FMO3-TMAO axis modulates the clinical outcome in chronic heart-failure patients with reduced ejection fraction: evidence from an Asian population / 医学前沿

The association among plasma trimethylamine-N-oxide (TMAO), FMO3 polymorphisms, and chronic heart failure (CHF) remains to be elucidated. TMAO is a microbiota-dependent metabolite from dietary choline and carnitine. A prospective study was performed including 955 consecutively diagnosed CHF patients with reduced ejection fraction, with the longest follow-up of 7 years. The concentrations of plasma TMAO and its precursors, namely, choline and carnitine, were determined by liquid chromatography-mass spectrometry, and the FMO3 E158K polymorphisms (rs2266782) were genotyped. The top tertile of plasma TMAO was associated with a significant increment in hazard ratio (HR) for the composite outcome of cardiovascular death or heart transplantation (HR = 1.47, 95% CI = 1.13-1.91, P = 0.004) compared with the lowest tertile. After adjustments of the potential confounders, higher TMAO could still be used to predict the risk of the primary endpoint (adjusted HR = 1.33, 95% CI = 1.01-1.74, P = 0.039). This result was also obtained after further adjustment for carnitine (adjusted HR = 1.33, 95% CI = 1.01-1.74, P = 0.039). The FMO3 rs2266782 polymorphism was associated with the plasma TMAO concentrations in our cohort, and lower TMAO levels were found in the AA-genotype. Thus, higher plasma TMAO levels indicated increased risk of the composite outcome of cardiovascular death or heart transplantation independent of potential confounders, and the FMO3 AA-genotype in rs2266782 was related to lower plasma TMAO levels.

Identification of dysregulated microRNAs involved in arachidonic acid metabolism regulation in dilated cardiomyopathy-mediated heart failure patients / 生理学报

Heart failure (HF), a clinical syndrome with high morbidity and mortality, is becoming a growing public health problem. Dilated cardiomyopathy (DCM) is one of the major causes of HF, yet the molecular mechanisms underlying DCM-mediated HF are not completely understood. Previous studies have shown that dysregulation of arachidonic acid (AA) metabolism could contribute to the development of HF. To explore the roles of microRNAs (miRNAs) in regulating AA metabolism in HF, we used two public datasets to analyze the expression changes of miRNAs in the patients of DCM-mediated HF. A total of 101 and 88 miRNAs with significant abundance alterations in the two dataset were obtained, respectively. Around 1/3 of these miRNAs were predicted to target AA metabolic pathway genes. We also investigated the distribution of known single nucleotide polymorphisms (SNPs) within the sequences of miRNAs dysregulated in DCM-mediated HF patients, and identified miRNAs harboring high number of SNPs in either the seed regions or the entire sequences. These information could provide clues for further functional studies of miRNAs in the pathogeny of DCM-mediated HF.

Effective components of Shengxian Decoction and its mechanism of action in treating chronic heart failure based on UHPLC-Q-TOF-MS integrated with network pharmacology / 中国中药杂志

This study aimed to elucidate the effective components of Shengxian Decoction and its mechanism of action in treating chronic heart failure. Firstly, UHPLC-Q-TOF-MS was established to identify the main chemical constituents in the rat serum after intragastric administration with Shengxian Decoction. Secondly, the absorbed components in serum were then used for the network pharmacology analysis to infer the mechanism and effective components. Targets for constituents in serum were predicted at TCMSP and Swiss-TargetPrediction database. An association network map was drawn by network visualization software Cytoscape 3.6.1. Finally, GO enrichment analysis and KEGG pathway enrichment analysis were carried out for the core target genes. By UHPLC-Q-TOF-MS, 18 prototype compounds were definitely identified, including five compounds from Astragali Radix, four compounds from Anemarrhenae Rhizoma, four compounds from Bupleuri Radix, four compounds from Cimicifugae Rhizoma, and one compound from Platycodonis Radix. Those components of Shengxian Decoction were closely associated with 13 key protein targets, including inflammatory factors, like IL6, IL1 B, TNF, PTGS2, IL10; redox enzymes CAT, HMOX1, and MPO; cardiovascular targets, like VEGFA, NOS3, and NOS2; and transmememial proteins CAV1 and INS. Network pharmacology analysis showed that the 18 compounds could be responsible for the treatment of chronic heart failure by regulating HIF-1 signaling pathways, PI3 K-Akt signaling pathways, cGMP-PKG signaling pathways, cAMP signaling pathways and TNF signaling pathways. This study provided a scientific basis for mechanism and effective ingredients of Shengxian Decoction.

