A Systematic Review and Meta-Analysis of Therapeutic Efficacy and Safety of Alirocumab and Evolocumab on Familial Hypercholesterolemia.

OBJECTIVES: The aim of this study was to provide the first study to systematically analyze the efficacy and safety of PCSK9-mAbs in the treatment of familial hypercholesterolemia (FH). METHODS: A computer was used to search the electronic Cochrane Library, PubMed/MEDLINE, and Embase databases for clinical trials using the following search terms: "AMG 145", "evolocumab", "SAR236553/REGN727", "alirocumab", "RG7652", "LY3015014", "RN316/bococizumab", "PCSK9", and "familial hypercholesterolemia" up to November 2020. Study quality was assessed with the Cochrane Collaboration's tool, and publication bias was evaluated by a contour-enhanced funnel plot and the Harbord modification of the Egger test. After obtaining the data, a meta-analysis was performed using R software, version 4.0.3. RESULTS: A meta-analysis was performed on 7 clinical trials (926 total patients). The results showed that PCSK9-mAbs reduced the LDL-C level by the greatest margin, WMD -49.14%, 95% CI: -55.81 to -42.47%, on FH versus control groups. PCSK9-mAbs also significantly reduced lipoprotein (a) (Lp (a)), total cholesterol (TC), triglycerides (TG), apolipoprotein-B (Apo-B), and non-high-density lipoprotein cholesterol (non-HDL-C) levels and increased HDL-C and apolipoprotein-A1 (Apo-A1) levels of beneficial lipoproteins. Moreover, no significant difference was found between PCSK9-mAbs treatment and placebo in common adverse events, serious events, and laboratory adverse events. CONCLUSION: PCSK9-mAbs significantly decreased LDL-C and other lipid levels with satisfactory safety and tolerability in FH treatment.

Altered Vascular Reactivity to Circulating Angiotensin II in Familial Hypercholesterolemia.

ABSTRACT: We have previously shown increased vascular reactivity to angiotensin (Ang) II in familial combined hyperlipidemia. However, this has not been well studied in familial hypercholesterolemia (FH), a condition with incipient endothelial dysfunction. This study aimed to examine microvascular and macrovascular responses to Ang II in FH. Therefore, we investigated the effects of a 3-hour infusion of Ang II on blood pressure and forearm skin microvascular function in 16 otherwise healthy patients with FH and matched healthy controls. Skin microvascular hyperemia was studied by laser Doppler fluxmetry during local heating. Microvascular resistance was determined by the ratio of mean arterial pressure to microvascular hyperemia. Macrovascular reactivity was assessed by changes in brachial blood pressure. Compared with the controls, the FH group had increased baseline systolic blood pressure (127 ± 14 vs. 115 ± 12 mm Hg; P = 0.02), while systolic blood pressure responses were similar (+24 ± 9 vs. +21 ± 7 mm Hg; P = 0.26) after 3 hours of Ang II infusion. At baseline, there were no group differences in microvascular hyperemia or resistance. However, after 3 hours of Ang II infusion, heat-induced microvascular hyperemia was less pronounced in FH (126 ± 95 vs. 184 ± 102 arbitrary units; P = 0.01), while microvascular resistance during heat-induced hyperemia was increased (1.9 ± 0.9 vs. 0.9 ± 0.8, P = 0.01), as compared to controls. Both these responses were further pronounced 1 hour after stopping Ang II. In conclusion, despite similar blood pressure responses to Ang II in the FH group and controls, microvascular dilatation capacity was impaired in the FH group, indicating endothelial dysfunction. These findings and increased microvascular resistance may lead to hypertension and microvascular complications in FH.

