Plasma Natriuretic Peptide Levels and the Risk of Cardiovascular Events and Death
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《新英格兰医药杂志》
ABSTRACT
Background The natriuretic peptides are counterregulatory hormones involved in volume homeostasis and cardiovascular remodeling. The prognostic significance of plasma natriuretic peptide levels in apparently asymptomatic persons has not been established.
Methods We prospectively studied 3346 persons without heart failure. Using proportional-hazards regression, we examined the relations of plasma B-type natriuretic peptide and N-terminal pro–atrial natriuretic peptide to the risk of death from any cause, a first major cardiovascular event, heart failure, atrial fibrillation, stroke or transient ischemic attack, and coronary heart disease.
Results During a mean follow-up of 5.2 years, 119 participants died and 79 had a first cardiovascular event. After adjustment for cardiovascular risk factors, each increment of 1 SD in log B-type natriuretic peptide levels was associated with a 27 percent increase in the risk of death (P=0.009), a 28 percent increase in the risk of a first cardiovascular event (P=0.03), a 77 percent increase in the risk of heart failure (P<0.001), a 66 percent increase in the risk of atrial fibrillation (P<0.001), and a 53 percent increase in the risk of stroke or transient ischemic attack (P=0.002). Peptide levels were not significantly associated with the risk of coronary heart disease events. B-type natriuretic peptide values above the 80th percentile (20.0 pg per milliliter for men and 23.3 pg per milliliter for women) were associated with multivariable-adjusted hazard ratios of 1.62 for death (P=0.02), 1.76 for a first major cardiovascular event (P=0.03), 1.91 for atrial fibrillation (P=0.02), 1.99 for stroke or transient ischemic attack (P=0.02), and 3.07 for heart failure (P=0.002). Similar results were obtained for N-terminal pro–atrial natriuretic peptide.
Conclusions In this community-based sample, plasma natriuretic peptide levels predicted the risk of death and cardiovascular events after adjustment for traditional risk factors. Excess risk was apparent at natriuretic peptide levels well below current thresholds used to diagnose heart failure.
Atrial natriuretic peptide and B-type natriuretic peptide are secreted from cardiomyocytes in response to atrial or ventricular wall stretch.1 The natriuretic peptides have a fundamental role in cardiovascular remodeling, volume homeostasis, and the response to ischemia.1,2,3,4 Clinical investigations of these peptides have focused on their diagnostic usefulness for heart failure and left ventricular dysfunction and their prognostic usefulness after acute coronary syndromes and heart failure.5,6,7,8,9,10,11,12
A few reports have suggested that elevated plasma natriuretic peptide levels in nonhospitalized persons are associated with an increased risk of death, but these studies have largely been restricted to very elderly persons.13,14,15,16 We were interested in examining the relations of natriuretic peptides to the incidence of cardiovascular events, heart failure, and atrial fibrillation in an ambulatory cohort. We prospectively studied a large, community-based sample of persons in whom plasma natriuretic peptide levels were routinely measured and who were followed for the occurrence of major cardiovascular events and death.
Methods
Study Sample
The design and selection criteria of the Framingham Offspring Study have been described previously.17 The 3532 participants who attended the sixth examination cycle (1995 through 1998) were eligible for the present investigation. We excluded 186 attendees for the following reasons: heart failure in 40, a serum creatinine level of more than 2.0 mg per deciliter (177 μmol per liter) in 16, unavailability of natriuretic peptide levels in 78, missing covariate data in 49, and missing follow-up data in 3. After exclusions, 3346 participants (95 percent) remained eligible. Participants underwent a clinical and laboratory evaluation and echocardiography, as described previously.5,18 Study protocols were approved by the institutional review board of Boston Medical Center. Written informed consent was obtained from all participants.
Natriuretic Peptide Assays
B-type natriuretic peptide and N-terminal pro–atrial natriuretic peptide were measured with the use of high-sensitivity, noncompetitive immunoradiometric assays (Shionogi). The lower limits of detection were 4 pg per milliliter for the assay of B-type natriuretic peptide and 94 pmol per liter for the assay of N-terminal pro–atrial natriuretic peptide. The average interassay coefficients of variation were 12.2 percent for B-type natriuretic peptide and 12.7 percent for N-terminal pro–atrial natriuretic peptide.
Outcomes
Participants were monitored regularly for the occurrence of cardiovascular outcomes and death. A committee of three investigators reviewed all suspected cardiovascular events by examining hospital records, clinic notes, and pathology reports. Investigators had no knowledge of the results of plasma natriuretic peptide measurements. A Framingham Heart Study neurologist evaluated participants with suspected cerebrovascular events, and a separate review committee that included a neurologist adjudicated these events.
Major cardiovascular events included recognized myocardial infarction, coronary insufficiency, death from coronary heart disease, heart failure, and stroke. Coronary heart disease included recognized or unrecognized myocardial infarction, coronary insufficiency, and angina pectoris. Prevalent cardiovascular disease was defined by prior coronary heart disease, stroke or transient ischemic attack, or intermittent claudication. Criteria for the diagnoses of cardiovascular events have been described elsewhere.18 Participants were also followed for the development of atrial fibrillation, defined as atrial fibrillation or atrial flutter on an electrocardiogram obtained from a hospital record, office visit, or Framingham Study clinic visit. Electrocardiographic findings were verified by a Framingham Heart Study cardiologist.
Statistical Analysis
We examined the association between base-line levels of plasma natriuretic peptides and six prespecified end points: death from any cause, a first major cardiovascular event, heart failure, atrial fibrillation, stroke or transient ischemic attack, and coronary heart disease. We analyzed plasma natriuretic peptide levels as categorical variables and as continuous variables after natural logarithmic transformation to normalize their distribution. In categorical analyses, we used prespecified thresholds corresponding to the 80th percentile values of each peptide. Owing to sex-based differences in the distributions of plasma natriuretic peptide levels,19,20 we established separate cutoff points for men and women. To assess whether a gradient of risk was present across natriuretic peptide values, we performed analyses using three categories: lowest third, middle third, and highest third. Because the threshold of detection of the assay censored 38 percent of plasma B-type natriuretic peptide values in men, values of 4 pg per milliliter in men were assigned to the lowest category, with the remaining values split evenly between the upper two categories.
Cumulative incidence curves were estimated according to Gray's method.21 We used multivariable proportional-hazards regression to examine the association of natriuretic peptide levels with each outcome.22 Analyses were restricted to participants who had never had the outcome being studied. For end points other than death, death was a censoring variable. We adjusted analyses for age, sex, the presence or absence of hypertension and diabetes, the ratio of total to high-density lipoprotein cholesterol, the body-mass index, the serum creatinine level, and smoking status. Additional covariates were included for specific end points on the basis of prior reports23,24,25: prevalent atrial fibrillation (for major cardiovascular events, heart failure, and stroke or transient ischemic attack), prior myocardial infarction (for heart failure and atrial fibrillation), systolic murmur of grade 3/6 or more or any diastolic murmur (for heart failure and atrial fibrillation), and prevalent cardiovascular disease (for death and stroke or transient ischemic attack).
