Glenn A. Hirsch

Quantitative myocardial infarction on delayed enhancement MRI. Part I: Animal validation of an automated feature analysis and combined thresholding infarct sizing algorithm

To develop a computer algorithm to measure myocardial infarct size in gadolinium‐enhanced magnetic resonance (MR) imaging and to validate this method using a canine histopathological reference.

Preliminary investigation of respiratory self-gating for free-breathing segmented cine MRI.

Segmented cine MRI generally requires breath‐holding, which can be problematic for many patients. Navigator echo techniques, particularly successful for free‐breathing coronary MRA, are incompatible with the acquisition strategies and SSFP pulse sequences commonly used for cine MRI. The purpose of this work is to introduce a new self‐gating technique deriving respiratory gating information directly from the raw imaging data acquired for segmented cine MRI. The respiratory self‐gating technique uses interleaved radial k‐space sampling to provide low‐resolution images in real time during the free‐breathing acquisition that are compared to target expiration images. Only the raw data‐producing images with high correlation to the target images are included in the final high‐resolution reconstruction. The self‐gating technique produced cine series with no significant differences in quantitative image sharpness to series produced using comparable breath‐held techniques. Because of the difficulties associated with breath‐holding, the respiratory self‐gating technique represents an important practical advance for cardiac MRI. Magn Reson Med 53:159–168, 2005. Published 2004 Wiley‐Liss, Inc.

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

OBJECTIVESnThe 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.nnnBACKGROUNDnAbnormal endothelial function mediates the initiation and progression of atherosclerosis and predicts cardiovascular events. However, direct measures of coronary endothelial function have required invasive assessment.nnnMETHODSnThe 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.nnnRESULTSnIn 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.nnnCONCLUSIONSnEndothelial-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.

Rapid-onset endothelial dysfunction with adriamycin: evidence for a dysfunctional nitric oxide synthase

Adriamycin (ADR) is a commonly used chemotherapeutic agent that is believed to exert its effects through the generation of oxygen free radicals. We hypothesized that administration of a single dose of ADR results in endothelial nitric oxide synthase (eNOS)-dependent generation of superoxide (O2 ·-) and acute endothelial dysfunction. A single dose of ADR (10 mg/kg i.v.) administered to rabbits resulted in rapid attenuation of agonist-dependent responses to acetylcholine and calcium ionophore (A23187). In vitro exposure of ring segments to ADR for <30 min resulted in O2 ·- generation measured by electron spin resonance (ESR) with the spin trap segments 5-tert-butoxycarbonyl-5-methyl-1-pyrroline N-oxide (BMPO) that was abolished by endothelial denudation and incubation with diphenyliodonium (DPI) (10 mM) but not L-NMMA (10 mM). Brachial artery flow-mediated dilation (FMD) in patients undergoing chemotherapy with ADR was markedly attenuated after a single dose of ADR (6.5 6 1.0 to 2.5 6 1.1% (p = 0.0004, time to end of infusion 27 6 8 min) while endothelial-independent dilatation with nitroglycerin was unchanged (16.3 6 3.1 and 14.33 6 2.1% respectively, p = 0.36). Serum nitrite and nitrate concentrations fell from 50 6 6 mmol/l pre-ADR to 33 6 6 mmol/l post-ADR infusion (p = 0.0005) while serum concentrations of CD141 thrombomodulin and von Wille-brand factor (vWF) activity remained unchanged after ADR infusion (36 6 13 to 52 6 22% ng/ml versus 3.25 6 0.98 to 3.01 6 0.91%, respectively, p = NS for pre versus post for both). Doppler indices of diastolic function (IVRT, DT and E/A ratios) were not altered in response to ADR. In conclusion, ADR administration results in rapid depletion of systemic NO· levels and attenuation of agonist-dependent responses in rabbits and flow-mediated dilation in the brachial artery of humans. ESR measurements in rabbit ring suggest an endothelial origin for radical production via flavin-containing oxido-reductases such as eNOS or NADPH cytochrome P450 reductase. These fi ndings may have implications for cardiovascular complications noted with ADR.

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.

