Molecular Imaging in the clinical evaluation of ... · resting MPI are being compared with myocardial viability study using new integrated diagnostic imaging modality Positron Emission

Abstract— Intact myocardial perfusion is a function of normal

sodium potassium adenosine triphosphatase (ATPase) pump

while normal myocardial viability is the function of intact

mitochondrium. Both molecular processes can be clinically

manipulated using non-invasive molecular imaging techniques.

Despite being a routine procedure, myocardial perfusion

imaging has inherent limitation in verifying viable myocardial

segments. Fluorodeoxyglucose (FDG), an analogue of glucose

molecule is a gold standard biomarker in demonstrating

viability. Integrating the two molecular processes in a clinical

study will define and classify viable from non viable

myocardial segments. The function of viable myocardial

segments may benefit revascularization procedure while

function has not been successfully revearsible after

revascularization in infarcted scared myocardium.

The objective of this study is to assess the concordant and

discordant results obtained when hypoperfused segments at

resting MPI are being compared with myocardial viability

study using new integrated diagnostic imaging modality

Positron Emission Tomography Computed Tomography

(PET/CT) with flourodeoxyglucose (FDG) as the biomarker.

The usefulness of flourodeoxyglucose as a potential viability

PET agent in the assessment of myocardium is elucidated

from this study.

I. METHODOLOGY

he study was conducted in collaboration between

Diagnostic Nuclear Imaging Centre, Universiti Putra

Malaysia (UPM), Cardiology Unit, Universiti Malaya

Medical Centre and Department of Cardiology and

Abdul Jalil Nordin1, Wan Himratul Azliza Wan Harun2 , Ahmad Zaid Fatah

Azman1, Ahmad Fazli Abdul Aziz1, Fathinul Fikri Ahmad Saad1, Zul Hilmi

Yaakob2 ,Annuar Rapaie3 , Wan Azman Wan Ahmad 2

1 Diagnostic Nuclear Imaging Centre, Universiti Putra Malaysia 2 Cardiology Unit, University Malaya, Kuala Lumpur, Malaysia 3 Serdang Hospital, Selangor, Malaysia

Department of Diagnostic Imaging , Serdang Hospital,

Malaysia upon approval by UPM Medical Ethic Committee.

Thirty one patients diagnosed coronary artery disease were

prospectively recruited. Only 19 patients were finally enrolled

since insufficient data in the remaining 12 patients. All

patients underwent pharmaceutical stress and rest myocardial

perfusion imaging (MPI) study using 99m

Tc-MIBI at Universiti

Malaya Medical Centre, Kuala Lumpur upon diagnosis

confirmation of ischaemic heart disease . The inclusion

criteria are clinical signs and symptoms of ischaemic heart

disease, raised cardiac enzymes, electrophysiological changes

and evident from imaging modalities like cardiac scintigraphy

using 99m

Tc-MIBI, echocardiography and Magnetic Resonance

Imaging.. Exclusion criteria include childrens and pregnant

mothers. Only patients who underwent pharmaceutical stress

and rest cardiac scintigraphy study are recruited.

Patients demonstrating perfusion defect during rest 99m

Tc-

MIBI were referred to Centre for Diagnostic Nuclear Imaging

of Universiti Putra Malaysia for further assessment using 18F-

FDG PET/CT . All patients were prepared using modified

glucose loading protocol as recommended by the updated

version of American Society of Nuclear Cardiology.

Patients were instructed to be fasting for at least 8 hours on the

day of examination. Patients known to have diabetes mellitus

follow routine medication. Fasting blood sugar was checked

early in the morning to ensure that patients are fasted. 1 hour

prior to serial blood glucose tests alternating with

subcutaneous short acting insulin, patients were given 200mg

of oral Niacin ingestion to facilitate myocardial glucose

uptake. Once the blood glucose reached the desired level, 8-

10mCi 18F-FDG given intravenously. Patient was rested for

not less than an hour prior to PET/CT image acquisition . 18F-FDG PET/CT study was conducted using 64MDCT/PET

Biograph Siemens Medical Systems, Germany. A CT scout

view was first obtained over the heart to plan the study. A low

dose CT was performed for attenuation correction and

anatomical correlation. The offset value is -30 to 0 on X and Y

respectively. List mode replay for gated study sampled 10

gates with 100% phase up to 600 second duration. The average

trigger rate is 64 per minute where trigger rejection threshold

Molecular Imaging in the clinical evaluation of

mitochondrial function in myocardium : The

potential role of integrated Positron Emission

Tomography Computed Tomography (PET/CT)

in cardiac imaging

Abdul Jalil Nordin, Wan Himratul Azliza Wan Harun, Ahmad Zaid Fatah Azman, Ahmad Fazli Abdul

