3.

LITERATURE REVIEW

In studies of disease prevalence by the World Health Organization (WHO), MI

was defined by a combination of two of three characteristics: typical symptoms (i.e.,
chest discomfort), enzyme rise and a typical ECG pattern involving the development
of Q waves. However, current clinical practice, health care delivery systems, as well
as epidemiologic studies and clinical trials, all require a more precise definition of MI.
Furthermore, the advent of sensitive and specific serologic biomarkers and precise
imaging techniques necessitate reevaluation of established definitions of MI. The
resulting increase in the sensitivity of the defining criteria for MI would mean more
cases identified; in contrast, an increase in specificity would lessen the number of
false positive MIs. Such changes in definition might have a profound effect on the
traditional monitoring of disease rates and outcomes (The Joint European Society of
Cardiology/American College of Cardiology Committee, 2000).

Myocardial cells are considered to be non-viable when some basic aspect of

cell behavior no longer functions. When CAD is present, the progression of
atherosclerosis causes arterial and stenosis and a gradual loss of arterial compliance,
resulting in a temporary reduction in blood flow and oxygen supply to meet demand
(myocardial ischemia). A principal symptom is chest pain upon exertion, believed to
be caused by lactate accumulation. Other changes include electrical conduction
abnormalities and loss of contractile function in the affected muscle. The loss of
functional integrity in ischemic but viable myocardium can be reversed if blood flow
is restored to the ischemic regions. However, when the flow is not restored,
insufficient oxygenation eventually causes the cells to die (myocardial infarction).

Two primary cellular functions can be used to measure viability: membrane

ion transport and intermediary metabolism. Under normal circumstances the sodium-
potassium (Na-K) ATPase membrane pump maintains cell function and volume
through high extracellular sodium ion concentration and high intracellular potassium
ion concentration. It is believed that the energy available for the pump is decreased
during ischemia, so that sodium ion along with chloride ions and water accumulate
within the cell and potassium ions leak out into the extracellular space. This process
decreases the intracellular-extracellular potassium ion concentration ratio and
produces a marked effect on membrane polarity and heart muscle function. This
disparity in ions shift is the basis for using potassium analogues such as 201Tl+ and
82Rb+ for imaging. These agents participate in the ion transport process in a manner
similar to potassium and are able to assess membrane integrity and cellular viability.
(Richard J. Kowalsky, Steve W. Falen; Radiopharmaceuticals in Nuclear Pharmacy
and Nuclear Medicine: 2nd edition)

3.1 Anatomy and Physiology of Coronary Circulation

When interpreting myocardial perfusion tomograms, it is often useful to

comment on the localization of disease to particular arterial territories, but it is also
important to note that the distribution of the coronary arteries is variable.

The adult heart weighs about 300 g and holds approximately 500 ml of blood.
The heart is located obliquely in the lower portion of thoracic cavity between the
lungs. The myocardium receives its oxygen supply from the right and left main
coronary arteries which arise from the aortic sinuses just above and behind the aortic
valve leaflets. The two coronary arteries give rise to branch that run along the outer
(epicardial) surface of the heart.

The left and right coronary arteries arise from the left and right coronary artery
sinuses, just distal to the aortic valve. Within 2.5 cm of its origin the left main
coronary divides into the left anterior descending artery (LAD), which runs in the
anterior interventricular groove, and the left circumflex artery (CX), which runs
posterior in the atrioventricular groove. The LAD gives branches to supply the
anterior part of the septum (septal perforators) and the anterior wall and the apex of
the left ventricle. The CX gives marginal branches that supply the lateral, posterior
and inferior segment of the left ventricle.

The right coronary artery (RCA) runs in the right atrioventricular groove,
giving branches that supply the right atrium, right ventricle and inferio-posterior
aspect of the left ventricle. The posterior descending artery run in the posterior
interventricular groove and supplies the back of the heart. This vessel is a branch of
the RCA in approximately 90% of people (dominant right system) and supplied by the
CX in the remainder (dominant left system) .The exact coronary anatomy varies
greatly from person to person and there are many normal variants. (Davidson, 2012)

The normal coronary blood flow is about 0.6 to 0.8 ml/min/g of myocardium.
With exercise or pharmacologic stress, however, both coronary flow and the cardiac
output may increase four to six-fold. Myocardial blood flow is greatest during diastole
because at this time the blood flows fastest through vessels that are not being
constricted by the surrounding cardiac muscle. When the narrowing of a coronary
vessel diameter is less than 50% of the diameter of the vessel, the effect on blood flow
generally is clinically significant. As diameter narrowing approaches 70%, the lesions
become much more haemodynamically significant; particularly during exercise.

The collaterals constitute direct arterial connection between one coronary

artery and another. If a coronary is occluded, the collateral may provide some degree
of arterial blood supply beyond the obstruction, thus protecting the myocardium distal
to the obstruction. After acute coronary occlusion of a proximal coronary artery,
small intramural collateral can supply less than 10% of the normal flow, and a more
extensive and predictable amount of myocardial damage results. However, in the
event of gradual chronic coronary artery obstruction, this small collateral may greatly
enlarge over time. Even after complete obstruction of the diseased coronary artery,
well-developed coronary collateral may provide normal or near-normal flow to the
distal segment of the diseased artery. Although the flow rate may be normal at rest,
the capacity to augment myocardial blood flow during exercise or stress (coronary
reserve) is usually limited in collateral vessels. (Fred A Mettler, Milton J Geriberteau,
1998).
Figure 3.1 - Anatomy of coronary arterial system

