Long-Term Prognostic Value of 13 N-Ammonia Myocardial Perfusion Positron Emission Tomography

Journal of the American College of Cardiology Vol. 54, No. 2, 2009 2009 by the American College of Cardiology Foundation ISSN 0735-1097/09/$36.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2009.02.069 Cardiac Imaging Long-Term Prognostic Value of 13 N-Ammonia Myocardial Perfusion Positron Emission Tomography Added Value of Coronary Flow Reserve Bernhard A. Herzog, MD,* Lars Husmann, MD,* Ines Valenta, MD,* Oliver Gaemperli, MD,* Patrick T. Siegrist, MD,* Fabian M. Tay, MD,* Nina Burkhard, MD,* Christophe A. Wyss, MD,* Philipp A. Kaufmann, MD* Zurich, Switzerland Objectives Background The goal of this study was to assess the predictive value of myocardial perfusion imaging with 13 N-ammonia positron emission tomography (PET) and coronary flow reserve (CFR) on long-term prognosis in patients with suspected myocardial ischemia. No prognostic data exist on the predictive value of CFR and 13 N-ammonia PET. Methods Perfusion and CFR were assessed in 256 patients using 13 N-ammonia PET, and follow-up was obtained in 245 (96%) patients. Sixteen early revascularized patients were excluded and 229 were assigned to normal versus abnormal perfusion or normal versus abnormal CFR ( 2.0). Major adverse cardiac events (MACE) (cardiac death, nonfatal myocardial infarction, late revascularization, or hospitalization for cardiac reasons) were assessed using the Kaplan-Meier method. Cox proportional hazard regression was used to identify independent predictors for cardiac events. Results Conclusions During follow-up (5.4 2.2 years), 78 patients had at least 1 cardiac event, including 29 cardiac deaths. Abnormal perfusion (n 126) was associated with a higher incidence of MACE (p 0.001) and cardiac death (p 0.05). In patients with normal perfusion, abnormal CFR was independently associated with a higher annual event rate over 3 years compared with normal CFR for MACE (1.4% vs. 6.3%; p 0.05) and cardiac death (0.5% vs. 3.1%; p 0.05). In abnormal perfusion, CFR remained predictive throughout the 10-year follow-up (p 0.001). Perfusion findings in 13 N-ammonia PET and CFR are strong outcome predictors. CFR allows further risk stratification, suggesting a warranty period of 3 years if normal CFR is associated with normal perfusion. Conversely, in patients with abnormal perfusion, an impaired CFR has added value for predicting adverse outcomes. (J Am Coll Cardiol 2009;54:150 6) 2009 by the American College of Cardiology Foundation A large body of literature has established evidence that myocardial perfusion imaging (MPI) with single-photon emission computerized tomography (SPECT) not only allows accurate detection of coronary artery disease (CAD) but also reliably discriminates between patients at low versus high risk of major adverse cardiovascular events (MACE) including cardiac death (1). A normal SPECT MPI may reliably exclude an adverse outcome, even in the presence of coronary lesions. This has recently From the *Cardiac Imaging Section, University Hospital Zurich, Zurich, Switzerland; and the Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. Dr. Kaufmann was supported by a grant from the Swiss National Science Foundation (SNSF-professorship grant no. PP00A-114706) and by the ZIHP (Zurich Center for Integrative Human Physiology, University of Zurich, Switzerland). Manuscript received October 7, 2008; revised manuscript received January 30, 2009, accepted February 17, 2009. been extended to MPI with perfusion emission tomography (PET) and 82 Rb (2), although data on head-tohead comparison in large trials is missing. PET has been reported to confer increased accuracy over SPECT (3 5). See page 157 The superiority of PET has been attributed to technical characteristics such as higher photon energy, improved resolution, and intrinsic attenuation correction. The latter has enabled PET to emerge as a unique technique for noninvasive assessment of absolute quantitative myocardial blood flow (MBF), from which coronary flow reserve (CFR) can be calculated (6). CFR has been proposed as an index to evaluate the coronary circulation in the epicardial coronary arteries and in microcirculation.

