University of Groningen
Role of quantitative and gated myocardial perfusion PET imaging
Monroy-Gonzalez, A. G.
DOI:
10.33612/diss.132603282
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2020
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Monroy-Gonzalez, A. G. (2020). Role of quantitative and gated myocardial perfusion PET imaging.
University of Groningen. https://doi.org/10.33612/diss.132603282
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CHAPTER
CONCLUDING REMARKS AND
FUTURE PERSPECTIVES
Chapter 8
The aim of this thesis was to expand our understanding of quantitative myocardial perfusion and ventricular synchrony measured by 13N-ammonia
positron emission tomography (PET). This thesis started with a brief description of the production, pharmacokinetic parameters and imaging protocol of 13N-ammonia. Furthermore, chapter 1 outlined the current clinical
role of myocardial perfusion with PET.
QUANTITATIVE MYOCARDIAL PERFUSION
PET allows for the quantification of stress myocardial blood flow (MBF) and myocardial flow reserve (MFR), which are parameters used to the establish diagnosis and prognosis of patients with suspected coronary artery disease (CAD) [1,2]. Because it is fundamental that quantitative PET perfusion parameters provide reproducible results, chapter 2 was focused on the importance of careful interpretation of PET myocardial perfusion quantification provided by different software packages (SPs). While previous studies had demonstrated an overall moderate-to-good agreement of SPs, those studies were mostly performed in populations with a low-to-intermediate likelihood of CAD, which do not represent the clinical daily practice of patients who undergo PET myocardial perfusion assessment [3–5]. The aim of this study was to explore agreement in quantification of myocardial perfusion parameters with
13N-ammonia PET by cross-comparison of three clinically implemented SPs
(QPET, SyngoMBF, and Carimas) in three distinguishable population profiles, namely: patients with normal perfusion imaging, patients with reversible perfusion defects, and patients with fixed perfusion defects. Our results showed that global PET myocardial perfusion quantifications frequently had an adequate agreement between the considered SPs. However, patients with reversible defects had the worst agreement in global stress MBF and MFR and discrepancies showed to be regional dependent. This study suggested that agreements between SPs are variable and that careful interpretations of PET myocardial perfusion quantification provided by different SPs are warranted, especially with findings compatible with myocardial ischemia. This chapter provided an insight on some of the technical challenges of myocardial perfusion quantification useful for the evaluation of the following chapters.
With regard to the clinical use of quantitative myocardial perfusion, chapter 3 and 4 focused on the diagnostic and prognostic value of PET in patients with microvascular dysfunction. In chapter 3 we presented the results from
Concluding remarks and future perspective
our study reporting the long-term prognostic value of quantitative myocardial perfusion in patients with chest pain and normal coronary arteries. It is known that many patients that are referred to invasive coronary angiography due to suspected obstructive CAD do not present significant coronary stenosis [6,7]. Since assessing the cardiovascular risk is a clinical challenge in this group of patients, we aimed to evaluate whether stress MBF and/or MFR could predict all-cause mortality and major adverse cardiac events (MACE) at long-term follow-up in patients with chest pain and normal or near-normal coronary arteries. After a median follow-up of 8 years, the results showed that patients with chest pain, normal coronary arteries, and low stress MBF and/or MFR have an increased risk for cardiovascular events. MFR was a good predictor of all-cause mortality, while MFR and stress MBF showed to be good predictors of MACE. In accordance with the conclusions from chapter 2, an adjusted analysis was needed to demonstrate the validity of our results despite the use of different cameras and software during the acquisition of PET scans. Hence, this study suggested that quantifying the impairment of microvascular function may help predict the onset of adverse cardiovascular events. Our results indicated that especially MFR could help clinicians to identify those patients who would benefit from a therapy aimed at preventing future cardiovascular events and to relieve symptoms of angina.
