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Phenotypic characterization and cardiovascular outcomes of patients with familial hypercholesterolemia Allard, Matthew 2013

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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. 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