Use of combination therapy is associated with improved LDL-cholesterol management: 1-year follow-up results from the European observational SANTORINI study.

AIM: To assess whether implementation of the 2019 ESC/EAS dyslipidaemia guidelines observed between 2020-2021 improved between 2021-2022 in the SANTORINI study. METHODS: High- or very-high cardiovascular (CV) risk patients were recruited across 14 European countries from March 2020-February 2021, with 1-year prospective follow-up until May 2022. Lipid-lowering therapy (LLT) and 2019 ESC/EAS risk-based low-density lipoprotein 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. . RESULTS: Of 9559 patients enrolled, 9136 (2626 high risk, 6504 very high risk) had any follow-up data, and 7210 (2033 high risk, 5173 very high risk) had baseline and follow-up LDL-C data. LLT 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 mmol/L 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%). CONCLUSIONS: LLT 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 implementation of combination LLT.

Cardiovascular diseases, a group of disorders of the heart and blood vessels, are the most common cause of death worldwide. Lowering low-density lipoprotein (LDL) cholesterol in the bloodstream reduces the risk of developing cardiovascular diseases, such as heart attacks and strokes. Guidelines recommend that those at highest risk of cardiovascular disease should achieve the lowest levels of LDL cholesterol. Several medications are available that help lower LDL cholesterol levels and prevent cardiovascular events, however, recent studies have shown that the majority of patients continue to have LDL cholesterol levels above optimal value in part due to suboptimal use of these medications. Here we report the results after 1 year of follow-up of the SANTORINI study (started in 2020) which aimed to document the management of LDL cholesterol in clinical practice across 14 countries in Europe. We found that better control of LDL cholesterol occurred when more than one drug was used (combination therapy). Use of combination therapy was low at the start of the study 25.6% but increased over 1 year to 37.9%, resulting in better control of LDL cholesterol at 1 year than observed at the start of the study. Nonetheless, only 31% of patients achieved their LDL cholesterol target levels based on the European guidelines. Greater use of combination therapies is needed in order to improve the overall population level control of LDL cholesterol.

Urinary Proteomics and Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Although several studies have addressed plasma proteomics in heart failure with preserved ejection fraction, limited data are available on the prognostic value of urinary proteomics. The objective of our study was to identify urinary proteins/peptides associated with death and heart failure admission in patients with heart failure with preserved ejection fraction. METHODS AND RESULTS: The study population included participants enrolled in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). The relationship between urine protein levels and the risk of death or heart failure admission was assessed using Cox regression, in both nonadjusted analyses and adjusting for urine creatinine levels, and the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score. A total of 426 (12.4%) TOPCAT participants had urinary protein data and were included. There were 40 urinary proteins/peptides significantly associated with death or heart failure admission in nonadjusted analyses, 21 of which were also significant adjusted analyses. Top proteins in the adjusted analysis included ANGPTL2 (angiopoietin-like protein 2) (hazard ratio [HR], 0.5731 [95% CI, 0.47-0.7]; P=3.13E-05), AMY2A (α amylase 2A) (HR, 0.5496 [95% CI, 0.44-0.69]; P=0.0001), and DNASE1 (deoxyribonuclease-1) (HR, 0.5704 [95% CI, 0.46-0.71]; P=0.0002). Higher urinary levels of proteins involved in fibrosis (collagen VI α-1, collagen XV α-1), metabolism (pancreatic α-amylase 2A/B, mannosidase α class 1A member 1), and inflammation (heat shock protein family D member 1, inducible T cell costimulatory ligand) were associated with a lower risk of death or heart failure admission. CONCLUSIONS: Our study identifies several novel associations between urinary proteins/peptides and outcomes in heart failure with preserved ejection fraction. Many of these associations are independent of clinical risk scores and may aid in risk stratification in this patient population.

Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even in the presence of increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF and have been used as an inclusion criterion for several recent randomized clinical trials. However, the underlying biologic differences between HFpEF participants with high and low NT-proBNP levels remain to be fully understood. METHODS: We measured 4928 proteins using an aptamer-based proteomic assay (SOMAScan) in available plasma samples from 2 cohorts: (1) Participants with HFpEF enrolled in the PHFS (Penn Heart Failure Study; n=253); (2) TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) participants in the Americas (n=218). We assessed the relationship between SOMAScan-derived plasma NT-proBNP and levels of other proteins available in the SOMAScan assay version 4 using robust linear regression, with correction for multiple comparisons, followed by pathway analysis. RESULTS: NT-proBNP levels exhibited prominent proteome-wide associations in PHFS and TOPCAT cohorts. Proteins most strongly associated with NT-proBNP in both cohorts included SVEP1 (sushi, von Willebrand factor type-A, epidermal growth factor, and pentraxin domain containing 1; ßTOPCAT=0.539; P<0.0001; ßPHFS=0.516; P<0.0001) and ANGPT2 (angiopoietin 2; ßTOPCAT=0.571; P<0.0001; ßPHFS=0.459; P<0.0001). Canonical pathway analysis demonstrated consistent associations with multiple pathways related to fibrosis and inflammation. These included hepatic fibrosis and inhibition of matrix metalloproteases. Analyses using cut points corresponding to estimated quantitative concentrations of 360 pg/mL (and 480 pg/mL in atrial fibrillation) revealed similar proteomic associations. CONCLUSIONS: Circulating NT-proBNP levels exhibit prominent proteomic associations in HFpEF. Our findings suggest that higher NT-proBNP levels in HFpEF are a marker of fibrosis and inflammation. These findings will aid the interpretation of NT-proBNP levels in HFpEF and may guide the selection of participants in future HFpEF clinical trials.

Proteomic Associations of Adverse Outcomes in Human Heart Failure.

BACKGROUND: Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization. METHODS AND RESULTS: The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2-sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin-like modifier 2 (standardized hazard ratio [sHR], 1.56; P<0.0001), growth differentiation factor-15 (sHR, 1.68; P<0.0001) for death, A disintegrin and metalloproteinase with thrombospondin motifs-like protein (sHR, 1.40; P<0.0001), and pulmonary-associated surfactant protein C (sHR, 1.24; P<0.0001) for DHFA. In pathway analyses, top canonical pathways associated with death and DHFA included fibrotic, inflammatory, and coagulation pathways. Genomic analyses provided evidence of nominally significant associations between levels of 6 genetically predicted proteins with DHFA and 11 genetically predicted proteins with death. CONCLUSIONS: This study implicates multiple novel proteins in HF and provides preliminary evidence of associations between genetically predicted plasma levels of 17 candidate proteins and the risk for adverse outcomes in human HF.

Population health management in Belgium: a call-to-action and case study.

BACKGROUND: Although there are already success stories, population health management in Belgium is still in its infancy. A health system transformation approach such as population health management may be suited to address the public health issue of atherosclerotic cardiovascular disease, as this is one of the main causes of mortality in Belgium. This article aims to raise awareness about population health management in Belgium by: (a) eliciting barriers and recommendations for its implementation as perceived by local stakeholders; (b) developing a population health management approach to secondary prevention of atherosclerotic cardiovascular disease; and (c) providing a roadmap to introduce population health management in Belgium. METHODS: Two virtual focus group discussions were organized with 11 high-level decision makers in medicine, policy and science between October and December 2021. A semi-structured guide based on a literature review was used to anchor discussions. These qualitative data were studied by means of an inductive thematic analysis. RESULTS: Seven inter-related barriers and recommendations towards the development of population health management in Belgium were identified. These related to responsibilities of different layers of government, shared responsibility for the health of the population, a learning health system, payment models, data and knowledge infrastructure, collaborative relationships and community involvement. The introduction of a population health management approach to secondary prevention of atherosclerotic cardiovascular disease may act as a proof-of-concept with a view to roll out population health management in Belgium. CONCLUSIONS: There is a need to instill a sense of urgency among all stakeholders to develop a joint population-oriented vision in Belgium. This call-to-action requires the support and active involvement of all Belgian stakeholders, both at the national and regional level.

