Precision and accuracy of cross-sectional area measurements used to measure coronary endothelial function with spiral MRI.

PURPOSE: Coronary endothelial function (CEF) reflects vascular health and conventional invasive CEF measures predict cardiovascular events. MRI can now noninvasively measure CEF by quantifying coronary artery cross-sectional area changes in response to isometric handgrip exercise, an endothelial-dependent stressor. Area changes (10 to 20% in healthy; 2 to -12% in impaired vessels) are only a few imaging voxels because of MRI's limited spatial resolution. Here, with numerical simulations and phantom studies, we test whether Fourier interpolation enables sub-pixel area measurement precision and determine the smallest detectable area change using spiral MRI. METHODS: In vivo coronary SNR with the currently used CEF protocol at 3T was measured in 7 subjects for subsequent in vitro work. Area measurements of circular vessels were simulated by varying partial volume, vessel diameter, voxel size, SNR, and Fourier interpolation factor. A phantom with precision-drilled holes (diameters 3-3.42 mm) was imaged 10 times with the current CEF protocol (voxel size, Δx = 0.89 mm) and a high-resolution protocol (Δx = 0.6 mm) to determine precision, accuracy, and the smallest detectable area changes. RESULTS: In vivo coronary SNR ranged from 30-76. Eight-fold Fourier interpolation improved area measurement precision by a factor 6.5 and 4.9 in the simulations and phantom scans, respectively. The current CEF protocol can detect mean area changes of 4-5% for SNR above 30, and 3-3.5% for SNR above 40 with a higher-resolution protocol. CONCLUSION: Current CEF spiral MRI with in vivo SNR allows detection of a 4-5% area change and Fourier interpolation improves precision several-fold to sub-voxel dimensions.

Regional coronary endothelial dysfunction is related to the degree of local epicardial fat in people with HIV.

BACKGROUND AND AIMS: Coronary artery disease (CAD) is now an important cause of premature death in people with HIV but the causes of accelerated CAD are poorly understood. Epicardial adipose tissue (EAT) is metabolically-active and thought to contribute to CAD development. We tested the hypothesis that abnormal coronary endothelial function (CEF), an early marker and mediator of atherosclerosis, is related to the amount of local pericoronary EAT in HIV. METHODS: We studied 36 participants with HIV and no CAD (HIV+ CAD-), 15 participants with HIV and known CAD (HIV+ CAD+), and 14 age-matched, healthy participants without HIV (HIV-CAD-). To measure CEF, coronary MRI was performed before and during isometric handgrip exercise (IHE), an endothelial-dependent stressor. EAT was measured with MRI at the same imaging plane as CEF. RESULTS: CEF was significantly depressed, as measured by IHE-induced % coronary cross sectional area (CSA) change, in HIV+ CAD- and HIV+ CAD+ as compared to HIV-CAD-participants (p<0.0001). EAT thickness was significantly greater in HIV+ CAD- and HIV+ CAD+ participants as compared to HIV-CAD-participants (p=0.001). There was a significant inverse relationship between CEF and local EAT thickness and area (R = -0.48 and R = -0.51 respectively, p<0.0001 for both) among participants with HIV even after adjustment for cardiovascular risk factors. In participants with multiple CEF measures, CEF was lower in segments with higher EAT, other factors being equivalent. CONCLUSIONS: There is a significant relationship between increased metabolically-active EAT and depressed local CEF in people with HIV, consistent with the hypothesis that increased epicardial fat contributes to accelerated CAD in persons with HIV.

Coronary artery endothelial dysfunction is present in HIV-positive individuals without significant coronary artery disease.

OBJECTIVE: HIV-positive (HIV+) individuals experience an increased burden of coronary artery disease (CAD) not adequately accounted for by traditional CAD risk factors. Coronary endothelial function (CEF), a barometer of vascular health, is depressed early in atherosclerosis and predict future events but has not been studied in HIV+ individuals. We tested whether CEF is impaired in HIV+ patients without CAD as compared with an HIV-negative (HIV-) population matched for cardiac risk factors. DESIGN/METHODS: In this observational study, CEF was measured noninvasively by quantifying isometric handgrip exercise-induced changes in coronary vasoreactivity with MRI in 18 participants with HIV but no CAD (HIV+CAD-, based on prior imaging), 36 age-matched and cardiac risk factor-matched healthy participants with neither HIV nor CAD (HIV-CAD-), 41 patients with no HIV but with known CAD (HIV-CAD+), and 17 patients with both HIV and CAD (HIV+CAD+). RESULTS: CEF was significantly depressed in HIV+CAD- patients as compared with that of risk-factor-matched HIV-CAD- patients (P < 0.0001) and was depressed to the level of that in HIV- participants with established CAD. Mean IL-6 levels were higher in HIV+ participants (P < 0.0001) and inversely related to CEF in the HIV+ patients (P = 0.007). CONCLUSION: Marked coronary endothelial dysfunction is present in HIV+ patients without significant CAD and is as severe as that in clinical CAD patients. Furthermore, endothelial dysfunction appears inversely related to the degree of inflammation in HIV+ patients as measured by IL-6. CEF testing in HIV+ patients may be useful for assessing cardiovascular risk and testing new CAD treatment strategies, including those targeting inflammation.

