Lipids, Lipoproteins, Cardiovascular disease

Coronary heart disease

disease of the blood vessels that supply the heart muscle

Cerebrovascular disease

disease of the blood vessels supplying the brain

peripheral artery disease

disease of blood vessels supply the arms and legs

Rheumatic heart disease

Damage to the heart muscle and heart valves from rheumatic fever caised by Streptococus pyogens

Congenital heart disease

malformations of heart structure existing at birth

Deep vein thrombosis / Pulmonary embolism

blood clots in the leg veins, which can dislodge and move to heart and lungs

Cholesterol

• Cholesterol (Free / active) = androgens

• Cholesterol ester = bound to fatty acid (ester storage) = exogenous

Glycerolipids

• Triglycerides

• Phospholipids

• Made up of glycerol back bone and fatty acid chain

Triglycerides TG

• Water insoluble lipids with three fatty acids (acyl groups) esterified to one glycerol molecule

• Source of metabolic energy

• Transport fatty acid in plasma / tissue cells

  • hydrolysis free up fatty acid for use (glycerol)

Lipoproteins

• Surface unilayer of free cholesterol and phospholipids

• made up of hydrophobic TGs and cholesteryl esters

Lipoproteins surface proteins

1. ApoB100 = produced in liver

2. ApoB48 = produced in intestines

3. ApoA-1 = produced in liver/intestines

Chylomicrons

• ApoB48

• Largest and least dense

• Account for turbidity of post-prandial plasma

• Deliver dietary lipids to hepatic and peripheral cells

• Creamy layer

• non-fasting sample

• Triglycerides 85%

• Protein 2%

• Cholesterol 1%

VLDL

• Produced in liver

• ApoB100, ApoE, and ApoC

• fasting hyperlipidemic plasma sample

• Major carrier of endogenous triglycerides

• transfer TGs from liver to the peripheral tissues

• 5:1 ratio of TGs to cholesterol TG/5

• Triglycerides 50%, Protein 10%, Cholesterol 20%

LDL

• Bad cholesterol, plaque tissue

• ApoB100

• More cholesterol rich

• derived from VLDLs and hepatically produced

• oxidzes and taken up by macrophages

• Foam cells, fatty streaks, precursor of atherosclerotic plaques

HDL

• Smallest and most dense lipoprotein

• ApoA-1

• Good choelsterol

• Maintain cholesterol homeostasis

• Triglycerides 3%, Protein 50%, Cholesterol 10%

Elevated LDL

• Increased risk of premature coronary heart disease and stroke

• Genetically determined

• Abnormal tails on LDL particles with kringle domains 

• KIV is similar to plasminogen

Measuring total cholesterol

• Lipoprotein electrophoresis based on lipid protein ratio

  • Higher density = higher protein content

• Clinical chemistry assay for detection of choelsterol development

Abell-Kendall method

• Former reference method

• 3 steps

1. Cholesterol is hydrolized with alcoholic KOH

2. Unesterified cholesterol is extracted with petroleum jelly

3. Measured using the Liebermann-Burchardt (L-B) reaction

Hypertriglyceridemia

• Elevated TGs = 200 - 500 mg/dL

• Remarkably high TGs = >500 mg/dL

• Due to ether genetic or hormonal abnormalities 

Hypercholesterolemia

• Lipids abnormality most linked to heart disease

• Familial hypercholesterolemia (FH) is genetic abnormality predisposing people to elevated cholesterol levels

• Homozygous = rare, heart attack in teens

• Heterozygotes = more common

Bloors method

• 2 step principle

• Cholesterol is extracted using an alcohol ether mixture

• Measured using L-B reaction

• Liebermann-Burchardt reaction

• Cholesterol + H2SO4 + Acetic anhydride —> blue green chromogen

Cholesterol Oxidase 

• Boors Method equation

• Read at 500nm, linear up to 1000 m/dL

• Not specific may react with phytosterols

• Vitamin C and Bilirubin interference

GC-MS Method

• Specifically measures cholesterol and does not detect related sterols

• More accurate

Measuring HDL Cholesterol

• Precipitate LDL and VLDL with to remove and isolate

  • dextran sulfate-magnesium chloride

  • heparin sulfate manganese chloride

  • Antibody apo-B100

• Enzymatic cholesterol assay

Measuring LDL cholesterol

• Friedewald Formula

  • LDL cholesterol = Total cholesterol - HDL - Triglycerides/5

• Ignores chylomicron, IDL, and Lp(a)

