ABSTRACT
BACKGROUND: The long-term excess risk of death associated with diabetes following acute myocardial infarction is unknown. We determined the excess risk of death associated with diabetes among patients with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) after adjustment for comorbidity, risk factors and cardiovascular treatments. METHODS: Nationwide population-based cohort (STEMI n=281â 259 and NSTEMI n=422â 661) using data from the UK acute myocardial infarction registry, MINAP, between 1 January 2003 and 30 June 2013. Age, sex, calendar year and country-specific mortality rates for the populace of England and Wales (n=56.9 million) were matched to cases of STEMI and NSTEMI. Flexible parametric survival models were used to calculate excess mortality rate ratios (EMRR) after multivariable adjustment. This study is registered at ClinicalTrials.gov (NCT02591576). RESULTS: Over 1.94 million person-years follow-up including 120â 568 (17.1%) patients with diabetes, there were 187â 875 (26.7%) deaths. Overall, unadjusted (all cause) mortality was higher among patients with than without diabetes (35.8% vs 25.3%). After adjustment for age, sex and year of acute myocardial infarction, diabetes was associated with a 72% and 67% excess risk of death following STEMI (EMRR 1.72, 95% CI 1.66 to 1.79) and NSTEMI (1.67, 1.63 to 1.71). Diabetes remained significantly associated with substantial excess mortality despite cumulative adjustment for comorbidity (EMRR 1.52, 95% CI 1.46 to 1.58 vs 1.45, 1.42 to 1.49), risk factors (1.50, 1.44 to 1.57 vs 1.33, 1.30 to 1.36) and cardiovascular treatments (1.56, 1.49 to 1.63 vs 1.39, 1.36 to 1.43). CONCLUSIONS: At index acute myocardial infarction, diabetes was common and associated with significant long-term excess mortality, over and above the effects of comorbidities, risk factors and cardiovascular treatments.
Subject(s)
Diabetes Mellitus/mortality , Myocardial Infarction/mortality , Aged , England/epidemiology , Female , Humans , Male , Myocardial Infarction/therapy , Registries , Risk Factors , Survival Analysis , Wales/epidemiologyABSTRACT
OBJECTIVES: To investigate geographic variation in guideline-indicated treatments for non-ST-elevation myocardial infarction (NSTEMI) in the English National Health Service (NHS). DESIGN: Cohort study using registry data from the Myocardial Ischaemia National Audit Project. SETTING: All Clinical Commissioning Groups (CCGs) (n=211) in the English NHS. PARTICIPANTS: 357â 228 patients with NSTEMI between 1 January 2003 and 30 June 2013. MAIN OUTCOME MEASURE: Proportion of eligible NSTEMI who received all eligible guideline-indicated treatments (optimal care) according to the date of guideline publication. RESULTS: The proportion of NSTEMI who received optimal care was low (48â 257/357â 228; 13.5%) and varied between CCGs (median 12.8%, IQR 0.7-18.1%). The greatest geographic variation was for aldosterone antagonists (16.7%, 0.0-40.0%) and least for use of an ECG (96.7%, 92.5-98.7%). The highest rates of care were for acute aspirin (median 92.8%, IQR 88.6-97.1%), and aspirin (90.1%, 85.1-93.3%) and statins (86.4%, 82.3-91.2%) at hospital discharge. The lowest rates were for smoking cessation advice (median 11.6%, IQR 8.7-16.6%), dietary advice (32.4%, 23.9-41.7%) and the prescription of P2Y12 inhibitors (39.7%, 32.4-46.9%). After adjustment for case mix, nearly all (99.6%) of the variation was due to between-hospital differences (median 64.7%, IQR 57.4-70.0%; between-hospital variance: 1.92, 95% CI 1.51 to 2.44; interclass correlation 0.996, 95% CI 0.976 to 0.999). CONCLUSIONS: Across the English NHS, the optimal use of guideline-indicated treatments for NSTEMI was low. Variation in the use of specific treatments for NSTEMI was mostly explained by between-hospital differences in care. Performance-based commissioning may increase the use of NSTEMI treatments and, therefore, reduce premature cardiovascular deaths. TRIAL REGISTRATION NUMBER: NCT02436187.