In secondary analyses, we also analyzed heart-failure outcomes using interim myocardial infarction (occurring after the base-line examination) as a time-dependent covariate to assess whether associations between natriuretic peptide levels and heart failure were mediated by an increased risk of myocardial infarction. Similarly, in the atrial-fibrillation analyses, we included a time-dependent covariate for the interim development of either myocardial infarction or heart failure, and in the analyses of stroke or transient ischemic attack, we adjusted for interim atrial fibrillation. In addition, we repeated the heart-failure analyses in a subgroup of participants without myocardial infarction at base line.
We repeated the multivariable analyses with adjustment for echocardiographically determined left atrial diameter, left ventricular mass, and ventricular systolic dysfunction. Left ventricular mass was calculated according to the formula of the American Society of Echocardiography.26 Left ventricular systolic dysfunction was defined as a qualitative reduction in the ejection fraction or fractional shortening of less than 0.29.5
We examined whether the relations of natriuretic peptide levels to the risk of events varied according to age, sex, body-mass index, or hypertension status by incorporating interaction terms in multivariable models with log-transformed natriuretic peptide values as predictor variables. We determined which peptide was more strongly associated with each outcome by examining which one could be entered first in stepwise multivariable regression models.
All analyses were performed with the use of SAS software (version 6.12).27 A two-sided P value of less than 0.05 was considered to indicate statistical significance.
Results
Base-Line Characteristics
Base-line characteristics of the participants are shown in Table 1. Findings on physical examination, such as a third heart sound or elevated jugular venous pressure, were rare, occurring in 0.1 percent and 0.2 percent of the sample, respectively. Median and 80th percentile plasma natriuretic peptide values were higher in women than in men. Only 2.2 percent of men and 1.5 percent of women had B-type natriuretic peptide levels exceeding 80 pg per milliliter.
Table 1. Base-Line Characteristics.
Incidence of Death or Cardiovascular Events
Table 2 shows the incidence of the various outcomes during a mean follow-up of 5.2 years. A total of 119 participants died, and 79 had a first cardiovascular event. The incidence rates of death, major cardiovascular events, heart failure, atrial fibrillation, and stroke or transient ischemic attack rose with increasing plasma natriuretic peptide levels. Figure 1 shows the cumulative incidence of death and of heart failure according to the level of B-type natriuretic peptide.
Table 2. Crude Incidence Rates According to the Plasma Natriuretic Peptide Level.
Figure 1. Cumulative Incidence of Death (Panel A) and Heart Failure (Panel B), According to the Plasma B-Type Natriuretic Peptide Level at Base Line.
The lowest third, middle third, and highest third of plasma B-type natriuretic peptide levels were 4.0 pg per milliliter or less, 4.1 to 12.7 pg per milliliter, and 12.8 pg per milliliter or more, respectively, for men and 5.9 pg per milliliter or less, 6.0 to 15.7 pg per milliliter, and 15.8 pg per milliliter or more, respectively, for women. Follow-up results are truncated after six years.
Multivariate Analysis of Outcomes
After adjustment for clinical risk factors, increasing plasma natriuretic peptide levels were associated with an elevated risk of death (an increase of 27 percent for B-type natriuretic peptide and 41 percent for N-terminal pro–atrial natriuretic peptide for each increment of 1 SD in log peptide values) (Table 3 and Table 4). Values above the 80th percentile were associated with an increase in the risk of death of 62 percent and 76 percent, respectively. There was a significant trend toward an increased risk of death across all three categories (lowest third, middle third, and highest third) of N-terminal pro–atrial natriuretic peptide levels (adjusted hazard ratio, 1.44 per category increment; P=0.01) but not of B-type natriuretic peptide levels. Plasma B-type natriuretic peptide levels and N-terminal pro–atrial natriuretic peptide levels were also associated with an elevated risk of a first major cardiovascular event (an increase of 28 percent and 30 percent, respectively, for each 1 SD increment in log peptide values) (Table 3 and Table 4). B-type natriuretic peptide levels above the 80th percentile were associated with a 76 percent increase in risk. There was no significant trend toward increasing cardiovascular risk across the three categories of peptide values.
Table 3. Multivariate Analysis of the Association of Plasma B-Type Natriuretic Peptide (BNP) Levels and Outcomes.
Table 4. Multivariate Analysis of the Association of Plasma N-Terminal Pro–Atrial Natriuretic Peptide (N-ANP) Levels and Outcomes.
The levels of B-type natriuretic peptide and N-terminal pro–atrial natriuretic peptide strongly predicted the risk of heart failure, with an increase in the adjusted risk of 77 percent and 94 percent, respectively, per 1 SD increment in log peptide values (Table 3 and Table 4). Peptide levels above the 80th percentile were associated with an increase in risk by a factor of three and five, respectively. There were significant trends toward an increasing risk of heart failure across the three categories of B-type natriuretic peptide values (adjusted hazard ratio, 1.99 per category increment; P=0.009) and N-terminal pro–atrial natriuretic peptide values (adjusted hazard ratio, 1.93 per category increment; P=0.02). Results were similar in analyses that adjusted for the occurrence of interim myocardial infarction (adjusted hazard ratios, 1.59 per 1 SD increment in log B-type natriuretic peptide values and 1.82 per 1 SD increment in log N-terminal pro–atrial natriuretic peptide values; P<0.003 for both comparisons) and in analyses restricted to participants without prior myocardial infarction (adjusted hazard ratios, 2.02 and 2.10, respectively; P<0.001 for both comparisons). The exclusion of participants with B-type natriuretic peptide levels of more than 80 pg per milliliter did not attenuate the findings (adjusted hazard ratio, 1.90 per 1 SD increment in log B-type natriuretic peptide values; P<0.001).
Plasma natriuretic peptide levels were also associated with the risk of atrial fibrillation (an increase in risk of 66 to 72 percent per SD increment in log peptide values) (Table 3 and Table 4). Values of either peptide that were above the 80th percentile were associated with a doubling of the risk. Trends across the three categories of peptide values were significant for both B-type natriuretic peptide (adjusted hazard ratio, 1.71 per category increment; P=0.004) and N-terminal pro–atrial natriuretic peptide (adjusted hazard ratio, 1.46 per increment; P=0.047). In analyses adjusting for the occurrence of interim myocardial infarction and heart failure, the hazard ratio remained significant: 1.49 per 1 SD increment in log B-type natriuretic peptide values (P=0.001) and 1.59 per 1 SD increment in log N-terminal pro–atrial natriuretic peptide values (P=0.002).
Plasma levels of B-type natriuretic peptide and N-terminal pro–atrial natriuretic peptide also predicted the risk of stroke or transient ischemic attack (adjusted hazard ratios of 1.53 and 1.37, respectively, per 1 SD increment in log peptide values) (Table 3 and Table 4). Values above the 80th percentile were associated with a doubling of the risk. There was a significant trend across the three categories of B-type natriuretic peptide levels (adjusted hazard ratio, 1.71 per category increment; P=0.01) but not of N-terminal pro–atrial natriuretic peptide levels (P=0.27). These results were unchanged after adjustment for the occurrence of interim atrial fibrillation (data not shown). In contrast to other cardiovascular events, the risk of coronary heart disease was not associated with plasma natriuretic peptide levels (Table 3 and Table 4).
