Vagal blocking improves glycemic control and elevated blood pressure in obese subjects with type 2 diabetes mellitus.

BACKGROUND: An active device that downregulates abdominal vagal signalling has resulted in significant weight loss in feasibility studies. OBJECTIVE: To prospectively evaluate the effect of intermittent vagal blocking (VBLOC) on weight loss, glycemic control, and blood pressure (BP) in obese subjects with DM2. METHODS: Twenty-eight subjects were implanted with a VBLOC device (Maestro Rechargeable System) at 5 centers in an open-label study. Effects on weight loss, HbA1c, fasting blood glucose, and BP were evaluated at 1 week to 12 months. RESULTS: 26 subjects (17 females/9 males, 51 ± 2 years, BMI 37 ± 1 kg/m(2), mean ± SEM) completed 12 months followup. One serious adverse event (pain at implant site) was easily resolved. At 1 week and 12 months, mean excess weight loss percentages (% EWL) were 9 ± 1% and 25 ± 4% (P < 0.0001), and HbA1c declined by 0.3 ± 0.1% and 1.0 ± 0.2% (P = 0.02, baseline 7.8 ± 0.2%). In DM2 subjects with elevated BP (n = 15), mean arterial pressure reduced by 7 ± 3 mmHg and 8 ± 3 mmHg (P = 0.04, baseline 100 ± 2 mmHg) at 1 week and 12 months. All subjects MAP decreased by 3 ± 2 mmHg (baseline 95 ± 2 mmHg) at 12 months. CONCLUSIONS: VBLOC was safe in obese DM2 subjects and associated with meaningful weight loss, early and sustained improvements in HbA1c, and reductions in BP in hypertensive DM2 subjects. This trial is registered with ClinicalTrials.gov NCT00555958.

Intra-abdominal vagal blocking (VBLOC therapy): clinical results with a new implantable medical device.

BACKGROUND: A new medical device uses high-frequency electrical algorithms to create intermittent vagal blocking (VBLOC therapy). The aim is to assess the effects of vagal blocking on excess weight loss (EWL), safety, dietary intake, and vagal function. METHODS: An open-label, 3-center study was conducted in obese subjects (body mass index [BMI] 35-50 kg/m(2)). Electrodes were implanted laparoscopically on both vagi near the esophagogastric junction to provide electrical block. Patients were followed for 6 months for body weight, safety, electrocardiogram, dietary intake, satiation, satiety, and plasma pancreatic polypeptide (PP) response to sham feeding. To specifically assess device effects alone, no diet or exercise programs were instituted. RESULTS: Thirty-one patients (mean BMI, 41.2 +/- 1.4 kg/m(2)) received the device. Mean EWL at 4 and 12 weeks and 6 months after implant was 7.5%, 11.6%, and 14.2%, respectively (all P < .001); 25% of patients lost >25% EWL at 6 months (maximum, 36.8%). There were no deaths or device-related serious adverse events (AEs). Calorie intake decreased by >30% at 4 and 12 weeks and 6 months (all P 25 pg/mL (P = .02). Three patients had serious AEs that required brief hospitalization, 1 each for lower respiratory tract, subcutaneous implant site seroma, and Clostridium difficile diarrhea. CONCLUSIONS: Intermittent, intra-abdominal vagal blocking is associated with significant EWL and a desirable safety profile.

Ventriculocoronary artery bypass results using a mesh-tipped device in a porcine model.

BACKGROUND: In this report we describe the in vivo evaluation of a device and ventriculocoronary artery bypass procedure that creates a permanent transmyocardial channel between the left ventricle and a coronary artery. METHODS: The transmyocardial device, an L-shaped titanium tube with a meshed distal tip and an exterior polyester cuff, was implanted from the base of the left ventricle to the proximal left anterior descending coronary artery in 11 healthy juvenile domestic pigs using a beating-heart approach. Flow rates were measured at implant. Patency was assessed at explant for surviving animals at 2 (n = 3) and 4 weeks (n = 4). RESULTS: Flow through the transmyocardial device after implantation was 74% of base line. Forward flow occurred during systole. Luminal patency was 100% at 2 weeks and 75% at 4 weeks. Histologic analysis showed little to no intimal proliferation at the coronary interface. CONCLUSIONS: This short-duration study shows promise for perfusing ischemic myocardium with systolic flow. The transmyocardial titanium conduit and treated coronary artery patency was good at 2 and 4 weeks and warrants further studies.

Ventriculocoronary artery bypass (VCAB), a novel approach to myocardial revascularization.

