scholarly journals Genetics of Hypercholesterolemia: Comparison Between Familial Hypercholesterolemia and Hypercholesterolemia Nonrelated to LDL Receptor

2020 ◽  
Vol 11 ◽  
Author(s):  
Estíbaliz Jarauta ◽  
Ana Ma Bea-Sanz ◽  
Victoria Marco-Benedi ◽  
Itziar Lamiquiz-Moneo
Keyword(s):  
Cardiovascular Risk ◽  
Familial Hypercholesterolemia ◽  
Genetic Defect ◽  
Genetic Diagnosis ◽  
Ldl Receptor ◽  
Lipid Lowering ◽  
Atherosclerotic Cardiovascular Disease ◽  
Single Nucleotide Variants ◽  
Cascade Screening ◽  
The Moment

Severe hypercholesterolemia (HC) is defined as an elevation of total cholesterol (TC) due to the increase in LDL cholesterol (LDL-C) >95th percentile or 190 mg/dl. The high values of LDL-C, especially when it is maintained over time, is considered a risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), mostly expressed as ischemic heart disease (IHD). One of the best characterized forms of severe HC, familial hypercholesterolemia (FH), is caused by the presence of a major variant in one gene (LDLR, APOB, PCSK9, or ApoE), with an autosomal codominant pattern of inheritance, causing an extreme elevation of LDL-C and early IHD. Nevertheless, an important proportion of serious HC cases, denominated polygenic hypercholesterolemia (PH), may be attributed to the small additive effect of a number of single nucleotide variants (SNVs), located along the whole genome. The diagnosis, prevalence, and cardiovascular risk associated with PH has not been fully established at the moment. Cascade screening to detect a specific genetic defect is advised in all first- and second-degree relatives of subjects with FH. Conversely, in the rest of cases of HC, it is only advised to screen high values of LDL-C in first-degree relatives since there is not a consensus for the genetic diagnosis of PH. FH is associated with the highest cardiovascular risk, followed by PH and other forms of HC. Early detection and initiation of high-intensity lipid-lowering treatment is proposed in all subjects with severe HC for the primary prevention of ASCVD, with an objective of LDL-C <100 mg/dl or a decrease of at least 50%. A more aggressive reduction in LDL-C is necessary in HC subjects who associate personal history of ASCVD or other cardiovascular risk factors.

Prognostic impact of cascade screening for familial hypercholesterolemia on cardiovascular events

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Tada ◽  
H Okada ◽  
A Nomura ◽  
A Nohara ◽  
M Yamagishi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Familial Hypercholesterolemia ◽  
Cardiovascular Events ◽  
Lipid Lowering ◽  
Funding Source ◽  
Atherosclerotic Cardiovascular Disease ◽  
Prognostic Impact ◽  
Cascade Screening ◽  
Ascvd Risk ◽  
The Impact

Abstract Background Early diagnosis and timely treatment for the patients with familial hypercholesterolemia (FH) can substantially lower the risk of atherosclerotic cardiovascular disease (ASCVD). In this sense, cascade screening could be one of the most useful options. However, few data exist regarding the impact of cascade screening for FH on the reduction of risk of ASCVD events. Objectives We aimed to evaluate the prognostic impact of cascade screening for FH. Methods We retrospectively investigated the health records of 1,050 patients with clinically diagnosed FH, including probands and their relatives who were cascade-screened. We used Cox models that were adjusted for established ASCVD risk factors to assess the association between cascade screening and major adverse cardiovascular events (MACE). The median period of follow-up was 12.3 years (interquartile range [IQR] = 9.1–17.5 years), and MACE included death from any causes or hospitalization due to ASCVD events. Results During the observation period, 246 participants experienced MACE. The mean age of patients identified through cascade screening was 18-years younger than that of the probands (38.7 yr vs. 57.0 yr, P<0.001), with a lower proportion of ASCVD risk factors. Interestingly, patients identified through cascade screening under milder lipid-lowering therapies were at reduced risk for MACE (hazard ratio [HR] = 0.36; 95% CI = 0.22 to 0.60; P<0.001) when compared with the probands, even after adjusting for those known risk factors. Conclusions The identification of patients with FH via cascade screening appeared to result in better prognoses. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Scientific research grants from the Ministry of Education, Science and Culture of Japan (no. 16K19394, 18K08064, and 19K08575)