Study on potential molecular mechanism of Mongolian medicine Bawei Sanxiang San in treatment of chronic heart failure based on network pharmacology and molecular docking / 中国中药杂志

To explore the potential molecular mechanism of Mongolian medicine Bawei Sanxiang San in the treatment of chronic heart failure(CHF) through network pharmacology and molecular docking technology. The active ingredients and potential targets of Bawei Sanxiang San were collected by applying TCMSP, BATMAN databases and literature mining. CHF-related genes were collected through TTD, GeneCards and CTD databases. After the potential common targets between Bawei Sanxiang San and CHF were disco-vered, the interaction network diagram of "compound-target-pathway" was constructed using Cytoscape. The intersecting targets were imported into the DAVID database for GO function and KEGG pathway enrichment analysis. Finally, the Autodock_vina software was used to molecularly dock the selected proteins with the active ingredients of Bawei Sanxiang San. The results showed that there were 60 active ingredients in Bawei Sanxiang San that might be used to treat CHF, involving 311 target genes and 7 signaling pathways that directly related to CHF, such as HIF-1 signaling pathway, TNF signaling pathway, adrenergic signaling in cardiomyocytes, aldosterone-regulated sodium reabsorption, calcium signaling pathway, cGMP-PKG signaling pathway, renin secretion. Additionally, molecular docking showed that the bioactive compounds had good binding activity with the protein receptors of key target genes. Bawei Sanxiang San might exert therapeutic effects on CHF by regulating cardiomyocytes, angiogenic and inflammation related targets and pathways in a multi-component, multi-target and multi-pathway manner.

Factores moleculares implicados en insuficiencia cardiaca / Molecular factors involved in heart failure

La insuficiencia cardiaca se define como un síndrome caracterizado por la incapacidad de proveer las necesidades metabólicas del organismo, presentando disnea y fatiga. Hasta ahora, se ha descrito la participación de varias moléculas involucradas en los mecanismos de señalización intracelular que conducen a la insuficiencia cardiaca y estimulan la síntesis de algunas proteínas, como colágeno, la cual induce a una hipertrofia cardiaca(AU)

Heart failure is defined as a syndrome characterized by the inability to meet the metabolic needs of the organism, causing dyspnea and fatigue.Descriptions are available of the involvement of several molecules in cell signaling mechanisms which lead to heart failure and prompt the synthesis of some proteins, such as collagen, inducing cardiac hypertrophy(AU)

Quantification of DNA Damage in Different Tissues in Rats with Heart Failure / Quantificação de Dano em DNA em Diferentes Tecidos em Ratos com Insuficiência Cardíaca

Abstract Background: Chronic heart failure (CHF) is a complex syndrome which comprises structural and functional alterations in the heart in maintaining the adequate blood demand to all tissues. Few investigations sought to evaluate oxidative DNA damage in CHF. Objective: To quantify the DNA damage using the comet assay in left ventricle (LV), lungs, diaphragm, gastrocnemius and soleus in rats with CHF. Methods: Twelve male Wistar rats (300 to 330 g) were selected for the study: Sham (n = 6) and CHF (n = 6). The animals underwent myocardial infarction by the ligation of the left coronary artery. After six weeks, the animals were euthanized. It was performed a cell suspension of the tissues. The comet assay was performed to evaluate single and double strand breaks in DNA. Significance level (p) considered < 0.05. Results: The CHF group showed higher values of left ventricle end-diastolic pressure (LVEDP), pulmonary congestion, cardiac hypertrophy and lower values of maximal positive and negative derivatives of LV pressure, LV systolic pressure (p < 0.05). CHF group showed higher DNA damage (% tail DNA, tail moment and Olive tail moment) compared to Sham (p < 0.001). The tissue with the highest damage was the soleus, compared to LV and gastrocnemius in CHF group (p < 0.05). Conclusion: Our results indicates that the CHF affects all tissues, both centrally and peripherically, being more affected in skeletal muscle (soleus) and is positively correlated with LV dysfunction.

Resumo Fundamento: A insuficiência cardíaca crônica (ICC) é uma síndrome complexa que compreende alterações estruturais e funcionais no coração, mantendo demanda sanguínea adequada a todos os tecidos. Poucas investigações procuraram avaliar o dano oxidativo ao DNA na ICC. Objetivo: Quantificar o dano ao DNA utilizando o ensaio cometa no ventrículo esquerdo (VE), pulmões, diafragma, gastrocnêmio e sóleo em ratos com ICC. Métodos: Doze ratos Wistar machos (300 a 330 g) foram selecionados para o estudo: placebo (n = 6) e ICC (n = 6). Os animais foram submetidos a infarto do miocárdio através de ligadura da artéria coronária esquerda. Após seis semanas, os animais foram sacrificados. Foi realizada uma suspensão celular dos tecidos. O ensaio cometa foi realizado para avaliar as quebras de fita simples e dupla no DNA. Nível de significância (p) < 0,05. Resultados: O grupo ICC apresentou maiores valores de pressão diastólica final do ventrículo esquerdo (PDFVE), congestão pulmonar, hipertrofia cardíaca e menores valores de derivados máximos positivos e negativos da pressão do VE, pressão sistólica do VE (p < 0,05). O grupo ICC apresentou maior dano ao DNA (% de DNA da cauda, momento da cauda e momento da cauda de Olive) em comparação ao placebo (p < 0,001). O tecido com maior dano foi o sóleo, comparado ao VE e ao gastrocnêmio no grupo ICC (p < 0,05). Conclusão: Nossos resultados indicam que a ICC afeta todos os tecidos, de maneira central e periférica, sendo mais afetada no músculo esquelético (sóleo) e está positivamente correlacionada com a disfunção do VE.

