Evaluating the Risk of Coronary Artery Disease:A Conceptual Approach

Texas-Wide Underwriting ConferenceCliff Titcomb, MDHannover Life ReMarch 19, 2012

How Much Myocardium is Already Lost?How Much Myocardium is At Short Term Risk?What is the Predisposition to Disease?How Much Myocardium Will Likely Be Jeopardized

in the Future and in What Time Frame?

2

Risk Assessment Revolves Around 4 Key Questions

Why the Questions?

Ultimately, the More Total Myocardium is Lost - the Greater the Risk for Adverse Morbidity and Mortality Outcomes• Loss of Pump Reduces Function• Losing More Than 40% of the Myocardium is Incompatible

with Life• Each Event Carries Risk of Fatal Arrhythmia

3

Question 1: How Much Myocardium Has Been Lost?

Numerous Studies Show an Increase in Mortality with Reduced Ventricular Function

Best Surrogate Marker is the Ejection FractionAn Alternative is the Left Ventricular End-Diastolic

Pressure (LVEDP)• Weaker Predictor• Subject to Other Factors

5

M o rta lity R isk B y D eg ree o f V en tricu la r D ysfu n ctio n

00.5

11.5

22.5

3

D e gre e of D ysfunction

Ris

k R

ati

o

Mortality R is k

Stahle et al., Ann Thorac Surg, 1997; 64:437-44.

R e la tiv e R is k w ith C AD a n d C H F

0 .0 0

0 .5 0

1 .0 0

1 .5 0

2 .0 0

2 .5 0

1 2 3 4

Rel

ativ

e R

isk

C H F

Caution - “Stunned” Myocardium

Transient Ventricular Dysfunction Due to Profound Ischemia

• Reversible with Improved Blood Flow• Common in the Early Post Infarction Period• Most Recent Evaluation is Probably the Best Estimate of Actual Function

8

Question 3: How Much Myocardium is at Short Term Risk?

How Much Myocardium is At Short-Term Risk?

Traditionally Referred to Ischemic BurdenNumber of Vessels with Hemodynamically

Significant Obstructive DiseaseMortality Clearly Varied with Number of “Diseased”

Vessels• Usually Defined as 50% or Greater Obstruction

10

Emond M, et al., Circulation, 1994; 90:2645-57.

S urv iv al B y N umbe r of D ise ase d Ve sse ls - C AS S D ata

0 %

2 0 %

4 0 %

6 0 %

8 0 %

1 0 0 %

De gre e of V e s s e l Involve m e nt

Sur

viva

l (%

)

1 2 Ye a r S u rviva l

R e lativ e R isk of M ultiv e sse l v s S ingle Ve sse l D ise ase

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

1 2 3 4 5 6 7

Rel

ativ

e R

isk

2 V es s el

3 V es s el

The Number of Diseased Vessels Does Scale Risk

But Not By the Mechanism Traditionally Thought to Be Operative

Get the Right Answer for the Wrong Reason Relates to the New Model of CAD

Three Elements are Critical in Acute Coronary Events

The Vulnerable PlaqueEndothelial DysfunctionThrombosis

14

The Relatively Innocent Looking Lesions are the Killers

Tight Stenosis Doesn’t Kill• Severe Stenosis Typically Causes Angina -- Not

InfarctionFor Major Coronary Events Quality Matters More

than Quantity in Terms of Atherosclerotic Material Gradual Obstruction May to Some Extent Be

Beneficial• Induces the Development of Collaterals Which Can Be

Protective

15

Vulnerable Plaques

Large Core of Oxidized Lipids• Thin Fibrous Cap

InflammationSome Degree of Calcium DepositionGenerally Non-ObstructiveDynamic

• Continuous Remodeling• Dependent on Risk Factors

16

Other Critical Elements

Endothelial Function• Abnormal Blood Vessel Response to Injury

–Spasm Instead of Dilatation–Reduced Production of Nitric Oxide

Thrombosis• Final Common Pathway for Acute Events

– Adverse Events Result from Clot with Occlusion

• Hypercoagulable State Increases Risk–Minor Plaque Ruptures Become Major Events–Important with Smoking

