Substernal Extravascular Implantable Cardioverter-Defibrillator System Infections in Large Animals.

The extravascular implantable cardioverter-defibrillator (EV ICD) with lead implantation in the substernal space may provide clinical advantages over transvenous and subcutaneous systems. This is the first reported examination of substernal infection in large animals implanted with the EV ICD system.The system was implanted in 13 large animals (canine, porcine, and ovine). The porcine were co-implanted with a transvenous cardiac resynchronization therapy with defibrillator (CRT-D) system. Infection was promoted through a cadence of immunosuppressive monitors and study interventions. The animals were monitored for clinical presentation of infection over 12-18 weeks, and cultures were collected to confirm infection. Treatment was bifurcated: 1) some infections were treated only with antibiotics ( "antibiotics only" ), whereas 2) some infections were treated with system removal and antibiotics ( "antibiotics + explant" ). Histopathology was conducted at the study closure.Five infections were confirmed over the course of the study, four of which involved infection of the EV ICD system and one infection of only the concomitantly implanted transvenous CRT-D system without EV ICD-related infection. Among the four EV ICD infections, two of two infections treated with antibiotics only did not resolve whereas two of two infections treated with antibiotics + explant resolved, as shown by histology. The transvenous CRT-D system infection progressed to septicemia and endocarditis, requiring early study discontinuation. No EV ICD-related infection progressed to blood stream infection, and the sternal bone did not become infected when infection was present in the substernal tissues.The study findings suggest that EV ICD-related infections are treatable with system removal and antibiotic therapy.

Three-year extraction experience of a novel substernal extravascular defibrillation lead in sheep.

BACKGROUND: The extravascular implantable cardioverter-defibrillator (EV ICD) with lead implantation in the substernal space may provide an alternative to transvenous and subcutaneous systems. This is the first-reported chronic extraction experience for EV ICD leads. The aim of the study is to evaluate the chronic encapsulation and extractability of EV ICD leads. METHODS: Two EV ICD leads and one transvenous lead were implanted in each of 24 mature sheep. A subset of animals was evaluated yearly for histology and lead extractability. Extractions were performed using simple traction or extraction tools. Histology evaluated the encapsulating tissue. RESULTS: At 1 year, extraction was performed successfully for two of five EV ICD leads with traction alone using ≤3.1 kg-force (kgf) and the remainder extracted successfully with extraction tools; no transvenous leads were removed with traction alone. At 2 years, no EV ICD or transvenous leads were extracted with traction alone, while at 3 years, one of eight EV ICD leads and two of four transvenous leads were extracted with traction (0.8 and ≤2.3 kgf, respectively). There was one observation of hemopericardium resulting in tamponade with EV ICD extraction but without injury to cardiovascular structures and related to the unique implant tract. Among transvenous leads, inversion of the ventricle with loss of cardiac output resulted in abandonment of traction for two animals. CONCLUSIONS: Chronic extraction of EV ICD leads from the substernal space was successfully performed using traction and simple tools through 3 years in sheep with one observation of hemopericardium that did not originate from cardiovascular injury.

First-in-Human Chronic Implant Experience of the Substernal Extravascular Implantable Cardioverter-Defibrillator.

OBJECTIVES: The aim of this study was to evaluate the safety and performance of an extravascular (EV) implantable cardioverter-defibrillator (ICD). BACKGROUND: Limitations of existing transvenous and subcutaneous ICD systems include lead reliability and morbidity issues associated with ICD lead implantation in the vasculature or lack of pacing therapies (e.g., antitachycardia pacing) in subcutaneous systems. The EV defibrillator uses a novel substernal lead placement to address these limitations. METHODS: This was a prospective, nonrandomized, chronic pilot study conducted at 4 centers in Australia and New Zealand. Participants were 21 patients referred for ICD implantation. Patients received EV ICD systems. Data collection included major systemic and procedural adverse events, defibrillation testing at implantation, and sensing and pacing thresholds. RESULTS: Among 20 patients who underwent successful implantation, the median defibrillation threshold was 15 J, and 90% passed defibrillation testing with a ≥10-J safety margin. Mean R-wave amplitude was 3.4 ± 2.0 mV, mean ventricular fibrillation amplitude was 2.8 ± 1.7 mV, and pacing was successful in 95% at ≤10 V. There were no intraprocedural complications. Two patients have undergone elective chronic system removal since hospital discharge. In the 15 patients presently implanted, the systems are stable in long-term follow-up. CONCLUSIONS: This first-in-human evaluation of an EV ICD demonstrated the feasibility of substernal lead placement, defibrillation, and pacing with a chronically implanted system. There were no acute major complications, and pacing, defibrillation, and sensing performance at implantation were successful in most patients. (Extravascular ICD Pilot Study [EV ICD]; NCT03608670).

Novel Doppler-guided subxyphoid approach to avoid coronary artery damage during left ventricular epicardial lead placement or ablation.

