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PURPOSE OF REVIEW LDL, triglyceride-rich lipoprotein (TRL) and lipoprotein(a) [Lp(a)] particles are the key atherogenic lipoproteins. Deranged metabolism of these lipoproteins accounts for a spectrum of clinically important dyslipidemias, such as FH, elevated Lp(a) and diabetic dyslipidemia. We review the findings from recent dynamic and tracer studies that have contributed to expanding knowledge in this field. RECENT FINDINGS Deficiency in LDL receptor activity does not only impair the catabolism of LDL-apoB-100 in FH, but also induces hepatic overproduction and decreases catabolism of TRLs. Patients with elevated Lp(a) are characterized by increased hepatic secretion of Lp(a) particles. Elevation of TRLs in diabetes is partly mediated by increased production of apoB-48 and apoC-III, and impaired clearance of apoB-48 in the postprandial state. Tracer kinetic studies show that proprotein convertase subtilisin/kexin type 9 mAbs alone or in combination with statin can increase the catabolism and decrease production of LDL and Lp(a) particles. By contrast, angiopoietin-like protein 3 inhibitors (e.g. evinacumab) reduce VLDL production and increase LDL clearance in FH. Glucagon-like peptide-1 receptor agonists can improve diabetic dyslipidemia by increasing the catabolism of apoB-48 and decreasing the production of apoB-48 and apoC-III. SUMMARY Dynamic studies of the metabolism of atherogenic lipoproteins provide new insight into the nature of dyslipidemias and point to how new therapies with complementary modes of action may have maximal clinical impact.

Background Lipoprotein(a) (Lp[a]) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Proprotein convertase subtilisin/kexin‐9 monoclonal antibodies (PCSK9mAbs) can lower Lp(a) levels in clinical trials, but their effects in patients with elevated Lp(a) in clinical practice remain unclear. Aims To investigate the effectiveness and safety of PCSK9mAbs in lowering plasma Lp(a) in patients with elevated Lp(a) concentrations in a lipid clinic. Methods This was an open‐label study of 53 adult patients with elevated Lp(a) concentration (≥0.5 g/L). Clinical, biochemical, and safety data were collected before and on treatment with evolocumab or alirocumab over a mean period of 11 months. Results Treatment with a PCSK9mAb resulted in a significant reduction of 0.29 g/L (−22%) in plasma Lp(a) concentration (p.05 in all). 7.5% and 47% of the patients attained a target concentration of Lp(a)

Purpose of review Elevated lipoprotein(a) [Lp(a)] is a genetic trait that indicates higher risk of atherosclerotic cardiovascular disease (ASCVD). We review novel strategies to mitigate behavioural risk-factors in this genetic condition. Recent findings Pharmacological and biological interventions are available for lowering Lp(a). However, the acceptability and feasibility of these approaches are questionable due to cost and lack of clinical evidence for their efficacy. A number of low-cost, minimal patient contact interventions are available for modifying behavioural risk-factors that are associated with increased risk of ASCVD familial hypercholesterolaemia and diabetes. These include lifestyle interventions designed to improve diet and physical activity. These interventions may be particularly important among individuals with elevated Lp(a) to manage their higher risk of diabetes and ASCVD. The following article outlines recent research that has examined such low-cost, minimal patient contact interventions. Summary The current research indicated that such interventions, which are grounded in psychological theory, can assist individuals to improve their diet and physical activity. These findings have implications for developing and implementing similar interventions for individuals with elevated Lp(a), so as to assist in reducing behavioural risk-factors associated with ASCVD.

Familial hypercholesterolaemia (FH) is characterised by a high, but variable risk of premature coronary artery disease (CAD). Cardiac computed tomography angiography (CCTA) can be employed to assess subclinical coronary atherosclerosis. We investigated the features and distribution of coronary artery plaques in asymptomatic patients with and without genetically confirmed heterozygous FH.We undertook an aged-matched case-control study of asymptomatic phenotypic FH patients with (cases, M+) and without (controls, M-) an FH-causing mutation. Coronary atherosclerosis was assessed by CCTA and calcium scoring. Coronary segments were evaluated for global and vessel-level coronary plaques and degree of stenosis.We studied 104 cases and 104 controls (mean age 49.9 ± 10.4 years), who had a similar spectrum of non-cardiovascular risk factors. Pre-treatment plasma LDL-cholesterol was higher in the M+ than M- group (7.8 ± 2.1 vs 6.2 ± 1.2 mmol/L, p0.001). There was a greater proportion of patients with mixed and calcified plaque, as well as a higher coronary artery calcium score and segment stenosis score (all p0.05), in the M+ compared with the M- group. M+ patients also had a significantly higher frequency of coronary artery calcium in the left main and anterior descending and right coronary arteries (all p0.05), but not in the left circumflex.Among patients with phenotypic FH, those with a genetically confirmed diagnosis had a higher frequency and severity of coronary atherosclerotic plaques, and specifically more advanced calcified plaques.

© 2020 British Journal of AnaesthesiaBackground: Accidental dural puncture is an uncommon complication of epidural analgesia and can cause postdural puncture headache (PDPH). We aimed to describe management practices and outcomes after PDPH treated by epidural blood patch (EBP) or no EBP. Methods: Following ethics committee approval, patients who developed PDPH after accidental dural puncture were recruited from participating countries and divided into two groups, those receiving EBP or no EBP. Data registered included patient and procedure characteristics, headache symptoms and intensity, management practices, and complications. Follow-up was at 3 months. Results: A total of 1001 patients from 24 countries were included, of which 647 (64.6%) received an EBP and 354 (35.4%) did not receive an EBP (no-EBP). Higher initial headache intensity was associated with greater use of EBP, odds ratio 1.29 (95% confidence interval 1.19–1.41) per pain intensity unit increase. Headache intensity declined sharply at 4 h after EBP and 127 (19.3%) patients received a second EBP. On average, no or mild headache (numeric rating score≤3) was observed 7 days after diagnosis. Intracranial bleeding was diagnosed in three patients (0.46%), and backache, headache, and analgesic use were more common at 3 months in the EBP group. Conclusions: Management practices vary between countries, but EBP was more often used in patients with greater initial headache intensity. EBP reduced headache intensity quickly, but about 20% of patients needed a second EBP. After 7 days, most patients had no or mild headache. Backache, headache, and analgesic use were more common at 3 months in patients receiving an EBP.

Background and aims Familial hypercholesterolaemia (FH) and elevated plasma lipoprotein(a) [Lp(a)] are inherited conditions independently associated with atherosclerotic cardiovascular disease. This study investigated the detection of new cases of elevated Lp(a) during cascade testing of relatives of probands with a definite diagnosis of FH and elevated Lp(a) (≥50 mg/dL). Methods Relatives from 62 adult probands were tested for FH genetically and for elevated Lp(a) using an immunoassay. The prevalence and yield of new cases of FH with or without elevated Lp(a) (≥50 mg/dL) among relatives and the association between the detection of elevated Lp(a) and the Lp(a) concentration of the probands were assessed. Results Among 162 relatives tested (136 adults and 26 children), the prevalence of FH and elevated Lp(a) was 60.5% and 41.4%, respectively: FH alone was detected in 31.5%, elevated Lp(a) alone in 12.3%, FH with elevated Lp(a) in 29.0%, and neither disorder in 27.2% of the relatives. Cascade testing detected a new case of FH, elevated Lp(a) and FH with elevated Lp(a) for every 1.5, 2.1 and 3.0 relatives tested, respectively. The proportion of relatives detected with elevated Lp(a) was significantly higher when tested from probands with Lp(a) ≥100 mg/dL compared with those from probands with Lp(a) between 50-99 mg/dL (53% vs 34%, p = 0.018). The concordance between the detection of FH and elevated Lp(a) was 56.2% (kappa statistic 0.154), indicating a poor agreement. Conclusions A dual approach to cascade testing families for FH and high Lp(a) from appropriate probands can effectively identify not only new cases of FH, but also new cases of elevated Lp(a) with or without FH. The findings accord with the co-dominant and independent heritability of FH and Lp(a).

