Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
DSpace
UBCV
Allard, Matthew
Master of Science - MSc
University of British Columbia
Background: Familial hypercholesterolemia (FH) is a common autosomal dominant disorder caused by mutations in the low-density lipoprotein (LDL) receptor, apolipoprotein B-100 gene, or proprotein convertase subtilisin/kexin type 9, resulting in very high blood cholesterol levels and premature cardiovascular disease (CVD). Hypotheses/ Objectives: 1. FH patients who have developed CVD differ from those free of CVD by specific risk factors. 2. The specific risk factors differ in FH patients who develop CVD early and those resistant to CVD 3. These risk factors risk factors differ between men and women. 4. These risk factors differ between ethnic groups. Methods: A retrospective chart review of patients in the Prevention Clinic was carried out to find individuals with “definite” FH according to the Dutch Lipid Clinic Network Criteria (DLCNC) and to determine which patients developed CVD. Cox proportional hazard regression analysis was used to assess the association of risk factors to hard cardiovascular outcomes in univariate and multivariate analyses. Results: A total of 446 patients were identified as having “definite” FH based upon the DLCNC with 116 (26%) patients having hard evidence of CVD. Male sex, smoking, family history of premature CVD, diabetes mellitus, low HDL-C and high Lp(a) proved to be significant, independent risk factors for CVD in the entire FH cohort. The same risk factors remained significant when comparing FH patients susceptible to CVD to those resistant to CVD. Of note, LDL-C and hypertension were not important risk factors for CVD in this cohort. In men, family history, diabetes and low levels of HDL-C were significant risk factors for CVD while in women smoking, diabetes mellitus, low levels of HDL-C and high Lp(a) were significant risk factors for CVD. There were minimal detectable differences in risk factors between ethnicities. Conclusion: In our ethnically diverse cohort the significant risk factors for CVD in decreasing order of importance were, male sex, diabetes, high Lp(a), smoking, family history of pre-mature CVD, and low HDL-C in both the entire group as well as in the most susceptible subgroup. Men and women differed in the impact of the risk factors on the presence of CVD.
Phenotypic ?Characterization ?and ?Cardiovascular ?Outcomes ?of ?Patients ?with ?Familial ?Hypercholesterolemia ?by ? ?Matthew ?Allard ? B.K., ?The ?University ?of ?British ?Columbia, ?2011 ? ?A ?THESIS ?SUBMITTED ?IN ?PARTIAL ?FULFILLMENT ?OF ?THE ?REQUIREMENTS ?FOR ?THE ?DEGREE ?OF ? ?MASTER ?OF ?SCIENCE ?in ?THE ?FACULTY ?OF ?GRADUATE ?AND ?POSTDOCTORAL ?STUDIES ?(Pathology ?and ?Laboratory ?Medicine) ? ? ? ?THE ?UNIVERSITY ?OF ?BRITISH ?COLUMBIA ? ?(Vancouver) ? ?October ?2013 ? ?? ?Matthew ?Allard, ?2013 ?ii ?Abstract ? ? ?Background: ? ?Familial ?hypercholesterolemia ?(FH) ?is ?a ?common ?autosomal ?dominant ?disorder ?caused ?by ?mutations ?in ?the ?low-??density ?lipoprotein ?(LDL) ?receptor, ?apolipoprotein ?B-??100 ?gene, ?or ?proprotein ?convertase ?subtilisin/kexin ?type ?9, ?resulting ?in ?very ?high ?blood ?cholesterol ?levels ?and ?premature ?cardiovascular ?disease ?(CVD). ? ? ?Hypotheses/ ?Objectives: ? ?1. FH ?patients ?who ?have ?developed ?CVD ?differ ?from ?those ?free ?of ?CVD ?by ?specific ?risk ?factors. ?2. The ?specific ?risk ?factors ?differ ?in ?FH ?patients ?who ?develop ?CVD ?early ?and ?those ?resistant ?to ?CVD ?3. These ?risk ?factors ?risk ?factors ?differ ?between ?men ?and ?women. ?4. These ?risk ?factors ?differ ?between ?ethnic ?groups. ? ? ?Methods: ?A ?retrospective ?chart ?review ?of ?patients ?in ?the ?Prevention ?Clinic ?was ?carried ?out ?to ?find ?individuals ?with ??definite? ?FH ?according ?to ?the ?Dutch ?Lipid ?Clinic ?Network ?Criteria ?(DLCNC) ?and ?to ?determine ?which ?patients ?developed ?CVD. ?Cox ?proportional ?hazard ?regression ?analysis ?was ?used ?to ?assess ?the ?association ?of ?risk ?factors ?to ?hard ?cardiovascular ?outcomes ?in ?univariate ?and ?multivariate ?analyses. ? ?Results: ? ?A ?total ?of ?446 ?patients ?were ?identified ?as ?having ??definite? ?FH ?based ?upon ?the ?DLCNC ?with ?116 ?(26%) ?patients ?having ?hard ?evidence ?of ?CVD. ?Male ?sex, ?smoking, ?family ?history ?of ?premature ?CVD, ?diabetes ?mellitus, ?low ?HDL-??C ?and ?high ?Lp(a) ?proved ?to ?be ?significant, ?independent ?risk ?factors ?for ?CVD ?in ?the ?entire ?FH ?cohort. ?The ?same ?risk ?factors ?remained ?significant ?when ?comparing ?FH ?patients ?susceptible ?to ?CVD ?to ?those ?resistant ?to ?CVD. ?Of ?note, ?LDL-??C ?and ?hypertension ?were ?not ?important ?risk ?factors ?for ?CVD ?in ?this ?cohort. ?In ?men, ?family ?history, ?diabetes ?and ?low ?levels ?of ?HDL-??C ?were ?significant ?risk ?factors ?for ?CVD ?while ?in ?women ?smoking, ?diabetes ?mellitus, ?low ?levels ?of ?HDL-??C ?and ?high ?Lp(a) ?were ?significant ?risk ?factors ?for ?CVD. ?There ?were ?minimal ?detectable ?differences ?in ?risk ?factors ?between ?ethnicities. ? ?Conclusion: ?In ?our ?ethnically ?diverse ?cohort ?the ?significant ?risk ?factors ?for ?CVD ?in ?decreasing ?order ?of ?importance ?were, ?male ?sex, ?diabetes, ?high ?Lp(a), ?smoking, ?family ?history ?of ?pre-??mature ?CVD, ?and ?low ?HDL-??C ?in ?both ?the ?entire ?group ?as ?well ?as ?in ?the ?most ?susceptible ?subgroup. ?Men ?and ?women ?differed ?in ?the ?impact ?of ?the ?risk ?factors ?on ?the ?presence ?of ?CVD. ? ? ?iii ?Preface ? ?A ?version ?of ?chapter ?II/III ?from ?this ?thesis ?will ?be ?submitted ?for ?publication. ?Allard ?M., ?Martinka ?M., ?Saeedi ?R., ?Al-??Saraaf, ?A., ?Holmes ?D., ?and ?Frohlich ?J. ?I ?was ?responsible ?for ?completing ?the ?work ?described ?in ?this ?paper, ?including ?chart ?review, ?data ?analysis ?and ?preparation ?of ?the ?first ?draft ?for ?submission ?upon ?authors ?/ ?reviewers ?suggestions. ?Martinka ?M. ?assisted ?in ?reviewing ?patient ?charts ?and ?finding ?suitable ?candidates ?for ?inclusion ?in ?the ?study. ?Saeedi ?R. ?and ?Al-??Saraaf, ?A. ?helped ?with ?the ?study ?design. ?Frohlich ?J. ?and ?Holmes ?D. ?are ?my ?co-??supervisors ?and ?the ?principal ?investigators ?being ?involved ?in ?all ?stages ?of ?this ?study. ?The ??Phenotyping ?and ?Cardiovascular ?Outcomes ?of ?Patients ?with ?Heterozygous ?Familial ?Hypercholesterolemia? ?study ?was ?approved ?by ?the ?Providence ?Health ?Care ?Research ?Ethics ?Board ?and ?ethics ?certificate ?number ?is ?H11-??00431, ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?iv ?Table ?of ?Contents ? ?Abstract ?........................................................................................................................ ?ii ?Preface ?........................................................................................................................ ?iii ?Table ?of ?Contents ?......................................................................................................... ?iv ?List ?of ?Tables ?................................................................................................................ ?vi ?List ?of ?Figures ?.............................................................................................................. ?vii ?List ?of ?Abbreviations ?.................................................................................................. ?viii ?Acknowledgement ?........................................................................................................ ?x ?CHAPTER ?1: ?INTRODUCTION ?........................................................................................ ?1 ?1.1 ? Prevalence ?of ?Cardiovascular ?Disease ?.......................................................................... ?1 ?1.2 ?Pathology ?of ?Atherosclerosis ?........................................................................................... ?2 ?1.2.1 ?Atherosclerotic ?Lesions ?................................................................................................... ?3 ?1.3 ?Risk ?Factors ?for ?Cardiovascular ?Disease ?........................................................................... ?6 ?1.3.1 ?Non-??Modifiable ?Risk ?Factors ?........................................................................................... ?6 ?1.3.2 ?Modifiable ?or ?Lifestyle ?Risk ?Factors ?................................................................................ ?8 ?1.3.3 ?Emerging/ ?Non-??Traditional ?Risk ?Factors ?....................................................................... ?12 ?1.3.4 ?CHD ?Risk ?Equivalents ?.................................................................................................... ?16 ?1.4 ?Normal ?Lipoprotein ?Metabolism ?................................................................................... ?16 ?1.5 ?Lipid ?Disorders ?.............................................................................................................. ?20 ?1.5.1 ?Secondary ?Lipid ?Disorders ?............................................................................................ ?20 ?1.5.2 ?Primary ?Lipid ?Disorders ?................................................................................................. ?21 ?1.6.1 ?Etiology, ?Incidence, ?and ?Prevalence ?of ?FH ?.................................................................... ?23 ?1.6.2 ?Causes ?of ?FH ?................................................................................................................. ?24 ?1.6.3 ?Clinical ?Features ?of ?FH ?.................................................................................................. ?27 ?1.6.4 ?Diagnostic ?Criteria ?of ?FH ?............................................................................................... ?27 ?1.6.5 ?Treatment ?of ?FH ?............................................................................................................ ?31 ?1.6.6 ?Cardiovascular ?Disease ?in ?FH ?........................................................................................ ?32 ?1.7 ?Rationale, ?Working ?Hypothesis, ?and ?Objectives ?............................................................ ?35 ?1.7.1 ?Overall ?Objective ?.......................................................................................................... ?36 ?1.7.2 ?Working ?Hypothesis ?...................................................................................................... ?36 ?1.8 ?Specific ?Aims ?................................................................................................................. ?37 ?CHAPTER ?2: ?Methods ?.................................................................................................. ?38 ?2.1 ?Details ?on ?Variables ?Recorded ?....................................................................................... ?39 ?2.2 ?Statistical ?Analysis ?......................................................................................................... ?44 ?2.2.1 ?Clinical ?Characteristics ?.................................................................................................. ?44 ?2.2.2 ?Cox ?proportional ?hazard ?regression ?analysis ?................................................................ ?44 ?CHAPTER ?3: ?Results ?..................................................................................................... ?48 ?3.1 ?Demographics ?and ?clinical ?characteristics ?...................................................................... ?48 ?3.1.1 ?Entire ?Cohort ?................................................................................................................ ?48 ?v ?3.1.2 ?Male ?and ?female ?FH ?patients ?........................................................................................ ?51 ?3.1.3 ?FH ?patients ?with ?Lp(a) ?data ?........................................................................................... ?51 ?3.1.4 ?FH ?patients ?in ?the ?extreme ?subgroup ?........................................................................... ?58 ?3.1.5 ?European ?FH ?patients ?................................................................................................... ?58 ?3.1.6 ?East ?Asian ?FH ?patients ?.................................................................................................. ?61 ?3.2 ?Relation ?between ?CVD ?and ?risk ?factors ?.......................................................................... ?61 ?3.2.1 ?Entire ?Cohort ?................................................................................................................ ?61 ?3.2.2 ?Entire ?cohort ?without ?anyone ?treated ?at ?worst ?visit ?.................................................... ?67 ?3.2.3 ?Male ?cohort ?.................................................................................................................. ?67 ?3.2.4 ?Female ?cohort ?............................................................................................................... ?67 ?3.2.5 ?Extreme ?subgroup ?........................................................................................................ ?67 ?3.2.6 ?Extreme ?subgroup ?without ?anyone ?treated ?at ?the ?worst ?visit ?..................................... ?72 ?3.2.7 ?CVD ?and ?ethnicity ?......................................................................................................... ?72 ?3.2.8 ?Ethnicity ?and ?CVD ?risk ?factors ?....................................................................................... ?72 ?CHAPTER ?4: ?Discussion ?................................................................................................ ?74 ?4.1 ?Risk ?Factors ?for ?Development ?of ?CVD ?in ?FH ?Patients ?...................................................... ?74 ?4.2 ?Sex-??specific ?Risk ?Factors ?for ?the ?Development ?of ?CVD ?in ?FH ?Patients ?............................. ?79 ?4.3 ?Ethnicity ?and ?Risk ?Factors ?for ?the ?Development ?of ?CVD ?in ?FH ?Patients ?........................... ?79 ?4.4 ?Summary ?...................................................................................................................... ?80 ?4.5 ?Conclusions ?................................................................................................................... ?81 ?4.6 ?Methodological ?Considerations ?..................................................................................... ?82 ?4.7 ?Future ?Directions ?.......................................................................................................... ?83 ?Works ?Cited ?................................................................................................................ ?85 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?vi ?List ?of ?Tables ?Table ?1. ? ? ? ?Lipoprotein ?classes ?and ?composition????????????????..... ? ? ? ?19 ?Table ?2. ? ? ? ?Other ?primary ?LDL-??C ?disorders????????????????????.. ? 22 ?Table ?3. ? ? ? ?MEDPED ?criteria????????????????????????????.. ? 29 ?Table ?4. ? ? ? ?Simon ?Broome ?criteria????????????????????????..... ? 29 ?Table ?5. ? ? ? ?Dutch ?Lipid ?Clinic ?Network ?criteria?????????????????..... ? 30 ?Table ?6. ? ? ? ?Characteristics ?of ?the ?entire ?cohort ?of ?familial ?hypercholesterolemia ?patients ?stratified ?by ?presence ?or ?absence ?of ?cardiovascular ?disease?????????????????????????.. ? ? ?49 ?Table ?7. ? ? ? ?Laboratory ?results ?and ?drug ?use ?of ?the ?entire ?cohort ?at ?patient?s ?worst ?visit???????????????????????????????..... ? ?50 ?Table ?8. ? ? ? ?Characteristics ?of ?the ?entire ?cohort ?of ?familial ?hypercholesterolemia ?patients ?stratified ?by ?sex??????????...... ? ?53 ?Table ?9. ? ? ? ?Laboratory ?results ?and ?drug ?use ?of ?men ?and ?women ?at ?patient?s ?worst ?visit???????????????????????????????..... ? ?54 ?Table ?10. ?Characteristics ?of ?the ?entire ?cohort ?of ?familial ?hypercholesterolemia ?patients ?stratified ?by ?sex ?and ?presence ?of ?cardiovascular ?disease?????????????????????????.. ? ? ?55 ?Table ?11. ?Laboratory ?results ?and ?drug ?use ?of ?men ?and ?women ?stratified ?by ?presence ?of ?cardiovascular ?disease ?at ?patient?s ?worst ?visit?????.. ? ?56 ?Table ?12. ?Lp(a) ?distribution ?statistics??????????????????????... ? 57 ?Table ?13. ?Notable ?characteristics ?of ?familial ?hypercholesterolemia ?patients ?stratified ?by ?CVD ?susceptible ?and ?CVD ?resistant ?patients??????.. ? ?60 ?Table ?14. ?Relative ?risk ?and ?95% ?confidence ?intervals ?for ?the ?presence ?of ?a ?risk ?factor ?for ?CVD ?in ?the ?entire ?cohort????????????????.. ? ?63 ?Table ?15. ?Relative ?risk ?and ?95% ?confidence ?intervals ?for ?the ?presence ?of ?a ?risk ?factor ?for ?CVD ?in ?men???????????????????????.. ? ?69 ?Table ?16. ?Relative ?risk ?and ?95% ?confidence ?intervals ?for ?the ?presence ?of ?a ?risk ?factor ?for ?CVD ?in ?women?????????????????????... ? ?70 ?Table ?17. ?Relative ?risk ?and ?95% ?confidence ?intervals ?for ?the ?presence ?of ?a ?risk ?factor ?for ?CVD ?in ?the ?extreme ?subgroup?????????????.. ? ?71 ?Table ?18. ?Comparison ?of ?categorical ?risk ?factors ?between ?ethnicities????..... ? 73 ?Table ?19. ?Comparison ?of ?continuous ?risk ?factors ?between ?ethnicities????..... ? 73 ? ? ? ? ? ? ? ?vii ?List ?of ?Figures ? ?Figure ?1. ? ? ?Sequences ?in ?progression ?of ?atherosclerosis?????????????... ? 4 ?Figure ?2. ? ? ?Lipoprotein(a) ?particle ?composition??????????????????. ? 14 ?Figure ?3. ? ? ?Lipoprotein ?metabolism ?pathway???????????????????.. ? 20 ?Figure ?4. ? ? ?LDL ?receptor ?pathway?????????????????????????... ? 26 ?Figure ?5. ? ? ?Lp(a) ?histogram????????????????????????????..... ? 57 ?Figure ?6. ? ? ?Cumulative ?event-??free ?survival ?based ?on ?Sex ?and ?Diabetes ?Mellitus? ? 64 ?Figure ?7. ? ? ?Cumulative ?event-??free ?survival ?based ?on ?Family ?History ?of ?Pre-??mature ?CVD ?and ?Smoking???????????????????????.. ? ?65 ?Figure ?8. ? ? ?Cumulative ?event-??free ?survival ?based ?on ?(E) ?HDL ?concentration ?(F) ?Lp(a) ?concentration??????????????????????????... ? ?66 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?viii ?List ?of ?Abbreviations ? ?CVD ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Cardiovascular ?Disease ?CHD ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Coronary ?Heart ?Disease ?MI ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Myocardial ?Infarction ?TIA ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Transient ?Ischemic ?Attack ?PAD ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Peripheral ?Arterial ?Disease ?SMC ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Smooth ?Muscle ?Cell ?NO ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Nitric ?Oxide ?LDL ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Low ?Density ?Lipoprotein ?ECM ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Extra ?Cellular ?Matrix ?DM ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Diabetes ?Mellitus ?NCEP-??ATP ?III ? ? ? ? ? ?National ?Cholesterol ?Education ?Program ?Third ?Adult ?Treatment ?Panel ?HDL-??C ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?High ?Density ?Lipoprotein ?Cholesterol ?BP ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Blood ?Pressure ?LDL-??C ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Low ?Density ?Lipoprotein ?Cholesterol ?BMI ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Body ?Mass ?Index ?CRP ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?C-?? ?Reactive ?Protein ?Lp(a) ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Lipoprotein ?(a) ?Apo-??B100 ? ? ? ? ? ? ? ? ? ? ? ? ?Apolipoprotein ?B100 ?TC ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Total ?Cholesterol ?Apo-?? ?A1 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Apolipoprotein-?? ?A1 ?VLDL ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Very ?Low ?Density ?Lipoprotein ?IDL ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Intermediate ?Density ?Lipoprotein ?HDL ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?High ?Density ?Lipoprotein ?LPL ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Lipoprotein ?Lipase ?ABCA1 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?ATP-??binding ?Cassette ?Transporter ?A1 ?LCAT ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Lecithin-??Cholesterol ?Acyltransferase ?SR-??B1 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Scavenger ?Receptor ?B1 ?CETP ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Cholesterol ?Ester ?Transfer ?Protein ?FH ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Familial ?Hypercholesterolemia ?ix ?LDL-??R ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Low ?Density ?Lipoprotein ?Receptor ?PCSK9 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Proprotein ?Convertase ?Subtilin/Kexin ?9 ?LDLRAP1 ? ? ? ? ? ? ? ? ? ? ? ? ? ?LDL ?Receptor ?Adapter ?Protein ?1 ?SREBP ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Sterol ?Regulatory ?Element ?Binding ?Protein ?EGF-??A ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Epidermal ?Growth ?Factor-??Like ?A ?MEDPED ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Make ?Early ?Diagnosis, ?Prevent ?Early ?Death ?DLCNC ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Dutch ?Lipid ?Clinic ?Network ?Criteria ?AST ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Aspartate ?Aminotrasnferase ?ALT ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Alanine ?Transaminase ?ALP ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Alkaline ?Phosphatase ? ?CK ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Creatine ?Kinase ?TSH ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Thyroid ?Stimulating ?Hormone ?CABG ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Coronary ?Artery ?Bypass ?Graft ?PCTA ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Percutaneous ?Transluminal ?Angioplasty ?MIBI ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Methoxyisobutylisonitrile ? ? ? ? ? ? ?EKG ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Electrocaridogram ?EST ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Exercise ?Stress ?Test ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?x ?Acknowledgement ? ?I ?owe ?my ?supervisors, ?Drs. ?Jiri ?Frohlich ?and ?Dan ?Holmes ?my ?extreme ?gratitude ?for ?their ?constant ?support ?during ?the ?past ?two ?yrs. ?Their ?guidance, ?encouragement ?and ?vast ?knowledge ?have ?been ?a ?tremendous ?asset ?to ?me ?and ?have ?allowed ?for ?this ?process ?to ?proceed ?as ?well ?as ?it ?has. ? ?Additionally, ?I ?must ?thank ?the ?members ?of ?my ?supervisory ?committee, ?Dr. ?David ?Granville, ?Dr. ?Haydn ?Pritchard, ?Dr. ?John ?Hill, ?and ?Dr. ?Gordon ?Francis, ?for ?bringing ?their ?immense ?experience ?to ?committee ?meetings ?and ?providing ?research ?direction ?and ?constructive ?suggestions. ?Thanks ?are ?also ?owed ?to ?my ?colleagues ?at ?the ?Atherosclerosis ?Specialty ?Lab ?and ?Healthy ?Heart ?Program, ?Michal ?Martinka, ?Eugene ?Chu, ?Daven ?Tai, ?Gautham ?Sarwal, ?Mackenzie ?Edgar, ?Min ?Li, ?Catalin ?Tarabonata, ?Luba ?Cermakova, ?and ?Alejandra ?Farias-??Godoy ?for ?their ?support. ?Further ?thanks ?to ?Dr. ?Karin ?Humphries, ?and ?Masoud ?Yousefi ?for ?advice ?and ?aide ?with ?statistical ?analysis. ?Thank ?you ?to ?Genzyme ?Inc. ?for ?providing ?me ?with ?the ?funding ?throughout ?the ?duration ?of ?my ?project. ?Special ?thanks ?are ?owed ?to ?Morgan ?Wood ?for ?her ?love ?and ?support ?throughout ?the ?process, ?to ?all ?my ?friends ?for ?your ?support ?and ?encouragement, ?to ?my ?sister, ?Lauren, ?and ?to ?my ?parents, ?Mike ?and ?Pat, ?who ?have ?supported ?me ?not ?only ?over ?the ?last ?2 ?yrs, ?but ?throughout ?my ?education, ?both ?morally ?and ?financially. ?This ?would ?not ?have ?been ?possible ?without ?you. ? ? ?1 ?CHAPTER ?1: ?INTRODUCTION ?1.1 Prevalence ?of ?Cardiovascular ?Disease ? ?Cardiovascular ?disease ?(CVD) ?is ?one ?of ?the ?leading ?causes ?of ?death ?worldwide ?and ?is ?extremely ?common ?in ?the ?general ?population ?affecting ?most ?adults ?past ?the ?age ?of ?60. ?In ?2012, ?CVD ?was ?estimated ?to ?result ?in ?17.3 ?million ?deaths ?per ?year ?globally ?(1). ? ?However, ?over ?the ?last ?4 ?decades ?the ?rates ?of ?CVD ?have ?declined ?substantially ?in ?developed ?countries ?with ?a ?70% ?decrease ?between ?1956 ?and ?2002, ?a ?50% ?decrease ?over ?the ?last ?20 ?yrs ?and ?a ?25% ?decrease ?in ?just ?the ?last ?10 ?yrs ?(2). ?Despite ?this ?decline ?over ?the ?last ?40 ?yrs, ?CVD ?remains ?a ?major ?cause ?of ?death ?and ?disability ?worldwide. ?In ?Canada, ?CVD ?caused ?more ?than ?69,500 ?deaths ?accounting ?for ?29% ?of ?all ?Canadian ?deaths ?in ?2008, ?while ?in ?the ?USA ?in ?2010 ?CVD ?accounted ?for ?approximately ?600,000 ?deaths ?(2,3). ?In ?addition ?to ?the ?consequences ?of ?death ?and ?disability, ?CVD ?also ?places ?a ?significant ?burden ?on ?the ?Canadian ?economy ?with ?costs ?in ?excess ?of ?20.9 ?billion ?every ?year ?for ?physician ?services, ?hospital ?costs, ?lost ?wages ?and ?decreased ?productivity ?(2). ? ?CVD ?is ?a ?broad ?term ?that ?refers ?to ?a ?number ?of ?diseases ?of ?the ?circulatory ?system ?affecting ?the ?heart ?and ?blood ?vessels. ? ?Four ?major ?areas ?of ?CVD ?are ?recognized ?as ?diagnostic ?categories ?(1). ?These ?include: ? ? ?? Coronary ?heart ?disease ?(CHD), ?characterized ?by ?myocardial ?infarction ?(MI), ?angina ?pectoris, ?heart ?failure ?and/or ?cardiac ? ?death, ?? Cerebrovascular ?disease, ?characterized ?by ?stroke ?and ?transient ?ischemic ?attack ?(TIA) ?? Peripheral ?artery ?disease ?(PAD), ?characterized ?by ?intermittent ?claudication ?? Aortic ?atherosclerosis ?and ?thoracic ?or ?abdominal ?aortic ?aneurysm ? ?CHD ?is ?the ?most ?prevalent ?form ?of ?CVD ?accounting ?for ?approximately ?one-??third ?to ?one-??half ?of ?all ?cases ?