Abstract
Background
In patients with symptoms of heart failure, elevations in B-type natriuretic peptide (BNP) accurately identify ventricular dysfunction. However, BNP levels are not specific for ventricular dysfunction in patients who do not have overt symptoms of heart failure, suggesting that other cardiac processes such as myocardial ischemia may also cause elevations in BNP.
Methods and Results
To determine whether BNP elevations are associated with myocardial ischemia, we measured plasma BNP levels before performing exercise treadmill testing with stress echocardiography in outpatients with stable coronary disease. Of the 355 participants, 113 (32%) had inducible ischemia. Compared with participants in the lowest BNP quartile (0 to 16.4 pg/mL), those in the highest quartile of BNP (≥105 pg/mL) had double the risk of inducible ischemia (adjusted relative risk, 2.0; 95% CI, 1.2 to 2.6; P=0.008). The relation between elevated BNP levels and inducible ischemia was especially evident in the 206 participants who had a history of myocardial infarction (adjusted relative risk, 2.6; 95% CI, 1.5 to 3.7, P=0.002) and was absent in those without a history of myocardial infarction (adjusted relative risk, 1.0; 95% CI, 0.3 to 2.2; P=0.9). This association between BNP levels and inducible ischemia remained strong after adjustment for measures of systolic and diastolic dysfunction.
Conclusions
Elevated levels of BNP are independently associated with inducible ischemia among outpatients with stable coronary disease, particularly among those with a history of myocardial infarction. The observed association between BNP levels and ischemia may explain why tests for BNP are not specific for ventricular dysfunction among patients with coronary disease.
Keywords: natriuretic peptides, ischemia, myocardial infarction, heart failure, coronary disease
B-type natriuretic peptide (BNP) is a hormone that is secreted from the cardiac ventricles in response to increased pressure and volume.1–3 Plasma levels of BNP are increased in patients with ventricular dysfunction and seem to have high sensitivity and specificity for identifying ventricular dysfunction in patients with symptoms of heart failure.4–9 However, BNP is not an accurate test for ventricular dysfunction among subjects who do not have overt symptoms of heart failure,10 especially those with underlying coronary disease.11 These observations suggest that BNP elevations may be associated with cardiac processes other than ventricular dysfunction.
One potential explanation is that elevations of BNP may be the result of ischemia in patients with stable coronary disease. BNP is known to be elevated in acute coronary syndromes and is a powerful predictor of short- and long-term mortality, independent of ventricular function.12–14 The possibility of an association between BNP and ischemia has been examined only in 3 small studies that have yielded conflicting results. 15–17 To determine whether circulating levels of BNP are associated with inducible ischemia, we measured resting BNP levels and performed exercise echocardiography in 355 patients with stable coronary disease.
Methods
Study Participants
The Heart and Soul Study is a prospective cohort study investigating how psychosocial factors influence the outcomes of patients with coronary disease. We recruited patients with coronary disease who were identified through administrative databases from 2 Department of Veterans Affairs Medical Centers (San Francisco and Palo Alto) and 1 university-based medical center (University of California, San Francisco). Eligible participants had at least 1 of the following: (1) history of myocardial infarction, (2) angiographic evidence of ≥50% stenosis in ≥1 coronary vessels, (3) evidence of exercise-induced ischemia by treadmill ECG or stress nuclear perfusion imaging, (4) a history of coronary revascularization, or (5) a clinical diagnosis of coronary disease as documented by an internist or a cardiologist.
All eligible patients were invited by mail to attend a baseline study appointment, and a total of 510 participants enrolled between September 2000 and December 2001. Patients were excluded if they were unable to walk 1 block or were planning to move out of the local area within 3 years. For this cross-sectional study, we excluded 4 participants who had inadequate echocardiographic data and 151 for whom we could not obtain a blood sample after the 30-minute rest period (because of dislodged or thrombosed butterfly needle), leaving a total of 355 participants for the analysis. The institutional review board at each of the sites described above approved this protocol. All participants provided written informed consent.
