Early Detection of myocardial strain impairments in a mouse model of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) affects 1 in 200 to 1 in 500 people, driven by genetic mutations that result in excessive myocardial contraction and complications (1). Conventional metrics like ejection fraction (EF) and fractional shortening (FS) fall short in capturing detailed cardiac dynamics, whereas MRI strain imaging offers more comprehensive assessment (2-3). This study employs cardiac MRI with feature tracking (CMR-FT) to assess myocardial strain in both left (LV) and right ventricles (RV) of an HCM mouse model, seeking to identify early imaging markers.

Methods:

We utilized a HCM model (Mybpc3-KI) which carries a point mutation in the Mybpc3 gene on a C57BL/6 background. The level of total cMyBP-C mRNA was reduced by 50% in heterozygotes (HET) representing early-phase HCM (4). To explore the potential of early-phase imaging markers, we conducted a detailed strain assessment in 7- to 8-week-old HET mice, corresponding to the early disease stage in humans, and compared them with wild-type (WT) controls. Both LV and RV strain were analyzed using Segment Version 4.0 (Medviso, Lund, Sweden), with endo- and epicardial borders manually delineated at end-systole and end-diastole from short-axis (SAX) and long-axis (LAX) CINE images (four chamber view). Figure 1 illustrate the experimental settings.

Results:

LV wall thickness did not differ significantly between HET and WT mice (Fig.2b). Functional assessments showed that HET mice had normal functional metrics, with no significant differences in LVEF or RVEF in both males and females compared to WT controls (Fig.2c).However, CMR-FT analysis revealed significant reductions in strain and strain rate values in HET mice, particularly in torsion (p=0.02), LV global longitudinal strain (LVGLS) (p=0.009), RV global longitudinal strain (RVGLS) (p=0.035), LV systolic longitudinal strain rate (LVSLST) (p=0.014), and LV diastolic radial strain rate (LVDRST) (p=0.037), with more pronounced abnormalities in females during the early age (Fig.3).

Conclusion:

Our study identified ventricular mechanical dysfunctions in HCM using CMR-FT, confirming that torsion, GLS, LVSLST, and LVDRST may serve as potential early imaging markers for HCM. Compared to traditional measures of ventricular function and wall thickness, strain analysis demonstrated superior sensitivity in detecting early abnormalities.

Figure 1: All mice underwent MRI according to the illustrated protocol. Functional assessment and strain analysis were performed on 7- to 8-week-old mice from both WT and HET groups. Strain analysis for both the left ventricle (LV) and right ventricle (RV) was conducted with endo- and epicardial borders manually delineated from short-axis (SAX) and long-axis (LAX) CINE images (four-chamber view).

Figure 2: Functional analysis of ventricular performance in mice with different genotypes and genders using CINE-CMR. a. Endocardial and epicardial borders were manually segmented for end-systole and end-diastole using a stack of short-axis CINE images. b. Left ventricular (LV) thickness was presented as mean values with standard deviation (SD) on a slice-by-slice basis. c. Functional assessment, including left ventricular ejection fraction (LVEF) and right ventricular ejection fraction (RVEF), was presented as mean values with SD on a slice-by-slice basis. Significance levels were determined using one-way ANOVA with Tukey's test, with p < 0.05 considered statistically significant.

Figure 3: Myocardial strain variations in the LV and RV of mice with different genotypes and genders obtained from CMR-FT.a. FT images displayed at different slices for various genotypes. b. LV strain assessments, including left ventricular global circumferential strain (LVGCS), left ventricular global radial strain (LVGRS), left ventricular global longitudinal strain (LVGLS), and torsion, were conducted on above images. c. RV strain assessments, including right ventricular global circumferential strain (RVGCS) and right ventricular global longitudinal strain (RVGLS), were also conducted on above images. d. LV strain rate measurements, including LV diastolic/systolic circumferential strain rate (LVDCST/LVSCST), LV diastolic/systolic radial strain rate (LVDRST/LVSRST), and LV diastolic/systolic longitudinal strain rate (LVDLST/LVSLST), were presented as mean values with standard deviation (SD) on a slice-by-slice basis. Significance levels were determined using one-way ANOVA with Tukey's test, with p < 0.05 considered statistically significant.