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Pathobiology of Pulmonary Pathobiology of Pulmonary Hypertension

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					  Pathobiology of Pulmonary
Hypertension in Congenital Heart
           Disease

          View from the ICN

           Jeffrey R. Fineman
         UCSF Children's Hospital
    Cardiovascular Research Institute
University of California, San Francisco USA
Communication Issues in CHD:
     The Hand Over
                Outline
                O tli


 P h h i l         f Pulmonary
  Pathophysiology of P l
  Hypertension 2o to CHD
   y
 Pathophysiology of Peri-operative PHT
 Therapeutic Implications
–PA Pressure >25 mm Hg at rest
>30 mmg Hg with exercise
 PVR
–PVR > 3 W d units
         Woods i
Dana Point 2008, JACC
Pulmonary Vascular Alterations in CHD
P l       V    l Alt ti        i

 Increased Pulmonary        Increased Pulmonary
  Blood Flow/Pressure         Venous Pressure
      Truncus Arteriosus         TAPVR
      A-V Septal Defects         Cor Triatriatum
      VSD/ASD/PDA                Mitral Valve Disease
      D-TGA                      LV Dysfunction
      SV Physiology              SV Physiology
Pathobiology of Pulmonary Vascular
Disease
           Gaine, S. JAMA 2000;284:3160-3168.




Rabinovitch, Clin. Invest. 118(7): 2372-2379 (2008)
                     REVERSIBLE
Grade A:                      Altered Reactivity
Abnormal extension
Mild medial hypertrophy

Grade B:                      Altered Reactivity
Abnormal extension                     y yp
                              Pulmonary Hypertension
Mod-severe medial
hypertrophy

Grade C:                      Altered Reactivity
Abnormal extension
                              Pulmonary Hypertension
Severe medial hypertrophy
                              Vascular Disease
 arterial size and #
                 IRREVERSIBLE
Natural History of Pulmonary Vascular
    Disease Associated with CHD

                        Increased Pulmonary Blood Flow
      Defect                      Risk of PVD                  Age
 Truncus Arteriosus                   100%                  <2 years
    AV
    A-V Canal                         100%                    2 years
       VSD                           15-20%                 >2 years
       PDA                           15-20%                 >2 years
  TGA with VSD                      70-100%                     y
                                                            1-2 years
       ASD                            20%                   >20 years
                      Increased Pulmonary Venous Pressure
       Defect                     Risk of PVD                Age
 Obstructed TAPVR                   Variable                Variable
  Cor Triatriatum                   Variable                Variable
  Mitral Stenosis                   Variable                Variable
                    ETIOLOGY

 Endothelial Disease
 Extracellular Matrix
  Disease
 Potassium Channel
  Disease
 Coagulation Disorders
 Genetic Disease
 Inflammatory Disease
McGoon M D, Kane G C Mayo Clin Proc. 2009;84:191-207
                  /
        PRESSURE +/or FLOW

           ENDOTHELIAL INJURY


               ALTERATIONS IN

  VASOACTIVE        ROS         EXTRACELLULAR
   FACTORS                          MATRIX




                            VASCULAR
VASOCONSTRICTION           REMODELING
  Pulmonary Endothelial Dysfunction in
      Pulmonary Vascular Disease
      P l       V     l Di



 Histologic Abnormalities
 Altered Von-Willebrand Factor
          Von Willebrand
 Imbalance in Eicosanoid Metabolism
 Alterations in the NO-cGMP Cascade
 Alterations in Endothelin-1
                 Endothelin 1
                                                                                                                                                                  Normal Pulmonary Artery
The image cannot be display ed. Your computer may not hav e enough memory to open the image, or the image may hav e been corrupted. Restart y our computer, and then open the file again. If the red x still appears, y ou may hav e to delete the image and then insert it again.
                                                                                                                                                                                                                                                                                     Hypertensive Pulmonary Artery
Normal Pulmonary Artery   Hypertensive Pulmonary Artery
  Prostaglandins and Congenital
     Heart Disease (Human)

D        d i              t b lit    d
 Decreased urinary PGI2 metabolites and
 increased TX metabolites in advanced
 disease

 Decreased PGI2 lung expression in
  advanced disease
       Thromboxane t Prostacyclin ratio in
       Th   b      to P t     li    ti i
                     CHD
                     6


