Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level.

Familial hypercholesterolemia is associated with premature atherosclerosis. Since endothelial dysfunction is an early event in atherogenesis, we used a noninvasive method to assess endothelial function in the systemic arteries of 30 children aged 7-17 yr (median 11) with familial hypercholesterolemia (2 homozygotes, 28 heterozygotes, total cholesterol 240-696 mg/dl) and 30 healthy age- and sex-matched controls. Using high resolution ultrasound, the diameter of the superficial femoral artery was measured at rest, in response to reactive hyperemia (with increased flow causing endothelium-dependent dilation), and after sublingual glyceryltrinitrate (causing endothelium-independent vasodilation). Flow-mediated dilation was present in the controls (7.5 +/- 0.7%) but was impaired or absent in the hypercholesterolemic children (1.2 +/- 0.4%, P < 0.0001). Total cholesterol was inversely correlated with flow-mediated dilation (r = -0.61, P < 0.0001). In the hypercholesterolemic children, flow-mediated dilation was inversely related to the lipoprotein(a) level (r = -0.61, P = 0.027) but not to other lipid fractions. Glyceryltrinitrate-induced dilation was present in all subjects but was lower in the hypercholesterolemia group (10.0 +/- 0.6% vs 12.4 +/- 0.8%, P = 0.023). Thus, impaired endothelium-dependent dilation is present in children with familial hypercholesterolemia as young as 7 yr of age and the degree of impairment is related to the lipoprotein(a) level.

Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults.

In hypercholesterolemic rabbits, oral L-arginine (the substrate for endothelium derived nitric oxide) attenuates endothelial dysfunction and atheroma formation, but the effect in hypercholesterolemic humans is unknown. Using high resolution external ultrasound, we studied arterial physiology in 27 hypercholesterolemic subjects aged 29+/-5 (19-40) years, with known endothelial dysfunction and LDL-cholesterol levels of 238+/-43 mg/dl. Each subject was studied before and after 4 wk of L-arginine (7 grams x 3/day) or placebo powder, with 4 wk washout, in a randomized double-blind crossover study. Brachial artery diameter was measured at rest, during increased flow (causing endothelium-dependent dilation, EDD) and after sublingual glyceryl trinitrate (causing endothelium-independent dilation). After oral L-arginine, plasma L-arginine levels rose from 115+/-103 to 231+/-125 micromol/liter (P<0.001), and EDD improved from 1.7+/-1.3 to 5.6+/-3.0% (P<0.001). In contrast there was no significant change in response to glyceryl trinitrate. After placebo there were no changes in endothelium-dependent or independent vascular responses. Lipid levels were unchanged after L-arginine and placebo. Dietary supplementation with L-arginine significantly improves EDD in hypercholesterolemic young adults, and this may impact favorably on the atherogenic process.

Long-term excess mortality associated with diabetes following acute myocardial infarction: a population-based cohort study.

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=281 259 and NSTEMI n=422 661) 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 120 568 (17.1%) patients with diabetes, there were 187 875 (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.

Arterial distensibility in adolescents: the influence of adiposity, the metabolic syndrome, and classic risk factors.

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.

Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo: relevance to endothelial dysfunction in hypercholesterolemia.

Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N:(G)monomethyl-L-arginine (5.3+/-1.2% versus 0.7+/-0.7%, P:<0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD. Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia, but the response to sustained hyperemia was normal. These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus. Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide, whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition. Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide-dependent pathway and preservation of non nitric oxide-mediated dilatation to sustained flow stimuli.

Glu298Asp endothelial nitric oxide synthase gene polymorphism interacts with environmental and dietary factors to influence endothelial function.

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.

Geographic variation in the treatment of non-ST-segment myocardial infarction in the English National Health Service: a cohort study.

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: 357 228 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 (48 257/357 228; 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.

Regional wall motion and abnormalities of electrical depolarization and repolarization in patients after surgical repair of tetralogy of Fallot.