Measurements
B-Type Natriuretic Peptide
Before the study appointment, participants completed an overnight fast except for taking their regularly prescribed medications. A 21-gauge butterfly needle was inserted intravenously in the forearm, and after a 30-minute supine rest, blood samples were drawn into chilled EDTA tubes, mixed with aprotinin, then divided into aliquots and stored at −70°C for up to 9 months. We used the Triage B-type natriuretic fluorescence immunoassay (Biosite Diagnostics) to measure BNP in frozen plasma samples thawed to room temperature. The lowest detectable measurement for this assay was 5 pg/mL. The interassay coefficient of variation was 10.1% for 28.8 pg/mL, 12.4% for 586 pg/mL, and 16.2% for 1180 pg/mL. The laboratory technician who measured BNP was at a different site and blinded to the characteristics of the patients and the results of the echocardiograms and stress tests.
Ischemia
After plasma was drawn and frozen for measurement of BNP, all participants underwent full exercise treadmill testing according to a standard Bruce protocol with continuous 12-lead ECG monitoring. An echocardiogram was performed immediately before and after exercise with an Acuson Sequoia Ultrasound System with a 3.5-MHz transducer. Inducible ischemia was defined as the presence of ≥1 new wall motion abnormalities at peak exercise. One of us (N.B.S.) interpreted all of the echocardiograms, blinded to the results of the BNP assay, the resting echocardiogram, and the clinical history.
Other Measurements
A complete resting 2D echocardiogram and Doppler ultrasound examination, including all standard views and subcostal imaging of the inferior vena cava, was performed. We obtained standard 2D parasternal short-axis and apical 2- and 4-chamber views during held inspiration; these were planimetered with a computerized digitization system to determine end-diastolic and end-systolic left ventricular volume. We calculated left ventricular ejection fraction (LVEF) as (end-diastolic volume−end-systolic volume)/end-diastolic volume. We defined 3 categories of diastolic dysfunction by peak early diastolic filling velocity (E velocity) and peak filling velocity at atrial contraction (A velocity): (1) impaired relaxation=E/A ratio <1.0 and systolic-dominant pulmonary vein flow, (2) pseudonormal=E/A ratio ≥1 and <2 and diastolic-dominant pulmonary vein flow, and (3) restrictive filling=E/A ratio ≥2 and diastolic-dominant pulmonary vein flow.18 Left ventricular hypertrophy was defined as left ventricular mass index >90 g/m2.
To account for ventricular dysfunction that might be manifest during exercise, we measured postexercise LVEF and wall motion score index. Postexercise LVEF was assessed immediately after exercise. We calculated a wall motion score index at peak exercise using the following method. Each of 16 wall segments in the left ventricle was scored on the basis of the contractility visualized at peak exercise (1=normal, 2=hypokinetic, 3=akinetic, 4=dyskinetic, 5=aneurysm, 0=not visualized). The wall motion score index was defined as the sum of wall motion scores divided by the number of segments visualized, with a normally contracting left ventricle receiving a wall motion score index of 1 (16/16=1) and higher wall motion scores indicating worse contractility.19
Age, sex, race/ethnicity, medical history, and smoking status were determined by patient questionnaire. Alcohol use was measured by use of the AUDIT-C questionnaire, with a score of ≥4 used to define regular alcohol use. We measured weight and height and calculated body mass index (kg/m2). Participants were instructed to bring their medication bottles to the study appointment, and study personnel recorded all current medications. Total cholesterol, HDL cholesterol, and LDL cholesterol levels were measured from sera after the overnight fast. We calculated creatinine clearance from 24-hour urine collections.
Analysis
We divided participants into quartiles on the basis of their plasma BNP levels. Differences in characteristics across quartiles were compared by ANOVA (or nonparametric equivalent) for continuous variables and χ2 tests for dichotomous variables. We compared median BNP values for various degrees of inducible ischemia using a Kruskal-Wallis rank test. To determine the independent association between BNP and inducible ischemia, we used logistic regression analyses with quartiles of BNP as the primary predictor and inducible ischemia as the outcome. To obtain adjusted risk estimates, we entered all variables, including quartiles of BNP, into a backward stepwise elimination model. Variables associated with inducible ischemia at P<0.1 were retained in the final model. Because BNP is known to be associated with systolic and diastolic dysfunction,5,6 we also examined the association between BNP and inducible ischemia with LVEF and diastolic dysfunction forced into the models. We converted odds ratios and 95% CIs from the multivariate logistic regression models into relative risks.20
We tested for interactions between the highest quartile of BNP (compared with the lowest) and history of myocardial infarction, history of coronary revascularization, left ventricular hypertrophy, LVEF, diastolic dysfunction, and use of cardiac medications. We performed analysis stratified by any variables with P<0.1 for interaction. All analyses were performed with Stata statistical software, version 7 (1996).
