Simultaneous acquisition cardiac positron emission tomography-magnetic resonance imaging (PET-MRI) provides anatomic and quantitative cardiac MRI and PET data in 1 imaging session. Specific PET radiotracers can provide information on myocardial perfusion, viability, and inflammation, yielding a thorough characterization of cardiomyopathies such as cardiac sarcoid, amyloid, and myocarditis. Although initial clinical and research efforts in PET-MRI have centered on oncologic and neurological applications, there have been many publications assessing PET-MRI for cardiac imaging applications.1–4
Simultaneous acquisition cardiac PET-MRI combines the reference standard for myocardial perfusion (PET) with the reference standard for functional assessment (gated cine MRI). In addition, cardiac PET-MRI has the ability to assess viability both by 18F-fluorodeoxyglucose (18F-FDG) PET and by MRI, specifically assessing regions of myocardial infarction and fibrosis by late gadolinium enhancement (LGE) or T1 mapping.5 Myocardial edema can be evaluated by T2 MRI, and molecular information on inflammation and macrophage presence and plaque rupture can be targeted by novel PET tracers.2,6 For example, 18F-sodium fluoride (NaF) has emerged as a tracer for assessing early calcification deposition in potential culprit coronary arteries in ischemia and myocardial infarction and7 has also been used in the assessment of aortic valve stenosis as a marker of active calcification.8 With the growing use of PET-MRI in cardiac imaging, a better understanding of the potential strengths and limitations relative to PET-computed tomography (CT) is needed (Fig. 1).
Two vendors make an integrated simultaneous PET-MRI system, namely, the Siemens Biograph mMR and the General Electric SIGNA PET-MRI. The Siemens mMR was released in 2011, a few years before the GE system received FDA approval (2014). Both systems feature 3 T MRI strength, a 60-cm inner bore, the use of lutetium-based crystals for PET photon detection, and simultaneous PET and MRI capability. To overcome the hardware limitation of traditional photomultiplier tubes that do not function within the strong magnetic field required for MRI, the Siemen mMR system uses avalanche photodiodes, whereas the GE SIGNA PET/MRI uses silicon-based photomultiplier for scintillation photon detection. The speed of electronic signal conversion of silicon-based photomultiplier allows the use of time-of-flight (TOF) in the GE SIGNA PET/MRI to improve image contrast,9 which the Siemen system does not have.
FEASIBILITY AND TECHNICAL CHALLENGES OF PET-MRI CARDIOVASCULAR IMAGING
From a technical standpoint, early adopters of cardiac PET-MRI have had to overcome certain challenges. These include methods of attenuation correction, cardiac and respiratory gating, an integrated PET-MRI workflow, and image analysis.
One of the major early limitations of routine clinical use of cardiac PET-MRI was the absence of validation of MRI for PET attenuation correction and methods to motion correct both PET and MRI. While several articles have been published validating MRI for attenuation correction in cardiac imaging,10–12 and methods exist to fuse diastolic-acquired list-mode data to diastolic MRI data, optimization of respiratory and cardiac motion correction methods is still in the process of being explored.
Motion correction is a potential area where PET-MRI could be advantageous relative to PET-CT. MRI-based motion attenuation correction methods allow for accurate respiratory phase matching between PET and MRI attenuation data sets. Simultaneous PET-MRI of the heart allows for both respiratory and cardiac motion correction.13 Without correction, motion has the potential to lead to segmentation errors and low signal-to-noise ratios, which will reduce the quantitative and qualitative accuracy of a cardiac PET-MRI examination. In addition, imaging that includes both respiratory and cardiac motion correction will improve registration accuracy, and thus the quantitative accuracy of PET-MRI data sets. A review article by Fayad et al14 discusses the current state of motion correction in cardiac PET-MRI.
