Background The level of the inactive N-terminal fragment ofpro–brain (B-type) natriuretic peptide (BNP) is a strongpredictor of mortality among patients with acute coronary syndromesand may be a strong prognostic marker in patients with chroniccoronary heart disease as well. We assessed the relationshipbetween N-terminal pro-BNP (NT-pro-BNP) levels and long-termmortality from all causes in a large cohort of patients withstable coronary heart disease.
Methods NT-pro-BNP was measured in baseline serum samples from1034 patients referred for angiography because of symptoms orsigns of coronary heart disease. The rate of death from allcauses was determined after a median follow-up of nine years.
Results At follow-up, 288 patients had died. The median NT-pro-BNPlevel was significantly lower among patients who survived thanamong those who died (120 pg per milliliter [interquartile range,50 to 318] vs. 386 pg per milliliter [interquartile range, 146to 897], P<0.001). Patients with NT-pro-BNP levels in thehighest quartile were older, had a lower left ventricular ejectionfraction (LVEF) and a lower creatinine clearance rate, and weremore likely to have a history of myocardial infarction, clinicallysignificant coronary artery disease, and diabetes than patientswith NT-pro-BNP levels in the lowest quartile. In a multivariableCox regression model, the hazard ratio for death from any causefor the patients with NT-pro-BNP levels in the fourth quartileas compared with those in the first quartile was 2.4 (95 percentconfidence interval, 1.5 to 4.0; P<0.001); the NT-pro-BNPlevel added prognostic information beyond that provided by conventionalrisk factors, including the patient's age; sex; family historywith respect to ischemic heart disease; the presence or absenceof a history of myocardial infarction, angina, hypertension,diabetes, or chronic heart failure; creatinine clearance rate;body-mass index; smoking status; plasma lipid levels; LVEF;and the presence or absence of clinically significant coronaryartery disease on angiography.
Conclusions NT-pro-BNP is a marker of long-term mortality inpatients with stable coronary disease and provides prognosticinformation above and beyond that provided by conventional cardiovascularrisk factors and the degree of left ventricular systolic dysfunction.
Brain (B-type) natriuretic peptide (BNP) is a peptide hormonereleased primarily from the cardiac ventricles in response tomyocyte stretch. It is synthesized as an inactive prohormonethat is split into the active hormone BNP and the inactive N-terminalfragment (NT-pro-BNP). BNP has a number of systemic effects,including vasodilation, increases in urinary volume and sodiumoutput, and inhibition of the sympathetic nervous system andthe renin–angiotensin–aldosterone system.1,2
It is widely believed that the predominant pathophysiologicalprocess underlying increased circulating levels of BNP and NT-pro-BNPis regional or global impairment of left ventricular systolicor diastolic function leading to increased left ventricularwall stretch. In addition, elevated BNP and NT-pro-BNP levelsmay not only reflect increased left ventricular wall stressbut may also result directly from cardiac ischemia.3
The prognostic importance of BNP and NT-pro-BNP has been extensivelystudied in patients with heart failure as well as in patientswith acute coronary syndromes, and both markers have been shownto be strong predictors of morbidity and mortality.4,5,6 Recently,data from the Framingham Heart Study identified BNP as a strongpredictor of morbidity and mortality in the general populationeven when BNP levels were below the threshold of 100 pg permilliliter normally used to identify patients with heart failure.7
However, the prognostic importance of natriuretic peptides inpatients with chronic coronary artery disease is unknown. Therefore,we undertook the present study to evaluate the effect of thelevel of NT-pro-BNP on long-term mortality from all causes ina large cohort of patients with stable coronary artery disease;our emphasis was on patients with angiographic evidence of coronarydisease and normal left ventricular systolic function.
Methods
Dr. Kragelund, Dr. Steffensen, and Dr. Hildebrandt designedthe study. Dr. Kragelund and Dr. Steffensen gathered the data.Dr. Kragelund, Dr. Køber, and Dr. Grønning analyzedthe data. Dr. Kragelund wrote the article, and vouches for thedata and the analyses. All authors critically reviewed the manuscript.Roche Diagnostics provided the assay kits and measured NT-pro-BNPbut had no other role in the study.
