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Aim Cardiac diseases remain a leading cause of cardiovascular disease (CVD) related hospitalisation and mortality. That is why research to improve our understanding of pathophysiological processes underlying cardiac diseases is of great importance. There is a strong need for healthy and diseased human cardiac tissue and related clinical data to accomplish this, since currently used animal and in vitro disease models do not fully grasp the pathophysiological processes observed in humans. This design paper describes the initiative of the Netherlands Heart Tissue Bank (NHTB) that aims to boost CVD-related research by providing an open-access biobank. Methods The NHTB, founded in June 2020, is a non-profit biobank that collects and stores biomaterial (including but not limited to myocardial tissue and blood samples) and clinical data of individuals with and without previously known cardiac diseases. All individuals aged ≥ 18 years living in the Netherlands are eligible for inclusion as a potential future donor. The stored samples and clinical data will be available upon request for cardiovascular researchers. Conclusion To improve the availability of cardiac tissue for cardiovascular research, the NHTB will include extensive (cardiac) biosamples, medical images, and clinical data of donors with and without a previously known cardiac disease. As such, the NHTB will function as a translational bridge to boost a wide range of cardiac disease-related fundamental and translational studies.

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Leiden University Medical Center Background Hospitalizations for decompensated heart failure are a marker for poor prognosis and pose a burden on patients and resources. The mainstay in preventing these hospitalizations is early detection of fluid retention and timely pharmacological intervention. The multisensory cardiac implantable electronic device (CIED) based HeartLogic™ algorithm can alert in case of upcoming congestion. The cumulative HeartLogic™ index is based on the following sensors: heart sounds, thoracic impedance, respiratory rate, night heart rate and patient activity levels. The current analysis investigates the performance of the HeartLogicTM algorithm in a real-world ambulant heart failure population. Methods All consecutive heart failure patients with a CIED and an activated HeartLogic™ algorithm were included for analysis. Patients were followed from 01-01-2018 until 01-09-2022 according to the heart failure care path (figure 1). HeartLogic™ automatically generated an alert if the index surpassed the preset threshold of 16. An alert was either true positive (≥2 signs/symptoms of fluid retention on top of the alert) or false positive (≤1 signs/symptoms). Without an alert a patient was true negative (≤1 signs/symptoms) or false negative (≥2 signs/symptoms). A logistic regression model with linear mixed models was used. Furthermore, patients with ≥2 true positive alerts and ≤1 false positive alerts per year were compared to patients without alerts to identify characteristics of patients who benefit most from the HeartLogic™ algorithm supported management. Results Data of 138 patients were included, median age was 69 [60 – 77], 78% was male and 50% had an ischemic etiology of heart failure. Majority of the patients had a CRT-D (n=90, 65%) and the remaining 48 patients had an ICD (35%). Total follow-up entailed of 297 patient years, median follow-up was 26 months [14 – 36]. During follow-up, 231 alerts were observed. After exclusion of 14 alerts (incomplete clinical information), 217 alerts were available for analysis. Majority of these alerts were true positive for fluid retention(n=161, 74%). Of interest, 21 of these alerts (13%) were not primarily heart failure related, but prompted clinical action (e.g. pneumonia or anemia). The remaining 59 (26%) alerts were deemed false positive. The sensitivity to detect impending fluid retention was 86%, the specificity 88%. The positive predictive value was 73% and the negative predictive value was 94%. Patients with HeartLogicTM alerts had a significantly higher baseline NT-Pro BNP, when compared to patients without alerts, p Conclusions In a real world heart failure population the HeartLogic™ algorithm supported care path adequately detects impending fluid retention. Patients who benefited most had higher levels of NT-Pro BNP at baseline.

Background Continuous-flow left ventricular assist device (CF-LVAD) patients require anticoagulation with vitamin K antagonists (VKAs). Good versus suboptimal anticoagulation control expressed as high versus low time in target range (TTR) of international normalized ratio results in less clinical events in atrial fibrillation patients. However, data in CF-LVAD patients are lacking. Purpose To study the association between TTR and clinical events in patients with CF-LVAD as destination therapy. Methods Single-centre cohort study in patients receiving CF-LVAD between 2010–2021. Patients were followed from start of VKAs until outcome or end of follow-up. Outcomes were combined major adverse events, thromboembolisms, major bleedings, neurologic events and all-cause mortality. The TTR (low vs. high; 50%) was calculated during the overall study period and over 1-month periods by the Rosendaal-method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox regression with time-dependent covariables, adjusted for confounding. Results 74 patients were included; median age 63 years [interquartile range 58–68], 77% males and 60%ischemic heart failure. During 191 years follow-up, 39 combined major adverse events, 14 thromboembolisms, 21 major bleeding, 22 neurologic events and 38 deaths occurred. For 1-month periods, high TTR was associated with less combined major adverse events (HR 0.3 95% CI 0.2–0.7), major bleeding (HR 0.4 95% CI 0.2–1.1), thromboembolism (HR 0.3 95% CI 0.1–1.3) and death (HR 0.2 95% CI 0.1–0.5) (Table 1). Results considering the overall study period were similar. Conclusion Good anticoagulation compared with suboptimal control during 1-month and the overall study period in CF-LVAD patients with destination therapy is associated with lower rates of combined major adverse events, major bleedings, pump thrombosis and death. Funding Acknowledgement Type of funding sources: None.