BACKGROUND: The long-term patency rate of saphenous vein grafts for myocardial revascularization is poor (50% at 10 years). Half of the patent grafts develop severe atherosclerosis. In this paper, we report on an implantation technique and an in vivo evaluation of a device that creates a ventriculocoronary artery bypass (VCAB), a permanent transmyocardial channel between the left ventricle and a coronary artery. METHODS: An L-shaped titanium tube with an exterior polyester cuff was implanted from the base of the left ventricle to the proximal left anterior descending coronary artery in 11 juvenile domestic pigs using a beating heart approach. Flow rates were measured at implantation. Patency was assessed when explanted at 2 weeks. RESULTS: The flow rate through the device after implantation was 76% of baseline. Forward flow occurred during systole. The patency rate was 91% at 2 weeks. Histologic analysis showed the formation of an organizing tissue at the coronary interface. CONCLUSIONS: These preliminary studies show the promise of perfusing ischemic myocardium with systolic flow. Patency of the transmyocardial titanium conduit was excellent at 2 weeks and warrants longer duration studies.

Human serum albumin and fibrinogen interactions with an adsorbed RGD-containing peptide.

The modification of polyethylene terephthalate (PET) and polytetrafluoroethylene (PTFE) with an arginine-glycine-aspartic acid cell adhesion peptide, RGD peptide (PepTite Adhesive Coating; Telios Pharmaceuticals, San Diego, CA) has been previously investigated. Initial animal studies showed this RGD peptide to accelerate healing and assist in the formation of an endothelial cell lining of the lumenal side of PET and PTFE fabrics in a cardiovascular application. It is of interest to determine how this RGD peptide is able to influence cellular events through intervening layers of plasma proteins that spontaneously adsorb upon implantation. This study examined the interaction of predeposited RGD-containing peptide with human serum albumin (HSA) or fibrinogen that was characterized using multiple attenuated internal reflection infrared (MAIR-IR) spectroscopy, ellipsometry, and contact angle analysis. It was determined that fibrinogen-containing films consistently exhibited more mass than films of the RGD peptide, HSA, or HSA adsorbed onto RGD peptide-containing films. MAIR-IR spectra of RGD peptide films before and after HSA adsorption were similar in absorption and intensity; however, ellipsometry indicated HSA introduction had created thicker, less dense films. Fibrinogen, on the other hand, when adsorbed onto RGD peptide films provided increased relative mass in a more compact arrangement. Contact angle analyses of each of the dried films showed their surface energies to remain high, but the polar components of RGD peptide films were reduced after either serum protein adsorption. These phenomena may be related to the minimal thrombus accumulation that was noted during the initial animal studies, that promoted subsequent healing.

Silver modification of polyethylene terephthalate textiles for antimicrobial protection.

The safety and in vitro effectiveness of applying silver to polyethylene terephthalate fabric mechanical heart valve (MHV) sewing cuffs for the prevention of prosthetic valve endocarditis (PVE) were evaluated. PVE is an infrequent but grave complication of cardiac surgery associated with mortality rates potentially exceeding 50%. A poor response to antibiotic therapy is partly responsible for the high mortality rates. Silver is a well known antimicrobial agent with broad effectiveness. Preliminary in vitro microbial challenge studies of the coated fabric using the New York State 63 bacteriostatic test and Dow Corning Shake Flask test showed a > or = 97% reduction for most organisms tested. Sheep mitral valve replacement studies suggest comparable tissue ingrowth of uncoated and coated fabric with a more organized, thinner pannus formed on silver coated fabric. Low levels of silver were present in the serum at all time periods. These results indicate MHVs with silver coated cuffs may provide additional protection against PVE.

Biocompatibility of silver-modified polyester for antimicrobial protection of prosthetic valves.

