Genes – ABC CARDIOL

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Case Report

Hereditary Transthyretin Cardiac Amyloidosis Associated with Two Pathogenic Variants in the TTR Gene

Victor Hugo Bonfim et al. Matheus Martins Monteiro Moisés Abtibol Machado Orlando Pereira da Silva Junior … Katia do Nascimento Couceiro Fábio Fernandes João Marcos Bemfica Barbosa Ferreira

Introduction

Amyloidosis encompasses a group of rare diseases characterized by the accumulation of amyloidosis. Amyloidosis is an abnormal formation of misfolded proteins in tissues and organs. These proteins adopt a highly stable beta-sheet structure, forming insoluble fibrils that are deposited in the extracellular space. Amyloidosis is classified according to the precursor protein and the type of polymer formed, resulting in different subtypes of the disease, each with distinct clinical manifestations.

Transthyretin amyloidosis (ATTR) has two primary subtypes: wild-type ATTR (wild-type ATTR, or ATTRw), formerly called “senile,” and variant ATTR (hereditary ATTR, or ATTRh), where individuals possess pathological variants in the transthyretin gene. To date, more than 120 variants have been identified. Clinical symptoms may present primarily as neuropathic, cardiac, or a combination of both.

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ABCHF

Review Article

The Role of TTN Gene Variants in Dilated Cardiomyopathy

Silas Ramos Furquim et al. Paula de Mendonça Senra Bianca Domit Werner Linnenkamp Kelvin Henrique Vilalva … Marjorie Hayashida Mizuta Bruno Moreira dos Santos Bruno de Oliveira Stephan Elisangela Aparecida da Silva Nara Alves Buriti Vitória Pelegrino do Val Fernanda Almeida Andrade Jose Eduardo Krieger

Abstract

Titin, encoded by the TTN gene, is the largest human protein, essential for maintaining muscle cell stability and regulating myocardial contraction. TTN truncating variants (TTNtv) have emerged as the most common genetic cause of dilated cardiomyopathy (DCM), accounting for up to 25% of familial cases and 18% of sporadic cases. This review examines the complex relationship between TTN variants and DCM, highlighting the challenges posed by incomplete penetrance and variable expressivity. While truncating variants primarily in the A-band region are linked to DCM, not all carriers exhibit clinical symptoms, indicating the influence of additional genetic and environmental factors. We also discuss the prognostic implications of TTN variants, which, despite similar clinical outcomes to other DCM cases, demonstrate a higher rate of reverse remodeling in response to heart failure treatment. Emerging therapeutic strategies targeting the underlying molecular mechanisms of TTN variants, including mTOR inhibitors and CRISPR-based gene editing, offer promising avenues for personalized treatment. Understanding the genetic underpinnings of TTN-related DCM is crucial for improving diagnosis, family screening, and therapeutic outcomes, paving the way for more effective management of this complex condition.

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ABC

Original Article

Bioinformatics and Systems Biology Approach to Identify the Pathogenetic Link between Heart Failure and Sarcopenia

Rui Xu et al. Ling-ling Ma Shuai Cui Ling Chen Hong Xu

Abstract

Background

Despite increasing evidence that patients with heart failure (HF) are susceptible to sarcopenia, the reason for the association is not well understood.

Objective

The purpose of this study is to explore further the molecular mechanism of the occurrence of this complication.

Methods

Gene expression datasets for HF (GSE57345) and Sarcopenia (GSE1428) were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using ‘edgeR’ and “limma” packages of R, and their functions were analyzed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Protein-protein interaction (PPI) networks were constructed and visualized using Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape. Hub genes were selected using the plugin cytoHubba and validation with GSE76701 for HF and GSE136344 for Sarcopenia. The related pathways and molecular mechanisms of the hub genes were performed by Gene set enrichment analysis (GSEA). The statistical analyses were performed using R software. P < 0.05 was considered statistically significant.

Results

A total of 114 common DEGs were found. Pathways related to growth factor, Insulin secretion and cGMP-PKG were enriched in both HF and Sarcopenia. CYP27A1, KCNJ8, PIK3R5, TIMP2, CXCL12, KIT, and VCAM1 were found to be significant hub genes after validation, with GSEA emphasizing the importance of the hub genes in the regulation of the inflammatory response.

Conclusion

Our study reveals that HF and Sarcopenia share common pathways and pathogenic mechanisms. These findings may suggest new directions for future research into the underlying pathogenesis.

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ABC

Review Article

Pharmacogenomics and Cardiovascular Disease: Where are We and Where do We go from Here?

