Retrieval of Chronically Implanted Dual-chamber Leadless Pacemakers in an Ovine Model.

BACKGROUND: The clinical utilization of leadless pacemakers (LPs) as an alternative to traditional transvenous pacemakers is likely to increase with the advent of dual-chamber LP systems. Since device retrieval to allow LP upgrade or replacement will become an important capability, the first such dual-chamber, helix-fixation LP system (Aveir DR; Abbott, Abbott Park, IL) was specifically designed to allow catheter-based retrieval. In this study, the preclinical performance and safety of retrieving chronically implanted dual-chamber LPs was evaluated. METHODS: Atrial and ventricular LPs were implanted in the right atrial appendage and right ventricular apex of 9 healthy ovine subjects. After ≈2 years, the LPs were retrieved using a dedicated transvenous retrieval catheter (Aveir Retrieval Catheter; Abbott) by snaring, docking, and unscrewing from the myocardium. Comprehensive necropsy/histopathology studies were conducted to evaluate device- and procedure-related outcomes. RESULTS: At a median of 1.9 years postimplant (range, 1.8-2.6), all 18 of 18 (100%) LPs were retrieved from 9 ovine subjects without complications. The median retrieval procedure duration for both LPs, from first-catheter-in to last-catheter-out, was 13.3 minutes (range, 2.5-36.4). Postretrieval, all right atrial, and right ventricular implant sites demonstrated minimal tissue disruption, with intact fibrous tissue limited to the distal device body. No significant device-related trauma, perforation, pericardial effusion, right heart or tricuspid valve injury, or chronic pulmonary thromboembolism were observed at necropsy. CONCLUSIONS: This preclinical study demonstrated the safe and effective retrieval of chronically implanted, helix-fixation, dual-chamber LP systems, paving the way for clinical studies of LP retrieval.

Preclinical safety and electrical performance of novel atrial leadless pacemaker with dual-helix fixation.

BACKGROUND: Complications associated with transvenous pacemakers, specifically those involving the lead or subcutaneous pocket, may be avoided with leadless pacemakers (LPs). The safety and efficacy of single-chamber right ventricular LPs have been demonstrated, but their right atrium (RA) use poses new design constraints. OBJECTIVES: The purpose of this study was to evaluate the implant success, electrical performance, and safety of a novel RA LP design in benchtop and preclinical studies. METHODS: A new LP was designed with a dual-helix fixation mechanism specific to the RA anatomy. A 12-week preclinical ovine study was conducted to evaluate implant success, electrical performance, mechanical stability, and safety in vivo, with supporting benchtop measurements to quantify the mechanical forces needed for device retrieval and dislodgment. RESULTS: LPs were successfully implanted in all 10 ovine subjects with no complications. The pacing capture threshold improved significantly over time from implant to week 12 (1.1 ± 0.7 V vs 0.4 ± 0.2 V, P = .008). Sensing amplitudes and pacing impedances were stable from implant to week 12 (4.8 ± 1.8 mV vs 6.0 ± 1.9 mV, P = .160; and 393 ± 77 Ω vs 398 ± 65 Ω, P = .922, respectively). Gross pathology and microscopic histology revealed no adverse interactions and no evidence of device dislodgment or clinically significant myocardial perforation. Benchtop ex vivo porcine atrial tissue measurements revealed greater pull forces required to dislodge the LP vs transvenous active fixation lead (0.42 ± 0.18 lbf vs 0.29 ± 0.08 lbf, P = .020), and greater rotational forces required for deliberate extraction (0.28 ± 0.04 lbf vs 0.14 ± 0.07 lbf, P <.001). CONCLUSION: The novel atrial LP demonstrated successful implantation, with acceptable electrical performance, mechanical stability, and safety in a 12-week preclinical study.

A novel suprachoroidal microinvasive glaucoma implant: in vivo biocompatibility and biointegration.