17

Mechanism - Acute Events

In Most Cases the Critical Step is the Rupture of a Non-Obstructive Vulnerable Plaque

• Fracture of Fibrous Cap Exposes Lipid Core to Circulating Blood

• Result is Acute Thrombosis, Endothelial Spasm and Vessel Occlusion

Tightly Stenotic Lesions Cause Only a Minority of Infarctions• More Likely to Cause Ischemia

–Angina or Equivalent Symptoms

18

Stenotic Lesions are Associated with Outcomes Because of the Company

They Keep

The Volume of Plaque Matters

Question 2 — Really a 2 Part Question

What is Total Plaque Burden?• How Many Plaques are There?

What is the Stability of the Plaques That are Present?• Are They Likely to Rupture?

21

Total Plaque Burden

Traditional Gold Standard – Cardiac Cath• Problem: Underestimates Volume of Plaque• Really a Lumenogram

–Only Sees Inner Surface of Vessel

• Vessel Remodeling Hides the True Volume of Disease–Vessel expands in Size to Compensate for Disease and Maintain Flow

• Not Effective at Finding Vulnerable Plaques–Predictive of Events But Poorly Predictive of the Actual Site of an Event

22

Traditional Non-Invasive Markers of Plaque Volume Primarily Detect

Obstructive Disease

Measure Ischemia Don’t Address Vulnerable Plaques

Direct Measures• Electron Beam CT Scan (EBCT)• Intravascular Ultrasound• Multi-Detector CT (MDCT)• MRA

Indirect Measures• Carotid Intima-Media Thickness (IMT)

24

Newer Non-Invasive Measure of Coronary Plaque BurdenDirect and Indirect

Electron Beam CT (EBCT)

Reflects Overall Plaque Burden• Measures Calcium Deposition in Plaque• Both Obstructive and Non-Obstructive Lesions

Overall Score is the Most Important Factor• Higher the Score the Greater the Likelihood of Obstructive

DiseaseDistribution of Plaque is also ImportantRelative Risk Correlates with Percentile Ranks By

Age and Sex• Where Do You Stand Relative to Your Peers?

25

EBCT

More Predictive of Risk of Cardiovascular Events Than Risk Factor Analysis

Ties the Risk Factors to the Individual• Relates Population Data to the End-Organ Results in the

Individual• Functions for CAD Like LVH for BP or Microalbumin for

Diabetes Identifies the Vulnerable Person

• Not Necessarily the Vulnerable Plaque

26

R e lativ e R isk for All C ause M ortalityB y R isk Factors and C alcium S core

0.51

1.52

2.53

3.54

4.5

Fem

ale

Dia

bete

s

FH

CA

D

Lipi

ds BP

Sm

okin

g

11-1

00

101-

400

401-

1000

> 1

000

Tradit ional R is k F ac tors Calc ium S c ore

Rel

ativ

e R

isk

A ll Caus e M orta lity

Shaw et al., Radiology, , 2003; 228:826-33.

R is k F a c to rs v s C a lc iu m S c o re s Hig h e s t v s L o we s t Q u a rtile

0

5

1 0

1 5

2 0

R is k Fa cto rs C a lc iu m S co re

Fa c tors

Ris

k R

atio

R is k R a tio

Raggi et al., Circulation, 2000; 101:850-55.

All C ause M ortality B y C alcium S core s

0

0.5

1

1.5

2

2.5

3

3.5

4

CA C 0 CA C 1-10 CA C > 10 V B T -NS

Mo

rtal

ity

Rat

e p

er 1

000

Rate/1000

Blaha et al., J Am Coll Cardiol Img, 2009; 2:692-700.

