08 01 18 Hunter Champion Presentation by gK7QZS

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									                        Disclosures
 • Financial Disclosures Relevant to this
   Presentation: None
 • Other Financial Disclosures: Speakers Bureau
   for Pfizer, GlaxoSmithKline, Novartis
 • Basic Science Grant to study PDE5A
   inhibition in models of COPD: Pfizer
 • Non-FDA Approved uses
     – None
Hunter C. Champion, MD, PhD
Pulmonary Hypertension
and Right Heart Failure in
      Scleroderma
  Hunter C. Champion, MD, PhD


       Division of Cardiology
       Department of Medicine
      Johns Hopkins University
        Baltimore, Maryland
               Acknowledgements
Johns Hopkins Hospital   Johns Hopkins Scleroderma Center
Baltimore, Maryland      Fred Wigley, MD
David A. Kass, M.D.      Laura Hummers, MD
Eiki Takimoto, MD, PhD   Francesco Boin, MD
Robert Wiess, MD         Peter Wung, MD
Anna Hemnes, MD
Paul Forfia, MD
Mobusher Mahmud, MD      NIH Pulmonary Hypertension
Tommy Mulhearn, MD          SCCOR
Ryan Tedford, MD         AHA Scientist Development Award
David Majure, MD         WW Smith Foundation
                         Bernard Family Foundation
Paul Hassoun, MD         PVRI
Reda Girgis, MD
Ari Zaiman, MD, PhD
Fred Wigley, MD
John Conte, MD
John Orens, MD
        200
        150
        100
        50
        0
              0   10 20 30 40




NOS3

GAPDH
JHH PAH Patient Survival 2001-2005

                     100
                                                                IPAH

                      75
  Percent survival




                      50

                                                                PAH-SSc
                      25

                               Log-rank p-value=0.002
                      0
                           0              1            2         3        4
                                                    Time (yr)
   Putting the Survival Curve into
             Perspective
• 70 patients in each group
• SSc patients had same mean PA pressure
  (39.5 ± 5.2 mmHg)
• SSc patients were not limited by comorbid
  state
• Patients died from RV failure or sudden
  death
• All were treated with bosentan, prostacylin,
  or investigational drugs
      Thinking differently about the
                disease
• Pulmonary HTN is not just
  high pressure and an
  elevated PVR
                                     Pulmonary Hypertension
• Patients don’t die from high
  pulmonary pressures. They                ?      ?
  die from the failure to
  compensate for the high
  pressures

• Perhaps our treatment
  currently has very little little
  or nothing to do with the
                                             BOTH
  small resistance arterioles
Not just IPAH
       Diagnosis   Prevalence (per   % with P(A)H                    Reference
                       million)
IPAH                     6               100        Humbert M. Am J Respir Crit Care Med.
                                                    2006;173:1023-1030
Group I PH               15              100

ESLD                   ?1,260            2-5        Perez A. J Gastroenterol Hepatol. 2004;19:289-
                                                    95
                                                    Budhiraja R. Chest. 2003;123:562-76
HF                     20,000            ?1-2       Butler J. J Am Coll Cardiol. 1999;34:1802-6
                                     (36 in class
                                        III/IV)
IPF                     430            ?40-80       Raghu G. Am J Respir Crit Care Med.
                                                    2006;174:810-6
                                                    Gagermeier J. Chest. 2005;128(Suppl):601S
                                                    Nadrous H. Chest. 2005;1128:2393-9
COPD                   40,000            ?1-2       www.cdc.gov/nchs/nhis.htm
                                        (10 in      Naeije R. Proc Am Thorac Soc. 2005;2:20-2
                                      advanced)
CTEPH                    15              100        Pengo V. New Engl J Med. 2004;350:2257-64
                                                    Tapson V. Proc Am Thorac Soc. 2006;3:564-7

Sarcoidosis             250               ?6        Fisher K. Chest. 2006;130:1481-8
                                        (74 in      Ryu J. Mayo Clin Proc. 2007;82:342-50
                                      advanced)
      We have gotten better

• Mean PA pressure in SSc patients
  2002: 43.68 mmHg
• Mean PA pressure in SSc patients
  2007: 28.91 mmHg

• Earlier treatment is having an impact
           THE PROBLEM
 PA = All PAH drugs have a modest effect on
               mPAP at best
RV=Difficult to measure given interdependence
          with pulmonary circulation

