CMR Identifies Early Dilated Cardiomyopathy in Genetically At-risk Individuals: Preliminary Results from the DCM Precision Medicine CMR Study.

Background: Dilated cardiomyopathy (DCM) has a substantial genetic basis. First-degree relatives (FDRs) of individuals with DCM (probands) are considered genetically at risk, particularly if they carry variants classified as pathogenic (P), likely pathogenic (LP) or uncertain significance (VUS) in DCM genes. Guidelines recommend that FDRs undergo serial imaging to identify left ventricular (LV) dilation and dysfunction – hallmarks of DCM. However, myocardial changes occur prior to overt DCM. We hypothesize that higher genetic risk in FDRs is associated with worse measures (a pre-DCM phenotype) on cardiovascular magnetic resonance (CMR) to an extent increasing with age.

Methods:

Methods: The DCM Precision Medicine CMR Study is enrolling FDRs of probands with and without P/LP/VUS variants in 36 established DCM genes and performing CMR exams at 4 sites. FDRs undergo standardized CMRs at 1.5T which include functional analysis, strain via strain encoded imaging (SENC), T1 and T2 mapping, and late gadolinium enhancement imaging. CMR images are centrally analyzed using validated software (Circle Cardiovascular Imaging, Calgary, Canada). SENC images are processed using MyoStrain (Myocardial Solutions, Mooresville, NC) and include global longitudinal and circumferential strain, and the MyoHealth score (% of normal segments with strain ≤-17%) with subclinical LV dysfunction defined as MyoHealth < 80% (1). All FDRs undergo genetic sequencing for their proband’s variants and are classified into genetic risk groups based on the most deleterious variant shared with the proband (negative, VUS, P/LP). Marginal means of myocardial measures for each genetic risk group and their differences were estimated using linear models with adjustment for sites and intrafamilial correlation.

Results:

Results: In total, 291 enrolled FDRs have undergone CMR; the current cohort comprises 170 FDRs with genetic sequencing completed (38 P/LP, 75 VUS, 57 negative). Given the age dependent presentation of DCM, genetic risk groups were compared below and above the median age at CMR of 40.5 years. Among FDRs above the median age, P/LP FDRs had higher indexed LV volumes and mass, worse longitudinal and circumferential strain, and lower MyoHealth scores compared to negative FDRs (Table). LV ejection fraction was lower compared to negative FDRs in both P/LP (-7.0% [CI: -12.7, -1.2], p=0.02) and VUS (-4.3% [CI: -7.7, -0.9], p=0.01) FDRs. Of note, the mean MyoHealth score was abnormal (< 80%) across all 3 genetic risk groups (Table).

Conclusion:

Conclusions: First degree relatives of DCM probands exhibit significant differences across CMR myocardial characteristics based on their degree of genetic risk. Although FDRs have similar CMR measures across genetic risk groups at younger ages, older P/LP FDRs had larger LV volumes, lower LV ejection fraction, and worse myocardial strain as compared to negative FDRs. Also, abnormal strain across all FDRs suggests unmeasured genetic risk in negative FDRs.