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Aims: To assess whether implementation of the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) dyslipidaemia guidelines observed between 2020 and 2021 improved between 2021 and 2022 in the SANTORINI study., Methods and Results: Patients with high or very high cardiovascular (CV) risk were recruited across 14 European countries from March 2020 to February 2021, with 1-year prospective follow-up until May 2022. Lipid-lowering therapy (LLT) and 2019 ESC/EAS risk-based low-density lipoprotein (LDL) cholesterol (LDL-C) goal attainment (defined as <1.4 mmol/L for patients at very high CV risk and <1.8 mmol/L for patients at high CV risk) at 1-year follow-up were compared with baseline. Of 9559 patients enrolled, 9136 (2626 high risk and 6504 very high risk) had any available follow-up data, and 7210 (2033 high risk and 5173 very high risk) had baseline and follow-up LDL-C data. Lipid-lowering therapy was escalated in one-third of patients and unchanged in two-thirds. Monotherapy and combination therapy usage rose from 53.6 and 25.6% to 57.1 and 37.9%, respectively. Mean LDL-C levels decreased from 2.4 to 2.0 mmol/L. Goal attainment improved from 21.2 to 30.9%, largely driven by LLT use among those not on LLT at baseline. Goal attainment was greater with combination therapy compared with monotherapy at follow-up (39.4 vs. 25.5%)., Conclusion: Lipid-lowering therapy use and achievement of risk-based lipid goals increased over 1-year follow-up particularly when combination LLT was used. Nonetheless, most patients remained above goal; hence, strategies are needed to improve the implementation of combination LLT., Competing Interests: Conflict of interest: K.K.R. has received honoraria for consulting, lectures from Abbott Laboratories, Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Cargene, CRISPR, Daiichi Sankyo, Eli Lilly Company, Emendobio, Esperion, Kowa, New Amsterdam Pharma, Novartis Corporation, Nodthera, GSK, Novo Nordisk, Pfizer, Regeneron, Sanofi, SCRIBE, Silence Therapeutics, and VAXXINITY. In addition, he has received research grant support to his institution from Amgen, Daiichi Sankyo, Sanofi, Regeneron, and Ultragenyx, plus stock options from New Amsterdam Pharma, Scribe, and Pemi 31. A.L.C. received research grant support from Amryt Pharma, Menarini, Ultragenyx, and Viatris, and lecturing fees from Amarin, Amgen, Amryt Pharma, AstraZeneca, Daiichi Sankyo, Esperion, Ionis Pharmaceutical, Medscaper, Menarini, Merck, Novartis, Peervoice, Pfizer, Recordati, Regeneron, Sandoz, Sanofi, The Corpus, Ultragenyx, and Viatris. M.A. received research grant support and lecturing fees from Alfasigma, Amgen, Amryt, Daiichi Sankyo, Ionis Pharmaceuticals/Akcea Therapeutics, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi, Sobi, Viatris, and Ultragenyx. A.B., R.C., M.L., and J.S. are employees of Daiichi Sankyo. H.T. received grant support and lecturing fees from Daiichi Sankyo and participated in an advisory board run by Daiichi Sankyo. T.S. received consulting fees from Amgen, Novartis, Orion Pharma, and Valio, and lecturing fees from Amarin, Pfizer, and GSK. He is a patient on statin and ezetimibe therapy. U.L. received grant support from Daiichi Sankyo, Novartis, and Amgen and lecturing fees from Daiichi Sankyo, Novartis, Amgen, Sanofi, Boehringer, MSD, Pfizer, Lilly, and AstraZeneca. He has also been a member of advisory boards for Daiichi Sankyo, Novartis, Amgen, Sanofi, Boehringer, and MSD, in addition to donning leadership/fiduciary roles with EAS, ESC, DGK, and DACH., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To investigate the prevalence of familial hypercholesterolaemia (FH) and compare the performance of clinical criteria and genetic testing in patients undergoing coronary angiography., Methods and Results: The prevalence of FH was determined with the Dutch Lipid Clinical Network (DLCN), US 'Make Early Diagnosis to Prevent Early Death' (US-MEDPED), Simon Broome (SB) criteria, the 'familial hypercholesterolaemia case ascertainment tool' (FAMCAT), and a clinical algorithm. Genetic screening was conducted with a custom array from Affymetrix (CARRENAL array) harbouring 944 FH mutations.The study cohort consisted of 3267 patients [78.6% with coronary artery disease (CAD)]. FH was diagnosed in 2.8%, 2.2%, 3.9%, and 7.9% using the