Another cardiac condition that is not necessarily related to obstructive CAD is myocardial bridging (MB). MB is a band of myocardium overlying a segment of a coronary artery that may produce a functional occlusion [8]. Until now, its clinical significance remains unclear since clinical presentation varies from asymptomatic patients to even sudden cardiac death [9,10]. In
chapter 4 we quantitatively evaluated the influence of MB of the left anterior
descending artery (LAD) on myocardial perfusion of the entire left ventricle. We found that LAD-MB was related to decreased MFR in the three coronary territories of the left ventricle, regardless of the anatomical characteristics of the MB. Assuming that quantitative myocardial perfusion parameters can predict adverse cardiovascular events, as mentioned in chapter 3, quantitative myocardial perfusion assessment may be a promising tool to help better understand the clinical significance of LAD-MB and to help identify patients who may benefit from further therapies. This hypothesis is consistent with a meta-analysis reporting that MB is related to major adverse cardiac events [5], however, prospective studies are needed to confirm whether stress MBF and MFR hold a prognostic value in patients with MB. Of note, this chapter
Chapter 8
highlights the possible utility of cardiac hybrid imaging with PET/coronary computed tomography angiography (CCTA) as a technique that allows anatomical and functional evaluation of the heart in a single study session.
The chapter that follows also could not have been performed without the use of cardiac hybrid imaging with PET/CCTA. Transluminal attenuation gradient (TAG) is a measurement representing the gradient of intraluminal contrast that decreases along a coronary vessel, which can be easily calculated with CCTA. It has previously been shown that TAG is more negative in patients with CAD than in patients without it, hence, it has been proposed as a parameter to identify hemodynamically significant stenosis [11,12]. In
Chapter 5 we explored whether myocardial perfusion parameters are related
to TAG. Therefore, we studied a consecutive group of patients who underwent a two-phase hybrid 13N-ammonia PET/CCTA. Results showed that TAG was
not only more negative in patients with CAD but also correlated with stress MBF and MFR. In this chapter we concluded that TAG could represent a complementary tool in assessing intermediate lesions, patients with severe calcification or when assessment of myocardial perfusion is not available.
VENTRICULAR SYNCHRONY
Ventricular mechanical synchrony by means of PET is a tool that is starting to gain popularity. Other non-invasive imaging modalities, such as echocardiography, equilibrium radionuclide angiocardiography, and single-photon emission computed tomography (SPECT), have been previously evaluated for the assessment of mechanical synchrony but less has been reported regarding the use of PET for this purpose. In chapter 6 we summarized the technical principles on the use of PET for mechanical synchrony. Furthermore, we reported previous studies that support the clinical use of myocardial synchrony measured by PET. Special attention is given to the detection of myocardial stunning and ischemia-induced dyssynchrony for the assessment of CAD and selection of patients with HF that may benefit of cardiac resynchronization therapy (CRT).
As mentioned in chapter 6, evaluation of ventricular mechanical synchrony may be of importance in patients with multivessel CAD and in HF patients who may benefit from CRT, as suggested by the independent inverse relationship between quantitative myocardial perfusion and PET ventricular synchrony [13].
Concluding remarks and future perspective
Chapter 7 explored the relationship between PET quantitative myocardial
perfusion, perfusion defects and synchrony parameters in patients with chronic HF. This study showed that stress MBF and MFR are not independent predictors of ventricular mechanical synchrony in patients with chronic HF. On the contrary, summed rest score, a marker of fixed defects, was the strongest independent predictor of peak stress ventricular mechanical synchrony parameters. The results suggested that in patients with HF, it may be more convenient to concentrate on the characterization of the fixed perfusion defects in order to improve the management of arguably relevant ventricular mechanical dyssynchrony.
FUTURE PERSPECTIVES
Due to the widespread of PET around the world, future studies should be performed to determine in more detail the contribution of myocardial perfusion and myocardial synchrony parameters measured by PET, in different populations.
Fundamentally, it is important to continue with the validation of technical aspects of PET. One of the issues that emerges from chapter 2 is that exchangeability between SPs was especially suboptimal among patients myocardial ischemia. This is important to consider because in this group of patients the referral question is whether intervention may be beneficial or not. This group also represents the target study population of many studies that aim to evaluate the diagnosis and prognostic value of PET in patients with CAD. Reproducibility of PET parameters is then needed to ensure an adequate comparison and extrapolation of results of different study populations. Resolution, proper attenuation correction, correction for partial volume effects, patient and cardiac motion, and image processing are important points to address that could refine reproducibility [14]. Deep learning and other new processing techniques are promising tools that are expected to additionally improve the reproducibility of clinical PET parameters. For example, motion correction with such processing techniques is the topic of an ongoing collaboration of the University Medical Center Groningen with A.A. Martinos Center/Massachusetts General Hospital and the PET/CT Unit from the Universidad Nacional Autónoma de México.