Secondary Analyses
Additional analyses were performed to investigate whether natriuretic peptide levels predicted the risk of events because of their association with increased left ventricular mass, left atrial diameter, or left ventricular systolic dysfunction. Adjustment for these three echocardiographic variables (in addition to the clinical covariates) attenuated the association between log B-type natriuretic peptide values and death (P=0.29), log B-type natriuretic peptide values and first major cardiovascular events (P=0.25), and log N-terminal pro–atrial natriuretic peptide values and first major cardiovascular events (P=0.32). However, both peptides continued to be significant predictors of the risk of heart failure (adjusted hazard ratios, 1.56 per 1 SD increment in log B-type natriuretic peptide values and 1.95 per 1 SD increment in log N-terminal pro–atrial natriuretic peptide values; P<0.02 for both comparisons) and atrial fibrillation (adjusted hazard ratios, 1.43 per 1 SD increment in log B-type natriuretic peptide values and 1.41 per 1 SD increment in log N-terminal pro–atrial natriuretic peptide values; both P<0.03). The association between log B-type natriuretic peptide values and the risk of stroke or a transient ischemic attack also remained significant (adjusted hazard ratio, 1.64 per 1 SD increment; P=0.004), as did the association between log N-terminal pro–atrial natriuretic peptide values and the risk of death (adjusted hazard ratio, 1.32 per 1 SD increment; P=0.02).
The association between natriuretic peptide levels and outcomes did not vary according to age, sex, body-mass index, or the presence or absence of hypertension. Additional analyses adjusting for systolic blood pressure, diastolic blood pressure, and the use of antihypertensive therapy (instead of the presence of hypertension) yielded results similar to those of the main analyses.
Plasma levels of B-type natriuretic peptide and N-terminal pro–atrial natriuretic peptide were highly correlated (Spearman coefficient, 0.67; P<0.001). In stepwise models adjusting for known risk factors, the log B-type natriuretic peptide value was selected before the log N-terminal pro–atrial natriuretic peptide value for all outcomes except death. For every model, the presence of either peptide prevented the other peptide from being included, when a P value of less than 0.05 was the criterion for inclusion.
Discussion
We found that plasma natriuretic peptide levels predicted a wide range of cardiovascular outcomes and provided information that was incremental to that obtained from established risk factors. The relation was strongest for heart failure and atrial fibrillation, but we also observed important associations between plasma natriuretic peptide levels and the risk of death from any cause, stroke or transient ischemic attack, and first major cardiovascular events. Although our results were consistent for both natriuretic peptides, B-type natriuretic peptide levels outperformed N-terminal pro–atrial natriuretic peptide levels with respect to most outcomes.
Several inferences can be drawn from our data. First, a single determination of plasma natriuretic peptide levels provides prognostic information in unselected members of the community. Second, plasma natriuretic peptide levels may be elevated before the onset of clinically apparent cardiovascular disease, a critical attribute if these assays are to be used in broader populations.28 Third, plasma natriuretic peptide values within a range currently regarded as normal may be associated with an increased risk of adverse outcomes. The prespecified B-type natriuretic peptide thresholds used to predict cardiovascular events in this cohort (80th percentile values of 20.0 pg per milliliter for men and 23.3 pg per milliliter for women) are well below contemporary thresholds used for the diagnosis of heart failure (80 to 100 pg per milliliter).8,29 It is unlikely that our results were driven by extreme B-type natriuretic peptide values, because less than 2 percent of the participants had levels above 80 pg per milliliter.
Studies of patients with symptomatic cardiac disease indicate that natriuretic peptide levels are markers of increased atrial or ventricular strain, typically from pressure or volume overload.30,31 In ambulatory persons, elevated natriuretic peptides probably reflect similar processes, but manifestations of this strain may be subtle, and the underlying causes less apparent. Although it is difficult to measure strain or filling pressures directly in an epidemiologic setting, echocardiographic features related to abnormal loading conditions (such as left ventricular mass and systolic dysfunction) correlate with natriuretic peptide levels,5,6 even after adjustment for other cardiovascular risk factors.6,32 Accordingly, adjustment for echocardiographic variables appears to attenuate the association between peptide levels and most outcomes.
We found that higher natriuretic peptide levels predicted the risk of heart failure and atrial fibrillation, even after accounting for left ventricular mass and systolic dysfunction. This observation may reflect a dissociation between echocardiographic findings and filling pressures in some persons, particularly in the presence of diastolic dysfunction.7 Additional mechanisms may also be important, such as up-regulation of the natriuretic peptide axis in the setting of subclinical vascular disease. The natriuretic peptides have a fundamental role in vascular function and remodeling, by potentiating the effects of nitric oxide,33 inhibiting lipid insudation in the vascular wall,34 and increasing parasympathetic tone.35
Prior studies relating natriuretic peptide levels to the risk of heart failure and atrial fibrillation have been cross-sectional36,37 or restricted to select samples.10,38 Stroke was one of our prespecified outcomes, because an association between polymorphisms of the gene for atrial natriuretic peptide and the risk of stroke has been noted.39,40 We found that plasma natriuretic peptide levels predict the risk of stroke.
We did not find an association between base-line plasma natriuretic peptide levels and the risk of coronary heart disease. Some studies have shown a correlation between plasma natriuretic peptide levels and myocardial infarction in patients with acute coronary syndromes, but these associations have been relatively weak.9,10,41,42 Data from patients with acute coronary syndromes may not apply to ambulatory persons.
The strengths of our investigation include the large, community-based sample, the use of high-sensitivity assays, and the use of continual surveillance for multiple outcomes according to standardized criteria. Nevertheless, our findings should be confirmed in other cohorts. Also, since the Framingham Study cohort is predominantly white, our results may not be generalizable to non-whites. We had limited statistical power to perform separate analyses of high-risk subgroups, such as persons with diabetes, or to examine the risk of death from cardiovascular causes separately from the risk of death from any cause.
Although our natriuretic peptide cutoff points were derived from a community-based sample, it is important to recognize that cutoff points vary among assays.20 Also, the risks associated with increasing natriuretic peptide levels may be continuous rather than restricted to values above a threshold. We had limited statistical power to evaluate a threshold effect. Studies with longer-term follow-up may provide further insight.
We report the prospective association between plasma natriuretic peptide levels and a range of cardiovascular outcomes in a community-based cohort. The prognostic information provided by plasma natriuretic peptide levels is incremental to that provided by traditional cardiovascular risk factors. Although echocardiography may provide more specific information regarding cardiac structure, its high cost makes it an impractical screening tool in asymptomatic persons.43 Furthermore, measurement of plasma natriuretic peptide levels and echocardiography may be complementary tests in some circumstances, because peptide levels may be a marker of elevated filling pressures, which may otherwise be detectable only with invasive tests.
Although these data raise the possibility that measurement of natriuretic peptides may aid in the early detection of cardiovascular disease, additional investigations are needed to validate our results and to evaluate the screening characteristics of these peptides, including comparisons with markers that were not investigated in our study (e.g., C-reactive protein). Further studies are also warranted to determine whether a finding of elevated plasma natriuretic peptide levels in asymptomatic persons should trigger further diagnostic tests, such as echocardiography.
Supported by grants (NO1-HC-25195; K23-HL074077-01, to Dr. Wang; and K24-HL-04334, to Dr. Vasan) from the National Institutes of Health, National Heart, Lung, and Blood Institute.
