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Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Disclosures/Conflicts of Interest
  8. References

High levels of B-type natriuretic peptide in cancer patients are poorly studied. Previously published data suggest that they are not related to fluid overload and are encountered mostly in solid cancers. The authors investigated the distribution of amino terminal pro-brain natriuretic peptide (NT-proBNP) between hematologic and solid organ malignancies and the relationship of NT-proBNP with volume status in oncologic patients. A total of 145 consecutive patients with at least one occurrence of NT-proBNP exceeding the upper normal range 10-fold were identified. The authors retrospectively reviewed their records including clinical, laboratory, and radiological data and echocardiograms. More than 70% of patients had hematologic malignancies. Patients with NT-proBNP >50,000 pg/mL had only hematologic malignancies, primarily multiple myeloma. There was no association between M-spike proteins and NT-proBNP. About 80% of patients had signs of fluid overload. The magnitude of NT-proBNP elevation was similar between those with and without heart failure or volume overload, as well as with solid cancers vs hematologic malignancies. Contrary to prior reports, it was found that very high NT-proBNP in cancer patients is usually encountered in the context of fluid overload and most often in hematologic malignancies.

In modern medicine, natriuretic peptides (NPs) such as amino terminal pro-brain natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP) are widely used as diagnostic biomarkers in the treatment of pathophysiologic heart conditions. When utilized in conjunction with clinical history and physical findings, these NPs may guide the initial work-up and treatment of patients with suspected heart failure (HF).[1-5] Monitoring their levels can also help gauge therapeutic response to treatment in patients with HF. A key understanding of how they work and what factors influence them is essential to their utility.

Various NPs have been found in the brain, kidney, and other organs, but are primarily associated with their production within cardiomyocytes of the atria and ventricles.[6, 7] They function to achieve natriuresis, vasodilatation, sympathetic nerve activity, and inhibition of renin and aldosterone production.[8, 9] The overall effect of these modifications is a net decrease in cardiac preload and afterload. Elevations in NPs are generally seen in response to an increase in cardiac end-diastolic wall stress, stiffness, and pressure load.[10, 11] To a lesser degree, renal dysfunction, female sex, and aging tend to increase NT-proBNP/BNP plasma concentrations, while obesity decreases their levels.[12-15] Both BNP and NT-proBNP are released in equimolar amounts after enzymatic cleavage because they are formed from the same precursor molecule (pro-BNP). Compared with BNP, NT-proBNP has a steady-state level that is 4- to 6-fold higher and has a longer half-life (60–90 minutes), which is largely attributed to different clearance mechanisms.[16]

Increased levels of NPs in conditions other than HF has been well documented, these include acute coronary syndrome, brain lesions, pulmonary hypertension, sepsis, and endocrine diseases.[17-20] One aspect that has yet to be adequately explored is the phenomena of markedly elevated natriuretic peptides in the cancer population. The first study dedicated to the subject was published by Burjonroppa and colleagues.[21] They analyzed the records of 99 consecutive cancer patients with BNP levels >1000 pg/mL (100 times the upper range limit). Their principal findings were that (1) markedly elevated BNP is more common in solid cancers than in hematologic malignancies, and (2) that in more than 70% of cancer patients with markedly elevated BNP, there are no signs of volume overload.

In our previous experience, findings were different, with about 90% of the cancer patients with high BNP having signs of HF.[22] We did not, however, focus on the type of malignancies associated with high NPs. This study was performed with the goal of investigating what types of malignancies are commonly associated with very high NP levels. Also, considering that some hematologic malignancies, such as multiple myeloma, are accompanied by synthesis of abnormal proteins in large amounts, we wanted to explore whether this condition causes elevations of NT-proBNP to a higher degree than other types of oncologic conditions.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Disclosures/Conflicts of Interest
  8. References

Study Population

This study was conducted at H. Lee Moffitt Cancer Center with approval by the hospital's internal review board. We retrospectively screened the hospital's electronic medical record database from June 2007 through October 2008 and identified hospitalized patients with NT-proBNP values >3000 ng/mL irrespective of their cancer diagnosis or reason for admission. This value was arbitrarily chosen to minimize false positives because it is 10 times the upper limit of diagnostic exclusion for HF. In total, 187 values representing 145 individuals were identified. Some patients had several NT-proBNP values within the specified range due to multiple admissions, serial monitoring or repeated checks, presumably due to clinician credence of laboratory error. In these cases, only the value closest to the date of chest radiography or 2-dimensional echocardiography was used with priority on the latter.