• Assumes fasting

• Only works TGs <400

Direct measure LDL

• Use detergents to block HDL and VLDL from reacting with dye

• Enzymatic assay

Cardiac risk ratio Total : HDL

• Men

  • 5.0 = Average risk

  • 3.4 = half average risk

  • 9.6 = twice average risk

• Women

  • 4.4

  • 3.3

  • 7.0

Cholesterol ref range Cardiac risk

140 - 200

Triglyceride ref range Cardiac risk

60 - 150

HDL ref range Cardiac risk

40 - 75

LDL ref range Cardiac risk

50 - 130

VLDL ref range Cardiac risk

5 - 40

Hyperlipoproteinemia

• Caused by malfunction in the synthesis, transport, or catabolism of lipoproteins

• Increased

  • LDL

  • VLDL

  • cholesterol

  • triglycerides

• Decreased HDL

  • Chylomicrons present

Familial hypercholesterolemia

• Autosomal recessive variant

• Loss of function of ABCG5/8 (moves cholesterol)

• Hyperabsorption of cholesterol

  • Increased plasma, tissue, phytosterols, 

  • Increased coronary heart disease risk

Niemann Pick C1 like 1 protein

• Loss of function of NPC1L1 used for active absorption of sterols

  • Decreased plasma, coronary heart disease risk

Cardiac damage markers

• Cell death releases, does not last in circulation

• Sensitive and specific

• LD and AST

• Creatine kinase

• Isoenzyme CK-MB

• Myoglobin

• Troponins

LD and AST

Nonspecific cardiac markers

Creatine kinase 

• CK

• 6-8 hours after onset of Myocardial infarction

• Peak at 24 hours

• Found in all cells not specific

Isoenzyme CK-MB

• More specific for cardiac injury

• still may be used for acute MI

Myoglobin

• More sensitive than CK and CKMB

• 1-4 hours detectable and AMI pts between 6-9 hours from onset

Troponins

• Favored marker

• not found in serum

• Troponin I and T are released from dying muscle fibers

• Indicate heart muscle fiber damage

• In bloodstream 7-21 days after MI

Troponin I TnI

1. Cardiac specific only found in myocardium

2. Inhibits contraction

3. After AMI, TnI increase 3-12 hr after onset

4. Peak at 12-24 hrs

5. Elevated 7-14 days

Troponin T TnT

1. Not as cardiac specific

2. Binds to tropomyosin

3. After AMI, TnT increase 3-12 hrs

4. Peaks at 12-24 hrs 

5. Elevated 8-21 days

High sensitivity cardiac troponin hs-cTn

1. hs-cTn assays confirm myocardial injury at lower concentrations

2. Easier to see increase (delta values) above the LoD but below URL

3. may not need serial sampling

4. Positive acute phase reactant

CRP vs hs-CRP

• CRP is sensitive acute phase protein indicating inflammation or tissue damage

• hs-CRP good indicator of impending myocardial infarction, especially in diabetics and women

  • Marker of inflammation and coagulation disorder

B-type Natriuretic Peptide BNP

• Marker for congestive heart failure

• Secreted by cardiac ventricles

• Na regulation and blood pressure

• In response to fluid expansion in coronary heart failure

  • acts on kidney

• Marker for edema due to coronary heart failure

Homocysteine

• Independent risk factor for cardiac disease

• amino acid in blood

• accumulation promotes vascular endothelial injury that predisposes blood vessels to atherosclerosis

• decreased levels of vit B6 / B12 and Folate B9