DIAGNOSTICS

Cardiac
Learning guide series

LEARNING GUIDE: CARDIAC 1

 ACKNOWLEDGEMENTS
EDITOR
Peter A. McCullough, M.D., M.P.H.
F.A.C.P., F.A.C.C., F.C.C.P., F.A.H.A., F.N.K.F., F.N.L.A., F.C.R.S.A.
Dr. Peter McCullough received a bachelor’s degree from Baylor University and then
earned a medical degree from the University of Texas Southwestern Medical School
in Dallas where he was honored as a member of Alpha Omega Alpha. He continued
his training with an internal medicine residency at the University of Washington in
Seattle and a cardiology fellowship at William Beaumont Hospital in Michigan where
he served as Chief Fellow. After completing his medical training, Dr. McCollough
earned a master’s degree in public health at the University of Michigan.
Dr. McCullough is an internationally recognized expert on the relationship between
chronic kidney disease and cardiovascular disease. He is a leader in research on
cardiac and renal disease and has contributed to the understanding of these
disease processes through the publication of more than one thousand published
medical communications. Likewise, he has successfully led many observational
and randomized controlled trials and has also been involved in the U.S. Food and
Drug Administration (FDA) approval process for numerous novel drugs and
diagnostic tests.
Dr. McCullough’s research and scholarship efforts have been recognized with
both the Simon Dack Award from the American College of Cardiology and the
International Vicenza Award in Critical Care Nephrology. In addition, he has
been invited to lecture at many prominent institutions, including the New York
Academy of Sciences, the National Institutes of Health, the FDA, and the
European Medicines Agency.
Dr. McCullough continues to work on improving the medical community’s
understanding of cardiac and renal disease. He is a founding member and
currently serves as president of the Cardio Renal Society of America. This
organization promotes collaboration between cardiologists and nephrologists
to identify and address the problem of cardiorenal syndromes. Moreover,
Dr. McCullough serves as an editorial board member for multiple specialty
journals and is also the co-editor of Reviews in Cardiovascular Medicine and
the associate editor of the American Journal of Cardiology.
Currently, Dr. McCullough is the Vice Chief of Medicine at Baylor University Medical
Center in Dallas and also serves as Principal Faculty in internal medicine for the
Texas A&M University Health Sciences Center. He is board certified in internal
medicine, cardiology, clinical lipidology, and echocardiography.

LEARNING GUIDE: CARDIAC 2

 ABBOTT DIAGNOSTICS
CARDIAC LEARNING GUIDE
INTENDED AUDIENCE
The Cardiac Learning Guide is intended to serve the basic educational needs of
healthcare professionals who are 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, and other physician office and laboratory support personnel.

The guide contains:

• a review of the anatomy and physiology of a healthy heart
• an explanation of the pathophysiology of two common conditions –
acute coronary syndrome and heart failure
• information on the role of cardiac biomarkers in the diagnosis, prognosis,
risk stratification, and therapy monitoring of various heart conditions

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 presented. Short quizzes at the end of the sections are
designed to help you recall and retain important information. 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.

A glossary of terms is also included at the end of this Learning Guide, featuring
commonly used terms in cardiology.

LEARNING GUIDE: CARDIAC 3

 CONTENTS
ACKNOWLEDGEMENTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

CARDIAC LEARNING GUIDE

INTENDED AUDIENCE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
HOW TO USE THIS LEARNING GUIDE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

SECTION 1
ANATOMY AND PHYSIOLOGY OF THE HEART. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

SECTION 2
ACUTE CORONARY SYNDROME. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

SECTION 3
THE ROLE OF CARDIAC BIOMARKERS IN ACUTE CORONARY SYNDROME. . . . . 23

SECTION 4
HEART FAILURE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

SECTION 5
THE ROLE OF CARDIAC BIOMARKERS IN HEART FAILURE. . . . . . . . . . . . . . . . . . . . . . 42

SECTION 6
PREVENTION OF CARDIOVASCULAR DISEASE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

APPENDIX
APPENDIX A: GLOSSARY OF TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
APPENDIX B: CORRECT RESPONSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
APPENDIX C: REFERENCES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

LEARNING GUIDE: CARDIAC 4

 SECTION 1
ANATOMY AND PHYSIOLOGY
OF THE HEART
LEARNING OBJECTIVES
When you complete this section, you will be able to:

1. Recognize key features of the cardiac anatomy including the heart chambers
and coronary arteries

2. Describe how blood flows through the heart, lungs, and body

3. Understand basic characteristics of the heart’s electrical conduction system

4. Explain systole and diastole and how this relates to blood flow

LEARNING GUIDE: CARDIAC 5

 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

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 a smaller left atrium above and a larger left ventricle below.

AORTA
PULMONARY ARTERY
SUPERIOR
VENA CAVA

PULMONARY VEIN

RIGHT ATRIUM LEFT ATRIUM

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

LEARNING GUIDE: CARDIAC 6

 BLOOD FLOW THROUGH THE HEART AND BODY
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.
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 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, passes through the mitral valve, and empties into the left ventricle. The left ventricle, which is the
largest and strongest of the four chambers of the heart, pumps the oxygen-rich blood through the aortic valve
and out into a 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

For the heart to maintain this continuous pumping process, it also requires a large amount of oxygen. The heart
is made up of a unique type of muscle tissue that is not found anywhere else in the body. This specialized muscle
tissue of the heart is referred to as the myocardium. The cells that make up the myocardium are called cardiac
myocytes. These myocytes are almost entirely dependent on aerobic metabolism, meaning they require oxygen
to function normally and depend upon an oxygen-binding protein known as myoglobin.
Blood Flow to the Myocardium
To continuously supply the heart muscle with oxygen, three major coronary arteries carry oxygen-rich blood
from the aorta to the myocardium (Figure 1-2). Different coronary arteries supply blood to various parts of the
myocardium. For example, the right coronary artery supplies blood to the right atrium, sections of both
ventricles, and portions of the heart’s electrical conduction system. Other major coronary arteries include the
left main coronary artery, which divides into the left circumflex artery, and the left anterior descending artery,
all of which are responsible for delivering blood to a particular part of the heart. In a similar network, several
large cardiac veins, including the aptly named great cardiac vein, collect the oxygen-poor blood from the tissue
and return it to the right 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 and nutrients flowing to that region of heart tissue.
Electrical Activity in the Heart
Cardiac muscle tissue has another distinctive quality. Unlike other types of muscle that require stimulation
by a nerve or hormone to contract, the myocytes of the myocardium stimulate their own contraction.
This self-stimulation is referred to as automaticity, and it means that the heart can stimulate its own muscle
contraction without any input from the body.

LEARNING GUIDE: CARDIAC 7

 Figure 1-2. Major arteries that supply blood to the myocardium

LEFT MAIN CORONARY ARTERY

CIRCUMFLEX ARTERY

LEFT ANTERIOR
DESCENDING ARTERY

RIGHT CORONARY ARTERY

The electrical impulses that cause the heart muscle to contract, or beat, in a regular fashion originate in the
sinoatrial node (SA node) which is located in the wall of the right atrium. Once the electrical activity in the
SA node has begun, it travels through both atria, stimulating the muscle to contract (or beat). After
stimulating the atria, the electrical impulse then travels to the atrioventricular node (AV node), down along a
band of fibers (called the bundle of His) to the right and left bundles in the right and left ventricles,
respectively. The electrical impulse then spreads to the walls of both ventricles through pathways called
Purkinje fibers and triggers the ventricles to contract (or beat). These electrical impulses that stimulate
contraction of the atrium and ventricles are what produce the rhythmic, coordinated pumping action of the
heart. In turn, this pumping action generates the stroke volume which is felt as the pulse—the regular beat
that can be monitored in the arteries throughout the body.

Although the heart creates its own electrical impulses, outside activity from nerves and hormones can
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.

LEARNING GUIDE: CARDIAC 8

 THE PUMPING ACTION OF THE HEART: SYSTOLE AND DIASTOLE
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 ventricles do not contract or relax at the same time. For a brief period, both atria and both ventricles
are in diastole allowing blood from the vena cava or pulmonary veins to flow in passively. Once the SA node
begins spreading its 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 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 right ventricle pumps to the pulmonary artery, and the left
ventricle pumps to the aorta). After systole is complete, 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,
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 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 function normally.

Understanding the process of systole and diastole in the heart can also help explain a health parameter
that is frequently measured in the clinical setting: blood pressure. More accurately termed arterial
blood pressure, 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 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 function and can lead to organ and tissue damage.

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.

LEARNING GUIDE: CARDIAC 9

 SECTION 1: REVIEW QUESTIONS
1. P
 lace the following term in the correct order to describe the flow of blood through the heart, lungs, and body.
Start with veins.
right atrium pulmonary artery right ventricle
veins pulmonary vein aorta
vena cava left atrium capillaries of organs and tissues
lungs left ventricle arteries

______________________________________________________________________________________________________________________________________________________________________

______________________________________________________________________________________________________________________________________________________________________

______________________________________________________________________________________________________________________________________________________________________

______________________________________________________________________________________________________________________________________________________________________

2. Which if the following statements about the heart is FALSE?

a. The cells of the myocardium function using aerobic metabolism and require a steady supply of oxygen
b. T
 he cells of the heart generate their own electrical impulses to stimulate cardiac contraction; this
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
d. The right atrium and ventricle contract first, pushing blood to the lungs, and the left atrium and ventricle
contract second, pushing blood to the rest of the body

3. _____________________________________________ arteries supply the myocardium with oxygen-rich blood.

4. Systole means _____________________________________________________ and diastole means ________________________________________________________ .

The ____________________________________________________ ventricle creates the strongest contraction because it must pump

blood to the entire body.

LEARNING GUIDE: CARDIAC 10

 SECTION 2
ACUTE CORONARY
SYNDROME
LEARNING OBJECTIVES
When you complete this section, you will be able to:

1. Describe the different types of acute coronary syndromes

2. Discuss the mechanisms of myocardial ischemia and infarction

3. Explain 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 acute coronary syndrome

LEARNING GUIDE: CARDIAC 11

 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, 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 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
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),
and unstable angina (UA).

Diagnosis of ACS

SYMPTOMS

AT LEAST 2/3 OF THESE MUST BE

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 administration of an intravenous medication called a thrombolytic or, more optimally, by an immediate
procedure called a primary percutaneous coronary intervention (primary PCI) performed at a hospital with
cardiac catheterization facilities. Both of these procedures will be discussed in more detail later in this section.
Any delay in the time to reperfusion can increase the amount of damage that occurs to the myocardium. Because
a STEMI leads to the death of the cardiac myocytes, cardiac biomarkers are always elevated, but biomarker
information is not required before proceeding to a reperfusion intervention.

LEARNING GUIDE: CARDIAC 12

 A 12-lead ECG shows different views of the electrical activity in the heart from 12 distinct angles.
During the test, a technician places a wire lead on 12 specific areas of the chest, arms, and legs.
The ECG traces the view of the heart’s electrical activity from each of these 12 areas of the body
because they each reflect a unique view of the heart. On the ECG report, each lead produces a
tracing, and the tracings are labeled I, II, III, aVR, aVL, aVF, V1, V2, V3, V4, V5, and V6. An ECG
is useful for diagnosing a range of cardiac problems, including arrhythmias. In ACS, paramedics,
nurses, and physicians use the ECG to differentiate a STEMI from other causes of ACS symptoms.
An ECG can even identify which coronary artery is likely obstructed by looking at which leads have
ST elevation (Figure 2-1).

ST Segment
Normal ECG

P T

QRS

STEMI

ST Segment ST Elevation

P T

QRS

NSTEMI ST Segment
ST Depression

P T

QRS

NSTEMI
ST Segment
T Inversion

P T

QRS

Figure 2-1. The name ST-elevation MI is describing the changes that happen during a STEMI on an ECG: the
ST segment in the ECG tracing is more elevated than normal. This test is useful for distinguishing a STEMI
from other types of MI.

LEARNING GUIDE: CARDIAC 13

 Non-ST-Elevation Myocardial Infarction
The second type of ACS, non-ST-elevation myocardial infarction or NSTEMI, also has serious consequences for
the heart. An NSTEMI is also a type of MI but is much more common than STEMI. Although estimates vary,
approximately 75 percent of patients presenting with MI are diagnosed with NSTEMI, and this is associated
with an 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 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 formation in a coronary artery. Other less common causes include vasospasm
of the coronary artery or an excessive accumulation of plaque inside the coronary artery that almost completely
occludes blood flow. Regardless of the cause, an NSTEMI does cause ischemia in the cardiac myocytes because
they are not receiving enough oxygen to function normally, and with time, this leads to the death of the
myocytes and permanent damage to the myocardium. Elevated cardiac biomarkers are a confirmation of this
damage and differentiate NSTEMI from unstable angina. Additionally, these elevated biomarkers, along with
other clinical factors, help identify higher-risk patients with NSTEMI who require cardiac catheterization.

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 of UA is changing with the advent of more sensitive biomarker measurements, such as high-
sensitivity troponin. Many experts now believe that most patients diagnosed with UA are likely experiencing an
NSTEMI, but the 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.

Symptoms and Biomarkers in Diagnosing ACS

Regardless of whether it is classified as a STEMI or NSTEMI, an MI is caused by an ischemic event that
results in 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).

Although the assessment process for acute MI begins with an ECG, clinicians must also consider the
symptoms the patient is experiencing and measure cardiac biomarkers. Cardiac troponins are the
preferred biomarker in this 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

LEARNING GUIDE: CARDIAC 14

 Table 2-1.

FOURTH UNIVERSAL DEFINITION OF MI

Criteria for ACUTE myocardial infarction (Types 1, 2 and 3 MI)

The term acute myocardial infarction should be used when there is acute myocardial injury with clinical evidence of
acute myocardial ischaemia and with detection of a rise and/or fall of cTn values with at least one value above the
99th percentile URL and at least one of the following:
• Symptoms of myocardial ischaemia
• New ischaemic ECG changes
• Development of pathological Q waves
• I maging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent
with an ischaemic aetiology
• Identification of a coronary thrombus by angiography or autopsy (not for type 2 or 3 MIs)
Post-mortem demonstration of acute athero-thrombosis in the artery supplying the infarcted myocardium meets
criteria for type 1 MI.
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.

Criteria for prior or silent/unrecognized myocardial infarction

Any one of the following criteria meets the diagnosis for prior or silent/unrecognized MI:
• 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

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.

LEARNING GUIDE: CARDIAC 15

 CLASSIFICATION OF MYOCARDIAL INFARCTIONS
For initial treatment stratification by emergency medicine providers and cardiologists, an MI is classified as a
STEMI or NSTEMI. However, there are additional classifications for MI that further explain the mechanism
leading to the ischemia. It is essential for providers to understand the cause of an MI to treat it appropriately.

Type 1: The Spontaneous MI

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 coronary artery. This rupture triggers the activation and aggregation of platelets, the initiation of the
coagulation cascade to produce fibrin, and ultimately the formation of a thrombus which causes complete or
partial occlusion of the artery. Plaque can accumulate inside any artery in the body, and the presence of plaque
in the arteries is called atherosclerosis. The presence of plaque in the coronary arteries is particularly
problematic, and when this occurs, it is termed coronary artery disease. Plaque changes how blood moves
through the arteries because it stiffens the walls of the artery and narrows the artery lumen. Plaque is also less
stable than walls of the artery and more prone to breakage or rupture. As blood travels through the coronary
arteries, occasionally the plaque will rupture. If the subsequent platelet aggregation and fibrin formation result
in a significant obstruction in the artery, a 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.

MI TYPE 1 MI TYPE 2

Plaque rupture Vasospasm or endothelial Fixed atherosclerosis and Supply-demand

with thrombus dysfunction supply-demand imbalance imbalance alone

Figure 2-2. Differentiation between myocardial infarction (MI) types 1 and 2 according to the condition
of the coronary arteries

LEARNING GUIDE: CARDIAC 16

 Type 2: The Ischemic Imbalance MI
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 the result of supply and demand imbalance in the heart where the coronary arteries are not supplying
adequate oxygen for the myocytes to function normally—the supply does not meet the demand. There are
many reasons that this can occur (Figure 2-2). Some type 2 MIs are caused by a vasospasm, or spasm of the
blood vessel wall, which can prevent blood from flowing appropriately to the myocardium, leading to ischemic
damage. Others can be caused by 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 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.

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 before increases in cardiac biomarkers can be identified, or MI is detected by autopsy
examination.

Other Types of MI
There are two other types of MI that should be mentioned for completeness. A type 4 MI is related to a
percutaneous 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, this guide will focus on type 1 and 2 as they are the most common in the clinical
setting.

The key concept to appreciate about MI is that anything that prevents the myocardium from receiving
adequate supplies of oxygen will lead to ischemia. If this ischemia is prolonged, it will lead to myocyte death
and tissue necrosis.

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.
LEARNING GUIDE: CARDIAC 17
 THE PROCESS OF CARE IN MYOCARDIAL INFARCTION
Because damage to the cardiac tissue happens quickly once an obstruction occurs, it is essential that medical
providers understand how to manage patients experiencing ACS efficiently. Figure 2-3 is a flowchart
explaining the process of care for patients with ACS. Any patient with ACS symptoms is classified as very high
acuity in the emergency department and requires rapid assessment and close monitoring. Nurses, physicians,
and other support staff must work together to ensure that this occurs in a timely and efficient manner.

