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OBJECTIVES:

At the end of this course the participant will be able to

1. Outline the Natriuretic Peptide system and its role in Heart Failure
2. Identify BNP as a uniquely valuable neurohormonal marker
3. Discuss BNP as a diagnostic tool in heart failure

INTRODUCTION:

Heart failure is the leading cause of hospital admission among patients over the age of 65 years and accounts for 3% of the total national health care budget (1).  Patients admitted with heart failure have significant hospital mortality and early readmission rates.  Heart failure is often difficult to diagnose.  The symptoms may be nonspecific, and physical findings are not sensitive enough to use as a basis for accurate diagnosis (2).

Congestive heart failure (CHF) is a debilitating disease often caused by a weakened heart muscle that is unable to pump enough oxygen-rich blood for the body. When the heart can’t pump enough blood, fluid accumulates in the lungs and the other areas of the body (peripheral edema).

Congestive heart failure can arise from many conditions. Chief among them are:

• Valvular heart disease from rheumatic fever or congenital defects.
• Weakened heart muscle from a heart attack or from high blood pressure (hypertension).
• Cardiomyopathy, a degeneration of the heart muscle linked to heredity, excessive alcohol intake and infections.

DISCUSSION:

CHF develops gradually over several months or years. There is no cure for many cases of CHF but it can be managed with proper therapy. Diagnosing individuals in the Emergency Room can be complicated when patients present with shortness of breath and an abnormal chest X-ray. Often the decision as to whether this is a result of pneumonia or CHF is a difficult one.

Until recently, there were no blood tests available for patients with heart failure. To provide cost-effective treatment for patients with CHF, rapid and accurate differentiation of congestive heart failure from other causes of dyspnea (shortness of breath) must be accomplished. In November 2000, the Food and Drug Administration approved the first assay for B-type natriuretic peptide (BNP) on a point of care testing platform. Availability of BNP testing will lead to more efficient management and therapy of heart failure patients (3).

BNP assay is a 15-minute blood test that is highly sensitive and fairly specific for diagnosing heart failure and is useful in evaluating suspected heart failure in outpatients and in emergency rooms. Other uses include screening for left ventricular dysfunction and predicting outcomes in patients with an established diagnosis of heart failure or myocardial infarction.  BNP, a cardiac neurohormone, was first discovered in the brain of pigs. In humans, the main source of BNP is the ventricles of the heart. BNP is secreted in response to increased ventricular volume and pressure. Circulating BNP levels increase in proportion to the severity of the disorder, and is detectable with minimal clinical symptoms. With a negative predictive value of greater than 95%, a normal BNP level can help exclude heart failure from other causes.

The natriuretic peptides, which include atrial natriuretic peptide (ANP) and BNP, help regulate blood pressure and fluid balance by counter balancing the renin angiotensin system. Whereas renin and angiotensin raise blood pressure, decrease urine output and cause vasoconstriction, the natriuretic peptides have the opposite effects. Both ANP and BNP increase excretion of sodium and water by increasing glomerular filtration and inhibiting renal sodium resorption (4). They also decrease secretion of aldosterone and renin and cause vasodilatation, reducing blood pressure and extracellular fluid volume.

B-type natriuretic peptide (BNP) is a 32 amino acid polypeptide containing a 17 amino acid ring structure common to all natriuretic peptides (5). Unlike A-type (ANP), whose major storage sites include both the atria and ventricles, the major source of plasma BNP is cardiac ventricles, suggesting that BNP may be a more sensitive and specific indicator of ventricular disorders than other natriuretic peptides (6). Patients with symptomatic left ventricular systolic dysfunction have increased BNP levels that correlate with New York Heart Association classification (Table 1). BNP is an independent, significant predictor of high left ventricular end-diastolic pressure in patients with CHF.

Although the New York Heart Association classification correlates with symptoms as well as mortality in patients with heart failure, the fact that such a subjective classification is still the major means used to describe the clinical condition of patients with heart failure underlies the need for more objective information. Because BNP levels correlate with elevated end-diastolic pressure and end-diastolic pressure correlates closely with the chief symptoms of CHF, it is not surprising that BNP correlates closely with the New York Heart Association’s classification.

