Canadian Journal of Cardiology 30 (2014) 159e160
Editorial
Endothelin as a Marker of Risk in Patients With Chest Pain? Todd J. Anderson, MD, FRCPC Libin Cardiovascular Institute of Alberta, Department of Cardiac Sciences, University of Calgary, Calgary, Alberta, Canada
See article by Haaf et al., pages 195-203 of this issue. There is much interest in the development of biomarkers to understand pathophysiology, develop therapies, serve as surrogate markers for clinical research, and aid clinicians in diagnosis and prognosis of various diseases. Although many have been shown to be associated with outcomes, very few fulfil the criteria to be widely used in clinical practice. Cardiac troponins, for example, have become the biomarker of choice to diagnose acute myocyte necrosis. Measures of vascular health have been extensively studied as biomarkers. The endothelium plays a key role in vascular homeostasis.1 Endothelial health is characterized by vasodilation, antiinflammatory and antiplatelet properties due to the effects of nitric oxide. Although nitric oxide cannot be directly measured we infer its activity by measuring vasomotion in various circulations.2 In response to risk factors or overt disease, nitric oxide bioactivity is decreased with concomitant increases in oxidative stress and endothelial-derived vasoconstrictors such as angiotensin II and endothelin (ET)-1. Therapies directed against the latter two have been developed and are widely used. ETs comprise a family of 21-amino acid peptides, ET-1, ET-2, and ET-3, derived from 3 different genes.3 ET-1 is the predominant form in vivo and the most potent vasoconstrictor known. It is produced locally in the endothelium for the most part and acts on smooth muscle cells. It acts on 2 G protein-coupled receptors, ETA and ETB. ET-1 acting on ETA in the smooth muscle causes vasoconstriction, whereas ET-1 that diffuses into plasma causes nitric oxide-mediated vasodilation through ETB receptors in the endothelium.4 Serum levels of ET-1 loosely reflect tissue activity and are difficult to measure because of the short half-life and variable binding to plasma proteins. More recently, a chemiluminescence immunoassay has become available to measure a more stable form, Cterminal proendothelin-1 (CT pro-ET-1).5 Elevated levels of ET-1 are believed to reflect endothelial activation. Received for publication December 13, 2013. Accepted December 13, 2013. Corresponding author: Dr Todd J. Anderson, Libin Cardiovascular Institute of Alberta, Department of Cardiac Sciences, University of Calgary, 8th Floor Cardiology, Rm C849, 1403 29th Street NW, Calgary, Alberta T2N 2T9, Canada. Tel.: þ1-403-944-1033; fax: þ1-403-944-1592. E-mail: [email protected] See page 160 for disclosure information.
In addition to causing vasoconstriction, ET-1 is proatherogenic through upregulation of angiotensin-II, leukocyte adhesion molecules, proinflammatory cytokines, and mitogens. Its actions lead to cardiac hypertrophy, no-reflow in ischemia-reperfusion, fibrosis, and adverse renal effects. ET receptor blockers have been studied in hypertension, congestive heart failure, and coronary disease with predominantly neutral results. These agents have however, become important therapies in pulmonary hypertension. Early after the discovery of ET-1, plasma levels were shown to be related to adverse outcomes after myocardial infarction (MI) including no-reflow at the time of reperfusion and late events up to several years after the event.6,7 These tended to be small studies with variability in ET-1 measurements. Two large studies have evaluated the prognostic significance of CT pro-ET-1. The first study demonstrated a relationship with this marker and proteinuria along with a lower ankle-brachial index in African-American hypertensive individuals.8 They also demonstrated an association with left ventricular hypertrophy. Khan and colleagues studied a variety of biomarkers in 983 subjects with acute MI. CT pro-ET-1 was associated with adverse outcomes along with other markers.9 They did not evaluate whether this was an independent predictor in addition to clinical risk engines or cardiac troponin. In the article by Haaf and colleagues in this issue of the Canadian Journal of Cardiology, the role of CT pro-ET-1 as a biomarker of diagnosis and prognosis in a population presenting with chest pain is evaluated.10 As part of an ongoing multicentre biomarker trial, patients (n ¼ 658) with suspected acute coronary syndromes had serial determinations of CT pro-ET-1, cardiac Troponin T (cTnT), high-sensitivity Troponin T (hs TnT), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and clinical determination of the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk scores. A number of interesting findings were reported. (1) At presentation, levels of CT proET-1 were higher in subjects with a diagnosis of MI compared with subjects with noncardiac chest pain or acute coronary syndrome. Subjects with a diagnosis of heart failure had the highest levels of all groups and there was no change in the levels in any of the diagnostic groups with serial testing over the first 6 hours after presentation. This would strongly suggest that CT pro-ET-1 levels are related to the chronic phenotype of the
