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    Dislipidemia: Prof. Dr. WH. Sibuea, SP - PD

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    andinarang
    This document discusses dyslipidemia and cardiovascular disease. It provides data showing that countries with lower total cholesterol and LDL cholesterol levels have lower mortality from cardiovascular disease and coronary heart disease. Studies are cited showing an association between lower cholesterol levels and lower mortality rates. Total cholesterol and LDL cholesterol are identified as modifiable risk factors for cardiovascular disease. The document summarizes the roles and effects of various lipoproteins such as HDL, LDL and triglycerides. It also discusses lipid-lowering therapies such as statins, their mechanisms and effects on lipid levels.

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    Dislipidemia: Prof. Dr. WH. Sibuea, SP - PD

    Uploaded by

    andinarang
    196 views37 pages
    This document discusses dyslipidemia and cardiovascular disease. It provides data showing that countries with lower total cholesterol and LDL cholesterol levels have lower mortality from cardiovascular disease and coronary heart disease. Studies are cited showing an association between lower cholesterol levels and lower mortality rates. Total cholesterol and LDL cholesterol are identified as modifiable risk factors for cardiovascular disease. The document summarizes the roles and effects of various lipoproteins such as HDL, LDL and triglycerides. It also discusses lipid-lowering therapies such as statins, their mechanisms and effects on lipid levels.

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    dislipidemia

    Original Title

    DISLIPIDEMIA

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    This document discusses dyslipidemia and cardiovascular disease. It provides data showing that countries with lower total cholesterol and LDL cholesterol levels have lower mortality from cardiovascular disease and coronary heart disease. Studies are cited showing an association between lower cholesterol levels and lower mortality rates. Total cholesterol and LDL cholesterol are identified as modifiable risk factors for cardiovascular disease. The document summarizes the roles and effects of various lipoproteins such as HDL, LDL and triglycerides. It also discusses lipid-lowering therapies such as statins, their mechanisms and effects on lipid levels.

    Copyright:

    © All Rights Reserved
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    196 views37 pages

    Dislipidemia: Prof. Dr. WH. Sibuea, SP - PD

    Uploaded by

    andinarang
    This document discusses dyslipidemia and cardiovascular disease. It provides data showing that countries with lower total cholesterol and LDL cholesterol levels have lower mortality from cardiovascular disease and coronary heart disease. Studies are cited showing an association between lower cholesterol levels and lower mortality rates. Total cholesterol and LDL cholesterol are identified as modifiable risk factors for cardiovascular disease. The document summarizes the roles and effects of various lipoproteins such as HDL, LDL and triglycerides. It also discusses lipid-lowering therapies such as statins, their mechanisms and effects on lipid levels.

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    DISLIPIDEMIA

    Prof. Dr. WH. Sibuea, Sp.PD


    Bagian Ilmu Penyakit Dalam FKUKI

    Mortality from CVD and CHD in Selected Countries


    Rate per 100,000 Population (men aged 3574 years)
    1500

    CVD deaths
    CHD deaths

    1000

    500

    0
    Russia Poland Finland New England/ USA
    Zealand Wales

    Italy

    Spain

    Japan

    (Adapted from 1998 World Health Statistics)

    Is Lower Better? Lower Cholesterol Levels


    are Associated with Lower Mortality Rates

    Mortality rate per 1000 men

    18
    16
    14
    12
    10
    8
    6
    4
    2
    0
    3.62
    (140)

    4.14
    (160)

    4.65
    (180)

    5.17
    (200)

    5.69
    (220)

    6.21
    (240)

    6.72
    (260)

    Serum total cholesterol, mmol/L (mg/dL)


    MRFIT study. Martin et al. Lancet 1986;ii:933936.