Instrumentation

Venous blood draws for NT-proBNP levels were done for clinical indications and tested on the same VITROS 3600 Immunodiagnostic System (Ortho-Clinical Diagnostics, Inc, Rochester, NY). The VITROS system utilizes an immunometric immunoassay, which recognizes epitopes located in the N-terminal region of proBNP. The reaction causes the release of chemiluminescent light, which is detected by the device. Per manufacturer guidelines, the range of the assay is 5 to 350,000 ng/mL with no high-dose hook effect up to 500,000 pg/mL.

Methods

The final sample size was comprised of 145 inpatients with various hematologic and oncologic malignancies. Their electronic medical records were reviewed for diagnosis, demographics, weight, radiologic imaging, and echocardiographic data. For each NT-proBNP value, laboratory findings including serum creatinine, hemoglobin, hematocrit, total protein, and albumin were recorded. Additionally, in patients with paraproteinemias, the closest temporal immunoglobulin level, serum M-spike type, and concentration were obtained. A statistical summary of the mean, standard deviation, median, minimum, maximum, and number of each value was tabulated.

Retrospective analysis of clinical documentation for findings of HF is problematic, particularly in cancer centers. The majority of clinician notes rarely comment on New York Heart Association (NYHA) functional class, the presence or absence of physical findings such as S3 gallop, hepatomegaly, or jugular venous distention. Furthermore, the ability to accurately distinguish these findings is largely physician-dependent. We consequently based the diagnosis of HF on chest radiography in conjunction with echocardiography findings of cardiomyopathy to eliminate as much subjective variability as possible. In patients who had inconclusive findings of HF on chest radiography, the medical records were manually reviewed for findings of cardiac decompensation or volume overload.

Radiograms were coded on the presence of HF based on the radiologic report. They were screened for key words/phrases suggestive of cardiac failure including cardiomegaly, Kerley B lines, vascular congestion, pleural effusion, and interstitial or alveolar edema. Findings of atelectasis or infiltrate were also used because these can often be misread or be the first signs of a developing effusion. All images with more than one finding, vascular congestion, pulmonary edema, or pleural effusions were graded as 3 (evidence of HF). If the chest imaging was read as “negative chest” or “no cardiopulmonary findings” it was coded as (1) (no evidence of HF). Radiograms with atelectasis, infiltrates, or with nonspecific findings were read as 2 (probable evidence of HF). All the charts categorized in these latter two groups were reviewed manually to confirm or rule out fluid overload, using Framingham criteria and results of additional imaging studies such as computer tomography of the chest.

Patient echocardiograms were performed by trained technicians according to the standards set by the American Society of Echocardiography guidelines utilizing the same instrumentation. The studies were individually analyzed by a trained cardiologist blinded to all clinical data and prior reports. Measurements, including left ventricular (LV) ejection fraction (EF) by Simpson's method, LV end-systolic and end-diastolic dimension, septal and posterior wall thickness, velocity of tricuspid and pulmonic regurgitation, and parameters of diastolic dysfunction were recorded. LVEF was considered preserved if ≥50% and reduced if <50% per the European Society of Cardiology guidelines.[23]

Statistical Analysis

The arbitrary cutoff of NT-proBNP concentrations >3000 pg/mL was chosen. Because the distribution was not normal, nonparametric tests had to be employed. We compared medians of NT-proBNP using Mann-Whitney's U test. Spearman's correlation coefficient was used for calculation of correlations.

We also tested the hypothesis that increased blood viscosity in paraproteinemias or other malignancies may increase the workload on the heart and result in increased secretion of NT-proBNP. An estimation of whole blood viscosity at 208 per seconds of shear stress was calculated using a formula based on hematocrit (h) and plasma protein concentration (p).

Whole blood viscosity (208 per second) = [0.12 × h] + [0.17 × p – 2.07].

This equation has been validated as a surrogate determinant of blood viscosity for hematocrit (32%–53%) and plasma protein (5.4–9.5 g/dL) concentrations.[24] It was used in this study as direct measurements were unavailable. For all values, statistical significance was defined as P<.05. Analyses were performed with SPSS (version 17.1; SPSS, Inc, Chicago, IL).