The BNP assay became available only recently and clinical studies are gradually providing data needed to define its appropriate uses. In heart failure, BNP levels are proportional to illness severity and may be as much as 25 times higher than in people without heart failure (Table 2). The sensitivity and specificity of BNP as a test for heart failure depends on the upper limit of normal used (normal value 0-100 pg/ml). A lower point is more sensitive but less specific, whereas a higher point is less sensitive but more specific.

Serial BNP measurement can predict outcomes in patients hospitalized for decompensated heart failure. In one study, BNP levels increased in 52% of patients who died or required readmission within 30 days. In contrast, BNP levels declined in 84% of patients who had good outcomes. BNP measurements are also a good indicator of heart failure severity and prognosis in outpatients. In general, an elevated BNP concentration indicates a greater risk of death and morbidity for heart failure patients, independent of underlying coronary artery disease. In a study comparing normal subjects, patients with coronary artery disease, and patients with heart failure, coronary artery disease did not cause BNP elevation unless the patient had coexistent left ventricular dysfunction.

CASE STUDY (7):

A study was approved by the University of California Institutional Review Board and conducted at the San Diego Veteran’s Healthcare System in 1999. Two hundred consecutive patients referred for echocardiograpgy to evaluate Left Ventricle (LV) function consented to be studied.

Echocardiographic results and classifications:

All study patients received echocardiography studies and were classified as follows:

• Normal ventricular function. Normal ventricular function was defined by normal LV end-diastolic and end-systolic dimensions, no major wall motion abnormalities, an ejection fraction of less than 50% and no evidence of impaired or restrictive relaxation abnormalities.
• Systolic dysfunction. Systolic dysfunction was defined by an ejection fraction less than 50% or either global hypokinesis or discrete wall motion abnormalities.
• Diastolic dysfunction. Diastolic dysfunction was defined as impaired relation, restrictive pattern and pseudo-normal pattern.
• Systolic plus diastolic restrictive. Systolic plus diastolic-restrictive was defined as ejection fraction less than 50% with global hypokinesis or discrete wall motion abnormalities and deceleration time less than 150.

Measurement of BNP levels and Statistical analysis

During initial evaluations, BNP was measured on each participant. The range of detectable levels are 1 to 1300 pg/ml. The average 95% confidence limit of the analytical sensitivity of the test is less than 5 pg/ml. There is no significant cross-reactivity with endothelin, alpha-atrial natriuretic peptide or aldosterone.

Group comparisons of BNP values were made for independent samples and analysis of variance. In all cases these were computed with raw BNP values and repeated with log-transformed BNP values. Both versions yielded the same conclusions.

Sensitivity, specificity and accuracy were computed for BNP with a selection of possible cut points. The diagnostic utility of BNP alone was compared with the echocardiographic probability of LV dysfunction.

RESULTS:

Fifty-two percent of patients had unsubstantiated complaints of dyspnea, whereas the remaining were essentially asymptomatic. Nearly all patients had risk factors for heart disease, including 46% with a history of coronary artery disease. Patients diagnosed with abnormal LV function (n=95) had a mean BNP concentration of 489 ± 75 pg/ml, whereas the normal LV function group (n= 105) had a mean BNP concentration of 29.5 ± 62.4 pg/ml.

Table 3 shows the breakdown of patients with abnormal LV function into systolic (n=53), diastolic (n=42) and combination of systolic plus diastolic (n=14) on the basis of echocardiography. Values for all abnormal LV function groups are higher than for the normal LV function group. Patients with systolic plus diastolic-restrictive dysfunction had significantly higher BNP values than systolic or diastolic function alone.

