From Idea to Reality: A Brief Tour Inside Our Research Lab

Background

The concept of evaluating pulses as a mechanical indicator of heart activity has ancient roots; the first clinical arrhythmia studies were a part of traditional Chinese medicine in the 5th century BC.¹ In 1902, a significant breakthrough of diagnosing cardiac arrhythmias occurred with the invention of the first human electrocardiogram by Willem Einthoven in Leiden, The Netherlands.² Nearly 80 years later, four electrophysiologists (Drs. J. Warren Harthorne, Victor Parsonnet, Seymour Furman, and Dryden Morse) recognized the importance of a society dedicated to pacing and electrophysiology, and established the North American Society of Pacing and Electrophysiology (NASPE) in 1979.³

Over the last decade, our knowledge in basic cardiac electrophysiology has undergone significant evolution due to the rapid improvement of cellular electrophysiology, molecular biology, genetics, three-dimensional imaging, and computer modeling. As a result, cardiac electrophysiology has become an important subspecialty in cardiovascular medicine.⁴

The Electrophysiology Clinical Research and Innovations (EPCRI) department at the Texas Heart Institute is focused on creating and developing an infrastructure for research and innovation in the field of cardiac arrhythmia research and management. With this mission in mind, the team continually strives towards improving quality of life and overall patient outcomes. To accomplish this goal, the lab is currently developing several novel techniques to deliver therapy. In this paper, we briefly review our current projects.

Carbon Nanotube Fibers (CNTF)

Cardiovascular disease is the leading cause of death worldwide. Almost 610,000 people die of heart disease each year in the United States, which is 1 in every 4 patients.⁵ Sudden cardiac death (SCD) affects an estimated 300,000 to 450,000 Americans annually.⁶ Ventricular tachycardia (VT) most commonly occurs in patients with structural heart disease and its progression can lead to ventricular fibrillation, which accounts for 80% of SCDs.⁶ Ischemic or scarred myocardium after myocardial infarction (MI) can make cardiac substrates more prone to VT.⁷

Implantable cardioverter-defibrillators (ICDs) are used to prevent SCD in patients with lethal arrhythmia by delivering either anti-tachycardia pacing (ATP) or a shock to terminate the VT, but this method of therapy has limited capacity to prevent VT as it does not have a restorative effect upon myocardial conduction velocity.⁸

The collaborative work with Rice University in evaluating the role of carbon nanotube fibers (CNTFs; Figure 1), funded by the American Heart Association (AHA), and has shown a great deal of promise in the ability of the fibers to reconstitute myocardial conduction in paced conditions on small animal models. The findings of this study are expected to be published soon. In this study, we found that CNTFs sewn across the epicardial scar acutely improve conduction in sheep. In addition, CNTFs maintain conduction for one month after AV node ablation without inflammatory or toxic responses in rats.⁹ Our lab is currently conducting further acute and chronic studies to demonstrate the capability of the fibers to provide myocardial conduction in large animals.

Development of Wirelessly Powered Leadless Pacemaker

Recent collaborations with Rice University and UCLA have resulted in the development of wirelessly powered leadless pacing and sensing nodes.¹⁰ Our preliminary work showed the ability to pace the atrium and both ventricles simultaneously using multiple miniature chips. Currently, we are optimizing the pacing chip design to further reduce power consumption and add additional features such as synchronized pacing (Figure 2). We aim to further develop this technology, test the use of the pacing chips to defibrillate through multisite pacing, and develop an endocardial deployment method in the upcoming months. Miniaturized sensing nodes across the myocardium open avenues for new diagnosis and therapy. While conventional pacemakers use two to three leads to diagnose, miniaturized nodes allow for sensing from numerous locations, creating spatially and temporally resolved electrophysiological maps.

Precise Detection of the Desired Locations for Ablation

The EPCRI lab is working with the Department of Electrical and Computer Engineering at Rice University on a National Science Foundation (NSF) funded machine learning project to develop an algorithm for electrophysiology applications for faster and more precise detection of the desired locations for ablation to treat different arrhythmias. The prediction of time-series has long been studied and remains an important machine learning paradigm.¹¹ The investigation and development of a model that could combine, remove nuisance, denoise, and have a high memory capability is at the epicenter of this field. Our proposed approach to develop algorithms using data from multiple channels across the heart allows for delivering therapies tailored towards individual pathologies and patients. Our machine learning algorithm will classify pathophysiologies and define the target for successful ablation by using the data recorded from multiple sites across the heart. This algorithm will boost the success rate of ablation therapy by helping the physician to quickly and more accurately find sources of arrhythmia.

