LEARNING GUIDE

CARDIAC

CORE DIAGNOSTICS

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ABBOT T CARDIAC CONTENTS
LEARNING GUIDE
CARDIAC LEARNING GUIDE
INTENDED AUDIENCE INTENDED AUDIENCE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
The Cardiac Learning Guide is intended to serve the basic educational needs of healthcare professionals who are HOW TO USE THIS LEARNING GUIDE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
involved in the laboratory or who manage patients who have or are at risk of developing heart disease. This includes,
but is not limited to, laboratory technicians, laboratory technologists, supervisors and managers, nurses, suppliers, SECTION 1
and other physician office and laboratory support personnel.
ANATOMY AND PHYSIOLOGY OF THE HEART. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
The guide contains:

• a review of the anatomy and physiology of a healthy heart SECTION 2

• an explanation of the pathophysiology of two common conditions – acute coronary syndrome and heart failure ACUTE CORONARY SYNDROME. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

• information on the role of cardiac biomarkers in the diagnosis, prognosis, risk stratification, and therapy monitoring
SECTION 3
of various heart conditions
THE ROLE OF CARDIAC BIOMARKERS IN ACUTE CORONARY SYNDROME. . . 22
HOW TO USE THIS LEARNING GUIDE
A set of learning objectives appear at the beginning of each section to help you focus on the key concepts being SECTION 4
presented. Short quizzes at the end of the sections are designed to help you recall and retain important information. HEART FAILURE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Answers are included to provide you with instant feedback; it is recommended that you revisit the topics you didn’t
recall correctly before moving to the next section.
SECTION 5
A glossary of terms is also included at the end of this Learning Guide, featuring commonly used terms in cardiology. THE ROLE OF CARDIAC BIOMARKERS IN HEART FAILURE. . . . . . . . . . . . . . . . . . . . . 41

SECTION 6
PREVENTION OF CARDIOVASCULAR DISEASE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

APPENDIX
APPENDIX A: GLOSSARY OF TERMS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
APPENDIX B: CORRECT RESPONSES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
APPENDIX C: REFERENCES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

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 SECTION 1 The heart, in the most simplistic of terms, is a pump. It continuously circulates blood through the body. The blood, in
turn, delivers oxygen (bound to hemoglobin inside red blood cells) and nutrients to all of the organs and tissues. Blood
also carries away the wastes and carbon dioxide produced by the organs and tissues so they can be removed from the
body. This movement of blood throughout the body is almost entirely dependent on the heart’s pumping ability.

BASIC HEART ANATOMY

ANATOMY AND PHYSIOLOGY A short review of cardiac anatomy is required to understand in more detail how the heart works. The heart is divided
into two sides, right and left (Figure 1-1). The right side of the heart is further divided into a smaller, upper chamber
called the right atrium and a lower, larger chamber called the right ventricle. Similarly, the left side is also divided into
OF THE HEART a smaller left atrium above and a larger left ventricle below.

AORTA
LEARNING OBJECTIVES
PULMONARY ARTERY
SUPERIOR
When you complete this section, you will be able to: VENA CAVA
1. R
 ecognize key features of the cardiac anatomy including the heart chambers and coronary arteries
PULMONARY VEIN
2. Describe how blood flows through the heart, lungs, and body

3. U
 nderstand basic characteristics of the heart’s electrical conduction system
RIGHT ATRIUM LEFT ATRIUM
4. Explain systole and diastole and how this relates to blood flow

MITRAL VALVE
TRICUSPID VALVE

AORTIC VALVE
PULMONARY VALVE

RIGHT VENTRICLE
LEFT VENTRICLE
SEPTUM

Figure 1-1. The four chambers of the heart and the major blood vessels that distribute and collect blood from other
parts of the body

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BLOOD FLOW THROUGH THE HEART AND BODY Figure 1-2. Major arteries that supply blood to the myocardium

Next, we must understand how blood circulates through the heart and body (Figure 1-1). Blood returning
from the body arrives in the heart through two large veins, the superior vena cava and the inferior vena cava. This
blood is oxygen-poor, meaning it contains a lower concentration of oxygen and carries a large amount of carbon
dioxide produced by body tissues. From the vena cava, the oxygen-poor blood flows into the right atrium, then
through a valve called the tricuspid valve, and into the right ventricle. From there, the blood is pumped out through
the pulmonary valve, into the pulmonary artery, and to the lungs. LEFT MAIN CORONARY ARTERY

In the lungs, the blood moves into capillaries, which are tiny, thin-walled blood vessels that allow for the exchange
of gases (like oxygen and carbon dioxide). The carbon dioxide in the oxygen-poor blood is exchanged for new oxygen CIRCUMFLEX ARTERY
from the air through the thin capillary walls. After this exchange, the blood contains high levels of oxygen and can be
described as oxygen-rich. The oxygen-rich blood then returns to the heart through the pulmonary veins.

From the pulmonary veins, the oxygen-rich blood enters the left atrium. The blood continues from the left atrium, LEFT ANTERIOR
passes through the mitral valve, and empties into the left ventricle. The left ventricle, which is the largest and DESCENDING ARTERY
strongest of the four chambers of the heart, pumps the oxygen-rich blood through the aortic valve and out into a RIGHT CORONARY ARTERY
very large vessel called the aorta. From the aorta, blood travels into smaller arteries, then into arterioles, and finally
capillaries of the organs and tissues of the body. It is here that oxygen is removed from the blood and carbon dioxide,
a waste product from cells, replaces it. Finally, the blood that is now oxygen poor moves from the capillaries into
venules, then into veins, and back into the superior or inferior vena cava to repeat the process.

THE CARDIAC TISSUE

Electrical Activity in the Heart
For the heart to maintain this continuous pumping process, it also requires a large amount of oxygen. The heart is Cardiac muscle tissue has another distinctive quality. Unlike other types of muscle that require stimulation
made up of a unique type of muscle tissue that is not found anywhere else in the body. This specialized muscle tissue by a nerve or hormone to contract, the myocytes of the myocardium stimulate their own contraction.
of the heart is referred to as the myocardium. The cells that make up the myocardium are called cardiac myocytes. This self-stimulation is referred to as automaticity, and it means that the heart can stimulate its own muscle
These myocytes are almost entirely dependent on aerobic metabolism, meaning they require oxygen to function contraction without any input from the body.
normally and depend upon an oxygen-binding protein known as myoglobin.
The electrical impulses that cause the heart muscle to contract, or beat, in a regular fashion originate in the sinoatrial
Blood Flow to the Myocardium node (SA node) which is located in the wall of the right atrium. Once the electrical activity in the SA node has begun,
To continuously supply the heart muscle with oxygen, three major coronary arteries carry oxygen-rich blood it travels through both atria, stimulating the muscle to contract (or beat). After stimulating the atria, the electrical
from the aorta to the myocardium (Figure 1-2). Different coronary arteries supply blood to various parts of the impulse then travels to the atrioventricular node (AV node), down along a band of fibers (called the bundle of His)
myocardium. For example, the right coronary artery supplies blood to the right atrium, sections of both ventricles, to the right and left bundles in the right and left ventricles, respectively. The electrical impulse then spreads to the
and portions of the heart’s electrical conduction system. Other major coronary arteries include the left main coronary walls of both ventricles through pathways called Purkinje fibers and triggers the ventricles to contract (or beat).
artery, which divides into the left circumflex artery, and the left anterior descending artery, all of which are These electrical impulses that stimulate contraction of the atrium and ventricles are what produce the rhythmic,
responsible for delivering blood to a particular part of the heart. In a similar network, several large cardiac veins, coordinated pumping action of the heart. In turn, this pumping action generates the stroke volume which is felt
including the aptly named great cardiac vein, collect the oxygen-poor blood from the tissue and return it to the right as the pulse—the regular beat that can be monitored in the arteries throughout the body.
atrium via the coronary sinus. Maintaining a healthy circulation of blood into the coronary arteries is necessary to
assure optimal cardiac function. If an obstruction develops in any of the coronary arteries blocking the flow of blood,
the myocytes that are supplied by the obstructed artery will experience distress, and there will be insufficient oxygen
Although the heart creates its own electrical impulses, outside activity from nerves and hormones can
and nutrients flowing to that region of heart tissue.
influence how often and strongly the heart muscle contracts. For example, when a person experiences a sudden
fright, the heart may beat much faster and more powerfully than normal. In this situation, the sympathetic
nervous system and the adrenal glands release a hormone called norepinephrine. Norepinephrine changes how
the heart responds to electrical stimulation resulting in an increased heart rate and contractility of the
pumping chambers.

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THE PUMPING ACTION OF THE HEART: SYSTOLE AND DIASTOLE SECTION 1: REVIEW QUESTIONS
Another concept that is important to understand about the heart is systole and diastole. In simple terms, systole
means contraction of the myocardium and diastole means relaxation of the myocardium. However, the atria and 1. P
 lace the following term in the correct order to describe the flow of blood through the heart, lungs, and body.
ventricles do not contract or relax at the same time. For a brief period, both atria and both ventricles are in diastole Start with veins.
allowing blood from the vena cava or pulmonary veins to flow in passively. Once the SA node begins spreading its
right atrium pulmonary artery right ventricle
electrical impulse, the muscles of atria begin contracting to create atrial systole. During atrial systole, the walls of the
left and right atrium contract to push blood into the ventricles (which are still in diastole). The atria quickly return to veins pulmonary vein aorta
diastole and begin refilling with more blood in preparation for the next contraction. At this time, systole of the
ventricles occurs, and the walls of both ventricles contract to push blood into the aorta and pulmonary artery (the vena cava left atrium capillaries of organs and tissues
right ventricle pumps to the pulmonary artery, and the left ventricle pumps to the aorta). After systole is complete, lungs left ventricle arteries
the ventricles return to diastole and begin refilling with blood again. Both systole and diastole are energy-dependent
phases of the cardiac cycle, meaning the cardiac cells require energy to perform these functions. Dysfunction of either _______________________________________________________________________________________________________________________
one or both of these phases can lead to heart failure.
_______________________________________________________________________________________________________________________
In a healthy heart, the muscle tissue has an elastic quality, meaning it stretches easily but can quickly return to
its original shape (similar to a rubber band). This quality is sometimes referred to as elasticity. During diastole, _______________________________________________________________________________________________________________________
the muscle actively stretches as the heart fills with blood, and during systole, it springs back and contracts to
smaller ventricular chamber sizes to pump the blood out. _______________________________________________________________________________________________________________________

Systole of the ventricles is significantly more powerful than systole of the atria because the ventricles are thicker
and force the blood to travel much further. The left ventricle, the largest and thickest of the four heart chambers,
2. Which if the following statements about the heart is FALSE?
creates the most powerful contraction during systole because it must pump blood to the entire body. Efficient
pumping of the left ventricle is essential because it pushes the oxygenated blood to the tissues and organs and helps a. The cells of the myocardium function using aerobic metabolism and require a steady supply of oxygen
maintain the pressure required for the oxygen and carbon dioxide to be exchanged in the capillaries. If the left
ventricle does not pump well, the tissues and organs of the body may not receive an adequate supply of oxygen to b. T
 he cells of the heart generate their own electrical impulses to stimulate cardiac contraction; this
function normally. electrical impulse originates in the SA node

c. A
 rterial blood pressure is a measure of the pressure in the arteries during ventricular systole and at the
end of ventricular diastole; it is important that blood pressure isn’t too high or too low
Understanding the process of systole and diastole in the heart can also help explain a health parameter that is
d. The right atrium and ventricle contract first, pushing blood to the lungs, and the left atrium and ventricle
frequently measured in the clinical setting: blood pressure. More accurately termed arterial blood pressure,
contract second, pushing blood to the rest of the body
this is a measure of the pressure in the arteries during ventricular systole and the pressure at the end of
ventricular diastole. For example, a blood pressure reading of 120/80 mmHg indicates that the blood vessels
have a pressure of 120 mmHg during ventricular systole and 80 mmHg at the end of ventricular diastole.
It is important that blood pressure not be too high or too low. Hypertension, the medical term for blood 3. _____________________________________________ arteries supply the myocardium with oxygen-rich blood.
pressure that is too high, can damage organs and tissues of the body over time because of the high pressures.
Correspondingly, hypotension, or blood pressure that is too low, will not create enough pressure to allow
oxygen to be exchanged into organs and tissues. This can deprive the cells of oxygen needed for basic 4. Systole means _____________________________________________________ and diastole means __________________________.
function and can lead to organ and tissue damage.
The ____________________________________________________ ventricle creates the strongest contraction because it must
pump blood to the entire body.

UNDERSTANDING EJECTION FRACTION

The last concept that is important to understand about the heart is ejection fraction. When a person is resting, only
about 60 percent (normal range approximately 50-70 percent) of the blood that was in the ventricle at the end of
diastole is pumped out (so the ventricle is never completely emptied). The percentage of blood pumped out during
systole is called the ejection fraction. The actual number or percentage of ejection fraction can change as a result of
physical activity or other demands on the cardiac muscle. Measuring ejection fraction is one of the ways clinicians
can assess the health of a heart.

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SECTION 2 Cardiovascular diseases are the most common causes of death worldwide, and they affect individuals from
all backgrounds, incomes, and nations.2 Of the estimated 17 million deaths attributed to cardiovascular disease
worldwide in 2015, the World Health Organization estimates that 7.4 million were due to coronary heart disease,
which is a disease of the coronary arteries.2 Coronary heart disease manifests most often in the form of acute
coronary syndrome, the general term used to describe a myocardial infarction (the medical term for heart attack)
and unstable angina (the medical term for chest pain from heart disease). The American Heart Association estimates
that in the United States, someone experiences a myocardial infarction every 42 seconds.3 Of these individuals,

ACUTE CORONARY
approximately 15 percent will die within one year as a result of the myocardial infarction.3 Similarly, in Europe,
coronary heart disease is the single leading cause of mortality and the most common cause of premature death
(before age 65 years).4 Despite significant medical progress in diagnosing and treating cardiovascular diseases, the
SYNDROME World Health Organization estimates that it will still be the most common cause of death worldwide in 2030.5

DEFINING ACUTE CORONARY SYNDROME

Acute coronary syndrome (ACS) is a general name for a group of conditions that indicate that the heart muscle
LEARNING OBJECTIVES is not receiving enough oxygen. This situation is termed myocardial ischemia. There are three subcategories
of ACS: ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI),
When you complete this section, you will be able to: and unstable angina (UA).

1. D
 escribe the different types of acute coronary syndromes Diagnosis of ACS
2. Discuss the mechanisms of myocardial ischemia and infarction
SYMPTOMS
3. E
 xplain the process of diagnosing and risk stratifying patients with suspected acute coronary syndrome

4. Understand the role of cardiac biomarkers in diagnosis and risk stratification for patients with suspected AT LEAST 2/3 OF THESE MUST BE
acute coronary syndrome ABNORMAL FOR ACS

BIOMARKERS ECG/EKG
(Always done first, if STEMI changes on ECG/EKG,
STEMI management protocol initiated)

ST-Elevation Myocardial Infarction

An ST-elevation myocardial infarction (STEMI) is often the most severe form of ACS, and it is a type of myocardial
infarction (MI). It is estimated that STEMI accounts for about 25 percent of all MI, but it carries a high risk of
mortality with 10 percent of patients dying in the first 30 days after the event.3 In a STEMI, characteristic changes
occur on an electrocardiogram (ECG or sometimes referred to as EKG), a test that assesses electrical changes in the
heart. If a STEMI is identified on an ECG, it indicates that an obstruction has occurred in one of the coronary arteries
preventing the flow of oxygen-rich blood to the cardiac tissue.6,7 This obstruction is usually caused by the rupture of
plaque in the coronary artery. Plaque is a substance that can accumulate inside the coronary artery and is made up
primarily of cholesterol, fat, and calcium. If plaque in a coronary artery ruptures, it triggers platelet activation and
adhesion as well as the initiation of the clotting cascade that results in the production of fibrin. These events can lead
to the formation of a clot or thrombus inside the coronary artery that completely blocks the flow of blood. As a result
of this thrombus, the tissues and myocytes that the artery normally supplies blood to are deprived of oxygen.
With time, the oxygen deprivation leads to the death of the myocytes and permanent damage to the myocardium
resulting in a scar.
When a STEMI is identified on an ECG, immediate intervention is required to reopen the blocked coronary artery
(the term reperfusion is often used to describe reopening the artery). Reperfusion can be accomplished by

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administration of an intravenous medication called a thrombolytic or, more optimally, by an immediate procedure Non-ST-Elevation Myocardial Infarction
called a primary percutaneous coronary intervention (primary PCI) performed at a hospital with cardiac The second type of ACS, non-ST-elevation myocardial infarction or NSTEMI, also has serious consequences for
catheterization facilities. Both of these procedures will be discussed in more detail later in this section. Any delay in the heart. An NSTEMI is also a type of MI but is much more common than STEMI. Although estimates vary,
the time to reperfusion can increase the amount of damage that occurs to the myocardium. Because a STEMI leads to approximately 75 percent of patients presenting with MI are diagnosed with NSTEMI, and this is associated with an
the death of the cardiac myocytes, cardiac biomarkers are always elevated, but biomarker information is not required 18 percent chance of death in the first 30 days after the event.3 As the name implies, in an NSTEMI, the ECG does not
before proceeding to a reperfusion intervention. have the characteristic ST elevation seen with STEMI. However, an NSTEMI shares many other similarities with a
STEMI. An NSTEMI occurs when an obstruction occurs in the coronary artery that prevents adequate amounts of
blood and oxygen to flow to the tissues, and with time, this results in tissue necrosis (tissue death).6,7 Many things can
cause this obstruction, but, similar to a STEMI, the most common cause is plaque rupture and subsequent thrombus
A 12-lead ECG shows different views of the electrical activity in the heart from 12 distinct angles. During the
formation in a coronary artery. Other less common causes include vasospasm of the coronary artery or an excessive
test, a technician places a wire lead on 12 specific areas of the chest, arms, and legs. The ECG traces the view of
accumulation of plaque inside the coronary artery that almost completely occludes blood flow. Regardless of the
the heart’s electrical activity from each of these 12 areas of the body because they each reflect a unique view of
cause, an NSTEMI does cause ischemia in the cardiac myocytes because they are not receiving enough oxygen to
the heart. On the ECG report, each lead produces a tracing, and the tracings are labeled I, II, III, aVR, aVL, aVF,
function normally, and with time, this leads to the death of the myocytes and permanent damage to the myocardium.
V1, V2, V3, V4, V5, and V6. An ECG is useful for diagnosing a range of cardiac problems, including arrhythmias.
Elevated cardiac biomarkers are a confirmation of this damage and differentiate NSTEMI from unstable angina.
In ACS, paramedics, nurses, and physicians use the ECG to differentiate a STEMI from other causes of ACS
Additionally, these elevated biomarkers, along with other clinical factors, help identify higher-risk patients with
symptoms. An ECG can even identify which coronary artery is likely obstructed by looking at which leads have
NSTEMI who require cardiac catheterization.
ST elevation (Figure 2-1).

Unstable Angina
The third type of ACS is unstable angina (UA). Unlike STEMI and NSTEMI, traditional cardiac biomarkers are not
elevated in UA, myocyte death does not appear to occur, and it is not classified an MI.6,7 However, this understanding
ST Segment STEMI of UA is changing with the advent of more sensitive biomarker measurements, such as high-sensitivity troponin.
Normal ECG ST Elevation
ST Segment Many experts now believe that most patients diagnosed with UA are likely experiencing an NSTEMI, but the
P T P T conventional biomarker measurements are not sensitive enough to detect it.8 As a result, the use of the term UA will
likely be phased out over time. As in NSTEMI, cardiac catheterization is commonly performed in patients with UA.
QRS QRS

NSTEMI ST Segment NSTEMI ST Segment

ST Depression T Inversion Symptoms and Biomarkers in Diagnosing ACS
P T P T Regardless of whether it is classified as a STEMI or NSTEMI, an MI is caused by an ischemic event that results in
QRS QRS death of the myocytes and permanent damage to the myocardium. The term necrosis is often used to describe the
death of the myocytes. It is important to understand the criteria for recognizing necrosis and, in turn, diagnosing an
acute MI (Table 2-1).
Figure 2-1. The name ST-elevation MI is describing the changes that happen during a STEMI on an ECG:
Although the assessment process for acute MI begins with an ECG, clinicians must also consider the symptoms the
the ST segment in the ECG tracing is more elevated than normal. This test is useful for distinguishing a
patient is experiencing and measure cardiac biomarkers. Cardiac troponins are the preferred biomarker in this
STEMI from other types of MI.
clinical setting. The cells of the myocardium contain three types of troponin: troponin I, T, and C. Troponin C is also
found in skeletal muscle, but troponins I and T are very specific to cardiac myocytes and are therefore clinically useful
for measuring damage to the myocardium. When extended ischemia occurs, the cells die and begin to break apart
releasing the troponin into the bloodstream.6 If high levels of troponin T or I are measured in the blood, in the correct
clinical setting, it is confirmation that there is necrosis in the cardiac tissue (Table 2-1).6 To be diagnostic for MI,
cardiac troponin must not only exceed the 99th percentile of the upper reference limit but also must be rising or
falling in a characteristic pattern over time. Serial measurements of troponin can determine if concentrations are
changing; when troponin concentrations remain constant over an extended duration, it suggests that an alternative
diagnosis should be considered, such as renal failure, heart failure, or sepsis.9

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Table 2-1. CLASSIFICATION OF MYOCARDIAL INFARCTIONS
For initial treatment stratification by emergency medicine providers and cardiologists, an MI is classified as a STEMI
FOURTH UNIVERSAL DEFINITION OF MI
or NSTEMI. However, there are additional classifications for MI that further explain the mechanism leading to the
Criteria for ACUTE myocardial infarction (Types 1, 2 and 3 MI) ischemia. It is essential for providers to understand the cause of an MI to treat it appropriately.

