Natalie J. Doughty

Elevated Levels of Inflammatory Cytokines Predict Survival in Idiopathic and Familial Pulmonary Arterial Hypertension

Background— Inflammation is a feature of pulmonary arterial hypertension (PAH), and increased circulating levels of cytokines are reported in patients with PAH. However, to date, no information exists on the significance of elevated cytokines or their potential as biomarkers. We sought to determine the levels of a range of cytokines in PAH and to examine their impact on survival and relationship to hemodynamic indexes. Methods and Results— We measured levels of serum cytokines (tumor necrosis factor-&agr;, interferon-&ggr; and interleukin-1&bgr;, -2, -4, -5, -6, -8, -10, -12p70, and -13) using ELISAs in idiopathic and heritable PAH patients (n=60). Concurrent clinical data included hemodynamics, 6-minute walk distance, and survival time from sampling to death or transplantation. Healthy volunteers served as control subjects (n=21). PAH patients had significantly higher levels of interleukin-1&bgr;, -2, -4, -6, -8, -10, and -12p70 and tumor necrosis factor-&agr; compared with healthy control subjects. Kaplan-Meier analysis showed that levels of interleukin-6, 8, 10, and 12p70 predicted survival in patients. For example, 5-year survival with interleukin-6 levels of >9 pg/mL was 30% compared with 63% for patients with levels ≤9 pg/mL (P=0.008). In this PAH cohort, cytokine levels were superior to traditional markers of prognosis such as 6-minute walk distance and hemodynamics. Conclusions— This study illustrates dysregulation of a broad range of inflammatory mediators in idiopathic and familial PAH and demonstrates that cytokine levels have a previously unrecognized impact on patient survival. They may prove to be useful biomarkers and provide insight into the contribution of inflammation in PAH.

Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension.

BACKGROUND There are currently no licensed medical therapies for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). METHODS In this double-blind, placebo-controlled pilot study, 19 subjects with inoperable CTEPH were randomly assigned to sildenafil or placebo for 12 weeks. The primary end point was change in 6-min walking distance (6MWD). Secondary end points included changes in World Health Organization (WHO) class, cardiopulmonary hemodynamics, quality of life (QOL) scores, and N-terminal pro brain natriuretic peptide (NT-proBNP). All subjects were transferred to open-label sildenafil at the end of the study and offered repeat assessment at 12 months. RESULTS There were no significant differences between the two groups with respect to change in exercise capacity. However significant improvements were seen in WHO class and pulmonary vascular resistance (PVR). Seventeen subjects were eligible for reassessment at 12 months and demonstrated significant improvements in 6MWD, activity and symptom components of QOL, cardiac index, PVR, and NT-proBNP. CONCLUSIONS Although this pilot study was insufficiently powered to test the primary end point, it did suggest beneficial effects in favor of sildenafil in several secondary end points at both 3 months and 12 months. Further larger-scale trials of sildenafil in inoperable CTEPH are required to confirm these findings and potentially increase the treatment options available for this devastating disease. TRIAL REGISTRATION The study protocol was registered with the UK National Research Register database (publication ID N0542136603).

Patient-Reported Outcomes Assessed by the CAMPHOR Questionnaire Predict Clinical Deterioration in Idiopathic Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension

BACKGROUND The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) is a disease-specific assessment tool used for the evaluation and follow-up of patients with pulmonary hypertension (PH). We describe a novel use for this questionnaire in its potential to predict clinical deterioration (CD) in two patient cohorts with subtypes of PH, idiopathic pulmonary arterial hypertension (IPAH), and chronic thromboembolic pulmonary hypertension (CTEPH) during an 8-year period. METHODS We retrospectively analyzed CAMPHOR scores obtained at baseline and at follow-up visits in patients under the care of our unit over an 8-year period to assess CD and survival, as well as 6-min walk distance (6MWD) and New York Heart Association (NYHA) class. RESULTS Using Cox regression, we demonstrated a significant predictive effect of CD from total CAMPHOR scores at study enrollment in IPAH and CTEPH (hazard ratios, 1.03 [95% CI, 1.01-1.05] and 1.04 [95% CI, 1.02-1.06] per unit score increase, respectively), as well as from CAMPHOR subscales as independent predictors. This predictive effect is diluted after adjusting for the prognostic effect of 6MWD and NYHA class. Repeated CAMPHOR assessment over time appears not to add predictive value of CD to that obtained at diagnosis, although it still informs physicians of important changes in self-reported symptoms. CONCLUSIONS When emphasis is placed on the evaluation of patient perceptions, CAMPHOR may represent an alternative method of estimating the likelihood of CD.

Log-transformation improves the prognostic value of serial NT-proBNP levels in apparently stable pulmonary arterial hypertension

N-terminal pro B-type natriuretic peptide (NT-proBNP) is a product of cleavage of the cardiac prohormone pro B-type natriuretic peptide into its active form. It has proven to be a useful biomarker in left heart failure. However, studies examining the utility of serial measurements of NT-proBNP in pulmonary arterial hypertension (PAH) patients have shown mixed results. We compared three methods of predicting adverse clinical outcomes in PAH patients: the change in 6 minute walk distance (6MWD), the change in absolute levels of NT-proBNP and the change in log-transformed levels of NT-proBNP. All PAH patients presenting from March–June 2007 were screened. Patients who were clinically unstable, had abnormal renal function or hemoglobin levels or lacked a prior NT-proBNP were excluded. 63 patients were followed up for adverse clinical outcomes (defined as death, transplantation, hospitalisation for right heart failure, or need for increased therapy). Three methods were used to predict adverse events, i.e.: (a) comparing a 6MWD performed in March–June 2007 and a previous 6MWD. A decrease in 6MWD of ≥30m was used to predict clinical deterioration; (b) comparing a NT-proBNP value measured in March–June 2007 and a previous NT-proBNP. An increase in NT-proBNP of ≥250pg/ml was used to predict clinical deterioration (250pg/ml represented approximately 30% change from the baseline median value of NT-proBNP for this cohort); and (c) comparing the loge equivalents of two consecutive NT-proBNP values. We used the formula: loge(current NT-proBNP) - loge(previous NT-proBNP)=x. A value of x≥+0.26 was used to predict adverse events. This is equivalent to a 30% change from baseline, and hence is comparable to the chosen cut-off for absolute levels of NT-proBNP. A loge difference of ≥+0.26 identifies patients at risk of adverse events with a specificity of 98%, a sensitivity of 60%, a positive predictive value of 89%, and a negative predictive value of 90%. A drop in 6MWD of ≥30m has a specificity of 29%, a sensitivity of 73%, a positive predictive value of 24% and a negative predictive value of 24%. It seems possible to risk-stratify apparently stable PAH patients by following the changes in their serial log-transformed NT-proBNP values. In this small pilot study, this method was better than relying on changes in the actual levels of NT-proBNP or changes in 6MWD. This needs to be validated prospectively in a larger cohort.

Response to Letter Regarding Article, “Elevated Levels of Inflammatory Cytokines Predict Survival in Idiopathic and Familial Pulmonary Arterial Hypertension”

We appreciate the opportunity to discuss the issues raised by Dr Montani et al. The Kaplan-Meier survival curves were presented according to quartile values for each cytokine to determine whether there was a dose-response effect, which is standard practice for this form of analysis. When we dichotomized the data by median values, it also resulted in significant differences in survival, but the separation of curves given by the median values was not as good as that given by the optimum values stated in Table 4 of our article.1 Because it is our intention to validate the use of these cytokines as biomarkers in clinical practice, we believe that presentation of both quartiles and optimum values for each cytokine is the best and …