the new gold standard for lipoprotein analysis · pdf filethe new gold standard for...
Post on 06-Mar-2018
227 Views
Preview:
TRANSCRIPT
The New Gold Standard for Lipoprotein Analysis
Adv
ance
d Te
stin
g fo
r C
ardi
ovas
cula
r Ris
k
Cardiovascular Disease Mortality Cardiovascular Disease Mortality Trends for Males and FemalesTrends for Males and FemalesUnited States: 1979United States: 1979--20022002
Source: CDC/NCHS.
380400420440460480500520
79 81 83 85 87 89 91 93 95 97 99 01
Years
Dea
ths
in T
hous
ands
Males Females
“The Lipid Panel”
Evolution of Lipoprotein TestingEvolution of Lipoprotein Testing
Direct LDL is Better
Total Cholesterol = VLDL + LDL + HDL
Calculated LDL = TC – (HDL + TG/5)Friedewald Equation: VLDL = TG/5
Lipoprotein Particle Numbers by Subgroup is Best
Consensus Statements: American Diabetes Association & American College of Cardiology (2008)
and now the National Lipid Association (2011)
Lipoprotein Particles or Apo B-100 Predict Risk Better than Cholesterol
NCEP Guidelines for Cardiovascular Disease NCEP Guidelines for Cardiovascular Disease
NCEP Identified a Number of New LipoproteinRisk Factors – To Help Assess Those at Risk
NCEP - ATP III50% of at Risk Individuals are Not Identified
50% of Heart Attack Victims have Normal Cholesterol
ATP IV to come out soon
NCEP New Lipoprotein Risk FactorsNCEP New Lipoprotein Risk Factors
Small Dense LDL –- 3-fold Greater Risk of CVD than Buoyant LDL- Penetrates Arterial Endothelial Lining Easily- Less Recognized by LDL Receptors therefore Increases
HDL 2b & 3 –- HDL 3 Picks Up Excess Cholesterol and Becomes HDL 2b in Reverse Cholesterol Transport
Lp(a) -- Small Particles that are Easily Oxidized- Competes with Plasminogen, Prevents Fibrinolysis
RLP (Remnant Lipoprotein)-- One of the Most Atherogenic Lipoproteins- Skips Oxidation Step in Forming Plaque
High in 25% of population
High in 25% of population
High in 25% of population
Low in 25% of population
Lp(a) Competes with Plasminogen and Lp(a) Competes with Plasminogen and Prevents FibrinolysisPrevents Fibrinolysis
Fibrin
Fibrinogen
Blood Clot(MI, Stroke
or DVT)
Fibrinolysis
Plasmin
Plasminogen
Many of the over 40 genetic variations of Lp(a) mimic plasminogen
Lp(a)
Possible Antithrombotic Therapy Indicated
To Determine the NCEP New Risk FactorsLipoprotein Subgroup Information is Needed
Advanced Lipoprotein Testing Advanced Lipoprotein Testing
What are Lipoproteins and their Subgroups?
How do they Cause Cardiovascular Disease?
Lipoprotein ParticlesLipoprotein Particles
ApolipoproteinA-1 (HDL) or B-100
(LDL)
Unesterified Cholesterol
Cholesterol Ester
Phospholipid
Triglyceride
Atherogenic ParticlesAtherogenic Particles
Size (nm)Size (nm)
Density (g/ml)Density (g/ml)
VLDLVLDL
1.0041.0045050
TGTG--rich rich LipoproteinsLipoproteins
RLPRLP
2525
1.0131.013
BuoyantBuoyantLDLLDL
2222
1.0231.023
DenseDenseLDLLDL
1919
1.0441.044
Mean EndothelialMean EndothelialPore SizePore Size
CETP in Cholesterol MetabolismCETP in Cholesterol Metabolism
HL
LDL1-2
LPLIDL
HL
LDL3-4
HDL Enters Cells &
Arterial Intima NascentHDL
Apo A-1
LiverCETPTG’s
CE
VLDL
Apo B-100
Liver
LCAT
HDL3Reverse
Cholesterol Transport
LCAT
HDL2b
Brewer HB et al. Am J Cardiol 2003;92:10K-16K.
