Renewed Application of an Old Method Improves Detection of Coronary : A Higher Standard of Care

Richard M. Fleming, MD, Gordon M. Harrington, PhD, Riaz Baqir, MD, Scott Jay, MD, Sridevi Challapalli, MD, Kayla Avery, CNMT, and Jim Green, CNMT

The diagnostic utility of traditional nuclear cardiac imaging is enhanced by using modern technology to compare absolute regional radioactive counts at two points in time during stress/stress testing.

uclear cardiac imaging began solute radioactive counts—although cardial perfusion measurements fol- in 1927 with the first in a se- the computer software to accomplish lowing a single injection of sestamibi ries of studies by Blumgart this is available. The extra step of to determine ischemia. We compared Nand Yens, which found that quantifying absolute counts allows the results of coronary angiogra- measuring the rate and magnitude of the clinician to better interpret disease phy—used to determine the extent of transfer from right arm to left by seeing information the computer coronary lumen disease—with (1) arm could diagnose the presence or uses to assign various shades of grey myocardial perfusion imaging (MPI) absence of heart disease.1 This work or color to the image. findings using a redistribution equa- was not only the first nuclear study When applied to multiple images tion we developed (the Fleming- of the heart, but the first description under the same state (namely, five- Harrington equation) to quantify of quantification of disease by using a minutes and 60-minutes poststress), absolute radioactive counts, and (2) . The radioactive tracer quantifiable absolute counts can then results of rest/stress imaging. thallium-201 was introduced in 1975, be compared using today’s single pho- followed by contemporary tracers, ton emission computed tomography BACKGROUND such as -99m sestamibi. (SPECT) cameras. Using these cam- In 1959, Gorlin demonstrated that Many studies have shown that eras, the clinician can look for the resting images were not diagnosti- knowledge of sestamibi redistribu- actual change in concentra- cally useful for ischemia and should tion, as revealed by sequential stress tion that results from various levels of not be used for this purpose.8 Fur- imaging, improves detection of heart ischemia—caused by differences in a ther discussions by Love questioned disease.2–6 While these studies quanti- coronary artery’s ability to vasodilate whether nuclear imaging would fied sestamibi differences in heart to to meet coronary blood flow demands ever be clinically useful due to the lung ratios, they did not quantify ab- and coronary artery blockage (Figure absence of clinically useable iso- 1)7. This clinical information is diag- topes.9 Although the introduction of Dr. Fleming, Dr. Jay, and Ms. Avery are all cardi- nostically important and allows the thallium-201 partially allayed those ologists at the Cardiovascular Institute of South- primary care physician to determine fears, the tracer was plagued with a ern Missouri, Poplar Bluffs, MO. Dr. Harrington is a professor in the department of psychology at whether medical management or an long half-life of 72 hours. None- the University of Northern Iowa, Cedar Falls, IA. invasive cardiac procedure is the next theless, thallium-201 was clinically Dr. Baqir is a cardiologist in the division of cardi- best step in caring for the patient. useable for detecting ischemia by ology at the VA Central Iowa Health Care System (VACIHCS), Des Moines, IA. Dr. Challapalli and To demonstrate the advantages of qualitatively evaluating two post- Mr. Green are both cardiologists at the Sierra Ne- obtaining absolute radioactive counts stress images (at one and four hours). vada Cardiology Associates (SNCA), Reno, NV. In in sequential stress imaging, we de- The unfortunate use of the terms addition, Dr. Fleming is a cardiologist at the SNCA 10 and was a cardiologist in the division of cardiol- signed a study to assess the clinical “stress” and “rest,” however, re- ogy at the VACIHCS. diagnostic utility of time-course myo- sulted in a misunderstanding of the

