2CVD risk factors, and especially lipid metabolism, exemplify gene / environment interactions Mainly geneticCo-dominant mutations: Either genetic allele affectedRecessive mutations: Both genetic alleles affectedPolymorphisms and SNPs: Alleles consistent with “normal” and markers in proximity to significant genetic effects. Genome-wide association studies (GWAS).Mainly environmental or secondary to other disorders.
3A missing piece of the genetic puzzle Uncommon geneswith large effectPathogenic mutationsAutosomalrecessiveAutosomaldominantClinicalEffectPolymorphismsCommon genes with small effectGene Prevalence
5Familial Hypercholesterolaemia: What goes wrong? NORMALFH
6Metabolic Defect in Familial Hypercholesterolemia -100INTESTINEVLDLLPLB-48CIIIBELPLRLDL-RBChylomicronsCIIELIVERCIIIDLLRPECIIISR-B1FHAIEBHLAIHDLCEO.AIIAILDLLCATBFCMacrophageOxLDLOtherSR-B1SR-ATissuesABCA1DAVIGNON 2006
7Metabolic Defect in Familial Defective ApoB-100 INTESTINEVLDLLPLB-48 ApoBCIIIBELPLRLDL-RBChylomicronsCIIELIVERCIIIDLLRPEAIAIIESR-B1HDLLCATOtherTissuesCEFCCIIIFDBAIBHLO.LDLBMacrophageOxLDLSR-AABCA1DAVIGNON 2006
8PCSK9 regulates the surface expression of LDLRs by targeting for lysosomal degradation 1. Qian YW, et al. J Lipid Res. 2007;48:2. Horton JD, et al. J Lipid Res. 2009;50:S172-S177.3. Zhang DW, et al. J Biol Chem. 2007;282:
9Clinical Characteristics Gain-of-Function Mutations in PCSK9 Cause Familial Hypercholesterolaemia (FH)PCSK9 VariantPopulationClinical CharacteristicsD374YBritish, Norwegian families, 1 Utah familyPremature CHDTendon xanthomasSevere hypercholesterolemiaS127RFrench, South African, Norwegian familiesTendon xanthomas; CHD, early MI, strokeR215HNorwegian familyBrother died at 31 from MI; strong family history of CVDAssociated with:High serum LDL-C2Premature CHD and MI2In vitro testing in many identified mutations show decreased levels of LDLRs31. Abifadel M, et al. Hum Gen. 2009;30:2. Horton JD, et al. J Lipid Res. 2009;50:S172-S177.3. Cameron J, et al. Hum Mol Genet. 2006;15:*For a full list of ADH mutations, please see refer to Abifadel reference.
10What is “FH”? What does it cause? FH isCo-dominant mutation of genes affecting formation or function of the LDL-receptorThis causes metabolic and clinical consequences including precocious cardiovascular disease (CVD)MetabolicIncreased LDL,Reduced clearance of remnants including LDL’s precursor, IDL.Increased Lp(a)?Reduced HDL?ClinicalDominant: 50% of each generation. Risk 50:50Premature CHD, CVD and PVDAortic stenosisTendon xanthomas (11%) specific?Corneal arcus (27%) non-specific > 40y?Xanthelasmas (12%) nonspecificNo signs highly sensitiveFH IS NOT JUST HIGH CHOLESTEROL IN A PATIENT AND THEIR RELATIVE(S)
11FH: Why is it important? Non-FH Women Non-FH Men FH Women 4/11/2017FH: Why is it important?1.0Non-FH Women0.9Non-FH Men0.8FH Women0.7FH Men0.6Cumulative Probability of Clinical CAD0.50.40.30.20.10.090+25-3030-3535-4040-4545-5050-5555-6060-6565-7070-7575-8080-8585-90AgeMED PED Registry 2001.