Subject(s)
Guideline Adherence , Healthcare Disparities , Hospitals , Myocardial Infarction/therapy , Residence Characteristics , State Medicine , Aged , Aged, 80 and over , Aspirin/therapeutic use , Cohort Studies , Echocardiography , England , Female , Humans , Male , Middle Aged , Mineralocorticoid Receptor Antagonists , Myocardial Infarction/drug therapy , Myocardial Ischemia , Platelet Aggregation Inhibitors/therapeutic use , Purinergic P2Y Receptor Antagonists/therapeutic use , Spatial AnalysisABSTRACT
BACKGROUND: Restrictive cardiomyopathy (RCM) is rare in childhood, but has a grave prognosis. The cause of disease in most cases is unknown. OBJECTIVE: To determine the prevalence of sarcomere protein gene mutations in children with idiopathic RCM. METHODS: Twelve patients (9 female, mean age 5.1 years) with idiopathic RCM referred between 1991 and August 2006 underwent detailed clinical and genetic evaluation. Nine had received cardiac transplants at the time of the study. The entire coding sequences of the genes encoding eight cardiac sarcomere proteins and desmin were screened for mutations. Familial evaluation was performed on first-degree relatives. RESULTS: Four patients (33%) had a family history of cardiomyopathy: RCM (n = 2); dilated cardiomyopathy (n = 1) and left ventricular non-compaction (n = 1). Sarcomere protein gene mutations were identified in four patients (33%): 2 in the cardiac troponin I gene (TNNI3) and 1 each in the troponin T (TNNT2) and alpha-cardiac actin (ACTC) genes. Two were de novo mutations and 3 were new mutations. All mutations occurred in functionally important and conserved regions of the genes. CONCLUSIONS: Sarcomere protein gene mutations are an important cause of idiopathic RCM in childhood. We describe the first mutation in ACTC in familial RCM. The identification of RCM in a child should prompt consideration of sarcomere protein disease as a possible cause and warrants clinical evaluation of the family.
Subject(s)
Actins/genetics , Cardiomyopathy, Restrictive/genetics , MAP Kinase Kinase Kinases/genetics , Troponin T/genetics , Adolescent , Amino Acid Sequence , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Hypertrophic, Familial/genetics , Cardiomyopathy, Restrictive/pathology , Carrier Proteins/genetics , Child , Child, Preschool , DNA Mutational Analysis/methods , Female , Genetic Linkage/genetics , Humans , Infant , Male , Mutation, Missense/genetics , Pedigree , Protein Serine-Threonine Kinases , Sarcomeres/genetics , Sarcomeres/physiologyABSTRACT
OBJECTIVES: To determine the relation of ambulatory systolic blood pressure to aortic obstruction and more extensive vascular dysfunction, assessed by central aortic, peripheral conduit arterial and resistance vessel function. METHODS: 12 adults (5 native, 7 recoarctation) were studied before, and 2 weeks and 6 months after aortic stenting. Systolic blood pressure was measured during normal daily living by 24-hour ambulatory monitoring. Central aortic function was assessed by pulse wave analysis (augmentation index). Brachial artery flow-mediated dilatation and dilatation in response to 25 mug of sublingual glyceryl trinitrate was assessed by ultrasound to measure peripheral conduit arterial and resistance vessel function. Baseline vascular measures were compared with those of 12 matched controls. RESULTS: Patients had a higher augmentation index, impaired endothelium-dependent and -independent dilatation, and forearm vascular resistance (p<0.02). After successful gradient relief by stenting, daytime ambulatory systolic blood pressure (151 (134, 166) mm Hg vs 138 (130, 150) mm Hg, p = 0.01) and the augmentation index (26 (15, 34) vs 23 (13, 30), p = 0.03) fell progressively over 6 months, but did not completely normalise. Endothelium-dependent and -independent dilatation, and forearm vascular resistance remained unchanged and impaired. CONCLUSION: Relief of aortic obstruction is associated with improvement in central aortic function and results in reduction of daytime ambulatory systolic blood pressure. Peripheral vascular dysfunction, however, remains unchanged and may contribute to residual hypertension.
