Xiangzhi Zhou

Detecting Myocardial Ischemia at Rest With Cardiac Phase-Resolved Blood Oxygen Level-Dependent Cardiovascular Magnetic Resonance

Noninvasive imaging approaches that can rapidly assess an ongoing ischemia can be of great value in managing patients with clinically significant coronary artery disease. Although a number of imaging approaches exist for the identification of myocardial territories supplied by stenotic coronary arteries, generally all available imaging methods require provocative stress and/or exogenous contrast media. The most desirable imaging approach is one that can non-invasively and rapidly identify ischemic territories prior to the onset of tissue specific changes (development of edema or necrosis) and can permit the assessment of functional/volumetric status while minimizing patient discomfort. Previous studies have shown that ongoing ischemia may be detected with CMR (Cardiac Magnetic Resonance) on the basis of stress perfusion and changes in functional indices. More recently, it has been shown that myocardial edema may be utilized as a marker of ongoing ischemia using animal models 1 and patients 2. While the edema approach eliminates the need for provocative stress, both approaches require separate acquisitions for accurate assessment of functional indices. In this work, we propose and test a new CMR approach for a rapid assessment of myocardial ischemia. The proposed method is based on cardiac phase-resolved steady-state free precession (SSFP) magnetic resonance (MR) signal changes originating primarily from alterations in oxygenation (%HbO2) and secondarily from changes in regional myocardial blood volume (MBV) in the myocardial territory supplied by a stenotic artery. Since the proposed approach can generate functional and tissue specific indices in one acquisition, the proposed approach can provide opportunities to rapidly determine the presence and territory of myocardial ischemia. It is known that (a) MBV is a function of cardiac phase, increasing during diastole and decreasing during systole 3,4; and (b) MBV directly determines the oxygen extraction by cardiomyocytes 5. Thus, MBV and %HbO2 are expected to be different between systole and diastole. Hence, under normal (healthy) conditions, one expects the MBV and oxygen extraction to be maximal during diastole, and minimal in systole. In addition to these effects, as MBV increases, each unit volume of ventricle, i.e., each voxel in a myocardial image, contains a slightly higher proportion of blood, and a correspondingly smaller proportion of myocardial tissue 6. Thus, even at a stable level of %HbO2, the number of deoxygenated hemoglobin molecules within a voxel increases as MBV increases. Moreover, a number of studies have also shown that with increasing grade of coronary stenosis, MBV in the myocardial territory supplied by a stenotic artery increases in systole 7–9. Thus based on these studies, the relative MBV and %HbO2 changes between systole and diastole are expected to be different between myocardial territories supplied by healthy and stenotic coronary arteries. Cardiac phase-resolved BOLD SSFP CMR might provide a unique opportunity to capture these physiological changes and hence assess ongoing ischemia. It is known that T1 of myocardium is dependent on blood volume 10 and that T2 is dependent on blood oxygenation saturation 11. Since BOLD SSFP signals are approximately T2/T1 weighted 12,13, it may be possible to capture the changes in MBV 4 (via T1) and %HbO2 14 (via T2) in one acquisition. In particular, since coronary artery stenosis leads to an increased systolic MBV that is expected to be accompanied by decreases in %HbO2 (due to increased oxygen extraction), we hypothesized that the BOLD SSFP method can be used to detect the presence of coronary stenosis even at rest (i.e. without pharmacological stress). Under conditions of coronary stenosis, the physiological changes in basal MBV and %HbO2 are expected to work synergistically to enhance the SSFP-based detection capacity of myocardial territories supplied by stenotic arteries. In this work, we test these hypotheses using a canine animal model of severe coronary artery stenosis and computer/numerical simulations. In particular, we examine whether the systolic to diastolic myocardial SSFP signal intensity ratio (S/D) is greater than 1 in health and is diminished during ischemia. In addition, we investigate the effects of acute coronary occlusion on ejection fraction, wall thickening, and myocardial edema.Background— Fast noninvasive identification of ischemic territories at rest (before tissue-specific changes) and assessment of functional status can be valuable in the management of severe coronary artery disease. This study investigated the use of cardiac phase–resolved blood oxygen level–dependent (CP-BOLD) cardiovascular magnetic resonance in detecting myocardial ischemia at rest secondary to severe coronary artery stenosis. Methods and Results— CP-BOLD, standard cine, and T2-weighted images were acquired in canines (n=11) at baseline and within 20 minutes of ischemia induction (severe left anterior descending stenosis) at rest. After 3 hours of ischemia, left anterior descending stenosis was removed, and T2-weighted and late-gadolinium-enhancement images were acquired. From standard cine and CP-BOLD images, end-systolic and end-diastolic myocardium was segmented. Affected and remote sections of the myocardium were identified from postreperfusion late-gadolinium-enhancement images. Systolic-to-diastolic ratio (S/D), quotient of mean end-systolic and end-diastolic signal intensities (on CP-BOLD and standard cine), was computed for affected and remote segments at baseline and ischemia. Ejection fraction and segmental wall thickening were derived from CP-BOLD images at baseline and ischemia. On CP-BOLD images, S/D was >1 (remote and affected territories) at baseline; S/D was diminished only in affected territories during ischemia, and the findings were statistically significant (ANOVA, post hoc P<0.01). The dependence of S/D on ischemia was not observed in standard cine images. Computer simulations confirmed the experimental findings. Receiver-operating characteristic analysis showed that S/D identifies affected regions with performance (area under the curve, 0.87) similar to ejection fraction (area under the curve, 0.89) and segmental wall thickening (area under the curve, 0.75). Conclusions— Preclinical studies and computer simulations showed that CP-BOLD cardiovascular magnetic resonance could be useful in detecting myocardial ischemia at rest. Patient studies are needed for clinical translation.

