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1.
Lancet ; 396(10253): 759-769, 2020 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-32871100

RESUMO

BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.


Assuntos
Benzilaminas/uso terapêutico , Miosinas Cardíacas/antagonistas & inibidores , Cardiomiopatia Hipertrófica/tratamento farmacológico , Uracila/análogos & derivados , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Benzilaminas/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Cardiomiopatia Hipertrófica/fisiopatologia , Fármacos Cardiovasculares/uso terapêutico , Método Duplo-Cego , Tolerância ao Exercício/fisiologia , Feminino , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Avaliação de Resultados da Assistência ao Paciente , Uracila/efeitos adversos , Uracila/uso terapêutico
2.
Proc Natl Acad Sci U S A ; 117(37): 23113-23124, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32859761

RESUMO

Currently there is an unmet need for treatments that can prevent hypertrophic cardiomyopathy (HCM). Using a murine model we previously identified that HCM causing cardiac troponin I mutation Gly203Ser (cTnI-G203S) is associated with increased mitochondrial metabolic activity, consistent with the human condition. These alterations precede development of the cardiomyopathy. Here we examine the efficacy of in vivo treatment of cTnI-G203S mice with a peptide derived against the α-interaction domain of the cardiac L-type calcium channel (AID-TAT) on restoring mitochondrial metabolic activity, and preventing HCM. cTnI-G203S or age-matched wt mice were treated with active or inactive AID-TAT. Following treatment, targeted metabolomics was utilized to evaluate myocardial substrate metabolism. Cardiac myocyte mitochondrial metabolic activity was assessed as alterations in mitochondrial membrane potential and flavoprotein oxidation. Cardiac morphology and function were examined using echocardiography. Cardiac uptake was assessed using an in vivo multispectral imaging system. We identified alterations in six biochemical intermediates in cTnI-G203S hearts consistent with increased anaplerosis. We also reveal that AID-TAT treatment of precardiomyopathic cTnI-G203S mice, but not mice with established cardiomyopathy, restored cardiac myocyte mitochondrial membrane potential and flavoprotein oxidation, and prevented myocardial hypertrophy. Importantly, AID-TAT was rapidly targeted to the heart, and not retained by the liver or kidneys. Overall, we identify biomarkers of HCM resulting from the cTnI mutation Gly203Ser, and present a safe, preventative therapy for associated cardiomyopathy. Utilizing AID-TAT to modulate cardiac metabolic activity may be beneficial in preventing HCM in "at risk" patients with identified Gly203Ser gene mutations.


Assuntos
Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mutação/genética , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Peptídeos/farmacologia , Troponina I/metabolismo
3.
Circ Heart Fail ; 13(6): e006853, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32498620

RESUMO

BACKGROUND: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by unexplained left ventricular (LV) hypertrophy associated with dynamic LV outflow tract obstruction. Current medical therapies are nonspecific and have limited efficacy in relieving symptoms. Mavacamten is a first-in-class targeted inhibitor of cardiac myosin, which has been shown to reduce LV outflow tract obstruction, improve exercise capacity, and relieve symptoms of oHCM in the PIONEER-HCM phase 2 study. METHODS: EXPLORER-HCM is a multicenter, phase 3, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of mavacamten in treating symptomatic oHCM. Eligible adults with oHCM and New York Heart Association Functional Class II or III are randomized 1:1 to receive once-daily, oral mavacamten, or matching placebo for 30 weeks. The primary composite functional end point is clinical response at week 30 compared to baseline defined as either (1) an increase in peak oxygen consumption ≥1.5 mL/kg/min and reduction of at least one New York Heart Association class; or (2) an improvement of ≥3.0 mL/kg/min in peak oxygen consumption with no worsening of New York Heart Association class. Secondary end points include change in postexercise LV outflow tract gradient, New York Heart Association class, peak oxygen consumption, and patient-reported outcomes assessed by the Kansas City Cardiomyopathy Questionnaire and a novel HCM-specific instrument. Exploratory end points aim to characterize the effect of mavacamten on multiple aspects of oHCM pathophysiology. CONCLUSIONS: EXPLORER-HCM is a phase 3 trial in oHCM testing a first-in-class, targeted strategy of myosin inhibition to improve symptom burden and exercise capacity through reducing LV outflow tract obstruction. Results of this trial will provide evidence to support the first disease-specific treatment for HCM. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03470545.


