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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Role of cardiac biomarkers in assessment of RV function and prognosis in chronic pulmonary hypertension

Anna Fijalkowska* and Adam Torbicki

Department of Chest Medicine, Institute of Tuberculosis and Lung Diseases, Ul Plocka 26, 01-138 Warszawa, Poland

* Corresponding author. Tel: +48 22 4312114; fax: +48 22 4312414. E-mail address: a.fijalkowska{at}igichp.edu.pl


   Abstract
Top
 Abstract
Introduction
 Serum uric acid
 Natriuretic peptides (atrial and...
 Cardiac troponin
 Summary
 References
 
Humoral biomarkers emerged within the last decade as an attractive non-invasive tool for assessment and monitoring of right ventricular (RV) dysfunction in patients with pulmonary hypertension (PH). Combined with clinical assessment, they offer the possibility to reduce the frequency of traditional, time-consuming, complex, and costly tests. Echocardiography, right heart catheterization (RHC), or cardiac magnetic resonance (CMR) could then be reserved for detailed initial evaluation and for resolving more complex emerging clinical problems. Biomarkers would be particularly useful for outpatient monitoring and daily clinical practice. Our paper reviews the evidence collected so far in this dynamically developing area of cardiovascular medicine.

Key Words: Biomarkers • Pulmonary hypertension • Chronic heart failure • Right ventricular function • Prognosis


   Introduction
Top
 Abstract
 Introduction
Serum uric acid
 Natriuretic peptides (atrial and...
 Cardiac troponin
 Summary
 References
 
Different biomarkers which could be considered useful for clinical monitoring have different physiological links with cardiovascular system.1 Uric acid (UA) is not a true cardiac marker. Its increased release is a consequence of disturbed cellular metabolism because of poor peripheral tissue perfusion. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) as well as troponin (cTn) originate from cardiac myocytes. However, although natriuretic peptides serve as physiological elements of haemodynamic and fluid homeostasis, cTn is a marker of excessive damage of either myocytes or their contractile proteins. BNP and especially cardiac troponins were found useful for risk stratification of patients with acute RV dysfunction because of pulmonary embolism.2 This report will review the evidence regarding clinical value of biomarkers for diagnosis and monitoring of RV dysfunction and predicting clinical outcome in chronic PH.


   Serum uric acid
Top
 Abstract
 Introduction
 Serum uric acid
Natriuretic peptides (atrial and...
 Cardiac troponin
 Summary
 References
 
As a final product of purine degradation, UA is a marker of impaired oxidative metabolism of ischaemic peripheral tissue. In brief, tissue hypoxia depletes adenosine triphosphate, thus promoting degradation of adenine nucleotides to compounds including UA. Analysing UA levels and haemodynamics in 99 patients with idiopathic pulmonary arterial hypertension (PAH), Voelkel et al. found strongest correlation between UA plasma level and mean right atrial pressure (mRAP, r = 0.64, P < 0.001). The authors suggested that UA may be related to RV failure and that RV myocardium may directly contribute to the elevation of plasma UA. Of note, UA decreased in 11 of 18 patients treated chronically with i.v. prostacycline.3

High UA levels were found to correlate with survival in patients with idiopathic PAH (IPAH). Two studies indicated UA level as an independent prognostic indicator,4,5 whereas subsequent receiver operating characteristic curve (ROC) analysis did not assign satisfactory predictive power to this variable.6 Despite low incidence of clinical symptoms of gout, it is common practice to prescribe allopurinol to patients with PAH and hyperuricaemia. In addition, diuretics influence its plasma levels. This makes clinical monitoring based on UA levels practically impossible.


   Natriuretic peptides (atrial and brain natriuretic peptide)
Top
 Abstract
 Introduction
 Serum uric acid
 Natriuretic peptides (atrial and...
Cardiac troponin
 Summary
 References
 
Endocrine function of the heart was suspected more than 50 years ago and confirmed in 1981 by deBold et al.7 Rats injected with extracts from atrial myocytes responded with intensive natriuresis and diuresis. Such effect is a net response to ANP and BNP, which share similar physiological properties. Both induce vasodilatation and natriuresis and are released from cardiac myocardium in response to wall stress. ANP is mostly stored in granules in the atria, whereas BNP is released to blood as a result of ongoing synthesis, mostly from ventricular myocardium. ANP has higher affinity to a specific natriuretic peptide receptor type C, which results in its shorter plasma half-time.8

