Insulin-like growth factor-1 enhances ventricular hypertrophy and function during the onset of experimental cardiac failure.

Abstract

To determine whether additional hypertrophy would be beneficial or maladaptive in cardiac failure, the effects of insulin-like growth factor (IGF-1) were investigated in rats with left ventricular (LV) dysfunction. In normal rats, 3 mg/kg per d of recombinant human IGF-1 for 14 d augmented LV wt (32%) and increased LV/body wt ratio (P < 0.01). 2 d after coronary occlusion, rats were randomized to IGF-1 (3 mg/kg per d) or placebo. After 2 wk, IGF-1-treated rats showed significant increases in LV wt (13%) and LV wt/tibial length ratio, but LV/body wt ratio was unchanged. By microangiography, compared with controls (n = 12) IGF-1-treated rats (n = 16) showed increased LV end-diastolic volume (19% ) and stroke volume (31% ) (both significant normalized to tibial length, but not to body wt). Average infarct size did not differ between groups. The LV ejection fraction (EF) was not significantly different between groups, but estimated cardiac output was higher in treated rats; there was a significant interaction for the EF between infarct size and treatment (P = 0.029) and a trend for EF to be higher in treated rats with large infarctions (EF 33.4 vs 25.1% in controls). Myocyte cross-sectional areas in noninfarcted LV zones tended to be larger in treated rats (232.1 vs 205.4 ,Im2; P = 0.10), but there was no difference in capillary density and collagen content did not differ between groups. In conclusion, IGF-1 administration caused hypertrophy of the normal heart in vivo. When stimulated by IGF-1, the severely dysfunctional heart in evolving myocardial infarction is capable of undergoing additional hypertrophy with evidence of improved function, suggesting a beneficial effect. Further investigation of the potential role of growth factor therapy in heart failure appears warranted. (J. Clin. Invest 1995. 95:619-627.) Key words: insulin-like growth factor-i * cardiac hypertrophy . left ventricular remodeling -myocardial cell size -collagen

Insulin-like growth factor (IGF-I) induces myotube hypertrophy associated with an increase in anaerobic glycolysis in a clonal skeletal-muscle cell model

“…This has some similarity to the physiological response to IGF-I seen in experimental animal models. Mice with experimental heart failure treated with IGF-I showed no induction of cardiac hypertrophy at baseline plasma levels of IGF-I (mean 229 ng\ml) but hypertrophy associated with an increase in cardiac output was seen at higher plasma IGF-I levels (mean 601 ng\ml) [38]. Importantly, normal myoblasts treated with media collected from IGF-I-secreting cells also showed a hypertrophic response, demonstrating the paracrine hypertrophic effects of IGF-I.…”

The Insulin-like Growth Factor 1 Receptor Induces Physiological Heart Growth via the Phosphoinositide 3-Kinase(p110α) Pathway

“…Duerr et al (10) suggested that the increase in the heart weight of rats administered IGF1 for 2 weeks was caused mainly by myocyte hypertrophy. However, in transgenic mice expressing IGF1 specifically in the heart, an increase in myocyte number was reported (12).…”

“…Pathway in the Heart-There is growing evidence to suggest that pathological and physiological cardiac hypertrophy are mediated by distinct signaling pathways (10,16,21,(33)(34)(35)(36)(37)(38)(39)(40). It is therefore likely that the transcriptional regulation of pathological and physiological hypertrophy will also be different.…”

“…IGF1 and IGF1 receptors (IGF1R) are present in the adult heart (2), and it has been shown that normal activation of the growth hormone-IGF1 axis is essential for myocardial performance (8,9). Further, it appears that short term administration of IGF1 is beneficial in improving cardiac function in the setting of heart failure (10), and IGF1 transgene expression has been reported to counteract the occurrence of apoptosis in a murine heart failure model (11). However, conflicting results obtained from clinical trials in which IGF1 was chronically administered to humans have questioned the therapeutic value of IGF1 (2,3).…”

Marked differences in the IGF system that are associated with migration in comparable populations of Gujaratis living in Sandwell, UK, and Gujarat, India

“…The IGF system has been implicated in the pathogenesis of hypertension [7], atheromatous vascular disease [8,9], cardiomegaly [10], ischaemic disease [11] and cardiac failure [12,13]. IGF bioactivity is modulated by a series of specific high-affinity IGFBPs [14].…”