DLCN, US-MEDPED, SB criteria, and the FAMCAT. The clinical algorithm identified the same patients as the SB criteria. Pathogenic FH mutations were found in 1.2% (1.2% in patients with CAD, 1.0% in patients without CAD). FH was more frequently diagnosed in younger patients. With genetic testing as reference, the clinical criteria achieved areas under the ROC curve [area under the curves (AUCs)] in the range of 0.56-0.68. Using only low-density lipoprotein cholesterol (LDL-C) corrected for statin intake, an AUC of 0.68 was achieved., Conclusion: FH is up to four-fold more prevalent in patients undergoing coronary angiography than in contemporary cohorts representing the general population. Different clinical criteria yield substantially different diagnosis rates, overestimating the prevalence of FH compared with genetic testing. LDL-C testing alone may be sufficient to raise the suspicion of FH, which then needs to be corroborated by genetic testing., Lay Summary: In this study, we investigated the frequency of familial hypercholesterolaemia-a common genetic condition leading to markedly elevated low-density lipoprotein (LDL) cholesterol and increased risk of atherosclerosis-in 3267 patients undergoing coronary angiography according to commonly used diagnostic scoring systems and genetic testing., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: We performed quality control of lipid-lowering therapy (LLT) in patients with acute coronary syndrome (ACS), with a view to proposing corrective actions., Methods and Results: Using a Define Measure Analysis Improve Control (DMAIC) approach applied to data from the ACS EuroPath IV survey, we measured attainment of two quality indicators (QIs) related to lipid-lowering treatment: (i) prescription of high-intensity statins (or equipotent treatment) before discharge, and (ii) proportion with LDL-cholesterol <55 mg/dL (1.4 mmol/L) during follow-up. A total of 530 European cardiologists responded and provided data for up to 5 patients from their centre, for acute and follow-up phases. Corrective measures are proposed to increase the rate of attainment of both QIs. Attainment of the first QI was measured in 929 acute-phase patients, 99% had LLT prescribed at discharge and 75% of patients fulfilled the first QI. Attainment of the second QI was assessed in 1721 patients with follow-up. The second QI was reached in 31% of patients. The DMAIC approach yielded 10 potential changes in prescription, 3 for the first and 7 for the second QI. The overall strategy is 'Fire to Target', i.e. early intensification of the LLT using statins, ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type-9 inhibitors, and is presented as an algorithm for routine application., Conclusion: Quality control for LLT, based on the ACS EuroPath IV survey, detected 10 potential changes in prescription that could enhance attainment of 2 QIs. Whether the Fire to Target strategy will be adopted and effective needs to be assessed in further steps of the EuroPath Quality programme., Competing Interests: Conflict of interest: F.S. has received research grants from and/or was speaker (with or without lecture fees) on a.o. (CME accredited) meetings sponsored by Amgen, Bayer, Novartis, Novo Nordisk, Sanofi Aventis, Recordati, Servier, Mylan, and AstraZeneca. A.S. has received honoraria, lecture fees, or research grants from Amgen, Daiichi Sankyo, Ferrer, Getinge, Novartis, Pfizer, Sanofi, and Zoll. A.L.C. has received honoraria, lecture fees, or research grants from: AstraZeneca, Aegerion, Amryt, Amarin, Daiichi Sankyo, Esperion, Ionis Pharmaceuticals, Kowa, Medscape, Mylan, Merck, Menarini, Novartis, Peer Voice, Pfizer, Recordati, Regeneron, Sandoz, Sanofi, and The Corpus. The work of A.L.C. relevant to this publication is supported by Ministero della salute Ricerca corrente. R.D.C. has received honoraria, lecture fees, or research grants from Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi Sankyo, Roche, Novartis, AstraZeneca, Milestone, Menarini, Guidotti, Lilly, Merck, and Portola. U.L. has received honoraria, lecture fees, or research grants from Amgen, Daiichi Sankyo, Novartis, and Sanofi. A.Z. has received honoraria, consulting, or lecture fees from Sanofi, Amgen, and Novartis. J.W.J. and his department has received research grants from and/or was speaker (with or without lecture fees) on a.o. (CME