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Advances in Cardiology and Cardiac Surgery

Cardiac Arrhythmias: Investigating Mechanisms of Action

Sudden cardiac death, primarily caused by ventricular arrhythmias, is one of the leading causes of mortality in the United States. In the Cardiac Electrodynamics Laboratory directed by David J. Christini, PhD, Vice Chair for Basic Research and Professor of Medicine in the Division of Cardiology at Weill Cornell Medical College, an integrated, multiscale approach is underway to better understand cardiac electrophysiological dynamics. From the cellular to the organ level, Dr. Christini and his colleagues are interested in revealing the mechanisms underlying arrhythmia initiation and utilizing this knowledge to develop new arrhythmia therapies.


Dr. David J. Christini

"Because of the complexity of electrophysiological dynamics we use a hybrid approach that combines computational, experimental, and clinical methods to bridge the gap between physics and biology," says Dr. Christini. "Computational modeling and experimental approaches -- primarily patch clamping and calcium imaging of isolated cardiac myocytes -- have provided novel insights into the ionic factors that cause instabilities in the cardiac action potential and how these channel level instabilities trigger cardiac arrhythmias in the whole heart."

Supported by funding from the National Institutes of Health, including three R01 projects, Dr. Christini's research teams are studying the dynamics of arrhythmias from single cells to whole hearts; biophysical mechanisms of electrophysiological instabilities and arrhythmia onset; and arrhythmia prevention through termination of arrhythmia trigger events.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the developed world. According to Dr. Christini, because AF has several variants, is multifactorial, and evolves over time, it is very difficult to study comprehensively in large animal models. "This is, in part, due to the inherent technical difficulties of imaging whole-atria electrophysiology in vivo," says Dr. Christini. "Predictive multiscale computational modeling has the potential to fill this research void."

Dr. Christini and his colleagues are developing a multiscale modeling framework using data, including human MRI structural information and electrophysiological data, to clarify the impact of common ion channel gene polymorphisms on drug-channel interactions. This work is enabling the evaluation of potential pharmacological and device-based atrial fibrillation therapies.


(A) Reentrant activity in computer simulations of normal tissue and (B) tissue with full electrical plus structural remodeling. Fig. A shows an example of non-sustained reentrant activity in normal tissue. In contrast, when simulating full electrical plus structural remodeling, reentry was sustained for 60 s in 18 of 21 simulations. Fig. B shows that with such electrical plus structural remodeling the wavelength is much shorter than in normal tissue, and the reentrant wave in the left atrial free wall does not self-terminate.

"AF often progresses unfavorably," says Dr. Christini. "In patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes." Previous research by others in the field has shown that AF is more prominent in the context of alterations in atrial tissue properties -- due to disease, arrhythmias, or age -- known as remodeling. In fact, AF itself leads to remodeling, causing electrophysiological, contractile, and structural changes. Although AF can typically be reversed in its early stages, it becomes more difficult to eliminate over time due to this remodeling.

In a recent study, Dr. Christini's lab investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria to represent its various disease states. It was the first such study of its type. The simulations demonstrated that disease-like modifications to cellular processes, as well as to the coupling between cells, perpetuate simulated atrial fibrillation by accelerating the rhythm and/or increasing the number of circulating activation waves.

"Given the model's ability to reproduce a number of clinically and experimentally important features, we believe that it presents a useful framework for future studies of atrial electrodynamics in response to ion channel mutations and various drugs," notes Dr. Christini.

Dr. Christini's lab is also investigating cardiac alternans, which is characterized by a beat-to-beat alternation in membrane potential that is known to trigger cardiac reentry in experiments and has been correlated with risk for clinical arrhythmias. "Although this phenomenon has been identified as a potential precursor to dangerous reentrant arrhythmias and sudden cardiac death, significant uncertainty remains regarding its mechanism and no clinically practical means of halting its occurrence or progression currently exists," says Dr. Christini. Studies have suggested that alternans may result from dynamical instabilities in either membrane voltage or calcium cycling. More recently, evidence for the calcium mechanism has accumulated, pushing that theory to the forefront.

Dr. Christini's lab has demonstrated that the two mechanisms are intertwined and play varying, but quantifiable, roles for different cardiac cell types. These findings have important implications for their ongoing investigations into device and drug therapy of repolarization-triggered arrhythmias.

To facilitate new experimental paradigms, the Christini lab has developed a highly versatile real-time biological experimentation system known as Real-Time eXperiment Interface (RTXI; www.rtxi.org). "The ability to perturb biological systems has traditionally been limited to rigid pre-programmed protocols," says Dr. Christini. "In contrast, 'real-time control' allows the researcher to dynamically probe a biological system with parameter perturbations that are calculated functions of instantaneous system measurements, thereby providing the ability to address diverse unanswered questions that are not amenable to traditional approaches."

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