β 2 -Adrenergic Receptor Overexpression Exacerbates Development of Heart Failure After Aortic Stenosis

Background —β-Adrenergic signaling is downregulated in the failing heart, and the significance of such change remains unclear.Methods and Results —To address the role of β-adrenergic dysfunction in heart failure (HF), aortic stenosis (AS) was induced in wild-type (WT) and transgenic (TG) mice with cardiac targeted overexpression of β2 -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; bothP <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%, allP <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/dtmax and heart rate were markedly higher in TG than WT mice (bothP <0.01). dP/dtmax 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/dtmax remained higher in TG than WT groups (P <0.05).Conclusions —Elevated cardiac β-adrenergic activity by β2 -AR overexpression leads to functional deterioration after pressure overload.