Brain natriuretic peptide ( BNP ) : A diagnostic marker in congestive heart failure-induced acute dyspnea

Department of Biochemistry, Maharishi Markandeshwar Institute of Medical Science & Research, Mullana, Ambala, Haryana, India Postgraduate, Department of Biochemistry, MMIMSR, Mullana, Haryana, India Assistant Professor, Department of Internal Medicine, MMIMSR, Mullana, Haryana, India Associate Professor, Department of Biochemistry, MMIMSR, Mullana, Haryana, India Assistant Professor, Department of Biochemistry, MMIMSR, Mullana, Haryana, India


INTRODUCTION
Heart failure (HF) is a clinical syndrome that occurs in patients who because of an inherited or acquired abnormality of cardiac structure and/or function develop a constellation of clinical symptoms (dyspnea and fatigue) and signs (edema and rales) that lead to frequent hospitalizations, a poor quality of life, and a shortened life expectancy. 1 Acute dyspnea is a common clinical finding with which the patient is admitted in the emergency department.A rapid and accurate investigation of acute dyspnea is vital since treatment of dyspnea can differ markedly depending on the initial clinical impression.However, the rapid and accurate differentiation of heart failure from other causes of dyspnea remains a clinical challenge.After evaluating patient's symptoms, conducting a physical examination, and performing electrocardiography (ECG) and chest radiography, the clinician is often left with considerable diagnostic uncertainty, which results in misdiagnosis and delays the initiation of appropriate therapy.Distinguishing between cardiac and non-cardiac causes of dyspnea is often challenging.Therefore, an assay with high sensitivity and high negative predictive value would be useful both in detecting dyspnea due to heart failure and in ruling out the diagnosis in patients with confounding co-morbid conditions. 2 A definitive congestive heart failure (CHF) diagnosis is often based on right heart catheterization or indirect measurement of ejection fraction by means of radionuclide scanning or echocardiography.Lack of immediate availability and high cost make these studies prohibitive as emergency department screening tests.As a result, an emergency diagnosis of CHF is often based on history and physical examination findings along with results of ancillary tests, such as chest radiography and ECG. 3 Therefore, a blood test that could rapidly and accurately confirm or exclude the diagnosis of CHF in the urgent care setting would be a valuable clinical tool.

NATRIURETIC PEPTIDES
Heart is an endocrine organ which secretes natriuretic peptides (Table 1). 4,5The natriuretic peptide family consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and three other structurally similar peptides: C-type natriuretic peptide (CNP) mostly of central nervous system and endothelial origin, urodilatin from the kidney and dendroaspis natriuretic peptide (DNP), which is of unknown significance. 6Since, these peptides are secreted in response to haemodynamic stress, they are promising markers of myocardial dysfunction and heart failure.
The main source of BNP is the ventricles of the heart, although it can also be demonstrated in the atria of the failing heart.BNP is synthesized in bursts and is released predominantly in response to stretching of the ventricular wall and volume overload.The biologic actions of BNP include vasodilatation, diuresis, natriuresis and inhibiting or antagonizing the actions of the renin-angiotensinaldosterone system, the sympathetic nervous system, arginine vasopressin and endothelin. 7Elevation of plasma BNP is one of the characteristics of patients with or at risk of diastolic heart failure among subjects with preserved left ventricular systolic function. 8Hence, the present study was undertaken to study the levels of BNP and to assess its diagnostic accuracy in CHF.

MATERIALS AND METHODS
This cross-sectional study was conducted in the Department of Biochemistry in collaboration with the Department of Internal Medicine of Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana, Ambala (Haryana).100 patients who were admitted in the ED with complaint of acute dyspnea from May 2011 to April 2012 were included in the study.
INCLUSION CRITERIA: Acute shortness of breath or dyspnea was defined as an abnormally uncomfortable awareness of breathing of less than 7 days duration.Those patients primarily presenting with acute shortness of breath (NYHA class III-IV) constituted the study group.
EXCLUSION CRITERIA: Patients with history of renal disease (serum creatinine >2.8 mg/dl), cirrhosis with ascitis, thyroid dysfunction, trauma chest wall, acute bronchial asthma, pneumonia, acute myocardial infarction, unstable angina and on chronic use of β-blockers, diuretics and digoxin, angiotensin-converting enzyme inhibitors.

