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1.
Thromb Res ; 122(1): 85-90, 2008.
Article in English | MEDLINE | ID: mdl-17996280

ABSTRACT

BACKGROUND: Impaired endothelial-dependent flow-mediated dilatation (FMD) has been used to demonstrate endothelial dysfunction in a wide variety of cardiovascular disease, but previous studies have excluded patients with atrial fibrillation(AF). We therefore hypothesised that endothelial dysfunction exists in AF and that this could be demonstrated by impaired FMD, and related to plasma indices of endothelial damage/dysfunction [soluble E-selectin (sE-sel), von Willebrand factor (vWf), and soluble thrombomodulin (sTM)], as well as total body nitrate/nitrite product (NOx, a measure of endothelial nitric oxide production). METHODS: We studied 40 patients with chronic permanent AF, who were compared to 26 sinus rhythm controls. Patients with AF were stable on rate-control and antithrombotic medication and were fasted for the study. High-resolution ultrasound was used to measure right brachial artery diameter at rest, during reactive hyperaemia (endothelium-dependent flow-mediated dilatation) and following endothelium-independent, GTN-mediated dilatation. RESULTS: Baseline brachial artery diameter did not differ significantly between AF and healthy control subjects. FMD was significantly impaired in AF patients in comparison to healthy controls (8.9% in controls vs 0.0% in AF, p<0.0001). There was no significant difference in endothelium-independent (GTN-induced) dilatation between the groups. Only AF and male sex were independent predictors of impaired FMD on stepwise multiple regression analysis(p<0.0001). sE-sel and vWf were higher in AF than controls (p<0.05), and NOx levels did not reach significance (p=0.1416). CONCLUSIONS: Endothelial dysfunction, as demonstrated by impairment of FMD and raised vWF and E-selectin, is present in AF. Such endothelial perturbation may contribute to the increased risk of stroke and thromboembolism in this common arrhythmia.


Subject(s)
Atrial Fibrillation/physiopathology , Blood Flow Velocity , E-Selectin/blood , Endothelium, Vascular/physiopathology , Vasodilation/physiology , von Willebrand Factor/metabolism , Aged , Atrial Fibrillation/blood , Biomarkers/blood , Blood Pressure , Cholesterol/blood , Chronic Disease , Female , Humans , Hypertension/complications , Male , Middle Aged , Myocardial Infarction/complications , Stroke/complications , Stroke Volume
2.
Chest ; 132(4): 1253-8, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17890461

ABSTRACT

BACKGROUND: Atrial fibrillation (AF) is associated with a prothrombotic state, which is related to endothelial damage/dysfunction. Plasma levels of soluble E-selectin (sE-sel), von Willebrand factor (vWf), and soluble thrombomodulin (sTM) have been used as indexes of endothelial activation, damage/dysfunction, and endothelial damage, respectively. Nitric oxide is also made by a healthy endothelium, and a total body nitrate/nitrite product (NOx) is used as a measure of endothelial nitric oxide production. We hypothesized that the levels of these markers of endothelial function would be abnormal in patients with paroxysmal, persistent, and permanent AF. METHODS: We studied 145 AF patients (paroxysmal AF, 35 patients; permanent AF, 50 patients; persistent AF, 60 patients) and 35 patients with "lone" AF. Plasma levels of sE-sel, vWf, and sTM (measured by enzyme-linked immunosorbent assay) and NOx (measured by a colorimetric assay based on the Griess reaction) were compared to 40 age-matched healthy control subjects in sinus rhythm. RESULTS: Patients with AF had significantly higher plasma levels of vWf (p < 0.001) and sE-sel (p = 0.005) compared with control subjects, but sTM and NOx levels were not significantly different. Levels did not differ significantly among the clinical subgroups of patients with paroxysmal, persistent, and permanent AF. Patients with lone AF had significantly higher vWF levels (p = 0.003) and significantly lower sTM levels (p = 0.0361) compared to control subjects, but sE-sel and NOx levels were not significantly different. There were no significant differences in the AF study population in vWF, sE-sel or sTM levels after 4 weeks of warfarin treatment. CONCLUSION: Endothelial perturbation exists in all clinical subgroups of patients with AF, including those with lone AF, which may contribute to the prothrombotic state seen in these patients.


