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Pulmonary vascular disease
Original article
C-reactive protein in adults with pulmonary arterial hypertension associated with congenital heart disease and its prognostic value
  1. Giancarlo Scognamiglio1,2,
  2. Aleksander Kempny1,3,4,
  3. Laura C Price1,5,
  4. Rafael Alonso-Gonzalez1,3,
  5. Philip Marino1,3,
  6. Lorna Swan1,3,
  7. Michele D’ Alto2,
  8. James Hooper1,
  9. Michael A Gatzoulis1,3,
  10. Konstantinos Dimopoulos1,3,
  11. Stephen J Wort1,3,5
  1. 1Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton Hospital, London, UK
  2. 2Department of Cardiology, Second University of Naples, Monaldi Hospital, Naples, Italy
  3. 3NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, London, UK
  4. 4Division of Adult Congenital and Valvular Heart Disease, Department of Cardiovascular Medicine, University Hospital Muenster, Muenster, Germany
  5. 5National Heart and Lung Institute, Imperial College School of Medicine, London, UK
  1. Correspondence to Dr Stephen Wort, Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton and Harefield NHS Foundation Trust, Sydney Street, London SW3 6NP, UK; s.wort{at}imperial.ac.uk

Abstract

Objectives To assess the relationship of C-reactive protein (CRP) to clinical outcome and mortality in adults with pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH).

Background Approximately 5–10% of adults with congenital heart disease (ACHD) develop PAH, which in turn is associated with substantial morbidity and mortality. Although CRP is known to predict outcome in idiopathic PAH, little is known regarding its prognostic value in CHD-PAH.

Methods We obtained and analysed 1936 CRP values in a total of 225 adults with CHD-PAH (median age at study entry 34.0 years (27.0–41.7); 32.9% male, 35% with Down syndrome), performed over a 12-year period. High CRP values related to infection or blood transfusions were excluded from the analysis.

Results During a median follow-up of 4.8 years (1149 patients-years), 50 patients died. The median CRP concentration on the last assessment was 5.0 mg/L (IQR 2.0–10.0), higher in deceased patients compared with survivors (11.5 mg/L (6.0–23.0) vs 4.0 mg/L (1.5–8.0), p<0.0001). Following univariate Cox regression analysis, CRP emerged as a strong predictor of mortality (HR 1.18; 95% CI 1.11 to 1.26, p<0.0001) and remained significant after adjustment for age, presence of Down syndrome and advanced PAH therapy. Survival–receiver–operator characteristic analysis identified an optimal cut-off value of 10 mg/L. Patients with CRP >10 mg/L had more than a threefold increased risk of death (HR 3.63, 95% CI 2.07 to 6.38, p<0.0001).

Conclusions Serum CRP is a simple but powerful marker of mortality in CHD-PAH patients and should be incorporated in the risk stratification and routine assessment of these patients.

https://doi.org/10.1136/heartjnl-2014-305494

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    Introduction

    Adults with congenital heart disease (ACHD) represent an expanding population within tertiary care. About 5–10% of ACHD patients will develop pulmonary arterial hypertension (PAH-CHD).1 Despite improvement in the outlook for patients with PAH-CHD, with the availability of disease targeting therapies, such as endothelin receptor antagonists and phosphodiesterase inhibitors, morbidity and mortality remains unacceptably high.2 To improve outcomes further, it is particularly important that we identify simple biomarkers that can risk-stratify patients and allow optimal medical management.

    Recently, there has been growing interest in the role of inflammation in the development of PAH, both idiopathic PAH and PAH associated with conditions such as connective tissue disease.3 For instance, increased plasma concentration of cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6), has been detected in the blood of patients with idiopathic PAH, and these negatively correlate with survival.4 In addition, increased concentration of C-reactive protein (CRP), a sensitive marker of inflammation, correlated with New York Heart Association (NYHA) functional class, right atrial pressure, six-minute walking distance (6MWD), response to therapy and overall survival in patients with idiopathic PAH and chronic thromboembolic pulmonary hypertension (CTEPH).5

    There is preliminary evidence implicating inflammation in the pathogenesis of PAH associated with CHD (CHD-PAH). For instance, serum concentration of cytokines such as IL-6 and tumour necrosis factor α (TNF-α) is also raised in patients with CHD-PAH.6 However, as yet there are no reports of CRP being a risk factor for patients with CHD-PAH as is the case in patients with idiopathic PAH or indeed other cardiovascular disease.7

    In this study, we aimed to investigate circulating CRP concentration in a large, single tertiary centre of patients with CHD-PAH, and its potential relationship to mortality.