12Why FH matters: Prevalence and Impact 5 – 10% of CHD events under age 60. J Lipid Res 34:269-77CVD death in >80% of FH cases.Absolute CVD risk differs from general population models.High risk profile from birth,Interaction differs (smoking, gender) Circulation 97:Risk algorithms underestimate risk Eur Heart J 19:A2-11Missed and misdiagnosedPrevalence:0.2 – 0.5% (1 : ) Atherosclerosis 173:55-68> 8 x 106 affected world-wide. Seminars in Vasc Med 4:87-92> 40,000 AustraliansEqual numbers of unaffected relativesUp to 1:60 in local groups with “founder effect”.Detection rates 0 – 44%World’s best 20-40%World average (including Australia) < 5%Molecular Medicine meets Public Health
13Case detection: Dutch Lipid Clinic Score? Diagnostic criteriaProcessCase detection: Dutch Lipid Clinic Score?Detecting index casesOptimal componentsDiagnosis assessmentAdultsClinical servicesChildren,AdolescentsModel of Care for FHLaboratory protocolGenetic testingManagementClinicalprotocolAdultsCascade ScreeningChildren,AdolescentsProcessLDL-Apheresis
14Severe triglyceride elevation due to recessive impairment of lipoprotein lipase Chylomicrons persist after fasting, massive levels of TG.Homozygous deficiency of Lipoprotein Lipase (LPL)Homozygous deficiency of the cofactor for L PL, Apo CIIImpaired transport of LPL to site of action (endothelium) due to homozygous defect in ANGPTL or GPIHBPCombined overproduction and undercatabolism of triglyceride-rich lipoproteins sufficient to saturate LPL, eg in Apo AV mutations.
15. Metabolic Defects affecting Lipoprotein Lipase B B B E B E E E B B DietaryfatINTESTINEB-100LPLB-48VLDLB-48CIICIIIETGLDL-RCRBChylomicronsECIILPLLIVERIDLELRPTGCIIIFFA + MGTGSR-B1AIEBHLAIHDLCEO.AIIAILDLLCATApoB-48 RBFCVLDLROtherOxLDLSR-B1ABCA1MacrophageTissuesSR-ADAVIGNON 2006
16. Metabolic defects saturating in LPL, eg Apo AV mutations B E B B B E ADIPOSETISSUESugarfatcaloriesNormalor reducedVLDLcatabolismAVINTESTINEB-100TG richVLDLOverproductionof VLDLHSLCIIILPLEB-48B-48CIIBCETPTG CEaGP + FFATGCRLPLEIDLELDLRLRPCIIIChylomicronsSR-B1CIIHLAVEBAIAIHDLO.sdLDLAIIAICESR-ABLCATFCVLDLRCD-36OxLDLOtherMacrophageLOX-1SR-B1TissuesABCA1SR-PSOXDAVIGNON 2006
18Autosomal recessive disorders have revealed HDL metabolism +A-INascent HDLA-ICELCATFCFCABCA1MacrophageRapid catabolismHomozygous (?heterozygous) Apo AI deficiency: AtherogenicTangier’s Disease: ABC-AI deficiency: Atherogenic?LCAT Deficiency: Non-atherogenic?Apo A1 Milano: Anti-atherogenic?
