scholarly journals Genotype-Related Clinical Characteristics and Myocardial Fibrosis and Their Association with Prognosis in Hypertrophic Cardiomyopathy

2020 ◽  
Vol 9 (6) ◽  
pp. 1671 ◽  
Author(s):  
Hyung Yoon Kim ◽  
Jong Eun Park ◽  
Sang-Chol Lee ◽  
Eun-Seok Jeon ◽  
Young Keun On ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Myocardial Fibrosis ◽  
Genetic Variants ◽  
Asian Patients ◽  
Pathogenic Variants ◽  
Clinical Events ◽  
Cerebrovascular Events ◽  
Genotypic Analysis ◽  
Uncertain Significance

Background: The spectrum of genetic variants and their clinical significance of Hypertrophic cardiomyopathy (HCM) have been poorly studied in Asian patients. The objectives of this study were to assess the spectrum of genetic variants and genotype–phenotype relationships within a Korean HCM population. Methods: Eighty-nine consecutive unrelated HCM patients were included. All patients underwent genotypic analysis for 23 HCM-associated genes. Clinical parameters including echocardiographic and cardiac magnetic resonance (CMR) parameters were evaluated. A composite of major adverse cardiac and cerebrovascular events was assessed. Results: Genetic variants were detected in 55 of 89 subjects. Pathogenic variants or likely pathogenic variants were identified in 27 of HCM patients in MYBPC3, TNNI3, MYH7, and MYL7. Variants of uncertain significance were identified in 28 patients. There were significant differences in the presence of non-sustained ventricular tachycardia (p = 0.030) and myocardial fibrosis on CMR (p = 0.029) in the detected compared to the not-detected groups. Event-free survival was superior in the not-detected group (p = 0.006). Conclusion: Genetic variants in patients with HCM are relatively common and are associated with adverse clinical events and myocardial fibrosis on CMR. Genotypic analysis may add important information to clinical variables in the assessment of long-term risk for HCM patients.

scholarly journals Genetic Testing in Patients with Hypertrophic Cardiomyopathy

2021 ◽  
Vol 22 (19) ◽  
pp. 10401
Author(s):  
Jiri Bonaventura ◽  
Eva Polakova ◽  
Veronika Vejtasova ◽  
Josef Veselka
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Genetic Basis ◽  
Molecular Genetic ◽  
Mendelian Disease ◽  
Sarcomeric Proteins ◽  
Pathogenic Variants ◽  
Large Numbers ◽  
Uncertain Significance ◽  
Common Clinical Practice

Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with an estimated prevalence of up to 1 in 200 individuals. In the majority of cases, HCM is considered a Mendelian disease, with mainly autosomal dominant inheritance. Most pathogenic variants are usually detected in genes for sarcomeric proteins. Nowadays, the genetic basis of HCM is believed to be rather complex. Thousands of mutations in more than 60 genes have been described in association with HCM. Nevertheless, screening large numbers of genes results in the identification of many genetic variants of uncertain significance and makes the interpretation of the results difficult. Patients lacking a pathogenic variant are now believed to have non-Mendelian HCM and probably have a better prognosis than patients with sarcomeric pathogenic mutations. Identifying the genetic basis of HCM creates remarkable opportunities to understand how the disease develops, and by extension, how to disrupt the disease progression in the future. The aim of this review is to discuss the brief history and recent advances in the genetics of HCM and the application of molecular genetic testing into common clinical practice.

scholarly journals Development of a Cardiac Sarcomere Functional Genomics Platform to Enable Scalable Interrogation of Human TNNT2 Variants

Circulation ◽  
2020 ◽  
Vol 142 (23) ◽  
pp. 2262-2275
Author(s):  
Anthony M. Pettinato ◽  
Feria A. Ladha ◽  
David J. Mellert ◽  
Nicholas Legere ◽  
Rachel Cohn ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stem Cell ◽  
Hypertrophic Cardiomyopathy ◽  
Dilated Cardiomyopathy ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Pathogenic Variants ◽  
Calcium Affinity ◽  
Uncertain Significance ◽  
Induced Pluripotent

