Multi-Scale Assessments of Cardiac Electrophysiology Reveal Regional Heterogeneity in Health and Disease

Abstract

The left and right ventricles of the four-chambered heart have distinct developmental origins and functions. Chamber-specific developmental programming underlies the differential gene expression of ion channel subunits regulating cardiac electrophysiology that persists into adulthood. Here, we discuss regional specific electrical responses to genetic mutations and cardiac stressors, their clinical correlations, and describe many of the multi-scale techniques commonly used to analyze electrophysiological regional heterogeneity.

Keywords: ECGI; cardiac development; electrophysiology; optical mapping.

Figure 1

Ectopic Wnt activation differentially affects the electrical phenotype of RV versus LV. (A,B) Reconstructed electrical activation pattern from optical mapping experiment during sinus rhythm in control (A) and Wnt GOF (B) mice. (C) Total epicardial activation time is significantly prolonged in Wnt GOF mice (4.4 ± 0.4 versus 11.5 ± 1.0 ms, n = 4 each genotype). (D–G) Representative electrical activation pattern of the LV and RV during epicardial stimulation in control (D,E) and Wnt GOF (F,G) mice. (H) Left ventricular (LV) longitudinal conduction velocity of Wnt GOF mice was slower during stimulation at each cycle length, and the difference between the two genotypes became larger at faster pacing rates (111 and 100 ms cycle lengths, n = 4). (I) Right ventricular (RV) longitudinal conduction velocity of Wnt GOF mice was also slower, and was more severely decreased than in the LV. One Wnt GOF mutant had an electrically inexcitable RV when paced at 143 ms cycle length, while two others had markedly decreased conduction velocity at slower cycle lengths and became inexcitable at pacing rates above 125 ms cycle interval. This is consistent with decremental conduction, a property of AV canal and AV nodal tissues. Note the different time scales between each experiment. Data are represented as mean ± SEM. Group comparison for conduction velocity was performed using a Student’s unpaired 2-tailed t-test at each cycle length. Group comparison for inexcitability was performed using a Chi squared test without Yate’s correction. * p < 0.05. Modified from Gillers et al., Canonical Wnt Signaling Regulates Atrioventricular Junction Programming and Electrophysiological Properties, Circulation Research, Volume 116, Issue 3, page 402. http://circres.ahajournals.org/cgi/pmidlookup?view=long&pmid=25599332

Figure 2

Activation and repolarization during sinus rhythm. (A) Activation times isochrone maps (AT). Insets, zoom on the RVOT. (B) Activation-recovery interval maps (ARI). (C) Recovery time (RT) maps. Epicardial breakthroughs are indicated by asterisks. Isochrones are depicted in thin black lines. Black arrows in the RVOT zoom maps of A point to slow conduction indicated by crowded isochronal lines. Red arrows in B and C point to regions with steep repolarization gradients. BrS indicates Brugada syndrome; LA, left atrium; LV, left ventricle; PT, pulmonary trunk; RA, right atrium; RV, right ventricle; and RVOT, right ventricular outflow tract. Modified from Zhang et al., Cardiac electrophysiological substrate underlying the ECG phenotype and electrogram abnormalities in Brugada syndrome patients, Circulation, Volume 131, Issue 22, page 1954. http://circ.ahajournals.org/content/131/22/1950.long