    Methods

    Data on all patients with CHD-PAH under active follow-up at the Royal Brompton Hospital between June 2000 and June 2012 were analysed retrospectively. Patients with evidence of PAH and a non-restrictive intracardiac or extracardiac communication were included. Patients with operated lesions were also included regardless of the presence of a residual shunt, provided that they had evidence of near-systemic PAH (eg, patients with late closure of a ventricular septal defect). All patients had a baseline echocardiographic assessment performed by operators specialised in assessment of patients with complex CHD. In most subjects, namely those with unrestricted post-tricuspid shunts and no right ventricular outflow tract obstruction, diagnosis was based on echocardiography. Cardiac catheterisation is routinely performed in our centre in patients with pretricuspid shunts or previously repaired lesions, in which the diagnosis of PAH cannot be reliably established by echocardiography alone. Demographic and clinical data were collected from a dedicated clinical database, and the patients’ functional class was determined at the time of the earliest clinical assessment within the study period.

    Cardiac lesions were classified into four categories according to the shunt type: pretricuspid (atrial septal defect), post-tricuspid (ventricular septal defect or patent ductus arteriosus in the absence of a pretricuspid shunt), complex anatomy (other shunt lesions including atrioventricular septal defects, univentricular physiology, transposition of the great arteries, aortopulmonary window and common arterial trunk) and operated lesions. In the context of univentricular physiology, severe PAH occurs when the pulmonary artery is directly connected to the ventricular mass in the absence of native pulmonary stenosis or an effective surgical pulmonary artery band. Patients with univentricular physiology were classified as having CHD-PAH when the aforementioned haemodynamics were present. Patients with univentricular physiology and a Glenn or Fontan-type operation were excluded. CRP was measured by turbidimetry using anti-CRP antibody-coated particles (Beckman Coulter Inc). Analytical sensitivity was 1.0 mg/L. The upper reference limit was 10 mg/L, the analytical range was 1–250 mg/L and the assay precision was 2.77% (coefficient of variation) at 4.9 mg/L and 1.17% at 54.0 mg/L. We thoroughly screened clinic records for evidence of infection, and CRP values obtained during these time-points were excluded from the analysis. Blood samples collected during documented inflammatory diseases or within 48 h post-blood transfusion were excluded from further analysis.

    6MWD data were available in 125 patients within 12 months of the CRP measurement. To investigate the relationship of CRP to 6MWD, we analysed the most recent pair of CRP and 6MWD in each patient. NYHA functional class was recorded in all patients at the time of CRP measurement. Survival status and time of death were assessed through the health service computer system, linked to the national database held by the Office of National Statistics.

    The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

    Statistical analysis

    Analyses were performed using R V.2.15.0 and the package survival.8 Clinical and demographic characteristics of the population refer to the clinical status of the patients at the baseline. Continuous variables were assessed for normality and are presented as mean±SD in case of normal distribution or median (IQR) in case of non-normal distribution. Categorical variables are presented as percentage of total. Unpaired comparisons were performed using χ2 test for categorical data and Wilcoxon's rank sum test for continuous variables. Comparisons of groups containing repeated measurements per subject were performed using mixed effects model. Univariate and multivariable Cox regression analysis and Kaplan–Meier method was used for survival analysis. The proportional hazards assumption was verified for each variable by testing for zero correlation between the scaled Schoenfeld residuals and survival time. Breslow method was used for handling ties and other options were set to default on the coxph function in R-package, which was used to fit the proportional hazard Cox regression model. On multivariable Cox regression analysis, a stepwise approach using Akaike information criterion was used for model selection. To account for repeated measurements, a time-dependent Cox model was used as described previously.2

    To demonstrate the distribution of CRP values on graphs, we used the density function in R-package providing kernel density estimates based on Gaussian kernel smoothing algorithm with default settings. Estimated survival and standardised mortality ratio (SMR) for a gender-matched cohort was based on the Interim Life Tables for England and Wales (2007–2009) published by the Government Actuary's Department.9 All p values were two-sided, and a p value of less than 0.05 was prespecified as indicative of statistical significance.

    Results

    Patient population

    In total, 225 patients (median age at study entry 34.0 years (27.0–41.7); 32.9% male) attending our tertiary centre were included (table 1). The majority of patients had a post-tricuspid shunt (51%), followed by patients with complex anatomy (37%), pretricuspid shunt (8.0%) and repaired lesions (4%). There were no significant differences in age among anatomical groups. Down syndrome was present in 34.2%. More patients with Down syndrome had a complex lesion (58% compared with 27% in non-Down patients, p<0.0001). Patients with Down syndrome were significantly younger at study entry (29.5 (22.4–35.6) vs 38.8 (29.7–45.9) years for non-Down patients, p<0.0001).