Ischemic Extent as a Biomarker for Characterizing Severity of Coronary Artery Stenosis with Blood Oxygen-Sensitive MRI

To investigate whether a statistical analysis of myocardial blood‐oxygen‐level‐dependent (mBOLD) signal intensities can lead to the identification and quantification of the ischemic area supplied by the culprit artery.

Determination of the optimal first-order gradient moment for flow-sensitive dephasing magnetization-prepared 3D noncontrast MR angiography

Flow‐sensitive dephasing (FSD) magnetization preparation has been developed for black‐blood vessel wall MRI and noncontrast MR angiography. The first‐order gradient moment, m1, is a measure of the flow‐sensitization imparted by an FSD preparative module. Determination of the optimal m1 for each individual is highly desirable for FSD‐prepared MR angiography. This work developed a 2D m1‐scouting method that evaluates a range of m1 values for their effectiveness in blood signal suppression in a single scan. The feasibility of using the 2D method to predict blood signal suppression in 3D FSD‐prepared imaging was validated on a flow phantom and the popliteal arteries of 5 healthy volunteers. Excellent correlation of the blood signal measurements between the 2D scouting and 3D FSD imaging was obtained. Therefore, the optimal m1 determined from the 2D m1‐scouting scan may be directly translated to 3D FSD‐prepared imaging. In vivo studies of additional 10 healthy volunteers and 2 patients have demonstrated the proposed method can help significantly improve the signal performance of FSD MR angiography, indicating its potential to enhance diagnostic confidence. Further systematic studies in patients are warranted to evaluate its clinical value. Magn Reson Med, 2011.

Artifact‐reduced two‐dimensional cine steady state free precession for myocardial blood‐ oxygen‐level‐dependent imaging

To minimize image artifacts in long TR cardiac phase‐resolved steady state free precession (SSFP) based blood‐oxygen‐level‐dependent (BOLD) imaging.

On the mechanisms enabling myocardial edema contrast in bSSFP-based imaging approaches.

