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Sex differences in acute myocardial infarction in younger adults Izadnegahdar, Mona A. 2013

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   SEX	
  DIFFERENCES	
  IN	
  ACUTE	
  MYOCARDIAL	
  INFARCTION	
  	
   IN	
  YOUNGER	
  ADULTS	
   	
   by	
   	
   	
   MONA	
  A.	
  IZADNEGAHDAR	
   	
   	
   B.Sc.,	
  The	
  University	
  of	
  British	
  Columbia,	
  Canada,	
  1996	
   M.Sc.,	
  The	
  University	
  of	
  Calgary,	
  Canada,	
  2001	
   	
   	
   	
   A	
  THESIS	
  SUBMITTED	
  IN	
  PARTIAL	
  FULFILLMENT	
  OF	
   THE	
  REQUIREMENTS	
  FOR	
  THE	
  DEGREE	
  OF	
   	
   DOCTOR	
  OF	
  PHILOSOPHY	
   	
   in	
   	
   	
   THE	
  FACULTY	
  OF	
  GRADUATE	
  STUDIES	
   	
   (Health	
  Care	
  and	
  Epidemiology)	
   	
   	
   	
   THE	
  UNIVERSITY	
  OF	
  BRITISH	
  COLUMBIA	
   (Vancouver)	
   	
   	
   January	
  2013	
   	
   	
   	
   ©	
  Mona	
  A.	
  Izadnegahdar,	
  2013	
    Abstract	
  	
   	
   Background:	
  Younger	
  adults	
  have	
  been	
  identified	
  as	
  an	
  emerging	
  ‘at-­‐risk’	
  population	
  with	
  a	
   rising	
  prevalence	
  of	
  cardiac	
  risk	
  factors	
  and	
  hospitalization	
  for	
  acute	
  myocardial	
  infarction	
   (AMI).	
  	
  Coupled	
  with	
  this	
  is	
  an	
  unexplained	
  excess	
  early	
  AMI	
  mortality	
  risk	
  in	
  younger	
   women	
  compared	
  to	
  younger	
  men.	
  	
  Self-­‐perceived	
  health	
  status	
  (symptoms,	
  physical	
   function	
  and	
  disease	
  perception)	
  has	
  been	
  proposed	
  as	
  a	
  contributing	
  factor;	
  however,	
  not	
   much	
  is	
  known	
  about	
  sex	
  differences	
  in	
  health	
  status	
  outcomes	
  of	
  younger	
  adults	
  post	
  AMI.	
  	
   The	
  overarching	
  goal	
  of	
  this	
  thesis	
  is	
  to	
  enhance	
  our	
  understanding	
  of	
  AMI	
  in	
  younger	
  adults	
   (20-­‐55	
  years).	
  	
  The	
  main	
  objectives	
  are:	
  1)	
  to	
  examine	
  sex	
  differences	
  and	
  10-­‐year	
  trends	
  in	
   AMI	
  hospitalization	
  and	
  early	
  AMI	
  mortality,	
  and	
  to	
  determine	
  whether	
  the	
  sex	
  gap	
  in	
  early	
   AMI	
  mortality	
  has	
  changed	
  in	
  recent	
  years,	
  and	
  2)	
  to	
  examine	
  the	
  sex	
  differences	
  and	
   changes	
  in	
  health	
  status	
  during	
  the	
  first	
  year	
  following	
  AMI.	
  	
   Methods:	
  The	
  age-­‐	
  and	
  sex-­‐specific	
  10-­‐year	
  trends	
  in	
  AMI	
  hospitalization	
  and	
  30-­‐day	
  AMI	
   mortality	
  were	
  based	
  on	
  population-­‐based,	
  administrative	
  data	
  in	
  British	
  Columbia	
  (BC)	
  and	
   assessed	
  using	
  negative	
  binomial	
  and	
  logistic	
  regression,	
  respectively.	
  	
  Sex	
  differences	
  and	
   changes	
  in	
  health	
  status	
  were	
  assessed	
  using	
  prospectively	
  collected	
  data	
  on	
  286	
  younger	
   AMI	
  patients,	
  in	
  BC.	
  	
  Linear	
  and	
  generalized	
  linear	
  mixed	
  models	
  were	
  used	
  to	
  assess	
  health	
   status	
  changes.	
  	
   Results:	
  	
  Between	
  2000-­‐2009,	
  younger	
  adults,	
  particularly	
  women,	
  did	
  not	
  experience	
  the	
   same	
  declining	
  AMI	
  hospitalization	
  rates	
  as	
  older	
  adults.	
  	
  Furthermore,	
  for	
  early	
  AMI	
    ii  mortality,	
  the	
  observed	
  sex	
  differences	
  among	
  younger	
  adults	
  persisted,	
  even	
  after	
   adjusting	
  for	
  comorbidities.	
  	
  While	
  health	
  status	
  in	
  both	
  men	
  and	
  women	
  diminished	
  in	
  the	
   first	
  month	
  following	
  AMI,	
  driven	
  by	
  worse	
  angina	
  and	
  physical	
  function,	
  it	
  improved	
   thereafter.	
  	
  Younger	
  women	
  consistently	
  had	
  significantly	
  worse	
  cardiac-­‐related	
  physical	
   function,	
  disease	
  perception,	
  and	
  overall	
  physical	
  and	
  mental	
  health	
  than	
  younger	
  men	
   during	
  the	
  first	
  year;	
  however,	
  the	
  changes	
  in	
  health	
  status	
  were	
  similar	
  in	
  men	
  and	
   women.	
   Conclusions:	
  The	
  findings	
  highlight	
  a	
  persistent	
  sex	
  difference	
  in	
  early	
  mortality	
  and	
  health	
   status	
  following	
  AMI	
  among	
  younger	
  adults.	
  The	
  first	
  month	
  after	
  AMI	
  is	
  a	
  critical	
  period	
  to	
   intensify	
  support	
  and	
  treatment	
  in	
  order	
  to	
  improve	
  outcomes.	
   	
   	
   	
   	
    iii  Preface	
   The	
  original	
  research	
  studies	
  described	
  in	
  Chapter	
  3	
  and	
  Chapter	
  4	
  were	
  approved	
  by	
  the	
   University	
  of	
  British	
  Columbia’s	
  Clinical	
  Research	
  Ethics	
  Board	
  (UBC	
  REB	
  Number	
  H10-­‐ 00255)	
  and	
  Behavioural	
  Research	
  Ethics	
  Board	
  (UBC	
  REB	
  Number	
  H08-­‐01700),	
  respectively.	
   A	
  version	
  of	
  Chapter	
  3	
  (Trend	
  Study)	
  has	
  been	
  submitted	
  for	
  publication	
  and	
  is	
  currently	
   under	
  revision.	
  	
  The	
  manuscript	
  is	
  entitled:	
  “Acute	
  Myocardial	
  Infarction	
  in	
  Younger	
  Adults:	
   10-­‐Year	
  Temporal	
  Changes	
  in	
  AMI	
  Hospitalization	
  and	
  Sex	
  Differences	
  in	
  Early	
  Mortality	
   Rates	
  (2000	
  to	
  2009)”;	
  M.	
  Izadnegahdar,	
  J.	
  Singer,	
  MK.	
  Lee,	
  M.	
  Gao,	
  CR.	
  Thompson,	
  J.	
   Kopec,	
  KH	
  Humphries.	
  	
  The	
  conceptualization,	
  design,	
  and	
  data	
  request	
  process	
  were	
   conducted	
  by	
  Mona	
  Izadnegahdar	
  with	
  input	
  from	
  supervisors	
  Dr.	
  Joel	
  Singer	
  and	
  Dr.	
  Karin	
   Humphries.	
  	
  Ms.	
  Izadnegahdar	
  conducted	
  data	
  analysis	
  under	
  the	
  guidance	
  of	
  Dr.	
  Gao	
  and	
   May	
  Lee,	
  who	
  also	
  assisted	
  with	
  data	
  preparation	
  and	
  linkage.	
  	
  The	
  manuscript	
  was	
  written	
   by	
  Ms.	
  Izadnegahdar	
  with	
  epidemiological	
  and	
  clinical	
  input	
  from	
  supervisors	
  Drs.	
  Joel	
   Singer	
  and	
  Karin	
  Humphries,	
  and	
  committee	
  members	
  Dr.	
  Min	
  Gao,	
  Dr.	
  Jacek	
  Kopec	
  and	
  Dr.	
   ChrisThompson.	
   Chapter	
  4	
  (AMI55	
  Study)	
  is	
  original	
  research	
  funded	
  by	
  the	
  Heart	
  and	
  Stroke	
  Foundation	
  of	
   BC	
  and	
  Yukon,	
  with	
  Dr.	
  Karin	
  Humphries	
  as	
  the	
  primary	
  investigator.	
  	
  Mona	
  Izadnegahdar	
   had	
  an	
  integral	
  role	
  in	
  the	
  conceptualization	
  and	
  development	
  of	
  the	
  study	
  design	
  and	
   preparation	
  of	
  the	
  operating	
  grant	
  for	
  the	
  AMI55	
  study.	
  	
  Furthermore,	
  as	
  the	
  study’s	
  central	
   coordinator,	
  Ms.	
  Izadnegahdar	
  was	
  responsible	
  for	
  preparing	
  the	
  study	
  materials,	
  including	
    iv  data	
  collection	
  forms	
  and	
  patient	
  questionnaires,	
  providing	
  training	
  and	
  guidance	
  to	
  the	
   research	
  nurses	
  at	
  each	
  site,	
  overseeing	
  patient	
  enrolment,	
  data	
  entry	
  and	
  preparation,	
  and	
   conducting	
  all	
  patient	
  follow-­‐ups.	
  	
  These	
  activities	
  were	
  accomplished	
  with	
  guidance	
  and	
   advice	
  from	
  Dr.	
  Karin	
  Humphries	
  and	
  Dr.	
  Joel	
  Singer	
  and	
  based	
  on	
  expert	
  methodological	
   and	
  clinical	
  input	
  from	
  Dr.	
  Min	
  Gao,	
  Dr.	
  Jacek	
  Kopec	
  and	
  Dr.	
  Chris	
  Thompson.	
  Mona	
   Izadnegahdar	
  conducted	
  the	
  statistical	
  analyses	
  with	
  guidance	
  and	
  statistical	
  advice	
  from	
   Dr.	
  Gao	
  and	
  May	
  Lee.	
  	
  	
  Some	
  preliminary	
  findings	
  of	
  AMI55	
  were	
  presented	
  by	
  Ms.	
   Izadnegahdar	
  at	
  the	
  2011	
  Canadian	
  Cardiology	
  Conference	
  (CCC).	
  The	
  accepted	
  abstracts	
   were	
  prepared	
  based	
  on	
  input	
  from	
  all	
  committee	
  members.	
   	
    v  Table	
  of	
  Contents	
   Abstract	
  ..............................................................................................................................	
  ii	
   Preface	
  ...............................................................................................................................	
  iv	
   Table	
  of	
  Contents	
  ..............................................................................................................	
  vi	
   List	
  of	
  Tables	
  ......................................................................................................................	
  ix	
   List	
  of	
  Figures	
  ......................................................................................................................	
  x	
   Acknowledgements	
  ...........................................................................................................	
  xi	
   Dedication	
  .......................................................................................................................	
  xiii	
   Chapter	
  1	
   Thesis	
  Overview	
  and	
  Research	
  Objectives	
  ......................................................	
  1	
   Chapter	
  2	
   Acute	
  Myocardial	
  Infarction	
  in	
  Younger	
  Adults	
  -­‐	
  A	
  Narrative	
  Review	
  of	
   the	
  Literature	
  ......................................................................................................................	
  6	
   2.1	
   Epidemiology	
  .........................................................................................................	
  8	
   2.1.1	
   Incidence	
  and	
  Prevalence	
  ...............................................................................	
  8	
   2.1.2	
   Etiology	
  and	
  Clinical	
  Presentation	
  .................................................................	
  11	
   2.1.3	
   Traditional	
  Cardiac	
  Risk	
  Factors	
  ....................................................................	
  17	
   2.1.4	
   Summary	
  of	
  Findings	
  and	
  Knowledge	
  Gaps	
  in	
  Epidemiology	
  ........................	
  24	
   2.2	
   Trends	
  ..................................................................................................................	
  25	
   2.2.1	
   Trends	
  in	
  Cardiac	
  Risk	
  Factors	
  .......................................................................	
  25	
   2.2.2	
   Trends	
  in	
  AMI	
  Hospitalization	
  Rates	
  .............................................................	
  27	
   2.2.3	
   Summary	
  of	
  Findings	
  and	
  Rationale	
  for	
  Objective	
  2A	
  ...................................	
  30	
   2.3	
   Mortality	
  Outcomes	
  .............................................................................................	
  31	
   2.3.1	
   Short-­‐Term	
  Mortality	
  Post	
  AMI	
  .....................................................................	
  31	
   2.3.2	
   Long-­‐Term	
  Mortality	
  Post	
  AMI	
  ......................................................................	
  36	
   2.3.3	
   Mortality	
  Prior	
  to	
  Hospitalization	
  .................................................................	
  37	
   2.3.4	
   Determinants	
  of	
  Excess	
  Mortality	
  in	
  Women	
  ...............................................	
  38	
   2.3.5	
   Summary	
  of	
  Findings	
  and	
  Rational	
  for	
  Objective	
  2B	
  .....................................	
  42	
   2.4	
   Self-­‐Perceived	
  Health	
  Status	
  ................................................................................	
  43	
   2.4.1	
   Generic	
  Measures	
  of	
  Health	
  Status	
  ...............................................................	
  46	
   2.4.1.1	
   Short	
  Form-­‐12	
  (SF-­‐12)	
  ...........................................................................	
  47	
   2.4.2	
   Disease	
  Specific	
  Measures	
  of	
  Health	
  Status	
  ..................................................	
  48	
   2.4.2.1	
   Seattle	
  Angina	
  Questionnaire	
  (SAQ)	
  ......................................................	
  48	
   2.4.3	
   Sex	
  and	
  Age	
  Differences	
  in	
  Health	
  Status	
  .....................................................	
  53	
   2.4.4	
   Health	
  Status	
  and	
  Adverse	
  Outcomes	
  ...........................................................	
  55	
   2.4.5	
   Determinants	
  of	
  Poor	
  Health	
  Status	
  .............................................................	
  57	
   2.4.6	
   Summary	
  of	
  Findings	
  and	
  Rationale	
  for	
  Objective	
  3	
  .....................................	
  59	
    vi  Chapter	
  3	
   Ten-­‐Year	
  Temporal	
  Trends	
  and	
  Sex	
  Differences	
  in	
  Acute	
  Myocardial	
   Infarction	
  Hospitalization	
  and	
  Early	
  Mortality	
  Rates	
  in	
  Younger	
  Adults	
  (2000	
  to	
  2009)	
  ..	
  60	
   3.1	
   Introduction	
  .........................................................................................................	
  60	
   3.2	
   Methods	
  ...............................................................................................................	
  61	
   3.2.1	
   Study	
  Design	
  and	
  Population	
  ........................................................................	
  61	
   3.2.2	
   Data	
  Sources	
  .................................................................................................	
  63	
   3.2.3	
   Key	
  Variables	
  of	
  Interest	
  and	
  Definitions	
  ......................................................	
  63	
   3.2.4	
   Statistical	
  Analysis	
  .........................................................................................	
  65	
   3.3	
   Results	
  ..................................................................................................................	
  67	
   3.3.1	
   Study	
  Cohort	
  and	
  Patient	
  Characteristics	
  .....................................................	
  67	
   3.3.2	
   Trends	
  in	
  AMI	
  Hospitalization	
  .......................................................................	
  74	
   3.3.3	
   Trends	
  in	
  Thirty-­‐day	
  Mortality	
  Post	
  AMI	
  .......................................................	
  76	
   3.4	
   Discussion	
  ............................................................................................................	
  79	
   Chapter	
  4	
   Sex	
  Differences	
  in	
  Health	
  Status	
  Among	
  Younger	
  Adults	
  Following	
  Acute	
   Myocardial	
  Infarction	
  (AMI55	
  Study)	
  ...............................................................................	
  85	
   4.1	
   Introduction	
  .........................................................................................................	
  85	
   4.2	
   Study	
  Outline/Framework	
  ...................................................................................	
  86	
   4.3	
   Methods	
  ...............................................................................................................	
  87	
   4.3.1	
   Study	
  Initiation	
  and	
  Progress	
  Timeline	
  .........................................................	
  87	
   4.3.2	
   Study	
  Design	
  and	
  Population	
  ........................................................................	
  91	
   4.3.3	
   Study	
  Outcomes	
  ............................................................................................	
  95	
   4.3.3.1	
   Primary	
  Outcome:	
  Cardiac-­‐Specific	
  Health	
  Status	
  .................................	
  95	
   4.3.3.2	
   Secondary	
  Outcome:	
  Generic	
  Health	
  Status	
  .........................................	
  96	
   4.3.4	
   Key	
  Variables	
  of	
  Interest	
  ...............................................................................	
  97	
   4.3.5	
   Sample	
  Size	
  Calculation	
  .................................................................................	
  99	
   4.3.6	
   Statistical	
  Analysis	
  .......................................................................................	
  101	
   4.4	
   Results	
  ................................................................................................................	
  105	
   4.4.1	
   Sex	
  Differences	
  in	
  Baseline	
  Characteristics	
  .................................................	
  107	
   4.4.2	
   Symptom	
  Presentation	
  ...............................................................................	
  114	
   4.4.3	
   Follow-­‐ups	
  ...................................................................................................	
  116	
   4.4.4	
   Sex	
  Differences	
  and	
  Changes	
  in	
  Cardiac	
  Specific	
  Health	
  Status	
  Over	
  Time	
  119	
   4.4.4.1	
   SAQ-­‐	
  Angina	
  Frequency	
  Outcome	
  .......................................................	
  119	
   4.4.4.2	
   SAQ-­‐	
  Physical	
  Limitation	
  Outcome	
  ......................................................	
  124	
   4.4.4.3	
   SAQ-­‐	
  Disease	
  Perception	
  Outcome	
  .....................................................	
  129	
   4.4.4.4	
   Clinically	
  Important	
  Changes	
  in	
  Cardiac-­‐Specific	
  Health	
  Status	
  ..........	
  134	
   4.4.4.5	
   SF-­‐12	
  Physical	
  and	
  Mental	
  Component	
  Summary	
  Scores	
  ...................	
  135	
   4.5	
   Missing	
  Data	
  .......................................................................................................	
  140	
   4.6	
   Discussion	
  ..........................................................................................................	
  145	
   Chapter	
  5	
   Conclusions	
  .................................................................................................	
  154	
   5.1	
   Key	
  Findings	
  .......................................................................................................	
  154	
   5.2	
   Strengths	
  and	
  Limitations	
  ..................................................................................	
  160	
   5.3	
   Study	
  Implications	
  and	
  Future	
  Research	
  ............................................................	
  161	
   vii  Reference	
  List	
  .................................................................................................................	
  165	
   Appendices	
  .....................................................................................................................	
  182	
   Appendix	
  1	
  Narrative	
  Review	
  Search	
  Sources	
  and	
  MeSH	
  Terms	
  ................................	
  182	
   Appendix	
  2	
  List	
  of	
  Comorbidities	
  Included	
  in	
  Charlson	
  Index	
  .....................................	
  183	
   Appendix	
  3	
  Short	
  Form-­‐12,	
  Version	
  2	
  (SF-­‐12v2)	
  .........................................................	
  184	
   Appendix	
  4a	
  Description	
  of	
  Seattle	
  Angina	
  Questionnaire’s	
  Domains	
  and	
  Items	
  ......	
  187	
   Appendix	
  4b	
  Seattle	
  Angina	
  Questionnaire	
  (SAQ)	
  ......................................................	
  188	
   Appendix	
  5	
  AMI55-­‐	
  Eligibility	
  Worksheet	
  ...................................................................	
  191	
   Appendix	
  6	
  AMI55-­‐	
  Informed	
  Consent	
  Form	
  ..............................................................	
  192	
   Appendix	
  7	
  Godin-­‐Shephard	
  Leisure-­‐Time	
  Physical	
  Activity	
  Questionnaire	
  ...............	
  193	
   Appendix	
  8	
  AMI55-­‐	
  Psychosocial	
  Measures	
  ...............................................................	
  194	
   a)	
  Depression:	
  The	
  Patient	
  Health	
  Questionnaire	
  (PHQ-­‐9)	
  .........................................	
  194	
   b)	
  Stress:	
  Perceived	
  Stress	
  Scale	
  (PSS)	
  ........................................................................	
  195	
   C)	
  Anxiety:	
  Hospital	
  Anxiety	
  and	
  Depression	
  Scale	
  (HADS-­‐A)	
  .....................................	
  196	
   d)	
  Social	
  Support:	
  The	
  ENRICHD	
  Social	
  Support	
  Instrument	
  (ESSI)	
  .............................	
  197	
   	
