CARDIAC MAGNETIC RESONANCE (E NAGEL AND V PUNTMANN, SECTION EDITORS)

Novel Approaches to Myocardial Perfusion: 3D First-Pass CMRPerfusion Imaging and Oxygenation-Sensitive CMR

Dominik P. Guensch & Matthias G. Friedrich

Published online: 14 February 2014# Springer Science+Business Media New York 2014

Abstract This article reviews technical aspects and the currentstatus of novel cardiovascular magnetic resonance (CMR) ap-proaches to assessing myocardial perfusion, specificallyoxygenation-sensitive magnetic resonance imaging, comparingtheir diagnostic targets and clinical role with those of otherimaging approaches. The paper includes discussions of relevantpathophysiological aspects of myocardial ischemia and theclinical context of revascularization in patients with suspectedor known coronary artery disease. Research using oxygenation-sensitive CMR may play an important role for a better under-standing of the interplay of coronary artery stenosis, blood flowreduction, and their impact on actual myocardial ischemia.

Keywords Cardiovascular magnetic resonance .

Oxygenation-sensitiveMR .Myocardial perfusion imaging .

Myocardial ischemia . Coronary artery disease . BOLDMRI

Introduction

Coronary artery disease has been traditionally understood as aprogressive narrowing of coronary arteries with subsequentreduction of coronary blood flow, resulting in acute or chronicepisodes of myocardial ischemia, ultimately leading to func-tional impairment. While the line of causalities can be backedby known physiology, the applicability of this model for ther-apeutic decision-making is limited due to several reasons: First,independent of the difficulties to accurately quantify coronaryartery stenosis, the measured severity often does not reflect itshemodynamic relevance [1, 2]. Second, coronary artery diseasetypically progresses in waves, and observations have led to theconcept of the “vulnerable patient” [3, 4] and the degree ofstenosis has a weak predictive value for acute coronary events[5]. This explains, why coronary “luminology” for decision-making with respect to revascularization does not improveoutcome, as multiple studies have shown [6, 7]. Third, incoronary artery stenosis, collateral arteries may counterbalancethe regional loss of blood flow in even severe stenosis [8, 9].Finally, even reduced blood flow may not necessarily lead tomyocardial ischemia.

In summary, currently used diagnostic markers, angiogra-phy, tracer uptake, contrast agent inflow, or fractional flowreserve do not allow to directly measure the impact of anobserved coronary artery stenosis on tissue oxygenation.

3D Myocardial Perfusion CMR

Myocardial perfusion imaging has been shown to accuratelydetect hemodynamically relevant coronary artery stenosis [10,11•]. Technical improvements have allowed for higher spatialor temporal resolution, which was used to develop 3-dimensional perfusion CMR [12] (Fig. 1). Compared withstandard, 2-dimensional perfusion only covers 2 to 5 slicesand thus, 3D perfusion imaging would be expected to increase

This article is part of the Topical Collection on Cardiac MagneticResonance

D. P. GuenschDepartment of Anaesthesiology and Pain Medicine, Bern UniversityHospital, Bern 3010, Switzerland

D. P. GuenschDepartments of Cardiology, Université de Montréal, Montréal,Canada

M. G. Friedrich (*)Philippa and Marvin Carsley CMR Centre at the Montreal HeartInstitute, 5000 Rue Belanger, Montréal H1T 1C8, QC, Canadae-mail: mgwfriedrich@gmail.com

M. G. FriedrichDepartments of Cardiology and Radiology, Université de Montréal,Montréal, Canada

M. G. FriedrichDepartments of Cardiac Sciences and Radiology, University ofCalgary, Calgary, Canada

Curr Cardiovasc Imaging Rep (2014) 7:9261DOI 10.1007/s12410-014-9261-5

accuracy. Indeed, in a recent study using fractional flowreserve and 50 % stenosis as a standard of truth, sensitivity,specificity, and diagnostic accuracy were found to be 91 %,90 %, and 91 % [13•] and 92 %, 74 % and 83 % [14],respectively. Yet, the comparative value of 3D perfusion im-aging vs high-resolution perfusion CMR (Fig. 2) is not clear[15•, 16•] and multi-center data on the clinical utility of 3Dfirst-pass perfusion CMR are still lacking. There is goodevidence that in patients with stable angina, at least 10 % ofthe myocardium may have to be subject to inducible ischemiafor a beneficial role of elective revascularization [17•]. Thus,full coverage of the myocardium by 3D methods (leaving lessthan 10 % of myocardium invisible) may appear more likelyto be associated with a positive impact on patient outcomesthan a high-resolution technique with incomplete coverage.

