Introduction to the Series on Computational Approaches to Cardiac Arrhythmias

Abstract

Of all the cardiac arrhythmias seen in clinical practice, atrial fibrillation (AF) and ventricular tachycardia/fibrillation (VT/VF) are among the leading causes of morbidity and mortality in the developed world. AF is the most common sustained arrhythmia and is associated with an increased risk of stroke, heart failure, dementia, and death.1–3 In developed nations overall prevalence of AF is 0.9% and the number of people affected is projected to more than double over the next 2 decades.3,4 VT/VF is the most important immediate cause of sudden cardiac death (SCD). Incidence of SCD is estimated to be 4 to 5 million cases per year worldwide.5,6 Thus arrhythmias and SCD are among the most significant manifestations of cardiovascular diseases worldwide, but their underlying mechanisms remain elusive. Arrhythmogenic substrates may be established by ischemia, infarction, heart failure and genetic mutations, all of which may cause inflammation, extracellular matrix remodeling, interstitial fibrosis, fatty infiltration, and changes in the 3-dimensional cellular architecture of the working myocardium.7,8 Over the last 17 years, the study of the molecular genetic basis of monogenic cardiac rhythm disorders, together with characterization of functional expression and biophysical properties of mutant channels from patients with inheritable ion channel diseases, has significantly advanced our understanding of the molecular basis of cardiac arrhythmias.9 Yet, this clearly has not been sufficient. Despite such advances, predictable prevention of AF or VF is currently not possible and the development of effective antiarrhythmic pharmacological agents has been extremely difficult. Not all questions related to arrhythmia mechanisms are directly answerable by reductionist experiments such as DNA sequencing or patch clamping. There is a hierarchy of questions whose levels are determined by the generality of the answers sought. Thus the question of what a mutation in an ion …