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1.
Br J Radiol ; 92(1104): 20190634, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31613647

RESUMO

OBJECTIVE: The aim of this study was to examine the local myocardial segments in hypertrophic cardiomyopathy (HCM) by MRI T1 and T2 mapping, and to investigate how tissue remodeling correlates with structural and functional remodeling in HCM. METHODS: 47 patients with HCM and 19 healthy volunteers were enrolled in this study. All subjects underwent cardiac MRI at 3.0 T. Native T1 and T2 values, end-diastolic wall thickness (EDTH), and percentage of systolic wall thickening (PSWT) were assessed in the left ventricular segments according to the American Heart Association model. Myocardial segments were categorized as normal, non-hypertrophic, mild-hypertrophic, moderate-hypertrophic, and severe-hypertrophic based on EDTH. The difference among all five groups, and the correlation between native T1 and T2 values, EDTH, and PSWT were evaluated. RESULTS: Native T1 and T2 values were significantly elevated in both non-hypertrophic and hypertrophic segments of HCM patients compared to controls (both p < 0.001). PSWT was preserved in non-hypertrophic segments (p = 0.838), while significantly impaired (p < 0.001) in hypertrophic segments. Native T1 value of severe hypertrophic segments in HCM was significantly higher than segments of mild and moderate hypertrophy (p < 0.05). CONCLUSION: In HCM patients, the non-hypertrophic myocardial segments already demonstrated significantly elevated T1 and T2 values, despite normal wall thickness and preserved contraction function. The finding suggests that tissue remodeling may precede morphological and functional remodeling in HCM. MRI native T1 and T2 mapping can provide additional value for HCM diagnosis at an early stage. ADVANCES IN KNOWLEDGE: Myocardial tissue remodeling, as detected by MRI native T1 and T2 mapping, occurs earlier than morphological and functional changes in HCM patients.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico por imagem , Coração/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Miocárdio/patologia , Adulto , Cardiomiopatia Hipertrófica/patologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
2.
Medicine (Baltimore) ; 98(27): e16183, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277123

RESUMO

RATIONALE: Apical hypertrophic cardiomyopathy (AHCM) is a rare form of hypertrophic cardiomyopathy which affects predominantly the apex of the left ventricle. Generally, left ventricular enlargement is not present in AHCM; additionally, endomyocardial fibrosis, and calcification are also rare. PATIENT CONCERNS: A 61-year-old female (Case 1) and a 60-year-old female (Case 2) both presented with the symptoms of atypical chest pain, dyspnoea, exercise intolerance, palpitations. DIAGNOSIS: Magnetic resonance and single-photon emission computed tomography (SPECT) revealed apical hypertrophic cardiomyopathy. Furthermore, 2D-transthoracic echocardiogram showed left atrium and ventricular enlargement, as well as endomyocardial fibrosis and calcification. Based on these findings, the patients were diagnosed with AHCM. INTERVENTIONS: Both the patients were treated with ACEI, metoprolol, and aspirin. Additionally, both these patient underwent genetic test. OUTCOMES: The results of the genetic test of the 2 cases for hypertrophic cardiomyopathy (HCM) were negative. However, the gene mutation for dilated cardiomyopathy (TMPO) was detected in one of the cases. No change in condition during follow-up. LESSONS: In past reports, Apical hypertrophic cardiomyopathy has been shown to have a benign prognosis. But in this case report, the imaging studies of the 2 patients suggest a poor prognosis. Furthermore, diagnosing cardiomyopathy should require multimodality imaging examinations to rule out differential diagnoses.


Assuntos
Calcinose/complicações , Cardiomiopatia Hipertrófica/complicações , Fibrose Endomiocárdica/complicações , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Aspirina/uso terapêutico , Calcinose/diagnóstico por imagem , Calcinose/tratamento farmacológico , Calcinose/patologia , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/patologia , Ecocardiografia , Eletrocardiografia , Fibrose Endomiocárdica/diagnóstico por imagem , Fibrose Endomiocárdica/tratamento farmacológico , Feminino , Humanos , Imagem por Ressonância Magnética , Metoprolol/uso terapêutico , Pessoa de Meia-Idade , Tomografia Computadorizada de Emissão de Fóton Único
3.
Life Sci ; 232: 116635, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31283925