Assessment of microvascular function and pharmacological regulation in genetically confirmed familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic lipid disorder leading to accelerated atherosclerosis, premature cardiovascular disease and death. Microvascular endothelial dysfunction is one of the earliest vascular pathology manifestations and may precede symptomatic atherosclerosis. METHODS: In this paper, microvascular endothelial function was assessed in FH patients and healthy controls using flow mediated skin fluorescence (FMSF), based on measurements of nicotinamide adenine dinucleotide fluorescence intensity during brachial artery occlusion (ischemic response, IR) and immediately after occlusion (hyperemic response, HR). Low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were used to assess its relation with microvascular parameters evaluated in vivo. RESULTS: LDL-C levels were significantly correlated to both HRmax (r = -0.548, p = 0.001) and HRindex (r = -0.514, p = 0.003). Similarly, there was a significant inverse correlation of TC levels and both HRmax (r = -0.538, p = 0.002) and HRindex (r = -0.512, p = 0.003). All FMSF parameters were found lower in FH patients compared to age- and sex-matched healthy controls. Hyperemic response (HRmax) was significantly higher in FH patients examined on statins compared to those without any lipid-lowering treatment (19.9 ± 3.1 vs. 16.4 ± 4.2 respectively, p = 0.022). CONCLUSIONS: This study shows that, in patients with FH, microvascular endothelial-dependent hyperemic response is impaired and inversely correlated to plasma cholesterol levels. Microvascular function was found better in FH patients receiving statins.

A case of homozygous familial hypercholesterolemia with an atypical phenotype and delayed clinical symptoms.

We describe the casuistry of a homozygous familial hypercholesterolemia female patient with a biallelic missense variant (NM_000527.4:c.1775G>A, p.Gly592Glu) in the LDLR gene, severe hypertriglyceridemia and late manifestation of coronary heart disease not earlier than at the age of 45 years. An atypical phenotype led to a delayed diagnosis.

Effect of PCSK9 inhibitors on pulse wave velocity and monocyte-to-HDL-cholesterol ratio in familial hypercholesterolemia subjects: results from a single-lipid-unit real-life setting.

AIMS: Subjects with familial hypercholesterolemia (FH) are characterized by an increased amount of low-density lipoprotein cholesterol (LDL-C) that promotes a continuous inflammatory stimulus. Our aim was to evaluate the effect of PCSK9-i on inflammatory biomarkers, neutrophil-to-lymphocyte ratio, monocyte-to-high-density lipoprotein ratio (MHR), and on early atherosclerosis damage analyzed by pulse wave velocity (PWV) in a cohort of FH subjects. METHODS: In this prospective observational study, we evaluated 56 FH subjects on high-intensity statins plus ezetimibe and with an off-target LDL-C. All subjects were placed on PCSK9-i therapy and obtained biochemical analysis as well as PWV evaluation at baseline and after six months of PCSK9-i therapy. RESULTS: After six months of add-on PCSK9-i therapy, only 42.9% of FH subjects attained LDL-C targets. As expected, a significant reduction of LDL-C (- 49.61%, p < 0.001) was observed after PCSK9-i therapy. Neutrophil count (NC) and MHR were reduced by PCSK9-i (-13.82% and -10.47%, respectively, p value for both < 0.05) and PWV significantly decreased after PCSK9-i therapy (- 20.4%, p < 0.05). Finally, simple regression analyses showed that ∆ PWV was significantly associated with ∆ LDL-C (p < 0.01), ∆ NC and ∆ MHR (p value for both < 0.05). CONCLUSIONS: In conclusion, PCSK9-i therapy significantly improved lipid and inflammatory profiles and PWV values in FH subjects; our results support the positive effect of PCSK9-i in clinical practice.

Familial hypercholesterolaemia and COVID-19: A two-hit scenario for endothelial dysfunction amenable to treatment.

Patients with familial hypercholesterolemia (FH) are likely at increased risk for COVID-19 complications in the acute phase of the infection, and for a long time thereafter. Because in FH patients the level of low density lipoprotein cholesterol (LDL-C) is elevated from birth and it correlates with the degree of systemic endothelial dysfunction, both heterozygous FH (HeFH) patients and, in particular, homozygous FH (HoFH) patients have a dysfunctional endothelium prone to further damage by the direct viral attack and the hyper-inflammatory reaction typical of severe COVID-19. Evidence to date shows the benefit of statin use in patients with COVID-19. In FH patients, the focus should therefore be on the effective lowering of LDL-C levels, the root cause of the expected excess vulnerability to COVID-19 infection in these patients. Moreover, the ongoing use of statins and other lipid-lowering therapies should be encouraged during the COVID pandemic to mitigate the risk of cardiovascular complications from COVID-19. For the reduction of the excess risk in FH patients with COVID-19, we advocate stringent adherence to the guideline determined LDL-C levels for FH patients, or maybe even to lower levels. Unfortunately, epidemiologic data are lacking on the severity of COVID-19 infections, as well as the number of acute cardiac events that have occurred in FH subjects during the COVID-19 pandemic. Such data need to be urgently gathered to learn how much the risk for, and the severity of COVID-19 in FH are increased.

