Association of genetic polymorphism in Pulmonary hypertension in COPD

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 PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland   1
Pulmonary hypertension in
 COPD: a possible role of
 genetic polymorphisms?
                 Silvia Ulrich Somaini, MD
                    Zürich, Switzerland


PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland   2
                                  Background
• PH is an important prognostic factor in
  COPD
• PH in COPD only weakly correlates with
  the degree of airway obstruction and
  hypoxia (Weitzenblum Thorax 1981 & Am Rev Respir Dis 1984, Scharf for
   NETT AJRCCM 2002)

• Genetic factors may contribute to the
  pathogenesis of PH in COPD

      PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland   3
                                 Background
• The serotonin- and nitric oxide system are
  involved in the pathogenesis of PH (Humbert JACC 04)
• Previous studies have shown an association
  between polymorphism of the serotonin
  transporter with the severity of PH in COPD
  (Eddahibi Circulation 2003)
• Polymorphism of the serotonin receptor 2a may
  be associated with systemic hypertension,
  myocardial infarction and psychiatric disorders
  (Yamada Arteriosclerosis 2000)
• Polymorphism of the endothelial nitric oxide
  synthetase are associated with heart disease
  and PH at altitude (Droma Circulation 2000)
     PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland   4
                                  Hypothesis
• Polymorphism of
  – the serotonin transporter (5HTT)
  – the serotonin 2a receptor (5HTR2a)
  – the endothelial nitric oxide synthetase
    (eNOS)
• might be associated with the severity of
  PH in COPD


    PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland   5
                                        Methods
• Severely dyspneic patients with COPD who had
  diagnostic right heart catheterization were asked
  to participate
• WHO functional class, 6 minute walk distance
  and arterial blood gases were assessed
• DNA was extracted from peripheral blood
  lymphocytes
• The 5HTT, 5HTR2A and eNOS polymorphisms
  were measured by polymerase chain reaction
  technology

    PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland   6
              Patient’s characteristics
                                                                                                               Numbers (%)
General and pulmonary function tests                                                                             means ±SD
Total number of patients                                                                                         59 (100)

Females/males                                                                                                 25/24 (42/58)

Age (years)                                                                                                          68 ± 8

BMI (kg/m2)                                                                                                          25 ± 4

Smokers                                                                                                           51 (86)
- current/past                                                                                                 7/44 (12/75)
- mean pack years smoked                                                                                         47 ± 21

WHO functional class II / III /IV                                                                           1/27/31 (2/46/52)
6 minute walking distance (m)                                                                                   309 ± 121
COPD severity by GOLD* stage I/II/III/IV                                                                 4/19/22/14 (7/32/37/24)
Pulmonary function tests (%predicted)
- Forced exspiratory volume in 1 sec (FEV1)                                                                      45 ± 21
- Forced vital capacity (FVC)                                                                                    76 ± 24
- FEV1/FVC                                                                                                       51 ± 12
- Total lung capacity (TLC)                                                                                      115 ± 25
- Residual volume (RV)                                                                                           183 ± 73
- Carbon monoxide diffusion capacity                                                                             48 ± 25

            PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland                 7
   Patient’s characteristics
                                                                                             Numbers (%)
Hemodynamics, blood gases (n= 59)                                                              means ±SD

Pulmonary hemodynamics (invasiv)
- Mean pulmonary arterial pressure (mmHg)                                                      31 ± 12
- Cardiac index (l/min/m2)                                                                    2.5 ± 0.6
- Pulmonary vascular resistance (dyn*sec*m-5)                                                 410 ± 226
- Right atrial pressure (mmHg)                                                                  7±5
- Pulmonary artery occlusion pressure (mmHg)                                                    10 ± 5



Blood gas analysis
- arterial oxygen saturation (%)                                                              89.7 ± 6.0
- arterial oxygen partial pressure (kPa)                                                       7.9 ± 1.2
- arterial carbon dioxide partial pressure (kPa)                                               5.3 ± 0.9
- mixed venous oxygen saturation (%)                                                            63 ± 8




 PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland    8
 Pulmonary Hypertension in this
        COPD cohort
• PH defined according to WHO as mean
  pulmonary artery pressure (mPAP) 
  25mmHg was present in 37 (64%) of the
  patients
• PH was usually mild, but
  disproportionately high in some patients:
  – 14 (24%) with mPAP > 40 mmHg
  – 6 (10%) with mPAP > 50 mmHg

   PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland   9
 PH in this COPD- cohort
                     % of COPD-patients with mean pulmonary artery
                        pressure above different thresholds (n=59)


              100

               90

               80

               70
                                                                        Disproportionate PH in
               60
                                                                                COPD:
               50
                                                                        A distinctive disease?
               40

               30

               20

               10

                 0
                       >20       >25       >30       >35       >40       >45        >50
                                                    m m Hg

PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland   10
Severity of PH negatively related
to degree of airway obstruction
                          100




                          80




                          60
                 FEV1 %




                          40




                          20


                                                                           R Sq Linear = 0.437


                                                                                 P < 0.001
                           0



                                10   20        30       40      50          60           70

                                          Mean pulmonary artery pressure



  PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland   11
Severity of PH weakly related to
     arterial oxygenation
                                                 10.00




                                                 9.00
                      Arterial oxygen pressure




                                                 8.00




                                                 7.00




                                                 6.00


                                                                                                R Sq Linear = 0.078



                                                                                                    P = 0.04
                                                 5.00



                                                         10   20        30       40      50         60         70

                                                                   Mean pulmonary artery pressure




  PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland              12
               5HTT Polymorphism
• As others (Eddahibi et al 2004), we found more
  LL-genotypes (long allelic variant) in COPD-
  patients with PH

                                            Genotypes N (%)                                Allele frequencies (%)

      5HTT                        SS                  SL                   LL                   S             L

Overall (N=59)                 16 (25)             35 (60)               9 (15)                55             45

No PH (N=22)                    8 (36)             12 (55)               2 (9)                 64             36

With PH (N=37)                  7 (19)             23 (62)               7 (19)                50             50




     PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland         13
            5HTT Polymorphism
• Patients with the L-allelic variant of the 5HTT
  tended to have higher pulmonary artery
  pressures and vascular resistances
                 100

                 90

                 80


                 70

                 60

                 50

                 40

                 30


                 20

                  10

                  0

                             SS                    SL                   LL
  PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland   14
            5HTR2a Polymorphism
• Patients with the TT-genotype had significantly
  lower mean cardiac indexes compared to
  patients with the TC and CC-genotypes (2.0, 2.5
  and 2.8 ml/min/m-2 for TT,CT and CC, p=0.021)
• No genotypic differences in COPD-patients with
  PH compared to without PH
        5HTR2a                      TT                   TC                  CC                    T             C


Overall (N=59)                     9 (15)              35 (59)             16 (26)                45             55

No PH (N=22)                       5 (23)              12 (54)              5 (23)                50             50

With PH (N=37)                     4 (11)              23 (62)             10 (27)                45             55



        PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland        15
                      eNOS- Polymorphism
    • No association between eNOS genotype and
      PH severity or frequency in COPD
        eNOS4a/b                      bb                   ab                    aa                    b            a

Overall (N=59)                     37 (63)               21 (35)                1 (2)                 81           19

No PH (N=22)                       14 (64)                8 (36)                  0                   82           18

With PH (N=37)                     23 (62)               13 (35)                1 (3)                 80           20

        eNOS298                    Glu/Glu              Glu/Asp              Asp/Asp                  Glu          Asp

Overall (N=59)                     32 (54)               25 (42)                2 (4)                 75           25

No PH (N=22)                       11 (50)                9 (41)                2 (9)                 70           30

With PH (N=37)                     21 (57)               16 (43)                  0                   78           22



          PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland         16
                              Conclusions
• We found no association between the
  degree of airway obstruction and the
  development of pulmonary hypertension in
  this severely dyspnoeic COPD population
• This indicates, that physicians should
  search for PH in dyspnoeic patients with
  COPD regardless of their FEV1


   PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland   17
                               Conclusions
• The disproportionately severe PH found in
  a subgroup of COPD patients supports a
  different pathogenetic mechanism
• Carriers of the L-allelic variant of the 5HTT
  might be more susceptible to PH in COPD
• The serotonin system might be
  pathogenetically involved in COPD


    PH in COPD and association to polymorphisms – ERS 08 – Silvia Ulrich Somaini, MD – Zürich, Switzerland   18

				
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