RESUMO

AIMS: The pathological cardiac hypertrophy will develop into heart failure, which has no effective treatment currently. Previous studies have proved that microRNAs (miRNAs) participate in the development of cardiac hypertrophy and regulate the pathological progress. In this study, we want to investigate the role of microRNA-92b-3p (miR-92b-3p) in cardiomyocyte hypertrophy and the mechanisms involved. MATERIALS AND METHODS: Neonatal mouse ventricular cells (NMVCs) were isolated from the hearts of 1-3-d-old newborn C57BL6 mice. The isolated NMVCs were induced hypertrophic phenotype by Angiotensin-II (Ang-II) and the cell size was examined by FITC-phalloidin staining assay. The expression of miR-92b-3p was determined by quantitative real-time PCR (qRT-qPCR). MRNA and protein level of ß-MHC, ACTA1 and HAND2 in NMVCs transfected with miR-92b-3p mimic and inhibition were assessed by RT-qPCR assay and western blot assay, respectively. Dual luciferase assay was used to verify the interaction between miR-92b-3p and the 3'-untranslated region (UTR) of HAND2 gene. KEY FINDINGS: MiR-92b-3p and HAND2 were significantly increased in Ang-II-induced NMVCs. Overexpression of miR-92b-3p can ameliorate Ang-II-induced cardiomyocyte hypertrophy. MiR-92b-3p negatively regulated HAND2 expression at the transcriptional level. Both miR-92b-3p mimic and HAND2 siRNA could efficiently inhibit Ang-II-induced hypertrophy in mouse cardiomyocytes. SIGNIFICANCE: MiR-92b-3p inhibits Ang-II-induced cardiomyocyte hypertrophy via targeting HAND2.


Assuntos
Angiotensina II/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/patologia , Regiões 3' não Traduzidas , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Modelos Animais de Doenças , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Ventrículos do Coração/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
5.
J Cardiovasc Med (Hagerstown) ; 20(6): 389-396, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30994509

RESUMO

AIMS: Left ventricular outflow tract (LVOT) obstruction is a key feature of hypertrophic cardiomyopathy (HCM) that identifies patients at increased risk of adverse outcomes. Previous studies have hypothesized that LVOT obstruction enhances myocardial fibrosis and increases left ventricular (LV) filling pressures, producing greater clinical deterioration. However, this hypothesis has not been demonstrated in a clinical cohort comparing obstructive and nonobstructive patients. METHODS: Patients with HCM in whom Doppler echocardiography was performed within 30 days of cardiac MRI were enrolled, using the E/e' ratio to assess LV diastolic function and late gadolinium enhancement to evaluate the extent of fibrosis. Data were assorted according to LVOT obstruction status at rest. RESULTS: The current study enrolled 67 patients who were mostly middle-aged (56.8 ±â€Š13.2 years old) men (75%) with preserved ejection fraction. Obstructive HCM presented a significant association with a high fibrosis extent [odds ratio (OR) 3.33; P = 0.034] which was maintained after adjusting for sex and age (OR 4.37; P = 0.016) but not for maximum LV wall thickness (OR 2.13; P = 0.225). Obstructive HCM was also associated with a clinically significant E/e' ratio more than 14 (OR 7.8; P = 0.001) which decreased slightly after adjusting for age, sex and maximum LV thickness (OR 6.54; P = 0.014). There was a significant association between an E/e' ratio more than 14 and the extent of fibrosis (OR 1.29; P < 0.001) which was maintained after adjusting for age, sex and maximum LV wall thickness (OR 1.36; P = 0.001). CONCLUSION: LVOT obstruction may play a role in the extent of fibrosis in HCM, possibly conditioning greater diastolic dysfunction.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico por imagem , Ecocardiografia Doppler , Imagem Cinética por Ressonância Magnética , Miocárdio/patologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Função Ventricular Esquerda , Obstrução do Fluxo Ventricular Externo/diagnóstico por imagem , Remodelação Ventricular , Adulto , Idoso , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Estudos Transversais , Feminino , Fibrose , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Volume Sistólico , Fatores de Tempo , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Obstrução do Fluxo Ventricular Externo/patologia , Obstrução do Fluxo Ventricular Externo/fisiopatologia , Pressão Ventricular
6.
Am J Cardiol ; 124(1): 113-121, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31027655