Subject(s)
Aortic Coarctation/surgery , Hypertension/etiology , Peripheral Vascular Diseases/etiology , Stents , Adult , Aortic Coarctation/complications , Aortic Coarctation/physiopathology , Blood Pressure Monitoring, Ambulatory , Brachial Artery/diagnostic imaging , Brachial Artery/physiopathology , Female , Follow-Up Studies , Forearm/blood supply , Humans , Hypertension/physiopathology , Male , Peripheral Vascular Diseases/physiopathology , Prospective Studies , Ultrasonography , Vascular Resistance , VasodilationABSTRACT
BACKGROUND: In adults with hypertrophic cardiomyopathy (HCM), plasma B-type natriuretic peptide (BNP) levels correlate with dyspnoea class and other markers of disease severity. In children with HCM, symptoms are a poor guide to disease severity and no studies have evaluated the clinical utility of BNP testing. OBJECTIVE: To assess the relation of BNP levels to symptoms and markers of disease severity in children with HCM. METHODS: Forty-four consecutive patients with HCM (27 male, age
Subject(s)
Cardiomyopathy, Hypertrophic/blood , Natriuretic Peptide, Brain/metabolism , Adolescent , Child , Child, Preschool , Diastole/physiology , Female , Humans , Infant , Male , Multivariate Analysis , Ventricular Dysfunction, Left/bloodABSTRACT
BACKGROUND: Atherosclerosis develops from childhood, but the determinants of this preclinical stage remain uncertain. We examined the relations of classic coronary risk factors, adiposity and its associated metabolic disturbances, to arterial distensibility (a marker of early arterial disease) in 13- to 15-year-olds, some of whom had previously been studied at ages 9 to 11 years. METHODS AND RESULTS: Brachial artery distensibility was measured by a noninvasive ultrasound technique in 471 British children in whom measures of adiposity, blood pressure, fasting blood lipids, and insulin had been made. All adiposity measures showed strong graded inverse relationships with distensibility. Inverse associations with distensibility were also observed for insulin resistance (homeostasis model assessment), diastolic pressure, C-reactive protein, and the number of metabolic syndrome components present, which had a graded relation to distensibility. Total and LDL cholesterol levels were also inversely related to distensibility, but less strongly than adiposity; homocysteine had no relation to distensibility. Although the relations of total and LDL cholesterol and diastolic pressure to distensibility had been present at 9 to 11 years of age, those of adiposity and insulin resistance were only apparent at 13 to 15 years. CONCLUSIONS: Adiposity and its metabolic consequences are associated with adverse changes in the arterial wall by the teenage years. The graded relation with increasing adiposity was stronger than that for cholesterol and was seen at body mass index levels well below those considered to represent "obesity." This emphasizes the importance of population-based strategies to control adiposity and its metabolic consequences in the young.
Subject(s)
Adipose Tissue/anatomy & histology , Atherosclerosis/epidemiology , Brachial Artery/physiology , Metabolic Syndrome/epidemiology , Adolescent , Blood Glucose/analysis , Blood Pressure , Child , Female , Follow-Up Studies , Humans , Insulin/blood , Lipids/blood , Male , Muscle, Smooth, Vascular/physiology , Risk FactorsABSTRACT
Vascular endothelial dysfunction describes a phenotype prone to atherogenesis and clinical complications of this disease process. Endothelium-dependent vasodilator function, reflecting local bioavailability of nitric oxide, can be measured clinically in the peripheral and coronary circulation and corresponds with other measures of endothelial biology including inflammatory status and thrombotic tendency. Although conventional risk factors are key determinants of endothelial dysfunction, many other factors, including the individual's genetic profile, also appear to exert important positive and negative functional influences. Thus, endothelial vasodilator function can be regarded as an integrated index of all atherogenic and atheroprotective factors acting on the vascular wall, reflecting underlying biology and inherent atherosclerotic risk. The potential clinical utility of endothelial vasomotor testing as a prognostic tool in risk assessment and for the monitoring of therapy requires further validation before recommending its wider routine use.