In summary, 3D first-pass techniques may be the preferredapproach to assessing myocardial perfusion by CMR yet stillrequire more research on its robustness and feasibility inclinical settings.

Oxygenation-Sensitive MR (OS-CMR)

Oxygenation-sensitive MR (OS-CMR) Imaging uses the so-called blood oxygen level-dependent (BOLD) effect to gen-erate contrast in the signal of myocardial tissue based on tissueoxygenation. Ogawa et al first pioneered a technique in neu-rologic studies referred to as functional magnetic resonanceimaging (fMRI) to assess changes of cerebral oxygenationrelated to metabolic activity [18]. The molecule that createsthe contrast in oxygenation sensitive sequences isdeoxyhemoglobin (deoxyHb). Linus Pauling first describedthe change of the magnetic property of hemoglobin whentransitioning from its oxygenated to its deoxygenated state[19]. In images acquired by oxygenation-sensitive MRI, thediamagnetic oxyhemoglobin (oxyHb) causes a weak stabili-zation of the magnetic field, while deoxyhemoglobin is para-magnetic and, thus, creates local magnetic field inhomogene-ities on a molecular level. These result in spin-spin dephasingand a decrease of transverse relaxation time, which results in a

Fig. 1 Three-dimensionalmyocardial first-pass perfusionimaging in humans with wholehear coverage [14]

Fig. 2 Comparison of standardresolution (left) and high-resolution (right) CMR perfusionimaging [16•]

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shortening in T2 and T2*. In oxygenation sensitive sequences,this causes a drop in signal intensity (Fig. 3). It has beenshown that the signal intensity drop closely correlates withO2 saturation of coronary sinus blood [20] and the left ventri-cle [21]. The observed changes have been validated againstnuclear cardiology methods, but also against fractional flowreserve and microspheres (Fig. 4).

The deoxyHb fraction depends on several factors:Hemoglobin saturation, perfusion rate, and metabolic activityof the extracting tissues. Normally, tissue perfusion is closelycoupled with the metabolic requirements of its subtendedtissues keeping tissue oxygenation constant. During constantperfusion rates, an increase in the metabolic activity of theinvestigated tissues would result in an increased oxygen ex-traction and, thus, in a signal intensity decrease. With constantoxygen extraction, vasodilation of the afferent blood vesselsleads to an excess perfusion of the tissue with a drop of thedeoxyHb fraction resulting in an increased tissue oxygenationand thus, a rise in signal intensity. A vasoconstrictiondecoupled from the tissue demands will result in a relativeincrease in deoxyHb assuming a constant oxygen extraction.

This will result in a decrease of signal intensity. OS-CMRimaging, therefore, has the potential to investigate physiologicchanges in tissue oxygenation as well as serving as an imagingtool to detect pathologies. In the heart 90 % of the myocardialblood volume resides in the capillaries. When investigatingoxygenation changes on a tissue level it is important to keep inmind that the actual SI predominantly originates from thevenous side of the capillary bed and not the perfused tissuesthemselves. Therefore, changes of signal intensity do notshow the oxygen content of the cardiomyocytes but reflectthe balance of oxygen supply and demand of the tissue.Neither does SI integrate information of possible physicallysolved oxygen or the overall blood oxygen content but isstrictly limited to hemoglobin bound oxygen.

While image quality is frequently affected in echo-planarand T2*-weighted sequences by motion or susceptibility arti-facts, modified oxygenation-sensitive steady-state-free-pre-cession sequences have shown promising results.

OS-CMR studies have been increasingly performed on 3 Tplatforms. Because higher field strengths are more prone tosusceptibility artifacts, the BOLD effect is increased by a

Fig. 3 Comparison of signalintensity in a short axisoxygenation-sensitive CMRimage at baseline (left) and afterexperimentally inducing severecoronary artery stenosis (right)[32]

Fig. 4 Comparison of signalintensity change in oxygenation-sensitive CMRwith microspheres[33]

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factor of about 2.5 when compared with a 1.5 T environment[22]. OS-CMR imaging is feasible at 1.5 T, yet suffers from alower signal to noise ratio and BOLD effect and thus, lowersensitivity to changes of deoxyhemoglobin.