Dr. Omland reports having received speaker's fees and consulting honoraria from Biosite, Roche Diagnostics, and Bayer Diagnostics.
We are indebted to Shionogi for performing the natriuretic peptide assays.
Source Information
From the Framingham Heart Study, Framingham, Mass. (T.J.W., M.G.L., D.L., E.J.B., E.P.L., P.A.W., R.S.V.); the Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston (T.J.W.); the National Heart, Lung, and Blood Institute, Bethesda, Md. (D.L.); the Cardiology Section (D.L., E.J.B., R.S.V.) and the Department of Neurology (P.A.W.), Boston Medical Center and Boston University School of Medicine, Boston; and the Department of Medicine, Akershus Hospital, Oslo, Norway (T.O.).
Address reprint requests to Dr. Vasan at the Framingham Heart Study, 73 Mt. Wayte Ave., #2, Framingham, MA 01702-5827, or at vasan@fram.nhlbi.nih.gov.
References
Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998;339:321-328.
Molkentin JD. A friend within the heart: natriuretic peptide receptor signaling. J Clin Invest 2003;111:1275-1277.
Kook H, Itoh H, Choi BS, et al. Physiological concentration of atrial natriuretic peptide induces endothelial regeneration in vitro. Am J Physiol Heart Circ Physiol 2003;284:H1388-H1397.
Goetze JP, Christoffersen C, Perko M, et al. Increased cardiac BNP expression associated with myocardial ischemia. FASEB J 2003;17:1105-1107.
Vasan RS, Benjamin EJ, Larson MG, et al. Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the Framingham Heart Study. JAMA 2002;288:1252-1259.
McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet 1998;351:9-13.
Lubien E, DeMaria A, Krishnaswamy P, et al. Utility of B-type natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation 2002;105:595-601.
Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161-167.
Richards AM, Nicholls MG, Espiner EA, et al. B-type natriuretic peptides and ejection fraction for prognosis after myocardial infarction. Circulation 2003;107:2786-2792.
de Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014-1021.
Omland T, Aakvaag A, Bonarjee VV, et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction: comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide. Circulation 1996;93:1963-1969.
Berger R, Huelsman M, Strecker K, et al. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation 2002;105:2392-2397.
Wallen T, Landahl S, Hedner T, Hall C, Saito Y, Nakao K. Atrial natriuretic peptides predict mortality in the elderly. J Intern Med 1997;241:269-275.
Knight EL, Kiely DK, Fish LC, Marcantonio ER, Minaker KL. Atrial natriuretic peptide level contributes to a model of future mortality in the oldest old. J Am Geriatr Soc 1998;46:453-457.
Ueda R, Yokouchi M, Suzuki T, Otomo E, Katagiri T. Prognostic value of high plasma brain natriuretic peptide concentrations in very elderly persons. Am J Med 2003;114:266-270.
McDonagh TA, Cunningham AD, Morrison CE, et al. Left ventricular dysfunction, natriuretic peptides, and mortality in an urban population. Heart 2001;86:21-26.
Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families: the Framingham Offspring Study. Am J Epidemiol 1979;110:281-290.
Kannel WB, Wolf PA, Garrison RJ, eds. The Framingham Study: an epidemiological investigation of cardiovascular disease. Section 34. Some risk factors related to the annual incidence of cardiovascular disease and death in pooled repeated biennial measurements: Framingham Heart Study, 30-year followup. Bethesda, Md.: National Heart, Lung, and Blood Institute, February 1987. (NIH publication no. 87-2703.)
Wang TJ, Larson MG, Levy D, et al. Impact of age and sex on plasma natriuretic peptide levels in healthy adults. Am J Cardiol 2002;90:254-258.
Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol 2002;40:976-982.
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988;16:1141-54.
Cox DR. Regression models and life-tables. J R Stat Soc 1972;34:187-220.
Wolf PA, D'Agostino RB, Belanger AJ, Kannel WB. Probability of stroke: a risk profile from the Framingham Study. Stroke 1991;22:312-318.
Kannel WB, D'Agostino RB, Silbershatz H, Belanger AJ, Wilson PW, Levy D. Profile for estimating risk of heart failure. Arch Intern Med 1999;159:1197-1204.
Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart Study. JAMA 1994;271:840-844.
Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072-1083.
SAS/STAT software: PHREG procedure: changes and enhancements through release 6.12. Cary, N.C.: SAS Institute, 1997:871-948.
Struthers AD, Morris AD. Screening for and treating left-ventricular abnormalities in diabetes mellitus: a new way of reducing cardiac deaths. Lancet 2002;359:1430-1432.
Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol 2001;37:379-385.
Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure: a substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990;82:1724-1729.
Yamamoto K, Burnett JC Jr, Jougasaki M, et al. Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension 1996;28:988-994.
Schirmer H, Omland T. Circulating N-terminal pro-atrial natriuretic peptide is an independent predictor of left ventricular hypertrophy in the general population: the Tromso Study. Eur Heart J 1999;20:755-763.
Brunner F, Wolkart G. Relaxant effect of C-type natriuretic peptide involves endothelium and nitric oxide-cGMP system in rat coronary microvasculature. Cardiovasc Res 2001;51:577-584.
Kohno M, Yokokawa K, Yasunari K, et al. Effect of natriuretic peptide family on the oxidized LDL-induced migration of human coronary artery smooth muscle cells. Circ Res 1997;81:585-590.
Herring N, Zaman JA, Paterson DJ. Natriuretic peptides like NO facilitate cardiac vagal neurotransmission and bradycardia via a cGMP pathway. Am J Physiol Heart Circ Physiol 2001;281:H2318-H2327.
Rossi A, Enriquez-Sarano M, Burnett JC Jr, Lerman A, Abel MD, Seward JB. Natriuretic peptide levels in atrial fibrillation: a prospective hormonal and Doppler-echocardiographic study. J Am Coll Cardiol 2000;35:1256-1262.
van den Berg MP, Tjeerdsma G, Jan de Kan P, Boomsma F, Crijns HJ, van Veldhuisen DJ. Longstanding atrial fibrillation causes depletion of atrial natriuretic peptide in patients with advanced congestive heart failure. Eur J Heart Fail 2002;4:255-262.
Davis KM, Fish LC, Elahi D, Clark BA, Minaker KL. Atrial natriuretic peptide levels in the prediction of congestive heart failure risk in frail elderly. JAMA 1992;267:2625-2629.
Rubattu S, Lee-Kirsch MA, DePaolis P, et al. Altered structure, regulation, and function of the gene encoding the atrial natriuretic peptide in the stroke-prone spontaneously hypertensive rat. Circ Res 1999;85:900-905.
Rubattu S, Ridker P, Stampfer MJ, Volpe M, Hennekens CH, Lindpaintner K. The gene encoding atrial natriuretic peptide and the risk of human stroke. Circulation 1999;100:1722-1726.
Morrow DA, De Lemos JA, Sabatine MS, et al. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18. J Am Coll Cardiol 2003;41:1264-1272.
James SK, Lindahl B, Siegbahn A, et al. 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;108:275-281.
