Median Low-density Lipoprotein Cholesterol Research Articles

Circulating Endothelial Progenitor Cells in Patients with Established Cardiovascular Disease Treated with PCSK9 Monoclonal Antibodies

BackgroundThe role of circulating endothelial progenitor cells (cEPCs) in vascular repair and their association to cardiovascular protection is well established. ObjectivesWe examined the effect of proprotein convertase subtilisin kexin type 9 monoclonal antibodies (PCSK9 mAb) on cEPCs in adults with hypercholesterolemia and cardiovascular disease, aiming to establish a pleotropic class effect. MethodsNon-interventional prospective study in patients with cardiovascular disease treated with either evolocumab or alirocumab. Patients were sampled for cEPCs at baseline, 1- and 3-months following initiation of PCSK9 mAb. cEPCs were assessed using flow cytometry by expression of CD34/CD133 and vascular endothelial growth factor receptor (VEGFR)-2, and functionally by formation of colony forming units (CFUs) and by Mitochondrial Tetrazolium (MTT) assay, indicative of cEPCs viability. Results51 patients (median age 67 (IQR 63,74) years;63 % male, median low-density lipoprotein-cholesterol (LDL-C) 125 (102,165) mg/dL) were initiated on PCSK9 mAb therapy (evolocumab n = 22, alirocumab n = 29) for secondary prevention. Following 3-month treatment with PCSK9 mAb, there was an increase in CD34(+)VEGFR-2(+) and CD133(+)VEGFR-2(+) levels (0.50 % [IQR 0.30,1.04] to 1.36 % [0.89, 1.73], p < 0.001 and 0.57 % [0.25,0.88] to 1.18 % [0.74,1.66], p < 0.001, respectively). Functionally, increase in EPCs-CFUs was evident (0.5 [0.0,1.0] to 2.0 [1.5,2.5], p < 0.001) with concomitant increase in MTT (0.11 [0.09,0.15] to 0.17 [0.12,0.21], p < 0.001). Stratifying by PCSK9 mAb, both agents were associated with an increase in cEPCs level and function. ConclusionsIn hypercholesterolemic patients with cardiovascular disease treated with PCSK9 mAb, there is an increase in cEPCs levels and function from baseline levels. These findings, which persist in both evolocumab and alirocumab, might suggest a novel pleiotropic class effect.

Unveiling the metabolic challenges in pulmonary arterial hypertension: Insights into thyroid, glycemic, lipid, and bone disorders

This study aimed to evaluate the prevalence of thyroid, glycemic, lipid and metabolic bone disorders among adult patients with pulmonary arterial hypertension (PAH). MethodsThis was an observational cross-sectional clinical study with patients with PAH, matched by sex and age with a control group without PAH. All individuals were enrolled into a clinical assessment, metabolic workup, thyroid ultrasound, and bone densitometry protocol. ResultsThe PAH group included 35 participants (34 females, 46 ± 15.5 years), and the control group, 40 (39 females, 41.8 ± 13.1 years). There was no difference in body mass index (BMI) between PAH and control group (27.5 ± 5.9 and 26.9 ± 4.3 kg/m2, respectively, p = 0.63; 95 % CI: −1.8, 2.94), neither in physical activity time per week (60.3 ± 103.3 and 98.9 ± 137.6, respectively, p = 0.17; 95 % CI: −95.23, 18.06). Although there was no difference in the prevalence of insulin resistance between the PAH (51.4 %) and the control group (47.5 %), p = 0.74, patients with PAH had a higher median of glycated hemoglobin (A1c) than the control group (6.1 % and 5.57 %, respectively, p = 0.006; 95 % CI: −0.14, 1.22). PAH group presented lower mean total cholesterol (170.46 ± 35.51 mg/dL) and median LDL-cholesterol [105 (83–129) mg/dL, median (P25–P75)] levels than the control group [192.1 ± 34.44 mg/dL, p = 0.009; 95 % CI = −37.76, 5.52 and 121.6 (97–145) mg/dL, p = 0.012; 95 % CI: −34.08, 0.77, respectively]. It was found a higher prevalence of hypothyroidism (22.9 %) in PAH group than in control group (2.5 %), p = 0.007. We found hyperparathyroidism (HPT) among 8 patients of PAH group (23 %), but none in the control group. Considering bone mineral density disorders, 12 patients from PAH group presented low bone mass, osteopenia, or osteoporosis (34 %), and 8 individuals in the control group (20 %), p = 0.032, which represented a 2.13 higher relative risk for those conditions for the former group. The patients with HPT presented a higher creatinine level (0.98 ± 0.12 mg/dL) than the PAH patients with normal parathyroid hormone (0.76 ± 0.14 mg/dL), p = 0.0004; 95 % CI: 0.12, 0.33. The PAH group also presented lower total hip (-0.15 ± 1.25) and femoral neck (−0.14 ± 1.07) bone mineral density (BMD) Z-scores than the control group (0.50 ± 1.13, p = 0.021; 95 % CI: −0.18, −0.027 and 0.35 ± 0.94, p = 0.038; 95 % CI: −0.16, −0.01, respectively). ConclusionIn this cohort, the findings of higher A1c levels, hypothyroidism prevalence, lower LDL and total cholesterol levels, and a higher prevalence of hyperparathyroidism, as well as lower total hip and femoral neck BMD Z-scores in the PAH group, compared to the control group and highlighting the dysregulation of various metabolic pathways in patients with HAP, suggesting the need for targeted interventions to enhance patient care. Additionally, they underscore the importance of gaining a deeper understanding of the mechanisms driving these changes and their potential pathophysiological connections to the disease.

