Allison G. Hays

Noninvasive visualization of coronary artery endothelial function in healthy subjects and in patients with coronary artery disease.

OBJECTIVES The goal was to test 2 hypotheses: first, that coronary endothelial function can be measured noninvasively and abnormal function detected using clinical 3.0-T magnetic resonance imaging (MRI); and second, that the extent of local coronary artery disease (CAD), in a given patient, is related to the degree of local abnormal coronary endothelial function. BACKGROUND Abnormal endothelial function mediates the initiation and progression of atherosclerosis and predicts cardiovascular events. However, direct measures of coronary endothelial function have required invasive assessment. METHODS The MRI was performed in 20 healthy adults and 17 patients with CAD. Cross-sectional coronary area and blood flow were quantified before and during isometric handgrip exercise, an endothelial-dependent stressor. In 10 severe, single-vessel CAD patients, paired endothelial function was measured in the artery with severe stenosis and the contralateral artery with minimal disease. RESULTS In healthy adults, coronary arteries dilated and flow increased with stress. In CAD patients, coronary artery area and blood flow decreased with stress (both p ≤ 0.02). In the paired study, coronary artery area and blood flow failed to increase during exercise in the mildly diseased vessel, but both area (p = 0.01) and blood flow (p = 0.02) decreased significantly in the severely diseased, contralateral artery. CONCLUSIONS Endothelial-dependent coronary artery dilation and increased blood flow in healthy subjects, and their absence in CAD patients, can now be directly visualized and quantified noninvasively. Local coronary endothelial function differs between severely and mildly diseased arteries in a given CAD patient. This novel, safe method may offer new insights regarding the importance of local coronary endothelial function and improved risk stratification in patients at risk for and with known CAD.

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.

Coronary Artery Distensibility Assessed by 3.0 Tesla Coronary Magnetic Resonance Imaging in Subjects With and Without Coronary Artery Disease

Coronary vessel distensibility is reduced with atherosclerosis and normal aging, but direct measurements have historically required invasive measurements at cardiac catheterization. Therefore, we sought to assess coronary artery distensibility noninvasively using 3.0 Telsa coronary magnetic resonance imaging (MRI) and to test the hypothesis that this noninvasive technique can detect differences in coronary distensibility between healthy subjects and those with coronary artery disease (CAD). A total of 38 healthy, adult subjects (23 men, mean age 31 ± 10 years) and 21 patients with CAD, diagnosed using x-ray angiography (11 men, mean age 57 ± 6 years) were studied using a commercial whole-body MRI system. In each subject, the proximal segment of a coronary artery was imaged for the cross-sectional area measurements using cine spiral MRI. The distensibility (mm Hg(-1) × 10(3)) was determined as (end-systolic lumen area - end-diastolic lumen area)/(pulse pressure × end-diastolic lumen area). The pulse pressure was calculated as the difference between the systolic and diastolic brachial blood pressure. A total of 34 healthy subjects and 19 patients had adequate image quality for coronary area measurements. Coronary artery distensibility was significantly greater in the healthy subjects than in those with CAD (mean ± SD 2.4 ± 1.7 mm Hg(-1) × 10(3) vs 1.1 ± 1.1 mm Hg(-1) × 10(3), respectively, p = 0.007; median 2.2 vs 0.9 mm Hg(-1) × 10(3)). In a subgroup of 10 patients with CAD, we found a significant correlation between the coronary artery distensibility measurements assessed using MRI and x-ray coronary angiography (R = 0.65, p = 0.003). In a group of 10 healthy subjects, the repeated distensibility measurements demonstrated a significant correlation (R = 0.80, p = 0.006). In conclusion, 3.0-Tesla MRI, a reproducible noninvasive method to assess human coronary artery vessel wall distensibility, is able to detect significant differences in distensibility between healthy subjects and those with CAD.

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.