Assuntos
Benzilaminas/uso terapêutico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Fármacos Cardiovasculares/uso terapêutico , Uracila/análogos & derivados , Benzilaminas/efeitos adversos , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/fisiopatologia , Fármacos Cardiovasculares/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Tolerância ao Exercício/efeitos dos fármacos , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Resultado do Tratamento , Uracila/efeitos adversos , Uracila/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos
4.
Int J Cardiovasc Imaging ; 36(9): 1751-1759, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32405733

RESUMO

Whether sex differences exist in cardiac magnetic resonance (CMR) findings in patients with hypertrophic cardiomyopathy (HCM) remain unknown. We sought to assess and compare CMR characteristics in male and female patients with HCM. From January-2006 to October-2017, 165 consecutive HCM patients evaluated with CMR were included. All clinical and complementary test information was prospectively collected. At the time of CMR evaluation women were older (70 [57-75] vs. 61 [47-72] years, p = 0.02) and more symptomatic in terms of dyspnea (New York Heart Association class II-IV 47.2 vs. 24.1%, p = 0.003) and palpitations (19.6 vs. 4.6%, p = 0.006) and received more frequently treatment with diuretics (49.1% vs. 23.4%, p = 0.001). On echocardiographic examination more women had obstructive physiology (45.1 vs. 20.6%, p = 0.002). On CMR evaluation, women showed smaller left ventricular end-systolic volume index (13 [10-15] vs. 16 [13-21] ml/m2, p < 0.001), higher left ventricular ejection fraction (77 [74-80] vs. 72 [66-78]%, p = 0.004), more marked left ventricular outflow tract acceleration (54.7 vs. 26.4%, p < 0.001) and mitral regurgitation (33.3 vs. 12.7%, p = 0.002). In multivariable analysis, female sex [OR 2.44 (1.04-5.73), p = 0.04] and left ventricular end-systolic volume index [OR 1.60 (1.08-2.38), p = 0.018] were independently associated with obstructive physiology. Women with HCM have more frequently obstructive physiology, a finding that could be related to the smaller left ventricular end-systolic volume.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico por imagem , Disparidades nos Níveis de Saúde , Imagem Cinética por Ressonância Magnética , Idoso , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/fisiopatologia , Diuréticos/uso terapêutico , Feminino , Disparidades em Assistência à Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Volume Sistólico , Fatores de Tempo , Função Ventricular Esquerda
6.
Expert Opin Pharmacother ; 21(2): 233-242, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31893930

RESUMO

Introduction: Hypertrophic cardiomyopathy (HCM) is one of the most common genetic heart diseases and represents a leading cause of sudden cardiac death as well as a prevalent cause of heart failure and stroke. HCM is characterized by a very complex pathophysiology, consisting of heterogeneous clinical manifestations and natural history. Left ventricular outflow tract (LVOT) obstruction has been considered the most knowable feature of HCM since the initial clinical descriptions of the disease.Areas covered: In this review, the authors discuss the most recent reports on the pharmacological treatment of obstructive HCM, mainly based on three different levels of intervention: control of symptoms, cardiac metabolism modulation and disease-modifying approaches, including genetic preventive therapies.Expert opinion: There are presently limited data supporting pharmacological interventions for this complex disease. However, an improved understanding of HCM pathophysiology will allow the development of novel treatment options. Two important key messages are to further study drugs with negative but limited previous results and to design new and larger trials for those molecules that have already produced positive results in HCM, especially for pressure gradients and symptoms control.


Assuntos
Cardiomiopatia Hipertrófica/tratamento farmacológico , Obstrução do Fluxo Ventricular Externo/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Humanos
8.
J Ethnopharmacol ; 249: 112404, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31739105