Study Patients
We conducted a prospective observational study of the prognosticvalue of NT-pro-BNP in a large consecutive series of patientswith symptoms or signs of coronary artery disease who were referredto the Rigshospitalet in Copenhagen for elective coronary angiographyfrom February 1, 1991, through February 1, 1993. If patientsunderwent angiography more than once, our analysis was basedonly on data obtained at the time of the first angiographicstudy. Patients with valve disease or a congenital disorderwere excluded. A total of 1078 consenting patients who had anginapectoris or had evidence of ischemia on exercise electrocardiographyor myocardial radionuclide imaging were enrolled. In 44 patients,no serum samples were available for subsequent measurement ofNT-pro-BNP. Consequently, the remaining 1034 patients were includedin the analysis. The Danish Health Authorities and the RegionalEthics Committee approved the study, and written informed consentwas obtained from all participating subjects.
Coronary Angiography and Left Ventriculography
At baseline, selective coronary angiography and left ventriculographywere performed, with recording on cineangiographic film. Twoexperienced invasive cardiologists, who were blinded to thepatients' NT-pro-BNP measurements, evaluated the angiograms.The left ventricular ejection fraction (LVEF) was calculatedfrom a single view (right anterior oblique, 30 degrees) by thearea–length method.8 Left ventricular end-diastolic pressurewas registered in a subgroup of 288 patients. The number ofstenotic vessels was recorded, and patients were classifiedas having one-, two-, or three-vessel disease or stenosis ofthe left main coronary artery. A narrowing of the lumen by morethan 70 percent of the prestenotic diameter was considered toindicate clinically significant stenosis, except for the leftmain artery, in which a narrowing of more than 50 percent wasconsidered clinically significant.
Baseline Measurements
In all patients, a thorough medical history was recorded, includingdetails of any previous myocardial infarction, previous revascularization,angina pectoris, arterial hypertension, suspected congestiveheart failure (defined by symptoms of shortness of breath orleg edema), previous stroke or transient ischemic attacks, diabetes,intermittent claudication, and smoking status; information camefrom medical records, directly from patients, or both.
In the morning of the day that angiography was performed withthe patient in the supine position, fasting blood samples weredrawn for measurement of plasma glucose, lipids, and creatinine.One sample was allowed to stand for 30 minutes for coagulation;the remaining serum was immediately frozen in plastic containersat –80°C. NT-pro-BNP was measured in January 2004with use of a commercially available immunoassay based on thesandwich technique (Elecsys proBNP, Roche Diagnostics). Thelower limit of detection was 5 pg per milliliter. Intraassayand interassay coefficients of variation at different concentrationsof NT-pro-BNP relevant to this study were as follows: at 175pg per milliliter, 2.7 percent and 3.2 percent, respectively;at 355 pg per milliliter, 2.4 percent and 2.9 percent; at 1068pg per milliliter, 1.9 percent and 2.6 percent; and at 4962pg per milliliter, 1.8 percent and 2.3 percent.
The creatinine clearance rate, expressed in milliliters perminute, was calculated from the equation of Cockcroft and Gault,as follows: [(140 – age) x weight in kilograms] ÷serum creatinine in micromoles per liter, multiplied by a constantof 1.25 for men and 1.03 for women.
Information on vital status was obtained from the Danish CentralPerson Registry by means of a computerized search performedon August 1, 2001. No patients were lost to follow-up.
Statistical Analysis
Baseline characteristics of the study patients, grouped accordingto quartiles of NT-pro-BNP, are presented as percentages fordichotomous variables and medians with interquartile rangesfor continuous variables. Baseline characteristics were comparedamong quartiles with use of the chi-square test for discretevariables and the Wilcoxon or Kruskal–Wallis rank-sumtest for continuous variables, as appropriate. Additional NT-pro-BNPanalyses were performed in subgroups defined according to LVEFand the results of angiography. Survival curves were generatedby means of Kaplan–Meier estimates, and differences insurvival were compared with use of the log-rank test. To evaluatethe effect of different levels of NT-pro-BNP on mortality, relativerisks and 95 percent confidence intervals were calculated ashazard ratios derived from the Cox proportional-hazards regressionmodel. Multivariable models were fitted with use of the availableclinical covariates. The assumptions underlying the proportional-hazardsmodel (proportional hazards, lack of interaction, and linearityof continuous variables) were tested and found valid unlessotherwise indicated.
The patients were classified according to the severity of coronaryartery disease as having no clinically significant disease,one-, two-, or three-vessel disease, or disease of the leftmain coronary artery. Patients with three-vessel and left maincoronary artery disease had similar mortality rates and weretherefore combined into one group in the regression analysis.Analyses were performed with NT-pro-BNP, in quartiles, as acategorical variable with the lowest quartile serving as referencefor the other three quartiles. A backward-elimination modelwas applied. Tests were two-sided, and a P value of less than0.05 was considered to indicate statistical significance. Allcalculations were generated by SAS software, version 8.2.
