Natriuretic Peptides—Relevance in Cardiovascular Disease

THE FAMILY of natriuretic peptides, which includes atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), has a regulatory and modulatory role in the cardiovascular system.^{1 - 2} ANP and BNP are circulating cardiac hormones. ANP is synthesized by myocytes mainly in the atria and stored in granules. BNP, also known as brain natriuretic peptide because it was first isolated from porcine brain, is synthesized primarily by cardiac myocytes in the ventricles and is not stored to the same extent as ANP. The nucleic acid sequence of the BNP gene contains the destabilizing sequence TATTTAT, which suggests that the turnover of BNP messenger RNA (mRNA) is high and that BNP is synthesized in bursts. In response to stretching of the right atrium by increased venous pressure, stored ANP is immediately released from atrial granules, whereas an increase in BNP secretion is preceded by an increase in mRNA.³ Thus, intravenous saline loading increases plasma ANP acutely, but there is no corresponding immediate increase in plasma BNP.⁴ In contrast, the increase in intravascular volume from dietary salt loading results in the expected increase in BNP.⁴ Similarly, a change in a patient's pacemaker mode from atrial to ventricular pacing leading to uncoordinated atrial contractions and high pressure waves causes a greater acute increase in plasma ANP than BNP.⁵ It therefore appears that BNP level reflects long-term intravascular volume status rather than momentary volume. Moreover, BNP is more stable than ANP in plasma and has a longer half-life,⁶ which may be attributable to its lesser affinity for clearance receptors. CNP is synthesized in the endothelium and has vasodilatory and antiproliferative effects on vascular smooth muscle. It has a local action in the blood vessels or within the organ where it is produced.

The natriuretic peptides are cleared from the circulation by at least 2 mechanisms. They bind to widely distributed natriuretic peptide clearance receptors (NPR-Cs) on endothelial cells and are then internalized and degraded.⁷ They are also metabolized by neutral endopeptidases that are widely distributed on cells of various tissues.²

Intravenous infusion of ANP or BNP has a potent natriuretic and diuretic effect in healthy subjects, and infusions of supraphysiological concentrations of these peptides also show some hypotensive effect and suppression of the renin-angiotensin-aldosterone system.^{6 ,8 - 9} The effects of ANP and BNP seem to be additive, which may be because ANP and BNP share a common receptor (NPR-A).⁶ Activation of this receptor leads to formation of cyclic guanosine monophosphate (cGMP), the second messenger mediating the effects of the natriuretic peptides.

Plasma ANP and BNP levels are markedly increased in congestive heart failure, the magnitude of increase being related to the degree of heart failure.² Because their actions include vasodilation, natriuresis, and suppression of the renin-angiotensin-aldosterone system, ANP and BNP may be endogenous hormones counteracting the development of heart failure. The physiological effects of exogenous ANP are blunted in patients with congestive heart failure compared with its effects in normal subjects.⁹ Proposed explanations for this resistance include receptor down-regulation and increased cGMP phosphodiesterase activity.² In contrast, BNP infused intravenously in patients with chronic congestive heart failure leads to a dose-dependent natriuretic response, a decrease in pulmonary capillary wedge pressure, and an increase in cardiac output.¹⁰

Plasma BNP level may be useful as an indicator of left ventricular diastolic and systolic function for screening, diagnosis, clinical management, and prognostic assessment. BNP levels can be readily measured by radioimmunoassay and the results available within 3 days at a cost similar to that of other hormone assays. However, BNP assays are currently available only in research laboratories.

Plasma BNP level correlates with pulmonary capillary wedge pressure and inversely with ejection fraction.^{11 - 12} Measurement of BNP level may be useful for detecting asymptomatic left ventricular systolic dysfunction and identifying patients with suspected heart failure who need further diagnostic evaluation, especially when echocardiography is not readily available, or for supplementing echocardiography in nonechogenic patients. In a community-based study,¹³ 1653 subjects between 25 and 74 years old randomly selected from patient lists of family physicians underwent echocardiography and electrocardiography. A BNP level of 5.2 pmol/L (17.9 pg/mL) or greater had a sensitivity of 76%, a specificity of 87%, and a negative predictive value of 97.5% for left ventricular systolic dysfunction. The positive predictive value was only 16% because the prevalence of left ventricular systolic dysfunction was only 3% in the unselected study population. A subgroup analysis of subjects aged 55 years or older with a history of ischemic heart disease increased the positive predictive value to 32%. In a study of 122 consecutive patients with suspected new heart failure referred by general practitioners to a rapid-access heart failure clinic for diagnostic confirmation, 35 (29%) of the referred patients met the case definition for new heart failure based on assessment by a cardiologist, chest radiography, and transthoracic echocardiography.¹⁴ A BNP level of 22.2 pmol/L (76.4 pg/mL) or higher, chosen for its negative predictive value of 98% for heart failure, had a sensitivity of 97%, a specificity of 84%, and a positive predictive value of 70%. BNP level may also be useful for distinguishing dyspnea due to heart failure from that of chronic airways obstruction, even though the latter can also cause a moderate increase in BNP level.¹² Serial measurements of BNP level may be useful in monitoring the progress of chronic heart failure and reduce the need for repeated echocardiography.

