OBJECTIVES

After completing this chapter, the reader should be able to

  • Explain the roles of the different biochemical markers in the diagnosis of acute coronary syndrome and heart failure

  • Assess the presence and type of acute coronary syndrome in a patient case

  • Assess the presence and type of heart failure in a patient case

The purpose of the heart is to pump blood throughout the body, delivering oxygen and nutrients to the tissues. The heart muscle has two basic properties: electrical and mechanical. Heart cells responsible for these properties are (1) pacemaker cells, or the “electrical power” of the heart; (2) electrical conducting cells, or the “hardwiring circuitry” of the heart; and (3) myocardial cells, or the contractile units of the heart. Disturbances in the electrical system result in rhythm disorders, also known as arrhythmias or dysrhythmias. The pumping action is accomplished by means of striated cardiac muscle, which largely composes the myocardium. Several cardiovascular diseases disrupt the mechanical function of the heart, including acute coronary syndrome (ACS), and heart failure.1

The management and potential complications of these disease states contribute greatly to the overall health of and cost incurred by society. Laboratory tests are essential for establishing the diagnosis and determining the prognosis of patients. Accurate and expeditious assessment of a patient presenting with symptoms suggestive of ACS guides individualized treatment to optimize a patient’s short-term and long-term outcomes. Conversely, rapid exclusion of the diagnosis permits early discharge from the coronary care unit or hospital. Laboratory and other diagnostic tests used in evaluating a patient with possible ACS or heart failure are discussed in this chapter.

CARDIAC PHYSIOLOGY

The heart consists of two pumping units that operate in parallel, one on the right side and the other on the left side. Each unit is composed of an upper chamber called the atrium and a lower chamber called the ventricle. The atrium receives blood into the heart and serves as a weak pump that helps move blood into the ventricle. The atrial contraction, or atrial kick, is responsible for 20% to 30% of ventricular filling. The right and left ventricles pump blood outside the heart and supply the primary force that propels blood through the pulmonary and peripheral circulation, respectively.1

The functional unit of the heart is comprised of a network of noncontractile cells that form the conduction system, which is responsible for originating and conducting action potentials from the atria to the ventricles. This leads to the excitation and contraction of the cardiac muscle, which is responsible for pumping blood to the other organs.1

The normal adult human heart contracts rhythmically at approximately 70 beats per minute. Each cardiac cycle is divided into a systolic and diastolic phase. During each cycle, blood from the systemic circulation is returned to the heart via the veins, and blood empties from the superior and inferior vena cavae into the right atrium.1 During the diastolic phase, blood passively fills the right ventricle through the tricuspid valve with an active filling phase by atrial contraction just prior to end-diastole. During the systole phase, blood is then pumped from the right ventricle through the pulmonary artery to the lungs, where carbon dioxide is removed and the blood is oxygenated. From the lungs, blood returns to the heart via the pulmonary veins and empties into the left atrium.1 Again, during diastole, blood empties from the left atrium through the mitral valve into the main pumping chamber, the left ventricle. With systole, the left ventricle contracts and blood is forcefully propelled into the peripheral circulation via the aorta. At rest, the normal heart pumps approximately 4 to 6 L of blood per minute, known as cardiac output (CO). Maintaining normal CO depends on the heart rate (HR) and stroke volume (SV).1
CO (mL/min)=HR (beats/min)×SV (mL/beat)

The SV, defined as the volume of blood ejected during systole, is determined by intrinsic and extrinsic factors, including myocardial contractility, preload, and afterload. The coronary arteries, which supply the heart muscle, branch from the aorta just beyond the aortic valve and are filled with blood primarily during diastole. In the face of increased myocardial metabolic needs, the heart can increase coronary blood flow by vasodilation to meet myocardial oxygen demand.1

Decreased CO compromises tissue perfusion and, depending on severity and duration, may lead to significant acute and chronic complications. Several cardiac conditions lead to decreased CO, including hypertensive heart diseases, heart failure, valvular heart diseases, congenital heart diseases, diseases of the myocardium, conduction abnormalities, stable ischemic heart disease (SIHD), and ACS. This chapter focuses on the various tests used in the diagnosis and assessment of patients presenting with ACS and heart failure.

