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Background Assessing the spectrum of disease risk associated with hypertriglyceridemia is needed to inform potential benefits from emerging triglyceride lowering treatments. We sought to examine the associations between a full range of plasma triglyceride concentration with five clinical outcomes. Methods We used linked data from primary and secondary care for 15 M people, to explore the association between triglyceride concentration and risk of acute pancreatitis, chronic pancreatitis, new onset diabetes, myocardial infarction and all-cause mortality, over a median of 6–7 years follow up. Results Triglyceride concentration was available for 1,530,411 individuals (mean age 56·6 ± 15·6 years, 51·4% female), with a median of 1·3 mmol/L (IQR: 0.9.to 1.9). Severe hypertriglyceridemia, defined as > 10 mmol/L, was identified in 3289 (0·21%) individuals including 620 with > 20 mmol/L. In multivariable analyses, a triglyceride concentration > 20 mmol/L was associated with very high risk for acute pancreatitis (Hazard ratio (HR) 13·55 (95% CI 9·15–20·06)); chronic pancreatitis (HR 25·19 (14·91–42·55)); and high risk for diabetes (HR 5·28 (4·51–6·18)) and all-cause mortality (HR 3·62 (2·82–4·65)) when compared to the reference category of ≤ 1·7 mmol/L. An association with myocardial infarction, however, was only observed for more moderate hypertriglyceridaemia between 1.7 and 10 mmol/L. We found a risk interaction with age, with higher risks for all outcomes including mortality among those ≤ 40 years compared to > 40 years. Conclusions We highlight an exponential association between severe hypertriglyceridaemia and risk of incident acute and chronic pancreatitis, new diabetes, and mortality, especially at younger ages, but not for myocardial infarction for which only moderate hypertriglyceridemia conferred risk.

Non-ST elevation acute coronary syndrome (NSTEACS) occurs more frequently in older patients with an increased occurrence of recurrent cardiac events following the index presentation. Telomeres are structures consisting of repeated DNA sequences as associated shelterin proteins at the ends of chromosomes. We aim to determine whether telomere length (TL) and telomerase activity (TA) predicted poor outcomes in older patients presenting with NSTEACS undergoing invasive care. Older patients undergoing invasive management for NSTEACS were recruited to the ICON-1 biomarker study (NCT01933581). Peripheral blood mononuclear cells (PBMC) were recovered on 153 patients. DNA was isolated and mean TL was measured by quantitative PCR expressed as relative T (telomere repeat copy number) to S (single copy gene number) ratio (T/S ratio), and a telomere repeat amplification assay was used to assess TA during index presentation with NSTEACS. Primary clinical outcomes consisted of death, myocardial infarction (MI), unplanned revascularisation, stroke and significant bleeding recorded at 1 year. TL and TA were divided into tertile groups for analysis. Cox proportional hazards regression was performed. Ordinal regression was performed to evaluate the relationship between TL and TA and traditional cardiovascular risk factors at baseline. 298 patients were recruited in the ICON-1 study of which 153 had PBMC recovered. The mean age was 81.0 ± 4.0 years (64% male). Mean telomere length T/S ratio was 0.47 ± 0.25 and mean TA was 1.52 ± 0.61 units. The primary composite outcome occurred in 44 (28.8%) patients. There was no association between short TL or low TA and incidence of the primary composite outcome (Hazard Ratio [HR] 1.50, 95% Confidence Interval [CI] 0.68-3.34, p = 0.32 and HR 1.33, 95% CI 0.52-3.36, p = 0.51 respectively). TL and TA are not found to be associated with the incidence of adverse outcomes in older patients presenting with NSTEACS undergoing invasive care. URL: https://www.clinicaltrials.gov Unique identifier: NCT01933581.

There is a higher incidence of vitamin D deficiency in older adults. This may play a plausible mechanistic role in the occurrence of increased adverse events after non-ST elevation acute coronary syndrome (NSTEACS). This study investigated whether total vitamin D levels at the time of presentation predicted adverse outcomes in older adults undergoing invasive management of NSTEACS. Of the 629 patients screened, 300 high-risk older adults with NSTEACS managed by an invasive strategy were recruited. Serum total 25-hydroxyvitamin D was measured at index presentation. The primary outcome was defined as 1-year composite of all-cause mortality, acute coronary syndrome (ACS), unplanned repeat revascularisation, significant bleeding or stroke. Mean age was 80.5±4.8 years (61.9% male). Median vitamin D level was 29.5nmol/L [interquartile range IQR 16.0-53.0 nmol/L] and was split equally by the median for analysis forming two groups: high (median vitamin D 53.0 nmol/L [IQR 40.0-75.0]) and low (16.0 nmol/L [11.0-23.0]). The primary outcome occurred in 76 patients (25.9%); 32 (21.9%) in the low group and 44 (29.9%) in the high group, p = 0.12. Multivariable analyses showed no significant difference in the primary composite outcome at 1 year between the low and high group of baseline serum vitamin D (Hazard Ratio 1.20 [95% Confidence Interval 0.72-2.0], p = 0.48). Serum total vitamin D, measured at the time of angiography, was not associated with adverse outcomes at one year in this high-risk older cohort of patients with NSTEACS undergoing invasive management.

