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Predictors of Natriuretic Peptide Non-Response in Patients Hospitalized With Acute Heart Failure
Predictors of Natriuretic Peptide Non-Response in Patients Hospitalized With Acute Heart Failure Ana Ribeiro, MDa,*, Patrícia Lourenço, MDa,b, Sérgio Silva, MDa,c, Francisco Cunha, MDa, João Vilaça, MDa, Filipa Gomes, MDa, José Paulo Araújo, MD, PhDa,b, and Paulo Bettencourt, MD, PhDa,b Increasing natriuretic peptide (NP) levels are associated with worse heart failure (HF) outcomes. Predictors of NP nonresponse have not been studied. The aim of this study was to identify predictors of nondecreasing NP levels during episodes of acute HF. A retrospective analysis was conducted in patients prospectively included in a registry of acute HF, with the primary diagnosis of acute HF. The objective under analysis was B-type NP (BNP) response, defined as a >30% decrease in BNP during hospitalization. Percentage of BNP variation was calculated as: % BNP variation [ [(admission BNP L discharge BNP)/admission BNP] 3 100. A logistic regression analysis was performed to study potential predictors of NP nonresponse. A multivariate model was built. A total of 496 patients were studied: 28.2% were considered nonresponders to the implemented HF treatment strategy. Identified predictors of nonresponse were older age, chronic HF, lower admission systolic blood pressure, anemia, renal dysfunction, and lower sodium on admission, as well as lower admission albumin and lower admission total cholesterol. Admission BNP was not a predictor of response. The only identified independent predictor of nonresponse was a low admission total cholesterol level (cutoff 125 mg/dl), with an odds ratio of 2.55 (95% confidence interval 1.59 to 4.11). This remained valid when the analysis was stratified according to admission BNP (cutoff 2,000 pg/ml) and according to statin use. In conclusion, a low admission total cholesterol level was a strong and independent predictor of BNP nonresponse in patients admitted with acute HF. The ability of cholesterol to predict BNP nonresponse was valid for patients with intrinsically low cholesterol and in those with statin-induced low cholesterol. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;-:-e-)
The use of plasma levels of natriuretic peptides (NP) to guide treatment of patients with heart failure (HF) has been investigated in a number of randomized controlled trials,1e10 but there is no consensus regarding the benefits of this approach.11,12 The Use of Peptides in Tailoring Heart Failure Project study was the first trial to emphasize the concept of “responder” and “nonresponder” patients.4 Responders were defined as patients whose NP levels decrease by >30% during a definite time period in response to the HF strategy in use. In a subgroup analysis, nonresponder patients had a worse prognosis. Knowledge of NP nonresponse predictors would allow the identification of patients at risk for worse outcome who might require more intensive treatment or novel therapeutic strategies. We aimed to characterize the profile of the nonresponder HF patients and to identify predictors of nondecreasing plasma B-type NP (BNP) levels in patients admitted for acute HF.
a Serviço de Medicina Interna, Centro Hospitalar São João, Porto, Portugal; bFaculdade de Medicina da Universidade do Porto, Unidade I&D Cardiovascular do Porto, Porto, Portugal; and cInstituto de Anatomia da Faculdade de Medicina da Universidade do Porto, Porto, Portugal. Manuscript received June 30, 2014; revised manuscript received and accepted September 20, 2014. See page 5 for disclosure information. *Corresponding author: Tel: þ35-1225512200; fax: þ35-1225512332. E-mail address: [email protected] (A. Ribeiro).
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.09.053
Methods We conducted a retrospective analysis in patients prospectively included in a registry of acute HF in the internal medicine department of a tertiary care academic hospital. From January 2009 to December 2010, all patients admitted to our department with the primary diagnosis of HF were included in an acute HF registry. The diagnosis of HF was made according to the 2008 European Society of Cardiology guidelines.13 Patients with systolic dysfunction and those with HF with preserved ejection fraction were included. Echocardiography was performed in all eligible patients during hospitalization. Severe left ventricular systolic dysfunction corresponded to a left ventricular ejection fraction (LVEF) <30%, moderate dysfunction to an LVEF of 30% to 40%, and mild dysfunction to an LVEF of 40% to 50%. An LVEF >50% was considered to indicate normal systolic function. Patients were excluded from the registry when acute coronary syndromes were the cause of acute HF and when symptoms were ultimately attributed to causes other than HF. Patients with no echocardiographic structural or functional abnormalities were also excluded from the registry. Treatment, timing of discharge, and discharge medications were at the discretion of the attending physicians. Physicians were aware of the ongoing HF registry. As part of the registry, all patients were collected fasting venous blood samples <48 hours after admission and again www.ajconline.org
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Table 1 Characteristics of study patients and comparison between BNP responders and nonresponders Variable Men Age (years), median (IQR) Hypertension Diabetes mellitus Atrial fibrillation Chronic Heart Failure Heart Failure hospitalization previous year Ischemic aetiology NYHA at admission IV (vs II/III) Admission SBP (mmHg), median (IQR) LVSD (vs HFpEF) Ejection fraction (%), median (IQR) Hemoglobin (g/dL), mean (SD) Sodium (mEq/L), median (IQR) Creatinine (mg/dL), median (IQR) C-reactive protein (mg/L) median (IQR) Troponin I (ng/mL), median (IQR) Albumin (g/L), mean (SD) BNP (pg/mL), median (IQR) Total cholesterol (mg/dL), median (IQR) Previous ACEi or ARB Previous Beta blocker, Previous Statin Length of hospital stay (days), median (IQR) Deaths at 6 months
All patients (496) 210 78 369 254 224 435 116 203 291 132 269 40 11.8 139 1.33 20.3 0.060 35.4 1637.8 150 311 248 236 8 93
(42.3%) (72-84) (74.4%) (51.0%) (45.2%) (87.7%) (23.4%) (40.9%) (58.7%) (115-154) (54.2%) (25-56) (2.2) (136-142) (1.09-1.80) (9.5-55.1) (0.030-0.143) (4.8) (915.0-2762.8) (126-186) (62.7%) (50.0%) (47.6%) (6-12) (18.8)
BNP responders (n¼356) 146 77 264 180 154 304 76 145 212 134 191 40 12.0 140 1.30 20.5 0.060 35.7 1743.4 156 218 183 166 8 48
(41.0%) (70-84) (74.1%) (50.6%) (43.2%) (85.4%) (21.3%) (40.7%) (59.6%) (117-156) (53.6%) (26-56) (2.2) (137-142) (1.08-1.69) (9.6-55.5) (0.030-0.129) (4.8) (959.5-2785.8) (131-194) (61.2%) (51.4%) (46.6%) (6-11) (13.5)
BNP non-responders (n¼140) 64 80 105 74 70 131 40 58 79 124 78 40 11.2 138 1.50 18.5 0.060 34.7 1363.8 130 93 65 70 8 45
(45.7%) (74-86) (75.0%) (52.9%) (50.0%) (93.6%) (28.6%) (41.4%) (56.4%) (110-146) (55.7%) (23-56) (1.9) (135-142) (1.16-2.02) (9.3-54.6) (0.030-0.188) (4.8) (796.9-2747.5) (110-163) (66.4%) (46.4%) (50.0%) (6-13) (32.1)
p-value 0.34 0.005 0.78 0.64 0.11 0.02 0.09 0.89 0.54 0.001 0.52 1.00 <0.001 <0.001 0.004 0.74 0.25 0.04 0.14 <0.001 0.30 0.30 0.52 0.15 <0.001
ACEi ¼ angiotensin converting enzyme inhibitors; ARB ¼ angiotensin receptor blockers; BNP ¼ B-type natriuretic peptide; IQR ¼ interquartile range; LVEF ¼ left ventricular ejection fraction; LVSD ¼ left ventricular systolic dysfunction; NYHA ¼ New York Heart Association; SBP ¼ systolic blood pressure; SD ¼ standard deviation.