Background In the ODYSSEY OUTCOMES trial (NCT01663402), alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowered low-density lipoprotein cholesterol from ∼2.3 mmol/L to ∼1.0 mmol/L at 4 months, reduced the risk of major adverse cardiovascular events (MACE: coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, unstable angina requiring hospitalization), and was associated with fewer deaths compared with placebo in 18924 patients (pts) with recent acute coronary syndrome followed for up to 5 years (yrs). Purpose In the ODYSSEY OUTCOMES trial, the overall safety of alirocumab and placebo was similar, except for an excess of local injection-site reactions with alirocumab. However, the safety among pts eligible for longer follow-up has not been fully explored. Methods The present post hoc analyses describe the efficacy and safety of alirocumab in a pre-specified subgroup (for efficacy) of pts eligible for a minimum of 3 and up to 5 yrs of follow-up. Results There were 8242 pts (43.5%) eligible for ≥3 yrs follow-up, of whom 8228 received at least one dose of study medication, comprising 24,610 pt-years of observation with a median follow-up of 3.3 yrs; 6651 pts were eligible for 3 up to 4 yrs, and 1574 patients were eligible for 4–5 yrs, follow-up. As previously reported in a pre-specified analysis of this subgroup, alirocumab significantly reduced death (4.7% vs. 5.9%; p=0.01) compared with placebo. In the present post hoc analysis, alirocumab also significantly reduced MACE vs. placebo (12.0% vs. 14.2%; Hazard Ratio 0.83 [95% CI 0.74 to 0.94]; p=0.003). In a safety analysis, 3217 (78.3%) vs. 3303 (80.2%) pts in the alirocumab vs. placebo group had at least one adverse event (AE) of whom 27.5% vs. 29.4% had a serious AE (Fig. 1). The frequency of permanent discontinuation of study drug due to AEs, incident diabetes, diabetes worsening or complications, neurocognitive events, elevations of ALT>3, AST>3, bilirubin>2, and creatine phosphokinase>10 times the upper limit of normal, were similar with alirocumab vs. placebo (Fig. 1). While pt-reported local injection-site reactions occurred more frequently with alirocumab, the Kaplan-Meier cumulative incidence for time to first local injection site reaction in the longer-term follow-up subgroup was Conclusions In an 8228-pt subgroup of the ODYSSEY OUTCOMES trial eligible for at least 3, and up to 5 yrs follow-up, the safety of alirocumab was similar to placebo except for an excess of local injection site reactions. This subgroup also derived significant benefit from reduced MACE and death. Thus, alirocumab appears to be both a safe and effective lipid-modifying treatment when used for up to 5 yrs. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi and Regeneron

Introduction Use of serial coronary computed tomography angiography (CCTA) allows for the early assessment of coronary plaque progression which may aid in the prevention of major adverse cardiac events (MACE). However, assessment of serial CCTA is done by using anatomical landmarks for matching baseline and follow-up scans. Recently, a tool has been developed allowing for automatic quantification of plaque progression dynamics in serial CCTA utilizing plaque delineation. Purpose The aim of this study was to determine the thresholds that define whether there is plaque progression and/or regression. These thresholds depend on the contrast to noise ratio (CNR) which is an objective marker for scan quality as the latter impacts the plaque delineation. Methods Thresholds and CNR ratios were determined on 50 patients referred for a CCTA due to thoracic complaints. Two scan phases were selected from each patient in which maximum and minimum differences in plaque delineation were measured. Also, CNR was calculated separately for all three major epicardial coronary vessels. A total of 100 scans were analyzed in the current analysis accounting for a total of 300 coronary vessels. First, vessel and lumen wall delineation was done semi-automatically for all major epicardial coronary vessels. Secondly, manual drawings of 7 regions of interest (ROI) per scan were used to quantify scan quality which was defined using the CNR and calculated for each vessel separately. As plaque differences of two scans at the same moment in time should always be zero, the minimum and maximum difference in plaque delineation was used in these scans along with the CNR in order to create calibration graphs on which a linear regression analysis was performed (Figure 1, charts A & B). Inter-observer measurements were calculated using Pearson's correlation coefficient. Results A total of 300 coronary vessels were assessed at CCTA. Semi-automatic vessel and lumen wall delineation as well as CNR calculation was successful in all cases. Subsequent linear regression analysis performed on the CNR and maximal and minimal plaque delineation differences and taking into account the standard error of the estimate revealed the following formulas for minimum and maximum cut-off values: Max = [(0.660 − (002 × CNR)] + 0.349 Min = [(−1.028 + (0.012 × CNR)) − 0.61 The average CNR values was 13.4±3.6. Average maximum and minimum difference in plaque delineation was 0.7±0.3mm and −0.9±0.6mm respectively. The inter-observer correlation for CNR values was excellent yielding a correlation coefficient of 0.872 (p Conclusion Development of vessel-specific quality-based thresholds for the quantification and visualization of plaque progression dynamics as assessed by serial CCTA seems feasible and may aid in the early detection of atherosclerosis progression. Funding Acknowledgement Type of funding sources: None.

Background/Introduction An anomalous coronary artery originating from the opposite sinus of Valsalva (ACAOS) with an interarterial course can be assessed using Computed Tomography Angiography (CTA) for the presence of high-risk characteristics associated with sudden cardiac death. These features include a slit-like ostium, acute angle take-off, and degree of proximal luminal narrowing. However, no robust CTA criteria currently exist to determine the presence of an intramural segment. Purpose The aim of this study is to deduct a method to accurately identify an intramural course of interarterial ACAOS on CTA imaging. Methods All consecutive adult patients with an interarterial ACAOS that were evaluated at the two academic hospitals between January 2010 and July 2019 were screened for inclusion. Inclusion criteria were availability of a preoperative CTA-scan (0.5–1mm slice-thickness) and peroperative confirmation of the intramural segment. Using multiplanar reconstruction of the CTA, the distance between the lumen of the aorta and the lumen of the ACAOS (defined as “interluminal space” (ILS)) was assessed at 2mm intervals along the intramural segment (Figure 1). Results Twenty-five patients (64% female, mean age 46 years, 88% right ACAOS) were included. Analysis showed a mean ILS of 0.69mm±0.15mm at 2mm from the ostium. At the end of the intramural segment where the ACAOS becomes non-intramural, the mean ILS was significantly larger (1.27±0.29mm, p Conclusion(s) The ILS is introduced as novel and robust CTA parameter to identify an intramural course of interarterial ACAOS. An ILS of ≤0.95mm is indicative of an intramural segment with 100% sensitivity and 84% specificity. Funding Acknowledgement Type of funding sources: None.

