European Atherosclerosis Journal

Antihypertensive and renal protection effects of lercanidipine and lercanidipine/enalapril

Nicola Ferri, Alberto Corsini, Roberto Pontremoli — Tue, 31 Dec 2024 00:00:00 +0000

Systemic arterial hypertension is the second most common cause of end-stage kidney disease (ESKD). Renal protection activity has been demonstrated for angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), gliflozins (dapagliflozin ed empagliflozin) and by the third-generation calcium channel blockers (CCB). Lercanidipine, a third-generation calcium channel blocker, has been shown to have a unique pharmacological and clinical profile, which translates into favorable renal hemodynamic changes. Here we summarized the pharmacological properties of lercanidipine and evaluate its ability to reduce proteinuria and preserve renal function when used as monotherapy or in combination with the angiotensin-converting enzyme (ACE) inhibitor enalapril. The fixed-dose combination lercanidipine/enalapril showed an excellent pharmacological profile with demonstrated clinical efficacy and tolerability in high-risk patients. Lercanidipine can be considered the preferred choice among calcium channel blocker drugs for the treatment of hypertensive patients at risk of renal impairment.

LDL-cholesterol goal attainment with ezetimibe and bempedoic acid in patients at high and very-high cardiovascular risk: A simulation study in the Italian cohort of the SANTORINI study

Tue, 31 Dec 2024 00:00:00 +0000

Aims: Data from the Italian cohort of the SANTORINI study, a European observational study focusing on lipid management in patients at high or very-high cardiovascular risk, were used to simulate the effect of sequential addition of ezetimibe and bempedoic acid in patients not at LDL-C goal with their current lipid-lowering therapy (LLT).
Methods: Eligible patients were selected based on criteria including LDL-C levels and LLT status. Patients who were not at LDL-C goal at baseline and had not received PCSK9 inhibitors (PCSK9i) or bempedoic acid underwent sequentially 1) simulation of adding ezetimibe in patients who had not previously received this drug, and 2) simulation of the effect of adding bempedoic acid in patients who did not achieve the LDL-C goal after treatment with ezetimibe (actual or simulated). Expected treatment efficacy was documented from randomised clinical trials. The simulation assumed no statin intensification beyond the baseline regimen. The simulation was run probabilistically 10,000 times for the patient cohort, calculating the mean LDL-C after each simulation step and estimating the proportion of patients achieving LDL-C goal at each stage and overall.
Results: The simulation resulted in a significant increase in patients achieving the LDL-C goal after each step (from 25.9% to 37.6% after ezetimibe and 55.4% after ezetimibe+bempedoic acid). The subgroup analysis showed similar trends in high-risk and very-high-risk patients.
Conclusions: The simulation of SANTORINI data shows that goal attainment in patients at high-risk and very-high-risk can be substantially increased by optimizing oral LLT with the addition of ezetimibe and bempedoic acid.

This is the update version of the article. A correction has been published:
EAJ 2024;3:93 - https://doi.org/10.56095/eaj.v3i3.86

Atherosclerotic cardiovascular disease and measurement of lipoprotein(a) levels in Italy

Elena Olmastroni, Manuela Casula, Sining Xie, Alberico L. Catapano — Tue, 31 Dec 2024 00:00:00 +0000

Background: Lipoprotein(a) [Lp(a)] is a relatively new but underutilized biomarker in the context of atherosclerotic cardiovascular disease (ASCVD).
Objectives: To explore the clinical implementation of Lp(a) measurement and current practices in hospital and specialised settings in Italy.
Methods: An anonymous online questionnaire was distributed to Italian physicians to examine the habits of Italian clinicians regarding Lp(a) measurement. The survey covered three topics: 1) information on the clinical setting of the physicians, 2) questions for physicians who reported not measuring Lp(a), to understand the reasons for not requesting the test, and 3) questions for physicians who measure Lp(a), to investigate its use in patient management.
Results: A total of 978 responses were received. Overall, 63.1% of physicians reported working in a hospital; 12.2% reported being a territorial specialist. Regular Lp(a) measurement was reported by 32.1% of clinicians. Among those who do not measure Lp(a), the main barriers to implementation include high cost and limited availability of the test. The threshold value for defining elevated Lp(a) levels varies significantly among professionals, with 36.7% considering levels above 30 mg/dL to be elevated and 32.7% considering levels above 50 mg/dL to be elevated. Clinical management of patients with elevated Lp(a) primarily includes intensification of lipid-lowering therapy (69.2%), management of cardiovascular risk factors (48.7%), and lifestyle recommendations (37.4%).
Conclusions: The survey highlights the heterogeneity in the approach to managing elevated Lp(a) levels among Italian clinicians, underscoring the importance of clear guidelines and greater accessibility to the test to optimize cardiovascular risk stratification and improve clinical outcomes.

