Cardiovascular Magnetic Resonance Contrast Agents

Introduction to the Biophysics of Magnetic Resonance Imaging

All contrast agents shorten both T1 and T2 relaxation times. However, it is useful to classify CMR contrast agents into two broad groups based on whether the substance increases the transverse relaxation rate (1/T2) by roughly the same amount that it increases the longitudinal relaxation rate (1/T1) or whether 1/T2 is altered to a much greater extent. The first category is referred to as “T1 agents” because, on a percentage basis, these agents alter 1/T1 of tissue more than 1/T2 as a result of endogenous transverse relaxation in tissue. With most pulse sequences, this dominant T1-lowering effect gives rise to increases in signal intensity, and thus these agents are referred to as “positive” contrast agents. The T2 agents largely increase the 1/T2 of tissue selectively and cause a reduction in signal intensity, and thus they are known as “negative” contrast agents. Paramagnetic gadolinium-based contrast agents are examples of T1 agents, whereas ferromagnetic large iron oxide particles are examples of T2 agents.

There are many mechanisms by which contrast agents shorten T1 and T2. Considerable chemistry and biophysics can be applied to understand or predict these mechanisms. However, in many cases, the effect of these mechanisms can be reduced to a single constant, called “relaxivity.” Fig. 3.1 shows the effect and definition of relaxivity.

Fig. 3.1A shows the effect of a typical contrast agent on the relaxation time of two hypothetical tissues, one with T1 = 1200 ms (similar to heart muscle at 1.5 T) and one with T1 = 400 ms. At low concentration (left side of the graph), it appears that the contrast agent has a larger effect (change in T1) on the tissue with the longer T1. At higher contrast agent concentrations (right side of Fig. 3.1A ), both tissues approach approximately the same T1. A simple way to quantify this effect is to consider the rate of relaxation, 1/T1 (sometimes denoted “R1”). In most cases in medical imaging, the contrast agent increases the relaxation rate proportional to the amount of contrast agent:

where T1 is the observed T1 with contrast agent in the tissue, T1 ₀ is the T1 before addition of the contrast agent, [CA] is the concentration of contrast agent, and r ₁ is the longitudinal relaxivity, often just “relaxivity.” The conventional units for r ₁ are mM ⁻¹ s ⁻¹ (per millimolar per second, sometimes L•mol ⁻¹ s ⁻¹ ). Thus, the slope of 1/T1 as a function of contrast agent concentration ( Fig. 3.1B ) shows the relaxivity, in this case, 4 mM ⁻¹ s ⁻¹ . Fig. 3.1B shows that the effect of the contrast agent on the relaxation rate is independent of the initial T1 of the tissue: that is, in terms of relaxation rate, the contrast agent has the same effect, regardless of initial T1. Transverse, or T2, relaxivity is defined in an analogous way:

For all contrast agents, r ₂ is larger than r ₁ . Relaxivity is dependent on magnetic field strength, on temperature, and in some instances can depend on protein binding, pH, or even the presence of enzymes.

Contrast agent behavior in vivo is seldom as simple as the pure linear effect relaxation rate shown in Fig. 3.1 . Even in the simple case of pure linear relaxation, the effect of the contrast agent on the CMR image is generally nonlinear. In traditional spin echo sequences, nonlinearity can be a result of T1 saturation or T2 signal loss. Once the contrast agent reduces T1 < repetition time (TR)/2, increasing contrast agent concentration will have little effect on increasing the available longitudinal magnetization because the tissue will have nearly fully recovered the magnetization before the next radiofrequency (RF) pulse. Furthermore, because contrast agents affect both T1 and T2 relaxation, at high enough concentration, the contrast agent will reduce T2 to the order of the echo time (TE), and will then decrease MR image intensity. These effects are seen in Fig. 3.2 , where signal intensity is plotted versus contrast agent concentration for T1- and T2-weighted spin echo sequences. Fig. 3.2 was generated assuming a contrast agent relaxivity of 4 mM ⁻¹ s ⁻¹ , typical of most commercial ECF gadolinium agents, and tissue relaxation times typical of myocardium at 1.5 T (T1 = 1200 ms, T2 = 50 ms). For the T1-weighted sequence (TE/TR = 15/600), Fig. 3.2A , signal intensity begins to level out at a contrast agent concentration between 0.5 and 1.0 mM. From Fig. 3.1A , this is the range at which the T1 of the myocardium decreased to approximately 300 ms, or TR/2. At concentrations >1 mM, the T1 effect is saturated, and the only imaging effect of the contrast agent is to make T2 shorter and cause signal loss, even on this T1-weighted sequence. Signal is lost because even a T1-weighted sequence has a finite TE, and T2 effects can enter when T2 is short enough.

The signal intensity plateau on the T2-weighted scan (TE/TR = 80/3000), Fig. 3.2B , occurs at much lower contrast agent concentration. Because TR is so long, the only real effect of the contrast agent is to reduce (rather than increase) signal intensity on this T2-weighted scan. However, this negative contrast can also be medically useful, and certain contrast agents (notably, the iron oxide particles) create negative contrast exactly by providing enhanced T2 relaxation, and thus darker images on T2-weighted scans.

