Stress Cardiovascular Magnetic Resonance: Clinical Myocardial Perfusion

Stress-Only Versus Stress-Rest Examination for the Detection of Hemodynamically Significant Lesions

In fundamental canine experiments, a reduction of coronary artery cross-sectional area was related to resting and hyperemic flow in the vessel. To assess the hemodynamic consequences of a coronary artery stenosis, the maximum hyperemic coronary blood flow during intracoronary adenosine infusion was measured. To compare maximum hyperemic flow in different coronary vessels, hyperemic flow was normalized with resting flow to correct for differences in mass of the vessel-dependent myocardium. Thus the assessment of hemodynamic significance of a coronary artery stenosis was achieved by dividing hyperemic blood flow by resting blood flow: that is, by calculating the coronary flow reserve (CFR). However, the influence of resting hemodynamics on resting flow, and thus on CFR, was recognized. By altering resting heart rate and blood pressure, CFR ranged from 2 to 12 in their experiments. To solve this problem, the relative CFR was proposed as hyperemic blood flow with stenosis divided by hyperemic blood flow without stenosis. This relative CFR eliminates the influence of resting hemodynamics on CFR because hyperemic stenosis flow is normalized by maximum adenosine-induced hyperemic flow that is uncoupled from myocardial oxygen demand. Consequently, this relative CFR remained stable during varying resting hemodynamics (standard deviation [SD] of 17% for relative CFR vs. 45% for the absolute CFR). These findings are in line with a recent CMR study in humans, demonstrating the important effect of resting hemodynamics such as heart rate, contractility, and loading conditions on resting myocardial blood flow and, hence, on absolute CFR. Further evidence that absolute CFR is affected by resting hemodynamics is provided by positron emission tomography (PET) studies on myocardial perfusion performed in patients with CAD. With this technique, a correlation of CFR with percent area stenosis was demonstrated; however, there was a tendency toward even better correlations for hyperemic myocardial flow alone. These data suggest that relating hyperemic flow supplied by stenosed coronary arteries to hyperemic flow supplied by nonstenosed coronary arteries (e.g., represented in a normal database) is advantageous because it eliminates the influence of resting hemodynamics as encountered with the CFR approach. This stress-only approach, which compares hyperemic stenosis flow with hyperemic flow of a normal database, has been successfully applied in several clinical CMR studies. Although the CFR measurements are affected by resting hemodynamics, two additional problems should be kept in mind: (1) matching myocardial regions, for example, the subendocardial layer, for both rest and hyperemic conditions may be difficult because geometry of the heart is changing with changing heart rate and loading, and (2) to obtain accurate results for the CFR calculation, the technique must guarantee a linear relationship between CMR-derived perfusion parameters and true flow over a wide range of flow conditions covering resting and hyperemic flow. A synopsis on advantages and disadvantages on the stress-only and stress-rest protocols is shown in Table 18.1 .

Options for Inducing Stress in Cardiac Perfusion Studies

From the considerations mentioned earlier, it appears mandatory to apply some kind of stress to the myocardium to assess stenoses that reduce maximum blood flow, but not resting flow. If oxygen demand of the myocardium is increased either by positive inotropic agents such as dobutamine or by direct physical stress, the supply-demand imbalance induces a vasodilation and a hyperemic reaction in the myocardium to meet demand ( Fig. 18.2 ). However, in myocardial regions supplied by a stenosed coronary artery, increased oxygen demand is not met by supply, causing ischemia and consequently regional hypokinesia or akinesia. In this latter situation, assessments of both myocardial (contractile) dysfunction and reduced hyperemic reaction allow detection of a hemodynamically significant stenosis. Alternatively, hyperemia can be induced directly by administration of vasodilators such as dipyridamole or adenosine. This strategy detects coronary artery stenoses by assessment of a compromised hyperemic flow, although ischemia (O ₂ supply-demand imbalance) is very rarely induced by vasodilators. To cause a steal effect by vasodilators, the stenosis has to be severe (i.e., >90%) as demonstrated in experimental studies. Consequently, when contractile function was assessed during vasodilator-induced stress, the sensitivity for detection of CAD in clinical studies was very low. Moreover, in comparison with positive inotropic approaches, the vasodilator approach as used for perfusion tests appears advantageous by reducing ischemia-associated side effects such as angina pectoris and arrhythmias. Adenosine causes hyperemia via A1 receptors, but it also induces negative chronotropic, dromotropic, and inotropic effects and, in addition, it can cause bronchospasm, atrioventricular (AV) block, and mast cell degranulation. Despite this profile, it is a very safe stressor as was shown in the EuroCMR registry with only two severe reactions in 18,840 patients. In clinical routine, an insufficient hemodynamic response to adenosine can occur. Karamitsos and colleagues proposed a high-dose regimen for adenosine (by increasing the standard dose of 140 µg/kg/min for 3 minutes to 210 µg/kg/min for 7 minutes), which was safely applied in patients with suspected CAD, increasing the proportion of adequate hemodynamic response (heart rate increase >10 beats per minute or systolic blood pressure decrease >10 mm Hg) from 82% to 98%. Conversely, dipyridamole induces hyperemia by blocking adenosine re-uptake. Finally, regadenoson represents a more selective adenosine 2A receptor, which is administered as a single intravenous (IV) bolus. This compound was shown to induce hyperemia at a similar degree to adenosine and it was also successfully used in studies on prognosis (see later).

