N a t r i u ret i c P e p t i d e s in H e a r t Fa i l u re w i t h P re s e r v e d E j e c t i o n F r a c t i o n A. Mark Richards, MB ChB, MD, PhD, FRACP, FRCPa,b,*, James L. Januzzi Jr, MDc, Richard W. Troughton, MB ChB, PhD, FRACPb KEYWORDS Heart failure Cardiac natriuretic peptides B-type natriuretic peptide N-terminal prohormone B-type natriuretic peptide Diagnosis Prognosis
KEY POINTS Threshold values of B-type natriuretic peptide (BNP) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) validated for diagnosis of undifferentiated acutely decompensated heart failure (ADHF) remain useful in patients with heart failure with preserved ejection fraction (HFPEF), with minor loss of diagnostic performance. BNP and NT-proBNP measured on admission with ADHF are powerfully predictive of in-hospital mortality in both HFPEF and heart failure with reduced EF (HFREF), with similar or greater risk in HFPEF as in HFREF associated with any given level of either peptide. In stable treated heart failure, plasma natriuretic peptide concentrations often fall below cut-point values used for the diagnosis of ADHF in the emergency department; in HFPEF, levels average approximately half those in HFREF. BNP and NT-proBNP are powerful independent prognostic markers in both chronic HFREF and chronic HFPEF, and the risk of important clinical adverse outcomes for a given peptide level is similar regardless of left ventricular ejection fraction. Serial measurement of BNP or NT-proBNP to monitor status and guide treatment in chronic heart failure may be more applicable in HFREF than in HFPEF.
Timely diagnosis, early introduction of appropriate treatment, accurate risk stratification, and optimal titration of therapy are all key to the management
of heart failure (HF). Plasma cardiac natriuretic peptides (NPs) are valuable aids in each of these elements of care. However, most data are derived from undifferentiated HF or HF with reduced ejection fraction (HFREF). The performance and best
Disclosures: Professor A.M. Richards is the recipient of speakers honoraria, consultancy fees and/or research grants (in cash or in kind) from Roche Diagnostics, Alere and Critical Diagnostics. Professor J.L. Januzzi is the recipient of speakers honoraria, consultancy fees, and/or research grants from Roche Diagnostics, Siemens, Thermo Fisher, Singulex, Critical Diagnostics, Zensun, Amgen, and Novartis. Professor R.W. Troughton is the recipient of grants and/or speakers honoraria/consulting fees from Roche Diagnostics and St. Jude Medical. a Cardiac Department, Cardiovascular Research Institute, National University Heart Centre, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 9, Singapore 119228, Singapore; b Department of Medicine, Christchurch Heart Institute, University of Otago, Christchurch, 2 Riccarton Avenue, Christchurch 8140, New Zealand; c Cardiac Intensive Care Unit, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA * Corresponding author. Cardiac Department, Cardiovascular Research Institute, National University Heart Centre, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 9, Singapore 119228, Singapore. E-mail addresses: [email protected]; [email protected] Heart Failure Clin - (2014) -–http://dx.doi.org/10.1016/j.hfc.2014.04.006 1551-7136/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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INTRODUCTION
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Richards et al application of NPs in heart failure with preserved ejection fraction (HFPEF) is less certain. This uncertainty is not unimportant, as a substantial percentage of patients with HF presently have HFPEF. This review outlines the evidence for the use of NPs in the evaluation and management of HFPEF. The bioactivity of atrial NP (ANP) and B-type NP (BNP) encompasses short-term and longterm hemodynamic, renal, neurohormonal, and trophic effects.1 The relationship between cardiac hemodynamic load, plasma concentrations of ANP and BNP, and the cardioprotective profile of NP bioactivity have led to investigation of both biomarker and therapeutic potential of NPs in HF. Use of parenteral human recombinant BNP received approval from the Food and Drug Administration for relief of symptoms of acutely decompensated heart failure (ADHF) and human ANP is used in Japan in the context of acute myocardial infarction.2,3 However, the accumulated evidence does not support any significant advantage of BNP therapy over other treatments, and NP infusions are not recommended for routine use in ADHF, although they may be of value in defined niche applications.4 Data on therapeutic value, or lack thereof, specifically in HFPEF are absent. Therefore, the remainder of this review is focused on the diagnostic, prognostic, and monitoring applications of measurement of plasma concentrations of NPs in HFPEF. Single or serial measurement of plasma NPs, particularly the B-type peptides including BNP and its cosecreted amino-terminal congener N-terminal prohormone BNP (NT-proBNP), is currently endorsed within authoritative guidelines on the diagnosis and management of HF.5,6 Best proven as an adjunct to the diagnosis of ADHF in patients presenting with new-onset breathlessness,7,8 both BNP and NT-proBNP are also acknowledged as powerful independent prognostic markers in acute and chronic HF,8–11 and serial measurement is gaining acceptance as a useful guide for titration of therapy and monitoring in chronic HF.12–15 Despite the growing array of candidate biomarkers in HFPEF,16,17 the B-type NPs are the best studied and have exhibited the strongest performance to date.
NATRIURETIC PEPTIDES AND THE DIAGNOSIS OF ADHF IN HFPEF Landmark trials of the NPs, including the Breathing Not Properly and the International Collaborative on NT-proBNP (ICON) studies, defined optimal
threshold values for BNP and NT-proBNP in diagnosing ADHF among heterogeneous populations of patients presenting to the emergency department (ED) with new-onset breathlessness.7,8 From the Breathing Not Properly trial, among a subgroup of 452 patients with an adjudicated diagnosis of ADHF and with echocardiographic estimates of left ventricular ejection fraction (LVEF) obtained within 30 days of their presentation, 165 (36.5%) had HFPEF (LVEF >45%) and 287 (63.5%) HFREF.18 Plasma BNP was lower in HFPEF than in HFREF (median 413 vs 821 pg/mL; P20% reduction) as well.14,15 The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment (GUIDEIT) trial (ClinicalTrials.gov NCT01685840) is under way, and will provide definitive data on application of the strategy in HFREF. Serial measurement of NPs for guiding treatment titration and improving outcomes is effective in HFREF but may not be as applicable in HFPEF.
