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Haptoglobin Phenotype Is Associated With High-Density Lipoprotein-Bound Hemoglobin Content and Coronary Endothelial
Rabea Asleh1, Andrew P Levy2, Nina S Levy2
1From the Department of Cardiovascular Diseases, Mayo Clinic and College of Medicine, Rochester, MN (R.A., A.A., R.G., L.O.L., A.L.).
Insights
Haptoglobin (Hp) phenotype is linked to coronary endothelial dysfunction (ED) in individuals with diabetes mellitus. Increased hemoglobin (Hb) bound to high-density lipoprotein (HDL) via Hp 2-2 is associated with this dysfunction.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Biochemistry
Background:
- Coronary endothelial dysfunction (ED) is an early marker of atherosclerosis.
- High-density lipoprotein (HDL) function is impaired in ED.
- A haptoglobin (Hp) gene polymorphism influences HDL structure and function.
Purpose of the Study:
- To investigate the association between Hp phenotype and coronary ED.
- To determine if hemoglobin (Hb) tethered to HDL via Hp is Hp-type dependent.
- To assess the relationship between HDL-bound Hb and ED.
Main Methods:
- Assessed microvascular and epicardial coronary endothelial function in 338 individuals with nonobstructive coronary artery disease.
- Measured Hb bound to HDL using ELISA after immune-affinity chromatography.
- Analyzed Hp phenotype, Hb-HDL levels, and ED in relation to diabetes mellitus (DM).
Main Results:
- Hp phenotype associated with microvascular (P=0.01) and epicardial ED (P=0.04) in DM individuals.
- HDL-bound Hb inversely correlated with coronary blood flow (r=-0.40) and diameter (r=-0.44).
- Hp 2-2 phenotype (OR, 1.9; P=0.03) and HDL-bound Hb (OR, 4.6; P<0.0001) independently predicted microvascular ED.
Conclusions:
- Hp phenotype is significantly associated with coronary ED in individuals with DM.
- Increased Hb tethering to HDL via Hp 2-2 in DM may explain this association.
- HDL-bound Hb is an independent predictor of both microvascular and epicardial ED.
Abstract:
Objective- Coronary endothelial dysfunction (ED) is an early stage of atherosclerosis and is associated with impaired high-density lipoprotein (HDL) function. A functional polymorphism at the haptoglobin (Hp) gene locus (rs72294371) has been associated with marked differences in HDL structure and function. We sought to determine whether Hp phenotype was associated with coronary ED and whether the amount of hemoglobin (Hb) tethered to HDL via Hp was Hp-type dependent and associated with ED. Approach and Results- Microvascular and epicardial coronary endothelial function was assessed in 338 individuals with nonobstructive coronary artery disease. Microvascular ED was defined as <50% change in coronary blood flow and epicardial ED as ≥20% decrease in coronary artery diameter after intracoronary acetylcholine infusion. The amount of Hb bound to HDL was measured by ELISA after HDL purification from plasma samples using immune-affinity chromatography. One hundred and seventy of the individuals in this study (50.3%) were diagnosed with microvascular ED, 143 (42.3%) with epicardial ED, and 67 (19.7%) had diabetes mellitus (DM). Hp phenotype was significantly associated with microvascular ( P=0.01) and epicardial ED ( P=0.04) among DM individuals. There was a significant and inverse correlation between the amount of HDL-bound Hb and change in coronary blood flow (r=-0.40; P<0.0001) and in coronary artery diameter (r=-0.44; P<0.0001) in response to acetylcholine infusion. Hb content of HDL was significantly increased in individuals with Hp 2-2 and DM. In a logistic regression model, Hp 2-2 phenotype was associated with microvascular ED (odds ratio, 1.9; P=0.03) and the amount of HDL-bound Hb was an independent predictor of both microvascular (odds ratio, 4.6 for each 1-SD increase; P<0.0001) and epicardial (odds ratio, 2.2; P<0.0001) ED. Conclusions- Hp phenotype is significantly associated with coronary ED in DM individuals. This association is likely related to increased Hb tethering to HDL via Hp 2-2 in DM.
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