet activation. We have demonstrated a coating for metal alloys with multifaceted biocompatibility that resists delamination and is non-thrombogenic, with implications for improving coronary stent efficacy.
Biomaterials 11/2010; 31(32):8332-40. · 7.40 Impact Factor
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ABSTRACT: Although there have been a multitude of studies, the mechanisms of angiogenesis remain incompletely understood. Increasing evidence suggests that cellular redox homeostasis is an important regulator of angiogenesis. The thioredoxin (TRX) system functions as an endogenous antioxidant that can exert influence over endothelial cell function via modulation of cellular redox status. It has become apparent that the cytosolic TRX1 isoform participates in both canonical and novel angiogenic signaling pathways and may represent an avenue for therapeutic exploitation. Recent studies have further identified a role for the mitochondrial isoform TRX2 in ischemia-induced angiogenesis. TRX-interacting protein (TXNIP) is the endogenous inhibitor of TRX redox activity that has been implicated in growth factor-mediated angiogenesis. As TXNIP is strongly induced by glucose, this molecule could be of consequence to disordered angiogenesis manifest in diabetes mellitus. This review will focus on data implicating the TRX system in endothelial cell homeostasis and angiogenesis.
Arteriosclerosis Thrombosis and Vascular Biology 11/2010; 30(11):2089-98. · 6.37 Impact Factor
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ABSTRACT: To modify blood-contacting stainless surfaces by covalently coating them with a serum-protease resistant form of tropoelastin (TE). To demonstrate that the modified TE retains an exposed, cell-adhesive C-terminus that persists in the presence of blood plasma proteases.
Recombinant human TE and a point mutant variant (R515A) of TE were labeled with (125)Iodine and immobilized on plasma-activated stainless steel (PAC) surfaces. Covalent attachment was confirmed using rigorous detergent washing. As kallikrein and thrombin dominate the serum degradation of tropoelastin, supraphysiological levels of these proteases were incubated with covalently bound TE and R515A, then assayed for protein levels by radioactivity detection. Persistence of the C-terminus was assessed by ELISA.
TE was significantly retained covalently on PAC surfaces at 88 ± 5% and 71 ± 5% after treatment with kallikrein and thrombin, respectively. Retention of R515A was 100 ± 1.3% and 87 ± 2.3% after treatment with kallikrein and thrombin, respectively, representing significant improvements over TE. The functionally important C-terminus was cleaved in wild-type TE but retained by R515A.
Protein persists in the presence of human kallikrein and thrombin when covalently immobilized on metal substrata. R515A displays enhanced protease resistance and retains the C-terminus presenting a protein interface that is viable for blood-contacting applications.
Pharmaceutical Research 11/2010; 28(6):1415-21. · 4.09 Impact Factor
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ABSTRACT: Despite increasing evidence implicating the pulmonary microcirculation in the pathogenesis of lung conditions such as pulmonary vascular disease, there remain few methods for its evaluation in vivo. We recently demonstrated that the novel index of Doppler-derived pulmonary flow reserve (PFR(dopp)=maximal hyperaemic/basal pulmonary flow) could be reliably measured in high primates. Noting that the microvasculature is the chief regulator of pulmonary blood flow, we hypothesised that PFR(dopp) may detect microcirculatory loss. We therefore studied the relationship between PFR(dopp) and experimentally induced pulmonary microvascular obstruction using microspheres in higher primates.
Under ketamine anaesthesia, Doppler sensor-guidewires were placed in the segmental pulmonary artery of three adult baboons. Doppler flow velocity and haemodynamics were recorded at rest and during hyperaemia [as induced by intrapulmonary artery adenosine (200 μg/kg/min)]. Serial PFR(dopp) evaluations were made after cumulative intrapulmonary artery ceramic microspheres administration.
Cumulative microsphere administration progressively reduced PFR(dopp) (1.54 ± 0.26, 1.48 ± 0.20, 1.12 ± 0.04 and 1.18 ± 0.09; baseline, 10(4), 10(5) and 10(6) microspheres boluses; p<0.02) without affecting pulmonary artery pressure, systemic artery pressure or heart rate.
Doppler-derived PFR can detect partial, progressive pulmonary microvascular obstruction in higher primates. PFR(dopp) may thus have a potential role in the assessment of the pulmonary microcirculation in vivo.
Heart Lung & Circulation 10/2010; 19(10):592-4. · 1.20 Impact Factor
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Andy S C Yong,
Gabrielle J Pennings,
Michael Chang,
Afiqah Hamzah,
Tommy Chung,
Miao Qi,
David Brieger,
Masud Behnia,
Steven A Krilis, Martin K C Ng,
Harry C Lowe,
Leonard Kritharides
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ABSTRACT: Recent in vitro studies have shown that shear stress can cause platelet activation by agonist-independent pathways. However, no studies have assessed the extent of shear-induced platelet activation within human coronary arteries. We sampled blood from the coronary arteries proximal and distal to coronary lesions and from the coronary sinus in humans with stable coronary disease who were taking both aspirin and clopidogrel. A novel, computationally based technique for estimating shear stress from 3-dimensional coronary angiographic images of these arteries was developed, and the effect of stenosis severity and calculated shear stress on in vivo platelet and related leukocyte activation pathways were determined. We provide evidence of intracoronary up-regulation of platelet P-selectin, platelet-monocyte aggregation, and monocyte CD11b without platelet glycoprotein IIb-IIIa activation or soluble P-selectin up-regulation. This correlates with intracoronary stenosis severity and calculated shear stress and occurs despite the concurrent use of aspirin and clopidogrel. Our results show for the first time shear-related platelet and monocyte activation in human coronary arteries and suggest this as a potential therapeutic target that is resistant to conventional antiplatelet agents.
Blood 09/2010; 117(1):11-20. · 9.90 Impact Factor
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ABSTRACT: The endothelium is a dynamic interface between the blood vessel and the circulating blood that plays a pivotal role in vascular homeostasis. As such, studies on sex steroid regulation of endothelial function are critical to understanding the role of sex steroids in cardiovascular health and disease. The classical model of steroid action involves liganded steroid receptors binding to specific response elements on target genes to regulate gene transcription. In whole organisms, the time lag between steroid administration and observable effects produced by newly synthesized protein is typically in the order of hours to days. And yet, some effects of steroids, such as vasodilatation, occur within seconds to minutes of steroid administration. Studies in multiple cell types have also shown that steroids can cause the rapid initiation of multiple signaling cascades and second messenger systems, prompting investigations into alternate, transcription independent mechanisms of steroid action. Studies of the endothelium over the past two decades have revealed fundamental mechanisms in rapid sex steroid signaling. In particular, endothelium-dependent vasodilatation by estradiol-induced activation of endothelial nitric oxide synthase has proven to be an uniquely informative model to study sex steroid signaling via classical sex steroid receptors localized to the cell membrane. Despite the complexity of feedback and cross talk between rapid sex steroid signaling and other modes of steroid action, recent studies in this field are facilitating the development of steroidal drugs that selectively target the ability of sex steroids to initiate signaling cascades.
Endocrinology 06/2010; 151(6):2411-22. · 4.46 Impact Factor