Results
The median BNP level in our sample was 36.6 pg/mL (interquartile range, 16.4 to 104 pg/mL). Compared with participants in the lowest quartile of BNP, those in the highest quartile were older, more likely to be white, and more likely to have left ventricular hypertrophy, lower LVEF, or diastolic dysfunction. They had lower exercise capacity, lower total and LDL cholesterol, and lower creatinine clearance. Participants in the highest quartile of BNP were more likely to be taking β-blockers, renin-angiotensin inhibitors, or diuretics than those in the lowest quartile (Table 1).
TABLE 1. Characteristics of 355 Participants With Stable Coronary Disease by Quartile of B-Type Natriuretic Peptide*.
| Quartile of B-Type Natriuretic Peptide, pg/mL | |||||
|---|---|---|---|---|---|
| I (0–16.4) |
II (16.5–36.6) |
III (37.0–104) |
IV (105–636) |
P | |
| Age, y | 63±12 | 68±9 | 71±10 | 75±8 | <0.001 |
| Male sex, % | 90 | 92 | 92 | 95 | 0.60 |
| White race/ethnicity, % | 50 | 68 | 69 | 71 | 0.01 |
| Hypertension, % | 62 | 72 | 65 | 76 | 0.19 |
| Chronic obstructive pulmonary disease, % | 20 | 16 | 18 | 11 | 0.36 |
| Diabetes, % | 25 | 25 | 20 | 33 | 0.28 |
| Previous myocardial infarction, % | 55 | 53 | 62 | 64 | 0.41 |
| Previous stroke, % | 8 | 14 | 18 | 17 | 0.21 |
| Previous revascularization, % | 64 | 68 | 65 | 71 | 0.77 |
| Current smoking, % | 21 | 18 | 11 | 9 | 0.08 |
| Regular alcohol consumption, % | 27 | 36 | 24 | 31 | 0.31 |
| Left ventricular hypertrophy, % | 4 | 10 | 3 | 24 | <0.001 |
| LVEF | 0.64±0.9 | 0.64±0.9 | 0.63±0.9 | 0.58±0.12 | <0.001 |
| Diastolic dysfunction, % | <0.001 | ||||
| Impaired relaxation | 62 | 61 | 51 | 40 | |
| Pseudonormal | 3 | 8 | 11 | 13 | |
| Restrictive | 0 | 0 | 7 | 16 | |
| Body mass index, kg/m2 | 29±6 | 28±4 | 28±4 | 28±5 | 0.31 |
| Exercise capacity, METS | 8.5±3.7 | 7.9±2.9 | 7.2±3.5 | 5.4±2.6 | <0.001 |
| Total cholesterol, mg/dL | 187±42 | 175±39 | 180±44 | 168±40 | 0.02 |
| LDL cholesterol, mg/dL | 110±33 | 102±32 | 102±30 | 97±31 | 0.05 |
| HDL cholesterol, mg/dL | 48±13 | 46±14 | 47±17 | 44±13 | 0.38 |
| Creatinine clearance, mL/min | 94±28 | 81±26 | 79±26 | 64±25 | <0.001 |
| Current β-blocker use, % | 42 | 60 | 67 | 69 | 0.001 |
| Current renin-angiotensin inhibitor use, % | 39 | 51 | 48 | 66 | 0.004 |
| Current diuretic use, % | 22 | 23 | 29 | 43 | 0.008 |
| Current aspirin use, % | 76 | 94 | 78 | 81 | 0.005 |
| Current statin use, % | 61 | 78 | 74 | 70 | 0.07 |
Plus-minus values are mean±SD.
Of the 355 participants, 113 (32%) had inducible ischemia. Plasma BNP levels ranged from 30.8 pg/mL (interquartile range, 14.4 to 73.9 pg/mL) in the 242 participants without evidence of exercise-induced ischemia to 48.7 pg/mL (interquartile range, 20.5 to 131 pg/mL) in the 79 participants with 1 exercise-induced wall motion abnormality to 71.7 pg/mL (interquartile range 20.5 to 131) in the 34 participants with >1 exercise-induced wall motion abnormality (P<0.001).