Abstract 13328: Impact of Cascade Screening for Familial Hypercholesterolemia on Cardiovascular Events

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Hayato Tada ◽  
Atsushi Nohara ◽  
Masakazu Yamagishi ◽  
Masayuki Takamura ◽  
Masa-aki Kawashiri
Keyword(s):  
Risk Factors ◽  
Familial Hypercholesterolemia ◽  
Cardiovascular Events ◽  
Lipid Lowering ◽  
Atherosclerotic Cardiovascular Disease ◽  
Prognostic Impact ◽  
Cascade Screening ◽  
Increased Risk ◽  
Ascvd Risk ◽  
The Impact

Background: Familial hypercholesterolemia (FH) is an autosomal dominant disorder mainly caused by mutations in the low-density lipoprotein (LDL) receptor or associated genes, resulting in elevated serum cholesterol levels and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Early diagnosis and timely treatment can substantially lower the risk of ASCVD. In this sense, cascade screening could be one of the most useful options. However, few data exist regarding the impact of cascade screening for FH on the reduction of risk of ASCVD events. We aimed to evaluate the prognostic impact of cascade screening for FH. Methods: We retrospectively investigated the health records of 1,050 patients with clinically diagnosed FH, including probands and their relatives who were cascade-screened, who were referred to our institute. We used Cox models that were adjusted for established ASCVD risk factors to assess the association between cascade screening and major adverse cardiovascular events (MACE). The median period of follow-up was 12.3 years (interquartile range [IQR] = 9.1-17.5 years), and MACE included death from any causes or hospitalization due to ASCVD events. Results: During the observation period, 246 participants experienced MACE. The mean age of patients identified through cascade screening was 18-years younger than that of the probands (38.7 yr vs. 57.0 yr, P < 2.2 х 10 –16 ), with a lower proportion of ASCVD risk factors. Interestingly, patients identified through cascade screening under milder lipid-lowering therapies were at reduced risk for MACE (hazard ratio [HR] = 0.36; 95%CI = 0.22 to 0.60; P = 6.3 х 10 –5 ) when compared with the probands, even after adjusting for those known risk factors. Conclusions: The identification of patients with FH via cascade screening appeared to result in better prognoses.

Abstract 15576: Cardiovascular Disease in Elderly Familial Hypercholesterolemia Individuals Attending a Cascade Screening Program

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
elaine coutinho ◽  
Marcio H Miname ◽  
Viviane Z Rocha ◽  
Marcio S Bittencourt ◽  
Cinthia Jannes ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Familial Hypercholesterolemia ◽  
High Intensity ◽  
Screening Program ◽  
Coronary Revascularization ◽  
Genetic Diagnosis ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Cvd Risk ◽  
Cascade Screening