JACC Vol. 54, No. 2, 2009 July 7, 2009:150 6 Herzog et al. Added Prognostic Value of CFR by PET 151 Outcome data on PET MPI are scarce, and outcome data on CFR are limited to subgroups of patients such as those with nonischemic dilative (7) or hypertrophic cardiomyopathy (8). The aim of the present study was to evaluate the long-term prognostic value of 13 N-ammonia PET and the potential added value of CFR in an unselected population of patients with suspected myocardial ischemia. Methods Patient population. This retrospective study included 256 patients who underwent PET imaging because of suspicion of impaired myocardial perfusion; 150 of these patients had known CAD. Follow-up was accomplished by obtaining a structured interview and a clinical history. Cardiovascular risk factors such as hypertension, hypercholesterolemia, smoking, diabetes mellitus, or positive family history for CAD were assessed at the time of PET imaging by reviewing patient charts. The protocol was reviewed by the local research ethics boards of the University Hospital Zurich, the need for written informed consent was waived, and verbal consent on the telephone was obtained. PET. 13 N-ammonia PET was assessed in a 1-day protocol at rest and during adenosine stress at a standard rate (0.14 mg/min/kg) over 7 min, as previously reported (9). All patients received a 700- to 900-MBq injection of 13 N- ammonia into a peripheral vein during 10 s as a slow bolus. Images were acquired in 2-dimensional mode either on a GE Advance PET scanner or on a discovery (LS/RX) PET/computed tomography (CT) scanner (both GE Healthcare, Milwaukee, Wisconsin), with a field of view between 14.6 and 15.7 cm. The optimal imaging position was determined on a CT scout scan or a 2-min short transmission scan with an external 68 Ge source. Dynamic acquisitions of the emission scans were performed using a standard protocol consisting of 9 10-s, 6 15-s, 3 20-s, and 1 900-s frames. Transmission scan for photon attenuation correction was performed with an external 68 Ge source or low-dose CT attenuation correction (nongated, 140 kv, 120 to 150 ma, and slice thickness: 3.75 to 4.75 mm) (10). Images were reconstructed using filtered back projection, and for review the images were resliced in short-axis as well as in vertical and horizontal long-axis orientation. Data analysis. Regional 13 N-ammonia uptake was assessed using the 17-segment model and the semiquantitative scoring system of defect severity and extent, as recommended by the American Society of Nuclear Cardiology (11). A scan was considered normal if the summed stress score (SSS) was 4, mildly abnormal if the SSS was between 4 and 8, and moderately to severely abnormal if the SSS was 8, as previously reported in PET studies (2). Image interpretation according to these definitions was performed by 2 experienced readers. Diverging interpretations were classified by consensus. Quantitative MBF was determined using the PMOD software package (version 2.1 to 2.8, PMOD Technologies Ltd., Zurich, Switzerland) developed and validated at our institution (12,13). Therefore, a spherical region of interest was placed into the blood pool of the left ventricle. Myocardial and blood pool time-activity curves were generated from the dynamic frames and corrected for radioisotope decay. MBF was estimated by model fitting of the blood pool and myocardial timeactivity curves (14) correcting for partial volume and spillover, as previously described (15). CFR was calculated as the ratio of hyperemic to resting MBF, and CFR 2.0 was considered normal (16). The CFR values of the 17 segments were assigned to the 3 coronary territories according to Cerqueira et al. (17). Territories with perfusion defects were Abbreviations and Acronyms CABG coronary artery bypass grafting CAD coronary artery disease CFR coronary flow reserve MACE major adverse cardiac advents MBF myocardial blood flow MPI myocardial perfusion imaging PCI percutaneous coronary intervention PET perfusion emission tomography SPECT single-photon emission computerized tomography SSS summed stress score assumed to be subtended by coronary vessels with CAD; the other segments were classified