Lecture given at National Lipid Association Annual 2018 Annual Sessions Las Vegas May 2018, and NYU Prevention Symposium May 2018

1. Are All FH Patients the Same? Risk Assessment and Treatment Paradigms
in Familial Hypercholesterolemia
James A. Underberg, MD, MS, FACPM, FACP, FNLA
Clinical Assistant Professor of Medicine NYU School of Medicine
NYU Langone Center for Cardiovascular Disease Prevention
Director,Bellevue Hospital Lipid Clinic, New York,NY
President, National Lipid Association

2. Disclosures
•
• Speaker Bureau Honoraria : Amgen, Sanofi, Regeneron,
Amarin, Alexion
• Consulting: Amarin, Amgen
• Advisory Boards: Amgen, Regeneron, Sanofi, Alexion, Akcea,
Invitae
• Contracted Research: Aegerion, Pfizer
• Steering Committee Member: Aegerion LOWER Registry
Trial
• Board of Directors: National Lipid Association, American
Society of Preventive Cardiology, Foundation of the
National Lipid Association
• Scientific Advisory Board: The FH Foundation

3. Case Presentation
• Susan is a 30 year old woman with a history of FH diagnosed at age
9 when her father had an MI at age 44. She was started on bile acid
sequestrants at the time, and over the next 21 years has been
treated subsequently with statins of increasing intensity and now
ezetimibe 10 mg. She currently takes 40 mg rosuvastatin with
ezetimibe 10 mg , and has an LDL-C of 104 mg/dL. Her LDL-C at
diagnosis was 220 mg/dL. She exercises 3x/week and follows a
heart heathy diet.
• Which of the following do you most agree with ??
• A. She is adequately treated and should continue current medications
and lifestyle
• B. She needs more aggressive LDL-C lowering
• C. Need more information to assess her clinical status

4. • The most common inheritable, autosomal dominant disorder associated with morbidity
and mortality in man – present in 1 in 250 people1,2
• Usually due to mutations in LDL receptor gene3-5 of which over 1600 have been described,
and result in decreased clearance of LDL1
• Other mutations include those in the ApoB and PCSK9 genes
• Results in severe hypercholesterolemia (LDL-C> 190 mg/dL) and lifelong accumulation of
LDL in tissues and arteries
• Evidence of CVD early in life
Familial Hypercholesterolemia FH: A Clinically Recognizable Genetic
Disorder
FH = familial hypercholesterolemia; CVD = cardiovascular disease.
1. Marais AD. Clin Biochem Rev. 2004;25:49-68. 2. Nordestgaard BG, et al. Eur Heart J. 2013;34:3478-90.
3. Mahley RW, et al. In: Kronenberg: Williams Textbook of Endocrinology. 2008. 4. Rader DJ, et al. J Clin Invest.
2003;111:1795-1803. 5. Hopkins PN, et al. J Clin Lipidol. 2011;5(3 Suppl):S9-175. 6. Williams RR, et al. JAMA.
1986;255(2):219-224. 7. Weigman A. Lancet. 2004;363(9406):369-70.

5. Genest et al. 1473 CCS Position Statement on Familial Hypercholesterolemia Canadian Journal of Cardiology 30 (2014) 1471e1481
Visible Signs of FH
Bilateral xanthelasma
(<25 yrs of age)
Bilateral Corneal Arcus
(<45 yrs of age)
Extensor Tendon Xanthoma of Hand
(Any time)
Extensor Tendon Xanthoma of Achilles
(Any Time)

6. B.G. Nordestgaard et al. European Heart Journal Advance Access published August 15, 2013
LDL Cholesterol Burden In FH

7. Objectives/Outline
• Risk of ASCVD and FH
• Risk Factors that identify high risk FH patients
• Genetic Testing
• Xanthoma and FH
• FH and Lipoprotein(a)
• ABO blood group, FH and ASCVD risk
• Guidelines and Recommendations
• Imaging
• Montreal FH Score

8. Objectives/Outline
• Risk of ASCVD and FH
• Genetic Testing
• Risk Factors that identify high risk FH patients
• Xanthoma and FH
• FH and Lipoprotein(a)
• ABO blood group, FH and ASCVD risk
• Guidelines and Recommendations
• Imaging
• Montreal FH Score /Safeheart FH Score

9. Patients with FH Are at Very High CVD Risk Before Age
40, Relative to the General Population
48.4
3.5
1.1
2.6
125.0
8.4
2.6
3.7
1
10
100
1000
20-39 40-59 60-79 Overall
RelativeriskofCHDinFHvs
generalpopulation
Age (years)
Scientific Steering Committee. Atherosclerosis. 1999;142:105-112.
*
*
*
*
*
*
*
Men (
* P <0.01 vs general
population.
Women
Risk of CHD in FH Patients/Risk of CHD in General Population
* P <0.01 vs general population.