Abstract 4113942: Validation of Changes in the Cutoff Values of Achilles Tendon Thickness on Radiography in the Clinical Criteria of Heterozygous Familial Hypercholesterolemia in Japan

Background: To increase sensitivity and maintain specificity, the 2022 Japan Atherosclerosis Society familial hypercholesterolemia (FH) clinical criteria was modified. In particular, the cutoff value of Achilles tendon thickness (ATT) on radiography was changed from ≥9 mm in both men and women to ≥8.0 mm in men and ≥7.5 mm in women. The current study aimed to validate the efficacy of this modification in independent samples. Methods: Patients with FH were retrospectively reviewed. The proportions of patients with pathogenic FH mutation who had an ATT of &lt;7.5/8.0 mm (group 1), ≥7.5/8.0 and &lt;9.0 mm (group 2), and ≥9 mm (group 3) were assessed. Results: In total, 492 patients were included in group 1, 102 in group 2, and 263 in group 3. Approximately 14.0%, 55.9%, and 79.8% of patients in groups 1, 2, and 3, respectively, exhibited FH mutation. Further, 37.3%, 77.3%, and 86.5% of patients with a low-density lipoprotein cholesterol level of ≥180 mg/dL in groups 1, 2, and 3, respectively, harbored FH mutation. Moreover, the median low-density lipoprotein cholesterol levels (157, 182, and 253 mg/dL, respectively) and the proportion of patients with protein-truncating mutation (3.8%, 16.7%, and 53.2%, respectively) had a significant trend. Conclusions: There was a substantial number of patients with FH who had an ATT of ≥7.5/8.0 and &lt;9.0 mm. These patients previously had a deferred diagnosis of FH. However, they were diagnosed with FH based on the new clinical guideline.

Inflammation and cholesterol associated residual cardiovascular risk and its dependence on chronic kidney disease in statin treated patients with coronary artery disease

Abstract Background/Aim In statin-treated patients with chronic coronary syndrome (CCS) there is uncertainty about the relative contribution of inflammation and dyslipidaemia to residual cardiovascular risk, particularly in the presence of chronic kidney disease. We thus aimed to evaluate high sensitive C-reactive protein (hsCRP) and low density lipoprotein-cholesterol (LDL-C) as predictors of future events in these patients, stratified by estimated glomerular filtration rate (eGFR). Methods We identified patients with CCS on stable statin treatment from a contemporary all-comers cohort recruited at a large tertiary care center in Germany. We excluded patients with active malignancy, infectious disease or in a post-operative state. Cox regression for major adverse cardiovascular events (MACE, composite of cardiovascular death, myocardial infarction, stroke) and all-cause death was performed adjusting for age, sex, arterial hypertension, diabetes mellitus, active smoking, body mass index and change in the intensity of statin therapy at discharge, with log(hsCRP) or LDL-C as the exposure variables. Interaction with eGFR (&amp;lt; vs. ≥ 60 ml/min/1.73m²) was investigated. Results 937 patients with CCS (mean age 71.1 years, 78.7% male, median hsCRP 2.0 mg/L, median LDL-C 73.0 mg/dl, median eGFR 71.3 ml/min/1.73m²) were followed-up over 4 years, with 101 cases of MACE and 171 cases of all-cause death recorded. The hazard ratios (HR) for MACE per standard deviation (SD) increase were as follows: log(hsCRP) 1.08 (95% confidence interval (CI) 0.87, 1.34; p = 0.48), LDL-C 1.10 (95% CI 0.89, 1.35; p = 0.37). For all-cause death the HRs for log(hsCRP) and LDL-C were 1.60 (95% CI 1.36, 1.88; p &amp;lt;0.001) and 0.88 (95% CI 0.74, 1.04; p = 0.14), respectively. Kaplan-Meier curves stratifying the cohort by median values of LDL-C and hsCRP consistently demonstrated a significantly higher risk of death in the subgroups with elevated hsCRP (Figure 1). Contrastingly for LDL-C, levels below (vs. above) the median were associated with a higher mortality rate. This is in part a reflection of a higher prevalence of high-intensity statin therapy in this subgroup (21.0 vs. 14.2%, p = 0.0081), in turn a reflection of greater severity of coronary artery disease (history of myocardial infarction 43.9 vs. 31.9%, p &amp;lt;0.001). Further confounding by unadjusted for diseases with a catabolic metabolism is possible. Interaction analysis with eGFR revealed that log(hsCRP) was predictive of all-cause mortality both in the presence and absence of chronic kidney disease, whilst lower LDL-C values were found to be predictive only at eGFR &amp;lt;60 ml/min/1.73m² (Table 1). Conclusion Residual inflammation as measured by hsCRP predicts all-cause mortality in statin-treated patients with CCS in this contemporary all-comers cohort, both in the presence and absence of chronic kidney disease. The predictive utility of LDL-C is limited, likely due to confounding e.g. by the intensity of lipid lowering medication.Kaplan-Meier curves (all-cause death)Interaction analysis with eGFR

Global burden of high-risk cardiovascular patients without prior myocardial infarction or stroke: VESALIUS-REAL - preliminary results from Germany