SUSPECTED ACS

12-LEAD ECG†

ST-ELEVATION NO ST-ELEVATION

Immediate reperfusion Risk Stratification

with primary PCI* Medical history, physical exam findings,
(or fibrinolytic if PCI unavailable) repeat ECG†, and serial biomarkers

Serial biomarkers Based on risk stratification

(results not needed prior to reperfusion) 1. Initiate pharmacotherapy for NSTEMI‡
ECG† monitoring after reperfusion 2. Begin additional diagnostic testing

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

Figure 2-3. Process of care for patients with suspected acute coronary syndrome (ACS)7,11,23

LEARNING GUIDE: CARDIAC 18

 ACS Symptoms
Any person experiencing symptoms of ACS should be evaluated immediately by a healthcare provider.
Chest pain, sometimes radiating down the left arm, is probably the most widely recognized symptom.
But many patients, especially women and the elderly, may experience other symptoms like chest pressure,
nausea, sweating, jaw or back pain, shortness of breath, dizziness, or light-headedness.10

STEMI
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 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 hospital arrival.

For the PCI procedure, the patient is promptly transferred to the cardiac catheterization laboratory (or cath
lab). First, a specialized catheter is threaded through a large artery (either the femoral artery in the groin or
the radial artery in the wrist) up into the heart. Next, the physician will use a dye to evaluate the blood flow
through the 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 be placed in the area of the blockage to prop the artery open.12 The PCI
procedure rapidly restores blood flow to the ischemic myocardium.

If PCI is unavailable, a physician will usually prescribe a thrombolytic drug for a patient experiencing
a STEMI. A thrombolytic promotes degradation of the fibrin in the thrombus, to quickly lyse the clot in
the coronary artery.13

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

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

LEARNING GUIDE: CARDIAC 19

 Next Steps
Although STEMI is the first type of ACS to be screened for and diagnosed, the majority of MIs are not STEMI.
It is estimated that approximately 75 percent of MIs are NSTEMI, and further testing is needed to establish this
diagnosis (Figure 2-3).3,11

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 the risk for MI and guide the next steps in treatment.

1 ECG Changes
After an initial ECG that is normal or non-diagnostic, current guidelines recommend that the ECG should
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
changes that could indicate ischemia. Additionally, the ECG can be checked any time there is a change
in patient status. It is common for patients with chest pain to have multiple ECGs over the course of
evaluation in the emergency department or hospitalization.

2 Cardiac Biomarkers
It can be several hours after an ischemic event occurs before the cardiac troponin is detected in the
blood using traditional assays; therefore, conventional cardiac troponins are measured several times in
the first hours after symptom onset and presentation to the hospital.7 The American Heart Association/
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
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

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
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
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

LEARNING GUIDE: CARDIAC 20

 NSTEMI
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 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.

In addition to treatment with medication, patients with NSTEMI usually undergo a coronary angiography
(cardiac catheterization) procedure to examine the coronary arteries.7 An angiography procedure, similar to
what is done for 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 evaluate the flow of blood through the coronary arteries.12 As the dye
flows through, it will opacify the coronary 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 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. 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.

Figure 2-5. An x-ray evaluating blood flow through the coronary arteries during a coronary angiography
Attribution: Suh I-W, Lee CW, Kim Y-H, et al. “Catastrophic Catecholamine-Induced Cardiomyopathy
Mimicking Acute Myocardial Infarction, Rescued by Extracorporeal Membrane Oxygenation (ECMO)
in Pheochromocytoma.” Journal of Korean Medical Science. 2008;23(2):350-354.

No MI Identified
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. 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

LEARNING GUIDE: CARDIAC 21

 SECTION 2: REVIEW QUESTIONS

1. Match the acronym or word with the correct description

Atherosclerosis ______ PCI ______ MI ______ Troponin ______ Calcium ______

a. A term used to describe an ischemic event that leads to permanent damage to the cardiac muscle
b. A procedure used to reopen a blocked coronary artery
c. A substance normally found in cardiac muscle cells that is released when the cells die
d. A substance that is a part of plaque deposits in the coronary arteries
e. A term used to describe plaque buildup inside the arteries

2. Describe the general mechanism for how myocardial damage occurs in a myocardial infarction

______________________________________________________________________________________________________________________________________________________________________

______________________________________________________________________________________________________________________________________________________________________

______________________________________________________________________________________________________________________________________________________________________

______________________________________________________________________________________________________________________________________________________________________

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
b. N
 ew changes to the ECG, imaging studies demonstrating new cardiac muscle damage,
or symptoms of cardiac ischemia such as chest pain
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
f. All of the above are correct

4. The preferred cardiac biomarker for diagnosing MI is _____________________________________________.

LEARNING GUIDE: CARDIAC 22

 SECTION 3
THE ROLE OF CARDIAC
BIOMARKERS IN ACUTE
CORONARY SYNDROME (ACS)
LEARNING OBJECTIVES
When you complete this section, you will be able to:

1. Describe the role of troponin in ACS

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

3. Understand important considerations for implementing high-sensitivity troponin

assays within an institution

4. Recognize other cardiac biomarkers with potential roles in ACS

LEARNING GUIDE: CARDIAC 23

 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
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 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 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

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

4. Macrotroponins: Consist of troponin bound to immunoglobulins (autoantibodies). Some assays may detect
these autoantibodies.150

LEARNING GUIDE: CARDIAC 24

 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 of this interaction when interpreting cardiac troponin results.

6. Hemolysis: A hemolyzed blood specimen can also result in inaccurate measurements of troponin assays.
Thus, hemolysis needs should be noted when troponin concentrations are reported, and attempts should be
made to redraw the specimen whenever possible.38

CONVENTIONAL TROPONIN ASSAYS

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 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

With conventional assays, troponin I or T can be measured in the blood six to 12 hours after the onset of ACS
symptoms.7,15 After an MI, troponins will typically remain elevated for four to ten days.7,15 The normal half-life
for 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 reference range but the troponin measurement must also be rising or falling in what is
considered a characteristic pattern for MI.7 The amount of rise or fall is not defined in the global consensus
document, Third Universal Definition of MI, which requires the individual clinician to interpret the pattern
of serial troponin values over time. A more 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 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 from the initial
value is required to meet the definition for rising or falling.7 The ACC/AHA guidelines also stress that the
clinical laboratory should clearly identify when a significant change has been identified in troponin
concentrations during serial measurements.7

The reason for the rising or falling requirement for troponin is to aid in differentiating between a true MI and
other potential causes for troponin elevation (Table 3-1). There are a variety of other cardiac conditions
that can be associated with elevated troponin concentrations, sometimes chronically. These can include
myocarditis, pericarditis, 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 elevations in troponin. Indeed, because troponin is partially removed
by the kidney, individuals with end-stage renal disease may have chronic elevations of troponin.7,24

LEARNING GUIDE: CARDIAC 25

 Table 3-1. Reasons for Troponin Elevations Not Related to Myocardial Infarction15,17,23

CARDIAC NON-CARDIAC
Hypertensive emergency Critical illness
Arrhythmias Sepsis
Heart failure Pulmonary embolism or hypertension
Myocarditis Kidney dysfunction
Cardiomyopathy Serious neurological events (e.g., stroke)
Aortic dissection Thyroid disease
Structural heart disease (e.g., valve disease) Drug toxicity (e.g., chemotherapy, cocaine)
Physical trauma to the heart Extreme endurance exercise
Heart surgery/procedure (e.g., PCI*) Rhabdomyolysis
*PCI – percutaneous coronary intervention

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 and assessing symptoms, followed by a physical examination, an electrocardiogram (ECG), and
then biomarker measurement. Only when all of these features are considered together can an accurate
diagnosis be made.

The ACC/AHA guidelines for NSTEMI recommend measuring either troponin I or T when a patient with
suspected ACS presents to the emergency department (ED).7 This measurement should be repeated three to
six hours after the symptoms started (or three to six hours after presentation) in all patients with ACS
symptoms.7 Additional measurements after six hours should be considered in patients who are stratified as
moderate or high risk for ACS.7

LIMITATIONS TO CONVENTIONAL TROPONIN ASSAYS

Due to the extended time required to detect troponin in the blood using conventional assays, there can
be a delay in the diagnosis of MI, which could also result in the delay of appropriate treatment. Following
clinical evaluation and assessment for STEMI via ECG, most patients presenting to an emergency department
(ED) with ACS symptoms will 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 positive result if a patient is experiencing an NSTEMI.
This process can result in prolonged ED admission times for patients who are ultimately “ruled out”
(not experiencing an MI) and delays in initiation of treatments for patients who are eventually determined
to be experiencing an NSTEMI.

Another limitation of conventional troponin assays is that they may lack enough sensitivity to detect small
elevations in troponin that can occur in a less extensive MI or in those with lower circulating levels of troponin,
such as women 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.

LEARNING GUIDE: CARDIAC 26

 HIGH-SENSITIVITY TROPONIN ASSAYS
Due to the shortcomings of conventional troponin measurements, high-sensitivity troponin (hsTn) assays have
been 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 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, but myocyte turnover and increased cell permeability have been suggested
as mechanisms.29,30
99th Percentile

PATIENTS WITH
NORMAL LEVELS

CARDIAC DAMAGE DUE

TO NON-AMI CAUSES

PATIENTS WITH
MYOCARDIAL NECROSIS

HIGH-SENSITIVITY TROPONIN ASSAY

4th gen troponin assay
1st-3rd gen troponin

LEVEL OF CARDIAC TROPONIN

Figure 3-2. The sensitivity of high-sensitivity troponin assays allows for measurement of troponin in normal
healthy individuals, whereas earlier generation assays were only sensitive enough to detect troponin elevation
resulting from significant necrosis in MI, or occasionally, severe damage from other causes
Adapted from: Garg P, Morris P, Fazlanie AL, et al. “Cardiac Biomarkers of Acute Coronary Syndrome:
from History to High-sensitivity Cardiac Troponin.” Internal and Emergency Medicine. 2017;12(2):147-155.
Used under CC BY http://creativecommons.org/licenses/by/4.0/ modified from original.

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 that hsTn assays be defined using two parameters:

• The total imprecision (coefficient of variation) at the 99th percentile value should be ≤10 percent28

• Measurable concentrations below the 99th percentile should be attainable with an assay at a concentration
value above the assay’s limit of detection (LOD) for at least 50 percent (and ideally >95 percent) of
healthy individuals28
– In 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

LEARNING GUIDE: CARDIAC 27

 Multiple high-sensitivity assays exist for troponin I, and one fifth-generation assay for troponin T is available.
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 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
evaluated diagnostic thresholds using a hsTnI assay; researchers found that when using hsTnI, a sex-specific
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

HIGH-SENSITIVITY TROPONIN ASSAYS IN PRACTICE: “RULE OUT” AND “RULE IN”

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.

Rule Out
One of the primary advantages of hsTn assays is that they have higher negative predictive value for acute MI
than 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 arrival to the ED using a risk-stratification algorithm, a negative hsTn measurement has over
95 percent negative predictive value for ruling out an MI.14,31 At three hours after presentation, this number rises
to over 99 percent, and accordingly, a repeat measurement of hsTn is recommended in all patients three to six
hours after presentation.32

The ability to rule out an MI more quickly shortens the ED admission time for many patients, overcoming one
of the primary limitations of conventional troponin assays (Figure 3-3).

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

In identifying patients with MI earlier and more often, the hsTn assays also overcome two problems
associated with the conventional assays. First, they reduce the delay to appropriate treatment for MI because it
shortens the time for diagnosis in many situations. And second, it reduces the risk of missing an MI completely
and the associated risk of cardiac complications and death (Figure 3-3).

LEARNING GUIDE: CARDIAC 28

 HsTn Assays: Things to Consider
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
can cause elevation of the conventional troponin assays also, to a greater degree, cause elevations of hsTn
measures (Table 3-1 on page 26). Multiple studies have found that the leading causes of “positive” high-
sensitivity troponin elevations are not MI. Thus, each patient with an elevated value needs careful consideration
for both the MI and non-MI determinants. As such, it is even more imperative that physicians employ good
clinical judgment when evaluating patients with suspected ACS. All aspects of the patient’s presentation should
be assessed to appropriately stratify a patient’s risk for ACS, including symptoms, medical history, physical exam
information, ECG, and troponin concentrations.

It is also important to remember that to meet the biomarker criteria for an MI; troponin concentrations must be
rising or falling over time. Given the increased sensitivity of these new assays, there has been renewed debate
about 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 on the percentage change in troponin concentrations required for MI are for
conventional assays.6, 7 However, researchers have been exploring how these new high-sensitivity assays may
modify the definition of change in troponin concentrations. A study by Keller et al. examining the use of high-
sensitivity troponin assays for early rule-out of MI demonstrated the value of using a 50 percent change
(or delta) between initial and three-hour troponin 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 although ultimately concluded that limitations exist
for any method that defines troponin change in MI.36

Prior generation cardiac

troponin assays
LEVEL OF CARDIAC TROPONIN

>8-12 hours
post event

Current generation cardiac

troponin assays
Onset of myocardial
infarction

2-6 hours High sensitivity cardiac

post event troponin assays

99th Percentile

Normal levels Ischemia or Necrosis Adapted from Hochholzer, Am Heart J, 2010

Micronecrosis F. Apple, AACC Webinar, Jan 2012

Figure 3-3. Troponin rise in the time after myocardial infarction. Older and current generation troponin
assays cannot detect troponin increases as quickly as the high-sensitivity troponin assays

LEARNING GUIDE: CARDIAC 29

 HnTn Assays: Effects on Patient Care
The high-sensitivity tests overcome the problem of prolonged diagnostic time for MI that can delay treatment.
They can also dramatically shorten patient evaluation time in the ED and have demonstrated that they can reduce
overall healthcare costs.37 Furthermore, they avoid the predicament of potentially missing an MI with a lesser
degree of troponin elevation.

However, with this increase in sensitivity, there is a loss of specificity. Clinicians need to be aware that there
may be more troponin elevations reported with the new assays that are not related to ACS, and as indicated
above, these cases will be in the majority. More than ever, troponins are only one piece to consider in the
comprehensive evaluation of the patient. Despite these concerns, when used appropriately, these high-
sensitivity tests have the potential to dramatically change how patients with ACS symptoms are managed,
saving lives and money.

IMPLEMENTING HIGH-SENSITIVITY TROPONIN TESTING

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
algorithm.23 Importantly, it should be understood that simply replacing a conventional assay in an existing
protocol with a hsTn assay does not allow the high-sensitivity assay to function to its full potential. Only when
used in an algorithm that accounts for the increased sensitivity can it be effective for decreasing cost and ED
admission time. Developing a new algorithm or modifying an existing algorithm for managing ACS patients will
be important to promote appropriate use of the new test.23 In addition, laboratory personnel will need to assess
the quality control measures required for the new assay and will also need to work with other key stakeholders
to decide on thresholds for the new assay, especially given that age and gender may influence normal values.28,38
Practical considerations in the collection and processing of specimens need to be considered as well; hemolysis
in the blood sample and the extent of centrifugation can both render the hsTn assays less accurate.38 Similarly,
practitioners should be reminded 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

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 presentation and then repeat it 3 hours later as part of a rule-out algorithm.23 The European guidelines
also emphasize 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 over 90 percent, whereas elevations less than three-fold over the upper
reference limit have a positive predictive value 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

Similarly, the National Institute for Health and Care Excellence (NICE) in the United Kingdom also recommends
the 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 evaluation is recommended.39

LEARNING GUIDE: CARDIAC 30

 OTHER CARDIAC BIOMARKERS
Although troponin is central in the determination of myocardial necrosis, a variety of other markers have
demonstrated some usefulness in the evaluation of patients with suspected ACS in the past, and more are
under investigation.

Myoglobin, an oxygen-carrying protein, was one of the earliest biomarkers used for MI.15 Although its
concentrations rise in response to injury of the cardiac tissue, it is no longer recommended as a biomarker for ACS.15

Creatinine kinase MB (CK-MB) is a marker that is mostly specific to the cardiac tissue and was traditionally
used in 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 for detecting an early reinfarction.23 In current practice, routine measurements of CK-MB
in patients with suspected ACS are no longer recommended.23

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 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 event.42 Although the US guidelines do not make a specific recommendation
on it, the ESC guidelines on NSTEMI do 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 to be superior to troponin in identifying MI.

The natriuretic peptides, B-type natriuretic peptide (BNP) and its inactive counterpart N-terminal proBNP
(NT-proBNP), are most often used in the setting of heart failure but also rise quickly after a myocardial ischemic
event.42 The natriuretic peptides can provide information about the size of the infarct area in the heart and also
the function 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

There are many other biomarkers currently being investigated for both diagnostic and prognostic use in ACS,
and their 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.

