HDL as Therapeutic Target · The Founder Effect in Genetics The founder effect occurs when the...

And: Novel Approaches in Severe Hyperlipidemias

Jacques Genest MD

Cardiovascular Research Laboratories

McGill University Health Center

Familial Hypercholesterolemia

Merck *

Pfizer

Novartis

AMGEN *

Roche *

AstraZeneca

Disclosure J. Genest MD 2014

Relevant disclosure: IMPROVE-IT, CANTOS , CAPREE steering Committees; REVEAL , ACCELERATE, AMG145 , Lilly Clinical Trials.

Advisory Board, Speaker’s Bureau, Consultant, Grants, Clinical Trials

Sanofi/Regeneron *

Lilly

Valeant

Genzyme *

Aegerion

Ascati

Stock ownership: none;

Off label use: none

* Scientific Advisory

Outline

Highlights of 2012 CCS Dyslipidemia Guidelines


Current strategies for achieving LDL-C goal

Opportunities for further LDL-C reduction: new agents

§ Subjects with an LDL-C ≥ 3.5 mmol/L should receive statin therapy. Subjects with an LDL-C < 3.5 mmol/L have the option of health behaviour modification or additional risk stratification based on alternate targets or secondary testing. Anderson TJ, Grégoire J, et al. 2012 Update of CCS Dyslipidemia Guidelines. Can J Cardiol. 2013; 29:151–167.

LDL-C Remains the Primary Target with Emerging Role for Non-HDL-C and ApoB as Alternate Targets

Strong, High: Strong Recommendation, High-Quality Evidence Strong, Moderate: Strong Recommendation, Moderate-Quality Evidence Anderson TJ, Grégoire J, et al. 2012 Update of CCS Dyslipidemia Guidelines. Can J Cardiol. 2013;29:151–167.

Risk level Initiate therapy if Primary target LDL-C Alternate target

High

FRS ≥ 20%

Consider treatment in all

(Strong, High)

≤ 2 mmol/L or ≥ 50% decrease

in LDL-C (Strong, High)

• ApoB ≤ 0.8 g/L

• Non HDL-C ≤ 2.6 mmol/L

(Strong, High)

Intermediate

FRS 10%-19%

• LDL-C ≥ 3.5 mmol/L (Strong,

Moderate)

• For LDL-C < 3.5 consider if: Apo B ≥

1.2 g/L or Non-HDL-C ≥ 4.3 mmol/L

(Strong, Moderate)

≤ 2 mmol/L or ≥ 50% decrease

in LDL-C (Strong, Moderate)

• ApoB ≤ 0.8 g/L

• Non HDL-C ≤ 2.6 mmol/L

(Strong, Moderate)

Low

FRS < 10%

• LDL-C ≥ 5.0 mmol/L

• Familial hypercholesterolemia

(Strong, Moderate)

≥ 50% decrease in LDL-C

(Strong, Moderate)

Alternate Targets: Non-HDL Lipoproteins

Include all ApoB Containing Particles

Size and Density of Important Lipoproteins

Adapted from Anderson TJ, Grégoire J, et al. 2012 Update of CCS Dyslipidemia Guidelines. Can J Cardiol. 2013;29:151–167.

VLDL

Chylomicron Remnants

IDL

LDL

HDL

Lp(a)

Non-HDL cholesterol (all ApoB-containing particles)

Diameter (nm)

0.95

1.00

1.02

1.06

1.10

1.20

5 10 20 40 60 80

Den

sity

(g

/ml)

Is the ACC/AHA Guidelines on the Treatment of

Blood Cholesterol a Game Changer?

Unclear Language Not very useful for a clinician

“is reasonable. Can be useful/effective/beneficial

Is probably recommended or indicated”

1. ASCVD

2. LDL-C

3. DM

4. Hi Risk

CANADIAN RESPONSE TO AHA/ACC GUIDELINES A Perspective from the CCS Dyslipidemia Panel

“After careful review our main recommendations to Canadian physicians are essentially unchanged in light of the new ACC/AHA Guidelines.” “We continue to recommend LDL-C (or alternative) targets as a useful concept for physicians and patients”

Anderson TJ, Grégoire J, et al. Can J Cardiol. 2014. doi: 10.1016/j.cjca.2014.01.009.