BACKGROUND AND AIMS OF THE STUDY: The biocompatibility of a silver-coated polyethylene terephthlate (PET, polyester) fabric for the inhibition of prosthetic valve endocarditis (PVE) associated with mechanical heart valves (MHVs) was assessed. The infrequency of PVE is outweighed by mortality rates commonly exceeding 50%. These high mortality rates have been attributed to the poor effect of antibiotic therapy on colonized valves and infected myocardial tissue. Silver has been used as an antimicrobial for centuries due to its general effectiveness and relative lack of toxicity. Our previous work has shown PET polyester fabric coated with metallic silver by an ion beam-assisted deposition (IBAD) process to: (i) be effective in vitro in the inhibition of microbial attachment and colonization; (ii) be tightly adherent and low leaching; and (iii) promote tissue ingrowth and the organization of tissue pannus in a short-duration (five weeks) sheep mitral mechanical heart valve model. METHODS: This paper addresses additional biocompatibility assessment consisting of a cell compatibility assay in which serum extracts of silver-coated fabric were exposed to fibroblasts for 48 hours, after which cell viability and function were measured. The amount of silver in the extract was measured using elemental analysis techniques. RESULTS: No signs of toxicity were seen in the cells until the extract concentration reached 1200 p.p.m. Ten-week duration mechanical valve replacement studies in sheep with uncoated or coated polyester sewing cuffs showed comparable tissue ingrowth and mature pannus with a suggestion of a thinner pannus on the silver-coated fabric. Additional antimicrobial testing confirmed the effectiveness of this coating in inhibiting colonization of polyester fabric. CONCLUSIONS: These current results, together with the earlier data, suggest that IBAD silver coating on polyester facilitates healing and may provide protection against PVE.

Platelet interaction with pyrolytic carbon heart-valve leaflets.

Although the newest generation of mechanical heart-valve prosthetics constructed either partially or wholly of lowtemperature isotropic pyrolytic carbon (LTIC) have significantly reduced thromboembolic complications compared with early-generation mechanical valves (e.g., Starr-Edwards), thromboembolism remains an important clinical complication. In the present study, high-resolution, lowvoltage scanning electron microscopy (HR-LV-SEM) was used to examine the structure and platelet interaction properties of LTIC valve leaflets manufactured by both Carbo Medics, Inc. and by St. Jude Medical, Inc. Valve leaflets from both manufacturers, prepared and polished exactly as used in clinical heart valves, had similar surface energetics and elemental composition. Examination with LV-SEM revealed a rough and complex three-dimensional surface structure with nanometer- to micron-size features. In vitro adhesion of human platelets on the LTIC materials and Formvar were evaluated in the presence of 1 mg/mL albumin. Platelet-surface activation, as evaluated by shape change, spread area, and deposition, was extremely extensive on the LTIC materials compared with the Formvar positive control material. LTIC-adherent platelets were extremely thin, and closely followed the rough LTIC contours, greatly limiting their visibility with conventional SEM. These observations demonstrate that LTIC surfaces can extensively activate platelets even in the presence of albumin, thereby suggesting that platelet interactions with pyrolytic carbon may have a significant role in mechanical-valve thromboembolism.

Platelets are deposited early post-operatively on the leaflet of a mechanical heart valve in sheep without post-operative anticoagulants or antiplatelet agents. A scanning electron microscopic observation of the pyrolytic carbon surface in a mechanical heart valve.

Pyrolytic carbon has been used for mechanical heart valves as a thromboresistant, wear resistant, and fatigue resistant material. Thrombosis and thromboembolism, however, remain major mechanical heart valve associated complications and may frequently occur during the early post-operative period. In depth morphologic studies on blood-pyrolytic carbon surface interactions are limited. The purpose of this study was to evaluate the blood compatibility of the pyrolytic carbon surface of St. Jude Medical mechanical heart valves that were implanted in the mitral position of sheep without the administration of post-operative anticoagulants or antiplatelet agents for 2, 4, and 6 weeks. Almost the entire leaflet and orifice ring surfaces were observed by scanning electron microscopy. Although the surfaces appeared clean macroscopically, when observed by electron microscopy, the surface were mottled, mainly by solitary platelets and aggregations. There were only a few leukocytes or red blood cells observed. No fibrin clots were observed on the leaflets. The density of platelet deposition was higher in the vicinity of the pivots and near the edges of the leaflets. The sizes of the platelet aggregations decreased with longer duration. The outer surfaces of the pivot guards were covered by various amounts of deposition composed of platelet aggregations and thrombi. Thus, the administration of antiplatelet agents is recommended during the early post-operative period after mechanical heart valve implantation.

Accelerated healing of cardiovascular textiles promoted by an RGD peptide.