Corrigendum: LDL-cholesterol goal attainment with ezetimibe and bempedoic acid in patients at high and very-high cardiovascular risk: A simulation study in the Italian cohort of the SANTORINI study

Editorial Office — Wed, 15 Jan 2025 00:00:00 +0000

This is a correction to:
European Atherosclerosis Journal 2024;3:57-66
https://doi.org/10.56095/eaj.v3i3.76

SMASH: An initiative for equitable access to precision medicine for rare or severe lipid disorders

Tue, 31 Dec 2024 00:00:00 +0000

Background. Despite significant improvements in our knowledge of the biological basis of rare or severe lipid disorders and the refinement of their clinical management, equity challenges and barriers to access are gradually emerging, particularly in low-middle-income countries or remote regions. SMASH (System and Molecular Approaches of Severe Hyperlipidemia) is a global initiative with the goal of making precision medicine innovations available without discrimination for patients affected by rare or severe lipid disorders.
Objectives. SMASH main objective is to facilitate access to accurate diagnosis and optimal treatment for patients affected by rare or severe lipid disorders regardless of where they live, their gender, ethnicity, or socioeconomic status.
Overview. SMASH is an international initiative comprising five interrelated components: SMASH-Access, -Natural History, -Trials, -e-Share, and -Biorepository. SMASH has selected as templates four severe lipid disorders that have in common the accelerated development of precise diagnosis and the emergence of innovative treatments that represent equity challenges: HoFH (homozygous familial hypercholesterolemia), persistent chylomicronemia, LCAT (lecithin-cholesterol acyl transferase) deficiency, and severely elevated Lp(a). Access issues are broad and not limited to clinical or socio-economic factors. Several environmental variables are also contributory.
Summary. SMASH is developed to conceive, support, or catalyze initiatives that might improve our understanding of rare or severe dyslipidemias and facilitate access to innovation for those affected. It will not duplicate ongoing initiatives but will support them. A system approach and a structured collaborative effort is mandatory to provide fair access to emerging treatments to patients in both developed countries and emerging economies.

The XVIII National Congress of the Società Italiana di Terapia Clinica e Sperimentale (SITeCS)

Tue, 31 Dec 2024 00:00:00 +0000

Investigating plasma and brain cholesterol esterification in patients with amyotrophic lateral sclerosis

Tue, 31 Dec 2024 00:00:00 +0000

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, with metabolic alterations, abnormal cholesterol and lipid levels in the bloodstream and central nervous system (CNS). Similar to plasma, cholesterol in the cerebrospinal fluid (CSF) is carried by lipoproteins known as "HDL-like particles," due to their close similarity in density and composition to plasma HDL. Lecithin cholesterol acyltransferase (LCAT) is a key enzyme in HDL metabolism, catalysing cholesterol esterification in both plasma and CSF, thus facilitating HDL maturation. This study aimed to investigate cholesterol esterification in plasma and CSF and to characterize HDL subclass distribution in patients with ALS. The study included 20 ALS patients and 20 controls, in whom lipoprotein profile and cholesterol esterification were evaluated in both plasma and CSF. Plasma lipid levels were similar between patients and controls; however, the amount of discoidal preβ-HDL was significantly reduced in ALS patients compared to controls (8.5±4.9% vs 13.6±4.1%, p<0.0001). A significant increase in CSF unesterified cholesterol levels was observed in ALS patients compared to controls (0.22±0.07 mg/dL vs 0.15±0.04 mg/dL, p<0.01), leading to an increased unesterified/total cholesterol ratio in ALS patients (0.52±0.12 vs 0.40±0.12, respectively). While plasma cholesterol esterification remained unchanged in ALS patients, the cholesterol esterification rate was significantly reduced in their CSF (0.12±0.08 vs 2.41±1.98, p<0.01), consistent with the previous data. In conclusion, these results suggest a hampered cholesterol esterification in the CSF of ALS patients. Whether this defect is related to the severity or progression of the disease remains to be defined.