19Event Free Survival ( % ) Carriers of the ApoAI Leu178Pro VariantAre at Increased Risk of Developing CAD10050family controls(n=147)Event Free Survival ( % )apoAI (L178P) carriers(n=54)p = 0.008ApoAI 50%HDL-C 63%18.9 x CAD riskAge ( years)Hovingh K et al. J Amer Coll Cardiol 44:1429, 2004DAVIGNON 2006
20Normal ApoAI and ApoAIMILANO Dimer Lipid Binding In Vivo CatabolismAIm/AIm1243173s3514318799AI24312520922066121165LCAT Activation Cholesterol Efflux“Receptor”BindingFranceschini G Eur J Clin Invest 26; 733, 1996DAVIGNON 2006
21Role of apolipoprotein E Apo E: ligand for hepatic removal of remnants.Apo E knockout model is atherogenicApo E2 has lower binding affinity (E4>E3>E2).E2:E2 only critical if lipids increase for other reasons.Other roles for Apo E (CNS lipid transport and neural repair).CREAICHYLOMICRONCIIITGOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOLPLLRPAIICCEHDLB48CIILipolysisproductsFC
22Metabolic Defects in Remnant Dyslipidaemia Apo E2 homozygosity plus apo B overproduction or Hepatic Lipase deficiencyDegradation (catabolic)Formation (anabolic)EBINTESTINEFC/PLFCLPLPLTPChylotoChyloReAILCATFCCECELIVERHLKidneySR-B1ABCA1LRPLDLRAIAIIECEAIECEHDL3HDL3CELLBAIBLDLOxLDLAILCATAIFC/PLHLHLETGECEBTGCEVLDLtoRemnCETPHDL2CEAIIAIICEModified fromDeeb SS et al. J Lipid Res 44:1279, 2003
24Genetic dyslipidaemias have motivated treatment discovery Clinical abnormalities represent real human problemsMassive yield on research into genetic dyslipidaemiaFamilial Hypercholesterolaemia: Receptor mediated endocytosis Statins, PCSK9 antisense and AbsFamilial Hyperchylomicronaemia: LPL gene therapyApo A1 Milano: Synthetic HDLDeficiency of Apo B or MTP MTP inhibitors, Apo B antisenseCETP Deficiency CETP inhibitorsApo E Valuable animal k/o model
25IT’S ALL RELATIVE : MANAGEMENT OF GENETIC DYSLIPIDAEMIA AAS MASTERCLASS5-6TH OCTOBER 2012IT’S ALL RELATIVE : MANAGEMENT OF GENETIC DYSLIPIDAEMIACASE 1
26HISTORY… Miss KM, 21year old Malay student nurse Referred to Specialist Llipid ClinicHypercholesterolaemia‘Yellowish butterfly patterned lesion’ around her eyesOn Pravastatin 20mg ONTC 13.7, LDL-c 11.6 mmol/LJuly 1997Cycling accident at her home townSustained minor soft tissue injuryNoted to have xanthelasma around her eyesLipid profile results:TC : 15.4 mmol/LLDL: 13.9 mmol/LReferred to Medical Clinic, home townStarted Pravastatin 20 mg/ON6th August 1998
27HISTORY……Noted ‘yellowish butterfly patterned lesion’ surrounding both eyes since primary school daysAsymptomatic, wellNo h/o chest pain, palpitation, shortness of breath or poor effort toleranceNo history of intermittent claudication or syncopal attacks.No h/o polyuria, polydipsiaNo h/o cold intolerance, lethargy or menstrual disturbanceNo past h/o jaundice, liver or renal diseasesNot HT, DMNo past surgical history
28The youngest out of 11 siblings 3 siblings died : HISTORY…The youngest out of 11 siblings3 siblings died :eldest brother : 43 years – AMI (HC)elder brother (6th) : 23 years – AMI (HC, xanthelasma)eldest sister (2nd) : 33 years - ?MI, ? SCDParents - consanguinous marriage (first cousins), not known to have DM/HPT/CAD
29HISTORY…Student nurse at a Teaching Hospital, KLSingleNon smokerNo history of alcohol intakeExercise - once weekly (jogging), 30minutesNormal diet, low fiber intake
30Physical Examination Anthropometry: BMI :Waist circumference : cm (<80cm)Waist-to-hip ratio: (<0.85)PR: 72/min, regular, BP : 120/62 mmHg, DRNMPeripheral pulses – present, carotid & renal bruit : absentOther systems: Normal
32Corneal Arcus Right Eye Left Eye Grade 4 Corneal Arcus grading: 0 – no arcus observable1- upper or lower segments affected2- both segments affected3- both segments and just confluent4- heavy confluent arcus(Wider et al, 1983)Corneal Arcus
34Test Result Reference range **FSL TC 15.4 13.7 < 5.7 mmol/L HDL-c Baseline(1997)1st visit to the SLCTC15.413.7< 5.7 mmol/LHDL-c1.51.6> 1.3 mmol/LLDL-c13.911.6<3.8 mmol/LTriglycerides1.01.1< 1.3 mmol/LOn pravastatin 20 mg / ON x 1 year
35Summary of KM’s risk factors Negative risk factors:Positive risk factors:HDL > 1.3 mmol/LNon smokerNot hypertensiveNot DMNot overweight/ obesePremenopausal femaleMarkedly elevated TC & LDL levelsStrong family history of premature CAD
39Other Investigations…. ECG – normalExercise stress test – normalECHO – Normal, no evidence of aortic stenosisCarotid artery IMT – normal, no evidence of atheromatous plaquesOther Investigations….