BACKGROUND: A major challenge for any glaucoma implant is their ability to provide long-term intraocular pressure lowering efficacy. The formation of a low-permeability fibrous capsule around the device often leads to obstructed drainage channels, which may impair the drainage function of devices. These foreign body-related limitations point to the need to develop biologically inert biomaterials to improve performance in reaching long-term intraocular pressure reduction. The aim of this study was to evaluate in vivo (in rabbits) the ocular biocompatibility and tissue integration of a novel suprachoroidal microinvasive glaucoma implant, MINIject™ (iSTAR Medical, Wavre, Belgium). RESULTS: In two rabbit studies, no biocompatibility issue was induced by the suprachoroidal, ab-externo implantation of the MINIject™ device. Clinical evaluation throughout the 6 post-operative months between the sham and test groups were similar, suggesting most reactions were related to the ab-externo surgical technique used for rabbits, rather than the implant material itself. Histological analysis of ocular tissues at post-operative months 1, 3 and 6 revealed that the implant was well-tolerated and induced only minimal fibroplasia and thus minimal encapsulation around the implant. The microporous structure of the device became rapidly colonized by cells, mostly by macrophages through cell migration, which do not, by their nature, impede the flow of aqueous humor through the device. Time-course analysis showed that once established, pore colonization was stable over time. No fibrosis nor dense connective tissue development were observed within any implant at any time point. The presence of pore colonization may be the process by which encapsulation around the implant is minimized, thus preserving the permeability of the surrounding tissues. No degradation nor structural changes of the implant occurred during the course of both studies. CONCLUSIONS: The novel MINIject™ microinvasive glaucoma implant was well-tolerated in ocular tissues of rabbits, with observance of biointegration, and no biocompatibility issues. Minimal fibrous encapsulation and stable cellular pore colonization provided evidence of preserved drainage properties over time, suggesting that the implant may produce a long-term ability to enhance aqueous outflow.

Pathology Approaches to Determine Safety and Efficacy of Cardiac Ablation Catheters.

Cardiac electrophysiology utilizes nonimplantable, catheter-based devices for diagnosis and treatment of arrhythmias as well as electroanatomical mapping of cardiac chambers. Gross pathology and histopathological assessments in preclinical studies play critical roles in determining the safety and efficacy of cardiac ablation systems used to treat tachyarrhythmias. The pathologist must assess ablation sites, adjacent structures and organs, and downstream organs to characterize the effects of the ablation treatment and determine whether adverse local reactions, collateral injury, or downstream thromboembolism are present. Histopathological assessment serves as an adjunct to electroanatomical data in determining efficacy in preclinical studies. Histopathology is the standard in definitively demonstrating transmurality of ablation lesions, which is necessary for complete conduction block, as well as showing the linear or circumferential distribution of a contiguous, transmural ablation lesion necessary for electroanatomical isolation of entire target structures such as pulmonary veins and the cavotricuspid isthmus, which are involved in propagating certain arrhythmias. This article will detail gross and histological methods for the pathology assessment of preclinical studies evaluating the safety and/or efficacy of cardiac ablation catheter systems as well as discuss correlation of pathology data with other supporting evidence for safety and efficacy such as acute, electroanatomical data.

Balloons and Stents and Scaffolds: Preclinical Evaluation of Interventional Devices for Occlusive Arterial Disease.

Atherosclerosis places a significant burden on humankind; it is the leading cause of mortality globally, and for those living with atherosclerosis, it can significantly impact quality of life. Fortunately, treatment advances have effectively reduced the morbidity and mortality related to atherosclerosis, with one such modality being percutaneous intervention (PCI) to open occluded arteries. Over the 40-year history of PCI, preclinical models have played a critical role in demonstrating proof of concept, characterizing the in vivo behavior (pharmacokinetics, degradation) and providing a reasonable assurance of biologic safety of interventional devices before entering into clinical trials. Further, preclinical models may provide insight into the potential efficacy of these devices with the appropriate study design and end points. While several species have been used in the evaluation of interventional devices, the porcine model has been the principal model used in the evaluation of safety of devices for both coronary and endovascular treatments. This article reviews the fundamentals of permanent stents, transient scaffolds, and drug-coated balloons and the models, objectives, and methods used in their preclinical evaluation.

Evaluation of absorbable PLA nasal implants in an ovine model.