22 • FEDERAL PRACTITIONER • JUNE 2010 established principles laid out by Blumgart and Yens—that compari- sons should be made under same- state conditions, either stress or rest. Maublant and Crane demonstrated that use of sestamibi had a washout of 28 minutes and that this washout Joe Gorman © 2010. increases under ischemic conditions because of mitochondrial calcium overload; the clinical importance of this finding had been underrecog- nized previously.11,12 Nuclear MPI using SPECT for the detection of ischemia is accomplished by comparing two images of the heart obtained at two points in time. While Blumgart emphasized comparisons under same-state conditions, clini- cians since have emphasized rest/ stress comparisons. The resting image more correctly can be used to determine if myocardial injury has occurred previously, but cannot be utilized to determine if ischemia is present.1,8 Nonetheless, most diagnosticians today compare the rest to stress im- ages and conclude that when the images have identical findings (matching defects) no ischemia is present. However, injury/infarction noted on the resting image in the ab- sence of ischemia (stress image) is in- consistent with the disease process as we know it, and matching defects hours but not after two hours.14,15 ter with today’s SPECT camera to clearly cannot mean that a region of The presence or absence of washin compare radioactive counts, both infarction has no ischemia; rather, it was attributed to viability and quantitatively and qualitatively, merely means that the infarction is thus, differentiated ischemia with in- has increased the diagnostic accu- the result of ischemia. In other words, farcted tissue (matched defects) from racy of detecting congestive heart one cannot have myocardial infarc- ischemia with viable tissue (non- failure, cardiomyopathy, coronary tion in the absence of an underlying matched defects). Most clinicians vasospasm, and, as our initial stud- ischemic insult to the region. There- treat contemporary tracers, such as ies established, the relationship fore, matching rest/stress images de- sestamibi, as though they do not un- between “” and coro- fine ischemia present at the site of dergo redistribution (washin or wash- nary artery disease.2–5,17–25 In recent injury/infarction and not a simplistic out), despite ample evidence to the work, we have better defined the re- absence of ischemia.13 contrary, including a recent investiga- lationship between sestamibi redis- Much controversy followed the tion by Fallahi and Beiki.2–6,10,12,16 tribution and the extent of actual institution of sequential stress imag- Recent research utilizing knowl- seen in the ing, which found instances of redis- edge of sestamibi redistribution and angiography suite—yielding substan- tribution with thallium-201 after four replacing Blumgart’s Geiger coun- tially increased diagnostic accuracy in

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the stress component of the study where they underwent either exercise (treadmill) or pharmacologic stress. Following standard protocols already described in the medical and scien- tific literature, we injected intrave- nously a bolus of sestamibi (28 to 32 mCi, 1036 to 1184 MBq) followed by a bolus of normal saline to ensure adequate delivery of the radioactive isotope into the venous system. Five minutes following delivery of sesta- mibi, a SPECT camera was used to obtain a five-minute image (anterior slice, single-head camera) or images (anterior and lateral slices, multiple- Coronary (stenosis) flow reserve Coronary head camera). Fifty-five minutes later (60-minutes poststress), participants returned to the lab for final images. Cummulative percent narrowing (blue = %DS, red = %ASa) Data Collection and Figure 1.7 Relationship between stenosis flow reserve and percent diameter stenosis Analysis (%DS), demonstrating that as arteries become more critically narrowed they are less able to vasodilate upon demand, requiring a longer time to achieve isotope equilibrium. Image comparisons and a%AS = percent area stenosis. redistribution calculations We evaluated rest/stress images using visual, qualitative slice-to-slice com- the detection and evaluation of coro- Patients arrived at the nuclear lab- parisons. For the redistribution cal- nary ischemia.26,27 The study we pres- oratory in a fasting state according culation, we drew regions of interest ent here is a follow-up to our most to each institution’s approved proto- (ROIs) using the five-minute post- recent work measuring sestamibi cols for MPI. Specific institutional re- stress images to quantify radioactive redistribution and comparing the view board (IRB) requirements were counts, including total heart and findings with results from coronary reviewed. Patients underwent addi- lung, basal and mid anterior, basal angiography and rest/stress images.28 tional imaging, but they did not re- and mid anterolateral, basal and mid ceive further injections of radioactive inferior-posterior, and basal and mid Study Design and materials nor were they placed under inferoseptal regions (Figure 3). We Participants additional exercise or pharmacologic avoided the issue of cardiac creep (a We studied 120 men and women “stress”; thus, the additional acqui- form of gradual internal heart mo- (aged 25 to 82 years) suspected of sition of redistribution information tion) by positioning the camera over having ischemic heart disease, using already present (but not previously the cardiac silhouette for each set of both the rest/stress image compari- collected) did not require additional images and not leaving the camera in sons approach and a one-day redis- IRB approval. Therefore, use of stan- a fixed position over the chest wall. tribution “stress/stress” approach dard patient informed consent was We obtained dynamic images (Figure 2). The individuals under- determined to be appropriate. 55 minutes later and drew ROIs to went exercise or pharmacologic stress We obtained intravenous access match the ROIs of the five-minute with injection of technetium-99m iso- and acquired resting images after in- images (Figure 4). Although we tope (sestamibi) per standardized MPI travenous injection of 9 to 11 mCi compared regional wall motion and protocols using lexiscan (n = 61), ad- (333 to 407 MBq) of sestamibi per ejection fraction information, we do enosine (n = 30), dobutamine (n = 4), protocol. Patients returned to the lab not report these findings here as they or treadmill (n = 25) stress. per institution protocol to undergo are not relevant to this investigation.