Figure 1. Kaplan-Meier survival curves according to the 4 groups. Responders with admission BNP <2,000 pg/ml: n ¼ 204, 16 deaths; responders with admission BNP >2,000 pg/ml: n ¼ 152, 32 deaths; nonresponders with admission BNP <2,000 pg/ml: n ¼ 83, 16 deaths; and nonresponders with admission BNP >2,000 pg/ml: 57 patients, 29 deaths. Responders with low admission BNP had a better prognosis, and nonresponders with high admission BNP had worse outcomes. The remaining patients had intermediate outcomes.
on the day of discharge, if patients were discharged alive. BNP was measured by way of a chemiluminescent immunoassay using an Architect i2000 automated analyzer (Abbott Diagnostics, Santa Clara, California). Serum sodium, creatinine, urea, albumin, total cholesterol, and Creactive protein were measured using conventional methods with an Olympus AU5400 automated clinical chemistry analyzer (Olympus, Center Valley, Pennsylvania). Hemoglobin was assessed using an automated blood counter. Demographic characteristics, medications in use, and comorbidities were recorded. Diabetes mellitus was defined as a known previous diagnosis, current prescription of either an oral hypoglycemic agent or insulin, a fasting venous blood glucose level >126 mg/dl, or a random glucose level >200 mg/dl. Arterial hypertension was defined as the presence of previous diagnosis, record of antihypertensive pharmacologic treatment, or blood pressure >140/90 mmHg. Anemia was considered if the hemoglobin level was <13 g/dl in men and <12 g/dl in women. Renal dysfunction was considered when plasma creatinine was >1.5 mg/dl. Hyponatremia was considered when serum sodium was <135 mEq/L. To participate in this registry, all patients provided written informed consent, and the study protocol conformed to the ethical guidelines of the Declaration of Helsinki. Patients included in the registry were followed for 6 months; hospital registries and telephone contact with patients or their relatives were used to assess patients’ vital status. The objective under analysis was BNP response, defined as a >30% decrease in BNP during hospital admission. To further
Heart Failure/Natriuretic Peptide Nonresponse in Heart Failure Table 2 Variables possibly associated with natriuretic peptides nonresponse during hospitalization: univariate approach Variable
Male sex Age 75 years Hypertension Diabetes mellitus Atrial fibrillation Chronic Heart failure Heart Failure hospitalization previous year Ischemic aetiology NYHA at admission IV (vs II/III) Admission systolic blood pressure 115mmHg LVSD (vs HFpEF) Ejection fraction (per %) Anaemia Hyponatremia Renal dysfunction C-reactive protein (per mg/L) Troponin I (per ng/mL) Albumin (per g/L) B-type natriuretic peptide (per 100pg/mL) B-type natriuretic peptide >2000pg/mL Total cholesterol < 125mg/dL Previous ACEi or ARB Previous Beta blocker Previous Statin Length of hospital stay (per day)
OR (95% Confidence Interval)
p-value
1.21 1.72 0.94 1.05 1.38 2.65 1.47 1.03 0.88 1.75
(0.82-1.80) (1.12-2.65) (0.59-1.48) (0.86-1.27) (0.93-2.05) (1.16-6.04) (0.94-2.30) (0.69-1.53) (0.59-1.31) (1.12-2.74)
0.34 0.01 0.78 0.64 0.11 0.02 0.09 0.89 0.54 0.01
1.14 1.00 2.13 1.59 1.82 1.00 1.00 0.96 1.00 0.92 3.32 0.67 0.80 1.14 1.02
(0.76-1.70) (0.99-1.01) (1.38-3.28) (0.97-2.63) (1.22-2.71) (1.00-1.00) (0.91-1.11) (0.92-1.00) (0.99-1.01) (0.62-1.37) (2.15-5.13) (0.42-1.06) (0.50-1.25) (0.77-1.68) (0.99-1.05)
0.52 0.92 0.001 0.07 0.003 0.85 0.93 0.04 0.61 0.69 <0.001 0.09 0.32 0.52 0.22
ACEi ¼ angiotensin converting enzyme inhibitors; ARB ¼ angiotensin receptor blockers; BNP ¼ B-type natriuretic peptide; LVEF ¼ left ventricular ejection fraction; LVSD ¼ left ventricular systolic dysfunction; NYHA ¼ New York Heart Association.