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.12.007
160
patient and will not be useful as a diagnostic test for acute events. This was a novel observation because other studies have not addressed this question. (2) CT pro-ET-1 was an independent predictor of 2-year mortality, being at least as powerful as NT-proBNP. In a Cox proportional hazard model, levels of ET were an independent predictor of outcome along with increasing age, history of coronary artery disease and Killip class. There were also favourable discrimination metrics and levels indicated improved integrated discrimination improvement in addition to a TIMI (but not GRACE) risk score. The incremental improvement for CT pro-ET-1 was very similar to that of NT-proBNP. The predicted cutoff level of 85 pmol/L corresponded closely with the upper quartile of levels within the cohort and was well above the 99th percentile of healthy populations. This is an interesting observation that expands on the previously reported study by Khan et al.9 Whereas Khan et al. were able to demonstrate a relationship between CT pro-ET-1 levels and outcome, the present study demonstrated that this was independent of more recently used clinical risk algorithms. In addition, the population studied included a wider range of patients, not only those with an MI. Within the present study it is clear that CT pro-ET-1 levels were higher in subjects who would be at increased risk of adverse events. In a univariate analysis (see Supplemental Table S1 in Haaf et al.10), subjects in the highest quartile were older, had more cardiovascular risk factors, were more likely to have a diagnosis of coronary artery disease, previous MI, revascularization, and stroke, and had decreased estimated glomerular filtration rate. It is likely that this biomarker is reflective of an underlying phenotype that portends increased risk. In some situations, the ET-1 levels might be related to the pathophysiology of the risk factor, such as hypertension.11 In others, the underlying condition might elevate ET levels secondarily. Separating out the independent prognostic significance of the biomarker from these other clinical factors would be difficult. Although the authors suggest that measurement of CT proET-1 might be beneficial in a clinical setting to risk-stratify patients with chest pain syndromes, this conclusion is premature. The study was relatively small with a limited number of end points to draw firm conclusions. A much larger validation cohort would be required. Also, the population was heterogeneous and included subjects with MI, left ventricular dysfunction, and heart failure, and cardiac risk factors alone. These conditions involve different pathophysiological effectors and, as such, it is unlikely that a single biomarker would be in the causal pathway for all. Although this is not mandatory for a successful biomarker, it is desirable. The data on long-term stability of CT pro-ET-1 would also be helpful to evaluate populations at risk. Would a measurement at another time point have been predictive? Because these patients were mainly well treated, it is unclear if there is an ability to alter the high-risk profile. Most patients with high levels of CT pro-ET-1 would be identified as high risk for other reasons and hence maximally treated. It does raise the possibility that blockade of ET-1 or its receptors could be evaluated as treatment strategies in those at high risk, but to date these agents have only been effective in pulmonary hypertension. One could view the observation from this study as
Canadian Journal of Cardiology Volume 30 2014