LEARNING GUIDE: CARDIAC 31

 SECTION 3: REVIEW QUESTIONS

1. C
 K-MB and troponin should always be used together to detect the presence of myocardial necrosis.

n True n False

2. Which of the following statements accurately reflects the definition for rising or falling troponin concentrations
using hsTn assays in an MI?

a. A rise or fall indicative of cardiac necrosis is a 25 percent or more change from the initial elevated value
b. T
 here is no consensus on the exact amount or percentage of rise or fall required for troponin changes
using hsTn assays to meet criteria for MI
c. The IFCC states that a rise or fall in cardiac troponin over six hours of 50 percent of more is diagnostic for MI
d. All of the above are correct

3. Which of the following statements about implementing hsTn is TRUE?

a. T
 he transition from a conventional troponin assay to a high-sensitivity assay requires education
for laboratory personnel only
b. W
 hen transitioning from conventional to high-sensitivity troponin measurements,
a multidisciplinary team is needed
c. P
 hysicians need to be educated that a positive high-sensitivity troponin measurement is diagnostic
for myocardial infarction
d. Hemolysis does not affect a hsTn result

4. List four biomarkers (other than troponin) that have been studied in ACS patients and shown definite
or possible benefit

______________________________________________________________________________________________________________________________________________________________________

______________________________________________________________________________________________________________________________________________________________________

LEARNING GUIDE: CARDIAC 32

 SECTION 4
HEART FAILURE
LEARNING OBJECTIVES
When you complete this section, you will be able to:

1. Understand the mechanism of how heart failure occurs

2. Describe the different types of heart failure and classification systems

3. Recognize the consequences of heart failure

4. Explain tests that can be used to assess patients with heart failure

LEARNING GUIDE: CARDIAC 33

 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

DEFINING HEART FAILURE

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 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 become maladaptive and are the targets for
diagnostic tests and therapies. For example, neurohormonal activation 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 failure, these
compensations worsen the functional ability of the heart rather than improving it. 50,51

DEFINING HEART FAILURE BY PUMP FUNCTION: HFPEF AND HFREF

To clarify the functional problem in heart failure, clinicians typically separate heart failure into two different
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)

Stretched and thin

Stiff and thick 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

LEARNING GUIDE: CARDIAC 34

 Heart Failure and a Preserved Ejection Fraction (HFpEF)
In HFpEF, as the name implies, the ejection fraction of the left ventricle is normal (usually over 45 percent), so
the heart is still pumping out the appropriate percentage of blood with each contraction.51 However, the problem
in HFpEF is an impairment in the heart’s ability to relax during the process of filling with blood.51,52 The left
ventricle cannot relax and fill with blood normally because its walls are abnormally stiff and thickened; the
walls of the ventricle are also not working in a coordinated fashion with the blood vessels that receive the
blood.51 This results in poor cardiac performance even though the ejection fraction is still within a normal range.
Women, the obese, and elderly individuals are more likely to be diagnosed with HFpEF than men, individuals in
a normal weight range, and younger people.51,53 Heart failure with preserved ejection fraction can be more
difficult to diagnose and manage than HFrEF, but almost half of the patients with heart failure in the US have
HFpEF.51,52,54 Unfortunately, at the time of this writing, there are no proven treatments for HFpEF that reduce
the risk of heart failure hospitalization or cardiovascular death.
Heart Failure with Reduced Ejection Fraction (HFrEF)
In HFrEF, the ejection fraction of the left ventricle is reduced. This means that with each pumping contraction
of the 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 is more straightforward in HFrEF than in HFpEF: patients with HFrEF
are more likely than those with HFpEF to 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 pulmonary disease.51,52,54 Patients with HFrEF also respond more
favorably to treatment with medications than those 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 receptor blockers, mineralocorticoid receptor
antagonists, certain beta-blocking agents, valsartan/sacubitril, ivabradine, the combination of long-acting
nitrates and hydralazine, and digoxin, as well as devices such as implantable cardioverter-defibrillators and
cardiac resynchronization devices.52,56

What is a Normal Ejection Fraction?

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 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

Heart Failure with Mid-Range Ejection Fraction (HFmrEF)

A new term, heart failure with mid-range ejection fraction, or HFmrEF, was recently described by the European
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 as a separate entity from HFpEF or HFrEF is to promote more study of interventions and
outcomes in this very specific population of individuals with heart failure.52 Because HFmrEF is a new term and
is not included in other guidelines and literature, it will not be a focus of this guide.

LEARNING GUIDE: CARDIAC 35

 DEFINING HEART FAILURE WITH CLASSIFICATION SYSTEMS: NYHA AND ACC/AHA
Several different classification schemes exist to quantify the severity of heart failure in a patient. The New York
Heart Association (NYHA) classification system is based primarily on the effects the heart failure has on the
patient’s ability to perform physical activity. The categories progress from an NYHA class I, indicating the
patient has no symptoms with normal physical activity, all the way to an NYHA class IV, indicating the patient
has symptoms of heart failure at rest or with the slightest physical activity.58 The NYHA classification system can
predict mortality in heart failure and can be a useful way to monitor the effectiveness of treatment.50,58

Another classification scheme from the American College of Cardiology Foundation (ACC) and the American
Heart Association (AHA) defines heart failure according to symptoms and structural changes to the heart
(Figure 4-2). The ACC/AHA classification scheme for chronic heart failure begins with stage A, which indicates
only that a patient is at high risk of developing heart failure as a result of comorbidities like coronary artery
disease, diabetes, and 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 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 medical therapy.58 Thus, the NYHA class is usually applied
to patients with symptomatic Stage C and D heart failure.

TIME
A Risk factors for heart failure

Structural changes to the heart

B WITHOUT symptoms/signs

Structural changes to the heart

C PLUS symptoms

ADVANCED HEART FAILURE

D Patients may be:
• Hospitalized frequently
• Evaluated for/receive an LVAD*
• Awaiting heart transplant
* Left Ventricular Assist Device

Figure 4-2. Stepwise progression of heart failure according to ACC/AHA stages

LEARNING GUIDE: CARDIAC 36

 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 prompt medical evaluation and treatment. In about two-thirds of cases, patients with AHF have already been
diagnosed with heart failure, but in the other one-third, AHF is the first sign of a heart failure problem.52,59 Often, a
patient with stable heart failure experiences an event that triggers the AHF episode. This event can be something
straightforward like neglecting to take prescribed heart failure medications or something more complex, such as a
new MI, a superimposed infection, development of abnormal heart rhythm (atrial fibrillation), or dietary changes
with increased intake of salt.52

Chronic heart failure, in contrast to acute, is the more stable, chronic manifestation of inadequate cardiac
function. Chronic heart failure is the term used to describe patients with heart failure who are not experiencing
an acute worsening of symptoms from AHF. The majority of patients with heart failure are classified as having
chronic heart failure. They are managed in the outpatient setting, and they only convert to a diagnosis of acute
heart failure in the 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.

CAUSES OF HEART FAILURE

Anything that causes damage to the myocardium can lead to heart failure. Coronary artery disease is the most
important predictor of heart failure, and it is estimated to be the primary cause of heart failure in over 60 percent
of patients in the US.55 However, other frequent causes of heart failure include hypertension (the medical term for
high blood pressure), problems with the valves in the heart, or cardiomyopathy (maladaptive changes in heart
structure caused by inflammation, infection, or unknown reasons).50,52 Approximately 90 percent of all heart
failure cases have antecedent hypertension (or hypertension before the diagnosis of heart failure). Thus it is
believed that high blood pressure contributes to all forms of heart failure as an additional risk condition.60 Other
less common causes of heart failure include myocarditis, pericarditis, drug toxicities (e.g., certain types of
chemotherapy, other cancer treatments, 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 HFrEF have a genetic predisposition with a superimposed insult
such as longstanding hypertension, excessive alcohol intake, or viral syndrome.61

CONSEQUENCES OF HEART FAILURE

As discussed in Section 1, maintaining strong pumping ability is essential for the heart to function appropriately.
When the heart doesn’t pump effectively as a result of heart failure, a cascade of negative effects occurs
throughout the body. Organs and tissues may not receive adequate oxygen to function appropriately, especially
if any additional 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

As a result of the continued neurohormonal activation in heart failure, the heart itself undergoes more changes.
The structure of the ventricle undergoes further modification, causing it to be even less effective at pumping
blood.62 This process is often termed remodeling, and it is the consequence of scar formation in the cardiac tissue
(this scarring is called cardiac fibrosis). Scar formation and fibrosis can initially be the result of a heart attack or
may develop more diffusely over time as a result of the heart failure process itself.63 The changes that lead to
fibrosis occur on the cellular level within the cardiac myocytes. In response to the original damage that led to heart
failure, the myocytes become enlarged and don’t function as efficiently.63 Poor myocyte function eventually leads to
an excessive accumulation of proteins between the myocyte cells that prevent normal movement of the cells and
cause stiffening of the myocytes. This stiffness of the myocytes produces the cardiac fibrosis.63

LEARNING GUIDE: CARDIAC 37

 The consequences of these structural changes in the heart are profound for the rest of the body. Humans have a
“closed circulatory system,” like a closed circuit; this means that blood can only go “back” when it cannot go
“forward.” When the heart does not pump the blood forward effectively as a result of stiffness or pump failure, the
blood begins to “back up” into the lungs. With blood moving more slowly through the pulmonary system, fluid
leaks out into the lungs and begins to accumulate. When a patient with heart failure stands or sits upright, this fluid
falls to the bottom of the lungs and may not interfere with breathing; however, when the patient lays down flat, the
fluid pools throughout the lungs which may lead to difficulty breathing. Eventually, the increased pressure in the
lungs may lead to congestion in the right ventricle. Because the right ventricle receives blood from the rest of the
body, as the right ventricular performance is affected, a further “back up” of blood will occur into the peripheral
tissues. This results in fluid accumulation in the peripheral tissues that manifests as swelling (or edema), first in the
legs and feet (due to gravity), and then it may spread to the abdomen and even to organs such as the liver. This
process whereby problems with the left ventricle lead to problems with the right ventricle, with congestion of the
lungs as well as the peripheral tissues, underlies what most doctors regard as true “congestive heart failure.”

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 symptoms of heart failure can be traced back to the changes in cardiac performance and can be collectively
termed “effort intolerance.” Shortness of breath (sometimes called dyspnea) is the most common symptom of heart
failure and is a sign that fluid is accumulating in the lungs as a result of poor left ventricular performance. Patients
with heart failure often present with other symptoms as well, such as orthopnea (shortness of breath when lying
down), paroxysmal nocturnal dyspnea (awakening from sleep with acute shortness of breath), exercise intolerance,
weakness, fatigue, and swelling of the ankles and feet.51,52 Again, these symptoms correlate with fluid accumulation
in the lungs and body as a result of the “back up” of blood in the heart. Heart failure most often limits a persons’
ability to perform strenuous or even low-intensity exercise. This can eventually progress to the point that
symptoms interfere with very basic functions such as walking, showering, dressing, and eating food as described in
NYHA class III and IV.64

On a physical exam, clinicians evaluate for signs of heart failure. In severe cases, the signs can be obvious; however,
if the patient’s heart failure has developed over a long time, the signs may be subtle. A patient may appear very
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 swelling or edema (as described above). Evaluation of the jugular vein in the neck can show
distension. Changes in how the heart sounds through a stethoscope and differences in where the heartbeat can be
felt in the chest can also be signs of heart failure; the heart rate may increase to the point where it seems to “gallop”
as it attempts to compensate for poor output.50,52

LEARNING GUIDE: CARDIAC 38

 THE ROLE OF ECG AND IMAGING
Electrocardiogram (ECG)
Although the electrocardiogram or ECG (Figure 4-3) is
essential in the assessment of patients with acute coronary
syndrome (ACS) symptoms, it is a less specific tool in heart
failure. Patients with heart failure can have mild or dramatic
abnormalities on an ECG, but it can be a useful tool in several
circumstances. First, an ECG can be helpful to rule out heart
failure—very rarely would a patient with heart failure have a
completely normal ECG.52 Second, it may identify the etiology
of the patient’s heart failure, such as a previous MI.52 And third,
it may detect a coexisting problem such as atrial fibrillation
(inappropriate, rapid beating of the atria) that requires
treatment.52 Importantly, in the setting of heart failure, there
are electrical conduction disturbances that can lead to heart
block (which is a lack of coordination of contraction of the
ventricles). For example, in HFrEF, patients can experience
several types of electrical conduction disturbances, such as
right bundle branch block, left bundle branch block, or
interventricular conduction delay; patients with these
abnormalities may benefit from an implanted cardiac Figure 4-3. The electrocardiogram can be
resynchronization device (discussed later in this section).52 a useful tool in several circumstances
Echocardiogram
Echocardiography, or ultrasound of the heart, is an essential tool in the diagnosis of heart failure (the test itself
is called an echocardiogram, often referred to as an echo). An echocardiogram provides information on the
function of the heart muscle during relaxation and contraction, the size of the ventricular walls and the interior
chamber, the performance of the valves, and the pressures in various parts of the heart.52 The echocardiogram
also measures ejection fraction and stiffness of the ventricle, necessary in the differentiation between HFrEF
and HFpEF.52
Cardiac Magnetic Resonance (CMR)
Cardiac magnetic resonance (CMR), or magnetic resonance imaging (MRI) of the heart, is another useful tool
for evaluating heart structure and characterizing changes in the cardiac tissue. It can be particularly helpful
when echocardiography is not adequate to assess structural abnormalities in heart failure, especially the right
side of the heart.52 The European heart failure guidelines recommend the use of CMR in patients with
complex congenital heart disease (a cardiac structure problem that a patient is born with) or with inadequate
imaging with echocardiography.52 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 Although CMR is the only imaging tool that can truly
characterize the actual cardiac tissue, it is not suitable for everyone, such as patients with certain metal
implants; it is also not available at all centers and may be more expensive than other imaging techniques.
Laboratory Testing
During an initial diagnostic workup for heart failure, a considerable amount of laboratory testing is
performed. Renal and liver panels, lipid measurements, thyroid function tests, complete blood counts, and
iron studies may be ordered to evaluate for underlying causes and comorbidities and also to assess the
appropriateness of heart failure therapies.52 In addition, several circulating biomarkers are useful in the
diagnosis and management of heart failure.

LEARNING GUIDE: CARDIAC 39

 Natriuretic Peptides
The natriuretic peptides (NPs), B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide
(NT-proBNP), play a central role in heart failure. Although BNP was initially called brain natriuretic peptide
because 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 released by the cardiac 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 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.

HEART FAILURE TREATMENT

Early identification, treatment of underlying causes, and control of risk factors are all essential first steps in the
management of heart failure. Once those areas are addressed, patients should be counseled on lifestyle
interventions such as eating a low-sodium diet, limiting fluid intake to a prescribed amount, weighing themselves
daily, engaging in light aerobic exercise, understanding the need for follow-up appointments with their physician,
and learning how best to manage the disease.58,62

Medications are typically prescribed to block the body’s maladaptive neurohormonal response to heart failure.
These can include drugs such as ACE inhibitors, beta-blockers, aldosterone antagonists, and diuretics.62 It is
essential that patients understand the importance of taking these medications because, when used appropriately,
these drugs can 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 determine the optimal drug regimens for treatment of HFpEF.58,62

Some patients with heart failure will also require intervention with cardiac devices. Certain individuals with
severe heart failure who have electrical conduction abnormalities (as outlined in the previous discussion of ECG in
heart failure) may be candidates for cardiac resynchronization therapy (often called a biventricular pacemaker),
which is an 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 and ACC/AHA stage D), a left-ventricular assist device (or LVAD) may be used to
support cardiac function. An LVAD increases the output of blood from the heart using a pump implanted into the
wall of the left ventricle.62,72 Although the pump itself is implanted in the chest, a wire runs out of the device and
through the skin to connect the LVAD to batteries and the control unit.58,62 Finally, in the most critical cases,
patients who are otherwise in good health and can tolerate the major surgery may undergo a cardiac transplant.62
Only about 3,000 people receive heart transplants in the US each year.73

LEARNING GUIDE: CARDIAC 40

 SECTION 4: REVIEW QUESTIONS

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 _________________
e. Heart failure resulting from the left ventricle’s inability to relax _________________
f. Heart failure resulting from poor contractility of the left ventricle _________________

2. List five symptoms of heart failure

______________________________________________________________________________________________________________________________________________________________________

______________________________________________________________________________________________________________________________________________________________________

______________________________________________________________________________________________________________________________________________________________________

______________________________________________________________________________________________________________________________________________________________________

______________________________________________________________________________________________________________________________________________________________________

3. The most commonly used biomarker in heart failure is

a. G
 alectin-3
b. N
 atriuretic 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.

LEARNING GUIDE: CARDIAC 41

 SECTION 5
THE ROLE OF CARDIAC
BIOMARKERS IN HEART FAILURE
LEARNING OBJECTIVES
When you complete this section, you will be able to:

1. Describe cardiac biomarkers used in heart failure

2. Explain the role of cardiac biomarkers in various aspects of heart failure care

3. Understand the guideline recommendations from several international

organizations for the use of cardiac biomarkers in heart failure

LEARNING GUIDE: CARDIAC 42

 As discussed in Section 4, the changes in cardiac function that occur in heart failure affect the entire body, so it
is essential that clinicians monitor the status of heart failure patients with diligence. Circulating biomarkers can
be especially helpful tools for gauging the presence, severity, and progression of heart failure. This section will
build on the previous discussions of biomarkers used in heart failure and also introduce several emerging
biomarkers for this disease process.

AS A GROUP, THE CARDIAC BIOMARKERS USED IN PATIENTS WITH HEART

FAILURE CAN GENERALLY BE CLASSIFIED INTO THREE AREAS
• M
 arkers of myocardial stretch/pressure and neurohormonal activation: These include natriuretic
peptides and several emerging biomarkers (MR-proADM, copeptin). Rising concentrations of these
biomarkers reflect increasing neurohormonal activation that can result from heart failure.
• M
 arkers of cardiac remodeling: These include galectin-3 and several emerging biomarkers (ST2, GDF15).
When markers in this group rise, they can indicate myocyte changes are occurring that lead to fibrosis in
heart failure.
• M
 arkers of myocardial injury/ischemia: These include cardiac troponins. Ischemia and injury may occur
in 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.
Evaluating each of these aspects of heart failure provides essential information on the status and prognosis of an
individual patient. However, the usefulness of various biomarkers differs according to the clinical scenario.

MARKERS OF MYOCARDIAL STRETCH/PRESSURE

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 natriuretic peptide (NT-proBNP), play a central role in heart failure. BNP is a hormone released by
the cardiac 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 and when neurohormonal activation occurs in response to heart failure.66 The 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 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 This section will describe NPs in more detail
and explain how they fit into the care of patients with heart failure.
The NPs are hormones that influence fluid and sodium balance in the body.74 Although only the B-type
(BNP and NT-proBNP) are measured routinely in clinical medicine, three types have been identified in total:
• A
 trial NP released from the atria
• B
 -type NP released from the ventricles
• C
 -type NP, which is found in the kidneys, blood vessels, and central nervous system74
Of note, BNP was originally called brain natriuretic peptide because it was first identified in the brains of pigs,
but it was later determined to be a misnomer because it is released by the ventricles of the heart.65 This guide
will focus on the B-type NPs (BNP and NT-proBNP), subsequently referred to as NPs, because they are most
specific to the pathophysiology of heart failure.