3.2 Pathophysiology of Coronary Artery Disease

Coronary blood flow brings oxygen to myocytes and removes waste products
such as carbondioxide , lactic acid , and hydrogen ions.The heart has a tremendously
high metabolic requirement ; although it account for only 0.3% of body weight, it is
responsible for 70% of the bodys resting oxygen consumption. Cellular ischaemia
occurs when there is either increased demand for oxygen relative to maximal arterial
supply or an absolute reduction in oxygen supply. Although situation of increased
demand such as thyrotoxicosis and aortic stenosis can cause myocardial ischaemia,
most clinical cases are due to decreased oxygen supply. Reduced oxygen supply can
rarely arise from decreased oxygen content in blood – such as occurs in carbon
monoxide poisoning or anaemia – but more commonly stems from coronary artery
abnormalities, particularly atherosclerotic disease. Myocardial ischaemia may arise
from a combination of increased demand and decreased supply.
 Atherosclerosis of large coronary arteries remains the predominant cause of
angina and myocardial infarction. Raised fatty streaks, which appear as yellow spots
or streaks in the vessel walls, are seen in coronary arteries in almost all members of
population by 20 years of age. They are found mainly in areas exposed to increased
shear stress such as bending points and bifurcation and are thought to arise from
isolated macrophage foam cells migrating into area of minimal chronic intimal
injury . In many people this process progress, with additional migration of foam cell,
smooth muscle cell proliferation, and extra cellular fat and collagen deposition. The
extent and incidence of these advanced lesions vary among persons in different
geographic regions and ethnic groups.

The underlying pathophysiologic processes differ for each clinical

presentation of coronary artery disease. In patients with stable angina, fixed
narrowing of one or several coronary arteries is usually present.Because the large
coronary arteries usually function as conduits and do not offer resistance to flow, the
arterial lumen must be decreased by 90% to produce cellular ischemia when the
patient is at rest. However, with exercise, a 50% reduction in lumen size can lead to
symptoms. In patients with unstable angina, fissuring of the atherosclerotic plaque can
lead to platelet accumulation and transient episodes of thrombotic occlusion, usually
lasting 10 -20 min. In addition, platelet release of vasoconstrictive factors such as
thromboxane A2 or serotonin and endothelial dysfunction may cause vasoconstriction
and contribute to decreased flow. In myocardial infarction, deep arterial injury from
plaque rupture may cause formation of a relatively fixed and persistent thrombus.

The heart receives its energy primarily from ATP generated by oxidative
phosphorylation of free fatty acids, although glucose and other carbohydrate can be
utilized. Within 60s after coronary artery occlusion, myocardial oxygen tension in
affected cells falls essentially to zero. Cardiac stores of high energy phosphates are
rapidly depleted, and the cell shift rapidly to anaerobic metabolism with consequent
lactic acid production. Dysfunction of myocardial relaxation and contraction occurs
within seconds, even before depletion of high- energy phosphates occur.
 The biochemical basis of this abnormality is not known. If perfusion is not
restored within 40-60 min, an irreversible stage of injury characterized by diffuse
mitochondrial swelling, damaged to cell membrane and marked depletion of glycogen
begins. The exact mechanism by which irreversible damage occurs is not clear, but
severe ATP depletion, increased extracellular calcium concentration, lactic acidosis,
and free radicals have all been postulated as possible causes. In experimental
preparations, if ischaemic myocardium is perfused within 5 min, systolic function
returns promptly where as diastolic abnormalities may take up to 40 min to normalize.
With prolong episodes of ischaemia up to 1 hour –it may take upto 1 month to restore
ventricular function. When the heart demonstrate this prolong period of decreased
function despite normal perfusion, the myocardium is said to be “stunned”. The
biochemical basis for stunning is poorly understood. If perfusion occurs later or not at
all, systolic function often will not return to the affected area. (Stephen et al, 2006)

Figure 3.2 – Histology of coronary vessel

The causes of coronary artery disease (ischemic heart disease) are as follow:

1. The coronary blood flow to a region of the myocardium may be reduced by an

obstruction due to artheroma, thrombo-embolic phenomenon and coronary artery
spasm.

2. There can be a decrease in the flow of oxygenated blood to the myocardium

due to anemia and hypotension.
3. An increased demand for oxygen may occur owing to an increase in cardiac
output (e.g., during exercise or in thyrotoxicosis) or myocardial hypertrophy (e.g.
from the aortic stenosis or hypertension). (Robbin, pathologic basic of disease, sixth
edition)

3.2.1 Myocardial response to ischaemic injury

Reversible injury: Within seconds of the onset of severe ischemia, there is an

abrupt change from predominantly aerobic to anaerobic metabolism. This results in a
drastic decrease in the production of high energy phosphates (HEP), namely
adenosine triphosphate (ATP) and phosphocreatine (PCr). Reversible injury is
difficult to identify with light microscopy, although disturbances in fluid and ionic
homeostasis may manifest in water vacuoles (hydropic change) and cellular swelling.
Electron microscopy is best suited to identify the ultrastructural changes associated
with reversible injury, namely mitochondrial swelling, loosening of intracellular
attachments, the presence of small, lipid-rich amorphous mitochondrial densities,
dilatation of the sarcoplasmic reticulum (SR), disaggregration of SR polysomes, and
myofibrillar relaxation. In canine model of severe ischaemia, flow ≤ 10% of normal,
these ultrastructural defects are entirely reversible if reperfusion occurs within 20-40
minutes. The myocardium is functionally sensitive to ischemia, however, and will
exhibit marked contractile dysfunction within 1 minute of acute onset. The length of
time of this contractile impairment remains profoundly influenced by the severity and
duration of ischaemic period and clearly by the development of irreversible injury.