The RV may not hold on while we try to reverse
   remodeling of the pulmonary circulation
There is a need to develop techniques to study
               RV-PA Coupling

    There is a need to move away from the
          “looks OK to me” mentality
             Sildenafil inhibits (and reverses) LVH induced
                   By transaortic constriction in mice
                                       B        3wk           9 wk



                              -Sil




                              +Sil




                              -Sil




                              +Sil




Takimoto, Champion, et al. Nature Medicine 2005; 11:214-222
       PDE5A: Localization to z-band
    DAPI        aActinin




    PDE5        Both




   Isolated myocyte/myofibril   Immuno EM
unpublished
Pulmonary Arterial Constriction (PAC)
Sham   PAC
Measurements in the Intact-chest Mouse




                            Left Anterior                              Right Anterior Oblique


                               1 cm/sec
                                 CO=10.4 mL/min
           D 0.4º C




                      20 mL 0.9% NaCl @ 23 º C
Champion HC et al. Am J Physiol Heart Circ Physiol. 2000;278:H8-H15.
      Simultaneous RV and LV PV Loops

                         125                               125


                         100                               100
      Pressure (mm Hg)




                          75                                75


                          50                                50


                          25                                25


                           0                                 0
                               0   20     40     60   80         0   20     40     60   80
                                     Volume (mL)                       Volume (mL)



Mouse exposed to TAC 1 wk.
      PDE-5A Activity in the RV Increases
                  With PAC
       PDE-5A inhibition results in marked increase in
                PKG activity in PAC hearts

           Total cGMP-PDE              Relative PDE-5A                            PKG Activity
                Activity                   Activity                                in the RV
                                                   60%
    200            *                             *   *                       80
                                  60                                                           *
                                        40%




                                                           (FU/mg protein)
    150                                                                      60
                                  40
(FP) 100                    (%)                                              40

     50                           20                                         20

      0                            0                                          0
            Con   2wPAC                Sil Tad   Sil Tad                          Sham      2wPAC

                                        Con      2wPAC                            Vehicle     Sildenafil

 Hemnes AR and Champion HC. Unpublished
    Effect of Chronic PDE-5A Inhibition:
                Remodeling
                                    CON                          PAC                          PAC+sildenafil




                                   30          *
           Myocyte diameter (µm)




                                                                                               *
                                                                                    6
                                   20                  **


                                                                       % fibrosis
                                                                                    4
                                   10
                                                                                    2
                                                                                                       **
                                    0                                               0
                                        CON   PAC    PAC                                CON   PAC     PAC
                                                    Sildenafil                                       Sildenafil


Hemnes AR and Champion HC. Unpublished
          Effect of Chronic PDE-5A Inhibition
                 on RV Hemodynamics
                           ESP                            PMX/EDV
                    75                                                  †
                                     *   *           40                     CON
                                                                            Sild
                    50                               30                     PAC




                                             mm Hg
       mm Hg




                                                     20                     PAC+Sild
                    25
                                                     10

                     0                                0

                          dP/dtmin                          TAUD
                     -8                              6
                                                                    †
    mm Hg/s × 103




                    -10
                                             msec

                                                     4
                                         †
                    -12
                                                     2
                    -14

                    -16                              0

Hemnes AR and Champion HC. Unpublished
 Influence of Sildenafil on Survival With
              Moderate PAC

          100


              75
                                                   PAC + sildenafil (n=9)
              50
      %
   survival
                                                                        p=0.0027
              25

                                              PAC + vehicle (n=9)
               0
                   0   25      50       75        100     125     150
                                       Time (d)

RV ESP= ~35 mm Hg.      Hemnes AR and Champion HC. Unpublished
            PDE5A Promotes Hypertrophy
                a                                                                      b                                                            e
                                                                                                                    400   P<0.0001




                                                                                                cGMP-PDE Activity
                                                        AdPDE5A (MOI)                                                     n=4
                                                                                                                                              #
                                                                                                                    300                  #              Adgal




                                                                                                   (% Control)
                                  Control           50          100   200
PDE5A
                                                                                                                    200
                                                                                                                                   *
                                                                                                                    100


