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Programmed death of myocytes occurs in the decompensated human heart in spite of the enhanced expression of BCL2; this phenomenon may contribute to the progression of cardiac dysfunction.

To determine the effects of loading on active and passive tensions, programmed cell death, superoxide anion formation, the expression of Fas on myocytes, and side-to-side slippage of myocytes, papillary muscles were exposed to 7-8 and 50 mN/mm2 and these parameters were measured over a 3-h period. Overstretching produced a 21-and a 2.4-fold increase in apoptotic myocyte and nonmyocyte cell death, respectively. Concurrently, the generation of reactive oxygen species increased 2.4-fold and the number of myocytes labeled by Fas protein 21-fold. Moreover, a 15% decrease in the number of myocytes included in the thickness of the papillary muscle was found in combination with a 7% decrease in sarcomere length and the inability of muscles to maintain stable levels of passive and active tensions. The addition of the NO-releasing drug, C87-3754, prevented superoxide anion formation, programmed cell death, and the alterations in active and passive tensions with time of overloaded papillary muscles. In conclusion, overstretching appears to be coupled with oxidant stress, expression of Fas, programmed cell death, architectural rearrangement of myocytes, and impairment in force development of the myocardium. (J. Clin. Invest. 1995. 96:2247-2259

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Transgenic mice were generated in which the cDNA for the human insulin-like growth factor 1B (IGF-1B) was placed under the control of a rat a-myosin heavy chain promoter. In mice heterozygous for the transgene, IGF-1B mRNA was not detectable in the fetal heart at the end of gestation, was present in modest levels at 1 day after birth, and increased progressively with postnatal maturation, reaching a peak at 75 days. Myocytes isolated from transgenic mice secreted 1.15 + 0.25 ng of IGF-1 per 106 cells per 24 hr versus 0.27 ± 0.10 ng in myocytes from homozygous wild-type littermates. The plasma level of IGF-1 increased 84% in transgenic mice. Heart weight was comparable in wild-type littermates and transgenic mice up to 45 days of age, but a 42%, 45%, 62%, and 51% increase was found at 75, 135, 210, and 300 days, respectively, after birth. At 45, 75, and 210 days, the number of myocytes in the heart was 21%, 31%, and 55% higher, respectively, in transgenic animals. In contrast, myocyte cell volume was comparable in transgenic and control mice at all ages. In conclusion, overexpression of IGF-1 in myocytes leads to cardiomegaly mediated by an increased number of cells in the heart. Insulin-like growth factor-1 (IGF-1) belongs to the insulin family of peptides and acts as a growth factor in many tissues and tumors (1). Limited information is available on the effects of IGF-1 on the growth of cardiac myocytes. In neonatal ventricular myocytes in culture, lGF-1 activates DNA synthesis (2, 3) and the expression of myosin light chain-2, troponin, and a-skeletal actin (4), which are consistent with a hyperplastic and hypertrophic response of these cells. However, long-term cultures of adult myocytes react to the addition of IGF-1 by increasing only the formation of myofibrils in the cytoplasm (5). An up-regulation of IGF-1 mRNA in the myocardium occurs in pressure overload hypertrophy in vivo (6, 7), and this adaptation has been linked to myocyte hypertrophy. Recent observations have reported that acute ventricular failure is characterized by enhanced expression of IGF-1 and IGF-1 receptor (IGF-1R) in the stressed myocytes, which is followed by DNA replication, nuclear mitotic division, and cell proliferation (8,9). In line with these findings, the decline in DNA synthesis and cellular hyperplasia with postnatal myocardial development (10) is accompanied by attenuation in the expression of IGF-1 and IGF-1 receptor in myocytes in spite of ongoing cellular hypertrophy (11). However, a cause and effect relationship between IGF-1 and myocyte growth in vivo has not been established. For this purpose, a construct was made in which the human IGF-1B cDNA was placed under the control of the rat a-myosin heavy chain (a-MHC) promoter (12), which was then introduced as a transgene in FVB/N mice. This communication presents the effects that this transgene has on cardiac myocytes and on the whole animal, in heterozygous mice, designated as FVB.Igf+/-. Moreover, the consequences of this transgene on the hemodynamic characterist...