OBJECTIVE: To examine biocompatibility and absorption profile of a poly (L-lactide-co-D,L-lactide) 70:30 nasal implant. METHODS: In an ovine model, 66 rod-shaped absorbable implants were placed in 11 nasal dorsa. The sheep were sacrificed at 1.5 (N = 3), 6 (N = 3), 12 (N = 3), 18 (N = 1), and 24 months (N = 1). The nasal dorsum was harvested from each animal. Gross and histopathological examinations were performed. RESULTS: There were no postoperative complications, signs of infection, or tissue rejection throughout follow-up time points. Upon sacrifice, no abnormalities were identified during gross pathological examinations. The histology of the implant sites at all time points showed the implants were fully encapsulated through 12 months. The inflammatory reaction to the implants was minimal to mild at 1.5, 6, and 12 months. At 18 months the implant material was in the mass loss phase, being actively absorbed. During this phase, the inflammatory reaction within the fibrous connective tissue capsule reached expected moderate levels. By 24 months, the inflammatory reaction had diminished in most implantation sites and complete absorption of the rod implants was noted at some sites with nodular bundles of mature collagenized fibrous tissue replacing the implant, devoid of an inflammatory infiltrate. CONCLUSION: Biocompatibility of the poly (L-lactide-co-D,L-lactide) 70:30 material was demonstrated when used as a nasal implant in the nasal dorsum ovine model. Absorption of the implant occurred approximately 18 to 24 months postoperatively, and the implant site was replaced with collagenized fibrous tissue. LEVEL OF EVIDENCE: NA.

Feasibility and efficacy of percutaneously delivered leadless cardiac pacing in an in vivo ovine model.

INTRODUCTION: In this in vivo ovine study, we describe the course of pacing and sensing parameters during follow-up as well as the gross and histopathological features at the implant site of the recently described leadless cardiac pacemaker (LCP). METHODS AND RESULTS: All sheep underwent LCP implantation in the right ventricular (RV) apex. Serial pacing/sensing thresholds were assessed. In the first cohort, 11 animals were followed up for a period of 3 months, followed by necropsy. In the second cohort, 7 additional sheep were followed for a period of up to 18 months. Mean pacing and sensing thresholds in the 3-month cohort were 1.0 ± 0.5 V and 9.0 ± 3.7 mV at implant, and 0.7 ± 0.2 V and 8.1 ± 3.9 mV at 90 days, respectively. At necropsy at 3 months, all devices were securely implanted at the RV apex without extrusion of helix beyond the RV wall. Besides endocardial reactive changes in the RV apex surrounding the distal portion of the LCP, there were no other grossly visible abnormalities. In the second cohort (7 sheep), mean pacing and sensing thresholds were 1.0 ± 0.5 V and 9.9 ± 3.8 mV at implant, and 0.86 ± 0.4 V and 4.25 ± 1 mV, respectively, at 18 months of follow-up. CONCLUSION: We demonstrate that after implantation of the LCP, pacing/sensing parameters remain adequate up to 18 months in follow-up. In addition, pathological changes at the implant site and within the RV are limited in severity at 90 days, supporting the efficacy and safety of this novel approach to pacing.

Comparison of scanning electron microscopy and optical coherence tomography for imaging of coronary bifurcation stents.

BACKGROUND: Optical coherence tomography (OCT) is a new intracoronary imaging modality that has excellent resolution and image quality and has been used to image neointimal coverage after stent implantation. OCT has been compared to histologic, intravascular ultrasound, and scanning electron microscopy (SEM) studies. However, OCT has not been compared with SEM for imaging stent coverage over side branches. OBJECTIVE: The aim of this study was to compare OCT with SEM in imaging neointimal coverage over stent struts bridging coronary side-branch ostia. METHODS: Using a balloon-overstretch in-stent restenosis model, we deployed 38 everolimus-eluting stents across coronary bifurcations in nine pigs. We performed OCT immediately after stenting and 4 weeks later; SEM was performed after euthanizing the pigs. OCT images of each stent were compared to the corresponding SEM image. RESULTS: We analyzed OCT frames (n=111) for strut-level neointimal coverage and compared them to corresponding SEM images. The concordance correlation coefficient was 0.809 (95%CI; 0.734-0.864) and 0.951 (95%CI; 0.930-0.966) for covered and uncovered struts, respectively. CONCLUSIONS: In a non-atherosclerotic pig model, we showed strong agreement between OCT and SEM in imaging coverage of stent struts bridging side-branch ostia.

