Isolation of pulmonary veins using a thermoreactive implantable device with external energy transfer : evaluation in a porcine model

Background: Pulmonary vein isolation (PVI) is a well-established method for the treatment of symptomatic paroxysmal atrial fibrillation, but is only partly successful with a high rate of electrical reconnection. We introduce a novel technique in which PVI is accomplished by noninvasive heating of a dedicated thermoresponse implant inserted into the pulmonary veins (PV), demonstrated in a porcine model. Methods: A self-expanding nitinol-based implant was positioned in the common inferior PV of 11 pigs, using a fluoroscopy-guided transatrial appendage approach. Ablation was performed through contactless energy transfer from a primary extracorporal coil to a secondary heat ring (HR) embedded in the proximal part of the implant. Electrophysiological conduction was assessed prior to and postablation, and at 3 months. Histological samples were obtained acutely (n=4) and after 3 months (n=7). Results: In total, 13 PV implants were successfully positioned in the inferior PVs of 11 animals. Ablation was performed without injury of adjacent structures. PVI and bidirectional block was electrophysiologically confirmed in all cases immediately at the time of implantation and 3 months later in seven chronic animals in whom testing was repeated. Marked evidence of ablation around the proximal HR was evident at 3 months postprocedure, with scar tissue formation and only mild neointimal proliferation. Conclusions: Successful PVI can be obtained by external electromagnetic heat transfer to a novel pulmonary vein implant

Intracoronary Injection of In Situ Forming Alginate Hydrogel Reverses Left Ventricular Remodeling After Myocardial Infarction in Swine

ObjectivesThis study sought to determine whether alginate biomaterial can be delivered effectively into the infarcted myocardium by intracoronary injection to prevent left ventricular (LV) remodeling early after myocardial infarction (MI).BackgroundAlthough injectable biomaterials can improve infarct healing and repair, the feasibility and effectiveness of intracoronary injection have not been studied.MethodsWe prepared a calcium cross-linked alginate solution that undergoes liquid to gel phase transition after deposition in infarcted myocardium. Anterior MI was induced in swine by transient balloon occlusion of left anterior descending coronary artery. At 4 days after MI, either alginate solution (2 or 4 ml) or saline was injected selectively into the infarct-related coronary artery. An additional group (n = 19) was treated with incremental volumes of biomaterial (1, 2, and 4 ml) or 2 ml saline and underwent serial echocardiography studies.ResultsExamination of hearts harvested after injection showed that the alginate crossed the infarcted leaky vessels and was deposited as hydrogel in the infarcted tissue. At 60 days, control swine experienced an increase in left ventricular (LV) diastolic area by 44%, LV systolic area by 45%, and LV mass by 35%. In contrast, intracoronary injection of alginate (2 and 4 ml) prevented and even reversed LV enlargement (p < 0.01). Post-mortem analysis showed that the biomaterial (2 ml) increased scar thickness by 53% compared with control (2.9 ± 0.1 mm vs. 1.9 ± 0.3 mm; p < 0.01) and was replaced by myofibroblasts and collagen.ConclusionsIntracoronary injection of alginate biomaterial is feasible, safe, and effective. Our findings suggest a new percutaneous intervention to improve infarct repair and prevent adverse remodeling after reperfused MI

Morphologic assessment of recipient pancreas and pancreatic islets following 90 days of implantation period.

<p>(<b>A</b>) A device after explanation. (<b>B</b>) The tissue surrounding the device at explantation. (<b>C–F</b>) Representative images of alginate/islet slabs (C,D - 10×; E, F - 40×). Left: HE; islets displayed an intact structure and no signs of disintegration within the alginate. Right: Immunohistochemistry for insulin showed intense cytoplasmic staining as typically seen in intact rat islets. (<b>G</b>) Representative image (2×) of a pancreas of a recipient animal at autopsy.</p

Function of macroencapsulated rat islet grafts.