Endogenous Contrast Media

Arterial spin labeling exploits the fact that unsaturated protons entering saturated tissue shorten the tissue T1. Using appropriate electrocardiogram (ECG)-triggered pulse sequences, T1 measurements are performed after global and slice-selective spin preparation. Absolute tissue perfusion is then calculated by assuming a two-compartment model. It should be kept in mind that this approach assumes that the direction of flowing blood in intramural vessels is orthogonal to the slice orientation, which is not the case for all myocardial layers. Furthermore, fiber orientations change during contraction and relaxation, making this approach problematic in the beating heart.

In blood-oxygen-level-dependent (BOLD) imaging, deoxygenated and thus paramagnetic hemoglobin shortens T2 relaxation time and therefore can be used as an endogenous contrast media (CM) (although oxygenated hemoglobin is slightly diamagnetic, causing less T2 shortening). A T2- or T2*-weighted pulse sequence allows for an estimation of an increased content of oxygenated blood. During pharmacologically induced hyperemia, oxygen content will increase in well-perfused myocardium but not in myocardium supplied by a stenosed vessel (which is associated with a higher O ₂ extraction). However, signal differences in normally perfused regions versus hyperemic regions (with a 4-fold increase in flow) were reported to be as low as 32% in an experimental study. These BOLD data correlated closely with microsphere data, but the slope of the correlation was as low as 0.08. This limitation in signal difference might be problematic, because CM first-pass studies suggested several hundred percent of signal change being required for a reliable stenosis detection. In another study applying BOLD, ΔR2 measurements yielded an adequate slope of 0.94. But again, the sensitivity to absolute flow changes was low, because a 100% increase in flow yielded a signal increase of only 5% (i.e., a change in myocardial R2 of 0.94/s) in that study. Accordingly, in a recent study in patients, R2 increased by only 16% during adenosine stress in nonstenotic areas (although adenosine is typically increasing flow 300%–500%). The BOLD approach is also sensitive to magnetic field inhomogeneities, predominantly occurring in the posterior wall close the coronary sinus draining deoxygenated blood. Considering these aspects, the robustness of the method is not yet fully explored.

Exogenous Contrast Media for Perfusion Cardiovascular Magnetic Resonance

These CM are typically injected into a peripheral vein, and the signal change in the myocardium occurring during the first-pass of the CM is measured by a fast CMR acquisition. All CM first-pass techniques either under development or in clinical routine are designed to meet the following requirements: (1) provide high spatial resolution to permit detection of small subendocardial perfusion deficits, (2) provide adequate cardiac coverage to allow for assessment of the extent of perfusion deficits, (3) feature high CM sensitivity to generate optimum contrast between normally and abnormally perfused myocardium during CM first pass, and (4) allow acquisition of perfusion data every one to two heartbeats to yield signal intensity–time curves of adequate temporal resolution that allow for extraction of various perfusion parameters (see later). To reach these goals, high-speed data acquisition and time-efficient magnetization schemes are most important. Because the first pass of CM during hyperemia lasts only 5 to 10 seconds, breathing motion is minimized by a breath-hold maneuver, although cardiac motion is eliminated by ECG triggering. This control of cardiac and breathing motion in perfusion CMR preserves its high spatial resolution of data acquisition: on the order of 1 to 2 mm × 1 to 2 mm. This is not the case for scintigraphic techniques with acquisition windows of several minutes, which preclude breath-holding for elimination of respiratory motion, and ECG triggering during single-photon emission computed tomography (SPECT) studies requires higher tracer amounts to improve counts statistics.

Extravascular Contrast Media

For perfusion CMR techniques, the relationship between myocardial CM concentration and myocardial signal depends on a variety of factors. Normal perfusion can cause a signal increase during first pass of a gadolinium (Gd) chelate when combined with a T1-weighted pulse sequence, although a T2-weighted sequence with a higher dose of a Gd chelate can even cause a signal drop during first pass. This is fundamentally different from ischemia detection based on the assessment of wall motion, where new onset of dysfunction unambiguously indicates the presence of ischemia.

Today, extravascular Gd chelates are most commonly used for first-pass perfusion CMR in combination with heavily T1-weighted pulse sequences. These CM are excluded from the intracellular compartment (i.e., from viable cells with intact cell membranes); therefore a perfusion deficit during the first pass reflects either hypoperfused viable myocardium (which would become ischemic during inotropic stress) and/or scar tissue (with severe reduction of perfusion even at rest). To differentiate hypoperfused tissue further, it is recommended to inject another dose of CM and to wait for the establishment of a dynamic equilibrium of CM concentrations in the various compartments (blood, viable myocardium, scar tissue), to obtain conditions where tissue CM concentrations are governed by distribution volumes (and no longer by perfusion). During this condition, which typically occurs within 10 to 20 minutes after CM injection in humans, late enhancement imaging (with the inversion time set to null normal myocardium) is ideal to discriminate hypoperfused but viable myocardium as dark tissue from scar, which appears bright. For viability assessment, scintigraphic techniques also exploit the equilibrium distribution of tracers, which is observed after rest injection or rest reinjections. However, the radioactive tracers are not taken up by scar tissue, which consequently appears as a cold spot, whereas viable tissue appears as a hot spot (see Table 18.1 ).

Several multicenter studies were performed for the assessment of the optimal CM dose for perfusion imaging. This is important because higher CM doses can cause susceptibility artifacts at the subendocardium, where differences in CM concentrations between blood and myocardium are high during first pass. Strongly T1-weighted sequences showed an absence of a susceptibility-induced signal drop in the subendocardial layer up to doses of 0.15 mmol/kg of an extravascular Gd chelate, which resulted in superior diagnostic performance of doses of 0.1 and 0.15 mmol/kg versus 0.05 mmol/kg for semiautomatic analysis of the upslope parameter ( Fig. 18.3 ).