The proportion of participants with inducible ischemia increased by quartile of BNP (Figure). Forty-six percent of participants in the highest quartile of BNP had inducible ischemia compared with 20% in the lowest quartile (unadjusted relative risk, 2.3; 95% CI, 1.6 to 3.2; P<0.001). After adjusting for potential confounders, we found that participants in the highest quartile of BNP had double the risk of inducible ischemia compared with those in the lowest quartile (Table 2). Because ventricular systolic and diastolic dysfunction is a potential mediator of the association between BNP and inducible ischemia, we evaluated the association of the highest quartile of BNP with inducible ischemia after adjustment for ventricular dysfunction. We found that the risk for inducible ischemia associated with the highest quartile of BNP remained present even after control for both systolic and diastolic dysfunction (Table 3).
Proportion of participants with inducible ischemia by quartile of BNP (probability value from χ2=0.002).
TABLE 2. Association Between B-Type Natriuretic Peptide and Inducible Ischemia in 355 Participants With Coronary Disease.
| B-Type Natriuretic Peptide, pg/mL | No. (%) With Inducible Ischemia | Adjusted Relative Risk* (95% CI) | P |
|---|---|---|---|
| Quartile I (0–16.4) | 18/90 (20) | 1.0 | … |
| Quartile II (16.5–36.6) | 26/88 (30) | 1.4 (0.7–2.1) | 0.29 |
| Quartile III (37.0–104.0) | 29/91 (32) | 1.5 (0.8–2.3) | 0.14 |
| Quartile IV (105–636) | 40/86 (46) | 2.0 (1.2–2.8) | 0.008 |
All variables from Table 1 were entered into backward elimination logistic regression models including B-type natriuretic peptide. The other variables associated with inducible ischemia (at P<0.1) were exercise capacity and aspirin use.
TABLE 3. Association of Highest Quartile of B-Type Natriuretic Peptide With Inducible Ischemia After Adjustment for Ventricular Dysfunction.
| Adjusted Relative Risk (95% CI)* | P | |
|---|---|---|
| Baseline model | 2.0 (1.2–2.8) | 0.008 |
| Adjusted for LVEF | 1.9 (1.2–2.8) | 0.01 |
| Adjusted for categories of diastolic dysfunction | 1.8 (1.1–2.7) | 0.02 |
| Adjusted for both LVEF and categories of diastolic dysfunction | 1.8 (1.0–2.7) | 0.04 |
Adjusted for exercise capacity and aspirin use.
We found no evidence for interaction between BNP and history of revascularization, left ventricular hypertrophy, LVEF, diastolic dysfunction, or use of renin-angiotensin inhibitors, β-blockers, diuretics, statins, or aspirin (all probability values >0.10). However, the association between BNP and inducible ischemia varied by history of myocardial infarction (P for interaction=0.05). We observed an association between BNP and ischemia among the 206 participants who reported a history of myocardial infarction but not among the 147 participants without a history of myocardial infarction (Table 4). Elevated BNP remained strongly associated with inducible ischemia among participants with a history of myocardial infarction even after exclusion of the 48 participants with LVEF <55%.
TABLE 4. Association Between Quartiles of B-Type Natriuretic Peptide and Inducible Ischemia, Stratified by History of Myocardial Infarction.
| BNP Quartile | No. (%) With Inducible Ischemia | Adjusted Relative Risk* (95%CI) | P |
|---|---|---|---|
| Participants without history of myocardial infarction (n=147)† | |||
| I | 9/40 (22) | 1.0 | … |
| II | 13/41(32) | 1.2 (0.5–2.5) | 0.57 |
| III | 8/35 (23) | 0.7 (0.2–1.9) | 0.61 |
| IV | 11/31 (31) | 1.0 (0.3–2.2) | 0.9 |
| Participants with history of myocardial infarction (n=206)† | |||
| I | 9/48 (19) | 1.0 | … |
| II | 13/47 (28) | 1.4 (0.6–2.6) | 0.37 |
| III | 21/56 (38) | 1.9 (1.0–3.1) | 0.04 |
| IV | 29/55 (53) | 2.6 (1.5–3.7) | 0.002 |
| Participants with history of myocardial infarction and LVEF >55% (n=158) | |||
| I | 6/34 (18) | 1.0 | … |
| II | 10/38 (26) | 1.4 (0.6–2.8) | 0.40 |
| III | 14/49 (29) | 1.6 (0.6–2.8) | 0.29 |
| IV | 23/37 (62) | 3.1 (1.8–4.2) | 0.001 |
Relative risk of inducible ischemia adjusted for exercise capacity and aspirin use.
