LMP301 2014 Lecture 7.pdf

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University of Toronto St. George
Laboratory Medicine and Pathobiology
Kenneth Yip

  Lecture  7:  Lipids  and  Cardiac  Disease   Ischemic  Heart  Disease   -­‐ ischemic  heart  disease  (IHD)  is  the  2  most  frequent  cause  of  death  in  Canada,  just  behind  cancer   -­‐ 50%+  of  these  deaths  are  said  to  be  preventable   -­‐ the  name  implies  there’s  ischemia  (some  kind  of  blockage)   –  oxygen  and  blood  flow  is  unable  to  get  to  the   heart   -­‐ cells  and  tissue  of  the  heart  begin   to  die  off,  the  heart  stops  working  à  heart  attack   -­‐ mortality  rate  has  been  declining  since  1970,  possibly  due  to  better   eating  habits,  more  exercise,  and  better  treatment   -­‐ IHD  kills  as  many  women  as  men,  but  few  women  develop   symptoms  before  age  60  years  (later  in  women)   -­‐ Symptoms  in  women  are  less  characteristic  than  those  in  men,   leading  to  under  diagnosis     Schematic  Time  Course  of  Human  Atherogenesis   -­‐ Cerebrovascular  disease:  strokes   -­‐ clot  à  blood  flow  cannot  get  to  brain   à  stroke   -­‐ peripheral  vascular  disease:  blood  is  not  able  to  flow     -­‐ similar  mechanism  of  progression:  some  kind  of  lesion     -­‐ lesion  may  develop  early  in  age,  but  no  symptoms  until  older     Anatomy  of  the  Atheroscierotic  Plaque   -­‐ lipid  and  cholesterol  is  taken  up  by  the  cells  that  line  the  vessel   -­‐ lumen:  interior  of  the  vessel  where  the  blood  is  flowing   -­‐ intima:  the  vessel  wall  there  the  lipid  is  taken  up  and  accumulates   -­‐ the  fibrous  cap  holds  the  wall  together       Lipids   -­‐ Cholesterol  –  hormones,  membranes   -­‐ Triglycerides  –  fuel   -­‐ Phospholipids  –  membranes,  signaling   -­‐ Fatty  Acids  –  fuel   -­‐ lipids  are  barely  soluble  in  water  (hydrophobic)  and  need  to  be  carried  around  by  other  molecules   -­‐ lipoproteins  are  amphipathic  (hydrophobic  and  hydrophilic  faces)  proteins  that  form  a  “skin”  around  circulating   lipids  to  carry  them  in  plasma  and  lymph   -­‐ carries  lipid  on  the  inside  so  it  can   circulate  around  the  body   -­‐ free  fatty  acids  are  carried  by  albumin   -­‐ not  carried  by  lipoproteins,  fatty  acids  bind  to  albumin     Lipid  Metabolism   EXOGENOUS  CYCLE  FOR  DIETARY  FAT   -­‐ start  off  with  the  intestines  where  you’ve  ingested  the  lipids   -­‐ lipids  then  get  carried  around  as  chylomicrons     -­‐ dietary  fat  gets  absorbed  by  the  body,  and  these  big  buoyant  particles  (chylomicrons)  carry  mainly  t riglycerides   and  as  it  reaches  muscles  and  adipose  cells  and  tissues  of  the  body,  it  gets  taken  up   -­‐ major  source  of  energy   -­‐ anything  not  used  and  gets  stored  goes  into  fat   cells   -­‐ as  triglycerides  get  used  up,  it  shrinks  into  a  smaller   particle  –  remnant   -­‐ remnant  is  then  taken  up  by  the  liver   FASTING  (ENDOGENOUS  PATHWAY)   -­‐ still  need  to  get  energy  to  muscles  and  tissues   -­‐ liver  generates  VLDL   -­‐ very  low  density  lipoprotein   -­‐ VLDL  carries  triglycerides  to  muscle  and  adipose   cells       -­‐ In  this  process  it  gets  smaller  à  becomes  IDL  (intermediate  density  lipoprotein)   -­‐ IDL  can  go  back  to  the  liver  OR  get  further  processed  into  a  LDL  particle  (low  density  lipoprotein)   -­‐ After  LDL  is  processed,  it  goes  back  to  the  liver   -­‐ Some  of  this  processing  includes  delivery  of  cholesterol  t o  Extra-­‐hepatic  cells   -­‐ Cholesterol  is  used  as  a  structural  molecule  or  for  hormones   -­‐ if  there  is  extra  cholesterol  that  is  lying  around,  body  removes  it  by  using  the  HDL  particle   -­‐ high  density  lipoprotein   -­‐ has  many  functions  –  one  of  it  is  reverse  cholesterol  transport   -­‐ has  the  ability  to  take  cholesterol  from  the  extra -­‐hepatic  cells,  and  return  it  to  the  liver   -­‐ can  take  cholesterol  lying  in  vessels  (from  the  endothelium)   à  good  cholesterol   -­‐ removing  cholesterol  before  it  has  a  chance  