Cardiovascular magnetic resonance of myocardial viability Kaandorp, T.A.M.

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Cardiovascular magnetic resonance of myocardial viability

Kaandorp, T.A.M.

Citation

Kaandorp, T. A. M. (2007, March 14). Cardiovascular magnetic resonance of myocardial viability. Department Radiology, Faculty of Medicine / Leiden University Medical Center (LUMC), Leiden University. Retrieved from https://hdl.handle.net/1887/11409

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/11409

Note: To cite this publication please use the final published version (if applicable).

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P P a a r r t t I I

Te T ec c h h ni n i ca c a l l e e v v a a l l u u a a t t io i on n

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C C h h a a p p t t e e r r 2 2

M M a a g g ne n et ti ic c r r es e so on na a nc n ce e i i m m ag a g i i n n g g of o f

c c o o r r o o n n a a r r y y a a r r t t e e r r i i e e s s , , t t h h e e i i s s c c h h e e m m i i c c

ca c as sc ca ad de e an a nd d m m yo y oc c a a r r di d ia al l i i n n fa f a r r ct c t io i on n

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2 Magnetic resonance imaging of coronary

arteries, the ischemic cascade and

myocardial infarction

TA Kaandorp, HJ Lamb, JJ Bax, EE van der Wall, A de Roos

Ameri c an Heart Journal 2005; 149; 200- 8

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Part I Technical evaluation - Chapter 2

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Introduction

Ischemic heart disease is the leading cause of morbidity and mortality in the W estern world¹. It is caused by a regional reduction of blood flow to the myocardium, secondary to obstructive atherosclerosis of the coronary arteries. This reduction causes an imbalance between oxygen supply and demand, leading to the so-called ischemic cascade ², which may result subsequently in perfusion abnormalities, metabolic changes (silent ischemia), wall motion abnormalities, systolic and diastolic dysfunction and finally myocardial infarction (Figure 1). Magnetic resonance imaging (MRI) techniques for assessing perfusion, function and viability are now mature for routine clinicalapplication and can therefore monitor these changes.

A comprehensive cardiac magnetic resonance study including assessment of myocardial perfusion and function at rest and under stress, delayed contrast- enhancement for viability imaging and coronary magnetic resonance angiography (MRA) for detecting stenosis can now be performed in a relatively short time ³.

In this article, magnetic resonance applications are reviewed for assessment of coronary arteries, the ischemic cascade and myocardial infarction in coronary artery disease (CAD).

Clinical assessment of coronary artery stenosis and bypass grafts

Several MRI techniques have been developed to image coronary artery stenosis and the underlying plaque composition. The major problem for coronary MRA is the complex three-dimensional motion of the heart caused by cardiac contraction and respiratory movements in combination with the small size of the coronary vessels.

Despite these limitations, free-breathing navigator MRA showed high accuracy for excluding significant CAD. This technique was applied in a multi-center-trialover 100 patients before elective X-ray coronary angiography was performed. In 84% of proximal and middle coronary segments the imaging results were interpretable.

Overall, this approach seems to be useful for excluding left main coronary artery or three-vessel disease ⁴. Recently, Bogaert et al⁵ reported their results using commercially available three-dimensional real-time navigator coronary MRA in a series of 21 patients. Their results were less favorable (sensitivities around 50%) for detecting CAD.

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MRI of coronary arteries, the ischemic cascade and myocardial infarction

Figure 1. Graphic representation of the ischemic cascade from the time of onset (lower-left) to the myocardial infarction (upper-right).