    7.24
    (280)

    7.75
    (300)

    Death rate from CHD/1000 men

    Relationship of Serum Cholesterol to Mortality


    (Seven Countries Study)
    35
    Northern Europe

    30
    25

    United States

    20
    15
    Southern Europe, inland

    10
    5

    Serbia

    Southern Europe, Mediterranean


    Japan

    0
    2.60

    3.25

    3.90

    4.50

    5.15

    5.80

    6.45

    7.10

    7.75

    8.40

    9.05

    Serum total cholesterol (mmol/l)


    (Adapted from Verschuren et al., 1995)

    Cholesterol A Modifiable Risk Factor ?

    In the USA:
    97 million people have total cholesterol
    > 200mg/dl (5.2mmol/l)
    38 million people have total cholesterol
    > 240mg/dl (6.2mmol/l)
    10% reduction in total cholesterol results in:
    15% reduction in CHD mortality (p<0.001)
    11% reduction in total mortality (p<0.001)
    Total cholesterol is a modifiable CV risk factor
    LDL-C is the primary target to prevent CHD
    Intensity of intervention depends on total CV risk

    Risk Factors for Cardiovascular


    Disease

    Modifiable
    Smoking
    Dyslipidaemia
    raised LDL cholesterol
    low HDL cholesterol
    raised triglycerides
    Raised blood pressure
    Diabetes mellitus
    Obesity
    Dietary factors
    Thrombogenic factors
    Lack of exercise
    Excess alcohol consumption

    Non-modifiable

    Personal history
    of CHD
    Family history
    of CHD
    Age
    Gender

    Levels of Risk Associated with Smoking,


    Hypertension and Hypercholesterolaemia
    Hypertension
    (SBP 195mmHg)

    x3
    x9

    x4.5

    x16
    x1.6

    Smoking

    x6

    x4

    Serum cholesterol level


    (8.5mmol/l, 330mg/dl)
    (Adapted from Poulter et al., 1993)

    Endothelial dysfunction:
    Final common pathway in CV diseases
    Hypertension

    DM

    Dyslipidemia

    Tobacco

    Oxidative Stress

    Endothelial Injury
    Myocardial
    Infarction

    Stroke
    Renal disease

    Erectile
    Dysfunction

    Normal Arterial Wall


    Tunica adventitia
    Tunica media
    Tunica intima
    Endothelium
    Subendothelial connective
    tissue
    Internal elastic membrane
    Smooth muscle cell
    Elastic/collagen fibres
    External elastic membrane

    Pathogenesis of Atherosclerotic
    Plaques
    Endothelial damage
    Protective response results in production of
    cellular adhesion molecules
    Monocytes and T lymphocytes attached to
    sticky surface of endothelial cells
    Migrate through arterial wall to subendothelial space
    Macrophages take up oxidised LDL cholesterol
    Lipid-rich foam cells
    Fatty streak and plaque

    Vasc. Cell ad. Mol.

    Necrotic center
    (cell debris, cholesterol crystal,
    foam cells, calcium)
    FIBROUS CAP
    (smooth
    muscle cells,
    macrophages,
    foam cells
    lymphocytes,
    collagen,
    elastin,
    proteoglycans)

    media

    The Tight Stenosis Is Not the Active


    Lesion
    A

    B
    A

    Atheroma
    Lumen

    Lipid Core
    Images supplied by Steven E. Nissen, MD, Cleveland Clinic.

    Rupture
    Site

    Pathophysiology of ACS:
    Disrupted Plaque
    Thin cap
    Plaque
    rupture
    High
    macrophage
    content
    Large lipid core

    Complete
    Incomplete
    coronary
    coronary
    occlusion
    occlusion
    Spontaneous lysis,
    repair, and wall remodeling

    Acute
    MI

    Temporary resolution
    Unstable angina
    of instability
    or nonQ-wave
    Future high-risk
    MI
    lesion

    Adapted from Yeghiazarians et al. N Engl J Med. 2000;342:101-114.

