T1 measurements identify extracellular volume expansion in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy

Abstract

Background: Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a potential substrate for arrhythmias and heart failure. Sarcomere mutations seem to induce profibrotic changes before left ventricular hypertrophy (LVH) develops. To further evaluate these processes, we used cardiac magnetic resonance with T1 measurements on a genotyped HCM population to quantify myocardial extracellular volume (ECV).

Methods and results: Sarcomere mutation carriers with LVH (G+/LVH+, n=37) and without LVH (G+/LVH-, n=29), patients with HCM without mutations (sarcomere-negative HCM, n=11), and healthy controls (n=11) underwent contrast cardiac magnetic resonance, measuring T1 times pre- and postgadolinium infusion. Concurrent echocardiography and serum biomarkers of collagen synthesis, hemodynamic stress, and myocardial injury were also available in a subset. Compared with controls, ECV was increased in patients with overt HCM, as well as G+/LVH- mutation carriers (ECV=0.36±0.01, 0.33±0.01, 0.27±0.01 in G+/LVH+, G+/LVH-, controls, respectively; P≤0.001 for all comparisons). ECV correlated with N-terminal probrain natriuretic peptide levels (r=0.58; P<0.001) and global E' velocity (r=-0.48; P<0.001). Late gadolinium enhancement was present in >60% of overt patients with HCM but absent from G+/LVH- subjects. Both ECV and late gadolinium enhancement were more extensive in sarcomeric HCM than sarcomere-negative HCM.

Conclusions: Myocardial ECV is increased in HCM sarcomere mutation carriers even in the absence of LVH. These data provide additional support that fibrotic remodeling is triggered early in disease pathogenesis. Quantifying ECV may help characterize the development of myocardial fibrosis in HCM and ultimately assist in developing novel disease-modifying therapy, targeting interstitial fibrosis.

Keywords: MRI; fibrosis; gadolinium; genetics; hypertrophic cardiomyopathy.

Figures

Figure 1. Estimating the myocardial extracellular volume from T1 measurements

CMR T1 measurements before and after gadolinium contrast administration are used to determine the change of the relaxation rate (R1=1/T1) in myocardial tissue relative to blood. Data are derived from the slope of a least-squares linear regression that is fit to the measured R1 data. The slope corresponds to the partition-coefficient for the extracellular gadolinium contrast in myocardial tissue. By multiplying the partition coefficient with (1-hematocrit), to adjust for the blood contrast volume of distribution, the extracellular volume (ECV) fraction of myocardial tissue can be estimated. An expansion of the extracellular space corresponds to an increase of the slope of the regression line. The figure insets illustrate the extracellular space and intact cardiac myocytes (from which gadolinium is excluded) in normal myocardium, and with expanded ECV.

Figure 2. The myocardial extracellular volume is significantly increased in HCM sarcomere mutation carriers with and without LVH

Compared to normal controls, ECV was 27% higher in G+/LVH− subjects and 42% higher in G+/LVH+ HCM patients. ECV in overt HCM subjects was 12% higher than G+/LVH− subjects (P ≤0.001 for all comparisons).

Figure 3. The myocardial extracellular volume is correlated to serum NT-proBNP levels and E’ velocity

a) ECV was significantly positively correlated to serum NT-proBNP levels in the overall cohort excluding sarcomere-negative HCM patients (serum biomarkers not available for this cohort). b) ECV was significantly inversely correlated echocardiographic global E’ velocities in the overall cohort

Figure 4. Graphic comparison of T1 measurements and late gadolinium enhancement

a) Bull’s eye representation of results from segmental analysis (numbers correspond to AHA segment numbering for basal and mid-level slices) of T1 measurements before and after gadolinium contrast administration. Compared to healthy controls (images on left), the myocardial extracellular volume was elevated in sarcomere mutation carriers (G+), both in the absence (middle) or presence (right) of LVH. In the G+/LVH+ subject, the ECV remained highly abnormal if LGE+ segments were excluded. b) Representative LGE images from the same subjects, in mid-level locations corresponding to one of the levels for the T1 measurements of ECV. LGE is not seen in the normal control or the G+/LVH− subject, despite significantly increased ECV in the latter. The G+/LVH+ subject with overt HCM demonstrates prominent LGE near the anterior LV-RV junction.