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1.
Nat Genet ; 53(2): 135-142, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33495597

RESUMO

Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most patients do not carry such variants. We report a genome-wide association study of 2,780 cases and 47,486 controls that identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h2g = 0.34 ± 0.02). A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomization identified diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM, with a one standard deviation increase in DBP increasing the HCM risk fourfold. Common variants and modifiable risk factors have important roles in HCM that we suggest will be clinically actionable.


Assuntos
Cardiomiopatia Hipertrófica/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Pressão Sanguínea/genética , Miosinas Cardíacas/genética , Proteínas de Transporte/genética , Estudos de Casos e Controles , Forminas/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/genética , Fatores de Risco , Sarcômeros/genética , Adulto Jovem
2.
Int Heart J ; 62(1): 127-134, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33455984

RESUMO

Mutations in the sarcomeric protein filamin C (FLNC) gene have been linked to hypertrophic cardiomyopathy (HCM), as they have been determined to increase the risk of ventricular arrhythmia and sudden death. Thus, in this study, we identified a novel missense mutation of FLNC in a Chinese family with HCM, and, interestingly, a second novel truncating mutation of MYLK2 was discobered in one family member with different phenotype.We performed whole-exome sequencing in a Chinese family with HCM of unknown cause. To determine and confirm the function of a novel mutation of FLNC, we introduced the mutant and wild-type gene into AC16 cells (human cardiomyocytes): we then used western blotting to analyze the expression of FLNC in subcellular fractions, and confocal microscope to observe the subcellular distribution of the protein.As per our findings, we were able to identify a novel missense single nucleotide variant (FLNC c.G5935A [p.A1979T]) in the family, which segregates with the disease. FLNC expression levels were observed to be equivalent in both wild-type and p.A1979T cardiomyocytes. However, the expression of the mutant protein has resulted in cytoplasmic protein aggregations, in contrast to wild-type FLNC, which was distributed in the cytoplasm and did not form aggregates. Unexpectedly, a second truncating mutation, NM_033118:exon8:c.G1138T:p.E380X of the MYLK2 gene, was identified in the mother of the proband with dilated cardiomyopathy, which was not found in other subjects.We then identified the FLNC A1979T mutation as a novel pathogenic variant associated with HCM in a Chinese family as well as a second causal mutation in a family member with a distinct phenotype. The possibility that there is more than one causal mutation in cardiomyopathy warrants clinical attention, especially for patients with atypical clinical features.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas de Ligação ao Cálcio/genética , Cardiomiopatias/genética , Filaminas/genética , Quinase de Cadeia Leve de Miosina/genética , Adulto , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/genética , Morte Súbita Cardíaca/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Mutação de Sentido Incorreto/genética , Miócitos Cardíacos/ultraestrutura , Linhagem , Fenótipo , Fatores de Risco , Fibrilação Ventricular/epidemiologia , Fibrilação Ventricular/mortalidade , Sequenciamento Completo do Exoma/métodos
4.
Nat Genet ; 53(2): 128-134, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33495596

RESUMO

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.


Assuntos
Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Dilatada/mortalidade , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Hipertrófica/mortalidade , Cardiomiopatia Hipertrófica/fisiopatologia , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Ventrículos do Coração/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Função Ventricular Esquerda/genética
5.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429969

RESUMO

The sarcomere as the smallest contractile unit is prone to alterations in its functional, structural and associated proteins. Sarcomeric dysfunction leads to heart failure or cardiomyopathies like hypertrophic (HCM) or restrictive cardiomyopathy (RCM) etc. Genetic based RCM, a very rare but severe disease with a high mortality rate, might be induced by mutations in genes of non-sarcomeric, sarcomeric and sarcomere associated proteins. In this review, we discuss the functional effects in correlation to the phenotype and present an integrated model for the development of genetic RCM.