Subject(s)
Atrial Fibrillation/blood , E-Selectin/blood , Endothelium, Vascular/physiopathology , Thrombomodulin/blood , von Willebrand Factor/analysis , Aged , Atrial Fibrillation/epidemiology , Atrial Fibrillation/pathology , Atrial Fibrillation/physiopathology , Colorimetry , Cross-Sectional Studies , Endothelium, Vascular/pathology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Hypercholesterolemia/epidemiology , Male , Middle Aged , Multivariate Analysis , Nitric Acid/metabolism
3.
Nephron Clin Pract ; 107(3): c109-16, 2007.
Article in English | MEDLINE | ID: mdl-17890873

ABSTRACT

BACKGROUND: Disturbances in mineral and vitamin D metabolism, which affect parathyroid hormone (PTH) synthesis, are well recognized in patients receiving dialysis. However, it is unclear at what stage of chronic kidney disease (CKD) these abnormalities develop. METHODS: The associations between CKD stages 3 and 5, and alterations of calcium, phosphate, vitamin D and PTH concentrations were assessed in 249 patients (mean age 61 years, 66% male) and 79 age- and sex-matched healthy controls. RESULTS: As compared to controls, serum phosphate concentrations were elevated among CKD patients (1.40 vs. 1.11 mmol/l; p < 0.0001). And levels of both 25-hydroxyvitamin D (42.1 vs. 60.4 nmol/l; p < 0.0001) and 1,25-dihydroxyvitamin D (58.2 vs. 119.5 pmol/l; p < 0.0001) were lower among patients with CKD, even among those with only stage 3 CKD and despite 73% of patients receiving vitamin D supplements. The ratio of 1,25-dihydroxy- to 25-hydroxyvitamin D was lower than controls, even among patients with stage 3 CKD (p = 0.0001), and this ratio diminished with advancing renal impairment. Concomitant elevations were observed in intact PTH (13.8 vs. 4.2 pmol/l; p < 0.0001) and whole PTH (7.9 vs. 2.7 pmol/l; p < 0.0001). CONCLUSION: Impaired conversion of 25-hydroxy- to 1,25-dihydroxyvitamin D is an early feature of renal disease, and progresses as renal function deteriorates.


Subject(s)
Calcium/blood , Hyperparathyroidism/blood , Kidney Failure, Chronic/blood , Parathyroid Hormone/blood , Phosphates/blood , Renal Dialysis/adverse effects , Vitamin D Deficiency/blood , Vitamin D/blood , Aged , Cross-Sectional Studies , Female , Homeostasis , Humans , Hyperparathyroidism/etiology , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/rehabilitation , Male , Middle Aged , Minerals/blood , Vitamin D Deficiency/etiology
5.
Prenat Diagn ; 27(2): 111-6, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17192963

ABSTRACT

OBJECTIVE: To report two cases of preimplantation genetic diagnosis (PGD) for myotonic dystrophy type I (DM1) where cross-over between the DMPK locus and a linked polymorphic marker APOC2 was detected. METHODS: Embryos from in vitro fertilisation (IVF) were biopsied at day 3 of development and single blastomeres collected. Diagnosis was performed by duplex or triplex fluorescent-polymerase chain reaction (F-PCR) to amplify DMPK and APOC2 loci, or DMPK with APOC2 and D19S112 polymorphic markers. RESULTS: A total of 22 oocytes were retrieved from the two patients, 20 were inseminated of which 15 fertilized (75%) and were suitable for biopsy on day 3. A diagnosis was obtained for 12 embryos (80%) and was confirmed in all un-transferred embryos. Crossover between DM1 and APOC2 was detected in two embryos from the two different couples. Transfer of two embryos took place in both cases resulting in two pregnancies. Each couple have had a healthy baby. CONCLUSION: The above cases highlight the importance of using more than one linked polymorphic marker in PGD-PCR protocols and emphasize the danger of using APOC2 as the sole marker to identify the DM1 mutation.


Subject(s)
Apolipoprotein C-II/genetics , Crossing Over, Genetic/genetics , Genetic Testing , Myotonic Dystrophy/diagnosis , Preimplantation Diagnosis/methods , Protein Serine-Threonine Kinases/genetics , Adult , Biopsy , Female , Fertilization in Vitro , Genetic Linkage , Genetic Markers/genetics , Humans , Male , Myotonic Dystrophy/genetics , Myotonin-Protein Kinase , Oocytes/chemistry , Oocytes/pathology , Polymerase Chain Reaction , Pregnancy
6.
Kidney Int ; 63(4): 1433-42, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12631359