                                                                                                                     0
                                                                                                                           C       25    50   100
                                                                                                                               AdPDE5A (M OI)
             c                                                                         d
                       2500
                                   P<0.0001
                                                                                                2500
                                                                                                                    P<0.0001            **              AdPDE5A
                                   n=6                                                                              n=6
   Cell Area ( m m )




                                                                            Cell Area ( m m )




                       2000                                                                     2000
                                                                                                                               *
   2




                                                                            2




                       1500                                     *                               1500

                       1000                                                                     1000

                       500                                                                        500

                         0                                                                              0
                                                                                                                                                    Sarcomere Organization
                                    tro
                                       l           al        5A                                                   ol          al         A
                                  on             g         E                                                 ntr           g        E5
                              C             Ad            PD                                                Co           Ad         PD
                                                        Ad                                                          AII
                                                                                                                       +
                                                                                                                                +A
                                                                                                                                   d
                                                                                                                             AII
The RV: “The Evil Side of the Heart”
             Cardiac Geometry in PH
              Short Axis View                             Long Axis View
        Normal            Pulmonary Hypertension

A                         B                         C    PH




 RV
              LV
 20
          120 mm Hg             RV       LV
mm Hg                                                      Normal


                                                            RV        LV




                                                   • Overall shape of RV more
                                                     conducive to traditional
                                                     measures of Ees and Ea
              Challenges in Assessing the
           Right Ventricle: Complex Geometry




    • Thin-walled, crescent-shaped
    • Intricate interdependence
      between loading conditions and
      performance
    • Linked to left ventricle

                                                    Courtesy of Kirk Spencer, MD and Lissa Sugeng, MD, MPH,
Voekel NF et al. Circulation. 2006;114:1883-1891.   University of Chicago.
         Reverse RV Remodeling Post PA
      Thromboendarectomy in CTEPH (n=17)
                                                                     MRI Short-Axis Images

                                   p<0.0001
                                            NS




                                                         Basal
                   0.4        p<0.001
                   0.3
Curvature (cm-1)




                   0.2
                   0.1
                   0.0
                   -0.1
                   -0.2   Before    After     Controls
                           PEA      PEA        (n=12)


                                                                 Before PEA          After PEA

Datea are mean ± SEM.
Reesink HJ et al. J Thorac Cardiovasc Surg. 2007;133:58.
                           RT3DE RV Analysis
                                     ES
                                                                                 Acquiring volumetric
 ED
                                                                                       data set
                                                                           •Create parallel
                                                                           tomographic short-axis
                                                                           slices
                                                                           •Trace area of each short
                                                                           axis
                                                                           •Similar to MRI RV EF




Courtesy of Kirk Spencer, MD and Lissa Sugeng, MD, MPH, University of Chicago.
       FDG PET Images of Patient With PPH
    Before and After Therapy With Epoprostenol
                   for 3 Months




Oikawa M et al. J Am Coll Cardiol. 2005;45:1849.
    Drawbacks to Newer Testing

• Expense
• Not easy
• Not necessarily good for the masses


• Is there something that we can do from a
  hemodynamic standpoint?
             Human Ventricular Myocytes
       PDE-5A            a-actinin       Overlay                                   100
                                                                                                          Isolated Myocytes            Whole Myocardium




                                                       independent PDE Activity)
                                                                                                                                            * *




                                                          (% Ca2+/calmodulin
                                                            PDE5A Activity
                                                                                                                *
NF                                                                                   50

RV
                                                                                         0
                                               25 mm                                                  NF         F                NF         H         F



                                                                                                              NF         Hypertrophy         Failure


 F                                                     PDE5A


RV                                                                                                    4                       P=0.0256




                                                                        (Arbitrary Units Normalized
                                                                        PDE5A Protein Expression
                                                                                                                     P=0.0167
                                                                                                                                         P=0.8606
                                                                                                      3




                                                                               to Nonfailing)
                                                                                                      2    n=6-7

 F                                                                                                    1
LV
                                                                                                      0
                                                                                                            Nonfailing    Hypertrophy            Failing

                                                                                                                   Whole Myocardium

Hemnes AR and Champion HC. Unpublished
 PDE-5A Activity in Human Myocardium
                          20                                                                     75
       PVR (Wood units)

                                   n=24                                                                    n=24




                                                                                   TPG (mm Hg)
                                   r 2=0.4323                                                              r 2=0.5396
                          15
                                   p=0.0005                                                      50        p < 0.0001
                          10

