Cardiac remodeling and contractile function in acid alpha-glucosidase knockout mice

Pompe's disease is an autosomal recessive and often fatal condition, caused by mutations in the acid alpha -glucosidase gene, leading to lysosomal gly cogen storage in heart and skeletal muscle. We investigated the cardiac phe notype of an acid alpha -glucosidase knockout (KO) mouse model. Left ventri cular weight-to-body weight ratios were increased 6.3 +/- 0.8 mg/g in seven KO compared with 3.2 +/- 0.2 mg/g in eight wild-type (WT) mice (P < 0.05). Echocardiography under ketamine-xylazine anesthesia revealed an increased left ventricular (LV) wall thickness (2.17 +/- 0.16 in KO vs. 1.18 +/- 0.10 mm in WT mice, P < 0.05) and a decreased LV lumen diameter (2.50 +/- 0.32 in KO vs. 3.21 +/- 0.14 mm in WT mice, P < 0.05), but LV diameter shortenin g was not different between KO and WT mice. The maximum rate of rise of lef t ventricular pressure (LV dP/dt(max)) was lower in KO than in WT mice unde r basal conditions (2,720 +/- 580 vs. 4,440 +/- 440 mmHg/s) and during dobu tamine infusion (6,220 +/- 800 vs. 8,730 +/- 790 mmHg/s, both P < 0.05). Si milarly, during isoflurane anesthesia LV dP/dt(max) was lower in KO than in WT mice under basal conditions (5,400 +/- 670 vs. 8,250 +/- 710 mmHg/s) an d during norepinephrine infusion (10,010 +/- 1,320 vs. 14,710 +/- 220 mmHg/ s, both P < 0.05). In conclusion, the markedly increased LV weight and wall thickness, the encroachment of the LV lumen, and LV dysfunction reflect ca rdiac abnormalities, although not as overt as in humans, of human infantile Pompe's disease and make these mice a suitable model for further investiga tion of pathophysiology and of novel therapies of Pompe's disease.