Small diameter helical vascular scaffolds support endothelial cell survival.

There is an acute clinical need for small-diameter vascular grafts as a treatment option for cardiovascular disease. Here, we used an intelligent design system to recreate the natural structure and hemodynamics of small arteries. Nano-fibrous tubular scaffolds were fabricated from blends of polyvinyl alcohol and gelatin with inner helices to allow a near physiological spiral flow profile, using the electrospinning technique. Human coronary artery endothelial cells (ECs) were seeded on the inner surface and their viability, distribution, gene expression of mechanosensitive and adhesion molecules compared to that in conventional scaffolds, under static and flow conditions. We show significant improvement in cell distribution in helical vs. conventional scaffolds (94% ± 9% vs. 82% ± 7.2%; P < 0.05) with improved responsiveness to shear stress and better ability to withhold physiological pressures. Our helical vascular scaffold provides an improved niche for EC growth and may be attractive as a potential small diameter vascular graft

Increasing the Metabolic Stress of an Unweighted Knee Exercise via Blood-flow Restriction Training: A Potential Treatment Adjunct for Physiotherapists

Background: Blood-flow Restriction Training [BfRT] involves the temporary, artificial reduction of blood flow through a limb, often during low-intensity resistance exercise. Following lower-limb injury or surgery, evidence suggests that BfRT can be used to minimise losses in thigh muscle size and strength or accelerate their return. However, the restriction equipment used in BfRT research is often inaccessible to frontline clinicians. There is also little evidence as to the acute metabolic effect of adding blood-flow restriction to un-resisted, or ‘no load’, rehabilitation exercises. Purpose: Using an inexpensive restriction device, this study investigated whether adding lower-limb bloodflow restriction to a rehabilitation-appropriate ‘no load’ knee exercise produced a significant change in the acute metabolic stress of the exercise session. Methods: The height, weight and leg measurements of n=16 healthy participants (n=9 male) were recorded. Participants attended four exercise sessions separated by at least 48 hours. Each session consisted of three, one-minute sets of a single-leg, unweighted knee-extension exercise. Throughout all sessions a 21cm-wide thigh blood-pressure cuff was wrapped around the thigh of the exercising limb. During the first exercise session the cuff was not inflated [control]. Over the remaining three sessions, the cuff was inflated to one preselected pressure [40/60/80mmHg] in order to restrict blood flow through the exercising limb. At the start of these sessions, the percentage of popliteal arterial blood-flow volume remaining after cuff inflation [BfR] was determined using Doppler ultrasound. To indicate metabolic stress, near infra-red spectroscopy was used to record deoxygenated haemoglobin mass [HHb] of the vastus lateralis muscle before and during every exercise session. Cohort differences in BfR and HHb change for each exercise session were then compared. Results: All participants completed all exercise sessions. BfR decreased as cuff pressure was increased, with 80mmHg inducing a mean BfR of 47.6% (95% CI 42.9% - 52.3%). HHb of the vastus lateralis muscle did not increase during the control session. HHb of the vastus lateralis muscle increased significantly when cuff pressures were applied during the three remaining sessions. (Repeated Measures ANOVA, p< 0.001, partial η2 0.65). Overall, a higher Body Mass Index was associated with smaller changes in HHb of the vastus lateralis muscle during sessions in which cuff pressures were applied (Pearson R -0.794, R² 0.630, p < 0.001). Conclusions: Results indicate that adding lower-limb blood-flow restriction significantly increased the local, acute metabolic stress of a rehabilitation-appropriate knee exercise without the need to increase exercise load or repetitions. At cuff pressures up to 80mmHg, the degree of metabolic stress experienced during ‘no load’ BfRT differed between individuals and was associated with their Body Mass Index. Implications: Using an inexpensive blood-pressure cuff as the restriction device, findings support the potential use of lower-limb BfRT as a treatment adjunct following lower-limb injury. To deliver a consistent level of metabolic stress among different individuals, clinicians may need to tailor the amount of thigh cuff pressure that they apply based upon an individual’s physical size. Further research is required to determine the potential magnitude of acute metabolic stress required to attenuate the effects of muscle disuse within injured populations

Home-based exercise with telemonitoring guidance in patients with coronary artery disease; Does it improve long-term physical fitness?