Background Many patients require arterial revascularization after an index ACS. Lipoprotein(a) is thought to play a pathogenic role in atherothrombosis. In the ODYSSEY OUTCOMES trial, the PCSK9 inhibitor alirocumab reduced major adverse cardiovascular events after ACS, with greater reduction among those with higher lipoprotein(a). Objectives We determined whether the risk of first coronary or any (coronary, peripheral artery or carotid) revascularization after ACS was modified by the level of lipoprotein(a) and treatment with alirocumab or placebo. Methods The ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18,924 patients with ACS and elevated atherogenic lipoproteins despite optimized statin treatment. Treatment effects were summarized by competing-risks proportional hazard models. Results A total of 1559 (8.2%) patients had coronary, 204 (1.1%) peripheral artery, and 40 (0.2%) carotid revascularization after randomization. Alirocumab reduced first coronary revascularization (9.6% vs. 11.3% at 4 years; hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.80–0.97; p=0.01) and any first revascularization (10.8% vs. 13.0%; HR 0.85, 95% CI 0.78–0.94; p=0.001). Baseline lipoprotein(a) quartile was directly associated with risk of coronary or any revascularization in the placebo arm (ptrend Conclusions Alirocumab reduced revascularization after ACS. The risk of revascularization and reduction in that risk with alirocumab were greatest in patients with elevated lipoprotein(a) at baseline. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): SanofiRegeneron Pharmaceuticals

Background While malignant bone sarcoma is rare in the general population, it is the second most common malignancy among children and young adults. (Neo)adjuvant systemic treatment carries a significant risk of cardiotoxicity (CTx) in the form of late-onset left ventricular dysfunction and heart failure. There are several long-term follow up protocols in place for survivors of childhood and adolescent cancers, but when sarcoma is diagnosed at higher age the best follow up practice is less clear and there is little known about the long-term risk and mode of onset of CTx. Purpose To evaluate the effect of age at sarcoma diagnosis on incidence of cardiotoxicity (CTx) and time-to-CTx. Methods This single-center retrospective analysis of CTx of sarcoma treatment was performed at a tertiary sarcoma center in the Netherlands (Leiden University Medical Center, LUMC) among patients with a high-grade osteosarcoma (OS) and Ewing sarcoma (ES). All patients were diagnosed and treated over a 36-year period (1982 and 2018) at LUMC, and followed up until August 2021. The main inclusion criterium was exposure to doxorubicin-containing chemotherapy regimens. The exposure of interest was age at cancer diagnosis with a cut-off for older age at ≥30 years (age30+) The primary study endpoint was incident clinically relevant CTx at follow up, defined as composite of pharmacological heart failure (HF) treatment initiation, HF admissions and ICD implantation. Cause-specific Cox modeling was performed to calculate the hazard ratio (HR) of age group and incidence of both the primary study endpoint and competing risk of all cause death. Results The study population consisted of 556 patients (69.0% OS, 31.0% ES) with a median age at sarcoma diagnosis of 19 [p25-p75: 15–30] years and the majority of patients were male (60.4%). 146 patients were in the age30+ group (26.3%). In a median follow up time of 5.5 [2.0–13.2] years, 27 patients reached the primary endpoint (4.9%). In 7/27 cases an urgent HF hospitalization was the first manifestation of HF and the remaining cases met the primary endpoint due to pharmacological HF treatment imitation. At the end of follow up mortality was 49.3% of patients. The vast majority of patients died of malignancy-related causes (95.6%). When correcting for female sex and sarcoma type, age30+ at sarcoma diagnosis was associated with a near 3.5 fold increased risk of HF compared to when sarcoma was diagnosed below 30: HR 3.39 (95% CI: 1.57–7.31), p=0.019. For the age30+ group whom experienced CTx the time-to-event was shorter compared to those diagnosed below 30 years at: respectively 5.5 years vs. 12.6 years (see Figure 1; Wilcoxon rank-sum test: p=0.012). Conclusions Sarcoma patients above 30 years at diagnosis have an increased risk of CTx and time to development of CTx was significantly shorter. Funding Acknowledgement Type of funding sources: None.

Cardiac diseases remain a leading cause of cardiovascular disease (CVD) related hospitalisation and mortality. That is why research to improve our understanding of pathophysiological processes underlying cardiac diseases is of great importance. There is a strong need for healthy and diseased human cardiac tissue and related clinical data to accomplish this, since currently used animal and in vitro disease models do not fully grasp the pathophysiological processes observed in humans. This design paper describes the initiative of the Netherlands Heart Tissue Bank (NHTB) that aims to boost CVD-related research by providing an open-access biobank.The NHTB, founded in June 2020, is a non-profit biobank that collects and stores biomaterial (including but not limited to myocardial tissue and blood samples) and clinical data of individuals with and without previously known cardiac diseases. All individuals aged ≥ 18 years living in the Netherlands are eligible for inclusion as a potential future donor. The stored samples and clinical data will be available upon request for cardiovascular researchers.To improve the availability of cardiac tissue for cardiovascular research, the NHTB will include extensive (cardiac) biosamples, medical images, and clinical data of donors with and without a previously known cardiac disease. As such, the NHTB will function as a translational bridge to boost a wide range of cardiac disease-related fundamental and translational studies.