Supravalvular Aortic Stenosis and the Risk of Premature Death Among Patients With Homozygous Familial Hypercholesterolemia.

Patients with homozygous familial hypercholesterolemia (HoFH) have a high risk for premature death. Supravalvular aortic stenosis (SVAS) is a common and the feature lesion of the aortic root in HoFH. The relation between SVAS and the risk of premature death in patients with HoFH has not been fully investigated. The present study analysis included 97 HoFH patients with mean age of 14.7 (years) from the Genetic and Imaging of Familial Hypercholesterolemia in Han Nationality Study. During the median (±SD) follow-up 4.0 (±4.0) years, 40 (41.2%) participants had SVAS and 17 (17.5%) participants experienced death. The proportion of premature death in the non-SVAS and SVAS group was 7.0% and 32.5%, respectively. Compared with the non-SVAS group, SVAS group cumulative survival was lower in the HoFH (log-rank test, p <0.001). This result was further confirmed in the multivariable Cox regression models. After adjusting for age, sex, low density lipoprotein cholesterol (LDL_C)-year-score, lipid-lowering drugs, cardiovascular disease, and carotid artery plaque, SVAS was an independent risk factor of premature death in HoFH on the multivariate analysis (hazard ratio 4.45; 95% confidence interval, 1.10 to 18.12; p = 0.037). In conclusion, a significantly increased risk of premature death was observed in HoFH patients with SVAS. Our study emphasized the importance of careful and aggressive management in these patients when appropriate.

Treatment of heterozygous familial hypercholesterolemia: what does the future hold?

INTRODUCTION: Heterozygous familial hypercholesterolemia (heFH) is a common metabolic disease associated with increased cardiovascular risk. Despite treatment with the currently available lipid-lowering agents (statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors), a substantial proportion of patients with heFH does not achieve low-density lipoprotein cholesterol (LDL-C) targets. AREAS COVERED: The PubMed database was reviewed for relevant papers published up to August 2020. The safety and efficacy of novel agents, namely inclisiran and bempedoic acid, that lower LDL-C levels and might be useful in the management of patients with heFH are discussed. EXPERT OPINION: The prolonged lipid-lowering effect of inclisiran might improve adherence to treatment in patients with heFH. Bempedoic acid provides additional reductions in LDL-C levels in patients on high-intensity statin treatment; oral administration of this agent might be attractive to some patients. However, it is important to evaluate the effects of these agents on cardiovascular morbidity before they are incorporated in the management of heFH. The cost/benefit of treatment should also be considered, given the increasing complexity of lipid-lowering treatment.

Mental status and physical activity in patients with homozygous familial hypercholesterolemia: A subgroup analysis of a nationwide survey (A-HIT1 registry).

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening disease due to high serum low-density lipoprotein (LDL) cholesterol levels. LDL cholesterol-lowering interventions are fundamental for patients with HoFH. OBJECTIVE: It was aimed to investigate the association between the mental status of patients with HoFH and healthy lifestyle behaviors. METHODS: This subgroup analysis of the A-HIT1 population included the data of patients aged ≥18 years with a clinical diagnosis of HoFH undergoing therapeutic LDL apheresis. Besides the demographic and clinical characteristics of patients, healthy lifestyle behaviors were assessed, and psychiatric symptoms were screened by Symptom Check List (SCL-90-R). RESULTS: The highest percentage for pathology was observed in dimensions of obsessive-compulsive, somatization, interpersonal sensitivity, and depression in SCL-90-R. Patients with any cardiovascular condition have more psychiatric symptoms in different fields of SCL-90-R. The outcomes of the correlative analysis indicated that lower the age of the first coronary event better the psychiatric status, probably denoting a better adaptation to disease and its treatment. Among 68 patients, 36 patients were not exercising regularly. Patients with regular physical activity had significantly lower scores in most dimensions of SCL-90-R and there was no association between regular physical activity and other investigated variables. The strongest predictor of regular exercising was global severity index of SCL-90-R. CONCLUSION: In the HoFH population, there was a high prevalence of mental disturbances. Better psychiatric status was associated with regular exercising. Therefore, assessing the mental status of patients with HoFH and referring patients in need, to a psychiatrist, may improve the outcome of patients.