ACUTE CORONARY SYNDROME

Acute coronary syndrome (ACS) is a medical emergency resulting from atherosclerotic plaque rupture in a coronary artery. This rupture results in an obstruction of the coronary lumen by a thrombus composed of platelet aggregates, fibrin, and entrapped blood cells. The obstruction caused by the thrombus leads to myocardial ischemia. When a coronary artery is occluded, the location, extent, rate, and duration of occlusion determine the severity of myocardial ischemia resulting in one of three types of ACS: unstable angina, non–ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial infarction (STEMI).2-4

Complications of a myocardial infarction (MI) include cardiogenic shock, heart failure, ventricular and atrial arrhythmias, ventricular rupture or ventricular septal defect formation, cardiac tamponade, pericarditis, papillary muscle rupture, mitral regurgitation, and embolism. Initial assessment of the patient presenting with ACS may be confounded by the presence and severity of the previously described complications.2-4

Myocardial infarction can be recognized by clinical presentation, electrocardiography, elevated biochemical markers of myocardial necrosis, and imaging. Clinical presentation of all types of ACS is similar and does not distinguish among unstable angina, NSTEMI, and STEMI. Interpretation of a 12-lead electrocardiogram (ECG) and the presence of positive biomarkers of necrosis are used to differentiate between the different types of ACS. Positive biomarkers, such as cardiac-specific troponins, are suggestive of NSTEMI and STEMI. In the era of reperfusion therapy, diagnosing ACS accurately and without delay is crucial for risk stratification and appropriate, life-saving treatment implementation. This section describes the laboratory and diagnostic tests used in the diagnosis of ACS.2-4

Laboratory Tests

Cardiac-Specific Troponins

Infarction of myocardial cells disrupts membrane integrity, leaking intracellular macromolecules into the peripheral circulation, where they are detected. Several biochemical cardiac markers are used in the diagnosis and evaluation of ACS. The cardiac-specific troponins (cTn) have several attractive features and have gained acceptance as the biochemical markers of choice in the evaluation of patients with ACS.5

The role of cTn within the cardiac tissue is to modulate the contractile function of the muscle. Troponin is a protein complex consisting of three subunits: troponin C (TnC), troponin I (TnI), and troponin T (TnT). The three subunits are located along thin filaments of myofibrils, and they regulate Ca+2-mediated interaction of actin and myosin necessary for the contraction of cardiac muscles. Troponin C binds Ca+2, TnI inhibits interaction with myosin heads, and TnT attaches to tropomyosin on the thin filaments.5 The TnC expressed by myocardial cells in cardiac and skeletal muscle is identical. In contrast, TnI and TnT isoforms are specific to cardiac myocytes. Monoclonal antibody-based immunoassays have been developed to detect cardiac-specific TnI (cTnI) and cardiac-specific TnT (cTnT).5

Cardiac-specific TnI and cTnT are highly specific and sensitive for myocardial injury.6-8 In the case of myocardial injury, serum cTnI and cTnT levels begin to rise above the upper reference limit within 3 to 12 hours, peak in 24 hours (cTnI) or 12 hours to 2 days (cTnT), and return to normal in 5 to 10 days (cTnI) or 5 to 14 days (cTnT) (Table 7-1). Levels typically increase more than 20 times above the reference limit. The prolonged time course of elevation of cTnI and cTnT is useful for the late diagnosis of MI.6-8

TABLE 7-1.
Biochemical Markers Used in the Diagnosis of ACS

MARKER

MOLECULAR WEIGHT (DA)

RANGE OF TIME TO INITIAL ELEVATIONS

MEAN TIME TO PEAK ELEVATIONS (Nonthrombolysis)

TIME TO RETURN TO NORMAL RANGE

cTnI

23,500

3–12 hr

24 hr

5–10 days

cTnT

33,000

3–12 hr

12 hr–2 days

5–14 days

Source: Adapted with permission from Adams JE 3rd, Bodor GS, Dávila-Román VG, et al. Cardiac troponin I. A marker with high specificity for cardiac injury. Circulation. 1993;88(1):101–106; Apple FS. Tissue specificity of cardiac troponin I, cardiac troponin T and creatine kinase-MB. Clin Chim Acta. 1999;284(2):151–159; Mair J, Morandell D, Genser N, et al. Equivalent early sensitivities of myoglobin, creatine kinase MB mass, creatine kinase isoform ratios, and cardiac troponins I and T for acute myocardial infarction. Clin Chem. 1995;41(9):1266–1272.

