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.


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-beta1 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 per thousand in control and group 1, 1.05 in group 2, and 6.05 per thousand in group 3. Death by oncosis was 0 per thousand in control, 3 per thousand in group 1, and increased to 5 per thousand (groups 2 and 3). Apoptosis was not detectable in control and group 3, but it was present at 0.02 per thousand in group 1 and 0.01 per thousand 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.
Hein
Stefan
S
Kerckhoff-Clinic, Department of Thoracic and Cardiovascular Surgery, Bad Nauheim, Germany. s.hein@kerckhoff.mpg.de
Arnon
Eyal
E
Kostin
Sawa
S
Schönburg
Markus
M
Elsässer
Albrecht
A
Polyakova
Victoria
V
Bauer
Erwin P
EP
Klövekorn
Wolf-Peter
WP
Schaper
Jutta
J
D000368:Aged; D001024:Aortic Valve Stenosis / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D002196:Capillaries / Q000033:anatomy & histology / Q000737:chemistry; D006332:Cardiomegaly / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D016923:Cell Death; D002467:Cell Nucleus / Q000235:genetics; D004247:DNA / Q000032:analysis; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D006333:Heart Failure / Q000209:etiology*; D006439:Hemodynamics; D006801:Humans; D007249:Inflammation / Q000209:etiology; D008297:Male; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000473:pathology / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000032:analysis; D007703:Peptidyl-Dipeptidase A / Q000032:analysis; D012261:Ribonucleoproteins; D000068103:Serine-Arginine Splicing Factors; D016212:Transforming Growth Factor beta / Q000032:analysis; D053773:Transforming Growth Factor beta1; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D017725:Ventricular Pressure
D009687:Nuclear Proteins; D012261:Ribonucleoproteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D004247:DNA; D007703:Peptidyl-Dipeptidase A