Mechanical factors play a key role in activation of cardiac growth factor response in hemodynamic overload, and both cooperate in myocardial remodeling. The present study was performed to investigate whether a different growth factor response is activated in the right and left ventricles in aortocaval fistula and its effects on regional myocardial adaptation. Relations between regional growth factor expression (angiotensin II, insulin-like growth factor-I, and endothelin-1), myocyte shape changes, and collagen deposition were investigated at mRNA and peptide levels in adult pigs after the creation of an aortocaval fistula distal to the renal arteries (n=15) and in sham-operated animals (n=15). The role of angiotensin II was investigated by the administration of angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist. In the left ventricle, pure volume overload was accompanied by persistent increase of insulin-like growth factor-I mRNA expression, peptide concentration (2.2-fold versus sham at 3 months, P<0.05), and significant increase of myocyte length (+29% at 3 months, P<0.05). Conversely, the mixed pressure-volume overload faced by the right ventricle resulted in significant regional overexpression of all growth factors investigated (angiotensin II, insulin-like growth factor-I, and endothelin-1), with corresponding increase of myocyte diameter and length and collagen deposition (+117% at 3 months). Collagen accumulation in the right ventricle as well as the increase in right ventricular end-diastolic pressure at the 3-month observation were inhibited by angiotensin II antagonism. The left and right ventricles respond differently to aortocaval fistula, and local growth factor expression is closely related to the regional myocardial adaptation.