Expression profile of circular RNAs in epicardial adipose tissue in heart failure / 中华医学杂志(英文版)

BACKGROUND@#Recent studies have reported circular RNA (circRNA) expression profiles in various tissue types; however, circRNA expression profile in human epicardial adipose tissue (EAT) remains undefined. This work aimed to compare circRNA expression patterns in EAT between the heart failure (HF) and non-HF groups.@*METHODS@#RNA-sequencing was carried out to compare circRNA expression patterns in EAT specimens from coronary artery disease cases between the HF and non-HF groups. Quantitative real-time polymerase chain reaction was performed for validation. Comparisons of patient characteristics between the two groups were using t test, Mann-Whitney U test, and Chi-squared test.@*RESULTS@#A total of 141 circRNAs substantially different between the HF and non-HF groups (P 2) were detected, including 56 up-regulated and 85 down-regulated. Among them, hsa_circ_0005565 stood out, for it had the highest fold change and was significantly increased in HF patients in quantitative real-time polymerase chain reaction validation. The top highly expressed EAT circRNAs corresponded to genes involved in cell proliferation and inflammatory response, including GSE1, RHOBTB3, HIPK3, UBXN7, PCMTD1, N4BP2L2, CFLAR, EPB41L2, FCHO2, FNDC3B, and SPECC1. The top enriched Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway were positive regulation of metabolic processes and insulin resistance, respectively.@*CONCLUSION@#These data indicate EAT circRNAs may contribute to the pathogenesis of metabolic disorders causing HF.

Influence of Angiotensin-converting Enzyme Insertion/Deletion Gene Polymorphism in Progression of Chagas Heart Disease

Abstract INTRODUCTION: Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi. One-third of infected patients will develop the cardiac form, which may progress to heart failure (HF). However, the factors that determine disease progression remain unclear. Increased angiotensin II activity is a key player in the pathophysiology of HF. A functional polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with plasma enzyme activity. In CD, ACE inhibitors have beneficial effects supporting the use of this treatment in chagasic cardiomyopathy. METHODS: We evaluated the association of ACE I/D polymorphism with HF, performing a case-control study encompassing 343 patients with positive serology for CD staged as non-cardiomyopathy (stage A; 100), mild (stage B1; 144), and severe (stage C; 99) forms of Chagas heart disease. For ACE I/D genotyping by PCR, groups were compared using unconditional logistic regression analysis and adjusted for nongenetic covariates: age, sex, and trypanocidal treatment. RESULTS: A marginal, but not significant (p=0.06) higher prevalence of ACE I/D polymorphism was observed in patients in stage C compared with patients in stage A. Patients in stage C (CD with HF), were compared with patients in stages A and B1 combined into one group (CD without HF); DD genotype/D carriers were prevalent in the HF patients (OR = 2; CI = 1.013.96; p = 0.04). CONCLUSIONS: Our results of this cohort study, comprising a population from the Northeast region of Brazil, suggest that ACE I/D polymorphism is more prevalent in the cardiac form of Chagas disease with HF.

Identification of the difference in the pathogenesis in heart failure arising from different etiologies using a microarray dataset

