Abstract

INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a hereditary disorder resulting in cardiac sarcomere protein gene mutations, which usually presents as otherwise unexplained left ventricular hypertrophy(1-4).Currently, myocardial extracellular volume (ECV) has been repeatedly histologically validated for quantification of diffuse myocardial fibrosis, and can be acquired noninvasively with T1 mapping before and after gadolinium administration(5-9).Diffusion weighted imaging (DWI) has been histologically validated in detecting regions of myocardial fibrosis in MI scar tissue(10) and diffuse myocardial fibrosis in the failing heart(11). Despite this sensitivity, its prognostic value for diffuse myocardial fibrosis and its relationship to the contractile function is still not investigated. We explore the prognostic value of the apparent diffusion coefficient (ADC) for detecting diffuse myocardial fibrosis and its relationship to dysfunction of global contractile function in hypertrophic cardiomyopathy (HCM). METHODS: A total of 45 HCM patients (25 male; 52 ±10 years) and 20 controls without previous cardiovascular diseases (9 male; 50 ± 6 years) underwent a 3.0-T cardiac magnetic resonance imaging (CMRI). The CMRI sequences included cine, T1 mapping, and DWI. The mean T1 value, ADC, extracellular volume (ECV) and three-dimensional (3D) tissue tracking for global strain (S) and strain rate (SR) were determined for each subject. RESULTS: The value of ECV was 23.6 ± 3.0% for control. ECV ≥ 29.6% and ECV < 29.6% groups were classified based on the ECV values (+2SD) of control subjects. ADC values in the ECV ≥ 29.6% group were significantly increased compared to the ECV < 29.6% group, (2.63 ± 0.23 μm2/ms vs. 2.18 ± 0.28 μm2/ms). ADC values were linearly associated with ECV values (R2 = 0.62) in HCM patients. Using the ECV values as the gold standard for the receiver operating characteristic (ROC), the area under the curve (AUC) was 0.93, 95% Confidence interval (CI) was 0.855 to 1.000 and the cut off value was 2.01 μm2/ms, sensitivity was 91.11% and specificity was 100%. The 3D LV GCS, GLS, GRS, GCSR, GLSR and GRSR in the ECV ≥ 29.6% group were significantly impaired compared to the ECV < 29.6% group. ADC values were linearly associated with 3D LV GCS, GLS, GCSR, GLSR and GRSR (R2 = 0.33, R2 = 0.30, R2 = 0.18, R2 = 0.14, R2 = 0.24, respectively). DISCUSSION: In this study, we demonstrated that ADC values were capable of not only detecting diffuse fibrosis, but also of characterizing the development of myocardial fibrosis in HCM patients. Moreover, we found that increased ADC values were linearly associated with the impaired deformation function in HCM patients. ADC values play a role in interpreting the underlying changes within the intracellular spaces of the myocardium. Recently, the potential of DWI to identify myocardial fibrosis in clinical configurations has been investigated. Pop et al and Nguyen et al demonstrated histological validation of the ADC value for detecting the replacement fibrosis in infarcted swine heart and showed that the ADC values were capable of detecting fibrosis defined by LGE with high sensitivity and specificity, respectively(10,12). Interestingly, the ADC values in the ECV < 29.6% group were higher than the cut off value derived from the ROC curve. The potential mechanisms that lead from sarcomere dysfunction to overt hypertrophy may be multi-factored and include impaired calcium cycling, interstitial fibrosis, myocardial oedema and microvascular dysfunction(13). All 3D LV global strain and strain rate values were significantly reduced in the ECV≥29.6% group, compared to the ECV<29.6% group, which suggests that diffuse myocardial fibrosis may result in the dysfunction of myocardial deformation. Previously, Swoboda et al(14) demonstrated that LV segment strain in an ECV abnormal group of HCM patients was significantly impaired. Additionally, Bogarapu et al(15) reported the utility of the 3D LV strain and strain rate derived from CMRI feature tracking in identifying myocardial fibrosis defined by LGE. In this study, 3D LV GCS, GLS, GCSR, GLSR and GRSR values were associated with increasing ADC values. Previously, we showed that increased values of the ADC were linearly associated with impaired end systolic circumferential global strain and end diastolic circumferential global strain rate in HTN patients(16). A possible mechanism linking the ADC value to decreased systolic strain in such patients is as follows: increased extracellular matrix deposition leads to increased LV stiffness, which decreased the end-diastolic muscle fibre length, and through the Frank-Starling mechanism, leads to decreased cardiac muscle contraction and LV systolic strain. CONCLUSION: Impairment of contractile function in HCM is predominantly associated with the contrast-free ADC value, which is a feasible alternative to ECV for the identification of myocardial fibrosis in patients with HCM.

Acknowledgements

Supported by National Natural Science Foundation of China (Youth Program No.81401403), Shanghai Municipal Commission of Health and Family Planning excellent young talent program（No. 2017YQ031) and Shanghai Jiao Tong University Medical engineering cross fund （YG2014MS48).