Table 3 Predictors of natriuretic peptide nonresponse: multivariate logistic regression model Characteristics
Total cholesterol<125mg/dL Anaemia Renal dysfunction Albumin < 35 g/L Chronic Heart Failure Hyponatremia B-type natriuretic peptide >2000pg/mL Admission systolic blood pressure 115mmHg Age75years
OR (95% Confidence Interval) 2.55 1.41 1.57 1.09 1.82 1.46 0.68 1.39
(1.59-4.11) (0.87-2.28) (1.00-2.46) (0.70-1.70) (0.77-4.35) (0.84-2.54) (0.43-1.07) (0.85-2.27)
1.51 (0.94-2.44)
p-value
<0.001 0.17 0.05 0.69 0.17 0.18 0.09 0.19 0.09
conduct this retrospective subanalysis, we excluded all patients who died in the hospital and hence had no discharge BNP measurements and no possible calculation of BNP variation. Statistical Analysis: Percentage of BNP variation during admission was calculated as: % BNP variation ¼ [(admission
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BNP discharge BNP)/admission BNP] 100. Responders were those patients in whom BNP decreased by >30%; the remaining patients were considered nonresponders. Responders and nonresponders were compared using chi-square tests for categorical variables and Student’s t tests and Mann-Whitney U tests for continuous variables normally and non-normally distributed, respectively. We calculated Spearman’s correlation coefficient between admission total cholesterol and BNP and between total cholesterol and BNP variation. Considering all-cause death as the event under analysis, a Cox regression analysis was performed to study the association of BNP nonresponse with prognosis. We built a multivariate model to assess the independent association of BNP response with better outcome. Patients were further cross-classified according to response (30% decrease during hospitalization) and admission BNP (cutoff 2,000 pg/ml) for additional prognostic information. Patients’ distribution was as follows: responders with low admission BNP, 204 patients; responders with high admission BNP, 152 patients; nonresponders with low admission BNP, 83 patients; and nonresponders with high admission BNP, 57 patients. The Kaplan-Meier method was used to display and compare survival curves according to the 4 groups created. A logistic regression analysis was performed to study potential predictors of NP nonresponse. A cutoff of 125 mg/dl was chosen for admission total cholesterol. A multivariate model was built. Analysis was then stratified according to admission BNP categories (cutoff 2,000 pg/ml) and also according to previous statin use. Interaction between statin use and admission cholesterol was formally tested. Results We studied 496 patients. Patients’ characteristics are listed in Table 1. During hospitalization, BNP levels decreased by >30% in 356 patients (71.8%), and the reminder 140 (28.2%) were considered nonresponders to HF treatment. Responders and nonresponders were compared (see Table 1). Nonresponders were older and more often had chronic HF; they were also admitted with lower systolic blood pressure. They had lower admission sodium, albumin, and hemoglobin levels and higher creatinine levels. Admission total cholesterol levels were also lower in nonresponders. Groups were similar concerning previous medication, admission BNP, and length of hospital stay. Six-month all-cause death occurred in 93 patients. Nonresponders had a multivariate-adjusted hazard ratio of 6-month death of 2.31 (95% confidence interval [CI] 1.48 to 3.61, p <0.001; adjustments to admission total cholesterol, hemoglobin, plasma creatinine, and albumin; admission BNP and admission systolic blood pressure; age and previous prognostic modifying therapy use). Nonresponse and higher admission BNP were the strongest independent predictors of worse outcome. The hazard ratio of death for admission BNP >2,000 pg/dl was 2.67 (95% CI 1.70 to 4.20). A nonsignificant trend toward higher all-cause mortality was seen in patients with admission cholesterol <125 mg/dl, with a hazard ratio of 1.42 (95% CI 0.92 to 2.22, p ¼ 0.12). When patients were cross-classified according to response and admission BNP, prognostic information was
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much increased. Among patients admitted with BNP levels <2,000 pg/ml, those who responded (n ¼ 204) had a 7.8% death rate and those not responding a 19.3% death rate. Among patients with higher admission BNP levels, nonresponders had a 50.9% death rate and responders a 21.1% death rate. Figure 1 shows the Kaplan-Meier survival curves according to these groups. Table 2 lists possible nonresponse predictors in a univariate approach. Admission BNP was not a predictor of response. The multivariate logistic regression model built for the identification of independent predictors of nonresponse in listed in Table 3. The only identified independent predictor of nonresponse was a low admission total cholesterol level (cutoff 125 mg/dl). Patients with higher admission BNP had lower total cholesterol levels: 141 mg/dl (118 to 170) in patients with admission BNP levels >2,000 pg/ml versus 155 mg/dl (130 to 196) in those with admission BNP levels <2,000 pg/ml. There was a weak negative correlation between admission BNP and total cholesterol: r ¼ 0.157 (p <0.001). Nonresponders had significantly lower cholesterol levels: 130 mg/dl (110 to 163) versus 156 mg/dl (131 to 194) in responders (p <0.001). There was a moderately strong and positive correlation between BNP variation and admission total cholesterol: r ¼ 0.308 (p <0.001). When patients were grouped according to admission BNP categories, a low admission total cholesterol level remained the only independent predictor of non-response, with an odds ratio of 2.18 (95% CI 1.13 to 4.22, p ¼ 0.02) for patients with admission BNP levels <2,000 pg/ml and an odds ratio of 3.78 (95% CI 1.79 to 7.95, p <0.001) for those with admission BNP levels >2,000 pg/ml. When analysis was stratified according to previous statin therapy, the power of a low admission cholesterol level in the prediction of NP nonresponse was observed in patients receiving and not receiving statins. Again, the predictive power was independent of other covariates: the odds ratio of BNP nonresponse was 2.91 (95% CI 1.37 to 6.17, p ¼ 0.005) for patients with intrinsically low cholesterol levels and 2.38 (95% CI 1.22 to 4.63, p ¼ 0.01) for those with statin-induced low cholesterol levels. There was no interaction between previous statin therapy and low admission cholesterol level. Discussion In 496 patients with acute HF, we reproduced the wellknown association of NP nonresponse with worse outcome. In our study population, nonresponders had a more than twofold higher risk for all-cause death at 6 months. This association with ominous prognosis was strong and independent of other prognostic predictors. Higher admission BNP and BNP nonresponse were the strongest independent predictors of all-cause death. As far as an extensive review of the published research could retrieve, predictors of NP nonresponse have never been specifically studied. The characterization of the nonresponder HF population as well as knowledge of predictors of nonresponse would help in the earlier identification (at admission) of the subgroup of patients with the most dismal outcomes in whom additional effort or the development of novel strategies should be investigated. The success of