Results
Demographic Characteristics
After a median follow-up of 9.2 years, 288 of the 1034 patients(28 percent) had died. The median NT-pro-BNP level for all subjectswas elevated (169 pg per milliliter; interquartile range, 63to 456) and was significantly lower among patients who survivedthan among those who died (120 pg per milliliter [interquartilerange, 50 to 318] vs. 386 pg per milliliter [146 to 897], P<0.001).The patients were divided into subgroups according to quartilesof NT-pro-BNP. Patients with NT-pro-BNP in the upper quartilewere older, had a higher left ventricular end-diastolic pressure,and were more likely to have a history of myocardial infarction,clinically significant coronary artery disease, and diabetes;the LVEF, body-mass index (the weight in kilograms divided bythe square of the height in meters), and creatinine clearancerate were lower than among patients with NT-pro-BNP levels inthe lowest quartile. Table 1 shows the baseline characteristicsaccording to quartiles of NT-pro-BNP.
Table 1. Baseline Clinical Characteristics According to Quartiles of NT-pro-BNP.
Relation of NT-pro-BNP Levels to Angiographic Status and LVEF
The NT-pro-BNP level increased with the severity of angiographicdisease and of left ventricular systolic dysfunction. In thesubgroup of the population with normal LVEF (i.e., 60 percent;506 patients), the level of NT-pro-BNP was significantly higherin patients with than in those without coronary artery disease.Table 2 shows the baseline characteristics of patients accordingto LVEF and the presence or absence of coronary artery disease.
Table 2. Baseline Clinical Characteristics According to the Left Ventricular Ejection Fraction (LVEF) and the Presence or Absence of Clinically Significant Coronary Artery Disease (CAD).
Relation of NT-pro-BNP and Mortality from All Causes
Kaplan–Meier estimates of survival for all subjects accordingto quartiles of NT-pro-BNP are shown in Figure 1. In a Cox regressionanalysis with the NT-pro-BNP level as a categorical variable,the unadjusted hazard ratios for death of patients with NT-pro-BNPlevels in the second, third, and fourth quartiles, as comparedwith those in the first quartile, were 2.1 (95 percent confidenceinterval, 1.3 to 3.3; P=0.002), 3.5 (95 percent confidence interval,2.3 to 5.4; P<0.001), and 6.1 (95 percent confidence interval,4.0 to 9.2; P<0.001), respectively. In a multivariable Coxregression model, the hazard ratio for death among patientsin the second quartile of NT-pro-BNP, as compared with thosein the first quartile, was 1.5 (95 percent confidence interval,0.94 to 2.6; P=0.09), that for the third quartile was 1.9 (95percent confidence interval, 1.2 to 3.0; P=0.007), and thatfor the fourth quartile was 2.4 (95 percent confidence interval,1.5 to 4.0; P<0.001).
Figure 1. Overall Survival among Patients with Stable Coronary Artery Disease, According to Quartiles of NT-pro-BNP.
The NT-pro-BNP levels were as follows: first quartile, less than 64 pg per milliliter; second quartile, 64 to 169 pg per milliliter; third quartile, 170 to 455 pg per milliliter; and fourth quartile, more than 455 pg per milliliter. P<0.001 by the log-rank test for the overall comparison among the groups.
NT-pro-BNP added prognostic information above and beyond thatprovided by age; sex; family history with respect to ischemicheart disease; presence or absence of previous and recent myocardialinfarction; presence or absence of angina; Canadian CardiovascularSociety (CCS) class; presence or absence of hypertension, diabetes,suspected heart failure, and prior revascularization; smokingstatus; results of stress testing; body-mass index; creatinineclearance rate; plasma lipid level; LVEF; left ventricular end-diastolicpressure; and severity of coronary artery disease at angiography.Excluding the 41 patients with CCS class 4 angina did not significantlychange the results (hazard ratio for the fourth quartile ascompared with the first, 1.8 [95 percent confidence interval,1.3 to 2.6]; P<0.001). Hazard ratios after the backward eliminationof the nonsignificant variables are shown in Table 3. AdjustedKaplan–Meier estimates of survival according to quartilesof NT-pro-BNP are shown in Figure 2.
Figure 2. Adjusted Estimates of Overall Survival among Patients with Stable Coronary Disease, According to Quartiles of NT-pro-BNP.
