Author + information
- Published online August 16, 2017.
- Ron Blankstein, MD∗ ( and )
- Vikram Agarwal, MD, MPH
- Cardiovascular Imaging Program, Departments of Radiology and Medicine, Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Ron Blankstein, Noninvasive Cardiovascular Imaging Program, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Cardiac fluorodeoxyglucose (FDG) positron emission tomography (PET) has emerged as an important examination for evaluating patients with known or suspected cardiac sarcoidosis (CS). The utility of this test relates to the fact that it can provide information across several clinically relevant domains: 1) diagnosis (estimate the likelihood of cardiac involvement); 2) prognosis (determine the risk of future adverse events, thereby helping decide on the role of therapies that might lower their occurrence); 3) treatment (identify individuals who have greater burden of myocardial inflammation and are more likely to benefit from anti-inflammatory therapies); and 4) follow response to therapy.
With respect to the prognostic information provided by cardiac PET, prior studies have determined that abnormal cardiac PET findings in patients with known or suspected CS are associated with a higher risk of ventricular tachycardia or death, with patients who demonstrate both perfusion abnormalities (i.e., scarring or compression of the microvasculature) and focal uptake of F18-FDG (i.e., focal inflammation) having the highest risk of such adverse outcomes. In a study evaluating 118 patients with known or suspected CS, the presence of both a resting perfusion defect and abnormal metabolism was associated with a hazard ratio of 4 for predicting sudden cardiac death or ventricular tachycardia over a mean follow-up of 1.5 years (1). Importantly, these findings persisted even after accounting for ejection fraction, clinical risk factors, and the presence of extracardiac FDG uptake. Interestingly, focal uptake of FDG by the right ventricle, although rare, was associated with an even higher event rate. Further supporting the prognostic value of cardiac PET, a study that evaluated 31 patients with known or suspected CS found that abnormal FDG uptake was associated with a higher risk of adverse events, using a composite outcome that included ventricular tachycardia, congestive heart failure, heart block, and other arrhythmias (2). Another study that evaluated 27 consecutive patients who presented with either ventricular tachycardia or atrioventricular conduction block who were diagnosed with CS based on the Japanese Ministry of Health and Welfare criteria found that patients who presented with ventricular tachycardia had significantly higher FDG uptake when compared with those with atrioventricular conduction block and asymptomatic control subjects (3).
In this issue of iJACC, Sperry et al. (4) report the findings from a retrospective study of 203 patients referred to FDG PET for the evaluation of CS. They sought to assess the association of various quantitative measures of CS disease activity with adverse prognosis. The study population was representative of patients with suspected CS, because 72% had known extra CS, 35% were treated with immunosuppressive therapies, 39% had a prior history of ventricular arrhythmias, and 50% had implantable cardioverter-defibrillators. Over a mean follow-up of 1.8 years there were 63 adverse events (death, ventricular arrhythmias, or heart transplantation). The authors found that when compared with a qualitative interpretation of the presence or absence of resting perfusion defects or focal areas of myocardial inflammation, a semiquantitative measure that incorporates the extent and severity of perfusion defects in segments showing myocardial inflammation (i.e., perfusion metabolism mismatch) and a quantitative analysis of the degree of FDG uptake heterogeneity provided the most robust risk stratification.
It is noteworthy to further explore these 2 scores. The strongest association with adverse events was present for a summed rest score (SRS) of all segments that showed a perfusion metabolism mismatch. The second score showing a significant association with adverse prognosis was the coefficient of variation (COV) of FDG signal, a measure of heterogeneity of metabolism that is calculated by dividing the standard deviation of the FDG uptake by the myocardium by the average uptake of the 17 segments. Because patients with active CS may simultaneously demonstrate various patterns of disease activity, patients with greater CS involvement often have considerable variability in the amount and intensity of FDG uptake. By quantifying this underlying heterogeneity, COV may provide a better measure of disease activity than a visual interpretation alone where differences in normalization and areas of incomplete FDG suppression by normal segments of myocardium may result in overestimation of disease activity.
Although determining the SRS in segments that have abnormal FDG uptake is a rapid semiquantitative technique that can be rapidly determined by viewing a standard cardiac display of the perfusion and FDG images, calculating the COV requires additional calculations and a workstation capable of measuring this parameter.
Aside from providing a measure of disease activity, the other advantage of using quantitative metrics of disease activity, rather than solely relying on a qualitative interpretation, is overcoming errors from differences in normalization present when “hot spot” imaging is performed. Such differences can lead to an overestimation of disease activity in the myocardium, but can also be appreciated when limited whole-body images are obtained, because normalization in such images is performed relative to the most intense area in the body, rather than the most intense signal in the heart. Another potential benefit of using COV is to identify patients without cardiac disease who may demonstrate diffuse uptake of FDG, especially in the presence of normal myocardial perfusion. However, no studies to date have shown whether COV can distinguish areas of abnormal FDG uptake from nonspecific physiological uptake.
As opposed to the SRS typically used in nuclear cardiology, which often reflects the overall extent and severity of scar (or hibernating myocardium), a resting perfusion in patients with CS can also be caused by intense inflammation that compresses the microvasculature. Prior studies have identified that patients who have both active inflammation and a resting perfusion defect have the worse prognosis, likely reflecting the fact that these individuals have more advanced disease, but also suggesting that having significant myocardial inflammation in itself may be associated with adverse events. However, Sperry et al. (4) found that a semiquantitative score of FDG uptake did not provide any significant incremental prognostic value. The limited value of such a score is related to the fact that FDG signal in the myocardium is affected by differences in normalization. For this reason, when assessing the extent of FDG uptake, it is advisable to use quantitative technique (i.e., quantifying the volume of increased FDG by the myocardium, as previously described by others [2,5,6]). In other words, a semiquantitative score of FDG uptake is unlikely to be accurate in truly representing the severity of FDG uptake. However, this may be less of an issue for evaluating the SRS of segments that have FDG uptake, and may be why the SRS was found to be a more robust measure than the 17-segment FDG score. The score proposed by Sperry et al. (4) also does not account for large area of scar (i.e., resting perfusion defects without inflammation), or areas of focal uptake of FDG uptake by the right ventricle.
The advantage of the “SRS in segments with abnormal FDG” score is that it is easy to perform and should be familiar to most nuclear cardiologists. However, the scores proposed by Sperry et al. (4) do require high-quality FDG PET imaging with careful attention to patient preparation and diet (7). Ultimately, suboptimal suppression of FDG uptake from the myocardium could lead to erroneous scores, in the same way that they would interfere with the visual interpretation of FDG PET imaging.
Although the study by Sperry et al. (4) provides important data on how to quantify and report CS PET studies (Tables 1 and 2), future studies are required to determine whether these semiquantitative or quantitative approaches lead to any improvement in patient management or outcomes.
In summary, Sperry et al. (4) should be congratulated on providing important data on the incremental prognostic value of quantitative FDG PET imaging. Although replication of these results is needed, they do pave the way for incorporating more quantitative approaches for evaluating patients with known or suspected CS referred for cardiac PET imaging.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
- Blankstein R.,
- Osborne M.,
- Naya M.,
- et al.
- McArdle B.A.,
- Birnie D.H.,
- Klein R.,
- et al.
- Sperry B.W.,
- Tamarappoo B.K.,
- Oldan J.D.,
- et al.
- Waller A.H.,
- Blankstein R.
- Osborne M.T.,
- Hulten E.A.,
- Murthy V.L.,
- et al.