To present an overview of studies using serial coronary computed tomography angiography (CCTA) as a tool for finding both quantitative (changes) and qualitative plaque characteristics as well as epicardial adipose tissue (EAT) volume changes as predictors of plaque progression and/or major adverse cardiac events (MACE) and outline the challenges and advantages of using a serial non-invasive imaging approach for assessing cardiovascular prognosis.A literature search was performed in PubMed, Embase, Web of Science, Cochrane Library and Emcare. All observational cohort studies were assessed for quality using the Newcastle-Ottawa Scale (NOS). The NOS score was then converted into Agency for Healthcare Research and Quality (AHRQ) standards: good, fair and poor.A total of 36 articles were analyzed for this review, 3 of which were meta-analyses and one was a technical paper. Quantitative baseline plaque features seem to be more predictive of MACE and/or plaque progression as compared to qualitative plaque features.A critical review of the literature focusing on studies utilizing serial CCTA revealed that mainly quantitative baseline plaque features and quantitative plaque changes are predictive of MACE and/or plaque progression contrary to qualitative plaque features. Significant questions regarding the clinical implications of these specific quantitative and qualitative plaque features as well as the challenges of using serial CCTA have yet to be resolved in studies using this imaging technique.• Use of (serial) CCTA can identify plaque characteristics and plaque changes as well as changes in EAT volume that are predictive of plaque progression and/or major adverse events (MACE) at follow-up. • Studies utilizing serial CCTA revealed that mainly quantitative baseline plaque features and quantitative plaque changes are predictive of MACE and/or plaque progression contrary to qualitative plaque features. • Ultimately, serial CCTA is a promising technique for the evaluation of cardiovascular prognosis, yet technical details remain to be refined.

Purpose of Review This review aims to summarize and discuss the recent findings in the field of using HDL mimetics for the treatment of patients with coronary artery disease. Recent Findings Following the largely disappointing results with the cholesteryl ester transfer protein inhibitors, focus moved to HDL functionality rather than absolute HDL cholesterol values. A number of HDL/apoA-I mimicking molecules were developed, aiming to enhance reverse cholesterol transport that has been associated with an atheroprotective effect. Three HDL mimetics have made the step from bench-testing to clinical trials in humans and are discussed here: apoA-I Milano, CSL-112, and CER-001. Unfortunately, with the exception of CSL-112 where the results of the clinical trial are not yet known, none of the agents was able to demonstrate a clinical benefit. Summary HDL mimetics have failed to date to prove a beneficial effect in clinical practice. Reverse cholesterol transport remains a challenging therapeutic pathway to be explored.

Coronary atherosclerosis is a common disease. The plaques developing inside coronary vessels may have serious consequences such as myocardial infarction. However, the course of this multifactorial and heterogeneous disease is difficult to predict and is different for each patient. Atherosclerosis is often described as a gradually progressive disease, but in addition to slow progression, a certain periodicity is often seen. There may be periods with more stability and periods of regression. Several processes are known to be involved in plaque development and their increasing vulnerability. We describe some of these processes in this article. Despite existing knowledge about these processes, atherosclerosis periodicity remains largely unexplained. More insight into this periodicity may potentially be relevant to the development of new therapies. Drug therapy to lower LDL-cholesterol is currently the cornerstone of treatment, in addition to lifestyle advice.

Context The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated. Objective To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A(2) to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction. Design, Setting, and Participants Individual records were available for 165 544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15 126 incident fatal or nonfatal CVD outcomes (10 132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years). Main Outcome Measures Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low ( = 20%) risk. Results The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A(2) mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100 000 adults aged 40 years or older, 15 436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A(2) mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines. Conclusion In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A(2) mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction. JAMA. 2012; 307(23):2499-2506 www.jama.com

Cardiovascular disease is currently one of the biggest causes of morbidity and mortality facing humanity. Such a paradigm shift of disease pattern over the last century has only worsened due to the alarming global prevalence of obesity and type 2 diabetes. In recent years there is increasing focus on inflammation as one of the key players in the patho-physiology of these disorders. In addition to these overt risk factors new research is unraveling the significance of a constellation of early metabolic abnormalities that include weight gain, insulin resistance, prehypertension and a specific pattern of dyslipidaemia. There exists a complex interrelationship of these various metabolic disorders and their effect on cardiovascular system. Simplified explanation can be that inflammation increases insulin resistance, which in turn leads to obesity while perpetuating diabetes, high blood pressure, prothrombotic state and dyslipidaemia. While inflammation and insulin resistance have direct adverse effects on cardiac muscle, these metabolic abnormalities as a whole cause causes cardiovascular complications; warranting a multi pronged therapeutic and preventive approach for the 'Cardiovascular Metabolic Syndrome' as an entity.

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

Postprandial inflammation is considered to be pro-atherogenic. Vitamin D can reduce inflammation and arterial stiffness. We hypothesized that vitamin D3 improves postprandial arterial elasticity by the modulation of leukocyte activation. Healthy volunteers underwent two oral fat-loading tests (OFLTs). The augmentation index (AIx) and flow cytometric quantification of leukocyte activation markers were measured. After the first OFLT, 100 000 IU of vitamin D3 was administered and a second OFLT was carried out 7 days later. Six men and six women were included. A favorable reduction in AIx was found after vitamin D3 supplementation (P=0.042) in both genders. After vitamin D3, exclusively in women a reduction in the area under the postprandial curve for monocytes CD11b and CD35 by 10.5% (P=0.016) and 12.5% (P=0.04) and neutrophil CD11b by 17.0% (P=0.014) was observed. In conclusion, vitamin D3 probably increased postprandial arterial elasticity in men and women, but reduced postprandial leukocyte activation exclusively in women.

