Translation to Practice: Accelerating the Cycle of Innovation to Impact.

The Office of Translation to Practice (OTP) is housed in the Center for Clinical and Translational Sciences at Mayo Clinic. Established in 2015, the office was tasked with developing and managing novel tools, mechanisms, and processes to facilitate and accelerate the translation of products, such as drugs, biological agents, and medical devices, into practice. Since its inception, the OTP is credited with creating valuable services through several strategic alliances and active scientific and project management involvement.

Percutaneous Epicardial Pacing using a Novel Insulated Multi-electrode Lead.

Introduction: Epicardial cardiac resynchronization therapy (CRT) permits unrestricted electrode positioning. However, this requires surgical placement of device leads and the risk of unwanted phrenic nerve stimulation. We hypothesized that shielded electrodes can capture myocardium without extracardiac stimulation.

Novel Techniques in Epilepsy Management: Venous Pacing and Capture of Electrical Activity in the Primate Cortex.

Objective: Pharmacotherapy for epilepsy is limited with 30% of patients refractory to this approach of suppressing seizures. Current surgical options are invasive and carry significant morbidities including infection, bleeding, and the potential for deleterious neurocognitive effects. As a result, there is a burgeoning need for innovation to develop safer and efficacious interventions.

Novel Percutaneous Epicardial Autonomic Modulation in the Canine for Atrial Fibrillation: Results of an Efficacy and Safety Study.

Background: Endocardial ablation of atrial ganglionated plexi (GP) has been described for treatment of atrial fibrillation (AF). Our objective in this study was to develop percutaneous epicardial GP ablation in a canine model using novel energy sources and catheters.

Methods: Phase 1: The efficacy of several modalities to ablate the GP was tested in an open chest canine model (n = 10).

Direct Pulmonary Vein Ablation With Stenosis Prevention Therapy.

Introduction: The dominant location of electrical triggers for initiating atrial fibrillation (AF) originates from the muscle sleeves inside pulmonary veins (PVs). Currently, radiofrequency ablation (RFA) is performed outside of the PVs to isolate, rather than directly ablate these tissues, due to the risk of intraluminal PV stenosis.

Methods: In 4 chronic canine experiments, we performed direct PV muscle sleeve RFA ± postablation drug-coated balloon (DCB) treatment with paclitaxel/everolimus.

Percutaneous ligation of the left atrial appendage results in atrial electrical substrate modification.

Debulking of electrically active atrial tissue may reduce the mass of fibrillating tissue during atrial fibrillation, eliminate triggers, and promote maintenance of normal sinus rhythm (NSR). We investigated whether left atrial appendage (LAA) ligation results in modification of atrial electrical substrate. Healthy male mongrel dogs (N = 20) underwent percutaneous epicardial LAA ligation.

Novel balloon catheter device with pacing, ablating, electroporation, and drug-eluting capabilities for atrial fibrillation treatment--preliminary efficacy and safety studies in a canine model.

Pulmonary vein isolation is an established therapeutic procedure for symptomatic atrial fibrillation (AF). This approach involves ablation of atrial tissue just outside the pulmonary veins. However, patient outcomes are limited because of a high rate of arrhythmia recurrence.

Transvenous stimulation of the renal sympathetic nerves increases systemic blood pressure: a potential new treatment option for neurocardiogenic syncope.

Background: Neurocardiogenic syncope (NCS) is a common and sometimes debilitating disorder, with no consistently effective treatment. NCS is due to a combination of bradycardia and vasodilation leading to syncope. Although pacemaker devices have been tried in treating the bradycardic aspect of NCS, no device-based therapy exists to treat the coexistent vasodilation that occurs.

Advances in radiofrequency ablation of the cerebral cortex in primates using the venous system: Improvements for treating epilepsy with catheter ablation technology.

Background: Pharmacology frequently fails for the treatment of epilepsy. Although surgical techniques are effective, these procedures are highly invasive. We describe feasibility and efficacy of minimally invasive mapping and ablation for the treatment of epilepsy.

Use of the aortoatrial continuity as means of providing left ventricular assist support without entering the ventricle: a feasibility study.

Background: Left ventricular assist devices (LVADs) are increasingly used to treat patients with refractory heart failure. Current-generation LVADs have major limitations, including the need for open chest surgery, limiting their widespread use. We hypothesized that the aortoatrial continuity could be used as a unique anatomic vantage point for entirely percutaneous LVAD placement.

Percutaneous epicardial left atrial appendage closure: intermediate-term results.

Unlabelled: Chronic Percutaneous Epicardial Appendage Closure.

Objectives: To assess the chronic safety and feasibility of percutaneous epicardial closure of the left atrial appendage (LAA) guided by electrical navigation.

