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-&beta;(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.

We tested the hypothesis that myocyte loss in failing human hearts occurs by different mechanisms: apoptosis, oncosis, and autophagic cell death. Explanted hearts from 19 patients with idiopathic dilated cardiomyopathy (EF< or =20%) and 7 control hearts were analyzed. Myocyte apoptosis revealed by caspase-3 activation and TUNEL staining occurred at a rate of 0.002+/-0.0005% (P<0.05 versus control) and oncosis assessed by complement 9 labeling at 0.06+/-0.001% (P<0.05). Cellular degeneration including appearance of ubiquitin containing autophagic vacuoles and nuclear disintegration was present at the ultrastructural level. Nuclear and cytosolic ubiquitin/protein accumulations occurred at 0.08+/-0.004% (P<0.05). The ubiquitin-activating enzyme E1 and the ligase E3 were not different from control. In contrast, ubiquitin mRNA levels were 1.8-fold (P<0.02) elevated, and the conjugating enzyme E2 was 2.3-fold upregulated (P<0.005). The most important finding, however, is the 2.3-fold downregulation of the deubiquitination enzyme isopeptidase-T and the 1.5-fold reduction of the ubiquitin-fusion degradation system-1, which in conjunction with unchanged proteasomal subunit levels and proteasomal activity results in massive storage of ubiquitin/protein complexes and in autophagic cell death. A 2-fold decrease of cathepsin D might be an additional factor responsible for the accumulation of ubiquitin/protein conjugates. It is concluded that in human failing hearts apoptosis, oncosis, and autophagy act in parallel to varying degrees. A disturbed balance between a high rate of ubiquitination and inadequate degradation of ubiquitin/protein conjugates may contribute to autophagic cell death. Together, these different types of cell death play a significant role for myocyte disappearance and the development of contractile dysfunction in failing hearts.

In the development of heart failure, extensive remodelling of the entire myocardium takes place. In this paper, findings on structural remodelling occurring in patients with severely reduced left ventricular function due to dilated cardiomyopathy are presented. This process involves all structural proteins of the myocytes; some of them are reduced (contractile proteins and most of the sarcomeric skeleton) and others are increased (cytoskeleton and membrane-associated proteins). Likewise, the connexin43 content of gap junctions is significantly reduced. The myocyte nuclei are enlarged by 20%, but the ratio of nuclear volume to cell volume is decreased. Nuclei contain less DNA and less of the splicing factor Sc-35 than normal myocardium, which might explain the depressed transcription and translation observed in failing hearts. The connective tissue including fibronectin, laminin and the different types of collagen is augmented, whereas the number of microvessels is decreased. This results in replacement fibrosis. Cell loss is caused by either ubiquitin-related autophagic cell death (most frequent) or by acute ischemic cell death (oncosis) but to a lesser degree by apoptosis. All of these modes of cell death contribute significantly to the loss of contractile function. The morphological alterations described here are the structural correlates of the typical clinical characteristics of heart failure in humans: reduced contractile function, increased ventricular stiffness and ventricular arrhythmias.