As absolute signal intensity values in MR images aresubject to many confounders, monitoring of oxygenationchanges requires baseline values for dynamic studies, or ref-erence tissue values in the same image. For monitoring chang-es of myocardial oxygenation by OS-CMR, vasodilators (eg,adenosine) have been typically used [23]. More recently,breathing maneuvers have been found to induce detectablechanges of myocardial perfusion [24••]. T2* mapping tech-niques may represent an alternative, yet this approach islimited by a very low temporal resolution, making dynamicstudies very difficult.

Wacker and colleagues used a segmented gradient echo pulsesequence for myocardial T2* myocardial at rest and during adipyridamole challenge in 16 normal controls and 16 patientswith single vessel coronary artery disease [25]. During infusion,T2* increased significantly from 35±3 ms to 40±4 ms inhealthy volunteers (P=0.01). Myocardial segments suppliedby a stenotic coronary artery however, showed a reduced T2*at rest and a modest response to dipyridamole. This can beexplained by a poststenotic vasodilation. To maintain oxygena-tion, arterioles downstream stenotic arteries are already dilated.While unaffected blood vessels dilate upon a vasodilator stim-ulus, the already dilated vessels lack that ability, therefor show-ing a lower or no increase in signal intensity or T2*.Myocardium subtended to diseased vessels can even exhibit adecrease in signal intensity/T2* if there is a presence of acoronary steal during vasodilation. Friedrich and colleaguescompared T2* OS-CMR with single-photon emission comput-ed tomography (SPECT) at 1.5 T [26]. This study included 25patients with exercise-induced angina and assessed oxygenationchanges at rest and during adenosine infusion in a single mid-ventricular short axis. Myocardial segments subtended by ves-sels with >75% stenosis showed a significant decrease in signalintensity compared with segments with no stenosis. Receiveroperator characteristics analysis of both oxygenation-sensitiveCMR and thallium SPECT as related to quantitative coronaryangiography revealed similar areas under the curve, 0.66 and0.73, respectively. More recently, Manka and colleagues per-formed T2* BOLD CMR at 3 T in 46 patients with known orsuspected coronary artery disease [27]. Their BOLD measure-ments at rest revealed significantly lower T2* values for ische-mic segments (27±12 ms) compared with normal segments (32±1 ms; P<0.0001) and nonischemic segments (31±12 ms; P=0.0003). During adenosine stress, T2* values demonstrated asignificant increase in normal segments only (37±15 ms;P<0.0001 compared with rest). In contrast, T2* values ofnonischemic (33±15 ms; P=0.19) and ischemic segments (27±12 ms; P=0.06) were not significantly different from restvalues. Using a cut-off value of 33.8 ms, sensitivity and

specificity for the detection of ≥50 % angiographic stenosisfor rest and hyperemia were 78 % and 21 %, and 78 % and68 %, respectively. Image quality was not consistent and wasgraded as moderate or poor in about 25 % of patients. Toovercome these problems with image quality and T2* BOLDmethods, several human studies have used T2-prepared steady-state free-precession sequences for oxygenation-sensitive imag-ing at 1.5 and 3 Tesla. Karamitsos and colleagues validatedoxygenation-sensitive CMR against myocardial perfusionassessed by positron emission tomography (PET) [28]. Theystudied 22 patients with single or 2-vessel CAD and 10 normalvolunteers and found that BOLD CMR and PET agreed on thepresence or absence of ischemia in 18 of the 22 patients (82 %)and in all normal subjects. Recently, OS-CMR was validatedagainst fractional flow reserve (FFR) in patients with CAD,whereWalcher et al found that segments subtended by coronaryvessels with an abnormal FFR had reduced BOLD SI changeupon hyperemia compared with segments with FFR >0.8 [29•].Although OS-CMR studies have been utilized to investigate thepotential of diagnosing coronary artery disease, other studiesshowed that OS-CMR may be useful to understand the patho-physiology of other diseases such asmicrovascular dysfunction.The ability of OS-CMR to detect microcirculatory changes hasalso been shown in patients with hypertension and in patientswith hypertrophic cardiomyopathy. Another recent studyshowed that patients with Syndrome X (chest pain, abnormalstress test, and normal coronary arteries on angiography) haveno evidence of hypoperfusion or deoxygenation using first-passperfusion CMR and OS-imaging at 3 T, respectively [30•].