RESUMO

Advances in treatment options for hypertrophic cardiomyopathy (HC) have proven effective in many patients for promoting favorable long-term outcomes. Whether this expectation is similar for patients with the most extreme expression of massive left ventricular (LV) hypertrophy, a particularly aggressive form of the disease is unresolved. Of 1,766 consecutive HC patients presenting to Tufts HC Institute (2004 to 2015), 92 were identified with extreme LV wall thickness (30 to 48 mm), and compared with 1,674 HC patients with less marked hypertrophy (13 to 29 mm). Follow-up assessment was over 5.3 ± 3.4 years. Patients with massive LV hypertrophy (n = 92) had higher sudden death event rates (3.0%/year) than did patients with lesser hypertrophy (0.8%/year; p <0.001). In 16 of the 92 patients (17%), potentially lethal ventricular tachyarrhythmia were successfully aborted by primary prevention implantable cardioverter defibrillator (ICD) therapy at 30 ± 13 years (n = 11), or by resuscitated cardiac arrest with external defibrillation (n = 5) and later by secondary prevention interventions (n = 3); no patient experienced arrhythmic sudden death. Aborted sudden death events (3.0%/year) exceeded HC-related mortality by 7-fold (n = 2; 0.4%/year; p <0.001). European Society of Cardiology risk score would have failed to identify 60% of patients with arrhythmic sudden death events, leaving them exposed to sudden death without ICDs. In addition, 35 patients required surgical myectomy for progressive heart failure due to LV outflow obstruction (improved to NYHA I/II in 30). Eighty-eight (96%) of the 92 patients have survived to age 38 ± 14 years (23% ≥ 50 years). All-cause mortality did not differ from an age and gender-matched general population (p = 0.62). In conclusion, in this referral-based population, patients with the most extreme expression of HC are at increased arrhythmic sudden death risk reliably prevented with prophylactic ICDs. Progressive heart failure secondary to outflow obstruction was reversible with surgical myectomy. Despite extreme phenotypic expression, with contemporary treatment interventions young HC patients have an opportunity to achieve extended survival with good quality of life.


Assuntos
Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/terapia , Adolescente , Adulto , Cardiomiopatia Hipertrófica/mortalidade , Criança , Estudos de Coortes , Gerenciamento Clínico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
7.
Cells ; 8(4)2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965672

RESUMO

Fabry disease (FD) is a rare inherited disorder characterized by a wide range of systemic symptoms; it is particularly associated with cardiovascular and renal problems. Enzyme replacement therapy and pharmacological chaperone migalastat are the only approved and effective treatment strategies for FD patients. It is well documented that alpha-galactosidase A (GLA) enzyme activity deficiency causes globotriaosylceramide (Gb3) accumulation, which plays a crucial role in the etiology of FD. However, the detailed mechanisms remain unclear, and the lack of a reliable and powerful disease model is an obstacle. In this study, we created such a model by using CRISPR/Cas9-mediated editing of GLA gene to knockout its expression in human embryonic stem cells (hESCs). The cardiomyocytes differentiated from these hESCs (GLA-null CMs) were characterized by the accumulation of Gb3 and significant increases of cell surface area, the landmarks of FD-associated cardiomyopathy. Furthermore, we used mass spectrometry to compare the proteomes of GLA-null CMs and parental wild type CMs and found that the Rab GTPases involved in exocytotic vesicle release were significantly downregulated. This caused impairment of autophagic flux and protein turnover, resulting in an increase of reactive oxygen species and apoptosis. To summarize, we established a FD model which can be used as a promising tool to study human hypertrophic cardiomyopathy in a physiologically and pathologically relevant manner and to develop new therapies by targeting Rab GTPases signaling-related exosomal vesicles transportation.


Assuntos
Autofagia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Doença de Fabry/complicações , Modelos Biológicos , alfa-Galactosidase/genética , Apoptose , Sistemas CRISPR-Cas , Cardiomiopatia Hipertrófica/etiologia , Linhagem Celular , Exossomos , Técnicas de Inativação de Genes , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Miócitos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Triexosilceramidas/metabolismo
8.
J Vet Med Sci ; 81(5): 734-738, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-30944272

