Are BNP plasma levels useful in heart failure diagnosis each time? A dyspneic patient with anasarca

Case Report

Are BNP plasma levels useful in heart failure diagnosis each time? A dyspneic patient with anasarca


Decompensated heart failure (DHF) is one of the most common causes of hospital admission linked to alterations in the body fluid content due to hemodynamic, cardiorenal, and neurohormonal changes. An accurate diagnosis of DHF is a challenge because signs/symptoms are sometimes nonspe- cific given the frequency of comorbidities; thus, B-type Natriuretic Peptide is associated with high probability of cardiogenic cause. However, the current methods to diagnose dyspnea due to DHF had to date many limitations; on the other hand, an early differentiation of cardiac cause from others may permit the institution of the appropriate treatment with improvement in clinical outcome. We describe a case of BNP pitfall in DHF diagnosis in a 58- year-old dyspneic man with history of rheumatic heart disease admitted with signs of severe fluid overload but normal BNP levels in the emergency department. The correct diagnosis and subsequent treatment were premised on medical history, clinical assessment, and body hydration estimation by bioelectrical impedance analysis. Our suspi- cion was confirmed by transthoracic echocardiography. This report teaches that DHF diagnosis based on BNP testing could place the patient at risk for misdiagnosis and that Neurohormonal activation may fall in such cases and contributes to fluid accumulation. We discuss the probable causes of this pitfall and suggest the obvious need to optimize the in-hospital management of DHF, integrating medical history, physical examination, neurohormonal markers, and instrumental data comprising new attractive diagnostic methods such as bioelectrical impedance analysis. We also propose the need for researchers to investigate the issues concerning the gray zone of the pathophysiology of DHF and BNP physiology.

Despite advances in diagnosis and treatment, heart failure remains a growing medical problem associated with major hospitalization, significant hospital mortality, and early readmission rates. The diagnostic assessment of dyspnea and edema, the most common clinical presentations of this syndrome, may be a challenge especially in patients presenting comorbidities, such as pulmonary disease, renal

insufficiency, and obesity [1]. Given that the signs and symptoms of decompensated HF (DHF) are heterogeneous, physicians may experience some difficulties in making a differential diagnosis. In this clinical setting, Natriuretic peptides are widely used as the first-line diagnostic complement to clinical and radiographic data reflecting the severity of the disease [2,3]. Nevertheless, B-type natriuretic peptide is reported to be inconclusive at levels in the midrange, particularly for patients without history of HF [4]. European Society of Cardiology/European Society of Hypertension guidelines instead state that HF may be excluded when BNP levels are less than 100 pg/mL. The pathophysiology of DHF, like known, is linked to alterations in the body fluid content and distribution due to cardiorenal, hemodynamic, and neurohormonal dysfunctional processes. pulmonary congestion, resulting from elevated left ventric- ular (LV) filling pressures, is generally recognized as the most common clinical event requiring hospitalization and the main therapeutic target in HF [5]. Consequently, intravenous diuretics have a central role in the treatment of DHF by reducing volume overload and pulmonary capillary wedge pressure [6]. Furthermore, congestion remains frequently undiagnosed and not appropriately treated in a timely manner before or during hospitalization. This may be partially responsible for pathologic processes that lead to a progres- sion of disease and a worsened prognosis. For this motivation, a rapid diagnostic assessment of these patients is needed to start the appropriate and suitable medical treatment. Bioelectrical impedance analysis (BIA), a rapid, safe, noninvasive, inexpensive, and reproducible diagnostic tool, is helpful in detecting body fluid composition in liver, kidney, and heart diseases and is used by us [7-10] in clinical practice to estimate body hydration status and to monitor diuretic therapy in HF. We describe and discuss a case of DHF in a man in whom BNP serum levels were always in the reference range, misleading diagnosis.