Comparison of International Cholesterol Guidelines


Definition and Molecular Basis

Prevalence and Cardiovascular disease

Treatment options

The Canadian FH Registry

SMASH


Heterozygous FH (HeFH): single copy of mutated gene

Homozygous FH (HoFH): two copies of mutated gene (either same mutation or compound heterozygous)

Pedigree of a family with familial hypercholesterolaemia.

Nordestgaard B G et al. Eur Heart J 2013;eurheartj.eht273

© The Author 2013. Published by Oxford University Press on behalf of the European Society of

Cardiology.

Homozygous FH

1/500

1/500

1/4

HoFH: 1/500 * 1/500 * ¼ = 1/106

Quebec: 1/270 * 1/270 * ¼ = 3.42936E-06 * 7.9M = 27

Clinical Presentation

• Familial

Hypercholesterolemia

• Heterozygous

• Frequency 1:500 (up

to 1:80 in Lac St-Jean)

• Tendinous xanthomas

• LDL-Receptor gene

defect

• LDL-C 2x ULN

Clinical Findings

Tendinous Xanthomas

Xanthelasmas Arcus Corneus

0

10

20

30

40

50

60

70

80

Xanthelasma Arcs cornéens

Xanthomes Tendineux

1979 (n = 371)

2000 (n = 270)

Fré

qu

en

ce (

%)

Hypercholestérolémie familiale hétérozygote:

Signes physiques; 1979 vs 2000 ( hommes et femmes > 20 ans)

Courtoisie Dr. C. Gagné Québec

Definition of FH

• MedPed (US)

• Simon-Broome (UK)

• Dutch criteria (Netherlands)

• Japanese Atherosclerosis Society

• Based on Age and LDL-C levels

• LDL-C and DNA, Family Hx, Xanthomas

• Point system (Definite, possible, probable)

Definition of FH

No “Gold Standard”

Changing nature of the phenotype

Mutation analysis of candidate genes: causal or SNP?

Proposed CCS definition of FH Major criterion LDL-C Low density lipoprotein-

cholesterol *

Adult: LDL-C >5.0

Pediatric > 4.0

DNA Mutation

Definite

Minor criteria

Affected First degree relative with

Major criterion

Probable

Presence of xanthomas in proband Probable

First degree relative with early

onset CAD

Probable

* secondary causes ruled out (nephrotic syndrome, obstructive jaundice, hypothyroidism)

http://en.wikipedia.org/wiki/Nephrotic_syndrome



http://en.wikipedia.org/wiki/Obstructive_jaundice

http://en.wikipedia.org/wiki/Hypothyroidism

Homozygous FH

True HoFH

Same allele

Co-sanguinous

Founder Effect

Compound HoFH

Different Alleles

Random

Severity depends on

cumulative effect


LDL-R 15 Kd CNV (Del) homozygote LDL-R Honduras homozygote

14 yo ♂ 30 yo ♂

The Founder Effect in Genetics

The founder effect occurs when the following conditions are met:

Small number of migrants

Evolutionary bottleneck (war, pestilence, natural catastrophe)

High birth rate and increase in inbreeding (co-sanguinous

marriages),

Low genetic variation (lack of genetic mixing)

This can be observed in Iceland, Faroe Islands, Easter

Islanders ,Pitcairn Island, Tangier Island.

Also in French Canadians, Ashkenazi Jews, South Afrikaners.

The Founder Effect in Genetics

Upper and lower Canada, 18th Century

Canada 2014

Unknown Lands

90% Live Here!

Mutations In LDL-R Gene

Clin Genet 19V7: 52: 1-6

Canada 2014

Unknown Lands

Ontario

FH in Ontario (and ROC)

Wang J, Huff E, Janecka L, Hegele RA. Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent. Hum Mutat. 2001 Oct;18(4):359.

“We found 25 LDLR mutations in 34 subjects. Eleven LDLR mutations were novel, including two in-frame deletions of a single amino acid (one each in exons 2 and 4), two larger deletions that shifted the reading frame (one each in exons 4 and 10), five missense mutations (C42R, A370T, T413M, L561P and E760D) and two splice acceptor mutations (one each in introns 3 and 8). The results indicate that FH is more genetically diverse in Ontario than in Quebec. ”

Wang J, Ban MR, Hegele RA. Multiplex ligation-dependent probe

amplification of LDLR enhances molecular diagnosis of familial

hypercholesterolemia. J Lipid Res. 2005 Feb;46(2):366.