10. Familial Hypercholesterolemia and ASCVD Risk
Circulation. 2016;134:9-19

11. Unadjusted rates of coronary heart disease death or nonfatal MI per 1000 person
years & underlying observed event numbers in (A) men and (B) women.
Circulation. 2016;134:9-19

12. Objectives/Outline
• Risk of ASCVD and FH
• Genetic Testing
• Risk Factors that identify high risk FH patients
• Xanthoma and FH
• FH and Lipoprotein(a)
• ABO blood group, FH and ASCVD risk
• Guidelines and Recommendations
• Imaging
• Montreal FH Score

13. 8
Similar phenotypes may not share the same genotype..
Slide from G. Kees Hovingh MD, PhD

14. Genes associated with cardiovascular disease in familial
hypercholesterolemia
Curr Opin Lipidol 2018, 29:000–000

15. Khera, A.V. et al. J Am Coll Cardiol.2016;67(22):2578–89

16. OR for
CAD
OR of CAD
adjusted for
LDL
LDL > 190 mg/dL
without FH
mutation
6 1.6
LDL > 190 mg/dL
with FH
mutation
22 4.2
Diagnostic Yield and Clinical Utility of
Sequencing Familial Hypercholesterolemia
Genes in Patients with Severe
Hypercholesterolemia
Khera et al, JACC 2016
OR for
CAD
LDL > 190 mg/dL
without FH
mutation
6
LDL > 190 mg/dL
with FH
mutation
22
Clinical impact of FH mutations?
Khera, A.V. et al. J Am Coll Cardiol.2016;67(22):2578–89

17. Multiple genes of small effect (polygenic)
Approximately 15-20% of individuals with severe
hypercholesterolemia likely have a polygenic etiology
Beyond FH genes: other causes of hypercholesterolemia
Curr Cardiol Rep (2017) 19: 44

19. Journal of Clinical Lipidology, Vol 11, No 3, June 2017
Frequency of (A) CVD events and (B) CAD events by
GRSCAD tertiles
Average number of cardiovascular events per individual
according to the GRSCAD

20. Objectives/Outline
• Risk of ASCVD and FH
• Genetic Testing
• Risk Factors that identify high risk FH patients
• Xanthoma and FH
• FH and Lipoprotein(a)
• ABO blood group, FH and ASCVD risk
• Guidelines and Recommendations
• Imaging
• Montreal FH Score

21. Clinical variables showing independent association with cardiovascular
disease in different large cohorts of FH
Curr Opin Lipidol 2018, 29:000–000

22. Journal of Clinical Lipidology, 2018 AIP

23. Conclusions
Despite long-term optimal LLT, 12% of FH patients
developed a cardiovascular event
In addition to lipid parameters, classical risk factors, especially
smoking and hypertension, contributed to the CV events.
Approximately 1/3 of statin-treated FH patients
with a CV event developed a subsequent event
associated with smoking and hypertension
Treatment of FH patients should, therefore, not only focus on
optimizing LDL-C levels but also on improving other CVD risk
factors.
Journal of Clinical Lipidology, 2018 AIP

24. Allard et al. Lipids in Health and Disease 2014, 13:65

25. • Focuses on risk of FH related to LDL burden (levels and exposure
duration)
• Role of genetic assessment
• Role of imaging
• Traditional risk factors such as age, male gender, smoking,
hypertension, higher LDL-C level and lower HDL-C level
• Lipoprotein(a)
Sharifi M, et al. Heart 2016;0:1–6.

26. J. Besseling et al. / Atherosclerosis 233 (2014) 219e223
Risk factors for CVD in heterozygous FH patients.

27. Objectives/Outline
• Risk of ASCVD and FH
• Risk Factors that identify high risk FH patients
• Genetic Testing
• Xanthoma and FH
• FH and Lipoprotein(a)
• ABO blood group, FH and ASCVD risk
• Guidelines and Recommendations
• Imaging
• Montreal FH Score

28. Criteria for the clinical diagnosis of FH
European Heart Journal (2013) 34, 962–971

29. Xanthoma
D.M. Oosterveer et al. / Atherosclerosis 207 (2009) 311–317

30. D.M. Oosterveer et al. / Atherosclerosis 207 (2009) 311–317
Xanthomas and risk of cardiovascular disease.
In patients with genetically confirmed FH, xanthomas
were associated with a 3.20-fold higher risk of CVD (95% CI
2.12–4.82, p < 0.01).

31. Arterioscler Thromb Vasc Biol. 2005;25:1960-1965
Percentage of HeFH subjects with tendon
xanthomas by deciles of age.
Percentage of HeFH subjects with cardiovascular disease
relative to the presence of tendon xanthomas by age groups and sex.

