title: Genetic predisposition in patients with hypertension and normal ejection fraction to oxidative stress.
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. We determined the prevalence of six 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 ejection fraction. Using echocardiography, 56/94 (60%) patients with hypertension had left ventricular (LV) diastolic dysfunction (HTDD+ group) and 38/94 (40%) patients had normal LV diastolic function (HTDD- group). Four SNPs (rs841, rs3783641, rs10483639, and rs807267) of guanosine triphosphate cyclohydrolase-1, the rate-limiting enzyme in BH4 synthesis, one (rs4880) of manganese superoxide dismutase, and one (rs1799983) of endothelial NOS genes were genotyped using real-time polymerase chain reaction method and Taqman probes. Protein carbonylation, BH4, and total biopterin levels were measured from plasma samples. No between-groups difference in minor allele frequency of SNPs was found. We calculated a genetic score indicating risk for OXS based on the minor allele frequencies of the SNPs. A high genetic risk for OXS was significantly associated with HTDD+ even after adjustment for confounding variables (odds ratio [95% confidence interval]:4.79 [1.12-20.54]; P = .035). In both patient groups protein carbonylation (P < .05 for both), plasma BH4 (P < .01 for both) and in the HTDD+ group total biopterin (P < .05) increased versus controls. In conclusion, in patients with hypertension and normal ejection fraction, a potential precursor of heart failure with preserved ejection fraction, a partly genetically determined increased OXS, seems to be associated with the presence of LV diastolic dysfunction.
authors.affiliation: 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Ádám
authors.initials: Á
authors.lastname: Fazakas
authors.affiliation: Heart Center, Semmelweis University, Budapest, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Szelényi
authors.affiliation: Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szénási
authors.affiliation: MTA-SE Molecular Medicine Research Group, Semmelweis University, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Nyírő
authors.affiliation: MTA-SE Molecular Medicine Research Group, Semmelweis University, Budapest, Hungary.
authors.forename: Péter M
authors.initials: PM
authors.lastname: Szabó
authors.affiliation: MTA-SE Lendulet Hereditary Endocrine Tumors Research Group, Semmelweis University, Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Patócs
authors.affiliation: Department of Neurology, Kútvölgyi Clinical Group, Semmelweis University, Budapest, Hungary.
authors.forename: Narcis
authors.initials: N
authors.lastname: Tegze
authors.affiliation: 2nd Department of Medicine, Military Hospital, Budapest, Hungary.
authors.forename: Bertalan C
authors.initials: BC
authors.lastname: Fekete
authors.affiliation: First Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Molvarec
authors.affiliation: First Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary.
authors.forename: Bálint
authors.initials: B
authors.lastname: Nagy
authors.affiliation: Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Jakus
authors.affiliation: Department of Applied Biology and Food Science, University of Technology, Budapest, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Örsi
authors.affiliation: 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Karádi
authors.affiliation: 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary. Electronic address: vereckei@kut.sote.hu.
authors.forename: András
authors.initials: A
authors.lastname: Vereckei
mesh_terms: D000368:Aged; D001708:Biopterins / Q000097:blood / Q000378:metabolism; D004452:Echocardiography; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000517:prevention & control; D006801:Humans; D006814:Hungary / Q000453:epidemiology; D006973:Hypertension / Q000000981:diagnostic imaging / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D050050:Protein Carbonylation; D060888:Real-Time Polymerase Chain Reaction; D013318:Stroke Volume; D013482:Superoxide Dismutase / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000235:genetics*
chemical_list: D001708:Biopterins; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D006136:GTP Cyclohydrolase
keywords: Heart failure with preserved ejection fraction; hypertension; oxidative stress