Plasma BNP levels are also elevated in patients with left ventricular diastolic dysfunction and left ventricular hypertrophy. In a study of patients with suspected heart disease,¹⁵ an increased BNP concentration (>15.7 pmol/L [54.0 pg/mL]) was found to have a sensitivity of 85% and a specificity of 74% for the detection of left diastolic dysfunction and a sensitivity of 81% and a specificity of 90% for echocardiographic left ventricular hypertrophy. In patients with hypertension, BNP levels were found to correlate with left ventricular mass¹⁶ and therefore may be useful in these patients for the detection of left ventricular hypertrophy, which is associated with increased cardiovascular morbidity and mortality.

After a myocardial infarction, plasma BNP level increases and peaks at about 21 hours.¹⁷ The rise in BNP level is more marked than the rise in ANP level and correlates with peak creatinine kinase concentrations and infarct size.¹⁷ BNP level in the acute phase of myocardial infarction has been shown to be an independent predictor of long-term survival after myocardial infarction.¹⁸ It may also be useful in identifying postinfarct patients with left ventricular systolic dysfunction likely to benefit from treatment with an angiotensin-converting enzyme inhibitor. In a cross-sectional study of left ventricular function in patients 2 to 8 days after an acute myocardial infarction, a BNP level higher than 15 pmol/L (52 pg/mL) had an 84% sensitivity and a 62% specificity to detect a left ventricular ejection fraction of 40% or less.¹¹

Plasma BNP level may also be a predictor of mortality. In a prospective study of 85 patients with chronic congestive heart failure followed up for 2 years, a high plasma BNP level was an independent predictor of mortality from a cardiac cause.¹⁹ In a cohort of 541 85-year-old subjects from a general population, BNP levels were significantly correlated with 5-year all-cause mortality, even in subjects without overt cardiovascular diseases at recruitment.²⁰ These intriguing studies suggest that individuals with a high plasma BNP level should be carefully investigated for cardiovascular disease.

The difficulty with using plasma BNP level as a guide to diagnosis or as a prognostic indicator is that moderate elevations lack specificity. Myocardial infarction, ventricular hypertrophy, cardiomyopathy, cardiac failure, renal failure, and chronic obstructive pulmonary disease can all increase the level of BNP. A high BNP level calls for further investigation; a normal or low BNP level has excellent negative predictive value for heart failure and may obviate the need for costly studies such as echocardiography.

Because ANP and BNP are peptides, exogenous ANP and BNP are expensive and unstable and cannot be given orally. Intravenous preparations of BNP are available for use in clinical research, and short-term infusion of BNP has been shown to increase cardiac output in patients with severe chronic congestive heart failure.¹⁰ Oral neutral endopeptidase inhibitors increase endogenous ANP and BNP levels by decreasing their degradation and may be a practical means of exploiting the therapeutic potential of these peptides.^{2 ,4} Although endopeptidase inhibitors lower pulmonary capillary wedge pressure,²¹ it remains to be shown whether they are useful in the long-term treatment of heart failure, especially since short-term hemodynamic response may not translate to long-term survival. The effect of the concomitant decrease in degradation of other peptides such as CNP, angiotensin II, and endothelin as a result of neutral endopeptidase inhibition also needs to be assessed.² Thus, therapeutic manipulation of plasma ANP and BNP concentrations for the treatment of patients with heart failure cannot be recommended as yet, but holds promise.

Plasma ANP and BNP concentrations are elevated in essential hypertension and correlate with blood pressure.² The efficacy of neutral endopeptidase inhibitors for lowering blood pressure has been studied in patients with hypertension, but the results of these studies are discrepant.^{22 - 23} Drugs of this class require further development before they can be used as antihypertensive agents.

An elevated BNP level is a sensitive marker of left ventricular dysfunction but not specific for any disease state. As an inexpensive blood test, determination of the BNP level may be useful for screening for cardiovascular disease, identifying patients with suspected heart failure who require further investigation, managing those with known cardiovascular disease, and as a prognostic indicator. Drugs that augment the endogenous levels of ANP and BNP are now being evaluated for the treatment of heart failure and hypertension.