Introduction: Familial hypercholesterolemia (FH) is associated with early onset of cardiovascular disease (CVD) and mortality. Lipid lowering treatment (LLT) may change the natural history of FH, however there is scant information about elderly individuals (older than 60 years) with FH. This study describes characteristics of elderly FH individuals presenting or not CVD. Hypothesis: Monogenic defects are important markers of CVD risk and initiation and long-term use of lipid lowering therapy (LLT) is relevant to minimize this risk. Methods: Cross-sectional analysis of clinical and laboratory of molecularly proven elderly FH (FH+) and non-affected (FH-) individuals attending a cascade screening program. FH+ were divided in those presenting or not CVD (defined as previous myocardial infarction or ischemic stroke, carotid or coronary revascularization and angina with stenosis ≥50% on angiography). Results: From 4,111 genotyped individuals, 462 (11.2%) elders were included (198 FH+ and 264 FH-). There was predominance of females in either groups, however with more men in FH+ 37.4% vs. 24.2%, p=0.002. No differences were seen between FH+ and FH- regarding age, [median (%25;75%)] 66 (62;71) and 66 (63;71) years, p=0.68; use of LLT 88.5% vs. 91.5%, p=0.29 and high intensity LLT 61.7 % vs. 55.8%, p=0.20, respectively. Despite longer LLT duration in FH+ 11(7;20) vs. 7 (3;13) years, p<0.001, in either groups LLT was started late, at 54 (47;61) and 59 (52;64) years, p <0.001, respectively in FH+ and FH-. FH+ had higher LDL-C at diagnosis, 243 (179;302) vs. 228 (209;251) mg/dL, p=0.013, as well as greater frequencies of previous CVD 40.9% vs. 27.3%, p=0.002, and early CVD 22.2% vs. 9.0%, p<0.001. In FH+, male sex [OR (95%CI)] 5.29 (2.25-12.45), p<0.001, and use of high intensity LLT 2.51 (1.08-5.87), p=0.03, were independently associated with CVD. Conclusions: The genetic diagnosis of FH was associated with higher rates of CVD and early CVD vs. FH- hypercholesterolemics. Elders with FH+ who survived despite late LLT initiation have a worse CVD history than FH- elders, emphasizing the relevance of a monogenic defect as cause of long-lasting hypercholesterolemia and CVD risk, particularly in men.

scholarly journals Improving Familial Hypercholesterolemia Index Case Detection: Sequential Active Screening from Centralized Analytical Data

2021 ◽  
Vol 10 (4) ◽  
pp. 749
Author(s):  
Fernando Sabatel-Pérez ◽  
Joaquín Sánchez-Prieto ◽  
Víctor Manuel Becerra-Muñoz ◽  
Juan Horacio Alonso-Briales ◽  
Pedro Mata ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Diagnostic Yield ◽  
Low Density Lipoprotein ◽  
Analytical Data ◽  
Genetic Diagnosis ◽  
Density Lipoprotein ◽  
Screening Strategy ◽  
Cascade Screening ◽  
Active Screening ◽  
Lipid Clinic

The majority of familial hypercholesterolemia index cases (FH-IC) remain underdiagnosed and undertreated because there are no well-defined strategies for the universal detection of FH. The aim of this study was to evaluate the diagnostic yield of an active screening for FH-IC based on centralized analytical data. From 2016 to 2019, a clinical screening of FH was performed on 469 subjects with severe hypercholesterolemia (low-density lipoprotein cholesterol ≥220 mg/dL), applying the Dutch Lipid Clinic Network (DLCN) criteria. All patients with a DLCN ≥ 6 were genetically tested, as were 10 patients with a DLCN of 3–5 points to compare the diagnostic yield between the two groups. FH was genetically confirmed in 57 of the 84 patients with DLCN ≥ 6, with a genetic diagnosis rate of 67.9% and an overall prevalence of 12.2% (95% confidence interval: 9.3% to 15.5%). Before inclusion in the study, only 36.8% (n = 21) of the patients with the FH mutation had been clinically diagnosed with FH; after genetic screening, FH detection increased 2.3-fold (p < 0.001). The sequential, active screening strategy for FH-IC increases the diagnostic yield for FH with a rational use of the available resources, which may facilitate the implementation of FH universal and family-based cascade screening strategies.

scholarly journals FAMILIAL HYPERCHOLESTEROLEMIA: DIAGNOSTIC ISSUES AND THERAPEUTIC POSSIBILITIES

2019 ◽  
Vol 26 (1) ◽  
pp. 175-186
Author(s):  
Vitalii K. Zafiraki ◽  
Alim M. Namitokov ◽  
Elena D. Kosmacheva
Keyword(s):  
Familial Hypercholesterolemia ◽  
Conflict Of Interest ◽  
Screening Program ◽  
Genetic Defect ◽  
Clinical Manifestations ◽  
Density Lipoprotein ◽  
Premature Death ◽  
Lipid Lowering ◽  
Monogenic Disease ◽  
Lipid Lowering Therapy