Typically, basic cardiac PET-MRI motion correction includes the collection of respiratory-gated and/or cardiac-gated PET data sets, along with simultaneous acquisition of a cardiac-gated anatomic MRI data set, with cardiac gating achieved by electrocardiogram acquisition during the examination. Alternatively, respiratory motion can be suppressed by the use of sensors, either internal to the sequence, such as an MRI navigator echo, or external to the sequence, such as spirometry, respiratory belt, or optical monitoring system.3 Respiratory data can also be directly extracted from the acquired PET or MRI data, with both the external sensor and the data-driven approach yielding comparable results.15–17 Respiratory gating alone for motion correction of PET data in PET-MRI maintains some limitations. Mainly, the gated images have a lower statistical count, and the respiratory motion analyzed solely in 1 dimension is not always predictable. As a result, more complex motion estimation models have been proposed, which require multiple steps that include acquiring a motion surrogate, estimating or modeling with subsequent correction. Multistep correction algorithms may be based on image or raw data machine learning and may involve significant data reconstruction; however, they are still experimental.15,18,19 Future directions aim to demonstrate the validity of these more sophisticated algorithms and their superiority in cardiac PET-MRI motion correction.
To be imaged properly, many organ systems need multiple MRI sequences, in addition to the PET data, to yield the optimal complementary information across anatomy, function, and specific molecular signals. Quantifying radiopharmaceutical uptake accurately strongly depends on attenuation correction of the PET signals. This is essential, as quantitative measurements of standardized uptake values (SUVs) are needed, in both research and clinical practice, for quantitative interpretation of the PET data.
In contrast to PET-CT, in PET-MRI, there is no CT-based μ-map for photon-based attenuation correction. Therefore, an early focus of PET-MRI cardiac research has been on addressing the validity of Dixon-based MRI attenuation correction. An important obstacle in attenuation correction in PET-MRI is that PET intensity adjacent to bony structures can be underestimated, leading to underdetection of weakly positive PET signal sources.3,20–22 Fortunately, this is less of a concern in cardiac PET-MRI, as there are no major bony structures in the immediate vicinity of the heart. Early validation studies showed feasibility of the 4-compartment MRI-based attenuation correction method in quantifying SUVs using PET-MRI.1,23 In the 4-compartment method, air, soft tissue, fat, and lung are separated and assigned appropriate tissue attenuation coefficients, using a 2-point T1-weighted Dixon sequence.
An early study by Nensa et al23 showed that, in 10 patients who underwent sequential cardiac PET-CT and PET-MRI, there was no significant difference in myocardial tracer uptake between PET-CT and PET-MRI (paired t test P=0.95). Similar findings were reported by Lau et al.10 In 30 patients who underwent sequential 18F-FDG PET-CT and PET-MRI, a strong correlation was noted between CT-based attenuation correction SUVs and MRI-based attenuation correction SUVs (Pearson correlation R 2=0.97).3,10
Although the MRI phased array coil, through its attenuation effect, may cause an ∼3% reduction of myocardial SUVs, in both of the aforementioned studies, the SUVs derived by MRI-attenuation correction were slightly higher than the SUVs derived by CT-attenuation correction. This is likely a systematic bias, as, in both of the studies, the PET-CT scans were performed before the PET-MRI scans, and thus there was more time for 18F-FDG to be taken up into the myocardium in the PET-MRI data set.
Also of importance, the presence of gadolinium (Gd)-based contrast agent injected immediately before attenuation correction sequence acquisition significantly alters the magnetic relaxivity and perturbs the acquisition of the Dixon images. The net effect is to produce a water image that reveals a disproportionate dimension of the myocardium, as compared with the same images without contrast agent.24 The net effect is thus to produce attenuation maps that exaggerate the attenuation in and around the heart, which then produce errors in segmentation.