The term acute myocardial infarction should be used when there is acute myocardial injury with clinical evidence of acute Type 1: The Spontaneous MI
myocardial ischaemia and with detection of a rise and/or fall of cTn values with at least one value above the 99th percentile The most common type of MI is a spontaneous, or type 1, MI (Figure 2-2).6 It is caused by rupture of plaque in a
URL and at least one of the following:
coronary artery. This rupture triggers the activation and aggregation of platelets, the initiation of the coagulation
• Symptoms of myocardial ischaemia cascade to produce fibrin, and ultimately the formation of a thrombus which causes complete or partial occlusion of
• New ischaemic ECG changes the artery. Plaque can accumulate inside any artery in the body, and the presence of plaque in the arteries is called
• Development of pathological Q waves atherosclerosis. The presence of plaque in the coronary arteries is particularly problematic, and when this occurs,
• I maging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an it is termed coronary artery disease. Plaque changes how blood moves through the arteries because it stiffens the
ischaemic aetiology walls of the artery and narrows the artery lumen. Plaque is also less stable than walls of the artery and more prone
• Identification of a coronary thrombus by angiography or autopsy (not for type 2 or 3 MIs) to breakage or rupture. As blood travels through the coronary arteries, occasionally the plaque will rupture. If the
Post-mortem demonstration of acute athero-thrombosis in the artery supplying the infarcted myocardium meets criteria for subsequent platelet aggregation and fibrin formation result in a significant obstruction in the artery, a type 1 MI
type 1 MI. occurs. Since a type 1 MI is caused by plaque (and coronary artery disease), much of the prevention and long-term
treatments focus on stabilizing current plaque (reducing the risk of rupture) and decreasing further plaque buildup.
Evidence of an imbalance between myocardial oxygen supply and demand unrelated to acute athero-thrombosis meets criteria
for type 2 MI.
Cardiac death in patients with symptoms suggestive of myocardial ischaemia and presumed new ischaemic ECG changes
before cTn values become available or abnormal meets criteria for type 3 MI.
There are additional types of MI (Types 4 and 5) that are very uncommon and are not included in this table.
For details of these types of MI, see “Other Types of MI” on page 17.
Criteria for myocardial injury

The term myocardial injury should be used when there is evidence of elevated cardiac troponin values (cTn) with at least one
value above the 99th percentile upper reference limit URL). The myocardial injury is considered acute if there is a rise and/or
fall of cTn values.
Cardiac troponin I (cTnI) and T (cTnT) are components of the contractile apparatus of myocardial cells and are expressed almost
exclusively in the heart. Increases in cTnI values have not been reported to occur following injury to non-cardiac tissues. The
situation is more complex for cTnT. Biochemical data indicate that injured skeletal muscle expresses proteins that are detected
by the cTnT assay, leading to some situations where elevations of cTnT could emanate from skeletal muscle. cent data suggest
that the frequency of such elevations in the absence of ischaemic heart disease may be higher than originally thought. cTnI and
cTnT are the preferred biomarkers for the evaluation of myocardial injury, and high-sensitivity (hs)-cTn assays are
recommended for routine clinical use. Other biomarkers, e.g., creatine kinase MB isoform (CKMB), are less sensitive and less
specific. Myocardial injury is defined as being present when blood levels of cTn are increased above the 99th percentile upper
reference limit (URL). The injury my be acute, as evidenced by a newly detected dynamic rising and/or falling pattern of cTn
values above the 99th percentile URL, or chronic, in the setting of persistently elevated cTn levels. MI TYPE 1 MI TYPE 2

Criteria for prior or silent/unrecognized myocardial infarction

Any one of the following criteria meets the diagnosis for prior or silent/unrecognized MI: Plaque rupture Vasospasm or endothelial Fixed atherosclerosis and Supply-demand
with thrombus dysfunction supply-demand imbalance imbalance alone
• Abnormal Q waves with or without symptoms in the absence of non-ischaemic causes
• Imaging evidence of loss of viable myocardium in a pattern consistent with ischaemic aetiology
• Patho-anatomical findings of a prior MI Figure 2-2. Differentiation between myocardial infarction (MI) types 1 and 2 according to the condition of the
coronary arteries

From: Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial
Infarction. Third universal definition of myocardial infarction. Eur Heart J. 2012; 33:2551–2567.
Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD, the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial
Infarction. Fourth universal definition of myocardial infarction. JACC. 2018.08.1038.

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Type 2: The Ischemic Imbalance MI THE PROCESS OF CARE IN MYOCARDIAL INFARCTION
Unlike a type 1 MI, a type 2 MI is not triggered by a thrombus forming in a coronary artery. Instead, a type 2 MI is
Because damage to the cardiac tissue happens quickly once an obstruction occurs, it is essential that medical
the result of supply and demand imbalance in the heart where the coronary arteries are not supplying adequate providers understand how to manage patients experiencing ACS efficiently. Figure 2-3 is a flowchart explaining
oxygen for the myocytes to function normally—the supply does not meet the demand. There are many reasons that the process of care for patients with ACS. Any patient with ACS symptoms is classified as very high acuity in the
this can occur (Figure 2-2). Some type 2 MIs are caused by a vasospasm, or spasm of the blood vessel wall, which can emergency department and requires rapid assessment and close monitoring. Nurses, physicians, and other support
prevent blood from flowing appropriately to the myocardium, leading to ischemic damage. Others can be caused by staff must work together to ensure that this occurs in a timely and efficient manner.
coronary artery disease where plaque accumulation can limit the blood flow through a coronary artery. If the heart
needs more oxygen because it is beating more rapidly than normal, as often occurs in a severe infection, and more
oxygen is unable to flow to the tissue because of the plaque accumulation, then a type 2 MI occurs. Moreover, in some
SUSPECTED ACS
cases, the coronary arteries may be completely normal and healthy, but something else has led to an imbalance in the
supply and demand resulting in an MI. Examples of this would include very high myocyte oxygen demand from an
ongoing high heart rate or severe anemia where there are too few red blood cells circulating to bring the myocytes
adequate oxygen. 12-LEAD ECG†

Type 3: Cardiac Death MI

Patients who suffer cardiac death, with symptoms suggestive of myocardial ischaemia accompanied by presumed new
ischaemic ECG changes or ventricular fibrillation, but die before blood samples for biomarkers can be obtained, or ST-ELEVATION NO ST-ELEVATION
before increases in cardiac biomarkers can be identified, or MI is detected by autopsy examination.

Immediate reperfusion Risk Stratification

Other Types of MI with primary PCI* Medical history, physical exam findings,
There are two other types of MI that should be mentioned for completeness. A type 4 MI is related to a percutaneous (or fibrinolytic if PCI unavailable) repeat ECG†, and serial biomarkers
coronary intervention (PCI) procedure or a problem with a stent (a thin, mesh wire tube that props open a blood
vessel) previously placed in a coronary artery.6 Lastly, a type 5 MI results from a coronary artery bypass graft surgery
(a surgical procedure that will be discussed later in this section).6 Although all types of MI are clinically important,
Serial biomarkers Based on risk stratification
this guide will focus on type 1 and 2 as they are the most common in the clinical setting.
(results not needed prior to reperfusion) 1. Initiate pharmacotherapy for NSTEMI‡
The key concept to appreciate about MI is that anything that prevents the myocardium from receiving adequate ECG† monitoring after reperfusion 2. Begin additional diagnostic testing
supplies of oxygen will lead to ischemia. If this ischemia is prolonged, it will lead to myocyte death and
tissue necrosis.
Begin adjunctive Angiography
pharmacotherapy Low risk Medium risk High risk
with possible PCI*
for STEMI**

Non-invasive testing Positive test

(e.g., stress testing)

Negative test

†
ECG – electrocardiogram
Non-cardiac chest pain,
* PCI – percutaneous coronary intervention
address any cardiac risk factors
‡
NSTEMI – non-ST-elevation myocardial infarction or alternative diagnoses; discharge
** STEMI – ST-elevation myocardial infarction may be considered if appropriate

Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD, the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial
Infarction. Fourth universal definition of myocardial infarction. JACC. 2018.08.1038. Figure 2-3. Process of care for patients with suspected acute coronary syndrome (ACS)7,11,23

16 | Learning Guide: Cardiac 17 | Learning Guide: Cardiac

ACS Symptoms Next Steps
Any person experiencing symptoms of ACS should be evaluated immediately by a healthcare provider. Chest pain, Although STEMI is the first type of ACS to be screened for and diagnosed, the majority of MIs are not STEMI.
sometimes radiating down the left arm, is probably the most widely recognized symptom. But many patients, It is estimated that approximately 75 percent of MIs are NSTEMI, and further testing is needed to establish this
especially women and the elderly, may experience other symptoms like chest pressure, nausea, sweating, jaw or diagnosis (Figure 2-3).3,11
back pain, shortness of breath, dizziness, or light-headedness.10
After the ECG is performed within 10 minutes of presentation and determined not to be a STEMI, cardiologists and
emergency medicine providers will consider five different aspects of the patient’s clinical status to further stratify
STEMI the risk for MI and guide the next steps in treatment.
The first step in the assessment of a patient with ACS symptoms is to perform an ECG (Figure 2-4). An ECG will be
used to determine if the patient is experiencing a STEMI. The characteristic ST elevation on ECG, in conjunction with
ACS symptoms and elevated cardiac biomarkers, are diagnostic for STEMI, but treatment should never be delayed
waiting for biomarker results once STEMI has been identified on ECG.6,11 A STEMI is most often a type 1 MI, and
1 ECG Changes
patients need immediate reperfusion therapy to open the occluded coronary artery and prevent further myocardial
damage from occurring. The preferred treatment for a STEMI is a primary PCI performed as soon as possible after After an initial ECG that is normal or non-diagnostic, current guidelines recommend that the ECG should
hospital arrival. be repeated several times during the first hour after presentation (usually at 15 or 30 minute intervals),
especially if the patient’s symptoms return.7 This will allow physicians to evaluate for any new ECG
For the PCI procedure, the patient is promptly transferred to the cardiac catheterization laboratory (or cath lab). changes that could indicate ischemia. Additionally, the ECG can be checked any time there is a change
First, a specialized catheter is threaded through a large artery (either the femoral artery in the groin or the radial in patient status. It is common for patients with chest pain to have multiple ECGs over the course of
artery in the wrist) up into the heart. Next, the physician will use a dye to evaluate the blood flow through the evaluation in the emergency department or hospitalization.
coronary arteries (this is called an angiogram) and identify the exact area of occlusion. Finally, the blocked coronary
artery is opened by inflating a tiny balloon-like device in the blocked region, and then a stent (or mesh wire tube) may 2 Cardiac Biomarkers
be placed in the area of the blockage to prop the artery open.12 The PCI procedure rapidly restores blood flow to the It can be several hours after an ischemic event occurs before the cardiac troponin is detected in the
ischemic myocardium. blood using traditional assays; therefore, conventional cardiac troponins are measured several times in
If PCI is unavailable, a physician will usually prescribe a thrombolytic drug for a patient experiencing a STEMI. the first hours after symptom onset and presentation to the hospital.7 The American Heart Association/
A thrombolytic promotes degradation of the fibrin in the thrombus, to quickly lyse the clot in the coronary artery.13 American College of Cardiology guidelines recommend measuring conventional cardiac troponin at the
time of initial presentation and then repeating this measurement three to six hours after the symptoms
began.7 If high-sensitivity troponin is available, it is recommended that this test be repeated three hours
after arrival in the emergency department for confirmation of a negative result.14 It is also necessary for
I aVR V1 V4 the diagnosis of MI to document that the cardiac troponin is rising or falling, rather than maintaining the
same concentration. Accordingly, the series of cardiac troponins is usually continued even if the first
measure is already elevated. Cardiac biomarkers will be discussed in more detail in Section 3.

3 Physical Exam Findings

II aVL V2 V5
On the initial physical exam, the clinician will determine if other, non-cardiac causes of chest pain need
to be considered and will evaluate for signs of myocardial damage, such as heart failure symptoms.7

4 Risk Factors for ACS

Many factors increase a patient’s risk for a cardiac event and need to be considered: older age, previous
III aVF V3 V6 myocardial infarction, family history of heart disease, smoking, hypertension, hyperlipidemia, obesity,
physical inactivity, and diabetes.7,10

5 Risk Assessment Tools

Clinicians will often use a risk prediction score such as the TIMI risk score, the GRACE score, or the
II
HEART risk score. These tools not only assist in predicting an MI but they also help identify patients in
need of urgent intervention with PCI and can estimate risk for death.7

Figure 2-4. Example of a 12-lead ECG

18 | Learning Guide: Cardiac 19 | Learning Guide: Cardiac

NSTEMI SECTION 2: REVIEW QUESTIONS
An NSTEMI is diagnosed when rising or falling cardiac biomarkers exceed the upper reference limit and the patient
meets the criteria for MI listed in Table 2-1 on page 15. Patients with NSTEMI are treated with antiplatelet 1. M
 atch the acronym or word with the correct description
medications, such as aspirin, and anticoagulant medications, such as heparin or enoxaparin, to prevent further
extension of the thrombus.7 However, thrombolytics are not used in NSTEMI. Atherosclerosis ________ PCI ________ MI ________ Troponin ________ Calcium ________

In addition to treatment with medication, patients with NSTEMI usually undergo a coronary angiography (cardiac a . A term used to describe an ischemic event that leads to permanent damage to the cardiac muscle
catheterization) procedure to examine the coronary arteries.7 An angiography procedure, similar to what is done for b
 . A procedure used to reopen a blocked coronary artery
STEMI, involves inserting a catheter into a large artery (in the groin or wrist) and threading it up to the heart. Once
in the heart, a dye is released that will flow into the coronary arteries, and the physician will use an x-ray device to c . A substance normally found in cardiac muscle cells that is released when the cells die 
evaluate the flow of blood through the coronary arteries.12 As the dye flows through, it will opacify the coronary
d
 . A substance that is a part of plaque deposits in the coronary arteries
arteries and display their branches like the branches of a tree (Figure 2-5). During this procedure, narrowings that
indicate a blockage or lesion may be seen. If a blockage is identified, sometimes it can be opened using a balloon and e . A term used to describe plaque buildup inside the arteries
stent (similar to the treatment of a STEMI), and sometimes extensive atherosclerosis of the coronary arteries is
identified that cannot be treated with PCI and stenting. Severe, extensive atherosclerosis may be treated with
coronary artery bypass grafting (CABG), which is sometimes referred to as open-heart bypass surgery.
2. Describe the general mechanism for how myocardial damage occurs in a myocardial infarction
Occasionally, there is no atherosclerosis, and the MI was caused by something else (as sometimes occurs with
type 2 MI). If this is the case, it is important to identify and treat the underlying cause of the MI to prevent further _____________________________________________________________________________________________________________________
myocardial ischemia.
_____________________________________________________________________________________________________________________

_____________________________________________________________________________________________________________________

_____________________________________________________________________________________________________________________

3. Select the statement(s) describing diagnostic requirements for a myocardial infarction

a . R
 ising or falling cardiac biomarkers with at least one measured over the 99th percentile
of the upper reference limit

Figure 2-5. An x-ray evaluating blood flow through the coronary arteries during a coronary angiography b
. N
 ew changes to the ECG, imaging studies demonstrating new cardiac muscle damage,
Attribution: Suh I-W, Lee CW, Kim Y-H, et al. “Catastrophic Catecholamine-Induced Cardiomyopathy Mimicking Acute Myocardial Infarction, Rescued
or symptoms of cardiac ischemia such as chest pain
by Extracorporeal Membrane Oxygenation (ECMO) in Pheochromocytoma.” Journal of Korean Medical Science. 2008;23(2):350-354.
c . Low levels of oxygen (low oxygen saturations) measured on pulse oximetry

d
 . A and B are both correct

e . B and C are both correct

No MI Identified
f . All of the above are correct
In many cases, patients presenting with symptoms of ACS are not experiencing an MI. Patients who have negative
biomarkers after repeat measurement are usually referred for additional testing based on their risk factors for ACS.
Patients at high risk for coronary artery disease may still undergo an angiography procedure, but many patients,
especially individuals with low or moderate risk for coronary artery disease, are referred for other types of tests. 4. The preferred cardiac biomarker for diagnosing MI is _____________________________________________.
Treadmill ECG, stress myocardial perfusion imaging, coronary CT angiography, and other diagnostic tests are useful,
non-invasive tools for identifying undiagnosed coronary artery disease in these patients.7 If a patient is determined to
have coronary artery disease, they are at an increased risk for having an MI. In this situation, doctors will work with
the patient to lower the risk of a future MI with medication and lifestyle changes.7

20 | Learning Guide: Cardiac 21 | Learning Guide: Cardiac

SECTION 3 As explained in Section 2, cardiac biomarkers, specifically cardiac troponin, are essential for the identification of
myocardial necrosis and infarction. However, advances in the measurements of cardiac troponins are changing how
acute coronary syndrome (ACS) patients are evaluated and risk-stratified. And new biomarkers are also emerging
that, in the future, may have potential roles in diagnosis and prognostic evaluation of patients with ACS.