(1). ? ?2 ?Although ?there ?are ?different ?types ?of ?underlying ?pathology ?that ?can ?be ?classified ?as ?CVD, ?it ?most ?often ?denotes ?damage ?caused ?by ?atherosclerosis, ?the ?most ?common ?vascular ?change ?seen ?in ?CVD. ?Atherosclerosis ?is ?a ?progressive ?disease ?of ?medium/large ?arteries ?that ?develops ?slowly ?and ?typically ?occurs ?in ?regions ?of ?branching ?and ?marked ?curvature ?of ?the ?arteries ?at ?areas ?of ?geometric ?irregularity ?(4). ?It ?is ?characterized ?by ?accumulation ?of ?inflammatory ?cells, ?smooth ?muscle ?cells ?(SMC), ?lipid ?and ?connective ?tissue ?within ?the ?arterial ?intima ?that ?ultimately ?cause ?asymmetric ?focal ?thickenings ?of ?the ?intima ?of ?the ?arteries, ?also ?known ?as ?plaque. ?These ?plaques ?may ?subsequently ?result ?in ?stable/unstable ?angina, ?acute ?MI, ?sudden ?cardiac ?death, ?or ?ischemic ?stroke. ?1.2 ?Pathology ?of ?Atherosclerosis ? ?The ?progressive ?development ?of ?atherosclerosis ?occurs ?through ?continual ?evolution ?of ?atherosclerotic ?lesions. ?These ?lesions ?grow ?by ?the ?accumulation ?of ?cholesterol-??rich ?lipids ?and ?the ?accompanying ?inflammatory ?response ?(5). ?Plaque ?formation ?begins ?with ?endothelial ?injury ?and ?consequent ?endothelial ?dysfunction. ?The ?endothelium ?is ?the ?major ?regulator ?of ?vascular ?homeostasis ?and ?it ?exerts ?a ?number ?of ?vasoprotective ?effects ?including ?vasodilation, ?suppression ?of ?SMC ?growth, ?and ?inhibition ?of ?inflammatory ?responses. ?A ?single ?molecule, ?Nitric ?Oxide ?(NO), ?is ?responsible ?for ?these ?regulatory ?processes ?(6). ?Endothelial ?dysfunction ?can ?be ?caused ?by ?a ?number ?of ?factors ?including ?genetics, ?hypercholesterolemia, ?smoking, ?hypertension ?and ?diabetes ?to ?name ?a ?few ?(5-??9). ?Damage ?to ?the ?endothelial ?cells ?has ?a ?number ?of ?effects. ?These ?include, ?for ?instance, ?increased ?permeability ?to ?lipoproteins, ?such ?as ?LDL, ?vasoconstriction, ?greater ?expression ?of ?adhesion ?molecules ?(P-?? ?and ?E-??selectins) ?enhances ?recruitment ?of ?monocytes ?and ?T-??cells ?into ?the ?vessel ?wall, ?and ?makes ?thrombosis ?more ?likely ?(10, ?11). ?The ?increasing ?amounts ?of ?LDL ?accumulating ?within ?the ?intima ?are ?oxidized ?by ?oxygen ?free ?radicals ?while ?the ?monocytes ?that ?have ?migrated ?to ?the ?intima ?are ?transformed ?into ?macrophages. ?Oxidized ?LDL ?is ?pro-?? ?atherogenic ?and ?stimulates ?endothelial ?cells ?to ?produce ?inflammatory ?markers, ?has ?cytotoxic ?effects ?on ?endothelial ?cells, ?inhibits ?the ?motility ?of ?tissue ?macrophages, ?and ?inhibits ?nitric ?oxide-??induced ?vasodilatation ?(10,12). ?The ?3 ?macrophages ?then ?engulf ?the ?oxidized ?LDL ?to ?form ?foam ?cells, ?so ?called ?because ?of ?the ?foamy ?histological ?appearance ?imparted ?by ?accumulation ?of ?lipid ?droplets ?in ?their ?cytoplasm. ?Furthermore, ?the ?T-??lymphocytes ?recruited ?to ?the ?intima ?interact ?with ?the ?macrophages ?and ?contribute ?to ?the ?generation ?of ?a ?chronic ?inflammatory ?state ?(10). ?As ?a ?result ?of ?this ?chronic ?inflammatory ?state, ?SMC ?proliferation ?and ?extra ?cellular ?matrix ?(ECM) ?synthesis ?is ?promoted. ?Initial ?SMC ?proliferation ?and ?ECM ?deposition ?convert ?a ?fatty ?streak, ?the ?earliest ?lesion ?seen ?in ?atherosclerosis ?and ?comprised ?of ?a ?collection ?of ?lipid-??laden ?macrophages ?in ?the ?intima, ?into ?a ?mature ?plaque. ?The ?recruited ?smooth ?muscle ?cells ?can ?synthesize ?ECM ?(primarily ?collagen) ?that ?stabilizes ?atherosclerotic ?plaques ?with ?an ?overlying ?fibrous ?cap. ?However, ?activated ?inflammatory ?cells ?can ?actually ?cause ?intimal ?SMC ?apoptosis ?and ?ECM ?catabolism ?resulting ?in ?instability ?of ?plaques ?with ?thinning ?of ?the ?fibrous ?cap. ?Eventually, ?the ?thinned ?and ?weakened ?fibrous ?cap ?may ?rupture, ?exposing ?underlying ?thrombogenic ?tissues. ?Plaque ?rupture ?can ?cause ?continued ?development ?of ?the ?atherosclerotic ?lesion ?by ?inducing ?further ?thrombus ?formation ?and ?release ?of ?more ?inflammatory ?mediators, ?resulting ?in ?continued ?luminal ?narrowing. ?The ?thrombus ?is ?formed ?as ?a ?consequence ?of ?activation ?of ?the ?coagulation ?cascade ?by ?exposure ?to ?tissue ?factor ?arising ?from ?plaque ?rupture. ?On ?the ?other ?hand, ?more ?drastic ?outcome ?of ?plaque ?rupture ?is ?arterial ?occlusion, ?which ?can ?result ?in ?MI, ?ischemic ?stroke, ?or ?critical ?ischemia ?in ?peripheral ?tissues ?(4-??14). ?1.2.1 ?Atherosclerotic ?Lesions ? ? ?Atherosclerotic ?lesions ?have ?been ?categorized ?based ?on ?morphology ?and ?temporal ?progression ?(Figure ?1). ?It ?is ?important ?to ?recognize ?that ?progression ?from ?one ?type ?of ?lesion ?to ?another ?is ?not ?necessarily ?sequential. ?The ?earliest ?type ?of ?lesion ?is ?intimal ? ?4 ? ? ?Figure ?1: ?Sequences ?in ?progression ?of ?atherosclerosis ? ?From ?Stary ?et ?al., ?(15) ?with ?permission ?from ?Elsevier ? ?5 ?media ?thickening ?characterized ?by ?collections ?of ?lipid ?filled ?macrophages ?(6, ?10). ?The ?layered ?architecture ?of ?the ?artery ?is ?maintained ?with ?changes ?only ?seen ?by ?microscopy ?(6, ?10). ?Fatty ?streaks ?or ?type ?II ?lesions ?are ?the ?earliest ?visible ?lesions ?in ?atherosclerosis. ?They ?are ?defined ?by ?the ?presence ?of ?macrophage-?? ?and ?SMC-?? ?derived ?foam ?cells, ?lymphocytes ?within ?the ?sub-??endothelial ?space, ?and ?extracellular ?lipid ?deposits ?that ?occur ?when ?foam ?cells ?are ?disrupted ?(7, ?10,13). ?Initially, ?the ?fatty ?streaks ?are ?multiple, ?tiny ?flat ?yellow ?spots ?that ?eventually ?coalesce ?and ?may ?be ?1cm ?or ?more ?in ?length. ?These ?lesions ?are ?not ?significantly ?raised ?and ?do ?not ?cause ?any ?flow ?disturbance ?(7). ?Intermediate ?or ?type ?III ?lesions ?have ?noticeable ?thickening ?of ?the ?intima, ?with ?an ?abundance ?of ?SMCs ?and ?lipid ?droplets ?that ?disrupt ?anatomical ?layers ?of ?the ?artery ?(10, ?14). ?An ?atheroma, ?the ?type ?IV ?lesion, ?can ?impinge ?on ?the ?lumen ?of ?the ?artery ?and ?grossly ?appear ?white ?to ?yellow ?with ?super-??imposed ?thrombus ?appearing ?red-??brown ?(7). ?These ?lesions ?usually ?involve ?only ?a ?portion ?of ?the ?arterial ?wall ?and ?therefore ?appear ?eccentric. ?Typically, ?there ?is ?a ?superficial ?fibrous ?cap ?composed ?of ?SMCs ?and ?dense ?collagen. ?Deep ?to ?the ?fibrous ?cap ?is ?a ?necrotic ?core, ?which ?consists ?of ?lipid ?(primarily ?cholesterol ?and ?cholesterol ?esters), ?cellular ?debris, ?foam ?cells, ?variably ?organized ?thrombus, ?and ?other ?plasma ?proteins ?(13). ?Advanced ?atheromas, ?or ?Type ?V ?lesions, ?are ?identified ?when ?significant ?quantities ?of ?fibrous ?connective ?tissue ?have ?collected ?in ?the ?lesion. ?Other ?characteristics ?prominent ?in ?advanced ?atheromas ?are ?neovascularization, ?the ?presence ?of ?proliferating ?capillaries, ?disrupted ?endothelium ?and ?lymphocyte ?infiltration ?of ?the ?adventitia ?(7, ?10,15). ?Atheromas ?have ?the ?ability ?to ?continuously ?change ?and ?progressively ?enlarge ?due ?to ?the ?processes ?of ?cell ?death ?and ?remodeling ?of ?ECM, ?as ?well ?as ?further ?accumulation ?of ?lipid ?with ?and ?without ?macrophages. ?Furthermore, ?atheromas ?are ?susceptible ?to ?several ?clinically ?important ?events ?including ?weakening ?and ?eventual ?rupture ?of ?the ?fibrous ?cap ?exposing ?the ?underlying ?thrombogenic ?tissues ?and ?formation ?of ?thrombus ?(7). ?In ?fact, ?rupture ?or ?erosion ?of ?type ?IV/V ?plaques ?may ?result ?in ?type ?VI ?or ?complicated ?lesions ?that ?results ?in ?thrombosis, ?or ?hemorrhage ?into ?the ?plaque ?(10). ?Plaque ?rupture ?can ?cause ?continued ?development ?of ?the ?atherosclerotic ?lesion ?by ?inducing ?further ?thrombus ?6 ?formation ?and ?release ?of ?more ?inflammatory ?mediators, ?resulting ?in ?continued ?luminal ?narrowing ?(7). ? ? ?1.3 ?Risk ?Factors ?for ?Cardiovascular ?Disease ? ?A ?number ?of ?large ?epidemiological ?studies ?such ?as ?the ?Framingham ?Heart ?study ?and ?the ?INTERHEART ?study ?have ?confirmed ?a ?collection ?of ?risk ?factors ?for ?CVD ?and ?atherosclerosis. ?For ?clinical ?and ?practical ?purposes, ?these ?risk ?factors ?have ?generally ?been ?classified ?as ?being ?either ?non-??modifiable ?(mainly ?inherited) ?or ?modifiable ?(with ?a ?large ?environmental ?component ?that ?are ?referred ?to ?as ?Lifestyle ?Risk ?Factors). ?Three ?risk ?factors ?that ?are ?major ?determinants ?of ?cardiovascular ?risk ?and ?atherosclerosis ?but ?are ?non-??modifiable ?are ?age, ?male ?sex ?and ?family ?history ?of ?premature ?CVD. ?According ?to ?the ?global ?INTERHEART ?study ?of ?patients ?from ?52 ?countries, ?9 ?modifiable ?risk ?factors ?account ?for ?over ?90% ?of ?MI ?cases. ?These ?risk ?factors ?are: ?dyslipidemia, ?cigarette ?smoking, ?diabetes ?mellitus ?(DM), ?blood ?pressure, ?abdominal ?obesity, ?psychosocial ?factors, ?daily ?consumption ?of ?fruits ?and ?vegetables, ?regular ?alcohol ?consumption, ?and ?regular ?physical ?activity ?(16). ?All ?of ?these ?risk ?factors ?have ?the ?potential ?to ?be ?modified ?through ?behavioral ?or ?pharmaceutical ?intervention. ? ?There ?are ?other ?risk ?factors ?that ?are ?perhaps ?less ?well ?established ?but ?have ?been ?reported ?to ?be ?associated ?with ?increased ?risk ?of ?CVD; ?these ?are ?referred ?to ?as ?emerging ?or ?non-??traditional ?risk ?factors. ?There ?are ?2 ?risk ?factors ?that ?are ?described ?as ??CHD ?risk ?equivalents? ?because ?the ?presence ?of ?one ?of ?them ?in ?a ?person ?without ?known ?CHD ?indicates ?a ?risk ?of ?having ?a ?cardiovascular ?event ?equal ?to ?that ?of ?a ?person ?with ?known ?CVD. ?These ?2 ?risk ?equivalents ?are ?DM ?and ?non-??coronary ?atherosclerotic ?disease. ?1.3.1 ?Non-??Modifiable ?Risk ?Factors ?1.3.1.1 ?Age ?and ?Gender ? ?Atherosclerotic ?burden ?increases ?with ?age, ?and ?as ?a ?result ?the ?risk ?for ?cardiovascular ?events ?increases ?with ?time. ?As ?one ?ages ?the ?frequency ?of ?risk ?factors ?increases ?(10,17). ?Men ?are ?more ?susceptible ?to ?developing ?atherosclerosis ?than ?are ?women ?(1). ?Male ?sex ?on ?its ?own ?may ?contribute ?to ?the ?risk ?of ?CVD ?and ?atherosclerosis, ?7 ?although ?the ?exact ?mechanisms ?behind ?this ?are ?unclear. ?Several ?studies, ?including ?the ?ONTARGET ?and ?TRANSCEND, ?have ?found ?that ?females ?had ?approximately ?a ?20% ?lower ?risk ?than ?males ?for ?all ?cardiovascular ?endpoints ?(18). ?The ?protective ?effects ?of ?estrogens ?in ?women ?may ?partially ?provide ?an ?explanation ?of ?these ?differences. ?Although, ?the ?risk ?of ?CVD ?in ?men ?has ?been ?traced ?to ?variations ?in ?the ?Y ?chromosome ?indicating ?that ?differences ?in ?the ?CVD ?risk ?within ?the ?male ?gender ?may ?be ?due ?to ?differences ?in ?inherited ?sex ?chromosomes ?(19). ? ?On ?the ?other ?hand, ?the ?increased ?risk ?may ?be ?due ?in ?large ?part ?to ?the ?increased ?presence ?of ?other ?risk ?factors ?in ?men ?as ?compared ?to ?women. ? ?1.3.1.2 ?Family ?History ?of ?Premature ?CVD ? ?Another ?non-??modifiable ?risk ?factor, ?which ?is ?an ?independent ?risk ?for ?CVD ?and ?atherosclerosis, ?is ?premature ?family ?history ?of ?CVD. ?There ?is ?some ?controversy ?as ?to ?what ?defines ?premature ?CVD. ?However, ?according ?to ?The ?National ?Cholesterol ?Education ?Program ?Third ?Adult ?Treatment ?Panel ?(NCEP-??ATP ?III), ?it ?is ?defined ?as ?MI, ?death ?from ?CVD, ?stroke ?and ?revascularization ?procedures ?in ?a ?first-??degree ?relative ?younger ?than ?55 ?yrs ?if ?male, ?and ?65 ? ?yrs ?if ?female ?(20). ?A ?number ?of ?large ?cohort ?studies ?that ?followed ?163,000 ?patients ?combined ?have ?shown ?that ?a ?positive ?family ?history ?is ?associated ?with ?an ?increased ?risk ?of ?developing ?CVD. ?Most ?of ?these ?studies ?showed ?a ?40 ?to ?60% ?increase ?in ?risk ?(1, ?21). ?Both ?genetic ?and ?environmental ?factors ?play ?a ?role ?in ?the ?increased ?risk ?of ?atherosclerosis ?seen ?in ?those ?with ?premature ?family ?history ?of ?CVD. ?Completely ?unrelated ?to ?presence ?of ?traditional ?CVD ?risk ?factors, ?inheritance ?of ?genetic ?factors ?contributes ?to ?increased ?atherosclerosis ?in ?families ?with ?a ?proven ?early ?onset ?of ?cardiovascular ?disease ?in ?one ?of ?their ?first-??degree ?relatives ?(22). ?In ?addition ?to ?carrying ?the ?same ?genetic ?alterations ?families ?also ?often ?share ?dietary, ?smoking, ?and ?drinking ?habits, ?physical ?activity ?patterns, ?and ?socio-??economical ?status ?(10, ?23). ? ? ? ?8 ?1.3.2 ?Modifiable ?or ?Lifestyle ?Risk ?Factors ? ?There ?are ?several ?modifiable ?or ?lifestyle ?factors ?that ?impact ?one?s ?risk ?of ?developing ?CVD ?and ?atherosclerosis ?including ?cigarette ?smoking, ?diet, ?exercise, ?obesity, ?regular ?alcohol ?consumption, ?psychosocial ?factors, ?hypertension, ?and ?dyslipidemia ?(1). ?1.3.2.1 ?Smoking ? ?The ?risk ?of ?myocardial ?infarctions ?shows ?a ?strong ?dose ?related ?relationship ?to ?smoking ?(1). ?The ?INTERHEART ?study ?demonstrated ?that ?smoking ?accounted ?for ?36% ?of ?the ?risk ?for ?a ?first ?MI ?(15). ?Furthermore, ?it ?has ?been ?shown ?that ?smoking ?cessation ?is ?beneficial ?regardless ?of ?the ?significance ?of ?a ?person?s ?smoking ?history ?with ?a ?50% ?reduction ?in ?recurrent ?MI ?risk ?for ?smokers ?within ?one ?year ?of ?smoking ?cessation ?and ?the ?risk ?fell ?to ?that ?of ?non-??smokers ?within ?5 ?yrs ?(24). ?1.3.2.2 ?Diet ? ?An ?additional ?lifestyle ?factor ?contributing ?to ?CVD ?and ?atherosclerosis ?risk ?is ?a ?person?s ?diet. ?There ?are ?a ?number ?of ?dietary ?factors ?that ?can ?contribute ?to ?increased ?risk ?including ?elevated ?glycemic ?load, ?high ?intake ?of ?red ?meat ?and ?high ?fat ?dairy ?products ?(1). ?One ?dietary ?factor ?that ?is ?increasingly ?becoming ?more ?evident ?is ?the ?extent ?of ?fruit ?and ?vegetable ?consumption. ?The ?INTERHEART ?study ?found ?that ?a ?lack ?of ?daily ?vegetable ?and ?fruit ?consumption ?accounted ?for ?14% ?of ?the ?risk ?for ?a ?first ?MI ?(16). ? ? ?1.3.2.3 ?Exercise ? ?A ?person?s ?exercise ?habits ?are ?another ?lifestyle ?factor ?that ?can ?contribute ?to ?CVD ?risk. ?Exercise ?is ?associated ?with ?a ?number ?of ?beneficial ?effects ?including ?beneficial ?alteration ?in ?blood ?lipid ?profiles ?(e.g., ?elevated ?high ?density ?lipoprotein ?cholesterol ?(HDL-??C), ?reduction ?in ?blood ?pressure, ?decreased ?insulin ?resistance ?and ?improved ?glycemic ?control, ?and ?weight ?loss ?(1). ?Even ?moderate ?levels ?of ?exercise ?have ?a ?protective ?affect ?against ?CVD ?and ?all ?cause ?mortality. ? ?The ?INTERHEART ?study ?found ?that ?a ?lack ?of ?regular ?physical ?activity ?accounts ?for ?12% ?of ?the ?risk ?for ?a ?first ?time ?MI ?(16). ? ?9 ?1.3.2.4 ?Abdominal ?Obesity ? ?Obesity ?is ?another ?risk ?factor ?that ?can ?be ?controlled. ?An ?increase ?in ?CHD ?events ?is ?correlated ?with ?an ?increase ?in ?obesity, ?according ?to ?the ?Framingham ?Heart ?Study(25). ?Furthermore, ?visceral ?fat ?depositions ?appear ?to ?be ?a ?better ?indicator ?of ?risk ?than ?subcutaneous ?fat ?(26). ?Obesity ?is ?associated ?with ?a ?number ?of ?risk ?factors ?for ?CVD ?including ?hypertension, ?insulin ?resistance, ?detrimental ?alterations ?in ?blood ?lipid ?profiles ?(e.g., ?hypertriglyceridemia ?and ?reduced ?HDL-??C), ?and ?low ?levels ?of ?adiponectin ?(27), ?an ?adipose-??derived ?plasma ?protein ?that ?is ?down-??regulated ?in ?subjects ?with ?obesity-??related ?disorders ?and ?actually ?has ?beneficial ?cardiovascular ?effects ?including ?inhibition ?of ?pro-??inflammatory ?and ?hypertrophic ?responses, ?and ?stimulation ?of ?endothelial ?cell ?responses ?(28, ?29). ?Additionally, ?in ?the ?Framingham ?Offspring ?study ?of ?approximately ?4800 ?adults, ?obesity ?independently ?predicted ?the ?occurrence ?of ?CVD ?even ?after ?adjusting ?for ?traditional ?risk ?factors ?(30). ? ?1.3.2.5 ?Psychosocial ? ?There ?is ?a ?link ?between ?psychological ?stress ?and ?CVD ?that ?is ?both ?direct, ?via ?damage ?to ?the ?endothelium ?caused ?by ?the ?overproduction ?of ?free ?radicals ?seen ?in ?mentally ?distressful ?situations, ?increased ?epinephrine ?and ?norepinephrine ?hormones ?together ?with ?cortisol, ?pro-??inflammatory ?cytokines ?and ?free ?fatty ?acids, ?and ?indirect, ?via ?magnification ?of ?traditional ?risk ?factors ?such ?as ?smoking, ?hypertension, ?lack ?of ?physical ?exercise, ?unhealthy ?diet, ?and ?lipid ?metabolism ?(31,32). ? ? ?1.3.2.6 ?Hypertension ? ?The ?INTERHEART ?study ?showed ?that ?hypertension ?accounted ?for ?18% ?of ?the ?risk ?for ?a ?first ?MI ?(16). ?This ?is ?believed ?to ?occur ?because ?of ?endothelial ?dysfunction, ?SMC ?proliferation ?and ?fibrosis ?caused ?by ?increased ?shear ?stress ?(10,33). ?It ?has ?been ?shown ?that ?in ?middle ?aged ?and ?older ?adults ?with ?hypertension, ?reducing ?systolic ?BP ?by ?10 ?mmHg ?reduces ?risk ?of ?death ?by ?an ?MI ?by ?22% ?and ?stroke ?by ?40% ?(34). ? ? ?10 ?1.3.2.7 ?Dyslipidemia ? ?The ?most ?important ?risk ?factor ?for ?developing ?CVD ?is ?dyslipidemia. ?This ?term ?generally ?refers ?to ?elevated ?levels ?of ?anyor ?all ?of: ?total ?cholesterol ?(TC), ?low ?density ?lipoprotein ?cholesterol ?(LDL-??C), ?triglyceride, ?or ?Lp(a) ?above ?the ?90th ?percentile ?or ?decreased ?levels ?of ?HDL-??C ?or ?apo-??A1 ?below ?the ?10th ?percentile ?of ?the ?general ?population ?(35). ?The ?significance ?of ?dyslipidemia ?as ?a ?risk ?factor ?for ?CVD ?is ?evidenced ?by ?the ?fact ?that ?75 ?to ?85% ?of ?patients ?with ?premature ?CHD ?have ?dyslipidemia ?as ?compared ?to ?only ?40 ?to ?48% ?of ?age ?matched ?controls ?without ?CHD ?(34). ?In ?the ?INTERHEART ?study ?dyslipidemia ?accounted ?for ?49% ?of ?the ?population ?attributable ?risk ?of ?a ?first ?MI ?(16). ? ?1.3.2.7.1 ?Epidemiology ? ? ?A ?direct, ?graded ?relation ?between ?cholesterol ?levels ?and ?coronary ?heart ?disease ?mortality ?has ?been ?observed ?independent ?of ?other ?risk ?factors ?(36). ? ?The ?Multiple ?Risk ?Factor ?Intervention ?Trial ?looked ?at ?356,222 ?men ?aged ?35 ?to ?57 ?yrs ?to ?analyze ?the ?relationship ?between ?serum ?cholesterol ?and ?coronary ?heart ?disease. ?They ?found ?that ?the ?age-??adjusted ?risks ?of ?CHD ?death ?in ?cholesterol ?quintiles ?2 ?through ?5 ?relative ?to ?the ?lowest ?cholesterol ?quintile ?were ?continuous, ?graded ?and ?strong ?(37). ? ?Information ?obtained ?form ?61 ?prospective ?observational ?studies ?consisting ?of ?almost ?900,000 ?adults ?without ?previous ?disease ?also ?showed ?that ?TC ?was ?positively ?associated ?with ?IHD ?mortality ?in ?both ?middle ?and ?old ?age ?and ?at ?all ?blood ?pressure ?levels ?(38). ? ? ?Low ?HDL-??C ?has ?also ?been ?proven ?to ?be ?a ?major ?independent ?risk ?factor ?for ?the ?development ?of ?CVD. ?One ?study ?analyzing ?the ?inverse ?relationship ?of ?HDL-??C ?and ?CAD ?separately ?in ?the ?Framingham ?Heart ?Study ?(FHS), ?Lipid ?Research ?Clinics ?Prevalence ?Mortality ?Follow-??up ?Study ?(LRCF) ?and ?Coronary ?Primary ?Prevention ?Trial ?(CPPT), ?and ?Multiple ?Risk ?Factor ?Intervention ?Trial ?(MRFIT) ?and ?found ?that ?for ?a ?0.03 ?mmol/L ? ?increase ?in ?HDL-??C ?there ?is ?a ?2-??3% ?decrease ?in ?CAD ?risk ?(39). ?11 ?Many ?epidemiologic ?studies ?have ?reported ?associations ?between ?serum ?triglyceride ?concentrations ?and ?the ?risk ?of ?coronary ?heart ?disease. ?However, ?establishing ?triglyceride ?level ?as ?an ?independent ?predictor ?of ?CAD ?has ?proven ?difficult. ?In ?a ?meta-?? ?analysis ?of ?262,525 ?participants ?in ?29 ?Western ?prospective ?studies, ?there ?was ?consistent ?evidence ?that ?moderate ?and ?highly ?significant ?associations ?between ?triglyceride ?values ?and ?coronary ?heart ?disease ?risk ?existed ?(40). ?However, ?the ?associations ?depended ?considerably ?on ?levels ?of ?established ?risk ?factors. ?Furthermore, ?it ?has ?been ?shown ?that ?reducing ?triglyceride ?concentrations ?has ?proven ?beneficial ?in ?reducing ?CAD ?risk, ?although ?it ?is ?unknown ?whether ?this ?can ?be ?attributed ?primarily ?to ?triglyceride ?lowering. ?1.3.2.7.2 ?Experimental ?Pathology ? ?The ?accumulation ?of ?cholesterol-??rich ?lipids ?and ?the ?accompanying ?inflammatory ?response ?contribute ?to ?the ?growth ?of ?atherosclerotic ?lesions. ?A ?number ?of ?risk ?factors ?including ?hypercholesterolemia, ?smoking, ?hypertension ?and ?diabetes ?cause ?endothelial ?dysfunction ?leading ?to ?vasoconstriction, ?increased ?platelet/ ?leukocyte ?adhesion, ?smooth ?muscle ?cell ?migration ?and ?growth, ?and ?increased ?lipid ?deposition, ?ultimately ?plaque ?formation. ? ?In ?addition ?to ?proven ?risk ?of ?plasma ?lipid ?concentrations ?in ?the ?development ?of ?CVD, ?the ?size ?and ?number ?of ?LDL ?and ?HDL ?particles ?has ?also ?proven ?an ?important ?factor. ?Small, ?dense ?LDL ?particles ?have ?been ?associated ?with ?CAD ?in ?a ?number ?of ?studies ?and ?are ?considered ?more ?atherogenic ?than ?large, ?buoyant ?LDL ?particles. ?They ?have ?a ?lower ?binding ?affinity ?for ?LDL ?receptors ?and ?may ?be ?more ?susceptible ?to ?oxidative ?modification ?and ?therefore ?are ?more ?likely ?to ?be ?endocytosed ?by ?SRB1(41). ?Number ?of ?LDL ?particles ?can ?be ?assessed ?as ?apolipoprotein-??B ?100 ?(apoB) ?as ?there ?is ?one ?per ?each ?LDL ?particle. ? ? ?The ?AMORIS ?study, ?which ?observed ?98,722 ?men ?and ?76,831 ?women ?over ?the ?age ?of ?60 ?yrs ?for ?approximately ?5 ?yrs, ?apoB ?proved ?to ?be ?more ?significant ?than ?LDL-??C ?and ?added ?predictive ?power ?to ?that ?of ?LDL-??C ?for ?calculation ?of ?the ?risk ?of ?fatal ?MI ?(42). ?In ?another ?large ?prospective ?study ?comprised ?of ?25,663 ?12 ?subjects ?in ?which ?1,003 ?developed ?CAD ?during ?the ?6 ?year ?follow-??up, ?LDL ?particle ?number ?and ?particle ?size ?were ?more ?closely ?associated ?with ?CAD ?than ?was ?LDL-??C ?level ?(43). ?Large ?and ?buoyant ?HDL ?particles ?(HDL2) ?are ?protective ?against ?the ?development ?of ?atherosclerosis ?whereas ?the ?effect ?of ?small, ?dense ?HDL ?particles ?(HDL3) ?remains ?controversial ?(41). ?In ?fact, ?some ?evidence ?suggests ?that ?the ?HDL3 ?particles ?are ?associated ?with ?an ?increased ?CVD ?risk. ? ?1.3.2.7.3 ?Clinical ?Trials ? ?LDL-??C ?is ?considered ?to ?be ?the ?major ?lipid ?risk ?factor ?and ?is ?the ?main ?target ?of ?lipid-??lowering ?therapy. ?Studies ?documenting ?pharmaceutical ?intervention ?provide ?powerful ?evidence ?for ?the ?importance ?of ?lowering ?LDL-??C. ?In ?a ?prospective ?meta-??analysis ?of ?data ?from ?90,056 ?individuals ?in ?14 ?randomized ?trials ?of ?statins, ?evidence ?was ?shown ?that ?statin ?use ?can ?safely ?reduce ?the ?5-??year ?incidence ?of ?major ?coronary ?events, ?coronary ?revascularization, ?and ?stroke ?by ?about ?one ?fifth ?per ?mmol/L ?reduction ?in ?LDL ?cholesterol ?(44). ?Furthermore, ?the ?Heart ?Protection ?Study ?carried ?out ?in ?20 ?536 ?adults ?living ?in ?the ?United ?Kingdom ?(aged ?40 ?to ?80 ?yrs) ?who ?were ?at ?high ?risk ?for ?a ?CVD ?event. ?Patients ?were ?randomly ?allocated ?either ?40 ?mg ?simvastatin ?daily ?or ?placebo. ?In ?those ?given ?simvastatin ?there ?was ?a ?24% ?reduction ?in ?major ?vascular ?events ?and ?a ?13% ?reduction ?in ?all-??cause ?mortality. ?1.3.2.7.4 ?Genetics ? ?In ?addition, ?significantly ?elevated ?CVD ?risk ?arising ?from ?genetic ?alterations ?that ?lead ?to ?dyslipidemia ?provide ?further ?strong ?support ?for ?its ?role ?as ?a ?very ?important ?risk ?factor. ?The ?focus ?of ?my ?work ?and ?dissertation ?is ?on ?one ?particular ?subset ?of ?genetic ?dyslipidemia, ?Familial ?Hypercholesterolemia. ? ?1.3.3 ?Emerging/ ?Non-??Traditional ?Risk ?Factors ?1.3.3.1 ?C-??Reactive ?Protein ? ?The ?most ?well ?documented ?and ?widely ?used ?non-??traditional ?risk ?factor ?for ?CVD ?is ?the ?inflammatory ?marker, ?C-??reactive ?protein ?(CRP). ?CRP ?is ?indicative ?of ?an ?individual?s ?baseline ?level ?of ?inflammation ?and ?is ?a ?predictor ?of ?long-??term ?risk ?of ?first ?MI, ?13 ?ischemic ?stroke ?or ?PAD. ? ?People ?with ?CRP ?levels ?in ?the ?highest ?quartile ?have ?approximately ?a ?1.5-??grearer ?risk ?for ?cardiovascular ?death ?and ?myocardial ?infarction ?than ?those ?in ?the ?lowest ?quartile ?(45, ?46) ?provided ?that ?the ?elevation ?is ?not ?attributable ?to ?any ?intercurrent ?illenss. ? ?1.3.3.2 ?Homocysteine ? ?Plasma ?level ?of ?total ?homocysteine, ?an ?amino ?acid ?derived ?from ?methionine ?metabolism, ?is ?another ?non-??traditional ?risk ?factor ?for ?CVD ?development ?(47). ?Potential ?mechanisms ?of ?homocysteine ?as ?a ?risk ?factor ?for ?CVD ?include ?injury ?and ?dysfunction ?of ?the ?endothelium, ?increased ?proliferation ?of ?SMCs, ?increased ?oxidation ?of ?LDL, ?enhances ?thrombin ?formation, ?and ?inhibits ?thrombolysis ?(10,48-??50). ?1.3.3.3 ?Lipoprotein(a) ? ?Lp(a) ?is ?a ?plasma ?lipoprotein ?composed ?of ?an ?LDL ?particle ?to ?which ?the ?glycoprotein ?apolipoprotein(a) ?is ?covalently ?linked ?by ?means ?of ?a ?disulfide ?bridge ?to ?apo-??B100 ?(51) ?(Figure ?2). ? ?Lp(a) ?has ?been ?shown ?to ?exert ?both ?pro-??atherogenic ?and ?pro-??thrombotic ?effects ?in ?the ?atherosclerotic ?process. ?As ?it ?is ?prone ?to ?oxidation ?and ?has ?a ?prolonged ?residence ?time ?in ?the ?intima ?Lp(a) ?may ?contribute ?to ?foam ?cell ?formation ?and ?SMC ?proliferation ?(52). ?Due ?to ?the ?fact ?apolipoprotein(a) ?bears ?a ? ?striking ?homology ?to ?plasminogen ?Lp(a) ?also ?exerts ?anti-?? ?fibrinolytic ?properties ? ?14 ? ? ? ?Figure ?2: ?Lipoprotein ?(a) ?particle ?composition ? ?From ?Terrados ?et ?al. ?(109) ?with ?permission ?from ?Doyma. ? ?