Dermot Neely

Endothelial Dysfunction and Coronary Artery Disease: A State of the Art Review

Atherosclerotic coronary artery disease (CAD) is a major cause of morbidity and mortality in the developed world. Endothelial dysfunction plays an important role in the development of atherosclerosis and predicts cardiovascular (CV) outcomes independent of conventional CV risk factors. In recent years, there have been tremendous improvements in the pharmacological prevention and management of CAD. In this review, the pathophysiology of endothelial dysfunction in relation to CAD is discussed and various techniques of invasive and noninvasive assessments of peripheral and coronary endothelial function described. In addition, evidence for the association of endothelial dysfunction and CV outcomes has been examined and finally the role of therapeutic interventions in endothelial dysfunction has been discussed.

Association of aging, arterial stiffness, and cardiovascular disease: a review.

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in the western world. Primary and secondary prevention strategies have improved tremendously. Conventional risk factors are identified and treated with intensive pharmacotherapy. Despite these measures, the incidence of CHD is on the rise in developed countries. Arterial stiffness has been identified as an independent risk factor for the development of CHD, both in the general population and in those with established CHD. This review examines the association of arterial stiffness with cardiovascular disease.

HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom.

This consensus statement addresses the current three main modalities of treatment of homozygous familial hypercholesterolaemia (HoFH): pharmacotherapy, lipoprotein (Lp) apheresis and liver transplantation. HoFH may cause very premature atheromatous arterial disease and death, despite treatment with Lp apheresis combined with statin, ezetimibe and bile acid sequestrants. Two new classes of drug, effective in lowering cholesterol in HoFH, are now licensed in the United Kingdom. Lomitapide is restricted to use in HoFH but, may cause fatty liver and is very expensive. PCSK9 inhibitors are quite effective in receptor defective HoFH, are safe and are less expensive. Lower treatment targets for lipid lowering in HoFH, in line with those for the general FH population, have been proposed to improve cardiovascular outcomes. HEART UK presents a strategy combining Lp apheresis with pharmacological treatment to achieve these targets in the United Kingdom (UK). Improved provision of Lp apheresis by use of existing infrastructure for extracorporeal treatments such as renal dialysis is promoted. The clinical management of adults and children with HoFH including advice on pregnancy and contraception are addressed. A premise of the HEART UK strategy is that the risk of early use of drug treatments beyond their licensed age restriction may be balanced against risks of liver transplantation or ineffective treatment in severely affected patients. This may be of interest beyond the UK.

Evaluation of NT-proBNP to predict outcomes in advanced heart failure.

Aims:u2002 To determine which factors predict outcomes in a group of patients with advanced heart failure, and in particular if NT‐proBNP provides additional clinical and prognostic information to other haemodynamic and biochemical data.

Single-centre study of the diagnostic performance of plasma metanephrines with seated sampling for the diagnosis of phaeochromocytoma/paraganglioma

Background Measurement of plasma metanephrines is regarded as one of the best screening tests for phaeochromocytoma/paraganglioma. Current guidelines recommend that samples are ideally collected in the supine position after 30u2009min rest and interpreted using supine reference ranges, in order to optimize the diagnostic performance of the test. Current practice in our centre is to collect samples for plasma metanephrines from seated patients. The aim of the study was to determine, if seated sampling for plasma metanephrines provides acceptable diagnostic performance in our centre. Methods Clinical and laboratory data of 113 patients, gathered over a four-year period 2010–2014, were reviewed. All had undergone preoperative plasma metanephrines measurement and had postoperative histopathology confirmation or exclusion of phaeochromocytoma/paraganglioma. Results Of 113 patients included in the study, 40 had a histological diagnosis of phaeochromocytoma/paraganglioma. The remaining 73 patients had an alternative adrenal pathology. The diagnostic sensitivity of normetanephrine or metanephrine above the upper limit of our in-house seated reference range was 93%. However, excluding three cases of paraganglioma determined clinically and biochemically to be non-functional raised the sensitivity to 100%. Diagnostic specificity was 90%. Applying published supine reference ranges made no difference to diagnostic sensitivity in this group of patients but decreased diagnostic specificity to 75%. Conclusions While these data are derived from a relatively small study population, they demonstrate acceptable diagnostic performance for seated plasma metanephrines as a screening test for phaeochromocytoma/paraganglioma. These data highlight a high diagnostic sensitivity for plasma metanephrines with seated sampling in our centre.