Trials of hormone-guided treatment in chronic HF have included approximately 2000 patients.14,15 Most participants (>90%) have had HFREF and, hence, our ability to assess the likely utility of this approach in HFPEF is severely limited. The TIMECHF investigators have provided the only dedicated report on this issue.44 TIME-CHF recruited patients 60 years of age or older with dyspnea (NYHA class II or more) and a history of admission for HF within the last 12 months, and NT-proBNP levels of 400 pg/mL or higher in those younger than 75 years and 800 pg/mL or higher in those older than 75. Both HFREF and HFPEF subjects were recruited, but these subgroups have been reported separately. In the 499 HFREF participants in TIME-CHF the average age was 77 years, mean LVEF about 30%, and plasma concentrations of NT-proBNP approximately 4000 pg/mL. Mortality (hazard ratio 0.68 [0.45–1.02], P 5 .06) and HF admissions (hazard ratio 0.68 [0.50–0.92], P 5 .01) were improved, and this was more apparent in those younger than 75 years (mortality hazard ratio 0.41 [0.19–0.87], P 5 .01).13 Recently, results from the 123 HFPEF participants in TIME-CHF have been published.44 Their average age was 80 years and LVEF 56%, and NT-proBNP levels (w2200 pg/mL) were lower than in HFREF participants in TIME-CHF (w4000 pg/mL). Worryingly, NT-proBNP–guided treatment was associated with worse clinical outcomes in HFPEF, with significant interactions between LVEF stratum and management strategy
for survival (HFPEF hazard ratio 1.82 [0.83–4.01] vs HFREF 0.68 [0.45–1.02]; P 5 .03 for interaction) and HF hospitalization-free survival (HFPEF hazard ratio 1.64 [0.89–3.0] vs HFREF 0.68 [0.5–0.92]; P 5 .01 for interaction). This discouraging signal from a single report on a small sample of HFPEF patients cannot be regarded as definitive, and corroboration in independent and larger samples is required. However, the pattern is consistent with the absence of proven therapies for HFPEF. If there is no proven therapy in HFPEF, titrating doses of ineffective therapy against plasma NP concentrations is likely to be futile. Moreover, the results from TIME-CHF raise the specter of harm from this approach in HFPEF. The pronounced sensitivity of ventricular filling pressures, systemic arterial pressure, and renal perfusion pressure in response to relatively subtle changes in circulating volume and pressures, such as those induced by vasodilator and diuretic drugs in patients with small, stiff HFPEF hearts, may underlie this result. Daily plasma BNP concentrations have been obtained using a finger-prick point-of-care technology in both HFREF and HFPEF participants in the recently reported HF Assessment with B-type Natriuretic Peptide in the Home (HABIT) study.45 Unlike the relatively slow evolving trends over days or weeks in plasma BNP observed in HFREF patients, a subset of HFPEF patients, without clinical ADHF, exhibited rapid spikes and falls in plasma BNP with clear elevation well above the normal range alternating with falls to frankly normal values, occurring at intervals of hours to 1 or 2 days only (Fig. 7). Again this may reflect the steeper relationship between shifts in circulating volumes and changes in intracardiac pressures that occur in HFPEF, compared with HFREF. This pattern may render marker-guided titration of therapy inapplicable to at least a subgroup of HFPEF.
INSIGHTS INTO NPS IN HFPEF FROM RANDOMIZED CONTROLLED THERAPEUTIC TRIALS The data yielded by 2 large trials, Val-HeFT and I-PRESERVE, on typical plasma concentrations of the BNPs in chronic HFREF and chronic HFPEF, respectively, and their respective relationships to prognosis, have been discussed earlier in this review.9,10 Randomized controlled trials of therapy in HFPEF suggest that plasma NT-proBNP is a valid surrogate end point.
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Fig. 7. Serial daily pin-prick BNP readings in a patient with HFPEF (upper) and another with HFREF (lower) without clinical evidence of acute decompensated heart failure in either case. Volatile spiking of plasma BNP from the normal to the acute heart failure range is observed in the HFPEF case, with cycles occurring over brief periods of 1 to 3 days. Upper axes show BNP (left axis, blue) and weight minus mean (right axis, green). Lower axes show symptoms (red squares) where SW is a day of swelling, SB is a day of shortness of breath, and WG is a day of weight gain (5 lb within 3 days). HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association functional class. (From Maisel A, Barnard D, Jaski B, et al. Primary results of the HABIT trial (heart failure assessment with BNP in the home). J Am Coll Cardiol 2013;61(16):1726–35; with permission.)
In general, because elevated BNP or NTproBNP are associated with higher risk, marker thresholds are included in selection criteria for inclusion in therapeutic trials to enrich the trial population and provide adequate event rates to help ensure the trial is powered to detect any clinically
significant effects of the experimental therapy on key clinical end points. The corollary is the added expectation that benefit will be more apparent and more easily detected in those with higher marker levels. In this regard, I-PRESERVE yielded an unexpected result: benefit of treatment with