(51). ?Furthermore, ?Lp(a) ?can ?bind ?to ?oxidized ?phospohlipids ?and ?destabilize ? ?atherosclerotic ?plaques ?through ?inflammation. ? ?Serum ?Lp(a) ?levels ?are ?primarily ?genetically ?determined ?and ?more ?than ?90% ?of ?the ?variation ?in ?Lp(a) ?levels ?can ?be ?determined ?by ?polymorphisms ?at ?the ?apo(a) ?gene ?locus. ?There ?is ?a ?strong ?inverse ?correlation ?between ?the ?apo(a) ?isoform ?size ?and ?the ?Lp(a) ?concentration ?(53). ?Although ?there ?have ?been ?some ?conflicting ?findings, ?studies ?have ?found ?that ?Lp(a) ?is ?a ?clinically ?important ?independent ?predictor ?of ?CVD. ?For ?instance, ?one ?study ?showed ?concentrations ?of ?Lp(a) ?above ?300 ?mg/L ?confer ?a ?two ?fold ?increase ?in ?risk ?for ?CAD ?particularly ?when ?associated ?with ?high ?LDL-??c ?levels ?(54). ?A ?large ?meta-??analysis ?that ?looked ?at ?over ?120,000 ?patient ?records ?from ?36 ?prospective ?studies ?explored ?the ?relationship ?between ?Lp(a) ?and ?CVD ?but ?found ?only ?a ?modest ?association ?between ?Lp(a) ?and ?CVD ?and ?after ?adjusting ?for ?multiple ?traditional ?risk ?factors ?(RR= ?1.13) ?(55). ? ?15 ?1.3.3.4 ?Hemoglobin ?A1C ? ?Hemoglobin ?A1C ?level ?in ?patients ?without ?diabetes ?has ?garnered ?interest ?as ?a ?potential ?risk ?factor ?for ?CVD. ?Two ?large ?prospective ?studies ?have ?shown ?a ?relationship ?between ?Hemoglobin ?A1C ?and ?CVD. ?The ?European ?Prospective ?Investigation ?Into ?Cancer ?(EPIC) ?study ?followed ?4662 ?men ?and ?5570 ?women, ?45 ?to ?79 ?yrs ?of ?age ?at ?baseline ?for ?7 ?yrs. ?In ?this ?population, ?an ?A1c ?<5.0% ?was ?associated ?with ?the ?lowest ?rates ?of ?CVD ?and ?mortality. ?However, ?for ?each ?1% ?increase ?in ?A1c ?there ?was ?an ?increase ?relative ?risk ?of ?death ?of ?1.24 ?in ?men ?and ?1.28 ?in ?women ?(56). ?Additionally, ?the ?Atherosclerosis ?Risk ?in ?Communities ?(ARIC) ?study ?analyzed ?11,092 ?subjects ?without ?a ?history ?of ?diabetes ?or ?CVD ?at ?enrolment ?and ?found ?that ?CHD ?risk ?increased ?with ?levels ?of ?A1c ?> ?5.0%. ?Furthermore, ?A1c ?levels ?between ?6.0% ?and ?6.5% ?had ?further ?elevated ?risk ?of ?CVD ?(57). ?1.3.3.5 ?Cholesterol ?Efflux ?Capacity ? ?The ?level ?of ?HDL-??C ?is ?an ?independent ?risk ?factor ?for ?the ?development ?of ?CVD. ?However, ?therapeutic ?interventions ?that ?have ?aimed ?to ?decrease ?CVD ?risk ?through ?specifically ?targeting ? ?HDL-??C ? ?have ?yielded ?disappointing ?results. ?The ?beneficial ?effects ?of ?HDL ?are ?likely ?driven ?by ?their ?ability ?to ?promote ?reverse ?cholesterol ?transport ?by ?accepting ?cholesterol ?from ?lipid-??laden ?macrophages ?(58). ?As ?a ?result, ?the ?static ?measurement ?of ?HDL-??C ?does ?not ?necessarily ?give ?a ?good ?indication ?of ?HDL ?particle ?function ?in ?vivo. ?Cholesterol ?efflux ?capacity, ?an ?integrated ?measure ?of ?HDL ?function, ?is ?a ?direct ?measure ?of ?the ?efficiency ?by ?which ?a ?person's ?HDL ?removes ?cholesterol ?from ?cholesterol-??laiden ?macrophages. ?A ?recent ?study ?by ?Rader ?et ?al. ?wished ?to ?show ?that ?cholesterol ?efflux ?capacity ?is ?a ?determinant ?of ?atherosclerotic ?burden ?that ?is ?independent ?of ?the ?HDL ?cholesterol ?level. ?They ?found ?that ?levels ?of ?HDL-??C ?and ?apolipoprotein ?A-??I ?accounted ?for ?<40% ?of ?efflux ?capacity ?and ?that ?serum ?cholesterol ?efflux ?capacity ?has ?an ?inverse ?correlation ?with ?the ?likelihood ?of ?coronary ?artery ?disease, ?independently ?of ?HDL-??C ?levels ?(59). ?Thus, ?diminished ?cholesterol ?efflux ?capacity ?appears ?to ?be ?a ?risk ?factor ?for ?the ?development ?of ?CVD. ? ?16 ?1.3.4 ?CHD ?Risk ?Equivalents ?1.3.4.1 ?Non-??Coronary ?Atherosclerotic ?Disease ? ?Non-??coronary ?atherosclerotic ?disease ?refers ?to ?the ?presence ?of ?carotid ?artery ?disease, ?PAD, ?or ?abdominal ?aortic ?aneurysm. ?These ?patients ?have ?a ?10-??year ?risk ?of ?developing ?CHD ?in ?excess ?of ?20% ?(1). ? ?1.3.4.2 ?Diabetes ?mellitus ? ?In ?the ?INTERHEART ?Study, ?the ?presence ?of ?diabetes ?accounted ?for ?10% ?of ?the ?risk ?of ?a ?first ?MI ?while ?other ?studies ?have ?shown ?that ?presence ?of ?diabetes ?increases ?the ?risk ?for ?cardiovascular ?disease ?two ?to ?four ?times ?(1,16). ?Additionally, ?other ?atherogenic ?risk ?factors ?(hypertension, ?obesity, ?increased ?total ?to ?HDL-??C ?ratio, ?hypertriglyceridemia, ?and ?elevated ?plasma ?fibrinogen) ?exert ?a ?greater ?effect ?in ?diabetics ?as ?compared ?to ?non-??diabetics ?counterparts ?(1). ? ?1.4 ?Normal ?Lipoprotein ?Metabolism ? ?The ?five ?primary ?lipoprotein ?classes ?in ?order ?of ?descending ?size ?and ?increasing ?density ?are ?chylomicrons, ?that ?primarily ?carry ?dietary ?lipid ?(triglycerides), ?very ?low ?density ?lipoproteins ?(VLDL), ?that ?carry ?endogenous ?triglycerides ?and ?to ?a ?lesser ?extent ?cholesterol ?esters, ?intermediate ?density ?lipoproteins ?(IDL), ?that ?carry ?a ?mixture ?of ?cholesterol ?esters ?and ?triglycerides, ?LDL ?particles, ?that ?carry ?mostly ?cholesterol ?esters, ?and, ?lastly, ?HDL ?particles, ?that ?also ?carry ?cholesterol ?esters ?(58)(Table ?1). ? ? ?Lipoprotein ?metabolism ?can ?be ?divided ?into ?the ?exogenous ?and ?endogenous ?pathways ?(Figure ?3). ?In ?the ?exogenous ?pathway, ?the ?intestine ?absorbs ?dietary ?fat ?and ?packages ?it ?into ?chylomicrons, ?which ?then ?enter ?the ?lymphatic ?circulation ?before ?being ?delivered ?to ?the ?peripheral ?blood ?by ?way ?of ?the ?lymphatic ?duct. ?In ?muscle ?and ?adipose ?tissues, ?lipoprotein ?lipase ?(LPL) ?hydrolyzes ?the ?triglycerides ?at ?the ?core ?of ?the ?chylomicron ?and ?releases ?free ?fatty ?acids ?into ?these ?tissues ?making ?the ?chylomicrons ?smaller, ?increasing ?their ?density ?and ?transforming ?them ?into ?17 ?chylomicron ?remnants. ?Subsequently, ?the ?chylomicron ?remnants ?can ?travel ?to ?the ?liver ?and ?bind ?to ?remnant ?receptors ?on ?the ?hepatocytes. ?To ?reach ?the ?receptors ?on ?the ?hepatocytes, ?the ?chylomicron ?remnants ?must ?pass ?through ?endothelial ?cell ?fenestrae ?followed ?by ?binding ?to ?the ?receptors ?that ?are ?bound ?to ?the ?hepatic ?microvilli ?(58).. ?While ?bound ?to ?the ?hepatocytes ?the ?chylomicron ?remnants ?undergo ?a ?further ?remodeling ?that ?facilitates ?their ?uptake ?by ?the ?liver ?and ?removal ?from ?the ?circulation ?via ?endocytosis. ? ? ?The ?endogenous ?pathway ?of ?lipoprotein ?metabolism ?begins ?with ?the ?formation ?of ?VLDL ?by ?the ?liver. ?The ?liver ?loads ?lipids ?onto ?apoB ?and ?releases ?VLDLs, ?which ?undergo ?lipolysis ?by ?LPL, ?hydrolyzing ?the ?triglyceride ?core ?generating ?VLDL ?remnants, ?also ?known ?as ?IDLs, ?which ?are ?depleted ?of ?triglyceride. ?IDL ?is ?either ?removed ?from ?the ?circulation ?either ?via ?remnant ?receptors ?or ?LDL ?receptors ?(LDL-??R) ?or ?remodeled ?into ?LDL ?particles ?by ?hepatic ?lipase ?(59). ?LDL ?particles ?are ?primarily ?comprised ?of ?a ?core ?of ?cholesterol ?esters ?and ?apoB-??100, ?an ?apolipoprotein ?that ?is ?the ?ligand ?for ?binding ?to ?the ?LDL ?receptor. ?Both ?hepatic ?and ?non-??hepatic ?tissues ?can ?internalize ?LDL. ?Hepatic ?cholesterol ?derived ?from ?LDL ?can ?be ?oxidized ?to ?bile ?acids ?that ?can ?then ?be ?secreted ?bile ?canaliculi ?and ?ultimately ?into ?the ?intestinal ?lumen, ?whereas ?non-??hepatic ?LDL ?can ?be ?used ?for ?steroid ?hormone ?production, ?cell ?membrane ?synthesis, ?or ?stored ?in ?the ?esterified ?form ?(59). ?LDL ?uptake ?is ?regulated ?via ?negative ?feedback ?control ?of ?the ?LDL-??R. ?For ?instance, ?if ?the ?cell ?has ?a ?sufficient ?amount ?of ?cholesterol, ?LDL ?receptor ?expression ?is ?suppressed. ?However, ?diminished ?activity ?of ?HMG ?CoA ?reductase, ?the ?enzyme ?catalyzing ?the ?rate ?limiting ?step ? ?of ?cholesterol ?synthesis ?by ?the ?cell, ?leads ?to ?decreased ?amounts ?of ?cholesterol ?in ?the ?cell, ?resulting ?in ?increased ?expression ?of ?the ?LDL ?receptor ?and ?increased ?(59) ?uptake ?of ?circulating ?LDL-??C ?leading ?to ?decreased ?plasma ?cholesterol ?concentration. ?The ?primary ?apolipoprotein ?associated ?with ?HDL, ?apolipoprotein ?A-??1 ?(apoA-??1), ?is ? ?produced ?by ?the ?liver ?and ?small ?bowel ?and ?is ?released ?into ?plasma ?as ?lipid ?poor ?apoA1. ?In ?a ?process ?referred ?to ?as ?reverse ?cholesterol ?transport, ?apoA1 ?stimulates ?ATP-??binding ?cassette ?transporter ?A1 ?(ABCA1), ?a ?trans-??membrane ?transporter, ?to ?remove ?excess ?cellular ?cholesterol ?and ?form ?pre-??beta ?HDL. ?Mature ?HDL ?is ?formed ?18 ?when ?lecithin-??cholesterol ?acyltransferase ?(LCAT) ?converts ?the ?un-??esterified ?(?free?) ?cholesterol ?into ?cholesterol ?esters. ?The ?mature ?HDL ?particles ?function ?to ?remove ?cholesterol ?from ?the ?body ?in ?one ?of ?two ?ways: ? ?(1) ?direct ?uptake ?of ?HDL-??C ?via ?the ?hepatic ?scavenger ?receptor-?? ?B1 ?(SR-??B1) ?or ?(2) ?the ?transfer ?of ?cholesterol ?ester ?by ?cholesterol ?ester ?transfer ?protein ?(CETP) ?to ?VLDL ?or ?LDL, ?with ?uptake ?by ?the ?liver ?through ?the ?LDL ?receptor ?(59). ?19 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?Lipoprotein ?Class ?Density ?(g ?mL-??1) ?Size ?(nm) ?Apolipoproteins ? % ?Protein ?% ?Cholesterol ?% ?Phospholipid ?% ?Triglyceride ?Chylomicron ? <0.95 ? 100-??1000 ?A-??I, ?A-??II, ?A-??IV, ?B-??48, ?C-??I, ?C-??II, ?C-??III ?<2 ? 8 ? 7 ? 84 ?VLDL ? 0.95-??1.006 ?30-??80 ? B-??100, ?C-??I, ?C-??II, ?C-??III, ?E ?10 ? 22 ? 18 ? 50 ?IDL ? 1.006-??1.019 ?25-??50 ? B-??100, ?C-??III, ?E ? 18 ? 29 ? 22 ? 31 ?LDL ? 1.019-??1.063 ?18-??28 ? B-??100 ? 25 ? 50 ? 21 ? 4 ?HDL ? 1.063-??1.210 ?5-??15 ? A-??I, ?A-??II, ?C-??I, ?C-??II, ?C-??III, ?D, ?E ?33 ? 30 ? 29 ? 8 ?Table ?1: ?Lipoprotein ?Classes ?and ?Composition; ?VLDL: ?Very ?Low ?Density ?Lipoprotein; ?IDL: ?Intermediate ?Density ?Lipoprotein; ?LDL: ?Low ?Density ?Lipoprotein; ?HDL: ?High ?Density ?Lipoprotein ? ?Data ?from ?Rosenson ?(59). ? ? ?20 ? ? ? ? ? ?Figure ?3: ?Lipoprotein ?Metabolism ?Pathway ?From ?Kwiterovich ?(110) ?with ?permission ?from ?Excerpta ?Medica ?Inc. ? ?1.5 ?Lipid ?Disorders ? ?There ?are ?a ?wide ?variety ?of ?lipid ?disorders ?that ?are ?classified ?as ?secondary, ?when ?the ?alterations ?are ?caused ?by ?lifestyle ?factors ?such ?as ?diet, ?an ?underlying ?disease, ?or ?drug ?use ?or ?primary, ?when ?they ?are ?caused ?by ?genetic ?mutations ?and ?are ?associated ?with ?an ?overproduction ?and/or ?impaired ?removal ?of ?lipoproteins. ? ?1.5.1 ?Secondary ?Lipid ?Disorders ? ?The ?secondary ?causes ?of ?dyslipidemia ?include ?type ?2 ?diabetes ?mellitus, ?cholestatic ?liver ?diseases, ?nephrotic ?syndrome, ?chronic ?renal ?failure, ?hypothyroidism, ?excessive ?alcohol ?consumption, ?cigarette ?smoking, ?obesity ?and ?drugs. ?It ?is ?thought ?that ?the ?2 ?21 ?most ?common ?secondary ?causes ?of ?dyslipidemia ?are ?type-??2 ?diabetes ?mellitus ?and ?excessive ?alcohol ?intake ?(35). ? ?1.5.2 ?Primary ?Lipid ?Disorders ? ?There ?are ?many ?different ?genetic ?disorders ?that ?cause ?high ?LDL-??C ?levels, ?low ?HDL-??C ?levels, ?hypertriglyceridemia, ?high ?Lp(a) ?levels ?or ?a ?combination ?of ?these. ?In ?fact, ?disturbance ?in ?lipoprotein ?metabolism ?is ?often ?familial ?in ?nature, ?with ?one ?study ?finding ?that ?54 ?percent ?of ?patients ?with ?CHD ?and ?70 ?percent ?of ?those ?with ?a ?lipid ?abnormality ?had ?a ?familial ?disorder ?(35). ? ? ?Primary ?lipoprotein ?disorders, ?such ?as ?the ?LDL-??C ?disorders, ?that ?lead ?to ?elevation ?in ?circulating ?levels ?of ?LDL-?? ?C ?can ?induce ?the ?development ?of ?atherosclerosis ?even ?in ?the ?absence ?of ?other ?risk ?factors. ? ?Circulating ?LDL-?? ?C ?can ?also ?enter ?macrophages ?and ?other ?tissues ?through ?the ?unregulated ?scavenger ?receptor ?leading ?to ?accumulation ?of ?excess ?cholesterol ?and ?foam ?cell ?formation ?that ?can ?subsequently ?lead ?to ?atheromatous ?plaque ?formation ?(35). ?There ?are ?a ?number ?of ?different ?disorders ?of ?LDL-??C ?that ?vary ?in ?the ?underlying ?genetic ?defect ?and ?their ?clinical ?manifestation ?(Table ?2). ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?22 ?Disorder ? Genetic ?Abnormalities ?Lipid ?Levels ? Physical ?Findings ?Familial ?Defective ?Apo-??B ?100 ?Defective ?Apo-??B ?100 ?(residue ?3500) ??LDL-??C, ?TG ?usually ?normal ?Tendon ?xanthoma ?Familial ?Combined ?Hyperlipidemia ?Upstream ?Transcription ?Factor ?1 ??TC ?and/or ?TG; ??Apo-??B ?-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-?? ?Polygenic ?Hypercholesterolemia ?Multiple ?abnormalities; ?LDL-??R; ?Defective ?Apo-??B ?100; ??synthesis ?Apo-??B; ?presence ?Apo ?E4 ?phenotype ?? ?LDL-??C, ?TG ?usually ?normal ?-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-??-?? ?Abetalipoproteinemia ? Microsomal ?Transfer ?Protein ?No ?Apo-??B ?containing ?lipoproteins ?Mental ?retardation; ?Growth ?abnormalities ?Hypobetalipoproteinemia ? Multiple ?abnormailities; ?Defective ?Apo-??B ?100 ??Apo-??B; ??LDL-??C ?Intestinal ?fat ?malabsorption; ?hepatic ?steatosis; ?fat-??soluble ?vitamin ?deficiencies ? ? ? ? ?Table ?2: ?Other ?Primary ?LDL-??C ?Disorders; ?TC: ?Total ?cholesterol; ?TG: ?Triglyerides; ?Apo-??B: ?Apolipoprotein ?B ? ?Modified ?from ?Rosenson ?et ?al. ?(111) ?with ?permission ?from ?Mosby ?Inc. ? ?23 ?1.6 ?Familial ?Hypercholesterolemia ? ?The ?focus ?of ?this ?thesis ?is ?on ?one ?particular ?primary ?disorder ?of ?LDL-??C ?metabolism, ?namely ?Familial ?Hypercholesterolemia ?(FH), ?the ?most ?common ?genetic ?cause ?of ?severe ?hypercholesterolemia ?resulting ?in ?premature ?coronary ?artery ?disease ?(60). ? ?People ?afflicted ?by ?FH, ?have ?severe ?elevations ?in ?both ?TC ?and ?LDL-??C, ?seen ?from ?birth, ?which ?lead ?to ?early ?development ?of ?atherosclerosis ?and ?increased ?risk ?for ?developing ?premature ?CVD. ?In ?fact, ?FH ?has ?been ?shown ?to ?decrease ?life ?expectancy ?by ?approximately ?20-??30 ?yrs ?(60). ?Moreover, ?if ?left ?untreated, ?it ?is ?estimated ?that ?about ?50% ?of ?men ?and ?12% ?of ?women ?will ?suffer ?a ?coronary ?episode ?before ?the ?age ?of ?50 ?(60, ?61). ?Additionally, ?the ?mean ?age ?of ?onset ?of ?CVD ?is ?between ?40 ?and ?45 ?yrs ?in ?males ?and ?10 ?yrs ?later ?in ?females ?with ?FH ?while ?the ?mean ?age ?of ?onset ?of ?CVD ?in ?the ?US ?population ?is ?65 ?in ?males ?and ?about ?5 ?yrs ?later ?in ?females ?(60). ?1.6.1 ?Etiology, ?Incidence, ?and ?Prevalence ?of ?FH ? ?FH ?is ?an ?autosomal ?dominant ?condition ?meaning ?that ?siblings ?and ?children ?of ?a ?person ?with ?FH ?have ?a ?50 ?per ?cent ?risk ?of ?having ?FH ?themselves. ?FH ?is ?primarily ?caused ?by ?mutations ?to ?the ?LDL ?receptor ?(LDL-??R) ?gene ?with ?more ?than ?90% ?of ?cases ?being ?caused ?by ?this ?abnormality ?(62-??66). ?Individuals ?with ?FH ?can ?inherit ?a ?defective ?gene ?for ?FH ?from ?one ?parent, ?making ?them ?heterozygous, ?or ?a ?defective ?gene ?for ?FH ?from ?each ?parent, ?making ?them ?homozygous. ?FH ?is ?inherited ?with ?a ?gene ?dosing ?effect ?in ?which ?homozygotes ?are ?much ?more ?severely ?affected ?than ?heterozygotes. ?In ?fact, ?it ?has ?been ?shown ?that ?the ?clearance ?of ?LDL-??C ?was ?reduced ?by ?27% ?in ?heterozygotes ?and ?53% ?in ?homozygotes ?(35). ?Fortunately, ?homozygous ?FH ?is ?extremely ?rare ?with ?a ?prevalence ?of ?1 ?case ?per ?million. ? ?The ?majority ?of ?individuals ?affected ?with ?FH ?have ?inherited ?a ?defective ?gene ?from ?only ?one ?parent ?and ?are, ?therefore, ?heterozygotes. ?Heterozygous ?FH ? ?(hFH) ?has ?a ?prevalence ?of ?1 ?in ?500 ?in ?the ?general ?population. ? ?hFH ?is ?more ?common ?than ?several ?well-??known ?conditions ?such ?as ?type ?1 ?DM, ?cystic ?fibrosis, ?and ?neonatal ?hypothyroidism. ?Although ?1 ?out ?of ?500 ?people ?in ?the ?general ?population ?is ?affected ?with ?FH, ?certain ?populations ?are ?affected ?at ?a ?higher ?rate ?that ?may ?approach ?1 ?in ?70 ?due ?to ?the ?founder ?effect. ?These ?include ?French ?Canadians, ?Finnish, ?Lebanese, ?Ashkenazi ?Jews ?and ?Afrikaners ?(62-??66). ?For ?24 ?yrs ?it ?was ?thought ?that ?FH ?was ?a ?monogenic ?disorder ?caused ?only ?by ?mutations ?to ?the ?LDL-??R ?gene, ?however, ?over ?time ?as ?genotyping ?became ?more ?common, ?patients ?were ?being ?discovered ?who ?possessed ?the ?typical ?phenotype ?of ?FH ?but ?were ?lacking ?the ?typical ?LDL-??R ?mutations. ?This ?led ?to ?the ?discovery ?that ?mutations ?to ?the ?ApoB ?gene ?and ?Proprotein ?Convertase ?Subtilin/Kexin ?9 ?gene ?(PCSK9) ?could ?also ?cause ?FH ?(67-??69). ? ?1.6.2 ?Causes ?of ?FH ?1.6.2.1 ?LDL ?Receptor ?Mutations ? ?Originally, ?it ?was ?believed ?that ?the ?underlying ?defect ?in ?FH ?was ?an ?overproduction ?of ?cholesterol. ?However, ?it ?was ?eventually ?discovered ?that ?the ?catabolic ?rate ?of ?LDL ?was ?lower ?in ?heterozygous ?FH ?individuals ?than ?in ?normal ?subjects. ?This ?difference ?is ?due ?to ?a ?malfunction ?in ?the ?ability ?to ?clear ?LDL ?from ?circulation. ?Brown ?and ?Goldstein ?were ?able ?to ?identify ?that ?the ?diminished ?removal ?of ?LDL ?in ?FH ?patients ?was ?caused ?by ?genetic ?defects ?in ?the ?LDL-??R ?(67-??69). ? ?In ?fact, ?they ?were ?able ?to ?characterize ?the ?LDL-??R ?pathway, ?which ?had ?far ?reaching ?implications ?(Figure ?4). ?The ?LDL-??R ?is ?a ?cell ?surface ?glycoprotein ?that ?is ?initially ?produced ?in ?the ?Golgi ?apparatus ?before ?being ?transported ?to ?the ?cell ?surface. ?While ?exposed ?at ?the ?surface ?the ?LDLR ?selectively ?binds ?apoB ?in ?circulating ?LDL ?particles. ?A ?receptor-??ligand ?complex ?is ?formed ?which ?is ?then ?internalized ?by ?endocytosis ?via ?clathrin-??coated ?pits ?through ?interactions ?involving ?the ?LDL ?receptor ?adaptor ?protein, ?LDLRAP1. ?Endosomes ?then ?transport ?the ?complex ?to ?the ?internal ?areas ?of ?the ?cell ?whereby ?the ?acidic ?environment ?dissolves ?the ?ligand-??receptor ?complex. ?The ?LDL-??R ?gets ?recycled ?to ?the ?cell ?surface ?and ?the ?cholesterol ?is ?released ?and ?utilized ?by ?the ?cell. ? ?As ?the ?cholesterol ?accumulates, ?this ?inactivates ?sterol ?regulatory ?element ?binding ?protein ?(SREBP), ?a ?transcription ?factor ?that ?drives ?expression ?of ?genes ?for ?enzymes ?involved ?in ?cholesterol ?synthesis ?and ?the ?LDL ?receptor. ?In ?this ?way ?the ?LDLR ?pathway ?maintains ?intracellular ?cholesterol ?homeostasis ?(67-??69). ? ? ?The ?LDLR ?gene ?is ?located ?on ?19p13 ?and ?is ?45 ?kb ?long. ?It ?is ?composed ?of ?18 ?exons ?that ?code ?for ?an ?860 ?amino ?acid ?protein. ?The ?LDLR ?protein ?has ?many ?different ?domains ?25 ?and ?mutations ?are ?distributed ?throughout ?the ?various ?domains ?(Figure ?6). ?The ?knowledge ?gained ?from ?the ?LDLR ?pathway ?allowed ?for ?the ?discovery ?that ?many ?different ?LDLR ?mutations ?cause ?FH, ?and ?additionally ?allowed ?for ?the ?classification ?of ?LDLR ?mutations ?in ?to ?5 ?classes: ?ligand-??binding ?defective; ?transport ?defective; ?internalization ?defective; ?recycling ?defective; ?and ?'null', ?which ?resulted ?in ?no ?detectable ?protein. ?To ?date, ?more ?than ?1600 ?gene ?mutations ?of ?the ?LDL-??R ?gene ?have ?been ?discovered ?that ?have ?a ?meaningful ?impact ?on ?receptor ?function. ?The ?mutations ?vary ?in ?the ?severity ?of ?cholesterol ?elevation ?and ?its ?consequences. ?There ?are ?certain ?mutations ?that ?are ?specific ?to ?different ?populations. ?For ?instance, ?in ?Tunisia ?there ?are ?5 ?LDLR ?mutations ?that ?are ?specific ?for ?the ?population ?with ?one ?of ?them ?accounting ?for ?29.67% ?of ?cases. ?Another ?example ?is ?the ?French ?Canadian ?population ?of ?Quebec ?where ?more ?than ?90% ?of ?the ?heterozygous ?FH ?patients ?have ?one ?of ?eleven ?LDL-??R ?mutations ?(67-??69). ?1.6.2.2 ?Apolipoprotein ?B-?? ?100 ?Mutations ? ?Five ?to ?10% ?of ?cases ?of ?FH ?are ?caused ?by ?mutations ?in ?the ?Apolipoprotein ?B-??100 ?protein. ?Apolipoprotein ?B-??100 ?is ?the ?protein ?component ?of ?the ?LDL ?particle. ?The ?gene ?is ?found ?on ?2p24-??p23 ?and ?is ?made ?up ?of ?29 ?exons ?spanning ?~43 ?Kb. ?ApoB ?is ?the ?ligand ?for ?the ?LDL-??R ?thus, ?when ?mutations ?are ?present ?circulating ?LDL ?is ?unable ?to ?properly ?bind ?the ?LDL-??R ?and ?concentrations ?of ?LDL ?remain ?high. ?Unlike ?mutations ?in ?the ?LDL-??R, ?there ?are ?a ?limited ?number ?of ?known ?ApoB ?mutations ?that ?cause ?the ?FH ?phenotype. ?The ?most ?well ?known ?is ?the ?Arg3500Gln ?variant ?which ?causes ?about ?2-??5% ?of ?FH ?cases ?in ?Europe ?(67-??69). ? ?26 ? ? ? ?Figure ?4: ?LDL ?Receptor ?Pathway ?From ?Soutar ?et ?al. ?(69) ?with ?permission ?from ?Nature ?Publishing ?Group ? ?1.6.2.3 ?Proprotein ?Convertase ?Subtilin/Kexin ?9 ?Mutations ? ?Finally, ?the ?mutations ?in ?the ?PCSK9 ?gene, ?which ?is ?located ?on ?1p32 ?is ?made ?up ?of ?12 ?exons ?and ?spans ?~25 ?Kb, ?could ?lead ?to ?the ?typical ?FH ?presentation. ?PCSK9 ?gene ?mutations ?are ?very ?rare ?and ?account ?for ?less ?than ?1% ?of ?FH ?cases. ?PCSK9 ?is ?a ?serine ?protease ?synthesized ?mainly ?by ?the ?liver ?that ?binds ?to ?the ?Epidermal ?Growth ?Factor-??Like ?Repeat ?A ?(EGF-??A) ?domain ?of ?the ?LDLR ?and ?induces ?its ?degradation. ?Thus, ?the ?normal ?functioning ?of ?PCSK9 ?can ?lead ?to ?a ?decrease ?in ?LDL-??R ?and ?an ?increase ?in ?LDL ?cholesterol ?levels ?(70). ?Thus ?PCSK9 ?levels ?tend ?to ?correlate ?directly ?with ?LDL-??C ?levels. ?Several ?mutations ?of ?PCSK9 ?have ?been ?identified ?that ?are ?associated ?with ?either ?a ?hypocholesterolemic ?or ?hypercholesterolemic ?phenotype. ??Loss-??of-??function? ?mutations ?decrease ?LDL ?receptor ?degradation ?and ?patients ?with ?these ?mutations ?have ?low ?LDL-??C ?concentrations ?and ?are ?protected ?from ?CHD ?(70). ?Although ?rare, ??gain ?of ?function? ?mutations ?in ?PCSK9 ?degrade ?surface ?LDLR ?and ?lead ?to ?a ?severe ?FH ?phenotype ?with ?elevated ?LDL-??C ?levels ?and ?heightened ?cardiovascular ?risk ?(68-??70). ? ? ? LDLInternalization viaclathrin-coated pits/LDLRAP1 (ARH)Dissociation ofligand?receptorcomplex in endosomeLDL degradedin lysosomePCSK9? PCSK9?Steral-mediated regulationof transcription of LDLRand enzymes involved incholesterol synthesisLDLR recycledto basolateralsurfaceSynthesis in the ERand maturationof LDLR in theGolgi apparatusapoBLDLRLipid corecholesteryl esters 27 ?1.6.3 ?Clinical ?Features ?of ?FH ? ? ?FH ?can ?be ?diagnosed ?either ?clinically ?or ?genetically. ?However, ?only ?a ?few ?countries ?currently ?have ?national ?genetic ?screening ?programs ?for ?FH, ?thus ?in ?most ?cases ?FH ?is ?diagnosed ?using ?clinical ?criteria. ?The ?most ?important ?characteristics ?used ?when ?diagnosing ?FH ?clinically ?are, ?first ?and ?foremost, ?elevated ?lipid ?levels, ?tendon ?xanthomas, ?and ?family ?history ?of ?hypercholesterolemia ?and/or ?premature ?CVD. ?In ?some ?cases, ?FH ?patients ?can ?present ?with ?typical ?physical ?findings ?including ?tendon ?xanthomas, ?which ?are ?cholesterol ?deposits ?in ?tendons ?found ?most ?commonly ?in ?the ?Achilles ?tendon, ?arcus ?cornealis, ?a ?white ?or ?opaque ?ring ?around ?the ?cornea ?caused ?by ?cholesterol ?deposits ?and ?occurring ?before ?the ?age ?of ?45, ?or ?xanthelasma, ?yellow ?papules ?and ?plaques ? ?above ?and ?below ?the ?medial ?canthus ?due ?to ?fatty ?deposits ?and ?present ?in ?patients ?under ?20 ?(63,64,71, ?72). ?The ?absence ?of ?these ?physical ?signs ?does ?not ?preclude ?the ?diagnosis ?of ?FH. ? ?1.6.4 ?Diagnostic ?Criteria ?of ?FH ? ?The ?3 ?most ?commonly ?used ?clinical ?criteria ?to ?diagnose ?FH ?are ?the ?US ?Make ?Early ?Diagnosis, ?Prevent ?Early ?Death ?(MEDPED) ?criteria, ?the ?Simon ?Broome ?Criteria, ?and ?the ?Dutch ?Lipid ?Clinic ?Network ?Criteria ?(DLCNC). ?(Table ?3, ?4, ?5) ?The ?MEDPED ?criteria ?utilize ?TC ?cut ?points ?that ?are ?specific ?to ?the ?individual?s ?age ?and ?family ?history. ?The ?cut ?points ?are ?set ?higher ?the ?older ?an ?individual ?is. ?In ?addition, ?the ?cut ?points ?are ?different ?for ?individuals ?who ?are ?either ?from ?the ?general ?population ?or ?are ?first-??, ?second-?? ?or ?third-??degree ?relatives ?of ?a ?patient ?with ?FH, ?because ?individuals ?with ?a ?relative ?with ?FH ?have ?a ?higher ?probability ?of ?having ?FH. ?The ?Simon ?Broome ?Criteria ?uses ?a ?more ?varied ?classification ?system ?that ?takes ?into ?account ?cholesterol ?concentrations, ?clinical ?characteristics, ?molecular ?diagnosis, ?and ?family ?history ?to ?assign ?a ?classification ?of ?either ??Definite? ?or ??Possible? ?FH. ?The ?DLCNC ?is ?similar ?to ?the ?Simon ?Broome ?Criteria, ?except ?that ?it ?uses ?a ?point ?system ?whereby, ?a ??definite? ?FH ?diagnosis ?requires ?8 ?or ?more ?points. ?Points ?are ?assigned ?for ?family ?history ?of ?hyperlipidaemia ?or ?heart ?disease, ?clinical ?characteristics ?such ?as ?tendinous ?xanthomata, ?elevated ?LDL ?cholesterol, ?and/or ?an ?identified ?mutation ?(63,64,71, ?72). ? ?28 ?A ?Danish ?study ?conducted ?by ?Damgaard ?et ?al. ?in ?2005 ?tested ?the ?ability ?of ?the ?3 ?different ?clinical ?criteria ?to ?predict ?the ?results ?of ?molecular ?genetic ?analysis. ?Four ?hundred ?and ?eight ?index ?individuals ?and ?385 ?relatives ?were ?included ?in ?the ?study. ?The ?MEDPED ?criteria ?had ?a ?mutation ?detection ?rate ?of ?53.5%, ?a ?sensitivity ?(true ?positive ?rate) ?of ?63.4%, ?and ?a ?specificity ?of ?73.4% ?(true ?negative ?rate). ?When ?looking ?at ?individuals ?who ?were ?classified ?as ??Definite? ?based ?upon ?the ?Simon ?Broome ?Criteria ?and ?the ?DLCNC, ?it ?is ?revealed ?that ?both ?performed ?similarly ?to ?one ?another ?while ?outperforming ?the ?MEDPED ?criteria. ?The ?Simon ?Broome ?Criteria ?had ?a ?61.3% ?mutation ?detection ?rate, ?a ?sensitivity ?of ?34.1%, ?and ?a ?specificity ?of ?89.4% ?while ?the ?DLCNC ?had ?a ?62.9% ?mutation ?detection ?rate, ?a ?sensitivity ?of ?41.5%, ?and ?a ?specificity ?of ?87.9% ?(71). ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?29 ?Total ?Cholesterol ?Cutpoints ? ? 