1. Phenotype vs. Genotype: Defining Severe Familial Hypercholesterolemia
Raul D. Santos
InCor-University of Sao Paulo Medical School Hospital
Preventive Medicine Centre and Cardiology Program Hospital Israelita Albert Einstein
Brazilian Society of Cardiology
Sao Paulo-Brazil

2. Familial Hypercholesterolemia: Need for Risk Stratification
Elevated lifetime risk of cardiovascular disease
However, heterogeneity in this risk
LDL levels
Mutation presence and type
Previous CVD
Other risk factors
Susceptibility= subclinical disease
Overlap of LDL-C among He and Ho FH forms
Newer treatments
PCSK9 inhibitors 6-14,000 US dollars year
Mipomersen/Lomitapide US ,000 year
Best cost effectiveness??

3. Phenotype vs. Genotype: Defining Severe Familial Hypercholesterolemia
Which is the best risk marker?

4. Serum cholesterol mmol/L (mg/dL)
Distribution of serum total cholesterol levels in normal subjects, and heterozygous and homozygous FH patients
100 90
Normal
Heterozygous FH
Homozygous FH 80 70 60 50
Number of patients 40 30 20 10
2.6
(100)
5.2
(200)
7.8
(300)
10.3
(400)
12.9
(500)
15.5
(600)
18.1
(700)
20.7
(800)
23.3
(900)
25.8
(1000)
Serum cholesterol mmol/L (mg/dL)
Harada-Shiba et al . J Atheroscler Thromb 2012;19:

5. The Continuum of FH: Molecular Defects and LDL-C Phenotype
+Polygenic
+Environmental effects
Adapted from Santos RD et al Lancet Diab Endocrinol 2016;4:

6. FH Mutation Presence and CVD Risk in Hypercholesterolemia
Do we need to know that?

7. FH Mutation Presence and CAD Risk

8. FH Mutation Presence and CVD Risk in Hypercholesterolemic Women
N-51 With mutations
Vs.
111 W/o Mutations
Ahmad Z et al. J Clin Lipidol 2016; 10:101–108

9. FH Mutation Presence and Higher CVD Risk in Hypercholesterolemia
Why is that?

10. The Higher the LDL-C the Greater The Presence of FH Variants
Wang J et al ATVB Nov 2016 e pub

11. FH Variants Are Associated With a Higher Cholesterol-Year Score
Khera A et al. J Am Coll Cardiol 2016;67:2578–89

12. Atherosclerosis 2016; 248:

13. age 1-75 years old, (31  16 years) Untreated and treated LDL-C
170 to 1052 mg/dL
101 to 785 mg/dL
30% had lower LDL-c < clinical HOFH diagnosis criteria
Average age of ASVCD =26 years (6 to 63 years)
2/3 no ASCVD
Those with previous ASCVD had higher untreated LDL-C even considering null or defective LDLR mutations
Raal FJ et al. Atherosclerosis 2016; 248:

14. Who is an FH Subject With a Higher CVD risk ?
And should be the preferential target for new higher cost treatments?

15. Secondary vs. Primary Prevention in FH and Mortality in the UK: Effects of Statins
N=3382 patients (FUP )
370 deaths
Standardized mortality ratios
All aged 20–79 years CHD mortality reduced by 37% from 3.4 to 2.1-fold excess.
Primary prevention: 48% reduction in CHD mortality from 2.0-fold excess to none
Secondary prevention: 25% reduction in CHD mortality from 5.2 to a 3.9-fold excess
Neil et al Eur Heart J 2008; 29:2625–2633

16. LDL-C > 310 mg/dl or 8 mmol/L
CVD risk vs. non severe FH
1.25 [95% CI: ], p= 0.015
LDL-C > 310 mg/dl or 8 mmol/L
Besseling et al. Atherosclerosis 2014;

17. Index Cases N=818 47 first events
Silva P et al . Atherosclerosis 2016;250:

18. Relatives
Silva P et al . Atherosclerosis 2016;250:

19. Lp(a), FH and Myocardial Infarction Risk : Prospective Data
Langested A et al. Lancet Diabetes Endocrinol Jul;4(7):577-87

20. Advanced Subclinical Coronary Atherosclerosis by Computed Tomography Angiography in FH and Cardiovascular Events
Tada et al. Am J Cardiol 2015;115:724e729

21. Santos RD et al Lancet Diab Endocrinol 2016;4: 850-61

22. Risk Conditions to Consider
Older > 40 years old without treatment
Smoking,
Male gender
Lp(a)>50 mg/dL
Low-HDL-C (<1mmol/L or 40 mg/dL),
Hypertension
Diabetes mellitus
Family history of early cardiovascular disease in first degree relatives (<55 years old in males and < 60 years old in females)
Chronic kidney disease (defined as an estimated glomerular filtration rare < 60 ml/min/1.73 m2
BMI >30 kg/m2
Santos RD et al Lancet Diab Endocrinol 2016;4:

23. Severe Familial Hypercholesterolemia: Treating the Continuum
At presentation
(untreated
LDL-C)
LDL –C >10 mmol/L (400 mg/dL)
LDL-C >8.0 mmol/L (310 mg/dL) + one high risk condition
LDL-C > 5 mmol/L (190 mg/dL) + two high risk conditions
Realistic goal: reduce ≥ 50%
LDL-C
Ideal goal: LDL-C < 2.5 mmol/L (100 mg/dL)
With subclinical atherosclerosis assessment
Advanced subclinical atherosclerosis
Coronary:
A-Coronary artery calcium (CAC) score > 100 Agatston units, or > 75th percentile for age and gender*
B-Computed tomography angiography (CTA) with obstructions > 50% or presence of non-obstructive plaques > one vessel.
Ideal goal : LDL-C < 1.8
mmol/L (70 mg/dL)
Presence of clinical atherosclerotic cardiovascular disease
Realistic goal: reduce LDL-C ≥ 50%
Ideal goal: LDL-C < 1.8 mmol/L (70 mg/dL)
Santos RD et al Lancet Diab Endocrinol 2016;4:

24. Conclusions The risk of CVD is heterogeneous in FH
Genotype and phenotype may not be concordant
Both phenotypic and genotypic information help identify higher risk individuals
Higher risk = more aggressive treatment
We need prospective risk equations in FH comprising both genotypic and phenotypic information