12 4 56

-200 0 200 400 600 800 1000

0 200 400 600 800 1000

time [ms]

flux [ml/s]

Myocardial infarction

Anginal chest pain

ECG disorders

Systolic dysfunction

Diastolic dysfunction

Metabolic disorders

Perfusion defect

Time from onset of ischemia

Using a contrast agent can improve image quality through changes of T1 and/ or T2 relaxitivity of the blood pool. Regenfus et al ⁶ evaluated gadolinium-enhanced three-dimensional breath-hold MRA for detection of coronary artery stenosis in 50 patients with suspected CAD. On a patient basis, magnetic resonance correctly identified 34 of 36 patients with and 8 of 14 patients without significant coronary stenosis as demonstrated by X-ray angiography. They concluded that contrast- enhanced MRA permitted identification of patients with coronary stenosis in the proximal and mid segments of the major coronary arteries with satisfactory accuracy.

A number of blood pool agents are currently under evaluation for improved coronary imaging⁷.

Grafted vein conduits show accelerated atherosclerosis. Several studies have been performed to assess the accuracy of MRA for evaluating bypass patency as well as

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stenosis^8;⁹. Langerak et al ¹⁰ used high-resolution navigator-gated 3-D MRA to detect vein graft disease. MRA was compared with conventional coronary angiography in 38 patients, with 56 vein grafts who presented with recurrent chest pain after bypass surgery. Interobserver agreement in assessing graft occlusion, 50% stenosis, and 70%

stenosis was, respectively, 94%, 72% and 82%. This study showed that MRA allows not only good differentiation between patent and occluded vein grafts but allows also the assessment of vein graft disease with a fair diagnostic accuracy.

Interestingly, magnetic resonance measurements of coronary blood flow reserve can be used to detect in-stent re-stenosis. Magnetic resonance flow mapping ^11;¹² in combination with MRA may be an alternative tool to study distal coronary arteries because baseline and stress flow in the proximal part of the graft is a functional measure of the entire vascular bed beyond the level of the flow measurement. In another study, Langerak et al ¹³ studied 69 patients with 166 grafts during baseline and adenosine-induced hyperaemia. Flow mapping was performed in the proximal part of the graft and perpendicular to the graft segment according to a standardized protocol.

Grafts were divided into groups with 50% and 70% stenosis in the graft or recipient vessels. Sensitivity and specificity in detecting single vein grafts with 50% and 70%

stenosis were 94% and 63%, respectively, 96% and 92%. Thus, MRI flow velocity measurements may be useful for detecting flow-limiting lesions in bypass grafts and recipient vessels. In Table 1, an overview of the recent literature for detection of coronary artery stenosis and bypass graft patency by coronary MRA is provided.

Figure 2 shows an example of a left anterior descending graft visualized by MRA.

New MRI techniques are now available for improved coronary imaging. The improvement of image contrast can be achieved through the use of steady state free precession, better known under their acronyms balanced FFE (fast field echo), FISP (fast imaging with steady state free precession) and FIESTA (fast imaging employing steady state acquisition). Bunce et al ¹⁴ compared the accuracy of true FISP with gadolinium-enhanced MRA for the detection of coronary artery bypass graft patency in 25 patients who had recently undergone conventional coronary angiography. With true FISP angiography, sensitivity for patency was 84%, specificity was 45% and accuracy was 78%. Using gadolinium-enhanced MRA, the sensitivity was 85%, specificity was 73% and accuracy was 84% for detecting graft patency. In this study, it was found that neither MRA nor true FISP angiography by themselves could be considered suitable alternatives to conventional coronary angiography for the evaluation of chest pain in patients with a coronary artery bypass graft.

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Clinical assessment of functional markers of the ischemic cascade

The ischemic cascade ² (Figure 1) represents a continuum that begins with the onset of hemodynamic abnormalities and terminates with recognized expressions of ischemia, loss of ventricular function, angina pectoris and can eventually lead to myocardial infarction. MRI can visualize different stages of the ischemic cascade.

Table 1. Sensitivity and specificity for detection of coronary artery stenosis and bypass graft patency by MRA; an overview of recent literature.

