How to perform an ultrasound contrast myocardial perfusion examination?

Applying the principle of the ischaemic cascade to functional stress testing, myocardial perfusion abnormalities occur earlier than abnormalities of myocardial function, ECG or symptoms. Moreover, abnormal myocardial function only occurs when perfusion abnormality exceeds 10% of the myocardial circumference.1 The ultrasound contrast agents (UCAs), which are microbubbles (MBB), are pure intravascular agents sufficiently small to cross capillary beds. Therefore, they allow quantification of myocardial blood flow (MBF) in addition to the evaluation of myocardial function at rest and during stress. Their added value for both the diagnosis and prognosis beyond myocardial function has been demonstrated in various settings and when compared with other functional tests.2–4 The coronary blood volume (CBV) encompasses the entire coronary circulatory system, which includes the epicardial coronary arteries, the arterioles, the capillary network, venules, veins, and the coronary sinus. Approximately one-third of the CBV resides within the ventricular myocardium. The myocardial blood volume (MBV) includes ‘microvessels’ of <300 μm in diameter, with ∼90% of the total MBV lying within the capillaries (6–7 μm in diameter). Because of the near complete extraction of O2 from red cells by the myocardium under basal conditions, any increase in myocardial O2 demand must be rapidly followed by increases in coronary blood flow. In the absence of a coronary stenosis, when myocardial O2 demand is increased, there is sufficient vasodilator reserve to allow coronary flow to increase by a factor of four- to six-fold above resting levels. The increased coronary flow in response to increased demand is achieved through a process of coronary autoregulation, controlled predominantly by the arterioles. The coronary microcirculation strives to maintain a minimum trans-capillary pressure of ∼30 mmHg. In the absence of a coronary stenosis, a resting patient with a mean aortic pressure of 90 mmHg will have a pre-capillary pressure of ∼45 mmHg. Normally the resistance between the aorta and the capillaries is provided by the arterioles, which offers up to 60% of the total coronary vascular resistance. In the presence of a normal coronary artery and increased myocardial oxygen demand, there is arteriolar vasodilation, reducing the resistance at the arteriolar level, resulting in a higher pre-capillary pressure, translating into increased red blood cell velocity across the capillary network, and opening dormant capillary networks in order to maintain mean trans-capillary pressure (capillary recruitment), thus increasing the overall MBV. As a result overall MBF is increased. In the presence of a non-flow limiting stenosis at rest, MBF remains normal because of arterial vasodilation. However, once a stenosis exceeds 90%, which is flow-limiting at rest, the arteriolar vasodilatatory capacity is exhausted resulting in reduced pre-capillary pressure and reduced MBF. However, patients with critical lesions may have collateral vessels, making assessment of resting perfusion a complex phenomenon. In patients with collaterals in the presence of critical stenosis or in the setting of a non-critical coronary stenosis, stress imaging to induce either increase myocardial oxygen-demand (exercise or dobutamine) or hyperaemia (vasodilator induced maximal arteriolar vasodilation with adenosine/dipyridamole/regadenoson) is required. During stress, augmentation of MBF (flow reserve) in the myocardial region subtended by a significantly stenosed coronary artery is limited as resting arteriolar vasodilation is already present. The pre-capillary pressure thus drops significantly due to low distal coronary pressure and a steal phenomenon may appear. With reduced pre-capillary pressure the only means of maintaining normal trans-capillary pressure is to increase the resistance of the capillary bed, which can only be achieved by capillary de-recruitment resulting in reduced capillary blood volume, which manifests as perfusion defect. The optimum imaging protocol for myocardial contrast echocardiography (MCE) is very low mechanical index (MI) contrast-specific imaging mode. MI refers to the acoustic power of the ultrasound field. At a MI > 1, MBB are easily destroyed, precluding continuous imaging of microbubbles. At very low MI (<0.2), MBB destruction is minimum and hence allows real-time imaging. Because MBB have the same rheology as red blood cells and remain entirely intravascular at a steady state after constant intravenous infusion, the acoustic intensity (AI) from the MBB represents relative MBV. Transient increase in MI > 0.9 (flash) will clear the MBB within the ultrasound beam elevation and the replenishment can be assessed reverting to very low MI imaging for 10 s or 10 cardiac cycles at a heart rate of 60 bpm. The rate of replenishment depicts MBB or blood flow velocity. Time versus AI curves can be generated from different myocardial regions and fitted to an exponential function, where A is the plateau of AI, and β is the rate constant that represents the rate of rise of AI. In this model the plateau (A) myocardial AI represents the MBV. The rate constant (representing rate of rise or the slope) (β) represents the mean myocardial red blood cell velocity and their product (A×β) represents MBF. The time gain compensation (TGC) should be set so that myocardial and left ventricular opacification appear uniform from apex to base. Typically, this requires moving the near field TGC upwards. The overall 2D gains should be maintained at around 65%. Background gains are set so that minimal tissue signal is seen. Following adjustment of machine settings, a diluted