Abstract Background Clinical trial data has shown that low-density lipoprotein cholesterol (LDL-C) lowering with PCSK9-inhibitors reduced cardiovascular (CV) endpoints in patients with established atherosclerotic cardiovascular disease (ASCVD). Intervening early in patients with high CV risk prior to myocardial infarction (MI) or stroke, while perceived to be less urgent, may result in larger public health benefits. The effect of evolocumab in this population is investigated in a phase-3 clinical trial (NCT03872401: Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke [VESALIUS-CV]). This observational study examines the global burden of VESALIUS-CV-like population in the REAL-World ("VESALIUS-REAL") in eight regions (Germany, Hong Kong, Japan, South Korea, Sweden, Taiwan, UK and US) using a unified protocol across multiple databases. The multi-database study is ongoing, and the current analysis focuses on characteristics of VESALIUS-CV like patients in Germany. Methods Eligibility criteria are shown in the Figure. Data were obtained from the German Disease Analyzer (2013-2022), a representative claims database from Germany. Criteria were aligned with the clinical trial, and real-world definitions were created using diagnosis and procedure codes. Results A total of 195,621 patients were included in the present analysis (Table). At baseline, the median age was 71 years (Q1-Q3: 64-79) and 48% of patients were women. Approximately two-thirds of patients had atherosclerosis (48.5% had coronary artery disease, 13.8% had cerebrovascular disease and 13.8% had peripheral artery disease) and 33.7% had high-risk diabetes mellitus (DM), defined as DM with microvascular complications or chronic insulin use. The median baseline LDL-C was 139 (Q1-Q3: 113-166) mg/dL [3.6 (2.9 - 4.3) mmol/L] and 110,867 patients (57%) had an LDL-C ≥130 mg/dL (≥3.4 mmol/L). Overall, 69% of VESALIUS-CV like patients were receiving no background LLT. Conclusions Despite having atherosclerosis and/or high-risk DM and LDL-C exceeding target thresholds, a large proportion of VESALIUS-CV like patients were not on any LLT in Germany. Final results from VESALIUS-REAL will be able to report if this treatment gap is also observed in other countries.

Lipid-lowering therapy with Inclisiran in the real-world setting: initial data from a national health care service

Abstract Introduction Inclisiran, a first-in-class siRNA enabling long-term inhibition of PCSK9 synthesis, demonstrates good safety and efficacy profile in randomized clinical trials. Challenges for real-life use of inclisiran include limited access to therapy, injections by medical staff, lack of cardiovascular outcome data, and concern from adverse effects considering the novel mechanism and long-term activity. Real-life data on the potential to attain lipid-goals and reduce treatment gaps is lacking. We investigated the implementation of inclisiran in real-world clinical setting in Israel. Methods Data from a nationwide healthcare organization on patients initiating inclisiran therapy during the period of 3/2022-11/2023. Patients’ characteristics, efficacy, use of combination lipid-lowering therapies, and attainment of low-density lipoprotein cholesterol (LDL-C) goals, were evaluated. Results Inclisiran was initiated by 503 patients (57% women; mean age 66±11 years). Atherosclerotic cardiovascular disease was present in 54%, and peak historical LDL-C levels &amp;gt;190 mg/dL documented in 64%. Prior exposure to PCSK9 monoclonal antibodies was evident in 28%. Follow-up lipid profile &amp;gt;2 months after filling first prescription, was available in 397 patients (347 with ≥2 injections). In patients treated by inclisiran only (n=254), median LDL-C reduction from peak historical levels was 57% (IQR, 48%-67%), and from pre-injection levels 40% (19%-54%). In those with concomitant oral lipid-lowering therapies (n=143), median LDL-C reduction from peak levels was 66% (IQR, 55%-73%), and from pre-injection levels 46% (23%-59%) (Figure). LDL-C &amp;lt;70 mg/dL was attained by 39% and LDL-C &amp;lt;55 mg/dL by 21.9%. Of those treated with concomitant statin therapy, 38% attained LDL-C &amp;lt;55 mg/dL. Overall, 6.5% did not persist with inclisiran therapy after initial injection. Conclusions In real-life practice, inclisiran showed good efficacy with positive short-term adherence. However, attainment rates of lipid-goals were suboptimal due to limited use of combination lipid-lowering therapy and high-rates of severe hypercholesterolemia in our patient population cohort.Waterfall Plot of LDL-C (%) Reduction

The high-dose statin treatment reduces neutrophil extracellular traps formation in patients with coronary artery disease

Abstract Background Neutrophil extracellular traps formation (NETosis) is currently considered as an important mediator in atherosclerosis and atherothrombosis. However, the impact of high-dose statin treatment, as potent cholesterol-lowering agents with pleiotropic effects, on NETosis in coronary artery disease (CAD) has been poorly described. Purpose We sought to assess whether in CAD patients the recommended statin treatment intensification is associated with changes in NETs-related markers and if such changes can alter fibrin clot properties. Methods 130 patients with advanced CAD, who did not achieve the target low-density lipoprotein cholesterol (LDL-C) were included. Before and at least 6 months after initiation of high-dose statin therapy (rosuvastatin 40 mg/d or atorvastatin 80 mg/d) citrullinated histone H3 (H3cit), myeloperoxidase (MPO) and neutrophil elastase (NE) as markers associated with NETosis were assessed in relation to C-reactive protein (CRP), thrombin generation, plasma clot permeability (Ks), clot lysis time (CLT), and fibrinolysis proteins. Results At baseline, NETosis did not differ depending on gender and cardiovascular risk factors but H3cit correlated with MPO (R=0.543, P&amp;lt;0.001) and CRP (R=0.540, P&amp;lt;0.001). All NETosis markers were inversely correlated with Ks. Median LDL-C reduction by 25% (P&amp;lt;0.001) on high-dose statin treatment was independent from H3cit reduction by 30.4%, MPO by 28.1%, and NE by 25.5% (in all P&amp;lt;0.001, Figure 1). The ΔH3cit and ΔMPO, but not ΔNE were associated with ΔCRP (R=0.855, P&amp;lt;0.001; R=0.250, P=0.004, respectively), Δthrombin activatable fibrinolysis inhibitor (TAFI) (R=0.385, P&amp;lt;0.001; R=0.245, P=0.005), and inversely with ΔKs (R=-0.315, P&amp;lt;0.001; R=-0.395, P=0.001). In multivariable analysis the H3cit decrease was independently associated with ΔCRP (β=0.771, P&amp;lt;0.001), ΔTAFI (β=0.125, P=0.013) and Δfibrinogen (β=0.106, P=0.034) but not with ΔLDL-C. Conclusions As has been shown for the first time high-dose statin treatment reduces levels of NETs-related markers, regardless of lipid-lowering effect in CAD patients.

