Simultaneous measurements of myocardial glucose metabolism and extracellular volumes with hybrid PET/MRI using concurrent injections of Gd-DTPA and [18F]FDG.

BACKGROUND: The aims of this study were to investigate the application of a constant infusion (CI) to mitigate the issue of constantly changing Gd-DTPA contrast levels in a bolus injection for extracellular volume (ECV) measurements by (a) comparing a CI alone to a bolus alone and a bolus followed by CI in healthy myocardium, (b) evaluating the impact of glucose suppression using heparin on ECV. METHODS: Five healthy canine subjects were imaged to compare three different protocols for injecting Gd-DTPA and FDG: bolus alone, CI alone, bolus followed by CI. Suppression of myocardial glucose uptake was induced using a continuous infusion of 20% lipid at a rate of 0.25 mL·min-1·kg-1 as well as 2000 units of intravenous heparin injected 20 minutes prior to FDG/Gd-DTPA injection. RESULTS: There was no significant effect on ECV measurement when heparin was used for glucose suppression at equilibrium irrespective of infusion protocol). Measurements of ECV in myocardium, regardless of infusion protocol showed no significant difference at all time points (P = 0.21) prior to washout. CONCLUSIONS: The suppression of myocardial uptake of [18F]FDG with heparin did not alter the determination of myocardial ECV though a larger sample size may show differences. Further, the infusion protocol (bolus or constant infusion) had no effect on the calculated ECV.

Tracking the progress of inflammation with PET/MRI in a canine model of myocardial infarction.

BACKGROUND: Following myocardial infarction, tissue undergoes pathophysiological changes involving inflammation and scar tissue formation. However, little is known about the pathophysiology and prognostic significance of any corresponding changes in remote myocardium. The aim of this study was to investigate the potential application of a combined constant infusion of 18F-FDG and Gd-DTPA to quantitate inflammation and extracellular volume (ECV) from 3 to 40 days after myocardial infarction. METHODS: Eight canine subjects were imaged at multiple time points following induction of an MI with a 60-minute concurrent constant infusion of Gd-DTPA and 18F-FDG using a hybrid PET/MRI scanner. RESULTS: There was a significant increase in ECV in remote myocardium on day 14 post-MI (P = .034) and day 21 (P = .021) compared to the baseline. ECV was significantly elevated in the infarcted myocardium compared to remote myocardium at all time points post-MI (days 3, 7, 14, 21, and 40) (P < .001) while glucose uptake was also increased within the infarct on days 3, 7, 14, and 21 but not 40. CONCLUSIONS: The significant increase in ECV in remote tissue may be due to an ongoing inflammatory process in the early weeks post-infarct.

Same day comparison of PET/CT and PET/MR in patients with cardiac sarcoidosis.

BACKGROUND: Inflammatory cardiac disorders, in particular, sarcoidosis, play an important role in left ventricular dysfunction, conduction abnormalities, and arrhythmias. In this study, we compared the imaging characteristics and diagnostic information obtained when patients were imaged sequentially with PET/CT and then with hybrid PET/MRI on the same day following a single 18F-FDG injection. METHODS: Ten patients with known or suspected sarcoidosis underwent imaging in sequence of (a) 99mTc-MIBI, (b) 18F-FDG with PET/CT, and (c) 18F-FDG with 3T PET/MRI. Images were compared quantitatively by determination of SUVmax and SUV on a voxel by voxel basis, and qualitatively by two experienced observers. RESULTS: When both platforms were compared quantitatively, similar data for the evaluation of enhanced 18F-FDG uptake were obtained. Qualitatively, there were (1) several instances of normal perfusion with delayed enhancement and/or focal 18F-FDG uptake, (2) comparable enhanced 18F-FDG uptake on PET/CT vs. PET/MRI, and (3) diversity in disease patterns with delayed enhancement only, increased 18F-FDG uptake only, or both. CONCLUSION: In this limited patient study, PET/CT and PET/MR provided similar diagnostic data for 18F-FDG uptake, and the concurrent acquisition of MR images provided further insight into the disease process.

