Genetic predisposition in patients with hypertension and normal ejection fraction to oxidative stress

Fazakas, Ádám and Szelényi, Zsuzsanna and Szénási, Gábor and Nyírő, Gábor and Szabó, Péter M and Patócs, Attila and Tegze, Narcis and Fekete, Bertalan Csaba and Molvarec, Attila and Nagy, Bálint and Jakus, Judit and Örsi, Ferenc and Karádi, István and Vereckei, András (2016) Genetic predisposition in patients with hypertension and normal ejection fraction to oxidative stress. Journal of the American Society of Hypertension, 10 (2). pp. 124-132. ISSN 1933-1711, ESSN: 1878-7436)

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Abstract

The role of oxidative stress (OXS) due to myocardial nitric oxide synthase (NOS) uncoupling related to oxidative depletion of its cofactor tetrahydrobiopterin (BH4) emerged in the pathogenesis of heart failure with preserved ejection fraction (HFPEF). We determined the prevalence of 6 single nucleotide polymorphisms (SNPs) of genes encoding enzymes related to OXS, BH4 metabolism and NOS function in >60-year-old 94 patients with hypertension and 18 age-matched controls with normal EF. Using echocardiography 56/94(60%) patients with hypertension had left ventricular (LV) diastolic dysfunction (HTDD+ group), 38/94(40%) patients had normal LV diastolic function (HTDD- group). Four SNPs (rs841, rs3783641, rs10483639, rs807267) of guanosine triphosphate cyclohydrolase-1, the rate limiting enzyme in BH4 synthesis, 1 (rs4880) of manganese superoxide dismutase, and 1 (rs1799983) of endothelial NOS genes were genotyped using real time PCR method and Taqman probes. Protein carbonylation (PC), BH4 and total biopterin levels were measured from plasma samples. No between-groups difference in minor allele frequency (MAF) of SNPs was found. We calculated a genetic score indicating risk for OXS based on the MAFs of the SNPs. A high genetic risk for OXS was significantly associated with HTDD+ even after adjustment for confounding variables [OR(95%CI):4.79(1.12-20.54); p=0.035]. In both patient groups PC (p<0.05 for both), plasma BH4 (p<0.01 for both) and in the HTDD+ group total biopterin (p<0.05) increased vs. controls. In conclusion, in patients with hypertension and normal EF, a potential precursor of HFPEF, a partly genetically determined increased OXS seems to be associated with the presence of LV diastolic dysfunction.

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