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MRI of Myocardial Perfusion
MRI of Myocardial Perfusion Michael Jerosch-Herold, PhD,* Olaf Muehling, MD,† and Norbert Wilke, MD‡ An overwhelming number of myocardial perfusion studies are done by nuclear isotope imaging. Magnetic resonance imaging during the first pass of an injected, contrast bolus has some significant advantages for detection of blood flow deficits, namely higher spatial resolution, absence of ionizing radiation, and speed of the test. Previous clinical studies have demonstrated that excellent sensitivity and specificity can be achieved with MR myocardial perfusion imaging for detecting coronary artery disease, and assessment of patients with acute chest pain. Furthermore, an absolute quantification of myocardial blood flow is feasible, as was demonstrated by comparison of MR perfusion imaging, to measurements with isotope labeled microspheres in experimental models. An integrated assessment of perfusion, function, and viability, is thus feasible by MRI to answer important clinical challenges such as the identification of stunned or hibernating, but viable myocardium. Semin Ultrasound CT MRI 27:2-10 © 2006 Elsevier Inc. All rights reserved.
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he need for detection of acute or chronic myocardial ischemia by perfusion imaging results in approximately 5 million nuclear cardiology procedures per year in the United States. The role of myocardial perfusion imaging is well established and encompasses diagnosis of coronary artery disease (CAD), risk stratification, prognosis,1-3 guidance for the choice of medical management or revascularization,4,5 and screening of high-risk patients, for example, before noncardiac surgery.6 Normal perfusion stress images in patients with documented CAD indicate a favorable prognosis.2 Magnetic resonance imaging (MRI) provides a novel approach for assessing myocardial perfusion with high spatial resolution and without exposure to ionizing radiation. Furthermore, MRI allows an integrated assessment of perfusion, function, and myocardial viability within a single examination. In comparison, positron emission tomography (PET) and single-photon emission tomography (SPECT) perfusion studies are time consuming. PET and SPECT have relatively low spatial resolution compared to perfusion imaging with MRI, and they may therefore be unsuitable for identifying perfusion deficits and infarcts limited to the subendocardial layer.7 Nuclear imaging also *Advanced Imaging Research Center and Department of Medicine, Oregon Health & Science University, Portland, OR. †Department of Medicine, University of Munich, Munich, Germany. ‡Department of Radiology, Health Science Center, University of Florida, Jacksonville, FL. Address reprint requests to Michael Jerosch-Herold, PhD, Advanced Imaging Research Center, MS L452, 3181 SW Sam Jackson Park Road, Portland, OR 97239. E-mail: [email protected].
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0887-2171/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.sult.2005.10.001
can be used for an integrated assessment of perfusion and function, but techniques such as multigated blood pool scans (MUGA) for left ventricle (LV) function evaluation are less accurate than MRI cine imaging.8 MRI therefore represents a compelling choice for myocardial perfusion imaging. The advantages of myocardial perfusion imaging by MRI are offset by a perception of complexity, a lack of training opportunities,9 the abundance of technical approaches, which has slowed down the establishment of a consensus, and the relative lack of tools that expedite the analysis and interpretation of MRI perfusion studies in a clinical setting. Also, MRI-safe implantable pacemaker technology is still sparse, and implanted heart devices, including cardiac defibrillators, generally rule out using MRI.
Clinical Applications Detection of Coronary Artery Disease MRI perfusion has been used for the detection of significant lesions in patients with CAD. Due to the low sensitivity of resting blood flow to epicardial coronary stenosis, a perfusion scan under stress conditions is of paramount importance for the evaluation of CAD. However, the confining environment of an MRI magnet renders exercise stress testing impractical, and pharmacological vasodilation is the method of choice for “stress” perfusion imaging. The flow resistance of the coronary circulation under baseline conditions is determined by the myocardial microcirculation. Only imaging during stress or hyperemia allows assessing the hemodynamic significance
MRI of myocardial perfusion of a coronary lesion in the epicardial conduit vessels. The severity of an epicardial coronary stenosis is directly related to the perfusion reserve, the ratio of myocardial blood flow during vasodilation, divided by baseline blood flow.10,11 Blood flow across the myocardium wall is not uniform,12 but instead favors the subendocardium to accommodate the higher workload and higher rate of oxygen consumption of the subendocardial layer. Under normal conditions the ratio of endocardial to epicardial blood flow is on the order of 1.2:1. With a coronary artery stenosis, blood flow is first diverted away from the subendocardial layer,13,14 and the endocardial to epicardial blood flow ratio is often less than 1:1, in particular under stress. The detection of coronary artery disease in patients is therefore more sensitive if the spatial resolution of the imaging technique allows separate assessment of the endomyocardial layer.
Microvascular Dysfunction The combination of chest pain, positive exercise testing, but normal coronary angiogram has been classified as cardiac syndrome X.15 Its pathogenic entity and cause remain controversial. Ischemia in the absence of flow-limiting stenoses has been recognized as a relevant clinical syndrome, in particular in postmenopausal women, as shown by the Women’s Ischemic Syndrome Evaluation (WISE) study. WISE investigators concluded that an abnormal microcirculation plays an important role in the pathogenesis of ischemic syndromes in women without obstructive coronary artery disease. A paucity of electrocardiographic changes and regional wall motion abnormalities in patients with microvascular disease can cast doubt on the value of standard tests in this population.16 Initial reports of perfusion studies in the WISE population17 described atypical perfusion patterns, which either masked or mimicked epicardial CAD. Other studies in cohorts with cardiac syndrome X have demonstrated the value of perfusion MRI for detecting ischemia related to microvascular dysfunction,18,19 in particular in combination with a quantitative assessment of the perfusion reserve. Perfusion imaging, by PET20 or MRI,18,19 has supported the notion that the chest pain may have an ischemic cause. In patients with cardiac syndrome X, the myocardial perfusion reserve measured by quantitative perfusion MRI was reduced and in good agreement with the invasively measured coronary flow reserve.19 The hypothesis of ischemia in cardiac syndrome X is supported by studies of highenergy metabolism by 31P MR spectroscopy.21 Blunting of the perfusion reserve was most pronounced in the subendocardial layer, in marked distinction to the pattern observed in controls.18
Microvascular Obstruction During the first 1 to 2 minutes after gadolinium contrast injection, areas in the core of an infarct may fail to show contrast enhancement because of microvascular obstruction22,23 (MO). This early phase of contrast enhancement can be observed in a perfusion scan, if it extends in time
3 over a minute or more after contrast injection. Regions with MO are identified by distinct and persistent hypoenhancement over the first 1 to 3 minutes.22,23 MO is associated with a worse prognosis, even after control for infarct size.24 The lack of contrast enhancement in the presence of MO, even after recanalization, is referred to as the noreflow phenomenon. It was shown by MRI that infarct remodeling was greatest in those patients with larger areas of MO.25,26 MRI appears to be an excellent modality for detecting MO with excellent spatial resolution, and reveals the heterogeneity of microvascular integrity and patency within an infarct zone. The detection of MO, with the patient at rest, does not require the same degree of temporal resolution as imaging during the first pass of a contrast agent to detect ischemia or a decrease of the perfusion reserve. Temporal resolution can be traded off against spatial resolution and contrast-to-noise. A distinction between severe hypoenhancement during the first pass27 and persistent lack of contrast enhancement26 may be important for prognosis and relate to the severity of MO and the presence of some residual collateral flow.27 One observes a delay in the arrival of contrast in collateral-dependent myocardium even in the absence of infarction and MO.28 Whether imaging during the first pass of a contrast bolus, or with some delay after contrast injection, is most appropriate to assess MO may not have been resolved conclusively.