Unveiling homozygous familial hypercholesterolemia in Greece: a comprehensive analysis of baseline traits and LDL goal achievement in adults from the HELLAS-FH Registry

Abstract Background Homozygous familial hypercholesterolemia (HoFH) is a severe genetic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) levels. This study aimed to analyze demographic characteristics, lipid profile, and rate in achieving LDL-C targets in adult HoFH patients in Greece. Methods This is a cross-sectional analysis of the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). Adults with genetically or clinically diagnosed HoFH were included. Median LDL-C levels were assessed during HoFH diagnosis and enrollment. Results Seventeen HoFH adults (mean age 41 years and mean age at diagnosis 31 years, men 58.8%). Genetic confirmation of HoFH was available in 10 patients, while the remaining were diagnosed based on clinical criteria. Family history of atherosclerotic cardiovascular disease was documented in 70.5% of patients. Clinical presentations varied, with 47.0% exhibiting tendon xanthomas, 17.6% xanthelasmas, 23.5% corneal arcus, and 52.9% premature coronary artery disease (CAD). Predominant treatment involved statins (88.2%), ezetimibe (58.8%),PCSK9i (23.5%), lomitapide (29.4%), while LDL apheresis was utilized in 23.5%. Median LDL-C levels were 407 mg/dL (10.53 mmol/L) at diagnosis and 226 mg/dL (5.84 mmol/L) at enrollment. None of the patients achieved the LDL-C target set by the 2019 EAS/ESC Guidelines. Conclusion The challenges of delayed diagnosis, undertreatment, and unattained LDL-C targets persist in HoFH management in Greece, emphasizing the critical need for effective lipid-lowering interventions to mitigate cardiovascular risk.

Lipid-lowering therapy after acute coronary syndromes: a multinational European survey.

Recent guidelines on acute coronary syndromes (ACS) recommend initiating lipid-lowering therapy (LLT) as early as possible to obtain >50% low-density-lipoprotein cholesterol (LDL-c) reduction and an LDL-c < 1.4 mmol/l. A multinational European survey study of ACS patients between 2021-2022 and acquired data on LLT and lipid levels on admission and during 1-year posthospitalization. We compared plasma lipid changes and adherence to post-ACS lipid targets across two in-hospital LLT groups: high-intensity statin (HIS) monotherapy (mono-HIS) and a combination of HIS and ezetimibe (combo-HIS). Of 286 patients, 268 (94%) received in-hospital HIS and were included in the final analysis. Patients (median age: 61.1 years) had a median baseline LDL-c of 3.3 mmol/l. Mono-HIS was the predominant in-hospital LLT (72.4%). In-hospital combo-HIS was administered in 27.6% of the cases. Patients from high-income countries (n = 141) were more likely to receive in-hospital combo-HIS than patients from middle-income countries [n = 127; 38.3% vs. 15.7% patients, P < 0.001). One-year post-ACS, 50 (26.5%) patients from the mono-HIS group received ezetimibe. The target of LDL-c ≤ 55 mg/dl was reached in 85 patients (31.7%), without significant difference between study groups [mono-HIS: 56 (28.9%) and combo-HIS: 29 (39.2%) patients, P = 0.10]. The target of >50% reduction was achieved more frequently among the combo-HIS group than in the mono-HIS group (50.0% vs. 29.9%, respectively, P = 0.002). LDL-c targets were achieved in less than half of the patients post-ACS, regardless of the LLT regimen. Combo-HIS was initiated in-hospital post-ACS in only 28% and was associated with greater LDL-c reduction compared to a staged approach of mono-HIS with up-titration at follow-up.

Is lipoprotein(a) measurement important for cardiovascular risk stratification in children and adolescents?