Subject(s)
Arteriosclerosis/physiopathology , Endothelial Cells/physiology , Endothelium, Vascular/physiopathology , Vasodilation/physiology , Adolescent , Adult , Arteriosclerosis/etiology , Child , Humans , Predictive Value of Tests , Risk Assessment , Vasomotor System/physiopathologyABSTRACT
BACKGROUND: The pulsatile nature of pulmonary blood flow is important for shear stress-mediated release of endothelium-derived nitric oxide (NO) and lowering pulmonary vascular resistance (PVR) by passive recruitment of capillaries. Normal pulsatile flow is lost or markedly attenuated after Fontan-type operations, but to date, there are no data on basal pulmonary vascular resistance and its responsiveness to exogenous NO at late follow-up in these patients. METHODS AND RESULTS: We measured indexed PVR (PVRI) using Fick principle to calculate pulmonary blood flow, with respiratory mass spectrometry to measure oxygen consumption, in 15 patients (median age, 12 years; range, 7 to 17 years; 12 male, 3 female) at a median of 9 years after a Fontan-type operation (6 atriopulmonary connections, 7 lateral tunnels, 2 extracardiac conduits). The basal PVRI was 2.11+/-0.79 Wood unit (WU) times m2 (mean+/-SD) and showed a significant reduction to 1.61+/-0.48 (P=0.016) after 20 ppm of NO for 10 minutes. The patients with nonpulsatile group in the pulmonary circulation dropped the PVRI from 2.18+/-0.34 to 1.82+/-0.55 (P<0.05) after NO inhalation. CONCLUSIONS: PVR falls with exogenous NO late after Fontan-type operation. These data suggest pulmonary endothelial dysfunction, related in some part to lack of pulsatility in the pulmonary circulation because of altered flow characteristics. Therapeutic strategies to enhance pulmonary endothelial NO release may have a role in these patients.
Subject(s)
Endothelium, Vascular/physiology , Fontan Procedure , Nitric Oxide/administration & dosage , Pulmonary Circulation/physiology , Vascular Resistance/physiology , Administration, Inhalation , Adolescent , Age Factors , Angiography , Blood Flow Velocity/drug effects , Blood Flow Velocity/physiology , Cardiac Catheterization , Child , Endothelium, Vascular/drug effects , Female , Heart Defects, Congenital/surgery , Hemodynamics/drug effects , Hemodynamics/physiology , Humans , Male , Oxygen Consumption/physiology , Pulmonary Circulation/drug effects , Pulsatile Flow/physiology , Time , Vascular Resistance/drug effectsABSTRACT
AIMS: To compare an echocardiographic method for detecting abnormal cardiac function before development of overt cardiomyopathy with a recently validated technique of quantifying myocardial iron load. METHODS AND RESULTS: We examined thalassaemia patients whose myocardial iron load had been evaluated with magnetic resonance imaging (MRI). By tissue Doppler echocardiography, myocardial velocities were sampled continuously from base to apex in the RV and LV free wall, and the septum in 52 patients aged 29.2 (14.2-43.1) years and 52 age-matched controls. Ninety-six percent of patients had normal LV ejection fraction by MRI. Thirty-eight (73%) had abnormal iron loading of the myocardium, and 33 of those had regional wall motion abnormalities detected in the septum (n=29), LV (n=2), RV (n=1), and septum plus LV (n=1). The incidence of wall motion abnormalities was significantly higher (P<0.04) in patients with myocardial iron overload (87%) than in the 14 without (35%). Furthermore, myocardial iron overload was suggested by a low T2(*)(15.1+/-15.8 ms) in patients with wall motion abnormalities vs those with normal wall motion (T2(*): 30+/-19 ms) (P<0.007). CONCLUSIONS: Wall motion abnormalities may represent an early sign of cardiac disease despite preserved global function. The regional abnormalities are related to iron overload and easily detectable with tissue Doppler echocardiography.