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiac fibrosis is a common characteristic of many cardiac diseases. Our previous results showed that TRPM7 channel played an important role in the fibrosis process. MicroRNA-135a was reported to get involved in the fibrotic process. Astragalus membranaceus (Fisch.) Bunge was widely used in Chinese traditional medicine and showed cardiac protective effects in previous researches. Astragaloside IV(ASG), which is regarded as the most important ingredient of Astragalus, has been showed the effect of cardiac protection via various mechanisms, while no data suggested its action related to miRNAs regulation. AIM OF THE STUDY: The objective of this article is to investigate the inhibition effect of ASG on cardiac fibrosis through the miR-135a-TRPM7-TGF-ß/Smads pathway. MATERIALS AND METHODS: We extracted the active components from herb according to the paper and measured the content of ASG from the mixture via HPLC. The inhibition potency of cardiac hypertrophy between total extract of Astragalus and ASG was compared. SD rats were treated with ISO (5 mg/kg/day) subcutaneously (s.c.) for 14 days, ASG (10 mg/kg/d) and Astragalus extract (AE) (4.35 g/kg/d, which contained about ASG 10 mg) were given p.o. from the 6th day of the modeling. Cardiac fibroblasts (CFs) of neonatal rats were incubated with ISO (10 µM) and treated with ASG (10 µM) simultaneously for 24 h. RESULTS: The results showed that both AE and ASG treatment reduced the TRPM7 expression from the gene level and inhibited cardiac fibrosis. ASG group showed similar potency as the AE mixture. ASG treatment significantly decreased the current, mRNA and protein expression of TRPM7 which was one of targets of miR-135a. The activation of TGF-ß/Smads pathway was suppressed and the expression of α-SMA and Collagen I were also decreased obviously. In addition, our results showed that there was a positive feedback between the activation of TGF-ß/Smads pathway and the elevation of TRPM7, both of which could promote the development of myocardial fibrosis. CONCLUSIONS: AE had the effect of cardiac fibrosis inhibition and decreased the mRNA expression of TRPM7. ASG, as one of the effective ingredients of AE, showed the same potency when given the same dose. ASG inhibited cardiac fibrosis by targeting the miR-135a-TRPM7-TGF-ß/Smads pathway.


Assuntos
Cardiomiopatia Hipertrófica/tratamento farmacológico , Miocárdio/patologia , Extratos Vegetais/farmacologia , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Animais Recém-Nascidos , Astrágalo (Planta)/química , Cardiomiopatia Hipertrófica/induzido quimicamente , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Humanos , Isoproterenol/toxicidade , Masculino , Medicina Tradicional Chinesa/métodos , MicroRNAs/metabolismo , Miocárdio/citologia , Miofibroblastos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Raízes de Plantas/química , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Saponinas/isolamento & purificação , Saponinas/uso terapêutico , Transdução de Sinais/genética , Proteínas Smad/metabolismo , Canais de Cátion TRPM/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Triterpenos/isolamento & purificação , Triterpenos/uso terapêutico
9.
Circ Heart Fail ; 12(12): e006231, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31813281

RESUMO

BACKGROUND: The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) targeted young sarcomeric gene mutation carriers with early-stage hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify disease progression. We describe the baseline characteristics of the VANISH cohort and compare to previous trials evaluating angiotensin receptor blockers. METHODS: Applying a randomized, double-blinded, placebo-controlled design, 178 participants with nonobstructive HCM (age, 23.3±10.1 years; 61% men) were randomized in the primary cohort and 34 (age, 16.5±4.9 years; 50% men) in the exploratory cohort of sarcomeric mutation carriers without left ventricular hypertrophy. RESULTS: In the primary cohort, maximal left ventricular wall thickness was 17±4 mm for adults and Z score 7.0±4.5 for children. Nineteen percent had late gadolinium enhancement on cardiac magnetic resonance. Mean peak oxygen consumption was 33 mL/kg per minute, and 92% of participants were New York Heart Association functional class I. New York Heart Association class II was associated with older age, MYH7 variants, and more prominent imaging abnormalities. Six previous trials of angiotensin receptor blockers in HCM enrolled a median of 24 patients (range, 19-133) with mean age of 51.2 years; 42% of patients were in New York Heart Association class ≥II, and sarcomeric mutations were not required. CONCLUSIONS: The VANISH cohort is much larger, younger, less heterogeneous, and has less advanced disease than prior angiotensin receptor blocker trials in HCM. Participants had relatively normal functional capacity and mild HCM features. New York Heart Association functional class II symptoms were associated with older age, more prominent imaging abnormalities, and MYH7 variants, suggesting both phenotype and genotype contribute to disease manifestations. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912534.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Mutação , Sarcômeros/genética , Valsartana/uso terapêutico , Adolescente , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Brasil , Canadá , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Criança , Dinamarca , Progressão da Doença , Método Duplo-Cego , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Valsartana/efeitos adversos , Adulto Jovem
10.
Circ Heart Fail ; 12(11): e005835, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31684756