Objectives: The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintained weight loss and reduction of dyslipidemia in experimental and human obesity. Brown adipose tissue (BAT) that burns lipids towards heat using UCP1, recently emerged as a major player in lipoprotein metabolism and is present and active in human adults. The aim of the present study was to elucidate the mechanism by which CB1R blockade reverses dyslipidemia and obesity, with special focus on BAT. Methods and results: Diet-induced obese APOE*3-Leiden.CETP transgenic mice, a well-established model for human-like lipoprotein metabolism, were treated with the systemic CB1R blocker rimonabant (10 mg/kg/day) for 4 weeks. Rimonabant persistently decreased body weight (-25%, pin vitro blockade of the CB1R in cultured brown adipocytes resulted in 2.5-fold upregulation of UCP1. Importantly, the in vivo results could be fully recapitulated using the strictly peripheral CB1R antagonist AM6545 (10 mg/kg/day) that does not induce hypophagia. Conclusion: CB1R blockade reduces dyslipidemia and obesity by peripheral activation of BAT. Selective targeting of peripheral CB1R in BAT has thus great therapeutic potential in decreasing dyslipidemia and obesity and ultimately cardiovascular diseases.

Introduction: The residual risk that remains after statin treatment has stimulated the search for secondary treatment targets. Epidemiological studies propose HDL-C as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to atherogenic (V)LDL. The CETP inhibitor anacetrapib decreases (V)LDL-C by ~15-40% and increases HDL-C by ~40-140% in clinical trials. We evaluated the effects of anacetrapib on lipid metabolism, HDL function and atherosclerosis, and examined possible additive/synergistic effects of anacetrapib on top of atorvastatin in APOE*3Leiden.CETP mice. Methods and results: Mice were fed a diet without or with ascending dosages of anacetrapib (0.03; 0.3; 3; 30 mg/kg/d), atorvastatin (2.4 mg/kg/d) alone or in combination with anacetrapib (0.3 mg/kg/d) for 21 weeks. Anacetrapib dose-dependently reduced CETP activity (-59% to -100%, P Anacetrapib dose-dependently reduced atherosclerotic lesion area (-41% to -92%, P Conclusions: Anacetrapib reduces atherosclerosis, and adds to the anti-atherogenic effect of atorvastatin. The anti-atherogenic effect is mainly ascribed to a reduction in nonHDL-C, as a consequence of an increased clearance. In addition, anacetrapib improves lesion stability.

In the past decade, research into cardiovascular diseases, such as atherosclerosis and restenosis, has been focused on the identification of genetic factors that determine disease risk besides clinical risk factors. Many genes in lipid metabolism, vascular homeostasis, haemostasis and inflammation have been found to be related to coronary artery disease1 and the multifactorial nature of the disease suggests a role for many other, yet uninvestigated genes. Previous research from our department has demonstrated the importance of genetics in restenosis after a percutaneous coronary intervention (PCI). Polymorphisms in several inflammatory genes, such as TNFα, eotaxin, CD14, GM-CSF, IL-10, caspase-1, but also noninflammatory genes, such as LPL, stromelysin-1 and the β adrenergic receptor have been found to be associated with the risk of restenosis.2-5 It has become clear, however, that part of the gene-environmental interactions relevant for complex diseases is regulated by epigenetic mechanisms such as histone acetylation and DNA methylation.

In response to vascular injury, smooth muscle cells (VSMC) adopt a proliferative, synthetic hypocontractile phenotype. This phenotype switch is deemed instrumental in vascular remodeling in both health and disease. Here, we detail a decisive role for the RNA-binding protein Quaking (QKI) in regulating VSMC plasticity. We identified that the RNA-binding protein Quaking (QKI) is highly expressed by neointimal VSMCs of human coronary restenotic lesions, but not in healthy vessels. In a mouse model of vascular injury, we observed reduced neointima hyperplasia in Qk v mice, which have decreased QKI expression. Concordantly, abrogation of QKI attenuated fibroproliferative properties of VSMCs, while potently inducing contractile apparatus protein expression, rendering non-contractile VSMCs with the capacity to contract. We identified that QKI localizes to the spliceosome in proliferative VSMCs, where it interacts with and impacts myocardin (pre)-mRNA metabolism by mediating myocardin exon 2a exclusion. As such, in vitro and in vivo experiments indicate that the modulation of QKI expression directly influences the myocardin_v3 / myocardin_v1 mRNA balance, which could play a role in shifting the Myocardin-induced transcriptional coactivation profile following arterial damage. We propose that QKI is a central regulator of VSMC phenotypic plasticity and that intervention in QKI activity can ameliorate pathogenic, fibroproliferative responses to vascular injury.