ABSTRACT

BACKGROUND: Chronic renal failure is associated with impaired endothelium-dependent vasodilation and accelerated atherogenesis. To examine whether endogenous reactive oxygen species (ROS) modify endothelial function in renal failure, we evaluated the effect of the antioxidant vitamin C on endothelium-dependent responses in both the conduit and resistance vasculature of subjects with severe renal impairment. METHODS: Endothelial function of the forearm resistance vasculature was assessed using plethysmography to measure the dilator response to intra-arterial acetylcholine (Ach) (25 to 100 nmol/min). Endothelial function of radial and brachial arteries was assessed using vascular ultrasound to measure the dilator response to flow during reactive hyperemia [flow-mediated dilatation (FMD)]. Studies were performed before and after administration of vitamin C by intra-arterial infusion (25 mg/min) in 33 predialysis patients or by intravenous infusion (3 g) in 17 hemodialysis patients. RESULTS: Parenteral administration of vitamin C resulted in a 100-fold increase (intra-arterial studies) and a 4.5-fold increase (intravenous studies) in serum antioxidant activity. Vitamin C administration increased the dilator response to ACh in resistance vessels (P = 0.01), but did not alter the dilator response to flow in conduit vessels of either dialysis (P = 0.3) or predialysis subjects (P = 0.8). In the presence of the nitric oxide (NO) synthase inhibitor NGmonomethyl-L-arginine (L-NMMA), there was no effect of vitamin C on resistance vessel endothelial function. In all cases the dilator response to the endothelium-independent dilators was unaffected by vitamin C. CONCLUSION: Acute administration of vitamin C reduces oxidant stress in renal failure and improves NO-mediated resistance vessel dilatation.


Subject(s)
Antioxidants/administration & dosage , Ascorbic Acid/administration & dosage , Endothelium, Vascular/physiology , Kidney Failure, Chronic/drug therapy , Kidney Failure, Chronic/physiopathology , Vascular Resistance/drug effects , Adult , Biomarkers , Brachial Artery/physiology , Endothelium, Vascular/drug effects , Female , Humans , Male , Middle Aged , Nitric Oxide/metabolism , Oxidative Stress/drug effects , Radial Artery/physiology , Renal Dialysis , Vasodilation/drug effects
7.
Eur J Heart Fail ; 5(2): 171-4, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12644008

ABSTRACT

BACKGROUND: Chronic elevation of plasma catecholamines and sympathetic stimulation in chronic heart failure (CHF) leads to increased production of free radicals, and so possibly to endothelial damage/dysfunction and atheroma formation. Abnormal oxidative stress may therefore be related to some of the high mortality and morbidity in CHF. The objective of the present prospective open study was to compare the effects of beta-blockers and ACE inhibitors in relation to oxidative stress and endothelial damage in CHF. METHODS: We studied 66 outpatients with CHF: 46 patients were established on an ACE inhibitor and were then started on a beta-blocker, and 20 patients not previously on ACE-inhibitors were started on lisinopril. Baseline levels of the measured parameters were compared to 22 healthy control subjects. Serum lipid hydroperoxides (LHP) and total antioxidant capacity (TAC) were determined as indices of oxidative damage and antioxidant defence, and plasma von Willebrand factor (vWf) as an index of endothelial damage/dysfunction. RESULTS: Baseline indices for the measures of oxidative damage and endothelial function in the 66 CHF patients were significantly higher than healthy control subjects [median LHP 7.5 (5.9-12.6) vs. 4.8 micromol/l, P=0.0022; TAC 428 (365-567) vs. 336 Trollox Eq. Units, P=0.0005; mean vWf 134+/-27 vs. 89+/-23 IU/dl, P<0.0001]. Following 3 months of maintenance therapy with beta-blockers, there was significant reduction in LHP levels, but not TAC or vWf. ACE inhibitor therapy also significantly reduced vWf levels, but failed to have any statistically significant effects on LHP or TAC. CONCLUSION: This pilot study suggests that oxidative stress in CHF may be due to increased free radical production or inefficient free radical clearance by scavengers. beta-Blockers, but not ACE inhibitors, reduced lipid peroxidation in patients with CHF. No relation was demonstrated between a reduction in oxidative damage and endothelial damage/dysfunction.


Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Heart Failure/drug therapy , Oxidative Stress/drug effects , Oxidative Stress/physiology , Aged , Biomarkers/blood , Bisoprolol/therapeutic use , Blood Pressure/drug effects , Carbazoles/therapeutic use , Carvedilol , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Female , Follow-Up Studies , Heart Failure/blood , Heart Failure/epidemiology , Humans , Lipid Peroxides/blood , Lisinopril/therapeutic use , Male , Middle Aged , Propanolamines/therapeutic use , Prospective Studies , Risk Factors , Treatment Outcome , von Willebrand Factor/metabolism
8.
Clin Sci (Lond) ; 102(4): 397-402, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11914101