40Question 1 What are the various criteria for the diagnosis of FH? Dutch Lipid Clinic Network diagnostic scoringSimon Broome’s criteriaMedPed criteria for FHNCEP ATPIII criteria
41Question 2According to the Dutch Lipid Clinic Network criteria, scoring for definite FH is:> 8 points6 – 8 points3 – 5 points
42Question 3In determining the Dutch Lipid Clinic diagnostic scoring for FH, the following are taken into account:Baseline LDL-c concentration: Yes/ NoClinical history of premature CAD: Yes/ NoClinical history of premature cerebral or PVD: Yes/ NoTendon xanthoma(ta) in the patient: Yes/ NoPremature corneal arcus in the patient: Yes/ NoFamily history of hypercholesterolaemia: Yes/ NoFamily history of premature CAD/PVD in 1st degree relatives: Yes/ NoFamily history of tendon xanthomata and/or corneal arcus in 1st degree relatives: Yes/ No
43Dutch Lipid Clinic – Diagnostic scoring for FH Criteria:Family history:1st degree relative with (a) premature CAD or vascular dis (men<55yrs, women<60yrs) OR (b) LDL > 95th percentile, in point and / or1st degree relative with tendon xanthomata and/or corneal arcus OR childhood (<18yrs) LDL > 95th percentile pointsClinical historyPatient with premature CAD (men<55, women <60yrs) pointsPatient with premature cerebral or PVD (men<55, women <60yrs) -1 pointPhysical Examination - patientTendon xanthomas - 6 pointspremature arcus pointsLab Analysis –LDL-c >8.5mmol/> pointsLDL-c 6.5 –LDL-cLDL-c 4.0 –DNA analysisFunctional DNA Mutation pointsCriteria:8 points - DNA Mutation, or LDL-C > 8.5mmol/L6 points - Tendon xanthomas5 points - LDL-C 6.5 – 8.4mmol/L4 points - premature corneal arcus < 45 yrs3 points - LDL 5.0 – 6.4mmol/L2 points - 1st degree relative with xanthomas or premature CA or childhood LDL > 95th percentile, or personal premature CAD1 point - 1st deg relative with premature CAD/ vascular dis or LDL > 95th percentile, or personal history of premature cerebral or PVD, or LDL-c 4.0 – 4.9mmol/LDefinite: > 8 points, Probable: 6 – 8 points, Possible FH: 3-5
44US MedPed Criteria vs Simon Broome criteria for the dx of FH Total cholesterol cutpoints (mmol/L)1st-degree vs 2nd-degree vs 3rd-degree relatives with FH vs General populationAge (years) 1st-degree 2nd degree 3rd degree General population<20–30–≥FH is diagnosed if TC levels exceed the cutpointKey: FH = familial hypercholesterolaemia
45Simon Broome Criteria - Diagnosis of FH Criteria Description(A) TC > 7.5 mmol/L in adults or TC > 6.7 mmol/L in children <16 years, or LDL-c > 4.9 mmol/L in adults or > 4.0 mmol/L in children(B) Tendon xanthomas in the patient, or a first-degree or second-degree relative(C ) DNA-based evidence of mutation in the LDLR, or apo- B100 or PCSK9 gene(D) Family history of premature CHD (age <50 years in a second-degree relative or <60 years in a first-degree relative)(E) Family history of raised TC >7.5 mmol/L in a first- or second-degree relative, or >6.7mmol/L in child, brother or sister <16yrs of ageDiagnosisDefinite FH diagnosis requires either A + B or A + CPossible FH diagnosis requires either A +D or A + EKey: FH = familial hypercholesterolaemia
46Summary Hypercholesterolaemia (LDL-c 13.9mmol/L) Xanthomata, corneal arcus, xanthelasmaNo evidence of personal CADStrong family history of premature CADPositive family history of HC – 1st and 2nd degree relativeConsanguityRuled out secondary causes of HC
48Question 4:Should risk estimation tools eg Framingham Risk Scoring be used for her?YESNO
49CHD Risk Stratification CHD estimation tools such as those based on the Framingham risk scoring SHOULD NOT be used because people with FH are already at high risk of premature CHD.Heterozygous FH has >50% risk of CHD in men by the age of 50years, >30% in women by the age of 60yearsNICE Clinical Guideline Identification and Mx of FH2.5.1 Individuals with FH are at high CHD risk. The 10-year CHD risk in the FH patient is not adequately predicted by any conventional risk assessment tools. Therefore, assessment of 10-year risk is not recommended.