A 58-year-old man, ex-smoker, with Metabolic syndrome (visceral obesity, body mass index [BMI] 38 kg/m2, hypocholesterolemia high-density lipoprotein, impaired fasting glucose) and history of rheumatic valvular heart disease and chronic atrial fibrillation, was admitted to our HF Unit at Biomedical Department of Internal and Specialty Medicine of Palermo for worsening of dyspnea, which was present after mild exertion, sometimes at rest, and during conversation (New York Heart Association functional class

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IV), and limb edema for 2 weeks. His medical history included also a tricuspid and mitral anuloplastic valve replacement when he was 17 years old, a mitral valvular prosthetic valve replacement when he was 53 years old, acute pancreatitis at 55 years old, and, from 2 ago a severe chronic hypochromic microcytic anemia attributed to myelodyspla- sia. He was never hospitalized for cardiac failure in the subsequent years after prosthetic valve replacement. On admission, he was on treatment with furosemide (50 mg/d),

Table 1 Laboratory data on hospital admission and discharge

Fig. 1 Signs of limb and scrotum edema on hospital admission

(A) and discharge (C) and particular of the “fovea” (B).

erythropoietin, canrenoate (50 mg/d), warfarin, and allopu- rinol. At hospital admission, he was dyspneic at exertion, systemic blood pressure was 110/70 mm/Hg, heart rate was

92 beats per minute, and clinical examination revealed marked signs of fluid overload with edema of the legs, scrotum, and abdomen. Body weight was 111 kg (Fig. 1). Electrocardiogram showed atrial fibrillation, incomplete left bundle block, and signs of LV overload. Chest radiograph and echotomography revealed, respectively, an ilar conges- tion with dilated cardiac silhouette, hepatosplenomegaly (with a congestive liver), bilateral pleural effusion, and mild ascites. laboratory examinations (Table 1) including arterial blood gas analysis, cardiac enzymes, blood cells count, D- dimer, C-reactive protein, Serum electrolytes, and renal and Hepatic function were within the reference range with the exception of hypoalbuminemia (2.5 mg/dL) and anemia (hemoglobin, 9.4 mg/dL). In the clinical suspicion of DHF, the rapid BNP testing was quickly required in the emergency department and resulted, surprisingly, in a very low value of

15.2 pg/mL (diagnostic cutoff is 100 pg/mL), which was confirmed many more times. Yet, 6 of the 15 diagnostic criteria of Framingham were fulfilled: orthopnea, cardiome- galy, limb edema, dyspnea at exertion, hepatomegaly, and pleural effusion. In the light of our preceding studies, to complete the diagnostic algorithm of HF before initiating treatment, the patient underwent assessment of body hydration with BIA using a tetrapolar plethysmograph. This testing showed parameters of resistance (270 ?) and




BNP (pg/ml)



Na (mEq/L)



Natriuria (mEq/24 h)



K (mEq/L)



Kaliuria (mEq/24 h)



Cl (mEq/L)



Hemoglobin (g/dL)



Hct (%)



Serum creatinine (mg/dL)



Blood urea (mg/dL)



MDRD (mL/[min 1.73 m2])



Cockroft-Gault (mL/[min 1.73 m2])



Albumin (g/dL)



Albuminuria (mEq/24 h)



Diuresis (mL/24 h)



SBP (mm Hg)



DBP (mm Hg)



HR (beat/min)



Rz (?)



Xc (?)



Rz/height (?/m)



Xc/height (?/m)



Weight (kg)



BMI (kg/m2)



reactance (15 ?) referable to anasarca. Fig. 3 shows position and trend of impedance vector on admission and during hospitalization until discharge after standardization of bioelectrical parameters for height according to R-Xc graph of Piccoli et al [8]. Furthermore, a transthoracic echocardi- ography was performed and revealed a heart globally dilated with a giant left atrium (134 cm2), moderate-severe tricuspid insufficiency, ejection fraction of 35%, and a normofunc- tional mitral prosthesis (Fig. 2). The determination of the plasma levels of renin and aldosterone showed a hyper- activation of this neurohormonal system. In consideration of anamnesis, physical examination, and instrumental data (chest x-ray, BIA, and echocardiography), the clinical suspicion of DHF was confirmed; and the patient began, for 13 days, a course of intravenous high doses of furosemide (125-250 mg BID) with small volumes of Hypertonic saline solutions, as previously described by us [11], associated to albumin supplementation. Patient experienced a rapid improvement of dyspnea at exertion with its clinical relief in 2 days. Moreover, diuresis rapidly improved (Fig. 4); and fluid accumulation progressively decreased significantly during hospitalization (Fig. 3). Furthermore, to guide medical therapy, body hydration was daily monitored with BIA that showed an improvement (increase) in bioelectrical parameters suggestive of the progressive normalization of body hydration state. The BNP plasma levels were also monitored during Intravenous treatment and did not show any significant changes. The BNP levels during hospitali- zation and at discharge were, respectively, 14.1 and 18.7 pg/ mL. During hospitalization, the patient was progressively well; and renal function and electrolytic balance were