Includes participants with both normal and depressed systolic function.
To explore potential mediators between BNP and inducible ischemia among participants with a previous myocardial infarction, we further adjusted for LVEF after exercise and wall motion score index measured at peak exercise. The association between BNP and inducible ischemia was present even after adjustment for these measures of inducible ventricular dysfunction (Table 5).
TABLE 5. Association Between B-Type Natriuretic Peptide and Inducible Ischemia in Participants With History of Myocardial Infarction, Adjusted for Potential Mediators.
| Participants With History of Myocardial Infarction | Participants With History of Myocardial Infarction and LVEF >55% | |||
|---|---|---|---|---|
| Adjusted Relative Risk* (95% CI) | P | Adjusted Relative Risk† (95% CI) | P | |
| Baseline model | 2.6 (1.5–3.7) | 0.002 | 3.1 (1.8–4.2) | 0.001 |
| Adjusted for postexercise LVEF | 2.0 (1.0–3.2) | 0.05 | 2.8 (1.4–4.0) | 0.005 |
| Adjusted for wall motion score index | 2.1 (1.0–3.3) | 0.06 | 2.6 (0.8–4.3) | 0.08 |
| Adjusted for postexercise LVEF and wall motion score index | 2.2 (1.0–3.5) | 0.04 | 2.6 (0.8–4.3) | 0.09 |
Comparing 55 participants in the highest BNP quartile with 48 participants in the lowest BNP quartile. All models adjusted for exercise capacity and aspirin use.
Comparing 37 participants in the highest BNP quartile with 34 participants in the lowest BNP quartile. All models adjusted for exercise capacity and aspirin use.
Discussion
We found that BNP was associated with inducible ischemia among patients with stable coronary disease. This association was seen most strongly among participants with a history of myocardial infarction and was independent of systolic and diastolic dysfunction. The association we observed between elevated BNP and inducible ischemia may explain why elevations in BNP are not specific for detecting asymptomatic ventricular dysfunction in patients with coronary disease. Our findings also offer a potential explanation for the increased risk of future coronary events associated with BNP elevations after acute coronary syndromes,12–14 although the causal pathway between BNP and inducible ischemia cannot be determined by this cross-sectional study.
Three previous studies have examined the association between BNP and inducible ischemia. One found higher resting BNP levels in 19 subjects with ischemia compared with 12 subjects without inducible ischemia, but this study was restricted to patients with hypertrophic cardiomyopathy, so its clinical implications are unclear.15 A second study found no difference in resting BNP levels between 10 patients with stable angina and 15 control subjects.17 However, a third study of 35 patients with known angina found that BNP levels increased after exercise. Indeed, the degree of BNP elevation corresponded with the size of ischemic territory, suggesting that inducible ischemia may lead to elevations in BNP.16
Our study found an association between resting BNP and ischemia in a large sample of outpatients with stable coronary disease. These results suggest that study participants who had inducible ischemia were probably also experiencing ischemia in their daily lives.21 Such daily ischemia may cause increased ventricular volume and wall stress, leading to elevations in BNP. Alternatively, it is possible that elevations in BNP are part of a process leading to ischemia, with elevated BNP reflecting increased ventricular filling pressures that may lead to increased demand and greater myocardial ischemia.
In stratified analyses, we observed the strongest association between BNP and inducible ischemia among participants with a previous myocardial infarction. These results suggest that participants with a history of myocardial infarction may be more likely to develop elevated filling pressures in response to ischemia, perhaps because of previous myocardial damage. Alternatively, previous myocardial damage may make participants with a history of myocardial infarction more likely to develop ischemia in response to increased volume and filling pressures. Finally, it is possible that myocardial infarction is simply an initial trigger for the release of BNP, as has been observed in other settings.22–25
The elevation of BNP in outpatients with inducible ischemia has implications for the use of BNP as a diagnostic test for systolic dysfunction. Many (including the European Society of Cardiology) have proposed that BNP should be used as a first-line test for patients with symptoms suggestive of ventricular dysfunction, particularly high-risk patients such as those with coronary disease.26,27 Our finding that BNP levels are elevated in patients with inducible ischemia independent of ventricular dysfunction suggests that symptomatic patients with BNP elevations may need further evaluation with ischemia testing, in addition to assessment of ventricular function, particularly because distinguishing symptoms of chronic ischemia from those of ventricular dysfunction can be problematic.
