- Email: [email protected]
Natriuretic peptides in acute coronary syndromes: A new role to predict recurrent ischemic event-related mortality?
Accepted Manuscript Natriuretic peptides in acute coronary syndromes: a new role to predict recurrent ischemic event-related mortality? Vasiliki Bistola, Eftihia Polyzogopoulou, John Parissis PII:
S1109-9666(18)30159-3
DOI:
10.1016/j.hjc.2018.03.008
Reference:
HJC 289
To appear in:
Hellenic Journal of Cardiology
Received Date: 23 March 2018 Accepted Date: 30 March 2018
Please cite this article as: Bistola V, Polyzogopoulou E, Parissis J, Natriuretic peptides in acute coronary syndromes: a new role to predict recurrent ischemic event-related mortality?, Hellenic Journal of Cardiology (2018), doi: 10.1016/j.hjc.2018.03.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Natriuretic peptides in acute coronary syndromes: a new role to predict recurrent ischemic event-related mortality?
1
Heart Failure Unit, Department of Cardiology, Attikon University Hospital, National
SC
and Kapodistrian University of Athens, Athens, Greece. 2
RI PT
Vasiliki Bistola1, Eftihia Polyzogopoulou2, John Parissis1,2
Emergency Medicine Department, Attikon University Hospital, National and
Corresponding author:
M AN U
Kapodistrian University of Athens, Athens, Greece.
TE D
John T. Parissis, Associate Professor of Cardiology
Navarinou 13, 15122, Maroussi, Athens, Greece, email: [email protected]
AC C
EP
Tel: +302106123720, Fax: +302105832195
1
ACCEPTED MANUSCRIPT ABSTRACT Risk stratification in acute coronary syndromes (ACS) have been based previously on severity of acute clinical presentation, presence of cardiovascular comorbidities and
RI PT
abnormalities of ischemia-specific biomarkers most importantly troponins. Natriuretic peptides (NPs), which become elevated upon increased myocardial wall stress, are established diagnostic and prognostic biomarkers in patients with heart
SC
failure. Recently, their prognostic potential in ACS has been reported, specifically as predictors of future new-onset heart failure or left ventricular systolic dysfunction. In
M AN U
the current issue of the Hellenic Journal of Cardiology, a new role of NPs is suggested in ACS as predictors of long-term mortality associated with recurrent cardiac ischemic events, specifically in patients with preserved or mid-range left ventricular ejection fraction upon index ACS. Potential pathophysiologic mechanisms explaining
TE D
the association between augmented NPs levels with recurrent myocardial ischemia are hypothesized including the potential of NPs to reflect augmented local and/or
EP
systemic inflammation, pro-thrombotic state and vascular dysregulation.
AC C
Keywords: natriuretic peptides; acute coronary syndromes; prognosis
2
ACCEPTED MANUSCRIPT Risk stratification in acute coronary syndromes (ACS) relies traditionally upon markers of severity of initial clinical presentation, ischemic electrocardiographic abnormalities and biomarkers of myocardial ischemia/necrosis, most importantly troponins, as well as presence of universal prognostic factors including age, diabetes
RI PT
mellitus and renal dysfunction1. Natriuretic peptides (NPs) become elevated in ACS in response to increased left ventricular (LV) wall stress due to systolic or diastolic dysfunction caused by myocardial ischemia2. The degree of NP rise has been
SC
correlated with infarct size and severity of LV dysfunction3. Clinical utility of NPs in
M AN U
ACS lies mostly upon their prognostic value although recently their diagnostic potential has emerged as part of a dual biomarker strategy combined with conventional or high sensitivity troponins to correctly re-classify patients with suspected ACS4. Regarding their prognostic role, pathologic NP levels during ACS
TE D
presentation are associated independently from troponins with increased all-cause mortality and new-onset heart failure long term5. In addition, elevations of NPs that persist at 3 to 6 months after an ACS have been shown to portend a higher risk for
EP
development of chronically impaired LV systolic function6. Moreover, increased predischarge NPs levels after an ACS have been associated with increased risk of sudden
AC C
cardiac death7.