Assuntos
Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Restritiva/genética , Insuficiência Cardíaca/genética , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Restritiva/complicações , Cardiomiopatia Restritiva/patologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/patologia , Humanos , Mutação/genética , Linhagem , Fenótipo
6.
Am J Physiol Heart Circ Physiol ; 320(2): H881-H890, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33337957

RESUMO

Morbidity and mortality associated with heart disease is a growing threat to the global population, and novel therapies are needed. Mavacamten (formerly called MYK-461) is a small molecule that binds to cardiac myosin and inhibits myosin ATPase. Mavacamten is currently in clinical trials for the treatment of obstructive hypertrophic cardiomyopathy (HCM), and it may provide benefits for treating other forms of heart disease. We investigated the effect of mavacamten on cardiac muscle contraction in two transgenic mouse lines expressing the human isoform of cardiac myosin regulatory light chain (RLC) in their hearts. Control mice expressed wild-type RLC (WT-RLC), and HCM mice expressed the N47K RLC mutation. In the absence of mavacamten, skinned papillary muscle strips from WT-RLC mice produced greater isometric force than strips from N47K mice. Adding 0.3 µM mavacamten decreased maximal isometric force and reduced Ca2+ sensitivity of contraction for both genotypes, but this reduction in pCa50 was nearly twice as large for WT-RLC versus N47K. We also used stochastic length-perturbation analysis to characterize cross-bridge kinetics. The cross-bridge detachment rate was measured as a function of [MgATP] to determine the effect of mavacamten on myosin nucleotide handling rates. Mavacamten increased the MgADP release and MgATP binding rates for both genotypes, thereby contributing to faster cross-bridge detachment, which could speed up myocardial relaxation during diastole. Our data suggest that mavacamten reduces isometric tension and Ca2+ sensitivity of contraction via decreased strong cross-bridge binding. Mavacamten may become a useful therapy for patients with heart disease, including some forms of HCM.NEW & NOTEWORTHY Mavacamten is a pharmaceutical that binds to myosin, and it is under investigation as a therapy for some forms of heart disease. We show that mavacamten reduces isometric tension and Ca2+ sensitivity of contraction in skinned myocardial strips from a mouse model of hypertrophic cardiomyopathy that expresses the N47K mutation in cardiac myosin regulatory light chain. Mavacamten reduces contractility by decreasing strong cross-bridge binding, partially due to faster cross-bridge nucleotide handling rates that speed up myosin detachment.


Assuntos
Benzilaminas/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Cardiomiopatia Hipertrófica/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Contração Miocárdica/efeitos dos fármacos , Cadeias Leves de Miosina/metabolismo , Músculos Papilares/efeitos dos fármacos , Uracila/análogos & derivados , Miosinas Ventriculares/antagonistas & inibidores , Animais , Cardiomiopatia Hipertrófica/enzimologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Modelos Animais de Doenças , Humanos , Cinética , Masculino , Camundongos Transgênicos , Mutação , Cadeias Leves de Miosina/genética , Músculos Papilares/enzimologia , Músculos Papilares/fisiopatologia , Uracila/farmacologia , Miosinas Ventriculares/metabolismo
7.
BMC Med Genet ; 21(1): 188, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993534

RESUMO

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic disorder mostly caused by sarcomeric gene mutations, but almost 10% of cases are attributed to inherited metabolic and neuromuscular disorders. First described in 2008 in an American-Italian family with scapuloperoneal myopathy, FHL1 gene encodes four-and-a-half LIM domains 1 proteins which are involved in sarcomere formation, assembly and biomechanical stress sensing both in cardiac and skeletal muscle, and its mutations are responsible for a large spectrum of neuromuscular disorders (mostly myopathies) and cardiac disease, represented by HCM, either isolated, or in conjunction with neurologic and skeletal muscle impairment. We thereby report a novel mutation variant in FHL1 structure, associated with HCM and type 6 Emery-Dreifuss muscular dystrophy (EDMD). CASE PRESENTATION: We describe the case of a 40 year old male patient, who was referred to our department for evaluation in the setting of NYHA II heart failure symptoms and was found to have HCM. The elevated muscular enzymes raised the suspicion of a neuromuscular disease. Rigid low spine and wasting of deltoidus, supraspinatus, infraspinatus and calf muscles were described by the neurological examination. Electromyography and muscle biopsy found evidence of chronic myopathy. Diagnosis work-up was completed by next-generation sequencing genetic testing which found a likely pathogenic mutation in the FHL1 gene (c.157-1G > A, hemizygous) involved in the development of X-linked EDMD type 6. CONCLUSION: This case report highlights the importance of multimodality diagnostic approach in a patient with a neuromuscular disorder and associated hypertrophic cardiomyopathy by identifying a novel mutation variant in FHL1 gene. Raising awareness of non-sarcomeric gene mutations which can lead to HCM is fundamental, because of diagnostic and clinical risk stratification challenges.