Polytetrafluoroethylene (PTFE) and polyethylene terephthalate (Dacron polyester) fabrics are used extensively in cardiovascular devices, e.g. heart valve sewing cuffs and vascular prostheses. While devices containing these fabrics are generally successful, it is recognized that fabrics cause complications prior to tissue ingrowth due to their thrombogenic nature. A surface active synthetic peptide, called PepTite Coating (PepTite), which was modeled after the cell attachment domain of human fibronectin has been marketed as a biocompatible coating. This peptide stimulates cell attachment through the arginine-glycine-aspartic acid (RGD) sequence. Modification of medical implants with PepTite has been shown to promote ingrowth of surrounding cells into the material leading to better tissue integration, reduced inflammation and reduced fibrotic encapsulation. In this study, polyester and PTFE textiles were modified with PepTite. The effectiveness of this coating in enhancing wound healing was investigated in a simple vascular and cardiac valve model. Our results indicate that the RGD-containing peptide, PepTite, promoted the formation of an endothelial-like cell layer on both polyester and PTFE vascular patches in the dog model. PepTite was also found to promote the formation of a significantly thinner neointima (pannus) on polyester as compared to that on its uncoated control. These results were corroborated in the cardiac valve model in which a greater amount of thin pannus and less thrombus were seen on coated polyester sewing cuffs than on control uncoated cuffs. This research shows the promising tissue response to RGD coated textiles and the potential role of this peptide in material passivation via accelerated healing.

Comparative biophysical study of adsorbed calf serum, fetal bovine serum and mussel adhesive protein films.

Varying concentrations of different sera and adhesive agents are routinely used to increase cellular attachment to substrata. The surface-chemical effects of some of these surface-altering materials have been examined using ellipsometry, contact angle analysis and multiple-attenuated internal reflection infrared (MAIR-IR) spectroscopy. Specifically, 15% fetal bovine serum (FBS), Ham's F-12 (containing 10% FBS + 1% penicillin/streptomycin), 10% calf serum and mussel adhesive protein (MAP) were allowed to adsorb on to similar and different surfaces and then compared. Each of these preparations is capable of altering the surface-chemical properties of substrata with varying resultant surface energies. It is therefore important to characterize serum in the proper concentrations on the substrata under consideration in order to understand the interfacial effects.

Neovascularization of surface demineralized dentin.

Uneventful healing of the wound site created by periodontal reconstructive surgery is crucial for the long term survival of the dentition. Wound healing has been shown to be initiated and mediated by matrix components and polypeptide growth factors. Neovascularization (or angiogenesis) is one of the most important events in the healing process of a wound site. Any increase in the degree and/or rate of neovascularization could result in more rapid or complete healing. Previously, we have shown that basic fibroblast growth factor (bFGF) selectively enhances periodontal ligament cell migration and proliferation. In addition, we have shown that FGF stimulates human umbilical vein endothelial cell migration and proliferation. In this study we examined whether human umbilical vein endothelial cells could be influenced to form capillary-like structures in a type I collagen stroma and on dentin surfaces in response to fibroblast growth factor (FGF). We observed tubule-like structures formed from a monolayer of endothelial cells within a type I collagen sponge in response to a gradient of FGF. Furthermore, we observed tubule-like structures formed from self-association of individual endothelial cells on partially demineralized dentin surfaces in response to FGF. Proliferation of human endothelial cells on dentin was dose dependent and maximally stimulated at a concentration of 10 ng/ml FGF. These data indicate that FGF can induce endothelial cell migration, proliferation and tubule formation on dentin.

Repopulation of dentin surfaces by periodontal ligament cells and endothelial cells. Effect of basic fibroblast growth factor.

The regeneration of connective tissue attachment is a major goal of clinical periodontics. Recent investigations on biochemically mediated periodontal regeneration have attempted to define the various biological response modifiers which may provide a mechanism for periodontal regeneration. Fibronectin and endothelial cell growth factor have been shown to selectively enhance periodontal ligament (PDL) cell adhesion, migration, and proliferation. In addition, dentin preconditioned with tetracycline HCl (TTC) or citric acid (CA) supports PDL cell adhesion, presumably by exposing collagen fibers. We have now extended these studies to include basic fibroblast growth factor (b-FGF) as a potential meditor of periodontal regeneration. Using AFSCM (assays for specific cell migration), b-FGF in concentrations as low as 10 ng per dentin block significantly stimulated PDL cell chemotaxis, while the antibody against b-FGF inhibited both the chemotactic and proliferative characteristics of the mitogen. We also found that 5 ng and above of b-FGF per dentin block significantly stimulated human endothelial cell migration and proliferation. Using 125I-b-FGF, we demonstrated that the factor binds to native dentin. This binding was increased when the dentin blocks were preconditioned by TTC or CA and reduced when the dentin was subsequently treated with collagenase. 125I-b-FGF also bound with moderate affinity to a type I collagen affinity column whereas the binding to a hydroxylapatite affinity column was negligible. The combination of FN and b-FGF was a marginally more potent chemo-attractant than b-FGF alone for PDL cells.(ABSTRACT TRUNCATED AT 250 WORDS)