Geographical Variation in Underlying Social Deprivation, Cardiovascular and Other Comorbidities in Patients with Potentially Curable Cancers in England: Results from a National Registry Dataset Analysis.

AIMS: To describe the prevalence of cardiovascular disease (CVD), multiple comorbidities and social deprivation in patients with a potentially curable cancer in 20 English Cancer Alliances. MATERIALS AND METHODS: This National Registry Dataset Analysis used national cancer registry data and CVD databases to describe rates of CVD, comorbidities and social deprivation in patients diagnosed with a potentially curable malignancy (stage I-III breast cancer, stage I-III colon cancer, stage I-III rectal cancer, stage I-III prostate cancer, stage I-IIIA non-small cell lung cancer, stage I-IV diffuse large B-cell lymphoma, stage I-IV Hodgkin lymphoma) between 2013 and 2018. Outcome measures included observation of CVD prevalence, other comorbidities (evaluated by the Charlson Comorbidity Index) and deprivation (using the Index of Multiple Deprivation) according to tumour site and allocation to Cancer Alliance. Patients were allocated to CVD prevalence tertiles (minimum: <33.3rd percentile; middle: 33.3rd to 66.6th percentile; maximum: >66.6th percentile). RESULTS: In total, 634 240 patients with a potentially curable malignancy were eligible. The total CVD prevalence for all cancer sites varied between 13.4% (CVD n = 2058; 95% confidence interval 12.8, 13.9) and 19.6% (CVD n = 7818; 95% confidence interval 19.2, 20.0) between Cancer Alliances. CVD prevalence showed regional variation both for male (16-26%) and female patients (8-16%) towards higher CVD prevalence in northern Cancer Alliances. Similar variation was observed for social deprivation, with the proportion of cancer patients being identified as most deprived varying between 3.3% and 32.2%, depending on Cancer Alliance. The variation between Cancer Alliance for total comorbidities was much smaller. CONCLUSION: Social deprivation, CVD and other comorbidities in patients with a potentially curable malignancy in England show significant regional variations, which may partly contribute to differences observed in treatments and outcomes.

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.

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.

Inflammatory Cytokines, Endothelial Function, and Chronic Allograft Vasculopathy in Children: An Investigation of the Donor and Recipient Vasculature After Heart Transplantation.

Chronic allograft vasculopathy (CAV) limits the lifespan of pediatric heart transplant recipients. We investigated blood markers of inflammation, endothelial dysfunction, and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from pediatric heart transplant recipients for markers of inflammation and endothelial activation. The systemic vasculature was investigated using brachial artery flow-mediated dilatation and carotid artery intima-medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima-media thickness (mIMT) > 0.5 mm was used to define significant CAV. Forty-eight children (25 male) aged 8-18 years were enrolled in the study. Patients were a median (interquartile range) 4.1 (2.2-8.7) years after transplant. Patients had increased levels of circulating IL6 (3.86 [2.84-4.95] vs. 1.66 [1.22-2.63] p < 0.0001), vascular cell adhesion molecule 1 (539 [451-621] vs. 402 [342-487] p < 0.001), intracellular adhesion molecule 1 305 (247-346) vs. 256 (224-294) p = 0.002 and thrombomodulin (7.1 [5.5-8.1] vs. 3.57 [3.03-4.71] p < 0.0001) and decreased levels of tumor necrosis factor-α, E selectin, and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum thrombomodulin. Posttransplant thrombomodulin levels are elevated after transplant but significantly lower in those with mIMT > 0.5 mm. This suggests that subclinical inflammation is present and that natural anticoagulant/thrombomodulin activity is important after transplant.

Overweight across the life course and adipokines, inflammatory and endothelial markers at age 60-64 years: evidence from the 1946 birth cohort.

