Downregulation of connexin43 (Cx43) in the failing heart has been implicated not only in arrhythmogenesis but in contractile dysfunction as well. Cx43-deficient mice exhibit reduced baseline conduction velocity and increased arrhythmias in response to ischemia. However, it is not known whether Cx43-deficient mice have any abnormalities in contractile function or, furthermore, whether cardiac dysfunction may be manifested in Cx43-deficient mice with advancing age. Therefore, we analyzed echocardiographic images from young and senescent Cx43-deficient C57BL/6Jx129 mice compared to wild-type littermate controls. Only a few, modest genotype-related differences were observed. LV wall thickness during systole and % fractional shortening were diminished by 8-10% in Cx43-deficient v wild-type mice. Aging alone had a greater effect on cardiac structure and function. LV mass and relative wall thickness were significantly increased in senescent v young mice independent of genotype. Percent fractional shortening and LV internal chamber dimension were significantly reduced in senescent v young mice. Thus, aging in mice, as in humans, is associated with concentric remodeling, mild systolic dysfunction and fibrosis. Although diminished Cx43 expression could contribute to contractile dysfunction in patients with advanced heart failure, genetic deficiency in Cx43 does not appear significantly to alter cardiac structure or function even in aged mice. Copyright 2002 Academic Press.