Probably the Best Test to Assess Overall Plaque Burden

Visualizes Both Soft and Calcified Plaque• Visualizes Lesions not Seen on Angiography

Positive Predictive Value (PPV) is Very Good and Negative Predictive Value (NPV) is Excellent for Significant Obstruction• Often Used Clinically to Rule Out Disease• Best Visualizes the Left Main and LAD• Worst Visualization is in the Circumflex

30

Multidetector CT Angiography

Heavy Calcification May Degrade ImagesNot All Segments are Visualized WellVisualization of In-Stent Stenosis is VariableMay not be Adequate for Planning for Surgery

• False Positives an Issue• Visualization of the Vascular Run Off

Radiation Exposure is Significant

31

Multidetector CT Angiography - Problems

M ultide te ctor C ompute d T omography B y P e rfusion and C ath S tatus

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

P erfus ion A bnorm al P erfus ion Norm al

S ca n S ta tu s

Per

cen

tag

e

M DCT N l

M DCT A bn

Nonobs truc t

B orderline

S evere

Cath O bs tr

Schuijf et al., J Am Coll Cardiol Img, 2008; 1:190-9.

C T Angiography (64 S lice ) to Ide ntify C AD - M e tanalyse s

88%

90%

92%

94%

96%

98%

100%

102%

1 2 3 4

S tu d ie s 2007-8

Per

cen

tag

e

NP V

P P V

But is the Plaque Vulnerable ?

Quality is as Important as Quantity

Plaque Stability Varies with Risk Factor Control

Important Revelation from Statin StudiesPlaques May Look the Same But They Don’t

RuptureInflammation is a Key ComponentReduction of Inflammation and Stabilization of

Plaques Leads to a Marked Decrease in Clinical Event Rates

35

C-Reactive Protein

Non-Specific Acute Phase Reactant• Measure of Inflammation

Produced in the Liver• Induced By Cytokines – Especially Interleukin 6

Highly Sensitive Test (hsCRP) Can Detect Low Grade Inflammation• Subdivide the Traditional Normal Range

36

C-Reactive Protein

Initially Appeared to Be Much More Predictive of Future Events Than Other Risk Factors

More Recent Studies Suggest Benefit May Be More Modest

Questionable if it Adds Substantially to Risk Assessment When Traditional Risk Factors are Taken into Account

Recent USPSTF analysis showed:• RR high risk v low risk = 1.58• RR average risk v low risk = 1.22

37

R e lativ e O dds for H e art D ise ase (U ppe r T hird v Lowe st T hird)

00.5

11.5

22.5

Tot

Cho

lest

erol

Sm

okin

g

Sys

tolic

BP

hsC

RP

Met

a C

RP

Risk F a cto r

Od

ds

Rat

io

O dds Rat io

Danesh et al., NEJM, 2004; 350:1387-97..

C-Reactive Protein — Practical Issues

Variability• Recommendation is Using Average of 2 Samples at Least

2 Weeks ApartLack of Specificity

• Other Causes of Inflammation–Likely for Levels > 10 mg/L–Measure again if levels are questionable

39

R isk of M I or C oronary D e ath B y C ombination C alcium S core & C R P Le v e l

01234567

Low M edium High

Ca lciu m S co re

Rel

ativ

e R

isk

CRP Low

CRP H igh

Park et al., Circulation, 2002; 106:2073-7..

Risk of All Cause Mortality is Increased

• 40-50% of Deaths in RA are From CV DiseaseInflammation Appears to Be the Mechanism

• The Disease Process in the Rheumatoid Joint is Similar to That in the Plaque

• Increased Adhesion Molecules and Inflammatory Cells with Production of Cytokines

Seropositive Status Increases CV Risk• Risk Increased with Elevated CRP and ESR, Joint

Swelling, RA Nodules, Vasculitis, Lung DiseaseEBCT Scores are Higher with RA

41

Plaque Stability - Rheumatoid Arthritis

Risk of Myocardial Infarction is Increased• Traditional Risk Factor Analysis Does Not Work as Well to Assess Risk

Increased Number of Vulnerable PlaquesMore Likely to Have Silent Disease

–Higher Risk of Sudden DeathRisk Higher with Longer Duration and Greater Severity

of RA DiseaseRisk of CHF is IncreasedTreatment with Disease Modification Drugs Seems to

Improve Risk

42

Plaque Stability - Rheumatoid Arthritis

C alcium S core B y Age and R A S e v e rity

0

50

100

150

200

250

300

350

Non RA RA M ild RA M od RA S evere

RA S e ve rity

Cal

ciu

m S

core 45-54

55-64

65 up

Giles et al., Arthritis Res Ther, 2009; 11:ePub

Question 3: What is the Individual’s Predisposition to Disease?

