Elsevier

Clinical Biochemistry

Volume 44, Issues 17–18, December 2011, Pages 1421-1424
Clinical Biochemistry

Study on the role of environmental parameters and HIF-1A gene polymorphism in coronary collateral formation among patients with ischemic heart disease

https://doi.org/10.1016/j.clinbiochem.2011.09.001Get rights and content

Abstract

Objectives

To evaluate the association between collateral formation and some environmental factors along with a polymorphism in HIF-1A gene in selected Iranian patients with CAD.

Design and methods

Patients with ≥ 70% narrowing in at least one coronary vessel according to coronary angiography were enrolled. The patients' demographic, clinical and biochemical data were collected. The presence of C1772T polymorphisms within HIF-1A was analyzed using the polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP).

Results

There is no significant difference between the patients with and without collaterals according to the frequency of T allele or HIF-1A variants. The higher severity of coronary vessel obstruction was positive predictor of collateral formation (OR = 1.026, 95%, CI: 1.02–0.04, p < 0.001), whereas aging and cigarette smoking were negative predictors (OR = 0.95, 95% CI: 0.91–0.99, p < 0.05; OR = 0.30, 95% CI: 0.11–0.79, p < 0.05; respectively).

Conclusions

The findings indicate not any significant association between collateral formation and polymorphic variants of HIF-1A and P582S substitution does not appear to influence the collateral formation in patients with myocardial ischemia

Introduction

The presence of a well-developed collateral circulation is likely to raise the chance of myocardium viability via supplying an alternative source of blood during a hypoxic situation [1], [2]. Thus, along with the previously well-defined risk factors for ischemic heart disease (IHD) [3], [4], the individual differences in collateral formation and myocardium sensitivity to ischemia should be considered as additional indicators for a reliable prediction of cardiac vulnerability [5], [6].

At present, it is not clear why there is a difference between IHD patients in terms of the development of a sufficient collateral circulation [7]. Collateral formation is a complex process affected by a combination of genetic and environmental factors, including age [8], [9], history of angina [10], severity of coronary arterial stenosis [11], anemia [12], hypercholestremia [13], [14], systemic hypertension [15], [16], cigarette smoking [11], [17], diabetes mellitus [18], and a number of common medications [17]. Furthermore, there is also a wide variation in the expression level of growth factors (particularly VEGF) [17], [19], [20] and endogenous angiogenesis inhibitors between subjects [17], [18].

Oxygen deprivation induces the formation of hypoxia-inducible factor-1 (HIF-1) (a heterodimeric protein consisting of two subunits: α and β), which regulates the expression of many genes involved in adaptive responses to oxygen deprivation and stimulates the development of new blood vessels through the release of various angiogenic-stimulating cytokines and growth factors [19], [21], [22], [23], [24]. The vascular endothelial growth factor (VEGF) is one of these angiogenic cytokines which may diffuse from hypoxic cells and bind to its receptor on endothelial cells and activate endothelial cell division and angiogenesis [19], [25], [26].

HIF-1A appears as a possible genetic target for regulating collateral formation since the expression of this protein has been associated with the presence of collateral vessels in patients with IHD [27]. C582–T582 polymorphisms in exon 12 of the human HIF1A gene affected the coding sequence of HIF-1α and transactivation capacity in a previous study on the renal cell carcinoma [28].

C1772T nucleotide substitution creates a change from a proline to serine at codon 582 (P582S) within the carboxyl-terminal domain of HIF-1α, which may adversely influence the expression of angiogenic growth factors through affecting protein stability and transcriptional activity [22], [29].

The current study sought to determine whether C582–T582 polymorphisms in HIF-1A along with other identified predisposing factors influence collateral formation in Iranian IHD patients.

Section snippets

Patients

The study participants were recruited consecutively from patients undergoing diagnostic coronary artery catheterization between May 2009 and February 2009 in Tehran Heart Center, Iran (n = 196, age = 58.8 ± 10.7 years, 71.4% male). The indications for catheterization in all the patients were the presence of stable/unstable angina pectoris or any remote myocardial infarction (> 7 days). Patients aged ≥ 18 years and at least one coronary stenosis of ≥ 70% (by visual analysis of the angiogram) were included

Results

Among the 196 patients studied, 113 (57.6%) had collaterals. The univariate analysis of the variables between the groups revealed that patients with collateral vessels had a significantly higher number of diseased artery (p value < 0.001), higher level of VEGF (p value < 0.01), and more severe vessel obstruction based on the Gensini score (p value < 0.001). The hemoglobin level significantly and the frequency of cigarette smoking somewhat significantly were lower in the patients with collaterals than

Discussion

In this study, we found no evidence indicating a possible association between CT or TT genotype for HIF-1A exon 12 and absence of collateral formation. The findings indicate that P582S substitution does not influence the adaptive collateralization in patients suffering from myocardial ischemia. Contrary to Resar et al., who reported a higher frequency of a more active polymorphic variant of HIF-1A (CC) in patients with collaterals [34], we did not find any association between HIF-1A

Acknowledgment

The present study was supported by a grant from Women Research Center for Biomedical Science, Alzahra University, Tehran, Iran and Tehran Heart Center, Tehran University of Medical Science, Tehran, Iran. We are grateful to nurses and stuff of the Tehran heart center particularly Roghayeh Kheiri for her help. We thank Dr. Mahmood SheikhFathollahi for data analysis.

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