BackgroundElevated lipoprotein (Lp(a)) levels are associated with increased risk of atherosclerotic processes and cardiovascular events in adults. The amount of Lp(a) is mainly genetically determined. Therefore, it is important to identify individuals with elevated Lp(a) as early as possible, particularly if other cardiovascular risk factors are present. The purpose of the study was to investigate whether, in a population of children and adolescents already followed for the presence of one or more cardiovascular risk factors (elevated blood pressure (BP), and/or excess body weight, and/or dyslipidemia), the measurement of Lp(a) can be useful for better stratifying their risk profile.MethodsIn a sample of 195 children and adolescents, height, body weight, waist circumference and systolic (SBP) and diastolic (DBP) BP were measured. Body Mass Index (BMI) and SBP and DBP z-scores were calculated. Plasma Lp(a), total cholesterol, high-density lipoprotein (HDL), triglycerides, glucose, insulin, uric acid and creatinine were assessed. Low-density lipoprotein (LDL) cholesterol was calculated with the Friedewald formula. High Lp(a) was defined as ≥ 75 nmol/L and high LDL cholesterol as ≥ 3.37 mmol/L.ResultsOur sample of children and adolescents (54.4% males, mean age 11.5 years) had median LDL cholesterol and Lp(a) values equal to 2.54 (interquartile range, IQR: 2.07–3.06) mmol/L and 22 (IQR: 7.8–68.6) nmol/L respectively. 13.8% of children had LDL cholesterol ≥ 3.37 mmol/L and 22.6 Lp(a) values ≥ 75 nmol/L. Lp(a) values were higher in children of normal weight than in those with excess weight (p = 0.007), but the difference disappeared if normal weight children referred for dyslipidemia only were excluded from the analysis (p = 0.210). 69.4% of children had normal Lp(a) and LDL cholesterol values and only 6.2% showed both elevated Lp(a) and LDL cholesterol levels. However, 16.6% of the sample, despite having normal LDL cholesterol, had elevated Lp(a) values. Multivariable analyses showed a significant association of LDL cholesterol both with Lp(a) values, and with the presence of elevated Lp(a) levels. For each mmol/L increase in LDL cholesterol the risk of having an elevated Lp(a) value increased by 73%. There was an inverse correlation between BMI z-score and Lp(a). Neither BP z-scores, nor other biochemical parameters were associated with Lp(a).ConclusionsIn our population more than one out of five children had elevated Lp(a) values, and in about 17% of children elevated Lp(a) values were present in the absence of increased LDL cholesterol. Our results suggest that Lp(a) measurement can be useful to better define the cardiovascular risk profile in children and adolescents already followed for the presence of other cardiovascular risk factors such as elevated BP, excess body weight and high LDL cholesterol.

The therapeutic effect of liver transplantation in 14 children with homozygous familial hypercholesterolemia: a prospective cohort: Liver transplant for familial hypercholesterolemia

ObjectivesHomozygous familial hypercholesterolemia (HoFH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and early-onset cardiovascular disease. To assess the therapeutic effects of liver transplantation (LT) on HoFH patients, we observed and analyzed the outcomes of HoFH children after LT. Study designThis prospective cohort study included all LT candidates under 18 years old diagnosed with HoFH at Ren Ji Hospital between November 2017 and July 2021. The patients were followed until October 2023. They were treated according to the standard protocol at our center. We collected data on changes in lipid profiles, clinical manifestations, and cardiovascular complications at different time points, and recorded postoperative recipient and graft survival. ResultsFourteen HoFH patients with a median age of 7 (2-12) years were included. Preoperatively, xanthomas and arcus corneas occurred in 14 and 3 patients, respectively, with 10 patients showing mild cardiovascular disease. All patients underwent LT. Recipient and graft survival rates were 100 % over a median follow-up duration of 35 (27-71) months. Median LDL-C levels dropped from 11.83 (7.99-26.14) mmol/L preoperatively to 2.3 (1.49-3.39) mmol/L postoperative at the last measurement. Thirteen patients discontinued lipid-lowering treatment after LT, while only one patient resumed statins 6 months post-operation. Xanthomas and arcus corneas significantly improved. Cardiovascular complications regressed in five patients, with no progression observed in the others. ConclusionsLT is a safe and effective treatment for severe HoFH patients beyond lipid-lowering control. Early LT improves prognosis and quality of life while minimizing the risk of cardiovascular complications.

MANAGING LIPID LEVELS IN THE LIFE-LONG REHABILITATION OF PATIENTS WITH CORONARY ARTERY DISEASE

Cardiac rehabilitation includes secondary prevention of cardiovascular events. Since the level of LDL cholesterol, which is an important risk factor for cardiovascular events, had been shown to be insufficiently controlled in persons included in the third phase of cardiac rehabilitation in the Coronary Club of Ljubljana, we aimed to explore if an additional educational program would improve the control of blood lipids and self-management ability in these subjects. Members of the Coronary Club of Ljubljana were invited to join a ten-month structured program for the management of cardiovascular risk factors with an emphasis on lipid control. Participation in the program activities was optional. A total of 146 subjects were enrolled. During the study, a slight decrease was seen in the following parameters: total cholesterol, HDL cholesterol, triglycerides and glycated haemoglobin (p&lt;0.05). In the whole group of participants, the median LDL cholesterol level decreased from 2.5 mmol/L (interquartile range [IQR], 1.8-3.4) to 2.2 mmol/L (IQR, 1.7-3.5), but the difference was not statistically significant (p=0.081), while in the participants who attended individual consultations or workshops, a significant decrease in LDL cholesterol levels was observed. At the beginning of the study, very high-risk patients had higher activation, indicated with higher median baseline Patient Activation Measure (PAM) score, than high-risk patients (60.6 versus 55.6). During the study, the median PAM score increased in high-risk patients (from 55.6 to 60.6), but not in very high-risk patients. Thus, an additional educational program can improve lipid control and patient activation in subjects included in the third phase of cardiac rehabilitation.