32. European Heart Journal (2010) 31, 1007–1012
The presence of tendon xanthomas in FH patients is associated with genetic variation in the RCT and LDL
oxidation pathways. These results support the hypothesis that xanthomas and atherosclerosis share
pathophysiological mechanisms.

33. European Heart Journal (2010) 31, 1007–1012

34. The risk of xanthomas per gene-load score of two
pathophysiological pathways.
oxidation pathway.
cholesterol transport
pathway.
Both pathways
combined.

35. Objectives/Outline
• Risk of ASCVD and FH
• Risk Factors that identify high risk FH patients
• Genetic Testing
• Xanthoma and FH
• FH and Lipoprotein(a)
• ABO blood group, FH and ASCVD risk
• Guidelines and Recommendations
• Imaging
• Montreal FH Score

36. FH and Lipoprotein(a)
J Am Coll Cardiol 2014;63:1982–9

37. FH
Non-FH
Kaplan-Meier Curves for CVD-Free Survival in
Subjects With FH According to Lp(a) Levels and SexCumulative Hazard for CVD and Lp(a) levels
Women Lp(a) <50 mg/dl.
Women Lp(a) >50 mg/dl.
Men Lp(a) <50 mg/dl
Men Lp(a) >50 mg/dl
J Am Coll Cardiol 2014;63:1982–9

38. Cox Proportional Hazards Model Showing
Relationships Between Different Cardiovascular
Risk Factors and CVD in Patients With FH
J Am Coll Cardiol 2014;63:1982–9

39. Objectives/Outline
• Risk of ASCVD and FH
• Risk Factors that identify high risk FH patients
• Genetic Testing
• Xanthoma and FH
• FH and Lipoprotein(a)
• ABO blood group, FH and ASCVD risk
• Guidelines and Recommendations
• Imaging
• Montreal FH Score

40. ABO Blood Group , FH & CV Risk

41. CVD, CAD, PVD, and cerebrovascular disease frequency according to the
blood group.
CVD CAD
PVD
cerebrovascular disease
Journal of Clinical Lipidology, 2017 AIP

42. Objectives/Outline
• Risk of ASCVD and FH
• Risk Factors that identify high risk FH patients
• Genetic Testing
• Xanthoma and FH
• FH and Lipoprotein(a)
• ABO blood group, FH and ASCVD risk
• Guidelines and Recommendations
• Imaging
• Montreal FH Score

43. Journal of Clinical Lipidology, Vol 5, No 3S, June 2011

44. Journal of Clinical Lipidology, Vol 5, No 3S, June 2011
Characteristics placing FH patient at the highest CVD risk

45. Cardiovascular risk factors in individuals with FH
Journal of Clinical Lipidology, Vol 5, No 3S, June 2011

46. 2017 NLA Expert Panel
PCSK9 Inhibitor
Recommendations
Journal of Clinical Lipidology. 2017 http://dx.doi.org/10.1016/j.jacl.2017.05.001
High Risk
History of uncontrolled high blood pressure, diabetes, current
cigarette smoking, or family history of premature ASCVD
Additional high risk markers (coronary calcium > 300
Agatston units or >75th percentile for the patient’s age,
gender, and ethnicity ; Lp(a) > 50 mg/dL using an isoform
insensitive assay, hs-CRP > 2 mg/L or CKD including
albumin/creatinine ratio > 30 mg/g).

47. 2017 Update of ESC/EAS Task Force on
practical clinical guidance for PCSK9i inhibition in FH
European Heart Journal (2017) 0, 1–13

48. Objectives/Outline
• Risk of ASCVD and FH
• Risk Factors that identify high risk FH patients
• Genetic Testing
• Xanthoma and FH
• FH and Lipoprotein(a)
• ABO blood group, FH and ASCVD risk
• Guidelines and Recommendations
• Imaging
• Montreal FH Score

49. CAD in FH Patients (Mutation or LDL-C>95th %tile Extent
by CAC Score: Netherlands Cohort
CAC=0
75%
25%
0%
0%
10%
20%
30%
40%
50%
60%
70%
80%
No CAD Non-Obs Obs CAD
CAD Extent CAC>400
0%
33%
67%
0%
10%
20%
30%
40%
50%
60%
70%
80%
No CAD Non-Obs Obs CAD
CAD Extent
n=20 n=24
Neefjes L. et al Heart 2011;97:1151-1157.

50. Coronary CTA and Outcomes in FH
101 patients with genetically determined FH and clinical CCTA
Mean age 52
~55% male
LDL-C 264
n=21 events (16 revasc)
Multivariable
Predictors MACE
HTN
HR 7.5 (1.6-38)
Plaque score >
median (2.78)
HR 5.4 (1.4-20.8)
Tada H. et al AJC 2015;115:724-729.