Natriuretic Peptides in HFPEF irbesartan was associated with baseline NTproBNP plasma concentrations below the median (339 pg/mL). This relationship between submedian NT-proBNP levels with therapeutic benefit was retained even after adjustment for 20 covariates, and was observed for the primary end point of all-cause mortality plus prespecified cardiovascular hospitalizations (hazard ratio 0.74 [0.60–0.90], P 5 .003), all-cause mortality (hazard ratio 0.75 [0.56–0.99], P 5 .046) and HF death or hospitalization (hazard ratio 0.57 [0.41–0.80], P 5 .001).11 Does this mean that irbesartan is only of benefit in earlier or milder stages of HFPEF? The result is surprising, but is derived from a large data set and is consistent across clinical end points. It casts doubt on the exact role, if any, of angiotensin-receptor antagonists in HFPEF, and it is confusing with respect to use of peptides for case-selection purposes in therapeutic trials. This finding requires corroboration. Another trial, Aldo-DHF, tested 25 mg spironolactone versus placebo in HFPEF (>50 years, LVEF 50% and NYHA class II or III, diastolic dysfunction on echo of grade I or higher, and peak oxygen uptake [VO2] of 25 mL/kg/min or less).46 Treatment reduced E/E0 and LV mass without improving symptoms or maximum VO2. NT-proBNP, a secondary end point, declined with spironolactone more than in the placebo group at 6 and 12 months of treatment (P 5 .03). It is notable that baseline levels of NT-proBNP were not markedly elevated, with median values of 165 and 152 pg/mL in the placebo and spironolactone group, respectively. These levels are half those seen in I-PRESERVE, and may reflect patient selection. Of note, a history of an episode of frank cardiac decompensation was not required for inclusion and, therefore, this trial may have selected for mild HF. In the Prospective Comparison of ARNI with ARB on Management of HFPEF (PARAMOUNT) study, 149 patients (LVEF 45%, NYHA class II–III, and NT-proBNP >400 pg/mL with a documented history of HF) were randomized to receive either valsartan or a novel drug (LCZ696) combining angiotensin-receptor blockade with neprilysin inhibition (NEPI).47 Neprilysin (EC 3.4.24.11) enzymatically cleaves the ring structure of mature bioactive carboxy-terminal bioactive ANP, BNP, and C-type NP. NEPI is thought to exert therapeutic effects via delayed NP clearance and increased plasma NP concentrations. NTproBNP is not a neprilysin substrate and, therefore, falling plasma levels still faithfully reflect cardiac decompression with associated reductions in cardiac release of NPs. About 80% had an LVEF greater than 50%. The primary end point
was decline in NT-proBNP over 12 weeks of treatment. Median NT-proBNP decreased from 783 pg/mL to 605 pg/mL in those on LCZ696, compared with 862 to 835 pg/mL in the valsartan group (P 5 .005). In addition, LCZ696 significantly reduced left atrial volumes and improved NYHA functional class. This population is clearly different to that recruited to Aldo-DHF, with NT-proBNP levels even higher than those recorded in I-PRESERVE and actually approximating values observed in HFREF participants in Val-HeFT (median 895 pg/mL). In contrast to I-PRESERVE, there was no interaction of baseline NT-proBNP levels with response to therapy. The long-awaited results of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial (NCT00094302)48 have been presented in major meetings but are yet to be published. This trial of spironolactone in HFPEF recruited 3445 patients older than 50 years with HF signs and symptoms, and either a history of hospitalization with HF in the past 12 months (n 5 2480) or elevated plasma B-type peptide levels (ie, BNP >100 pg/mL or NT-proBNP >360 pg/mL, n 5 965). Although no improvement in all-cause mortality or sudden cardiac death was observed, rates of HF hospitalization were improved. Of note, outcomes were more clearly improved in the subset of patients selected according to the nominated BNP or NT-proBNP thresholds.
SUMMARY Data on BNP and NT-proBNP specifically in HFPEF are scant in comparison with undifferentiated acute HF and certainly less well defined than in patients with HFREF.
Plasma NPs are useful in HFPEF for: 1. Diagnosis in ADHF 2. Prognosis 3. As a surrogate end point in therapeutic trials Plasma NPs are not currently applicable in HFPEF for: 1. Community screening for early HFPEF 2. Excluding HFPEF in stable treated patients 3. Guiding treatment in chronic HFPEF by serial measurement
Population screening using BNP or NT-proBNP to detect early HFPEF is unlikely to be fruitful. In chronic HF, BNP or NT-proBNP are equally strong independent predictors of important adverse end
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Richards et al points in both HFREF and HFPEF. Across the span of plasma levels for both peptides, a 4- to 6-fold range of risk in both phenotypes and absolute levels of BNP and NT-proBNP are associated with similar levels of risk in HFREF and HFPEF. Change in BNP levels may be a valid surrogate end point in therapeutic trials in HFPEF. Whether trial case selection according to BNP values is an effective strategy to enrich trial populations for treatment “responders” is unclear. Guided treatment of chronic HFPEF according to serial NP measurements may be less useful in HFPEF than in HFREF. Plasma BNP or NT-proBNP is on average lower (about half) in both ADHF and chronic HF in HFPEF when compared with HFREF. However, the elevation of BNP or NT-proBNP concentrations in HFPEF with ADHF still provides sufficient signal to noise to provide good diagnostic performance. Acute elevations measured at the time of hospitalization for ADHF are associated with similar risks of in-hospital mortality in both HFREF and HFPEF. In early HFPEF or in stable, treated HFPEF, plasma NP levels will be lower than in HFREF and may well be normal in many cases, and diagnostic cut-points are not well defined. On a background of near normal levels, confounding factors including obesity, age, and renal function are important, and may preclude the use of NPs to rule out compensated HFPEF.
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REFERENCES 1. Espiner EA, Richards AM. Atrial natriuretic peptide. An important factor in sodium and blood pressure regulation. Lancet 1989;333:707–10. 2. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32–43. 3. Saito Y. Roles of atrial natriuretic peptide and its therapeutic use. J Cardiol 2010;56:262–70. 4. Mentzer RM, Oz MC, Sladen RN, et al. Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery. The NAPA trial. J Am Coll Cardiol 2007;49:716–26. 5. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33:1787–847. http://dx.doi.org/10.1093/eurheartj/ ehs104. 6. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/ AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on
13.
14.
15.
16.
17.