Proportion of High-Risk/Very High-Risk Patients in Europe with Low-Density Lipoprotein Cholesterol at Target According to European Guidelines: A Systematic Review.

OBJECTIVE: Assess achievement of low-density lipoprotein cholesterol (LDL-C) targets in European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines. DESIGN: Systematic literature review. DATA SOURCES: Medline, EMBASE, Cumulated Index to Nursing and Allied Health Literature. ELIGIBILITY CRITERIA: Observational studies reporting LDL-C levels/target attainment, measured between 1 August 2006 to 31 August 2017, in European adults with established cardiovascular disease (CVD), diabetes with target organ damage, familial hypercholesterolaemia (FH) or 10-year risk of fatal CVD ≥ 5% (assessed by Systematic Coronary Risk Evaluation [SCORE]). DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted relevant studies and assessed study quality using the Risk of Bias for Non-Randomised Studies-Interventions (ROBINS-I) tool. Primary outcome was the proportion of patients achieving LDL-C targets in the 2011/2016 ESC/EAS guidelines. Where available, patient characteristics were presented as means weighted by sample size. The proportions of patients achieving LDL-C targets in the 5 years before and after publication of the 2011 guidelines were compared using a chi-square test. RESULTS: Across 81 eligible studies (303,534 patients), achievement of LDL-C < 1.8 mmol/L was poor among patients with established CVD (16%; range 9-56%) and at very high risk of CVD (SCORE ≥ 10% [18%; 14-25%]). In individuals with FH, SCORE 5-10%, or diabetes and target organ damage, LDL-C < 2.5 mmol/L was achieved by 15% (9-22%), 46% (21-55%) and 13% (6-34%), respectively. Comparing the 5 years before/after publication of the 2011 guidelines, target achievement increased significantly over time but remained suboptimal (LDL-C < 1.8, 22% versus 15%; LDL-C < 2.5, 68% versus 61%; both p < 0.001; established CVD group only). CONCLUSIONS: These data show suboptimal LDL-C control among European patients at high risk of CVD. Those at greatest overall risk (clinically established CVD or at least a 10% 10-year risk of fatal CVD) had the lowest achievement of 2011/2016 EAS/ESC LDL-C targets. With lower LDL-C targets advocated in 2019 ESC/EAS guidelines, this unmet need will increase. PROTOCOL REGISTRATION: PROSPERO registration number; CRD77844.

Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: A role for the LDL receptor and cholesterol metabolism in adult neural precursor cells.

OBJECTIVE: In familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies have revealed an association between FH and hippocampus-related memory and mood impairment. We here asked whether hippocampal pathology in FH might be a consequence of compromised adult hippocampal neurogenesis. METHODS: We evaluated hippocampus-dependent behavior and neurogenesis in adult C57BL/6JRj and LDLr-/- mice. We investigated the effects of elevated cholesterol and the function of LDLr in neural precursor cells (NPC) isolated from adult C57BL/6JRj mice in vitro. RESULTS: Behavioral tests revealed that adult LDLr-/- mice showed reduced performance in a dentate gyrus (DG)-dependent metric change task. This phenotype was accompanied by a reduction in cell proliferation and adult neurogenesis in the DG of LDLr-/- mice, suggesting a potential direct impact of LDLr mutation on NPC. Exposure of NPC to LDL as well as LDLr gene knockdown reduced proliferation and disrupted transcriptional activity of genes involved in endogenous cholesterol synthesis and metabolism. The LDL treatment also induced an increase in intracellular lipid storage. Functional analysis of differentially expressed genes revealed parallel modulation of distinct regulatory networks upon LDL treatment and LDLr knockdown. CONCLUSIONS: Together, these results suggest that high LDL levels and a loss of LDLr function, which are characteristic to individuals with FH, might contribute to a disease-related impairment in adult hippocampal neurogenesis and, consequently, cognitive functions.