Non-Invasive Detection of Coronary Endothelial Response to Sequential Handgrip Exercise in Coronary Artery Disease Patients and Healthy Adults

Objectives Our objective is to test the hypothesis that coronary endothelial function (CorEndoFx) does not change with repeated isometric handgrip (IHG) stress in CAD patients or healthy subjects. Background Coronary responses to endothelial-dependent stressors are important measures of vascular risk that can change in response to environmental stimuli or pharmacologic interventions. The evaluation of the effect of an acute intervention on endothelial response is only valid if the measurement does not change significantly in the short term under normal conditions. Using 3.0 Tesla (T) MRI, we non-invasively compared two coronary artery endothelial function measurements separated by a ten minute interval in healthy subjects and patients with coronary artery disease (CAD). Methods Twenty healthy adult subjects and 12 CAD patients were studied on a commercial 3.0 T whole-body MR imaging system. Coronary cross-sectional area (CSA), peak diastolic coronary flow velocity (PDFV) and blood-flow were quantified before and during continuous IHG stress, an endothelial-dependent stressor. The IHG exercise with imaging was repeated after a 10 minute recovery period. Results In healthy adults, coronary artery CSA changes and blood-flow increases did not differ between the first and second stresses (mean % change ±SEM, first vs. second stress CSA: 14.8%±3.3% vs. 17.8%±3.6%, p = 0.24; PDFV: 27.5%±4.9% vs. 24.2%±4.5%, p = 0.54; blood-flow: 44.3%±8.3 vs. 44.8%±8.1, p = 0.84). The coronary vasoreactive responses in the CAD patients also did not differ between the first and second stresses (mean % change ±SEM, first stress vs. second stress: CSA: −6.4%±2.0% vs. −5.0%±2.4%, p = 0.22; PDFV: −4.0%±4.6% vs. −4.2%±5.3%, p = 0.83; blood-flow: −9.7%±5.1% vs. −8.7%±6.3%, p = 0.38). Conclusion MRI measures of CorEndoFx are unchanged during repeated isometric handgrip exercise tests in CAD patients and healthy adults. These findings demonstrate the repeatability of noninvasive 3T MRI assessment of CorEndoFx and support its use in future studies designed to determine the effects of acute interventions on coronary vasoreactivity.

Clinical applications for cardiovascular magnetic resonance imaging at 3 Tesla

Cardiovascular magnetic resonance (CMR) imaging has evolved rapidly and is now accepted as a powerful diagnostic tool with significant clinical and research applications. Clinical 3 Tesla (3 T) scanners are increasingly available and offer improved diagnostic capabilities compared to 1.5 T scanners for perfusion, viability, and coronary imaging. Although technical challenges remain for cardiac imaging at higher field strengths such as balanced steady state free precession (bSSFP) cine imaging, the majority of cardiac applications are feasible at 3 T with comparable or superior image quality to that of 1.5 T. This review will focus on the benefits and limitations of 3 T CMR for common clinical applications and examine areas in development for potential clinical use.

Eosinophil-derived IL-4 drives progression of myocarditis to inflammatory dilated cardiomyopathy

Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in children and young adults. DCMi develops in up to 30% of myocarditis patients, but the mechanisms involved in disease progression are poorly understood. Patients with eosinophilia frequently develop cardiomyopathies. In this study, we used the experimental autoimmune myocarditis (EAM) model to determine the role of eosinophils in myocarditis and DCMi. Eosinophils were dispensable for myocarditis induction but were required for progression to DCMi. Eosinophil-deficient &Dgr;dblGATA1 mice, in contrast to WT mice, showed no signs of heart failure by echocardiography. Induction of EAM in hypereosinophilic IL-5Tg mice resulted in eosinophilic myocarditis with severe ventricular and atrial inflammation, which progressed to severe DCMi. This was not a direct effect of IL-5, as IL-5Tg&Dgr;dblGATA1 mice were protected from DCMi, whereas IL-5−/− mice exhibited DCMi comparable with WT mice. Eosinophils drove progression to DCMi through their production of IL-4. Our experiments showed eosinophils were the major IL-4–expressing cell type in the heart during EAM, IL-4−/− mice were protected from DCMi like &Dgr;dblGATA1 mice, and eosinophil-specific IL-4 deletion resulted in improved heart function. In conclusion, eosinophils drive progression of myocarditis to DCMi, cause severe DCMi when present in large numbers, and mediate this process through IL-4.

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.

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. Magn Reson Med, 2013.