50Management Statin therapy - continued, titrated Add-on lipid lowering Lifestyle modificationReferred to dieticianReferred to :- Cardiology- Plastic surgeryFamily tracing, cascade screening and counselling
56Genetic testing was performed on KM and her family members Question 5:What genes have been implicated in FH?LDL ReceptorLipoprotein lipaseApo B100Apo CIIPCSK9
57Low Density Protein Receptor (LDLR) Gene Cytogenetic Location: 19p13.2Size: 44,469 basesMosaic protein of ~840 amino acids (after removal of signal peptide); Molecular weight 95,376 Dalton
58LDLR PROTEINMade up of a number of functionally distinct domains that can function independently of each other.Ex 1 contains a signal sequence that localizes the receptor to the ER for transport to the cell surfaceEx 2-6 code the ligand binding regionEx 7-14 code the EGFP domainEx 15 codes the oligosaccharide rich regionEx 16 (and some of 17) code the membrane spanning regionEx 18 (with the rest of 17) code the cytosolic domain.
59PCR PRODUCT ANALYSIS OF LDLR EXON 5 – DNA CHIP CAPILLARY GEL ELECTROPHORESIS 182bpAmplification of Exon 5 of LDLR gene by PCR. PCR products were analysed on an automated on-chip capillary gel electrophoresis (Agilent Bioanalyser).Lanes from left to right; 1-Kb ladder, Negative control sample, patients samples and normal control sample. The green band represent lower marker and purple band represent upper marker. The PCR products were detected at 182bp.
60DHPLC RESULTS – LDLR Exon 5 Mutation Screening by DHPLCHeteroduplex peaks of FH patientswith variant in exon 5Wash peakg.763T>AHomoduplex peak of NC sample (wild type sample)Heteroduplex peaks of FH patientswith variant in exon 5g.763T>AThe DHPLC chromatogram profiles of FH patients showed presence of heteroduplex peaks eluted at 5.2 mins and 5.8 mins at denaturing temperature of C. The presence of heteroduplex peaks were suggestive of disease-causing variants and subjected to DNA sequencing to confirm the variants.
61DNA SEQUENCING RESULTS FH Patient IDAffected LDLR regionsDNA SequenceDescription of variant and effectKM, SFM & WC (3 members of a Malay Family)Exon 5Reference :GCCGGCAGTGTGACCGVariant :GCCGGCAGAGTGACCGg.763T>A; Cysteine (C) to Serine (S); Homozygous and Heterozygous mutation C234SNYKExon 9Reference : CTTCACCAACCGGCACGVariant : CTTCACCAACTGGCACGg.1216C>T; Arginine (R) to Tryptophan (W), Heterozygous mutation R385W
62Description of variant and effect DNA SEQUENCING RESULTSReference sequencefrom normal controlHomozygous:Substitution T>A at nucleotide position 763 (g.763T>A)DNA sequence ofHomozygous FH patientAffected LDLR regionDNA SequenceDescription of variant and effectExon 5Reference: GCCGGCAGTGTGACCGVariant : GCCGGCAGAGTGACCGg.763T>A; Cysteine(C) to Serine (S) at codon 234. Identified as homozygous mutation C234S.
