Myocyte apoptosis occurs early during the development of pressure-overload hypertrophy in infant myocardium.
OBJECTIVE
Abnormal hemodynamic loading often accompanies congenital heart disease both before and after surgical repair. Adaptive and maladaptive myocardial responses to increased load are numerous. This study examined the hypothesis that myocyte loss occurs during compensatory hypertrophic growth in the developing infant myocardium subjected to progressive pressure overload.


METHODS
Pressure-overload left ventricular hypertrophy was induced in 7- to 10-day-old rabbits by banding the thoracic aorta. Left ventricular function and mechanics were quantified by serial echocardiography and noninvasive left ventricular wall stress analysis. Left ventricular tissue sections were examined for fibrosis by using Masson's trichrome stain and for myocyte apoptosis by using a myocyte-specific DNA fragmentation assay and caspase-3 activation (specific fluorescent substrate).


RESULTS
Significant myocyte apoptosis (198 +/- 37/10(6) myocytes, P < .01 vs control) and caspase-3 activation were present in early hypertrophy when left ventricular contractility was preserved and compensatory hypertrophy had normalized wall stress. By 6 weeks, multiple indices of left ventricular contractility were reduced, and left ventricular wall stress was increased. Myocyte apoptosis was accelerated (361 +/- 56/10(6) myocytes), caspase-3 activity further increased, and the estimated total number of left ventricular myocytes was significantly reduced by 18% +/- 4%.


CONCLUSIONS
In experimental infant left ventricular hypertrophy, myocyte apoptosis is initiated in the face of normalized wall stress and preserved contractility. The ongoing rate of apoptosis causes a measurable decrease in myocyte number that is coincident with the onset of ventricular dysfunction. It thus appears that pressure overload, even at its earliest stages, is not well tolerated by the developing ventricle.
Choi
Yeong-Hoon
YH
Department of Anesthesiology and Perioperative and Pain Medicine, Children's Hospital Boston, and Harvard Medical School, Boston, Mass 02115, USA. yh.choi@uk-koeln.de
Cowan
Douglas B
DB
Moran
Adrian M
AM
Colan
Steven D
SD
Stamm
Christof
C
Takeuchi
Koh
K
Friehs
Ingeborg
I
del Nido
Pedro J
PJ
McGowan
Francis X
FX
D000222:Adaptation, Physiological; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D002452:Cell Count; D018450:Disease Progression; D005355:Fibrosis / Q000473:pathology; D006352:Heart Ventricles / Q000000981:diagnostic imaging; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology*; D011817:Rabbits; D013314:Stress, Mechanical; D014463:Ultrasonography; D017725:Ventricular Pressure
D053148:Caspase 3