LEARNING GUIDE: CARDIAC 43

 Differences in Natriuretic Peptide Assay Types
Although most studies indicate that BNP and NT-proBNP assays have similar sensitivity and specificity,
clinicians should be aware of several differences.66 For example, NT-proBNP has a longer half-life than BNP,
although this does not appear to have significant clinical implications.66 In addition, because the normal value
ranges differ between the 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 of both tests (Figure 5-1).66 Notably, BNP and NT-proBNP values are
not interchangeable: there is no recognized “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 for NT-proBNP. Most laboratories give
a spectrum of upper limit values based on age categories ranging from 125 pg/mL to 2000 pg/mL, depending
on the study population and assay used.66

BNP
Clinical Gray Zone* Elevated
NORMAL

100 pg/mL 500 pg/mL 1000 pg/mL 1500 pg/mL

NT-proBNP
Age Gray Zone† Elevated
Normal Clinical Gray Zone*

450 pg/mL
0 125 pg/mL 500 pg/mL 1000 pg/mL 1500 pg/mL 2000 pg/mL 2500 pg/mL

* Clinical Gray Zone: other non-heart failure conditions may be contributing to elevation
† Age Gray Zone: age over 50 years or renal dysfunction

Figure 5-1. Ranges of normal, gray zone, and elevated BNP and NT-proBNP

USING NATRIURETIC PEPTIDES IN CLINICAL PRACTICE

Diagnosis of Acute and Chronic Heart Failure
For patients who seek emergency medical attention for acute shortness of breath, NPs are an essential test for
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
as an exacerbation of chronic obstructive pulmonary disease or a pulmonary embolism.56,75 NPs have very high
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 is not experiencing AHF), can be avoided.56,75 This is also true for patients who present with shortness of
breath in the outpatient setting; many of the signs and symptoms of heart failure are non-specific and can easily
be attributable to other causes (like chronic obstructive pulmonary disease). Hence, a BNP or NT-proBNP
measurement is a simple method to either exclude heart failure or identify patients who require more diagnostic
testing to determine if heart failure is present (Figure 5-2).52,56

LEARNING GUIDE: CARDIAC 44

 Figure 5-2. Using natriuretic peptides in clinical practice for non-acute symptoms52,56

CONSIDER
SUSPECT • Medical history SCREEN WITH
HEART • Physical exam NATRIURETIC Consider other
FAILURE findings PEPTIDE: ELEVATED NO causes of
DUE TO BNP or symptoms
SYMPTOMS • ECG NT-proBNP
abnormalities

YES ECHOCARDIOGRAM
(as an aid in diagnosis)

Prognosis in Acute and Chronic Heart Failure

Another critical role for NPs in clinical practice is in providing prognostic information. For patients with
AHF admitted to the hospital, high concentrations of NP upon admission are associated with increased risk
of in-hospital mortality (for both cardiac causes and all causes).56 In addition, measurement of BNP at discharge
is useful for prediction of readmission within 30 and 60 days.70 Readmission for heart failure shortly after
discharge is often considered a preventable hospitalization, and it is a target of hospital and government quality
improvement initiatives.76 Consequently, identifying patients at high risk for this outcome is essential to
improving quality of heart failure patient care.76
It is also well established that NP measurements can provide prognostic information in the outpatient setting.
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 evidence without a proven benefit in heart failure patient outcomes, guidelines do not recommend
monitoring NP levels to guide therapy.56,58,77
Identifying Patients at Risk for Heart Failure
The natriuretic peptide assays BNP and NT-proBNP have established usefulness in stratifying patients who are
at high risk for heart failure based on risk factors like diabetes, hypertension, and vascular disease.56 Elevated
NP concentrations have demonstrated utility in identifying patients in the general population who are at
increased risk for developing heart failure, both in individuals who already have some high-risk characteristic
and in individuals without high-risk characteristics (although NPs appear to be stronger predictors for
individuals already at high risk).75,78,79 However, they appear to be a better tool for identifying patients at risk
for heart failure with reduced ejection fraction (HFrEF) than heart failure with preserved ejection fraction
(HFpEF).80 Importantly, NP measurements have demonstrated relevance in identifying patients who benefit
from medical intervention to prevent heart failure, ultimately resulting in improved patient outcomes. In a
large-scale trial (STOP-HF), NP concentrations were used to screen and stratify individuals at risk for heart
failure; participants with BNP concentrations over 50 pg/mL in the intervention group were evaluated with
echocardiography and received collaborative care interventions from primary care and cardiology specialists.
Compared with participants in 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.

LEARNING GUIDE: CARDIAC 45

 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
terms of how the cardiac dysfunction occurs. This difference also translates into disparities in NP release. In
chronic HFpEF, NP elevations appear to be slightly more modest than what is measured in HFrEF.75 They can
even decrease to almost normal concentrations if the patient is free of symptoms.75 Although NPs don’t appear
to be as elevated in patients with HFpEF compared to patients with HFrEF, they are still recommended as
general screening tools for heart failure and are an essential component in establishing a diagnosis of HFpEF.52,56
The ESC guidelines use the 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 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 concentrations that strongly correlate to heart failure (BNP > 500 pg/mL
or NT-proBNP > 2000 pg/mL), concentrations in the “gray-zone” indicating it could be heart failure or could
be another problem (BNP 100–500 pg/mL or NT-proBNP 450–2000 pg/mL), or normal concentrations
(BNP < 100 pg/mL or NT-proBNP < 125 pg/mL) (Figure 5-1).66 Of note, compared with BNP, NT-proBNP has
a much wider “gray zone” which may be attributed to advanced age (over 50 years) or renal dysfunction with
NT-proBNP values in the range 125-450 pg/mL or higher.82 This results in more “indeterminate” results when
using this assay in older patients; BNP does not have this limitation.82 Evaluating the entire patient
presentation in addition to biomarker results, including symptoms, physical examination findings, and other
diagnostic test results, is essential to establishing a correct diagnosis for every patient.
Confounding Factors in the Measurement of Natriuretic Peptides
Several disease processes and patient characteristics can confound the results of NP assays – clinicians must
interpret 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 with kidney disease than BNP.66 In severe kidney disease, BNP is also affected, but
NT-proBNP continues to be more severely altered.66 Likewise, several studies have also documented that
NT-proBNP is increased in patients with atrial fibrillation; because this is a common comorbidity in patients
with heart failure, clinicians must consider this when evaluating NT-proBNP measurements.83,84 Increasing age
and female sex both appear to increase the NP measurements regardless of underlying cardiac function,
whereas obesity may decrease measured NP concentrations.85 Lastly, a newer class of drug for heart failure,
the angiotensin receptor neprilysin inhibitors (ARNI), may influence BNP concentrations because BNP is one
of multiple peptides that can be cleaved by neprilysin. However, there is evidence that human BNP may be
less sensitive to neprilysin degradation while retaining affinity for it. At the high concentrations of BNP
(>916 pg/mL) that are frequently seen in HF patients, neprilysin activity may actually be inhibited or
impaired.86,87 This would limit the efficacy of drugs designed to inhibit the enzyme such as ARNI. Overall,
there is insufficient evidence to determine if there are clinically significant differences in measured
concentrations or adverse effects on patient outcomes and further research is ongoing.88 Other common
causes for NP elevation are included in Table 5-1 on the next page.

LEARNING GUIDE: CARDIAC 46

 Table 5-1. Conditions that Confound B-type Natriuretic Peptide Concentrations56,85

INFLUENCE ON B-TYPE NATRIURETIC PEPTIDE CONCENTRATIONS

BNP NT-proBNP
Obesity Decrease Decrease
Kidney disease Slight increase Significant increase
Female sex Increase Increase
Increasing age Increase Increase
Severe pneumonia Increase Increase
Obstructive sleep apnea Increase Increase
Pulmonary hypertension Increase Increase
Severe burns Increase Increase
Critical illness Increase Increase
Sepsis Increase Increase
Atrial fibrillation Increase Increase
Acute coronary syndromes Increase Increase
Cardiac valve disease Increase Increase
Myocarditis/Pericarditis Increase Increase
Cardiac surgery Increase Increase
Cardioversion Increase Increase
Toxins (e.g., chemotherapy) Increase Increase

MARKERS OF CARDIAC REMODELING

Galectin-3
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 autoimmune diseases.89 In heart failure, galectin-3 is secreted by macrophages in the myocardium after
a cardiac injury.90 It serves as a mediator for the development of fibrosis and also appears to contribute to
inflammation in the 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.
In clinical studies of patients with heart failure, galectin-3 is more useful for long-term prognosis than initial
diagnosis. When galectin-3 is measured over time, an increase of 15 percent or more has been correlated with
an increased risk of mortality and rehospitalization for heart failure.91 Galectin-3 has also shown added
benefit when 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 individuals with low concentrations of NP on presentation.92 Galectin-3 is also a
useful marker to measure at 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 with HFpEF, which is an area where other biomarkers are
less helpful.70,93

LEARNING GUIDE: CARDIAC 47

 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 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 all-cause mortality (death from any cause) in this same group.95 Furthermore, in another study, serial
measurements 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
Notably, in the PREVEND study, researchers found that women and older individuals had higher galectin-3
levels than men and younger individuals.95 Hemolysis in the specimen, presence of rheumatoid factor,
or anti-mouse antibodies can also contribute to inaccuracies in the galectin-3 results.97

MARKERS OF MYOCARDIAL STRESS OR INJURY/ISCHEMIA

High-Sensitivity Troponin
Although cardiac troponin assays such as high-sensitivity troponin (hsTn) were discussed extensively in
Section 3, their utility in heart failure should also be mentioned. In the setting of heart failure, similar to its role
in acute 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 occur in acute or chronic heart failure as an indicator of myocardial stress.99 With the
development of high-sensitivity troponin assays, it has been established that most patients with heart failure
have detectable troponin levels and many of these may be above the upper reference limit used to identify ACS.98
Importantly, in this context, troponin elevations remain stable and do not demonstrate the rapid rise seen over
several hours in ACS.98 As such, cardiac troponins have demonstrated promise in providing additional
prognostic information when measured in patients with heart failure and those at risk.
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
evaluated the combination of NT-proBNP and hsTnI for predicting heart failure in a population of individuals
with 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 predictors of a heart failure hospitalization than either marker alone over a long period.100 Another
trial found that using a panel of biomarkers (that included hsTnI) in combination with a risk assessment model
was more effective in predicting future heart failure risk in patients with coronary artery disease than the risk
assessment model alone.101
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 stay.102 Likewise, at discharge, elevations in hsTnI have been associated with increased risk for
readmission and death in patients with AHF.103 In addition, hsTn may aid in identifying patients with a low
mortality risk during an episode of acute heart failure and may provide long-term mortality risk information
in elderly patients with chronic heart failure.104,105
As noted in Section 3, hsTn assays are very sensitive tests, but with this sensitivity, there is a loss of specificity
if specific protocols, particularly those involving “deltas” or changes over time, are not used. The other
non-cardiac clinical scenarios that can cause hsTn elevations in ACS, such as sepsis and respiratory failure,
also cause elevations when evaluating heart failure.

LEARNING GUIDE: CARDIAC 48

 OTHER BIOMARKERS FOR HEART FAILURE
A number of other biomarkers are being studied for assessing different facets of heart failure. This section will
discuss five that have demonstrated promise in heart failure management. Although researchers have identified
these biomarkers as potentially useful in this population, none of these markers are currently used in routine
clinical practice. Whether these emerging biomarkers provide additional clinical information beyond what can
be gained from NPs and other established biomarkers remains to be determined.
Soluble ST2
Soluble ST2, or suppression of tumorigenicity 2, is a biomarker in the interleukin-1 receptor family that denotes
biomechanical strain, myocardial stress, and fibrosis.106 As such, it has been investigated as a marker for
remodeling in heart failure. Unlike the NPs, ST2 concentrations do not appear to be influenced by age, gender,
kidney function, or obesity.106 In preliminary studies, measuring ST2 has shown usefulness in predicting the risk
of death after an episode of acute heart failure.106
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 information over prognostic information available from NPs remains to be determined.106
GDF15
Growth differentiation factor 15 (GDF15) is a cytokine that is upregulated in the setting of inflammation.107
Although 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 failure and death after a myocardial infarction.107 Similar to ST2, although GDF15 shows
promise, it has not demonstrated superiority over biomarkers in current use.
MR-proADM
Several markers of neurohormonal activation in heart failure apart from the natriuretic peptides have been
identified. One such biomarker is mid-regional pro-adrenomedullin (MR-proADM) which is measured because
it is a precursor of adrenomedullin which has an array of neurohormonal effects in the body including dilation of
the blood vessels.108 Adrenomedullin and MR-proADM concentrations increase in heart failure.108 Several studies
have demonstrated that concentrations of MR-proADM are predictors of mortality as well as heart failure
hospitalizations independent of NP measurements.99 Although this biomarker appears promising, further study
is needed to determine its place in heart failure management.
Copeptin
A second marker that primarily measures neurohormonal activation, copeptin, was discussed in Section 3 for
ACS. It is a small part of a precursor for the arginine vasopressin hormone released from neurons that originate
in the hypothalamus, and it serves as a surrogate marker for arginine vasopressin concentrations.109 This
biomarker has 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 over biomarkers already in use.
MR-proANP
Another natriuretic peptide called mid-regional pro-atrial natriuretic peptide (MR-proANP) serves as a
surrogate marker for atrial NP. It may be useful for diagnosing acute heart failure in patients presenting to the
emergency departments with dyspnea.110 Moreover, in preliminary studies, it has shown some effectiveness in
predicting long-term risk of death after an episode of acute heart failure.110 How MR-proANP may fit into the
care of patients with acute heart failure remains to be determined.

LEARNING GUIDE: CARDIAC 49

 GUIDELINES FOR BIOMARKERS
The European Society of Cardiology (ESC) recommends using the NPs as a method for screening patients with
symptoms of heart failure. The screening cutoff point for ruling out stable, chronic heart failure in symptomatic
individuals is a BNP < 35 pg/mL or an NT-proBNP < 125 pg/mL.52 For any patient with concentrations
measuring above these cutoff points, ESC recommends echocardiography for a definitive diagnosis.52 The ESC
Guidelines do not make any specific recommendations about other biomarkers for heart failure due to lack
of conclusive evidence of benefit.52

Table 5-2. Biomarker Recommendations in the 2016 ESC Guidelines for Heart Failure52

STRENGTH OF
RECOMMENDATION
USE RECOMMENDATION AND LEVEL OF
EVIDENCE TO SUPPORT
RECOMMENDATION

DIAGNOSIS: NPs can be an

initial diagnostic test in patients
with suspected heart failure;
recommended for ruling out
rather than establishing a diagnosis

For patients with newly diagnosed

HF, NPs should be considered
to assess the appropriateness Moderate recommendation with a
DIAGNOSIS: Chronic setting of specific therapies to identify weak level of evidence
reversible/treatable causes of Should be considered
HF and evaluate co-morbidities
affecting HF

For patients presenting with acute

dyspnea and suspected heart
failure, an NP measurement Strong recommendation with a
DIAGNOSIS: Acute setting is recommended to aid in high level of evidence
differentiating between AHF and Is recommended
other non-cardiac causes of
acute dyspnea

NP – natriuretic peptides; HF – heart failure; AHF – acute heart failure

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.

LEARNING GUIDE: CARDIAC 50

 Table 5-3. Biomarker Recommendations in the 2017 ACC/AHA/HFSA Focused Update of the
2013 ACCF/AHA Guidelines for the Management of Heart Failure56

STRENGTH OF
RECOMMENDATION
USE RECOMMENDATION AND LEVEL OF
EVIDENCE TO SUPPORT
RECOMMENDATION

The NP biomarkers are

recommended for supporting Strong recommendation for use
DIAGNOSIS or excluding a diagnosis of with high-quality evidence
HF in a patient who presents Is recommended
with dyspnea

In chronic HF, a BNP or Strong recommendation for use

NT-proBNP measurement is with high-quality evidence
recommended for determining
prognosis or disease severity Is recommended

In AHF, measurement of an
NP and/or cardiac troponin at Strong recommendation for use
the time of hospital admission with high-quality evidence
is recommended to provide Is recommended
prognostic information
PROGNOSIS OR RISK
STRATIFICATION Moderate recommendation for
During hospitalization for HF, use (reasonable to use) with a
measurements of a predischarge moderate quality of evidence
NP level is reasonable to establish from non-randomized trials*
a prognosis after discharge
Is reasonable

In chronic HF, it may be Weak recommendation for use

reasonable to use other clinically (may be reasonable to use) with
available tests (e.g., biomarkers of a moderate quality of evidence
fibrosis or myocardial injury) for from non-randomized trials*
additional risk stratification May be reasonable
In individuals at risk of developing
HF, screening with an NP
biomarker followed by a Moderate recommendation for
team-based intervention (which use (reasonable to use) with a
PREVENTION includes cardiovascular specialist moderate quality of evidence
care and optimization of GDMT) from non-randomized trials*
is reasonable to prevent Is reasonable
new-onset HF or the development
of left 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

LEARNING GUIDE: CARDIAC 51

 SECTION 5: REVIEW QUESTIONS

1. L
 ist one patient factor that can decrease measured levels of NP: _____________________________________________ . List five

non-cardiac factors that can increase NP levels: _________________________________________ , _________________________________________ ,

__________________________________________ , __________________________________________ , and _____________________________________________ .

