Ursodeoxycholic Acid for Trans Intestinal Cholesterol Excretion Stimulation: A Randomized Placebo Controlled Crossover Study.

BACKGROUND: The trans intestinal cholesterol excretion (TICE) pathway is a potential therapeutic target to reduce plasma low-density lipoprotein (LDL) cholesterol levels. TICE encompasses the direct excretion of cholesterol by enterocytes into feces. In mice, TICE has been shown to be stimulated by a hydrophilic bile acid pool, resulting in increased fecal neutral sterol loss and reduced plasma cholesterol levels. We investigated whether treatment with a hydrophilic bile acid, ursodeoxycholic acid (UDCA), would increase fecal neutral sterols in humans as a proxy for TICE. METHODS AND RESULTS: We performed a randomized, double-blind, placebo-controlled, cross-over trial in 20 male participants aged >18 years, with plasma LDL cholesterol levels ≥2.6 mmol/L. After a run-in period of ezetimibe 20 mg once daily for 3 weeks, patients were randomized to UDCA 600 mg or placebo orally once daily for 2 weeks. After a 3 week washout, patients underwent the alternate treatment. At baseline, mean (SD) age, body mass index, and plasma LDL cholesterol were 59±11.3 years, 26.4±3.1 kg/m2, and 3.9±0.8 mmol/L, respectively. After UDCA treatment, the plasma bile acid hydrophobicity index was reduced compared with placebo (-118.7% versus +2.3%, P<0.001). The fecal neutral sterols did not change (-5.8% versus +18.8%, P=0.51) and treatment with UDCA increased LDL cholesterol with 0.39 mmol/L (+8.1% versus -3.64%, P=0.002) when compared with placebo. CONCLUSIONS: UDCA in combination with ezetimibe increased plasma bile acid hydrophilicity in healthy subjects with LDL cholesterol levels >2.6 mmol/L but did not result in increased fecal neutral sterols or decreased LDL cholesterol. This suggests that TICE is not stimulated by an increase in the hydrophilicity of the bile acid pool in humans.

Interleukin 6 plasma levels are associated with progression of coronary plaques.

BACKGROUND: Inflammation plays a pivotal role in atherogenesis and is a causal risk factor for atherosclerotic cardiovascular disease. Non-invasive coronary CT angiography (CCTA) enables evaluation of coronary plaque phenotype. This study investigates the relationship between a comprehensive panel of inflammatory markers and short-term plaque progression on serial CCTA imaging, hypothesising that inflammation is associated with increased plaque volume. METHODS: A total of 161 patients aged ≥40 years with stable multivessel coronary artery disease were included, who underwent CCTA at baseline and 12 months follow-up. Baseline plasma levels of interleukin 6 (IL-6), high-sensitivity C-reactive protein and other inflammatory markers were measured. Plaque volumes were assessed using semiautomated software, calculating total, noncalcified, calcified and low-attenuation noncalcified plaque volumes. Linear regression models, adjusted for ASSIGN score, segment involvement score and body mass index, evaluated associations between inflammatory markers and plaque volume changes. RESULTS: The mean±SD age was 65.4±8.4 years, with 129 (80.6%) male participants. Baseline total plaque volume was 1394 (1036, 1993) mm³. After 12 months, total plaque volume changed by 78 (-114, 244) mm³. IL-6 levels were associated with a 4.9% increase in total plaque volume (95% CI: 0.9 to 8.9, p=0.018) and a 4.8% increase in noncalcified plaque volume (95% CI: 0.7 to 8.9, p=0.022). No significant associations were observed for other inflammatory markers. CONCLUSIONS: Plasma IL-6 levels are significantly associated with increased total and noncalcified short-term plaque progression in patients with stable coronary artery disease. This supports the potential of IL-6 as a target for reducing plaque progression and cardiovascular risk.

Oral Anaerobutyricum soehngenii augments glycemic control in type 2 diabetes.

