Contemporary Paradigm Shifts and Associated Implications in Cardiac Electrophysiology

 

Peeyush Shrivastava

Ohio State University

Publication Date: January 1, 2015

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1. Abstract

The current paradigm for voltage recordings in cellular electrophysiology is the direct product of a significantly improved understanding of voltage gated ion channels, their dynamics as mechanisms for cardiac arrhythmia, as well as the spatial and mechanistic differences from channel to channel. Cellular electrophysiology is strongly reliant upon patch clamp recording data, a tool which enables scientists to isolate the particular ion currents involved in the cardiac action potential, and characterize the activity of those currents in diseased and healthy isolated cardiac cells. Paired with this technique is a concise quantification tool, which has remained unchanged over the last several decades, and is meant to characterize voltage gated ion channel activity. However, the application of said quantification has remained minimally impactful from a clinical and diagnostic standpoint, in that there are no units, or means of interpreting the outputs of the equation. With a call to change current clinical and non-clinical paradigms for arrhythmia assessment, the industry is now being flooded with various electrophysiology screening tools and electroanatomic voltage maps – techniques by which clinicians and scientists may be able to better predict and improve outcomes for arrhythmia patients.

1.1. Drug Induced Arrhythmogenesis

In the development of an ion channel modulating drug, it is imperative to consider the various effects of the compound on the net flux changes in ion activities in the heart. However, with the current state of tools for assessing this ion-modulating impact, real progress for individualized drug therapy intervention has remained bleak. On July 14th, 2000, the FDA stopped the marketing of Cisapride, a drug that was developed to increase motility of the upper GI tract. The United States and United Kingdom had noticed a serious problem with this drug – one that has become a large topic of interest for clinical cardiac electrophysiologists. Cisapride, like many other medications, had been shown to prolong the QT interval, as well as induce often times fatal ventricular arrhythmia events.

The case of Cisapride, where 341 users reported heart rhythm abnormalities, 80 of which were fatal, is sadly not an isolated one. Clinical cardiac electrophysiologists, upon diagnosis of Long QT Syndrome, reference a complex list of co-prescribed drug effects, assessing which combinations of drugs can prove fatal to their patients. In general, there has not been a single antiarrhythmic agent to emerge from the pipeline and into the market in over a decade. For heart failure; it is now 25 years without a new innovative drug to hit the market.

1.2. Voltage Gated Ion Channels in Cardiac Arrhythmia Events

Cardiomyocytes are initially negatively charged at approximately -80 to -90 mV. Sodium influx via sodium channels (INa) depolarizes the cell membrane, resulting in a positive (+25 to 30 mV) charge on an intracellular level. The cell membrane is then depolarized through potassium efflux (Ito, IKv etc.). The cardiac action potential is differentiated throughout different anatomical areas of the heart, as the cell specializations themselves are quite distinct.

The cardiac action potential is propagated via the influx and efflux of the ions above, as well as calcium ions, which are simple, yet versatile. The movement of these ions across membranes is enabled via structurally and functionally complex voltage gated ion channels. Each ion has its own specific channels, and these channels contribute to an overall current. It is the contemporary understanding of these currents and their manual patch clamp recordings in isolated myocytes that have built up an understanding of the complex cardiac action potential.

When analyzing a case of Atrial Fibrillation, it is well known that the most common underlying ions associated are potassium and calcium – basic science has even yielded understanding of which channels, via patch clamp and manual clamp voltage and action potential recordings. However, Atrial Fibrillation remains poorly understood, in that there are several distinctions with the disease population – identifying individualistic therapies and treatments remains nearly impossible with current procedures and diagnostic tools.

1.3. Comprehensive In-Vitro Proarrhythmia Assay

The CiPA initiative, introduced by the Cardiac Safety Research Consortium at FDA Headquarters several months ago, is a paradigm changing effort to create in vitro and in silico models for assessing key factors underlying the optimization of individual therapeutic interventions:

1. Identifying and differentiating patient risk profiles based off individual physiology

2. Screening drug efficacy with blocking IKr alone is insufficient

3. There is a need for better quantification tools that will characterize tangible impacts of arrhythmogenic factors of interest.

1.4. Electrophysiology Pipeline Innovations

One of the key innovations being developed is a tool that enables clinicians to shorten interventional AF treatments from 7 hour, $27,000 procedures to 90 minute, $5,000 procedures. The innovation here is to empower 3D mapping of the heart’s electrophysiology, providing for a thorough analysis of the activities and propagated signals of each anatomically and functionally distinct area of the heart. This electroanatomic voltage map approach enables a clear context of arrhythmia anatomy for the user, while also pointing out certain electrophysiological components of activation that could only be predicted before. Indeed, the paradigm for electrophysiological imaging, mapping and characterization of the heart are newly emerging fields, now incentivized by the CiPA Approach. But one of the key components of the electrophysiological world that has remained elusive, and yet vitally necessary, is the need for a tool to quantify ion activity. This is an endpoint that possesses a major market and scientific opportunity – one that could completely alter the way that the cardiac myocyte is understood and interfaced with from both a clinical and scientific standpoint.

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