Background and objectives: A lack of public and health professional awareness about familial hypercholesterolaemia (FH) leads to an estimated 90,000 Australians remaining undiagnosed. The aim of this study was to establish the level of knowledge and awareness of FH in Australian general practices. Method: A qualitative descriptive methodology was used to explore baseline knowledge and perceptions of practice staff about diagnosing and managing FH. Overall, 63 interviews were conducted with general practice staff at 15 practices taking part in a National Health and Medical Research Council partnership grant study (GNT1142883). Results: Data were analysed thematically and coded into themes - knowledge/awareness/recall, management, use of guidelines/referrals, and contacting family members. Most general practitioners treated the high cholesterol component as their primary focus. Guidelines and referrals were rarely used. Discussion: This research reflected a lack of knowledge, awareness and use of guidelines similar to that shown in other published studies. Improved primary care infrastructure, knowledge and awareness of FH need to be addressed.

BACKGROUND Diagnostic tools for familial hypercholesterolemia (FH) rely on estimation of LDL cholesterol concentration. However, routine measurement or calculation of LDL cholesterol concentration using the Friedewald equation contains a cholesterol contribution from lipoprotein(a) [Lp(a)]. We investigated whether Lp(a) influences the phenotypic diagnosis of FH by commonly used clinical criteria. METHODS A cohort of 907 adult index patients attending a clinic were studied. The Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) diagnostic criteria were estimated before and after adjusting LDL cholesterol concentration for the cholesterol content (30%) of Lp(a). Diagnostic reclassification rates and area under the ROC (AUROC) curves in predicting an FH mutation were also compared. RESULTS Seventy-four patients defined by DLCN criteria (8.2%) and 207 patients defined by SB criteria (22.8%) were reclassified to “unlikely” FH after adjusting LDL cholesterol for Lp(a) cholesterol. The proportion of FH patients defined by DLCN (probable/definite) and SB (possible/definite) criteria decreased significantly in patients with increased Lp(a) (>0.5 g/L; n = 330) after Lp(a) cholesterol adjustment (P < 0.01). The overall reclassification rate was significantly higher in patients with Lp(a) concentration >1.0 g/L (P < 0.001). The AUROC curve for LDL cholesterol concentration ≥191 mg/dL (≥5.0 mmol/L), DLCN criteria, and SB criteria in predicting an FH mutation increased significantly after adjustment (P < 0.001). There was no significant difference in AUROC curve before and after Lp(a) cholesterol adjustment at an LDL cholesterol concentration ≥251 mg/dL (≥6.5 mmol/L). CONCLUSIONS Adjusting LDL cholesterol concentration for Lp(a) cholesterol improves the diagnostic accuracy of DLCN and SB criteria, especially with Lp(a) >1.0 g/L and LDL cholesterol

BackgroundLipoprotein(a) [Lp(a)] is a low-density lipoprotein‒like particle containing apolipoprotein(a) [apo(a)]. Patients with elevated Lp(a), even when treated with statins, are at increased risk of cardiovascular disease. We investigated the kinetic basis for elevated Lp(a) in these patients.ObjectivesApo(a) production rate (PR) and fractional catabolic rate (FCR) were compared between statin-treated patients with and without elevated Lp(a).MethodsThe kinetics of apo(a) were investigated in 14 patients with elevated Lp(a) and 15 patients with normal Lp(a) levels matched for age, sex, and body mass index using stable isotope techniques and compartmental modeling. All 29 patients were on background statin treatment. Plasma apo(a) concentration was measured using liquid chromatography–mass spectrometry.ResultsThe plasma concentration and PR of apo(a) were significantly higher in patients with elevated Lp(a) than in patients with normal Lp(a) concentration (all P < 0.01). The FCR of apo(a) was not significantly different between the groups. In univariate analysis, plasma concentration of apo(a) was significantly associated with apo(a) PR in both patient groups (r = 0.699 and r = 0.949, respectively; all P < 0.01). There was no significant association between plasma apo(a) concentration and FCR in either of the groups (r = 0.160 and r = −0.137, respectively).ConclusionElevated plasma Lp(a) concentration is a consequence of increased hepatic production of Lp(a) particles in these patients. Our findings provide a kinetic rationale for the use of therapies that target the synthesis of apo(a) and production of Lp(a) particles in patients with elevated Lp(a).

Lipoprotein(a) [Lp(a)] is a highly atherogenic lipoprotein characterized by apolipoprotein(a) [apo(a)] covalently bounded to apoB-100 (apoB). However, the metabolism of apo(a) and apoB within plasma Lp(a) particles in patients on statins remains unclear.The kinetics of Lp(a)-apo(a) and Lp(a)-apoB were determined in 20 patients with elevated Lp(a) (≥0.8 g/L; n = 10) and normal Lp(a) (≤0.3 g/L; n = 10) using stable isotope techniques and compartmental modeling. Plasma apo(a) concentration was measured using liquid chromatography-mass spectrometry. All patients were on statin therapy and were studied in the fasting state.The fractional catabolic rate (FCR) of Lp(a)-apo(a) was not significantly different from that of Lp(a)-apoB in statin-treated patients with elevated or normal Lp(a) (P 0.05 in both). Lp(a)-apo(a) FCR was significantly correlated with Lp(a)-apoB in patients with elevated and normal Lp(a) concentrations (r = 0.970 and r = 0.979, respectively; all P 0.001) with Lin's concordance test showing substantial agreement between the FCRs of Lp(a)-apo(a) and Lp(a)-apoB in patients with elevated and normal Lp(a) concentrations (rOur data indicate that the apo(a) and apoB proteins within Lp(a) particles have similar FCR and are therefore tightly coupled as an Lp(a) holoparticle in statin-treated patients with elevated and normal Lp(a) concentrations.

