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Vasoreactive phenotype in children with pulmonary arterial hypertension and syncope

Alexandra N. Linder, Jill Hsia, Sheila V. Krishnan, Erika B. Rosenzweig, Usha S. Krishnan
ERJ Open Research 2022 8: 00223-2022; DOI: 10.1183/23120541.00223-2022
Alexandra N. Linder
1Division of Pediatric Cardiology, Dept of Pediatrics, Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, NY, USA
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Jill Hsia
2Division of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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Sheila V. Krishnan
1Division of Pediatric Cardiology, Dept of Pediatrics, Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, NY, USA
3Stonybrook University School of Medicine, New York, NY, USA
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Erika B. Rosenzweig
1Division of Pediatric Cardiology, Dept of Pediatrics, Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, NY, USA
4Co-senior authors
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Usha S. Krishnan
1Division of Pediatric Cardiology, Dept of Pediatrics, Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, NY, USA
4Co-senior authors
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  • For correspondence: usk1@cumc.columbia.edu
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  • FIGURE 1
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    FIGURE 1

    Survival in pulmonary arterial hypertension patients with and without syncope. a) Survival probability over time (in years) showed no difference in survival at 10 years between those with syncope during their clinical course compared to those without. b) Patients with syncope had significantly worse survival over the entire follow-up period.

  • FIGURE 2
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    FIGURE 2

    Survival in patients with Group 1 pulmonary arterial hypertension stratified by syncope and acute vasodilator testing (AVT) response. a) There was no significant difference in survival at 10 years regardless of syncope or AVT response. b) Over the entire follow-up period (range 0.17–30.2 years), those with and without syncope and positive response to AVT had 100% survival. Those with syncope and without response to acute vasodilator testing had the worst survival, with the poorest survival in patients with syncope on medications. Dx: diagnosis.

  • FIGURE 3
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    FIGURE 3

    Survival of idiopathic pulmonary arterial hypertension patients stratified by syncope and acute vasodilator testing (AVT) response. All patients with idiopathic pulmonary arterial hypertension who responded to AVT had 100% survival regardless of syncope. Those with syncope and without response to acute vasodilator testing had the worst survival. Dx: diagnosis.

Tables

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  • TABLE 1

    Patient characteristics

    SyncopeNon-syncopep-value
    Subjects n47122
    Sex, female29 (62)66 (54)0.40
    Median age years7.9 (0.4–19)3.0 (0–18.4)0.002
    Symptoms
     Dyspnoea on exertion43 (91)118 (97)0.08
     Chest pain20 (43)30 (25)0.022
     Failure to thrive9 (19)40 (33)0.075
     Fatigue34 (72)57 (47)0.003
    PAH classification
     Idiopathic PAH36 (76)37 (30)<0.00001
     Heritable PAH3 (6)2 (2)0.13
     APAH-CHD10 (21)79 (65)<0.00001
      Repaired5 (50)53 (67)0.29
      Unrepaired5 (50)26 (33)
     APAH-CTD1 (2)4 (3)​1
     APAH–portal hypertension02 (1)1

    Data are expressed as median (range) or n (%) unless indicated otherwise. Bold p-values represent statistically significant differences. PAH: pulmonary arterial hypertension; APAH: associated pulmonary hypertension; APAH-CHD: PAH associated with congenital heart disease; APAH-CTD: PAH associated with connective tissue disease.

    • TABLE 2

      Cardiac catheterisation data at presentation

      nSyncope at diagnosis#nSyncope on medication¶,+nNon-syncope§p-value
      Baseline
       Mean RAP mmHg7 (5–10)7 (6–10)7 (6–9)0.86
       Mean PAP mmHg53 (37–65)66.5 (51.8–72)48.5 (36–64)0.18
       sPAP/sSAP0.80 (0.50–0.99)0.83 (0.76–1.10)660.75 (0.50–0.95)0.47
       PVRi WU·m213.7 (8.8–22.0)20.1 (9.2–25.1)669.05 (5.3–14.5)0.04
       Rp/Rs300.7 (0.5–1)50.7 (0.3–1.5)590.6 (0.33–0.94)0.42
       CI L·min−1·m−23.0 (2.2–3.8)2.8 (2.5–3.2)663.5 (2.5–4.2)0.19
      AVT with iNO564
       Mean RAP mmHg256 (4–8.5)37 (2–8)447 (6–8.5)
       Mean PAP mmHg3538 (27–60)63 (53–66.5)37.5 (28–56.5)0.15
       sPAP/sSAP340.60 (0.40–0.92)0.77 (0.67–1.16)590.65 (0.46–0.89)0.30
       PVRi WU·m2339.3 (5.1–17.3)15.1 (11.9–19.5)616.5 (3.7–11)0.02
       Rp/Rs210.46 (0.29–0.72)N/A330.45 (0.21–0.83)0.99
       CI L·min−1·m−2333.2 (2.4–3.8)3.1 (2.7–3.8)583.6 (2.6–4.6)0.18
      AVT responders (Barst)14 (40)015 (22)0.047
      AVT responders (Sitbon)8 (23)09 (13)0.27

