We previously reported on well preserved right ventriculo (RV)-arterial coupling in growing piglets with pulmonary arterial hypertension (PAH) induced by three-month aortapulmonary shunting. We hypothesized that a more prolonged period of shunting would induce more severe pulmonary hypertension and RV failure. Sixteen three-week old piglets were randomized to a modified Blalock-Taussig- or a SHAM-operation. Six months later, the animals underwent hemodynamic evaluation followed by pulmonary and myocardial tissue sampling for morphometry and pathobiological evaluation (by real-time quantitative polymerase chain reaction and Western Blotting). Six-month chronic systemic-to-pulmonary shunting induced similar pulmonary vascular changes than previously described in three-month shunted piglets, with pulmonary vascular resistance (PVR) increased from 2.8±0.3 to 6.4±1.0 mmHg.L-1.min.m-2 and increased arteriolar medial thickness compared to SHAM-operated piglets. However, cardiac output was decreased (5.4±0.6 vs 3.0±0.1 L/min), in relation to a RV-arterial uncoupling as shown by a ratio of end-systolic to arterial elastances (Ees/Ea) decreased from 1.4±0.1 to 0.7±0.1. At pathobiological level, pro-apoptotic Bax/Bcl2 mRNA ratio and caspase-3 activation were signifycantly increased in right ventricular tissue, with associated increased mRNA expressions in natriuretic peptide precursors A (NPPA) and B (NPPB). Proinflammatory cytokines, such as interleukin-1alpha and -1beta, were upregulated in the failing right ventricle, while expressions of antagonist (IL1RN) and receptor (IL1R) didn't change. Prolonged aorta-pulmonary shunting in piglets does not further aggravate pulmonary hypertension, but induced a RV failure, which appears related to mechanical stress-induced myocardial inflammatory response probably responsible for the induction of apoptotic pathways and increased expression of hypertrophic markers.