Low-Density Lipoprotein Cholesterol, Cardiovascular Disease Risk, and Mortality in China

Limited evidence supports the association between low-density lipoprotein cholesterol (LDL-C) and mortality across different atherosclerotic cardiovascular disease (ASCVD) risk stratifications. To explore the associations between LDL-C levels and mortality and to identify the optimal ranges of LDL-C with the lowest risk of mortality in populations with diverse ASCVD risk profiles. The ChinaHEART project is a prospective cohort study that recruited residents aged 35 to 75 years from 31 provinces in mainland China between November 2014 and December 2022. Participants were categorized into low-risk, primary prevention, and secondary prevention cohorts on the basis of their medical history and ASCVD risk. Data analysis was performed from December 2022 to October 2023. The primary end point was all-cause mortality, and secondary end points included cause-specific mortality. Mortality data were collected from the National Mortality Surveillance System and Vital Registration. The association between LDL-C levels and mortality was assessed by using Cox proportional hazard regression models with various adjusted variables. A total of 4 379 252 individuals were recruited, and 3 789 025 (2 271 699 women [60.0%]; mean [SD] age, 56.1 [10.0] years) were included in the current study. The median (IQR) LDL-C concentration was 93.1 (70.9-117.3) mg/dL overall at baseline. During a median (IQR) follow-up of 4.6 (3.1-5.8) years, 92 888 deaths were recorded, including 38 627 cardiovascular deaths. The association between LDL-C concentration and all-cause or cardiovascular disease (CVD) mortality was U-shaped in both the low-risk cohort (2 838 354 participants) and the primary prevention cohort (829 567 participants), whereas it was J-shaped in the secondary prevention cohort (121 104 participants). The LDL-C levels corresponding to the lowest CVD mortality were 117.8 mg/dL in the low-risk group, 106.0 mg/dL in the primary prevention cohort, and 55.8 mg/dL in the secondary prevention cohort. The LDL-C concentration associated with the lowest all-cause mortality (90.9 mg/dL vs 117.0 mg/dL) and CVD mortality (87 mg/dL vs 114.6 mg/dL) were both lower in individuals with diabetes than in individuals without diabetes in the overall cohort. This study found that the association between LDL-C and mortality varied among different ASCVD risk cohorts, suggesting that stricter lipid control targets may be needed for individuals with higher ASCVD risk and those with diabetes.

Cardiovascular outcomes in patients with homozygous familial hypercholesterolaemia on lipoprotein apheresis initiated during childhood: long-term follow-up of an international cohort from two registries

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence. In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis. The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037). Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life. Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health.

Prescription of lipid-lowering therapy, LDLc control, and risk of MACE in patients after ST-elevation myocardial infarction in Mexico

Abstract Funding Acknowledgements None. Background/Introduction Optimal control of low-density lipoprotein cholesterol (LDLc) has been demonstrated to reduce cardiovascular event rates after ST-elevation myocardial infarction (STEMI). However, real-world data shows that a low proportion of patients achieve LDLc targets. Furthermore, the association of LDLc levels and major cardiovascular adverse events (MACE) in post-STEMI patients is limited in developing countries. Purpose In this study, we aimed to assess the prescription patterns of lipid-lowering therapies, LDLc control, and their impact on the risk of MACE after STEMI in Mexico. Methods We conducted a prospective observational study of patients with STEMI. LDLc levels and prescriptions of lipid-lowering therapy were assessed during the first scheduled visit following STEMI hospital discharge. LDLc control was determined in accordance with the 2023 European Society of Cardiology Acute Coronary Syndrome Guidelines, which recommend achieving LDLc levels below 55 mg/dL for secondary prevention. Patients were categorized as controlled (if LDLc &amp;lt;55 mg/dL) and not controlled (if LDLc &amp;gt;55 mg/dL) and were followed for a median of 4.5 years to evaluate the rate of MACE, including cardiovascular death, cardiogenic shock, recurrent MI, and heart failure. Results We included 447 patients with a mean age of 57.87 (± 10.5 years), predominantly male (84.5%). Hypertension (43.8%), smoking (41.1%), type 2 diabetes mellitus (33.5%), obesity (26.6%), and dyslipidemia (21.4%) were highly prevalent. The median LDLc level in the total population was 65.4 mg/dL (IQR 49.2- 87.7). Among these, 34% (152) were considered controlled, while 66% (295) were not. Baseline clinical characteristics did not significantly differ among the groups. Prescription of high-intensity statins reached 94.7%, and ezetimibe and PCSK-9i were used in 1.8% and 0.4% of cases, respectively. We observed no statistically significant difference (Hazard ratio: 1.03, 95% confidence interval 0.74-1.73) in the rate of MACE based on LDLc control (Fig.1). The risk of MACE was also not different based on the use of high-intensity statins. Conclusions In this real-world study of patients post-STEMI, LDLc control was achieved in just one-third of the population. While the prescription of high-intensity statins was high, combination therapy was low. We did not observe a statistically significant association with an increased long-term risk of MACE; however, we noted a higher rate of events compared with other series.

Pragmatic Trial of Messaging to Providers About Treatment of Hyperlipidemia (PROMPT-LIPID): A Randomized Clinical Trial.