In this issue of the Hellenic Journal of Cardiology, Chrysohoou et al.
investigated the prognostic role of natriuretic peptides in patients with ACS8. Although the topic has been explored before, some novel and noteworthy findings emerge from their study: 1. The association of increased NP levels with mortality due to recurrent ACS, 2. The differential prognostic effect of NPs according to LV ejection fraction (LVEF) category, and 3. The independent prognostic effect of increased NPs 3
ACCEPTED MANUSCRIPT from comorbid renal dysfunction. Association of increased NPs with recurrent fatal ischemic events is a novel finding. Although the primary stimulus for NP synthesis by myocardial cells is increased LV wall stress, other pathophysiologic mechanisms have been also implicated including myocardial ischemia, activation of sympathetic
RI PT
nervous system, inflammation and renin-angiotensin-aldosterone axis, all of which
are activated in the setting of an ACS9. Moreover, a recent analysis has revealed an
SC
independent prognostic role of increased NP levels with stroke in atrial fibrillation, suggesting that NPs may also reflect –possibly indirectly as a marker of atrial
M AN U
dysfunction - a heightened pro-thrombotic state in cardiovascular conditions10, which might explain the increased rate of recurrent ACS in the study by Chrysohoou et al. However, as previous studies have reported limited association of NPs with future ischemic events in stable and unstable coronary artery disease, this finding
TE D
needs further confirmation11.
A second noteworthy finding in the study by Chrysohoou et al. is that increased NPs are associated with adverse outcomes only in patients with mid-range
EP
and preserved LVEF but not in patients with reduced LVEF. This finding is important
AC C
because it suggests that NPs could be used for further risk stratification of the postACS HFmrEF and HFpEF patients, who are collectively considered lower risk based on LVEF only12. Therefore, pathologically increased NP levels may identify higher risk HFmrEF and HFpEF patients necessitating a closer follow up and possibly intensification of appropriate therapies. On the other hand, the absence of a significant prognostic value of NPs in the HFrEF subgroup may be explained by specific patient characteristics in this study or may reflect the already compromised
4
ACCEPTED MANUSCRIPT prognosis of the ACS sub-population with reduced LVEF so that the prognostic effect of NPs becomes diluted. Lastly, authors have shown that BNP maintains its independent prognostic
RI PT
value when adjusted for eGFR in the multivariable prognostic model. Renal dysfunction is a known cause of increased NPs levels even without the presence of heart failure. The mechanisms underlying the increase in NPs in renal disease are
SC
both pathologic cardio-renal interactions and reduced renal clearance of NPs. Renal dysfunction is frequently associated with increased atrial pressure and cardiac
M AN U
hypertrophy, conditions that could result in higher “physiologic” values of NPs. On the other hand, a decrease of eGFR to rates <60ml/min/1.73m2 reduces NP renal clearance resulting in increasing NP levels due to plasma accumulation. Renal clearance contributes more to the plasma clearance of amino terminal fragment of
TE D
the b-type natriuretic peptide (NT-proBNP) as compared to the active BNP molecule which clearance is mediated also by membrane bound natriuretic peptide receptor C (NPR-C) and neutral endopeptidases other than the kidney. In the presence of renal
EP
dysfunction NPs maintain their diagnostic accuracy for heart failure, although cut-off
AC C
levels are adjusted higher13. Moreover, several studies have shown that the prognostic value of NPs in patients with heart failure remains significant independently from the presence of renal dysfunction14. Therefore, this study confirms the prognostic value of NPs independently from renal dysfunction also in patients with ACS. Overall, this study extends previous knowledge on the prognostic value of NPs in ACS, suggesting a possible role to predict recurrent fatal ischemic events,
5
ACCEPTED MANUSCRIPT most significantly in patients exhibiting preserved or mildly reduced LVEF after the acute event. Further investigation of the intricate pathophysiologic mechanisms underlying the link between acutely increased NPs during an ACS and predisposition to future severe acute ischemic events (e.g. inflammation, vascular dysfunction, pro-
RI PT
thrombotic state) is warranted (Figure).
