Abstract

Heart Failure (HF) represents a major burden on the health care system, and has increased the need for developing better interventions to combat this condition and reduce the rate of hospitalizations. Cardiac biomarkers have recently emerged as important diagnostic and prognostic tools. The constantly evolving role of biomarkers stems from the need for a rapid, objective and reliable test with good specificity and sensitivity for identifying patients with acute dyspnea presenting to the emergency department (ED) who have acute HF. The purpose of this review is to explore the superiority of mid- regional proANP (MR- proANP) in diagnosing HF with respect to other biomarkers such as BNP and NT– pro BNP.

Introduction

Natriuretic peptides are released from the heart due to increased myocardial wall stretch caused by volume and pressure overload. The most important members of this family include atrial natriuretic peptide (ANP) and B- type natriuretic peptide (BNP) and their amino terminal fragments NT-proANP and NT-proBNP. ANP is derived as the cleavage product of proANP, a 126-amino acid polypeptide⁽¹⁾ and its secretion is accompanied by the release of the N-terminal part of the pro-atrial natriuretic peptide NT-proANP.⁽²⁾ Both ANP and BNP are useful for diagnosing HF^{(3, 4)} as well as to risk stratify patients with decompensated HF.^(5-7) ANP is rapidly released into the circulation in response to atrial wall stretch, but due to its extremely short-half life (2-5 min) is not a useful tool in a clinical setting. However, NT- proANP is a more reliable substrate than ANP⁽¹⁾, although its diagnostic and prognostic performance is inferior to BNP/NT-proBNP^(8-10) mainly due to its suboptimal assay design and not due to the analyte itself. BNP and NT-proBNP are considered superior to ANP/NT–proANP, but their testing is limited by caveats that may make their interpretation difficult at times.

MR-proANP is the mid regional epitope of the ANP prohormone isolated by directing antibodies to the mid-region of the molecule⁽¹¹⁾ and in comparison to BNP/NT-proBNP is a more robust analyte in the circulation and is a more reliable substrate for analysis that may provide clinically relevant diagnostic and prognostic information in addition to standard natriuretic peptide testing for the assessment of HF.

MRproANP Levels and the Diagnosis of HF

The large multinational BACH trial⁽¹²⁾, evaluated 1641 patients with dyspnea presenting to the ED to evaluate the diagnostic utility of MR-proANP in acute HF. Adjudication was performed by two cardiologists blinded to the other’s assessment. The study demonstrated that MR-proANP at a predefined cutpoint of 120pmol/L was noninferior to BNP at a predefined cutpoint of 100 pg/mL for the diagnosis of acute HF. BNP had a sensitivity of 96%, specificity of 62%, positive predictive value of 57%, and a negative predictive value of 96%. In comparison, MR-proANP at a cutpoint of 120pmol/L had a sensitivity of 97%, specificity of 60%, positive predictive value of 56%, and a negative predictive value of 97%. Combining MR-proANP and BNP increased the overall diagnostic accuracy from 73.6% for BNP alone to 76.6%. Moreover, receiver operating characteristic (ROC) analysis of MR-proANP (Figure 1A) in diagnosing acute HF had an area under the curve (AUC) of 0.90 for MR-proANP (95% CI: 0.88-0.91; p<0.0001) and AUC of 0.91 (0.90-0.93; p<0.0001) for BNP. The study also demonstrated a strong association between BNP and MR-proANP (Figure 1B). Thus, MR-proANP was found to be non – inferior to both BNP/NT-proBNP in diagnosing HF in patients presenting with shortness of breath to the ED./p>

A study by Potocki et al.⁽¹³⁾ compared the accuracy of MR- proANP to that of NT proBNP in the diagnosis of HF. Of the 287 participants enrolled in this study, 154 (54%) were diagnosed with HF. The median MR- proANP concentration was higher in patients with HF as compared to patients without HF (400 pmol/L vs. 92 pmol/L, p< 0.001). ROC analysis for diagnosing HF produced an AUC of 0.92 for MR-proANP identical to the AUC of 0.92 for NT-proBNP. Moreover, when MR-proANP levels > 206pmol/L was added to clinical judgment, it increased the diagnostic accuracy to almost 88% (P<0.001) similar to NT–proBNP which was 86.4%, resulting in fewer misdiagnosed false negative patients with HF. MR-proANP also provided incremental diagnostic information to BNP and NT-proBNP in patients presenting with levels in the grey zone (100-500 pg/ml), thus reducing one of the major limitations associated with their clinical use. The findings from this large observational cohort study showed that MR-proANP is a comparatively accurate marker for the diagnosis of HF.

