Impact of smoking on health-related quality of Life after percutaneous coronary intervention treated with drug-eluting stents: a longitudinal observational study.

BACKGROUND: Smoking has been shown to reduce health-related quality of life (HRQOL) in patients with coronary artery disease (CAD) undergoing percutanous coronary intervention (PCI) either by means of balloon angioplasty or with the use of bare-metal stents (BMS). Drug-eluting stents (DES) have now been widely used and are related to substantial reduction of restenosis and significantly improved HRQOL compared with BMS. This study aimed to evaluate the effects of smoking on HRQOL in patients after PCI in DES era. METHODS: A cohort of 649 patients admitted for CAD and treated with drug-eluting stents were included in this prospective, observational study. Patients were classified as non-smokers (n = 351, 54.1%), quitters (n = 126, 19,4%), or persistent smokers (n = 172, 26.5%) according to their smoking status at the time they first admitted to hospital and during the first year of follow-up. Each patient was prospectively interviewed at baseline, 6 months and 1 year following PCI. HRQOL was assessed with the use of Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). RESULTS: For the overall population, HRQOL scores at 1-year follow-up were significantly higher than baseline for all 8 domains. At 1-year follow-up, the HRQOL scores in persistent smokers were still lower than that in non-smokers in 6 domains except for bodily pain and mental health, and than that in quitters in 5 domains except for bodily pain, role emotional and mental health. There were no significant differences with regard to the scores between non-smokers and quitters except role emotional for which non-smokers had higher scores. After adjustment, persistent smokers demonstrated significantly less improvements in HRQOL than non-smokers in 6 domains except for bodily pain and social functioning and significantly less improvement than quitters for general health. Improvements of quitters were comparable to that of non-smokers in all domains. Multivariate linear regression analyses showed persistent smoking was an independent risk factor for PCS and MCS improvements. CONCLUSIONS: Persistent smoking substantially diminishes the potential quality-of-life benefits of DES. Efforts should be made to promote smoking cessation after DES implantation which could greatly improve the health quality outcomes.

Protease-activated receptor 1 and 2 contribute to angiotensin II-induced activation of adventitial fibroblasts from rat aorta.

Adventitial fibroblasts (AFs) can be activated by angiotensin II (Ang II) and exert pro-fibrotic and pro-inflammatory effects in vascular remodeling. Protease-activated receptor (PAR) 1 and 2 play a significant role in fibrogenic and inflammatory diseases. The present study hypothesized that PAR1 and PAR2 are involved in Ang II-induced AF activation and contribute to adventitial remodeling. We found that direct activation of PAR1 and PAR2 with PAR1-AP and PAR2-AP led to AF activation, including proliferation and differentiation of AFs, extracellular matrix synthesis, as well as production of pro-fibrotic cytokine TGF-ß and pro-inflammatory cytokines IL-6 and MCP-1. Furthermore, PAR1 and PAR2 mediated Ang II-induced AF activation, since both PAR1 and PAR2 antagonists inhibited Ang II-induced proliferation, migration, differentiation, extracellular matrix synthesis and production of pro-fibrotic and pro-inflammatory cytokines in AFs. Finally, mechanistic study showed that Ang II, via Ang II type I receptor (AT1R), upregulated both PAR1 and PAR2 expression, and transactivated PAR1 and PAR2, as denoted by internalization of both proteins. In conclusion, our results suggest that PAR1 and PAR2 play a critical role in Ang II-induced AF activation, and this may contribute to adventitia-related pathological changes.

Perivascular adipose tissue-derived complement 3 is required for adventitial fibroblast functions and adventitial remodeling in deoxycorticosterone acetate-salt hypertensive rats.