Wang TJ, Levy D, Benjamin EJ, Vasan RS. The epidemiology of "asymptomatic" left ventricular systolic dysfunction: implications for screening. Ann Intern Med 2003;138:907-916.(Thomas J. Wang, M.D., Mar)
Background The natriuretic peptides are counterregulatory hormones involved in volume homeostasis and cardiovascular remodeling. The prognostic significance of plasma natriuretic peptide levels in apparently asymptomatic persons has not been established.
Methods We prospectively studied 3346 persons without heart failure. Using proportional-hazards regression, we examined the relations of plasma B-type natriuretic peptide and N-terminal pro–atrial natriuretic peptide to the risk of death from any cause, a first major cardiovascular event, heart failure, atrial fibrillation, stroke or transient ischemic attack, and coronary heart disease.
Results During a mean follow-up of 5.2 years, 119 participants died and 79 had a first cardiovascular event. After adjustment for cardiovascular risk factors, each increment of 1 SD in log B-type natriuretic peptide levels was associated with a 27 percent increase in the risk of death (P=0.009), a 28 percent increase in the risk of a first cardiovascular event (P=0.03), a 77 percent increase in the risk of heart failure (P<0.001), a 66 percent increase in the risk of atrial fibrillation (P<0.001), and a 53 percent increase in the risk of stroke or transient ischemic attack (P=0.002). Peptide levels were not significantly associated with the risk of coronary heart disease events. B-type natriuretic peptide values above the 80th percentile (20.0 pg per milliliter for men and 23.3 pg per milliliter for women) were associated with multivariable-adjusted hazard ratios of 1.62 for death (P=0.02), 1.76 for a first major cardiovascular event (P=0.03), 1.91 for atrial fibrillation (P=0.02), 1.99 for stroke or transient ischemic attack (P=0.02), and 3.07 for heart failure (P=0.002). Similar results were obtained for N-terminal pro–atrial natriuretic peptide.
Conclusions In this community-based sample, plasma natriuretic peptide levels predicted the risk of death and cardiovascular events after adjustment for traditional risk factors. Excess risk was apparent at natriuretic peptide levels well below current thresholds used to diagnose heart failure.
Atrial natriuretic peptide and B-type natriuretic peptide are secreted from cardiomyocytes in response to atrial or ventricular wall stretch.1 The natriuretic peptides have a fundamental role in cardiovascular remodeling, volume homeostasis, and the response to ischemia.1,2,3,4 Clinical investigations of these peptides have focused on their diagnostic usefulness for heart failure and left ventricular dysfunction and their prognostic usefulness after acute coronary syndromes and heart failure.5,6,7,8,9,10,11,12
A few reports have suggested that elevated plasma natriuretic peptide levels in nonhospitalized persons are associated with an increased risk of death, but these studies have largely been restricted to very elderly persons.13,14,15,16 We were interested in examining the relations of natriuretic peptides to the incidence of cardiovascular events, heart failure, and atrial fibrillation in an ambulatory cohort. We prospectively studied a large, community-based sample of persons in whom plasma natriuretic peptide levels were routinely measured and who were followed for the occurrence of major cardiovascular events and death.
Methods
Study Sample
The design and selection criteria of the Framingham Offspring Study have been described previously.17 The 3532 participants who attended the sixth examination cycle (1995 through 1998) were eligible for the present investigation. We excluded 186 attendees for the following reasons: heart failure in 40, a serum creatinine level of more than 2.0 mg per deciliter (177 μmol per liter) in 16, unavailability of natriuretic peptide levels in 78, missing covariate data in 49, and missing follow-up data in 3. After exclusions, 3346 participants (95 percent) remained eligible. Participants underwent a clinical and laboratory evaluation and echocardiography, as described previously.5,18 Study protocols were approved by the institutional review board of Boston Medical Center. Written informed consent was obtained from all participants.
Natriuretic Peptide Assays
B-type natriuretic peptide and N-terminal pro–atrial natriuretic peptide were measured with the use of high-sensitivity, noncompetitive immunoradiometric assays (Shionogi). The lower limits of detection were 4 pg per milliliter for the assay of B-type natriuretic peptide and 94 pmol per liter for the assay of N-terminal pro–atrial natriuretic peptide. The average interassay coefficients of variation were 12.2 percent for B-type natriuretic peptide and 12.7 percent for N-terminal pro–atrial natriuretic peptide.
Outcomes
Participants were monitored regularly for the occurrence of cardiovascular outcomes and death. A committee of three investigators reviewed all suspected cardiovascular events by examining hospital records, clinic notes, and pathology reports. Investigators had no knowledge of the results of plasma natriuretic peptide measurements. A Framingham Heart Study neurologist evaluated participants with suspected cerebrovascular events, and a separate review committee that included a neurologist adjudicated these events.
Major cardiovascular events included recognized myocardial infarction, coronary insufficiency, death from coronary heart disease, heart failure, and stroke. Coronary heart disease included recognized or unrecognized myocardial infarction, coronary insufficiency, and angina pectoris. Prevalent cardiovascular disease was defined by prior coronary heart disease, stroke or transient ischemic attack, or intermittent claudication. Criteria for the diagnoses of cardiovascular events have been described elsewhere.18 Participants were also followed for the development of atrial fibrillation, defined as atrial fibrillation or atrial flutter on an electrocardiogram obtained from a hospital record, office visit, or Framingham Study clinic visit. Electrocardiographic findings were verified by a Framingham Heart Study cardiologist.
Statistical Analysis
We examined the association between base-line levels of plasma natriuretic peptides and six prespecified end points: death from any cause, a first major cardiovascular event, heart failure, atrial fibrillation, stroke or transient ischemic attack, and coronary heart disease. We analyzed plasma natriuretic peptide levels as categorical variables and as continuous variables after natural logarithmic transformation to normalize their distribution. In categorical analyses, we used prespecified thresholds corresponding to the 80th percentile values of each peptide. Owing to sex-based differences in the distributions of plasma natriuretic peptide levels,19,20 we established separate cutoff points for men and women. To assess whether a gradient of risk was present across natriuretic peptide values, we performed analyses using three categories: lowest third, middle third, and highest third. Because the threshold of detection of the assay censored 38 percent of plasma B-type natriuretic peptide values in men, values of 4 pg per milliliter in men were assigned to the lowest category, with the remaining values split evenly between the upper two categories.
Cumulative incidence curves were estimated according to Gray's method.21 We used multivariable proportional-hazards regression to examine the association of natriuretic peptide levels with each outcome.22 Analyses were restricted to participants who had never had the outcome being studied. For end points other than death, death was a censoring variable. We adjusted analyses for age, sex, the presence or absence of hypertension and diabetes, the ratio of total to high-density lipoprotein cholesterol, the body-mass index, the serum creatinine level, and smoking status. Additional covariates were included for specific end points on the basis of prior reports23,24,25: prevalent atrial fibrillation (for major cardiovascular events, heart failure, and stroke or transient ischemic attack), prior myocardial infarction (for heart failure and atrial fibrillation), systolic murmur of grade 3/6 or more or any diastolic murmur (for heart failure and atrial fibrillation), and prevalent cardiovascular disease (for death and stroke or transient ischemic attack).
