Electrophysiology devices and the regulatory approval process within the U.S. FDA and abroad.

Almost all electrophysiology (EP) devices need to obtain premarket approval before they can be commercially sold and available for use in the community. The US Food and Drug Administration (FDA) has different paths to market approval depending on the intended use and the associated risks of the device. The European Union and Japan have device approval processes that have many similarities as well as differences to the US regulatory system. This paper describes some of the history and background of the US device approval process with an emphasis on EP devices. It provides an overview of the different regulatory pathways in the USA that are currently being utilized and contrasts them to the procedures often used in the European Union and in Japan. It also touches on the impact of the twenty-first Century Cures Act and how the balance between premarket and postmarket regulatory oversight is continually being examined and refined.

Emerging role of cardiac computed tomography in heart failure.

Despite medical advancements, the prognosis of patients with heart failure remains poor. While echocardiography and cardiac magnetic resonance imaging remain at the forefront of diagnosing and monitoring patients with heart failure, cardiac computed tomography (CT) has largely been considered to have a limited role. With the advancements in scanner design, technology, and computer processing power, cardiac CT is now emerging as a valuable adjunct to clinicians managing patients with heart failure. In the current manuscript, we review the current applications of cardiac CT to patients with heart failure and also the emerging areas of research where its clinical utility is likely to extend into the realm of treatment, procedural planning, and advanced heart failure therapy implementation.

Multiple Shifts of the Earliest Retrograde Atrial Activation Site Along the Tricuspid Annulus During the Fast-Slow Form of Atrioventricular Nodal Reentrant Tachycardia by Radiofrequency Modification.

A 70-year-old woman was admitted for treatment of supraventricular tachycardia. Ventriculoatrial conduction was revealed through programmed ventricular stimulation; the coronary sinus ostium (CSos) was the earliest atrial activation site. The fast-slow forms of atrioventricular nodal reentrant tachycardia (AVNRT) were induced by ventricular extra-stimuli. During tachycardia, the earliest atrial activation site was located at the bottom of CSos. Radiofrequency (RF) energy application to this site resulted in the delay of local electrical potential, prolongation of tachycardia cycle length, and a shift of the earliest retrograde activation site to the roof of CSos. Subsequent ablation induced a similar shift to the inferior tricuspid annulus and to the right posterior septum. Finally, RF energy application to the right posterior septum resulted in the termination of tachycardia, which was not induced afterward. Multiple shifts in the earliest retrograde atrial activation site along the tricuspid annulus after each slow pathway ablation suggested that annular tissue plays a substantial role as a substrate for AVNRT.

High-speed mechano-active multielectrode array for investigating rapid stretch effects on cardiac tissue.

Systematic investigations of the effects of mechano-electric coupling (MEC) on cellular cardiac electrophysiology lack experimental systems suitable to subject tissues to in-vivo like strain patterns while simultaneously reporting changes in electrical activation. Here, we describe a self-contained motor-less device (mechano-active multielectrode-array, MaMEA) that permits the assessment of impulse conduction along bioengineered strands of cardiac tissue in response to dynamic strain cycles. The device is based on polydimethylsiloxane (PDMS) cell culture substrates patterned with dielectric actuators (DEAs) and compliant gold ion-implanted extracellular electrodes. The DEAs induce uniaxial stretch and compression in defined regions of the PDMS substrate at selectable amplitudes and with rates up to 18 s-1. Conduction along cardiomyocyte strands was found to depend linearly on static strain according to cable theory while, unexpectedly, being completely independent on strain rates. Parallel operation of multiple MaMEAs provides for systematic high-throughput investigations of MEC during spatially patterned mechanical perturbations mimicking in-vivo conditions.

Organic Electrochemical Transistor Arrays for In Vitro Electrophysiology Monitoring of 2D and 3D Cardiac Tissues.

Here, a multichannel organic electrochemical transistor (OECT) array is reported for electrophysiological monitoring and mapping of action potential propagation of a wide range of cardiac cells, including cell lines, primary cell lines, and human-sourced stem cell derivatives in 2D and 3D structures. The results suggest that the ability to exploit this OECT-based platform to map 2D action potential propagation provides a viable strategy to better characterize cardiac cells in response to various chronotropic drugs. The effects of chronotropic agents Isoproterenol and Verapamil on cardiac tissues validate the utility of OECT for drug screening capability, and a preliminary demonstration of a 64-channel OECT array to monitor the cardiac action potentials for better spatial resolution is presented. The study demonstrates that OECT will be a viable and versatile platform for applications in medical and pharmacological industries.

A review of bioelectrodes for clinical electrophysiologists.

