Efficacy of statins in familial hypercholesterolaemia: a long term cohort study

Versmissen, Jorie; Oosterveer, Daniëlla M.; Yazdanpanah, Mojgan; Defesche, Joep C.; Basart, D.C.G.; Liem, Anho; Heeringa, Jan; Witteman, Jacqueline C. M.; Lansberg, Peter; Kastelein, John J.P.; Sijbrands, Eric J.G.

doi:10.1136/bmj.a2423

Cited by 652 publications

(427 citation statements)

References 16 publications

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“…Although statin use has proved effective for primary prevention of cardiovascular events,12, 13, 14, 15, 16 the underlying mechanisms are still not well understood because there has been no appropriate analysis. By producing human‐like advanced coronary plaques in our LDLR knockout pigs, we justified, on the basis of histopathologic examination, early statin treatment before the formation of atherosclerotic plaques.…”

Section: Discussionmentioning

confidence: 99%

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Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

Fuchimoto

Sudo

et al. 2016

JAHA

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BackgroundAlthough clinical trials have proved that statin can be used prophylactically against cardiovascular events, the direct effects of statin on plaque development are not well understood. We generated low‐density lipoprotein receptor knockout (LDLR −/−) pigs to study the effects of early statin administration on development of atherosclerotic plaques, especially advanced plaques.Methods and Results LDLR −/− pigs were generated by targeted deletion of exon 4 of the LDLR gene. Given a standard chow diet, LDLR −/− pigs showed atherosclerotic lesions starting at 6 months of age. When 3‐month‐old LDLR −/− pigs were fed a high‐cholesterol, high‐fat (HCHF) diet for 4 months (HCHF group), human‐like advanced coronary plaques developed. We also fed 3‐month‐old LDLR −/− pigs an HCHF diet with pitavastatin for 4 months (Statin Prophylaxis Group). Although serum cholesterol concentrations did not differ significantly between the 2 groups, intravascular ultrasound revealed 52% reduced plaque volume in statin‐treated pigs. Pathological examination revealed most lesions (87%) in the statin prophylaxis group were early‐stage lesions, versus 45% in the HCHF diet group (P<0.01). Thin‐cap fibroatheroma characterized 40% of the plaques in the HCHF diet group versus 8% in the statin prophylaxis group (P<0.01), intraplaque hemorrhage characterized 11% versus 1% (P<0.01), and calcification characterized 22% versus 1% (P<0.01).ConclusionsResults of our large animal experiment support statin prophylaxis before the occurrence of atherosclerosis. Early statin treatment appears to retard development of coronary artery atherosclerosis and ensure lesion stability. In addition, the LDLR −/− pigs we developed represent a large animal model of human‐like advanced coronary plaque suitable for translational research.

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Section: Discussionmentioning

confidence: 99%

“…Several compelling clinical trials have supported statin treatment as prophylaxis against cardiovascular events 12, 13, 14, 15, 16. With development of our LDLR −/− pigs, we sought to take the next step in the research process to examine the direct effects of statin on the development of plaques, especially advanced plaques.…”

Section: Introductionmentioning

confidence: 99%

Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

Fuchimoto

Sudo

et al. 2016

JAHA

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“…[10][11][12] Therefore, it has been suggested that incidental detection of variants leading to FH should be communicated to the affected individual and the family. 13 In fact, owing to the high frequency of FH, several guidelines recommend programs to systematically unravel variants and to facilitate medical treatment already at young age.…”

Section: Introductionmentioning

confidence: 99%

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

et al. 2015

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Familial hypercholesterolemia (FH) is an oligogenic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDLC) levels. Variants in four genes have been reported to cause the classical autosomal-dominant form of the disease. FH is largely under-diagnosed in European countries. As FH increases the risk for coronary artery disease (CAD) and myocardial infarction (MI), it might be specifically overlooked in the large number of such patients. Here, we systematically examined the frequency of potential FH-causing variants by exome sequencing in 255 German patients with premature MI and a positive family history for CAD. We further performed co-segregation analyses in an average of 5.5 family members per MI patient. In total, we identified 11 potential disease-causing variants that co-segregate within the families, that is, 5% of patients with premature MI and positive CAD family history had FH. Eight variants were previously reported as disease-causing and three are novel (LDLR.c.811G4A p.(V271I)), PCSK9.c.610G4A (p. (D204N)) and STAP1.c.139A4G (p. (T47A))). Co-segregation analyses identified multiple additional family members carrying one of these FH variants and the clinical phenotype of either FH (n = 2) or FH and premature CAD (n = 15). However, exome sequencing also revealed that some variants in FH genes, which have been reported to cause FH, do not co-segregate with FH. The data reveal that a large proportion of FH patients escape the diagnosis, even when they have premature MI. Hence, systematic molecular-genetic screening for FH in such patients may reveal a substantial number of cases and thereby allow a timely LDLC-lowering in both FH/MI patients as well as their variantcarrying family members.