Number of patients

Sensitivity Specificity

Breath-hold approach van Geuns et al 2000³⁸

38 68% (LM and LAD 77%;

LCX 50%; RCA 64%)

97% (LM and LAD 97%;

LCX 100%; RCA 94%)

Contrast-enhanced & breath-hold Regenfus et al

2000⁶

50 94% (overall result)^* 57% (overall result)^*

Wintersperger et al 1998³⁹

76 95% (venous grafts 94%;

arterial grafts 96%)

67-85% (venous grafts 85%;

arterial grafts 67%)

Navigator approach Kim et al 2001⁴

109 NA (LM 67%; LAD 88%;

LCX 53%; RCA 93%)

NA (LM 90%; LAD 52%;

LCX 70%; RCA 72%) Langerak et al

2002¹⁰

56 83% (only vein grafts) 98-100% (only vein grafts)

Bogaert et al 2003⁵

21 44.4-55.5% (overall result) 95.1-83.7% (overall result)

*Calculated on a patient-basis instead of segment-basis. LAD: left anterior descending coronary artery;

LCX: left circumflex coronary artery; LM: left main coronary artery; NA: not available; .RCA: right coronary artery.

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Figure 2. Four original transverse slices of two grafts using a high-resolution navigator-gated 3D MRA technique without contrast agents. The venous sequential graft to the first diagonal branch and left anterior descending artery is indicated by an exclamation point, and the venous sequential graft to the anterolateral branch, obtuse marginal branch, and posterior descending artery is represented by an asterisk. Ao: ascending aorta; AP: pulmonary artery; LAD: left anterior descending artery; LCX: left circumflex coronary artery. Reprinted from Langerak et al

42 with permission.

LAD

LCX

Detection of perfusion defects

Firstly, atherosclerosis can cause reduction of blood flow that may result in a perfusion defect. Generally, perfusion imaging relies on a sequence to create images that enhance the myocardium compared with pre-contrast images with passage of a contrast agent. The perfusion defect is identified by attenuation or absence of this brightening in the myocardium and can demonstrate the transmural extent. A typical contrast-enhanced perfusion study at rest is shown in Figure 3.

Coronary blood flow at rest is not reduced until the stenosis exceeds 90% of the normal vessel diameter¹⁵. However, when using a stress agent, blood flow is already

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reduced at a stenosis of 50% of the vessel diameter. Therefore perfusion imaging should be performed in conjunction with pharmacological vasodilatation in order to identify subcritical coronary stenosis. To compare perfusion images, a myocardial perfusion reserve index (MPRI) can be calculated. Cullen et al ¹⁶ used an inversion recovery sequence with gadolinium first-pass contrast-enhancement to evaluate this MPRI in normal human volunteers compared to patients with CAD. Both patients and volunteers underwent perfusion examinations both at rest and under stress (adenosine). The MPRI was significantly reduced in patients compared with normal subjects. Regions supplied by vessels with <40% diameter stenosis (non-flow limiting) had a significantly higher MPRI than regions supplied by stenosis of ‘intermediate’

severity, that is, >40% to 59% diameter stenosis. Of note, even regions supplied by vessels with <40% diameter stenosis had a significantly lower MPRI than volunteers.

Thus, MPRI derived from first-pass MRI studies can distinguish between normal subjects and patients with CAD. Schwitter et al ¹⁷ compared the assessment of compromised myocardium detected with magnetic resonance myocardial perfusion imaging,¹³N-ammonia positron emission tomography and coronary angiography in 48 patients and healthy subjects. Signal intensity upslope as a measure of myocardial perfusion was calculated in 32 sectors per heart in the subendocardial layer and for full wall thickness. Receiver operating characteristic analysis of subendocardial upslope MRI data revealed a sensitivity and specificity of 91% and 94%, respectively, for the

Figure 3. Frames of multi-slice first-pass perfusion magnetic resonance study. In horizontal direction four time points are shown after administration of gadolinium DTPA. Note the first image without contrast; the second image shows an enhanced right ventricle; the third image shows an enhanced left and right ventricle; on the fourth image, a septal perfusion defect in the myocardium can be seen (arrow). RV: right ventricle; LV: left ventricle.