Recent Developments–Endogenous Modulationof Vasomotor Response

While the use of OS-CMR does not require the use of injectedcontrast agents for visualizing regional differences in perfusion,

Fig. 5 Response of signal intensity change (% change SI; reflectingmyocardial oxygenation) to hyperventilation (HV) and breath-holds(BH) of various lengths [24••]

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currently used protocols still require vasodilators such as aden-osine for inducing coronary hyperemia. Adenosine however,has some frequent side effects such as headaches, chest discom-fort, dyspnea, andmay lead to intermittent AV block. The risk ofbronchospasm and severe arrhythmia require the presence of atrained physician. The FDA recently issued a warning for theuse of adenosine and regadenoson due to the risk of heart attacksand death. The same is true for pharmacologic agents inducingcardiac stress such as dobutamine, which, in a positive test,induces ischemic contractile dysfunction. Recently, breathingmaneuvers were successfully applied in a swine model tomodulate myocardial perfusion and oxygenation [31•], wheremyocardial oxygenation could be increased by 60 seconds ofapnea. Results were strongly correlated to the increase in paCO2

during the breath-hold (r=0.90, P=0.01), despite a decrease inpaO2 and a parallel signal intensity decrease of the left ventric-ular blood pool in oxygenation-sensitive images. The fact thatmyocardial workload did not change significantly, confirmedpaCO2-modulated vasodilation as the main mechanism. The“luxury perfusion” caused by vasodilation without a matchingincrease of oxygen consumption leads to a relative decrease ofdeoxyHb amount and an increase in myocardial oxygenation/signal intensity in OS-CMR images. Although regional bloodflow is tightly bound to the tissue requirements by its metabo-lites such as CO2, a systemic increase of paCO2 by breath-holding overrides local vasomotor control and results in a globalvasodilation of myocardial arterioles. These results were con-firmed at 1.5 T in healthy humans [24••]. The results in thesesubjects indicated a dose-response relationship between thelength of breath-holds (35, 58, and 177 seconds, respectively),and changes of myocardial oxygenation/signal intensity (+3.6±2.0; P=n.s., +6.9±3.7; P=n.s., and +8.2±2.8 %; P<0.05, re-spectively), even when capillary pO2 (−16.3±5.5) and signalintensity in the left ventricular blood pool (−6.8 %; P=0.02)decreased in the 117 s group (Fig. 5). Again, the signal intensityincrease was correlated to the change in capillary pCO2 (r=0.58; P<0.01 n=29), and not to changes in pO2.Interestingly, hyperventilation of 2 minutes was able to reversethe effect and resulted in a drop of myocardial SI and oxygen-ation (−7.5±1.8 %; P=0.02). These results can be explained byvasoconstriction caused by hypocapnia, a well-known phenom-enon. While there was an increase in heart rate, this was not aconfounder.

These data indicate that OS-CMR may be an interestingalternative for diagnosing cardiac disease that result in amismatch of oxygen demand and supply. With oxygenation-sensitive CMR already being free of radiation and contrastagents, breathing maneuvers have the potential to even re-move vasodilator or stress agents from testing for myocardialischemia. While the preliminary data indicate a similar effectof breathing maneuvers as that induced by pharmacologicvasodilators, future research however, will need to havehead-to-head comparison studies to confirm that breath-hold

maneuvers have a similar effect and diagnostic accuracy.Furthermore, there is a lack of data on clinical feasibility andsafety of breathing maneuvers in patients.

In summary, while further research is still required beforewidespread clinical use, oxygenation-sensitive CMR usingT2*-weighted imaging has a strong potential to become thesafest and most accurate technique to verify myocardialischemia.

Compliance with Ethics Guidelines

Conflict of Interest M. G. Friedrich is board member, advisor, andshareholder of Circle Cardiovascular Imaging Inc., the manufacturer ofcvi42, a cardiovascular MR postprocessing and evaluation software. D. P.Guensch and M. G. Friedrich have a pending patent (US Patent Pending61_680,981) on the use of breathing maneuvers for diagnosing heartdisease.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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