Chronic HCV (CHC) infection is associated with autoimmunity. IgG autoantibodies to apolipoprotein A-I (AAA-I) predict all-cause mortality. We evaluated AAA-I in CHC patients and in those who were not viraemic, either because of spontaneous resolution (SR) of infection or HCV clearance following sustained virological response (SVR) after interferon therapy. We limited the study to HCV genotypes 1 and 3, the dominant HCV genotypes circulating in the UK. Serum samples from 126 CHC patients and 114 nonviraemic individuals (25 SR and 89 SVR) were assayed for AAA-I and lipoproteins. AUC was calculated for AAA-I and HDL-related parameters and used to predict cirrhosis. Fibronectin (FN) and FN-mRNA were measured in human hepatic stellate cells (LX-2) in the presence or absence of AAA-I. AAA-I was found in 47% of patients with CHC, 37% of SVR patients, and 16% of SR individuals (CHC vs. SR, = 0.004). AAA-I levels in CHC patients were higher in those with cirrhosis ( = 0.0003). The AUC for AAA-I, apoA-I, and HDL-C in predicting cirrhosis was 0.72 ( < 0.001), 0.65 ( = 0.01), and 0.64 ( = 0.02). After 48 h in the presence of AAA-I, LX-2 cells showed an 80% increase in FN-mRNA compared to the LX-2/IgG control ( = 0.028) and higher levels of FN ( = 0.0016). CHC is often associated with AAA-I, and these can persist after SVR. AAA-I is a robust predictor of cirrhosis in CHC infection. LX-2 cells exposed to AAA-I showed increased FN. Further studies are warranted to define the role of AAA-I in promoting not only viral persistence but also fibrosis.

Lipids play essential roles in the hepatitis C virus (HCV) life cycle and patients with chronic HCV infection display disordered lipid metabolism which resolves following successful anti-viral therapy. It has been proposed that HCV genotype 3 (HCV-G3) infection is an independent risk factor for hepatocellular carcinoma and evidence suggests lipogenic proteins are involved in hepatocarcinogenesis. We aimed to characterise variation in host lipid metabolism between participants chronically infected with HCV genotype 1 (HCV-G1) and HCV-G3 to identify likely genotype-specific differences in lipid metabolism. We combined several lipidomic approaches: analysis was performed between participants infected with HCV-G1 and HCV-G3, both in the fasting and non-fasting states, and after sustained virological response (SVR) to treatment. Sera were obtained from 112 fasting patients (25% with cirrhosis). Serum lipids were measured using standard enzymatic methods. Lathosterol and desmosterol were measured by gas-chromatography mass spectrometry (MS). For further metabolic insight on lipid metabolism, ultra-performance liquid chromatography MS was performed on all samples. A subgroup of 13 participants had whole body fat distribution determined using in vivo magnetic resonance imaging and spectroscopy. A second cohort of (non-fasting) sera were obtained from HCV Research UK for comparative analyses: 150 treatment naïve patients and 100 non-viraemic patients post-SVR. HCV-G3 patients had significantly decreased serum apoB, non-HDL cholesterol concentrations, and more hepatic steatosis than those with HCV-G1. HCV-G3 patients also had significantly decreased serum levels of lathosterol, without significant reductions in desmosterol. Lipidomic analysis showed lipid species associated with reverse cholesterol transport pathway in HCV-G3. We demonstrated that compared to HCV-G1, HCV-G3 infection is characterised by low LDL cholesterol levels, with preferential suppression of cholesterol synthesis via lathosterol, associated with increasing hepatic steatosis. The genotype-specific lipid disturbances may shed light on genotypic variations in liver disease progression and promotion of hepatocellular cancer in HCV-G3.