RESUMO

Beta-blockers are used to treat cats with hypertrophic obstructive cardiomyopathy (HOCM). However, there are various hemodynamic responses to beta-blockers. This retrospective study aimed to explore the relationship between the response to carvedilol and the presence of geometric abnormalities. Medical records were reviewed for 16 cats diagnosed with HOCM. Cats were divided into two groups based on the velocity of the left-ventricular outflow-tract after carvedilol treatment (responder: eight cats, non-responder: eight cats). Baseline intergroup comparison revealed that anterior mitral valve leaflet length and diastolic left-ventricular posterior-wall thickness were significantly greater in the non-responder group. Longer anterior mitral valve leaflet and thicker left-ventricular posterior-wall may cause poor response to carvedilol. Thus, these properties may predict a lack of response to carvedilol therapy.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Cardiomiopatia Hipertrófica/veterinária , Carvedilol/uso terapêutico , Doenças do Gato/tratamento farmacológico , Valva Mitral/patologia , Animais , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/patologia , Gatos , Ecocardiografia/veterinária , Feminino , Masculino , Estudos Retrospectivos
9.
Vet Pathol ; 56(4): 565-575, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30895910

RESUMO

vHypertrophic cardiomyopathy (HCM) is the most commonly diagnosed cardiac disease in cats. The complex pathophysiology of HCM is still far from clear, but myocardial remodeling is a key process, and cardiomyocyte disarray, interstitial fibrosis, leukocyte infiltration, and vascular dysplasia are described histopathologic features. The present study systematically investigated the pathological processes in HCM, with the aim to shed more light on its pathogenesis. Hearts from 18 HCM cases and 18 cats without cardiac disease (controls) were examined, using light and transmission electron microscopy, immunohistochemistry, and morphometric approaches to identify and quantify the morphological changes. Reverse transcription-quantitative polymerase chain reaction was applied to provide additional mechanistic data on remodeling processes. In HCM, the left and right ventricular free wall and septal myocardium exhibited a significantly reduced overall cellularity, accompanied by a significant increase in interstitial Iba1-positive cells with macrophage morphology. In addition, the myocardium of almost half of the diseased hearts exhibited areas where cardiomyocytes were replaced by cell-rich fibrous tissue with abundant small and medium-sized vessels. HCM hearts also showed significantly higher transcription levels for several inflammatory and profibrotic mediators. Our findings suggest that HCM is the consequence of cardiac remodeling processes that are the result of cardiomyocyte damage and to which macrophages contribute by maintaining an inflammatory and profibrotic environment.


Assuntos
Cardiomiopatia Hipertrófica/veterinária , Doenças do Gato/patologia , Animais , Cardiomiopatia Hipertrófica/patologia , Gatos , Feminino , Imuno-Histoquímica/veterinária , Macrófagos/patologia , Masculino , Miocárdio/patologia , Miócitos Cardíacos/patologia , Remodelação Ventricular
10.
Int J Cardiovasc Imaging ; 35(7): 1347-1355, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30838504

RESUMO

Myocardial crypts can be recognized in patients with hypertrophic cardiomyopathy (HCM) using magnetic resonance imaging, but similar studies using computed tomography (CT) are sparse. The aim of the present study was to evaluate the prevalence and morphology of myocardial crypts in patients with HCM, arterial hypertension, and aortic valve stenosis using contrast-enhanced CT. We also investigated the added value of a finding of myocardial crypts on CT scan to the diagnosis of HCM. The study cohort included 73 patients with HCM, 100 patients with arterial hypertension, 120 patients with aortic valve stenosis, and 100 subjects without cardiovascular disease (normal control group). All underwent evaluation for the presence and dimensions of myocardial crypts using 256-slice CT. Crypts were identified in 18 patients (24.7%) with HCM, 7 patients (7%) with hypertension, 8 patients (6.7%) with aortic valve stenosis, and 4 (4%) normal subjects (P < 0.001). Values of crypt length, width, area, and penetration into myocardium were highest in the HCM group. Crypt area differentiated patients with HCM from patients with arterial hypertension and aortic valve stenosis, and from normal control subjects. Crypt area was an accurate predictor of HCM, with an area under the receiver-operator characteristic curve of 0.88 (95% CI 0.80-0.96). Myocardial crypts identified by CT are more prevalent and larger in area in HCM than in arterial hypertension and aortic valve stenosis. Crypt area could potentially help to improve the diagnosis of HCM by CT beyond the assessment of left ventricular thickness or mass.


