doi: 10.1161/CIRCULATIONAHA.105.551853
(Circulation. 2005;112:9-11.)
© 2005 American Heart Association, Inc.
Editorial |
N-Terminal-Pro-B–Type Natriuretic Peptide
Universal Marker of Cardiovascular Risk?
From the Department of Medicine, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand.
Correspondence to Prof A. Mark Richards, Dept of Medicine, Christchurch School of Medicine and Health Sciences, PO Box 4345, Riccarton Ave, Christchurch, New Zealand. E-mail mark.richards{at}cdhb.govt.nz
Key Words: Editorials • cardiovascular diseases • coronary disease • natriuretic peptides • renin
Plasma brain-type natriuretic peptide (BNP) and amino-terminal proBNP (NTproBNP) provide prognostic information on cardiovascular morbidity and mortality beyond that provided by standard risk factors. Clinical applications of B-type peptides under ongoing research include their use in diagnosing acute heart failure (HF), in risk stratification in both acute and established HF, in acute coronary syndromes (ACS), in asymptomatic populations at cardiovascular risk (older adults and people with hypertension), and as part of a screening strategy for detection of left ventricular impairment and prediction of cardiovascular risk in the general population.1,2 In this issue of Circulation, Campbell and colleagues3 assess the ability of NTproBNP to predict myocardial infarction (MI) in subjects who have experienced a cerebrovascular event. NTproBNP (reflecting cardiac distension) is compared with C-reactive protein (a systemic marker of inflammation) and renin (a marker of sodium status regulated by renal perfusion and delivery of sodium to the renal glomerulus).
See p 110
The nested case-control study is from the 6105 participants in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a placebo-controlled study of converting enzyme inhibitor–based therapy in patients with previous cerebrovascular events.4 Within PROGRESS, 206 subjects incurred an MI during 3.9 years of follow-up. The investigators matched those incurring an MI with control PROGRESS patients avoiding MI from time of randomization to time of case ascertainment. Cases and controls were matched for age, gender, treatment allocation, region, and cerebrovascular qualifying event. The form of matching meant that individual patients may have been controls initially and subsequently became cases on incurring an MI during further follow-up. Matching in this fashion may confuse the interpretation of the nonconditioned analysis of baseline variables.
Comparing the 206 cases with 412 controls at randomization, the investigators report that in addition to higher systolic blood pressure, more frequent known coronary disease, more frequent peripheral arterial disease, more frequent valvular disease, and higher cholesterol, the 2 groups did differ significantly for 2 of the biomarkers. NTproBNP and C-reactive protein in the infarct patients were, respectively, 1.6- and 1.3-fold higher than in controls. Renin was not significantly elevated in the MI group. Cases were then combined with controls, creating a selective population within which the risk of incurring MI was compared between marker quartiles generated from the 618 patients. This interquartile comparison was conducted with 2 models: the first unadjusted except for the previously mentioned matched variables, and the second adjusted for baseline variables that showed significant univariate associations with MI, ie, systolic blood pressure, cholesterol status, and presence or absence of a history of coronary heart disease, valvular heart disease, and peripheral arterial disease. In both models, NTproBNP in the upper quartile was associated with a 2- to 3-fold increase in risk of MI as compared with the first quartile. C-reactive protein exhibited a similar 2-fold increase in risk in the first model, but in the second, CRP had no significant association with increased risk of MI. Renin, not seen to be significantly different in a simple univariate comparison between cases and controls, became significant when considered as a putative independent predictor in the adjusted models. Upper-quartile renin was associated with a 1.7- to 1.9-fold increase in risk of MI as compared with the bottom quartile. Combining NTproBNP with renin added predictive power, and individuals with both NTproBNP and renin in the highest quartiles had 4.5 times the risk of MI as compared with both in the lowest quartile.
