Inflammation and oxidative stress caused by nitric oxide synthase uncoupling might lead to left ventricular diastolic and systolic dysfunction in patients with hypertension

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The mechanism of reduced longitudinal left ventricular systolic function in hypertensive patients with normal ejection fraction

Background: MacIver and Townsend’s hypothesis predicts, based on a mathematical model of left ventricular (LV) contraction, that preserved absolute radial wall thickening (radWT) due to LV hypertrophy is responsible for the normal ejection fraction (EF) in patients with heart failure with preserved ejection fraction (HFPEF). Methods: We tested the validity of this hypothesis by detailed echocardiography including evaluation of ventricular myocardial strain (S) using speckle tracking imaging in >60-year-old 18 controls and 94 hypertensive patients with normal EF. Results: Echocardiography revealed no LV diastolic dysfunction in 38/94(40%) patients with HT (HTDD- group), and 56/94(60%) patients had diastolic dysfunction (HTDD+ group). The absolute values of global longitudinal LV peak systolic S were significantly reduced in both patient groups (p<0.05 for HTDD-, p<0.01 for HTDD+ groups) versus the controls. There were no significant between-groups differences in circumferential and radial peak LV systolic Ss, radWT and EF. LV mass (LVM) (p<0.001), LVM/body mass index (BMI) (p<0.01) increased in the HTDD+ group and EF/LVM/BMI decreased in both patient groups (p<0.01 for HTDD-, p<0.001 for HTDD+ groups) versus the controls. LVM increased, EF/LVM/BMI decreased in the HTDD+ group versus the HTDD- group (p<0.05 and p<0.01 respectively). Conclusions: We demonstrated decreased longitudinal LV systolic function, and showed that preserved EF was due to preserved absolute radWT and not to increased radial or circumferential systolic function in patients with HT and normal EF, a potential HFPEF precursor condition. Instead of EF, rather EF/LVM/BMI might be used to detect subtle LV systolic dysfunction in hypertension and HFPEF

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

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