This randomized, double-blind, placebo-controlled trial investigated the impact of 14-day Anaerobutyricum soehngenii L2-7 supplementation on postprandial glucose levels in 25 White Dutch males with type 2 diabetes (T2D) on stable metformin therapy. The primary endpoint was the effect of A. soehngenii versus placebo on glucose excursions and variability as determined by continuous glucose monitoring. Secondary endpoints were changes in ambulatory 24-h blood pressure, incretins, circulating metabolites and excursions of plasma short-chain fatty acids (SCFAs) and bile acids upon a standardized meal. Results showed that A. soehngenii supplementation for 14 days significantly improved glycemic variability and mean arterial blood pressure, without notable changes in SCFAs, bile acids, incretin levels, or anthropometric parameters as compared to placebo-treated controls. Although well-tolerated and effective in improving glycemic control in the intervention group, further research in larger and more diverse populations is needed to generalize these findings.

Polygenic Risk Is Associated With Long-Term Coronary Plaque Progression and High-Risk Plaque.

BACKGROUND: The longitudinal relation between coronary artery disease (CAD) polygenic risk score (PRS) and long-term plaque progression and high-risk plaque (HRP) features is unknown. OBJECTIVES: The goal of this study was to investigate the impact of CAD PRS on long-term coronary plaque progression and HRP. METHODS: Patients underwent CAD PRS measurement and prospective serial coronary computed tomography angiography (CTA) imaging. Coronary CTA scans were analyzed with a previously validated artificial intelligence-based algorithm (atherosclerosis imaging-quantitative computed tomography imaging). The relationship between CAD PRS and change in percent atheroma volume (PAV), percent noncalcified plaque progression, and HRP prevalence was investigated in linear mixed-effect models adjusted for baseline plaque volume and conventional risk factors. RESULTS: A total of 288 subjects (mean age 58 ± 7 years; 60% male) were included in this study with a median scan interval of 10.2 years. At baseline, patients with a high CAD PRS had a more than 5-fold higher PAV than those with a low CAD PRS (10.4% vs 1.9%; P < 0.001). Per 10 years of follow-up, a 1 SD increase in CAD PRS was associated with a 0.69% increase in PAV progression in the multivariable adjusted model. CAD PRS provided additional discriminatory benefit for above-median noncalcified plaque progression during follow-up when added to a model with conventional risk factors (AUC: 0.73 vs 0.69; P = 0.039). Patients with high CAD PRS had an OR of 2.85 (95% CI: 1.14-7.14; P = 0.026) and 6.16 (95% CI: 2.55-14.91; P < 0.001) for having HRP at baseline and follow-up compared with those with low CAD PRS. CONCLUSIONS: Polygenic risk is strongly associated with future long-term plaque progression and HRP in patients suspected of having CAD.

Moving from lipids to leukocytes: inflammation and immune cells in atherosclerosis.

Atherosclerotic cardiovascular disease (ASCVD) is the most important cause of morbidity and mortality worldwide. While it is traditionally attributed to lipid accumulation in the vascular endothelium, recent research has shown that plaque inflammation is an important additional driver of atherogenesis. Though clinical outcome trials utilizing anti-inflammatory agents have proven promising in terms of reducing ASCVD risk, it is imperative to identify novel actionable targets that are more specific to atherosclerosis to mitigate adverse effects associated with systemic immune suppression. To that end, this review explores the contributions of various immune cells from the innate and adaptive immune system in promoting and mitigating atherosclerosis by integrating findings from experimental studies, high-throughput multi-omics technologies, and epidemiological research.

Plasma C-reactive protein is associated with a pro-inflammatory and adverse plaque phenotype.

