Left ventricular hypertrophy in ascending aortic stenosis mice - Anoikis and the progression to early failure

Backgrorund-To determine potential mechanisms of the transition from hypert rophy to very early failure, we examined apoptosis in a model of ascending aortic stenosis (AS) in male FVB/n mice. Methods and Results-Compared with age-matched controls, 4-week and 7-week A S animals (n = 12 to 16 per group) had increased ratios of left ventricular weight to body weight (4.7+/-0.7 versus 3.1+/-0.2 and 5.7+/-0.4 versus 2.7 +/-0.1 mg/g, respectively, P<0.05) with similar body weights. Myocyte width was also increased in 4-week and 7-week AS mice compared with controls (19 .0+/-0.8 and 25.2+/-1.8 versus 14.1+/-0.5 mu m, respectively, P<0.01). By 7 weeks, AS myocytes displayed branching with distinct differences in interc alated disk size and staining for beta(1)-integrin on both cell surface and adjacent extracellular matrix. In vivo left ventricular systolic developed pressure per gram as well as endocardial fractional shortening were simila r in 4-week AS and controls but depressed in 7-week AS mice. Myocyte apopto sis estimated by in situ nick end-labeling (TUNEL) was extremely rare in 4- week AS and control mice; however, a low prevalence of TUNEL-positive myocy tes and DNA laddering were detected in 7-week AS mice. The specificity of T UNEL labeling was confirmed by in situ ligation of hairpin oligonucleotides , Conclusions-Our findings indicate that myocyte apoptosis develops during th e transition from hypertrophy to early failure in mice with chronic biomech anical stress and support the hypothesis that the disruption of normal myoc yte anchorage to adjacent extracellular matrix and cells, a process called anoikis, may signal apoptosis.