Circulating miR-6821-5p levels and coronary calcification in asymptomatic familial hypercholesterolemia patients.

BACKGROUND AND AIMS: Premature atherosclerotic cardiovascular disease (CVD) is a clinic characteristic of familial hypercholesterolemia (FH). Coronary calcium score (CCS) is a highly used imaging modality to evidence atherosclerotic plaque burden. microRNAs (miRNAs) are non-coding RNAs that epigenetically regulate gene expression. Here, we investigated whether CCS associates with a specific miRNA-signature in FH-patients. METHODS: Patients with genetic diagnosis of FH (N = 86) from the nationwide SAFEHEART-cohort were investigated by computed tomography angiography imaging and classified depending on the presence of coronary calcification in FH-CCS (+) and FH-CCS (-) groups by the Agatston score. Differential miRNA profiling was performed in two stages: first by Affymetrix microarray technology (high-throughput differential profiling-studies) and second by RT-PCR using TaqMan-technology (analytical RT-qPCR study) in plasma of the two patient groups. RESULTS: miR-193a-5p, miR-30e-5p and miR-6821-5p levels were significantly higher in FH-CCS (+) compared to FH-CCS (-). miR-6821-5p was the best miRNA to discriminate FH-patients CCS(+), according to receiver operating characteristic (ROC) analysis (AUC: 0.70 ± 0.06, p = 0.006). High miR-6821-5p levels were associated with older age (p = 0.03) and high LDL-burden (p = 0.014) using a ROC-derived cut-off value. However, miR-6821-5p did not correlate with age in either the CCS- or CCS + group. Genes involved in calcification processes were identified by in silico analysis. The relation of cell-calcification and expression levels of miR-6821-5p, BMP2 and SPP1 was validated experimentally in human vascular smooth muscle cell cultures. CONCLUSIONS: Up-regulated levels of miR-6821-5p are found in the plasma of asymptomatic FH-patients with coronary calcified atherosclerotic plaques, as well as in isolated human vascular smooth muscle cells expressing the pro-calcification genes BMP2 and SPP1. These findings highlight the impact of epigenetic regulation on the development of subclinical atherosclerosis.

Improved lipid-lowering treatment and reduction in cardiovascular disease burden in homozygous familial hypercholesterolemia: The SAFEHEART follow-up study.

AIM: We aimed to describe clinical and genetic characteristics, lipid-lowering treatment and atherosclerotic cardiovascular disease (ASCVD) outcomes over a long-term follow-up in homozygous familial hypercholesterolemia (HoFH). METHODS: SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) is a long-term study in molecularly diagnosed FH. Data analyzed in HoFH were prospectively obtained from 2004 until 2022. ASCVD events, lipid profile and lipid-lowering treatment were determined. RESULTS: Thirty-nine HoFH patients were analyzed. The mean age was 42 ± 20 years and nineteen (49%) were women. Median follow-up was 11 years (IQR 6,18). Median age at genetic diagnosis was 24 years (IQR 8,42). At enrolment, 33% had ASCVD and 18% had aortic valve disease. Patients with new ASCVD events and aortic valve disease at follow-up were six (15%), and one (3%), respectively. Median untreated LDL-C levels were 555 mg/dL (IQ 413,800), and median LDL-C levels at last follow-up was 122 mg/dL (IQR 91,172). Most patients (92%) were on high intensity statins and ezetimibe, 28% with PCSK9i, 26% with lomitapide, and 23% with lipoprotein-apheresis. Fourteen patients (36%) attained an LDL-C level below 100 mg/dL, and 10% attained an LDL-C below 70 mg/dL in secondary prevention. Patients with null/null variants were youngers, had higher untreated LDL-C and had the first ASCVD event earlier. Free-event survival is longer in patients with defective variant compared with those patients with at least one null variant (p=0.02). CONCLUSIONS: HoFH is a severe life threating disease with a high genetic and phenotypic variability. The improvement in lipid-lowering treatment and LDL-C levels have contributed to reduce ASCVD events.

Characteristics of Coronary Atherosclerosis Related to Plaque Burden Regression During Treatment With Alirocumab: The ARCHITECT Study.