1st ?Degree ?Relative ?with ?FH ?2nd ?Degree ?Relative ?with ?FH ?3rd ?Degree ?Relative ?with ?FH ?General ?Population ?Age ?(yrs) ? ? ? ? ?<20 ? 5.7 ? 5.9 ? 6.2 ? 7.0 ?20-??29 ? 6.2 ? 6.5 ? 6.7 ? 7.5 ?30-??39 ? 7.0 ? 7.2 ? 7.5 ? 8.8 ??40 ? 7.5 ? 7.8 ? 8.0 ? 9.3 ?Diagnosis: ?FH ?is ?diagnosed ?if ?total ?cholesterol ?levels ?exceed ?the ?cutpoint ?Table ?3: ?MEDPED ?Criteria ? ? ?Data ?from ?Marks ?et ?al. ?(64) ?with ?permission ?from ?Elsevier ? ? ? ? ? ? ? ? ?Definite ?FH ? Possible ?FH ?Total ?Cholesterol ?>6.7mmol/L ?(LDL ?>4.0mmol/L) ?in ?children ?under ?16 ?Or ?>7.5mmol/L ?(LDL ?>4.9mmol/L) ?in ?adults ?Plus ?either ?Tendon ?xanthomas ?in ?patient ?or ?1st ?or ?2nd ?degree ?relative ?Plus ?either ?Family ?history ?of ?myocardial ?infarction ?<50 ?yrs ?in ?2nd ?degree ?relative ?or ?<60 ?yrs ?in ?1st ?degree ?relative ?Or ?DNA ?Confirmation ?Or ?Family ?history ?of ?total ?cholesterol ?>7.5mmol/L ?in ?1st ?or ?2nd ?degree ?relative ?Table ?4: ?Simon ?Broome ?Criteria ? ?Data ?from ?Marks ?et ?al. ?(64) ?with ?permission ?from ?Elsevier ? ? ? ? ? ? ?30 ? ?Table ?5: ?Dutch ?Lipid ?Clinic ?Network ?Criteria ?Modified ?from ?Civeira ?(112) ?with ?permission ?from ?Elsevier. ? ? ? ? ? ? ? ? ? Score ?Family ?History ?First ?degree ?relative ?with ?known ?premature ?coronary ?and ?vascular ?disease ?(Men ?<55 ?yrs, ?Females ?<60 ?yrs), ?OR ?First ?degree ?relative ?with ?LDL ?cholesterol ?above ?the ?95th ?percentile ?for ?age ?and ?sex ?1 ?First ?degree ?relative ?with ?tendionous ?xanthomata ?and/or ?arcus ?cornealis, ?OR ?Children ?<18 ?yrs ?with ?LDL ?cholesterol ?above ?the ?95th ?percentile ?for ?age ?and ?sex ?2 ?Clinical ?History ?Patient ?with ?premature ?coronary ?artery ?disease ?(ages ?as ?above) ? 2 ?Patient ?with ?premature ?cerebral ?or ?peripheral ?vascular ?disease ?(ages ?as ?above) ?1 ?Physical ?Examination ?Tendinous ?xanthomata ? 6 ?Arcus ?cornealis ?prior ?to ?age ?45 ?yrs ? 4 ?LDL ?cholesterol ?(mmol/L) ? ? ? LDL-??C ?? ?8.5 ? 8 ? ? LDL-??C ?6.5-??8.4 ? 5 ? ? LDL-??C ?5.0-??6.4 ? 3 ? ? LDL-??C ?4.0-??4.9 ? 1 ?DNA ?Analysis-?? ?Functional ?mutation ?in ?the ?LDLR, ?APOB, ?or ?PCSK9 ?gene ? ? 8 ?Stratification ? Total ?Score ?Definite ?FH ? ?8 ?Probable ?FH ? 6-??7 ?Possible ?FH ? 3-??5 ?Unlikely ?FH ? <3 ?31 ?1.6.5 ?Treatment ?of ?FH ? ?In ?contrast ?to ?many ?other ?genetic ?diseases, ?treatment ?in ?the ?form ?of ?lifestyle ?management ?and ?lipid ?lowering ?medications ?is ?highly ?effective ?in ?preventing ?not ?only ?CVD ?but ?also ?total ?mortality ?in ?these ?individuals. ?The ?initial ?treatment ?is ?lifestyle ?management. ?There ?are ?many ?modifiable ?lifestyle ?factors ?that ?can ?either ?directly ?or ?indirectly ?lead ?to ?atherogenesis ?through ?the ?detrimental ?alteration ?of ?lipid ?levels. ?These ?modifiable ?risk ?factors ?that ?can ?be ?targeted ?in ?lifestyle ?management ?include ?cigarette ?smoking, ?diet, ?exercise, ?obesity, ?alcohol ?consumption ?and ?psychosocial ?factors ?(1). ?Long-??term ?drug ?therapy ?of ?patients ?with ?FH ?can ?substantially ?reduce ?or ?remove ?the ?excess ?lifetime ?risk ?of ?CHD ?due ?to ?the ?genetic ?disorder ?and ?can ?lower ?CHD ?event ?rates ?in ?FH ?patients ?to ?levels ?similar ?to ?those ?of ?the ?general ?population ?(73). ?The ?primary ?target ?of ?treatment, ?based ?upon ?results ?from ?clinical ?trials, ?is ?LDL-??C. ?It ?has ?been ?shown ?that ?for ?every ?1.0mmol/L ?reduction ?in ?LDL-??C, ?there ?is ?a ?22% ?reduction ?in ?CVD ?morbidity ?and ?mortality ?(74). ?All ?of ?the ?available ?data ?indicates ?that ?optimal ?risk ?reductions ?are ?seen ?when ?LDL-??C ?is ?lowered ?to ?below ?1.8mmol/L. ?The ?most ?important ?form ?of ?pharmacotherapy ?that ?is ?currently ?administered ?for ?this ?purpose ?is ?statins. ? ?They ?are ?a ?class ?of ?drugs ?that ?act ?as ?HMG-??CoA ?reductase ?inhibitors, ?thus ?decreasing ?the ?amount ?of ?intracellular ?cholesterol ?and ?consequently ?increasing ?the ?expression ?of ?LDL-??R ?on ?the ?cell ?surface, ?which ?results ?in ?increased ?uptake ?of ?LDL-??C ?from ?the ?blood. ?Large-??scale ?statin ?clinical ?trials ?have ?shown ?that ?the ?risk ?for ?major ?coronary ?events ?was ?reduced ?by ?23% ?per ?mmol/L ?LDL-??C ?reduction ?(75). ? ?In ?the ?majority ?of ?FH ?patients, ?due ?to ?the ?severely ?elevated ?lipid ?levels, ?to ?reach ?target ?it ?may ?be ?necessary ?to ?prescribe ?additional ?therapy ?using ?an ?agent ?that ?inhibits ?cholesterol ?absorption ?(ezetimibe), ?bile ?acid ?reabsorption ?(cholestyramine, ?colestipol) ?and/or ?the ?concomitant ?use ?of ?niacin ?(74). ?These ?combinations ?can ?further ?reduce ?LDL-??C ?by ?about ?10-??15% ?for ?bile ?acid ?resins ?and ?about ?20% ?for ?ezitimibe ?and ?niacin ?(74). ?In ?rare ?cases ?of ?homozygous ?or ?severe ?hFH, ?neither ?statin ?monotherapy ?or ?combination ?therapy ?will ?be ?sufficient ?to ?reach ?target, ?thus ?using ?an ?expensive ?but ?effective ?technique, ?LDL ?apheresis, ?where ?LDL ?and ?Lp(a) ?are ?removed ?from ?plasma ?during ?extracorporeal ?circulation ?weekly ?or ?every ?other ?32 ?week. ?Not ?only ?has ?drug ?treatment ?proven ?to ?be ?extremely ?effective ?but ?it ?has ?also ?shown ?to ?be ?highly ?cost ?effective; ?identifying ?and ?successfully ?treating ?3 ?hFH ?subjects ?prevents ?one ?premature ?MI. ?Cost-?? ?benefit ?analyses ?has ?shown ?that ?drug ?treatment ?of ?FH ?represents ?good ?value ?for ?the ?money ?(66). ?1.6.6 ?Cardiovascular ?Disease ?in ?FH ? ?Despite ?being ?a ?genetically ?well-??characterized ?disorder ?caused ?by ?only ?3 ?genes ?(LDL-??R, ?ApoB, ?PCSK9), ?the ?clinical ?expression ?of ?FH ?varies ?considerably ?particularly ?with ?regard ?to ?cholesterol ?levels ?and ?the ?age ?of ?onset ?and ?severity ?of ?CAD ?(60). ?In ?comparison ?to ?the ?general ?population, ?the ?primary ?risk ?factor ?in ?FH ?patients ?is ?high ?(2-?? ?to ?3-??fold ?elevated) ?plasma ?LDL-??C ?levels ?that ?can ?lead ?to ?atherosclerotic ?lesions ?that ?may ?ultimately ?cause ?MI. ? ?FH ?is ?both ?under-??diagnosed ?and ?undertreated ?compounding ?the ?dangers ?associated ?with ?this ?disease. ?FH ?was ?not ?given ?an ?independent ?code ?in ?the ?World ?Health ?Organisation ?International ?Classification ?of ?Diseases ?and ?in ?most ?countries ?less ?than ?1% ?of ?people ?living ?with ?FH ?are ?properly ?diagnosed. ?Although ?FH ?can ?be ?effectively ?treated, ?under ?treatment ?of ?FH ?patients ?is ?a ?significant ?problem ?with ?only ?about ?50% ?of ?FH ?patients ?being ?on ?statin ?therapy. ?The ?risk ?of ?CHD ?in ?FH ?patients ?not ?receiving ?statins ?was ?increased ?13 ?fold, ?while ?the ?risk ?of ?CHD ?in ?FH ?patients ?on ?statins ?was ?increased ?10 ?fold. ?This ?indicates ?that ?even ?those ?FH ?patients? ?receiving ?statins ?the ?dose ?given ?is ?insufficiently ?lowering ?cholesterol. ?Among ?FH ?patients ?the ?variation ?in ?phenotypic ?expression, ?specifically ?the ?occurrence ?of ?CVD ?in ?FH ?is ?affected ?by ?the ?contributions ?of ?additional ?metabolic, ?environmental ?and ?genetic ?risk ?factors, ?acting ?in ?conjunction ?with ?severe ?hypercholesterolaemia ?(60, ?67,76-??82). ? ?1.6.6.1 ?Genetic ?Mutations ?as ?Risk ?Factors ?in ?FH ? ?As ?previously ?mentioned ?there ?are ?more ?than ?1600 ?LDL-??R ?mutations ?and ?a ?number ?of ?different ?ApoB ?and ?PCSK9 ?mutations ?that ?can ?lead ?to ?FH. ?The ?severity ?of ?an ?individual?s ?phenotype ?can ?often ?depend ?upon ?which ?mutation ?they ?are ?afflicted ?with. ?Most ?importantly, ?LDL-??R ?mutations ?are ?generally ?associated ?with ?a ?more ?severe ?phenotype ?than ?ApoB ?mutations ?(80-??82). ?LDLR ?mutations ?can ?be ?grouped ?33 ?into ?2 ?broad ?classes: ?receptor ?defective ?alleles ?and ?receptor ?negative ?alleles. ?As ?is ?expected, ?those ?individuals ?with ?receptor ?negative ?alleles ?typically ?have ?a ?more ?severe ?phenotype ?as ?evidenced ?by ?higher ?LDL-?? ?C ?levels ?and ?higher ?risk ?for ?CVD ?(35,80-??82). ?In ?addition ?to ?those ?mutations ?know ?to ?cause ?FH, ?genetic ?variants ?in ?a ?variety ?of ?other ?genes ?can ?increase ?an ?FH ?patient?s ?risk ?of ?developing ?CVD. ?The ?largest ?exploratory ?study ?on ?association ?of ?genetic ?variants ?and ?CVD ?risk ?in ?hFH ?found ?that ?G20210A ?polymorphism ?in ?the ?prothrombin ?gene ?was ?most ?strongly ?related ?to ?increased ?risk ?of ?CVD. ?This ?polymorphism ?increases ?the ?serum ?level ?of ?prothrombin ?leading ?to ?an ?increased ?risk ?of ?venous ?thrombosis. ?Four ?other ?polymorphisms ?were ?described ?as ?associated ?with ?CVD. ?Two ?were ?associated ?with ?increased ?CVD ?risk, ?namely ?the ?Met235Thr ?variant ?in ?the ?angiotensinogen ?gene, ?which ?was associated with increased levels of angiotensinogen and a corresponding increase in the risk of hypertension, ?and ?the ?Thr347Ser ?variant ?in ?the ?apoA4 ?gene, ?which ?is ?thought ?to ?have ?an ?effect ?on ?triglyceride ?levels. ?In ?contrast, ?the ?Ser311Cys ?substitution ?in ?the ?paraoxonase-??2 ?gene ?and ?the ?C1100T ?variant ?in ?the ?apoC3 ?gene ?were ?associated ?with ?decreased ?CVD ?risk ?(80). ?Another ?study ?assessed ?ABCG8 ?variants, ?a ?member ?of ?the ?adenosine ?triphosphate ?binding ?cassette ?(ABC) ?transporter ?family ?that ?helps ?to ?prevent ?the ?accumulation ?of ?plant ?sterols. ?It ?has ?been ?suggested ?that ?moderately ?elevated ?plasma ?concentrations ?of ?plant ?sterols ?increase ?CVD ?risk. ?In ?keeping ?with ?this ?idea ?the ?study ?found ?that ?carrying ?the ?risk ?genotype ?of ?both ?ABCG8 ?polymorphisms, ?D19H ?and ?T400K, ?was ?associated ?with ?an ?increased ?risk ?of ?CVD ?and ?CHD ?(83). ? 1.6.6.2 ?Traditional ?Risk ?Factors ?in ?FH ? ?Even ?in ?cases ?where ?families ?or ?populations ?share ?identical ?mutations ?there ?is ?still ?substantial ?phenotypic ?variability. ?Studies ?that ?evaluated ?the ?contribution ?of ?traditional ?risk ?factors ?to ?the ?development ?of ?CVD ?in ?FH ?patients ?have ?found ?that ?age, ?male ?gender, ?smoking, ?BMI, ?hypertension, ?diabetes ?mellitus, ?elevated ?triglycerides, ?elevated ?TC/HDL ?ratio ?and ?low ?HDL-??C ?appeared ?to ?be ?significant ?independent ?risk ?factors ?for ?CVD ?in ?FH ?(60, ?66,67, ?76-??87). ?Age ?and ?gender ?have ?consistently ?been ?34 ?shown ?as ?independent ?risk ?factors ?for ?developing ?CVD ?among ?FH ?patients ?whereas ?hypertension, ?BMI ?and ?diabetes ?are ?also ?often ?seen ?as ?risk ?factors ?but ?less ?consistently. ? ?FH ?patients ?with ?CVD ?have ?often ?shown ?greater ?lipid ?abnormalities ?than ?FH ?patients ?without ?CVD, ?such ?as ?elevated ?TC, ?LDL-??C ?and ?TG, ?and ?decreased ?HDL-??C. ?However, ?findings ?pertaining ?to ?the ?differences ?in ?lipid ?abnormalities ?between ?FH ?patients ?with ?and ?without ?CVD ?are ?inconsistent. ? ?TC ?and ?LDL-??C ?levels ?were ?shown ?to ?be ?elevated ?in ?FH ?patients ?with ?CVD ?as ?compared ?to ?FH ?patients ?without ?CVD ?although ?frequently ?not ?to ?statistical ?significance. ?The ?abnormalities ?of ?TG ?and ?HDL-??C ?among ?FH ?patients ?with ?CVD ?are ?consistent ?in ?most ?studies ?(60, ?66,67, ?76-??87). ? ?1.6.6.3 ?Emerging ?Risk ?Factors ?in ?FH ? ?One ?risk ?factor/ ?biomarker ?that ?has ?been ?extensively ?studied ?and ?appears ?to ?be ?a ?significant ?contributor ?to ?the ?development ?of ?CVD ?in ?FH ?patients ?is ?the ?plasma ?level ?of ?Lp(a). ?Although ?there ?have ?been ?some ?conflicting ?findings ?(89-??92), ?studies ?have ?generally ?found ?that ?Lp(a) ?is ?a ?clinically ?important ?independent ?predictor ?of ?CVD ?in ?FH ?patients ?(51, ?52, ?54, ?76, ?93-??97). ?Two ?of ?the ?more ?recent ?large ?scale ?studies ?analyzing ?Lp(a) ?as ?a ?risk ?factor ?for ?CVD ?in ?FH ?found ?that ?it ?was ?a ?significant, ?independent ?risk ?factor ?for ?CVD ?in ?FH ?and ?that ?in ?multivariate ?analyses ?had ?odds ?ratios ?of ?2.59 ?and ?1.50, ?respectively ?(51, ?76). ?A ?different ?study ?found ?that ?FH ?patients ?with ?evidence ?of ?early ?CVD ?events ?had ?significantly ?higher ?levels ?than ?FH ?patients ?with ?late ?or ?no ?CHD ?events. ?Lp(a)?s ?effect ?was ?particularly ?striking ?in ?females ?with ?elevated ?cholesterol ?levles ?(52). ?One ?other ?study ?indicated ?that ?it ?was ?the ?small ?apo(a) ?isoform ?size ?in ?combination ?with ?high ?Lp(a) ?levels ?that ?lead ?to ?the ?greatest ?risk ?of ?developing ?CVD ?in ?FH ?patients ?(91). ? ?Another ?biomarker ?that ?has ?garnered ?interest ?in ?FH ?patients ?is ?serum ?level ?of ?bilirubin. ?Serum ?total ?bilirubin ?concentrations ?have ?been ?shown ?to ?be ?inversely ?associated ?with ?the ?risk ?for ?cardiovascular ?disease; ?in ?large ?part ?due ?to ?its ?ability ?to ?prevent ?oxidation ?of ?LDL-?? ?C. ?One ?study ?found ?significantly ?lower ?serum ?total ?bilirubin ?levels ?in ?FH ?patients ?with ?CVD ?as ?compared ?to ?FH ?patients ?without ?CVD ?(98). ? ?35 ?Another ?emerging ?factor ?thought ?to ?be ?connected ?to ?development ?of ?CVD ?in ?FH ?patients ?is ?the ?atherogenic ?index ?of ?plasma ?(AIP=log ?[triglycerides/HDL-??cholesterol]. ?It ?has ?consistently ?been ?shown ?that ?the ?AIP ?value ?(log[TG/HDL-??C]) ?strongly ?correlates ?with ?the ?size ?of ?the ?lipoprotein ?particles ?(99). ?In ?other ?words, ?the ?AIP ?value ?accurately ?reflects ?the ?presence ?of ?atherogenic ?small ?LDL ?particles ?and ?small ?HDL ?particles, ?and ?is ?a ?sensitive ?predictor ?of ?cardiovascular ?risk ?in ?the ?general ?population. ?Notably, ?one ?study ?was ?able ?to ?show, ?the ?AIP ?value ?was ?significantly ?higher ?among ?FH ?patients ?with ?CVD ?than ?those ?without ?CVD ?(99). ?1.6.6.4 ?ApoE ?Genotype ?in ?FH ? ?One ?other ?potential ?biomarker ?that ?has ?stimulated ?much ?research ?is ?the ?ApoE ?genotype. ?ApoE ?plays ?an ?important ?role ?in ?lipoprotein ?metabolism ?and ?serves ?as ?a ?ligand ?for ?different ?receptors ?including ?the ?LDL-??R. ?There ?are ?3 ?common ?polymorphisms ?of ?ApoE ?(E2, ?E3, ?and ?E4) ?that ?are ?well ?known ?to ?be ?associated ?with ?different ?LDL-??c ?concentrations ?and ?coronary ?risk ?in ?the ?general ?population. ?In ?fact, ?the ?E4 ?allele ?had ?a ?higher ?coronary ?risk ?in ?the ?general ?population ?than ?E2 ?or ?E3 ?carriers ?(79, ?100). ? ?However, ?the ?relationship ?between ?ApoE ?genotype ?on ?lipid ?values ?and ?coronary ?risk ?in ?FH ?has ?yielded ?conflicting ?results ?and ?does ?not ?appear ?to ?follow ?the ?established ?relationship ?in ?the ?general ?population ?(79, ?100). ? ? ?There ?are ?many ?environmental ?and ?genetic ?risk ?factors ?that ?can ?increase ?the ?susceptibility ?of ? ?FH ?patients ?to ?CVD. ?With ?the ?availability ?of ?effective ?treatments ?identifying ?patients ?who ?possess ?these ?high ?risk ?traits ?and ?treating ?them ?earlier ?and ?more ?aggressively ?can ?help ?improve ?outcomes ?in ?this ?cohort. ?1.7 ?Rationale, ?Working ?Hypothesis, ?and ?Objectives ? ?Accounting ?for ?29% ?of ?all ?deaths, ?CVD ?is ?a ?major ?health ?concern ?in ?Canada ?(2). ?In ?order ?to ?successfully ?implement ?primary ?prevention, ?early ?identification ?of ?the ?individuals ?at ?highest ?risk ?is ?required. ?FH ?is ?the ?most ?common ?genetic ?disease ?associated ?with ?CVD ?and, ?as ?a ?result, ?people ?with ?FH ?are ?automatically ?considered ?36 ?high ?risk ?for ?developing ?this ?condition. ?However, ?the ?clinical ?expression ?of ?FH ?varies ?considerably ?particularly ?with ?regard ?to ?cholesterol ?levels ?and ?the ?age ?of ?onset ?and ?severity ?of ?CAD ?(60). ?The ?variation ?in ?phenotypic ?expression, ?and ?specifically ?the ?occurrence ?of ?CVD ?in ?FH ?is ?affected ?by ?contributions ?of ?additional ?metabolic, ?environmental ?and ?genetic ?risk ?factors, ?acting ?in ?conjunction ?with ?severe ?hypercholesterolemia. ?Treatment ?of ?FH ?with ?lipid ?lowering ?therapy ?has ?proven ?to ?be ?both ?highly ?effective ?and ?cost ?efficient ?(66). ?Despite ?the ?proven ?benefits ?of ?early ?diagnosis ?and ?treatment ?of ?FH, ?only ?a ?minority ?of ?patients ?are ?diagnosed ?and ?treated ?adequately ?and ?the ?majority ?remains ?untreated ?or ?improperly ?treated ?at ?the ?present ?time. ? ?Both ?lay ?people ?and ?health ?professionals ?currently ?lack ?full ?awareness ?of ?hFH, ?its ?diagnostic ?features, ?and ?its ?consequences. ?Moreover, ?standard ?assessment ?tools ?(eg. ?Framingham) ?do ?not ?accurately ?quantify ?risk ?in ?these ?patients. ?Thus, ?a ?better ?means ?of ?identifying ?and ?characterizing ?risk ?in ?these ?patients ?is ?required. ?1.7.1 ?Overall ?Objective ? ?The ?overall ?objective ?of ?my ?thesis ?is ?to ?develop ?a ?better ?means ?of ?stratifying ?risk ?in ?hFH ?patients. ?To ?accomplish ?this, ?I ?will ?identify ?and ?phenotypically ?characterize ?patients ?in ?the ?Healthy ?Heart ?Prevention ?Clinic ?at ?St. ?Paul?s ?Hospital ?with ?FH ?and ?by ?combining ?these ?data ?with ?outcome ?information ?with ?relevant ?databases ?the ?characteristics ?in ?hFH ?patients ?that ?increases ?their ?risk ?of ?developing ?CVD ?will ?be ?determined. ? ?1.7.2 ?Working ?Hypothesis ? ?1. FH ?patients ?who ?have ?developed ?CVD ?differ ?from ?those ?free ?of ?CVD ?by ?specific ?lipid ?and ?non-??lipid ?risk ?factors. ?2. The ?specific ?lipid ?and ?non-??lipid ?risk ?factors ?differ ?in ?FH ?patients ?who ?develop ?CVD ?early ?(men<45, ?women<55 ?with ?evidence ?of ?CVD) ?and ?those ?resistant ?to ?CVD ?patients ?(men>60, ?women>70 ?with ?no ?evidence ?of ?CVD). ?3. These ?risk ?factors ?differ ?between ?men ?and ?women. ?4. These ?risk ?factors ?differ ?between ?ethnic ?groups. ? ?37 ?The ?knowledge ?gained ?from ?this ?research ?will ?provide ?insight ?into ?the ?specific ?type ?of ?FH ?patients ?attending ?the ?Healthy ?Heart ?Prevention ?Clinic ?who ?are ?most ?susceptible ?to ?CVD ?and ?most ?in ?need ?of ?aggressive ?treatment. ? ?1.8 ?Specific ?Aims ? ?My ?working ?hypothesis ?will ?be ?tested ?using ?the ?following ?four ?specific ?aims. ?Specific ?Aim ?1: ?To ?review ?patients ?with ?hFH ?in ?the ?Prevention ?Clinic ?at ?St. ?Paul?s ?Hospital ?Healthy ?Heart ?Program ?and ?establish ?the ?diagnosis ?of ?definite ?FH ?according ?to ?the ?Dutch ?Lipid ?Clinic ?Network ?Criteria. ? ? ?Specific ?Aim ?2: ?To ?record ?hFH ?patients? ?lipid ?levels ?over ?a ?number ?of ?visits ?in ?the ?clinic, ?both ?before ?and ?after ?treatment. ? ?Specific ?Aim ?3: ?To ?record ?other ?major ?risk ?factors ?(age, ?gender, ?smoking, ?hypertension, ?diabetes, ?family ?and/or ?personal ?history ?of ?CVD) ?in ?the ?above ?subjects. ? ?Specific ?Aim ?4: ?To ?assess ?FH ?patients? ?clinical ?outcomes ?(eg. ?CVD, ?death ?from ?CVD), ?particularly ?the ?presence ?or ?absence ?of ?cardiovascular ?disease. ? ? ? ? ? ? ? ? ?38 ?CHAPTER ?2: ?Methods ? ?This ?is ?a ?retrospective ?cohort ?study ?performed ?in ?the ?Healthy ?Heart ?Prevention ?Clinic ?at ?St. ?Paul?s ?Hospital. ?In ?this ?clinic, ?medical ?charts ?are ?kept ?with ?each ?patient?s ?demographic, ?anthropometric, ?laboratory ?and ?diagnostic ?data ?are ?maintained. ?Patients ?included ?in ?the ?study ?were ?18 ?yrs ?or ?older ?and ?diagnosed ?as ??Definite? ?FH ?patients ?based ?upon ?the ?Dutch ?Lipid ?Clinic ?Network ?Criteria ?(Table ?5). ?Each ?patient ?included ?in ?the ?study ?signed ??consent ?for ?research ?form? ?in ?his ?or ?her ?chart ?in ?accordance ?with ?hospital ?and/or ?government ?regulations. ?Patients ?excluded ?from ?the ?study ?were ?those ?aged ?less ?than ?18 ?yrs, ?those ?with ?a ?diagnosis ?of ?homozygous ?FH, ?those ?with ?secondary ?causes ?of ?dyslipidemia, ?including ?hypothyroidism, ?liver ?disease, ?renal ?disease, ?HIV-??induced ?dyslipidemia, ?and ?drug-??induced ?dyslipidemia ?and ?those ?with ?other ?known ?genetic ?dyslipidemias ?such ?as ?Type ?III ?disease. ? ?After ?a ?patient ?was ?determined ?as ?eligible ?for ?the ?study ?a ?detailed ?phenotypic ?characterization ?was ?completed ?using ?a ?designed ?template. ?The ?following ?variables ?were ?recorded: ? ? ?Date ?of ?1st ?admission, ?age, ?gender, ?family ?history, ?ethnicity, ?BMI, ?smoking, ?statin ?intolerance, ?diabetes, ?hypertension, ?pulmonary ?disease, ?lipid ?profile ?including ?Lp(a), ?blood ?glucose ?level, ?AST, ?ALT, ?ALP, ?creatinine, ?CK, ?TSH, ?medications ?used, ?physical ?findings, ?specifically ?presence ?of ?arcus ?cornealis, ?tendon ?xanthomas, ?cardiovascular ?assessment. ?Presence ?or ?absence ?of ?vascular ?disease ?was ?established ?using ?the ?patient ?charts ?which ?has ?records ?on ?all ?cardiac ?procedures ?and ?diagnosis ?of ?patients. ?Thus, ?the ?time, ?data, ?nature ?of ?the ?intervention ?or ?diagnosis ?can ?be ?established ?for ?every ?subject ?in ?our ?database. ?Data ?acquisition ?was ?limited ?to ?the ?patient ?records, ?and ?as ?a ?result ?no ?information ?after ?the ?most ?recent ?visit ?was ?obtained. ?The ?personal ?and ?family ?history ?focused ?on ?any ?cardiovascular ?events/endpoints ?(hard ?and ?soft) ?including ?angina, ?myocardial ?infarction, ?TIA's, ?stroke, ?peripheral ?vascular ?disease, ?or ?aortic ?aneurysm ?and ?aortic ?valve ?disorders. ?Much ?of ?this ?39 ?personal ?history ?was ?determined ?through ?recording ?the ?results ?from ?a ?number ?of ?diagnostic ?tests ?including ?carotid ?ultrasound, ?electrocardiogram, ?exercise ?stress ?test, ?CT, ?coronary ?angiogram ?and ?MIBI. ? ?2.1 ?Details ?on ?Variables ?Recorded ? ?Personal ?Cardiovascular ?Assessment: ?Each ?patient?s ?cardiovascular ?assessment ?was ?twofold ?and ?included ?both ?assessment ?of ?hard ?and ?soft ?endpoints. ?The ?various ?hard ?and ?soft ?endpoints ?were ?assigned ?a ?different ?number ?code ?that ?ranged ?from ?1-??15. ?Hard ?Endpoints: ?The ?hard ?cardiovascular ?endpoints ?were ?considered ?to ?be ?4:MI, ?5: ?CABG, ?6: ?PCTA/ ?Stent, ?7: ?Stroke, ?9: ?Angiogram ?with ?>50% ?occlusion, ?12: ?Carotid ?endarterectomy, ?13: ?Femoral ?popliteal ?bypass, ?14: ?Cardiac ?death, ?15:Aortic ?valve ?replacement ? ?Soft ?Endpoints: ?The ?soft ?cardiovascular ?endpoints ?were ?considered ?to ?be ?1:Angina, ?2: ?Claudication, ?3: ?Plaque ?w/ ?carotid ?ultrasound, ?8: ?TIA, ?9: ?Angiogram ?with ?<50% ?occlusion, ?10: ?Abnormal ?MIBI, ?11: ?Positive ?Stress ?Test ?The ?patient ?was ?considered ?to ?have ?CVD ?if ?they ?had ?evidence ?of ?one ?of ?the ?hard ?endpoints ?or ?had ?a ?positive ?coronary ?angiogram ?with ?occlusion ?greater ?than ?50%. ? ?Family ?History: ?A ?person?s ?family ?history ?was ?recorded ?using ?a ?3 ?-??point ?scale ?(0, ?1 ?or ?2). ?A ?patient?s ?1st ?degree ?relative ?was ?considered ?to ?have ?CVD ?when ?there ?was ?evidence ?of ?MI, ?CABG, ?PCTA/ ?Stent, ?stroke, ?carotid ?endarterectomy, ?femoral ?popliteal ?bypass, ?cardiac ?death, ?or ?aortic ?valve ?replacement. ? ?A ?0 ?indicated ?no ?family ?history ?of ?cardiovascular ?disease, ?a ?1 ?indicated ?evidence ?of ?CVD ?in ?a ?male ?1st ?degree ?relative ?over ?the ?age ?of ?55 ?or ?a ?female ?1st ?degree ?relative ?over ?the ?age ?of ?60 ?and ?a ?2 ?indicated ?evidence ?of ?CVD ?in ?a ?male ?1st ?degree ?relative ?under ?the ?age ?of ?55 ?or ?a ?female ?1st ?degree ?relative ?under ?the ?age ?of ?60. ? ?Ethnicity: ?Each ?patient?s ?ethnicity ?was ?recorded ?by ?looking ?at ?the ?family ?tree ?located ?at ?the ?back ?of ?each ?medical ?chart. ?Ethnicity ?was ?assigned ?a ?different ?number ?code ?that ?ranged ?from ?1-??10 ?and ?were ?1: ?European ?except ?for ?those ?of ?French ?descent, ?2: ?40 ?French ?and ?French ?Canadian, ?3: ?Afrikaner, ?4: ?Lebanese, ?5: ?East ?Asia ?(Chinese, ?Japanese, ?Korean), ?6: ?South ?Asia ?(Indian, ?Pakistani, ?Sri ?Lankan, ?Thai, ?Malaysian, ?Vietnamese, ?Phillipino), ?7: ?West ?Asia ?(Iraqi, ?Israeli, ?Lebanese, ?Turkish, ?Iranian, ?Syrian, ?Palestinian), ?8: ?First ?Nations, ?9: ?Others, ?10: ?Ashkenazi ?Jewish ? ?BMI: ?Each ?patient?s ?height ?and ?weight ?was ?recorded ?as ?seen ?at ?first ?visit ?to ?allow ?for ?calculation ?of ?BMI ?in ?kg/m2. ? ? ?Smoking: ?Each ?patient?s ?smoking ?history ?was ?recorded ?using ?a ?3-??point ?scale ?(0,1 ?or ?2). ?A ?lifelong ?non-??smoker ?was ?assigned ?a ?0, ?a ?current ?smoker ?was ?assigned ?a ?1, ?and ?an ?ex-??smoker ?was ?assigned ?a ?2. ? ?Statin ?Intolerance: ?Each ?patient?s ?ability ?to ?tolerate ?statins ?was ?recorded ?using ?a ?3-??point ?scale ?(0,1 ?or ?2). ?A ?person ?exhibiting ?no ?statin ?intolerance ?was ?assigned ?a ?0, ?a ?person ?who ?has ?shown ?an ?adverse ?reaction ?that ?resulted ?in ?either ?switching ?the ?type ?of ?statin ?or ?lowering ?the ?dosage ?of ?statin ?was ?assigned ?a ?1, ?a ?person ?who ?has ?shown ?adverse ?reactions ?that ?resulted ?in ?complete ?termination ?of ?statin ?use ?was ?assigned ?a ?2. ? ?Carotid ?Ultrasound: ?Each ?patient?s ?carotid ?ultrasound ?results ?were ?recorded ?using ?a ?3-??point ?scale. ?In ?some ?case ?a ?patient ?had ?not ?undergone ?a ?carotid ?ultrasound ?and ?they ?were ?assigned ?an ?NA. ?There ?is ?increased ?CVD ?risk ?signified ?by ?the ?presence ?of ?carotid ?plaque ?of ?any ?size, ?however, ?when ?diameter ?reduction ?is ?greater ?than ?70% ?an ?immediate ?procedure ?may ?be ?necessary ?