NP-tailored therapy is far from agreed upon, and this is possibly due to incorrect selection of the target population in which it should be applied. In our acute HF population, the only independent predictor of nonresponse was low admission total cholesterol (<125 mg/dl). An admission total cholesterol level <125 mg/dl was associated with a >2.5fold higher rate of BNP nonresponse. This remained valid no matter the admission BNP. The ability of a low admission cholesterol level to predict BNP nonresponse was also valid for patients with intrinsically low cholesterol and those with statin-induced low cholesterol. Hypercholesterolemia is a cardiovascular risk factor that is associated with plaque formation, atherosclerosis, and morbidity and mortality in patients with coronary heart disease.14,15 In HF, a reverse epidemiologic phenomenon has been suggested: higher cholesterol confers a survival advantage and decreased cholesterol predicts an adverse prognosis.16e19 Although most studies have observed this association, some did not reproduce it.20,21 It is still a matter of debate whether cholesterol has a direct protective effect in HF or if it is merely an innocent bystander. A direct protective effect could derive from the ability of lipoproteins to bind bacterial lipopolysaccharide and downregulate the HF inflammatory response.22,23 Alternatively, cholesterol may not have any causal effect and may simply be a marker of undernutrition, cachexia, and more severe or advanced HF.21,24 In our study, total cholesterol was not a mortality predictor, but it was an independent predictor of nonresponse. Patients with higher BNP levels had significantly lower cholesterol levels, and nonresponders also had significantly lower cholesterol levels. We reported a weak, although significant, negative correlation between admission cholesterol and admission BNP and a moderately strong and positive correlation between BNP variation and admission cholesterol. A negative correlation between total cholesterol and BNP has already been suggested in a very small study in patients without HF.25 A correlation with variation in BNP has never been reported. The lipolytic effect of BNP is well established.26e29 An effect on cholesterol synthesis inhibition in adrenocortical cells has been suggested.30 Angiotensin II upregulates genes responsible for de novo cholesterol synthesis (including hydroxymethylglutaryl coenzyme A reductase), genes responsible for the expression of membrane receptors for cholesterol uptake, transporters into the mitochondria, and several genes involved in the steroid synthetic pathway. All these genes upregulated by angiotensin II are inhibited by cotreatment with BNP.30 These observations suggest that a chronic elevation of BNP can be responsible for lower cholesterol levels. The use of relative instead of absolute values of BNP respects the interindividual variability concerning neurohumoral activation. Each patient with HF establishes his or her own “natriuretostat,” and perhaps more important than the absolute value of BNP of the established “natriuretostat” is the patient’s ability to respond to HF therapies and the remaining magnitude of BNP variation still possible. According to this hypothesis, patients with higher downregulation of cholesterol biosynthesis would be those with the highest “natriuretostat” and the lowest magnitude of possible BNP variation around it. An admission total cholesterol level <125 mg/dl would predict inability to respond with BNP decrease irrespective of the
Heart Failure/Natriuretic Peptide Nonresponse in Heart Failure
admission BNP. In our population, admission BNP was not a predictor of response; only a low cholesterol level predicted nonresponse, and this is so probably because it reflects a consistently high BNP value on a patient-to-patient basis. The association of a low total cholesterol level with BNP nonresponse was valid for patients taking and not taking statins. This suggests that the suppressor effect of BNP on cholesterol synthesis may overcome that of statins. The inhibitory effect of BNP on cholesterol biosynthesis was observed only in the adrenocortical cells and has not been studied for the major cholesterol producer, the liver. The single-center nature of the study creates generalizability concerns. Despite the prospective recruitment as part of a registry, the retrospective nature of this specific analysis and the transversal data collection make the establishment of causality relations impossible. The fact that the physicians treating the patients with HF were aware of the ongoing registry may have created a bias. The nonindependent association with worse outcome but prediction of nonresponse, an established predictor of ominous outcome, favors total cholesterol as a marker of disease severity rather than causally implicated in disease progression. The relation between BNP and total cholesterol, and its fractions, should merit further study. Better knowledge and a full characterization of the nonresponder profile would help clinicians and investigators in the process of tailoring HF therapy.
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Disclosures The authors have no conflicts of interest to disclose.
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independent risk factor for mortality in chronic heart failure. Lancet 1997;349:1050e1053. 25. Takeuchi H, Sata M. The relationship among brain natriuretic peptide (BNP), cholesterol and lipoprotein. Heart Asia 2012;4:11e15. 26. Taegtmeyer H. Metabolic crosstalk in heart failure new roles for B-type natriuretic peptide. J Am Coll Cardiol 2011;58: 1126e1127. 27. Polak J, Kotrc M, Wedellova Z, Jabor A, Malek I, Kautzner J, Kazdova L, Melenovsky V. Lipolytic effects of B-type natriuretic peptide 1-32 in adipose tissue of heart failure patients compared with healthy controls. J Am Coll Cardiol 2011;58:1119e1125.
28. Lafontan M, Moro C, Berlan M, Crampes F, Sengenes C, Galitzky J. Control of lipolysis by natriuretic peptides and cyclic GMP. Trends Endocrinol Metab 2008;19:130e137. 29. Sengenès C, Berlan M, De Glisezinski I, Lafontan M, Galitzky J. Natriuretic peptides: a new lipolytic pathway in human adipocytes. FASEB J 2000;14:1345e1351. 30. Liang F, Kapoun AM, Lam A, Damm DL, Quan D, O’Connell M, Protter AA. B-Type natriuretic peptide inhibited angiotensin IIstimulated cholesterol biosynthesis, cholesterol transfer, and steroidogenesis in primary human adrenocortical cells. Endocrinology 2007;148:3722e3729.
