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Biomedical subjects

Warren J Manning

Publications and source records attributed to Warren J Manning.

At least 19 recordsLinked to original sources
PubMed2003

Ventricular-specific expression of angiotensin II type 2 receptors causes dilated cardiomyopathy and heart failure in transgenic mice.

The angiotensin II type 2 (AT2) receptor is upregulated in the left ventricle in heart failure, but its pathophysiological roles in vivo are not understood. In the present study, AT2 receptors were expressed in transgenic (TG) mice using the ventricular-specific myosin light-chain (MLC-2v) promoter. In TG compared with nontransgenic (NTG) mice, in vivo left ventricular (LV) systolic pressure and peak +dP/dt were depressed while LV diastolic pressure was elevated (P < 0.05). Echocardiography showed severely depressed LV fractional shortening, increased systolic and diastolic dimensions, and wall thinning (P < 0.05). Confocal and electron microscopy studies revealed an increase in the size of myocytes and interstitial spaces as well as an increase in interstitial collagen, disruption of the Z-band, and changes in cytochrome c localization. The changes were most prominent in the highest-expressing TG line, which implies a dose-response relationship. AT2 overexpression was also directly associated with the increase of phosphorylated protein levels of PKC-alpha, PKC-beta, and p70S6 kinase. These data demonstrate that ventricular myocyte-specific expression of AT2 receptors promotes the development of dilated cardiomyopathy and heart failure in vivo.

Animals↗
PubMed2003

Rapamycin attenuates load-induced cardiac hypertrophy in mice.

BACKGROUND: Cardiac hypertrophy, or an increase in heart size, is an important risk factor for cardiac morbidity and mortality. The mammalian target of rapamycin (mTOR) is a component of the insulin-phosphoinositide 3-kinase pathway, which is known to play a critical role in the determination of cell, organ, and body size. METHODS AND RESULTS: To examine the role of mTOR in load-induced cardiac hypertrophy, we administered rapamycin, a specific inhibitor of mTOR, to mice with ascending aortic constriction. Activity of p70 ribosomal S6 kinase 1 (S6K1), an effector of mTOR, was increased by 3.8-fold in the aortic-constricted heart. Pretreatment of mice with 2 mg. kg-1. d-1 of rapamycin completely suppressed S6K1 activation and S6 phosphorylation in response to pressure overload. The heart weight/tibial length ratio of vehicle-treated aortic-banded mice was increased by 34.4+/-3.6% compared with vehicle-treated sham-operated mice. Rapamycin suppressed the load-induced increase in heart weight by 67%. Attenuation of cardiac hypertrophy by rapamycin was associated with attenuation of the increase in myocyte cell size induced by aortic constriction. Rapamycin did not cause loss of body weight, lethality, or left ventricular dysfunction. CONCLUSIONS: mTOR or its target(s) seems to play an important role in load-induced cardiac hypertrophy. Because systemic administration of rapamycin has been used successfully for the treatment of transplant rejection in clinical practice, it may be a useful therapeutic modality to suppress cardiac hypertrophy in patients.

Animals↗
PubMed2003

Comparison of aortic elasticity determined by cardiovascular magnetic resonance imaging in obese versus lean adults.

The vascular properties of large vessels in the obese have not been adequately studied. We used cardiovascular magnetic resonance imaging to quantify the cross-sectional area and elastic properties of the ascending thoracic and abdominal aorta in 21 clinically healthy obese young adult men and 25 men who were age-matched lean controls. Obese subjects had greater maximal cross-sectional area of the ascending thoracic aorta (984 +/- 252 vs 786 +/- 109 mm(2), p <0.01) and of the abdominal aorta (415 +/- 71 vs 374 +/- 51 mm(2), p <0.05). When indexed for height the differences persisted, but when indexed for body surface area, a significant difference between groups was found only for the maximal abdominal aortic cross-sectional area. The obese subjects also had decreased abdominal aortic elasticity, characterized by 24% lower compliance (0.0017 +/- 0.0004 vs 0.0021 +/- 0.0005 mm(2)/kPa/mm, p <0.01), 22% higher stiffness index beta (6.0 +/- 1.5 vs 4.9 +/- 0.7, p <0.005), and 41% greater pressure-strain elastic modulus (72 +/- 25 vs 51 +/- 9, p <0.005). At the ascending thoracic aorta, only the pressure-strain elastic modulus was different between obese and lean subjects (85 +/- 42 vs 65 +/- 26 kPa, respectively; p <0.05), corresponding to a 31% difference-but arterial compliance and stiffness index were not significantly different between groups. In clinically healthy young adult obese men, obesity is associated with increased cross-sectional aortic area and decreased aortic elasticity.