accredited) meetings sponsored by Amarin, Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, The Netherlands Heart Foundation, CardioVascular Research The Netherlands (CVON), The Netherlands Heart Institute, and the European Community Framework KP7 Programme., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To evaluate the rate of new-onset atrial fibrillation (AF) and the potential improved outcome in heart failure (HF) patients using non-invasive remote patient management (RPM) compared with usual care (UC)., Methods and Results: This analysis assessed a subgroup of 1538 patients of the TIM-HF2 trial with chronic HF, New York Heart Association Class II or III, admission to hospital for HF within 12 months before randomization, and a left ventricular ejection fraction (LVEF) of 45% or lower. Patients with AF in the baseline electrocardiogram (ECG), with an implanted cardiac device, a history of ablation therapy, and recent anticoagulation were excluded, leaving 347 patients for final analysis (RPM = 175; UC = 172). The percentage of days lost due to unplanned cardiovascular hospitalization or death of any cause (primary endpoint of TIM-HF2), the rate of newly detected AF, and the hospitalization rate due to AF were analysed. For patients with new AF, there was a significant reduction for the primary endpoint in the RPM group [5.5%, 95% confidence interval (CI) 0-11.6 vs. UC: 14.6%, 95% CI 8.0-21.2; P  < 0.001]. Within the first 3 months, the detection rate of new AF was significantly higher in the RPM group (5.1%) compared with UC (1.2%), P  = 0.035. After 1 year, 23 patients (13.1%) assigned to RPM and 12 patients (7.0%) assigned to UC had newly detected AF, P  = 0.056. Unplanned hospitalizations related to AF were significantly lower in the RPM group (2 out of 23 patients vs. UC: 10 out of 12 patients; P  < 0.001)., Conclusion: In this subgroup of HF patients in the TIM-HF2 trial, non-invasive daily ECG transmission leads to a four times higher detection rate of new AF compared with UC. This was associated with a significant reduction of days lost due to unplanned cardiovascular hospitalizations, especially hospitalizations related to AF., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown., Methods and Results: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality., Conclusion: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: The aim of this study was to evaluate the low-density lipoprotein cholesterol lowering efficacy and safety of a bempedoic acid 180 mg and ezetimibe 10 mg fixed-dose combination in patients with hypercholesterolemia and a high risk of cardiovascular disease receiving maximally tolerated statin therapy., Methods: This phase 3, double-blind clinical trial enrolled adult patients at high risk of cardiovascular disease due to atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors. Patients were randomly assigned (2:2:2:1) to treatment with the fixed-dose combination, bempedoic acid 180 mg, ezetimibe 10 mg or placebo added to stable background statin therapy for 12 weeks. The primary efficacy endpoint was the percentage change from baseline to week 12 in low-density lipoprotein cholesterol., Results: Among the 301 patients included in the primary analysis, the mean baseline low-density lipoprotein cholesterol level was 3.87 mmol/L (149.8 mg/dL). At week 12, the fixed-dose combination lowered low-density lipoprotein cholesterol (-36.2%) significantly more than placebo (1.8% (placebo-corrected difference -38.0%); P  < 0.001), ezetimibe alone (-23.2%; P  < 0.001) or bempedoic acid alone (-17.2%; P  < 0.001). The fixed-dose combination lowered low-density lipoprotein cholesterol levels similarly across subgroups, including patients receiving high-intensity, other-intensity or no statin therapy. Improvements with the fixed-dose combination were also observed in secondary efficacy endpoints, including high-sensitivity C-reactive protein. In this trial, fixed-dose combination treatment had a generally similar safety profile compared with bempedoic acid, ezetimibe or placebo., Conclusion: The bempedoic acid and ezetimibe fixed-dose combination significantly lowered low-density lipoprotein cholesterol versus placebo or other oral monotherapies and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk., Trial Registration: ClinicalTrials.gov identifier: NCT03337308.