The use of plasma levels of natriuretic peptides (NP) to guide treatment of patients with heart failure (HF) has been investigated in a number of randomized controlled trials,1e10 but there is no consensus regarding the benefits of this approach.11,12 The Use of Peptides in Tailoring Heart Failure Project study was the first trial to emphasize the concept of “responder” and “nonresponder” patients.4 Responders were defined as patients whose NP levels decrease by >30% during a definite time period in response to the HF strategy in use. In a subgroup analysis, nonresponder patients had a worse prognosis. Knowledge of NP nonresponse predictors would allow the identification of patients at risk for worse outcome who might require more intensive treatment or novel therapeutic strategies. We aimed to characterize the profile of the nonresponder HF patients and to identify predictors of nondecreasing plasma B-type NP (BNP) levels in patients admitted for acute HF.
a Serviço de Medicina Interna, Centro Hospitalar São João, Porto, Portugal; bFaculdade de Medicina da Universidade do Porto, Unidade I&D Cardiovascular do Porto, Porto, Portugal; and cInstituto de Anatomia da Faculdade de Medicina da Universidade do Porto, Porto, Portugal. Manuscript received June 30, 2014; revised manuscript received and accepted September 20, 2014. See page 5 for disclosure information. *Corresponding author: Tel: þ35-1225512200; fax: þ35-1225512332. E-mail address: [email protected] (A. Ribeiro).
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.09.053
Methods We conducted a retrospective analysis in patients prospectively included in a registry of acute HF in the internal medicine department of a tertiary care academic hospital. From January 2009 to December 2010, all patients admitted to our department with the primary diagnosis of HF were included in an acute HF registry. The diagnosis of HF was made according to the 2008 European Society of Cardiology guidelines.13 Patients with systolic dysfunction and those with HF with preserved ejection fraction were included. Echocardiography was performed in all eligible patients during hospitalization. Severe left ventricular systolic dysfunction corresponded to a left ventricular ejection fraction (LVEF) <30%, moderate dysfunction to an LVEF of 30% to 40%, and mild dysfunction to an LVEF of 40% to 50%. An LVEF >50% was considered to indicate normal systolic function. Patients were excluded from the registry when acute coronary syndromes were the cause of acute HF and when symptoms were ultimately attributed to causes other than HF. Patients with no echocardiographic structural or functional abnormalities were also excluded from the registry. Treatment, timing of discharge, and discharge medications were at the discretion of the attending physicians. Physicians were aware of the ongoing HF registry. As part of the registry, all patients were collected fasting venous blood samples <48 hours after admission and again www.ajconline.org
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Table 1 Characteristics of study patients and comparison between BNP responders and nonresponders Variable Men Age (years), median (IQR) Hypertension Diabetes mellitus Atrial fibrillation Chronic Heart Failure Heart Failure hospitalization previous year Ischemic aetiology NYHA at admission IV (vs II/III) Admission SBP (mmHg), median (IQR) LVSD (vs HFpEF) Ejection fraction (%), median (IQR) Hemoglobin (g/dL), mean (SD) Sodium (mEq/L), median (IQR) Creatinine (mg/dL), median (IQR) C-reactive protein (mg/L) median (IQR) Troponin I (ng/mL), median (IQR) Albumin (g/L), mean (SD) BNP (pg/mL), median (IQR) Total cholesterol (mg/dL), median (IQR) Previous ACEi or ARB Previous Beta blocker, Previous Statin Length of hospital stay (days), median (IQR) Deaths at 6 months
All patients (496) 210 78 369 254 224 435 116 203 291 132 269 40 11.8 139 1.33 20.3 0.060 35.4 1637.8 150 311 248 236 8 93
(42.3%) (72-84) (74.4%) (51.0%) (45.2%) (87.7%) (23.4%) (40.9%) (58.7%) (115-154) (54.2%) (25-56) (2.2) (136-142) (1.09-1.80) (9.5-55.1) (0.030-0.143) (4.8) (915.0-2762.8) (126-186) (62.7%) (50.0%) (47.6%) (6-12) (18.8)
BNP responders (n¼356) 146 77 264 180 154 304 76 145 212 134 191 40 12.0 140 1.30 20.5 0.060 35.7 1743.4 156 218 183 166 8 48
(41.0%) (70-84) (74.1%) (50.6%) (43.2%) (85.4%) (21.3%) (40.7%) (59.6%) (117-156) (53.6%) (26-56) (2.2) (137-142) (1.08-1.69) (9.6-55.5) (0.030-0.129) (4.8) (959.5-2785.8) (131-194) (61.2%) (51.4%) (46.6%) (6-11) (13.5)
BNP non-responders (n¼140) 64 80 105 74 70 131 40 58 79 124 78 40 11.2 138 1.50 18.5 0.060 34.7 1363.8 130 93 65 70 8 45
(45.7%) (74-86) (75.0%) (52.9%) (50.0%) (93.6%) (28.6%) (41.4%) (56.4%) (110-146) (55.7%) (23-56) (1.9) (135-142) (1.16-2.02) (9.3-54.6) (0.030-0.188) (4.8) (796.9-2747.5) (110-163) (66.4%) (46.4%) (50.0%) (6-13) (32.1)
p-value 0.34 0.005 0.78 0.64 0.11 0.02 0.09 0.89 0.54 0.001 0.52 1.00 <0.001 <0.001 0.004 0.74 0.25 0.04 0.14 <0.001 0.30 0.30 0.52 0.15 <0.001
ACEi ¼ angiotensin converting enzyme inhibitors; ARB ¼ angiotensin receptor blockers; BNP ¼ B-type natriuretic peptide; IQR ¼ interquartile range; LVEF ¼ left ventricular ejection fraction; LVSD ¼ left ventricular systolic dysfunction; NYHA ¼ New York Heart Association; SBP ¼ systolic blood pressure; SD ¼ standard deviation.