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Disclosures/Conflicts of Interest
  8. References

The total population of the study included 145 hospitalized patients; the majority was white (85%) and male (62%) with a combined median age of 63. Other baseline characteristics are summarized in Table 1. All patients had a diagnosis of cancer with a predominance with hematologic malignancies (72%) compared with solid tumor malignancies (28%). Of the 105 patients with hematologic cancers, 42 (40%) had leukemia, 23 (22%) had lymphoma, 30 (28%) had paraproteinemias (multiple myeloma, Waldenstroms macroglobulinemia, amyloidosis), 5 (5%) had myelodysplastic syndrome, and 5 (5%) miscellaneous. In patients with solid tumor cancers, 6 (15%) were gastrointestinal, 4 (10%) breast, 4 (10%) lung, 3 (8%) prostate, 6 (15%) renal/bladder, 3 (8%) sarcoma, 2 (5%) tongue/larynx, 2 (5%) ovarian, and various others (25%).

Table 1. Patient Characteristics
Patient CharacteristicNo. (%)
  1. Abbreviations: BUN, serum urea nitrogen; EF, ejection fraction; IVC, inferior vena cava; IVSD, interventricular septal thickness at end-diastole; LAD, left atrial diameter; LVEDD, left ventricular end diastolic dimension; LVESD, left ventricular end systolic dimension; PWD, pulsed-wave Doppler; PASP, pulmonary artery systolic pressure; SD, standard deviation; TRV, tricuspid regurgitation velocity.

Total included145
Male90 (62)
Age median (range), y62.8 (21–93)
White124 (85)
Black 9 (6)
Hispanic 2 (1)
Other/unknown10 (8)
Type of malignancy
Oncologic40 (28)
Hemotologic105 (72)
Laboratory dataMean (±SD)
Albumin2.9 (0.6)
Total protein6.0 (1.3)
Creatinine1.7 (1.5)
BUN31.9 (23.6)
Hemoglobin9.9 (1.5)
Hematocrit29.5 (4.6)
Echocardiographic feature
EF, %52.5 (15.2)
IVSd, mm1.1 (0.3)
PWD, mm1.1 (0.2)
LVESD, mm3.3 (0.9)
LVEDD, mm4.8 (0.8)
TRV, m/S2.8 (0.5)
PASP, mm Hg43.8 (12.5)

The median NT-proBNP level for the study was 14,730 ng/mL with a range of 3000–187,000 ng/mL. Patients with hematologic malignancies did not differ by NT-proBNP compared with those with solid tumor malignancies. NT-proBNP levels were similar in the group with evidence of HF on both echocardiography and chest radiography. Other clinical characteristics include a mean creatinine of 1.7 mg/dL (0.4–10.8), mean serum urea nitrogen of 32 mg/dL (5–144), mean hemoglobin of 9.9 mg/dL (7.1–14.8), and mean hematocrit of 30% (14.5–42.7). In patients with multiple myeloma, NT-proBNP did not correlate with either total protein or the serum M-spike level. There was also no correlation with kappa or lambda light chains. Of all the immunoglobin classes, only IgM correlated with elevated NT-proBNP. The estimated serum viscosity of this group was not statistically different from patients with other hematologic or oncologic diagnosis.

Eight of our patients had NT-proBNP >50,000 pg/mL. All of them had hematologic malignancies (multiple myeloma [4], acute leukemia [2], myelodysplastic syndrome [1], and non-Hodgkin's lymphoma [1].

In 141 patients, chest radiography was available within 3 days of NT-proBNP measurements. Ninety-two patients (65%), regardless of type of malignancy, had signs of vascular congestion and/or pulmonary edema. Probable HF was seen in 35 (25%) patients. Eleven (8%) chest radiograms showed no evidence of HF (Table 2). Of these cases, 3 had decreased LVEF (20%, 25%, and 30%), one had no 2-dimensional echocardiography on file, and the remaining 4 patients had normal systolic function (EF ≥50%). Overall, 30 of 145 patients (20.7%) did not have evidence of cardiac decompensation/volume overload after manual review of their charts. The mean NT-proBNP in this population was 11,165 and was not significantly different from patients with HF.

Table 2. NT-proBNP Subgroup Analysis
Type of MalignancyNo.NT-proBNP, ng/L Median (Range)
  1. Abbreviation: NT-proBNP, amino terminal pro-brain natriuretic peptide. Findings of heart failure (HF) were determined by chest radiography. If findings were inconclusive or no evidence of HF was seen, the medical charts were manually reviewed.