Utility of NT-proBNP as a rule-out test for left ventricular dysfunction in very old people with limiting dyspnoea: the Newcastle 85+ Study

BackgroundGuidelines advocate using B-type natriuretic peptides in the diagnostic work-up of suspected heart failure (HF). Their main role is to limit echocardiography rates by ruling out HF/LV dysfunction where peptide level is low. Recommended rule-out cut points vary between guidelines. The utility of B-type natriuretic peptides in the very old (85+) requires further investigation, with optimal cut points yet to be established. We examined NT-proBNPs utility, alone and in combination with history of myocardial infarction (MI), as a rule-out test for LV dysfunction in very old people with limiting dyspnoea.MethodsDesign: Cross-sectional analysis.Setting: Population-based sample; North-East England.Participants: 155 people (aged 87-89) with limiting dyspnoea.Measures: Dyspnoea assessed by questionnaire. Domiciliary echocardiography performed; LV systolic/diastolic function graded. NT-proBNP measured (Roche Diagnostics). Receiver operating characteristic analyses examined NT-proBNPs diagnostic accuracy for LV dysfunction.ResultsAUC for LVEF less than or equal to 50% was poor (0.58, 95% CI 0.49-0.65), but good for LVEF less than or equal to 40% (0.80, 95% CI 0.73-0.86). At ESC cut point (125ng/l), few cases of systolic dysfunction were missed (NPV 94-100%, depending on severity), but echocardiography (88%) and false positive rates (56-81 per 100 screened) were high. At NICE cut point (400ng/l), echocardiography (51%) and false positive rates (33-45) were lower; exclusionary performance was good for LVEF less than or equal to 40% (1 case missed per 100 screened, 15% of cases; NPV 97%), but poor for LVEF less than or equal to 50% (16 cases missed per 100 screened, 45% of cases; NPV 68%). Incorporating isolated moderate/severe diastolic dysfunction into target condition increased the proportion of cases missed (lower NPV), whilst improving case detection. Incorporating MI history as an additional referral prompt slightly reduced the number of cases missed at expense of higher echocardiography and false positive rates.ConclusionsHigh echocardiography rates and poor exclusionary performance for mild degrees of systolic dysfunction and for diastolic dysfunction limit NT-proBNPs utility as a rule-out test for LV dysfunction in very old people with limiting dyspnoea. Incorporating MI history as an additional echocardiography prompt yields no overall benefit compared to using NT-proBNP level alone.

Maximum levels of hepatitis C virus lipoviral particles are associated with early and persistent infection

Hepatitis C virus (HCV) is bound to plasma lipoproteins and circulates as an infectious lipoviral particle (LVP). Experimental evidence indicates that LVPs have decreased susceptibility to antibody‐mediated neutralisation and higher infectivity. This study tested the hypothesis that LVPs are required to establish persistent infection, and conversely, low levels of LVP in recent HCV infection increase the probability of spontaneous HCV clearance.

Autoantibody to apolipoprotein A-1 in hepatitis C virus infection: a role in atherosclerosis?