(101). ?A ?person ?with ?a ?negative ?carotid ?ultrasound ?was ?assigned ?a ?0, ?a ?person ?with ?a ?positive ?carotid ?ultrasound ?with ?diameter ?reduction ?less ?than ?70% ?was ?assigned ?a ?1, ?and ?a ?person ?with ?a ?positive ?carotid ?ultrasound ?with ?diameter ?reduction ?greater ?than ?70% ?was ?assigned ?a ?2. ? ?Electrocardiogram: ?Each ?patient?s ?EKG ?results ?were ?recorded ?using ?a ?3-??point ?scale. ?In ?some ?case ?a ?patient ?had ?not ?undergone ?a ?EKG ?and ?they ?were ?assigned ?an ?NA. ?An ?EKG ?is ?a ?test ?that ?checks ?for ?problems ?with ?the ?electrical ?activity ?of ?your ?heart ?and ?41 ?converts ?the ?electrical ?currents ?of ?the ?heart ?into ?line ?tracings ?on ?paper. ?EKG ?results ?were ?identified ?from ?the ?patient ?medical ?record. ?Physician ?interpretations ?were ?categorized ?as ?normal ?or ?nonspecific, ?abnormal ?but ?not ?ischemic, ?or ?evidence ?of ?ischemia. ? ?A ?person ?with ?a ?normal ?or ?nonspecific ?EKG ?was ?assigned ?a ?0, ?a ?person ?with ?an ?abnormal ?but ?not ?ischemic ?EKG ?was ?assigned ?a ?1, ?and ?a ?person ?having ?evidence ?of ?ischemia ?on ?their ?EKG ?was ?assigned ?a ?2. ? ?Exercise ?Stress ?Test: ?Each ?patient?s ?EST ?results ?were ?recorded ?using ?a ?3-??point ?scale. ?In ?some ?case ?a ?patient ?had ?not ?undergone ?an ?EST ?and ?they ?were ?assigned ?an ?NA. ?An ?EST ?is ?used ?to ?quantify ?the ?amount ?of ?exercise ?related ?stress ?the ?heart ?can ?endure ?before ?developing ?either ?an ?abnormal ?rhythm ?or ?evidence ?of ?ischemia. ?The ?test ?is ?usually ?conducted ?using ?a ?treadmill ?or ?pedaling ?a ?stationary ?bike ?at ?increasing ?levels ?of ?difficulty, ?with ?blood ?pressure ?monitoring ?and ?cardiac ?telemetry. ? ?EST ?results ?were ?identified ?from ?the ?chart ?and ?categorized ?as ?negative ?or ?uninterpretable, ?equivocal, ?or ?positive. ?A ?person ?with ?a ?negative ?or ?uninterpretable ?EST ?was ?assigned ?a ?0, ?a ?person ?with ?an ?equivocal ?EST ?was ?assigned ?a ?1, ?and ?a ?person ?with ?a ?positive ?EST ?was ?assigned ?a ?2. ? ?Coronary ?Angiogram: ?Each ?patient?s ?coronary ?angiogram ?results ?were ?recorded ?using ?a ?3-??point ?scale. ?In ?some ?cases ?a ?patient ?had ?not ?undergone ?a ?coronary ?angiogram ?and ?they ?were ?assigned ?an ?NA. ?CAD ?is ?defined ?as ?more ?than ?50% ?angiographic ?diameter ?stenosis ?in ?one ?or ?more ?of ?the ?epicardial ?coronary ?arteries. ?In ?general, ?stenoses ?less ?than ?50% ?are ?considered ?as ?non?symptom ?generating ?(102). ?A ?person ?with ?a ?negative ?coronary ?angiogram ?was ?assigned ?a ?0, ?a ?person ?with ?a ?positive ?coronary ?angiogram ?with ?diameter ?reduction ?less ?than ?50% ?was ?assigned ?a ?1, ?and ?a ?person ?with ?a ?positive ?coronary ?angiogram ?with ?diameter ?reduction ?greater ?than ?or ?equal ?to ?50% ?was ?assigned ?a ?2. ? ?CT ?Angiogram: ?Each ?patient?s ?CT ?angiogram ?results ?were ?recorded ?using ?a ?3-??point ?scale. ?In ?some ?case ?a ?patient ?had ?not ?undergone ?a ?CT ?angiogram ?and ?they ?were ?assigned ?an ?NA. ?CT ?angiography ?combines ?the ?technology ?of ?a ?conventional ?CT ?scan ?42 ?with ?that ?of ?traditional ?angiography ?to ?create ?detailed ?images ?of ?the ?blood ?vessels ?in ?the ?body. ?Angiography ?involves ?the ?injection ?of ?contrast ?dye ?into ?a ?large ?blood ?vessel, ?in ?the ?case ?of ?CT ?angiography, ?it ?is ?a ?vein ?so ?it ?is ?less ?invasive ?than ?an ?angiogram ?(103). ?A ?person ?with ?a ?negative ?CT ?angiogram ?was ?assigned ?a ?0, ?a ?person ?with ?a ?positive ?CT ?angiogram ?with ?diameter ?reduction ?less ?than ?50% ?was ?assigned ?a ?1, ?and ?a ?person ?with ?a ?positive ?CT ?angiogram ?with ?diameter ?reduction ?greater ?than ?or ?equal ?to ?50% ?was ?assigned ?a ?2. ? ?MIBI: ?Each ?patient?s ?MIBI ?stress ?test ?results ?were ?recorded ?using ?a ?3 ?point ?scale ?(0, ?1, ?or ?2). ? ?In ?some ?cases ?a ?patient ?had ?not ?undergone ?a ?MIBI ?stress ?test ?and ?they ?were ?assigned ?an ?NA. ?A ?MIBI ?stress ?test ?measures ?the ?amount ?of ?blood ?in ?one?s ?myocardium ?at ?rest ?and ?during ?exercise, ?using ?a ?radioactive ?tracer ?such ?as ?Technetium ?(99Tc) ?sestamibi ?to, ?to ?determine ?areas ?of ?the ?myocardium ?that ?may ?not ?be ?receiving ?adequate ?perfusion ?(102). ?The ?results ?of ?the ?patients ?that ?have ?undergone ?a ?MIBI ?stress ?test ?were ?found ?in ?their ?medical ?chart ?where ?a ?physician ?will ?have ?interpreted ?the ?test ?and ?labeled ?it ?as ?normal, ?probably ?abnormal, ?or ?abnormal. ? ?A ?person ?with ?a ?normal ?MIBI ?stress ?test ?was ?assigned ?a ?0, ?a ?person ?with ?a ?probably ?abnormal ?MIBI ?stress ?test ?was ?assigned ?a ?1, ?and ?a ?person ?with ?an ?abnormal ?MIBI ?stress ?test ?was ?assigned ?a ?2. ? ? ?Diabetes ?Mellitus: ?Diabetes ?mellitus ?was ?indicated ?when ?a ?patient ?had ?fasting ?blood ?glucose ?readings ?greater ?than ?7.0 ?mmol/L ?on ?2 ?separate ?occasions. ?Absence ?of ?diabetes ?mellitus ?was ?recorded ?with ?a ?0 ?and ?presence ?of ?diabetes ?mellitus ?with ?a ?1. ? ?Hypertension: ?Hypertension ?was ?indicated ?when ?a ?patient ?had ?a ?systolic ?blood ?pressure ?reading ?greater ?than ?140 ?mmHg ?or ?a ?diastolic ?blood ?pressure ?reading ?greater ?than ?90mmHg ?that ?was ?confirmed ?at ?a ?follow ?up ?appointment. ?Absence ?of ?hypertension ?was ?recorded ?with ?a ?0 ?and ?presence ?of ?hypertension ?with ?a ?1. ?Tendon ?xanthomas: ?Each ?patient?s ?chart ?was ?screened ?for ?evidence ?of ?the ?presence ?of ?tendon ?xanthomas ?in ?the ?physicians ?discourse ?under ?the ??physical ?examination? ?section. ?Tendon ?xanthomas ?can ?be ?in ?a ?number ?of ?locations ?including ?the ?Achilles ?43 ?tendon, ?finger ?extensors, ?plantar ?fascia, ?and ?sometimes ?the ?extensor ?tendons ?of ?the ?toes. ?Absence ?of ?tendon ?xanthomas ?was ?recorded ?with ?a ?0 ?and ?presence ?of ?tendon ?xanthomas ?with ?a ?1. ? ?Arcus ?Cornealis: ?Each ?patient ?chart ?was ?screened ?for ?evidence ?of ?the ?presence ?of ?arcus ?cornealis ?prior ?to ?the ?age ?of ?45 ?in ?the ?physicians ?discourse ?under ?the ??physical ?examination? ?section. ?Absence ?of ?arcus ?cornealis ?was ?recorded ?with ?a ?0 ?and ?presence ?of ?arcus ?cornealis ?with ?a ?1. ? ?Lipid ?Profile: ?Each ?patient ?had ?laboratory ?measurements ?recorded ?at ?a ?number ?of ?different ?clinic ?visits. ?These ?measurements ?were ?recorded ?at ?the ?patients ?first ?ever ?visit ?to ?the ?lipid ?clinic ?as ?well ?as ?their ?5 ?most ?recent ?visits ?to ?the ?clinic. ?The ?criteria ?for ?recording ?these ?measurements ?were ?strictly ?based ?upon ?these ??milestone? ?visits. ?Thus, ?these ?measurements ?were ?not ?necessarily ?at ?identical ?time ?intervals ?across ?each ?of ?the ?different ?patients. ?In ?addition, ?the ?patients ?worst ?seen ?lipid ?results ?were ?recorded ?regardless ?of ?whether ?this ?was ?before ?or ?after ?the ?patient ?had ?attended ?the ?lipid ?clinic. ?The ?worst ?lipid ?test ?was ?defined ?as ?the ?time ?at ?which ?the ?patient?s ?LDL-??C ?level ?was ?at ?its ?highest. ?The ?laboratory ?measurements ?recorded ?were: ?TC ?in ?mmol/L, ?LDL-??C ?in ?mmol/L, ?HDL-??C ?in ?mmol/L, ?triglycerides ?in ?mmol/L, ?TC/HDL-??C ?ratio, ?apo-??B ?in ?g/L, ?Lp(a) ?in ?mg/L, ?fasting ?blood ?glucose ?level ?in ?mmol/L, ?AST ?in ?U/L, ?ALT ?in ?U/L, ?ALP ?in ?U/L, ?creatinine ?in ??mol/L, ?CK ?in ?U/L, ?TSH ?mU/L. ?All ?tests ?were ?performed ?in ?clinical ?laboratories ?using ?well-??established ?methods ?with ?appropriate ?internal ?and ?external ?quality ?controls ?and ?acceptable ?CV?s. ?TC, ?HDL-??C, ?triglycerides ?were ?measured ?by ?standard ?methods. ?LDL-??C ?was ?calculated ?with ?the ?Friedewald ?formula. ? ?Medications: ?In ?addition ?to ?recording ?laboratory ?measurements, ?each ?patient ?had ?the ?class ?of ?medication ?they ?were ?taking ?recorded. ?Specifically, ?the ?4 ?classes ?of ?medications ?of ?interest ?were: ?statins, ?ezitimibe, ?bile ?acid ?binding ?resins ?and ?niacin. ?For ?simplicity, ?neither ?dosage ?nor ?specific ?brand ?or ?formulation ?of ?each ?drug ?was ?recorded. ? ? ?44 ?Mortality: ?In ?addition ?to ?the ?detailed ?phenotypic ?characterization ?carried ?out ?on ?each ?patient ?included ?in ?the ?study, ?which ?included ?information ?on ?cardiovascular ?outcomes, ?data ?on ?mortality ?in ?the ?cohort ?was ?acquired ?from ?British ?Columbia ?(BC) ?Vital ?Statistics. ?The ?data ?obtained ?included ?information ?on ?the ?year ?of ?death, ?the ?age ?at ?which ?the ?person ?died, ?and ?the ?cause ?of ?death ?in ?particular ?whether ?the ?death ?was ?of ?a ?cardiovascular ?nature. ? ?2.2 ?Statistical ?Analysis ?2.2.1 ?Clinical ?Characteristics ? ?All ?statistical ?analyses ?were ?performed ?using ?the ?SPSS ?package ?(Version ?21.0). ?The ?normally ?distributed ?continuous ?characteristics ?including ?TC, ?LDL-??C, ?HDL-??C, ?TC/HDL-??C ?ratio, ?Apo-??B, ?fasting ?blood ?glucose ?level, ?and ?creatinine ?were ?presented ?as ?means ?and ?standard ?deviations. ? ?The ?continuous ?clinical ?characteristics ?with ?skewed ?distributions ?including ?triglycerides ?and ?Lp(a) ?were ?presented ?as ?medians ?and ?interquartile ?ranges. ?Categorical ?variables ?were ?presented ?as ?numbers ?with ?corresponding ?percentages. ?Differences ?in ?clinical ?characteristics ?between ?patients ?with ?and ?without ?CVD ?were ?tested ?with ?chi-??square ?statistics ?for ?categorical ?variables, ?the ?non-??parametric ?test ?Mann ?Whitney ?U ?Test ?for ?Lp(a) ?and ?triglycerides, ?and ?t-??tests ?for ?the ?normally ?distributed ?continuous ?characteristics. ?2.2.2 ?Cox ?proportional ?hazard ?regression ?analysis ? ?Cox ?proportional ?hazard ?regression ?analysis ?was ?used ?to ?assess ?the ?association ?of ?risk ?factors ?to ?hard ?cardiovascular ?outcomes ?in ?univariate ?and ?multivariate ?analyses. ?To ?analyze ?the ?effect ?of ?a ?single ?risk ?factor, ?a ?single ?covariate ?was ?included ?in ?a ?univariate ?Cox ?regression ?model. ?To ?analyze ?the ?effects ?of ?single ?risk ?factors, ?adjusted ?for ?all ?other ?covariates, ?only ?covariates ?that ?were ?significant ?in ?univariate ?analysis ?were ?included ?concomitantly ?in ?a ?multivariate ?Cox ?regression ?model. ?Follow-??up ?started ?at ?birth ?and ?ended ?for ?each ?individual ?at ?the ?date ?of ?the ?first ?occurrence ?of ?established ?CVD. ?Patients ?without ?CVD ?were ?censored ?at ?the ?date ?of ?the ?last ?lipid ?clinic ?visit ?or ?at ?the ?date ?of ?death ?attributable ?to ?other ?causes. ? ?45 ?The ?following ?variables ?were ?entered ?into ?the ?analyses: ?sex ?(male ?or ?female), ?BMI ?(kg/m2), ?smoking ?(ever ?or ?never), ?family ?history ?of ?pre-??mature ?CVD ?(yes ?or ?no), ?diabetes ?(yes ?or ?no), ?hypertension ?(yes ?or ?no), ?LDL-??C ?at ?worst ?visit ?(mmol/L), ?HDL-??C ?at ?worst ?visit(mmol/L), ?TG ?at ?worst ?visit(mmol/L), ? ?and ?Lp(a) ?(high: ?above ?684 ?mg/L ?or ?low: ?below ?684 ?mg/L). ?Due ?to ?the ?retrospective ?nature ?of ?this ?study, ?the ?manner ?in ?which ?subjects ?were ?chosen ?for ?inclusion ?and ?the ?manner ?of ?data ?collection ?a ?number ?of ?different ?groups ?needed ?to ?be ?separately ?analyzed. ?Ideally, ?analysis ?would ?have ?been ?performed ?on ?lipid ?panels ?free ?of ?treatment-??related ?effects. ?However, ?untreated ?lipid ?panels ?were ?not ?available ?in ?all ?subjects ?and ?in ?these ?cases ?a ?patient?s ??worst? ?lipid ?panel ?served ?as ?a ?surrogate. ? ?This ?was ?defined ?as ?the ?lipid ?panel ?at ?which ?LDL-??C ?is ?at ?it?s ?highest ?point ?ever ?recorded ?wherein ?it ?was ?assumed ?that ?there ?was ?no ?prescription ?or ?poor ?compliance. ?In ?this ?cohort ?the ?patients ?with ?established ?CVD ?had ?lower ?levels ?of ?TC ?and ?LDL-??C ?when ?compared ?to ?the ?patients ?without ?CVD.. ?Accordingly ?groups ?and ? ?subgroups ?of ?interest ?were ?analyzed ?in ?several ?different ?ways. ?The ?clinical ?characteristics ?and ?Cox ?proportional ?hazard ?regression ?analysis ?were ?done ?for ?both ?the ?entire ?group ?and ?for ?the ?same ?group ?without ?anyone ?who ?was ?taking ?lipid ?lowering ?treatment ?at ?the ?time ?of ?the ??worst? ?lipid ?panel ?so ?as ?to ?account ?for ?the ?confounding ?effects ?of ?treatment. ? ?2.2.2.1 ?Entire ?Cohort ? ?The ?entire ?cohort ?(446 ?subjects) ?stratified ?by ?presence ?or ?absence ?of ?CVD ?was ?analyzed ?using ?univariate ?and ?multivariate ?Cox ?proportional ?hazard ?regression ?analysis. ?Next, ?the ?same ?cohort ?without ?anyone ?treated ?at ?the ??worst? ?lipid ?panel ?had ?the ?same ?Cox ?proportional ?hazard ?regression ?analysis ?done. ?Further, ?the ?entire ?cohort ?was ?split ?into ?males ?and ?females ?and ?the ?same ?Cox ?proportional ?hazard ?regression ?analyses ?were ?done ?to ?determine ?if ?any ?risk ?factors ?were ?sex ?specific. ? ? ? ? ?46 ?2.2.2.2 ?Subgroup ?Analysis ? ?In ?addition ?to ?comparing ?all ?FH ?patients ?with ?CVD ?to ?all ?FH ?patients ?without ?CVD ?in ?the ?cohort, ?an ?analysis ?was ?carried ?out ?on ??extreme? ?subgroups ?to ?see ?if ?we ?could ?identify ?any ?specific ?risk ?factors ?that ?separated ?the ?most ?high-??risk ?patients ?from ?the ?most ?protected ?FH ?patients. ?These ?subgroups ?were ?termed ??CVD ?susceptible ?FH ?patients? ?and ??CVD ?resistant ?FH ?patients?. ??CVD ?susceptible ?FH ?patients? ?were ?defined ?as ?those ?FH ?patients ?who ?had ?hard ?evidence ?of ?CVD ?prior ?to ?the ?age ?of ?45 ?in ?men ?and ?55 ?in ?women. ??CVD ?resistant ?FH ?patients? ?were ?defined ?as ?those ?FH ?patients ?who ?had ?no ?evidence ?of ?CVD ?(hard ?or ?soft ?endpoints), ?prior ?to ?the ?age ?of ?60 ?in ?men ?and ?70 ?in ?women. ?The ??resistant? ?patients ?had ?no ?evidence ?of ?soft ?endpoints ?including ?angina, ?TIA, ?claudication, ?negative ?carotid ?ultrasound, ?negative ?angiogram, ?normal ?MIBI ?and ?negative ?stress ?test. ?The ?same ?Cox ?proportional ?hazard ?regression ?analysis ?that ?was ?carried ?out ?on ?the ?FH ?patients ?with ?and ?without ?CVD ?were ?also ?carried ?out ?on ?the ?extreme ?subgroups. ? ?2.2.2.3 ?Patients ?with ?Lp(a) ?Data ? ?In ?the ?entire ?446 ?subject ?cohort ?32.0% ?of ?subjects ?had ?no ?Lp(a) ?data ?making ?it ?incompatible ?with ?the ?Cox ?proportional ?hazard ?regression ?analysis. ?As ?a ?result ?another ?subgroup ?containing ?only ?those ?with ?Lp(a) ?data ?was ?created ?to ?analyze ?Lp(a) ?and ?it?s ?relation ?to ? ?CVD ?and ?other ?contributory ?variables. ?As ?with ?the ?other ?groups ?being ?analyzed ?all ?analysis ?was ?also ?carried ?out ?on ?people ?with ?Lp(a) ?data ?but ?no ?lipid ?lowering ?treatment ?at ?the ?time ?of ?the ??worst? ?lipid ?panel. ?2.2.2.4 ?Ethnicities ? ?One ?of ?the ?strengths ?of ?the ?current ?study ?is ?the ?multi-??ethnic ?makeup ?of ?the ?cohort ?with ?10 ?different ?ethnicities ?being ?accounted ?for ?in ?the ?cohort. ?We ?wanted ?to ?determine ?whether ?certain ?ethnicities ?were ?at ?higher ?risk ?for ?developing ?CVD ?and ?to ?explore ?differences ?in ?clinical ?characteristics ?and ?other ?risk ?factors ?between ?the ?ethnicities. ?The ?fact ?that ?there ?were ?10 ?different ?ethnicities, ?some ?with ?only ?a ?few ?subjects ?each ?made ?analysis ?challenging. ?As ?a ?result, ?a ?subgroup ?was ?created ?47 ?containing ?only ?the ?subjects ?belonging ?to ?the ?2 ?most ?prevalent ?ethnicities: ?Europeans ?of ?non-??French ?descent ?and ?East ?Asians ?(Chinese, ?Japanese, ?Korean). ?The ?chi ?square ?test. ?was ?used ?to ?determine ?whether ?one ?of ?these ?ethnicities ?was ?at ?higher ?risk ?of ?developing ?CVD. ?We ?also ?wanted ?to ?know ?whether ?there ?were ?any ?differences ?in ?risk ?factors ?between ?the ?ethnicities. ?Chi-??square ?was ?also ?used ?to ?compare ?the ?various ?categorical ?risk ?factors ?including ?sex, ?smoking, ?family ?history ?of ?pre-??mature ?CVD, ?diabetes, ?and ?hypertension ?between ?these ?two ?groups. ?Likewise, ?continuous ?variables ?such ?as ?age, ?age ?at ?first ?endpoint, ?BMI, ?LDL-??C ?at ?worst ?visit, ?HDL-??C ?at ?worst ?visit, ?triglycerides ?at ?worst ?visit ?and ?Lp(a) ?were ?compared ?using ?the ?t-??test ?or ?Mann ?Whitney ?U ?test ?as ?appropriate. ? ? ?48 ?CHAPTER ?3: ?Results ?3.1 ?Demographics ?and ?clinical ?characteristics ?3.1.1 ?Entire ?Cohort ? ?After ?reviewing ?~4000 ?patient ?charts, ?446 ?patients ?were ?identified ?as ?having ??definite? ?FH ?as ?determined ?by ?the ?DLCNC ?(Table ?5) ?(197 ?males ?and ?249 ?females). ?One ?hundred ?and ?sixteen ?(26%) ?patients ?had ?hard ?evidence ?of ?CVD. ?Patients ?suffered ?either ?from ?coronary ?artery ?disease ?(n= ?96, ?82.8%), ?cerebrovascular ?disease ?(n= ?9, ?7.8%), ?peripheral ?ischaemic ?disease ?(n= ?4, ?3.4%) ?or ?aortic ?valve ?disease ?(n= ?7, ?6.0%). ?Of ?the ?116 ?having ?hard ?evidence ?of ?CVD ?in ?the ?entire ?cohort, ?58.6% ?were ?male. ?The ?mean ?(SD) ?age ?of ?onset ?of ?CVD ?was ?49.5 ?yrs ?(?12.2) ?in ?males ?and ?56.5 ?yrs ?(?16.0) ?in ?females. ?As ?shown ?in ?the ?data ?obtained ?from ?BC ?Vital ?Statistics, ?a ?total ?of ?25 ?patients ?(13 ?men, ?12 ?women) ?died ?in ?between ?the ?yrs ?1985-??2012. ?Thirteen ?of ?these ?patients ?(52.0%) ?died ?of ?a ?cardiovascular ?event ?and ?for ?4 ?of ?these ?it ?was ?the ?first ?evidence ?of ?CVD. ? ?Demographics ?and ?clinical ?characteristics ?of ?all ?FH ?patients ?with ?and ?without ?CVD ?are ?shown ?in ?Table ?6 ?and ?7. ?Patients ?with ?CVD ?were ?older, ?more ?often ?males ?and ?smokers, ?with ?a ?higher ?prevalence ?of ?hypertension, ?diabetes ?mellitus ?and ?family ?history ?of ?premature ?CVD ?than ?patients ?without ?CVD. ?Additionally, ?there ?was ?a ?higher ?mortality ?in ?the ?CVD ?group. ?In ?the ?entire ?cohort ?considering ?the ?worst ?lipid ?profile, ?a ?higher ?TC ?and ?LDL-??C ?level ?was ?observed ?in ?non-??CVD ?patients, ?HDL-??C ?levels ?were ?significantly ?lower ?in ?patients ?with ?CVD ?while ?FBS ?and ?creatinine ?were ?higher ?in ?the ?CVD ?patients, ?although ?significance ?could ?not ?be ?determined ?due ?to ?missing ?data. ?Moreover, ?patients ?with ?CVD ?tended ?to ?have ?higher ?Lp(a) ?(371 ?mg ?L-??1 ?vs. ?283 ?mg ?L-??1). ?In ?the ?cohort ?without ?treatment ?at ?the ?visit ?associated ?with ?the ?worst ?lipid ?profile, ?the ?same ?significant ?differences ?remain ?between ?the ?CVD ?and ?non-??CVD ?groups, ?however, ?LDL-??C ?level ?did ?not ?reach ?significance. ?49 ?Table ?6: ?Characteristics ?of ?the ?entire ?cohort ?of ?familial ?hypercholesterolemia ?patients ?stratified ?by ?presence ?or ?absence ?of ?cardiovascular ?disease; ?% ?missing: ?percentage ?of ?patients ?missing ?data ? ? ?Risk ?Factor ? ?With ?CVD ? Without ?CVD ?P ?Value ?N= ?116 ?% ?Missing ?N=330 ?% ?Missing ?Age ?(yrs) ?Mean ?(SD) ? ? 66.4 ?(?13.3) ? 0.0 ? 57.1(?16.3) ? 0.0 ? <0.001 ?Age ?at ?1st ?CVD ?endpoint ?(yrs) ?Mean ?(SD) ? ? 52.3 ?(?14.2) ? 0.0 ? NA ? NA ? NA ?Age ?at ?1st ?Lipid ?Clinic ?Visit ?(yrs) ?Mean ?(SD) ? ? ? 50.8 ?(?13.1) ? 0.0 ? 43.9 ?(?14.8) ? 0.0 ? <0.001 ?Age ?at ?death ?(yrs) ?Mean ?(SD) ? ? 72.7 ?(?7.4) ? 0.0 ? 72.0 ?(?11.9) ? ? 0.270 ?Sex ?(M/F,%) ? ? 58.6/41.4 ? 0.0 ? 39.1/ ?60.9 ? 0.0 ? <0.001 ?BMI ?(kg/m2) ?Mean ?(SD) ? ? 26.4 ?(?4.5) ? 1.7 ? 26.0 ?(?5.0) ? ?0.9 ? 0.454 ?BMI ??30 ?(kg/ ?m2)(%) ? 21.6 ? 1.7 ? 17.9 ? 0.9 ? 0.384 ?Family ?history ?(%) ? ? ? ? ? ? ?No ?family ?history ? ? ? ? ? ? ? ?Family ?history ?of ?CVD; ?pre-??mature ? ?42.3 ?57.8 ?0.0 ? ? ? ? ? ? ? ? ? ?52.1 ?47.9 ?0.9 ? 0.020 ?Smoking ?(%) ? ?Never ?smoked ?Ever ?Smoked ? ?39.7 ?60.3 ?0.0 ? ?64.2 ?35.8 ?0.0 ? <0.001 ?Statin ?Intolerance ?(%) ? ?No ?Intolerance ? ? ?Partial ?Intolerance ? ?Full ?Intolerance ? ?68.1 ?28.4 ?3.4 ?0.0 ? ?73.6 ?20.8 ?5.6 ?0.0 ? 0.188 ?Diabetes ?(%) ? ? 12.9 ? 0.0 ? 3.3 ? 0.0 ? 0.001 ?Hypertension ?(%) ? ? 34.5 ? 0.0 ? 17.3 ? 0.0 ? 0.001 ?Tendon ?Xanthoma ?(%) ? ? 61.2 ? 0.0 ? 55.2 ? 0.0 ? 0.258 ?Deaths ? ?(%) ? ? 15.5 ? 0.0 ? 2.1 ? 0.0 ? <0.001 ?Cardiovascular ?Cause ?(%) ? ? 72.2 ? 0.0 ? 0.0 ? 0.0 ? <0.001 ?Cancer ?Cause ?(%) ? ? 22.2 ? 0.0 ? 71.4 ? 0.0 ? 0.021 ? ? ? ? ? ? ? ?50 ?Risk ?Factor ?With ?CVD ? Without ?CVD ? P ?Value ?N= ?116 ? % ?Missing ? N=330 ? % ?Missing ? ?Total ?Cholesterol ?(mmol/L) ?Mean ?(SD) ? ? 9.3 ?(2.1) ? 0.0 ? 10.0 ?(2.0) ? 0.0 ? 0.002 ?HDL ?Cholesterol ?(mmol/L) ?Mean ?(SD) ? ? 1.2 ?(0.3) ? 1.7 ? 1.36 ?(0.37) ? 0.9 ? 0.000 ?LDL-??Cholesterol ?(mmol/L) ?Mean ?(SD) ? ? 7.3 ?(2.1) ? 0.9 ? 7.85 ?(1.89) ? 0.0 ? 0.010 ?Triglycerides ?(mmol/L) ?Mean ?(SD) ? ? 1.7 ?(0.8) ? 2.6 ? 1.74 ?(0.97) ? 0.6 ? 0.893 ?Log(TG/HDL) ?Mean ?(SD) ? ? 0.2 ?(0.2) ? 2.6 ? 0.11 ?(0.27) ? 0.6 ? 0.108 ?TC/HDL ?Mean ?(SD) ? ? 8.3 ?(3.5) ? 2.6 ? 7.90 ?(2.81) ? 3.0 ? 0.240 ?Apo-??B ?(g/L) ?Mean ?(SD) ? ? 1.8 ?(0.5) ? 56.0 ? 1.85(0.50) ? 69.7 ? NA** ?Lp(a) ?(mg/L)* ?Median ?(IQR) ? ? 371.3 ?26.0, ?853.7) ?0.0 ? 282.87 ?(106.0, ?626.6) ?0.0 ? 0.121 ?Fasting ?blood ?sugar ?(mmol/L) ?Mean ?(SD) ? ? 5.4 ?(0.6) ? 44.9 ? 5.17 ?(0.70) ? 38.5 ? NA** ?Creatinine ?(?mol/L) ?Mean ?(SD) ? ? 89.9 ?(24.1) ? 73.3 ? 78.3 ?(15.4) ? 79.7 ? NA** ?Statin ?use ?(%) ? ? 20.7 ? 0.0 ? 9.4 ? 0.0 ? 0.001 ?Resin ?(%) ? ? 6.0 ? 0.0 ? 3.0 ? 0.0 ? 0.146 ?Ezetrol ?(%) ? ? 4.3 ? 0.0 ? 1.5 ? 0.0 ? 0.080 ?Niacin ?(%) ? ? 6.9 ? 0.0 ? 2.4 ? 0.0 ? 0.026 ? ?Table ?7: ?Laboratory ?results ?and ?drug ?use ?of ?the ?entire ?cohort ?at ?patient?s ?worst ?visit; ?mmol/L: ?millimoles ?per ?litre; ?g/L: ?grams ?per ?litre; ?mg/L: ?milligrams ?per ?litre; ?IQR: ?interquartile ?range; ??mol/L: ?micromoles ?per ?litre; ?% ?missing: ?percentage ?of ?patients ?missing ?data; ?*: ?Lp(a) ?data ?corresponds ?to ?only ?the ?295 ?patients ?with ?Lp(a) ?data ?available; ?**: ?significance ?cannot ?be ?determined ?when ?more ?than ?25% ?of ?the ?group ?is ?missing ?data ? ? ? ?51 ?3.1.2 ?Male ?and ?female ?FH ?patients ? ?Demographic ?and ?clinical ?characteristics ?of ?all ?male ?and ?female ?FH ?patients ?are ?shown ?in ?Tables ?8 ?and ?9. ?Male ?FH ?patients ?were ?younger, ?had ?larger ?BMI, ?and ?more ?statin ?intolerance ?than ?females. ?At ?worst ?visit, ?a ?lower ?TC ?and ?HDL-??C ?level ?was ?observed ?in ?male ?patients, ?while ?triglycerides ?and ?TC/HDL-??C ?ratio ?were ?significantly ?higher ?in ?male ?FH ?patients. ?Moreover, ?female ?FH ?patient ?tended ?to ?have ?higher ?Lp(a) ?(299 ?mg ?L-??1 ?vs. ?286 ?mg ?L-??1) ?although ?this ?did ?not ?reach ?significance. ? ?Demographic ?and ?clinical ?characteristics ?of ?male ?and ?female ?FH ?patients ?with ?CVD ?are ?shown ?in ?Tables ?10 ?and ?11. ?Males ?with ?CVD ?were ?younger ?and ?had ?their ?first ?CVD ?event ?7 ?yrs ?earlier ?than ?did ?females ?with ?CVD ?(50 ?vs. ?57). ?At ?the ?worst ?visit, ?males ?had ?significantly ?lower ?HDL-??C ?levels ?and ?significantly ?higher ?TC/HDL ?ratio. ?Moreover, ?female ?FH ?patients ?with ?CVD ?had ?significantly ?higher ?median ?Lp(a) ?levels ?(554 ?mg ?L-??1 ?vs. ?303 ?mg ?L-??1). ?3.1.3 ?FH ?patients ?with ?Lp(a) ?data ? ?In ?order ?to ?analyze ?the ?relationship ?between ?Lp(a) ?and ?CVD, ?a ?subgroup ?analysis ?was ?performed ?on ?patients ?for ?whom ?Lp(a) ?results ?were ?available. ?The ?significant ?differences ?between ?the ?CVD ?group ?and ?the ?non-??CVD ?group ?seen ?in ?the ?entire ?cohort ?remained ?in ?the ?Lp(a) ?subgroup. ? ?3.1.3.1 ?Lp(a) ?Distribution ?Statisitics ? ?The ?Lp(a) ?distribution ?of ?the ?cohort ?showed ?positive ?skewing. ?The ?median ?(interquartile ?range) ?was ?294 ?(115-??684) ?mg ?L-??1, ?and ?there ?was ?no ?significant ?difference ?in ?the ?median ?Lp(a) ?concentration ?between ?men ?and ?women ?(P ?= ?0.36, ?Mann?Whitney ?test). ?The ?Lp(a) ?descriptive ?statistics ?are ?summarized ?in ?Table ?12 ?and ?the ?distribution ?shown ?in ?a ?histogram ?(Figure ?5). ?There ?were ?222 ?patients ?whose ?Lp(a) ?concentration ?was ?in ?the ?lowest ?3 ?quartiles ?(<684 ?mg ?L-??1) ?and ?73 ?in ?the ?highes ?(>75th ?percentile, ?>684 ?mg ?L-??1). ?Of ?these, ?58 ?patients ?(26.1%) ?in ?the ?low ?group ?had ?a ?first ?CVD ?event ?in ?the ?follow-??up ?period ?compared ?with ?28 ?(38.4%) ?in ?the ?52 ?high ?group. ?The ?mean ?age ?of ?first ?CVD ?event ?was ?53.9 ?yrs ?(range, ?23?84 ?yrs) ?in ?the ?cohort ?as ?a ?whole: ?54.8 ?yrs ?in ?the ?low ?Lp(a) ?group ?(range, ?23? ?84 ?yrs) ?and ?52.0 ?yrs ?(range, ?32?73 ?yrs) ?in ?the ?high ?Lp(a) ?group ?(P ?= ?0.59). ?Additionally, ?when ?comparing ?the ?FH ?patients ?with ?CVD ?to ?those ?without ?CVD ?there ?is ?a ?trend ?to ?increased ?median ?Lp(a) ?in ?the ?CVD ?group ?that ?does ?not ?reach ?significance ?(341 ?mg ?L-??1 ?vs. ?290 ?mg ?L-??1). ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?53 ?Risk ?Factor ?Males ? Females ?P ?Value ?N= ?197 ? % ?Missing ? N=229 ? % ?Missing ?Age ?(yrs) ?Mean ?(SD) ? ? 56.5(15.0) ? 0.0 ? 61.9 ?(16.5) ? 0.0 ? <0.001 ?Age ?at ?1st ?CVD ?endpoint ?(yrs) ?Mean ?(SD) ? ? 49.5(12.2) ? 0.0 ? 56.5 ?(16.0) ? 0.0 ? 0.013 ?Age ?at ?1st ?Lipid ?Clinic ?Visit ?(yrs) ?Mean ?(SD) ? ? ? 43.2(13.8) ? 0.0 ? 47.7 ?(15.1) ? 0.0 ? 0.001 ?Age ?at ?death ?(yrs) ?Mean ?(SD) ? ? 73.7(8.6) ? 0.0 ? 78.8 ?(9.1) ? 0.0 ? 0.166 ?Sex ?(M/F,%) ? ? NA ? NA ? NA ? NA ? NA ?BMI ?(kg/m2) ?Mean ?(SD) ? ? 26.9 ?(4.3) ? 1.5 ? 25.5 ?(5.1) ? ?0.8 ? 0.002 ?BMI ??30 ?(kg/ ?m2)(%) ? 20.3 ? 1.5 ? 14.9 ? 0.8 ? 0.004 ?Family ?history ?(%) ? ? ? ? ? ? ?No ?family ?history ?Family ?history ?of ?CVD; ?pre-??mature ? ?50.3 ?48.2 ?1.5 ? ?47.4 ?52.2 ? ?0.4 ? 0.471 ?Smoking ?(%) ?Never ?Smoked ?Ever ?Smoked ? ? ? ?52.8 ?47.2 ?0.0 ? ?61.8 ?38.2 ?0.0 ? 0.054 ?Statin ?Intolerance ?(%) ? ?No ?Intolerance ? ? ?Partial ?Intolerance ? ?Full ?Intolerance ? ?77.7 ?19.3 ?3.0 ?0.0 ? ?67.5 ?25.7 ?6.8 ?0.0 ? 0.037 ?Diabetes ?(%) ? ? 5.6 ? 0.0 ? 6.0 ? 0.0 ? 0.844 ?Hypertension ?(%) ? ? 18.3 ? 0.0 ? 24.5 ? 0.0 ? 0.114 ?Tendon ?Xanthoma ?(%) ? ? 55.3 ? 0.0 ? 57.8 ? 0.0 ? 0.596 ?Deaths ? ?(%) ? ? 6.6 ? 0.0 ? 4.8 ? 0.0 ? 0.417 ?Cardiovascular ?Cause ?(%) ? ? 53.8 ? 0.0 ? 50.0 ? 0.0 ? 0.848 ?Cancer ?Cause ?(%) ? ? 30.8 ? 0.0 ? 41.7 ? 0.0 ? 0.571 ? ? ? ? ? ? ? ?Table ?8: ?Characteristics ?of ?the ?entire ?cohort ?of ??definite? ?familial ?hypercholesterolemia ?patients ?stratified ?by ?sex ? ? ? ?54 ?Risk ?Factor ?Males ? Females ?P ?Value ?N= ?197 ? % ?Missing ? N=249 ? % ?Missing ?Total ?Cholesterol ?(mmol/L) ?Mean ?(SD) ? ? 9.56 ?(2.0) ? 0.0 ? 10.0 ?(2.0) ? 0.0 ? 0.037 ?HDL ?Cholesterol ?(mmol/L) ?Mean ?(SD) ? ? 1.2 ?(0.3) ? 1.5 ? 1.4 ?(0.4) ? 0.8 ? <0.001 ?LDL-??Cholesterol ?(mmol/L) ?Mean ?(SD) ? ? 7.6(1.9) ? 0.5 ? 7.8 ?(2.0) ? 0.0 ? 0.150 ?Triglycerides ?(mmol/L) ?Mean ?(SD) ? ? 1.9(0.9) ? 1.5 ? 1.6 ?(0.9) ? 0.8 ? 0.003 ?Log(TG/HDL) ?Mean ?(SD) ? ? 0.2 ?(0.3) ? 1.5 ? 0.1 ?(0.3) ? 0.8 ? 0.057 ?TC/HDL ?Mean ?(SD) ? ? 8.8 ?(3.3) ? 2.5 ? 7.4 ?(2.6) ? 3.2 ? <0.001 ?Apo-??B ?(g/L) ?Mean ?(SD) ? ? 1.8 ?