BACKGROUND AND AIMS: Systemic low-grade inflammation, measured by plasma high-sensitivity C-reactive protein (hsCRP) levels, is an important risk factor for atherosclerotic cardiovascular disease (ASCVD). To date, however, it is unknown whether plasma hsCRP is associated with adverse histological plaque features. METHODS: Plaques were derived during carotid endarterectomy. Patients with hsCRP levels ≥2 mg/L were evaluated for pro-inflammatory and adverse plaque characteristics, as well as future ASCVD events, and compared with patients with low hsCRP levels. Logistic and linear regression analyses in addition to subdistribution hazard ratios were conducted, adjusted for cardiovascular risk factors. RESULTS: A total of 1096 patients were included, of which 494 (46.2 %) had hsCRP levels ≥2 mg/L. Elevated hsCRP levels 2 mg/L were independently associated with levels of plaque interleukin 6, beta coefficient of 109.8 (95 % confidence interval (CI): 33.4, 186.5; p = 0.005) pg/L, interleukin 8 levels, 194.8 (110.4, 378.2; p = 0.03) pg/L and adiponectin plaque levels, -16.8 (-30.1, -3.6; p = 0.01) µg/L, compared with plaques from patients with low hsCRP levels. Histological analysis revealed increased vessel density in high hsCRP patients, odds ratio (OR) of 1.57 (1.20, 2.09; p = 0.001), larger lipid core, 1.35 (1.02, 1.73; p = 0.04), and increased macrophage content, 1.32 (1.02, 1.73; p = 0.04). Over a 3-year follow-up period, hsCRP levels ≥2 mg/L were associated with a hazard ratio of 1.81 (1.03, 3.16; p = 0.04) for coronary artery disease event risk. CONCLUSIONS: The distinct inflammatory and histological features observed in carotid plaques among individuals with hsCRP levels ≥2 mg/L underscore the utility of plasma hsCRP as a potent identifier for patients harboring high-risk plaques.

LDLR variant classification for improved cardiovascular risk prediction in familial hypercholesterolemia.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a genetic disorder marked by high LDL cholesterol and an increased premature coronary artery disease (CAD) risk. Current dichotomous classification of LDL receptor gene (LDLR) variants may inadequately capture patient variability in LDL cholesterol levels and CAD risk. This study assessed a novel approach for determining LDLR variant severity using variant-specific LDL cholesterol percentiles. METHODS: Participants of the Dutch FH cascade screening program were screened for 456 LDLR variants. For each LDLR variant carrier, a sex- and age-specific LDL cholesterol percentile was derived from the LDL cholesterol level measured at study entry, i.e. generally from the blood drawn for DNA analysis. These percentiles were used to calculate the mean LDL cholesterol percentile for each variant. Based on the variant-specific LDL cholesterol percentiles, carriers were grouped into the following LDL cholesterol strata: <75th, 75th-88th, 88th-92nd, 92nd-96.5th, 96.5th-98th, and ≥98th percentile. Additionally, variants were categorized into class 1 (LDLR deficient) and non-class 1 (often LDLR defective) variants. CAD risk between carriers in the different LDL cholesterol strata and non-carriers was compared using a Cox proportional hazard model. RESULTS: Out of 35,067 participants, 12,485 (36 %) LDLR variant carriers (mean age 38.0 ± 20.0 years, 47.7 % male) were identified. Carriers had a 5-fold higher CAD risk compared with non-carriers. Hazard ratios for CAD increased gradually from 2.2 (95%CI 0.97-5.0) to 12.0 (95%CI 5.5-24.8) across the LDL cholesterol strata. A 7.3-fold and 3.9-fold increased CAD risk was observed in carriers of class 1 and non-class 1 LDLR variants, respectively. CONCLUSIONS: This study presents a refined approach for classifying LDLR variants based on their impact on LDL cholesterol levels, allowing for more precise, genotype-specific CAD risk estimation in FH patients compared with traditional methods.

Lipoprotein(a) and Long-Term Plaque Progression, Low-Density Plaque, and Pericoronary Inflammation.

