B-type natriuretic peptide (BNP) is used widely to exclude heart failure (HF) in patients with dyspnea. However, most studies of BNP have focused on diagnosing HF with reduced ejection fraction (EF). The aim of this study was to test the hypothesis that a normal BNP level (≤100 pg/ml) is relatively common in HF with preserved EF (HFpEF), a heterogenous disorder commonly associated with obesity. A total of 159 consecutive patients enrolled in the Northwestern University HFpEF Program were prospectively studied. All subjects had symptomatic HF with EF >50% and elevated pulmonary capillary wedge pressure. BNP was tested at baseline in all subjects. Clinical characteristics, echocardiographic parameters, invasive hemodynamics, and outcomes were compared among patients with HFpEF with normal (≤100 pg/ml) versus elevated (>100 pg/ml) BNP. Of the 159 patients with HFpEF, 46 (29%) had BNP ≤100 pg/ml. Subjects with normal BNP were younger, were more often women, had higher rates of obesity and higher body mass index, and less commonly had chronic kidney disease and atrial fibrillation. EFs and pulmonary capillary wedge pressures were similar in the normal and elevated BNP groups (62 ± 7% vs 61 ± 7%, p = 0.67, and 25 ± 8 vs 27 ± 9 mm Hg, p = 0.42, respectively). Elevated BNP was associated with enlarged left atrial volume, worse diastolic function, abnormal right ventricular structure and function, and worse outcomes (e.g., adjusted hazard ratio for HF hospitalization 4.0, 95% confidence interval 1.6 to 9.7, p = 0.003). In conclusion, normal BNP levels were present in 29% of symptomatic outpatients with HFpEF who had elevated pulmonary capillary wedge pressures, and although BNP is useful as a prognostic marker in HFpEF, normal BNP does not exclude the outpatient diagnosis of HFpEF.
Heart failure (HF) with preserved ejection fraction (HFpEF) is common, increasing in prevalence, and associated with high morbidity and mortality. HFpEF, a heterogenous syndrome more common in elderly, female, and obese patients, is defined by HF symptoms in the presence of a normal left ventricular (LV) ejection fraction (EF) (>50%). The diagnosis of HFpEF is challenging because symptoms are nonspecific and can be due to several alternative noncardiac conditions, such as anemia, chronic kidney disease, and chronic lung disease. The European Society of Cardiology has developed algorithms for the diagnosis and exclusion of HFpEF based in part on serum natriuretic peptides, but the utility of this diagnostic schema in the clinical realm is unknown. Natriuretic peptides (e.g., B-type natriuretic peptide [BNP]) are excellent biomarkers for the diagnosis of HF with reduced EF (HFrEF), but BNP is less sensitive for the diagnosis of HFpEF, and BNP levels are lower in patients with HFpEF compared to those with HFrEF. The European Society of Cardiology guidelines for HFpEF diagnosis recommend the exclusion of HFpEF in the setting of a normal BNP level (≤100 pg/ml). However, in our clinical practice of the care of a large number of patients with HFpEF, we have found that BNP is frequently within the normal range (≤100 pg/ml) despite clinical, echocardiographic, and invasive hemodynamic evidence of HFpEF. The reasons for normal BNP levels in some patients with HFpEF are unclear and may relate to the high prevalence of obesity in this patient population. We therefore sought to explore the frequency, clinical phenotype, and outcomes of patients with HFpEF and normal BNP.
Methods
Consecutive patients were prospectively enrolled from March 2008 to October 2009 from the outpatient clinic of the Northwestern University HFpEF Program as part of a systematic observational study of HFpEF ( ClinicalTrials.gov identifier NCT01030991 ). Patients with possible HF were initially identified by an automated daily query of the inpatient electronic medical record at Northwestern Memorial Hospital, as described previously. The list of patients generated was screened daily, and only those patients who had LV EFs >50% and who met Framingham criteria for HF were offered postdischarge follow-up in a specialized HFpEF outpatient program. Once a patient was evaluated as an outpatient in the HFpEF clinic, the diagnosis of HF was confirmed by a board-certified HF specialist. The diagnosis of HFpEF was based on previously published criteria, which require an LV EF >50% and an LV end-diastolic volume index <97 ml/m 2 . As in previous studies, patients with significant valvular disease (defined as greater than moderate in severity), previous cardiac transplantation, history of reduced LV EF <40%, or constrictive pericarditis were excluded.
