Role of Transcytolemmal Water-Exchange in Magnetic Resonance Measurements of Diffuse Myocardial Fibrosis in Hypertensive Heart Disease

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 N-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. Connective tissue volume fraction was quantified, using Masson trichrome stain. L-NAME induced hypertrophy (weight-indexed left-ventricular mass 2.2 +/- 0.3 versus 4.1 +/- 0.4 g/g, P<0.001), and increased connective tissue volume fraction (8.6%+/- 1.5 versus 2.58%+/- 0.6, P<0.001), were compared with controls. MECVF was higher in L-NAME-treated animals (0.43 +/- 0.09 versus 0.26 +/- 0.03, P<0.001), and correlated with connective tissue volume fraction and weight-indexed left-ventricular mass (r=0.842 and r=0.737, respectively, both P<0.0001). Neglecting transcytolemmal water-exchange caused a significant underestimate of MECVF changes. Ten patients with history of hypertension had significantly higher MECVF (0.446 +/- 0.063) compared with healthy controls (0.307 +/- 0.030, P<0.001). Conclusions Cardiac magnetic resonance allowed detection of myocardial extracellular matrix expansion in a mouse model and in patients with a history of hypertension. Accounting for the effects of transcytolemmal water-exchange can result in a substantial difference of MECVF, compared with assuming fast transcytolemmal water-exchange.