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Novel magnetic resonance imaging marker of diffuse myocardial fibrosis in hypertensive heart disease: the role of transcytolemmal water-exchange


Transcytolemal water exchange and its effect on myocardial T1 relaxation can, if neglected, lead to a significant underestimate of the myocardial extracellular volume fraction, a novel marker of diffuse fibrosis.


LGE may fail to detect diffuse fibrosis in several cardiac conditions. A novel approach uses the myocardial extracellular volume-fraction (MECVF), measured as distribution volume of a gadolinium constrast, as a marker of extracellular expansion. Previous studies have assumed the fast-exchange (FX) limit for the transcytolemal water-exchange, yet the administration of an extracellular-agent can create significant transcytolemal T1-differences, and cause an underestimation of extracellular volume fraction under the FX assumption. We hypothesized that the quantitative measure of MECVF with using a 2-site H-exchange model (2SX-model) correlates positively with the extracellular volume fraction, while the FX approach underestimates extra-cellular matrix expansion in a rodent model of hypertensive heart disease and diffuse myocardial fibrosis created by administration of L-NAME.


L-NAME(3mg/ml) or placebo was administered respectively to 22(bw=36.9±2.3g) and 15(bw=37.6±2.5g) wild-type mice. Animals were imaged at baseline and 7-weeks after treatment on a 4.7T small-animal MRI-system. T1(#of T1’s>5/mouse) was quantified with a modified Look-Locker gradient-echo-cine technique, before and after fractionated Gd-DPTA administration(mean max. R1 in blood post-contrast=5.0±2.26 1/s). MECVF obtained from the T1 measurements with the 2SX and FX-models, and by using blood hematocrit to adjust the partition coefficient. Connective tissue volume fraction (CTVF) was measured using Masson’s trichrome.


L-NAME-treated animals demonstrated hypertrophy (weight-indexed LVmass 4.1±0.4 vs. 2.2±0.3 μg/g, p<0.001) and increased CTVF (8.6%±1.5 vs. 2.58%±0.6, P<0.001) as compared to controls. MECVF was substantially higher in L-NAME-treated animals (0.43±0.09 vs, 0.26±0.03, p<0.001 with 2SX-model; 0.20±0.03 vs. 0.20±0.05, p=0.82 without TWE with FX assumption). MECVF from 2SX-model showed a good correlation with CTVF and weight-indexed LVmass (both r=0.8, p<0.0001), while MECVF from FX-model did not correlate significantly with CTVF(p=0.44) and LVmass(p=0.80)(fig-1). MECVF from the 2SX model also correlated with the LVEF at 7-weeks(r=0.48, p=0.01). Bland-Altman analysis demonstrated that neglect of the transcytolemal water exchange causes a significant underestimate MECVF expansion(fig-2), which worsens with extracellular matrix expansion and LVH.

Figure 1
figure 1

Correlation: MECVF (2-site H-exchange and Fast-exchange) and connective tissue volume fraction

Figure 2
figure 2

Bland-Altman analysis


CMR MECVF quantification provides a robust measure of myocardial extracellular matrix expansion and interstitial fibrosis, though any break-down of the FX assumption for transcytolemmal exchange can result in a significant underestimation of MECVF. Importantly, underestimates of MECVF due to the FX assumption depend on the degree of cell-hypertrophy, and the maximum T1 in the blood pool. A break-down of the FX assumption cannot be detected with protocols limited to a pair of pre/post-contrast T1 measurements. A generalization of the model for determination of MECVF brings important benefits for an early detection of diffuse fibrosis.


Supported by the American Heart Association (AHA 11POST5550053) and the National Institutes of Health/NHLBI (1R01HL090634-01A1).

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Coelho-Filho, O.R., Mitchell, R.N., Moreno, H. et al. Novel magnetic resonance imaging marker of diffuse myocardial fibrosis in hypertensive heart disease: the role of transcytolemmal water-exchange. J Cardiovasc Magn Reson 14 (Suppl 1), O115 (2012).

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