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BY
Dr.Liniyanti D.Oswari, MNS, MSc.
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To understand the lipid & lipoproteinmetabolism in the body.
Recognize the significance of dyslipidemia inAtherosclerosis on CVD & CHD, including therole of HDL-C as a protective risk factor forCVD &CHD
Recognize the relationship dyslipidemia with
central obesity & Insulin resistance Examine recent clinical trials of dyslipidemia
as it relates to the prevention and treatmentof CVD & CHD
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Clusters of lipids associated withproteins that serve as transport vehiclesfor lipids in the lymph and blood
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Chylomicrons
VLDL Very low density lipoprotein
IDL Intermediate densitylipoprotein
LDL Low density lipoprotein
HDL High density lipoprotein
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Distinguished by sizeand density
Each containsdifferent kinds andamounts of lipids andproteins
The more lipid, thelower the density
The more protein, thehigher the density
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Class Size (nm) Lipids Major
Apoproteins
Chylomicra 100-500 Dietary TG B-48,C-II,E
VLDL 30-80 EndogenousTG
B-100,C-II,E
IDL 25-50 CEs & TGs B-100, E
LDL 18-28 CEs B-100
HDL 5-15 CEs A,C-II,E
Lp (a) 25-30 CEs B-100 &glycoproteins
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Lipid Chylomicron VLDL IDL LDL HDL
Cholesterol 9 22 35 47 19
Triglyceride 82 52 20 9 3
Phospholipid 7 18 20 23 28
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Made by intestinal cells Most of lipid is triglyceride
Little protein ApoA-I, ApoA-II, ApoB-48, ApoC
Deliver fatty acids via lipoprotein lipase
Chylomicron remnants Lipoprotein particle that remains after a
chylomicron has lost most of its fatty acids Taken up by liver
Contents reused or recycled
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Liver Synthesizes & metabolizes lipids
Central command center for relation of lipidmetabolism
Makes additional lipoproteins
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Vessel wallCholestAA
FA
P,
glycerol
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Liver
Fecal bile acidsand neutralsterols
Exogenous
Extrahepatic
tissues
Endogenous
Dietarycholesterol
(~300700 mg/day) Intestine
Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In Textbookof Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728-777; Ginsberg HN, Goldberg IJ. InHarrisons Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149; Shepherd J Eur Heart J
Suppl2001;3(suppl E):E2-E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082-1150.
Biliary
cholesterol(~1000 mg/day) ~700 mg/day
Synthesis(~800 mg/day)
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Cholesterol is obtained from endogenous and exogenoussources. Endogenous cholesterol is synthesized in all tissues,but primarily the liver, intestine, adrenal cortex, and reproductivetissues, including the placenta. Exogenous cholesterol isabsorbed by the intestine from dietary and biliary sources and
transported to the liver.1,2 In individuals eating a relatively low-cholesterol diet, the liver produces about 800 mg of cholesterolper day to replace bile salts and cholesterol lost in the feces.2Depending on diet, people typically consume 300 to 700 mg ofcholesterol daily.3,4 Approximately 1000 mg of cholesterol issecreted by the liver into the bile. Thus, approximately 1300 to
1700 mg of cholesterol per day passes through the intestines,4of which about 700 mg per day is absorbed.5 Because plasmacholesterol levels are maintained within a relatively narrow rangein healthy individuals, a reduction in the amount of dietarycholesterol leads to increased synthesis in the liver andintestine.2
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1000 mg
Resins
Plant stanols NPC1L1(Ezetimibe)
Inhibitors
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Cholesterol that is absorbed from the intestinal lumencomes from two sources: dietary cholesterol andbiliary cholesterol (which is by far the greater of the
two in quantity). Cholesterol is emulsified by bile acids and packaged
in lipid micelles.
These lipid micelles are transported to the brush
border of jejunal enterocytes. At the brush border of the enterocyte, the cholesterol
is released from the lipid micelle and then enters theenterocyte.
