Measuring and Lowering Cholesterol

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Measuring and Lowering Cholesterol

• Mary P. McGowan, MD
• Director Cholesterol Treatment Center
• Concord Hospital
• Assistant Professor of Medicine
• University of Massachusetts Medical Center

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Outline

• Magnitude of CAD in the United States
• Lipid levels/lipid goals
• Advanced lipid testing
• Lowering Lipids
• Diet
• Exercise
• Supplements
• Medications
• Familial hypercholesterolemia/LDL Apheresis

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Magnitude of CAD in the US

• 79.4 Million People in the US living with CVD
• 700,000 Americans will have a first MI this year
• 500,000 Americans will have a recurrent MI
• 125,000 Americans will have a silent MI
• 1,285,000 Angioplasties per Year (incld stents)
• 427,000 Bypass Procedures per Year
• Total Cost CHD gt151.6 Billion Dollars/Year
• Heart and Stroke Statistical Update, AHA 2007

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Plaque Rupture
Fibrouscap
Thrombus
1 mm ___________
Lipid core
Illustration courtesy of Frederick J. Schoen, MD,
PhD, with permission.
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Lipid Profile

• TC Trig/5 HDL LDL
• Advanced lipid testing can include
• lipoprotein subfractions
• Lipoprotein (a)
• Highly Sensitive C Reactive Protein (HS-CRP)
• Apo B, Apo A
• /- Homocysteine

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Evolution of NHLBI Supported Guidelines
Updated NCEP ATP III 2004
AHA/ACC Update 2006
NCEP ATP I 1988
NCEP ATP II 1993
NCEP ATP III 2001
More Intensive Treatment Recommendations
Angiographic trials (FATS, POSCH, SCOR, STARS,
Ornish, MARS) Meta-analyses(Holme, Rossouw)
FraminghamMRFITLRC-CPPTCoronary Drug
ProjectHelsinki HeartCLAS
4SWOSCOPSCARELIPIDAFCAPS/ TexCAPS
HPSPROVE-IT ASCOT-LLA PROSPER ALLHAT-LLT
TNT IDEAL
NHLBI National Heart, Lung, and Blood
Institute. NCEP ATP National Cholesterol
Education Panel Adult Treatment Panel. AHA
American Heart Association. ACC American
College of Cardiology.
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VBWG
ATP III update LDL-C goals and cutpointsfor
treatment
Risk category LDL-C goal Initiate TLC Consider
drug therapy High risk CHD or CHD risk lt100
mg/dL 100 mg/dL 100 mg/dLequivalents (10-yr
risk gt20) Moderately high risk 2 risk
factors lt130 mg/dL 130 mg/dL 130 mg/dL (10-yr
risk 1020) Moderate risk 2 risk
factors lt130 mg/dL 130 mg/dL 160 mg/dL (10-yr
risk lt10) Lower risk 01 risk factors lt160
mg/dL 160 mg/dL 190 mg/dL (160189
mg/dL drugs optional)
(optional goallt70 mg/dL)
(lt100 mg/dLconsider drug options)
(optional goallt100 mg/dL)
(100129 mg/dLconsider drug options)
Diabetes or other noncoronary atherosclerotic
disease Favored for very high-risk subset No
changes in moderate and lower-risk category TLC
therapeutic lifestyle change
Grundy SM et al. Circulation. 2004110227-39.
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Triglyceride/HDL Goals

• Triglycerides Desirable lt 150 mg/dL (no CAD)
• lt
  100 mg/dL (CAD)
• HDL Desirable Men gt 45 mg/dL
• Desirable Women gt 50 mg/dL