Introduction The residual risk of cardiovascular disease that remains after statin treatment has triggered the search for a secondary treatment target. Epidemiological studies propose HDL-cholesterol (HDL-C) as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to atherogenic (V)LDL. In human intervention trials, the CETP inhibitor anacetrapib decreases (V)LDL-C by 30-40% and increases HDL-C by 40-140%. Hypothesis Complete inhibition of CETP activity may result in adverse effects as compared to partial inhibition due to the appearance of a dysfunctional HDL. We, therefore, evaluated the effect of a broad treatment window of anacetrapib-induced CETP inhibition with partial to full inhibition, as well as the combination of atorvastatin and anacetrapib on atherosclerosis development in APOE*3Leiden.CETP mice. Methods Female mice were fed a Western-type diet containing 0.1% cholesterol without or with incremental dosages of anacetrapib (0.03; 0.3; 3; 30 mg/kg/d), atorvastatin (2.4 mg/kg/d) or a combination of anacetrapib (0.3 mg/kg/d) and atorvastatin (2.4 mg/kg/d) for 20 weeks. Effects on plasma lipids, CETP activity and levels, as well as atherosclerotic lesion size and severity were assessed. Results Anacetrapib dose-dependently reduced CETP activity (-60% to -100%, P Conclusions Anacetrapib dose-dependently decreases atherosclerosis development and adds to the beneficial effects of atorvastatin in APOE*3Leiden.CETP mice. Total blockage of CETP activity does not reveal adverse effects as compared to partial blockage.

Acute coronary syndromes contribute a substantial part of the global disease burden. To realize a reduction in mortality and morbidity, the management of patients with these conditions involves the integration of several different approaches. Timely delivery of appropriate care is a key factor, as the beneficial effect of reperfusion is greatest when performed as soon as possible. Innovations in antithrombotic therapy have also contributed significantly to improvements in the prevention of ischaemic complications. However, with the use of such treatment, an increase in the risk of bleeding is inevitable. Therefore, the greatest challenge is now to obtain an optimal balance between the prevention of ischaemic complications and the risk of bleeding. In this regard, identification of patients at highest risk of either one is essential.

BACKGROUND : Statin therapy reduces the risk of coronary heart disease (CHD); however, the variability in response to statin therapy is not well understood. We investigated the effect of genetic variation on the reduction of CHD events by pravastatin therapy. METHODS : We genotyped 682 CHD cases from CARE and 383 CHD cases from WOSCOPS, two randomized placebo-controlled studies of pravastatin using the Illumina OMNI1 bead array. Single nucleotide polymorphisms (SNPs) that were associated with differential CHD event reduction by pravastatin therapy were investigated in PROSPER, a randomized placebo-controlled study of pravastatin in the elderly. RESULTS : A combined case-only analysis of CARE and WOSCOPS identified 62 SNPs associated with differential event reduction by pravastatin therapy (P int int =0.001 in CARE, P int =0.01 in WOSCOPS, P int =0.002 in PROSPER, and P int =3X10 -7 in a combined analysis of CARE, WOSCOPS and PROSPER (Figure). CONCLUSIONS : We have identified a SNP that is associated with differential event reduction by pravastatin therapy in CARE, WOSCOPS, and PROSPER. This SNP merits investigation in additional randomized studies of pravastatin and other statins.

The prevalence and burden of cardiovascular disease (CVD) is high, and it remains the leading cause of death worldwide. Unfortunately, many individuals who are at high risk for CVD are not recognized and/or treated. Therefore, programs are available to ensure individuals at risk for CVD are identified through appropriate risk classification and offered optimal preventative interventions. The use of algorithms to determine a global risk score may help to achieve these goals. Such global risk-scoring algorithms takes into account the synergistic effects between individual risk factors, placing increases in individual risk factors into context relative to the overall disease, allowing for a continuum of disease risk to be expressed, and identifying patients most likely to derive benefit from an intervention. The predictive value of risk scoring such as using the Framingham equation is reasonable, analogous to cervical screening, with area under the receiver operated characteristic curve a little over 70%. However, limitations do exist, and as they are identified adjustments can be made to the global risk-scoring algorithms. Limitations include patient-specific issues, such as variations in lifetime risk level, ethnicity or socio-economic strata, and algorithm-specific issues, such as discrepancies between different algorithms arising from varying risk factors evaluated. The use of currently developed algorithms is low in general practice, in part, because of the belief that the assessment may oversimplify the risk and/or lead to medication overuse. Additional hindrances to the use of risk scoring include government or local health policy, patient compliance issues and lack of time. A thorough, easy-to-use, and standardized tool for risk estimation would allow for improvements in the primary prevention of CVD.

Atherosclerosis is a type of arteriosclerosis. It comes from the Greek words athero (meaning gruel or paste) and sclerosis (hardness). Atherosclerosis is the pathophysiological basis of the majority of morbidity and mortality in Western societies. In recent years, progression has been made in unraveling the exact cause for atherosclerosis. It is considered to have a complex pathophysiology, and is a disease of the arterial intima leading to the formation of fibrous (atheromatous) plaques and to stenosis/occlusion of the lumen (Fig. 22.1).1 Atherosclerosis affects large and medium-sized arteries. The artery and position of the plaque varies with each person. In general, atherosclerosis is a slowly progressive disease that may start in childhood. In some people this disease progresses rapidly in their third decade. In others, it does not become threatening until they are in their 50s or 60s.1,2 As mentioned above, the development of atherosclerosis is a complex process, and several major risk factors3 and a growing number of novel risk markers4 have been reported to play a role in its development. Evidence accumulated over decades convincingly demonstrates that family history of atherosclerosis in a parent or a sibling is an important risk factor associated with atherosclerotic coronary artery disease (CAD).5

Background: Achievement of lipid targets is particularly important in individuals with diabetes mellitus (DM) and the metabolic syndrome (MS) because their cardiovascular (CV) risk is high. This analysis of the L-TAP 2 population compared goal attainment by DM status and number of MS components. Methods: In L-TAP 2, patients aged ≥20 years with dyslipidemia on stable lipid lowering therapy were assessed at investigation sites in 9 countries (US, Spain, Canada, Netherlands, Korea, France, Taiwan, Mexico, and Brazil) between September 2006 and April 2007. Lipid levels were determined once in each patient at time of enrollment. Achievement of LDL-C success (according to National Cholesterol Education Program Adult Treatment Panel III guidelines), triglycerides (TG) goals (40 mg/dL in men or >50 mg/dL in women) was compared using logistic regression by DM status and number of MS components (BMI ≥30 kg/m 2 , TG ≥150 mg/dL, HDL-C Results: A total of 9955 patients were evaluated. Patients with DM, compared with those without DM, had significantly lower achievement of LDL-C success (67% vs 75%), TG goals (55% vs 64%), and HDL-C success (62% vs 75%; P P P P P Conclusions: This analysis indicates that despite their increased CV risk, patients with DM remain undertreated. Furthermore, as the number of MS components increases, lipid goal success rates decrease.