SC
References
AC C
EP
TE D
M AN U
1. de Araujo Goncalves P, Ferreira J, Aguiar C and Seabra-Gomes R. TIMI, PURSUIT, and GRACE risk scores: sustained prognostic value and interaction with revascularization in NSTEACS. Eur Heart J. 2005;26:865-72. 2. Morita E, Yasue H, Yoshimura M, Ogawa H, Jougasaki M, Matsumura T, Mukoyama M and Nakao K. Increased plasma levels of brain natriuretic peptide in patients with acute myocardial infarction. Circulation. 1993;88:82-91. 3. Uusimaa P, Ruskoaho H, Vuolteenaho O, Niemela M, Lumme J, Ikaheimo M, Jounela A and Peuhkurinen K. Plasma vasoactive peptides after acute myocardial infarction in relation to left ventricular dysfunction. Int J Cardiol. 1999;69:5-14. 4. Truong QA, Bayley J, Hoffmann U, Bamberg F, Schlett CL, Nagurney JT, Koenig W and Januzzi JL. Multi-marker strategy of natriuretic peptide with either conventional or highsensitivity troponin-T for acute coronary syndrome diagnosis in emergency department patients with chest pain: from the "Rule Out Myocardial Infarction using Computer Assisted Tomography" (ROMICAT) trial. Am Heart J. 2012;163:972-979 e1. 5. de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, Hall C, Cannon CP and Braunwald E. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med. 2001;345:1014-21. 6. Lindahl B, Lindback J, Jernberg T, Johnston N, Stridsberg M, Venge P and Wallentin L. Serial analyses of N-terminal pro-B-type natriuretic peptide in patients with non-ST-segment elevation acute coronary syndromes: a Fragmin and fast Revascularisation during In Stability in Coronary artery disease (FRISC)-II substudy. J Am Coll Cardiol. 2005;45:533-41. 7. Tapanainen JM, Lindgren KS, Makikallio TH, Vuolteenaho O, Leppaluoto J and Huikuri HV. Natriuretic peptides as predictors of non-sudden and sudden cardiac death after acute myocardial infarction in the beta-blocking era. J Am Coll Cardiol. 2004;43:757-63. 8. Chrysohoou C, Georgiopoulos G, Kosyfa H, Kotsopoulou-Haritou I, Kouvari M, Filippou A, Iosifidis S, Tsiamis E, Aggelopoulos P, Pitsavos C and Tousoulis D. Brain Natriuretic Peptide mediates the prognostic role of renal function towards 10-year cardiovascular mortality in patients with Acute Coronary Syndrome: the HHF study (2006-2016). Hellenic Journal of Cardiology. 2018;In press. 9. Bruneau BG, Piazza LA and de Bold AJ. Alpha 1-adrenergic stimulation of isolated rat atria results in discoordinate increases in natriuretic peptide secretion and gene expression and enhances Egr-1 and c-Myc expression. Endocrinology. 1996;137:137-43. 10. Hijazi Z, Oldgren J, Andersson U, Connolly SJ, Ezekowitz MD, Hohnloser SH, Reilly PA, Vinereanu D, Siegbahn A, Yusuf S and Wallentin L. Cardiac biomarkers are associated with an 6
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy. Circulation. 2012;125:1605-16. 11. James SK, Lindahl B, Siegbahn A, Stridsberg M, Venge P, Armstrong P, Barnathan ES, Califf R, Topol EJ, Simoons ML and Wallentin L. N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy. Circulation. 2003;108:275-81. 12. Agra Bermejo R, Cordero A, Garcia-Acuna JM, Gomez Otero I, Varela Roman A, Martinez A, Alvarez Rodriguez L, Abou-Jokh C, Rodriguez-Manero M, Cid Alvarez B, LopezPalop R, Carrillo P and Gonzalez-Juanatey JR. Determinants and Prognostic Impact of Heart Failure and Left Ventricular Ejection Fraction in Acute Coronary Syndrome Settings. Rev Esp Cardiol (Engl Ed). 2017. 13. Lamb EJ, Vickery S and Price CP. Amino-terminal pro-brain natriuretic peptide to diagnose congestive heart failure in patients with impaired kidney function. J Am Coll Cardiol. 2006;48:1060-1; author reply 1061. 14. Anwaruddin S, Lloyd-Jones DM, Baggish A, Chen A, Krauser D, Tung R, Chae C and Januzzi JL, Jr. Renal function, congestive heart failure, and amino-terminal pro-brain natriuretic peptide measurement: results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. J Am Coll Cardiol. 2006;47:91-7.