BACKGROUND/OBJECTIVES: There is growing evidence that early development of obesity increases cardiovascular risk later in life, but less is known about whether there are effects of long-term excess body weight on the biological drivers associated with the atherosclerotic pathway, particularly adipokines, inflammatory and endothelial markers. This paper therefore investigates the influence of overweight across the life course on levels of these markers at retirement age. SUBJECTS/METHODS: Data from the Medical Research Council National Survey of Health and Development (n=1784) were used to examine the associations between overweight status at 2, 4, 6, 7, 11, 15, 20, 26, 36, 43, 53 and 60-64 years (body mass index (BMI)⩾25 kg m(-2) for adult ages and gender-specific cut-points for childhood ages equivalent to BMI⩾25 kg m(-2)) and measurements of adipokines (leptin and adiponectin), inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6)) and endothelial markers (E-selectin, tissue plasminogen activator (t-PA) and von Willebrand factor) at 60-64 years. In addition, the fit of different life course models (sensitive periods/accumulation) were compared using partial F-tests. RESULTS: In age- and sex-adjusted models, overweight at 11 years and onwards was associated with higher leptin, CRP and IL-6 and lower adiponectin; overweight at 15 years and onwards was associated with higher E-selectin and t-PA. Associations between overweight at all ages earlier than 60-64 with leptin, adiponectin, CRP and IL-6 were reduced but remained apparent after adjustment for overweight at 60-64 years; whereas those with E-selectin and t-PA were entirely explained. An accumulation model best described the associations between overweight across the life course with adipokines and inflammatory markers, whereas for the endothelial markers, the sensitive period model for 60-64 years provided a slightly better fit than the accumulation model. CONCLUSIONS: Overweight across the life course has a cumulative influence on adipokines, inflammatory and possibly endothelial markers. Avoidance of overweight from adolescence onwards is likely important for cardiovascular disease prevention.

International comparisons of the management of patients with non-ST segment elevation acute myocardial infarction in the United Kingdom, Sweden, and the United States: The MINAP/NICOR, SWEDEHEART/RIKS-HIA, and ACTION Registry-GWTG/NCDR registries.

OBJECTIVES: To compare management of patients with acute non-ST segment elevation myocardial infarction (NSTEMI) in three developed countries with national ongoing registries. BACKGROUND: Results from clinical trials suggest significant variation in care across the world. However, international comparisons in "real world" registries are limited. METHODS: We compared the use of in-hospital procedures and discharge medications for patients admitted with NSTEMI from 2007 to 2010 using the unselective MINAP/NICOR [England and Wales (UK); n=137,009], the unselective SWEDEHEART/RIKS-HIA (Sweden; n=45,069), and the selective ACTION Registry-GWTG/NCDR [United States (US); n=147,438] clinical registries. RESULTS: Patients enrolled among the three registries were generally similar except those in the US who were younger but had higher rates of smoking, diabetes, hypertension, prior heart failure, and prior MI than in Sweden or in UK. Angiography and percutaneous coronary intervention (PCI) were performed more often in the US (76% and 44%) and Sweden (65% and 42%) relative to the UK (32% and 22%). Discharge betablockers were also prescribed more often in the US (89%) and Sweden (89%) than in the UK (76%). In contrast, discharge statins, angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB), and dual antiplatelet agents (among those not receiving PCI) were higher in the UK (92%, 79%, and 71%) than in the US (85%, 65%, 41%) and Sweden (81%, 69%, and 49%). CONCLUSIONS: The care for patients with NSTEMI differed substantially among the three countries. These differences in care among countries provide an opportunity for future comparative effectiveness research as well as identify opportunities for global quality improvement.

Trends in hospital treatments, including revascularisation, following acute myocardial infarction, 2003-2010: a multilevel and relative survival analysis for the National Institute for Cardiovascular Outcomes Research (NICOR).