BACKGROUND: Intensive lipid-lowering therapy may induce coronary atherosclerosis regression. Nevertheless, the factors underlying the effect of lipid-lowering therapy on disease regression remain poorly characterized. Our aim was to determine which characteristics of atherosclerotic plaque are associated with a greater reduction in coronary plaque burden (PB) after treatment with alirocumab in patients with familial hypercholesterolemia. METHODS: The ARCHITECT study (Effect of Alirocumab on Atherosclerotic Plaque Volume, Architecture and Composition) is a phase IV, open-label, multicenter, single-arm clinical trial to assess the effect of the treatment with alirocumab for 78 weeks on the coronary atherosclerotic PB and its characteristics in subjects with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. Participants underwent a coronary computed tomographic angiography at baseline and a final one at 78 weeks. Every patient received alirocumab 150 mg subcutaneously every 14 days in addition to high-intensity statin therapy. RESULTS: One hundred and four patients were enrolled. Median age was 53.3 (46.2-59.4) years and 54 were women (51.9%). The global coronary PB changed from 34.6% (32.5%-36.8%) at entry to 30.4% (27.4%-33.4%) at follow-up, which is -4.6% (-7.7% to -1.9%; P<0.001) reduction. A decrease in the percentage of unstable core (fibro-fatty+necrotic plaque; from 14.1 [7.9-22.3] to 8.0 [6.4-10.6]; -6.6%; P<0.001) was found. A greater PB (ß, 0.36 [0.13-0.59]; P=0.002) and a higher proportion of unstable core (ß, 0.15 [0.08-0.22]; P<0.001) were significantly related to PB regression. CONCLUSIONS: Treatment with alirocumab in addition to high-intensity statin therapy might produce a greater PB regression in patients with familial hypercholesterolemia with higher baseline PB and in those with larger unstable core. Further studies are needed to corroborate the hypothesis raised by these results. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05465278.

International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia.

This contemporary, international, evidence-informed guidance aims to achieve the greatest good for the greatest number of people with familial hypercholesterolaemia (FH) across different countries. FH, a family of monogenic defects in the hepatic LDL clearance pathway, is a preventable cause of premature coronary artery disease and death. Worldwide, 35 million people have FH, but most remain undiagnosed or undertreated. Current FH care is guided by a useful and diverse group of evidence-based guidelines, with some primarily directed at cholesterol management and some that are country-specific. However, none of these guidelines provides a comprehensive overview of FH care that includes both the lifelong components of clinical practice and strategies for implementation. Therefore, a group of international experts systematically developed this guidance to compile clinical strategies from existing evidence-based guidelines for the detection (screening, diagnosis, genetic testing and counselling) and management (risk stratification, treatment of adults or children with heterozygous or homozygous FH, therapy during pregnancy and use of apheresis) of patients with FH, update evidence-informed clinical recommendations, and develop and integrate consensus-based implementation strategies at the patient, provider and health-care system levels, with the aim of maximizing the potential benefit for at-risk patients and their families worldwide.

Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients with Familial Hypercholesterolemia: The ARCHITECT Study.

BACKGROUND: The effect of alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, on coronary plaque burden in patients with familial hypercholesterolemia has not been addressed. Our aim was to assess changes in coronary plaque burden and its characteristics after treatment with alirocumab by quantification and characterization of atherosclerotic plaque throughout the coronary tree on the basis of a noninvasive analysis of coronary computed tomographic angiography in asymptomatic subjects with familial hypercholesterolemia receiving optimized and stable treatment with maximum tolerated statin dose with or without ezetimibe. METHODS: This study is a phase IV, open-label, multicenter, single-arm clinical trial to assess changes in coronary plaque burden and its characteristics after 78 weeks of treatment with alirocumab in patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. Participants underwent an initial coronary computed tomographic angiography at baseline and another at 78 weeks. Every patient received 150 mg of alirocumab subcutaneiously every 14 days in addition to high-intensity statin therapy. The main outcome was the change on coronary plaque burden and its characteristics by quantification and characterization of atherosclerotic plaque throughout the coronary tree on the basis of analysis of coronary computed tomographic angiography. RESULTS: The study was completed by 104 patients. The median age was 53.3 (46.2-59.4) years. Of these patients, 54 were women (51.9%). Median low-density lipoprotein cholesterol was 138.9 (117.5-175.3) mg/dL at entry and 45.0 (36.0-65.0) mg/dL at follow-up (P<0.001). Coronary plaque burden changed from 34.6% (32.5%-36.8%) at entry to 30.4% (27.4%-33.4%) at follow-up (P<0.001). A significant change in the characteristics of the coronary atherosclerosis was also found: an increase in the proportion of calcified (+0.3%; P<0.001) and mainly fibrous (+6.2%; P<0.001) plaque, accompanied by a decrease in the percentage of fibro-fatty (-3.9%; P<0.001) and necrotic plaque (-0.6%; P<0.001). CONCLUSIONS: Treatment with alirocumab in addition to high-intensity statin therapy resulted in significant regression of coronary plaque burden and plaque stabilization on coronary computed tomographic angiography over 78 weeks in these groups of patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. ARCHITECT (Effect of Alirocumab on Atherosclerotic Plaque Volume, Architecture and Composition) could link and explain ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) results. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT05465278.