Aziz, Fathinul Fikri Ahmad Saad, Zul Hilmi Yaakob, Annuar Rapaie , Wan Azman Wan Ahmad

T

Proceedings of the World Medical Conference

ISBN: 978-1-61804-036-7 118

based on approximately 20% of average. The total acquisition

time was 30 min for emission (three-dimensional mode) and

CT transmission at the cardiac region. Attenuation-corrected

data were reconstructed using a 3-dimensional iterative 4 and

subsets 8. The Gausan filter is being utilized with full width

height maximum of 5 mm with a zoom factor of 2 and pixel

size of 2.03642.

Images were analyzed by Nuclear Radiologist and

Cardiologist blinded to other imaging results particularly the

myocardial SPECT MPI using 99m

Tc-MIBI. All images were

aligned to cardiac planes in short axis, vertical and horizontal

long axis. A 20-segment model was used with the anterior

insertion of the right ventricular free wall into the left ventricle

serving as the landmark. The quality of uptake by myocardium

and distribution are assessed. Hot iron scale and grey scale

were employed for image analysis. The alignment of the PET

and CT images were checked and manually corrected to ensure

the rim of FDG activity align well with the wall of

myocardium. Perfusion defects as defined as absent or no

perfusion is seen as visual decrease or absent in radioactivity.

All segments were examined systematically. Apparent defects

as a result of artefacts from bowel activities and patient

movement shall be excluded. Gated dynamic images examined

thoroughly looking for generalized and segmental movement

disorders. The ejection fraction, end diastolic and systolic

volume were assessed. The conclusions recorded following

careful evaluation of above mentioned parameters. A resting

sestamibi SPECT myocardial perfusion defect which is seen to

be reperfused during FDG PET/CT study is considered viable

or hibernating. A matched resting MPI and viability defect is

considered as infarcted or scarred myocardium. Results were

analyzed using SPSS version18.

II. RESULTS

Data from these patients (n=19) were analyzed (Table 1) .

Male gender predominate female. The mean age is 58.4 ± 10.8

(mean ± sd) ranging between 41 to 79.

6 patients demonstrated normal left ventricular function where

2 showed evidence of hibernating myocardium and remaining

4 having 1 infarcted segment at viability study . 9 patients had

evidence of ischaemic cardiomyopathy with cardiomegaly and

poor ejection fraction. The highest number of myocardial

segments involvement is 11 where the patient demonstrate

gross cardiomegaly and ejection fraction below 20%. 4

patients demonstrated poor ejection fraction with normal size

of left ventricular chamber. The most frequent vascular

territory affected is the left circumflex artery followed by right

coronary artery and left anterior descending artery. 31% had

single vascular disease and 69% had multiple vascular disease

involvement.

A total of 99 abnormal hypoperfused segments were identified

during stress MPI . Discordant and concordant stress and rest

perfusion results tabulated in table 2. Among the 99 segments,

90 segments demonstrated persistent defect at rest MPI study

while the remaining 9 segments showed reperfusion at resting

image (table 2).

Patients demonstrating persistent defects at stress and rest

study had undergone further evaluation using 18F-FDG

PET/CT for comparison. The discordant and concordant

between rest MPI and FDG viability findings are tabled

(table 3).

There were 36 concordance and 63 discordance between rest 99m

Tc-MIBI and 18F-FDG viability. The contingency table

(table 4) demonstrate low sensitivity (11.4%) in detecting

viable but hibernating segments in visibly myocardial defect

at rest MPI study. Thus, poor negative predictive value

(NPV=31.1%) in differentiating hibernating from infarcted

segments in this study. K test demonstrate non-statistical

significant with p >0.05.

III. DISCUSSION

Conventional imaging technique like MR, CT and

echocardiography have been widely utilized for myocardial

viability assessment in addition to 201

Thallium and 99m

Technetium tagged agents. In PET, 18F-FDG is the tracer

most frequently used to assess myocardial viability. Since 18F-

FDG is a glucose analogue, the substance is used to evaluate

cardiac glucose utilization where mitochondria plays pivotal

role in its utilization . The initial uptake in myocardial tissue is

comparable to glucose uptake. After phosphorylation, 18F-

FDG-6-PO4 is trapped within cardiac tissues and the

metabolism ends before the Kreb Cycle enabling imaging due

to the strong signal from radiation source emitted by 18F-

isotope. Cardiac uptake of FDG is depending on several

factors including plasma levels of insulin and free fatty acids.

