Stress Cardiovascular MR Imaging

Oliver Strohm and Matthias G. Friedrich
Dept. of Cardiac Sciences and Radiology, University of Calgary, Calgary, Alberta, Canada

Address for correspondence:
Oliver Strohm, MD, FESC
Stephenson CMR Centre, Departments of Cardiac
Sciences and Radiology, University of Calgary, Suite
700 – SSB, Foothills Medical Centre, 1403 29th St. NW,
Calgary, Alberta, T2N 2T9, Canada
Tel: +1-(403)-944-8806 Fax: +1-(403)-944-8510
Email: oliver.strohm@ucalgary.ca


Abstract
Stress testing in patients with ischaemic heart disease is commonly applied in clinical practice. Cardiovascular MRI has the ability to obtain precise information about left ventricular function, inducible myocardial ischaemia during pharmacological stress and viability in an integrated examination. Adenosine may be used for vasodilatory stress for first-pass perfusion studies and dobutamine stress may be used to monitor wall motion abnormalities. After i.v. application of gadolinium-based contrast agents, areas of fibrosis or chronic infarcts are detected and may be characterized as 'ischaemic' or 'non-ischaemic' scar. The high image quality and the well-tolerated contrast agents may allow cardiovascular MRI to evolve into a routine tool for the serial assessment of patients with known or suspected ischaemic heart disease.

Introduction
Ischaemic heart disease remains one of the leading causes of morbidity and mortality in industrialised countries. Evaluation of patients with ischaemic heart disease (IHD) requires precise measurements of global and regional left ventricular function, identification or exclusion of myocardial ischaemia, assessment of myocardial infarction (MI) and myocardial viability and - in symptomatic patients with significant stenosis - visualisation of luminal changes of the coronary arteries. Cardiovascular magnetic resonance imaging (CMR) has important features for the assessment of patients with IHD and has evolved into a routine tool in larger centres.

CMR can utilise several approaches to diagnose and assess the relevance of IHD:

  • Functional imaging for detecting regional and global wall motion abnormalities at rest and during stress (e.g. dobutamine)
  • First-pass perfusion techniques for visualisation of inducible ischaemia with contrast-enhanced techniques
  • Contrast-enhanced inversion-recovery prepared CMR ('late gadolinium (Gd) enhancement') for identifying and quantifying myocardial fibrosis e.g. after infarction
  • MR angiography of coronary arteries
Both first-pass perfusion studies and late Gd enhancement have shown prognostic value.

As CMR is non-invasive and does not require iodinated contrast agents or ionizing radiation, it is well suited for serial assessment of patients with IHD. The contrast agents used are gadolinium-based and have less nephrotoxic effects due to low volumes injected in MR procedures. However, patients with severe reduction of kidney function may be at risk of acquiring a rare disease called Nephrogenic Systemic Fibrosis (NSF) which can be fatal [1].

With the growing number of centres performing CMR studies, there is an increasing need for training and education for both physicians and technologists, for standardisation and optimisation of CMR protocols. Combined protocols for the assessment of left ventricular function, ischaemia and viability will play an essential role in diagnostic and therapeutic decision-making in patients with IHD.

MR assessment of left ventricular function
Diastolic (a) and systolic (b) four-chamber view of long-axis cine (SSFP).
Figure 1. Diastolic (a) and systolic (b) four-chamber view of long-axis cine (SSFP).
Cine-CMR is generally accepted as the most accurate and reproducible imaging technique for the assessment of global and regional left ventricular morphology, function and mass. With the development of steady-state free precession (SSFP) techniques, the blood-myocardial contrast improved substantially, image quality has become more robust, and acquisition times have shortened. Due to its excellent reproducibility, CMR is ideally suited for serial functional studies, e.g. after therapeutic interventions. In addition, the sample size required to detect significant changes in clinical trials can be substantially reduced as compared to other imaging modalities [2,3].