Hypertriglyceridaemia is a common clinical problem. Epidemiologic and genetic studies have established that triglyceride-rich lipoproteins (TRL) and their remnants as important contributors to ASCVD while severe hypertriglyceridaemia raises risk of pancreatitis. While low-density lipoprotein is the primary treatment target for lipid lowering therapy, secondary targets that reflect the contribution of TRL such as apoB and non-HDL-C are recommended in the current guidelines. Reduction of severely elevated triglycerides is important to avert or reduce the risk of pancreatitis. Here we discuss interventions for hypertriglyceridaemia, including diet and lifestyle, established treatments such as fibrates and omega-3 fatty acid preparations and emerging therapies, including various biological agents., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: It is unknown whether different training modalities exert differential cellular effects. Telomeres and telomere-associated proteins play a major role in cellular aging with implications for global health. This prospective training study examines the effects of endurance training, interval training (IT), and resistance training (RT) on telomerase activity and telomere length (TL)., Methods and Results: One hundred and twenty-four healthy previously inactive individuals completed the 6 months study. Participants were randomized to three different interventions or the control condition (no change in lifestyle): aerobic endurance training (AET, continuous running), high-intensive IT (4 × 4 method), or RT (circle training on 8 devices), each intervention consisting of three 45 min training sessions per week. Maximum oxygen uptake (VO2max) was increased by all three training modalities. Telomerase activity in blood mononuclear cells was up-regulated by two- to three-fold in both endurance exercise groups (AET, IT), but not with RT. In parallel, lymphocyte, granulocyte, and leucocyte TL increased in the endurance-trained groups but not in the RT group. Magnet-activated cell sorting with telomerase repeat-ampliflication protocol (MACS-TRAP) assays revealed that a single bout of endurance training-but not RT-acutely increased telomerase activity in CD14+ and in CD34+ leucocytes., Conclusion: This randomized controlled trial shows that endurance training, IT, and RT protocols induce specific cellular pathways in circulating leucocytes. Endurance training and IT, but not RT, increased telomerase activity and TL which are important for cellular senescence, regenerative capacity, and thus, healthy aging.

Aims: To objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke or cataract., Methods and Results: A literature search covering 2000-2017 was performed. The Panel critically appraised the data and agreed by consensus on the categorization of reported adverse effects. Randomized controlled trials (RCTs) and genetic studies show that statin therapy is associated with a modest increase in the risk of new-onset diabetes mellitus (about one per thousand patient-years), generally defined by laboratory findings (glycated haemoglobin ≥6.5); this risk is significantly higher in the metabolic syndrome or prediabetes. Statin treatment does not adversely affect cognitive function, even at very low levels of low-density lipoprotein cholesterol and is not associated with clinically significant deterioration of renal function, or development of cataract. Transient increases in liver enzymes occur in 0.5-2% of patients taking statins but are not clinically relevant; idiosyncratic liver injury due to statins is very rare and causality difficult to prove. The evidence base does not support an increased risk of haemorrhagic stroke in individuals without cerebrovascular disease; a small increase in risk was suggested by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels study in subjects with prior stroke but has not been confirmed in the substantive evidence base of RCTs, cohort studies and case-control studies., Conclusion: Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above; statin-associated muscle symptoms were discussed in a previous Consensus Statement. Importantly, the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects.

Background Acute vascular effects of high intensity physical activity are incompletely characterized. Circulating microparticles are cellular markers for vascular activation and damage. Methods Microparticles were analysed in 99 marathon runners (49 ± 6 years, 22% female) of the prospective Berlin Beat of Running study. Blood samples were taken within three days before, immediately after and within two days after the marathon run. Endothelial-derived microparticles were labelled with CD144, CD31 and CD62E, platelet-derived microparticles with CD62P and CD42b, leukocyte-derived microparticles with CD45 and monocyte-derived microparticles with CD14. Results Marathon running induced leukocytosis (5.9 ± 0.1 to 14.8 ± 0.3 10 9 /l, p < 0.0001) and increased platelet counts (239 ± 4.6 to 281 ± 5.9 10 9 /l, p < 0.0001) immediately after the marathon. Blood monocytes increased and lymphocytes decreased after the run ( p < 0.0001). Endothelial-derived microparticles were acutely increased ( p = 0.008) due to a 23% increase of apoptotic endothelial-derived microparticles ( p = 0.007) and returned to baseline within two days after the marathon. Thrombocyte-derived microparticles acutely increased by 38% accompanied by an increase in activated and apoptotic thrombocyte-derived microparticles ( p ≤ 0.0001) each. Both monocyte- and leukocyte-derived microparticles were decreased immediately after marathon run ( p < 0.0001) and remained below baseline until day 2. Troponin T increased from 12 to 32 ng/l ( p < 0.0001) immediately after the run and returned to baseline after two days. Conclusion Circulating apoptotic endothelial- and thrombocyte-derived microparticles increased after marathon running consistent with an acute pro-thrombotic and pro-inflammatory state. Exercise-induced vascular damage reflected by microparticles could indicate potential mechanisms of post-exertional cardiovascular complications. Further studies are warranted to investigate microparticles as markers to identify individuals prone to such complications.

