Cardiovascular magnetic resonance imaging (MRI) has moved from niche applications to the center of cardiovascular decision-making. Today, cardiovascular MRI offers several options for detecting ischemia in patients with known or suspected coronary artery disease (CAD). Over the last few years, much evidence has been accumulated of the diagnosis of CAD and heart failure with cardiovascular MRI.1–3
Safety and Feasibility
MRI is contraindicated in patients with non-compatible biometallic implants, pacemakers, and implanted cardioverter–defibrillators (ICDs), and in patients with claustrophobia.4 Coronary stents, sternal wires, and the majority of prosthetic valve types do not represent a contraindication for cardiovascular MRI. Ischemia can be detected by stress imaging techniques such as dobutamine stress MR (DSMR) or myocardial perfusion imaging; the patient’s heart rate and blood pressure and rhythm need to be monitored throughout the duration of the process.5
Detection of Ischemia and Coronary Artery Stenoses
Two fundamentally different strategies for assessing the presence of significant coronary artery lesions are available. The first is the direct visualization of the coronary arteries, which provides identical information to invasive angiography, such as the location and degree of coronary artery stenosis. The second is the assessment of physiological information by DSMR or first-pass perfusion imaging to induce and visualize myocardial ischemia.
The assessment of hemodynamics rather than the degree of stenosis has several advantages as luminal narrowing is only mildly related to a reduction of blood flow. Therefore, positive perfusion studies with normal epicardial coronary arteries may occur in specific situations, e.g. syndrome X (microvascular dysfunction), diabetes mellitus, or LV hypertrophy. Similarly, negative stress studies can be found in patients with higher-grade luminal stenosis, e.g. if they have sufficient collateralization. However, symptoms and prognosis of patients are closely related to the existence and severity of myocardial ischemia.Dobutamine Stress Magnetic Resonance
State-of-the-art scanners allow us to perform high-resolution cine imaging of the heart at rest and under stress conditions up to heart rates of 200 beats per minute. A feature of 1.5 Tesla MR scanners is standard sequence steady-state free precession (SSFP), which provides excellent visualization of the endocardial border due to the high contrast between blood and myocardium without the need for contrast agent injection. In the MR environment pharmacological stress is used, which is a well-documented alternative stress method to ergometry.
Dobutamine Stress Magnetic Resonance Protocol
Stress protocols for MRI follow the standard high-dose dobutamine/atropine regimen as used in stress echocardiography. The 17-segment model for the segmentation of the myocardium is used for data analysis and reporting. At rest, each of these segments is presented in at least two standard views (apical-, mid-, and basal short-axis view; four-, two-, and three-chamber view). Dobutamine is infused intravenously at three-minute intervals at doses of 10 up to 40μg/kg/minute, and imaging is repeated in all views at each stress level. If the target heart rate is not reached at the maximum dobutamine dose, up to 2mg atropine can be applied in 0.25mg fractions. Identical termination criteria to those of DS echocardiography (ECG) are used.6 A study with 1,000 DSMR examinations demonstrated a similar safety profile to DS ECG.5
For MR cine imaging, the patients usually lie in the supine position and a surface coil is placed on the thorax for signal detection. Image acquisition is performed during ECG triggering. A cine loop of more than 25 phases per cardiac cycle can be acquired during an expiratory breath-hold of around four to six seconds. The cine images are displayed within one second after data acquisition and can be simultaneously transferred to an independent viewing station. This allows the physician to evaluate the images during the stress test for the occurrence of new or worsening wall motion abnormalities.Diagnostic Criteria
A synchronized display of the different dobutamine dose levels at the same time is used for a standardized assessment of wall motion abnormalities. Wall motion is classified as normokinetic, hypokinetic, akinetic, or dyskinetic. During DSMR, a lack of increase in wall motion or systolic wall thickening or a reduction of wall motion or thickening are regarded as pathological findings. DSMR has been shown to be superior to DS ECG for the detection of inducible wall motion abnormalities in patients with suspected coronary artery disease,7 patients with wall motion abnormalities at rest,8 and patients not well suited for second harmonic echocardiography.9 The superiority of DSMR has been primarily attributed to the consistently high endocardial border visualization. In patients with inadequate acoustic windows or limited ECG image quality, the advantage in diagnostic accuracy is particularly high. A recently published multicenter study showed that DSMR has low inter-observer variability.10 In a recent review, a meta-analysis of DSMR for identifying coronary atherosclerosis demonstrated a sensitivity of 87% with a specificity of 83%.11