Background: Atrial fibrillation (AF) is associated with stroke, and LAA occlusion may be a useful nonpharmacologic strategy for stroke prevention in AF.

Future Developments in Nonsurgical Epicardial Therapies.

The unique anatomic position of the pericardium in juxtaposition to central cardiac structures enables it to serve as the ideal vantage point for the delivery of novel cardiovascular therapies. Development of new tools to permit delivery of therapy in the closed pericardial space holds promise for near-surgical access to the heart, without open surgical morbidity. Early observations raise hope for the availability of epicardial leads to enhance cardiac resynchronization therapy designed for subxiphoid nonsurgical percutaneous delivery.

Synchronous ventricular pacing without crossing the tricuspid valve or entering the coronary sinus--preliminary results.

Background: Right ventricular apical (RVA) pacing promotes tricuspid regurgitation (TR), electromechanical dyssynchrony, and ventricular dysfunction. We tested a novel intramyocardial bipolar lead to assess whether stimulation of the atrioventricular septum (AVS) produces synchronous ventricular activation without crossing the tricuspid valve (TV).

Methods: A lead with an active external helix and central pin was placed on the AVS and the RVA in three dogs.

Percutaneous epicardial left atrial appendage closure: preliminary results of an electrogram guided approach.

Background: Pharmacologic therapies to prevent stroke in atrial fibrillation (AF) have numerous limitations, prompting the development of device-based therapies. We investigated whether an electrogram-based approach using a novel hollow suture can safely capture and ligate the left atrial appendage (LAA).

Methods And Results: A novel system for closure of the LAA within the confines of the closed pericardium with a single sheath puncture was tested in 4 dogs.

Intramyocardial pacing and sensing for the enhancement of cardiac stimulation and sensing specificity.

Background: Intracardiac electrodes create an "antenna" capable of unintentionally recording and stimulating tissue beyond the chamber in which they are positioned, resulting in far-field R wave oversensing in pacemakers and inappropriate detection in defibrillators. This feasibility study sought to determine whether a specially constructed lead with two distal totally intramyocardial electrodes could overcome these limitations.

Methods: Two mongrel dogs were anesthetized and a median sternotomy performed.

Membrane localization of v-ErbB is required but not sufficient for ligand-independent transformation.

The v-ErbB retroviral oncogene is a transduced, mutated copy of the avian EGF receptor gene, and its expression is sufficient to induce tumor formation in vivo. The structural alterations that release the oncogenic potential of the v-ErbB oncogene are similar to EGFR gene mutations described in human tumors. Thus, the study of v-ErbB tumor biology offers a useful model through which we can gain insight into the mechanism of EGFR-induced malignancies.

Grb2 regulation of the actin-based cytoskeleton is required for ligand-independent EGF receptor-mediated oncogenesis.

Mutations within members of the EGF/ErbB receptor family frequently release the oncogenic potential of these receptors, resulting in the activation of downstream signaling events independent of ligand regulatory constraints. We previously have demonstrated that the signal transduction events originating from S3-v-ErbB, a ligand-independent, oncogenic EGF receptor mutant, are qualitatively distinct from the ligand-dependent mitogenic signaling pathways associated with the wild-type EGF receptor. Specifically, expression of S3-v-ErbB in primary fibroblasts results in anchorage-independent growth, increased invasive potential, and the formation of a transformation-specific phosphoprotein signaling complex, all in a Ras-independent manner.

Ligand-independent oncogenic signaling by the epidermal growth factor receptor: v-ErbB as a paradigm.

Relay of information from the extracellular environment into the cell often results from a peptide growth factor binding to its cognate cell surface receptor; this event is an integral mechanism by which many cellular functions occur, including cell growth, motility, and survival. In recent years, however, this requirement for ligand binding has been shown to be surpassed by several distinct mechanisms, including cell surface receptor cross-talk (e.g.

The EGF/ErbB receptor family and apoptosis.

The ErbB receptor family can activate a multitude of cell signaling pathways that involve many aspects of cellular function. The four members of the ErbB receptor family interact with diverse ligands and substrates, as well as with each other through cell surface heterodimerization. The sum of these diverse interactions is a signaling network that is complex but also finely regulated.

Ligand-independent oncogenic transformation by the EGF receptor requires kinase domain catalytic activity.

The retroviral oncogene S3-v-erbB is a transduced, truncated form of the avian EGF (ErbB-1) receptor. Infection of avian fibroblasts with a retroviral vector expressing S3-v-ErbB results in ligand-independent cell transformation, which is accompanied by the assembly of a transformation-specific phosphoprotein signaling complex and anchorage-independent cell growth. It previously had been reported, using lysine-721 mutants (K721), that kinase domain function was required for ErbB-mediated cell transformation.