Hibernation and Stunning In combination with imaging of delayed contrast enhancement for myocardial viability, perfusion imaging can play a unique role in the detection of hibernating myocardium. From a clinical standpoint, the identification of hibernating myocardium is important because of the potential to improve function and therefore prognosis of the patient. Whether resting blood flow is reduced in chronic hibernating myocardium remains controversial. A recent review of studies on this issue29 concluded that the evidence seemed to favor the hypothesis that baseline blood flow is significantly reduced. At the very least, studies that did not detect a reduction of baseline blood flow suffered from inadequate spatial resolution, and one could therefore not exclude the possibility of a significant subendocardial flow reduction. Alternatively, the state of hibernation may result from transient reductions of blood flow and repetitive stunning, with a low likelihood of chronically depressed myocardial blood flow during resting conditions. It is well known that even small differences in blood flow during ischemia result in large differences in postischemic function,30 suggesting that the ability to quantify flow in the low flow range is of importance to predict the probability of postischemic recovery. MRI offers unsurpassed abilities to interrogate regional perfusion with sufficient spatial resolution, and it may therefore become feasible to resolve these controversies on the causes of chronic stunning. A recent MRI study supports the notion that resting blood
M. Jerosch-Herold, O. Muehling, and N. Wilke
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Figure 1 Perfusion images, shown in panel (A), were acquired in an overweight male patient at 3 T (Philips Intera 3T) with a 0.03 mmol/kg dosage of Gd-DTPA contrast, using a fast gradient echo sequence with saturation-recovery magnetization preparation. The body coil of the MRI system was used due to the body habitus of the patient. The intravenously injected contrast bolus first causes contrast enhancement in the right ventricular cavity, followed by enhancement in the left ventricular cavity, and then myocardial contrast enhancement. The patient had a resting perfusion deficit in the inferior wall. An image of the delayed contrast enhancement in (B) shows an infarct region that matches the location of the rest perfusion defect. (C) The graph shows the variation of the signal intensity during the transit of the contrast bolus for two transmural myocardial sectors, in the anterior and inferior wall respectively. Contrast enhancement in the inferior sector is delayed and occurs at a markedly lower rate than in the anterior sector. The dotted line is a linear approximation to the signal intensity curve to calculate an up-slope parameter, which has been shown to vary in proportion to changes in blood flow.
flow is impaired in hibernating myocardial segments supplied by severely stenosed coronary arteries.31
and is feasible in the evaluation of patients with acute coronary syndromes.
Acute Chest Pain Assessment
Cardiomyopathies
As MRI techniques have matured, investigators have applied these new and increasingly robust tools in the evaluation of acute chest pain. One pioneering study by Kwong et al32 showed that with use of a comprehensive MRI protocol, which included perfusion imaging under resting conditions, MRI accurately identified a high fraction of patients with non-ST elevation myocardial infarction (with or without an elevated troponin). Perfusion imaging was applied to identify myocardial segments with preserved viability, but hypoperfusion under resting conditions. More recently Plein et al33 tested an MRI protocol for evaluation of patients with acute coronary syndromes by using a comprehensive analysis of wall motion, perfusion, delayed contrast enhancement, and coronary imaging with high sensitivity and specificity. When individual components of the MRI protocol were considered, they found that perfusion imaging gave the highest sensitivity and overall accuracy of any protocol component and was deemed to be most useful for predicting the need for revascularization.33 Which protocol component proves to be most beneficial for prognosis probably depends on the patient population, but perfusion imaging by MRI is of high value
Myocardial perfusion imaging by MRI has been applied in a genetically homogeneous population of patients with hypertrophic cardiomyopathy to evaluate the association between hypertrophy and perfusion.34 The attenuation of the perfusion reserve index was shown to be associated with the degree of LV hypertrophy. An estimate of the global average of myocardial perfusion was measured with MRI in patients with idiopathic dilated cardiomyopathy (IDC). Instead of applying perfusion imaging, an estimate of the global average of myocardial blood flow was arrived at by the use of phase-contrast velocity measurements of blood flow in the coronary sinus, and cine imaging for LV mass determination.35 PET studies have shown that the myocardial blood flow (MBF) reserve is reduced in patients with IDC, which was interpreted as a flow-impairment in the coronary microcirculation in the absence of epicardial lesions. Of note is that in a recent study of heart failure patients, an absence of focal delayed contrast enhancement was reported for 59% of the patients with dilated cardiomyopathy and no evidence of CAD.36 The presence of scar and fibrosis in patients with
MRI of myocardial perfusion dilated cardiomyopathies may be quite heterogenous in this population, and warrant further studies of regional perfusion patterns, in particular in IDC patients which do not show delayed contrast enhancement.
Techniques Acquisition Rapid imaging of contrast enhancement during the first pass of a bolus-injected contrast agent is currently the method of choice for assessing myocardial perfusion with MRI. Figure 1 gives an example, showing the application of this technique. Gadolinium-based contrast agents provide excellent contrast enhancement in the heart, with single-shot T1-weighted imaging. Electrocardiogram-gated, T1-weighted techniques, with image acquisition times of less than 200 ms, are sufficiently fast to freeze cardiac motion and cover 3 to 5 slices per heart beat. The contrast agent is bolus-injected intravenously, for example, in the antecubital fossa. Although one strives to cover the entire heart during a perfusion scan, this is currently still challenging; but recent advancements such as parallel imaging have brought this goal within close grasp. Nevertheless the imaging techniques continue to be based on two-dimensional (2D) acquisitions, rather than 3D acquisitions, as the former represent an easier approach to freezing cardiac motion at each slice level. Pulse sequence types applied for myocardial perfusion imaging range from gradient echo to echo-planar imaging, with hybrid forms37 as compromises that combine advantages at both extremes of the pulse sequence spectrum. Gradient echo images can be acquired in approximately 150 to 250 ms in myocardial perfusion studies. Echo-planar imaging is approximately 2 to 3 times faster than gradient echo imaging, but due to the use of long gradient echo trains, the effective T2 is relatively long, resulting in a degradation of image quality due to cardiac motion, magnetic susceptibility effects, and/or limited ability to achieve good magnetic field homogeneity over the heart at higher field strengths (⬎⬃1 Tesla). For quantitative perfusion imaging, it has been challenging to extract an arterial input with echo planar imaging from the contrast enhancement in the LV cavity. These adverse effects of long echo trains are reduced with hybrid echo-planar sequences, with echo train lengths on the order of 3 to 6 echoes being used for myocardial perfusion imaging. Standard gradient echo imaging sequences are mostly limited by signal-to-noise due to the relatively low Ernst angle of 15 ° to 20°, which defines the flip angle beyond which signalto-noise starts to decrease with further increases of the flip angle. Gradient echo imaging with steady-state free precession (SSFP) circumvents this limitation by balancing the gradient waveforms such that the coherence of the transverse magnetization is maximized before application of each radiofrequency pulse.38-40 In the SSFP mode, the magnetization components are toggled between the longitudinal and transverse orientations with a minimum of spoiling of the transverse magnetization. The SSFP state is quite sensitive to frequency offsets, which can give rise to banding artifacts and
5 signal voids, but nevertheless gradient echo imaging with SSFP has been successfully applied to myocardial perfusion imaging.41 SSFP has yielded remarkable improvements in contrast-to-noise compared to standard gradient echo imaging, and were it not for its propensity to show image artifacts, one could foresee it being the technique of choice for myocardial perfusion imaging. Contrast enhancement during the first pass of a contrast agent is determined by the degree of T1 weighting of the signal. Gradient echo sequences with short repetition time (TR) and echo time (TE) give a reasonable degree of T1 weighting if the flip angle is not too low, but the application of magnetization preparation pulses, which precede the image readout, can boost the T1 weighting. Nonselective inversion or saturation pulses are built into the pulse sequences for this purpose. The saturation pulse preparation is especially attractive because it renders the contrast enhancement independent from the heart rate or the rate at which images are acquired, and as a patient’s heart beat can be irregular it also avoids fluctuations in the signal intensity due to arrythmias.42 The possible options for combining control of T1 contrast, with fast imaging, and possibly monitoring of respiratory motion is illustrated in Fig 2. The perfusion reserve, defined as the ratio of hyperemic perfusion, normalized by resting perfusion is determined by two separate contrast bolus injections, performed at least 15 to 20 minutes apart to avoid reduced contrast enhancement during the first pass of the bolus due to contrast agent still lingering in the blood pool due to the previous injection. When it is anticipated that loss of myocardial viability can lead to contrast hyperenhancement in an infarct zone, one should perform the study with vasodilatation first, as it carries a higher prognostic value than the rest study. In the presence of contrast hyperenhancement it becomes difficult to assess perfusion by further bolus injections. With gadolinium (Gd)-based contrast agents such as GdDTPA, dosages used for perfusion studies typically range from 0.04 to 0.1 mmol/kg. With the higher dosage the contrast enhancement is striking, but at least in the blood pool the signal increase during contrast transit may reach a limit of saturation, which may adversely affect the quantification of the perfusion reserve. Also, with higher contrast agent dosages it becomes more likely that the differences in magnetic susceptibility between blood loaded with contrast, and myocardium that has not enhanced appreciably, give rise to dark rim artifacts. A slow infusion of contrast will lead to a loss of sensitivity for assessing blood flow. A power injector is preferably used to administer a contrast bolus at a rate on the order of 4 to 6 mL/s through an intravenous needle. A rapid contrast injection, combined with fast imaging of several slices during each heart beat with a T1-weighted gradient echo imaging technique, results in adequate depiction of the first pass of the contrast bolus.