BACKGROUND: Abnormal depolarization-repolarization in patients with repaired tetralogy of Fallot (TOF) is a risk factor for malignant ventricular tachycardia and sudden death. It is unclear whether ECG abnormalities are associated with abnormal regional right ventricular (RV) function. METHODS AND RESULTS: Seventy-four patients (37 patients <18 and 37 >18 years old) who had had TOF repair at 4.0 years old (0.1 to 47 years old) were examined when they were 18.7 years old (1.7 to 61.1 years old), as were 112 control subjects with normal hearts. Regional function was evaluated with tissue Doppler imaging of the RV and left ventricular (LV) free wall and the septum. Myocardial velocities were sampled continuously from base to apex. Synchronous ECG was analyzed for QRS, QT, and JT duration and QRS, QT, and JT dispersion. All 74 TOF patients had normal LV myocardial velocities. Forty-eight patients (24 patients <18 and 24 >18 years old) had reversed myocardial velocities in diastole in the RV free wall, which were associated with reversed systolic myocardial velocities in 22 and additional reverse diastolic myocardial velocities in the septum in 19. Those 48 patients had a longer QRS duration (151+/-31 versus 124+/-27 ms) and greater QRS (47+/-18 versus 29+/-12 ms), QT (73+/-27 versus 52+/-22 ms), and JT (96+/-31 versus 67+/-35 ms) dispersion. Compared with normal control subjects, all 74 TOF patients had decreased systolic and diastolic myocardial velocities and a longer isovolumic relaxation time. CONCLUSIONS: RV wall-motion abnormalities are a common finding late after TOF repair and are associated with repolarization-depolarization abnormalities. These data further underscore a likely mechanoelectrical interaction as an important part of the pathogenesis of RV disease in these patients.

Impact of low birth weight and cardiovascular risk factors on endothelial function in early adult life.

BACKGROUND: Low birth weight is related to increased risk of coronary heart disease in adults and recently has been associated with vascular endothelial dysfunction in children. We investigated whether the relation between birth weight and endothelial function was still present in early adult life and whether there was an interaction with emerging risk factors. METHODS AND RESULTS: In 315 adults (165 women, 150 men, aged 20 to 28 years), high-resolution ultrasound was used to determine endothelium-dependent and -independent vascular responses of the brachial artery. Vascular measures were related to classic risk factors (smoking history, lipid profile, blood pressure, fasting insulin, exercise capacity, body mass index, and combined risk score) and birth weight. Low birth weight was associated with reduced flow-mediated dilation (coefficient=0.18 kg(-1), 95% CI 0.004 to 0.35, P:=0.04) but not with endothelium-independent dilation. The difference in flow-mediated dilation between the top and bottom fifths of birth weight was the same as between smokers and nonsmokers. Increasing levels of acquired risk factors overwhelmed the association, and there was a significant interaction of risk score with the birth weight-endothelial function relation (coefficient of interaction term [birth weightxrisk score] = -0.12, 95% CI -0.22 to -0.03, P:=0.01). CONCLUSIONS: Low birth weight is associated with endothelial dysfunction in young adults. This is most marked in individuals with lower risk factor profiles and may be relevant to the pathogenesis of atherosclerosis in later life.

Does oral folic acid lower total homocysteine levels and improve endothelial function in children with chronic renal failure?

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.

Basal pulmonary vascular resistance and nitric oxide responsiveness late after Fontan-type operation.

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.

Effects of respiration and gravity on infradiaphragmatic venous flow in normal and Fontan patients.

BACKGROUND: In the Fontan circulation, pulmonary and systemic vascular resistances are in series. The implications of this unique arrangement on infradiaphragmatic venous physiology are poorly understood. METHODS AND RESULTS: We studied the effects of respiration and gravity on infradiaphragmatic venous flows in 20 normal healthy volunteers (control) and 48 Fontan patients (atriopulmonary connection [APC] n=15, total cavopulmonary connection [TCPC] n=30). Hepatic venous (HV), subhepatic inferior vena caval (IVC), and portal venous (PV) flow rates were measured with Doppler ultrasonography during inspiration and expiration in both the supine and upright positions. The inspiratory-to-expiratory flow rate ratio was calculated to reflect the effect of respiration, and the supine-to-upright flow rate ratio was calculated to assess the effect of gravity. HV flow depended heavily on inspiration in TCPC compared with both control and APC subjects (inspiratory-to-expiratory flow rate ratio 3.4, 1.7, and 1.6, respectively; P:<0.0001). Normal PV flow was higher in expiration, but this effect was lost in TCPC and APC patients (inspiratory-to-expiratory flow rate ratio 0.8, 1.0, and 1.1, respectively; P:=0.01). The respiratory influence on IVC flow was the same in all groups. Gravity decreased HV flow more in APC than in TCPC patients (supine-to-upright flow rate ratio 3.2 versus 2.1, respectively; P:<0.04) but reduced PV flow equally in all groups. CONCLUSIONS: Gravity and respiration have important influences on infradiaphragmatic venous return in Fontan patients. Although gravity exerts a significant detrimental effect on lower body venous return, which is more marked in APC than in TCPC patients, the beneficial effects of respiration in TCPC patients are mediated primarily by an increase in HV flow. These effects may have important short- and long-term implications for the hemodynamics of the Fontan circulation.

