SBIR-STTR Award

The broad and long-term objective of this research project is to use, develop and market an instrument for the simultaneous recording of sympathetic nerve activity (SNA) and electrocardiogram (ECG) using electrodes on the skin. This method (neuECG) was discovered in Dr. Chen's research laboratory at the Krannert Institute of Cardiology, and a patent application has been filed by Indiana University. Arrhythmotech LLC was developed to further advance this concept and we propose that neuECG has a significant commercial value by providing a new non-invasive tool for arrhythmia prediction and detection. Sympathetic tone is important in cardiac arrhythmogenesis. Heart rate variability analyses and microneurography recordings are standard techniques to assess sympathetic tone. However, these techniques have multiple limitations. The neuECG was developed to record ECG and nerve activity simultaneously on the skin of human subjects. In collaboration with Dr. Chen's lab, we have obtained strong preliminary results in human patients to document the successful recording of neuECG in normal volunteers and in patients with postoperative atrial fibrillation and electrical storm. In these preliminary studies, neuECG recording showed electrical signals consistent with SNA, and that the SNA correlated with heart rate acceleration, atrial fibrillation and ventricular arrhythmias. We propose that the neuECG may serve as a new diagnostic tool for the prediction of cardiac arrhythmias and sudden cardiac death. In addition, it may be helpful in the diagnosis of diseases involving the peripheral nervoussystem, such as neuromuscular diseases. In this Phase 1 application, we have designed two clinical studies to document the feasibility and utility of neuECG recording in normal volunteers and in patients with cardiac arrhythmias. Once this is complete, we will immediately apply for Phase 2 funding to commercialize the neuECG for human use. Specific Aim 1: To record simultaneous ECG and SNA in normal volunteers and correlate the nerve activity to heart rate. We will consent normal volunteers for this study. We will place ECG electrodes on the skin using standard limb lead and chest lead configurations. The signals are digitized and filtered to record ECG and SNA simultaneously. After baseline recordings, the patients will undergo 2-min cold water immersion test, followed by Valsalva maneuver. The data will be analyzed to test the hypothesis that it is feasible to simultaneously record SNA from the skin, and that SNA recordings correlate with heart rate acceleration in normal volunteers. Specific Aim 2: To record simultaneous ECG and SNA in patients with cardiac arrhythmias and correlate an increase in nerve activity to arrhythmia onset. We will perform continuous neuECG recording at the bedside in patients with recurrent cardiac arrhythmias. The data will be analyzed to determine if the SNA are present on the skin of the diseased patients, and if the SNA correlates with the onset of cardiac arrhythmias. The results will be used to test the hypothesis that a continuous neuECG recording is feasible in patients with heart diseases, and that SNA predicts the impending onset of cardiac arrhythmias.

Thesaurus Terms:
Acceleration;Arrhythmia;Atrial Fibrillation;Autonomic Nerve;Canis Familiaris;Cardiac;Cardiology;Chest;Clinical Research;Collaborations;Consent;Data;Death, Sudden, Cardiac;Design;Detection;Development;Disease Diagnosis;Electrocardiogram;Electrodes;Funding;Heart Atrium;Heart Diseases;Heart Failure;Heart Rate;Heart Rate Variability;Human;Human Subject;Immersion Investigative Technique;Implant;Improved;Indiana;Institutes;Instrument;Laboratory Research;Lead;Legal Patent;Limb Structure;Marketing;Measures;Methods;Modeling;Nerve;Neuromuscular Diseases;Novel Diagnostics;Patients;Peripheral Nervous System;Phase;Postoperative Period;Procedures;Public Health Relevance;Recurrence;Research Project Grants;Response;Risk;Signal Transduction;Sinus;Skin;Stratification;Structure Of Stellate Ganglion;Subcutaneous;Subcutaneous Tissue;Techniques;Testing;Thoracotomy;Tool;Universities;Valsalva Maneuver;Ventricular Arrhythmia;Ventricular Fibrillation;Ventricular Tachycardia;Volunteer;Water;

