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136 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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PART II
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SYSTEM DISORDERS AND
DIAGNOSTIC TESTS
7. Cardiac Function and Related Tests ....139
Jessica DeAngelo and Jacqueline Finger
8. Lipid Disorders ................................. 149
Jill S. Borchert and Kathy E. Komperda
9. Endocrine Disorders ........................ 165
Eva Vivian
10. Renal Function and Related Tests .... 201
Kimmy T. Nguyen
11. Electrolytes, Other Minerals, and
Trace Elements
Lingtak-Neander Chan and
Jasmine S. Mangrum
................................. 229
12. Interpretation of Laboratory Tests
Associated with the Assessment
of Nutritional Status
Lingtak-Neander Chan and Sharon Wu
13. Arterial Blood Gases and
Acid–BaseBalance .......................... 287
Jeffrey F. Barletta
14. Pulmonary Function and Related
Tests.................................................. 301
Lori A. Wilken and Min J. Joo
15. Liver and Gastroenterology Tests ... 315
Paul Farkas, Joanna Sampson,
Matthew Slitzky,and Jason Altman
16. Hematology: Red and White Blood
Cell Tests .......................................... 355
Michael D. Katz and Timothy C. Jacisin
17. Hematology: Blood Coagulation
Tests.................................................. 377
Lea E. Dela Peña
......................... 275
137
18. Infectious Diseases: Bacteria .......... 403
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Sharon M. Erdman, Rodrigo M. Burgos,
and Keith A. Rodvold
19. Infectious Diseases: Fungi,
Viruses, and Mycobacteria
Rodrigo M. Burgos, Sharon M. Erdman,
and Keith A. Rodvold
.............. 445
20. Rheumatic Diseases ........................ 491
Susan P. Bruce
21. Cancers and Tumor Markers ........... 513
Sarah A. Schmidt
22. Drug Screens and Toxicological
Tests.................................................. 543
Peter A. Chyka
138
7
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Cardiac Function and Related Tests
Jessica DeAngelo and Jacqueline Finger
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
DOI 10.37573/9781585286423.007
e purpose of the heart is to pump blood throughout the body, delivering oxygen
and nutrients to the tissues. e 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. e 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.
e 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.
1
CARDIAC PHYSIOLOGY
e heart consists of two pumping units that operate in parallel, one on the right side
and the other on the le side. Each unit is composed of an upper chamber called the
atrium and a lower chamber called the ventricle. e atrium receives blood into the
heart and serves as a weak pump that helps move blood into the ventricle. e atrial
contraction, or atrial kick, is responsible for 20% to 30% of ventricular lling. e
right and le ventricles pump blood outside the heart and supply the primary force
that propels blood through the pulmonary and peripheral circulation, respectively.
e 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. is leads to the excitation and
contraction of the cardiac muscle, which is responsible for pumping blood to the
other organs.
e 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 lls the right ventricle through the tricuspid valve with an active lling 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 le atrium.1 Again, during diastole, blood empties from the le
atrium through the mitral valve into the main pumping chamber, the le ventricle.
With systole, the le ventricle contracts and blood is forcefully propelled into the
peripheral circulation via the aorta. At rest, the normal heart pumps approximately
1
1
139
140 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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4 to 6L 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)
e SV, dened as the volume of blood ejected during systole, is determined by intrinsic and extrinsic factors, including
myocardial contractility, preload, and aerload. e coronary
arteries, which supply the heart muscle, branch from the aorta
just beyond the aortic valve and are lled with blood primarily during diastole. In the face of increased myocardial metabolic needs, the heart can increase coronary blood ow by
vasodilation to meet myocardial oxygen demand.
1
Decreased CO compromises tissue perfusion and, depending on severity and duration, may lead to signicant 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. is 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.
is rupture results in an obstruction of the coronary lumen by a
thrombus composed of platelet aggregates, brin, and entrapped
blood cells. e 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).
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.
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 dierentiate between
the dierent types of ACS. Positive biomarkers, such as cardiac-specic troponins, are suggestive of NSTEMI and STEMI.
In the era of reperfusion therapy, diagnosing ACS accurately
and without delay is crucial for risk stratication and appropriate, life-saving treatment implementation. is section
describes the laboratory and diagnostic tests used in the diagnosis ofACS.