RV LV

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detection of CAD as defined by positron emission tomography compared to 87% and 85%, respectively, for quantitative coronary angiography. The number of pathological sectors per patient on positron emission tomography and magnetic resonance studies correlated linearly. That study showed that magnetic resonance is a reliable method for identification of coronary artery stenosis and that magnetic resonance can provide information on the amount of compromised myocardium even when perfusion abnormalities are confined to the subendocardial layer.

More recently, Chiu et al ¹⁸ combined first-pass perfusion and delayed contrast- enhancement in patients with acute coronary syndromes as compared to conventional coronary angiograms. First-pass magnetic resonance images were obtained at rest and during infusion of adenosine and were assessed qualitatively for abnormal regional perfusion (hypoenhancement). A stenosis more than 50% in diameter in any coronary artery was considered significant. First-pass stress perfusion studies depicted 25 segments of hypoenhancement in 11 patients. Comparison of first-pass perfusion defects with findings on coronary angiograms indicated an overall sensitivity of 92%

and specificity of 92% in detection of significant CAD. Infarcts were detected on delayed contrast-enhanced images in 8 segments in 5 patients. This indicates that combined stress perfusion and delayed contrast-enhanced MRI was feasible in patients with acute coronary syndromes and that first-pass magnetic resonance perfusion defects compare well with the presence of significant coronary artery stenosis on conventional angiograms.

Detection of metabolic abnormalities

Metabolic abnormalities are the second stage in the ischemic cascade. ³¹P-NMR spectroscopy can be used for the non-invasive assessment of the human myocardial energy metabolism. It is presently not part of the daily clinical assessment of patients, and mainly used as a research tool. Maintenance of cellular levels of high-energy phosphates is required for myocardial function and preservation. Severe myocardial ischemia is characterized by the rapid loss of phosphocreatine and a decrease in the ratio of phosphocreatine to ATP. ³¹P spectra obtained using magnetic resonance spectroscopy at rest and during stress allows the observation of the earliest metabolic responses to myocardial ischemia ¹⁹.

Buchthal et al ²⁰ investigated women, hospitalized for chest pain without clinically significant coronary artery obstruction, but suspected of myocardial ischemia

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and compared them with a healthy control group. Myocardial high-energy phosphates were measured with ³¹P-NMR spectroscopy before, during, and after isometric handgrip exercise at a level that was 30 percent of the maximal voluntary grip strength. In 20% the ratio of phosphocreatine to ATP decreased significantly below the control group, the most likely cause being microvascular CAD ²⁰. Recently, the prognostic implications of the finds in this study were investigated. The conclusion was that women without CAD but with reduced phosphocreatine adenosine triphosphate ratio, consistent with myocardial ischemia, predicted cardiovascular outcome, notably higher rates of anginal hospitalization, repeat catheterization, and greater treatment costs ²¹.

Assessment of diastolic function

Diastolic dysfunction is third in the ischemic cascade and the first manifestation of active ischemia. Distinction between diastolic function and systolic function is important because diastolic heart failure is associated with better long-term survival

22;23. It is presently not part of the daily clinical assessment of patients, however MRI techniques are well suited to assess diastolic function. Well-known discriminants in assessment of diastolic dysfunction are the mitral inflow velocities, the waves that correspond to the early flow (E) during left ventricular (LV) relaxation and subsequent contribution from atrial contraction (A).

Houlind et al ²⁴ described early LV diastolic inflow using magnetic resonance velocity mapping in 46 patients with recent acute myocardial infarction and in 43 age- matched normal volunteers. Diastolic mitral valve blood flow patterns in patients were characterized by impaired LV relaxation and therefore impaired diastolic function.

Paelinck et al ²⁵ recently reviewed the use of magnetic resonance for assessment of diastolic function.

