Hypoxia-Inducible Factor 1α Polymorphism and Coronary Collaterals in Patients With Ischemic Heart Disease

doi:10.1378/chest.128.2.787

Chest

Volume 128, Issue 2, August 2005, Pages 787-791

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Study objectives

Marked variability exists in coronary artery collaterals in patients with ischemic heart disease. Although multiple factors are thought to play a role in collateral development, the contribution of genetic factors is largely unknown. Hypoxia inducible factor 1 (HIF-1), a transcriptional activator that functions as a master regulator of oxygen homeostasis, is one possible genetic factor that could play an important role in modulating collateral development

Design, setting, and participants

Collateral vessels were determined in 100 patients with ≥ 70% narrowing of at least one coronary artery without acute myocardial infarction or prior revascularization. DNA was genotyped for the presence of a single nucleotide (C to T) polymorphism that changes residue 582 of HIF-1α from proline to serine

Measurements and results

The frequency of the T allele was significantly higher among patients without collaterals compared to patients with collaterals (0.188 vs 0.037, p < 0.001). In multivariate analyses, two variables affecting collateral formation were detected: two-or three-vessel coronary artery disease was a significant positive predictor (odds ratio [OR], 4.17; 95% confidence interval [CI], 1.61 to 10.8; p = 0.001), whereas the presence of HIF-1α genotype CT or TT was a negative predictor (OR, 0.19; 95% CI, 0.04 to 0.84; p = 0.03)

Conclusions

These data suggest that variations in HIF-1α genotype may influence development of coronary artery collaterals in patients with significant coronary artery disease

Section snippets

Patient Recruitment

The study was approved by the institutional review board of Johns Hopkins University. Written informed consent was obtained from all subjects. Study participants were recruited consecutively from those patients undergoing diagnostic coronary artery catheterization. The indications for catheterization in all patients were the presence of stable or unstable angina pectoris or suspected significant myocardial ischemia. Exclusion criteria were age < 18 years, presence of anemia, acute myocardial

Results

Among 100 patients studied, 68 had collaterals (Table 1). Among patients with collaterals, there was a significantly increased frequency of multivessel coronary artery disease (p = 0.002), hypercholesterolemia (p = 0.03), and statin treatment (p = 0.04) as compared to patients without collaterals.

All patients were homozygous for the G allele encoding Ala at codon 588 (Ala/Thr polymorphism). For the polymorphism involving codon 582 (Pro/Ser polymorphism), the overall frequencies of the C and T

Discussion

In this study, we have presented evidence that the CT or TT genotype for theHIF1Aexon 12 polymorphism was associated with absence of coronary collaterals in the setting of coronary artery disease. The CT or TT genotype was also associated with single-vessel as compared to multivessel disease and was observed in 0 of 30 patients with triple-vessel disease. These data provide the first evidence that genetic variation at theHIF1Alocus encoding HIF-1α influences the pathogenesis of ischemic heart

Acknowledgments

We are grateful to the nurses and staff of The Johns Hopkins Hospital Cardiac Catheterization Laboratory for their help. We thank Dr. Aravinda Chakravarti for advice on study design and data analysis.

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This work was supported in part by grants R01-HL55338 and P01-HL65608 from the National Institutes of Health (Dr. Semenza).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml)

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Chest

Clinical Investigations CardiologyHypoxia-Inducible Factor 1α Polymorphism and Coronary Collaterals in Patients With Ischemic Heart Disease

Study objectives

Design, setting, and participants

Measurements and results

Conclusions

Section snippets

Patient Recruitment

Results

Discussion

Acknowledgments

Am Heart J

Microvasc Res

Atherosclerosis

Am J Cardiol

Am J Cardiol

Atherosclerosis

Coronary collaterals: an important and underexposed aspect of coronary artery disease

Circulation

Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects

J Am Coll Cardiol

Clinical Investigations Cardiology
Hypoxia-Inducible Factor 1α Polymorphism and Coronary Collaterals in Patients With Ischemic Heart Disease