There has also been some concern as to whether MRI-based Gd contrast administration might affect PET SUVs apart from segmentation; however, a recent study demonstrated that the effect of MRI-based Gd contrast on PET SUV data is minimal.25
An important limitation of the Dixon MRI scan is that the MRI field of view (FOV) is limited to 50 cm in the transverse direction, whereas the PET FOV reaches ≥66 cm. In the event that the patient’s arms or body extend beyond the MRI FOV, the attenuation maps will thus be underestimated. To circumvent this limitation, the manufacturers have implemented an algorithm that iteratively estimates the attenuation and the activity concentration simultaneously using a maximum likelihood approach. The MLAA (Maximum Likelihood Activity and Attenuation) approach exploits the inconsistency of the measured attenuation with the emission data to calculate an extended attenuation map. More recently, the use of TOF in PET-MRI has been proposed to improve the Dixon-measured attenuation using the MLAA approach.26,27 More recently, the B0 homogenization using gradient enhancement algorithm has been introduced.28 This method extends the MRI FOV by determining an optimal readout gradient field that locally compensates for B0 inhomogeneities and gradient nonlinearities.
Overall, for general clinical use, the 2-point Dixon MRI examination has been determined to be a suitable method for myocardial attenuation correction, provided that no contrast agent is used immediately before or during the Dixon sequence. If the patient is scanned with arms along the body, then the application of the MLAA algorithm (without or with TOF), or application of the homogenization using gradient enhancement algorithm is necessary to produce complete attenuation maps.
Optimizing Myocardial PET Signal Uptake and the Examination Protocol
18F-FDG is a glucose analog used to assess metabolic function. It is used extensively in oncologic imaging in the detection of malignant lesions. Furthermore, it can be applied to cardiac PET imaging in several clinical scenarios. 18F-FDG can be used to diagnose myocardial viability as well as evaluation of nonischemic cardiomyopathies and inflammation. Patient preparation protocols can be tailored to better evaluate the clinical question. For myocardial viability assessment, it is necessary to enhance myocardial 18F-FDG uptake, in order to differentiate viable, glucose-consuming myocardium from the nonviable, non–glucose-consuming myocardium. In such instances, a carbohydrate-loading patient preparation protocol can be performed on the day of imaging29,30 (Fig. 2, middle column, row 1). When assessing for nonischemic cardiomyopathies, such as sarcoidosis, suppression of 18F-FDG uptake in the normal myocardium is necessary, so that areas of inflammation can be detected. In these patients, a high-fat, no carbohydrate meal preparation can be used29,30 (Fig. 2, middle column, row 3).
For myocardial ischemia assessment, a 13N-NH3 PET-MRI regadenoson stress protocol is performed (Fig. 2, middle column, row 2).
In the simultaneously acquired cardiac PET-MRI examination, MRI sequences are obtained during the PET acquisition, in order to shorten the examination time. MRI sequences must be acquired nonbreathhold in order to avoid PET misregistration. All cardiac MRI sequences acquired during PET acquisition should be performed using nonbreathhold cardiac MRI motion-suppression techniques. These include sequences that use single-shot k-space acquisition,31 multiple averages,32 respiratory navigator gating,33,34 or nonrigid motion correction methods.35 Real-time rather than segmented acquisition cine sequences can be obtained during PET acquisition, as these sequences also are robust to respiratory motion, or segmented breathhold cine steady-state free precession sequences can be performed before the PET acquisition, or after the PET acquisition has been completed.
As we have discussed, PET-MRI also has the potential to incorporate cardiac motion information derived from MRI in to the PET image reconstruction (see the Motion correction section). Alternatively, novel PET data-driven motion correction methodologies using the PET data alone have been proposed. One example is a mass preserving optical flow algorithm.36,37 Such algorithms use EKG gating information or cardiac motion information derived from the list mode data to produce gated PET images that can be nonrigidly deformed using optical flow techniques. Depending on the clinical indication, the simultaneous PET-MRI protocol should be modified, so that only the most relevant sequences are acquired. Less relevant MRI sequences can be dropped in favor of shorter examination time. MRI sequences requiring breath-holding can be acquired upon completion of the PET data acquisition at the expense of a longer overall scan time. Given the longer acquisition time relative to PET, MRI sequences often serve as the time-limiting factor of a cardiac PET-MRI examination. Figure 2 shows examples of imaging protocols for various cardiovascular disease indications. Additional information on patient preparation for optimal PET imaging of the myocardium in disease entities may be found in society guidelines for cardiac PET imaging.38
APPLICATION OF PET-MRI IN SPECIFIC CLINICAL CARDIOVASCULAR CONDITIONS
PET-MRI Assessment of Myocardial Viability and Infarction
In one of the earlier studies of simultaneous cardiac PET-MRI, Nensa et al39 examined a mixed group of 20 patients with acute and chronic myocardial infarction. This study demonstrated a substantial agreement between the reduced 18F-FDG in PET and contrast enhancement in LGE MRI in the setting of myocardial infarction. In addition, there was an association between the reduced 18F-FDG in PET and wall motion abnormality on MRI cine images of infarcted myocardial tissue. Both PET-CT and PET-MRI modalities provided similar SUVs of 18F-FDG uptake.
