Targeted Knockdown of Hepatic SOAT2 With Antisense Oligonucleotides Stabilizes Atherosclerotic Plaque in ApoB100-only LDLr-/- Mice.

OBJECTIVE: To test the hypothesis that the attenuation of cholesterol oleate packaging into apoB-containing lipoproteins will arrest progression of pre-existing atherosclerotic lesions. APPROACH AND RESULTS: Atherosclerosis was induced in apoB-100 only, LDLr(-/-) mice by feeding a diet enriched in cis-monounsaturated fatty acids for 24 weeks. A subset of mice was then euthanized to quantify the extent of atherosclerosis. The remaining mice were continued on the same diet (controls) or assigned to the following treatments for 16 weeks: (1) a diet enriched in n-3 polyunsaturated fatty acids, (2) the cis-monounsaturated fatty acid diet plus biweekly injections of an antisense oligonucleotide specific to hepatic sterol-O-acyltransferase 2 (SOAT2); or (3) the cis-monounsaturated fatty acid diet and biweekly injections of a nontargeting hepatic antisense oligonucleotide. Extent of atherosclerotic lesions in the aorta was monitored morphometrically in vivo with magnetic resonance imaging and ex vivo histologically and immunochemically. Hepatic knockdown of SOAT2 via antisense oligonucleotide treatment arrested lesion growth and stabilized lesions. CONCLUSIONS: Hepatic knockdown of SOAT2 in apoB100-only, LDLr(-/-) mice resulted in remodeling of aortic atherosclerotic lesions into a stable phenotype, suggesting SOAT2 is a viable target for the treatment of atherosclerosis.

Adverse effect of increased left ventricular wall thickness on five year outcomes of patients with negative dobutamine stress.

BACKGROUND: To determine if patients without dobutamine induced left ventricular wall motion abnormalities (WMA) but an increased LV end-diastolic wall thickness (EDWT) exhibit a favorable cardiac prognosis. RESULTS: Between 1999 and 2001, 175 patients underwent a dobutamine stress cardiovascular magnetic resonance (DCMR) procedure utilizing gradient-echo cines. Participants had a LV ejection fraction >55% without evidence of an inducible WMA during peak dobutamine/atropine stress. After an average of 5.5 years, all participants were contacted and medical records were reviewed to determine the post-DCMR occurrence of cardiac death, myocardial infarction (MI), and unstable angina (USA) or congestive heart failure (CHF) warranting hospitalization.In a multivariate analysis, that took into account Framingham and other risk factors associated with cardiac events, a cine gradient-echo derived LV EDWT > or =12 mm was associated independently with an increase in cardiac death and MI (HR 6.0, p = 0.0016), and the combined end point of MI, cardiac death, and USA or CHF warranting hospitalization (HR 3.0, p = 0.0005). CONCLUSION: Similar to echocardiography, CMR measures of increased LV wall thickness should be considered a risk factor for cardiac events in individuals receiving negative reports of inducible ischemia after dobutamine stress. Additional prognostic studies of the importance of LV wall thickness and mass measured with steady-state free precession techniques are warranted.

Location of arterial stiffening differs in those with impaired fasting glucose versus diabetes: implications for left ventricular hypertrophy from the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: To determine whether middle-aged and older individuals with impaired fasting glucose (IFG), but no clinical evidence of cardiovascular disease, exhibit abnormal changes in proximal thoracic aortic stiffness or left ventricular (LV) mass when compared with healthy counterparts. RESEARCH DESIGN AND METHODS: From the Multi-Ethnic Study of Atherosclerosis, 2,240 subjects with normal fasting glucose (NFG), 845 with IFG, and 414 with diabetes, all aged 45 to 85 years and without preexisting coronary artery disease, underwent MRI determinations of total arterial and proximal thoracic aortic stiffness and LV mass. The presence or absence of other factors known to influence arterial stiffness was assessed. RESULTS: After adjustment for clinical factors known to modify arterial stiffness, proximal thoracic aortic stiffness was not increased in those with IFG compared with those with NFG (1.90 +/- 0.05 versus 1.91 +/- 0.04 10(-3) mmHg(-1), respectively, P = 0.83). After accounting for clinical factors known to influence LV mass, LV mass was increased in those with diabetes relative to those with NFG (150.6 +/- 1.4 versus 145.8 +/- 0.81 g, P < 0.0009) but not in those with IFG in comparison with NFG (145.2 +/- 1.03 versus 145.8 +/- 0.81 g, P = 0.56). CONCLUSIONS: Middle-aged and older individuals with the pre-diabetes state of IFG do not exhibit abnormal proximal thoracic distensibility or LV hypertrophy relative to individuals with NFG. For this reason, an opportunity may exist in those with IFG to prevent LV hypertrophy and abnormal aortic stiffness that is observed in middle-aged and older individuals with diabetes.

