Progression From Compensated Hypertrophy to Failure in the Pressure-Overloaded Human Heart

Abstract

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] Ͼ50%, nϭ12; group 2: EF 30% to 50%, nϭ12; group 3: EF Ͻ30%, nϭ10) undergoing aortic valve replacement. Control patients were patients with mitral valve stenosis but normal LV (nϭ6). Myocyte hypertrophy was accompanied by increased nuclear DNA and Sc-35 (splicing factor) content. ACE and TGF-␤ 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‰ in control and group 1, 1.05 in group 2, and 6.05‰ in group 3. Death by oncosis was 0‰ in control, 3‰ in group 1, and increased to 5‰ (groups 2 and 3). Apoptosis was not detectable in control and group 3, but it was present at 0.02‰ in group 1 and 0.01‰ 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.

The role of autophagy in the heart

“…Autophagy has been observed in failing myocardium caused by dilated cardiomyopathy, 17,22,38 by valvular disease 39 and by ischemic heart disease. [40][41][42] In patients with terminal heart failure, secondary to ischemic cardiomyopathy or dilated cardiomyopathy, cellular degeneration with granular cytoplasmic ubiquitin inclusion is detected in 0.3% of the cardiomyocytes.…”

Recycle or die: The role of autophagy in cardioprotection

“…In contrast, there are reports that upregulation of autophagy can be detrimental to the heart. Increased numbers of autophagosomes have been observed in cardiac tissues from patients with cardiovascular disorders such as dilated cardiomyopathy [33], aortic stenosis [34], and hibernating myocardium [35]. However, the functional significance of autophagy in those diseases is still not clear.…”

Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis-induced myocardial dysfunction

“…Phosphorylation at Thr-69 and Thr-71 of ATF-2 is mediated through both p38-MAPK as well as JNK (Raingeaud et al, 2006;Xia et al, 1995). Activation of p38-MAPK-mediated upregulation of BCl 2 , BCl 2 family-related protein Bax, and activation of caspase-3 have been reported to be among the main pathways for apoptosis and hypertrophy in cardiac myocytes obtained from spontaneously hypertensive rats (Cheng et al, 1995;Chien et al, 1999;Hein et al, 2003).…”