Neutrophil behavior during the metabolic adaptations to short term high fat feeding

Tue, 31 Dec 2024 00:00:00 +0000

Background and Aims: Neutrophils participate to the chronic metabolic consequences of High Fat Diet (HFD). Nevertheless, neutrophils are characterized by short half-life which is determined by a fine tuning in expression and function of CXCR4, which dictates the egress from the bone marrow (BM), and CXCR2, which facilitates their mobilization from BM and the patrolling activity in the periphery. In the quest to study the behavior of the neutrophil with the short-term consequences of HFD feeding, we studied whether the metabolic adaptations affect blood neutrophil count and the membrane expression of their indirect markers of function.
Methods: To assess the gluco-metabolic impact of a short-term HFD feeding, indirect calorimetry and plasma glucose dosage were performed on mice previously fed a HFD (60% Kcal from fat) for seven days, followed by immunophenotyping of blood over 24 hours. To test whether changes in circulating neutrophil count during short-term HFD feeding were related to a differential egress from the BM, we repeated the same experimental design in mice harboring a conditional deletion of CXCR4 (CXCR4fl/flMrp8Cre+).
Results: Short-term HFD feeding was sufficient to induce a profound metabolic impact (e.g. reduced respiratory exchange ratio, increased energy expenditure, and insulin levels), and to induce an increase of circulating neutrophils (p=0,052), without impacting other leukocytic fractions over 24 hours, compared to chow diet feeding mice (20% Kcal from fat). HFD feeding significantly altered the expression pattern of multiple membrane markers of neutrophil function (CD11b, CD62L, CXCR2) over 24 hours, driving neutrophils toward a phenotype featuring increased migration and activation. Finally, the CXCR4fl/flMrp8Cre+ mice, which present significantly higher circulating neutrophilia, showed lower insulin sensitivity upon HFD compared to WT.
Conclusions: We suggest that the metabolic adaptations induced by a short-term exposure to HFD affect neutrophil behavior, surmising it as an appealing target for cardio-metabolic diseases.

Modulation of mitochondrial dynamism in Kupffer cells impacts systemic metabolism

Tue, 31 Dec 2024 00:00:00 +0000

Background: Kupffer cells (KCs) are hepatoresident macrophages that are essential for liver physiology and contribute to the development of nonalcoholic hepatic steatosis (NAFLD). The liver of patients with MAFLD shows different expressions of some key regulators of inner mitochondrial membrane fusion compared with healthy subjects, including OPA1 protein, which is a mitochondrial protein whose activity promotes mitochondrial fusion and modulation of oxidative phosphorylation.
Aims: Given the close interaction that KCs have with cells in the hepatic niches, they play both a crucial immune and metabolic role, which is why their mitochondria are critical for their function. This project aims to investigate how modulation of OPA1-driven mitochondrial fusion in KCs can affect lipid metabolism and immune response at the systemic and hepatic levels.
Methods: Mice selectively lacking OPA1 in the KCs were fed a Standard Diet or a High Fat Diet for 20 weeks. The immune phenotype was assessed by cytofluorimetry while the metabolic profile by in vivo indirect calorimetry and with plasma and tissue lipid profile analysis. Single cell RNA sequencing was also performed to profile the impact of OPA1 deficiency on KC function and possible paracrine effects on hepatocytes.
Results: Under standard dietary conditions, mice selectively lacking OPA1 in KCs show a different metabolic substrate preference compared to wild type, with an immunophenotype characterized by a higher proportion of pro-resolution KC2 than pro-inflammatory KC1. Functionally, KCs also exhibit dissimilar phagocytic and proliferative capacity. During the high-fat diet, we observed a significant reduction in liver fibrosis.
Conclusions: Taken together, these data suggest that OPA1 plays a key role in the function of Kupffer cells and that the lack of OPA1, causing metabolic reprogramming, affects their interaction with resident liver cells, influencing the development of fibrosis and the progression of MAFLD.