(0.4) ? 68.0 ? 1.9 ?(0.6) ? 64.7 ? NA** ?Lp(a) ?(mg/L)* ?Median ?(IQR) ? ? 286.4 ?(93.0, ?617.8) ?0.0 ? 299.0 ?(130.1, ?713.3) ?32.9 ? 0.357 ?Fasting ?blood ?sugar ?(mmol/L) ?Mean ?(SD) ? ? 5.4 ?(0.7) ? 46.2 ? 5.2(0.7) ? 35.3 ? NA** ?Creatine ?(?mol/L) ?Mean ?(SD) ? ? 93.4 ?(20.6) ? 80.2 ? 74.4 ?(14.0) ? 76.3 ? NA** ?Statin ?use ?(%) ? ? 13.2 ? 0.0 ? 11.6 ? 0.0 ? 0.621 ?Resin ?(%) ? ? 5.6 ? 0.0 ? 2.4 ? 0.0 ? 0.082 ?Ezetrol ?(%) ? ? 2.5 ? 0.0 ? 2.0 ? 0.0 ? 0.707 ?Niacin ?(%) ? ? 3.0 ? 0.0 ? 4.0 ? 0.0 ? 0.584 ? ?Table ?9: ?Laboratory ?Results ?and ?drug ?use ?of ?men ?and ?women ?at ?patient?s ?worst ?visit; ?*: ?Lp(a) ?data ?corresponds ?to ?only ?the ?FH ?patients ?with ?Lp(a) ?data ?available ?**: ?significance ?cannot ?be ?determined ?when ?more ?than ?25% ?of ?the ?group ?is ?missing ?data ? ? ? ?55 ?Risk ?Factor ?Males ?w/ ?CVD ? Females ?w/ ?CVD ?P ?Value ?N= ?68 ?% ?Missing ?N=48 ?% ?Missing ?Age ?(yrs) ?Mean ?(SD) ? ? 63.4 ?(12.8) ? 0.0 ? 70.5 ?(13.1) ? 0.0 ? 0.004 ?Age ?at ?1st ?CVD ?endpoint ?(yrs) ?Mean ?(SD) ? ? 49.5 ?(12.2) ? 0.0 ? 56.5 ?(16.0) ? 0.0 ? 0.013 ?Age ?at ?1st ?Lipid ?Clinic ?Visit ?(yrs) ?Mean ?(SD) ? ? ? 49.3 ?(12.9) ? 0.0 ? 52.9 ?(13.2) ? 0.0 ? 0.148 ?Age ?at ?death ?(yrs) ?Mean ?(SD) ? ? 75.4 ?(7.5) ? 0.0 ? ?81.4 ?(5.8) ? ? 0.074 ?Sex ?(M/F,%) ? ? NA ? NA ? NA ? NA ? NA ?BMI ?(kg/m2) ?Mean ?(SD) ? ? 27.0 ?(3.8) ? 2.9 ? ?25.5 ?(5.1) ? ?0.0 ? 0.089 ?BMI ??30 ?(kg/ ?m2)(%) ? 20.6 ? 2.9 ? 18.8 ? 0.0 ? 0.231 ?Family ?history ?(%) ? ? ? ? ? ? ?No ?family ?history ?Family ?history ?of ?CVD; ?pre-??mature ? ?42.6 ?55.9 ?1.5 ? ?39.6 ?60.4 ? ?0.0 ? 0.692 ?Smoking ?(%) ? ?Never ?smoked ?Ever ?Smoked ? ?41.2 ?58.8 ?0.0 ? ?37.5 ?62.5 ?0.0 ? 0.690 ?Statin ?Intolerance ?(%) ? ?No ?Intolerance ? ? ?Partial ?Intolerance ? ?Full ?Intolerance ? ?42.6 ?55.9 ?98.5 ?0.0 ? ?68.8 ?29.2 ?2.1 ?0.0 ? 0.740 ?Diabetes ?(%) ? ? 8.8 ? 0.0 ? 18.8 ? 0.0 ? 0.117 ?Hypertension ?(%) ? ? 29.4 ? 0.0 ? 41.7 ? 0.0 ? 0.171 ?Tendon ?Xanthoma ?(%) ? ? 54.4 ? 0.0 ? 70.8 ? 0.0 ? 0.074 ?Deaths ? ?(%) ? ? 16.2 ? 0.0 ? 14.6 ? 0.0 ? 0.815 ?Cardiovascular ?Cause ?(%) ? ? 63.6 ? 0.0 ? 85.7 ? 0.0 ? 0.308 ?Cancer ?Cause ?(%) ? ? 18.2 ? 0.0 ? 28.6 ? 0.0 ? 0.605 ? ? ? ? ? ? ? ?Table ?10: ?Characteristics ?of ?the ?entire ?cohort ?of ?familial ?hypercholesterolemia ?patients ?stratified ?by ?sex ?and ?presence ?of ?cardiovascular ?disease ? ? ? ?56 ?Risk ?Factor ?Males ?w/ ?CVD ? Females ?w/ ?CVD ?P ?Value ?N= ?68 ? % ?Missing ? N=48 ? % ?Missing ?Total ?Cholesterol ?(mmol/L) ?Mean ?(SD) ? ? 9.3 ?(2.2) ? 0.0 ? 9.3 ?(2.0) ? 0.0 ? 0.952 ?HDL ?Cholesterol ?(mmol/L) ?Mean ?(SD) ? ? 1.1 ?(0.3) ? 2.9 ? 1.3 ?(0.3) ? 0.0 ? 0.001 ?LDL-??Cholesterol ?(mmol/L) ?Mean ?(SD) ? ? 7.3 ?(2.2) ? 1.5 ? 7.2 ?(2.0) ? 0.0 ? 0.850 ?Triglycerides ?(mmol/L) ?Mean ?(SD) ? ? 1.8 ?(0.9) ? 2.9 ? 1.6 ?(0.7) ? 2.1 ? 0.143 ?Log(TG/HDL) ?Mean ?(SD) ? ? 0.2 ?(0.2) ? 2.9 ? 0.1 ?(0.3) ? 2.1 ? 0.054 ?TC/HDL ?Mean ?(SD) ? ? 8.9 ?(3.7) ? 2.9 ? 7.5 ?(2.9) ? 2.1 ? 0.024 ?Apo-??B ?(g/L) ?Mean ?(SD) ? ? 1.8 ?(0.4) ? 58.8 ? 1.8 ?(0.6) ? 52.1 ? NA** ?Lp(a) ?(mg/L)* ?Median ?(IQR) ? ? 303.2 ?(88.8, ?620.3) ?30.9 ? 553.9 ?(164.0, ?945.8) ?0.0 ? 0.036 ?Fasting ?blood ?sugar ?(mmol/L) ?Mean ?(SD) ? ? 5.5 ?(0.6) ? 45.6 ? 5.3 ?(0.7) ? 43.8 ? NA** ?Creatine ?(?mol/L) ?Mean ?(SD) ? ? 98.6 ?(27.5) ? 76.5 ? 80.5 ?(15.7) ? 68.8 ? NA** ?Statin ?use ?(%) ? ? 19.1 ? 0.0 ? 22.9 ? 0.0 ? 0.619 ?Resin ?(%) ? ? 8.8 ? 0.0 ? 2.1 ? 0.0 ? 0.133 ?Ezetrol ?(%) ? ? 2.9 ? 0.0 ? 6.3 ? 0.0 ? 0.387 ?Niacin ?(%) ? ? 7.4 ? 0.0 ? 6.3 ? 0.0 ? 0.817 ? ?Table ?11: ?Laboratory ?results ?and ?drug ?use ?of ?men ?and ?women ?stratified ?by ?presence ?of ?CVD ?at ?patient?s ?worst ?visit; ?% ?missing: ?percentage ?of ?patients ?missing ?data; ?**: ?significance ?cannot ?be ?determined ?when ?more ?than ?25% ?of ?the ?group ?is ?missing ?data ? ? ? ?57 ? ? ? ? ? ? ?Table ?12: ?Lp(a) ?distribution ?statistics ? ? ? ? ? ? ? ?Range ? 16.5-??2493.0 ?Mean ?(SD) ? 434.1 ?(406.0) ?Median ?for ?entire ?cohort ?(IQR) ? 293.7 ?(114.7, ?683.9) ?Median ?for ?men ?( ?IQR ?) ? 286.4 ?(93.0, ?617.8) ?Median ?for ?Women ?( ?IQR ?) ? 299.0 ?(130.1, ?713.3) ?Figure ?5: ?Lp(a) ?Histogram ? ?58 ?3.1.4 ?FH ?patients ?in ?the ?extreme ?subgroup ? ?In ?the ??extreme? ?subgroup ?comparison, ?51 ?people ?were ?identified ?as ??CVD ?susceptible? ?FH ?patients ?(men<45 ?yrs, ?women<55 ?yrs ?with ?evidence ?of ?CVD) ?and ?45 ?people ?were ?identified ?as ??CVD ?resistant? ?FH ?patients ?(men>60 ?yrs, ?women>70 ?yrs ?with ?no ?evidence ?of ?CVD). ?The ??CVD ?susceptible? ?patients ?suffered ?either ?from ?coronary ?artery ?disease ?(n= ?45, ?88.2%), ?cerebrovascular ?disease ?(n= ?2, ?3.9%), ?peripheral ?ischaemic ?disease ?(n= ?1, ?2.0%) ?or ?aortic ?valve ?disease ?(n= ?3, ?5.9%). ?The ?mean ?age ?of ?onset ?of ?CVD ?in ?the ??CVD ?susceptible? ?group ?was ?39.8 ?(?5.1) ?in ?males ?and ?40.9 ?(?9.2) ?in ?females. ?As ?shown ?in ?the ?data ?obtained ?from ?BC ?Vital ?Statistics, ?a ?total ?of ?5 ?of ?these ?patients ?died ?in ?between ?the ?yrs ?1985-??2012. ? ?Two ?of ?these ?patients ?(40%) ?died ?of ?a ?cardiovascular ?event. ? ?Demographics ?and ?clinical ?characteristics ?of ?CVD ?susceptible ?FH ?patients ?and ?CVD ?resistant ?FH ?patients ?are ?shown ?in ?Table ?13. ?CVD ?susceptible ?FH ?patients ?were ?more ?often ?males ?and ?smokers, ?had ?a ?higher ?prevalence ?of ?diabetes ?mellitus ?and ?family ?history ?of ?premature ?CVD ?than ?CVD ?resistant ?FH ?patients. ?In ?contrast ?to ?the ?analysis ?of ?the ?entire ?cohort ?no ?difference ?was ?seen ?in ?prevalence ?of ?hypertension. ?In ?the ?extreme ?cohort ?at ?worst ?visit, ?the ?only ?difference ?seen ?in ?the ?lipids ?was ?a ?significantly ?lower ?HDL-??C ?level ?in ?the ?CVD ?susceptible ?group. ?Moreover, ?CVD ?susceptible ?FH ?patients ?had ?higher ?median ?Lp(a) ?(742 ?mg ?L-??1 ?vs. ?254 ?mg ?L-??1) ? ?although ?this ?value ?did ?not ?reach ?significance. ? ?3.1.5 ?European ?FH ?patients ? ? ?There ?were ?75 ?European ?patients ?identified ?as ?having ?established ?CVD ?and ?186 ?European ?FH ?patients ?identified ?as ?having ?no ?established ?CVD. ? ?European ?patients ?with ?CVD ?were ?older ?(69 ?vs. ?61), ?were ?more ?often ?males ?(52% ?vs. ?48%) ?and ?smokers ?(67% ?vs. ?40.3%), ?and ?had ?a ?higher ?prevalence ?of ?hypertension ?(39% ?vs. ?21%), ?and ?diabetes ?mellitus ?(12% ?vs. ?2%) ?than ?patients ?without ?CVD. ?Additionally, ?more ?people ?died ?in ?the ?CVD ?group ?(20% ?vs. ?4%). ?In ?the ?entire ?cohort ?at ?worst ?visit, ?a ?higher ?TC ?(10.0mmol/L ?vs. ?9.4 ?mmol/L) ?and ?LDL-??C ?level ?(7.9 ?mmol/L ?vs. ?7.3 ?59 ?mmol/L) ?was ?observed ?in ?non-??CVD ?patients ?and ?HDL-??C ?levels ?were ?significantly ?lower ?(1.2 ?mmol/L ?vs. ?1.4 ?mmol/L) ?in ?patients ?with ?CVD. ?Moreover, ?patients ?with ?CVD ?tended ?to ?have ?higher ?median ?Lp(a) ?(341 ?mg ?L-??1 ?vs. ?236 ?mg ?L-??1) ?although ?this ?value ?did ?not ?reach ?significance. ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?60 ?Risk ?Factor ?CVD ?Susceptible ? CVD ?Resistant ?P ?Value ?N= ?51 ? % ?Missing ? N=45 ?% ?Missing ?Age ?(yrs) ?Mean ?(SD) ? ? 57.1 ?(?10.5) ? 0.0 ? 77.1 ?(8.3) ? 0.0 ? <0.001 ?Age ?at ?1st ?CVD ?endpoint ?(yrs) ?Mean ?(SD) ? ? 40.2 ?(?6.9) ? 0.0 ? NA ? NA ? NA ?Age ?at ?1st ?Lipid ?Clinic ?Visit ?(yrs) ?Mean ?(SD) ? ? ? 42.6 ?(?10.5) ? 0.0 ? 59.8 ?(?7.4) ? 0.0 ? <0.001 ?Age ?at ?death ?(yrs) ?Mean ?(SD) ? ? ? 0.0 ? 79.0(?12.2) ? 0.0 ? 0.550 ?Sex ?(M/F,%) ? ? 60.8/39.2 ? 0.0 ? 35.6/ ?63.4 ? 0.0 ? 0.014 ?Family ?history ?(%) ? ? ? ? ? ? ?No ?Family ?history ? ? ? ?Family ?history ?of ?pre-??mature ?CVD ? ?25.5 ?74.5 ?0.0 ? ?51.1 ?48.9 ?0.0 ? 0.008 ?Smoking ?(%) ?Never ?Smoked ?Ever ?Smoked ? ? ?37.3 ?62.7 ?0.0 ? ?62.2 ?37.8 ?0.0 ? 0.015 ?Diabetes ?(%) ? ? 17.6 ? 0.0 ? 0.0 ? 0.0 ? 0.007 ?Tendon ?Xanthoma ?(%) ? ? 64.7 ? 0.0 ? 57.8 ? 0.0 ? 0.369 ?HDL ?Cholesterol ?(mmol/L) ?Mean ?(SD) ? ? 1.2 ?(0.3) ? 0.0 ? 1.4 ?(0.4) ? 2.2 ? 0.003 ? ? ? ? ? ? ? ?Table ?13: ?Notable ?Characteristics ?of ?familial ?hypercholesterolemia ?patients ?stratified ?by ?CVD ?susceptible ?and ?CVD ?resistant ?patients ? ? ? ?61 ?3.1.6 ?East ?Asian ?FH ?patients ? ? ?There ?were ?14 ?East ?Asian ?patients ?identified ?as ?having ?established ?CVD ?and ?50 ?East ?Asian ?FH ?patients ?identified ?as ?having ?no ?established ?CVD. ?East ?Asian ?patients ?with ?CVD ?were ?older ?(62 ?vs. ?51) ?and ?had ?a ?trend, ?which ?did ?not ?reach ?significance, ?to ?being ?more ?often ?males ?(80% ?vs. ?56%) ?than ?patients ?without ?CVD. ?In ?the ?East ?Asian ?FH ?patients ?at ?worst ?visit, ?a ?significantly ?higher ?TC ?(10.0 ?mmol/L ?vs. ?7.9 ?mmol/L), ?LDL-??C ?(8.0 ?mmol/L ?vs. ?6.0 ?mmol/L), ?triglycerides ?(1.7 ?mmol/L ?vs. ?1.2 ?mmol/L), ?and ?TC/HDL ?level ?(8.8 ?vs. ?6.0) ?was ?observed ?in ?non-??CVD ?patients. ?Moreover, ?patients ?with ?CVD ?tended ?to ?have ?higher ?Lp(a) ?(543 ?mg ?L-??1 ?vs. ?367 ?mg ?L-??1) ?although ?this ?value ?did ?not ?reach ?significance. ?3.2 ?Relation ?between ?CVD ?and ?risk ?factors ? ?3.2.1 ?Entire ?Cohort ? ?Table ?14 ?provides ?the ?relative ?risks ?and ?95% ?confidence ?intervals ?of ?the ?risk ?factors ?in ?univariate ?and ?multivariate ?analyses ?for ?the ?entire ?cohort. ?In ?univariate ?Cox ?survival ?analysis, ?male ?sex, ?smoking, ?premature ?family ?history ?of ?CVD, ?diabetes ?mellitus ?and ?high ?Lp(a) ?all ?significantly ?increased ?CVD ?risk, ?while ?HDL-??C ?at ?worst ?visit ?decreased ?risk ?for ?CVD. ?Additionally, ?in ?a ?paradoxical ?finding ?LDL-??C ?at ?worst ?visit ?appeared ?to ?decrease ?risk ?for ?CVD. ?In ?multivariate ?analysis ?male ?sex, ?smoking, ?family ?history, ?diabetes ?mellitus ?and ?Lp(a) ?were ?significant ?risk ?factors ?for ?CVD ?while ?higher ?levels ?of ?HDL-??C ?significantly ?decreased ?risk ?of ?CVD. ?Compared ?with ?the ?results ?of ?univariate ?analysis, ?LDL-??C ?was ?not ?significant. ?As ?mentioned ?earlier ?the ?fact ?that ?in ?univariate ?analyses ?LDL-??C ?appears ?to ?be ?protective, ?that ?is ?as ?LDL-??C ?level ?rises ?a ?person?s ?risk ?for ?CVD ?is ?decreased ?is ?likely ?due ?to ?the ?confounding ?effects ?of ?treatment. ?Those ?individuals ?in ?the ?CVD ?group ?have ?been ?more ?aggressively ?treated ?and ?as ?a ?result ?on ?the ?whole ?their ?LDL-??C ?are ?lower ?than ?those ?in ?the ?non-??CVD ?group. ?To ?account ?for ?this ?the ?same ?analyses ?were ?performed ?on ?the ?cohort ?without ?anyone ?being ?treated ?at ?the ?worst ?visit. ?Kaplan ?Meier ?curves ?were ?constructed ?for ?the ?statistically ?significant ?variables, ?sex, ?62 ?diabetes ?mellitus, ?family ?history ?of ?pre-??mature ?CVD, ?smoking, ?HDL ?concentration, ?and ?Lp(a) ?concentration ?(Figure ?6). ?Separation ?of ?the ?survival ?curves ?was ?significant ?for ?each ?of ?the ?variables ?(P<0.05, ?log ?rank ?test). ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?63 ? ? ? Univariate ? Multivariate ?(n=446) ? ? RR ? 95% ?CI ? P ?value ? RR ? 95% ?CI ? P ?value ?Diabetes ?(present ?vs. ?absent) ? 3.2 ? 1.9-??5.6 ? <0.001 ? 2.9 ? 1.7-??5.2 ? <0.001 ?Male ?Sex ? 2.9 ? 2.0-??4.2 ? <0.001 ? 2.3 ? 1.5-??3.5 ? <0.001 ?Lp(a) ?(High ?vs. ?Low)* ? 1.7 ? 1.1-??2.7 ? 0.018 ? 2.1 ? 1.3-??3.4 ? 0.002 ?Smoking ?(ever ?vs. ?never) ? 2.1 ? 1.5-??3.1 ? <0.001 ? 1.7 ? 1.1-??2.5 ? 0.009 ?HDL-??C ?(mmol ?L-??1) ? 0.3 ? 0.1-??0.5 ? <0.001 ? 0.4 ? 0.2-??0.8 ? 0.009 ?Family ?History ?Pre-??mature ?CVD ? 1.5 ? 1.0-??2.2 ? 0.038 ? 1.6 ? 1.1-??2.3 ? 0.027 ?Hypertension ?(present ?vs. ?absent) ? 1.2 ? 0.8-??1.7 ? 0.467 ? -?? ? -?? ? -?? ?LDL-??C ?(mmol ?L-??1) ? 0.9 ? 0.8-??1.0 ? 0.039 ? -?? ? -?? ? -?? ?Triglycerides ?(mmol ?L-??1) ? 0.9 ? 0.7-??1.1 ? 0.276 ? -?? ? -?? ? -?? ?BMI ?(kg ?m-??2) ? 1.0 ? 1.0-??1.1 ? 0.230 ? -?? ? -?? ? -?? ? ?Table ?14: ?Relative ?risks ?(RR) ?and ?95% ?confidence ?intervals ?(95% ?CI) ?for ?the ?presence ?of ?a ?risk ?factor ?for ?cardiovascular ?disease ?in ?the ?entire ?cohort; ?*: ?Lp(a) ?analysis ?carried ?out ?on ?the ?295 ?FH ?patients ?with ?Lp(a) ?data ?available ? ? ? ?64 ? A ? B ? Figure ?6: ?Cumulative ?event-??free ?survival ?based ?on ?(A) ?Sex ?(B) ?Diabetes ?Mellitus ? ?(A) ?green ?line, ?males; ?blue ?line, ?females ?(P ?<0.001, ?log-??rank ?test). ?(B) ?green ?line, ?negative ?for ?diabetes; ?blue ?line, ?positive ?for ?diabetes(P ?<0.001, ?log-??rank ?test ? ? ? ?65 ? ? ?C ? ? ?D ? ?Figure ?7: ?Cumulative ?event-??free ?survival ?based ?on ?(C) ?Family ?History ?of ?Pre-??mature ?CVD ?(D) ?Smoking ? ?(C) ?green ?line, ?positive ?family ?history ?of ?premature ?CVD; ?blue ?line, ?negative ?family ?history ?of ?premature ?CVD ?(P ?<0.035, ?log-??rank ?test). ?(D) ?green ?line, ?history ?of ?smoking; ?blue ?line, ?no ?history ?of ?smoking ?(P ?<0.001, ?log-??rank ?test). ? ? ?66 ? ?E ? ?F ? ?Figure ?8: ?Cumulative ?event-??free ?survival ?based ?on ?(E) ?HDL ?concentration ?(F) ?Lp(a) ?concentration ? ?(E) ?green ?line, ?high ?HDL; ?blue ?line, ?low ?HDL(P ?<0.001, ?log-??rank ?test). ?(F) ?green ?line, ?Lp(a) ?>684 ?mg ?L-??1; ?blue ?line, ?Lp(a) ?<684 ?mg ?L-??1 ?(P ?=0.016, ?log-??rank ?test). ? ?67 ?3.2.2 ?Entire ?cohort ?without ?anyone ?treated ?at ?worst ?visit ? ?The ?only ?observed ?difference ?between ?the ?subset ?of ?patients ?who ?were ?untreated ?at ?the ?time ?of ?their ?worst ?lipid ?results and ?the ?remainder ?of ?the ?cohort ?is ?that ?LDL-??C ?is ?not ?a ?significant ?risk ?factor ?in ?univariate ?Cox ?analysis ?and ?smoking ?is ?not ?a ?significant ?risk ?factor ?in ?multivariate ?Cox ?analysis. ?All ?other ?significant ?results ?remain ?the ?same. ? ?3.2.3 ?Male ?cohort ? ?Table ?15 ?provides ?the ?relative ?risks ?and ?95% ?confidence ?intervals ?of ?the ?risk ?factors ?in ?univariate ?and ?multivariate ?analyses ?for ?all ?males. ?In ?univariate ?Cox ?survival ?analysis, ?premature ?family ?history ?of ?CVD ?and ?diabetes ?mellitus ?significantly ?increased ?CVD ?risk, ?while ?LDL-??C ?at ?worst ?visit ?decreased ?risk ?for ?CVD. ?In ?multivariate ?Cox ?hazard ?regression ?analysis ?family ?history ?and ?diabetes ?mellitus ?were ?significant ?risk ?factors ?for ?CVD. ?Compared ?with ?the ?results ?of ?univariate ?analysis ?LDL-??C ?was ?not ?significant. ?3.2.4 ?Female ?cohort ? ?Table ?16 ?provides ?the ?relative ?risks ?and ?95% ?confidence ?intervals ?of ?the ?risk ?factors ?in ?univariate ?and ?multivariate ?analyses ?for ?all ?females. ?In ?univariate ?Cox ?survival ?analysis, ?smoking, ?diabetes ?mellitus, ?and ?high ?Lp(a) ?significantly ?increased ?CVD ?risk, ?while ?higher ?LDL-??C ?and ?HDL-??C ?at ?worst ?visit ?decreased ?risk ?for ?CVD. ?In ?multivariate ?Cox ?survival ?analysis, ?smoking, ?diabetes ?mellitus ?and ?high ?Lp(a) ?were ?significant ?risk ?factors ?for ?CVD ?while ?higher ?levels ?of ?HDL-??C ?and ?LDL-??C ?appeared ?to ?significantly ?decrease ?risk ?of ?CVD. ? ?3.2.5 ?Extreme ?subgroup ? ?Table ?17 ?provides ?the ?relative ?risks ?and ?95% ?confidence ?intervals ?of ?the ?risk ?factors ?in ?univariate ?and ?multivariate ?analyses ?for ?the ?extreme ?cohort ?consisting ?of ?CVD ?susceptible ?and ?CVD ?resistant ?FH ?patients. ?In ?univariate ?Cox ?survival ?analysis, ?male ?sex, ?smoking, ?family ?history ?of ?premature ?CVD ?and ?diabetes ?mellitus ?all ?significantly ?increased ?CVD ?risk, ?while ?HDL-??C ?at ?worst ?visit ?decreased ?risk ?for ?CVD. ?In ?multivariate ?analysis ?male ?sex, ?smoking, ?family ?history, ?and ?diabetes ?mellitus ?were ?68 ?significant ?risk ?factors ?for ?CVD ?while ?higher ?levels ?of ?HDL-??C ?significantly ?decreased ?risk ?for ?CVD. ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?69 ? ? Univariate ? Multivariate ?(n=197) ? ? RR ? 95% ?CI ? P ?value ? RR ? 95% ?CI ? P ?value ?Diabetes ?(present ?vs. ?absent) ? 2.8 ? 1.2-??6.5 ? 0.019 ? 3.2 ? 1.4-??7.6 ? 0.008 ?Family ?History ?Pre-??mature ?CVD ? 1.8 ? 1.1-??2.9 ? 0.017 ? 1.9 ? 1.2-??3.1 ? 0.010 ?HDL-??C ?(mmol ?L-??1) ? 0.4 ? 0.2-??1.1 ? 0.068 ? -?? ? -?? ? -?? ?Smoking ?(ever ?vs. ?never) ? 1.3 ? 0.8-??2.1 ? 0.345 ? -?? ? -?? ? -?? ?BMI ?(kg ?m-??2) ? 1.0 ? 1.0-??1.1 ? 0.623 ? -?? ? -?? ? -?? ?Hypertension ?(present ?vs. ?absent) ? 1.1 ? 0.7-??1.9 ? 0.689 ? -?? ? -?? ? -?? ?Lp(a) ?(high ?vs. ?low)* ? 1.0 ? 0.5-??2.1 ? 0.955 ? -?? ? -?? ? -?? ?Triglycerides ?(mmol ?L-??1) ? 0.9 ? 0.7-??1.1 ? 0.215 ? -?? ? -?? ? -?? ?LDL-??C ?(mmol ?L-??1) ? 1.0 ? 0.9-??1.2 ? 0.969 ? -?? ? -?? ? -?? ? ?Table ?15: ?Relative ?risk ?(RR) ?and ?95% ?confidence ?interval ?(95% ?CI) ?for ?the ?presence ?of ?a ?risk ?factor ?for ?cardiovascular ?disease ?in ?men; ?*: ?Lp(a) ?analysis ?carried ?out ?on ?the ?128 ?male ?FH ?patients ?with ?Lp(a) ?data ?available ? ? ? ?70 ? ? Univariate ? Multivariate ?(n=249) ? ? RR ? 95% ?CI ? P ?value ? RR ? 95% ?CI ? P ?value ?Diabetes ?(present ?vs. ?absent) ? 5.3 ? 2.5-??11.2 ? <0.001 ? 3.3 ? 1.5-??7.1 ? 0.003 ?Lp(a) ?(high ?vs. ?low)* ? 3.3 ? 1.7-??6.2 ? <0.001 ? 2.9 ? 1.5-??5.7 ? 0.002 ?Smoking ?(ever ?vs. ?never) ? 2.9 ? 1.6-??5.2 ? <0.001 ? 2.6 ? 1.4-??4.7 ? 0.002 ?HDL-??C ?(mmol ?L-??1) ? 0.4 ? 0.2-??0.9 ? 0.028 ? 0.3 ? 0.1-??0.8 ? 0.020 ?LDL-??C ?(mmol ?L-??1) ? 0.8 ? 0.7-??1.0 ? 0.041 ? 0.8 ? 0.7-??0.9 ? 0.007 ?Family ?History ?Pre-??mature ?CVD ? 1.4 ? 0.8-??2.6 ? 0.221 ? -?? ? -?? ? -?? ?Hypertension ?(present ?vs. ?absent) ? 1.4 ? 0.8-??2.4 ? 0.314 ? -?? ? -?? ? -?? ?BMI ?(kg ?m-??2) ? 1.0 ? 0.9-??1.1 ? 0.993 ? -?? ? -?? ? -?? ?Triglycerides ?(mmol ?L-??1) ? 0.8 ? 0.5-??1.1 ? 0.160 ? -?? ? -?? ? -?? ? ?Table ?16: ?Relative ?risk ?(RR) ?and ?95% ?confidence ?interval ?(95% ?CI) ?for ?the ?presence ?of ?a ?risk ?factor ?for ?cardiovascular ?disease ?in ?women; ?*: ?Lp(a) ?analysis ?carried ?out ?on ?the ?167 ?female ?FH ?patients ?with ?Lp(a) ?data ?available ? ? ? ?71 ? ? Univariate ? Multivariate ?(n=96) ? ? RR ? 95% ?CI ? P ?value ? RR ? 95% ?CI ? P ?value ?Family ?History ?Pre-??mature ?CVD ? 2.2 ? 1.2-??4.1 ? 0.016 ? 2.3 ? 1.2-??4.5 ? 0.012 ?Diabetes ?(present ?vs. ?absent) ? 3.0 ? 1.5-??6.0 ? 0.002 ? 2.3 ? 1.1-??5.0 ? 0.032 ?Male ?Sex ? 2.1 ? 1.2-??3.7 ? 0.012 ? 2.1 ? 1.2-??4.0 ? 0.016 ?HDL-??C ?(mmol ?L-??1) ? 0.3 ? 0.1-??0.6 ? 0.003 ? 0.3 ? 0.1-??0.8 ? 0.017 ?Smoking ?(ever ?vs. ?never) ? 2.1 ? 1.2-??3.6 ? 0.013 ? 2.0 ? 1.1-??3.5 ? 0.020 ?Lp(a) ?(high ?vs. ?low)* ? 1.5 ? 0.8-??2.8 ? 0.237 ? -?? ? -?? ? -?? ?Hypertension ?(present ?vs. ?absent) ? 0.8 ? 0.4-??1.3 ? 0.332 ? -?? ? -?? ? -?? ?BMI ?(kg ?m-??2) ? 1.0 ? 1.0-??1.1 ? 0.397 ? -?? ? -?? ? -?? ?Triglycerides ?(mmol ?L-??1) ? 0.8 ? 0.6-??1.2 ? 0.243 ? -?? ? -?? ? -?? ?LDL-??C ?(mmol ?L-??1) ? 1.0 ? 0.9-??1.1 ? 0.568 ? -?? ? -?? ? -?? ? ?Table ?17: ?Relative ?risk ?(RR) ?and ?95% ?confidence ?interval ?(95% ?CI) ?for ?the ?presence ?of ?a ?risk ?factor ?for ?cardiovascular ?disease ?in ?the ?extreme ?subgroup; ?Lp(a) ?analysis ?carried ?out ?on ?the ?78 ??extreme? ?FH ?patients ?with ?Lp(a) ?data ?available ? ? ? ? ?72 ?3.2.6 ?Extreme ?subgroup ?without ?anyone ?treated ?at ?the ?worst ?visit ? ?When ?looking ?at ?the ?extreme ?subgroup ?without ?anyone ?treated ?with ?lipid ?lowering ?therapy ?at ?the ?worst ?visit ?the ?sample ?size ?(n=68) ?becomes ?too ?small ?to ?make ?many ?significant ?conclusions. ?In ?univariate ?Cox ?survival ?analysis, ?male ?sex, ?smoking, ?family ?history ?of ?premature ?CVD ?and ?diabetes ?mellitus ?all ?significantly ?increased ?CVD ?risk, ?while ?HDL-??C ?at ?worst ?visit ?decreased ?risk ?for ?CVD. ?In ?multivariate ?Cox ?survival ?analysis, ?male ?sex ?and ?diabetes ?mellitus ?were ?significant ?risk ?factors ?for ?CVD ?while ?higher ?levels ?of ?HDL-??C ?significantly ?decreased ?risk ?of ?CVD. ?Compared ?with ?the ?results ?of ?univariate ?analysis, ?smoking ?and ?family ?history ?of ?premature ?CVD ?were ?not ?significant. ?The ?differences ?from ?the ?entire ?extreme ?subgroup ?are ?likely ?due ?to ?lack ?of ?sufficient ?sample ?size. ?3.2.7 ?CVD ?and ?ethnicity ? ?The ?chi ?square ?tests ?exploring ?whether ?there ?are ?any ?differences ?in ?developing ?CVD ?between ?the ?different ?ethnicities ?showed ?no ?significant ?results. ? ?28.7% ?of ?Europeans ?developed ?CVD ?and ?21.9% ?of ?East ?Asians ?developed ?CVD ?(p=0.48) ?3.2.8 ?Ethnicity ?and ?CVD ?risk ?factors ? ?Table ?18 ?provides ?the ?results ?of ?the ?chi ?square ?tests ?exploring ?differences ?in ?the ?categorical ?CVD ?risk ?factors ?between ?ethnicities. ?The ?only ?risk ?factors ?showing ?significant ?differences ?were ?sex ?and ?smoking. ?Europeans ?had ?a ?significantly ?lower ?prevalence ?of ?males ?and ?higher ?prevalence ?of ?smokers ?than ?East ?Asians. ?Table ?19 ?provides ?the ?results ?of ?t-??tests ?and ?Mann ?Whitney ?U ?tests ?exploring ?the ?differences ?in ?continuous ?CVD ?risk ?factors ?between ?ethnicities. ?Europeans ?had ? ?significantly ?higher ?BMI, ?LDL-??C ?at ?worst ?visit ?and ?TG ?at ?worst ?visit ?than ?East ?Asians. ? ?73 ? ? ? ? ? Ethnicity ? ? European ?(n=75) ?East ?Asian ?(n=15) ?P-?? ?Value ?Sex ?(%) ? 52.0 ? 78.6 ? 0.028 ?Smoking ?(%) ? 66.7 ? 28.6 ? 0.018 ?Family ?history ?of ?pre-??mature ?CVD ?(%) ? 60.8 ? 50.0 ? 0.752 ?Diabetes ?(%) ? 12.0 ? 7.1 ? 0.631 ?Hypertension ?(%) ? 38.7 ? 28.6 ? 0.572 ?Tendon ?Xanthoma ?(%) ? 64.0 ? 78.6 ? 0.281 ?Death ?(%) ? 20.0 ? 0.0 ? 0.185 ? ?Table ?18: ?Comparison ?of ?categorical ?risk ?factors ?between ?ethnicities; ?*: ?significant ?difference ?<0.05 ?between ?2 ?groups ? ? ? ? ? ? ? ?Table ?19: ?Comparison ?of ?continuous ?risk ?factors ?between ?ethnicities; ?*: ?significant ?difference ?<0.05 ?between ?2 ?groups ? ? ? ? Ethnicity ? ? European ?(n=75) ?East ?Asian ?(n=15) ?P-?? ?Value ?Age ?(yrs) ? ? 69.0(?12.0) ? 61.6(?14.2) ? 0.138 ?BMI ?(kg ?m-??2) ?* ? 26.8 ?(?4.5) ? 23.6(?3.6) ? 0.032 ?Age ?at ?first ?endpoint ?(mmol ?L-??1) ? 54.5 ?(?15.1) ? 49.5(?12.4) ? 0.473 ?LDL-??C ?at ?worst ?visit ?(mmol ?L-??1)* ? 7.32(2.08) ? 6.02 ?(1.56) ? 0.044 ?HDL-??C ?at ?worst ?visit ?(mmol ?L-??1) ? 1.24 ?(0.36) ? 1.39 ?(0.25) ? 0.199 ?Triglycerides ?at ?worst ?visit ?(mmol ?L-??1)* ? 1.87 ?(0.79) ? 1.15 ?(0.65) ? 0.007 ?Lp(a) ?(mg/L) ?(median) ? 351.05 ? 543.01 ? 0.342 ?74 ?CHAPTER ?4: ?Discussion ? ?In ?this ?retrospective ?study, ?we ?assessed ?the ?contribution ?of ?risk ?factors ?to ?the ?development ?of ?CVD ?in ?a ?large, ?multi-??ethnic ?cohort ?of ?FH ?patients ?from ?the ?Healthy ?Heart ?Prevention ?Clinic ?at ?St.Paul?s ?Hospital ?to ?identify ?those ?most ?susceptible ?to ?the ?development ?of ?CVD. ?In ?our ?cohort ?the ?CVD ?risk ?factors ?found ?to ?be ?significant, ?in ?decreasing ?order ?of ?importance, ?were ?male ?sex, ?diabetes, ?high ?Lp(a), ?smoking, ?family ?history ?of ?pre-??mature ?CVD, ?and ?low ?HDL-??C. ? ?Of ?note ?is ?that ?both ?LDL-??C ?and ?hypertension, ?well ?known ?risk ?factors ?in ?the ?general ?population, ?were ?not ?independent ?risk ?factors ?in ?our ?study. ? ?In ?contrast ?to ?the ?general ?population ?where ?LDL-??C ?level ?is ?one ?of ?the ?most ?important ?factors ?in ?stratifying ?CVD ?risk, ?in ?the ?FH ?population ?where ?LDL-??C ?level ?is ?uniformly ?elevated ?other ?risk ?factors ?may ?take ?precedence. ?Other ?findings ?of ?particular ?interest ?were ?that ?several ?risk ?factors ?were ?sex ?specific. ?These ?included ?family ?history ?of ?premature ?CVD ?in ?men ?and ?smoking ?history, ?HDL-??C ?level ?and ?Lp(a) ?level ?in ?women. ?An ?important ?aspect ?of ?our ?study ?was ?the ?multi-??ethnic ?nature ?of ?the ?cohort. ?However, ?exploration ?of ?the ?two ?most ?prominent ?ethnicities ?in ?this ?cohort ?(Europeans ?and ?East ?Asians) ?indicated ?no ?significant ?differences ?in ?their ?susceptibility ?to ?develop ?CVD. ?There ?were, ?however, ?several ?differences ?between ?these ?groups ?in ?risk ?factors ?contributing ?to ?the ?development ?of ?CVD ?including ?age, ?sex, ?prevalence ?of ?smokers, ?and ?BMI. ? ?This ?study ?has ?enriched ?the ?study ?of ?FH ?cohorts ?in ?that, ?unlike ?most ?other ?studies ?that ?focus ?on ?one ?particular ?ethnicity ?or ?gene ?mutation, ?it ?has ?encompassed ?multiple ?ethnicities ?and ?gene ?mutations. ?Thus, ?these ?results ?are ?more ?applicable ?to ?the ?type ?of ?FH ?patients ?seen ?in ?lipid ?clinics ?across ?North ?America. ? ?4.1 ?Risk ?Factors ?for ?Development ?of ?CVD ?in ?FH ?Patients ? ?Besides ?age, ?male ?sex ?is ?the ?most ?important ?predictor ?of ?CVD ?risk ?and ?not ?surprisingly, ?it ?was ?found ?to ?be ?a ?significant ?predictor ?of ?CVD ?in ?our ?study, ?as ?it ?has ?been ?in ?all ?other ?studies ?of ?FH ?cohorts. ?In ?our ?study ?the ?relative ?risk ?for ?male ?sex ?was ?2.26 ?(95% ?confidence ?interval ?(CI), ?1.47-??3.48) ?and ?was ?very ?comparable ?to ?other ?studies ?with ?relative ?risks ?ranging ?from ?1.70-??5.64(51, ?60, ?76, ?77, ?79, ?80,82, ?85-??88). ?75 ?While ?smoking ?is ?undoubtedly ?an ?important ?risk ?factor ?of ?CVD, ?its ?role ?in ?FH ?is ?not ?entirely ?clear. ?We ?found ?that ?a ?history ?of ?smoking ?was ?a ?significant, ?independent ?risk ?factor ?of ?CVD ?in ?the ?entire ?cohort ?with ?a ?relative ?risk ?of ?1.68 ?(95% ?CI, ?1.14-??2.49) ?but ?was ?only ?significant ?for ?CVD ?in ?females ?with ?a ?relative ?risk ?of ?2.59 ?(95% ?CI, ?1.42-??4.73). ?Our ?results ?were ?consistent ?with ?many ?other ?FH ?studies ?that ?found ?smoking ?to ?be ?a ?significant ?risk ?factor ?for ?CVD ?with ?odds ?ratios ?ranging ?from ?1.67-??2.71 ?(76, ?82, ?85, ?86). ?However, ?a ?few ?FH ?studies ?found ?either ?no ?effect ?from ?smoking ?(80), ?an ?increased ?but ?non-??significant ?risk ?(51) ?or ?a ?male ?sex ?specific ?effect ?(79). ?It ?can ?be ?hypothesized ?that ?some ?studies ?did ?not ?find ?smoking ?history ?to ?be ?a ?significant ?risk ?factor ?for ?CVD ?because ?they ?had ?smaller ?number ?of ?both ?smokers ?and ?CVD ?events ?and ?thus, ?lacked ?the ?statistical ?power ?(76). ?Additionally, ?the ?different ?ways ?in ?which ?smoking ?history ?was ?recorded ?in ?each ?study ?will ?have ?an ?impact ?on ?the ?results. ?Some ?studies ?only ?considered ?current ?smokers ?in ?their ?analysis ?and ?did ?not ?account ?for ?previous ?smoking ?history ?