Evaluation of systolic function

It is widely accepted that cardiovascular magnetic resonance is the reference standard for the non-invasive assessment of global cardiac function. The overall reproducibility is high with low inter- and intra-observer variability ²⁶. Evaluation of LV function includes left ventricular ejection fraction (LVEF), LV volumes and regional wall motion.

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For viability assessment, low-dose dobutamine (10-20 µg/kg/min) is used. An example of viability assessment can be seen in Figure 4. Sandstede et al ²⁷ tested the diagnostic value of dobutamine stress MRI for predicting recovery of regional myocardial contractility after revascularization. In 25 patients with CAD, cine images at rest and during low-dose dobutamine stress (10 µg/kg/min). Patients were re- examined at rest 3 and 6 months after revascularization. They concluded that dobutamine stress MRI allowed prediction of global functional recovery of akinetic myocardial regions after revascularization with a high positive predictive value and high specificity.

Magnetic resonance can also be used for the analysis of stress-induced ischemia.

Nagel et al ²⁸ compared echocardiography and magnetic resonance for the detection of

Figure 4. Wall motion before and after low-dose dobutamine. Note the viable tissue in slice 8 (anteroseptal), whereas in slices 6 and 4 there is no viable tissue visible.

Rest Stress

End diastole End systole End diastole End systole

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stress-induced wall motion abnormalities in 208 patients with suspected CAD before selective cardiac catheterization. With dobutamine stress magnetic resonance, sensitivity for detecting a greater than 50% diameter stenosis was increased from 74.3% to 86.2% and specificity from 69.8% to 85.7% compared with dobutamine stress echocardiography. The conclusion was that high-dose dobutamine magnetic resonance can be performed with a standard dobutamine/atropine stress protocol and that detection of wall motion abnormalities by dobutamine stress magnetic resonance yields a significantly higher diagnostic accuracy in comparison to dobutamine stress echocardiography. Hundley et al ²⁹ performed a similar study to determine if the presence of inducible ischemia identified during MRI stress tests could be used to identify those at risk of sustaining a future cardiac event. Because of poor LV endocardial visualization with echocardiography, 279 patients were referred for dobutamine/atropine MRI for the detection of inducible ischemia and were followed for an average of 20 months. In a multivariate analysis, the presence of inducible ischemia or an LVEF <40% was associated with future myocardial infarction or cardiac death independent of the presence of risk factors for coronary arteriosclerosis.

Thus, in patients with poor echocardiograms, the results of cardiac MRI stress tests can be used to forecast myocardial infarction or cardiac death.

Clinical assessment of myocardial infarction

Beyond the possible reversible events of the ischemic cascade, magnetic resonance can be used for assessment of the extent of a myocardial infarction using delayed contrast-enhanced images (Table 2). After administration of a contrast agent, normal myocardium will show increased signal intensity during first-pass, followed by washout from the tissue. In infarcted myocardium, contrast agent follows different washout kinetics than in normal myocardial tissue. This tissue is termed ‘hyperenhanced’ or

‘delayed enhanced’. Several studies have shown the potential use of gadolinium-based contrast agents to identify infarcted myocardium ^30;31.

Klein et al ³² compared delayed contrast-enhanced MRI with PET as a gold standard for detection and quantification of myocardial scar tissue in 31 patients with ischemic heart failure. Sensitivity and specificity of MRI for identifying patients and segments with matched flow/metabolism defects was 0.96 of 1.0 and 0.86 of 0.94, respectively. Quantitatively assessed MRI infarct mass correlated well with PET infarct size. Thus, in severe ischemic heart failure, delayed contrast-enhanced MRI as a

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Table 2. Sensitivity and specificity for detection of myocardial infarction by magnetic resonance delayed contrast-enhancement; an overview of recent literature.