RESUMO

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disorder, primarily involving mutations in sarcomeric proteins. HCM patients present with hypertrophy, diastolic dysfunction, and fibrosis, but there is no specific treatment. The sphingosine-1-phosphate receptor modulator, FTY720/fingolimod, is approved for treatment of multiple sclerosis. We hypothesize that modulation of the sphingosine-1-phosphate receptor by FTY720 would be of therapeutic benefit in sarcomere-linked HCM. METHODS: We treated mice with an HCM-linked mutation in tropomyosin (Tm-E180G) and nontransgenic littermates with FTY720 or vehicle for 6 weeks. Compared with vehicle-treated, FTY720-treated Tm-E180G mice had a significant reduction in left atrial size (1.99±0.19 [n=7] versus 2.70±0.44 [n=6] mm; P<0.001) and improvement in diastolic function (E/A ratio: 2.69±0.38 [n=7] versus 5.34±1.19 [n=6]; P=0.004) as assessed by echocardiography. RESULTS: Pressure-volume relations revealed significant improvements in the end-diastolic pressure volume relationship, relaxation kinetics, preload recruitable stroke work, and ejection fraction. Detergent-extracted fiber bundles revealed a significant decrease in myofilament Ca2+-responsiveness (pCa50=6.15±0.11 [n=13] versus 6.24±0.06 [n=14]; P=0.041). We attributed these improvements to a downregulation of S-glutathionylation of cardiac myosin binding protein-C in FTY720-treated Tm-E180G mice and reduction in oxidative stress by downregulation of NADPH oxidases with no changes in fibrosis. CONCLUSIONS: This is the first demonstration that modulation of S1PR results in decreased myofilament-Ca2+-responsiveness and improved diastolic function in HCM. We associated these changes with decreased oxidative modification of myofilament proteins via downregulation of NOX2. Our data support the hypothesis that modification of sphingolipid signaling may be a novel therapeutic approach in HCM.


Assuntos
Função do Átrio Esquerdo/efeitos dos fármacos , Remodelamento Atrial/efeitos dos fármacos , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cloridrato de Fingolimode/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Receptores de Esfingosina-1-Fosfato/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/fisiopatologia , Diástole , Modelos Animais de Doenças , Feminino , Fibrose , Predisposição Genética para Doença , Masculino , Camundongos Mutantes , Mutação , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miofibrilas/efeitos dos fármacos , Miofibrilas/metabolismo , Miofibrilas/patologia , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Receptores de Esfingosina-1-Fosfato/metabolismo , Tropomiosina/genética
11.
Int J Cardiol ; 297: 75-82, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615649

RESUMO

BACKGROUND: Significant left-ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) may result in symptoms and is associated with adverse outcomes. Although disopyramide can reduce resting gradients, nearly 30% of HCM patients do not respond. We sought to study the clinical and echocardiographic variables associated with disopyramide-induced LVOT-gradient reduction. METHODS: Forty-one disopyramide-treated HCM patients (average daily-dose 305 mg) were subdivided into two groups: (1) nineteen responders, with a reduction of LVOT-gradients of at least 30% from baseline, and (2) twenty-two non-responders, in whom LVOT-gradients did not change or increased following treatment. All patients had a thorough clinical and echocardiographic assessment pre- and post-treatment initiation. RESULTS: Patients who responded to disopyramide had better pretreatment left ventricular (LV) systolic function (LV ejection fraction of 67.9 ±â€¯5.6% vs. 59.7 ±â€¯5.8%, p = 0.0001), better LV global longitudinal strain (-17.9 ±â€¯2.3% vs. -16.1 ±â€¯2.5%, p = 0.048), less mitral regurgitation, smaller LV size (indexed LV end-systolic volume of 16.2 ±â€¯5.1 ml/m2 vs. 23.2 ±â€¯6.8 ml/m2, p = 0.001), and lower LV maximal wall thickness (17.2±3 mm vs.19.2 ±â€¯3.4 mm, p = 0.046). Baseline left atrial (LA) volumes were significantly lower in the responders, with higher indices of LA ejection fraction (62 ±â€¯11.2% vs. 50.5 ±â€¯12.2%, p = 0.005), systolic LA strain (34 ±â€¯12.4% vs. 25.8 ±â€¯10.6%, p = 0.04), and LA strain-rate (1.34 ±â€¯0.49%/sec vs. 0.99 ±â€¯0.24%/sec, p = 0.012). In multivariable analysis, the presence of reduced LV systolic function and systolic LA strain-rate remained independently associated with poor response to disopyramide. CONCLUSIONS: Obstructive HCM patients with more severe disease at baseline tend to respond less to disopyramide treatment. In those patients, early referral for alcohol septal ablation or myectomy surgery should be considered.