OBJECTIVE: To examine the role of perivascular adipose tissue (PVAT)-derived factors in the regulation of adventitial fibroblast (AF) function in vitro and in vivo. METHODS AND RESULTS: PVAT is an active component of blood vessels. Bioactive substances released from PVAT play regulatory roles in vascular function. However, their effects on vascular AFs remain unclear. PVAT-conditioned medium stimulated AF migration using a transwell technique, and differentiation was evaluated by α-smooth muscle-actin induction. We identified the secretome of PVAT by liquid chromatography-tandem mass spectrometry. One of the major secretory proteins in PVAT is complement 3 (C3). The C3 antagonist and neutralizing antibody attenuated PVAT-conditioned medium-induced AF migration and differentiation. Similar to PVAT-conditioned medium, C3 recombinant protein stimulated AF migration and differentiation. We demonstrated that the effects of PVAT-derived C3 were mediated by the c-Jun N-terminal kinase pathway. Moreover, we found morphological changes in perivascular adipocytes and increased expression of C3 in PVAT that was tightly associated with adventitial thickening and myofibroblast clustering around PVAT in deoxycorticosterone acetate-salt hypertensive rats. CONCLUSIONS: PVAT-derived C3 stimulated AF migration and differentiation via the c-Jun N-terminal kinase pathway. PVAT-derived C3 may contribute to adventitial remodeling in a deoxycorticosterone acetate-salt hypertensive model.

Effects of Smoking Cessation with Nicotine Replacement Therapy on Vascular Endothelial Function, Arterial Stiffness, and Inflammation Response in Healthy Smokers.

The effects of nicotine replacement therapy (NRT)-aided smoking cessation on vascular function are not fully clarified. We investigated 100 healthy smokers who were motivated to quit and received NRT for a 3-month period. Vascular endothelial function (measured by reactive hyperemia-peripheral arterial tonometry [RH-PAT]), arterial stiffness (measured by augmentation index [AI] and brachial-ankle pulse wave velocity [baPWV]), and systemic inflammation markers (including serum soluble intercellular adhesion molecule-1 [sICAM-1] and interleukin-1ß [IL-1ß]) were assessed at baseline and 3 and 12 months of follow-up. After 3 months of intervention, endothelial function, arterial stiffness, and inflammatory markers significantly improved (RH-PAT increased, AI and baPWV decreased, sICAM-1 and IL-1ß decreased, all P < .05) for the participants who abstained from smoking completely, but for those who did not abstained completely, RH-PAT, AI, baPWV, and IL-1ß remained unchanged. At 12 months follow-up, endothelial function (RH-PAT), arterial stiffness (AI and baPWV), and inflammatory markers (sICAM-1 and IL-1ß) were further improved in participants who abstained from smoking (P < .001), while the above parameters deteriorated in continued smokers (P < .05). In conclusion, vascular dysfunction can be reversible after NRT-aided smoking cessation in healthy smokers and vascular function could be further damaged if they continue smoking.

Characterisation of a soft elastomer poly(glycerol sebacate) designed to match the mechanical properties of myocardial tissue.

The myocardial tissue lacks significant intrinsic regenerative capability to replace the lost cells. Therefore, the heart is a major target of research within the field of tissue engineering, which aims to replace infarcted myocardium and enhance cardiac function. The primary objective of this work was to develop a biocompatible, degradable and superelastic heart patch from poly(glycerol sebacate) (PGS). PGS was synthesised at 110, 120 and 130 degrees C by polycondensation of glycerol and sebacic acid with a mole ratio of 1:1. The investigation was focused on the mechanical and biodegrading behaviours of the developed PGS. PGS materials synthesised at 110, 120 and 130 degrees C have Young's moduli of 0.056, 0.22 and 1.2 MPa, respectively, which satisfy the mechanical requirements on the materials applied for the heart patch and 3D myocardial tissue engineering construction. Degradation assessment in phosphate buffered saline and Knockout DMEM culture medium has demonstrated that the PGS has a wide range of degradability, from being degradable in a couple of weeks to being nearly inert. The matching of physical characteristics to those of the heart, the ability to fine tune degradation rates in biologically relevant media and initial data showing biocompatibility indicate that this material has promise for cardiac tissue engineering applications.

Surface functionalization of Bioglass-derived porous scaffolds.