to  build  up   -­‐ another  way  of  getting  rid  of  cholesterol:  bile   -­‐ liver  secretes  bile,  at  the  same  time,  processes  some  of  the  cholesterol  brought  back  to  it   -­‐ then  this  goes  into  the  intestine   -­‐ some  may  get  reabsorbed  and  into  this  cycle  again     Lipid  Metabolism     -­‐ if  you  were  to  take  serum/plasma  and  centrifuge  it,  you  can  separate  out  these  different  lipid  fractions   -­‐ most  buoyant  ones  (lightest  ones)  =  chylomicrons   à  float  to  the  top   1) Chylomicrons  (CM)   -­‐ largest  and  least  dense   -­‐ mainly  made  of  triglycerides   -­‐ transport  mainly  triglycerides  (TG)  and  some  cholesterol  (TC)   -­‐ arise  from  intestine  during  absorption  of  dietary  fat   -­‐ TG  load  is  carried  to  the  adipose  and  muscle  tissue   -­‐ The  “remnant”  is  metabolized  by  the  liver  to  give  VLDL   2) Very  Low  Density  Lipoprotein  (VLDL)   -­‐ lightest  one   -­‐ Triglycerides  secreted  by  the  liver  during  fasting   -­‐ carries  mostly  TG  and  some  TC  to  adipose  and  muscle  tissue   -­‐ essentially  triglyceride  is  lost  and  becomes  an  IDL   -­‐ some  of  its  surface  components  are  lost  in  the  transfer   -­‐ VLDL  becomes  IDL   3) Intermediate  Density  Lipoprotein  (IDL)   -­‐ IDL  returns  to  the  liver,  OR   -­‐ Is  converted  to  LDL   4) Low  Density  Lipoprotein  (LDL)   -­‐ LDL  carries  mostly  TC    (total  cholesterol)  to  the  peripheral  tissues   -­‐ There  are  receptors  on  extra  hepatic  and  hepatic  cells,  which  bind  to  this  particle  and  take  it  up  and  in corporate   the  lipid   -­‐ Binds  to  specific  receptors  on  the  peripheral  and  liver  cells   -­‐ LDL  is  atherogenic  form  à  the  “bad”  cholesterol   -­‐ Too  much  LDL?  Higher  risk  of  heart  disease   -­‐ Drugs  like  statins  target  LDL  and  try  to  lower  it   -­‐ Involved  in  forming  plaques  which  block  blood  flow  in  arteries   5) High  Density  Lipoprotein  (HDL)   -­‐ Very  heavy  –  goes  to  bottom  if  centrifuged   -­‐ densest  particle;  composed  mostly  of  protein  and  phospholipids   -­‐ synthesized  by  the  liver   -­‐ accepts  TC  from  other  lipoproteins  and  increases  in  size  from  HDL -­‐1  to  HDL-­‐2  to  HDL-­‐3   -­‐ can  be  brought  back  to  liver  for  removal   -­‐ carries  cholesterol  from  peripheral  tissues  to  the  liver;  process  called  “Reverse  Cholesterol  Transport”   à   “GOOD”  cholesterol   -­‐ liver  is  the  only  organ  that  can  excrete  significant  amounts  of  cholesterol;  done  through  bile  salts   -­‐ bile  salts  are  important  for  absorbing  fat -­‐soluble  vitamins  (A,  D,  E,  K)  in  the  intestines     Lipid  Disease   1) Inherited   à  Genetic  Factors       -­‐ familial  hypercholesterolemia  (FHC)   -­‐ familial  hypertriglyceridemia     -­‐ also  combined  forms   -­‐ mutations  that  cause  very  high  elevations  of  cholesterol  or  triglycerides  (combined  forms  are  possible   –  elevations   in  both)   -­‐ FHC  is  due  to  a  defect  in  LDL  receptor  function   -­‐ LDL  particles  are  supposed  to   go  back  to  the  liver  and  taken  up   -­‐ If  receptor  for  LDL  is  not  working?  LDL  will  accumulate  in  the  blood,  and  lying  around  in  vessels  and  other   areas  to  be  built  up   -­‐ Approximately  1  in  500  are  heterozygous  and  may  have  myocardial  infarcts   (heart  attacks)  in  their  30s   -­‐ Approximately  1  in  1,000,000  are  homozygous  and  may  have  myocardial  infarcts  in  childhood   -­‐ Can  be  identified  by  the  presence  of   Xanthoma  (lipid  deposits)   à  xanthomas  on  the  tendons  are  an  obvious  sign  of   this  problem   -­‐ Xanthomas:  build  up  of  cholesterol  and  fatty  deposit   à  tends  to  happen  in  tendenous  soft  tissues   -­‐ Defect  in  the  synthesis  of  LDL  (cannot  make  LDL)  =  less  chance  of  heart  attack     2) Acquired  (Risk  Factors  for  Cardiovascular  Disease)   § age  (major  determinant  of  risk)   § male  gender   § smoker   § chronic  kidney  disease,  diabetes  mellitus  ( especially  type  2)   § cholesterol  levels   § family  history  of  IHD   § inflammatory  biomarkers  (esp.  