Dysregulation of metalloproteins in ischemic heart disease patients with systolic dysfunction.

Ischemic heart disease (IHD) is the leading cause of mortality worldwide. Metalloproteins have been linked to human health and diseases. The molecular functions of metalloproteins in IHD is not well understood and require further exploration. The objective of this study was to find out the role of metalloproteins in the pericardial fluid of IHD patients having normal (EF > 45) and impaired (EF < 45) left ventricular ejection fraction (LVEF). IHD patients were grouped into two categories: LVEF<45 (n = 12) and LVEF >45 (n = 33). Pooled samples of pericardial fluid were fractionated by using ZOOM-isoelectric focusing (IEF) followed by further processing using one-dimensional gel electrophoresis (1D SDS-PAGE) and filter-aided sample preparation (FASP). Tryptic peptides of each fraction and differential bands were then analyzed by nano-LC-ESI-MS/MS. Protein identification was performed through a Mascot search engine using NCBI-Prot and SwissProt databases. A total of 1082 proteins including 154 metalloproteins were identified. In the differential bands, 60 metalloproteins were identified, while 115 metalloproteins were identified in all ZOOM-IEF fractions. Twelve differentially expressed metalloproteins were selected in the intense bands according to their molecular weight (MW) and isoelectric point (pI). The 12 differentially expressed metalloprotein includes ceruloplasmin, Prothrombin, Vitamin K-dependent protein, Fibulin-1, Ribosomal protein S6 kinase alpha-6, nidogen, partial, Serum albumin, Hemopexin, C-reactive protein, Serum amyloid P-component, and Intelectin-1 protein which were all up-regulated while serotransferrin is the only metalloprotein that was down-regulated in impaired (LVEF<45) group. Among the metalloproteins, Zn-binding proteins are 36.5 % followed by Ca-binging 32.2 %, and Fe-binging 12.2 %. KEGG, pathway analysis revealed the association of ceruloplasmin and serotransferrin with the ferroptosis pathway. In conclusion, 154 metalloproteins were identified of them the Zn-binding protein followed by Ca-binding and Fe-binding proteins were the most abundant metalloproteins. The two metalloproteins, the Cu-binding protein ceruloplasmin, and Fe-binding protein serotransferrin are involved in the ferroptosis pathway, an iron-dependent form of regulated cell death that has been linked to cardiac pathology, especially in IHD patients having impaired systolic (LVEF<45) dysfunction. However, further research is required to validate these findings.

Understanding of metals dysregulation in patients with systolic and diastolic dysfunction in ischemic heart disease.

Ischemic heart disease (IHD) is the leading cause of death and chronic disability in the world. IHD affects both the systolic and diastolic function of the heart which progressively leads to heart failure; a structural and functional impairment of filling or ejection of blood from the heart. In this study, the progression of systolic and diastolic dysfunction characterized according to their echocardiographic parameters including left ventricular ejection fraction (EF), grades of diastolic dysfunction and ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e'), were correlated with differential regulation of various metals in patients sera samples (n = 62) using inductive coupled plasma-mass spectrometry (ICP-MS). Chromium, nickel and selenium were found significant (p < 0.05) in patients having EF < 45% compared with EF > 45%. In patients with systolic dysfunction (EF < 45%), the level of selenium was decreased while the level of chromium and nickel was increased compared to patients with EF > 45%. Selenium level was also decreased significantly (p < 0.05) in grade 1A and 2 patients that are considered as higher grades of diastole dysfunction in comparison to grade 0-1. Overall, selenium deficiency was identified in both systolic and diastolic dysfunctions of IHD patients corresponding to the progression of disease that could be related to many metabolic and translational pathways specifically which involve selenoproteins.

Pericardial fluid proteomic label-free quantification of differentially expressed proteins in ischemic heart disease patients with systolic dysfunction by nano-LC-ESI-MS/MS analysis.