OBJECTIVES: Clinically, patients with chronic heart failure arising from different etiologies receive the same treatment. However, the prognoses of these patients differ. The purpose of this study was to elucidate whether the pathogenesis of heart failure arising from different etiologies differs. METHODS: Heart failure-related dataset GSE1145 was obtained from the Gene Expression Omnibus database. Differentially expressed genes were identified using R. A protein-protein interaction network of the differentially expressed genes was constructed using Search Tool for the Retrieval of Interacting Genes. The modules in each network were analyzed by Molecular Complex Detection of Cytoscape. The Database for Annotation, Visualization and Integrated Discovery was used to obtain the functions of the modules. RESULTS: Samples contained in GSE1145 were myocardial tissues from patients with dilated cardiomyopathy, familial cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, and post-partum cardiomyopathy. The differentially expressed genes, modules, and functions of the modules associated with different etiologies varied. Abnormal formation of extracellular matrix was overlapping among five etiologies. The change in cytoskeleton organization was specifically detected in dilated cardiomyopathy. The activation of the Wnt receptor signaling pathway was limited to hypertrophic cardiomyopathy. The change in nucleosome and chromatin assembly was associated with only familial cardiomyopathy. Germ cell migration and disrupted cellular calcium ion homeostasis were solely detected in ischemic cardiomyopathy. The change in the metabolic process of glucose and triglyceride was detected in only post-partum cardiomyopathy. CONCLUSION: These results indicate that the pathogenesis of heart failure arising from different etiologies varies, which may provide molecular evidence supporting etiology-based treatment for heart failure patients.

Angiotensin-Converting Enzyme ID Polymorphism in Patients with Heart Failure Secondary to Chagas Disease / Polimorfismo da Enzima Conversora da Angiotensina (ECA D/I) em Pacientes com Insuficiência Cardíaca de Etiologia Chagásica

Abstract Background: Changes in the angiotensin-converting enzyme (ACE) gene may contribute to the increase in blood pressure and consequently to the onset of heart failure (HF). The role of polymorphism is very controversial, and its identification in patients with HF secondary to Chagas disease in the Brazilian population is required. Objective: To determine ACE polymorphism in patients with HF secondary to Chagas disease and patients with Chagas disease without systolic dysfunction, and to evaluate the relationship of the ACE polymorphism with different clinical variables. Methods: This was a comparative clinical study with 193 participants, 103 of them with HF secondary to Chagas disease and 90 with Chagas disease without systolic dysfunction. All patients attended the outpatient department of the General Hospital of the Federal University of Goias general hospital. Alleles I and D of ACE polymorphism were identified by polymerase chain reaction of the respective intron 16 fragments in the ACE gene and visualized by electrophoresis. Results: In the group of HF patients, 63% were male, whereas 53.6% of patients with Chagas disease without systolic dysfunction were female (p = 0,001). The time from diagnosis varied from 1 to 50 years. Distribution of DD, ID and II genotypes was similar between the two groups, without statistical significance (p = 0,692). There was no difference in clinical characteristics or I/D genotypes between the groups. Age was significantly different between the groups (p = 0,001), and mean age of patients with HF was 62.5 years. Conclusion: No differences were observed in the distribution of (Insertion/Deletion) genotype frequencies of ACE polymorphism between the studied groups. The use of this genetic biomarker was not useful in detecting a possible relationship between ACE polymorphism and clinical manifestations in HF secondary to Chagas disease.

Resumo Fundamento: Alterações no gene da Enzima Conversora de Angiotensina (ECA) podem contribuir para o aumento da pressão arterial e consequentemente para o surgimento de insuficiência cardíaca (IC). O papel do polimorfismo ainda é bastante controverso, sendo necessária sua identificação em pacientes com IC de etiologia chagásica na população brasileira. Objetivo: Determinar o polimorfismo da ECA em portadores de IC com etiologia chagásica e pacientes com doença de Chagas sem disfunção sistólica, e avaliar a relação do polimorfismo ECA com diferentes variáveis clínicas. Métodos: Trata-se um estudo clínico comparativo com 193 participantes, destes, 103 com IC de etiologia chagásica e 90 pacientes com doença de Chagas sem disfunção sistólica, todos em atendimento ambulatorial no Hospital das Clínicas da Universidade Federal de Goiás. Os alelos D e I do polimorfismo da ECA foram identificados por reação em cadeia da polimerase dos respectivos fragmentos provenientes do íntron 16 no gene da ECA e visualizados em eletroforese. Resultados: Dos portadores de IC, 63 % eram do gênero masculino, enquanto nos portadores de doença de Chagas sem disfunção sistólica 53,6% eram do gênero feminino (p = 0,001). O tempo de diagnóstico variou de 1 a 50 anos. A distribuição dos genótipos DD, DI e II foi semelhante entre os dois grupos, não apresentando significância estatística (p = 0,692). Nenhuma interação foi observada em relação às características clínicas e os genótipos D/I entre os grupos. A idade foi significativamente diferente entre os grupos (p = 0,001), e a média de idade dos pacientes com IC foi de 62,5 anos. Conclusão: Não foram observadas diferenças na distribuição das frequências dos genótipos (Deleção/Inserção) do polimorfismo ECA entre os grupos estudados. A utilização deste biomarcador genético não se mostrou útil na tentativa de se conhecer a existência da relação do polimorfismo ECA e as manifestações clínicas da IC de etiologia chagásica.