    viii  List	
  of	
  Tables	
   Table	
  2.1	
  	
  Examples	
  of	
  Data	
  Sources	
  Used	
  for	
  Estimating	
  AMI	
  Burden	
  ...........................	
  10	
   Table	
  2.2	
  Studies	
  on	
  Age-­‐	
  and	
  Sex-­‐	
  Differences	
  in	
  Early	
  Mortality	
  Following	
  AMI	
   Hospitalization	
  ......................................................................................................	
  33	
   Table	
  2.3	
  Instruments	
  for	
  the	
  Assessment	
  of	
  Health	
  Status	
  in	
  patients	
  with	
  Heart	
   Disease	
  ..................................................................................................................	
  45	
   Table	
  3.1	
  Characteristics	
  of	
  AMI	
  Patients	
  by	
  Age,	
  Sex	
  and	
  Odds	
  Ratios	
  (95%	
  CI)*	
  for	
   Women	
  Relative	
  to	
  Men	
  .......................................................................................	
  69	
   Table	
  3.2	
  Trends*	
  in	
  Baseline	
  Characteristics	
  of	
  AMI	
  Patients	
  by	
  Sex,	
  Year	
  and	
  Odds	
   Ratios	
  (95%	
  CI)**	
  for	
  Women	
  Relative	
  to	
  Men	
  ....................................................	
  71	
   Table	
  3.3	
  Percentage	
  of	
  AMI	
  Patients	
  with	
  Hospital	
  Transfers	
  During	
  their	
  AMI	
   Admission,	
  by	
  Sex,	
  Age	
  and	
  Year	
  of	
  Admission	
  ....................................................	
  73	
   Table	
  4.1	
  Criteria	
  Used	
  for	
  AMI	
  Diagnosis	
  ........................................................................	
  91	
   Table	
  4.2	
  Number	
  of	
  Enrolled	
  Patients	
  at	
  each	
  Site	
  .......................................................	
  105	
   Table	
  4.3	
  Baseline	
  Socio-­‐Demographic	
  Characteristics	
  ..................................................	
  108	
   Table	
  4.4	
  Baseline	
  Cardiac	
  Risk	
  Factors	
  and	
  Clinical	
  Characteristics	
  ..............................	
  110	
   Table	
  4.5	
  Cardiac	
  Interventions	
  during	
  Hospitalization	
  for	
  AMI	
  ....................................	
  111	
   Table	
  4.6	
  Baseline	
  Psychosocial	
  and	
  Health	
  Status	
  Characteristics	
  ................................	
  113	
   Table	
  4.7	
  Reasons	
  for	
  Loss	
  to	
  Follow-­‐up	
  ........................................................................	
  116	
   Table	
  4.8	
  Loss	
  to	
  Follow-­‐up	
  According	
  to	
  Sex	
  and	
  Follow-­‐up	
  Time	
  ................................	
  117	
   Table	
  4.9	
  Missingness	
  Pattern	
  for	
  Patient	
  Follow-­‐ups	
  ...................................................	
  118	
   Table	
  4.10	
  Counts	
  and	
  Percentages	
  of	
  Young	
  AMI	
  Patients	
  with	
  Different	
  Levels	
  of	
   Angina,	
  According	
  to	
  Sex	
  and	
  Follow-­‐up	
  Time	
  ...................................................	
  120	
   Table	
  4.11	
  Counts	
  and	
  Percentages	
  of	
  Young	
  AMI	
  Patients	
  with	
  Different	
  Levels	
  of	
   Physical	
  Limitation,	
  According	
  to	
  Sex	
  and	
  Follow-­‐up	
  Time	
  ................................	
  126	
   Table	
  4.12	
  Counts	
  and	
  Percentages	
  of	
  Young	
  AMI	
  Patients	
  with	
  Different	
  Levels	
  of	
   Disease	
  Perception,	
  According	
  to	
  Sex	
  and	
  Follow-­‐up	
  Time	
  ................................	
  130	
   Table	
  4.13	
  Estimates	
  for	
  Mean	
  Differences	
  in	
  Disease	
  Perception	
  Scores	
  Based	
  on	
   the	
  Linear	
  Mixed	
  Effects	
  Model	
  III	
  ......................................................................	
  132	
   Table	
  4.14	
  Clinically	
  Important	
  Changes	
  in	
  SAQ	
  Scores	
  from	
  Baseline	
  ..........................	
  134	
   Table	
  4.15	
  Estimates	
  for	
  Mean	
  Differences	
  in	
  SF-­‐12	
  Physical	
  Component	
  Summary	
   Score	
  ...................................................................................................................	
  136	
   Table	
  4.16	
  Estimates	
  for	
  Mean	
  Differences	
  in	
  SF-­‐12	
  Mental	
  Component	
  Summary	
   Score	
  ...................................................................................................................	
  138	
   Table	
  4.17	
  Baseline	
  Characteristics	
  of	
  Complete	
  Non-­‐responders	
  ................................	
  143	
    ix  List	
  of	
  Figures	
   Figure	
  2.1	
  Conceptual	
  Framework	
  for	
  Dimensions	
  of	
  Health*	
  .........................................	
  44	
   Figure	
  3.1	
  Study	
  Flow	
  Chart	
  ..............................................................................................	
  62	
   Figure	
  3.2	
  Trends	
  in	
  Age-­‐Standardized	
  AMI	
  Hospitalization	
  Rates,	
  by	
  Sex	
  ......................	
  74	
   Figure	
  3.3	
  Linear	
  Trends	
  in	
  Age-­‐	
  and	
  Sex-­‐Specific	
  AMI	
  Hospitalization	
  Rates	
  and	
  the	
   Corresponding	
  Estimated	
  Annual	
  Percentage	
  Change	
  (EAPC)*	
  ...........................	
  75	
   Figure	
  3.4	
  Trends	
  in	
  30-­‐day	
  AMI	
  Mortality	
  Rates,	
  by	
  Sex	
  .................................................	
  76	
   Figure	
  3.5	
  Age-­‐	
  and	
  Sex-­‐Specific	
  Post	
  AMI	
  30-­‐day	
  Mortality	
  Rates	
  ..................................	
  77	
   Figure	
  3.6	
  Age-­‐Specific	
  Temporal	
  Changes	
  in	
  Unadjusted	
  Odds	
  Ratios*	
  (95%	
  CI)	
  for	
   30-­‐day	
  Mortality	
  Rates	
  of	
  Women	
  Relative	
  to	
  Men	
  .............................................	
  78	
   Figure	
  4.1	
  AMI55-­‐	
  Study	
  Outline/	
  Framework	
  .................................................................	
  89	
   Figure	
  4.2.	
  AMI55-­‐	
  Study	
  Initiation	
  and	
  Timeline	
  .............................................................	
  90	
   Figure	
  4.3	
  AMI55-­‐	
  Enrolment	
  Process	
  ............................................................................	
  106	
   Figure	
  4.4	
  Pain	
  Symptoms	
  during	
  AMI	
  in	
  Young	
  Adults	
  .................................................	
  115	
   Figure	
  4.5	
  General	
  Symptoms	
  during	
  AMI	
  in	
  Young	
  Adults	
  ...........................................	
  115	
   Figure	
  4.6	
  Bar	
  Plots	
  for	
  Levels	
  of	
  Angina	
  in	
  Young	
  AMI	
  Patients	
  According	
  to	
  Sex	
  and	
   Follow-­‐up	
  Time	
  ...................................................................................................	
  120	
   Figure	
  4.7	
  Estimated	
  Odds	
  Ratios	
  (95%	
  CI)	
  for	
  Presence	
  of	
  Angina	
  (Women	
  Relative	
   to	
  Men),	
  at	
  each	
  Time	
  Point	
  and	
  Changes	
  Over	
  Time	
  (from	
  Baseline),	
  based	
   on	
  Generalized	
  Mixed	
  Effects	
  Model	
  I	
  ................................................................	
  123	
   Figure	
  4.8	
  Bar	
  Plots	
  for	
  Levels	
  of	
  Physical	
  Limitation	
  in	
  Young	
  AMI	
  Patients,	
   According	
  to	
  Sex	
  and	
  Follow-­‐up	
  Time	
  ................................................................	
  126	
   Figure	
  4.9	
  Estimated	
  Odds	
  Ratios	
  (95%	
  CI)	
  for	
  Presence	
  of	
  Physical	
  Limitation	
   (Women	
  Relative	
  to	
  Men),	
  at	
  Each	
  Time	
  Point	
  and	
  Changes	
  Over	
  Time	
  (from	
   Baseline),	
  based	
  on	
  the	
  Generalized	
  Mixed	
  Effects	
  Model	
  II	
  .............................	
  128	
   Figure	
  4.10	
  Bar	
  Plots	
  for	
  Levels	
  of	
  Disease	
  Perception	
  in	
  Young	
  AMI	
  Patients,	
   According	
  to	
  Sex	
  and	
  Follow-­‐up	
  Time	
  ................................................................	
  130	
   Figure	
  4.11	
  Estimated	
  Mean	
  SAQ-­‐Disease	
  Perception	
  Scores	
  of	
  Young	
  AMI	
  Patients	
   Over	
  Time,	
  According	
  to	
  Sex	
  ...............................................................................	
  133	
   Figure	
  4.12	
  Estimated	
  Mean	
  SF-­‐12-­‐Physical	
  Component	
  Summary	
  Score	
  of	
  Young	
   AMI	
  Patients	
  Over	
  Time,	
  According	
  to	
  Sex	
  .........................................................	
  137	
   Figure	
  4.13	
  Estimated	
  Mean	
  SF-­‐12-­‐Mental	
  Component	
  Summary	
  Score	
  of	
  Young	
  AMI	
   Patients	
  Over	
  Time,	
  According	
  to	
  Sex*	
  ...............................................................	
  139	
   	
  	
   	
   	
   	
    x  Acknowledgements	
   This	
  thesis	
  would	
  not	
  have	
  been	
  possible	
  without	
  the	
  continuous	
  guidance	
  and	
  support	
  of	
   my	
  two	
  supervisors,	
  Dr.	
  Karin	
  Humphries	
  and	
  Dr.	
  Joel	
  Singer.	
  	
  Thank	
  you	
  for	
  believing	
  in	
  my	
   abilities	
  from	
  day	
  one,	
  for	
  accepting	
  to	
  be	
  my	
  supervisors,	
  and	
  for	
  giving	
  me	
  the	
  opportunity	
   to	
  learn	
  from	
  your	
  expertise	
  and	
  to	
  follow	
  your	
  path	
  and	
  love	
  for	
  research.	
  	
  Karin,	
  your	
   mentorship	
  and	
  the	
  rich	
  research	
  environment,	
  which	
  you	
  have	
  provided	
  me	
  over	
  the	
  years,	
   gave	
  me	
  the	
  opportunity	
  to	
  grow	
  as	
  a	
  researcher	
  and	
  to	
  pursue	
  my	
  academic	
  dreams.	
  	
  I	
  am	
   truly	
  grateful	
  for	
  this.	
  	
  Joel,	
  your	
  research	
  expertise	
  and	
  support	
  throughout	
  this	
  journey,	
   and	
  your	
  timely	
  humour	
  during	
  the	
  challenging	
  times,	
  were	
  often	
  all	
  that	
  I	
  needed	
  to	
  move	
   forward	
  and	
  see	
  the	
  light	
  at	
  the	
  end	
  of	
  the	
  tunnel.	
  I	
  thank	
  you	
  so	
  much	
  for	
  this.	
  	
  	
   I	
  would	
  like	
  to	
  express	
  my	
  deepest	
  gratitude	
  and	
  appreciation	
  to	
  my	
  thesis	
  committee	
   members,	
  Dr.	
  Min	
  Gao,	
  Dr.	
  Jacek	
  Kopec	
  and	
  Dr.	
  Chris	
  Thompson.	
  	
  Thank	
  you	
  for	
  always	
   being	
  available	
  to	
  meet,	
  answer	
  questions,	
  and	
  share	
  your	
  expertise	
  during	
  this	
  process,	
   from	
  the	
  planning	
  stages	
  to	
  the	
  final	
  days	
  of	
  completing	
  this	
  thesis.	
  	
  Most	
  importantly,	
   thank	
  you	
  for	
  your	
  invaluable	
  feedback,	
  and	
  the	
  time	
  you	
  spent	
  on	
  revisions	
  of	
  my	
  thesis.	
   I	
  would	
  also	
  like	
  to	
  acknowledge	
  all	
  the	
  hard	
  work	
  of	
  the	
  cardiac	
  research	
  nurses	
  in	
  enrolling	
   patients	
  for	
  the	
  AMI55	
  study.	
  This	
  study	
  would	
  not	
  have	
  been	
  possible	
  without	
  your	
   continuous	
  efforts.	
  You	
  are	
  an	
  amazing	
  group	
  and	
  I	
  feel	
  privileged	
  to	
  have	
  worked	
  with	
  you.	
  	
   I	
  would	
  like	
  to	
  acknowledge	
  the	
  help	
  of	
  Dr.	
  Eric	
  Sayer	
  in	
  assisting	
  me	
  with	
  the	
  design	
  and	
   development	
  of	
  the	
  web-­‐based	
  questionnaires,	
  while	
  working	
  on	
  his	
  own	
  PhD,	
  and	
  Stanko	
    xi  Kovacevic,	
  for	
  his	
  assistance	
  with	
  creating	
  the	
  data	
  entry	
  forms	
  in	
  the	
  Oracle	
  system.	
  I	
  am	
  so	
   appreciative	
  of	
  all	
  the	
  long	
  hours	
  you	
  both	
  spent	
  to	
  make	
  this	
  happen.	
  	
  Many	
  thanks	
  to	
   Laurel	
  Slaney,	
  Justin	
  Tao,	
  and	
  Stephanie	
  Sylvain	
  for	
  their	
  constant	
  help	
  with	
  all	
  aspects	
  of	
   AMI55	
  study,	
  encouraging	
  words,	
  and	
  never-­‐fading	
  enthusiasm	
  for	
  the	
  study.	
  	
  Without	
  your	
   help,	
  I	
  would	
  still	
  be	
  going	
  through	
  those	
  thousand	
  case	
  report	
  forms	
  and	
  questionnaires.	
  	
   I	
  would	
  like	
  to	
  thank	
  all	
  my	
  colleagues	
  in	
  our	
  team,	
  and	
  beyond,	
  for	
  their	
  valuable	
  advice	
   and	
  expertise,	
  and	
  constant	
  cheers.	
  	
  I	
  have	
  learned	
  so	
  much	
  from	
  each	
  of	
  you.	
  	
  I	
  am	
   especially	
  grateful	
  to	
  May	
  Lee	
  for	
  her	
  integral	
  role	
  during	
  this	
  journey	
  as	
  a	
  colleague	
  and	
  a	
   friend	
  -­‐	
  thank	
  you	
  for	
  all	
  the	
  hours	
  you	
  spent	
  (literally	
  day	
  and	
  night)	
  to	
  teach	
  me	
  new	
   concepts	
  and	
  for	
  your	
  constant	
  emotional	
  support	
  and	
  encouragement,	
  particularly	
  during	
   the	
  final	
  months	
  of	
  this	
  thesis.	
  	