Hybrid PET/MR imaging in myocardial inflammation post-myocardial infarction.

Hybrid PET/MR imaging is an emerging imaging modality combining positron emission tomography (PET) and magnetic resonance imaging (MRI) in the same system. Since the introduction of clinical PET/MRI in 2011, it has had some impact (e.g., imaging the components of inflammation in myocardial infarction), but its role could be much greater. Many opportunities remain unexplored and will be highlighted in this review. The inflammatory process post-myocardial infarction has many facets at a cellular level which may affect the outcome of the patient, specifically the effects on adverse left ventricular remodeling, and ultimately prognosis. The goal of inflammation imaging is to track the process non-invasively and quantitatively to determine the best therapeutic options for intervention and to monitor those therapies. While PET and MRI, acquired separately, can image aspects of inflammation, hybrid PET/MRI has the potential to advance imaging of myocardial inflammation. This review contains a description of hybrid PET/MRI, its application to inflammation imaging in myocardial infarction and the challenges, constraints, and opportunities in designing data collection protocols. Finally, this review explores opportunities in PET/MRI: improved registration, partial volume correction, machine learning, new approaches in the development of PET and MRI pulse sequences, and the use of novel injection strategies.

CCS/CAR/CANM/CNCS/CanSCMR joint position statement on advanced noninvasive cardiac imaging using positron emission tomography, magnetic resonance imaging and multidetector computed tomographic angiography in the diagnosis and evaluation of ischemic heart disease--executive summary.

BACKGROUND: Over the past few decades, advanced imaging modalities with excellent diagnostic capabilities have emerged. The aim of the present position statement was to systematically review existing literature to define Canadian recommendations for their clinical use. METHODS: A systematic literature review to 2005 was conducted for positron emission tomography (PET), multidetector computed tomographic angiography and magnetic resonance imaging (MRI) in ischemic heart disease. Papers that met the criteria were reviewed for accuracy, prognosis data and study quality. Recommendations were presented to primary and secondary panels of experts, and consensus was achieved. RESULTS: Indications for PET include detection of coronary artery disease (CAD) with perfusion imaging, and defining viability using fluorodeoxyglucose to determine left ventricular function recovery and/or prognosis after revascularization (class I). Detection of CAD in patients, vessel segments and grafts using computed tomographic angiography was considered class IIa at the time of the literature review. Dobutamine MRI is class I for CAD detection and, along with late gadolinium enhancement MRI, class I for viability detection to predict left ventricular function recovery. Imaging must be performed at institutions and interpreted by physicians with adequate experience and training. CONCLUSIONS: Cardiac imaging using advanced modalities (PET, multidetector computed tomographic angiography and MRI) is useful for CAD detection, viability definition and, in some cases, prognosis. These modalities complement the more widespread single photon emission computed tomography and echocardiography. Given the rapid evolution of technology, initial guidelines for clinical use will require regular updates. Evaluation of their integration in clinical practice should be ongoing; optimal use will require proper training. A joint effort among specialties is recommended to achieve these goals.

Gd-DTPA bolus tracking in the myocardium using T1 fast acquisition relaxation mapping (T1 FARM).