Subject(s)
Cardiomyopathies/diagnostic imaging , Iron Overload/diagnostic imaging , beta-Thalassemia/complications , Adolescent , Adult , Cardiomyopathies/diagnosis , Cardiomyopathies/physiopathology , Chelating Agents/therapeutic use , Deferoxamine/therapeutic use , Echocardiography, Doppler , Humans , Iron Overload/diagnosis , Iron Overload/physiopathology , Magnetic Resonance Imaging , Ventricular Dysfunction/diagnosis , Ventricular Dysfunction/physiopathology , Ventricular Function/physiology , beta-Thalassemia/physiopathologyABSTRACT
An endothelial nitric oxide synthase (eNOS) gene polymorphism (Glu298Asp) has been associated with cardiovascular disease. We investigated whether carriage of the polymorphism was associated with functional changes in the endothelium, and how genotype altered the harmful and beneficial impact of environmental influences on the endothelium. Endothelium-dependent, flow-mediated brachial artery dilatation (FMD) and endothelium-independent dilatation response to glyceryl trinitrate were measured using high-resolution ultrasound in 248 subjects (131 female, 117 male, aged 20 to 28) genotyped for the Glu298Asp polymorphism. Vascular function was compared between genotype groups and interactions with the proatherogenic risk factor, smoking, and the antiatherogenic influence of n-3 fatty acids (n-3FA) were investigated. Vascular function was not related to genotype in the group as a whole or within sexes. However, among males, smoking was associated with lower FMD in Asp298 carriers (nonsmokers 0.125+/-0.085 mm versus smokers 0.070+/-0.060 mm, P=0.006) but not in Glu298 homozygotes (nonsmokers 0.103+/-0.090 mm versus smokers 0.124+/-0.106, P=0.5). In the whole group, n-3FA levels were positively related to FMD in Asp298 carriers (reg coeff=0.023 mm/%, P=0.04, r=0.20) but not in Glu298 homozygotes (reg coeff=-0.019 mm/%, P=0.1). These differences between genotype groups were significant in interaction models. The Glu298Asp polymorphism is associated with differences in endothelial responses to both smoking and n-3 FA in healthy young subjects. These findings raise the possibility of genotype-specific prevention strategies in cardiovascular disease.
Subject(s)
Diet , Endothelium, Vascular/physiology , Nitric Oxide Synthase/genetics , Smoking , Adult , Amino Acid Substitution , Aspartic Acid/genetics , Blood Flow Velocity , Blood Pressure/physiology , Brachial Artery/drug effects , Brachial Artery/physiology , Endothelium, Vascular/enzymology , Fatty Acids, Omega-3/blood , Female , Genotype , Glutamic Acid/genetics , Humans , Lipids/blood , Male , Nitric Oxide Synthase Type III , Nitroglycerin/pharmacology , Polymorphism, Genetic , Risk Factors , Vasodilation/drug effectsABSTRACT
BACKGROUND: Accelerated vascular disease is common in chronic renal failure (CRF) and accounts for significant mortality and morbidity. Elevated homocysteine levels may contribute by an effect on endothelial function. METHODS AND RESULTS: We performed a double-blind placebo-controlled randomized crossover trial of folic acid at 5 mg/m2 in 25 normotensive children 12+/-3 (7 to 17) years of age with CRF (glomerular filtration rate 26.8+/-13.2 mL/min per 1.73 m2) of noninflammatory etiology. Each subject underwent two 8-week periods of folic acid and placebo separated by an 8-week washout period. The effect of folic acid on homocysteine levels, LDL oxidation, and both endothelial-dependent and -independent vascular function were measured. After oral folic acid, serum folate levels rose from 11.7+/-4.25 to 635+/-519 microg/L (P=0.001), red cell folate levels rose from 364+/-195 to 2891+/-2623 microg/L (P<0.001), and total homocysteine levels fell from 10.28+/-4.16 to 8.62+/-2.32 micromol/L (P=0.03). In addition, there was a significant improvement in flow-mediated dilatation (FMD) (endothelial-dependent dilatation) from 7.21+/-2.8% to 8.47+/-3.01% (P=0.036) with no change in response to glyceryl trinitrate (endothelial-independent dilatation). There was no significant change in FMD or glyceryl trinitrate during the placebo phase. There was, however, no significant difference in final FMD after placebo or folic acid. Lag times for LDL oxidation were prolonged during the treatment phase (58.4+/-18.7 to 68.1+/-25.9 minutes, P=0.01). CONCLUSION: Folic acid supplementation in children with CRF may improve endothelial function with an increased resistance of LDL to oxidation.