Left ventricular systolic dysfunction (LVSD) is common in patients with pre-existing ischemic heart disease (IHD) and myocardial infarction. An untargeted proteomic approach is used to improve the understanding of the molecular mechanisms associated with LVSD and to find out potential proteomic signatures in pericardial fluid. The pericardial fluid of IHD (n = 45) patients was grouped into two categories according to the left ventricular ejection fraction, LVEF ≥45 (n = 33) and LVEF <45 (n = 12), and analyzed by using nano-liquid chromatography-mass spectrometry (nano-LC-MS/MS) technique. The nano-LC-MS/MS analysis resulted in the identification of 709 pericardial fluid (PF) proteins in both normal and impaired systolic functional groups (LVEF ≥45 vs. LVEF <45). Sixteen proteins were found to be differentially expressed (p < 0.05, fold change >2) including 12 down-regulated and 4 up-regulated in the impaired systolic functional group (LVEF <45) compared to the normal group (LVEF ≥45). Among the differentially expressed proteins the inflammatory marker albumin, atherosclerosis marker apolipoprotein A-IV and hedgehog-interacting protein marker of angiogenesis were predominantly associated with the impaired LVEF <45 group. KEGG pathway analysis revealed that the hedgehog (Hh) signalling pathway is up-regulated in LVSD reflecting the underlying molecular and pathophysiological processes.

Ionomic profiling of pericardial fluid in ischemic heart disease.

Metals are essential cofactors that play a crucial role in heart function at the cell and tissue level. Information regarding the role of metals in the pericardial fluid and its ionome in ischemic heart disease (IHD) is limited. We aimed to determine the association of elements in pericardial fluid and serum samples of IHD patients and their correlation with systolic and diastolic function. IHD patients have been studied with systolic and diastolic dysfunction categorized on the basis of echocardiographic parameters. We measured concentrations of sixteen elements in the pericardial fluid and serum of 46 patients obtained during open heart surgery with IHD by ICP-MS. The levels of chromium and nickel in pericardial fluid were significantly higher as compared with serum samples of IHD patients (p < 0.05). The chromium, nickel and manganese levels in pericardial fluid were lower in patients with ejection fraction (EF) < 45% as compared to EF > 45% (p < 0.05). There was no significant difference in pericardial concentrations of elements in diastolic dysfunction grade 0-1 with 2 in IHD patients. We also found that decreased concentration of these elements in pericardial fluid is associated with decreased systolic function. These results suggest that pericardial fluid concentrations of these metals may reflect the extent of ischemic heart disease. These findings are hypothesis generating with regards to a role in the pathogenesis of the disorder.

Untargeted metabolomic analysis of coronary artery disease patients with diastolic dysfunction show disturbed oxidative pathway.

INTRODUCTION: Left ventricular diastolic dysfunction (LVDD) is common in patients with coronary artery disease (CAD) with prevalence estimates of 34% and constitutes a predictor of all-cause mortality. Although diastolic dysfunction is induced by myocardial ischemia and has been shown to alter the clinical course, the role of coronary artery disease in the diastolic dysfunction and its progression into heart failure has not been completely elucidated. OBJECTIVE: The present study was conducted to identify possible metabolites in coronary artery disease patients that are differentially regulated in patients with diastolic dysfunction. METHODS: The serum of CAD (n = 75) patients and young healthy volunteers (n = 43) were analysed by using gas chromatography mass spectrometry (GC-MS) technique. Pre-processing of data results in 1547 features; among them 1064 features were annotated using NIST library. RESULTS AND CONCLUSION: Fifteen metabolites were found to be statistically different between cases and control. Variation in metabolites were identified and correlated with several clinically important echocardiography parameters i.e. LVDD grades, ejection fraction (EF) and E/e' values. The results suggested that metabolic products of fatty acid oxidation and glucose oxidation pathways such as oleic acid, stearic acid, palmitic acid, linoleic acid, galactose, pyruvic and lactic acids are predominantly up regulated in patients with coronary artery disease and severity of diastolic dysfunction appears to be linked to increase in fatty acid oxidation and inflammation. The metabolic fingerprints of these patients give us an insight into the pathophysiological mechanism of diastolic dysfunction in coronary artery disease patients although it did not identify validated novel markers.