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J Thorac Cardiovasc Surg 2009;137:1356-1362
© 2009 The American Association for Thoracic Surgery

Congenital Heart Disease

Myocyte apoptosis occurs early during the development of pressure-overload hypertrophy in infant myocardium

^a Department of Anesthesiology and Perioperative and Pain Medicine, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
^b Department of Cardiac Surgery, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
^c Department of Cardiology, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
^d Anesthesia/Critical Care Medicine Research Laboratory, Children's Hospital Boston, and Harvard Medical School, Boston, Mass

Received for publication July 1, 2008; revisions received November 20, 2008; accepted for publication December 22, 2008.

^_* Address for reprints: Yeong-Hoon Choi, MD, Children's Hospital Boston and Harvard Medical School, Department of Cardiac Surgery, 300 Longwood Avenue, Boston, MA 02115. Current address: Heartcenter of the University of Cologne, Department of Cardiothoracic Surgery and Center of Molecular Medicine Cologne, Kerpener Str 62, 50924 Cologne, Germany. (Email: yh.choi{at}uk-koeln.de).

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 ± 37/10⁶ 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 ± 56/10⁶ myocytes), caspase-3 activity further increased, and the estimated total number of left ventricular myocytes was significantly reduced by 18% ± 4%.

Conclusion: 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.