In secondary analyses, we also analyzed heart-failure outcomes using interim myocardial infarction (occurring after the base-line examination) as a time-dependent covariate to assess whether associations between natriuretic peptide levels and heart failure were mediated by an increased risk of myocardial infarction. Similarly, in the atrial-fibrillation analyses, we included a time-dependent covariate for the interim development of either myocardial infarction or heart failure, and in the analyses of stroke or transient ischemic attack, we adjusted for interim atrial fibrillation. In addition, we repeated the heart-failure analyses in a subgroup of participants without myocardial infarction at base line.
We repeated the multivariable analyses with adjustment for echocardiographically determined left atrial diameter, left ventricular mass, and ventricular systolic dysfunction. Left ventricular mass was calculated according to the formula of the American Society of Echocardiography.26 Left ventricular systolic dysfunction was defined as a qualitative reduction in the ejection fraction or fractional shortening of less than 0.29.5
We examined whether the relations of natriuretic peptide levels to the risk of events varied according to age, sex, body-mass index, or hypertension status by incorporating interaction terms in multivariable models with log-transformed natriuretic peptide values as predictor variables. We determined which peptide was more strongly associated with each outcome by examining which one could be entered first in stepwise multivariable regression models.
All analyses were performed with the use of SAS software (version 6.12).27 A two-sided P value of less than 0.05 was considered to indicate statistical significance.
Results
Base-Line Characteristics
Base-line characteristics of the participants are shown in Table 1. Findings on physical examination, such as a third heart sound or elevated jugular venous pressure, were rare, occurring in 0.1 percent and 0.2 percent of the sample, respectively. Median and 80th percentile plasma natriuretic peptide values were higher in women than in men. Only 2.2 percent of men and 1.5 percent of women had B-type natriuretic peptide levels exceeding 80 pg per milliliter.
Table 1. Base-Line Characteristics.
Incidence of Death or Cardiovascular Events
Table 2 shows the incidence of the various outcomes during a mean follow-up of 5.2 years. A total of 119 participants died, and 79 had a first cardiovascular event. The incidence rates of death, major cardiovascular events, heart failure, atrial fibrillation, and stroke or transient ischemic attack rose with increasing plasma natriuretic peptide levels. Figure 1 shows the cumulative incidence of death and of heart failure according to the level of B-type natriuretic peptide.
Table 2. Crude Incidence Rates According to the Plasma Natriuretic Peptide Level.
Figure 1. Cumulative Incidence of Death (Panel A) and Heart Failure (Panel B), According to the Plasma B-Type Natriuretic Peptide Level at Base Line.
The lowest third, middle third, and highest third of plasma B-type natriuretic peptide levels were 4.0 pg per milliliter or less, 4.1 to 12.7 pg per milliliter, and 12.8 pg per milliliter or more, respectively, for men and 5.9 pg per milliliter or less, 6.0 to 15.7 pg per milliliter, and 15.8 pg per milliliter or more, respectively, for women. Follow-up results are truncated after six years.
Multivariate Analysis of Outcomes
After adjustment for clinical risk factors, increasing plasma natriuretic peptide levels were associated with an elevated risk of death (an increase of 27 percent for B-type natriuretic peptide and 41 percent for N-terminal pro–atrial natriuretic peptide for each increment of 1 SD in log peptide values) (Table 3 and Table 4). Values above the 80th percentile were associated with an increase in the risk of death of 62 percent and 76 percent, respectively. There was a significant trend toward an increased risk of death across all three categories (lowest third, middle third, and highest third) of N-terminal pro–atrial natriuretic peptide levels (adjusted hazard ratio, 1.44 per category increment; P=0.01) but not of B-type natriuretic peptide levels. Plasma B-type natriuretic peptide levels and N-terminal pro–atrial natriuretic peptide levels were also associated with an elevated risk of a first major cardiovascular event (an increase of 28 percent and 30 percent, respectively, for each 1 SD increment in log peptide values) (Table 3 and Table 4). B-type natriuretic peptide levels above the 80th percentile were associated with a 76 percent increase in risk. There was no significant trend toward increasing cardiovascular risk across the three categories of peptide values.
Table 3. Multivariate Analysis of the Association of Plasma B-Type Natriuretic Peptide (BNP) Levels and Outcomes.
Table 4. Multivariate Analysis of the Association of Plasma N-Terminal Pro–Atrial Natriuretic Peptide (N-ANP) Levels and Outcomes.
The levels of B-type natriuretic peptide and N-terminal pro–atrial natriuretic peptide strongly predicted the risk of heart failure, with an increase in the adjusted risk of 77 percent and 94 percent, respectively, per 1 SD increment in log peptide values (Table 3 and Table 4). Peptide levels above the 80th percentile were associated with an increase in risk by a factor of three and five, respectively. There were significant trends toward an increasing risk of heart failure across the three categories of B-type natriuretic peptide values (adjusted hazard ratio, 1.99 per category increment; P=0.009) and N-terminal pro–atrial natriuretic peptide values (adjusted hazard ratio, 1.93 per category increment; P=0.02). Results were similar in analyses that adjusted for the occurrence of interim myocardial infarction (adjusted hazard ratios, 1.59 per 1 SD increment in log B-type natriuretic peptide values and 1.82 per 1 SD increment in log N-terminal pro–atrial natriuretic peptide values; P<0.003 for both comparisons) and in analyses restricted to participants without prior myocardial infarction (adjusted hazard ratios, 2.02 and 2.10, respectively; P<0.001 for both comparisons). The exclusion of participants with B-type natriuretic peptide levels of more than 80 pg per milliliter did not attenuate the findings (adjusted hazard ratio, 1.90 per 1 SD increment in log B-type natriuretic peptide values; P<0.001).
Plasma natriuretic peptide levels were also associated with the risk of atrial fibrillation (an increase in risk of 66 to 72 percent per SD increment in log peptide values) (Table 3 and Table 4). Values of either peptide that were above the 80th percentile were associated with a doubling of the risk. Trends across the three categories of peptide values were significant for both B-type natriuretic peptide (adjusted hazard ratio, 1.71 per category increment; P=0.004) and N-terminal pro–atrial natriuretic peptide (adjusted hazard ratio, 1.46 per increment; P=0.047). In analyses adjusting for the occurrence of interim myocardial infarction and heart failure, the hazard ratio remained significant: 1.49 per 1 SD increment in log B-type natriuretic peptide values (P=0.001) and 1.59 per 1 SD increment in log N-terminal pro–atrial natriuretic peptide values (P=0.002).
Plasma levels of B-type natriuretic peptide and N-terminal pro–atrial natriuretic peptide also predicted the risk of stroke or transient ischemic attack (adjusted hazard ratios of 1.53 and 1.37, respectively, per 1 SD increment in log peptide values) (Table 3 and Table 4). Values above the 80th percentile were associated with a doubling of the risk. There was a significant trend across the three categories of B-type natriuretic peptide levels (adjusted hazard ratio, 1.71 per category increment; P=0.01) but not of N-terminal pro–atrial natriuretic peptide levels (P=0.27). These results were unchanged after adjustment for the occurrence of interim atrial fibrillation (data not shown). In contrast to other cardiovascular events, the risk of coronary heart disease was not associated with plasma natriuretic peptide levels (Table 3 and Table 4).