TROPONIN

THE ROLE OF CARDIAC

Troponin is an abundant protein contained in the cardiac myocytes. It works inside the cell as part of the contractile
mechanism to facilitate myocyte contraction. The troponin complex in a cardiac myocyte has three subunits,
troponins C, T, and I (Figure 3-1).15 Both skeletal and cardiac muscle synthesize troponin C, but troponin T and I are
BIOMARKERS IN ACUTE highly specific to cardiac muscle. Together, troponin T and I are considered the cardiac troponins. In the appropriate
clinical setting, if significant elevations of these troponins are detected in the blood, and they are determined to be

CORONARY SYNDROME (ACS) rising or falling, they are a useful tool for confirming cardiac necrosis.15 Notably, most healthy individuals have small
but measurable concentrations of troponin in the bloodstream in a normal physiologic state possibly as a result of cell
turnover (the normal life and death cycle of a cell).15 However, at these low concentrations, only high-sensitivity
assays can detect it.15

TnI TnC TnT

LEARNING OBJECTIVES
When you complete this section, you will be able to:

1. D
 escribe the role of troponin in ACS

2. Discuss differences between high-sensitivity and conventional troponin assays

3. U
 nderstand important considerations for implementing high-sensitivity troponin assays within an institution

4. Recognize other cardiac biomarkers with potential roles in ACS

ACTIN TROPOMYOSIN
Figure 3-1. The troponin complex

Although the troponin protein was initially identified in 1965, the first assay for measuring troponin I in the
serum was not developed until 1987.16 An assay for troponin T followed in 1989.16 Through the 1990s and 2000s,
improvements in the immunoassays significantly increased the precision and sensitivity of these tests.
The conventional troponin assays in current use are one hundred to one thousand times more sensitive than
the original assays developed in the 1980s.17

Assays for troponins T and I are both used today in the care of patients with suspected ACS, which may exhibit one
or more of the following biological variations:

1. D
 iurnal variation: The amount of circulating troponin may vary throughout the day in individuals not experiencing
myocardial infarction (MI).18

2. Kidney disease and diseases of the skeletal muscle: Some assays measuring troponin in these settings exhibits
less variation than other assays, and some troponins can be chronically elevated in patients with End Stage
Renal Disease.19,20,21,25

3. S
 T-elevation myocardial infarction (STEMI): In this category of patients, the concentration of some subunits of
troponin appear to follow a linear decline after the event, whereas some appear to decline and then peak again
shortly after the MI.22

22 | Learning Guide: Cardiac 23 | Learning Guide: Cardiac

4. Macrotroponins: Consist of troponin bound to immunoglobulins (autoantibodies). Some assays may detect Table 3-1. Reasons for Troponin Elevations Not Related to Myocardial Infarction15,17,23
these autoantibodies.150
CARDIAC NON-CARDIAC
5. B
 iotin interference: It was recently reported that some immunoassays, including troponin assays, are susceptible
to interference from biotin (or vitamin B7) supplements.147 Laboratory personnel and clinicians should be mindful Hypertensive emergency Critical illness
of this interaction when interpreting cardiac troponin results. Arrhythmias Sepsis
6. Hemolysis: A hemolyzed blood specimen can also result in inaccurate measurements of troponin assays. Heart failure Pulmonary embolism or hypertension
Thus, hemolysis needs should be noted when troponin concentrations are reported, and attempts should be Myocarditis Kidney dysfunction
made to redraw the specimen whenever possible.38 Cardiomyopathy Serious neurological events (e.g., stroke)
Aortic dissection Thyroid disease
Structural heart disease (e.g., valve disease) Drug toxicity (e.g., chemotherapy, cocaine)
CONVENTIONAL TROPONIN ASSAYS Physical trauma to the heart Extreme endurance exercise
Heart surgery/procedure (e.g., PCI*) Rhabdomyolysis
In the United States (US), conventional troponin I and T assays are still in widespread use. Although these assays are
not sensitive enough to measure troponin in most healthy individuals, they are very reliable for detecting troponin
*PCI – percutaneous coronary intervention
levels that exceed the 99th percentile of a healthy reference population.17 The performance target for these
conventional assays is to measure troponins with a 10 percent coefficient of variation at the 99th percentile of their
reference population, but not all currently available assays achieve this.17 Because troponin elevation can have other, non-cardiac causes, it is essential that clinicians employ good clinical
judgment during the risk stratification process for ACS. This process begins by taking a history from the patient
With conventional assays, troponin I or T can be measured in the blood six to 12 hours after the onset of ACS
and assessing symptoms, followed by a physical examination, an electrocardiogram (ECG), and then biomarker
symptoms.7,15 After an MI, troponins will typically remain elevated for four to ten days.7,15 The normal half-life for
measurement. Only when all of these features are considered together can an accurate diagnosis be made.
troponin in the plasma is about two hours, and it is at least partially removed by the kidneys.15

To meet the biomarker criteria for MI, not only must at least one troponin measurement be over the 99th percentile of The ACC/AHA guidelines for NSTEMI recommend measuring either troponin I or T when a patient with suspected
the reference range but the troponin measurement must also be rising or falling in what is considered a characteristic ACS presents to the emergency department (ED).7 This measurement should be repeated three to six hours after
pattern for MI.7 The amount of rise or fall is not defined in the global consensus document, Third Universal Definition the symptoms started (or three to six hours after presentation) in all patients with ACS symptoms.7 Additional
of MI, which requires the individual clinician to interpret the pattern of serial troponin values over time. A more measurements after six hours should be considered in patients who are stratified as moderate or high risk for ACS.7
specific definition is included in the American College of Cardiology and American Heart Association (ACC/AHA)
non-ST-elevation MI (NSTEMI) guidelines; this document describes an increase or decrease of 20 percent from the
LIMITATIONS TO CONVENTIONAL TROPONIN ASSAYS
initial elevated value when using conventional troponin assays.7 In addition, these guidelines also suggest if the initial
value is near or below the 99th percentile of the reference range, a change of ≥3 standard deviations of the variation Due to the extended time required to detect troponin in the blood using conventional assays, there can be a delay in
from the initial value is required to meet the definition for rising or falling.7 The ACC/AHA guidelines also stress that the diagnosis of MI, which could also result in the delay of appropriate treatment. Following clinical evaluation and
the clinical laboratory should clearly identify when a significant change has been identified in troponin concentrations assessment for STEMI via ECG, most patients presenting to an emergency department (ED) with ACS symptoms will
during serial measurements.7 undergo a “rule-in” or “rule-out” protocol where serial cardiac markers are measured. Measuring the conventional
troponin several times over a three- to six-hour period (or even longer period for higher risk patients) should yield a
The reason for the rising or falling requirement for troponin is to aid in differentiating between a true MI and other
positive result if a patient is experiencing an NSTEMI. This process can result in prolonged ED admission times for
potential causes for troponin elevation (Table 3-1). There are a variety of other cardiac conditions that can be
patients who are ultimately “ruled out” (not experiencing an MI) and delays in initiation of treatments for patients
associated with elevated troponin concentrations, sometimes chronically. These can include myocarditis, pericarditis,
who are eventually determined to be experiencing an NSTEMI.
tachyarrhythmias, acute or chronic heart failure, and significant trauma to the heart.7 Likewise, a myriad of non-
cardiac problems, such as renal dysfunction, sepsis, burns, respiratory failure, and drug toxicity, can also cause Another limitation of conventional troponin assays is that they may lack enough sensitivity to detect small elevations
elevations in troponin. Indeed, because troponin is partially removed by the kidney, individuals with end-stage renal in troponin that can occur in a less extensive MI or in those with lower circulating levels of troponin, such as women
disease may have chronic elevations of troponin.7,24 or patients presenting early after the onset of symptoms.26,27 This scenario could cause an NSTEMI patient to be
erroneously sent home, where they may go on to suffer cardiac complications or, in the worst case, may die.

The potential to miss the diagnosis of MI completely (incorrect “rule-out”) and the extended time required to identify
MI (delayed “rule-in”) are the primary limitations of conventional troponin tests in clinical practice. The need to
overcome these limitations led to the development of more sensitive and precise troponin assays.

24 | Learning Guide: Cardiac 25 | Learning Guide: Cardiac

HIGH-SENSITIVITY TROPONIN ASSAYS There have been varying proposals on how to define and differentiate high-sensitivity assays from conventional
troponin assays. In 2012, a task force created by the International Federation of Clinical Chemistry (IFCC) proposed
Due to the shortcomings of conventional troponin measurements, high-sensitivity troponin (hsTn) assays have been
that hsTn assays be defined using two parameters:
developed. The hsTn assays have been used for several years outside the US. These assays are 10 to 100-fold more
sensitive than the conventional troponin assays and can detect the very low levels of troponin that circulate in healthy • The total imprecision (coefficient of variation) at the 99th percentile value should be ≤10 percent28
individuals (Figure 3-2).28 Though troponin was once thought only to enter the circulation when myocytes had been
damaged, we now know that it can be found in normal individuals. The reasons for this have yet to be fully elucidated, • Measurable concentrations below the 99th percentile should be attainable with an assay at a concentration value
but myocyte turnover and increased cell permeability have been suggested as mechanisms.29,30 above the assay’s limit of detection (LOD) for at least 50 percent (and ideally >95 percent) of healthy individuals28

– I n 2018, the IFCC/AACC Task Force expanded on this point by requiring both men and women individually attain
measurable concentrations, with at least 50% measurable concentrations above the assay’s LoD148

Multiple high-sensitivity assays exist for troponin I, and one fifth-generation assay for troponin T is available.
99th Percentile When compared directly, both types of troponin assays provide similar sensitivity and specificity for the biomarker
requirement for MI.27 The hsTnI assay may provide greater sensitivity for detecting acute MI in patients who present
to the ED shortly after the onset of symptoms.27 Both assays also provide prognostic information and have
PATIENTS WITH
NORMAL LEVELS demonstrated the ability to predict mortality risk in ACS patients.

It should also be noted that there appear to be differences in troponin values based on age and sex, although this
variation may depend on the assay used.28 A study comparing women and men presenting with suspected ACS
CARDIAC DAMAGE DUE evaluated diagnostic thresholds using a hsTnI assay; researchers found that when using hsTnI, a sex-specific
TO NON-AMI CAUSES threshold for MI diagnosis doubled the diagnosis of MI in female participants.26 Employing sex-specific thresholds
also aided in identifying women at high risk for complications and death after MI.26

PATIENTS WITH HIGH-SENSITIVITY TROPONIN ASSAYS IN PRACTICE: “RULE OUT” AND “RULE IN”
MYOCARDIAL NECROSIS
The hsTn assays have several significant advantages over the conventional assays that can be categorized as
improving either “rule-in” or “rule-out” of MI.
HIGH-SENSITIVITY TROPONIN ASSAY
4th gen troponin assay
Rule Out
1st-3rd gen troponin
One of the primary advantages of hsTn assays is that they have higher negative predictive value for acute MI than
LEVEL OF CARDIAC TROPONIN conventional tests. Since they can reliably detect very low levels of troponin, physicians can rule out MI in patients
with these very low levels with more confidence than ever before (very low levels were unreportable with
conventional assays). When studied in the clinical setting, the hsTn assays have shown a great deal of promise.
There is increasing evidence to indicate that when patients with suspected ACS are tested with a hsTn assay on
Figure 3-2. The sensitivity of high-sensitivity troponin assays allows for measurement of troponin in normal healthy
arrival to the ED using a risk-stratification algorithm, a negative hsTn measurement has over 95 percent negative
individuals, whereas earlier generation assays were only sensitive enough to detect troponin elevation resulting from predictive value for ruling out an MI.14,31 At three hours after presentation, this number rises to over 99 percent, and
significant necrosis in MI, or occasionally, severe damage from other causes accordingly, a repeat measurement of hsTn is recommended in all patients three to six hours after presentation.32
Adapted from: Garg P, Morris P, Fazlanie AL, et al. “Cardiac Biomarkers of Acute Coronary Syndrome: from History to High-sensitivity Cardiac The ability to rule out an MI more quickly shortens the ED admission time for many patients, overcoming one of the
Troponin.” Internal and Emergency Medicine. 2017;12(2):147-155. Used under CC BY http://creativecommons.org/licenses/by/4.0/ modified primary limitations of conventional troponin assays (Figure 3-3).
from original.

Rule In
The other key advantage of hsTn assays is the ability to detect an acute MI very early before conventional tests
would be positive.23,27 Using conventional assays, there is a “troponin-blind” period during the first hours after the
onset of MI when troponin concentrations are still reported as negative.23 The hsTn assays significantly shorten this
“troponin-blind” period, so patients experiencing an MI are more likely to have measurable troponin elevations when
they first present to the ED.23 Studies where hsTn have been measured at presentation and then repeated one-hour
later have shown promise in improving early “rule-in” as well as “rule-out”.33 Moreover, this increase in sensitivity
reduces the risk of missing an MI with less troponin elevation completely.23 This can be a significant problem in
women, and, predictably, the use of hsTn assays have demonstrated the ability to increase the diagnosis of MI
in women.26

26 | Learning Guide: Cardiac 27 | Learning Guide: Cardiac

In identifying patients with MI earlier and more often, the hsTn assays also overcome two problems associated with However, researchers have been exploring how these new high-sensitivity assays may modify the definition of change
the conventional assays. First, they reduce the delay to appropriate treatment for MI because it shortens the time for in troponin concentrations. A study by Keller et al. examining the use of high-sensitivity troponin assays for early
diagnosis in many situations. And second, it reduces the risk of missing an MI completely and the associated risk of rule-out of MI demonstrated the value of using a 50 percent change (or delta) between initial and three-hour troponin
cardiac complications and death (Figure 3-3). measurements, a strategy known as a scaled troponin approach.34 Other groups have advocated for the use of an
absolute change, rather than a percent change, for meeting the criteria of rising or falling troponin with high-
sensitivity assays.35 A position statement from the IFCC outlined the potential benefits of using this method
HsTn Assays: Things to Consider
although ultimately concluded that limitations exist for any method that defines troponin change in MI.36
It is essential to emphasize that the high-sensitivity assays for troponin trade specificity for increased sensitivity.
There may be more troponin elevations detected with hsTn assays that are not related to ACS. But it remains
important for clinicians to be mindful that other conditions such as heart failure, sepsis, and kidney failure that HnTn Assays: Effects on Patient Care
can cause elevation of the conventional troponin assays also, to a greater degree, cause elevations of hsTn measures The high-sensitivity tests overcome the problem of prolonged diagnostic time for MI that can delay treatment.
(Table 3-1 on page 26). Multiple studies have found that the leading causes of “positive” high-sensitivity troponin They can also dramatically shorten patient evaluation time in the ED and have demonstrated that they can reduce
elevations are not MI. Thus, each patient with an elevated value needs careful consideration for both the MI and overall healthcare costs.37 Furthermore, they avoid the predicament of potentially missing an MI with a lesser
non-MI determinants. As such, it is even more imperative that physicians employ good clinical judgment when degree of troponin elevation.
evaluating patients with suspected ACS. All aspects of the patient’s presentation should be assessed to appropriately However, with this increase in sensitivity, there is a loss of specificity. Clinicians need to be aware that there may be
stratify a patient’s risk for ACS, including symptoms, medical history, physical exam information, ECG, more troponin elevations reported with the new assays that are not related to ACS, and as indicated above, these cases
and troponin concentrations. will be in the majority. More than ever, troponins are only one piece to consider in the comprehensive evaluation of
It is also important to remember that to meet the biomarker criteria for an MI; troponin concentrations must be the patient. Despite these concerns, when used appropriately, these high-sensitivity tests have the potential to
rising or falling over time. Given the increased sensitivity of these new assays, there has been renewed debate about dramatically change how patients with ACS symptoms are managed, saving lives and money.
how this rise or fall should be defined, and at the time of this publication, there is no formal consensus. Notably, none
of the prior definitions of MI utilized high-sensitivity troponin values, and the AHA/ACC guideline recommendations
IMPLEMENTING HIGH-SENSITIVITY TROPONIN TESTING
on the percentage change in troponin concentrations required for MI are for conventional assays.6, 7
When introducing hsTn testing to an institution, a variety of factors need to be considered. A multidisciplinary
approach is essential, and representatives from all key areas affected by the change need to be included in the
implementation process. Education is of particular importance; physicians, mid-level providers, nurses, and other
healthcare personnel must understand the differences in sensitivity and specificity of the high-sensitivity assay.38
Likewise, protocols and workflow, particularly in the ED, may need to be modified before implementing an assay
with greater sensitivity.38 The hsTn assays are most useful when they are used as part of an ACS risk assessment
Prior generation cardiac algorithm.23 Importantly, it should be understood that simply replacing a conventional assay in an existing protocol
troponin assays
LEVEL OF CARDIAC TROPONIN

with a hsTn assay does not allow the high-sensitivity assay to function to its full potential. Only when used in an
>8-12 hours algorithm that accounts for the increased sensitivity can it be effective for decreasing cost and ED admission time.
post event
Developing a new algorithm or modifying an existing algorithm for managing ACS patients will be important to
Current generation cardiac promote appropriate use of the new test.23 In addition, laboratory personnel will need to assess the quality control
troponin assays measures required for the new assay and will also need to work with other key stakeholders to decide on thresholds
Onset of myocardial for the new assay, especially given that age and gender may influence normal values.28,38 Practical considerations in
infarction
the collection and processing of specimens need to be considered as well; hemolysis in the blood sample and the
2-6 hours High sensitivity cardiac extent of centrifugation can both render the hsTn assays less accurate.38 Similarly, practitioners should be reminded
post event troponin assays of other potential non-cardiac causes of troponin elevations, such as the increase in troponin T in patients with
skeletal muscle disease or damage.20,21
99th Percentile
In the 2015 NSTEMI guidelines, the European Society of Cardiology (ESC) recommends the use of hsTnT or hsTnI
over conventional troponin assays.23 In addition, ESC makes the general recommendation to measure hsTn at
Normal levels Ischemia or Necrosis Adapted from Hochholzer, Am Heart J, 2010 presentation and then repeat it 3 hours later as part of a rule-out algorithm.23 The European guidelines also emphasize
Micronecrosis F. Apple, AACC Webinar, Jan 2012
that hsTn is a quantitative measure, so the higher the number, the greater the likelihood of myocardial necrosis.23 For
example, a hsTn more than five-fold over the upper reference limit has a positive predictive value for a type 1 MI of
Figure 3-3. Troponin rise in the time after myocardial infarction. Older and current generation troponin assays over 90 percent, whereas elevations less than three-fold over the upper reference limit have a positive predictive value
cannot detect troponin increases as quickly as the high-sensitivity troponin assays of only 50-60 percent. Importantly, these guidelines also highlight the benefit of developing new algorithms for the
management of patients with ACS around the hsTn test that allow for the rapid assessment of patients presenting to
the ED with ACS symptoms and the appropriate use of the hsTn test.23

28 | Learning Guide: Cardiac 29 | Learning Guide: Cardiac

Similarly, the National Institute for Health and Care Excellence (NICE) in the United Kingdom also recommends the SECTION 3: REVIEW QUESTIONS
use of hsTn as part of an early rule-out protocol for NSTEMI. According to the NICE recommendations, hsTn should
be measured at presentation and repeated three hours later; if NSTEMI is not ruled out in this protocol, further 1. C
 K-MB and troponin should always be used together to detect the presence of myocardial necrosis.
evaluation is recommended.39
True False

OTHER CARDIAC BIOMARKERS

Although troponin is central in the determination of myocardial necrosis, a variety of other markers have demonstrated 2. Which of the following statements accurately reflects the definition for rising or falling troponin concentrations
some usefulness in the evaluation of patients with suspected ACS in the past, and more are under investigation. using hsTn assays in an MI?
Myoglobin, an oxygen-carrying protein, was one of the earliest biomarkers used for MI.15 Although its concentrations rise a . A rise or fall indicative of cardiac necrosis is a 25 percent or more change from the initial elevated value
in response to injury of the cardiac tissue, it is no longer recommended as a biomarker for ACS.15
b
. T
 here is no consensus on the exact amount or percentage of rise or fall required for troponin changes
Creatinine kinase MB (CK-MB) is a marker that is mostly specific to the cardiac tissue and was traditionally used in using hsTn assays to meet criteria for MI
conjunction with older generation troponin assays. It remains elevated for a shorter time than troponin after MI,
and it may provide additional clinical information regarding the timing of a myocardial injury and is sometimes useful c . T
 he IFCC states that a rise or fall in cardiac troponin over six hours of 50 percent of more is
for detecting an early reinfarction.23 In current practice, routine measurements of CK-MB in patients with suspected diagnostic for MI
ACS are no longer recommended.23
d
 . All of the above are correct
Copeptin is a small portion of a precursor for the arginine vasopressin hormone.40 Although it is not specific to
the cardiac tissue, copeptin does increase significantly in the early stages of MI.40 In some studies, it has shown promise
when used in conjunction with troponin for facilitating earlier rule-out of myocardial infarction to differentiate between 3. Which of the following statements about implementing hsTn is TRUE?
patients with NSTEMI and no NSTEMI.23,41 Copeptin concentrations may also provide prognostic information in ACS
patients; higher copeptin levels have been correlated with greater mortality and risk for heart failure after an ACS a . T
 he transition from a conventional troponin assay to a high-sensitivity assay requires education
event.42 Although the US guidelines do not make a specific recommendation on it, the ESC guidelines on NSTEMI do for laboratory personnel only
suggest that copeptin may be useful to facilitate early rule-out of MI, especially if high-sensitivity troponin assays are
unavailable.23 Despite this recommendation, copeptin is infrequently used in clinical practice because it has not proved b
. W
 hen transitioning from conventional to high-sensitivity troponin measurements,
to be superior to troponin in identifying MI. a multidisciplinary team is needed

The natriuretic peptides, B-type natriuretic peptide (BNP) and its inactive counterpart N-terminal proBNP (NT- c . P
 hysicians need to be educated that a positive high-sensitivity troponin measurement is diagnostic
proBNP), are most often used in the setting of heart failure but also rise quickly after a myocardial ischemic event.42 for myocardial infarction
The natriuretic peptides can provide information about the size of the infarct area in the heart and also the function
d
 . Hemolysis does not affect a hsTn result
of the left ventricle before and during the ischemic event.42 Perhaps more importantly, natriuretic peptides provide
additional prognostic information for patients experiencing STEMI and NSTEMI and can predict mortality and heart
failure after an ACS event.42 BNP has been approved by the FDA as a prognostic aid in acute coronary syndromes.43
4. List four biomarkers (other than troponin) that have been studied in ACS patients and shown definite
There are many other biomarkers currently being investigated for both diagnostic and prognostic use in ACS, and their or possible benefit
exact role in the management of patients has not yet been defined. Ischemia-modified albumin has been cleared by the
FDA as a diagnostic test for ischemia in patients with suspected acute coronary syndromes.44 Cardiac myosin-binding _____________________________________________________________________________________________________________________
protein C (or cMyC) recently demonstrated usefulness in early identification of acute MI, but researchers are still unsure
_____________________________________________________________________________________________________________________
if it offers any advantage over hsTn.45 Similarly, two other emerging biomarkers have shown some promise for improving
prognostic information in patients with ACS: GDF15 and ST2. The GDF15 protein is one of the transforming growth
factor-ß cytokines. In studies, it has shown some usefulness in predicting future cardiovascular disease events and
mortality.42,46 Likewise, ST2, an FDA approved biomarker for ventricular strain in patients with heart failure, appears to
provide additional prognostic information regarding mortality and complications after an ACS event.42,46 Whether either
GDF15 or ST2 provide additional prognostic information over currently used biomarkers remains to be determined.