Blood samples for BNP measurement were collected by venipuncture into tubes containing ethylenediaminetetraacetic acid upon initial outpatient HFpEF clinic evaluation (at the time of study enrollment). Blood samples were kept at room temperature and analyzed within 4 hours using the Triage BNP assay (Biosite, Inc., San Diego, California). The Triage meter was used to measure the BNP concentration by detecting a fluorescent signal that reflected the amount of BNP in the sample. Precision, analytic sensitivity, interferences, and stability have all been previously described.
We collected and analyzed the following clinical characteristics of the study participants: demographics, ethnicity, New York Heart Association functional class, HF symptoms, co-morbidities, vital signs, physical findings, and laboratory data, which included hemoglobin, serum sodium, blood urea nitrogen, and creatinine. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease (MDRD) equation.
Hypertension was defined as systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg, a physician-documented history of hypertension, or the use of antihypertensive medications. Diabetes was defined as the presence of a physician-documented history of diabetes or the use of oral hypoglycemic agents or insulin for the treatment of hyperglycemia. Coronary artery disease was defined as the presence of a physician-documented history of coronary artery disease, known coronary stenosis >50%, history of myocardial infarction, percutaneous intervention, coronary artery bypass grafting, or abnormal stress test results consistent with myocardial ischemia. Obesity was defined as a body mass index >30 kg/m 2 . Chronic kidney disease was defined as an estimated glomerular filtration rate <60 ml/m 2 . Chronic obstructive pulmonary disease and asthma were defined as a physician-documented history or pulmonary function test results consistent with obstructive lung disease.
All study participants underwent comprehensive 2-dimensional echocardiography with Doppler and tissue Doppler imaging. All standard echocardiographic views were obtained. Echocardiography was performed using commercially available ultrasound systems with harmonic imaging (Philips iE33 or 7500, Philips Medical Systems, Andover, Massachusetts; or Vivid 7, GE Healthcare, Waukesha, Wisconsin). Cardiac structure and function (including LV systolic and diastolic function and right-sided cardiac structure and function) were quantified as recommended by the American Society of Echocardiography. All echocardiographic measurements were made by an experienced research sonographer blinded to all other clinical data using ProSolv version 4.0 echocardiographic analysis software (ProSolv Cardiovascular, Indianapolis, Indiana) and verified by a board-certified echocardiographer.
Within 30 days of the initial outpatient HFpEF clinic evaluation (date of study enrollment), right-sided cardiac and pulmonary arterial catheterization was performed from either the right internal jugular or right femoral vein approach using the standard Seldinger technique under fluoroscopic guidance. Participants underwent recording of invasive hemodynamics (mean right atrial pressure; systolic, diastolic, and mean pulmonary arterial pressure; and pulmonary capillary wedge pressure) using a fluid-filled, 6Fr pulmonary arterial catheter (Edwards Lifesciences, Irvine, California) and a properly zeroed pressure transducer. Pressure recordings were analyzed off-line using a WITT Hemodynamic Workstation (Philips Medical Systems) at a paper speed of 50 mm/s with adjustment of pressure (millimeters of mercury) scale as needed. All hemodynamic pressure measurements were made at end-expiration and in duplicate using a standardized measurement protocol, by a physician blinded to all clinical data. Cardiac output was calculated using the thermodilution method.
All study participants were evaluated clinically in the Northwestern University HFpEF Program after enrollment into the study as clinically indicated but no less frequently than every 6 months. At each clinic visit, intercurrent hospitalizations were documented. For each reported hospitalization, chart review was performed to categorize the hospitalization as due to HF, cardiovascular (including HF), or noncardiovascular. Every 6 months, participants (or their proxies) were also contacted to determine vital status. Finally, the Social Security Death Index was also queried for additional verification of vital status. Enrollment date was defined as the date of first visit to the outpatient HFpEF clinic, and date of last follow-up was defined as date of death or date of last HFpEF clinic visit. Follow-up was complete in all patients.