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“…26 However, once a heterozygote form of FH is diagnosed, it can be treated with statins or combined lipidlowering therapies. 27 According to our study findings, patients with a family history of FH were less likely to make progress in overall lipid parameter variations. Further detailed evaluation may be required among these patients due to inadequate improvement of variance, and more aggressive types of treatment could be applied.…”

Section: Discussionmentioning

confidence: 56%

Impact of predictors upon the reduction of lipid parameters in family medicine practice

et al. 2015

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CONTEXT AND OBJECTIVE: To evaluate predictors of changes in lipid parameters consisting of LDL-C (low-density lipoprotein cholesterol), TC (total cholesterol) and non-HDL-C (non-high density lipoprotein cholesterol) among primary care patients. DESIGN AND SETTING: Retrospective study conducted on family medicine patients. METHODS: Demographic features and other clinically relevant information were abstracted from medical records. The primary outcome was the difference in LDL-C level from initial testing to the index test. Secondary outcomes were the changes in TC and non-HDL-C levels between two measurements. RESULTS: Three hundred and eleven participants were included in the final secondary analysis. Multiple linear regression revealed that male patients (β = 4.97, P = 0.040), diabetes (β = 9.75, P = 0.003) and higher LDL-C levels at baseline (β = 0.35, P < 0.001) were positively associated with LDL variance, whereas longer time period (β = -0.15, P = 0.045) and familial hypercholesterolemia history (β = -7.56, P = 0.033) were negatively associated. Male patients (β = 8.45, P = 0.002), DM (β = 9.26, P = 0.011), higher TC levels at baseline (β = 0.35, P < 0.001) and taking statins (β = 7.31, P = 0.023) were positively associated with TC variance, whilst longer time period (β = -0.183, P = 0.031) and familial hypercholesterolemia (β = -10.70, P = 0.008) were negatively associated. CONCLUSION: In the present study, patients who were male, on statin treatment, diagnosed with diabetes and had higher baseline lipid values were more likely associated with better lipid outcomes at future testing.RESUMO CONTEXTO E OBJETIVO: Avaliar preditores de alterações nos parâmetros lipídicos que consistem em LDL-C (colesterol de lipoproteína de baixa densidade), TC (colesterol total) e não HDL-C (não colesterol de lipoproteína de alta densidade) entre os pacientes de cuidados primários. TIPO DE ESTUDO E LOCAL: Estudo retrospectivo realizado em pacientes de medicina familiar. MÉTODOS: Aspectos demográficos e outras informações clinicamente relevantes foram extraídos dos prontuários médicos. O desfecho primário foi a diferença de nível de LDL-C entre os exames iniciais e o exame índice. Os desfechos secundários foram as mudanças dos níveis de TC e não HDL-C entre as duas medidas. RESULTADOS: Trezentos e onze participantes foram incluídos na análise secundária final. Regressão linear múltipla revelou que os pacientes do sexo masculino (β = 4,97, P = 0,040), diabetes (DM) (β = 9,75, P = 0,003) e níveis de LDL mais elevados no início do estudo (β = 0,35, P < 0,001) foram associados positivamente com variância LDL, enquanto longo período de tempo (β = -0,15, P = 0,045) e história hipercolesterolemia familiar (β = -7,56, P = 0,033) foram associados negativamente. Pacientes do sexo masculino (β = 8,45, P = 0,002), com DM (β = 9,26, P = 0,011), níveis elevados de CT na linha de base (β = 0,35, P < 0,001) e tomar estatinas (β = 7,31, P = 0,023) associaram-se positivamente com a variância TC, enquanto longo período de tempo (β = -0,1...

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Efficacy of statins in familial hypercholesterolaemia: a long term cohort study

Cited by 652 publications

References 16 publications

Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

Impact of predictors upon the reduction of lipid parameters in family medicine practice

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