30 | Learning Guide: Cardiac 31 | Learning Guide: Cardiac

SECTION 4 Heart failure, in the simplest of terms, indicates that a problem with the ventricles is preventing the heart from filling
and/or pumping correctly. It is the result of a complex mechanical and neurohumoral syndrome resulting in stasis (or
slow movement) of blood in the lungs and peripheral tissues. It is estimated that over 26 million people worldwide are
living with heart failure, and it is the number one cause of hospitalization in the United States (US) and Europe.47
In the US, it is estimated that over 6.5 million adults are living with heart failure and that figure is predicted to
grow to over eight million by 2030.48 Registries of heart failure patients in the US and Europe report mortality to
be anywhere from 23 to 36 percent during the first year after a heart failure hospitalization.49

THE ROLE OF CARDIAC DEFINING HEART FAILURE

BIOMARKERS IN ACUTE Heart failure initiates structural, functional, and neurohumoral abnormalities that prevent the ventricles from either
properly filling with blood or properly ejecting blood. Regardless of the underlying mechanism, this results in poor

CORONARY SYNDROME (ACS) cardiac performance. Section 1 of this guide described the basic consequences of poor cardiac performance: the
tissues of the body may not receive enough oxygen if the heart is not providing enough pressure to allow for perfusion
of oxygen and nutrients from the blood into the tissues. The body does attempt to compensate for this loss of
perfusion. It begins to release hormones and neurotransmitters (chemical messengers in the body) that increase the
blood pressure and promote retention of water by the kidneys to increase blood volume; this is termed neurohormonal
activation.50,51 In the short term, these compensation mechanisms are adaptive, but over the longer term, they clearly
LEARNING OBJECTIVES
become maladaptive and are the targets for diagnostic tests and therapies. For example, neurohormonal activation
When you complete this section, you will be able to: facilitates the maintenance of perfusion to the organs if the body is experiencing acute blood loss, minimizing organ
damage from this event. However, when neurohormonal activation occurs over a long period, as it does in heart
1. D
 escribe the role of troponin in ACS failure, these compensations worsen the functional ability of the heart rather than improving it. 50,51
2. Discuss differences between high-sensitivity and conventional troponin assays
DEFINING HEART FAILURE BY PUMP FUNCTION: HFPEF AND HFREF
3. U
 nderstand important considerations for implementing high-sensitivity troponin assays within an institution
To clarify the functional problem in heart failure, clinicians typically separate heart failure into two different
4. Recognize other cardiac biomarkers with potential roles in ACS categories: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction
(HFrEF) (Figure 4-1). In HFpEF, the primary problem is the left ventricle not filling properly with blood.51
Conversely, in HFrEF, the primary problem is poor ejection of blood from the left ventricle.51

DIASTOLIC (HFpEF) SYSTOLIC (HFrEF)

Stiff and thick Stretched and thin

chambers chambers

Heart can’t fill Heart can’t pump

Figure 4-1. Structural changes to the ventricles of the heart in heart failure: in HFpEF (left) the ventricle walls stiffen
and can’t fill appropriately and in HFrEF (right) the ventricle dilates and the walls are stretched thin, impairing the
normal pumping activity

32 |32
Learning
| Learning
Guide: Cardiac
Guide: Cardiac 33 | Learning Guide: Cardiac
Heart Failure and a Preserved Ejection Fraction (HFpEF) Defining Heart Failure with Classification Systems: NYHA and ACC/AHA
In HFpEF, as the name implies, the ejection fraction of the left ventricle is normal (usually over 45 percent), Several different classification schemes exist to quantify the severity of heart failure in a patient. The New York Heart
so the heart is still pumping out the appropriate percentage of blood with each contraction.51 However, the problem Association (NYHA) classification system is based primarily on the effects the heart failure has on the patient’s ability
in HFpEF is an impairment in the heart’s ability to relax during the process of filling with blood.51,52 The left ventricle to perform physical activity. The categories progress from an NYHA class I, indicating the patient has no symptoms
cannot relax and fill with blood normally because its walls are abnormally stiff and thickened; the walls of the with normal physical activity, all the way to an NYHA class IV, indicating the patient has symptoms of heart failure at
ventricle are also not working in a coordinated fashion with the blood vessels that receive the blood.51 This results rest or with the slightest physical activity.58 The NYHA classification system can predict mortality in heart failure and
in poor cardiac performance even though the ejection fraction is still within a normal range. Women, the obese, can be a useful way to monitor the effectiveness of treatment.50,58
and elderly individuals are more likely to be diagnosed with HFpEF than men, individuals in a normal weight range, Another classification scheme from the American College of Cardiology Foundation (ACC) and the American Heart
and younger people.51,53 Heart failure with preserved ejection fraction can be more difficult to diagnose and manage Association (AHA) defines heart failure according to symptoms and structural changes to the heart (Figure 4-2).
than HFrEF, but almost half of the patients with heart failure in the US have HFpEF.51,52,54 Unfortunately, at the time The ACC/AHA classification scheme for chronic heart failure begins with stage A, which indicates only that a patient
of this writing, there are no proven treatments for HFpEF that reduce the risk of heart failure hospitalization or is at high risk of developing heart failure as a result of comorbidities like coronary artery disease, diabetes, and
cardiovascular death. hypertension.58 Stage B in this classification scheme indicates that there is evidence of structural changes in the heart
associated with heart failure, but the patient is not experiencing signs or symptoms.58 In Stage C, patients have
Heart Failure with Reduced Ejection Fraction (HFrEF) evidence of structural changes in the heart and also signs and symptoms of heart failure.58 Finally, stage D indicates
that the patient is experiencing end-stage heart failure: symptoms at rest or with minimal exertion despite maximized
In HFrEF, the ejection fraction of the left ventricle is reduced. This means that with each pumping contraction of the
medical therapy.58 Thus, the NYHA class is usually applied to patients with symptomatic Stage C and D heart failure.
heart, a smaller percentage of blood, usually less than 45 percent, is forced out into the aorta. The interior cavity of the
left ventricle is typically dilated in HFrEF, and the heart muscle is less effective when it contracts.51 Unlike HFpEF,
HFrEF is the more common cause of heart failure in men and younger individuals.52 Approximately two-thirds of
HFrEF is attributed to a prior myocardial infarction and damage to the heart resulting in scar formation.55 Diagnosis TIME
is more straightforward in HFrEF than in HFpEF: patients with HFrEF are more likely than those with HFpEF to A Risk factors for heart failure
have common symptoms of heart failure. Also, because they are younger, patients with HFrEF are less likely than
those with HFpEF to have other diseases that the symptoms could be attributed to, like chronic obstructive Structural changes to the heart
pulmonary disease.51,52,54 Patients with HFrEF also respond more favorably to treatment with medications than those B
WITHOUT symptoms/signs
with HFpEF.51,52 Indeed multiple classes of medications, as well as implantable devices, reduce the risk of heart failure
hospitalization and cardiovascular death in HFrEF. These include medications such as ACE inhibitors, angiotensin Structural changes to the heart
C
receptor blockers, mineralocorticoid receptor antagonists, certain beta-blocking agents, valsartan/sacubitril, PLUS symptoms
ivabradine, the combination of long-acting nitrates and hydralazine, and digoxin, as well as devices such as ADVANCED HEART FAILURE
implantable cardioverter-defibrillators and cardiac resynchronization devices.52,56 D Patients may be:
• H
 ospitalized frequently
• E
 valuated for/receive an LVAD*
• A
 waiting heart transplant
What is a Normal Ejection Fraction?
* Left Ventricular Assist Device
Heart failure is often defined in terms of the heart’s left ventricular ejection fraction (or EF), so what is a
normal EF for the left ventricle? Although definitions vary, the normal range of EF (measured when a person
is at rest) is generally described as approximately 50 to 70 percent. However, in 2015, the American Society of Figure 4-2. Stepwise progression of heart failure according to ACC/AHA stages
Echocardiography and the European Association of Cardiovascular Imaging released collaborative
recommendations that offer a more precise definition. In this document, a normal left ventricular EF was
defined as 52 to 72 percent for men and 54 to 74 percent for women.57 DEFINING HEART FAILURE BY PRESENTATION:
ACUTE AND CHRONIC HEART FAILURE
Acute heart failure (AHF) is a term often used in the emergency department (ED) and hospital setting. This term
refers to an acute, rapid worsening of heart failure symptoms that can be life-threatening.52 Patients with AHF need
Heart Failure with Mid-Range Ejection Fraction (HFmrEF)
prompt medical evaluation and treatment. In about two-thirds of cases, patients with AHF have already been
A new term, heart failure with mid-range ejection fraction, or HFmrEF, was recently described by the European
diagnosed with heart failure, but in the other one-third, AHF is the first sign of a heart failure problem.52,59 Often, a
Society of Cardiology (ESC). In the explanation for this new classification, the ESC defines HFmrEF with the same
criteria used for HFpEF diagnosis but with an ejection fraction of 40-49 percent.52 Their purpose in defining HFmrEF patient with stable heart failure experiences an event that triggers the AHF episode. This event can be something
as a separate entity from HFpEF or HFrEF is to promote more study of interventions and outcomes in this very straightforward like neglecting to take prescribed heart failure medications or something more complex, such as a
specific population of individuals with heart failure.52 Because HFmrEF is a new term and is not included in other new MI, a superimposed infection, development of abnormal heart rhythm (atrial fibrillation), or dietary changes
guidelines and literature, it will not be a focus of this guide. with increased intake of salt.52

34 | Learning Guide: Cardiac 35 | Learning Guide: Cardiac

Chronic heart failure, in contrast to acute, is the more stable, chronic manifestation of inadequate cardiac function. fluid accumulation in the peripheral tissues that manifests as swelling (or edema), first in the legs and feet (due to
Chronic heart failure is the term used to describe patients with heart failure who are not experiencing an acute gravity), and then it may spread to the abdomen and even to organs such as the liver. This process whereby problems
worsening of symptoms from AHF. The majority of patients with heart failure are classified as having chronic heart with the left ventricle lead to problems with the right ventricle, with congestion of the lungs as well as the peripheral
failure. They are managed in the outpatient setting, and they only convert to a diagnosis of acute heart failure in the tissues, underlies what most doctors regard as true “congestive heart failure.”
setting of acute symptom worsening. Once a patient is hospitalized for heart failure, there is a much higher risk of
repeat hospitalization within the next several months, and this often becomes a progressive cycle.
SYMPTOMS AND SIGNS OF HEART FAILURE
One of the most important characteristics to evaluate in patients with heart failure is symptoms. Notably, many of the
CAUSES OF HEART FAILURE
symptoms of heart failure can be traced back to the changes in cardiac performance and can be collectively termed
Anything that causes damage to the myocardium can lead to heart failure. Coronary artery disease is the most “effort intolerance.” Shortness of breath (sometimes called dyspnea) is the most common symptom of heart failure
important predictor of heart failure, and it is estimated to be the primary cause of heart failure in over 60 percent of and is a sign that fluid is accumulating in the lungs as a result of poor left ventricular performance. Patients with heart
patients in the US.55 However, other frequent causes of heart failure include hypertension (the medical term for high failure often present with other symptoms as well, such as orthopnea (shortness of breath when lying down),
blood pressure), problems with the valves in the heart, or cardiomyopathy (maladaptive changes in heart structure paroxysmal nocturnal dyspnea (awakening from sleep with acute shortness of breath), exercise intolerance, weakness,
caused by inflammation, infection, or unknown reasons).50,52 Approximately 90 percent of all heart failure cases have fatigue, and swelling of the ankles and feet.51,52 Again, these symptoms correlate with fluid accumulation in the lungs
antecedent hypertension (or hypertension before the diagnosis of heart failure). Thus it is believed that high blood and body as a result of the “back up” of blood in the heart. Heart failure most often limits a persons’ ability to perform
pressure contributes to all forms of heart failure as an additional risk condition.60 Other less common causes of heart strenuous or even low-intensity exercise. This can eventually progress to the point that symptoms interfere with very
failure include myocarditis, pericarditis, drug toxicities (e.g., certain types of chemotherapy, other cancer treatments, basic functions such as walking, showering, dressing, and eating food as described in NYHA class III and IV.64
and alcohol), endocrine disorders like thyroid disease, collagen vascular diseases like scleroderma, and arrhythmias
with persistently elevated heart rates.50,52 In the absence of coronary artery disease, it is believed that most cases of On a physical exam, clinicians evaluate for signs of heart failure. In severe cases, the signs can be obvious; however,
HFrEF have a genetic predisposition with a superimposed insult such as longstanding hypertension, excessive alcohol if the patient’s heart failure has developed over a long time, the signs may be subtle. A patient may appear very
intake, or viral syndrome.61 congested (often referred to as “wet”) or may not have obvious congestion at rest (referred to as “dry”). If “wet,” fluid
in the lungs can be heard with a stethoscope as crackles (“rales” or “crepitations”), and the patient may be visibly short
of breath with evidence of low oxygen levels, such as blue skin. Fluid in the peripheral tissues can be seen and felt as
CONSEQUENCES OF HEART FAILURE swelling or edema (as described above). Evaluation of the jugular vein in the neck can show distension. Changes in
As discussed in Section 1, maintaining strong pumping ability is essential for the heart to function appropriately. how the heart sounds through a stethoscope and differences in where the heartbeat can be felt in the chest can also be
When the heart doesn’t pump effectively as a result of heart failure, a cascade of negative effects occurs throughout signs of heart failure; the heart rate may increase to the point where it seems to “gallop” as it attempts to compensate
the body. Organs and tissues may not receive adequate oxygen to function appropriately, especially if any additional for poor output.50,52
strain (like exercise or illness) is placed on the cardiac system.62 The kidneys, in particular, are remarkably sensitive to
the changes in cardiac performance and, as a result, many patients with heart failure have coexisting kidney disease.62 THE ROLE OF ECG AND IMAGING
As a result of the continued neurohormonal activation in heart failure, the heart itself undergoes more changes. The Electrocardiogram (ECG)
structure of the ventricle undergoes further modification, causing it to be even less effective at pumping blood.62 This Although the electrocardiogram or ECG (Figure 4-3) is essential in the assessment of patients with acute coronary
process is often termed remodeling, and it is the consequence of scar formation in the cardiac tissue (this scarring is syndrome (ACS) symptoms, it is a less specific tool in heart failure. Patients with heart failure can have mild or
called cardiac fibrosis). Scar formation and fibrosis can initially be the result of a heart attack or may develop more dramatic abnormalities on an ECG, but it can be a useful tool in several circumstances. First, an ECG can be helpful
diffusely over time as a result of the heart failure process itself.63 The changes that lead to fibrosis occur on the cellular to rule out heart failure—very rarely would a patient with heart failure have a completely normal ECG.52 Second, it
level within the cardiac myocytes. In response to the original damage that led to heart failure, the myocytes become may identify the etiology of the patient’s heart failure, such as a previous MI.52 And third, it may detect a coexisting
enlarged and don’t function as efficiently.63 Poor myocyte function eventually leads to an excessive accumulation of problem such as atrial fibrillation (inappropriate, rapid beating of the atria) that requires treatment.52 Importantly,
proteins between the myocyte cells that prevent normal movement of the cells and cause stiffening of the myocytes. in the setting of heart failure, there are electrical conduction disturbances that can lead to heart block (which is a
This stiffness of the myocytes produces the cardiac fibrosis.63 lack of coordination of contraction of the ventricles). For example, in HFrEF, patients can experience several types
The consequences of these structural changes in the heart are profound for the rest of the body. Humans have a of electrical conduction disturbances, such as right bundle branch block, left bundle branch block, or interventricular
“closed circulatory system,” like a closed circuit; this means that blood can only go “back” when it cannot go conduction delay; patients with these abnormalities may benefit from an implanted cardiac resynchronization device
“forward.” When the heart does not pump the blood forward effectively as a result of stiffness or pump failure, the (discussed later in this section).52
blood begins to “back up” into the lungs. With blood moving more slowly through the pulmonary system, fluid leaks Echocardiogram
out into the lungs and begins to accumulate. When a patient with heart failure stands or sits upright, this fluid falls to Echocardiography, or ultrasound of the heart, is an essential tool in the diagnosis of heart failure (the test itself is
the bottom of the lungs and may not interfere with breathing; however, when the patient lays down flat, the fluid pools called an echocardiogram, often referred to as an echo). An echocardiogram provides information on the function
throughout the lungs which may lead to difficulty breathing. Eventually, the increased pressure in the lungs may lead of the heart muscle during relaxation and contraction, the size of the ventricular walls and the interior chamber,
to congestion in the right ventricle. Because the right ventricle receives blood from the rest of the body, as the right the performance of the valves, and the pressures in various parts of the heart.52 The echocardiogram also measures
ventricular performance is affected, a further “back up” of blood will occur into the peripheral tissues. This results in ejection fraction and stiffness of the ventricle, necessary in the differentiation between HFrEF and HFpEF.52

36 | Learning Guide: Cardiac 37 | Learning Guide: Cardiac

Cardiac Magnetic Resonance (CMR) HEART FAILURE TREATMENT
Cardiac magnetic resonance (CMR), or magnetic resonance imaging (MRI) of the heart, is another useful tool for
Early identification, treatment of underlying causes, and control of risk factors are all essential first steps in the
evaluating heart structure and characterizing changes in the cardiac tissue. It can be particularly helpful when
management of heart failure. Once those areas are addressed, patients should be counseled on lifestyle interventions
echocardiography is not adequate to assess structural abnormalities in heart failure, especially the right side of the
such as eating a low-sodium diet, limiting fluid intake to a prescribed amount, weighing themselves daily, engaging in
heart.52 The European heart failure guidelines recommend the use of CMR in patients with complex congenital heart
light aerobic exercise, understanding the need for follow-up appointments with their physician, and learning how best
disease (a cardiac structure problem that a patient is born with) or with inadequate imaging with echocardiography.52
to manage the disease.58,62
Both the US and European heart failure guidelines also state that CMR can be helpful in establishing a cause of heart
failure and characterizing the fibrotic changes in the cardiac tissue particularly in the setting of sarcoidosis.52,58 Medications are typically prescribed to block the body’s maladaptive neurohormonal response to heart failure. These
Although CMR is the only imaging tool that can truly characterize the actual cardiac tissue, it is not suitable for can include drugs such as ACE inhibitors, beta-blockers, aldosterone antagonists, and diuretics.62 It is essential that
everyone, such as patients with certain metal implants; it is also not available at all centers and may be more expensive patients understand the importance of taking these medications because, when used appropriately, these drugs can
than other imaging techniques. prevent hospitalizations and decrease the risk of death from heart failure, especially in patients with HFrEF.58,62
Although these medications can also be beneficial to patients with HFpEF, researchers are still attempting to
Laboratory Testing determine the optimal drug regimens for treatment of HFpEF.58,62

During an initial diagnostic workup for heart failure, a considerable amount of laboratory testing is performed. Renal Some patients with heart failure will also require intervention with cardiac devices. Certain individuals with severe
and liver panels, lipid measurements, thyroid function tests, complete blood counts, and iron studies may be ordered heart failure who have electrical conduction abnormalities (as outlined in the previous discussion of ECG in heart
to evaluate for underlying causes and comorbidities and also to assess the appropriateness of heart failure therapies.52 failure) may be candidates for cardiac resynchronization therapy (often called a biventricular pacemaker), which is an
In addition, several circulating biomarkers are useful in the diagnosis and management of heart failure. implantable device that uses electrical impulses to aid both ventricles in contracting at the same time. Other patients
with very low ejection fractions may require an implantable cardioverter-defibrillator, which can help the heart recover
from life-threatening arrhythmias.62 For patients experiencing the most severe heart failure symptoms (NYHA class IV
Natriuretic Peptides
and ACC/AHA stage D), a left-ventricular assist device (or LVAD) may be used to support cardiac function. An LVAD
The natriuretic peptides (NPs), B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide
increases the output of blood from the heart using a pump implanted into the wall of the left ventricle.62,72 Although the
(NT-proBNP), play a central role in heart failure. Although BNP was initially called brain natriuretic peptide because
pump itself is implanted in the chest, a wire runs out of the device and through the skin to connect the LVAD to batteries
it was first identified in the brains of pigs, this was a misnomer as it is very specific to the heart.65 BNP is a hormone
and the control unit.58,62 Finally, in the most critical cases, patients who are otherwise in good health and can tolerate
released by the cardiac myocytes when they are under strain, and NT-proBNP is an inactive fragment cleaved from
the major surgery may undergo a cardiac transplant.62 Only about 3,000 people receive heart transplants in the US
the BNP molecule.66 These NPs are released when the ventricles, particularly the left ventricle, experience volume
each year.73
and pressure overload and when neurohormonal activation occurs in response to heart failure.66 Measuring NPs have
shown benefit in almost every aspect of heart failure care. In the hospital setting, NPs can assist in distinguishing
the cause of acute shortness of breath, determine prognostic information about mortality risk in AHF, and, when
measured at discharge, can identify long-term prognosis after an AHF admission.52,56,67 They can also be used as a
screening tool in the outpatient setting to rule out heart failure or identify patients in need of early intervention to
prevent heart failure.52,56 Finally, they can provide long-term prognostic information for patients with chronic heart
failure.67 Section 5 will discuss the NPs in more detail.

