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

What is known about the topic•Increased oxidative stress is present in hypertensive patients with normal ejection fraction, which can lead to left ventricular (LV) diastolic dysfunction.•LV diastolic dysfunction, LV hypertrophy, and atrial dysfunction are considered important determinants of transition of hypertensive heart disease to heart failure with preserved ejection fraction.What this study adds•To the best of our knowledge, so far only the single nucleotide polymorphisms of individual genes encoding enzymes related to oxidative stress were studied in hypertensive patients and this is the first study with the aim to investigate the genetic predisposition of hypertensive patients to oxidative stress.•We have shown that increased oxidative stress in patients with hypertension and normal ejection fraction is at least partly genetically determined by calculation of a genetic score based on the minor allele frequencies of six single nucleotide polymorphisms of genes encoding enzymes related to oxidative stress.•Genetic predisposition to oxidative stress indicated by the genetic score increased in line with the presence of LV diastolic dysfunction.•Our genetic score can be applied for the prediction of progression of LV diastolic dysfunction, and in addition to LV diastolic dysfunction, LV mass and atrial dysfunction might be a useful marker of the transition of hypertensive heart disease to heart failure with preserved ejection fraction.

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.