Assuntos
Cardiomiopatia Hipertrófica/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Proteínas Musculares/genética , Doenças Musculares/genética , Mutação , Adulto , Cardiomiopatia Hipertrófica/diagnóstico , Saúde da Família , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Linhagem
8.
Radiol Med ; 125(11): 1056-1071, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32946001

RESUMO

Cardiomyopathies are a heterogeneous entity. The progress in the field of genetics has allowed over the years to determine its origin more and more often. The classification of these pathologies has changed over the years; it has been updated with new knowledge. Imaging allows to define the phenotypic characteristics of the different forms of cardiomyopathy. Cardiac magnetic resonance (CMR) allows a morphological evaluation of the associated (and sometimes pathognomonic) cardiac findings of any form of cardiomyopathy. The tissue characterization sequences also make magnetic resonance imaging unique in its ability to detect changes in myocardial tissue. This review aims to define the features that can be highlighted by CMR in hypertrophic and dilated forms and the possible differential diagnoses. In hypertrophic forms, CMR provides: precise evaluation of wall thickness in all segments, ventricular function and size and evaluation of possible presence of areas of fibrosis as well as changes in myocardial tissue (measurement of T1 mapping and extracellular volume values). In dilated forms, cardiac resonance is the gold standard in the assessment of ventricular volumes. CMR highlights also the potential alterations of the myocardial tissue.


Assuntos
Técnicas de Imagem Cardíaca/métodos , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Adulto , Idoso , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/genética , Meios de Contraste , Diagnóstico Diferencial , Feminino , Gadolínio , Septos Cardíacos/diagnóstico por imagem , Septos Cardíacos/patologia , Humanos , Hipertrofia/diagnóstico por imagem , Hipertrofia/patologia , Aumento da Imagem/métodos , Masculino , Pessoa de Meia-Idade
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(10): 1113-1116, 2020 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-32924113

RESUMO

OBJECTIVE: To explore the predictive value of overall longitudinal strain for the development of cardiomyopathy without hypertrophic changes. METHODS: Sixty five patients with suspected hypertrophic cardiomyopathy (HCM) but without hypertrophic changes were selected. Genetic variant, overall longitudinal strain, left ventricular ejection fraction, end diastolic volume, end systolic volume, interventricular septal thickness, left ventricular diameter and end diastolic diameter were detected. The risk factors of HCM were analyzed. RESULTS: Forty four variants of 16 genes were identified, among which MYBPC3 13659G>A was the commonest (73.20%) and MYH7 13252C>T was the second (31.25%). MYBPC3 GG genotype, overall longitudinal strain and apical longitudinal strain were correlated with HCM (P<0.05). CONCLUSION: The increase of longitudinal strain is of great value in predicting the occurrence of HCM.


Assuntos
Cardiomiopatia Hipertrófica , Função Ventricular Esquerda , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genética , Diástole , Ventrículos do Coração , Humanos , Valor Preditivo dos Testes , Volume Sistólico , Sístole
11.
Am J Physiol Heart Circ Physiol ; 319(2): H306-H319, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32618513

RESUMO

Dilated cardiomyopathy (DCM) is clinically characterized by dilated ventricular cavities and reduced ejection fraction, leading to heart failure and increased thromboembolic risk. Mutations in thin-filament regulatory proteins can cause DCM and have been shown in vitro to reduce contractility and myofilament Ca2+-affinity. In this work we have studied the functional consequences of mutations in cardiac troponin T (R131W), cardiac troponin I (K36Q) and α-tropomyosin (E40K) using adenovirally transduced isolated guinea pig left ventricular cardiomyocytes. We find significantly reduced fractional shortening with reduced systolic Ca2+. Contraction and Ca2+ reuptake times were slowed, which contrast with some findings in murine models of myofilament Ca2+ desensitization. We also observe increased sarcoplasmic reticulum (SR) Ca2+ load and smaller fractional SR Ca2+ release. This corresponds to a reduction in SR Ca2+-ATPase activity and increase in sodium-calcium exchanger activity. We also observe dephosphorylation and nuclear translocation of the nuclear factor of activated T cells (NFAT), with concordant RAC-α-serine/threonine protein kinase (Akt) phosphorylation but no change to extracellular signal-regulated kinase activation in chronically paced cardiomyocytes expressing DCM mutations. These changes in Ca2+ handling and signaling are common to all three mutations, indicating an analogous pathway of disease pathogenesis in thin-filament sarcomeric DCM. Previous work has shown that changes to myofilament Ca2+ sensitivity caused by DCM mutations are qualitatively opposite from hypertrophic cardiomyopathy (HCM) mutations in the same genes. However, we find several common pathways such as increased relaxation times and NFAT activation that are also hallmarks of HCM. This suggests more complex intracellular signaling underpinning DCM, driven by the primary mutation.NEW & NOTEWORTHY Dilated cardiomyopathy (DCM) is a frequently occurring cardiac disorder with a degree of genetic inheritance. We have found that DCM mutations in proteins that regulate the contractile machinery cause alterations to contraction, calcium-handling, and some new signaling pathways that provide stimuli for disease development. We have used guinea pig cells that recapitulate human calcium-handling and introduced the mutations using adenovirus gene transduction to look at the initial triggers of disease before remodeling.