MRI methods currently used for bolus tracking in the myocardium, such as saturation recovery turbo-fast low-angle shot (FLASH) (srTFL), are limited by signal intensity (SI) saturation at high contrast agent (CA) concentrations. By using T1 fast acquisition relaxation mapping (T1 FARM), a Gd-DTPA bolus (0.075 vs. 0.025 mmol/kg) may be injected without causing saturation. This study tested the feasibility of in vivo T1 FARM bolus tracking under rest/stress conditions in seven beagles with multiple permanently occluded branches of the left anterior descending (LAD) coronary artery. Although it underestimated the myocardial perfusion reserve (MPR) measured ex vivo using radioactive microspheres (mean +/- SEM; 3.60 +/- 0.26), the MPR determined upon application of the modified Kety model (1.86 +/- 0.10) enabled distinction between normal and infarcted tissue. The partition coefficient (lambda) estimated at rest and stress using the modified Kety model underestimated ex vivo radioactive measurements in infarcted tissue (0.25 +/- 0.01 vs. 0.26 +/- 0.01 vs. 0.79 +/- 0.08 ml/g, P < 0.0001) yet was accurate in normal tissue (0.28 +/- 0.01 vs. 0.30 +/- 0.01 vs. 0.33 +/- 0.01 ml/g, P = NS). Thus, although unsuitable for myocardial viability assessment, T1 FARM bolus tracking shows potential for assessment of myocardial perfusion.

Examining a canine model of stunned myocardium with Gd-DTPA-enhanced MRI.

It has previously been shown that the distribution volume of Gd-DTPA (lambda) in infarcted, canine myocardium is higher than that of normal tissue. The purpose of this study was to determine whether stunned myocardium exhibits increased lambda. Stunning was produced in beagles by means of 30 min LAD occlusion followed by 3 weeks (n = 4) reperfusion. Gd-DTPA was infused at each imaging session and lambda determined in vivo using a saturation recovery turboFLASH sequence; cine imaging was used to assess ventricular wall thickening (%WT). (201)Tl uptake was used as an independent assessment of viability. %WT data confirmed that the brief insult caused prolonged, yet reversible, regional contractile dysfunction in each animal. %WT was not significantly different from baseline values by 3 weeks post-reflow. Normal (201)Tl uptake confirmed the absence of infarction. The lambda of stunned tissue (lambda = 0.381 +/- 0.030 ml/g) was not elevated above that of normal tissue (lambda = 0.398 +/- 0.027 ml/g, P = NS), at any time point studied, in vivo. These data suggest that an increase in lambda is a specific indicator of irreversible damage.

The use of Gd-DTPA as a marker of myocardial viability in reperfused acute myocardial infarction.

At present, accurate assessment of the extent of myocardial viability after acute myocardial infarction is limited due to the spatial resolution of currently available imaging modalities. MR cardiac imaging, with its superior spatial resolution, would be used if viable and infarcted tissue could be separated based on signal intensity. In infarcted tissue, cell membrane breakdown allows the entry of the MR contrast agent Gd-DTPA which is normally extracellular. The increased space for Gd-DTPA distribution (partition coefficient, lambda) in this infarcted tissue results in increased Gd-DTPA concentration and hence increased signal intensity on T1-weighted MR images. In a canine model of ischemia/reperfusion injury, the partition coefficient in infarcted tissue increased as early as 1 min post reperfusion. lambda in infarcted tissue stayed increased over that in normal tissue for at least 8 weeks. The accuracy of contrast-enhanced MRI was confirmed by results of 201Tl SPECT and a cine MRI dobutamine wall motion study in a patient 1 week after an acute myocardial infarction. Thus, contrast-enhanced MRI shows great promise for the non-invasive determination of myocardial viability after acute myocardial infarction.

Contrast-enhanced MRI for the assessment of myocardial viability after permanent coronary artery occlusion.

Previous studies in a model of ischemia/reperfusion using a constant infusion of Gd-DTPA have shown that distribution volume (lambda) is increased in infarcted myocardial tissue. This study examined this technique in the setting of permanent coronary artery occlusion. Ten beagles underwent permanent occlusion of a coronary artery for 2 days (N = 3), 1 week (N = 4), or 3 weeks (N = 3). Imaging was performed at 2 days and, depending on the length of occlusion, 1 week, 2 weeks, and 3 weeks to follow changes in lambda in vivo. At sacrifice, (201)Tl was injected and the extent of the hyperenhanced region was compared to pathology. lambda was increased in infarcted tissue by 2 days post occlusion and this increase persisted for 3 weeks. At sacrifice, lambda correlated strongly with (201)Tl uptake (r = -0.86 to -0.95, P < 0.05; i.e., lambda increased in infarcted tissue) and the size of the hyperenhanced region was comparable to pathological infarct size (slope 1.006, r = 0.96, P < 0.0001). Thus, beyond 2 days after coronary occlusion, MRI, during a constant infusion of Gd-DTPA, can assess myocardial viability regardless of the success of reperfusion. Magn Reson Med 44:309-316, 2000.