A Key Step in Customizing the Mortality Assessment is Linking the Disease Process

to the Individual

Critical Step is Identifying the Age of Diagnosis or

Age Standardized Percentile Rank for Disease Burden

Age Related Disease Burden Does 2 Things:

Provides an Estimate of the Slope of Initial Progression • By Extrapolation, the Likely Future Course

Provides a Context for Interpreting Risk Factors• Ties the Risk Factors to the Individual• Terms such as High or Low are Relative Values and

Depend on Context for Meaning

46

Need to Interpret Baseline and Individual Factors in Light of the Pattern Mortality

with the Disease

C AB G M ortality R atios B y Age of O nse t and C urre nt AgeP opulation C omparison

0

50

100

150

200

250

300

350

400

40's 50's 60's 70's 80's

Cu rre n t Ag e

Mo

rtal

ity

Rat

io

40's

50's

60's

70's

80's

M ortality R atios B y D uration P ost B ypass

139

213

181

132

113

59

0

50

100

150

200

250

0-5 5-10 10-15 15-20 20-25 25-30

Ye a rs S in ce Byp a ss

Mo

rtal

ity

Rat

io

M ortality Rat io

van Domburg et al., Eur Heart J, 2009; 30:453-8.

M o rta lity Ra te P o st CABG b y Du ra tio n

0

0.005

0.01

0.015

0.02

0.025

0.03

0.035

0.04

0.045

1 3 3-15 15-20 >20

Ye ar s Po s t Byp as s

Mo

rtal

ity

Rat

e

Morta lity Rate

van Domburg et al., Eur Heart J, 2009; 30:453-8

Re in te rve n tio n Ra te P o st Byp a ss

0

0.005

0.01

0.015

0.02

0.025

0.03

0.035

0.04

0.045

0-8 8-13 13-20 > 20

Ye ar s Po s t Byp as s

Rei

nte

rven

tio

n R

ate

Reinterv ention Rate

van Domburg et al., Eur Heart J, 2009; 30:453-8

M I M ortality R atios B y Age of O nse t and C urre nt AgeP opulation C omparison

0

100

200

300

400

500

600

700

800

900

50's 60's 70's 80's 90's

Cu rre n t Ag e

Mo

rtal

ity

Rat

io

50's

60's

70's

80's

90's

A g e o f On s e t

M ortality R atio B y D uration P ost R andomiz ation - M e dical T he rapy

0

50

100

150

200

250

300

350

400

450

500

0-5 5-10 10-15 15-20 20-22

Du ra tio n

Mo

rtal

ity

Rat

io v

s P

op

ula

tio

n

M R

Peduzzi et al., Am J Cardiol, 1998; 81:1393-99

M ortality R atios B y D uration P ost M I and Age

0

50

100

150

200

250

300

350

< 55 55-64 65-74 75-84 85 up

Ag e

Mo

rtal

ity

Rat

ios

vs P

op

ula

tio

n

1-5

5-10

Goldberg et al., Am J Cardiol, 1998; 82:1311-7

M ortality R atios B y D uration P ost B ypass

139

213

181

132

113

59

0

50

100

150

200

250

0-5 5-10 10-15 15-20 20-25 25-30

Ye a rs S in ce Byp a ss

Mo

rtal

ity

Rat

io

M ortality Rat io

van Domburg et al., Eur Heart J, 2009; 30:453-8.

Overall Plaque BurdenStability of the Plaques That are PresentCurrent Ventricular Function and Likely Cardiac

Reserve

56

Questions 1 and 2 - Establish the Baseline

Age of Onset - Sets the Track and the Slope of Progression Over Time

Without Disease Modification this Historical Slope of Progression Will Likely Continue Going Forward

57

Question 3 – Permits Estimation of the Likely Future Course

The Younger the Onset, the Higher the Overall Level of Risk Now and in the

Future

Weintraub et al., Circulation, 2003; 107:1271-7.