63Heterozygous FH patient Description of variant and effect DNA SEQUENCING RESULTSReference sequencefrom normal controlHeterozygous:Substitution T>A at nucleotide position 763 (g.763T>A)DNA sequence ofHeterozygous FH patientAffected LDLR regionDNA SequenceDescription of variant and effectExon 5Reference: GCCGGCAGTGTGACCGVariant : GCCGGCAGAGTGACCGg.763T>A; Cysteine(C) to Serine (S) at codon 234. Identified as heterozygous mutation C234S.
64KM is now married with 2 children Questions 5:What is the probablity that her children may have FH with every pregnancy?50%25%Questions 6:When should diagnostic tests be done for her children?At birthBy the age of 10 years or earliest opportunity thereafter
65AD, one affected parent – 1:2 (50%) chance of heterozygous with every pregnancy In children with one affected parent, the following Dx-tic tests should be done by the age of 10yrs or at the earliest opportunity thereafter:DNA test if the family mutation is knownLDL-c if the family mutation is not known. To exclude the Dx of FH, LDL-c should be repeated after puberty - LDL-c concentration changes at puberty to almost similar to that of adult concentrationsCascade testing – combination of DNA testing and LDL-c to identify affected relativesIn children at risk of homozygous FH (2 affected parents or presence of clinical signs eg cutaneous xanthomata), measure LDL-c before 5yrs of age or at the earliest opportunity thereafter. If LDL >11mmol/L, clinical Dx of homozygous FH should be consideredNICE Clinical Guideline Identification and Mx of FH
66Question 7: Who can be considered for LDL apheresis treatment? Adults and children/young people withHomozygous FHHeterozygous FH
67LDL lowering apheresis Treatment of adults and children/ young adults with homozygous FHIn children with 2 affected parentsPresence of clinical signs eg cutaneous lipid deposits (xanthomata)LDL-c should be measured before 5 yrs of age, or earliest opportunity thereafterLDL-c > 13mmol/L (adults), > 11mmol/L (children/ young adults) – consider clinical diagnosis of homozygous FHExceptional cases of heterozygous FH –progressive symptomatic CHD despite maximal tolerated lipid-modifying drug therapy, optimal medical and surgical therapySpecialist centreCost implication
68Question 8: What are the future lipid lowering therapy? Antisense oligonucleotides (ASO) to inhibit Apolipoprotein B production –eg MipomersenPCSK9 targeted therapy –eg PCSK9 inhibitorMicrosomal TG Transfer Protein Inhibitors –eg lomitapideThyroid Mimetics – eg eprotiromeCholesterol Ester Transfer Protein (CETP) Inhibitors - anacetrapib, dalcetrapib
69(1) ANTISENSE OLIGONUCLEOTIDES (ASO) – MIPOMERSEN Subcutaneous 200mg 1x/wk – phase 3 CT, LDL reduction lasted for 4/52 after last dose. No clinically relevant interactions wrt clearance of statins and ezetimide - impt as add-on therapyYu et al Clin Pharmacokinet 2009;48:39-50Homo FH (n=51) - Recent double blind CT, sc mipomersen 200mg/wk vs placebo x26wks – 25% vs 3% LDL reduction, 27% reduction apoB, 21% reduction TCRaal FJ et al. Lancet 2010;375:Hetero FH (n=124), CAD+ on max tolerated statins: 45% of these high risk subjects achieved target LDL of < 100mg/dL (2.6mmol/L)EAS Congress 2011
702. PCSK9 TARGETED THERAPYAnimal studies – beneficial up to 80% LDL lowering, human studies not published yetFrank-Kamenetsky et al. Proc Natl Acad Sci USA 2008;105:Chan JC et al. Proc Natl Acad Sci USA 2009;106:9820-5Statins and fibrates induce increase PCSK9 expression, thus PCSK9 inhibition could induce robust LDL reduction as add-on therapy in FH