Aims: To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD)., Methods and Results: We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects., Conclusion: Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD., (© The Author 2017. Published on behalf of the European Society of Cardiology)

Aims: The vascular effects of high-density lipoproteins (HDL) differ under certain clinical conditions. The composition of HDL is modified in patients with chronic kidney disease (CKD). As a consequence, uremic HDL induces endothelial dysfunction. We have previously shown that accumulation of symmetric dimethylarginine (SDMA) in HDL causes these adverse effects of HDL in CKD. The aim of the study is to determine the impact of the accumulation of SDMA on the association between HDL and mortality., Methods and Results: Mortality, renal function, serum SDMA and HDL-cholesterol (HDL-C) were assessed in the LURIC study including 3310 subjects undergoing coronary angiography. All-cause mortality was 30.0% during median follow-up of 9.9 years. Serum SDMA levels significantly predicted all-cause and cardiovascular mortality, and were significantly correlated with SDMA accumulation in HDL. Notably, higher serum SDMA was independently associated with lower cholesterol efflux (P = 0.004) as a measure of HDL functionality. In subjects with low SDMA levels, higher HDL-C was associated with significantly lower mortality. In contrast, in subjects with high SDMA, HDL-C was associated with higher mortality. These findings were confirmed in 1424 participants of the MONICA/KORA S3 cohort. Of note, we derived an algorithm allowing for calculation of biologically effective HDL-C' based on measured HDL-C and SDMA. We corroborated these clinical findings with invitro evidence showing that SDMA accumulation abolishes the anti-inflammatory and regenerative properties of HDL., Conclusion: The data identify SDMA as a marker of HDL dysfunction. These findings highlight on the pivotal role of SDMA accumulation in HDL as a mediator of pre-mature cardiovascular disease in patients with CKD., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Aims: High-density lipoproteins (HDLs) are considered as anti-atherogenic. Recent experimental findings suggest that their biological properties can be modified in certain clinical conditions by accumulation of serum amyloid A (SAA). The effect of SAA on the association between HDL-cholesterol (HDL-C) and cardiovascular outcome remains unknown., Methods and Results: We examined the association of SAA and HDL-C with mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, which included 3310 patients undergoing coronary angiography. To validate our findings, we analysed 1255 participants of the German Diabetes and Dialysis study (4D) and 4027 participants of the Cooperative Health Research in the Region of Augsburg (KORA) S4 study. In LURIC, SAA concentrations predicted all-cause and cardiovascular mortality. In patients with low SAA, higher HDL-C was associated with lower all-cause and cardiovascular mortality. In contrast, in patients with high SAA, higher HDL-C was associated with increased all-cause and cardiovascular mortality, indicating that SAA indeed modifies the beneficial properties of HDL. We complemented these clinical observations by in vitro experiments, in which SAA impaired vascular functions of HDL. We further derived a formula for the simple calculation of the amount of biologically 'effective' HDL-C based on measured HDL-C and SAA from the LURIC study. In 4D and KORA S4 studies, we found that measured HDL-C was not associated with clinical outcomes, whereas calculated 'effective' HDL-C significantly predicted better outcome., Conclusion: The acute-phase protein SAA modifies the biological effects of HDL-C in several clinical conditions. The concomitant measurement of SAA is a simple, useful, and clinically applicable surrogate for the vascular functionality of HDL., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Objective: In patients with refractory cardiogenic shock (CS) mechanical assistance by venous-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy may be considered to reach haemodynamic stabilization. In this first-in-man study, we analysed the applicability of the new i-cor VA-ECMO assist device equipped with a diagonal pump system., Methods and Results: In total, 15 patients with refractory CS were treated with the i-cor assist device in three tertiary care centres. In 71%, CS was due to acute myocardial infarction (AMI). At baseline, patients