Assuntos
Cardiomiopatia Hipertrófica/tratamento farmacológico , Disopiramida/uso terapêutico , Obstrução do Fluxo Ventricular Externo/tratamento farmacológico , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Idoso , Função Atrial , Cardiomiopatia Hipertrófica/etiologia , Cardiomiopatia Hipertrófica/fisiopatologia , Estudos de Coortes , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico , Resultado do Tratamento , Função Ventricular Esquerda , Obstrução do Fluxo Ventricular Externo/complicações
12.
BMC Vet Res ; 15(1): 376, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660967

RESUMO

BACKGROUND: Inconsistency of treatment response in cats with obstructive hypertrophic cardiomyopathy is well recognized. We hypothesized that the difference in response to beta-blockers may be caused by myocardial functional abnormalities. This study was designed to compare myocardial function in cats with obstructive hypertrophic cardiomyopathy with and without response to beta-blockers. Twenty-one, client-owned, hypertrophic cardiomyopathy cats treated with carvedilol were analyzed. After carvedilol treatment, cats with decreased left ventricular outflow tract velocity were categorized as responders (n = 10); those exhibiting no response (no decrease in the left ventricular outflow tract velocity) were categorized as non-responders (n = 11). The cats were examined using layer-specific assessment of the myocardial function (whole, endocardial, and epicardial layers) longitudinally and circumferentially by two-dimensional speckle-tracking echocardiography, before and after carvedilol treatment. RESULTS: The non-responder cats had a significantly higher age, end-diastolic left ventricular posterior-wall thickness, peak velocity of left ventricular outflow tract, and dose of carvedilol than the responders (p = 0.04, p < 0.01, p < 0.01, and p < 0.01, respectively). The circumferential strain in the epicardial layer was lower and circumferential endocardial to epicardial strain ratio was higher in non-responders than responders (p < 0.001 and p = 0.006). According to the multivariate analysis, circumferential strain in the epicardial layer was the only independent correlate of treatment response with carvedilol. CONCLUSIONS: Myocardial function, assessed by two-dimensional speckle-tracking echocardiography, differed in cats with hypertrophic cardiomyopathy with and without response to beta-blockers. The determination of layer-specific myocardial function may facilitate detailed pathophysiologic assessment and treatment response in cats with hypertrophic cardiomyopathy.


Assuntos
Cardiomiopatia Hipertrófica/veterinária , Carvedilol/uso terapêutico , Doenças do Gato/patologia , Coração/fisiologia , Animais , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/patologia , Doenças do Gato/tratamento farmacológico , Gatos , Variações Dependentes do Observador
13.
J Pediatr Endocrinol Metab ; 32(10): 1181-1185, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31473688

RESUMO

Mitochondrial acyl-CoA dehydrogenase 9 (ACAD9) deficiency is one of the common causes of respiratory chain complex I deficiency, which is characterized by cardiomyopathy, lactic acidemia, and muscle weakness. Infantile cardiomyopathy is the most common phenotype and is usually lethal by the age of 5 years. Riboflavin treatment is known to be effective in ~65% of the patients; however, the remaining are unresponsive to riboflavin and are in need of additional treatment measures. In this report, we describe a patient with ACAD9 deficiency who developed progressive cardiomyopathy at 8 months of age. As the patient's left ventricular ejection fraction (LVEF) kept decreasing to 45.4% at 1 year 8 months, sodium pyruvate treatment was introduced together with a beta-blocker and coenzyme Q10. This resulted in a steady improvement, with full and sustained normalization of cardiac function without riboflavin. The therapy, therefore, might be a useful addition for the treatment of ACAD9 deficiency.