as remote. Mean regional CFR was assessed for CAD and remote segments. Long-term follow-up. Patient follow-up was obtained by use of a questionnaire that was assessed by a phone call to all patients and/or general practitioners or cardiologists. If unsuccessful, an identical written questionnaire was sent. Additional information was gathered from medical charts and the registry of government authorities in case of death. The mean follow-up was 5.5 2.1 years. End points were defined as cardiac death or MACE, including cardiac death (as declared in the medical charts), nonfatal myocardial infarction (18), and hospitalization for any cardiac reasons including late percutaneous coronary intervention (PCI) or late coronary artery bypass grafting (CABG). CABG and PCI within 60 days after PET scan were considered to be triggered by the scan and therefore were excluded from further analysis. The date of the last examination or consultation was used to determine follow-up. Statistical analysis. Continuous data were expressed as mean SD. Differences in survival over time were analyzed by the Kaplan-Meier method. The log-rank test was used to compare the survival curves. Univariate and multivariate Cox proportional hazard regression models were used to identify independent predictors of cardiac events. Variables were selected in a stepwise forward selection manner; entry and retention sets with a p 0.05 were considered to indicate a significant difference. Variables included in the models were age, male sex, hypertension, hypercholesterolemia, smoking, diabetes mellitus, a positive family history for CAD, abnormal perfusion, and an impaired CFR ( 2.0). A variable s risk was expressed as hazard ratio with

152 Herzog et al. JACC Vol. 54, No. 2, 2009 Added Prognostic Value of CFR by PET July 7, 2009:150 6 corresponding 95% confidence interval. A p value 0.05 was considered significant. All statistical analysis was conducted using SPSS software (version 15.0, SPSS Inc., Chicago, Illinois). Results Patient characteristics. 13 N-ammonia PET was performed in 256 patients. Follow-up was successful in 245 (96%) patients. Of these, 16 patients were excluded due to early revascularization ( 60 days). Baseline characteristics of the remaining 229 patients in the final analysis are given in Table 1. Perfusion findings and CFR. 13 N-ammonia uptake was normal in 103 patients and abnormal in 126 patients. The detailed distribution of patients with normal or reduced CFR in relation to perfusion findings is given in Table 2. In 109 of 126 patients with abnormal perfusion, regional CFR values were available. CFR was significantly lower in the defect zone (1.8 0.7) than in remote territories (2.3 0.9; p 0.001). Outcome data. During 5.5 2.1 years of follow-up, cardiac death occurred in 29 patients, and there were hospitalizations due to any cardiac reason in 47 patients, including CABG in 14 patients, and late PCI and nonfatal myocardial infarction in 30 patients. The Kaplan-Meier survival curves indicated that patients with an abnormal PET perfusion had a significantly higher rate of MACE (p 0.001) and cardiac death (p 0.05) compared with those with normal perfusion (Fig. 1A). Similarly, patients with abnormal CFR had a significantly higher rate of MACE (p 0.001) and cardiac death (p 0.05) than those with normal CFR (Fig. 1B). The predictive values of Baseline Characteristics Table 1 Baseline Characteristics n 229 Age, yrs 60 12 Males 69 Females 31 Hypertension 60 Hypercholesterolemia 59 Diabetes mellitus 18 Smoking 42 Positive family history 36 Coronary artery disease 66 Previous revascularization PCI 29 CABG 24 Angina symptoms (CCS class 2) 62 Dyspnea (NYHA functional class II) 24 Medication Platelet aggregation inhibitor 91 Anti-ischemic agents 82 Lipid-lowering agents 66 Data are presented as mean SD or % of patients. CABG coronary artery bypass grafting; CCS Canadian Cardiovascular Society; NYHA New York Heart Association; PCI percutaneous coronary intervention. Incidence Cardiac Death of MACE (10-Year and Follow-Up) Table 2 both perfusion and CFR findings proved to be significant (p 0.001 and p 0.05, respectively) by Cox regression analysis and were