7
ACCEPTED MANUSCRIPT Figure. Established and hypothesized (?) pathophysiologic mechanisms of
AC C
EP
TE D
M AN U
SC
RI PT
augmented NP synthesis in ACS.
8
S1109-9666(18)30159-3
DOI:
10.1016/j.hjc.2018.03.008
Reference:
HJC 289
To appear in:
Hellenic Journal of Cardiology
Received Date: 23 March 2018 Accepted Date: 30 March 2018
Please cite this article as: Bistola V, Polyzogopoulou E, Parissis J, Natriuretic peptides in acute coronary syndromes: a new role to predict recurrent ischemic event-related mortality?, Hellenic Journal of Cardiology (2018), doi: 10.1016/j.hjc.2018.03.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Natriuretic peptides in acute coronary syndromes: a new role to predict recurrent ischemic event-related mortality?
1
Heart Failure Unit, Department of Cardiology, Attikon University Hospital, National
SC
and Kapodistrian University of Athens, Athens, Greece. 2
RI PT
Vasiliki Bistola1, Eftihia Polyzogopoulou2, John Parissis1,2
Emergency Medicine Department, Attikon University Hospital, National and
Corresponding author:
M AN U
Kapodistrian University of Athens, Athens, Greece.
TE D
John T. Parissis, Associate Professor of Cardiology
Navarinou 13, 15122, Maroussi, Athens, Greece, email: [email protected]
AC C
EP
Tel: +302106123720, Fax: +302105832195
1
ACCEPTED MANUSCRIPT ABSTRACT Risk stratification in acute coronary syndromes (ACS) have been based previously on severity of acute clinical presentation, presence of cardiovascular comorbidities and
RI PT
abnormalities of ischemia-specific biomarkers most importantly troponins. Natriuretic peptides (NPs), which become elevated upon increased myocardial wall stress, are established diagnostic and prognostic biomarkers in patients with heart
SC
failure. Recently, their prognostic potential in ACS has been reported, specifically as predictors of future new-onset heart failure or left ventricular systolic dysfunction. In
M AN U
the current issue of the Hellenic Journal of Cardiology, a new role of NPs is suggested in ACS as predictors of long-term mortality associated with recurrent cardiac ischemic events, specifically in patients with preserved or mid-range left ventricular ejection fraction upon index ACS. Potential pathophysiologic mechanisms explaining
TE D
the association between augmented NPs levels with recurrent myocardial ischemia are hypothesized including the potential of NPs to reflect augmented local and/or
EP
systemic inflammation, pro-thrombotic state and vascular dysregulation.
AC C
Keywords: natriuretic peptides; acute coronary syndromes; prognosis
2
ACCEPTED MANUSCRIPT Risk stratification in acute coronary syndromes (ACS) relies traditionally upon markers of severity of initial clinical presentation, ischemic electrocardiographic abnormalities and biomarkers of myocardial ischemia/necrosis, most importantly troponins, as well as presence of universal prognostic factors including age, diabetes
RI PT
mellitus and renal dysfunction1. Natriuretic peptides (NPs) become elevated in ACS in response to increased left ventricular (LV) wall stress due to systolic or diastolic dysfunction caused by myocardial ischemia2. The degree of NP rise has been
SC
correlated with infarct size and severity of LV dysfunction3. Clinical utility of NPs in
M AN U
ACS lies mostly upon their prognostic value although recently their diagnostic potential has emerged as part of a dual biomarker strategy combined with conventional or high sensitivity troponins to correctly re-classify patients with suspected ACS4. Regarding their prognostic role, pathologic NP levels during ACS
TE D
presentation are associated independently from troponins with increased all-cause mortality and new-onset heart failure long term5. In addition, elevations of NPs that persist at 3 to 6 months after an ACS have been shown to portend a higher risk for
EP
development of chronically impaired LV systolic function6. Moreover, increased predischarge NPs levels after an ACS have been associated with increased risk of sudden
AC C
cardiac death7.
