Non-ischemic Primary and Secondary Cardiomyopathy

1355091 - Alterations in Left Ventricular End-Systolic Strain in Mice with Familial Hypertrophic Cardiomyopathy

Wednesday, January 25, 2023

Location: E-POSTER

Presenting Author(s)

JW

Jonathan F. Wenk, PhD

Gill Associate Professor
University of Kentucky
Lexington, Kentucky, United States

Primary Author(s)

JW

Jonathan F. Wenk, PhD

Gill Associate Professor
University of Kentucky
Lexington, Kentucky, United States

Co-Author(s)

Steve W. Leung, MD, FSCMR

Associate Professor
University of Kentucky
Lexington, Kentucky, United States
CM

Charles K. Mann, PhD

Postdoc
University of Kentucky, United States
HS

Hossein Sharifi, MSc

PhD Candidate
University of Kentucky, United States
MM

Mohammad Mehri, MSc

PhD Student
University of Kentucky, United States
AW

Austin G. Wellette-Hunsucker, MSc

PhD Student
University of Kentucky, United States
KH

Kory R. Heier, MSc

Biomedical Data Science Assistant
University of Kentucky, United States
CS

Christine E. Seidman, MD

Thomas W. Smith Professor of Medicine
Harvard Medical School, United States
JS

Jonathan G. Seidman, PhD

Henrietta B. and Frederick H. Bugher Foundation Professor of Genetics
Harvard Medical School, United States
KC

Kenneth S. Campbell, PhD

Professor of Cardiovascular Medicine
University of Kentucky, United States

Disclosure(s):

Steve W. Leung, MD, FSCMR: No relevant disclosure to display

Background: Familial hypertrophic cardiomyopathy (HCM) is the most frequently inherited heart defect and most common cause of cardiac death in youth [1]. Genetic mutations underlying HCM affect either the motor protein myosin or sarcomeric proteins that regulate myosin, leading to hypercontractility. Transgenic HCM mice, which have the heterozygous human α-myosin heavy chain R403Q mutation, have been shown to replicate human HCM including the development of hypertrophy, myocyte disarray, and fibrosis [2]. Although previous studies have investigated morphological changes in these animals [3], none have used CMR to assess alterations in ventricular mechanics. Thus, the goal of our ongoing study is to measure changes in ventricular strain patterns due to the presence of HCM. Here, we report our most recent findings.

Methods: Ten male heterozygous R403Q mice and 10 male control mice were used. CMR was performed on a 7T system (ClinScan, Bruker) when the animals were 16 and 28 weeks of age. A cardiac and respiratory self-gated UTE sequence was used with the following parameters: 15 frames per cardiac cycle, field of view 25mm x 25mm, pixel size 0.13mm, slice thickness 1mm, TR 9ms, flip angle 10 degrees. Five short-axis and 3 long-axis images were acquired. Feature-tracking analysis was performed by a level-3 trained CMR reader (CMR42, v5.6.3, Circle Cardiovascular Imaging, Inc., Calgary, Canada) (Figure 1). Circumferential (Ecc), longitudinal (Ell), and radial (Err) strains were calculated by averaging the mid-ventricular AHA segments at end-systole. Each 16-week measurement was subtracted from the 28-week measurement, and that difference was analyzed between the control and R403Q groups using a Welch two sample t-test (R Foundation for Statistical Computing, Vienna, Austria).

Results: It can be seen in Figure 2 that the magnitudes of Ecc and Err strain decrease between 16 and 28 weeks for the R403Q group, but not for the control group. The mean differences in strain between the two time points for the control and R403Q groups are shown in Figure 3. The change in Ecc between 16 and 28 weeks (-20.44±0.95 vs -17.20±0.68) for the R403Q group was significantly larger than the control group (-17.50±0.48 vs -17.41±0.65). This was also the case for Err, where the change between time points for the R403Q group (38.63±2.56 vs 31.77±2.20) was significantly larger than the control group (28.52±1.14 vs 29.29±1.73). There were no significant differences when comparing the Ell strains.

Conclusion: In this preliminary study, the elevated magnitudes of strain in R403Q mice at 16 weeks (relative to controls) suggest that the ventricle is hypercontractile and tissue structure is organized. Interestingly, the magnitude of strain decreases significantly as the animals age. The development of disarray and fibrosis may reduce the deformation generated during systole, despite the myocytes being hypercontractile. Histological and cellular force measurements are ongoing to confirm this hypothesis.