Risk factors for cardiovascular events in patients with heterozygous familial hypercholesterolaemia: protocol for a systematic review.

INTRODUCTION: Heterozygous familial hypercholesterolaemia (heFH) is the most common monogenic cause of premature atherosclerotic cardiovascular disease. The precise diagnosis of heFH is established by genetic testing. This systematic review will investigate the risk factors that predict cardiovascular events in patients with a genetic diagnosis of heFH. METHODS AND ANALYSIS: Our literature search will cover publications from database inception until June 2023. We will undertake a search of CINAHL (trial), clinicalKey, Cochrane Library, DynaMed, Embase, Espacenet, Experiments (trial), Fisterra, ÍnDICEs CSIC, LILACS, LISTA, Medline, Micromedex, NEJM Resident 360, OpenDissertations, PEDro, Trip Database, PubPsych, Scopus, TESEO, UpToDate, Web of Science and the grey literature for eligible studies. We will screen the title, abstract and full-text papers for potential inclusion and assess the risk of bias. We will employ the Cochrane tool for randomised controlled trials and non-randomised clinical studies and the Newcastle-Ottawa Scale for assessing the risk of bias in observational studies. We will include full-text peer-reviewed publications, reports of a cohort/registry, case-control and cross-sectional studies, case report/series and surveys related to adults (≥18 years of age) with a genetic diagnostic heFH. The language of the searched studies will be restricted to English or Spanish. The Grading of Recommendations, Assessment, Development and Evaluation approach will be used to assess the quality of the evidence. Based on the data available, the authors will determine whether the data can be pooled in meta-analyses. ETHICS AND DISSEMINATION: All data will be extracted from published literature. Hence, ethical approval and patient informed consent are not required. The findings of the systematic review will be submitted for publication in a peer-reviewed journal and presentation at international conferences. PROSPERO REGISTRATION NUMBER: CRD42022304273.

Persistence with long-term PCSK9 inhibitor treatment and its effectiveness in familial hypercholesterolaemia: data from the SAFEHEART study.

AIMS: Most heterozygous familial hypercholesterolaemia (FH) patients require intensive lipid-lowering therapy (LLT) including PCSK9 inhibitors (PCSK9is) to reach current low-density lipoprotein cholesterol (LDL-C) goals. Persistence with chronic treatment is important to reduce the burden of atherosclerotic cardiovascular disease. We analysed persistence, efficacy, and impact on quality of life (QoL) of PCSK9i in FH patients in clinical practice setting. METHODS AND RESULTS: Spanish Familial Hypercholesterolaemia Cohort Study (SAFEHEART) is an open, prospective study in genetically defined FH patients in Spain. Patients ≥18 years of age (n = 696, 46% females) on stable LLT treated with PCSK9i were analysed. Median LDL-C at starting PCSK9i was 145 mg/dL [interquartile range (IQR), 123-177], 3.8 mmol/L (IQR 3.2-4.6). After a median follow up of 3.7 years (IQR 2.3-4.8), 27 patients (4%) discontinued PCSK9i treatment: 5 temporarily (0.7%) and 22 permanently (3.2%). Persistence with PCSK9i was 96.1% in the whole period. Median LDL-C levels and % LDL-C reduction attained after 1 year of treatment and in the last follow-up visit were 63 mg/dL (IQR 43-88), 1.6 mmol/L (IQR 1.1-2.23); 61 mg/dL (IQR 44-82), 1.6 mmol/L (IQR 1.1-2.1); 57.6% (IQR 39.5-69); and 58% (IQR 44-68), respectively. 2016 and 2019 ESC/EAS LDL-C goals were attained by 77 and 48% of patients, respectively, at the last follow-up visit (P < 0.001). Mean QoL score increased slightly in the first year and remained stable. CONCLUSION: Long-term persistence with PCSK9i in FH patients is very high, with a good QoL. Effectiveness in LDL-C reduction and LDL-C goal achievement dramatically improved with PCSK9i in this high-risk population in clinical practice setting. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02693548.