We dichotomized participants into 2 groups on the basis of the clinical cut-off for abnormal BNP (>100 pg/ml). Clinical characteristics, laboratory data, echocardiographic parameters, and invasive hemodynamic data were compared between groups using t tests for normally distributed continuous variables (or nonparametric equivalent when appropriate). Chi-square tests (or Fisher’s exact tests when appropriate) were used to compare categorical variables between groups. A 2-sided p value <0.05 was considered statistically significant. Continuous data with a normal distribution are displayed as mean ± SD. Right-skewed data were log-transformed and are presented as medians and interquartile ranges. To determine the independent associations of clinical parameters with normal BNP, we performed multiple logistic regression with normal BNP as the dependent variable. We first investigated which demographic, clinical, physical examination, and laboratory variables were associated with normal BNP on univariate analysis. Variables associated with BNP ≤100 pg/ml on univariate analysis (p <0.05) were carried forward to a multivariate model to determine the clinical factors independently associated with BNP ≤100 pg/ml. Finally, adjusted Cox proportional-hazards regression analyses and Kaplan-Meier curves were used to examine the association between BNP ≤100 pg/ml and outcomes. All analyses were done in Stata version 10.1 (StataCorp LP, College Station, Texas).
Results
A total of 159 patients were prospectively enrolled into our invasive hemodynamic study of BNP in HFpEF. All patients met criteria for HFpEF: all were previously hospitalized for HF, all had preserved EF (>50%), and all had elevated pulmonary capillary wedge pressure (>15 mm Hg) at time of cardiac catheterization. In addition, at the time of post-HF hospitalization outpatient follow-up in the Northwestern University HFpEF Program (i.e., the date of enrollment into the present study), most still had symptoms and physical signs of HF: 91% had exertional dyspnea, 48% had orthopnea, 29% had paroxysmal nocturnal dyspnea, 72% had elevated jugular venous pressure (mean 10.4 ± 2.8 cm water), 28% had crackles, and 66% had lower-extremity edema. Study patients also had echocardiographic abnormalities consistent with HFpEF: LV mass index (mean 53 ± 22 g/m 2.7 ) and left atrial volume index (mean 34 ± 15 ml/m 2 ) were elevated, and most (83%) had evidence of moderate or greater diastolic dysfunction. The median BNP level in the entire cohort was 234 pg/ml (interquartile range 71 to 603, mean 521 ± 852). Despite having symptoms and signs of HF, abnormal cardiac structure and function on echocardiography, and elevated filling pressures on invasive hemodynamic testing, 46 of 159 study patients (29%) had normal BNP levels (≤100 pg/ml).
Patients with normal BNP were younger, more often women, and more frequently had obesity but had lower rates of chronic kidney disease, atrial fibrillation, and coronary artery disease ( Table 1 ). Although obesity was more prevalent in patients with normal BNP, there were some patients in our cohort (n = 5 of 34 [15%]) with normal body mass index (<25 kg/m 2 ) who had normal BNP and HFpEF, thereby showing that normal BNP can occur even in patients with HFpEF who are not obese. HF symptoms were similar across the 2 groups. LV size, EF, and mass were also similar between patient groups ( Table 2 ). Diastolic function was worse in patients with elevated BNP, with a higher frequency of severe diastolic dysfunction grade, higher E/e′ ratios, higher E/A ratios, and larger left atrial volumes. Patients with HFpEF with elevated BNP also had larger right ventricular size, increased right ventricular wall thickness, larger right atrial size, and worse right ventricular systolic function compared to those with normal BNP. Table 3 illustrates lower right atrial pressure, mean pulmonary arterial pressure, and pulmonary vascular resistance in patients with normal BNP. Pulmonary capillary wedge pressure and cardiac index were similar between the 2 groups. However, pulmonary artery saturation, a marker of cardiac output independent of body size, was higher in the normal BNP group.