Lipid-lowering therapy (LLT) is underutilized for very high-risk atherosclerotic cardiovascular disease. PROMPT-LIPID (PRagmatic Trial of Messaging to Providers about Treatment of HyperLIPIDemia) sought to determine whether electronic health record (EHR) alerts improve 90-day LLT intensification in patients with very high-risk atherosclerotic cardiovascular disease. PROMPT-LIPID was a pragmatic trial in which cardiovascular and internal medicine clinicians within Yale New Haven Health (New Haven, CT) were cluster-randomized to receive an EHR alert with individualized LLT recommendations or no alert for outpatients with very high-risk atherosclerotic cardiovascular disease and LDL-C (low-density lipoprotein cholesterol), ≥70 mg/dL. The primary outcome was 90-day LLT intensification (change to high-intensity statin and addition of ezetimibe or PCSK9i [proprotein subtilisin/kexin type 9 inhibitors]). Secondary outcomes included LDL-C level, proportion of patients with LDL-C of <70 or < 55 mg/dL, rate of major adverse cardiovascular events, ED visit incidence, and 6-month mortality. Results were analyzed using logistic and linear regression clustered at the provider level. The no-alert group included 47 clinicians and 1370 patients (median age, 71 years; 50.1% female, median LDL-C, 93 mg/dL); the alert group included 49 clinicians and 1130 patients (median age, 72 years; 47% female, median LDL-C 91, mg/dL). The primary outcome was observed in 14.1% of patients in the alert group as compared with 10.4% in the no-alert group. There were no differences in any secondary outcomes at 6 months. Among 542 patients whose clinicians (n=46) did not dismiss the EHR alert recommendations, LLT intensification was significantly greater (21.2% versus 10.4%, odds ratio, 2.33 [95% CI, 1.48-3.66]). With a real-time, targeted, individualized EHR alert as compared with usual care, the proportion of patients with atherosclerotic cardiovascular disease with LLT intensification was numerically higher but not statistically significant. Among clinicians who did not dismiss the alert, there was a > 2-fold increase in LLT intensification. EHR alerts, coupled with strategies to reduce clinician dismissal, may help address persistent gaps in LDL-C management. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04394715, https://www.clinicaltrials.gov/ct2/show/study/NCT04394715.

Lipoprotein-associated phospholipase A2 predicts cardiovascular death in patients on maintenance hemodialysis: a 7-year prospective cohort study

BackgroundCardiovascular diseases (CVD) is the leading cause of death among maintenance hemodialysis patients, with dyslipidemia being a prevalent complication. The paradoxical relationship between cardiovascular outcomes and established lipid risk markers, such as low-density lipoprotein cholesterol (LDL-C), complicates lipid management in this population. This study investigated Lipoprotein-associated phospholipase A2 (Lp-PLA2), an emerging biomarker known for its proinflammatory and proatherogenic properties, as a potential cardiovascular prognostic marker in this cohort. In this context, the association between Lp-PLA2 levels and cardiovascular outcomes was evaluated, with the aim to facilitate more accurate stratification and identification of high-risk individuals.MethodsFrom August 2013 to January 2014, 361 hemodialysis patients were prospectively enrolled. Lp-PLA2 activity and laboratory measures at baseline were quantified. Comorbidities and medications were recorded. All patients were followed until the end of April, 2022. The individual and combined effects of Lp-PLA2 activity and LDL-C on patient outcomes were examined. The association between Lp-PLA2 activity and all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACEs) was analyzed.ResultsThe median Lp-PLA2 activity was 481.2 U/L. In subjects with Lp-PLA2 activity over 481.2 U/L, significantly higher total cholesterol (4.89 vs. 3.98 mmol/L; P < 0.001), LDL-C (3.06 vs. 2.22 mmol/L; P < 0.001), and apolipoprotein B (0.95 vs. 0.75 mmol/L; P < 0.001) were observed. Over a median follow-up of 78.1 months, 182 patients died, with 77 cases identified as cardiovascular death, 88 MACEs happened. Cardiovascular mortality and MACEs, but not all-cause mortality, were significantly increased in the high Lp-PLA2 group. Cox regression analyses showed that high Lp-PLA2 activity was associated with cardiovascular mortality and MACE occurrence. After comprehensive adjustment, high Lp-PLA2 activity was independently associated with cardiovascular mortality(as a dichotomous variable: HR:2.57, 95%CI:1.58,4.18, P < 0.001; as a continuous variable: HR:1.25, 95%CI:1.10,1.41, P = 0.001) and MACEs(as a dichotomous variable: HR:2.17, 95%CI:1.39,3.40, P = 0.001; as a continuous variable: HR:1.20, 95%CI:1.07,1.36, P = 0.002). When participants were grouped by median Lp-PLA2 activity and LDL-C values, those with high Lp-PLA2 and low LDL-C had the highest CV mortality. The addition of Lp-PLA2 significantly improved reclassification (as a dichotomous variable NRI = 42.51%, 95%CI: 5.0%,61.33%; as a continuous variable, NRI = 33.32%, 95% CI: 7.47%,56.21%).ConclusionsHigh Lp-PLA2 activity is an independent risk factor for cardiovascular mortality and MACEs occurrence in patients on hemodialysis. The combined measures of Lp-PLA2 and LDL-C help to identify individuals with a higher risk of cardiovascular death.

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron.