Predicting resilience in heterozygous familial hypercholesterolaemia: A cohort study of octogenarian patients.

Defining patients with familial hypercholesterolemia (FH) destined not to develop clinical atherosclerotic cardiovascular disease (ASCVD) has significant implications for precision and discovery medicine. We investigated the predictors of resilience to ASCVD in a cohort of 248 octogenarian patients with FH enrolled in the SAFEHEART study. Median age at the time of analysis was 84.7 years (82.3-88.1) and 83.6 years (81.9-86.4) in the octogenarian resilient FH (OR-FH) and octogenarian controls non-resilient FH (OCNoR-FH) groups, respectively (p=0.073); 92 (80.0%) and 68 (51.1%) patients were female in the first compared with the second group (p<0.001). Multivariate logistic regression showed that a low 10-year score in SAFEHEART-Risk Equation was the only independent predictor of OR-FH. Application of this simple and validated risk equation may potentially be useful for predicting patients ultra-resilient to the ASCVD sequelae of FH who may require less intensive use of healthcare resources.

Is Liver Transplant Curative in Homozygous Familial Hypercholesterolemia? A Review of Nine Global Cases.

INTRODUCTION: Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening, inherited condition characterized by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C). Patients are at high risk of atherosclerotic cardiovascular disease, adverse cardiovascular events, and associated early mortality. Liver transplant is sometimes used with curative intent. The objective of the current case series was to evaluate the follow-up of a range of patients who have undergone liver transplant for the treatment of HoFH. METHODS: Patients with clinical and/or genetic diagnoses of HoFH were treated according to local practices in four units in Europe and the Middle East. All patients underwent liver transplantation. Baseline and long-term follow-up data were collected, including LDL-C levels, DNA mutations, lipid-lowering medications, and complications due to surgery and immunosuppressive therapy. RESULTS: Nine patients were included with up to 22 years' follow-up (mean ± SD 11.7 ± 11.7 years; range 0.5-28 years). Three of the patients died as a result of complications of transplant surgery (mortality rate 33%). Among the surviving six patients, four required continued lipid-lowering therapy (LLT) to maintain LDL-C levels and two patients show signs of increasing LDL-C levels that require management. One case (11%) required two consecutive transplants to achieve a viable graft and is awaiting a third transplant because of graft failure. CONCLUSIONS: Liver transplant did not enable attainment of recommended LDL-C targets in most patients with HoFH, and the majority of patients still required post-transplant LLT. Liver transplant was not curative in most of the patients with HoFH followed. Guidelines suggest that transplant is a treatment of last resort if contemporary treatments are not available or possible.

Familial Hypercholesterolemia and Lipoprotein(a): Two Partners in Crime?

PURPOSE OF REVIEW: Familial hypercholesterolemia is a high cardiovascular risk disorder. We will review the role of lipoprotein(a) in cardiovascular risk and in aortic valve stenosis in familial hypercholesterolemia, as well as its association with their phenotype, and strategies to identify this high-risk population. RECENT FINDINGS: Patients with familial hypercholesterolemia have higher lipoprotein(a) levels mainly due to an increased frequency of LPA variants, and the cardiovascular risk is increased twofolds when both conditions coexist. Also, an increased risk for aortic valve stenosis and valve replacement has been observed with high lipoprotein(a) levels. Assessment of lipoprotein(a) during the cascade screening for familial hypercholesterolemia is a good opportunity to identify this high-risk population. High cardiovascular risk in familial hypercholesterolemia is increased even more when lipoprotein(a) is also elevated. Measurement of lipoprotein(a) in these patients is crucial to identify those subjects who need to intensify LDL-cholesterol reduction pending availability of lipoprotein(a)-specific treatments.