Fig. 2 Transthoracic echocardiography (2-dimensional apical 4- chamber view) showing a dilated heart with a giant left atrium (134 cm2).

Fig. 3 R-Xc graph according to Piccoli finalized to estimate the hydration process [8]. Position and migration of patient’s impedance vector resulting from bioelectrical resistance and reactance (in ohms) on hospital admission (A) and at discharge (B).

preserved with a mild decline in calculated glomerular filtration rate related to drastic diuretic (Fig. 4). He was discharged after 17 in-hospital days, in eupneic state (New York Heart Association class II) and good general clinical health, without edema and pleural or Abdominal effusion, with a weight loss of 20 kg (final body weight of 91 kg; BMI, 91 kg/m2), and with a stable increase of diuresis in comparison with admission. Body hydration improved significantly at discharge (resistance, 414 ?; reactance, 32 ?) (Fig. 3). He left the hospital on treatment with furosemide 250 mg twice a day, warfarin, and fluid restriction of a maximum of 1 L/d. A short-term ambulatory follow-up was programmed at 2 weeks and 1 month after hospital discharge to closely monitor clinical picture, hemodynamic condition (with echocardiography), and hydration state (with BIA) and to tailor medical treatment with fluid restriction, oral diuretics, angiotensin-converting enzyme inhibitors, and sodium intake as described in previous works. During this follow-up, the patient was well, in stable hemodynamic status, diuresis, body hydration, and weight. No significant changes in clinical, laboratory, and hemodynamic para- meters were observed in this period.

The clinical diagnosis of DHF is frequently a challenge because signs and symptoms may be nonspecific and misleading [12]. In primary care, at least 25% to 60% of

Fig. 4 Changes of renal function parameters (blood urea, creatinine, calculated glomerular filtration rate), diuresis, BNP plasma levels, and body weight during hospitalization.

patients referred for evaluation of cardiac dysfunction because of clinical suspicion of HF fulfill the diagnosis [13]. Recently, BNP has entered with merit the diagnostic armamentarium of HF because of its high sensitivity and specificity. In fact, various studies had demonstrated the utility of this peptide as biomarker of fluid overload and ventricular filling pressure, and in diagnosing and stratifying outcome in HF. Synthesis and secretion of BNP are stimulated by increased atrial and particularly ventricular wall stress during volume and/or pressure overload. Its effects are improvement of diuresis, natriuresis, vasodilata- tion, and Renin-angiotensin-aldosterone system inhibition.

However, recent studies have also demonstrated a reduced neurohormonal activation in obese patients with

cardiac decompensation [14]. Whereas the studies have broadly suggested a plasma level of BNP of less than 100 pg/ mL for excluding the diagnosis of DHF and a value of greater than 400 to 500 pg/mL for predicting strongly this condition, an inverse relation between BNP levels and BMI was observed. The results from the Breathing Not Properly Multinational Study showed that BMI influences the selection of cut points for BNP in diagnosing Acute HF [15]. According to this work, a lower cut point (BNP

>=54 pg/mL) should be used in severely obese patients to preserve sensitivity and a higher cut point (BNP >=170 pg/

