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Lipoprotein disorders and cardiovascular diseases
Date-28-03-2017
GENERAL STRUCTURE OF LIPO PROTEINSGENERAL STRUCTURE OF LIPO PROTEINS
Lipoproteins consist of a nonpolar core and a single...
GENERAL STRUCTURE OF LIPO PROTEINSGENERAL STRUCTURE OF LIPO PROTEINS
Some apolipoproteins are integral and cannot be remov...
04/02/17 4
Classification of LipoproteinsClassification of Lipoproteins
Lipoproteins with high lipid content will have low density, l...
APOLIPOPROTEINSAPOLIPOPROTEINS
One or more apolipoproteins (proteins or polypeptides)
are present in each lipoprotein.
T...
04/02/17 7
LIPOPROTEIN METABOLISM AND TRANSPORTLIPOPROTEIN METABOLISM AND TRANSPORT
04/02/17 8
04/02/17 9
04/02/17 10
LIPOPROTEIN DISORDERSLIPOPROTEIN DISORDERS
04/02/17 11
04/02/17 12
Provided a useful conceptual framework.
 This classification had many drawbacks:
A)did not give much emphasis on HDL-C,
...
GENETIC LIPOPROTEIN DISORDERSGENETIC LIPOPROTEIN DISORDERS
04/02/17 14
(TYPE II HYPERLIPIDEMIA)
FAMILIAL HYPERCHOLESTEROLEMIAFAMILIAL HYPERCHOLESTEROLEMIA
Affected subjects have an elevated LDL-C level greater
than th...
PROPROTEIN CONVERTASE, SUBTILISIN/KEXINPROPROTEIN CONVERTASE, SUBTILISIN/KEXIN
TYPE 9 GENETYPE 9 GENE
An autosomal domina...
04/02/17 17
March 17th
, 2017
AUTOSOMAL RECESSIVEAUTOSOMAL RECESSIVE
HYPERCHOLESTEROLEMIAHYPERCHOLESTEROLEMIA
HYPOBETALIPOPROTEINEMIA
Mutations within ...
ABETALIPOPROTEINEMIA
Results from a mutation in the gene coding for the
microsomal triglyceride transfer protein (MTP),
r...
Acanthocytosis in PBF
Oral fat intolerance, steatorrhea, diarrhea, fat
malabsorption, lipid accumulation in enterocytes,...
SITOSTEROLEMIA
A rare condition of increased intestinal absorption and
decreased excretion of plant sterols (sitosterol a...
04/02/17
Othman et al. Non-cholesterol sterols and
cholesterol metabolism in sitosterolemia. Atherosclerosis.
2013;231(2):...
LIPOPROTEIN(a)LIPOPROTEIN(a)
Lp(a) (pronounced “lipoprotein little a”) consists of an
LDL particle linked covalently with...
TRIGLYCERIDE-RICH LIPOPROTEINSTRIGLYCERIDE-RICH LIPOPROTEINS
FAMILIAL HYPERTRIGLYCERIDEMIA (TYPE IV
HYPERLIPOPROTEINEMIA)...
04/02/17
(Adult Treatment Panel III): final report. NIH publication
no.: 02-5215. Bethesda, Md.: National Heart, Lung, and...
04/02/17
(Adult Treatment Panel III): final report. NIH publication
no.: 02-5215. Bethesda, Md.: National Heart, Lung, and...
FAMILIAL HYPERCHYLOMICRONEMIA (TYPE I
HYPERLIPIDEMIA)
Elevations in fasting plasma triglycerides to greater
than >1000 m...
DIAGNOSIS/MANAGEMENTDIAGNOSIS/MANAGEMENT
Based on the assay of LPL enzyme activity in plasma
following intravenous admini...
TYPE III HYPERLIPOPROTEINEMIA
(Dysbetalipoproteinemia or Broad Beta Disease)
Increased cardiovascular risk.
Pathognomoni...
Treatment of dysbetalipoproteinemia is the same as for
hypertriglyceridemia.
 Weight loss, diet fat restriction and trea...
