Administration of an intravenous perfluorocarbon contrast agent improves echocardiographic determination of left ventricular volumes and ejection fraction: comparison with cine magnetic resonance imaging.

OBJECTIVES: The purpose of this study was to determine whether contrast-enhanced transthoracic echocardiography improves the evaluation of left ventricular (LV) volumes and ejection fraction (EF). BACKGROUND: Echocardiographic assessment of LV volumes and EF is widely used but may be inaccurate when the endocardium is not completely visualized. Recently the intravenous (i.v.) administration of perfluorocarbon microbubbles has been shown to enhance opacification of the LV cavity, but the utility of these agents to improve the echocardiographic assessment of LV systolic function is unknown. METHODS: In 40 subjects (29 men and 11 women, aged 24 to 81 years) an assessment of LV volumes and EF was performed with a magnetic resonance imaging examination, followed immediately by a transthoracic echocardiogram before and after the intravenous administration of 2% dodecafluoropentane emulsion (EchoGen; Sonus Pharmaceuticals, Bothell, Washington). RESULTS: Contrast enhanced the echocardiographic assessment of LV end diastolic volume (p < 0.02), end systolic volume (p < 0.01) and LVEF (p < 0.03). The percentage of subjects in whom the correct echocardiographic classification EF was normal, mild to moderately depressed or severely reduced improved significantly after contrast enhancement (from 71% before contrast to 94% after, p < 0.03). These findings were most striking in the subjects with two or more adjacent endocardial segments not visualized at baseline. CONCLUSIONS: Administration of an intravenous contrast agent improves the ability to accurately assess LV volumes and EF in humans. Contrast enhancement is most useful in subjects with two or more adjacent endocardial segments not seen at baseline.

Effects of afterload reduction on vena contracta width in mitral regurgitation.

OBJECTIVES: We used color Doppler flow mapping to determine whether vena contracta width (VCW) is a load-independent measure of the severity of mitral regurgitation. BACKGROUND: VCW has been proposed to be a relatively load-independent measure of mitral regurgitation severity in flow models using a fixed orifice. However, in patients with mitral regurgitation, VCW may not be load independent because of a dynamic regurgitant orifice. METHODS: VCW, effective regurgitant orifice area and regurgitant volume were measured by quantitative Doppler mapping in 31 patients with chronic mitral regurgitation at baseline and during nitroprusside infusion. Patients with rheumatic heart disease, annular calcification or endocarditis were considered to have a fixed regurgitant orifice, whereas patients with mitral valve prolapse, dilated cardiomyopathy or ischemia were considered to have a dynamic regurgitant orifice. RESULTS: Systolic blood pressure (148 +/- 27 to 115 +/- 25 mm Hg) and end-systolic wall stress (121 +/- 50 to 89 +/- 36) decreased with nitroprusside (p < 0.05). Although nitroprusside did not significantly change mean values for VCW (0.5 +/- 0.2 to 0.5 +/- 0.2 cm), regurgitant volume (69 +/- 47 to 69 +/- 56 ml) or effective regurgitant orifice area (0.5 +/- 0.4 to 0.5 +/- 0.6 cm2), individual patients exhibited marked directional variability. Specifically, VCW decreased in 16 patients (improved mitral regurgitation), remained unchanged in 7 patients and increased in 8 patients (worsened mitral regurgitation) with nitroprusside. Also, the VCW response to nitroprusside was concordant with changes in effective regurgitant orifice area and regurgitant volume, and was not different between dynamic and fixed orifice groups. CONCLUSIONS: Contrary to the results from in vitro studies, VCW is not load independent in patients with mitral regurgitation caused by dynamic changes in the regurgitant orifice. The origin of mitral regurgitation does not predict accurately whether the regurgitant orifice is fixed or dynamic. Finally, short-term vasodilation with nitroprusside may significantly worsen the severity of mitral regurgitation in some patients.

Effect of contrast enhancement on transthoracic echocardiographic assessment of left ventricular regional wall motion.

The use of contrast-enhanced transthoracic echocardiography to evaluate left ventricular regional wall motion was determined by comparison of echocardiographic data with assessments obtained by magnetic resonance imaging. When left ventricular endocardial segments are well visualized after contrast enhancement, the ability to determine normal versus abnormal endocardial thickening with echocardiography is similar to cine magnetic resonance imaging.

Comparison of quantitative Doppler with magnetic resonance imaging for assessment of the severity of mitral regurgitation.

We compared quantitative Doppler echocardiography and cine magnetic resonance imaging for calculation of regurgitant volume and regurgitant fraction in mitral regurgitation. A good correlation was present between the 2 methods with some scatter in patients with severe mitral regurgitation and high regurgitant volumes.

Human B-cell lymphoma in severe combined immunodeficient mice after active infection with Epstein-Barr virus.