Adult↗
PubMed2003

The impact of spatial resolution and respiratory motion on MR imaging of atherosclerotic plaque.

PURPOSE: To examine the impact of spatial resolution and respiratory motion on the ability to accurately measure atherosclerotic plaque burden and to visually identify atherosclerotic plaque composition. MATERIALS AND METHODS: Numerical simulations of the Bloch equations and vessel wall phantom studies were performed for different spatial resolutions by incrementally increasing the field of view. In addition, respiratory motion was simulated based on a measured physiologic breathing pattern. RESULTS: While a spatial resolution of > or = 6 pixels across the wall does not result in significant errors, a resolution of < or = 4 pixels across the wall leads to an overestimation of > 20%. Using a double-inversion T2-weighted turbo spin echo sequence, a resolution of 1 pixel across equally thick tissue layers (fibrous cap, lipid, smooth muscle) and a respiratory motion correction precision (gating window) of three times the thickness of the tissue layer allow for characterization of the different coronary wall components. CONCLUSIONS: We found that measurements in low-resolution black blood images tend to overestimate vessel wall area and underestimate lumen area.

Arteriosclerosis↗
PubMed2003

Coronary magnetic resonance angiography.

Coronary magnetic resonance angiography (CMRA) is a technique in clinical evolution. Current clinical applications include assessment for coronary anomalies, aneurysms, bypass graft patency, and, in experienced centers, the exclusion of proximal and multivessel coronary artery disease (CAD). As local expertise increases and more extensive multicenter data become available, additional applications will be established. CMRA promises to supplement and in some cases obviate the need for X-ray contrast angiography, and to expand our understanding of the pathophysiology of CAD.

Coronary Aneurysm↗
PubMed2003

Valvular flow abnormalities are often identified by a resting focused Doppler examination performed at the time of stress echocardiography.

BACKGROUND: Patients are usually referred for stress echocardiography to assess whether there is inducible myocardial ischemia. At some centers, a focused Doppler examination is also performed. We sought to determine the clinical value of this additional study by examining how often valvular flow abnormalities were identified that might affect clinical care. METHODS: We reviewed 1272 consecutive stress echocardiogram reports from a 1-year period, including 1223 tests that contained focused Doppler data. Important Doppler findings were defined as at least moderate mitral regurgitation, at least mild aortic regurgitation, any aortic or mitral valve stenosis, or any resting left ventricular outflow tract gradient. RESULTS: Overall, focused Doppler identified an important Doppler abnormality in 214 patients (17%). At least moderate mitral regurgitation was identified in 67 patients (5%) and at least mild aortic regurgitation was identified in 163 patients (13%). In addition, aortic stenosis (n = 14; 1%), mitral stenosis (n = 5; 0.4%), and resting outflow tract gradient (n = 2; 0.2%) were noted. A prior echocardiogram had been performed at our institution in 317 patients (26%). For this subset, a new important Doppler finding, a two-step change in regurgitant grade, or a one-step change in stenosis severity was noted in 28 patients (9%). Among patients who had a previous study, the prevalence of new findings was the same (9%) in those who had been studied within the previous year as in those whose previous study had been performed more than 2 years before. CONCLUSION: Focused Doppler documents valvular flow abnormalities in 17% of patients referred for stress echocardiography, thereby enhancing the potential overall value of the test. The frequency of new findings was independent of the time interval from the previous Doppler study. These data should be considered when clinicians choose a stress imaging modality.

Aged↗
PubMed2003

Nkx2.5 homeoprotein regulates expression of gap junction protein connexin 43 and sarcomere organization in postnatal cardiomyocytes.

