RESUMEN
BACKGROUND: Galectin-3 is a marker of myocardial inflammation and fibrosis shown to correlate with morbidity and mortality in heart failure (HF). We examined the utility of galectin-3 as a marker of the severity of HF, the response of galectin-3 levels to ventricular assist device (LVAD) implantation or heart transplantation (HTx), and its use as a prognostic indicator. METHODS: Plasma galectin-3 was measured using a commercially available ELISA assay in patients with stable HF (n = 55), severe HF (n = 63), at 3 (n = 17) and 6 (n = 14) months post-LVAD and at LVAD explantation (n = 23), patients following HTx (n = 85) and healthy controls (n = 30). RESULTS: Galectin-3 levels increase with the severity of HF (severe HF: 28.2 ± 14, stable HF: 19.7 ± 13, p = 0.001; controls: 13.2 ± 9 ng/ml, p = 0.02 versus stable HF). Following LVAD implantation, galectin-3 levels are initially lower (3 months: 23.7 ± 9, 6 months: 21.7 ± 9 versus 29.2 ± 14 ng/ml implantation; p = NS) but are higher at explantation (40.4 ± 19 ng/ml; p = 0.005 versus pre-LVAD). Galectin-3 levels >30 ng/ml are associated with lower survival post-LVAD placement (76.5 % versus 95.0 % at 2 years, p = 0.009). After HTx, galectin-3 levels are lower (17.8 ± 7.1 ng/ml post-HTx versus 28.2 ± 14 pre-HTx; p < 0.0001). Patients with coronary allograft vasculopathy (CAV) post-HTx showed higher galectin-3 levels (20.5 ± 8.8 ng/ml versus 16.8 ± 6.3, p = 0.1) and the degree of CAV correlated with levels of galectin-3 (r (2) = 0.17, p < 0.0001). CONCLUSIONS: Galectin-3 is associated with the severity of HF, exhibits dynamic changes during mechanical unloading and predicts survival post-LVAD. Further, galectin-3 is associated with the development on CAV post-HTx. Galectin-3 might serve as a novel biomarker in patients with HF, during LVAD support and following HTx.
Asunto(s)
Galectina 3/sangre , Insuficiencia Cardíaca/terapia , Trasplante de Corazón , Corazón Auxiliar , Contracción Miocárdica , Función Ventricular Izquierda , Adulto , Anciano , Área Bajo la Curva , Biomarcadores/sangre , Fenómenos Biomecánicos , Proteínas Sanguíneas , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/etiología , Ensayo de Inmunoadsorción Enzimática , Femenino , Galectinas , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Trasplante de Corazón/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Diseño de Prótesis , Curva ROC , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
The mammalian heart, the body's largest energy consumer, has evolved robust mechanisms to tightly couple fuel supply with energy demand across a wide range of physiologic and pathophysiologic states, yet, when compared with other organs, relatively little is known about the molecular machinery that directly governs metabolic plasticity in the heart. Although previous studies have defined Kruppel-like factor 15 (KLF15) as a transcriptional repressor of pathologic cardiac hypertrophy, a direct role for the KLF family in cardiac metabolism has not been previously established. We show in human heart samples that KLF15 is induced after birth and reduced in heart failure, a myocardial expression pattern that parallels reliance on lipid oxidation. Isolated working heart studies and unbiased transcriptomic profiling in Klf15-deficient hearts demonstrate that KLF15 is an essential regulator of lipid flux and metabolic homeostasis in the adult myocardium. An important mechanism by which KLF15 regulates its direct transcriptional targets is via interaction with p300 and recruitment of this critical co-activator to promoters. This study establishes KLF15 as a key regulator of myocardial lipid utilization and is the first to implicate the KLF transcription factor family in cardiac metabolism.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Metabolismo de los Lípidos , Proteínas Musculares/metabolismo , Miocardio/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Animales , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patología , Línea Celular , Proteínas de Unión al ADN/genética , Proteína p300 Asociada a E1A/genética , Proteína p300 Asociada a E1A/metabolismo , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Ratones , Ratones Noqueados , Proteínas Musculares/genética , Miocardio/patología , Proteínas Nucleares/genética , Oxidación-Reducción , Factores de Transcripción/genéticaRESUMEN
Apolipoprotein C-I (apoC-I) is a 6.6kDa serum protein associated with high density lipoproteins (HDL) and triglyceride-rich lipoproteins. In this study, apoC-I was examined in high density lipoprotein subfractions from individuals with and without coronary artery disease (CAD). New isoforms of apoC-I, were detected in the cohort of individuals with CAD using mass spectrometry while the expected apoC-I isoforms were absent. In addition, the apoC-I mass spectra for the CAD cohort had satellite peaks indicative of the involvement of oxidative processes. Further analysis of the mass spectra of the CAD and non-CAD cohorts suggest that the origin of these new isoforms may be due to genetic mutations that could compromise the function of apoC-I.