Galectin-3
Galectin-3 is another biomarker that increases with worsening heart failure. Galectin-3 concentrations appear to
increase when fibroblasts and macrophages are activated in the cardiac tissue.63,68 These cells are involved in the
remodeling of cardiac muscle that occurs in heart failure. Consequently, galectin-3 appears to be a good marker
for the presence of cardiac remodeling and the development of cardiac fibrosis. In clinical studies, galectin-3 has
demonstrated usefulness as a prognostic indicator and as a screening tool for assessing readmission risk after a
heart failure hospitalization.69,70 Section 5 will discuss galectin-3 in more detail.

Troponin
High-sensitivity troponin assays have an emerging role in heart failure and may provide useful prognostic
information about the heart failure risk for patients experiencing an MI. Elevations in high-sensitivity troponin I
concentrations in patients with suspected ACS strongly correlate with risk of future hospitalization for heart failure.71
High-sensitivity troponin assays will be discussed in more detail in Section 5.

38 | Learning Guide: Cardiac 39 | Learning Guide: Cardiac

SECTION 4: REVIEW QUESTIONS SECTION 5

1. Decide which type of heart failure is being explained in each description (HFpEF, HFrEF, or AHF)

a. A rapid worsening of symptoms that requires immediate evaluation __________________

b. This type of heart failure is easier to diagnose and is more responsive to chronic treatment _________________

c. This type of heart failure is more common in older individuals and women _________________

d. This can be triggered by failing to take prescribed medications for heart failure _________________
THE ROLE OF CARDIAC
e. Heart failure resulting from the left ventricle’s inability to relax _________________ BIOMARKERS IN HEART FAILURE
f. Heart failure resulting from poor contractility of the left ventricle _________________

2. List five symptoms of heart failure LEARNING OBJECTIVES

When you complete this section, you will be able to:
______________________________________________________________________________________________________________________
1. D
 escribe cardiac biomarkers used in heart failure
______________________________________________________________________________________________________________________
2. Explain the role of cardiac biomarkers in various aspects of heart failure care
______________________________________________________________________________________________________________________
3. U
 nderstand the guideline recommendations from several international organizations for the use of cardiac
______________________________________________________________________________________________________________________ biomarkers in heart failure

______________________________________________________________________________________________________________________

3. The most commonly used biomarker in heart failure is

a. Galectin-3

b. Natriuretic peptides

c. Troponin

d. All of the above

4. Fill in the blanks

a. A
 s a result of the poor cardiac pumping performance in heart failure, the body attempts to compensate by using
_____________________________________________ and _____________________________________________ to raise blood pressure
and retain more water. This is called _____________________________________________ activation.

b. The organs most sensitive to changes in cardiac performance are the ______________________________________.

c. S
 erious, long-term structural changes occur in the heart as a result of heart failure. Cardiac _____________________
occurs as a result of the accumulation of proteins between the myocyte cells that
causes the cells to stiffen.

40 | Learning Guide: Cardiac 41 | Learning Guide: Cardiac

As discussed in Section 4, the changes in cardiac function that occur in heart failure affect the entire body, so it is Differences in Natriuretic Peptide Assay Types
essential that clinicians monitor the status of heart failure patients with diligence. Circulating biomarkers can be Although most studies indicate that BNP and NT-proBNP assays have similar sensitivity and specificity, clinicians
especially helpful tools for gauging the presence, severity, and progression of heart failure. This section will build on should be aware of several differences.66 For example, NT-proBNP has a longer half-life than BNP, although this does
the previous discussions of biomarkers used in heart failure and also introduce several emerging biomarkers for this not appear to have significant clinical implications.66 In addition, because the normal value ranges differ between the
disease process. two types of assays, NT-proBNP concentrations measure higher and have more variability than BNP concentrations.
It is essential that clinicians be aware of which assay is being used in the facility and be familiar with normal ranges
AS A GROUP, THE CARDIAC BIOMARKERS USED IN PATIENTS WITH HEART of both tests (Figure 5-1).66 Notably, BNP and NT-proBNP values are not interchangeable: there is no recognized
FAILURE CAN GENERALLY BE CLASSIFIED INTO THREE AREAS “conversion factor” that works to convert a BNP result into an NT-proBNP result. Finally, all commercially available
BNP assays standardize to an upper limit of normal of 100 pg/ml.66 However, there is no universal cutpoint for normal
• Markers of myocardial stretch/pressure and neurohormonal activation: These include natriuretic peptides for NT-proBNP. Most laboratories give a spectrum of upper limit values based on age categories ranging from 125 pg/
and several emerging biomarkers (MR-proADM, copeptin). Rising concentrations of these biomarkers reflect mL to 2000 pg/mL, depending on the study population and assay used.66
increasing neurohormonal activation that can result from heart failure.

• Markers of cardiac remodeling: These include galectin-3 and several emerging biomarkers (ST2, GDF15). When
BNP
markers in this group rise, they can indicate myocyte changes are occurring that lead to fibrosis in heart failure.
Clinical Gray Zone* Elevated
Clinical Gray Zone* Elevated
• Markers of myocardial injury/ischemia: These include cardiac troponins. Ischemia and injury may occur in NORMAL
NORMAL
heart failure, and biomarkers that reflect this process have demonstrated prognostic capability in heart failure
patients. As discussed in Sections 2 and 3, the primary application of these markers is in patients with suspected
acute coronary syndromes, but their potential utility in heart failure is outlined on page 48.
100 pg/mL 500 pg/mL 1000 pg/mL 1500 pg/mL
Evaluating each of these aspects of heart failure provides essential information on the status and prognosis of an 100 pg/mL 500 pg/mL 1000 pg/mL 1500 pg/mL
individual patient. However, the usefulness of various biomarkers differs according to the clinical scenario.
NT-proBNP
Age Gray Zone† Elevated
Age Gray Zone† Elevated
MARKERS OF MYOCARDIAL STRETCH/PRESSURE Normal
Normal
Clinical Gray Zone*
Clinical Gray Zone*
AND NEUROHORMONAL ACTIVATION
Natriuretic Peptides
As discussed in Section 4, the natriuretic peptides (NPs), B-type natriuretic peptide (BNP) and N-terminal pro-B-type 450 pg/mL
0 125 pg/mL 450 500pg/mL
pg/mL 1000 pg/mL 1500 pg/mL 2000 pg/mL 2500 pg/mL
natriuretic peptide (NT-proBNP), play a central role in heart failure. BNP is a hormone released by the cardiac 0 125 pg/mL 500 pg/mL 1000 pg/mL 1500 pg/mL 2000 pg/mL 2500 pg/mL
myocytes when they are under strain, and NT-proBNP is an inactive fragment cleaved from the BNP molecule.66
These NPs are released when the ventricles, particularly the left ventricle, experience volume and pressure overload * Clinical Gray Zone: other non-heart failure conditions may be contributing to elevation
and when neurohormonal activation occurs in response to heart failure.66 The NPs have shown benefit in almost † Age Gray Zone: age over 50 years or renal dysfunction
every aspect of heart failure care. In the hospital setting, NPs can assist in distinguishing the cause of acute shortness
Figure 5-1. Ranges of normal, gray zone, and elevated BNP and NT-proBNP
of breath and determine prognostic information during the admission and after discharge.52,56,67 They can be used as
a screening tool in the outpatient setting to rule out heart failure or identify patients in need of early intervention to
prevent heart failure.52,56 They also provide prognostic information for patients with chronic heart failure.67 USING NATRIURETIC PEPTIDES IN CLINICAL PRACTICE
This section will describe NPs in more detail and explain how they fit into the care of patients with heart failure.
Diagnosis of Acute and Chronic Heart Failure
The NPs are hormones that influence fluid and sodium balance in the body. Although only the B-type (BNP and
74
For patients who seek emergency medical attention for acute shortness of breath, NPs are an essential test for
NT-proBNP) are measured routinely in clinical medicine, three types have been identified in total: determining the cause. These patients may be experiencing an episode of acute heart failure (AHF), and an NP
measurement can assist clinicians in differentiating AHF from other causes of acute shortness of breath such
• Atrial NP released from the atria
as an exacerbation of chronic obstructive pulmonary disease or a pulmonary embolism.56,75 NPs have very high
• B-type NP released from the ventricles negative predictive value (NPV) for AHF—if the NP value is not elevated, heart failure can usually be ruled out,
and unnecessary heart failure treatment, such as diuretics (which could harm the kidneys if given to a patient who
• C-type NP, which is found in the kidneys, blood vessels, and central nervous system74
is not experiencing AHF), can be avoided.56,75 This is also true for patients who present with shortness of breath in
Of note, BNP was originally called brain natriuretic peptide because it was first identified in the brains of pigs, but it the outpatient setting; many of the signs and symptoms of heart failure are non-specific and can easily be attributable
was later determined to be a misnomer because it is released by the ventricles of the heart.65 This guide will focus on to other causes (like chronic obstructive pulmonary disease). Hence, a BNP or NT-proBNP measurement is a simple
the B-type NPs (BNP and NT-proBNP), subsequently referred to as NPs, because they are most specific to the method to either exclude heart failure or identify patients who require more diagnostic testing to determine if heart
pathophysiology of heart failure. failure is present (Figure 5-2).52,56

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Figure 5-2. Using natriuretic peptides in clinical practice for non-acute symptoms52,56 Natriuretic Peptides in HFpEF versus HFrEF
Another important aspect of BNP and NT-proBNP measurements is that the type of heart failure influences the
concentrations of NPs in the blood. As discussed in Section 4, HFpEF and HFrEF have different mechanisms in
SUSPECT CONSIDER SCREEN WITH terms of how the cardiac dysfunction occurs. This difference also translates into disparities in NP release. In chronic
HEART • Medical history NATRIURETIC HFpEF, NP elevations appear to be slightly more modest than what is measured in HFrEF.75 They can even decrease
FAILURE • Physical exam PEPTIDE: Consider other to almost normal concentrations if the patient is free of symptoms.75 Although NPs don’t appear to be as elevated in
DUE TO findings BNP or ELEVATED NO causes of patients with HFpEF compared to patients with HFrEF, they are still recommended as general screening tools for
SYMPTOMS NT-proBNP symptoms
• ECG heart failure and are an essential component in establishing a diagnosis of HFpEF.52,56 The ESC guidelines use the
abnormalities cutoff of BNP concentration over 35 pg/mL or an NT-proBNP concentration over 125 pg/mL for meeting the
biomarker criteria for HFpEF.52 Both of these cutpoints are well within the normal range of NPs for both tests and
YES ECHOCARDIOGRAM
(as an aid in diagnosis) hence this recommendation should be viewed circumspectly. It should be noted that NP levels will be elevated in
acute heart failure (AHF) regardless of whether the underlying mechanism is HFpEF or HFrEF.75

Interpretation of Natriuretic Peptide Results

As with other diagnostic tests, natriuretic peptide measurements should always be one of many considerations for
clinicians during the evaluation of a patient with possible heart failure. The test itself may result in very elevated NP
Prognosis in Acute and Chronic Heart Failure concentrations that strongly correlate to heart failure (BNP > 500 pg/mL or NT-proBNP > 2000 pg/mL),
Another critical role for NPs in clinical practice is in providing prognostic information. For patients with AHF concentrations in the “gray-zone” indicating it could be heart failure or could be another problem (BNP 100–500 pg/
admitted to the hospital, high concentrations of NP upon admission are associated with increased risk of in-hospital mL or NT-proBNP 450–2000 pg/mL), or normal concentrations (BNP < 100 pg/mL or NT-proBNP < 125 pg/mL)
mortality (for both cardiac causes and all causes).56 In addition, measurement of BNP at discharge is useful for (Figure 5-1).66 Of note, compared with BNP, NT-proBNP has a much wider “gray zone” which may be attributed to
prediction of readmission within 30 and 60 days.70 Readmission for heart failure shortly after discharge is often advanced age (over 50 years) or renal dysfunction with NT-proBNP values in the range 125-450 pg/mL or higher.82
considered a preventable hospitalization, and it is a target of hospital and government quality improvement
This results in more “indeterminate” results when using this assay in older patients; BNP does not have this
initiatives.76 Consequently, identifying patients at high risk for this outcome is essential to improving quality of
limitation.82 Evaluating the entire patient presentation in addition to biomarker results, including symptoms,
heart failure patient care.76
physical examination findings, and other diagnostic test results, is essential to establishing a correct diagnosis
It is also well established that NP measurements can provide prognostic information in the outpatient setting.
for every patient.
Increasing NP concentrations are associated with an increased mortality risk in ambulatory patients with heart
failure.58 NPs may also offer information about the changing status of heart failure within a patient and have been
used to guide changes and adjustments to medication therapy; however, this is controversial, and due to conflicting Confounding Factors in the Measurement of Natriuretic Peptides
evidence without a proven benefit in heart failure patient outcomes, guidelines do not recommend monitoring NP
Several disease processes and patient characteristics can confound the results of NP assays – clinicians must interpret
levels to guide therapy.56,58,77
the NP measurements with caution in these clinical scenarios. Because NT-proBNP is eliminated primarily by the
kidneys and BNP is eliminated through multiple pathways, NT-proBNP is more susceptible to elevations in patients
Identifying Patients at Risk for Heart Failure with kidney disease than BNP.66 In severe kidney disease, BNP is also affected, but NT-proBNP continues to be more
The natriuretic peptide assays BNP and NT-proBNP have established usefulness in stratifying patients who are at severely altered.66 Likewise, several studies have also documented that NT-proBNP is increased in patients with atrial
high risk for heart failure based on risk factors like diabetes, hypertension, and vascular disease.56 Elevated NP fibrillation; because this is a common comorbidity in patients with heart failure, clinicians must consider this when
concentrations have demonstrated utility in identifying patients in the general population who are at increased risk evaluating NT-proBNP measurements.83,84 Increasing age and female sex both appear to increase the NP
for developing heart failure, both in individuals who already have some high-risk characteristic and in individuals measurements regardless of underlying cardiac function, whereas obesity may decrease measured NP
without high-risk characteristics (although NPs appear to be stronger predictors for individuals already at high concentrations.85 Lastly, a newer class of drug for heart failure, the angiotensin receptor neprilysin inhibitors (ARNI),
risk).75,78,79 However, they appear to be a better tool for identifying patients at risk for heart failure with reduced may influence BNP concentrations because BNP is one of multiple peptides that can be cleaved by neprilysin.
ejection fraction (HFrEF) than heart failure with preserved ejection fraction (HFpEF).80 Importantly, However, there is evidence that human BNP may be less sensitive to neprilysin degradation while retaining affinity
NP measurements have demonstrated relevance in identifying patients who benefit from medical intervention for it. At the high concentrations of BNP (>916 pg/mL) that are frequently seen in HF patients, neprilysin activity may
to prevent heart failure, ultimately resulting in improved patient outcomes. In a large-scale trial (STOP-HF), NP actually be inhibited or impaired.86,87 This would limit the efficacy of drugs designed to inhibit the enzyme such as
concentrations were used to screen and stratify individuals at risk for heart failure; participants with BNP ARNI. Overall, there is insufficient evidence to determine if there are clinically significant differences in measured
concentrations over 50 pg/mL in the intervention group were evaluated with echocardiography and received concentrations or adverse effects on patient outcomes and further research is ongoing.88 Other common causes for NP
collaborative care interventions from primary care and cardiology specialists. Compared with participants in elevation are included in Table 5-1 on the next page.
the control group (those who received usual care), participants in the screening and intervention group had lower
rates of left ventricular dysfunction and heart failure several years later.81 Section 6 will discuss biomarkers for
screening of asymptomatic individuals in more detail.

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Table 5-1. Conditions that Confound B-type Natriuretic Peptide Concentrations56,85 A key characteristic of galectin-3 is that concentrations appear to increase before heart failure manifests.
As a result, it may be a useful screening tool for patients who are at risk for heart failure but have not developed it
INFLUENCE ON B-TYPE NATRIURETIC PEPTIDE CONCENTRATIONS yet.94 And it has demonstrated effectiveness for screening in a general population. In the PREVEND study, galectin-3
concentrations were strongly correlated with cardiovascular risk in the general population and also predicted
BNP NT-proBNP all-cause mortality (death from any cause) in this same group.95 Furthermore, in another study, serial measurements
Obesity Decrease Decrease of galectin-3 in the general population also demonstrated the ability to identify individuals at high risk for a new onset
of heart failure.96
Kidney disease Slight increase Significant increase
Female sex Increase Increase Notably, in the PREVEND study, researchers found that women and older individuals had higher galectin-3 levels
Increasing age Increase Increase than men and younger individuals.95 Hemolysis in the specimen, presence of rheumatoid factor, or anti-mouse
Severe pneumonia Increase Increase antibodies can also contribute to inaccuracies in the galectin-3 results.97

Obstructive sleep apnea Increase Increase

Pulmonary hypertension Increase Increase MARKERS OF MYOCARDIAL STRESS OR INJURY/ISCHEMIA
Severe burns Increase Increase High-Sensitivity Troponin
Critical illness Increase Increase Although cardiac troponin assays such as high-sensitivity troponin (hsTn) were discussed extensively in Section 3,
Sepsis Increase Increase their utility in heart failure should also be mentioned. In the setting of heart failure, similar to its role in acute
Atrial fibrillation Increase Increase coronary syndrome (ACS), cardiac troponins are considered a biomarker for cardiac stress or injury.98 Troponin
elevations will occur in heart failure patients who are experiencing a myocardial infarction (MI), but they can also
Acute coronary syndromes Increase Increase
occur in acute or chronic heart failure as an indicator of myocardial stress.99 With the development of high-sensitivity
Cardiac valve disease Increase Increase troponin assays, it has been established that most patients with heart failure have detectable troponin levels and many
Myocarditis/Pericarditis Increase Increase of these may be above the upper reference limit used to identify ACS.98 Importantly, in this context, troponin
Cardiac surgery Increase Increase elevations remain stable and do not demonstrate the rapid rise seen over several hours in ACS.98 As such, cardiac
Cardioversion Increase Increase troponins have demonstrated promise in providing additional prognostic information when measured in patients
with heart failure and those at risk.
Toxins (e.g., chemotherapy) Increase Increase
In patients presenting with ACS symptoms, hsTnI measurements over the upper reference limit may be useful
predictors of heart failure hospitalizations during the 12 months after presentation.71 Moreover, a recent study
MARKERS OF CARDIAC REMODELING evaluated the combination of NT-proBNP and hsTnI for predicting heart failure in a population of individuals with
Galectin-3 risk factors. All study participants had at least one risk factor for heart failure, but normal left ventricular ejection
fraction (approximately 50 percent or more); research found that the combination of the two biomarkers were better
Galectin-3 is a protein that mediates inflammation and fibrosis throughout the body.89 Elevated concentrations
of galectin-3 are associated with a variety of diseases, including heart failure, cancer, liver disease, diabetes, and predictors of a heart failure hospitalization than either marker alone over a long period.100 Another trial found that
autoimmune diseases.89 In heart failure, galectin-3 is secreted by macrophages in the myocardium after a cardiac using a panel of biomarkers (that included hsTnI) in combination with a risk assessment model was more effective in
injury.90 It serves as a mediator for the development of fibrosis and also appears to contribute to inflammation in the predicting future heart failure risk in patients with coronary artery disease than the risk assessment model alone.101
cardiac tissue.90 Galectin-3 can be categorized as a biomarker for cardiac remodeling because concentrations increase
when the cardiac tissue experiences inflammation and progressing fibrosis. The hsTn assays have also shown usefulness as prognostic tools in patients hospitalized for AHF; elevated hsTnI
on admission has been associated with worsening heart failure during hospitalization and increased the length of
In clinical studies of patients with heart failure, galectin-3 is more useful for long-term prognosis than initial stay.102 Likewise, at discharge, elevations in hsTnI have been associated with increased risk for readmission and
diagnosis. When galectin-3 is measured over time, an increase of 15 percent or more has been correlated with an
death in patients with AHF.103 In addition, hsTn may aid in identifying patients with a low mortality risk during an
increased risk of mortality and rehospitalization for heart failure.91 Galectin-3 has also shown added benefit when
episode of acute heart failure and may provide long-term mortality risk information in elderly patients with chronic
used in conjunction with NP measurements in patients presenting to the emergency department with acute shortness
of breath. In this scenario, galectin-3 can provide long-term prognostic information about mortality, especially in heart failure.104,105
individuals with low concentrations of NP on presentation.92 Galectin-3 is also a useful marker to measure at
As noted in Section 3, hsTn assays are very sensitive tests, but with this sensitivity, there is a loss of specificity
discharge after a heart failure hospitalization, as it provides prognostic data on the likelihood of readmission within
60 days.70 Importantly, galectin-3 has also shown particular promise in providing prognostic information in patients if specific protocols, particularly those involving “deltas” or changes over time, are not used. The other non-cardiac
with HFpEF, which is an area where other biomarkers are less helpful.70,93 clinical scenarios that can cause hsTn elevations in ACS, such as sepsis and respiratory failure, also cause elevations
when evaluating heart failure.