2. Match the biomarker with the aspect of heart failure that it evaluates.

a. Marker for myocardial stress or injury

b. Marker for neurohormonal activation
c. Marker for cardiac remodeling

Copeptin _______

NP _______

Galectin-3 _______

hsTn _______

Soluble ST2 _______

GDF15 _______

3. T
 he US and European guidelines recommend using a _____________________________________________ assay for screening

individuals with shortness of breath to support or exclude a diagnosis of heart failure. The US guidelines

suggest that NP measurements can be helpful for _____________________________________________ individuals who are at

high risk of developing heart failure. They also recommend that _____________________________________________ assays

can be helpful for determining prognosis in acute and chronic heart failure and that other biomarkers

that assess for _____________________________________________ or _____________________________________________ may be useful for risk

stratification in patients with acute or chronic heart failure.

LEARNING GUIDE: CARDIAC 52

 SECTION 6
PREVENTION OF
CARDIOVASCULAR DISEASE
LEARNING OBJECTIVES
When you complete this section, you will be able to:

1. Describe the importance of prevention of cardiovascular diseases

2. Understand guideline recommendations for preventing cardiovascular diseases

3. E
 xplain risk stratification tools and biomarkers used for assessing the risk of
cardiovascular diseases in the general population

LEARNING GUIDE: CARDIAC 53

 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, 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 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.

CARDIOVASCULAR
DEATH

27%

73%
ALL OTHER CAUSES
OF DEATH

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

LEARNING GUIDE: CARDIAC 54

 For anyone determined to be at high risk for ASCVD events in the next 10 years (typically a 10-year risk for an
ASCVD event of 7.5 percent or more), the ACC/AHA guidelines recommend tailoring interventions to each
patient.111 Clinicians are referred to the specific guidelines available for the management of cholesterol, diabetes,
hypertension, obesity, and lifestyle modifications.111-13 Importantly, the prevention guidelines note that it is still
appropriate for clinicians to counsel individuals with low or moderate estimated risk (a 10-year risk of less than
7.5 percent) on lifestyle interventions to reduce future risk of CVD.111 The ACC/AHA guidelines recommend
repeating assessment for ASCVD risk every four to six years in asymptomatic individuals.111
European Guidelines
A joint guideline on the prevention of cardiovascular disease was issued in 2016 by the European Society of
Cardiology (ESC) in conjunction with 10 other groups. These guidelines do not recommend a risk stratification
tool for asymptomatic individuals known to be at high or very high risk for CVD events, such as patients with
diabetes who are over 40 years of age or individuals with specific high-risk characteristics such as familial
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 the SCORE tool, which estimates the 10-year risk of a fatal cardiovascular event.114 The SCORE tool
uses age, gender, smoking status, cholesterol, and blood pressure to assess overall risk. However, like the US
guidelines, the European guidelines suggest that other factors should be considered when evaluating a patient’s
risk for CVD, particularly for individuals at a moderate 10-year risk for events. These factors include
socioeconomic status, obesity, family history of premature CVD, coronary calcium scoring, and ankle-brachial
index measurements.114 Notably, the European guidelines do not recommend the use of biomarkers for risk
stratification purposes.114
The European guidelines stress that the highest risk individuals benefit the most from preventative intervention,
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 Specific targets are recommended for individuals in these risk groups, including avoidance of tobacco,
eating a healthy diet, performing adequate amounts of physical activity, and achieving a healthy body mass
index.114 Blood pressure, glycemic, and cholesterol control should also be addressed and can be managed
with or without medication.114

RISK STRATIFICATION TOOLS

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
The ASCVD Tool
The ASCVD scoring tool was developed by the ACC/AHA workgroup during the development of the risk
assessment guidelines published in 2013. The workgroup’s goal was to create a tool that was representative
of the population in the US, including data on African American, white, female, and male cohorts, which also
provided relevant information about the risk for a first ASCVD event.111 The group defined an ASCVD event
as the first nonfatal stroke, first nonfatal myocardial infarction, or cardiac heart disease-related death.111 The
ASCVD tool is designed to be used 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 calculator is also available at http://tools.acc.org/ASCVD-Risk-
Estimator-Plus/#!/calculate/estimate/.

LEARNING GUIDE: CARDIAC 55

 The ASCVD tool has several limitations. First, the cohorts used to develop the tool did not include adequate
numbers of people from other races (e.g., Asian, Hispanic, and Native American populations) so the tool may not
be as useful in individuals who are not white or African American.111 Second, there are also a variety of factors
that the tool does not account for that can increase CVD risk, such as obesity, family history of CVD, and
sedentary lifestyle (Table 6-1).111
SCORE
The Systemic Coronary Risk Estimation (or SCORE) tool was developed to guide risk assessment in the
European population. The tool itself was created because other cohort risk calculators, such as the Framingham
risk assessment tool, used data from cohorts living in the US rather than Europe; it was unclear if this
appropriately predicted risk in non-American populations due to cultural and ethnic differences.114 The SCORE
tool was developed using data from 12 cohort studies in Europe that included 250,000 patients.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
Although the tool itself does not incorporate this, the European guidelines suggest that overall risk for fatal plus
non-fatal CVD events is approximately three times the risk calculated for fatal events.114 It is important to note
that the SCORE tool separates Europe into high- and low-risk countries, reflecting different CVD risk profiles in
different regions. These charts can be accessed at https://www.escardio.org/static_file/Escardio/Subspecialty/
EACPR/Documents/score-charts.pdf.
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 incorporate other known risk factors for CVD, as outlined in Table 6-1.114

Table 6-1. Comparison of Factors Used in Four Cardiovascular Disease Risk Stratification Tools111,114-5,118-9

FRAMINGHAM REYNOLDS
ASCVD SCORE 2008 RISK SCORE
Age    
Sex    
Race *
Cholesterol ‡  § 
Blood pressure ‡  ‡ 
Blood pressure treated
 
with medication
Smoking status    
Diabetes  
BMI §
Country/Region †
Aspirin use 
hsCRP 
Parental history of MI 
BMI – body mass index; hsCRP – high-sensitivity C-reactive protein; MI – myocardial infarction
* Only African American and White
† Differentiates between high- and low-risk countries in Europe
§ Framingham uses either cholesterol or BMI
‡ Incorporates treated and untreated

LEARNING GUIDE: CARDIAC 56

 Framingham General CVD Risk Tool
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 for coronary heart disease. The Framingham General CVD tool broadened this focus to predict
CVD risk, which included cerebrovascular events (such as stroke and transient ischemic attack), peripheral
arterial disease, and heart failure in addition to coronary heart disease events.115 It was developed using
information from a US cohort, but it has been validated as a useful tool in other nations throughout the world.116
The tool incorporates age, gender, smoking, blood pressure, diabetes diagnosis, and either cholesterol or body
mass index to assess a 10-year risk for a CVD event.115 An online risk calculator is available at
https://www.framinghamheartstudy.org/risk-functions/cardiovascular-disease/10-year-risk.php.
The Framingham General CVD tool can assess risk in a broader age range, 30 to 74 years, and it also
incorporates obesity as a risk factor if the body mass index version is used.115 Limitations of the Framingham
CVD risk tool include that it is based on information from a comparatively small cohort of participants in the US
and there are other major CVD risks not incorporated into the score, such as lifestyle factors and family history
of CVD (Table 6-1).117
Reynolds Risk Score
The Reynolds risk score is another tool designed to predict the 10-year risk of cardiovascular disease in healthy
individuals without diabetes.118 Unlike the previously discussed tools, the Reynolds score incorporates a family
history of CVD and the biomarker hsCRP into the risk calculation.118-19 Smoking status, age, gender, blood
pressure, and cholesterol measurements are also included in the score.118-19 The Reynolds score was created with
information from two US-based cohorts, the Women’s Health Study and the Physicians Health Study-II.118-19
An online calculator is available at http://www.reynoldsriskscore.org.
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 biomarker information and family history, other lifestyle factors are not incorporated into the risk
score (Table 6-1).118-19
Limitations of Scoring Tools
Although an array of risk assessment tools are available for predicting CVD, there are significant limitations to
using these tools alone for determining an individual’s risk of developing CVD. First, many of the risk factors
evaluated in these scoring tools are not specific to cardiac disease; elevations in blood pressure, for example,
increase the risk of other problems, such as stroke. A second limitation is that many of these tools have not been
externally validated (which means tested to determine if they are still accurate in other patient sample groups),
and most have also not been compared head-to-head to provide clinicians with information about which tool has
the best risk prediction capability.120 Third, all scoring tools are based on a limited number of factors influencing
CVD risk; because 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 the ASCVD tool, several Framingham risk scores (including the general
CVD tool), and the Reynolds score in men and women used data from a multi-ethnic US cohort of individuals
without cardiovascular disease. Researchers found that after monitoring participants for approximately 10
years, all tools overestimated risk of CVD in men, 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 was the best-calibrated tool for women in this study.121
As discussed previously, over and underestimation of risk have potentially serious consequences, so refining
currently available tools to improve predictive accuracy for CVD is critical for appropriate patient care.

LEARNING GUIDE: CARDIAC 57

 CONSIDERATIONS FOR BIOMARKERS IN CARDIOVASCULAR
DISEASE RISK STRATIFICATION
To overcome the limitations presented by traditional scoring tools, researchers have begun focusing on circulating
biomarkers as useful alternatives for assessing CVD risk. They comprise an easy, non-invasive test that may
identify CVD risk more accurately than traditional risk-stratification tools alone. A number of biomarkers have
demonstrated value in predicting CVD risk, and several have shown particular promise when used in conjunction
with these traditional scoring tools. This portion of the guide will focus on specific considerations for using
biomarkers in CVD risk assessment, discuss a number of biomarkers with data to support their use for CVD risk
stratification, and briefly review several emerging biomarkers for CVD risk prediction.
Considerations for Biomarkers: Defining Normal
One difficulty in the assessment of CVD risk in an asymptomatic population is determining what the normal
range for a biomarker should be. There is a great deal of variability in the way normal subjects are selected for
determining normal ranges of clinical laboratory measures; some are screened using a simple method like a
health questionnaire 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 variable given the variation in the selection process for normal subjects. Methods that
determine if subjects are truly healthy (with biomarkers or ECG testing) are most likely better than those
relying on self-reported information for identifying a biomarker’s true normal range.122 However, because there
is no standard in how manufacturers or researchers determine the normal range for a biomarker, there is
significant variation between studies in how this process occurs and how the normal range is defined.122 This
variation is of particular importance for high-sensitivity tests like troponin, where the accuracy of the 99th
percentile measure may be impacting therapy decisions. Although there have been calls to make more specific
determinations about defining a normal population, there 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 selecting, participants for a normal reference
population to define the 99th percentile value for cardiac troponin.122

Table 6-2. Useful Tools for Identifying Normal Individuals (a Normal Reference Population) to Determine 99th
Percentile Values for Cardiac Troponin122

POTENTIAL PROBLEM IN
SURROGATE MARKER OR DEFINITION FOR SCREENING
NORMAL INDIVIDUALS

• Minimum of 600 participants (50 percent male/female)

• Diverse racial and ethnic backgrounds (40 percent white/40 percent
Population diversity
African American/20 percent mix of Asian/Hispanic/other)
• Age diversity (18 to 70+ years)

Clinical history Assess for cardiovascular disease and medication use

Diabetes Hemoglobin A1c

Myocardial dysfunction BNP or NT-proBNP

Renal disease Creatinine (for eGFR)

Coronary artery disease Imaging to directly examine for atherosclerosis

LEARNING GUIDE: CARDIAC 58

 Considerations for Biomarkers: Determining Clinical Value
Establishing the clinical value of a particular biomarker is another essential aspect in determining its role in
patient care. Useful biomarkers will need to demonstrate two qualities: 1) accuracy in predicting future cardiac
risk and 2) provision of additional information beyond what current methods offer.123 These qualities can be
evaluated using 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 something called a c-statistic test.123 Second, a biomarker must demonstrate through a
statistical assessment that it is calibrated to what it measures, or that the biomarker’s prediction aligns with the
observed results.123 And third, a biomarker must demonstrate that it improves a patient’s risk characterization
over previous methods, a concept known as net reclassification improvement.123

CARDIOVASCULAR RISK BIOMARKERS

Lipids
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 circulating biomarkers used for assessing cardiovascular risk. Moreover, when medications, specifically
statins, are employed to normalize certain lipid biomarkers, the rate of cardiovascular events and death is
significantly reduced. As such, lipids are a cornerstone of cardiovascular risk assessment and are included in
many risk prediction scoring tools.
TOTAL CHOLESTEROL
Higher concentrations of total cholesterol have long been associated with an increased risk for CVD.124-25
Because of this correlation, total cholesterol concentrations are included in many CVD risk assessment tools.
Although this measure remains a helpful tool for evaluating risk, it is no longer used as a target for
intervention with lipid-lowering medication.
LOW-DENSITY LIPOPROTEIN
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 patients with elevated LDL concentrations reduces the risk of cardiovascular events and death.113,126 Both the
US 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 identifying risk and guiding medication interventions to lower risk of CVD and death.
HIGH-DENSITY LIPOPROTEIN
High-density lipoprotein (HDL), sometimes referred to as “good cholesterol,” is inversely associated with
CVD; 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, 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 cessation are interventions that can raise HDL and
decrease cardiovascular risk, the benefits of these interventions are not entirely due to their effect on HDL.

LEARNING GUIDE: CARDIAC 59

 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.
High-Sensitivity C-Reactive Protein
Inflammation is an important mediator of cardiovascular disease and is linked to atherosclerosis, ischemic heart
disease, and stroke.130 High-sensitivity C-reactive protein, or hsCRP, becomes elevated in the presence of
multiple cardiovascular risk factors including abdominal adiposity (fat accumulation in the abdomen), diabetes,
hypertension, smoking, and hyperlipidemia (high lipid concentrations).130 Hence, hsCRP is an integrated
measure of CVD risk because of its complex associations with conventional risk factors. However, even when
these other factors are considered, hsCRP has an independent risk relationship with CVD. As a biomarker for
inflammation, hsCRP has demonstrated usefulness in identifying individuals at risk for CVD events.118-19,131
Elevated hsCRP is associated with an increased risk of diabetes, cardiovascular disease, and mortality.132 This
predictive ability appears to improve when hsCRP is measured over time; prolonged elevations of hsCRP are
stronger predictors of these outcomes than one-time measurements.132 Importantly, hsCRP as a predictor for
CVD events has been evaluated in different ethnic cohorts in different areas of the world.130 Although studies
indicate that there are race and geographic differences in normal hsCRP ranges (making the definition of
normal ranges difficult to define for international populations), there is evidence that higher hsCRP
concentrations correlate to a higher incidence of CVD events across all populations.130
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 performed consistently in predicting CVD risk in several large study populations. Researchers evaluating
the use of hsCRP in the participants of two large, long-term study groups, NHANES and ARIC, found that
measuring hsCRP did not add any significant predictive effectiveness over traditional scoring tools and
traditional risk factors (such as 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

LEARNING GUIDE: CARDIAC 60

 High-Sensitivity Troponin
Unlike hsCRP, high-sensitivity troponin (hsTn) T and I are biomarker assays that are very specific to the
cardiac muscle.149 Although they have demonstrated usefulness in acute coronary syndromes and heart failure,
they also have recently established their value as prognostic indicators in the general, apparently-healthy
population. In this context, the concentration of hsTn may be a reflection of the health of the myocardium.
A long-term study of over 3,000 men with elevated cholesterol but no history of myocardial infarction,
WOSCOPS, monitored participants for over five years and also assigned some participants to treatment with
a statin.135 Researchers measured hsTn at study entry and one year later; the change (rise or fall) in hsTn over
that one-year period was strongly correlated with future risk of coronary disease, regardless of a change in
cholesterol concentrations.135 It was noted that treatment with the statin appeared to lower hsTn concentrations
at the one-year measurement, which also correlated with a lower risk of coronary disease events.135 Another
trial, JUPITER, which examined the effectiveness of rosuvastatin (another statin medication) for preventing
CVD events in individuals without cardiovascular disease, also evaluated hsTnI as a biomarker in over 12,000
participants.136 In this trial, participants with the highest hsTnI concentrations also had the highest risk of a
cardiovascular event or death from any cause.136 Treatment with rosuvastatin lowered the risk of CVD events in
individuals with and without elevated hsTnI concentrations.136 Both of these trials highlight that the
information provided by hsTnI can be used to help improve patient outcomes; not only is hsTnI useful in
identifying patients who are at risk, but these patients will also benefit from intervention (treatment with a statin).
The use of hsTn in conjunction with traditional scoring tools has also been examined. In the BiomarCARE
study, investigators examined data from multiple trials that included more than 74,000 European participants
who were free from cardiovascular disease.137 Researchers determined that hsTnI measurements provide better
prognostic data for predicting CVD and CVD-related death when used in conjunction with the SCORE risk
assessment tool than the SCORE tool alone.137 In another study of over 9,000 individuals without cardiovascular
disease, hsTnI performed better than hsCRP at predicting cardiovascular risk over more than 13 years of
follow-up.149 Furthermore, when hsTnI was added to established cardiovascular disease risk prediction models,
it led to significantly greater net reclassification improvement than adding hsCRP to the models.149
An important difference in normal troponin concentrations between men and women has also been identified
with the advent of high-sensitivity assays. The HUNT study found not only do women in a normal population
have a lower hsTnI concentration than men, but hsTnI concentrations were stronger predictors of death due to
cardiovascular disease in women than in men.138 Another group of researchers used data from a long-term
population study, the Dallas Heart Study, to evaluate sex-specific differences in an array of biomarkers,
including hsTn.139 Similar to findings in the HUNT study, women were found to have lower concentrations of
hsTn than men.139
Evidence indicates that measuring circulating sensitive cardiac biomarkers such as hsTnI improves
cardiovascular risk stratification in the general population; however the majority of the prior evidence and
biomarker thresholds were derived in Western populations. Whether these data are similarly applicable to
Asia Pacific populations and may be effectively used to target high risk individuals for primary prevention
strategies warrant further study.151