solution of MBB is administered intravenously at a constant infusion rate with the use of an infusion pump device connected to a dedicated intravenous line. The infusion rate will vary according to the product used. For Sonovue®, the initial dose is ∼1 mL/min. For Luminity/Definity® or Optison®, it is 3–5 mL/min. MCE is performed in the three apical views. Following 1 min after the commencement of MBB infusion when steady state of MBB in the circulation is usually obtained, imaging should begin. The infusion rate should be adjusted to obtain the best possible myocardial opacification with minimal attenuation. Once optimized, the machine settings should be kept constant throughout the study. The focus should be set at the mitral valve level but moved towards the apex when an apical perfusion defect is seen to eliminate near field bubble destruction artefact. Nonstandard apical views (e.g. bringing the lateral wall into the sector field) maybe used to overcome basal attenuation artefacts. In large left ventricles, each myocardial wall (i.e. inferior and anterior walls) maybe imaged separately when artefacts are observed in the peripheral fields. Flash echocardiography at a high MI (>0.7) using 3–5 frames can be used to clear myocardial microbubbles completely and observe replenishment at very low MI imaging. If MBB are not well cleared as noted by residual myocardial signal then first increase the number of flash frames to 10 then to 20 frames—if still not successful then increase the MI to 0.9. Also care needs to be taken not to overly clear MBB from LV cavity as it will delay appearance of MBB in the myocardium due to delay of transit from the pre-capillary level not at the capillary level, which can affect perfusion evaluation. Following flash, acquire 10–15 cardiac cycles (∼10 s) both in real-time and in triggered end-systolic mode in each view. At peak stress, the same sequence should follow. Slow bolus doses may also be used (SonoVue® 0.4 or 0.3 mL, Optison® followed by 5 mL of normal saline over 20 s) or Luminity/Definity® 0.2 mL diluted 1 mL normal saline over 20 s. However, with bolus quantification may not be as robust. For Regadenoson®—a new cardiac-specific adenosine 2A vasodilator acquire images within 2 min after a bolus dose of 400 μg. For treadmill or bicycle exercise, acquire peak images immediately after treadmill or at peak stress during bicycle ergometry. Commence microbubble administration at peak stress for both modalities. Acquire perfusion images soon after wall motion loops are acquired. End-systolic frames should be analysed to avoid imaging the arteriolar bed which is more prominent in diastole. The capillaries are most prominent at end-systole as arterioles and venules are squeezed of blood into arteries and capillaries respectively. A qualitative score may be assigned at rest as 2: homogenous opacification within 5 s; 1: heterogeneous opacification after 5 s; and 0 no opacification even after 10 s. This gives an assessment of myocardial viability—Grade 2 suggests good myocardial viability and 0 no myocardial viability. Grade 1 intermediates probability of myocardial viability. These scores are assigned to each of the evaluable myocardial segments in the standard 17 segment model. Perfusion abnormalities during stress are defined as replenishment of the myocardial segments beyond 2 s after flash destruction at peak stress accompanied by subendocardial defect or transmural defect replenishing from subepicardial to subendocardial (Figure 1). (A) Illustrates MBB cleaning and replenishment within the myocardium overtime after a high MI burst of ultrasound (flash). (B) The qualitative grading at rest for viability assessment, based on replenishment overtime (Grade 2 = viability, Grade 1 = probable viability, and Grade 0 = no viability). (C) The qualitative and quantitative evaluation of stress perfusion defect, a rapid complete or partial replenishment indicating ischaemia and MBF reserve <2 indicating abnormal flow reserve/ischaemia. MBB, microbubbles; MI, mechanical index; Nl, normal. Regions of interest (ROI) are placed in the myocardium at rest and the corresponding segments at peak stress across the entire thickness of the myocardium, excluding the high-intensity endocardial and epicardial borders. Basal segments may be excluded because of frequent attenuation artefacts. Other segments with artefacts or attenuation should also be excluded. Each successively selected end-systolic frame is then reviewed to verify appropriate placement of the ROI, with slight adjustments when necessary to correct for cardiac translation due to respiration. Frames showing wide variation in contrast intensity should be discarded to minimize errors in the analysis. It has been shown previously that, among the quantitative parameters, MBF velocity (β) and β reserve (i.e. stress β/rest β) most accurately reflected MBF and MBF reserve, respectively. So β parameter may be used to assess as a surrogate marker of MBF. A MBF reserve <2 is considered abnormal (Figure 1). It is important to assess both wall motion and perfusion. With low-dose dipyridamole, wall motion abnormalities occur rarely so perfusion assessment is paramount for diagnostic purposes. Although MCE has been shown to be safe,5 some allergic reactions can occur. Therefore, material and medications to treat these types of side effects should be available when performing MCE. Conflict of interest: BC has no conflict of interest, AH has received speaker fees from Bracco imaging Konstanz, HLP has received speaker fees from Lantheus medical imaging, RS has received speaker fees from Bracco imaging, Lantheus imaging, General Electric healthcare and Philips Healthcare.

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