Genetic disruption of angiotensin II type 1a receptor improves long-term survival of mice with chronic severe aortic regurgitation.
BACKGROUND
Aortic regurgitation (AR) causes left ventricular (LV) volume overload, leading to progressive LV dilatation and dysfunction. In the present study it was examined whether blockade of angiotensin II type 1 receptor (AT1) could improve survival in cases of chronic severe AR.


RESULTS
AR was induced by puncturing the aortic valves of wild-type (WT) and AT1a knockout (KO) mice. Mice that survived for 4 weeks after the operation were deemed to be a model of chronic severe AR and were followed up for 50 weeks (WT, n=29; KO, n=31). Baseline measurements made 4 weeks after surgery showed similar LV cavity and function in both genotypes. These conditions progressively worsened in both genotypes, but 16 weeks after baseline, KO mice showed significantly less LV dilatation, hypertrophy and interstitial fibrosis than WT mice. Cardiac mRNA expression of B-type natriuretic peptide and type I collagen was lower in KO than WT mice. The 50-week mortality rate was significantly lower among KO (45.2%) than WT (86.2%) mice, and postmortem findings indicated that the lower mortality was attributable to a lower incidence of congestive heart failure.


CONCLUSIONS
In cases of chronic severe AR, blockade of AT1 attenuates the progression of LV dilatation, hypertrophy and fibrosis, thereby mitigating heart failure and improving long-term survival.
Nakanishi
Michio
M
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan.
Harada
Masaki
M
Kishimoto
Ichiro
I
Kuwahara
Koichiro
K
Kawakami
Rika
R
Nakagawa
Yasuaki
Y
Yasuno
Shinji
S
Usami
Satoru
S
Kinoshita
Hideyuki
H
Adachi
Yuichiro
Y
Fukamizu
Akiyoshi
A
Saito
Yoshihiko
Y
Nakao
Kazuwa
K
D000818:Animals; D001022:Aortic Valve Insufficiency / Q000401:mortality / Q000628:therapy*; D002908:Chronic Disease; D004195:Disease Models, Animal; D006333:Heart Failure; D051379:Mice; D018345:Mice, Knockout; D020097:Natriuretic Peptide, Brain / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D015996:Survival Rate; D018487:Ventricular Dysfunction, Left; D020257:Ventricular Remodeling
D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D020097:Natriuretic Peptide, Brain