Assuntos
Acidose/tratamento farmacológico , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenases/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Cardiomiopatias/tratamento farmacológico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Carvedilol/administração & dosagem , Doenças Mitocondriais/tratamento farmacológico , Debilidade Muscular/tratamento farmacológico , Piruvatos/administração & dosagem , Ubiquinona/análogos & derivados , Acidose/complicações , Acidose/patologia , Antagonistas Adrenérgicos beta/administração & dosagem , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Cardiomiopatias/complicações , Cardiomiopatias/patologia , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/patologia , Quimioterapia Combinada , Feminino , Humanos , Recém-Nascido , Doenças Mitocondriais/complicações , Doenças Mitocondriais/patologia , Debilidade Muscular/complicações , Debilidade Muscular/patologia , Prognóstico , Ubiquinona/administração & dosagem , Vitaminas/administração & dosagem
14.
Am J Med Genet A ; 179(8): 1408-1409, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31355539
15.
Trends Mol Med ; 25(9): 775-790, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31324451

RESUMO

Hypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular disease where cardiac dysfunction often associates with mutations in sarcomeric genes. Various models based on tissue explants, isolated cardiomyocytes, skinned myofibrils, and purified actin/myosin preparations have uncovered disease hallmarks, enabling the development of putative therapeutics, with some reaching clinical trials. Newly developed human pluripotent stem cell (hPSC)-based models could be complementary by overcoming some of the inconsistencies of earlier systems, whilst challenging and/or clarifying previous findings. In this article we compare recent progress in unveiling multiple HCM mechanisms in different models, highlighting similarities and discrepancies. We explore how insight is facilitating the design of new HCM therapeutics, including those that regulate metabolism, contraction and heart rhythm, providing a future perspective for treatment of HCM.


Assuntos
Cardiomiopatia Hipertrófica/etiologia , Cardiomiopatia Hipertrófica/metabolismo , Suscetibilidade a Doenças , Modelos Biológicos , Animais , Biomarcadores , Sistemas CRISPR-Cas , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Modelos Animais de Doenças , Edição de Genes , Humanos , Terapia de Alvo Molecular , Contração Muscular , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Sarcômeros/genética , Sarcômeros/metabolismo
16.
Am J Case Rep ; 20: 1006-1010, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31296836

RESUMO

BACKGROUND In the setting of acute decompensated heart failure (ADHF), tolvaptan, a selective V2 receptor antagonist, did not alter plasma renin activity or angiotensin II level, but significantly increased plasma aldosterone by the activation of V1ₐ receptor, suggesting that a high-dose mineralocorticoid receptor antagonist (MRA) combined with a V2 receptor antagonist might be of interest, especially in ADHF patients. However, in the setting of ADHF, the short-term and long-term efficacy of a high-dose MRA combined with tolvaptan remains unclear. CASE REPORT An 86-year-old woman with a history of chronic HF with a preserved ejection fraction due to obstructive hypertrophic cardiomyopathy and severe aortic stenosis was transferred to our hospital complaining of persistent dyspnea (New York Heart Association class IV). She did not respond to standard therapy with tolvaptan (15.0 mg/day). However, the present case demonstrated that adding high-dose spironolactone (100 mg/day) to low-dose tolvaptan (15.0 mg/day) is safe and well tolerated, resulting in an increase in urine output and improvement of the symptoms or signs of ADHF in a patient who was refractory to loop diuretics and tolvaptan. CONCLUSIONS The short- and long-term efficacy of high-dose spironolactone combined with low-dose tolvaptan may be associated with an attenuation of the aldosterone level, which is increased through V1ₐ activation by vasopressin during tolvaptan administration.