    View this table:
    Table 1

    Patient characteristics

    CRP concentration

    During the cumulative follow-up of 1148.5 patient-years, 1936 CRP measurements were performed. The median number of CRP measurements per patient was 4.0 (2.0–10.0), with 81% having had two or more assessments. Median serum concentration of CRP at baseline was 6.0 mg/L (3.0–11.0) (figure 1); 121 (53.8%) patients had at least one CRP value >10 mg/L during the study period.

    Figure 1
    Figure 1

    C-reactive protein concentration: all values (including repeated measurements, grey area), first measurement for each patient (black line), last measurement for each patient (dotted line) and highest value for each patient (red line).

    There was no significant difference in CRP between anatomic subgroups, males and females (p=0.4 for both) and patients with and without Down syndrome (p=0.3). Patients with NYHA functional class ≥3 had significantly higher CRP values compared with the remainder (p=0.019); CRP values were significantly higher on the last assessment in patients who died during follow-up compared with survivors (11.5 mg/L (6.0–23.0) vs 4.0 mg/L (1.5–8.0), respectively, p<0.0001). There was a weak negative correlation between CRP concentration and 6MWD (r=−0.38, p<0.0001); patients with normal CRP (≤10 mg/L) had a significantly longer walking distance on the latest test available compared with patients with elevated CRP (326 m (235–395) vs 220 m (162–314), p<0.001, respectively, figure 2). Furthermore, there was a weak correlation between CRP and age (r=0.14, p<0.0001), creatinine (r=0.17, p<0.0001), white cell count (r=0.13, p<0.0001), haemoglobin (r=−0.15, p<0.0001), serum iron (r=−0.17, p<0.0001), brain natriuretic peptide (BNP) (r=0.17, p<0.0001) and resting oxygen saturation (r=−0.26, p<0.0001).

    Figure 2
    Figure 2

    Comparison of six-minute walking distance in patients with low and high C-reactive protein values. A significant difference in exercise capacity was observed.

    CRP and advanced PAH therapies

    Twenty-one patients were on PAH advanced therapies at baseline assessment, while another 76 patients were commenced on advanced therapies during the study. Among patients receiving advanced therapies, 68 (70.1%) were on endothelin receptor antagonists, 50 (51.5%) on phosphodiesterase type 5 inhibitors, and 2 (2.0%) on prostanoids at last assessment. Twenty-four patients (24.7%) went on combination therapy at any point during the study. There was no significant change in CRP concentration after initiation of advanced therapies (4.9 (2.0–11.0) vs 5.0 (1.0–9.5), respectively, p=0.9). However, initiation of advanced therapies was associated with a small but significant increase in 6MWD (280 m (225–375) vs 294 m (255–395), p=0.032, figure 3).

    Figure 3
    Figure 3

    Comparison of six-minute walk test distance before and after initiation of advanced therapies for pulmonary arterial hypertension. A modest, but statistically significant increase in walking distance was observed.

    Mortality and predictors of outcome

    During a median follow-up of 4.8 (range 2.3–7.6) years, 50 (22%) patients died. Table 2 illustrates the causes of death in our population. Mortality was 19 times higher than in age-matched and gender-matched UK controls (SMR 19.2; 95% CI 14.0 to 26.3, log rank p<0.0001, figure 4). The median age at death was 41.2 years (33.8–50.1). Several parameters emerged as predictors of outcome on univariate Cox regression analysis (table 3), including oxygen saturation (HR 0.91 per 1%; 95% CI 0.87 to 0.95, p<0.0001), serum CRP (HR 1.18/10 mg/L; 95% CI 1.11 to 1.26, p<0.0001), serum CRP change on serial measurements (HR 1.18/10 mg/L; 95% CI 1.05 to 1.32, 0.0049) and serum creatinine (HR 1.06/10 μmol/L; 95% CI 1.02 to 1.10, p=0.001). In contrast, age, NYHA functional class ≥3, female gender and white blood cell count were not predictive of outcome.

    View this table:
    Table 2

    Causes of death

    View this table:
    Table 3

    Results of the univariate Cox regression analysis for mortality

    Figure 4
    Figure 4

    Survival curves. (A) Kaplan–Meier curve for survival in patients with pulmonary arterial hypertension associated with congenital heart disease (blue), with 95% CI. This is compared with age-matched and gender-matched UK population (black dashed line). SMR, standard mortality ratio. (B) Survival in patients with normal C-reactive protein (CRP) compared with patients with elevated CRP, based on the Cox model with CRP as a time-dependent covariate.

