Cardiovascular Magnetic Resonance Assessment of Myocardial Oxygenation

Myocardial Oxygenation: Supply Versus Demand

Under physiologic conditions, myocardial blood flow (MBF), myocardial oxygen consumption (MVO ₂ ), and myocardial mechanics are intimately related. Therefore it is not surprising that the key disease processes involving the heart manifest from imbalances between myocardial oxygen supply and demand. Consequently, the noninvasive assessment of imbalances in myocardial oxygen supply and demand, particularly on a regional basis, is of critical importance in both clinical cardiology and for cardiovascular research. The noninvasive quantification of MVO ₂ was not possible until it was shown that positron emission tomography (PET), using ¹¹ C-acetate, permits accurate quantification of MVO ₂ . Using this approach, numerous studies have demonstrated the salutary effects of restoring nutritive perfusion on MVO ₂ and cardiac function and the importance of preserving MVO ₂ as a descriptor and probable determinant of myocardial viability in both acute and chronic ischemic disease. However, PET studies are limited by relatively poor spatial resolution, limited availability mainly due to short-life radiotracers, and potentially harmful ionizing radiation, especially when repeated examinations are needed.

Magnetic resonance imaging (MRI) has become an important clinical imaging modality because it is noninvasive, does not require iodinated contrast media or ionizing radiation, and is widely available. MRI can also provide structural and functional information as well as report on several important biomarkers in the same setting. To date, multiple cardiovascular magnetic resonance (CMR) applications have been developed, including anatomic imaging of the heart and great vessels, coronary artery imaging, methods to characterize myocardial infarction with or without gadolinium (Gd) contrast media, methods for characterizing extracellular space, methods for evaluating myocardial wall motion, and first-pass perfusion (FPP) for the identification of perfusion defects in the myocardium. Over the past two decades, efforts have also been made to use CMR to determine regional myocardial blood oxygenation levels. The blood oxygenation state of the myocardium reflects the combined effects of MBF and oxygen extraction (which together reflect MVO ₂ ). Thus a change in myocardial blood oxygenation secondary to imbalances in oxygen supply and demand would be useful in evaluating disease processes such as coronary artery disease (CAD) or microvascular disease (MVD), which can lead to impaired myocardial perfusion reserve. Noninvasive assessment of myocardial venous blood oxygenation may permit the measurement of oxygen extraction. When coupled with flow, these data would allow for measurement of MVO ₂ . Anatomic, functional, and metabolic information can then be obtained in a single CMR study, thereby providing a comprehensive examination for the diagnosis of ischemic heart disease and the evaluation of therapies for improving the balance between MBF and oxygen demand.

If we assume that the blood oxygen saturation of hemoglobin in the arterial blood is 100% and is Y in the venous pool, then the MVO ₂ can be estimated to first order by Fick's law as

{MVO}_{2} = F \times Hct \times (1 - Y)

${MVO}_{2} = F \times Hct \times (1 - Y)$

where F (in mL/g/min) is the blood flow to the myocardium and Hct (in percent) is the hematocrit of the blood. Hence if F, Y, and Hct are known, it is possible to estimate MVO ₂ .