FAMILIAL COMBINED HYPERLIPIDEMIA
Characterized by the presence of elevated total
cholesterol and/or triglyceride levels ...
HIGH-DENSITY LIPOPROTEINSHIGH-DENSITY LIPOPROTEINS
Disorders of High-Density Lipoprotein Biogenesis
Apolipoprotein A-I G...
TANGIER DISEASE AND FAMILIAL HIGH-DENSITY
LIPOPROTEIN DEFICIENCY.
The cellular defect - consists of reduced cellular
cho...
DIAGNOSISDIAGNOSIS
Other tests:
1. 2D electrophoresis with
subsequent anti-apoA-I
immunoblotting.
2.Cholesterol efflux as...
MANAGEMENTMANAGEMENT
To date, the only definite therapeutic intervention for
Tangier patients is a very low fat diet, thu...
Niemann-Pick type C disease is a disorder of lysosomal
cholesterol transport.
In patients with Niemann-Pick type C disea...
DISORDERS OF HIGH-DENSITY LIPOPROTEIN–DISORDERS OF HIGH-DENSITY LIPOPROTEIN–
PROCESSING ENZYMESPROCESSING ENZYMES
LECITHIN...
CHOLESTERYL ESTER TRANSFER PROTEIN
DEFICIENCY
 Patients without CETP have very elevated levels of HDL-
C, which is enrich...
SECONDARY CAUSES OF DYSLIPOPROTEINEMIASSECONDARY CAUSES OF DYSLIPOPROTEINEMIAS
04/02/17 39
DYSLIPIDEMIA MANAGEMENTDYSLIPIDEMIA MANAGEMENT
04/02/17 40
2013 ACC/AHA Guidelines:2013 ACC/AHA Guidelines:
Statins without any lipid “goals”Statins without any lipid “goals”
Circul...
04/02/17 42
INDIAN GUIDELINESINDIAN GUIDELINES
43
  INDIAN DYSLIPIDEMIAINDIAN DYSLIPIDEMIA
  
  
RISK FACTORSRISK FACTORS
NON TRADITIONAL CV RISKS IN INDIANON TRADITIONAL CV RISKS IN INDIA
04/02/17 46
CORONARY CALCIUM
Both LDL-C and HDL-C were found to be
independent predictors of CAC
CAC score >400 had 100% specificity
CIMT
 For 0.1 mm increase in CIMT the future risk of MI increased by 10-15%
 A 10% reduction in LDL-C per year accounted...
Lp(a)
 more common
among CAD patients
with existing family
history
 Lp(a) levels in Asian
Indian newborns were
significa...
Presence of obesity
and/or metabolic
syndrome in an
individual who is
otherwise at low 10-year
risk of ASCVD should
indic...
A 5-μmol/L tHcy increment elevates CAD risk by as much
as cholesterol increases of 0.5 mmol/L (20 mg/dL)
Very high preva...
CRP
 significant ASCVD risk
reduction with statin in
individuals with elevated CRP
despite relatively normal LDL-C
 A va...
JBS3: LIFETIME ASCVD RISK CALCULATOR
Estimate lifetime risk
Validated in indians
Non-conventional risk
factors
<30% = L...
The Indian ApproachThe Indian Approach
1. History of MI or documented CAD
2. History of ischemic stroke or TIA
3. Hemodynamically significant carotid plaque
4. A...
30-44%
risk
>45%
risk
Moderate
risk
High
risk
INDIANINDIAN
RISKRISK
STRATIFICATIONSTRATIFICATION
SETTING INDIAN TARGETSSETTING INDIAN TARGETS
04/02/17 57
Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279
04/02/17 59
RESIDUAL CVD RISK WITH INTENSIVE STATIN
THERAPY LESS, BUT STILL UNACCEPTABLY HIGH
PatientsExperiencing
MajorCVDEvents,%
PR...
BEYOND TARGETING LDL
There are several atherogenic
lipoproteins and LDL
accounts for only about 75%
of them
Residual ris...
increased non-HDL-C is associated
with increased risk of future CV events
even if LDL-C is under
control with statin
Better correlate of ASCVD than LDL
Includes TG and Lp(a)
Does not need fasting
Can be easily calculated by total chole...