OBJECTIVE: To investigate temporal changes in survival after acute myocardial infarction (AMI) by early invasive strategy. METHODS: Accelerated failure time and 6-month relative survival analyses stratified by thrombolysis or primary percutaneous coronary intervention (PPCI) for ST elevation myocardial infarction (STEMI) and coronary angiography for non-STEMI (NSTEMI) encompassing 583 466 patients across 247 hospitals in England and Wales over hospital admission periods 2003-2004, 2005-2006, 2007-2008 and 2009-2010. RESULTS: Survival improved significantly for STEMI patients who received reperfusion therapy (time ratio (TR) 1.47, 95% CI 1.22 to 2.78) and was stable for those who did not (TR 1.02, 95% CI 0.85 to 1.22). While there were significant improvements in survival for NSTEMI patients who underwent coronary angiography (TR 1.39, 95% CI 1.18 to 1.62), there was a significant decline for those who did not (TR 0.70, 95% CI 0.65 to 0.75). Patients without reperfusion therapy or coronary angiography had a greater number of comorbidities, but the use of secondary prevention medications was comparable with patients who received reperfusion therapy or coronary angiography. There was a significant hospital-level survival effect, with higher crude 6-month mortality in hospitals in the lowest coronary angiography and PPCI quartiles (angiography Q1: 16.4% vs Q4: 12.8%; PPCI Q1: 15.8% vs Q4: 12.4%). CONCLUSIONS: Survival rates after AMI have improved. Whereas survival estimates for STEMI patients who did not receive reperfusion therapy were stable, they worsened for NSTEMI patients not receiving coronary angiography.

Preliminary study of video imaging of blood vessels in tissues lining the gingival sulcus in periodontally healthy individuals.

BACKGROUND AND OBJECTIVE: The aim of this study was to obtain in vivo images of the microcirculation in tissues lining the gingival crevice in periodontally healthy volunteers and to assess the repeatability of the parameters measured. MATERIAL AND METHODS: Video microscopy images of the microcirculation of tissues lining the gingival crevice were obtained from 20 periodontally healthy volunteers. Images were obtained with a single 1 mm diameter 1 pitch gradient index lens with a high numerical aperture and with a plain glass lens and illumination with a green 525 nm light-emitting diode and recorded using a video microscope. RESULTS: The morphological features of the vessels (including vessel diameter, vessel density, loops, branches, dilated vessels) were similar to those described previously in other mammals. The Kappa values for the assessment of morphology of the vessels using the gradient index lens range from 0.83 for branching to 0.91 for dilated and using the glass lens 0.47 for branching and 0.38 for dilated. CONCLUSIONS: This novel system allowed for a consistent and repeatable assessment of the gingival microvasculature. However, there was some evidence of possible pressure artefacts in those cases where the measurements of separation between vessels exceeded 150 µm.

Age-dependent inequalities in improvements in mortality occur early after acute myocardial infarction in 478,242 patients in the Myocardial Ischaemia National Audit Project (MINAP) registry.

BACKGROUND: Mortality rates after acute myocardial infarction (AMI) have declined, but there is uncertainty regarding the extent of improvements in early mortality in the elderly. METHODS: Mixed-effects regression analysis of 30-day mortality using data from 478,242 patients with AMI at 215 hospitals in England and Wales stratified by STEMI/NSTEMI, sex, and age group. A hospital opportunity-based composite score (OBCS) for aspirin, ACE-inhibitor, statin, ß blocker, and referral for cardiac rehabilitation was used as measure of quality of hospital care. RESULTS: 30-day mortality rates (95% CI) fell from 10.7% (10.6 to 10.9%) in 2004/5 to 8.4% (8.3 to 8.6%) in 2008/9. The median (IQR) hospital OBCSs increased over time, 2004/5: 87.3 (7.2), 2006/7: 88.9 (6.3), 2008/9: 90.3 (6.1), P<0.001, and were similar between age groups (18 to <65 years, 65 to 79 years, and ≥ 80 years) for STEMI: 89.4 (6.5) vs. 89.4 (6.6), vs. 89.2 (6.5) and NSTEMI: 88.6 (7.3) vs. 88.8 (7.0) vs. 88.9 (7.0), respectively For males, all age groups except patients <65 years demonstrated a significant decrease in adjusted mortality. For females, only patients ≥ 80 years demonstrated a significant reduction in adjusted mortality. A 1% increase in hospital OBCS was associated with a 1% decrease in 30-day mortality (95% CI: 0.99 to 0.99, P<0.001). CONCLUSION: In England and Wales, for patients with AMI there are age and sex-dependent differences in improvements in 30-day mortality. Whereas young males with AMI have reached an acceptable performance plateau, all other groups are either improving or, more importantly, are yet to demonstrate this.