Usefulness of Gemcabene in Homozygous Familial Hypercholesterolemia (from COBALT-1).

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated plasma low-density lipoprotein-cholesterol (LDL-C), and premature atherosclerotic cardiovascular disease. Depending on residual LDL receptor (LDLR) function, most HoFH patients respond modestly to statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. However, LDL-C typically remains markedly elevated necessitating additional therapies, including apheresis. Gemcabene is a novel lipid-lowering agent with a mechanism of action independent of the LDLR, which has previously demonstrated the ability to reduce levels of LDL-C on top of maximally tolerated statins. The present study (COBALT-1) assessed efficacy, tolerability, and safety of gemcabene as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients. Eight patients with either a clinical or genetic diagnosis of HoFH on stable standard of care, including statins, ezetimibe, and PCSK9 inhibitors, were treated with gemcabene in an open-label study for 12 weeks. DNA analysis for mutations in the LDLR, apolipoprotein B, and PCSK9 genes was performed. Patients received 300 mg gemcabene for the first 4 weeks, 600 mg for the next 4 weeks, and 900 mg for the final 4 weeks. All patients completed the 12-week study. Mean change from baseline in LDL-C was -26% (p = 0.004) at Week 4 (300 mg), -30% (p = 0.001) at Week 8 (600 mg), and -29% (p = 0.001) at Week 12 (900 mg). In conclusion, the COBALT-1 study demonstrates gemcabene has potential to significantly reduce LDL-C levels when used as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients.

Addition of marine omega-3 fatty acids to statins in familial hypercholesterolemia does not affect in vivo or in vitro endothelial function.

BACKGROUND: Prestatin trials reported positive effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) in cardiovascular disease, whereas recent studies and meta-analyses have not reproduced these results. The effect of n-3 PUFA in patients with familial hypercholesterolemia (FH), a group with particularly high risk of cardiovascular disease, is not well established. OBJECTIVE: We investigated the effect of n-3 PUFA in the early stage of atherosclerosis in FH patients by evaluating in vivo (peripheral arterial tonometry [PAT]) and in vitro (plasma asymmetric dimethylarginine and E-selectin) endothelial function. METHODS: This was a double-blind, placebo-controlled cross-over study with 34 FH patients on statin treatment (mean age 46.6 years). In random order, all individuals were treated for 3 months with high-dose n-3 PUFA (2 g, ×2) and 3 months placebo (olive oil, 2 g ×2), separated by a 3-month washout period. Anthropometric data, blood samples, and PAT were collected at 4 time points. RESULTS: There were no significant changes in reactive hyperemia index measured by PAT after n-3 PUFA compared with placebo, median reactive hyperemia index after n-3 PUFA was 1.98 and after placebo 1.96 (P = .51). No significant changes were detected in the soluble endothelial marker asymmetric dimethylarginine (in 2 different assays) when comparing n-3 PUFA and placebo (P = .92 and .14, respectively). Finally, the level of E-selectin did not change significantly during the trial (P = .26). CONCLUSION: Addition of n-3 PUFA to standard lipid-lowering treatment in genetically verified FH patients did not affect the in vivo endothelial function or soluble endothelial markers.

Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients.

BACKGROUND AND AIMS: More than 4970 variants in the low-density lipoprotein receptor (LDLR) gene and 350 variants in the proprotein convertase subtilisin/kexin 9 (PCSK9) gene have been reported in familial hypercholesterolemia (FH) patients. However, the effects of these variants on FH pathophysiology have not been fully clarified. We aimed to update the LDLR and PCSK9 variants in Japanese heterozygous FH (HeFH) patients and annotate their clinical significance for the genetic diagnosis of HeFH. METHODS: A genetic analysis of the LDLR and PCSK9 genes was performed in 801 clinically diagnosed HeFH patients. The association of the pathogenic variants with the clinical FH phenotype was examined. RESULTS: Pathogenic variants in the LDLR and PCSK9 genes were found in 46% (n = 296) and 7.8% (n = 51) of unrelated FH patients (n = 650), respectively. The prevalence of Achilles tendon thickness was low (44%) in patients harbouring PCSK9 pathogenic variants. Furthermore, 17% of unrelated FH patients harboured one of five frequent LDLR pathogenic variants: c.1845+2T > C, c.1012T > A: p.(Cys338Ser), c.1297G > C: p.(Asp433His), c.1702C > G: p.(Leu568Val), and c.2431A > T: p.(Lys811*). Patients harbouring the c.1845+2T > C and c.1702C > G: p.(Leu568Val) variants had significantly lower serum LDL-cholesterol levels and higher serum HDL-cholesterol levels, respectively, compared with those harbouring the other LDLR pathogenic variants. The proportion of LDLR pathogenic variants was higher in patients with a younger age of coronary artery disease (CAD) onset and significantly decreased as the age of CAD onset increased. CONCLUSIONS: This study annotated the clinical significance and characteristics of LDLR and PCSK9 pathogenic variants in Japanese HeFH patients.