Alpine altitude climate treatment for severe and uncontrolled asthma: An EAACI position paper.

Currently available European Alpine Altitude Climate Treatment (AACT) programs combine the physical characteristics of altitude with the avoidance of environmental triggers in the alpine climate and a personalized multidisciplinary pulmonary rehabilitation approach. The reduced barometric pressure, oxygen pressure, and air density, the relatively low temperature and humidity, and the increased UV radiation at moderate altitude induce several physiological and immunological adaptation responses. The environmental characteristics of the alpine climate include reduced aeroallergens such as house dust mites (HDM), pollen, fungi, and less air pollution. These combined factors seem to have immunomodulatory effects controlling pathogenic inflammatory responses and favoring less neuro-immune stress in patients with different asthma phenotypes. The extensive multidisciplinary treatment program may further contribute to the observed clinical improvement by AACT in asthma control and quality of life, fewer exacerbations and hospitalizations, reduced need for oral corticosteroids (OCS), improved lung function, decreased airway hyperresponsiveness (AHR), improved exercise tolerance, and improved sinonasal outcomes. Based on observational studies and expert opinion, AACT represents a valuable therapy for those patients irrespective of their asthma phenotype, who cannot achieve optimal control of their complex condition despite all the advances in medical science and treatment according to guidelines, and therefore run the risk of falling into a downward spiral of loss of physical and mental health. In the light of the observed rapid decrease in inflammation and immunomodulatory effects, AACT can be considered as a natural treatment that targets biological pathways.

A resilient type of familial hypercholesterolaemia: case-control follow-up of genetically characterized older patients in the SAFEHEART cohort.

AIMS: Knowledge of the features of patients with familial hypercholesterolaemia (FH) who are protected from atherosclerotic cardiovascular disease (ASCVD) is important for the clinical and prognostic care of this apparently high-risk condition. Our aim was to investigate the determinant and characteristics of patients with FH who are protected from ASCVD and have normal life expectancy, so-called 'resilient' FH (R-FH). METHODS AND RESULTS: Spanish Familial Hypercholesterolaemia cohort study (SAFEHEART) is an open, multicentre, nation-wide, long-term prospective cohort study in genetically defined patients with heterozygous FH in Spain. Patients in the registry who at the time of analysis were at least 65 years or those who would have reached that age had they not died from an ASCVD event were analysed as a case-control study. Resilient FH was defined as the presence of a pathogenic mutation causative of FH in a patient aged ≥65 years without clinical ASCVD. Nine hundred and thirty registrants with FH met the study criteria. A defective low-density lipoprotein (LDL)-receptor mutation, higher plasma level of high-density lipoprotein cholesterol (HDL-C), younger age, female gender, absence of hypertension, and lower plasma lipoprotein (a) [Lp(a)] concentration were independently predictive of R-FH. In a second model, higher levels of HDL-C and lower 10-year score in SAFEHEART-RE were also independently predictive of R-FH. CONCLUSION: Resilient FH may be typified as being female and having a defective LDL-receptor mutation, higher levels of plasma HDL-C, lower levels of Lp(a), and an absence of hypertension. The implications of this type of FH for clinical practice guidelines and the value for service design and optional care of FH remains to be established. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02693548.

Association of dietary patterns and components with atherosclerosis risk biomarkers in familial hypercholesterolemia.