In this issue of the Hellenic Journal of Cardiology, Chrysohoou et al.
investigated the prognostic role of natriuretic peptides in patients with ACS8. Although the topic has been explored before, some novel and noteworthy findings emerge from their study: 1. The association of increased NP levels with mortality due to recurrent ACS, 2. The differential prognostic effect of NPs according to LV ejection fraction (LVEF) category, and 3. The independent prognostic effect of increased NPs 3
ACCEPTED MANUSCRIPT from comorbid renal dysfunction. Association of increased NPs with recurrent fatal ischemic events is a novel finding. Although the primary stimulus for NP synthesis by myocardial cells is increased LV wall stress, other pathophysiologic mechanisms have been also implicated including myocardial ischemia, activation of sympathetic
RI PT
nervous system, inflammation and renin-angiotensin-aldosterone axis, all of which
are activated in the setting of an ACS9. Moreover, a recent analysis has revealed an
SC
independent prognostic role of increased NP levels with stroke in atrial fibrillation, suggesting that NPs may also reflect –possibly indirectly as a marker of atrial
M AN U
dysfunction - a heightened pro-thrombotic state in cardiovascular conditions10, which might explain the increased rate of recurrent ACS in the study by Chrysohoou et al. However, as previous studies have reported limited association of NPs with future ischemic events in stable and unstable coronary artery disease, this finding
TE D
needs further confirmation11.
A second noteworthy finding in the study by Chrysohoou et al. is that increased NPs are associated with adverse outcomes only in patients with mid-range
EP
and preserved LVEF but not in patients with reduced LVEF. This finding is important
AC C
because it suggests that NPs could be used for further risk stratification of the postACS HFmrEF and HFpEF patients, who are collectively considered lower risk based on LVEF only12. Therefore, pathologically increased NP levels may identify higher risk HFmrEF and HFpEF patients necessitating a closer follow up and possibly intensification of appropriate therapies. On the other hand, the absence of a significant prognostic value of NPs in the HFrEF subgroup may be explained by specific patient characteristics in this study or may reflect the already compromised
4
ACCEPTED MANUSCRIPT prognosis of the ACS sub-population with reduced LVEF so that the prognostic effect of NPs becomes diluted. Lastly, authors have shown that BNP maintains its independent prognostic
RI PT
value when adjusted for eGFR in the multivariable prognostic model. Renal dysfunction is a known cause of increased NPs levels even without the presence of heart failure. The mechanisms underlying the increase in NPs in renal disease are
SC
both pathologic cardio-renal interactions and reduced renal clearance of NPs. Renal dysfunction is frequently associated with increased atrial pressure and cardiac
M AN U
hypertrophy, conditions that could result in higher “physiologic” values of NPs. On the other hand, a decrease of eGFR to rates <60ml/min/1.73m2 reduces NP renal clearance resulting in increasing NP levels due to plasma accumulation. Renal clearance contributes more to the plasma clearance of amino terminal fragment of
TE D
the b-type natriuretic peptide (NT-proBNP) as compared to the active BNP molecule which clearance is mediated also by membrane bound natriuretic peptide receptor C (NPR-C) and neutral endopeptidases other than the kidney. In the presence of renal
EP
dysfunction NPs maintain their diagnostic accuracy for heart failure, although cut-off
AC C
levels are adjusted higher13. Moreover, several studies have shown that the prognostic value of NPs in patients with heart failure remains significant independently from the presence of renal dysfunction14. Therefore, this study confirms the prognostic value of NPs independently from renal dysfunction also in patients with ACS. Overall, this study extends previous knowledge on the prognostic value of NPs in ACS, suggesting a possible role to predict recurrent fatal ischemic events,
5
ACCEPTED MANUSCRIPT most significantly in patients exhibiting preserved or mildly reduced LVEF after the acute event. Further investigation of the intricate pathophysiologic mechanisms underlying the link between acutely increased NPs during an ACS and predisposition to future severe acute ischemic events (e.g. inflammation, vascular dysfunction, pro-
RI PT
thrombotic state) is warranted (Figure).