BACKGROUND: There is a lack of information on the health care of familial hypercholesterolemia (FH).OBJECTIVE: The objective of this study was to compare the health care of FH in countries of the Asia-Pacific region and Southern Hemisphere.METHODS: A series of questionnaires were completed by key opinion leaders from selected specialist centers in 12 countries concerning aspects of the care of FH, including screening, diagnosis, risk assessment, treatment, teaching/training, and research; the United Kingdom (UK) was used as the international benchmark.RESULTS: The estimated percentage of patients diagnosed with the condition was low (overall

Funding Acknowledgements Type of funding sources: None. Background/Introduction Elevated lipoprotein(a)[Lp(a)] is an inherited and independent risk factor for atherosclerotic cardiovascular diseases (ASCVD). However, it is an under detected condition with no specific therapy available at present for lowering Lp(a). Hence, identifying the distribution of modifiable cardiovascular and behavioural risk factors is important for implementing an effective intervention programme to mitigate the overall risk of ASCVD in high-risk individuals with elevated Lp(a). Purpose The primary aim was to describe and compare the distribution of modifiable cardiovascular and behavioural risk factors in both index cases and their relatives with elevated Lp(a) identified through cascade testing at the Lipid Disorders Clinic, Royal Perth Hospital. Methods We studied 51 index cases and 71 relatives cascade tested with elevated Lp(a) (≥0.5 g/L). Questionnaires were completed concerning aspects of cardiovascular health (cholesterol level, blood pressure and blood glucose level) and behavioural health metrics (diet, smoking, physical activity, body-mass-index [BMI]). Lp(a) was measured by an immunoassay having minimal dependence on apolipoprotein(a) isoform size. The health metrics were described as proportions and statistical analyses performed using Student’s t-test or Chi-square where appropriate. Results Compared with the index cases, a higher proportion of their affected relatives were female (62% vs 43%, p = 0.039), younger (43 years vs 53 years, p Conclusion(s) Although the younger affected relatives with elevated Lp(a) have a lower cardiovascular risk compared with the index cases, a focus on modifiable behavioural changes, such as a healthy diet and an ideal body weight, is still required to mitigate the overall risk of ASCVD.

Objectives: The aim of this study was to evaluate the differences in surgical capacity for head and neck cancer in the UK between the first wave (March‐June 2020) and the current wave (Jan‐Feb 2021) of the COVID‐19 pandemic. Design: REDcap online based survey of hospital capacity. Setting: UK secondary and tertiary hospitals providing head and neck cancer surgery. Participants: One representative per hospital was asked to report the capacity for head and neck cancer surgery in that institution. Main Outcome Measures: The principal measures of interests were new patient referrals, capacity in outpatients, theatres and critical care; therapeutic compromises constituting delay to surgery, de‐escalated surgery and therapeutic migration to non‐surgical primary modality. Results: Data was returned from approximately 95% of UK hospitals with a head and neck cancer surgery specialist service. 50% of UK head and neck cancer patients requiring surgery have significantly compromised treatments during the second wave: 28% delayed, 10% have received radiotherapy‐based treatment instead of surgery and 12% have received de‐escalated surgery. Surgical capacity has been more severely constrained in the second wave (58% of pre‐pandemic level) compared with the first wave (62%) despite the time to prepare. Conclusions: Some hospitals are overwhelmed by COVID‐19 and unable to offer essential cancer surgery, but all have neighbouring hospitals in their region retaining good (or even normal) capacity. It is noteworthy that very few patients have been appropriately re‐directed away from the hospitals most constrained by their burden of COVID‐19. The paucity of an effective central or regional strategic response to this evident mismatch between demand and surgical capacity is to the detriment of our head and neck cancer patients.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a convertase enzyme mostly produced by the liver. It is a key regulator of LDL metabolism because of its ability to enhance degradation of the LDL receptor. PCSK9 also regulates the metabolism of lipoprotein(a) [Lp(a)] and triglyceride-rich lipoproteins (TRLs). Its key role in modulating atherosclerotic cardiovascular disease (ASCVD) is supported by genetic studies and clinical outcome trials. Kinetic studies provide mechanistic insight into the role of PCSK9 in regulating the physiology and pathophysiology of plasma lipids and lipoproteins. Kinetic data have demonstrated that plasma PCSK9 concentration is inversely associated with the clearance of LDL in men. Gain-of-function mutations of PCSK9 markedly increase plasma LDL-cholesterol concentrations due to impaired LDL-apoB catabolism. Conversely, PCSK9 deficiency results in low LDL-cholesterol associated with enhanced LDL-apoB clearance. Inhibition of PCSK9 with monoclonal antibodies (such as evolocumab or alirocumab) lowers plasma LDL-cholesterol and apoB levels chiefly by upregulating the catabolism of LDL particles in healthy individuals. As monotherapy, PCSK9 inhibitor reduced Lp(a) concentrations by decreasing the production rate. However, as combination therapy, it reduced the plasma concentration of Lp(a) by increasing the fractional catabolism of Lp(a) particles. In statin-treated patients with high Lp(a), PCSK9 inhibition lowers plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. The effect of PCSK9 inhibition on TRL metabolism has been studied in healthy individuals and in patients with type 2 diabetes. These findings suggest that PCSK9 appears to play a less important role in TRL than LDL metabolism. Kinetic studies of PCSK9 inhibition therapy on lipoprotein metabolism in diverse high risk patient populations (such as familial hypercholesterolemia) and new therapeutic combination also merit further investigation.

ObjectiveFamilial hypercholesterolaemia (FH) is characterised by elevated low-density lipoprotein (LDL)-cholesterol and increased risk of cardiovascular disease. However, FH remains substantially underdiagnosed and undertreated. We employed a two-stage pragmatic approach to identify and manage patients with FH in primary healthcare.MethodsMedical records for 232 139 patients who attended 15 general practices at least once in the previous 2 years across five Australian States were first screened for potential risk of FH using an electronic tool (TARB-Ex) and confirmed by general practitioner (GP) clinical assessment based on phenotypic Dutch Lipid Clinic Network Criteria (DLCNC) score. Follow-up GP consultation and management was provided for patients with phenotypic FH.ResultsA total of 1843 patients were identified by TARB-Ex as at potential risk of FH (DLCNC score ≥5). After GP medical record review, 900 of these patients (49%) were confirmed with DLCNC score ≥5 and classified as high-risk of FH. From 556 patients subsequently clinically assessed by GPs, 147 (26%) were diagnosed with phenotypic FH (DLCNC score >6). Follow-up GP consultation and management for 77 patients resulted in a significant reduction in LDL-cholesterol (−16%, pConclusionsA pragmatic approach integrating electronic medical record tools and clinical GP follow-up consultation is a feasible method to identify and better manage patients with FH in the primary healthcare setting.Trial registration number12616000630415.

Purpose of Review Statins are first-line therapy for lowering low-density lipoprotein (LDL) cholesterol in familial hypercholesterolemia (FH), particularly in heterozygous patients. We review advances and new questions on the use of statins in FH. Recent Findings Cumulative evidence from registry data and sub-analyses of clinical trials mandates the value of statin therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in FH. Statins are safe in children and adolescents with FH, with longer term cardiovascular benefits. The potentially toxic effects of statins in pregnancy need to be considered, but no association has been reported in prospective cohort studies with birth defects. There is no rationale for discontinuation of statins in elderly FH unless indicated by adverse events. FH is undertreated, with > 80% of statin-treated FH patients failing to attain LDL cholesterol treatment targets. This may relate to adherence, tolerability, and genetic differences in statin responsiveness. Statin treatment from childhood may reduce the need for stringent cholesterol targets. Combination of statins with ezetimibe and PCSK9 inhibitors significantly improves the efficacy of treatment. Whether statin use could improve the clinical course of FH patients with COVID-19 and other respiratory infections remains an unsolved issue for future research. Summary Statins are the mainstay for primary and secondary prevention of ASCVD in FH. Sustained long-term optimal statin treatment from an early age can effectively prevent ASCVD over decades of life. Despite their widespread use, statins merit further investigation in FH.