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We calculated redistribution results A. One-day stress/rest for total heart and lung and each of Stress Rest the eight vascular regions from the 0 10–20 0 30–60 ROIs using the following equation (the Fleming-Harrington redistri- Gated imaging Gated imaging (optional) bution washin-washout [FHRWW] rate)2,26,27: R (%) = (ROI counts [region] at 5 minutes – ROI counts [region] at 60 Inject Inject minutes) ∕ (ROI counts [region] at 5 stress rest minutes) x 100 – 10 dose dose The calculation of washout is a reflection of changes in radioactive B. One-day rest/stress counts in each ROI measured at five Rest Stress minutes and again at 60 minutes. 0 30–60 0 10–20 To obtain percent change, the result is multiplied by 100. Finally, if ses- Gated imaging (optional) Gated imaging tamibi were to be retained and not washout, a decay of 10% would be expected during the 55 minutes be- tween the five-minute and 60-minute Inject Inject images; for that reason, 10% is sub- rest stress tracted from the result to reflect the dose dose true change in the amount of sesta- C. Two-day stress/rest mibi over the course of time between the two images. This equation may be Stress Rest simplified mathematically as follows: 0 10–20 0 30–60 If the 5-minute counts = x, the Gated imaging Gated imaging (optional) 60-minute counts = y, and the percent washout = w multiplied by 100, then: w = (x – y) ∕ x – 0.1 = x ∕ x – y ∕ x – 0.1 = 1.0 – y ∕ x – 0.1 = 0.9 – y ∕ x = .9 – 60-minute counts ∕ 5-minute Inject Inject stress rest counts. dose dose

Comparison with coronary D. One-day stress/stress FHRWWa protocol angiography Stress Stress We then compared results of FHRWW for each vascular territory with both 0 4 9 14–15 60 the rest/stress imaging results and the First heart Second heart b coronary angiography results. Angi- image(s) image with gating & EF ography was performed using insti- tutional standard practice guidelines to determine the extent of coronary artery narrowings (percent diameter Inject single stenosis [%DS]) for each of the three stress dose epicardial (left an- terior, circumflex, and right coronary Figure 2. Multiple imaging protocols indicating time (in minutes) when doses should be administered and when imaging should be conducted. aFHRWW = Fleming-Harrington artery) and their branches in indi- redistribution washin-washout. bEF = ejection fraction. viduals who had findings of ischemia

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A B

Figure 3. Radioactive counts at five-minutes poststress. Colored circles indicate regions of interest (ROIs). (A) shows ROIs for the (1) basal anterolateral, (2) mid anterolateral, (3) basal inferoseptal, (4) mid inferoseptal, (5) total heart, and (6) total lung. (B) shows ROIs for the (1) basal anterior, (2) mid anterior, (3) basal inferior-posterior, and (4) mid inferior.