The biophysical mechanisms influencing balanced steady‐state free precession (bSSFP) based edema imaging in the setting of acute myocardial infarction are not well understood. To assess the various mechanisms that enable the detection of myocardial edema on bSSFP‐based imaging approaches (cine bSSFP and T2‐prepared bSSFP), experiments were conducted in canine models subjected to ischemia‐reperfusion injury. Results showed that in addition to relaxation effects, the alteration in thermal equilibrium (M0) (including magnetization transfer) has a significant contribution to the image contrast between edematous and healthy myocardium. The relative signal‐intensity ratios between edematous and healthy myocardium were: 1.51 ± 0.18 (cine bSSFP) and 1.58 ± 0.20 (T2‐prepared bSSFP); the theoretically estimated relative relaxation and M0 effects were: 1.17 ± 0.09 and 1.30 ± 0.19, respectively (cine bSSFP), and 1.49 ± 0.23 and 1.06 ± 0.07, respectively (T2‐prepared bSSFP). There were no significant difference between cine bSSFP and T2‐prep bSSFP relative signal‐intensity ratios. However, the relative relaxation effect in cine bSSFP was significantly lower than in T2‐prep bSSFP (P < 0.05), and the M0 effect in cine bSSFP was significantly higher than in T2‐prep bSSFP (P < 0.05). Hence the acquisition strategies that wish to maximize myocardial edema contrast in cine bSSFP imaging should take both relaxation and M0 effects into account. Magn Reson Med, 2011.

T2-weighted STIR imaging of myocardial edema associated with ischemia-reperfusion injury: The influence of proton density effect on image contrast

To investigate the contribution of proton density (PD) in T2‐STIR based edema imaging in the setting of acute myocardial infarction (AMI).

Cine-MRI and 31P-MRS for evaluation of myocardial energy metabolism and function following coronary artery bypass graft

Previous studies investigated the effect of successful coronary artery bypass grafting (CABG) upon left ventricular function. The relationship between myocardial metabolism and heart function after CABG remains unclear. We investigated the relationship between high-energy phosphate (HEP) and cardiac function following CABG using cine magnetic resonance imaging (cine-MRI) and phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS). A retrospective study was approved by the institutional review board. MRI and (31)P-MRS examinations were reviewed of 37 patients with multivessel disease who underwent CABG. 13 of these patients selected for the retrospective analysis had >or=70% stenosis in the proximal left anterior descending artery (LAD) and left ventricular ejection fraction (LVEF) <40%. LVEF was evaluated using cine-MRI. HEP such as phosphocreatine (PCr) and adenosine triphosphate (beta-ATP) was measured using (31)P-MRS to calculate PCr/beta-ATP ratio. Cine-MRI and (31)P-MRS measurements were performed before and after CABG, respectively. Ten normal healthy volunteers served as controls. (31)P-MRS in 13 patients showed that post-CABG PCr/beta-ATP ratio was significantly higher than that of pre-CABG (pre-CABG vs. post-CABG, 1.43+/-0.24 vs. 1.71+/-0.29, P<.05), but both ratios were significantly lower than control group (2.13+/-0.21, P<.05). With the change of the ratio, the left ventricle function was significantly improved (LVEF: pre-CABG vs. post-CABG: 35.7+/-12.9 vs. 45.6+/-17.2, P<.05). The ability of (31)P-MRS and cine-MRI to non-invasively assess changes of metabolism and function in myocardium may prove important for patient-specific optimization of treatment strategies.