Background Mathematical predictive models for ovarian tumors have an advantage over subjective assessment due to their relative simplicity, and therefore usefulness for less experienced sonographers. It is currently unclear which predictive model is best at predicting the nature of an ovarian tumor. Purpose To compare the diagnostic predictive accuracy of the International Ovarian Tumour Analysis Simple Rules (IOTA SR) with Risk of Malignancy Index (RMI), to differentiate between benign and malignant ovarian tumors. Material and Methods A total of 202 women diagnosed with ovarian tumor(s) were included. Preoperatively, patients were examined through transvaginal ultrasonography and CA-125 (U/mL) levels were measured. RMI and IOTA SR were determined, and where possible compared to definitive histopathological diagnosis. Results Of the 202 women with ovarian tumors, 168 women were included in this cohort study. Of these tumors, 118 (70.2%) were benign, 17 (10.1%) were borderline, and 33 (19.7%) were malignant. The sensitivity, specificity, and area under the curve for the RMI were 72.0%, 90.7%, and 0.896, respectively. For the IOTA SR, these were 90.0%, 68.6%, and 0.793, respectively. Conclusion This cohort study shows that the RMI is a relatively useful diagnostic model in characterizing ovarian tumors, compared to the IOTA SR. However, due to the relatively low sensitivity of the RMI and high rate of inconclusive results of the IOTA SR, both diagnostic tests do not seem discriminative enough. Therefore, alternative diagnostic models are necessary.

Lipoprotein(a) [Lp(a)] and diabetes are independently associated with premature coronary artery disease (pCAD). However, there is an inverse relationship between Lp(a) concentration and type 2 diabetes (T2D) risk. We examine whether Lp(a) distribution in patients with pCAD differs between those with or without T2D, and whether elevated Lp(a) is associated with pCAD in patients with T2D.Lp(a) concentration was measured in consecutive acute coronary syndrome (ACS) patients in two coronary care units (study one: ACS with or without diabetes, study two: ACS and diabetes). Elevated Lp(a) mass concentration was defined as ≥0.5 g/L and pCAD where CAD was diagnosed age60 years. The association between elevated Lp(a) and pCAD was assessed using logistic regression.Of 449 patients, 233 (51.9%) had pCAD and 278 (61.9%) had T2D. In patients with pCAD, those with T2D had a significantly lower median Lp(a) concentration (0.13 g/L versus 0.27 g/L, p=0.004). In patients with T2D, elevated Lp(a) was significantly associated with pCAD (OR 2.419, 95% CI 1.513-3.867, p0.001). After adjusting for gender, smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides, elevated Lp(a) remained significantly associated with pCAD (OR 2.895, 95% CI 1.427-5.876, p=0.003) in patients with T2D.In coronary care patients with pCAD, patients with T2D had lower Lp(a) concentrations than those without T2D. Despite this, elevated Lp(a) remained predictive of pCAD in patients with T2D. Measurement of Lp(a) should be considered in younger adults with T2D to identify who may benefit from earlier preventative therapies to reduce pCAD burden.

The rs3798220 and rs10455872 single nucleotide polymorphisms (SNPs) in LPA are associated with increased plasma concentrations of lipoprotein(a) [Lp(a)] and coronary artery disease (CAD).We investigated the association between rs3798220 and rs10455872 and prevalent CAD in 763 patients with suspected familial hypercholesterolaemia (FH). The rs3798220 and rs10455872 SNPs in LPA were detected using a SEQUENOM platform.Both LPA SNPs were significantly associated with CAD, but only rs3798220 after adjustment for other risk factors (odds ratio [OR] 2.05; 95% confidence interval [CI] 1.02-4.12; p = 0.045), and neither after adjustment for Lp(a) concentrations. Both SNPs were positively and independently associated with increased Lp(a) (rs3798220: OR 1.27; 95% CI 0.96-1.57; p 0.001. rs10455872: OR 1.41; 95% CI 1.24-1.58; p 0.001). Plasma concentrations of Lp(a) were independently associated with prevalent CAD (OR 1.28; 95% CI 1.08-1.52, p = 0.005) after adjustment for LPA SNPs and other cardiovascular risk factors. While both the rs3798220 and rs10455872 SNPs were associated with Lp(a) concentrations and prevalent CAD in patients with suspected FH, this was not independent of Lp(a) concentration.Quantification of Lp(a) is more likely to be useful than assessment of these Lp(a)-associated SNPs to augment CAD risk prediction.

Background Familial hypercholesterolaemia (FH) is under-diagnosed and under-treated worldwide, including Australia. National registries play a key role in identifying patients with FH, understanding gaps in care and advancing the science of FH to improve care for these patients. Methods The FH Australasia Network has established a national web-based registry to raise awareness of the condition, facilitate service planning and inform best practice and care services in Australia. We conducted a cross-sectional analysis of 1,528 FH adults enrolled in the registry from 28 lipid clinics. Results The mean age at enrolment was 53.4±15.1 years, 50.5% were male and 54.3% had undergone FH genetic testing, of which 61.8% had a pathogenic FH-causing gene variant. Only 14.0% of the cohort were family members identified through cascade testing. Coronary artery disease (CAD) was reported in 28.0% of patients (age of onset 49.0±10.5 years) and 64.9% had at least one modifiable cardiovascular risk factor. The mean untreated LDL-cholesterol was 7.4±2.5 mmol/L. 80.8% of patients were on lipid-lowering therapy with a mean treated LDL-cholesterol of 3.3±1.7 mmol/L. Among patients receiving lipid-lowering therapies, 25.6% achieved an LDL-cholesterol target of Conclusion Patients in the national FH registry are detected later in life, have a high burden of CAD and risk factors, and do not achieve guideline-recommended LDL-cholesterol targets. Genetic and cascade testing are under-utilised. These deficiencies in care need to be addressed as a public health priority.

Background The aim of this study was to assess the relationship between serum lipoprotein (a) (Lp[a]) concentration and the requirement for peripheral artery disease ( PAD ) operations or incidence of major adverse cardiovascular events. Methods and Results A total of 1472 people with PAD presenting with intermittent claudication (n=355), abdominal aortic aneurysm (n=989) or critical limb ischemia (n=128) were prospectively recruited from 4 outpatient clinics in Australia. Lp(a) was measured in serum samples collected at recruitment using an immunoassay. Participants were followed for a median (interquartile range) of 2.4 (0.1–6.1) years to record requirement for any PAD operation, defined to include any open or endovascular PAD intervention (lower limb peripheral revascularization, abdominal aortic aneurysm repair, other aneurysm repair, or carotid artery revascularization). Myocardial infarctions, strokes, and deaths were also recorded. The association of Lp(a) with events was assessed using Cox proportional hazard analysis adjusting for traditional risk factors. Participants with Lp(a) ≥30 mg/dL had a greater requirement for any PAD operation (hazard ratio, 1.20, 95% CI , 1.02–1.41) and lower limb peripheral revascularization alone ( hazard ratio 1.33, 95% CI , 1.06–1.66) but no increased risk of major adverse cardiovascular events or all‐cause mortality. Lp(a) ≥50 mg/dL and a 40 mg/dL increase in Lp(a) were also associated with an increased risk of lower limb peripheral revascularization alone but not with other outcomes. Conclusions In participants with PAD referred for hospital management those with high Lp(a) had greater requirement for lower limb peripheral revascularization but Lp(a) was not consistently associated with other clinical events.

Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) particle containing apolipoprotein(a) (apo(a)) covalently linked to apolipoprotein B-100 (apoB). Statin-treated patients with elevated Lp(a) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Recent trials show that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition decreases Lp(a) and cardiovascular events, particularly in high risk patients with elevated Lp(a). We investigated the kinetic mechanism whereby alirocumab, a PCSK9 inhibitor, lowers Lp(a) in statin-treated patients with high Lp(a) and ASCVD.The effects of 12-week alirocumab treatment (150 mg every 2 weeks) on apo(a) kinetics were studied in 21 patients with elevated Lp(a) concentration (0.5 g/L). Apo(a) fractional catabolic rate (FCR) and production rate (PR) were determined using intravenous D3-leucine administration, mass spectrometry and compartmental modelling. All patients were on long-term statin treatment.Alirocumab significantly decreased plasma concentrations of total cholesterol (-39%), LDL-cholesterol (-67%), apoB (-56%), apo(a) (-25%) and Lp(a) (-22%) (P0.001 for all). Alirocumab also significantly lowered plasma apo(a) pool size (-26%, P0.001) and increased the FCR of apo(a) (+28%, P0.001), but did not alter apo(a) PR, which remained significantly higher relative to a reference group of patients on statins with normal Lp(a) (P0.001).In statin-treated patients, alirocumab lowers elevated plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. This may be consequent on marked upregulation of hepatic receptors (principally for LDL) and/or reduced competition between Lp(a) and LDL particles for these receptors; the mechanism could contribute to the benefit of PCSK9 inhibition with alirocumab on cardiovascular outcomes.

Supplemental Digital Content is available in the text., Objective— Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) and statins are known to lower plasma LDL (low-density lipoprotein)-cholesterol concentrations. However, the comparative effects of these treatments on the postprandial metabolism of TRLs (triglyceride-rich lipoproteins) remain to be investigated. Approach and Results— We performed a 2-by-2 factorial trial of the effects of 8 weeks of subcutaneous evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on postprandial TRL metabolism in 80 healthy, normolipidemic men after ingestion of an oral fat load. We evaluated plasma total and incremental area under the curves for triglycerides, apo (apolipoprotein)B-48, and VLDL (very-LDL)-apoB-100. We also examined the kinetics of apoB-48 using intravenous D3-leucine administration, mass spectrometry, and multicompartmental modeling. Atorvastatin and evolocumab independently lowered postprandial VLDL-apoB-100 total area under the curves (P

Dysregulated lipoprotein metabolism is a major cause of atherosclerotic cardiovascular disease (ASCVD). Use of stable isotope tracers and compartmental modelling have provided deeper understanding of the mechanisms underlying lipid disorders in patients at high risk of ASCVD, including familial hypercholesterolemia (FH), elevated lipoprotein(a) [Lp(a)] and metabolic syndrome (MetS). In patients with FH, deficiency in low-density lipoprotein (LDL) receptor activity not only impairs the catabolism of LDL, but also induces hepatic overproduction and decreases catabolism of triglyceride-rich lipoproteins (TRLs). Patients with elevated Lp(a) are characterized by increased hepatic secretion of Lp(a) particles. Atherogenic dyslipidemia in MetS patients relates to a combination of overproduction of very-low density lipoprotein-apolipoprotein (apo) B-100, decreased catabolism of apoB-100-containing particles, and increased catabolism of high-density lipoprotein-apoA-I particles, as well as to impaired clearance of TRLs in the postprandial state. Kinetic studies show that weight loss, fish oils, statins and fibrates have complementary modes of action that correct atherogenic dyslipidemia. Defining the kinetic mechanisms of action of proprotein convertase subtilisin/kexin type 9 and angiopoietin-like 3 inhibitors on lipid and lipoprotein mechanism in dyslipidemic subjects will further our understanding of these therapies in decreasing the development of ASCVD. “Everything changes but change itself. Everything flows and nothing remains the same... You cannot step twice into the same river, for other waters and yet others go flowing ever on.” Heraclitus (c.535- c. 475 BCE)

Objectives To assess risk and predictive factors for depression and well-being, 3 and 12 months after elective hysterectomy. Secondary objectives were to assess the incidence of depression, level of well-being, and feelings of femininity. Study design A prospective multicenter cohort study was performed among 419 women, undergoing hysterectomy for benign indication. Data were collected in the week prior to surgery, and in the per- and postoperative period up to the fourth postoperative day and 3 and 12 months after surgery. Sociodemographic variables, baseline health status, psychosocial predictors, and surgery data were assessed. Outcome measures were Center for Epidemiological Studies-Depression scale (CES-D, range 0–60), the 12-item well-being questionnaire energy and positive well-being subscales (range 0–12), and feelings of femininity. Predictor analyses were performed using linear mixed model analyses. Results Levels of depression, energy, and positive well-being after hysterectomy were predicted by their corresponding baseline levels (estimate 0.62 p 0.001, 0.39 p 0.001, 0.37 p 0.001, respectively) and baseline pain (0.31 p = 0.003, −0.09 p = 0.026, −0.10 p = 0.008). Postoperative infection reported at 12 months affected CES-D and energy level. Several other gynaecological, psychosocial, or perioperative factors were also predictive for one of the outcomes. Prevalence of depression at baseline, 3 and 12 months was 24%, 19%, and 21%, respectively. In general, well-being scores were slightly higher 3 and 12 months after hysterectomy than at baseline. Feelings of femininity were not negatively affected in 92% of the patients. Conclusions Preoperative psychosocial status, perioperative pain, and postoperative infection were found as predictors of psychological outcome after hysterectomy. In the majority of patients we observed small but significant improvements with regard to postoperative depression and well-being, while feelings of femininity were unaffected.

Background: Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid-regulating pharmacotherapies. Methods: We conducted a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very-low-density lipoprotein (VLDL)–apolipoprotein B-100 (apoB), intermediate-density lipoprotein–apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling. Results: Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB ( P P .032, respectively), intermediate-density lipoprotein–apoB ( P =0.021 and P =.002, respectively), and LDL-apoB ( P P =0.043) and LDL-apoB ( P P Conclusions: In healthy, normolipidemic subjects, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in intermediate-density lipoprotein and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin. These kinetic findings provide a metabolic basis for understanding the potential benefits of PCSK9 monoclonal antibodies incremental to statins in on-going clinical end point trials. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02189837.

Increased arterial stiffness is closely linked with raised blood pressure that contributes substantially to enhanced risk of coronary heart disease in high risk individuals with familial hypercholesterolaemia (FH). Omega-3 fatty acid (ω3-FA) supplementation has been demonstrated to lower blood pressure in subjects with a high cardiovascular disease risk. Whether ω3-FA supplementation improves arterial stiffness in FH subjects, on background statin therapy, has yet to be investigated.We carried out an 8-week randomized, crossover intervention trial to test the effect of 4 g/d ω3-FA supplementation (46% eicosapentaenoic acid and 38% docosahexaenoic acid) on arterial elasticity in 20 adults with FH on optimal cholesterol-lowering therapy. Large and small artery elasticity were measured by pulse contour analysis of the radial artery. ω3-FA supplementation significantly (P 0.05 in all) increased large artery elasticity (+9%) and reduced systolic blood pressure (-6%) and diastolic blood pressure (-6%), plasma triglycerides (-20%), apoB concentration (-8%). In contrast, ω3-FAs had no significant effect on small artery elasticity. The change in large artery elasticity was not significantly associated with changes in systolic blood pressure or plasma triglyceride concentration.ω3-FA supplementation improves large arterial elasticity and arterial blood pressure independent of statin therapy in adults with FH.https://www.clinicaltrials.com/NCT01577056.