The objective of this Phase II STTR grant application is to continue the R/R&D efforts initiated in Phase I. The long-term objective for Arrhythmotech is to develop and market an instrument for the simultaneous recording of sympathetic nerve activity (SNA) and electrocardiogram (ECG) using electrodes on the skin. This method (neuECG) was discovered in Dr. Chen's research laboratory at the Krannert Institute of Cardiology, and a patent application has been filed by Indiana University. Arrhythmotech LLC was founded to further advance this concept, and we propose that neuECG will have significant commercial value by providing a new tool for arrhythmia prediction and detection. Significant progress has been made with the Phase I STTR funding. Phase II will expand the clinical research to firmly validate the neuECG as a method to estimate cardiac sympathetic tone, and to develop and test prototypes that can be used for future clinical investigations, while laying th groundwork for Phase III commercialization of the first application. Sympathetic tone is important in cardiac arrhythmogenesis. However, the existing method of SNA measurement is either invasive or not accurate. We have therefore developed methods to directly record SNA from either subcutaneous tissues or on the surface of the skin in canine models. We found that both subcutaneous nerve activity (SCNA) and superficial skin sympathetic nerve activity (SKNA) closely correlate with stellate ganglia nerve activity (SGNA) in ambulatory dogs. With the generous support of a Phase I STTR grant, we were able to obtain preliminary results in human patients that strongly suggest the validity of SKNA in estimating sympathetic tone. We have successfully developed prototypes that can be used for long-term SKNA recording. We will pursue the following Specific Aims. Specific Aim 1: Unequivocally validate SKNA as a highly accurate non-invasive measure of skin SNA with simultaneous microelectrode recordings. These studies will be performed by Dr. Ronald Victor of Cedars-Sinai Medical Center. Specific Aim 2: To test the hypothesis that lidocaine injection into the stellate ganglion or surgical stellectomy will reduce or eliminate the SKNA recorded from the arms. These studies will be done by Dr. Yong-Mei Cha of the Mayo Clinic. In addition to validating SKNA as a measure of skin SNA, these studies may also lead to commercial applications by providing a tool to measure the success of neuromodulation procedures. Specific Aim 3: Demonstrate that SKNA as measured by neuECG can serve as a novel biomarker for testing atrial fibrillation vulnerability. These studies will be done at Indiana University. Our preliminary results indicate that specific SKNA patterns are closely associated with the spontaneous occurrence of paroxysmal AF. Those specific patterns can be considered as novel biomarkers that are useful in arrhythmia management, such as guiding radiofrequency catheter ablation procedures and predict the long term success of these procedures. Successful completion of these 3 specific aims will give Arrhythmotech, LLC an excellent platform for future commercial applications.

Public Health Relevance Statement:


Public Health Relevance:
The purpose of this STTR Phase II application is to unequivocally validate skin sympathetic nerve activity as a highly accurate non-invasive measure of sympathetic tone. Because sympathetic tone is important in the pathogenesis of diseases, the ability to non-invasively measure sympathetic tone from the skin is highly clinically significant.

NIH Spending Category:
Cardiovascular; Clinical Research; Drug Abuse (NIDA only); Heart Disease; Neurosciences; Substance Abuse

Project Terms:
Applications Grants; arm; Arousal; Arrhythmia; Atrial Fibrillation; autonomic nerve; Canis familiaris; Cardiac; Cardiology; Clinic; clinical investigation; Clinical Research; clinically significant; Cocaine; commercial application; commercialization; Detection; Devices; Dexmedetomidine; Disease; Electrocardiogram; Electrodes; Funding; Future; Ganglionic Blockers; Grant; Heart Atrium; Heart failure; heart rate variability; Human; human subject; Indiana; Injection of therapeutic agent; Institutes; instrument; Laboratories; Laboratory Research; Lead; Legal patent; Lidocaine; Marketing; Measurement; Measures; median nerve; Medical center; Methods; Microelectrodes; Modeling; Muscle; Myocardial; Nerve; neuroregulation; novel marker; Operative Surgical Procedures; Pathogenesis; Patients; Pattern; Phase; phase 2 study; Physiologic pulse; Procedures; prototype; public health relevance; Radiofrequency Catheter Ablation; Research; research and development; response; Risk; Sinus; Skin; Small Business Technology Transfer Research; Stimulus; Stratification; Structure of stellate ganglion; Structure of ulnar nerve; subcutaneous; Subcutaneous Tissue; success; Surface; Techniques; Testing; Thoracotomy; tool; Universities; Ventricular Arrhythmia