Assuntos
Sinalização do Cálcio , Cardiomiopatia Dilatada/genética , Proteínas dos Microfilamentos/genética , Mutação , Contração Miocárdica , Miócitos Cardíacos/enzimologia , Fatores de Transcrição NFATC/metabolismo , Proteína Oncogênica v-akt/metabolismo , Função Ventricular Esquerda , Animais , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/fisiopatologia , Células Cultivadas , Predisposição Genética para Doença , Cobaias , Masculino , Proteínas dos Microfilamentos/metabolismo , Fenótipo , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Tropomiosina/genética , Tropomiosina/metabolismo , Troponina I/genética , Troponina I/metabolismo , Troponina T/genética , Troponina T/metabolismo
13.
Am Heart J ; 225: 108-119, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32480058

RESUMO

INTRODUCTION: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. METHODS AND RESULTS: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10-5; U.S. cohort, P = 2.2×10-13). CONCLUSION: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.


Assuntos
Cardiomiopatias/genética , Heterozigoto , Mutação com Perda de Função , Proteínas Musculares/genética , Mutação de Sentido Incorreto , Proteínas Quinases/genética , Anormalidades Múltiplas/genética , Adulto , Idade de Início , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Ecocardiografia , Eletrocardiografia , Humanos , Lactente , Fenótipo
14.
Pediatr Cardiol ; 41(6): 1180-1189, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32474737

RESUMO

Hypertrophic cardiomyopathy (HCM) is a prevalent cardiomyopathy in children, with variable etiologies, phenotypes, and associated syndromic genetic disorders (GD). The spectrum of evaluation in this heterogeneous population has not been well described. We aimed to describe mortality and medical management in the pediatric HCM population, and compare HCM pediatric patients with GD to those without GD. Children (< 18 years) with HCM from the claims-based Truven Health Analytics MarketScan Research Database for years 2013-2016 were identified. Outcomes, including patient visits, diagnostic tests, procedures, medications, and mortality, were reported across demographic and clinical characteristics. Multivariable negative binomial, logistic, and survival models were utilized to test the association between those with and without GD by outcomes. 4460 patients were included, with a median age of 11 years (IQR 3-16), 61.7% male, 17.7% with GD, and 2.1% who died during the study period. There were 0.36 inpatient admissions per patient-year. Patients with GD were younger [8 years (IQR 1-14) vs 12 years (IQR 3-16) (p < 0.0001)], had more echocardiograms (1.77 vs 0.93) p < 0.0001; and ambulatory cardiac monitoring per year (0.32 vs 0.24); p = 0.0002. Adjusting for potential confounders including age, other chronic medical conditions, procedures, and heart failure, GD had increased risk of mortality [HR 2.46 (95% CI 1.62, 3.74)], myectomy [HR 1.59 (95% CI 1.08, 2.35)], and more annual admissions [OR 1.36 (CI 1.27, 1.45]. Patients with HCM show higher rates of death, admission, testing, and myectomy when concomitant syndromic genetic disorders are present, suggesting that the disease profile and resource utilization are different from HCM patients without GD.