Insulin stimulates cardiac glucose uptake but free fatty acids

inhibit. We mimicked the situation in our patients by oral

glucose loading and stimulate insulin level by intramuscular

injection and successfully demonstrate satisfactory segmental

FDG uptake in the myocardium using this technique except in

one patient. Myocardial preference in using fatty acid rather

than glucose for metabolism is unpredictable among diabetics

such as in this particular case where a defect was found during

FDG viability study despite good segmental perfusion.

Myocardial hibernation and stunning are two entities that may

coexist in patients with ischemic cardiomyopathy. The uptake

and retention of sestamibi are dependent on perfusion, cell

membrane integrity, and mitochondrial function. Thus,

sestamibi uptake during MPI is also a marker for viability of

myocytes. Rahimtoola described hybernating as chronic

sustained abnormal contraction attributable to chronic

underperfusion in patients who have coronary artery disease

and in whom revascularization causes the recovery of LV

function. While myocardial stunning is defined as reversible

myocardial contractile dysfunction in the presence of normal

resting myocardial blood flow .

In this study, the initial prediction of a total of 90 non viable

segments using 99m

Tc-sestamibi were further stratified and

down sized using FDG PET/CT where only 28 segments were

actually non viable with the remaining 62 segments viable but

hibernating. The latter group will benefit revascularization

while the rest may not . As such the sensitivity of myocardial

perfusion imaging using sestamibi in detecting viability is low


ISBN: 978-1-61804-036-7 119

(11.4%). Therefore, careful interpretation should be exercised

involving segments with perfusion defect at rest during MPI

study.The importance of accurate ientification of viable

segments has been shown in previous study.

In studies conducted by D Carli and Marwick TH, they

revealed clinical evidence of improved heart failure

symptoms after revascularization which occurred

predominantly in patients with viable myocardium. The study

conducted using data from 333 patients also found improved

left ventricular ejection fraction (LVEF) in patients with viable

myocardium where in patients with-out viable myocardium,

the LVEF remained unchanged

In addition, informations obtained from FDG PET/CT study

can help predicting the outcome of our patients. We identified

9 patients with poor left ventricular ejection fraction (<50%)

and remodeling ( LV volume > 150 mls). These patients are

predicted having poor outcome. While 4 patients will

potentially benefit from revascularization procedure as they

demonstrated no clinical evidence of regional functional

abnormality. Rohatgi et al demonstrated that revascularization

in patients with a substantial amount of viable myocardium

reduces the number of hospital readmissions for congestive

heart failure. In our study, base on available evidence, almost

all our patients should get improvement in global function as

more than 20% of the left ventricular wall are found to be

viable.

We also derived a clinical prediction rule from our study

(table 5). Negative perfusion on MPI study and FDG viability

study or matched defect is defined as infarction (figure 1) .

While a negative perfusion on MPI study in the presence of

positive FDG uptake or mis-matching defect is termed as

viable but hibernating segments (figure 2) similar to the term

suggested by Maddahi and colleagues. This study warrants

long term follow-up in our patients to observe the final clinical

outcome and determining the actual prognosis, thus creating

better understanding in the clinical role of FDG PET/CT

viability studies .

Our study was conducted with challenging limitation where

there is lacking in real time integration of both images from

MPI and viability study. Analysis was restricted by software

incompatibility since the studies were conducted at two

different institutions.

IV. CONCLUSION

The results of our study support the importance of FDG as a

gold standard biomarker in determining myocardial viability.

Myocardial perfusion imaging using 99m

Tc MIBI are limited

by its low sensitivity and poor negative predictive value thus,

inability to recognized infarcted from viable but hibernating

myocardial segments. Without viability, those patients whom

will not benefit from high risk revascularization surgical

procedure shall be avoided.