Serial troponin levels should be obtained at presentation and 3 to 6 hours after onset of symptoms. A level of cTnT and cTnI that exceeds the decision level on at least one occasion during the first 24 hours after an index clinical ischemic event indicates MI. Most commercial immunoassays measure cTnI. A pattern that shows rising and falling troponin levels is required for the diagnosis of ACS. This is especially helpful in differentiating troponin elevation caused by MI from that caused by chronic conditions. Additional troponin levels should be obtained beyond 6 hours if the clinical index of suspicion for ACS is high.9

Cardiac troponins have been endorsed internationally as the standard biomarkers for the detection of myocardial injury, diagnosis of MI, and risk stratification in patients with suspected ACS.3,4,9,10 Significant prognostic information may be inferred from troponin levels. In a study of patients presenting to the emergency department with chest pain, negative qualitative bedside testing of cTnI and cTnT was associated with low risk for death or MI within 30 days (event rates of 0.3 and 1.1, respectively).11 Other large clinical trials have documented that elevated troponin levels are strong, independent predictors of mortality and serious adverse outcome 30 to 42 days after ACS.12-16 Troponin levels should always be used in conjunction with other clinical findings. In one study, in-hospital mortality was as high as 12.7% in a troponin-negative subgroup of patients with ACS.17 While cTn levels are most commonly elevated in ACS, it is important to note that there are other causes of detectable cTn (Table 7-2).5 “See Minicase 1 for an example of the use of these laboratory values to assess a patient presenting with ACS.”

TABLE 7-2.
Causes of Detectable Serum Levels of Troponins in the Absence of Acute Coronary Syndrome

Aortic dissection

Bradycardia or tachycardia

Burns affecting >30% of body surface area

Cardiac contusion or trauma (cardiac surgery, ablation, pacing, implantable cardioverter-defibrillator shocks, cardioversion, endomyocardial biopsy)

Cardiomyopathy

Cardiotoxicity (doxorubicin, fluorouracil, trastuzumab)

Cardiopulmonary resuscitation

Coronary angioplasty or vasospasm

Critical illness (respiratory failure, sepsis)

Heart failure (chronic and acute decompensation)

Heart transplant rejection

Infiltrative disorders with cardiac involvement (amyloidosis, sarcoidosis)

Left ventricular hypertrophy

Myocarditis or pericarditis

Neurologic diseases, acute (cerebrovascular accident, subarachnoid hemorrhage)

Pulmonary embolism or severe pulmonary hypertension

Rhabdomyolysis with cardiac injury

Renal failure and hemodialysis

Source: Adapted with permission from Richards M, Nicholls MG, Espiner EA, et al. Comparison of B-type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease. J Am Coll Cardiol. 2006;47(1):52–60; Jernberg T, Stridsberg M, Venge P, Lindahl B. N-terminal pro brain natriuretic peptide on admission for early risk stratification of patients with chest pain and no ST-segment elevation. J Am Coll Cardiol. 2002;40(3):437–445; James SK, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Global Utilization of Strategies to Open occluded arteries (GUSTO)-IV substudy. Circulation. 2003;108(3):275–281.
High-sensitivity troponins

High-sensitivity troponin I (hsTnI) and troponin T (hsTnT) assays have been developed to increase the clinical sensitivity for detection of myocardial injury. High-sensitivity troponin assays detect concentrations of the same proteins that conventional sensitivity assays are aimed at detecting but in much lower concentrations. These assays have substantially lower limits of detection (in the picogram/milliliter range versus the current assays in the nanogram/milliliter range) as well as improved assay precision. To be classified as high-sensitivity assays, concentrations below the 99th percentile should be detectable above the assay’s limit of detection for >50% of healthy individuals in the population of interest. High-sensitivity assays, by expert consensus, should have a coefficient of variance of <10% at the 99th percentile value in the population of interest.18-21

Studies suggest that high-sensitivity troponins provide enhanced diagnostic and prognostic accuracy. In one study, hsTnT was superior to TnT but equivalent to third-generation TnI for the diagnosis of MI, and hsTnT was the most likely assay to be elevated at baseline. The study also showed that change in troponin levels increase specificity but reduce sensitivity for the detection of acute MI.22 Another study comparing hsTnI (Architect STAT hsTnI assay, Abbott Diagnostics Scarborough, Inc.) and cTnI (Architect STAT cTnI assay, Abbott Diagnostics Scarborough, Inc.) revealed that measurement at 3 hours after admission may help rule out MI. Troponin measured using either assay was superior to other biomarkers (including creatinine kinase [CK] and creatinine kinase-myocardial band [CK-MB]) in ruling in or ruling out MI. The sensitivity and negative predictive values of the hsTnI assay were higher than the cTnI assay at admission (82.3% and 94.7% versus 79.4% and 94%, respectively); however, the negative predictive value of both assays was 99.4% at 3 hours. For patients with detectable troponin on admission (using the 99th percentile diagnostic cutoff value) and a 250% increase in troponin level at 3 hours, the probability of MI was 95.8%.23