    Both CRP and oxygen saturation remained significant predictors of outcome on multivariate Cox regression analysis (table 4). Furthermore, survival–receiver–operator characteristic analysis suggested an optimal cut-off for CRP of 10 mg/L (area under the curve (AUC)=0.74, sensitivity=62%, specificity=81%). Patients with CRP >10 mg/L had an approximate four times higher risk of death compared with patients with normal CRP (HR 3.63; 95% CI 2.07 to 6.38, p<0.0001, figure 4); the risk of death was almost seven times higher when an elevated CRP >10 mg/L was combined with profound cyanosis (SO2<80%) (HR 6.75, 95% CI 3.36 to 13.62, p<0.0001). CRP change over time was also predictive of mortality on univariate (HR 1.18, 95% CI 1.05 to 1.32, p=0.0049) but not multivariate analysis (table 3).

    View this table:
    Table 4

    Results of the multivariate Cox regression analysis for mortality for predictors of outcome identified in the univariate analysis

    Discussion

    Our study has shown that CRP concentration is commonly raised in adult patients with CHD-PAH and that CRP elevation (>10 mg/mL) is associated with an approximate four times greater risk of death. CRP concentration was higher in patients in NYHA functional class ≥3, but there was no association between CRP and type of congenital heart defect, the presence of Down syndrome and the use of advanced therapies.

    CRP is a well-recognised acute-phase protein synthesised by hepatocytes in response to cytokines, such as IL-6, and represents a suitable and widely available marker to assess inflammation in clinical practice. A significant amount of evidence has clearly demonstrated its association with increased risk in healthy subjects and also patients with a range of cardiovascular diseases including coronary artery disease, heart failure and, recently, idiopathic PAH and CTEPH.5 CRP is also related to raised pulmonary arterial pressures in patients with chronic obstructive pulmonary disease, systemic lupus erythematosus and Gaucher's disease.10–12

    The relation between CRP and mortality in our CHD-PAH cohort and other types of pulmonary hypertension raises several interesting questions.5 Does the presence of raised CRP, and its relationship to outcome, suggest that pulmonary vascular remodelling in CHD-PAH is, at least in part, driven by inflammation? Or is an elevated CRP rather an epiphenomenon, not reflective of underlying inflammatory mechanism, but, nevertheless, becoming a marker of severity of disease and prognosis? It is now well accepted that inflammation is likely to play some part in pulmonary vascular remodelling observed not only in recognised ‘inflammatory conditions’ such as mixed connective tissue disease, lupus and POEMS syndrome but also in idiopathic PAH.3 In the latter, circulating and tissue concentration of cytokines and chemokines are elevated,4 ,13 with key mediators including IL-1, IL-6 and CXCL8 correlating with increased mortality.4 Furthermore, the nuclear factor kappa B (NF-κB), a transcription factor central to many inflammatory processes, is increased in vascular cells and macrophages in the lungs of patients with idiopathic PAH.14 Some of these mediators, including IL-6, are directly pro-proliferative to vascular cells in vitro15 and are strongly implicated in in vivo pulmonary hypertension models.16 ,17 Finally, clinical improvement has been observed in subtypes of PAH, such as the aforementioned mixed connective tissue disease, lupus and POEMS syndrome, when treated incidentally with anti-inflammatory therapies.18 ,19

    The evidence for inflammation in the development of pulmonary vascular remodelling associated with Eisenmenger syndrome, or other CHD, is sparser but nevertheless compelling. Eisenmenger syndrome is the final consequence of large intracardiac or extracardiac left to right shunts, which, when not repaired, lead in most of the cases to progressive PAH with ultimate reversal of flow and cyanosis. Whereas in idiopathic PAH, where it is possible that inflammation or an inflammatory insult such as an infection may precipitate the pathogenesis of PAH, this is clearly not the case in PAH-CHD. In the latter, pulmonary vascular disease is triggered by high pulmonary blood flow, high shear stress and/or hypoxaemia, which are known stimuli of inflammatory pathways and can propagate vascular remodelling. The effect of high pulmonary blood flow on the pulmonary vasculature has been demonstrated in a rodent model of monocrotaline (MCT) undergoing pneumonectomy (with increased flow in the remaining lung). The addition of pneumonectomy resulted in increased levels of inflammation, measured as oxidative stress, compared with MCT alone.20 We have previously shown that in the later and irreversible stages of CHD-PAH, there is an increased concentration of cytokines such as TNF-α and IL-6.6 There is also histological evidence of increased numbers of inflammatory cells, including macrophages and mast cells around the remodelled vessels of patients with CHD-PAH.21 ,22

