scholarly journals Management of Familial Hypercholesterolemia: Current Status and Future Perspectives

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
David T W Lui ◽  
Alan C H Lee ◽  
Kathryn C B Tan
Keyword(s):  
Familial Hypercholesterolemia ◽  
Ldl Cholesterol ◽  
Genetic Disorder ◽  
Lipid Lowering ◽  
Current Status ◽  
Atherosclerotic Cardiovascular Disease ◽  
Inadequate Response ◽  
Cholesterol Lowering ◽  
Cholesterol Levels ◽  
Pubmed Database

Abstract Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with premature atherosclerotic cardiovascular disease. Early diagnosis and effective treatment can significantly improve prognosis. Recent advances in the field of lipid metabolism have shed light on the molecular defects in FH and new therapeutic options have emerged. A search of PubMed database up to March 2020 was performed for this review using the following keywords: “familial hypercholesterolemia,” “diagnosis,” “management,” “guideline,” “consensus,” “genetics,” “screening,” “lipid lowering agents.” The prevalence rate of heterozygous FH is approximately 1 in 200 to 250 and FH is underdiagnosed and undertreated in many parts of the world. Diagnostic criteria have been developed to aid the clinical diagnosis of FH. Genetic testing is now available but not widely used. Cascade screening is recommended to identify affected family members, and the benefits of early interventions are clear. Treatment strategy and target is currently based on low-density lipoprotein (LDL) cholesterol levels as the prognosis of FH largely depends on the magnitude of LDL cholesterol-lowering that can be achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment and are cost-effective. Addition of newer medications like PCSK9 inhibitors is able to further lower LDL cholesterol levels substantially, but the cost is high. Lipoprotein apheresis is indicated in homozygous FH or severe heterozygous FH patients with inadequate response to cholesterol-lowering therapies. In conclusion, FH is a common, treatable genetic disorder, and although our understanding of this disease has improved, many challenges still remain for its optimal management.

scholarly journals Imputation of Baseline LDL Cholesterol Concentration in Patients with Familial Hypercholesterolemia on Statins or Ezetimibe

2018 ◽  
Vol 64 (2) ◽  
pp. 355-362 ◽  
Author(s):  
Isabelle Ruel ◽  
Sumayah Aljenedil ◽  
Iman Sadri ◽  
Émilie de Varennes ◽  
Robert A Hegele ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Ldl Cholesterol ◽  
Genetic Disorder ◽  
Pathogenic Mutation ◽  
Pharmacological Therapy ◽  
Cholesterol Concentration ◽  
Atherosclerotic Cardiovascular Disease ◽  
Percent Reduction ◽  
The Mean ◽  
The Individual

Abstract BACKGROUND Familial hypercholesterolemia (FH) is the most frequent genetic disorder seen clinically and is characterized by increased LDL cholesterol (LDL-C) (>95th percentile), family history of increased LDL-C, premature atherosclerotic cardiovascular disease (ASCVD) in the patient or in first-degree relatives, presence of tendinous xanthomas or premature corneal arcus, or presence of a pathogenic mutation in the LDLR, PCSK9, or APOB genes. A diagnosis of FH has important clinical implications with respect to lifelong risk of ASCVD and requirement for intensive pharmacological therapy. The concentration of baseline LDL-C (untreated) is essential for the diagnosis of FH but is often not available because the individual is already on statin therapy. METHODS To validate a new algorithm to impute baseline LDL-C, we examined 1297 patients. The baseline LDL-C was compared with the imputed baseline obtained within 18 months of the initiation of therapy. We compared the percent reduction in LDL-C on treatment from baseline with the published percent reductions. RESULTS After eliminating individuals with missing data, nonstandard doses of statins, or medications other than statins or ezetimibe, we provide data on 951 patients. The mean ± SE baseline LDL-C was 243.0 (2.2) mg/dL [6.28 (0.06) mmol/L], and the mean ± SE imputed baseline LDL-C was 244.2 (2.6) mg/dL [6.31 (0.07) mmol/L] (P = 0.48). There was no difference in response according to the patient's sex or in percent reduction between observed and expected for individual doses or types of statin or ezetimibe. CONCLUSIONS We provide a validated estimation of baseline LDL-C for patients with FH that may help clinicians in making a diagnosis.

Targeting the Cholesterol Paradigm in the Risk Reduction for Atherosclerotic Cardiovascular Disease: Does the Mechanism of Action of Pharmacotherapy Matter for Clinical Outcomes?

2021 ◽  
pp. 107424842110236
Author(s):  
Ruihai Zhou ◽  
George A. Stouffer ◽  
Sidney C. Smith
Keyword(s):  
Cardiovascular Disease ◽  
Clinical Outcomes ◽  
Mechanism Of Action ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Blood Cholesterol ◽  
Atherosclerotic Cardiovascular Disease ◽  
Pcsk9 Inhibitors ◽  
Cholesterol Lowering ◽  
Cholesterol Levels

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as “bad” cholesterol and high-density lipoprotein cholesterol (HDL-C) as “good” cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.

scholarly journals The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 66
Author(s):  
Alexey Meshkov ◽  
Alexandra Ershova ◽  
Anna Kiseleva ◽  
Evgenia Zotova ◽  
Evgeniia Sotnikova ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Significant Proportion ◽  
Density Lipoprotein ◽  
Genetic Diagnostics ◽  
Atherosclerotic Cardiovascular Disease ◽  
Gene Variants ◽  
Systematic Analysis ◽  
Pcsk9 Gene ◽  
Cholesterol Levels

