Proceedings of the World Medical Conference

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

Department of Diagnostic Imaging , Serdang Hospital, Abstract— Intact myocardial perfusion is a function of normal Malaysia upon approval by UPM Medical Ethic Committee. sodium potassium adenosine triphosphatase (ATPase) pump Thirty one patients diagnosed were while normal myocardial viability is the function of intact prospectively recruited. Only 19 patients were finally enrolled mitochondrium. Both molecular processes can be clinically since insufficient data in the remaining 12 patients. All manipulated using non-invasive molecular imaging techniques. patients underwent pharmaceutical stress and rest myocardial Despite being a routine procedure, myocardial perfusion perfusion imaging (MPI) study using 99mTc-MIBI at Universiti imaging has inherent limitation in verifying viable myocardial Malaya Medical Centre, Kuala Lumpur upon diagnosis segments. Fluorodeoxyglucose (FDG), an analogue of glucose confirmation of ischaemic heart disease . The inclusion molecule is a gold standard biomarker in demonstrating criteria are clinical signs and symptoms of ischaemic heart viability. Integrating the two molecular processes in a clinical disease, raised cardiac enzymes, electrophysiological changes study will define and classify viable from non viable and evident from imaging modalities like cardiac scintigraphy myocardial segments. The function of viable myocardial using 99mTc-MIBI, and Magnetic Resonance segments may benefit revascularization procedure while Imaging.. Exclusion criteria include childrens and pregnant function has not been successfully revearsible after mothers. Only patients who underwent pharmaceutical stress revascularization in infarcted scared myocardium. and rest cardiac scintigraphy study are recruited. The objective of this study is to assess the concordant and Patients demonstrating perfusion defect during rest 99mTc- discordant results obtained when hypoperfused segments at MIBI were referred to Centre for Diagnostic Nuclear Imaging resting MPI are being compared with myocardial viability of Universiti Putra Malaysia for further assessment using 18F- study using new integrated diagnostic imaging modality FDG PET/CT . All patients were prepared using modified Positron Emission Tomography Computed Tomography glucose loading protocol as recommended by the updated (PET/CT) with flourodeoxyglucose (FDG) as the biomarker. version of American Society of Nuclear . The usefulness of flourodeoxyglucose as a potential viability Patients were instructed to be fasting for at least 8 hours on the PET agent in the assessment of myocardium is elucidated day of examination. Patients known to have diabetes mellitus from this study. 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 I. METHODOLOGY subcutaneous short acting insulin, patients were given 200mg he study was conducted in collaboration between of oral Niacin ingestion to facilitate myocardial glucose Diagnostic Nuclear Imaging Centre, Universiti Putra uptake. Once the blood glucose reached the desired level, 8- 18 TMalaysia (UPM), Cardiology Unit, Universiti Malaya 10mCi F-FDG given intravenously. Patient was rested for Medical Centre and Department of Cardiology and 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 Abdul Jalil Nordin1, Wan Himratul Azliza Wan Harun2 , Ahmad Zaid Fatah view was first obtained over the heart to plan the study. A low Azman1, Ahmad Fazli Abdul Aziz1, Fathinul Fikri Ahmad Saad1, Zul Hilmi 2 3 2 dose CT was performed for attenuation correction and Yaakob ,Annuar Rapaie , Wan Azman Wan Ahmad anatomical correlation. The offset value is -30 to 0 on X and Y

1 Diagnostic Nuclear Imaging Centre, Universiti Putra Malaysia respectively. List mode replay for gated study sampled 10 2 Cardiology Unit, University Malaya, Kuala Lumpur, Malaysia gates with 100% phase up to 600 second duration. The average 3 Serdang Hospital, Selangor, Malaysia trigger rate is 64 per minute where trigger rejection threshold

