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

Abstract

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. Diabetes 54:2802-2806, 2005 P atients with diabetes presenting with acute myocardial infarction (AMI) have a poor in-hospital and long-term prognosis (1). The excess in-hospital mortality and morbidity correlates primarily with an increased incidence of congestive heart failure (1,2), with heart failure developing at about twice the rate in patients with diabetes than in patients without diabetes(1). Diabetes is also a risk factor for cardiogenic shock in the setting of acute ischemic syndromes (3).The susceptibility to diabetic complications is partially controlled by complex unknown genetic factors (4,5). One such genetic factor appears to be a functional allelic polymorphism in the haptoglobin (Hp) gene (6 -11). In humans, there are two major alleles, denoted 1 and 2, for the Hp gene (12,13). We have recently shown that patients who are homozygous for the Hp 1 allele (Hp 1-1) are at a lower risk of developing both microvascular (6,7,10) and macrovascular complications associated with diabetes (8,9,14). We have proposed that susceptibility to diabetic vascular disease conferred by the Hp type is the result of marked differences in the antioxidant protection against hemoglobin-induced oxidation provided by the Hp 1 and Hp 2 allelic protein products (15-17). Specifically, we have shown in vitro and in vivo in mice genetically modified at the Hp locus that the Hp 1 and Hp 2 protein products differ in a diabetes-dependent fashion in their ability to prevent the release of redox active iron from hemoglobin and in the rate at which the hemoglobin-Hp complex is cleared via the CD163 scavenger receptor on monocyte/macrophages (15)(16)(17).In the present study, we sought to prospectively test the hypothesis that Hp type is related to the outcome of patients presenting with AMI. Because previous studies have shown that the effect of Hp type might be especially important in pat...

Neovascularization in Human Atherosclerosis

“…An intermediate risk was found in individuals with the Hp-2-1 genotype (heterozygote). 55,[57][58][59] Remarkably, these studies have demonstrated that the cardiovascular risk of Hp-1-1 individuals with DM is not significantly different from that found in individuals without DM; apparently, the Hp-1-1 genotype mitigates the effect of DM on the development of cardiovascular disease. The mechanisms responsible for the increased importance of the Hp genotype on the development of diabetic cardiovascular disease may be related to the increased development of plaque neovessels in the diabetic state and the increased propensity of these neovessels to rupture and hemorrhage.…”

Genótipos de haptoglobina e hipertensão refratária em pacientes com diabete melito tipo 2

“…They found that diabetic patients with the Hp1-1 phenotype had smaller infarction sizes, whereas patients with Hp2-1 and Hp2-2 phenotypes sustained larger infarctions and consequently had a higher rate of heart failure and mortality 19 .…”

“…In addition, Suleiman et al 19 demonstrated that the Hp phenotype is an important predictor of 30-day mortality and heart failure among individuals with diabetes and acute myocardial infarction. They found that diabetic patients with the Hp1-1 phenotype had smaller infarction sizes, whereas patients with Hp2-1 and Hp2-2 phenotypes sustained larger infarctions and consequently had a higher rate of heart failure and mortality 19 .…”

“…It has been suggested that the Hp phenotype is an independent risk factor for CVD in patients with diabetes mellitus and that the Hp2-2 protein may provide less protection against vascular complications than the two other types of Hp 17,19 . Levy et al 17 in a matched case-control analysis of the Strong Heart Study, which investigated a group of American Indians, observed that diabetic individuals with the Hp2-2 phenotype have five times more risk of developing CVD than those who have the Hp1-1 phenotype.…”

“…It has been suggested that diabetic patients carrying the Hp2-2 genotype have increased risk of developing CVD [16][17][18][19][20] . However, this does not seem to be a consensual observation, and would appear to depend on the population and aspects analyzed.…”