Background: Exercise and physical activity are an essential part of contemporary coronary artery disease (CAD) management. However, evidence shows that patients experience clear difficulties in maintaining a physically active lifestyle following completion of a structured and supervised phase II exercise-based CR program. Home-based (HB) interventions have been shown to enhance a patient’s self-efficacy and might facilitate the lifelong uptake of a physically active lifestyle. Yet, data on the long-term effectiveness of HB exercise training on physical activity (PA) and exercise capacity (EC) are scarce. Objective: The main purpose of the TeleRehabilitation in Coronary Heart disease (TRiCH) study was to compare the long-term effects of the implementation of a short HB phase III exercise program with telemonitoring guidance to a prolonged center-based (CB) phase III program in patients with CAD. Primary outcome measure was exercise capacity. Secondary outcome measures included physical activity behaviour, cardiovascular risk profile and health related quality of life. Methods: Ninety CAD patients were randomized to three months of HB (=30), CB (=30) or a control group (CG) (=30) on a 1:1:1 basis after completion of their phase II ambulatory CR program. Outcome measures were assessed at discharge of the phase II program and after one year. Results: Eighty patients (91%, 72 men and mean age 62.6 years old) completed the one-year follow-up measurements. Exercise capacity (VO2P), cardiovascular risk factors and health related quality of life were preserved in all three groups (p-time >0.05 for all), irrespective of the intervention (p-interaction >0.05 for all). 85 % of patients met the international guidelines for PA (p-time < 0.05). No interaction effect was found for PA (steps, amount of active time, and amount of sedentary time) over the one-year period after discharge of a phase II program. Conclusion: Although exercise capacity remained stable over time, our HB exercise intervention did not result in higher levels of fitness or PA at one year of FU compared to the other two interventions

Tetramethoxystilbene-Loaded Liposomes Restore Reactive-Oxygen-Species-Mediated Attenuation of Dilator Responses in Rat Aortic Vessels Ex vivo

The methylated analogue of the polyphenol resveratrol (RV), 2,3′,4,5′-tetramethoxystilbene (TMS) displays potent antioxidant properties and is an effective cytochrome P450 (CYP) 1B1 inhibitor. The bioavailability of TMS is low. Therefore, the use of liposomes for the encapsulation of TMS is a promising delivery modality for enhanced uptake into tissues. We examined the effect of delivery of TMS in liposomes on the restoration of vasodilator responses of isolated aortic vessels after acute tension elevation ex vivo. Aortic vessels from young male Wistar rats were isolated, and endothelial-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside, SNP) responses assessed. Acute tension elevation (1 h) significantly reduced ACh dilator responses, which were restored following incubation with superoxide dismutase or apocynin (an NADPH oxidase inhibitor). Incubation with TMS-loaded liposomes (mean diameter 157 ± 6 nm; PDI 0.097) significantly improved the attenuated dilator responses following tension elevation, which was sustained over a longer period (4 h) when compared to TMS solution. Endothelial denudation or co-incubation with L-NNA (Nω-nitro-l-arginine; nitric oxide synthase inhibitor) resulted in loss of dilator function. Our findings suggest that TMS-loaded liposomes can restore attenuated endothelial-dependent dilator responses induced by an oxidative environment by reducing NADPH-oxidase-derived ROS and potentiating the release of the vasodilator nitric oxide. TMS-loaded liposomes may be a promising therapeutic strategy to restore vasodilator function in vascular disease

Real-time observation of aortic vessel dilation through delivery of sodium nitroprusside via slow release mesoporous nanoparticles

Spherical mesoporous nanoparticles (MNPs) with a diameter of ∼100 nm were synthesised via a sol-gel method in the presences of organic template (with and without fluorescein dye encapsulation). The template molecules were removed by acidic extraction to form a regular pore lattice structure. The nanoparticle size and morphology were analysed using transmission electron microscopy and dynamic light scattering analysis. The MNPs were further characterised by zeta potential, nitrogen adsorption measurements and infra-red spectroscopy. The interior pores had an average diameter of ∼3 nm and were loaded with an endothelial-independent vasodilator, sodium nitroprusside (SNP). The optimal drug loading and drug release was determined in high potassium physiological salt solution using dialysis and atomic absorption spectroscopy. We demonstrate that the initial instantaneous release is due to the surface desorption of the drug followed by diffusion from the pores. Furthermore, these drug loaded MNPs (with and without fluorescein dye encapsulation) were added to viable aortic vessels and release in real-time was observed, ex vivo. MNPs and loaded with and without SNP were incubated with the vessel (at 1.96 × 1012 NP mL−1) over a 3 h time period. The real-time exposure to unloaded MNPs resulted in a small attenuation in constriction that occurred after approximately 1 h. In contrast, MNPs loaded with SNP led to a rapid relaxation of aortic vessels that was sustained over the 3 h period (p < 0.001)