Furthermore knowledge of myocardial venous blood oxygenation can permit noninvasive evaluation of myocardial perfusion reserve, defined as the ratio between the peak myocardial perfusion rate at maximum vasodilation and rest. Under pharmacologic vasodilation, such as that in response to dipyridamole or adenosine, normal coronary blood flow increases several fold, whereas the oxygen consumption remains relatively unaltered, leading to an increase in myocardial venous blood oxygen saturation. However, with progressive coronary lumen narrowing or with microvascular dysfunction, the maximal increase in MBF under vasodilatory stress is blunted proportionately relative to the healthy myocardium. This is illustrated in the case of CAD in Fig. 8.1 . Such perfusion abnormalities lead to regional differences in myocardial venous blood oxygenation, allowing for the assessment of the functional significance of CAD. Extensive clinical support now exists for imaging myocardial perfusion research with CMR using Gd-based contrast agents (GBCAs). However, it is contraindicated in severe chronic kidney disease (CKD, stage 4 or 5). According to the National Institutes of Health (NIH) and the United States Renal Data System (USRDS), the prevalence and the cost of treating new cases of CKD has more than doubled in the past 10 years and this trend is predicted to grow given the increasing prevalence of diabetes and its contribution to the development of CKD. Moreover, recent imaging/autopsy studies from Italy, the United States, and Japan have shown that even in patients with normal kidney function, there are retained Gd deposits in the brain—a finding that is contrary to the widely held belief that Gd is fully cleared from the body within hours of infusion. These observations are central to the growing interest and emphasis on non–Gd-based approaches for studying myocardial perfusion, particularly based on changes in blood oxygenation, in all subjects suspected of having ischemic heart disease.

FIG. 8.1, A schematic showing the relationship between the coronary flow and coronary arterial pressure. The solid curve represents the normal relationship. At a constant level of myocardial metabolic demand, coronary artery flow is maintained constant over a wide range of coronary artery pressures, between the bounds of maximum coronary vasodilation and constriction (dashed curves) . The solid circle represents the normal operating point under basal conditions; the solid triangle is the flow observed at the same pressure during maximum vasodilation. Myocardial flow reserve is the ratio of flow during vasodilation to that measured before vasodilation. Note that the flow reserve decreases in a nonlinear manner with reduction of coronary pressure (or coronary artery stenosis). Also note that hypertrophy, increased heart rate, and increased preload all decrease the coronary flow reserve.

In this chapter, we provide an overview of the basic biophysical concepts that allow for the assessment of myocardial changes in blood oxygenation. We then summarize the preclinical and clinical literature to date in the assessment of myocardial oxygenation. This is followed by growing literature on image-processing methods that have the capacity to enable accurate visualization and quantification of blood-oxygen-level-dependent (BOLD) signal changes in the myocardium. Finally, we review the emerging methods that show promising evidence into how BOLD CMR can become a reliable tool for examining ischemic heart disease in the clinical arena and conclude with a brief outlook on the future of myocardial BOLD CMR.

Biophysics of Myocardial BOLD Contrast

Blood is a magnetically inhomogeneous medium in which the magnetic susceptibility of red blood cells is strongly dependent on the blood oxygen saturation (%O ₂ ), defined as the percentage of hemoglobin that is oxygenated. Because the susceptibility of blood plasma is generally invariant, the cooperative binding of oxygen to the heme molecules within the red blood cells results in a detectable susceptibility difference between plasma and the red blood cells. This susceptibility variation gives rise to local magnetic field inhomogeneities, resulting in local frequency variations that lead changes in T2* and apparent T2 of whole blood. This observation has allowed for the acquisition of oxygen-sensitive images permitting the discrimination between arteries and veins. Its utility for detecting chronic mesenteric ischemia and the identification and quantification of cardiac shunts associated with congenital abnormalities have also been demonstrated.

An extension of this phenomenon into the microcirculation opened the door for assessing myocardial oxygenation changes. In the myocardium, nearly 90% of the blood volume is within the capillaries ; accordingly, our discussions will be limited to capillary beds. A change in blood oxygenation in the capillary bed leads to changes in magnetic field variations between the red blood cells and plasma and between the intravascular and extravascular spaces. Following the excitation of the magnetization onto the transverse plane, these field variations cause the spins to lose coherence, leading to a decay of the magnetic resonance (MR) signal. In particular, the severity of the field variation due to changes in blood oxygen saturation directly determines the rate of loss of the spin coherence (MR signal). This phenomenon, referred to as the BOLD effect, implies that when the capillaries contain deoxygenated blood, with all else remaining the same, the MR signal associated with the deoxygenated state (rest) will be lower than that of the hyperemic state (vasodilation) when the capillary oxygenation is substantially higher (~30% [resting] vs. ~80% [hyperemic]). This allows for detecting regional myocardial oxygen differences as regions of signal loss with imaging sequences sensitive to local field inhomogeneities. In addition, the sensitivity of the MR signal to the BOLD effect is dependent on the blood volume, hematocrit, and choice of pulse sequences used. Both gradient and spin echo sequences as well as balanced steady-state free precession (bSSFP) methods have been used to probe these effects.

