Psoriasis and Risk of Coronary Artery Disease by alicejenny

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									Psoriasis and Risk of Coronary Artery
     Disease: Detection of Early
           Atherosclerosis




           Eric H. Yang, MD, FACC
       Assistant Professor of Medicine
      Director of the Coronary Care Unit
           Interventional 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?
                “The good physician treats the disease;
                  the great physician treats the patient
                         who has the disease.”




William Osler


                “Why? Why do you care what happens
                        outside of America?”
                                            July 2, 2008




George Bush
                  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
Leading Causes of Death for All Males and Females
                                        United States: 2002

                      500
                                    Cardiovascular
                                                                 Males
Deaths in Thousands




                                       Disease
                      400                                        Females


                      300

                      200

                      100

                        0
                            A   B     C     D        E   A   B   D   F     E

    A Total CVD                 D Chronic Lower Respiratory
    (Preliminary)               Diseases
    B Cancer                    E Diabetes Mellitus
    C Accidents                 F Alzheimer’s Disease
                                                          Source: CDC/NCHS
                     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 Psoriasis
                        Multivariate 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 Psoriasis
                          Multivariate 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 MI
                                      Based on Patient Age


                    10
                                                       Severe Psoriasis
                                                       Mild Psoriasis

                                                    Inverted Risk For
Relative Risk                                              Age




                    1.0




                     .5

                          20     30   40       50         60      70      80


                                           Age (years)
JAMA 2006;14:1735
                             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


                    3        2.91                                      0-39
                                                          Age          40-59
                   2.5                                                 >60
                                     2.2

                    2                              1.92
                                                                1.85
                                            1.71
   Odds Ratio                                                           1.56
                   1.5



                    1



                   0.5



                    0
                             Ischemic Heart Dis.   Cerebrovasc. Dis


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.
     ECONOMY




“Ok. We Have a Problem, But
 What Do We Do About it?”
     Therapy and Prevention
                     Associated Conventional Risk
                      35
                               Factors
                                   Control
                                   Mild Psor.
                                                                                               30
                      30           Severe Psor.
                                                                                        27.9


                      25
        % Patients




                                                                                 21.3
                                                                          19.9
                      20

                                                                       14.6
                      15
                                                                11.9

                      10
                                       7
                                                          5.9
                                 4.3                4.6
                       5   3.3                3.3



                       0
                                 DM          Hyperlipidemia            HTN         Smoking
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

                    45             44
                                                                                11-100
                    40                                                          101-399
                    35                                                          >400
     Hazard Ratio




                    30

                    25                         22.19

                    20

                    15
                            11.6
                    10                     8.86

                     5                  2.56                               3
                         1.94                           2.1 2       1.93        1.521.69
                     0
                          <40 y/o       40-49 y/o       50-59 y/o   60-69 y/o    70-79 y/o
                                                       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
                            4


                           3.5               LDL             CRP                                               3.4


                            3
             RR CV Event




                           2.5                                                                 2.4


                            2
                                                                               1.7
                                                                                                     1.6
                                                           1.5
                           1.5                                                       1.4
                                                                     1.2
                                 1       1         1
                            1


                           0.5


                            0
                                     1                 2                   3               4               5

                                                                   Quintile

Ridker NEJM 2002;347:1557-65
                              CRP in a Population Based Study

             Risk Factor
             Total Cholesterol

             Cigarette Use

             Systolic BP                                N = 2459

             CRP

             ESR

             Von Willebrand


                                 1               2                 4

                                 Odds Ratio for Coronary Heart Disease
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

                                                             16.4-199.5
                           95
          % Free of MACE




                           90                                199.9-266.3



                           85        N = 504
                                                             266.5-884.7
                                     P = 0.009


                                 0        1      2       3                 4

                                                 Years




Brilakis EurHeartJ 2005;26:137-144
        Long Term Longitudinal Population Based
                        Study
                          100
                                         LP-PLA2 by
                                           Quartile
                          90
            % Free MACE




                          80                          1st Quartile

                                                      2nd Quartile
                          70
                                                      3rd Quartile

                          60                          4th Quartile


                          50



                                5   10          15      20

                                    Years
Daniels JACC 2008
                   Lp-PLA2: Coronary Endothelial
                        Dysfunction ( N=172)

              Lp-PLA2 > 240
                                                              3.3
                  ng/ml
            Total Cholesterol
                                        1.2
               >200mg/dl

             LDL >160 mg/dl             1.2

                   HDL <40                          2.2


                Triglycerides                 1.8

                                0   1         2           3         4   5    6    7
                                    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
                                        Platelets
                                                Monocytes
                    Glucose                                      Glucose
                               Thr NO

     DAG          PLC                MCP-1Selectins
                                                                          Endothelium
                                                     ICAM-1
     ET-1         PKC        eNOS                   VCAM-1 PGI2PGIS COX-2
            NAD(P)H Ox O2-                    NFkBO2

                                                               ONOO– TxA2
                   O2-      NO     ONOO– TNF               Foam cell
                                            ILs
          ETB
    ETA         NAD(P)H Ox
                             cGMP                                         Smooth
                                                                          muscle
                                                                          cells

• Function
  – Regulation and prevention of thrombosis.
  – Regulation of vasomotor tone and coronary
    blood flow.
    Clinical Consequences of
     Endothelial Dysfunction

• Coronary Endothelial
  Dysfunction is clearly
  associated with adverse
  cardiac events.
• May be considered a
  marker for early CAD
                    Endothelial Dysfunction
                              In Patients with Psoriasis

                          9
                                         8.2
                                                  P < 0.04
                          8

                          7
                                                    6.3
                          6

     Flow Mediated
                          5
      Dilation (%)
                          4

                          3


                          2

                          1


                          0
                                        Control   Psoriasis




Arthritis Care & Research 2007;57:287
   Assessment of Endothelial Function


• Invasive
• Brachial Flow Mediated Dilation
• Peripheral Artery Tone
 Endothelial Function Protocol
 Diagnostic   Adenosine IC
angiography     24-36 µg


          Ach 10-6   Ach 10-5   Ach 10-4    NTG


                      Hemodynamic data
                        Doppler velocity
                     Diagnostic angiogram



Infusion catheter
  Doppler wire
      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.”

								
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