Familial hypercholesterolaemia (FH) is associated with increased risk of coronary artery disease (CAD); however, risk prediction and stratification remain a challenge. Genetic risk scores (GRS) may have utility in identifying FH patients at high CAD risk. The study included 811 patients attending the lipid disorders clinic at Royal Perth Hospital with mutation-positive (n = 251) and mutation-negative (n = 560) FH. Patients were genotyped for a GRS previously associated with CAD. Associations between the GRS, clinical characteristics, and CAD were assessed using regression analyses. The average age of patients was 49.6 years, and 44.1% were male. The GRS was associated with increased odds of a CAD event in mutation-positive [odds ratio (OR) = 3.3; 95% confidence interval (CI) = 1.3-8.2; P = .009] and mutation-negative FH patients (OR = 1.8; 95% CI = 1.0-3.3; P = .039) after adjusting for established predictors of CAD risk. The GRS was associated with greater subclinical atherosclerosis as assessed by coronary artery calcium score (P = .039). A high GRS was associated with CAD defined clinically and angiographically in FH patients. High GRS patients may benefit from more intensive management including lifestyle modification and aggressive lipid-lowering therapy. Further assessment of the utility of the GRS requires investigation in prospective cohorts, including its role in influencing the management of FH patients in the clinic.

Background Elevated lipoprotein(a) (Lp(a)), a low‐density lipoprotein‐like particle bound to the polymorphic apolipoprotein(a) (apo(a)), may be causal for cardiovascular disease. However, the metabolism of Lp(a) in humans is poorly understood. Methods and Results We investigated the kinetics of Lp(a)‐apo(a) and low‐density lipoprotein‐apoB‐100 in 63 normolipidemic men. The fractional catabolic rate ( FCR ) and production rate PR ) were studied. Plasma apo(a) concentration was significantly and inversely associated with apo(a) isoform size ( r =−0.536, P FCR ( r =−0.363, P PR ( r =0.877, P FCR s of apo(a) and low‐density lipoprotein‐apoB‐100. Subjects with smaller apo(a) isoform sizes (≤22 kringle IV repeats) had significantly higher apo(a) PR ( P FCR ( P PR ( r =0.930, P FCR ( r =−0.012, P >0.05) in subjects with smaller apo(a) isoform size. In contrast, both apo(a) PR and FCR were significantly associated with plasma apo(a) concentrations ( r =0.744 and −0.389, respectively, P PR and apo(a) isoform size were significant predictors of plasma apo(a) concentration independent of low‐density lipoprotein‐apoB‐100 FCR and background therapy with atorvastatin and evolocumab. Conclusions In normolipidemic men, the plasma Lp(a) concentration is predominantly determined by the rate of production of Lp(a) particles, irrespective of apo(a) isoform size and background therapy with a statin and a proprotein convertase subtilisin‐kexin type 9 inhibitor. Our findings underscore the importance of therapeutic targeting of the hepatic synthesis and secretion of Lp(a) particles. Lp(a) particle catabolism may only play a modest role in determining Lp(a) concentration in subjects with larger apo(a) isoform size. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02189837.

Background: Experimental data suggest that apolipoprotein (apo) C-II and C-III regulate triglyceride-rich lipoprotein (TRL) metabolism, but there are limited studies in humans. We investigated the metabolic associations of TRLs with apoC-II and apoC-III concentrations and kinetics in women. Material and methods: The kinetics of plasma apoC-II, apoC-III and very low-density lipoprotein (VLDL) apoB-100 and triglycerides were measured in the postabsorptive state using stable isotopic techniques and compartmental modeling in 60 women with wide-ranging body mass index (19.5-32.9kg/m2). Results: Plasma apoC-II and apoC-III concentrations were positively associated with the concentration of plasma triglycerides, VLDL1- and VLDL¬2- apoB-100 and triglyceride (all P Conclusions: In women, plasma apoC-II and apoC-III concentrations are regulated by their respective production rates and are significant, independent determinants of the kinetics and plasma concentrations of TRLs.

Aim To investigate the effects of extended-release (ER) niacin on apolipoprotein B-48 (apoB-48) kinetics in statin-treated patients with type 2 diabetes (T2DM). Methods A total of 12 men with T2DM were randomized to rosuvastatin or rosuvastatin plus ER niacin for 12 weeks and then crossed to the alternate therapy. Postprandial metabolic studies were performed at the end of each treatment period. D3-leucine tracer was administered as subjects consumed a high-fat liquid meal. ApoB-48 kinetics were determined using stable isotope tracer kinetics with fractional catabolic rates (FCRs) and secretion rates derived using a non-steady-state compartmental model. Area-under-the-curve (AUC) and incremental AUC (iAUC) for plasma triglyceride and apoB-48 were also calculated over the 10-h period after ingestion of the fat meal. Results In statin-treated patients with T2DM, apoB-48 concentration was lower with ER niacin (8.24 ± 1.98 vs 5.48 ± 1.14 mg/l, p = 0.03) compared with statin alone. Postprandial triglyceride and apoB-48 AUC were also significantly lower on ER niacin treatment (-15 and -26%, respectively; p < 0.05), without any change to triglyceride and apoB-48 iAUC. ApoB-48 secretion rate in the basal state (3.21 ± 0.34 vs 2.50 ± 0.31 mg/kg/day; p = 0.04) and number of apoB-48-containing particles secreted in response to the fat load (1.35 ± 0.19 vs 0.84 ± 0.12 mg/kg; p = 0.02) were lower on ER niacin. ApoB-48 FCR was not altered with ER niacin (8.78 ± 1.04 vs 9.17 ± 1.26 pools/day; p = 0.79). Conclusions ER niacin reduces apoB-48 concentration by lowering fasting and postprandial apoB-48 secretion rate. This effect may be beneficial for lowering atherogenic postprandial lipoproteins and may provide cardiovascular disease risk benefit in patients with T2DM.

Familial hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol and increased risk of premature coronary artery disease (CAD). Lipoprotein(a) [Lp(a)] increases CAD in FH, although the independence of this association relative to other CAD risk factors remains unclear. In this study, we examined the association between Lp(a) and other cardiovascular risk factors and prevalent CAD in patients with FH.A cross-sectional study of 390 patients with genetically confirmed FH were studied. Clinical and biochemical parameters of FH patients with and without CAD were compared.FH patients with CAD were older and more often male and had a higher prevalence of hypertension, smoking, diabetes, obesity, reduced eGFR, and elevated plasma Lp(a) and pre-treatment LDL-cholesterol and triglyceride (or low HDL-cholesterol) than FH patients without CAD (P0.05 for all). In univariate analyses, age, male gender, smoking, hypertension, reduced eGFR, diabetes, obesity, plasma creatinine, Lp(a) and pretreatment LDL-cholesterol, triglycerides and HDL-cholesterol levels were significant predictors of CAD in the FH patients (P0.05 for all). Elevated LDL-cholesterol, raised Lp(a), hypertension and reduced eGFR remained significant independent predictors of CAD (P0.05 for all) in FH after adjusting for other modifiable risk factors.Elevated Lp(a), hypertension and renal insufficiency are independent risk factors beyond elevated pretreatment LDL-cholesterol which predict CAD in patients with FH. In spite of the cross-sectional design of our study, we propose the need for identifying and managing these abnormalities to reduce excess CAD risk in FH patients. However, this proposal remains to be formally tested in a prospective study.