Nkx2.5, an evolutionarily conserved homeodomain containing transcription factor, is one of the earliest cardiogenic markers. Although its expression continues through adulthood, its function in adult cardiomyocytes is not well understood. To examine the effect of Nkx2.5 in terminal differentiated postnatal cardiomyocytes, we generated transgenic mice expressing either wild-type Nkx2.5 (TG-wild), a putative transcriptionally active mutant (carboxyl-terminus deletion mutant: TG-DeltaC) or a DNA non-binding point mutant of Nkx2.5 (TG-I183P) under alpha-myosin heavy chain promoter. Most TG-wild and TG-DeltaC mice died before 4 months of age with heart failure associated with conduction abnormalities. Cardiomyocytes expressing wild-type Nkx2.5 or a putative transcriptionally active mutant (DeltaC) had dramatically reduced expression of connexin 43 and changed sarcomere structure. Wild-type Nkx2.5 adenovirus-infected adult cardiomyocytes demonstrated connexin 43 downregulation as early as 16 h after infection, indicating that connexin 43 downregulation is due to Nkx2.5 overexpression but not due to heart failure phenotype in vivo. These studies indicate that overexpression of Nkx2.5 in terminally differentiated cardiomyocytes dramatically alters cardiac cell structure and function.

Adenoviridae↗
PubMed2003

Coronary MR angiography clinical applications and potential for imaging coronary artery disease.

Over the past decade, CMRA has emerged as a unique clinical imaging tool with applications in selected populations. Patients with suspected coronary artery anomalies and patients with Kawasaki disease and coronary aneurysms are among those for whom CMRA has demonstrated clinical usefulness. For assessment of patients with atherosclerotic CAD, CMRA is useful for detection of patency of bypass grafts. At centers with appropriate expertise and resources, CMRA also appears to be of value for exclusion of severe proximal multivessel CAD in selected patients. Data from multicenter trials will continue to define the clinical role of CMRA, particularly as it relates to assessment of CAD. Future developments and enhancements of CMRA promise better lumen and coronary artery wall imaging. This may become the new target in noninvasive evaluation of CAD.

Coronary Disease↗
PubMed2003

Cardiac structure and function in the obese: a cardiovascular magnetic resonance imaging study.

BACKGROUND: Obesity is a major health problem in the Western world. Among obese subjects cardiac pathology is common, but conventional noninvasive imaging modalities are often suboptimal for detailed evaluation of cardiac structure and function. We investigated whether cardiovascular magnetic resonance imaging (CMR) can better characterize possible cardiac abnormalities associated with obesity, in the absence of other confounding comorbidities. METHODS: In this prospective cross-sectional study, CMR was used to quantify left and right ventricular volumes, ejection fraction, mass, cardiac output, and apical left ventricular rotation in 25 clinically healthy obese men and 25 age-matched lean controls. RESULTS: Obese subjects had higher left ventricular mass (203 +/- 38 g vs. 163 +/- 22 g, p < 0.001), end-diastolic volume (176 +/- 29 mL vs. 156 +/- 25 mL, p < 0.05), and cardiac output (8.2 +/- 1.2 L/min vs. 6.4 +/- 1.3 L/min, p < 0.001). The obese also had increased right ventricular mass (105 +/- 25 g vs. 87 +/- 18 g, p < 0.005) and end-diastolic volume (179 +/- 36 mL vs. 155 +/- 28 mL, p < 0.05). When indexed for height, differences in left and right ventricular mass, and left ventricular end-diastolic volume remained significant. Apical left ventricular rotation and rotational velocity patterns were also different between obese and lean subjects. CONCLUSIONS: Obesity is independently associated with remodeling of the heart. Cardiovascular magnetic resonance imaging identifies subtle cardiac abnormalities and may be the preferred imaging technique to evaluate cardiac structure and function in the obese.

Adult↗
PubMed2002

C-reactive protein is associated with subclinical epicardial coronary calcification in men and women: the Framingham Heart Study.

BACKGROUND: High C-reactive protein (CRP) levels are associated with an increased risk of cardiovascular events, even in apparently healthy individuals. It has not been established whether elevated CRP reflects an increased burden of subclinical coronary atherosclerosis. METHODS AND RESULTS: We studied a stratified random sample of 321 men and women (mean age 60 years) from the Framingham Heart Study who were free of clinically apparent cardiovascular disease. Subjects underwent electron-beam computed tomography to assess the number of coronary calcifications and the coronary artery calcification (CAC) Agatston score. Spearman correlation coefficients between CRP and CAC score were calculated and adjusted for age, age plus individual risk factors, and age plus the Framingham coronary heart disease risk score. For both sexes, CRP was significantly correlated with the Agatston score (age-adjusted Spearman correlation: 0.25 for men, 0.26 for women; both P<0.01). After adjustment for age and Framingham risk score, the correlation remained significant (P=0.01) for both sexes. Further adjustment for body mass index attenuated the correlation coefficient for women (0.14, P=0.09) but not for men (0.19, P<0.05). CONCLUSIONS: High CRP levels are associated with increased coronary calcification. Among individuals with elevated CRP, subclinical atherosclerosis may contribute to an increased risk for future cardiovascular events.

