Skip to main content
Top
Published in: Clinical Research in Cardiology 8/2021

Open Access 01-08-2021 | Cardiomyopathy | Original Paper

Prognostic value of NT-proBNP for myocardial recovery in peripartum cardiomyopathy (PPCM)

Authors: J. Hoevelmann, E. Muller, F. Azibani, S. Kraus, J. Cirota, O. Briton, M. Ntsekhe, N. A. B. Ntusi, K. Sliwa, C. A. Viljoen

Published in: Clinical Research in Cardiology | Issue 8/2021

Login to get access

Abstract

Introduction

Peripartum cardiomyopathy (PPCM) is an important cause of pregnancy-associated heart failure worldwide. Although a significant number of women recover their left ventricular (LV) function within 12 months, some remain with persistently reduced systolic function.

Methods

Knowledge gaps exist on predictors of myocardial recovery in PPCM. N-terminal pro-brain natriuretic peptide (NT-proBNP) is the only clinically established biomarker with diagnostic value in PPCM. We aimed to establish whether NT-proBNP could serve as a predictor of LV recovery in PPCM, as measured by LV end-diastolic volume (LVEDD) and LV ejection fraction (LVEF).

Results

This study of 35 women with PPCM (mean age 30.0 ± 5.9 years) had a median NT-proBNP of 834.7 pg/ml (IQR 571.2–1840.5) at baseline. Within the first year of follow-up, 51.4% of the cohort recovered their LV dimensions (LVEDD < 55 mm) and systolic function (LVEF > 50%). Women without LV recovery presented with higher NT-proBNP at baseline. Multivariable regression analyses demonstrated that NT-proBNP of ≥ 900 pg/ml at the time of diagnosis was predictive of failure to recover LVEDD (OR 0.22, 95% CI 0.05–0.95, P = 0.043) or LVEF (OR 0.20 [95% CI 0.04–0.89], p = 0.035) at follow-up.