were hypotensive (systolic/diastolic blood pressure 97 ± 4/62 ± 4 mm Hg) despite high doses of catecholamines. Under ECMO therapy, a significant reduction in vasopressor therapy and serum lactate levels was observed (norepinephrine: 0.69 ± 0.1 µg/kg/min at baseline vs 0.21 ± 0.08 µg/kg/min on the last day of treatment, p<0.0001; serum lactate: 6.7 ± 1.4 mmol/l at baseline versus 1.3 ± 0.1 mmol/l on the last day, p<0.001). Inspiratory oxygen concentration was significantly reduced during the course of VA-ECMO support (80.4 ± 7.0% at baseline vs 42.7 ± 2.4% on final day; p<0.001). At baseline, three patients (20%) were on continuous haemodialysis treatment. Of the 12 patients without haemodialysis at baseline, only one patient required haemodialysis during the course of ECMO treatment. Glomerular filtration rate (GFR) significantly increased with treatment (41.2 ± 7.4 at baseline vs 69.0 ± 10.8 on last day; p=0.006). Bleeding at the insertion site was recorded in two patients (13.3%). Overall, 11 patients (73.3%) needed blood transfusion. Three patients (20%) developed signs of limb ischaemia that were fully reversible. Haemolysis was recorded in five patients (33%). None of the complications required the interruption of ECMO therapy. Overall mortality was 33.3% (five patients); two patients died during, and three patients after, ECMO therapy., Conclusion: This first-in-man analysis suggests that the i-cor ECMO device is successfully applicable in humans. The data set the stage for further evaluation of this novel system and provide the necessary basis to design randomised evaluations., (© The European Society of Cardiology 2014.)

Aims: Pathological cardiac hypertrophy is a major predictor for the development of cardiac diseases. It is associated with chronic neurohumoral stimulation and with altered cardiac Ca(2+) signalling in cardiomyocytes. TRPC proteins form agonist-induced cation channels, but their functional role for Ca(2+) homeostasis in cardiomyocytes during fast cytosolic Ca(2+) cycling and neurohumoral stimulation leading to hypertrophy is unknown., Methods and Results: In a systematic analysis of multiple knockout mice using fluorescence imaging of electrically paced adult ventricular cardiomyocytes and Mn(2+)-quench microfluorimetry, we identified a background Ca(2+) entry (BGCE) pathway that critically depends on TRPC1/C4 proteins but not others such as TRPC3/C6. Reduction of BGCE in TRPC1/C4-deficient cardiomyocytes lowers diastolic and systolic Ca(2+) concentrations both, under basal conditions and under neurohumoral stimulation without affecting cardiac contractility measured in isolated hearts and in vivo. Neurohumoral-induced cardiac hypertrophy as well as the expression of foetal genes (ANP, BNP) and genes regulated by Ca(2+)-dependent signalling (RCAN1-4, myomaxin) was reduced in TRPC1/C4 knockout (DKO), but not in TRPC1- or TRPC4-single knockout mice. Pressure overload-induced hypertrophy and interstitial fibrosis were both ameliorated in TRPC1/C4-DKO mice, whereas they did not show alterations in other cardiovascular parameters contributing to systemic neurohumoral-induced hypertrophy such as renin secretion and blood pressure., Conclusions: The constitutively active TRPC1/C4-dependent BGCE fine-tunes Ca(2+) cycling in beating adult cardiomyocytes. TRPC1/C4-gene inactivation protects against development of maladaptive cardiac remodelling without altering cardiac or extracardiac functions contributing to this pathogenesis., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Recurrent stroke is a frequent and disabling event. A high heart rate is associated with cardiovascular outcomes. We investigated the effects of the resting heart rate on cardiovascular and neurological outcomes after recurrent stroke in the high-risk population of the PRoFESS study., Methods and Results: A total of 20,165 patients after ischaemic stroke (mean age 66.1, SD 8.6 years) assigned to the treatment arms of the PRoFESS trial were pooled divided by quintiles of the baseline heart rate and analysed according to cardiovascular and functional outcomes after stroke: recurrent stroke and major cardiovascular outcomes such as stroke, myocardial infarction, and worsening or new-onset heart failure as well as death from cardiovascular and non-cardiovascular causes. Pre-defined endpoints were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and the Barthel index at 3 months, and cognitive function, assessed with the Mini-Mental State Examination (MMSE) score at 4 weeks after