RESUMO
Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn, which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. By generating skeletal muscle specific Ostn knock-out and overexpressing mice, we demonstrate that reduced skeletal muscle Musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload. Mechanistically, Musclin enhances the abundance of C-type natriuretic peptide (CNP), thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling. Because we also find reduced OSTN expression in skeletal muscle of heart failure patients, augmentation of Musclin might serve as therapeutic strategy.
Assuntos
Caquexia/genética , Fibrose Endomiocárdica/genética , Insuficiência Cardíaca/genética , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Fatores de Transcrição/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Caquexia/metabolismo , Caquexia/fisiopatologia , Caquexia/prevenção & controle , Estudos de Casos e Controles , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Modelos Animais de Doenças , Fibrose Endomiocárdica/metabolismo , Fibrose Endomiocárdica/fisiopatologia , Fibrose Endomiocárdica/prevenção & controle , Feminino , Regulação da Expressão Gênica , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Testes de Função Cardíaca , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Musculares/agonistas , Proteínas Musculares/antagonistas & inibidores , Proteínas Musculares/deficiência , Atrofia Muscular/metabolismo , Atrofia Muscular/fisiopatologia , Atrofia Muscular/prevenção & controle , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Fatores de Transcrição/agonistas , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/deficiênciaRESUMO
Background Patients with breast cancer can be affected by cardiotoxic reactions through cancer therapies. Cardiac biomarkers, like NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin T, might have predictive value. Methods and Results Echocardiography, ECG, hemodynamic parameters, NT-proBNP and high-sensitivity cardiac troponin T were assessed in 853 patients with early-stage breast cancer randomized in the German Breast Group GeparOcto-GBG 84 phase III trial. Patients received neo-adjuvant dose-dense, dose-intensified epirubicin, paclitaxel, and cyclophosphamide (iddEPC group, n=424) or paclitaxel, non-pegylated doxorubicin, and in triple negative breast cancer, (paclitaxel, non-pegylated doxorubicin, carboplatin group, n=429) treatment for 18 weeks. Patients positive for human epidermal growth receptor 2 (n=354, 41.5%) received monoclonal antibodies on top of allocated therapy; 119 (12.9%) of all patients showed a cardiotoxic reaction during therapy (15 [1.8%] using a more strict definition). Presence of cardiotoxic reactions was irrespective of treatment allocation (P=0.31). Small but significant increases in NT-proBNP developed early in patients with a cardiotoxic reaction as compared with those without in whom NT-proBNP rose only towards the end of therapy (P=0.04). High-sensitivity cardiac troponin T rose early in both groups. Logistic regression showed that NT-proBNP (odds ratio [OR], 1.03; 95% CI, 1.008-1.055; P=0.01) and hemoglobin (OR, 1.31; 95% CI, 1.05-1.63; P=0.02) measured at 6 weeks after treatment initiation were significantly associated with cardiotoxic reactions. Conclusions NT-proBNP and hemoglobin are significantly associated with cardiotoxic reactions in patients with early-stage breast cancer undergoing dose-dense and dose-intensified chemotherapy, but high-sensitivity cardiac troponin T is not. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT02125344.
Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/epidemiologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Troponina T/sangue , Adulto , Biomarcadores/sangue , Cardiotoxicidade/sangue , Cardiotoxicidade/diagnóstico , Estudos de Coortes , Ecocardiografia , Feminino , Alemanha , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Fatores de Risco , Volume SistólicoRESUMO
BACKGROUND: Skeletal muscle wasting is an extremely common feature in patients with heart failure, affecting approximately 20% of ambulatory patients with even higher values during acute decompensation. Its occurrence is associated with reduced exercise capacity, muscle strength, and quality of life. We sought to investigate if the presence of muscle wasting carries prognostic information. METHODS: Two hundred sixty-eight ambulatory patients with heart failure (age 67.1 ± 10.9 years, New York Heart Association class 2.3 ± 0.6, left ventricular ejection fraction 39 ± 13.3%, and 21% female) were prospectively enrolled as part of the Studies Investigating Co-morbidities Aggravating Heart Failure. Muscle wasting as assessed using dual-energy X-ray absorptiometry was present in 47 patients (17.5%). RESULTS: During a mean follow-up of 67.2 ± 28.02 months, 95 patients (35.4%) died from any cause. After adjusting for age, New York Heart Association class, left ventricular ejection fraction, creatinine, N-terminal pro-B-type natriuretic peptide, and iron deficiency, muscle wasting remained an independent predictor of death (hazard ratio 1.80, 95% confidence interval 1.01-3.19, P = 0.04). This effect was more pronounced in patients with heart failure with reduced than in heart failure with preserved ejection fraction. CONCLUSIONS: Muscle wasting is an independent predictor of death in ambulatory patients with heart failure. Clinical trials are needed to identify treatment approaches to this co-morbidity.