Background/purposeOne to three per cent of the world’s population has hepatitis C virus (HCV) infection, which is not only a major cause of liver disease and cancer but also associated with an increased risk of atherosclerosis, despite an ostensibly favourable lipid profile. Autoantibodies are frequent in HCV infection and emerging evidence shows that autoantibodies could be valuable for cardiovascular disease (CVD) risk stratification. This study investigated a novel independent biomarker of CVD, autoantibodies to apolipoprotein A-1 (anti-apoA-1 IgG) and lipids in patients with chronic HCV before, during and after direct-acting anti-viral (DAA) therapy.MethodsEighty-nine blinded serum samples from 27 patients with advanced chronic HCV were assayed for lipids and anti-apoA-1 IgG by ELISA.ResultsPre-treatment HCV viral load correlated with high-density lipoprotein cholesterol (HDL-C, rxa0=xa00.417; pxa0=xa00.042) and negatively with apolipoprotein (apo)B (rxa0=xa0−xa00.497; pxa0=xa00.013) and markers of CVD risk, the apoB/apoA-1 ratio (rxa0=xa0−xa00.490; pxa0=xa00.015) and triglyceride level (TG)/HDL-C ratio (rxa0=xa0−xa00.450; pxa0=xa00.031). Fourteen (52%) of 27 patients had detectable anti-apoA-1 IgG autoantibodies pre-treatment; only two became undetectable with virological cure. Autoantibody-positive sera had lower apoA-1 (pxa0=xa00.012), HDL-C (pxa0=xa00.009) and total cholesterol (pxa0=xa00.006) levels.ConclusionsThis is the first report of the presence of an emerging biomarker for atherosclerosis, anti-apoA-1 IgG, in some patients with HCV infection. It may be induced by apoA-1 on the surface of HCV lipoviral particles. The autoantibodies inversely correlate with apoA-1 and HDL levels and may render HDL dysfunctional. Whether these hypothesis-generating findings have clinical implications in HCV patients requires further study.

56 High serum parathyroid hormone level is independently associated with carotid intima-media thickness in older patients undergoing invasive management of non-st elevation myocardial infarction

Introduction Serum parathyroid hormone (PTH) levels, which are intimately linked to vitamin D status, are associated with an increased risk of cardiovascular events and mortality and may directly influence atherogenesis. Elevated carotid intima-media thickness (CIMT) is a non-invasive marker of subclinical atherosclerosis and is associated with cardiovascular disease, providing predictive power above traditional risk factors. The association between PTH levels and CIMT was evaluated in older patients undergoing invasive management of non ST-elevation acute coronary syndrome (NSTEACS). Methods High-risk older patients (n=160, aged 65u2009years) attending a tertiary centre for invasive management of NSTEACS had CIMT of the left and right posterior carotid artery measured using B-mode ultrasound (Vivid-I®, GE Healthcare). The largest CIMT measurement was used for analysis. Serum PTH was measured by electrochemiluminescent immunoassay. Statistical modelling was performed using multiple regression, controlled by the hierarchical addition of a priori selected potential confounders. Results Mean age was 80.4±4.0u2009years (64.7% male). Median PTH level was 5.6u2009pmol/L [IQR 4.0–6.8 pmol/L]. A significant relationship existed between logarithmically transformed serum PTH and CIMT (regression coefficient (B)=0.230, standard error of B(SEB)=0.086, standardised regression coefficient (&Icaron;²)=0.208, p=0.008) (Figure 1). The association was unchanged after adjustment for age, sex, glomerular filtration rate, body mass index, smoking status, hypertension and hypercholesterolemia (B=0.219, SEB=0.94, β=0.199, p=0.021). Addition of serum vitamin D resulted in a<10%u2009change in the regression coefficient of PTH (β=0.199u2009to β=0.213, 7.0%) and was not a significant predictor of CIMT (p=0.209), suggesting that the relationship was not mediated by vitamin D. Conclusion In this high-risk older cohort, high serum PTH levels are associated with increased CIMT independent of traditional atherosclerotic risk factors.Abstract 56 Figure 1

A comparison of plasma copeptin and AVP responses during saline infusion studies

Copeptin is the C-terminal fragment of proAVP and secreted in equimolar amounts with AVP. While AVP is unstable in vitro and has proved difficult to measure in clinical practice, copeptin is relatively stable and can be measured using an automated immunoassay. Therefore copeptin measurement offers potential as a more practical alternative to the direct measurement of AVP in the investigation of polyuria/polydipsia.