Acknowledgement

The study was supported by Centre for Diagnostic Nuclear

Imaging of Universiti Putra Malaysia


ISBN: 978-1-61804-036-7 120

No Age Sex

Race

MPI

FDG

Viability

LVF

Polar Map

Stress

Rest

Vol EF

LAD

LCX

RCA

Neg

Pos

Neg

Pos

Neg

Pos

mls

%

1 70 F Chi 1 19 1 0 0 1 233 40% Yes No Yes

2 53 M Mly 6 14 6 0 3 3 157 48% No Yes Yes

3 52 M Chi 13 7 12 1 11 2 294 18% Yes Yes Yes

4 49 F Mly 7 13 7 0 2 5 64 11% Yes Yes Yes

5 74 M Chi 4 16 4 0 0 4 105 51% Yes Yes Yes

6 41 M Mly 5 15 5 0 0 5 204 14% Yes No No

7 51 M Mly 3 17 2 1 1 2 105 51% No No Yes

8 75 M Chi 5 15 4 1 0 5 104 43% No Yes Yes

9 70 F Chi 3 17 3 0 1 2 153 38% No Yes No

10 56 M Ind 5 15 4 1 4 1 158 32% Yes Yes Yes

11 54 M Mly 5 15 5 0 4 1 160 43% Yes Yes Yes

12 68 F Mly 5 15 5 0 1 4 75 61% No Yes No

13 58 M Ind 7 13 2 5 0 7 111 21% No No No

14 50 M Chi 3 17 3 0 0 3 105 60% No No No

15 79 M Ind 3 17 3 0 0 3 84 96% Yes Yes Yes

16 48 M Ind 8 12 8 0 2 6 107 36% Yes No Yes

17 57 M Chi 5 15 5 0 0 5 113 50% No No No

18 51 M Ind 5 15 5 0 0 5 213 13% No Yes No

19 53 M Mly 6 14 6 0 0 6 203 24% No Yes No

MPI=myocardial perfusion imaging ; neg=negative; pos=positive ; FDG= Fluorodeoxyglucose; LV=left

ventricular; vol = volume; EF=Ejection Fraction ; LAD=left anterior descending; LCX=left circumflex;

RCA=Right coronary artery

Table 1. Results demonstrating patient demography, relationship between myocardial perfusion and viability, left

ventricular function and vascular territorial involvement derived from polar map. The numbers in MPI and FDG

viability columns are representing number of segments affected.


ISBN: 978-1-61804-036-7 121

Rest Perfusion MIBI

Total Neg Pos

Stress

MPI

Neg

ativ

e Count 90 9 99

% Stress Perfusion MIBI 90.9% 9.1% 100.0%

% Rest Perfusion MIBI 100.0% 100.0% 100.0%

Total

Count 90 9 99

% Stress Perfusion MIBI 90.9% 9.1% 100.0%


Neg= negative ; pos=positive

Table 2 . Stress Perfusion MIBI * Rest Perfusion MIBI * Crosstabulation

FDG Viability

Total Neg Pos

Rest MPI

Neg

Count 28 62 90


% FDG Viability 96.6% 88.6% 90.9%

Pos

Count 1 8 9


% FDG Viability 3.4% 11.4% 9.1%

Total

Count 29 70 99


% FDG Viability 100.0% 100.0% 100.0%

Neg= negative ; pos=positive

Table 3 . Rest Perfusion MIBI * FDG Viability Crosstabulation

The Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of MPI Rest is 88.9% and

31.1%. (Table 4) This result of PPV and NPV needs to interpret with caution. A low-ish NPV of MPI Rest

may be attributed to the high prevalence of viable/hibernating segments within the study population.

Additionally, test of agreement shows non-statistically significant, moderate agreement between the two

test (Kappa = 0.49, p = 0.29).


ISBN: 978-1-61804-036-7 122

FDG Viability

+ve -ve

MPI Rest

+ve 8 1 9

-ve 62 28 90

70 29 99

Table 4. Contingency table of MPI Rest vs. FDG Viability

*Kappa = 0.49 (p = 0.20

From our study, we found 62% may benefit revascularization since more than 30% of the segments were

viable while the remaining 28% may not benefit the procedure.

Segment

n (%)

Infarct 28 (28.3)

Hibernate 62 (62.6)

Viable 8 (8.0)

Table 5: Percentage of segmental viability according to Clinical Prediction Rule


ISBN: 978-1-61804-036-7 123

Figure 1 , A 52 year old man known ischaemic cardiomyopathy underwent

pharmaceutical induced stress-rest MPI study and FDG viability. Top are transaxial

images during MPI and viability during FDG PET/CT . Bottom Vertical long axis and

horizontal long axis images. There are matching defect in the apical region in keeping

with infarcted myocardium


ISBN: 978-1-61804-036-7 124

Figure 2. Transaxial images of the left ventricle of a 72 year old woman demonstrating

revearsible defect in the septal region on viability study (bottom row) indicating

hibernating myocardium.

Figure 3. Longitudinal long axis of MPI and FDG viability PET/CT demonstrating stress

induced ischaemia on MPI (top row) in the apical region but viable in FDG PET/CT study

(bottom row).


ISBN: 978-1-61804-036-7 125

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Molecular Imaging in the clinical evaluation of ... · resting MPI are being compared with myocardial viability study using new integrated diagnostic imaging modality Positron Emission