LEARNING GUIDE: CARDIAC 61

 Natriuretic Peptides
Although the natriuretic peptides (NPs) are used extensively in the management of patients with heart failure,
they also have a role in screening the asymptomatic population for CVD. Even small elevations of NP levels, below
the threshold for diagnosis of heart failure, have demonstrated usefulness as a prognostic marker for predicting
the risk of cardiovascular events and death.136,140 In a meta-analysis examining data from 11 studies on NT-proBNP
for identification of risk in the general population, NT-proBNP elevation correlated with an increased
cardiovascular mortality and mortality from any cause.141 Moreover, there is also data to support that NPs are
useful predictors of outcomes over long periods; BNP concentrations were strongly correlated with risk of
CVD-related death in a cohort of middle-aged men followed for an average of 15 years.142
Importantly, the STOP-HF trial (as discussed in Section 5) evaluated interventions to prevent or delay the onset of
heart failure in individuals with risk factors for heart failure. In the intervention group (the group that
experienced the experimental care) of this trial, a BNP concentration over 50 pg/mL was used as a screening
cutoff; patients with measurements above this received preventative interventions designed to reduce the risk for
heart failure.81 The participants that received the preventative interventions had lower rates of heart failure than
the patients in the control group (the group that received normal care) at the end of the trial.81 This trial
highlights the real-world value of BNP as a biomarker for prevention. Patients were screened using BNP and
received intervention if they were high-risk according to the biomarker; this intervention, in turn, resulted in
improved patient outcomes (i.e., lower rates of heart failure).81
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 targets in prior guidelines. Further study of these two lipid fractions is ongoing.
Another biomarker, homocysteine, 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 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 instability in atherosclerotic plaques.
Multiple studies have found an association between increasing Lp-PLA2 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 currently used prognostic
tools has not been determined.
Biomarkers in Clinical Practice
Biomarkers for cardiovascular disease are continuously evolving, and although the roles for certain biomarkers,
such as NPs and cardiac troponins, are well defined in specific aspects of cardiac care, the roles for many newer
biomarkers are still being determined. One area that needs further clarification is how best to incorporate
biomarker 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 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 in cardiovascular diseases will likely continue to evolve, ideally providing
clinicians with better tools for caring for their patients.

LEARNING GUIDE: CARDIAC 62

 SECTION 6: REVIEW QUESTIONS

1. Which of the following may be useful for determining an asymptomatic patient’s risk for future CVD events?

a. SCORE risk assessment tool

b. A biomarker measurement, such as hsCRP or hsTnI
c. Assessing other risk factors such as obesity, sedentary lifestyle, and family history of CVD events
d. All of the above are useful considerations

2. The ACC/AHA guidelines recommend against the use of biomarkers to assess an asymptomatic patient’s
risk for future CVD events.

n True n False

3. To demonstrate clinical usefulness, a biomarker needs to show all of the following EXCEPT...

a. Net reclassification improvement

b. Adherence to ACC/AHA guidelines
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

LEARNING GUIDE: CARDIAC 63

 APPENDIX
APPENDIX A:
GLOSSARY OF TERMS
APPENDIX B:
CORRECT RESPONSES
APPENDIX C:
REFERENCES

LEARNING GUIDE: CARDIAC 64

 APPENDIX A: GLOSSARY OF TERMS
A
ACE inhibitors: A class of medication used to treat heart failure and high blood pressure; in heart failure, these drugs block
neurohormonal changes.
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 norepinephrine.
Aerobic exercise: Exercise that stimulates the heart rate and breathing rate to increase.
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 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.
Aspirin: An antiplatelet medication used to prevent blood from clotting; it is often used in the treatment and prevention of
myocardial infarction.
Atherosclerosis: The buildup of plaque inside the arteries.
Atrial fibrillation: An abnormal heart rhythm where the atria beat inappropriately fast; this sometimes also results in the
ventricles beating too fast.
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.
Atrium (plural: Atria): The two upper chambers of the heart; they receive blood from the vena cava and the pulmonary
vein and move it into the ventricles.
Autoimmune disease: A disease characterized by the body’s immune system producing antibodies that attack its
own tissue.
Automaticity: The heart tissue’s ability to generate its own electrical impulses to stimulate contraction.

LEARNING GUIDE: CARDIAC 65

 B
B-natriuretic peptide (BNP): A protein released by the ventricles of the heart when they are under strain or stress; most
often used as a biomarker for diagnosing and monitoring heart failure.
Beta blocker: A medication used to slow the heart rate and control blood pressure; beta blockers are often used in patients
who have had a myocardial infarction; some beta blockers are useful for blocking the neurohormonal changes associated
with heart failure.
Biomarker: A measurable characteristic that can be used to evaluate normal body processes, disease, or response to
treatment. This guide focuses on circulating biomarkers, which are markers that circulate in the bloodstream.
Blood: The liquid that travels through the blood vessels of the body that is made up of specific types of cells (i.e., red blood
cells, white blood cells, platelets). Blood carries oxygen and nutrients to body tissues and carries waste and carbon dioxide
away from tissues.
Blood pressure (or arterial blood pressure): The measure of pressure inside the arteries that is created by the force and
rate of the heart beating and the elasticity of the arteries.
Blood vessel: A general term used to describe the tubes that carry blood through the body: arteries, veins, and capillaries.
Bundle of His: Part of the cardiac electrical conduction system, it transmits electrical signals from the atrioventricular (AV)
node to the ventricles.

C
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).
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.
Calibration (or calibrated): In statistics, how well a prediction aligns with the observed results.
Capillaries: The smallest blood vessels; they allow nutrients, oxygen, and carbon dioxide to be exchanged between cells
and the blood.
Carbon dioxide: A gas which is a waste product of cell energy production.
Cardiac catheterization: See “angiography.”
Cardiac catheterization laboratory (cath lab): The department within a facility (often a hospital) where angiography
procedures are performed.
Cardiac magnetic resonance (CMR): A magnetic resonance imaging (or MRI) test that examines the structure
of the heart.
Cardiac myosin-binding protein C (cMyC): An emerging, circulating biomarker that may be useful in early identification
of myocardial infarction.
Cardiac resynchronization device/therapy: An implantable device that uses electrical impulses to aid both ventricles in
contracting at the same time. It is used to treat certain electrical conduction abnormalities.
Cardiomyopathy: Maladaptive changes in heart structure caused by myocardial infarction, neurohormonal activation,
genetic, abnormal cell signaling, or unknown reasons.
Cardioversion: A procedure used to treat an abnormal cardiac rhythm that involves either delivering a specific amount of
electricity (a shock) to the heart or administering medication to promote return to a normal rhythm.
Cell: The smallest unit (“building block”) within a living organism.
Cerebrovascular event: A term used to describe a situation where the brain is not receiving enough oxygen to 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).
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.
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.

LEARNING GUIDE: CARDIAC 66

 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.
Coefficient of variation (CV): A statistical measurement used to describe variation within a data sample; coefficient of
variation is calculated by dividing the standard deviation (a measure that describes the amount of variation in a group of
numbers) by the mean (or average) of those numbers. It is usually expressed as a percentage.
Congenital heart disease: A structural abnormality in the heart that is present at birth.
Coning: A term used to describe selection of a population for a scientific measurement.
Copeptin: An emerging, circulating biomarker that may be used for identifying myocardial infarction.
Coronary artery: An artery that supplies blood to the heart muscle.
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 myocardium.
Coronary CT angiography: A type of imaging test that allows clinicians to visualize the inside of the coronary arteries
using a powerful, detailed X-ray.
Coronary heart disease: A condition that results from atherosclerosis in the coronary arteries.
Contraction: Tension that occurs in the muscle fibers in response to a stimulus.
Creatinine kinase MB (CK-MB): An older circulating biomarker that was previously used to identify myocardial necrosis,
related to myocardial infarction.

D
Degradation: Breaking down into parts.
Delta: A change or difference between two numbers measuring the same thing.
Diabetes: A disease characterized by either the inability to make insulin or resistance to insulin that results in elevated
concentrations of glucose (a basic form of sugar) in the body. Diabetes significantly increases the risk of heart disease.
Diastole: The relaxation phase of the heart pumping cycle that results in relaxation of the heart muscle, allowing the heart
chambers to fill with blood.
Digoxin: A medication used to treat symptoms of heart failure or control the heart rate in atrial fibrillation.
Discrimination: In statistics, the ability to differentiate between individuals who will and will not develop a disease;
usually measured with the c-statistic test.
Diurnal variation: A scenario where concentrations of substances in the body vary throughout different times of the day.
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.

E
Echocardiography: A test the uses ultrasound to visualize the heart and its function.
Ejection fraction: The percentage of blood pumped out of the left ventricle with each contraction; normal range is
approximately 55-75%.
Elasticity: Stretchiness.

LEARNING GUIDE: CARDIAC 67

 Electrocardiogram (ECG or EKG): A test that measures the electrical activity of the heart, visualizing the electrical
activity of the heart from 12 different angles; used to evaluate for a type of myocardial infarction, cardiac arrhythmias, and
other cardiac abnormalities.
End-stage renal disease (ESRD): Chronic, irreversible failure of the kidneys; patients require either dialysis or a kidney
transplant at this stage.
Enoxaparin: A medication that interferes with the clotting cascade used to thin the blood; it is used in many clinical
scenarios, including myocardial infarction.
Enzyme: A protein produced by the body that encourages a chemical or biological reaction to occur more quickly.

F
Fat: An oily substance found in the body and also ingested in food; it is a building block for many substances in the body.
Fibrin: A protein formed after activation of the clotting cascade that creates a clot or thrombus.
Fibrinolytic: A medication that breaks down fibrin and a fibrin-based clot.
Fibrosis: In the heart, scar formation in tissue in response to an injury.
Framingham general CVD risk score: A scoring tool for predicting risk of a cardiovascular event in individuals without
known cardiovascular disease.

G
Galectin-3: A protein that mediates inflammation and fibrosis throughout the body; as a circulating biomarker, it is useful
for providing prognostic information in patients with heart failure.
Growth-differentiation factor-15 (GDF15): A cytokine that is upregulated in the setting of inflammation; it may be useful
as an emerging, circulating biomarker for cardiac remodeling and a prognostic indicator for individuals with heart failure.
GRACE score: A scoring tool used to risk stratify a patient with suspected acute coronary syndrome.

H
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 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).
Heart: The organ in the body responsible for pumping blood to other body organs and tissues.
Heart failure: A condition in which a problem with the ventricles is preventing the heart from 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.
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.
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.
Heparin: A medication that interferes with the clotting cascade used to thin the blood; it is used in many clinical scenarios,
including myocardial infarction.
HFmrEF (Heart failure with mid-range ejection fraction): A newer heart failure classification used to describe 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.
HFrEF (Heart failure with reduced ejection fraction): A heart failure classification used to describe patients with heart
failure symptoms and a reduced ejection fraction, usually under 45 percent.

LEARNING GUIDE: CARDIAC 68

 High-sensitivity C-reactive protein (hsCRP): A circulating biomarker for inflammation in the body; in cardiology
practice, it can be used as a screening tool for identifying patients at risk for cardiac disease when other tools are
not adequate.

Homocysteine: An amino acid synthesized by the body; elevated concentrations are associated with inflammation
and an increased risk of ischemic heart disease and stroke in a generally healthy population, but its usefulness as a
screening tool is uncertain.

Hormone: A “messenger” substance produced by the body that is released into body fluids to stimulate the activity of a
different tissue or organ.

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).

Hyperlipidemia: The medical term for higher-than-normal cholesterol concentrations in the blood.

Hypertension: The medical term for high blood pressure that indicates that the pressure inside the arteries is
higher than normal.

Hypotension: The medical term for low blood pressure that indicates that the pressure inside the arteries is too low and
may not be adequate for perfusion of oxygen into the tissues.

I
Ischemia: A scenario where tissues are not receiving enough oxygen.

Immunoassay: A test that measures the presence or concentrations of proteins (often antibodies) in a fluid (usually blood).

Implantable cardioverter-defibrillator: An implantable device that can detect abnormal, dangerous cardiac rhythms and
can send a small, electrical shock to the heart to return it to a normal rhythm.

Ischemia modified albumin: An FDA-approved, circulating biomarker for identifying myocardial infarction.

K
Kidneys: The organs of the body that create urine, remove waste from the blood, and regulate fluid balance.

Kidney failure (or renal failure): Impairment of normal kidney function; there is a spectrum of impairment that occurs,
ranging from mild to chronic, irreversible impairment (known as end-stage renal disease).

L
Left-ventricular assist device (LVAD): An implantable device, using a pump implanted into the wall of the left 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 batteries and control unit.

Lesion: In the coronary arteries, another name for an area inside the artery with plaque buildup.

Lipoprotein-associated phospholipase A2 (Lp-PLA2): An enzyme linked to inflammation and instability in

atherosclerotic plaques; it has been studied as a possible biomarker for screening asymptomatic populations for
cardiovascular disease.

Low-sodium diet: A diet low in salt.

Lumen: An opening; in the case of blood vessels, this term describes the opening inside the vessel.

LEARNING GUIDE: CARDIAC 69

 M
Maladaptive: Counterproductive; inadequate adjustment to a change or environment.

Mineralocorticoid receptor antagonist: See “Aldosterone antagonist.”

Mortality: Death or dying.

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

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

Myocardial: Relating to the heart.

Myocardial infarction: Permanent damage to the heart as a result of inadequate blood flow to the cardiac tissue.

Myocarditis: Inflammation of the heart muscle, often as a result of a viral infection.

Myocardium: The heart’s muscle tissue.

Myocyte: A cell in the heart tissue.

Myoglobin: An oxygen-binding protein similar to hemoglobin; it was one of the earliest circulating biomarkers for
myocardial infarction, but it is no longer used for this purpose.

N
Natriuretic peptide: Hormones that influence fluid and sodium balance in the body. Although there are several other
known natriuretic peptides, this term is often used to describe BNP and its inactive counterpart, NT-proBNP.

Necrosis: Death of all or most of the cells in an area of the body.

Negative predictive value (NPV): The probability that an individual with a negative result on a screening test does not
have a disease or problem.

Neprilysin: An enzyme involved in an array of biochemical processes in the body; neprilysin is involved in the
breakdown of BNP.

Net reclassification improvement: In statistics, the ability of a new test or marker to demonstrate that it improves
predictive ability over previously used methods (e.g., more individuals were provided with accurate predictions with the
new method than with previous methods).

Neurohormonal activation: The release of hormones and neurotransmitters that increase the blood pressure and 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.

Neurotransmitter: Chemical messengers in the body that stimulate a nerve.

Nitrate (long-acting): A type of medication used for patients with certain cardiac problems; in heart failure, they can be
beneficial when used in combination with hydralazine, especially in individuals of African descent.

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.

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.

LEARNING GUIDE: CARDIAC 70

 O
Obese: Significantly overweight.

Obesity: The state of being significantly overweight.

Obstructive sleep apnea: A sleep disorder in which patients stop and restart breathing many times through the night; it has
a variety of negative health implications and is a risk factor for certain cardiac problems.

Occlusion: Blockage.

Organ: A self-contained part of the body that has a specific function.

Oxygen: An element and a gas necessary for normal function of the body cells.

P
Percutaneous coronary intervention (PCI): An angiography procedure done to treat a blockage in a coronary artery that
involves threading a wire device into the coronary artery, opening the blocked artery with a tiny, balloon-like device, and
then propping the artery open with a mesh wire tube called a stent.

Perfusion: Passage of fluid (in this case, blood) into the capillaries of an organ or tissue.

Pericarditis: Inflammation of the lining around the heart, often due to a viral infection.

Peripheral/periphery: Situated away from the center; in the case of the body, this often refers to the arms, legs,
hands, and feet.

Permeability: How well liquids and other substances can pass through a structure.

Plaque: A substance that can accumulate inside an artery; it is made up primarily of cholesterol, fat, and calcium.

Pneumonia: An infection in the lungs, caused by either a bacterium or a virus.

Prognostic: Predicting the likelihood of something.

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.

Pulmonary hypertension: A life-threatening disease that causes high blood pressure in the arteries of the lungs and the
right side of the heart.

Pulmonary veins: The veins that bring oxygenated blood from the lungs back to the heart.

Purkinje fibers: Fibers in the heart that conduct electrical impulses to the left and right ventricle, to stimulate the
heart to beat.

Q
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
substance is present or not).

LEARNING GUIDE: CARDIAC 71

 R
Remodeling: In the heart, the process of structural changes to the cardiac tissue as a result of heart failure, tissue injury, or
other factors.

Renal: See “kidney.”

Renal Failure: See “kidney failure.”

Reperfusion: Restoring blood flow to a tissue or organ.

Retention: Holding on to a substance.

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

Rheumatoid factor: An antibody directed against the body’s own tissue; elevated concentrations can be a sign of an
autoimmune disease such as rheumatoid arthritis.

S
Sarcoidosis: A chronic inflammatory disease that causes abnormal tissue to form in different parts of the body, including
the lungs, skin, and heart.

Sepsis: The body’s response to a serious infection that can be life-threatening if not treated promptly.

Sinoatrial node (SA node): The area of the right atrium where electrical impulses originate.

Skeletal muscle: A muscle connected to the skeleton that participates in the mechanical, voluntary movement of the body.