Prediction of cardiac events in patients with reduced left ventricular ejection fraction with dobutamine cardiovascular magnetic resonance assessment of wall motion score index.

OBJECTIVES: The purpose of this study was to assess the utility of dobutamine cardiovascular magnetic resonance (DCMR) results for predicting cardiac events in individuals with reduced left ventricular ejection fraction (LVEF). BACKGROUND: It is unknown whether DCMR results identify a poor cardiac prognosis when the resting LVEF is moderately to severely reduced. METHODS: Two hundred consecutive patients ages 30 to 88 (average 64) years with an LVEF 40%. CONCLUSIONS: In individuals with mild to moderate reductions in LVEF (40% to 55%), dobutamine-induced increases in WMSI forecast MI and cardiac death to a greater extent than an assessment of resting LVEF. In those with an LVEF <40%, a dobutamine-induced increase in WMSI does not predict MI and cardiac death beyond the assessment of resting LVEF.

Left ventricular spherical remodeling and apical myocardial relaxation: cardiovascular MR imaging measurement of myocardial segments.

PURPOSE: To prospectively evaluate left ventricular (LV) shape and regional relaxation to determine if rapid, early relaxation of the LV is lost with spherical remodeling of the LV. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review board. All participants gave written informed consent. Cardiovascular magnetic resonance (MR) imaging and transthoracic echocardiography (TTE) were performed in 18 individuals. Each participant was classified into one of three groups according to LV shape and TTE-derived mitral filling parameters. Pairwise comparisons of cardiovascular MR imaging measurements of LV relaxation were made between healthy individuals and those with spherically shaped LVs. RESULTS: The LV regional relaxation rates were determined in a total of 108 basal, middle, and apical myocardial segments in 18 participants (13 women, five men; age range, 35-76 years). Participants with a spherically shaped LV (sphericity index, <1.5) and a mitral inflow velocity E wave/A wave ratio of less than 1.0 exhibited apical thinning velocities that were lower than those of healthy individuals (sphericity index, > or =1.5) (P < .01). The ratio of LV relaxation velocities in the apical versus middle LV segments correlated significantly with sphericity index (R(2) = 0.53; P = .0005). CONCLUSION: LV apical relaxation velocities in participants with LV spherical remodeling (sphericity index, <1.5) were reduced compared with those of healthy individuals (sphericity index, > or =1.5).

Leg flow-mediated arterial dilation in elderly patients with heart failure and normal left ventricular ejection fraction.

BACKGROUND: flow-mediated arterial dilation (FMAD), an indicator of endothelial function, is reduced in patients with heart failure and reduced left ventricular ejection fraction (HFREF). Many elderly patients with heart failure exhibit a normal left ventricular ejection fraction (HFNEF). It is unknown whether FMAD is severely reduced in the elderly with HFNEF. METHODS AND RESULTS: 30 participants >60 yr of age, 11 healthy, 9 with HFNEF, and 10 with HFREF, underwent a cardiovascular magnetic resonance (CMR) assessment of FMAD in the superficial femoral artery followed within 48 h by symptom-limited exercise with expired gas analysis. Elderly patients with HFREF and HFNEF had severely reduced peak oxygen consumption (Vo(2 peak); 12 +/- 2 and 13 +/- 1 ml.kg(-1).min(-1), respectively) vs. their healthy age-matched contemporaries (20 +/- 3 ml.kg(-1).min(-1)). FMAD was 3.8 +/- 1.3% (0.85 +/- 0.22 mm(2)) in patients with HFREF; it was 12.1 +/- 3.6% (3.1 +/- 1.2 mm(2)) and 13.7 +/- 5.9% (3.9 +/- 1.7 mm(2)), respectively, in patients with HFNEF and age-matched healthy older individuals. After adjustment for age and gender, the association of FMAD with Vo(2) was high in healthy and HFREF subjects (P = 0.05 and 0.02, respectively) but less so in HFNEF participants (P = 0.58). CONCLUSIONS: elderly patients with HFNEF do not exhibit marked reduction in leg FMAD. These data suggest that mechanisms other than impaired femoral arterial endothelial function contribute to the severe exercise intolerance experienced by these individuals.

Cardiovascular magnetic resonance measurement of coronary arterial blood flow at rest and after submaximal exercise.