<p>STZ-induced diabetic minipigs were transplanted with 6,730±475 IEQ/kg BW of rat islets immobilized and integrated into the macrochamber system. ivGTT was performed prior to graft implantation, 2 weeks after implantation, and after retrieval of the graft. BW was recorded daily throughout the observation period. (<b>A</b>) Fasting blood glucose levels (black) of group one transplanted minipigs (n = 5). The graft was removed on day 30 and hyperglycemia recurred demonstrating that graft function was responsible for normoglycemia during the implantation period. Rat C-peptide levels (grey) are presented as 4^th grade polynomial curves. Error bars represent SD. <i>P</i><0.001 for comparing glucose levels during the implantation period vs the pre- and post-implantation periods (t-test). (<b>B</b>) Blood glucose levels during ivGTT of transplanted animals at two weeks (black circles) and after retrieval of the graft-containing device (black triangles). Diabetic minipigs (n = 24; double grey), naïve healthy mini-pigs (n = 11; black dashed) and naïve healthy rats (n = 36; grey dashed) served as controls. Error bars represent SD. <i>P</i><0.001 for comparing AUCs (diabetic minipigs) in the implantation period vs the pre- and post-implantation periods (t-test). (<b>C</b>) Two-day continuous glucose monitoring records of an implanted animal during week 2. (<b>D</b>) Fasting blood glucose levels (black) of group 2 transplanted minipigs (n = 3) and corresponding BW (grey). Normoglycemia was achieved rapidly after transplantation and was retained until the BW increased to a critical level of >160% of the initial BW. Data are presented as 5^th grade polynomial curves. <i>P</i><0.001 for comparing glucose levels during the first 75 days of the implantation period vs the pre-implantation period (t-test).</p

Oxygen partial pressure in the gas chamber.

<p>Levels of oxygen at the end of successive 24 h cycles were monitored in the central cavity and in the 2 side chambers. Solid black line, central cavity; solid grey line, side chambers. Data are presented as the 3^rd grade polynomial curves.</p

Barrier function of the membrane system for viral transmission.

<p>MRC-5 primary fibroblasts cultured in 24-transwell plates were separated from suspension containing reporter Lentiviruses by the membrane system for a period of 72 h. Infection rates were quantified by FACS analyses. Regardless of the MOI level, no relevant infection was detected in the membrane group (squares). In the control group (naïve membrane; circles), infection levels corresponded to increasing MOI levels from 40% up to 99.5%.</p

Determination of the barrier function of the chamber system.

<p>(<b>A</b>) Biopsies from alginate/islet slabs were taken at 30 days (left panel, slabs 1 and 2) and at 90 days (right panel, slab 3) to test for porcine DNA contamination inside the chamber. At both time points, no porcine DNA was detectable in any of the samples. Non-tissue samples were used as negative controls (NC). Tissue extracts from porcine muscle (M), spleen (S), and liver (L) served as positive controls (PC). (<b>B</b>) Serum samples of rat islet graft recipients were taken at various time points throughout the observation period of up to 90 days to test for development of anti-rat immunoglobulin. The 2 graphs show data of 2 individual recipients (left, 1709; right, 1736). Squares: positive control (sensitized animal); circles: negative control (healthy animal); triangles: diabetic minipig transplanted with encapsulated rat islets.</p

Chamber system for islet macroencapsulation.

<p>(<b>A</b>) Schematic view of the chamber composition. The core of the device is built as a gas module, connected to access ports for exogenous oxygen refueling. Active transport of solutes is achieved via a membrane impregnated with alginate (left, virgin; right, ready to use). Separated by gas permeable membranes, 2 compartments surround the central gas cavity that houses alginate-immobilized pancreatic islets. The plastic housing of the chamber has a latticelike design at both external surfaces and covered by hydrophylized PTFE porous membranes. (<b>B</b>) Photographic image of a completely assembled chamber with connected access ports. (<b>C</b>) X-ray image of an implanted recipient.</p