CRP)   § lack  of  exercise;  overweight  and  obesity     Thrombosis  of  a  Disrupted  Atheroma   -­‐ although  plaque  restricts  blood  flo w  and  limit  oxygen  supply,  what   really  causes  the  big  damage  is  when  you  have  a  plaque  rupture   -­‐ cause  of  most  Acute  coronary  Syndromes   -­‐ results  from:   -­‐ weakening  of  the  fibrous  cap   § when  cap  ruptures  and  breaks  and  contents  get  out,   thrombus  is  initiated  à  cause  clotting  to  form   § all  these  platelets  then  come  in,  and  when  clot  gets   there,  blood  flow  is  completely  stopped   -­‐ thrombogenicity  of  the  lipid  core   Plaque  Rupture  with  Thrombosis   -­‐ to  treat  heart  attacks/strokes,  a  “clot  buster”  is  given   -­‐ enzymes  that  may  try  to  dissolve  and  break  down  the   clot   -­‐ in  some  cases,  they  may  try  to  open  it  back  up  –   putting  in  a  balloon  and  inflating  it       Pathogenesis  of  IHD     1) Oxidant  Status   -­‐ cholesterol  rich  LDL  is  found  in  the  lipid  plaques  that  coat  the   inside  of  the  blood  vessels  in  IHD   -­‐ LDL-­‐Cholesterol  appears  to  be  converted  to  an  “oxidized  form”  by  free  radical  damage   -­‐ Intensive  research  has  tried  to  shift  the  antioxidant  status  of  the  individuals  to  decrease  their  risk   -­‐ Serum  level  of  homocysteine  (a  reducing  amino  acid)  are  increased  in  some  patients  that  have  early  onset  heart   attacks   -­‐ Homocysteine  :  has  a  property  that  it’s  a  reducing  amino  acids   -­‐ Increased  levels  are  linked  to  an  early  onset  of  heart  attacks   -­‐ Trials  with  vitamin  C  and  E  did  not  work  to  stop  heart  attacks   –  not  enough   2) Inflammatory  Response  Markers   -­‐ tissue  damage  at  the  site  of  the  atheroma  (site  of  deposit  –  enlargement  of  vessel  at  the  site  of  lipid  deposition)   triggers  an  inflammatory  response       -­‐ oxidation  of  LDL  =  increase  in  inflammatory  response  à  immune  system  was  triggered  to  attack   -­‐ C-­‐reactive  protein  (CRP)  is  an  acute  phase  reactant  and  very  sensitive  marker  of  body  response  to  inflammation   or  infection   -­‐ acute  =  happens  very  quickly  when  you  have  an  inflammation/infection   -­‐ Measures  inflammation   -­‐ Since  heart  disease  progresses  over  years,  this  increase  in  CRP  doesn’t  go  as  high  as  if  you  had  an  infection,   but  goes  higher  than  normal     -­‐ May  help  identify  those  at  higher  risk  than  based  on  the  risk  score  alone   3) Lipoprotein  (a),  Lp(a)   -­‐ Lipoprotein  (a)  consists  of  ordinary  LDL  combined  with  an  additional  protein  –  like  fused  together   -­‐ One  hypothesis  for  its  role  in  IHD  is  that  lipoprotein  (a)  interferes  with  the  action  of  another  protein,  plasminogen   (anti-­‐thrombic  property)   -­‐ Similar  structure  to  plasminogen,  may  interfere  wi th  anti-­‐thrombotic  process   -­‐ The  lipoprotein  (a)  protein  has  a  similar  structure  to  plasminogen  and  the  DNA  that  codes  it  is  found  next  to  that   coding  for  plasminogen   -­‐ Increase  levels  of  Lp(a)  =  myocardial  infarcts  at  young  age   -­‐ Individuals  expressing  this  gene  can  have  myocardial  infarcts  as  young  as  8  years  of  age     Prevention  of  Disease   -­‐ population  screening  of  serum  cholesterol  level  (routine  once  you  hit  40  years  old)   -­‐ fast  lipid  profile  (fasting  lipid  profile):   -­‐ total  cholesterol  à  measured   § sum  of  LDL  cholesterol   -­‐ HDL  cholesterol  à  measured   -­‐ Triglyceride  à  measured   -­‐ LDL  cholesterol  à  calculated  or  measured   -­‐ Lipids  are  very  interrelated  in  regards  to  their  metabolism,  its  possible  to  measure  the  first  3  and  you  can  calculate   the  last  one  (most  of  the  time  LDL  is  calculated)   -­‐ total  cholesterol  =  LDL-­‐C  +  HDL-­‐C  +  VLDL-­‐C     -­‐ most  of  VLDL  is  made  of  triglycerides,  you  can  estimate  the  amount  of  VLDL  from  triglyceride   measurement  à  only  accurate  if  fasting   § VLDL  cholesterol  =  TG/2.2  (when  fasting)   -­‐ LDL-­‐C  =  TC  –  (HDL-­‐C  +  TG/2.2)   -­‐
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