HDL REMOVESEXCESS LIPIDS
ARTERIAL INTIMA
MACROPHAGE CELL
FOAMCELLSBUILD
PLAQUE
RLP
Atherosclerotic Plaque FormationAtherosclerotic Plaque Formation
ARTERIAL LUMEN
DENSELDL
Lp(a)
INFLAMMATION RUPTURES PLAQUE
LDL
OXIDIZEDLDL
MONOCYTE CELL
FOAM CELL
Why Have the LPP Test ?Why Have the LPP Test ?Provides a More Complete Risk Answer
than the Standard Cholesterol Test
1. NCEP’s New Lipoprotein Risk FactorsLPP Has Three Risk Identifying Components
2. Lipoprotein Particle Numbers vs. Cholesterol Content
These Components IdentifyMany at Risk Individuals that are Missed
3. Non-Lipid Risk Factors: CRP, Insulin and Homocysteine
Lipoprotein Particle Profile (LPPLipoprotein Particle Profile (LPP™™) Process) Process
Separates by Density using Analytical Ultracentrifugation
The New Gold Standard - Enhancements
Clinically Relevant Lipoprotein Particlesare Detected Not the Surrogate Marker Cholesterol
the CDCCDC’’s Gold Standards Gold Standard
Continuous Gradient
Lipoprotein Particle MeasurementLipoprotein Particle MeasurementFluorescent Dye – a Phospholipid Analog
Hydrophobic EndFluorescent - Hydrophilic End
When Hydrophobic EndImbeds into the Phospholipid Shell of the Lipoprotein the Hydrophilic End Fluoresces
The Fluorescence is a Direct Measurement of Particle Number
Separation by DensitySeparation by DensityCentrifuge Tube with Mixture of Serum, Gradient and Dye
Proteins
LDL
VLDL
HDL
Intense Gravitational Force
Separated Lipoproteins
600,000 G’s
Density (g/ml)
1.030
1.006
1.300
1.000
1.100
1.063
RLP LDLLDLVLDLVLDL HDLHDL
LPP Test LPP Test -- Lipoprotein Groups and SubgroupsLipoprotein Groups and Subgroups
Accurate Densities
Particle Measurement
Dense -Small
HDL3HDL2bBuoyant - Large
Atherogenic ProfileHealthy ProfileLPP showing NCEPLPP showing NCEP’’s New Lipoprotein Risk Factorss New Lipoprotein Risk Factors
Low RLPHigh HDL 2b High RLP Dense LDL Low HDL 2bBuoyant LDL
30
50
70
90
110
130
150
170
190
300 500 700 900 1100 1300 1500 1700 1900
LPP (VLDL + LDL) Particle Numbers (nmol/L)
Apo
B-1
00 (m
g/dL
)LPP Non-HDL Particle Numbers vs Apo B-100
Correlation of Apo B and LPPnon-HDL Particle Numbers is Excellent
One Apo BMolecule per non-HDL Particle
ADA and ACC Consensus: Apo B More Predictive of CVD Risk than Cholesterol*
* Diabetes Care, Volume 31, Number 4, April 2008
r = 0.93n = 2990
Lipoprotein Particle NumbersLipoprotein Particle Numbers
125 mg/dL
Risk
All of These Patients have the Same LDL “Cholesterol”
125 mg/dL125 mg/dL125 mg/dLDCBA
IncreasedLowParticle Numbers or Apo B-100
Increased High
Large - BuoyantDepleted
TG’s &CETP
Large - Buoyant
LDL Particles with Varying Cholesterol Content
Small - DenseEnriched
-TG’s &CETP
Small - DenseDepleted
TG’s &CETP
Relevance of Lipoprotein Particle NumbersRelevance of Lipoprotein Particle Numbers
The LPP Test is Like Having Apo B-100 Broken Down into Subgroups for a Better Therapeutic Approach
30% of the Population is Cholesterol Depleted20% of the Population is Cholesterol Enriched
A Disconnect Exists between Lipoprotein Particle Number and Cholesterol Number
Reference Value
Green is NormalYellow is BorderlineRed is High
The Magnitude of the Result is Easy to Judge with Respect to the Reference Value
Color Highlighted Numerical Results
Test Report Page 1Test Report Page 1
Test Report Page 2Test Report Page 2
Primary Risk Assessment& Therapeutic Approach
Includes Apo B-100, Lp(a), Metabolic Syndrome LPP+ C-Reactive Protein, Insulin and Homocysteine
Lipid Panel
Risk Modification
Direct Measurement of Lipoprotein Particle Numbers
Graph – Quick Assessment
Interrelation Between Atherosclerosis and Interrelation Between Atherosclerosis and Metabolic Syndrome Metabolic Syndrome -- Insulin ResistanceInsulin Resistance
HypertensionHypertension
ObesityObesity
High GlucoseHigh GlucoseMetabolic Syndrome
InsulinResistance
Metabolic Syndrome Metabolic Syndrome InsulinInsulin
ResistanceResistanceAtherosclerosisRisk Increases
AtherosclerosisAtherosclerosisRisk IncreasesRisk Increases
Six Possible Traits
High TriglyceridesHigh Triglycerides
Small, Dense LDLSmall, Dense LDL
Low HDLLow HDL
The Role of CETP and TGThe Role of CETP and TG’’s s in Metabolic Syndromein Metabolic Syndrome
Bays H. Expert Rev Cardiovasc Ther 2004;2:89-105.