Inhibition of cholesteryl ester transfer protein (CETP) is generally regarded as a promising strategy to reduce atherosclerosis by increasing HDL cholesterol. Therefore, the potent CETP inhibitor torcetrapib was given in addition to atorvastatin in half of the 15,067 patients with a high cardiovascular risk in the randomized, double-blind 'Investigation of lipid level management to understand its impact in atherosclerotic events' (ILLUMINATE) study. Torcetrapib caused a large increase of 72.1% in HDL cholesterol and a concomitant reduction of 24.9% in LDL-cholesterol. However, the trial was terminated prematurely because of an increased risk of cardiovascular events and death. Besides increasing blood pressure, torcetrapib decreased potassium and increased sodium, bicarbonate and aldosterone in serum. Post hoc analyses showed an increased risk of death in patients whose change in electrolytes was greater than the median change. These adverse effects of torcetrapib are presumably compound-specific, but should be taken into account in future studies with novel CETP inhibitors. Furthermore, it is suggested that the efficacy of CETP inhibition with regard to cardiovascular event reduction may depend on the lipid profile of the patient.

Item does not contain fulltext BACKGROUND: KCNJ11 mutations are a common cause of diabetes diagnosed in the first 6 months of life, and approximately 25% of patients have neurological features. Sulphonylureas have been shown to improve glycaemic control and also motor function, but the impact on cognitive function has not been extensively addressed previously. METHODS: The patient had a low birth weight and was found to have diabetes at the age of 2 days. The patient was treated with insulin from diagnosis. The child also had marked developmental delay so that his average functional age was 2.5 years when he was 12 years old. A V59M mutation in KCNJ11 was found on sequencing, resulting in a diagnosis of intermediate developmental delay, epilepsy, neonatal diabetes (DEND) syndrome. Identification of a Kir6.2 mutation allowed insulin injections to be replaced by glibenclamide tablets. RESULTS: This resulted not only in improved glycaemic control (HbA(1c) fell from 8.1 to 6.5%), but also an impressive improvement in many aspects of cognitive function, with the functional age increasing to 4 years within 6 months of treatment change. CONCLUSIONS: This is the first clear report of cognitive function improving in a patient with the neurological features associated with a K(ATP) channel mutation following transfer to sulphonylureas. The finding of cognitive improvement suggests that glibenclamide is likely to be acting directly on the brain and not just on nerve and muscle, improving muscle strength.

Background: It is generally accepted that low density lipoprotein cholesterol (LDL-C) or calculated ratios such as LDL-C to high density lipoprotein cholesterol (HDL-C) (LDL-C/HDL-C) are useful predictors of risk of cardiovascular disease in the primary as well as in the secondary prevention setting. However, there is accumulating evidence that the ratio of the corresponding apolipoproteins (apoB/A1) might be superior in some populations. Little is known with regard to the prognostic significance of apoB/A1 in patients treated with statins according to the guidelines. Objective: The present study assesses the prognostic value of apoB/A1 in such patients receiving statin therapy. Methods: This study was performed in a population of 593 statin-treated patients with known coronary heart disease (CHD). It is a post-hoc analysis of a published study on the effect of folic acid on cardiovascular risk. The association of lipids and apolipoproteins with cardiovascular events was evaluated using univariate and multivariate Cox regression models. Results: The apoB/A1 ratio was associated with clinical outcome when corrected for standard risk factors, whereas LDL-C/HDL-C was not, which could indicate additional significant prognostic value of apoB/A1 over and above this classic lipid ratio. However, this additional prognostic value was not confirmed by receiver operating characteristic (ROC) curves, which showed no increase in the area under the curve. Conclusion: In statin-treated patients with known CHD, apoB/A1 is positively associated with clinical events, whereas the LDL-C/HDL-C is not, but apoB/A1 does not increase the area under the curve

Objective: All factors of the metabolic syndrome (MetS) are reported to be associated with elevated C-reactive protein (CRP) levels. As CRP levels have been found to decrease as a result of statin treatment, the present study was intended to explore the relationship between CRP and the MetS in statin treated patients.Methods: In this study, the relationship between the components of the MetS and CRP level were analysed and factors determining CRP were identified in patients with longstanding intensive lipid lowering therapy with known cardiovascular disease.Results: In this population CRP levels are still associated with the MetS, with waist circumference, fasting glucose level and smoking being the most important determinants of CRP levels.Conclusions: CRP levels are still associated with the MetS in patients treated with intensive lipid lowering therapy.

Obesity is an important healthcare issue. --Recent research has led to insights into the role of the endocannabinoid system in the regulation of body weight. --Rimonabant is a CB1-endocannabinoid-receptor antagonist. --Four trials were published recently on the efficacy and safety of rimonabant in the treatment of people with obesity. --When combined with a hypocaloric diet, rimonabant 20 mg/day was more effective than placebo in achieving and maintaining weight loss. In addition, treatment with rimonabant had beneficial effects on insulin resistance, HDL-cholesterol and hypertriglyceridaemia. --There is concern regarding the increased incidence of depression during treatment. --Whether the beneficial effects of rimonabant on weight reduction and cardiovascular risk factors translate into a reduction in cardiovascular morbidity and mortality remains to be established in large phase III trials.

