Mechanistic insights from targeted molecular profiling of repolarization alternans in the intact human heart.

Michele Orini,Gareth Jones,Andrew Smith,Pier D Lambiase,Peter Taggart,Halina Dobrzynski,Joseph Yanni,Henggui Zhang,Xiao Jie,Ben Hanson,Mark R Boyett,Martin Hayward,Michael Colman

doi:10.1093/europace/euz007

Abstract

AimsAction potential duration (APD) alternans is an established precursor or arrhythmia and sudden cardiac death. Important differences in fundamental electrophysiological properties relevant to arrhythmia exist between experimental models and the diseased in vivo human heart. To investigate mechanisms of APD alternans using a novel approach combining intact heart and cellular cardiac electrophysiology in human in vivo.Methods and resultsWe developed a novel approach combining intact heart electrophysiological mapping during cardiac surgery with rapid on-site data analysis to guide myocardial biopsies for laboratory analysis, thereby linking repolarization dynamics observed at the organ level with underlying ion channel expression. Alternans-susceptible and alternans-resistant regions were identified by an incremental pacing protocol. Biopsies from these sites (n = 13) demonstrated greater RNA expression in Calsequestrin (CSQN) and Ryanodine (RyR) and ion channels underlying IK1 and Ito at alternans-susceptible sites. Electrical restitution properties (n = 7) showed no difference between alternans-susceptible and resistant sites, whereas spatial gradients of repolarization were greater in alternans-susceptible than in alternans-resistant sites (P = 0.001). The degree of histological fibrosis between alternans-susceptible and resistant sites was equivalent. Mathematical modelling of these changes indicated that both CSQN and RyR up-regulation are key determinants of APD alternans.ConclusionCombined intact heart and cellular electrophysiology show that regions of myocardium in the in vivo human heart exhibiting APD alternans are associated with greater expression of CSQN and RyR and show no difference in restitution properties compared to non-alternans regions. In silico modelling identifies up-regulation and interaction of CSQN with RyR as a major mechanism underlying APD alternans.

Highlights

Action potential duration (APD) alternans, an alternation of the APD on an every other beat basis, has long been recognized and linked to arrhythmogenesis.[1]
We developed a novel approach combining intact heart electrophysiological mapping during cardiac surgery with and results rapid on-site data analysis to guide myocardial biopsies for laboratory analysis, thereby linking repolarization dynamics observed at the organ level with underlying ion channel expression
Whereas a great deal of vital information has been obtained from a range of experimental models, extrapolation from these models to the human is by no means straightforward owing to the well-known species differences in cardiomyocyte electrophysiology and species-dependent mechanisms underlying arrhythmias.[4]

Summary

Introduction

Action potential duration (APD) alternans, an alternation of the APD on an every other beat basis, has long been recognized and linked to arrhythmogenesis.[1]. The mechanism underlying repolarization alternans has been the subject of much investigation, as has the mechanism by which alternans may initiate arrhythmia. An important challenge remains to advance our understanding of the physiological and pathophysiological function of the human heart in vivo in order to combat the continuing high mortality due to cardiac arrhythmias. Whereas a great deal of vital information has been obtained from a range of experimental models, extrapolation from these models to the human is by no means straightforward owing to the well-known species differences in cardiomyocyte electrophysiology and species-dependent mechanisms underlying arrhythmias.[4] Here, we have implemented a unique in vivo approach that enables the investigation of electrophysiological properties relevant to fatal arrhythmias. Detailed biophysical cellular and tissue models were used to elucidate the mechanisms that link the identified cellular properties and electrophysiological abnormalities

Results

Discussion

Conclusion