  Also,	
  muchas	
  gracias	
  to	
  Monica	
  Norena	
  ,	
  for	
  always	
  being	
   available	
  to	
  help	
  at	
  any	
  time	
  and	
  for	
  your	
  friendship	
  over	
  the	
  years.	
  	
  Thank	
  you	
  to	
  all	
  my	
   friends	
  and	
  classmates,	
  for	
  sharing	
  those	
  much-­‐needed	
  breaks	
  and	
  laughter	
  along	
  the	
  way.	
  	
   I	
  would	
  like	
  to	
  also	
  acknowledge	
  the	
  School	
  of	
  Population	
  and	
  Public	
  Health	
  and	
  UBC	
   Graduate	
  Studies	
  for	
  providing	
  me	
  the	
  opportunity	
  to	
  gain	
  the	
  knowledge	
  and	
  the	
  skills	
   needed	
  to	
  contribute	
  to	
  our	
  understanding	
  of	
  the	
  health	
  and	
  wellbeing	
  of	
  heart	
  disease	
   patients.	
  	
  Many	
  thanks	
  to	
  Population	
  Data	
  BC,	
  for	
  providing	
  the	
  data	
  used	
  in	
  Chapter	
  3,	
  and	
   in	
  particular,	
  Tim	
  Choi,	
  for	
  all	
  his	
  technical	
  support.	
  	
  I	
  am	
  also	
  grateful	
  to	
  the	
  Heart	
  and	
   Stroke	
  Foundation	
  of	
  British	
  Columbia	
  and	
  Yukon,	
  the	
  Canadian	
  Cardiovascular	
  Outcomes	
   Research	
  Team,	
  and	
  the	
  Canadian	
  Health	
  Research	
  Institute	
  for	
  their	
  financial	
  support,	
   whether	
  through	
  the	
  operating	
  grant	
  or	
  PhD	
  fellowships,	
  that	
  I	
  benefited	
  from.	
  	
    xii  Dedication	
   To	
  the	
  participants	
  of	
  the	
  AMI55	
  study,	
  thank	
  you	
  so	
  much	
  for	
  believing	
  in	
  the	
  value	
  of	
  this	
   research	
  and	
  giving	
  your	
  time	
  when	
  you	
  were	
  faced	
  with	
  many	
  new	
  challenges	
  in	
  your	
  lives.	
  	
   I	
  can	
  assure	
  you	
  that	
  you	
  have	
  made	
  a	
  great	
  contribution	
  towards	
  our	
  understanding	
  of	
   heart	
  disease	
  in	
  younger	
  adults.	
  	
  Your	
  wishes	
  and	
  heartfelt	
  messages	
  at	
  the	
  end	
  of	
  the	
   questionnaires	
  were	
  always	
  a	
  big	
  energy	
  boost	
  for	
  me	
  to	
  continue	
  on.	
   To	
  Mr.	
  Jones,	
  a	
  teacher,	
  a	
  friend,	
  and	
  an	
  angel	
  who	
  saved	
  my	
  family,	
  in	
  the	
  most	
  challenging	
   times.	
  The	
  impact	
  that	
  heart	
  disease	
  had	
  on	
  your	
  life	
  was	
  painful	
  to	
  watch.	
  Those	
  memories	
   were	
  a	
  constant	
  source	
  of	
  motivation	
  for	
  me	
  to	
  keep	
  going	
  and	
  gave	
  even	
  more	
  meaning	
   and	
  purpose	
  to	
  do	
  this	
  research.	
  I	
  wish	
  you	
  were	
  still	
  among	
  us	
  as	
  I	
  am	
  sure	
  you	
  would	
  have	
   really	
  enjoyed	
  having	
  a	
  philosophical	
  conversation	
  about	
  these	
  findings.	
  I	
  know	
  you	
  could	
   relate	
  to	
  a	
  lot	
  of	
  it.	
  You	
  will	
  always	
  be	
  in	
  our	
  hearts.	
   Lastly,	
  and	
  most	
  importantly,	
  to	
  every	
  member	
  of	
  my	
  family,	
  big	
  and	
  small,	
  short	
  and	
  tall,	
   near	
  and	
  far	
  -­‐	
  the	
  support,	
  encouragement,	
  and	
  love,	
  each	
  and	
  every	
  one	
  of	
  you	
  has	
   provided	
  me	
  along	
  this	
  journey,	
  made	
  it	
  all	
  possible.	
  I	
  thank	
  you	
  from	
  the	
  bottom	
  of	
  my	
   heart	
  for	
  always	
  doing	
  everything	
  possible,	
  from	
  food	
  delivery,	
  to	
  child	
  care,	
  to	
  emotional	
   and	
  intellectual	
  support,	
  in	
  order	
  to	
  help	
  me	
  pursue	
  this	
  goal	
  from	
  day	
  one.	
  	
  To	
  my	
  parents,	
   who	
  planted	
  the	
  seeds	
  of	
  curiosity	
  and	
  love	
  of	
  learning	
  in	
  us	
  from	
  early	
  ages	
  -­‐	
  thank	
  you	
  for	
   the	
  great	
  sacrifices	
  you	
  made	
  in	
  your	
  life	
  for	
  us.	
  You	
  crossed	
  continents	
  to	
  make	
  many	
   ‘impossibles’	
  possible	
  for	
  us	
  and	
  I	
  am	
  forever	
  grateful	
  for	
  this.	
    xiii  To	
  my	
  husband,	
  my	
  friend,	
  and	
  my	
  champion,	
  you	
  have	
  been	
  through	
  so	
  much	
  with	
  me	
   during	
  this	
  journey	
  on	
  a	
  daily	
  basis.	
  	
  Words	
  cannot	
  describe	
  my	
  love	
  for	
  you	
  and	
  gratitude	
   for	
  all	
  you	
  have	
  done	
  for	
  our	
  family	
  throughout	
  this	
  journey.	
  	
  Thank	
  you	
  for	
  keeping	
  our	
  life	
   together	
  and	
  for	
  providing	
  the	
  peace	
  I	
  needed	
  at	
  home	
  to	
  make	
  this	
  happen.	
  	
  And	
  to	
  the	
   love	
  of	
  our	
  life,	
  this	
  journey	
  began	
  when	
  you	
  were	
  only	
  a	
  toddler.	
  Your	
  constant	
  sense	
  of	
   curiosity	
  and	
  love	
  for	
  everything	
  around	
  you	
  kept	
  me	
  going	
  through	
  some	
  challenging	
  days.	
   Thank	
  you	
  for	
  helping	
  with	
  stamping	
  and	
  labeling	
  all	
  those	
  study	
  envelopes	
  and	
  for	
  being	
  so	
   patient	
  with	
  me	
  when	
  I	
  had	
  to	
  miss	
  family	
  fun	
  and	
  sit	
  behind	
  my	
  desk.	
  	
  I	
  am	
  happy	
  to	
  tell	
   you	
  that	
  at	
  last,	
  it's	
  done,	
  and	
  we	
  will	
  celebrate	
  just	
  the	
  way	
  you	
  like…	
  with	
  two	
  big	
  buckets	
   of	
  ice	
  cream	
  to	
  share	
  with	
  everyone!	
    xiv  Chapter	
  1 Thesis	
  Overview	
  and	
  Research	
  Objectives	
   According	
  to	
  the	
  World	
  Health	
  Organization,	
  ischemic	
  heart	
  disease	
  (IHD)	
  remains	
  the	
   leading	
  cause	
  of	
  mortality	
  in	
  middle-­‐	
  and	
  high-­‐income	
  countries.(1)	
  	
  In	
  2010,	
  based	
  on	
  the	
   most	
  recent	
  findings	
  of	
  the	
  Global	
  Burden	
  of	
  Disease	
  (GBD)	
  Study,	
  IHD	
  ranked	
  first	
  as	
  the	
   leading	
  cause	
  of	
  years	
  of	
  life	
  lost	
  due	
  to	
  premature	
  mortality	
  (YLLs).(2)	
  	
  In	
  Canada,	
  in	
  2009,	
   21.6%	
  of	
  deaths	
  in	
  men	
  and	
  19.7%	
  of	
  deaths	
  in	
  women	
  were	
  due	
  to	
  IHD.	
  	
  The	
  two	
  most	
   common	
  manifestations	
  of	
  IHD	
  are	
  angina	
  and	
  acute	
  myocardial	
  infarction	
  (AMI)1.	
  	
   Although	
  the	
  overall	
  incidence	
  of	
  acute	
  myocardial	
  infarction	
  is	
  lower	
  in	
  women,	
  its	
   consequences	
  are	
  not	
  benign.	
  	
  Compared	
  to	
  their	
  male	
  counterparts,	
  women	
  are	
  at	
  a	
   greater	
  risk	
  of	
  death	
  within	
  the	
  first	
  few	
  weeks	
  of	
  their	
  hospitalization	
  for	
  AMI.(3-­‐5)	
  	
  It	
  is	
   also	
  estimated	
  that	
  47%	
  of	
  women,	
  as	
  compared	
  to	
  36%	
  of	
  men,	
  would	
  die	
  within	
  5	
  years	
   following	
  their	
  first	
  AMI.(6)	
  	
  	
   Research	
  focused	
  on	
  understanding	
  this	
  sex	
  gap	
  in	
  AMI	
  outcomes,	
  as	
  well	
  as	
  differences	
  in	
   presentation	
  and	
  management	
  of	
  ischemic	
  heart	
  disease	
  in	
  men	
  and	
  women,	
  has	
  served	
  as	
   the	
  stepping-­‐stone	
  in	
  the	
  development	
  of	
  campaigns	
  on	
  heart	
  disease	
  awareness	
  and	
   prevention	
  in	
  women,	
  such	
  as	
  “Go	
  Red	
  for	
  Women”	
  and	
  the	
  “Heart	
  Truth”.	
  	
  However,	
   historically,	
  most	
  of	
  the	
  research	
  in	
  this	
  area	
  has	
  focused	
  on	
  older	
  adults,	
  mainly	
  due	
  to	
  the	
   fact	
  that	
  women	
  typically	
  present	
  with	
  AMI	
  at	
  much	
  older	
  ages	
  than	
  men.	
  	
  It	
  is	
  believed	
  that	
   1  	
  Angina	
  refers	
  to	
  symptom	
  of	
  chest	
  pain	
  or	
  discomfort	
  that	
  occurs	
  when	
  an	
  area	
  of	
  the	
  heart	
  is	
  deprived	
  of	
   oxygen.	
  It	
  is	
  typically	
  described	
  as	
  a	
  crushing	
  or	
  squeezing	
  sensation	
  in	
  the	
  chest	
  and	
  may	
  radiate	
  to	
  the	
   jaw,	
  shoulders,	
  arm	
  or	
  back.	
  Acute	
  myocardial	
  infarction	
  occurs	
  when	
  blood	
  flow	
  to	
  a	
  part	
  of	
  heart	
  is	
   blocked	
  for	
  a	
  long	
  enough	
  time	
  that	
  part	
  of	
  the	
  heart	
  muscle	
  is	
  damaged	
  or	
  dies.	
  The	
  clinical	
  definition	
  of	
   AMI	
  is	
  provided	
  in	
  Chapter	
  2.	
   1  the	
  lower	
  likelihood	
  of	
  developing	
  AMI	
  in	
  younger	
  women,	
  particularly	
  in	
  pre-­‐menopausal	
   women,	
  is	
  related	
  to	
  the	
  protective	
  effect	
  of	
  endogenous	
  estrogen	
  hormones.(7)	
   Although	
  the,	
  overall,	
  incidence	
  of	
  AMI	
  among	
  younger	
  adults	
  is	
  lower,	
  when	
  it	
  does	
  occur,	
   it	
  can	
  have	
  immense	
  clinical,	
  psychological,	
  and	
  economic	
  impact	
  on	
  patients,	
  their	
  families,	
   and	
  society	
  as	
  a	
  whole.	
  	
  The	
  importance	
  of	
  understanding	
  AMI	
  in	
  younger	
  adults	
  was	
  noted	
   in	
  the	
  literature	
  as	
  early	
  as	
  in	
  the	
  1960s	
  (8)	
  but	
  due	
  to	
  its	
  relatively	
  lower	
  incidence	
  and	
  the	
   resulting	
  difficulty	
  in	
  enrolling	
  younger	
  AMI	
  patients	
  in	
  studies,	
  research	
  in	
  this	
  population	
   has	
  remained	
  limited.	
  	
  However,	
  in	
  more	
  recent	
  years,	
  the	
  increasing	
  prevalence	
  of	
  cardiac	
   risk	
  factors,	
  such	
  as	
  diabetes,	
  obesity	
  and	
  sedentary	
  life	
  style	
  among	
  younger	
  adults	
  in	
  the	
   general	
  population,	
  has	
  raised	
  concerns	
  about	
  the	
  imminent	
  risk	
  of	
  heart	
  disease	
  in	
  this	
  age	
   group.	
  	
  Consequently,	
  in	
  2009,	
  the	
  Heart	
  and	
  Stroke	
  Foundation	
  of	
  Canada	
  identified	
   younger	
  adults,	
  particularly	
  women,	
  as	
  a	
  vulnerable,	
  and	
  ‘at-­‐risk’	
  population	
  for	
  heart	
   disease.(9)	
  	
  	
   Currently,	
  it	
  is	
  estimated	
  that	
  AMI	
  among	
  younger	
  adults	
  accounts	
  for	
  about	
  8-­‐25%	
  of	
  all	
   AMI	
  hospitalizations,	
  depending	
  on	
  the	
  study	
  population,	
  year,	
  and	
  the	
  definition	
  used	
  to	
   identify	
  younger	
  adults.(10-­‐12)	
  	
  Emerging	
  but	
  limited	
  evidence	
  suggests	
  increasing	
  trends	
  in	
   AMI	
  hospitalization	
  rates	
  as	
  well	
  as	
  a	
  smaller	
  reduction	
  in	
  mortality	
  rates	
  of	
  younger	
  adults	
   compared	
  to	
  the	
  older	
  population.	
  However,	
  a	
  more	
  comprehensive	
  and	
  population-­‐based	
   analysis	
  of	
  the	
  temporal	
  changes	
  in	
  AMI	
  hospitalization,	
  and	
  early	
  mortality	
  rates	
  of	
   younger	
  adults	
  following	
  AMI	
  is	
  needed	
  to	
  gain	
  a	
  better	
  understanding	
  of	
  the	
  burden	
  and	
   impact	
  of	
  heart	
  disease	
  in	
  this	
  population.	
  	
  	
    2  Furthermore,	
  evidence	
  suggests	
  that	
  the	
  greatest	
  sex	
  gap	
  in	
  prognosis	
  of	
  AMI	
  exists	
  among	
   those	
  younger	
  than	
  55	
  years	
  of	
  age,	
  with	
  younger	
  women	
  experiencing	
  greater	
  mortality	
   and	
  morbidity	
  than	
  their	
  male	
  counterparts;	
  a	
  finding	
  that	
  is	
  not	
  explained	
  by	
  any	
   traditional	
  cardiac	
  risk	
  factors.(4)	
  	
  In	
  the	
  overall	
  coronary	
  artery	
  disease	
  (CAD)	
  population,	
   non-­‐traditional	
  factors	
  such	
  as	
  self-­‐perceived	
  health	
  status	
  (patients’	
  perception	
  of	
  how	
   their	
  disease	
  impacts	
  their	
  symptoms,	
  function	
  and	
  quality	
  of	
  life)	
  have	
  been	
  shown	
  to	
  be	
   associated	
  with	
  increased	
  morbidity	
  and	
  mortality.	
  	
  In	
  particular,	
  self-­‐perceived	
  health	
   status	
  has	
  been	
  shown	
  to	
  be	
  an	
  independent	
  predictor	
  of	
  morbidity	
  and	
  mortality,	
  even	
   after	
  taking	
  patients’	
  comorbidities	
  and	
  disease	
  burden	
  into	
  account.(13)	
  	
  Some	
  suggest	
   that	
  a	
  plausible	
  mechanism,	
  or	
  explanation,	
  for	
  this	
  association	
  is	
  that	
  self-­‐perceived	
  health	
   status	
  is	
  a	
  reflection	
  of	
  other	
  unmeasured	
  disease	
  burden	
  and	
  mortality	
  risks.(14)	
  	
  Others	
   argue	
  that	
  the	
  independent	
  association	
  between	
  health	
  status	
  and	
  poor	
  outcomes	
  indicates	
   that	
  the	
  patients’	
  perception	
  on	
  how	
  their	
  disease	
  is	
  affecting	
  their	
  life,	
  and	
  their	
  outlook	
  on	
   life,	
  in	
  the	
  context	
  of	
  their	
  disease,	
  is	
  a	
  driving	
  factor	
  in	
  and	
  of	
  itself.	
  	
   Because	
  of	
  the	
  observed	
  association	
  between	
  self-­‐perceived	
  health	
  status	
  and	
  morbidity	
   and	
  mortality,	
  it	
  has	
  been	
  hypothesized	
  that	
  the	
  sex	
  differences	
  in	
  the	
  prognosis	
  of	
  younger	
   adults,	
  particularly	
  during	
  the	
  early	
  recovery	
  period	
  post	
  AMI,	
  may	
  be	
  due	
  to	
  worse	
  self-­‐ perceived	
  health	
  status	
  in	
  younger	
  women	
  than	
  younger	
  men.	
  	
  However,	
  this	
  hypothesis	
   has	
  yet	
  to	
  be	
  studied.	
  	