The peri-infarct gray zone, which is the “at-risk” area surrounding the myocardial infarction scar, was evaluated in an additional study by this group. Twenty-five patients with acute coronary occlusion who received interventional reperfusion and underwent simultaneous cardiac 18F-FDG PET-MRI showed that the PET and MRI estimations of peri-infarct “gray zone” correlated well, with PET showing a slightly larger area of reduced 18F-FDG uptake than the area of MRI LGE.39 Indeed, this is a phenomenon that we have noticed as well, occasionally, with the area of decreased metabolic activity on 18F-FDG PET considerably larger than the enhancing scar on LGE MRI (Fig. 3).
MRI T2 mapping has also been investigated as a means of providing additive information, along with MRI LGE and 18F-FDG PET, in patients with acute myocardial infarction.40 Areas with no MRI LGE but which had increased T2 signal and reduced 18F-FDG uptake were shown to be highly salvageable in follow-up studies.3
PET-MRI in Detecting Myocardial Ischemia and Assessing Coronary Artery Atherosclerosis
Coronary artery disease (CAD) is the leading cause of death in many parts of the developed world. CAD is a potential area of increased use of simultaneous PET-MRI with profound clinical implications.
A PET-MRI stress test is carried out similarly to a PET-CT stress test, with the added benefit of characterization of infarct and peri-infarct areas by LGE, functional assessment by MRI cine imaging, internal validation between PET and MRI perfusion results, and better resolution of arterial walls by MRI. Our group has reported feasibility of a 13N-NH3 PET-MRI stress test.41 Fifteen patients had a 13N-NH3 PET-MRI perfusion stress test, and results were compared with single photon photon emission tomography (SPECT) and coronary angiogram findings. In this small cohort of patients, the PET-MRI stress test had a nonsignificant superior diagnostic accuracy when compared with SPECT.
The utility of a cardiac PET-MRI stress imaging in complex myocardial physiology has also been shown in a case study.42 A patient believed to have mixed infarct and ischemia by SPECT stress test turned out to in actuality have hibernating myocardium rather than infarcted myocardium, as determined by simultaneous 13N-NH3 PET-MRI stress test and subsequent quantitative myocardial blood flow analysis.
A commonly used radiotracer in PET-CT myocardial perfusion imaging is Rubidium-82. However, this radiotracer is challenging to use with PET-MRI, as it has a half-life of 75 seconds and, hence, needs an in-room generator. As Rubidium-82 generators are not MRI compatible, its use requires extra tubing run through an RF port, with the tubing dead space filled with wasted tracer.
Coronary artery atherosclerosis can also be directly imaged by PET-MRI by either 18F-FDG or 18F-NaF, as shown in early feasibility studies.7 Twenty-three patients with known CAD underwent simultaneous 18F-FDG or 18F-NaF PET-MRI examinations, and areas of coronary artery plaques were shown to have target-to-background PET signal ratio of 1.61 for 18F-FDG, and 1.55 for 18F-NaF. In this study, a novel free-breathing algorithm was used for attenuation correction and compared favorably with standard breath-hold approach in imaging the coronary arteries.