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Lipoprotein Sub-Classes

Chylomicron
0.95
1.006
IDL
Density (g/ml)
1.02
LDL
1.06
Lp(a)
1.10
HDL3DL3
pre-ß2 HDL
1.20
pre-ß1 HDL
1000
5
10
20
40
60
80
Particle Size (nm)
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Framingham CHD Risk Assessment in Men
Note Risk estimates were derived from the
experience of the Framingham Heart Study, a
predominantly Caucasian population in
Massachusetts, USA. Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA. 20012852486-2497.
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Framingham CHD Risk Assessment in Men
Note Risk estimates were derived from the
experience of the Framingham Heart Study, a
predominantly Caucasian population in
Massachusetts, USA. Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA. 20012852486-2497.
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Framingham CHD Risk Assessment in Men
Note Risk estimates were derived from the
experience of the Framingham Heart Study, a
predominantly Caucasian population in
Massachusetts, USA. Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA. 20012852486-2497.
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Framingham CHD Risk Assessment in Men
Note Risk estimates were derived from the
experience of the Framingham Heart Study, a
predominantly Caucasian population in
Massachusetts, USA. Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA. 20012852486-2497.
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Framingham CHD Risk Assessment in Men
Initiate LDL gt 100
Target LDL lt 100
Initiate LDL gt 130
Risk 10 - 20/10 yr
Risk gt 20/10 yr
Initiate LDL gt 70
Target LDL lt 70
Note Risk estimates were derived from the
experience of the Framingham Heart Study, a
predominantly Caucasian population in
Massachusetts, USA. Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA. 20012852486-2497.
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General Risk CategoriesGreenland et al.
Circulation 2001(15)1863-7
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How Good is ATP III at Predicting MI

• Akosah and colleagues identified 222 younger
  patients (men lt 55 and women lt 65) who were
  hospitalized for an acute MI
• Their mean lipid levels were normal and only 25
  of all patients (18 of women) would have met the
  criteria for initiation of lipid lowering therapy
• Akosah et al. JACC. 200341147S

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The Limitations of LDL-C Not All LDL Particles
Are the Same
Larger, More Buoyant LDL
Small, Dense LDL
LDL130 mg/dL
LDL130 mg/dL
Apo B
More Apo B
Cholesterol Ester
More Atherogenic
Less Atherogenic
Otvos JD, Jeyarajah EJ, Cromwell WC. Am J
Cardiol. 20029022i-29i.
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Why are Lipoprotein Subclasses Measured?

• Detect Atherogenic Dyslipidemia
• Sm dense LDL more atherogenic?
• Large HDL more protective?
• TG rich remnants
• Detect Metabolic Syndrome
• W/ Elevated TG, low HDL, sm LDL
• Clinical Judgement
• Measurement of subclasses could better
  characterize risk/ allow better treatment
• Subclass measurements go beyond current NCEP
  guidelines
• NCEP ATP III does not recommend sm. Dense LDL
  analysis in routine practice
• Waymack P. A perspective on HDL-LDL subclass..GR
  NIH 12/6/06

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Measuring Non-Traditional Lipoprotein
Subfractions

• Vertical ultracentrifugation (VAP) Atherotech
• Gradient gel electrophoresis (GGE) Berkeley
• NMR spectroscopy (NMR) Liposcience

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Basic Principles of Vertical Ultracentrifugation
100 uL Specimen is added to KBr solution (1.21
g/mL density)
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Second Generation Technology Direct
Measurement of Cholesterol in All Lipoprotein
Fractions
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LDL-C Subclasses by Software Convolution
J Lipid Research 1995
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Vertical Ultracentrifucation Technology Lipid
Subfractions

• Because of the improved resolution with the
  second generation commercial systems individual
  lipoprotein curves can be further divided into
  subfractions
• LDL-Creal into four density subfractions
• also reported as Pattern A, B, or AB
• HDL into five density subfractions
• also reported as HDL2 and HDL3
• VLDL into multiple subfractions
• also reported as VLDL3 subfraction
• Second
  Generation technology

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HDL-C Subclasses by Software Deconvolution
J Lipid Research 1994
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Potential Benefits VAP

• Identification of pattern B
• Might allow more intensive therapy
• Might direct therapy toward drugs which shift
  pattern from B to A (Fibric Acid Derivatives
  Niacin)
• Identification of small and large HDL particles

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Advanced Lipid Testing GGE

• Gradient Gel Electrophoresis
• First commercially available separates LDL into
  7 regions by size/ HDL subfractions
• Breaks down LDL-I, IIab, IIIab, etc., IDL, apoB,
  Lp(a) and a regular lipid profile
• Directly correlates with ANUC
• Fairly time consuming technique

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What is GGE?