Conclusions

We have demonstrated that NT-proBNP has a prognostic value in predicting LV recovery of patients with PPCM. Patients with NT-proBNP of ≥ 900 pg/ml were less likely to show any improvement in LVEF or LVEDD. Our findings have implications for clinical practice as patients with higher NT-proBNP might require more aggressive therapy and more intensive follow-up. Point-of-care NT-proBNP for diagnosis and risk stratification warrants further investigation.
Literature
1.
go back to reference Sliwa K, Hilfiker-Kleiner D, Petrie MC, Mebazaa A, Pieske B, Buchmann E et al (2010) Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy. Eur J Heart Fail 12(8):767–778CrossRef Sliwa K, Hilfiker-Kleiner D, Petrie MC, Mebazaa A, Pieske B, Buchmann E et al (2010) Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy. Eur J Heart Fail 12(8):767–778CrossRef
2.
go back to reference Bauersachs J, Konig T, van der Meer P, Petrie MC, Hilfiker-Kleiner D, Mbakwem A et al (2019) Pathophysiology, diagnosis and management of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on peripartum cardiomyopathy. Eur J Heart Fail 21(7):827–843CrossRef Bauersachs J, Konig T, van der Meer P, Petrie MC, Hilfiker-Kleiner D, Mbakwem A et al (2019) Pathophysiology, diagnosis and management of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on peripartum cardiomyopathy. Eur J Heart Fail 21(7):827–843CrossRef
4.
go back to reference Goland S, Bitar F, Modi K, Safirstein J, Ro A, Mirocha J et al (2011) Evaluation of the clinical relevance of baseline left ventricular ejection fraction as a predictor of recovery or persistence of severe dysfunction in women in the United States with peripartum cardiomyopathy. J Card Fail 17(5):426–430CrossRef Goland S, Bitar F, Modi K, Safirstein J, Ro A, Mirocha J et al (2011) Evaluation of the clinical relevance of baseline left ventricular ejection fraction as a predictor of recovery or persistence of severe dysfunction in women in the United States with peripartum cardiomyopathy. J Card Fail 17(5):426–430CrossRef
5.
go back to reference McNamara DM, Elkayam U, Alharethi R, Damp J, Hsich E, Ewald G et al (2015) Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC Study (Investigations of pregnancy-associated cardiomyopathy). J Am Coll Cardiol 66(8):905–914CrossRef McNamara DM, Elkayam U, Alharethi R, Damp J, Hsich E, Ewald G et al (2015) Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC Study (Investigations of pregnancy-associated cardiomyopathy). J Am Coll Cardiol 66(8):905–914CrossRef
6.
go back to reference Haghikia A, Podewski E, Libhaber E, Labidi S, Fischer D, Roentgen P et al (2013) Phenotyping and outcome on contemporary management in a German cohort of patients with peripartum cardiomyopathy. Basic Res Cardiol 108(4):366CrossRef Haghikia A, Podewski E, Libhaber E, Labidi S, Fischer D, Roentgen P et al (2013) Phenotyping and outcome on contemporary management in a German cohort of patients with peripartum cardiomyopathy. Basic Res Cardiol 108(4):366CrossRef
7.
go back to reference Amos AM, Jaber WA, Russell SD (2006) Improved outcomes in peripartum cardiomyopathy with contemporary. Am Heart J 152(3):509–513CrossRef Amos AM, Jaber WA, Russell SD (2006) Improved outcomes in peripartum cardiomyopathy with contemporary. Am Heart J 152(3):509–513CrossRef
8.
go back to reference Blauwet LA, Libhaber E, Forster O, Tibazarwa K, Mebazaa A, Hilfiker-Kleiner D et al (2013) Predictors of outcome in 176 South African patients with peripartum cardiomyopathy. Heart 99(5):308–313CrossRef Blauwet LA, Libhaber E, Forster O, Tibazarwa K, Mebazaa A, Hilfiker-Kleiner D et al (2013) Predictors of outcome in 176 South African patients with peripartum cardiomyopathy. Heart 99(5):308–313CrossRef
9.
go back to reference Haghikia A, Rontgen P, Vogel-Claussen J, Schwab J, Westenfeld R, Ehlermann P et al (2015) Prognostic implication of right ventricular involvement in peripartum cardiomyopathy: a cardiovascular magnetic resonance study. ESC Heart Fail 2(4):139–149CrossRef Haghikia A, Rontgen P, Vogel-Claussen J, Schwab J, Westenfeld R, Ehlermann P et al (2015) Prognostic implication of right ventricular involvement in peripartum cardiomyopathy: a cardiovascular magnetic resonance study. ESC Heart Fail 2(4):139–149CrossRef
10.