Influence of Angiotensin-Converting-Enzyme Gene Polymorphism on Echocardiographic Data of Patients with Ischemic Heart Failure / Influência do Polimorfismo Genético da Enzima Conversora de Angiotensina em Dados Ecocardiográficos de Pacientes com Insuficiência Cardíaca Isquêmica

Abstract Background: Association between angiotensin-converting-enzyme (ACE) gene polymorphisms and different clinical and echocardiographic outcomes has been described in patients with heart failure (HF) and coronary artery disease. Studying the genetic profile of the local population with both diseases is necessary to assess the occurrence of that association. Objectives: To assess the frequency of ACE gene polymorphisms in patients with ischemic HF in a Rio de Janeiro population, as well as its association with echocardiographic findings. Methods: Genetic assessment of I/D ACE polymorphism in association with clinical, laboratory and echocardiographic analysis of 99 patients. Results: The allele frequency was: 53 I alleles, and 145 D alleles. Genotype frequencies were: 49.5% DD; 47.48% DI; 3.02% II. Drug treatment was optimized: 98% on beta-blockers, and 84.8% on ACE inhibitors or angiotensin-receptor blocker. Echocardiographic findings: difference between left ventricular diastolic diameters (ΔLVDD) during follow-up: 2.98±8.94 (DD) vs. 0.68±8.12 (DI) vs. -11.0±7.00 (II), p=0.018; worsening during follow-up of the LV systolic diameter (LVSD): 65.3% DD vs. 19.0% DI vs. 0.0% II, p=0.01; of the LV diastolic diameter (LVDD): 65.3% DD vs. 46.8% DI vs. 0.0% II, p=0.03; and of the LV ejection fraction (LVEF): 67.3% DD vs. 40.4% DI vs. 33.3% II, p=0.024. Correlated with D allele: ΔLVEF, ΔLVSD, ΔLVDD. Conclusions: More DD genotype patients had worsening of the LVEF, LVSD and LVDD, followed by DI genotype patients, while II genotype patients had the best outcome. The same pattern was observed for ΔLVDD.

Resumo Fundamentos: Associação entre polimorfismos genéticos da enzima conversora da angiotensina (ECA) e diferentes evoluções clínicas e ecocardiográficas foi descrita em pacientes com insuficiência cardíaca (IC) e coronariopatia. O estudo do perfil genético da população local com as duas doenças torna-se necessário para verificar a ocorrência dessa associação. Objetivos: Avaliar a frequência dos polimorfismos genéticos da ECA em pacientes com IC de etiologia isquêmica de uma população do Rio de Janeiro e sua associação com achados ecocardiográficos. Métodos: Avaliação genética do polimorfismo I/D da ECA associada a análise de dados clínicos, laboratoriais e ecocardiográficos de 99 pacientes. Resultados: Foram encontrados 53 alelos I, 145 alelos D, quanto aos genótipos da ECA: 49,5% DD, 47,48% DI, 3,02% II. O tratamento medicamentoso foi otimizado com 98% usando betabloqueadores e 84,8%, IECA ou bloqueador do receptor de angiotensina. Achados ecocardiográficos: diferença entre os diâmetros diastólicos do ventrículo esquerdo (ΔVED): 2,98±8,94 (DD) vs. 0,68±8,12 (DI) vs. -11,0±7,00 (II), p=0,018; piora evolutiva do diâmetro sistólico do VE (VES): 65,3 % DD vs. 19,0 % DI vs. 0,0 % II, p=0,01; do diâmetro diastólico do VE (VED): 65,3 % DD vs. 46,8 % DI vs. 0,0 % II, p=0,03; e da fração de ejeção do VE (FEVE): 67,3 % DD vs. 40,4 % DI vs. 33,3 % II, p=0,024. Correlação com alelo D: ΔFEVE, ΔVES, ΔVED. Conclusões: Foram identificados mais pacientes com piora evolutiva da FEVE e dos diâmetros cavitários do VE no genótipo DD, seguido do DI, sendo o II o de melhor evolução. O mesmo padrão foi observado na ΔVED.