• GGE Gradient Gel Electrophoresis
• GGE utilizes a gel to sift apart the different
  lipoproteins based on their characteristic
  sizes, which are equivalent to diameter
• Need 2 gel runs if both LDL HDL data needed
• Measures percentages of particles bysize ( not
  individual lipoprotein cholesterol measurement)
• Labs measure (Lp(a) separately
• LDL-C calculated by Freidwald formula

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How Does GGE Typically Work?
Before Run
Sample loaded onto gel
Note the different pore sizes
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The pore sizes get smaller as you go down the gel
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15
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GGE After Run
Lipoproteins migrate this way
5
10
15
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Optical Densitometry Analysis After Gel Run
Optical Density
Pattern B
Pattern A
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GGE Interpretation
1
2
3
4
5
6
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Optical Density
IVb
IIb
IIIa
IIIb
IVa
I
IIa
Denotes Pattern B that still has a large amount
of Pattern A
Denotes Pattern A that still has a large amount
of Pattern B
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Potential Benefits GGE

• Patient report gives of LDL in each sub class
  esp important to look at III a b and IV a b
  which correlate with angiographic progression of
  CAD
• Also provides Apo B, Lp(a) by other technology

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Advanced Lipid Testing NMR Spectroscopy

• Commercially available technology
• measures numberof particles present
• determines by proton NMR properties (shift and
  line width) of methyl resonance from lipids in
  VLDL, LDL, and HDL
• provides VLDL 1 through 6, IDL, LDL 1 through 3,
  and HDL 1 through 5
• directly correlates with electron microscopy

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NMR Lipoprotein Subclass Measurement
Potential Benefits on NME Other traditional
measurement methods involve 2 steps 1)
Separation - by size or density 2)
Quantification - dye stain or cholesterol
Separation steps are laborious, time-consuming,
and potentially introduce sources of measurement
variability
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Total Cholesterol ()
NMR Association with CHD Positive () or
Negative (-)
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Comparisons of LDL Subclass Methods

• Goal Assess differences between leading
  technologies for LDL subclasses
• Collected 4 simultaneous samples from 40 subjects
  and sent to the labs performing each assay
• LDL subclasses evaluated for particle size and
  LDL phenotype (pattern A or B)
• Complete agreement with regard to LDL subclass
  phenotypes in 8 (3 of 40) subjects
• Clin chem 2006521722-7

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Comparisons of LDL Subclass Methods

• Authors Conclude
• Measurement of subclasses is not standardized
• Predicting pattern A or B can be done just as
  reliably using triglycerides gt / lt 150 mg/dL
• There is significant variation among currently
  available methods
• Clin chem 2006521722-7

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Comparisons of LDL Subclass Methods

• My Conclusions
• Advanced Lipid testing may be beneficial in
  certain circumstances
• If you are planning to assess treatment use the
  same lab each time

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Lp(a) - Introduction

• Lp(a) is a lipoprotein of hepatic origin composed
  of apo(a) covalently linked to a single apo B-100
  containing particle (identical to LDL with lipid
  core phospholipid shell)
• Lp(a) is associated with an increased risk for
  atherosclerosis (both CHD/PVD) via a variety of
  proposed mechanisms
• Lp(a) is felt to be about 10x as atherogenic as
  LDL

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The Genetics of Lp(a)

• Lp(a) Levels determined by autosomal co-dominant
  gene on long arm of chromosome 6 (adjacent to
  plasminogen gene)
• unrelated to age or gender
• adult levels reached by age 8 months, remain
  constant
• environmental factors (except certain diseases
  or agents) have little influence on levels
• In populations Lp(a) exhibit wide variability
  with ranges from 0 to 100 mg/dL

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Lp(a) and Apo(a)Structure and Function

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Epidemiology of Lp(a)

• Subpopulation with Lp(a)gt30 mg/dL vary, appear
  early in life 2X more common in CHD
• African American 30
• Asian Indians 25
• American caucasians 19
• Mexican-Americans 8
• Lp(a) is felt to increase risk in all populations
  except American blacks may be more predictive
  in younger age groups
• Mean Lp(a) in US is 13.3mg median is 6.7
• highly skewed distribution 33 have Lp(a)lt4