Smooth muscle: Muscles in the gut and other internal organs that move involuntarily (i.e., not conscientiously controlled).

Standard deviation: In statistics, a number that specifies how much members of a group differ from the group average.

Stasis: A slow down or complete stoppage of a normal flow.

STEMI (pronounced: stem–eee): A type of myocardial infarction characterized by ST-elevation on an

electrocardiogram test.

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.

Stress myocardial perfusion imaging: An imaging test that evaluates how well blood flows into the cardiac tissue.

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.

Stroke: A potentially life-threatening event where adequate blood supply to a portion of the brain is cutoff, resulting in
permanent damage. There are two primary mechanisms for this: 1) ischemic, which is usually caused by a blood clot and 2)
hemorrhagic, which is caused by a blood vessel in the brain bursting.

Superimposed: Occurring in addition to or on top of something else.

Systole: The phase of the cardiac pumping cycle that involves contraction of the heart muscle, pushing out blood.

LEARNING GUIDE: CARDIAC 72

 T
Tachyarrhythmia: A general term describing an abnormal, fast, heart rhythm.

Thrombin: An enzyme in the blood that works in the clotting cascade to create fibrin.

Thrombolytic: A medication that breaks down or dissolves a blood clot.

Thrombosis: The process of a blood clot forming inside a blood vessel.

Thrombus: A blood clot.

TIMI score: A scoring tool used to risk stratify patients with suspected acute coronary syndrome.

Tissue: Material inside the body made up of specialized cells.

Transient ischemic attack (TIA): A temporary period of abnormal brain functioning caused by temporary loss of blood
flow to an area of the brain; sometimes called a “mini-stroke,” it is a risk factor for future strokes.

Treadmill ECG: A test for coronary artery disease where a patient undergoes continuous ECG monitoring while doing
exercise, such as running on a treadmill or riding a bicycle.

Troponin: A protein that is abundant in the cardiac myocytes; it works inside the cell as part of the contractile mechanism
to facilitate myocyte contraction; troponins T and I are both useful as biomarkers in the evaluation of individuals with
possible myocardial infarction.

U
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.

V
Valsartan/sacubitril: A medication used for heart failure that blocks the body’s maladaptive neurohormonal response.

Vascular disease: A type of disease characterized by blood vessel abnormalities; it is a general classification that
encompasses an array of different conditions, including coronary heart disease.

Vasospasm: Spasm of the blood vessel wall.

Vein: Blood vessels that carry oxygen-poor blood from the capillaries back to the heart.

Vena cava: The largest vein in the body which delivers blood into the right ventricle.

Ventricles: The larger, lower two chambers of the heart.

Venules: Smaller veins that deliver blood to the capillaries.

LEARNING GUIDE: CARDIAC 73

 APPENDIX B: CORRECT RESPONSES
SECTION 1
1. Veins >> vena cava >> right atrium >> right ventricle >> pulmonary artery >> lungs >> pulmonary veins >>
left atrium >> left ventricle >> aorta >> arteries >> capillaries of organs and tissues
2. d
3. Coronary
4. Contraction, relaxation, left

SECTION 2
1. Atherosclerosis: e
PCI: b
MI: a
Troponin: c
Calcium: d
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 plaque buildup, or anything that causes inadequate flow of oxygen into the tissues.
3. d
4. Cardiac troponin

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

LEARNING GUIDE: CARDIAC 74

 SECTION 5
1. Obesity; any 5 of the following: kidney disease, female sex, increasing age, severe pneumonia,
obstructive sleep apnea, pulmonary hypertension, severe burns, critical illness
2. Copeptin: b
NP: b
Galectin-3: c
hsTn: a
Soluble ST2: c
GDF15: c
3. NP, screening, NP, fibrosis or myocardial injury

SECTION 6
1. d
2. False
3. b
4. c

LEARNING GUIDE: CARDIAC 75

 APPENDIX C: REFERENCES
1. Martini FH, Nath JL, Bartholomew EF. Fundamentals of Anatomy and Physiology. 10th ed. Pearson; 2015.

2. Cardiovascular Disease (CVDs) Fact Sheet. World Health Organization Web site.
http://www.who.int/mediacentre/factsheets/fs317/en/. Updated May 2017. Accessed September 15, 2017.

3. Mozaffarian D, Benjamin EJ, Go AS, et al. American Heart Association Statistics Committee and Stroke Statistics
Subcommittee. Executive Summary: Heart Disease and Stroke Statistics – 2016 Update.
Circulation. 2016; 133: 447-454.

4. Wilkins E, Wilson L, Wickramasinghe K, et al. European Cardiovascular Disease Statistics 2017. European Heart
Network (online). http://www.ehnheart.org/component/downloads/downloads/2452. Accessed September 15, 2017.

5. About Cardiovascular Disease. World Health Organization Web site. http://www.who.int/cardiovascular_diseases/

about_cvd/en/. Updated 2017. Accessed September 18, 2017.

6. 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.

7. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 ACC/AHA guideline for the management of patients with
non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. Circulation. 2014; 130: e344-e426.

8. Braunwald E, Morrow DA. Unstable angina: is it time for a requiem? Circulation. 2013; 127(24): 2452-2457.

9. Shah AS, Newby DE, Mills NL. High sensitivity cardiac troponin in patients with chest pain. BMJ. 2013; 347: f4222.

10. Acute Coronary Syndrome. American Heart Association Web site. http://www.heart.org/HEARTORG/Conditions/
HeartAttack/AboutHeartAttacks/Acute-Coronary-Syndrome_UCM_428752_Article.jsp#.Wbaj6xiZNo4.
Updated April 26, 2017. Accessed September 11, 2017.

11. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation
myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task
Force on Practice Guidelines. Circulation. 2013; 127: 1-64.

12. Angioplasty and stent placement – heart. U.S. National Library of Medicine: Medline Plus Web site.
https://medlineplus.gov/ency/article/007473.htm. Updated September 5, 2017. Accessed September 15, 2017.

13. Retavase [package insert]. Cary, North Carolina: Chiesi USA, Inc.; June 2017.

14. Shah ASV, Anand A, Sandoval Y, et al. High-sensitivity cardiac troponin I at presentation in patients with suspected
acute coronary syndrome: a cohort study. Lancet. 2015; 386(10012): 2481-2488.

15. Garg P, Morris P, Fazlanie AL, et al. Cardiac biomarkers of acute coronary syndrome: from history to high-sensitivity
cardiac troponin. Intern Emerg Med. 2017; 12(2): 147-155.

16. Danese E, Montagnana M. An historical approach to the diagnostic biomarkers of acute coronary syndrome.
Ann Transl Med. 2016; 4(10): 194.

17. Jarolim P. High-sensitivity cardiac troponin assays in the clinical laboratories. Clin Chem Lab Med. 2015; 53(5): 635-652.

18. Klinkenberg LJ, Wildi K, van der Linden N, et al. Diurnal Rhythm of Cardiac Troponin: Consequences for the
Diagnosis of Acute Myocardial Infarction. Clin Chem. 2016; 62(12): 1602-1611.

19. Twerenbold R, Wildi K, Jaeger C, et al. Optimal Cutoff Levels of More Sensitive Cardiac Troponin Assays for the
Early Diagnosis of Myocardial Infarction in Patients With Renal Dysfunction. Circulation. 2015; 131: 2041-2050.

20. Jaffe AS, Vasile VC, Milone M, Saenger AK, Olson KN, Apple FS. Diseased skeletal muscle: a noncardiac source of
increased circulating concentrations of cardiac troponin T. J Am Coll Cardiol. 2011; 58(17): 1819-1824.

21. Wens SC, Schaaf GJ, Michels M, et al. Elevated Plasma Cardiac Troponin T Levels Caused by Skeletal Muscle
Damage in Pompe Disease. Circ Cardiovasc Genet. 2016; 9(1): 6-13.

LEARNING GUIDE: CARDIAC 76

 22. Laugaudin G, Kuster N, Petiton A, et al. Kinetics of high-sensitivity cardiac troponin T and I differ in patients with
ST-segment elevation myocardial infarction treated by primary coronary intervention.
Eur Heart J Acute Cardiovasc Care. 2016; 5(4): 354-363.

23. Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the Management of Acute Coronary Syndromes in
Patients Presenting Without Persistent ST-segment Elevation. Rev Esp Cardiol (Engl Ed). 2015; 68(12): 1125.

24. Lippi G, Cervellin G. High-sensitivity troponin T is more susceptible than high-sensitivity troponin I to impaired
renal function. Am J Cardiol. 2013; 112: 1985.

25. Aviles RJ, Askari AT, Lindahl B, et al. Troponin T levels in patients with acute coronary syndromes, with or without
renal dysfunction. N Engl J Med. 2002; 346(26): 2047-2052.

26. Shah ASV, Griffiths M, Lee KK, et al. High sensitivity cardiac troponin and the under-diagnosis of myocardial
infarction in women: prospective cohort study. BMJ. 2015; 350: g7873.

27. Gimenez MR, Twerenbold R, Reichlin T, et al. Direct comparison of high-sensitivity-cardiac troponin I vs. T for the
early diagnosis of acute myocardial infarction. Eur Heart J. 2014; 35(34): 2303-2311.

28. Apple FS, Collinson PO. Analytical characteristics of high-sensitivity cardiac troponin assays.
Clin Chem. 2012; 58: 54-61.

29. White HD. Pathobiology of troponin elevations: do elevations occur with myocardial ischemia as well as necrosis?
J Am Coll Cardiol. 2011; 57(24): 2406-2408.

30. Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal in humans.
Science (New York, NY). 2009; 324(5923): 98-102.

31. Carlton EW, Cullen L, Than M, Gamble J, Khattab A, Greaves K. A novel diagnostic protocol to identify patients
suitable for discharge after a single high-sensitivity troponin. Heart. 2015; 101(13): 1041-1046.

32. Shah ASV, Newby DE, Mills NL. High sensitivity cardiac troponin in patients with chest pain. BMJ. 2013; 347: f4222.

33. Reichlin T, Schindler C, Drexler B, et al. One-hour rule-out and rule-in of acute myocardial infarction using
high-sensitivity cardiac troponin T. Arch Intern Med. 2012; 172: 1211-1218.

34. Keller T, Zeller T, Ojeda F, et al. Serial Changes in Highly Sensitive Troponin I Assay and Early Diagnosis of
Myocardial Infarction. JAMA. 2011; 306(24): 2684-2693.

35. Reichlin T, Irfan A, Twerenbold R, et al. Utility of Absolute and Relative Changes in Cardiac Troponin
Concentrations in the Early Diagnosis of Acute Myocardial Infarction. Circulation. 2011; 124(2): 136-145.

36. Apple FS, Jaffe AS, Collinson P, et al. International Federation of Clinical Chemistry (IFCC) Task Force on Clinical
Applications of Cardiac Bio-Markers. IFCC educational materials on selected analytical and clinical applications of
high sensitivity cardiac troponin assays. Clin Biochem. 2015; 48(4-5): 201-203.

37. Jülicher P, Greenslade JH, Parsonage WA, et al. The organisational value of diagnostic strategies using high-
sensitivity troponin for patients with possible acute coronary syndromes: a trial-based cost-effectiveness analysis.
BMJ Open. 2017; 7: e013653.

38. Korley FK, Jaffe AS. High Sensitivity Cardiac Troponin Assays – How to Implement them Successfully.
EJIFCC. 2016; 27(3): 217-223.

39. Myocardial infarction (acute): Early rule out using high-sensitivity troponin tests (Elecsys) Troponin T high-
sensitive, ARCHITECT STAT High Sensitive Troponin-I and AccuTnI+3 assays). National Institute for Health
and Care Excellence (NICE) Web site. https://www.nice.org.uk/guidance/dg15/chapter/1-Recommendations.
Updated October 2014. Accessed September 25, 2017.

40. Möckel M, Searle J. Copeptin – Marker of Acute Myocardial Infarction. Curr Atheroscler Rep. 2014; 16(7): 421.

41. Calmarza P, Lapresta C, García-Castañón S, López-Perales C, Pérez-Guerrero A, Portolés A. Usefulness of copeptin

in the diagnosis of acute coronary syndrome in the emergency department of a tertiary hospital.
Clin Investig Arterioscler. 2016; 28(5): 209-215.

42. Eggers KM, Lindahl B. Prognostic Biomarkers in Acute Coronary Syndromes: Risk Stratification Beyond Cardiac
Troponins. Curr Cardiol Rep. 2017; 19(4): 29.

43. Vassiliadis E, Barascuk N, Didangelos A, Karsdal MA. Novel Cardiac-Specific Biomarkers and the Cardiovascular
Continuum. Biomark Insights. 2012; 7: 45-57.

LEARNING GUIDE: CARDIAC 77

 44. Bhakthavatsala Reddy C, Cyriac C, Desle HB. Role of “Ischemia Modified Albumin” (IMA) in acute coronary
syndromes. Indian Heart J. 2014; 66(6): 656-662.

45. Kaier TE, Twerenbold R, Puelacher C, et al. Direct Comparison of Cardiac Myosin-Binding Protein C with Cardiac
Troponins for the Early Diagnosis of Acute Myocardial Infarction. Circulation. 2017; 136(16): 1495-1508.

46. Salvagno GL, Pavan C. Prognostic biomarkers in acute coronary syndrome. Ann Transl Med. 2016; 4(13): 258.

47. Ambrosy AP, Fonarow GC, Butler J, et al. The global health and economic burden of hospitalizations for heart
failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol. 2014; 63(12): 1123-1133.

48. Benjamin EJ, Blaha M, Chiuve SE, et al. Heart Disease and Stroke Statistics – 2017 Update: A Report From the
American Heart Association. Circulation. 2017; 135: e146-e603.

49. Savarese G, Lund LH. Global Public Health Burden of Heart Failure. Card Fail Rev. 2017; 3(1): 7-11.

50. King M, Kingery J, Casey B. Diagnosis and Evaluation of Heart Failure. Am Fam Physician. 2012; 85(12): 1161-1168.

51. Inamdar AA, Inamdar AC. Heart Failure: Diagnosis, Management and Utilization. De Rosa S, ed.
J Clin Med. 2016; 5(7): 62.

52. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic
heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European
Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the
ESC. Eur J Heart Fail. 2016; 18(8): 891-975.

53. Eaton CB, Pettinger M, Rossouw J, et al. Risk Factors for Incident Hospitalized Heart Failure With Preserved vs
Reduced Ejection Fraction in a Multiracial Cohort of Postmenopausal Women. Circ Heart Fail. 2016; 9(10): e002883.

54. Andersson C, Vasan RS. Epidemiology of heart failure with preserved ejection fraction.
Heart Fail Clin. 2014; 10(3): 377-388.

55. Komanduri S, Jadhao Y, Guduru SS, Cheriyath P, Wert Y. Prevalence and risk factors of heart failure in the USA:
NHANES 2013-2014 epidemiological follow-up study. J Community Hosp Intern Med Perspect. 2017; 7(1): 15-20.

56. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for
the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association
Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
Circulation. 2017; 136(6): e137-e161.

57. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for Cardiac Chamber Quantification by Echocardiography
in Adults: An Update from the American Society of Echocardiography and the European Association of
Cardiovascular Imaging. J Am Soc Echocardiogr. 2015; 28: 1-39.

58. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure.
Circulation. 2013; 128: e240-e327.

59. Gheorghiade M. Acute Heart Failure Syndromes. US Cardiology. 2006; 2005: 2(1): 202-208.

60. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure.
JAMA. 1996; 275: 1557-1562.

61. Owens AT, Brozena SC, Jessup M. New Management Strategies in Heart Failure. Circ Res. 2016; 118: 480- 495.

62. Hobbs R, Boyle A. Heart Failure. Cleveland Clinic Center for Continuing Education Web site. http://www.
clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/heart-failure/#bib1.
Updated March 2014. Accessed October 2, 2017.

63. McCullough PA, Olobatoke A, Vanhecke TE. Galectin-3: A novel blood test for the evaluation and management of
patients with heart failure. Rev Cardiovasc Med. 2011; 12(4): 200-210.

64. Dunlay SM, Manemann SM, Chamberlain AM, et al. Activities of Daily Living and Outcomes in Heart Failure.
Circ Heart Fail. 2015; 8(2): 261-267.

65. Pandit K, Mukhopadhyay P, Ghosh S, Chowdhury S. Natriuretic peptides: Diagnostic and therapeutic use.
Indian J Endocrinol Metab. 2011; 15(Suppl 4): S345-S353.

66. McCullough PA, Neyou A. Comprehensive Review of the Relative Clinical Utility of B-Type Natriuretic Peptide and
N-Terminal Pro-B-Type Natriuretic Peptide Assays in Cardiovascular Disease. Open Heart Failure J. 2009; 2: 6-17.

LEARNING GUIDE: CARDIAC 78

 67. Maisel AS, Daniels LB. Breathing Not Properly 10 Years Later: what we have learned and what we still need to learn.
J Am Coll Cardiol. 2012; 60(4): 277-282.

68. De Boer RA, Yu L, van Veldhuisen DJ. Galectin-3 in Cardiac Remodeling and Heart Failure.
Curr Heart Fail Rep. 2010; 7(1): 1-8.

69. Meijers WC, de Boer RA, van Veldhuisen DJ, et al. Biomarkers and low risk in heart failure.
Data from COACH and TRIUMPH. Eur J Heart Fail. 2015; 17(12): 1271-1282.

70. Sudharshan S, Novak E, Hock K, Scott MG, Geltman EM. Use of Biomarkers to Predict Readmission for Congestive
Heart Failure. Am J Cardiol. 2017; 119(3): 445-451.