Efficacy of oral semaglutide on cardiovascular risk in patients with type 2 diabetes mellitus: A real-life study

Tue, 31 Dec 2024 00:00:00 +0000

Background: The efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in glycemic control and cardiovascular risk reduction in type 2 diabetes mellitus (T2DM) is well established.
Real-world, non-interventional studies are increasingly essential to gather information from routine clinical practice.
Objective of the Study: This multicenter, observational, retrospective, single-arm study aims to assess the effect of oral semaglutide on surrogate markers of cardio-metabolic risk (such as Visceral Adiposity Index, triglyceride-glucose index, Lipid Accumulation Product), as well as on glycemic control, renal function markers (creatinine, eGFR, microalbuminuria), and lipid profile, in adult patients with T2DM who are naive to GLP-1 RA therapy.
Materials and Methods: A total of 154 adult diabetic patients (106 male, 48 female; mean age 64.4±10.5 years) with an average disease duration of 10 years (10.1±8.4) were evaluated. Patients initiated oral semaglutide treatment according to AIFA note 100 guidelines and were followed at diabetes outpatient clinics in ASST Bergamo Ovest, Garda, and Mantova. Clinical, biochemical, and anthropometric data for each patient were collected at the beginning of treatment (T0) and after 12 months (T12).
Results: The main results are presented in the table below:

Variables	T0	T12	P-value
BMI, Kg/m2 (mean±SD)	31.2±5.2	29.6±5.1	<0.001
Waist circumference, cm (mean±SD)	105.9±10.3	99.9±9.9	<0.001
Fasting glucose, mg/dL (mean±SD)	154.7±43.1	124.8±30.5	<0.001
HbA1c, % (mean±SD)	7.8±1.2	6.7±0.9	<0.001
Total cholesterol, mg/dL (mean±SD)	171.9±40.0	154±34.7	<0.001
HDL cholesterol, mg/dL (mean±SD)	47.7±11.9	52.0±12.2	<0.001
LDL cholesterol, mg/dL (mean±SD)	93.8±36.1	81.5±80.8	0.05
Triglycerides, mg/dL (mean±SD)	157.2±74.2	132.9±57.0	<0.001
eGFR, ml/min/1.73m² (mean±SD)	62.8±17.2	67.7±20.6	<0.001
Urinary albumin/creatinine ratio, mg/g [median (IQR)]	38.5 (14.3-81.8)	12 (5.6-34.3)	<0.001
Systolic blood pressure, mmHg (mean±SD)	134.8±14.6	131.4±15.2	0.015
Diastolic blood pressure, mmHg (mean±SD)	78.3±8.7	75.8±8.5	0.003
Visceral Adiposity Index [median (IQR)]	2.4 (1.6-3.4)	1.7 (1.0-2.6)	<0.001
Triglyceride-glucose index [median (IQR)]	5.9 (4.8-5.2)	4.8 (4.7-4.9)	<0.001
Lipid Accumulation Product [median (IQR)]	77.0 (52.8-111.6)	56.1 (35.2-80.9)	<0.001

Conclusions: Exposure to oral semaglutide for 12 months in T2DM patients resulted in significant improvements in glycemic control, renal function parameters, and surrogate markers of cardiovascular risk.

A retrospective cohort study on factors influencing the initiation of lipid-lowering therapy in hospitalized patients following a cardio-cerebrovascular event