randomization and at the penultimate visit. Patients in the two highest quintiles of heart rate (77-82 and >82 b.p.m.) were at a higher risk for total death [hazard ratio (HR) 1.42, 95% CI 1.19-1.69 and HR 1.74, 95% CI 1.48-2.06, P < 0.0001] compared with the lowest quintile. Similar results were observed for vascular death [71-≤76 b.p.m., HR 1.39 (1.11-1.74), P < 0.0001] and non-vascular death [from >82 b.p.m., HR 1.66 (1.29-2.13), P = 0.0016]. Myocardial infarction (P = 0.7084) and recurrent stroke (P = 0.1379) were not significantly associated with the baseline heart rate. Hazard ratios were adjusted to multiple confounders including the baseline blood pressure. In the group of patients with a recurrent stroke, an association of a lower heart rate to better outcomes was measured with the Barthel index across all heart rate groups. In addition, there was a significant association of the baseline heart rate to the occurrence of significant cognitive decline according to an MMSE score ≤24 points at 1 month and at the penultimate visit or a decline of ≥2 points between these two time periods. Better independence score at a low heart rate were observed., Conclusion: The heart rate is a risk indicator for mortality in patients with stroke and, importantly, a low heart rate is associated with a better functional outcome and less cognitive decline after an ischaemic stroke., Trial Registration: ClinicalTrials.gov, number NTC00153062.

Aims: Microalbuminuria (MAU) is a marker for endothelial dysfunction and a predictor of increased cardiovascular risk. Physical activity improves endothelial function. This analysis aims to explore the impact of regular physical exercise on the prevalence and the degree of MAU in hypertensive individuals at high cardiovascular risk., Methods and Results: The International Survey Evaluating microAlbuminuria Routinely by Cardiologists in patients with Hypertension (I-SEARCH) studied the prevalence of MAU in 20,786 hypertensive patients at high cardiovascular risk. Herein, we investigated the relationship between self-reported physical activity and MAU in relation to the number of cardiovascular risk factors, medication and co-morbidities. A total of 7123 patients (34.3%) performed regular physical exercise (moderate or strenuous, at least 4 hours per week). The prevalence of MAU was significantly lower in active than in inactive patients (54% vs 61%; P < 0.0001). This association was observed in all classes of blood pressure and heart rate and was similar in patients with and without diabetes mellitus. Urinary albumin excretion (UAE) was lower in active than in inactive patients (UAE 80 mg/l: 11.6% vs 13.5%, P < 0.0001; UAE 150 mg/l: 7.5% vs 10%; P < 0.0001). In a multivariate analysis adjusted for age, gender, blood pressure, heart rate, renal function, medication and comorbidities, regular physical activity was associated with a 25% lower risk for MAU (odds ratio (OR) 0.75; 95% confidence interval (CI), 0.67-0.84; P < 0.0001). Risk reduction for MAU was more pronounced in strenuously active (OR 0.66; 95%CI, 0.47-0.95; P < 0.05) than in moderately active patients (OR 0.76; 95%CI, 0.68-0.85; P < 0.0001)., Conclusion: In hypertensive patients at high cardiovascular risk, physical activity is an independent predictor for a decreased risk of microalbuminuria.

Ambivalent effects of interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of interleukin-6 after stroke have not been investigated. Here, we subjected interleukin-6 knockout (IL-6(-/-)) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6(-/-) mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6(-/-) mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6(-/-) mice. In addition, systemic neoangiogenesis was impaired in IL-6(-/-) mice. Transplantation of interleukin-6 competent bone marrow into IL-6(-/-) mice (IL-6(chi)) did not rescue interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6(chi) mice recapitulated the major effects of interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with interleukin 6-induced robust interleukin-6 messenger RNA transcription in each case, whereas oxygen-glucose deprivation did not. However, oxygen-glucose deprivation of organotypic brain slices resulted in strong upregulation of interleukin-6 messenger RNA along with increased transcription of key angiogenesis-associated genes. In conclusion, interleukin-6 produced locally by resident brain cells promotes post-stroke angiogenesis and thereby affords long-term histological and functional protection.

