Genetic basis of cardiomyopathy and the genotypes involved in prognosis and left ventricular reverse remodeling

Abstract

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically heterogeneous. Cardiac function is improved after treatment in some cardiomyopathy patients, but little is known about genetic predictors of long-term outcomes and myocardial recovery following medical treatment. To elucidate the genetic basis of cardiomyopathy in Japan and the genotypes involved in prognosis and left ventricular reverse remodeling (LVRR), we performed targeted sequencing on 120 DCM (70 sporadic and 50 familial) and 52 HCM (15 sporadic and 37 familial) patients and integrated their genotypes with clinical phenotypes. Among the 120 DCM patients, 20 (16.7%) had TTN truncating variants and 13 (10.8%) had LMNA variants. TTN truncating variants were the major cause of sporadic DCM (21.4% of sporadic cases) as with Caucasians, whereas LMNA variants, which include a novel recurrent LMNA E115M variant, were the most frequent in familial DCM (24.0% of familial cases) unlike Caucasians. Of the 52 HCM patients, MYH7 and MYBPC3 variants were the most common (12 (23.1%) had MYH7 variants and 11 (21.2%) had MYBPC3 variants) as with Caucasians. DCM patients harboring TTN truncating variants had better prognosis than those with LMNA variants. Most patients with TTN truncating variants achieved LVRR, unlike most patients with LMNA variants.

Figure 1

Flowchart summarizing the variant categorization. The number of variants is described in each category. DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; PM, pathogenic mutation; VUS, variant of uncertain significance; MAF, minor allele frequency; CADD, combined annotation-dependent depletion.

Figure 2

Genetic profiles of cardiomyopathies. Genetic profiles of DCM (a) and HCM (b) are represented. Only genes closely linked to cardiomyopathy (yellow) are shown. Colored cells represent the presence of PM (orange), VUS (blue), or PM and VUS (black). DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; PM, pathogenic mutation; VUS, variant of uncertain significance.

Figure 3

Survival free of life-threatening arrhythmia in DCM patients with TTN truncating variants (n = 20), DCM patients with LMNA variant (n = 13), and other DCM patients (n = 87). Kaplan–Meier curves illustrating survival free of life-threatening arrhythmia throughout lifespan (a) and during follow-up (b). Probability values were calculated using log-rank tests. DCM, dilated cardiomyopathy.

Figure 4

Heart transplant- or death-free survival in DCM patients with TTN truncating variants (n = 20), DCM patients with LMNA variants (n = 13), and other DCM patients (n = 87). Kaplan–Meier curves illustrating heart transplant- or death-free survival throughout lifespan (a) and during follow-up (b). Probability values were calculated using log-rank tests. DCM, dilated cardiomyopathy.

Figure 5

Changes in LVEF, LVEDD, and LVESD during follow-up in DCM patients harboring TTN truncating variants (n = 11), DCM patients harboring LMNA variants (n = 7), and other DCM patients (n = 27). The bar plot represents the changes in LVEF, LVEDD, and LVESD in patients with TTN truncating variants (a), patients with LMNA variants (b), and other patients (c) at diagnosis, mid-term (around 24 months), and last follow-up. Data are expressed as mean ± SD. *Represents p < 0.05 versus onset. DCM, dilated cardiomyopathy; LVEF, left ventricular ejection fraction; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter.

Figure 6

Genetic basis and genotypes involved in prognosis and left ventricular reverse remodeling of DCM patients. Genetic analysis was performed on 120 DCM patients. Among them, 78 (65.0%) patients had variants. TTN truncating variants were the most frequent. TTN truncating variants were associated with better prognosis and the presence of left ventricular reverse remodeling. LMNA variants were the second-most frequent. LMNA variants were associated with poor prognosis.