Adolescent↗
PubMed2002

Impact of a specific echocardiographic report comment regarding endocarditis prophylaxis on compliance with American Heart Association recommendations.

BACKGROUND: There is substantial underuse and overuse of antibiotic prophylaxis. Current American Heart Association (AHA) recommendations are heavily dependent on echocardiographic data that may not be familiar to referring physicians. We sought to determine the impact of a specific prophylaxis report comment on compliance with AHA recommendations. METHODS AND RESULTS: Using a standardized electronic reporting system, physicians interpreting approximately 50% of echocardiograms included a concluding comment classifying endocarditis risk and stating whether prophylaxis was indicated. The remaining reports were identical in format/content but did not include such comments. Of 1461 eligible outpatients during a 6-month period, 969 (66.3%) responded to a mail survey regarding prophylaxis instructions. Overall, 50% reported taking prophylaxes. Compliance with AHA recommendations was greater among those with a comment (73.2% versus 65.4% for those receiving versus those not receiving comments, respectively; P=0.011), with particular improvement among moderate-risk patients (69.5% versus 59.9%, P=0.024). CONCLUSIONS: An echocardiographic report statement regarding endocarditis risk and need for prophylaxis is a simple low-cost intervention that improves compliance with AHA recommendations. Interpreting physicians should become familiar with AHA recommendations and include a concluding statement addressing prophylaxis.

Adult↗
PubMed2002

Three-dimensional black-blood cardiac magnetic resonance coronary vessel wall imaging detects positive arterial remodeling in patients with nonsignificant coronary artery disease.

BACKGROUND: Direct noninvasive visualization of the coronary vessel wall may enhance risk stratification by quantifying subclinical coronary atherosclerotic plaque burden. We sought to evaluate high-resolution black-blood 3D cardiovascular magnetic resonance (CMR) imaging for in vivo visualization of the proximal coronary artery vessel wall. METHODS AND RESULTS: Twelve adult subjects, including 6 clinically healthy subjects and 6 patients with nonsignificant coronary artery disease (10% to 50% x-ray angiographic diameter reduction) were studied with the use of a commercial 1.5 Tesla CMR scanner. Free-breathing 3D coronary vessel wall imaging was performed along the major axis of the right coronary artery with isotropic spatial resolution (1.0x1.0x1.0 mm(3)) with the use of a black-blood spiral image acquisition. The proximal vessel wall thickness and luminal diameter were objectively determined with an automated edge detection tool. The 3D CMR vessel wall scans allowed for visualization of the contiguous proximal right coronary artery in all subjects. Both mean vessel wall thickness (1.7+/-0.3 versus 1.0+/-0.2 mm) and wall area (25.4+/-6.9 versus 11.5+/-5.2 mm(2)) were significantly increased in the patients compared with the healthy subjects (both P<0.01). The lumen diameter (3.6+/-0.7 versus 3.4+/-0.5 mm, P=0.47) and lumen area (8.9+/-3.4 versus 7.9+/-3.5 mm(2), P=0.47) were similar in both groups. CONCLUSIONS: Free-breathing 3D black-blood coronary CMR with isotropic resolution identified an increased coronary vessel wall thickness with preservation of lumen size in patients with nonsignificant coronary artery disease, consistent with a "Glagov-type" outward arterial remodeling. This novel approach has the potential to quantify subclinical disease.

Adult↗
PubMed2002

Age and sex distribution of subclinical aortic atherosclerosis: a magnetic resonance imaging examination of the Framingham Heart Study.