Familial hypercholesterolemia (FHC) is a common monogenic disease that occurs with a frequency of ~1:250 and is characterised by a high content of low-density lipoprotein (LDL) in the blood. This disease leads to the early development of atherosclerotic cardiovascular diseases (ACVD). Although the screening and diagnostics issues concerned with FHC are well developed and the modern lipid-lowering therapy can significantly improve the prognosis, the detectability of this disease remains extremely low. In recent years, the concept of FHC has undergone significant changes under the influence of large epidemiological studies, including verification of the FHC diagnosis using genetic tests. The article is aimed at discussing the clinical manifestations of FHC, as well as modern medical and extracorporal approaches to its treatment.Conclusion.Until the advent of modern lipid-lowering drugs, FHC had remained to be a disease with a poor prognosis due to early ACVD and the associated premature death. Today, the diseases is amenable to successful treatment, which, though not eliminating the genetic defect, allows almost the same life duration as in the general population to be achieved. However, all the possibilities of modern approaches to the treatment of this serious disease can be realized provided that a state-level screening program for such patients has been implemented.Conflict of interest: the authors declare no conflict of interest.

scholarly journals Monoclonal Antibodies in the Management of Familial Hypercholesterolemia: Focus on PCSK9 and ANGPTL3 Inhibitors

2021 ◽  
Vol 23 (12) ◽  
Author(s):  
Angela Pirillo ◽  
Alberico L. Catapano ◽  
Giuseppe D. Norata
Keyword(s):  
Monoclonal Antibodies ◽  
High Risk ◽  
Familial Hypercholesterolemia ◽  
Plasma Levels ◽  
Low Density Lipoprotein ◽  
Genetic Defect ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Low Density ◽  
Premature Cardiovascular Disease

Abstract Purpose of Review Familial hypercholesterolemia (FH) is a monogenic disorder characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C) since birth and a high risk of premature cardiovascular disease. The genetic defect is carried in only one allele in heterozygous FH (HeFH) or in both in the most severe homozygous FH (HoFH). Current guidelines recommend to reduce substantially LDL-C levels in these high-risk patients, with the need to use association therapy combining agents with different mechanisms of action. As most cases of FH are attributable to mutations in the gene encoding the low-density lipoprotein receptor (LDLR), statins, even in combination with ezetimibe, are less effective in reducing LDL-C plasma levels in FH patients, who require a more intensive approach with additional lipid-lowering agents. Additional targets playing key roles in regulating LDL-C levels are represented by PCSK9 and ANGPTL3. Recent Findings Two monoclonal antibodies (mAbs) targeting PCSK9, evolocumab and alirocumab, significantly reduce LDL-C levels in HeFH patients. In patients with HoFH, the efficacy of mAbs to PCSK9 is strictly related to the presence of a residual LDLR activity; thus, patients carrying null mutations do not respond to the therapy with these mAbs, whereas some effects can be appreciated in HoFH bearing defective mutations. Conversely, evinacumab, the mAb targeting ANGPTL3, is highly effective in reducing LDL-C levels even in HoFH patients carrying null LDLR mutations, thanks to its LDLR-independent mechanism of action. Summary Monoclonal antibodies inhibiting PCSK9 have shown a robust effect in FH patients presenting a residual LDLR activity, while ANGPTL3 inhibitors appear to be promising even in patients carrying null LDLR mutations.

Abstract 12169: LDL-C Levels and Treatment Patterns Among Adults With Heterozygous Familial Hypercholesterolemia in the United States: Data From the CASCADE-FH Registry

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Emil M deGoma ◽  
Zahid S Ahmad ◽  
Emily O'Brien ◽  
Iris Kindt ◽  
Peter Shrader ◽  
...  
Keyword(s):  
Statin Therapy ◽  
Familial Hypercholesterolemia ◽  
High Intensity ◽  
The United States ◽  
Treatment Patterns ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cascade Screening ◽  
Cross Sectional ◽  
Lowering Therapy ◽  
Care Gaps