Simultaneous Noninvasive Assessment of Systemic and Coronary Endothelial Function.

BACKGROUND: Normal endothelial function is a measure of vascular health and dysfunction is a predictor of coronary events. Nitric oxide-mediated coronary artery endothelial function, as assessed by vasomotor reactivity during isometric handgrip exercise (IHE), was recently quantified noninvasively with magnetic resonance imaging (MRI). Because the internal mammary artery (IMA) is often visualized during coronary MRI, we propose the strategy of simultaneously assessing systemic and coronary endothelial function noninvasively by MRI during IHE. METHODS AND RESULTS: Changes in cross-sectional area and blood flow in the right coronary artery and the IMA in 25 patients with coronary artery disease and 26 healthy subjects during IHE were assessed using 3T MRI. In 8 healthy subjects, a nitric oxide synthase inhibitor was infused to evaluate the role of nitric oxide in the IMA-IHE response. Interobserver IMA-IHE reproducibility was good for cross-sectional area (R=0.91) and blood flow (R=0.91). In healthy subjects, cross-sectional area and blood flow of the IMA increased during IHE, and these responses were significantly attenuated by monomethyl-l-arginine (P<0.01 versus placebo). In patients with coronary artery disease, the right coronary artery did not dilate with IHE, and dilation of the IMA was less than that of the healthy subjects (P=0.01). The blood flow responses of both the right coronary artery and IMA to IHE were also significantly reduced in patients with coronary artery disease. CONCLUSIONS: MRI-detected IMA responses to IHE primarily reflect nitric oxide-dependent endothelial function and are reproducible and reduced in patients with coronary artery disease. Endothelial function in both coronary and systemic (IMA) arteries can now be measured noninvasively with the same imaging technique and promises novel insights into systemic and local factors affecting vascular health.

Coronary vasomotor responses to isometric handgrip exercise are primarily mediated by nitric oxide: a noninvasive MRI test of coronary endothelial function.

Endothelial cell release of nitric oxide (NO) is a defining characteristic of nondiseased arteries, and abnormal endothelial NO release is both a marker of early atherosclerosis and a predictor of its progression and future events. Healthy coronaries respond to endothelial-dependent stressors with vasodilatation and increased coronary blood flow (CBF), but those with endothelial dysfunction respond with paradoxical vasoconstriction and reduced CBF. Recently, coronary MRI and isometric handgrip exercise (IHE) were reported to noninvasively quantify coronary endothelial function (CEF). However, it is not known whether the coronary response to IHE is actually mediated by NO and/or whether it is reproducible over weeks. To determine the contribution of NO, we studied the coronary response to IHE before and during infusion of N(G)-monomethyl-l-arginine (l-NMMA, 0.3 mg·kg(-1)·min(-1)), a NO-synthase inhibitor, in healthy volunteers. For reproducibility, we performed two MRI-IHE studies ~8 wk apart in healthy subjects and patients with coronary artery disease (CAD). Changes from rest to IHE in coronary cross-sectional area (%CSA) and diastolic CBF (%CBF) were quantified. l-NMMA completely blocked normal coronary vasodilation during IHE [%CSA, 12.9 ± 2.5 (mean ± SE, placebo) vs. -0.3 ± 1.6% (l-NMMA); P < 0.001] and significantly blunted the increase in flow [%CBF, 47.7 ± 6.4 (placebo) vs. 10.6 ± 4.6% (l-NMMA); P < 0.001]. MRI-IHE measures obtained weeks apart strongly correlated for CSA (P < 0.0001) and CBF (P < 0.01). In conclusion, the normal human coronary vasoactive response to IHE is primarily mediated by NO. This noninvasive, reproducible MRI-IHE exam of NO-mediated CEF promises to be useful for studying CAD pathogenesis in low-risk populations and for evaluating translational strategies designed to alter CAD in patients.