OBJECTIVE: Because most daily activities are conducted at submaximal exercise level, treatments are implemented to improve submaximal coronary artery blood flow (CABF). We sought to validate the reproducibility of cardiovascular magnetic resonance imaging measurements of submaximal CABF. METHODS: We measured CABF in the left anterior descending artery in 11 healthy postmenopausal women at rest and after submaximal bike exercise on 2 occasions 8 to 16 weeks apart. RESULTS: After exercise, CABF increased by 42% and 47% on the first and second examination, respectively. These changes in CABF in the 2 examinations were highly correlated (r=0.86). CONCLUSIONS: These data indicate that cardiovascular magnetic resonance assessments of CABF before and after submaximal exercise are feasible, reproducible, and consistent with those obtained invasively. In future studies, 24 patients would be needed per group to detect a 20% change of submaximal exercise blood flow at 80% power.

Effect of the transmural extent of myocardial scar on left ventricular systolic wall thickening during intravenous dobutamine administration.

Using magnetic resonance imaging, the extent of scar tissue due to chronic infarction and quantification of dobutamine systolic wall thickening (SWT) can be measured simultaneously in human subjects. To determine whether the transmural extent of scar tissue determines dobutamine SWT in chronic ischemic heart disease, we assessed the transmural extent of hyperenhancement and dobutamine SWT with magnetic resonance imaging in 16 patients. The transmural extent of hyperenhancement correlated inversely with dobutamine SWT (r = -0.7, p <0.001). All segments with dobutamine SWT >/=2 mm showed a transmural extent of hyperenhancement of <50%.

Cardiovascular magnetic resonance imaging.

Recent advancements in magnetic resonance imaging hardware and software permit the assessment of cardiovascular structure and function at rest and during exercise or pharmacology-induced cardiac stress. With these developments, knowledge of cardiovascular imaging protocols in the magnetic resonance imaging environment is critical for nursing personnel. The purpose of this article is to review information pertinent to working in a magnetic resonance imaging environment and to describe the requirements of nursing personnel performing cardiovascular magnetic resonance imaging examinations.

Relation of cardiac prognosis to segment location with apical left ventricular ischemia.

Previously, we have shown that myocardial ischemia induced during intravenous dobutamine in the distal segments composing the left ventricular apex is associated with a heightened risk of future myocardial infarction or cardiac death. In this study, we find this heightened risk is present independent of the location of the distal segment within the left ventricular apex.

Feasibility to detect severe coronary artery stenoses with upright treadmill exercise magnetic resonance imaging.

We performed treadmill exercise magnetic resonance imaging in 27 patients with exertional chest pain who were referred for contrast coronary angiography to determine the feasibility of this method to identify severe coronary artery stenoses. The sensitivity and specificity for detecting >70% coronary artery luminal diameter narrowings on contrast coronary angiography were 79% and 85%, respectively.

Assessment of cardiac function with MR imaging.

A variety of black or white blood imaging techniques are available for assessing global and regional LV and RV function during cardiovascular MR imaging examinations. In addition to providing information about LV function at rest, these techniques provide diagnostic and prognostic information regarding myocardial ischemia and viability during MR imaging stress tests.

Automated analysis of phase-contrast magnetic resonance images in the assessment of endothelium-dependent flow-mediated dilation.

Measurement of flow-mediated arterial dilation (FMAD) provides information regarding the status of peripheral arterial endothelial function. Although phase-contrast magnetic resonance imaging (PC-MRI) can be used to measure FMAD, the manual analysis of one study (tracing regions of interest and processing data on 100 images) can require six or more hours. To enhance the clinical utility of the PC-MRI assessment of FMAD, we hypothesized that an automated technique (Multi-Stage Intensity Thresholding or MSIT) for determining femoral arterial area and flow before and after cuff inflation over the thigh could be used to evaluate FMAD in a rapid, accurate, and reproducible manner. Compared with manual analysis, automated analysis detected a similar percentage change in peak FMAD between healthy individuals (17.2% vs 16.5%) and patients with congestive heart failure (4.0% vs 5.1%). The correlation between percentage changes in arterial area after cuff release derived manually and automatically was very good (r = 0.93). Analysis time for 100 images averaged 10 minutes with MSIT vs. 6 hours for manual analysis. In conclusion, rapid, accurate assessments of femoral artery FMAD can be obtained using Multi-Stage Intensity Thresholding. This methodology may prove useful for the rapid MRI assessment of peripheral arterial endothelial function in a clinical setting when studying patients with cardiovascular disease.

Detection of pseudoaneurysm of the left ventricle by fast imaging employing steady-state acquisition (FIESTA) magnetic resonance imaging.

This report highlights the importance of interpretating images throughout the course of a dobutamine MRI stress test. Upon review of the baseline images, the left ventricular (LV) endocardium was not well seen due to flow artifacts associated with low intracavitary blood-flow velocity resulting from a prior myocardial infarction. Physicians implemented a cine fast imaging employing steady-state acquisition (FIESTA) technique that was not subject to low flow artifact within the LV cavity. With heightened image clarity, physicians unexpectedly identified a LV pseudoaneurysm.