  As	
  a	
  first	
  step	
  towards	
  addressing	
  this	
  knowledge	
  gap,	
  an	
   examination	
  of	
  sex	
  differences	
  in	
  self-­‐perceived	
  health	
  status	
  and	
  its	
  changes	
  over	
  time	
   following	
  an	
  AMI	
  event,	
  among	
  younger	
  adults,	
  is	
  merited.	
    3  As	
  such,	
  the	
  three	
  main	
  objectives	
  of	
  this	
  thesis	
  are	
  as	
  follows:	
   Objective	
  1:	
  Provide	
  a	
  comprehensive	
  narrative	
  review	
  of	
  the	
  current	
  knowledge	
  regarding	
   epidemiology	
  and	
  outcome	
  of	
  myocardial	
  infarction	
  in	
  younger	
  adults	
  and	
  highlight	
  the	
   existing	
  knowledge	
  gaps	
  in	
  this	
  area	
  of	
  research	
  (Chapter	
  2).	
   Objective	
  2:	
  A)	
  Examine	
  the	
  sex	
  differences	
  and	
  recent	
  temporal	
  changes	
  in	
  AMI	
   hospitalization	
  and	
  AMI	
  related	
  comorbidities,	
  in	
  a	
  population-­‐based	
  setting,	
  over	
  a	
  10-­‐year	
   period	
  and	
  B)	
  Examine	
  the	
  temporal	
  changes	
  in	
  30-­‐day	
  mortality	
  rates	
  following	
  AMI	
   hospitalization	
  and	
  determine	
  whether	
  the	
  sex	
  gap	
  in	
  30-­‐day	
  mortality,	
  among	
  younger	
   adults,	
  has	
  changed	
  in	
  recent	
  years	
  (Chapter	
  3).	
   Objective	
  3:	
  Assess	
  the	
  sex	
  differences	
  in	
  the	
  socio-­‐demographic,	
  clinical	
  and	
  psychosocial	
   characteristics	
  of	
  young	
  AMI	
  patients	
  and	
  examine	
  the	
  sex	
  differences	
  and	
  changes	
  in	
  their	
   health	
  status	
  outcomes	
  during	
  the	
  first	
  12	
  months	
  following	
  their	
  AMI	
  hospitalization	
   (Chapter	
  4).	
  	
   To	
  this	
  end,	
  Chapters	
  3	
  and	
  4	
  represent	
  two	
  separate	
  original	
  studies.	
  	
  Chapter	
  3	
  is	
  based	
  on	
   retrospectively	
  collected,	
  administrative	
  data	
  in	
  British	
  Columbia	
  (linked	
  BC	
  hospitalization	
   and	
  vital	
  statistics),	
  between	
  the	
  years	
  2000	
  to	
  2009	
  (Trend	
  Study).	
  	
  Both	
  objectives	
  2A	
  and	
   2B	
  of	
  Chapter	
  3	
  are	
  based	
  on	
  the	
  same	
  study	
  population	
  and	
  data	
  sources.	
  	
  On	
  the	
  other	
   hand,	
  Chapter	
  4	
  presents	
  the	
  results	
  of	
  prospectively	
  collected	
  data	
  on	
  286	
  younger	
  AMI	
   patients	
  in	
  British	
  Columbia	
  between	
  the	
  years	
  2008	
  to	
  2011	
  (AMI55	
  Study).	
    4  Chapter	
  5,	
  the	
  concluding	
  chapter,	
  provides	
  a	
  summary	
  and	
  an	
  integrated	
  discussion	
  of	
  the	
   findings,	
  the	
  strengths	
  and	
  limitations	
  of	
  these	
  studies,	
  their	
  collective	
  implications,	
  and	
   suggestions	
  for	
  future	
  research.	
  	
   	
    5  Chapter	
  2 Acute	
  Myocardial	
  Infarction	
  in	
  Younger	
  Adults	
  -­‐	
  A	
   Narrative	
  Review	
  of	
  the	
  Literature	
   The	
  objective	
  of	
  this	
  narrative	
  literature	
  review	
  is	
  to	
  compile,	
  synthesise,	
  and	
  summarize	
   the	
  findings	
  of	
  the	
  currently	
  available	
  research	
  on	
  acute	
  myocardial	
  infarction	
  in	
  younger	
   adults	
  and	
  highlight	
  some	
  of	
  the	
  existing	
  knowledge	
  gaps,	
  which	
  the	
  original	
  research	
   presented	
  in	
  this	
  thesis	
  aims	
  to	
  address.	
  	
  This	
  literature	
  review	
  is	
  divided	
  into	
  four	
  main	
   sections:	
  2.1)	
  epidemiology	
  of	
  AMI	
  in	
  younger	
  adults	
  (i.e.	
  incidence	
  and	
  prevalence,	
   etiology,	
  clinical	
  presentation,	
  and	
  risk	
  factors),	
  2.2)	
  trends	
  in	
  AMI	
  risk	
  factors	
  and	
   hospitalization	
  rates,	
  2.3)	
  AMI	
  mortality	
  outcomes,	
  and	
  2.4)	
  patient-­‐reported	
  health	
  status	
   outcomes	
  following	
  AMI.	
  	
  While	
  the	
  main	
  focus	
  of	
  this	
  chapter	
  is	
  to	
  examine	
  sex	
  differences	
   in	
  the	
  younger	
  age	
  group,	
  in	
  order	
  to	
  provide	
  a	
  broader	
  context,	
  each	
  section	
  begins	
  with	
   information,	
  if	
  available,	
  on	
  the	
  overall	
  characteristics	
  of	
  younger	
  adults	
  compared	
  to	
  older	
   adults.	
  	
  Also	
  each	
  section	
  will	
  end	
  with	
  a	
  summary	
  of	
  the	
  findings	
  and	
  the	
  existing	
   knowledge	
  gap,	
  which	
  led	
  to	
  the	
  development	
  of	
  objectives	
  2	
  and	
  3	
  of	
  this	
  thesis.	
  	
  A	
   description	
  of	
  the	
  search	
  databases	
  and	
  medical	
  subject	
  headings	
  (MeSH)	
  used	
  for	
   conducting	
  this	
  narrative	
  review	
  are	
  provided	
  in	
  Appendix	
  1.	
   Before	
  continuing	
  on	
  to	
  the	
  main	
  sections	
  of	
  this	
  literature	
  review,	
  it	
  is	
  important	
  to	
  clearly	
   define	
  the	
  terms	
  ‘younger	
  adults’	
  and	
  ‘acute	
  myocardial	
  infarction’:	
   Younger	
  Adults:	
  In	
  the	
  context	
  of	
  myocardial	
  infarction,	
  there	
  is	
  no	
  consistent	
  definition	
  for	
   the	
  terms	
  ‘young’	
  or	
  ‘younger’	
  adults	
  in	
  the	
  literature	
  as	
  these	
  terms	
  have	
  been	
  used	
  in	
    6  different	
  studies	
  to	
  define	
  different	
  age	
  groups.	
  	
  This	
  inconsistency	
  partially	
  stems	
  from	
  an	
   unclear	
  definition	
  of	
  premature	
  acute	
  coronary	
  syndrome,	
  and	
  the	
  age	
  group	
  that	
  the	
  term	
   ‘premature’	
  refers	
  to,	
  as	
  well	
  as	
  the	
  differences	
  in	
  the	
  rationale	
  for	
  choosing	
  specific	
  patient	
   populations.	
  	
  For	
  the	
  purposes	
  of	
  this	
  literature	
  review,	
  these	
  terms	
  may	
  be	
  used	
   interchangeably	
  and	
  refer	
  to	
  different	
  age	
  groups	
  ranging	
  from	
  20	
  to	
  65	
  years	
  of	
  age	
  in	
   order	
  to	
  reflect	
  the	
  exact	
  definition	
  used	
  in	
  each	
  cited	
  study.	
  	
  However,	
  in	
  Chapters	
  3	
  and	
  4	
   of	
  this	
  thesis,	
  which	
  are	
  based	
  on	
  original	
  studies,	
  ‘younger	
  adults’	
  refers	
  to	
  those	
  between	
   20-­‐55	
  years	
  of	
  age.	
  This	
  definition	
  was	
  chosen	
  because,	
  in	
  the	
  literature,	
  this	
  is	
  the	
  age	
   group	
  that	
  has	
  been	
  identified	
  to	
  have	
  the	
  greatest,	
  unexplained	
  sex	
  gap	
  in	
  early	
  mortality	
   following	
  an	
  acute	
  myocardial	
  infarction.	
   Acute	
  Myocardial	
  Infarction	
  (AMI):	
  Acute	
  myocardial	
  infarction	
  is	
  the	
  acute	
  manifestation	
   of	
  an	
  underlying	
  coronary	
  artery	
  disease	
  (CAD).	
  The	
  diagnosis	
  of	
  acute	
  myocardial	
  infarction	
   is	
  based	
  on	
  detection	
  of	
  elevated	
  levels	
  of	
  biomarkers	
  for	
  cardiac	
  necrosis	
  (e.g.	
  troponin	
  or	
   creatine	
  kinase	
  MB)	
  and	
  supportive	
  evidence	
  suggestive	
  of	
  AMI	
  (e.g.	
  prolonged	
  ischemic	
   signs/symptoms	
  and	
  electrocardiographic	
  findings).	
  	
  The	
  definition	
  of	
  AMI	
  was	
  modified	
  in	
   the	
  year	
  2000	
  to	
  distinguish	
  between	
  the	
  two	
  subtypes	
  of	
  AMI:	
  ST-­‐elevation	
  MI	
  (STEMI)	
  and	
   Non-­‐ST	
  elevation	
  MI	
  (NSTEMI).(15)	
  	
  In	
  general,	
  STEMI	
  patients	
  have	
  higher	
  in-­‐hospital	
   mortality	
  rates	
  and	
  are	
  more	
  likely	
  to	
  be	
  younger	
  and	
  male	
  compared	
  to	
  NSTEMI	
  patients.	
  	
   For	
  the	
  purposes	
  of	
  this	
  thesis,	
  the	
  term	
  ‘mixed	
  AMI	
  population’	
  will	
  be	
  used	
  to	
  refer	
  to	
   studies	
  where	
  both	
  STEMIs	
  and	
  NSTEMIs	
  were	
  included,	
  but	
  the	
  findings	
  were	
  not	
  reported	
   by	
  type	
  of	
  AMI.	
  	
  When	
  available,	
  the	
  results	
  will	
  be	
  reported	
  by	
  AMI	
  type.	
    7  2.1 Epidemiology	
   2.1.1 Incidence	
  and	
  Prevalence	
   Incidence	
   Estimating	
  the	
  ‘true’	
  incidence	
  of	
  AMI	
  (i.e.	
  the	
  number	
  of	
  new	
  cases	
  in	
  a	
  given	
  period	
  of	
   time	
  and	
  population)	
  is	
  complex	
  and	
  often	
  not	
  attainable	
  due	
  to	
  the	
  lack	
  of	
  reliable	
  and	
   accurate	
  cause-­‐specific	
  mortality	
  data	
  on	
  fatal	
  AMIs	
  that	
  occurred	
  prior	
  to	
  hospitalization.	
  	
   As	
  such,	
  most	
  studies	
  rely	
  on	
  AMI	
  hospitalizations,	
  based	
  on	
  population-­‐based	
  hospital	
   discharge	
  data	
  or	
  AMI	
  registries,	
  and	
  may	
  use	
  rigorous	
  methods	
  and	
  long	
  washout	
  periods	
   to	
  identify	
  the	
  first	
  AMI	
  event	
  for	
  each	
  patient.	
  	
   In	
  Canada,	
  using	
  the	
  hospital	
  Discharge	
  Abstract	
  Database	
  (DAD),	
  the	
  Canadian	
  Institute	
  for	
   Health	
  Information	
  (CIHI)	
  estimates	
  the	
  annual	
  overall	
  age-­‐standardized	
  rates	
  of	
   hospitalization	
  for	
  AMI	
  in	
  adults	
  >20	
  years	
  of	
  age.	
  In	
  the	
  year	
  2010,	
  the	
  overall	
  age-­‐ standardized	
  AMI	
  hospitalization	
  rates	
  were	
  133/100,000	
  population	
  in	
  women	
  and	
   293/100,000	
  population	
  in	
  men.	
  	
  In	
  British	
  Columbia,	
  with	
  the	
  lowest	
  rates	
  of	
  AMI	
   hospitalizations	
  in	
  Canada,	
  the	
  age-­‐standardized	
  rates	
  were	
  97/100,000	
  and	
  235/100,000	
   population	
  in	
  women	
  and	
  men,	
  respectively.(16)	
  	
  It	
  has	
  been	
  consistently	
  shown	
  that	
  the	
   overall	
  incidence	
  of	
  AMI	
  is	
  lower	
  in	
  women	
  than	
  men.	
  	
  	
   With	
  respect	
  to	
  AMI	
  in	
  younger	
  adults,	
  a	
  recently	
  published	
  analysis	
  of	
  the	
  ‘incident’	
  cases	
   of	
  AMI	
  hospitalizations	
  between	
  the	
  years	
  1975-­‐2005,	
  based	
  on	
  the	
  U.S	
  Worcester	
  Heart	
   Attack	
  Study	
  (WHAS),	
  found	
  that	
  approximately	
  20%	
  of	
  all	
  AMI	
  hospitalizations	
  occurred	
  in	
   adults	
  <55	
  years	
  of	
  age	
  with	
  a	
  rate	
  of	
  66/100,000	
  population	
  (95%CI:	
  63	
  to	
  69/100,000).(17)	
   8  This	
  study,	
  however,	
  did	
  not	
  evaluate	
  sex-­‐	
  specific	
  rates	
  within	
  this	
  young	
  population.	
  	
  The	
   few	
  available	
  reports	
  on	
  sex-­‐specific	
  AMI	
  hospitalization	
  rates	
  in	
  younger	
  adults	
  have	
   observed	
  that,	
  similar	
  to	
  the	
  overall	
  AMI	
  population,	
  hospitalization	
  rates	
  are	
  higher	
  in	
   younger	
  men	
  than	
  in	
  their	
  female	
  counterparts	
  (18-­‐21),	
  with	
  a	
  male	
  to	
  female	
  ratio	
  of	
  4	
  to	
  1	
   for	
  the	
  number	
  of	
  AMI	
  hospitalizations	
  in	
  those	
  younger	
  than	
  55	
  years	
  of	
  age	
  (re-­‐calculated	
   from	
  their	
  Table	
  1).(22)	
  	
  It	
  has	
  been	
  shown	
  that	
  this	
  ratio	
  decreases	
  with	
  increasing	
  age	
  and	
   becomes	
  nearly	
  1.7	
  to	
  1	
  among	
  AMI	
  patients	
  older	
  than	
  75	
  years	
  of	
  age	
  (19),	
  indicating	
  that	
   among	
  younger	
  adults,	
  men	
  have	
  a	
  greater	
  risk	
  of	
  AMI	
  hospitalization	
  than	
  women.	
   Prevalence	
   The	
  prevalence	
  of	
  self-­‐reports	
  of	
  physician-­‐diagnosed	
  heart	
  disease,	
  including	
  AMI,	
  has	
   been	
  estimated	
  in	
  Canada	
  and	
  the	
  U.S	
  using	
  community	
  health	
  surveys	
  such	
  as	
  the	
   Canadian	
  Community	
  Health	
  Survey	
  (CCHS)	
  and	
  the	
  National	
  Health	
  and	
  Nutrition	
   Examination	
  Survey	
  (NHANES),	
  respectively.	
  	
  Based	
  on	
  NHANES,	
  in	
  the	
  year	
  2006,	
  a	
  total	
  of	
   7.9	
  million	
  adults	
  reported	
  having	
  “ever	
  had	
  a	
  heart	
  attack”,	
  with	
  the	
  overall	
  prevalence	
  of	
   4.7%	
  in	
  men	
  and	
  2.7%	
  in	
  women.(23)	
  	
  In	
  Canada,	
  based	
  on	
  CCHS	
  2000/01,	
  the	
   corresponding	
  prevalence	
  is	
  estimated	
  to	
  be	
  2.7%	
  in	
  men	
  and	
  1.5%	
  in	
  women2.(24)	
  	
  In	
  a	
   study	
  by	
  Towfighi	
  et	
  al.,	
  based	
  on	
  the	
  U.S	
  NHANES	
  1999-­‐2004	
  data,	
  the	
  prevalence	
  of	
  self-­‐ reported	
  history	
  of	
  AMI	
  among	
  younger	
  adults	
  (35-­‐54	
  years)	
  was	
  2.2%	
  in	
  men	
  and	
  1.0%	
  in	
   women.(25)	
  	
  Table	
  2.1	
  provides	
  a	
  summary	
  of	
  some	
  of	
  the	
  data	
  sources	
  which	
  have	
  been	
   used	
  to	
  estimate	
  the	
  burden	
  of	
  AMI	
  in	
  different	
  populations.	
  	