Background: We measured plasma PCSK9 concentrations in healthy men with a PCSK9 (proprotein convertase subtilisin/kexin type 9) loss-of-function variant (p.R46L), in statin-treated patients with a clinical diagnosis of familial hypercholesterolemia (FH) and carrying a PCSK9 gain-of-function mutation (p.D374Y), and in statin-treated patients with FH due to different genetic causes. Methods: PCSK9 was measured with a previously described ELISA. Results: In 81 healthy middle-aged Caucasian men, the PCSK9 concentration was significantly associated with the concentrations of total cholesterol (r = 0.42; P < 0.0001), LDL cholesterol (r = 0.34; P = 0.01), and triglycerides (r = 0.25; P = 0.02). In p.R46L carriers, mean (SD) concentrations of PCSK9 were 15% lower than in RR individuals [65.5 μg/L (21.6 μg/L) vs 77.5 μg/L (18.2 μg/L); P = 0.03]. In patients with the p.D374Y variant (n = 7), the mean PCSK9 concentration was significantly lower than in the combined group of patients with an LDLR (low density lipoprotein receptor) mutation (n = 25), an APOB [apolipoprotein B (including Ag(x) antigen)] variant encoding p.R3527Q (n = 6), or no detectable mutation (n = 14) [96.4 μg/L (42.5 μg/L) vs 151.6 μg/L (69.6 μg/L); P = 0.02]. Two of the 14 patients with no mutation had PCSK9 concentrations below the mean for p.D374Y carriers; sequencing of the PCSK9 gene and promoter revealed no mutations. Among 409 FH patients, we identified 6 carriers of the promoter variant −287G>A (1.5%), a frequency similar to that (1.0%) previously reported for 2772 healthy men in the UK. In neither group was the −287G>A variant associated with differences in lipid traits. Conclusions: The loss-of-function p.R46L variant is associated with the expected lower concentrations of circulating PCSK9; the gain-of-function p.D374Y mutation is also associated with lower concentrations, presumably because of the higher affinity of this variant for the LDL receptor and its more rapid clearance. In treated FH patients, a low plasma PCSK9 concentration does not appear to be a useful screening tool for identifying novel PCSK9 mutations.

Summary Aims The aims of this study were to determine the diagnostic yield of a dedicated heart failure diagnosis clinic and the impact of using different guideline recommended N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) referral thresholds on diagnosis and referral patterns. Methods and results Patients referred by primary care between September 2011 and May 2013 were included in the analysis. Data collected included baseline characteristics, NT‐proBNP levels, echocardiographic and clinical findings, final diagnosis and outcome. The impact of using Newcastle (locally modified age‐adjusted NT‐proBNP thresholds), National Institute for Health and Care Excellence (NICE) and European Society of Cardiology (ESC) NT‐proBNP thresholds on diagnosis and referrals was determined by applying the different guidelines to this population. A total of 208 patients were referred; median age 77.5 years and 62.5% were women. Thirty‐four patients (16.3%) had systolic heart failure, 50 patients (24.0%) had heart failure with preserved ejection fraction. One hundred and six patients (51.0%) did not have heart failure. Using NICE guidelines (NT‐proBNP ≥ 400 ng/l) instead of the Newcastle age‐adjusted NT‐proBNP referral thresholds results in 59 fewer referrals, but eight heart failure diagnoses were missed. Using the ESC cut‐off of NT‐proBNP ≥ 125 ng/l would result in 88 additional referrals; one diagnosis of heart failure would be missed. Over a mean follow‐up of 16.8 ± 6 months there were 21 deaths and 47 hospital admissions. Conclusion The Newcastle age‐adjusted thresholds led to more referrals in comparison to NICE guidelines but are more sensitive in diagnosing heart failure. Using ESC recommended thresholds results in a similar diagnostic yield to our age‐adjusted thresholds, but has the potential to significantly increase the referrals in patients ≥ 75 years, which may result in a lower diagnostic yield.

BackgroundThe density of hepatitis C virus (HCV) in plasma is heterogeneous but the factors which influence this are poorly understood. Evidence from animal models and cell culture suggest that low-density apolipoprotein B (apoB)-associated HCV lipoviral particles (LVP) are more infectious than high-density HCV.ObjectiveTo measure LVP in patients with chronic hepatitis C genotype 1 (CHC-G1) and examine metabolic determinants of LVP load.Patients51 patients with CHC-G1 infection.MethodsFasting lipid profiles and homeostasis model assessment of insulin resistance (HOMA-IR) were determined in 51 patients with CHC-G1. LVP and non-LVP viral load were measured by real-time PCR of plasma at density <1.07 g/ml and >1.07 g/ml, respectively, following iodixanol density gradient ultracentrifugation. The LVP ratio was calculated using the formula: LVP/(LVP + non-LVP).ResultsThe mean LVP ratio was 0.241 but varied 25-fold (from 0.029 to 0.74). Univariate analysis showed that the LVP ratio correlated with HOMA-IR (p=0.004) and the triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio (p=0.004), but not with apoB. In multivariate analysis, HOMA-IR was the main determinant of LVP load (log10IU/ml) (R2=16.6%; p=0.037) but the TG/HDL-C ratio was the strongest predictor of the LVP ratio (R2=24.4%; p=0.019). Higher LVP ratios were associated with non-response to antiviral therapy (p=0.037) and with greater liver stiffness (p=0.001).ConclusionIR and associated dyslipidaemia are the major determinants of low-density apoB-associated LVP in fasting plasma. This provides a possible mechanism to explain why IR is associated with more rapidly progressive liver disease and poorer treatment outcomes.