04/02/17 65
 Prevalence of low HDL-C levels was much higherlow HDL-C levels was much higher in the
South Asian populations than in th...
THERAPY FOR INDIAN DYSLIPIDEMIATHERAPY FOR INDIAN DYSLIPIDEMIA
04/02/17 68
Smoking
It is never too late to quit
smoking. After quitting
smoking,
the ASCVD risk decreases by
50% within 2 years.
A...
DIET AND NUTRITIONDIET AND NUTRITION
Statin doses
STATINSSTATINS
Statin adr
FIBRATESFIBRATES
A meta-analysis of 18 trials
providing data for 45058
participants, including
2870 major CV events,
4552...
Look for reversible causes
Eg.DM, hypothyroidsm, CKD,
immuocomprised
LSM
TG<500 TG>500
Statin
Achieve LDL target
Achieve n...
CURRENT LAI GUIDELINES – KEY POINTSCURRENT LAI GUIDELINES – KEY POINTS
Enas EA, Dharmarajan T S. The Lipid Association of ...
TAKE HOME MESSAGETAKE HOME MESSAGE
LIFE SIMPLE SEVENLIFE SIMPLE SEVEN
1. No tobacco
2. Physical activity: ≥150 min moderat...
THANKSTHANKS
04/02/17 76
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Lipoprotein disorders

  1. 1. Lipoprotein disorders and cardiovascular diseases Date-28-03-2017
  2. 2. GENERAL STRUCTURE OF LIPO PROTEINSGENERAL STRUCTURE OF LIPO PROTEINS Lipoproteins consist of a nonpolar core and a single surface layer of amphipathic lipids The nonpolar lipid core consists of mainly triacylglycerol and cholesteryl ester and is surrounded by a single surface layer of amphipathic phospholipid and cholesterol molecules These are oriented so that their polar groups face outward to the aqueous medium. The protein moiety of a lipoprotein is known as an apolipoprotein or apoprotein. 04/02/17 2
  3. 3. GENERAL STRUCTURE OF LIPO PROTEINSGENERAL STRUCTURE OF LIPO PROTEINS Some apolipoproteins are integral and cannot be removed, whereas others can be freely transferred to other lipoproteins. 04/02/17 3
  4. 4. 04/02/17 4
  5. 5. Classification of LipoproteinsClassification of Lipoproteins Lipoproteins with high lipid content will have low density, larger size and so float on centrifugation. Those with high protein content sediment easily, have compact size and have a high density.04/02/17 5
  6. 6. APOLIPOPROTEINSAPOLIPOPROTEINS One or more apolipoproteins (proteins or polypeptides) are present in each lipoprotein. The major apolipoproteins of HDL (α-lipoprotein) are designated A. The main apolipoprotein of LDL (β -lipoprotein) is apolipoprotein B (B-100), which is found also in VLDL. Chylomicons contain a truncated form of apo B (B-48) that is synthesized in the intestine, while B-100 is synthesized in the liver. Apo E is found in VLDL, HDL, Chylomicons, and chylomicron remnants. 04/02/17 6
  7. 7. 04/02/17 7
  8. 8. LIPOPROTEIN METABOLISM AND TRANSPORTLIPOPROTEIN METABOLISM AND TRANSPORT 04/02/17 8
  9. 9. 04/02/17 9
  10. 10. 04/02/17 10
  11. 11. LIPOPROTEIN DISORDERSLIPOPROTEIN DISORDERS 04/02/17 11
  12. 12. 04/02/17 12
  13. 13. Provided a useful conceptual framework.  This classification had many drawbacks: A)did not give much emphasis on HDL-C, B)it does not differentiate severe monogenic lipoprotein disorders from the more common polygenic disorders.  World Health Organization, the European Atherosclerosis Society, and more recently, the National Cholesterol Education Program (NCEP) classified lipoprotein disorders on the basis of arbitrary cut points. 04/02/17 13
  14. 14. GENETIC LIPOPROTEIN DISORDERSGENETIC LIPOPROTEIN DISORDERS 04/02/17 14 (TYPE II HYPERLIPIDEMIA)