Irreversible Injury: Irreversible injury, i.e., infarction follows a distinct

geographic pattern in the myocardium, beginning in subendocardial tissue and
progressing towards the subpericardium. In canine, experimental models of acute
myocardial infarction (AMI), myofibril death begins after approximately 40 minutes
and reaches its full, transmural extent in as little as 3-6 hours. The time course is
somewhat more protracted in humans, taking generally as long as 6-12 hours for the
complete infarction of the myocardium at risk. Despite the presence of markers of loss
of cellular integrity, i.e., cardiac enzymes and proteins in the serum as early as 2 hours
post infarction; the necrotic changes are seldom evident, histologically, until at least
4-12 hours after onset.

The microscopic changes associated with irreversible myocyte damage include

the denaturation of cytoplasmic proteins, swelling, and enzymatic digestion of
organelles and sarcolemma. On a gross level, immature myocardial infarcts have
poorly defined borders. The margins of the infarcts demonstrate inflammatory
hyperemia, which is incited by the necrotic tissue itself. With time, macrophages will
arrive on the scene of injury and engulf the remaining cellular debris. Finally,
connective tissue grows into the area of fibrinous exudates, ultimately transforming
the original site of necrosis into a mature, collagenous, noncontratile scar.

In addition to the obvious early necrotic process, apoptosis or ‘programmed

cell death’ is now recognized as a consequence of ischaemia and reperfusion. Unlike
necrosis, however, the apoptotic process incites no inflammatory reaction and it is
therefore much more difficult to identify with conventional histology. Techniques that
detect DNA fragmentation- a hallmark of apoptosis- have confirmed that it is a
contributor to irreversible injury in the setting of AMI. The time course of apoptotic
cascade in the context of myocardial ischaemia is still unclear. In the greater scheme
of irreversible ischaemic damage, apoptosis is believed to contribute very little, on the
order of ~8% of total myocyte deaths. However, a large number of earlier basic
studies of myocardial infarction using isolated heart preparations or intact animal
models may have underestimated the extent of myocardial necrosis by not waiting a
sufficient long period of time for the evolution of apoptosis , a process that appears to
require at least days to become manifest.

Reperfusion: The overwhelming priority in the acute management of patient

post-AMI is to limit the extent of necrosis. With severe ischaemia of less than
approximately 6 hours duration, restoring the blood supply to normal or near normal
level can salvage at least some fraction of the area at risk. Thrombolytic therapy or
angioplasty is frequently used when electrocardiographic evidence of transmural
ischaemia is evident, in an attempt to establish reperfusion. (Rebecca E. Thornhill,
Frank S. Prato, Gerald Wisenberg; 2002)

3.3 Investigation for Diagnosis of Coronary Artery Disease

The basic for the diagnosis of coronary artery disease is history of angina pectoris,
myocardial infarction, cardiac failure, or arrhythmia. Non-specific abnormalities such
as increased erythrocyte sedimentation rate (ESR) and a polymorphonuclear
leucocytosis may occur in the first few days following myocardial infarction.
Enlarged heart size (increased cardiothoracic ratio) and calcification in the
cardiovascular system can be seen on the postero-anterior and lateral chest X-rays.

Various invasive and non-invasive diagnostic modalities have been used to detect
abnormalities in coronary circulation, degree of myocardial ischemia, and
dysfunction.

The non-invasive diagnostic modalities are:

1. Cardiac enzymes

2. Resting electrocardiography (Resting EKG)

3. Continuous EKG monitoring (Holter monitoring)

4. Exercise EKG(Exercise tolerance test –ETT)

5. Echocardiography
6. Cardiac scintigraphy (Radionuclide study)

7. Magnetic resonance imaging (MRI), and

8. CT scanning.

The only invasive diagnostic modality is:

9. Coronary angiography.

3.3.1 Cardiac enzyme

Necrotic area of cardiac tissue releases cellular enzymes, such as creatine

phosphokinase (CK), aspertate aminotransferase (AST), lactate dehydrogenase
(LDH) and proteins like troponin T, troponin I and myoglobin. Amore sensitive and
cardiospecific isoform of enzyme CK-MB starts to rise at 4-6 hours, peak at about 12
hours and falls to normal within 48-72 hours. The most sensitive markers of
myocardial cell damage are the cardiac troponin T and I, which are released within 4-
6 hours and remain elevated for up to 2 weeks. The American College of Cardiology
and the European Society of Cardiology defined MI as a typical rise in cardiac
troponin T or I, or CK-MB above the 99th centile of normal.

3.3.2 Resting Electrocardiography

The electrocardiography (EKG) is a recording of the electrical activity of the

heart. The value of EKG in the diagnosis and localization of ischemic injury and acute
myocardial infarction is irrefutable. Serial EKG is more helpful than an isolated
recording, as EKG may be normal in between the attacks. In orthodox EKG language,
acute myocardial injury implies abnormal ST segment shifts; myocardial necrosis
implies abnormal Q waves and myocardial ischemia implies T wave inversion. The
electrocardiography (EKG) is particularly useful for the diagnosis of myocardial
infarction. In the majority of cases, the development of a full thickness myocardial
infarction is associated with evolving EKG features. The EKG changes are best seen
in the leads which ‘face’ the infracted area.
3.3.3 Continuous EKG Monitoring (Holter Monitoring)

This is a technique for recording transient changes such as a brief paroxysm of

tachycardia, an occasional pause in the rhythm, or intermittent ST segment shifts. A
conventional 12-leads EKG is recorded in less than a minute and usually samples less
than 20 complexes. In a 24-hour period, over 100,000 complexes are recorded.
Continuous EKG recordings may also be used to monitor the level of the ST segment
and to record transient ST segment depression. Both arrhythmia and ST, T waves
changes of ischaemia can be detected in this way and the time of their occurrence can
be correlated with the events in the patient’s life. (Cheitlin MD, ed al)

3.3.4 Exercise EKG (Exercise Tolerance Test)

This is a technique to assess the cardiac response to exercise. The EKG is recorded
while the patient is walking or running on a motorized treadmill machine or cycles on
a stationary cycle ergometer.

