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B-type natriuretic peptide, which is also called brain-type natriuretic peptide (BNP), was first isolated from brain, but later discovered to be a cardiac hormone. Ventricular cardiac myocytes constitute the major source of BNP related peptides. Only small amounts of BNP are stored within the cytoplasmic granules of myocytes. Following myocardial wall stress, there is rapid gene expression and de novo synthesis of a natriuretic prohormone. Upon release into the circulation this prohormone is cleaved into the biologically active BNP, which represents the C-terminal fragment, and the biologically inactive N-terminal fragment (NT-proBNP).

Natriuretic peptides have numerous physiological effects including natriuresis/diuresis, peripheral vasodilatation, and inhibition of the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system (SNS). Secretion of natriuretic peptides may limit the degree of vasoconstriction, sodium retention and pathologic remodeling that occurs in patients with heart failure.

The circulating half-life of NT-proBNP is 120 minutes which is six times longer than BNP. In healthy individuals, plasma concentrations of BNP and NT-proBNP are similar. However, in patients with left ventricular dysfunction, plasma NT-proBNP is approximately four to six times higher than BNP, even though both molecules are secreted in equimolar proportions. Most of our knowledge regarding the value and performance of BNP and NT-proBNP testing has been derived from studies of patients presenting with acute dyspnea to the emergency department. In general, levels of BNP and NT-proBNP are directly related to the severity of heart failure symptoms and to the severity of the cardiac abnormality.

Numerous commercial assays for BNP and NT-proBNP are available. BNP values obtained with different methods are not comparable and no equation has been devised that reliably allows for the conversion of BNP to NT-proBNP levels or vice-versa. BNP has classically had two cutoff points; a lower one with a high negative predictive value to reliably exclude heart failure as the cause of dyspnea and a second higher one with a positive predictive value to rule in heart failure as the cause of dyspnea. The cutpoints for BNP have been 100 and 400 pg/mL irrespective of age.

The International Collaborative for NT-proBNP recommends age-stratified cutoff points for NT-proBNP (Am Heart J. 2005;149:744–50). For patients <50, 50 to 75, and >75 years of age, the optimal plasma NT-proBNP cutoffs for diagnosing heart failure are 450 pg/mL, 900 pg/mL, and 1800 pg/mL respectively. Overall, these cutoffs yield a sensitivity and specificity of 90 and 84 percent, respectively. Across the entire population, NT-proBNP levels below 300 pg/mL are optimal for excluding a diagnosis of heart failure, with a negative predictive value of 98 percent.

Variability in peptide measurements must be considered when interpreting serial NT-proBNP results. Intraindividual biologic variation as well as analytic variation contribute to total variation. Total variability determines the percentage change needed to demonstrate a significant difference in results over time. An 11% decrease in NT-proBNP is considered to be a significant within day change, a 25% decrease is considered to be a significant day to day change and a 47% decline is required for a significant week to week change (AH Wu. Am Heart J 2006;152:828). During hospitalization, only two NT-proBNP levels are recommended; an initial value and a pre-discharge value to assess response to therapy. Plasma BNP cannot be measured during administration of nesiritide (BNP 1-32), since nesiritide is detected as an increase in plasma BNP concentration. In contrast, the NT-proBNP assay does not detect nesiritide and can be used to monitor response to this therapy.

BNP is cleared from plasma by binding to the natriuretic peptide receptor and by proteolysis. In contrast, NT-proBNP is mainly cleared by renal excretion. Since NT-proBNP is cleared by the kidney, plasma concentration is often elevated in patients with renal insufficiency alone, whether or not they have clinically diagnosed heart failure. Insufficient data is available to establish clear cut-off values for NT-proBNP in patients with renal failure. One study has suggested that a cutoff of at least 1200 pg/mL should be used to diagnose heart failure in patients 50 t0 75 years of age with a GFR between 30 and 60 mL/min per 1.73 m2 (J Am Coll Cardiol 2006;47:91). NT-proBNP in unreliable in patients with GFR <30.

Both BNP and NT-proBNP are elevated in many disorders besides heart failure and renal failure. Examples include left and right ventricular hypertrophy, valvulopathy, atrial fibrillation, myocarditis, acute coronary syndrome, congenital heart disease, cardiac surgery, pulmonary hypertension, pulmonary embolism, severe anemia, and sepsis. Falsely negative results may occur in patients with right heart failure, mild heart failure and chronically treated heart failure. Obesity causes down regulation of the natriuretic peptide system, resulting in lower BNP and NT-proBNP levels.

BNP is stable in whole blood with EDTA at room temperature for only 24 hours, whereas NT-proBNP is stable for at least 72 hours and requires no additives. The increased stability of NT-proBNP makes it more suitable for outpatient testing. Specimen requirement for NT-proBNP is a green top tube of blood.

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