SC
References
AC C
EP
TE D
M AN U
1. de Araujo Goncalves P, Ferreira J, Aguiar C and Seabra-Gomes R. TIMI, PURSUIT, and GRACE risk scores: sustained prognostic value and interaction with revascularization in NSTEACS. Eur Heart J. 2005;26:865-72. 2. Morita E, Yasue H, Yoshimura M, Ogawa H, Jougasaki M, Matsumura T, Mukoyama M and Nakao K. Increased plasma levels of brain natriuretic peptide in patients with acute myocardial infarction. Circulation. 1993;88:82-91. 3. Uusimaa P, Ruskoaho H, Vuolteenaho O, Niemela M, Lumme J, Ikaheimo M, Jounela A and Peuhkurinen K. Plasma vasoactive peptides after acute myocardial infarction in relation to left ventricular dysfunction. Int J Cardiol. 1999;69:5-14. 4. Truong QA, Bayley J, Hoffmann U, Bamberg F, Schlett CL, Nagurney JT, Koenig W and Januzzi JL. Multi-marker strategy of natriuretic peptide with either conventional or highsensitivity troponin-T for acute coronary syndrome diagnosis in emergency department patients with chest pain: from the "Rule Out Myocardial Infarction using Computer Assisted Tomography" (ROMICAT) trial. Am Heart J. 2012;163:972-979 e1. 5. de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, Hall C, Cannon CP and Braunwald E. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med. 2001;345:1014-21. 6. Lindahl B, Lindback J, Jernberg T, Johnston N, Stridsberg M, Venge P and Wallentin L. Serial analyses of N-terminal pro-B-type natriuretic peptide in patients with non-ST-segment elevation acute coronary syndromes: a Fragmin and fast Revascularisation during In Stability in Coronary artery disease (FRISC)-II substudy. J Am Coll Cardiol. 2005;45:533-41. 7. Tapanainen JM, Lindgren KS, Makikallio TH, Vuolteenaho O, Leppaluoto J and Huikuri HV. Natriuretic peptides as predictors of non-sudden and sudden cardiac death after acute myocardial infarction in the beta-blocking era. J Am Coll Cardiol. 2004;43:757-63. 8. Chrysohoou C, Georgiopoulos G, Kosyfa H, Kotsopoulou-Haritou I, Kouvari M, Filippou A, Iosifidis S, Tsiamis E, Aggelopoulos P, Pitsavos C and Tousoulis D. Brain Natriuretic Peptide mediates the prognostic role of renal function towards 10-year cardiovascular mortality in patients with Acute Coronary Syndrome: the HHF study (2006-2016). Hellenic Journal of Cardiology. 2018;In press. 9. Bruneau BG, Piazza LA and de Bold AJ. Alpha 1-adrenergic stimulation of isolated rat atria results in discoordinate increases in natriuretic peptide secretion and gene expression and enhances Egr-1 and c-Myc expression. Endocrinology. 1996;137:137-43. 10. Hijazi Z, Oldgren J, Andersson U, Connolly SJ, Ezekowitz MD, Hohnloser SH, Reilly PA, Vinereanu D, Siegbahn A, Yusuf S and Wallentin L. Cardiac biomarkers are associated with an 6
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy. Circulation. 2012;125:1605-16. 11. James SK, Lindahl B, Siegbahn A, Stridsberg M, Venge P, Armstrong P, Barnathan ES, Califf R, Topol EJ, Simoons ML and Wallentin L. N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy. Circulation. 2003;108:275-81. 12. Agra Bermejo R, Cordero A, Garcia-Acuna JM, Gomez Otero I, Varela Roman A, Martinez A, Alvarez Rodriguez L, Abou-Jokh C, Rodriguez-Manero M, Cid Alvarez B, LopezPalop R, Carrillo P and Gonzalez-Juanatey JR. Determinants and Prognostic Impact of Heart Failure and Left Ventricular Ejection Fraction in Acute Coronary Syndrome Settings. Rev Esp Cardiol (Engl Ed). 2017. 13. Lamb EJ, Vickery S and Price CP. Amino-terminal pro-brain natriuretic peptide to diagnose congestive heart failure in patients with impaired kidney function. J Am Coll Cardiol. 2006;48:1060-1; author reply 1061. 14. Anwaruddin S, Lloyd-Jones DM, Baggish A, Chen A, Krauser D, Tung R, Chae C and Januzzi JL, Jr. Renal function, congestive heart failure, and amino-terminal pro-brain natriuretic peptide measurement: results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. J Am Coll Cardiol. 2006;47:91-7.
7
ACCEPTED MANUSCRIPT Figure. Established and hypothesized (?) pathophysiologic mechanisms of
AC C
EP
TE D
M AN U
SC
RI PT
augmented NP synthesis in ACS.
8