C umulativ e S urv iv al P ost B ypass B y Age G roup

0

0.2

0.4

0.6

0.8

1

5 10 15 20

Ye a r P o st Byp a ss

Cu

mu

lati

ve

Su

rviv

al (

%) A ge < 50

A ge 50-60

A ge 60-70

A ge > 70

0100200300400500600700

0-5 5-10 10-15 15-20

Mo

rtal

ity

Rat

io (%

)

Years Post Surgery

Relative Mortality for CAD By Age BandGroup Life Table

Age < 50

Age 50-60

Age 60-70

Age 70up

Weintraub et al., Circulation, 2003; 107:1271-7.

61Age of Onset

Sev

erit

y o

f D

isea

seEffect of Predisposition

45 6555

Risk Factors Must Also Be Evaluated in Light of Individual Predisposition to

Disease

Normal vs. Abnormal is Not a Numeric Value or Even a Population Average

It is a Level That Produces An End Organ Effect in An Individual

Question 4: How Much Myocardium Will Become at Risk in the Future and How

Soon Will It Occur?

Factors that Affect Risk May or May Not Be Modifiable

Equivalent to Having a Previous MI in a Non-Diabetic

Risk is Worse in Type 1 DMExtensive Disease is More LikelyOutcomes are Worse in Diabetics for Any Given

Extent of Disease• If Present with Unstable Angina – More Likely to Have an

MI• If Have an MI – Twice as Likely to Die

66

Diabetes - Increases Mortality Risk

R e lativ e R isk of M ortaltiy with C AD and D M

0.00

0.50

1.00

1.50

2.00

2.50

3.00

1 2 3 4 5 6 7 8 9 10

Rel

ativ

e R

isk

DM

Smoking

Converts Minor Plaque Ruptures into Major Events• Effect is Primarily on Thrombosis Leg of the Triad

Active Smokers Have Highest RiskRisk Persists into Older AgesQuitters Have Reduced Risk

• Some Studies Suggest Relative Risk Post MI is Lower in Quitters Than Lifelong Nonsmokers

• Reason: Major Risk Factor Leading to Events Has Been Removed

68

Myers et al., J Am Coll Cardiol, 1999; 33:488-98.

H az ard Function for S moking - P ost B ypass C ass D ata

0

2

4

6

8

1 0

1 m o n th 5 1 0 1 5

Dura tion

Haz

ard

Func

tion N e ve r S m o ke d

Q u it S m o kin g

C u rre n t S m o ke rs

Kinjo et al., Circ J, 2005; 69:7-12.

Ad ju sted H az ard R atio fo r All-C au se D eath P a tien ts W ith Acu te M yo card ia In fa rc tio n

0

0 .5

1

1 .5

2

2 .5

No n e F o rme r Q u itte r Pe rs is te n t

S m o kin g S ta tu s

Ha

zard

Ra

tio

Mu ltiva r ia te Ha za rdR a tio

Lipids

Multiple Studies Have Demonstrated Increased Risk with Elevated Lipids

Control Clearly Reduces RiskReduction in Acute Event Rates Occurs At

Minimum within Months• May Occur Within Weeks or Sooner

Cholesterol/HDL Ratio is the Best Single Lipid Measure

71

Re la tive Risk By F a cto r

0

0.51

1.5

2

2.53

3.5

Lp(a) Homoc y s t TC LDL A po B TC:HDL

Facto r

Rel

ativ

e R

isk

Relativ e Ris k

Clin Chem, 47;2001.

R e lativ e R isk of M ortality with H ype rlip ide miaM ultiv ariate S tudie s

0

0.5

1

1.5

2

2.5

3

1 2 3 4

S tu d ie s

Rel

ativ

e R

isk

Relat ive R is k

Hypertension

Multiple Potential Adverse Effects• Progression of Atherosclerosis• Mechanical Stress That May Destabilize Plaques• Development or Progression of LVH• Synergistic Effect with Diabetes

Effects Greater with Systolic BPPulse Pressure is ImportantOverall Relative Risk is Modest in Most Studies –

Probably Maximum of 1.3-1.4

74

Type of Therapy

Choice of CABG v PTCI is Still Somewhat Controversial• Some Data Suggests That Outcome is Better with CABG

for Three Vessel and Left Main Disease–Especially if High Risk with Reduced EF–Diabetics–Older Individuals