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Made by liver Contains large amounts of triglyceride
Delivers fatty acids to cells
More dense than chylomicrons A bit more protein (8%)
ApoB-100, ApoC, ApoE
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1- Assembly andsecretion
2- Hydrolysis by LPL
3- Direct uptake byhepatocyte
4- Flux of pathway
into LDL
3
1
2
4
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Lipoprotein that results from loss of fattyacids from VLDL
Major lipid is cholesterol esters
Proteins similar to VLDL but greaterpercentage (15%) ApoB-100, ApoC, ApoE
Taken up by liver or remain in circulation
Converted to low-density lipoproteins (LDL)
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Bad cholesterol; major lipid in LDL Delivers cholesterol from liver to cells
Cell membranes Hormone production
Protein (21%) ApoB-100 Binds to specific LDL receptor
LDL receptors Membrane-bound proteins that bind LDL,
causing them to be taken up & dismantled
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Increase LDL SFAs
Transfatty acids
High cholesterol
intake Lifestyle factors
Genetics
Decrease LDL High PUFA diet
-3 fatty acids
Dietary fiber
Lifestyle factors Genetics
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Insulin resistanceincreased NEFA andglucose flux to liver
Insulin resistanceand decreasedapo-Bdegradation
InsulinresistanceanddecreasedLPL
IR impairs
LDLR
IncreasedVLDL
FCHL
DM II
Metabolicsyndrome
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Direct Association Longer residence time inplasma than normal sizedLDL due to decreasedrecognition by receptors inliver
Enhanced interaction withscavenger receptorpromoting foam cellformation
More susceptible tooxidation due to decreasedantioxidants in the core
Enter and attach more easilyto arterial wall
Endothelial cell dysfunction
IndirectAssociation Inverse relationshipwith HDL Marker for atherogenicTG remnantaccumulation Insulin resistance
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Good cholesterol; major lipid isphospholipid Lipoprotein made by liver that circulatesin the blood to collect excess cholesterol
from cells Lowest lipid-to-protein ratio Protein (50%) ApoA, ApoC, ApoE
Reverse cholesterol transport Salvage excess cholesterol from cells Transported back to liver
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HMG-CoA reductase-reduces HMG-CoA to mevalonicacid in the rate-limiting step of cholesterolbiosynthesis (mainly liver and intestine)
Lipoprotein Lipase- digests TG core of CMC and VLDL
Hepatic Lipase-conversion of IDL to LDL
CETP-transfers cholesteryl esters from HDL to otherlipoproteins in exchange for TG LCAT(lecithin cholesterol acyl transferase) conversion
of cholesterol to cholesterol esters Apolipoprotein A-major protein of HDL activating
many reactions Apo-B-major protein of VLDL, IDL, and LDL
Apo-CII and Apo E obtained from HDL by CMC andVLDL for activation of LPL and receptor recognitionrespectively
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Why Does HDL-C Protect?
HDL-C
Protection againstoxidation
Modulation ofendothelial function
Protection of the vessel wall
Cholesterol
acceptor
Cholesterylester
donor
Reverse Cholesterol
Transport (RCT)
Endothelial repair
Anti-thrombotic
Anti-inflammatory
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What raises HDL? Uncertain if low carbohydrate diets offer
protection
High MUFA intake
Lifestyle factors ( Exercise)
Genetic factors influence HDL
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Reverse cholesterol transport
Maintenance of endothelial function
Protection against thrombosis
With Apo A-I inhibits generation of calcium-induced procoagulant activity on erythrocytesby stabilizing cell membrane
Low blood viscosity via permitting red celldeformability
Anti-oxidant properties-may be related toenzymes called paraoxonase
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Elevated triglycerides
Post-prandial lipemia
Small dense LDL (type B)
Elevated LDL
Low HDL cholesterol
Elevated Total
Cholesterol
Nature Medicine 2002
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Fat Cells
TG
Apo B
VLDL
Liver
IR
Insulin
FFA
CE (CETP) TG
(lipoprotein
or
hepatic lipase)
Kidney
Apo A-1
VLDL
LDL
CE
(CETP)
TG
HDL
SD
LDL
(hepatic lipase)
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Increased Apo B Triglycerides VLDL LDL and SmallDense LDL
Decreased HDL Apo A-I
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VLDL1 gives rise tosmall dense LDL
Increase TG/Chol
content throughCETP
Increasedelipidation by
hepatic lipase
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HDL-3, larger with apoA, C-II, & C-III
HDL-2, largest, withadditional apo E.