Analysis Adequate tools for postprocessing of images and quantitative analysis of perfusion (reserve) have been slow in becoming
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Figure 2 MRI pulse sequence techniques for T1-weighted myocardial perfusion imaging can be thought of as comprising modules for image contrast control (prepulse module), image acquisition, slice tracking (“NAV”), and sampling of the arterial input with low spatial resolution in the left ventricular cavity (not shown). The prepulse can be applied only once and shared for all imaged slices, although this results in different contrast characteristics for each slice, but saves some time. Common perfusion sequence implementations only contain the first two ingredients (prepulse and image acquisition). The perfusion scan is generally electrocardiogram gated, and under ideal conditions enough images are acquired during each cardiac cycle to allow sufficient spatial coverage (eg, several parallel slices in the short-axis orientation from base to apex). Rapid image acquisitions also effectively freeze cardiac motion. Sampling of the arterial input can be performed by low-resolution imaging with a contrast weighting that is optimized for the contrast bolus without saturation of the signal enhancement near the peak bolus concentration. Monitoring of breathing motion with a navigator pulse can be included to adjust the position of slices during free breathing and consistently track contrast enhancement without slice misregistration.
available and presumably hampered the clinical implementation of MR perfusion imaging. The goal of an analysis is to quantify the regional contrast enhancement and extract a quantitative measure such as absolute myocardial blood flow or perfusion reserve to relate it to other clinical variables, for prognosis, and to gauge therapeutic effects. Whether it is necessary to quantify absolute myocardial blood flow continues to be controversial and depends on the clinical scenario calling for the application of myocardial perfusion imaging. With PET imaging it has been demonstrated that the absolute quantification of myocardial perfusion has numerous benefits.43 Any semiquantitative or quantitative analysis is based on assessing the contrast enhancement in user-defined myocardial sectors or in coronary territories. Perfusion images are segmented along the endo- and epicardial borders and landmarks are identified for the purpose of defining myocardial sectors. Contrast enhancement in myocardial sectors or regions of interest is presented in the form of curves of signal intensity values versus time. An example of typical signal intensity curves is shown in the graph of Fig 1. In the steady
state the difference of signal intensity pre and post contrast administration in tissue and blood pool provides a measure of the relative distribution volume, and can be expressed as milliliters per gram or milliliters of tissue. The signal changes in myocardium are sensitive to blood flow during the first pass of the contrast bolus. The central volume principle relates the contrast enhancement of tissue to the arterial input through the flow-weighted impulse response.44 The impulse response can be thought of as a probability distribution for the time a contrast molecule remains within a region of interest. The factor that relates this probability distribution to the measured tissue response equals the blood flow, that is, it equals the amplitude of the flow-weighted impulse response. In numerical terms, the impulse response and flow can be calculated by deconvolution of the measured tissue response with the arterial input, and this can be done without much or any user input.45,46 A conceptually simpler and widely used approach relies on the quantification of an up-slope parameter, equivalent to an observer applying a ruler to the portion of the signal intensity curve between the start of contrast enhancement and the
MRI of myocardial perfusion
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Figure 3 A 62-year-old male with chest pain showed lateral wall ST depression during exercise at 125 W (see electrocardiogram traces on the left). A perfusion defect was observed with myocardial perfusion imaging by MRI during the first pass of a gadolinium bolus, after maximal hyperemia had been induced by 140 /kg/min of adenosine intravenously over 4 minutes. Coronary angiography confirmed the presence of a significant stenosis, located in the second obtuse marginal branch of the left circumflex coronary artery.
point where it peaks, and determining the steepness of the signal rise.19,47-49 The graph in Fig 1 provides examples of the up slope. Computer algorithms calculate this parameter in an observer independent and largely automated manner, for example, by using a fit of a gamma-variate function to the signal intensity curve to derive the up-slope parameter. The slope parameter is sufficiently sensitive to myocardial blood flow to fulfill the role of semiquantitative perfusion index, and ratios of such indices for rest and hyperemia can be calculated to estimate the perfusion reserve.49 It is important to correct the up-slope index for variations in the arterial input between rest and stress.
Results In terms of methodological advances, myocardial perfusion imaging has achieved a stage where absolute quantification of blood flow can be reliably achieved as shown by several stud-
ies in animal models,46,50-53 with comparisons of the blood flow estimates obtained by MRI to measurements with radioisotope-labeled microspheres. Both intravascular and extracellular contrast agents are suitable for blood flow quantification by MRI. PET has been widely applied for the absolute quantification of blood flow; but to the best of our knowledge, the perfusion reserves obtained by both MRI and PET were only compared in one study,54 by using a method based on the up-slope parameter to quantify the perfusion reserve with MRI. It is clear from experimental animal studies that the perfusion reserve is underestimated, if the slope parameter is used,51 although this does not exclude use of this parameter for the detection of hemodynamically significant coronary lesions, if cutoffs specific to the analysis method are used. The in-plane spatial resolution achievable in perfusion studies by MRI has reached the order of 2 mm at 3 Tesla and is therefore unmatched by nuclear imaging. Due to its spatial
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Figure 4 A patient with akinesis in the anterior and anterior-septal wall, as evidenced by the two cine MRI frames in the top row, underwent a rest perfusion study. An area with persistent lack of contrast enhancement during the first pass matched the segments with akinesis. A further 0.15 mmol/kg of contrast was injected after the first pass perfusion study, and imaging of delayed contrast enhancement revealed a zone of nonviable myocardium, with a small subendocardial core with microvascular obstruction.