3.3.5 Echocardiography

It is a non-invasive procedure that causes the patient no discomfort and is harmless.

Studies are performed by a physician or a technician and a comprehensive
examination takes 15-30 minutes. It uses echoes of ultrasound waves to map the heart
and study its function.

A technique called M-mode is used to document in detail the motion patterns

of individual structures. M-mode recordings are obtained from the left parasternal
position (long and short axis planes) to document motion patterns of the aorta, aortic
valve, left atrium, mitral valve and the ventricles. The echo signals of heart valves are
indicated by zigzag lines.

3.3.6 Magnetic Resonance Imaging (MRI)

In MRI, a powerful magnetic field is used to line-up the protons in the hydrogen
atoms of the body, each of which can be thought of as a tiny magnet. A
radiofrequency emission distorts this line-up, but when the radiowaves are turned off,
the atoms return to their previous position and gives off energy. This energy can be
reconstituted as an image. MRI of the heart is complicated because the heart is a
moving structure, but the technique is already finding clinical application for imaging
vascular structures.

3.3.7 Computed Tomographic Imaging (CT)

This is useful for imaging the chamber of the heart, the great vessels, the pericardium
and surrounding structures. In practice it is most useful for imaging the aorta in
suspected aortic dissection.

3.3.8 Cardiac scintigraphy (Radionuclide Scan)

The major techniques used in nuclear cardiology can be categorized as: first pass
angiocardiography, multigated blood pool imaging, myocardial perfusion imaging and
receptor and metabolic imaging. The data derived from these studies can be used for
diagnosis, prognosis, treatment monitoring and assessment of viability in heart
diseases, particularly in coronary artery disease.

Nuclear imaging technique is primarily used in ischemic heart disease.

Myocardial perfusion imaging is recognized to be the most accurate non-invasive
means of detecting CAD and assessing the severity and extent of perfusion defects in
patients with coronary stenosis. A normal perfusion scan after exercise makes
significant coronary artery disease unlikely.

3.3.8.1 Instrumentation of Radionuclide Scan

Radionuclide imaging to detect CAD can be performed in three different ways.

1. Planar imaging

2. SPECT/CT

3. PET
3.3.8.1.1 Planar imaging

Planar imaging is an acceptable method for performing myocardial perfusion

studies. An Anger gamma camera with a 10 inch diameter detector and ¼ inch crystal
is preferred for planar imaging. An all purpose, parallel hole collimator is used for
planar imaging. A dual window with a 25% window over the 80 keV X-ray peak and
20% window over the 167 keV gamma peak is used for 201 Thallium imaging. A
single 20% window over the 140keV energy peak is used for Technetium-99m
imaging.

Most gamma camera are interfaced to a computer. Digital computers are necessary to
acquire, analyze, store and display a great deal of complex information. The x, y and z
pulses, which are sent to CRT in an analog camera ,are directed to the computer
interface, an analog to digital converter (ADC), which converts the pulses to digital
information.

3.3.8.1.2 SPECT (Single Photon Emission Computed Tomography) imaging

Most nuclear imaging laboratories perform SPECT imaging which was

introduced in the late 1970s.The SPECT imaging approach yields images slices of the
heart without interference of activity from no cardiac or overlapping myocardial
regions and is similar in principle to X-ray computed tomography.
Figure 3.3 – Tomographic image of myocardial perfusion scan

A gamma camera with a large field of view and a 3/8 inch thick crystal is used
for tomographic imaging. Recently, multi-detector camera systems have been
introduced with advanced electronics and significantly improved sensitivity,
resolution, and overall image quality. A high-resolution, parallel-hole collimator is
used to assure higher counting statistics. Energy window is the same as acquired on
computer disk or magnetic tape for data processing. The acquisition is usually
performed on a 128×128 matrix for tomographic imaging.

In SPECT imaging, the scintillation camera rotates around the heart in an 180◦
arc. Detector orbits can be elliptical or circular. Elliptical orbits are characterized by
having the detector closer to the patient during rotation, preserving spatial resolution
as the detector is far from the patient during image acquisition. However, there is
more regional non-uniformity with elliptical orbits, which can create image artifacts.
(Allman, 2002).

The most commonly employed mode of SPECT acquisition is called a step

and shot method. Multiple planar projections (usually 32) are obtained while
travelling through this orbit. Each of the projections is corrected for field non-
uniformity and for misalignment of center of rotation with respect to the
reconstruction matrix.
 Ramp filter (high-pass filter) corrects for the blurring from unfiltered back-
projection. Garcia states that filtered back-projection may be thought of as, first,
extracting the edges of a three dimensional (3-D) radioactive source from different
angles and, second, back-projecting the edges from the different angles to generate the
count distribution in a transaxial tomogram. As a result of enhancing higher
frequencies, the Ramp filter may propagate high-frequency noise, the Ramp filter is
usually combined with a low pass (smoothing) filter (e.g., the Butterworth filter).

After applying a filter to the raw projection images, back-projection is

performed to produce transaxial images. Subsequently, further filtering and three-
dimensional computer reconstruction is performed. Tomographic slices (short axis,
vertical long axis slices) are reconstructed perpendicular to the anatomical axis of the
heart from the transaxial images after reorientation.

As with planar imaging, SPECT images are affected by the relative

distribution of radiopharmaceutical in the heart, as well as by the effect of radiation
attenuation. The major advantage of SPECT imaging is that surrounding organs are
separated in space from the heart, which slows more precise analysis of the regional
distribution of the radiopharmaceutical within the heart.