CATEGORIZATION OF PATIENTS:
Those patients fulfilling the Framingham's criteria 9 (Table 2) were classified as having dyspnoea due to congestive heart failure (CHF) and those not meeting the criteria, as dyspnea not due to CHF.

SERUM BNP ASSAY:
After taking informed and written consent, 10 ml of blood sample was withdrawn from a peripheral vein by a plastic disposable syringe and collected in an air tight lavender top EDTA (ethylenediamino-tetra-acetic acid) plastic tube.The sample was centrifuged and BNP was assayed by chemiluminescence method. 10CNP is to stimulate long bone growth.

Major criteria
Minor criteria • Paroxysmal nocturnal dyspnea.
• Decreased vital capacity by 1/3 from maximum value recorded.• Central venous pressure ≥16 cm of H 2 O.
• Hepatojugular reflux.• Pulmonary oedema, visceral congestion, or cardiomegaly at autopsy.• Weight loss ≥4.5 kg in 5 days in response to treatment of congestive heart failure.

STATISTICAL ANALYSIS:
The data obtained was compiled and analyzed using Epi-info version 6.0.Diagnostic accuracy of BNP was evaluated by calculating sensitivity, specificity, positive predictive value and negative predictive value with 95% confidence intervals.

RESULTS
The study sample comprised of 100 patients (55 males and 45 females), out of which 60 were diagnosed as having CHF and 40 as no CHF where final diagnosis was supported by echocardiography.Serum BNP was more than 100 pg/ml in 54 patients with CHF and 8 patients without CHF and it was less than 100 pg/ml in 6 patients with CHF and 32 patients without CHF (Table 3).Higher mean BNP levels were observed with advancing age particularly in patients with CHF with highest mean BNP levels of 770.02 pg/ml in age group of more than 75 years in males and 706 pg/ml in age group of 66-75 years in females.However, lower BNP levels were observed in patients without CHF with lowest mean BNP levels of 51.05 pg/ml in age group of 56-65 years in males, whereas 63.06 pg/ml in age group of 15-25 years in females (Table 4, Figures 1, 2).It was also observed that out of 60 patients diagnosed to have CHF, majority had BNP levels more than 400 pg/ml (Table 5).

DISCUSSION
In the present study, 100 patients of different age groups were studied whose predominant symptom was dyspnea of acute onset (<7 days).Out of 100 patients, 55% were males and 45% were females.Patients of dyspnea were clinically evaluated which included complete history and examination, ECG and X-ray chest.Subsequently, patients were divided into two groups namely CHF group and No CHF group.Out of 100 patients, 47 were diagnosed to have CHF and 53 were not having CHF.Cut off of <100 pg/ml BNP levels was taken to exclude heart failure.It was observed that according to BNP levels alone 62 patients had heart failure (BNP levels of >100 pg/ml) and 38 patients had dyspnea not due to heart failure (BNP levels < 100 pg/ml.).In this study, the final diagnosis of CHF was made in 60 patients and 40 patients were included in No-CHF group (those  Furthermore, it was seen that 18 patients had BNP levels of more than 700 pg/ml at the time of admission.These patients had severe heart failure and majority had markedly reduced ejection fraction.Out of these, 8 died within 7 days of hospital stay which indicates the correlation of BNP levels with severity of CHF and also its prognostic significance.Martin and Ricou 12 also reported that raised BNP has a prognostic value to predict mortality after CHF.

CONCLUSION
There is strong and convincing evidence that BNP is a reliable and useful biomarker in acute dyspnea due to CHF and has a diagnostic as well as prognostic value.Used in conjunction with other clinical information, rapid measurement of BNP may reduce the total treatment cost of patients.Due to its prognostic implication it is recommended that BNP should be measured in all the patients with clinical signs of CHF even if the diagnosis is apparent.A careful history and examination of the patient and a systematic search for complicating factors is necessary for the appropriate analysis and the correct use of these biomarkers.