Phosphatase-inhibitor-1 (I-1) is a distal amplifier element of beta-adrenergic signaling by preventing dephosphorylation of its downstream targets. I-1 is downregulated in failing hearts and overexpression of a constitutively active mutant form (I-1c) reversed contractile dysfunction in failing hearts, suggesting that I-1c may be a candidate for gene therapy. Here we generated conditional double-transgenic mice (Tet-Off system) with cardiomyocyte-restricted expression of I-1c (dTG-I-1c) on an I-1 knockout (KO) background. Transactivator only mice on a KO background (tTA) served as controls. Young adult dTG-I-1c mice exhibited enhanced cardiac contractility as determined by echocardiography. However, this phenotype turned into contractile dysfunction and ventricular dilatation when mice were subjected to chronic catecholamine infusion. Telemetric ECG recordings revealed typical catecholamine-induced ventricular tachycardia in dTG-I-1c and sudden death. Abnormalities in dTG-I-1c were reversed by shutting-off I-1c expression and were absent in tTA. Hearts from dTG-I-1c showed hyperphosphorylation of phospholamban and the ryanodine receptor, which could account for the hypercontractile phenotype and may increase the propensity for spontaneous Ca²⁺-release, respectively. Indeed, isolated myocytes from dTG-I-1c showed a higher frequency of catecholamine-induced Ca²⁺-sparks, consistent with a higher susceptibility for triggered arrhythmia. Notably, aging dTG-I-1c mice developed a cardiomyopathic phenotype. Taken together, transgenic expression of I-1c enhanced contractile function in young animals, but promoted catecholamine/stress-induced arrhythmias and structural cardiac pathology. Longterm expression of dTG-I-1c induced cardiomyopathy. These data point to fundamental risks of I-1c gene therapy in chronic heart failure.