Are there socioeconomic inequalities in cardiovascular risk factors in childhood, and are they mediated by adiposity? Findings from a prospective cohort study.

BACKGROUND: Socioeconomic gradients in adiposity were not present during childhood for previous generations, but have emerged in contemporary children. It is unknown whether this translates to socioeconomic gradients in associated cardiovascular risk factors in children, with consequent implications for inequalities in coronary heart disease (CHD) and diabetes when these children reach adulthood. METHODS: Using data from 7772 participants aged 10-years from the Avon Longitudinal Study of Parents and Children, we examined the association between maternal education and a large number of cardiovascular risk factors (cholesterol, triglycerides, high-density lipoprotein, apolipoprotein, adiponectin, leptin, C-reactive protein (CRP), interleukin-6 (IL-6) and systolic and diastolic blood pressure), and examined whether inequalities were mediated by adiposity, measured by dual energy X-ray absorptiometry (DXA)-assessed total fat mass. RESULTS: There were socioeconomic differences in a number of the cardiovascular risk factors (apolipoprotein B, systolic and diastolic blood pressure, CRP, leptin and IL-6). Inequalities were greater in girls than boys. Inequalities in CRP and leptin were completely mediated by adiposity. Inequalities in other cardiovascular risk factors were partially mediated by adiposity. CONCLUSION: This study showed important socioeconomic inequalities in adiposity and associated cardiovascular risk factors in a contemporary UK population of 10-year-old children. Differences between contemporary children and previous generations in the socioeconomic patterning of cardiovascular risk factors suggest future adults may have greater inequalities in diabetes and CHD than current adults. These findings highlight the importance of interventions aimed at preventing obesity in childhood, particularly among those of lower socioeconomic position.

Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes.

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.

B-type natriuretic peptide predicts disease severity in children with hypertrophic cardiomyopathy.

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 10 (area under the receiver operator characteristic curve = 0.875 (p<0.001)). CONCLUSIONS: BNP levels correlate with non-invasive parameters of disease severity in children with HCM, including measures of raised LV filling pressures. For patients in whom evaluation of symptoms is difficult, BNP may be a useful additional tool in the assessment of disease severity.

Impact of aortic stenting on peripheral vascular function and daytime systolic blood pressure in adult coarctation.

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.

Assessment of differential branch pulmonary blood flow: a comparative study of phase contrast magnetic resonance imaging and radionuclide lung perfusion imaging.

OBJECTIVES: To test whether magnetic resonance (MR) imaging can be used to assess differential lung blood flow as accurately as isotope lung perfusion studies in patients investigated for congenital heart disease. METHODS AND RESULTS: Radionuclide lung perfusion and MR imaging were performed in 12 children with suspected unilateral branch pulmonary artery stenosis (mean age 12.1 (5.9) years, range 3.1-17.2 years). A non-breath hold, fast gradient echo phase contrast MR sequence was used to measure flow in the pulmonary trunk and one pulmonary artery to calculate differential flow. Good agreement was shown between the two imaging methods by Bland-Altman analysis. There was excellent correlation between the radionuclide and MR phase contrast calculated total lung blood flow (r = 0.98, p < 0.0001). CONCLUSION: MR phase contrast is an accurate method for measuring differential total right and left lung blood flow. If MR imaging is performed to assess the branch pulmonary arteries, differential lung blood flow can be also measured, avoiding the need for an additional radionuclide lung perfusion scan and reducing the overall radiation burden to this group of patients.

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.

Endothelial cell function testing: how does the method help us in evaluating vascular status?

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.

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.

Tissue Doppler echocardiography in patients with thalassaemia detects early myocardial dysfunction related to myocardial iron overload.

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.

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.