MR-proANP Levels in the Prognosis of CHF

MR- proANP is not only a useful biomarker for diagnosing HF, it has also proved to be an useful marker for risk stratification. Strong evidence regarding its prognostic performance was demonstrated by Moertl et al.⁽¹⁴⁾ who conducted a study on 797 patients with HF to detect left ventricular systolic dysfunction along with BNP and NT- proBNP. Left ventricular ejection fraction (LVEF), glomerular filtration rate (GFR), and the presence of ankle edema were independent predictors of the natriuretic peptides, whereas age and BMI were not. ROC curves for detection of LVEF <40% were similar between MR-proANP (0.799 [95% CI: 0.753 - 0.844]), BNP (0.803 [95% CI: 0.757 - 0.849]), and NT- proBNP (0.730 [95% CI: 0.681 -0.778]). ROC derived cutoff values for the detection of LVEF <40% showed MR- proANP at a cutpoint of 122mmol/L had a sensitivity of 67.3% and specificity of 81.1%, NT-proBNP at a cutpoint of 1869 pg/mL had a sensitivity of 71.8% and specificity of 62.0% and BNP at a cutpoint of 218pg/mL had a sensitivity of 80.9% and specificity of 70.7%, respectively. MR- proANP (4.4%) clearly outperformed NT- proBNP (2.5%) and BNP (2.4%) for predicting death. The reason for this prognostic superiority of MR- proANP might be explained by the higher biological stability of the molecule and the use of an assay directed to the midregion of the molecule. This study emphasized that despite similarities in influencing factors and detection of reduced LVEF, MR- proANP outperformed BNP and NT- proBNP for predicting death in chronic HF.

Conclusion

Despite advances in managing patients with HF, it remains a burgeoning problem on the health care system.^{(15, 16)} Recent advance have shown that natriuretic peptides have aided in the diagnosis and prognosis of such patients. Given the importance of risk stratification, additional biomarkers that probe different neurohormonal pathways may further help to prevent disease progression and prognosis. While the studies discussed above are few, they conclusively point to the value of MR-proANP for the diagnosis and prognosis of patients with HF. While it is considered the third valid natriuretic peptide marker for HF patients, its use may also be helpful when diagnostic uncertainity exists after measurement of BNP or NT–proBNP.

---

References

1. Vesely DL. Atrial natriuretic peptide prohormone gene expression: hormones and diseases that upregulate its expression. IUBMB Life 2002; 53:153–9.
2. Ruskoaho H. Cardiac hormones as diagnostic tools in heart failure. Endocr Rev 2003; 24:341–56.
3. Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet 1997; 350:1349–53.
4. Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med 2004; 350:647–54.
5. Omland T, Aakvaag A, Bonarjee VV, et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide. Circulation 1996; 93:1963–9.
6. Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (VAL-HEFT). Circulation 2003; 107:1278–83.
7. ChengV, KazanagraR, GarciaA, etal. ArapidbedsidetestforB-type peptide predicts treatment outcomes in patients admitted for decom- pensated heart failure: a pilot study. J Am Coll Cardiol 2001; 37:386–91.
8. Choy AM, Darbar D, Lang CC, et al. Detection of left ventricular dysfunction after acute myocardial infarction. Br Heart J 1994; 72:16–22.
9. Yamamoto K, Burnett JC Jr., Jougasaki M, et al. Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension 1996; 28:988–94.
10. Hammerer-Lercher A, Neubauer E, Muller S, Pachinger O, Puschen- dorf B, Mair J. Head-to-head comparison of N-terminal pro-brain natriuretic peptide, brain natriuretic peptide and N-terminal pro-atrial natriuretic peptide in diagnosing left ventricular dysfunction. Clin Chim Acta 2001; 310:193–7.
11. Morgenthaler NG Struck J, Thomas B, BergmannA. Immunoluminometric assay for the midregion of pro-atrial natriuretic peptide in human plasma. Clin Chem 2004; 50:234–6.
12. Maisel A S et al. Mid-Region Pro-Hormone Markers for Diagnosis and Prognosis in Acute Dyspnea-Results from the BACH (Biomarkers in Acute Heart Failure) Trial. J Am Coll Cardiol 2010; 55:2062-76.
13. Potocki M, Breidthardt T, Reichlin T et al. Comparison of midregional pro-atrial natriuretic peptide with N-terminal pro-B-type natriuretic peptide in the diagnosis of heart failure. J Intern Med 2010; 267:119-29.
14. Moertl D et al. Comparison of Midregional Pro-Atrial and B-Type Natriuretic Peptides in Chronic Heart Failure. J Am Coll Cardiol 2009; 53:1783-90.
15. McMurray J, Cohen-Solal A, Dietz R, et al. Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice. Eur J Heart Failure 2005; 7:710e21.
16. Bristow MR, Saxon LA, Boehmer J, et al; for the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. New Engl J Med 2004; 350:2140e50.

Keywords: Dyspnea, Edema, Glomerular Filtration Rate, Half-Life, Heart Failure, Atrial Natriuretic Factor, Prognosis, ROC Curve, Cohort Studies, Biomarkers, Disease Progression, Area Under Curve, Natriuretic Peptide, Brain

< Back to Listings