Psoriasis and Risk of Coronary Artery Disease: Detection of Early

Atherosclerosis

Eric H. Yang, MD, FACCAssistant Professor of Medicine

Director of the Coronary Care UnitInterventional Cardiology

University of North Carolina at Chapel Hill

Case • 35 year old white male with psoriasis.

• PASI score 52

• Being evaluated for systemic therapy.

1. Is it true that psoriasis increases this patient’s risk of having a coronary event?

2. If so, does treating the disease decrease the risk of future cardiac events?

William Osler

George Bush

“The good physician treats the disease; the great physician treats the patient

who has the disease.”

“Why? Why do you care what happens outside of America?”

July 2, 2008

Outline

I. Background

II. Invasive Detection of CAD

III. Non-Invasive Detection of Early CAD

IV. Surrogate Biomarkers

V. Endothelial Function

“Great Advances in Cardiovascular Medicine”

• Pharmacology:– Beta Blockers, ACEI, Statins, Thrombolytics

• Coronary Interventions:– Angioplasty, Stents, Distal Protection

Devices

• Prevention:– Smoking Cessation, Cardiac Rehab

0

100

200

300

400

500

A B C D E A B D F E

MalesFemales

De

ath

s in

Th

ou

sa

nd

sLeading Causes of Death for All Males and Females

United States: 2002

A Total CVD (Preliminary)B CancerC Accidents

D Chronic Lower Respiratory DiseasesE Diabetes MellitusF Alzheimer’s Disease

Source: CDC/NCHS

Cardiovascular Disease

Epidemiology

• 1.7 Million Americans per year suffer from a AMI, 290,000 of which are STEMI.

• It is estimated that the number of years of life lost due to an AMI is 14.2 years.

• The direct and indirect cost of myocardial infarction to the American Society is billions of dollars per year.

• 12% of those who make it to a hospital will die from their STEMI.

AHA Statistical Update 2006

“Whatcha Talkin Bout Willis?”Psoriasis and CAD: Epidemiological Data

General Practice Research Database (GPRD)

• 8 Million UK residents with > 35 million years of follow up.

• Gelfand Study: Divided population into 3 Groups:– Mild Psoriasis: Not on Systemic Therapy (N =

127,139)– Severe Psoriasis: On systemic Therapy (N=3837)– Matched Controls: N= 556,955

JAMA 2006;14:1735

Mild PsoriasisMultivariate Cox Proportional Hazard of MI

OR 95% CI

History of MI 3.24 3.07-3.41

Hyperlipidemia 3.08 2.93-3.23

Male sex 2.12 2.04-2.19

Diabetes 1.61 1.53-1.7

Psoriasis 1.54 1.24-1.91

Smoking 1.15 1.10-1.20

HTN 1.11 1.07-1.16

JAMA 2006;14:1735

Severe PsoriasisMultivariate Cox Proportional Hazard of MI

OR 95% CI

Psoriasis 7.08 3.06-16.4

History of MI 3.31 3.13-3.51

Hyperlipidemia 3.18 3.02-3.36

Male sex 2.14 2.05-2.22

Diabetes 1.62 1.53-1.7

Smoking 1.16 1.11-1.21

HTN 1.12 1.07-1.17

JAMA 2006;14:1735

Adjusted Relative Risk of MIBased on Patient Age

JAMA 2006;14:1735

20 30 40 50 60 70 80

1.0

.5

10Severe Psoriasis

Mild Psoriasis

Age (years)

Relative RiskInverted Risk For

Age

Swedish Inpatient Registry

• National Database of all Inpatient Admissions/Discharges in Sweden since 1947.

• Mallbris et. al. selected 8991 patients hospitalized for psoriasis.

• Compared Cardiovascular Mortality to general population

Eur. J Epi 2004;19:225-230

Inverted Risk for Age

2.91

1.92

2.2

1.85

1.561.71

0

0.5

1

1.5

2

2.5

3

Ischemic Heart Dis. Cerebrovasc. Dis

0-3940-59>60

Odds Ratio

Age

Eur. J Epi 2004;19:225-230

Summary

• Psoriasis appears to be an independent risk factor for CAD.

• The risk is greatest in those with severe psoriasis.

• There is an “Inverted Risk for Age”, that is, psoriasis is a greater risk factor for CAD in the younger population.

“Ok. We Have a Problem, But What Do We Do About it?”