Figure 1. Kaplan-Meier survival curves according to the 4 groups. Responders with admission BNP <2,000 pg/ml: n ¼ 204, 16 deaths; responders with admission BNP >2,000 pg/ml: n ¼ 152, 32 deaths; nonresponders with admission BNP <2,000 pg/ml: n ¼ 83, 16 deaths; and nonresponders with admission BNP >2,000 pg/ml: 57 patients, 29 deaths. Responders with low admission BNP had a better prognosis, and nonresponders with high admission BNP had worse outcomes. The remaining patients had intermediate outcomes.
on the day of discharge, if patients were discharged alive. BNP was measured by way of a chemiluminescent immunoassay using an Architect i2000 automated analyzer (Abbott Diagnostics, Santa Clara, California). Serum sodium, creatinine, urea, albumin, total cholesterol, and Creactive protein were measured using conventional methods with an Olympus AU5400 automated clinical chemistry analyzer (Olympus, Center Valley, Pennsylvania). Hemoglobin was assessed using an automated blood counter. Demographic characteristics, medications in use, and comorbidities were recorded. Diabetes mellitus was defined as a known previous diagnosis, current prescription of either an oral hypoglycemic agent or insulin, a fasting venous blood glucose level >126 mg/dl, or a random glucose level >200 mg/dl. Arterial hypertension was defined as the presence of previous diagnosis, record of antihypertensive pharmacologic treatment, or blood pressure >140/90 mmHg. Anemia was considered if the hemoglobin level was <13 g/dl in men and <12 g/dl in women. Renal dysfunction was considered when plasma creatinine was >1.5 mg/dl. Hyponatremia was considered when serum sodium was <135 mEq/L. To participate in this registry, all patients provided written informed consent, and the study protocol conformed to the ethical guidelines of the Declaration of Helsinki. Patients included in the registry were followed for 6 months; hospital registries and telephone contact with patients or their relatives were used to assess patients’ vital status. The objective under analysis was BNP response, defined as a >30% decrease in BNP during hospital admission. To further
Heart Failure/Natriuretic Peptide Nonresponse in Heart Failure Table 2 Variables possibly associated with natriuretic peptides nonresponse during hospitalization: univariate approach Variable
Male sex Age 75 years Hypertension Diabetes mellitus Atrial fibrillation Chronic Heart failure Heart Failure hospitalization previous year Ischemic aetiology NYHA at admission IV (vs II/III) Admission systolic blood pressure 115mmHg LVSD (vs HFpEF) Ejection fraction (per %) Anaemia Hyponatremia Renal dysfunction C-reactive protein (per mg/L) Troponin I (per ng/mL) Albumin (per g/L) B-type natriuretic peptide (per 100pg/mL) B-type natriuretic peptide >2000pg/mL Total cholesterol < 125mg/dL Previous ACEi or ARB Previous Beta blocker Previous Statin Length of hospital stay (per day)
OR (95% Confidence Interval)
p-value
1.21 1.72 0.94 1.05 1.38 2.65 1.47 1.03 0.88 1.75
(0.82-1.80) (1.12-2.65) (0.59-1.48) (0.86-1.27) (0.93-2.05) (1.16-6.04) (0.94-2.30) (0.69-1.53) (0.59-1.31) (1.12-2.74)
0.34 0.01 0.78 0.64 0.11 0.02 0.09 0.89 0.54 0.01
1.14 1.00 2.13 1.59 1.82 1.00 1.00 0.96 1.00 0.92 3.32 0.67 0.80 1.14 1.02
(0.76-1.70) (0.99-1.01) (1.38-3.28) (0.97-2.63) (1.22-2.71) (1.00-1.00) (0.91-1.11) (0.92-1.00) (0.99-1.01) (0.62-1.37) (2.15-5.13) (0.42-1.06) (0.50-1.25) (0.77-1.68) (0.99-1.05)
0.52 0.92 0.001 0.07 0.003 0.85 0.93 0.04 0.61 0.69 <0.001 0.09 0.32 0.52 0.22
ACEi ¼ angiotensin converting enzyme inhibitors; ARB ¼ angiotensin receptor blockers; BNP ¼ B-type natriuretic peptide; LVEF ¼ left ventricular ejection fraction; LVSD ¼ left ventricular systolic dysfunction; NYHA ¼ New York Heart Association.
Table 3 Predictors of natriuretic peptide nonresponse: multivariate logistic regression model Characteristics
Total cholesterol<125mg/dL Anaemia Renal dysfunction Albumin < 35 g/L Chronic Heart Failure Hyponatremia B-type natriuretic peptide >2000pg/mL Admission systolic blood pressure 115mmHg Age75years
OR (95% Confidence Interval) 2.55 1.41 1.57 1.09 1.82 1.46 0.68 1.39
(1.59-4.11) (0.87-2.28) (1.00-2.46) (0.70-1.70) (0.77-4.35) (0.84-2.54) (0.43-1.07) (0.85-2.27)
1.51 (0.94-2.44)
p-value
<0.001 0.17 0.05 0.69 0.17 0.18 0.09 0.19 0.09
conduct this retrospective subanalysis, we excluded all patients who died in the hospital and hence had no discharge BNP measurements and no possible calculation of BNP variation. Statistical Analysis: Percentage of BNP variation during admission was calculated as: % BNP variation ¼ [(admission
3
BNP discharge BNP)/admission BNP] 100. Responders were those patients in whom BNP decreased by >30%; the remaining patients were considered nonresponders. Responders and nonresponders were compared using chi-square tests for categorical variables and Student’s t tests and Mann-Whitney U tests for continuous variables normally and non-normally distributed, respectively. We calculated Spearman’s correlation coefficient between admission total cholesterol and BNP and between total cholesterol and BNP variation. Considering all-cause death as the event under analysis, a Cox regression analysis was performed to study the association of BNP nonresponse with prognosis. We built a multivariate model to assess the independent association of BNP response with better outcome. Patients were further cross-classified according to response (30% decrease during hospitalization) and admission BNP (cutoff 2,000 pg/ml) for additional prognostic information. Patients’ distribution was as follows: responders with low admission BNP, 204 patients; responders with high admission BNP, 152 patients; nonresponders with low admission BNP, 83 patients; and nonresponders with high admission BNP, 57 patients. The Kaplan-Meier method was used to display and compare survival curves according to the 4 groups created. A logistic regression analysis was performed to study potential predictors of NP nonresponse. A cutoff of 125 mg/dl was chosen for admission total cholesterol. A multivariate model was built. Analysis was then stratified according to admission BNP categories (cutoff 2,000 pg/ml) and also according to previous statin use. Interaction between statin use and admission cholesterol was formally tested. Results We studied 496 patients. Patients’ characteristics are listed in Table 1. During hospitalization, BNP levels decreased by >30% in 356 patients (71.8%), and the reminder 140 (28.2%) were considered nonresponders to HF