71. Stelzle D, Shah AS, Anand A, et al. High-sensitivity cardiac troponin I and risk of heart failure in patients with
suspected acute coronary syndrome: a cohort study. Eur Heart J Qual Care Clin Outcomes. 2017; 0: 1-7.

72. Ventricular Assist Device. Medline Plus Web site. https://medlineplus.gov/ency/article/007268.htm.

Updated May 5, 2016. Accessed October 2, 2017.

73. Organ Procurement and Transplantation Network. National Data on Heart Transplants. US Department of Health
and Human Services Web site. https://optn.transplant.hrsa.gov/data/. Updated September 30, 2017.
Accessed October 18, 2017.

74. Bavishi C, Messerli FH, Kadosh B, Ruilope LM, Kario K. Role of neprilysin inhibitor combinations in hypertension:
insights from hypertension and heart failure trials. Eur Heart J. 2015; 36, 1967-1973.

75. Meijers WC, van der Velde AR, de Boer RA. Biomarkers in heart failure with preserved ejection fraction.
Neth Heart J. 2016; 24(4): 252-258.

76. Ziaeian B, Fonarow GC. The Prevention of Hospital Readmissions in Heart Failure.
Prog Cardiovasc Dis. 2016; 58(4): 379-385.

77. Felker GM, Anstrom KJ, Adams KF, et al. Effect of Natriuretic Peptide-Guided Therapy on Hospitalization or
Cardiovascular Mortality in High-Risk Patients With Heart Failure and Reduced Ejection Fraction: A Randomized
Clinical Trial. JAMA. 2017; 318(8): 713-720.

78. Mogelvang R, Goetze JP, Pedersen SA, et al. Preclinical systolic and diastolic dysfunction assessed by tissue
Doppler imaging is associated with elevated plasma pro-B-type natriuretic peptide concentrations.
J Card Fail. 2009; 15: 489-495.

79. Brouwers FP, van Gilst WH, Damman K, et al. Clinical risk stratification optimizes value of biomarkers to predict
new-onset heart failure in a community-based cohort. Circ Heart Fail. 2014; 7(5): 723-731.

80. Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic
peptide to detect preclinical ventricular systolic or diastolic dysfunction: a community-based study.
Circulation. 2004; 109(25):3176-3181.

81. Ledwidge M, Gallagher J, Conlon C, et al. Natriuretic peptide-based screening and collaborative care for heart
failure: the STOP-HF randomized trial. JAMA. 2013; 310(1): 66-74.

82. Januzzi JL, van Kimmenade R, Lainchbury J, et al. NT-proBNP testing for diagnosis and short-term prognosis in
acute destabilized heart failure: an international pooled analysis of 1256 patients: The International Collaborative of
NT-proBNP Study. Eur Heart J. 2006; 27(3): 330-337.

83. Hijazi Z, Wallentin L, Siegbahn A, et al. N-terminal pro-B-type natriuretic peptide for risk assessment in patients
with atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for the Prevention of Stroke in Subjects With
Atrial Fibrillation). J Am Coll Cardiol. 2013; 61(22): 2274-2284.

84. McKelvie RS, Komajda M, McMurray J, et al. Baseline plasma NT-proBNP and clinical characteristics: results from
the irbesartan in heart failure with preserved ejection fraction trial. J Card Fail. 2010; 16(2): 128-134.

85. Luchner A, Behrens G, Stritzke J, et al. Long-term pattern of brain natriuretic peptide and N-terminal pro brain
natriuretic peptide and its determinants in the general population: contribution of age, gender, and cardiac and
extra-cardiac factors. Eur J Heart Fail. 2013; 15(8): 859-867.

86. Pankow K, Schwiebs A, Becker M, Siems WE, Krause G, Walther T. Structural substrate conditions required for
neutral endopeptidase-mediated natriuretic peptide degradation. J Mol Biol. 2009; 393: 496-503.

87. Vodovar N, Seronde MR, Laribi S, et al. Elevated plasma B-type natriuretic peptide concentrations directly inhibit
circulating neprilysin activity in heart failure. J Am Coll Cardiol HF. 2015; 3: 629-636.

LEARNING GUIDE: CARDIAC 79

 88. Jaffe AS, Apple FS, Mebazaa A, Vodovar N. Unraveling N-terminal pro-B-type natriuretic peptide: another piece to a
very complex puzzle in heart failure patients. Clin Chem. 2015; 61: 1016-1018.

89. Eliaz I. The Role of Galectin-3 as a Marker of Cancer and Inflammation in a Stage IV Ovarian Cancer Patient with
Underlying Pro-Inflammatory Comorbidities. Case Rep Oncol. 2013; 6(2): 343-349.

90. Amin HZ, Amin LZ, Wijaya IP. Galectin-3: a novel biomarker for the prognosis of heart failure.
Clujul Med. 2017; 90(2): 129-132.

91. van der Velde AR, Gullestad L, Ueland T, et al. Prognostic value of changes in galectin-3 levels over time in patients
with heart failure: data from CORONA and COACH. Circ Heart Fail. 2013; 6: 219-226.

92. deFilippi CR, Felker GM. Galectin-3 In Heart Failure – Linking Fibrosis, Remodeling, and Progression.
Eur Cardiol. 2010: 6(2): 33-36.

93. de Boer RA, Lok DJ, Jaarsma T, et al. Predictive value of plasma galectin-3 levels in heart failure with reduced and
preserved ejection fraction. Ann Med. 2011; 43(1): 60-68.

94. Iqbal N, Wentworth B, Choudhary R, et al. Cardiac biomarkers: new tools for heart failure management.
Cardiovasc Diagn Ther. 2012; 2(2): 147-164.

95. de Boer RA, van Veldhuisen DJ, Gansevoort RT, et al. The fibrosis marker galectin-3 and outcome in the general
population. J Intern Med. 2012; 272: 55-64.

96. van der Velde AR, Meijers WC, Ho JE, et al. Serial galectin-3 and future cardiovascular disease in the general
population. Heart. 2016; 102: 1134-1141.

97. Christenson RH, Duh SH, Wu AH, et al. Multi-center determination of galectin-3 assay performance characteristics:
Anatomy of a novel assay for use in heart failure. Clin Biochem. 2010; 43(7-8): 683-690.

98. Lyons KS, McKeeman G, McVeigh GE, Harbinson MT. High-sensitivity troponin T is detectable in most patients
with clinically stable heart failure. Br J Cardiol. 2014; 21: 33-36.

99. Gaggin HK, Januzzi JL. Cardiac Biomarkers and Heart Failure. American College of Cardiology.
http://www.acc.org/latest-in-cardiology/articles/2015/02/09/13/00/cardiac-biomarkers-and-heart-failure.
Updated February 10, 2015. Accessed October 9, 2017.

100. Okuyama R, Ishii J, Takahashi H, et al. Combination of high-sensitivity troponin I and N-terminal pro-B-type
natriuretic peptide predicts future hospital admission for heart failure in high-risk hypertensive patients with
preserved left ventricular ejection fraction. Heart Vessels. 2017; 32(7): 880-892.

101. Driscoll A, Barnes EH, Blankenberg S, et al. Predictors of incident heart failure in patients after an acute coronary
syndrome: The LIPID heart failure risk-prediction model. Int J Cardiol. 2017; 248: 361-368.

102. Felker GM, Hasselblad V, Tang WH, et al. Troponin I in acute decompensated heart failure: insights from the
ASCEND-HF study. Eur J Heart Fail. 2012; 14(11): 1257-1264.

103. Xue Y, Clopton P, Peacock WF, Maisel AS. Serial changes in high-sensitive troponin I predict outcome in patients
with decompensated heart failure. Eur J Heart Fail. 2011; 13: 37-42.

104. Pang PS, Teerlink JR, Voors AA, at al. Use of High-Sensitivity Troponin T to Identify Patients With Acute Heart
Failure at Lower Risk for Adverse Outcomes: An Exploratory Analysis From the RELAX-AHF Trial.
JACC Heart Fail. 2016 Jul; 4(7): 591-599.

105. Gravning J, Askevold ET, Nymo SH, et al. Prognostic Effect of High-Sensitive Troponin T Assessment in Elderly
Patients With Chronic Heart Failure. Circ Heart Fail. 2014; 7: 96-103.

106. Villacorta H, Maisel AS. Soluble ST2 Testing: A Promising Biomarker in the Management of Heart Failure.
Arq Bras Cardiol. 2016; 106(2): 145-152.

107. George M, Jena A, Srivatsan V, Muthukumar R, Dhandapani VE. GDF 15 – A Novel Biomarker in the Offing for
Heart Failure. Curr Cardiol Rev. 2016; 12(1): 37-46.

108. Peacock WF. Novel biomarkers in acute heart failure: MR-pro-adrenomedullin.

Clin Chem Lab Med. 2014; 52(10): 1433-1435.

109. Maisel A, Xue Y, Shah K, et al. Increased 90-day mortality in patients with acute heart failure with elevated
copeptin: secondary results from the Biomarkers in Acute Heart Failure (BACH) study.
Circ Heart Fail. 2011; 4: 613-620.

LEARNING GUIDE: CARDIAC 80

 110. Shah RV, Truong QA, Gaggin HK, Pfannkuche J, Hartmann O, Januzzi JL. Mid-regional pro-atrial natriuretic
peptide and pro-adrenomedullin testing for the diagnostic and prognostic evaluation of patients with acute
dyspnoea. Eur Heart J. 2012; 33(17): 2197-2205.

111. Goff DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk.
Circulation. 2014; 129: S49-S73.

112. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular
risk: a report of the American College of Cardiology American/Heart Association Task Force on Practice Guidelines.
Circulation. 2014; 129(25 Suppl 2): S76-99.

113. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to
reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. Circulation. 2014; 125(25 Suppl 2): S1-45.

114. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical
practice. The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular
Disease Prevention in Clinical Practice. Eur Heart J. 2016; 37(29): 2315-2381.

115. D’Agostino RB, Vasan RS, Pencina MJ, et al. General Cardiovascular Risk Profile for Use in Primary Care.
Circulation. 2008; 117: 743-753.

116. Chia YC, Gray SYW, Ching SM, et al. Validation of the Framingham general cardiovascular risk score in a
multiethnic Asian population: a retrospective cohort study. BMJ Open. 2015; 5: e007324.

117. Ruwanpathirana T, Owen A, Reid CM. Review on Cardiovascular Risk Prediction. Cardiovasc Ther. 2015; 33: 62-67.

118. Ridker PM, Buring JE, Rifai N, Cook NR. Development and Validation of Improved Algorithms for the Assessment
of Global Cardiovascular Risk in Women: The Reynolds Risk Score. JAMA. 2007; 297(6): 611-619.

119. Ridker PM, Paynter NP, Rifai N, Gaziano JM, Cook NR. C-Reactive Protein and Parental History Improve Global
Cardiovascular Risk Prediction: The Reynolds Risk Score for Men. Circulation. 2008; 118(22): 2243-2251.

120. Damen JA, Hooft L, Schuit E, et al. Prediction models for cardiovascular disease risk in the general population:
systematic review. BMJ. 2016; 353: i2416.

121. DeFilippis AP, Young R, Carrubba CJ, et al. An Analysis of Calibration and Discrimination Among Multiple
Cardiovascular Risk Scores in a Modern Multiethnic Cohort. Ann Intern Med. 2015; 162(4): 266-275.

122. Sandoval Y, Apple FS. The Global Need to Define Normality: The 99th Percentile Value of Cardiac Troponin.
Clin Chem. 2014; 60(3): 455-462.

123. Gilstrap LG, Wang TJ. Biomarkers and Cardiovascular Risk for Primary Prevention: An Update.
Clin Chem. 2012; 58(1): 72-82.

124. Castelli WP, Anderson K, Wilson PW, Levy D. Lipids and risk of coronary heart disease. The Framingham Study.
Ann Epidemiol. 1992; 2(1-2): 23-28.

125. Verschuren WM, Jacobs DR, Bloemberg BP, et al. Serum total cholesterol and long-term coronary heart disease
mortality in different cultures: Twenty-five-year follow-up of the seven countries study. JAMA. 1995; 274(2): 131-136.

126. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias.
Eur Heart J. 2016; 37(39): 2999-3058.

127. Boekholdt SM, Arsenault BJ, Hovingh GK, et al. Levels and changes of HDL cholesterol and apolipoprotein A-I in
relation to risk of cardiovascular events among statin-treated patients; a meta-analysis. Circulation. 2013; 128(14): 10.

128. März W, Kleber ME, Scharnagl H, et al. HDL cholesterol: reappraisal of its clinical relevance.
Clin Res Cardiol. 2017; 106(9): 663-675.

129. Singh AK, Singh R. Triglyceride and cardiovascular risk: A critical appraisal.
Indian J Endocrinol Metab. 2016; 20(4): 418-428.

130. Fonseca FAH, de Oliveira Izar MC. High-Sensitivity C-Reactive Protein and Cardiovascular Disease Across
Countries and Ethnicities. Clinics. 2016; 71(4): 235-242.

131. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy.
N Engl J Med. 2005; 352(1): 20-28.

LEARNING GUIDE: CARDIAC 81

 132. Parrinello CM, Lutsey PL, Ballantyne CM, Folsom AR, Pankow JS, Selvin E. Six-year change in high-sensitivity
C-reactive protein and risk of diabetes, cardiovascular disease, and mortality. Am Heart J. 2015; 170(2): 380-389.

133. Folsom AR, Chambless LE, Ballantyne CM, et al. An Assessment of Incremental Coronary Risk Prediction
Using C-Reactive Protein and Other Novel Risk Markers The Atherosclerosis Risk in Communities Study.
Arch Intern Med. 2006; 166(13): 1368-1373.

134. Miller M, Zhan M, Havas S. High attributable risk of elevated C-reactive protein level to conventional coronary
heart disease risk factors: the Third National Health and Nutrition Examination Survey.
Arch Intern Med. 2005; 165(18): 2063-2068.

135. Ford I, Shah ASV, Zhang R, et al. High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary
Heart Disease. J Am Coll Cardiol. 2016; 68(25): 2719-2728.

136. Everett BM, Zeller T, Glynn RJ, Ridker PM, Blankenberg S. High-Sensitivity Cardiac Troponin I and B-Type
Natriuretic Peptide as Predictors of Vascular Events in Primary Prevention. Circulation. 2015; 131: 1851-1860.

137. Blankenberg S, Salomaa V, Makarova N, et al. Troponin I and cardiovascular risk prediction in the general
population: the BiomarCaRE consortium. Eur Heart J. 2016; 37(30): 2428-2437.

138. Omland T, de Lemos JA, Holmen OL, et al. Impact of Sex on the Prognostic Value of High-Sensitivity Cardiac
Troponin I in the General Population: The HUNT Study. Clin Chem. 2015; 61(4): 646-656.

139. Lew J, Sanghavi M, Ayers CR, et al. Sex-Based Differences in Cardiometabolic Biomarkers.
Circulation. 2017; 135: 544-555.

140. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, et al. Plasma natriuretic peptide levels and the risk
of cardiovascular events and death. N Engl J Med. 2004; 350: 655-663.

141. Geng Z, Huang L, Song M, Song Y. N-terminal pro-brain natriuretic peptide and cardiovascular or all-cause
mortality in the general population: A meta-analysis. Sci Rep. 2017; 7: 41504.

142. Patterson CC, Blankenberg S, Ben-Shlomo Y, et al. Which biomarkers are predictive specifically for cardiovascular
or for non-cardiovascular mortality in men? Evidence from the Caerphilly Prospective Study (CaPS).
Int J Cardiol. 2015; 201:113-118.

143. Jacobson TA. Lipoprotein(a), cardiovascular disease, and contemporary management.

Mayo Clin Proc. 2013; 88(11): 1294-1311.

144. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.
JAMA. 2002; 288(16): 2015-2022.

145. 1Epps KC, Wilensky RL. Lp-PLA2 – a novel risk factor for high-risk coronary and carotid artery disease.
J Intern Med. 2011; 269: 94-106.

146. World Health Organization. Top 10 Causes of Death Fact Sheet.

http://www.who.int/mediacentre/factsheets/fs310/en/. Accessed November 9, 2017. Updated January 2017.

147. Colon PJ, Greene DN. Biotin Interference in Clinical Immunoassays. J Appl Lab Med. 2018, jalm.2017.024257;
DOI:10.1373/jalm.2017.024257.

148. Wu AHB, Christenson RH, Greene DN, et al. Clinical Laboratory Practice Recommendations for the Use of Cardiac
Troponin in Acute Coronary Syndrome: Expert Opinion from the Academy of the American Association for Clinical
Chemistry and the Task Force on Clinical Applications of Cardiac Bio-Markers of the International Federation of
Clinical Chemistry and Laboratory Medicine. Clin Chem. 2018; 64(4): 645-655.

149. Sigurdardottir FD, Lyngbakken MN, Holmen OL, et al. Relative Prognostic Value of Cardiac Troponin I and
C-Reactive Protein in the General Population (from the Nord-Trøndelag Health [HUNT] Study). Am J Cardiol.
2018;121(8):949-955.

150. Warner JV, Marshall GA. High incidence of macrotroponin I with a high-sensitivity troponin I assay. Clin Chem Lab
Med. 2016;54(11):1821-1829.

151. Lam CSP, et al. High-sensitivity troponin I for cardiovascular risk stratification in the general asymptomatic
population: Perspectives from Asia-Pacific. Int J Cardiol. 2019;282:93-98. doi: 10.1016/j.ijcard.2019.01.107.
Epub 2019 Feb 1.

LEARNING GUIDE: CARDIAC 82

LEARNING GUIDE: CARDIAC 83
WWW.CORELABORATORY.ABBOTT

© 2019 Abbott Laboratories. ADD-00061942