Aims: Collateral arteries protect tissue from ischaemia. Heart rate correlates with vascular events in patients with arterial obstructive disease. Here, we tested the effect of heart-rate reduction (HRR) on collateral artery growth., Methods and Results: The I(f)-channel inhibitor ivabradine reduced heart rate by 11% in wild-type and 15% in apolipoprotein E (ApoE)(-/-) mice and restored endothelium-dependent relaxation in aortic rings of ApoE(-/-) mice. Microsphere perfusion and angiographies demonstrated that ivabradine did not change hindlimb perfusion in wild-type mice but improved perfusion in ApoE(-/-) mice from 40.5 ± 15.8-60.2 ± 18.5% ligated/unligated hindlimb. Heart rate reduction (13%) with metoprolol failed to improve endothelial function and perfusion. Protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS, and eNOS activity were increased in collateral tissue following ivabradine treatment of ApoE(-/-) mice. Co-treatment with nitric oxide-inhibitor N (G)-nitro-L-arginine methyl ester abolished the effects of ivabradine on arteriogenesis. Following ivabradine, classical inflammatory cytokine expression was lowered in ApoE(-/-) circulating mononuclear cells and in plasma, but unaltered in collateral-containing hindlimb tissue, where numbers of perivascular macrophages also remained unchanged. However, ivabradine reduced expression of anti-arteriogenic cytokines CXCL10and CXCL11 and of smooth muscle cell markers smoothelin and desmin in ApoE(-/-) hindlimb tissue. Endothelial nitric oxide synthase and inflammatory cytokine expression were unchanged in wild-type mice. Ivabradine did not affect cytokine production in HUVECs and THP1 mononuclear cells and had no effect on the membrane potential of HUVECs in patch-clamp experiments., Conclusion: Ivabradine-induced HRR stimulates adaptive collateral artery growth. Important contributing mechanisms include improved endothelial function, eNOS activity, and modulation of inflammatory cytokine gene expression.

Stroke contributes significantly to morbidity, mortality, and disability worldwide. Despite the successes accomplished in the acute treatment and rehabilitation of stroke, the global burden of this disease can only be tackled with co-ordinated approaches for primary prevention. Stroke is a heterogeneous disease and the contribution of individual risk factors to its occurrence estimated by population attributable risk differs from coronary heart disease. Here, we review evidence to demonstrate the prominent role of elevated blood pressure (BP) and heart disease on risk of stroke, while the influence of lipids on stroke is less clear; we also demonstrate that stroke is an important complication of heart failure. Current approaches to primary preventive action emphasize the need to target the absolute risk of cardiovascular diseases rather than individual risk factors. Lifestyle interventions serve as a basis for primary prevention of cardiovascular diseases. It is estimated that 70% of strokes are potentially preventable by lifestyle modification but prospective evidence is needed to support these hypotheses derived from epidemiological studies. Different strategies for drug interventions in primary prevention are discussed, including the polypill strategy. Additional measures are needed for the primary prevention of stroke which focus on BP, chronic heart failure, and possibly lipids.

Current guidelines from large randomised trials recommend that all patients with diabetes type 2 or coronary artery disease after myocardial infarction should be treated with statin drugs. However, the recent 4D and CORONA trials show no improvement in mortality in elderly patients with ischaemic heart failure and patients with diabetes and end-stage renal disease receiving haemodialysis with the onset of statin treatment. The survival benefit from statin treatment appears to stem primarily from the prevention of progression of coronary artery disease. In clinical conditions where coronary artery disease does not significantly contribute to the cause of death statins seem to be less effective. In patients at risk for organ damage, statin treatment, therefore, has to be started early in the course of the disease. The effect of statin withdrawal in ischaemic heart failure or in patients with advanced renal disease is not known. On the basis of the available evidence, current statin treatment should not be stopped in these patients.