resolution, MRI allows selective assessment of endomyocardial perfusion.18,55,56 Using quantitative perfusion imaging, a transmural myocardial gradient and differences between endo- and epimyocardial perfusion in a group of healthy volunteers were determined.57 Mean myocardial resting perfusion in the endomyocardial layer of the left ventricle was significantly higher compared to the perfusion in the epimyocardium. The Endo/Epi gradient at rest was approximately 46%. The perfusion reserve in the endomyocardium was significantly lower than in the epimyocardium, with a gradient of approximately 31%. Its high spatial resolution gives MRI a unique position in the assessment of selective endo- and epimyocardial perfusion in patients. Quantitative MRI perfusion was used to assess perfusion in heart transplant recipients with transplantarteriopathy (TPA). It was possible to detect patients with TPA by a reduced Endo/Epi perfusion
ratio with a negative predictive value of 100% when LV hypertrophy and/or prior rejection were excluded.58 In addition, absolute quantification of perfusion in the endomyocardium demonstrated a reduced perfusion already at rest in patients with TPA versus a matched healthy transplanted group.56 MRI perfusion can detect significant coronary artery stenosis as shown by several groups in single center studies. Al-Saadi et al49 and Nagel et al59 convincingly demonstrated the value of MRI perfusion for the detection of ischemia in CAD patients. The myocardial perfusion reserve was shown to improve after coronary intervention, with the most pronounced increase after stenting in comparison to angioplasty.60 In a prospective study of 48 patients with suspected CAD who were referred for coronary angiography, Schwitter et al55 compared MRI and PET for detection of single and
MRI of myocardial perfusion multivessel disease. They found that MR data of signal intensity up slope, particularly from the subendocardial layer, are highly reliable in the detection of hemodynamically significant disease. In the unselected patients in the study by Schwitter et al,55 the sensitivity and specificity for detecting anatomically defined CAD were 87% and 85%, respectively, which compared favorably with the values obtained with PET. A recent European multicenter study61 achieved somewhat higher sensitivity (93%) and lower specificity (75%) for the detection of coronary disease, with the best results achieved with a gadolinium dosage of 0.1 to 0.15 mmol/kg for the particular hybrid echo-planar pulse sequence used in that study.
Case Examples Two case examples shown in Figs 3 and 4 are representative of current applications of myocardial perfusion by MRI in patients with CAD. They also illustrate the interplay between components of an MRI protocol for detection of coronary disease. Cine MRI is used for detection of wall motion defects. Imaging of delayed contrast enhancement is applied to depict areas of infarction.
Outlook Myocardial perfusion imaging by MRI has reached a level where its clinical application is an attractive alternative to current tests. Despite the considerable promise of MRI for myocardial perfusion imaging, the use of MRI contrast agents has not been approved in the United States for any cardiacrelated indication, including perfusion imaging in coronary disease patients. In the mean time the use of SPECT for myocardial perfusion imaging has grown at an annual rate of 10% to 20% over the last decade. While single-center studies have shown that MRI perfusion imaging can be useful, larger multicenter studies are needed to advance the field and obtain the necessary data for approval of indications for myocardial perfusion imaging by MRI.
Acknowledgment MJH gratefully acknowledges support through grants R01 HL65394 and R01 HL65580 from NIH/NHBLI, and previous support from The Whitaker Foundation. OM gratefully acknowledges support for a CMR research fellowship from the Deutsche Forschungsgemeinschaft.
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9 4. Berman DS, Kiat H, Friedman JD, et al: Clinical applications of exercise nuclear cardiology studies in the era of healthcare reform. Am J Cardiol 75:3D-13D, 1995 5. Hachamovitch R, Hayes SW, Friedman JD, et al: Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 107:2900-2907, 2003 6. Berman DS, Hachamovitch R: Risk assessment in patients with stable coronary artery disease: Incremental value of nuclear imaging. J Nucl Cardiol 3(6 Pt 2):S41-S49, 1996 7. Wagner A, Mahrholdt H, Holly TA, et al: Contrast-enhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: An imaging study. Lancet 361:374-379, 2003 8. Debatin JF, Nadel SN, Paolini JF, et al: Cardiac ejection fraction: phantom study comparing cine MR imaging, radionuclide blood pool imaging, and ventriculography. J Magn Reson Imaging 2:135-142, 1992 9. Reichek N: Cardiac magnetic resonance imaging and core cardiology training II (COCATS-2): can we get there from here? J Am Coll Cardiol 43:2113-2115, 2004 10. Wilson RF, Marcus ML, White CW: Prediction of the physiologic significance of coronary arterial lesions by quantitative lesion geometry in patients with limited coronary artery disease. Circulation 75:723-732, 1987 11. Uren NG, Melin JA, De Bruyne B, et al: Relation between myocardial blood flow and the severity of coronary-artery stenosis. N Engl J Med 330:1782-1788, 1994 12. Hoffman JI: Heterogeneity of myocardial blood flow. Basic Res Cardiol 90:103-111, 1995 13. Canty JM Jr, Klocke FJ: Reductions in regional myocardial function at rest in conscious dogs with chronically reduced regional coronary artery pressure. Circ Res 61(5 Pt 2):II107-II116, 1987 14. Laxson DD, Dai XZ, Homans DC, et al: Coronary vasodilator reserve in ischemic myocardium of the exercising dog. Circulation 85:313-322, 1992 15. Cannon RO 3rd, Schenke WH, Quyyumi A, et al. Comparison of exercise testing with studies of coronary flow reserve in patients with microvascular angina. Circulation 83(5 Suppl):III77-III81, 1991 16. Pepine CJ, Balaban RS, Bonow RO, et al: Women’s ischemic syndrome evaluation: Current status and future research directions: Report of the National Heart, Lung and Blood Institute workshop, October 2-4, 2002: Section 1: Diagnosis of stable ischemia and ischemic heart disease. Circulation 109:e44-e46, 2004 17. Doyle M, Fuisz A, Kortright E, et al: The impact of myocardial flow reserve on the detection of coronary artery disease by perfusion imaging methods: An NHLBI WISE study. J Cardiovasc Magn Reson 5:475485, 2003 18. Panting JR, Gatehouse PD, Yang GZ, et al: Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med 346:1948-1953, 2002 19. Wilke N, Jerosch-Herold M, Wang Y, et al: Myocardial perfusion reserve: Assessment with multisection, quantitative, first-pass MR imaging. Radiology 204:373-384, 1997 20. Shelton ME, Senneff MJ, Ludbrook PA, et al: Concordance of nutritive myocardial perfusion reserve and flow velocity reserve in conductance vessels in patients with chest pain with angiographically normal coronary arteries. J Nucl Med 34:717-722, 1993 21. Buchthal SD, den Hollander JA, Merz CN, et al: Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N Engl J Med 342: 829-835, 2000 22. Wu KC, Kim RJ, Bluemke DA, et al: Quantification and time course of microvascular obstruction by contrast-enhanced echocardiography and magnetic resonance imaging following acute myocardial infarction and reperfusion. J Am Coll Cardiol 32:1756-1764, 1998 23. Rochitte CE, Lima JA, Bluemke DA, et al: Magnitude and time course of microvascular obstruction and tissue injury after acute myocardial infarction. Circulation 98:1006-1014, 1998