Ser-Phosphorylation of PCSK9 (Proprotein Convertase Subtilisin-Kexin 9) by Fam20C (Family With Sequence Similarity 20, Member C) Kinase Enhances Its Ability to Degrade the LDLR (Low-Density Lipoprotein Receptor).

OBJECTIVE: PCSK9 (proprotein convertase subtilisin-kexin 9) enhances the degradation of the LDLR (low-density lipoprotein receptor) in endosomes/lysosomes. This study aimed to determine the sites of PCSK9 phosphorylation at Ser-residues and the consequences of such posttranslational modification on the secretion and activity of PCSK9 on the LDLR. Approach and Results: Fam20C (family with sequence similarity 20, member C) phosphorylates serines in secretory proteins containing the motif S-X-E/phospho-Ser, including the cholesterol-regulating PCSK9. In situ hybridization of Fam20C mRNA during development and in adult mice revealed a wide tissue distribution, including liver, but not small intestine. Here, we show that Fam20C phosphorylates PCSK9 at Serines 47, 666, 668, and 688. In hepatocytes, phosphorylation enhances PCSK9 secretion and maximizes its induced degradation of the LDLR via the extracellular and intracellular pathways. Replacing any of the 4 Ser by the phosphomimetic Glu or Asp enhanced PCSK9 activity only when the other sites are phosphorylated, whereas Ala substitutions reduced it, as evidenced by Western blotting, Elisa, and LDLR-immunolabeling. This newly uncovered PCSK9/LDLR regulation mechanism refines our understanding of the implication of global PCSK9 phosphorylation in the modulation of LDL-cholesterol and rationalizes the consequence of natural mutations, for example, S668R and E670G. Finally, the relationship of Ser-phosphorylation to the implication of PCSK9 in regulating LDL-cholesterol in the neurological Fragile X-syndrome disorder was investigated. CONCLUSIONS: Ser-phosphorylation of PCSK9 maximizes both its secretion and activity on the LDLR. Mass spectrometric approaches to measure such modifications were developed and applied to quantify the levels of bioactive PCSK9 in human plasma under normal and pathological conditions.

Hipercolesterolemia familiar. Enfoque desde la Pediatría / Familial hypercholesterolemia. A pediatric focus

La Hipercolesterolemia Familiar (HF) es una enfermedad hereditaria frecuente que se caracteriza por niveles elevados de colesterol ligado a las lipoproteínas de baja densidad (C-LDL). El exceso de LDL se acumula en las arterias produciendo aterosclerosis prematura. El diagnóstico y tratamiento desde la infancia mejoran el pronóstico de la enfermedad. Existe subdiagnóstico de la HF lo que provoca muertes prematuras por enfermedad cardiovascular (ECV). Para mejorar el subdiagnóstico la Sociedad Argentina de Pediatría propuso en el año 2015 realizar tamizaje universal al ingreso escolar. Es relevante entonces que el pediatra pueda diagnosticar la hipercolesterolemia y diferenciar las hipercolesterolemias monogénicas o familiares, de las secundarias (AU)

Familial hypercholesterolemia (FH) is a common hereditary disease that is characterized by high cholesterol levels, linked to low-density lipoproteins (LDL). Excess LDL accumulates in the arteries leading to premature atherosclerosis. Early diagnosis and treatment since childhood improve the prognosis of the disease. FH is underdiagnosed resulting in premature death due to cardiovascular disease (CVD). To improve diagnosis, in 2015 the Argentine Society of Pediatrics proposed a universal screening program at school age. It is relevant, therefore, for the pediatrician to be able to diagnose hypercholesterolemia and differentiate monogenic or familial from secondary hypercholesterolemia (AU)

Indications of PCSK9 inhibitors in clinical practice. Recommendations of the Spanish Sociey of Arteriosclerosis (SEA), 2019. / Indicaciones de los inhibidores de PCSK9 en la práctica clínica. Recomendaciones de la Sociedad Española de Arteriosclerosis (SEA), 2019.