                                                                                                 25
                           5


                          0                                                                        0
                               0   10   20    30   40   50   60   70   80   90                         0    10   20    30   40   50   60   70   80   90


                          75                                                                     3.0
                                   n=24
    mPAP (mm Hg)




                                   r 2=0.5076


                                                                                 TAPSE (cm)
                                                                                                 2.5
                          50       p < 0.0001
                                                                                                 2.0

                          25                                                                               n=24
                                                                                                 1.5
                                                                                                           r 2=0.2215
                                                                                                           p =0.0203
                          0                                                                      1.0
                               0   10   20    30   40   50   60   70   80   90                         0   10    20    30   40   50   60   70   80   90

                                             PDE-5A Activity                                                          PDE-5A Activity

Hemnes AR and Champion HC. Unpublished
Expression of RhoA / ROCK in Human
    PAH/SSc PAH Heart Biopsies
              Control    IPAH     SSc-PAH




       RhoA




               Control   IPAH   SSc-PAH

     Rho
    kinase
PKC-alpha Activity (Heart Failure “Switch”)

                                           PKCa Activity
                       400                                                      **
                                                                                *
                       300
         (% Control)




                       200
                                            *                          *
                       100


                        0
                                 ol




                                                      F)
                                            )




                                                                   )


                                                                               )
                                         VD




                                                                 VD


                                                                             VD
                               tr




                                                   VE
                             on



                                        R




                                                                R


                                                                            R
                                                  R


                                                            ild
                                      re




                                                                           re
                         C




                                                  L
                                    e




                                                                       ve
                                                (N


                                                           (m
                                 ev




                                                                      e
                                            c
                                (s




                                                                   (s
                                                       c
                                           SS


                                                      SS
                           H




                                                                   c
                                                                SS
                         PA
  Data suggest that a greater proportion of patients
  with SScPAH die from right heart failure than in
  other forms of PAH?


                     Why?

•Greater arterial load?
•More advanced RV dysfunction?
•Combination of the two; aka Poor RV-PA coupling?
     Common Misconceptions…

• BP is measure of afterload; BP results from
  interaction b/w cardiac function (ie, force of
  contraction/volume ejected) and arterial circuit
  (would make ventricle source of its own afterload)
• Wall stress is afterload (PD/h)—When? Wall
  stress is time-varying, with changes in chamber
  geometry and wall thickness through systole
• Resistance is only component of ventricular
  afterload  especially untrue in system where
  pulsatility is exaggerated, ie, aging, HTN
  (systemic or pulmonary), COPD, hypoxemic
  diseases, and Scleroderma
The Arterial Circuit as Load
                Interface 1
                              Nl 2m/s

                PA PWV
                               PAH >4 m/s


                                  Interface 2




                         Distance to site of
                         reflection 25 cm
  Getting More From the RHC
 Pressure-based Measurements

dP/dtmax
                            dP/dt max
dP/dtmin

dP/dtmax/IP
                      tau    dP/dt min
Tau           RVEDP
 Pulmonary Artery Input Impedance (Z)

• Distal catheter; PA P and                                        Resistance (0 frequency Z)
  F waveforms obtained at




                                 Modulus (dyne-sec cm-3)
  PA inlet—subjected to                                               Z1 (timing of wave reflection-
                                                                      speaks to V-A coupling)
  Fourier series—resolve P
  and F into harmonic
  components                                                       Freq 1st min (PWV)
                                                                                            Characteristic
                                                                                            impedance (large
• Graphical display of P/F                                                                  vessel stiffness)

  relationship at multiples of
  fundamental frequency
  (harmonics); 1st harmonic                                0   2     4     6     8    10     12
  is HR                                                                  (Hz)
                             Impedance Spectra in Humans
                         7
                                                   PAH-SSc (n=5)
                                                   IPAH (n=4)




                                                                        Modulus (dyne-sec cm-3)
                         6                                                                                Resistance (0 frequency Z)
                                                   Control (n=4)
  (103 dynes-sec cm-3)
  Impedance modulus




                         5                                                                                Z1 (timing of wave reflection-
                                                                                                          speaks to V-A coupling)
                                               Frequency of 1st min                                                          Characteristic
                         4                     impedance modulus                                                             impedance
                         2                                                                                    Freq 1st min
                                                                                                                             (large vessel
                                                                                                              (PWV)
                                                                                                                             stiffness)