These findings add to reports indicating the predictive power of B-type peptides for all-cause mortality and cardiovascular mortality and/or morbidity.1 Clinical application may be difficult, however. The clinician does not seek the relative risk of an MI in a given patient who has experienced a cerebrovascular event as compared with another individual with cerebrovascular disease of the same gender and similar age. Rather, clinicians require the best possible assessment of the absolute risk for an individual patient, taking all risk factors into account as far as possible. The clinician will note gender, age, ethnic background, blood pressure, lipid status, a range of possible ECG abnormalities, presence or absence of diabetes, renal function, and the presence or absence of a history of adverse arterial events (coronary, cerebrovascular, renovascular, or other peripheral vascular disease) and may also be privileged to have cardiac imaging and/or stress test data in hand. In this regard, it would have been an informative corroborative exercise for the authors to have undertaken a multivariate time-to-event analysis of all 5918 subjects from PROGRESS who had blood samples available and to have provided readers with absolute event rates and hazard ratios for the risk of MI (and other morbid events) adjusted not only in the manner conducted in the present nested case-control study but, as far as possible, for all of the above-mentioned established indicators of coronary risk.
Curiously, in the analysis by Campbell and colleagues, cases and controls have a similar prevalence of smoking, diabetes, and levels of plasma creatinine—powerful established predictors of MI within the general population and within populations with overt arterial disease. The later multivariate analyses conducted by Campbell et al are not therefore subject to any adjustment for these powerful predictors, which may individually and collectively confound their conclusions.
It is notable that in suggesting NTproBNP independently predicts MI, this article is at odds with several existing reports. Within the Framingham offspring study, BNP levels, though associated with increased risk of death and first cardiovascular event, did not predict coronary heart disease events.5 Campbell et al suggest this reflects the difference between the Framingham offspring participants and PROGRESS patients, who were older and had established vascular disease as evidenced by a preceding cerebrovascular event. If this explanation held true, BNP and NTproBNP should have independent predictive power of MI in coronary disease; however, this is not the case. De Lemos et al conducted a substudy in 2525 participants in the Orbofiban in Patients with Unstable coronary Syndromes, Thrombolysis In Myocardial Infarction 16 (OPUS-TIMI 16) trial of an oral glycoprotein IIb/IIIa inhibitor in ACS.6 BNP had a powerful univariate association with the risk of MI at 30 days and 10 months; however, on multivariate analysis, though predictive of all-cause mortality independent of age, troponin, HF, renal insufficiency, ST-segment changes or left bundle-branch block on the ECG, Killip class, and diabetes, BNP was not an independent predictor of MI. Similarly, Jernberg et al, in 755 patients admitted with chest pain, found BNP predicted all-cause mortality independent of age, gender, diabetes, hypertension, past MI, treatment, HF, ECG changes, troponin, or renal function, but it was not reported to independently predict MI.7 Sabatine and colleagues inspected BNP and C-reactive protein in >2000 ACS patients from OPUS-TIMI 16 and Treat angina with Aggrastat and determine Costs of Therapy with Invasive or Conservative Strategies—Thrombolysis In Myocardial Infarction 18 (TACTICS-TIMI 18) trials.8 They found both to be predictors of the composite end point of mortality, MI, and/or HF independent of age, diabetes, previous MI, HF, and ECG changes but did not report BNP as an independent predictor of MI as a lone end point. James et al measured NTproBNP, troponin T, and C-reactive protein in 6809 patients with non–ST-segment elevation ACS participating in the Global Utilization of Streptokinase and tPA for Occluded arteries IV (GUSTO-IV) trial of the glycoprotein IIb/IIIa inhibitor abciximab.9 Increasing quartiles of NTproBNP were powerfully related to short- and long-term mortality. Levels of troponin T and C-reactive protein and creatinine clearance were also independently related to 1-year mortality. These authors carefully assessed the possible association of NTproBNP with later MI, employing a comprehensive multivariate model that included elements that were absent from the Campbell et al analysis. Troponin T, creatinine clearance, and ST-segment depression on the ECG all were independently related to risk of future MI after adjustment for age, smoking status, angina, previous MI, heart failure, diabetes, ECG changes, heart rate, and creatinine clearance, but NTproBNP was not. An exception to the general reported absence of independent prediction of MI by BNP/NTproBNP in coronary populations is the report by Richards et al.10 This study is one of a very few that include ventricular imaging. The authors found that NTproBNP independently predicted subsequent MI only in subjects with reduced left ventricular function after their index MI. This result may reflect the greater vulnerability of the dilated, adversely remodeled ventricle (with areas of increased wall stress, a reduced coronary perfusion pressure gradient, and a more adverse neurohumoral milieu) to undergo detectable myocyte necrosis for any given acute reduction in coronary perfusion. In this regard, it would be of interest to know the prevalence of previous unrecognized left ventricular dysfunction in the MI cases in the PROGRESS trial. The almost universal finding that BNP/NTproBNP predict all-cause mortality may reflect the independent associations of the peptides, not only with cardiac function but also with age and renal function.1,6–10 Hence, the plasma BNP/NTproBNP level integrates several powerful independent predictors of mortality.