Percutaneous Retrieval of Implanted Leadless Pacemakers: Feasibility at 2.5 Years Post-Implantation in an In Vivo Ovine Model.

OBJECTIVES: This in vivo ovine study describes the feasibility and safety of retrieving implanted leadless pacemakers (LPs). BACKGROUND: Although LPs have been shown to be removable soon after implantation, there are no data on the feasibility of removing chronically implanted LPs. METHODS: This study was performed in 2 phases. In the mid-term cohort, 10 chronically (5.3 months) implanted animals underwent retrieval, followed by: 1) immediate necropsy in 5; and 2) in the remaining 5, reimplantation of a new LP followed by necropsy at 6 weeks. In the long-term cohort, 8 additional sheep underwent retrieval at 2.3 ± 0.1 years followed by necropsy. Retrieval was performed using either a single or triple loop snare. All 18 LPs (100%) were successfully retrieved. The time from retrieval catheter insertion to retrieval was 2:35 ± 01:11 and 3:04 ± 01:13 minutes in the mid-term and long-term study groups, respectively. RESULTS: There were no significant differences in retrieval times using either snare. Intracardiac echocardiography was used pre- and post-retrieval to confirm the absence of pericardial effusion in all 8 sheep. On necropsy, there was no evidence of pericardial bleeding or perforation. Only minor tissue disruption and hemorrhage was noted at the implant site after retrieval. Histology demonstrated fibrous connective tissue at the contact sites of endocardium and LP can and at the helix. There was no evidence of pulmonary thromboembolism. CONCLUSIONS: We demonstrate the feasibility and safety of percutaneous, catheter-based retrieval in chronic LP implants of a maximum duration of approximately 2.5 years.

Effective method to remove wound bacteria: comparison of various debridement modalities in an in vivo porcine model.

BACKGROUND: Debridement is one of the crucial steps for successful wound care. In addition to removing necrotic tissue, debridement has been shown to reduce wound-associated bacteria that delay healing. Using an in vivo porcine model, we compared the effects of various methods of debridement, including hydrosurgery and plasma-mediated bipolar radiofrequency ablation (PBRA), on bacterial removal and wound healing. METHODS: One hundred thirty-five deep dermal wounds were inoculated with methicillin resistant Staphylococcus aureus (MRSA) and covered with a polyurethane dressing for 48 h to allow for biofilm formation. Wounds were then treated with either PBRA (at two settings), hydrosurgery, sharp debridement, or no debridement. Biopsies were collected for microbiology and histologic assessment on d 0, 2, 9, and 21 post-treatment. RESULTS: All treatment groups showed a statistically significant reduction in MRSA counts relative to no debridement at all times points (P < 0.05). PBRA at a maximum setting had the lowest MRSA counts at all recovery times and, compared with all other treatment groups, a statistically significant difference was observed on d 21 (P < 0.05). No detrimental effects on the healing process were noted with any of the debridement methods. CONCLUSION: While sharp debridement has been established as the traditional gold standard for rapid removal of necrotic, infected tissue, our results suggest that novel debridement modalities show clinical promise for the treatment of chronic ulcers and burn wounds, especially when bacteria are present.

Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety.

BACKGROUND: Renal sympathetic hyperactivity is associated with hypertension, a leading cause of mortality worldwide. Renal sympathetic denervation via the Symplicity Catheter System has been shown to decrease blood pressure by 33/11 mmHg by 6 months, with no radiofrequency (RF)-related adverse sequelae visible by CT/MR angiography or renal duplex ultrasound 6 months after the procedure. Here, we present preclinical work predating those clinical results. We performed therapeutic renal sympathetic denervation in a swine animal model to characterize the vascular safety and healing response 6 months after renal denervation therapy. METHODS: In December 2007, seven domestic swine received a total of 32 radiofrequency ablations via the Symplicity Catheter System and were euthanatized 6 months later. Renal angiography was done before, immediately after, and 6 months after procedure. The renal vessels were examined histologically with H&E and Movat pentachrome stains to identify evidence of vascular and neural injury. The kidneys and urinary system were also examined for evidence of gross and microscopic abnormalities. RESULTS: Renal nerve injury involved primarily nerve fibrosis, replacement of nerve fascicles with fibrous connective tissue, and thickening of the epineurium and perineurium. Renal arterial findings included fibrosis of 10-25% of the total media and underlying adventitia, with mild disruption of the external elastic lamina. No significant smooth muscle hyperplasia or inflammatory components were observed. There was no renal arterial stenosis or thrombosis observed by angiography or histology. No gross or microscopic device-related abnormalities were noted in the kidney, surrounding stroma, or urinary bladder. CONCLUSIONS: In a swine model, renal denervation via the Symplicity Catheter System resulted in no clinically significant adverse renal artery or renal findings 6 months after the procedure. This is corroborated by the vascular safety profile demonstrated in subsequent human clinical studies.