2-4
2-4
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. e
cardiac-specic troponins (cTn) have several attractive features
and have gained acceptance as the biochemical markers of
choice in the evaluation of patients with ACS.
e 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), troponinI
(TnI), and troponin T (TnT). e three subunits are located
along thin laments of myobrils, 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 laments.5 e TnC expressed by myocardial
cells in cardiac and skeletal muscle is identical. In contrast, TnI
and TnT isoforms are specic to cardiac myocytes. Monoclonal
antibody-based immunoassays have been developed to detect
cardiac-specic TnI (cTnI) and cardiac-specic TnT (cTnT).
Cardiac-specic TnI and cTnT are highly specic 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
12hours to 2 days (cTnT), and return to normal in 5 to 10days
(cTnI) or 5 to 14 days (cTnT) (Table 7-1). Levels typically
increase more than 20 times above the reference limit. e prolonged time course of elevation of cTnI and cTnT is useful for
the late diagnosis of MI.
6-8
Serial troponin levels should be obtained at presentation and
3 to 6 hours aer onset of symptoms. A level of cTnT and cTnI
that exceeds the decision level on at least one occasion during
the rst 24 hours aer an index clinical ischemic event indicates
MI. Most commercial immunoassays measure cTnI. Apattern that shows rising and falling troponin levels is required
for the diagnosis of ACS. is is especially helpful in dierentiating 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 stratication in patients with suspected ACS.
3,4,9,10
Signicant 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 and1.1,
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 aer
12-16
ACS.
Troponin levels should always be used in conjunction
with other clinical ndings. In one study, in-hospital mortal
ity was as high as 12.7% in a troponin-negative subgroup of
5
5
-
CHAPTER 7 • CARdiAC FunCTion And RElATEd TEsTs 141
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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 specicity
for cardiac injury. Circulation. 1993;88(1):101–106; Apple FS. Tissue specicity 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
mass, creatine kinase isoform ratios, and cardiac troponins I and T for acute myocardial infarction. Clin Chem. 1995;41(9):1266–1272.
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 (Table7-2).5 “See Minicase 1 for an example
of the use of these laboratory values to assess a patient presenting with ACS.”
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. Highsensitivity troponin assays detect concentrations of the same
proteins that conventional sensitivity assays are aimed at detecting but in much lower concentrations. ese 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 classied as
high-sensitivity assays, concentrations below the 99thpercentile should be detectable above the assay’s limit of detection for
>50% of healthy individuals in the population of interest. Highsensitivity assays, by expert consensus, should have a coecient
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. e study also showed that change in
troponin levels increase specicity 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 aer admission
al. Equivalent early sensitivities of myoglobin, creatine kinase MB
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-debrillator shocks,
cardioversion, endomyocardial biopsy)
Cardiomyopathy
Cardiotoxicity (doxorubicin, uorouracil, trastuzumab)
Cardiopulmonary resuscitation
Coronary angioplasty or vasospasm
Critical illness (respiratory failure, sepsis)
Heart failure (chronic and acute decompensation)
Heart transplant rejection
Inltrative 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
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. e 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 cuto 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
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 stratication 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.
142 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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MINICASE 1
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 4hours. He appears in distress. His vital signs include
BP 150/90mm 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.
Anechocardiogram reveals normal left ventricular size with an
estimated ejection fraction of 50% and anterior wall motion akinesis.
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 cuto values, sensitivity, specicity, and clinical interpretation among the dierent available
24
assays.
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.
e CK-MB isoenzyme is most specic for myocardial tissue
and has been used for the diagnosis of ACS. Serum CK-MB concentrations begin to rise 6 to 12 hours aer 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
Cardiac Enzymes
Creatine kinase
Normal range: male patients, 55 to 170 IU/L (0.92 to
2.84µkat/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 trans-
fer 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.
e enzyme CK is a dimer of two B monomers (CK-BB), two
M monomers (CK-MM), or a hybrid of the two (CK-MB). e
three isoenzymes are found in dierent sources: CK-BB isfound
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 specicity of the test for MI.
4
25
HEART FAILURE
Heart failure is a clinical syndrome in which the heart is unable
to pump sucient blood to meet the demands of the body. Heart
failure is diagnosed based on history and physical examination.
Although no specic test is used to diagnose heart failure, it is
classied based on an indirect measurement of the contractility of the le ventricle, called le ventricular ejection fraction
(LVEF). Heart failure is currently dened 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 lling during diastole. Patients
falling in an intermediate group with LVEF between 41% and
49% are classied as having HFpEF, borderline. Patients with
current LVEF >40% and a history of HFrEF in the past are classied as having HFpEF, improved.