IntroductionA large proportion of older patients with cardiovascular disease have low serum vitamin D levels. Such deficiency states have been linked with lower health-related quality of life (HRQoL). The Improve Cardiovascular Outcomes in High Risk PatieNts (ICON-1) study (NCT01933581) has previously demonstrated that serum vitamin D levels do not predict major adverse cardiovascular events (MACE) at 1 year in high-risk older adults being managed invasively for non-ST elevation acute coronary syndrome (NSTEACS). However, the relationship between serum vitamin D levels and HRQoL in older patients with NSTEACS is unclear. This further analysis of the ICON-1 cohort aims to investigate the relationship between serum vitamin D and HRQoL in high-risk, older adults managed invasively for NSTEACS.MethodsPatients aged ≥75 years presenting with NSTEACS (n=293) were recruited to the multi-centre prospective cohort ICON-1 study. Baseline serum total vitamin D was measured by electrochemiluminescent immunoassay prior to coronary angiography, split into two groups by the median for analysis. HRQoL was assessed within 24 hours post-procedure using the Short Form 36 Health Survey (SF-36) (License Number QM033917), values reported as norm-based scores. At one-year follow-up SF-36 scores were repeated. SF-36 consists of 4 physical subscales, summarised as Physical Component Summary. Statistical differences between groups were assessed with Kruskal-Wallis testing. Multi-variate linear regression was used to probe the impact of serum vitamin D on HRQoL adjusted for the a priori co-variates of age and sex.ResultsMean age was 80.4±4.8 years (61.8% male). Baseline median vitamin D was 29.0 [IQR 16.0–53.0] nmol/L. Patients were split by the median baseline vitamin D: low serum vitamin D (n=147, median 16.0 [IQR 12.0–23.0] nmol/L) and high serum vitamin D (n=146, median 53.0 [IQR 40.0–75.0] nmol/L). Both at baseline and at 1 year, those with a high serum vitamin D had significant higher scores in physical functioning (P<0.0001 at baseline and P=0.002 at 1 year, respectively) and physical component score (P=0.002 at baseline and P=0.038 at 1 year) compared to those with a low serum vitamin D (Table 1). At baseline, there was a significant association between serum vitamin D and a higher physical functioning (β=0.15, P=0.028) and physical component scores (β=0.16, P=0.009), after adjustment for age and sex (Table 2). This association was also apparent at 1-year follow-up, with a significant adjusted association between serum vitamin D and physical functioning (β=0.21, P=0.003).Abstract 36 Table 1Norm-based SF-36 domain differences between those with high serum vitamin D versus those with low serum vitamin D, both at baseline and at 1-year follow-up. SF-36, Short Form 36 SF-36 domain BASELINE ONE YEAR FOLLOW-UP Low vs. High serum vitamin D P value Low vs. High serum vitamin D P value Physical functioning 34.1 [27.8 – 44.6] vs. 44.6 [29.9 – 50.9]< 0.000139.4 [27.8 – 48.8] vs. 46.7 [34.1 – 55.0]0.002 Physical component score 32.4 [27.0 – 40.7] vs. 39.2 [29.3 – 50.1]0.00238.3 [28.8 – 48.3] vs. 44.7 [31.7 – 52.4]0.038Abstract 36 Table 2Multiple linear regression analysis of serum vitamin D (high vs. low) and physical SF-36 scores. SF-36, Short Form 36; B, regression coefficient; SE(B), standard error of B; and β, standardised regression coefficient. BASELINE ONE YEAR FOLLOW-UP Physical functioningPhysical component scorePhysical functioningPhysical component score Model 1 – Unadjusted analysisB=5.4SE(B)=1.39β=0.21B=4.68SE(B)=1.42β=0.20B=5.25SE(B)=1.76β=0.21B=3.51SE(B)=1.80β=0.14P=0.003P=0.001P=0.003P=0.05 Model 2 – Adjusted for age and sexB=2.1SE(B)=1.20β=0.15B=3.74SE(B)=1.42β=0.21B=3.86SE(B)=1.74β=0.15B=-1.45SE(B)=1.61β=0.12P=0.028P=0.009P=0.03P=0.13ConclusionsThere is an association, independent of age and sex, between serum vitamin D and physical health-related quality of life at both presentation and at 1-year follow-up after invasive management of NSTEACS in high-risk older adults. Although vitamin D deficiency has not been shown to predict MACE, it may play a plausible role in the significant morbidity experienced by older adults with cardiovascular disease.Conflict of InterestNone to declare