Treatment gaps in the implementation of LDL cholesterol control among high- and very high-risk patients in Europe between 2020 and 2021: the multinational observational SANTORINI study.

Background: European data pre-2019 suggest statin monotherapy is the most common approach to lipid management for preventing cardiovascular (CV) events, resulting in only one-fifth of high- and very high-risk patients achieving the 2019 ESC/EAS recommended low-density lipoprotein cholesterol (LDL-C) goals. Whether the treatment landscape has evolved, or gaps persist remains of interest. Methods: Baseline data are presented from SANTORINI, an observational, prospective study that documents the use of lipid-lowering therapies (LLTs) in patients ≥18 years at high or very high CV risk between 2020 and 2021 across primary and secondary care settings in 14 European countries. Findings: Of 9602 enrolled patients, 9044 with complete data were included (mean age: 65.3 ± 10.9 years; 72.6% male). Physicians reported using 2019 ESC/EAS guidelines as a basis for CV risk classification in 52.0% (4706/9044) of patients (overall: high risk 29.2%; very high risk 70.8%). However, centrally re-assessed CV risk based on 2019 ESC/EAS guidelines suggested 6.5% (308/4706) and 91.0% (4284/4706) were high- and very high-risk patients, respectively. Overall, 21.8% of patients had no documented LLTs, 54.2% were receiving monotherapy and 24.0% combination LLT. Median (interquartile range [IQR]) LDL-C was 2.1 (1.6, 3.0) mmol/L (82 [60, 117] mg/dL), with 20.1% of patients achieving risk-based LDL-C goals as per the 2019 ESC/EAS guidelines. Interpretation: At the time of study enrolment, 80% of high- and very high-risk patients failed to achieve 2019 ESC/EAS guidelines LDL-C goals. Contributory factors may include CV risk underestimation and underutilization of combination therapies. Further efforts are needed to achieve current guideline-recommended LDL-C goals. Trial registration: ClinicalTrials.gov Identifier: NCT04271280. Funding: This study is funded by Daiichi Sankyo Europe GmbH, Munich, Germany.

Proteomic Analysis of Effects of Spironolactone in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) suggested clinical benefits of spironolactone treatment among patients with heart failure with preserved ejection fraction enrolled in the Americas. However, a comprehensive assessment of biologic pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction has not been performed. METHODS: We conducted aptamer-based proteomic analysis utilizing 5284 modified aptamers to 4928 unique proteins on plasma samples from TOPCAT participants from the Americas (n=164 subjects with paired samples at baseline and 1 year) to identify proteins and pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction. Mean percentage change from baseline was calculated for each protein. Additionally, we conducted pathway analysis of proteins altered by spironolactone. RESULTS: Spironolactone therapy was associated with proteome-wide significant changes in 7 proteins. Among these, CARD18 (caspase recruitment domain-containing protein 18), PKD2 (polycystin 2), and PSG2 (pregnancy-specific glycoprotein 2) were upregulated, whereas HGF (hepatic growth factor), PLTP (phospholipid transfer protein), IGF2R (insulin growth factor 2 receptor), and SWP70 (switch-associated protein 70) were downregulated. CARD18, a caspase-1 inhibitor, was the most upregulated protein by spironolactone (-0.5% with placebo versus +66.5% with spironolactone, P<0.0001). The top canonical pathways that were significantly associated with spironolactone were apelin signaling, stellate cell activation, glycoprotein 6 signaling, atherosclerosis signaling, liver X receptor activation, and farnesoid X receptor activation. Among the top pathways, collagens were a consistent theme that increased in patients receiving placebo but decreased in patients randomized to spironolactone. CONCLUSIONS: Proteomic analysis in the TOPCAT trial revealed proteins and pathways altered by spironolactone, including the caspase inhibitor CARD18 and multiple pathways that involved collagens. In addition to effects on fibrosis, our studies suggest potential antiapoptotic effects of spironolactone in heart failure with preserved ejection fraction, a hypothesis that merits further exploration.

