Left ventricular wall stress as a direct correlate of cardiomyocyte apoptosis in patients with severe dilated cardiomyopathy.
BACKGROUND
Apoptosis has been implicated as a possible mechanism in the development of heart failure (HF), but the mechanisms involved remain unclear. In patients with severe dilated cardiomyopathy, we evaluated cardiomyocyte apoptosis in relation to the transmural distribution of Bax and Bcl-2 proteins (2 molecules inhibiting or promoting apoptosis, respectively) and left ventricular wall stresses.


METHODS
We studied the presence and distribution of cardiomyocyte apoptosis in 90 tissue samples obtained from 8 patients who were undergoing left ventricular reduction with the Batista (ventricular remodeling) operation. Apoptosis was assessed in tissue samples taken from the entire left ventricular thickness (subdivided in subepicardial, midmyocardial, and subendocardial sections) with the terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labeling (TUNEL) technique and DNA agarose gel electrophoresis. The expression of Bcl-2 and Bax proteins were determined with both Western analysis and immunohistochemistry.


RESULTS
TUNEL-positive cells (apoptotic index) were 2.3% +/- 1.4%. Apoptotic cells were predominantly distributed in the subendocardium, where higher levels of Bax protein were detected. The ratio of Bax to Bcl-2 proteins (Bax/Bcl-2) was similar in the midmyocardium or subepicardium, but increased in the subendocardium, where it was directly related to systolic wall stress (y = 0.009x - 0.629; r2 = 0.85, P <.001). The apoptotic index was also directly related to systolic and end-diastolic stresses calculated from hemodynamic and echocardiographic data (r2 = 0.77, P <.001 and r2 = 0.40, P <.01, respectively).


CONCLUSIONS
In patients with dilated cardiomyopathy, in whom cardiomyocyte apoptosis is an important cause of cell loss, apoptosis is more extensively localized in the subendocardium and strictly related to ventricular wall stresses and the Bax/Bcl-2 ratio.
Di Napoli
Pericle
P
Laboratory of Experimental Cardiology, Department of Clinical Sciences and Bioimaging, Chieti, Italy.
Taccardi
Alfonso A
AA
Grilli
Alfredo
A
Felaco
Mario
M
Balbone
Angela
A
Angelucci
Domenico
D
Gallina
Sabina
S
Calafiore
Antonio M
AM
De Caterina
Raffaele
R
Barsotti
Antonio
A
D000368:Aged; D000704:Analysis of Variance; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000503:physiopathology* / Q000601:surgery; D053938:DNA Fragmentation; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000032:analysis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D012044:Regression Analysis; D013314:Stress, Mechanical; D016277:Ventricular Function, Left / Q000502:physiology; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D015415:Biomarkers; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein