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Background-The myocardial extracellular volume fraction (MECVF) has been used to detect diffuse fibrosis. Estimation of MECVF relies on quantification of the T1 relaxation time after contrast enhancement, which can be sensitive to equilibrium transcytolemmal water-exchange. We hypothesized that MECVF, quantified with a parsimonious 2-space water-exchange model, correlates positively with the connective tissue volume fraction in a rodent model of hypertensive heart disease, whereas the widely used analysis based on assuming fast transcytolemmal water-exchange could result in a significant underestimate of MECVF. Methods and Results-Nω-nitro-L-arginine-methyl-ester (L-NAME) or placebo was administered to 22 and 15 wild-type mice, respectively. MECVF was measured at baseline and 7-week follow-up by pre-and postcontrast T1 cardiac magnetic resonance imaging at 4.7 T, using a 2-space water-exchange model.