Outcomes are Probably Equivalent for One and Two Vessel Disease

Benefit of CABG for Diabetics Continues to 10 Years

75

Type of Therapy — Invasive

Stents Clearly Improve Short-Term Outcomes• Reduced Restenosis Rate• Restenosis is Reduced Further with Drug Eluting Stents

(DES)–DES is Associated with Late Stent Thrombosis (Rare)–No Real Survival Benefit of DES vs Bare Metal Stents

• Limited Benefit Long Term–Most Adverse Outcomes Result from Progression of Disease in

Vessels without a Stent

76

Type of Therapy — Invasive

Outcomes Better with Use of Internal Mammary Artery (LIMA)• Hazard Ratio – 1.34 with a Vein Graft Alone

–Data Suggests Two IMA is Better Than One (HR=0.81)• Now Standard of Care for Bypass

Radial Arteries also Superior to Vein Grafts• May Not Be as Good as Using Both LIMA and RIMA

Type of Therapy — Non-Invasive

Clear Benefit of Medical Therapy – Multiple StudiesDifferent Types – Benefit Additive

• Statins• Beta-Blockers• ACE Inhibitors• Aspirin/Platelet Agents• Anticoagulation

78

For Stable CAD w Multivessel Disease and Good EF - Mortality Outcomes are Similar for Medical Therapy, PTCI and

CABG

More Interventions with Med Rx and PTCI

C-Reactive Protein (CRP)B-Natriuretic Peptide (BNP)TroponinWBC CountMicroalbuminuriaCystatin CMidregional Proadrenomedullin (MR-proADM)FibrinogenIL-6

80

New Biomarkers

Individually Have Shown Some Increase in Hazard Ratios in Multivariate Analysis

For the Most Part the Effect on the Disease Classification Has Been Modest

Combinations of Markers Have Been Tried with Mixed Results• Some Combos Have Shown Some Improvement of

Risk AssessmentB-Natriuretic Peptide Appears to Be the Best of the

Current Group

81

New Biomarkers

Peptide Hormone Released from Ventricles in Response to Myocyte Stretch

Associated with Regional or Global Ventricular Dysfunction

Provides Value Independent of EFFound to Be a Predictor of Long-Term Increase in

Mortality in Multiple Scenarios• Stable Coronary Disease (RR 2.4)• Acute Coronary Syndromes (RR 2.4)• Myocardial Infarction

82

B-Natriuretic Peptide

R ela tive R isk b y N T -p ro B N P L eve ls M ean Ag e 59

0.00

0.50

1.00

1.50

2.00

2.50

3.00

< 64 64-169 170-455 > 455

BNP L e ve ls

Relat ive R is k

Kragelund et al., N Engl J Med, 2005; 352:666-75.

84

Has a Variety of Effects

• Smooth Muscle Cell Proliferation• Reduces Inflammation• Vascular Calcification • Renin-Angiotensin System• Blood Pressure

Low Levels are Associated with:• Increasing Age• Female Sex• Non-White Race• Diabetes• Hypertension• Current Smoking• Lower Physical Activity• Winter Season

25-Hydroxyvitamin D

Deficiency was Present in 22% of the NHANES III Population Age 18 up (16,603)

Self Reported CV Disease is Higher with Lower Levels in NHANES III• RR=1.20

Relative Risk of MI is Increased Comparing Lowest to Highest Quartile Levels

• RR=2.09Multiple Studies Show an Increase in All-Cause and

CV Mortality (Highest v Lowest Quartiles) When Controlling for Other Risk Factors

85

25-Hydroxyvitamin D

M o rta lity B y 25 -H yd ro xyv itam in D L eve l n g /m l (n m o l/L )

0

0.2

0.4

0.6

0.8

1

1.2

1.4

> 32.1(80.1) 24.4(60.9)-32.1(80.1)

17.8(44.4)-24.3(60.7)

< 17.8(44.4)

L e ve l

Rel

ativ

e R

isk

A ll Caus e

CV

Melamed et al., Arch Intern Med, 2008; 168:1629-37.