(77), ?which ?may ?contribute ?to ?the ?lack ?of ?significance. ?Although ?the ?presence ?of ?diabetes ?mellitus ?was ?one ?of ?the ?strongest ?risk ?factors ?for ?CVD ?in ?our ?study ? ?(RR=2.94, ?95% ?CI, ?1.65-??5.23) ?in ?the ?entire ?cohort ?and ?statistical ?significance ?in ?both ?males ?and ?females, ?this ?finding ?has ?not ?been ?reported ?in ?all ?FH ?studies ?(77,80, ?82, ?85). ?A ?similar ?study ?of ?FH ?patients ?found ?the ?presence ?of ?diabetes ?mellitus ?to ?be ?a ?significant ?risk ?factor ?for ?CVD ?(relative ?risk ?=2.19) ?with ?the ?increased ?remnant ?lipoproteins ?caused ?by ?DM ?accelerating ?coronary ?atherosclerosis ?(76). ?Jensen ?et. ?al. ?(76) ?speculate ?that ?some ?studies ?did ?not ?find ?DM ?to ?be ?a ?significant ?risk ?factor ?for ?CVD ?due ?to ?differences ?in ?study ?design ?and ?a ?lack ?of ?statistical ?power. ?Similar ?to ?diabetes, ?hypertension ?as ?a ?risk ?factor ?of ?CVD ?in ?FH ?patients ?is ?not ?universally ?agreed ?upon. ?Some ?studies ?found ?that ?hypertension ?was ?a ?significant ?risk ?factor ?with ?relative ?risks ?ranging ?from ?1.36-??1.82, ?(76, ?77) ?while ?a ?number ?of ?studies ?reported ?that ?hypertension ?was ?not ?a ?significant ?risk ?factor ?(51,80, ?85, ?100) ?or ?that ?it ?was ? ?significant ?in ?females ?only(79). ?Our ?study ?did ?not ?find ?hypertension ?to ?be ?a ?significant ?risk ?factor ?for ?CVD. ?Studies ?finding ?no ?significant ?effect ?of ?hypertension ?to ?CVD ?risk ?may ?be ?confounded ?by ?the ?use ?of ?anti-??hypertensive ?medications, ?which ?are ?76 ?standard ?of ?care. ?Anti-??hypertensive ?medication ?is ?known ?to ?reduce ?risk ?of ?CVD ?and ?as ?a ?result ?may ?have ?weakened ?the ?relative ?risk ?for ?hypertension. ?In ?our ?study, ?anti-??hypertensive ?medication ?was ?not ?recorded ?but ?may ?explain ?our ?findings. Although ?family ?history ?of ?premature ?CVD ?is ?an ?established ?independent ?risk ?factor ?for ?CVD ?and ?atherosclerosis ?in ?the ?general ?population, ?none ?of ?the ?similar ?FH ?cohort ?studies ?have ?explored ?it ?as ?a ?risk ?factor. ?We ?found ?it ?to ?be ?a ?significant ?and ?independent ?risk ?factor ?for ?CVD ?in ?our ?entire ?cohort ?with ?a ?relative ?risk ?of ?1.55 ?(95% ?CI, ?1.05-??2.27) ?but ?interestingly ?it ?was ?significant ?only ?in ?males ?with ?a ?relative ?risk ?of ?1.92 ?(95% ?CI, ?1.17-??3.12). ?It ?is ?likely ?a ?combination ?of ?the ?family?s ?lifestyle ?(diet, ?smoking, ?physical ?activity) ?and ?the ?inherited ?genetic ?predisposition ?that ?contribute ?to ?the ?increased ?risk ?in ?those ?with ?a ?family ?history ?of ?premature ?CVD. ?A ?study ?by ?de ?Jong ?et ?al. ?showed ?that ?family ?history ?is ?important ?in ?FH ?and ?found ?that ?endothelial ?function, ?a ?predictor ?of ?future ?cardiovascular ?events, ?was ?impaired ?in ?children ?with ?FH ?having ?family ?history ?of ?premature ?cardiovascular ?events ?(104). ?HDL-??C ?has ?been ?proven ?to ?be ?a ?strong, ?protective ?factor ?for ?CVD ?in ?our ?entire ?cohort ?with ?a ?relative ?risk ?of ?0.42 ?(95% ?CI, ?0.22-??0.81), ?but ?was ?significant ?only ?in ?females ?with ?a ?relative ?risk ?of ?0.30 ?(95% ?CI, ?0.11-??0.83), ?in ?multivariate ?Cox ?hazard ?regression ?analysis. ? ?Unlike ?some ?other ?lipids, ?FH ?studies ?have ?consistently ?found ?HDL-??C ?to ?be ?a ?strong, ?independent ?factor ?for ?CVD ?with ?relative ?risks ?ranging ?from ?0.39-?? ?0.72 ?(76, ?77, ?79, ?80, ?82, ?86). ?One ?FH ?study ?explored ?HDL ?as ?a ?categorical ?risk ?factor, ?comparing ?individuals ?with ?low ?and ?high ?HDL, ?and ?found ?a ?relative ?risk ?of ?3.92 ?in ?those ?with ?low ?HDL ?(105). ? ?Some ?studies ?have ?found ?HDL-??C ?level ?to ?be ?a ?significant ?independent ?predictor ?of ?risk only ?in ?men ?(79), ?only ?in ?women ?(82), ?or ?in ?both ?sexes ?(76,77, ?80, ?86, ?105). ?In ?fact ?in ?one ?study, ?with ?subjects ?of ?similar ?age, ?gender, ?body ?mass ?index, ?systolic ?and ?diastolic ?blood ?pressure, ?and ?genetic ?factors ?that ?could ?influence ?CVD ?risk, ?low ?HDL-??C ?was ?the ?most ?important ?risk ?factor ?for ?CVD ?with ?a ?relative ?risk ?of ?3.92(105). ?In ?a ?number ?of ?studies ?including ?ours, ?use ?of ?lipid ?lowering ?therapy ?in ?the ?cohort ?could ?have ?artificially ?raised ?HDL-??C ?levels ?and ?diluted ?the ?observed ?association ?to ?risk ?(85). ?However, ?in ?our ?study, ?HDL-??C ?remained ?a ?77 ?significant, ?independent ?risk ?factor ?for ?CVD ?when ?analyzing ?the ?untreated ?cohort. In ?keeping ?with ?a ?number ?of ?other ?FH ?studies, ?LDL-??C ?was ?not ?found ?to ?be ?a ?significant ?risk ?factor ?for ?CVD ?in ?multivariate ?Cox ?hazard ?regression ?analysis ?(51, ?76, ?77, ?79, ?82, ?85). ?Despite ?LDL-??C ?being ?the ?primary ?risk ?factor ?for ?CVD ?in ?FH ?patients ?when ?compared ?to ?the ?general ?population ?most ?FH ?studies ?have ?not ?found ?LDL-??C ?to ?be ?a ?significant ?risk ?factor ?when ?compared ?to ?other ?FH ?patients. ?It ?has ?been ?hypothesized ?that ?this ?is ?due ?to ?the ?fact ?that ?all ?FH ?patients ?have ?high ?LDL-??C ?and ?when ?comparisons ?are ?made ?between ?two ?groups ?of ?people ?with ?similarly ?high ?LDL-??C, ?the ?range ?of ?values ?is ?so ?narrow ?that ?statistical ?power ?is ?insufficient ?to ?observe ?an ?effect ?(51,77). ?The ?diagnosis ?of ?FH ?patients ?in ?this ?study, ?and ?in ?a ?number ?of ?other ?studies ?where ?LDL-??C ?did ?not ?achieve ?significance ?as ?a ?risk ?factor, ?was ?based ?upon ?high ?LDL-??C ?levels. ?This ?further ?narrows ?the ?range ?of ?LDL-??C ?seen. ?Additionally, ?it ?has ?ben ?observed ?that ?patients ?identified ?as ?very ?high ?risk, ?those ?with ?very ?high ?LDL-??C ?or ?with ?established ?CVD, ?are ?being ?much ?more ?aggressively ?treated. ?Elevated ?Lp(a) ?has ?been ?confirmed ?as ?a ?causal ?risk ?factor ?for ?CVD ?in ?the ?general ?population. ?However, ?in ?the ?FH ?population ?the ?findings ?are ?less ?clear. ?A ?number ?of ?earlier ?FH ?studies ?with ?smaller ?numbers ?of ?subjects ?did ?not ?find ?Lp(a) ?to ?be ?a ?significant ?risk ?factor ?for ?CVD ?(89, ?90, ?91, ?92, ?96). ?In ?addition, ?earlier ?studies ?with ?larger ?numbers ?ranging ?from ?198 ?to ?811 ?also ?did ?not ?find ?Lp(a) ?to ?be ?significantly ?correlated ?with ?CVD ?(79, ?80, ?82, ?85, ?86, ?98, ?100). ?However, ?two ?recent ?studies ?exploring ?Lp(a) ?as ?a ?risk ?factor ?for ?CVD ?in ?the ?FH ?population ?both ?found ?strong, ?significant ?relationships ?supporting ?the ?role ?of ?Lp(a) ?as ?a ?risk ?factor ?in ?FH. ?A ?study ?by ?Jansen ?et ?al., ?had ?Lp(a) ?data ?on ?1698 ?FH ?patients ?and ?the ?relative ?risk ?of ?CVD ?for ?Lp(a) ?>300 ?mg/L ?was ?1.50 ?(76). ?A ?study ?by ?Holmes ?et ?al., ?with ?Lp(a) ?data ?on ?388 ?FH ?patients ?concluded ?that ?the ?relative ?risk ?of ?CVD ?for ?subjects ?with ?Lp(a) ?>than ?560 ?mg/L ?was ?2.59. ?The ?results ?of ?our ?study ?are ?in ?accordance ?with ?the ?results ?of ?Jansen ?and ?Holmes. ?We ?had ?Lp(a) ?data ?available ?on ?295 ?FH ?patients ?and ?the ?relative ?risk ?of ?CVD ?for ?Lp(a) ?>684mg/L ?was ?2.11 ?(95% ?CI, ?1.32-??3.40) ?for ?the ?entire ?cohort. ?The ?fact ?that ?the ?relative ?risk ?in ?my ?study ?more ?closely ?mirrors ?that ?seen ?in ?Holmes ?et ?al. ?78 ?study, ?is ?due ?to ?the ?use ?of ?a ?higher ?cut-??point ?and ?the ?similarity ?of ?the ?cohorts, ?both ?coming ?from ?the ?Healthy ?Heart ?Program ?at ?St. ?Paul?s ?Hospital. ?The ?fact ?that ?the ?relative ?risk ?seen ?in ?our ?study ?is ?slightly ?lower ?than ?that ?seen ?in ?Holmes ?et ?al., ?can ?likely ?be ?explained ?by ?the ?differences ?in ?the ?cohort. ?Holmes ?et ?al. ?used ?the ?Simon ?Broome ?criteria ?to ?diagnose ?FH ?patients ?and ?included ??definite?, ??probable? ?and ??possible? ?FH ?patients ?whereas ?we ?chose ?to ?use ?the ?DLCNC ?and ?only ?selected ??definite? ?FH ?patients. ? ?Interestingly, ?in ?our ?study ?median ?Lp(a) ?levels ?between ?female ?and ?male ?FH ?patients ?when ?comparing ?Lp(a) ?values ?within ?our ?total ?FH ?study ?population ?were ?similar ?(299 ?mg ?L-??1 ?vs. ?286 ?mg ?L-??1). ?However, ?when ?comparing ?Lp(a) ?levels ?between ?female ?FH ?patients ?with ?CVD ?to ?male ?FH ?patients ?without ?CVD, ?the ?females ?Lp(a) ?level ?was ?significantly ?higher ?(554 ?mg ?L-??1 ?vs. ?303 ?mg ?L-??1). ?In ?accordance ?with ?this ?finding, ?Lp(a) ?level ?was ?found ?to ?be ?a ?significant ?risk ?factor ?in ?females ?with ?a ?relative ?risk ?of ?2.89 ?(95% ?CI, ?1.47-??5.68) ?but ?not ?in ?males. ?A ?study ?by ?Nenseter ?et ?al. ?(52) ?of ?Lp(a) ?in ?CVD ?resistant ?vs. ?CVD ?susceptible ?patients ?similarly ?found ?that ?Lp(a) ?levels ?were ?more ?important ?in ?women. ?They ?found ?that ?CVD-??susceptible ?women ?had ?significantly ?higher ?levels ?of ?Lp(a) ?compared ?to ?CVD-??resistant ?women, ?and ?CVD-??resistant ?women ?had ?significantly ?lower ?Lp(a) ?levels ?compared ?to ?CVD-??resistant ?men ?(52). ?The ?findings ?of ?our ?study ?and ?those ?by ?Nenseter ?et ?al., ?suggest ?that ?Lp(a) ?is ?a ?much ?more ?important ?risk ?factor ?in ?women. ?Other ?than ?small ?sample ?size, ?another ?reason ?Lp(a) ?did ?not ?reach ?statistical ?significance ?in ?several ?of ?the ?FH ?studies ?could ?be ?due ?to ?the ?absence ?of ? ?appropriate ?analytical ?standards ?for ?Lp(a) ?measurement. ?In ?some ?of ?the ?larger ?studies ?where ?Lp(a) ?levels ?did ?not ?reach ?significance ?as ?a ?risk ?factor, ?the ?method ?used ?to ?measure ?Lp(a) ?is ?isoform-??dependent ?and ?is ?known ?to ?underestimate ?the ?Lp(a) ?concentration ?of ?small ?apolipoprotein(a) ?which ?is ?more ?atherogenic ?and ?known ?to ?be ?elevated ?in ?FH ?patients ?with ?CVD ?(77). ?A ?number ?of ?FH ?studies ?have ?shown ?that ?triglycerides ?are ?not ?a ?significant ?risk ?factor ?for ?CVD ?(76, ?77, ?85). ?Results ?from ?our ?study ?corroborated ?those ?of ?others ?by ?79 ?showing ?that ?triglycerides ?were ?not ?a ?risk ?factor. ?These ?results ?are ?in ?keeping ?with ?the ?fact ?that ?FH ?patients ?do ?not ?usually ?have ?elevated ?triglycerides. ?A ?well-??documented ?finding ?in ?both ?the ?general ?and ?FH ?population ?is ?that ?men ?have ?a ?higher ?prevalence ?of ?CVD ?and ?develop ?it ?earlier ?than ?women. ?This ?held ?true ?in ?our ?cohort ?with ?35% ?of ?men ?developing ?CVD ?compared ?to ?only ?19% ?of ?women. ?Additionally, ?the ?men ?in ?our ?cohort ?developed ?CVD ?at ?an ?average ?age ?of ?50 ?whereas ?the ?women ?in ?our ?cohort ?developed ?CVD ?at ?an ?average ?age ?of ?57. ?The ?finding ?that ?male ?FH ?patients ?developed ?CVD ?on ?average ?7 ?yrs ?earlier ?than ?female ?FH ?patients ?was ?very ?consistent ?across ?other ?FH ?studies ?(76, ?77, ?79, ?80, ?82, ?85). ?The ?difference ?in ?prevalence ?of ?CVD ?can ?likely ?be ?explained ?by ?the ?differences ?in ?a ?number ?of ?risk ?factors. ?Women ?have ?significantly ?lower ?BMI, ?have ?less ?obesity, ?significantly ?higher ?HDL-??C, ?significantly ?lower ?triglycerides ?and ?the ?protective ?sex ?hormone ?estrogen. ?We ?had ?only ?limited ?data ?on ?apo-??B, ?creatinine, ?apoA1 ?and ?CRP ?and ?for ?these ?reasons ?no ?analysis ?was ?undertaken. ?4.2 ?Sex-??specific ?Risk ?Factors ?for ?the ?Development ?of ?CVD ?in ?FH ?Patients ? ?Although ?a ?number ?of ?the ?risk ?factors ?explored ?using ?the ?Cox ?multivariate ?survival ?analysis ?were ?significant ?within ?the ?entire ?cohort, ?of ?particular ?interest ?were ?the ?few ?risk ?factors ?that ?were ?sex ?specific. ?For ?instance, ?family ?history ?of ?pre-??mature ?CVD ?was ?a ?significant ?risk ?factor ?of ?CVD ?in ?males ?with ?a ?relative ?risk ?of ?1.89 ?(95% ?CI, ?1.14-??3.16). ?In ?contrast, ?smoking, ?with ?a ?relative ?risk ?of ?2.75 ?(95% ?CI, ?1.48-??5.12), ?HDL-??C, ?with ?a ?relative ?risk ?of ?0.30 ?(95% ?CI, ?0.11-??0.83) ?and ?Lp(a), ?with ?a ?relative ?risk ?of ?3.29 ?(95% ?CI, ?1.71-??6.33), ?were ?of ?significance ?only ?in ?females. ?These ?results ?suggest ?that ?there ?are ?certain ?risk ?factors ?more ?detrimental ?to ?one ?sex. ? ? ?4.3 ?Ethnicity ?and ?Risk ?Factors ?for ?the ?Development ?of ?CVD ?in ?FH ?Patients ? ?An ?important ?contribution ?of ?the ?present ?study ?is ?that ?it ?is ?one ?of ?the ?few ?FH ?cohort ?studies ?that ?dealt ?with ?an ?ethnically ?or ?genetically ?heterogeneous ?population. ?Other ?FH ?cohort ?studies ?were ?conducted ?on ?homogenous ?Caucasian ?cohorts ?such ?a ?Norwegians ?with ?genetically ?proven ?LDL-??R ?mutations ?(52), ?Dutch ?with ?genetically ?80 ?proven ?LDL-??R ?mutations ?(76, ?77), ?British ?(86), ?and ?Spanish ?with ?genetically-??proven ?LDL-??R ?mutations(82,106). ? ?Our ?cohort ?included ?more ?than ?10 ?different ?ethnicities ?(European, ?French ?Canadian, ?Afrikaner, ?Lebanese, ?East ?Asian, ?South ?Asian, ?West ?Asian, ?First ?Nations, ?Ashkenazi ?Jewish ?and ?Others). ?We ?focused ?analysis ?on ?the ?two ?most ?represented ?ethnicities ?namely ?Europeans ?and ?East ?Asians. ?No ?significant ?differences ?in ?susceptibility ?to ?CVD ?were ?seen ?between ?these ?two ?ethnicities ?with ?28.7% ?of ?Europeans ?and ?21.9% ?of ?East ?Asians ?having ?established ?CVD. ?The ?only ?risk ?factors ?that ?showed ?significant ?differences ?were ?sex, ?smoking, ?age ?and ?BMI. ?Europeans ?were ?significantly ?older, ?had ?a ?significantly ?higher ?BMI, ?had ?a ?significantly ?lower ?prevalence ?of ?males ?and ?a ?significantly ?higher ?prevalence ?of ?smokers ?than ?East ?Asians. ?The ?trend ?towards ?higher ?prevalence ?of ?CVD ?seen ?in ?European ?FH ?patients ?may ?be ?partly ?attributed ?to ?the ?presence ?of ?more ?risk ?factors ?than ?found ?in ?East ?Asians ?including ?age, ?BMI ?and ?smoking. ?To ?date ?no ?other ?FH ?studies ?have ?explored ?the ?difference ?in ?susceptibility ?to ?CVD ?of ?various ?ethnicities. ?4.4 ?Summary ? ?The ?presence ?of ?specific ?lipid ?and ?non-??lipid ?risk ?factors ?can ?identify ?the ?phenotype ?of ?FH ?patient ?most ?susceptible ?to ?the ?development ?of ?CVD. ?The ?type ?of ?patient ?most ?susceptible ?to ?developing ?CVD ?is ?a ?diabetic ?male, ?with ?a ?history ?of ?smoking, ? ?positive ?family ?history ?of ?pre-??mature ?CVD, ?low ?levels ?of ?HDL-??C ?and ?high ?levels ?of ?Lp(a). ?An ?FH ?patient ?presenting ?with ?some ?or ?all ?of ?these ?risk ?factors ?should ?be ?most ?aggressively ?treated. ?The ?most ?noteworthy ?findings ?were ?that ?Lp(a) ?was ?a ?risk ?factor ?only ?in ?women, ?suggesting ?that ?high ?Lp(a) ?is ?more ?detrimental ?in ?women, ?that ?family ?history ?of ?premature ?CVD, ?a ?risk ?factor ?seldom ?explored ?in ?other ?FH ?cohort ?studies, ?was ?significant ?only ?in ?men ?and ?that ?LDL-??C, ?the ?primary ?risk ?factor ?for ?CVD ?when ?compared ?to ?the ?general ?population, ?appeared ?to ?play ?no ?role ?in ?differentiating ?CVD ?susceptibility ?among ?FH ?patients. ?The ?INTERHEART, ?a ?large ?standardized ?case-??control ?study, ?determine ?the ?impact ?of ?modifiable ?risk ?factors ?on ?acute ?myocardial ?infarction ?in ?the ?general ?population. ?The ?risk ?factors ?analyzed ?were ?dyslipidemia, ?cigarette ?smoking, ?diabetes ?mellitus, ?blood ?pressure, ?abdominal ?obesity, ?psychosocial ?factors, ?daily ?consumption ?of ?fruits ?and ?81 ?vegetables, ?regular ?alcohol ?consumption, ?and ?regular ?physical ?activity ?(16). ?According ?to ?the ?results ?of ?the ?study, ?these ?9 ?modifiable ?risk ?factors ?account ?for ?over ?90% ?of ?MI ?cases. ? ?In ?decreasing ?order ?of ?importance ?the ?INTERHEART ?study ?found, ?raised ?ApoB/ApoA1 ?ratio ?(or ?dyslipidemia), ?smoking, ?psychosocial ?factors, ?diabetes, ?history ?of ?hypertension, ?abdominal, ?daily ?consumption ?of ?fruits ?and ?vegetables, ?regular ?physical ?activity ?and ?regular ?alcohol ?consumption ?to ?be ?significant ?independent ?risk ?factors ?of ?MI ?(16). ?Of ?interest ?the ?risk ?factors ?of ?dyslipidemia, ?smoking, ?hypertension, ?and ?diabetes ?in ?the ?INTERHEART ?cohort ?obtained ?from ?the ?general ?population ?overlap ?substantially ?with ?our ?analysis ?of ?an ?FH ?cohort. ?The ?most ?notable ?differences ?between ?our ?FH ?cohort ?and ?the ?INTERHEART ?cohort ?were ?that ?LDL-??C ?(we ?included ?no ?analysis ?on ?apoB/apoA1 ?ratio) ?and ?hypertension ?were ?not ?independent ?predictors ?of ?risk ?in ?our ?cohort ?but ?were ?for ?INTERHEART. ?Furthermore, ?in ?our ?cohort ?diabetes ?was ?a ?more ?significant ?risk ?factor ?than ?was ?smoking. ?This ?comparison ?of ?risk ?factors ?in ?an ?FH ?cohort ?and ?a ?population ?based ?cohort ?indicate ?that, ?although ?there ?are ?obvious ?commonalities, ?there ?are ?likewise, ?important ?differences. ?4.5 ?Conclusions ? ?In ?conclusion, ?we ?have ?performed ?a ?retrospective ?cohort ?study ?on ??Definite? ?FH ?patients ?to ?evaluate ?the ?impact ?of ?a ?number ?of ?factors ?on ?CVD ?risk. ?An ?important ?distinction ?and ?contribution ?of ?our ?study ?is ?that ?it ?studied ?an ?ethnically ?heterogeneous ?population ?that ?made ?it ?more ?widely ?applicable ?to ?the ?lipid ?clinic ?population ?seen ?across ?North ?America. ? ?In ?our ?ethnically ?diverse ?cohort ?the ?significant ?and ?independent ?risk ?factors ?for ?CVD ?in ?decreasing ?order ?of ?importance ?were, ?male ?sex, ?diabetes, ?high ?Lp(a), ?smoking, ?family ?history ?of ?pre-??mature ?CVD, ?and ?low ?HDL-??C ?in ?both ?the ?entire ?group ?as ?well ?as ?in ?the ?extreme ?subgroup. ?LDL-??C ?and ?hypertension ?were ?not ?important ?risk ?factors ?for ?CVD ?in ?this ?FH ?cohort, ?despite ?being ?important ?in ?the ?general ?population. ?Of ?importance ?were ?the ?findings ?that ?Lp(a), ?HDL-??C ?and ?smoking ?were ?significant ?risk ?factors ?in ?women ?and ?family ?history ?of ?pre-??mature ?CVD ?was ?a ?significant ?risk ?factor ?only ?in ?men. ?Overall, ?the ?results ?of ?this ?study ?supported ?and ?agreed ?with ?the ?majority ?of ?other ?studies ?evaluating ?the ?82 ?risk ?factors ?for ?CVD ?among ?FH ?patients. ?It ?can ?be ?concluded ?that ?FH ?patients ?referred ?to ?a ?North ?American ?lipid ?clinic ?and ?presenting ?with ?one ?or ?more ?of ?the ?following ?risk ?factors ?being ?male, ?having ?diabetes, ?having ?a ?high ?Lp(a), ?having ?a ?smoking ?history, ?having ?a ?family ?history ?of ?pre-??mature ?CVD, ?and/or ?having ?a ?low ?HDL-??C ?should ?be ?treated ?early ?and ?most ?aggressively ?treated ?as ?they ?are ?at ?the ?highest ?risk ?for ?developing ?CVD. ?4.6 ?Methodological ?Considerations ? ?The ?primary ?strengths ?associated ?with ?the ?present ?study ?compared ?to ?other ?similar ?retrospective ?studies ?are ?the ?heterogeneous ?nature ?of ?the ?cohort ?and ?the ?objective ?definition ?used ?to ?define ?CVD ?endpoints. ?The ?majority ?of ?studies ?have ?examined ?at ?ethnically ?homogeneous ?populations ?whereas ?this ?study, ?analyzing ?patients ?at ?the ?Health ?Heart ?Prevention ?Clinic, ?focused ?on ?an ?ethnically ?heterogeneous ?population ?of ?FH ?patients. ?Other ?FH ?studies ?often ?examined ?risk ?factors ?in ?a ?cohort ?containing ?only ?one ?type ?of ?gene ?mutation ?whereas, ?although ?genetic ?information ?was ?unavailable ?to ?us ?for ?our ?study, ?it ?can ?be ?expected ?that ?there ?will ?be ?a ?variety ?of ?mutations ?contained ?within ?the ?cohort. ?This ?is ?important ?because ?instead ?of ?only ?being ?applicable ?to ?a ?subset ?of ?FH ?patients ?the ?findings ?can ?be ?extrapolated ?to ?a ?more ?generalized ?and ?diverse ?FH ?population. ?Our ?study ?chose ?to ?use ?CVD ?endpoints ?that ?were ?unambiguous ?such ?as ?MI, ?CABG, ?PCTA/ ?Stent, ?stroke, ?carotid ?endartarectomy, ?femoral-??popliteal ?bypass, ?cardiac ?death, ?aortic ?valve ?replacement ?and ?positive ?coronary ?angiogram ?with ?greater ?than ?50% ?occlusion. ?We ?wanted ?to ?avoid ?any ?endpoints ?that ?might ?be ?questionable ?such ?as ?angina, ?TIA, ?nuclear ?medicine ?tests, ?and ?exercise ?stress ?tests. ?Although ?this ?certainly ?limited ?the ?number ?of ?subjects ?defined ?as ?having ?CVD, ?it ?makes ?the ?results ?more ?meaningful. ?The ?present ?study ?has ?a ?number ?of ?limitations ?largely ?due ?to ?its ?retrospective ?nature. ? ?The ?collection ?of ?data ?was ?performed ?using ?each ?patient?s ?medical ?record. ?Thus, ?there ?was ?great ?reliance ?upon ?the ?accuracy ?of ?the ?physician?s ?written ?record. ?Another ?limitation ?was ?that ?certain ?information ?was ?impossible ?to ?ascertain ?from ?a ?patient?s ?medical ?record ?retrospectively. ?Patient ?information ?that ?would ?have ?been ?interesting ?to ?obtain ?but ?wasn?t ?available ?included ?exercise ?participation, ?diet, ?83 ?detailed ?blood ?pressure ?and ?genetic ?information. ?Other ?FH ?studies ?recorded ?lipid ?levels ?in ?patients ?who ?were ?not ?using ?lipid ?lowering ?therapy ?for ?a ?period ?of ?time ?whereas, ?due ?to ?the ?retrospective ?nature ?of ?data ?collection, ?we ?recorded ?lipid ?values ?at ?a ?patient?s ??worst? ?visit ?which ?was ?the ?only ?representation ?of ?off ?treatment ?values. ?The ?patients ?in ?the ?CVD ?group, ?were ?being ?more ?aggressively ?treated, ?thus, ?confounding ?the ?lipid ?values ?we ?recorded. ?Due ?to ?this, ?the ?non-??CVD ?group ?had ?a ?less ?optimal ?lipid ?panel ?than ?the ?CVD ?group. ?Furthermore, ?there ?were ?a ?number ?of ?variables ?that ?we ?did ?collect ?that ?were ?available ?in ?some ?but ?not ?all ?patients ?resulting ?in ?a ?lot ?of ?missing ?data ?fields. ?These ?variables ?included ?many ?of ?the ?diagnostic ?tests ?(carotid ?ultrasound, ?exercise ?stress ?test, ?MIBI, ?coronary ?angiogram, ?EKG ?and ?coronary ?CT), ?apoB, ?apoA1, ?creatinine, ?and ?CRP. ? ?In ?the ?cases ?of ?apoB, ?apoA1, ?creatinine, ?and ?CRP ?we ?had ?hoped ?to ?analyze ?them ?as ?risk ?factors ?in ?uni ?and ?multivariate ?Cox ?hazard ?regression ?analysis ?but ?the ?amount ?of ?missing ?information ?was ?too ?high ?to ?obtain ?meaningful ?results. ?There ?was ?also ?a ?recruitment ?bias ?present ?in ?this ?study ?as ?a ?result ?of ?the ?manner ?we ?chose ?to ?diagnose ?patients ?with ?FH. ?Genetic ?information/ ?diagnosis ?was ?unavailable ?on ?most ?patients ?and ?as ?a ?result ?we ?used ?clinical ?criteria ?to ?diagnose ?FH. ?We ?limited ?our ?cohort ?to ?people ?who ?were ?identified ?as ??Definite ?FH? ?based ?upon ?the ?DLCNC. ?This ?resulted ?in ?a ?specific ?type ?of ?FH ?patient ?(very ?high ?LDL-??C, ?tendon ?xanthomas ?and ?arcus ?cornealis) ?that ?may ?not ?be ?indicative ?of ?the ?FH ?population ?as ?a ?whole. ? ?Additionally, ?the ?cohort ?of ?patients ?analyzed ?consisted ?solely ?of ?those ?who ?were ?referred ?to ?the ?lipid ?clinic ?and ?may ?not ?be ?representative ?of ?the ?entire ?cohort ?of ?FH ?patients. ?4.7 ?Future ?Directions ? ?As ?mentioned, ?the ?fact ?that ?our ?cohort ?was ?ethnically ?diverse ?and ?contained ?FH ?patients ?with ?a ?multitude ?of ?different ?gene ?mutations ?was ?a ?strength ?of ?our ?study. ?However, ?we ?did ?not ?have ?access ?to ?any ?of ?the ?genetic ?information ?on ?these ?patients ?and ?genotyping ?the ?cohort ?and ?determining ?the ?specific ?gene ?mutations ?could ?be ?explored ?in ?the ?future. ?Although ?we ?had ?data ?on ?FH ?patients ?of ?10 ?ethnicities, ?some ?of ?the ?groups ?were ?very ?small. ?In ?the ?future ?acquiring ?information ?on ?FH ?patients ?of ?specific ?ethnicities ?would ?be ?of ?value. ?84 ?Based ?upon ?the ?results ?seen ?in ?Rader?s ?study ?on ?cholesterol ?efflux ?capacity ?and ?CAD, ?it ?would ?be ?of ?interest ?to ?determine ?the ?effect ?of ?cholesterol ?efflux ?capacity ?on ?CAD ?in ?FH ?patients. ?A ?recently ?published ?study, ?found ?that ?the ?reverse ?cholesterol ?transport ?(RCT) ?pathway ?is ?defective ?in ?FH ?patients ?and ?contributes ?to ?the ?development ?of ?CVD ?in ?this ?cohort. ?Cellular ?free ?cholesterol ?efflux ?capacity, ?CETP-??mediated ?cholesteryl ?ester ?(CE) ?transfer ?from ?HDL ?to ?apolipoprotein ?B?containing ?lipoproteins ?and ?hepatic ?HDL-??CE ?uptake ?(107) ?were ?found ?to ?be ?defective ?and ?thus ?may ?contribute ?to ?the ?atherogenicity ?seen ?in ?FH ?patients. ?Of ?particular, ?note ?is ?that ?cellular ?free ?cholesterol ?efflux ?capacity ?was ?significantly ?lower ?in ?FH ?patients ?than ?in ?normal ?controls ?and ?that ?there ?was ?a ?significant ?inverse ?relationship ?between ?cellular ?free ?cholesterol ?efflux ?capacity ?and ?carotid ?intima ?media ?thickness ?(107). ? ? ? ?Cholesterol ?associated ?with ?HDL ?can ?be ?taken ?up ?by ?either ?interaction ?with ?hepatic ?receptors ?or ?through ?transferring ?CE ?content ?of ?HDL ?particles ?to ?apo-??B ?containing ?lipoproteins ?through ?the ?action ?of ?CETP ?which ?can ?then ?be ?taken ?up ?by ?hepatic ?LDL-??R ?(108). ?It ?has ?been ?demonstrated ?that ?this ?process ?accounts ?for ?50% ?OF ?RCT ?in ?humans ?(107). ? ?The ?study ?by ?Guerin ?et ?al., ?showed ?that ?uptake ?by ?CETP-??mediated ?CE ?transfer ?from ?HDL ?to ?apolipoprotein ?B?containing ?lipoproteins ?was ?increased ?in ?FH ?patients ?meaning ?that ?there ?was ?more ?cholesterol ?in ?LDL ?particles. ? ?Additionally, ?they ?showed ?that ?hepatic ?HDL-??CE ?uptake ?was ?diminished. ?Both ?of ?these ?findings ?are ?consistent ?with ?an ?increased ?plasma ?atherogenecity ?