Cholesterol and arterial distensibility in the first decade of life: a population-based study.

BACKGROUND: Blood cholesterol levels are a key determinant of coronary heart disease risk in adults, but the importance of lipid levels in the general population during childhood is less clear. We related arterial distensibility, a marker of vascular function known to be altered early in atherosclerosis, to the lipid profile of a population-based sample of children aged 9 to 11 years. METHODS AND RESULTS: A noninvasive ultrasound technique was used to measure arterial distension during the cardiac cycle in the brachial arteries of 361 children from 4 towns in the United Kingdom. This measure was related to their pulse pressure to assess arterial distensibility. All the children had previously had a comprehensive assessment of cardiovascular risk including a full lipid profile, cotinine-assessed smoke exposure, serum glucose, and questionnaire data on socioeconomic and dietary factors. Mean total cholesterol in the population was 4.72 [SD 0.75] mmol/L. There was a significant, inverse relation between cholesterol and distension of the artery across this range (linear regression coefficient -11.8 microm. mmol(-1). L(-1), P=0.003). Similar relationships were demonstrated with LDL and apolipoprotein B (-12.9 microm. mmol(-1). L(-1), P=0. 005 and -36.9 microm/mmol/L, P=0.01). HDL and triglyceride levels showed no consistent association with distensibility. CONCLUSIONS: LDL cholesterol levels had an impact on arterial distensibility in the first decade of life. Furthermore, the functional differences in the arterial wall were demonstrated within the lipid range found in normal children, a finding that raises the possibility that cholesterol levels in the general population during childhood may already be relevant to the development of vascular disease.

Mental stress induces transient endothelial dysfunction in humans.

BACKGROUND: Mental stress has been linked to increased morbidity and mortality in coronary artery disease and to atherosclerosis progression. Experimental studies have suggested that damage to the endothelium may be an important mechanism. METHODS AND RESULTS: Endothelial function was studied in 10 healthy men (aged 50. 4+/-9.6 years) and in 8 non-insulin-dependent diabetic men (aged 52. 0+/-7.2 years). Brachial artery flow-mediated dilation (FMD, endothelium dependent) and response to 50 microg of sublingual glyceryl trinitrate (GTN, endothelium independent) were measured noninvasively by use of high-resolution ultrasound before and after (30, 90, and 240 minutes) a standardized mental stress test. The same protocol without mental stress was repeated on a separate occasion in the healthy men. In healthy subjects, FMD (5.0+/-2.1%) was significantly (P:<0.01) reduced at 30 and 90 minutes after mental stress (2.8+/-2.3% and 2.3+/-2.4%, respectively) and returned toward normal after 4 hours (4.1+/-2.0%). Mental stress had no effect on the response to GTN. In the repeated studies without mental stress, FMD did not change. The diabetic subjects had lower FMD than did the control subjects (3.0+/-1.5% versus 5.0+/-2.1%, respectively; P:=0.02) but showed no changes in FMD (2.7+/-1.1% after 30 minutes, 2.8+/-1.9% after 90 minutes, and 3.1+/-2.3% after 240 minutes) or GTN responses after mental stress. CONCLUSIONS: These findings suggest that brief episodes of mental stress, similar to those encountered in everyday life, may cause transient (up to 4 hours) endothelial dysfunction in healthy young individuals. This might represent a mechanistic link between mental stress and atherogenesis.

Vascular dysfunction after repair of coarctation of the aorta: impact of early surgery.

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.

Acute systemic inflammation impairs endothelium-dependent dilatation in humans.