                         1
                                                                                                  0   2   4    6   8   10 12

                                                                                                      Frequency (Hz)
                         0
                             0   2   4     6   8    10   12   14   16
                                         Frequency (Hz)




Hemnes AR and Champion HC. Unpublished
                                Effect of Sildenafil on PWV

                                                                            Baseline
                         8                                                  Sildenafil
  Frequency of 1st min




                         6

                                                                      *
                         4                            *
                                           *                 *


                         2



                         0
                             Control   IPAH    SSc        COPD    Elderly   rPVH
                              (10)      (14)   (18)        (13)    (35)      (21)


Hemnes AR and Champion HC. Unpublished
RV Pressure-Volume Loop Analysis

     60




     40




     20




     0
          0   100   200   300   400
               Effect of Sildenafil on Systolic and
                   Diastolic Function in PAH
                                                 Baseline (n=14)
                                                 Sildenafil (20 mg po tid x 4-6 mo; n=14)

               250

               200
                                                         *
  % baseline




                                         *
               150

               100
                                                                          *
                                                                                           *
                50

                0
                     mPAP        dP/dt / IP   PWRmax/EDV           dP/dtmin         Tau
                     mPAP            Systolic function                Diastolic function



Hemnes AR and Champion HC. Unpublished
              Pulmonary Vascular Stiffness
                                                                        Augmentation index
                                                                           = DP/PAPP
                     130
                                                                 sPAP
                                                         DP
                             PAPP

          Pressure                                               Pi
          (mm Hg)


                                                                                dPAP
                       20
                                    Ti                                       250 ms
                                         Systolic Time                        Time
                                               Heart Period


dPAP= diastolic PAP; PAPP=pulmonary artery pulse pressure;
Pi=PAP at inflexion point; sPAP=systolic PAP; Ti=transit time.
Differences Between IPAH and SSc-PAH
  Indexes of Wave Reflection as Measured by Time-domain Analysis


                                                 IPAH (n=7)     PAH-SSc (n=8)
      Pi (mm Hg)                                    86 ± 11        74 ± 10
      Augmentation index
                                                  0.09 ± .004    0.31 ± 0.06*
      (∆P/PAPP)
      Ti (ms)                                      125 ± 15        86 ± 12*
      Ti/systolic time                            0.42 ± 0.04    0.29 ± 0.03*
      Ti/BSA                                         70 ± 9        41 ± 4*


*p<0.05 vs IPAH. Values are means ± SD.
BSA = body surface area; Pi = PAP systolic inflection point;
PAPP = pulmonary artery pulse pressure; Ti = transit time.


Hemnes AR and Champion HC. Unpublished
  Right Heart Cath Data and Indexes of Wave
  Reflection in PAH-SSc With Sildenafil (N=6)

                                              Baseline     3-5 Mo Follow-up
       mPAP (mm Hg)                          42.5 ± 5.68      39.7 ± 6.0
       CI (L/min/BSA)                        2.25 ± 0.3       2.49 ± 0.28
       PCWP (mm Hg)                          12.8 ± 4.16      11 ± 1.79
       PVR (mm Hg/L/min)                     7.40 ± 1.58      6.15 ± 1.05
       RAP (mm Hg)                           7.67 ± 2.33      7.16 ± 2.13
       TAPSE (cm)                            1.90 ± 0.05     2.23 ± 0.09*
       Augmentation index
                                            0.38 ± 0.007     0.21 ± 0.09*
       (DP/PAPP)


 *p<0.05 compared to baseline. Values are means ± SD.
 TAPSE = echocardiographic assessment of RV function
 (tricuspid annular plane systolic excursion).

Hemnes AR and Champion HC. Unpublished
                  Treatment



                                Pulmonary
RV Hemodynamics               Hemodynamics
                 What Else are we doing?

• Endomyocardial biopsy
    • Inflammation
    • Fibrosis
    • Plaquenil toxicity
    • Pathways of Disease
• Correlating hemodynamics with non-
    invasive measures
•   Therapy for patients with mean PA
    pressures 20-25mmHg
                    How we think about PH
• RV/LV
  Interdependence


• Determinants of RV
  Failure

• Development of
  Treatments for
  RVH/Failure

• Study of Differences
  in Signaling Pathways
  in RV and LV

								
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