Assuntos
Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/mortalidade , Doenças Genéticas Inatas/complicações , Adolescente , Procedimentos Cirúrgicos Cardíacos/métodos , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/terapia , Criança , Pré-Escolar , Ecocardiografia , Feminino , Insuficiência Cardíaca/epidemiologia , Hospitalização , Humanos , Masculino , Fatores de Risco , Taxa de Sobrevida
15.
Mayo Clin Proc ; 95(7): 1354-1368, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32448590

RESUMO

OBJECTIVE: To explore the transcriptomic differences between patients with hypertrophic cardiomyopathy (HCM) and controls. PATIENTS AND METHODS: RNA was extracted from cardiac tissue flash frozen at therapeutic surgical septal myectomy for 106 patients with HCM and 39 healthy donor hearts. Expression profiling of 37,846 genes was performed using the Illumina Human HT-12v3 Expression BeadChip. All patients with HCM were genotyped for pathogenic variants causing HCM. Technical validation was performed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. This study was started on January 1, 1999, and final analysis was completed on April 20, 2020. RESULTS: Overall, 22% of the transcriptome (8443 of 37,846 genes) was expressed differentially between HCM and control tissues. Analysis by genotype revealed that gene expression changes were similar among genotypic subgroups of HCM, with only 4% (1502 of 37,846) to 6% (2336 of 37,846) of the transcriptome exhibiting differential expression between genotypic subgroups. The qRT-PCR confirmed differential expression in 92% (11 of 12 genes) of tested transcripts. Notably, in the context of coronavirus disease 2019 (COVID-19), the transcript for angiotensin I converting enzyme 2 (ACE2), a negative regulator of the angiotensin system, was the single most up-regulated gene in HCM (fold-change, 3.53; q-value =1.30×10-23), which was confirmed by qRT-PCR in triplicate (fold change, 3.78; P=5.22×10-4), and Western blot confirmed greater than 5-fold overexpression of ACE2 protein (fold change, 5.34; P=1.66×10-6). CONCLUSION: More than 20% of the transcriptome is expressed differentially between HCM and control tissues. Importantly, ACE2 was the most up-regulated gene in HCM, indicating perhaps the heart's compensatory effort to mount an antihypertrophic, antifibrotic response. However, given that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 for viral entry, this 5-fold increase in ACE2 protein may confer increased risk for COVID-19 manifestations and outcomes in patients with increased ACE2 transcript expression and protein levels in the heart.


Assuntos
Betacoronavirus , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/virologia , Infecções por Coronavirus/complicações , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Adolescente , Adulto , Idoso , Cardiomiopatia Hipertrófica/metabolismo , Estudos de Casos e Controles , Criança , Genótipo , Humanos , Pessoa de Meia-Idade , Miocárdio/metabolismo , Pandemias , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Adulto Jovem
16.
PLoS One ; 15(5): e0232427, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32369506

RESUMO

Hypertrophic cardiomyopathy (HCM) is the most frequent genetic cardiac disease with a prevalence of 1:500 to 1:200. While most patients show obstructive HCM and a relatively stable clinical phenotype (stage II), a small group of patients progresses to end-stage HCM (stage IV) within a relatively brief period. Previous research has shown sex-differences in stage II HCM with more diastolic dysfunction in female than in male patients. Moreover, female patients more often show progression to heart failure. Here we investigated if differences in functional and structural properties of the heart may underlie sex-differences in disease progression from stage II to stage IV HCM. Cardiac tissue from stage II and IV patients was obtained during myectomy (n = 54) and heart transplantation (n = 10), respectively. Isometric force was measured in membrane-permeabilized cardiomyocytes to define active and passive myofilament force development. Titin isoform composition was assessed using gel electrophoresis, and the amount of fibrosis and capillary density were determined with histology. In accordance with disease stage-dependent adverse cardiac remodeling end-stage patients showed a thinner interventricular septal wall and larger left ventricular and atrial diameters compared to stage II patients. Cardiomyocyte contractile properties and fibrosis were comparable between stage II and IV, while capillary density was significantly lower in stage IV compared to stage II. Women showed more adverse cellular remodeling compared to men at stage II, evident from more compliant titin, more fibrosis and lower capillary density. However, the disease stage-dependent reduction in capillary density was largest in men. In conclusion, the more severe cellular remodeling in female compared to male stage II patients suggests a more advanced disease stage at the time of myectomy in women. Changes in cardiomyocyte contractile properties do not explain the progression of stage II to stage IV, while reduced capillary density may underlie disease progression to end-stage heart failure.