Background: Pathogenic TNNT2 variants are a cause of hypertrophic and dilated cardiomyopathies, which promote heart failure by incompletely understood mechanisms. The precise functional significance for 87% of TNNT2 variants remains undetermined, in part, because of a lack of functional genomics studies. The knowledge of which and how TNNT2 variants cause hypertrophic and dilated cardiomyopathies could improve heart failure risk determination, treatment efficacy, and therapeutic discovery, and provide new insights into cardiomyopathy pathogenesis, as well. Methods: We created a toolkit of human induced pluripotent stem cell models and functional assays using CRISPR/Cas9 to study TNNT2 variant pathogenicity and pathophysiology. Using human induced pluripotent stem cell–derived cardiomyocytes in cardiac microtissue and single-cell assays, we functionally interrogated 51 TNNT2 variants, including 30 pathogenic/likely pathogenic variants and 21 variants of uncertain significance. We used RNA sequencing to determine the transcriptomic consequences of pathogenic TNNT2 variants and adapted CRISPR/Cas9 to engineer a transcriptional reporter assay to assist prediction of TNNT2 variant pathogenicity. We also studied variant-specific pathophysiology using a thin filament–directed calcium reporter to monitor changes in myofilament calcium affinity. Results: Hypertrophic cardiomyopathy–associated TNNT2 variants caused increased cardiac microtissue contraction, whereas dilated cardiomyopathy–associated variants decreased contraction. TNNT2 variant–dependent changes in sarcomere contractile function induced graded regulation of 101 gene transcripts, including MAPK (mitogen-activated protein kinase) signaling targets, HOPX , and NPPB . We distinguished pathogenic TNNT2 variants from wildtype controls using a sarcomere functional reporter engineered by inserting tdTomato into the endogenous NPPB locus. On the basis of a combination of NPPB reporter activity and cardiac microtissue contraction, our study provides experimental support for the reclassification of 2 pathogenic/likely pathogenic variants and 2 variants of uncertain significance. Conclusions: Our study found that hypertrophic cardiomyopathy–associated TNNT2 variants increased cardiac microtissue contraction, whereas dilated cardiomyopathy–associated variants decreased contraction, both of which paralleled changes in myofilament calcium affinity. Transcriptomic changes, including NPPB levels, directly correlated with sarcomere function and can be used to predict TNNT2 variant pathogenicity.

scholarly journals Effect of sarcomere and mitochondria-related mutations on myocardial fibrosis in patients with hypertrophic cardiomyopathy

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Hyemoon Chung ◽  
Yoonjung Kim ◽  
Chul-Hwan Park ◽  
Jong-Youn Kim ◽  
Pil-Ki Min ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Myocardial Fibrosis ◽  
Nuclear Dna ◽  
Volume Fraction ◽  
Wide Spectrum ◽  
Extracellular Volume ◽  
Extracellular Volume Fraction ◽  
Gadolinium Enhancement ◽  
Uncertain Significance ◽  
Mutation Group

Abstract Background Myocardial fibrosis is an important prognostic factor in hypertrophic cardiomyopathy (HCM). However, the contribution from a wide spectrum of genetic mutations has not been well defined. We sought to investigate effect of sarcomere and mitochondria-related mutations on myocardial fibrosis in HCM. Methods In 133 HCM patients, comprehensive genetic analysis was performed in 82 nuclear DNA (33 sarcomere-associated genes, 5 phenocopy genes, and 44 nuclear genes linked to mitochondrial cardiomyopathy) and 37 mitochondrial DNA. In all patients, cardiovascular magnetic resonance (CMR) was performed, including 16-segmental thickness, late gadolinium enhancement (LGE), native and post-T1, extracellular volume fraction (ECV), and T2, along with echo-Doppler evaluations. Results Patients with sarcomere mutation (SM, n = 41) had higher LGE involved segment, % LGE mass, ECV and lower post-T1 compared to patients without SM (n = 92, all p < 0.05). When classified into, non-mutation (n = 67), only mitochondria-related mutation (MM, n = 24), only-SM (n = 36) and both SM and MM (n = 5) groups, only-SM group had higher ECV and LGE than the non-mutation group (all p < 0.05). In non-LGE-involved segments, ECV was significantly higher in patients with SM. Within non-SM group, patients with any sarcomere variants of uncertain significance had higher echocardiographic Doppler E/e’ (p < 0.05) and tendency of higher LGE amount and ECV (p > 0.05). However, MM group did not have significantly higher ECV or LGE amount than non-mutation group. Conclusions SMs are significantly related to increase in myocardial fibrosis. Although, some HCM patients had pathogenic MMs, it was not associated with an increase in myocardial fibrosis.