treatment. Responders and nonresponders were compared (see Table 1). Nonresponders were older and more often had chronic HF; they were also admitted with lower systolic blood pressure. They had lower admission sodium, albumin, and hemoglobin levels and higher creatinine levels. Admission total cholesterol levels were also lower in nonresponders. Groups were similar concerning previous medication, admission BNP, and length of hospital stay. Six-month all-cause death occurred in 93 patients. Nonresponders had a multivariate-adjusted hazard ratio of 6-month death of 2.31 (95% confidence interval [CI] 1.48 to 3.61, p <0.001; adjustments to admission total cholesterol, hemoglobin, plasma creatinine, and albumin; admission BNP and admission systolic blood pressure; age and previous prognostic modifying therapy use). Nonresponse and higher admission BNP were the strongest independent predictors of worse outcome. The hazard ratio of death for admission BNP >2,000 pg/dl was 2.67 (95% CI 1.70 to 4.20). A nonsignificant trend toward higher all-cause mortality was seen in patients with admission cholesterol <125 mg/dl, with a hazard ratio of 1.42 (95% CI 0.92 to 2.22, p ¼ 0.12). When patients were cross-classified according to response and admission BNP, prognostic information was
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much increased. Among patients admitted with BNP levels <2,000 pg/ml, those who responded (n ¼ 204) had a 7.8% death rate and those not responding a 19.3% death rate. Among patients with higher admission BNP levels, nonresponders had a 50.9% death rate and responders a 21.1% death rate. Figure 1 shows the Kaplan-Meier survival curves according to these groups. Table 2 lists possible nonresponse predictors in a univariate approach. Admission BNP was not a predictor of response. The multivariate logistic regression model built for the identification of independent predictors of nonresponse in listed in Table 3. The only identified independent predictor of nonresponse was a low admission total cholesterol level (cutoff 125 mg/dl). Patients with higher admission BNP had lower total cholesterol levels: 141 mg/dl (118 to 170) in patients with admission BNP levels >2,000 pg/ml versus 155 mg/dl (130 to 196) in those with admission BNP levels <2,000 pg/ml. There was a weak negative correlation between admission BNP and total cholesterol: r ¼ 0.157 (p <0.001). Nonresponders had significantly lower cholesterol levels: 130 mg/dl (110 to 163) versus 156 mg/dl (131 to 194) in responders (p <0.001). There was a moderately strong and positive correlation between BNP variation and admission total cholesterol: r ¼ 0.308 (p <0.001). When patients were grouped according to admission BNP categories, a low admission total cholesterol level remained the only independent predictor of non-response, with an odds ratio of 2.18 (95% CI 1.13 to 4.22, p ¼ 0.02) for patients with admission BNP levels <2,000 pg/ml and an odds ratio of 3.78 (95% CI 1.79 to 7.95, p <0.001) for those with admission BNP levels >2,000 pg/ml. When analysis was stratified according to previous statin therapy, the power of a low admission cholesterol level in the prediction of NP nonresponse was observed in patients receiving and not receiving statins. Again, the predictive power was independent of other covariates: the odds ratio of BNP nonresponse was 2.91 (95% CI 1.37 to 6.17, p ¼ 0.005) for patients with intrinsically low cholesterol levels and 2.38 (95% CI 1.22 to 4.63, p ¼ 0.01) for those with statin-induced low cholesterol levels. There was no interaction between previous statin therapy and low admission cholesterol level. Discussion In 496 patients with acute HF, we reproduced the wellknown association of NP nonresponse with worse outcome. In our study population, nonresponders had a more than twofold higher risk for all-cause death at 6 months. This association with ominous prognosis was strong and independent of other prognostic predictors. Higher admission BNP and BNP nonresponse were the strongest independent predictors of all-cause death. As far as an extensive review of the published research could retrieve, predictors of NP nonresponse have never been specifically studied. The characterization of the nonresponder HF population as well as knowledge of predictors of nonresponse would help in the earlier identification (at admission) of the subgroup of patients with the most dismal outcomes in whom additional effort or the development of novel strategies should be investigated. The success of
NP-tailored therapy is far from agreed upon, and this is possibly due to incorrect selection of the target population in which it should be applied. In our acute HF population, the only independent predictor of nonresponse was low admission total cholesterol (<125 mg/dl). An admission total cholesterol level <125 mg/dl was associated with a >2.5fold higher rate of BNP nonresponse. This remained valid no matter the admission BNP. The ability of a low admission cholesterol level to predict BNP nonresponse was also valid for patients with intrinsically low cholesterol and those with statin-induced low cholesterol. Hypercholesterolemia is a cardiovascular risk factor that is associated with plaque formation, atherosclerosis, and morbidity and mortality in patients with coronary heart disease.14,15 In HF, a reverse epidemiologic phenomenon has been suggested: higher cholesterol confers a survival advantage and decreased cholesterol predicts an adverse prognosis.16e19 Although most studies have observed this association, some did not reproduce it.20,21 It is still a matter of debate whether cholesterol has a direct protective effect in HF or if it is merely an innocent bystander. A direct protective effect could derive from the ability of lipoproteins to bind bacterial lipopolysaccharide and downregulate the HF inflammatory response.22,23 Alternatively, cholesterol may not have any causal effect and may simply be a marker of undernutrition, cachexia, and more severe or advanced HF.21,24 In our study, total cholesterol was not a mortality predictor, but it was an independent predictor of nonresponse. Patients with higher BNP levels had significantly lower cholesterol levels, and nonresponders also had significantly lower cholesterol levels. We reported a weak, although significant, negative correlation between admission cholesterol and admission BNP and a moderately strong and positive correlation between BNP variation and admission cholesterol. A negative correlation