go back to reference Irizarry OC, Levine LD, Lewey J, Boyer T, Riis V, Elovitz MA et al (2017) Comparison of clinical characteristics and outcomes of peripartum cardiomyopathy between african american and non-african american women. JAMA Cardiol 2(11):1256–1260CrossRef Irizarry OC, Levine LD, Lewey J, Boyer T, Riis V, Elovitz MA et al (2017) Comparison of clinical characteristics and outcomes of peripartum cardiomyopathy between african american and non-african american women. JAMA Cardiol 2(11):1256–1260CrossRef
11.
go back to reference Goland S, Modi K, Hatamizadeh P, Elkayam U (2013) Differences in clinical profile of African-American women with peripartum cardiomyopathy in the United States. J Card Fail 19(4):214–218CrossRef Goland S, Modi K, Hatamizadeh P, Elkayam U (2013) Differences in clinical profile of African-American women with peripartum cardiomyopathy in the United States. J Card Fail 19(4):214–218CrossRef
12.
go back to reference Mueller C, McDonald K, de Boer RA, Maisel A, Cleland JGF, Kozhuharov N et al (2019) Heart failure association of the european society of cardiology practical guidance on the use of natriuretic peptide concentrations. Eur J Heart Fail 21(6):715–731CrossRef Mueller C, McDonald K, de Boer RA, Maisel A, Cleland JGF, Kozhuharov N et al (2019) Heart failure association of the european society of cardiology practical guidance on the use of natriuretic peptide concentrations. Eur J Heart Fail 21(6):715–731CrossRef
13.
go back to reference Santaguida PL, Don-Wauchope AC, Oremus M, McKelvie R, Ali U, Hill SA et al (2014) BNP and NT-proBNP as prognostic markers in persons with acute decompensated heart failure: a systematic review. Heart Fail Rev 19(4):453–470CrossRef Santaguida PL, Don-Wauchope AC, Oremus M, McKelvie R, Ali U, Hill SA et al (2014) BNP and NT-proBNP as prognostic markers in persons with acute decompensated heart failure: a systematic review. Heart Fail Rev 19(4):453–470CrossRef
14.
go back to reference Taylor KS, Verbakel JY, Feakins BG, Price CP, Perera R, Bankhead C et al (2018) Diagnostic accuracy of point-of-care natriuretic peptide testing for chronic heart failure in ambulatory care: systematic review and meta-analysis. BMJ 361:k1450CrossRef Taylor KS, Verbakel JY, Feakins BG, Price CP, Perera R, Bankhead C et al (2018) Diagnostic accuracy of point-of-care natriuretic peptide testing for chronic heart failure in ambulatory care: systematic review and meta-analysis. BMJ 361:k1450CrossRef
15.
go back to reference Forster O, Hilfiker-Kleiner D, Ansari AA, Sundstrom JB, Libhaber E, Tshani W et al (2008) Reversal of IFN-gamma, oxLDL and prolactin serum levels correlate with clinical improvement in patients with peripartum cardiomyopathy. Eur J Heart Fail 10(9):861–868CrossRef Forster O, Hilfiker-Kleiner D, Ansari AA, Sundstrom JB, Libhaber E, Tshani W et al (2008) Reversal of IFN-gamma, oxLDL and prolactin serum levels correlate with clinical improvement in patients with peripartum cardiomyopathy. Eur J Heart Fail 10(9):861–868CrossRef
16.
go back to reference Li W, Li H, Long Y (2016) Clinical characteristics and long-term predictors of persistent left ventricular systolic dysfunction in peripartum cardiomyopathy. Can J Cardiol 32(3):362–368CrossRef Li W, Li H, Long Y (2016) Clinical characteristics and long-term predictors of persistent left ventricular systolic dysfunction in peripartum cardiomyopathy. Can J Cardiol 32(3):362–368CrossRef
17.
go back to reference Resnik JL, Hong C, Resnik R, Kazanegra R, Beede J, Bhalla V et al (2005) Evaluation of B-type natriuretic peptide (BNP) levels in normal and preeclamptic women. Am J Obstet Gynecol 193(2):450–454CrossRef Resnik JL, Hong C, Resnik R, Kazanegra R, Beede J, Bhalla V et al (2005) Evaluation of B-type natriuretic peptide (BNP) levels in normal and preeclamptic women. Am J Obstet Gynecol 193(2):450–454CrossRef
18.
go back to reference Doust JA, Pietrzak E, Dobson A, Glasziou P (2005) How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. BMJ (Clin Res ed). 330(7492):625CrossRef Doust JA, Pietrzak E, Dobson A, Glasziou P (2005) How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. BMJ (Clin Res ed). 330(7492):625CrossRef
19.
go back to reference Sokolow M, Lyon TP (1949) The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J 37(2):161–186CrossRef Sokolow M, Lyon TP (1949) The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J 37(2):161–186CrossRef
20.
go back to reference Bazett HC (1997) An Analysis of the Time-Relations of Electrocardiograms. Ann Noninvasive Electrocardiol 2(2):177–194CrossRef Bazett HC (1997) An Analysis of the Time-Relations of Electrocardiograms. Ann Noninvasive Electrocardiol 2(2):177–194CrossRef