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OTHER BIOMARKERS FOR HEART FAILURE MR-proANP
Another natriuretic peptide called mid-regional pro-atrial natriuretic peptide (MR-proANP) serves as a surrogate
A number of other biomarkers are being studied for assessing different facets of heart failure. This section marker for atrial NP. It may be useful for diagnosing acute heart failure in patients presenting to the emergency
will discuss five that have demonstrated promise in heart failure management. Although researchers have identified departments with dyspnea.110 Moreover, in preliminary studies, it has shown some effectiveness in predicting long-
these biomarkers as potentially useful in this population, none of these markers are currently used in routine clinical term risk of death after an episode of acute heart failure.110 How MR-proANP may fit into the care of patients with
practice. Whether these emerging biomarkers provide additional clinical information beyond what can be gained acute heart failure remains to be determined.
from NPs and other established biomarkers remains to be determined.

GUIDELINES FOR BIOMARKERS

Soluble ST2
Soluble ST2, or suppression of tumorigenicity 2, is a biomarker in the interleukin-1 receptor family that denotes The European Society of Cardiology (ESC) recommends using the NPs as a method for screening patients with
biomechanical strain, myocardial stress, and fibrosis.106 As such, it has been investigated as a marker for remodeling symptoms of heart failure. The screening cutoff point for ruling out stable, chronic heart failure in symptomatic
in heart failure. Unlike the NPs, ST2 concentrations do not appear to be influenced by age, gender, kidney function, individuals is a BNP < 35 pg/mL or an NT-proBNP < 125 pg/mL.52 For any patient with concentrations measuring
or obesity.106 In preliminary studies, measuring ST2 has shown usefulness in predicting the risk of death after an above these cutoff points, ESC recommends echocardiography for a definitive diagnosis.52 The ESC Guidelines
episode of acute heart failure.106 do not make any specific recommendations about other biomarkers for heart failure due to lack of conclusive
evidence of benefit.52
In addition, because it changes quickly, ST2 may eventually prove useful in providing clinical information for guiding
heart failure therapies in the hospital setting when serial measurements are used.106 For patients with chronic heart
failure, it appears to predict the risk of death or cardiac transplantation, but whether this test provides any additional Table 5-2. Biomarker Recommendations in the 2016 ESC Guidelines for Heart Failure52
information over prognostic information available from NPs remains to be determined.106
STRENGTH OF
RECOMMENDATION AND LEVEL
GDF15 USE RECOMMENDATION
OF EVIDENCE TO SUPPORT
Growth differentiation factor 15 (GDF15) is a cytokine that is upregulated in the setting of inflammation.107 Although RECOMMENDATION
it is also found in other body tissues, in the myocardium, it appears to be a marker for remodeling and may be a good
prognosticator for mortality in individuals with heart failure.107 It may also be useful in predicting the risk of heart DIAGNOSIS: NPs can be an
failure and death after a myocardial infarction.107 Similar to ST2, although GDF15 shows promise, it has not initial diagnostic test in patients with
demonstrated superiority over biomarkers in current use. suspected heart failure; recommended
for ruling out rather than establishing
a diagnosis
MR-proADM
Several markers of neurohormonal activation in heart failure apart from the natriuretic peptides have been identified.
For patients with newly diagnosed HF,
One such biomarker is mid-regional pro-adrenomedullin (MR-proADM) which is measured because it is a precursor
NPs should be considered to assess the Moderate recommendation with a
of adrenomedullin which has an array of neurohormonal effects in the body including dilation of the blood vessels.108 appropriateness of specific therapies
DIAGNOSIS: Chronic setting weak level of evidence
Adrenomedullin and MR-proADM concentrations increase in heart failure.108 Several studies have demonstrated that to identify reversible/treatable causes
concentrations of MR-proADM are predictors of mortality as well as heart failure hospitalizations independent of NP of HF and evaluate co-morbidities Should be considered
measurements.99 Although this biomarker appears promising, further study is needed to determine its place in heart affecting HF
failure management.

For patients presenting with acute

Copeptin dyspnea and suspected heart failure, an Strong recommendation with a
A second marker that primarily measures neurohormonal activation, copeptin, was discussed in Section 3 for ACS. NP measurement is recommended to high level of evidence
DIAGNOSIS: Acute setting
It is a small part of a precursor for the arginine vasopressin hormone released from neurons that originate in the aid in differentiating between AHF
and other non-cardiac causes of Is recommended
hypothalamus, and it serves as a surrogate marker for arginine vasopressin concentrations.109 This biomarker has
acute dyspnea
demonstrated prognostic usefulness in patients with acute heart failure, and it may identify patients at high risk of
several endpoints: mortality within 90 days of presentation, heart failure hospitalizations, and emergency department
visits.109 Similar to other emerging biomarkers, research is still needed to determine if copeptin adds clinical value NP – natriuretic peptides; HF – heart failure; AHF – acute heart failure
over biomarkers already in use.

In the 2017 focused update to the 2013 heart failure guidelines, the American College of Cardiology (ACC), American
Heart Association (AHA), and Heart Failure Society of America (HFSA) make a variety of recommendations about
biomarkers. These are summarized in Table 5-3 on the next page.

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Table 5-3. Biomarker Recommendations in the 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA SECTION 5: REVIEW QUESTIONS
Guidelines for the Management of Heart Failure56
1. List one patient factor that can decrease measured levels of NP: _______________________________________________ .
STRENGTH OF
RECOMMENDATION AND LEVEL List five non-cardiac factors that can increase NP levels: _______________________________, _________________________,
USE RECOMMENDATION
OF EVIDENCE TO SUPPORT
RECOMMENDATION __________________________________________ , __________________________________________ , and _______________________.

The NP biomarkers are recommended Strong recommendation for use with

for supporting or excluding a diagnosis high-quality evidence 2. Match the biomarker with the aspect of heart failure that it evaluates.
DIAGNOSIS
of HF in a patient who presents
with dyspnea Is recommended
a . Marker for myocardial stress or injury

b
 . Marker for neurohormonal activation
In chronic HF, a BNP or Strong recommendation for use with
NT-proBNP measurement is high-quality evidence c . Marker for cardiac remodeling
recommended for determining
prognosis or disease severity Is recommended C
 opeptin _______

N
 P _______
In AHF, measurement of an NP and/or Strong recommendation for use with
cardiac troponin at the time of hospital high-quality evidence G
 alectin-3 _______
admission is recommended to provide
prognostic information Is recommended h
 sTn _______
PROGNOSIS OR RISK
S
 oluble ST2 _______
STRATIFICATION Moderate recommendation for use
During hospitalization for HF, (reasonable to use) with a moderate
measurements of a predischarge G
 DF15 _______
quality of evidence from non-
NP level is reasonable to establish randomized trials*
a prognosis after discharge
Is reasonable
3. T
 he US and European guidelines recommend using a _____________________________________________ assay for
Weak recommendation for use (may
In chronic HF, it may be reasonable to be reasonable to use) with a moderate screening individuals with shortness of breath to support or exclude a diagnosis of heart failure. The US
use other clinically available tests (e.g., quality of evidence from non-
biomarkers of fibrosis or myocardial randomized trials* guidelines suggest that NP measurements can be helpful for _____________________________________________
injury) for additional risk stratification
May be reasonable individuals who are at high risk of developing heart failure. They also recommend that _________________________

In individuals at risk of developing ___________________ assays can be helpful for determining prognosis in acute and chronic heart failure and that
HF, screening with an NP biomarker Moderate recommendation for use
followed by a team-based intervention other biomarkers that assess for _____________________________________________ or _________________________________
(reasonable to use) with a moderate
(which includes cardiovascular specialist quality of evidence from non-
PREVENTION __________ may be useful for risk stratification in patients with acute or chronic heart failure.
care and optimization of GDMT) is randomized trials*
reasonable to prevent new-onset
HF or the development of left Is reasonable
ventricular dysfunction

NP – natriuretic peptide; HF – heart failure; AHF – acute heart failure; GDMT – guideline-directed medical therapy
*Randomized trials are preferred (and provide better evidence) over non-randomized trials

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SECTION 6 THE IMPORTANCE OF PREVENTING CARDIOVASCULAR DISEASES
Each year, over 17 million people across the globe die of cardiovascular diseases (Figure 6-1).2 This number is
projected to increase to over 23 million deaths per year by 2030.5 The World Health Organization (WHO) emphasizes
that although cardiovascular disease (CVD) is the number one cause of death worldwide, many of these deaths are
preventable.2 Modifiable behaviors, such as tobacco use, physical inactivity, poor dietary choices, and the resultant
obesity are major contributors to CVD.2 In addition, initiating therapies for diseases associated with CVD, such as
hypercholesterolemia, diabetes, and hypertension, can also reduce risk.2 Accurate risk stratification of patients at low,
PREVENTION OF moderate, and high risk for developing CVD is a crucial component to reversing the advance of cardiovascular disease.
For moderate and high-risk patients, accurate stratification allows for appropriate treatment to prevent the many

CARDIOVASCUL AR DISEASE complications that arise from cardiovascular disease, whereas in low-risk patients, it allows clinicians to avoid
unnecessary investigation and treatment. If patients are not accurately risk stratified, patients who are truly high
risk (but classified incorrectly as low or moderate risk) may not receive the needed preventative treatment. Likewise,
patients who are low risk (but mistakenly classified as higher risk) will be exposed to treatments and tests that may
be costly and may have serious adverse effects without experiencing a significant benefit.

LEARNING OBJECTIVES
CARDIOVASCULAR
When you complete this section, you will be able to: DEATH
1. D
 escribe the importance of prevention of cardiovascular diseases

2. Understand guideline recommendations for preventing cardiovascular diseases ALL OTHER

27%
CAUSES OF DEATH
3. E
 xplain risk stratification tools and biomarkers used for assessing the risk of cardiovascular diseases in
the general population

Figure 6-1. Cardiovascular disease was the most common cause of death worldwide in 2015 146

GUIDELINE RECOMMENDATIONS FOR PREVENTING

CARDIOVASCULAR DISEASES
American Guidelines
The American College of Cardiology and the American Heart Association (ACC/AHA) published guidelines in
2013 on the prevention of CVD. These guidelines focus on stratifying asymptomatic individuals based on their risk of
experiencing a CVD event related to atherosclerosis in the next 10 years.111 An atherosclerotic cardiovascular disease
(ASCVD) scoring tool is recommended to provide an estimated 10-year risk for an ASCVD event and also an estimate
of lifetime risk for an ASCVD event.111 The ASCVD tool calculates risk using sex, race, cholesterol concentrations,
smoking status, blood pressure, and several aspects of a patient’s medical history.111 In addition to the scoring tool,
the guidelines suggest that other factors, including family history of CVD, the biomarker high-sensitivity C-reactive
protein (hsCRP), and coronary artery calcium scoring (a method of visualizing coronary atherosclerosis by computed
tomography) can be considered if there is still uncertainty about a person’s risk for CVD disease.111

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For anyone determined to be at high risk for ASCVD events in the next 10 years (typically a 10-year risk for The ASCVD Tool
an ASCVD event of 7.5 percent or more), the ACC/AHA guidelines recommend tailoring interventions to each The ASCVD scoring tool was developed by the ACC/AHA workgroup during the development of the risk assessment
patient.111 Clinicians are referred to the specific guidelines available for the management of cholesterol, diabetes, guidelines published in 2013. The workgroup’s goal was to create a tool that was representative of the population in
hypertension, obesity, and lifestyle modifications.111-13 Importantly, the prevention guidelines note that it is still the US, including data on African American, white, female, and male cohorts, which also provided relevant
appropriate for clinicians to counsel individuals with low or moderate estimated risk (a 10-year risk of less than 7.5 information about the risk for a first ASCVD event.111 The group defined an ASCVD event as the first nonfatal stroke,
percent) on lifestyle interventions to reduce future risk of CVD.111 The ACC/AHA guidelines recommend repeating first nonfatal myocardial infarction, or cardiac heart disease-related death.111 The ASCVD tool is designed to be used
assessment for ASCVD risk every four to six years in asymptomatic individuals.111 in patients 40 to 79 years of age who do not have cardiovascular disease, and it was also incorporated into the ACC/
AHA cholesterol guidelines issued in 2013.111,113 Table 6-1 provides the information assessed into the tool. An online
European Guidelines calculator is also available at http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/.
A joint guideline on the prevention of cardiovascular disease was issued in 2016 by the European Society of The ASCVD tool has several limitations. First, the cohorts used to develop the tool did not include adequate numbers
Cardiology (ESC) in conjunction with 10 other groups. These guidelines do not recommend a risk stratification of people from other races (e.g., Asian, Hispanic, and Native American populations) so the tool may not be as useful in
tool for asymptomatic individuals known to be at high or very high risk for CVD events, such as patients with individuals who are not white or African American.111 Second, there are also a variety of factors that the tool does not
diabetes who are over 40 years of age or individuals with specific high-risk characteristics such as familial account for that can increase CVD risk, such as obesity, family history of CVD, and sedentary lifestyle (Table 6-1).111
hypercholesterolemia.114 Instead, these patients should automatically be offered treatment to prevent CVD and the
associated complications.114 For other individuals over the age of 40, the European guidelines recommend the use of SCORE
the SCORE tool, which estimates the 10-year risk of a fatal cardiovascular event.114 The SCORE tool uses age, gender, The Systemic Coronary Risk Estimation (or SCORE) tool was developed to guide risk assessment in the European
smoking status, cholesterol, and blood pressure to assess overall risk. However, like the US guidelines, the European population. The tool itself was created because other cohort risk calculators, such as the Framingham risk assessment
guidelines suggest that other factors should be considered when evaluating a patient’s risk for CVD, particularly for tool, used data from cohorts living in the US rather than Europe; it was unclear if this appropriately predicted risk in
individuals at a moderate 10-year risk for events. These factors include socioeconomic status, obesity, family history non-American populations due to cultural and ethnic differences.114 The SCORE tool was developed using data from
of premature CVD, coronary calcium scoring, and ankle-brachial index measurements.114 Notably, the European 12 cohort studies in Europe that included 250,000 patients.114
guidelines do not recommend the use of biomarkers for risk stratification purposes.114
The SCORE tool is designed to predict the 10-year risk of a fatal CVD event in individuals 40 to 65 years of age.114
The European guidelines stress that the highest risk individuals benefit the most from preventative intervention, Although the tool itself does not incorporate this, the European guidelines suggest that overall risk for fatal plus
and they classify anyone with a risk of five percent or more as high risk and anyone over 10 percent as very high risk.114 non-fatal CVD events is approximately three times the risk calculated for fatal events.114 It is important to note that
Specific targets are recommended for individuals in these risk groups, including avoidance of tobacco, eating a healthy the SCORE tool separates Europe into high- and low-risk countries, reflecting different CVD risk profiles in different
diet, performing adequate amounts of physical activity, and achieving a healthy body mass index.114 Blood pressure, regions. These charts can be accessed at https://www.escardio.org/static_file/Escardio/Subspecialty/EACPR/
glycemic, and cholesterol control should also be addressed and can be managed Documents/score-charts.pdf.
with or without medication.114
The SCORE tool has limitations similar to those found with ASCVD. Although it is specific to European populations,
it may have less predictive capability for individuals in minority ethnic groups.114 Like the ASCVD tool, it does not
RISK STRATIFICATION TOOLS incorporate other known risk factors for CVD, as outlined in Table 6-1.114
Risk stratification tools are essential in the assessment of the many factors that contribute to CVD risk. As noted
above, accurate CVD risk stratification allows for early intervention to prevent adverse events in the case of moderate
and high-risk patients, and it avoids unnecessary investigation and treatment in individuals with low risk.114
The ASCVD scoring tool from ACC/AHA and the SCORE tool have already been mentioned briefly, but a variety
of other tools have been used to quantify the risk of cardiovascular disease in asymptomatic individuals.
This guide will discuss four commonly employed CVD risk assessment tools.

• ASCVD from ACC/AHA

• SCORE

• Framingham General CVD Risk Tool

• Reynolds Risk Score

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Table 6-1. Comparison of Factors Used in Four Cardiovascular Disease Risk Stratification Tools111,114-5,118-9 One of the significant limitations of the Reynolds score is that the cohorts it is modeled from are mostly comprised
of white participants within a relatively specific socioeconomic range.118-19 And although the Reynolds tool includes
ASCVD SCORE FRAMINGHAM 2008 REYNOLDS RISK SCORE biomarker information and family history, other lifestyle factors are not incorporated into the risk score
(Table 6-1).118-19
Age    
Sex    
Limitations of Scoring Tools
Race *
Although an array of risk assessment tools are available for predicting CVD, there are significant limitations
Cholesterol ‡  § 
to using these tools alone for determining an individual’s risk of developing CVD. First, many of the risk factors
Blood pressure ‡  ‡  evaluated in these scoring tools are not specific to cardiac disease; elevations in blood pressure, for example, increase
Blood pressure treated the risk of other problems, such as stroke. A second limitation is that many of these tools have not been externally
 
with medication validated (which means tested to determine if they are still accurate in other patient sample groups), and most have
Smoking status     also not been compared head-to-head to provide clinicians with information about which tool has the best risk
Diabetes   prediction capability.120 Third, all scoring tools are based on a limited number of factors influencing CVD risk; because
BMI § of this, an individual tool will not completely and accurately assess risk for all patients.120 Finally, when these scoring
tools have been compared and studied for external validation, their accuracy appears to be mixed. A study comparing
Country/Region †
the ASCVD tool, several Framingham risk scores (including the general CVD tool), and the Reynolds score in men
Aspirin use  and women used data from a multi-ethnic US cohort of individuals without cardiovascular disease. Researchers
hsCRP  found that after monitoring participants for approximately 10 years, all tools overestimated risk of CVD in men,
Parental history of MI  but the Reynolds score was the most accurately calibrated tool in this group.121 Notably, most of the tools also
overestimated risk in women, except the Reynolds score, which underestimated risk. The Framingham general CVD
BMI – body mass index; hsCRP – high-sensitivity C-reactive protein; MI – myocardial infarction was the best-calibrated tool for women in this study.121 As discussed previously, over and underestimation of risk have
* Only African American and White potentially serious consequences, so refining currently available tools to improve predictive accuracy for CVD is
† Differentiates between high- and low-risk countries in Europe
critical for appropriate patient care.
§ Framingham uses either cholesterol or BMI
‡ Incorporates treated and untreated

Framingham General CVD Risk Tool CONSIDERATIONS FOR BIOMARKERS IN CARDIOVASCULAR

DISEASE RISK STRATIFICATION
The Framingham General CVD Risk Tool (sometimes known as Framingham 2008) was developed to predict the
10-year risk of CVD. It was a modification of an earlier tool, the Framingham risk assessment, which calculated risk To overcome the limitations presented by traditional scoring tools, researchers have begun focusing on circulating
for coronary heart disease. The Framingham General CVD tool broadened this focus to predict CVD risk, which biomarkers as useful alternatives for assessing CVD risk. They comprise an easy, non-invasive test that may identify
included cerebrovascular events (such as stroke and transient ischemic attack), peripheral arterial disease, and heart CVD risk more accurately than traditional risk-stratification tools alone. A number of biomarkers have demonstrated
failure in addition to coronary heart disease events.115 It was developed using information from a US cohort, but it has value in predicting CVD risk, and several have shown particular promise when used in conjunction with these
been validated as a useful tool in other nations throughout the world.116 The tool incorporates age, gender, smoking, traditional scoring tools. This portion of the guide will focus on specific considerations for using biomarkers in CVD
blood pressure, diabetes diagnosis, and either cholesterol or body mass index to assess a 10-year risk for a CVD risk assessment, discuss a number of biomarkers with data to support their use for CVD risk stratification, and briefly
event.115 An online risk calculator is available at https://www.framinghamheartstudy.org/risk-functions/ review several emerging biomarkers for CVD risk prediction.
cardiovascular-disease/10-year-risk.php.
Considerations for Biomarkers: Defining Normal
The Framingham General CVD tool can assess risk in a broader age range, 30 to 74 years, and it also incorporates One difficulty in the assessment of CVD risk in an asymptomatic population is determining what the normal range
obesity as a risk factor if the body mass index version is used.115 Limitations of the Framingham CVD risk tool include for a biomarker should be. There is a great deal of variability in the way normal subjects are selected for determining
that it is based on information from a comparatively small cohort of participants in the US and there are other major normal ranges of clinical laboratory measures; some are screened using a simple method like a health questionnaire
CVD risks not incorporated into the score, such as lifestyle factors and family history of CVD (Table 6-1).117 whereas others are subjected to more detailed assessments such as a physical examination by a clinician,
electrocardiogram testing, or measurement of other surrogate biomarkers.122 Resulting normal values can be quite
Reynolds Risk Score
variable given the variation in the selection process for normal subjects. Methods that determine if subjects are truly
The Reynolds risk score is another tool designed to predict the 10-year risk of cardiovascular disease in healthy healthy (with biomarkers or ECG testing) are most likely better than those relying on self-reported information for
individuals without diabetes.118 Unlike the previously discussed tools, the Reynolds score incorporates a family history identifying a biomarker’s true normal range.122 However, because there is no standard in how manufacturers or
of CVD and the biomarker hsCRP into the risk calculation.118-19 Smoking status, age, gender, blood pressure, and researchers determine the normal range for a biomarker, there is significant variation between studies in how this
cholesterol measurements are also included in the score.118-19 The Reynolds score was created with information from process occurs and how the normal range is defined.122 This variation is of particular importance for high-sensitivity
two US-based cohorts, the Women’s Health Study and the Physicians Health Study-II.118-19 An online calculator is tests like troponin, where the accuracy of the 99th percentile measure may be impacting therapy decisions.
available at http://www.reynoldsriskscore.org.