All1457540 (3000–187,000)
Solid oncologic 409295 (3000–42,000)
Hematologic 1056875 (3150–187,000)
Hematologic excluding multiple myeloma787125 (3180–109,000)
Multiple myeloma 275730 (3150–187,000)
Findings of HF
Some or definite 1157770 (3050–187,000)
No evidence306205 (3000–71,100)
Definite927770 (3050–109,000)
Probable or no evidence536710 (3000–187,000)

Echocardiograms were available for 121 of 145 patients (83%). In 29 cases they were performed on the same day as NT-proBNP, in 52 more cases within 5 days, and in 41 cases the time interval was longer. The mean EF measurement for the study was 51%, with a majority (72%) of patients with normal ventricular function. Spearman's correlation coefficient was significant for NT-proBNP and LVEF (−0.3, P=.001), septal wall thickness (−0.24, P=.009), posterior wall thickness (−0.24, P=.01), LV end-systolic dimension (0.31, P=.001), and pulmonary regurgitation end-diastolic velocity (−0.47, P=.05). The analysis was repeated for the cases with same-day echocardiography and NT-proBNP. No new relationship was revealed although the correlation was superior (−0.52, P=.001) for LVEF for septal thickness (−0.48, P=.009) and left ventricular end-systolic diameter (0.55, P=.002). Findings are summarized in Table 1.

Of 30 patients without any signs of HF, distribution of hematologic (19 patients [63.3%]) and solid malignancies were not different from the total cohort. Only one of these patients was septic. No plausible reason for marked NT-proBNP elevation was identified in other 29 patients. Five of them were hypovolemic on examination.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Disclosures/Conflicts of Interest
  8. References

Markedly elevated NPs such as NT-proBNP are not uncommon in cancer patients. NT-proBNP is a quantitative marker of HF affected by both systolic and diastolic LV dysfunction.[25, 26] Its effectiveness as a clinical and diagnostic marker of volume overload has consistently been demonstrated. The International Collaborative of NT-proBNP (ICON) study defined the NT-proBNP cutoff value for HF rule out at 300 pg/mL.[27] Several prior studies have shown that other NPs at levels >3000 pg/mL are not reliable markers of clinical HF.[21, 22, 28]

In the present study we demonstrate that in most cancer patients (~80%) with NT-proBNP >3000 pg/mL there was evidence of fluid overload. In the remaining 20%, no signs of HF could be identified on manual review of hospital charts. Levels of NT-proBNP were not different in patients with signs of volume overload or without them. Most of them (72%) had hematologic malignancies and the remaining had various solid cancers. NT-proBNP was equally elevated regardless of the type of oncologic diagnosis. No relationship could be identified between paraproteinemias and NT-proBNP.

The exact mechanism of what is causing these extremely elevated NPs in the cancer population is unclear. In many cases, unnecessary workup including chest imaging, repeated laboratory tests, echocardiograms, and cardiac consultations are sought on the basis of this one unexplained laboratory value. A better understanding is critical to controlling hospital costs and resources.

Some studies have suggested that NPs themselves may be released from certain cancer cells.[29] A number of the patients were undergoing treatment at the time their NT-proBNP levels were measured. In the Burjonroppa study, similar findings were seen with more than half of their patients receiving chemotherapy within 1 month of BNP measurement.[21] Elevation of NPs following treatment of various malignancies with chemotherapy has been documented.[30-32] Most of the reports have attributed this to anthracycline-induced cardiotoxicity, although there are numerous other chemotherapies that are also cardiotoxic. It is possible that the destruction of the cancer cells themselves during treatment is causing the release of NPs. In both studies, the spectrum of cancer diagnosis was extensive. This observation suggests that there may not be a specific chemotherapy-related cause and there are other influences beyond chemotherapeutic agents alone.

Of all diagnoses, patients with paraproteinemias represented the largest subset of any malignancy in our patient population. A possible explanation is that these cancers are producing antibodies that are cross-reacting during the chemical immunoassay used to detect the natriuretic peptides. To further evaluate this, we looked specifically at the 27 patients with multiple myeloma. If the serum M-spike or immunoglobin levels were elevated, the measured NT-proBNP may be concordantly increased and explain the falsely elevated NP levels seen out of proportion to findings of HF.

We were unable to show a correlation between serum M-spike levels or elevations in immunoglobulins. It is feasible that if there is an interaction, it is likely with another molecule not being measured or the levels were not drawn close enough to the NT-proBNP measurements to be statistically significant.

Many cancers produce tumor antigens, which, by a similar mechanism, may also be altering the detected levels of NPs. Interestingly, recent data have shown a relationship between NT-proBNP levels and response to chemotherapeutic agents in patients with certain cancers.[33] The implication of these findings, if any, has yet to be completely explored and warrants further investigation.