BACKGROUND: We tested the hypothesis that endothelial dysfunction underlies the association between an acute inflammatory episode and the transiently increased risk of a cardiovascular event by examining the effects of an experimental inflammatory stimulus on endothelium-dependent vasodilation. METHODS AND RESULTS: Salmonella typhi vaccine was used to generate a systemic inflammatory response in healthy volunteers. In 12 subjects, dilatation of the brachial artery to flow and to sublingual nitroglycerin (NTG) was recorded (conduit vessel response), and in 6 subjects, venous occlusion plethysmography was used to measure forearm blood flow during intrabrachial infusion of the endothelium-dependent dilators acetylcholine (ACh) and bradykinin (BK) and the endothelium-independent dilators NTG and verapamil (resistance vessel response). Responses were assessed 16 hours before and 8 and 32 hours after vaccination. Vaccination resulted in elevations in white cell count and serum levels of interleukin-6 and interleukin-1 receptor antagonist. Eight hours after vaccination, resistance vessel responses to BK (P:=0.0099) and ACh (P:=0.0414) were markedly attenuated, and brachial artery flow-mediated dilatation was depressed. Resistance vessel responses to verapamil and NTG were unchanged, as was the conduit vessel response to NTG. Thirty-two hours after vaccination, resistance vessel responses to BK and ACh had returned to normal. CONCLUSIONS: S typhi vaccine generates a mild inflammatory reaction associated with temporary but profound dysfunction of the arterial endothelium in both resistance and conduit vessels to both physical and pharmacological dilator stimuli. This finding might explain the association between infection and inflammation and the enhanced risk of an acute cardiovascular event.

Variability of episodic ST segment depression in chronic stable angina: implications for individual and group trials of therapeutic efficacy.

OBJECTIVES: This study was conducted to quantify the variability of episodic ST segment depression in chronic stable angina and enable assessment of the impact of interventions in individual patients and clinical trials. BACKGROUND: Episodic myocardial ischemia can be detected by ST segment depression on ambulatory electrocardiographic (ECG) monitoring and may be important for the assessment of outcome. Variability of the number and duration of episodes has important implications for monitoring and therapeutic strategies. METHODS: We studied 36 patients, aged 37 to 77 years (median 60), with stable angina and coronary artery disease by serial ambulatory ECG monitoring for a total of 415 days. A nested analysis of variance was carried out to assess the sources of spontaneous variation, and power function analyses were performed. RESULTS: During 415 days of monitoring, 1,882 episodes of ST segment depression were detected (mean frequency +/- SD, 4.5 +/- 4.1/day, duration 67 +/- 87 min/day, 25% in association with pain). Considerable variability was found within and between patients for both the number and the duration of ischemic episodes. For a patient monitored for 24 h before and after treatment, an 81% reduction in the number of episodes would be required to show a significant benefit; if monitoring were performed for 4 days four times before and after therapy, a 46% decrease would be significant. In clinical trials, a true reduction of > or = 15% in ischemic episodes is required to have sufficient power to obtain statistical significance. CONCLUSIONS: The natural variability of transient myocardial ischemia in patients with chronic stable angina can be quantified and this information used to study the effectiveness of interventions in both individual patients and clinical trials.

Congenitally corrected transposition and Ebstein's anomaly of the systemic atrioventricular valve: association with aortic arch obstruction.

Aortic arch abnormalities are uncommon in patients with congenitally corrected transposition of the great arteries. Over a 20-year period, 10 patients with congenitally corrected transposition and Ebstein's anomaly of the systemic atrioventricular (AV) valve were identified. Five neonates had severe systemic AV valve regurgitation with severe coarctation of the aorta (n = 4) or aortic atresia (n = 1) and presented with heart failure. Four died in the neonatal period and one who had coarctation repair died 7 months postoperatively. The remaining five patients with congenitally corrected transposition and Ebstein's anomaly had mild left AV valve regurgitation; none of these had aortic arch obstruction. In neonates who have coexisting Ebstein's anomaly of the systemic AV valve and congenitally corrected transposition, obstruction to aortic arch flow is common. Severe systemic AV valve regurgitation with a morphologic systemic right ventricle may have contributed to low anterograde flow in the ascending aorta prenatally and thereby to the aortic arch abnormality.