practice guidelines. Circulation 2013;128:e240–327. http://dx.doi.org/10.1161/CIR. 0b013e31829e8776. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161–7. Januzzi JL, van Kimmenade R, Lainchbury J, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients the International Collaborative of NT-proBNP Study. Eur Heart J 2006;27:330–7. Masson S, Latini R, Anand IS, et al. Direct comparison of B-type natriuretic peptide (BNP) and aminoterminal proBNP in a large population of patients with chronic and symptomatic heart failure: the valsartan heart failure (Val-HeFT) data. Clin Chem 2006;52:1528–38. Komajda M, Carson PE, Hetzel S, et al. Factors associated with outcome in heart failure with preserved ejection fraction findings from the irbesartan in heart failure with preserved ejection fraction study (I- PRESERVE). Circ Heart Fail 2011;4:27–35. Anand IS, Rector TS, Cleland JG, et al. Prognostic value of baseline plasma amino-terminal pro-brain natriuretic peptide and its interactions with irbesartan treatment effects in patients with heart failure and preserved ejection fraction: findings from the I-PRESERVE trial. Circ Heart Fail 2011;4:569–77. Lainchbury JG, Troughton RW, Strangman KM, et al. N-terminal Pro–B-type natriuretic peptide-guided treatment for chronic heart failure results from the BATTLESCARRED (NT-proBNP–assisted treatment to lessen serial cardiac readmissions and death) trial. J Am Coll Cardiol 2010;55:53–60. Pfisterer M, Buser P, Rickli H, et al. (TIME-CHF) randomized trial elderly patients with congestive heart failure the trial of intensified vs standard medical therapy in BNP-guided vs symptom-guided heart failure therapy. JAMA 2009;301:383–92. Savarese G, Trimarco B, Dellegrottaglie S, et al. Natriuretic peptide-guided therapy in chronic heart failure: a meta-analysis of 2,686 patients in 12 randomized trials. PLoS One 2013;8:58287. http://dx. doi.org/10.1371/journal.pone.0058287. Troughton RW, Frampton CM, Brunner-La Rocca HP, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J 2014. http://dx.doi.org/10.1093/ eurheartj/ehu090. O’Meara E, de Denus S, Rouleau J-L, et al. Circulating biomarkers in patients with heart failure and preserved ejection fraction. Curr Heart Fail Rep 2013;10:350–8. Cheng JM, Akkerhuis KM, Battes LC, et al. Biomarkers of heart failure with normal ejection
Natriuretic Peptides in HFPEF
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
fraction: a systematic review. Eur J Heart Fail 2013; 15:1350–62. Maisel AS, McCord J, Nowak RM, et al. Bedside Btype natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction results from the breathing not properly multinational study. J Am Coll Cardiol 2003;41:2010–7. Januzzi JL, Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) study. Am J Cardiol 2005;95:948–54. O’Donoghue M, Chen A, Baggish AI, et al. The effects of ejection fraction on N-terminal ProBNP and BNP levels in patients with acute CHF: analysis from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study. J Card Fail 2005;11(Suppl 5):S9–14. Troughton RW, Prior DL, Pereira JJ, et al. Plasma BNP levels in systolic heart failure: the importance of left ventricular diastolic and right ventricular function. J Am Coll Cardiol 2004;43:416–22. Troughton RW, Richards AM. B-type natriuretic peptides and echocardiographic measures of cardiac structure and function. JACC Cardiovasc Imaging 2009;2:216–25. Jaubert MP, Armero S, Bonello L, et al. Predictors of B-type natriuretic peptide and left atrial volume index in patients with preserved left ventricular systolic function: an echocardiographic-catheterization study. Arch Cardiovasc Dis 2010;103:3–9. Iwanaga Y, Nishi I, Furuichi S, et al. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure comparison between systolic and diastolic heart failure. J Am Coll Cardiol 2006;47:742–8. Kraigher-Krainer E, Shah AM, Gupta DK, et al. Impaired systolic function by strain imaging in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014;63:447–56. Richards AM, Di Somma S, Mueller C, et al. Atrial fibrillation impairs the diagnostic performance of cardiac natriuretic peptides in dyspneic patients: results from the biomarkers in acute heart failure (BACH) study. JACC Heart Fail 2013;1:192–9. Linssen GC, Rienstra M, Jaarsma T, et al. Clinical and prognostic effects of atrial fibrillation in heart failure patients with reduced and preserved left ventricular ejection fraction. Eur heart J 2011;13:1111–20. McKelvie RS, Komajda M, Mc Murray J, et al. Baseline plasma NT-proBNP and clinical characteristics: results from the irbesartan in heart failure with preserved ejection fraction trial. J Card Fail 2010;16: 128–34. Anjan VY, Loftus TM, Burke MA, et al. Prevalence, clinical phenotype, and outcomes associated with normal B-type natriuretic peptide levels in heart
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
failure with preserved ejection fraction. Am J Cardiol 2012;110:870–6. Hildebrandt P, Collinson PO, Doughty RN, et al. Agedependent values of N-terminal pro-B-type natriuretic peptide are superior to a single cutpoint for ruling out suspected systolic dysfunction in primary care. Eur Heart J 2010;31:1881–9. Costello-Boerrigter LC, Boerrigter G, Redfield RM, et al. Amino-terminal Pro-B-type natriuretic peptide and B-type natriuretic peptide in the general community. Determinants and detection of left ventricular dysfunction. J Am Coll Cardiol 2006; 47:345–53. Mason JM, Hancock HC, Close H, et al. Utility of biomarkers in the differential diagnosis of heart failure in older people: findings from the heart failure in care homes (HFinCH) diagnostic accuracy study. PLoS One 2013;8:e53560. Paulus WJ, Tscho¨pe C, Sanderson JE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28: 2539–50. Sudoh T, Kangawa K, Minamino N, et al. A new natriuretic peptide in porcine brain. Nature 1988; 332:78–81. Hunt PJ, Yandle TG, Nicholls MG, et al. The aminoterminal portion of pro-brain natriuretic peptide (Pro-BNP) circulates in human plasma. Biochem Biophys Res Commun 1995;214:1175–83. Wang TJ, Larsen MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004;350:655–63. McDonagh TA, Cunningham AD, Morrison CE, et al. Left ventricular dysfunction, natriuretic peptides, and mortality in an urban population. Heart 2001; 86:21–6. Baptista R, Jorge E, Sousa E, et al. B type natriuretic peptide predicts long-term prognosis in a cohort of critically ill patients. Heart Int 2011;6:e18. http://dx. doi.org/10.4081/hi. 2011.e18. Kucher N, Printzen G, Goldhaber SZ. Prognostic role of brain natriuretic peptide in acute pulmonary embolism. Circulation 2003;107:2545–7. Hsich EM, Grau-Sepulveda MV, Hernandez AF, et al. Relationship between sex, ejection fraction, and B-type natriuretic peptide levels in patients hospitalized with heart failure and associations with inhospital outcomes: findings from the Get with the Guideline—Heart Failure registry. Am Heart J 2013; 166:1063–71. Fonarow GC, Peacock WF, Phillips CO, et al. Admission B-type natriuretic peptide levels and in-hospital mortality in acute decompensated heart failure. J Am Coll Cardiol 2007;49:1943–50.
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Richards et al 42. van Veldhuisen DJ, Linssen GC, Jaarsma T, et al. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol 2013;61:1498–506. 43. Latini R, Masson S, Anand I, et al. The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure enrolled in Val-HeFT. Eur Heart J 2004;25:292–9. 44. Maeder MT, Rickenbacher P, Rickli H, et al. N-terminal pro brain natriuretic peptide-guided management in patients with heart failure and preserved ejection fraction: findings from the trial of intensified versus standard medical therapy in elderly patients with congestive heart failure (TIME-CHF). Eur J Heart Fail 2013;15:1148–56. 45. Maisel A, Barnard D, Jaski B, et al. Primary results of the HABIT trial (heart failure assessment with
BNP in the home). J Am Coll Cardiol 2013;61: 1726–35. 46. Edelmann F, Wachter R, Schmidt AG, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction. The Aldo-DHF randomized controlled trial. JAMA 2013;309:781–91. 47. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 doubleblind randomised controlled trial. Lancet 2012;380: 1387–95. 48. Desai AS, Lewis EF, Li R, et al. Rationale and design of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial: a randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction. Am Heart J 2011;162:966–72.