| Characteristic | BNP (pg/ml) | p Value | |
|---|---|---|---|
| ≤100 | >100 | ||
| (n = 46) | (n = 113) | ||
| BNP (pg/ml) | 37 (21–63) | 379 (205–789) | |
| Age (years) | 62 ± 11 | 66 ± 12 | 0.038 |
| Women | 33 (72%) | 62 (55%) | 0.049 |
| European American | 21 (46%) | 65 (58%) | 0.17 |
| African American | 20 (43%) | 38 (34%) | 0.24 |
| Other | 5 (11%) | 10 (8%) | 0.77 |
| New York Heart Association functional class | 0.63 | ||
| I | 4 (9%) | 8 (7%) | |
| II | 22 (48%) | 46 (41%) | |
| III | 20 (43%) | 57 (50%) | |
| IV | 0 | 2 (2%) | |
| Exertional dyspnea | 43 (93%) | 102 (90%) | 0.52 |
| Orthopnea | 22 (48%) | 54 (48%) | 0.99 |
| Paroxysmal nocturnal dyspnea | 13 (28%) | 33 (29%) | 0.91 |
| Coronary artery disease ⁎ | 13 (28%) | 51 (45%) | 0.049 |
| Systemic hypertension † | 37 (80%) | 89 (79%) | 0.81 |
| Hyperlipidemia ‡ | 30 (65%) | 61 (54%) | 0.19 |
| Chronic kidney disease | 13 (28%) | 75 (66%) | <0.0001 |
| Diabetes mellitus | 15 (33%) | 37 (33%) | 0.99 |
| Atrial fibrillation | 5 (11%) | 44 (39%) | 0.001 |
| Current smoker | 8 (17%) | 15 (13%) | 0.50 |
| Obesity § | 32 (70%) | 53 (47%) | 0.009 |
| Chronic obstructive pulmonary disease or asthma | 19 (42%) | 49 (43%) | 0.90 |
| Obstructive sleep apnea | 21 (47%) | 44 (39%) | 0.37 |
| Heart rate (beats/min) | 71 ± 16 | 71 ± 14 | 0.97 |
| Systolic blood pressure (mm Hg) | 124 ± 17 | 125 ± 21 | 0.71 |
| Diastolic blood pressure (mm Hg) | 71 ± 11 | 69 ± 12 | 0.30 |
| Pulse pressure (mm Hg) | 53 ± 15 | 57 ± 18 | 0.26 |
| Body mass index (kg/m 2 ) | 35 ± 9 | 31 ± 9 | 0.005 |
| Jugular venous pressure (cm water) | 9 ± 2 | 11 ± 3 | 0.002 |
| Pulmonary crackles | 13 (28%) | 32 (28%) | 0.99 |
| Lower-extremity edema | 30 (65%) | 75 (66%) | 0.89 |
| Serum sodium (mEq/L) | 139 ± 3 | 138 ± 3 | 0.14 |
| Blood urea nitrogen (mg/dl) | 20 ± 14 | 28 ± 19 | 0.012 |
| Serum creatinine (mg/dl) | 1.0 (0.8–1.2) | 1.2 (1.0–1.8) | 0.0001 ∥ |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 70 ± 25 | 53 ± 27 | 0.0002 |
| Hemoglobin (g/dl) | 12.2 ± 1.4 | 11.6 ± 1.9 | 0.08 |
⁎ Defined as the presence of a physician-documented history of coronary artery disease, known coronary stenosis >50%, history of myocardial infarction, percutaneous intervention, coronary artery bypass grafting, or abnormal stress test results consistent with myocardial ischemia.
† Defined as blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg, a physician-documented history of hypertension, or current use of antihypertensive medications.
‡ Defined as a physician-documented history of hyperlipidemia or current use of lipid-lowering medications.