Assuntos
Estenose da Valva Aórtica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Angiografia por Tomografia Computadorizada/métodos , Angiografia Coronária/métodos , Ventrículos do Coração/diagnóstico por imagem , Hipertensão/diagnóstico por imagem , Tomografia Computadorizada Multidetectores/métodos , Miocárdio/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/epidemiologia , Estenose da Valva Aórtica/patologia , Técnicas de Imagem de Sincronização Cardíaca , Cardiomiopatia Hipertrófica/epidemiologia , Cardiomiopatia Hipertrófica/patologia , Diagnóstico Diferencial , Eletrocardiografia , Feminino , Ventrículos do Coração/patologia , Humanos , Hipertensão/epidemiologia , Hipertensão/patologia , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Estudos Retrospectivos
11.
Orphanet J Rare Dis ; 14(1): 29, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30732632

RESUMO

BACKGROUND: The RASopathies are a class of developmental disorders caused by germline mutations in the RAS-mitogen-activated protein kinase (MAPK) pathway. Hypertrophic cardiomyopathy (HCM) has been frequently described in children with RASopathy, but only a minority of patients have received formal genotyping. The purpose of this study was to evaluate the genetic basis and clinical outcome of pediatric patients with RASopathy-associated HCM. METHODS: We retrospectively reviewed the mutation spectrum and clinical outcome of all the patients with RASopathy derived from 168 pediatric HCM cases referred to our institution between January 2012 and July 2018. RESULTS: A heterozygous missense mutation in one of known RASopathy genes was identified in 46 unrelated children with HCM. Mutations in the PTPN11 gene were the most prevalent (19/46); this was followed by mutations in RAF1 (11/46), KRAS (5/46), RIT1 (4/46), BRAF (3/46), SOS1 (2/46), HRAS (1/46), and SHOC2 (1/46). Moreover, two compound heterozygous missense mutations in the LZTR1 gene were identified in one patient with the Noonan syndrome phenotype and HCM. The median age at the diagnosis of HCM was 3.0 months (range 0 months to 8.1 years). Twenty-one of the patients had significant left ventricular outflow tract obstruction and 32 had concomitant congenital heart disease. Three patients with a mutation in exon 13 of the PTPN11 gene died of cardiac failure at the ages of 3.0, 3.5, and 6.0 months. The remaining 44 patients were alive after an average follow-up time of 3.9 years (0.5 to 17.1 years, median 2.9 years) from the initial diagnosis of HCM, including 5 patients with spontaneous regression of their cardiac hypertrophy. CONCLUSIONS: RASopathy-associated HCM is a heterogeneous genetic condition characterized by early-onset cardiac hypertrophy and a high prevalence of co-existing congenital heart disease, which is most frequently related to specific mutations in the PTPN11 gene. Rapidly progressive HCM, resulting in an early death, is uncommon in RASopathy patients except those with specific mutations in exon 13 of the PTPN11 gene.


Assuntos
Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Proteínas Quinases Ativadas por Mitógeno/genética , Criança , Pré-Escolar , Estudos de Coortes , Éxons/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação de Sentido Incorreto/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Estudos Retrospectivos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
12.
Cells ; 8(2)2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30699940

RESUMO

During the development of hypertrophic cardiomyopathy, the heart returns to fetal energy metabolism where cells utilize more glucose instead of fatty acids as a source of energy. Metabolism of glucose can increase synthesis of the extracellular glycosaminoglycan hyaluronan, which has been shown to be involved in the development of cardiac hypertrophy and fibrosis. The aim of this study was to investigate hyaluronan metabolism in cardiac tissue from patients with hypertrophic cardiomyopathy in relation to cardiac growth. NMR and qRT-PCR analysis of human cardiac tissue from hypertrophic cardiomyopathy patients and healthy control hearts showed dysregulated glucose and hyaluronan metabolism in the patients. Gas phase electrophoresis revealed a higher amount of low molecular mass hyaluronan and larger cardiomyocytes in cardiac tissue from patients with hypertrophic cardiomyopathy. Histochemistry showed high concentrations of hyaluronan around individual cardiomyocytes in hearts from hypertrophic cardiomyopathy patients. Experimentally, we could also observe accumulation of low molecular mass hyaluronan in cardiac hypertrophy in a rat model. In conclusion, the development of hypertrophic cardiomyopathy with increased glucose metabolism affected both hyaluronan molecular mass and amount. The process of regulating cardiomyocyte size seems to involve fragmentation of hyaluronan.