Use of inclisiran in a real-world setting: results from the italian Cholinet registry

Abstract Background Real world data indicate that PCSK9 inhibitors (PCSK9i) are started in very high-risk patients at higher LDL cholesterol (LDL-C) values than those recommended by guidelines. Different reimbursement rules may have an impact on access to injectable therapy among different countries. In Italy, reimbursement of injectable lipid lowering therapies (LLT) (i.e., PCSK9i and inclisiran) has been recently allowed for very high risk patients with LDL-C levels &amp;gt;70 mg/dl while on statin/ezetimibe LLT or statin intolerant, and, thereafter, inclisiran has been introduced in clinical practice. No data are available on inclisiran real world use in Italy and on the impact of new reimbursement rules on patient access to inclisiran. Purpose Cholinet (Cholesterol inclisiran Italian network) is an Italian multicenter prospective phase 4 registry involving 21 Italian centers, designed to assess efficacy, safety, adherence and persistence, as well characteristics of very high risk patients with atherosclerotic CV disease (ASCVD) and/or familial hypercholesterolemia (FH) receiving inclisiran. Methods From November 2022 through February 2023, the Cholinet registry enrolled patients receiving inclisiran due to elevated LDL-C levels in Italian centers as part of their medical therapy. Baseline characteristics, concomitant therapies, blood chemistry, were recorded at the time of first prescription and at follow-up. Results We enrolled 105 patients (14% FH, 30% female, mean age 64 years) receiving inclisiran according to standard clinical practice. 37 of them reached 3 months follow up (i.e., time of first reinjection dose) and none of them missed the reinjection dose. At the time of inclisiran first prescription median LDL-C was 96.6 mg/dl and reached 48.8 mg/dl at the time of 3 months observation (49% reduction). In patients with ASCVD median LDL-C at baseline was 90.4 mg/dL and 44.4 mg/dl at follow-up (51% reduction). In patients with FH median LDL-C at baseline was 177.4 mg/dL and 109.5 mg/dL at follow-up (38% reduction). Of 105 patients enrolled, 92 patients (88%) were on LLT. Heterogeneity was found on the LDL-C reduction across our cohort (Figure 1) (Shapiro-Wilk test p&amp;lt;0.05) that appeared to be influenced by background LLT (Kruskal-Wallis rank for previous PCSK9i exposure p=0.0028, for background LLT p=0.0435) (Figure 2), but not by baseline LDL-C levels (ANOVA p=0.06). LDL-C target was achieved in 21 (66%) of 32 patients receiving background LLT and in 2 (40%) of 5 patients who did not. No patient reported side effects. Conclusion These preliminary results from the Cholinet registry show that, in a context of facilitated reimbursement access, inclisiran is introduced at substantially lower baseline LDL-C values than previously reported for PCSK9i, reflecting a favorable change in clinical practice. Inclisiran effectively and safely reduces LDL-C in patients with ASCVD or FH, with some etherogeneity that was associated with background LLT.Kernel density plot, LDL-C % reductionStratified Kernel density plot

Prognostic impact of inflammation in myocardial infarction with non-obstructive coronary arteries

Abstract Background The prognosis of patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) is worse than that of the general population. Nevertheless, the predictors for a worse outcome in patients with MINOCA are not fully determined. Purpose The aim of this study was to evaluate the prognostic value of C-Reactive Protein (CRP) in MINOCA patients. Methods Retrospective analysis of 706 consecutively admitted patients due to acute myocardial infarction (AMI), in whom coronary angiography revealed absence of obstructive coronary artery disease (≥50% stenosis). CRP levels were measured at admission. Demographic characteristics, symptoms at presentation, past medical history, laboratory characteristics and medication at discharge were examined. The primary endpoint analysed was all-cause mortality at 5 years. Possible predictors of the endpoint were assessed by Cox regression models. When statistically significant values were found in univariable analysis, multivariate analysis was used to determine whether CRP was an independent predictor of the outcome. Results In the studied sample, 55% of the patients were male. Median age was 64 [interquartile range (IQR) 55–72] and median body mass index was 27.3 kg/m2 (IQR 24.6-30.1). Regarding past medical history, 76.5% were hypertensive, 77.8% were dyslipidemic, 12.6% were smokers, 37.4% were diabetic and 59.3% had a previous history of angina. At presentation, 94.8% were in Killip 1, 3.8% were in Killip 2, 1% were in Killip 3 and 0.4% were in Killip 4. At admission, median CRP was 0.38 mg/dL (IQR 0.14-0.81), median Troponin I was 0.09 ng/ml (IQR 0.04-1.65), median creatinine was 0.85 mg/dL (IQR 0.73-1), median low density lipoprotein cholesterol (LDL-C) was 121.5 mg/dL (IQR 97.5-146), median haemoglobin was 13.6 g/dL (IQR 12.5-14.6) and median left ventricular ejection fraction (LVEF) was 58% (IQR 50-60). At discharge, 74.2% had a beta-blocker prescribed, 88.4% had a renin-angiotensin system inhibitor (RASi) prescribed, 98.2% had a statin prescribed and 76.5% had aspirin prescribed. All-cause mortality at 5 years was 8.5%. In univariable analysis, CRP was significantly associated with the endpoint [hazard ratio (HR) 1.138 per 1 mg/dL increase, 95% CI 1.090–1.188, p&amp;lt;0.001], as was age, diabetes, Killip class, troponin I, creatinine, LDL-C, haemoglobin, LVEF and absence of prescription of RASi. In multivariate analysis, CRP remained significantly associated with the endpoint (HR 1.141, 95% CI 1.087–1.199, p&amp;lt;0.001), as did age, creatinine and absence of prescription of RASi. Conclusions CRP at admission seems to be an independent predictor of all-cause mortality at the 5-year mark. This could indicate that inflammation has an important role in the pathophysiology and prognosis of MINOCA patients. It would be interesting to investigate if targeting inflammation would improve the long-term prognosis of these patients.