Functional Assessment of Viable Myocardium
In addition to the assessment of ischemia, DSMR offers the possibility of detecting viable myocardium after myocardial infarction (MI). This information is based on the recruitment of hibernating myocardium with doses of 10–20μg/kg/minute dobutamine stimulation. In areas with viable myocardium a ‘biphasic response’ is observed, characterized by wall motion abnormality at rest, improvement at low dose, and worsening at higher dobutamine doses. Low-dose dobutamine has a similar value to MR scar imaging (late enhancement) for the prediction of functional recovery after revascularization and may be superior in patients with 25–75% transmurality of necrosis.12
Prognostic Value of Dobutamine Stress Magnetic Resonance
In a single-center study, Hundley et al.13 found that the presence of inducible wall motion abnormalities during DSMR identifies patients at risk for MI and cardiac death, independent of the presence of traditional risk factors for CAD. For patients with a left ventricular ejection fraction (LVEF) >40%, a low cardiac event rate (2% over two years) was demonstrated.Jahnke et al.14 reported a cumulative cardiac event rate (death or MI) of 1.2, 2.6, and 3.3% in the first three years in patients with a normal DSMR. In contrast, patients with a positive DSMR had a significantly higher event rate (7.3, 10.3, and 18.8% in the first three years).
In patients with moderate or worse ECG image quality, DSMR can be regarded as the imaging method of choice. It can prove or exclude ischemia with strong prognostic value. In addition, low-dose DSMR yields a functional answer on the presence of viable (hibernating) myocardium.
The first multicenter trials have shown promising results for MR first-pass perfusion imaging15,16 for the detection of ischemia. A major advantage of MR perfusion imaging in comparison with other perfusion imaging techniques, e.g. single photon emission computed tomography (SPECT) or positron emission tomography (PET), is its ability to visualize subendocardial perfusion defects due to its superior spatial resolution. PET and SPECT have additional limitations compared with MR perfusion, such as the application of radioactive tracers and the occurrence of attenuation artifacts for SPECT.
For MR perfusion imaging, pharmacological vasodilatation is induced with adenosine or dipyridamole. Adenosine stimulation causes an increase of blood flow in myocardial areas supplied by normal coronary arteries, whereas no change or even a reduction is found in areas supplied by stenotic coronary arteries. With an intravenous infusion of 140μcg/ kg/minute adenosine for four to six minutes, maximal coronary vasodilation can be safely achieved. Possible side effects—such as first-, second-, and third-degree atrioventricular (AV) block, sinus bradycardia, and dyspnea— are transient and usually do not require medical intervention.Contrast Agents and Injection Scheme
MR perfusion imaging is performed during a rapid bolus injection of a low dose of standard gadolinium-containing extracellular contrast agent. Usually, contrast agent doses between 0.05 and 0.15mmol/kg with injection speeds of 3–6ml/kg are used. First-pass myocardial perfusion imaging is completed within 30–50 seconds immediately after the contrast agent administration and is normally performed during a breath hold. The whole examination consists of cine wall motion imaging at rest, followed by perfusion imaging at stress (adenosine), then 10 minutes later at rest, and finally delayed enhancement imaging (DE) as described below.17
Analysis of Magnetic Resonance Perfusion Studies
A visual analysis of the data is performed in most centers. A semiquantitative evaluation of MR perfusion imaging is recommended for a more accurate interpretation. In areas with ischemia inflow, the contrast agent will be reduced and slower in comparison with normal areas, which leads to a reduction of signal intensity in ischemic myocardium (see Figure 1). In patients with previous MI, the dark zones must be larger than or in a different area from the enhancement to make the diagnosis of ischemia.18 Recently, a significant number of studies19–22 have underlined the accuracy of MR perfusion imaging, which is a least as accurate as SPECT if performed in an experienced center.