Every year, a considerable number of patients present at the Emergency Department (ED) with acute chest pain complaints. In these patients, determining accurate diagnosis of acute coronary syndrome (ACS) remains clinically challenging. In general, triage is based on the initial clinical assessment including (stress) ECG and serial serum markers measurements. While management is relatively straightforward in case of ECG changes and elevated serum markers, a considerable number of patients presents with both serum markers and ECG that are either within normal limits or inconclusive. In these patients, non-invasive cardiac imaging has become an important tool in decision-making. Recently, non-invasive visualization of the coronary arteries has become possible with computed tomography (CT) techniques. Both electron beam CT (EBCT) and multi-slice CT (MSCT) allow assessment of coronary calcium burden as a marker of coronary artery disease (CAD). More recently, non-invasive coronary angiography can also be performed, for which MSCT in particular is increasingly used. Potentially these techniques could become useful in the clinical work-up of patients presenting with suspected ACS. The purpose of the present review is to discuss the potential roles of calcium scoring and non-invasive coronary angiography in patients presenting with suspected ACS.

We examined the relationship between granulocyte, lymphocyte and monocyte counts and risk of coronary heart disease (CHD) and cardiovascular disease (CVD) in men and women. There is paucity of data on the differential leucocyte count and its relationship with the risk of CHD and CVD.This prospective study comprised 7073 men and 9035 women who were 45-79 years of age and were residents of Norfolk. United Kingdom.During an average of 8 years of follow-up we identified 857 incident CHD events and 2581 CVD incident events. Increased total leucocyte count was associated with increased risk for both CHD and CVD. The highest quartile of granulocyte count was associated with increased risk when compared to lowest quartile for CHD (men HR 1.70 95% CI: 1.30-2.21; women HR 1.24 95% CI: 0.91-1.69) and for CVD (men HR 1.46 95% CI: 1.24-1.71; women HR 1.20 95% CI: 1.02-1.42). The association remained unchanged when the analyses were restricted to nonsmokers and when risk was assessed for every 1000 cells L(-1) increase in cell count. In multivariable models, despite adjusting for C-reactive protein (CRP), the granulocyte count remained an independent predictor of CHD and CVD risk, especially amongst men. Lymphocyte or monocyte counts were not significantly associated with increased risk. In all analyses, additionally adjusting for CRP did not affect the results materially.In conclusion, we found that the higher risk for CHD and CVD associated with increased total leucocyte count seems to be accounted for by the increased granulocyte count.

In the Netherlands, coronary-vascular disease is still the main cause of death with around 48,000 deaths each year. This means that one out of three deaths is due to coronary-vascular disease. Therefore knowledge of epidemiology, diagnosis and treatment (by medication, PCI or CABG) of vascular disease is of utmost importance. This issue of the Netherlands Heart Journal is dedicated to coronary artery disease and deals with several of its aspects, by means of interesting case reports and reports on imaging modalities.

Objective: Paraoxonase-1 (PON-1) is a highdensity lipoprotein (HDL) associated enzyme involved in the protective mechanisms of HDL. Our aim was to compare the effect of treatment with rosuvastatin and atorvastatin on serum PON-1 activity.Methods: We performed a prespecif ied prospective study in 68 patients, part of a larger, multicentre randomized study - RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport). Patients aged 40-80 years, all men, with established cardiovascular disease and high-density lipoprotein cholesterol (HDL-C) Results: After 18 weeks, the rosuvastatin arm showed a significant increase of PON-1 activity (6.39 U/L, p = 0.02) whereas this was not observed in the atorvastatin arm (1.84U/L, p = 0.77). The difference between groups did not reach significance (p = 0.11). Both rosuvastatin and atorvastatin resulted in significant (p = 0.0001) and similar increases in HDL-C after 6 weeks [0.06mmol/L (2.32 mg/dL) vs. 0.05 mmol/L (1.93 mg/dL] and after 18 weeks [0.10 mmol/L (3.87 mg/dL) vs. 0.10 mmol/L (3.87 mg/dL)].Conclusions: Rosuvastatin treatment resulted in a significant increment of serum PON-1 activity with increasing dose while this was not observed with atorvastatin.

It is assumed that the combined effects of multiple common genetic variants explain a large part of variation of high-density lipoprotein cholesterol (HDL-C) plasma levels, but little evidence exists to corroborate this assumption. It was our objective to study the contribution of multiple common genetic variants of HDL-C-related genes to variation of HDL-C plasma levels. A well-characterized cohort of 546 Caucasian men with documented coronary artery disease was genotyped for common functional variants in genes that control reverse cholesterol transport: ATP-binding cassette transporter A1, apolipoprotein A-I and apolipoprotein-E, cholesteryl ester transfer protein, hepatic lipase, lecithin : cholesterol-acyl transferase, lipoprotein lipase, and scavenger receptor class B type 1. Multivariate linear regression showed that these variants, in conjunction, explain 12.4% (95% confidence interval: 6.9-17.9%) of variation in HDL-C plasma levels. When the covariates smoking and body mass index were taken into account, the explained variation increased to 15.3% (9.4-21.2%), and when 10 two-way interactions were incorporated, this percentage rose to 25.2% (18.9-31.5%). This study supports the hypothesis that multiple, mildly penetrant, but highly prevalent genetic variants explain part of the variation of HDL-C plasma levels, albeit to a very modest extent. Multiple environmental and genetic influences on HDL-C plasma levels still have to be elucidated.