PURPOSE OF REVIEW: Familial hypercholesterolemia (FH) is a relatively common genetic disorder associated with elevated atherosclerotic risk. Dietary interventions can modulate processes associated with cardiovascular risk and potentiate the impact of pharmacological lipid-lowering therapies. This review evaluates recent findings of dietary patterns and their components on risk biomarkers in people with FH. RECENT FINDINGS: Diets lower in saturated fatty acids (SFA) may reduce low-density lipoprotein-cholesterol (LDL-C); however, their effects seem to be modest. A Mediterranean style diet apparently exerts more robust effects on plasma LDL-C, apolipoprotein B and C reactive protein concentrations than one restricted in SFA. Supplementation of plant sterols and stanols reduces LDL-C especially in children with FH. Caloric restricted diets may reduce weight and improve triglyceride levels in individuals with FH and excess body weight. SUMMARY: Despite the strong impact of genetic variants, dietary patterns mostly low in SFA and especially the Mediterranean diet may influence risk biomarkers in FH. However, most available studies are limited by cross-sectional design, small number of study subjects and short-term follow-ups. Robust interventional studies are necessary to test the impact of dietary patterns in people with FH.

Detection of Familial Hypercholesterolemia through centralized analytical data. HF HUELVA DETECTA Program.

BACKGROUND: Familial Hypercholesterolemia is the most frequent genetic cause of premature coronary heart disease. The delay in the diagnosis prevents the correct early treatment. There are no effective screening strategies at the national level that ensure a correct diagnosis. OBJECTIVE: To determine the capacity of a centralized laboratory for the diagnosis of Familial Hypercholesterolemia through the creation of a health program for population screening in the province of Huelva. METHOD: Active search of patients with primary hypercholesterolemia through the blood tests carried out in the reference laboratories with results of low-density lipoprotein cholesterol greater than 200 mg/dl and assessment in the Lipid Unit of Huelva to identify index cases, with subsequent family cascade screening. RESULTS: 37,440 laboratory tests with lipid profile were examined. After screening, 846 individuals were seen in the Lipid Unit, of which they were diagnosed according to criteria of the Dutch Lipid Clinic Network as possible 654 and probable/definitive 192 individuals, representing 1.74% and 0.51% of the general population examined respectively. CONCLUSIONS: The point prevalence of Familial Hypercholesterolemia in patients submitted to laboratory lipid profile tests was 1:195, higher compared to the prevalence of Familial Hypercholesterolemia in the general population (based on 1 in 200-300). The opportunistic search strategy of the index case through a laboratory alert and centralized screening is an efficient strategy to implement a national screening for the diagnosis of Familial Hypercholesterolemia.

The Added Value of Coronary Calcium Score in Predicting Cardiovascular Events in Familial Hypercholesterolemia.

OBJECTIVES: This study aimed at investigating the additional contribution of coronary artery calcium (CAC) score to SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) risk equation (SAFEHEART-RE) for cardiovascular risk prediction in heterozygous familial hypercholesterolemia (HeFH). BACKGROUND: Common cardiovascular risk equations are imprecise for HeFH. Because of the high phenotype variability of HeFH, CAC score could help to better stratify the risk of atherosclerotic cardiovascular disease (ASCVD). METHODS: REFERCHOL (French Registry of Familial Hypercholesterolemia) and SAFEHEART are 2 ongoing national registries on HeFH. We analyzed data from primary prevention HeFH patients undergoing CAC quantification. We used probability-weighted Cox proportional hazards models to estimate HRs. Area under the receiver-operating characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare the incremental contribution of CAC score when added to the SAFEHEART-RE for ASCVD prediction. ASCVD was defined as coronary heart disease, stroke or transient ischemic attack, peripheral artery disease, resuscitated sudden death, and cardiovascular death. RESULTS: We included 1,624 patients (mean age: 48.5 ± 12.8 years; men: 45.7%) from both registries. After a median follow-up of 2.7 years (interquartile range: 0.4-5.0 years), ASCVD occurred in 81 subjects. The presence of a CAC score of >100 was associated with an HR of 32.05 (95% CI: 10.08-101.94) of developing ASCVD as compared to a CAC score of 0. Receiving-operating curve analysis showed a good performance of CAC score alone in ASCVD prediction (AUC: 0.860 [95% CI: 0.853-0.869]). The addition of log(CAC + 1) to SAFEHEART-RE resulted in a significantly improved prediction of ASCVD (AUC: 0.884 [95% CI: 0.871-0.894] for SAFEHEART-RE + log(CAC + 1) vs AUC: 0.793 [95% CI: 0.779-0.818] for SAFEHEART-RE; P < 0.001). These results were confirmed also when considering only hard cardiovascular endpoints. The addition of CAC score was associated with an estimated overall net reclassification improvement of 45.4%. CONCLUSIONS: CAC score proved its use in improving cardiovascular risk stratification and ASCVD prediction in statin-treated HeFH.