Clusters of risk factors in metabolic syndrome and their influence on central blood pressure in a global study.

The effect of metabolic syndrome (MetS) and clusters of its components on central blood pressure (CBP) has not been well characterized. We aimed to describe the effect of MetS and clusters of its components on CBP in a large population and to identify whether this effect differs in men and women. We studied 15,609 volunteers (43% women) from 10 cohorts worldwide who participated in the Metabolic syndrome and Artery REsearch Consortium. MetS was defined according to the NCEP-ATP III criteria (GHTBW, glucose, high-density lipoprotein cholesterol, triglyceride, blood pressure, waist circumference). CBP was measured noninvasively and acquired from pulse wave analysis by applanation tonometry. MetS was associated with a 50% greater odds of having higher CSBP. After controlling for age, male sex, non HDL cholesterol, diabetes mellitus, and mean arterial pressure, only specific clusters of MetS components were associated with a higher CSBP; and some of them were significant in women but not in men. We identified "risky clusters" of MetS variables associated with high CSBP. Future studies are needed to confirm they identify subjects at high risk of accelerated arterial aging and, thus, need more intensive clinical management.

Acute Effects of Cocoa Flavanols on Blood Pressure and Peripheral Vascular Reactivity in Type 2 Diabetes Mellitus and Essential Hypertension.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with a high risk of vascular complications. Interestingly, cocoa flavanols (CF) can exert beneficial vascular effects in non-diabetic subjects. However, these effects have only been scarcely studied in T2DM. Therefore, we performed a study to assess the effects on vascular reactivity of a single dose of CF (790 mg) in T2DM and whether certain antihypertensive drugs may modulate these effects. METHODS: 24 non-diabetic and 11 T2DM subjects were studied in a cross-over design. Fasting blood samples, blood pressure (BP), and arterial vasoreactivity (flow-mediated dilation) were assessed before and 70 min after capsule ingestion. Muscle microvascular reactivity was only assessed after capsule ingestion. Age, waist-to-hip ratio, BP at baseline, and the use of antihypertensive drugs were regarded as covariates in a mixed models analysis. RESULTS: CF ingestion did not affect any parameter. However, independent of the type of capsules ingested, a decrease in diastolic BP by 3 mmHg (95% CI: -4.0; -2.0) and an increase in the change in brachial artery diameter (pre vs. post occlusion) by 0.06 mm (95% CI: 0.01; 0.12) were detected in the non-diabetic group, while they remained unchanged in the T2DM group. CONCLUSION: No beneficial effects of CF were detected on vascular reactivity parameters in T2DM and non-diabetic participants.

Comparison of cerebral blood flow in subjects with and without chronic obstructive pulmonary disease from the population-based Rotterdam Study.