Importance: Lipoprotein(a) (Lp[a]) is a causal risk factor for cardiovascular disease; however, long-term effects on coronary atherosclerotic plaque phenotype, high-risk plaque formation, and pericoronary adipose tissue inflammation remain unknown. Objective: To investigate the association of Lp(a) levels with long-term coronary artery plaque progression, high-risk plaque, and pericoronary adipose tissue inflammation. Design, Setting, and Participants: This single-center prospective cohort study included 299 patients with suspected coronary artery disease (CAD) who underwent per-protocol repeated coronary computed tomography angiography (CCTA) imaging with an interscan interval of 10 years. Thirty-two patients were excluded because of coronary artery bypass grafting, resulting in a study population of 267 patients. Data for this study were collected from October 2008 to October 2022 and analyzed from March 2023 to March 2024. Exposures: The median scan interval was 10.2 years. Lp(a) was measured at follow-up using an isoform-insensitive assay. CCTA scans were analyzed with a previously validated artificial intelligence-based algorithm (atherosclerosis imaging-quantitative computed tomography). Main Outcome and Measures: The association between Lp(a) and change in percent plaque volumes was investigated in linear mixed-effects models adjusted for clinical risk factors. Secondary outcomes were presence of low-density plaque and presence of increased pericoronary adipose tissue attenuation at baseline and follow-up CCTA imaging. Results: The 267 included patients had a mean age of 57.1 (SD, 7.3) years and 153 were male (57%). Patients with Lp(a) levels of 125 nmol/L or higher had twice as high percent atheroma volume (6.9% vs 3.0%; P = .01) compared with patients with Lp(a) levels less than 125 nmol/L. Adjusted for other risk factors, every doubling of Lp(a) resulted in an additional 0.32% (95% CI, 0.04-0.60) increment in percent atheroma volume during the 10 years of follow-up. Every doubling of Lp(a) resulted in an odds ratio of 1.23 (95% CI, 1.00-1.51) and 1.21 (95% CI, 1.01-1.45) for the presence of low-density plaque at baseline and follow-up, respectively. Patients with higher Lp(a) levels had increased pericoronary adipose tissue attenuation around both the right coronary artery and left anterior descending at baseline and follow-up. Conclusions and Relevance: In this long-term prospective serial CCTA imaging study, higher Lp(a) levels were associated with increased progression of coronary plaque burden and increased presence of low-density noncalcified plaque and pericoronary adipose tissue inflammation. These data suggest an impact of elevated Lp(a) levels on coronary atherogenesis of high-risk, inflammatory, rupture-prone plaques over the long term.

Lipoprotein(a) and Calcific Aortic Valve Stenosis Progression: A Systematic Review and Meta-Analysis.

Importance: There are currently no pharmacological treatments available to slow hemodynamic progression of aortic stenosis. Plasma lipoprotein(a) concentrations predict incident aortic stenosis but its association with hemodynamic progression is controversial. Objective: To determine the association between plasma lipoprotein(a) concentrations and hemodynamic progression in patients with aortic stenosis. Design, Settings and Participants: The study included patients with aortic stenosis from 5 longitudinal clinical studies conducted from March 2001 to March 2023 in Canada and the UK. Of 757 total patients, data on plasma lipoprotein(a) concentrations and rates of hemodynamic progression assessed by echocardiography were available for 710, who were included in this analysis. Data were analyzed from March 2023 to April 2024. Exposure: Cohort-specific plasma lipoprotein(a) concentration tertiles. Main Outcomes and Measures: Hemodynamic aortic stenosis progression on echocardiography as assessed by annualized change in peak aortic jet velocity, mean transvalvular gradient, and aortic valve area. Results: Among the included patients, 497 (70%) were male and 213 (30%) were female. The mean (SD) age was 65.2 (13.1) years. Patients in the top lipoprotein(a) tertile demonstrated 41% (estimate, 1.41; 95% CI, 1.13-1.75) faster progression of peak aortic jet velocity and 57% (estimate, 1.57; 95% CI, 1.18-2.10) faster progression of mean transvalvular gradient than patients in the bottom tertile. There was no evidence of heterogeneity across the individual cohorts. Progression of aortic valve area was comparable between groups (estimate, 1.23; 95% CI, 0.71-2.12). Similar results were observed when plasma lipoprotein(a) concentrations were treated as a continuous variable. Conclusions and Relevance: In this study, higher plasma lipoprotein(a) concentrations were associated with faster rates of hemodynamic progression in patients with aortic stenosis. Lowering plasma lipoprotein(a) concentrations warrants further investigation in the prevention and treatment of aortic stenosis.