KEY POINTS Threshold values of B-type natriuretic peptide (BNP) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) validated for diagnosis of undifferentiated acutely decompensated heart failure (ADHF) remain useful in patients with heart failure with preserved ejection fraction (HFPEF), with minor loss of diagnostic performance. BNP and NT-proBNP measured on admission with ADHF are powerfully predictive of in-hospital mortality in both HFPEF and heart failure with reduced EF (HFREF), with similar or greater risk in HFPEF as in HFREF associated with any given level of either peptide. In stable treated heart failure, plasma natriuretic peptide concentrations often fall below cut-point values used for the diagnosis of ADHF in the emergency department; in HFPEF, levels average approximately half those in HFREF. BNP and NT-proBNP are powerful independent prognostic markers in both chronic HFREF and chronic HFPEF, and the risk of important clinical adverse outcomes for a given peptide level is similar regardless of left ventricular ejection fraction. Serial measurement of BNP or NT-proBNP to monitor status and guide treatment in chronic heart failure may be more applicable in HFREF than in HFPEF.
Timely diagnosis, early introduction of appropriate treatment, accurate risk stratification, and optimal titration of therapy are all key to the management
of heart failure (HF). Plasma cardiac natriuretic peptides (NPs) are valuable aids in each of these elements of care. However, most data are derived from undifferentiated HF or HF with reduced ejection fraction (HFREF). The performance and best
Disclosures: Professor A.M. Richards is the recipient of speakers honoraria, consultancy fees and/or research grants (in cash or in kind) from Roche Diagnostics, Alere and Critical Diagnostics. Professor J.L. Januzzi is the recipient of speakers honoraria, consultancy fees, and/or research grants from Roche Diagnostics, Siemens, Thermo Fisher, Singulex, Critical Diagnostics, Zensun, Amgen, and Novartis. Professor R.W. Troughton is the recipient of grants and/or speakers honoraria/consulting fees from Roche Diagnostics and St. Jude Medical. a Cardiac Department, Cardiovascular Research Institute, National University Heart Centre, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 9, Singapore 119228, Singapore; b Department of Medicine, Christchurch Heart Institute, University of Otago, Christchurch, 2 Riccarton Avenue, Christchurch 8140, New Zealand; c Cardiac Intensive Care Unit, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA * Corresponding author. Cardiac Department, Cardiovascular Research Institute, National University Heart Centre, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 9, Singapore 119228, Singapore. E-mail addresses: [email protected]; [email protected] Heart Failure Clin - (2014) -–http://dx.doi.org/10.1016/j.hfc.2014.04.006 1551-7136/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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INTRODUCTION
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Richards et al application of NPs in heart failure with preserved ejection fraction (HFPEF) is less certain. This uncertainty is not unimportant, as a substantial percentage of patients with HF presently have HFPEF. This review outlines the evidence for the use of NPs in the evaluation and management of HFPEF. The bioactivity of atrial NP (ANP) and B-type NP (BNP) encompasses short-term and longterm hemodynamic, renal, neurohormonal, and trophic effects.1 The relationship between cardiac hemodynamic load, plasma concentrations of ANP and BNP, and the cardioprotective profile of NP bioactivity have led to investigation of both biomarker and therapeutic potential of NPs in HF. Use of parenteral human recombinant BNP received approval from the Food and Drug Administration for relief of symptoms of acutely decompensated heart failure (ADHF) and human ANP is used in Japan in the context of acute myocardial infarction.2,3 However, the accumulated evidence does not support any significant advantage of BNP therapy over other treatments, and NP infusions are not recommended for routine use in ADHF, although they may be of value in defined niche applications.4 Data on therapeutic value, or lack thereof, specifically in HFPEF are absent. Therefore, the remainder of this review is focused on the diagnostic, prognostic, and monitoring applications of measurement of plasma concentrations of NPs in HFPEF. Single or serial measurement of plasma NPs, particularly the B-type peptides including BNP and its cosecreted amino-terminal congener N-terminal prohormone BNP (NT-proBNP), is currently endorsed within authoritative guidelines on the diagnosis and management of HF.5,6 Best proven as an adjunct to the diagnosis of ADHF in patients presenting with new-onset breathlessness,7,8 both BNP and NT-proBNP are also acknowledged as powerful independent prognostic markers in acute and chronic HF,8–11 and serial measurement is gaining acceptance as a useful guide for titration of therapy and monitoring in chronic HF.12–15 Despite the growing array of candidate biomarkers in HFPEF,16,17 the B-type NPs are the best studied and have exhibited the strongest performance to date.
NATRIURETIC PEPTIDES AND THE DIAGNOSIS OF ADHF IN HFPEF Landmark trials of the NPs, including the Breathing Not Properly and the International Collaborative on NT-proBNP (ICON) studies, defined optimal
threshold values for BNP and NT-proBNP in diagnosing ADHF among heterogeneous populations of patients presenting to the emergency department (ED) with new-onset breathlessness.7,8 From the Breathing Not Properly trial, among a subgroup of 452 patients with an adjudicated diagnosis of ADHF and with echocardiographic estimates of left ventricular ejection fraction (LVEF) obtained within 30 days of their presentation, 165 (36.5%) had HFPEF (LVEF >45%) and 287 (63.5%) HFREF.18 Plasma BNP was lower in HFPEF than in HFREF (median 413 vs 821 pg/mL; P20% reduction) as well.14,15 The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment (GUIDEIT) trial (ClinicalTrials.gov NCT01685840) is under way, and will provide definitive data on application of the strategy in HFREF. Serial measurement of NPs for guiding treatment titration and improving outcomes is effective in HFREF but may not be as applicable in HFPEF.