As functional studies at rest cannot distinguish between viable and nonviable myocardium - both may show impaired regional contraction - inotropic stimulation with low-dose dobutamine (10 µg/kg/minute) is used to assess viability in segments with reduced contractility at rest [4]. Compared to echocardiography, CMR is more independent of the operator's skills and has significantly better image quality in all imaging planes, increasing its diagnostic yield [5].
Systolic phases of short-axis cine (SSFP) during dobutamine stress (a = Rest; b = 10 µg/kg/min; c = 20 µg/kg/min; d = 40 µg/kg/min). Normal study; constant decrease in LV diameter with increasing levels of stress.
Figure 2. Systolic phases of short-axis cine (SSFP) during dobutamine stress (a = Rest; b = 10 µg/kg/min; c = 20 µg/kg/min; d = 40 µg/kg/min). Normal study; constant decrease in LV diameter with increasing levels of stress.
High-dose dobutamine (up to 40 µg/kg/minute) increases both myocardial contractility and the ratepressure- product, thus increasing myocardial oxygen demand and causing ischaemia with related regional decrease in contractility in myocardial segments with flow-limiting stenosis of the related epicardial arteries. Stress echocardiography with high-dose dobutamine has been established as a routine modality for diagnosing myocardial ischaemia, but a substantial number of patients have suboptimal or nondiagnostic images in one or more imaging planes. Compared with stress-echocardiography, dobutamine-stress CMR has a significantly higher diagnostic accuracy in patients with coronary artery disease (CAD) due to its significantly better image quality, even in obese patients. The sensitivity and specificity values of high-dose dobutamine CMR for detecting significant CAD are reported as 83% and 86% [5,6]. It may be more specific than adenosine stress for detecting significant coronary stenosis, although recent data found comparable accuracies for both modalities [5]. Additional complex functional information can be evaluated by using myocardial tagging. Here, a pre-pulse labels the myocardium with a shortly persisting dark grid, and enables more detailed analysis of regional rotation, shortening and strain of the myocardium [7].

Stress Perfusion CMR
Accurate assessment of myocardial ischaemia caused by flow-limiting stenosis in the epicardial coronary arteries is important for the evaluation of patients with chest pain and in the management of patients after coronary interventions. As myocardial blood flow at rest is not altered in stenoses up to 90% (due to autoregulation of the coronary circulation), vasodilator stress is needed to relax the arterioles and induces a noticeable difference between normal and ischaemic myocardium [8]. The pharmacological agents most commonly used for vasodilator stress are adenosine and dipyridamole, both having an excellent safety profile and a high diagnostic accuracy for the detection of CAD [9-11]. Comparison between perfusion deficits at rest and during vasodilator stress can be used in 'integrated' imaging protocols to assess the clinical relevance of regional changes in the perfusion properties. Due to the better image quality of the first perfusion study and to avoid filling-up of fibrotic areas, most centres start with the vasodilator stress study and append the rest perfusion study after assessment of myocardial late enhancement at the end of the CMR study [10].

First-pass perfusion CMR sequences need to fulfil several requirements, including high spatial and temporal resolution, high contrast-to-noise ratio, and coverage of large parts of the myocardium, few artefacts and high reproducibility. Saturation recovery fast gradient-echo sequences, SSFP and hybrid echo-planar sequences have been the most widely used for first-pass CMR studies [12,13]. The optimal sequence for first-pass perfusion studies has not been determined yet, and image quality is still undergoing improvements, especially regarding suppression of subendocardial artefacts, which may mimic true subendocardial perfusion deficits. These ring artefacts in the subendocardial layers are primarily caused by Gibbs ringing [14] and cardiac motion. Increased spatial resolution and shorter acquisition times seem to reduce the artefact. Direct comparison of stress and rest perfusion images is sometimes useful to distinguish between artefacts and a true, stress-induced subendocardial hypoperfusion, e.g. in patients with left ventricular hypertrophy due to hypertension [15].

Stress-CMR with pharmacological vasodilator stress has been shown to have a high diagnostic accuracy. Schwitter et al. reported a sensitivity of 91% and sensitivity of 94% using a multi-slice hybrid echoplanar sequence as compared to positron emission tomography and a sensitivity of 87% and specificity of 85% compared to quantitative coronary angiography [16]. Nagel et al., using a gradient echo/echo-planar hybrid series, found a sensitivity of 88% and specificity of 90% assessing myocardial perfusion reserve index. Wolff et al., using a low contrast dose of 0.05 mmol/kg, reported a sensitivity of 93% and a specificity of 75%.
Figure 3. Adenosine-stress perfusion, short axis view. Septal deficit in
Figure 3. Adenosine-stress perfusion, short axis view. Septal deficit in LAD stenosis.
Figure 4. Adenosine-stress perfusion, short axis view. Lateral deficit in
Figure 4. Adenosine-stress perfusion, short axis view. Lateral deficit in LCX stenosis.