Ricardo Stein et al. Thaís Beuren Luis Ramudo Cela Filipe Ferrari

Introduction, the DNA and the Genes

Pharmacogenomics (PGx) is the science of understanding the interaction between genes and drugs. The analysis of specific areas of the DNA provides information about a certain drug metabolism and about the expected response to a certain treatment. PGx also aims to reduce the incidence of adverse drug events (ADEs).^, Many studies in this area have focused on the identification of genes that predispose to diseases, modulate drug response, affect drug concentration and correlate with adverse effects of patients exposed to different types of drugs, so the desired therapeutic benefit is achieved.

The causes of individual responses to a same drug dosage include age, genetic and immunological factors, comorbidities and interaction between active principles. Genetic variability may influence not only pharmacodynamics, but also pharmacokinetics, which studies the relationship of the absorption, metabolism and excretion of the drug to its systemic concentration.

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ABC

Review Article

Hypertrophic Cardiomyopathy: How do Mutations Lead to Disease?

Júlia Daher Carneiro Marsiglia et al. Alexandre Costa Pereira

Hypertrophic cardiomyopathy (HCM) is the most common monogenic genetic cardiac disease, with an estimated prevalence of 1:500 in the general population. Clinically, HCM is characterized by hypertrophy of the left ventricle (LV) walls, especially the septum, usually asymmetric, in the absence of any cardiac or systemic disease that leads to a secondary hypertrophy. The clinical course of the disease has a large inter- and intrafamilial heterogeneity, ranging from mild symptoms of heart failure late in life to the onset of sudden cardiac death at a young age and is caused by a mutation in one of the genes that encode a protein from the sarcomere, Z-disc or intracellular calcium modulators. Although many genes and mutations are already known to cause HCM, the molecular pathways that lead to the phenotype are still unclear. This review focus on the molecular mechanisms of HCM, the pathways from mutation to clinical phenotype and how the disease’s genotype correlates with phenotype.

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Artigo Original

Study of mutations causing hypertrophic cardiomyopathy in a group of patients from Espirito Santo, Brazil

Júlia Daher Carneiro Marsiglia et al. Maria do Carmo Pimentel Batitucci Flávia de Paula Clara Barbirato … Edmundo Arteaga Aloir Queiroz de Araújo

BACKGROUND: Hypertrophic cardiomyopathy (HC) is the most frequent cardiac hereditary disease, caused by mutations in sarcomere protein coding genes. Although more than 430 mutations have been identified in several continents and countries, there have been no reports of mutations in Brazil. OBJECTIVE: To carry out a genetic study to identify genetic mutations that cause HC in a group of patients in Espirito Santo, Brazil. METHODS: Using the SSCP technique, 12 exons from the three main genes involved in HC were studied: exons 15, 20, 21, 22 and 23 of the β-myosin heavy chain gene (MYH7), exons 7, 16, 18, 22 and 24 of the myosin binding protein C gene (MYBPC3) and exons 8 and 9 of troponin T gene (TNNT2). RESULTS: 16 alterations were found, including two mutations, one of them possibly pathogenic in the MYBPC3 gene (p. Glu441Lys) and another pathogenic one, previously described in the TNNT2 gene (p.Arg92Trp), 8 rare sequence variations and 6 sequence variations with allelic frequency higher than 1% (polymorphisms). CONCLUSION: These data allow the conclusion that the genotyping of patients is feasible in our country. It is possible that the isolated p.Glu441Lys variant identified in exon 16 of the MYBPC3 gene is pathogenic, promoting a milder phenotype than that found when in association with other mutations. The p.Arg92Trp variant in the exon 9 of TNNT2 gene does not promote such a homogeneous phenotype as previously described and it can lead to severe hypertrophy.

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Hereditary Transthyretin Cardiac Amyloidosis Associated with Two Pathogenic Variants in the TTR Gene

Introduction

The Role of TTN Gene Variants in Dilated Cardiomyopathy

Abstract

Bioinformatics and Systems Biology Approach to Identify the Pathogenetic Link between Heart Failure and Sarcopenia

Abstract

Background

Objective

Methods

Results

Conclusion

Pharmacogenomics and Cardiovascular Disease: Where are We and Where do We go from Here?

Introduction, the DNA and the Genes

Hypertrophic Cardiomyopathy: How do Mutations Lead to Disease?

Study of mutations causing hypertrophic cardiomyopathy in a group of patients from Espirito Santo, Brazil

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