    Development of Atherosclerotic
    Plaques
    Fatty streak
    Lipid rich plaque
    Normal
    Foam cells

    Fibrous cap

    Complex plaque

    Thrombus

    Lipid core

    Clinical Manifestations of
    Atherosclerosis

    Coronary heart disease

    Cerebrovascular disease

    Angina pectoris, myocardial infarction, sudden


    cardiac death
    Transient ischaemic attacks, stroke

    Peripheral vascular disease

    Intermittent claudication, gangrene

    Lipid dalam Plasma


    - Asam Lemak
    - Lemak netral ( trigliserida ) : 3 AL + 1 gliserol
    - Fosfolipid :

    Estergliserol + 2 AL dan fosfat,


    fosfat inositol, fosfat kolin dll

    - Sterol

    Hormon steroid, cholesterol

    Lipid dalam plasma dibawa oleh :


    - Asam Lemak oleh albumin
    - Cholesterol
    - Trigliserid
    - Fosfolipid

    Dibawa oleh
    lipoprotein

    Structure of Lipoproteins
    Free cholesterol
    Phospholipid

    Apolipoprotein

    Triglyceride

    Cholesteryl ester

    Lipoprotein terdiri dari : inti hidrofobik : trigliserid dan ester kolesteril,


    dikelilingi oleh fosfo lipid dan protein (apolipoprotein)

    LIPOPROTEIN

    * Very low density lipoproteins; ** Intermediate-density lipoproteins; *** Low


    density lipoproteins; **** High density lipoproteins

    Peningkatan Trigliserid (TG) menyebabkan meningkatnya transfer kolesterol


    ester dari HDL ke VDL dan juga dari LDL ke VDL. Hal ini menyebabkan HDL
    menurun dan partikel LDL kecil padat meningkat. Kolesterol ester transfer
    protein.

    Classification of Lipoproteins
    Based on density:
    Chylomicrons
    Very low-density lipoprotein (VLDL)
    Intermediate-density lipoprotein (IDL)
    Low-density lipoprotein (LDL)
    High-density lipoprotein (HDL)

    LDL Cholesterol

    Strongly associated with atherosclerosis and CHD


    events
    10% increase results in a 20% increase in CHD risk
    Modified by other risk factors
    low HDL cholesterol
    smoking
    hypertension
    diabetes

    Triglycerides

    Associated with increased risk of CHD events


    Link with increased CHD risk is complex

    may be related to low HDL levels and highly


    atherogenic forms of LDL cholesterol

    May have accompanying dyslipidaemias


    Normal triglyceride levels <200mg/dl
    (2.3mmol/l)
    Very high triglycerides (>1000mg/dl,
    11.3mmol/l) increased pancreatitis risk

    HDL Cholesterol
    HDL cholesterol has a protective effect for risk
    of atherosclerosis and CHD
    The lower the HDL cholesterol level, the higher
    the risk for atherosclerosis and CHD

    low level (<35mg/dl, 0.9mmol/l) increases risk

    HDL cholesterol tends to be low when


    triglycerides are high
    HDL cholesterol is lowered by smoking, obesity
    and physical inactivity

    Apolipoproteins
    Main protein content of lipoproteins
    Functions include:

    facilitation of lipid transport


    activation of three enzymes in lipid metabolism
    lecithin cholesterol acyltransferase (LCAT)
    lipoprotein lipase (LPL)
    hepatic triglyceride lipase (HTGL)

    binding to cell surface receptors

    Exogenous Pathway of Lipid


    Metabolism
    Dietary
    triglycerides
    and cholesterol

    Intestine

    Chylomicron

    LP lipase

    Bile acids + cholesterol

    LP lipase

    TGs
    TGs
    Skeletal muscle

    Chylomicron
    remnant
    Adipose
    tissue

    Liver
    Remnant
    receptor

    Endogenous Pathway of Lipid


    Metabolism
    LPL

    Lipoprotein lipase
    d
    Mo
    LDL

    IDL

    LDL
    receptor

    Extrahepatic
    Tisue
    LPL
    LPL

    Hepatic lipase
    Hepatic lipase

    Liver

    Macrophage

    n
    o
    i
    t
    a
    ific

    VLDL
    HDL

    Effect of Lipid-lowering Therapies on Lipids

    Therapy

    TC

    LDL

    HDL

    TG

    Patient
    tolerability

    Bile acid
    sequestrants

    Down
    20%

    Down
    1530%

    Up
    35%

    Neutral or up

    Poor

    Nicotinic acid

    Down
    25%

    Down
    25%

    Up
    1530%

    Down
    2050%

    Poor to
    reasonable

    Fibrates
    (gemfibrozil)