  15. 15. FAMILIAL HYPERCHOLESTEROLEMIAFAMILIAL HYPERCHOLESTEROLEMIA Affected subjects have an elevated LDL-C level greater than the 95th percentile for age and sex.  In adulthood, clinical manifestations include corneal arcus, tendinous xanthomas over the extensor tendons (metacarpophalangeal joints, patellar, triceps, and Achilles tendons), and xanthelasmas. Transmission is autosomal codominant. FH affects approximately 1 in 500. Patients with FH have high risk for the development of CAD by the third to fourth decade in men and approximately 8 to 10 years later in women. 04/02/17 15
  16. 16. PROPROTEIN CONVERTASE, SUBTILISIN/KEXINPROPROTEIN CONVERTASE, SUBTILISIN/KEXIN TYPE 9 GENETYPE 9 GENE An autosomal dominant form of hypercholesterolemia that maps to chromosome 1p34.1 involves a mutation within the PCSK9 gene. PCSK9 codes for a proprotein convertase belonging to the subtilase family of convertases. Gain-of-function mutations in the PCSK9 gene decrease surface availability of the LDL-R protein and cause accumulation of LDL-C in plasma.  Subjects with a loss-of-function mutation of PCSK9 have markedly lower LDL-C than do subjects without the mutation. 04/02/17 Cohen J et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 354:1264, 2006. 16
  17. 17. 04/02/17 17 March 17th , 2017
  18. 18. AUTOSOMAL RECESSIVEAUTOSOMAL RECESSIVE HYPERCHOLESTEROLEMIAHYPERCHOLESTEROLEMIA HYPOBETALIPOPROTEINEMIA Mutations within the APOB gene can lead to truncations of the mature apo B100 peptide.  Many such mutations cause a syndrome characterized by reduced LDL-C and VLDL-C but little or no clinical manifestations and no known risk for CVD, a condition referred to as hypobetalipoproteinemia . 04/02/17 Curr Opin Lipidol. 2014 June ; 25(3): 161–168. 18
  19. 19. ABETALIPOPROTEINEMIA Results from a mutation in the gene coding for the microsomal triglyceride transfer protein (MTP), required for assembly of apo B–containing lipoproteins in the liver and the intestine. Lack of apo B–containing lipoproteins in plasma causes a marked deficiency of fat-soluble vitamins (A, D, E, and K) that circulate in lipoproteins. Results in mental and developmental retardation in affected children. 04/02/17 Curr Opin Lipidol. 2014 June ; 25(3): 161–168. 19
  20. 20. Acanthocytosis in PBF Oral fat intolerance, steatorrhea, diarrhea, fat malabsorption, lipid accumulation in enterocytes, failure to thrive and deficiency of fat-soluble vitamins A and E. Deficiency of vitamin E leads to progressive degeneration of the central nervous system and death. Unless treated early with vitamin E, subjects develop atypical retinitis pigmentosa, spinocerebellar degeneration with ataxia and a bleeding diathesis secondary to malabsorption of fat-soluble vitamins 04/02/17 20
  21. 21. SITOSTEROLEMIA A rare condition of increased intestinal absorption and decreased excretion of plant sterols (sitosterol and campesterol) can mimic severe FH with extensive xanthoma formation. Premature atherosclerosis,occurs in patients with sitosterolemia. Patients with sitosterolemia have homozygous (or compound heterozygous) mutations in the ABCG5 and ABCG8 genes. A defect in either of the genes inactivates the transport mechanism across the intestinal lumen, and net accumulation of plant sterols (because of impaired elimination) ensues . 04/02/17 21
  22. 22. 04/02/17 Othman et al. Non-cholesterol sterols and cholesterol metabolism in sitosterolemia. Atherosclerosis. 2013;231(2):291–9. Quintás-Cardama A et al .Long-term follow-up of a patient with sitosterolemia and hemolytic anemia with excellent response to ezetimibe. J Genet Disord Genet Rep. 2013;2:1. 22
