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

Choi, Yeong-Hoon; Cowan, Douglas B.; Moran, Adrian M.; Colan, Steven D.; Stamm, Christof; Takeuchi, Koh; Friehs, Ingeborg; del Nido, Pedro J.; McGowan, Francis X.

doi:10.1016/j.jtcvs.2008.12.020

« Previous Next »The Journal of Thoracic and Cardiovascular Surgery
Volume 137, Issue 6 , Pages 1356-1362.e3, June 2009

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

Yeong-Hoon Choi, MD
- Department of Anesthesiology and Perioperative and Pain Medicine, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
- Department of Cardiac Surgery, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
- Anesthesia/Critical Care Medicine Research Laboratory, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
- 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.
Douglas B. Cowan, PhD
- Department of Anesthesiology and Perioperative and Pain Medicine, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
- Anesthesia/Critical Care Medicine Research Laboratory, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
Adrian M. Moran, MBBS
- Department of Cardiology, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
Steven D. Colan, MD
- Department of Cardiology, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
Christof Stamm, MD
- Department of Cardiac Surgery, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
Koh Takeuchi, MD
- Department of Cardiac Surgery, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
Ingeborg Friehs, MD
- Department of Cardiac Surgery, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
Pedro J. del Nido, MD
- Department of Cardiac Surgery, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
Francis X. McGowan Jr., MD
- Department of Anesthesiology and Perioperative and Pain Medicine, Children's Hospital Boston, and Harvard Medical School, Boston, Mass
- Anesthesia/Critical Care Medicine Research Laboratory, Children's Hospital Boston, and Harvard Medical School, Boston, Mass

Received 1 July 2008; received in revised form 20 November 2008; accepted 22 December 2008. published online 12 March 2009.

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.

Abbreviations and Acronyms: ESS, end-systolic stress, FS, fiberstress, LV, left ventricular, mw, midwall, SF, shortening fraction, SSI, stress shortening index, SVI, stress velocity index, TUNEL, terminal deoxynucleotide transferase-mediated dUTP nick-end labeling, VCFc, rate of circumferential fiber shortening