Enhanced identification of familial hypercholesterolemia using central laboratory algorithms.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a highly prevalent genetic disorder resulting in markedly elevated LDL cholesterol levels and premature coronary artery disease. FH underdiagnosis and undertreatment require novel detection methods. This study evaluated the effectiveness of using an LDL cholesterol cut-off ≥99.5th percentile (sex- and age-adjusted) to identify clinical and genetic FH, and investigated underutilization of genetic testing and undertreatment in FH patients. METHODS: Individuals with at least one prior LDL cholesterol level ≥99.5th percentile were selected from a laboratory database containing lipid profiles of 590,067 individuals. The study comprised three phases: biochemical validation of hypercholesterolemia, clinical identification of FH, and genetic determination of FH. RESULTS: Of 5614 selected subjects, 2088 underwent lipid profile reassessment, of whom 1103 completed the questionnaire (mean age 64.2 ± 12.7 years, 48% male). In these 1103 subjects, mean LDL cholesterol was 4.0 ± 1.4 mmol/l and 722 (65%) received lipid-lowering therapy. FH clinical diagnostic criteria were met by 282 (26%) individuals, of whom 85% had not received guideline-recommended genetic testing and 97% failed to attain LDL cholesterol targets. Of 459 individuals consenting to genetic validation, 13% carried an FH-causing variant, which increased to 19% in clinically diagnosed FH patients. CONCLUSIONS: The identification of a substantial number of previously undiagnosed and un(der)treated clinical and genetic FH patients within a central laboratory database highlights the feasibility and clinical potential of this targeted screening strategy; both in identifying new FH patients and in improving treatment in this high-risk population.

Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome.

BACKGROUND: Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III. METHODS: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis. RESULTS: A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group. CONCLUSIONS: In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.).

Unexpected gaps in knowledge of familial hypercholesterolaemia among Dutch general practitioners.

BACKGROUND: Familial hypercholesterolaemia (FH) warrants early diagnosis to prevent premature atherosclerotic cardiovascular disease (CVD). However, underdiagnosis and undertreatment of FH persist. This study aimed to assess the knowledge and practice of FH care among general practitioners (GPs) in the Netherlands. METHODS: An internationally standardised, online questionnaire was sent to Dutch GPs between February 2021 and July 2022. The survey assessed knowledge and awareness of FH, encompassing general familiarity, awareness of management guidelines, inheritance, prevalence, CVD risk, and clinical practice related to FH. Comparative analysis was performed using data on primary care physicians from Western Australia, the Asia-Pacific region and the United Kingdom. RESULTS: Of the 221 participating GPs, 62.4% rated their familiarity with FH as above average (score > 4 on a 1-7 scale), with 91.4% considering themselves familiar with FH treatment and referral guidelines. Correct identification of the FH definition, typical lipid profile, inheritance pattern, prevalence and CVD risk was reported by 83.7%, 87.8%, 55.7%, 19.5%, and 13.6% of the respondents, respectively. Of the participants, 58.4% answered fewer than half of the 8 knowledge questions correctly. Dutch GPs reported greater FH familiarity and guideline awareness compared with their international counterparts but exhibited similar low performance on FH knowledge questions. CONCLUSION: Despite the Netherlands' relatively high FH detection rate, substantial knowledge gaps regarding FH persist among Dutch GPs, mirroring global trends. Enhanced FH education and awareness in primary care are imperative to improve FH detection and ensure adequate treatment. Targeting the global suboptimal understanding of FH might require international efforts.

Development and Validation of a Quantitative Coronary CT Angiography Model for Diagnosis of Vessel-Specific Coronary Ischemia.