  23. 23. LIPOPROTEIN(a)LIPOPROTEIN(a) Lp(a) (pronounced “lipoprotein little a”) consists of an LDL particle linked covalently with one molecule of apo (a).  The apo (a) moiety consists of a protein with a high degree of homology with plasminogen. The pathogenesis of Lp(a) may result from an antifibrinolytic potential and/or ability to bind oxidized lipoproteins. Prospective epidemiologic studies have shown a positive (albeit weak) association between Lp(a) and CAD. 04/02/17 Di Angelantonio E, Gao P, Pennells L, et al: Lipid-related markers and cardiovascular disease prediction. JAMA 307:2499, 2012. 23
  24. 24. TRIGLYCERIDE-RICH LIPOPROTEINSTRIGLYCERIDE-RICH LIPOPROTEINS FAMILIAL HYPERTRIGLYCERIDEMIA (TYPE IV HYPERLIPOPROTEINEMIA) Clinical signs such as corneal arcus, xanthoma, and xanthelasmas are absent.  Plasma triglycerides, VLDL-C, and VLDL triglycerides are moderately to markedly elevated; the LDL-C level is usually low, as is HDL-C. Total cholesterol is normal or elevated, depending on VLDL-C levels. Fasting plasma concentrations of triglycerides are in the range - 200 to 500 mg/dL. Weaker relationship with CAD 04/02/17 24
  25. 25. 04/02/17 (Adult Treatment Panel III): final report. NIH publication no.: 02-5215. Bethesda, Md.: National Heart, Lung, and Blood Institute, 2002 25
  26. 26. 04/02/17 (Adult Treatment Panel III): final report. NIH publication no.: 02-5215. Bethesda, Md.: National Heart, Lung, and Blood Institute, 2002 26
  27. 27. FAMILIAL HYPERCHYLOMICRONEMIA (TYPE I HYPERLIPIDEMIA) Elevations in fasting plasma triglycerides to greater than >1000 mg/dL. Patients have recurrent bouts of pancreatitis and eruptive xanthomas. Can also be associated with xerostomia, xerophthalmia, and behavioral abnormalities. The hypertriglyceridemia results from markedly reduced or absent LPL activity or, more rarely, absence of its activator apo C-II 04/02/17 27
  28. 28. DIAGNOSIS/MANAGEMENTDIAGNOSIS/MANAGEMENT Based on the assay of LPL enzyme activity in plasma following intravenous administration of heparin. Detection of very low or absent LPL enzyme activity in an assay system that contains either normal plasma or apoprotein C-II and excludes hepatic lipase is diagnostic of familial LPL deficiency. Treatment – 1. Medical nutrition therapy to maintain plasma triglyceride concentration at less than 1000 mg/dL. 2. Restriction of dietary fat to no more than 20 g/day or 15% of a total energy intake is usually sufficient. 3. The acute pancreatitis episode is treated with standard care.04/02/17 28
  29. 29. TYPE III HYPERLIPOPROTEINEMIA (Dysbetalipoproteinemia or Broad Beta Disease) Increased cardiovascular risk. Pathognomonic tuberous xanthomas and palmar striated xanthomas are present. Increased cholesterol and triglyceride levels and reduced HDL-C.  Remnant lipoproteins (partly catabolized chylomicrons and VLDL) accumulate in plasma resulting from abnormal apo E, which does not bind to hepatic receptors that recognize apo E as a ligand.  Ratio of VLDL cholesterol to triglycerides, normally less than 0.7 is elevated in patients with type III hyperlipoproteinemia because of cholesteryl ester enrichment of remnant particles.04/02/17 29
  30. 30. Treatment of dysbetalipoproteinemia is the same as for hypertriglyceridemia.  Weight loss, diet fat restriction and treatment of secondary factors, such as diabetes and hypothyroidism are important for all dysbetalipoproteinemia patients. Administration of fibrates, statins, omega-3 fatty acids and niacin or their combinations is very effective. However, it has to be underlined that fibrates, with or without statin, seem to comprise the cornerstone of dysbetalipoproteinemia treatment. 04/02/17 Marais AD, et al. Crit Rev Clin Lab Sci 2014; 51: 46-62 30