    Could CRP itself be a mediator of vascular remodelling? CRP has been directly linked to the development of atherosclerosis and vascular remodelling in vitro. CRP was shown to attenuate nitric oxide production in endothelial cells and inhibit angiogenesis.23 Furthermore, CRP has pro-inflammatory effects on both human systemic vascular smooth muscle24 and endothelial cells.25 ,26 Finally, and of direct relevance to our findings, the stimulation of human pulmonary artery smooth muscle cells with increasing concentrations of CRP resulted in release of IL-6 and monocyte chemo-attractant protein-1 (MCP-1), as well as activation of NF-κB. This effect was completely abrogated with atorvastatin.27

    CRP could, on the other hand, be just a marker of disease severity.28 Irrespective of mediator or marker status, CRP appears to be a valid clinical tool for predicting outcome in CHD-PAH and other cardiovascular diseases, such as ischaemic heart disease and heart failure.29

    No relation was found in our study between CRP and the use of advanced therapies despite both being individually related to mortality.2 We believe there are good reasons to explain this paradox. It is debatable whether a high CRP is secondary to the high pressures in pulmonary vasculature or to the pulmonary vascular disease. Unlike BNP and NYHA functional class, which mostly reflect the hemodynamic burden, CRP concentration more likely represents a complementary aspect of the disease severity, linked to the inflammatory component of the pathogenesis. Importantly, the exact source of CRP production in CHD-PAH remains unknown. While advanced therapies can alter haemodynamics and oxygen tissue delivery,30 thus reducing the ischaemic burden to the liver (an important source of CRP), it is possible that advanced therapies may also potentiate the inflammatory component in the pulmonary circulation by augmenting pulmonary blood flow in patients with an unrestricted communication. Should this be the case, it would support CRP as a mediator rather than as a marker of disease severity.

    The main limitation of this study is its retrospective nature. We are a national, tertiary referral centre, therefore we may report on a biased population of patients with more symptoms and complex disease. However, we believe that our patient cohort is representative of current tertiary care practice of CHD-PAH. Future, prospective studies should validate our results and the accuracy of the survival prediction model, as well as shed additional light on both pathophysiology and response to advanced therapies, potentially inclusive of anti-inflammatory agents and/or statins.

    Both sensitivity and specificity of CRP as a single parameter for mortality risk stratification were suboptimal in our study. Previous studies have shown the association of echocardiographic data, 6MWD, oxygen saturation, as well as electrocardiographic data to mortality in this setting.31–33 Future studies combining multiple predictors into a risk stratification model are needed for accurate prognostication.

    In conclusion, our study demonstrates that serum CRP is a simple but powerful marker of mortality in CHD patients with PAH and should be therefore incorporated in the risk stratification and periodic assessment of these patients, irrespective of underlying anatomy or the presence of Down syndrome.

    Key messages

    What is already known on this subject?

    • There is increasing evidence supporting a role for inflammation in the pathogenesis of pulmonary arterial hypertension (PAH). The information on the role of inflammation in PAH related to congenital heart disease (CHD-PAH) is, however, limited.

    What this study adds?

    • Our study shows high prevalence of increased C-reactive protein (CRP) in CHD-PAH patients and provides lacking evidence for the value of CRP in mortality risk stratification.

    How might this impact on clinical practice?

    • CRP may be used as additional risk for mortality risk stratification and facilitate decision making in these complex patients.

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    Footnotes

    • GS and AK contributed equally. KD and SJW are equal last authors.

    • Contributors All authors have sufficiently contributed to the conception and design of the study, analysis and interpretation of data, drafting of the manuscript and revising it to justify authorship.

    • Funding This project was supported by the NIHR cardiovascular Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.

    • Competing interests AK is supported by a grant from Actelion UK. MAG, KD and the Royal Brompton Hospital Adult congenital Centre and Centre for Pulmonary Hypertension have received unrestricted education grants. MAG and KD have acted as consultants for Actelion UK, Pfizer UK and GSK UK. RA-G has acted as a consultant for Lilly Spain and Pfizer Spain. SJW has received unrestricted education and research grants from Bayer UK, Pfizer UK, Actelion UK and GSK UK as well as the Pulmonary Hypertension Association (UK). MAG and the Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension have received support from the Clinical Research Committee and the British Heart Foundation.

    • Ethics approval Research & Development Department of the Royal Brompton Hospital.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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