713. MICROSOMAL TG TRANSFER PROTEIN (MTP) INHIBITORS MTP inhibition with BMS in homozygous FH (n=6), dose 1mg/kg/day - 50% LDL reduction but noted to induce hepatic steatosisCuchel et al. New Engl J Med 2007;356:148-56MTP inhibition in homozygous FH (n=10) , dose 60mg/D – 44% LDL reduction; less steatosisCuchel et al.Circulation 2009;120:S441Ezetimibe 10mg vs MTP inhibition by lomitapide (5-10mg/ D x4/52) – 20% vs 20-30% in a dose-dependant mannerCombined therapy (ezetimide + lomitapide) – similar but larger dose dependent LDL reduction (35-45%); SE: Mild ALT increase, diarrhoeaSamaha et al. Nat Clin Pract Cardivasc Med 2009;2010:906-16Potential attractive candidate for lipid lowering in FH patients if administered in lower doses
724. THYROID MIMETICSThyroid hormone analogues – reduce LDL but associated with cardiac and bone related SEsMore recently differential molecular mechanisms (cpds that act on TR-beta mainly expressed in the liver, do not affect TR-alpha expressed in brain and heart) – eg eprotirome, selective TR beta agonists (under Ix)Statin + placebo/ eprotirome for 12/52 – 20-30% additional reduction of LDL; no SE on heart or boneLadenson et al. Use of thyroid hormone analoque eprotirome in statin-treated dyslipidaemia. New Engl J Med 2012;362:906-16
735. CETP (CHOLESTEROL ESTER TRANSFER PROTEIN) INHIBITORS X2 approaches to inhibit CETP(a) Vaccine - CETi-1 synthetic CETP peptide vaccine, immune response anti CETP- AbsAnimal studies of this vaccine – increase HDL, reduce aortic atherosclerosis but human studies poor response of autoAB productionRittershaus et al. Vaccine induced Abs inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis, ATVB 2000;20:Davidson et al. The safety and immunogenicity of a CETP vaccine in healthy adults. Atherosclerosis 2003;169:113-20(b) Small molecule CETP inhibitors – eg Torcetrapib, anacetrapib, dalcetrapib - antagonize CETP activity by binding to it.RADIANCE I – 800 FH pts, torce + atorva: No reduction in atherosclerosis (IMT) despite reduction in LDL (20%) and increase HDL (52%)Kasteleine JJ et al. Effect of torcetrapid on carotid atherosclerosis in FH. NEJM 2007;356:
74Cont……. 5. CETP (CHOLESTEROL ESTER TRANSFER PROTEIN) INHIBITORS ILLUMINATE – torce + atorva, prematurely terminated, unexpected increase in M&M – exact mechanisms unclear ?torce induced increase BPBarter et al. Effects of tercetrapid in patients at high risk of coronary event, NEJM 2007;357:Xie et al. Drug discovery using chemical systems biology:identidfication of the protein-ligand binding network to explain the side effects of CETP inhibitors. PLoS Comput Biol 2009;5:e2 other CETP inhibitors have no effect on BP – molecule-specific off-target effectAnacetrapid and dalcetrapib – phase 3 clinical trials , mild HC and pts with CVD risk, effective lipid modifiersPending CV outcome trials (DAL-outcomes I and II and HPS3/REVEAL)CETP inhibition likely to benefit patients with FH
75SummaryA 21year old Malay female student nurse who presented with incidental xanthelasma and severe hypercholesterolaemia associated with a strong family h/o premature CAD, xanthomata and grade 4 corneal arcus. There was consanguity between her parents. She is slim, non-smoker, euglycaemic, normotensive and has good HDL-c levels (>1.3mmol/L). Family tracing was performed. Molecular analyses confirmed the presence of homozygous FH with exon 5, position 763 T>A mutation of the LDLR, coding for the LDL binding domain.The updates on the present and future management, and the molecular pathogenesis of FH have been discussed.
76Learning Issues FH criteria for diagnosis High coronary risk category, should not use risk assessment toolsLDL Receptor protein and geneGenetic testing – when to test for children?Lifestyle modificationCurrent treatment, targetsPlasma apheresis – when is it indicated?Future lipid lowering therapy