Although the use of high-sensitivity troponin assays has been longstanding in Europe, these assays have only been recently approved for use in the United States. Several hsTnT and hsTnI assays are now available and being implemented in health systems across the United States. As the use of these newer tests becomes more widespread, it is important to recognize that there is variability in cutoff values, sensitivity, specificity, and clinical interpretation among the different available assays.24

Acute Coronary Syndrome

Ethan W., a 68-year-old man with history of hypertension, dyslipidemia, and type 2 diabetes, presents to the emergency department with reports of substernal chest discomfort that radiates to the left arm, shortness of breath, and palpitations for the past 4 hours. He appears in distress. His vital signs include BP 150/90 mm Hg, HR 130 beats/min, and RR 24 breaths/min. His jugular venous pressure (JVP) is normal, and his lungs are clear. Cardiac exam reveals tachycardia with no murmurs or rub appreciated. A benign abdominal exam, with no hepatojugular reflux and lower extremities, reveals no edema. Chest radiograph does not show any evidence of cardiomegaly or congestion. ECG reveals ST elevation in anterior leads. At presentation, cTnI is 9 ng/mL. The institution’s diagnostic level is cTnI ≥0.3 ng/mL. BNP is 300 pg/mL. An echocardiogram reveals normal left ventricular size with an estimated ejection fraction of 50% and anterior wall motion akinesis.

QUESTION: What is the most likely assessment of this patient’s presentation?

DISCUSSION: This patient is considered at high risk for cardiac events given his history of diabetes, hypertension, and dyslipidemia. Based on the ECG findings, along with the symptoms and the elevated troponin level at presentation, he is experiencing an acute anterior STEMI. In addition, the wall motion abnormality noted on echocardiography is consistent with MI. He is not showing evidence of heart failure on exam, and the chest radiograph reveals no evidence of congestion. Elevated BNP levels in ACS have been shown to be prognostic of a poor outcome, even in the absence of clinical evidence of heart failure.

Cardiac Enzymes

Creatine kinase

Normal range: male patients, 55 to 170 IU/L (0.92 to 2.84 µkat/L); female patients, 30 to 135 IU/L (0.5 to 2.25 µkat/L)

Creatine kinase isoenzymes

Normal range: CK-MB ≤6 ng/mL (≤6 mcg/L)

Creatine kinase (CK) is an enzyme that stimulates the transfer of high-energy phosphate groups, and it is found in skeletal muscle, the myocardium, and the brain. Circulating serum CK is directly related to an individual’s muscle mass.

Given the availability and characteristics of cardiac troponins, CK and CK-MB measurements are no longer useful for the diagnosis of ACS. However, CK-MB may still be used by some clinicians to estimate size of infarct.4

The enzyme CK is a dimer of two B monomers (CK-BB), two M monomers (CK-MM), or a hybrid of the two (CK-MB). The three isoenzymes are found in different sources: CK-BB is found in the brain, lungs, and intestinal tract; CK-MM is found primarily in skeletal and cardiac muscle; and CK-MB is found predominantly in the myocardium but also in skeletal muscle. Fractionation of total CK into three isoenzymes increases the diagnostic specificity of the test for MI.25

The CK-MB isoenzyme is most specific for myocardial tissue and has been used for the diagnosis of ACS. Serum CK-MB concentrations begin to rise 6 to 12 hours after the onset of symptoms, peak in 24 hours, and return to baseline in 2 to 3 days.26,27 Other causes for elevated CK-MB levels include trauma, strenuous exercise, skeletal muscle injury, kidney failure, intramuscular injection, and exposure to toxins or drugs.28