The theory of bioelectrodes describes the rules governing the passage of electrical charge between electrodes and electrolytes. In this review, we explain the basis of bioelectrodes with focus on clinical electrophysiology. The central concept is the double-layer capacitance that forms in the interface between the electrode and tissue. This phenomenon controls charge transfer between electrodes and tissues and contributes to detrimental effects such as electrode polarization and motion artifacts. Many methods critical to the practice of electrophysiology, including fractally coated pacemaker leads, biphasic stimuli, signal filtering, and the use of nonpolarizable electrodes, are devised to mitigate these problems. Our goal is to provide a robust and intuitive background on these topics for practicing electrophysiologists to help them better understand how catheters and leads work and to assist them with optimizing and troubleshooting electrophysiology systems.

Simultaneous electrical recording of cardiac electrophysiology and contraction on chip.

Prevailing commercialized cardiac platforms for in vitro drug development utilize planar microelectrode arrays to map action potentials, or impedance sensing to record contraction in real time, but cannot record both functions on the same chip with high spatial resolution. Here we report a novel cardiac platform that can record cardiac tissue adhesion, electrophysiology, and contractility on the same chip. The platform integrates two independent yet interpenetrating sensor arrays: a microelectrode array for field potential readouts and an interdigitated electrode array for impedance readouts. Together, these arrays provide real-time, non-invasive data acquisition of both cardiac electrophysiology and contractility under physiological conditions and under drug stimuli. Human induced pluripotent stem cell-derived cardiomyocytes were cultured as a model system, and used to validate the platform with an excitation-contraction decoupling chemical. Preliminary data using the platform to investigate the effect of the drug norepinephrine are combined with computational efforts. This platform provides a quantitative and predictive assay system that can potentially be used for comprehensive assessment of cardiac toxicity earlier in the drug discovery process.

The Current State and Future Potential of Pediatric and Congenital Electrophysiology.

Pediatric electrophysiologists specialize in the diagnosis and treatment of rhythm abnormalities in pediatric, congenital heart disease, and inherited arrhythmia syndrome patients. The field originated out of the unique knowledge base that rhythm management in young patients required. In the 1970s, pediatric electrophysiology was recognized as a distinct cardiac subspecialty and it has evolved rapidly since that time. Despite the considerable growth in personnel, technology, and complexity that the field has undergone, further opportunities to progress pediatric electrophysiology exist. In this review, we highlight some of the clinical focus of pediatric and adult congenital electrophysiologists to date and identify areas within this specialty where the pediatric and congenital electrophysiology community could come together in order to drive improvements in rhythm management for patients.

Non-fluoroscopic catheter tracking for fluoroscopy reduction in interventional electrophysiology.

A technological platform (MediGuide) has been recently introduced for non-fluoroscopic catheter tracking. In several studies, we have demonstrated that the application of this non-fluoroscopic catheter visualization system (NFCV) reduces fluoroscopy time and dose by 90-95% in a variety of electrophysiology (EP) procedures. This can be of relevance not only to the patients, but also to the nurses and physicians working in the EP lab. Furthermore, in a subset of indications such as supraventricular tachycardias, NFCV enables a fully non-fluoroscopic procedure and allows the lab staff to work without wearing lead aprons. With this protocol, we demonstrate that even complex procedures such as ablations of atrial fibrillation, that are typically associated with fluoroscopy times of >30 min in conventional settings, can safely be performed with a reduction of >90% in fluoroscopy exposure by the additional use of NFCV.

Electrophysiological characterization of spontaneously contracting cell aggregates obtained from rainbow trout larvae with multielectrode arrays.

BACKGROUND/AIMS: Safety pharmacology requires novel model systems for the detection of cardiac side effects. Ranging from cell-based systems to model organisms, no model available to date reflects the complexity of the human heart and evokes the great need for improved and more affordable systems. Many drugs interact with hERG potassium channels and consequently cause life threatening ventricular arrhythmias, further highlighting the importance of suitable model systems. METHODS: Spontaneously Contracting Cell aggregates (SCC) as a 3D in vitro heart-syncytium obtained from rainbow trout larvae represent a novel model system for cardiac safety pharmacology. SCCs can be harvested cost-effectively and kept in culture for several weeks while retaining their functionality and displaying contraction rates similar to the human heart. RESULTS: Extracellular field potential recordings with multielectrode arrays revealed significant prolongation of field potential duration upon administration of common hERG potassium channel blockers. Infusion of 1 µM Dofetilide and 10 µM Terfenadine prolonged field potentials 10 fold and 2 fold, respectively. In addition, SCCs enabled analysis of autonomous contraction frequencies. CONCLUSION: Thus, SCCs represent a novel and low-cost cardiac model system of the human heart for application in safety pharmacology.