BACKGROUND: Noninvasive stress testing is commonly used for detection of coronary ischemia but possesses variable accuracy and may result in excessive health care costs. OBJECTIVES: This study aimed to derive and validate an artificial intelligence-guided quantitative coronary computed tomography angiography (AI-QCT) model for the diagnosis of coronary ischemia that integrates atherosclerosis and vascular morphology measures (AI-QCTISCHEMIA) and to evaluate its prognostic utility for major adverse cardiovascular events (MACE). METHODS: A post hoc analysis of the CREDENCE (Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia) and PACIFIC-1 (Comparison of Coronary Computed Tomography Angiography, Single Photon Emission Computed Tomography [SPECT], Positron Emission Tomography [PET], and Hybrid Imaging for Diagnosis of Ischemic Heart Disease Determined by Fractional Flow Reserve) studies was performed. In both studies, symptomatic patients with suspected stable coronary artery disease had prospectively undergone coronary computed tomography angiography (CTA), myocardial perfusion imaging (MPI), SPECT, or PET, fractional flow reserve by CT (FFRCT), and invasive coronary angiography in conjunction with invasive FFR measurements. The AI-QCTISCHEMIA model was developed in the derivation cohort of the CREDENCE study, and its diagnostic performance for coronary ischemia (FFR ≤0.80) was evaluated in the CREDENCE validation cohort and PACIFIC-1. Its prognostic value was investigated in PACIFIC-1. RESULTS: In CREDENCE validation (n = 305, age 64.4 ± 9.8 years, 210 [69%] male), the diagnostic performance by area under the receiver-operating characteristics curve (AUC) on per-patient level was 0.80 (95% CI: 0.75-0.85) for AI-QCTISCHEMIA, 0.69 (95% CI: 0.63-0.74; P < 0.001) for FFRCT, and 0.65 (95% CI: 0.59-0.71; P < 0.001) for MPI. In PACIFIC-1 (n = 208, age 58.1 ± 8.7 years, 132 [63%] male), the AUCs were 0.85 (95% CI: 0.79-0.91) for AI-QCTISCHEMIA, 0.78 (95% CI: 0.72-0.84; P = 0.037) for FFRCT, 0.89 (95% CI: 0.84-0.93; P = 0.262) for PET, and 0.72 (95% CI: 0.67-0.78; P < 0.001) for SPECT. Adjusted for clinical risk factors and coronary CTA-determined obstructive stenosis, a positive AI-QCTISCHEMIA test was associated with aHR: 7.6 (95% CI: 1.2-47.0; P = 0.030) for MACE. CONCLUSIONS: This newly developed coronary CTA-based ischemia model using coronary atherosclerosis and vascular morphology characteristics accurately diagnoses coronary ischemia by invasive FFR and provides robust prognostic utility for MACE beyond presence of stenosis.

Breaking the chains of lipoprotein lipase deficiency: A pediatric perspective on the efficacy and safety of Volanesorsen.

RATIONALE: Lipoprotein lipase (LPL) deficiency, a rare inherited metabolic disorder, is characterized by high triglyceride (TG) levels and life-threatening acute pancreatitis. Current treatment for pediatric patients involves a lifelong severely fat-restricted diet, posing adherence challenges. Volanesorsen, an EMA-approved RNA therapy for adults, effectively reduces TG levels by decreasing the production of apolipoprotein C-III. This 96-week observational open-label study explores Volanesorsen's safety and efficacy in a 13-year-old female with LPL deficiency. METHODS: The patient, with a history of severe TG elevations, 53 hospital admissions, and life-threatening recurrent pancreatitis despite dietary restrictions, received weekly subcutaneous Volanesorsen injections. We designed a protocol for this investigator-initiated study, primarily focusing on changes in fasting TG levels and hospital admissions. RESULTS: While the injections caused occasional pain and swelling, no other adverse events were observed. TG levels decreased during treatment, with more measurements below the pancreatitis risk threshold compared to pre-treatment. No hospital admissions occurred in the initial 14 months of treatment, contrasting with 21 admissions in the 96 weeks before. In the past 10 months, two pancreatitis episodes may have been linked to dietary noncompliance. Dietary restrictions were relaxed, increasing fat intake by 65% compared to baseline. While not fully reflected in the PedsQL, both parents and the patient narratively reported an improved quality of life. CONCLUSION: This study demonstrates, for the first time, that Volanesorsen is tolerated in a pediatric patient with severe LPL deficiency and effectively lowers TG levels, preventing life-threatening complications. This warrants consideration for expanded access in this population.

Accumulation of Iron Oxide-Based Contrast Agents in Rabbit Atherosclerotic Plaques in Relation to Plaque Age and Vulnerability Features.