Several limitations should be considered in interpreting our results. First, we are unable to determine the causal pathway between BNP and ischemia because of the nature of our cross-sectional study design. Second, although we chose a common definition for diastolic dysfunction18 and found that diastolic dysfunction did not mediate the association between BNP and ischemia, definitions of diastolic dysfunction are the subject of much debate. Thus, we cannot exclude the possibility that other definitions might reveal diastolic dysfunction as a mediator of this association. Finally, BNP levels may vary by sex,28 and given the predominantly male population, our study does not allow for an assessment of the association between BNP and inducible ischemia in women.
In summary, we found that BNP is associated with inducible ischemia among patients with stable coronary disease and that this association is strongest among those with a history of myocardial infarction. The association we observed between BNP and ischemia suggests a potential explanation for the increased risk of future coronary events associated with elevations in BNP and may also explain why BNP is not an accurate screening test for ventricular dysfunction in patients with stable coronary disease.
Acknowledgments
This work was supported by the Department of Veterans Affairs (Epidemiology Merit Review Program), the Robert Wood Johnson Foundation (Generalist Physician Faculty Scholars Program), the American Federation for Aging Research (Paul Beeson Faculty Scholars in Aging Research Program), and the Ischemia Research and Education Foundation. Dr Whooley is also supported by an Advanced Research Career Development Award from the Department of Veterans Affairs Health Services Research and Development Service.
Footnotes
The online version of this article, along with updated information and services, is located on the World Wide Web at:
References
- 1.Yoshimura M, Yasue H, Okumura K, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation. 1993;87:464–469. doi: 10.1161/01.cir.87.2.464. [DOI] [PubMed] [Google Scholar]
- 2.Nakagawa O, Ogawa Y, Itoh H, et al. Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiocyte hypertrophy. J Clin Invest. 1995;96:1280–1287. doi: 10.1172/JCI118162. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Maeda K, Tsutamoto T, Wada A, et al. Plasma brain natriuretic peptide as a biochemical marker of high left ventricular end-diastolic pressure in patients with symptomatic left ventricular dysfunction. Am Heart J. 1998;135:825–832. doi: 10.1016/s0002-8703(98)70041-9. [DOI] [PubMed] [Google Scholar]
- 4.Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet. 1997;350:1349–1353. doi: 10.1016/S0140-6736(97)06031-5. [DOI] [PubMed] [Google Scholar]
- 5.Maisel AS, Koon J, Krishnaswamy P, et al. Utility of B-natriuretic peptide as a rapid, point-of-care test for screening patients undergoing echocardiography to determine left ventricular dysfunction. Am Heart J. 2001;141:367–374. doi: 10.1067/mhj.2001.113215. [DOI] [PubMed] [Google Scholar]
- 6.Lubien E, DeMaria A, Krishnaswamy P, et al. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation. 2002;105:595–601. doi: 10.1161/hc0502.103010. [DOI] [PubMed] [Google Scholar]
- 7.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. doi: 10.1161/01.hyp.28.6.988. [DOI] [PubMed] [Google Scholar]
- 8.Yamamoto K, Burnett JC, Jr, Bermudez EA, et al. Clinical criteria and biochemical markers for the detection of systolic dysfunction. J Card Fail. 2000;6:194–200. doi: 10.1054/jcaf.2000.9676. [DOI] [PubMed] [Google Scholar]
- 9.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. Circulation. 1996;93:1963–1969. doi: 10.1161/01.cir.93.11.1963. [DOI] [PubMed] [Google Scholar]
- 10.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. doi: 10.1001/jama.288.10.1252. [DOI] [PubMed] [Google Scholar]