The survival estimates have been adjusted for age, presence or absence of diabetes, smoking status, left ventricular ejection fraction, presence or absence of suspected heart failure, and severity of angiographic coronary disease. The NT-pro-BNP levels were as follows: first quartile, less than 64 pg per milliliter; second quartile, 64 to 169 pg per milliliter; third quartile, 170 to 455 pg per milliliter; and fourth quartile, more than 455 pg per milliliter. P<0.001 by the log-rank test for the overall comparison among the groups.
Further analyses of subgroups of patients with LVEF values of60 percent or more and less than 60 percent yielded the sameresults. In patients with LVEF values of less than 60 percent,the adjusted hazard ratio for death in the fourth quartile ofNT-pro-BNP, as compared with the first quartile, was 3.1 (95percent confidence interval, 1.2 to 8.1; P<0.001). Amongpatients with an LVEF above 60 percent and clinically significantcoronary artery disease on angiography, NT-pro-BNP remaineda strong prognostic marker, with an adjusted hazard ratio of1.9 (95 percent confidence interval, 1.2 to 3.3; P=0.01) forthe fourth versus the first quartile of NT-pro-BNP. Among patientswith an LVEF of 60 percent or more but without angiographicevidence of coronary artery disease, the same trend was observed,but was not significant, presumably because of the lower numberof patients.
Discussion
Our study demonstrates that NT-pro-BNP measured immediatelybefore coronary angiography in patients with stable coronaryheart disease provides prognostic information on mortality fromall causes that is independent of invasive measurements of leftventricular function and the severity of coronary artery disease.These results extend currently available information about thevalue of NT-pro-BNP and BNP as markers of risk in the generalpopulation and among patients with acute coronary syndromesto a new population of patients with stable coronary diseasewho are at "intermediate" risk, thereby widening the spectrumof clinical usefulness of NT-pro-BNP as a prognostic marker.
The findings of the present study support previous studies suggestingthat the elevation of NT-pro-BNP is associated with coronaryheart disease.9,10 However, unlike previous investigators, weused angiographically diagnosed coronary artery disease to defineexisting coronary heart disease. Patients with high NT-pro-BNPlevels had a significantly higher prevalence of coronary diseaseat angiography than patients with low concentrations of NT-pro-BNP.Interestingly, this association was also seen in the group ofpatients with normal left ventricular systolic function.
In this study, NT-pro-BNP was elevated in patients with stableangina, a condition characterized by transient ischemic episodes.It was also elevated in patients with angiographically verifiedcoronary atherosclerosis, regardless of left ventricular systolicfunction. Recent studies have suggested that ischemia itself,rather than changes in left ventricular wall stress secondaryto ischemia, promotes the release of BNP,11 but the responsiblemechanisms still remain to be fully elucidated.
In support of this notion, it is well known that acute myocardialinfarction is associated with activation of the neurohormonalsystem that causes increases in levels of natriuretic peptides,12in particular NT-pro-BNP,13 which predicts poor short-term andlong-term outcome, independently of ventricular function.5,14,15,16Nevertheless, only a few studies have examined the associationbetween BNP and NT-pro-BNP and ischemia, and the results havebeen conflicting.17,18,19
The study by Bibbins-Domingo and colleagues,19 which included355 patients with stable coronary disease, showed that elevatedlevels of BNP were associated with inducible ischemia, suggestingan explanation for the increased risk of subsequent coronaryevents in patients with elevated BNP. Furthermore, BNP is associatedwith the occurrence of transient ischemic episodes during percutaneoustransluminal coronary angioplasty. In a study by Tateishi andcolleagues,20 the transient increase in BNP during balloon inflationwas independent of hemodynamic variables. However, there wasno correlation between BNP and the volume of ischemic myocardiumor the duration of ischemia. The mechanism involved remainsunclear, but two studies have demonstrated increased cardiacBNP gene expression in the ischemic left ventricle, suggestingthat elevated levels of BNP and NT-pro-BNP may result from cardiacischemia.3,21
NT-pro-BNP has repeatedly been shown to be elevated in patientswith left ventricular dysfunction.4,14,22 We measured the LVEFwith single-plane contrast ventriculography, previously regardedas the gold standard for LVEF measurements. In our study population,with more than half of patients having had a previous myocardialinfarction and therefore likely to have abnormal left ventriculargeometry, this technique may have some limitations, as it relieson geometric assumptions and therefore may overestimate LVEF.Despite these limitations, previous studies have found a relativelygood correlation between LVEF as determined by echocardiographyand as determined by contrast ventriculography.23 However, thepossibility remains that the elevated NT-pro-BNP levels in patientswith normal LVEF, as determined by standard imaging methodssuch as echocardiography, reflect unrecognized left ventricularremodeling that is detectable only by high-definition methods,such as magnetic resonance imaging.24