mL) could be used in lean patients to increase specificity. Recent clinical observations have also demonstrated that in patients with advanced disease, the plasma level of BNP may be low (b100 pg/mL) in 10% and associated with a poor outcome [16]. The decline of BNP in end-stage HF possibly reflects an exhaustion of the biosynthesis mechanism by myocardiocytes or a decreased clearance of natriuretic peptides [17]. In our patient with increased BMI, the BNP value was normal and decisively under the diagnostic cutoff for obese patients. Thus, the clinical history and presentation (Framingham criteria), bioimpedance measurement, and echocardiography were suggestive of the correct diagnosis of DHF and led to appropriate treatment. Assuming that BNP indirectly reflects LV filling pressures beyond global myocardial dysfunction, we observed the failure of BNP activation to predict this cardiac decompensation despite the documented activation of other neurohormones (renin and aldosterone) in this patient with a long history of heart valvular disease, a normal renal function, and progressive fluid overload within years. In our opinion, it is due to 4 likely motivations: myocardiocytic exhaustion in biosynthe- sis because of extreme cardiac dilatation and insufficiency; a paradox mechanism of BNP synthesis suppression to preserve the effective plasmatic volume in the advanced stage of disease; a genetic predisposition to secrete BNP; an increased clearance of the peptide; the elevated BMI. Few studies, as of now, support these hypotheses [14,17]; and such results do not sustain the theory that ventricular exhaustion with inability to synthesize and secrete natriuretic peptides is the mechanism underlying decompensation in advanced illness [18]. However, the described motivations, altogether or singularly, may elucidate the progressive and considerable accumulation of fluids during years (20 kg was lost at discharge) contributing to disease evolution. Thus, these facts confirm the difficulties in diagnosing HF on the basis of BNP determination. Another case is described in the literature about the limitations of BNP in DHF assessment [19]. Yet, it is the first report that describes normal plasma levels of BNP associated to symptomatic dilated heart disease and anasarca, suggesting that the test cannot replace or surpass the judgment of the clinician.

We further suppose that in such patient with HF and dilated heart, it is probably a progressive and chronic fluid accumulation that determines a remodeling in BNP secretion conducing to low plasma levels or, conversely, that a

decreased compensatory mechanism of BNP synthesis due to other conditions may lead to a reduced diuresis and a excessive fluid overload.

The more probable physiopathologic reason of the BNP pitfall in this patient is that the extreme dilatation of the heart with a progressive increasing of the telediastolic volume during the many years of illness led to a chronic decrease in the LV wall stretch with a consequent adaptative decline in BNP secretion, instituting a vicious circle of fluid accumu- lation. Furthermore, the increased BMI in this patient may contribute to the reduction of BNP levels; and the feasible mechanism is abundant clearance receptors expressed on adipocytes that participate in the removal of natriuretic peptide from circulation inducing salt and water retention [20]. For all of the preceding considerations, we suggest that BNP testing alone cannot always be used extensively in routine DHF assessment if not in conjunction with patients’ medical history and clinical picture, underlining the great importance of the clinical eye of the physician. In fact, laboratory tests cannot and should not be used as a substitute for a through clinical assessment by a competent health care provider, especially because the goal of treatment is to improve the symptoms experienced by the patient and not the values on a laboratory test.

Moreover, this clinical case challenges the usefulness of bedside BNP in intrahospital stratification of acute HF, in the decision-making process, and as a tool for “tailored therapy” [21].

In conclusion, because clinicians require the ability to discriminate early and timely cardiac dyspnea from other causes, our case suggests the need to optimize the systematic use of BNP in clinical practice, particularly in obese patients, focusing attention on clinical signs/symptoms and on complementary tests finalized to differentiate patients presenting with acute dyspnea. For this purpose, BIA may represent a useful and attractive adjunct in the in-hospital management of DHF, integrating BNP determination, physical examination, and instrumental data, and contribut- ing to the proper diagnosis and tailored treatment. This report is a paradigmatic case which underlines for clinicians an obvious need to standardize DHF management [1] and for researchers to investigate issues concerning the gray zone of the pathophysiology of DHF. Additional study is needed to define the role of routine BNP measurements in the diagnosis and management of HF. Attenuation mechanisms of the neurohormonal compensatory systems, in particular its genetic determinants, ought to be further investigated.

Gaspare Parrinello MD Daniele Torres MD Salvatore Paterna MD Caterina Trapanese MD Marina Pomilla MD Umberto Lupo MD Giuseppe Licata MD

Biomedical Department of Internal and Specialty Medicine (Di. Bi. M. I. S.), Heart Failure Unit

A.O.U.P. Policlinico Paolo Giaccone

University of Palermo

Palermo, Italy E-mail address: [email protected]



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