Familial hypercholesterolemia (FH) is a common autosomal codominant disorder, characterized by elevated low-density lipoprotein cholesterol levels causing premature atherosclerotic cardiovascular disease. About 2900 variants of LDLR, APOB, and PCSK9 genes potentially associated with FH have been described earlier. Nevertheless, the genetics of FH in a Russian population is poorly understood. The aim of this study is to present data on the spectrum of LDLR, APOB, and PCSK9 gene variants in a cohort of 595 index Russian patients with FH, as well as an additional systematic analysis of the literature for the period of 1995–2020 on LDLR, APOB and PCSK9 gene variants described in Russian patients with FH. We used targeted and whole genome sequencing to search for variants. Accordingly, when combining our novel data and the data of a systematic literature review, we described 224 variants: 187 variants in LDLR, 14 variants in APOB, and 23 variants in PCSK9. A significant proportion of variants, 81 of 224 (36.1%), were not described earlier in FH patients in other populations and may be specific for Russia. Thus, this study significantly supplements knowledge about the spectrum of variants causing FH in Russia and may contribute to a wider implementation of genetic diagnostics in FH patients in Russia.

Increased Superoxide Anion Production by Platelets in Hypercholesterolemic Patients

2002 ◽  
Vol 87 (05) ◽  
pp. 796-801 ◽  
Author(s):  
Valerio Sanguigni ◽  
Pasquale Pignatelli ◽  
Daniela Caccese ◽  
Fabio Pulcinelli ◽  
Luisa Lenti ◽  
...  
Keyword(s):  
Superoxide Anion ◽  
Ldl Cholesterol ◽  
Experimental Studies ◽  
Human Platelets ◽  
Superoxide Anion Production ◽  
Cholesterol Lowering ◽  
Platelet Production ◽  
Cholesterol Levels ◽  
Anion Production ◽  
O2 Production

SummaryThe purpose of this study was to investigate the relationship between hypercholesterolemia and superoxide anion production.Experimental studies demonstrated that hypercholesterolemia is associated with enhanced cellular superoxide anion (O2 −) production. Aim of the study was to assess whether the same phenomenon occurs in humans.Lipid profile and platelet O2 − production were measured in 28 patients with hypercholesterolemia, compared with 25 age- and sexmatched healthy subjects, and in 21 out of the 28 patients after 8-week treatment with 10 mg/day atorvastatin (a HMGCoA reductase inhibitor). In order to assess the mechanism by which LDL cholesterol interferes with platelet production of O2 −, human platelets were incubated with LDL cholesterol in the presence of either an inhibitor of the phospholipaseA2 enzyme, AACOCF3, or an inhibitor of NADH/NADPH oxidases, DPI.O2 − platelet generation was significantly higher (p <0.001) and significantly related to LDL cholesterol (p < 0.001 ) in patients as compared to controls. 8-week treatment with 10 mg/day atorvastatin significantly reduced both LDL cholesterol and O2 − platelet production. This effect was partially related to the cholesterol-lowering, in that three days of treatment with atorvastatin significantly decreased platelet O2 − production, while no significant change in LDL-cholesterol levels was observed. Platelets incubated with LDL cholesterol showed O2 − release by atorvastatin is partially related to cholesterol lowering effect, suggesting that other mechanisms could be responsible for the antioxidant activity of the drug.

scholarly journals Cerebrovascular Disease and Statins

2021 ◽  
Vol 8 ◽  
Author(s):  
Luis M. Beltrán Romero ◽  
Antonio J. Vallejo-Vaz ◽  
Ovidio Muñiz Grijalvo
Keyword(s):  
Ischemic Stroke ◽  
Secondary Prevention ◽  
Cerebrovascular Disease ◽  
Small Vessel Disease ◽  
Recurrent Stroke ◽  
Public Health Problem ◽  
Lipid Lowering ◽  
Major Public Health Problem ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cholesterol Levels

Elevated low-density lipoprotein-cholesterol (LDL-C) is a causal factor for the development of atherosclerotic cardiovascular disease (ASCVD); accordingly, LDL-C lowering is associated with a decreased risk of progression of atherosclerotic plaques and development of complications. Currently, statins play a central role in any ASCVD management and prevention strategies, in relation to their lipid-lowering action and potentially to pleiotropic effects. After coronary artery disease, stroke is the most frequent cause of ASCVD mortality and the leading cause of acquired disability, a major public health problem. There is often a tendency to aggregate all types of stroke (atherothrombotic, cardioembolic, and haemorrhagic), which have, however, different causes and pathophysiology, what may lead to bias when interpreting the results of the studies. Survivors of a first atherothrombotic ischemic stroke are at high risk for coronary events, recurrent stroke, and vascular death. Although epidemiological studies show a weak relationship between cholesterol levels and cerebrovascular disease as a whole compared with other ASCVD types, statin intervention studies have demonstrated a decrease in the risk of stroke in patients with atherosclerosis of other territories and a decrease in all cardiovascular events in patients who have had a stroke. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial demonstrated the benefit of high doses of atorvastatin in the secondary prevention of ischemic stroke. In this review, we discuss the evidence, use and recommendations of statins in the primary and secondary prevention of stroke, and their role in other scenarios such as the acute phase of ischemic stroke, cerebral hemorrhage, cardioembolic stroke, small vessel disease, and cognitive impairment.

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