Detecting Myocardial Ischemia at Rest with Cardiac Phase-Resolved BOLD CMR

Noninvasive imaging approaches that can rapidly assess an ongoing ischemia can be of great value in managing patients with clinically significant coronary artery disease. Although a number of imaging approaches exist for the identification of myocardial territories supplied by stenotic coronary arteries, generally all available imaging methods require provocative stress and/or exogenous contrast media. The most desirable imaging approach is one that can non-invasively and rapidly identify ischemic territories prior to the onset of tissue specific changes (development of edema or necrosis) and can permit the assessment of functional/volumetric status while minimizing patient discomfort. Previous studies have shown that ongoing ischemia may be detected with CMR (Cardiac Magnetic Resonance) on the basis of stress perfusion and changes in functional indices. More recently, it has been shown that myocardial edema may be utilized as a marker of ongoing ischemia using animal models 1 and patients 2. While the edema approach eliminates the need for provocative stress, both approaches require separate acquisitions for accurate assessment of functional indices. In this work, we propose and test a new CMR approach for a rapid assessment of myocardial ischemia. The proposed method is based on cardiac phase-resolved steady-state free precession (SSFP) magnetic resonance (MR) signal changes originating primarily from alterations in oxygenation (%HbO2) and secondarily from changes in regional myocardial blood volume (MBV) in the myocardial territory supplied by a stenotic artery. Since the proposed approach can generate functional and tissue specific indices in one acquisition, the proposed approach can provide opportunities to rapidly determine the presence and territory of myocardial ischemia. It is known that (a) MBV is a function of cardiac phase, increasing during diastole and decreasing during systole 3,4; and (b) MBV directly determines the oxygen extraction by cardiomyocytes 5. Thus, MBV and %HbO2 are expected to be different between systole and diastole. Hence, under normal (healthy) conditions, one expects the MBV and oxygen extraction to be maximal during diastole, and minimal in systole. In addition to these effects, as MBV increases, each unit volume of ventricle, i.e., each voxel in a myocardial image, contains a slightly higher proportion of blood, and a correspondingly smaller proportion of myocardial tissue 6. Thus, even at a stable level of %HbO2, the number of deoxygenated hemoglobin molecules within a voxel increases as MBV increases. Moreover, a number of studies have also shown that with increasing grade of coronary stenosis, MBV in the myocardial territory supplied by a stenotic artery increases in systole 7–9. Thus based on these studies, the relative MBV and %HbO2 changes between systole and diastole are expected to be different between myocardial territories supplied by healthy and stenotic coronary arteries. Cardiac phase-resolved BOLD SSFP CMR might provide a unique opportunity to capture these physiological changes and hence assess ongoing ischemia. It is known that T1 of myocardium is dependent on blood volume 10 and that T2 is dependent on blood oxygenation saturation 11. Since BOLD SSFP signals are approximately T2/T1 weighted 12,13, it may be possible to capture the changes in MBV 4 (via T1) and %HbO2 14 (via T2) in one acquisition. In particular, since coronary artery stenosis leads to an increased systolic MBV that is expected to be accompanied by decreases in %HbO2 (due to increased oxygen extraction), we hypothesized that the BOLD SSFP method can be used to detect the presence of coronary stenosis even at rest (i.e. without pharmacological stress). Under conditions of coronary stenosis, the physiological changes in basal MBV and %HbO2 are expected to work synergistically to enhance the SSFP-based detection capacity of myocardial territories supplied by stenotic arteries. In this work, we test these hypotheses using a canine animal model of severe coronary artery stenosis and computer/numerical simulations. In particular, we examine whether the systolic to diastolic myocardial SSFP signal intensity ratio (S/D) is greater than 1 in health and is diminished during ischemia. In addition, we investigate the effects of acute coronary occlusion on ejection fraction, wall thickening, and myocardial edema.Background— Fast noninvasive identification of ischemic territories at rest (before tissue-specific changes) and assessment of functional status can be valuable in the management of severe coronary artery disease. This study investigated the use of cardiac phase–resolved blood oxygen level–dependent (CP-BOLD) cardiovascular magnetic resonance in detecting myocardial ischemia at rest secondary to severe coronary artery stenosis. Methods and Results— CP-BOLD, standard cine, and T2-weighted images were acquired in canines (n=11) at baseline and within 20 minutes of ischemia induction (severe left anterior descending stenosis) at rest. After 3 hours of ischemia, left anterior descending stenosis was removed, and T2-weighted and late-gadolinium-enhancement images were acquired. From standard cine and CP-BOLD images, end-systolic and end-diastolic myocardium was segmented. Affected and remote sections of the myocardium were identified from postreperfusion late-gadolinium-enhancement images. Systolic-to-diastolic ratio (S/D), quotient of mean end-systolic and end-diastolic signal intensities (on CP-BOLD and standard cine), was computed for affected and remote segments at baseline and ischemia. Ejection fraction and segmental wall thickening were derived from CP-BOLD images at baseline and ischemia. On CP-BOLD images, S/D was >1 (remote and affected territories) at baseline; S/D was diminished only in affected territories during ischemia, and the findings were statistically significant (ANOVA, post hoc P<0.01). The dependence of S/D on ischemia was not observed in standard cine images. Computer simulations confirmed the experimental findings. Receiver-operating characteristic analysis showed that S/D identifies affected regions with performance (area under the curve, 0.87) similar to ejection fraction (area under the curve, 0.89) and segmental wall thickening (area under the curve, 0.75). Conclusions— Preclinical studies and computer simulations showed that CP-BOLD cardiovascular magnetic resonance could be useful in detecting myocardial ischemia at rest. Patient studies are needed for clinical translation.

