Neural modulation of cardiac arrhythmias and sudden cardiac death.

In our opinion one of the most important—and vexing—questions in clinical cardiology today can be phrased quite simply: “Why did he die on Tuesday and not on Monday?”1 Superficially, one might challenge the naivete of such a question. But, after further examination, the query may be more profound than it initially appears because it relates to the question of the proximate precipitator of sudden cardiac death (SCD), i.e., the event that transformed an electrophysiologically stable heart into one that fibrillated. For the clinician, the answer might lie in what activity the patient engaged prior to the SCD. For example, did swimming, an argument, angina, or a febrile state precede and possibly precipitate the SCD? The translational clinician-scientist might dig deeper, peeling back another layer, and ponder the electrophysiologic mechanism by which ischemia, sympathetic stimulation or another stimulus might have triggered a ventricular tachyarrhythmia. The basic scientist, mining still further, could explore the alterations in automaticity, triggered activity, conduction and reentry in the structurally abnormal heart, the heart with a channelopathy or heart failure2, and the role of sympathetic stimulation or ischemia on these properties. Finally, on a molecular level, one could study the distribution of ion channels and the modulation of protein expression by autonomic stimulation, the influence of single nucleotide polymorphisms,3 the role of gap junctions, and other factors. Over the next years, each of these areas will continue to undergo intense exploration to uncover answers to the fundamental question posed above.4 Hopefully, we will be better able to predict the individual at risk for SCD and how to prevent it, using new and more powerful imaging techniques (MRI, CT, PET, ECGI [noninvasive electrocardiographic imaging modality]),5 genetic and proteomic screening, and other approaches. Likely, we will find an increasing number of genetic substrates predisposing to sudden death and understand why genotype often does not predict phenotype. Such work will also lead to "repair" of electrical and contractile disorders using stem cells or other techniques. Conceivably, we might be able to ablate arrhythmogenic sites noninvasively using focused ultrasound or other external energy sources. Implantable cardioverter defibrillators (ICDs) will no longer be “one size fits all” as, in one direction, they will become simpler possibly with a subcutaneous implant, and in the other, more complex to monitor co-morbidities such as heart failure, atrial fibrillation, ischemia, diabetes, etc. Devices will communicate with the physician and patient and an "outpatient CCU" approach to treatment will become a reality. ICDs will become smaller, more reliable, longer lasting and, hopefully, cheaper. Widespread deployment of automated external defibrillators will reduce the appalling SCD mortality. And new therapies, perhaps better drugs (assuming pharmaceutical companies desist in creating the “son of quinidine” in one form or another), approaches to understanding arrhythmia mechanisms6 and innovative devices, will be developed to reduce cardiovascular mortality further.