LDL-R mutations: Functional Classes

1. Mutations disrupt the synthesis of the LDL receptor and no precursor is produced (null alleles).

2. Mutations block transport to the Golgi apparatus: Class 3 mutations produce proteins that reach the membrane but fail to bind the LDL.

3. Mutations produce a receptor that binds the lipoprotein but which cannot be internalised.

4. Mutations block the acid-dependent dissociation of the receptor and the ligand in the endosome.

Hobbs et al 1992

LDL Receptor Mutations

Exon 3 mutation

15 Kb CNV (Del) mutation

Deletion in the Gene for LDL-R in a Majority of French Canadians with Familial Hypercholesterolemia Helen H. Hobbs N Engl J Med 1987; 317:734

Homozygous FH: Cholesterol Levels

Moorjani S et al.

Lancet 1993;341:1303




Treatment options


SMASH

Overlap of clinical and mutation diagnosis of heterozygous familial hypercholesterolaemia.



Cardiology.

LDL accumulates to cause CHD early

in life in FH

Normal

Female

Male Hypertension

Diabetes Smoking

Threshold

for CHD

0

5

10

1 20 40 60 80

Cu

mu

lati

ve

LD

L-C

(g/d

L-y

ears

)

Threshold for CHD reached by:

– Age >60 y in healthy individuals

Age Patients Meet CHD Threshold

Age (years)

Adapted from Horton JD, et al. J Lipid Res. 2009;50(Suppl):S172-S177.

LDL accumulates to cause CHD early

in life in FH

Normal

Female

Male Hypertension

Diabetes Smoking

HeFH HoFH

Threshold

for CHD

0

5

10

1 20 40 60 80

Cu

mu

lati

ve

LD

L-C

(g/d

L-y

ears

)

Threshold for CHD reached by:

– Age 15 y in HoFH patients

– Age 40 y in HeFH patients

– Age >60 y in healthy individuals

Age Patients Meet CHD Threshold

Age (years)

Adapted from Horton JD, et al. J Lipid Res. 2009;50(Suppl):S172-S177.

LDL cholesterol burden in individuals with or without familial hypercholesterolaemia as a

function of the age of initiation of statin therapy.



Cardiology.

Kaplan–Meier curve estimates of cumulative CHD-free survival among individuals with

familial hypercholesterolaemia according to statin treatment (P < 0.001 for difference).



Cardiology.




Treatment options


SMASH

Medications

Statins

Ezetimibe

Fibrates

Niacin

BAR

CETP inh

MTP inh

ApoB iRNA

PCSK9 mAb

Cholestérol-LDL et suivi de 25 ans d’un patient avec une HFHe

0.0

1.0

2.0

3.0

4.0

5.0

6.0

Ch

ole

sté

rol-

LD

L (

mm

ol/L

)

PAC

cholestyramine lova simva atorva

eze

1979-89 1989-93 1993-99 1999-2004 2004-05

Courtoisie Dr. C. Gagné Québec

Medications

Statins

Ezetimibe

Fibrates

Niacin

BAR

CETP inh

MTP inh

ApoB iRNA

PCSK9 mAb

Anacetrapib: Effects on LDL-C and HDL-C

HDL-C

Study Week

Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76

HD

L-C

(m

g/d

L)

(SE

)

0

20

40

60

80

100

120

Anacetrapib

Placebo

Anacetrapib n = 776 757 718 687 647 607 572 543

Placebo n = 766 761 741 744 736 711 691 666

LDL-C

Study Week

Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76

LD

L-C

(m

g/d

L)

(SE

)

0

20

40

60

80

100

Anacetrapib

Placebo

Anacetrapib n = 804 771 716 687 646 604 568 540

Placebo n = 803 759 741 743 735 711 691 666

-39.8% (p<0.001) +138.1% (p<0.001)

Medications

Statins

Ezetimibe

Fibrates

Niacin

BAR

CETP inh

MTP inh

ApoB iRNA

PCSK9 mAb

Molecular Causes of Familial

Hypercholesterolemia (FH)

LDL-R:

Primary familial

hypercholesterolemia

ARH:

Autosomal recessive familial


PCSK9:

Proprotein convertase

subtilisin/kexin type 9

ApoB:

Familial defective Apo B

Cohen J. et al. NEJM 2006;354:1264

(African-Americans)

PCSK9 Gene Mutation

Comparison of the Different Types of

Therapeutics

Monoclonal Antibody (e.g. AMG 145)

Antisense Agent (e.g. mipomersen)

Small Molecule (e.g. statins)

Size ~ 150 kDa ~ 0.5 kDa

Structure Immunoglobulin Single-stranded nucleic acid Chemical entity

Target Extracellular Intracellular Intracellular, CNS

Target Specificity High High Low(er)

Metabolism RES, target-mediated disposition Hepatic/renal Hepatic/renal

Administration SC or IV SC or IV PO

Dosing Frequency ~ Q1W–Q4W ~Q1W ~ Daily

Crossing BBB No Potentially yes Potentially yes

Commmon AEs Injection site reactions Injection site reactions and

flu-like symptoms Myopathy, GI disturbance

Liver Toxicity No evidence Liver fat accumulation

observed Rare

Terminology of Monoclonal Antibodies

1. Weiner LM. J Immunother. 2006;29:1-9.; 2. Yang XD, et al. Crit Rev Oncol Hematol. 2001;38:17-23.; 3. Lonberg N. Nat Biotechnol. 2005;23:1117-1125.; 4. Gerber DE. Am Fam Physician. 2008;77:311-319.

Mouse (0% human)

Fully Human (100% human)

Humanized (> 90% human)

Chimeric (65% human)

-umab -zumab -ximab -omab Generic suffix:

Source (% human protein)

High Low Potential for immunogenicity

AMG 145 (Evolocumab) FULLY HUMAN MONOCLONAL ANTIBODY

AMG 145 Phase 2 Summary: Percent Change

from Baseline in LDL-C at Week 12

0

-10

-20

-30

-40

-50

-60

10


N=406, monotherapy,

MENDEL

Q2W Q4W

LAPLACE- TIMI57 Hypercholesterolemia

N=631

Statin-Intolerant

N=160

GAUSS

Q4W

RUTHERFORD

Q4W

HeFH

N=167

Placebo AMG 145 Ezetimibe Pe

rce

nt

ch

an

ge

fro

m b

as

eli

ne in

L

DL

-C a

t w

eek 1

2

-70

-80

420 mg

420 mg

140 mg

420 mg

Q2W Q4W

420 mg

420 mg

AMG 145 + EZ

140 mg

Summary of Treatment-Emergent Adverse Events with

AMG 145

*Percents are based on subjects with normal values at baseline

Combined Treatment Groups

Placebo (N=301)

AMG 145 (N=951)

Ezetimibe (N=45)

Placebo Q4W/ Ezetimibe

(N=32)

420 mg Q4W/ Ezetimibe

(N=30)

Treatment-Emergent AE, % 48% 57% 58% 59% 67%

Serious AEs, % 1.3% 2.1% 0 0 0

Treatment-Related AE, % 8.3% 11.4% 6.7% 21.9% 16.7%

Injection Site Reactions, % 3.3% 4.0% N/A 3.1% 6.7%

Muscle AEs, % 3.0% 5.6% 2.2% 12.5% 20.0%

ALT or AST >3x, % 0.3% 0.4% 0 3.1% 0

Total bilirubin ≥ 2x, % 0 0.2% 0 3.1% 0

SAR236553/REGN727 (Alirocumab) FULLY HUMAN MONOCLONAL ANTIBODY

SAR236553/REGN727 Summary: Percent Change in

LDL-C at Week 8/12 with SAR236553 150 mg Q2W

*P<0.0001 vs. Placebo + Atorvastatin (A) 80 mg Koren MJ. et al. 2012.