between total cholesterol and BNP has already been suggested in a very small study in patients without HF.25 A correlation with variation in BNP has never been reported. The lipolytic effect of BNP is well established.26e29 An effect on cholesterol synthesis inhibition in adrenocortical cells has been suggested.30 Angiotensin II upregulates genes responsible for de novo cholesterol synthesis (including hydroxymethylglutaryl coenzyme A reductase), genes responsible for the expression of membrane receptors for cholesterol uptake, transporters into the mitochondria, and several genes involved in the steroid synthetic pathway. All these genes upregulated by angiotensin II are inhibited by cotreatment with BNP.30 These observations suggest that a chronic elevation of BNP can be responsible for lower cholesterol levels. The use of relative instead of absolute values of BNP respects the interindividual variability concerning neurohumoral activation. Each patient with HF establishes his or her own “natriuretostat,” and perhaps more important than the absolute value of BNP of the established “natriuretostat” is the patient’s ability to respond to HF therapies and the remaining magnitude of BNP variation still possible. According to this hypothesis, patients with higher downregulation of cholesterol biosynthesis would be those with the highest “natriuretostat” and the lowest magnitude of possible BNP variation around it. An admission total cholesterol level <125 mg/dl would predict inability to respond with BNP decrease irrespective of the
Heart Failure/Natriuretic Peptide Nonresponse in Heart Failure
admission BNP. In our population, admission BNP was not a predictor of response; only a low cholesterol level predicted nonresponse, and this is so probably because it reflects a consistently high BNP value on a patient-to-patient basis. The association of a low total cholesterol level with BNP nonresponse was valid for patients taking and not taking statins. This suggests that the suppressor effect of BNP on cholesterol synthesis may overcome that of statins. The inhibitory effect of BNP on cholesterol biosynthesis was observed only in the adrenocortical cells and has not been studied for the major cholesterol producer, the liver. The single-center nature of the study creates generalizability concerns. Despite the prospective recruitment as part of a registry, the retrospective nature of this specific analysis and the transversal data collection make the establishment of causality relations impossible. The fact that the physicians treating the patients with HF were aware of the ongoing registry may have created a bias. The nonindependent association with worse outcome but prediction of nonresponse, an established predictor of ominous outcome, favors total cholesterol as a marker of disease severity rather than causally implicated in disease progression. The relation between BNP and total cholesterol, and its fractions, should merit further study. Better knowledge and a full characterization of the nonresponder profile would help clinicians and investigators in the process of tailoring HF therapy.
8.
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11. 12. 13.
Disclosures The authors have no conflicts of interest to disclose.
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1. Eurlings LW, van Pol PE, Kok WE, van Wijk S, Lodewijks-van der Bolt C, Balk AH, Lok DJ, Crijns HJ, van Kraaij DJ, de Jonge N, Meeder JG, Prins M, Pinto YM. Management of chronic heart failure guided by individual N-terminal pro-B-type natriuretic peptide targets: results of the PRIMA (Can Pro-Brain-Natriuretic Peptide Guided Therapy of Chronic Heart Failure Improve Heart Failure Morbidity and Mortality?) study. J Am Coll Cardiol 2010;56:2090e2100. 2. Shah MR, Califf RM, Nohria A, Bhapkar M, Bowers M, Mancini DM, Fiuzat M, Stevenson LW, O’Connor CM. The STARBRITE trial: a randomized, pilot study of B-type natriuretic peptide-guided therapy in patients with advanced heart failure. J Card Fail 2011;17:613e621. 3. Persson H, Erntell H, Eriksson B, Johansson G, Swedberg K, Dahlström U. Improved pharmacological therapy of chronic heart failure in primary care: a randomized Study of NT-proBNP Guided Management of Heart FailureeSIGNAL-HF (Swedish Intervention study - Guidelines and NT-proBNP Analysis in Heart Failure). Eur J Heart Fail 2010;12:1300e1308. 4. Karlsrtöm P, Alehagen U, Boman K, Dahlström U; UPSTEP-Study Group. Brain natriuretic peptide-guided treatment does not improve morbidity and mortality in extensively treated patients with chronic heart failure: responders to treatment have a significantly better outcome. Eur J Heart Fail 2013;13:1096e1103. 5. Lainchbury JG, Troughton RW, Strangman KM, Frampton CM, Pilbrow A, Yandle TG, Hamid AK, Nicholls MG, Richards AM. N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNPAssisted Treatment to Lessen Serial Cardiac Readmissions and Death) trial. J Am Coll Cardiol 2009;55:53e60. 6. Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000;355:1126e1130. 7. Jourdain P, Jondeau G, Funck F, Gueffet P, Le Helloco A, Donal E, Aupetit JF, Aumont MC, Galinier M, Eicher JC, Cohen-Solal A, Juillière Y. Plasma brain natriuretic peptide-guided therapy to improve
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independent risk factor for mortality in chronic heart failure. Lancet 1997;349:1050e1053. 25. Takeuchi H, Sata M. The relationship among brain natriuretic peptide (BNP), cholesterol and lipoprotein. Heart Asia 2012;4:11e15. 26. Taegtmeyer H. Metabolic crosstalk in heart failure new roles for B-type natriuretic peptide. J Am Coll Cardiol 2011;58: 1126e1127. 27. Polak J, Kotrc M, Wedellova Z, Jabor A, Malek I, Kautzner J, Kazdova L, Melenovsky V. Lipolytic effects of B-type natriuretic peptide 1-32 in adipose tissue of heart failure patients compared with healthy controls. J Am Coll Cardiol 2011;58:1119e1125.
28. Lafontan M, Moro C, Berlan M, Crampes F, Sengenes C, Galitzky J. Control of lipolysis by natriuretic peptides and cyclic GMP. Trends Endocrinol Metab 2008;19:130e137. 29. Sengenès C, Berlan M, De Glisezinski I, Lafontan M, Galitzky J. Natriuretic peptides: a new lipolytic pathway in human adipocytes. FASEB J 2000;14:1345e1351. 30. Liang F, Kapoun AM, Lam A, Damm DL, Quan D, O’Connell M, Protter AA. B-Type natriuretic peptide inhibited angiotensin IIstimulated cholesterol biosynthesis, cholesterol transfer, and steroidogenesis in primary human adrenocortical cells. Endocrinology 2007;148:3722e3729.