  31. 31. FAMILIAL COMBINED HYPERLIPIDEMIA Characterized by the presence of elevated total cholesterol and/or triglyceride levels . Prevalence of approximately 1 in 50 . Accounts for 10% to 20% of patients with premature CAD. Corneal arcus, xanthomas, and xanthelasmas occur infrequently. Diagnosis of familial combined hyperlipoproteinemia requires identification of the disorder in at least one first-degree relative.  Underlying metabolic disorders appear to include hepatic overproduction of apo B–containing lipoproteins, delayed postprandial clearance of TRLs, and increased flux of FFAs to the liver.04/02/17 31
  32. 32. HIGH-DENSITY LIPOPROTEINSHIGH-DENSITY LIPOPROTEINS Disorders of High-Density Lipoprotein Biogenesis Apolipoprotein A-I Gene Defects Primary defects affecting the production of HDL particles may be caused by mutations in the apo A-I–C-III–A-IV gene complex. 04/02/17 32
  33. 33. TANGIER DISEASE AND FAMILIAL HIGH-DENSITY LIPOPROTEIN DEFICIENCY. The cellular defect - consists of reduced cellular cholesterol efflux in skin fibroblasts and macrophages from affected subjects.  A more common entity, familial HDL deficiency, was also found to result from decreased cellular cholesterol. Tangier disease and familial HDL deficiency result from mutations in the ABCA1 gene, which encodes the ABCA1 transporter . Increased risk for CAD 04/02/17 33
  34. 34. DIAGNOSISDIAGNOSIS Other tests: 1. 2D electrophoresis with subsequent anti-apoA-I immunoblotting. 2.Cholesterol efflux assay on cultivated skin fibroblasts. 04/02/17 von Eckardstein A, et al.. Atherosclerosis 1998; 138: 25-34 Joyce C, et al.. Arterioscler Thromb Vasc Biol 2003; 23: 965-71 34
  35. 35. MANAGEMENTMANAGEMENT To date, the only definite therapeutic intervention for Tangier patients is a very low fat diet, thus reducing the potential to develop fatty liver. CETP Inhibitors- Torcetrapib(ILLUMINATE), Dalcetrapib(dal-VESSEL). 04/02/17 35
  36. 36. Niemann-Pick type C disease is a disorder of lysosomal cholesterol transport. In patients with Niemann-Pick type C disease, mental retardation and neurologic manifestations occur frequently.  The cellular phenotype involves markedly decreased cholesterol esterification and a defect in the cellular transport of cholesterol to the Golgi apparatus. 04/02/17 36
  37. 37. DISORDERS OF HIGH-DENSITY LIPOPROTEIN–DISORDERS OF HIGH-DENSITY LIPOPROTEIN– PROCESSING ENZYMESPROCESSING ENZYMES LECITHIN-CHOLESTEROL ACYLTRANSFERASE DEFICIENCY Deficiencies of LCAT, the enzyme that catalyzes the formation of cholesteryl esters in plasma, cause corneal infiltration of neutral lipids and hematologic abnormalities as a result of the abnormal constitution of red blood cell membranes . “FISH EYE DISEASE” No increased risk of cad. 04/02/17 37
  38. 38. CHOLESTERYL ESTER TRANSFER PROTEIN DEFICIENCY  Patients without CETP have very elevated levels of HDL- C, which is enriched in cholesteryl esters as it facilitates the transfer of HDL cholesteryl esters into TRLs.  CETP deficiency is not associated with premature CAD. Niemann-Pick type I disease (subtypes A and B), which is caused by mutations in the sphingomyelin phosphodiesterase-1 (SMPD1) gene, is associated with a low HDL-C level . Decrease in LCAT reaction because of abnormal HDL constituents.04/02/17 38
