Recent studies suggest a cardioprotective role for IGF-1. Also age-related changes of myocardial structure and function seem to be associated with the GH/IGF-1 signalling pathway. Clinical studies indicate a correlation between reduced IGF-1 levels in aged patients with an enhanced risk of heart failure (Framingham survey, Rotterdam survey).

In the current study we aim to investigate the age dependent influence of IGF-1 signalling in maintenance of cardiac structure and function. Therefore we used young adult – (3 month old) and senescent mice (6–10 month old) with a cardiomyocyte specific, 4hydroxy-tamoxifen(OHTX)-inducible knock out (KO) of the IGF-1 receptor (IGFR). rtPCR revealed that 10 days of OHTX treatment led to an effective excision of the ligand binding domain of the receptor and thereby to receptor inactivation. After induction of the KO we repeatedly monitored cardiac function by echocardiography. The group of 3 month old mice did not show any tendency of changed cardiac function after IGF1R-KO over a period of up to 9 week. These data were confirmed by magnetic resonance imaging (MRI) in a subpopulation of the 3 month old mice (n=8–9). Cardiac function in 3 month old mice was also evaluated by P/V-catheter measurements (n=7). In accordance to the other techniques catheter measurements did not show functional changes in IGF1R-KO mice, neither in the cardiac volumes, nor in the pressure values. In contrast to the young mice IGF1R-KO in older mice impaired cardiac function. Echocardiography indicated the development of left ventricular dilatation in IGF1R-KO mice. Impairment of cardiac function could also be shown by P/V-catheter measurements in the group of old animals 6 weeks after induction of the KO (significant changes: Pmax: control 88.8916.28 mmHg; KO 71.117.53mmHg; dP/dtmin control -6067.071261.76 mmHg/s; KO -4618.18438.04mmHg/s; n=8–15). First volume data obtained from the older animals hinted to the development of left ventricular dilatation after IGF1R KO (ESV: control 104.5; KO 19.5 1.5ml/EDV: control 18.31.9; KO 27.65.4ml; n=3). Histological studies, performed in the young and the old group, displayed no changes in the CM diameter, the content of collagen fibres (Sirius red staining) or the rate of apoptosis (activated caspase-3; TUNEL) in the hearts of IGF1R-KO mice.

Surprisingly our results indicate that CM-specific IGF-1 signalling appears to be dispensable for the integrity of cardiac function in the healthy heart of young adult animals. In older animals however loss of IGF-1 signalling results in functional depression. To what extend the unexpected benign phenotype is the result of compensatory mechanisms remains to be elucidated.