21.
go back to reference Rautaharju PM, Surawicz B, Gettes LS, Bailey JJ, Childers R, Deal BJ, et al. (2009) AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized. Electrocardiology. J Am Coll Cardiol 53(11):982–91 Rautaharju PM, Surawicz B, Gettes LS, Bailey JJ, Childers R, Deal BJ, et al. (2009) AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized. Electrocardiology. J Am Coll Cardiol 53(11):982–91
22.
go back to reference Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L et al (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 28(1):1-39 e14CrossRef Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L et al (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 28(1):1-39 e14CrossRef
23.
go back to reference Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG (2009) Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 42(2):377–381CrossRef Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG (2009) Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 42(2):377–381CrossRef
24.
go back to reference Tanous D, Siu SC, Mason J, Greutmann M, Wald RM, Parker JD et al (2010) B-type natriuretic peptide in pregnant women with heart disease. J Am Coll Cardiol 56(15):1247–1253CrossRef Tanous D, Siu SC, Mason J, Greutmann M, Wald RM, Parker JD et al (2010) B-type natriuretic peptide in pregnant women with heart disease. J Am Coll Cardiol 56(15):1247–1253CrossRef
25.
go back to reference Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS et al (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 37(27):2129–2200CrossRef Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS et al (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 37(27):2129–2200CrossRef
26.
go back to reference Malhame I, Hurlburt H, Larson L, Poppas A, Nau C, Bourjeily G et al (2019) Sensitivity and specificity of B-type natriuretic peptide in diagnosing heart failure in pregnancy. Obstet Gynecol 134(3):440–449CrossRef Malhame I, Hurlburt H, Larson L, Poppas A, Nau C, Bourjeily G et al (2019) Sensitivity and specificity of B-type natriuretic peptide in diagnosing heart failure in pregnancy. Obstet Gynecol 134(3):440–449CrossRef
27.
go back to reference Bauersachs J, Arrigo M, Hilfiker-Kleiner D, Veltmann C, Coats AJ, Crespo-Leiro MG et al (2016) Current management of patients with severe acute peripartum cardiomyopathy: practical guidance from the Heart Failure Association of the European Society of Cardiology Study Group on peripartum cardiomyopathy. Eur J Heart Fail 18(9):1096–1105CrossRef Bauersachs J, Arrigo M, Hilfiker-Kleiner D, Veltmann C, Coats AJ, Crespo-Leiro MG et al (2016) Current management of patients with severe acute peripartum cardiomyopathy: practical guidance from the Heart Failure Association of the European Society of Cardiology Study Group on peripartum cardiomyopathy. Eur J Heart Fail 18(9):1096–1105CrossRef
28.
go back to reference Kampman MA, Balci A, van Veldhuisen DJ, van Dijk AP, Roos-Hesselink JW, Sollie-Szarynska KM et al (2014) N-terminal pro-B-type natriuretic peptide predicts cardiovascular complications in pregnant women with congenital heart disease. Eur Heart J 35(11):708–715CrossRef Kampman MA, Balci A, van Veldhuisen DJ, van Dijk AP, Roos-Hesselink JW, Sollie-Szarynska KM et al (2014) N-terminal pro-B-type natriuretic peptide predicts cardiovascular complications in pregnant women with congenital heart disease. Eur Heart J 35(11):708–715CrossRef
29.
go back to reference Hartmann F, Packer M, Coats AJ, Fowler MB, Krum H, Mohacsi P et al (2004) Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial. Circulation 110(13):1780–1786CrossRef Hartmann F, Packer M, Coats AJ, Fowler MB, Krum H, Mohacsi P et al (2004) Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial. Circulation 110(13):1780–1786CrossRef
30.
go back to reference Hoevelmann J, Hahnle L, Hahnle J, Sliwa K, Viljoen C (2020) Detection and management of arrhythmias in peripartum cardiomyopathy. Cardiovasc Diagn Ther 10(2):325–335CrossRef Hoevelmann J, Hahnle L, Hahnle J, Sliwa K, Viljoen C (2020) Detection and management of arrhythmias in peripartum cardiomyopathy. Cardiovasc Diagn Ther 10(2):325–335CrossRef
31.