                                       Qp/Qs
                                       Q /Q > 2
                     5


                                               g
                                       Eisenmenger
                     4


             THX/                       Control
             Prost
             P t     3




                     2




                     1




                     0
                                   1




Adatia et al. Circulation, 1993.
Prostacyclin Synthase Expression is Decreased
  in Advanced Pulmonary Vascular Disease




Tuder et al.
  NO and Congenital Heart Disease
            (Human)
 Early and late impaired endothelium-
  d     d t l               dil ti
  dependent pulmonary vasodilation


 Decreased eNOS gene expression in
  advanced disease
        p
eNOS Expression is Decreased in
 Patients with Advanced PHTN




                    Giaid et al. NEJM, 1995
Aortopulmonary shunt: Experimental
             d l f
          model of CHD
Progressive Impairment of Endothelium-Dependent
             Pulmonary Vasodilation
Progressive Decrease in the NOx/NOS Activity Ra
Increased Superoxide and Nit t d P t i
I       dS        id    d Nitrated Proteins
             in Shunt Lambs
    O2- Can Decrease Bioavailable NO
      Smooth Muscle Cell                       Impaired
                                               Vasodilation
        NADPH               O2-
        Oxidase
                                                sGC



                             O2-
          ONOO-
                                                      Bioavailable
?                           NO     NO                    NO



                                      NO
       ET 1
       ET-1                                         L- Arginine
                                                    L

                                              NOS


                           Endothelial Cell
Endothelin mechanism of action
         in th l
         i pathology

    ET
   ETB
                                Big ET-1
                Extravasation   ECE
                Inflammation

                                  ET
   PGI2 NO




  Relaxation
               Contraction
               Proliferation     Fibrosis
 ET-1 and congenital heart disease
             (Human)
             (H      )

 Increased plasma ET-1 concentrations in
  children with CHD and increased PBF


 Increased ET levels and preproET-1 gene
    p
  expression in advanced PH disease
   Yoshibayashi et al. Ci
   Y hib                  l ti  1991; 84 2280 5
             hi t l Circulation 1991 84:2280-5.


                                                p<0.005
             24                                                                                 p<0.001
                                                                                       5
                                         p<0.005
             22
                                                 §§
                                                             **                        4
             20                            §§
                                                   **
             18                                                                        3
Plasma ET-LI                                                           ET-LI (PV-RV)
concentration        §               §                                    (pg/ml)
   (pg/ml)    16             §
                         *                 *                                           2
                                 *
             14
                                                                                       1
             12

             10                                                                        0
              0
                     VC RA RV PA                        PV                                 PH             Non-PH


                   Sampling site in patients                      Normal
                   with congenital heart defects                  subjects
Increased ET plasma levels and ET production
      in  l         t i lh      t   i
      i pulmonary arterial hypertension

                        30         ***

                        25
               pg/ml)




                                                    Normal
                -1




                        20
        sma ET-
       ration (p




                        15
    Plas
 oncentr




                        10
                                                          PAH
co




                        5


                        0
                             PAH         Control
                                                   Giaid A, et al. N Engl J Med 1993; 328:1732
ET-1 Cascade – L b Summary
ET 1 C    d    Lamb S

   Alterations of ET-1 cascade
     I       d ET-1 levels – 1 week
      Increased ET 1 l   l         k
     Loss of ETB mediated vasodilation – 1 week
      Increased ETA protein – 4 weeks
      Increased ETB protein – 8 weeks
      Emergence of ETB-mediated constriction – 8
     weeks
One-week-old lambs
O      k ld l b



               600             *

               500

               400
 Lung tissue
 L     ti
     ET-1
               300
   (pg/gm)
               200

               100

                 0

                     Control
                     Shunt
One-week-old lambs
O      k ld l b



                                1.25


                                1.00
                                                 *

                       Relative 0.75
                     ETB receptor
                       protein
                                0.50
                                0 50


                                0.25


                                0.00

                                       Control
                                       Shunt
Four-week-old lambs
F       k ld l b

                      Relative ETA receptor protein


                      3.0                  *

                      2.5

                      20
                      2.0

            3         1.5

                      1.0

                      0.5

                      0.0
                             Control     Shunt
8-Week-old l b
8 W k ld lambs



                    Control   Shunt

     ETB receptor
           +
      SMC actin



             p
     ETB receptor




      SMC actin
      CPB-Induced Alt
      CPB I d           ti
                d Alterations

