Endothelial dysfunction and increased oxidative stress in mitochondrial diseases.

MDs (mitochondrial diseases) are a clinically heterogeneous group of disorders characterized by impairment of the respiratory chain function with altered oxidative phosphorylation. We tested the hypothesis that the function of vascular endothelium is affected by increased oxidative stress in MDs. A total of 12 patients with MDs and pair-matched controls were studied. Endothelial function was assessed by measuring FMD (flow-mediated vasodilation) of brachial and common femoral arteries. The test was repeated after vitamin C (500 mg, twice a day) and E (400 mg, once a day) supplementation for 30 days and 90 days after vitamin withdrawal. FMD was reduced in patients compared with controls [AUC/τ (time-averaged area under the curve) for the brachial artery, 1.05±0.24 compared with 4.19±0.59% respectively, P<0.001; AUC/τ for the femoral artery, 0.98±0.19 compared with 2.36±0.29% respectively, P=0.001; values are means±S.E.M.] and correlated (brachial artery) with plasma lactate (r=-0.63, P<0.01). Urinary 8-iso-PGF2α (8-iso-prostaglandin F2α) was higher in patients than controls (505.6±85.9 compared with 302.5±38.7 pg/mg of creatinine; P<0.05) and correlated with plasma lactate (r=0.70, P<0.05). Immunohistochemical analysis showed 8-iso-PGF2α staining in MD-affected striated muscle cells and in blood vessels in muscle biopsies of patients. Antioxidant vitamins transiently restored FMD in patients [ΔAUC/τ (change in AUC/τ) for the brachial artery, +1.38±0.49%, P<0.05; ΔAUC/τ for the femoral artery, +0.98±0.24%, P<0.01] but had no effect on FMD in controls (brachial artery, -1.3±0.63%; and common femoral artery, -0.58±0.30%), thus abolishing the differences between patients and controls. The results of the present study indicate that oxidative stress is increased and is, at least partly, responsible for endothelial dysfunction in MDs.

Autonomic system activity and 24-hour blood pressure variations in subjects with normal- and high-tension glaucoma.

PURPOSE: As suggested by findings of abnormal responses to posture in patients with normal-tension glaucoma (NTG), cardiovascular autoregulation may also be defective in primary open-angle glaucoma (POAG). PATIENTS AND METHODS: Both 24-hour ambulatory blood pressure monitoring and the head-up tilt test were performed in 17 subjects with NTG and in 13 subjects with high-tension POAG (ht-POAG). These groups were compared with 17 age-matched healthy individuals. Subjects undergoing cardiovascular therapy were excluded. RESULTS: No significant differences in diurnal and nocturnal blood pressure and heart rate were found between the groups. A significant reduction in diurnal heart rate variability was found in NTG (12.1 +/- 2.8 bpm) compared with the ht-POAG (15.0 +/- 2.4 bpm, P < 0.01) and control groups (15.8 +/- 3.0 bpm, P = 0.01]). Nocturnal diastolic blood pressure variability was also reduced in NTG (6.9 +/- 2.2 mm Hg) compared with controls (8.6 +/- 2.3 mm Hg, P < 0.05]) as was heart rate variability (6.3 +/- 1.4 vs 8.3 +/- 2.6 in ht-POAG, P < 0.05), suggesting blunted blood pressure and heart rate modulation in NTG subjects. Spectral analysis of short-term heart rate variability showed a significant reduction of total power in the supine position (1064 +/- 600 in NTG vs 1688 +/- 889 ms2 in controls, P < 0.05]). This was not accompanied either by a physiological reduction in total power or in a high-frequency component during the passive orthostatic stimulus. These differences tend to become more prominent in the clinically more severe forms of NTG (as identified by scores based on the extent of optic disk excavation, visual field damage, and progression of disease). This would suggest a correlation between the extent of autonomic disorder and severity of glaucoma. The alpha index (root-square of low-frequency heart rate to low-frequency blood pressure ratio) was lower in the supine position in NTG subjects (8.1 +/- 3.1 vs 10.6 +/- 3.3 ms/mm Hg in controls, P < 0.05), confirming the reduced baroreflex sensitivity. CONCLUSIONS: The results confirm the hypothesis that dysfunction of autonomic control of the cardiovascular response may be a contributing pathogenetic factor in NTG, inducing a chronic ischemia of the optic nerve.