Subjects Gold standard Goal Sensitivity;

specificity

Klein et al ³² 31 patients PET Viability

assessment

83%;

88%

Kittigawa et al ⁴⁰ 22 patients after AMI MR regional wall thickening at follow up

Viability assessment

98%;

92%

Motoyasu et al ⁴¹ 23 patients after AMI MR functional recovery at follow up

Stress versus contrast

83%;

72%

Kwong et al ³⁶ 161 patients guidelines AHA Acute coronary syndrome

84%;

85%

AHA: American Heart Association; AMI: acute myocardial infarction; MR: magnetic resonance.

marker of myocardial scar closely agrees with PET data. Examples of delayed enhancement in chronic infarction can be seen in Figure 5.

Kim et al ³³ investigated if delayed contrast-enhanced MRI, could be used to distinguish between reversible and irreversible myocardial ischemic injury in patients with CAD before they underwent revascularization. In the dysfunctional segments, the likelihood of improvement in regional contractility after revascularization decreased progressively as the transmural extent of hyperenhancement before revascularization increased. It was concluded that reversible myocardial dysfunction could be identified by delayed contrast-enhanced MRI before coronary revascularization.

Delayed contrast-enhanced MRI identifies scar tissue, low-dose dobutamine MRI is used to demonstrate the presence of contractile reserve in dysfunctional myocardium and thus identifies viable myocardium. To investigate the precise relation between these two techniques, a comparison was performed in patients with CAD in our institution ³⁴. The agreement was high in the extremes (subendocardial scar and transmural scar). However, segments with an intermediate extent of scar tissue on MRI have contractile reserve in 42% (and lack contractile reserve in 58%). In these segments, low-dose dobutamine MRI may be needed, additionally to delayed contrast-

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Figure 5. Example of delayed contrast-enhancement in lateral, subendocardial, and inferior wall. Note the sharp contrast between infarction, blood pool, and healthy myocardium. LA:

left atrium; LV: left ventricle; RA: right atrium; RV: right ventricle.

RV LV

RV

RA

LA

LV

enhanced MRI, to optimally differentiate myocardium with high and low likelihood of functional recovery after revascularization. This was investigated by Wellnhofer et al

35, who found that for prediction of improvement of wall motion after revascularization, low-dose dobutamine magnetic resonance testing is superior to delayed contrast-enhanced MRI, especially in segments with delayed enhancement of the myocardial wall between 1% and 74%.

MRI may be a valuable part of triage of patients with chest pain in the emergency department. Kwong et al ³⁶ hypothesized that cardiac MRI at rest can effectively assess possible or probable acute coronary syndrome with a combined examination of regional contractile function, perfusion and viability in the emergency department. The diagnostic performance of MRI was evaluated in a prospective study of 161 consecutive patients, with 30 minutes of chest pain compatible with myocardial ischemia but an electrocardiogram (ECG) not diagnostic of acute myocardial infarction. MRI was performed within 12 hours of presentation. The sensitivity and specificity, respectively, for detecting acute coronary syndrome were 84% and 85% by MRI, 80% and 61% by an abnormal ECG, 16% and 95% for strict ECG criteria for ischemia. Performed urgently to evaluate chest pain, MRI accurately detected a high

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fraction of patients with acute coronary syndrome, including patients with enzyme- negative unstable angina.

Conclusion

This review illustrates the clinical applicability and relevance of cardiac MRI in many aspects of the ischemic cascade and myocardial infarction. Relevant functional information on all aspects of the heart including global and regional function, flow patterns, valve function, myocardial perfusion and viability can all be obtained in a non-invasive manner, as components of a comprehensive magnetic resonance examination. Direct anatomic imaging of the heart and coronary arteries will complement the obtained functional information. Furthermore, this combined examination may be cost-effective by limiting the use of multiple, costly other investigations ³⁷. Further studies are required to define the role of MRI in larger patient groups and in relationship with clinical outcome.

Acknowledgements

This work was supported by The Netherlands Organization for Scientific Research (NWO), grant number 902-37-124 (H. J. Lamb, Leiden, The Netherlands).

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