Like standard tissue culture plates, tissue engineering scaffolds can be chemically treated to couple proteins without losing the conformation and thus biological function of the proteins; a process called surface functionalization. In this work, the surface of novel 45S5 Bioglass-derived foam-like scaffolds, which exhibit adequate mechanical stability and tailorable bioresorbability, have been modified by applying 3-aminopropyl-triethoxysilane. The efficiency and stability of the surface modification were satisfactorily and quantitatively assessed by X-ray photoemission spectroscopy. It was also found that treatment in buffered (pH 8) water solution at 80 degrees C for 4h, applied during the surface functionalization procedure, accelerated the bioreactive kinetics of the scaffolds, i.e. the transition of the relatively bioinert but mechanically competent crystalline structure of the struts to a biodegradable but mechanically weak amorphous network during immersion in simulated body fluid. Thus the aqueous heat treatment is confirmed to be an important factor that must be considered in the design of these Bioglass-derived glass-ceramic scaffolds. Possible mechanisms responsible for the accelerated bioreactivity are proposed.

Low fT3 is associated with diminished health-related quality of life in patients with acute coronary syndrome treated with drug-eluting stent: a longitudinal observational study.

Acute coronary syndrome (ACS) patients with low triiodothyronine (T3) syndrome characterized by low free T3 (fT3) levels with normal thyroxine (T4) and thyroid-stimulating hormone (TSH) have a higher rate of death. The impact of fT3 on Health related quality of life (HRQOL) in patients with ACS is still unknown. 528 ACS patients treated with drug-eluting stent (DES) were included in this prospective, observational study. Patients were classified into low fT3 group (n=126) and normal fT3 group (n=402) according to serum fT3 level. Every patient was prospectively interviewed at baseline and 1 year following percutaneous coronary intervention (PCI). HRQOL was assessed with the use of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Low fT3 patients had poorer HRQOL than normal fT3 patients both at baseline and 1-year follow-up (all p<0.05). During 1-year follow-up, HRQOL scores for all patients were significantly higher than baseline. Low fT3 patients had lesser gains in physical functioning, bodily pain, general health, vitality, social functioning and role emotional (all p<0.05). Generally, low fT3 patients demonstrated less improvement in Physical Component Score (PCS) (p=0.008) and Mental Component Score (MCS) (p=0.001). The percentage of patients reaching MCID for PCS and MCS was lower in low fT3 group than that in normal fT3 group (p<0.001). Multivariate linear regression analyses showed that low level of fT3 was an independent risk factor for PCS and MCS improvements. In conclusion, a low fT3 level is a predictor of worse HRQOL improvement in ACS patients treated with DES.

Long-term prescription of beta-blocker delays the progression of heart failure with preserved ejection fraction in patients with hypertension: A retrospective observational cohort study.

BACKGROUND: Hypertension complicated with left ventricular hypertrophy (LVH) and diastolic dysfunction is one of the most common risks for heart failure with preserved ejection fraction (HFpEF). This study was designed to evaluate the influences of long-term beta-blocker prescription in these patients. METHODS: This retrospective analysis included eligible patients diagnosed with hypertension, LVH (left ventricular (LV) mass index >125 g/m(2) for men and >110 g/m(2) for women) and suspected diastolic dysfunction (E/E' ratio between 8 and 15) and without clinical signs or symptoms of heart failure in our hospital medical record database (January 2005-December 2009). A total of eligible 1498 patients were enrolled, of whom 803 received beta-blocker prescription and 695 accepted non-beta-blocker therapy. RESULTS: With a median follow-up of 7.2 years, the new-onset symptomatic HFpEF occurred in 48 of 803 patients in the beta-blocker group (6.0%) and 92 of 695 patients in the non-beta-blocker group (13.2%, p < 0.001). Beta-blockers also generated more prominent improvement in diastolic function and LVH. And Cox proportional hazards model revealed that beta-blocker (hazard ratio (HR) 0.327, 95% confidence interval (CI): 0.121-0.540, p = 0.009) or angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) exposure (HR 0.422, 95% CI: 0.210-0.699, p = 0.015) was associated with a reduced risk of new onset of symptomatic HFpEF, and the elevation of LVMI (HR 1.210, 95% CI: 1.069-1.362, p = 0.040) or E/E' (HR 1.398, 95% CI: 1.306-1.541, p = 0.032) was associated with a high risk of new onset of symptomatic HFpEF. CONCLUSIONS: Long-term beta-blocker exposure was associated with protective effects in terms of the incidence of new-onset symptomatic HFpEF, LV diastolic dysfunction and LVH, which might be beneficial for the delay of HFpEF progression.

Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation.

Vascularization of an artificial graft represents one of the most significant challenges facing the field of bone tissue engineering. Over the past decade, strategies to vascularize artificial scaffolds have been intensively evaluated using osteoinductive calcium phosphate (CaP) biomaterials in animal models. In this work, we observed that CaP-based biomaterials implanted into rat calvarial defects showed remarkably accelerated formation and mineralization of new woven bone in defects in the initial stages, at a rate of ∼60 µm/day (0.8 mg/day), which was considerably higher than normal bone growth rates (several µm/day, 0.1 mg/day) in implant-free controls of the same age. Surprisingly, we also observed histological evidence of primary osteon formation, indicated by blood vessels in early-region fibrous tissue, which was encapsulated by lamellar osteocyte structures. These were later fully replaced by compact bone, indicating complete regeneration of calvarial bone. Thus, the CaP biomaterial used here is not only osteoinductive, but vasculogenic, and it may have contributed to the bone regeneration, despite an absence of osteons in normal rat calvaria. Further investigation will involve how this strategy can regulate formation of vascularized cortical bone such as by control of degradation rate, and use of models of long, dense bones, to more closely approximate repair of human cortical bone.

Anti-stiffness effect of apocynin in deoxycorticosterone acetate-salt hypertensive rats via inhibition of oxidative stress.

This study sought to determine if apocynin, a nicotinamide adenine dinucleotide phosphate oxidase inhibitor, would attenuate arterial stiffness in salt-sensitive hypertensive rats via structural and functional changes in conduit arteries. We showed that tail blood pressure was significantly higher in deoxycorticosterone acetate-salt-induced hypertensive (DSH) rats compared with the sham control group (P<0.01). Morphological analysis and biochemical assay showed that large arteries in DSH rats underwent significant remodeling including increased medial thickness in carotid arteries compared with the control rats (194.25±5.66 vs. 120.48±7.93 µm, P<0.05) and increased collagen deposition in thoracic aorta (1.03±0.09 vs. 0.85±0.04 mg cm(-1), P<0.05). These changes were associated with increases in reactive oxygen species (ROS) level and increased thoracic aortic stiffness compared with the control rats (6.21±0.79 m s(-1) vs. 4.64±0.59 m s(-1), P<0.01). Treatment with apocynin significantly prevented ROS increases and collagen deposition (0.84±0.04 vs. 1.03±0.09 mg cm(-1), P<0.05), and reduced arterial stiffness as shown by decreased pulse wave velocity in the thoracic aorta (5.31±0.88 vs. 6.21±0.79 m s(-1), P<0.01). Additionally, apocynin prevented carotid artery wall thickening (58.57±3.40 vs. 78.89±4.10 µm, P<0.05). In conclusion we have shown that increased ROS level is associated with increased aortic stiffness, and deposition of collagen in the aortic arterial wall in DSH rats. Apocynin prevented ROS increases and arterial stiffness in DSH rats. Antioxidant therapy may be a potential treatment of large arterial stiffness in salt-sensitive hypertension.

Fabrication and characterization of sol-gel derived 45S5 Bioglass®-ceramic scaffolds.