Evaluation of a novel ventricular support device with defibrillation capabilities in canine and porcine animal models.

INTRODUCTION: Sudden death is prevalent in heart failure patients. We tested an implantable ventricular support device consisting of a wireform harness with one or two pairs of integrated defibrillation electrode coils. METHODS AND RESULTS: The device was implanted into six pigs (36-44 kg) through a subxiphoid incision. Peak voltage (V) defibrillation thresholds (DFT) were determined for five test configurations compared with a control transvenous lead (RV to CanPect). Defibrillator can location (abdominal or pectoral) and common coil separation on the implant (0 degrees or 60 degrees ) were studied.(.) The DFT for RV60 to LV60 + CanPect was significantly less than control (348 +/- 57 vs 473 +/- 27 V, P < 0.05). The DFTs for other vectors were similar to control except for RV0 to LV0 + CanAbd (608 +/- 159 V). The device was implanted into 12 adult dogs for 42, 90, or 180 days with DFT and pathological examination performed at the terminal study. Cardiac pressures were determined at baseline, after implantation, and at the terminal study. The DFT was also determined in a separate group of four dogs at 42 days following implantation of the support device with one pair of defibrillation electrodes. The DFTs at implant and explant in dogs with one pair (8 +/- 1.5 Joules [J] and 6 +/- 1.9 J) or two pairs (8 +/- 3.4 J and 7 +/- 1.9 J) of defibrillation electrodes were not significantly different from each other but significantly less than control measured at the terminal study (18 +/- 3.4 J). Left-sided pressures were significantly decreased at explant but within expected normal ranges. Right-sided pressures were not different except for RV systolic. Histopathology indicated mild to moderate epicardial inflammation and fibrosis, consistent with a foreign body healing response. CONCLUSIONS: This defibrillation-enabled ventricular support system maintained mechanical functionality for up to 6 months while inducing typical chronic healing responses. The DFT was equal to or lower than a standard transvenous vector.

A placebo controlled, dose-ranging, safety study of allogenic mesenchymal stem cells injected by endomyocardial delivery after an acute myocardial infarction.

AIMS: Although mesenchymal stem cells (MSCs) show promising signs in reducing myocardial infarct (MI) size, the safety of endomyocardial delivery and the most efficacious dose is unknown. METHODS AND RESULTS: Three days after MI, female Yorkshire swine (25-32 kg, age 2 months, n = 32) were randomized to endomyocardial delivery of one of three MSC doses (2.4 x 10(7), 2.4 x 10(8), 4.4 x 10(8) cells) or vehicle control. Animals were sacrificed at 12 weeks. There were no safety issues related to cell delivery and all animals tolerated the procedure. By magnetic resonance imaging infarct size (g) was decreased in the experimental groups and increased in the control group; 2.4 x 10(7): Delta -2.5 +/- 2.5 g, 2.4 x 10(8): -0.9 +/- 2.71 g, 4.4 x 10(8): -1.6 +/- 5.8 g, and control +3.6 +/- 3.4 g (P = 0.002, P = 0.016, and P = 0.055 compared with control, respectively). There was no effect on ejection fraction or left ventricular volumes. By histology there were no toxic effects of MSC delivery, however, few engrafted MSCs were observed. CONCLUSION: Direct MSC delivery into infarcted myocardium was safe and produced a local but not a functional effect. There was no dose-dependent effect. The effect of MSCs on infarct reduction may result from transient residence and subsequent paracrine effects.