It has been estimated that as much as 38% of patients with multiple myeloma will develop amyloidosis during the course of their disease. Abnormal levels of NT-proBNP in systemic amyloid light-chain amyloidosis are a highly sensitive marker for cardiac dysfunction and can detect inapparent heart involvement in otherwise asymptomatic patients.[34] In our study there was no evidence of cardiac amyloidosis by echocardiogram in the subset of patients with multiple myeloma. None of these patients had undergone cardiac biopsy.

Contrary to prior reports that looked at elevated BNP,[21] our study showed a higher proportion of patients with hematologic malignancies compared with oncologic malignancy. One possible reason for this is that there may be a relationship between whole blood viscosity and NT-proBNP elevation. Blood viscosity is increased in patients with polycythemia, hyperlipidemia, elevated erythrocyte sedimentation rate, and hypoxemic states such as smoking.[35-40] A combination of these findings is common in the cancer population. Plasma hyperviscosity syndromes have been reported in hematologic cancers including leukemias and paraproteinemias. All 8 patients with NT-proBNP levels >50,000 pg/mL had hematologic malignancies. An elevated blood viscosity would theoretically increase atrial and ventricular wall stress during contraction. This chronically elevated strain may lead to greater continuous release of NPs from the cardiomyoctes.

In our study, there was not a trend that correlated hematologic, oncologic, or paraproteinemias and NT-proBNP. This may be due in part to the use of an equation to estimate blood viscosity and not a direct measurement. A comparison of blood viscosity as it relates to natriuretic peptides would shed light on this unexplored area.

Patients with hematologic malignancies are also more likely to undergo transfusions during the course of their treatment than patients with solid tumor diagnosis. Chronic transfusion may lead to iron-induced cardiomyopathy in a percentage of patients. A study by Delaporta and colleagues[41] found that there is a correlation between cardiac iron concentration and NT-proBNP in patients with transfusion-dependent thalassemia major quantified by cardiac MRI techniques. Our database was not screened for patients requiring frequent transfusions but could be a contributing factor in the discrepancy.

The association between NT-proBNP and clinical severity of HF based on NYHA functional class is well established.[42] Due to high intra-individual NT-proBNP variability, a clear understanding of its influences is critical to its interpretation. Several factors, including age, sex, obesity, and renal function have all been known to affect NT-proBNP levels.[43-49] Although we did not correct for these variables, the measured values are still significantly higher than would be expected.

In patients with normal heart function with or without hypertension, pro-BNP is properly enzymatically cleaved into NT-proBNP and BNP. However, several studies have shown that with NYHA class III and IV patients, the enzymatic activity is diminished with a predominance of pro-BNP.[50, 51] This was verified by two studies that utilized advanced methods to compare these levels in patients with NYHA class IV. In both studies there was a predominance of immunoreactive parent BNP molecules with low amounts of endogenous bioactive BNP.[52, 53] Furthermore, most immunoassays used to detect NT-proBNP cannot differentiate uncleaved parent peptides from the NT-proBNP itself. We hypothesize that in some patients with malignancy enzymatic conversion to the active form is diminished and the measured levels are reflecting the sum of proBNP and its NT-proBNP derivatives. The effect of these molecules on the overall measured NT-proBNP is currently unknown.

Our prior studies in 2007 and 2010 showed that there is a good relationship between elevated BNP levels and severity of HF when mildly or moderately elevated; however, that correlation was not as clear when levels were extreme (>3000 ng/mL).[22, 28] Within the cancer population, serial NPs are often monitored to detect LV dysfunction in patients undergoing chemotherapy. The study by Burjonroppa and colleagues[21] suggested that elevated BNP values (>1000 pg/mL) in cancer patients are not associated with clinical evidence of volume overload or LV dysfunction and occur predominantly with solid tumor malignancies. Our observations, to the contrary, indicated that in the majority of cases, cancer patients with high NPs have evidence of fluid overload. Moreover, the most extreme NP concentrations were seen in hematologic malignancies. We undertook this study in order to establish what kind of malignancies are associated with highest concentrations of NT-proBNP and how The NT-proBNP levels are related to volume overload.

Conclusions

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Disclosures/Conflicts of Interest
  8. References

Contrary to prior reports, significantly elevated natriuretic peptide levels in the cancer population are seen predominantly in hematologic malignancy in the context of fluid overload. The exact mechanism as to what is causing these elevations is still unknown. Further investigation regarding NT-proBNP, plasma viscosity, tumor protein cross-reactivity, and the malignancies themselves is warranted.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Disclosures/Conflicts of Interest
  8. References
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