Clinical assessment of myocardial viability using MRI during a constant infusion of Gd-DTPA.

This study assessed the accuracy and feasibility of magnetic resonance imaging (MRI) during a constant infusion of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) for the determination of myocardial viability in patients with recent acute myocardial infarction (AMI). Nine patients were studied within 10 days of AMI. Rest-redistribution 201Thallium (201Tl) single photon emission computed tomography (SPECT) was used as a gold standard for viability. Using MRI, regional perfusion was assessed using dynamic imaging during a bolus injection of Gd-DTPA and viability was assessed during a continuous infusion. Finally, cine MR images were acquired at baseline, during low-dose dobutamine infusion and after recovery. To assess viability, the left ventricle was divided into 16 segments and signal intensity in corresponding MRI and redistribution SPECT segments were compared. Wall thickening index (WTI) was determined at each step during the dobutamine study. The results revealed that in five patients, reduced perfusion in infarcted regions was observed qualitatively during dynamic first pass imaging. There was a significant inverse correlation between 201Tl uptake and MRI signal intensity, i.e. infarcted tissue (low 201Tl uptake) had increased MR signal intensity. Segments were separated into normal (201Tl uptake > 90%) and infarcted (< 601%). lnfarcted MRI segments had greater signal intensity than normal segments (179 +/- 50 vs. 102 +/- 14%; P < 0.0001). WTI in normal segments increased by 18 +/- 8.5% (P < 0.0001) from baseline to 10 microg/kg per min of dobutamine while infarcted tissue WTI decreased 2.8 +/- 7.2% (P = 0.17). Thus regions of myocardium that were infarcted as defined by reduced 201Tl uptake and absent contractile reserve showed greatly increased MRI signal intensity during a constant infusion of Gd-DTPA. The use of MRI during a constant infusion of Gd-DTPA is accurate and feasible for the determination of myocardial necrosis in a clinical setting.

Assessment of myocardial viability using MRI during a constant infusion of Gd-DTPA: further studies at early and late periods of reperfusion.

It was previously shown in a canine model of ischemia/reperfusion injury that the partition coefficient of gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) (lambda) increases in infarcted tissue. That previous study used a non-magnetic resonance imaging (MRI) method to measure lambda and only investigated reperfusion times from 2 hr to 3 weeks. This study presents evidence suggesting that lambda starts to increase as early as 1 min after reperfusion of a 2 hr occlusion and continues to rise for up to 2 hr or more; lambda stays increased as late as 8 weeks, reaching peak values at 1-11 days and subsequently decreasing. It was also demonstrated that lambda can be accurately measured in vivo using a saturation recovery turbo fast low-angle shot (FLASH) sequence. The results of this study show that MRI during a constant infusion of Gd-DTPA has great potential for the non-invasive determination of myocardial viability as early as 1 min to as late as 8 weeks following reperfusion of acute myocardial infarction.

Noninvasive assessment of pharmaceutical intervention during myocardial ischemia-reperfusion in a canine model using two-dimensional 31P chemical shift imaging.