SUMMARY

Early detection of LV dysfunction enables administration of treatment that can improve survival and increase well being. A review of recent literature suggests that BNP is most useful for excluding the diagnosis of heart failure in cases in which the differential diagnosis would normally suggest it. For example, in a patient without a diagnosis of heart failure but with any of its classic signs or symptoms and a BNP level in the normal range, a clinician should strongly consider an alternative diagnosis. Because conditions other than heart failure can result in an elevated BNP, the clinical context of a patient with a positive BNP must be considered. An elevated BNP level should prompt routine tests to confirm the diagnosis in addition to evaluating the cause and defining the type of heart failure (e.g., electrocardiography, chest x-ray, and echocardiography). As for using BNP levels to monitor patients with diagnosed chronic heart failure, levels correlate well with treatment efficacy. Following an exacerbation of heart failure, a declining BNP indicates a good response to therapy and indicates a more favorable outcome. A rising BNP suggests a greater risk of adverse outcome, warranting a more aggressive treatment strategy. An elevated BNP level 48 hours after myocardial infarction strongly predicts heart failure or death within the next year, and appropriate treatment and monitoring strategies should be considered for this group of patients.

References:

1. Stevenson L.W, Braunwald E. Recognition and management of patients with heart failure. In: Goldman L. Braunwald E., editors. Primary Cardiology Philadelphia, PA: W.B. Saunders, 1998:310-29
2. StevensonLW, Perloff JK. The limited reliability of physical signs for estimating hemodynamic in chronic heart failure. JAMA 1989:261:884-8.
3. Konstam M, Dracup K, Kaber D, et al. Heart Failure: Evaluation and Care of Patients with Left-Ventricular Systolic Dysfunction. Clinical Practice Guideline No. 11. AHCPR Publication No. 904-0612. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services, June, 1994
4. Struthers AD. Ten years of natriuretic peptide research: a new dawn for their diagnostic and therapeutic use? BMJ 1994: 308:1615-1619
5. Grantham JA. Burnett JC Jr. BNP: increasing importance in the pathophysiology and diagnosis of congestive heart failure. Circulation. 1997:96:388-390.
6. Yandle TG. Biochemistry of natriuretic peptides. J intern Med. 1994:235:561-576.
7. Maisel A. S., et al, from the Division of Cardiology and Department of Medicine, Veteran’s Affairs Medical Center and University of California, San Diego: Utility of B-natriuretic peptide as a rapid, point-of-care test for screening patients undergoing echocardiography to determine left ventricular dysfunction. August 2000.

B-Type Natriuretic Peptide Questions

Select the one best answer. - Go here to get a printable answer/registration form

1. What is the leading cause of hospital admission among patients over the age of 65?
1. Heart Failure
2. Cancer
3. Diabetes
4. Obesity


2. BNP secretion is regulated by:
1. Auricular end-diastolic pressure
2. Fluid accumulation in the lungs
3. Volume and pressure of blood in the ventricles
4. Edema in the abdomen and ankles


3. A patient presents in the emergency room with labored breathing, abnormal chest x-ray. The BNP level is 62 pg/ml. Of the following, which is the most likely diagnosis?
1. Congestive Heart Failure
2. Pneumonia
3. Stroke
4. Myocardial Infarction


4. Most effective test to differentiate Congestive Heart Failure from other causes of dyspnea:
1. Troponin
2. Myoglobin
3. ANP
4. BNP


5. BNP was first discovered:
1. In the brain of humans
2. In the brain of pigs
3. In the plasma of humans
4. In the plasma of pigs


6. Circulating BNP levels:
1. Increase in proportion to severity of congestive heart failure
2. Decrease in proportion to severity of congestive heart failure
3. Do not change in congestive heart failure
4. Are detected in only the first hour of congestive heart failure


7. BNP helps to regulate blood pressure and fluid balance by:
1. Decreasing urine output
2. Causing vasoconstriction
3. Rising blood pressure
4. Causing vasodilatation


8. Patients with coronary artery disease have BNP levels which are:
1. Increased with severity of the disease
2. Decreased with severity of the disease
3. Not elevated with the disease unless the disease coexists with left ventricular dysfunction
4. Not elevated with the disease unless the disease coexists with diabetes


9. Which test is not used to confirm congestive heart failure with an elevated BNP:
1. Electroencephalography
2. Electrocardiography
3. Chest x-ray
4. Echocardiography


10. BNP levels are used for evaluating all but which of the following:
1. Ventricular function
2. Severity of Congestive Heart Failure
3. Left ventricular diastolic pressure
4. Severity of renal disease