Assuntos
Cardiomiopatia Hipertrófica/metabolismo , Ácido Hialurônico/metabolismo , Miocárdio/metabolismo , Animais , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Tamanho Celular , Análise Fatorial , Feminino , Regulação da Expressão Gênica , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Septos Cardíacos/cirurgia , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Peso Molecular , Miocárdio/patologia , Miócitos Cardíacos/patologia , Ratos Wistar
13.
Int J Cardiovasc Imaging ; 35(7): 1309-1318, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30790116

RESUMO

Hypertrophic cardiomyopathy (HCM) is associated with increased left ventricular (LV) mass, decreased myocardial strain, and the presence of LV fibrosis and scar. The relationship between LV scar and fibrosis with left atrial (LA) fibrosis in the setting of HCM has not been examined. The purpose of this study is to demonstrate a correlation between the degree of LA fibrosis and LV parameters in subjects with HCM. Twenty-eight subjects with HCM were imaged on a 1.5T MRI scanner with cine, LV and LA late gadolinium enhancement (LGE) sequences. LA LGE and LA measurements were correlated with LV measurements of volumes, mass, strain, and LGE. Other clinical conditions and medication usage were also examined and evaluated for correlation with LA and LV parameters. LV LGE was identified in 24 (86%) of the cases and LA LGE was identified in all of the cases. Extent of LA fibrosis significantly correlated with percent LV LGE (r = 0.64, p = 0.001), but not with indexed LV mass or maximum wall thickness. Extent of LA fibrosis also moderately correlated with decreased LV global strain (radial, r = - 0.50, p = 0.013; circumferential, r = 0.47, p = 0.02; longitudinal, r = 0.52, p = 0.013). Increased LA systolic volume correlated moderately with LV end diastolic volume (r = 0.50, p = 0.006). Patients on therapy with Renin-Angiotensin-Aldosterone System (RAAS) Inhibition had significantly less LA LGE compared to those without (18.6% vs 10.8%, p = 0.023). LA fibrosis, as measured by LGE, is prevalent in HCM and is correlated with LV LGE. The correlation between LA and LV LGE might suggest either that LA fibrosis is a consequence of LV remodeling, or that LA and LV fibrosis are both manifestations of the same cardiomyopathic process. Further study is warranted to determine the causality of LA scar in this population.


Assuntos
Função do Átrio Esquerdo , Remodelamento Atrial , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Átrios do Coração/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Disfunção Ventricular Esquerda/diagnóstico por imagem , Função Ventricular Esquerda , Remodelação Ventricular , Adulto , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Função do Átrio Esquerdo/efeitos dos fármacos , Remodelamento Atrial/efeitos dos fármacos , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Meios de Contraste/administração & dosagem , Feminino , Fibrose , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos/administração & dosagem , Valor Preditivo dos Testes , Estudos Retrospectivos , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
14.
Pediatr Dev Pathol ; 22(4): 386-390, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30665336

RESUMO

Noonan syndrome is a genetic condition with a heterogeneous phenotype and multisystem involvement. The pathogenesis of this disorder has been attributed to the mutations in the RAS/MAPK signaling pathway involved in cell proliferation and differentiation. The most common clinical presentations are related to cardiovascular abnormalities with congestive heart failure as the most common mechanism of death. We present the autopsy findings from a Noonan syndrome patient who died as a result of an unusual form of right ventricular obstruction associated with a rare PTPN11 variant previously reported without details of the cardiac findings. Discussion follows that includes overview of the incidence, genetic causes, types of right-sided obstructive lesions, PTPN11 genotype-cardiac phenotype correlations, and other potential mechanisms that may contribute to disease heterogeneity.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Síndrome de Noonan/diagnóstico , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Transdução de Sinais/genética , Autopsia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Humanos , Recém-Nascido , Masculino , Mutação , Mutação de Sentido Incorreto , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Fenótipo
15.
Genome Med ; 11(1): 5, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696458