Differential effects of resveratrol on the dilator responses of femoral arteries, ex vivo

Resveratrol is a plant-derived phytoalexin with antioxidant, anti-inflammatory and cardio-protective properties and may be a promising therapeutic intervention strategy in cardiovascular disease. Here, we investigated the acute direct effects of trans-resveratrol (RV), on acetylcholine (ACh)-induced and flow-mediated dilation (FMD) of isolated pressurized femoral arteries of young (4-month-old) and old (26-month-old) mice. Vessel exposure to RV enhanced ACh (0.01- 1.0 mM)-induced dilation (p<0.05), but not FMD (@ 5-10 Lmin-1) (p<0.05) in both young and old mice. After RV incubation, acute nitric oxide (NO) production by cultured endothelial cells was increased in response to 0.01 mM ACh, but reduced by flow (5-10 Lmin-1; p<0.05). In isolated femoral arteries from endothelial nitric oxide synthase knockout (eNOS-/-) mice, RV had no overall effect on flow mediated dilation, but potentiated ACh induced dilation, that was completely abolished by potassium channel blockers, Apamin and Tram 34 (p<0.01). We demonstrate that the non-metabolised form of RV stimulates ACh-induced dilation via the NO and EDHF pathways, but not FMD by interaction with the cyclo-oxygenase pathway. Our findings have important implications in the use of RV (for both young and aged) under ‘normal’ non-diseased physiological states

Internal Mammary Arteries as a Model to Demonstrate Restoration of the Impaired Vasodilation in Hypertension, Using Liposomal Delivery of the CYP1B1 Inhibitor, 2,3′,4,5′-Tetramethoxystilbene

A significant number of patients with severe cardiovascular disease, undergoing coronary artery bypass grafting (CABG), present with hypertension. While internal mammary arteries (IMAs) may be a better alternative to vein grafts, their impaired vasodilator function affects their patency. Our objectives were to (1) determine if inhibition of the cytochrome P450 enzyme CYP1B1, using liposome-encapsulated 2,3′,4,5′-tetramethoxystilbene (TMS), can potentiate vasodilation of IMAs from CABG patients, and (2) assess mechanisms involved using coronary arteries from normal rats, in an ex vivo model of hypertension. PEGylated liposomes were synthesized and loaded with TMS (mean diameter 141 ± 0.9 nm). Liposomal delivery of TMS improved its bioavailability Compared to TMS solution (0.129 ± 0.02 ng/mL vs. 0.086 ± 0.01 ng/mL at 4 h; p &lt; 0.05). TMS-loaded liposomes alleviated attenuated endothelial-dependent acetylcholine (ACh)-induced dilation in diseased IMAs (@ACh 10−4 M: 56.9 ± 5.1%; n = 8 vs. 12.7 ± 7.8%; n = 6; p &lt; 0.01) for TMS-loaded liposomes vs. blank liposomes, respectively. The alleviation in dilation may be due to the potent inhibition of CYP1B1 by TMS, and subsequent reduction in reactive oxygen species (ROS) moieties and stimulation of nitric oxide synthesis. In isolated rat coronary arteries exposed to a hypertensive environment, TMS-loaded liposomes potentiated nitric oxide and endothelium-derived hyperpolarization pathways via AMPK. Our findings are promising for the future development of TMS-loaded liposomes as a promising therapeutic strategy to enhance TMS bioavailability and potentiate vasodilator function in hypertension, with relevance for early and long-term treatment of CABG patients, via the sustained and localized TMS release within IMAs

On the issue of transparency and reproducibility in nanomedicine.

Following our call to join in the discussion over the suitability of implementing a reporting checklist for bio-nano papers, the community responds