Although Bioglass® has existed for nearly half a century its ability to trigger bone formation and tuneable degradability is vastly superior to other bioceramics, such as SiO(2)-CaO bioactive glasses. The sol-gel process of producing glass foams is well established for SiO(2)-CaO compositions, but not yet established for 45S5 composites containing Na(2)O. In this work the sol-gel derived 45S5 Bioglass® has for the first time been foamed into highly porous three-dimensional scaffolds using a surfactant, combined with vigorous mechanical stirring and subsequent sintering at 1000°C for 2 h. It was found that the mechanical strength of the sintered sol-gel derived Bioglass® scaffolds was significantly improved, attributable to the small fraction of material on the pore walls. More importantly, the compressive strength of the three-dimensional scaffolds produced by this surfactant foaming method could be predicted using Gibson and Ashby's closed cell model of porous networks. A comparative experiment revealed that ion release from the sol-gel derived Bioglass® foams was faster than that of counterparts produced by the replication technique. In vitro evaluation using osteoblast-like cells demonstrated that the sol-gel derived 45S5 Bioglass foams supported the proliferation of viable cell populations on the surface of the scaffolds, although few cells were observed to migrate into the virtually closed pores within the foams. Further work should be focused on modifications of the reaction conditions or alternative foaming techniques to improve pore interconnection.

Manipulation of mechanical compliance of elastomeric PGS by incorporation of halloysite nanotubes for soft tissue engineering applications.

Poly (glycerol sebacate) (PGS) is a promising elastomer for use in soft tissue engineering. However, it is difficult to achieve with PGS a satisfactory balance of mechanical compliance and degradation rate that meet the requirements of soft tissue engineering. In this work, we have synthesised a new PGS nanocomposite system filled with halloysite nanotubes, and mechanical properties, as well as related chemical characters, of the nanocomposites were investigated. It was found that the addition of nanotubular halloysite did not compromise the extensibility of material, compared with the pure PGS counterpart; instead the elongation at rupture was increased from 110 (in the pure PGS) to 225% (in the 20 wt% composite). Second, Young's modulus and resilience of 3-5 wt% composites were ∼0.8 MPa and >94% respectively, remaining close to the level of pure PGS which is desired for applications in soft tissue engineering. Third, an important feature of the 1-5 wt% composites was their stable mechanical properties over an extended period, which could allow the provision of reliable mechanical support to damaged tissues during the lag phase of the healing process. Finally, the in vitro study indicated that the addition of halloysite slowed down the degradation rate of the composites. In conclusion, the good compliance, enhanced stretchability, stable mechanical behavior over an extended period, and reduced degradation rates make the 3-5 wt% composites promising candidates for application in soft tissue engineering.

In vitro enzymatic degradation of poly (glycerol sebacate)-based materials.

Enzymatic degradation is a major feature of polyester implants in vivo. An in vitro experimental protocol that can simulate and predict the in vivo enzymatic degradation kinetics of implants is of importance not only to our understanding of the scientific issue, but also to the well-being of animals. In this study, we explored the enzymatic degradation of PGS-based materials in vitro, in tissue culture medium or a buffer solution at the pH optima and under static or cyclic mechanical-loading conditions, in the presence of defined concentrations of an esterase. Surprisingly, it was found that the in vitro enzymatic degradation rates of the PGS-based materials were higher in the tissue culture medium than in the buffered solution at the optimum pH 8. The in vitro enzymatic degradation rate of PGS-based biomaterials crosslinked at 125°C for 2 days was approximately 0.6-0.9 mm/month in tissue culture medium, which falls within the range of in vivo degradation rates (0.2-1.5mm/month) of PGS crosslinked at similar conditions. Enzymatic degradation was also further enhanced in relation to mechanical deformation. Hence, in vitro enzymatic degradation of PGS materials conducted in tissue culture medium under appropriate enzymatic conditions can quantitatively capture the features of in vivo degradation of PGS-based materials and can be used to indicate effective strategies for tuning the degradation rates of this material system prior to animal model testing.

The mechanical characteristics and in vitro biocompatibility of poly(glycerol sebacate)-bioglass elastomeric composites.