Polymorphisms of the Beta Adrenergic Receptor Predict Left Ventricular Remodeling Following Acute Myocardial Infarction

PurposePrior studies demonstrate an association between specific beta-adrenergic receptor (β-AR) polymorphisms and clinical outcomes in patients with chronic heart failure and following acute coronary syndromes. The underlying mechanism may be due to differences in left ventricular remodeling. This study was undertaken to explore the relationship between LV remodeling after myocardial infarction and polymorphisms in the cardiac β1-AR and β2-AR genes.MethodsAfter first ST-segment elevation myocardial infarction (STEMI), 122 patients on chronic β1 receptor antagonist therapy underwent baseline and 6-month LV volume evaluation. We assessed the relationships between changes in LV volumes and the polymorphisms in β1-AR, β1-Arg389Gly and β1-Ser49Gly, and in β2-AR, β2-Gly16Arg and β2-Gln27Glu.ResultsWe found that patients homozygous for the β2-Glu27 variant were 5.2 times more likely to be in the group with the highest end systolic volume (ESV) progression (OR 5.2, 95%CI 1.4–19.0). They were also more likely to have the largest progression of end diastolic volume (EDV) and decrease in LV ejection fraction (LVEF). For those with baseline LV dysfunction, being homozygous for Arg at amino acid position 389 in β1-AR was associated with decreases in ESV (−46xa0mL, CI −3.1, -88) and EDV (−40xa0mL, CI −1.1, −79) and an increase in LVEF (11%, CI 0.3, 22).ConclusionWe found that polymorphisms of the β1-AR and β2-AR genes are associated with differential LV remodeling in patients treated with a β1 receptor antagonist following STEMI.

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%, pu200a=u200a0.24; PDFV: 27.5%±4.9% vs. 24.2%±4.5%, pu200a=u200a0.54; blood-flow: 44.3%±8.3 vs. 44.8%±8.1, pu200a=u200a0.84). 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%, pu200a=u200a0.22; PDFV: −4.0%±4.6% vs. −4.2%±5.3%, pu200a=u200a0.83; blood-flow: −9.7%±5.1% vs. −8.7%±6.3%, pu200a=u200a0.38). 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.

Usefulness of Non-High-Density Lipoprotein Cholesterol Determinations in the Diagnosis and Treatment of Dyslipidemia

N lipoprotein (non-HDL) cholesterol, calculated as total cholesterol minus highdensity lipoprotein (HDL) cholesterol, encompasses the apolipoprotein B (Apo B)–containing particles that promote atherosclerosis, including low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol, lipoprotein (a), and intermediate-density lipoprotein cholesterol; therefore, it may represent an accurate marker for coronary heart disease (CHD) risk. The Adult Treatment Panel (ATP) III guidelines have introduced non-HDL cholesterol as a secondary target of therapy for patients with elevated levels of triglycerides.1 The aim of this review was to compare LDL and non-HDL cholesterol as markers of atherosclerotic disease and to discuss treatment options for reducing non-HDL cholesterol.

Gadolinium Enhanced MR Coronary Vessel Wall Imaging at 3.0 Tesla

Purpose. We evaluated the influence of the time between low-dose gadolinium (Gd) contrast administration and coronary vessel wall enhancement (LGE) detected by 3T magnetic resonance imaging (MRI) in healthy subjects and patients with coronary artery disease (CAD). Materials and Methods. Four healthy subjects (4 men, mean age 29 ± 3 years and eleven CAD patients (6 women, mean age 61 ± 10 years) were studied on a commercial 3.0 Tesla (T) whole-body MR imaging system (Achieva 3.0 T; Philips, Best, The Netherlands). T1-weighted inversion-recovery coronary magnetic resonance imaging (MRI) was repeated up to 75 minutes after administration of low-dose Gadolinium (Gd) (0.1u2009mmol/kg Gd-DTPA). Results. LGE was seen in none of the healthy subjects, however in all of the CAD patients. In CAD patients, fifty-six of 62 (90.3%) segments showed LGE of the coronary artery vessel wall at time-interval 1 after contrast. At time-interval 2, 34 of 42 (81.0%) and at time-interval 3, 29 of 39 evaluable segments (74.4%) were enhanced. Conclusion. In this work, we demonstrate LGE of the coronary artery vessel wall using 3.0 T MRI after a single, low-dose Gd contrast injection in CAD patients but not in healthy subjects. In the majority of the evaluated coronary segments in CAD patients, LGE of the coronary vessel wall was already detectable 30–45 minutes after administration of the contrast agent.