Low-Energy, Painless Cardioversion

The underlying mechanism by which an electrical shock directly leads to defibrillation is still widely studied. The most prevalent mechanism is called the “virtual electrode hypothesis”.¹² Per this hypothesis, an electrical stimulation can create “virtual” electrodes around the area of the stimulation, which causes further depolarization of the cardiac tissue. This, in turn, can “reset” the heart. Direct current cardioversion (DCCV) is a method to extinguish arrhythmia by supplying large amounts of energy as an electrical shock to the patient. While effective, this method comes with possible complications. Some studies have explored pacing mediated cardioversion by pacing from multiple sites across the myocardium.¹³ These studies have shown that pacing from multiple sites simultaneously can lead to cardioversion of the heart at an energy much lower than current DCCV techniques. The EPCRI lab, in an aim to develop imperceptible low-energy defibrillation, is currently researching a multisite pacing therapy to restore myocardial conduction. Preliminary large animal studies have shown that pacing from multiple sites (five sites in each atria) can extinguish arrhythmia using energies that are typically required for pacing. Future studies aim to provide statistical significance to these findings.

Safe Access to the Pericardial Space

The pericardium is a double-layered fibroserous sac that is made up of an outer layer known as parietal, and an inner layer known as visceral, which is invaginated by the heart. The pericardial cavity is filled with 20-25 cc of fluid and has a limited amount of space between the layers, which increases the risk of damage to the myocardial wall (usually the right ventricle) and/or epicardial vessels during epicardial access for the treatment of cardiac arrhythmias.¹⁴ We are working to develop a device to ensure safe access to the pericardial space, using a technique based on real-time continuous bioimpedance monitoring. This project is funded by the Roderick D. MacDonald Research Fund. We have performed a series of animal studies to demonstrate the ability of this device to identify different tissues by bioimpedance in real time. We have received very promising results from our experiments, and have developed a modified 21 G micropuncture needle that can be used to safely access the pericardial space (Figure 3). Initial experience with the needle has shown that the pericardial sac has a unique impedance spectrum that can be leveraged for developing an algorithm to guide physicians during access.

Left Atrial Appendage Isolation with Alcohol

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and the risk of stroke is four to five times higher in these patients compared to those without AF due to thrombus formation. More than 90% of thrombus accumulation occurs in the left atrial appendage (LAA).¹⁵

Circumferential pulmonary vein isolation (PVI) is the standard therapy for paroxysmal atrial fibrillation (PAF), but ablation of longstanding persistent (LSP) atrial fibrillation is more challenging and requires more than just PV isolation. The BELIEF (Effect of Empirical Left Atrial Appendage Isolation on Long-term Procedure Outcome in Patients With Persistent or Longstanding Persistent Atrial Fibrillation Undergoing Catheter Ablation) showed that LAA isolation improves long-term freedom from atrial arrhythmias without increasing complications.¹⁶ In addition, LAA closure is a recommended treatment to prevent strokes in high-risk patients with nonvalvular AF who are not candidates for oral anticoagulation (OAC) therapy or in whom OAC therapy has failed.¹⁷

Our lab is working on developing a catheter-based device that can electrically isolate the LAA safely using alcohol ablation (Figure 4). LAA alcohol ablation could be used as a standalone method for isolating the LAA to increase success rates of PVI in patients with LSP-AF, or in combination with mechanical excluders of the LAA to possibly decrease AF burden as well as to prevent stroke. Furthermore, the use of alcohol ablation instead of radiofrequency catheter ablation ensures that an interventionalist can perform the procedure without the need for a specialized electrophysiologist. Alcohol ablation may also facilitate LAA ablation by decreasing the chance of LAA perforation, but should be tested further in animal and clinical studies. 

Disclosures: The authors have no conflicts of interest to report regarding the content herein. Outside the submitted work, Brian D. Greet, MD reports he is named in patents for pericardial access and novel pacing devices; Mathews M. John, MEng reports two patents pending.

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