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10 24. Wu KC, Zerhouni EA, Judd RM, et al: Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation 97:765-772, 1998 25. Gerber BL, Rochitte CE, Melin JA, et al: Microvascular obstruction and left ventricular remodeling early after acute myocardial infarction. Circulation 101:2734-2741, 2000 26. Hombach V, Grebe O, Merkle N, et al: Sequelae of acute myocardial infarction regarding cardiac structure and function and their prognostic significance as assessed by magnetic resonance imaging. Eur Heart J 26:549-557, 2005 27. Lund GK, Stork A, Saeed M, et al: Acute myocardial infarction: evaluation with first-pass enhancement and delayed enhancement MR imaging compared with 201Tl SPECT imaging. Radiology 232:49-57, 2004 28. Jerosch-Herold M, Hu X, Murthy NS, et al. Time delay for arrival of MR contrast agent in collateral-dependent myocardium. IEEE Trans Med Imaging 23:881-890, 2004 29. Heusch G, Schulz R, Rahimtoola SH: Myocardial hibernation: A delicate balance. Am J Physiol Heart Circ Physiol 288:H984-H999, 2005 30. Bolli R, Zhu W-X, Thornby JI, et al: Time course and determinants of recovery of function after reversible ischemia in conscious dogs. Am J Physiol 254:H102-H114, 1988 31. Selvanayagam J, Jerosch-Herold M, Porto I, et al: Resting myocardial blood flow is impaired in hibernating myocardium: An MR study of quantitative perfusion assessment. Circulation 112:3289-3296, 2005 32. Kwong RY, Schussheim AE, Rekhraj S, et al: Detecting acute coronary syndrome in the emergency department with cardiac magnetic resonance imaging. Circulation 107:531-537, 2003 33. Plein S, Greenwood JP, Ridgway JP, et al: Assessment of non-ST-segment elevation acute coronary syndromes with cardiac magnetic resonance imaging. J Am Coll Cardiol 44:2173-2181, 2004 34. Sipola P, Lauerma K, Husso-Saastamoinen M, et al: First-pass MR imaging in the assessment of perfusion impairment in patients with hypertrophic cardiomyopathy and the Asp175Asn mutation of the {alpha}-tropomyosin gene. Radiology 226:129-137, 2003 35. Kawada N, Sakuma H, Yamakado T, et al: Hypertrophic cardiomyopathy: MR measurement of coronary blood flow and vasodilator flow reserve in patients and healthy subjects. Radiology 211:129-135, 1999 36. McCrohon JA, Moon JC, Prasad SK, et al: Differentiation of heart failure related to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance. Circulation 108:54-59, 2003 37. Reeder SB, Atalar E, Faranesh AZ, et al: Multi-echo segmented k-space imaging: An optimized hybrid sequence for ultrafast cardiac imaging. Magn Reson Med 41:375-385, 1999 38. Schreiber WG, Schmitt M, Kalden P, et al: Dynamic contrast-enhanced myocardial perfusion imaging using saturation-prepared TrueFISP. J Magn Reson Imaging 16:641-652, 2002 39. Nitz WR: Fast and ultrafast non-echo-planar MR imaging techniques. Eur Radiol 12:2866-2882, 2002 40. Hunold P, Maderwald S, Eggebrecht H, et al: Steady-state free precession sequences in myocardial first-pass perfusion MR imaging: Comparison with TurboFLASH imaging. Eur Radiol 14:409-416, 2004 41. Klocke FJ, Simonetti OP, Judd RM, et al: Limits of detection of regional differences in vasodilated flow in viable myocardium by first-pass magnetic resonance perfusion imaging. Circulation 104:2412-2416, 2001 42. Tsekos NV, Zhang Y, Merkle H, et al: Fast anatomical imaging of the heart and assessment of myocardial perfusion with arrhythmia insensitive magnetization preparation. Magn Reson Med 34:530-536, 1995 43. Bianco JA, Alpert JS: Physiologic and clinical significance of myocardial blood flow quantitation: What is expected from these measurements in
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the clinical ward and in the physiology laboratory? Cardiology 88:116-126, 1997 Zierler KL: Equations for measuring blood flow by external monitoring of radioisotopes. Circ Res 16:309-321, 1965 Jerosch-Herold M, Seethamraju RT, Swingen CM, et al: Analysis of myocardial perfusion MRI. J Magn Reson Imaging 19:758-770, 2004 Jerosch-Herold M, Swingen C, Seethamraju RT: Myocardial blood flow quantification with MRI by model-independent deconvolution. Med Phys 29:886-897, 2002 Matheijssen NA, Louwerenburg HW, van Rugge FP, et al: Comparison of ultrafast dipyridamole magnetic resonance imaging with dipyridamole SestaMIBI SPECT for detection of perfusion abnormalities in patients with one-vessel coronary artery disease: Assessment by quantitative model fitting. Magn Reson Med 35:221-228, 1996 Keijer JT, van Rossum AC, Wilke N, et al: Magnetic resonance imaging of myocardial perfusion in single-vessel coronary artery disease: Implications for transmural assessment of myocardial perfusion. J Cardiovasc Magn Reson 2:189-200, 2000 Al-Saadi N, Nagel E, Gross M, et al: Noninvasive detection of myocardial ischemia from perfusion reserve based on cardiovascular magnetic resonance. Circulation 101:1379-1383, 2000 Christian TF, Rettmann DW, Aletras AH, et al: Absolute myocardial perfusion in canines measured by using dual-bolus first-pass MR imaging. Radiology 232:677-684, 2004 Jerosch-Herold M, Hu X, Murthy NS, et al: MRI of myocardial contrast enhancement with MS-325 and its relation to myocardial blood flow and the perfusion reserve. J Magn Reson Imaging 18:544-554, 2003 Kroll K, Wilke N, Jerosch-Herold M, et al: Accuracy of modeling of regional myocardial flows from residue functions of an intravascular indicator. Am J Physiol (Heart Circ Physiol) 40:H1643-H1655, 1996 Wilke N, Kroll K, Merkle H, et al: Regional myocardial blood volume and flow: First-pass MR imaging with polylysine-Gd-DTPA. J Magn Reson Imaging 5:227-237, 1995 Ibrahim T, Nekolla SG, Schreiber K, et al: Assessment of coronary flow reserve: Comparison between contrast- enhanced magnetic resonance imaging and positron emission tomography. J Am Coll Cardiol 39:864870, 2002 Schwitter J, Nanz D, Kneifel S, et al: Assessment of myocardial perfusion in coronary artery disease by magnetic resonance: A comparison with positron emission tomography and coronary angiography. Circulation 103:2230-2235, 2001 Muehling O, Panse P, Jerosch-Herold M, et al. Cardiac magnetic resonance perfusion imaging identifies transplant arteriopathy by a reduced endomyocardial resting perfusion. J Heart Lung Transplant 24:11221123, 2005 Mühling OM, Jerosch-Herold M, Panse P, et al: Regional heterogeneity of myocardial perfusion in healthy human myocardium: Assessment with magnetic resonance perfusion imaging. J Cardiovasc Magn Reson 6:499-507, 2004 Mühling OM, Wilke NM, Panse P, et al: Transmural myocardial perfusion in transplanted human hearts assessed by magnetic resonance imaging. J Am Coll Cardiol 42:1054-1060, 2003 Nagel E, Klein C, Paetsch I, et al: Magnetic resonance perfusion measurements for the noninvasive detection of coronary artery disease. Circulation 108:432-437, 2003 Al-Saadi N, Nagel E, Gross M, et al: Improvement of myocardial perfusion reserve early after coronary intervention: Assessment with cardiac magnetic resonance imaging. J Am Coll Cardiol 36:1557-1564, 2000 Giang TH, Nanz D, Coulden R, et al: Detection of coronary artery disease by magnetic resonance myocardial perfusion imaging with various contrast medium doses: First European multi-centre experience. Eur Heart J 25:1657-1665, 2004
T
he need for detection of acute or chronic myocardial ischemia by perfusion imaging results in approximately 5 million nuclear cardiology procedures per year in the United States. The role of myocardial perfusion imaging is well established and encompasses diagnosis of coronary artery disease (CAD), risk stratification, prognosis,1-3 guidance for the choice of medical management or revascularization,4,5 and screening of high-risk patients, for example, before noncardiac surgery.6 Normal perfusion stress images in patients with documented CAD indicate a favorable prognosis.2 Magnetic resonance imaging (MRI) provides a novel approach for assessing myocardial perfusion with high spatial resolution and without exposure to ionizing radiation. Furthermore, MRI allows an integrated assessment of perfusion, function, and myocardial viability within a single examination. In comparison, positron emission tomography (PET) and single-photon emission tomography (SPECT) perfusion studies are time consuming. PET and SPECT have relatively low spatial resolution compared to perfusion imaging with MRI, and they may therefore be unsuitable for identifying perfusion deficits and infarcts limited to the subendocardial layer.7 Nuclear imaging also *Advanced Imaging Research Center and Department of Medicine, Oregon Health & Science University, Portland, OR. †Department of Medicine, University of Munich, Munich, Germany. ‡Department of Radiology, Health Science Center, University of Florida, Jacksonville, FL. Address reprint requests to Michael Jerosch-Herold, PhD, Advanced Imaging Research Center, MS L452, 3181 SW Sam Jackson Park Road, Portland, OR 97239. E-mail: [email protected].