being hypothesis-generating for future treatments as opposed to being a helpful clinical biomarker. There are myriad biomarkers, including measures of endothelial dysfunction, involved in many cardiovascular diseases that have been shown to be associated with outcomes including death. To date, few have survived rigourous scrutiny and are being used to make clinical decisions. The authors provide another potential target for future study and therapeutic decision-making. Funding Sources T.J.A. is supported by Merck Frosst Chair, Cardiovascular Research. Disclosures The author has no conflicts of interest to disclose. References 1. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011;473:317-25. 2. Anderson TJ, Charbonneau F, Title LM, et al. Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters And Their Endothelium (FATE) study. Circulation 2011;123:163-9. 3. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332: 411-5. 4. Pernow J, Shemyakin A, Bohm F. New perspectives on endothelin-1 in atherosclerosis and diabetes mellitus. Life Sci 2012;91:507-16. 5. Behnes M, Papassotiriou J, Walter T, et al. Long-term prognostic value of mid-regional pro-adrenomedullin and C-terminal pro-endothelin-1 in patients with acute myocardial infarction. Clin Chem Lab Med 2008;46: 204-11. 6. Eitel I, Nowak M, Stehl C, et al. Endothelin-1 release in acute myocardial infarction as a predictor of long-term prognosis and no-reflow assessed by contrast-enhanced magnetic resonance imaging. Am Heart J 2010;159: 882-90. 7. Omland T, Lie RT, Aakvaag A, Aarsland T, Dickstein K. Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation 1994;89:1573-9. 8. Habib A, Al-Omari MA, Khaleghi M, et al. Plasma C-terminal proendothelin-1 is associated with target-organ damage in African Americans with hypertension. Am J Hypertens 2010;23:1204-8. 9. Khan SQ, Dhillon O, Struck J, et al. C-terminal pro-endothelin-1 offers additional prognostic information in patients after acute myocardial infarction: Leicester Acute Myocardial infarction Peptide (LAMP) study. Am Heart J 2007;154:736-42. 10. Haaf P, Zellweger C, Reichlin T, et al. Utility of c-terminal proendothelin in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction. Can J Cardiol 2014;30:195-203. 11. Cardillo C, Kilcoyne CM, Waclawiw M, Cannon RO 3rd, Panza J. Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension 1999;33:753-8.
Editorial
Endothelin as a Marker of Risk in Patients With Chest Pain? Todd J. Anderson, MD, FRCPC Libin Cardiovascular Institute of Alberta, Department of Cardiac Sciences, University of Calgary, Calgary, Alberta, Canada
See article by Haaf et al., pages 195-203 of this issue. There is much interest in the development of biomarkers to understand pathophysiology, develop therapies, serve as surrogate markers for clinical research, and aid clinicians in diagnosis and prognosis of various diseases. Although many have been shown to be associated with outcomes, very few fulfil the criteria to be widely used in clinical practice. Cardiac troponins, for example, have become the biomarker of choice to diagnose acute myocyte necrosis. Measures of vascular health have been extensively studied as biomarkers. The endothelium plays a key role in vascular homeostasis.1 Endothelial health is characterized by vasodilation, antiinflammatory and antiplatelet properties due to the effects of nitric oxide. Although nitric oxide cannot be directly measured we infer its activity by measuring vasomotion in various circulations.2 In response to risk factors or overt disease, nitric oxide bioactivity is decreased with concomitant increases in oxidative stress and endothelial-derived vasoconstrictors such as angiotensin II and endothelin (ET)-1. Therapies directed against the latter two have been developed and are widely used. ETs comprise a family of 21-amino acid peptides, ET-1, ET-2, and ET-3, derived from 3 different genes.3 ET-1 is the predominant form in vivo and the most potent vasoconstrictor known. It is produced locally in the endothelium for the most part and acts on smooth muscle cells. It acts on 2 G protein-coupled receptors, ETA and ETB. ET-1 acting on ETA in the smooth muscle causes vasoconstriction, whereas ET-1 that diffuses into plasma causes nitric oxide-mediated vasodilation through ETB receptors in the endothelium.4 Serum levels of ET-1 loosely reflect tissue activity and are difficult to measure because of the short half-life and variable binding to plasma proteins. More recently, a chemiluminescence immunoassay has become available to measure a more stable form, Cterminal proendothelin-1 (CT pro-ET-1).5 Elevated levels of ET-1 are believed to reflect endothelial activation. Received for publication December 13, 2013. Accepted December 13, 2013. Corresponding author: Dr Todd J. Anderson, Libin Cardiovascular Institute of Alberta, Department of Cardiac Sciences, University of Calgary, 8th Floor Cardiology, Rm C849, 1403 29th Street NW, Calgary, Alberta T2N 2T9, Canada. Tel.: þ1-403-944-1033; fax: þ1-403-944-1592. E-mail: [email protected] See page 160 for disclosure information.