§ Defined as body mass index >30 kg/m 2 .
| Parameter | BNP (pg/ml) | p Value | |
|---|---|---|---|
| ≤100 | >100 | ||
| (n = 46) | (n = 113) | ||
| LV end-diastolic volume index (ml/m 2 ) | 38 ± 10 | 42 ± 12 | 0.21 |
| LV end-systolic volume index (ml/m 2 ) | 15 ± 6 | 16 ± 7 | 0.28 |
| LV EF (%) | 62 ± 7 | 61 ± 7 | 0.67 |
| LV mass index (g/m 2.7 ) | 49 ± 17 | 55 ± 23 | 0.17 |
| Left atrial volume index (ml/m 2 ) | 27 ± 11 | 36 ± 16 | 0.002 |
| Early mitral inflow (E) velocity (cm/s) | 97 ± 30 | 112 ± 43 | 0.059 |
| Late (atrial) mitral inflow (A) velocity (cm/s) | 84 ± 23 | 77 ± 31 | 0.28 |
| E/A ratio | 1.2 ± 0.6 | 1.6 ± 0.7 | 0.020 |
| Early mitral inflow deceleration time (ms) | 212 ± 43 | 239 ± 79 | 0.059 |
| Isovolumic relaxation time (ms) | 78 ± 18 | 85 ± 21 | 0.06 |
| Tissue Doppler e′ velocity (cm/s) | 9.9 ± 4.2 | 8.9 ± 3.5 | 0.19 |
| E/e′ ratio | 11 ± 5 | 14 ± 8 | 0.017 |
| LV diastolic function | 0.010 | ||
| Normal | 7 (15%) | 4 (4%) | |
| Impaired relaxation (grade 1) | 5 (11%) | 5 (4%) | |
| Pseudonormal (grade 2) | 15 (33%) | 32 (28%) | |
| Restrictive (grade 3) | 9 (20%) | 46 (41%) | |
| Indeterminate | 10 (22%) | 26 (23%) | |
| RV end-diastolic area index (cm 2 /m 2 ) | 12.1 ± 2.0 | 14.6 ± 4.2 | 0.001 |
| RV end-systolic area index (cm 2 /m 2 ) | 6.5 ± 1.3 | 8.7 ± 3.1 | 0.0001 |
| RV fractional area change | 0.46 ± 0.06 | 0.41 ± 0.07 | 0.0003 |
| Tricuspid annular plane systolic excursion (cm) | 2.2 ± 0.6 | 1.9 ± 1.7 | 0.001 |
| RV wall thickness index (cm/m 2 ) | 0.23 ± 0.04 | 0.26 ± 0.06 | 0.012 |
| Right atrial area index (cm 2 /m 2 ) | 8.8 ± 2.8 | 11.6 ± 4.2 | 0.0002 |
| Hemodynamic Parameter | BNP (pg/ml) | p Value | |
|---|---|---|---|
| ≤100 | >100 | ||
| (n = 46) | (n = 113) | ||
| Right atrial pressure (mm Hg) | 12 ± 5 | 15 ± 6 | 0.02 |
| Pulmonary artery systolic pressure (mm Hg) | 46 ± 11 | 55 ± 18 | 0.008 |
| Pulmonary artery diastolic pressure (mm Hg) | 27 ± 8 | 29 ± 9 | 0.37 |
| Mean pulmonary artery pressure (mm Hg) | 33 ± 8 | 37 ± 11 | 0.045 |
| Pulmonary capillary wedge pressure (mm Hg) | 25 ± 8 | 27 ± 9 | 0.42 |
| Cardiac index (L/min/m 2 ) | 3.1 ± 0.8 | 2.9 ± 0.9 | 0.28 |
| Pulmonary artery saturation (%) | 71 ± 7 | 67 ± 9 | 0.002 |
| Systemic vascular resistance (dyne · s/cm 5 ) | 1,227 ± 507 | 1,292 ± 566 | 0.55 |
| Pulmonary vascular resistance (dyne · s/cm 5 ) | 87 (64–112) | 142 (90–229) | 0.0005 ⁎ |
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