Impacto do polimorfismo genetico da enzima conversora da angiotensina no remodelamento cardiaco / Angiotensin-converting enzyme genetic polymorphism: its impact on cardiac remodeling

Fundamento: O papel dos polimorfismos genéticos da enzima de conversão da angiotensina na insuficiência cardíaca, como preditor de desfechos ecocardiográficos, ainda não está estabelecido. é necessário identificar o perfil local para observar o impacto desses genótipos na população brasileira, sendo inédito o estudo da insuficiência cardíaca de etiologia exclusivamente não isquêmica em seguimento mais longo que 5 anos. Objetivo: Determinar a distribuição das variantes do polimorfismo genético da enzima de conversão da angiotensina e sua relação com a evolução ecocardiográfica de pacientes com insuficiência cardíaca de etiologia não isquêmica. Métodos: Análise secundária de prontuários de 111 pacientes e identificação das variantes do polimorfismo genético da enzima de conversão da angiotensina, classificadas como DD (Deleção/Deleção), DI (Deleção/Inserção) ou II (Inserção/Inserção). Resultados: As médias da coorte foram: seguimento de 64,9 meses, idade de 59,5 anos, 60,4% eram homens, 51,4% eram brancos, 98,2% faziam uso de betabloqueadores e 89,2% de inibidores da enzima de conversão da angiotensina ou de bloqueador do receptor da angiotensina. A distribuição do polimorfismo genético da enzima de conversão da angiotensina foi: 51,4% de DD; 44,1% de DI; e 4,5% de II. Não se observou nenhuma diferença das características clínicas ou de tratamento entre os grupos. O diâmetro sistólico do ventrículo esquerdo final foi a única variável ecocardiográfica isolada significativamente diferente entre os polimorfismos genéticos da enzima de conversão da angiotensina: 59,2 ± 1,8 para DD versus ...

Background: The role of angiotensin-converting enzyme genetic polymorphisms as a predictor of echocardiographic outcomes on heart failure is yet to be established. The local profile should be identified so that the impact of those genotypes on the Brazilian population could be identified. This is the first study on exclusively non-ischemic heart failure over a follow-up longer than 5 years. Objective: To determine the distribution of angiotensin-converting enzyme genetic polymorphism variants and their relation with echocardiographic outcome of patients with non-ischemic heart failure. Methods: Secondary analysis of the medical records of 111 patients and identification of the angiotensin-converting enzyme genetic polymorphism variants, classified as DD (Deletion/Deletion), DI (Deletion/Insertion) or II (Insertion/Insertion). Results: The cohort means were as follows: follow-up, 64.9 months; age, 59.5 years; male sex, 60.4%; white skin color, 51.4%; use of beta-blockers, 98.2%; and use of angiotensin-converting-enzyme inhibitors or angiotensin receptor blocker, 89.2%. The angiotensin-converting enzyme genetic polymorphism distribution was as follows: DD, 51.4%; DI, 44.1%; and II, 4.5%. No difference regarding the clinical characteristics or treatment was observed between the groups. The final left ventricular systolic diameter was the only isolated echocardiographic variable that significantly differed between the angiotensin-converting enzyme genetic polymorphisms: 59.2 ± 1.8 for DD versus 52.3 ± 1.9 for DI versus 59.2 ± 5.2 for II (p = 0.029). Considering the evolutionary behavior, all echocardiographic variables (difference between the left ventricular ejection fraction at the last and first consultation; difference between the left ventricular systolic diameter at the last and first consultation; and difference between the left ventricular diastolic diameter at the last and first consultation) differed ...

Polimorfismo G894T da óxido nítrico-sintetase endotelial e o prognóstico na insuficiência cardíaca / Genetic polymorphism G894T and the prognosis of heart failure outpatients

FUNDAMENTO: Estudos prévios avaliaram o papel do polimorfismo genético da enzima óxido nítrico-sintetase endotelial sobre o prognóstico na insuficiência cardíaca. Entretanto, faltam estudos relacionando o G894T e a insuficiência cardíaca na população brasileira. OBJETIVO: Avaliar a associação do G894T com o prognóstico de amostra de pacientes brasileiros com insuficiência cardíaca. MÉTODOS: Coorte com 145 pacientes com insuficiência cardíaca sistólica, num segmento de 40 meses (média = 22 meses), em dois hospitais universitários do Estado do Rio de Janeiro. Foi avaliada a relação do G894T com os desfechos: remodelamento reverso; melhora da classe funcional (NYHA); taxas de mortalidade e hospitalização. Os diâmetros do átrio e ventrículo esquerdos e a fração de ejeção do ventrículo esquerdo foram medidos na admissão e após 6 meses, para avaliação do remodelamento reverso. A melhora na classe funcional foi avaliada após 6 meses e as taxas de mortalidade e de hospitalização durante todo o seguimento. A raça foi autodeclarada. O polimorfismo G894T foi analisado por reação em cadeia de polimerase e por análise do polimorfismo dos fragmentos de restrição. RESULTADOS: A frequência genotípica foi GG (40%), GT (48,3%) e TT (11,7%), e a frequência alélica foi guanina (64,1%) e tiamina (35,8%). Não houve diferença entre as frequências genotípica ou alélica conforme a raça autodeclarada, tampouco conforme as características basais. Não houve relação entre o genótipo ou a frequência alélica e os desfechos analisados. CONCLUSÃO: Não se observou associação do polimorfismo G894T (Glu298Asp) com o prognóstico de amostra de pacientes ambulatoriais brasileiros com insuficiência cardíaca sistólica.

