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Gerald F Watts - One of the best experts on this subject based on the ideXlab platform.

  • prevalence of Familial Hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease a systematic review and meta analysis
    Circulation, 2020
    Co-Authors: Kanika I. Dharmayat, Gerald F Watts, Kausik K. Ray, Jacques Genest, C Stevens, Mansour T A Sharabiani, Rebecca S Jones, Antonio J Vallejovaz
    Abstract:

    Background: Contemporary studies suggest that Familial Hypercholesterolemia (FH) is more frequent than previously reported and increasingly recognized as affecting individuals of all ethnicities an...

  • long term evolocumab in patients with Familial Hypercholesterolemia
    Journal of the American College of Cardiology, 2020
    Co-Authors: Raul D Santos, Gerald F Watts, Kees G Hovingh, Evan A Stein, Dirk J Blom, Handrean Soran, Antonio J G Lopez, Sarah Bray, Christopher E Kurtz
    Abstract:

    Abstract Background Proprotein convertase subtilisin/kexin type 9 inhibitor therapy is a treatment option for patients with Familial Hypercholesterolemia (FH) who are unable to reach low-density lipoprotein cholesterol (LDL-C) goals. Objectives The aim of this study was to provide long-term safety and efficacy data for evolocumab in patients with homozygous FH (HoFH) and severe heterozygous FH (HeFH). Methods In this open-label, single-arm study, patients with HoFH or severe HeFH ≥12 years of age and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint was the incidence of treatment-emergent adverse events; secondary endpoints were changes in LDL-C and other lipids. Results In total, 300 patients (106 with HoFH, including 14  Conclusions Evolocumab was well tolerated and effectively reduced plasma LDL-C levels in patients with HoFH and severe HeFH over a median of 4.1 years.

  • value of measuring lipoprotein a during cascade testing for Familial Hypercholesterolemia
    Journal of the American College of Cardiology, 2019
    Co-Authors: Katrina L Ellis, Gerald F Watts, Leopoldo Perez De Isla, Rodrigo Alonso, Francisco Fuentes, Pedro Mata
    Abstract:

    Abstract Background Familial Hypercholesterolemia (FH) and elevated lipoprotein(a) [Lp(a)] are inherited disorders associated with premature atherosclerotic cardiovascular disease (ASCVD). Cascade testing is recommended for FH, but there are no similar recommendations for elevated Lp(a). Objectives This study investigated whether testing for Lp(a) was effective in detecting and risk stratifying individuals participating in an FH cascade screening program. Methods Family members (N = 2,927) from 755 index cases enrolled in SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) were tested for genetic FH and elevated Lp(a) via an established screening program. Elevated Lp(a) was defined as levels ≥50 mg/dl. The authors compared the prevalence and yield of new cases of high Lp(a) in relatives of FH probands both with and without high Lp(a), and prospectively investigated the association between elevated Lp(a) and ASCVD events among family members. Results Systematic screening from index cases with both FH and elevated Lp(a) identified 1 new case of elevated Lp(a) for every 2.4 screened. Opportunistic screening from index cases with FH, but without elevated Lp(a), identified 1 individual for 5.8 screened. Over 5 years’ follow-up, FH (hazard ratio [HR]: 2.47; p = 0.036) and elevated Lp(a) (HR: 3.17; p = 0.024) alone were associated with a significantly increased risk of experiencing an ASCVD event or death compared with individuals with neither disorder; the greatest risk was observed in relatives with both FH and elevated Lp(a) (HR: 4.40; p  Conclusions Testing for elevated Lp(a) during cascade screening for FH is effective in identifying relatives with high Lp(a) and heightened risk of ASCVD, particularly when the proband has both FH and elevated Lp(a).