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,
29
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MINICASE 2
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) 190/105mm Hg, heart rate (HR) 100 beats/min, and
respiration rate (RR) 30breaths/min. O2 saturation is 86% on room
air. Physical exam reveals elevated JVP at 18cm 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 1.5mg/dL with an estimated
peripheral edema, pulmonary congestion and edema, and dyspnea) and hypoperfusion (eg, tachycardia, cold extremities, cyanosis, and fatigue).
29
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 identied
with atrial natriuretic peptide and B-type natriuretic peptide
(BNP) being cardiac-specic peptides. e two peptides are
structurally similar and exert potent diuretic, natriuretic, and
vascular smooth muscle-relaxing eects. A 28-amino acid (aa)
peptide, atrial natriuretic peptide, is primarily secreted by the
atrial myocytes in response to increased atrial wall tension.
A32-aa peptide, BNP, is primarily secreted by the le ventricular myocytes in response to volume overload and increased
ventricular wall tension.
e precursor for BNP is PreproBNP, a 134-aa peptide that is
enzymatically cleaved into proBNP, a 108-aa peptide. e 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
30
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).
endopeptidase and natriuretic peptide receptor-mediated endocytosis, whereas NT-proBNP is cleared renally. e elimination
half-life of BNP is signicantly shorter than that of NT-proBNP
(20 minutes versus 120 minutes, respectively).
30
e 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 stratication of patients with heart failure and ACS.31
Inconjunction with standard clinical assessment, BNP and
NT-proBNP levels at the approved cuto points are highly sensitive and specic 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 Classication.
32,33
Inaddition, 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 le ventricular dysfunction during
hospitalization.
34-40
e 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
41-46
alone.
A meta-analysis of these trials conrmed the ndings 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
144 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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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 insuciency at an estimated glomerular ltration rate (GFR) <60mL/min/1.73m2 may
impact the interpretation of the measured natriuretic peptides.
Signicant correlation between NT-proBNP level and GFRs has
been shown, more so than that between BNP level and GFRs.
is 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 insuciency. 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 cutos for dierent GFR ranges may be necessary for
optimal interpretation in patients with renal insuciency.
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
e 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 cuto 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 specicity of BNP
levels for heart failure in obese and lean patients, a diagnostic
cuto level of ≥54 pg/mL for severely obese patients and a cuto 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
e 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. is
could potentially translate to earlier intervention and improved
outcome.
63,64
B-type natriuretic peptide
Diagnostic level: 100 pg/mL (100 ng/L)
e clinical diagnostic cuto 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 specicity of 90% for heart failure in a patient presenting
with shortness of breath.65 e 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 (Table7-3).
48
A study investigating the prognostic value of BNP levels in
patients with heart failure showed that the risk ratio of all-cause
mortality and rst morbid event (dened 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 signicantly higher than for patients with values below the
median. Furthermore, the study revealed a signicant quartiledependent increase in mortality and rst 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
TABLE 7-3. Interpretation of BNP and NT-proBNP Levels in Patients with Acute Dyspnea
a
BNP
NT-pro-BNP
a
In patients with estimated GFR <60 mL/min/1.73 m2 and BMI >35 kg/m2, different decision limits must be used.
b
In 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.
AGE
HEART FAILURE
UNLIKELY GRAY ZONE
HEART FAILURE
LIKELY
All <100 pg/mL 100–500 pg/mL >500 pg/mL
b
<50 yr <300 pg/mL >450 pg/mL
50–75 yr >900 pg/mL
>75 yr >1,800 pg/mL
CHAPTER 7 • CARdiAC FunCTion And RElATEd TEsTs 145
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mortality. Another study showed that admission BNP and cardiac troponin levels are signicant independent predictors of inhospital 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 cuto 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 specic
for the diagnosis of acute heart failure (Table7-3).
33,48
e 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 aected 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 day7.
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 stratication in the ambulatory/outpatient
and acute settings.
29,73
SUMMARY
e heart is a muscle that circulates blood rst to the lungs for
oxygenation and then throughout the vascular system to supply
oxygen and nutrients to each cell in the body. Many conditions
aect the heart’s ability to function eectively, 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. e
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 conrming 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 dierentiating systolic (reduced LVEF) from diastolic (preserved LVEF) heart failure so therapy may be targeted accordingly.
e 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 signicance greatly
impacts decisions regarding the implementation of appropriate
medication management strategies and preventive measures.
ACKNOWLEDGMENTS
e 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, specically NSTEMI or STEMI.
2.
Discuss the release kinetics of cardiac specic troponins
and recommendations for measurement of this labora
tory 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
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