Assuntos
Estenose da Valva Aórtica/tratamento farmacológico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Espironolactona/administração & dosagem , Tolvaptan/administração & dosagem , Doença Aguda , Idoso de 80 Anos ou mais , Antagonistas dos Receptores de Hormônios Antidiuréticos/administração & dosagem , Estenose da Valva Aórtica/complicações , Cardiomiopatia Hipertrófica/complicações , Quimioterapia Combinada , Dispneia , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem
17.
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
18.
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
19.
Circ J ; 83(8): 1747-1754, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31257313

RESUMO

BACKGROUND: There is limited information about the clinical profiles of patients with hypertrophic cardiomyopathy (HCM) and thromboembolic events in a community-based Japanese patient cohort.Methods and Results:In 2004, we established a cardiomyopathy registration network in Kochi Prefecture that comprised 9 hospitals, and finally 293 patients with HCM were followed. The mean age at registration was 63±14 years, and 197 patients (67%) were men. At registration, 86 patients (29%) had documented atrial fibrillation (AF). During a mean follow-up period of 6.1±3.2 years, thromboembolic events, including 3 embolic stroke deaths, occurred in 23 patients. The 5-year embolic event rate was 5.5%. During the follow-up period, an additional 31 patients (11%) had documentation of AF and finally a total of 117 patients (40%) developed AF. The 5-year embolic event rate in those 117 patients with AF was 12.3%. Of the 23 patients with embolic events, 12 had AF prior to the embolic complications and another 6 had documented AF after thromboembolism. AF was not detected in the remaining 5 patients. The CHADS2score did not correlate with the embolic outcome in HCM patients. CONCLUSIONS: In this community-based registry, thromboembolic events were not rare in patients with HCM. All patients with HCM in whom AF develops should be given anticoagulation therapy regardless of their CHADS2score.


Assuntos
Fibrilação Atrial/epidemiologia , Cardiomiopatia Hipertrófica/epidemiologia , Tromboembolia/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/mortalidade , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/mortalidade , Criança , Feminino , Humanos , Incidência , Japão/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Sistema de Registros , Medição de Risco , Fatores de Risco , Tromboembolia/diagnóstico , Tromboembolia/mortalidade , Tromboembolia/prevenção & controle , Fatores de Tempo , Adulto Jovem
20.
Mol Med Rep ; 20(1): 549-558, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180540

RESUMO

Hypertrophic cardiomyopathy (HCM) is a complex inherited cardiovascular disease. The present study investigated the long noncoding (lnc)RNA/microRNA (mi)RNA/mRNA expression pattern of patients with HCM and aimed to identify key molecules involved in the development of this condition. An integrated strategy was conducted to identify differentially expressed miRNAs (DEmiRs), differentially expressed lncRNAs (DElncs) and differentially expressed genes (DEGs) based on the GSE36961 (mRNA), GSE36946 (miRNA), GSE68316 (lncRNA/mRNA) and GSE32453 (mRNA) expression profiles downloaded from the Gene Expression Omnibus datasets. Bioinformatics tools were employed to perform function and pathway enrichment analysis, protein­protein interaction, lncRNA­miRNA­mRNA and hub gene networks. Subsequently, DEGs were used as targets to predict drugs. The results indicated that a total of 2,234 DElncs (1,120 upregulated and 1,114 downregulated), 5 DEmiRs (2 upregulated and 3 downregulated) and 42 DEGs (35 upregulated and 7 downregulated) were identified in 4 microarray profiles. Gene ontology analysis revealed that DEGs were mainly involved in actin filament and stress fiber formation and in calcium ion binding, whereas Kyoto Encyclopedia of Genes and Genomes pathway analysis identified the hypoxia inducible factor­1, transforming growth factor­ß and tumor necrosis factor signaling pathways as the main pathways involved in these processes. The hub genes were screened using cytoHubba. A total of 1,086 lncRNA­miRNA­mRNA interactions including 67 lncRNAs, 5 miRNAs and 25 mRNAs were mined in the present study based on prediction websites. Drug prediction indicated that the targeted drugs mainly included angiotensin converting enzyme inhibitors or ß­blockers. A comprehensive bioinformatics analysis of the molecular regulatory lncRNA­miRNA­mRNA network was performed and potential therapeutic applications of drugs were predicted in HCM patients. The data may unravel the future molecular mechanism of HCM.


Assuntos
Cardiomiopatia Hipertrófica/tratamento farmacológico , Descoberta de Drogas/métodos , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Biologia Computacional/métodos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular/métodos , Mapas de Interação de Proteínas/efeitos dos fármacos
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