  • attainment of ldl cholesterol treatment goals in patients with Familial Hypercholesterolemia 5 year safeheart registry follow up
    Journal of the American College of Cardiology, 2016
    Co-Authors: Leopoldo Perez De Isla, Gerald F Watts, Rodrigo Alonso, Nelva Mata, Ovidio Muniz, Jose Luis Diazdiaz, Raimundo De Andres, Francisco Fuentes, Adriana Saltijeral Cerezo, Daniel Zambon
    Abstract:

    Abstract Background Familial Hypercholesterolemia (FH) is the most common genetic disorder associated with premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data on attainment of treatment targets; large registries that reflect real-life clinical practice can uniquely provide this information. Objectives We sought to evaluate the achievement of low-density lipoprotein cholesterol (LDL-C) treatment goals in FH patients enrolled in a large national registry. Methods The SAFEHEART study (Spanish Familial Hypercholesterolemia Cohort Study) is a large, ongoing registry of molecularly defined patients with heterozygous FH treated in Spain. The attainment of guideline-recommended plasma LDL-C goals at entry and follow-up was investigated in relation to use of lipid-lowering therapy (LLT). Results The study recruited 4,132 individuals (3,745 of whom were ≥18 years of age); 2,752 of those enrolled were molecularly diagnosed FH cases. Mean follow-up was 5.1 ± 3.1 years; 71.8% of FH cases were on maximal LLT, and an LDL-C treatment target  Conclusions Despite the use of intensified LLT, many FH patients continue to experience high plasma LDL-C levels and, consequently, do not achieve recommended treatment targets. Type of LDL-receptor mutation, use of ezetimibe, coexistent diabetes, and ASCVD status can bear significantly on the likelihood of attaining LDL-C treatment goals.

  • Familial Hypercholesterolemia a missed opportunity in preventive medicine
    Nature Reviews Cardiology, 2007
    Co-Authors: Gerald F Watts, Barry Lewis, David R Sullivan
    Abstract:

    Although Familial Hypercholesterolemia is eminently treatable, the majority of cases go undetected, and this disorder remains a major challenge for preventive medicine. In this timely Viewpoint, Gerald Watts, Barry Lewis, and David Sullivan discuss how new genetic screening initiatives, together with a co-operative approach to treatment, could result in a quantum leap for coronary disease prevention.

Evan A Stein - One of the best experts on this subject based on the ideXlab platform.

John J P Kastelein - One of the best experts on this subject based on the ideXlab platform.

  • evinacumab for homozygous Familial Hypercholesterolemia
    The New England Journal of Medicine, 2020
    Co-Authors: Frederick J Raal, Robert S Rosenson, Laurens F Reeskamp, Kees G Hovingh, John J P Kastelein, P Rubba, Shazia Ali, Poulabi Banerjee, Kuochen Chan, Daniel A Gipe
    Abstract:

    Abstract Background Homozygous Familial Hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. Th...

  • 20 year follow up of statins in children with Familial Hypercholesterolemia
    The New England Journal of Medicine, 2019
    Co-Authors: Ilse K Luirink, John J P Kastelein, Albert Wiegman, Meeike D Kusters, Michel H Hof, Jaap W Groothoff, Eric De Groot, Barbara A Hutten
    Abstract:

    Abstract Background Familial Hypercholesterolemia is characterized by severely elevated low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. The short-term efficac...

  • association between Familial Hypercholesterolemia and prevalence of type 2 diabetes mellitus
    JAMA, 2015
    Co-Authors: Joost Besseling, John J P Kastelein, Joep C Defesche, Barbara A Hutten, Kees G Hovingh
    Abstract:

    Importance Familial Hypercholesterolemia is characterized by impaired uptake of cholesterol in peripheral tissues, including the liver and the pancreas. In contrast, statins increase the cellular cholesterol uptake and are associated with increased risk for type 2 diabetes mellitus. We hypothesize that transmembrane cholesterol transport is linked to the development of type 2 diabetes. Objective To assess the association between type 2 diabetes prevalence and Familial Hypercholesterolemia. Design, Setting, and Participants Cross-sectional study in all individuals (n = 63 320) who underwent DNA testing for Familial Hypercholesterolemia in the national Dutch screening program between 1994 and 2014. Exposures Deleteriousness and nondeleteriousness of Familial Hypercholesterolemia mutations were based on literature or laboratory function testing. Low-density lipoprotein (LDL) receptor mutations were considered more severe than apolipoprotein B gene ( APOB ) mutations, and receptor-negative LDL receptor mutations were considered more severe than receptor-deficient mutations. Main Outcomes and Measures Prevalence of type 2 diabetes. Results The prevalence of type 2 diabetes was 1.75% in Familial Hypercholesterolemia patients (n = 440/25 137) vs 2.93% in unaffected relatives (n = 1119/38 183) ( P P APOB vs LDL receptor gene was 1.91% vs 1.33% (OR, 0.65 [95% CI, 0.48-0.87] vs OR, 0.45 [95% CI, 0.38-0.54]), and the prevalence for receptor-deficient vs receptor-negative mutation carriers was 1.44% vs 1.12% (OR, 0.49 [95% CI, 0.40-0.60] vs OR, 0.38 [95% CI, 0.29-0.49]), respectively ( P for trend Conclusions and Relevance In a cross-sectional analysis in the Netherlands, the prevalence of type 2 diabetes among patients with Familial Hypercholesterolemia was significantly lower than among unaffected relatives, with variability by mutation type. If this finding is confirmed in longitudinal analysis, it would raise the possibility of a causal relationship between LDL receptor-mediated transmembrane cholesterol transport and type 2 diabetes.