2
0887-2171/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.sult.2005.10.001
can be used for an integrated assessment of perfusion and function, but techniques such as multigated blood pool scans (MUGA) for left ventricle (LV) function evaluation are less accurate than MRI cine imaging.8 MRI therefore represents a compelling choice for myocardial perfusion imaging. The advantages of myocardial perfusion imaging by MRI are offset by a perception of complexity, a lack of training opportunities,9 the abundance of technical approaches, which has slowed down the establishment of a consensus, and the relative lack of tools that expedite the analysis and interpretation of MRI perfusion studies in a clinical setting. Also, MRI-safe implantable pacemaker technology is still sparse, and implanted heart devices, including cardiac defibrillators, generally rule out using MRI.
Clinical Applications Detection of Coronary Artery Disease MRI perfusion has been used for the detection of significant lesions in patients with CAD. Due to the low sensitivity of resting blood flow to epicardial coronary stenosis, a perfusion scan under stress conditions is of paramount importance for the evaluation of CAD. However, the confining environment of an MRI magnet renders exercise stress testing impractical, and pharmacological vasodilation is the method of choice for “stress” perfusion imaging. The flow resistance of the coronary circulation under baseline conditions is determined by the myocardial microcirculation. Only imaging during stress or hyperemia allows assessing the hemodynamic significance
MRI of myocardial perfusion of a coronary lesion in the epicardial conduit vessels. The severity of an epicardial coronary stenosis is directly related to the perfusion reserve, the ratio of myocardial blood flow during vasodilation, divided by baseline blood flow.10,11 Blood flow across the myocardium wall is not uniform,12 but instead favors the subendocardium to accommodate the higher workload and higher rate of oxygen consumption of the subendocardial layer. Under normal conditions the ratio of endocardial to epicardial blood flow is on the order of 1.2:1. With a coronary artery stenosis, blood flow is first diverted away from the subendocardial layer,13,14 and the endocardial to epicardial blood flow ratio is often less than 1:1, in particular under stress. The detection of coronary artery disease in patients is therefore more sensitive if the spatial resolution of the imaging technique allows separate assessment of the endomyocardial layer.
Microvascular Dysfunction The combination of chest pain, positive exercise testing, but normal coronary angiogram has been classified as cardiac syndrome X.15 Its pathogenic entity and cause remain controversial. Ischemia in the absence of flow-limiting stenoses has been recognized as a relevant clinical syndrome, in particular in postmenopausal women, as shown by the Women’s Ischemic Syndrome Evaluation (WISE) study. WISE investigators concluded that an abnormal microcirculation plays an important role in the pathogenesis of ischemic syndromes in women without obstructive coronary artery disease. A paucity of electrocardiographic changes and regional wall motion abnormalities in patients with microvascular disease can cast doubt on the value of standard tests in this population.16 Initial reports of perfusion studies in the WISE population17 described atypical perfusion patterns, which either masked or mimicked epicardial CAD. Other studies in cohorts with cardiac syndrome X have demonstrated the value of perfusion MRI for detecting ischemia related to microvascular dysfunction,18,19 in particular in combination with a quantitative assessment of the perfusion reserve. Perfusion imaging, by PET20 or MRI,18,19 has supported the notion that the chest pain may have an ischemic cause. In patients with cardiac syndrome X, the myocardial perfusion reserve measured by quantitative perfusion MRI was reduced and in good agreement with the invasively measured coronary flow reserve.19 The hypothesis of ischemia in cardiac syndrome X is supported by studies of highenergy metabolism by 31P MR spectroscopy.21 Blunting of the perfusion reserve was most pronounced in the subendocardial layer, in marked distinction to the pattern observed in controls.18
Microvascular Obstruction During the first 1 to 2 minutes after gadolinium contrast injection, areas in the core of an infarct may fail to show contrast enhancement because of microvascular obstruction22,23 (MO). This early phase of contrast enhancement can be observed in a perfusion scan, if it extends in time
3 over a minute or more after contrast injection. Regions with MO are identified by distinct and persistent hypoenhancement over the first 1 to 3 minutes.22,23 MO is associated with a worse prognosis, even after control for infarct size.24 The lack of contrast enhancement in the presence of MO, even after recanalization, is referred to as the noreflow phenomenon. It was shown by MRI that infarct remodeling was greatest in those patients with larger areas of MO.25,26 MRI appears to be an excellent modality for detecting MO with excellent spatial resolution, and reveals the heterogeneity of microvascular integrity and patency within an infarct zone. The detection of MO, with the patient at rest, does not require the same degree of temporal resolution as imaging during the first pass of a contrast agent to detect ischemia or a decrease of the perfusion reserve. Temporal resolution can be traded off against spatial resolution and contrast-to-noise. A distinction between severe hypoenhancement during the first pass27 and persistent lack of contrast enhancement26 may be important for prognosis and relate to the severity of MO and the presence of some residual collateral flow.27 One observes a delay in the arrival of contrast in collateral-dependent myocardium even in the absence of infarction and MO.28 Whether imaging during the first pass of a contrast bolus, or with some delay after contrast injection, is most appropriate to assess MO may not have been resolved conclusively.
Hibernation and Stunning In combination with imaging of delayed contrast enhancement for myocardial viability, perfusion imaging can play a unique role in the detection of hibernating myocardium. From a clinical standpoint, the identification of hibernating myocardium is important because of the potential to improve function and therefore prognosis of the patient. Whether resting blood flow is reduced in chronic hibernating myocardium remains controversial. A recent review of studies on this issue29 concluded that the evidence seemed to favor the hypothesis that baseline blood flow is significantly reduced. At the very least, studies that did not detect a reduction of baseline blood flow suffered from inadequate spatial resolution, and one could therefore not exclude the possibility of a significant subendocardial flow reduction. Alternatively, the state of hibernation may result from transient reductions of blood flow and repetitive stunning, with a low likelihood of chronically depressed myocardial blood flow during resting conditions. It is well known that even small differences in blood flow during ischemia result in large differences in postischemic function,30 suggesting that the ability to quantify flow in the low flow range is of importance to predict the probability of postischemic recovery. MRI offers unsurpassed abilities to interrogate regional perfusion with sufficient spatial resolution, and it may therefore become feasible to resolve these controversies on the causes of chronic stunning. A recent MRI study supports the notion that resting blood
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Figure 1 Perfusion images, shown in panel (A), were acquired in an overweight male patient at 3 T (Philips Intera 3T) with a 0.03 mmol/kg dosage of Gd-DTPA contrast, using a fast gradient echo sequence with saturation-recovery magnetization preparation. The body coil of the MRI system was used due to the body habitus of the patient. The intravenously injected contrast bolus first causes contrast enhancement in the right ventricular cavity, followed by enhancement in the left ventricular cavity, and then myocardial contrast enhancement. The patient had a resting perfusion deficit in the inferior wall. An image of the delayed contrast enhancement in (B) shows an infarct region that matches the location of the rest perfusion defect. (C) The graph shows the variation of the signal intensity during the transit of the contrast bolus for two transmural myocardial sectors, in the anterior and inferior wall respectively. Contrast enhancement in the inferior sector is delayed and occurs at a markedly lower rate than in the anterior sector. The dotted line is a linear approximation to the signal intensity curve to calculate an up-slope parameter, which has been shown to vary in proportion to changes in blood flow.
flow is impaired in hibernating myocardial segments supplied by severely stenosed coronary arteries.31
and is feasible in the evaluation of patients with acute coronary syndromes.