-80 Placebo SAR236553/REGN727

0

-10

-20

-30

-40

-50

-60

-70 LS

Me

an

% C

ha

ng

e i

n L

DL

-C L

eve

l

at

We

ek

8/1

2 L

OC

F

HeFH

Pooled Studies 11565 + 1003

Placebo n=46

Q2W n=45

150 mg

*

Hypercholesterolemia N=88

Study 11566

Q2W + A 10 mg

n=29

Q2W + A 80 mg

n=29

Placebo + A 80 mg

n=30

*

150 mg

150 mg

150 mg

Summary of Treatment-Emergent Adverse

Events with SAR236553/REGN727

Population

Placebo (n=77)

150 mg Q2W (n=108)

Any AEs 42 (54.5%) 63 (58.3%)

Any Serious AEs 2 (2.6%) 1 (0.9%)

AEs Leading to Death 0 0

Injection Site Reactions 4 (5.2%) 12 (11.1%)

ALT >3X ULN 0 0

Skin Disorders 0 7 (6.5%)

Respiratory Disorders 3 (3.9%) 7 (6.5%)

Recent clinical data for PCSK9

OSLER: Effects of Evolocumab (AMG 145) or

SOC on LDL-C over 52 weeks

60

• Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively.

• No neutralizing antibodies detected.

Week 12

UC

LD

L-C

Per

cen

tage

Ch

ange

fro

m

Bas

elin

e to

Wee

k 5

2, M

ean

(SE

)

-60

0 Baseline

OSLER Study Week

-50

-40

-30

-20

-10

0

10

Parent Study

12 24 36 48 52

Evolocumab / SOC Only (n = 272)

Evolocumab / Evolocumab + SOC (n = 544) -52%

-3%

• OSLER is an open label extension of AMG 145 Phase 2 Studies (MENDEL, LAPLACE, RUTHERFORD, GAUSS) to assess long term safety and efficacy

-2%

-52%

Not Evolocumab / SOC Only (n = 96)

Not Evolocumab / Evolocumab + SOC (n = 192)

Low LDL-C and AE

Low LDL-C and Adverse Events

Conclusions: No increase in AE with low LDL-C

Medications for Homozygous FH

Statins

Ezetimibe

Fibrates

Niacin

BAR

CETP inh

MTP inh

ApoB iRNA

PCSK9 mAb

VLDL Assembly and secretion

Mipomersen

Lomatipibe

67

(Juxtapid®)

68

(Kynamro®)

69

Extracorporeal LDL Filtration

Liposorber (Kaneka)

HELP (Braun)

Courtoisie Dr Jean Bergeron

Mean

LD

L-C

(m

mo

l/L

)

Time (years)

+ Atorvastatin

Apheresis 1

99

2

19

93

1994

19

95

19

96

19

97

19

98

400

300

200

100

Mean

LD

L-C

(m

g/d

L) 500

19

99

Extracorporeal LDL Filtration (HELP)

Genest J. NEJM 1999;341:490

A

C D

B

1989 1999




Treatment options


SMASH

ACS Quality Improvement Initiatives

• NRMI Registry: STEMI and NSTEMI

– 1990-2006: > 2.5 million patients

• GRACE Registry: UA, NSTEMI, STEMI

– 1999-2007: ~ 102,000 patients

• CRUSADE QI Initiative: UA and NSTEMI

– 2001-2006: ~ 202,000 patients

• Get With the Guidelines (GWTG) CAD Module

– 2000-2009: ~ 514,00 patients

• ACTION Registry-GWTG: NSTEMI and STEMI

– 2007-Present: ~ 450,000 patients

H O

CANADA

FH

HF

FH/HF Canada Canadian Familial Hypercholesterolemia Registry

Régistre Canadien d’hypercholestérolémie familiale

McPherson Ooi

Frohlich

Hegele

Gaudet

McCrindle Genest Brophy Ruel

Bergeron Couture

Carpentier Perron

St-Pierre

Engert

Gupta Leiter

Henderson Leberge

Junaid Katz Mymin Nguyen

Mancini Francis Saeedi

Morrison Pare

Raggi Romney

Bose

Lau Wong

Bewick

Ransom

Chandurkan

Hoag Pearson

Patient Flowthrough

Subject with high LDL-C

Cascade screening New case identification

No

SMASH Registry

FH Criteria satisfied

Yes

Consent form signed

Clinical evaluation Baseline lipid profile

Demographic info

Secondary causes R/O

Clinical evaluation Family history

Clinical evaluation Longitudinal F/U

Annual data capture

BioBanking

Plasma/Serum

DNA

FH Registry

Central DNA Biobank (Chicoutimi)




Treatment options


SMASH

SMASH: Systems and Molecular

Approaches to Severe Hyperlipidemias

Mutations causing FH, next-gen sequencing gene-gene interactions.

