Reductionist Approach to Arrhythmia

A dramatic increase in understanding of the molecular mechanisms of normal and abnormal cellular electrophysiology led to development of new theories of arrhythmia. A number of these theories have been supported by a convincing empirical evidence "from cell to bedside."1'2 And, as a result, the field has been propelled by promises to society of elegant, "silver bullet" pharmacological solutions against lethal cardiac arrhythmias. Nearly every generation of electrophysiologists has come up with a target of their own "silver bullet": sodium channel, calcium channel, potassium channel, gap junction, and so forth. Visions of several generations have crystallized into the recent development of theory of chanelopathies.3

According to one saying, every new thought is a long forgotten old one. The state of the arrhythmia research is reminiscent in some sense of an earlier history of the elementary particle physics. It appeared to many physicists at the time that the foundation of laws of matter can be eloquently explained by the interaction of very few elementary particles and very few fundamental laws governing these interactions. Yet, as more and more unexpected particles or peculiar properties of the existing particles were uncovered, the increasingly more sophisticated theories were produced, making irrelevant the elegance and eloquence of the earlier theories. And this process goes on.

Cardiac electrophysiology went along a very similar path in search of antiarrhythmia therapy. A giant of the field, Carl J. Wiggers, drafted a road map more than a half a century ago:

As to the fundamental mechanisms of fibrillation we have plenty of theories, but none is universally accepted . . . they all center around two ideas, viz., (a) that the impulses arise from centers, or pacemakers, or (b) that the condition is caused by the re-entry of impulses and the formation of circles of excitation.4

The old ion channel-based theory seemed to have done a pretty good job explaining both focal and reentrant theories of arrhythmia. These early theories of arrhythmia, with their four classes of antiarrhythmic drugs, were almost Aristotelian. But they fell under the pressure of empirical evidence5: ever multiplying channel isoforms and subunits; alternative splicing variants of these proteins; mutations in genes encoding ion channels; numerous increasingly complex signaling pathways; unexpected proteins expressed and functioning in concert with channels. These important players had been unknown, overlooked, or neglected in the past and present new opportunities in the future.

Can a cardiac arrhythmia with broad clinical impact be explained within a framework based on a single channel biophysics or even a single cell physiology? And, most importantly, can a treatment be developed for it based on such a mechanism? Despite the explosion in the number of filed patents offering exactly such answers, it is becoming more and more apparent that these questions will not be so easy to answer. Integrative approaches are needed to synthesize the wealth of knowledge obtained by the reductionists.

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