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Eur Heart J 2013; 34: 3478-3490.. Heterozygous familial hypercholesterolaemia (FH) Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490.

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Presentation on theme: "Eur Heart J 2013; 34: 3478-3490.. Heterozygous familial hypercholesterolaemia (FH) Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490."— Presentation transcript:

1 Eur Heart J 2013; 34:

2 Heterozygous familial hypercholesterolaemia (FH) Nordestgaard et al. Eur Heart J 2013; 34:

3 Pathophysiology & genetics Nordestgaard et al. Eur Heart J 2013; 34:

4 Pathophysiology of heterozygous familial hypercholesterolaemia. Nordestgaard B G et al. Eur Heart J 2013;34: © The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

5 Atherosclerosis Myocardial infarction Angina pectoris Elevated LDL cholesterol Mutations in LDL receptor, apolipoproteinB or PCSK9 Liver with only 50% functional LDL receptors Coronary heart disease Heterozygous familial hypercholesterolaemia Nordestgaard et al. Eur Heart J 2013; 34:

6 LDL cholesterol burden in individuals with or without familial hypercholesterolaemia as a function of the age of initiation of statin therapy. Nordestgaard B G et al. Eur Heart J 2013;34: © The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

7 35yrs 53yrs 48yrs 55yr 12.5yrs Start high dose statin Start low dose statin Threshold for CHD Female sex Smoking Hypertension Diabetes  Triglycerides  HDL-C  Lipoprotein(a) Without FH Homozygous FHHeterozygous FH Age in years Adapted from Steve Humphries 2013 Coronary disease & death before age 20 Untreated coronary disease before age 55/60

8 Underdiagnosis & undertreatment Nordestgaard et al. Eur Heart J 2013; 34:

9 Estimated per cent of individuals diagnosed with familial hypercholesterolaemia in different countries/territories, as a fraction of those theoretically predicted based on a frequency of 1/500 in the general population. Nordestgaard B G et al. Eur Heart J 2013;34: © The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

10 Netherlands Norway Iceland Switzerland UK Spain Belgium Slovak Republic Denmark South Africa Australia Hong Kong France Taiwan Italy Oman USA Canada Japan Chile Brazil Mexico Diagnosed FH (estimated), % of estimated number in country Number of FH (estimated based on 1/500) Diagnosed FH (estimated) 71% 43% 19% 13% 12% 6% 4% 4% 4% 3% 1% 1% 1% <1% <1% <1% <1% <1% <1% <1% <1% <1% 33,300 9, , ,600 92,200 22,200 10,900 11, ,000 45,000 14, ,900 46, ,000 5, ,200 68, ,800 34, , ,900 Numbers from Livingston, Descamps & Humphries ~ 200 countries or territories in the World Nordestgaard et al. Eur Heart J 2013; 34:

11 Prevalence of definite or probable familial hypercholesterolaemia according to Dutch Lipid Clinic Network Criteria in the Copenhagen General Population Study by 20-year age groups and by gender. Nordestgaard B G et al. Eur Heart J 2013;34: © The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

12 Adapted from Benn et al J Clin Endocrin Metab 2012; 97: Dutch Lipid Clinic Network criteria: Definite or probable FH Screening 69,000 persons from the Copenhagen General Population Study

13 Estimated millions of individuals worldwide with familial hypercholesterolaemia by WHO regions and by income groups. Nordestgaard B G et al. Eur Heart J 2013;34: © The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

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15 Risk of coronary heart disease as a function of the Dutch Lipid Clinic Network Criteria for a diagnosis of familial hypercholesterolaemia in individuals on or off statin from the general population. Nordestgaard B G et al. Eur Heart J 2013;34: © The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

16 Whom to screen: how to find index cases? Nordestgaard et al. Eur Heart J 2013; 34:

17 We recommend: children, adults, and families should be screened for FH if Family member presents with FH P-cholesterol in adult ≥8mmol/L (≥310mg/dL) P-cholesterol in child ≥6mmol/L (≥230mg/dL) Premature CHD Tendon xanthomas Sudden premature cardiac death Nordestgaard et al. Eur Heart J 2013; 34:

18 Death 76 yrs No CHD LDL 3.8 mmol/L Age 78 yrs CHD 58 yrs LDL 7.4 mmol/L Age 48 yrs CHD 48 yrs LDL 8.3 mmol/L Age 47 yrs No CHD LDL 2.4 mmol/L Age 50 yrs No CHD LDL 3.3 mmol/L Index case: start of cascade screening Age 18 yrs LDL 2.2 mmol/L Age 8 yrs LDL 5.6 mmol/L Age 15 yrs LDL 6.1 mmol/L FH ManWoman Family pedigree Nordestgaard et al. Eur Heart J 2013; 34:

19 DUTCH FH CRITERIA

20 Clinical diagnosis versus mutation diagnosis Nordestgaard et al. Eur Heart J 2013; 34:

21 Overlap of clinical and mutation diagnosis of heterozygous familial hypercholesterolaemia. Nordestgaard B G et al. Eur Heart J 2013;34: © The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

22 Clinical diagnosis Mutation diagnosis Mutation without clinical diagnosis Clinical diagnosis without mutation Patient: treat LDL Family: monitor LDL & consider treatment Patient: treat LDL Family: mutation test, monitor LDL, & consider treatment Patient: monitor LDL & consider treatment Family: monitor LDL & consider treatment Adapted from Luis Masana

23 Cascade screening preferred method Nordestgaard et al. Eur Heart J 2013; 34:

24 Pedigree of a family with familial hypercholesterolaemia. Nordestgaard B G et al. Eur Heart J 2013;34: © The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

25 Death 76 yrs No CHD LDL 3.8 mmol/L Age 78 yrs CHD 58 yrs LDL 7.4 mmol/L Age 48 yrs CHD 48 yrs LDL 8.3 mmol/L Age 47 yrs No CHD LDL 2.4 mmol/L Age 50 yrs No CHD LDL 3.3 mmol/L Index case: start of cascade screening Age 18 yrs LDL 2.2 mmol/L Age 8 yrs LDL 5.6 mmol/L Age 15 yrs LDL 6.1 mmol/L FH ManWoman Family pedigree Nordestgaard et al. Eur Heart J 2013; 34:

26 LDL cholesterol targets: (heterozygous & homozygous FH) <3.5mmol/L(<135mg/dL) for children <2.5mmol/L(<100mg/dL) for adults <1.8mmol/L(<70mg/dL) for adults with known CHD or diabetes Nordestgaard et al. Eur Heart J 2013; 34:

27 LDL lowering treatment Nordestgaard et al. Eur Heart J 2013; 34:

28 Based on a consensus of opinions of experts small studies, retrospective studies, and registries However effect of LDL cholesterol lowering in individuals without FH based on: randomised trials and meta-analyses Nordestgaard et al. Eur Heart J 2013; 34:

29 Kaplan–Meier curve estimates of cumulative CHD-free survival among individuals with familial hypercholesterolaemia according to statin treatment (P < for difference). Nordestgaard B G et al. Eur Heart J 2013;34: © The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

30 Adapted from Vermissen et al. BMJ 2008; 337: a2423

31 In addition to lifestyle and dietary counselling, treatment priorities are Children (from age 8-10): 1.Statin 2.Ezetimibe 3.Bile acid binding resin 4.Lipoprotein apheresis in homozygotes Adults: 1.Maximal potent statin dose 2.Ezetimibe 3.Bile acid binding resins 4.Lipoprotein apheresis in homozygotes & treatment-resistant heterozygotes with CHD Nordestgaard et al. Eur Heart J 2013; 34:

32 Summary of diagnostic and treatment strategies. Nordestgaard B G et al. Eur Heart J 2013;34: © The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

33 Disclosures Supported by unrestricted educational grants to EAS from Amgen, Aegerion, AstraZeneca, Genzyme, Hoffman-La Roche, Kowa Europe, Novartis, and Sanofi-Aventis/Regeneron. These companies were not present at the Consensus Panel meetings, had no role in the design or content of the Consensus Statement, and had no right to approve or disapprove the final document. Eur Heart J 2013; 34:


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