OBJECTIVES: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cerebrovascular disease, which might be associated with decreases in cerebral blood flow. Since studies examining cerebral blood flow in COPD remain scarce and are limited by sample size, we aimed to study cerebral blood flow in participants with and without COPD. DESIGN: Observational cohort study. SETTING: Population-based Rotterdam Study. PARTICIPANTS: 4177 participants (age 68.0±8.5 years; 53% females) with and without COPD. PREDICTOR VARIABLE: Spirometry and pulmonary diffusing capacity. OUTCOME MEASURES: Cerebral blood flow by two-dimensional phase-contrast cerebral MRI. RESULTS: Compared with subjects with normal spirometry (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ≥0.7 and FEV1 ≥80%), multivariable adjusted cerebral blood flow (mL/min) was preserved in subjects with COPD Global initiative for Chronic Obstructive Lung Disease (GOLD1) (FEV1/FVC <0.7 and FEV1 ≥80%), but significantly lower in subjects with COPD GOLD2-3 (FEV1/FVC <0.7 and FEV1 <80%), even after adjustment for cardiovascular comorbidities. In sex-stratified analyses, this difference in cerebral blood flow was statistically significant in women but not in men. Cerebral blood flow was lowest in subjects with FEV1, FVC and diffusion lung capacity for carbon monoxide % predicted values in the lowest quintile, even after adjustment for cardiovascular comorbidities and cardiac function. CONCLUSION: We observed a lowered cerebral blood flow in subjects with COPD GOLD2-3.

Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases.

Fibromuscular dysplasia (FMD) is an arteriopathy associated with hypertension, stroke and myocardial infarction, affecting mostly women. We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We find an estimate of SNP-based heritability compatible with FMD having a polygenic basis, and report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identifies one additional locus (SLC24A3). We characterize open chromatin in arterial primary cells and find that FMD associated variants are located in arterial-specific regulatory elements. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We find significant genetic overlap between FMD and more common cardiovascular diseases and traits including blood pressure, migraine, intracranial aneurysm, and coronary artery disease.

Acute Effects of Cocoa Flavanols on Blood Pressure and Peripheral Vascular Reactivity in Type 2 Diabetes Mellitus and Essential Hypertension: A Protocol for an Acute, Randomized, Double-Blinded, Placebo-Controlled Cross-Over Trial.

Introduction: Patients with type 2 diabetes mellitus are at high risk to develop vascular complications resulting in high morbidity and mortality. Cocoa flavanols are promising nutraceuticals with possible beneficial vascular effects in humans. However, limited research is currently available on the vascular effects in a diabetic population with inconsistent results. Possible reasons for this inconsistency might be heterogeneity in the given intervention (dose per time and day, single dose vs. split-dose, placebo formula) and the studied population (blood pressure at baseline, duration of diabetes, use of vasoactive antihypertensive and antidiabetic drugs, sex). Therefore, we aimed to develop a randomized, double-blinded, placebo-controlled cross-over trial to investigate whether cocoa flavanols have an acute impact on blood pressure and vascular reactivity in patients with type 2 diabetes with and without arterial hypertension. Methods and Analysis: We will include participants in four groups: (i) patients with type 2 diabetes without arterial hypertension, (ii) patients with type 2 diabetes with arterial hypertension and 1 antihypertensive drug, (iii) non-diabetic participants with essential hypertension and 1 antihypertensive drug, and (iv) healthy controls. All participants will complete the same protocol on both testing days, consuming high-flavanol cocoa extract (790 mg flavanols) or placebo. Macrovascular endothelial function (flow-mediated dilation) and blood pressure will be measured before and after capsule ingestion. Forearm muscle vasoreactivity (near-infrared spectroscopy) and brachial artery blood flow (echo-doppler) will be assessed in response to a dynamic handgrip exercise test after capsule ingestion. Data will be analyzed with a random intercept model in mixed models. Clinical Trial Registration: www.Clinicaltrials.gov, identifier: NCT03722199.

Quantitative Proteomic Analysis of Diabetes Mellitus in Heart Failure With Preserved Ejection Fraction.

Diabetes mellitus (DM) is associated with a higher risk of heart failure hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Using SomaScan assays and proteomics analysis of plasma from participants in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial and the Penn Heart Failure Study, this study identified 10 proteins with significantly different expression in patients with HFpEF and DM. Of these, apolipoprotein M was found to mediate 72% (95% CI: 36% to 100%; p < 0.001) of the association between DM and the risk of cardiovascular death, aborted cardiac arrest, and heart failure hospitalization.