Abstract 12149: Impact of Elevated Cardiac Troponin and Increased Fibrosis on Clinical Manifestations in Hypertrophic Cardiomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Takashi Nakamura
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Myocardial Fibrosis ◽  
Cardiac Troponin ◽  
Clinical Manifestations ◽  
Gadolinium Enhancement ◽  
Combined Analysis ◽  
Clinical Events ◽  
Myocyte Injury ◽  
The Relationship ◽  
Sensitive Marker

Introduction: Recently, in patients with hypertrophic cardiomyopathy (HCM), an abnormal serum concentration of cardiac troponin (cTn), which is a sensitive marker of myocyte injury, was reported to be an independent predictor of the adverse outcome. In addition, late gadolinium-enhancement (LGE) cardiac magnetic resonance (CMR) imaging, which has been used to uniquely characterize the extent of myocardial fibrosis, has prognostic value in HCM. However, the relationship between myocyte injury, fibrosis, and clinical events/manifestations remains unclear. Hypothesis: A combined analysis using cTn and LGE by CMR may help to identify the clinical events/manifestations in patients with HCM. Methods: Eighty-seven HCM patients receiving regular outpatient treatment underwent CMR (cine and LGE imaging). LV myocardial fibrosis mass index (FMI) was quantified and the distribution/pattern of LGE was analyzed using 17 segment model. Serum cTnI was measured within a week around CMR testing. cTnI elevation was defined as ≥ 0.05ng/mL. Clinical events were defined as heart failure (HF) admission, ventricular tachycardia (VT), atrial fibrillation, and syncope. Results: In total patients, mean age was 65.7 ± 15.0 years old and female patients were 41.4%. HF and VT events were observed in 22 (25%) and 16 (18%) patients, respectively. Both elevated cTnI and higher FMI were associated with the combined clinical events (P<0.01 and P<0.05, respectively). Elevated cTnI was associated not with HF (P=0.06), but with VT (P<0.001). In contrast, higher FMI was associated with HF (P=0.01), but not with VT (P=0.67). A grouping according to both cTnI and FMI showed the good stratification for clinical events as shown in the figure. Conclusions: In HCM patients, both cTn and FMI were significant markers for clinical events in HCM patients. In particular, elevated cTn was strongly associated with VT. Combined analysis of cTn and CMR may be useful in clinical practice for HCM.

scholarly journals Genetic contributions to the expression of acquired causes of cardiac hypertrophy in non-ischemic sudden cardiac death victims

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lauri Holmström ◽  
Katri Pylkäs ◽  
Anna Tervasmäki ◽  
Juha Vähätalo ◽  
Katja Porvari ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Genetic Variants ◽  
Cardiac Death ◽  
Heart Weight ◽  
Gene Variants ◽  
Myocardial Disease ◽  
Myocardial Diseases ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
Genetic Contributions

AbstractThe contribution of genetic variants to non-ischemic sudden cardiac death (SCD) due to acquired myocardial diseases is unclear. We studied whether SCD victims with hypertension/obesity related hypertrophic myocardial disease harbor potentially disease associated gene variants. The Fingesture study has collected data from 5869 autopsy-verified SCD victims in Northern Finland. Among SCD victims, 740 (13%) had hypertension and/or obesity as the most likely explanation for myocardial disease with hypertrophy and fibrosis. We performed next generation sequencing using a panel of 174 cardiac genes for 151 such victims with the best quality of DNA. We used 48 patients with hypertension and hypertrophic heart as controls. Likely pathogenic variants were identified in 15 SCD victims (10%) and variants of uncertain significance (VUS) were observed in additional 43 SCD victims (28%). In controls, likely pathogenic variants were present in two subjects (4%; p = 0.21) and VUSs in 12 subjects (25%; p = 0.64). Among SCD victims, presence of potentially disease-related variants was associated with lower mean BMI and heart weight. Potentially disease related gene variants are common in non-ischemic SCD but further studies are required to determine specific contribution of rare genetic variants to the extent of acquired myocardial diseases leading to SCD.

scholarly journals Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants

2020 ◽  
Vol 9 (3) ◽  
Author(s):  
Tess D. Pottinger ◽  
Megan J. Puckelwartz ◽  
Lorenzo L. Pesce ◽  
Avery Robinson ◽  
Samuel Kearns ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Genetic Variants ◽  
African Ancestry ◽  
Left Ventricular ◽  
Whole Genome Sequence ◽  
European Ancestry ◽  
Internal Diameter ◽  
Variants Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Uncertain Significance