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Although there have been calls to make more specific determinations about defining a normal population, there CARDIOVASCULAR RISK BIOMARKERS
remains significant variation in these practices, so it is up to the individual clinician to evaluate how normal values
were obtained in various studies.122 Table 6-2 outlines one expert opinion on the best method for “coning,” or Lipids
selecting, participants for a normal reference population to define the 99th percentile value for cardiac troponin.122 Circulating lipids often referred to as cholesterol, are essential building blocks for plaque in atherosclerotic disease.
As such, lipid measurements are useful as predictors of cardiovascular disease and were some of the earliest
Considerations for Biomarkers: Determining Clinical Value circulating biomarkers used for assessing cardiovascular risk. Moreover, when medications, specifically statins,
Establishing the clinical value of a particular biomarker is another essential aspect in determining its role in patient are employed to normalize certain lipid biomarkers, the rate of cardiovascular events and death is significantly
care. Useful biomarkers will need to demonstrate two qualities: 1) accuracy in predicting future cardiac risk and 2) reduced. As such, lipids are a cornerstone of cardiovascular risk assessment and are included in many risk
provision of additional information beyond what current methods offer.123 These qualities can be evaluated using prediction scoring tools.
three complementary statistical techniques. First, a biomarker must demonstrate discrimination capability, or the
ability to differentiate between individuals who will and will not develop a disease, which is usually evaluated with TOTAL CHOLESTEROL
something called a c-statistic test.123 Second, a biomarker must demonstrate through a statistical assessment that it is Higher concentrations of total cholesterol have long been associated with an increased risk for CVD.124-25 Because
calibrated to what it measures, or that the biomarker’s prediction aligns with the observed results.123 And third, of this correlation, total cholesterol concentrations are included in many CVD risk assessment tools. Although this
a biomarker must demonstrate that it improves a patient’s risk characterization over previous methods, measure remains a helpful tool for evaluating risk, it is no longer used as a target for intervention with lipid-
a concept known as net reclassification improvement.123 lowering medication.

Table 6-2. Useful Tools for Identifying Normal Individuals (a Normal Reference Population) to Determine 99th LOW-DENSITY LIPOPROTEIN
Percentile Values for Cardiac Troponin122 Low-density lipoprotein (LDL) is also very strongly correlated with risk of cardiovascular disease: as LDL
concentrations increase, so does the risk for cardiovascular events.113,124,126 Importantly, use of statin medication in
POTENTIAL PROBLEM IN SURROGATE MARKER OR DEFINITION patients with elevated LDL concentrations reduces the risk of cardiovascular events and death.113,126 Both the US
NORMAL INDIVIDUALS FOR SCREENING and European guidelines for lipid management use LDL as the primary biomarker for determining CVD risk and
the need for intervention with medication therapy.113,126 Of all the lipid markers, LDL is the most established for
• Minimum of 600 participants (50 percent male/female) identifying risk and guiding medication interventions to lower risk of CVD and death.
• Diverse racial and ethnic backgrounds (40 percent white/40 percent African
Population diversity
American/20 percent mix of Asian/Hispanic/other) HIGH-DENSITY LIPOPROTEIN
• Age diversity (18 to 70+ years)
High-density lipoprotein (HDL), sometimes referred to as “good cholesterol,” is inversely associated with CVD;
Clinical history Assess for cardiovascular disease and medication use so, unlike other forms of lipid biomarkers, as HDL increases, the risk of CVD declines.124,127 The concentrations of
HDL are reported in most lipid panels and provide clinicians with additional insight about CVD risk. However,
Diabetes Hemoglobin A1c unlike LDL, drug therapies to raise HDL do not appear to reduce the risk of cardiovascular events in clinical trials,
and it is unlikely that low HDL itself is a cause of CVD.128-29 Although lifestyle factors such as exercise and smoking
Myocardial dysfunction BNP or NT-proBNP
cessation are interventions that can raise HDL and decrease cardiovascular risk, the benefits of these
Renal disease Creatinine (for eGFR) interventions are not entirely due to their effect on HDL.

Coronary artery disease Imaging to directly examine for atherosclerosis

TRIGLYCERIDES
Triglycerides are another lipid measurement typically reported on a lipid panel. Although some clinical
trials examining the risk associated with triglyceride elevation have found a strong association with CVD,
other lipid biomarkers may have better predictive power.129 Moreover, at the time of this publication, studies of
medications to lower triglycerides have not demonstrated improvement in cardiovascular outcomes, although
there are ongoing clinical trials in this area.129

LIPID FRACTIONS
The term lipid fraction is used to describe different lipid measurements, including LDL, HDL, and triglycerides.
This term is also used to describe newer lipid biomarkers, such as triglyceride-related lipoprotein and
apolipoprotein B. And finally, lipid fraction can be used to describe the ratios in the concentration of two
circulating lipids, such as triglyceride/HDL and total cholesterol/HDL. Studies are ongoing to identify the ideal
lipid fraction for predicting CVD risk and to determine which lipid fractions are the best targets for medication
therapies to reduce the rates of future CVD events.

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High-Sensitivity C-Reactive Protein The use of hsTn in conjunction with traditional scoring tools has also been examined. In the BiomarCARE study,
Inflammation is an important mediator of cardiovascular disease and is linked to atherosclerosis, ischemic heart investigators examined data from multiple trials that included more than 74,000 European participants who were
disease, and stroke.130 High-sensitivity C-reactive protein, or hsCRP, becomes elevated in the presence of multiple free from cardiovascular disease.137 Researchers determined that hsTnI measurements provide better prognostic data
cardiovascular risk factors including abdominal adiposity (fat accumulation in the abdomen), diabetes, hypertension, for predicting CVD and CVD-related death when used in conjunction with the SCORE risk assessment tool than the
smoking, and hyperlipidemia (high lipid concentrations).130 Hence, hsCRP is an integrated measure of CVD risk SCORE tool alone.137 In another study of over 9,000 individuals without cardiovascular disease, hsTnI performed
because of its complex associations with conventional risk factors. However, even when these other factors are better than hsCRP at predicting cardiovascular risk over more than 13 years of follow-up.149 Furthermore, when
considered, hsCRP has an independent risk relationship with CVD. As a biomarker for inflammation, hsCRP has hsTnI was added to established cardiovascular disease risk prediction models, it led to significantly greater net
demonstrated usefulness in identifying individuals at risk for CVD events.118-19,131 Elevated hsCRP is associated with an reclassification improvement than adding hsCRP to the models.149
increased risk of diabetes, cardiovascular disease, and mortality.132 This predictive ability appears to improve when An important difference in normal troponin concentrations between men and women has also been identified with
hsCRP is measured over time; prolonged elevations of hsCRP are stronger predictors of these outcomes than one-time the advent of high-sensitivity assays. The HUNT study found not only do women in a normal population have a lower
measurements.132 Importantly, hsCRP as a predictor for CVD events has been evaluated in different ethnic cohorts in hsTnI concentration than men, but hsTnI concentrations were stronger predictors of death due to cardiovascular
different areas of the world.130 Although studies indicate that there are race and geographic differences in normal disease in women than in men.138 Another group of researchers used data from a long-term population study, the
hsCRP ranges (making the definition of normal ranges difficult to define for international populations), there is Dallas Heart Study, to evaluate sex-specific differences in an array of biomarkers, including hsTn.139 Similar to
evidence that higher hsCRP concentrations correlate to a higher incidence of CVD events across all populations.130 findings in the HUNT study, women were found to have lower concentrations
of hsTn than men.139
One of the biggest shortcomings of hsCRP is its lack of specificity to the heart; any inflammatory condition, such
as rheumatoid arthritis or inflammatory bowel disease, can cause elevations in hsCRP. In addition, hsCRP has not Evidence indicates that measuring circulating sensitive cardiac biomarkers such as hsTnI improves cardiovascular
performed consistently in predicting CVD risk in several large study populations. Researchers evaluating the use of risk stratification in the general population; however the majority of the prior evidence and biomarker thresholds
hsCRP in the participants of two large, long-term study groups, NHANES and ARIC, found that measuring hsCRP were derived in Western populations. Whether these data are similarly applicable to Asia Pacific populations and
did not add any significant predictive effectiveness over traditional scoring tools and traditional risk factors (such as may be effectively used to target high risk individuals for primary prevention strategies warrant further study.151
blood pressure and cholesterol).133-34 Despite this, hsCRP was cited in the ACC/AHA guidelines as possibly helpful if
the benefit of treatment is uncertain after traditional risk assessment with the ASCVD scoring tool.111
Natriuretic Peptides
Although the natriuretic peptides (NPs) are used extensively in the management of patients with heart failure,
High-Sensitivity Troponin they also have a role in screening the asymptomatic population for CVD. Even small elevations of NP levels, below
Unlike hsCRP, high-sensitivity troponin (hsTn) T and I are biomarker assays that are very specific to the cardiac the threshold for diagnosis of heart failure, have demonstrated usefulness as a prognostic marker for predicting the
muscle.149 Although they have demonstrated usefulness in acute coronary syndromes and heart failure, they also have risk of cardiovascular events and death.136,140 In a meta-analysis examining data from 11 studies on NT-proBNP for
recently established their value as prognostic indicators in the general, apparently-healthy population. In this context, identification of risk in the general population, NT-proBNP elevation correlated with an increased cardiovascular
the concentration of hsTn may be a reflection of the health of the myocardium. A long-term study of over 3,000 men mortality and mortality from any cause.141 Moreover, there is also data to support that NPs are useful predictors of
with elevated cholesterol but no history of myocardial infarction, WOSCOPS, monitored participants for over five outcomes over long periods; BNP concentrations were strongly correlated with risk of CVD-related death in a cohort
years and also assigned some participants to treatment with a statin.135 Researchers measured hsTn at study entry of middle-aged men followed for an average of 15 years.142
and one year later; the change (rise or fall) in hsTn over that one-year period was strongly correlated with future Importantly, the STOP-HF trial (as discussed in Section 5) evaluated interventions to prevent or delay the onset of
risk of coronary disease, regardless of a change in cholesterol concentrations.135 It was noted that treatment with the heart failure in individuals with risk factors for heart failure. In the intervention group (the group that experienced
statin appeared to lower hsTn concentrations at the one-year measurement, which also correlated with a lower risk the experimental care) of this trial, a BNP concentration over 50 pg/mL was used as a screening cutoff; patients with
of coronary disease events.135 Another trial, JUPITER, which examined the effectiveness of rosuvastatin (another measurements above this received preventative interventions designed to reduce the risk for heart failure.81 The
statin medication) for preventing CVD events in individuals without cardiovascular disease, also evaluated hsTnI as participants that received the preventative interventions had lower rates of heart failure than the patients in the
a biomarker in over 12,000 participants.136 In this trial, participants with the highest hsTnI concentrations also had control group (the group that received normal care) at the end of the trial.81 This trial highlights the real-world
the highest risk of a cardiovascular event or death from any cause.136 Treatment with rosuvastatin lowered the risk value of BNP as a biomarker for prevention. Patients were screened using BNP and received intervention if they
of CVD events in individuals with and without elevated hsTnI concentrations.136 Both of these trials highlight that were high-risk according to the biomarker; this intervention, in turn, resulted in improved patient outcomes
the information provided by hsTnI can be used to help improve patient outcomes; not only is hsTnI useful in (i.e., lower rates of heart failure).81
identifying patients who are at risk, but these patients will also benefit from intervention (treatment with a statin).

Other Biomarkers
A variety of other biomarkers have been evaluated to assess CVD risk in the general population, but their exact role in
CVD risk assessment remains unclear. Lipoprotein (a) is a circulating lipoprotein similar to LDL, and its concentration
in plasma has been consistently associated with CVD events.143 Specific treatments to lower the production of Lp(a)
are in development. Similarly, the total triglyceride concentration and the non-HDL fraction (total cholesterol minus
HDL) of the lipid panel may reflect the “total atherogenicity” of the lipid profile and hence have been treatment

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targets in prior guidelines. Further study of these two lipid fractions is ongoing. Another biomarker, homocysteine, SECTION 6: REVIEW QUESTIONS
is an amino acid synthesized by the body. Elevated homocysteine concentrations are associated with inflammation
and an increased risk of ischemic heart disease and stroke in a generally healthy population.144 However, clinical trials 1. Which of the following may be useful for determining an asymptomatic patient’s risk for future CVD events?
evaluating folic acid and B-vitamins for decreasing homocysteine concentrations did not demonstrate any decrease
in CVD risk. Finally, lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme linked to inflammation and a . SCORE risk assessment tool
instability in atherosclerotic plaques. Multiple studies have found an association between increasing Lp-PLA2 b
 . A biomarker measurement, such as hsCRP or hsTnI
concentrations and increased risk of cardiac events.145 But similar to homocysteine, clinical trials of specifics drugs
for lowering Lp-PLA2 did not reduce the risk of CVD. Whether any of these markers provides an advantage over c . Assessing other risk factors such as obesity, sedentary lifestyle, and family history of CVD events
currently used prognostic tools has not been determined. d
 . All of the above are useful considerations

Biomarkers in Clinical Practice

Biomarkers for cardiovascular disease are continuously evolving, and although the roles for certain biomarkers, 2. The ACC/AHA guidelines recommend against the use of biomarkers to assess an asymptomatic patient’s
such as NPs and cardiac troponins, are well defined in specific aspects of cardiac care, the roles for many newer risk for future CVD events.
biomarkers are still being determined. One area that needs further clarification is how best to incorporate biomarker True False
information into traditional risk stratification tools. Another area that requires more study is whether using a panel
of biomarkers is better than measuring one or two individual markers. Theoretically, a panel may be a more useful
approach because it includes markers for multiple pathways affected by CVD, but the value of this type of assessment 3. To demonstrate clinical usefulness, a biomarker needs to show all of the following EXCEPT...
is unclear in the clinical setting. Likewise, a third area that requires study is how incorporating biomarkers into risk
assessment for CVD influences clinical outcomes in patients. Even with these unresolved questions, biomarker use a . Net reclassification improvement
in cardiovascular diseases will likely continue to evolve, ideally providing clinicians with better tools for caring for b
 . Adherence to ACC/AHA guidelines
their patients.
c . Discrimination capability

d
 . Calibration to what is measured

4. Which of the following statements is TRUE about normal values for biomarkers?

a . A
 health questionnaire is preferred over surrogate biomarkers for determining normal values
in a population

b
. A
 standardized, normal range must be established for every biomarker marketed in the US and Europe,
and this standard must be adhered to by all manufacturers

c . T
 here is no standard for defining a normal population in studies of biomarkers or how that normal population
is selected

d
 . All of the above statements are true

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 APPENDIX A: GLOSSARY OF TERMS

ACE inhibitors: A class of medication used to treat heart failure and high blood pressure; in heart failure, these drugs
block neurohormonal changes.

APPENDIX Acute coronary syndrome: A spectrum of problems ranging from ST-elevation MI to unstable angina that indicates
the heart tissue is not receiving adequate supplies of oxygen.

Acute heart failure: Acute, rapid worsening of heart failure symptoms that can be life-threatening.

Adrenal glands: Glands that sit directly above the kidneys that produce a variety of hormones, including
APPENDIX A: GLOSSARY OF TERMS norepinephrine.

Aerobic exercise: Exercise that stimulates the heart rate and breathing rate to increase.
APPENDIX B: CORRECT RESPONSES
Aerobic respiration: The process used by the cells of the body to produce energy that relies on oxygen.

Aggregation (of platelets): Platelets clumping together in the process of forming a plug to stop bleeding from a
APPENDIX C: REFERENCES
blood vessel.

Aldosterone antagonists: Diuretic drugs used in heart failure that block the neurohormonal effects of heart failure.

Anemia: A condition resulting from an insufficient amount of healthy red blood cells circulating in the bloodstream.

Angina: The medical term for chest pain related to the heart.

Antibodies: Proteins used by the immune system to neutralize foreign, potentially harmful substances found in
the body.

Anticoagulant: Medications that decrease the blood’s ability to clot (thin the blood) by interfering with the body’s
normal clotting cascade.

Antiplatelet: Medications that decrease the blood’s ability to clot (thin the blood) by interfering with the normal
activity of platelets.

Angiography: A procedure done to examine the blood flow in the coronary arteries; it involves inserting a catheter
into a large artery (in the groin or wrist) and threading it up to the heart. In the heart, a dye is released that will flow
into the coronary arteries, and an x-ray device is used to evaluate the flow of blood through the coronary arteries.

Angiotensin receptor blocking agents (ARB): A class of medication used in patients with heart failure and high
blood pressure; in heart failure, it can block some of the maladaptive neurohormonal activity.

Angiotensin II receptor-neprilysin inhibitors (ARNI): A new class of medication for heart failure that blocks the
maladaptive neurohormonal response.

Aorta: The largest artery in the body; it receives blood pumped out of the left ventricle.

Artery: Blood vessels that carry oxygen-rich blood from the heart to the organs and tissues.

ASCVD scoring tool: A scoring tool used to assess risk for future atherosclerotic cardiovascular disease events in
the general population of individuals without known cardiovascular disease.

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APPENDIX A: GLOSSARY OF TERMS APPENDIX A: GLOSSARY OF TERMS

Aspirin: An antiplatelet medication used to prevent blood from clotting; it is often used in the treatment and C
prevention of myocardial infarction.

Atherosclerosis: The buildup of plaque inside the arteries. C-statistic test: A statistical test used to evaluate the discrimination capability of a particular test (e.g., the ability to
differentiate between individuals who will and will not develop a disease).
Atrial fibrillation: An abnormal heart rhythm where the atria beat inappropriately fast; this sometimes also results
in the ventricles beating too fast. Calcium: A chemical element that is very abundant in the body. Calcium is used to build bones and contract skeletal
and cardiac muscle; it is needed for blood to clot normally.
Atrioventricular node (AV node): Part of the cardiac electrical conduction system, it receives impulses from the
sinoatrial (SA) node and transmits them to the ventricles, stimulating the ventricles to beat. Calibration (or calibrated): In statistics, how well a prediction aligns with the observed results.

Atrium (plural: Atria): The two upper chambers of the heart; they receive blood from the vena cava and the Capillaries: The smallest blood vessels; they allow nutrients, oxygen, and carbon dioxide to be exchanged between
pulmonary vein and move it into the ventricles. cells and the blood.

Autoimmune disease: A disease characterized by the body’s immune system producing antibodies that attack its Carbon dioxide: A gas which is a waste product of cell energy production.
own tissue. Cardiac catheterization: See “angiography.”
Automaticity: The heart tissue’s ability to generate its own electrical impulses to stimulate contraction. Cardiac catheterization laboratory (cath lab): The department within a facility (often a hospital) where
angiography procedures are performed.