Increasing the relaxivity ( r ₁ or r ₂ ) will have the effect of pushing the simulated curves in Fig. 3.2A to the left, which means that peak signal and subsequent signal loss will occur at lower contrast agent concentrations. A more linear response of signal to contrast agent can be achieved with a fast three-dimensional (3D) spoiled gradient recalled echo (GRE) sequence. This is seen in Fig. 3.2C , where signal intensity is plotted versus contrast agent concentration using the same tissue relaxation times and relaxivities as in Fig. 3.2A and B for a typical fast 3D spoiled GRE sequence, TE/TR/flip = 2.2/9.0/40 degrees. The short TR and very short TE ensure that signal intensity increases across the entire concentration range. At high concentration, the effect of the contrast agent is becoming nonlinear, but the signal is still increasing with increasing contrast agent concentration.

Extracellular Agents

The most common contrast agents used clinically are ECF agents. Although several are approved for clinical use, as mentioned previously, none is specifically FDA approved for cardiac applications. These all behave in a very similar manner, and are typically referred to as “gadolinium” or “gado” agents. Fig. 3.3 shows the chemical structures of several approved ECF agents. Chemically, these compounds exhibit three similar features: they all contain Gd, they all contain an 8-coordinate ligand binding to Gd, and they all contain a single water molecule coordination site to Gd. Nomenclature for contrast agents can be confusing: there is a generic name (e.g., gadopentetate dimeglumine), a trade name (e.g., Magnevist), and usually a chemical code name or abbreviation (e.g., Gd-diethylenetriaminepentaacetic acid or Gd-DTPA). Any of these three names may be used in the scientific literature.

The multidentate ligand is required for safety. The ligand encapsulates the Gd, resulting in a high thermodynamic stability and kinetic inertness with respect to metal loss. This enables the contrast agent to be excreted intact, an important property because these contrast agents tend to be much less toxic than their substituents. For example, the DTPA ligand and gadolinium chloride both have an LD ₅₀ of 0.5 mmol/kg in rats (LD ₅₀ = dose that causes death in 50% of the animals), whereas the Gd-DTPA complex has a safety margin that is higher by nearly a factor of 20, with an LD ₅₀ of 8 mmol/kg for the Gd-DTPA complex.

The Gd ion and coordinated water molecule are essential to providing contrast. The Gd (III) ion has a high magnetic moment and a relatively slow electronic relaxation rate, properties that make it an excellent relaxer of water protons. The proximity of the coordinated water molecule leads to efficient relaxation. The coordinated water molecule is in rapid chemical exchange (10 ⁶ exchanges/s) with solvating water molecules. This rapid exchange leads to a catalytic effect whereby the Gd complex effectively shortens the relaxation times of the bulk solution.

The ECF agents have very similar properties, and these are summarized in Table 3.1 . They are all very hydrophilic complexes with similar relaxivities and excellent safety profiles. In addition, they can be formulated at high concentrations. On injection, these ECF agents quickly and freely distribute to the extracellular space. Administration of any of these agents (with rare exceptions) yields similar diagnostic information.

TABLE 3.1

Approved (December 2016) Magnetic Resonance Imaging Contrast Agents: Relaxivity, Osmolality, and Viscosity

Generic Name	Product Name	Chemical Abbreviation	r 1 , 0.47 T 40°C	r 2 , 0.47 T 40°C	Osmolality a (Osmol/kg)	Viscosity a (cP)
Gadopentetate	Magnevist (Bayer HealthCare Pharmaceuticals)	Gd-DTPA	3.4	4.0	1.96	2.9
Gadoterate	Dotarem (Guerbet Group)	Gd-DOTA	3.4	4.1	1.35 (4.02)	2.0
Gadodiamide	Omniscan (GE Healthcare)	Gd-DTPA-BMA	3.5	3.8	0.79 (1.90)	3.9
Gadoteridol	ProHance (Bracco Diagnostics, Inc.)	Gd-HPDO3A	3.1	3.7	0.63 1.91	1.3 (3.9)
Gadobutrol	Gadovist (Bayer HealthCare, Inc.)	Gd-DO3A-butrol	3.7	5.1	0.57 (1.39)	1.4 (3.7)
Gadoversetamide	OptiMARK (Mallinckrodt, Inc.)	GD-DTPA-BMEA	4.2	5.2	1.11	2.0
Gadobenate	Multihance (Bracco Diagnostics, Inc.)	Gd-BOPTA	4.2	4.8	1.10	5.3mPas
Gadofosveset	Ablavar (Lantheus Medical, Inc.)	MS-325	5.8	6.7	0.83	3.0
Gadoxetic acid	Eovist (Bayer HealthCare Pharmaceuticals)	Gd-EOB-DTPA	5.3	6.2	0.69	1.2

a All concentrations 0.5 M except those in parentheses, which are 1 M.

There are some differences among the physical properties. The diamide complexes gadodiamide and gadoversetamide have considerably lower thermodynamic stability (log K ~ 17 vs. log K > 21 for other Gd complexes). The nonionic (neutral) compounds gadodiamide, gadoteridol, gadoversetamide, and gadobutrol were designed to minimize the osmolality of the formulation. This was prompted by the distinct reduction in toxicity and side effects brought on by the development of nonionic x-ray contrast media. However, for CMR, the injection volumes are much smaller than the volumes used for x-ray angiography or computed tomography (CT) angiography. Thus the overall increase in osmolality after injection of a CMR contrast agent is minimal. Unlike with x-ray contrast, there is no documented safety benefit in using nonionic CMR contrast agents. One benefit of the nonionic compounds is the ability to formulate them at high concentration (1 M) without drastically increasing osmolality or viscosity (see Table 3.1 ). These high-concentration formulations may be useful in fast dynamic studies, such as dynamic MRA or myocardial perfusion. These ECF agents, as with iodinated preparations used for x-ray and CT, are excreted by the kidneys. As a result, clearance is impaired in patients with impaired/reduced renal function (discussed later).