Abstract
Disturbed redox balance in heart failure (HF) might contribute to impairment of cardiac function, by oxidative damage, or by regulation of cell signaling. The role of polymorphism in glutathione transferases (GSTs), involved both in antioxidant defense and in regulation of apoptotic signaling pathways in HF, has been proposed. We aimed to determine whether GST genotypes exhibit differential risk effects between coronary artery disease (CAD) and idiopathic dilated cardiomyopathy (IDC) in HF patients. GSTA1, GSTM1, GSTP1, and GSTT1 genotypes were determined in 194 HF patients (109 CAD, 85 IDC) and 274 age- and gender-matched controls. No significant association was found for GSTA1, GSTM1, and GSTT1 genotypes with HF occurrence due to either CAD or IDC. However, carriers of at least one variant GSTP1∗Val (rs1695) allele were at 1.7-fold increased HF risk than GSTP1∗Ile/Ile carriers (p = 0.031), which was higher when combined with the variant GSTA1∗B allele (OR = 2.2, p = 0.034). In HF patients stratified based on the underlying cause of disease, an even stronger association was observed in HF patients due to CAD, who were carriers of a combined GSTP1(rs1695)/GSTA1 “risk-associated” genotype (OR = 2.8, p = 0.033) or a combined GSTP1∗Ile/Val+Val/Val (rs1695)/GSTP1∗AlaVal+∗ValVal (rs1138272) genotype (OR = 2.1, p = 0.056). Moreover, these patients exhibited significantly decreased left ventricular end-systolic diameter compared to GSTA1∗AA/GSTP1∗IleIle carriers (p = 0.021). Higher values of ICAM-1 were found in carriers of the GSTP1∗IleVal+∗ValVal (rs1695) (p = 0.041) genotype, whereas higher TNFα was determined in carriers of the GSTP1∗AlaVal+∗ValVal genotype (rs1138272) (p = 0.041). In conclusion, GSTP1 polymorphic variants may determine individual susceptibility to oxidative stress, inflammation, and endothelial dysfunction in HF.
Highlights
For more than a decade, it has been suggested that a complex interplay between oxidative stress and chronic inflammation represents one of the underlying mechanisms of gradual cardiac depression in heart failure (HF) [1,2,3]
In HF patients stratified based on the underlying cause of disease, an even stronger association was observed in HF patients due to coronary artery disease (CAD), who were carriers of a combined GSTP1(rs1695)/GSTA1 “risk-associated” genotype (OR = 2 8, p = 0 033) or a combined GSTP1∗Ile/Val+Val/Val/GSTP1∗AlaVal+∗ValVal genotype (OR = 2 1, p = 0 056)
Based on different roles of GSTs and considering the fact that in the setting of heart failure the disturbances of redox regulation can contribute to disease progression, in this study, we investigated the effect of common GST polymorphisms regarding specific HF entities
Summary
For more than a decade, it has been suggested that a complex interplay between oxidative stress and chronic inflammation represents one of the underlying mechanisms of gradual cardiac depression in heart failure (HF) [1,2,3]. Regarding the mechanisms of oxidative stress in HF, both enhanced free radical production and diminished antioxidative defense are involved in the occurrence and progression of HF [5]. It is important to note that increased free radical production and inflammation are involved in cardiomyocyte apoptosis and progression of HF. Structural changes and activation of metalloproteinases are dependent on free radicals produced in the course of fibroblast to myofibroblast transformation. Taken together, all these free radical-dependent processes contribute to the occurrence of end-stage HF [5]. Several biomarkers of oxidative distress, such as isoprostanes, malondialdehyde, uric acid, and protein carbonyl groups, have been shown to be elevated in different stages of HF [7, 8]
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