Genetic treatment of heart rhythm disorders—where do we stand?

Abstract

C d a i p p Groundbreaking discoveries on genetic loci that underlie arrhythmia syndromes, which commenced in the early 1990s, have immensely increased our understanding of these syndromes. These discoveries also rigorously changed daily clinical practice for cardiologists who were faced with the enquiries of presymptomatic family members of symptomatic individuals who were known with an arrhythmia syndrome. Now it has become possible to screen the genome for the risk of arrhythmias or even sudden death and, understandingly, this took a flight. Still, the holy grail of genetic discoveries in disease is in its therapeutic applicability and that promise is indeed coming our way. For example, in Duchenne muscular dystrophy, the increasing knowledge of the diseased locus has recently led to therapeutic gene therapy in a relatively small number of patients in whom the diseased exon was selectively bypassed. For rrhythmia syndromes, we are still in a preclinical phase, ut efforts to find curative options by means of genetic herapy are growing. Currently, genetic therapy for atrial brillation and bradycardia/conduction disease seems to dominate the field, but ventricular arrhythmias in ischemic conditions are also thoroughly investigated (for a recent review, see, eg, Boink and Rosen). The first in-human studies into the use of gene therapy in heart failure are even underway. In this issue of HeartRhythm, Soucek and colleagues from Heidelberg, Germany, presnt to us their preclinical work on genetic therapy for atrial brillation. Delay of atrial repolarization is considered one pproach to genetic therapy for atrial fibrillation, as coninuing propagation or reentry of fibrillation waves can be mpeded by prolonging the atrial effective refractory period ERP). The main currents responsible for the atrial ERP are outward potassium currents: IKr, IKur, IKs, and IK1. In their tudy, Soucek et al focused on suppressing the IKr current y means of introducing an engineered gene that encodes an Kr-suppressing (dominant-negative) protein into the atria of pigs with the use of an adenovirus vector. Their aim was to