    Down
    15%

    Down
    515%

    Up
    20%

    Down
    2050%

    Good

    Probucol

    Down
    25%

    Down
    1015%

    Down
    2030%

    Neutral

    Reasonable

    Down
    1530%

    Down
    2450%

    Up
    612%

    Down
    1029%

    Good

    Statins*

    TCtotal cholesterol, LDLlow density lipoprotein, HDLhigh density lipoprotein, TG


    triglyceride. * Daily dose of 40mg of each drug (cerivastatin 0.3mg)
    (Adapted from Yeshurun 1995, Knopp 1999)

    Mechanism of Action of Statins


    Cholesterol Synthesis Pathway
    acetyl CoA
    HMG-CoA synthase
    HMG-CoA reductase

    HMG-CoA

    X Statins
    mevalonic acid

    mevalonate pyrophosphate
    isopentenyl pyrophosphate
    geranyl pyrophosphate
    ubiquinones

    farnesyl pyrophosphate

    Squalene synthase

    squalene
    cholesterol

    dolichols

    Pharmacokinetics of Statins
    Statin

    Metabolised
    by CYP450

    Protein
    binding (%)

    Lipophilic

    Halflife (h)

    lovastatin

    Yes

    >95%

    Yes

    ~2

    pravastatin

    No

    ~50%

    No

    ~2

    simvastatin

    Yes

    958%

    Yes

    ~3

    atorvastatin

    Yes

    >98%

    Yes

    ~15

    cerivastatin

    Yes

    >99%

    Yes

    ~3

    fluvastatin

    Yes

    >98%

    No

    ~3

    (Adapted from Horsmans 1999, Vaughan et al, 2000)

    Effects of Statins on Lipids


    LDL-C
    % change

    HDL-C
    % change

    Triglycerides
    % change

    atorvastatin

    -50

    +6

    -29

    simvastatin

    -41

    +12

    -18

    pravastatin

    -34

    +12

    -24

    lovastatin

    -34

    +8.6

    -16

    cerivastatin

    -28

    +10

    -13

    fluvastatin

    -24

    +8

    -10

    Daily dose of 40mg of each drug (cerivastatin 0.3mg)

    (Adapted from Knopp 1999)

    4S Cardiovascular End Points Post-MI or Angina


    Patients with Raised Cholesterol
    Number of events
    Outcomes

    placebo
    (n=2223)

    simvastatin
    (n=2221)

    Risk
    reduction (%)

    p-value

    Total mortality*

    256

    182

    30

    <0.001

    Coronary death

    189

    111

    42

    <0.001

    Major coronary events

    622

    431

    34

    <0.001

    PCTA/CABG

    383

    252

    37

    <0.001

    * primary end point

    WOSCOPS Cardiovascular End Points


    Subjects with no Previous MI but Raised
    Cholesterol
    Number of events
    Outcomes

    placebo
    (n=3293)

    Non-fatal MI/CHD death*


    CHD death
    Non-fatal MI
    PCTA/CABG
    Stroke
    All cardiovascular deaths
    Total mortality#

    248
    52
    204
    80
    51
    73
    135

    pravastatin
    (n=3302)

    Risk
    reduction (%)

    p-value

    174
    38
    143
    51
    46
    50
    106

    31
    28
    31
    37
    0
    32
    22

    <0.001
    ns
    <0.001
    0.009
    ns
    0.033
    0.051 ns

    * primary end point


    #
    study not powered to detect differences in this end point

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