Trials of hormone-guided treatment in chronic HF have included approximately 2000 patients.14,15 Most participants (>90%) have had HFREF and, hence, our ability to assess the likely utility of this approach in HFPEF is severely limited. The TIMECHF investigators have provided the only dedicated report on this issue.44 TIME-CHF recruited patients 60 years of age or older with dyspnea (NYHA class II or more) and a history of admission for HF within the last 12 months, and NT-proBNP levels of 400 pg/mL or higher in those younger than 75 years and 800 pg/mL or higher in those older than 75. Both HFREF and HFPEF subjects were recruited, but these subgroups have been reported separately. In the 499 HFREF participants in TIME-CHF the average age was 77 years, mean LVEF about 30%, and plasma concentrations of NT-proBNP approximately 4000 pg/mL. Mortality (hazard ratio 0.68 [0.45–1.02], P 5 .06) and HF admissions (hazard ratio 0.68 [0.50–0.92], P 5 .01) were improved, and this was more apparent in those younger than 75 years (mortality hazard ratio 0.41 [0.19–0.87], P 5 .01).13 Recently, results from the 123 HFPEF participants in TIME-CHF have been published.44 Their average age was 80 years and LVEF 56%, and NT-proBNP levels (w2200 pg/mL) were lower than in HFREF participants in TIME-CHF (w4000 pg/mL). Worryingly, NT-proBNP–guided treatment was associated with worse clinical outcomes in HFPEF, with significant interactions between LVEF stratum and management strategy
for survival (HFPEF hazard ratio 1.82 [0.83–4.01] vs HFREF 0.68 [0.45–1.02]; P 5 .03 for interaction) and HF hospitalization-free survival (HFPEF hazard ratio 1.64 [0.89–3.0] vs HFREF 0.68 [0.5–0.92]; P 5 .01 for interaction). This discouraging signal from a single report on a small sample of HFPEF patients cannot be regarded as definitive, and corroboration in independent and larger samples is required. However, the pattern is consistent with the absence of proven therapies for HFPEF. If there is no proven therapy in HFPEF, titrating doses of ineffective therapy against plasma NP concentrations is likely to be futile. Moreover, the results from TIME-CHF raise the specter of harm from this approach in HFPEF. The pronounced sensitivity of ventricular filling pressures, systemic arterial pressure, and renal perfusion pressure in response to relatively subtle changes in circulating volume and pressures, such as those induced by vasodilator and diuretic drugs in patients with small, stiff HFPEF hearts, may underlie this result. Daily plasma BNP concentrations have been obtained using a finger-prick point-of-care technology in both HFREF and HFPEF participants in the recently reported HF Assessment with B-type Natriuretic Peptide in the Home (HABIT) study.45 Unlike the relatively slow evolving trends over days or weeks in plasma BNP observed in HFREF patients, a subset of HFPEF patients, without clinical ADHF, exhibited rapid spikes and falls in plasma BNP with clear elevation well above the normal range alternating with falls to frankly normal values, occurring at intervals of hours to 1 or 2 days only (Fig. 7). Again this may reflect the steeper relationship between shifts in circulating volumes and changes in intracardiac pressures that occur in HFPEF, compared with HFREF. This pattern may render marker-guided titration of therapy inapplicable to at least a subgroup of HFPEF.
INSIGHTS INTO NPS IN HFPEF FROM RANDOMIZED CONTROLLED THERAPEUTIC TRIALS The data yielded by 2 large trials, Val-HeFT and I-PRESERVE, on typical plasma concentrations of the BNPs in chronic HFREF and chronic HFPEF, respectively, and their respective relationships to prognosis, have been discussed earlier in this review.9,10 Randomized controlled trials of therapy in HFPEF suggest that plasma NT-proBNP is a valid surrogate end point.
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Fig. 7. Serial daily pin-prick BNP readings in a patient with HFPEF (upper) and another with HFREF (lower) without clinical evidence of acute decompensated heart failure in either case. Volatile spiking of plasma BNP from the normal to the acute heart failure range is observed in the HFPEF case, with cycles occurring over brief periods of 1 to 3 days. Upper axes show BNP (left axis, blue) and weight minus mean (right axis, green). Lower axes show symptoms (red squares) where SW is a day of swelling, SB is a day of shortness of breath, and WG is a day of weight gain (5 lb within 3 days). HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association functional class. (From Maisel A, Barnard D, Jaski B, et al. Primary results of the HABIT trial (heart failure assessment with BNP in the home). J Am Coll Cardiol 2013;61(16):1726–35; with permission.)
In general, because elevated BNP or NTproBNP are associated with higher risk, marker thresholds are included in selection criteria for inclusion in therapeutic trials to enrich the trial population and provide adequate event rates to help ensure the trial is powered to detect any clinically
significant effects of the experimental therapy on key clinical end points. The corollary is the added expectation that benefit will be more apparent and more easily detected in those with higher marker levels. In this regard, I-PRESERVE yielded an unexpected result: benefit of treatment with
Natriuretic Peptides in HFPEF irbesartan was associated with baseline NTproBNP plasma concentrations below the median (339 pg/mL). This relationship between submedian NT-proBNP levels with therapeutic benefit was retained even after adjustment for 20 covariates, and was observed for the primary end point of all-cause mortality plus prespecified cardiovascular hospitalizations (hazard ratio 0.74 [0.60–0.90], P 5 .003), all-cause mortality (hazard ratio 0.75 [0.56–0.99], P 5 .046) and HF death or hospitalization (hazard ratio 0.57 [0.41–0.80], P 5 .001).11 Does this mean that irbesartan is only of benefit in earlier or milder stages of HFPEF? The result is surprising, but is derived from a large data set and is consistent across clinical end points. It casts doubt on the exact role, if any, of angiotensin-receptor antagonists in HFPEF, and it is confusing with respect to use of peptides for case-selection purposes in therapeutic trials. This finding requires corroboration. Another trial, Aldo-DHF, tested 25 mg spironolactone versus placebo in HFPEF (>50 years, LVEF 50% and NYHA class II or III, diastolic dysfunction on echo of grade I or higher, and peak oxygen uptake [VO2] of 25 mL/kg/min or less).46 Treatment reduced E/E0 and LV mass without improving symptoms or maximum VO2. NT-proBNP, a secondary end point, declined with spironolactone more than in the placebo group at 6 and 12 months of treatment (P 5 .03). It is notable that baseline levels of NT-proBNP were not markedly elevated, with median values of 165 and 152 pg/mL in the placebo and spironolactone group, respectively. These levels are half those seen in I-PRESERVE, and may reflect patient selection. Of note, a history of an episode of frank cardiac decompensation was not required for inclusion and, therefore, this trial may have selected for mild HF. In the Prospective Comparison of ARNI with ARB on Management of HFPEF (PARAMOUNT) study, 149 patients (LVEF 45%, NYHA class II–III, and NT-proBNP >400 pg/mL with a documented history of HF) were randomized to receive either valsartan or a novel drug (LCZ696) combining angiotensin-receptor blockade with neprilysin inhibition (NEPI).47 Neprilysin (EC 3.4.24.11) enzymatically cleaves the ring structure of mature bioactive carboxy-terminal bioactive ANP, BNP, and C-type NP. NEPI is thought to exert therapeutic effects via delayed NP clearance and increased plasma NP concentrations. NTproBNP is not a neprilysin substrate and, therefore, falling plasma levels still faithfully reflect cardiac decompression with associated reductions in cardiac release of NPs. About 80% had an LVEF greater than 50%. The primary end point
was decline in NT-proBNP over 12 weeks of treatment. Median NT-proBNP decreased from 783 pg/mL to 605 pg/mL in those on LCZ696, compared with 862 to 835 pg/mL in the valsartan group (P 5 .005). In addition, LCZ696 significantly reduced left atrial volumes and improved NYHA functional class. This population is clearly different to that recruited to Aldo-DHF, with NT-proBNP levels even higher than those recorded in I-PRESERVE and actually approximating values observed in HFREF participants in Val-HeFT (median 895 pg/mL). In contrast to I-PRESERVE, there was no interaction of baseline NT-proBNP levels with response to therapy. The long-awaited results of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial (NCT00094302)48 have been presented in major meetings but are yet to be published. This trial of spironolactone in HFPEF recruited 3445 patients older than 50 years with HF signs and symptoms, and either a history of hospitalization with HF in the past 12 months (n 5 2480) or elevated plasma B-type peptide levels (ie, BNP >100 pg/mL or NT-proBNP >360 pg/mL, n 5 965). Although no improvement in all-cause mortality or sudden cardiac death was observed, rates of HF hospitalization were improved. Of note, outcomes were more clearly improved in the subset of patients selected according to the nominated BNP or NT-proBNP thresholds.