BACKGROUND: Previous studies have analyzed the role of the genetic polymorphism of endothelial nitric oxide synthase on heart failure prognosis. However, there are no studies relating the G894T and heart failure in Brazil. OBJECTIVE: To evaluate the association between G894T GP and the prognosis of a sample of Brazilian outpatients with heart failure. METHODS: Cohort study included 145 patients with systolic heart failure, followed for up to 40 months (mean = 22), at two university hospitals, in the State of Rio de Janeiro. We evaluated the relationship between G894T and the following outcomes: reverse remodeling, improvement in functional class (NYHA), and mortality and hospitalization rates. The diameters of the left atrium and ventricle, as well as the ejection fraction of the left ventricle, were evaluated at baseline and at 6 months to assess reverse remodeling. The improvement in functional class was evaluated after 6 months, and mortality rate and hospitalization were evaluated during follow-up. Race was self-declared. G894T polymorphism was analyzed by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: The genotypic frequencies were GG (40%), GT (48.3%) and TT (11.7%). The allele frequency was guanine (64.1%) and thiamine (35.8%). There were no differences between the genotype or allelic frequencies according to self-declared race, either as baseline characteristics. There was no relationship between genotype or allele frequency and the outcome measures. CONCLUSION: No association was observed between the G894T polymorphism (Glu298Asp) and prognosis in this sample of Brazilian outpatients with systolic heart failure.

Os polimorfismos dos receptores adrenérgicos na insuficiência cardíaca: o que a genética explica? / Adrenergic receptor polymorphisms in heart failure: what can genetics explain?

A insuficiência cardíaca (IC) é uma doença complexa, onde diversos mecanismos fisiopatológicos atuam e diferentes polimorfismos genéticos estão envolvidos. O sistema adrenérgico está diretamente relacionado a esta patologia participando da auto-regulação cardiovascular, tendo papel crucial na deteriorização da função cardíaca. Os beta-bloqueadores surgiram como um grande avanço da cardiologia no tratamento da IC, no entanto a resposta medicamentosa varia para cada paciente podendo estar relacionado a diversos fatores, entre eles o genético. A determinação pela genética do desenvolvimento da IC, da resposta medicamentosa e prognóstico são questões que serão abrangidas nesta revisão.

Heart failure (HF) is a complex disease, which involves several physiopathological mechanisms and different genetic polymorphisms. The adrenergic system is directly related to this pathology, as it participates in cardiovascular autoregulation and has a crucial role in the deterioration of cardiac function. The beta-blockers appeared as a great advance in cardiology for the treatment of HF; however, the drug response varies according to each patient, as several factors are associated, such as the genetic one. This review aims at assessing the genetic involvement in the development of HF, the drug response and the prognosis.

Impact of β-2 Thr164Ile and combined β-adrenergic receptor polymorphisms on prognosis in a cohort of heart failure outpatients

Genetic polymorphisms of adrenergic receptors (ARs) have been associated with the development, progression, and prognosis of patients with heart failure (HF), with few data for the Brazilian population. We evaluated the role of the β2-AR Thr164Ile polymorphism at codon 164 on prognosis in a prospective study on 315 adult Brazilian HF patients, predominantly middle-aged Caucasian men in functional class I-II, with severe left ventricular systolic dysfunction. Genomic DNA was extracted from peripheral blood and β2-AR164 genotypes were detected by PCR followed by restriction fragment length analysis. During a median follow-up of 3 years, 95 deaths occurred and 57 (60 percent) were HF-related. Unexpectedly, Ile164 carriers (N = 12) had no HF-related events (log-rank P value = 0.13). Analysis using genotype combination with β1-AR polymorphisms at codons 49 and 389 identified patients with favorable genotypes (Thr164Ile of β2-AR, Gly49Gly of β1-AR and/or Gly389Gly of β1-AR), who had lower HF-related mortality (P = 0.01). In a Cox proportional hazard model adjusted for other clinical characteristics, having any of the favorable genotypes remained as independent predictor of all-cause (hazard ratio (HR): 0.41, 95 percentCI: 0.17-0.95) and HF-related mortality (HR: 0.12, 95 percentCI: 0.02-0.90). These data show that the β2-AR Thr164Ile polymorphism had an impact on prognosis in a Brazilian cohort of HF patients. When combined with common β1-AR polymorphisms, a group of patients with a combination of favorable genotypes could be identified.

Homocysteine, Hydrogen sulfide (H2S) and NMDA-Receptor in Heart Failure.