Tue, 31 Dec 2024 00:00:00 +0000

Introduction: Current European guidelines on cardiovascular prevention recommend lipid-lowering therapies for patients who have experienced an atherosclerotic cardiovascular disease (ASCVD) event.
Objectives: This study aims to provide updated data on the prescription of lipid-lowering therapies in patients discharged after an ASCVD event and to investigate the characteristics associated with a higher likelihood of receiving such therapy following the event.
Methods: Using administrative data from the Lombardy region, individuals of both sexes aged ≥40 years hospitalized for an incident ASCVD event during the first nine months of 2019 were identified. The prevalence of those receiving a prescription for lipid-lowering therapy within 90 days of the event was assessed. A multivariable logistic regression model was applied to evaluate the impact of various factors on the likelihood of initiating treatment (odds ratio [OR] and 95% confidence intervals [95%CI]).
Results: In a cohort of 18,370 individuals with an incident ASCVD event, 50.70% did not receive a prescription for any lipid-lowering therapy. The likelihood of initiating therapy was higher in individuals who experienced a cardiovascular event compared to a cerebrovascular event (OR 2.94, 95%CI 2.74-3.14), in patients aged 51-60 years (OR 1.22, 95%CI 1.10-1.36, compared to 61-70 years), and in those receiving antidiabetic (OR 1.42, 95%CI 1.25-1.61) or antihypertensive therapy (OR 1.77, 95%CI 1.64-1.92). Conversely, older age (71-80 years: OR 0.70, 95%CI 0.64-0.77; >80 years: OR 0.38, 95%CI 0.35-0.42), female sex (OR 0.81, 95%CI 0.75–0.87), prior exposure to antithrombotic medication (OR 0.67, 95%CI 0.60-0.73), and excessive polypharmacy (OR 0.57, 95%CI 0.49-0.66 for ≥10 medications) were associated with a lower likelihood of initiating treatment after the event.
Conclusions: The study highlights a suboptimal initiation of lipid-lowering therapy in patients discharged after an ASCVD event. Additionally, the results emphasize the importance of understanding influencing factors to improve patient management in secondary prevention.

Angiopoietin-like 3 (ANGPTL3) deficiency alters metabolic substrates utilization and reprograms hepatic metabolism

Tue, 31 Dec 2024 00:00:00 +0000

Angiopoietin-like 3 (ANGPTL3) is a lipases-inhibiting hepatokine, thus prevents VLDL and LDL-derived triglycerides, regulating fluxes of triglycerides to the tissues.
Aim of this study is to investigate the association between hypolipidemia-induced metabolic alteration, due to ANGPTL3 deficiency, and potential hepatic responses, depending on the source of energetic substrates available.
Full-knockout (KO) mice and littermate controls (WT) underwent a standard chow diet or High Fat Diet (HFD, 60% kcal from fat) regimen for 16 weeks. Metabolic responses have been assessed through indirect calorimetry, lipid, glucose and insulin tolerance test, and circulating lipid levels have been evaluated.
ANGPTL3 KO mice are hypolipidemic at fasting, postprandially and in fast refeeding, both at chow and HFD.
After an oil gavage, ANGPTL3 KO mice absorb less triglycerides both at fasting (area under curve: HO:3320.8mg/dL*min±1214.9vsWT:17303 mg/dL*min±11765.2, p=0.07) and postprandially (area under curve: HO:447.3mg/dL*hr±20.9vsWT: 938.2mg/dL*hr ±294.9, p=0.016), and this associates with a lesser hepatic lipoprotein production, also at HFD. Glucose metabolism is not affected, and liver histology of KO mice at chow and HFD do not show increased steatosis compared to control group.
Indirect calorimetry data show an increased trend of oxidative metabolism in the postprandial phase compared to controls (Respiratory Exchange Ratio at ZeitgeberTime21: HO: 0.889±0.102vsWT: 0.969±0.089; p=0.074).
Hepatic mTOR activation has been investigated with western blotting, to understand a possible nutrient sensing alteration, by evaluating the phosphorylation of downstream effectors S6K (fold on housekeeping: HO:0.28±0.122vsWT:0.647±0.119; p=0.021) and 4E-BP1 (fold on housekeeping: HO: 0.503±0.193vsWT:1.043±0.270, p=0.048) and a dampened activation is observed. This is associated with a lower protein synthesis.
RNA sequencing data confirmed that at chow diet KO mice face the activation of metabolic pathways such as urea cycle and bile acids production. Hepatic signalling pathways, like LXR, are blunted, at chow and HFD.
ANGPTL3 deficiency alters the metabolic phenotype, reducing circulating lipemia, and an adaptive metabolic response occurs depending on the metabolic substrate availability.