  39. 39. SECONDARY CAUSES OF DYSLIPOPROTEINEMIASSECONDARY CAUSES OF DYSLIPOPROTEINEMIAS 04/02/17 39
  40. 40. DYSLIPIDEMIA MANAGEMENTDYSLIPIDEMIA MANAGEMENT 04/02/17 40
  41. 41. 2013 ACC/AHA Guidelines:2013 ACC/AHA Guidelines: Statins without any lipid “goals”Statins without any lipid “goals” Circulation 2014; 129: S1-S45 • Clinical ASCVD* • LDL-C ≥190 mg/dL, Age ≥21 years • Primary prevention – Diabetes: Age 40-75 years, LDL-C 70-189 mg/dL • Primary prevention - No Diabetes†: ≥7.5%‡ 10-year ASCVD risk, Age 40-75 years, LDL-C 70-189 mg/dL *Atherosclerotic cardiovascular disease † Requires risk discussion between clinician and patient before statin initiation ‡ Statin therapy may be considered if risk decision is uncertain after use of ASCVD risk calculator Circulation. 2014;129[suppl 2]:S1-S45
  42. 42. 04/02/17 42
  43. 43. INDIAN GUIDELINESINDIAN GUIDELINES 43
  44. 44.   INDIAN DYSLIPIDEMIAINDIAN DYSLIPIDEMIA      
  45. 45. RISK FACTORSRISK FACTORS
  46. 46. NON TRADITIONAL CV RISKS IN INDIANON TRADITIONAL CV RISKS IN INDIA 04/02/17 46
  47. 47. CORONARY CALCIUM Both LDL-C and HDL-C were found to be independent predictors of CAC CAC score >400 had 100% specificity
  48. 48. CIMT  For 0.1 mm increase in CIMT the future risk of MI increased by 10-15%  A 10% reduction in LDL-C per year accounted for a reduction of CIMT by 0.73  presence of carotid plaques is a marker of already existing ASCVD
  49. 49. Lp(a)  more common among CAD patients with existing family history  Lp(a) levels in Asian Indian newborns were significantly higher than in Chinese in Singapore  Level > 20 mg/dL indicates increased ASCVD risk in Indians
  50. 50. Presence of obesity and/or metabolic syndrome in an individual who is otherwise at low 10-year risk of ASCVD should indicate high lifetime ASCVD risk. OBESITY/ MET Syn.OBESITY/ MET Syn.
  51. 51. A 5-μmol/L tHcy increment elevates CAD risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL) Very high prevalence of hyperhomocystinemia (>15 µmol/L) in 75% of subjects in India, which was strongly correlated with cobalamin deficiency Impaired cobalamin status appears more important than folate deficiency among Asian Indians HOMOCYSTEINEHOMOCYSTEINE
  52. 52. CRP  significant ASCVD risk reduction with statin in individuals with elevated CRP despite relatively normal LDL-C  A value of > 2 mg/l of hs-CRP indicates increased ASCVD risk.  When the value is >10 mg/L, it usually indicates a non- atherosclerotic cause of Inflammation  But Quality control and proper standardization of hs-CRP is challenging in India
  53. 53. JBS3: LIFETIME ASCVD RISK CALCULATOR Estimate lifetime risk Validated in indians Non-conventional risk factors <30% = LOW RISK 30-44% = MODERATE RISK >45% = HIGH RISK
  54. 54. The Indian ApproachThe Indian Approach
  55. 55. 1. History of MI or documented CAD 2. History of ischemic stroke or TIA 3. Hemodynamically significant carotid plaque 4. Atherosclerotic peripheral arterial disease(ABPI<0.9) 5. Atherosclerotic aortic aneurysms 6. Atherosclerotic renal artery stenosis Pre-existing ASCVDPre-existing ASCVD
  56. 56. 30-44% risk >45% risk Moderate risk High risk INDIANINDIAN RISKRISK STRATIFICATIONSTRATIFICATION
  57. 57. SETTING INDIAN TARGETSSETTING INDIAN TARGETS 04/02/17 57
  58. 58. Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279
  59. 59. 04/02/17 59