Therapy and Prevention

ECONOMY

Associated Conventional Risk Factors

3.3 3.3

11.9

21.3

4.3 4.6

14.6

27.9

75.9

19.9

30

0

5

10

15

20

25

30

35

DM Hyperlipidemia HTN Smoking

Control

Mild Psor.

Severe Psor.

% P

atie

nts

JAMA 2006;14:1735

Conventional Risks

• Blood Pressure Control

• Smoking Cessation

• Aggressive Lipid Therapy

• Glucose Control

Disease Specific Therapy

• Does disease specific therapy for psoriasis reduce the risk for future cardiac events?

• No current large scale trials investigating this question.

• In order to study effect of disease specific therapy on cardiac risk, we need a method for detecting early CAD.

Ideal Test

• Low risk and cost to patient

• Easy to perform in serial fashion

• Reliable predictor of future cardiac events.

Invasive Assessment of CAD

Coronary Angiography

• “Gold Standard”• Limited ability to

detect early phases of atherosclerosis.

• Invasive

Intravascular Ultrasound• Small ultrasound probe that is

placed intracoronary via a guiding catheter and wire.

• Allows “look inside” vessel.• Able to detect and quantify amount

of early atherosclerotic disease.• Modality used in statin trials

investigating plaque regression with therapy.

• Requires advance skill set to perform.

• More Invasive than coronary angiography.

Summary

• Coronary angiography is of limited technical and practical use in detecting early atherosclerosis.

• IVUS can both detect and quantify amount of CAD in the early stages of atherosclerosis. It’s use for routine clinical early detection is limited by it’s invasive nature.

Non-Invasive Imaging

CT Angiography

• Uses CT technology to perform “coronary angiogram” non-invasively.

• Sensitivity “ok” for large vessels with significant stenosis.

• Poor resolution in small vessels and unable to detect early disease.

• Significant radiation and contrast dye exposure limits use for serial studies.

Coronary Calcium

• Based on theory that coronary atherosclerosis is associated with calcification of vessels.

• Detection method requires less radiation than CT angio.

• No contrast dye needed

Risk Adjusted Hazard Ratios for Coronary Event based on Age and Coronary Calcium

Score

1.94 2.56 2.1 1.93 1.52

11.6

8.86

2 31.69

22.19

44

0

5

10

15

20

25

30

35

40

45

<40 y/o 40-49 y/o 50-59 y/o 60-69 y/o 70-79 y/o

11-100101-399>400

Haz

ard

Rat

io

Age Group

Raggi JACC 2008;52:17-23

Summary

• CT angiography is of limited use in detecting early disease due its limited spatial resolution.

• Coronary Calcium scoring may be practical for early detection.

Biomarkers“Can we predict events by charting levels of stuff?”

CRP

• Coronary atherosclerosis is believed to be a chronic inflammatory disease.

• The role of CRP in the mechanism of CAD is unknown.

• It may be directly involved in the mechanism or a bystander.

CRP and CAD

1 1

1.2

1.4

1.6

1

1.51.7

2.4

3.4

0

0.5

1

1.5

2

2.5

3

3.5

4

1 2 3 4 5

LDL CRP

RR

CV

Eve

nt

Quintile

Ridker NEJM 2002;347:1557-65

CRP in a Population Based Study

1 2 4

Risk Factor

Total Cholesterol

Cigarette Use

Systolic BP

CRP

ESR

Von Willebrand

Odds Ratio for Coronary Heart Disease

N = 2459

Danesh NEJM 2004;350

Lipoprotein-Associated Phospholipase A2

• Lp-PLA2 ….NOT Lp(a)• Member of the phospholipase A2 family of enzymes.• Produced by macrophages, T lymphocytes, and mast

cells. • Hydrolyzes the sn2 ester bond in phospholipids

whose fatty acid moiety has been shortened or altered by oxidation to yield oxidized fatty acid and lysophosphatidylcholine.

• These metabolites have proinflammatory properties16, and lysophosphatidylcholine has been shown to have adverse effects on endothelial function.