Sex differences in the association between arterial hypertension, blood pressure, and sleep apnea in the general population.

STUDY OBJECTIVES: To assess sex-related differences in the relationship between hypertension (HT), blood pressure (BP), and sleep apnea in the general population. METHODS: We performed home polygraphy in a cohort of 1809 men and women in the general population. Office BP was measured. Presence of HT (drug-treated, physician-diagnosed, or high BP during study visit) was also recorded. HT rate and BP were assessed over a range of 7 sleep apnea severity categories based on the respiratory event index (REI). RESULTS: The age-adjusted HT prevalence rate increased with higher REI in both sexes. After additional adjustment for obesity the association remained significant in women but not in men. In participants not treated with antihypertensive medications, age-adjusted BP increased with REI. Remarkably, the association was already significant within the normal range (REI < 5 events/h). The REI threshold for higher BP was situated at a distinctly lower cutoff point in women compared to men. After additional adjustment for obesity, the associations remained significant for diastolic but not systolic BP. CONCLUSIONS: Significant increases in the age-adjusted BP and HT rate in the general population were present at lower REI cutoffs in women compared to men. Even a very low number of respiratory events was associated with higher BP and HT prevalence. Adjustment for obesity attenuated these associations, especially in men. Sex differences in BP susceptibility across the sleep apnea spectrum may be present.

Longitudinal Changes of Input Impedance, Pulse Wave Velocity, and Wave Reflection in a Middle-Aged Population: The Asklepios Study.

[Figure: see text].

Feasibility and cost of FH cascade screening in Belgium (BEL-CASCADE) including a novel rapid rule-out strategy.

BACKGROUND: Familial hypercholesterolaemia (FH) is underdiagnosed in most countries. We report our first experience from a national pilot project of cascade screening in relatives of FH patients. METHODOLOGY: Participating specialists recruited consecutive index patients (IP) with Dutch Lipid Clinic Network (DLCN) score ≥6. After informed consent, the relatives were visited by the nurses to collect relevant clinical data and perform blood sampling for lipid profile measurement. FH diagnosis in the relatives was based on the DLCN and/or MEDPED FH (Make-Early-Diagnosis-to-Prevent-Early-Deaths-in-FH) criteria. RESULTS: In a period of 18 months, a total of 127 IP (90 with definite FH and 37 with probable FH) were enrolled in 15 centres. Out of the 270 relatives visited by the nurses, 105 were suspected of having FH: 31 with DCLN score >8, 33 with DLCN score 5-8 and 41 with MEDPED FH criteria. In a post-hoc analysis, another set of MEDPED FH criteria established in the Netherlands and adapted to Belgium allowed to detect FH in 51 additional relatives. CONCLUSION: In a country with no national FH screening program, our pilot project demonstrated that implementing a simple phenotypical FH cascade screening strategy using the collaboration of motivated specialists and two nurses, allowed to diagnose FH in 127 index patients and an additional 105 of their relatives over the two-year period. Newly developed MEDPED FH cut-offs, easily applicable by a nurse with a single blood sample, might further improve the sensitivity of detecting FH within families.

Evaluation of contemporary treatment of high- and very high-risk patients for the prevention of cardiovascular events in Europe - Methodology and rationale for the multinational observational SANTORINI study.