A group of experts convened by the Spanish Society of Arteriosclerosis (SEA) has been in charge of updating the SEA document on the indications of PCSK9 inhibitors (PCSK9i) in clinical practice that was published in 2016. This update is justified by the fact that the data from clinical trials carried out on a large scale with PCSK9i have shown that in addition to their high potency to lower atherogenic cholesterol, they reduce the risk of atherosclerotic cardiovascular disease, both in patients with stable disease, and with recent disease, and with a high degree of security. This update provides the recommendations and level of evidence for the prescription of iPCSK9 in patients with homozygous and heterozygous familial hypercholesterolemia, with atherosclerotic cardiovascular disease, and in primary prevention in patients with very high cardiovascular risk. These recommendations have been established taking into account the concentration of LDL-C, the clinical situation of the patient, the additional risk factors and the cost-effectiveness of their use.

Review of the long-term safety of lomitapide: a microsomal triglycerides transfer protein inhibitor for treating homozygous familial hypercholesterolemia.

INTRODUCTION: Homozygous familial hypercholesterolemia (HoFH) is a rare and life-threatening lipid disorder characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) concentrations and premature atherosclerotic cardiovascular disease (CVD). Conventional lipid-lowering agents remain insufficient in managing this disease, which emphasize the unmet medical need for potential therapies capable of lowering LDL-C and decreasing CVD risk in this patient population. AREAS COVERED: Novel LDL receptor (LDLR) independent drugs have been recently approved or are in development for the treatment of HoFH, including lomitapide (Juxtapid®). This oral microsomal triglyceride transfer protein (MTP) inhibitor was approved in 2012 in several countries as an adjunct to a low-fat diet and other lipid-lowering drugs with or without LDL apheresis to treat patients with HoFH. This review summarizes key safety and efficacy data of lomitapide from clinical trials and 'real-life' experience. EXPERT OPINION: While lomitapide is an interesting therapy for treating HoFH, long-term safety, as well as cardiovascular outcome data, are yet to be provided. Precision medicine has recently contributed to the development of several agents designed to address the unmet medical need of HoFH. However, combining safety, efficacy, accessibility, and affordability in a single therapy constitutes very challenging individual and societal paradigms in HoFH treatment.

Differential impact of severe familial hypercholesterolemia on regional skeletal muscle and organ blood flows during exercise: Effects of PDE5 inhibition.

OBJECTIVE: Swine with familial hypercholesterolemia (FH) exhibit attenuated exercise-induced systemic vasodilation that is restored by phosphodiesterase 5 (PDE5) inhibition. Whether the impacts of FH and PDE5 inhibition to impair and restore exercise-induced vasodilation, respectively, results from tissue-specific or generalized effects remains unclear. Thus, we hypothesized that FH induces generalized impairment of skeletal muscle vasodilation that would be alleviated by PDE5 inhibition. METHODS: Systemic vascular responses to exercise were assessed in chronically instrumented normal and FH swine before and after PDE5 inhibition with EMD360527. Skeletal muscle and organ blood flows and conductances were determined via the microsphere technique. RESULTS: As previously reported, vs normal swine, FH swine have pronounced elevation of total cholesterol and impaired exercise-induced vasodilation that is restored by PDE5 inhibition. Blood flows to several, not all, skeletal muscle vascular beds were severely impaired by FH associated with reduced blood flow to many visceral organs. PDE5 inhibition differentially impacted skeletal muscle and organ blood flows in normal and FH swine. CONCLUSIONS: These data indicate that FH induces regional, not generalized, vasomotor dysfunction and that FH and normal swine exhibit unique tissue blood flow responses to PDE5 inhibition thereby adding to accumulating evidence of vascular bed-specific dysfunction in co-morbid conditions.