BACKGROUND: Subxyphoid active left ventricular epicardial (LVE) lead implants or VT ablation are attractive but remain a challenge due to concerns of coronary artery damage. We aimed to see if Doppler-guided positioning could permit safe LVE lead placement without coronary angiography. We evaluated the feasibility of a Doppler flow-guided subxyphoid epicardial screw-in lead fixation in a swine model. METHODS: Acute subxyphoid access to the pericardial space was performed in an anesthetized swine model using a deflectable sheath and a modified needle-derived Doppler flow meter. The audio signal and visual display from the Doppler flow meter were recorded. Coronary angiography was performed to verify the catheter location. A SelectSecure Model 3830 lead (Medtronic) was used to assess pacing in the procedure. RESULTS: In both of two swine, the deflectable catheter was inserted into pericardial space via subxyphoid access. The tip of the deflectable catheter with the Doppler was directed to several locations, from quiet (no nearby coronary artery expected) to typical rhythmic pulsatile sound locations which were maximal when superimposed on a coronary artery. Repeated coronary angiograms confirmed the expected findings. A 3830 active lead was fixed into a quiet location for LVE pacing, and confirmed by angiography as distant from a coronary artery. CONCLUSIONS: Doppler-guided subxyphoid epicardial screw-in lead placement is feasible once the catheter tip is directed and stabilized in a desired LVE location. This obviates the need for repeated (or any) coronary angiography. The Doppler-guided subxyphoid epicardial procedure may also be applicable for epicardial ventricular arrhythmia ablation procedures.

Motor behaviors in the sheep evoked by electrical stimulation of the subthalamic nucleus.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is used to treat movement disorders, including advanced Parkinson's disease (PD). The pathogenesis of PD and the therapeutic mechanisms of DBS are not well understood. Large animal models are essential for investigating the mechanisms of PD and DBS. The purpose of this study was to develop a novel sheep model of STN DBS and quantify the stimulation-evoked motor behaviors. To do so, a large sample of animals was chronically-implanted with commercial DBS systems. Neuroimaging and histology revealed that the DBS leads were implanted accurately relative to the neurosurgical plan and also precisely relative to the STN. It was also possible to repeatedly conduct controlled evaluations of stimulation-evoked motor behavior in the awake-state. The evoked motor responses depended on the neuroanatomical location of the electrode contact selected for stimulation, as contacts proximal to the STN evoked movements at significantly lower voltages. Tissue stimulation modeling demonstrated that selecting any of the contacts stimulated the STN, whereas selecting the relatively distal contacts often also stimulated thalamus but only the distal-most contact stimulated internal capsule. The types of evoked motor behaviors were specific to the stimulation frequency, as low but not high frequencies consistently evoked movements resembling human tremor or dyskinesia. Electromyography confirmed that the muscle activity underlying the tremor-like movements in the sheep was consistent with human tremor. Overall, this work establishes that the sheep is a viable a large-animal platform for controlled testing of STN DBS with objective motor outcomes. Moreover, the results support the hypothesis that exaggerated low-frequency activity within individual nodes of the motor network can drive symptoms of human movement disorders, including tremor and dyskinesia.

Microembolism and catheter ablation II: effects of cerebral microemboli injection in a canine model.

BACKGROUND: Asymptomatic cerebral lesions have been observed on diffusion weighted MRI (DWI) scans shortly after catheter ablation of atrial fibrillation, but the pathogenesis of these lesions is incompletely understood. METHODS AND RESULTS: Twelve dogs underwent selective catheterization of the internal carotid or vertebral arteries. Either a microbubbled mixture of air (1.0-4.0 mL), blood, contrast, and saline (n=5), or heat-dried pulverized blood (particle size <600 µm) mixed with saline and contrast (n=6) was injected. One sham control experiment was performed. MRI scans were performed preinjection, and at 1, 2, and 4 days postinjection. Neurological tests were performed daily. Gross pathology and histopathology were performed on the brains after being euthanized on day 4. Three animals died <24 hours after injection. Hyperintense lesions were observed on DWI (median maximum diameter 3.1 mm) in 2 of 4 animals after air embolism and in 3 of 5 animals after particulate embolism. No DWI lesions were detected in the remaining 5 animals (including the sham control). Lesions seen on DWI and confirmed on the fluid attenuating inversion recovery sequence correlated well with anatomic lesions on histopathology. CONCLUSIONS: Cerebral embolization of air microbubbles or microparticulate debris that approximate the embolic sources from catheter ablation can create hyperintense DWI punctate lesions in a canine model. The location and size of the DWI/fluid attenuating inversion recovery lesions correlate with pathological findings.

Methods for the development and assessment of atrial fibrillation and heart failure dog models.

