beta(2)-adrenergic receptor overexpression exacerbates development of heart failure after aortic stenosis.
BACKGROUND
Beta-adrenergic signaling is downregulated in the failing heart, and the significance of such change remains unclear.


RESULTS
To address the role of beta-adrenergic dysfunction in heart failure (HF), aortic stenosis (AS) was induced in wild-type (WT) and transgenic (TG) mice with cardiac targeted overexpression of beta(2)-adrenergic receptors (ARs), and animals were studied 9 weeks later. The extents of increase in systolic arterial pressure (P<0.01 versus controls), left ventricular (LV) hypertrophy (TG, 94+/-6 to 175+/-7 mg; WT, 110+/-6 to 168+/-10 mg; both P<0.01), and expression of ANP mRNA were similar between TG and WT mice with AS. TG mice had higher incidences of premature death and critical illness due to heart failure (75% versus 23%), pleural effusion (81% versus 45%), and left atrial thrombosis (81% versus 36%, all P<0.05). A more extensive focal fibrosis was found in the hypertrophied LV of TG mice (P<0.05). These findings indicate a more severe LV dysfunction in TG mice. In sham-operated mice, LV dP/dt(max) and heart rate were markedly higher in TG than WT mice (both P<0.01). dP/dt(max) was lower in both AS groups than in sham-operated controls, and this tended to be more pronounced in TG than WT mice (-32+/-5% versus -16+/-6%, P=0.059), although dP/dt(max) remained higher in TG than WT groups (P<0.05).


CONCLUSIONS
Elevated cardiac beta-adrenergic activity by beta(2)-AR overexpression leads to functional deterioration after pressure overload.
Du
X J
XJ
Baker Medical Research Institute, Melbourne, Australia. xiaojun.du@baker.edu.au
Autelitano
D J
DJ
Dilley
R J
RJ
Wang
B
B
Dart
A M
AM
Woodcock
E A
EA
D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001835:Body Weight; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D006339:Heart Rate; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D010996:Pleural Effusion / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000502:physiology*; D013599:Systole; D014158:Transcription, Genetic
D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D009320:Atrial Natriuretic Factor