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In the present study, we have tested whether the cardiac phenotype is, at least in part, the consequence of primary cardiac effects of fibulin-4. We have found fibulin-4 expression to be activated throughout the myocardium in wildtype (fibulin-4<jats:sup>+\/+<\/jats:sup>) C57Bl\/6J;129\u2009Sv mice subjected to transverse aortic constriction (TAC). In contrast, haploinsufficient fibulin-4<jats:sup>+\/R<\/jats:sup> mice exposed to severe TAC do not show this increase in myocardial fibulin-4 expression, but display altered physical properties of myocardial tissue. Moreover, TAC-induced cardiac fibrosis, pulmonary congestion, and mortality are aggravated in fibulin-4<jats:sup>+\/R<\/jats:sup> mice. In vitro investigations of myocardial tissue show that fibulin-4 deficiency results in cardiomyocyte hypertrophy, and a decreased beating frequency and contractile force. 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