Citations

Abstract Objectives This study defined the modulating actions of sulfonylurea on acute release of atrial natriuretic peptide (ANP) in experimental acute heart failure. Background Sulfonylurea drugs, blockers of cardioprotective ATP-sensitive K+ (KATP) channels, may increase the risk of early cardiovascular mortality. In cardiovascular diseases such as acute heart failure, early release of ANP is essential for cardiorenal homeostasis. Although KATP channels regulate secretion of hormones, such as insulin, it is unknown whether sulfonylureas interfere with ANP release in acute heart failure. Methods The effects of acute administration of glyburide (0.3 mg/kg), a prototype sulfonylurea, on ANP release and sodium excretion were measured in vivo in a canine model of pacing-induced acute heart failure characterized by acute atrial stretch. Immunoreactivity, in atrial tissue, for ANP and the KATP channel subunit, Kir6.2, was determined using specific antibodies. Results With increased left atrial pressure in heart failure, plasma levels of ANP increased rapidly and peaked within 25±3 min. Glyburide delayed the time required for peak plasma ANP secretion to 48±5 min. This resulted in reduced natriuresis from 84±17 μEq/min in the absence of glyburide, to 34±9 μEq/min in the presence of glyburide. However, glyburide did not alter the renal natriuretic responsiveness to exogenously administered ANP in normal dogs. In atrial tissue, both ANP and the KATP channel subunit, Kir6.2, displayed strong immunoreactivity and co-localization. Conclusions Glyburide delays release of ANP in acute heart failure resulting in impaired natriuresis. This cannot be ascribed to an antinatriuretic effect on the kidney, but rather may be due to interference with KATP channel-dependent ANP secretion from the atrium. Such adverse outcome of sulfonylurea drug use could reduce the compensatory capacity to preserve cardiorenal homeostasis in acute heart failure.

Abstract We have recently described a modified model of progressive rapid ventricular pacing-induced heart failure which evolves over a period of 38 days. To further characterize left ventricular remodeling during the progression of heart failure, we assessed left ventricular geometry, wall stress, and atrial natriuretic peptide (ANP) gene expression and protein content during control conditions, asymptomatic left ventricular dysfunction, and overt congestive heart failure (CHF). Although asymptomatic left ventricular dysfunction was characterized by a significant increase in systolic and diastolic left ventricular dimension (+30% and +6%, respectively, P<0.05 each) and a marked increase in left ventricular systolic wall stress (+68%, P<0.01), left ventricular ANP gene expression was unchanged as compared to control. In contrast, strong left ventricular ANP gene expression (+449%, P<0.05) was observed during overt CHF in the absence of further significant increases in left ventricular systolic wall stress. The onset of strong left ventricular ANP gene expression was associated with increased ANP content (+88%, P<0.05) and left ventricular mass index (+13%, P<0.05). In contrast, left atrial ANP gene expression and left ventricular diastolic wall stress increased progressively during asymptomatic left ventricular dysfunction (+39%, P=n.s. and +131%, P<0.01) and overt CHF (+76% and +336% vs. control, P<0.01 each). Progressive rapid ventricular pacing is associated with the induction of left ventricular ANP gene expression and protein synthesis exclusively during overt CHF. The current studies provide new insight into the temporal pattern of ANP-activation and the disparity between left ventricular systolic wall stress and ANP-activation in a large animal model of progressive CHF.

Ectomesenchymomas (EM) are rare malignant neoplasms usually consisting of rhabdomyosarcoma (RMS) with a neural component. Only 21 cases have been previously reported. Here we extend the clinicopathologic spectrum of EM by describing our findings in 15 cases. Only 5 patients were infants; 10 were ≤3 years old and 5 were ≥6 years old. No male predilection was observed; 7 were female. The originating institutional diagnoses were; RMS (12), undifferentiated sarcoma (1), or EM (2), suggesting underdiagnosis of this entity. The primary tumor sites included external genital (5), pelvis/abdomen (6), head and neck (3), and extremity (1). The size of the primary neoplasm was usually ≥5 cm at diagnosis but dissemination only occurred in a minority. Local infiltration was not uncommon. These neoplasms were typically multilobate, thinly encapsulated, hemorrhagic, and necrotic. Light microscopic features were highly variable, but embryonal RMS with scattered or clustered ganglion cells, often in lacunae, was characteristic. In some cases, primitive neuroblastic or neuroectodermal areas were found and/or a component of alveolar RMS was seen. Focal anaplasia was occasionally observed. Mitotic activity appears higher than previously appreciated and some necrosis was invariably present. Electron microscopy was performed in 11 cases, which confirmed skeletal muscle ± neural differentiation. Cytogenetic studies performed in five cases revealed no specific abnormality. Monoclonal neuron-specific enolase was the best marker of ganglion cells and primitive neural elements. MIC-2 (CD99) membrane expression was not definitively present in any of the six cases examined. A number of the above parameters appear to be of some prognostic significance, but overall, these neoplasms appear to have a similar outcome as would be predicted for their RMS element alone (exclusive of any neural component), with respect to the RMS subtype, age of the patient, and anatomic location of the neoplasm.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, and 75% of such cases in the United States are reviewed at the Pathology Center for the Intergroup Rhabdomyosarcoma Study Group (IRSG). The first four generations of IRSG therapeutic trials (IRS I–IV) and supportive pathologic studies have generated a new International Classification of Rhabdomyosarcoma (ICR) that offers new morphologic concepts to the practicing pathologist. The objective of this report is to clearly define emerging histopathologic categories of RMS as defined by the ICR, and to emphasize correlative immunohistochemical or molecular studies. Emerging ICR variants of RMS place the patient in widely divergent prognostic categories (superior, botryoid or spindle cell variants; poor, solid alveolar or diffusely anaplastic variants). The cardinal histopathologic features of the ICR combined with results of studies of fusion genes seen with t(1;13) and t(2;13) will help delineate therapeutic subgroups of RMS for the fifth generation (IRS V) of IRSG studies. Consequently, it is imperative for the practicing pathologist to be familiar with the practical workup and diagnosis of RMS in childhood.

The pathologic assessment of definitive surgical specimens in patients treated for osteosarcoma can be rapidly accomplished using a few pieces of special equipment. Rapid decalcification with formic acid–formalin and routine tissue processing allow the histology laboratory to rapidly prepare histologic slides for pathologic evaluation. A simple qualitative assessment of tumor response to chemotherapy allows the pathologist to classify the tumor response rapidly and reproducibly, and a simple report format allows for unambiguous communication with the patient and physician.