Electrophysiologic remodeling of the left ventricle in pressure overload-induced right ventricular failure.
OBJECTIVE
The purpose of this study was to analyze the electrophysiologic remodeling of the atrophic left ventricle (LV) in right ventricular (RV) failure (RVF) after RV pressure overload.


BACKGROUND
The LV in pressure-induced RVF develops dysfunction, reduction in mass, and altered gene expression, due to atrophic remodeling. LV atrophy is associated with electrophysiologic remodeling.


METHODS
We conducted epicardial mapping in Langendorff-perfused hearts, patch-clamp studies, gene expression studies, and protein level studies of the LV in rats with pressure-induced RVF (monocrotaline [MCT] injection, n = 25; controls with saline injection, n = 18). We also performed epicardial mapping of the LV in patients with RVF after chronic thromboembolic pulmonary hypertension (CTEPH) (RVF, n = 10; no RVF, n = 16).


RESULTS
The LV of rats with MCT-induced RVF exhibited electrophysiologic remodeling: longer action potentials (APs) at 90% repolarization and effective refractory periods (ERPs) (60 ± 1 ms vs. 44 ± 1 ms; p < 0.001), and slower longitudinal conduction velocity (62 ± 2 cm/s vs. 70 ± 1 cm/s; p = 0.003). AP/ERP prolongation agreed with reduced Kcnip2 expression, which encodes the repolarizing potassium channel subunit KChIP2 (0.07 ± 0.01 vs. 0.11 ± 0.02; p < 0.05). Conduction slowing was not explained by impaired impulse formation, as AP maximum upstroke velocity, whole-cell sodium current magnitude/properties, and mRNA levels of Scn5a were unaltered. Instead, impulse transmission in RVF was hampered by reduction in cell length (111.6 ± 0.7 μm vs. 122.0 ± 0.4 μm; p = 0.02) and width (21.9 ± 0.2 μm vs. 25.3 ± 0.3 μm; p = 0.002), and impaired cell-to-cell impulse transmission (24% reduction in Connexin-43 levels). The LV of patients with CTEPH with RVF also exhibited ERP prolongation (306 ± 8 ms vs. 268 ± 5 ms; p = 0.001) and conduction slowing (53 ± 3 cm/s vs. 64 ± 3 cm/s; p = 0.005).


CONCLUSIONS
Pressure-induced RVF is associated with electrophysiologic remodeling of the atrophic LV.
Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands.
Maxim
M
Hardziyenka
Maria E
ME
Campian
Arie O
AO
Verkerk
Sulaiman
S
Surie
Antoni C G
AC
van Ginneken
Sara
S
Hakim
André C
AC
Linnenbank
H A C M Rianne
HA
de Bruin-Bon
Leander
L
Beekman
Mart N
MN
van der Plas
Carol A
CA
Remme
Toon A B
TA
van Veen
Paul
P
Bresser
Jacques M T
JM
de Bakker
Hanno L
HL
Tan
D000200:Action Potentials; D000818:Animals; D001284:Atrophy; D056149:Epicardial Mapping; D006352:Heart Ventricles / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000503:physiopathology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015222:Sodium Channels / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000503:physiopathology*; D017725:Ventricular Pressure / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568322:Scn5a protein, rat; D015222:Sodium Channels