Objective— The effects of extended-release niacin (ERN; 1–2 g/d) on the metabolism of lipoprotein(a) (Lp(a)) and apolipoprotein (apo) B-100–containing lipoproteins were investigated in 11 statin-treated white men with type 2 diabetes mellitus in a randomized, crossover trial of 12-weeks duration. Approach and Results— The kinetics of Lp(a) and very low–density lipoprotein (VLDL), intermediate-density lipoprotein, and low-density lipoprotein (LDL) apoB-100 were determined following a standardized oral fat load (87% fat) using intravenous administration of D 3 -leucine, gas chromatography–mass spectrometry, and compartmental modeling. ERN significantly decreased fasting plasma total cholesterol, LDL cholesterol, and triglyceride concentrations. These effects were achieved without significant changes in body weight or insulin resistance. ERN significantly decreased plasma Lp(a) concentration (−26.5%) and the production rates of apo(a) (−41.5%) and Lp(a)-apoB-100 (−32.1%); the effect was greater in individuals with elevated Lp(a) concentration. ERN significantly decreased VLDL (−58.7%), intermediate-density lipoprotein (−33.6%), and LDL (−18.3%) apoB-100 concentrations and the corresponding production rates (VLDL, −49.8%; intermediate-density lipoprotein, −44.7%; LDL, −46.1%). The number of VLDL apoB-100 particles secreted increased in response to the oral fat load. Despite this, total VLDL apoB-100 production over the 10-hour postprandial period was significantly decreased with ERN (−21.9%). Conclusions— In statin-treated men with type 2 diabetes mellitus, ERN decreased plasma Lp(a) concentrations by decreasing the production of apo(a) and Lp(a)-apoB-100. ERN also decreased the concentrations of apoB-100–containing lipoproteins by decreasing VLDL production and the transport of these particles down the VLDL to LDL cascade. Our study provides further mechanistic insights into the lipid-regulating effects of ERN.

Objective Although there is no consensus on how to use an electrocardiogram (ECG) in patients with hyperkalemia, physicians often obtain it in the acute setting when diagnosing and treating hyperkalemia. The objective of this study is to evaluate if physicians are able to detect hyperkalemia based on the ECG. Methods The study was conducted at a large county hospital with a population of end stage renal disease (ESRD) patients who received hemodialysis (HD) solely on an emergent basis. Five hundred twenty eight ECGs from ESRD patients were evaluated. The prevalence of hyperkalemia was approximately 60% in this cohort, with at least half of them in the severe hyperkalemia range (K ≥ 6.5 mEq/L). Results The mean sensitivity and specificity of the emergency physicians detecting hyperkalemia were 0.19 (± 0.16) and 0.97(± 0.04) respectively. The mean positive predictive value of evaluators for detecting hyperkalemia was 0.92 (±0.13) and the mean negative predictive value was 0.46 (± 0.05). In severe hyperkalemia (K ≥ 6.5 mEq/L), the mean sensitivity improved to 0.29 (± 0.20), while specificity decreased to 0.95 (±0.07). Conclusion An ECG is not a sensitive method of detecting hyperkalemia and should not be relied upon to rule it out. However, the ECG has a high specificity for detecting hyperkalemia and could be used as a rule in test.

Background Lipoprotein apheresis effectively lowers lipoprotein(a) [Lp(a)] and low-density lipoprotein (LDL) by approximately 60%-70%. The rebound of LDL and Lp(a) particle concentrations following lipoprotein apheresis allows the determination of fractional catabolic rate (FCR) and hence production rate (PR) during non-steady state conditions. We aimed to investigate the kinetics of Lp(a) and LDL apolipoprotein B-100 (apoB) particles in patients with elevated Lp(a) and coronary artery disease undergoing regular apheresis. Patients and methods A cross-sectional study was carried out in 13 patients with elevated Lp(a) concentration (>500 mg/L) and coronary artery disease. Lp(a) and LDL-apoB metabolic parameters, including FCR and PR were derived by the fit of a compartment model to the Lp(a) and LDL-apoB concentration data following lipoprotein apheresis. Results The FCR of Lp(a) was significantly lower than that of LDL-apoB (0.39 [0.31, 0.49] vs 0.57 [0.46, 0.71] pools/day, P = 0.03) with no significant differences in the corresponding PR (14.80 [11.34, 19.32] vs 15.73 [11.93, 20.75] mg/kg/day, P = 0.80). No significant associations were observed between the FCR and PR of Lp(a) and LDL-apoB. Conclusions In patients with elevated Lp(a), the fractional catabolism of Lp(a) is slower than that of LDL-apoB particles, implying that different metabolic pathways are involved in the catabolism of these lipoproteins. These findings have implications for new therapies for lowering apolipoprotein(a) and apoB to prevent atherosclerotic cardiovascular disease.

Early lowering of blood pressure is advised for patients with severe hypertension associated with signs of impending or progressive organ damage, whereas aggressive treatment is not recommended in patients with asymptomatic severe hypertension. As treatment goals for asymptomatic hypertension and true hypertensive emergency drastically differ, it is essential to identify patients with evidence of impending or progressive organ damage. Biomarkers may assist providers in identifying high-risk patients who would benefit from early blood pressure reduction. In this review, we discuss both currently available and investigational biomarkers that may help identify patients who might benefit from more aggressive therapy. We focus on serum and urinary biomarkers associated with acute cardiovascular, renal, and cerebrovascular damage. There is a dearth of literature regarding the use of biomarkers to assess acute hypertension-related target organ damage. We are primarily forced to draw conclusions on the use of biomarkers from studies of related conditions such as acute heart failure. Further research is needed on the clinical significance of abnormal levels of novel biomarkers of renal, cardiac, and cerebral dysfunction in the setting of severe hypertension, particularly in those patients without overt clinical signs of organ failure.

Depression is the most common psychiatric illness in the general community, with 3% to 4% of depressives dying by suicide today. Studies have shown that depression has considerable morbidity and mortality. This article focuses on depressed patients and their management within the emergency department. Understanding the intricacies of the interview process and identifying which patients need immediate attention are important skills for the emergency physician.

Objectives— Patients with obesity and diabetes mellitus have increased risk of cardiovascular disease. A major cause is an atherogenic dyslipidemia related primarily to elevated plasma concentrations of triglyceride-rich lipoproteins. The aim of this study was to clarify determinants of plasma triglyceride concentration. We focused on factors that predict the kinetics of very-low density lipoprotein 1 (VLDL 1 ) triglycerides. Approach and Results— A multicenter study using dual stable isotopes (deuterated leucine and glycerol) and multicompartmental modeling was performed to elucidate the kinetics of triglycerides and apoB in VLDL 1 in 46 subjects with abdominal obesity and additional cardiometabolic risk factors. Results showed that plasma triglyceride concentrations were dependent on both the secretion rate ( r =0.44, P r =0.45, P r =0.49, P r =0.55, P 1 -triglycerides and VLDL 1 -apoB. Liver fat mass was independently and directly associated with secretion rates of VLDL 1 -triglycerides ( r =0.56, P 1 -apoB ( r =0.53, P 1 -triglycerides ( r =0.48, P 1 -apoB ( r =0.51, P Conclusions— Plasma triglyceride concentrations in abdominal obesity are determined by the kinetics of VLDL 1 subspecies, catabolism being mainly dependent on apoC-III concentration and secretion on liver fat content. Reduction in liver fat and targeting apoC-III may be an effective approach for correcting triglyceride metabolism atherogenic dyslipidemia in obesity.