Nagaya et al.9 found similar rate of elevation of both natriuretic peptides in patients with volume overload. In contrast, ANP was much less responsive to RV pressure overload than BNP. A significant decrease in ANP, but not BNP plasma level, could be found in patients with idiopathic PH, who acutely responded with vasodilatation to inhaled nitric oxide. However, individual changes in ANP induced by the test were quite variable among the eight reported patients. In contrast, both ANP and BNP plasma levels halved as a result of a mean of 35 days of prostaglandin E (five patients) or prostacyclin (four patients) treatment. Nagaya et al. and later Tulevsky et al. showed similar significant correlations of both ANP and BNP with RV ejection fraction (RVEF), measured with electron beam computed tomography (EBCT)9 and CMR,10 respectively. In addition, similar correlations were found for both ANP and BNP with haemodynamic variables, including mRAP and RV end-diastolic pressure (RVEDP).9 However, a head-to-head comparison of the two natriuretic peptides showed ANP to be much less related to the effects of treatment and survival in patients with primary PH.11 Altogether, compared with BNP, ANP seemed a faster but relatively short-term responder, mostly to volume overload. This is why the interest regarding clinical application of natriuretic peptides in monitoring RV failure due to chronic PH focused on BNP.

BNP is produced mainly in ventricular cardiomyocites in response to ventricular volume or pressure overload. Diastolic wall stress is the main determinant of plasma BNP levels both in systolic and in diastolic ventricular failure.12 BNP synthesis and secretion are regulated at the gene level and the protein is directly released to circulating blood. More precisely, the final step of synthesis consists of a high-molecular-weight precursor, proBNP. It is then cleaved into biologically inactive N-terminal segment (NT-proBNP) and the proper low-molecular-weight BNP.13 BNP binds to the natriuretic peptide receptor type A, increasing intracellular cyclic guanosine monophosphate (GMP) production responsible for its biological effects. They include diuresis, vasodilatation, inhibition of renin and aldosterone production, and cardiac and vascular myocyte growth.14 Responding to increased ventricular wall stress, both BNP and NT-proBNP levels, was found useful in the diagnosis of left ventricular (LV) heart failure.5,15–17 However, NT-proBNP has longer half-life and better stability, both in circulating blood and after sampling. Although plasma concentrations of NT-proBNP and BNP are similar in normal subjects, NT-proBNP rises significantly higher in patients with LV dysfunction, suggesting that it may be a more discerning marker of cardiac dysfunction.16,18 In addition, in three independently assessed groups of patients with pre-capillary PH, mean plasma levels of NT-proBNP were more than 10 times higher than normal values.19–21

Brain natriuretic peptide for screening and diagnosis of right ventricular dysfunction
Theoretically, BNP and NT-proBNP should have limited utility in screening asymptomatic patients for mild PAH, not affecting RV function. However, in a pilot study involving 49 patients, NT-proBNP was reported to screen for PAH in scleroderma patients (cut-off >395 pg/mL, sensitivity 69%, and specificity 100%).22 Later, the same group assessed 109 patients with systemic sclerosis (SSc). According to RHC results, 68 individuals had PAH. At an NT-proBNP level of 395 pg/mL, the sensitivity and specificity for predicting the presence of SSc-PAH were 56 and 95%, respectively.21

NT-proBNP was also assessed in persistent PH of the newborns (PPHN). Newborns with respiratory distress due to PPHN had significantly higher mean level of BNP when compared with the levels found in the presence of other respiratory diseases or in healthy newborns.23

The first to investigate the secretion of BNP in isolated RV overload was Nagaya et al. They studied 44 patients with either atrial septal defect or idiopathic or thrombo-embolic PH. Plasma BNP correlated significantly with right-sided haemodynamic variables including mean pulmonary artery pressure (mPAP), total pulmonary resistance (TPR), mRAP, RVEDP, and cardiac output (CO). BNP correlated also with EBCT-derived RV myocardial mass and RVEF (Figure 1). Plasma concentrations of BNP were higher when sampled from the main pulmonary artery, but correlated with those taken from the femoral vein.9 Two subsequent trials assessed, respectively, 60 and 28 patients with IPAH. Both reported correlations of BNP with haemodynamic markers of RV dysfunction. BNP was also related to the clinical and functional status of the patients.11,24


Figure 1
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  		Figure 1 Correlation between brain natriuretic peptide and right ventricular ejection fraction (A) and right ventricular end-diastolic volume index. (B) According to Nagaya et al.9

 
The studies that focused on NT-proBNP reported similar observations. Significant correlations between plasma NT-proBNP and RAP, mPAP, cardiac index (CI), and indexed pulmonary vascular resistance have been shown in 22 patients with IPAH studied by Souza et al.,25 in 61 patients with various forms of chronic pre-capillary PH studied by Andreassen et al.,19 and in 68 patients with PAH and scleroderma reported by Williams et al.21 Although not all the studies found relationship between NT-proBNP and mPAP, correlations with haemodynamic markers of RV function were confirmed.20,26 In a group of 55 patients with PAH or chronic thrombo-embolic hypertension, we found that NT-proBNP levels correlated with echocardiographic indices of RV overload such as diastolic RV/LV ratio area and acceleration time of RV ejection.20 Recently, Gan et al.26 using CMR confirmed correlations of NT-proBNP with RV end-diastolic volume index and RVEF, but not with RV mass index. We also found that NT-proBNP increased significantly with the severity of functional class and that serum NT-proBNP showed a negative correlation with 6 min walk distance.20