HEART FAILURE

Heart failure is a clinical syndrome in which the heart is unable to pump sufficient blood to meet the demands of the body. Heart failure is diagnosed based on history and physical examination. Although no specific test is used to diagnose heart failure, it is classified based on an indirect measurement of the contractility of the left ventricle, called left ventricular ejection fraction (LVEF). Heart failure is currently defined as either heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). HFrEF occurs when the LVEF is ≤40%. HFrEF is also referred to as systolic heart failure because the underlying issue is related to poor ventricular contraction during systole. HFpEF occurs when the LVEF is ≥50%. HFpEF is also referred to as diastolic heart failure because the problem is related to impaired ventricular filling during diastole. Patients falling in an intermediate group with LVEF between 41% and 49% are classified as having HFpEF, borderline. Patients with current LVEF >40% and a history of HFrEF in the past are classified as having HFpEF, improved.29

Common etiologies for heart failure include coronary artery disease, valvular diseases, and hypertension. Signs and symptoms consistent with heart failure may be attributed to volume overload and congestion (eg, elevated jugular venous pressure, peripheral edema, pulmonary congestion and edema, and dyspnea) and hypoperfusion (eg, tachycardia, cold extremities, cyanosis, and fatigue).29

Heart Failure

Ruth G. is a 76-year-old woman with a history of poorly controlled hypertension and coronary artery disease who presents to the emergency department with 2 weeks of progressive dyspnea on exertion and now shortness of breath at rest. She reports sleeping in a recliner for the last three nights to breathe more comfortably. She denies any chest discomfort and admits to smoking and medication nonadherence.

On examination, Ruth G. is unable to complete full sentences secondary to breathing difficulty. Her vital signs include blood pressure (BP) 190/105 mm Hg, heart rate (HR) 100 beats/min, and respiration rate (RR) 30 breaths/min. O2 saturation is 86% on room air. Physical exam reveals elevated JVP at 18 cm H2O. Lung exam reveals bibasilar dullness to percussion with diffuse crackles. Cardiac exam reveals a regular tachycardic rate; S1, S2, S3 with 2/6 holosystolic murmur at apex and laterally displaced point of maximal intensity. She has a positive hepatojugular reflux and 2+ pitting edema in the lower extremities, bilaterally. Chest radiographs reveal an enlarged cardiac silhouette with moderate bilateral effusions and cephalization of vasculature. Blood work results are significant: sodium 132 mmol/L, potassium 3.7 mmol/L, blood urea nitrogen 30 mg/dL, creatinine 1.5 mg/dL with an estimated GFR 46 mL/min/1.73 m2, troponin I level of 0.06 ng/mL (remained at same level with repeat measurements), and BNP level of 2,156 pg/mL. Echocardiogram reveals a dilated left ventricle with global hypokinesis and moderately depressed systolic function with an estimated ejection fraction of 38%.

QUESTION: How should this patient’s findings and laboratory values be interpreted?

DISCUSSION: This patient has multiple risk factors for heart failure, including a history of coronary artery disease and poorly controlled hypertension. Her clinical presentation is compatible with acute decompensated heart failure with evidence of volume overload on physical exam (elevated JVP, positive hepatojugular reflux, 2+ lower extremity pitting edema). Her chest radiograph confirms findings of heart failure. Her BNP level is also significantly elevated and is indicative of heart failure. The low troponin level that did not rise is likely the result of a silent subendocardial ischemia given her poorly controlled hypertension and heart failure in the setting of a decreased creatinine clearance. The clinical presentation, BNP level, and LVEF of 38% measured by echocardiography—the findings—are all consistent with a diagnosis of heart failure with reduced ejection fraction (HFrEF).

Laboratory Tests

Natriuretic Peptides

Natriuretic peptides are naturally secreted hormones that are released by various cells in response to increased volume or pressure. Several natriuretic peptides have been identified with atrial natriuretic peptide and B-type natriuretic peptide (BNP) being cardiac-specific peptides. The two peptides are structurally similar and exert potent diuretic, natriuretic, and vascular smooth muscle-relaxing effects. A 28-amino acid (aa) peptide, atrial natriuretic peptide, is primarily secreted by the atrial myocytes in response to increased atrial wall tension. A 32-aa peptide, BNP, is primarily secreted by the left ventricular myocytes in response to volume overload and increased ventricular wall tension.30

The precursor for BNP is PreproBNP, a 134-aa peptide that is enzymatically cleaved into proBNP, a 108-aa peptide. The latter is then further cleaved into the biologically active C-terminal 32-aa BNP and the biologically inactive amino-terminal portion of the prohormone, N-terminal-proBNP (NT-proBNP). Plasma levels of both BNP and NT-proBNP are elevated in response to increased volume and ventricular myocyte stretch in patients with heart failure. Once released into the peripheral circulation, BNP is cleared by enzymatic degradation via endopeptidase and natriuretic peptide receptor-mediated endocytosis, whereas NT-proBNP is cleared renally. The elimination half-life of BNP is significantly shorter than that of NT-proBNP (20 minutes versus 120 minutes, respectively).30

