Matrix-Binding, N-Cadherin-Targeting Chimeric Peptide Inhibits Intimal Thickening but Not Endothelial Repair in Balloon-Injured Carotid Arteries.

BACKGROUND: Treatment of occluded vessels can involve angioplasty, stenting, and bypass grafting, which can be limited by restenosis and thrombosis. Drug-eluting stents attenuate restenosis, but the current drugs used are cytotoxic, causing smooth muscle cell (SMC) and endothelial cell (EC) death that may lead to late thrombosis. N-cadherin is a junctional protein expressed by SMCs, which promotes directional SMC migration contributing to restenosis. We propose that engaging N-cadherin with mimetic peptides can act as a cell type-selective therapeutic strategy to inhibit polarization and directional migration of SMCs without negatively impacting ECs. METHODS: We designed a novel N-cadherin-targeting chimeric peptide with a histidine-alanine-valine cadherin-binding motif, combined with a fibronectin-binding motif from Staphylococcus aureus. This peptide was tested in SMC and EC culture assays of migration, viability, and apoptosis. Rat carotid arteries were balloon injured and treated with the N-cadherin peptide. RESULTS: Treating scratch-wounded SMCs with the N-cadherin-targeting peptide inhibited migration and reduced polarization of wound-edge cells. The peptide colocalized with fibronectin. Importantly, EC junction, permeability, or migration was not impacted by peptide treatment in vitro. We also demonstrated that the chimeric peptide persisted for 24 hours after transient delivery in the balloon-injured rat carotid artery. Treatment with the N-cadherin-targeting chimeric peptide reduced intimal thickening in balloon-injured rat carotid arteries at 1 and 2 weeks after injury. Reendothelialization of injured vessels after 2 weeks was unimpaired by peptide treatment. CONCLUSIONS: These studies show that an N-cadherin-binding and fibronectin-binding chimeric peptide is effective in inhibiting SMC migration in vitro and in vivo and limiting neointimal hyperplasia after balloon angioplasty without affecting EC repair. These results establish the potential of an advantageous SMC-selective strategy for antirestenosis therapy.

Heart Rate Variability Responses of Individuals With and Without Saline-Induced Obstructive Sleep Apnea.

STUDY OBJECTIVES: Postoperative development of obstructive sleep apnea (OSA) has been attributed to the fluid overloaded state of patients during the postoperative period. In this context, alterations in cardiac autonomic regulation caused by OSA may explain the increased postoperative risk for adverse cardiovascular events. This study tests the hypothesis that individuals with fluid overload-induced OSA will experience autonomic dysregulation, compared to those without fluid overload-induced OSA. METHODS: Twenty-one normotensive, nonobese (mean body mass index 24.5 kg/m2) males (mean age 37 years) underwent a sleep study. Participants were randomly assigned to infusion with saline during sleep either at the minimum rate (control) or as a bolus of 22 mL/kg body weight (intervention). Participants were blinded to the intervention and crossed over to the other study arm after 1 week. Measures of heart rate variability were calculated from electrocardiography recordings presaline and postsaline infusion in the intervention arm. Heart rate variability measures computed were: standard deviation of the RR interval; root mean square of successive differences; low-frequency, high-frequency, and total power; and the ratio of low-frequency to high-frequency power. RESULTS: Although presaline infusion values were similar, postsaline infusion values of the standard deviation of the RR interval and high-frequency power were lower in the group whose apnea-hypopnea index increased in response to saline infusion, compared to the group whose apnea-hypopnea index did not increase in response to saline infusion (P < .05 for both). CONCLUSIONS: Fluid overload-induced OSA is accompanied by a reduction in heart rate variability, consistent with vagal withdrawal. Future work should explore autonomic dysregulation in the postoperative period and its association with adverse events.

The Effect of Electrical Stimulation of the Calf Muscle on Leg Fluid Accumulation over a Long Period of Sitting.

Leg fluid accumulation during sedentary behaviours such as sitting can lead to leg edema and associated adverse health consequences. This study investigates the use calf muscle electrical stimulation (ES) to reduce seated leg fluid accumulation. Thirteen non-obese, normotensive men (mean age 51 yr.) with sleep apnea were enrolled in the study. Participants first lay supine for 30 minutes to equalize fluid distribution and then sat for 150 minutes. While seated, participants received either active or sham ES of the calf muscles, according to random assignment. Participants returned one-week later to cross over to the other study condition. Leg fluid was measured continuously while sitting using the bioelectrical impedance method. Fluid accumulation in the leg was reduced by more than 40% using active ES, compared to sham ES (∆ = 51.9 ± 8.8 ml vs. ∆ = 91.5 ± 8.9 ml, P < 0.001). In summary, calf muscle ES is an effective method for reducing accumulation of fluid during long sedentary periods and has potential use as a device for preventing leg edema to treat associated health consequences in at-risk groups and settings.

Leg fluid accumulation during prolonged sitting.

The accumulation of fluid in the legs due to sedentariness can be a health risk in extreme cases. Negative health impacts associated with leg fluid accumulation include leg edema and risk of blood clots. Furthermore, fluid accumulating in the legs is accompanied by fluid shift into the upper body which is also associated with health risks such as: increased blood pressure when lying down, respiratory problems in people with heart failure, and increased sleep apnea. Understanding the pattern by which fluid accumulates in the legs can aid in the development of devices for reducing leg fluid accumulation. The purpose of this study was to characterize the time course of fluid accumulation over a two-and-half-hour seated period. Non-obese participants with sleep apnea and no other co-morbidities were included in the sample as part of a larger study. Leg fluid was measured continuously using a method of bioelectrical impedance. Participants were first asked to lie supine for 30 minutes as a washout, and then sat with their legs still for two and a half hours. The main finding of this study is that the pattern of leg fluid accumulation differed in the first 45 minutes compared to the latter 105 minutes. In the first 45 minutes, fluid accumulated according to first order exponential function. In the latter period, fluid accumulated according to a linear function. The initial exponential accumulation is likely due to the large increase in capillary pressure caused by rapid blood flow into the legs due to gravity, leading to substantial filtration of blood plasma into the tissue spaces. The latter linear portion likely represents continued slow filtration of fluid out of the vasculature and into the tissue spaces. This is the first study to show that fluid accumulation in the legs is a combination of an exponential and linear functions. The linear increase identifies that there is no foreseeable point in which leg fluid stops accumulating while sitting for prolonged periods.