51. Carotid Plaque Prevalence by
Ultrasound in FH
Rubba et al. Eur J Prev Card 2017, 24:1051-1059.
263 Patients with presumed FH
OR Prevalent Premature CVD
=4.2 (1.3-13.9)

53. EAS/ESC Updated Guidelines PCSK9 for ASCVD or FH
Landmesser U et al, EHJ 2017, epub

54. EAS/ESC Updated Guidelines PCSK9 for ASCVD or FH
Landmesser U et al, EHJ 2017, epub
“Imaging may also have a role in guiding therapy, as
evidence of increased plaque burden with ultrasound
evaluation or CTA has been shown to be indicative of
premature ASCVD and high risk for cardiovascular
events”

55. Objectives/Outline
• Risk of ASCVD and FH
• Risk Factors that identify high risk FH patients
• Genetic Testing
• Xanthoma and FH
• FH and Lipoprotein(a)
• ABO blood group, FH and ASCVD risk
• Guidelines and Recommendations
• Imaging
• Montreal FH Score

56. Journal of Clinical Lipidology, Vol 11, No 1, February 2017

57. Independent multivariate predictors of CVD
CVD points for the Montreal-FH-SCORE
Journal of Clinical Lipidology, Vol 11, No 5, October 2017

58. ROC Prevalence of cardiovascular disease (CVD) by
(A) score categories and (B) score groups
Journal of Clinical Lipidology, Vol 11, No 5, October 2017

59. Journal of Clinical Lipidology, Vol 11, No 5, October 2017

60. Combined Score
ROC curves for CVD prediction in the
combined cohort of familial hypercholesterolemia (FH) using
the Montreal-FH-SCORE and the Combined-FH-SCORE.
Journal of Clinical Lipidology, Vol 11, No 5, October 2017

61. Montreal FH Score
•Patients with a high MFHS score presented a significant
8.8-fold increased odd of CVD events compared with
patients with a low score
•The addition of lipoprotein(a) to the score did not
improve the prediction of CVD events area under the
receiver operating characteristic curve
•MFHS is a strong predictor of prevalent CVD in FH

62. SAFEHEART is a multicenter, nationwide, long-term prospective cohort study of a molecularly
defined population with FH with or without previous ASCVD.
2404 adult patients with FH who were followed up for a mean of 5.5 years
12 (0.5%) and 122 (5.1%) suffered fatal and nonfatal incident ASCVD
Age, male sex, history of previous ASCVD, high blood pressure,
increased body mass index, active smoking, and low-density lipoprotein cholesterol and
lipoprotein(a) levels were independent predictors of incident ASCVD
Circulation. 2017;135:2133–2144.

63. Circulation. 2017;135:2133–2144.
Five- vs 10-year risk
of developing incident
atherosclerotic
cardiovascular disease
(ASCVD) for 66-year-old men
with familial
hypercholesterolemia
and low-density lipoprotein
cholesterol (LDL-C) <100
mg/dL.
Five- vs 10-year risk
of developing incident
atherosclerotic
cardiovascular disease
(ASCVD) for 20-year-old women
with familial hypercholesterolemia
and low-density lipoprotein
cholesterol (LDL-C) <100
mg/dL.

64. Our Patient Revisited
• Susan is a 30 year old woman with a history of FH diagnosed at age 9 when
her father had an MI at age 44. She was started on bile acid sequestrants at
the time, and over the next 21 years has been treated subsequently with
statins of increasing intensity and now ezetimibe 10 mg. She currently
takes 40 mg rosuvastatin with ezetimibe 10 mg , and has an LDL-C of 104
mg/dL. Her LDL-C at diagnosis was 220 mg/dL. She exercises 3x/week and
follows a heart heathy diet.
• Additional Information
• A. Lp(a) 90 mg/dL
• B. HDL-C 43 mg/dL
• C. Bilateral irregular thickened Achilles tendons
Which of the following do you most agree with ??
A. She is adequeately treated and should continue current medications
and lifestyle
B. She needs more aggressive LDL-C lowering
C. Need more information to assess her clinical status

65. Summary/Take Home Messages
• FH patients are at increased risk for ASCVD events
• Within the spectrum of FH, risk is variable
• Xanthoma predicts risk of ASCVD events in FH patients
• Lp(a) predicts risk of ASCVD events in FH patients but does not add to
further discrimination in the MRFS
• ABO Blood group may add to risk stratification
• While Genetic and Imaging may play a role in risk assessment , use of
traditional risk factor assessment can help to identify higher risk patients.
• Hypertension, Low HDL-C, Smoking , Age and Sex are useful components of
the MRFS but not Lp(a)