SUMMARY Data on BNP and NT-proBNP specifically in HFPEF are scant in comparison with undifferentiated acute HF and certainly less well defined than in patients with HFREF.
Plasma NPs are useful in HFPEF for: 1. Diagnosis in ADHF 2. Prognosis 3. As a surrogate end point in therapeutic trials Plasma NPs are not currently applicable in HFPEF for: 1. Community screening for early HFPEF 2. Excluding HFPEF in stable treated patients 3. Guiding treatment in chronic HFPEF by serial measurement
Population screening using BNP or NT-proBNP to detect early HFPEF is unlikely to be fruitful. In chronic HF, BNP or NT-proBNP are equally strong independent predictors of important adverse end
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Richards et al points in both HFREF and HFPEF. Across the span of plasma levels for both peptides, a 4- to 6-fold range of risk in both phenotypes and absolute levels of BNP and NT-proBNP are associated with similar levels of risk in HFREF and HFPEF. Change in BNP levels may be a valid surrogate end point in therapeutic trials in HFPEF. Whether trial case selection according to BNP values is an effective strategy to enrich trial populations for treatment “responders” is unclear. Guided treatment of chronic HFPEF according to serial NP measurements may be less useful in HFPEF than in HFREF. Plasma BNP or NT-proBNP is on average lower (about half) in both ADHF and chronic HF in HFPEF when compared with HFREF. However, the elevation of BNP or NT-proBNP concentrations in HFPEF with ADHF still provides sufficient signal to noise to provide good diagnostic performance. Acute elevations measured at the time of hospitalization for ADHF are associated with similar risks of in-hospital mortality in both HFREF and HFPEF. In early HFPEF or in stable, treated HFPEF, plasma NP levels will be lower than in HFREF and may well be normal in many cases, and diagnostic cut-points are not well defined. On a background of near normal levels, confounding factors including obesity, age, and renal function are important, and may preclude the use of NPs to rule out compensated HFPEF.
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REFERENCES 1. Espiner EA, Richards AM. Atrial natriuretic peptide. An important factor in sodium and blood pressure regulation. Lancet 1989;333:707–10. 2. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32–43. 3. Saito Y. Roles of atrial natriuretic peptide and its therapeutic use. J Cardiol 2010;56:262–70. 4. Mentzer RM, Oz MC, Sladen RN, et al. Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery. The NAPA trial. J Am Coll Cardiol 2007;49:716–26. 5. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33:1787–847. http://dx.doi.org/10.1093/eurheartj/ ehs104. 6. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/ AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on
13.
14.
15.
16.
17.
practice guidelines. Circulation 2013;128:e240–327. http://dx.doi.org/10.1161/CIR. 0b013e31829e8776. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161–7. Januzzi JL, van Kimmenade R, Lainchbury J, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients the International Collaborative of NT-proBNP Study. Eur Heart J 2006;27:330–7. Masson S, Latini R, Anand IS, et al. Direct comparison of B-type natriuretic peptide (BNP) and aminoterminal proBNP in a large population of patients with chronic and symptomatic heart failure: the valsartan heart failure (Val-HeFT) data. Clin Chem 2006;52:1528–38. Komajda M, Carson PE, Hetzel S, et al. Factors associated with outcome in heart failure with preserved ejection fraction findings from the irbesartan in heart failure with preserved ejection fraction study (I- PRESERVE). Circ Heart Fail 2011;4:27–35. Anand IS, Rector TS, Cleland JG, et al. Prognostic value of baseline plasma amino-terminal pro-brain natriuretic peptide and its interactions with irbesartan treatment effects in patients with heart failure and preserved ejection fraction: findings from the I-PRESERVE trial. Circ Heart Fail 2011;4:569–77. Lainchbury JG, Troughton RW, Strangman KM, et al. N-terminal Pro–B-type natriuretic peptide-guided treatment for chronic heart failure results from the BATTLESCARRED (NT-proBNP–assisted treatment to lessen serial cardiac readmissions and death) trial. J Am Coll Cardiol 2010;55:53–60. Pfisterer M, Buser P, Rickli H, et al. (TIME-CHF) randomized trial elderly patients with congestive heart failure the trial of intensified vs standard medical therapy in BNP-guided vs symptom-guided heart failure therapy. JAMA 2009;301:383–92. Savarese G, Trimarco B, Dellegrottaglie S, et al. Natriuretic peptide-guided therapy in chronic heart failure: a meta-analysis of 2,686 patients in 12 randomized trials. PLoS One 2013;8:58287. http://dx. doi.org/10.1371/journal.pone.0058287. Troughton RW, Frampton CM, Brunner-La Rocca HP, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J 2014. http://dx.doi.org/10.1093/ eurheartj/ehu090. O’Meara E, de Denus S, Rouleau J-L, et al. Circulating biomarkers in patients with heart failure and preserved ejection fraction. Curr Heart Fail Rep 2013;10:350–8. Cheng JM, Akkerhuis KM, Battes LC, et al. Biomarkers of heart failure with normal ejection
Natriuretic Peptides in HFPEF
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
