Cardiac Magnetic Resonance Imaging with Blood Pool Agents

Magnetic resonance imaging (MRI) is a powerful imaging modality for diagnostic cardiology and research. This imaging method provides combined diagnostic information of different tissue characteristics, such as the visualisation of the vascular tree and cardiac anatomy and function, as well as measurements of blood flow in the vessels, ventricular wall motion, myocardial perfusion and viability. The inherent contrast between blood and myocardium with MRI depends largely on the proton concentration and longitudinal (T₁) and transverse (T₂) relaxation times. The use of MRI contrast agents or different pulse sequences can modulate this inherent contrast.¹ Most of the current applications for cardiovascular magnetic resonance (CMR) use contrast agents either to improve image quality (e.g. angiography) or generate contrast (e.g. late gadolinium enhancement or perfusion). Today, in most clinical applications contrast agents – which are based on gadolinium chelates – are used, causing significant shortening of T₁ (leading to signal enhancement in T₁ weighted images) and a minor shortening of T₂. Until recently, all these agents had been extracellular respectively interstitial agents since they leak rapidly from the vascular into the interstitial space but not into the cell, typically with a plasma half-life in the order of 20 minutes.² Blood pool contrast agents (BPCAs) may have considerable advantages since they remain in the vascular space (thus causing no or minimal background enhancement) and have a longer half-life and a stronger T₁ relaxivity. The plasma half-life for BPCAs differs between 10 and 30min for Gadomer-17,³ 120 and 180min for gadofosveset⁴ and 224±30min for B-22956.⁵ In addition, gadolinium-based BPCAs have relaxivity values that are two to five times higher than those of extracellular contrast agents.^6,7

The most promising indications for CMR with BPCAs are angiography, perfusion imaging and coronary artery imaging. Additional advantages of BPCAs are the ability to measure tissue blood volume and perfusion by using principles of indicator-dilution, and the ability to evaluate changes in capillary membrane integrity, which may be advantageous for pathology characterisation.

BPCAs are either paramagnetic or superparamagnetic agents. Most paramagnetic agents are gadolinium-based, whereas superparamagnetic agents are iron oxide particles.⁸ Several strategies can be applied to restrict the distribution of the contrast agent to the intravascular space, as follows.

• Creation of large molecules by conjugating the paramagnetic ligand to different back-bones, such as dextran, polylysine and dendrimers. However, care needs to be taken to allow for renal filtration.
• Addition of a site that reversibly binds to human serum albumin. The advantages of this concept are the increased T₁ relaxivity (due to the slow tumbling rate) and the renal filtration of the fraction of the contrast agent that is unbound. However, the unbound fraction also diffuses into the interstitium, reducing the net gain of these agents.

Different BPCAs have been developed and tested for cardiovascular application in humans.⁹ A few clinical trials have been performed using gadofosveset;^10–12 Gadomer-17;^1,3,13,14 NC100150 superparamagnetic agent (Vistarem);^1,15 and gadocoletic acid (B-22956).^5,16

However, currently there is only one European Medicines Agency (EMEA)-approved BPCA (gadofosveset; tradename Vasovist^®; Bayer- Schering Pharma AG Germany, development name MS-325, Epix Pharmaceuticals, US) for abdominal and peripheral angiographies in humans; at present, none of the agents is approved for cardiac imaging.¹⁷

Angiography

For MRI angiography the advantages of BPCA can be used in several ways.

• The higher relaxivity leads to a higher blood signal, which can improve diagnostic accuracy, spatial resolution or dose reduction.
• The longer plasma half-life without increase of background signal allows for longer scan times and repetitive imaging, independent of the first pass.^8,9

In dogs, NC100150 injection increases vessel conspicuity and allows visualisation of extensive anatomic regions including aorta, iliac, femoral, popliteal and peripheral arteries.⁸ In direct comparison with two extracellular contrast agents, Gadomer-17 led to a three- to four-fold increase in signal-to-noise ratio (SNR) during the arterial and equilibrium phases of thoracic and abdominal MRI angiography. Gadomer-17 improved the visualisation of the aorta, the inferior cava vein, the portal vein, the renal arteries and veins, the celiac trunk, the superior mesenteric artery and the pulmonary artery and veins.¹⁸

Gadofosveset allowed for an excellent visualisation of the vessels, with selective arterial enhancement during and immediately after contrast injection, and with arterial and venous enhancement at steady-state. Mean arterial SNR and contrast-to-noise ratio (CNR) decreased by only approximately 10% between 5 and 50 minutes after contrast injection.¹¹ In patients with suspected carotid artery disease, gadofosveset allowed for the detection of stenoses and ulcerations,¹⁹ and its efficiency and safety for use in dynamic as well as in steady-state MRI angiography has been demonstrated in several studies in humans.¹²

Perfusion

The wash-in kinetics and the local T₁/T₂ shortening in the myocardial tissue depend on the concentration of the contrast agent, the flow rate, diffusion of the contrast agent into the interstitium, relative tissue volume fractions, bolus duration and recirculation effects.²⁰ For perfusion imaging, BPCAs differ from conventional agents in several ways. The vascular retention may allow for quantitative perfusion measurements, since several assumptions on the speed and amount of interstitial distribution are no longer necessary. In addition, the quantification of blood volume may be possible from T₁ values. The small distribution volume (only 5–10% of the myocardial volume consists of blood)2 causes a lower contrast effect of the injection, which may reduce its efficacy for perfusion imaging. The higher relaxivity of BPCAs versus extracellular agents may compensate for the smaller distribution volume.