The quantitative measurements of BNP and NT-proBNP levels are indicated for the evaluation of patients suspected of having heart failure, assessment of the severity of heart failure, and risk stratification of patients with heart failure and ACS.31 In conjunction with standard clinical assessment, BNP and NT-proBNP levels at the approved cutoff points are highly sensitive and specific for the diagnosis of acute heart failure and correlate well with the severity of heart failure symptoms as evaluated by the New York Heart Association Classification.32,33 In addition, BNP and NT-proBNP are strong independent markers of clinical outcomes in patients with heart failure, IHD, and ACS, even in the absence of previous history of heart failure or objective evidence of left ventricular dysfunction during hospitalization.34-40

The value of serial BNP and NT-proBNP measurements to guide optimal heart failure therapy has been investigated. Several randomized trials of patients with chronic heart failure have compared standard heart failure therapy plus BNP or NT-proBNP-guided therapy to standard heart failure treatment alone.41-46 A meta-analysis of these trials confirmed the findings that BNP-guided heart failure therapy reduces all-cause mortality in patients with chronic heart failure compared with usual clinical care in patients younger than 75 years but not in those older than 75 years of age. Mortality reduction might be attributable to the higher percentage of patients achieving target doses of angiotensin-converting enzyme inhibitors and β blockers—classes of agents shown to delay or halt progression of cardiac dysfunction and improve mortality in patients with heart failure.47 A >30% reduction in BNP levels in response to heart failure treatment indicates a good prognosis.48

Several factors impact the BNP and NT-proBNP levels, including gender, age, renal function, and obesity. Plasma BNP and NT-proBNP levels in normal volunteers are higher in women and increase with age. In addition, renal insufficiency at an estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m2 may impact the interpretation of the measured natriuretic peptides. Significant correlation between NT-proBNP level and GFRs has been shown, more so than that between BNP level and GFRs. This is because renal clearance is the primary route of elimination of NT-proBNP, and the measured levels of the biomarker are elevated in patients with mild renal insufficiency. However, evaluation of patients with GFRs as low as 14.8 mL/min/1.73 m2 revealed that the test continues to be valuable for the evaluation of the patient with dyspnea regardless of renal function.51 Higher diagnostic cutoffs for different GFR ranges may be necessary for optimal interpretation in patients with renal insufficiency.

Plasma levels of BNP and NT-proBNP are reduced in obese patients, limiting the clinical interpretation of the tests in these patients. An inverse relationship between the levels of these markers and body mass index (BMI) is observed.49,50 The exact mechanism for this is not known, but a BMI-related defect in natriuretic peptide secretion has been suggested.51 In one study, NT-proBNP levels were found to be lower in obese patients presenting with dyspnea (with or without acute heart failure), but the test seemed to retain its diagnostic and prognostic capacity across all BMI categories.52 Similarly in another study, in patients with advanced systolic heart failure, the test predicted worse symptoms, impaired hemodynamics, and higher mortality at all levels of BMI. Although BNP levels were relatively lower in overweight and obese patients, optimal BNP cutoff levels for prediction of death or urgent transplant in lean, overweight, and obese patients were reported to be 590 pg/mL, 471 pg/mL, and 342 pg/mL, respectively.53 To increase the specificity of BNP levels for heart failure in obese and lean patients, a diagnostic cutoff level of ≥54 pg/mL for severely obese patients and a cutoff level of ≥170 pg/mL in lean patients have been suggested.54

Despite the fact that BNP and NT-proBNP have no role in the diagnosis of ACS, they are powerful prognostic markers and predictors of mortality in these patients.48,55-58 The use of BNP levels in the assessment of cardiotoxicity associated with anthracycline chemotherapy has also been studied.59-62 Several studies have shown an improvement in early detection of chemotherapy-related cardiotoxicity when biomarkers such as BNP and hsTnI were used in addition to serial evaluation of LVEF. This could potentially translate to earlier intervention and improved outcome.63,64

B-type natriuretic peptide

Diagnostic level: 100 pg/mL (100 ng/L)