Acquisition parameters for Gated SPECT technetium-99m tetrofosmin

imaging have been formulated. Images were acquired in 6-degree increments,
35seconds per stop, following the body contour in a noncircular orbit. High-
resolution, low-energy, parallel-hole collimators were used to record data onto a 128 x
128 image matrix. Events registering 140 keV ± 15% were accepted. The detector is
rotated 180 degree arc of rotation beginning at left posterior oblique (LPO) and
ending at right anterior oblique (RAO). Using zoom-1,pixel-4.8mm, detector
configuration is 90, starting angle of -45degree orbit- NCO, images are obtained for
total study period time of 20 minutes.

Gated acquisition using eight time frames per cardiac cycle was done when
possible using the patient's average R-R interval ± 40%. Reconstruction of the raw
data was performed using a Butterworth (Elscint, Boston, MA) filter without
attenuation correction with a cutoff frequency of 0.4cycle/pixel and an order of 5.
After acquisition, the images are reconstructed by using a Cedar – Sinai Quantitative
Gated SPECT processing software. Images were immediately reviewed by a licensed
nuclear cardiologist, with each study read as being normal, abnormal, or equivocal by
visual qualitative and quantitative analysis.

Patient positioning is important in case of SPECT imaging. The most common

cause of suboptimum SPECT 99mTc setamibi imaging is patient motion. Acquisition
parameters for gated SPECT 99mTc sestamibi imaging have been formulated.
Acquisition usually involves using a high-resolution, parallel-hole collimator with a
step-and –shoot circular, patient-centered orbit with 180◦ imaging arc with no zoom
and eight frames per cardiac cycle. Summed frames are prefiltered with a Ramp filter
and then filtered with the 2-D Butterworth filter (critical frequency, 0.52; power,
5.0).Frames are typically reconstructed one pixel thick. Slice display is as single slices
of 6.4 mm thickness or in staged pairs with a thickness of 12 .8 mm.

One of the drawbacks of MPI is the non-homogeneous photon attenuation in

the thorax which may reduce both specificity and sensitivity of MPI. Whereas non-
uniform regional perfusion defects may be misinterpreted as a perfusion defect and
therefore may impact specificity of MPI, sensitivity may be reduced due to
improperly scaling of images to regions suppressed by attenuation, potentially
masking true perfusion defects. Correcting for these attenuation artifacts in cardiac
imaging remains being a challenge because of cardiac and respiratory motion. CT as
part of hybrid SPECT/CT imaging technique seems to have the potential to overcome
these problems as using the CT component for attenuation correction improved the
specificity of SPECT MPI to 80–90 %. However, one needs to take into account, that
despite the fact, that SPECT/CT studies have shown that low- dose CT acquisition is
feasible for attenuation correction in cardiac imaging, a potential misalignment
between emission and transmission data might cause incomplete correction and,
consequently, artificial perfusion defects. Therefore, careful quality control to avoid
reconstruction artifacts is mandatory. It was recently shown that the frequency of
these misalignments is quite high with significant clinical consequences in case they
are not corrected. Notably, mainly because of the lower spatial resolution of SPECT,
the effect of misalignments is less severe for cardiac SPECT/CT compared to cardiac
PET/CT. Usually, the alignment of emission and transmission data is currently
performed manually, which may lead to a relevant variability. However, steps towards
automated methods for quality control have already been made and might offer a
solution to overcome this drawback in the future.

Advantages of SPECT over planar perfusion images are:

1. Improved resolution

2. Differentiation of overlapping myocardial regions

3. Depiction in planes familiar to cardiologists

4. Comparability with other cardio logical imaging techniques such as

echocardiography

5. Color images improve interpretation and presentation

6. Improved sensitivity and specificity of diagnosis

7. Depiction of images in same orientation irrespective of cardiac position, and

8. Improved clinical acceptance and development of further interest (Pennell DJ,

Prvulovich E; 1995)

3.3.8.1.3 PET (Positron Emission Tomography)

Positron emission tomography affords superior spatial resolution compared

with SPECT and also offers the use of wide variety of physiologically, biochemically,
and metabolically useful radiopharmaceuticals. PET is available in a limited number
of institution but provides a horizon for the future of nuclear cardiology. PET studies
of the heart can now also be accomplished using specially modified gamma
scintillation camera with high energy collimators appropriately shielded camera heads
or newly available dural headed coincidence system. In a patient with symptoms
suggestive of coronary artery disease (CAD), an important clinical decision point is to
determine whether a coronary angiogram is necessary for further work-up. A variety
of non-invasive imaging tests, including PET (using rubidium-82) and SPECT scans,
have been investigated as a means of identifying reversible perfusion defects, which
may reflect coronary artery disease, and thus identify patients who may benefit from
further work-up with an angiogram. Below is a summary of the ACC guidelines for
myocardial reperfusion for both SPECT and PET scans in patients with an
intermediate risk of coronary artery disease.

Positron Emission Tomography (PET) affords quantitative noninvasive

imaging of regional concentration of positron-emitting tracers. Various short-lived
positron-emitting tracers are Carbon-11, Nitrogen-13, Oxygen-15, Fluorine-18, and
Rubidium-82.Positrons, positively charged particles, are detected by a pair of
radiation detectors positioned 180◦ from each other and connected by coincidence
circuitry. An unpaired photon that strikes only one of the detectors is not counted or
corrected. Since the two photons were emitted at an angle of 180◦, the site of the
annihilation event can be located within the field between the scintillation detectors.

Static or dynamic transaxial tomographic images of the uptake, retention, and

clearance of positron-emitting tracers in the myocardium can be obtained with the
positron camera. The transaxial images can be reoriented into short-axis and long-axis
sections of the left ventricular myocardium. The static images display the relative
uptake and retention of the positron radionuclide in the myocardium. Dynamic image
acquisition allows measurement of the arterial input function of a radiotracer and what
happens in the myocardium after tracer delivery. Spatial resolution is usually 5-6 mm
full width half maximum (FWHM).Also, the smaller the detector, the higher is the
spatial resolution.

