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

Tobita, Takashige; Nomura, Seitaro; Fujita, Takanori; Morita, Hiroyuki; Asano, Yoshihiro; Onoue, Kenji; Ito, Masamichi; Imai, Yasushi; Suzuki, Atsushi; Ko, Toshiyuki; Satoh, Masahiro; Fujita, Kanna; Naito, Atsuhiko T.; Furutani, Yoshiyuki; Toko, Haruhiro; Harada, Mutsuo; Amiya, Eisuke; Hatano, Masaru; Takimoto, Eiki; Shiga, Tsuyoshi; Nakanishi, Toshio; Sakata, Yasushi; Ōno, Minoru; Saito, Yoshihiko; Takashima, Seiji; Hagiwara, Nobuhisa; Aburatani, Hiroyuki; Komuro, Issei

doi:10.1038/s41598-018-20114-9

Cited by 97 publications

(105 citation statements)

References 36 publications

(36 reference statements)

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“…LMNA genotype-positive subjects seem to have a younger age of diagnosis of DCM and larger left atrial than those negative patients, but the outcome difference was not significant. www.nature.com/scientificreports www.nature.com/scientificreports/ Our study showed that about one third DCM patients carried pathogenic or likely pathogenic variants, a frequency similar to those reported in in Japanese and Finish populations 8,13 . TTN truncating variants remain the most common variants in our Chinese cohort.…”

Section: Discussionsupporting

confidence: 86%

“…Akinrinade and colleagues concluded in the Finnish population that adverse outcomes in patients with TTN truncating variants were indistinct from those other gene variant groups except LMNA variants 8 . In several other studies, however, patients with TTN truncating variants were reported to be less severe at presentation and to be associated with a favorable response to treatment than patients with LMNA variants or patients negative for TTN and LMNA genes 13,19 . Altogether, the published data on genotype-phenotype associations in DCM cannot provide a clear correlation between TTN truncating variants and clinical phenotype.…”

Section: Discussionmentioning

confidence: 90%

“…As TTN truncating variant frequency varied with the disease severity of DCM, with a higher frequency in patients with severe, end-stage or clearly familial cases of DCM 5 , it is plausible that the relatively low frequency in our cohort was due to the exclusion of familial DCM and the inclusion of all DCM patients in hospital and the outpatient clinic in our analysis. Ethnic difference cannot be simply attributed to and needs further investigation, as no correlation between ethics and frequency of TTN truncating variants has been noted: a Caucasian population reported a frequency of 12.0% 14 , and a Japanese study reported 16.7% 13 .…”

Section: Discussionmentioning

confidence: 99%

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Genetic Basis and Genotype–Phenotype Correlations in Han Chinese Patients with Idiopathic Dilated Cardiomyopathy

Zhang

Xie

Lan

et al. 2020

Sci Rep

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Dilated cardiomyopathy (DcM) is one of the leading causes of heart failure. A large proportion of genetic cause remains unexplained, especially in idiopathic DcM. We performed target next-generation sequencing of 102 genes which were known causes or candidate genes for cardiomyopathies and channelpathies in 118 prospectively recruited Han Chinese patients with idiopathic DCM. 41 of the 118 patients carried 40 pathogenic or likely pathogenic variants, providing a molecular diagnosis in 34.7% of patients. 32 of these variants were novel. TTN truncating variants were predominant, with a frequency of 31.0%, followed by variants of LMNA (14.3%), RBM20 (4.8%), and NEXN (4.8%). These 4 genes accounted for over half variants identified. No significant difference in clinical characteristics or rates of reaching the composite end point (cardiac transplantation and death from cardiac causes) between pathogenic or likely pathogenic variant carriers and noncarriers (hazard ratio 1.11, 95% CI: 0.41 to 3.00), or between patients with TTN truncating variants or without (hazard ratio 0.49, 95% CI: 0.36 to 6.10). In our prospective study, we first determined the overall genetic profiles and genotype-phenotype correlations in Han Chinese idiopathic DCM patients, which could provide insight for genetic diagnosis of DcM in this population.Dilated cardiomyopathy (DCM) is the one of the leading causes of heart failure and sudden death, and the most common cause of heart transplantation, affecting approximately 1 in 250 individuals 1 . DCM is a progressive disease, with 50% of patients reported to die within 5 years of diagnosis without transplantation 2 . DCM frequently has a genetic etiology, and multiple causative genes have been discovered. The genetic basis of DCM is highly diverse; over 30 genes have been identified as the potentially disease-causing genes 1,3 . About 25-30% of individuals with DCM have a familial form of the disease 1,4 . Truncating variants in TTN, which encodes titin, account for up to 25% of familial DCM 5 . A large proportion of genetic cause of DCM remains unexplained, especially in idiopathic DCM 6 .Next-generation sequencing (NGS) approaches have enabled rapid genetic testing, particularly for large genes such as TTN which are hard to sequence with traditional methods. Using NGS, researchers have characterized the genetic atlas of DCM in Caucasian population 7,8 . Zhao and colleagues performed NGS of 25 genes in 21 Chinese patients 9 , but the number of genes and patients were limited, and the most commonly pathogenic gene in DCM-TTN was not included in their sequencing panel. Also, understanding the potential genotype-phenotype correlations may identify high-risk patients in this condition. In this study, we developed a custom "cardiomyopathy panel" containing 102 genes which were known causes or candidate genes for cardiomyopathies and channelpathies. We prospectively recruited 118 unrelated patients with idiopathic DCM and performed target NGS in this cohort to determine the molecular characterization o...