Alternative C3 Complement System: Lipids and Atherosclerosis.

Familial hypercholesterolemia (FH) is increasingly associated with inflammation, a phenotype that persists despite treatment with lipid lowering therapies. The alternative C3 complement system (C3), as a key inflammatory mediator, seems to be involved in the atherosclerotic process; however, the relationship between C3 and lipids during plaque progression remains unknown. The aim of the study was to investigate by a systems biology approach the role of C3 in relation to lipoprotein levels during atherosclerosis (AT) progression and to gain a better understanding on the effects of C3 products on the phenotype and function of human lipid-loaded vascular smooth muscle cells (VSMCs). By mass spectrometry and differential proteomics, we found the extracellular matrix (ECM) of human aortas to be enriched in active components of the C3 complement system, with a significantly different proteomic signature in AT segments. Thus, C3 products were more abundant in AT-ECM than in macroscopically normal segments. Furthermore, circulating C3 levels were significantly elevated in FH patients with subclinical coronary AT, evidenced by computed tomographic angiography. However, no correlation was identified between circulating C3 levels and the increase in plaque burden, indicating a local regulation of the C3 in AT arteries. In cell culture studies of human VSMCs, we evidenced the expression of C3, C3aR (anaphylatoxin receptor) and the integrin αMß2 receptor for C3b/iC3b (RT-PCR and Western blot). C3mRNA was up-regulated in lipid-loaded human VSMCs, and C3 protein significantly increased in cell culture supernatants, indicating that the C3 products in the AT-ECM have a local vessel-wall niche. Interestingly, C3a and iC3b (C3 active fragments) have functional effects on VSMCs, significantly reversing the inhibition of VSMC migration induced by aggregated LDL and stimulating cell spreading, organization of F-actin stress fibers and attachment during the adhesion of lipid-loaded human VSMCs. This study, by using a systems biology approach, identified molecular processes involving the C3 complement system in vascular remodeling and in the progression of advanced human atherosclerotic lesions.

Efficacy of PCSK9 inhibitors in the treatment of heterozygous familial hypercholesterolemia: A clinical practice experience.

BACKGROUND: PCSK9 inhibitors are a treatment option for patients with familial hypercholesterolemia not on low-density lipoprotein cholesterol goals despite the use of maximally tolerated high intensity-statins dose. OBJECTIVE: To evaluate the efficacy of alirocumab and evolocumab in LDL-C reduction and targets attainment in patients with heterozygous familial hypercholesterolemia in clinical practice setting. METHODS: SAFEHEART is an open, long-term prospective study of a cohort of subjects with molecular diagnosis of familial hypercholesterolemia. This study analyze subjects ≥ 20 years of age on stable lipid-lowering therapy, who received PCSK9 inhibitors during the period 2016 to January 2020. RESULTS: 433 patients (mean age 55 years, 53% male, 39% with cardiovascular disease) were included and followed-up for a median of 2.5 years (IQR 1.6-3.0). Median LDL-C level prior to PCSK9 inhibitors was 145 mg/dL (IQR 125-173). The addition of PCSK9 inhibitors (211 alirocumab, 222 evolocumab) reduced LDL-C by 58% (IQR 41-70) p<0.001, in men and women, achieving a median LDL-C level of 62 mg/dL (IQR 44-87) without differences between both PCSK9 inhibitors. Out of them 67% with and 80% without cardiovascular disease reached 2016 ESC/EAS LDL-C targets, and 46% very high risk and 50% high risk patients achieved 2019 ESC/EAS LDL-C goals. Independent predictor factors for attainment of 2019 ESC/EAS LDL-C goals were to be male, smoking and the use of statins with ezetimibe. Both inhibitors were well tolerated. CONCLUSIONS: PCSK9 inhibitors on top of maximum lipid-lowering treatment significantly reduced LDL-C levels in patients with familial hypercholesterolemia and improved the achievement of LDL-C targets.