Certain errors can influence the quality of the PET scintigrams. They include
positional changes between transmission and emission images, low count statistics,
partial volume effect, and activity spillover. Corrections for the partial-volume effect
leading to underestimation of true tracer tissue concentrations can be made with
knowledge of regional wall thickness.

In myocardial perfusion study, Nitrogen-13 labeled ammonia and Rubidium-

82 have been used as markers. Their short half-lives have permitted rapid sequential
studies of time varying process, or response to various stresses in investigation of
myocardial ischemia. (ACNP/SNM Task Force in clinical PET. 1987)

3.3.8.2 Radiopharmaceuticals

The ideal tracer for the assessment of myocardial perfusion imaging would
possess the following properties:

• Distribution in the myocardium in linear proportion to blood flow over the

range of values experienced in health and disease,

• Efficient myocardial extraction from the blood on the first passage through the
heart,

• Stable retention within the myocardium during data acquisition,

• Rapid elimination allowing repeat studies under different conditions,

• Ready availability,

• Competitive pricing, and

• Good imaging characteristics (short half life, high photon flux, energy
between 100 and 200 keV, low radiation burden to the patient) (Pennell DJ, ed al
1977)

The radiopharmaceuticals used to evaluate heart disease fall into four main
groups: (1) perfusion agents (SPECT and PET) for evaluation of coronary artery
blood flow and ischemia, (2) blood pool agents for evaluating heart function, (3)
infarct-avid agents for assessing MI, and (4) metabolism agents for assessing
myocardial viability.
 The principle agents used in SPECT imaging are 99mTc-labeled red blood
cells for blood pool studies and 201Tl-thallos chloride, 99mTc-sestamibi, and 99mTc-
tetrofosmin for myocardial perfusion studies.18F-fludeoxyglucose (18F-FDG) is the
main PET agent used for myocardial viability studies. Its reasonably long half-life
allows it to be available from regional PET nuclear pharmacies. The other agents used
in PET imaging are 82Rb-rubidium chloride, 15O-water, 13N-ammonia for perfusion
studies and 11C-acetate and 11C-palmitate of metabolism studies. These agents,
because of their very short half-lives, are primarily used at facilities that have their
own cyclotron and radiochemistry laboratories. Infarct-avid agents for localization
MI, such as 99mTc-pyrophosphate, are now infrequently used; however, newer agents
are being developed for this application. (Richard J. Kowalsky, Steve W. Falen;
Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine: 2nd edition)

3.3.9 Percutaneous Coronary Angiogram

Coronary angiography is an x-ray examination of the coronary arteries which

are the tubes a few millimeters wide that lie on the outside surface of the heart, taking
blood to the heart muscle. Just as an engine needs petrol, the heart needs blood to do
its job of pumping blood around the body. Slow build-up of fatty plaque within the
artery wall can cause the artery to narrow, leading to reduced blood flow. Sudden
changes in the plaque may cause angina to worsen or may cause a heart attack. Other
tests performed during the coronary angiogram include measuring pressures within
the heart chambers, checking function of some of the valves and checking how well
the heart muscle is pumping. Percutaneous Coronary Intervention (PCI) means ways
of opening up narrowings in coronary arteries using fine tubes called catheters,
introduced from the wrist or groin. Severe narrowings may be treated with stents (fine
mesh tubes).

3.4 Assessment of Myocardial Viability

1. Stress Echocardiography

2. Single-Photon Emission Computed Tomography

3. Positron Emission Tomography (PET)

4. Magnetic Resonance Imaging (MRI)

3.4.1 Stress Echocardiography

In present clinical applications, the technique requires pharmacological stress,

either with an inotrope (dobutamine) or a vasodilator (typically, dipyridamole). The
hallmark of echo viability is the presence of stress-induced contractile reserve. With
increasing doses of dobutamine, viable tissue exhibits a biphasic response with
improved contractility at low doses (5 to 10 μg/kg per minute) and regression to
abnormal wall motion at higher doses (≥15 μg/kg per minute). Dipyridamole leads to
transiently increased coronary flow, which leads to improved contractility in viable
myocardium. Stress echo has numerous limitations that impair its sensitivity. Optimal
acoustic windows are often difficult to obtain. Echocardiography is generally assessed
qualitatively with high interobserver variation. Lastly, diagnostic accuracy is reduced
in the setting of increasing extents of regional and global LV dysfunction. Recent
innovations have been proposed to improve accuracy. One approach is tissue Doppler
imaging (TDI), which is a modification of conventional Doppler and measures
myocardial velocity. In theory, viable tissue retains enough sufficient active
contraction that is detected as positive velocities by TDI. TDI has been used to
differentiate transmural from nontransmural infarction after reperfusion. TDI has
recently been shown to improve the accuracy of dobutamine echo in detecting
hibernating myocardium.

3.4.2 Single-Photon Emission Computed Tomography

Some routinely used tests of SPECT are described as follow-

3.4.2.1 201Tl Stress Redistribution

The uptake of 201Tl is an energy-dependent process requiring intact cell membrane

integrity, and the presence of 201Tl implies preserved myocyte cellular viability. The
redistribution properties of 201Tl have been used as an important marker of
myocardial viability in stress imaging followed by a 3- to 4-hour redistribution image.
The presence of a reversible perfusion defect and/or preserved 201Tl uptake on the 3-
to 4-hour redistribution images is an important sign of regional viability.

3.4.2.2 201Tl Reinjection

The 2 most widely studied protocols for assessing viability in the presence of an
inconclusive result on initial stress/ redistribution imaging involve 201Tl reinjection
and late redistribution imaging. The presence of a severe 201Tl defect after
reinjection identifies areas with a very low probability of improvement in function.