Purpose: In this study, a detailed characterization of a rabbit model of atherosclerosis was performed to assess the optimal time frame for evaluating plaque vulnerability using superparamagnetic iron oxide nanoparticle (SPION)-enhanced magnetic resonance imaging (MRI). Methods: The progression of atherosclerosis induced by ballooning and a high-cholesterol diet was monitored using angiography, and the resulting plaques were characterized using immunohistochemistry and histology. Morphometric analyses were performed to evaluate plaque size and vulnerability features. The accumulation of SPIONs (novel dextran-coated SPIONDex and ferumoxytol) in atherosclerotic plaques was investigated by histology and MRI and correlated with plaque age and vulnerability. Toxicity of SPIONDex was evaluated in rats. Results: Weak positive correlations were detected between plaque age and intima thickness, and total macrophage load. A strong negative correlation was observed between the minimum fibrous cap thickness and plaque age as well as the mean macrophage load. The accumulation of SPION in the atherosclerotic plaques was detected by MRI 24 h after administration and was subsequently confirmed by Prussian blue staining of histological specimens. Positive correlations between Prussian blue signal in atherosclerotic plaques, plaque age, and macrophage load were detected. Very little iron was observed in the histological sections of the heart and kidney, whereas strong staining of SPIONDex and ferumoxytol was detected in the spleen and liver. In contrast to ferumoxytol, SPIONDex administration in rabbits was well tolerated without inducing hypersensitivity. The maximum tolerated dose in rat model was higher than 100 mg Fe/kg. Conclusion: Older atherosclerotic plaques with vulnerable features in rabbits are a useful tool for investigating iron oxide-based contrast agents for MRI. Based on the experimental data, SPIONDex particles constitute a promising candidate for further clinical translation as a safe formulation that offers the possibility of repeated administration free from the risks associated with other types of magnetic contrast agents.

Beyond early LDL cholesterol lowering to prevent coronary atherosclerosis in familial hypercholesterolaemia.

AIMS: Familial hypercholesterolaemia (FH) patients are subjected to a high lifetime exposure to low density lipoprotein cholesterol (LDL-C), despite use of lipid-lowering therapy (LLT). This study aimed to quantify the extent of subclinical atherosclerosis and to evaluate the association between lifetime cumulative LDL-C exposure and coronary atherosclerosis in young FH patients. METHODS AND RESULTS: Familial hypercholesterolaemia patients, divided into a subgroup of early treated (LLT initiated <25 years) and late treated (LLT initiated ≥25 years) patients, and an age- and sex-matched unaffected control group, underwent coronary CT angiography (CCTA) with artificial intelligence-guided analysis. Ninety genetically diagnosed FH patients and 45 unaffected volunteers (mean age 41 ± 3 years, 51 (38%) female) were included. Familial hypercholesterolaemia patients had higher cumulative LDL-C exposure (181 ± 54 vs. 105 ± 33 mmol/L ∗ years) and higher prevalence of coronary plaque compared with controls (46 [51%] vs. 10 [22%], OR 3.66 [95%CI 1.62-8.27]). Every 75 mmol/L ∗ years cumulative exposure to LDL-C was associated with a doubling in per cent atheroma volume (total plaque volume divided by total vessel volume). Early treated patients had a modestly lower cumulative LDL-C exposure compared with late treated FH patients (167 ± 41 vs. 194 ± 61 mmol/L ∗ years; P = 0.045), without significant difference in coronary atherosclerosis. Familial hypercholesterolaemia patients with above-median cumulative LDL-C exposure had significantly higher plaque prevalence (OR 3.62 [95%CI 1.62-8.27]; P = 0.001), compared with patients with below-median exposure. CONCLUSION: Lifetime exposure to LDL-C determines coronary plaque burden in FH, underlining the need of early as well as potent treatment initiation. Periodic CCTA may offer a unique opportunity to monitor coronary atherosclerosis and personalize treatment in FH.

This study reveals that young patients with familial hypercholesterolaemia (FH), as compared with individuals without FH, have a higher build-up of coronary artery plaque, linked directly to their increased lifetime exposure to LDL cholesterol. Genetically confirmed FH patients have a higher coronary plaque burden than those without FH, with every 75 mmol/L ∗ years increase in lifetime cumulative LDL cholesterol exposure resulting in a two-fold increase in total plaque volume. Early and potent LDL cholesterol lowering treatments are crucial for FH patients to prevent future cardiovascular diseases.