go back to reference Biteker M, Ilhan E, Biteker G, Duman D, Bozkurt B (2012) Delayed recovery in peripartum cardiomyopathy: an indication for long-term follow-up and sustained therapy. Eur J Heart Fail 14(8):895–901CrossRef Biteker M, Ilhan E, Biteker G, Duman D, Bozkurt B (2012) Delayed recovery in peripartum cardiomyopathy: an indication for long-term follow-up and sustained therapy. Eur J Heart Fail 14(8):895–901CrossRef
32.
go back to reference Hilfiker-Kleiner D, Kaminski K, Podewski E, Bonda T, Schaefer A, Sliwa K et al (2007) A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 128(3):589–600CrossRef Hilfiker-Kleiner D, Kaminski K, Podewski E, Bonda T, Schaefer A, Sliwa K et al (2007) A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 128(3):589–600CrossRef
33.
go back to reference Halkein J, Tabruyn SP, Ricke-Hoch M, Haghikia A, Nguyen NQ, Scherr M et al (2013) MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. J Clin Invest 123(5):2143–2154CrossRef Halkein J, Tabruyn SP, Ricke-Hoch M, Haghikia A, Nguyen NQ, Scherr M et al (2013) MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. J Clin Invest 123(5):2143–2154CrossRef
34.
go back to reference Liu J, Wang Y, Chen M, Zhao W, Wang X, Wang H et al (2014) The correlation between peripartum cardiomyopathy and autoantibodies against cardiovascular receptors. PLoS One 9(1):e86770CrossRef Liu J, Wang Y, Chen M, Zhao W, Wang X, Wang H et al (2014) The correlation between peripartum cardiomyopathy and autoantibodies against cardiovascular receptors. PLoS One 9(1):e86770CrossRef
35.
go back to reference Haghikia A, Kaya Z, Schwab J, Westenfeld R, Ehlermann P, Bachelier K et al (2015) Evidence of autoantibodies against cardiac troponin I and sarcomeric myosin in peripartum cardiomyopathy. Basic Res Cardiol 110(6):60CrossRef Haghikia A, Kaya Z, Schwab J, Westenfeld R, Ehlermann P, Bachelier K et al (2015) Evidence of autoantibodies against cardiac troponin I and sarcomeric myosin in peripartum cardiomyopathy. Basic Res Cardiol 110(6):60CrossRef
36.
go back to reference Daubert MA, Adams K, Yow E, Barnhart HX, Douglas PS, Rimmer S et al (2019) NT-proBNP Goal achievement is associated with significant reverse remodeling and improved clinical outcomes in HFrEF. JACC Heart Fail 7(2):158–168CrossRef Daubert MA, Adams K, Yow E, Barnhart HX, Douglas PS, Rimmer S et al (2019) NT-proBNP Goal achievement is associated with significant reverse remodeling and improved clinical outcomes in HFrEF. JACC Heart Fail 7(2):158–168CrossRef
37.
go back to reference Hoevelmann J, Viljoen CA, Manning K, Baard J, Hahnle L, Ntsekhe M et al (2019) The prognostic significance of the 12-lead ECG in peripartum cardiomyopathy. Int J Cardiol 276:177–184CrossRef Hoevelmann J, Viljoen CA, Manning K, Baard J, Hahnle L, Ntsekhe M et al (2019) The prognostic significance of the 12-lead ECG in peripartum cardiomyopathy. Int J Cardiol 276:177–184CrossRef
38.
go back to reference Bugge C, Sether EM, Pahle A, Halvorsen S, Sonbo Kristiansen I (2018) Diagnosing heart failure with NT-proBNP point-of-care testing: lower costs and better outcomes A decision analytic study. BJGP Open. 2(3):bjgpopen18X101596CrossRef Bugge C, Sether EM, Pahle A, Halvorsen S, Sonbo Kristiansen I (2018) Diagnosing heart failure with NT-proBNP point-of-care testing: lower costs and better outcomes A decision analytic study. BJGP Open. 2(3):bjgpopen18X101596CrossRef
39.
go back to reference Morbach C, Buck T, Rost C, Peter S, Gunther S, Stork S et al (2018) Point-of-care B-type natriuretic peptide and portable echocardiography for assessment of patients with suspected heart failure in primary care: rationale and design of the three-part Handheld-BNP program and results of the training study. Clin Res Cardiol 107(2):95–107CrossRef Morbach C, Buck T, Rost C, Peter S, Gunther S, Stork S et al (2018) Point-of-care B-type natriuretic peptide and portable echocardiography for assessment of patients with suspected heart failure in primary care: rationale and design of the three-part Handheld-BNP program and results of the training study. Clin Res Cardiol 107(2):95–107CrossRef
Metadata
Title
Prognostic value of NT-proBNP for myocardial recovery in peripartum cardiomyopathy (PPCM)
Authors
J. Hoevelmann
E. Muller
F. Azibani
S. Kraus
J. Cirota
O. Briton
M. Ntsekhe
N. A. B. Ntusi
K. Sliwa
C. A. Viljoen
Publication date
01-08-2021
Publisher
Springer Berlin Heidelberg
Published in
Clinical Research in Cardiology / Issue 8/2021
Print ISSN: 1861-0684
Electronic ISSN: 1861-0692
DOI
https://doi.org/10.1007/s00392-021-01808-z

Other articles of this Issue 8/2021

Clinical Research in Cardiology 8/2021 Go to the issue