The clinical diagnostic cutoff level for heart failure is a BNP level of >100 pg/mL. In addition to standard clinical evaluation, a BNP level of >100 pg/mL is associated with sensitivity and specificity of 90% for heart failure in a patient presenting with shortness of breath.65 The test has a high negative predictive value in ruling out heart failure as a primary cause for the presentation. A BNP level of 100 to 500 pg/mL is suggestive, whereas a level >500 pg/mL is indicative of heart failure as the likely etiology of acute dyspnea (Table 7-3).48

TABLE 7-3.
Interpretation of BNP and NT-proBNP Levels in Patients with Acute Dyspnea

AGE

HEART FAILURE UNLIKELY

GRAY ZONE

HEART FAILURE LIKELY

BNPa

All

<100 pg/mL

100–500 pg/mL

>500 pg/mL

NT-pro-BNPb

<50 yr

<300 pg/mL

>450 pg/mL

50–75 yr

>900 pg/mL

>75 yr

>1,800 pg/mL

aIn patients with estimated GFR <60 mL/min/1.73 m2 and BMI >35 kg/m2, different decision limits must be used.

bIn patients with estimated GFR <60 mL/min/1.73 m2, different decision limits must be used.

Source: Adapted with permission from Thygesen K, Mair J, Mueller C, et al. Recommendations for the use of natriuretic peptides in acute cardiac care: a position statement from the Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care. Eur Heart J. 2012;33(16):2001–2006.

A study investigating the prognostic value of BNP levels in patients with heart failure showed that the risk ratio of all-cause mortality and first morbid event (defined as death, sudden death with resuscitation, hospitalization for heart failure, or intravenous inotropic or vasodilator therapy for at least 4 hours) for patients with baseline BNP above the median level of 97 pg/mL was significantly higher than for patients with values below the median. Furthermore, the study revealed a significant quartile-dependent increase in mortality and first morbid event (baseline values for BNP in quartiles were <41, 41 to <97, 97 to <238, and ≥238 pg/mL). Patients with the greatest percent decrease in BNP from baseline to 4- and 12-month follow-up periods had the lowest morbidity and mortality, whereas patients with greatest percent increase in BNP had the highest morbidity and mortality. Another study showed that admission BNP and cardiac troponin levels are significant independent predictors of in-hospital mortality in patients with acutely decompensated heart failure. Patients with BNP levels ≥840 pg/mL and increased troponin levels were at particularly high risk for mortality.66

N-terminal-proBNP

Diagnostic level: 300 pg/mL (300 ng/L)

N-terminal-proBNP (NT-proBNP) is a more stable form of BNP that correlates well with BNP in patients with heart failure, although its levels are typically higher than BNP levels. In addition, NT-proBNP levels are elevated in elderly persons and, accordingly, the clinical diagnostic cutoff level for heart failure is higher in older patients. An NT-proBNP level <300 pg/mL was optimal for ruling out acute heart failure, with a negative predictive value of 99%. For cut points of >450 pg/mL for patients younger than 50 years and >900 pg/mL for patients older than 50 years, NT-proBNP levels were highly sensitive and specific for the diagnosis of acute heart failure (Table 7-3).33,48

The angiotensin receptor neprilysin inhibitor (ARNI) drug combination contains the neprilysin inhibitor called sacubitril. By inhibiting neprilysin, the ARNI results in increased levels of natriuretic peptides.67 Because BNP is a substrate for neprilysin, the ARNI leads to increased BNP levels. Note that NT-proBNP is not a substrate for neprilysin, so levels of NT-proBNP are not directly affected by the use of an ARNI.

Other Biochemical Markers

Elevated cardiac troponin levels in patients with heart failure have been shown to be related to the severity of heart failure and worse outcomes.68-70 In patients presenting with acute decompensated heart failure, routine measurement of troponin levels is recommended.42 In addition to baseline troponin levels, serial troponin measurements may be useful in predicting outcomes.71 In a recent study of patients hospitalized for acute heart failure, 60% of patients had detectable cTnT levels (>0.01 ng/mL or >0.01 mcg/L) levels and 34% had positive values (>0.03 ng/mL or >0.03 mcg/L) at baseline. Of the patients with negative troponin level at baseline, 21% had elevated cTnT levels by day 7. Positive troponin levels at baseline and conversion to detectable levels were associated with a poor prognosis.72