Severe hypertriglyceridemia

HDL Deficiency

Molecular basis of rare lipid disorders

New Genes Causing FH

Exome Wide NextGen Sequencing

• Sequenced over 180,000 exomes.

• Approximately 54,000 variants were identified.

• Removed variants unlikely to be causal in the LDL-C GWAS, variants with a minor allele frequency >5%, synonymous or intronic variants and variants that did not fit a dominant model of transmission.

• Ended with 49 missense mutations. APOE gene Leu167del mutation most likely candidate.

• Sanger sequenced to confirm results obtained.

Patient 303 Heterozygous sister

Normal: AAG CGG CTC CTC CGC GAT GCC GAT Deletion:AAG CGG CTC CTC CGC GAT GCC GAT Protein: R L L R D 166 167

CCTGCGCAAGCTGCGTAAG CGG CTC C(TC C)GC GAT GCC GAT GACCTGCAGAAGCGCCTGGCAG

Revised Feb 2013

1 MKVLWAALLV TFLAGCQAKV EQAVETEPEP ELRQQTEWQS GQRWELALGR FWDYLRWVQT

61 LSEQVQEELL SSQVTQELRA LMDETMKELK AYKSELEEQL TPVAEETRAR LSKELQAAQA

121 RLGADMEDVC GRLVQYRGEV QAMLGQSTEE LRVRLASHLR KLRKRLLRDA DDLQKRLAVY 181 QAGAREGAER GLSAIRERLG PLVEQGRVRA ATVGSLAGQP LQERAQAWGE RLRARMEEMG

241 SRTRDRLDEV KEQVAEVRAK LEEQAQQIRL QAEAFQARLK SWFEPLVEDM QRQWAGLVEK

301 VQAAVGTSAA PVPSDNH

A

B

C

Awan Z et al. Atheroscelrosis 2013

Next Gen exome sequencing Molecular modeling

Long-Term Complications of HoFH

Severe, premature aortic calcification in FH represents a new clinical finding. Progression despite treatment suggests independence of cholesterol concentration.

A gene-dosage effect of the LDLR is observed in vascular (Aortic) calcifications.

Aortic Valve

Awan et al; Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):606-7

Aortic Valve Ascending Aorta



Aortic Arch



Aortic Arch Descending Aorta




Suprarenal Aorta




Suprarenal Aorta Infrarenal Aorta




Suprarenal Aorta Infrarenal Aorta

Bifurcation of Aorta


Aortic Valve

Gene Dosage Effect of the LDL-R gene on Aortic Calcification

Alrasadi K et al; Am Heart J. 2009 Jan;157(1):170-6.

Correlation between Age and Abdominal Aortic calcium Score for Homozygous FH,Heterozygous FH and Controls.

0 25 50 75 1000

2500

5000

7500

10000

12500Homozygous FH

Heterozygous FH

Control

Age

Ab

do

min

al

Ao

rtic

Calc

ium

Sco

re

10 20 30 40 50

IHD

PCI

AVR

CABG

Years

Chol (mg/dL)

Long-Term Follow-Up of HoFH

Patients

0

200

400

600

800

1000

1200

0

5

10

15

20

25

30

00 10 20 30 40 50

0

5

10

15

20

25

30

00 10 20 30 40 50

0

5

10

15

20

25

30

00 10 20 30 40 50

0

5

10

15

20

25

30

00 10 20 30 40 50

0

5

10

15

20

25

30

00 10 20 30 40 50

A

B

D

C

E

F

G

I

H

J

N

M K

L

O

P Q

S

R

T

U V

Y

X W

Age

Cholesterol

IHD

PCI

AVR

CABG

3D Print of aortic valve and Asc. aorta

Courtoisie Dr. N. Piazza, McGill

Conclusions

Familial Hypercholesterolemia represents the most common monogenic disorder associated with CAD

Molecular genetics are increasingly complex

Late complications include severe vascular calcifications

Treatment options may alter the natural history of the disease.

Conclusions

The FH Registry will allow the treatment of patients with a genetic disorder putting them at a 10-20 fold increase in CVD

HDL as Therapeutic Target · The Founder Effect in Genetics The founder effect occurs when the...

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