Although it is well known that either myocardial- specific reduction in endothelial nitric oxide synthase (eNOS) activity or an induction of the profibrotic cytokine transforming growth factor (TGF)-b1 contribute to the transition from myocardial hypertrophy to heart failure neither mice with an eNOS knock down nor mice with TGF- b1 overexpression develop heart failure. We hypothesized that both pathways must be linked to each other by TGF-b1-dependent activation of the polyamine metabolism, as characterized by an increased expression of its rate limiting enzyme ornithine decarboxylase (ODC). This should increase the susceptibility to heart failure due to a competition between the NO and ODC pathways to arginine. The hypothesis was challenged by crossing eNOS knockout mice with TGF-b1 overexpressing mice. In this newly developed transgenic mouse model, complete loss of eNOS in TGF-b overexpressing mice led to high intrauterine mortality and reduced survival of the remaining founders. Noteworthy, mice with TGF-b1 overexpression and only one allele of eNOS survived but developed a higher incidence of heart disease with a more severe phenotype than in their littermates not expressing TGF-b1. They developed severe myocardial hypertrophy, strong ventricular and atrial expression of ODC and mitochondrial uncoupling protein (UCP)-2 as we found by using real time RT-PCR and Western Blot analysis. By contrast, a less severe phenotype was seen in heterozygous eNOS knockout mice with less UCP-2/3 expression. In human patients undergoing a surgery due to valve stenosis we found a similar correlation between ODC/eNOS expression and ANF expression that was used as a hypertrophic marker and UCP3 expression and ANF expression. In conclusion, ODC expression is directly linked to the severity of hypertrophy-associated heart failure in hearts with limited eNOS bioavailability.