Subject(s)
Endothelium, Vascular/physiopathology , Folic Acid/therapeutic use , Homocysteine/blood , Kidney Failure, Chronic/drug therapy , Administration, Oral , Adolescent , Child , Cross-Over Studies , Dietary Supplements , Double-Blind Method , Endothelium, Vascular/drug effects , Female , Folic Acid/administration & dosage , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/physiopathology , Lipids/blood , Male , Nitroglycerin/pharmacology , Oxidative Stress , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Vasomotor System/drug effectsABSTRACT
AIMS: Atherosclerosis is a chronic inflammatory condition, manifest in its early stages by endothelial dysfunction. Interleukin-6 (IL6) plays a key role in driving this process through stimulation of acute phase protein synthesis. We have examined the effect of the IL6 gene -174G > C promoter polymorphism on endothelial function in a group of healthy subjects. METHODS: 248 adults aged 20-28 years participated. Polymerase chain reaction was performed for the -174G > C polymorphism. Brachial artery diameter was measured at rest and after forearm cuff occlusion by high-resolution ultrasound. Responses were represented as absolute flow mediated dilatation (FMDA). RESULTS: Overall there was a trend towards greater FMDA for genotype CC, P = 0.14. No effect was seen in women; however, in men, following multivariate analysis, there was a significant association between genotype and FMDA, P = 0.04. In addition, a significant detrimental effect of smoking on FMDA was only seen in males of genotype CC (P < 0.05) when compared to nonsmokers of the same genotype. CONCLUSION: IL6-174G > C promoter polymorphism influences endothelial function in healthy male subjects. The detrimental effect of smoking on endothelial function is most clearly seen in men of genotype -174 CC, suggesting a genotype-specific interaction with smoking.
Subject(s)
Endothelium, Vascular/physiology , Interleukin-6/genetics , Polymorphism, Single Nucleotide , Promoter Regions, Genetic/genetics , Adult , Arteriosclerosis/epidemiology , Arteriosclerosis/genetics , Arteriosclerosis/immunology , Brachial Artery/physiology , Female , Genotype , Humans , Male , Risk Factors , Sex Distribution , SmokingABSTRACT
AIMS: Fish consumption is inversely associated with cardiovascular mortality, presumably because of n-3 fatty acids in fish. Whether the protection of n-3 fatty acids extends beyond clinical coronary disease to influence the early vascular biology of atherosclerosis remains unclear. This study determined whether circulating levels of n-3 fatty acids are associated with vascular endothelial function in early adulthood. METHODS AND RESULTS: Three hundred and twenty-six adults (157 males, 169 females, aged 20 to 28 years) had high-resolution ultrasound measurements of flow-mediated brachial artery dilatation (FMD) (endothelium-dependent) and arterial response to glyceryl trinitrate (endothelium-independent). Levels of the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid in plasma and erythrocyte membranes of subjects were measured. n-3 Fatty acid levels were not related to vascular function in the whole group. In smokers, however, n-3 fatty acids were positively related to flow-mediated dilatation (plasma DHA vs. FMD: 0.045 mm. %(-1), 95% CI 0.011 to 0.079, P=0.01). Flow-mediated dilatation was also associated with n-3 fatty acid levels in subjects in the top third of the insulin, glucose and triglyceride distributions. CONCLUSION: In young smokers and those with higher fasting insulin, glucose or triglyceride concentrations (factors associated with endothelial dysfunction), n-3 fatty acid levels were positively associated with flow-mediated dilatation. This raises the possibility that physiological levels of circulating n-3 fatty acids may protect the endothelium from early adulthood.