B Cardiac magnetic resonance (CMR): A magnetic resonance imaging (or MRI) test that examines the structure
of the heart.
B-natriuretic peptide (BNP): A protein released by the ventricles of the heart when they are under strain or stress;
Cardiac myosin-binding protein C (cMyC): An emerging, circulating biomarker that may be useful in early
most often used as a biomarker for diagnosing and monitoring heart failure.
identification of myocardial infarction.
Beta blocker: A medication used to slow the heart rate and control blood pressure; beta blockers are often used in
Cardiac resynchronization device/therapy: An implantable device that uses electrical impulses to aid both
patients who have had a myocardial infarction; some beta blockers are useful for blocking the neurohormonal changes
ventricles in contracting at the same time. It is used to treat certain electrical conduction abnormalities.
associated with heart failure.
Cardiomyopathy: Maladaptive changes in heart structure caused by myocardial infarction, neurohormonal
Biomarker: A measurable characteristic that can be used to evaluate normal body processes, disease, or response to
activation, genetic, abnormal cell signaling, or unknown reasons.
treatment. This guide focuses on circulating biomarkers, which are markers that circulate in the bloodstream.
Cardioversion: A procedure used to treat an abnormal cardiac rhythm that involves either delivering a specific
Blood: The liquid that travels through the blood vessels of the body that is made up of specific types of cells (i.e.,
amount of electricity (a shock) to the heart or administering medication to promote return to a normal rhythm.
red blood cells, white blood cells, platelets). Blood carries oxygen and nutrients to body tissues and carries waste
and carbon dioxide away from tissues. Cell: The smallest unit (“building block”) within a living organism.
Blood pressure (or arterial blood pressure): The measure of pressure inside the arteries that is created by the force Cerebrovascular event: A term used to describe a situation where the brain is not receiving enough oxygen to
and rate of the heart beating and the elasticity of the arteries. function normally. This can mean a stroke (which results in permanent damage to the brain) or a transient ischemic
attack (where symptoms are only temporary, and permanent damage does not occur).
Blood vessel: A general term used to describe the tubes that carry blood through the body: arteries, veins,
and capillaries. Chemotherapy: A type of medication used to treat severe illnesses, such as cancer, that can be toxic to the cells of the
body including cardiomyocytes.
Bundle of His: Part of the cardiac electrical conduction system, it transmits electrical signals from the
atrioventricular (AV) node to the ventricles. Cholesterol: A fat-like substance found in body tissues that is necessary to make hormones, vitamin D, and parts of
cells. Too much of certain types of cholesterol can raise the risk of heart disease.

Clot: A clump of blood composed of fibrin, platelets, and erythrocytes that are stuck together, usually to stop bleeding
from a damaged blood vessel.

Clotting cascade (or Coagulation cascade): A complex series of reactions that occur within the body as a result of a
blood vessel injury, ultimately resulting in the formation of a clot or thrombus.

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APPENDIX A: GLOSSARY OF TERMS APPENDIX A: GLOSSARY OF TERMS

Coefficient of variation (CV): A statistical measurement used to describe variation within a data sample; coefficient E
of variation is calculated by dividing the standard deviation (a measure that describes the amount of variation in a Echocardiography: A test the uses ultrasound to visualize the heart and its function.
group of numbers) by the mean (or average) of those numbers. It is usually expressed as a percentage.
Ejection fraction: The percentage of blood pumped out of the left ventricle with each contraction; normal range is
Congenital heart disease: A structural abnormality in the heart that is present at birth. approximately 55-75%.
Coning: A term used to describe selection of a population for a scientific measurement. Elasticity: Stretchiness.
Copeptin: An emerging, circulating biomarker that may be used for identifying myocardial infarction. Electrocardiogram (ECG or EKG): A test that measures the electrical activity of the heart, visualizing the electrical
Coronary artery: An artery that supplies blood to the heart muscle. activity of the heart from 12 different angles; used to evaluate for a type of myocardial infarction, cardiac arrhythmias,
and other cardiac abnormalities.
Coronary artery bypass grafting (CABG): A type of surgery used to treat severe coronary heart disease. Surgeons
use healthy blood vessels from another part of the body to create a new route for oxygen-rich blood to travel to the End-stage renal disease (ESRD): Chronic, irreversible failure of the kidneys; patients require either dialysis or a
myocardium. kidney transplant at this stage.

Coronary CT angiography: A type of imaging test that allows clinicians to visualize the inside of the coronary Enoxaparin: A medication that interferes with the clotting cascade used to thin the blood; it is used in many clinical
arteries using a powerful, detailed X-ray. scenarios, including myocardial infarction.

Coronary heart disease: A condition that results from atherosclerosis in the coronary arteries. Enzyme: A protein produced by the body that encourages a chemical or biological reaction to occur more quickly.

Contraction: Tension that occurs in the muscle fibers in response to a stimulus.

F
Creatinine kinase MB (CK-MB): An older circulating biomarker that was previously used to identify myocardial
necrosis, related to myocardial infarction. Fat: An oily substance found in the body and also ingested in food; it is a building block for many substances in
the body.
D Fibrin: A protein formed after activation of the clotting cascade that creates a clot or thrombus.

Degradation: Breaking down into parts. Fibrinolytic: A medication that breaks down fibrin and a fibrin-based clot.

Delta: A change or difference between two numbers measuring the same thing. Fibrosis: In the heart, scar formation in tissue in response to an injury.

Diabetes: A disease characterized by either the inability to make insulin or resistance to insulin that results in Framingham general CVD risk score: A scoring tool for predicting risk of a cardiovascular event in individuals
elevated concentrations of glucose (a basic form of sugar) in the body. Diabetes significantly increases the risk of without known cardiovascular disease.
heart disease.

Diastole: The relaxation phase of the heart pumping cycle that results in relaxation of the heart muscle, allowing the G
heart chambers to fill with blood.
Galectin-3: A protein that mediates inflammation and fibrosis throughout the body; as a circulating biomarker,
Digoxin: A medication used to treat symptoms of heart failure or control the heart rate in atrial fibrillation. it is useful for providing prognostic information in patients with heart failure.
Discrimination: In statistics, the ability to differentiate between individuals who will and will not develop a disease; Growth-differentiation factor-15 (GDF15): A cytokine that is upregulated in the setting of inflammation; it may
usually measured with the c-statistic test. be useful as an emerging, circulating biomarker for cardiac remodeling and a prognostic indicator for individuals
Diurnal variation: A scenario where concentrations of substances in the body vary throughout different times of with heart failure.
the day. GRACE score: A scoring tool used to risk stratify a patient with suspected acute coronary syndrome.
Diuretic: A type of medication used in patients with heart failure that triggers the kidneys to remove more water
from the body (in the urine).

Dyspnea: Difficulty breathing.

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APPENDIX A: GLOSSARY OF TERMS APPENDIX A: GLOSSARY OF TERMS

H I

Half-life: In the body, the time it takes for the concentration of a substance to decrease by half (e.g., a half-life of 20 Ischemia: A scenario where tissues are not receiving enough oxygen.
hours would mean it takes 20 hours for a drug’s concentration in the body to drop from 10 ng/mL to 5 ng/mL).
Immunoassay: A test that measures the presence or concentrations of proteins (often antibodies) in a fluid
Heart: The organ in the body responsible for pumping blood to other body organs and tissues. (usually blood).
Heart failure: A condition in which a problem with the ventricles is preventing the heart from pumping correctly; Implantable cardioverter-defibrillator: An implantable device that can detect abnormal, dangerous cardiac
it is the result of a complex mechanical and neurohumoral syndrome resulting in stasis (or slow movement) of blood rhythms and can send a small, electrical shock to the heart to return it to a normal rhythm.
in the lungs and peripheral tissues.
Ischemia modified albumin: An FDA-approved, circulating biomarker for identifying myocardial infarction.
HEART score: A scoring tool used to risk stratify a patient with suspected acute coronary syndrome.

Hemoglobin: The protein in red blood cells that carries oxygen.

J
Hemolysis: Rupture or breaking apart of red blood cells; this rupture of red blood cells can occur in a specimen
collection tube (during or after removing the blood from the body) and can affect the accuracy of certain
laboratory tests. K
Heparin: A medication that interferes with the clotting cascade used to thin the blood; it is used in many clinical
Kidneys: The organs of the body that create urine, remove waste from the blood, and regulate fluid balance.
scenarios, including myocardial infarction.
Kidney failure (or renal failure): Impairment of normal kidney function; there is a spectrum of impairment that
HFmrEF (Heart failure with mid-range ejection fraction): A newer heart failure classification used to describe
occurs, ranging from mild to chronic, irreversible impairment (known as end-stage renal disease).
patients with heart failure symptoms and a left ventricular ejection fraction of 40- 49 percent.

HFpEF (Heart failure with preserved ejection fraction): A heart failure classification used to describe patients
with heart failure symptoms and an ejection fraction in the normal range, usually over 45 percent. L
HFrEF (Heart failure with reduced ejection fraction): A heart failure classification used to describe patients with Left-ventricular assist device (LVAD): An implantable device, using a pump implanted into the wall of the left
heart failure symptoms and a reduced ejection fraction, usually under 45 percent. ventricle, which is used in patients with end-stage heart failure to support cardiac function. The pump itself is
implanted in the chest, but a wire runs out of the device and through the skin to connect the LVAD to the external
High-sensitivity C-reactive protein (hsCRP): A circulating biomarker for inflammation in the body; in cardiology
batteries and control unit.
practice, it can be used as a screening tool for identifying patients at risk for cardiac disease when other tools are
not adequate. Lesion: In the coronary arteries, another name for an area inside the artery with plaque buildup.
Homocysteine: An amino acid synthesized by the body; elevated concentrations are associated with inflammation Lipoprotein-associated phospholipase A2 (Lp-PLA2): An enzyme linked to inflammation and instability in
and an increased risk of ischemic heart disease and stroke in a generally healthy population, but its usefulness as a atherosclerotic plaques; it has been studied as a possible biomarker for screening asymptomatic populations for
screening tool is uncertain. cardiovascular disease.
Hormone: A “messenger” substance produced by the body that is released into body fluids to stimulate the activity Low-sodium diet: A diet low in salt.
of a different tissue or organ.
Lumen: An opening; in the case of blood vessels, this term describes the opening inside the vessel.
Hydralazine: A medication used for blood pressure that has also shown benefit in certain heart failure patients,
particularly those of African descent, when used in combination with another medication (a long-acting nitrate).
M
Hyperlipidemia: The medical term for higher-than-normal cholesterol concentrations in the blood.
Maladaptive: Counterproductive; inadequate adjustment to a change or environment.
Hypertension: The medical term for high blood pressure that indicates that the pressure inside the arteries is
higher than normal. Mineralocorticoid receptor antagonist: See “Aldosterone antagonist.”
Hypotension: The medical term for low blood pressure that indicates that the pressure inside the arteries is too low Mortality: Death or dying.
and may not be adequate for perfusion of oxygen into the tissues.

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APPENDIX A: GLOSSARY OF TERMS APPENDIX A: GLOSSARY OF TERMS

MR-proADM: An emerging, circulating biomarker for neurohormonal activation in heart failure. O

MR-proANP: An emerging, circulating biomarker for neurohormonal activation in heart failure.
Obese: Significantly overweight.
Myocardial: Relating to the heart.
Obesity: The state of being significantly overweight.
Myocardial infarction: Permanent damage to the heart as a result of inadequate blood flow to the cardiac tissue.
Obstructive sleep apnea: A sleep disorder in which patients stop and restart breathing many times through the
Myocarditis: Inflammation of the heart muscle, often as a result of a viral infection. night; it has a variety of negative health implications and is a risk factor for certain cardiac problems.

Myocardium: The heart’s muscle tissue. Occlusion: Blockage.

Myocyte: A cell in the heart tissue. Organ: A self-contained part of the body that has a specific function.

Myoglobin: An oxygen-binding protein similar to hemoglobin; it was one of the earliest circulating biomarkers for Oxygen: An element and a gas necessary for normal function of the body cells.
myocardial infarction, but it is no longer used for this purpose.
P
N
Percutaneous coronary intervention (PCI): An angiography procedure done to treat a blockage in a coronary
Natriuretic peptide: Hormones that influence fluid and sodium balance in the body. Although there are several other artery that involves threading a wire device into the coronary artery, opening the blocked artery with a tiny,
known natriuretic peptides, this term is often used to describe BNP and its inactive counterpart, NT-proBNP. balloon-like device, and then propping the artery open with a mesh wire tube called a stent.

Necrosis: Death of all or most of the cells in an area of the body. Perfusion: Passage of fluid (in this case, blood) into the capillaries of an organ or tissue.

Negative predictive value (NPV): The probability that an individual with a negative result on a screening test does Pericarditis: Inflammation of the lining around the heart, often due to a viral infection.
not have a disease or problem.
Peripheral/periphery: Situated away from the center; in the case of the body, this often refers to the arms, legs,
Neprilysin: An enzyme involved in an array of biochemical processes in the body; neprilysin is involved in the hands, and feet.
breakdown of BNP.
Permeability: How well liquids and other substances can pass through a structure.
Net reclassification improvement: In statistics, the ability of a new test or marker to demonstrate that it improves
Plaque: A substance that can accumulate inside an artery; it is made up primarily of cholesterol, fat, and calcium.
predictive ability over previously used methods (e.g., more individuals were provided with accurate predictions with
the new method than with previous methods). Pneumonia: An infection in the lungs, caused by either a bacterium or a virus.

Neurohormonal activation: The release of hormones and neurotransmitters that increase the blood pressure and Prognostic: Predicting the likelihood of something.
promote retention of water by the kidneys to increase blood volume. This occurs in response to a loss of perfusion and
can be helpful for short-term problems, like acute blood loss, or harmful in the case of heart failure. Pulmonary embolism: A potentially life-threatening event caused by a substance (usually a blood clot) that travels
through the veins, then gets wedged into a branch of the pulmonary artery and creates a blockage.
Neurotransmitter: Chemical messengers in the body that stimulate a nerve.
Pulmonary hypertension: A life-threatening disease that causes high blood pressure in the arteries of the lungs and
Nitrate (long-acting): A type of medication used for patients with certain cardiac problems; in heart failure, they can the right side of the heart.
be beneficial when used in combination with hydralazine, especially in individuals of African descent.
Pulmonary veins: The veins that bring oxygenated blood from the lungs back to the heart.
Norepinephrine (or Noradrenaline): A hormone released by the adrenal glands and certain nerves that promotes
vasoconstriction (narrowing of the blood vessels) and increases in the blood pressure. Purkinje fibers: Fibers in the heart that conduct electrical impulses to the left and right ventricle, to stimulate the
heart to beat.
NSTEMI (pronounced: en-stem-eee): A type of myocardial infarction that does not result in characteristic ST-
elevation on an electrocardiogram.

NT-proBNP: An inactive fragment cleaved from BNP; used clinically as a circulating biomarker in patients with
heart failure.

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APPENDIX A: GLOSSARY OF TERMS APPENDIX A: GLOSSARY OF TERMS

Q ST2: An emerging circulating biomarker used in heart failure and acute coronary syndromes.

Stent: Mesh wire tube placed inside a blood vessel to prop it open.
Quantitative: Measuring the quantity of something; in the laboratory setting, quantitative measures provide an exact
number describing the concentration of a substance (this is in contrast to a qualitative measure, which tells only if a Stress myocardial perfusion imaging: An imaging test that evaluates how well blood flows into the cardiac tissue.
substance is present or not).
Stethoscope: A medical instrument most often used to externally evaluate the heart and lungs; one end of the device
fits into the clinician’s ears and the other, round end is placed against the chest wall.
R
Stroke: A potentially life-threatening event where adequate blood supply to a portion of the brain is cutoff, resulting
Remodeling: In the heart, the process of structural changes to the cardiac tissue as a result of heart failure, tissue in permanent damage. There are two primary mechanisms for this: 1) ischemic, which is usually caused by a blood
injury, or other factors. clot and 2) hemorrhagic, which is caused by a blood vessel in the brain bursting.

Renal: See “kidney.” Superimposed: Occurring in addition to or on top of something else.

Renal Failure: See “kidney failure.” Systole: The phase of the cardiac pumping cycle that involves contraction of the heart muscle, pushing out blood.

Reperfusion: Restoring blood flow to a tissue or organ.

T
Retention: Holding on to a substance.
Tachyarrhythmia: A general term describing an abnormal, fast, heart rhythm.
Reynolds risk score: A scoring tool used to assess risk for future cardiovascular events in the general population of
individuals without cardiovascular disease. Thrombin: An enzyme in the blood that works in the clotting cascade to create fibrin.

Rheumatoid factor: An antibody directed against the body’s own tissue; elevated concentrations can be a sign of an Thrombolytic: A medication that breaks down or dissolves a blood clot.
autoimmune disease such as rheumatoid arthritis.
Thrombosis: The process of a blood clot forming inside a blood vessel.

Thrombus: A blood clot.

S
TIMI score: A scoring tool used to risk stratify patients with suspected acute coronary syndrome.
Sarcoidosis: A chronic inflammatory disease that causes abnormal tissue to form in different parts of the body,
Tissue: Material inside the body made up of specialized cells.
including the lungs, skin, and heart.
Transient ischemic attack (TIA): A temporary period of abnormal brain functioning caused by temporary loss of
Sepsis: The body’s response to a serious infection that can be life-threatening if not treated promptly.
blood flow to an area of the brain; sometimes called a “mini-stroke,” it is a risk factor for future strokes.
Sinoatrial node (SA node): The area of the right atrium where electrical impulses originate.
Treadmill ECG: A test for coronary artery disease where a patient undergoes continuous ECG monitoring while
Skeletal muscle: A muscle connected to the skeleton that participates in the mechanical, voluntary movement doing exercise, such as running on a treadmill or riding a bicycle.
of the body.
Troponin: A protein that is abundant in the cardiac myocytes; it works inside the cell as part of the contractile
Smooth muscle: Muscles in the gut and other internal organs that move involuntarily (i.e., not conscientiously mechanism to facilitate myocyte contraction; troponins T and I are both useful as biomarkers in the evaluation of
controlled). individuals with possible myocardial infarction.

Standard deviation: In statistics, a number that specifies how much members of a group differ from the
group average. U
Stasis: A slow down or complete stoppage of a normal flow. Unstable angina: A type of acute coronary syndrome where cardiac biomarkers are not elevated and myocyte death
does not appear to occur; it is not classified a myocardial infarction.
STEMI (pronounced: stem–eee): A type of myocardial infarction characterized by ST-elevation on an
electrocardiogram test.

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APPENDIX A: GLOSSARY OF TERMS APPENDIX B: CORRECT RESPONSES

V SECTION 1
1. Veins >> vena cava >> right atrium >> right ventricle >> pulmonary artery >> lungs >> pulmonary veins >>
Valsartan/sacubitril: A medication used for heart failure that blocks the body’s maladaptive left atrium >> left ventricle >> aorta >> arteries >> capillaries of organs and tissues
neurohormonal response.
2. d
Vascular disease: A type of disease characterized by blood vessel abnormalities; it is a general classification that 3. Coronary
encompasses an array of different conditions, including coronary heart disease.
4. Contraction, relaxation, left
Vasospasm: Spasm of the blood vessel wall.

Vein: Blood vessels that carry oxygen-poor blood from the capillaries back to the heart. SECTION 2
Vena cava: The largest vein in the body which delivers blood into the right ventricle. 1. Atherosclerosis: e
PCI: b
Ventricles: The larger, lower two chambers of the heart.
MI: a
Venules: Smaller veins that deliver blood to the capillaries. Troponin: c
Calcium: d

W 2. In a myocardial infarction, adequate amounts of blood and oxygen cannot reach a portion of the myocardial tissue.
This leads to the death of the cells in the affected area. Most often, an MI is caused by a thrombus forming in a
coronary artery as a result of plaque rupture, but it can also be caused by a spasm of the blood vessel, excessive
X plaque buildup, or anything that causes inadequate flow of oxygen into the tissues.
3. d
Y 4. Cardiac troponin

Z SECTION 3
1. False
2. b
3. b
4. Any four of the following: copeptin, BNP, NT-proBNP, cMyC, GDF15, ST2

SECTION 4
1. a. AHF b. HFrEF c. HFpEF d. AHF e. HFpEF f. HFrEf
2. Any 5 of the following: dyspnea (shortness of breath), orthopnea (shortness of breath when lying down),
paroxysmal nocturnal dyspnea (awakening from sleep with acute shortness of breath), exercise intolerance,
weakness, fatigue, swelling of the ankles or feet
3. b
4. Blanks are:
a. Hormones and neurotransmitters, neurohormonal
b. Kidneys
c. Fibrosis

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APPENDIX B: CORRECT RESPONSES APPENDIX C: REFERENCES

SECTION 5 1. Martini FH, Nath JL, Bartholomew EF. Fundamentals of Anatomy and Physiology. 10th ed. Pearson; 2015.

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Soluble ST2: c 5. About Cardiovascular Disease. World Health Organization Web site. http://www.who.int/cardiovascular_diseases/about_
cvd/en/. Updated 2017. Accessed September 18, 2017.
GDF15: c
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3. NP, screening, NP, fibrosis or myocardial injury
Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction.
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SECTION 6 7. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 ACC/AHA guideline for the management of patients with non-ST-
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19. Twerenbold R, Wildi K, Jaeger C, et al. Optimal Cutoff Levels of More Sensitive Cardiac Troponin Assays for the Early
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21. Wens SC, Schaaf GJ, Michels M, et al. Elevated Plasma Cardiac Troponin T Levels Caused by Skeletal Muscle Damage in
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