Role of transcytolemmal water-exchange in magnetic resonance measurements of diffuse myocardial fibrosis in hypertensive heart disease

Abstract

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. 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 μg/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.

Figure 1

Representative examples of myocardial tissue stained with Masson’s trichrome in a mid-level myocardial slice from the control group (a) and the L-NAME group (b) shows a visually clear difference of blue-colored, connective tissue. Connective tissue fraction, shown in (c), and defined as the number of pixels with a bluish hue, divided by the total number of myocardial pixels in the slice, was significantly different between controls, and L-NAME treated mice.

Figure 2

(A) The relation between myocardial R1 and blood pool R1 was fit with a two-space 1H exchange model (2SX), to account for transcytolemmal water exchange (solid black line). Assuming fast water exchange (FX) predicts a linear relationship between myocardial R1 and blood R1. For lower R1 values (grey dashed line) this gives reasonable agreement, but results in a 80% underestimate of MECVF (0.38 vs. 0.21) if the FX model is used over the entire R1 range (black dashed line). (B) MECVF correlated significantly with the connective tissue fraction obtained from myocardial slices stained with Masson’s trichrome stain. (C) No significant correlation could be observed when the R1 relationship was analyzed with the fast 1H exchange assumption.

Figure 3

Chronic L-NAME treatment caused myocardial extracellular volume expansion (a), increased LV mass indexed to body weight significantly (b), and significantly reduced LV ejection fraction (c). Data were analyzed by t-test and paired t-test as appropriate.

Figure 4

Correlations (Spearman’s ρ) between MECVF and A) mean blood pressure (7 weeks), B) Left ventricular (LV) ejection fraction, and C) LV mass indexed by body weight.

Figure 5

In a 82-year old male with a history of hypertension, and no evidence of ischemic heart disease, myocardial R1 versus blood R1 was fit with a two-space 1H exchange model (2SX), shown as solid line. Similarly to Figure 2, the myocardial R1 initially increases linearly (shown as grey dashed line, extrapolated to larger R1 values), and then develops a convex shape as the rate of transcytolemmal moves away from the fast exchange condition. If all R1 data points are included for a fit with a linear model, one obtains a 67% lower value for MECVF (0.18), compared to the analysis with the 2SX model (0.54).