BOLD effect was first demonstrated in the brain, before being adopted for cardiac applications. However, there are important biophysical differences between BOLD CMR of the heart and brain. Specifically, the heart has a larger blood volume fraction than the brain (~10% vs. ~4%) and the venous blood oxygen saturation in the heart is approximately 30%, compared with approximately 60% in the brain. This allows for a wider range of signal change with vasodilator-induced flow in the myocardium compared with the brain, which provides greater BOLD sensitivity in the heart. However, in contrast to brain imaging, the challenge for myocardial BOLD CMR has been imaging artifacts from motion (cardiac, respiratory, and pulsatile blood flow), as well as bulk susceptibility shifts between heart and lung interface.

Vasodilators in the Assessment of Myocardial Oxygenation

Common Pharmacologic Vasodilators

Presently, vasodilators appear to be essential for assessing myocardial blood oxygenation, especially in the context of ischemic heart disease. Their importance was first demonstrated in human subjects with multigradient echo methods using two different pharmacologic stress agents: dipyridamole and dobutamine. Both agents induce hyperemia, but with different effects on myocardial venous blood oxygenation. Dipyridamole is a potent coronary vasodilator that typically induces a 3- to 4-fold increase in MBF with minimal effect on MVO ₂ . Consequently, myocardial venous blood oxygen saturation increases as oxygen supply (blood flow) exceeds demand (oxygen consumption). In contrast, dobutamine is a potent beta-agonist with a primary pharmacologic effect to increase cardiac work. This results in a concomitant increase in MVO ₂ , which triggers an increase in MBF. Thus oxygen supply and demand remain largely balanced, and there is little to no change in myocardial venous blood oxygen saturation.

Vasodilators have also facilitated direct demonstration of the in vivo correlation between BOLD CMR response (via changes in R2* [or 1/T2*]) and venous blood oxygen saturation. In a well-controlled canine model, a wide range of global myocardial venous blood oxygen saturation levels were created. Hyperemic conditions were induced by the intravenous administration of dipyridamole and dobutamine. To induce hypoxemia, the oxygen content of the inspired gas was reduced by ventilating dogs with a mixture of 10% oxygen and 90% nitrogen, which reduced the oxygen saturation in both arteries and veins. To correlate myocardial R2* with global venous blood oxygenation, venous blood oxygen saturation levels were measured directly by coronary sinus sampling. MBF was quantified invasively by the administration of radiolabeled microspheres. Measurements of myocardial R2* were obtained at baseline, during and after infusion of dipyridamole and dobutamine, and when the dogs were ventilated with hypoxic air. Paired arterial and coronary sinus blood samples were withdrawn at the six different stages of the study. Blood oxygen saturation levels were measured by using a blood gas analyzer interfaced with an oximeter. Coronary sinus blood oxygen saturation levels ranged from 9% to 80% with experimental interventions with dipyridamole, dobutamine, or hypoxic air. Administration of dipyridamole and dobutamine and ventilation of hypoxic air all increased MBF significantly, but significant decrease in myocardial R2* was observed only with dipyridamole infusion, which indicates that myocardial R2* is a reflection of MBF only when myocardial oxygenation demand is not significantly altered between rest and hyperemia. The relationship between the changes of myocardial R2* from baseline and the %O ₂ in the coronary sinus showed a linear regression ( r = 0.84), indicating a strong correlation between myocardial R2* and %O ₂ in the coronary sinus.