In addition to causing vasoconstriction, ET-1 is proatherogenic through upregulation of angiotensin-II, leukocyte adhesion molecules, proinflammatory cytokines, and mitogens. Its actions lead to cardiac hypertrophy, no-reflow in ischemia-reperfusion, fibrosis, and adverse renal effects. ET receptor blockers have been studied in hypertension, congestive heart failure, and coronary disease with predominantly neutral results. These agents have however, become important therapies in pulmonary hypertension. Early after the discovery of ET-1, plasma levels were shown to be related to adverse outcomes after myocardial infarction (MI) including no-reflow at the time of reperfusion and late events up to several years after the event.6,7 These tended to be small studies with variability in ET-1 measurements. Two large studies have evaluated the prognostic significance of CT pro-ET-1. The first study demonstrated a relationship with this marker and proteinuria along with a lower ankle-brachial index in African-American hypertensive individuals.8 They also demonstrated an association with left ventricular hypertrophy. Khan and colleagues studied a variety of biomarkers in 983 subjects with acute MI. CT pro-ET-1 was associated with adverse outcomes along with other markers.9 They did not evaluate whether this was an independent predictor in addition to clinical risk engines or cardiac troponin. In the article by Haaf and colleagues in this issue of the Canadian Journal of Cardiology, the role of CT pro-ET-1 as a biomarker of diagnosis and prognosis in a population presenting with chest pain is evaluated.10 As part of an ongoing multicentre biomarker trial, patients (n ¼ 658) with suspected acute coronary syndromes had serial determinations of CT pro-ET-1, cardiac Troponin T (cTnT), high-sensitivity Troponin T (hs TnT), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and clinical determination of the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk scores. A number of interesting findings were reported. (1) At presentation, levels of CT proET-1 were higher in subjects with a diagnosis of MI compared with subjects with noncardiac chest pain or acute coronary syndrome. Subjects with a diagnosis of heart failure had the highest levels of all groups and there was no change in the levels in any of the diagnostic groups with serial testing over the first 6 hours after presentation. This would strongly suggest that CT pro-ET-1 levels are related to the chronic phenotype of the
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.12.007
160
patient and will not be useful as a diagnostic test for acute events. This was a novel observation because other studies have not addressed this question. (2) CT pro-ET-1 was an independent predictor of 2-year mortality, being at least as powerful as NT-proBNP. In a Cox proportional hazard model, levels of ET were an independent predictor of outcome along with increasing age, history of coronary artery disease and Killip class. There were also favourable discrimination metrics and levels indicated improved integrated discrimination improvement in addition to a TIMI (but not GRACE) risk score. The incremental improvement for CT pro-ET-1 was very similar to that of NT-proBNP. The predicted cutoff level of 85 pmol/L corresponded closely with the upper quartile of levels within the cohort and was well above the 99th percentile of healthy populations. This is an interesting observation that expands on the previously reported study by Khan et al.9 Whereas Khan et al. were able to demonstrate a relationship between CT pro-ET-1 levels and outcome, the present study demonstrated that this was independent of more recently used clinical risk algorithms. In addition, the population studied included a wider range of patients, not only those with an MI. Within the present study it is clear that CT pro-ET-1 levels were higher in subjects who would be at increased risk of adverse events. In a univariate analysis (see Supplemental Table S1 in Haaf et al.10), subjects in the highest quartile were older, had more cardiovascular risk factors, were more likely to have a diagnosis of coronary artery disease, previous MI, revascularization, and stroke, and had decreased estimated glomerular