Prognostic Value of Oxidative Stress Markers in Patients with Pulmonary Arterial or Chronic Thromboembolic Pulmonary Hypertension

Abstract

Oxidative stress is regarded to play a crucial role in the pathophysiology of pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). This study evaluated the prognostic value of serum oxidative stress markers (malondialdehyde (MDA), total antioxidant capacity (TAC), catalase activity (CAT), and superoxide activity (SOD)) in patients with PAH and CTEPH (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi>n</mml:mi><mml:mo>=</mml:mo><mml:mn>45</mml:mn></mml:math>). During 13 months of follow-up (median 9 months), clinical deterioration occurred in 14 patients (including 2 deaths). On the Cox regression analysis, MDA, TAC, and CAT were associated with clinical deterioration (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.0068</mml:mn></mml:math>,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mtext>HR</mml:mtext><mml:mo>=</mml:mo><mml:mn>1.42</mml:mn></mml:math>, 95% CI: 1.10-1.82;<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.0038</mml:mn></mml:math>,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M5"><mml:mtext>HR</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.033</mml:mn></mml:math>, 95% CI: 0.0032-0.33; and<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M6"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.046</mml:mn></mml:math>,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M7"><mml:mtext>HR</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.20</mml:mn></mml:math>, 95% CI: 0.04-0.98, respectively). There was no significant difference in SOD (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M8"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.53</mml:mn></mml:math>,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M9"><mml:mtext>HR</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.97</mml:mn></mml:math>, 95% CI: 0.87-1.08). The cut-off value derived from ROC curve analysis was 3.79 μ M (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M10"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.0048</mml:mn></mml:math>,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M11"><mml:mtext>AUC</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.76</mml:mn></mml:math>, 95% CI: 0.62-0.91) for MDA, 0.49 mM (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M12"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.027</mml:mn></mml:math>,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M13"><mml:mtext>AUC</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.71</mml:mn></mml:math>, 95% CI: 0.18-0.47) for TAC, and 1.34 U/L (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M14"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.029</mml:mn></mml:math>,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M15"><mml:mtext>AUC</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.71</mml:mn></mml:math>, 95% CI: 0.55-0.86) for CAT. MDA in the group with deterioration was higher (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M16"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.0041</mml:mn></mml:math>), while TAC as well as CAT were lower (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M17"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.027</mml:mn></mml:math>and<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M18"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.028</mml:mn></mml:math>, respectively) when compared to stable patients. Survival without clinical deterioration was significantly longer in patients with lower MDA (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M19"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.037</mml:mn></mml:math>,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M20"><mml:mtext>HR</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.37</mml:mn></mml:math>, 95% CI: 0.12-1.14, log-rank), higher TAC (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M21"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.0018</mml:mn></mml:math>,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M22"><mml:mtext>HR</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.19</mml:mn></mml:math>, 95% CI: 0.06-0.60, log-rank), and higher CAT (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M23"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.044</mml:mn></mml:math>,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M24"><mml:mtext>HR</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.31</mml:mn></mml:math>95% CI: 0.11-0.88, log-rank). Markers of oxidative stress such as MDA, TAC, and CAT were associated with adverse clinical outcomes in patients with PAH and inoperable or residual CTEPH.