PET-MRI in Detecting Carotid Atherosclerosis
Cardiac PET-MRI also has the potential for assessment of carotid atherosclerosis.43 MRI is currently the reference standard for assessment of arterial vessel wall anatomy, but PET adds a potential molecular component, assessing inflammation with 18F-FDG, early plaque calcification with 18F-NaF,44 or hypoxic macrophages with copper-64 labeled diacetyl-bis N(4)-methylthiosemicarbazone to target hypoxic macrophages.45 These tracers all have the potential to assess various elements of the plaque suggestive of vulnerability and/or rupture. Of note, there is strong agreement of SUVs obtained on carotid PET-MRI and PET-CT studies using 18F-FDG, the PET tracer in common use in clinical practice.46
A study assessing patients with ischemic stroke investigated the utility of PET-MRI.47 This study showed a high prevalence of complex atherosclerotic plaques on the ipsilateral carotid artery. Higher 18F-FDG uptake was detected in these lesions in comparison with other less complex lesions in the same patients and showed that morphologic and biological features of high-risk plaques can be detected and coregistered in stroke patients.
In addition, we reported a group of 22 high-risk patients and characterized the carotid lesions seen on simultaneous MRI and on 18F-FDG PET imaging.48 Hemodynamically insignificant, lipid-pool lesions by MRI were shown to be metabolically more active on 18F-FDG PET in comparison with fibrous plaque. In another group, up to 40% of patients with cryptogenic ischemic stroke (i.e., without hemodynamically significant carotid artery disease) were found to have metabolically active complex plaques,49 suggesting a potential benefit of early detection of potentially unstable or inflamed carotid atherosclerosis by 18F-FDG PET-MRI.
In looking toward the future, specialized targeted radiotracers have potential for characterizing the stability of atherosclerosis, including 18F-galacto-RGD for targeting angiogenesis, 18F-NaF for targeting calcification, copper-64 labeled diacetyl-bis N(4)-methylthiosemicarbazone for targeting hypoxia, and 64Cu-DOTATATE for targeting macrophages.50
PET-MRI in Nonischemic Cardiomyopathies and Inflammatory Heart Diseases
Besides myocardial infarct and ischemia assessment, various nonischemic cardiomyopathies and inflammatory cardiovascular diseases are other disease entities that have attracted interest in ongoing PET-MRI research. A review by Kircher and Lapa51 summarizes the current state of PET tracers for detecting cardiac inflammations. Nonischemic cardiomyopathies and conditions associated with myocardial inflammation, such as cardiac sarcoidosis (Fig. 4), amyloid, myocarditis, etc., have the potential to be more fully evaluated by cardiac PET-MRI than either cardiac MRI or PET alone.52–54 However, whether the sensitivity and specificity of using a simultaneous modality is additive is yet to be investigated.
One of the nonischemic cardiomyopathy conditions that is reasonably well studied by use of simultaneous PET-MRI is Anderson-Fabry disease.55 This cross-linked lysosomal storage disease is known to cause characteristic basal inferolateral wall fibrosis that is visible on MRI studies. A PET-MRI study of 13 patients with known disease demonstrated that all patients had increased myocardial 18F-FDG uptake in the characteristic location; however, only few had corresponding LGE on MRI. Further studies are needed to determine how PET-MRI can be used to assist in clinical decision making with regard to early enzyme replacement therapy.55
Another nonischemic cardiomyopathy that can be potentially evaluated with PET-MRI is hypertrophic cardiomyopathy. This autosomal dominant disease has varying expressivity and penetrance for development of abnormal left ventricular hypertrophy, myocardial fibrosis, cardiac arrhythmia, and sudden cardiac death in individuals. A comprehensive PET-MRI examination may allow customization of decision making with regard to implantable cardiac defibrillator implantation. In a case study, Kong et al56 conducted a simultaneous PET-MRI examination in a young individual with hypertrophic cardiomyopathy who demonstrated reduced myocardial blood flow in the 30 mm hypertrophic septum, with colocalization of reduced 18F-FDG uptake and LGE in the area, leading to eventual decision of implantable cardiac defibrillator implantation.