Secondary Analyses
Additional analyses were performed to investigate whether natriuretic peptide levels predicted the risk of events because of their association with increased left ventricular mass, left atrial diameter, or left ventricular systolic dysfunction. Adjustment for these three echocardiographic variables (in addition to the clinical covariates) attenuated the association between log B-type natriuretic peptide values and death (P=0.29), log B-type natriuretic peptide values and first major cardiovascular events (P=0.25), and log N-terminal pro–atrial natriuretic peptide values and first major cardiovascular events (P=0.32). However, both peptides continued to be significant predictors of the risk of heart failure (adjusted hazard ratios, 1.56 per 1 SD increment in log B-type natriuretic peptide values and 1.95 per 1 SD increment in log N-terminal pro–atrial natriuretic peptide values; P<0.02 for both comparisons) and atrial fibrillation (adjusted hazard ratios, 1.43 per 1 SD increment in log B-type natriuretic peptide values and 1.41 per 1 SD increment in log N-terminal pro–atrial natriuretic peptide values; both P<0.03). The association between log B-type natriuretic peptide values and the risk of stroke or a transient ischemic attack also remained significant (adjusted hazard ratio, 1.64 per 1 SD increment; P=0.004), as did the association between log N-terminal pro–atrial natriuretic peptide values and the risk of death (adjusted hazard ratio, 1.32 per 1 SD increment; P=0.02).
The association between natriuretic peptide levels and outcomes did not vary according to age, sex, body-mass index, or the presence or absence of hypertension. Additional analyses adjusting for systolic blood pressure, diastolic blood pressure, and the use of antihypertensive therapy (instead of the presence of hypertension) yielded results similar to those of the main analyses.
Plasma levels of B-type natriuretic peptide and N-terminal pro–atrial natriuretic peptide were highly correlated (Spearman coefficient, 0.67; P<0.001). In stepwise models adjusting for known risk factors, the log B-type natriuretic peptide value was selected before the log N-terminal pro–atrial natriuretic peptide value for all outcomes except death. For every model, the presence of either peptide prevented the other peptide from being included, when a P value of less than 0.05 was the criterion for inclusion.
Discussion
We found that plasma natriuretic peptide levels predicted a wide range of cardiovascular outcomes and provided information that was incremental to that obtained from established risk factors. The relation was strongest for heart failure and atrial fibrillation, but we also observed important associations between plasma natriuretic peptide levels and the risk of death from any cause, stroke or transient ischemic attack, and first major cardiovascular events. Although our results were consistent for both natriuretic peptides, B-type natriuretic peptide levels outperformed N-terminal pro–atrial natriuretic peptide levels with respect to most outcomes.
Several inferences can be drawn from our data. First, a single determination of plasma natriuretic peptide levels provides prognostic information in unselected members of the community. Second, plasma natriuretic peptide levels may be elevated before the onset of clinically apparent cardiovascular disease, a critical attribute if these assays are to be used in broader populations.28 Third, plasma natriuretic peptide values within a range currently regarded as normal may be associated with an increased risk of adverse outcomes. The prespecified B-type natriuretic peptide thresholds used to predict cardiovascular events in this cohort (80th percentile values of 20.0 pg per milliliter for men and 23.3 pg per milliliter for women) are well below contemporary thresholds used for the diagnosis of heart failure (80 to 100 pg per milliliter).8,29 It is unlikely that our results were driven by extreme B-type natriuretic peptide values, because less than 2 percent of the participants had levels above 80 pg per milliliter.
Studies of patients with symptomatic cardiac disease indicate that natriuretic peptide levels are markers of increased atrial or ventricular strain, typically from pressure or volume overload.30,31 In ambulatory persons, elevated natriuretic peptides probably reflect similar processes, but manifestations of this strain may be subtle, and the underlying causes less apparent. Although it is difficult to measure strain or filling pressures directly in an epidemiologic setting, echocardiographic features related to abnormal loading conditions (such as left ventricular mass and systolic dysfunction) correlate with natriuretic peptide levels,5,6 even after adjustment for other cardiovascular risk factors.6,32 Accordingly, adjustment for echocardiographic variables appears to attenuate the association between peptide levels and most outcomes.
We found that higher natriuretic peptide levels predicted the risk of heart failure and atrial fibrillation, even after accounting for left ventricular mass and systolic dysfunction. This observation may reflect a dissociation between echocardiographic findings and filling pressures in some persons, particularly in the presence of diastolic dysfunction.7 Additional mechanisms may also be important, such as up-regulation of the natriuretic peptide axis in the setting of subclinical vascular disease. The natriuretic peptides have a fundamental role in vascular function and remodeling, by potentiating the effects of nitric oxide,33 inhibiting lipid insudation in the vascular wall,34 and increasing parasympathetic tone.35
Prior studies relating natriuretic peptide levels to the risk of heart failure and atrial fibrillation have been cross-sectional36,37 or restricted to select samples.10,38 Stroke was one of our prespecified outcomes, because an association between polymorphisms of the gene for atrial natriuretic peptide and the risk of stroke has been noted.39,40 We found that plasma natriuretic peptide levels predict the risk of stroke.
We did not find an association between base-line plasma natriuretic peptide levels and the risk of coronary heart disease. Some studies have shown a correlation between plasma natriuretic peptide levels and myocardial infarction in patients with acute coronary syndromes, but these associations have been relatively weak.9,10,41,42 Data from patients with acute coronary syndromes may not apply to ambulatory persons.
The strengths of our investigation include the large, community-based sample, the use of high-sensitivity assays, and the use of continual surveillance for multiple outcomes according to standardized criteria. Nevertheless, our findings should be confirmed in other cohorts. Also, since the Framingham Study cohort is predominantly white, our results may not be generalizable to non-whites. We had limited statistical power to perform separate analyses of high-risk subgroups, such as persons with diabetes, or to examine the risk of death from cardiovascular causes separately from the risk of death from any cause.
Although our natriuretic peptide cutoff points were derived from a community-based sample, it is important to recognize that cutoff points vary among assays.20 Also, the risks associated with increasing natriuretic peptide levels may be continuous rather than restricted to values above a threshold. We had limited statistical power to evaluate a threshold effect. Studies with longer-term follow-up may provide further insight.
We report the prospective association between plasma natriuretic peptide levels and a range of cardiovascular outcomes in a community-based cohort. The prognostic information provided by plasma natriuretic peptide levels is incremental to that provided by traditional cardiovascular risk factors. Although echocardiography may provide more specific information regarding cardiac structure, its high cost makes it an impractical screening tool in asymptomatic persons.43 Furthermore, measurement of plasma natriuretic peptide levels and echocardiography may be complementary tests in some circumstances, because peptide levels may be a marker of elevated filling pressures, which may otherwise be detectable only with invasive tests.
Although these data raise the possibility that measurement of natriuretic peptides may aid in the early detection of cardiovascular disease, additional investigations are needed to validate our results and to evaluate the screening characteristics of these peptides, including comparisons with markers that were not investigated in our study (e.g., C-reactive protein). Further studies are also warranted to determine whether a finding of elevated plasma natriuretic peptide levels in asymptomatic persons should trigger further diagnostic tests, such as echocardiography.
Supported by grants (NO1-HC-25195; K23-HL074077-01, to Dr. Wang; and K24-HL-04334, to Dr. Vasan) from the National Institutes of Health, National Heart, Lung, and Blood Institute.
Dr. Omland reports having received speaker's fees and consulting honoraria from Biosite, Roche Diagnostics, and Bayer Diagnostics.