RESUMO

BACKGROUND: International guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false-positive rate over test sensitivity and diagnostic yield. Genetic testing is also more likely informative in individuals with well-characterised variants from extensively studied European-ancestry populations. Inherited cardiomyopathies are relatively common Mendelian diseases that allow empirical calibration and assessment of this framework. METHODS: We compared rare variants in large hypertrophic cardiomyopathy (HCM) cohorts (up to 6179 cases) to reference populations to identify variant classes with high prior likelihoods of pathogenicity, as defined by etiological fraction (EF). We analysed the distribution of variants using a bespoke unsupervised clustering algorithm to identify gene regions in which variants are significantly clustered in cases. RESULTS: Analysis of variant distribution identified regions in which variants are significantly enriched in cases and variant location was a better discriminator of pathogenicity than generic computational functional prediction algorithms. Non-truncating variant classes with an EF ≥ 0.95 were identified in five established HCM genes. Applying this approach leads to an estimated 14-20% increase in cases with actionable HCM variants, i.e. variants classified as pathogenic/likely pathogenic that might be used for predictive testing in probands' relatives. CONCLUSIONS: When found in a patient confirmed to have disease, novel variants in some genes and regions are empirically shown to have a sufficiently high probability of pathogenicity to support a "likely pathogenic" classification, even without additional segregation or functional data. This could increase the yield of high confidence actionable variants, consistent with the framework and recommendations of current guidelines. The techniques outlined offer a consistent and unbiased approach to variant interpretation for Mendelian disease genetic testing. We propose adaptations to ACMG/AMP guidelines to incorporate such evidence in a quantitative and transparent manner.


Assuntos
Cardiomiopatia Hipertrófica/genética , Testes Genéticos/normas , Mutação , Cardiomiopatia Hipertrófica/patologia , Humanos , Guias de Prática Clínica como Assunto
16.
Genet Med ; 21(7): 1576-1584, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30531895

RESUMO

PURPOSE: Increasing numbers of genes are being implicated in Mendelian disorders and incorporated into clinical test panels. However, lack of evidence supporting the gene-disease relationship can hinder interpretation. We explored the utility of testing 51 additional genes for hypertrophic cardiomyopathy (HCM), one of the most commonly tested Mendelian disorders. METHODS: Using genome sequencing data from 240 sarcomere gene negative HCM cases and 6229 controls, we undertook case-control and individual variant analyses to assess 51 genes that have been proposed for HCM testing. RESULTS: We found no evidence to suggest that rare variants in these genes are prevalent causes of HCM. One variant, in a single case, was categorized as likely to be pathogenic. Over 99% of variants were classified as a variant of uncertain significance (VUS) and 54% of cases had one or more VUS. CONCLUSION: For almost all genes, the gene-disease relationship could not be validated and lack of evidence precluded variant interpretation. Thus, the incremental diagnostic yield of extending testing was negligible, and would, we propose, be outweighed by problems that arise with a high rate of uninterpretable findings. These findings highlight the need for rigorous, evidence-based selection of genes for clinical test panels.


Assuntos
Cardiomiopatia Hipertrófica/genética , Sarcômeros , Adolescente , Adulto , Idoso , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/patologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Sequenciamento Completo do Genoma , Adulto Jovem
17.
FEBS J ; 286(1): 151-168, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30430732

RESUMO

Myosin regulatory light chain (RLC) phosphorylation is important for cardiac muscle mechanics/function as well as for the Ca2+ -troponin/tropomyosin regulation of muscle contraction. This study focuses on the arginine to glutamine (R58Q) substitution in the human ventricular RLC (MYL2 gene), linked to malignant hypertrophic cardiomyopathy in humans and causing severe functional abnormalities in transgenic (Tg) R58Q mice, including inhibition of cardiac RLC phosphorylation. Using a phosphomimic recombinant RLC variant where Ser-15 at the phosphorylation site was substituted with aspartic acid (S15D) and placed in the background of R58Q, we aimed to assess whether we could rescue/mitigate R58Q-induced structural/functional abnormalities in vitro. We show rescue of several R58Q-exerted adverse phenotypes in S15D-R58Q-reconstituted porcine cardiac muscle preparations. A low level of maximal isometric force observed for R58Q- versus WT-reconstituted fibers was restored by S15D-R58Q. Significant beneficial effects were also observed on the Vmax of actin-activated myosin ATPase activity in S15D-R58Q versus R58Q-reconstituted myosin, along with its binding to fluorescently labeled actin. We also report that R58Q promotes the OFF state of myosin, both in reconstituted porcine fibers and in Tg mouse papillary muscles, thereby stabilizing the super-relaxed state (SRX) of myosin, characterized by a very low ATP turnover rate. Experiments in S15D-R58Q-reconstituted porcine fibers showed a mild destabilization of the SRX state, suggesting an S15D-mediated shift in disordered-relaxed (DRX)↔SRX equilibrium toward the DRX state of myosin. Our study shows that S15D-phosphomimic can be used as a potential rescue strategy to abrogate/alleviate the RLC mutation-induced phenotypes and is a likely candidate for therapeutic intervention in HCM patients.