A B

Figure 4. Radioactive counts at 60-minutes poststress. Colored circles indicate regions of interest (ROIs). (A) shows ROIs for the (1) basal anterolateral, (2) mid anterolateral, (3) basal inferoseptal, (4) mid inferoseptal, (5) total heart, and (6) total lung. (B) shows ROIs for the (1) basal anterior, (2) mid anterior, (3) basal inferior-posterior, and (4) mid inferior. on either the rest/stress imaging or or no coronary artery disease in other Of total study participants, 55% FHRWW redistribution measurement vascular territories provided compari- underwent coronary angiography (Table 1). Participants with significant sons of redistribution in regions with based on clinician preference as well %DS in a particular artery with little little coronary artery disease. as findings of ischemia on either re-

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Table 1.a Comparison of sestamibi redistribution (FHRWW)b and coronary angiography data Artery matched Artery matched IDc Total FHRWW Anterior FHRWW Inferior FHRWW anterior %DSd inferior %DSe 1 42 19 54 30 98 2 34 33 54 25 94 3 50 32 55 80 60 4 42 21 45 20 30 5 51 39 28 0 0 6 71 77 79 90 50 7 32 –39 –4 80 0 8 52 48 53 50 30 9 19 3 23 30 0 10 52 52 55 80 95 11 31 3 24 0 70 12 49 –11 57 90 100 13 –46 16 19 50 30 14 –58 –100 –65 85 20 15 0 0 4 0 0 16 47 42 47 100 70 17 42 21 42 60 80 18 52 32 66 25 70 19 48 22 42 40 50 20 63 40 61 85 98 aTable includes data for only a partial list of study participants. bFHRWW = Fleming-Harrington redistribution washin-washout. cID = identifying number of individual. dArtery matched anterior %DS = percent diameter stenosis anteriorly for artery in region of FHRWW. eArtery matched inferior %DS = percent diameter stenosis inferiorly for artery in region of FHRWW. distribution or rest/stress imaging, comparisons—a common procedure. ages and FHRWW images. Statistical obtained from a variety of commonly These absolute quantified counts were analysis and graphics were developed used protocols (Table 2). The varia- recorded with calculations of washout using R-2.6.0 and GGobi software. tion in the dose as noted above. injections in these protocols illus- Correlation coefficients, confidence RESULTS trates the absence of a single accepted intervals (CIs), and P values were de- No differences were observed be- approach to MPI. termined between %DS and washout tween individuals who were stressed using product-moment correlation either physically or pharmacologi- Statistical analysis and least squares regression fitting the cally. Outcomes were not changed We quantified absolute isotope counts hypothesized model of y = cx2. Using by the stressor used, as the compari- using the specific nuclear computer the null hypothesis for n = 120 pa- son between rest/stress and FHRWW software provided by each of the tients, we estimated odds ratios (ORs) determination of redistribution was nuclear camera companies; doing so for predicting final diagnosis from independent of the type of stress. allowed us to avoid the errors that nuclear procedures. ORs were deter- The use of regional wall motion in- occur when images are interpreted mined against coronary angiography formation was used with both the by making pixel-to-pixel qualitative results for both the rest/stress im- rest/stress protocol and the FHRWW

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Table 2. Radiopharmaceutical doses for MPIa protocols Range of technetium-99m doses, MBq (mean) Technetium-99m Stress Stress protocol Rest (5-minute static) (60-minute dynamic) Total One-day stress/rest26 888–1332 (1110) 296–444 (370) 1184–1776 (1480) One-day rest/stress26 296–444 (370) 888–1332 (1110) 1184–1776 (1480) Two-day stress/rest26 888–1332 (1110) 888–1332 (1110) 1776–2664 (2220) One-day stress/stress24,25 1110 1110 aMPI = myocardial perfusion imaging.

