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CLINICAL RESEARCH: ATHEROSCLEROSIS

Haptoglobin Genotype Is a Major Determinant of the Amount of Iron in the Human Atherosclerotic Plaque

Pedro R. Moreno, MD, FACC^_*, K. Raman Purushothaman, MD^_*, Meera Purushothaman, PhD^_*, Paul Muntner, PhD^_*, Nina S. Levy, PhD, Valentin Fuster, MD, PhD, FACC^_*, John T. Fallon, MD, PhD, Patrick A. Lento, MD, Aaron Winterstern, BS and Andrew P. Levy, MD, PhD, FACC^,_*

^_* Department of Medicine (Cardiology), Mount Sinai Medical Center, New York, New York
Department of Pathology, Mount Sinai Medical Center, New York, New York
Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel

Manuscript received April 7, 2008; revised manuscript received June 5, 2008, accepted June 6, 2008.

^_* Reprint requests and correspondence: Dr. Andrew P. Levy, Technion Faculty of Medicine, POB 9649, Haifa, Israel 31096 (Email: alevy{at}tx.technion.ac.il).

Objectives: We sought to test the hypothesis that haptoglobin (Hp) genotype is a determinant of the amount of iron in the atherosclerotic plaque.

Background: In atherosclerotic lesions, intraplaque hemorrhage releases free hemoglobin (Hb), whose incorporated iron can act as an oxidant and inflammatory stimulus. These effects are antagonized by Hp, which binds free Hb and facilitates its clearance from the plaque. The Hp gene has 2 alleles (1 and 2), giving rise to 3 genotypes: Hp 1-1, Hp 2-1, and Hp 2-2. We previously hypothesized that Hp 2-2 individuals with diabetes mellitus (DM) have impaired clearance of Hb and its iron cargo from the plaque.

Methods: We identified the presence or absence of Perl's iron stain in 189 plaques obtained from 37 decedents at autopsy.

Results: Among DM, the prevalence of Perl's iron stain was increased in Hp 2-2 compared with that seen in Hp 1-1 or 2-1 (46.2% vs. 11.8%). After accounting for the within-decedent correlation of plaques, the prevalence ratio of Perl's iron stain associated with Hp 2-2 was 3.97 (95% confidence interval: 1.38 to 11.5; p = 0.025). In non-DM plaques, there was a nonsignificant trend towards a higher prevalence of iron staining in Hp 2-2 compared with that in Hp 1-1 or 2-1 (26.8% vs. 11.1%; prevalence ratio =2.40 [95% confidence interval: 0.81 to 7.09]; p = 0.114).

Conclusions: These data support an impaired clearance of Hb from plaques in Hp 2-2 individuals, particularly in DM. The higher prevalence of plaque iron in Hp 2-2 DM individuals may contribute to the increased incidence of atherothrombotic events in these patients.

Key Words: atherosclerotic plaque • iron • intraplaque hemorrhage • diabetes mellitus

Abbreviations and Acronyms   DM = diabetes mellitus   Hb = hemoglobin   Hp = haptoglobin   TCFA = thin-cap fibroatheromas

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J. Am. Coll. Cardiol. 2008 52: A34. [Full Text] [PDF]