      Data are expressed as median (interquartile range) or n (%). Bold p-values represent statistically significant differences. n: number of patients; RAP: right atrial pressure; PAP: pulmonary artery pressure; sPAP/sSAP: ratio of pulmonary artery/systemic arterial systolic pressure; PVRi: indexed pulmonary vascular resistance; Rp/Rs: ratio of pulmonary vascular resistance/systemic vascular resistance; CI: cardiac index; AVT: acute vasodilator testing; iNO: inhaled nitric oxide. #: n=36; ¶: n=6; +: one patient with syncope on medication did not have a catheterisation available from the time of diagnosis; §: n=67.

      • TABLE 3

        Catheterisation data with acute vasodilator testing (AVT) for syncope patient responders versus non-responders using Barst criteria

        nAVT responders#nAVT negative with syncope at diagnosis¶nAVT negative with syncope on medications+p-value
        Room air
         Mean RAP mmHg6.5 (3–11)7 (5–9)9 (8–10)0.36
         Mean PAP mmHg49 (32–66)57 (43–70)67 (61–81)0.12
         PVRi WU·m211.1 (8.6–22)16.3 (8.7–26)620.0 (7.8–26.3)0.80
         Rp/Rs110.7 (0.4–1)200.9 (0.7–1)61.3 (0.7–2.4)0.14
         CI L·min−1·m−22.8 (2.3–3.9)202.98 (1.9–3.6)3.8 (2.2–4.4)0.45
        AVT with iNO
         Mean RAP mmHg96 (4–7)158 (5–9)69.5 (7.3–10.3)0.07
         Mean PAP mmHg28 (20–31)§58 (41–77)64 (61–82)0.0003
         PVRi WU·m2125.1 (3.8–8.0)§16.5 (9.3–22.7)522.5 (7.5–26.9)0.002
         Rp/Rs70.2 (0.2–0.4)§130.7 (0.5–1.1)51.1 (0.5–2.3)0.0015
         CI L·min−1·m−23.3 (2.6–3.9)203.3 (2.2–3.8)3.4 (2.4–4.2)0.72

        Data are expressed as median (interquartile range). Bold p-values represent statistically significant differences between AVT responders and AVT negative. One patient who responded to AVT on her initial catheterisation (included in that category in table 1) lost AVT response by time of syncope as reflected in her later catheterisation used here. RAP: right atrial pressure; PAP: pulmonary artery pressure; PVRi: indexed pulmonary vascular resistance; Rp/Rs: ratio of pulmonary vascular resistance/systemic vascular resistance; CI: cardiac index; iNO: inhaled nitric oxide. #: n=14; ¶: n=21; +: n=7; §: represents statistically significant differences on room air compared to AVT.

        • TABLE 4

          Catheterisation data with acute vasodilator testing (AVT) for syncope patient responders versus non-responders using Sitbon criteria

          nAVT responders#nAVT negative with syncope at diagnosis¶nAVT negative with syncope on medications+p-value
          Room air
           Mean RAP mmHg8 (1–16)7 (5–9)9 (8–10)0.33
           Mean PAP mmHg52 (41–66)54.5 (32–69.8)67 (61–81)0.15
           PVRi WU·m219.5 (11.8–23.7)14.2 (8.2–24.5)620.0 (7.8–26.3)0.67
           Rp/Rs60.7 (0.6–0.8)250.9 (0.5–1)61.3 (0.7–2.4)0.22
           CI L·min−1·m−22.3 (1.8–3.2)273.1 (2.3–3.8)3.8 (2.2–4.4)0.15
          AVT with iNO
           Mean RAP mmHg46 (3–9)206.5 (5–8.8)69.5 (7.3–10.3)0.13
           Mean PAP mmHg29 (28–31)52.5 (26.3–74.8)64 (61–82)0.01
           PVRi WU·m257.9 (6–8)13.2 (4.7–20.9)522.5 (7.5–26.9)0.22
           Rp/Rs30.4 (0.2–0.4)170.7 (0.3–1)51.1 (0.5–2.3)
           CI L·min−1·m−23.1 (2.6–4.4)273.4 (2.3–3.8)3.4 (2.4–4.2)0.73

          Data are expressed as median (interquartile range). Bold p-value represents statistically significant difference between AVT responders and AVT negative by Sitbon criteria. RAP: right atrial pressure; PAP: pulmonary artery pressure; PVRi: indexed pulmonary vascular resistance; Rp/Rs: ratio of pulmonary vascular resistance/systemic vascular resistance; CI: cardiac index; iNO: inhaled nitric oxide. #: n=7; ¶: n=28; +: n=7.