Table 3. ORsa for predicting final diagnosis from nuclear procedures Patients, no. Petob ORs Ischemic Normal Total OR CIc (95%) logd (OR) SEe Diagnostic test Diagnosis 52g 68g 120 Rest/stress Ischemic 30 14 44 4.88 2.3–10.3 1.57 0.37 Normal 22 54 76 FHRWWf Ischemic 52 0 52 56.7 27.5–117.2 4.04 0.36 Normal 0 68 68 aORs = odds ratios. bPeto = alternative to the classic odds ratio. cCI = confidence interval.d log = logarithm. eSE = standard error. fFHRWW = Fleming- Harrington redistribution washin-washout. gnumber of patients determined by coronary angiography. approach, which made it possible to for each of the eight ROIs. (We could The standard rest/stress images also look for wall motion abnormalities do this only with the redistribution yielded a specificity of 88%; of which, and ejection fraction using either ap- data, which provide quantitative re- only one participant (0.8%) who un- proach. Since these observations are sults to compare with quantitative re- derwent a coronary angiogram had an identical, regardless of which method sults obtained angiographically.) adverse outcome requiring cardiopul- was used to report ischemia, we do Comparison of the rest/stress monary resuscitation.29 This patient not report them here. image results with the angiographic had a normal sestamibi redistribution We analyzed the results of rest/ results showed a sestamibi rest/stress using FHRWW (Figure 5). stress image comparisons and imaging sensitivity of 67%. Of the FHRWW redistribution images and false negative results (n = 22), 18% DISCUSSION compared them with findings ob- (n = 4) had critically narrowed arter- Many of the limitations of compar- tained from coronary angiography. For ies or arteries with vulnerable plaques ing rest/stress images of the heart the rest/stress images, the OR for de- whose 60-minute images appeared result from tissue attenuation prob- tecting ischemia was 4.88 with a CI completely normal.26,27 However, lems seen with breast artifact and (95%) of 2.3 to 10.3. For FHRWW, the evaluation of the 5-minute images for diaphragmatic attenuation, flow OR was 56.7 with a CI (95%) of 27.5 redistribution (using FHRWW), re- anomalies arising from left bundle to 117.2 (Table 3). When the results of vealed both qualitative and quantita- branch block, hypertrophic obstruc- these ORs were compared, the t value tive decreased uptake, demonstrating tive cardiomyopathy, and other well was greater than 6.6 (P < .0001). a washin effect. The 60-minute post- known and similar problems. The We obtained results of %DS for stress images miss these washin phe- FHRWW redistribution approach is each of the epicardial arteries and nomena when looked at independent not associated with these difficulties their branches, and plotted these re- of the five-minute images, yielding because it compares regions of the sults against the redistribution results incorrect results. heart under same-state (poststress)

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conditions, allowing us to look for absolute changes (redistribution) in isotope concentrations. In this study, results of rest/stress image comparisons and FHRWW re- distribution image comparisons were not affected by the method used to administer stress. Therefore, institu- tions with a preference for exercise or pharmacologic stress (regardless of which agent is used) can continue to utilize their preferred approach with the FHRWW method for de- A tecting ischemia. They also will be able to save additional camera time by avoiding rest imaging unless they are looking for evidence of injury/ infarction.8,30 The ORs in this study provide fur- ther confirmation that determination of sestamibi redistribution improves the detection of ischemia compared with the rest/stress method—most pronouncedly in individuals with more severe disease. The ability to obtain these images of the heart and to measure ROIs requires the use of today’s SPECT cameras with their im- B aging and software capabilities (built into the camera systems) for compar- Figure 5. Normal redistribution/washout in a patient with no evidence of ischemia on cor- ing five-minute and 60-minute im- onary angiography. (A) shows results of absolute radioactive counts in each of eight myo- ages of the heart. cardial regions at five-minutes poststress. The absolute total heart count was 280,026. Previous research has shown (B) shows results of absolute radioactive counts in each of eight myocardial regions at a parabolic relationship in humans 60-minutes poststress. The absolute total heart count was 236,089, representing a 5.7% between stenosis flow reserve (as washout and indicating no significant ischemia. determined by emission to- mography) and %DS (as measured by quantitative coronary angiography).7 severe ischemia, but improves with lular function are not compromised. The current study demonstrates a time. The consequence of such is that Individuals with less critical, but still parabolic relationship (one variable a significant amount of myocardium present, ischemia can be detected by depends on the square of the other) is at risk of injury/infarction. washout of sestamibi and, using the between the findings of sestamibi re- A washout rate of ≤ 10% to 15%— parabolic relationship, practitioners distribution (as measured from im- consistent with the expected 10% ra- can make decisions about needed ages of the heart obtained by SPECT dioactive decay of technetium-99m medical or interventional treatment. imaging) and %DS found in the car- compounds—is evidence of minimal Also worth noting is that the rest/ diac catheterization laboratory (Fig- or no ischemia because the amount stress protocol requires a greater ure 6). This parabolic relationship of tracer that myocardial tissue takes amount of radioactive isotope (1480 reveals that during sestamibi washin, up and the amount it releases reaches MBq) compared with the redistri- a critical reduction in isotope activ- equilibrium early (within five min- bution stress/stress protocol (1110 ity initially occurs in the presence of utes) only when blood flow and cel- MBq). Not only does the patient