    2  	
  The	
  variable	
  “ever	
  had	
  a	
  heart	
  attack”	
  (CCCA_12A)	
  is	
  no	
  longer	
  included	
  in	
  the	
  more	
  recent	
  cycles	
  of	
  CCHS	
   (i.e.	
  cycles	
  3.1	
  or	
  4.1),	
  as	
  such,	
  comparison	
  with	
  data	
  from	
  more	
  recent	
  cycles	
  of	
  CCHS	
  was	
  not	
  possible.	
   9  Table	
  2.1	
  	
  Examples	
  of	
  Data	
  Sources	
  Used	
  for	
  Estimating	
  AMI	
  Burden	
   Data Source  	
    Population  Description  Population Estimates  Canadian Institute for Health Information (CIHI)(26)  All Canadian Provinces except Quebec  Incidence of AMI hospitalizations (based on discharges or patients).  Nationwide Inpatient Sample (NIS)(27) and  NIS: sample of U.S. hospitals in 45 states  National Hospital Discharge (NHDS)(28)  NHDS: sample of all U.S. hospitals  Using Discharge Abstract Database (DAD), CIHI captures population-based administrative, clinical and demographic information on all hospital discharges NIS- part of Health Care Utilization Project in U.S.; captures information on allpayer hospital inpatient stay and care  Hospital Discharge Data:  * differ in their sampling methods  Incidence of AMI hospitalizations (based on discharges or patients).  NHDS- part of Centre for Disease Control and Prevention (CDC); captures information on inpatient discharges from non-Federal short-stay hospitals  AMI Registries: Worcester Heart Attack Study (WHSA)(29)  All Worcester residents admitted with a confirmed diagnosis of AMI  Multinational Monitoring of Trends and Determinants of Cardiovascular Disease (MONICA) project(30) Community Surveys:  AMI confirmed cases in patients 35-64 years  Canadian Community Health Survey (CCHS)(31)  Sample of Canadian population (12 years and older) in 10 provinces and 3 territories Sample of American population (all ages)  National Health and Nutrition Examination Survey (NHANES)(32) National Health Interview Survey (NHIS)(33)  Community-based, prospective study of AMI hospitalizations to any of the metropolitan Worcester (U.S) hospitals between years 1975-2003 Based on 27 countries  Cross-sectional household survey that collects information related to health status, health care utilization and health determinants for the Canadian population NHANES: collects health and nutritional information on adults and children in the U.S by interviews and health examinations  Incidence of AMI hospitalizations  Incidence and prevalence of coronary heart disease hospitalizations  Self-reported, physician-diagnosed, prevalence of coronary heart disease (including heart attack) in the general population Self-reported, physician-diagnosed, prevalence of coronary heart disease (including heart attack) in the general population  NHIS: cross-sectional household survey; collects information on health, and health care utilization  10  2.1.2 Etiology	
  and	
  Clinical	
  Presentation	
   Etiology	
   The	
  underlying	
  etiology	
  of	
  myocardial	
  infarction	
  in	
  younger	
  adults	
  is	
  believed	
  to	
  be	
  mainly	
   due	
  to	
  coronary	
  atherosclerosis	
  (hardening	
  of	
  arteries	
  due	
  to	
  plaque	
  formation	
  consisting	
  of	
   fatty	
  substances	
  such	
  as	
  cholesterol)	
  and	
  traditional	
  cardiac	
  risk	
  factors.	
  	
  In	
  approximately	
   20%	
  of	
  young	
  patients	
  presenting	
  with	
  an	
  AMI,	
  the	
  underlying	
  etiology	
  may	
  be	
  non-­‐ atherosclerotic,	
  such	
  as	
  coronary	
  artery	
  embolism,	
  spontaneous	
  coronary	
  artery	
  dissection,	
   or	
  congenital	
  coronary	
  abnormalities.	
  	
  Further	
  information	
  on	
  these	
  non-­‐atherosclerotic	
   causes,	
  which	
  is	
  not	
  the	
  focus	
  of	
  this	
  review,	
  can	
  be	
  found	
  in	
  two	
  review	
  papers	
  by	
  Osula	
  et	
   al.(34),	
  and	
  Rubin	
  et	
  al.(35)	
   New	
  research	
  focusing	
  on	
  the	
  pathophysiology	
  and	
  etiology	
  of	
  AMI	
  suggests	
  that	
   microvascular	
  disease,	
  atherosclerosis	
  with	
  plaque	
  disruption	
  (particularly	
  among	
  patients	
   with	
  no	
  obvious	
  stenosis),	
  as	
  well	
  as	
  endothelial	
  dysfunction,	
  are	
  important	
  contributors	
  to	
   the	
  underlying	
  mechanisms	
  for	
  AMI	
  onset	
  in	
  women.(36,	
  37)	
  	
  Describing	
  and	
  understanding	
   the	
  sex	
  differences	
  in	
  pathophysiology	
  of	
  AMI	
  are	
  beyond	
  the	
  scope	
  of	
  this	
  thesis	
  and	
  as	
   such	
  are	
  not	
  included	
  in	
  this	
  review.	
   Angiographic	
  Findings	
   When	
  summarizing	
  and	
  interpreting	
  data	
  on	
  differences	
  in	
  the	
  angiographic	
  profile	
  of	
  men	
   and	
  women,	
  one	
  important	
  potential	
  selection	
  bias	
  needs	
  to	
  be	
  noted.	
  	
  It	
  has	
  been	
  well	
   documented	
  that	
  overall	
  women	
  with	
  CAD	
  are	
  less	
  likely	
  than	
  men	
  to	
  undergo	
  coronary	
   angiography.	
  	
  It	
  may	
  be	
  that,	
  systematically,	
  only	
  women	
  with	
  more	
  severe	
  symptoms	
  of	
   11  CAD	
  are	
  selected	
  to	
  undergo	
  coronary	
  angiography,	
  in	
  which	
  case,	
  women	
  who	
  received	
   angiography	
  will	
  not	
  be	
  representative	
  of	
  all	
  women	
  with	
  CAD.	
  	
  Some	
  evidence	
  suggests	
   that	
  sex	
  differences	
  in	
  receiving	
  coronary	
  angiography	
  also	
  exist	
  among	
  patients	
  who	
   already	
  have	
  had	
  a	
  cardiac	
  event	
  such	
  as	
  an	
  AMI.(38,	
  39)	
  	
  However,	
  data	
  on	
  sex	
  differences	
   in	
  coronary	
  angiography	
  rates	
  among	
  younger	
  AMI	
  patients	
  are	
  limited.	
  	
  Furthermore,	
   whether	
  this	
  potential	
  selection	
  bias	
  also	
  applies	
  to	
  younger	
  AMI	
  patients	
  has	
  not	
  been	
   evaluated;	
  nonetheless,	
  it	
  is	
  a	
  limitation	
  that	
  needs	
  to	
  be	
  acknowledged.	
  	
  	
   Overall,	
  it	
  has	
  consistently	
  been	
  shown	
  that	
  women	
  undergoing	
  cardiac	
  angiography	
  for	
   suspected	
  ischemic	
  heart	
  disease	
  are	
  more	
  likely	
  to	
  present	
  with	
  normal	
  (i.e.	
  no	
  evidence	
  of	
   visible	
  disease	
  on	
  angiogram)	
  or	
  single-­‐vessel	
  disease,	
  while	
  men	
  are	
  more	
  likely	
  to	
  present	
   with	
  three-­‐vessel	
  disease.(39,	
  40)	
   Studies	
  on	
  angiographic	
  findings	
  of	
  AMI	
  patients	
  by	
  age	
  subgroups	
  have	
  found	
  that	
   ‘younger’	
  patients	
  are	
  more	
  likely	
  to	
  present	
  with	
  normal	
  or	
  single-­‐vessel	
  disease	
  than	
   ‘middle-­‐aged’	
  or	
  ‘older’	
  patients	
  (63%	
  vs.	
  40%	
  vs.	
  20%,	
  respectively).(12,	
  41)	
  	
  However,	
   some	
  evidence	
  based	
  on	
  two	
  small	
  studies	
  of	
  angiographic	
  findings	
  in	
  very	
  young	
  AMI	
   patients	
  (<35	
  years)	
  suggests	
  that,	
  although	
  younger	
  patients	
  mainly	
  present	
  with	
  less	
   extensive	
  coronary	
  artery	
  disease,	
  the	
  rate	
  of	
  total	
  occlusion	
  (a	
  complete	
  blockage	
  of	
   coronary	
  artery)	
  is	
  relatively	
  high	
  in	
  this	
  young	
  age	
  group.(42,	
  43)	
   With	
  respect	
  to	
  sex	
  differences	
  in	
  angiographic	
  findings	
  among	
  younger	
  AMI	
  patients,	
  only	
  a	
   limited	
  number	
  of	
  studies	
  are	
  available	
  but	
  the	
  findings	
  are	
  consistent	
  with	
  sex	
  differences	
   observed	
  in	
  the	
  overall	
  AMI	
  population.	
  Two	
  recent	
  studies	
  of	
  young	
  AMI	
  patients	
  (≤45	
   12  years	
  old),	
  by	
  Sozzi	
  et	
  al.	
  in	
  a	
  mixed	
  AMI	
  population	
  (44),	
  and	
  by	
  Lawesson	
  et	
  al.	
  in	
  a	
  STEMI	
   population	
  (45),	
  observed	
  that	
  younger	
  women	
  were	
  more	
  likely	
  to	
  present	
  with	
  single-­‐ vessel	
  disease,	
  while	
  younger	
  men	
  were	
  more	
  likely	
  to	
  present	
  with	
  multi-­‐vessel	
  coronary	
   disease.	
  	
  Additionally,	
  in	
  the	
  study	
  by	
  Sozzi	
  et	
  al.	
  the	
  authors	
  showed	
  that	
  younger	
  women	
   were	
  also	
  more	
  likely	
  to	
  present	
  with	
  normal	
  coronary	
  arteries	
  than	
  their	
  male	
  counterparts	
   (24%	
  vs.	
  9%;	
  p<0.05);	
  however,	
  this	
  finding	
  was	
  not	
  observed	
  among	
  young	
  STEMI	
  patients	
   who	
  rarely	
  presented	
  with	
  normal	
  coronary	
  arteries	
  (women:	
  5.8%,	
  men:	
  5.6%;	
  p=0.95).(45)	
   The	
  authors	
  also	
  examined	
  the	
  location	
  of	
  the	
  coronary	
  artery	
  lesions,	
  by	
  age	
  and	
  sex,	
  and	
   found	
  no	
  significant	
  age	
  differences	
  among	
  men	
  or	
  women;	
  however,	
  it	
  appeared	
  that	
   lesions	
  in	
  the	
  left	
  anterior	
  descending	
  artery	
  (LAD)	
  were	
  more	
  common	
  in	
  younger	
  patients,	
   particularly	
  men,	
  than	
  older	
  patients.(46)	
  	
  Furthermore,	
  Sozzi	
  et	
  al.	
  showed	
  that	
  while	
  in	
   both	
  younger	
  men	
  and	
  women	
  presenting	
  with	
  AMI	
  the	
  most	
  common	
  location	
  of	
  coronary	
   artery	
  lesion	
  was	
  the	
  LAD	
  (women:	
  55%,	
  men:	
  52%;	
  p=0.7),	
  younger	
  women	
  were	
  less	
  likely	
   to	
  present	
  with	
  lesions	
  in	
  the	
  right	
  coronary	
  artery	
  (RCA)	
  (women:	
  19%,	
  men:	
  41%;	
  p<0.05)	
   and	
  left	
  circumflex	
  coronary	
  artery	
  (LCx)	
  (women:	
  15%,	
  men:	
  29%;	
  p<0.05)	
  than	
  their	
  male	
   counterparts.(44)	
   Symptom	
  Presentation	
   Given	
  the	
  crucial	
  role	
  of	
  symptoms	
  for	
  the	
  timely	
  and	
  accurate	
  recognition	
  of	
  AMI,	
  several	
   studies	
  have	
  explored	
  sex	
  differences	
  in	
  disease	
  presentation,	
  with	
  respect	
  to	
  AMI	
   symptoms.	
  	
  However,	
  the	
  findings	
  have	
  been	
  inconsistent.	
  	
  Based	
  on	
  the	
  National	
  Registry	
   of	
  Myocardial	
  Infarction	
  (NRMI)	
  data,	
  in	
  1999,	
  Vaccarino	
  et	
  al.	
  reported	
  that	
  overall,	
  63.2%	
    13  of	
  women	
  and	
  72.3%	
  of	
  men	
  presented	
  with	
  chest	
  pain	
  at	
  the	
  time	
  of	
  their	
  AMI	
   hospitalization.(4)	
  	
  Based	
  on	
  a	
  review	
  of	
  the	
  literature	
  on	
  AMI	
  symptoms,	
  Canto	
  et	
  al.	
  also	
   concluded	
  that	
  women	
  are	
  more	
  likely	
  than	
  men	
  to	
  present	
  with	
  no	
  chest	
  pain	
  and	
  to	
  have	
   ‘atypical’	
  AMI	
  presentation.(47)	
  	
  In	
  contrast,	
  other	
  studies,	
  including	
  recent	
  findings	
  by	
   Mackay	
  et	
  al.,	
  showed	
  no	
  sex	
  differences	
  in	
  chest	
  pain	
  symptoms	
  during	
  ischemia.(48,	
  49)	
  	
   These	
  inconsistencies	
  are	
  mainly	
  due	
  to	
  variations	
  in	
  study	
  population,	
  data	
  sources,	
  and	
   symptom	
  definitions	
  in	
  these	
  studies.	
   In	
  addition	
  to	
  chest	
  pain,	
  a	
  number	
  of	
  studies	
  have	
  examined	
  other	
  AMI	
  symptoms	
  and	
   have	
  shown	
  that	
  women	
  are	
  more	
  likely	
  to	
  have	
  a	
  wider	
  range	
  of	
  symptoms	
  such	
  as	
  nausea,	
   back	
  pain,	
  dizziness,	
  palpitation,	
  and	
  throat/jaw	
  discomfort,	
  although	
  chest	
  pain	
  remained	
   the	
  most	
  common	
  presenting	
  symptoms	
  in	
  both	
  men	
  and	
  women.(48,	
  50,	
  51)	
  	
  Overall,	
   women	
  were	
  more	
  likely	
  to	
  experience	
  ≥3	
  symptoms	
  during	
  an	
  AMI	
  event,	
  compared	
  to	
   men	
  (73.0%	
  vs.	
  48.0%,	
  respectively).(50)	
   To	
  date,	
  very	
  few	
  studies	
  have	
  specifically	
  evaluated	
  sex	
  differences	
  in	
  symptoms	
  of	
  AMI	
   among	
  young	
  adults.	
  	
  Subgroup	
  analyses	
  of	
  studies	
  of	
  the	
  overall	
  AMI	
  population	
  indicated	
   that	
  any	
  observed	
  sex-­‐difference	
  in	
  chest	
  pain	
  symptoms	
  was	
  non-­‐existent	
  when	
  results	
   were	
  adjusted	
  for	
  age,	
  indicating	
  that	
  age	
  plays	
  an	
  important	
  role	
  when	
  assessing	
  AMI	
   symptoms.(51)	
  	
  In	
  a	
  study	
  by	
  Vaccarino	
  et	
  al.,	
  an	
  age-­‐stratified	
  presentation	
  of	
  patients’	
   characteristics	
  revealed	
  that	
  the	
  proportion	
  of	
  younger	
  patients	
  presenting	
  with	
  chest	
  pain,	
   at	
  the	
  time	
  of	
  their	
  AMI,	
  was	
  greater	
  than	
  in	
  older	
  adults	
  and	
  that	
  sex	
  differences	
  in	
  chest	
   pain	
  were	
  minimal	
  within	
  each	
  age	
  group.	
  	
  In	
  this	
  study,	
  chest	
  pain	
  was	
  present	
  in	
  81.5%	
  of	
    14  younger	
  women	
  and	
  85.0%	
  of	
  younger	
  men	
  vs.	
  in	
  64.6%	
  of	
  older	
  women	
  and	
  69.6%	
  of	
  older	
   men.(11)	
   In	
  a	
  recent	
  study	
  by	
  Canto	
  et	
  al.	
  the	
  authors	
  examined	
  whether	
  the	
  association	
  between	
   presenting	
  without	
  chest	
  pain	
  and	
  sex	
  varies	
  by	
  age	
  and	
  found	
  a	
  significant	
  sex-­‐age	
   interaction.(52)	
  	
  Their	
  findings	
  revealed	
  that	
  the	
  sex	
  differences	
  in	
  presenting	
  without	
  chest	
   pain	
  was	
  greatest	
  among	
  younger	
  patients	
  and	
  progressively	
  decreased	
  with	
  increasing	
  age.	
  	
   It	
  is	
  important	
  to	
  note	
  that,	
  although	
  the	
  greatest	
  sex	
  gap	
  in	
  chest	
  pain	
  presentation	
  was	
   shown	
  to	
  exist	
  among	
  the	
  younger	
  patients,	
  the	
  proportions	
  of	
  younger	
  women	
  (81.4%)	
  and	
   younger	
  men	
  (87.03%)	
  who	
  presented	
  with	
  chest	
  pain	
  were	
  still	
  higher	
  than	
  men	
  and	
   women	
  in	
  all	
  other	
  age	
  groups.(53)	
  	
  These	
  findings,	
  however,	
  were	
  misinterpreted	
  by	
  media	
   and	
  reported	
  in	
  news	
  headlines	
  as	
  “women	
  under	
  55	
  having	
  an	
  MI	
  are	
  more	
  likely	
  to	
   present	
  without	
  chest	
  pain	
  than	
  older	
  women	
  or	
  men”.(54)	
   The	
  length	
  of	
  delay	
  time,	
  from	
  symptom	
  onset	
  to	
  presenting	
  to	
  the	
  hospital,	
  is	
  another	
   important	
  aspect	
  of	
  symptom	
  presentation	
  that	
  can	
  impact	
  the	
  timely	
  management	
  and	
   subsequent	
  outcome	
  of	
  an	
  AMI	
  event.	
  	
  Based	
  on	
  a	
  mixed	
  AMI	
  population	
  (both	
  STEMIs	
  and	
   NSTEMIs),	
  data	
  suggests	
  existence	
  of	
  a	
  sex	
  gap	
  in	
  delay	
  time,	
  with	
  women,	
  particularly	
   younger	
  women,	
  being	
  more	
  likely	
  to	
  delay	
  presenting	
  to	
  hospital	
  for	
  their	
  AMI	
  symptoms	
   than	
  their	
  male	
  counterparts	
  (4);	
  however,	
  when	
  stratified	
  by	
  AMI	
  type,	
  the	
  findings	
  of	
   Champney	
  et	
  al.	
  suggest	
  that	
  only	
  among	
  STEMI	
  patients	
  are	
  women	
  more	
  likely	
  to	
  delay	
   presentation	
  than	
  men	
  -­‐	
  a	
  finding	
  that	
  was	
  consistent	
  in	
  all	
  age	
  groups	
  but	
  more	
   pronounced	
  among	
  patients	
  younger	
  than	
  50	
  years	
  of	
  age.(55)	
  	
  Even	
  though	
  a	
  study	
  of	
    15  younger	
  (≤	
  45	
  years)	
  STEMI	
  patients,	
  by	
  Lawesson	
  et	
  al.,	
  found	
  no	
  statistically	
  significant	
   differences	
  in	
  the	
  median	
  (Q1,	
  Q3)	
  delay	
  times	
  of	
  younger	
  men	
  and	
  women	
  [symptoms	
  to	
   door	
  time	
  (hr:min):	
  1:52	
  (1:00,	
  4:42)	
  in	
  women	
  vs.	
  1:45	
  (1:00,	
  3:49)	
  in	
  men;	
  p=0.18)],	
  the	
   75th	
  percentile	
  was	
  longer	
  in	
  women	
  by	
  one	
  hour.(45)	
   AMI	
  Type	
  and	
  Infarct	
  Location	
  	
   Rogers	
  et	
  al.,	
  based	
  on	
  2006	
  U.S	
  National	
  Registry	
  of	
  Myocardial	
  Infarction	
  (NRMI)	
  data,	
   found	
  that,	
  overall,	
  men	
  and	
  younger	
  patients	
  were	
  more	
  likely	
  to	
  present	
  with	
  STEMI.	
   Approximately	
  50%	
  of	
  patients	
  ≤55	
  years	
  of	
  age	
  presented	
  with	
  STEMI,	
  the	
  highest	
   percentage	
  among	
  all	
  age	
  groups.	
  	