Best negative correlateCAD
Other functionsattributed to HDL:inhibits monocyte
chemotaxis, LDLoxidation
Tulenko 2002 J Nuclear Cardiology 9:638
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CETPinhibitors
Low HDL-cholesterol
Increased catabolism of small dense HDLLow HDL cholesterol by both content and #particles
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High triglycerides
Post-prandiallipemia
Small dense LDL(type B)
Low HDLcholesterol
ABCA-1
CETP
Niacin
Statin
Fibrate
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Familial Hypercholesterolemia High LDL-C(Type IIA)
Polygenic Familial Hypercholesterolemia Familial Combined Hyperlipidemia High LDL-
C and/or high TG levels Familial Dyslipidemias High TG and low HDL
Familial Dysbetalipoproteinemia (Type III)
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Type Lipoprotein ElevationI ChylomicronsIIa LDLIIb LDL + VLDLIII IDL (LDL1)IV VLDLV VLDL + Chylomicrons
47
IDL, intermediate-density lipoproteinLDL, low-density lipoproteinVLDL, very-low-density lipoprotein
Fredrickson-Levy-Lees Classification
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7thEdition: http://www.accesspharmacy.com
Lipid Phenotype Plasma Lipid Levels Lipoprotein PhenotypeClinical Signs
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[mmol/L (mg/dL)] Elevated Isolated hypercholesterolemiaFamilialhypercholesterolemia
Heterozygotes TC =713 (275500)
LDL IIa Usually developxanthomas in adulthoodand vascular disease at3050 years
Homozygotes TC>13 (>500)
LDL IIa Usually developxanthomas in adulthoodand vascular disease inchildhood
Familial defective
Apo B-100
Heterozygotes TC =
713 (275500)
LDL IIa
Polygenichypercholesterolemia
TC = 6.59 (250350)
LDL IIa Usually asymptomaticuntil vascular diseasedevelops; no xanthomas
Isolated hypertriglyceridemiaFamilial
hypertriglyceridemia
TG = 2.88.5 (250
750)
VLDL IV Asymptomatic; may be
associated with increasedrisk of vascular disease
Familial LPLdeficiency
TG >8.5 (750) Chylomicrons, VLDL
I, V May be asymptomatic;may be associated withpancreatitis, abdominalpain,hepatosplenomegaly
Familial Apo C-II TG >8.5 (>750) Chylomicron I, V As above 48DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7thEdition: http://www.accesspharmacy.com
Lipid Phenotype Plasma Lipid Levels Lipoprotein Phenotype Clinical Signs
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[mmol/L (mg/dL)] ElevatedHypertriglyceridemia and hypercholesterolemiaCombined
hyperlipidemia
TG = 2.88.5 (250
750); TC = 6.513(250500)
VLDL, LDL IIb Usually asymptomatic
until vascular diseasedevelops; familialform may present asisolated high TG orisolated high LDLcholesterol
Dysbetalipo-
proteinemia
TG = 2.88.5 (250
750); TC = 6.513(250500)
VLDL, IDL;
LDL normal
III Usually asymptomatic
until vascular diseasedevelops; may havepalmar ortuboeruptivexanthomas
49DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7thEdition: http://www.accesspharmacy.com
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Many genetic abnormalities & environmentalfactors lead to lipoprotein abnormalities
Current laboratory values can not defineunderlying abnormality
2 hyperlipidemia should be initiallymanaged by correcting underlyingabnormality when possible
50 50
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Genetic disorder resulting in production offaulty HDL particles that cannot take upcholesterol from cells
High risk for developing cardiovascular
disease
Can see the platelet
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Image courtesy of the Internet Stroke Center at Washington University - www.strokecenter.org
aggregation in response to thefoam cell chemicals and tissuedamage
The platelets will activate thecoagulation cascade, resultingin the production of fibrinstrands which trap platelets,
red and white blood cells overthe area = thrombusIn larger vessels, it takeslonger to develop a thrombusbig enough to completely
block the vessel so you getwarning signs (TIA, UA) ofstroke and MIThis process happens
everywhere (brain, heart)
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Image courtesy of the Internet Stroke
Center at Washington University -www.strokecenter.org
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General term for all diseases of the heart and
blood vessels Atherosclerosis is the main cause of CVD
Atherosclerosis leads to blockage of bloodsupply to the heart, damage occurs (coronaryheart disease, CHD) Cardio = heart Vascular = blood vessels
Lipoproteins and cardiovascular disease
(CVD) risk- LDL is positively associated with CVD
- HDL is negatively associated with CVD
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Age
Men: 45 years
Women: 55 years or premature menopause without estrogen replacementtherapy
Family history of premature CHD (definite myocardial infarction or sudden
death before age 55 years in father or other male first-degree relative, orbefore age 65 years in mother or other female first-degree relative)
Cigarette smoking
Hypertension (140/90 mm Hg or taking antihypertensive medication)
Low HDL cholesterol (60 mg/dL counts as "negative" risk factor; its presence removes one riskfactor from the total count.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7thEdition: http://www.accesspharmacy.com
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Athrogenesis
MVS 110: Lecture #11
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1. Vasodilatory Endothelial Dysfunction:Brachial Ultrasound Flow-Mediated Dilation.