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Other Medical Conditions with Observed Lp(a)
Elevation

• Liver disease FH
• CRF/Nephrotic Syndrome
• CRF Lp(a) 3x normal
• Hypothyroidism/ DM with proteinuria
• Acute Phase Reactions (marked)

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New Method of Evaluating Lp(a)

• The expression of Lp(a) values in terms of total
  Lp(a) mass (mg/dL) should be abandoned as this
  reflects the protein component of Lp(a) and not
  its lipid and carbohydrate content.
• To correctly reflect the number of Lp(a)
  particles and to compare the data from different
  studies, the values should be expressed in terms
  of nmol/L of Lp(a)
• Marcovina SM. Et al. Clin Chem 2003 491786-96

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Inflammation and CV Events The Role of hsCRP

• C- reactive protein has been identified as a
  marker for underlying systemic inflammation.
• CRP is an acute phase reactant protein/Hepatic
  production regulated by Il6
• Inflammation has been implicated in both the
  initiation and progressions of atherosclerosis
  and anti-inflammatory agents may have a role in
  the prevention of cardiovascular disease.

1. Munro JM, Lab Invest. 198858249-61 2. Ross R
Nature. 1993362801-809 3. Alexander RW, N Engl
J Med. 1994331(7)468-469
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CRP as a Risk Factor For Future CVD Primary
Prevention Cohorts
Kuller MRFIT 1996 CHD Death Ridker PHS
1997 MI Ridker PHS 1997 Stroke Tracy
CHS/RHPP 1997 CHD Ridker PHS 1998,2001 PAD Rid
ker WHS 1998,2000 CVD Koenig MONICA
1999 CHD Roivainen HELSINKI 2000 CHD Mendall
CAERPHILLY 2000 CHD Danesh BRHS
2000 CHD Gussekloo LEIDEN 85 Fatal
Stroke Lowe SPEEDWELL 2001 CHD Packard WOSCOPS
2001 CV Events Ridker AFCAPS 2001 CV
Events Rost FHS 2001 Stroke Pradhan WHI
2002 MI,CVDdeath Albert PHS
2002 SuddenDeath
0 1.0 2.0 3.0 4.0 5.0 6.0
Relative Risk (upper vs lower quartile)
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WHS Risk Factors for Future Cardiovascular Events
Lipoprotein(a) Homocysteine IL-6 TC LDLC sICA
M-1 SAA Apo B TC HDLC hs-CRP hs-CRP TC
HDLC
0 1.0 2.0 4.0 6.0
Relative Risk of Future Cardiovascular Events
N Engl J Med 2000342836-43
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Modified Recommendations for hs-CRP Laboratory
Testing (AHA/CDC)

• High Sensitivity (hs)-CRP testing
• Verify abnormal results( perform twice-2 weeks
  apart)
• Average results (expressed as mg/L)
• May be nonfasting, in afebrile metabolically
  stable patients
• Low Specificity
• Elevated levels may occur with many infections
  or other inflammation chronic conditions (ie. RA)
• High levels (gt10.0 mg/L) should be repeated after
  3 weeks if Acute Phase Reaction suggested

Adapted from Pearson TA et al. Circulation.
2003107499-511.
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Recommendations for Use of hs-CRP in Clinical
Practice (AHA/CDC)

• hs-CRP measurement is independent marker of CVD
  risk, and adds to TC/HDL ratio
• In Primary prevention patients at intermediate
  risk (1020 risk of CHD per 10 years)
• hs-CRP may help direct further evaluation,
  therapy in primary prevention
• In patients with stable coronary disease
  andacute coronary syndromes
• hs-CRP measurement may be useful as independent
  marker of prognosis for recurrent events

Modified from Pearson TA et al. Circulation.
2003107499-511.
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Lifestyle/ Genetics

• Most Cardiac Disease is caused by a less than
  perfect lifestyle layered on a less than perfect
  genetic background
• Henry Ginsberg, MD

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Age Adjusted Prevalence of Overweight and
Obesity BMI gt 25Ogden CL, et al. JAMA.
20062951549-1555
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If you grow up to be half the man your father is,
that's plenty."
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Therapeutic Strategies for LDL Goal Attainment