An unresolved question is the optimal contrast dose used for first-pass perfusion studies. With lower doses (0.025-0.05 mmol/kg), a linear relationship between contrast concentration in the blood and the MR signal intensity is maintained even at peak contrast inflow, allowing for quantitative assessment of myocardial perfusion and for calculation of perfusion indices. On the other hand, higher doses (0.075-0.1 mmol/kg) of Gd increase myocardial enhancement and achieve a better contrast between normal and ischaemic myocardium [8,9,17].

Stress perfusion CMR has several advantages over nuclear medicine techniques and may be used as an alternative to these methods: no need for radioactive tracers and significantly higher spatial resolution, allowing for a detection of subendocardial ischaemia which may be missed by standard stress testing [18].

Figure 5. Late enhancement study, short axis view. Large transmural scar in the anteroseptal and anterior wall in chronic infarction.
Figure 5. Late enhancement study, short axis view. Large transmural scar in the anteroseptal and anterior wall in chronic infarction.
 Figure 6. Late enhancement study, long axis view. Non-ischaemic lateral scar in a patient with acute myocarditis.
Figure 6. Late enhancement study, long axis view.
Non-ischaemic lateral scar in a patient with acute myocarditis.


Assessment of viability by CMR
Precise information about myocardial viability is mandatory in the management and risk stratification of patients with IHD. Late enhancement after Gd application has become increasingly important as a reliable tool to assess viability non-invasively and can be added to all cardiac protocols with contrast enhancement. For best results, inversion-recovery CMR images are acquired 5 to 15 minutes after i.v. application of 0.1-0.2 mmol/kg Gd. In the equilibrium phase, Gd distributes non-specifically into the extracellular space, which is increased in infarcted tissue due to a loss of the intracellular fraction of myocardium [19,20]. To achieve optimal contrast between viable and non-viable myocardium, an inversion pulse is applied to null the signal of normal myocardial tissue. To achieve a high contrast-tonoise ratio, the inversion time has to be carefully selected for each patient and each set of images [21].

Nephrogenic Systemic Fibrosis has been reported in patients with severe renal disease, typically on dialysis, receiving high and repeated doses of Gd and the potential benefits of CMR should be considered against the risks in such patients.

Late Gd enhancement CMR is considered the gold standard for predicting recovery of function after coronary revascularisation, with the extent of transmural scarring being a powerful predictor [22]. A major advantage of viability assessment by CMR, in comparison with nuclear medicine techniques, is the significantly higher spatial resolution, thus allowing for the visualisation of non-transmural infarcts, which may be missed by SPECT imaging [18]. In addition to identifying ischaemic scars in the myocardium, late enhancement imaging may be used to detect non-ischaemic myocardial changes as in myocarditis or other forms of cardiomyopathy [23,24].

Conclusions
Cardiovascular magnetic resonance imaging is a versatile and accurate imaging tool for patients with ischaemic heart disease. Due to its multi-modality properties and the completely non-invasive nature without the need for radiation or iodinated contrast agents, it can be used to assess left ventricular function and ischaemia at stress and rest in combination with a viability study during a single examination. CMR has several advantages over echocardiography and nuclear medicine studies, but suffers from its complex nature and the lower patient throughput in comparison with these modalities. In experienced centres, CMR should be used as the firstchoice imaging modality for comprehensive assessment of patients with IHD.

Key Learning
  • Cardiovascular magnetic resonance (CMR) can be used to assess myocardial ischaemia with either inotropic stress (e.g. dobutamine) and/or vasodilator stress (e.g. adenosine)
  • Late gadolinium enhancement allows for a completely non-invasive assessment of myocardial viability with high accuracy
  • CMR allows for an integrated cardiac study for ischaemic heart disease, assessing left ventricular function, valvular function, ischaemia and viability in one examination
  • The assessment of coronary artery anatomy using 3D-angiography sequences may give additional valuable information for the treatment options