Prognostic Value of Magnetic Resonance Perfusion
Patients with normal stress myocardial perfusion have an excellent prognosis. Jahnke et al. demonstrated that a negative perfusion study was related with 0.7, 0.7, and 2.3% cumulative cardiac event rates for the first three years, respectively. There was a significantly lower event rate than in patients with a positive MR myocardial perfusion study: 6.2, 12.2, and 16.3% in the first three years, respectively.14 In a recent study from Ingkanisorn23 et al. in patients with acute chest pain, negative troponin-I test results, and non-diagnostic ECG findings, adenosine-stress perfusion MR demonstrated a sensitivity of 100% and a specificity of 93% for the detection of future adverse cardiac outcomes. In patients with a negative perfusion scan, no adverse cardiac outcomes occurred during the first year of follow-up.
Myocardial perfusion imaging produces accurate information on the presence of myocardial ischemia and will become an integral part of the assessment of cardiovascular patients.
Late Gadolinium Enhancement
Late gadolinium enhancement (LGE) MRI by use of gadolinium-based contrast agents has become increasingly important for demonstrating MI and detection of myocardial viability. Due to its high spatial resolution, LGE-MR can clearly demarcate infarcted tissue and viable myocardium within the myocardium (see Figure 2).17
Usually, LGE-MR images are acquired 10–15 minutes after the contrast injection.24 The use of DE is based on the fact that in the equilibrium phase, gadolinium-containing contrast agents distribute into the extracellular space. In contrast to healthy myocardium, the distribution volume of the contrast agent is substantially increased in infarcted tissue,25 resulting in enhancement of necrotic areas in inversion recovery (IR)-prepared MR images.24,26 Usually, a dose of 0.1–0.2mmol/kg of an extracellular gadolinium contrast agent is given intravenously. To optimally suppress the signal of healthy myocardium to achieve the optimal contrast between infarcted and viable myocardium, the inversion time (TI) needs to be adapted to every patient. To differentiate between acute and chronic MI, T2-weighted images allow infarct-related myocardial edema to be depicted as a marker of acute MI.27
The assessment of the extent of myocardial necrosis on LGE-MR has been shown to be useful in predicting functional recovery of dysfunctional myocardium in patients after MI. The likelihood of a functional improvement after revascularization was negatively correlated with the transmural extent of enhancement in both chronic28 and acute MI.29
A study showed that infarct size—defined as spatial extent on contrast-enhanced MRI—was a stronger predictor of all-cause mortality than LVEF and LV volumes.30 In addition, in patients with a prior MI the extent of the peri-infarct zone characterized by cardiovascular MRI provides incremental prognostic value beyond LV systolic volume index or EF.31
Recent reports have identified a possible link between a new scleroderma-like disorder, nephrogenic systemic fibrosis (NSF), and exposure to gadolinium-containing contrast agents in patients with end-stage renal disease.32 The pharmacokinetic properties of gadolinium are similar to those of iodinated X-ray contrast, but with less nephrotoxicity and a lower anaphylaxis risk. A study in almost 700,000 patients showed that the rate of adverse reactions was low and the rate of serious allergic reactions was <0.01%.33,34 Typically, gadolinium-containing agents are excreted rapidly and almost completely via glomerular filtration. However, in renally diseased patients the clearance of gadolinium-containing contrast agents is exceedingly prolonged compared with that seen in healthy humans.35 The US Food and Drug Administration (FDA) and European medicines agencies recommend that in patients with severe renal impairment and neonates, gadolinium-containing agents should be used only if clinically essential.32
DSMR provides the opportunity to quantify the extent of myocardial necrosis and detect even small subendocardial MI. The evaluation of the transmural extent of scarred tissue is useful for predicting functional recovery of dysfunctional myocardium.