- 11.McClure SJ, Caruana L, Davie AP, et al. Cohort study of plasma natriuretic peptides for identifying left ventricular systolic dysfunction in primary care. BMJ. 1998;317:516–519. doi: 10.1136/bmj.317.7157.516. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.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. doi: 10.1056/NEJMoa011053. [DOI] [PubMed] [Google Scholar]
- 13.Omland T, de Lemos JA, Morrow DA, et al. Prognostic value of N-terminal pro-atrial and pro-brain natriuretic peptide in patients with acute coronary syndromes. Am J Cardiol. 2002;89:463–465. doi: 10.1016/s0002-9149(01)02271-8. [DOI] [PubMed] [Google Scholar]
- 14.Sabatine MS, Morrow DA, de Lemos JA, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation. 2002;105:1760–1763. doi: 10.1161/01.cir.0000015464.18023.0a. [DOI] [PubMed] [Google Scholar]
- 15.Nakamura T, Sakamoto K, Yamano T, et al. Increased plasma brain natriuretic peptide level as a guide for silent myocardial ischemia in patients with non-obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2002;39:1657–1663. doi: 10.1016/s0735-1097(02)01813-2. [DOI] [PubMed] [Google Scholar]
- 16.Marumoto K, Hamada M, Hiwada K. Increased secretion of atrial and brain natriuretic peptides during acute myocardial ischaemia induced by dynamic exercise in patients with angina pectoris. Clin Sci (Lond) 1995;88:551–556. doi: 10.1042/cs0880551. [DOI] [PubMed] [Google Scholar]
- 17.Talwar S, Squire IB, Downie PF, et al. Plasma N terminal pro-brain natriuretic peptide and cardiotrophin 1 are raised in unstable angina. Heart. 2000;84:421–424. doi: 10.1136/heart.84.4.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Angeja BG, Grossman W. Evaluation and management of diastolic heart failure. Circulation. 2003;107:659–663. doi: 10.1161/01.cir.0000053948.10914.49. [DOI] [PubMed] [Google Scholar]
- 19.Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2:358–367. doi: 10.1016/s0894-7317(89)80014-8. [DOI] [PubMed] [Google Scholar]
- 20.Zhang J, Yu KF. What's the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA. 1998;280:1690–1691. doi: 10.1001/jama.280.19.1690. [DOI] [PubMed] [Google Scholar]
- 21.Deedwania P, Carbajal E. Silent ischemia during daily life is an independent predictor of mortality in stable angina. Circulation. 1990;81:748–756. doi: 10.1161/01.cir.81.3.748. [DOI] [PubMed] [Google Scholar]
- 22.Yoshitomi Y, Nishikimi T, Kojima S, et al. Plasma natriuretic peptides as indicators of left ventricular remodeling after myocardial infarction. Int J Cardiol. 1998;64:153–160. doi: 10.1016/s0167-5273(98)00026-6. [DOI] [PubMed] [Google Scholar]
- 23.Nagaya N, Nishikimi T, Goto Y, et al. Plasma brain natriuretic peptide is a biochemical marker for the prediction of progressive ventricular remodeling after acute myocardial infarction. Am Heart J. 1998;135:21–28. doi: 10.1016/s0002-8703(98)70338-2. [DOI] [PubMed] [Google Scholar]
- 24.Nagaya N, Goto Y, Nishikimi T, et al. Sustained elevation of plasma brain natriuretic peptide levels associated with progressive ventricular remodelling after acute myocardial infarction. Clin Sci (Lond) 1999;96:129–136. [PubMed] [Google Scholar]
- 25.Crilley JG, Farrer M. Left ventricular remodelling and brain natriuretic peptide after first myocardial infarction. Heart. 2001;86:638–642. doi: 10.1136/heart.86.6.638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.McMurray JV, McDonagh TA, Davie AP, et al. Should we screen for asymptomatic left ventricular dysfunction to prevent heart failure? Eur Heart J. 1998;19:842–846. doi: 10.1093/eurheartj/19.6.842. [DOI] [PubMed] [Google Scholar]
- 27.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. doi: 10.1016/S0140-6736(02)08358-7. [DOI] [PubMed] [Google Scholar]
- 28.Redfield MM, Rodeheffer RJ, Jacobsen SJ, et al. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol. 2002;40:976–982. doi: 10.1016/s0735-1097(02)02059-4. [DOI] [PubMed] [Google Scholar]