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