Subject(s)
Blood Circulation/drug effects , Blood Circulation/physiology , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiology , Fatty Acids, Omega-3/blood , Fatty Acids, Omega-3/pharmacology , Adult , Cardiovascular Diseases/blood , Cardiovascular Diseases/physiopathology , Cholesterol, HDL/blood , Cholesterol, HDL/drug effects , Cholesterol, LDL/blood , Cholesterol, LDL/drug effects , Erythrocytes/chemistry , Erythrocytes/metabolism , Female , Humans , Male , Risk Factors , Sex Factors , Smoking/adverse effects , Triglycerides/blood , United Kingdom/epidemiologyABSTRACT
BACKGROUND: Epidemiological studies have reported an inverse relationship between vitamin E status and coronary heart disease. This relationship has not, however, been confirmed by the majority of intervention studies, which have been carried out relatively late in the disease process. The protective effects of vitamin E may be more important earlier in life, before vascular changes have become established. This study investigated whether dietary vitamin E could prevent preclinical arterial changes in young adults relevant to the development of cardiovascular disease. MATERIALS AND METHODS: Measures of vascular function (arterial distensibility and endothelial-dependent and -independent vascular responses) were assessed by noninvasive high resolution ultrasound and related to plasma vitamin E and total antioxidant concentrations in 326 adults, aged 20-28 years. RESULTS: Neither vitamin E (alone or adjusted for lipids) nor total antioxidant status were significantly related to vascular endothelial function or arterial distensibility in either sex. There was no threshold level of vitamin E above which vascular function improved and neither vitamin E nor total antioxidant status interacted with any risk factor, such as smoking or increased low-density lipoprotein concentrations. CONCLUSIONS: Neither plasma vitamin E concentrations nor total antioxidant status achieved by dietary intake during young adulthood were related to vascular endothelial function or arterial distensibility.
Subject(s)
Antioxidants/analysis , Endothelium, Vascular/physiology , Muscle, Smooth, Vascular/physiology , Vitamin E/blood , Adult , Brachial Artery/diagnostic imaging , Cardiovascular Diseases/etiology , Elasticity , Endothelium, Vascular/diagnostic imaging , Female , Humans , Male , Muscle, Smooth, Vascular/diagnostic imaging , Regional Blood Flow , Regression Analysis , Risk Assessment , UltrasonographyABSTRACT
BACKGROUND: Reduced activity of the nitric oxide (NO) pathway has been implicated in the endothelial dysfunction that occurs in patients with renal failure. NO is generated from L-arginine by NO synthase, and certain uremic toxins including asymmetrical dimethyl-L-arginine (ADMA), inhibit NO synthase and might contribute to endothelial dysfunction. We hypothesized that exogenous L-arginine might improve endothelial function in patients with renal failure by overcoming the effects of uremic toxins. METHODS: Endothelial function of the forearm resistance vasculature was assessed using plethysmography to measure the dilator response to intra-arterial acetylcholine (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 dilation; FMD). Studies were performed before and after administration of L-arginine by intra-arterial infusion (50 micromol/min) in 8 pre-dialysis patients or by intravenous infusion (10 g) in 18 hemodialysis patients. RESULTS: Local L-arginine did not improve the dilator response of forearm resistance vessels (AUC 23.1 +/- 6.4 pre, 23.1 +/- 5.1 post; P = 0.9) or FMD of the radial artery (6.5 +/- 1.2% pre, 6.3 +/- 0.8% post; P = 0.8). Systemic L-arginine did not improve FMD of the brachial artery (4.1 +/- 1.1% pre, 3.0 +/- 1.1% post; P = 0.07). These data demonstrate that acute local or systemic administration of L-arginine did not improve endothelial function in resistance or conduit arteries of patients with chronic renal failure. CONCLUSION: The results suggest that competitive inhibition of nitric oxide synthase (NOS) by circulating inhibitors is not the principal explanation for impaired endothelial dilator function in chronic renal failure.