The additive effect of combining NTproBNP with renin is of interest and reminds us of early reports of the relationship between renin and coronary risk.11,12 Again, however, the manner in which this multimarker approach may be applied in clinical practice is unclear. The renin measurements employed in the analysis by Campbell et al3 were undertaken in the absence of an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker. Therefore, clinicians would have to apply these measurements (in a combined marker strategy) in the absence of what is now a commonly prescribed drug class in the population experiencing cerebrovascular events. The analyses conducted by Campbell et al are somewhat inconsistent in retaining renin, which did not differ between cases and controls by univariate comparison, for examination in the 2 multivariate analyses comparing marker quartiles within the combined groups. Meanwhile, they discarded a previous diagnosis of hypertension, smoking status, use of certain drugs, diabetes, and renal function, all of which likewise did not differ between cases and controls but all of which are well-established determinants of cardiovascular risk. Furthermore, unlike NTproBNP assays, renin assays remain widely variable in their methodology and reference ranges throughout the world, and clinicians would have to pay careful attention to the methods, reference ranges, and quality control within their local laboratories to enable correct interpretation of their locally provided renin results. Renin is influenced by medications, being elevated by diuretics and converting enzyme inhibitors and suppressed by ß-blockers. It is also responsive to sodium status, physical activity, and posture via concurrent changes in renal perfusion pressure, intraglomerular sodium flux, and sympathetic traffic to the juxtaglomerular apparatus. Renin levels differ substantially between ethnic groups. This vulnerability to the influence of ethnicity, commonly prescribed drugs, commonplace changes in sodium and volume status, posture, and activity suggests that the application of renin as a risk marker in the individual patient will remain fraught with difficulties.
The unimpressive performance of C-reactive protein in the adjusted models included in the Campbell et al analysis is of interest and, as the authors point out, is concordant with recent publications suggesting that C-reactive protein may be a more modest predictor of coronary heart disease than previously reported.13,14 They rightly point out that the presence of drugs, including aspirin, may well have attenuated the predictive power of C-reactive protein within this population. The increasingly widespread prescription of statins may also reduce C-reactive protein levels and may modify its predictive power for later events in arteriopathic patients. Nevertheless, the findings of Campbell et al remain at variance to those from studies in larger groups with coronary disease in which such drugs are widely used.8,9
NTproBNP stands out as the strongest of the 3 markers in the current comparison; however, its independent association with subsequent MI is at odds with the bulk of existing reports, including some derived from large coronary disease cohorts subjected to analysis incorporating comprehensive multivariate models. The report by Campbell et al analyzes a selective group of patients and requires confirmation in further cerebrovascular cohorts with analyses that directly lend themselves to potential application for risk stratification in "real-life" clinical settings.
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Acknowledgments |
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Disclosure
Dr Richards has received a research grant from, has served on the speakers’ bureau of and/or received honoraria from, and has consulted for and/or served on the advisory board of Roche Diagnostics. Dr Richards has also consulted for and/or served on the advisory board of Synex.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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[Abstract/Free Full Text]
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Related Article:
- Prediction of Myocardial Infarction by N-Terminal-Pro-B-Type Natriuretic Peptide, C-Reactive Protein, and Renin in Subjects With Cerebrovascular Disease
- Duncan J. Campbell, Mark Woodward, John P. Chalmers, Samuel A. Colman, Alicia J. Jenkins, Bruce E. Kemp, Bruce C. Neal, Anushka Patel, and Stephen W. MacMahon
Circulation 2005 112: 110-116.[Abstract] [Full Text]
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