2. Atherosclerosis Burden/End-organ Damage:Carotid IMT, # plaques (based on carotid US),
IVUS, EBCT, advanced CT, MRI3. General Inflammatory Marker:
hs-C Reactive Protein
4. Markers of Inflamed Endothelium:ICAM, VCAM, e-Selectin, vWf
5. Other: Homocysteine
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Libby et al. Circulation2002;105:1135-1143.
E-Selectin,P-Selectin
LDL
OxLDL
L-Selectin,Integrins
VCAM-1,
ICAM-1
M-CSF
MCP-1
MacrophageActivation & Division
Monocyte
Intima
Media
Smooth Muscle CellMigration
Otherinflammatory triggers
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Oxidation of low-density lipoprotein (LDL) initiates the
atherosclerotic process in the vessel wall by acting as apotent stimulus for the induction of inflammatory geneproducts in vascular endothelial cells. By activating thenuclear factor B (NFB) transcription factor, oxidized
LDL (oxLDL) stimulates increased expression of cellularadhesion molecules. There are several different types ofadhesion molecules with specific functions in theendothelialleukocyte interaction: The selectins tether
and trap monocytes and other leukocytes. Importantly,vascular cell adhesion molecules (VCAMs) andintercellular adhesion molecules (ICAMs) mediate firmattachment of these leukocytes to the endothelial layer.
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OxLDL also augments expression of monocyte
chemoattractant protein 1 (MCP-1) and macrophage-colony stimulating factor (M-CSF). MCP-1 mediatesthe attraction of monocytes and leukocytes and theirdiapedesis through the endothelium into the intima.M-CSF plays an important role in the transformation ofmonocytes to macrophage foam cells. Macrophagesexpress scavenger receptors and take up and
internalize oxLDL in their transformation into foamcells. Migration of smooth muscle cells (SMCs) fromthe intima into the media is another early eventinitiating a sequence that leads to formation of a
fibrous atheroma.
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Primary Pro-inflamatory Cytokines(eg, IL-1, TNF-a)
IL-6Messenger
CytokineICAM-1
Selectins, HSPs, etc.
Proinflammatory RiskFactors
Endotheliumand other cells
CRPSAA
Circulation
Adapted from Libby and Ridker. Circulation. 1999;100:1148-1150.
HSPs=heat shock proteins; SAA=serum amyloid-A.
