Progression from compensated hypertrophy to failure in the pressure-overloaded human heart -: Structural deterioration and compensatory mechanisms

Background-The progression of compensated hypertrophy to heart failure (HF) is still debated. We investigated patients with isolated valvular aortic stenosis and differing degrees of left ventricular (LV) systolic dysfunction to test the hypothesis that structural remodeling, as well as cell death, contributes to the transition to HF. Methods and Results-Structural alterations were studied in LV myectomies from 3 groups of patients (group 1: ejection fraction [EF] >50%, n=12; group 2: EF 30% to 50%, n=12; group 3: EF <30%, n=10) undergoing aortic valve replacement. Control patients were patients with mitral valve stenosis but normal LV (n=6). Myocyte hypertrophy was accompanied by increased nuclear DNA and Sc-35 (splicing factor) content. ACE and TGF-β(1) were upregulated correlating with fibrosis, which increased 2.3-, 2.2-, and 3.2-fold over control in the 3 groups. Myocyte degeneration increased 10, 22, and 32 times over control. A significant correlation exists between EF and myocyte degeneration or fibrosis. Ubiquitin-related autophagic cell death was 0.5&PTSTHOUSND; in control and group 1, 1.05 in group 2, and 6.05&PTSTHOUSND; in group 3. Death by oncosis was 0&PTSTHOUSND; in control, 3&PTSTHOUSND; in group 1, and increased to 5&PTSTHOUSND; (groups 2 and 3). Apoptosis was not detectable in control and group 3, but it was present at 0.02&PTSTHOUSND; in group 1 and 0.01&PTSTHOUSND; in group 2. Cardiomyocyte mitosis was never observed. Conclusions-These structure-function correlations confirm the hypothesis that transition to HF occurs by fibrosis and myocyte degeneration partially compensated by hypertrophy involving DNA synthesis and transcription. Cell loss, mainly by autophagy and oncosis, contributes significantly to the progression of LV systolic dysfunction.