References
  1. Wiginton CD, Kelly B, Oto A, et al. Gadolinium-based contrast exposure, nephrogenic systemic fibrosis, and gadolinium detection in tissue. AJR Am J Roentgenol 2008;190:1060-8.
  2. Bellenger NG, Davies LC, Francis JM, et al. Reduction in sample size for studies of remodeling in heart failure by the use of cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2000;2:271-8.
  3. Strohm O, Schulz-Menger J, Pilz B, et al. Measurement of left ventricular dimensions and function in patients with dilated cardiomyopathy. J Magn Reson Imaging 2001;13:367-71.
  4. Wellnhofer E, Olariu A, Klein C, et al. Magnetic resonance low-dose dobutamine test is superior to SCAR quantification for the prediction of functional recovery. Circulation 2004;109:2172-4.
  5. Nagel E, Lehmkuhl HB, Bocksch W, et al. Noninvasive diagnosis of ischemia-induced wall motion abnormalities with the use of highdose dobutamine stress MRI: comparison with dobutamine stress echocardiography. Circulation 1999;99:763-70.
  6. Hundley WG, Hamilton CA, Thomas MS, et al. Utility of fast cine magnetic resonance imaging and display for the detection of myocardial ischemia in patients not well suited for second harmonic stress echocardiography. Circulation 1999;100:1697-702.
  7. Epstein FH. MRI of left ventricular function. J Nucl Cardiol 2007;14:729-44.
  8. Pennell DJ. Cardiovascular magnetic resonance and the role of adenosine pharmacologic stress. Am J Cardiol 2004;94:26D-31D.
  9. Bernhardt P, Engels T, Knuf B, et al. Cardiac magnetic resonance in outpatients in Germany - indications, complications and protocol suggestions from a high-volume center. Int J Cardiol 2006;111:86-91.
  10. Bernhardt P, Levenson B, Engels T, et al. Contrast-enhanced adenosinestress magnetic resonance imaging - feasibility and practicability of a protocol for detection or exclusion of ischemic heart disease in an outpatient setting. Clin Res Cardiol 2006;95:461-7.
  11. Bernhardt P, Steffens M, Kleinertz K et al. Safety of adenosine stress magnetic resonance imaging using a mobile cardiac magnetic resonance system. J Cardiovasc Magn Reson 2006;8:475-8.
  12. Elkington AG, Gatehouse PD, Cannell TM, et al. Comparison of hybrid echo-planar imaging and FLASH myocardial perfusion cardiovascular MR imaging. Radiology 2005;235:237-43.
  13. Schreiber WG, Schmitt M, Kalden P, et al. Dynamic contrast-enhanced myocardial perfusion imaging using saturation-prepared TrueFISP. J Magn Reson Imaging 2002;16:641-52.
  14. Amartur S, Haacke EM. Modified iterative model based on data extrapolation method to reduce Gibbs ringing. J Magn Reson Imaging 1991;1:307-17.
  15. Bernhardt P, Levenson B, Albrecht A, et al. Detection of cardiac small vessel disease by adenosine-stress magnetic resonance. Int J Cardiol 2007;121:261-6.
  16. 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 2001;103:2230-5.
  17. Christian TF, Rettmann DW, Aletras AH, et al. Absolute myocardial perfusion in canines measured by using dual-bolus first-pass MR imaging. Radiology 2004;232:677-84.
  18. 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 2003;361:374-9.
  19. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 1999;100:1992-2002.
  20. Arheden H, Saeed M, Higgins CB, et al. Measurement of the distribution volume of gadopentetate dimeglumine at echo-planar MR imaging to quantify myocardial infarction: comparison with 99mTc-DTPA autoradiography in rats. Radiology 1999;211:698-708.
  21. Messroghli DR, Radjenovic A, Kozerke S, et al. Modified Look-Locker inversion recovery (MOLLI) for high-resolution T1 mapping of the heart. Magn Reson Med 2004;52:141-6.
  22. Kim RJ, Wu E, Rafael A, et al. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med 2000;343:1445-53.
  23. Mahrholdt H, Goedecke C, Wagner A, et al. Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation 2004;109:1250-8.
  24. Mahrholdt H, Wagner A, Judd RM, et al. Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies. Eur Heart J 2005;26:1461-74.



06-2008 BUY1163660/JB3272/MB002753CMC Int'l English 16th Edition