Five-year follow-up after balloon pulmonary valvuloplasty.

OBJECTIVES: The aim of this study was to assess results 5 years after balloon pulmonary valvuloplasty. BACKGROUND: Since the technique of balloon pulmonary valvuloplasty was first reported in 1982, it has become the treatment of choice for pulmonary valve stenosis. In contrast to surgical valvotomy, the long-term outcome after balloon pulmonary valvuloplasty is unknown. METHODS: We reviewed the findings in 34 patients 5.2 +/- 0.8 (mean +/- SD) years after balloon pulmonary valvuloplasty: 27 with isolated pulmonary stenosis, 5 with Noonan syndrome and 2 with previous surgical valvotomy. In eight patients (three with Noonan syndrome), a second balloon valvuloplasty was the index procedure for analysis. RESULTS: The transpulmonary gradient (mm Hg) was 74 +/- 34 before balloon pulmonary valvuloplasty, 36 +/- 26 immediately after, 22 +/- 9 at cardiac catheterization in 29 patients 6 +/- 0.6 months later and 19 +/- 10 by Doppler study at 5 years. At 5 years 26 patients (group A) had a residual gradient of < or = 20 mm Hg; the remaining 8 (group B) had a gradient of > 20 mm Hg. Four group B patients had Noonan syndrome (p = 0.01). Balloon/pulmonary valve diameter ratio was larger for group A patients than for group B patients with isolated pulmonary stenosis (1.20 +/- 0.10 vs. 1.00 +/- 0.07, p = 0.005); larger balloons were used in group B patients with Noonan syndrome (1.30 +/- 0.10). Group A patients were more likely than group B patients to have significant pulmonary incompetence (6 of 24 vs. 0 of 8) and had a greater right ventricle/left ventricle long-axis diastolic dimension ratio (0.47 +/- 0.10 vs. 0.35 +/- 0.04, p = 0.05). In the subgroup of five patients with Noonan syndrome and two with prior surgical valvotomy, the transpulmonary gradient was reduced from 74 +/- 24 mm Hg before balloon valvuloplasty to 23 +/- 12 mm Hg at 5 years. In addition, two patients with isolated pulmonary valve stenosis had pulmonary valve dysplasia by angiographic criteria: transpulmonary gradients of 85 and 56 mm Hg were reduced to 20 and 11 mm Hg, respectively, at 5 years. CONCLUSIONS: Relief of obstruction persists at 5 years especially if oversized balloons are used. Acceptable results can be obtained in patients with a dysplastic valve. More complete relief of right ventricular outflow gradient is associated with increased right ventricular dimension, probably because more pulmonary incompetence is induced. This is well tolerated at 5 years but may be important in the longer term.

Arrhythmia and prognosis in infants, children and adolescents with hypertrophic cardiomyopathy.

In adults with hypertrophic cardiomyopathy, the annual mortality rate from sudden death is 2 to 3%, and the finding of nonsustained ventricular tachycardia during electrocardiographic (ECG) monitoring provides a marker of the patient who is at increased risk. In the young, the annual mortality rate from sudden death is even higher, approximately 6%, but the prognostic significance of arrhythmia is unknown. To determine the prevalence of arrhythmia and its relation to prognosis, 2 days of ECG monitoring was performed in 6 infants, 14 children and 33 adolescents with hypertrophic cardiomyopathy receiving no cardioactive medications. An additional 1 to 9 days (median 2) of monitoring was performed in 29 patients. All patients had sinus rhythm; 4 adolescents had episodes of paroxysmal supraventricular tachycardia, a child with the Wolff-Parkinson-White syndrome had symptomatic reentrant atrioventricular tachycardia and 5 adolescents had asymptomatic nonsustained ventricular tachycardia. During follow-up of 1 week to 7 years (median 3 years), five patients died suddenly and two had successful resuscitation from out-of-hospital ventricular fibrillation; none of these seven patients had ventricular arrhythmias during 2 to 7 days (median 3) of ECG monitoring. The two patients with ventricular fibrillation, the five with ventricular tachycardia, the one with Wolff-Parkinson-White syndrome and the seven with recurrent syncope or adverse family history, or both, received low dose amiodarone. None of these "high risk" patients died during 6 months to 6 years (median 3 years) of follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)