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. 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.

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 contraction, that preserved absolute radial wall thickening (radWT) due to left ventricular hypertrophy is responsible for the normal ejection fraction 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 at least 60-year-old 18 controls and 94 hypertensive patients with normal ejection fraction. RESULTS: Echocardiography revealed no left ventricular diastolic dysfunction in 38 out of 94 (40%) patients with hypertension (HTDD-negative group), and 56 out of 94 (60%) patients had diastolic dysfunction (HTDD-positive groups). The absolute values of global longitudinal left ventricular peak systolic S were significantly reduced in both patient groups (P < 0.05 for HTDD-negative, P < 0.01 for HTDD-positive groups) vs. the controls. There were no significant between-groups differences in circumferential and radial peak left ventricular systolic Ss, radWT and ejection fraction. Left ventricular mass (LVM) (P < 0.001), LVM/BMI (P < 0.01) increased in the HTDD-positive group and ejection fraction/LVM/BMI decreased in both patient groups (P < 0.01 for HTDD-negative, P < 0.001 for HTDD-positive groups) vs. the controls. LVM increased, ejection fraction/LVM/BMI decreased in the HTDD-positive group vs. the HTDD-negative group (P < 0.05 and P < 0.01, respectively). CONCLUSION: We demonstrated decreased longitudinal left ventricular systolic function and showed that preserved ejection fraction was due to preserved absolute radWT and not due to increased radial or circumferential systolic function in patients with hypertension and normal ejection fraction, a potential HFPEF precursor condition. Instead of ejection fraction, rather ejection fraction/LVM/BMI might be used to detect subtle left ventricular systolic dysfunction in hypertension and HFPEF.

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

OBJECTIVE: To investigate the role of oxidative stress, inflammation, hypercoagulability and neuroendocrine activation in the transition of hypertensive heart disease to heart failure with preserved ejection fraction (HFPEF). METHODS: We performed echocardiography for 112 patients (≥ 60 years old) with normal EF (18 controls and 94 with hypertension), and determined protein carbonylation (PC), and tetrahydrobiopterin (BH4), C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), fibrinogen, plasminogen activator inhibitor type-I (PAI-I), von Willebrand factor, chromogranin A (cGA) and B-type natriuretic peptide (BNP) levels from their blood samples. RESULTS: We found that 40% (38/94) of the patients with hypertension (HT) had no diastolic dysfunction (HTDD-), and 60% (56/94) had diastolic dysfunction (HTDD+). Compared to the controls, both patient groups had increased PC and BH4, TNF-α, PAI-I and BNP levels, while the HTDD+ group had elevated cGA and CRP levels. Decreased atrial and longitudinal left ventricular (LV) systolic and diastolic myocardial deformation (strain and strain rate) was demonstrated in both patient groups versus the control. Patients whose LV diastolic function deteriorated during the follow-up had elevated PC and IL-6 level compared to their own baseline values, and to the respective values of patients whose LV diastolic function remained unchanged. Oxidative stress, inflammation, BNP and PAI-I levels inversely correlated with LV systolic, diastolic and atrial function. CONCLUSIONS: In patients with HT and normal EF, the most common HFPEF precursor condition, oxidative stress and inflammation may be responsible for LV systolic, diastolic and atrial dysfunction, which are important determinants of the transition of HT to HFPEF.