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Genetic Basis and Genotype–Phenotype Correlations in Han Chinese Patients with Idiopathic Dilated Cardiomyopathy

Zhang

Xie

Lan

et al. 2020

Sci Rep

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“…[55] have found that deletion of pyruvate dehydrogenase kinase 4 (PDK4) prevented angiotensin II-induced cardiac hypertrophy and improved cardiac glucose oxidation and energy usage. MeSH-based disease analysis demonstrated that significant changes in cardiomyocyte genes (decreased MYL2 and MYH6 and increased RYR2, HCN4, CORIN, NPPA, ERBB2, and MYH7) in LV of obese ZSF1 rats were strongly associated with dilated cardiomyopathy, LV hypertrophy, and HF (Fig 5F), and were similar to those observed in human genetic studies [56]. The array of expression changes in LV heart abundant genes in obese ZSF1 rats would help us to better understand the cardiac metabolic shift and cardiomyopathy in CMS; to allocate the major players mediating the crosstalk between glucose, lipid metabolism, and development of CVD; and to potentially identify key markers of cardiac energy status and heart injury grade.…”

Section: Discussionsupporting

confidence: 82%

The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15

Stolina

Luo

Dwyer

et al. 2020

Preprint

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19Cardiometabolic syndrome has become a global health issue. Heart failure is a common 20 comorbidity of cardiometabolic syndrome. Successful drug development to prevent 21 cardiometabolic syndrome and associated comorbidities requires preclinical models predictive 22 of human conditions. To characterize the heart failure component of cardiometabolic 2 23 syndrome, cardiometabolic, metabolic, and renal biomarkers were evaluated in obese and lean 24 ZSF1 20-to 22-week-old male rats. Cardiac function, exercise capacity, and left ventricular 25 gene expression were also analyzed. Obese ZSF1 rats exhibited multiple features of human 26 cardiometabolic syndrome by pathological changes in systemic renal, metabolic, and 27 cardiovascular disease circulating biomarkers. Hemodynamic assessment, echocardiography, 28 and decreased exercise capacity confirmed heart failure with preserved ejection fraction. RNA-29 seq results demonstrated changes in left ventricular gene expression associated with fatty acid 30 and branched chain amino acid metabolism, cardiomyopathy, cardiac hypertrophy, and heart 31 failure. Twelve weeks of growth differentiation factor 15 (GDF15) treatment significantly 32 decreased body weight, food intake, blood glucose, and triglycerides and improved exercise 33 capacity in obese ZSF1 males. Systemic cardiovascular injury markers were significantly 34 lower in GDF15-treated obese ZSF1 rats. Obese ZSF1 male rats represent a preclinical model 35 for human cardiometabolic syndrome with established heart failure with preserved ejection 36 fraction. GDF15 treatment mediated dietary response and demonstrated a cardioprotective 37 effect in obese ZSF1 rats.3 38 Introduction 39 Cardiometabolic syndrome (CMS)-a condition that encompasses impaired 40 metabolism (insulin resistance [IR], impaired glucose tolerance), dyslipidemia, hypertension, 41 renal dysfunction, central obesity, and heart failure (HF)-is now recognized as a disease by 42 the World Health Organization (WHO) and the American Society of Endocrinology [1]. 43 Obesity and diabetes mellitus comorbidities are associated with progressive left ventricular 44 (LV) remodeling and dysfunction. Also, these comorbidities are commonly observed in HF 45 with preserved ejection fraction (HFpEF) [2]. Results from a recent epidemiological study 46 (cohort of 3.5 million individuals) demonstrated an incremental increase in the hazard ratio 47 (HR) for HF; HRs were 1.8 in normal weight individuals with three metabolic abnormalities, 48 2.1 in overweight individuals with three metabolic abnormalities, and up to 3.9 in obese 49 individuals with three metabolic abnormalities. Incidence of HFpEF, which currently 50 represents approximately 50% of all HF cases, continues to rise and its prognosis fails to 51 improve partly due to the lack of therapies available to treat this disease [3]. 52 An important step in the development of novel therapeutic agents against CMS is the 53 establishment of a preclinical model that represents a cluster of cardiometabolic disturbances ...

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“…Target enrichment system and next-generation sequencing technologies have enabled simple and efficient comprehensive gene screening for cardiomyopathy. Recent comprehensive targeted sequencing studies showed that approximately 40% of patients with DCM have pathogenic mutations in genes reported to be causal for cardiomyopathy [4,5]. Although there are some ethnic differences in the proportion of mutated genes, titin (TTN) truncating mutations and lamin A/C (LMNA) mutations are considered to be major factors for the development of DCM.…”

Section: Genomic Architecture Of Cardiomyopathymentioning

confidence: 99%

Genetic and non-genetic determinants of clinical phenotypes in cardiomyopathy

Nomura¹

2019

Journal of Cardiology

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

Cited by 97 publications

References 36 publications

Genetic Basis and Genotype–Phenotype Correlations in Han Chinese Patients with Idiopathic Dilated Cardiomyopathy

Genetic Basis and Genotype–Phenotype Correlations in Han Chinese Patients with Idiopathic Dilated Cardiomyopathy

The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15

Genetic and non-genetic determinants of clinical phenotypes in cardiomyopathy

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