Liver
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Total cholesterol: 6mmol/L)
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LDL-C = (Past) < 130 mg/dl (2001 < 100)
LDL-C=total cholesterol - (HDL-C + .2TG)
HDL-C = (Past) >35 mg/dl (2001) > 40)
HDL-C = > 60 mg/dl will negate one risk factor
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Normal TG = < 200 mg/dl
Borderline high = 200-400 mg/dl
High = 400-1000 mg/dl
Very High = > 1000 mg/dl
Life style is a Driver of CVD
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Chronicheart failure
ArrhythmiaArterial & venous
thrombosis/cardiac & cerebral events
AtherosclerosisAtherosclerosis
HypertensionDiabetes
Dyslipidaemia
Obesity
StressSmoking
Physicalinactivity
Excessivefood intakeLife style intervention
Risk factormodification
Life style is a Driver of CVD
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At least 3 of
Abdominal obesity: waist circumference > 102 cm (M)
> 88 cm (F)
Hypertriglyceridemia > 150 mg/dl
Low HDL cholesterol < 40 mg/dl (M)
< 50 mg/dl (F)
Hypertension (> 130/85 mm Hg)
Impaired Fasting Glucose or Type 2 diabetes (> 100
mg/dl)
(ATP III. JAMA 285:2486, 2001)
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Type 2 Diabetes
Hypertension
DyslipidemiaCentral obesity
Insulin
Resistance
Pathophysiology of the metabolic syndrome leading
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Reilly & Rader 2003;
Eckel et al 2005
Plaque rupture/thrombosis
Cardiovascular events
Atherosclerosis
Insulin resistance
Tg Metabolic syndrome HDL BP
Inflammatory markers
p y gy y gto atherosclerotic CV disease
Adipocyte Monocyte/
macrophag
Genetic variationEnvironmental factors
Abdominal obesity
CytokinesAdipokines
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Treatment NCEP ATP-III guidelines
Modification of lipids and major risk factors
See Table 15.9
Medications
See Table 15.10
Procedures
Angioplasty
CABG
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Nicotinic Acid (Niaspan)
Bile Acid Sequestrants (cholestyramine andcolestipol)
HMG CoA Reductase Inhibitors (lovastatin,pravastatin, simvastatin)
Fibric Acid Derivatives (Clofibrate, gemfibrozil)
Probucol
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Nutrition Therapy Therapeutic Lifestyle Changes (TLC) developed
as component of ATP-III
Modifications in fat, cholesterol
Rich in fruits, vegetables, grains, fiber Limit sodium to 2400 mg
Include stanol esters
See the next Table for summary
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Nutrient RecommendedIntake
Saturated fat < 7% of total calories
Polyunsaturated fat Up to 10% of totalcalories
Monounsaturated fat Up to 20% of total
calories Total fat 25-30% of total calories
Carbohydrates 50-60% of total calories
Fiber 20-30 grams/day
Protein Approx. 15% of totalcalories
Limit Cholesterol intake
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Nutrition Therapy - Other Increase sources of soluble fiber
Increase intake of plant sterols
Weight loss BMI 18.5-24.9 Regular physical activity
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CoronaryAngioplasty
Coronary BypassSurgery (CABG)
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Fish Oil (source of omega-3 polyunsaturated fatty acids) Salmon, flaxseed, canola oil, soybean oil and nuts At high doses > 6 grams/day reduces TG by inhibition of VLDL-TGsynthesis and apolipoprotein B Possibly decreases small LDL (by inhibiting CETP) Several studies have shown lower risk of coronary events 2 servings of fish/week recommended?? Pharmacologic use restricted to refractory hypertriglyceridemia Number of undesirable side effects (mainly GI)
Soy Source of phytoestrogens inhibiting LDL oxidation 25-50 grams/day reduce LDL by 4-8% Effectiveness in postmenopausal women is questionable
Garlic Mixed results of clinical trials In combination with fish oil and large doses (900-7.2 grams/d), decreases
in LDL observed Cholesterol-lowering Margarines
Benecol and Take Control containing plant sterols and stanols Inhibit cholesterol absorption but also promote hepatic cholesterol synthesis 10-20% reduction in LDL and TC however no outcome studies AHA recommends use only in hypercholesterolemia pts or those with a cardiac
event requiring LDL treatment
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Other agents include soluble fiber, nuts (esp. walnuts),green tea
Overall a combination diet with multiple cholesterol-lowering agents causes much more significant LDLreductions
Fiber: Decreases LDL; increases HDL Carrots/Grapefruit: Fiber and pectin (whole fruits most
beneficial) Avocado: monounsaturated fat Beans: High in fiber, low fat; contain lecithin Phytosterols: sesame, safflower, spinach, okra,
strawberries, squash, tomatoes, celery, ginger. Shiitake mushrooms: contain lentinan (25% reduction in
animal studies) Garlic, onion oil: lowers chol. 10-33% Omega 3 fish oils