 Ischemia-Reperfusion Injury


 Inflammation


 Endothelial Injury
                          g
      Alterations Following CPB
 Increased Pulmonary Vascular Resistance

 Increased Pulmonary Vascular Reactivity

 Parenchymal Lung Injury

 Myocardial Dysfunction

 Capillary Leak
         y              y
 Pulmonary Endothelial Dysfunction
            After CPB
       l             l
 Histologic Abnormalities
          Von Willebrand
 Altered Von-Willebrand Factor
 Imbalance in Eicosanoid Metabolism

                     NO cGMP
 Alterations in the NO-cGMP Cascade
 Alterations in Endothelin-1
                      Time course of endothelin
                      after CPB in CHD patients
                      15       p<0.05 vs m-PH
                           *                                       #
                                                                       §
                                                                               #
                                                                                   §
                           #   p<0.05 vs LF                        *          *
                           §   p<0.05 vs before CPB   #
                                                          §
  ndothelin (pg/ml)




                                                      *
                      10                                                               §

                                                                                   §        s-PH
                                                                                           §
                           #                              §   *                              LF
                           *        *                                              §
                       5                                                                    m-PH
 En




                       0
                       Before Before After After                  3 hrs       6 hrs 24 hrs
                         CPB rewarm rewarm CPB                             After CPB
CPB = cardiopulmonary bypass; LF = low pulmonary blood flow;
m-PH and s-PH = mild and severe pulmonary hypertension.
                                                      Hiramatsu T et al. Ann Thorac Surg 1997; 63:648-52.
       Peri-op
       Peri op PHT: Clinical Issues
 A t P i           i d f t            ti it
  Acute- Peri-op period of extreme reactivity
      CBP-induced endothelial injury, ROS generation,
       inflammation, and ischemia
                   ,
        –RV Failure
        –Hypoxemia
        –Cardiopulmonary failure
 Sub-acute- Vascular remodeling
      Increased PVR
      RV Dysfunction
 Chronic- PHT
      Advanced pulmonary vascular disease
      “modest” remodeling limits SV options
            PATHOPHYSIOLOGY OF PHT CRISES
                                     PAP

Metabolic                                                    Hypoxia
Acidosis                                                    Respiratory
                                                             Acidosis




            RV Failure       RVEDP            Dead Space
            Ischemia         RVEDV            Ventilation



           y
        Arrythmias
                         Septal Shift
 Cardiac
 Output

                LVEDV                   PBF + Airway            V/Q
                                         Obstruction         Mismatch
      Recognition of PHT Crises
      R     iti    f     Ci

 Increase PAP
 I        i     P
  Increase in RA Pressure
 Decrease in Systemic Saturation
               y
 Decrease in SAP
 Stiff Chest Wall
                    Endothelial Based Therapies
Arginine
                              Alter ROS
                 L-Arginine                          Prepro-ET-1

                                                      Big ET-1
                 eNOS
   EC                                                ECE-1
                                                     ECE 1          EC
                   NO                      ETB        ET-1
                                                                     BQ123
                        Sildenafil                                  Bosentan
iNO               sGC
                                                      ETA
sGC
Activators
                              PDE5
                 cGMP                GMP


               Vasodilation                      Vasoconstriction
             Anti-mitogenesis                      Mitogenesis        ETB
                                      SMC
Never surrender!!!
    Nitric Oxide After CPB:
     Pulmonary Circulation
                  h l
 Decreased endothelium-dependent
  p       y
  pulmonary vasodilation.

 Decreased basal NO and cGMP
D        db   l      d GMP
 p
 production??
  – Decreased exhaled NO concentrations.
  – Plasma NO metabolites and cGMP??
Beghetti et al. Ann Thorac Surg 1998
Hiramatsu et al. Ann Thorac Surg, 1997.
                         y
 NO Alterations: Pulmonary
        Circulation


 Impaired Agonist-Induced NO
  Activity
  A ti it

 Impaired Basal NO Production????
    Endothelin-1
    Endothelin 1 After CPB

 Increased Plasma Concentrations

 Plasma ET-1 correlates with Post-Op
            Hemodynamics.
  Pulmonary Hemodynamics
                   Summary

 AT ONE-WEEK
                    ET-1
      Alterations of ET 1 cascade
        – Increased ET-1 levels
        – Increased ECE-1 protein
                         p
        – Decreased ETB protein and loss
          of ETB -mediated dilation
                      Summary