Heart failure is a clinical syndrome that results from the impairment of ventricular filling or ejection of blood and affects millions of people worldwide. Diagnosis may not be straightforward and at times may be difficult in an undifferentiated patient. However, rapid evaluation and diagnosis is important for the optimal management of acute heart failure. We review the many aspects of diagnosing and treating acute heart failure in the emergency department.

Background Acute pancreatitis (AP) is a common presentation in the emergency department (ED). Severity of pancreatitis is an important consideration for ED clinicians making admission judgments. Validated scoring systems can be a helpful tool in this process. Objective The aim of this review is to give a general outline on the subject of AP and compare different criteria used to predict severity of disease for use in the ED. Discussion This review updates the classifications and scoring systems for AP and the relevant parameters of each. This article assesses past and current scoring systems for AP, including Ranson criteria, Glasgow criteria, Acute Physiology and Chronic Health Evaluation II (APACHE II), computed tomography imaging scoring systems, Bedside Index of Severity in Acute Pancreatitis (BISAP) score, Panc 3, Harmless Acute Pancreatitis Score (HAPS), and the Japanese Severity Score. This article also describes the potential use of single variable predictors. Finally, this article discusses risk factors for early readmission, an outcome pertinent to emergency physicians. These parameters may be used to risk-stratify patients presenting to the ED into mild, moderate, and severe pancreatitis for determination of appropriate disposition. Conclusion Rapid, reliable, and validated means of predicting patient outcome from rapid clinical assessment are of value to the emergency physician. Scoring systems such as BISAP, HAPS, and single-variable predictors may assist in decision-making due to their simplicity of use and applicability within the first 24 h.

The objective of the study was to examine post hoc associations between plasma sphingolipids and lipoprotein kinetics in men with the metabolic syndrome after rosuvastatin treatment.Plasma sphingolipid profiling, determined by tandem mass spectrometry, was performed in a randomized, double-blind, triple-crossover trial (n = 12) of 5-week treatment periods with placebo or rosuvastatin (10 or 40 mg/d) with 2-week washouts between treatments.Baseline plasma ceramides were associated with very low-density lipoprotein (VLDL) apolipoprotein (apo)-B-100 concentration (r = 0.58, P.05) and inversely with VLDL apoB-100 fractional catabolic rate (FCR; r = -0.67, P = .02). Posttreatment changes with rosuvastatin (40 mg/d) in plasma ceramides were inversely associated with VLDL apoB-100 FCR (r = -0.62, P = .03) independent of changes in plasma triglycerides, cholesterol, and low-density lipoprotein-cholesterol. By contrast, baseline and postrosuvastatin treatment plasma sphingomyelin levels were not associated with apoB-100 kinetics. Plasma ceramides and sphingomyelin were not associated with the kinetics or concentrations of high-density lipoprotein apoA-I, and low-density lipoprotein apoB. In the metabolic syndrome, the ability of rosuvastatin to increase VLDL apoB-100 FCR may reflect ceramide-specific mechanistic actions and/or sphingolipid exchange.

Postprandial lipaemia, due to elevated plasma apolipoprotein (apo) B-48 concentrations, contributes to increased cardiovascular (CV) risk in obesity. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and apoC-III may play a role in regulating triacylglycerol-rich lipoprotein (TRL)–apoB-48 metabolism. We investigated the associations between plasma PCSK9 and apoC-III concentrations and the kinetics of apoB-48 in obese subjects. Seventeen obese subjects were given an oral fat load. ApoB-48 tracer/tracee ratios were measured after an intravenous 2H3-leucine administration using GC–MS. Kinetic parameters, including secretion and fractional catabolic rates (FCRs), were derived using a multi-compartmental model. Plasma PCSK9 and apoC-III concentrations were significantly and positively (P0.05 in all) with basal secretion or the number of TRL–apoB-48 secreted over the postprandial period. In the stepwise regression analysis, plasma PCSK9 was the best predictor of the total and incremental AUCs for plasma apoB-48 and the FCR of TRL–apoB-48. The association between plasma PCSK9 and apoC-III and TRL–apoB-48 FCR remained significant (P

Aims Lipoprotein(a) [Lp(a)], a low-density lipoprotein (LDL) particle covalently bound to apolipoprotein(a) [apo(a)], is a potentially potent heritable risk factor for cardiovascular disease. We investigated the mechanism whereby evolocumab, a monoclonal antibody against proprotein convertase subtilisin-kexin type 9 (PCSK9), lowers Lp(a). Methods and results We studied the kinetics of Lp(a) particles in 63 healthy men, with plasma apo(a) concentration >5 nmol/L, participating in an 8-week factorial trial of the effects of evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on lipoprotein metabolism. Lipoprotein(a)-apo(a) kinetics were studied using intravenous D3-leucine administration, mass spectrometry, and compartmental modelling; Lp(a)-apoB kinetics were also determined in 16 subjects randomly selected from the treatment groups. Evolocumab, but not atorvastatin, significantly decreased the plasma pool size of Lp(a)-apo(a) (-36%, P

Dysregulated chylomicron metabolism may account for hypertriglyceridemia and increased risk of cardiovascular disease in obese subjects. Supplementation with ω-3 fatty acid ethyl ester (FAEE) decreases plasma triglyceride. However, its effect on postprandial chylomicron metabolism in obese subjects on a weight-loss diet has not yet been investigated.We aimed to examine the effect of ω-3 FAEE supplementation on apolipoprotein (apo) B-48 kinetics in obese subjects on a weight-loss diet.We carried out a 12-week, randomized trial of a hypocaloric diet plus 4 g/d ω-3 FAEE supplementation (46% eicosapentaenoic acid and 38% docosahexaenoic acid) (n = 13) compared with a hypocaloric diet alone (n = 12) on postprandial apoB-48 kinetics in obese subjects after ingestion of an oral load. The apoB-48 kinetics were determined using stable isotope tracer kinetics and multicompartmental modeling.We evaluated plasma total and incremental apoB-48 0- to 10-hour area under the curves (AUCs) as well as apoB-48 secretion and fractional catabolic rate.Weight loss with or without ω-3 FAEE supplementation significantly reduced body weight, total fat mass, homeostasis model assessment score, fasting triglyceride concentration, postprandial triglyceride AUC, and increased plasma high-density lipoprotein cholesterol concentration (P.05 in all). Compared with weight loss alone, weight loss plus ω-3 FAEE significantly (all P.05) decreased fasting triglyceride (-11%), apoB-48 (-36%) concentrations, postprandial triglyceride (-21%), and apoB-48 (-22%) total AUCs, as well as incremental postprandial triglyceride AUCs (-32%). The ω-3 FAEE also significantly decreased apoB-48 secretion in the basal state, without a significant effect during the postprandial period (3-6 hours). The fractional catabolic rate of apoB-48 increased with both interventions with no significant independent effect of ω-3 FAEE supplementation.Addition of ω-3 FAEE supplementation to a moderate weight-loss diet in obese subjects can significantly improve chylomicron metabolism by independently decreasing the secretion of apoB-48.