Background and aims: Clinical practice before 2019 suggests a substantial proportion of high and very high CV risk patients taking lipid-lowering therapy (LLT) would not achieve the new LDL-C goals recommended in the 2019 ESC/EAS guidelines (<70 and < 55 mg/dL, respectively). To what extent practice has changed since the last ESC/EAS guideline update is uncertain, and quantification of remaining implementation gaps may inform health policy. Methods: The SANTORINI study is a multinational, multicentre, prospective, observational, non-interventional study documenting patient data at baseline (enrolment) and at 12-month follow-up. The study recruited 9606 patients ≥18 years of age with high and very high CV risk (as assigned by the investigators) requiring LLT, with no formal patient or comparator groups. The primary objective is to document, in the real-world setting, the effectiveness of current treatment modalities in managing plasma levels of LDL-C in high- and very high-risk patients requiring LLT. Key secondary effectiveness objectives include documenting the relationship between LLT and levels of other plasma lipids, high-sensitivity C-reactive protein (hsCRP) and overall predicted CV risk over one year. Health economics and patient-relevant parameters will also be assessed. Conclusions: The SANTORINI study, which commenced after the 2019 ESC/EAS guidelines were published, is ideally placed to provide important contemporary insights into the evolving management of LLT in Europe and highlight factors contributing to the low levels of LDL-C goal achievement among high and very high CV risk patients. It is hoped the findings will help enhance patient management and reduce the burden of ASCVD in Europe.

Abnormal Aortic Wall Properties in Women with Turner Syndrome.

BACKGROUND: Turner syndrome (TS) is associated with aortic dilatation and dissection, but the underlying process is unclear. The aim of this study was to investigate the elastic properties and composition of the aortic wall in women with TS. METHODS: In this cross-sectional study, 52 women with TS aged 35 ± 13 years (50% monosomy, 12 with bicuspid aortic valve [BAV] and 4 with coarctation) were investigated using carotid-femoral pulse wave velocity (CF-PWV) by echocardiography and ascending aortic distensibility (AAD) and aortic arch pulse wave velocity (AA-PWV) by magnetic resonance imaging (MRI). As control group, 13 women with BAV without TS and 48 healthy patients were included. RESULTS: Women with TS showed a higher AA-PWV (ß = 1.08, confidence interval [CI]: 0.54-1.62) after correcting for age and comorbidities compared with controls. We found no significant difference in AAD and CF-PWV. In women with TS, the presence of BAV, coarctation of the aorta, or monosomy (45, X) was not associated with aortic stiffness. In addition, aortic tissue samples were investigated with routine and immunohistochemical stains in five additional women with TS who were operated. The tissue showed more compact smooth muscle cell layers with abnormal deposition and structure of elastin and diminished or absent expression of contractile proteins desmin, actin, and caldesmon, as well as the progesterone receptor. CONCLUSION: Both aortic arch stiffness measurements on MRI and histomorphological changes point toward an inherent abnormal thoracic aortic wall in women with TS.

Impact of varying diastolic pressure fitting technique for the reservoir-wave model on wave intensity analysis.

The reservoir-wave model assumes that the measured arterial pressure is made of two components: reservoir and excess. The effect of the reservoir volume should be excluded to quantify the effects of forward and backward traveling waves on blood pressure. Whilst the validity of the reservoir-wave concept is still debated, there is no consensus on the best fitting method for the calculation of the reservoir pressure waveform. Therefore, the aim of this parametric study is to examine the effects of varying the fitting technique on the calculation of reservoir and excess components of pressure and velocity waveforms. Common carotid pressure and flow velocity were measured using applanation tonometry and doppler ultrasound, respectively, in 1037 healthy humans collected randomly from the Asklepios population, aged 35 to 55 years old. Different fitting techniques to the diastolic decay of the measured arterial pressure were used to determine the asymptotic pressure decay, which in turn was used to determine the reservoir pressure waveform. The corresponding wave speed was determined using the PU-loop method, and wave intensity parameters were calculated and compared. Different fitting methods resulted in significant changes in the shape of the reservoir pressure waveform; however, its peak and time integral remained constant in this study. Although peak and integral of excess pressure, velocity components and wave intensity changed significantly with changing the diastolic decay fitting method, wave speed was not substantially modified. We conclude that wave speed, peak reservoir pressure and its time integral are independent of the diastolic pressure decay fitting techniques examined in this study. Therefore, these parameters are considered more reliable diagnostic indicators than excess pressure and velocity which are more sensitive to fitting techniques.