Chapter 8
Despite the fact that the current main clinical utility of myocardial perfusion with PET is to diagnose functional CAD, as mentioned in chapter 1, it is still unclear the clinical application of each non-invasive functional test. The 2018 guideline on myocardial revascularization from the European Society of Cardiology (ECS) only recommends non-invasive functional tests in stable patients with CAD before elective invasive procedures for CAD [15]. Similarly, the current guideline of the Dutch College of General Practitioners for the assessment of patients with angina pectoris only limits itself to mention the use of stress-ECG for the assessment of patients with intermediate risk of CAD. More recently, the 2019 guideline from the ESC for the diagnosis and management of chronic coronary syndromes initially recommends CCTA or non-invasive functional testing for diagnosing CAD [16]. Therefore, future research is needed to fill the current gap of knowledge from the current guidelines [14,15]. Especially, the cost-benefit of only stress myocardial perfusion imaging tests that allows reduction of radiation exposure [16], the comparison of advantages and disadvantages of PET versus other functional tests, such as SPECT, or CMR, as well as the possible benefits from the use of multimodality imaging in different clinical scenarios represents a wide interesting field to address. Also, it may be interesting to compare PET to new techniques, such as TAG. Whether TAG may increase the diagnostic value of CCTA or have prognostic value comparable to quantitative myocardial perfusion parameters for the detection of CAD (as mentioned in chapter 3) is an interesting hypothesis for future studies.
Some other clinical presentations in which the use of quantitative PET appear to be a potential option are left main or multi-vessel disease, intermediate lesions, normal coronaries accompanied by angina, anomalous coronary artery anatomy, cardiomyopathies, high risk asymptomatic adults, fistulas or myocardial bridging, complicated multiple previous revascularizations (CABG/PCI) [17]. In those populations, the use of absolute myocardial perfusion quantification and flow reserve could allow for risk classification despite the absence of visual perfusion defects. However, current guidelines are still vague as already mentioned. Presently, the use of PET for the assessment of suspected coronary microvascular angina is considered as a IIb class recommendation B level of evidence [16]. This thesis suggests that assessment of vasodilator capacity may improve the identification of patients with an increased cardiovascular risk. Women, which represent up to 50% of patients with normal coronary arteries referred to invasive
Concluding remarks and future perspective
coronary angiography due to suspected obstructive CAD, could potentially benefit from future research focused on the role of quantitative PET for the estimation of cardiovascular risk. Furthermore, this thesis suggests that prospective studies using PET in patients with MB may explain the increased adverse cardiovascular consequences on this group of patients. Whether PET could also guide therapies when significant CAD is present remains an open question, however, long-term prospective studies will be needed in order to achieve all these goals.
Moreover, it is important to remember than an integrative assessment of myocardial PET studies may increase the diagnostic and prognostic information provided by the scan. It is currently ambitioned that assessment of dyssynchrony PET will provide useful information in the case of patients with ischemia who will undergo CRT to improve their left ventricular function. Until now, selection of patients with HF who may undergo CRT is inaccurate and the ESC 2013 guidelines on cardiac pacing and cardiac resynchronization therapy only report higher proportions of CRT responders among patients with wider QRS, left bundle branch block (LBBB), females, and non-ischemic cardiomyopathy as well as lower proportions of responders among male patients, ischemic cardiomyopathy, patients with narrower QRS (<150 ms), and no-LBBB [18]. It is expected that no single measure will predict response to CRT, however, the use of PET for the assessment of myocardial perfusion in combination with ventricular mechanical synchrony is a promising tool that needs to be better studied in different heterogeneous populations.
In conclusion, even though PET has gained popularity for the assessment of CAD, progress still needs to be made in order to standardize protocols and to understand other potential clinical applications, such as the assessment of vasodilator capacity as a marker of cardiovascular risk or the assessment of mechanical synchrony in patients with HF.
Chapter 8
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