The Renin-Angiotensin system mediates the effects of stretch on conduction velocity, connexin43 expression, and redistribution in intact ventricle.
Effect of Stretch on Conduction and Cx43.


BACKGROUND
In disease states such as heart failure, myocardial infarction, and hypertrophy, changes in the expression and location of Connexin43 (Cx43) occur (Cx43 remodeling), and may predispose to arrhythmias. Stretch may be an important stimulus to Cx43 remodeling; however, it has only been investigated in neonatal cell cultures, which have different physiological properties than adult myocytes. We hypothesized that localized stretch in vivo causes Cx43 remodeling, with associated changes in conduction, mediated by the renin-angiotensin system (RAS).


RESULTS
In an open-chest canine model, a device was used to stretch part of the right ventricle (RV) by 22% for 6 hours. Activation mapping using a 312-electrode array was performed before and after stretch. Regional stretch did not change longitudinal conduction velocity (post-stretch vs baseline: 51.5 ± 5.2 vs 55.3 ± 8.1 cm/s, P = 0.24, n = 11), but significantly reduced transverse conduction velocity (28.7 ± 2.5 vs 35.4 ± 5.4 cm/s, P < 0.01). It also reduced total Cx43 expression, by Western blotting, compared with nonstretched RV of the same animal (86.1 ± 32.2 vs 100 ± 19.4%, P < 0.02, n = 11). Cx43 labeling redistributed to the lateral cell borders. Stretch caused a small but significant increase in the proportion of the dephosphorylated form of Cx43 (stretch 9.95 ± 1.4% vs control 8.74 ± 1.2%, P < 0.05). Olmesartan, an angiotensin II blocker, prevented the stretch-induced changes in Cx43 levels, localization, and conduction.


CONCLUSIONS
Myocardial stretch in vivo has opposite effects to that in neonatal myocytes in vitro. Stretch in vivo causes conduction changes associated with Cx43 remodeling that are likely caused by local stretch-induced activation of the RAS.
Hussain
Wajid
W
Department of Cardiac Electrophysiology, Imperial College & St. Mary's Hospital, London, UK.
Patel
Pravina M
PM
Chowdhury
Rasheda A
RA
Cabo
Candido
C
Ciaccio
Edward J
EJ
Lab
Max J
MJ
Duffy
Heather S
HS
Wit
Andrew L
AL
Peters
Nicholas S
NS
D000818:Animals; D018031:Connexin 43 / Q000378:metabolism*; D004285:Dogs; D055119:Elastic Modulus / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006329:Heart Conduction System / Q000502:physiology*; D009200:Myocardial Contraction / Q000502:physiology*; D009431:Neural Conduction / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000502:physiology*; D014018:Tissue Distribution; D016278:Ventricular Function, Right / Q000502:physiology*
D018031:Connexin 43