Although BNP and NT-proBNP are related to the severity of RV dysfunction, cut-off levels that could help in its clinical staging have not been determined. This is partly due to reported high individual variability of the concentrations of natriuretic peptides, probably resulting from genetically determined variations in BNP secretion.13 In addition, BNP increases with age, renal insufficiency,27 and female gender and is influenced by obesity.28 Therefore, BNP seems better suited for long-term monitoring rather than for initial assessment of individual patients (Figures 2 and 3). In contrast, due to its relatively long half-time, BNP/NT-proBNP levels are questionable in assessing acute response to vasodilators.9,25


Figure 2
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  		Figure 2 NT-proBNP trends in 60-year-old man with idiopathic pulmonary arterial hypertension. Fall of NT-proBNP after first 3 months of treatment with sildenafil, progressive increase levels with peaks related to acute medical disease, or exacerbation of idiopathic pulmonary arterial hypertension. Improvement in clinical status and lowering level of NT-proBNP after adding s.c. treprostinil.

 

Figure 3
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  		Figure 3 Forty-year-old woman with idiopathic pulmonary arterial hypertension: significant decline of NT-proBNP concentration after the start of treatment with sildenafil paralleled with clinical and haemodynamic improvement. Temporal increases of NT-proBNP level related to acute medical conditions.

 
Brain natriuretic peptide and prognosis
RV failure is the main cause of death in PAH. As BNP/NT-proBNP levels reflect the severity of RV dysfunction, they could be considered as potential prognostic markers in this disease. In the study of Nagaya et al., baseline median value of BNP (150 pg/mL) discriminated patients with better and worse prognosis. In 49 of 60 patients, BNP measurement was repeated after 3 months of vasodilator therapy and again supramedian level (>180 pg/mL) was related to worse long-term outcome (Figure 4).11 Plasma BNP significantly decreased in survivors, but increased in non-survivors despite treatment. In the multivariate analysis, BNP was the only independent non-invasive marker of poor outcome during subsequent 2-year follow-up. When analysis was combined with haemodynamic indices, BNP still provided independent prognostic information. Among follow-up variables, only the BNP level assessed after 3 months of treatment was an independent predictor of mortality. Moreover, the ROC analysis suggested that the prognostic value of BNP was superior to CO.11 The applicability of those results is somewhat limited by applied treatment, which consisted mostly of oral beraprost, not approved outside Japan and Korea.


Figure 4
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  		Figure 4 Kaplan–Meier survival curves according to median values at baseline and at 3-month follow-up brain natriuretic peptide in patients with idiopathic pulmonary arterial hypertension, according to Nagaya et al.11

 
In a trial involving 68 patients with PAH associated with scleroderma, NT-proBNP below median of 553 pg/mL was related to 6-month and 1-year survival of 97 and 96%, respectively. Among patients with supra-median level, 82 and 73% survived 6 months and 1 year, respectively. This study also assessed prognostic significance of changes in NT-proBNP. In a subgroup of 52 patients with PAH due to scleroderma, NT-proBNP was sampled at 3-monthly intervals up to 1 year. For every 10-fold increase in baseline NT-proBNP level, there was a five-fold increased risk of death (HR 4.82, 95% CI 1.29, 18.05; P = 0.002), whereas for follow-up NT-proBNP values, a 10-fold increase was related to four-fold increased risk of dying (HR 3.82, 95% CI, 1.46, 9.96; P = 0.006).21

Using the ROC analysis, we identified serum NT-proBNP cut-off point at 1400 pg/mL as most predictive of 3-year outcome in 55 patients with severe pre-capillary PH.20 The same cut-off point was found optimal for a subgroup of 36 patients with idiopathic PAH (Figure 5). Serum NT-proBNP below 1400 pg/mL seemed particularly useful for identification of patients with good prognosis, who would not need escalation of treatment in the nearest future. Interestingly, similar cut-off value of 168 pmol/L (corresponding to 1418 pg/mL) was reported by Andreassen et al.19 in their study involving 61 patients with chronic pre-capillary PH. Stepwise multivariate analysis confirmed the significance of NT-proBNP as an independent prognostic marker.11,20 However, larger outcome trials are still required to verify the universal value of the suggested cut-off levels for NT-proBNP.