BACKGROUND: B-cell lymphomas (BCL) occur with increased frequency in immunosuppressed patients. BCL develop in severe combined immunodeficient (SCID) mice after engraftment with human peripheral blood leukocytes (PBL; hu-PBL-SCID mice) and infection with Epstein-Barr virus (EBV). The contributions of latent and active EBV infection to BCL development, the potential enhancing effects of immunosuppressive therapy, and inhibitory effects of antiviral therapy on the development of BCL in this model were studied. METHODS: SCID mice were engrafted with PBL from EBV-seropositive donors (latent infection), PBL from EBV-seronegative donors followed by infection with EBV (active infection), PBL from EBV-seropositive donors followed by infection with EBV (latent plus active infection), or EBV-transformed B-lymphoblastoid cells and monitored for the development of BCL. Hu-PBL-SCID mice were treated with the immunosuppressive agents cyclosporine or methylprednisolone or the antiviral agents acyclovir or ganciclovir. RESULTS: Tumors developing in hu-PBL-SCID mice were high-grade lymphomas of human B-cell origin and contained EBV-DNA. BCL developed in 70% of mice 11 to 14 weeks after latent infection. BCL developed after 4 to 7 weeks in all hu-PBL-SCID mice after active infection. Treatment with cyclosporine or methylprednisolone had no effect on BCL development after active infection, but inhibited rather than enhanced the development of BCL in latently infected mice. Ganciclovir, but not acyclovir, inhibited BCL development after active infection. CONCLUSIONS: The hu-PBL-SCID mouse provides an in vivo model of BCL associated with immunosuppression. Active EBV infection results in the rapid development of BCL in this model even when latently infected B cells are present. Inhibition of BCL development in latently infected hu-PBL-SCID mice by immunosuppressive therapy may reflect inhibition of a T-cell/B-cell interaction necessary for B-cell activation. Inhibition of BCL development by granciclovir suggests a possible role for this agent in the management of BCL associated with immunosuppression.

Effects of cyclosporine on human B-cell lymphoma development in vivo.

Cyclosporine (CsA) is a potent immunosuppressive agent primarily affecting T-lymphocyte function. Patients receive CsA following organ transplantation to prevent rejection. These patients are at high risk for developing Epstein-Barr virus (EBV)-induced lymphoproliferative disease (LPD) or B-cell lymphoma (BCL). Severe Combined Immunodeficient (SCID) mice reconstituted with human peripheral blood leukocytes (PBL) develop fatal B-cell lymphomas of human origin following latent or active infection with EBV. This model was utilized to determine the role of CsA in the development of human BCL. SCID mice were reconstituted with PBL, latently or actively infected with EBV, and treated with CsA. Following active EBV infection, mice developed human BCL with or without CsA treatment. In contrast, treatment with CsA prevented the development of BCL in mice latently infected with EBV. This suggests a T-cell interaction with latently infected B-cells which is perturbed by CsA. Further understanding of this interaction and the occurrence of human BCL may allow the development of strategies to prevent, detect, or treat malignancies associated with immunosuppression.

Spontaneous variability of left ventricular outflow tract gradient in hypertrophic obstructive cardiomyopathy.

BACKGROUND: Improvement in the left ventricular outflow tract (LVOT) gradient has been used as a means of assessing response to therapy in patients with hypertrophic obstructive cardiomyopathy (HOCM). To our knowledge, no data exist regarding the spontaneous day-to-day variability of the LVOT gradient in patients with HOCM. Defining the magnitude of such variability is critical to properly understand how much improvement in LVOT gradient must be present to invoke a therapeutic response. METHODS AND RESULTS: We studied the spontaneous variation in the continuous-wave, Doppler-derived pressure gradient on 5 consecutive days in 12 HOCM patients and 5 aortic stenosis control subjects. While in some patients the day-to-day variability in resting gradient was small, in others it varied markedly. The 95% confidence interval for attributing a change in LVOT gradient to factors other than random variation is +/-32 mm Hg for resting gradient and +/-50 mm Hg for provoked gradient. The mean coefficient of variation for gradient across 5 days for the group was 0.52+/-0.33 for resting gradient and 0.46+/-0.16 for provoked gradient. The day-to-day variability in pressure gradient could not be explained by changes in heart rate, blood pressure, or left ventricular end-diastolic dimension, each of which had a coefficient of variation <.11. Moreover, technical factors related to the performance or interpretation of the studies did not account for it because the coefficient of variation for gradient in aortic stenosis was <10% and interobserver and intraobserver agreement was excellent (r=.96 and .98, respectively). CONCLUSIONS: The LVOT pressure gradient varies considerably from day to day in stable patients with HOCM. A single measurement of pressure gradient is not adequate to define the severity of dynamic LVOT obstruction in HOCM.

Proliferation index in various stages of breast cancer determined by Ki-67 immunostaining.

To investigate factors involved in progression of breast cancer, we estimated the growth fraction of malignant cell populations in various stages of mammary cancer growth. Frozen sections were immunostained with the Ki-67 monoclonal antibody and the proliferation index determined using static image analysis. Pure intraductal carcinoma, intraductal carcinoma coexisting with invasive disease, and metastatic sites coexisting with primary tumors were studied. The proliferation index of pure intraductal carcinomas (mean 4.5%, median 1.8%) was not significantly different from invasive mammary cancers (mean 5.1%, median 2.2%). The proliferation index determined for the in situ component of primary cancers (mean 3.8%, median 1.5%) was not significantly different from values obtained from the invasive component of growth (mean 4.2%, median 2.1%). Variability between in situ and invasive components for individual cases was minimal in tumors whose proliferation index was less than 3.0%; for tumors with higher proliferation indices, the differences were greater. However, there was no trend toward a decrease or increase in growth fraction for the two components of primary tumor growth. The mean proliferative index for primary tumors (mean 4.9%, median 4.0%) was not significantly different from the mean proliferative score from a matched group of metastatic sites in the same patients (mean 5.7%, median 5.5%). Comparison of individual cases uncovered differences in some tumors; again no consistent trends in either direction were noted. An increase (or decrease) in growth activity does not accompany the transition from intraductal (in situ) disease to invasive mammary cancer, nor does a change in growth fraction necessarily accompany progression of mammary cancer from the primary to regional metastatic site.