• Diet
• Exercise
• Supplements
• Medications

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FRENCH FRIES
30 Years Ago
Today
210 Calories 2.4 ounces
610 Calories 6.9 ounces
How many calories are in these fries?
Calorie Difference 400 Calories
How to burn 400 calories   Walk 2 hr 20 Minutes
Based on 130 pound person
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Look AHEAD Study design
Look Action for Health in Diabetes
N 5145 45-74 years with T2DM, BMI 25 kg/m2
(27 kg/m2 if taking insulin)
Usual medical care lifestyle intervention for
4 years, with maintenance counseling thereafter
Usual medical care diabetes support and
education for 4 years
Total follow-up 11.5 years
Primary endpoint CV death, nonfatal MI, nonfatal
stroke
7 mean weight loss with hypocaloric diet
pharmacologic therapy 175 min/week moderate
physical activity Diet 1200-1500 kcal/day
(lt250 lbs) or1500-1800 kcal/day (250 lbs)
Look AHEAD Research Group. Control Clin Trials.
200324610-28 Obesity. 200614737-52.
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Look AHEAD Trial Improvement in Metabolic
Syndrome Components at 1 Year
Look AHEAD Research Group. Diabetes Care.
2007301374-1383.
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Walking the dog
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10,000 Step Program

• Average American walks
• lt 65 y.o. 4000 steps/day
• gt 65 y.o. 2000 steps/day
• Each additional 3000 steps/day (½ hour)
• 15 lb ?/yr
• 15-50 ? CHD
• doesnt have to be continuous
• incorporate into daily activities

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Supplements

• Cholestene
• Plant stanols plant sterols
• Flaxseed
• Walnuts
• Soy protein
• Fiber
• Profile Diet stanols, almonds, soy, viscous
  fiber
• Guggulipid, Cinnamon, Policosanol (do not work)
• Fish oil (Triglycerides)

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Effect of Drugs on LDL-C Levels
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Effects of Drugs on HDL-C

• Nicotinic acid ? 1535
• Fibrates ? 1015
• Statins ? 515

Modified from Belalcazar LM et al. Progress in
Cardiovascular Disease 199841151-174.
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Effects of Drugs on Triglycerides

• Fibrates -35 - 45
• Fish oil -30 40 (high
  dose)
• Nicotinic acid -20 - 25
• Statins -10 - 15

Modified from Belalcazar LM et al. Progress in
Cardiovascular Disease 199841151-174.
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LIPOSORBER SYSTEM
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LDL-Apheresis
LIPOSORBER SYSTEM
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LIPOSORBER SYSTEM
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LIPOSORBER SYSTEM
ACUTE PRECENTAGE REDUCTIONS

• Acute PercentageLipid/Lipoprotein Reduction ()
• Total Cholesterol 61 - 71
• LDL-C 73 - 83
• HDL-C 3 - 14
• Lp(a) 53 - 76
• Triglycerides 47 - 68

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LIPOSORBER SYSTEM
LDL-C
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LDL-Apheresis
ACUTE PRECENTAGE REDUCTIONS

• Acute PercentageLipid/Lipoprotein Reduction ()
• Total Cholesterol 61 - 71
• LDL-C 73 - 83
• HDL-C 3 - 14
• Lp(a) 53 - 76
• Triglycerides 47 - 68

Liposorber System
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Stormie Jones

• Age 6 diagnosed with FH

-TPC 1200 mg/dl -TG 150 mg/dl -LDL 1130
mg/dl(normal lt110 mg/dl) -Progressive
xanthomas -No LDL receptors on fibroblasts

• Age 6 yr 6 mo, Angina and double coronary bypass

• Age 6 yr 8 mo, Second bypass

• Age 6 yr 9 mo, Heart failure

• Age 6 yr 9 mo, Combined heart and liver transplant

-TC dropped to about 250 mg/dl

• Age 12 yr 6 mo, (Nov. 90) Died due to rejection
  of her second transplant

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Outline

• Magnitude of CAD in the United States
• Lipid levels/lipid goals
• Advanced lipid testing
• Lowering Lipids
• Diet
• Exercise
• Supplements
• Medications
• Familial hypercholesterolemia/LDL Apheresis