Robust volume-targeted balanced steady-state free-precession coronary magnetic resonance angiography in a breathhold at 3.0 Tesla: a reproducibility study.

BACKGROUND: Transient balanced steady-state free-precession (bSSFP) has shown substantial promise for noninvasive assessment of coronary arteries but its utilization at 3.0 T and above has been hampered by susceptibility to field inhomogeneities that degrade image quality. The purpose of this work was to refine, implement, and test a robust, practical single-breathhold bSSFP coronary MRA sequence at 3.0 T and to test the reproducibility of the technique. METHODS: A 3D, volume-targeted, high-resolution bSSFP sequence was implemented. Localized image-based shimming was performed to minimize inhomogeneities of both the static magnetic field and the radio frequency excitation field. Fifteen healthy volunteers and three patients with coronary artery disease underwent examination with the bSSFP sequence (scan time = 20.5 ± 2.0 seconds), and acquisitions were repeated in nine subjects. The images were quantitatively analyzed using a semi-automated software tool, and the repeatability and reproducibility of measurements were determined using regression analysis and intra-class correlation coefficient (ICC), in a blinded manner. RESULTS: The 3D bSSFP sequence provided uniform, high-quality depiction of coronary arteries (n = 20). The average visible vessel length of 100.5 ± 6.3 mm and sharpness of 55 ± 2% compared favorably with earlier reported navigator-gated bSSFP and gradient echo sequences at 3.0 T. Length measurements demonstrated a highly statistically significant degree of inter-observer (r = 0.994, ICC = 0.993), intra-observer (r = 0.894, ICC = 0.896), and inter-scan concordance (r = 0.980, ICC = 0.974). Furthermore, ICC values demonstrated excellent intra-observer, inter-observer, and inter-scan agreement for vessel diameter measurements (ICC = 0.987, 0.976, and 0.961, respectively), and vessel sharpness values (ICC = 0.989, 0.938, and 0.904, respectively). CONCLUSIONS: The 3D bSSFP acquisition, using a state-of-the-art MR scanner equipped with recently available technologies such as multi-transmit, 32-channel cardiac coil, and localized B0 and B1+ shimming, allows accelerated and reproducible multi-segment assessment of the major coronary arteries at 3.0 T in a single breathhold. This rapid sequence may be especially useful for functional imaging of the coronaries where the acquisition time is limited by the stress duration and in cases where low navigator-gating efficiency prohibits acquisition of a free breathing scan in a reasonable time period.

Spatially selective implementation of the adiabatic T2Prep sequence for magnetic resonance angiography of the coronary arteries.

In coronary magnetic resonance angiography, a magnetization-preparation scheme for T2-weighting (T2Prep) is widely used to enhance contrast between the coronary blood-pool and the myocardium. This prepulse is commonly applied without spatial selection to minimize flow sensitivity, but the nonselective implementation results in a reduced magnetization of the in-flowing blood and a related penalty in signal-to-noise ratio. It is hypothesized that a spatially selective T2Prep would leave the magnetization of blood outside the T2Prep volume unaffected and thereby lower the signal-to-noise ratio penalty. To test this hypothesis, a spatially selective T2Prep was implemented where the user could freely adjust angulation and position of the T2Prep slab to avoid covering the ventricular blood-pool and saturating the in-flowing spins. A time gap of 150 ms was further added between the T2Prep and other prepulses to allow for in-flow of a larger volume of unsaturated spins. Consistent with numerical simulation, the spatially selective T2Prep increased in vivo human coronary artery signal-to-noise ratio (42.3 ± 2.9 vs. 31.4 ± 2.2, n = 22, P < 0.0001) and contrast-to-noise-ratio (18.6 ± 1.5 vs. 13.9 ± 1.2, P = 0.009) as compared to those of the nonselective T2Prep. Additionally, a segmental analysis demonstrated that the spatially selective T2Prep was most beneficial in proximal and mid segments where the in-flowing blood volume was largest compared to the distal segments.

Three-dimensional regional strain analysis in porcine myocardial infarction: a 3T magnetic resonance tagging study.