Biodegradable elastomeric materials have gained much recent attention in the field of soft tissue engineering. Poly(glycerol sebacate) (PGS) is one of a new family of elastomers which are promising candidates used for soft tissue engineering. However, PGS has a limited range of mechanical properties and has drawbacks, such as cytotoxicity caused by the acidic degradation products of very soft PGS and degradation kinetics that are too fast in vivo to provide sufficient mechanical support to the tissue. However, the development of PGS/based elastomeric composites containing alkaline bioactive fillers could be a method for addressing these drawbacks and thus may pave the way towards wide clinical applications. In this study, we synthesized a new PGS composite system consisting of a micron-sized Bioglass filler. In addition to much improved cytocompatibility, the PGS/Bioglass composites demonstrated three remarkable mechanical properties. First, contrary to previous reports, the addition of microsized Bioglass increases the elongation at break from 160 to 550%, while enhancing the Young's modulus of the composites by up to a factor of four. Second, the modulus of the PGS/Bioglass composites drops abruptly in a physiological environment (culture medium), and the level of drop can be tuned such that the addition of Bioglass does not harden the composite in vivo and thus the desired compliance required for soft tissue engineering are maintained. Third, after the abrupt drop in modulus, the composites exhibited mechanical stability over an extended period. This latter observation is an important feature of the new composites, because they can provide reliable mechanical support to damaged tissues during the lag phase of the healing process. These mechanical properties, together with improved biocompatibility, make this family of composites better candidates than plastic and related composite biomaterials for the applications of tissue engineering.

A new sol-gel process for producing Na(2)O-containing bioactive glass ceramics.

The sol-gel process of producing SiO(2)-CaO bioactive glasses is well established, but problems remain with the poor mechanical properties of the amorphous form and the bioinertness of its crystalline counterpart. These properties may be improved by incorporating Na(2)O into bioactive glasses, which can result in the formation of a hard yet biodegradable crystalline phase from bioactive glasses when sintered. However, production of Na(2)O-containing bioactive glasses by sol-gel methods has proved to be difficult. This work reports a new sol-gel process for the production of Na(2)O-containing bioactive glass ceramics, potentially enabling their use as medical implantation materials. Fine powders of 45S5 (a Na(2)O-containing composition) glass ceramic have for the first time been successfully synthesized using the sol-gel technique in aqueous solution under ambient conditions, with the mean particle size being approximately 5 microm. A comparative study of sol-gel derived S70C30 (a Na(2)O-free composition) and 45S5 glass ceramic materials revealed that the latter possesses a number of features desirable in biomaterials used for bone tissue engineering, including (i) the crystalline phase Na(2)Ca(2)Si(3)O(9) that couples good mechanical strength with satisfactory biodegradability, (ii) formation of hydroxyapatite, which may promote good bone bonding and (iii) cytocompatibility. In contrast, the sol-gel derived S70C30 glass ceramic consisted of a virtually inert crystalline phase CaSiO(3). Moreover, amorphous S70C30 largely transited to CaCO(3) with minor hydroxyapatite when immersed in simulated body fluid under standard tissue culture conditions. In conclusion, sol-gel derived Na(2)O-containing glass ceramics have significant advantages over related Na(2)O-free materials, having a greatly improved combination of mechanical capability and biological absorbability.

Magnetic resonance imaging evaluation of remodeling by cardiac elastomeric tissue scaffold biomaterials in a rat model of myocardial infarction.

Grafting of elastomeric biomaterial scaffolds may offer a radical strategy for the prevention of heart failure after myocardial infarction by increasing efficacy of stem cell delivery as well as acting as mechanical restraint devices to constrain scar expansion. Biomaterials can be partially optimized in vitro, but their in vivo performance is most critical and should ideally be monitored serially and noninvasively. We used magnetic resonance imaging (MRI) to assess three scaffold materials with a range of structural moduli equal to or greater than myocardial tissue: poly(glycerol sebacate) (PGS), poly(ethyleneterephathalate)/dimer fatty acid (PED), and TiO(2)-reinforced PED (PED-TiO(2)). Patches, 1 cm in diameter, were grafted onto the hearts of infarcted rats, with biomaterial-free infarcted rat hearts used as controls. MRI was able to determine scaffold size and location on the heart and identified unexpectedly rapid in vivo degradation of the PGS compared with previous in vitro testing. PED patches did not withstand in vivo attachment, but the more rigid PED-TiO(2) material was detrimental to heart function, increasing chamber and scar sizes and reducing ejection fractions compared with controls. In contrast, the mechanically compatible PGS scaffold successfully reduced hypertrophy, giving it potential for limiting excessive postinfarct remodeling. PGS was unable to support systolic function, but it would be suitable for strategies to deliver cardiac stem/progenitor cells, to limit remodeling during the period of functional cellular integration, and to degrade after cell assimilation by the heart. This work has also shown for the first time the value of using MRI as a noninvasive tool for evaluating and optimizing therapeutic biomaterials in vivo.