Acute myocarditis elicits an intense inflammatory reaction in the myocardium and can confer severe morbidity and mortality. Cardiac MRI allows the assessment for decreased myocardial function, myocardial edema, myocardial hyperemia, and LGE in leaky myocytes.57 A 2016 study investigated 65 patients with suspected myocarditis with simultaneous PET-MRI.58 There was generally good agreement between 18F-FDG PET and MRI T2 and LGE findings, with a good spatial agreement between PET and cardiac MRI (k=0.56). Questions remain as to whether the addition of PET to MRI can improve disease prognostication or guide management (i.e., institution of early steroid therapy).
Amyloidosis offers yet another promising area of potential PET-MRI application. The advance of several PET tracers such as 11C-Pib florbetapir, florbetaben, and flutemetamol allows the possibility of targeted molecular imaging.59 One study looked at amyloid using 18F-NaF60 and was able to differentiate immunoglobulin light-chain (AL) amyloid from transthyretin-related type amyloid (ATTR): in a study of 14 patients (7 controls, 3 with AL amyloid, 4 with ATTR amyloid), 18F-NaF uptake was significantly higher in patients with ATTR compared with control patients and patients with AL amyloid. Thus, PET-MRI may have the potential to be a “1-stop shop,” to diagnose amyloid and differentiate the subtypes of amyloid, all in 1 study.
PET-MRI in Assessing Cardiac Masses
Common intracardiac findings of masses (often incidental) include thrombus, benign tumors, and malignancies. Among malignant conditions, metastatic diseases are more common than primary cardiac malignancies, and cardiac MRI is widely accepted as the imaging modality of choice for cardiac mass imaging,61,62 owing to its superb capacity in accurately characterizing the location, size, vascularity, and tissue characteristics of the intracardiac masses.
As oncologic application is one of the main areas of PET-MRI investigations, cardiac oncology rightfully attracts research interest. In a study of 20 patients with cardiac masses, PET-MRI has a 100% sensitivity and 92% specificity in differentiating malignant from benign lesions.63 Despite the excellent findings, as cardiac MRI alone already has high sensitivity and specificity on its own, questions remain as to whether the addition of PET significantly improves diagnosis and/or prognostication in cardiac oncologic assessment, to justify routine use of this more expensive yet potentially superior modality. It is still worth noting, nevertheless, that PET is more sensitive in the detection and surveillance of distant metastasis than cardiac MRI alone.
Limitations and Future Directions
Cardiac PET-MRI offers potential in comprehensive imaging of myocardial infarction, ischemia, and nonischemic cardiomyopathies. However, unlike stand-alone cardiac MRI and cardiac PET-CT, which have found their respective niches in clinical cardiology, cardiac PET-MRI remains mostly a research and preclinical investigative tool. To date, the enthusiasm for this technology has not been met with solid data from clinical trials, demonstrating superior capacity in aiding clinical diagnosis or decision making.62,63 Most of the published studies remain small and have focused on feasibility rather than patient outcomes. Thus, we are still lacking studies that show added diagnostic benefit or cost effectiveness of simultaneous cardiac PET-MRI.64,65 This is particularly important in the current health care environment, where medical expenditure is increasingly scrutinized. The high cost of a PET-MRI machine and physician lack of familiarity also limits the availability of PET-MRI in most centers, preventing it from more widespread use. Although PET-MRI delivers less ionizing radiation than PET-CT, however, in cases where PET-MRI is used in place of stand-alone cardiac MRI, the addition of ionizing radiation from PET needs to be justified.
Cardiovascular PET-MRI provides a promising and powerful imaging tool, which combines high spatial and contrast resolution soft tissue anatomic data with functional, metabolic, and physiological data. The literature demonstrates the feasibility of a clinical PET-MRI examination, with continued improvement in handling its unique technical challenges. Some of the areas in cardiovascular medicine that show promise for utilizing PET-MRI include ischemia detection, infarct characterization, atherosclerotic plaque imaging, and evaluation of nonischemic cardiomyopathy. Availability and cost remain a concern, and future studies are needed to demonstrate the validity and added clinical value of cardiovascular PET-MRI.
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