Mitochondrial mechanism of oxidative stress and matrix metalloproteinase (MMP) activation was unclear. Our recent data suggested that MMPs are localized to mitochondria and activated by peroxynitrite, which causes cardiovascular remodeling and failure. Recently, we have demonstrated that elevated levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy) increase oxidative stress in the mitochondria. Although HHcy causes heart failure, interestingly, it is becoming very clear that Hcy can generate hydrogen sulfide (H2S), if the enzymes cystathionine β-synthase (CBS) and cystathionine -lyase (CGL) are present. H2S is a strong anti-oxidant and vasorelaxing agent. Paradoxically, it is interesting that Hcy, a precursor of H2S can be cardioprotective. The CGL is ubiquitous, while the CBS is not present in the vascular tissues. Therefore, under normal condition, only half of Hcy can be converted to H2S. However, there is strong potential for gene therapy of CBS to vascular tissue that can mitigate the detrimental effects of Hcy by converting it to H2S. This scenario is possible, if the activities of both the enzymes (CBS and CGL) are increased in tissues by gene therapy.

Interacción entre los polimorfismos del receptor ß1 y ß2 adrenérgico como predictor de riesgo de insuficiencia cardiaca crónica / Interactions between ß1 and ß2 adrenergic receptor polymorphisms as risk factors for chronic heart failure

Background: ß adrenergic receptors (AR) are highly polymorphic and important regulators of cardiovascular homeostasis. Among these, ß1 and ß2 AR regulate cardiac contractility and frequency and are important pharmacological targets. Aim: To evaluate genotype and gene-gene interaction between ß1-AR Arg389Gly and ß2-AR ArglSGly GlnZ7Gly and Thrl 64Ile polymorphisms, as risk factors for HF. Material and methods: Eighty chronic HF patients and eighty-eight controls matched by age and sex were genotyped for ß1 -AR Arg389Gly ß2-AR ArgWGly, GlnZ7Glu and Thr164Ile polymorphisms. Results: The presence of ß2-AR Glu afiele was a risk predictor for HF (odds ratio (OR) =2.81; 95 percent confidence intervals (CI) =1.49-5.31). Interactions that increased the risk for HF were found in patients carrying at least one of the ß2-AR Glu and ß2-AR Gly allele (OR =3.81; 95 percent CI =1.50-0.70) and ß2-AR Glu and ß1 -AR Gly allele combination (OR =5.51; 95 percent CI =2.19-13.86). Furthermore, the frequency of ß2-AR Glu allele was higher among patients with a history ofacute myocardial infarction (with infarction: 0.534, without: 0.313, p =0.01). Conclusions: ß2-AR Glu allele could be a risk predictor for HF. This risk could be enhanced by the additional presence of ß2-AR GlyW or ß1-AR Arg389 alleles. The frequency of ß2-AR Gln27 Glu allele was higher among patients with a history of myocardial infarction.

Effect of exercise training and carvedilol treatment on cardiac function and structure in mice with sympathetic hyperactivity-induced heart failure

The present investigation was undertaken to study the effect of â-blockers and exercise training on cardiac structure and function, respectively, as well as overall functional capacity in a genetic model of sympathetic hyperactivity-induced heart failure in mice (alpha2A/alpha2CArKO). alpha2A/alpha2CArKO and their wild-type controls were studied for 2 months, from 3 to 5 months of age. Mice were randomly assigned to control (N = 45), carvedilol-treated (N = 29) or exercise-trained (N = 33) groups. Eight weeks of carvedilol treatment (38 mg/kg per day by gavage) or exercise training (swimming sessions of 60 min, 5 days/week) were performed. Exercise capacity was estimated using a graded treadmill protocol and HR was measured by tail cuff. Fractional shortening was evaluated by echocardiography. Cardiac structure and gastrocnemius capillary density were evaluated by light microscopy. At 3 months of age, no significant difference in fractional shortening or exercise capacity was observed between wild-type and alpha2A/alpha2CArKO mice. At 5 months of age, all alpha2A/alpha2CArKO mice displayed exercise intolerance and baseline tachycardia associated with reduced fractional shortening and gastrocnemius capillary rarefaction. In addition, alpha2A/ alpha2CArKO mice presented cardiac myocyte hypertrophy and ventricular fibrosis. Exercise training and carvedilol similarly improved fractional shortening in alpha2A/alpha2CArKO mice. The effect of exercise training was mainly associated with improved exercise tolerance and increased gastrocnemius capillary density while beta-blocker therapy reduced cardiac myocyte dimension and ventricular collagen to wild-type control levels. Taken together, these data provide direct evidence for the respective beneficial effects of exercise training and carvedilol in alpha2A/alpha2CArKO mice preventing cardiac dysfunction. The different mechanisms associated with beneficial effects of exercise...