An elastomeric patch derived from poly(glycerol sebacate) for delivery of embryonic stem cells to the heart.

We hypothesize that a combinatorial approach of ventricle constraint and stem cell therapy would offer a greater benefit for the treatment of heart failure than either strategy alone. A heart patch would serve two therapeutic purposes: biomechanical support and cell delivery. In this study, we describe a hybrid heart patch engineered from a synthetic elastomer, poly(glycerol sebacate) (PGS), supplemented with cardiomyocytes differentiated from human embryonic stem cells (hESCs). In line with two therapeutically relevant considerations, i.e. biocompatibility and cell delivery efficiency, the PGS was (a) pre-conditioned in culture medium for 6 days, and (b) prepared without gelatin coatings to facilitate detachment and delivery of cardiomyocytes following patch implantation. Following pre-conditioning under physiological conditions, the PGS patch material without gelatin coating was found to satisfactorily support cardiomyocyte viability and attachment, with active cell beating for periods of longer than 3 months until interrupted. Dynamic culture studies revealed that cells detached more efficiently from the uncoated surface of PGS than from gelatin-coated PGS. No significant differences were detected between the beating rates of human embryonic stem cell-derived cardiomyocytes on tissue culture plate and the pre-conditioned and gelatin-uncoated PGS. PGS patches sutured over the left ventricle of rats in vivo remained intact over a 2 week period without any deleterious effects on ventricular function. We conclude that PGS is a suitable biomaterial for stem cell-based regeneration strategies to restore cardiomyocyte function, and the hybrid heart patch engineered under optimal conditions would be a promising support device for the cardiac repair.

N-acetylcysteine-induced vasodilation involves voltage-gated potassium channels in rat aorta.

AIMS: N-acetylcysteine (NAC) has a protective effect against vascular dysfunction by decreasing the level of reactive oxygen species (ROS) in experimental and human hypertension. This study was designed to examine whether NAC would relax vascular rings in vitro via nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, extracellular Ca2+ and/or K+ channels. MAIN METHODS: Rat aortic arteries were mounted in an organ bath, contracted with 0.1, 0.5 or 1 micromol/L phenylephrine to plateau, and the vasodilatory effect of NAC was examined in the absence or presence of ROS scavengers, inhibitors of NO-cGMP pathway or K+ channels. Vascular smooth muscle cells (VSMCs) were loaded with a calcium sensitive fluorescent dye fluo-3 AM, and [Ca2+](i) was determined with laser-scanning confocal microscopy. KEY FINDINGS: NAC (0.1-4 mmol/L) dose-dependently relaxed rat aorta pre-contracted with phenylephrine. Endothelium removal, endothelial nitric oxide synthase inhibitor N(omega)-Nitro-l-arginine (L-NNA) (100 micromol/L) or soluble guanylyl cyclase (sGC) inhibitor (ODQ) (10 micromol/L) did not affect NAC-induced vasodilation. In contrast, NAC-induced vasodilation was blunted after extracellular calcium was removed and calcium imaging showed that 4 mmol/L NAC quickly decreased [Ca2+](i) in fluo-3 AM loaded VSMCs. NAC-induced vasodilation was significantly reduced in the presence of voltage-gated K+ channels (Kv) inhibitor 4-aminopyridine (4-AP). SIGNIFICANCE: The vasodilatory effect of NAC may be explained at least partly by activation of voltage-gated K+ channels.