Several animal studies have shown that the detection of perfusion defects during vasodilatation is feasible with intravascular contrast agents. The use of Gadomer-17 to depict perfusion defects in a closed-chest swine model of single-vessel coronary artery disease provided more prolonged differentiation of ischaemic from remote myocardium than that with gadopentetate dimeglumine.²¹ Another investigation proved the utility of BPCAs for differentiating acutely ischaemic from normally perfused myocardium with first-pass MRI.²² Zheng et al. demonstrated a single-session magnetic resonance coronary angiography and myocardial perfusion imaging using gadocoletic acid (B-22956) in a porcine model of coronary artery disease.¹⁶ Absolute quantification of myocardial tissue perfusion has been performed in pigs with left anterior descending (LAD) stenoses using NC100150. A correlation of r=0.96 was found between magnetic resonance perfusion imaging and microsphere quantification.⁹

Comparing gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA) and Gadomer-17, Gerber and co-workers demonstrated that the peak signal intensity change in the myocardium using Gadomer-17 correlated better with myocardial blood flow as defined by means of microspheres and, furthermore, that myocardial perfusion defects can be defined longer than with Gd-DTPA.²³ First applications in patients have shown promising results (see Figure 1).²⁴

Magnetic Resonance Coronary Angiography

For magnetic resonance coronary angiography (MRCA), extracellular contrast agents are not useful in combination with relatively long navigator gated acquisitions, since the contrast agent concentration in the blood diminishes rapidly. These sequences, however, are most suited to MRCA, since spatial resolution, image quality and diagnostic accuracy are significantly higher than breath-hold approaches.²⁵ BPCAs have the advantage of providing adequate equilibrium-phase visualisation of the coronary vasculature with high SNR on three-dimensional MRI coronary angiography (see Figure 2), due to the greater T₁ relaxivity and longer plasma half-life than extracellular agents, resulting in a greater blood signal but less myocardial enhancement. Therefore, inversion-recovery sequences instead of T₂-prepulse preparation sequences can be used, leading to a better suppression of the myocardial signal. Herborn et al. found that the administration of Gadomer-17 improved the CNR in the coronary arteries up to 30 minutes after infusion.³

Investigations of our group, using intravascular contrast agents (Gadomer-17 – SH L 643 A; Bracco – B-22956; Clariscan – NC100150; Vasovist – gadofosveset) resulted in a significant improvement of MRI angiographic parameters for delineation of coronary artery segments in volunteers,^3,26 and increased overall diagnostic accuracy for stenosis detection in patients.^5,27,28

Late Gadolinium Enhancement

There are only a few reports about delayed enhancement with BPCAs. In an animal study in pigs with a combined protocol for evaluation of myocardial perfusion and viability with P792 in comparison with an extracellular contrast agent in a nonreperfused infarction model, Peukert et al. described how the BPCA allowed evaluation of myocardial viability.²⁹

Saeed et al. reported on the use of P792 (Vistarem, Guerbet Group), in an animal study in pigs, that with a BPCA, acute myocardial infarctions can be discriminated from chronic myocardial infarctions by the combined use of an extracellular and intravascular contrast agent. They described delayed enhancement in acute myocardial infarctions in both intra-vascular and extra-vascular contrast; however, in chronic infarctions delayed enhancement was by extracellular, but not by BPCA.³⁰

It was shown that in case of coronary occlusion and coronary stenosis, intravascular MRI contrast agents provide longer delineation of the area at risk than extracellular agents.¹⁴ It was demonstrated that in small animal models intravascular agents are more suitable than extracellular agents for the prolonged delineation of no-reflow zones and for defining small (few pixels) microvascular obstruction areas.³¹ Thus, these agents may be useful for delineating micro-embolisation in humans. Furthermore, intravascular agents have been used to demonstrate the progressive growth in the size of the no-reflow zone in mild, moderate and severe myocardial injury³¹ and the effect of the duration of reperfusion on the size of the no-reflow zone (up to 24 hours after reperfusion).³²

Our group could show that gadofosveset allows for detection of chronic myocardial infarctions in patients. Preliminary results indicate that comparing this with an extracellular contrast agent, the transmural amount of scar and the number of scarred left ventricular segments was reduced.³²

Interventional Magnetic Resonance Imaging

A future application of BPCAs may be the application in interventional procedures, since the longer diagnostic window provides the opportunity to obtain MRI angiographies of multiple regions of the body during a single study and throughout a longer lasting procedure.⁸

Conclusion

BPCAs provide advantages in enhanced depiction of blood vessels due to greater relaxivity and shortening of the intravascular T₁ than do extravascular contrast agents over a longer period of time. They offer the possibility of avoiding the background enhancement, as the T₁ changes remain confined to the intraluminal spaces. BPCAs are effective in dynamic and steady-state MRI angiography. In myocardium, they are useful for assessing myocardial perfusion, microvascular permeability and viability.⁸