OBJECTIVE: To report Medtronic experiences with the development of animal models for atrial fibrillation (AF) and chronic heart failure (CHF) using high-rate pacing for AF and microemboli for CHF. METHODS: For the AF model, an atrial lead was attached to a Medtronic Synergy™ neurostimulator, which was programmed to stimulate at 50 Hz in an on-off duty cycle. Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and N-terminal pro brain natriuretic peptide (NT-proBNP) were assayed at select time points. For CHF model, a serial injection of 90 µm polystyrene microspheres at 62,400 beads/mL (Polybead, Polysciences, Inc.) was performed to induce global ischemia, either with weekly monitoring and embolization schedule (group 1, n = 25) or with biweekly monitoring and emboliation schedule (group 2, n = 36 ). Echocardiograms were used along with ventriculograms and magnetic resonance imaging scans weekly to assess cardiac function and ANP, BNP and NT-proBNP were monitored. RESULTS: For the AF model, the days to sustained AF for four animals following surgery were 7, 25, 21 and 19, respectively; For the CHF model, the days to meet CHF endpoints were 116 in group 1 and 89 in group 2. For both AF and CHF models, NT-proBNP correlated well with the development of disease states. CONCLUSION: Our experience for the development and assessment of AF and CHF dog models may help researchers who are in search for animal model for assessing the safety and efficacy of a device-based therapy.

Surgical approaches to vascular access for large-caliber devices in preclinical research models.

Percutaneous vascular access options in preclinical models are often smaller than the relevant structures in humans or undersized for early-prototype research devices. Here we describe the surgical approaches and results for surgical vascular access sites in preclinical swine and sheep models. Fourteen adult miniature swine underwent successful 18-French vascular access by means of thoracotomy to the brachiocephalic artery. In addition, 11 swine and 10 sheep underwent successful 22-French vascular access by means of retroperitoneal laparotomy to the abdominal aorta. The relevancy of approach angles and vessel tortuosity should be considered when selecting appropriate preclinical models and techniques. The techniques described are effective for delivery of large-caliber devices in preclinical testing.

Feasibility of using an implantable system to measure thoracic congestion in an ambulatory chronic heart failure canine model.

BACKGROUND: Noninvasive measures of impedance reflect alterations in thoracic fluid and pulmonary edema in acute animal and human studies. MATERIALS AND METHODS: We evaluated the feasibility of using an implantable impedance measuring device and cardiac lead system to monitor intrathoracic congestion in a pacing-induced heart failure canine model. Three devices were implanted in each of five dogs: a modified pacemaker to measure impedance from a defibrillation lead implanted in the right ventricle; an implantable hemodynamic monitoring device to measure left ventricular end diastolic pressure (LVEDP) and a second pacemaker to deliver rapid (240 pulses per minute) ventricular pacing to induce heart failure. RESULTS: All five dogs developed severe heart failure after 3-4 weeks of rapid pacing and recovered following pacing termination. The LVEDP increased and impedance decreased during pacing-induced heart failure and recovered after pacing cessation. At the end of pacing, there was a mean impedance reduction of 10.6 +/- 8.3% and a mean LVEDP increase of 18.1 +/- 4.5 mmHg compared to baseline. The impedance and LVEDP were inversely correlated (r =-0.41 to -0.85, all P < 0.05). CONCLUSIONS: In the canine model, measurement of chronic intrathoracic impedance with an implantable system effectively revealed changes in thoracic congestion due to heart failure reflected by LVEDP. These data suggest that implantable device-based impedance measurement merits further investigation as a tool to monitor the fluid status of heart failure patients.

Myoplasmic calcium regulation in myotubes from horses with recurrent exertional rhabdomyolysis.

OBJECTIVE: To determine whether alterations in myoplasmic calcium regulation can be identified in muscle cell cultures (myotubes) and intact muscle fiber bundles derived from Thoroughbreds affected with recurrent exertional rhabdomyolysis (RER). ANIMALS: 6 related Thoroughbreds with RER and 8 clinically normal (control) Thoroughbred or crossbred horses. PROCEDURES: Myotube cell cultures were grown from satellite cells obtained from muscle biopsy specimens of RER-affected and control horses. Fura-2 fluorescence was used to measure resting myoplasmic calcium concentration as well as caffeine- and 4-chloro-m-cresol (4-CMC)-induced increases in myoplasmic calcium. In addition, intact intercostal muscle fiber bundles were prepared from both types of horses, and their sensitivities to caffeine- and 4-CMC-induced contractures were determined. RESULTS: Myotubes of RER-affected and control horses had identical resting myoplasmic calcium concentrations. Myotubes from RER-affected horses had significantly higher myoplasmic calcium concentrations than myotubes from control horses following the addition of > or = 2mM caffeine; however, there was no difference in their response to 4-CMC (> or = 1 mM). Caffeine contracture thresholds for RER and control intact muscle cell bundles (2 vs 10mM, respectively) were significantly different, but 4-CMC contracture thresholds of muscle bundles from RER-affected and control horses (500 microM) did not differ. CONCLUSIONS AND CLINICAL RELEVANCE: An increase in caffeine sensitivity of muscle cells derived from a family of related RER-affected horses was detected in vitro by use of cell culture with calcium imaging and by use of fiber bundle contractility techniques. An alteration in muscle cell calcium regulation is a primary factor in the cause of this heritable myopathy.