The metabolic effects during myocardial ischemia and sustained reperfusion of the antianginal agents diltiazem (n = 10) and propranolol (n = 10) were monitored with noninvasive phosphorus nuclear magnetic resonance spectroscopy to establish any correlation between metabolic changes and infarct size. Spectroscopy followed changes in high-energy phosphate concentrations and myocardial intracellular pH during 2 h of left anterior descending coronary artery occlusion and 3 subsequent weeks of reperfusion, in a closed chest canine infarct model. Gadolinium-DTPA enhanced magnetic resonance imaging was used to assess the extent of myocardial injury (infarct size). Microspheres were used to document the zone at risk and the success of reperfusion. Whereas diltiazem appeared to reduce the derangement in high-energy phosphates during coronary occlusion, there was no significant change in infarct size when compared with a previously studied control group. Propranolol, which produced a lesser decline in pH during occlusion and smaller pH changes during early reperfusion, was associated with a significant reduction in the degree of tissue necrosis (compared with controls). There was an inverse correlation (r = -0.51) between the change in myocardial pH (occlusion end to immediate reperfusion) and the recovery index (an index of myocardial salvage). By 1 h into reperfusion, there was a stronger inverse correlation between pH and infarct size (r = -0.75), implying a protective effect of delaying pH recovery during early reperfusion and indicating the potential use of this parameter as a predictor of tissue viability.

Myocardial infarction in a canine model monitored by two-dimensional 31P chemical shift spectroscopic imaging.

We have developed a closed chest animal model that allows noninvasive monitoring of cardiac high energy phosphate metabolism before, during, and for at least 3 weeks after a myocardial infarction. Ten beagles underwent 2 h of coronary occlusion followed by 3 weeks of reperfusion. Myocardial high energy phosphates from 12-ml voxels were noninvasively tracked using 31P two-dimensional chemical shift imaging. Gadolinium enhanced 1H MRI identified the zone at risk, and radioactive microspheres assessed regional blood flow and partition coefficients. Occlusion of the left anterior descending coronary artery produced infarcts that were 13.7+/-8.8% (mean+/-SD) of the left ventricular volume. Rapid changes in the phosphocreatine and inorganic phosphate levels were observed during occlusion, whereas adenosine triphosphate levels decreased more slowly. All metabolites recovered to base-line levels 2 weeks after occluder release. Multiple inorganic phosphate peaks in the infarct voxel spectra indicated that more than one metabolically compromised tissue zone developed during occlusion and reperfusion. Microsphere data indicating three distinct blood flow zones during ischemia and reperfusion (<0.3, 0.3-0.75, and >0.75 ml/min/g) supported the grouping of pH values into three distinct metabolic distributions.

Controlled reperfusion after myocardial ischemia in a canine model monitored by two-dimensional phosphorus 31 chemical shift spectroscopic imaging.

Phosphorus 31 magnetic resonance spectroscopy at 2 T was used to monitor high-energy phosphate metabolism over a 3-week period in a canine model of myocardial infarction and reperfusion. Twenty animals were divided into two groups: group 1 (n = 11) received intravenous nitroglycerin beginning at the onset of coronary occlusion; group 2 (n = 9) received a 105-minute infusion of superoxide dismutase (SOD) beginning at the onset of reperfusion. A metabolic protective effect was observed (vs controls) with both agents, manifested by a reduction in the degree of pH decline from baseline values and preservation of the adenosine triphosphate/total phosphate ratio during occlusion and reperfusion. Further, both treatments, compared with controls, produced a lower infarct/zone at risk ratio: controls, 1.5 +/- 1.2; nitroglycerin, 0.52 +/- 0.50; and SOD, 0.64 +/- 0.40. The technique of 31P magnetic resonance spectroscopy demonstrated its use for the noninvasive assessment of myocardial metabolism in response to therapeutic intervention.

The determination of myocardial viability using Gd-DTPA in a canine model of acute myocardial ischemia and reperfusion.

The partition coefficient of Gd-DTPA was thought to vary with the amount of cellular membrane damage after an acute myocardial infarction. The relationship between the partition coefficient of Gd-DTPA (lambda) and the uptake of 201Tl (as a marker of tissue viability) was studied 2 h to 3 weeks after reperfusion of a 2-h occlusion to the left anterior descending coronary artery in a canine model. Gd-DTPA was infused as a bolus followed by a prolonged constant infusion, and this infusion protocol was optimized such that the concentration of Gd-DTPA was directly related to lambda. After this infusion, MR images of excised hearts showed regions of increased signal intensity corresponding to increased Gd-DTPA concentration. At all time points, lambda and 201Tl uptake were strongly negatively correlated indicating that lambda is an accurate indicator of myocardial viability. Furthermore, lambda in the infarcted regions was increased relative to normal regions after 2 h of reperfusion and stayed elevated up to 3 weeks. At all time points, lambda in the infarcted and normal regions were significantly different. As well, this data showed a trend that lambda in infarcted regions decreased monotonically from 1 day to 3 weeks. This trend was confirmed with MR imaging by examining the change in signal intensity of in vivo images from 4 days to 3 weeks in two animals. These results suggest that MRI with Gd-DTPA could be used to measure the extent of myocardial damage after an acute myocardial infarction.

Techniques for the measurement of the local myocardial extraction efficiency for inert diffusible contrast agents such as gadopentate dimeglumine.

We have previously shown that the concentration of Gd-DTPA as a function of time ([Gd-DTPA]t(t)) in the myocardium following an intravenous bolus injection of Gd-DTPA can be modeled using the Modified Kety Equation. Fitting this model to measurements of [Gd-DTPA]t(t) in a region of myocardium would allow the determination of myocardial distribution volume (lambda) and the product of flow (F) and extraction efficiency (E), i.e., FE. Thus, to measure F, E must be known. We describe here techniques developed to measure local values of E in normal and diseased myocardium. These techniques are valid for any inert diffusible MR contrast agent.

Measurement of the extraction efficiency and distribution volume for Gd-DTPA in normal and diseased canine myocardium.

We have previously shown that the myocardial Gd-DTPA concentration ([Gd-DTPA]t(t)) after a bolus injection of Gd-DTPA can be predicted by the Modified Kety Equation (MKE). If [Gd-DTPA]t(t) can be determined by MRI and the data fit to the MKE, then the distribution volume (lambda) of Gd-DTPA and the myocardial flow (F) times the extraction efficiency (E), i.e., the FE product, can be determined. Therefore F can only be quantified if E is known. We measured the global E in vivo in normal canine myocardium, and measured E and lambda, in vitro, locally in normal, acute ischemic (n = 5; coronary artery occlusion < 4 h), infarcted (n = 4; coronary artery occlusion, 6 days) and reperfused (n = 4; coronary artery occlusion 2 h, and reperfusion 2 h and 6 days) myocardium. Results indicate that E differs with F and with individuals and consequently, F cannot be quantified using the MKE unless the local E is also determined in vivo.

Effects of dipyridamole infusion on human renal function observed using technetium-99m-DTPA.

Our observation that a prolonged dipyridamole infusion reduced or eliminated blood clearance of Gd-DTPA in dogs led us to investigate if dipyridamole, infused intravenously at rates comparable to those used in thallium myocardial perfusion tests, would alter renal filtration in humans. Renal filtration was assessed using a bolus injection of 10 mCi of 99mTc-DTPA in five males (19-63 yr old) with normal serum urea and creatinine. Twenty minutes following the bolus injection a 10-min intravenous infusion of either dipyridamole (0.14 mg/kg/min) or saline sham was given. Four to 10 min following the start of the dipyridamole infusion, a paradoxical rise in counts in the kidney region of interest was observed and persisted for 10 to 27 min. During this time, a 13% to 52% (mean +/- s.d., 40% +/- 16%, p less than 0.007) reduction in the exponential slope defining the clearance of counts from the cardiac region of interest occurred (implying a reduction of glomerular filtration rate), mean heart rate increased 27 +/- 5 bpm, p less than 0.002 and mean diastolic pressure decreased 12.9 +/- 6.4 mmHg, p less than 0.028. This finding indicates that renal clearance of tracers such as thallium or contrast agents such as Gd-DTPA is reduced during dipyridamole infusion.