Relation of aortic distensibility determined by magnetic resonance imaging in patients > or =60 years of age to systolic heart failure and exercise capacity.

Aortic stiffness increases with advancing age and is associated with the age-related decline in exercise capacity in healthy persons. Previous studies have suggested that aortic compliance is reduced in heart failure (HF). Older persons with systolic HF can have particularly severe exercise intolerance. However, the relation between increased aortic stiffness and exercise intolerance in elderly patients with systolic HF has not been examined. Therefore, aortic distensibility of the proximal ascending aorta (assessed by magnetic resonance imaging) and exercise tolerance (assessed by maximal exercise ergometry with expired gas analysis) was measured in 28 subjects (10 healthy subjects aged 20 to 30 years, 10 healthy subjects aged > or =60 years, and 8 subjects aged > or =60 years with systolic HF). Compared with healthy older subjects, patients with systolic HF had markedly decreased distensibility of the proximal aorta (0.5 +/- 0.4 vs 2.2 +/- 1.2 10(-3) mm Hg(-1), p <0.002), decreased peak exercise volume of oxygen consumption (VO2) (858 +/- 248 vs 1,436 +/- 344 ml/min, p <0.001), and increased aortic wall thickness (3.6 +/- 0.7 vs 2.9 +/- 0.4 mm, p <0.04). Aortic distensibility was significantly correlated with peak VO2 (r = 0.80, p <0.0001) and remained so even after being adjusted for age and left ventricular (LV) ejection fraction. These data suggest that decreased aortic distensibility may contribute to exercise intolerance in older patients with HF due to LV systolic dysfunction.

Magnetic resonance imaging determination of cardiac prognosis.

BACKGROUND: Regional assessments of left ventricular (LV) wall motion obtained during MRI cardiac stress tests can be used to identify myocardial injury and ischemia, but the utility of MRI stress test results for the assessment of cardiac prognosis is not known. METHODS AND RESULTS: Two hundred seventy-nine patients referred (because of poor LV endocardial visualization with echocardiography) for dobutamine/atropine MRI for the detection of inducible ischemia were followed for an average of 20 months. After MRI stress testing, the occurrence of myocardial infarction, cardiac death, death attributable to any cause, coronary arterial revascularization, and unstable angina or congestive heart failure requiring hospitalization was determined. In a multivariate analysis, the presence of inducible ischemia (hazard ratio 3.3, CI 1.1 to 9.7) or an LV ejection fraction <40% (hazard ratio 4.2, CI 1.3 to 13.9) was associated with future MI or cardiac death independent of the presence of risk factors for coronary arteriosclerosis. CONCLUSIONS: In patients with poor echocardiograms, the results of cardiac MRI stress tests can be used to forecast myocardial infarction or cardiac death.

Effects of phase encode order and segment interpolation methods on the quality and accuracy of myocardial tags during assessment of left ventricular contraction.

Tissue tagging can be implemented during cardiovascular magnetic resonance imaging exams to assist with the quantification of left ventriculargeometry, volume and ejection fraction, endocardial thickening and relaxation, and myocardial stress-strain relationships. During tagged cine gradient echo image acquisitions of left ventricular wall motion, rows of k-space data can be acquired with various phase-encoding orders, and the reconstruction of supplemental images can be accomplished using a variety of interpolation techniques. In this study, we investigated the utility of various phase order and segment interpolation methods for determining accurate tag displacement trajectories. Center-out phase order image acquisition with reconstruction using linear interpolation provided the highest tag position and displacement accuracy. Therefore, it is recommended that myocardial tagging exams be acquired with center-out phase encode order and reconstructed using linear segment interpolation when used for performing quantitative analysis of cardiovascular structure and function.

Noninvasive Imaging of the Thoracic Aorta.

Thoracic aortic disease is a common problem affecting the geriatric population of the U.S. Thoracic aortic aneurysms and aortic dissection and its variants are the most common diseases of the thoracic aorta, often leading to death if not treated immediately. Contrast aortography is no longer considered to be the diagnostic gold standard for evaluating the thoracic aorta. This is a review of those abnormalities most commonly seen in the geriatric population: thoracic aortic aneurysms, aortic dissections, intramural hematomas, and penetrating ulcers. The roles of multiplanar transesophageal echocardiography (TEE), spiral computed tomography (CT), and magnetic resonance imaging (MRI) are discussed in the evaluation of each of these disease entities. Although each has been shown to have high sensitivities and specificities for the diagnosis of aneurysms and dissections and its variants, TEE and MRI are thought to be superior to spiral CT because of their ability to evaluate the aortic valve apparatus. However, spiral CT is perhaps the easiest and most cost effective modality to screen patients with known or suspected aortic dissection. (c)1999 by CVRR, Inc.