Acute Chest Pain Assessment
Cardiomyopathies
As MRI techniques have matured, investigators have applied these new and increasingly robust tools in the evaluation of acute chest pain. One pioneering study by Kwong et al32 showed that with use of a comprehensive MRI protocol, which included perfusion imaging under resting conditions, MRI accurately identified a high fraction of patients with non-ST elevation myocardial infarction (with or without an elevated troponin). Perfusion imaging was applied to identify myocardial segments with preserved viability, but hypoperfusion under resting conditions. More recently Plein et al33 tested an MRI protocol for evaluation of patients with acute coronary syndromes by using a comprehensive analysis of wall motion, perfusion, delayed contrast enhancement, and coronary imaging with high sensitivity and specificity. When individual components of the MRI protocol were considered, they found that perfusion imaging gave the highest sensitivity and overall accuracy of any protocol component and was deemed to be most useful for predicting the need for revascularization.33 Which protocol component proves to be most beneficial for prognosis probably depends on the patient population, but perfusion imaging by MRI is of high value
Myocardial perfusion imaging by MRI has been applied in a genetically homogeneous population of patients with hypertrophic cardiomyopathy to evaluate the association between hypertrophy and perfusion.34 The attenuation of the perfusion reserve index was shown to be associated with the degree of LV hypertrophy. An estimate of the global average of myocardial perfusion was measured with MRI in patients with idiopathic dilated cardiomyopathy (IDC). Instead of applying perfusion imaging, an estimate of the global average of myocardial blood flow was arrived at by the use of phase-contrast velocity measurements of blood flow in the coronary sinus, and cine imaging for LV mass determination.35 PET studies have shown that the myocardial blood flow (MBF) reserve is reduced in patients with IDC, which was interpreted as a flow-impairment in the coronary microcirculation in the absence of epicardial lesions. Of note is that in a recent study of heart failure patients, an absence of focal delayed contrast enhancement was reported for 59% of the patients with dilated cardiomyopathy and no evidence of CAD.36 The presence of scar and fibrosis in patients with
MRI of myocardial perfusion dilated cardiomyopathies may be quite heterogenous in this population, and warrant further studies of regional perfusion patterns, in particular in IDC patients which do not show delayed contrast enhancement.
Techniques Acquisition Rapid imaging of contrast enhancement during the first pass of a bolus-injected contrast agent is currently the method of choice for assessing myocardial perfusion with MRI. Figure 1 gives an example, showing the application of this technique. Gadolinium-based contrast agents provide excellent contrast enhancement in the heart, with single-shot T1-weighted imaging. Electrocardiogram-gated, T1-weighted techniques, with image acquisition times of less than 200 ms, are sufficiently fast to freeze cardiac motion and cover 3 to 5 slices per heart beat. The contrast agent is bolus-injected intravenously, for example, in the antecubital fossa. Although one strives to cover the entire heart during a perfusion scan, this is currently still challenging; but recent advancements such as parallel imaging have brought this goal within close grasp. Nevertheless the imaging techniques continue to be based on two-dimensional (2D) acquisitions, rather than 3D acquisitions, as the former represent an easier approach to freezing cardiac motion at each slice level. Pulse sequence types applied for myocardial perfusion imaging range from gradient echo to echo-planar imaging, with hybrid forms37 as compromises that combine advantages at both extremes of the pulse sequence spectrum. Gradient echo images can be acquired in approximately 150 to 250 ms in myocardial perfusion studies. Echo-planar imaging is approximately 2 to 3 times faster than gradient echo imaging, but due to the use of long gradient echo trains, the effective T2 is relatively long, resulting in a degradation of image quality due to cardiac motion, magnetic susceptibility effects, and/or limited ability to achieve good magnetic field homogeneity over the heart at higher field strengths (⬎⬃1 Tesla). For quantitative perfusion imaging, it has been challenging to extract an arterial input with echo planar imaging from the contrast enhancement in the LV cavity. These adverse effects of long echo trains are reduced with hybrid echo-planar sequences, with echo train lengths on the order of 3 to 6 echoes being used for myocardial perfusion imaging. Standard gradient echo imaging sequences are mostly limited by signal-to-noise due to the relatively low Ernst angle of 15 ° to 20°, which defines the flip angle beyond which signalto-noise starts to decrease with further increases of the flip angle. Gradient echo imaging with steady-state free precession (SSFP) circumvents this limitation by balancing the gradient waveforms such that the coherence of the transverse magnetization is maximized before application of each radiofrequency pulse.38-40 In the SSFP mode, the magnetization components are toggled between the longitudinal and transverse orientations with a minimum of spoiling of the transverse magnetization. The SSFP state is quite sensitive to frequency offsets, which can give rise to banding artifacts and
5 signal voids, but nevertheless gradient echo imaging with SSFP has been successfully applied to myocardial perfusion imaging.41 SSFP has yielded remarkable improvements in contrast-to-noise compared to standard gradient echo imaging, and were it not for its propensity to show image artifacts, one could foresee it being the technique of choice for myocardial perfusion imaging. Contrast enhancement during the first pass of a contrast agent is determined by the degree of T1 weighting of the signal. Gradient echo sequences with short repetition time (TR) and echo time (TE) give a reasonable degree of T1 weighting if the flip angle is not too low, but the application of magnetization preparation pulses, which precede the image readout, can boost the T1 weighting. Nonselective inversion or saturation pulses are built into the pulse sequences for this purpose. The saturation pulse preparation is especially attractive because it renders the contrast enhancement independent from the heart rate or the rate at which images are acquired, and as a patient’s heart beat can be irregular it also avoids fluctuations in the signal intensity due to arrythmias.42 The possible options for combining control of T1 contrast, with fast imaging, and possibly monitoring of respiratory motion is illustrated in Fig 2. The perfusion reserve, defined as the ratio of hyperemic perfusion, normalized by resting perfusion is determined by two separate contrast bolus injections, performed at least 15 to 20 minutes apart to avoid reduced contrast enhancement during the first pass of the bolus due to contrast agent still lingering in the blood pool due to the previous injection. When it is anticipated that loss of myocardial viability can lead to contrast hyperenhancement in an infarct zone, one should perform the study with vasodilatation first, as it carries a higher prognostic value than the rest study. In the presence of contrast hyperenhancement it becomes difficult to assess perfusion by further bolus injections. With gadolinium (Gd)-based contrast agents such as GdDTPA, dosages used for perfusion studies typically range from 0.04 to 0.1 mmol/kg. With the higher dosage the contrast enhancement is striking, but at least in the blood pool the signal increase during contrast transit may reach a limit of saturation, which may adversely affect the quantification of the perfusion reserve. Also, with higher contrast agent dosages it becomes more likely that the differences in magnetic susceptibility between blood loaded with contrast, and myocardium that has not enhanced appreciably, give rise to dark rim artifacts. A slow infusion of contrast will lead to a loss of sensitivity for assessing blood flow. A power injector is preferably used to administer a contrast bolus at a rate on the order of 4 to 6 mL/s through an intravenous needle. A rapid contrast injection, combined with fast imaging of several slices during each heart beat with a T1-weighted gradient echo imaging technique, results in adequate depiction of the first pass of the contrast bolus.
