E.S.G. Stroes

Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society

Aims The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). Methods and results Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD. Conclusion Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.

Endothelial glycocalyx as potential diagnostic and therapeutic target in cardiovascular disease.

Purpose of review The endothelial glycocalyx has emerged as a potential orchestrator of vascular homeostasis. Under physiological conditions, the glycocalyx is an important contributor to the regulation of vascular permeability for macromolecules as well for the adhesion of circulating cells. In line, the potential role of the glycocalyx in maintaining the antiatherogenic properties of the vessel wall may have important clinical implications. In the present review, we provide an overview of recent developments and a glance at the future of establishing endothelial glycocalyx as a crucial player in cardiovascular protection. Recent findings Novel methods to estimate glycocalyx dimensions in vivo (using Orthogonal Polarization Spectral imaging or Sideview Darkfield imaging) as well as progressive insight into the enzymes involved in glycocalyx synthesis will be crucial in the assessment of this structure as a potential surrogate marker or therapeutic target for cardiovascular risk. The validation of these ‘imaging’ techniques and the integration with glycocalyx degradation products in plasma will allow us to test the value of the endothelial glycocalyx in estimating cardiovascular risk. Summary The endothelial glycocalyx, protecting the vascular wall against atherogenic influents, could be used for cardiovascular risk stratification. For this purpose, new methods to estimate glycocalyx dimension are promising.

Atherogenesis in rheumatology

Atherosclerosis is a chronic inflammatory disorder characterized by immune cell activation, inflammation driven plaque formation and subsequent destabilization. In other disorders of an inflammatory nature, the chronic inflammatory state per se has been linked to acceleration of the atherosclerotic process which is underlined by an increased incidence of cardiovascular disease (CVD) in disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and antiphopholipid (Hughes) syndrome (APS). In addition to systemic inflammation, additional mechanisms have been put forward that are more specific for the pathophysiology of the individual chronic inflammatory disorders.

High daily insulin exposure in patients with type 2 diabetes is associated with increased risk of cardiovascular events.

AIMSnIntensive glucose control, often involving insulin treatment, failed to improve cardiovascular outcomes in several clinical trials. Observational studies reported an association between insulin use and cardiovascular disease (CVD) risk. It has therefore been suggested that insulin adversely affects CVD risk. To investigate the feasibility of this hypothesis, we studied the association between insulin dose and CVD risk in type 2 diabetes.nnnMETHODSnA case-control study was conducted of new users of oral antidiabetics who were prescribed insulin, using the Dutch Pharmo database. Cases were hospitalized for a cardiovascular event (CVE) and matched 1:2 to patients who were not hospitalized for a CVE, by sex, age, duration of diabetes and type of oral antidiabetic. Patients were divided into tertiles according to mean daily insulin dose. Conditional logistic regression analyses were used to explore the association between insulin exposure and CVE risk.nnnRESULTSnWe included 836 patients (517 (62%) male, mean age 66 years). After adjusting for available potential confounders, including HbA1c and triglycerides, insulin exposure was positively related to CVE risk (odds ratios for high (≥53.0 U/day) and intermediate (24.3-52.9 U/day) vs. low exposure (≤24.2 U/day): 3.00 [95% confidence interval (CI) 1.70 to 5.28] and 2.03 [95% CI 1.17 to 3.52].nnnCONCLUSIONnOur findings are in line with the suggestion that high-dose insulin therapy adversely affects CVD risk, but need to be interpreted with caution due to the observational nature of the study. The role of particularly high-dose insulin in the progression of CVD warrants further investigation.

Issues Affecting Quality of Life and Disease Burden in Lipoprotein Lipase Deficiency (Lpld) – First Step Towards a Pro Measure in Lpld

PRM141 Issues AffectIng QuAlIty of lIfe And dIseAse BuRden In lIPoPRoteIn lIPAse defIcIency (lPld) – fIRst steP towARds A PRo MeAsuRe In lPld Johnson C1, Stroes ES2, Soran H3, Wierzbicki A4, Moulin P5, Bruckert E6, Steinhagen-Thiessen E7, Gaudet D8, Iotti G9, Rastelletti I9, Ossenkoppele B10, Dippel M10, Leclerc M11, Averna M12 1University Hospital Southampton, Southampton, UK, 2Department of Vascular Medicine, Amsterdam Medical Center, Amsterdam, The Netherlands, 3Cardiovascular Trials Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK, 4Guy ́s & St. Thomas ́ Hospitals, London, UK, 5Department of Endocrinology, CarMeN – Research Laboratory in Cardiovascular, Metabolism, Diabetes and Nutrition, Lyon, France, 6Hôpital Pitié Salpêtrière Charles Foix, Paris, France, 7Interdisciplinary Metabolism Center, Charité, University of Berlin, Berlin, Germany, 8Community Genomic Medicine Centre and Lipid Clinic, University of Montréal, Chicoutimi, QC, Canada, 9Chiesi Farmaceutici, Parma, Italy, 10uniQure B.V., Amsterdam, The Netherlands, 11Kantar Health, Montrouge, France, 12Centro regionale delle malattie rare del metabolismo dell’ adulto (CERMMET), Policlinico “P.Giaccone”, University of Palermo, Palermo, Italy objeCtives: LPLD is an ultra-orphan genetic lipid disorder (prevalence 1-2/million). It is associated with severe hypertriglyceridemia and an increased risk of acute pancreatitis. Other manifestations include eruptive xanthoma, fatigue, difficulty with concentrating and cardiopulmonary symptoms. Associated symptoms, complications and the fat-restricted diet affect Quality of Life (QOL). Currently no disease-specific measure exists to assess QOL and the burden of LPLD. As part of post approval commitments of alipogene tiparvovec, regulatory bodies requested the development of a reliable measure of QOL in LPLD. This study evaluates existing EORTC questionnaires QLQ-C30 and QLQ-PAN26, and a new questionnaire of disease burden devised by clinicians with experience in treating LPLD. Methods: To date, eight genetically confirmed LPLD-patients from four countries assessed the relevance and importance of each item of the three questionnaires. Patients’ ratings were discussed during an in-depth, face-to-face interview and the disease burden questionnaire was comprehensively discussed, analyzed and then modified where necessary. Results: Quantitative assessment showed that 25 (45%) of the QLQ-C30 and QLQ-PAN26 questions were relevant to the majority of patients. The most relevant items were pain (6), fatigue and sleeping problems (4), digestive and dietary factors (4), work, daily and social activity restrictions (4) and impact on emotional functioning (3). Qualitative and quantitative analysis of the new questionnaire highlighted the unpredictability of pancreatitis attacks and the impact of the strict low fat diet on social and emotional factors. Less common clinical manifestations of LPLD (xanthoma, dyspnea) were very important to those affected. The new questionnaire has been modified and items on alcohol use and painkillers added for ongoing evaluation. ConClusions: Five QOL domains relevant to LPLD have been identified using existing questionnaires. A new disease-specific questionnaire identifies significant impacts on patients’ lives. These instruments may help clinicians to effectively use pharmacological and genetic therapy to manage LPLD patients.