In our study of the prognostic importance of NT-pro-BNP in intermediate-riskpatients with stable coronary disease, we found NT-pro-BNP tobe a prognostic marker of long-term mortality from all causes.BNP and NT-pro-BNP have previously been shown to be predictorsof cardiovascular morbidity and mortality in the general population,7among patients with acute coronary syndromes, and among patientswith heart failure.4,5,25
The increased risk of death we observed among patients withelevated NT-pro-BNP may be a consequence of a higher frequencyof coronary events. The mortality rate among our patients wassimilar to the rates in other recent studies of patients withangiographic evidence of coronary artery disease.26 Informationon the causes of death was not available in our study, but otherstudies of patients with stable coronary heart disease and similarmortality rates have demonstrated that the chief causes of deathare myocardial infarction and sudden death.27 Moreover, theassociation of NT-pro-BNP in our study was independent of bothLVEF and left ventricular end-diastolic pressure, thus providingfurther evidence in support of the hypothesis that ischemiadirectly promotes the release of NT-pro-BNP, in a manner thatis independent of left ventricular wall stress.
To explore this hypothesis further, we adjusted our prognosticmodels for the severity of coronary artery disease on angiography.Because angiographic measures may not fully account for eccentricatherosclerotic lesions in the coronary vessel wall, the possibilityremains that the severity of coronary artery disease on angiographydoes not fully reflect the functional ischemic burden. One couldtherefore speculate that including the results of measurementsof cardiac ischemia that may be more sensitive, such as radionuclidestress testing, in the multivariable analysis might attenuatethe prognostic value of NT-pro-BNP. Unfortunately, only 10 percentof the patients in our study underwent radionuclide stress testing;the data sample was therefore insufficient for any attemptsat a meaningful analysis.
Other potential confounders of the association between increasinglevels of NT-pro-BNP and mortality include atrial fibrillationand left ventricular systolic dysfunction, which a convincingbody of evidence shows is strongly associated with BNP and NT-pro-BNP.Unfortunately, information on atrial fibrillation was not available.We adjusted for left ventricular dysfunction, but the possibilityof undetected systolic and diastolic dysfunction remains.
For the purpose of optimal risk stratification and for the targetingof treatment strategies, a multimarker strategy has become increasinglycommon in the management of acute coronary syndromes.16,28,29In stable coronary disease, early identification of specificgroups of patients at increased risk or even at very low riskis equally justified. With limited resources, careful risk stratificationcould potentially identify patients who would benefit the mostfrom specific treatment strategies and make it possible to avoidovertreating patients at low risk. In this study we have identifiedNT-pro-BNP as a marker of increased risk, one independent ofinvasive measures of left ventricular dysfunction and the severityof coronary disease. Further studies will show whether treatmentstrategies guided by NT-pro-BNP levels will decrease morbidityand mortality in patients with stable coronary disease and whetherNT-pro-BNP will find a place in the routine clinical stratificationof risk among such patients.
Supported by the Danish Pharmacists Foundation. Dr. Kragelundis the recipient of a junior research fellowship from the DanishHeart Foundation (grant no. 00-2-9-10-22011). Roche Diagnosticssupplied the assay kits and measured NT-pro-BNP in patients'samples.
Dr. Hildebrandt reports having received consulting and lecturefees from Roche Diagnostics.
Source Information
From the Department of Cardiology and Endocrinology, Frederiksberg Hospital, Frederiksberg (C.K., B.G., P.H.); the Department of Cardiology, Rigshospitalet, Copenhagen (L.K.); and the Department of Cardiology, Hillerød University Hospital, Copenhagen (R.S.) — all in Denmark.
Address reprint requests to Dr. Kragelund at the Department of Cardiology and Endocrinology, Frederiksberg Hospital, University of Copenhagen, Nordre Fasanvej 57, DK-2000 Frederiksberg, Denmark, or at kragelund{at}dadlnet.dk.
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60 percent; 506 patients), the level of NT-pro-BNP was significantly higher in patients with than in those without coronary artery disease. Table 2 shows the baseline characteristics of patients according to LVEF and the presence or absence of coronary artery disease. 
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