All C ause M ortality B y 25 H ydroxyv itamin D Le v e l ng /ml(nmol/L)

0

0.5

1

1.5

2

2.5

23.6(58.9)-33.5(83.6)

14.6(36.4)-22.8(56.9)

10.4(26.0)-16.8(41.9)

5.8(14.5)-10.1(25.2)

L e ve l

Haz

ard

Rat

io

A ll Caus e

Dobnig et al., Arch Intern Med, 2008; 168:1340-9.

Exercise Tolerance and Heart Rate Recovery

Important Considerations in Long-Term PrognosisSurvival Rate Decreases in Proportion to Reduction

of Exercise Duration and VO2 MaxHR Recovery Adds Additional Information to That

Supplied by Exercise Tolerance

88

Even Mild Renal Insufficiency (Serum Creatinine > 1.4 mg/dl-1.5 mg/dl/123.8 umol/L-132.6 umol/L) is Associated with a Worsened Outcome with CAD• Common Finding in the Elderly

Outcome is Worse with Overt Renal FailureIncreased Risk Occurs in Multiple Scenarios

• Chronic Stable Angina • Acute Coronary Syndrome• Myocardial Infarction• CABG and PTCI

89

Renal Insufficiency

Left Ventricular Hypertrophy (LVH)

Associated with Coronary Disease Itself and Comorbid Conditions Like Hypertension

In CAD, Increases Risk Compared to Those Without LVH• Relative Risk - 1.5-1.8 Range

Certain Treatments May Decrease LV Mass• Unclear if Reducing Mass Reduces Risk

90

Ventricular Arrhythmias

Ventricular Fibrillation in the Setting of an Acute Event Does Not Reduce Long-Term Survival• Provided No Ongoing Arrhythmias

Sustained Ventricular Tachycardia, Even in the First 24 Hours, is an Adverse Prognostic Indicator• Associated with Larger Infarcts, LV Aneurysm• Non-Sustained VT is a Much Weaker Predictor of Adverse

Outcome

91

Ventricular Arrhythmias

Mortality Risk is Increased with Even Relatively Few PVCs Present Beyond the Setting of the Acute Event• Outcome Depends Heavily on Presence of Ongoing

Ischemia and Especially Status of Ventricular Function• No Good Evidence That Treatment Affects Survival

Incident AF Occurs in 5-13% of Acute Infarctions in Recent Studies (Higher in Older Ones)• New AF has a Higher Risk than Chronic AF

Older Age, Heart Failure, Elevated Heart Rate, Hypertension Increased the Risk of Developing AF

AF Increases the Risk of Stroke and In-Hospital Mortality Post MI

AF Increases Long-Term Mortality• Even When Controlling for Co-Morbid Conditions• RR is in the 1.25-1.35 Range

93

Atrial Fibrillation

Peripheral or Cerebrovascular Disease

Indicators of Diffuse Vascular InvolvementOutcomes are Worse for Those With CAD and

Peripheral or Cerebrovascular Disease

• RR Approximately 1.5Diffuse Vascular Disease is Associated with Risk

Factor Profiles That Magnify Risk• Diabetes• Smoking

94

Homocysteine

Data is Mixed• Retrospective Studies Suggested Very High Relative Risk• Prospective Studies – Generally Less Impressive

Overall Association with Increased Risk is Probably Mild to Moderate

Other Factors• Technical Problems with Assay • Difficulties with Collection• Expensive

Does Not Appear That Lowering Level Reduces Risk

95

Lipoprotein (a)

Genetics Play a Large Role in Determining Level – Important in Some Groups

Homology with PlasminogenRisk Tied to LDL Cholesterol LevelsDifficult to Treat

• Does Not Respond to Statins• Benefit – Estrogens, Nicotinic Acid

Relatively Weak Predictor• May Be More Important in Select Cases

96

R e lativ e R isk B y Factor

00 .5

11 .5

22 .5

33 .5

Fa c tor

Rel

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R e la tive R is k

Clin Chem, 47;2001.

Age of Onset

Sev

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Where the Questions Fit

45 6555

1, 2

3

4

Baseline Amount of Disease

Initial Progression Slope

Future Rate of Progression