Autopsy data demonstrate a correlation between subclinical aortic atherosclerosis and cardiovascular disease. Therefore, noninvasive cardiovascular magnetic resonance (CMR) of subclinical atherosclerosis may provide a novel measure of cardiovascular risk, but it has not been applied to an asymptomatic population-based cohort to establish age- and sex-specific normative data. Participants in the Framingham Heart Study offspring cohort who were free of clinically apparent coronary disease were randomly sampled from strata of sex, quartiles of age, and quintiles of Framingham Coronary Risk Score. Subjects (n=318, aged 60+/-9 years, range 36 to 78 years, 51% women) underwent ECG-gated T2-weighted black-blood thoracoabdominal aortic CMR scanning. CMR evidence of aortic atherosclerosis was noted in 38% of the women and 41% of the men. Plaque prevalence and all measures of plaque burden increased with age group and were greater in the abdomen than in the thorax for both sexes and across all age groups. In addition, the Framingham Coronary Risk Score was significantly correlated with all plaque prevalence and burden measures for women but only for men after age adjustment. These noninvasive CMR data extend the prior autopsy-based prevalence estimates of subclinical atherosclerosis and may help to lay the foundation for future studies of risk stratification and treatment of affected individuals.

Adult↗
PubMed2002

Gender differences and normal left ventricular anatomy in an adult population free of hypertension. A cardiovascular magnetic resonance study of the Framingham Heart Study Offspring cohort.

OBJECTIVES: We sought to derive gender-specific cardiovascular magnetic resonance (CMR) reference values for normative left ventricular (LV) anatomy and function in a healthy adult population of clinically relevant age. BACKGROUND: Cardiovascular magnetic resonance imaging is increasingly applied in the clinical setting, but age-relevant, gender-specific normative values are currently unavailable. METHODS: A representative sample of 318 Framingham Heart Study (FHS) Offspring participants free of clinically overt cardiovascular disease underwent CMR examination to determine LV end-diastolic and end-systolic volume (EDV and ESV, respectively), mass, ejection fraction (EF) and linear dimensions (wall thickness, cavity length). Subjects with a clinical history of hypertension or those with a systolic blood pressure > or =140 mm Hg or diastolic pressure > or =90 mm Hg at any FHS cycle examination were excluded, leaving 142 subjects (63 men, 79 women; age 57 +/- 9 years). RESULTS: All volumetric (EDV, ESV, mass) and unidimensional measures were significantly greater (p < 0.001) in men than in women and remained greater (p < 0.02) after adjustment for subject height. Volumetric measures were greater (p < 0.001) in men than in women after adjustment for body surface area (BSA), but there were increased linear dimensions in women after adjustment for BSA. In particular, end-diastolic dimension indexed to BSA was greater in women (p < 0.001) than in men. There were no gender differences in global LVEF (men = 0.69; women = 0.70). CONCLUSIONS: Cardiovascular magnetic resonance measures of LV volumes, mass and linear dimensions differ significantly according to gender and body size. This study provides gender-specific normal CMR reference values, uniquely derived from a population-based sample of persons free of cardiovascular disease and clinical hypertension. These data may serve as a reference to identify LV pathology in the adult population.

Adult↗
PubMed2002

Coronary magnetic resonance angiography in adolescents and young adults with kawasaki disease.

BACKGROUND: In patients with Kawasaki disease, serial evaluation of the distribution and size of coronary artery aneurysms (CAA) is necessary for risk stratification and therapeutic management. Although transthoracic echocardiography is often sufficient for this purpose initially, visualization of the coronary arteries becomes progressively more difficult as children grow. We sought to prospectively compare coronary magnetic resonance angiography (MRA) and x-ray coronary angiography findings in patients with CAA caused by Kawasaki disease. METHODS AND RESULTS: Six subjects (age 10 to 25 years) with known CAA from Kawasaki disease underwent coronary MRA using a free-breathing T2-prepared 3D bright blood segmented k-space gradient echo sequence with navigator gating and tracking. All patients underwent x-ray coronary angiography within a median of 75 days (range, 1 to 359 days) of coronary MRA. There was complete agreement between MRA and x-ray angiography in the detection of CAA (n=11), coronary artery stenoses (n=2), and coronary occlusions (n=2). Excellent agreement was found between the 2 techniques for detection of CAA maximal diameter (mean difference=0.4 +/- 0.6 mm) and length (mean difference=1.4 +/- 1.6 mm). The 2 methods showed very similar results for proximal coronary artery diameter (mean difference=0.2 +/- 0.5 mm) and CAA distance from the ostia (mean difference=0.1 +/- 1.5 mm). CONCLUSION: Free-breathing 3D coronary MRA accurately defines CAA in patients with Kawasaki disease. This technique may provide a non-invasive alternative when transthoracic echocardiography image quality is insufficient, thereby reducing the need for serial x-ray coronary angiography in this patient group.

Adolescent↗