HL
TG’s
Small DenseHDL3
TG’s
HL
SmallDenseLDL 3-4
CETPCECECE
TGTGTG’’’sss
HDL
Depleted
CECECE
CETP
TGTGTG’’’sss
LDL1-2
Depleted
Low HDL fromRenal Clearance
of Apo A1
TG’sRLP
LPL
VLDLApo B-100
LiverHigh TG’s
Atherogenic Profile with High TG’s, Low HDL and Dense LDL. Patient has Metabolic Syndrome
High Triglycerides
Dense LDL
Low HDL
Three Lipid Traits is a Probable Diagnosis of Metabolic Syndrome
Most Likely the Patient has One or More non-Lipid Traits:1. Hypertension2. Obesity3. High glucose
Risk Level Increases
Check for Insulin Resistance
Primary Risk Assessment using Non-HDL
Particle Numbers
1
Modify Risk Level Using Metabolic Syndrome Traits
Lp(a), CRP and Insulin
2
Direct Therapeutic Approach Based on LDL and HDL
Subgroup Distributions and Lp(a)
3
LPP Treatment StrategyLPP Treatment Strategy
Important Benefits of the LPPImportant Benefits of the LPP™™ TestTest
Identification of the NCEP New Risk Factors
Measurement of Lipoprotein Particles Numbers with Lipid Panel in Cholesterol Equivalents
Identification of Lipid Metabolic Syndrome Traits
LPP+ Adds Additional Risk Factors hs-CRP plus Insulin and Homocysteine
Male Patient on 4 gm EPA & DHA OmegaMale Patient on 4 gm EPA & DHA Omega--33’’s, s, adding 10 mg adding 10 mg RosuvastatinRosuvastatin and then 145 mg and then 145 mg TricorTricor
10 mg Statin
10 mg RosuvastatinLDL decreased
(48%)145 mg Tricor
145mg TricorDense LDL
decreased 29%
TG’s decreased57%
Metabolic Syndrome Traits
from 2 to 0
62 year old female MD with a healthy profile like shown found that her calcium score was in the 90th
percentile
Examples of the Atherogenic Apo CExamples of the Atherogenic Apo C--1 Enriched HDL1 Enriched HDLand Low Birth Weight Babies (~6 lb and Low Birth Weight Babies (~6 lb vsvs ~7 lb)* ~7 lb)*
Apo C-1 HDL at d = 1.06
Low TG’s, VLDL and RLP
Apo C-1 HDL Characteristics Observed in 1-2% of Specimens
High and Very Buoyant HDL
ProinflammatoryHDL Associated with Endothelial Dysfunction
Kwiterovich P. et al. JAMA 2005;293(15) 1891.
High Very Buoyant HDL High Very Buoyant HDL –– Apo CApo C--1 or Lp(a) ?1 or Lp(a) ?Profile Most Likely has Apo C-1 Enriched HDL Since Lp(a) is Low
Lp(a) = <5 mg/dL
If Patient History Indicates a Low Birth Weight the Probability Would Increase
Confirmation with an Apo C-1 assay is Currently Only Done as Research
Mass Spectrometry shows two isoforms of Apo C-1, one appears to always be associated with CVD*.
*Moore D, McNeal C, Macfarlane R, Biochem Biophys Res Commun 2011;404(4),1034-8.
Lipoprotein Therapeutic Statins Niacin Fibrates Estrogens Resins Absorption Omega-3’s Alcohol Life Style Inhibitors EPA & DHA (moderate) Changes (diet & exercise)
VLDL (Triglycerides) ♥ ♥ ♥♥ ♥♥ X X ♥ ♥♥ ■
RLP (IDL) ♥ ♥ ♥ ♥ X X ♥ ♥♥** ■
LDL I & II - buoyant ♥ ♥♥ ♥ ♥ ♥ ♥ ♥ ♥ ** ■
LDL III - dense ♥ ♥** ♥♥ ♥ ♥♥ ♥ ♥ ■ ■
LDL IV or Lp(a) ■ ■ ♥♥ ■ ♥ ■ ■ ■ ■
HDL 2b - buoyant ♥♥ ♥ ♥ ♥ ♥ ■ ■ ■ ♥
HDL 2a & 3 ♥ ♥ ♥♥ ♥ ♥ ■ ■ ■ ♥ __________________________________________________________________________________________________________________
♥♥ Therapeutic ♥ Beneficial ■ Little or No Effect X Negative Result *These guidelines provide some of the treatment options available to modify lipoprotein particle numbers determined by the LPPTM test. **Spectracell Laboratories observed response to treatment. The National Cholesterol Education Program (NCEP) guidelines provide dosage information on the treatment options.
Lipoprotein Particle Numbers Lipoprotein Particle Numbers Therapeutic GuidelinesTherapeutic Guidelines
top related