Abstract
BackgroundWhether mitral leaflet elongation is a primary phenotype of hypertrophic cardiomyopathy (HCM) is controversial. We investigated the genetic relevance and determinants of mitral leaflet size by performing extensive gene analyses in patients with HCM.MethodsAnterior mitral leaflet (AML) lengths were measured in HCM patients (n = 211) and age- and sex-matched controls (n = 30) using echocardiography with hemodynamic and chamber geometric assessments. We analyzed 82 nuclear DNA (8 sarcomeric genes, 74 other HCM-associated genes) and mitochondrial DNA. Cardiac magnetic resonance imaging (CMR) was performed in the 132 HCM patients.ResultsAverage indexed AML was significantly longer for HCM than for controls (17.2 ± 2.3 vs. 13.3 ± 1.6 mm/m2, P < 0.001). Average AML length correlated with body surface area (BSA), left ventricular (LV) end-systolic volume (P < 0.001) and LV mass by CMR (P < 0.001). Average indexed AML by BSA of pure-apical HCM was significantly shorter than other typed HCM (16.6 ± 2.0 vs. 17.4 ± 2.4 mm/m2, P = 0.025). Indexed AML was independently correlated with left atrial wall stress. The thin filament mutation group showed larger average AML (31.9 ± 3.8 vs. 29.6 ± 3.8 mm, P = 0.045), but this was not significant with the indexed value. No difference in AML size among subgroups was observed based on the presence of sarcomere protein or mitochondria-related gene variants (P > 0.05).ConclusionAML elongation was a unique finding of HCM. However, the leaflet size was more related to chamber geometry and hypertrophy pattern rather than genetic factors within overt HCM.
Highlights
Mitral leaflet elongation is related to obstructive hypertrophic cardiomyopathy (HCM) [1]
Genetic characteristics Based on the American College of Medical Genetics and Genomics guideline, [16] 67 of 211 (31.8%) cases had 71 pathogenic or likely pathogenic variants in 33 sarcomere-associated genes (33 MYBPC3, 19 MYH7, 14 TNNI3, 2 MYH6, 1 JPH2, 1 TNNC1, and 1 MYL3)
We identified homozygous or compound heterozygous variants in MYBPC3 in one patient and co-variants in three patients
Summary
Mitral leaflet elongation is related to obstructive hypertrophic cardiomyopathy (HCM) [1]. A recent study further confirmed that leaflet elongation is a primary phenotype in subclinical HCM patients with pathogenic sarcomere gene mutations [7]. These investigations mainly focused on variants in classical pathogenic sarcomere genes such as MYBPC3 and MYH7, regardless of the morphologic phenotype of the hypertrophy pattern [2,3,4, 7]. Regarding mitral leaflet size, there was no comparison study between pathogenic variant group and non-variant group within overt hypertrophy patients It is still unclear whether mitral leaflet size in overt HCM is mainly determined by genotype or by additional geometric or hemodynamic factors.
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