          • TABLE 5

            Treatment at last follow-up

            SyncopeAVT+AVT–Non-syncopeAVT+AVT–p-value (syncope versus non-syncope)
            Subjects n421428671453
            CCB for vasoresponsiveness10 (24)10#06 (6)6#00.03
            CCB monotherapy3 (6)3¶03 (3)3¶00.67
            Single PAH therapy6 (14)4218 (27)5130.12
            Dual PAH therapy13 (31)31011 (16)1100.07
            Triple PAH therapy18 (43)3¶1523(34)3210.37
            No medication2 (4)1112 (18)2100.046
            IV/SQ prostanoid20 (48)1 (7)19+ (68)15 (22)1 (7)14 (26)0.006

            Data are expressed as n or n (%). Bold p-values represent statistically significant differences between patients with and without syncope. AVT: acute vasodilator testing; CCB: calcium channel blocker; PAH: pulmonary arterial hypertension; IV: intravenous; SQ: subcutaneous. #: p for AVT+ versus AVT– <0.00001; ¶: p for AVT+ versus AVT– <0.05 (for syncope CCB only, p=0.03; for syncope triple PAH therapy, p=0.047; for non-syncope CCB only, p=0.007); +: p for AVT+ versus AVT– =0.0002.

            • TABLE 6

              Cardiac catheterisation data with acute vasodilator testing for idiopathic pulmonary arterial hypertension patients

              nSyncope#nNon-syncope¶p-value
              Baseline
               Mean RAP mmHg7 (5–10)6 (5–8)0.45
               Mean PAP mmHg54 (40–69)52 (37–76)0.90
               sPAP/sSAP0.81 (0.58–1.00)0.84 (0.55–1.10)0.74
               PVRi WU·m216.7 (9.3–24.8)11.0 (5.5–20.2)0.10
               Rp/Rs280.75 (0.60–1.00)310.7 (0.40–1.10)0.51
               CI L·min−1·m−22.7 (2.0–3.4)343.55 (2.8–4.6)0.0047
              AVT with iNO34​
               Mean RAP mmHg247 (4.5–8.5)276 (5–8)0.72
               Mean PAP mmHg44 (27–64)41 (31–57)0.88
               sPAP/sSAP330.70 (0.40–0.93)330.70 (0.46–0.91)0.63
               PVRi WU·m23213.2 (5.7–18.9)338.1 (3.6–12.2)0.037
               Rp/Rs180.50 (0.30–0.72)190.45 (0.25–0.90)0.93
               CI L·min−1·m−2333.3 (2.5–3.7)333.8 (2.7–5.3)0.013
              AVT responders (Barst)12 (35)8 (23)0.19
              AVT responders (Sitbon)6 (18)5 (14)0.70

              Data are expressed as median (interquartile range) or n (%). Bold p-values represent statistically significant differences. n: number of patients; RAP: right atrial pressure; PAP: pulmonary artery pressure; sPAP/sSAP: ratio of pulmonary artery/systemic arterial systolic pressure; PVRi: indexed pulmonary vascular resistance; Rp/Rs: ratio of pulmonary vascular resistance/systemic vascular resistance; CI: cardiac index; AVT: acute vasodilator testing; iNO: inhaled nitric oxide. #: n=34; ¶: n=35.

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              Vasoreactive phenotype in children with pulmonary arterial hypertension and syncope
              Alexandra N. Linder, Jill Hsia, Sheila V. Krishnan, Erika B. Rosenzweig, Usha S. Krishnan
              ERJ Open Research Oct 2022, 8 (4) 00223-2022; DOI: 10.1183/23120541.00223-2022

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              Vasoreactive phenotype in children with pulmonary arterial hypertension and syncope
              Alexandra N. Linder, Jill Hsia, Sheila V. Krishnan, Erika B. Rosenzweig, Usha S. Krishnan
              ERJ Open Research Oct 2022, 8 (4) 00223-2022; DOI: 10.1183/23120541.00223-2022
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