Novel Diagnostic Markers in Heart Failure: An Emerging Paradigm Shift?

Patients who present to urgent-care physicians complaining of dyspnea can be exceedingly difficult to manage, as the differential diagnosis of this problem is very broad. Recognizing heart failure is a critical task in this setting, and important to accurately ascertain so that appropriate management strategies can be applied.¹ Conversely, the wrong diagnosis may deprive the patient of appropriate therapy and therefore carries grave risk. Unfortunately, the physical examination, even when performed by an experienced clinician, is not sensitive enough to be relied on for diagnosis.¹ Echocardiography may not be readily available, is expensive, and does not always provide an answer, since heart failure can occur even in the presence of preserved systolic function. A rapid, point-of-care blood test that can discriminate heart failure would be an extremely beneficial resource to the urgent-care physician. In this report, we describe a case that offers a diagnostic dilemma and discuss the potentially important role of rapid brain natriuretic peptide (BNP) testing in assisting in the correct diagnostic stratification of heart failure in an initially nebulous situation.

Case Report

A 55-year-old, obese male smoker with a long-standing history of hypertension and hyperlipidemia presented to an emergency department complaining of increasing fatigue and exertional shortness of breath associated with wheezing at night. He had smoked a pack of cigarettes daily for 30 years and gave a history of a 15-pound weight gain over the previous year. His medications included amlodipine 5 mg once daily and atorvastatin 10 mg once daily. On admission, his pulse was 90 beats/min, blood pressure 156/98 mm Hg, respirations 24 breaths/min, and temperature 38.0°C. On physical examination, jugular venous distension was difficult to evaluate due to the short and stocky neck area. The heart rhythm was regular, with no murmurs or gallops. The chest was increased in antero-posterior diameter and hyper-resonant on percussion, and auscultation revealed distant breath sounds. Trace bilateral pedal edema was noted. A chest radiograph was obtained, which revealed a slightly enlarged cardiac silhouette and decreased lung markings. An electrocardiogram showed nonspecific ST and T wave changes in the precordial leads. The patient was found to have an ejection fraction of 45% by echo-cardiography. A ventilation-perfusion scan was nondiagnostic, and lower-extremity duplex Doppler ultrasonography was negative. Due to the ambiguity of clinical signs and symptoms and lack of a clear segregation into a primary cardiac or pulmonary presentation, the patient was scheduled to undergo right heart catheterization. In the interim, a rapid BNP assay established a markedly elevated BNP level (850 pg/mL). Thus, intravenous diuresis was begun, following which the patient's symptoms abated. The right heart catheterization was cancelled due to enhanced appreciation of the diagnosis and clinical improvement. Angiotensin-converting enzyme inhibitor therapy was begun and the patient was discharged within 24 hours for outpatient follow-up.

Discussion

This case illustrates that the history, physical examination, and current testing modalities can leave the physician with more questions than answers. There is a need for a readily available, minimally invasive, point-of-care blood test that can detect decompensated heart failure.

BNP is a natriuretic neurohormone similar to atrial natriuretic peptide (ANP); it was first described in the brain and was later discovered to be produced by ventricular myocytes in response to stretch.² In normal subjects, the plasma concentration of ANP is roughly five times higher than that of BNP. However, in patients with decompensated heart failure, the BNP level can surpass that of ANP. Elevation of both hormones has been correlated with a decline in the ejection fraction,^3,4 but BNP may be a superior marker for this disease process because of its derivation. This principle is supported by published work suggesting that, from the standpoint of accuracy, BNP is the most useful natriuretic peptide in the detection of decreased left ventricular function associated with heart failure.^5,6

Studies have established a correlation between elevated BNP levels and New York Heart Association (NYHA) classification,⁷ left ventricular end-diastolic pressure,⁸ and mortality in certain populations.⁹ More recently, Cheng et al.¹⁰ found that in 72 subjects hospitalized with NYHA class III or IV decompensated heart failure, daily BNP levels correlated strongly with readmission within 30 days, and with increased mortality. This suggested to the authors that BNP levels could be used to direct the treatment of patients with decompensated heart failure. Supporting this conclusion, Troughton et al.¹¹ demonstrated that patients with an ejection fraction of <40% who received tailored pharmacotherapy based on BNP levels had fewer total cardiovascular events and prolongation of the time to an initial event, relative to those who received treatment based on traditional clinical assessment.

While the evidence suggests that the serum BNP level is potentially helpful to physicians in both diagnosis and treatment of heart failure, until recently there has not been a rapid assay for this neurohormone. Thus, because of the prolonged assay time, while the theoretical value of this blood test at the point of care was clear, no means existed to make use of it. The advent of a rapid assay has now given clinicians the ability to analyze BNP levels at the bedside. The test (Triage^®, Biosite Diagnostics, San Diego, CA) is performed by a hand-held device that utilizes fluorescence immunoassay to quantify the amount of BNP in plasma or whole blood samples in approximately 15 minutes.

Utilizing this system, Quyen et al.¹²designed a study¹² to assess the use of BNP levels to diagnose congestive heart failure (CHF) in an urgent-care setting. They analyzed the BNP levels of 250 patients presenting with a primary complaint of dyspnea to the urgent-care area of a Veterans Administration hospital. Later, two cardiologists blinded to the BNP results used the Framingham criteria¹³ and all available clinical data to assign a probability of decompensated heart failure for each patient. The authors found that the mean BNP blood concentration was significantly higher (p<0.0001) in patients with decompensated heart failure. The “CHF” group (n=97) had a mean BNP concentration of 1076±138 pg/mL and the “no CHF” group (n=139) had a mean BNP concentration of 38±4 pg/mL. A subgroup of 14 patients found to have underlying ventricular dysfunction without acute exacerbation had a mean BNP concentration of 141±31 pg/mL. A relationship between severity of decompensated heart failure and BNP values was also demonstrated. As the severity of heart failure increased, the median concentration of BNP increased (p<0.001). Univariate analysis revealed that a BNP cut-off level of 80 pg/mL had a positive predictive value of 95%, a negative predictive value of 98%, a sensitivity of 96%, and a specificity of 96%. Multivariate analysis revealed that addition of BNP levels substantially increased the explanatory power of the model, suggesting that BNP measurements provided meaningful diagnostic information not disclosed by other clinical variables. The addition of BNP levels to the model could have conceivably corrected 29 of 30 misdiagnoses made by the acute-care doctors. From these results, the authors concluded that BNP measurement appeared to be a sensitive and specific test for the identification of patients with heart failure in the urgent-care setting.

Conclusions

A point-of-care blood test that rapidly and reliably rules out heart failure could revolutionize the way physicians diagnose and manage patients presenting with a prominent complaint of dyspnea. There are more than 400,000 new cases of heart failure diagnosed each year in the United States.^14,15 If clinical research continues to confirm the relationship between BNP and decompensated heart failure, point-of-care BNP assays may become as useful and commonplace in health care as the electrocardiogram.