 AT 8-WEEKS
                    ET-1
      Alterations of ET 1 cascade
       –Increased ET-1 levels
       –ETA protein
                      p
       –Increased ETB protein
             Emergence of ETB-mediated
       constriction
ET levels correlate with NYHA
class and ventricular impairment
         ANOVA p<0 0001
               p<0.0001                                      p<0.01
                                                       ANOVA p<0 01
                                                                                  l/
                                                                               pmol/L
                                                                   p<0.05

pmol/L                                                       p<0.01
                          p=0.0003
                          p                              p=0.001
                                                         p=0 001
 3.5                                                                                6
                   p<0.0001

 3.0                                                                                5
 2.5         p<0.05
                                                                                    4
 2.0
                                                                                    3
 1.5
                                                                                    2
 1.0
 0.5                                                                                1

  0                                                                                 0
         Control
         C t l        I          II   III/IV   N
                                               Normal Mild
                                                    l        Mod
                                                             M d      S
                                                                      Severe
                NYHA Class                      Ventricular
                                                impairment
                                                                       Bolger, et al. Circulation 2002.
  Eight-week-old lambs
  Ei ht    k ld l b



           60                                      100
                         *
                                                                  *         *
                                   *                75
           40

                                                     50
% Change in                               % Change in
            20
   MPAP                                      LPVR
                                                     25

             0
                                                      0



           -20                                      -25
                  ET-1       4 ALA-ET-1                    ET-1       4 ALA-ET-1

                 Control                                  Control
                 Shunt                                    Shunt
Eight-week-old lambs
Ei ht    k ld l b



                 4


                                       *
                 3


    Relative
  ETB receptor   2
    protein

                 1
                           *

                 0
                     Control   Shunt
                     4 Weeks
                     8 Weeks
            Genetic susceptibility?
Normal             Permissive
                   Genotype
                                       Dex, HIV,
                                      CHD,TOS?
                                                            PPH
Platelets                Serotonin

                                                          Serotonin
                         NO+PGI2
  Endothelium            ET-1/TxA2

            SMCs
                           Kv1.5                            SMC
    Adventitia            ?Kv2.1                        Proliferation


                          Elastase
                           MMPs s
                                                    Tenascin
  Collagen, Elastin
                                Adapted from Archer S, et al. Circulation 2000; 102:2781.
                   Summary

 AT 4-WEEKS
     4-
                    ET-
      Alterations of ET-1 cascade
                  ET-
       –Increased ET-1 levels
                  ECE-
       –Increased ECE-1 protein
                      p
       –Increased ETA protein and ETA-mediated
       constriction
                         p
       –Decreased ETB protein and loss of ETB-
       mediated dilation
                            i
                      BMPR2 in CHD
      6% (40 adults and 66 children)1
                     ADULTS                           CHILDREN
            TOTAL   REPAIRED    BMPR2       TOTAL     REPAIRED       BMPR2
    PDA        2       0          0           6           3            0
    ASD       17       7          0           21          5            1
ASD/PAPVR      3       0          0           0           0            1
    VSD        8       1          0           15          8            0
  PAPVR        1       0          0           3           2            0
    TGA        3       3          0           7           3            0
   AVSD        4       1          3           6           3            0
  RARE         2       0          0           8           5            1
  TOTAL       40       12         3           66         29            3


     8% fenfluramine2
     26% IPAH
     50% familial PAH                  1. Roberts, et al. Eur Resp J 2004; 24:371.
                                     2. Humbert M, et al. Eur Resp J 2002; 20:518.
                    Shear stress


             Shear stress:
     V flow, viscosity and radius3
           ,         y                  Circumferential stretch



           Transduce haemodynamic stress
               into biochemical signals

Stress   cytoskeleton    integrins   messengers   cellular response
           Progression of lesions


       .

Endothelium
elastic            Serum leak
            injury S     l k
lamina

                                                              EVE
                                                   elastin peptides
 SMC           ELASTASE             FGF TGF
                    (EVE)                release   Fibronectin
                                Tenascin
                    SMC PROLIFERATION              SMC MIGRATION
                        HYPERTROPHY, CT
                           SYNTHESIS
      Bronchospasm and pulmonary
             hypertension




Cutz et al:Lab Invest:1986:54:14a
Heath, Yacoub et al Histopathology:1990:16:21

				
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