Subject(s)
Arginine/therapeutic use , Arteries/physiopathology , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiopathology , Kidney Failure, Chronic/drug therapy , Kidney Failure, Chronic/physiopathology , Adult , Arteries/drug effects , Brachial Artery/drug effects , Brachial Artery/physiopathology , Enzyme Inhibitors/pharmacology , Humans , Kidney Failure, Chronic/therapy , Middle Aged , Nitric Oxide Synthase/antagonists & inhibitors , Radial Artery/physiopathology , Regional Blood Flow/physiology , Renal Dialysis , Vascular Resistance/drug effects , Vasodilation/drug effects , Vasodilation/physiology , omega-N-Methylarginine/pharmacologyABSTRACT
BACKGROUND: Patients with repaired coarctation are at increased risk of hypertension and cardiovascular disease despite successful repair. We studied the function of conduit arteries in upper and lower limbs of patients late after successful coarctation repair and its relation to age at surgery. METHODS AND RESULTS: Flow-mediated dilatation (FMD) and the dilatation after sublingual nitroglycerin (NTG, 25 microgram) were measured by using high-resolution ultrasound in the brachial artery in 64 coarctation patients (44 males and 20 females, aged 19+/-10 years; median age at operation 4 months) and 45 control subjects (28 males and 17 females, aged 19+/-10 years) and in the posterior tibial artery in 37 patients and 22 control subjects. Arterial stiffness was determined by pulse-wave velocity (PWV) of the brachioradial and femoral-dorsalis pedis tracts. Patients, compared with control subjects, had lower brachial FMD (7.16+/-3.4% versus 8.62+/-2.3%, respectively; P=0.02) and NTG (11.46+/-4.3% versus 13.21+/-4.6%, respectively; P=0.046) and higher brachioradial PWV (9.17+/-3.1 versus 8.06+/-1.9 m/s, respectively; P=0.05). In contrast, posterior tibial FMD, NTG, and lower limb PWV were comparable. Age (months) at the time of repair was related to brachioradial PWV (r=0.42, P=0.002) but not to brachial FMD or NTG. CONCLUSIONS: Patients with repaired aortic coarctation have impaired conduit artery function, with abnormal responses to flow and NTG, and increased vascular stiffness confined to the upper part of the body. Early repair is associated with preserved elastic properties of conduit arteries, but reduced reactivity remains.
Subject(s)
Aortic Coarctation/surgery , Cardiovascular Surgical Procedures , Vascular Diseases/diagnosis , Vascular Diseases/physiopathology , Adult , Age Factors , Blood Flow Velocity , Brachial Artery/diagnostic imaging , Brachial Artery/drug effects , Brachial Artery/physiopathology , Cardiovascular Surgical Procedures/adverse effects , Female , Humans , Infant , Male , Nitroglycerin , Phenotype , Regression Analysis , Tibial Arteries/diagnostic imaging , Tibial Arteries/drug effects , Tibial Arteries/physiopathology , Ultrasonography , Vascular Diseases/etiology , Vascular Patency/drug effects , Vasodilation/drug effects , Vasodilator AgentsABSTRACT
BACKGROUND: Circulating inhibitors of endothelial function have been implicated in the pathogenesis of vascular disease in chronic renal failure. The aim of this study was to determine if lowering the plasma concentration of these and other dialysable toxins improves endothelial function. To do this we compared the acute effects on endothelial function of single episodes of haemodialysis with automated peritoneal dialysis. We hypothesized that endothelial function would improve after dialysis, with a greater effect seen after haemodialysis due to more substantial clearance of endothelial toxins per-treatment. METHODS: Subjects with end-stage renal failure undergoing haemodialysis (n=16) or automated peritoneal dialysis (n=14) were investigated. Endothelial function was determined using vascular ultrasound to measure flow-mediated dilatation of the brachial artery and was compared with the dilatation caused by sublingual glyceryl trinitrate. Endothelial function was assessed before and after a single dialysis treatment. Plasma concentrations of the inhibitors of endothelial function, asymmetric dimethyl-l-arginine and homocysteine were measured. Flow-mediated dilatation was expressed as percentage change from basal diameter and analysed using Student's t test. RESULTS: The plasma concentration of circulating inhibitors of endothelial function was reduced after haemodialysis but not peritoneal dialysis. Haemodialysis increased flow-mediated dilatation from 4.0+/-1.0% to 5.8+/-1.2% (P<0.002). These changes persisted for 5 h but returned to baseline by 24 h. Automated peritoneal dialysis had no acute effect on flow-mediated dilatation (5.9+/-1.1% vs 5.4+/-0.8% after, P>0.5). There were no effects of either dialysis modality on dilatation to glyceryl trinitrate. CONCLUSIONS: Short-term reduction of circulating inhibitors of endothelial function by haemodialysis is associated with increased flow-mediated dilatation. These data suggest that dialysable endothelial toxins have deleterious effects on endothelial function that are rapidly reversible.