A conformal, bio-interfaced class of silicon electronics for mapping cardiac electrophysiology.

In all current implantable medical devices such as pacemakers, deep brain stimulators, and epilepsy treatment devices, each electrode is independently connected to separate control systems. The ability of these devices to sample and stimulate tissues is hindered by this configuration and by the rigid, planar nature of the electronics and the electrode-tissue interfaces. Here, we report the development of a class of mechanically flexible silicon electronics for multiplexed measurement of signals in an intimate, conformal integrated mode on the dynamic, three-dimensional surfaces of soft tissues in the human body. We demonstrate this technology in sensor systems composed of 2016 silicon nanomembrane transistors configured to record electrical activity directly from the curved, wet surface of a beating porcine heart in vivo. The devices sample with simultaneous submillimeter and submillisecond resolution through 288 amplified and multiplexed channels. We use this system to map the spread of spontaneous and paced ventricular depolarization in real time, at high resolution, on the epicardial surface in a porcine animal model. This demonstration is one example of many possible uses of this technology in minimally invasive medical devices.

Pressure-frequency sensing subxiphoid access system for use in percutaneous cardiac electrophysiology: prototype design and pilot study results.

We have designed, built, and tested an early prototype of a novel subxiphoid access system intended to facilitate epicardial electrophysiology, but with possible applications elsewhere in the body. The present version of the system consists of a commercially available insertion needle, a miniature pressure sensor and interconnect tubing, read-out electronics to monitor the pressures measured during the access procedure, and a host computer with user-interface software. The nominal resolution of the system is < 0.1 mmHg, and it has deviations from linearity of < 1%. During a pilot series of human clinical studies with this system, as well as in an auxiliary study done with an independent method, we observed that the pericardial space contained pressure-frequency components related to both the heart rate and respiratory rate, while the thorax contained components related only to the respiratory rate, a previously unobserved finding that could facilitate access to the pericardial space. We present and discuss the design principles, details of construction, and performance characteristics of this system.

Einthoven's string galvanometer: the first electrocardiograph.

Willem Einthoven (1860--1927), known as the creator of the electrocardiograph, won a Nobel Prize in 1924 for his contributions to the field of electrocardiography. He was dedicated to research and learning. In developing the electrocardiograph, Einthoven built on the work of earlier physiologists who had studied the electrical mechanisms of the heart. Each earlier invention proved important by contributing concepts and knowledge that would shape Einthoven's device. Herein, we review the history of the electrocardiograph, with a focus on Willem Einthoven's quest to make the device a practical clinical instrument in the diagnosis of cardiac abnormalities.

Novel dry electrodes for ECG monitoring.

The development, fabrication and characterization of two novel dry bioelectrodes--conductive and capacitive ones--for biopotential monitoring are presented. The new electrodes have the potential to improve the applicability of dry electrodes in ambulant recording of ECG by reducing motion artifacts as well as the contact impedance to the skin. Furthermore, a passive filter network is integrated into the new electrodes to suppress slow offset fluctuation of the ECG signal caused e.g. by motions like breathing or changes in the electrode-skin interface properties. Compared to standard gel electrodes these new electrodes exhibit equivalent and superior contact impedances and biosignals. The integrated filter network effectively suppresses fluctuating offset potentials.

Health technology assessment on reprocessing single-use catheters for cardiac electrophysiology: results of a three-years study.

The study aims to define the technical, ethical, juridical and economic issues involved in the assessment of a reprocessing policy for single-use interventional cardiac devices (SUDs). The feasibility of reprocessing was evaluated for cardiac electrophysiology catheters by comparing the chemical, physical and functional properties of new and reprocessed devices. The issue of hygiene was addressed by developing microbiological tests for the quantification of bioburden, sterility and pyrogenic load. The results of more than 1500 tests, conducted on 531 catheters, suggested a precautionary number of regenerations of five cycles. The ethical aspects were reviewed and the European juridical framework was assessed, revealing a need for harmonization. Applying a specific economic model, potential savings were calculated for a representative cardiology department and estimated at national and European level. Potential savings of 41.2% and 32.9% were calculated for diagnostic and ablation catheters, respectively. Safe and effective reprocessing of SUDs could be pursued if quality control processes and certified procedures are met. A reprocessing policy in EP laboratory could lead to savings of about 27,250 euros per 100,000 population, but the economic benefits are strongly dependent on the maximum number of regenerations and the regeneration rate.