ABSTRACT

Cardiac parasympathetic control has prognostic significance in heart failure, but the control mechanisms of this system remain poorly defined. We have demonstrated previously a facilitatory role for nitric oxide (NO) in the parasympathetic control of heart rate in young healthy human subjects. In view of the complex abnormalities of regional NO activity observed in chronic heart failure, we now aim to establish if this mechanism is active in subjects with this condition. Groups of 12 heart failure patients [NYHA class II-III; mean age 52 years (range 38-67 years)] and 12 age/sex-matched healthy control subjects [mean age 50 years (range 36-62 years)] were studied. Heart rate variability and baroreflex sensitivity were measured during inhibition of endogenous NO production with N(G)-monomethyl-l-arginine (l-NMMA; 3 mg.h(-1).kg(-1)) and during administration of an equipressor dose of the control vasoconstrictor phenylephrine (12-36 microg.h(-1).kg(-1)). Basal levels of nitrate+nitrite were measured in the plasma as an indication of systemic NO production. In the heart failure patients, despite an equal rise in blood pressure with both drugs, high-frequency indices of heart rate variability increased less with l-NMMA than with phenylephrine: RMSSD (root mean square of successive RR-interval differences) increased by 4+/-2 compared with 26+/-8 ms (P<0.001) and high-frequency power increased by 97+/-62 compared with 1372+/-861 ms(2) (P<0.001). The increases in cross-spectral baroreflex sensitivity were also lower with l-NMMA than with phenylephrine [high-frequency alpha-index, 2.2+/-1.3 and 12.6+/-3.8 ms/mmHg respectively (P<0.001); low-frequency alpha-index, 1.3+/-0.9 and 4.3+/-1.7 ms/mmHg respectively (P<0.05)]. Healthy subjects showed a similar discrepancy in the response of high-frequency indices of heart rate variability to the two drugs, although baroreflex sensitivity responses were significantly different only for the high-frequency alpha-index. Levels of plasma nitrate+nitrite were significantly higher in the heart failure patients compared with controls. These data demonstrate that baroreflex-mediated cardiac parasympathetic activation in human heart failure, as in health, is dependent upon endogenous NO synthesis.


Subject(s)
Heart Failure/physiopathology , Nitric Oxide/physiology , Parasympathetic Nervous System/physiopathology , Adult , Aged , Baroreflex/drug effects , Blood Pressure/drug effects , Cardiotonic Agents/pharmacology , Cross-Over Studies , Enzyme Inhibitors/pharmacology , Female , Heart Rate/drug effects , Humans , Male , Middle Aged , Nitrates/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Nitrites/pharmacology , Phenylephrine/pharmacology , Single-Blind Method , Vasoconstrictor Agents/pharmacology , omega-N-Methylarginine/pharmacology
9.
Hypertension ; 39(1): 51-6, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11799078

ABSTRACT

Cardiac vagal control has prognostic significance in cardiac disease, but the control mechanisms of this system remain poorly understood. We have previously demonstrated a role for NO in promoting vagal control of heart rate in humans. Here we examine the influence of L-arginine, the substrate for NO synthase, on this mechanism in healthy human subjects. Eleven healthy volunteers (9 men; age, 20 to 25 years) underwent measurement of heart rate variability and baroreflex sensitivity before and during a systemic infusion of L-arginine (1 g/min; total, 30 g). To control for the fall in blood pressure, comparison was made with an infusion of the control vasodilator hydralazine. Stereospecificity of observed effects was investigated by infusion of D-arginine. Urinary nitrate and nitrite (NO(x)) and cGMP concentrations were measured as indexes of NO generation. L-Arginine infusion produced a drop in mean arterial pressure of 5 mm Hg. This fall in blood pressure was matched by hydralazine infusion and was not observed with either D-arginine or saline infusion. Although RR interval duration, heart rate variability, and baroreflex sensitivity all fell significantly with hydralazine, the same degree of baroreflex unloading with L-arginine produced an increase in RR interval duration and no change or even slight increases in heart rate variability and baroreflex sensitivity. In contrast, D-arginine produced falls in high-frequency indexes of heart rate variability compared with saline. Only L-arginine increased urinary NO(x) and cGMP excretion. In conclusion, these data demonstrate that short-term L-arginine infusion facilitates vagal control of heart rate in healthy humans, probably via increased NO synthesis.


Subject(s)
Arginine/pharmacology , Heart/drug effects , Vagus Nerve/drug effects , Adult , Baroreflex/drug effects , Baroreflex/physiology , Blood Pressure/drug effects , Cross-Over Studies , Female , Heart/physiology , Heart Rate/drug effects , Heart Rate/physiology , Humans , Hydralazine/pharmacology , Male , Nitric Oxide/metabolism , Nitric Oxide/physiology , Single-Blind Method , Stereoisomerism , Vagus Nerve/physiology , Vasodilator Agents/pharmacology
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