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Stenosis - 0.011 Washout2 dioactivity under same-state (stress/ stress) conditions after taking multi- ple images of the heart. The parabolic 50– relationship between redistribution and ischemia shows not only the rel- evance of washin and washout, but 40– also that relatively small differences No Ischemia in percent redistribution reflect much (5 minute counts larger differences in ischemia. Using 30– = 60 minute counts) Washout our redistribution washin-washout (5 minute counts equation, we can accurately detect > 60 minute counts) the presence of ischemia and com- 20– pare these redistribution results with

Stenosis (%D) results obtained in the cardiac cath- 10– eterization laboratory to improve de- tection of heart disease. In addition to our work over 0– the last decade, Sheikine and col- Wash In leagues have discovered the impor- (5 minute counts –40 –20 0 20 40 60 tance of sestamibi redistribution in < 60 minute counts) Washout (%) the detection of ischemic heart dis- ease missed by imaging 60-minutes Figure 6. Parabolic relationship between redistribution washin-washout and coronary poststress. The authors confirm our artery narrowing as seen on angiogram. A greater than 10% washout indicates ischemia. work stating, “...where Tc-99m-ses- When ischemia is critical, isotope entry and retention are delayed, which is demonstrated tamibi exhibited marked redistribu- by washin. If blood flow and myocyte function are normal, a 10% reduction in measur- tion between early (6–8 min) and late able isotope will be detected due to the decay curve of technetium-99m. a%D = percent (60–70 min) poststress imaging [led] diameter. to an underestimation of the extent and severity of ischemia on late im- ages.”31 This paradigm shift, which receive less in the redis- on patient outcomes. These studies we introduce today, will improve the tribution protocol—along with a re- are being conducted at independent detection of ischemic heart disease, duction in exposure by hospital staff hospitals, clinics, and in university unmasking those missed by rest/ and the general public—but this ap- settings. Our initial reports in the lit- stress imaging. ● proach optimizes use of our radio- erature have demonstrated that as- isotope resources during a time of sessment of sestamibi and other Acknowledgement national and international shortage. technetium-99m acquired The authors would like to express their Limitations of the current study at rest will provide additional insight appreciation to Dr. Ronald Flory of include a failure to submit patients into tissue viability30 in addition to Waterloo, IA, who reviewed the man- to coronary angiography and its as- ischemia. Further studies are needed. uscript and provided the insight of a sociated risks if both rest/stress and family practitioner. FHRWW indicated no reason to sub- CONCLUSION ject the patient to an invasive proce- Blumgart’s original work demon- Author disclosures dure. Study participants also included strated that sequential measurement The authors report no actual or poten- individuals who were thought to have of radioactivity obtained in same- tial conflicts of interest with regard to that would support further di- state conditions could detect heart this article. agnostic evaluation. disease. Today’s SPECT cameras Additional centers are currently allow us to replace Blumgart’s Geiger Disclaimer studying FHRWW as the new stan- counter method with our own mod- The opinions expressed herein are those dard of care to be implemented based ern measuring device to measure ra- of the authors and do not necessarily

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