BACKGROUND: Previous studies of mechanical strain anomalies in myocardial infarction (MI) have been largely limited to analysis of one-dimensional (1D) and two-dimensional (2D) strain parameters. Advances in cardiovascular magnetic resonance (CMR) methods now permit a complete three-dimensional (3D) interrogation of myocardial regional strain. The aim of this study was to investigate the incremental value of CMR-based 3D strain and to test the hypothesis that 3D strain is superior to 1D or 2D strain analysis in the assessment of viability using a porcine model of infarction. METHODS: Infarction was induced surgically in 20 farm pigs. Cine, late gadolinium enhancement, and CMR tagging images were acquired at 11 days before (baseline), and 11 days (early) and 1 month (late) after induction of infarct. Harmonic phase analysis was performed to measure circumferential, longitudinal, and radial strains in myocardial segments, which were defined based on the transmurality of delayed enhancement. Univariate, bivariate, and multivariate logistic regression models of strain parameters were created and analyzed to compare the overall diagnostic accuracy of 3D strain analysis with 1D and 2D analyses in identifying the infarct and its adjacent regions from healthy myocardium. RESULTS: 3D strain differed significantly in infarct, adjacent, and remote segments (p<0.05) at early and late post-MI. In univariate, bivariate, and multivariate analyses, circumferential, longitudinal, and radial strains were significant factors (p<0.001) in differentiation of infarct and adjacent segments from baseline values. In identification of adjacent segments, receiver operating characteristic analysis using the 3D strain multivariate model demonstrated a significant improvement (p<0.01) in overall diagnostic accuracy in comparison with 2D (circumferential and radial) and 1D (circumferential) models (3D: 96%, 2D: 81%, and 1D: 71%). A similar trend was observed in identification of infarct segments. CONCLUSIONS: Cumulative 3D strain information accurately identifies infarcts and their neighboring regions from healthy myocardium. The 3D interrogation of myocardial contractility provides incremental diagnostic accuracy in delineating the dysfunctional and nonviable myocardium in comparison with 1D or 2D quantification of strain. The infarct neighboring regions are the major beneficiaries of the 3D assessment of regional strain.

VESSEL CENTERLINE TRACKING AND BOUNDARY SEGMENTATION IN CORONARY MRA WITH MINIMAL MANUAL INTERACTION.

Magnetic resonance angiography (MRA) provides a noninvasive means to detect the presence, location and severity of atherosclerosis throughout the vascular system. In such studies, and especially those in the coronary arteries, the vessel luminal area is typically measured at multiple cross-sectional locations along the course of the artery. The advent of fast volumetric imaging techniques covering proximal to mid segments of coronary arteries necessitates automatic analysis tools requiring minimal manual interactions to robustly measure cross-sectional area along the three-dimensional track of the arteries in under-sampled and non-isotropic datasets. In this work, we present a modular approach based on level set methods to track the vessel centerline, segment the vessel boundaries, and measure transversal area using two user-selected endpoints in each coronary of interest. Arterial area and vessel length are measured using our method and compared to the standard Soap-Bubble reformatting and analysis tool in in-vivo non-contrast enhanced coronary MRA images.

Regional coronary endothelial function is closely related to local early coronary atherosclerosis in patients with mild coronary artery disease: pilot study.

BACKGROUND: Coronary endothelial function is abnormal in patients with established coronary artery disease and was recently shown by MRI to relate to the severity of luminal stenosis. Recent advances in MRI now allow the noninvasive assessment of both anatomic and functional (endothelial function) changes that previously required invasive studies. We tested the hypothesis that abnormal coronary endothelial function is related to measures of early atherosclerosis such as increased coronary wall thickness. METHODS AND RESULTS: Seventeen arteries in 14 healthy adults and 17 arteries in 14 patients with nonobstructive coronary artery disease were studied. To measure endothelial function, coronary MRI was performed before and during isometric handgrip exercise, an endothelial-dependent stressor, and changes in coronary cross-sectional area and flow were measured. Black blood imaging was performed to quantify coronary wall thickness and indices of arterial remodeling. The mean stress-induced change in cross-sectional area was significantly higher in healthy adults (13.5%±12.8%, mean±SD, n=17) than in those with mildly diseased arteries (-2.2%±6.8%, P<0.0001, n=17). Mean coronary wall thickness was lower in healthy subjects (0.9±0.2 mm) than in patients with coronary artery disease (1.4±0.3 mm, P<0.0001). In contrast to healthy subjects, stress-induced changes in cross-sectional area, a measure of coronary endothelial function, correlated inversely with coronary wall thickness in patients with coronary artery disease (r=-0.73, P=0.0008). CONCLUSIONS: There is an inverse relationship between coronary endothelial function and local coronary wall thickness in patients with coronary artery disease but not in healthy adults. These findings demonstrate that local endothelial-dependent functional changes are related to the extent of early anatomic atherosclerosis in mildly diseased arteries. This combined MRI approach enables the anatomic and functional investigation of early coronary disease.