  However,	
  these	
  findings	
  were	
  not	
  stratified	
  by	
  both	
  age	
   and	
  sex	
  and	
  therefore	
  sex-­‐differences	
  in	
  AMI	
  type	
  among	
  younger	
  patients	
  could	
  not	
  be	
   assessed.(56)	
   Location	
  of	
  infarct	
  area	
  in	
  AMI	
  is	
  routinely	
  categorized	
  into	
  the	
  following	
  main	
  categories:	
   inferior,	
  anterior,	
  lateral	
  and	
  right-­‐ventricle.	
  	
  In	
  one	
  of	
  the	
  earliest	
  studies	
  of	
  age	
  differences	
   in	
  clinical	
  characteristics	
  of	
  AMI	
  patients,	
  Hoit	
  et	
  al.	
  compared	
  the	
  infarct	
  location	
  among	
   three	
  different	
  age	
  subsets:	
  younger	
  (≤45	
  years),	
  middle-­‐aged	
  (46-­‐74	
  years)	
  and	
  older	
  (>75	
   years)	
  adults.	
  	
  The	
  authors	
  found	
  that	
  the	
  frequency	
  of	
  inferior	
  AMI	
  significantly	
  differed	
   among	
  the	
  groups,	
  with	
  the	
  younger	
  patients	
  being	
  the	
  most	
  likely	
  group	
  to	
  present	
  with	
   inferior	
  AMI	
  (younger:	
  43%,	
  middle-­‐aged:	
  39%,	
  older:	
  30%;	
  p<0.001).(12)	
  	
  A	
  similar	
   observation	
  can	
  be	
  made	
  based	
  on	
  the	
  results	
  of	
  a	
  recent	
  study	
  by	
  Canto	
  et	
  al.,	
  where	
   patients	
  were	
  stratified	
  by	
  age	
  (<65	
  vs.	
  ≥65	
  years),	
  sex,	
  and	
  presence/absence	
  of	
  chest	
  pain	
    16  at	
  the	
  time	
  of	
  AMI	
  presentation.(52)	
  	
  In	
  this	
  study,	
  younger	
  AMI	
  patients	
  were	
  more	
  likely	
   to	
  present	
  with	
  inferior	
  AMI	
  than	
  older	
  patients,	
  regardless	
  of	
  sex	
  or	
  their	
  chest	
  pain	
  status.	
  	
  	
   Not	
  much	
  information	
  is	
  available	
  on	
  the	
  sex	
  differences	
  in	
  infarct	
  location	
  of	
  younger	
  AMI	
   patients.	
  	
  Based	
  on	
  Canto	
  et	
  al.’s	
  study,	
  it	
  appears	
  that	
  women	
  were	
  as	
  likely	
  to	
  present	
   with	
  anterior	
  AMI,	
  but	
  less	
  likely	
  to	
  present	
  with	
  inferior	
  AMI	
  than	
  men,	
  regardless	
  of	
  their	
   chest	
  pain	
  status.	
  	
  Infarct	
  location	
  was	
  not	
  the	
  focus	
  of	
  this	
  paper	
  and	
  as	
  such	
  not	
  enough	
   detailed	
  information	
  was	
  provided	
  to	
  draw	
  any	
  meaningful	
  conclusions	
  in	
  this	
  regard.	
   2.1.3 Traditional	
  Cardiac	
  Risk	
  Factors	
   In	
  the	
  early	
  1940’s,	
  the	
  seminal	
  prospective	
  Framingham	
  Heart	
  Study,	
  led	
  by	
  Dr.	
  Thomas	
   Royle	
  Dawber,	
  began	
  following	
  5,029	
  patients	
  between	
  the	
  ages	
  of	
  30	
  and	
  62,	
  from	
  the	
   town	
  of	
  Framingham,	
  Massachusetts,	
  in	
  order	
  to	
  examine	
  the	
  epidemiology	
  of	
   cardiovascular	
  disease	
  and	
  find	
  patient	
  characteristics	
  that	
  contribute	
  to	
  the	
  development	
   of	
  heart	
  disease.	
  	
  Over	
  the	
  years,	
  the	
  Framingham	
  Heart	
  Study	
  identified	
  age,	
  sex,	
  smoking,	
   high	
  blood	
  pressure,	
  high	
  blood	
  cholesterol,	
  and	
  diabetes	
  as	
  major	
  cardiac	
  risk	
  factors	
  and	
   this	
  led	
  to	
  the	
  development	
  of	
  the	
  Framingham	
  Risk	
  Score	
  for	
  cardiovascular	
  disease.(57)	
   Several	
  other	
  large	
  studies,	
  including	
  a	
  more	
  recent	
  global	
  case-­‐control	
  study	
  of	
  risk	
  factors	
   for	
  acute	
  myocardial	
  infarction,	
  the	
  INTERHEART	
  study,	
  extended	
  these	
  prior	
  findings.	
  	
  The	
   INTERHEART	
  study	
  identified	
  nine	
  modifiable	
  risk	
  factors,	
  which	
  collectively	
  were	
  shown	
  to	
   explain	
  more	
  than	
  ninety	
  percent	
  of	
  the	
  population-­‐attributable	
  risk	
  (PAR)	
  for	
  AMI	
  in	
  men	
   and	
  women,	
  indicating	
  that	
  the	
  risk	
  of	
  AMI	
  could	
  be	
  reduced	
  by	
  more	
  than	
  ninety	
  percent	
  if	
    17  all	
  these	
  nine	
  risk	
  factors	
  were	
  eliminated.(58)	
  	
  These	
  modifiable	
  risk	
  factors	
  include:	
   smoking,	
  hypertension,	
  abnormal	
  lipids,	
  diabetes,	
  abdominal	
  obesity,	
  high-­‐risk	
  diet,	
   psychosocial	
  factors,	
  lack	
  of	
  physical	
  activity	
  and	
  moderate	
  alcohol	
  intake.(59)	
   All	
  the	
  established	
  traditional	
  cardiac	
  risk	
  factors	
  identified	
  in	
  older	
  adults	
  also	
  play	
  a	
  role	
  in	
   CAD	
  development	
  and	
  progression	
  within	
  the	
  younger	
  population.	
  	
  However,	
  based	
  on	
  the	
   findings	
  of	
  the	
  INTERHEART	
  study,	
  Anand	
  et	
  al.	
  found	
  that	
  some	
  risk	
  factors	
  have	
  a	
  stronger	
   association	
  with	
  AMI	
  in	
  younger	
  adults	
  than	
  in	
  older	
  adults.	
  	
  These	
  included	
  current	
   smoking	
  status,	
  lipid	
  abnormalities,	
  diabetes	
  and	
  hypertension	
  among	
  younger	
  women,	
   compared	
  with	
  older	
  women,	
  and	
  current	
  smoking	
  status,	
  lipids	
  abnormalities,	
   hypertension,	
  and	
  abdominal	
  obesity	
  in	
  younger	
  men,	
  compared	
  to	
  older	
  men.(58)	
   Contrary	
  to	
  the	
  common	
  belief	
  that	
  young	
  adults	
  are	
  not	
  at	
  risk	
  for	
  heart	
  disease	
  and	
  that	
   the	
  prevalence	
  of	
  cardiac	
  risk	
  factors	
  among	
  them	
  is	
  low,	
  it	
  is	
  estimated	
  that	
  when	
   presenting	
  with	
  CAD,	
  only	
  10.4%	
  of	
  younger	
  women	
  (≤55	
  years)	
  and	
  12.7%	
  of	
  younger	
  men	
   do	
  not	
  have	
  any	
  of	
  the	
  traditional	
  cardiac	
  risk	
  factors	
  (i.e.	
  smoking,	
  hyperlipidemia,	
  diabetes	
   and	
  hypertension)	
  as	
  compared	
  to	
  16.5%	
  of	
  women	
  and	
  23.3%	
  of	
  men	
  older	
  than	
  55	
  years	
   of	
  age.(60)	
  	
   Of	
  these,	
  three	
  risk	
  factors	
  that	
  have	
  been	
  shown	
  to	
  be	
  particularly	
  important	
  among	
  young	
   adults,	
  not	
  only	
  because	
  of	
  their	
  strong	
  association	
  with	
  increased	
  risk	
  of	
  CAD	
  in	
  both	
  men	
   and	
  women,	
  but	
  also	
  due	
  to	
  their	
  higher	
  prevalence	
  in	
  the	
  younger	
  population	
  compared	
  to	
   older	
  adults,	
  are	
  smoking,	
  lipid	
  abnormalities,	
  and	
  family	
  history	
  of	
  CAD.	
  	
  	
    18  a)	
  Cigarette	
  Smoking	
   Among	
  young	
  AMI	
  patients,	
  smoking	
  is	
  the	
  most	
  prevalent	
  cardiac	
  risk	
  factor	
  in	
  both	
   women	
  and	
  men,	
  with	
  more	
  than	
  two-­‐thirds	
  of	
  patients	
  being	
  either	
  former	
  or	
  current	
   smokers.(44,	
  45,	
  55)	
  	
  Furthermore,	
  based	
  on	
  the	
  Framingham	
  Heart	
  Study,	
  Kannel	
  et	
  al.	
   found	
  that	
  among	
  young	
  adults	
  (35-­‐44	
  year)	
  smoking	
  was	
  associated	
  with	
  a	
  three-­‐fold	
   increase	
  in	
  risk	
  of	
  developing	
  CAD.(61)	
  	
  Similar	
  findings	
  were	
  also	
  observed	
  in	
  a	
  more	
  recent	
   study	
  by	
  Oliveira	
  et	
  al.	
  which	
  reported	
  an	
  up	
  to	
  eight-­‐fold	
  increase	
  in	
  risk	
  of	
  AMI,	
  when	
   comparing	
  young	
  (<45	
  years),	
  heavy	
  smokers	
  (>25	
  cigarette/day)	
  to	
  young	
  non-­‐ smokers.(62)	
   When	
  comparing	
  younger	
  (<60	
  years	
  of	
  age)	
  to	
  older	
  men	
  and	
  women,	
  Anand	
  et	
  al.,	
  based	
   on	
  the	
  findings	
  from	
  the	
  INTERHEART	
  study,	
  observed	
  that	
  the	
  association	
  of	
  smoking	
  with	
   AMI	
  is	
  stronger	
  among	
  younger	
  adults.	
  	
  In	
  this	
  study,	
  when	
  comparing	
  cases	
  (AMI	
  patients)	
   to	
  controls	
  (individuals	
  with	
  no	
  AMI,	
  from	
  hospital	
  or	
  community	
  sources),	
  the	
  odds	
  ratio	
   (OR)	
  for	
  current	
  smoking	
  status	
  was	
  4.40	
  (95%	
  CI:	
  3.54,	
  5.48)	
  among	
  younger	
  women	
  as	
   compared	
  to	
  2.29	
  (95%	
  CI:	
  1.85,	
  2.82)	
  among	
  older	
  women	
  (p-­‐value	
  of	
  interaction	
  for	
  smoking	
   and	
  age	
  =0.0005)	
  and	
  was	
  3.42	
  (95%	
  CI:	
  3.14,	
  3.73)	
  among	
  younger	
  men	
  as	
  compared	
  to	
  2.28	
    (95%	
  CI:	
  2.04,	
  2.56)	
  among	
  older	
  men	
  (p-­‐value	
  of	
  interaction	
  for	
  smoking	
  and	
  age	
  <0.0001).	
  	
  The	
   alarmingly	
  high	
  prevalence	
  of	
  smoking	
  among	
  younger	
  adults	
  makes	
  it	
  one	
  of	
  the	
  greatest	
   public	
  health	
  concerns	
  and	
  challenges	
  in	
  this	
  population.	
    19  b)	
  Dyslipidemia	
   Dyslipidemia	
  (abnormalities	
  in	
  blood	
  levels	
  of	
  low-­‐density	
  lipoprotein	
  (LDL),	
  high-­‐density	
   lipoprotein	
  (HDL),	
  or	
  triglycerides)	
  is	
  another	
  prevalent	
  cardiac	
  risk	
  factor	
  among	
  young	
  AMI	
   patients	
  and	
  is	
  estimated	
  to	
  be	
  present	
  in	
  approximately	
  25-­‐67%	
  of	
  the	
  young	
  AMI	
  patients,	
   depending	
  on	
  the	
  study	
  population	
  and	
  definition	
  of	
  dyslipidemia.(63,	
  64)	
  	
  Furthermore,	
   presence	
  of	
  genetic	
  lipid	
  disorders	
  such	
  as	
  Familial	
  Hypercholesterolemia,	
  characterised	
  by	
   the	
  body’s	
  inability	
  to	
  remove	
  low-­‐density	
  lipoprotein	
  (LDL)	
  from	
  the	
  bloodstream,	
  has	
  been	
   shown	
  to	
  be	
  strongly	
  associated	
  with	
  increased	
  risk	
  of	
  an	
  AMI	
  at	
  a	
  younger	
  age.(65)	
   Based	
  on	
  the	
  findings	
  of	
  the	
  INTERHEART	
  study,	
  the	
  presence	
  of	
  lipid	
  abnormalities	
  (as	
   measured	
  by	
  levels	
  of	
  lipoproteins	
  ApoB/ApoA1	
  ratio)	
  in	
  younger	
  women	
  is	
  more	
  strongly	
   associated	
  with	
  AMI	
  than	
  the	
  presence	
  of	
  lipid	
  abnormalities	
  in	
  older	
  women	
  with	
  an	
  OR	
  of	
   4.85	
  (95%	
  CI:	
  3.76,	
  6.28)	
  among	
  younger	
  women	
  as	
  compared	
  to	
  OR	
  of	
  2.65	
  (95%	
  CI:	
  2.21,	
   3.18)	
  among	
  older	
  women	
  (p-­‐value	
  of	
  interaction	
  for	
  lipid	
  abnormalities	
  and	
  age	
  =0.0005).	
  	
  The	
  same	
   pattern	
  was	
  observed	
  in	
  men	
  with	
  an	
  OR	
  of	
  3.63	
  (95%	
  CI:	
  3.22,	
  4.08)	
  among	
  younger	
  men	
  as	
   compared	
  to	
  OR	
  of	
  2.02	
  (95%	
  CI:	
  1.77,	
  2.31)	
  among	
  older	
  men	
  (p-­‐value	
  of	
  interaction	
  for	
  lipid	
   abnormalities	
  and	
  age	
  <0.0001).	
    c)	
  Family	
  History	
  of	
  Premature	
  CAD	
   Family	
  history	
  of	
  premature	
  coronary	
  artery	
  disease	
  (defined	
  as	
  CAD	
  in	
  a	
  first-­‐degree	
  female	
   family	
  member	
  ≤65	
  and	
  male	
  family	
  member	
  ≤55	
  years	
  of	
  age)	
  is	
  also	
  a	
  particularly	
   important	
  risk	
  factor	
  among	
  younger	
  adults.(66,	
  67)	
  	
  It	
  has	
  been	
  shown	
  that	
  approximately	
   40%	
  of	
  young	
  adults	
  with	
  AMI	
  have	
  a	
  family	
  history	
  of	
  CAD.(3,	
  41,	
  68)	
  	
  One	
  of	
  the	
  earlier	
    20  studies	
  of	
  AMI	
  in	
  young	
  adults	
  examined	
  risk	
  factors	
  of	
  2,643	
  AMI	
  patients	
  enrolled	
  from	
   several	
  hospitals,	
  including	
  Vancouver	
  General	
  Hospital,	
  British	
  Columbia.	
  The	
  results	
   showed	
  that	
  aside	
  from	
  smoking	
  and	
  lipid	
  abnormalities,	
  family	
  history	
  of	
  premature	
  CAD	
   was	
  more	
  prevalent	
  in	
  younger	
  patients	
  (<45	
  years)	
  than	
  middle	
  age	
  or	
  older	
  patients	
  (41%	
   of	
  young,	
  28%	
  of	
  middle-­‐aged	
  and	
  12%	
  of	
  elderly	
  patients;	
  p<0.001).(12)	
   Furthermore,	
  a	
  recent	
  study	
  of	
  young	
  patients	
  (males≤55	
  years	
  and	
  females≤65	
  years)	
  with	
   angiographic	
  evidence	
  for	
  CAD,	
  during	
  a	
  follow-­‐up	
  period	
  of	
  over	
  two	
  years,	
  found	
  family	
   history	
  of	
  CAD	
  to	
  be	
  the	
  strongest	
  independent	
  predictor	
  of	
  incidence	
  of	
  AMI	
  (Hazard	
   Ratio=2.60,	
  95%CI:	
  1.41,	
  4.79;	
  p=0.002).(69)	
  	
  These	
  findings	
  highlight	
  one	
  of	
  the	
   shortcomings	
  of	
  the	
  Framingham	
  Risk	
  Score	
  for	
  predicting	
  10-­‐year	
  risk	
  of	
  cardiovascular	
   disease	
  in	
  young	
  adults,	
  as	
  it	
  does	
  not	
  include	
  family	
  history	
  of	
  CAD.	
   In	
  addition	
  to	
  smoking,	
  lipid	
  abnormalities,	
  and	
  family	
  history	
  of	
  CAD,	
  other	
  cardiac	
  risk	
   factors,	
  particularly	
  diabetes,	
  hypertension	
  and	
  obesity	
  are	
  also	
  important	
  contributing	
   factors	
  in	
  the	
  development	
  of	
  CAD	
  in	
  both	
  young	
  men	
  and	
  women,	
  but	
  they	
  are	
  not	
  as	
   prevalent	
  in	
  younger	
  patients,	
  particularly	
  those	
  under	
  45	
  years	
  of	
  age,	
  as	
  compared	
  to	
   older	
  AMI	
  patients.(12,	
  41,	
  70)	
  	
  However,	
  it	
  is	
  important	
  to	
  note	
  that	
  these	
  patterns	
  may	
   change	
  in	
  the	
  future	
  as	
  data	
  on	
  temporal	
  changes	
  in	
  cardiac	
  risk	
  factors	
  suggest	
  that	
  the	
   prevalence	
  of	
  these	
  risk	
  factors	
  among	
  younger	
  adults	
  is	
  on	
  the	
  rise	
  (as	
  further	
  discussed	
  in	
   section	
  2.2.1).	
    21  Sex	
  Differences	
  in	
  Cardiac	
  Risk	
  Profile	
  	
   The	
  existence	
  of	
  sex	
  differences	
  in	
  the	
  characteristics	
  of	
  patients	
  presenting	
  with	
  AMI	
  have	
   been	
  consistently	
  demonstrated.	
  	