Analysis Adequate tools for postprocessing of images and quantitative analysis of perfusion (reserve) have been slow in becoming
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Figure 2 MRI pulse sequence techniques for T1-weighted myocardial perfusion imaging can be thought of as comprising modules for image contrast control (prepulse module), image acquisition, slice tracking (“NAV”), and sampling of the arterial input with low spatial resolution in the left ventricular cavity (not shown). The prepulse can be applied only once and shared for all imaged slices, although this results in different contrast characteristics for each slice, but saves some time. Common perfusion sequence implementations only contain the first two ingredients (prepulse and image acquisition). The perfusion scan is generally electrocardiogram gated, and under ideal conditions enough images are acquired during each cardiac cycle to allow sufficient spatial coverage (eg, several parallel slices in the short-axis orientation from base to apex). Rapid image acquisitions also effectively freeze cardiac motion. Sampling of the arterial input can be performed by low-resolution imaging with a contrast weighting that is optimized for the contrast bolus without saturation of the signal enhancement near the peak bolus concentration. Monitoring of breathing motion with a navigator pulse can be included to adjust the position of slices during free breathing and consistently track contrast enhancement without slice misregistration.
available and presumably hampered the clinical implementation of MR perfusion imaging. The goal of an analysis is to quantify the regional contrast enhancement and extract a quantitative measure such as absolute myocardial blood flow or perfusion reserve to relate it to other clinical variables, for prognosis, and to gauge therapeutic effects. Whether it is necessary to quantify absolute myocardial blood flow continues to be controversial and depends on the clinical scenario calling for the application of myocardial perfusion imaging. With PET imaging it has been demonstrated that the absolute quantification of myocardial perfusion has numerous benefits.43 Any semiquantitative or quantitative analysis is based on assessing the contrast enhancement in user-defined myocardial sectors or in coronary territories. Perfusion images are segmented along the endo- and epicardial borders and landmarks are identified for the purpose of defining myocardial sectors. Contrast enhancement in myocardial sectors or regions of interest is presented in the form of curves of signal intensity values versus time. An example of typical signal intensity curves is shown in the graph of Fig 1. In the steady
state the difference of signal intensity pre and post contrast administration in tissue and blood pool provides a measure of the relative distribution volume, and can be expressed as milliliters per gram or milliliters of tissue. The signal changes in myocardium are sensitive to blood flow during the first pass of the contrast bolus. The central volume principle relates the contrast enhancement of tissue to the arterial input through the flow-weighted impulse response.44 The impulse response can be thought of as a probability distribution for the time a contrast molecule remains within a region of interest. The factor that relates this probability distribution to the measured tissue response equals the blood flow, that is, it equals the amplitude of the flow-weighted impulse response. In numerical terms, the impulse response and flow can be calculated by deconvolution of the measured tissue response with the arterial input, and this can be done without much or any user input.45,46 A conceptually simpler and widely used approach relies on the quantification of an up-slope parameter, equivalent to an observer applying a ruler to the portion of the signal intensity curve between the start of contrast enhancement and the
MRI of myocardial perfusion
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Figure 3 A 62-year-old male with chest pain showed lateral wall ST depression during exercise at 125 W (see electrocardiogram traces on the left). A perfusion defect was observed with myocardial perfusion imaging by MRI during the first pass of a gadolinium bolus, after maximal hyperemia had been induced by 140 /kg/min of adenosine intravenously over 4 minutes. Coronary angiography confirmed the presence of a significant stenosis, located in the second obtuse marginal branch of the left circumflex coronary artery.
point where it peaks, and determining the steepness of the signal rise.19,47-49 The graph in Fig 1 provides examples of the up slope. Computer algorithms calculate this parameter in an observer independent and largely automated manner, for example, by using a fit of a gamma-variate function to the signal intensity curve to derive the up-slope parameter. The slope parameter is sufficiently sensitive to myocardial blood flow to fulfill the role of semiquantitative perfusion index, and ratios of such indices for rest and hyperemia can be calculated to estimate the perfusion reserve.49 It is important to correct the up-slope index for variations in the arterial input between rest and stress.
Results In terms of methodological advances, myocardial perfusion imaging has achieved a stage where absolute quantification of blood flow can be reliably achieved as shown by several stud-
ies in animal models,46,50-53 with comparisons of the blood flow estimates obtained by MRI to measurements with radioisotope-labeled microspheres. Both intravascular and extracellular contrast agents are suitable for blood flow quantification by MRI. PET has been widely applied for the absolute quantification of blood flow; but to the best of our knowledge, the perfusion reserves obtained by both MRI and PET were only compared in one study,54 by using a method based on the up-slope parameter to quantify the perfusion reserve with MRI. It is clear from experimental animal studies that the perfusion reserve is underestimated, if the slope parameter is used,51 although this does not exclude use of this parameter for the detection of hemodynamically significant coronary lesions, if cutoffs specific to the analysis method are used. The in-plane spatial resolution achievable in perfusion studies by MRI has reached the order of 2 mm at 3 Tesla and is therefore unmatched by nuclear imaging. Due to its spatial
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Figure 4 A patient with akinesis in the anterior and anterior-septal wall, as evidenced by the two cine MRI frames in the top row, underwent a rest perfusion study. An area with persistent lack of contrast enhancement during the first pass matched the segments with akinesis. A further 0.15 mmol/kg of contrast was injected after the first pass perfusion study, and imaging of delayed contrast enhancement revealed a zone of nonviable myocardium, with a small subendocardial core with microvascular obstruction.
resolution, MRI allows selective assessment of endomyocardial perfusion.18,55,56 Using quantitative perfusion imaging, a transmural myocardial gradient and differences between endo- and epimyocardial perfusion in a group of healthy volunteers were determined.57 Mean myocardial resting perfusion in the endomyocardial layer of the left ventricle was significantly higher compared to the perfusion in the epimyocardium. The Endo/Epi gradient at rest was approximately 46%. The perfusion reserve in the endomyocardium was significantly lower than in the epimyocardium, with a gradient of approximately 31%. Its high spatial resolution gives MRI a unique position in the assessment of selective endo- and epimyocardial perfusion in patients. Quantitative MRI perfusion was used to assess perfusion in heart transplant recipients with transplantarteriopathy (TPA). It was possible to detect patients with TPA by a reduced Endo/Epi perfusion
ratio with a negative predictive value of 100% when LV hypertrophy and/or prior rejection were excluded.58 In addition, absolute quantification of perfusion in the endomyocardium demonstrated a reduced perfusion already at rest in patients with TPA versus a matched healthy transplanted group.56 MRI perfusion can detect significant coronary artery stenosis as shown by several groups in single center studies. Al-Saadi et al49 and Nagel et al59 convincingly demonstrated the value of MRI perfusion for the detection of ischemia in CAD patients. The myocardial perfusion reserve was shown to improve after coronary intervention, with the most pronounced increase after stenting in comparison to angioplasty.60 In a prospective study of 48 patients with suspected CAD who were referred for coronary angiography, Schwitter et al55 compared MRI and PET for detection of single and
MRI of myocardial perfusion multivessel disease. They found that MR data of signal intensity up slope, particularly from the subendocardial layer, are highly reliable in the detection of hemodynamically significant disease. In the unselected patients in the study by Schwitter et al,55 the sensitivity and specificity for detecting anatomically defined CAD were 87% and 85%, respectively, which compared favorably with the values obtained with PET. A recent European multicenter study61 achieved somewhat higher sensitivity (93%) and lower specificity (75%) for the detection of coronary disease, with the best results achieved with a gadolinium dosage of 0.1 to 0.15 mmol/kg for the particular hybrid echo-planar pulse sequence used in that study.
Case Examples Two case examples shown in Figs 3 and 4 are representative of current applications of myocardial perfusion by MRI in patients with CAD. They also illustrate the interplay between components of an MRI protocol for detection of coronary disease. Cine MRI is used for detection of wall motion defects. Imaging of delayed contrast enhancement is applied to depict areas of infarction.
Outlook Myocardial perfusion imaging by MRI has reached a level where its clinical application is an attractive alternative to current tests. Despite the considerable promise of MRI for myocardial perfusion imaging, the use of MRI contrast agents has not been approved in the United States for any cardiacrelated indication, including perfusion imaging in coronary disease patients. In the mean time the use of SPECT for myocardial perfusion imaging has grown at an annual rate of 10% to 20% over the last decade. While single-center studies have shown that MRI perfusion imaging can be useful, larger multicenter studies are needed to advance the field and obtain the necessary data for approval of indications for myocardial perfusion imaging by MRI.
Acknowledgment MJH gratefully acknowledges support through grants R01 HL65394 and R01 HL65580 from NIH/NHBLI, and previous support from The Whitaker Foundation. OM gratefully acknowledges support for a CMR research fellowship from the Deutsche Forschungsgemeinschaft.
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