Recommendations for Measurement of Biochemical Markers

Measurement of BNP or NT-proBNP is useful for (1) supporting clinical decision-making regarding the diagnosis of heart failure in ambulatory patients with dyspnea or in a patient with acutely decompensated heart failure, especially in the setting of clinical uncertainty and (2) establishing prognosis or disease severity in patients with chronic and acute decompensated heart failure. BNP/NT-proBNP–guided heart failure therapy can be useful to achieve optimal dosing in select patients with clinical euvolemia in the ambulatory care setting, but they are less well established in patients with acute decompensated heart failure. However, it is recommended to obtain a baseline BNP or NT-proBNP at the time of hospital admission for prognostic purposes. In addition, a predischarge BNP or NT-proBNP level may aid in determining postdischarge prognosis. Lastly, measuring cardiac troponins as biomarkers of myocardial injury is helpful for establishing prognosis and risk stratification in the ambulatory/outpatient and acute settings.29,73

SUMMARY

The heart is a muscle that circulates blood first to the lungs for oxygenation and then throughout the vascular system to supply oxygen and nutrients to each cell in the body. Many conditions affect the heart’s ability to function effectively, including SIHD, ACS, and heart failure. Various diagnostic laboratory tests and procedures can be employed to diagnose these conditions.

Gold standard evaluation for SIHD includes noninvasive testing, such as exercise or pharmacologic stress testing. The classic laboratory workup for ACS includes measurement of cardiac troponin level to evaluate for presence of cTnI or cTnT or the more recently approved hsTnI or hsTnT. Classic ECG changes, such as T-wave inversion, ST-segment depression or elevation, and Q-wave appearance, may also be present and are useful in evaluating patients who present with ACS. In addition to confirming an equivocal diagnosis, imaging techniques may localize and estimate the size of MIs. For diagnosis and assessment of heart failure, BNP or NT-proBNP measurement is considered the gold standard laboratory test. Determining LVEF via echocardiography is essential for differentiating systolic (reduced LVEF) from diastolic (preserved LVEF) heart failure so therapy may be targeted accordingly.

The clinician must be well informed of various tests used to diagnose and assess patients with SIHD, ACS, and heart failure. Knowledge of these tests and their clinical significance greatly impacts decisions regarding the implementation of appropriate medication management strategies and preventive measures.

ACKNOWLEDGMENTS

The authors would like to acknowledge the contributions of Dr. Samir Y. Dahdal and Dr. Wafa Y. Dahdal, who authored this chapter in previous editions of this textbook.

LEARNING POINTS

1. Explain the function of cTn within cardiac tissue and its role in diagnosing ACS.

ANSWER: The role of cTn in cardiac myoctes is to modulate the contractile function of the muscle. When myocardial injury occurs, cTn levels may be detected in the serum. Presence of serum cTn above the upper reference limit is suggestive of an ACS event, specifically NSTEMI or STEMI.

2. Discuss the release kinetics of cardiac specific troponins and recommendations for measurement of this laboratory test in patients presenting with chest pain.

ANSWER: cTnI and cTnT levels are detectable above the upper reference limit by 3 hours from the onset of symptoms. Mean time to peak elevation levels without reperfusion therapy is 24 hours for cTnI and 12 hours to 2 days for cTnT. Because of continuous release from injured myocytes, cTnI levels may remain elevated for 5 to 10 days after an MI versus 5 to 14 days for cTnT. Levels are obtained at initial presentation of patients with chest discomfort and repeated 3 to 6 hours later to confirm the diagnosis of MI.

3. Describe the mechanism of action of the ARNI and its effect on serum BNP and NT-proBNP.

ANSWER: The ARNI contains the angiotensin receptor blocker drug called valsartan and the neprilysin inhibitor drug called sacubitril. Sacubitril inhibits the enzyme neprilysin, which is responsible for the breakdown of BNP. Because BNP is a substrate for neprilysin, the inhibition of neprilysin by the ARNI leads to increased BNP levels. In contrast, NT-proBNP is not a substrate of neprilysin, so its serum levels remain relatively unaffected by the ARNI.

4. Define the use of BNP levels in the clinical assessment of patients presenting with heart failure.

ANSWER: The BNP levels are a good marker of left ventricular dysfunction and a strong marker to predict morbidity and mortality in patients with heart failure. In conjunction with the standard clinical assessment, BNP is used to establish or exclude the diagnosis of heart failure in patients presenting to the emergency department for evaluation of acute dyspnea. Serum BNP levels correlate with the clinical severity of heart failure as assessed by New York Heart Association classification.

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