Assuntos
Cardiomiopatia Hipertrófica/patologia , Remodelação Ventricular/fisiologia , Adolescente , Adulto , Idoso , Capilares/patologia , Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Criança , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Cadeias Pesadas de Miosina/genética , Fatores de Risco , Caracteres Sexuais , Troponina T/genética , Remodelação Ventricular/genética , Adulto Jovem
17.
Zhonghua Xin Xue Guan Bing Za Zhi ; 48(4): 287-293, 2020 Apr 24.
Artigo em Chinês | MEDLINE | ID: mdl-32370479

RESUMO

Objective: To evaluate the cardiac functional changes in hypertrophic cardiomyopathy(HCM) patients with ß-myosin heavy chain gene (MYH7) mutations by three-dimensional (3D) speckle tracking imaging(3D-STI) and conventional echocardiography modalities, and then to explore the potential predictors of adverse cardiovascular events in these patients. Methods: A consecutive series of 192 HCM patients admitted in our center from October 2014 to October 2016 were genetically screened to identify MYH7 mutations in this retrospective study. A total of 43 HCM patients with MYH7 mutations were enrolled. The patients were divided into events group(n=13) and no event group(n=30) according to the presence or absence of adverse cardiovascular events(primary and secondary endpoints). All patients were followed up to January 2019 after comprehensive evaluation of 3D-STI, two-dimensional and Doppler echocardiography. The adverse cardiovascular events were recorded. Results: The median follow up time was 1 012 (812, 1 330) days. During follow-up, 13 patients (30.2%) reached endpoints: 6 cases of the primary endpoints(2 cases of sudden cardiac death(SCD), 3 cases of survival after defibrillation, and 1 case of appropriate implantable cardioverter-defibrillator(ICD) discharge); 7 cases of the second endpoints(5 cases of heart failure hospitalization, 1 case of syncope and cardioversion due to supraventricular tachycardia, and 1 case of end-stage HCM). Patients with adverse cardiovascular events had higher prevalence of syncope and risk of SCD, enlarged left atrial volume index(LAVI) and reduced 3D left ventricular global longitudinal train (3D-GLS), as compared to those without adverse events(all P<0.05). The multivariate Cox regression analysis showed that reduced 3D-GLS(HR=0.814, 95%CI 0.663-0.999, P=0.049) was an independent predictor for adverse cardiovascular events. The cutoff value of 3D-GLS≤13.67% was linked with significantly increased risk of adverse cardiovascular events in this patient cohort(AUC=0.753, 95%CI 0.558-0.948, sensitivity 86%, specificity 69%, P<0.05). The Kaplan-Meier analysis indicated that the patients with the 3D-GLS≤ 13.67% faced higher risk of death than those with 3D-GLS>13.67%. Conclusion: 3D-GLS is useful on predicting adverse cardiovascular events in HCM patients with MYH7 mutations.


Assuntos
Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica , Cadeias Pesadas de Miosina/genética , Cardiomiopatia Hipertrófica/genética , Ecocardiografia , Humanos , Mutação , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco
18.
PLoS Genet ; 16(5): e1008639, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453731

RESUMO

Hypertrophic cardiomyopathy (HCM) is characterized by thickening of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the most C-terminal of the three EF-hand domains in MYL2. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and the infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2-fs variant showed a marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stop-gain variants (p.E22*, p.K62*, p.E97*) that result in loss of the EF domains are stably expressed but show impaired localization. The degradation of the MYL2-fs can be rescued by inhibiting the cell's proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2-homolog (Mlc2) knockdown model indicate that neither the MYL2-fs nor the MYL2:p.Gly162Arg variant supports normal cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants in infantile HCM and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathy.


Assuntos
Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica/genética , Família , Mutação da Fase de Leitura , Cadeias Leves de Miosina/genética , Adulto , Animais , Animais Geneticamente Modificados , Cardiomiopatia Hipertrófica/classificação , Cardiomiopatia Hipertrófica/congênito , Cardiomiopatia Hipertrófica/patologia , Células Cultivadas , Consanguinidade , Drosophila , Evolução Fatal , Feminino , Genes Dominantes , Genes Recessivos , Heterozigoto , Humanos , Lactente , Morte do Lactente , Recém-Nascido , Masculino , Linhagem , Fenótipo , Irmãos
19.
Open Heart ; 7(1): e001220, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32341788