3.4.2.3 Late Redistribution Imaging

Although improvement in uptake on late redistribution images (24 to 48 hours after

the initial stress 201Tl injection) has good positive predictive value for identifying
regions with potential improvement in function, the negative predictive value is
suboptimal in some patients.

3.4.2.4 201Tl Rest Redistribution

The identification of a “reversible resting defect” (in 3- to 4-hour versus 15- to

20-minute images) generally reflects preserved viability. The finding appears to be an
insensitive though specific sign of potential improvement in regional function.

3.4.2.5 99mTc-Sestamibi and Tetrofosmin

Although the 99mTc-based tracers sestamibi and tetrofosmin do not share the
redistribution properties of 201Tl, their performance characteristics for predicting
improvement in regional function after revascularization appear to be similar to those
seen with 201Tl.

Sensitivity and specificity of radionuclide study in myocardial perfusion and

myocardial viability Overall sensitivity of 90% with 99mTc- sestamibi and 83% with
201Tl, for individual vessel 82% with 99mTc-MIBI and 66% with 201Tl , and the
specificity of 93% with 99mTc-MIBI and 80% with 201Tl for those who are normal
arteriogram, for low likelihood 100% with 99mTc-MIBI and 77% with 201Tl, for
individual vessel 77% with 99mTc-MIBI and 75% with 201Tl.

The sensitivity of SPECT imaging for the diagnosis of coronary artery disease
was 90% with either thallium-201 or technetium-99m. The specificity of SPECT
myocardial perfusion scan was 60 to 70%. The normalcy rate with <5% likelihood of
coronary artery disease was 90% or better. (Frans J.Th.Wacker, 1996)

In detection of coronary artery disease, Kyin Myint studied same-day stress-

rest protocol by using 99mTc-MIBI, overall sensitivity was 85%, with one vessel
disease was 70%, two vessel disease was 88.9% and for three vessel disease
was100%. (Kyin Myint, 1998)

A study of Gated SPECT myocardial perfusion imaging at rest in YGH

revealed sensitivity of 85.7%, accuracy of 70.49% and negative predictive value of
93.9%. (Su Thet Oo, 2008)

The study of the assessment of myocardial viability by nitroglycerine

augmented gated single photon emission computed tomography (Gated SPECT)
myocardial perfusion imaging technique in cases of previous myocardial infarction
(MI) and chronic coronary artery disease at YGH showed 35 (56.98%) out of
61patients demonstrated viable myocardium. (Htin Zar, 2014)

99mTc labeled myocardial perfusion agents which is used in assessment of the

viability of myocardium .In recent years, several 99mTc labeled myocardial perfusion
agents have been under investigation to determine their efficacy in assessing regional
myocardial blood flow and cellular viability. (Berman, Beller, 1990, 1991)

These can be classified as follow:

1. Isonitriles group

2. Boronic acid adduct of technetium dioxime (BATO), and

3. Diphosphine compounds
3.4.2.5.1 Isonitriles Group

In 1982, Jones et al. developed several compounds in the hexakis-alkyl-isonitrile

technetium (I) action family that concentrated in the human myocardium. The 99mTc
labeled isonitrile complexes have the general formula [Tc(CNR)6]+, where R is an
alkyl group (such as methyl, ethyl, n-propyl, tertiary butyl or methoxy-isobutyl
substituents).

In 1984, Holman et al. presented the first human 99mTc perfusion imaging
studies, done with 99mTc-tertiary butyl isonitrile (TBI). The clinical usefulness of
this agent was hampered by persistently high hepatic and lung activity. To minimize
the uptake of TBI in liver and lung relative to myocardium, a number of other
isonitriles were investigated.99mTc-carboxyl isopropyl isonitrile (CPI) and 99mTc-
hexakis-2-methoxy-2-isobutyl isonitrile (HEXAMIBI), were tested in human subjects.
CPI showed prompt hepatobiliary clearance, minimal lung uptake, and faster lung
clearance and gave reasonably good myocardial images with high myocardial-to-
background ratios. However, its liver uptake is appreciably high.

Among these agents, HEXAMIBI showed the most favorable myocardial-

background ratio for myocardial imaging of any of the isonitriles. It has high
myocardial uptake combined with rapid clearance from blood pool, liver and lung.
High-quality myocardial images can be obtained with this agent at 5-10 minutes after
injection, and retention of the tracer in the myocardium is longer than CPI. 99mTc
sestamibi has emerged as the most clinically applicable of various isonitrile
compounds.

99mTc-MIBI consists of 6-methoxy-isobutyl-isonitrile molecules complexing

an atom of 99mTc.It is lipophilic and after injection it distributes in the myocardium
in proportion to blood flow and is about 1.4% of injected dose during exercise and
1.0% at rest. Like 201Tl, 99mTc-MIBI underestimates the blood flow at high flow
rates.
 99mTc-MIBI diffuses out of the capillary into cardiac myocytes and is
associated with mitochondria within the cell. Cardiac uptake of 99mTc-MIBI is
therefore dependent on normal mitochondrial function. Uptake is depressed and
washout is increased when there is cellular hypoxia secondary to severe myocardial
ischemia. Blood clearance studies indicate rapid clearance with a half-life of 4.3
minutes at rest and 1.6 minutes under exercise conditions. First-pass extraction is 40-
60% which is lower than 201Tl.

The maximum dose recommended in UK is 300MBq for planar imaging and

400MBq for tomography for the two-day protocol. For the one-day protocol, total
doses of 800MBq and 1000MBq respectively are permitted. The injection of
1000MBq 99mTc-MIBI is associated with an effective dose equivalent of
approximately 8mSv. Highest concentration of activity is found in the liver,
gallbladder and heart. Activity accumulating in the liver and gallbladder is excreted
into the bowel, which receives the highest radiation doses from 99mTc-Sestamibi.