Figure 5
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  		Figure 5 Kaplan–Meier curves were significantly worse at 36 months in patients with severe pulmonary hypertension with initial NT-proBNP levels of ≥1400 pg/mL. Left: entire study group and right: subgroup with idiopathic pulmonary arterial hypertension, according to Fijalkowska et al.20

 
Monitoring of treatment with brain natriuretic peptide
Nagaya et al. were the first to show that the decrease of plasma BNP in nine patients treated with prostacyclin or prostaglandin E1 significantly correlated with the decrease in TPR after mean follow-up of 35 days. They suggested that BNP may be a potential marker of the efficacy of long-term treatment.9 A more recent study of 30 patients with PAH treated with modern pharmacotherapy in whom BNP was measured at baseline and after 12.6 ± 1.5 months supported this suggestion. Absolute changes of BNP levels paralleled the changes in RAP, PAP, and PVR and correlated negatively with the changes in CI and 6 min walk distance.29 Significant fall of plasma BNP/NT-proBNP levels was also reported after successful thromboendarterectomy in chronic thrombo-embolic PH.30 Our own unpublished observations of patients with PAH treated with sildenafil within the SUPER-1 trial as well as recent congress report (N. Galie, American Thoracic Society 2006) regarding patients treated with ambrisentan in the ARIES trial suggest that NT-proBNP may reflect beneficial effects of oral pharmacotherapy in PAH. In contrast, as already discussed, treatment failure was strongly suggested by the rise in serially assessed NT-proBNP levels in patients with PAH associated with scleroderma.21 However, it should be reminded that serial measurement of NT-proBNP may be also influenced by exacerbations of RV dysfunction unrelated to progression of PAH. We observed significant increase in NT-proBNP because of infections, hyperthyreosis, and similar clinical conditions (Figures 1 and 2).


   Cardiac troponin
Top
 Abstract
 Introduction
 Serum uric acid
 Natriuretic peptides (atrial and...
 Cardiac troponin
Summary
 References
 
Troponin is a contractile regulatory protein complex of striated muscles consisting of three components C, I, and T. Cardiac troponin T (cTnT) and troponin I (cTnI) are established specific markers of myocardial damage and prognostic indicators in coronary syndromes. There are only few reports concerning importance of elevated levels of troponin in patients with chronic RV dysfunction.

Basal cTnT measured before cardiac catheterization in 48 children with different congenital heart defects was significantly elevated and further increased with cardiac catheterization in subgroup with concomitant PH. The authors suggested that it might be caused by an ongoing subtle myocardial ischaemia.31

A single trial assessed prognostic significance of cTnT in patients with RV dysfunction because of chronic pre-capillary PH (51 patients with PAH and five with chronic thrombo-embolic PH). Cardiac TnT leakage was assessed with a high sensitivity test detecting plasma levels down to 0.01 ng/mL. Elevated cTnT was an independent predictor of fatal outcome during 2-year follow-up (Figure 6). Most haemodynamic variables, including RAP, PAP, and CI, were similar in patients with and without detectable plasma cTnT. In contrast, heart rate was markedly increased in patients with detectable cTnT. This could suggest that excessive sympathetic activation induced by systemic hypotension contributed to RV myocardial injury.32 It is not clear whether cTnT leak detected with high-sensitive test is merely a prognostic marker or also indicates ongoing clinically relevant necrosis of the myocytes contributing to RV failure. A recent experimental study in rats with monocrotaline-induced PH seems to suggest intracellular degradation of cTnT in the failing RV myocardium.33


Figure 6
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  		Figure 6 Kaplan–Meier cumulative survival curves for 56 patients with severe pulmonary hypertension. In the troponin T (+) group, the overall survival rates were significantly worse than those in group troponin T (–), according to Torbicki et al.32

 
Whichever the mechanism, elevated cTnT indicated worse prognosis in patients with PAH or chromic thrombo-embolic pulmonary hypertension (CTEPH). Interestingly, in some patients, cTnT disappeared from plasma either temporarily or permanently after the introduction of treatment. The role of monitoring of cTnT level in patients with PH still requires confirmation in future studies. However, in contrast to BNP, its main role in chronic PH should probably be in identifying very high-risk patients requiring intensification of therapy.


   Summary
Top
 Abstract
 Introduction
 Serum uric acid
 Natriuretic peptides (atrial and...
 Cardiac troponin
 Summary
References
 
Biochemical markers seem to carry clinically relevant information regarding RV function and prognosis in patients with chronic PH. Each month brings new data allowing for more precise assessment of their value and limitations. However, already it is clear that, at least, BNP/NT-proBNP will probably contribute to everyday clinical practice by improving and simplifying follow-up of patients with PAH.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Serum uric acid
 Natriuretic peptides (atrial and...
 Cardiac troponin
 Summary
 References
 

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