RESUMO

Objective: The myosin-binding protein C (MYBPC3) c.927-2A>G founder mutation accounts for >90% of sarcomeric hypertrophic cardiomyopathy (HCM) in Iceland. This cross-sectional observational study explored the penetrance and phenotypic burden among carriers of this single, prevalent founder mutation. Methods: We studied 60 probands with HCM caused by MYBPC3 c.927-2A>G and 225 first-degree relatives. All participants underwent comprehensive clinical evaluation and relatives were genotyped. Results: Genetic and clinical evaluation of relatives identified 49 genotype-positive (G+) relatives with left ventricular hypertrophy (G+/LVH+), 59 G+without LVH (G+/LVH-) and 117 genotype-negative relatives (unaffected). Compared with HCM probands, G+/LVH+ relatives were older at HCM diagnosis, had less LVH, a less prevalent diastolic dysfunction, fewer ECG abnormalities, lower serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I levels, and fewer symptoms. The penetrance of HCM was influenced by age and sex; specifically, LVH was present in 39% of G+males but only 9% of G+females under age 40 years (p=0.015), versus 86% and 83%, respectively, after age 60 (p=0.89). G+/LVH- subjects had normal wall thicknesses, diastolic function and NT-proBNP levels, but subtle changes in LV geometry and more ECG abnormalities than their unaffected relatives. Conclusions: Phenotypic expression of the Icelandic MYBPC3 founder mutation varies by age, sex and proband status. Men are more likely to have LVH at a younger age, and disease manifestations were more prominent in probands than in relatives identified via family screening. G+/LVH- individuals had subtle clinical differences from unaffected relatives well into adulthood, indicating subclinical phenotypic expression of the pathogenic mutation.


Assuntos
Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Efeito Fundador , Heterozigoto , Mutação , Sarcômeros/genética , Função Ventricular Esquerda/genética , Remodelação Ventricular/genética , Adulto , Idade de Início , Idoso , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/fisiopatologia , Estudos Transversais , Feminino , Predisposição Genética para Doença , Hemodinâmica/genética , Hereditariedade , Humanos , Islândia , Masculino , Pessoa de Meia-Idade , Linhagem , Penetrância , Fenótipo , Fatores de Risco
20.
Cardiovasc J Afr ; 31(4): 180-184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32159583

RESUMO

BACKGROUND: Isolated left ventricular non-compaction (ILVNC), dilated cardiomyopathy (DCMO) and hypertrophic cardiomyopathy (HCM) are diseases that may be present in family members of patients with ILVNC. The primary aim of this study was to identify the prevalence and spectrum of cardiomyopathy in first-degree relatives of patients with ILVNC. A secondary aim was to compare a strategy of clinical screening, utilising only a clinical assessment and electrocardiogram (ECG), compared to one that included echocardiography for screening of family members of patients with ILVNC. METHODS: Eighty-three close relatives of 38 unrelated patients from the ILVNC clinic at the Chris Hani Baragwanath Hospital underwent a detailed clinical history, physical examination, ECG and echocardiogram. RESULTS: Echocardiographic screening revealed unexplained left ventricular (LV) dysfunction in 10 (12.05%) relatives. Nine out of the 10 individuals satisfied the criteria for diagnosis of DCMO. No cases of HCM or LVNC were identified. A strategy of clinical assessment and ECG had a sensitivity of 76% and a specificity of 42% versus the gold standard of echocardiographic screening. CONCLUSIONS: Echocardiographic screening detected DCMO in 10.8% of subjects. A strategy of clinical screening that included electrocardiography was sub-optimal as a screening strategy compared to echocardiographic screening.


Assuntos
Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Hipertrófica/diagnóstico , Ecocardiografia , Eletrocardiografia , Frequência Cardíaca , Miocárdio Ventricular não Compactado Isolado/diagnóstico , Função Ventricular Esquerda , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Cardiomiopatia Dilatada/etnologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Hipertrófica/etnologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Feminino , Predisposição Genética para Doença , Frequência Cardíaca/genética , Hereditariedade , Humanos , Miocárdio Ventricular não Compactado Isolado/etnologia , Miocárdio Ventricular não Compactado Isolado/genética , Miocárdio Ventricular não Compactado Isolado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Valor Preditivo dos Testes , Prevalência , Estudos Retrospectivos , África do Sul/epidemiologia , Função Ventricular Esquerda/genética , Adulto Jovem
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