Introduction: In the US, LDL-C levels and treatment patterns of patients with familial hypercholesterolemia (FH) – a group prioritized for statin therapy in the 2013 ACC/AHA cholesterol guidelines – remain poorly described. In 2013 the FH Foundation launched the CAscade SCreening for Awareness and DEtection (CASCADE) of FH Registry, the only active US FH patient registry addressing this knowledge gap. Methods: We conducted a 2-year (2013-2015) cross-sectional analysis among 1,295 adults with heterozygous FH enrolled in the CASCADE FH Registry from 10 US lipid clinics. Results: Mean (SD) age at enrollment was 54 (16) years; mean age at FH diagnosis was 45 (19) years; 59% were female; and 80% were white. Mean pretreatment and post-treatment LDL-C levels were 256 (66) and 156 (71) mg/dl, respectively. At enrollment, 43% of patients were taking high-intensity statin therapy; 25% were not taking a statin; and 45% received >1 LDL-lowering therapy. Among FH patients on LDL-lowering therapy, 25% achieved an LDL-C <100 mg/dl, and 41% achieved a ≥50% LDL-C reduction (Table). Factors associated with a ≥50% LDL-C reduction included high-intensity statin use (adjusted OR 2.24, 95% CI 1.47-3.42) and use of >1 LDL-lowering therapy (1.94, 1.29-2.93) (Figure). Atherosclerotic cardiovascular disease (ASCVD) was present in 37%, of whom 44% achieved a ≥50% LDL-C reduction and 9% achieved an LDL-C <70 mg/dl. Conclusions: Despite the high prevalence of ASCVD, several care gaps exist for FH patients enrolled in the CASCADE US registry: lack of early diagnosis, insufficient use of high-intensity statin therapy, and failure to achieve adequate LDL-C reductions.

Cardiovascular risk in patients with familial hypercholesterolemia using optimal lipid-lowering therapy

2018 ◽  
Vol 12 (2) ◽  
pp. 409-416 ◽  
Author(s):  
Annette M. Galema-Boers ◽  
Mattie J. Lenzen ◽  
Sophie R. Engelkes ◽  
Eric J. Sijbrands ◽  
Jeanine E. Roeters van Lennep
Keyword(s):  
Cardiovascular Risk ◽  
Familial Hypercholesterolemia ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Lowering Therapy

scholarly journals Hypercholesterolemia in children and adolescents: focus on the familial variant

2021 ◽  
pp. 294-299
Author(s):  
I. N. Zakharova ◽  
I. M. Osmanov ◽  
I. I. Pshenichnikova ◽  
T. M. Tvorogova ◽  
I. N. Kholodova ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Familial Hypercholesterolemia ◽  
Age Groups ◽  
Index Patient ◽  
Vascular Lesions ◽  
Cholesterol Concentration ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Cascade Screening ◽  
Lowering Therapy

Familial hypercholesterolemia is characterized by a significant increase in serum low-density lipoprotein cholesterol concentration, which even in the absence of other risk factors leads to the development of atherosclerotic vascular lesions beginning in childhood. With significant prevalence in the population, familial hypercholesterolemia is rarely diagnosed in time due to the Long absence of clinical manifestations. Today the urgent task is to develop and implement programs of primary detection of familial hypercholesterolemia in children and adolescents. Early detection of patients with familial hypercholesterolemia and timely initiation of adequate lipid-lowering therapy will curb the rate of atherosclerosis progression, which will significantly reduce disability and mortality from cardiovascular diseases in older age groups. There are four types of screening: cascade, targeted, opportunistic and universal. Cascade screening is currently considered the most effective and cost-effective way to identify new patients with familial hypercholesterolemia among relatives of an index patient, the patient with the established diagnosis. Targeted screening is based on searching for individuals with familial hypercholesterolemia among groups of patients with the early development of atherosclerotic vascular lesions, for example, in cardiology or neurology hospitals. Opportunistic screening is a non-systematic, sporadic determination of cholesterol levels in patients seeking medical care for any reason. It is most applicable in primary care health care settings. Universal screening is a mass screening of certain age groups and is a highly effective way of early diagnosis, especially in combination with reverse cascade screening of parents, siblings, and other relatives of the index patient. Implementation of programs of early childhood detection of familial hypercholesterolemia, setting up systems of adequate routing of patients, timely prescription of effective lipid-lowering therapy will contribute to health preservation and prolongation of working age, development, and preservation of labor potential of the country.

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