fraction: a systematic review. Eur J Heart Fail 2013; 15:1350–62. Maisel AS, McCord J, Nowak RM, et al. Bedside Btype natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction results from the breathing not properly multinational study. J Am Coll Cardiol 2003;41:2010–7. Januzzi JL, Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) study. Am J Cardiol 2005;95:948–54. O’Donoghue M, Chen A, Baggish AI, et al. The effects of ejection fraction on N-terminal ProBNP and BNP levels in patients with acute CHF: analysis from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study. J Card Fail 2005;11(Suppl 5):S9–14. Troughton RW, Prior DL, Pereira JJ, et al. Plasma BNP levels in systolic heart failure: the importance of left ventricular diastolic and right ventricular function. J Am Coll Cardiol 2004;43:416–22. Troughton RW, Richards AM. B-type natriuretic peptides and echocardiographic measures of cardiac structure and function. JACC Cardiovasc Imaging 2009;2:216–25. Jaubert MP, Armero S, Bonello L, et al. Predictors of B-type natriuretic peptide and left atrial volume index in patients with preserved left ventricular systolic function: an echocardiographic-catheterization study. Arch Cardiovasc Dis 2010;103:3–9. Iwanaga Y, Nishi I, Furuichi S, et al. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure comparison between systolic and diastolic heart failure. J Am Coll Cardiol 2006;47:742–8. Kraigher-Krainer E, Shah AM, Gupta DK, et al. Impaired systolic function by strain imaging in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014;63:447–56. Richards AM, Di Somma S, Mueller C, et al. Atrial fibrillation impairs the diagnostic performance of cardiac natriuretic peptides in dyspneic patients: results from the biomarkers in acute heart failure (BACH) study. JACC Heart Fail 2013;1:192–9. Linssen GC, Rienstra M, Jaarsma T, et al. Clinical and prognostic effects of atrial fibrillation in heart failure patients with reduced and preserved left ventricular ejection fraction. Eur heart J 2011;13:1111–20. McKelvie RS, Komajda M, Mc Murray J, et al. Baseline plasma NT-proBNP and clinical characteristics: results from the irbesartan in heart failure with preserved ejection fraction trial. J Card Fail 2010;16: 128–34. Anjan VY, Loftus TM, Burke MA, et al. Prevalence, clinical phenotype, and outcomes associated with normal B-type natriuretic peptide levels in heart
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
failure with preserved ejection fraction. Am J Cardiol 2012;110:870–6. Hildebrandt P, Collinson PO, Doughty RN, et al. Agedependent values of N-terminal pro-B-type natriuretic peptide are superior to a single cutpoint for ruling out suspected systolic dysfunction in primary care. Eur Heart J 2010;31:1881–9. Costello-Boerrigter LC, Boerrigter G, Redfield RM, et al. Amino-terminal Pro-B-type natriuretic peptide and B-type natriuretic peptide in the general community. Determinants and detection of left ventricular dysfunction. J Am Coll Cardiol 2006; 47:345–53. Mason JM, Hancock HC, Close H, et al. Utility of biomarkers in the differential diagnosis of heart failure in older people: findings from the heart failure in care homes (HFinCH) diagnostic accuracy study. PLoS One 2013;8:e53560. Paulus WJ, Tscho¨pe C, Sanderson JE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28: 2539–50. Sudoh T, Kangawa K, Minamino N, et al. A new natriuretic peptide in porcine brain. Nature 1988; 332:78–81. Hunt PJ, Yandle TG, Nicholls MG, et al. The aminoterminal portion of pro-brain natriuretic peptide (Pro-BNP) circulates in human plasma. Biochem Biophys Res Commun 1995;214:1175–83. Wang TJ, Larsen MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004;350:655–63. McDonagh TA, Cunningham AD, Morrison CE, et al. Left ventricular dysfunction, natriuretic peptides, and mortality in an urban population. Heart 2001; 86:21–6. Baptista R, Jorge E, Sousa E, et al. B type natriuretic peptide predicts long-term prognosis in a cohort of critically ill patients. Heart Int 2011;6:e18. http://dx. doi.org/10.4081/hi. 2011.e18. Kucher N, Printzen G, Goldhaber SZ. Prognostic role of brain natriuretic peptide in acute pulmonary embolism. Circulation 2003;107:2545–7. Hsich EM, Grau-Sepulveda MV, Hernandez AF, et al. Relationship between sex, ejection fraction, and B-type natriuretic peptide levels in patients hospitalized with heart failure and associations with inhospital outcomes: findings from the Get with the Guideline—Heart Failure registry. Am Heart J 2013; 166:1063–71. Fonarow GC, Peacock WF, Phillips CO, et al. Admission B-type natriuretic peptide levels and in-hospital mortality in acute decompensated heart failure. J Am Coll Cardiol 2007;49:1943–50.
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Richards et al 42. van Veldhuisen DJ, Linssen GC, Jaarsma T, et al. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol 2013;61:1498–506. 43. Latini R, Masson S, Anand I, et al. The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure enrolled in Val-HeFT. Eur Heart J 2004;25:292–9. 44. Maeder MT, Rickenbacher P, Rickli H, et al. N-terminal pro brain natriuretic peptide-guided management in patients with heart failure and preserved ejection fraction: findings from the trial of intensified versus standard medical therapy in elderly patients with congestive heart failure (TIME-CHF). Eur J Heart Fail 2013;15:1148–56. 45. Maisel A, Barnard D, Jaski B, et al. Primary results of the HABIT trial (heart failure assessment with
BNP in the home). J Am Coll Cardiol 2013;61: 1726–35. 46. Edelmann F, Wachter R, Schmidt AG, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction. The Aldo-DHF randomized controlled trial. JAMA 2013;309:781–91. 47. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 doubleblind randomised controlled trial. Lancet 2012;380: 1387–95. 48. Desai AS, Lewis EF, Li R, et al. Rationale and design of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial: a randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction. Am Heart J 2011;162:966–72.
![[Heart failure with preserved ejection fraction (HFpEF)].](/assets/img/hold.png)