We are indebted to Shionogi for performing the natriuretic peptide assays.
Source Information
From the Framingham Heart Study, Framingham, Mass. (T.J.W., M.G.L., D.L., E.J.B., E.P.L., P.A.W., R.S.V.); the Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston (T.J.W.); the National Heart, Lung, and Blood Institute, Bethesda, Md. (D.L.); the Cardiology Section (D.L., E.J.B., R.S.V.) and the Department of Neurology (P.A.W.), Boston Medical Center and Boston University School of Medicine, Boston; and the Department of Medicine, Akershus Hospital, Oslo, Norway (T.O.).
Address reprint requests to Dr. Vasan at the Framingham Heart Study, 73 Mt. Wayte Ave., #2, Framingham, MA 01702-5827, or at vasan@fram.nhlbi.nih.gov.
References
Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998;339:321-328.
Molkentin JD. A friend within the heart: natriuretic peptide receptor signaling. J Clin Invest 2003;111:1275-1277.
Kook H, Itoh H, Choi BS, et al. Physiological concentration of atrial natriuretic peptide induces endothelial regeneration in vitro. Am J Physiol Heart Circ Physiol 2003;284:H1388-H1397.
Goetze JP, Christoffersen C, Perko M, et al. Increased cardiac BNP expression associated with myocardial ischemia. FASEB J 2003;17:1105-1107.
Vasan RS, Benjamin EJ, Larson MG, et al. Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the Framingham Heart Study. JAMA 2002;288:1252-1259.
McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet 1998;351:9-13.
Lubien E, DeMaria A, Krishnaswamy P, et al. Utility of B-type natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation 2002;105:595-601.
Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161-167.
Richards AM, Nicholls MG, Espiner EA, et al. B-type natriuretic peptides and ejection fraction for prognosis after myocardial infarction. Circulation 2003;107:2786-2792.
de Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014-1021.
Omland T, Aakvaag A, Bonarjee VV, et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction: comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide. Circulation 1996;93:1963-1969.
Berger R, Huelsman M, Strecker K, et al. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation 2002;105:2392-2397.
Wallen T, Landahl S, Hedner T, Hall C, Saito Y, Nakao K. Atrial natriuretic peptides predict mortality in the elderly. J Intern Med 1997;241:269-275.
Knight EL, Kiely DK, Fish LC, Marcantonio ER, Minaker KL. Atrial natriuretic peptide level contributes to a model of future mortality in the oldest old. J Am Geriatr Soc 1998;46:453-457.
Ueda R, Yokouchi M, Suzuki T, Otomo E, Katagiri T. Prognostic value of high plasma brain natriuretic peptide concentrations in very elderly persons. Am J Med 2003;114:266-270.
McDonagh TA, Cunningham AD, Morrison CE, et al. Left ventricular dysfunction, natriuretic peptides, and mortality in an urban population. Heart 2001;86:21-26.
Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families: the Framingham Offspring Study. Am J Epidemiol 1979;110:281-290.
Kannel WB, Wolf PA, Garrison RJ, eds. The Framingham Study: an epidemiological investigation of cardiovascular disease. Section 34. Some risk factors related to the annual incidence of cardiovascular disease and death in pooled repeated biennial measurements: Framingham Heart Study, 30-year followup. Bethesda, Md.: National Heart, Lung, and Blood Institute, February 1987. (NIH publication no. 87-2703.)
Wang TJ, Larson MG, Levy D, et al. Impact of age and sex on plasma natriuretic peptide levels in healthy adults. Am J Cardiol 2002;90:254-258.
Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol 2002;40:976-982.
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988;16:1141-54.
Cox DR. Regression models and life-tables. J R Stat Soc 1972;34:187-220.
Wolf PA, D'Agostino RB, Belanger AJ, Kannel WB. Probability of stroke: a risk profile from the Framingham Study. Stroke 1991;22:312-318.
Kannel WB, D'Agostino RB, Silbershatz H, Belanger AJ, Wilson PW, Levy D. Profile for estimating risk of heart failure. Arch Intern Med 1999;159:1197-1204.
Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart Study. JAMA 1994;271:840-844.
Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072-1083.
SAS/STAT software: PHREG procedure: changes and enhancements through release 6.12. Cary, N.C.: SAS Institute, 1997:871-948.
Struthers AD, Morris AD. Screening for and treating left-ventricular abnormalities in diabetes mellitus: a new way of reducing cardiac deaths. Lancet 2002;359:1430-1432.
Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol 2001;37:379-385.
Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure: a substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990;82:1724-1729.
Yamamoto K, Burnett JC Jr, Jougasaki M, et al. Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension 1996;28:988-994.
Schirmer H, Omland T. Circulating N-terminal pro-atrial natriuretic peptide is an independent predictor of left ventricular hypertrophy in the general population: the Tromso Study. Eur Heart J 1999;20:755-763.
Brunner F, Wolkart G. Relaxant effect of C-type natriuretic peptide involves endothelium and nitric oxide-cGMP system in rat coronary microvasculature. Cardiovasc Res 2001;51:577-584.
Kohno M, Yokokawa K, Yasunari K, et al. Effect of natriuretic peptide family on the oxidized LDL-induced migration of human coronary artery smooth muscle cells. Circ Res 1997;81:585-590.
Herring N, Zaman JA, Paterson DJ. Natriuretic peptides like NO facilitate cardiac vagal neurotransmission and bradycardia via a cGMP pathway. Am J Physiol Heart Circ Physiol 2001;281:H2318-H2327.
Rossi A, Enriquez-Sarano M, Burnett JC Jr, Lerman A, Abel MD, Seward JB. Natriuretic peptide levels in atrial fibrillation: a prospective hormonal and Doppler-echocardiographic study. J Am Coll Cardiol 2000;35:1256-1262.
van den Berg MP, Tjeerdsma G, Jan de Kan P, Boomsma F, Crijns HJ, van Veldhuisen DJ. Longstanding atrial fibrillation causes depletion of atrial natriuretic peptide in patients with advanced congestive heart failure. Eur J Heart Fail 2002;4:255-262.
Davis KM, Fish LC, Elahi D, Clark BA, Minaker KL. Atrial natriuretic peptide levels in the prediction of congestive heart failure risk in frail elderly. JAMA 1992;267:2625-2629.
Rubattu S, Lee-Kirsch MA, DePaolis P, et al. Altered structure, regulation, and function of the gene encoding the atrial natriuretic peptide in the stroke-prone spontaneously hypertensive rat. Circ Res 1999;85:900-905.
Rubattu S, Ridker P, Stampfer MJ, Volpe M, Hennekens CH, Lindpaintner K. The gene encoding atrial natriuretic peptide and the risk of human stroke. Circulation 1999;100:1722-1726.
Morrow DA, De Lemos JA, Sabatine MS, et al. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18. J Am Coll Cardiol 2003;41:1264-1272.
James SK, Lindahl B, Siegbahn A, et al. 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;108:275-281.
Wang TJ, Levy D, Benjamin EJ, Vasan RS. The epidemiology of "asymptomatic" left ventricular systolic dysfunction: implications for screening. Ann Intern Med 2003;138:907-916.(Thomas J. Wang, M.D., Mar)