Lp-PLA2 Adverse Cardiac Events

100

95

90

85

0 1 2 3 4

Years

% F

ree

of M

AC

E

16.4-199.5

199.9-266.3

266.5-884.7N = 504

P = 0.009

Brilakis EurHeartJ 2005;26:137-144

Long Term Longitudinal Population Based Study

100

90

80

70

60

50

5 10 15 20

Years

% F

ree

MA

CE

1st Quartile

LP-PLA2 by Quartile

2nd Quartile

3rd Quartile

4th Quartile

Daniels JACC 2008

Lp-PLA2: Coronary Endothelial Dysfunction ( N=172)

1.8

2.2

1.2

1.2

3.3

0 1 2 3 4 5 6 7

Triglycerides

HDL <40

LDL >160 mg/dl

Total Cholesterol>200mg/dl

Lp-PLA2 > 240ng/ml

Odds ratio (95 percent confidence interval)

Yang ATVB 2006;26:106-11

Summary

• Many biomarkers exists.• CRP has been shown to be predictive

of future events. It is however affected by numerous other factors.

• LP-PLA2 has been shown to be predictive of future cardiac events. It may also be directly involved in causing endothelial dysfunction.

Endothelial Dysfunction“Is this the cause of everything that is wrong

with me?”

Coronary Endothelium

• Function– Regulation and prevention of thrombosis.– Regulation of vasomotor tone and coronary blood flow.

Smoothmuscle cells

Smoothmuscle cells

ONOOONOO––ONOOONOO––

EndotheliumEndotheliumEndotheliumEndothelium

TxATxA22TxATxA22Foam cellFoam cellFoam cellFoam cellTNFTNF

ILsILsTNFTNFILsILs

GlucoseGlucoseGlucoseGlucoseMonocytesMonocytesMonocytesMonocytes

ONOOONOO––ONOOONOO––NO NO NO NO

PlateletsPlateletsPlateletsPlatelets

GlucoseGlucoseGlucoseGlucoseThrThrThrThr NONONONO

MCP-1MCP-1MCP-1MCP-1SelectinsSelectinsSelectinsSelectinseNOSeNOSeNOSeNOS

PLCPLCPLCPLC

PKCPKCPKCPKCDAGDAGDAGDAGET-1ET-1ET-1ET-1

NAD(P)H OxNAD(P)H OxNAD(P)H OxNAD(P)H Ox OO22--OO22--

OO22--OO22--

NAD(P)H OxNAD(P)H OxNAD(P)H OxNAD(P)H Ox

cGMPcGMPcGMPcGMP

ETETBBETETAA

NFkBNFkBO2O2NFkBNFkBO2O2 PGIPGI22PGIPGI22 PGISPGISPGISPGIS COX-2COX-2COX-2COX-2

ICAM-1ICAM-1VCAM-1VCAM-1ICAM-1ICAM-1VCAM-1VCAM-1

Clinical Consequences of Endothelial Dysfunction

• Coronary Endothelial Dysfunction is clearly associated with adverse cardiac events.

• May be considered a marker for early CAD

Endothelial DysfunctionIn Patients with Psoriasis

8.2

6.3

0

1

2

3

4

5

6

7

8

9

Control Psoriasis

Flow Mediated Dilation (%)

Arthritis Care & Research 2007;57:287

P < 0.04

Assessment of Endothelial Function

• Invasive

• Brachial Flow Mediated Dilation

• Peripheral Artery Tone

Endothelial Function Protocol

Infusion catheterInfusion catheterDoppler wireDoppler wire

DiagnosticDiagnosticangiographyangiography

Adenosine ICAdenosine IC24-36 µg24-36 µg

AchAch 1010-6-6 Ach 10Ach 10-5-5 Ach 10Ach 10-4-4 NTGNTG

Hemodynamic dataHemodynamic dataDoppler velocityDoppler velocity

Diagnostic angiogramDiagnostic angiogram

Brachial Flow Mediated Dilation

• Measure Brachial Flow at rest and after occlusion.

• Correlates with future cardiac events.

• Non-invasive• Technically

demanding

Peripheral Artery Tone

• Non-Invasive• Less Technically

Demanding than Brachial flow.

• Correlates with invasive coronary endothelial functional assessment.

Summary

• Endothelial dysfunction occurs during the early stages of CAD.

• Assessment of endothelial function can be used as a method to detect early disease progression and regression.

• Invasive and Non-invasive methods exist.

Conclusion

• Severe psoriasis is associated with an increased risk of CAD.

• The risk is highest in younger patients.• Future studies are needed to determine

if systemic therapy reduces this risk.• These studies should included

biomarkers and assessment of endothelial function.

“The good physician treats the disease; the great physician treats the patient

who has the disease.”