Assuntos
Cálcio/metabolismo , Cardiomiopatia Hipertrófica/prevenção & controle , Mutação , Contração Miocárdica , Cadeias Leves de Miosina/genética , Cadeias Leves de Miosina/metabolismo , Actinas/metabolismo , Animais , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/patologia , Humanos , Camundongos , Camundongos Transgênicos , Cadeias Leves de Miosina/química , Fenótipo , Fosforilação , Suínos
18.
Cardiol Clin ; 37(1): 27-33, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30447713

RESUMO

Cardiac MRI (CMR) is an essential tool for the evaluation of the patient with hypertrophic cardiomyopathy (HCM). First, the accurate morphologic imaging and measures that are possible with CMR help to ascertain the diagnosis. Second, the tissue characterization that can be done with MRI helps to define the abnormalities in the myocardium and to identify areas of fibrosis that have been linked to increase risk of sudden cardiac death and heart failure. In addition, CMR can help distinguish HCM from similar disease processes.


Assuntos
Cardiomiopatia Hipertrófica/patologia , Angiografia por Ressonância Magnética , Meios de Contraste , Fibrose/patologia , Gadolínio , Humanos , Insuficiência da Valva Mitral/patologia , Imagem de Perfusão do Miocárdio/métodos , Miocárdio/patologia , Fatores de Risco , Disfunção Ventricular Esquerda/patologia , Obstrução do Fluxo Ventricular Externo/patologia
19.
Cardiol Clin ; 37(1): 63-72, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30447717

RESUMO

Hypertrophic cardiomyopathy (HCM) is associated with an increased risk of sudden cardiac death (SCD), although perhaps not as significantly as previously believed. Given the heterogeneous nature of this disease entity, risk stratification of individuals with HCM remains challenging. The recent HCM risk-SCD prediction model seems to perform well in assessing individual SCD risk. Even though implantable cardiac defibrillators (ICDs) are effective in preventing SCD in patients at increased risk, the importance of shared decision making in deciding whether or not to undergo ICD implantation cannot be understated.


Assuntos
Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis , Adolescente , Adulto , Fatores Etários , Idoso , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/patologia , Criança , Pré-Escolar , Morte Súbita Cardíaca/patologia , Terapia por Exercício , Genótipo , Aneurisma Cardíaco/complicações , Aneurisma Cardíaco/patologia , Humanos , Hipertensão/complicações , Hipertensão/patologia , Lactente , Recém-Nascido , Angiografia por Ressonância Magnética , Pessoa de Meia-Idade , Linhagem , Fenótipo , Medição de Risco , Síncope/etiologia , Síncope/patologia , Taquicardia Ventricular/patologia , Taquicardia Ventricular/prevenção & controle , Fibrilação Ventricular/patologia , Fibrilação Ventricular/prevenção & controle , Obstrução do Fluxo Ventricular Externo/complicações , Obstrução do Fluxo Ventricular Externo/patologia , Adulto Jovem
20.
Cardiol Clin ; 37(1): 73-82, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30447718

RESUMO

Hypertrophic cardiomyopathy affects 0.5% of the population. Advanced testing is considered, including cardiac catheterization, endomyocardial biopsy, and cardiopulmonary exercise testing. Right and left heart catheterization provides essential hemodynamic data, identifies patients who might benefit from septal reduction therapy, and assesses for comorbidities. Pathologic analysis reveals ventricular hypertrophy, myocardial disarray, and endocardial and interstitial fibrosis. Routine endomyocardial biopsy is not recommended unless other conditions that cause hypertrophy need to be ruled out. Cardiopulmonary exercise testing provides useful physiologic data, allows monitoring of the response to medication and surgical interventions, estimates prognosis, and guides referral for orthotopic heart transplantation.


Assuntos
Cardiomiopatia Hipertrófica/patologia , Hemodinâmica/fisiologia , Miocárdio/patologia , Biópsia/métodos , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/fisiopatologia , Teste de Esforço/métodos , Fibrose/patologia , Transplante de Coração/métodos , Humanos , Guias de Prática Clínica como Assunto , Prognóstico , Medição de Risco/métodos
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