Differences in Cardiac Mechanics among Genetically At-Risk First-Degree Relatives: The DCM Precision Medicine Study

Abstract

AimsAmong genetically at-risk first-degree relatives (FDRs) of probands with dilated cardiomyopathy (DCM), the ability to detect changes in left ventricular (LV) mechanics with normal LV size and ejection fraction (LVEF) remains incompletely explored. We sought to define a pre-DCM phenotype among at-risk FDRs, including those with variants of uncertain significance (VUSs), using echocardiographic measures of cardiac mechanics. Methods and ResultsLV structure and function, including speckle-tracking analysis for LV global longitudinal strain (GLS), were evaluated in 124 FDRs (65% female; median age 44.9 [IQR: 30.6-60.3] years) of 66 DCM probands of European ancestry sequenced for rare variants in 35 DCM genes. FDRs had normal LV size and LVEF. Negative FDRs of probands with pathogenic or likely pathogenic (P/LP) variants (n=28) were a reference group to which negative FDRs of probands without P/LP variants (n=30), FDRs with only VUSs (n=27), and FDRs with P/LP variants (n=39) were compared. In an analysis accounting for age-dependent penetrance, FDRs below the median age showed minimal differences in LV GLS across groups while those above it with P/LP variants or VUSs had lower absolute values than the reference group (-3.9 [95% CI: -5.7, -2.1] or -3.1 [-4.8, -1.4] %-units) and negative FDRs of probands without P/LP variants (-2.6 [-4.0, -1.2] or -1.8 [-3.1, -0.6]). ConclusionsOlder FDRs with normal LV size and LVEF who harbored P/LP variants or VUSs had lower absolute LV GLS values, indicating that some DCM-related VUSs are clinically relevant. LV GLS may have utility for defining a pre-DCM phenotype. Clinical Trial Registrationclinicaltrials.gov, NCT03037632 Graphical AbstractDifferences in Cardiac Mechanics among Genetically At-Risk First-Degree Relatives: The DCM Precision Medicine Study. DCM = dilated cardiomyopathy, FDR = first-degree relative, GLS = global longitudinal strain, HF = heart failure, LP = likely pathogenic, LV = left ventricular, LVEF = left ventricular ejection fraction, P = pathogenic, VUS = variant of uncertain significance. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/23290123v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@1a1a86aorg.highwire.dtl.DTLVardef@37eadcorg.highwire.dtl.DTLVardef@11c4f2dorg.highwire.dtl.DTLVardef@192234f_HPS_FORMAT_FIGEXP M_FIG C_FIG