filtration rate. It is likely that this biomarker is reflective of an underlying phenotype that portends increased risk. In some situations, the ET-1 levels might be related to the pathophysiology of the risk factor, such as hypertension.11 In others, the underlying condition might elevate ET levels secondarily. Separating out the independent prognostic significance of the biomarker from these other clinical factors would be difficult. Although the authors suggest that measurement of CT proET-1 might be beneficial in a clinical setting to risk-stratify patients with chest pain syndromes, this conclusion is premature. The study was relatively small with a limited number of end points to draw firm conclusions. A much larger validation cohort would be required. Also, the population was heterogeneous and included subjects with MI, left ventricular dysfunction, and heart failure, and cardiac risk factors alone. These conditions involve different pathophysiological effectors and, as such, it is unlikely that a single biomarker would be in the causal pathway for all. Although this is not mandatory for a successful biomarker, it is desirable. The data on long-term stability of CT pro-ET-1 would also be helpful to evaluate populations at risk. Would a measurement at another time point have been predictive? Because these patients were mainly well treated, it is unclear if there is an ability to alter the high-risk profile. Most patients with high levels of CT pro-ET-1 would be identified as high risk for other reasons and hence maximally treated. It does raise the possibility that blockade of ET-1 or its receptors could be evaluated as treatment strategies in those at high risk, but to date these agents have only been effective in pulmonary hypertension. One could view the observation from this study as
Canadian Journal of Cardiology Volume 30 2014
being hypothesis-generating for future treatments as opposed to being a helpful clinical biomarker. There are myriad biomarkers, including measures of endothelial dysfunction, involved in many cardiovascular diseases that have been shown to be associated with outcomes including death. To date, few have survived rigourous scrutiny and are being used to make clinical decisions. The authors provide another potential target for future study and therapeutic decision-making. Funding Sources T.J.A. is supported by Merck Frosst Chair, Cardiovascular Research. Disclosures The author has no conflicts of interest to disclose. References 1. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011;473:317-25. 2. Anderson TJ, Charbonneau F, Title LM, et al. Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters And Their Endothelium (FATE) study. Circulation 2011;123:163-9. 3. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332: 411-5. 4. Pernow J, Shemyakin A, Bohm F. New perspectives on endothelin-1 in atherosclerosis and diabetes mellitus. Life Sci 2012;91:507-16. 5. Behnes M, Papassotiriou J, Walter T, et al. Long-term prognostic value of mid-regional pro-adrenomedullin and C-terminal pro-endothelin-1 in patients with acute myocardial infarction. Clin Chem Lab Med 2008;46: 204-11. 6. Eitel I, Nowak M, Stehl C, et al. Endothelin-1 release in acute myocardial infarction as a predictor of long-term prognosis and no-reflow assessed by contrast-enhanced magnetic resonance imaging. Am Heart J 2010;159: 882-90. 7. Omland T, Lie RT, Aakvaag A, Aarsland T, Dickstein K. Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation 1994;89:1573-9. 8. Habib A, Al-Omari MA, Khaleghi M, et al. Plasma C-terminal proendothelin-1 is associated with target-organ damage in African Americans with hypertension. Am J Hypertens 2010;23:1204-8. 9. Khan SQ, Dhillon O, Struck J, et al. C-terminal pro-endothelin-1 offers additional prognostic information in patients after acute myocardial infarction: Leicester Acute Myocardial infarction Peptide (LAMP) study. Am Heart J 2007;154:736-42. 10. Haaf P, Zellweger C, Reichlin T, et al. Utility of c-terminal proendothelin in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction. Can J Cardiol 2014;30:195-203. 11. Cardillo C, Kilcoyne CM, Waclawiw M, Cannon RO 3rd, Panza J. Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension 1999;33:753-8.