confirmed to be noninteracting predictors by the interaction test. In addition, by multivariate analysis, CFR and perfusion were independently associated with MACE (CFR, p 0.05; perfusion, p 0.001). CFR was also independently associated with death (p 0.05); this analysis fell short of statistical significance for perfusion defect (p 0.05) (Table 3). Moreover, chi-squared values significantly improved when CFR was added to the multivariate analysis (MACE, p 0.05; cardiac death, p 0.01). In patients with abnormal perfusion, CFR allowed further stratification of cardiac risk throughout the full follow-up of 10 years (Fig. 2A). The added predictive value of CFR for MACE (p 0.05) and cardiac death (p 0.05) was preserved even if the abnormal perfusion group was further subdivided into mild and moderate to severe defects. In patients with normal perfusion CFR did not allow prediction of events throughout the full 10-year period of observation (Fig. 2B); the survival curves started to converge after the third follow-up year, resulting in an average annual rate of 1.7% per year for MACE and 0.07% for cardiac death. For the first 3 years, however, pathologic CFR was associated with a significantly higher annual event rate for MACE (6.25% vs. 1.4% per year; p 0.05) and cardiac death (3.1% vs. 0.5% per year; p 0.05) compared with normal CFR (Fig. 3). Discussion Incidence of MACE and Cardiac Death (10-Year Follow-Up) Outcomes Separate predictive value of perfusion and CFR Perfusion CFR MACE (n 76) Cardiac Death (n 29) p Value Normal (n 103) 17 (16.5%) 7 (6.8%) 0.001 Abnormal (n 126) 59 (46.8%) 22 (17.5%) 0.05 Normal (n 127) 30 (23.6%) 8 (6.3%) 0.001 Abnormal (n 102) 46 (45.1%) 21 (20.6%) 0.05 Added value of CFR combined with perfusion Perfusion normal CFR normal (n 71) 10 (14.1%) 4 (5.6%) NS CFR abnormal (n 32) 7 (21.9%) 3 (9.4%) NS Perfusion abnormal CFR normal (n 56) 20 (35.7%) 4 (7.1%) 0.05 CFR abnormal (n 70) 39 (55.7%) 18 (25.7%) 0.05 p values indicate results from log-rank test. CFR coronary flow reserve; MACE major adverse cardiac events; NS nonsignificant. The advantage of PET over SPECT has often been attributed to the ability of PET to assess CFR. However, no data exist on outcomes in an unselected population group, although CFR has been reported to inversely correlate to the Framingham risk score (19). Our results demonstrate an

JACC Vol. 54, No. 2, 2009 July 7, 2009:150 6 Herzog et al. Added Prognostic Value of CFR by PET 153 Figure 1 Kaplan-Meier Survival Curves (Unadjusted) for the Entire Study Population (A) Perfusion findings predict major adverse cardiac events (MACE) (left) and cardiac death (right) in the entire study population. (B) Coronary flow reserve (CFR) predicts MACE (left) and cardiac death (right) in the entire study population. Predictors of Events at Univariate and Multivariate Analyses Table 3 Predictors of Events at Univariate and Multivariate Analyses added prognostic predictive value of CFR over perfusion findings alone because CFR was an independent predictor of adverse outcome. In fact, in patients with normal perfusion, an abnormal CFR allowed further discrimination of patients with high annual event rates from those with low annual event rates. This predictive value was maintained Major Adverse Cardiac Events Cardiac Death Predictors Univariate Multivariate Univariate Multivariate Age 1.04 (1.02 1.06) 0.001 1.03 (1.01 1.05) 0.01 1.06 (1.02 1.10) 0.01 1.05 (1.01 1.09) 0.01 Male 2.90 (1.52 5.44) 0.001 NA NS 1.99 (0.76 5.23) NS NA NS Hypertension 1.28 (0.80 2.04) NS NA NS 0.98 (0.47 2.05) NS NA NS Hypercholesterolemia 1.23 (0.77 1.96) NS NA NS 0.93 (0.44 1.95) NS NA NS Diabetes mellitus 1.80 (1.07 3.01) 0.05 1.94 (1.14 2.87) 0.05 0.74 (0.47 2.86) NS NA NS Smoking 1.78 (1.14 2.79) 0.05 1.78 (1.10 2.87) 0.05 2.24 (1.06 4.76) NS 2.40 (1.13 5.11) 0.05 Positive family history 1.13 (0.71 1.80) NS NA NS 0.70 (0.31 1.57) NS NA NS Abnormal perfusion 3.46 (2.02 5.94) 0.001 2.58 (1.48 4.49) 0.001 2.68 (1.14 6.27) 0.05 NA 0.05 Impaired CFR 2.14 (1.35 3.37) 0.001 1.60 (1.00 2.57) 0.05 3.53 (1.56 7.97) 0.01 2.86 (1.24 6.59) 0.05 CFR coronary flow reserve; CI confidence interval; NA not applicable; NS nonsignificant.