(106). ?Our ?pilot ?study ?followed ?Rader?s ?method ?and ?focused ?specifically ?on ?the ?cholesterol ?efflux ?capacity ?of ?whole ?plasma ?and ?it?s ?relation ?to ?CVD ?in ?FH ?patients. ?The ?study ?by ?Guerin ?et ?al. ?only ?showed ?an ?inverse ?relationship ?between ?cellular ?free ?cholesterol ?efflux ?capacity ?and ?carotid ?intima ?media ?thickness ?whereas ?the ?aim ?of ?our ?future ?study ?is ?to ?prove ?that ?a ?significant ?inverse ?relationship ?exists ?between ?diminished ?cholesterol ?efflux ?capacity ?and ?objective ?evidence ?of ?CVD ?through ?more ?strict ?criteria. ?In ?addition, ?while ?Guerin ?et ?al.?s ?study ?had ?12 ?FH ?patients ?and ?12 ?normal ?controls ?our ?study ?will ?have ?much ?larger ?numbers ?in ?each ?of ?our ?experimental ?groups, ?which ?include ?normal ?controls, ?FH ?patients ?with ?CVD, ?and ?risk ?factor ?matched ?FH ?patients ?without ?CVD. ? ?85 ?Works ?Cited ?1. Wilson ?P. ?Overview ?of ?the ?risk ?equivalents ?and ?established ?risk ?factors ?for ?cardiovascular ?disease. ?Available ?at: ?www.uptodate.com/contents/overview-??of-??the-??risk-??equivalents-??and-??established-??risk-??factors-??for-??cardiovascular-??disease. ?Accessed ?January, ?16th, ?2013. ? ?2. Heart ?and ?Stroke ?Foundation ?of ?Canada-?? ?Statistics. ?Available ?at: ?http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm. ?Accessed ?Novemeber, ?20th, ?2012. ? ?3. Centers ?for ?Disease ?Control ?and ?Prevention: ?Fast ?Stats ?Heart ?Disease. ?Available ?at: ?http://www.cdc.gov/nchs/fastats/heart.htm. ?Accessed ?November, ?20th, ?2012. ? ?4. Public ?Health ?Agency ?of ?Canada: ?Six ?Types ?of ?Cardiovascular ?Disease. ?Available ?at: ?http://www.phac-??aspc.gc.ca/cd-??mc/cvd-??mcv/cvd-??mcv-??eng.php. ?Accessed ?November, ?20th, ?2012. ? ?5. Insull ?W. ?The ?Pathology ?of ?Atherosclerosis: ?Plaque ?Development ?and ?Plaque ?Responses ?to ?Medical ?Treatment. ?Am ?J ?Med. ?2009;122:S3-??S14. ? ?6. Fuster ?V, ?Moreno ?P, ?Fayad ?Z, ?Corti ?R, ?Badimon ?J. ?Atherothrombosis ?and ?high-??risk ?plaque: ?part ?I: ?evolving ?concepts. ?J ?Am ?Coll ?Cardiol. ?2005;46:937-??954. ? ?7. Rubin ?E, ?Gorstein ?F, ?Rubin ?R, ?Schwarting ?R, ?Strayer ?D. ?Atherosclerosis. ?In: ?Rubin ?E, ?ed. ?Rubin's ?Pathology: ?Clinicopathologic ?Foundations ?of ?Medicine. ?4th ?Edition ?ed. ?Baltimore, ?Maryland: ?Lippincott, ?Williams ?and ?Wilkins; ?2005:483-??498. ? ?8. Skalen ?K, ?Gustafsson ?M, ?Rydberg ?E, ?et ?al. ?Subendothelial ?retention ?of ?atherogenic ?lipoproteins ?in ?early ?atherosclerosis. ?. ?Nature. ?2002;417:750-??754. ? ?9. Tesfamariam ?B, ?DeFelice ?AF. ?Endothelial ?injury ?in ?the ?initiation ?and ?progression ?of ?vascular ?disorders. ?Vascul ?Pharmacol. ?2007;46(4):229-??37. ?Epub ?2006 ?Dec ?6. ?86 ?10. Taraboanta ?C. ?Impact ?of ?Family ?History ?of ?Premature ?Coronary ?Artery ?Disease ?on ?Carotid ?Ultrasound ?and ?Coronary ?Calcium ?Findings. ?[MSc.]. ?Circle: ?University ?of ?British ?Columbia; ?2008. ?11. Singh ?R, ?Mengi ?S, ?Xu ?Y, ?Arneja ?A, ?Dhalla ?N. ?Pathogenesis ?of ?atherosclerosis: ?A ?multifactorial ?process. ?Exp ?Clin ?Cardiol. ?2002;7:40-??53. ? ?Niki ?E. ?Do ?free ?radicals ?play ?causal ?role ?in ?atherosclerosis? ?Low ?density ?lipoprotein ?oxidation ?and ?vitamin ?E ?revisited. ?J ?Clin ?Biochem ?Nutr. ?2011;48:3-??7. ? ?12. Stary ?H, ?Chandler ?A, ?Glagov ?S, ?et ?al. ?A ?definition ?of ?initial, ?fatty ?streak, ?and ?intermediate ?lesions ?of ?atherosclerosis. ?Circ. ?1994;89:2462-??2478. ? ?13. Katz ?SS, ?Shipley ?GG, ?Small ?DM. ?Physical ?chemistry ?of ?the ?lipids ?of ?human ?atherosclerotic ?lesions. ?Demonstration ?of ?a ?lesion ?intermediate ?between ?fatty ?streaks ?and ?advanced ?plaques. ?J ?Clin ?Invest. ?1976;58(1):200-??11 ?14. Stary ?H, ?Chandler ?A, ?Glagov ?S, ?et ?al. ?A ?definition ?of ?advanced ?types ?of ?atherosclerotic ?lesions ?and ?a ?histological ?classification ?of ?atherosclerosis. ?Circ. ?1995;92:1355-??1374. ? ?15. Yusuf ?S, ?Hawken ?S, ?Ounpuu ?S, ?et ?al. ?Effect ?of ?potentially ?modifiable ?risk ?factors ?associated ?with ?myocardial ?infarction ?in ?52 ?countries ?(the ?INTERHEART ?study): ?case-??control ?study. ?Lancet. ?2004;364:937-??952. ?16. Conlan ?MG, ?Folsom ?AR, ?Finch ?A, ?et ?al. ?Antithrombin ?III: ?associations ?with ?age, ?race, ?sex ?and ?cardiovascular ?disease ?risk ?factors. ?The ?Atherosclerosis ?Risk ?in ?Communities ?(ARIC) ?Study ?Investigators. ?Thromb ?Haemost. ?1994;72(4):551-??6. ?17. Kappert ?K, ?B?hm ?M, ?Schmieder ?R, ?et ?al. ?Impact ?of ?sex ?on ?cardiovascular ?outcome ?in ?patients ?at ?high ?cardiovascular ?risk: ?analysis ?of ?the ?Telmisartan ?Randomized ?Assessment ?Study ?in ?ACE-??Intolerant ?Subjects ?With ?Cardiovascular ?Disease ?(TRANSCEND) ?and ?the ?Ongoing ?Telmisartan ?Alone ?and ?in ?Combination ?With ?Ramipril ?Global ?End ?Point ?Trial ?(ONTARGET). ?Circ. ?2012;126:934-??941. ?18. Charchar ?F, ?Bloomer ?L, ?Barnes ?T. ?Inheritance ?of ?coronary ?artery ?disease ?in ?men: ?an ?analysis ?of ?the ?role ?of ?the ?Y ?chromosome. ?. ?Lancet. ?2012;379:915-??87 ?922. ?19. Gotto ?A, ?Whitney ?E, ?Stein ?E, ?et ?al. ?Application ?of ?the ?National ?Cholesterol ?Education ?Program ?and ?joint ?European ?treatment ?criteria ?and ?clinical ?benefit ?in ?the ?Air ?Force/Texas ?Coronary ?Atherosclerosis ?Prevention ?Study ?(AFCAPS/TexCAPS). ?Eur ?Heart ?J. ?2000;21:1627-??1633. ?20. Myer ?R, ?Kiely ?D, ?Cupples ?L, ?Kannel ?W. ?Parental ?history ?is ?an ?independent ?risk ?factor ?for ?coronary ?artery ?disease: ?the ?Framingham ?Study. ?Am ?Heart ?J. ?1990;120:963-??969 ?21. Andresdottir ?M, ?Sigurdsson ?G, ?Sigvaldason ?H, ?Gudnason ?V. ?Fifteen ?percent ?of ?myocardial ?infarctions ?and ?coronary ?revascularizations ?explained ?by ?family ?history ?36 ?unrelated ?to ?conventional ?risk ?factors. ?The ?Reykjavik ?Cohort ?Study. ?Eur ?Heart ?J. ?2002;23:1655-??1663. ?22. Burke ?GL, ?Evans ?GW, ?Riley ?WA, ?et ?al. ?Arterial ?wall ?thickness ?is ?associated ?with ?prevalent ?cardiovascular ?disease ?in ?middle-??aged ?adults. ?The ?Atherosclerosis ?Risk ?in ?Communities ?(ARIC) ?Study. ?Stroke. ?1995;26(3):386-??91. ?23. Wu ?J, ?and ?Sin ?D. ?Improved ?patient ?outcome ?with ?smoking ?cessation: ?when ?is ?it ?too ?late?. ?Int ?J ?Chron ?Obstruct ?Pulmon ?Dis. ?2011;6:259-??267. ?24. Hubert ?HB, ?Feinleib ?M, ?McNamara ?PM, ?et ?al. ?Obesity ?as ?an ?independent ?risk ?factor ?for ?cardiovascular ?disease: ?a ?26-??year ?follow-??up ?of ?participants ?in ?the ?Framingham ?Heart ?Study. ?Circulation. ?1983;67(5):968-??77. ?25. Hamdy ?O, ?Porramatikul ?S, ?Al-??Ozairi ?E. ?Metabolic ?obesity: ?the ?paradox ?between ?visceral ?and ?subcutaneous ?fat. ?Curr ?Diabetes ?Rev. ?2006;2(4):367-??73. ?26. Eckel ?R, ?York ?D, ?Rossner ?S, ?et ?al. ?Prevention ?Conference ?VII: ?Obesity, ?a ?worldwide ?epidemic ?related ?to ?heart ?disease ?and ?stroke: ?executive ?summary. ?. ?Circ. ?2004;110:2968-??2975. ?27. Wolk ?R, ?Berger ?P, ?Lennon ?R, ?Brilakis ?E, ?Davison ?D, ?Somers ?V. ?Association ?between ?plasma ?adiponectin ?levels ?and ?unstable ?coronary ?syndromes. ?Eur ?Heart ?J ?2007; ?28:292.. ?Eur ?Heart ?J. ?2007;28:292-??298. ?28. 28.Shibata ?R, ?Ouchi ?N, ?Murohara ?T. ?Adiponectin ?and ?Cardiovascular ?88 ?Disease. ?Circ. ?2009;73:608-??614. ?29. Hubert ?H, ?Feinleib ?M, ?McNamara ?P, ?Castelli ?W. ?Obesity ?as ?an ?independent ?risk ?factor ?for ?cardiovascular ?disease: ?a ?26-??year ?follow-??up ?of ?participants ?in ?the ?Framingham ?Heart ?Study. ?Circ. ?1983;67:968-??977. ?30. Rozanski ?A, ?Blumenthal ?J, ?Kaplan ?J. ?Impact ?of ?psychological ?factors ?on ?the ?pathogenesis ?of ?cardiovascular ?disease ?and ?implications ?for ?therapy. ?Circ. ?1999;99:2192-??2217. ?31. Black ?P. ?The ?inflammatory ?consequences ?of ?psychologic ?stress: ?relationship ?to ?insulin ?resistance, ?obesity, ?atherosclerosis ?and ?diabetes ?mellitus, ?type ?II. ?Med ?Hypotheses. ?2006;67:879-??891. ?32. Chobanian ?A. ?Overview: ?hypertension ?and ?atherosclerosis. ?Am ?Heart ?J. ?1988;116(1 ?Pt ?2):319-??22. ?33. Grossman ?E. ?Blood ?Pressure: ?The ?Lower, ?the ?Better. ?Dia ?Care. ?2011;34:S308-??S312 ?34. Rosenson ?R, ?de ?Ferranti ?S. ?Primary ?disorders ?of ?LDL-?? ?cholesterol ?metabolism. ?Available ?at: ?www.uptodate.com/contents/primary-??disorders-??of-??LDL-??cholesterol-??metabolism. ?Accessed ?December, ?10th, ?2012. ?35. Law ?MR, ?Wald ?NJ, ?Wu ?T, ?et ?al. ?Systematic ?underestimation ?of ?association ?between ?serum ?cholesterol ?concentration ?and ?ischaemic ?heart ?disease ?in ?observational ?studies: ?data ?from ?the ?BUPA ?study. ?Bmj. ?1994;308(6925):363-??6. ?36. Stamler ?J, ?Wentworth ?D, ?Neaton ?J. ?Is ?relationship ?between ?serum ?cholesterol ?and ?risk ?of ?premature ?death ?from ?coronary ?heart ?disease ?continuous ?and ?graded? ?Findings ?in ?356,222 ?primary ?screenees ?of ?the ?Multiple ?Risk ?Factor ?Intervention ?Trial ?(MRFIT). ?JAMA. ?1986;256:2823-??2828. ?37. Lewington ?S, ?Whitlock ?G, ?Clarke ?R, ?et ?al. ?Blood ?cholesterol ?and ?vascular ?mortality ?by ?age, ?sex, ?and ?blood ?pressure: ?a ?meta-??analysis ?of ?individual ?data ?from ?61 ?prospective ?studies ?with ?55,000 ?vascular ?deaths. ?Lancet. ?2008;372:1829-??1839. ?89 ?38. Gordon ?D, ?Probstfield ?J, ?Garrison ?R, ?et ?al. ?High-??density ?lipoprotein ?cholesterol ?and ?cardiovascular ?disease. ?Four ?prospective ?American ?studies.. ?Circ. ?1989;79:8-??15. ?39. Sarwar ?N, ?Danesh ?J, ?Eiriksdottir ?G, ?et ?al. ?Triglycerides ?and ?the ?risk ?of ?coronary ?heart ?disease: ?10,158 ?incident ?cases ?among ?262,525 ?participants ?in ?29 ?Western ?prospective ?studies. ?Circ. ?2007;115:450-??457. ?40. Soska ?V, ?Jarkovsky ?J, ?Ravcukova ?B, ?Tichy ?L, ?Fajkusova ?L, ?Freiberger ?T. ?The ?logarithm ?of ?the ?triglyceride/HDL-??cholesterol ?ratio ?is ?related ?to ?the ?history ?of ?cardiovascular ?disease ?in ?patients ?with ?familial ?hypercholesterolemia. ?Clin ?Biochem. ?2012;45:96-??100. ?41. Walldius ?G, ?Jungner ?I, ?Holme ?I. ?High ?apolipoprotein ?B, ?low ?apolipoprotein ?A-??I, ?and ?improvement ?in ?the ?prediction ?of ?fatal ?myocardial ?infarction ?(AMORIS ?study): ?a ?prospective ?study. ?Lancet. ?2001;358:2026-??2033. ?42. El ?Harchaoui ?K, ?van ?der ?Steeg ?W, ?Stroes ?E, ?et ?al. ?Value ?of ?low-??density ?lipoprotein ?particle ?number ?and ?size ?as ?predictors ?of ?coronary ?artery ?disease ?in ?apparently ?healthy ?men ?and ?women: ?the ?EPIC-??Norfolk ?Prospective ?Population ?Study. ?J ?Am ?Coll ?Cardiol ?2007 ?Feb ?6;49(5):547-??53. ?2007;49:547-??553. ?43. CTT ?Contributors. ?Efficacy ?and ?safety ?of ?cholesterol-??lowering ?treatment: ?prospective ?meta-??analysis ?of ?data ?from ?90 ?056 ?participants ?in ?14 ?randomised ?trials ?of ?statins. ?Lancet. ?2005;366:1267-??1278. ?44. Ridker ?P, ?Rifai ?N, ?Rose ?L, ?Buring ?J, ?Cook ?N. ?Comparison ?of ?C-??reactive ?protein ?and ?low-?? ?density ?lipoprotein ?cholesterol ?levels ?in ?the ?prediction ?of ?first ?cardiovascular ?events. ?N ?Engl ?J ?Med. ?2002;347:1557-??1565. ?45. Danesh ?J, ?Wheeler ?JG, ?Hirschfield ?GM, ?et ?al. ?C-??reactive ?protein ?and ?other ?circulating ?markers ?of ?inflammation ?in ?the ?prediction ?of ?coronary ?heart ?disease. ?N ?Engl ?J ?Med. ?2004;350(14):1387-??97. ?46. Nygard ?O, ?Nordrehaug ?J, ?Refsum ?H, ?Ueland ?P, ?Farstad ?M, ?Vollse ?S. ?Plasma ?homocysteine ?levels ?and ?mortality ?in ?patients ?with ?coronary ?artery ?disease. ?. ?N ?Engl ?J ?Med. ?1997;337:230-??236. ? ?47. Toole ?J, ?Malinow ?M, ?Chambless ?L, ?et ?al. ?Lowering ?homocysteine ?in ?patients ?90 ?with ?ischemic ?stroke ?to ?prevent ?recurrent ?stroke, ?myocardial ?infarction, ?and ?death: ?the ?Vitamin ?Intervention ?for ?Stroke ?Prevention ?(VISP) ?randomized ?controlled ?trial. ?J ?Am ?Med ?Assoc. ?2004;291:565-??575. ?48. Splaver ?A, ?Lamas ?G, ?Hennekens ?C. ?Homocysteine ?and ?cardiovascular ?disease: ?biological ?mechanisms, ?observational ?epidemiology, ?and ?the ?need ?for ?randomized ?trials. ?Am ?Heart ?J. ?2004;148:34-??40. ?49. Chambers ?J, ?Obeid ?O, ?Kooner ?J. ?Physiological ?increments ?in ?plasma ?homocysteine ?induce ?vascular ?endothelial ?dysfunction ?in ?normal ?human ?subjects. ?. ?Arterioscler ?Thromb ?Vasc ?Biol. ?1999;19:2922-??2927. ?50. Holmes ?D, ?Schick ?B, ?Humphries ?K, ?Frohlich ?J. ?Lipoprotein(a) ?is ?and ?independent ?risk ?factor ?for ?cardiovascular ?disease ?in ?heterozygous ?familial ?hypercholesterolemia. ?J ?Clin ?Chem. ?2005;51:2067-??2073. ? ?51. Nenseter ?M, ?Lindvig ?H, ?Ueland ?T, ?et ?al. ?Lipoprotein(a) ?levels ?in ?coronary ?heart ?disease-??susceptible ?and ?-??resistant ?patients ?with ?familial ?hypercholesterolemia. ?Atherosclerosis. ?2011;216:426-??432. ?52. Rosenson ?R, ?Stein ?J. ?Lipoprotein(a) ?and ?cardiovacular ?disease. ?Available ?at: ?www.uptodate.com/contents/lipoprotein-??a-??and-??cardiovascular-??disease. ?Accessed ?August, ?4th, ?2011. ? ?53. Bard ?L, ?Arveiler ?D, ?Ferrieres ?J, ?et ?al. ?Lipoprotein ?(a) ?as ?a ?predictor ?of ?coronary ?heart ?disease: ?the ?PRIME ?Study. ?Atherosclerosis. ?2002;163:377-??384. ? ?54. Erqou ?S, ?Kaptoge ?S, ?Perry ?P, ?et ?al. ?Lipoprotein(a) ?concentration ?and ?the ?risk ?of ?coronary ?heart ?disease, ?stroke, ?and ?nonvascular ?mortality. ?JAMA. ?2009;302:412-??423. ?55. Khaw ?K, ?Wareham ?N, ?Bingham ?S, ?Luben ?R, ?Welch ?A, ?Day ?N. ?Association ?of ?hemoglobin ?A1c ?with ?cardiovascular ?disease ?and ?mortality ?in ?adults: ?the ?European ?prospective ?investigation ?into ?cancer ?in ?Norfolk. ?. ?Ann ?Intern ?Med. ?2004;141:413-??420. ?56. Selvin ?E, ?Steffes ?M, ?Zhu ?H, ?Smith ?J. ?Glycated ?hemoglobin, ?diabetes, ?and ?cardiovascular ?risk ?in ?nondiabetic ?adults ?. ?N ?Engl ?J ?Med. ?2010;362:800-??811. ?91 ?57. Khera ?A, ?Cuchel ?M, ?Llera-??Moya ?M, ?et ?al. ? ?Cholesterol ?Efflux ?Capacity, ?High-??Density ?Lipoprotein ?Function, ?and ?Atherosclerosis ? ?N ?Engl ?J ?Med. ?2011;364:127-??135. ?58. Rosenson ?R. ?Lipoprotein ?Classification; ?Meatbolism; ?and ?Role ?in ?Atherosclerosis. ?Available ?at: ?http://www.uptodate.com/contents/lipoprotein-??classification-??mtabolism-??and-??role-??in-??atherolsclerosis. ?Accessed ?December ?2nd, ?2012. ?59. Alonso ?R, ?Mata ?N, ?Badimon ?L, ?Perez-??Jimenez ?F, ?Mata ?P. ?Prognostic ?factors ?of ?cardiovascular ?disease ?mortality ?and ?morbidity ?in ?a ?cohort ?of ?families ?with ?genetic ?diagnoses ?of ?familial ?hypercholesterolemia. ?Nature. ?2009;6:23-??27. ?60. Manuel ?D, ?Leung ?M, ?Nguyen ?K, ?Tanuseputro ?P, ?Johansen ?H. ?Burden ?of ?cardiovascular ?disease ?in ?Canada. ?Can ?J ?Cardiol. ?2003;19:997-??1004. ?61. DeMott ?K, ?Nherera ?L, ?Shaw ?E. ?Clinical ?Guidelines ?and ?Evidence ?Review ?for ?Familial ?Hypercholesterolaemia: ?The ?Identification ?and ?Management ?of ?Adults ?and ?Children ?with ?Familial ?Hypercholesterolaemia. ?London: ?National ?Collaborating ?Centre ?for ?Primary ?Care ?and ?Royal ?College ?of ?General ?Practitioners.; ?2008. ?62. Goldberg ?A, ?Hopkins ?P, ?Toth ?P, ?et ?al. ?Familial ?Hypercholesterolemia: ?Screening, ?diagnosis ?and ?management ?of ?pediatric ?and ?adult ?patients. ?J ?Clin ?Lipid. ?2011;5:S1-??S8. ?63. Marks ?D, ?Thorogood ?M, ?Neil ?A, ?Humphries ?S. ?A ?review ?on ?the ?diagnosis, ?natural ?history, ?and ?treatment ?of ?familial ?hypercholesterolaemia. ?Atherosclerosis. ?2003;168:1-??14. ? ?64. Morrell ?J. ?Familial ?Hypercholesterolemia: ?Recognizing ?the ?Unrecognizable. ?J ?Cardiol. ?2008;15:79-??81. ? ?65. Yuan ?G, ?Wang ?J, ?Hegele ?R. ?Heterozygous ?familial ?hypercholesterolemia: ?an ?underrecognized ?cause ?of ?early ?cardiovascular ?disease. ?Can ?Med ?Assoc ?J. ?2006;174:1124-??1129. ?66. Chaves ?F, ?Real ?J, ?Garcia-??Garcia ?A, ?et ?al. ?Genetic ?diagnosis ?of ?familial ?hypercholesterolemia ?in ?a ?South ?European ?outbreed ?population: ?influence ?92 ?of ?low-??density ?lipoprotein ?receptor ?gene ?mutations ?on ?treatment ?response ?to ?simvastatin ?in ?total, ?LDL ?and ?high-?? ?density ?lipoprotein ?cholesterol. ?J ?Clin ?Endocrinol ?Metab. ?2001;86:4926-??4932. ?67. Fahed ?A, ?Nemer ?G. ?Familial ?Hypercholesterolemia: ?The ?Lipids ?or ?the ?Genes?. ?Nutr ?Metab. ?2011;8:23. ? ?68. Soutar ?A, ?Naoumova ?R. ?Mechanisms ?of ?Disease: ?genetic ?causes ?of ?familial ?hypercholesterolemia. ?Nat ?Clin ?Pract ?Cardiovasc. ?2007;4:214-??225. ? ?69. Raal ?F, ?Panz ?V, ?Immelman ?A, ?Pilcher ?G. ?Elevated ?PCSK9 ?Levels ?in ?Untreated ?Patients ?With ?Heterozygous ?or ?Homozygous ?Familial ?Hypercholesterolemia ?and ?the ?Response ?to ?High ??Dose ?Statin ?Therapy. ?J ?Am ?Heart ?Assoc. ?2013;112:1-??12. ?70. Damgaard ?D, ?Larsen ?M, ?Nissen ?P, ?et ?al. ?The ?relationship ?of ?molecular ?genetic ?to ?clinical ?diagnosis ?of ?familial ?hypercholesterolemia ?in ?a ?Danish ?population. ?Atherosclerosis. ?2005;180:155-??160. ?71. Herman ?K, ?Van ?Heyningen ?C, ?Wile ?D. ?Cascade ?screening ?for ?familial ?hypercholesterolaemia ?and ?its ?effectiveness ?in ?the ?prevention ?of ?vascular ?disease. ?Br ?J ?Diabetes ?Vasc ?Dis. ?2009;9:171-??174. ?72. Reiner ?Z, ?Catapano ?A, ?De ?Backer ?G, ?et ?al. ?ESC/EAS ?Guidelines ?for ?the ?management ?of ?dyslipidaemias. ?Eur ?Heart ?J. ?2011;32:1769-??1818. ? ?73. Genest ?J, ?McPherson ?R, ?Frohlich ?J, ?et ?al. ?2009 ?Canadian ?Cardiovascular ?Society/ ?Canadian ?guidelines ?for ?the ?diagnosis ?and ?treatment ?of ?dyslipidemia ?and ?prevention ?of ?cardiovascular ?disease ?in ?the ?adult-?? ?2009 ?recommendations. ?Can ?J ?Cardiol. ?2009;25:567-??579. ?74. Vermissen ?J, ?Oosterveer ?D, ?Yazdanpanah ?M, ?et ?al. ?Efficacy ?of ?statins ?in ?familial ?hypercholesterolaemia: ?a ?long ?term ?cohort ?study. ?Br ?Med ?J. ?2008;337:2423-??2428. ? ?75. Jansen ?A, ?van ?Aalst-??Cohen ?E, ?Tanck ?M, ?et ?al. ?The ?contribution ?of ?classical ?risk ?factors ?to ?cardiovascular ?disease ?in ?familial ?hypercholesterolaemia: ?data ?in ?2400 ?patients. ?J ?Intern ?Med. ?2004;256:482-??490. ?76. De ?Sauvage ?Nolting ?P, ?Defesche ?J, ?Buirma ?R, ?Hutten ?B, ?Lansberg ?P, ?Kastelein ?J. ?Prevalence ?and ?significance ?of ?cardiovascular ?risk ?factors ?in ?a ?93 ?large ?cohort ?of ?patients ?with ?familial ?hypercholesterolaemia. ?J ?Intern ?Med. ?2003;253:161-??168. ?77. Austin ?M, ?Hutter ?C, ?Zimmern ?R, ?Humphries ?S. ?Familial ?Hypercholesterolemia ?and ?Coronary ?Heart ?Disease: ?A ?HuGE ?Association ?Review. ?Am ?J ?Epidemiol. ?2004;160:421-??429. ? ?78. Hill ?J, ?Hayden ?M, ?Frohlich ?J, ?Pritchard ?H. ?Genetic ?and ?Environmental ?Factors ?Affecting ?the ?Incidence ?of ?Coronary ?Artery ?Disease ?in ?Heterozygous ?Familial ?Hypercholesterolemia. ?Arterioscler ?Thromb. ?1991;11:290-??297. ?79. Ferri?res, ?J.; ?Lambert, ?D.; ?PhD; ?Lussier-??Cacan, ?J.; ?Davignon, ?J. ?Coronary ?Artery ?Disease ?in ?Heterozygous ?Familial ?Hypercholesterolemia ?Patients ?With ?the ?Same ?LDL ?Receptor ?Gene ?Mutation. ?Circulation.1995; ?92: ?290-??295. ?80. Jansen ?A, ?van ?Aalst-??Cohen ?E, ?Tanck ?M, ?et ?al. ?Genetic ?Determinants ?of ?Cardiovascular ?Disease ?Risk ?in ?Familial ?Hypercholesterolemia. ?Arterioscler ?Thromb ?Vasc ?Biol. ?2005;25:1475-??1481. ?81. Alonso ?R, ?Mata ?N, ?Castillo ?S, ?Fuentes ?F, ?Saenz ?P, ?Mu?iz ?O. ?Cardiovascular ?disease ?in ?familial ?hypercholesterolaemia: ?influence ?of ?low-??density ?lipoprotein ?receptor ?mutation ?type ?and ?classic ?risk ?factors.. ?Atherosclerosis. ?2008;200:315-??321. ?82. Humphries ?S, ?Whittall ?R, ?Hubbart ?C, ?Maplebeck ?S, ?Cooper ?J, ?Soutar ?A. ?Genetic ?causes ?of ?familial ?hypercholesterolaemia ?in ?patients ?in ?the ?UK: ?relation ?to ?plasma ?lipid ?levels ?and ?coronary ?heart ?disease ?risk.. ?J ?Med ?Genet. ?2006;43:943-??949. ?83. Koeijvoets ?K, ?van ?der ?Net ?J, ?Dallinga-??Thie ?G, ?et ?al. ?ABCG8 ?gene ?polymorphisms, ?plasma ?cholesterol ?concentrations, ?and ?risk ?of ?cardiovascular ?disease ?in ?familial ?hypercholesterolemia. ?Atherosclerosis. ?2009;204:453-??458. ?84. Hopkins ?P, ?Stephenson ?S, ?Wu ?L, ?Riley ?W, ?Xin ?Y, ?Hunt ?S. ? ?Evaluation ?of ?Coronary ?Risk ?Factors ?in ?Patients ?With ?Heterozygous ?Familial ?Hypercholesterolemia ? ?Am ?J ?Cardiol. ?2001;87:547-??553. ?94 ?85. Neil ?H, ?Seagroatt ?V, ?Betteridge ?D, ?et ?al. ? ? ?Established ?and ?emerging ?coronary ?risk ?factors ?in ?patients ?with ?heterozygous ?familial ?hypercholesterolaemia ? ?Heart. ?2004;90:1431-??1437. ?86. van ?der ?Net ?J, ?Janssens ?C, ?Defesche ?J, ?Kastelein ?J, ?Sijbrands ?E, ?Steyerberg ?E. ? ?Usefulness ?of ?Genetic ?Polymorphisms ?and ?Conventional ?Risk ?Factors ?to ?Predict ?Coronary ?Heart ?Disease ?in ?Patients ?With ?Familial ?Hypercholesterolemia ? ?Am ?J ?Cardiol ?2009;103:375?380. ?2009;103:375-??380. ?87. Yanagi ?K, ?Yamashita ?Y, ?Kihara ?S, ?et ?al. ? ?Characteristics ?of ?coronary ?artery ?disease ?and ?lipoprotein ?abnormalities ?in ?patients ?with ?heterozygous ?familial ?hypercholesterolemia ?associated ?with ?diabetes ?mellitus ?or ?impaired ?glucose ?tolerance ? ?Atherosclerosis. ?1997;132:43-??51. ?88. Carmena ?R, ?Lussier-??Cacan ?S, ?Roy ?M, ?Minnich ?A, ?Lingenhel ?A, ?Kronenberg ?F. ?Lp(a) ?levels ?and ?atherosclerotic ?vascular ?disease ?in ?a ?sample ?of ?patients ?with ?familial ?hypercholesterolemia ?sharing ?the ?same ?gene ?defect. ?Arterioscler ?Thromb ?Vasc ?Biol. ?1996;16:129-??136. ?89. Real ?J, ?Ascaso ?J, ?Chaves ?F, ?Tenes ?S, ?Priego ?M, ?Puig ?O. ?Plasma ?Lp(a) ?values ?in ?familial ?hypercholesterolemia ?and ?its ?relation ?to ?coronary ?heart ?disease. ?Nutr ?Metab ?Cardiovasc ?Dis. ?1999;9:41-??44. ?90. Bowden ?J, ?Pritchard ?H, ?Hill ?J, ?Frohlich ?J. ?Lp(a) ?concentration ?and ?apo(a) ?isoform ?size. ?Relation ?to ?the ?presence ?of ?coronary ?artery ?disease ?in ?familial ?hypercholesterolemia. ?Arterioscler ?Thromb. ?1994;14:1561-??1568. ?91. Mbewu ?A, ?Bhatnagar ?D, ?Durrington ?P, ?Hunt ?L, ?Ishola ?M, ?Arrol ?S. ?Serum ?lipoprotein(a) ?in ?patients ?heterozygous ?for ?familial ?hypercholesterolemia, ?their ?relatives, ?and ?unrelated ?control ?populations. ?. ?Arterioscler ?Thromb. ?1991;11:940-??946. ?92. Wiklund ?O, ?Angelin ?B, ?Olofsson ?S, ?Eriksson ?M, ?Fager ?G, ?Berglund ?L. ? ? ?Apolipoprotein(a) ?and ?ischaemic ?heart ?disease ?in ?familial ?hypercholesterolaemia. ?. ?Lancet. ?1990;335:1360-??1363. ?93. Seed ?M, ?Hoppichler ?F, ?Reaveley ?D, ?McCarthy ?S, ?Thompson ?G, ?Boerwinkle ?E. ? ? ?Relation ?of ?serum ?lipoprotein(a) ?concentration ?and ?apolipoprotein(a) ?95 ?phenotype ?to ?coronary ?heart ?disease ?in ?patients ?with ?familial ?hypercholesterolemia. ?. ?N ?Engl ?J ?Med. ?1990;322:1494-??1499. ?94. Houlston ?R, ?Quiney ?J, ?Mount ?J, ?Watts ?G, ?Lewis ?B. ?Lipoprotein(a) ?and ?coronary ?heart ?disease ?in ?familial ?hypercholesterolaemia.. ?Lancet. ?1988;2:405. ?95. Tat? ?F, ?Keller ?C, ?Schuster ?H, ?Spengel ?F, ?Wolfram ?G, ?Z?llner ?N. ? ?Relation ?of ?lipoprotein(a) ?to ?coronary ?heart ?disease ?and ?duplexsonographic ?findings ?of ?the ?carotid ?arteries ?in ?heterozygous ?familial ?hypercholesterolemia. ?Atherosclerosis. ?1993;101:69-??77. ?96. Ors? ?E, ?Ahrens ?N, ?Kilali ?D, ?Schmitz ?G. ?Familial ?hypercholesterolemia ?and ?lipoprotein(a) ?hyperlipidemia ?as ?independent ?and ?combined ?cardiovascular ?risk ?factors. ?Atherosclerosis ?Supp. ?2009;10:74-??78. ?97. de ?Sauvag ?Nolting ?P, ?Kusters ?D, ?Hutten ?B, ?Kastelein ?J. ?Serum ?bilirubin ?levels ?in ?familial ?hypercholesterolemia: ?a ?new ?risk ?marker ?for ?cardiovascular ?disease? ?J ?Lipid ?Res. ?2011;52:1755-??1759. ?98. Soska ?V, ?Jarkovsky ?J, ?Ravcukova ?B, ?Tichy ?L, ?Fajkusova ?L, ?Freiberger ?T. ?The ?logarithm ?of ?the ?triglyceride/HDL-??cholesterol ?ratio ?is ?related ?to ?the ?history ?of ?cardiovascular ?disease ?in ?patients ?with ?familial ?hypercholesterolemia. ?Clin ?Biochem. ?2012;45:96-??100. ?99. Mozas ?P, ?Reyes ?G, ?Civeira ?F, ?et ?al. ?Apolipoprotein ?E ?genotype ?is ?not ?associated ?with ?cardiovascular ?disease ?in ?heterozygous ?subjects ?with ?familial ?hypercholesterolemia. ?Am ?Heart ?J. ?2003;145:999-??1005. ?100. CARDIA ?sonographer ?manual-?? ?carotid ?ultrasound. ?In: ?CARDIA ?Manual ?of ?Operations. ?Vol ?1. ?New ?England ?Medical ?Center; ?2005:1-??29. ?101. Nikus ?K. ?Coronary ?angiography. ?In: ? ?Multimodal ?Cardiovascular ?Imaging: ?Principles ?and ?Clinical ?Applications ?McGraw-??Hill ?Global ?Education ?Holdings; ?2004:71-??80. ?102. Raff ?G, ?Abidov ?A, ?Achenbach ?S, ?et ?al. ?SCCT ?guidelines ?for ?the ?interpretation ?and ?reporting ?of ?coronary ?computed ?tomographic ?angiography. ?J ?Cardiovasc ?CT. ?2009:1-??15. ? ?96 ?103. Germano ?G, ?Berman ?D. ?Clinical ?Gated ?Cardiac ?SPECT. ?New ?York: ?Futura ?Publishing ?Company ?Inc.; ?1999. ?104. de Jongh S, Lilien M, Bakker H, Hutten B, Kastelein J, Stroes E. Family history of cardiovascular events and endothelial dysfunction in children with familial hypercholesterolemia. Atherosclerosis. 2002;163:193-197. ?105. Real J, Chaves F, Mart ?<1);-Uso ? I, Garc ?<%??5'%52??%40)1%? ? Importance of HDL cholesterol levels and the total/ HDL cholesterol ratio as a risk factor *24?'2421%4:?,)%46?(-5)%5)?-1?02/)'7/%4/:?()*-1)(?,)6)42;:+275?familial hypercholesterolaemia Eur Heart J. 2001;22:465-471. ?106. Bellanger ?N, ?Orsoni ?A, ?Julia ?Z, ?Fournier ?N, ?Frisdal ?E. ? ?Atheroprotective ?Reverse ?Cholesterol ?Transport ?Pathway ?Is ?Defective ?in ?Familial ?Hypercholesterolemia ? ?Arterioscler ?Thromb ?Vasc ?Biol. ?2011;31:1675-??1681. ?107. Guerin ?M. ?Reverse ?cholesterol ?transport ?in ?familial ?hypercholesterolemia. ?Curr ?Opin ?Lipidol. ?2012;23:377-??385. ?108. )-(%1??5-%?? %6;? ?Plasma lipids and antidiabetic agents: a brief overview. Diabetes Care. 2002; 2: 40-43. ?109. Terrados ?N, ?Valcarcel ?G, ?Venta ?R. ?New ?cardiovascular ?risk ?factors ?and ?physical ?activity. ?Apunts ?Med ?Esport. ?2010; ?45:201-??208. ?110. Kwiterovich P. The metabolic pathways of high-density lipoprotein, low-density lipoprotein, and triglycerides: a current review. Am J Cardiol. 2000; 86:5-10 ?111. 25)1521? ?4%7)1,)-0?$?"%1+1):??Dyslipidemias and the secondary prevention of coronary heart disease. Dis Mon. 1994; 40: 369-464. ?112. -8)-4%??7-()/-1)5?*24?6,)?(-%+125-5?%1(?0%1%+)0)16?2*?,)6)42;:+275?familial hypercholesterolemia. Atherosclerosis. 2004;173:55-68. ? ? ? ?
Thesis/Dissertation
eng
Pathology and Laboratory Medicine
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Phenotypic characterization and cardiovascular outcomes of patients with familial hypercholesterolemia
Text