  • carotid intima media thickness in children with Familial Hypercholesterolemia
    Circulation Research, 2014
    Co-Authors: D M Kusters, John J P Kastelein, Albert Wiegman, Barbara A Hutten
    Abstract:

    Rationale: Familial Hypercholesterolemia (FH) predisposes patients to premature cardiovascular disease, with the process of atherosclerosis initiated in early childhood. Objective: As part of an ongoing trial to assess the efficacy and safety of rosuvastatin in children with FH aged 6 to 17 years, we report the differences in carotid intima-media thickness (cIMT) at baseline between children with FH and their unaffected siblings. Methods and Results: B-mode ultrasound measurements of the carotid artery were made in 196 children with FH and 64 of their siblings. Mean (±SE) cIMT in children with FH was significantly greater than that of unaffected siblings (0.398±0.052 versus 0.377±0.045 mm; P Conclusions: The difference in mean cIMT between children with FH and their unaffected siblings may be significant as early as age 8 years. This study confirms the need for early cholesterol lowering in this high-risk population. These patients participating in a carefully monitored study will help assess the long-term efficacy on cIMT and safety of statin therapy in young children.

  • efficacy and safety of rosuvastatin therapy for children with Familial Hypercholesterolemia
    Journal of the American College of Cardiology, 2010
    Co-Authors: Hans J Avis, John J P Kastelein, Barbara A Hutten, Albert Wiegman, Claude Gagne, Gisle Langslet, Brian W Mccrindle, Judith Hsia, Evan A Stein
    Abstract:

    Objectives: This study was undertaken to evaluate the efficacy and safety of rosuvastatin therapy for children with Familial Hypercholesterolemia.Background: Familial Hypercholesterolemia is a comm...

Frederick J Raal - One of the best experts on this subject based on the ideXlab platform.

  • evinacumab for homozygous Familial Hypercholesterolemia
    The New England Journal of Medicine, 2020
    Co-Authors: Frederick J Raal, Robert S Rosenson, Laurens F Reeskamp, Kees G Hovingh, John J P Kastelein, P Rubba, Shazia Ali, Poulabi Banerjee, Kuochen Chan, Daniel A Gipe
    Abstract:

    Abstract Background Homozygous Familial Hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. Th...

  • inclisiran for the treatment of heterozygous Familial Hypercholesterolemia
    The New England Journal of Medicine, 2020
    Co-Authors: Frederick J Raal, Kausik K. Ray, David Kallend, Traci Turner, Wolfgang Koenig, Scott R Wright, Peter Wijngaard, Danielle Curcio, Mark Jaros
    Abstract:

    Abstract Background Familial Hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascula...

  • Inclisiran for the treatment of heterozygous Familial Hypercholesterolemia
    'Massachusetts Medical Society', 2020
    Co-Authors: Frederick J Raal, Kallend D, Kk Ray, Turner T, Koenig W, Rs Wright, Wijngaard Plj, Curcio D, Mj Jaros, La Leiter
    Abstract:

    BACKGROUND: Familial Hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous Familial Hypercholesterolemia. METHODS: In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous Familial Hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540. RESULTS: The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P

  • Familial Hypercholesterolemia treatments guidelines and new therapies
    Atherosclerosis, 2018
    Co-Authors: Frederick J Raal, Kees G Hovingh, Alberico L Catapano
    Abstract:

    Familial Hypercholesterolemia (FH) is a genetic disorder resulting from mutations in genes encoding proteins involved in the metabolism of low density lipoproteins (LDL) and characterized by premature cardiovascular disease due to the exposure to high levels of LDL-cholesterol (LDL-C) from birth. Thus, the early identification of FH subjects, followed by appropriate treatment is essential to prevent or at least delay the onset of cardiovascular events. However, FH is largely underdiagnosed; in addition, FH patients are frequently not adequately treated, despite the availability of several pharmacological therapies to significantly reduce LDL-C levels. Current guidelines recommend LDL-C targets for FH (either heterozygotes [HeFH] or homozygotes [HoFH]) <100 mg/dL (<2.6 mmol/L) for adults or <70 mg/dL (<1.8 mmol/L) for adults with CHD or diabetes, and <135 mg/dL (<3.5 mmol/L) for children. With the pharmacological options now available, which include statins as a first approach, ezetimibe, and the recently approved monoclonal antibodies targeting PCSK9, the guideline recommended LDL-C target levels can be achieved in the majority of heterozygous FH subjects, while for the most severe forms of homozygous FH, the addition of therapies such as lomitapide either with or without apheresis may be required.

  • effect of the proprotein convertase subtilisin kexin 9 monoclonal antibody amg 145 in homozygous Familial Hypercholesterolemia
    Circulation, 2013
    Co-Authors: Evan A Stein, Narimon Honarpour, Scott M Wasserman, Rob Scott, Frederick J Raal
    Abstract:

    Background—Homozygous Familial Hypercholesterolemia is a rare, serious disorder with a substantial reduction in low-density lipoprotein (LDL) receptor function, severely elevated LDL cholesterol, cardiovascular disease, and often death in childhood. Response to conventional drug therapies is modest. Monoclonal antibodies to proprotein convertase subtilisin/kexin 9 (PCSK9) reduce LDL cholesterol in heterozygous Familial Hypercholesterolemia. The effect in homozygous Familial Hypercholesterolemia is unknown and uncertain. We evaluated the efficacy and safety of AMG 145 in an open-label, single-arm, multicenter, dose-scheduling pilot study in patients with homozygous Familial Hypercholesterolemia. Methods and Results—Eight patients with LDL receptor–negative or –defective homozygous Familial Hypercholesterolemia on stable drug therapy were treated with subcutaneous 420 mg AMG 145 every 4 weeks for ≥12 weeks, followed by 420 mg AMG 145 every 2 weeks for an additional 12 weeks. All patients completed both trea...

Barbara A Hutten - One of the best experts on this subject based on the ideXlab platform.

  • 20 year follow up of statins in children with Familial Hypercholesterolemia
    The New England Journal of Medicine, 2019
    Co-Authors: Ilse K Luirink, John J P Kastelein, Albert Wiegman, Meeike D Kusters, Michel H Hof, Jaap W Groothoff, Eric De Groot, Barbara A Hutten
    Abstract:

    Abstract Background Familial Hypercholesterolemia is characterized by severely elevated low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. The short-term efficac...

  • association between Familial Hypercholesterolemia and prevalence of type 2 diabetes mellitus
    JAMA, 2015
    Co-Authors: Joost Besseling, John J P Kastelein, Joep C Defesche, Barbara A Hutten, Kees G Hovingh
    Abstract:

    Importance Familial Hypercholesterolemia is characterized by impaired uptake of cholesterol in peripheral tissues, including the liver and the pancreas. In contrast, statins increase the cellular cholesterol uptake and are associated with increased risk for type 2 diabetes mellitus. We hypothesize that transmembrane cholesterol transport is linked to the development of type 2 diabetes. Objective To assess the association between type 2 diabetes prevalence and Familial Hypercholesterolemia. Design, Setting, and Participants Cross-sectional study in all individuals (n = 63 320) who underwent DNA testing for Familial Hypercholesterolemia in the national Dutch screening program between 1994 and 2014. Exposures Deleteriousness and nondeleteriousness of Familial Hypercholesterolemia mutations were based on literature or laboratory function testing. Low-density lipoprotein (LDL) receptor mutations were considered more severe than apolipoprotein B gene ( APOB ) mutations, and receptor-negative LDL receptor mutations were considered more severe than receptor-deficient mutations. Main Outcomes and Measures Prevalence of type 2 diabetes. Results The prevalence of type 2 diabetes was 1.75% in Familial Hypercholesterolemia patients (n = 440/25 137) vs 2.93% in unaffected relatives (n = 1119/38 183) ( P P APOB vs LDL receptor gene was 1.91% vs 1.33% (OR, 0.65 [95% CI, 0.48-0.87] vs OR, 0.45 [95% CI, 0.38-0.54]), and the prevalence for receptor-deficient vs receptor-negative mutation carriers was 1.44% vs 1.12% (OR, 0.49 [95% CI, 0.40-0.60] vs OR, 0.38 [95% CI, 0.29-0.49]), respectively ( P for trend Conclusions and Relevance In a cross-sectional analysis in the Netherlands, the prevalence of type 2 diabetes among patients with Familial Hypercholesterolemia was significantly lower than among unaffected relatives, with variability by mutation type. If this finding is confirmed in longitudinal analysis, it would raise the possibility of a causal relationship between LDL receptor-mediated transmembrane cholesterol transport and type 2 diabetes.

