NT-ProBNP
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, cardiac myocytes rapidly synthesize prepro-BNP, which consists of 134 amino acids. During secretion from myocytes, a 26 amino acid signal peptide is removed. In the bloodstream, pro-BNP is further cleaved into a 32 amino acid biologically active hormone called BNP and a biologically inactive 76 amino acid N-terminal fragment, called NT-proBNP.
BNP has 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.
Most physicians can identify patients with New York Heart Association Class III and IV heart failure. These patients exhibit classic symptoms including shortness of breath upon light activity, rales, pitting edema of lower extremities and distended jugular veins. Patients with Class I and II heart failure do not complain of physical limitations and lack obvious symptoms. Measurement of NT-ProBNP has the greatest value in detecting patients with early heart failure.
BNP is cleared from the circulation in three ways; renal filtration, catabolism of hormone bound to cell receptors and degradation by circulating proteases. NT-proBNP is cleared only by the kidneys. The circulating half-life of NT-proBNP is 120 minutes which is six times longer than BNP. Even though BNP and NT-proBNP are secreted in equimolar quantities, the circulating concentration of these two markers is significantly different, particularly in patients with heart failure and compromised renal function.
The cutoff for NT-proBNP in the acute setting 300 pg/mL for patients under the age of 75. A value less than 300 has a strong negative predictive value for ruling out heart failure. The rule-out cutoff value for patients aged 75 or older is 450 pg/mL.
The grey zone for accepted cutoffs where heart failure is possible is 300-450 pg/mL for patients <50 years of age, 300-900 for patients 50 to 74 years of age, and 450-1800 pg/mL for patients 75 years of age or older.
If NT-proBNP is above these cut points, physicians should calculate the PRIDE score which includes:
- Age adjusted elevated NT-proBNP cutoffs (4 points
- Intersititial edema on chest xray (2 points)
- Orthopnea (2 points)
- Lack of fever (2 points)
- Current loop diuretic use (1 point)
- Age >75 years (1 point)
- Rales (1 point)
- Lack of cough (1 point)
Heart failure is highly unlikely if NT-proBNP is below the age adjusted cutoff and/or the PRIDE score is <7. If the PRIDE score is 7 or above, heart failure is likely. If NT-proBNP is above the age adjusted cutoff and the PRIDE score is 7 or above, heart failure is likely. Heart failure is likely when NT-proBNP is >10,000 pg/mL.
The rule-in cutoffs for heart failure for NT-proBNP is >450 pg/mL for patients <50 years of age, >900 pg/mL for patients 50 to 74 years, and >1,800 pg/mL for patients 75 years and older.
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, pericarditis, acute coronary syndrome, congenital heart disease, pulmonary hypertension, pulmonary embolism, severe anemia, and sepsis. They are also elevated after cardiac surgery and cardioversion.
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 assays have not been standardized and assays from different manufacturers give significantly different results. NT-proBNP assays have stricter licensing requirements including use of the same antibodies. NT-proBNP results from different instruments are much more commutable. No equation has been devised that reliably allows for the conversion of BNP to NT-proBNP levels or vice-versa.
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 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.