These studies also showed that both dipyridamole and hypoxic air increased myocardial blood volume (MBV) fraction in excess of 50%. However, their effects on R2* are manifested differently. With administration of dipyridamole, %O ₂ in coronary sinus increases, which leads to a decrease in R2*. However, the blood volume fraction in the myocardium also increases, which increases the hematocrit content of a voxel, which tends to increase myocardial R2*; this is the opposite of the effect of increased oxygen saturation. Because a decrease in myocardial R2* was observed in these studies, increased oxygen saturation clearly has the dominant effect over increased blood volume, but the apparent R2* change as a function of %O ₂ is reduced because of the accompanied blood volume effect. In contrast, during hypoxia, both %O ₂ in coronary sinus and the blood volume fraction increase, and their effects enhance each other. As a result, the apparent change in R2* as a function of %O ₂ is greater than that if blood volume fraction remained the same. These studies showed that by measuring MBV fraction changes using technetium-99m-labeled ( ^99m Tc-labeled) red blood cells at each of the interventions and correcting their effects on myocardial R2*, a more linear relationship was found between R2* and the blood oxygen saturation. Thus an accurate assessment of myocardial oxygen saturation using CMR will probably require a correction for blood volume.

Hypercapnia as a New Potent Coronary Vasodilator

It has long been known that carbon dioxide (CO ₂ ) may act as a vasodilator in the heart, but its sensitivity to impart sufficient coronary vasodilation to assess regional changes in MBF has not been clear. Recent studies, enabled by prospective gas control allowing for rapid and independent control of arterial CO ₂ and O ₂ , have made it possible to directly relate the influence of arterial CO ₂ on coronary vasodilation. The use of targeted increases in arterial CO ₂ to vasodilate the coronary arteries and invoke changes in myocardial oxygenation and its relation to adenosine in the preclinical models and healthy human subjects has been demonstrated ( Fig. 8.2 ). However, its utility to assess changes in myocardial oxygenation in patients with ischemic/nonischemic heart disease has not been demonstrated.

FIG. 8.2, Effect of changing arterial carbon dioxide (CO 2 ) on blood-oxygen-level-dependent (BOLD) cardiovascular magnetic resonance signal intensities in healthy humans. (A) Representative short-axis BOLD cardiovascular magnetic resonance images collected from a healthy human at baseline (end-tidal CO 2 [PETCO 2 ] = 37 mm Hg) and hypercapnia (PETCO 2 = 47 mm Hg). BOLD signal intensity increased during hypercapnia. For ease of visualization, color overlays of the left ventricle (with color bar showing BOLD signal intensity in arbitrary units [a.u.]) corresponding to the gray-scale images are shown directly below. (B) Box plot showing the dependence of % hyperemic BOLD response on PETCO 2 and standard dose of adenosine: % hyperemic response increased at higher PETCO 2 values; response at Plus 10 did not differ from that because of standard adenosine infusion. % hyperemic BOLD response for adenosine is from reported values in the literature. 80 Asterisk denotes statistically significant difference relative to rest ( P < .05). Top and bottom of boxes indicate upper limit +1 standard deviation (SD) and lower limit −1 SD, respectively; error bars (whiskers) are maximum and minimum of data. The mean and median are represented as a point and a band within the box, respectively. For adenosine, the whiskers represent the boundaries of 1st and 99th percentile of the data.

An alternate approach for modulating PaCO ₂ is through breathing maneuvers, where a subject is asked to hyperventilate, typically for 30 seconds, and then suspend breathing during imaging to invoke a hyperemic response. The combined hyperventilation/suspension of breathing is expected to provide a significant change in PaCO ₂ to invoke a hyperemic blood flow response in the heart. To date, the value of this approach in modulating the BOLD CMR response has been demonstrated in healthy human subjects. Comparative studies between this approach and prospective gas control methods to probe myocardial oxygenation changes in response to hypercapnia are yet to be conducted.

Myocardial BOLD CMR: Preclinical Studies

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