3.4.2.5.2 Boronic Acid Adduct of Technetium Dioxime (BATO)

It is 99mTc teboroxime. The trade name is Cardiotec, manufactures by

Amersham International. It is a highly lipophilic agent. After injection, it is regionally
distributed in the myocardium in proportion to blood flow. Myocardial uptake is
evident by one minute after injection and occurs by diffusion. Following intravenous
injection, approximately 90% of the dose is cleared from the blood after the first
circulation. The proportion of the injected dose taken up by the myocardium is
relatively high, being more than 3% at one minute. It has a very short half-life,
approximately 12 minutes, which mandates a speedy imaging protocol.

3.4.2.5.3 Diphosphine Compounds

There are two forms of diphosphine compounds, such as 99mTc-tetrofosmin,

and 99mTc-phosfurimine.
 99mTc tetrofosmin which is cationic complex [99mTc-(tetrofosmin)2O2]+.
The trade name is Myoview, manufactured by Squibb. It has been synthesized and
evaluated for possible use as myocardial perfusion agent.99mTc tetrofosmin is a
lipophilic agent and is rapidly cleared from the blood after intravenous injection, with
less than 5% residual activity by 10 minutes. Uptake in the myocardium is rapid,
reaching a maximum of 1.2% of the injected dose within 5 minutes. The complex
shows good myocardial uptake with rapid clearance from blood and liver and little
uptake in lungs. The mechanism of myocardial uptake is again related to diffusion
along an electro potential gradient. It is regionally distributed within the myocardium
in proportion to blood flow at the time of injection. As with other flow tracers,
relative 99mTc tetrofosmin activity underestimates flow at high flow rate above 2.0
ml/ min/g. The radio pharmacy preparation is quite straight forward with labeling in
the kit vial at room temperature.

99mTc phosfurimine (Q12) is taken up in the myocardium in proportion to

blood flow, like the other 99mTc tracers. Gerson et al. showed this agent no
significant “redistribution” over time, similar to what has been reported for the other
99mTc labeled perfusion agents. They also showed that 99mTcQ12 myocardial
activity is proportional to actual myocardial blood flow from 0-2ml/min/g. There was
good overall concordance between 201Tl and 99mTcQ12 in normal and irreversible
regions.

3.4.2.6 Nitrate which is used in testing of myocardial viability

All forms of nitroglycerin preparations release nitric oxide in vascular smooth

muscle cells. Nitric oxide activates soluble guanylyl cyclase, leading to the production
of guanosine 3, 5-cyclic monophosphate (cGMP) that facilitates smooth muscle cell
relaxation through the dephosphorylation of myosin light chains. This inhibits the
interaction between myosin and actin and prevents smooth muscle contraction.
Nitroglycerin causes marked relaxation of all components of the vascular system and
dramatically decreases pulmonary vascular pressure, intraventricular pressure,
chamber size, and cardiac output. Nitroglycerin therefore may improve myocardial
perfusion via a reduction in wall tension (Laplace relation) and myocardial oxygen
demand.

Nitroglycerin decreases coronary vascular resistance and increases the

diameter of large conduit vessels (>100μm); the degree of smaller vessel dilation
exceeds that of larger vessels only after the highest doses of nitroglycerin. However,
total coronary flow does not increase in the presence of obstructive CAD.
Nitroglycerin selectively dilates micro vessels distal to coronary stenosis, but
myocardial perfusion remains constant. The anti-ischemic effect of nitroglycerin
might also be attributable to the redistribution of coronary flow from normal to
ischemic myocardium through dilation of collateral vessels.

Nitroglycerin may also preserve myocardial perfusion through the inhibition

of platelet thrombus formation. Nitric oxide is capable of activating soluble guanylyl
cyclase in platelets. This stimulates cGMP production and inhibits thrombin-induced
platelet aggregation to adenosine diphosphate by approximately 80%, and it decreases
platelet aggregation to thrombin. Nitric oxide also up-regulates endothelial cell cyclo-
oxygenase activity, resulting in a marked increase in the release of the stable
metabolite of prostaglandin I2, 6-keto prostaglandin F1alpha, and this metabolite
enhances the antithrombotic effects of nitrates by approximately 10-fold. Continuous
nitroglycerin infusion markedly decreases platelet thrombus formation without
affecting coronary flow. The antiplatelet effects are subject to tolerance.

3.4.2.7 Effects of nitrates on myocardial viability

Nitrates have been used in rest studies to enhance the ability of MPI to detect
viable myocardium because they decrease myocardial oxygen demand and improve
flow to ischemic areas (by directly dilating stenosed coronary arteries feeding the
ischemic myocardium or by redistributing collateral flow to the ischemic
myocardium). In positron emission tomography (PET) studies, pre-treatment with
nitrates increased tracer uptake in the ischemic myocardium compared with that in the
nonviable myocardium, resulting in improved viability detection. Pre-treatment with
nitrates improved detection of viable myocardium and predicted post-
revascularization recovery in different studies that used resting MPI with the
technetium-labeled tracers (tetrofosmin, sestamibi) and with thallium-201. In patients
with ischemic cardiomyopathy, the prognostic value of SPECT MPI after nitrate was
comparable to that of PET imaging. (J Am Coll Cardio; 2008)

3.4.3 PET

Positron tracers of blood flow and metabolism have been extensively studied
for evaluation of myocardial viability. The most commonly used PET protocol
involves evaluation of myocardial glucose metabolism with 18F-FDG in conjunction
with PET or SPECT examination of MBF with 13N ammonia or 99mTc-sestamibi,
respectively. This approach appears to have slightly better overall accuracy for
predicting recovery of regional function after revascularization than do single-photon
techniques. The magnitude of improvement in heart failure symptoms after
revascularization in patients with LV dysfunction correlates with the preoperative
extent of 18F-FDG “mismatch” pattern.