  • carotid intima media thickness in children with Familial Hypercholesterolemia
    Circulation Research, 2014
    Co-Authors: D M Kusters, John J P Kastelein, Albert Wiegman, Barbara A Hutten
    Abstract:

    Rationale: Familial Hypercholesterolemia (FH) predisposes patients to premature cardiovascular disease, with the process of atherosclerosis initiated in early childhood. Objective: As part of an ongoing trial to assess the efficacy and safety of rosuvastatin in children with FH aged 6 to 17 years, we report the differences in carotid intima-media thickness (cIMT) at baseline between children with FH and their unaffected siblings. Methods and Results: B-mode ultrasound measurements of the carotid artery were made in 196 children with FH and 64 of their siblings. Mean (±SE) cIMT in children with FH was significantly greater than that of unaffected siblings (0.398±0.052 versus 0.377±0.045 mm; P Conclusions: The difference in mean cIMT between children with FH and their unaffected siblings may be significant as early as age 8 years. This study confirms the need for early cholesterol lowering in this high-risk population. These patients participating in a carefully monitored study will help assess the long-term efficacy on cIMT and safety of statin therapy in young children.

  • efficacy and safety of rosuvastatin therapy for children with Familial Hypercholesterolemia
    Journal of the American College of Cardiology, 2010
    Co-Authors: Hans J Avis, John J P Kastelein, Barbara A Hutten, Albert Wiegman, Claude Gagne, Gisle Langslet, Brian W Mccrindle, Judith Hsia, Evan A Stein
    Abstract:

    Objectives: This study was undertaken to evaluate the efficacy and safety of rosuvastatin therapy for children with Familial Hypercholesterolemia.Background: Familial Hypercholesterolemia is a comm...

  • pregnancy in women suffering from Familial Hypercholesterolemia a harmful period for both mother and newborn
    Current Opinion in Lipidology, 2009
    Co-Authors: Hans J Avis, John J P Kastelein, Barbara A Hutten, Marcel Th B Twickler, Joris A M Van Der Post, Anton F H Stalenhoef, Maud N Vissers
    Abstract:

    PURPOSE OF REVIEW: The present review aims to highlight the consequences for mother and child of profound Hypercholesterolemia during pregnancy of women with Familial Hypercholesterolemia. RECENT FINDINGS: Familial Hypercholesterolemia is increasingly diagnosed in younger patients due to the existence of screening programs and more widespread cholesterol testing. Increasing numbers of young female patients with Familial Hypercholesterolemia raise the issue of pregnancy and its consequences for the Familial Hypercholesterolemia patient herself but also for her offspring. When pregnancy is considered, lipid-lowering drugs are often discontinued because of the fear for teratogenic effects. The evidence for teratogenesis associated with statin use is scant and conflicting. On the other hand, several studies do suggest that pronounced Hypercholesterolemia during pregnancy has adverse effects on both fetus and mother. In fact, human and animal studies reveal an enhanced tendency toward atherosclerosis in the offspring of women who suffer from Hypercholesterolemia during pregnancy. In animal studies, some evidence exists that this can be reversed by treatment with lipid-lowering and antioxidative agents. Until today, however, no human studies exist that have evaluated efficacy or safety of lipid-lowering interventions in pregnant women with Familial Hypercholesterolemia. SUMMARY: Altogether, the suggested relationship between severe Hypercholesterolemia and enhanced atherosclerosis in offspring and possibly the mother warrants further confirmation and, consequently, studies that focus on therapeutic strategies that can safely lower cholesterol levels during pregnancy in these women.