ISBN: 978-1-61804-036-7 118 Proceedings of the World Medical Conference

based on approximately 20% of average. The total acquisition PET/CT for comparison. The discordant and concordant time was 30 min for emission (three-dimensional mode) and between rest MPI and FDG viability findings are tabled CT transmission at the cardiac region. Attenuation-corrected (table 3). data were reconstructed using a 3-dimensional iterative 4 and There were 36 concordance and 63 discordance between rest subsets 8. The Gausan filter is being utilized with full width 99mTc-MIBI and 18F-FDG viability. The contingency table height maximum of 5 mm with a zoom factor of 2 and pixel (table 4) demonstrate low sensitivity (11.4%) in detecting size of 2.03642. viable but hibernating segments in visibly myocardial defect Images were analyzed by Nuclear Radiologist and at rest MPI study. Thus, poor negative predictive value Cardiologist blinded to other imaging results particularly the (NPV=31.1%) in differentiating hibernating from infarcted myocardial SPECT MPI using 99mTc-MIBI. All images were segments in this study. K test demonstrate non-statistical aligned to cardiac planes in short axis, vertical and horizontal significant with p >0.05. 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 III. DISCUSSION and distribution are assessed. Hot iron scale and grey scale Conventional imaging technique like MR, CT and were employed for image analysis. The alignment of the PET echocardiography have been widely utilized for myocardial and CT images were checked and manually corrected to ensure viability assessment in addition to 201Thallium and the rim of FDG activity align well with the wall of 99mTechnetium tagged agents. In PET, 18F-FDG is the tracer myocardium. Perfusion defects as defined as absent or no most frequently used to assess myocardial viability. Since 18F- perfusion is seen as visual decrease or absent in radioactivity. FDG is a glucose analogue, the substance is used to evaluate All segments were examined systematically. Apparent defects cardiac glucose utilization where mitochondria plays pivotal as a result of artefacts from bowel activities and patient role in its utilization . The initial uptake in myocardial tissue is movement shall be excluded. Gated dynamic images examined comparable to glucose uptake. After phosphorylation, 18F- thoroughly looking for generalized and segmental movement FDG-6-PO4 is trapped within cardiac tissues and the disorders. The ejection fraction, end diastolic and systolic metabolism ends before the Kreb Cycle enabling imaging due volume were assessed. The conclusions recorded following to the strong signal from radiation source emitted by 18F- careful evaluation of above mentioned parameters. A resting isotope. Cardiac uptake of FDG is depending on several sestamibi SPECT myocardial perfusion defect which is seen to factors including plasma levels of insulin and free fatty acids. be reperfused during FDG PET/CT study is considered viable Insulin stimulates cardiac glucose uptake but free fatty acids or hibernating. A matched resting MPI and viability defect is inhibit. We mimicked the situation in our patients by oral considered as infarcted or scarred myocardium. Results were glucose loading and stimulate insulin level by intramuscular analyzed using SPSS version18. injection and successfully demonstrate satisfactory segmental FDG uptake in the myocardium using this technique except in II. RESULTS one patient. Myocardial preference in using fatty acid rather Data from these patients (n=19) were analyzed (Table 1) . than glucose for metabolism is unpredictable among diabetics Male gender predominate female. The mean age is 58.4 ± 10.8 such as in this particular case where a defect was found during (mean ± sd) ranging between 41 to 79. FDG viability study despite good segmental perfusion. 6 patients demonstrated normal left ventricular function where 2 showed evidence of hibernating myocardium and remaining Myocardial hibernation and stunning are two entities that may 4 having 1 infarcted segment at viability study . 9 patients had coexist in patients with ischemic . The uptake evidence of ischaemic cardiomyopathy with and and retention of sestamibi are dependent on perfusion, cell poor ejection fraction. The highest number of myocardial membrane integrity, and mitochondrial function. Thus, segments involvement is 11 where the patient demonstrate sestamibi uptake during MPI is also a marker for viability of gross cardiomegaly and ejection fraction below 20%. 4 myocytes. Rahimtoola described hybernating as chronic patients demonstrated poor ejection fraction with normal size sustained abnormal contraction attributable to chronic of left ventricular chamber. The most frequent vascular underperfusion in patients who have coronary artery disease territory affected is the left circumflex artery followed by right and in whom revascularization causes the recovery of LV coronary artery and left anterior descending artery. 31% had function. While myocardial stunning is defined as reversible single vascular disease and 69% had multiple vascular disease myocardial contractile dysfunction in the presence of normal involvement. resting myocardial blood flow . A total of 99 abnormal hypoperfused segments were identified during stress MPI . Discordant and concordant stress and rest In this study, the initial prediction of a total of 90 non viable perfusion results tabulated in table 2. Among the 99 segments, segments using 99mTc-sestamibi were further stratified and 90 segments demonstrated persistent defect at rest MPI study down sized using FDG PET/CT where only 28 segments were while the remaining 9 segments showed reperfusion at resting actually non viable with the remaining 62 segments viable but image (table 2). hibernating. The latter group will benefit revascularization Patients demonstrating persistent defects at stress and rest while the rest may not . As such the sensitivity of myocardial study had undergone further evaluation using 18F-FDG perfusion imaging using sestamibi in detecting viability is low

ISBN: 978-1-61804-036-7 119 Proceedings of the World Medical Conference

(11.4%). Therefore, careful interpretation should be exercised Acknowledgement involving segments with perfusion defect at rest during MPI The study was supported by Centre for Diagnostic Nuclear study.The importance of accurate ientification of viable Imaging of Universiti Putra Malaysia segments has been shown in previous study.

In studies conducted by D Carli and Marwick TH, they revealed clinical evidence of improved 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 99mTc 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.

ISBN: 978-1-61804-036-7 120 Proceedings of the World Medical Conference

MPI LVF Polar Map FDG Race Viability

No Age Sex 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 Proceedings of the World Medical Conference

Rest Perfusion MIBI

Neg Pos Total Count 90 9 99 % Stress Perfusion MIBI 90.9% 9.1% 100.0% MPI MPI Stress Stress

Negative % Rest Perfusion MIBI 100.0% 100.0% 100.0% Count 90 9 99 Total % Stress Perfusion MIBI 90.9% 9.1% 100.0% % Rest Perfusion MIBI 100.0% 100.0% 100.0%

Neg= negative ; pos=positive

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

FDG Viability

Neg Pos Total Count 28 62 90 % Rest Perfusion MIBI 31.1% 68.9% 100.0% Neg Neg % FDG Viability 96.6% 88.6% 90.9%

Count 1 8 9 Rest MPI Rest % Rest Perfusion MIBI 11.1% 88.9% 100.0% Pos % FDG Viability 3.4% 11.4% 9.1% Count 29 70 99 Total % Rest Perfusion MIBI 29.3% 70.7% 100.0% % 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 Proceedings of the World Medical Conference

FDG Viability +ve -ve +ve 8 1 9 MPI Rest -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 Proceedings of the World Medical Conference

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 Proceedings of the World Medical Conference

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