Background Genome sequencing coupled with electronic heath record data can uncover medically important genetic variation. Interpretation of rare genetic variation and its role in mediating cardiovascular phenotypes is confounded by variants of uncertain significance. Methods and Results We analyzed the whole genome sequence of 900 racially and ethnically diverse biobank participants selected from a single US center. Participants were equally divided among European, African, Hispanic, and mixed races/ethnicities. We evaluated the American College of Medical Genetics and Genomics medically actionable list of 59 genes, focusing on the cardiac genes. Variation was interpreted using the most recent reports in ClinVar, a database of medically relevant human variation. We identified 19 individuals with pathogenic or likely pathogenic variants in cardiac actionable genes (2%) and found evidence of related clinical correlates in the electronic health record. Participants of African ancestry, compared with those of European ancestry, had more variants of uncertain significance in the medically actionable genes including the 30 cardiac actionable genes, even when normalized to total variant count per person. Longitudinal measures of left ventricle size from ≈400 biobank participants (1723 patient‐years) were correlated with genetic findings. The presence of ≥1 uncertain variant in the actionable cardiac genes and a cardiomyopathy diagnosis correlated with increased left ventricular internal diameter in diastole and in systole. In particular, MYBPC 3 was identified as a gene with excess variants of uncertain significance. Conclusions These data indicate that a subset of uncertain genetic variants may confer risk and should not be considered benign.

scholarly journals Protein haploinsufficiency drivers identify MYBPC3 mutations that cause hypertrophic cardiomyopathy

2020 ◽  
Author(s):  
Carmen Suay-Corredera ◽  
Maria Rosaria Pricolo ◽  
Elías Herrero-Galán ◽  
Diana Velázquez-Carreras ◽  
David Sánchez-Ortiz ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Protein Stability ◽  
Rna Splicing ◽  
Specific Gene ◽  
Gene Encoding ◽  
Pathogenic Variants ◽  
Myosin Binding Protein ◽  
Disease Mutations ◽  
Uncertain Significance ◽  
Molecular Phenotypes

ABSTRACTHypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Mutations in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are a leading cause of HCM. However, it remains challenging to define whether specific gene variants found in patients are pathogenic or not, limiting the reach of cardiovascular genetics in the management of HCM. Here, we have examined cMyBP-C haploinsufficiency drivers in 68 clinically annotated non-truncating variants of MYBPC3. We find that 45% of the pathogenic variants show alterations in RNA splicing or protein stability, which can be linked to pathogenicity with 100% and 94% specificity, respectively. Relevant for variant annotation, we uncover that 9% of non-truncating variants of MYBPC3 currently classified as of uncertain significance induce one of these molecular phenotypes. We propose that alteration of RNA splicing or protein stability caused by MYBPC3 variants provide strong evidence of their pathogenicity, leading to improved clinical management of HCM patients and their families.

scholarly journals AmazonForest: In-silico Meta-Prediction of Pathogenic Variants

2020 ◽  
Author(s):  
Helber Palheta ◽  
Wanderson Gonçalves Gonçalves ◽  
Leonardo Miranda Brito ◽  
Arthur Ribeiro dos Santos ◽  
Marlon Matsumoto ◽  
...  
Keyword(s):  
Random Forest ◽  
Prediction Model ◽  
Genetic Variants ◽  
Area Under Curve ◽  
Support Vector ◽  
Genetic Associations ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
Characteristic Area ◽  
High Pathogenic

ClinVar is a web platform that stores around 774k curated entries, which allows exploring genetic variants and their associations with complex phenotypes. A partial set of ClinVar&rsquo;s genetic associations were reported with conflict of interpretation or uncertain clinical impact significance, which currently challenges clinicians and geneticists. Here, we evaluate the performance of data pre-processing methods combined with classical prediction methods, such as Naive Bayes, Random Forest, and Support Vector Machine to build a meta-prediction model aiming to improve genetic pathogenicity interpretation. Models were trained with ClinVar data (September 2020), and genetic variants were annotated with eight functional impact predictors catalogued with SnpEff/SnpSift (v4.3). A 10-fold cross-validation strategy was performed for evaluation by accuracy, F1-Score, Receiver Operating Characteristic, Area Under Curve. The best meta-prediction model raises by combining one-hot encoding with tree-based classifiers as Random Forest, which shows Area Under Curve &ge; 0,93. We predict pathogenicity for 109k genetic variants, which were found labeled as uncertain significance or conflict of interpretation. Additionally, we implemented AmazonForest (https://www.lghm.ufpa.br/amazonforest), a web tool to query data for a set of 5k variants that were predicted with high pathogenic probability (RFprob &gt;= 0.9).

RF42 LONG TERM RESULTS OF SEPTAL MYECTOMY IN OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY

2018 ◽  
Vol 19 ◽  
pp. e76-00
Author(s):  
G. Saitto ◽  
F. Grimaldi ◽  
A. Varrica ◽  
A. Biondi ◽  
A. Garatti ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Long Term Results ◽  
Septal Myectomy ◽  
Obstructive Hypertrophic Cardiomyopathy
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