  60. 60. RESIDUAL CVD RISK WITH INTENSIVE STATIN THERAPY LESS, BUT STILL UNACCEPTABLY HIGH PatientsExperiencing MajorCVDEvents,% PROVE IT-TIMI 222 IDEAL3 TNT4 n LDL-C* mg/dL 1 Superko HR. Br J Cardiol. 2006;13:131-136. 2 Cannon CP et al. N Engl J Med. 2004;350:1495-1504. 3 Pedersen TR et al. JAMA. 2005;294:2437-2445. 4 LaRosa JC et al. N Engl J Med. 2005;352:1425-1435. 4162 8888 10,001 95 *Mean or median LDL-C after treatment 62 104 81 101 77 Statistically significant, but clinically inadequate CVD reduction1 Standard statin therapy Intensive high-dose statin therapy
  61. 61. BEYOND TARGETING LDL There are several atherogenic lipoproteins and LDL accounts for only about 75% of them Residual risk of ASCVD in statin-treated patients remains as high as 55%-70%.  It is thus evident that in order to reduce ASCVD effectively, we need to concentrate on all atherogenic lipoproteins, and not just LDL alone
  62. 62. increased non-HDL-C is associated with increased risk of future CV events even if LDL-C is under control with statin
  63. 63. Better correlate of ASCVD than LDL Includes TG and Lp(a) Does not need fasting Can be easily calculated by total cholesterol and HDL Surrogate for small dense LDL NON HDL CHOLESTEROLNON HDL CHOLESTEROL BETTER THAN LDL?BETTER THAN LDL?
  64. 64. 04/02/17 65
  65. 65.  Prevalence of low HDL-C levels was much higherlow HDL-C levels was much higher in the South Asian populations than in the other populations (82% vs 60% of acute MI cases)  Increaseing HDL-C was associated with a mere 13% reduction in MI risk in South Asians as compared to 23% risk reduction in the other Asians  The patients with low HDL-C are three times more likely to die after an acute coronary event INTERHEART: HDL IN INDIANSINTERHEART: HDL IN INDIANS
  66. 66. THERAPY FOR INDIAN DYSLIPIDEMIATHERAPY FOR INDIAN DYSLIPIDEMIA 04/02/17 68
  67. 67. Smoking It is never too late to quit smoking. After quitting smoking, the ASCVD risk decreases by 50% within 2 years. Alcohol consumption was not found to be protective among South Asians INTERHEARTINTERHEART Alcohol
  68. 68. DIET AND NUTRITIONDIET AND NUTRITION
  69. 69. Statin doses STATINSSTATINS Statin adr
  70. 70. FIBRATESFIBRATES A meta-analysis of 18 trials providing data for 45058 participants, including 2870 major CV events, 4552 coronary events, and 3880 deaths. It was found that fibrates could reduce the risk of major CV events predominantly by prevention of coronary events. Patients with higher baseline TG and lower HDL-C levels benefited from fenofibrate therapy in addition to pre-existing simvastatin (ACCORD).
  71. 71. Look for reversible causes Eg.DM, hypothyroidsm, CKD, immuocomprised LSM TG<500 TG>500 Statin Achieve LDL target Achieve non HDL cholesterol Non-statin drugs Fibrate Achieve TG target Statin Achieve LDL and non HDL cholesterol target Hyper TG
  72. 72. CURRENT LAI GUIDELINES – KEY POINTSCURRENT LAI GUIDELINES – KEY POINTS Enas EA, Dharmarajan T S. The Lipid Association of India Expert Consensus Statement 2016: A sea change for management of dyslipidemia in Indians. J Clin Prev Cardiol 2016;5:62-6
  73. 73. TAKE HOME MESSAGETAKE HOME MESSAGE LIFE SIMPLE SEVENLIFE SIMPLE SEVEN 1. No tobacco 2. Physical activity: ≥150 min moderate intensity or equivalent exercise per week 3. Body-mass index <23 kg/m2 4. Healthy diet: achieving at least four of the five important dietary components, focusing on fruits and vegetables, fish, fibre, and sodium intake and sweetened beverage intake 5. LDL-C level should be below 100mg/dl 6.Blood pressure: <120/80 mmHg 7. Fasting plasma glucose level: <100 mg/d 04/02/17 75
  74. 74. THANKSTHANKS 04/02/17 76
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