Haptoglobin Polymorphism Predicts 30-Day Mortality and Heart Failure in Patients With Diabetes and Acute Myocardial Infarction

Technion - Israel Institute of Technology, H̱efa, Haifa, Israel
Diabetes (Impact Factor: 8.1). 10/2005; 54(9):2802-6. DOI: 10.2337/diabetes.54.9.2802
Source: PubMed


Patients with diabetes presenting with acute myocardial infarction (AMI) have an increased rate of death and heart failure. Patients with diabetes homozygous for the haptoglobin (Hp) 1 allele (Hp 1-1) develop fewer vascular complications. We tested the hypothesis that Hp type is related to the outcome of patients with diabetes presenting with AMI. We prospectively assessed the relationship between Hp type and 30-day mortality and heart failure in 1,437 patients with AMI (506 with diabetes). Multivariate logistic regression identified a significant interaction between Hp type and diabetes status on these outcome measures. Hp type was not related to outcome among patients without diabetes. In contrast, Hp 1-1 was associated with a strong protective effect with regard to the primary end point of death (OR 0.14, P = 0.015) and for death and heart failure (OR 0.35; 95% CI 0.15-0.86, P = 0.018) among patients with diabetes. Finally, among patients with diabetes, Hp 1-1 was associated with smaller infarct size. This study demonstrates that in patients with diabetes and AMI, the Hp type is an important determinant of clinical outcome and infarct size.

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    • "More recent investigations employing native Hp:Hb ligand appeared to suggest poor or even lack of dependence on CD163 for IL-6 or IL-10 signalling pathways, depending on the type of polymorphic haptoglobin variant employed [17] [18]. Since the haptoglobin 2 allele is linked to a host of adverse clinical cardiovascular events, [19] [20] [21] [22] [23] it is important to understand Hp genotype-dependent disease mechanisms in CD163 + macrophages in greater detail, to guide informed interdictions in vulnerable individuals. Here we have examined IL-10 signalling pathways during scavenging of polymorphic Hp2-2:Hb versus Hp1-1:Hb complexes in CD163 + human monocyte-derived macrophages. "
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    ABSTRACT: Intraplaque hemorrhage causes adaptive remodelling of macrophages towards a protective phenotype specialized towards handling iron and lipid overload, denoted Mhem. The Mhem phenotype expresses elevated levels of hemoglobin (Hb) scavenger receptor, CD163, capable of endocytosing pro-oxidant free Hb complexed to acute phase protein haptoglobin (Hp). It is notable that individuals homozygous for the Hp 2 allele (a poorer antioxidant) are at increased risk of cardiovascular disease compared to the Hp 1 allele. In this study, we examined whether scavenging of polymorphic Hp:Hb complexes differentially generated downstream anti-inflammatory signals in cultured human macrophages culminating in interleukin (IL)-10 secretion. We describe an anti-inflammatory signalling pathway involving phosphatidylinositol-3-kinase activation upstream of Akt phosphorylation (pSer473Akt) and IL-10 secretion. The pathway is mediated specifically through CD163 and is blocked by anti-CD163 antibody or phagocytosis inhibitor. However, levels of pSer473Akt and IL-10 were significantly diminished when scavenging polymorphic Hp2-2:Hb complexes compared to Hp1-1:Hb complexes ( P < 0.05 ) . Impaired anti-inflammatory macrophage signaling through a CD163/pAkt/IL-10 axis may thus represent a possible Hp2-2 disease mechanism in atherosclerosis.
    04/2013; 2013(24):980327. DOI:10.1155/2013/980327
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    • "AGEs are a class of complex glycoxidized products, produced during the reaction between reducing sugars and free amino groups of proteins. The reaction begins with the formation of a Schiff base between the carbonyl group of the reducing sugar and e-amino group of a protein, that further rearranges to form stable Amadori product [5] [6] [7]. Circulating AGEs exert their deleterious effects through interactions with their cell surface receptor RAGE (receptor for AGE), resulting in post receptor activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in endothelial cells, mesangial cells and macrophages [8]. "
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    ABSTRACT: Aim: This study aimed to evaluate whether hyperglycemia mediated increased formation of advanced glycation end products (AGEs) was associated with erythrocyte antioxidant enzyme activity in subjects with different stages of diabetic retinopathy (DR). Methods: Serum level of AGEs was determined by enzyme linked immunosorbent assay. Erythrocyte superoxide dismutase (SOD), glutathione reductase (GR) and catalase activity were estimated by enzymatic reaction based spectrophotometric assay in patients with type 2 diabetes with proliferative diabetic retinopathy (PDR), non-proliferative diabetic retinopathy (NPDR) and no retinopathy (DNR) and also in healthy non-diabetic controls (HC). Result: Erythrocyte SOD and GR activity was significantly lower among NPDR (p=0.024, 0.0017, respectively) and PDR (p=0.0003, 0.0001, respectively) subjects compared with DNR individuals. A significant inverse correlation was observed between serum AGEs and erythrocyte SOD or GR activity in DNR (p=0.0019; r=-0.3033, p=0.0021; r=-0.3015, respectively), NPDR (p=0.0001; r=-0.4602, p=0.0003; r=-0.4161, respectively), and PDR (p<0.0001; r=-0.6753, p<0.0001; r=-0.5854, respectively) individuals. Conclusion: Poor glycemia may be the key factor enhancing AGE formation, which may be associated with lower erythrocyte SOD and GR activity along with increased catalase activity in DR.
    Diabetes research and clinical practice 04/2013; 100(3). DOI:10.1016/j.diabres.2013.03.031 · 2.54 Impact Factor
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    • "One study [19] found that individuals with T2DM and the HP2-2 genotype had increased risk for CVD events. In addition, Suleiman et al. in 2005 [20] found that individuals with T2DM and the HP 1–1 phenotype had decreased 30-day mortality and heart failure after acute myocardial infarction compared to individuals with the HP 2–2 phenotype, again suggesting the HP 2-2 phenotype as the risk phenotype. This association was not seen in individuals without T2DM. "
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    ABSTRACT: Haptoglobin (HP) is an acute phase protein that binds to freely circulating hemoglobin. HP exists as two distinct forms, HP1 and HP2. The longer HP2 form has been associated with cardiovascular (CVD) events and mortality in individuals with type 2 diabetes (T2DM). This study examined the association of HP genotypes with subclinical CVD, T2DM risk, and associated risk factors in a T2DM-enriched sample. Haptoglobin genotypes were determined in 1208 European Americans (EA) from 473 Diabetes Heart Study (DHS) families via PCR. Three promoter SNPs (rs5467, rs5470, and rs5471) were also genotyped. Analyses revealed association between HP2-2 duplication and increased carotid intima-media thickness (IMT; p = 0.001). No association between HP and measures of calcified arterial plaque were observed, but the HP polymorphism was associated with triglyceride concentrations (p = 0.005) and CVD mortality (p = 0.04). We found that the HP2-2 genotype was associated with increased T2DM risk with an odds ratio (OR) of 1.49 (95% CI 1.18-1.86, p = 6.59x10-4). Promoter SNPs were not associated with any traits. This study suggests association between the HP duplication and IMT, triglycerides, CVD mortality, and T2DM in an EA population enriched for T2DM. Lack of association with atherosclerotic calcified plaque likely reflect differences in the pathogenesis of these CVD phenotypes. HP variation may contribute to the heritable risk for CVD complications in T2DM.
    Cardiovascular Diabetology 02/2013; 12(1):31. DOI:10.1186/1475-2840-12-31 · 4.02 Impact Factor
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