  Women	
  are	
  older,	
  have	
  a	
  higher	
  burden	
  of	
  risk	
  factors,	
   and	
  have	
  more	
  pre-­‐existing	
  comorbid	
  conditions,	
  such	
  as	
  heart	
  failure	
  and	
  stroke.	
  	
   However,	
  there	
  are	
  fewer	
  studies	
  examining	
  sex-­‐differences	
  in	
  characteristics	
  of	
  younger	
   AMI	
  patients.	
  	
  	
   One	
  of	
  the	
  earlier	
  studies	
  reporting	
  on	
  sex	
  differences	
  in	
  risk	
  profile	
  and	
  outcomes	
  of	
  young	
   adults	
  was	
  based	
  on	
  the	
  National	
  Registry	
  of	
  Myocardial	
  infarction	
  (NRMI),	
  a	
  prospective	
   registry	
  of	
  consecutive	
  AMI	
  patients	
  admitted	
  to	
  1,658	
  participating	
  U.S	
  hospitals.	
  	
  This	
   study	
  revealed	
  that	
  young	
  women	
  were	
  more	
  likely	
  to	
  have	
  history	
  of	
  diabetes,	
   hypertension	
  and	
  prior	
  stroke	
  but	
  were	
  less	
  likely	
  to	
  have	
  hypercholesterolemia	
  or	
  be	
   current	
  smokers	
  (4),	
  a	
  finding	
  that	
  was	
  also	
  subsequently	
  observed	
  in	
  two	
  European	
   studies.(3,	
  71)	
  	
  Additionally,	
  these	
  two	
  European	
  studies	
  found	
  that	
  younger	
  women	
  were	
   more	
  likely	
  than	
  younger	
  men	
  to	
  have	
  family	
  history	
  of	
  CAD,	
  but	
  this	
  difference	
  was	
  not	
   statistically	
  significant	
  in	
  either	
  study.(3,	
  71)	
   Other	
  than	
  the	
  reported	
  sex	
  differences	
  in	
  hypercholesterolemia,	
  limited	
  information	
  is	
   available	
  on	
  sex	
  differences	
  in	
  lipid	
  abnormalities	
  among	
  younger	
  adults.	
  	
  A	
  study,	
  designed	
   to	
  assess	
  the	
  performance	
  of	
  the	
  National	
  Cholesterol	
  Education	
  Panel	
  (NCEP)	
  Guidelines	
  in	
   the	
  U.S,	
  examined	
  sex	
  differences	
  in	
  the	
  lipid	
  profile	
  of	
  young	
  AMI	
  patients	
  (male≤55	
  years	
   and	
  female≤65	
  years).	
  	
  Akosah	
  et	
  al.	
  found	
  that,	
  although	
  the	
  mean	
  total	
  cholesterol	
  was	
   the	
  same	
  in	
  both	
  young	
  men	
  and	
  women,	
  young	
  women	
  presenting	
  with	
  AMI	
  were	
  more	
    22  likely	
  to	
  have	
  statistically	
  lower	
  mean	
  LDL	
  cholesterol	
  levels	
  (117	
  ±	
  40	
  mg/dl	
  vs.	
  129	
  ±	
  38	
   mg/dl;	
  p=0.014)	
  but	
  significantly	
  higher	
  mean	
  triglyceride	
  levels	
  than	
  young	
  men	
  (160	
  ±	
  76	
   mg/dl	
  vs.	
  140	
  ±	
  77mg/dl;	
  p=0.043).(68)	
   More	
  recent	
  studies	
  stratified	
  their	
  analysis	
  of	
  sex	
  differences	
  in	
  cardiac	
  risk	
  factors	
  and	
   comorbidities	
  by	
  both	
  age	
  and	
  AMI	
  type	
  (STEMI,	
  NSTEMI).	
  	
  Similar	
  to	
  the	
  findings	
  of	
  studies	
   with	
  mixed	
  AMI	
  populations	
  (4),	
  their	
  findings	
  revealed	
  that,	
  regardless	
  of	
  the	
  type	
  of	
  AMI,	
   younger	
  women	
  have	
  a	
  greater	
  burden	
  of	
  risk	
  factors,	
  with	
  a	
  higher	
  prevalence	
  of	
  diabetes,	
   obesity,	
  heart	
  failure,	
  stroke,	
  renal	
  insufficiency,	
  and	
  chronic	
  obstructive	
  pulmonary	
  disease	
   but	
  a	
  lower	
  prevalence	
  of	
  hyperlipidemia,	
  compared	
  to	
  younger	
  men.(55,	
  72)	
  Interestingly,	
   the	
  observed	
  sex	
  differences	
  among	
  the	
  younger	
  AMI	
  patients	
  in	
  some	
  of	
  these	
  cardiac	
  risk	
   factors,	
  such	
  as	
  diabetes,	
  obesity,	
  heart	
  failure,	
  and	
  prior	
  stroke,	
  were	
  less	
  pronounced	
  or	
   non-­‐existing	
  among	
  older	
  patients,	
  regardless	
  of	
  AMI	
  type.(55,	
  72)	
  	
  	
   However,	
  among	
  young	
  STEMI	
  patients,	
  the	
  odds	
  of	
  being	
  a	
  smoker	
  was	
  slightly	
  higher	
   among	
  women	
  (50-­‐59	
  years)	
  than	
  men	
  [OR=	
  1.07;	
  96%CI:	
  1.01-­‐1.14)].(55)	
  	
  Furthermore,	
  a	
   higher	
  overall	
  rate	
  of	
  smoking	
  was	
  observed	
  in	
  young	
  STEMI	
  men	
  and	
  women	
  as	
  compared	
   to	
  NSTEMI	
  patients.	
  	
  Similar	
  findings	
  were	
  reported	
  in	
  a	
  Swedish	
  study,	
  in	
  which	
  64%	
  of	
   young	
  women	
  (≤	
  45years)	
  with	
  STEMI	
  were	
  current	
  smokers	
  at	
  the	
  time	
  of	
  their	
  first	
  AMI,	
   as	
  compared	
  to	
  58%	
  of	
  young	
  men	
  (p=0.04).(45)	
  	
    23  2.1.4 Summary	
  of	
  Findings	
  and	
  Knowledge	
  Gaps	
  in	
  Epidemiology	
   In	
  summary,	
  younger	
  adults	
  represent	
  about	
  8-­‐25%	
  of	
  all	
  AMI	
  hospitalizations	
  and	
  have	
   distinct	
  risk	
  profiles	
  and	
  clinical	
  characteristics.	
  	
  The	
  current	
  literature	
  has	
  shown	
  that	
  a	
   number	
  of	
  risk	
  factors,	
  such	
  as	
  smoking	
  and	
  dyslipidemia,	
  play	
  a	
  more	
  significant	
  role	
  in	
   development	
  of	
  AMI	
  in	
  younger	
  than	
  older	
  adults.	
  	
  The	
  prevalence	
  of	
  smoking	
  among	
  young	
   AMI	
  patients,	
  particularly	
  those	
  presenting	
  with	
  STEMI,	
  is	
  alarming,	
  with	
  approximately	
  2	
   out	
  of	
  every	
  3	
  young	
  AMI	
  patients	
  being	
  a	
  current	
  or	
  past	
  smoker.	
  	
  With	
  respect	
  to	
  clinical	
   presentation,	
  overall,	
  younger	
  patients	
  are	
  more	
  likely	
  to	
  present	
  with	
  typical	
  chest	
  pain,	
   inferior	
  AMI	
  and	
  less	
  extensive	
  coronary	
  disease	
  than	
  older	
  patients.	
  	
   Furthermore,	
  a	
  few	
  recent	
  studies	
  have	
  highlighted	
  that	
  the	
  sex	
  differences	
  in	
  cardiac	
  risk	
   factors	
  and	
  comorbidities,	
  at	
  the	
  time	
  of	
  AMI	
  hospitalization,	
  are	
  more	
  pronounced	
  among	
   younger	
  patients	
  than	
  older	
  patients.	
  	
  Younger	
  women	
  with	
  AMI	
  are	
  also	
  more	
  likely	
  to	
   present	
  with	
  a	
  less	
  severe	
  extent	
  of	
  disease	
  compared	
  to	
  younger	
  men;	
  however,	
  in	
   general,	
  information	
  on	
  sex	
  differences	
  in	
  other	
  clinical	
  characteristics	
  of	
  young	
  AMI	
   patients,	
  including	
  symptoms	
  presentation	
  and	
  infarct	
  location,	
  are	
  not	
  well	
  described	
  in	
   the	
  current	
  literature.	
  	
  In	
  our	
  prospective	
  study	
  of	
  young	
  AMI	
  patients	
  in	
  British	
  Columbia	
   (named	
  the	
  AMI55	
  study),	
  the	
  existence	
  of	
  these	
  sex	
  differences	
  is	
  examined	
  and	
  will	
  be	
   presented	
  as	
  part	
  of	
  Chapter	
  4.	
    24  2.2 Trends	
  	
   2.2.1 Trends	
  in	
  Cardiac	
  Risk	
  Factors	
   The	
  2010	
  Heart	
  and	
  Stroke	
  Foundation	
  of	
  Canada’s	
  Annual	
  Report,	
  titled	
  “A	
  Perfect	
  Storm”,	
   highlights	
  the	
  rising	
  trends	
  in	
  the	
  prevalence	
  of	
  several	
  cardiac	
  risk	
  factors	
  in	
  the	
  general	
   population,	
  particularly	
  among	
  younger	
  adults.(9,	
  73)	
  	
  This	
  report	
  is	
  mainly	
  based	
  on	
  the	
   findings	
  of	
  a	
  study	
  by	
  Lee	
  et	
  al.	
  who	
  assessed	
  the	
  temporal	
  changes	
  in	
  a	
  number	
  of	
   modifiable	
  risk	
  factors	
  using	
  self-­‐reported	
  data	
  from	
  the	
  National	
  Population	
  Health	
  Survey	
  	
   and	
  the	
  Canadian	
  Community	
  Health	
  Survey	
  (CCHS).(9,	
  73)	
  	
  This	
  study	
  revealed	
  increasing	
   trends	
  in	
  obesity,	
  hypertension	
  and	
  diabetes,	
  particularly	
  in	
  Canadians	
  younger	
  than	
  50	
   years	
  of	
  age.	
  Overall,	
  among	
  adults	
  35-­‐49	
  years,	
  hypertension	
  (irrespective	
  of	
  being	
  on	
   antihypertensive	
  treatment)	
  increased	
  from	
  5.6%	
  to	
  13.2%,	
  diabetes	
  from	
  1.6%	
  to	
  2.6%,	
   and	
  obesity	
  from	
  13.5%	
  to	
  16.2%,	
  between	
  the	
  years	
  1994	
  and	
  2005.	
  	
  Although	
  these	
   increasing	
  trends	
  were	
  observed	
  in	
  both	
  younger	
  men	
  and	
  women,	
  the	
  relative	
  change	
   from	
  1994	
  to	
  2005	
  was	
  greater	
  among	
  younger	
  men,	
  particularly	
  with	
  respect	
  to	
  obesity.	
  	
   The	
  only	
  modifiable	
  cardiac	
  risk	
  factor	
  that	
  was	
  shown	
  to	
  decline,	
  in	
  both	
  men	
  and	
  women	
   regardless	
  of	
  their	
  age,	
  was	
  the	
  prevalence	
  of	
  smoking.	
   Similar	
  to	
  CCHS	
  data,	
  the	
  self-­‐reported	
  National	
  Health	
  and	
  Nutrition	
  Examination	
  Surveys	
   (NHANES)	
  has	
  been	
  used	
  in	
  the	
  United	
  States	
  to	
  report	
  on	
  age-­‐	
  and	
  sex-­‐specific	
  trends	
  in	
   the	
  cardiac	
  risk	
  profile	
  of	
  the	
  general	
  population	
  between	
  the	
  1999-­‐2010.(74)	
  	
  Among	
   younger	
  adults	
  (<55	
  years),	
  similar	
  increasing	
  trends	
  in	
  diabetes	
  and	
  obesity	
  were	
  observed	
   in	
  the	
  general	
  American	
  population.	
  	
  However,	
  the	
  prevalence	
  of	
  hypertension	
  and	
  high	
    25  cholesterol	
  levels	
  [serum	
  total	
  cholesterol	
  greater	
  than	
  or	
  equal	
  to	
  240	
  mg/dl	
  (6.2	
  mmol/l)	
   or	
  taking	
  cholesterol-­‐lowering	
  medications]	
  either	
  declined	
  or	
  remained	
  the	
  same	
  in	
  the	
   most	
  recent	
  NHANES	
  cycles	
  (2003-­‐2006	
  to	
  2007-­‐2010).	
  	
  Using	
  the	
  same	
  NHANES	
  data,	
   Towfighi	
  et	
  al.	
  assessed	
  the	
  temporal	
  changes	
  in	
  Framingham	
  Coronary	
  Risk	
  Score	
  in	
  young	
   adults	
  (<	
  55	
  years).(25)	
  	
  Their	
  findings	
  revealed	
  that	
  while	
  the	
  Framingham	
  Coronary	
  Risk	
   Score	
  of	
  young	
  men	
  improved	
  from	
  NHANES	
  1988-­‐1994	
  to	
  NHANES	
  1999-­‐2004,	
  it	
  remained	
   unchanged	
  in	
  young	
  women.	
  	
  The	
  improvement	
  in	
  the	
  Framingham	
  Coronary	
  Risk	
  Score	
  of	
   men	
  was	
  mainly	
  related	
  to	
  the	
  greater	
  decline	
  in	
  smoking	
  rates	
  and	
  blood	
  pressure	
  levels.	
   However,	
  during	
  this	
  period	
  the	
  prevalence	
  of	
  obesity	
  increased	
  in	
  both	
  young	
  men	
  and	
   women.	
   Considering	
  the	
  association	
  of	
  obesity	
  with	
  other	
  cardiac	
  risk	
  factors	
  including	
  diabetes	
  and	
   hypertension	
  (75),	
  the	
  reports	
  of	
  the	
  rising	
  prevalence	
  of	
  obesity	
  among	
  young	
  adults	
   during	
  the	
  recent	
  decade	
  is	
  worrisome.	
  	
  Based	
  on	
  the	
  most	
  recent	
  available	
  data	
  in	
  Canada	
   and	
  the	
  U.S,	
  obesity	
  (defined	
  as	
  body	
  mass	
  index	
  (BMI)	
  greater	
  than	
  or	
  equal	
  to	
  30	
  kg/m2)	
   has	
  been	
  reported	
  to	
  be	
  present	
  in	
  more	
  than	
  one	
  third	
  of	
  young	
  American	
  men	
  and	
   women	
  between	
  the	
  ages	
  40-­‐59	
  years	
  (76),	
  and	
  approximately	
  in	
  23%	
  of	
  young	
  Canadian	
   men	
  and	
  17%	
  of	
  young	
  women	
  between	
  the	
  ages	
  of	
  35-­‐54.(77)	
  	
   It	
  is	
  expected	
  that	
  these	
  unfavourable	
  trends	
  among	
  young	
  adults	
  in	
  the	
  general	
  population	
   would	
  be	
  reflected	
  in	
  the	
  risk	
  profile	
  of	
  young	
  patients	
  presenting	
  with	
  AMI;	
  however,	
  only	
   a	
  few	
  studies	
  have	
  assessed	
  the	
  temporal	
  changes	
  in	
  risk	
  factors	
  of	
  young	
  adults	
  with	
  AMI	
  in	
   recent	
  years.	
  	
  Similar	
  to	
  their	
  earlier	
  reports	
  of	
  worsening	
  cardiac	
  risk	
  profile	
  among	
  all	
    26  adult	
  patients	
  in	
  recent	
  decades	
  (10),	
  the	
  Worcester	
  Heart	
  Study	
  also	
  demonstrated	
  a	
   worsening	
  cardiac	
  risk	
  profile	
  among	
  young	
  patients	
  presenting	
  with	
  their	
  first	
  AMI	
  event,	
   including	
  increasing	
  trends	
  in	
  diabetes	
  and	
  hypertension.(17)	
  	
  Furthermore,	
  a	
  recent	
  study,	
   based	
  on	
  four	
  nationwide	
  French	
  registries,	
  indicated	
  that	
  the	
  proportion	
  of	
  young	
  patients	
   (<60	
  years),	
  particularly	
  women,	
  who	
  present	
  with	
  smoking	
  and/or	
  obesity	
  as	
  their	
  sole	
  risk	
   factors	
  at	
  the	
  time	
  of	
  their	
  hospitalization	
  for	
  STEMI,	
  has	
  continuously	
  increased	
  between	
   the	
  years	
  1995	
  to	
  2010.(78)	
  	
  Based	
  on	
  this	
  2012	
  study,	
  approximately	
  45%	
  of	
  young	
  French	
   women	
  and	
  40%	
  of	
  young	
  men	
  presented	
  with	
  smoking	
  and/or	
  obesity	
  as	
  their	
  only	
  risk	
   factors.	
  	