Assessment of distribution and evolution of mechanical dyssynchrony in a porcine model of myocardial infarction by cardiovascular magnetic resonance.

BACKGROUND: We sought to investigate the relationship between infarct and dyssynchrony post- myocardial infarct (MI), in a porcine model. Mechanical dyssynchrony post-MI is associated with left ventricular (LV) remodeling and increased mortality. METHODS: Cine, gadolinium-contrast, and tagged cardiovascular magnetic resonance (CMR) were performed pre-MI, 9 ± 2 days (early post-MI), and 33 ± 10 days (late post-MI) post-MI in 6 pigs to characterize cardiac morphology, location and extent of MI, and regional mechanics. LV mechanics were assessed by circumferential strain (eC). Electro-anatomic mapping (EAM) was performed within 24 hrs of CMR and prior to sacrifice. RESULTS: Mean infarct size was 21 ± 4% of LV volume with evidence of post-MI remodeling. Global eC significantly decreased post MI (-27 ± 1.6% vs. -18 ± 2.5% (early) and -17 ± 2.7% (late), p < 0.0001) with no significant change in peri-MI and MI segments between early and late time-points. Time to peak strain (TTP) was significantly longer in MI, compared to normal and peri-MI segments, both early (440 ± 40 ms vs. 329 ± 40 ms and 332 ± 36 ms, respectively; p = 0.0002) and late post-MI (442 ± 63 ms vs. 321 ± 40 ms and 355 ± 61 ms, respectively; p = 0.012). The standard deviation of TTP in 16 segments (SD16) significantly increased post-MI: 28 ± 7 ms to 50 ± 10 ms (early, p = 0.012) to 54 ± 19 ms (late, p = 0.004), with no change between early and late post-MI time-points (p = 0.56). TTP was not related to reduction of segmental contractility. EAM revealed late electrical activation and greatly diminished conduction velocity in the infarct (5.7 ± 2.4 cm/s), when compared to peri-infarct (18.7 ± 10.3 cm/s) and remote myocardium (39 ± 20.5 cm/s). CONCLUSIONS: Mechanical dyssynchrony occurs early after MI and is the result of delayed electrical and mechanical activation in the infarct.

Statistical Fusion of Continuous Labels: Identification of Cardiac Landmarks.

Image labeling is an essential task for evaluating and analyzing morphometric features in medical imaging data. Labels can be obtained by either human interaction or automated segmentation algorithms. However, both approaches for labeling suffer from inevitable error due to noise and artifact in the acquired data. The Simultaneous Truth And Performance Level Estimation (STAPLE) algorithm was developed to combine multiple rater decisions and simultaneously estimate unobserved true labels as well as each rater's level of performance (i.e., reliability). A generalization of STAPLE for the case of continuous-valued labels has also been proposed. In this paper, we first show that with the proposed Gaussian distribution assumption, this continuous STAPLE formulation yields equivalent likelihoods for the bias parameter, meaning that the bias parameter-one of the key performance indices-is actually indeterminate. We resolve this ambiguity by augmenting the STAPLE expectation maximization formulation to include a priori probabilities on the performance level parameters, which enables simultaneous, meaningful estimation of both the rater bias and variance performance measures. We evaluate and demonstrate the efficacy of this approach in simulations and also through a human rater experiment involving the identification the intersection points of the right ventricle to the left ventricle in CINE cardiac data.

IDENTIFICATION OF MYOCARDIAL INFARCTION USING THREE-DIMENSIONAL STRAIN TENSOR FRACTIONAL ANISOTROPY.

Accurate localization of myocardial viability is important in diagnosis of infarction. Regional strain function provides excessive information for clinical decision making but comparison of strain tensor profiles across differing tissue types is usually difficult due to multivariate nature of tensors. It is desirable to describe tensors with simplified scalar indices which are more mathematically and statistically intuitive. In this work, anisotropy of tensors in healthy and experimental infarct regions in a large animal model is assessed and compared to directional components of strain tensors which are currently the most popular indices in active use. Myocardial strain tensors are computed using zHARP, a magnetic resonance (MR) tagging technique that provides quantification of cardiac function with direct computation of three-dimensional tensors from two-dimensional short axis MR images. Fractional anisotropy of strain tensors shows high correlation with late gadolinium enhanced images and is capable of discrimination between healthy and infarcted regions.