Magnetic resonance imaging/magnetic resonance spectroscopy biomarkers evaluation of stunned myocardium in canine model.

Objectives:To evaluate whether dynamic alterations in high-energy phosphate (HEP) occur in postischemic “stunned” myocardium (SM) in canine model and to investigate the correlation between HEP and cardiac function, using cine magnetic resonance imaging (cine-MRI) and phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Materials and Methods:Dogs (n = 13) underwent cine MRI and 31P-MRS at 60 minutes, 8 days after 10 minutes full left anterior descending occlusion followed by reperfusion. The same MRI/MRS experiments were repeated on 5 reference animals (dogs without ischemic reperfusion) at the same time points to serve as internal reference myocardium (RM). After MR data acquisitions, the SM dogs (n = 3 at 60 minutes; n = 10 at 60 minutes and day 8) and RM dogs (n = 5) were euthanized and myocardial tissues were sampled for histologic study by triphenyltetrazolium chloride staining, hematoxylin and eosin staining, and electron microscopic examination. Results:The myocardial stunning at 60 minutes was confirmed by electron microscopy examinations from the 3 randomly chosen animals with SM. The phosphocreatine (PCr)/&bgr;- adenosine triphosphate (ATP) ratio of SM was significantly lower at 60 minutes than that at day 8 (1.07 ± 0.20 vs. 1.97 ± 0.28, P < 0.05). However, no significant difference was found between 60 minutes and day 8 in RM group (1.91 ± 0.14 at 60 minutes vs. 1.89 ± 0.16 at day 8, P > 0.05). At 60 minutes, the PCr/&bgr;-ATP ratio has significant difference between SM and RM groups; while at day 8, the ratio shows no significant difference between the 2 groups. The same results were obtained for left ventricle ejection fraction (LVEF). In SM group, LVEF has good correlation with myocardial PCr/&bgr;-ATP ratios at 60 minutes (R2 = 0.71, P < 0.05) and at day 8 (R2 = 0.73, P < 0.05), respectively. Conclusions:The HEP alterations were confirmed by 31P-MRS in SM and there is a good correlation between PCr/&bgr;-ATP ratio and LVEF for SM at 60 minutes and recovered myocardium at day 8. The combined MRS/MRI method offers the potential to systematically assess the cardiac function, morphology, and metabolism of SM. These MRS/MRI biomarker datasets could be used to dynamically monitor therapeutic efficiency and predict cardiac events.

Parametric dependence of myocardial blood oxygen level dependent, balanced steady-state free-precession imaging at 1.5 T: theory and experiments.

Myocardial blood oxygen level dependent, balanced steady‐state free precession (bSSFP) imaging is a relatively new technique for evaluating myocardial oxygenation changes in the presence of coronary artery stenosis. However, the dependence of myocardial bSSFP blood oxygen level dependent signal on imaging parameters has not been well studied. In this work, modeling capillaries as cylinders that act as magnetic perturbers, the Monte Carlo method was used to simulate spin relaxation via diffusion in a field variation inside and outside blood vessels. bSSFP signal changes at various levels of capillary blood oxygen saturation, for a range of pulse repetition times, flip angle, capillary blood volume fraction, vessel wall permeability, water diffusion coefficient, vessel angle to static magnetic field, and the impact of bulk frequency shifts were studied. The theoretical dependence of bSSFP blood oxygen level dependent contrast on pulse repetition times and flip angle was confirmed by experiments in an animal model with controllable coronary stenosis. Results showed that, with the standard bSSFP acquisition, optimum bSSFP blood oxygen level dependent contrast could be obtained at pulse repetition times = 6.0 ms and flip angle = 70°. Additional technical improvements that preserve the image quality may be necessary to further increase the myocardial bSSFP blood oxygen level dependent sensitivity at 1.5 T through even longer pulse repetition times. Magn Reson Med, 2010.