  Contrary	
  to	
  the	
  findings	
  of	
  WHAS,	
  in	
  this	
  French	
  STEMI	
  population	
  the	
  rates	
  of	
   diabetes	
  and	
  hypertension	
  in	
  both	
  young	
  men	
  and	
  women	
  had	
  either	
  declined	
  or	
  remained	
   the	
  same.	
  This	
  inconsistency	
  underscores	
  the	
  potential	
  regional	
  variations	
  in	
  cardiac	
  risk	
   factors,	
  which	
  need	
  to	
  be	
  taken	
  into	
  account	
  when	
  comparing	
  findings.	
   2.2.2 Trends	
  in	
  AMI	
  Hospitalization	
  Rates	
   To	
  date,	
  few	
  studies	
  have	
  examined	
  temporal	
  changes	
  in	
  sex-­‐	
  and	
  age-­‐specific	
  rates	
  of	
  AMI	
   hospitalization.	
  	
  In	
  a	
  European	
  setting,	
  based	
  on	
  the	
  World	
  Health	
  Organization	
  MONICA	
   project,	
  Lundblad	
  et	
  al.	
  examined	
  the	
  differences	
  in	
  sex-­‐	
  and	
  age-­‐	
  specific	
  trends	
  of	
  first	
  AMI	
   hospitalization	
  in	
  Sweden	
  from	
  1985	
  to	
  2004.	
  	
  The	
  authors	
  reported	
  significant	
  declines	
  in	
   AMI	
  hospitalization	
  rates	
  in	
  both	
  men	
  and	
  women	
  55-­‐64	
  years	
  of	
  age;	
  however,	
  no	
   declining	
  trends	
  were	
  observed	
  among	
  the	
  younger	
  age	
  group	
  (24-­‐54	
  years),	
  irrespective	
  of	
   sex,	
  in	
  this	
  time	
  period.(79)	
    27  With	
  more	
  recent	
  data,	
  using	
  the	
  Nationwide	
  Inpatient	
  Sample	
  (NIS),	
  between	
  the	
  years	
   2001	
  to	
  2007,	
  Wang	
  et	
  al.	
  reported	
  a	
  greater	
  absolute	
  and	
  relative	
  decline	
  in	
  AMI	
   hospitalization	
  rates	
  in	
  older	
  adults	
  than	
  in	
  younger	
  adults.	
  	
  Overall,	
  the	
  reduction	
  in	
   hospitalization	
  rates	
  were	
  24.6%,	
  26.7%,	
  34.0%,	
  34.8%,	
  32.4%	
  in	
  adults	
  <45,	
  45	
  to	
  <55,	
  55	
  to	
   <65,	
  65	
  to	
  <75	
  and	
  ≥75	
  years	
  of	
  age,	
  respectively.(20)	
  	
  Using	
  the	
  same	
  data	
  source,	
  Towfighi	
   et	
  al.	
  specifically	
  examined	
  sex-­‐	
  specific	
  AMI	
  hospitalization	
  trends	
  in	
  younger	
  adults.(18)	
  	
   Their	
  results	
  indicated	
  that	
  young	
  women,	
  particularly	
  those	
  <45	
  years	
  of	
  age,	
  did	
  not	
   benefit	
  from	
  the	
  same	
  decreasing	
  trends	
  observed	
  in	
  young	
  males.	
  	
  This	
  study	
  was	
  based	
  on	
   a	
  sample	
  of	
  US	
  hospitals	
  and	
  only	
  focused	
  on	
  patients	
  <	
  65	
  years	
  of	
  age.	
  	
  In	
  Canada,	
  a	
   national	
  study	
  of	
  age-­‐	
  and	
  sex-­‐	
  specific	
  AMI	
  hospitalization	
  rates	
  showed	
  an	
  11.0%	
  increase,	
   between	
  1994	
  and	
  2004,	
  in	
  young	
  women,	
  while	
  all	
  other	
  women	
  and	
  men	
  between	
  20-­‐74	
   years	
  of	
  age	
  benefited	
  from	
  declining	
  rates	
  of	
  AMI	
  hospitalization.(21)	
  	
  As	
  the	
  findings	
  of	
   this	
  study	
  were	
  based	
  on	
  two	
  time-­‐point	
  comparisons,	
  it	
  is	
  not	
  possible	
  to	
  draw	
  any	
   conclusions	
  about	
  the	
  changes	
  in	
  rates	
  of	
  AMI	
  hospitalization	
  over	
  the	
  entire	
  10	
  year	
   period.	
   It	
  is	
  important	
  to	
  note	
  that	
  most	
  of	
  these	
  studies	
  were	
  conducted	
  in	
  predominantly	
   Caucasian	
  populations,	
  and	
  data	
  on	
  ethnic	
  differences	
  in	
  AMI	
  hospitalization	
  rates,	
  overall	
   and	
  among	
  young	
  adults,	
  remains	
  limited.	
  	
  In	
  an	
  American	
  population,	
  Wang	
  et	
  al.	
  not	
  only	
   reported	
  higher	
  rates	
  of	
  AMI	
  hospitalizations	
  among	
  black	
  men	
  and	
  women,	
  regardless	
  of	
   age,	
  but	
  also	
  showed	
  that	
  AMI	
  hospitalization	
  rates	
  did	
  not	
  decline	
  in	
  young	
  black	
  men	
  and	
   women	
  <45	
  years	
  of	
  age	
  over	
  the	
  study	
  period.(20)	
  	
  One	
  other	
  study	
  reported	
  on	
  age-­‐,	
  sex-­‐	
   and	
  ethnicity-­‐specific	
  AMI	
  hospitalization	
  rates	
  in	
  a	
  Canadian	
  population.	
  	
  Using	
  hospital	
   28  administrative	
  discharge	
  data	
  for	
  all	
  AMI	
  hospitalizations	
  in	
  British	
  Columbia,	
  between	
  the	
   years	
  1994	
  to	
  2003,	
  Nijjar	
  et	
  al.	
  showed	
  that	
  among	
  young	
  males	
  <55	
  years	
  of	
  age,	
  the	
  rate	
   of	
  AMI	
  hospitalization	
  was	
  greatest	
  in	
  South	
  Asian	
  men,	
  as	
  compared	
  to	
  Asian	
  and	
   Caucasian	
  young	
  men.	
  	
  In	
  contrast,	
  in	
  young	
  women,	
  Caucasians	
  had	
  the	
  greatest	
  AMI	
   hospitalization	
  rate	
  among	
  the	
  three	
  ethnic	
  groups	
  under	
  study.(22)	
   With	
  respect	
  to	
  AMI	
  type,	
  based	
  on	
  the	
  National	
  Registry	
  of	
  Myocardial	
  Infarction	
  (NRMI)	
  in	
   the	
  U.S.,	
  Rogers	
  et	
  al.	
  showed	
  that,	
  from	
  1990	
  to	
  2005,	
  the	
  proportion	
  of	
  patients	
   presenting	
  with	
  STEMI	
  declined	
  significantly,	
  regardless	
  of	
  age.(56)	
  	
  Yeh	
  et	
  al.	
  reported	
  on	
  a	
   more	
  recent	
  population	
  trends	
  in	
  STEMI	
  and	
  NSTEMI	
  hospitalizations,	
  between	
  1999	
  and	
   2008.(80)	
  	
  During	
  this	
  period,	
  the	
  age-­‐	
  and	
  sex-­‐	
  adjusted	
  rates	
  of	
  STEMI	
  hospitalizations	
   continuously	
  decreased	
  with	
  a	
  relative	
  decrease	
  of	
  62%	
  (p<0.001	
  for	
  linear	
  trends),	
  whereas	
   the	
  NSTEMI	
  hospitalization	
  rates	
  increased	
  up	
  to	
  year	
  2004	
  and	
  then	
  decreased	
  between	
   2004	
  and	
  2008.	
   Finally,	
  the	
  most	
  recent	
  study	
  of	
  temporal	
  changes	
  in	
  the	
  characteristics	
  of	
  STEMI	
  patients	
   admitted	
  to	
  cardiac	
  care	
  units,	
  based	
  on	
  four	
  French	
  registries	
  [including	
  the	
  French	
   Registry	
  of	
  Acute	
  ST-­‐Elevation	
  or	
  non-­‐ST-­‐Elevation	
  Myocardial	
  Infarction	
  (FAST-­‐MI)],	
   reported	
  that	
  the	
  percentage	
  of	
  younger	
  women	
  (out	
  of	
  all	
  women	
  admitted	
  to	
  CCU	
  or	
  ICU	
   with	
  STEMI)	
  has	
  significantly	
  increased	
  between	
  the	
  years	
  1995	
  and	
  2012.(78)	
  	
  This	
  study,	
   published	
  in	
  August	
  2012,	
  received	
  considerable	
  attention	
  for	
  this	
  specific	
  finding.	
  	
   However,	
  an	
  important	
  limitation	
  of	
  this	
  study	
  is	
  that	
  the	
  observed	
  trend	
  was	
  based	
  on	
  four	
   different	
  registries	
  conducted	
  5	
  years	
  apart,	
  each	
  for	
  a	
  1-­‐month	
  period,	
  in	
  years	
  1995,	
  2000,	
    29  2005	
  and	
  2010.	
  	
  It	
  is	
  not	
  clear	
  whether	
  the	
  participating	
  hospitals,	
  and	
  therefore	
  the	
   underlying	
  patient	
  populations,	
  captured	
  by	
  these	
  registries,	
  at	
  each	
  of	
  these	
  time	
  points,	
   remained	
  the	
  same	
  over	
  the	
  15-­‐year	
  time	
  period.	
  Furthermore,	
  the	
  increase	
  in	
  percentage	
   of	
  younger	
  women	
  (out	
  of	
  all	
  women)	
  over	
  time	
  could	
  also	
  simply	
  be	
  the	
  result	
  of	
  the	
   observed	
  decline	
  in	
  the	
  percentage	
  of	
  older	
  STEMI	
  women	
  over	
  the	
  same	
  period	
  of	
  time.	
  	
  	
   2.2.3 Summary	
  of	
  Findings	
  and	
  Rationale	
  for	
  Objective	
  2A	
   While	
  studies	
  of	
  cardiac	
  risk	
  factors	
  in	
  the	
  general	
  population,	
  using	
  community-­‐based	
   surveys,	
  have	
  consistently	
  shown	
  that	
  the	
  rates	
  of	
  diabetes	
  and	
  obesity	
  in	
  younger	
  adults	
   are	
  on	
  the	
  rise,	
  information	
  on	
  temporal	
  changes	
  in	
  cardiac	
  risk	
  factors,	
  in	
  younger	
  AMI	
   patients,	
  remains	
  limited.	
  	
  Furthermore,	
  a	
  consistent	
  decline	
  in	
  the	
  overall	
  rates	
  of	
  AMI	
   hospitalization	
  has	
  been	
  observed,	
  in	
  both	
  men	
  and	
  women.	
  	
  However,	
  these	
  reported	
   declines,	
  based	
  on	
  the	
  overall	
  age-­‐	
  and	
  sex-­‐	
  standardized	
  rates	
  or	
  age-­‐	
  standardized	
  rates	
   for	
  women	
  and	
  men,	
  potentially	
  conceal	
  important	
  differences	
  between	
  different	
  age-­‐sex	
   groups.	
  	
  When	
  assessed	
  according	
  to	
  both	
  age	
  and	
  sex,	
  emerging	
  but	
  limited	
  data	
  suggests	
   that	
  the	
  rates	
  of	
  AMI	
  hospitalization	
  among	
  younger	
  women	
  are	
  in	
  fact	
  on	
  the	
  rise.	
  	
  These	
   trends	
  need	
  to	
  be	
  examined	
  in	
  a	
  population-­‐based	
  setting	
  and	
  not	
  just	
  based	
  on	
  the	
   comparison	
  of	
  a	
  few	
  time	
  points.	
  	
  Therefore,	
  Objective	
  2A	
  of	
  this	
  thesis	
  will	
  extend	
  the	
  prior	
   findings,	
  by	
  examining	
  the	
  rates	
  of	
  AMI	
  hospitalization	
  in	
  a	
  contemporary,	
  population-­‐based	
   setting,	
  with	
  a	
  particular	
  focus	
  on	
  younger	
  adults.	
  	
  The	
  results	
  of	
  a	
  10-­‐year	
  trend	
  analysis	
  of	
   the	
  age-­‐	
  and	
  sex-­‐specific	
  rates	
  of	
  AMI	
  hospitalization	
  and	
  select	
  comorbidities	
  will	
  be	
   presented	
  in	
  Chapter	
  3.	
    30  2.3 Mortality	
  Outcomes	
  	
   2.3.1 Short-­‐Term	
  Mortality	
  Post	
  AMI	
   Over	
  the	
  past	
  few	
  decades,	
  post-­‐	
  AMI	
  mortality	
  rates	
  have	
  improved	
  in	
  both	
  men	
  and	
   women,	
  in	
  the	
  U.S,	
  Canada	
  and	
  Europe;	
  however,	
  there	
  remain	
  some	
  important	
  sex-­‐ differences	
  in	
  outcomes	
  of	
  AMI	
  patients.	
  	
  Overall,	
  women	
  have	
  higher	
  rates	
  of	
  short-­‐term	
   mortality	
  following	
  an	
  AMI.(4,	
  38,	
  81-­‐84)	
  	
  Given	
  women’s	
  older	
  age	
  at	
  the	
  time	
  of	
   presentation	
  for	
  AMI,	
  adjustment	
  for	
  age	
  has	
  been	
  shown	
  to	
  attenuate	
  the	
  observed	
  sex-­‐ differences.(84,	
  85)	
  	
  However,	
  assessing	
  age-­‐specific,	
  rather	
  than	
  age-­‐standardized,	
  sex	
   differences	
  reveals	
  that	
  the	
  association	
  between	
  sex	
  and	
  early	
  AMI	
  mortality	
  is	
  in	
  fact	
   modified	
  by	
  age.	
  	
  Vaccarino	
  et	
  al.	
  were	
  the	
  first	
  to	
  demonstrate	
  the	
  existence	
  of	
  a	
   statistically	
  significant	
  sex-­‐age	
  interaction	
  on	
  early	
  mortality,	
  with	
  younger,	
  but	
  not	
  older,	
   women	
  having	
  higher	
  rates	
  of	
  death	
  during	
  hospitalization	
  for	
  MI	
  than	
  men	
  of	
  a	
  similar	
   age.(86)	
  	
  Using	
  data	
  from	
  the	
  NRMI	
  registry,	
  Vaccarino	
  et	
  al.	
  demonstrated	
  that	
  the	
   mortality	
  rate	
  during	
  hospitalization	
  in	
  patients	
  less	
  than	
  50	
  years	
  of	
  age	
  was	
  more	
  than	
   twice	
  as	
  high	
  in	
  women	
  than	
  in	
  men	
  (6.1%	
  vs.	
  2.9%,	
  respectively);	
  however,	
  the	
  observed	
   sex	
  difference	
  in	
  early	
  mortality	
  decreased	
  with	
  increasing	
  age	
  and	
  was	
  no	
  longer	
  significant	
   for	
  patients	
  aged	
  74	
  years	
  and	
  over	
  (overall	
  age-­‐sex	
  interaction	
  p<0.001).	
  	
  When	
  age	
  was	
   assessed	
  as	
  a	
  continuous	
  variable,	
  the	
  unadjusted	
  odds	
  of	
  death	
  during	
  hospitalization,	
  in	
   women	
  compared	
  to	
  men,	
  increased	
  by	
  11.1%	
  (95%	
  CI:	
  10.1-­‐12;	
  p<0.001)	
  for	
  every	
  five-­‐year	
   decrease	
  in	
  age.	
  	
  This	
  important	
  finding	
  of	
  a	
  survival	
  disadvantage	
  in	
  younger	
  women,	
   compared	
  to	
  their	
  male	
  counterparts,	
  was	
  later	
  confirmed	
  in	
  several	
  other	
  studies	
  of	
  mixed	
   AMI	
  populations	
  (3,	
  5,	
  11,	
  81)(Table	
  2.2).	
  	
  A	
  study	
  by	
  Marrugat	
  et	
  al.	
  reported	
  contradicting	
   31  findings	
  with	
  the	
  largest	
  sex-­‐gap	
  being	
  among	
  older	
  women	
  and	
  no	
  significant	
  sex-­‐ differences	
  among	
  patients	
  <65	
  years;	
  however,	
  this	
  study	
  only	
  included	
  a	
  select	
  group	
  of	
   AMI	
  patients	
  (only	
  those	
  with	
  first	
  Q-­‐wave	
  AMI),	
  who	
  comprised	
  only	
  10%	
  of	
  the	
  patients	
  in	
   the	
  study	
  by	
  Vaccarino	
  et	
  al.(87)	
  	
  Given	
  that	
  the	
  Marrugat	
  study’s	
  population	
  was	
  not	
   comparable	
  to	
  the	
  others	
  listed,	
  it	
  was	
  not	
  included	
  in	
  Table	
  2.2.	
  	
   One	
  study	
  has	
  suggested	
  that	
  the	
  sex	
  gap	
  in	
  early	
  mortality,	
  among	
  younger	
  adults,	
  may	
   have	
  narrowed	
  over	
  the	
  years.(11)	
  	
  However,	
  the	
  evidence	
  for	
  a	
  narrowing	
  of	
  the	
  sex	
  gap