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CRP in Pulmonary Hypertension
Abstract & commentary
By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.
Source: Quarck R, et al. C-reactive protein. A new predictor of adverse outcome in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;53:1211-1218.
New markers for a variety of diseases have recently received considerable attention, specifically B-type natriuretic peptide (BNP), N-terminal-pro-BNP, C-reactive protein, or CRP, and CRP-hs (high sensitivity). Levels of these compounds are useful guides in assessing the severity of important medical conditions, such as congestive heart failure and acute myocardial infarction chest pain. CRP-hs is not disease-specific and, generally, increased levels reflect inflammation or infection. CRP elevations are found in a variety of diseases/conditions. A new study assesses the value of measuring CRP levels in severe pulmonary hypertension (PH) subjects. The results are encouraging, demonstrating that CRP levels are useful predictors of mortality in several types of PH.
Two types of PH were evaluated: consecutive patents with classic pulmonary artery hypertension (PAH), characterized by distal pulmonary arterial arteriopathy; chronic thromboembolic pulmonary hypertension (CTEPH) with "occasional" proximal vessel occlusions and distal vessel remodeling; and normal controls. An inflammatory substrate has been suggested by some in PAH; recent data have reported increased interleukin-1, interleukin-6, and CX chemokine macrophage inflammatory-chalk protein-1 alpha. CTEPH with "dysregulated thrombus" may contribute to the pathophysiology of PH. CCL2 chemokine monocyte chemoattractive protein is unregulated in large pulmonary arteries in CTEPH subjects. Thus, significant inflammation in PH patients is not certain, but is probable, with CRP serving as a marker for inflammation.
This study seeks to see if CRP levels could be predictive of PAH severity and subsequent outcomes. The protocol employed was a prospective study of consecutive PAH and CTEPH subjects, all of whom underwent right heart catheterization (University of Leuven) between 2004-2008. Parameters studied included functional class, a 6-min walking test (6 MWD), medications, and right heart hemodynamic data (right-sided catheterization); survival rates were documented. C-reactive protein blood samples were analyzed. Specific levels of CRP were expressed in log mg per liter and will not be reported in this narrative, as they are not commonly used in U.S. labs' reporting of CRP levels.
Baseline survival and event-free Kaplan-Meier survival curves were generated, contrasting subjects with CRP above and below the upper limit of normal. Sensitivity and specificity of CRP to predict survival was assessed via ROC operating characteristics. Cox regression was utilized, and multiple variables were included.
Results: Two pulmonary hypertension patient populations were examined, 104 with PAH, 79 with CTEPH, and a control group of 95 healthy subjects. Half of the PAH patients had idiopathic PAH and half had associated diseases. In the CTEPH cohort, 75% had a history of acute venous pulmonary thromboembolism, with 66% having at least one thrombophilic disorder. Overall, 35 patients died, 44 CETPH had a pulmonary endarterectomy, five PAH had a living transplant, and 11 were started on prostacyclin analogs.
CRP was higher than controls but not different between CTEPH and PAH subjects. In PAH patients, CRP levels correlated with NYHA functional class, RA pressure and, inversely, with the 6-min walk test. CRP levels were higher in NYHA III-IV patients and non-survivors, who had lower functional class, higher RAP, and poorer 6-min walk outcomes. Kaplan-Meier curves showed that all PAH, idiopathic PAH, and treatment-naive patients had a lower two-year survival (65% vs. 82%, p = 0.02) with high CRP levels. Subjects with CRP above the upper limits of normal had a lower event-free survival (two years 57% vs. 75%). Lower levels of CRP were associated with better event-free survival at two years. NYHA class, CRP, 6 MWD, etiology, and RAP predicted increased mortality in PAH. Disease-specific medication in PAH subjects was associated with a significant decrease in PVR. Patients with disease-specific treatments had better outcomes overall. Patients who normalized CRP (responders) had higher survival rate at three years.
The authors conclude, "...CRP levels were higher in patients with pulmonary hypertension compared to those with control subjects. Severe pulmonary hypertension was associated with increased circulatory CRP levels....CRP predicted mortality and clinical worsening." The key observation: "The novelty of the present study is a potential role of CRP as a predictor of adverse responses to therapy in PAH."
Quarck et al propose that CRP is an independent predictor of outcomes in PAH, as suggested in prior studies of COPD patients. They suggest adding CRP to NT-pro-BNP as a biomarker in the evaluation of pulmonary hypertension. They conclude that CRP can help predict outcomes and response to therapy in PAH. Subjects who had normalization of CRP concentrations "had a significantly better survival with a decrease in NYHA functional class and an increase in cardiac index." The data suggest that the beneficial effects of prostacyclin analogues can be suggested by a fall in CRP into the normal range. CRP levels were noted to improve after pulmonary artery endarterectomy, suggesting another role for CRP. The low-cost, low-risk measurement of CRP should be considered in the evaluation of patients with pulmonary hypertension and in the selection of therapeutic options.
C-reactive protein or CRP is a marker of inflammation which has been valuable in assessing outcomes in various settings. The recent JUPITER trial suggests that elevated CRP-hs in subjects without overt vascular disease and normal LDL cholesterol identifies patients who may benefit from statin therapy. This report deals with a very different population severe pulmonary hypertension of various causation. Evidence of inflammation as an important player in PAH patients is suggested by this report, with elevated inflammation markers and compounds. These data are consistent with evidence that CRP can play a role in determining severity and, perhaps, outcomes of PAH of various causation.
The number of subjects in each category or etiology of pulmonary artery hypertension is relatively small; 104 with typical pulmonary arterial hypertension (PAH); 79 with CTEPH or chronic thromboembolic hypertension; and 95 control subjects. Also, therapy was not standardized or adjusted based upon the CRP levels, so the role of CRP in selecting and adjusting therapy is speculative. The data support the view that a CRP higher than "normal" is associated with an increased risk of death, no matter the cause of PAH. However, increased mortality is seen in patients with poor LV function, high NYHA class, high right-atrial pressure and a poor 6-min walk test.
NT-pro-PNP has also been used as a marker of outcomes in PAH. Quarck et al emphasize that, in addition, CRP has prognostic value and is low cost. I agree that it may be worthwhile to obtain serial CRP measurements, and the data in this study suggest it can guide potential treatment with various new approaches during follow-up. Much more data are needed, particularly regarding the use of CRP cut-off points to predict outcomes, which seem somewhat of a blunt instrument.