154 Herzog et al. JACC Vol. 54, No. 2, 2009 Added Prognostic Value of CFR by PET July 7, 2009:150 6 Figure 2 Kaplan-Meier Survival Curves (Unadjusted) Showing Prognostic Value of CFR in Patients With Abnormal Versus Normal Perfusion (A) CFR predicts MACE (left) and cardiac death (right) in patients with abnormal perfusion findings. (B) The prognostic value of CFR to predict MACE (left) and cardiac death (right) in patients with normal perfusion is confirmed to the first 3 years; survival curves merge throughout the subsequent years of follow-up. Abbreviations as in Figure 1. over 3 years of follow-up; the survival curves converged during the following years. This may suggest a warranty period of about 3 years for a normal perfusion associated with a normal CFR by 13 N-ammonia PET; a normal CFR in patients with normal perfusion cannot predict long-term disease onset. However, patients with normal perfusion and impaired CFR seem to be at increased risk for cardiac events and death. In these patients, CFR probably reflects coronary endothelial and microcirculatory dysfunction, and relevant epicardial coronary obstructive disease is unlikely. In fact, in the past 2 decades, a number of studies have reported that abnormalities in function and structure of the coronary microcirculation occur in many clinical conditions. In some cases, dysfunction of the coronary microcirculation may be an indicator of early atherosclerosis preceding overt CAD (16). Therefore, coronary microvascular dysfunction in the absence of obstructive CAD has been described as a functional counterpart of traditional coronary risk factors. Since this type of dysfunction is at least partly reversible, its assessment might be used to guide interventions aimed at reducing the burden of risk factors (16). Similarly, a recent study found an increased calcium score as a predictor of adverse outcome in patients with normal MPI PET using 82 Rb (20). This supports our findings, as an increased calcium score has been associated with coronary endothelial dysfunction (21). Invasively assessed coronary endothelial dysfunction has also been associated with adverse outcome in patients with cardiovascular risk factors (22). Our study extends this observation to an unselected patient population by noninvasive assessment of CFR, which allows its clinical application in clinical routine. As CFR can be repeatedly assessed due to its noninvasive nature, it has been suggested

JACC Vol. 54, No. 2, 2009 July 7, 2009:150 6 Herzog et al. Added Prognostic Value of CFR by PET 155 Figure 3 Kaplan-Meier Survival Curves (Unadjusted) Showing Added Value of CFR in Predicting Outcome up to 3 Years Normal perfusion (3-year follow-up). Abnormal CFR predicts adverse outcome, that is, MACE (A) and cardiac death (B), despite normal perfusion. This is reflected by the higher annual event rate (% per year) in abnormal CFR (C). Abbreviations as in Figure 1. as a tool for monitoring effects of risk factor modification such as lipid-lowering treatment (23). Whether this translates into improved risk modification and prognostic benefit remains to be elucidated. Interestingly, in patients with overt ischemia, as evidenced by abnormal PET perfusion, CFR is a strong prognostic predictor. In contrast to the finding in normal perfusion, this predictive value was maintained to the end of follow-up. It appears that CFR is a strong predictor of disease progression once disease is present. This may be due to the fact that impaired CFR may indicate extension of the disease beyond the epicardial coronary arteries down to the microcirculation, representing a more advanced disease stage that is, thus, more prone to deterioration. Study limitations. A limitation of the present study may be the use of global but not regional CFR, because in the global value the regional findings may be diluted. Although CFR was lower in CAD segments, the effect of dilution may be counterbalanced by the fact that CFR may also be impaired in remote segments of CAD patients, which is in line with previous reports (24). In addition, global CFR values represent an integration of both extent and severity of perfusion defects, as a small defect with very low CFR and a larger defect with slightly decreased CFR will result in the same reduction in global CFR, appropriately indicating the same risk. This may explain why global CFR proved an independent predictor of risk in our study and is in line with the concept of SSS as a global risk predictor according to the American Society of Nuclear Cardiology (11). However, the global CFR seems to be most appropriate to include the aspect of microcirculatory dysfunction without or in addition to epicardial coronary disease. Furthermore, for reasons of practicality, the use of global CFR seems preferable over regional CFR values because the repeatability and the reproducibility of global CFR are substantially superior to those of regional CFR (25,26). The retrospective nature of this study and the limited number of patients, particularly in the subgroup with normal perfusion and impaired CFR, may represent a limitation. Therefore, larger prospective studies to further support the prognostic value of quantitative PET imaging are needed. Furthermore, the Kaplan-Meier survival curves are not risk-adjusted. However, the independent added value of CFR in predicting outcome was documented by multivariate Cox analysis. Finally, it could be perceived as a weakness of our study that we included an unselected patient population with and without CAD and/or other myocardial diseases. However, the aim of the present study was to evaluate the added value of CFR in a general patient group referred for PET, which allows the noninvasive assessment of CFR. Nevertheless, the annual event rates for MACE (1.7%) and for cardiac death (0.7%) for the total 10-year period in patients with normal perfusion are well within the previously reported values of 1.6% to 1.8% for MACE (2,27,28) in normal SPECT and PET and 0.9% for

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