T-wave alternans, an important arrhythmogenic factor, has recently been described in human fetuses. Here we sought to determine whether alternans can be induced in the embryonic mouse hearts, despite its underdeveloped sarcoplasmic reticulum (SR) and, if so, to analyze the response to pharmacological and autonomic interventions. Immunohistochemistry confirmed minimal sarcoplasmic-endoplasmic reticulum Ca-ATPase 2a expression in embryonic mouse hearts at embryonic day (E) 10.5 to E12.5, compared with neonatal or adult mouse hearts. We optically mapped voltage and/or intracellular Ca (Ca(i)) in 99 embryonic mouse hearts (dual mapping in 64 hearts) at these ages. Under control conditions, ventricular action potential duration (APD) and Ca(i) transient alternans occurred during rapid pacing at an average cycle length of 212 +/- 34 ms in 57% (n = 15/26) of E10.5-E12.5 hearts. Maximum APD restitution slope was steeper in hearts developing alternans than those that did not (2.2 +/- 0.6 vs. 0.8 +/- 0.4; P < 0.001). Disabling SR Ca(i) cycling with thapsigargin plus ryanodine did not significantly reduce alternans incidence (44%, n = 8/18, P = 0.5), whereas isoproterenol (n = 14) increased the incidence to 100% (P < 0.05), coincident with steepening APD restitution slope. Verapamil abolished Ca(i) transients (n = 9). Thapsigargin plus ryanodine had no major effects on Ca(i)-transient amplitude or its half time of recovery in E10.5 hearts, but significantly depressed Ca(i)-transient amplitude (by 47 +/- 8%) and prolonged its half time of recovery (by 18 +/- 3%) in E11.5 and older hearts. Embryonic mouse ventricles can develop cardiac alternans, which generally is well correlated with APD restitution slope and does not depend on fully functional SR Ca(i) cycling.

Author contributions: Shriki J served as the primary author and wrote and finalized the manuscript; Rongey C and Ghosh B researched and wrote the clinical histories of the patients presented; Daneshvar S obtained echocardiographic images and contributed to the sections of the manuscript discussing the echocardiographic appearance of caseous mitral annular calcifications; Colletti PM contributed to the discussion regarding the cardiac MR findings in the patients who were discussed; Farvid A assisted in the discussion of the clinical significance of mitral annular calcifications, and obtained IRB approval for this review; Wilcox A assisted in editing and finalizing the manuscript. AbstractThe authors report herein a series of 3 patients with caseous mitral annular calcifications (MAC). One of the patients presented with mass-like, caseous MAC as an incidental finding on a staging computed tomography (CT) for metastatic colorectal carcinoma. Another patient presented with a nodule on a chest radiograph, which was later found on CT to be due to caseous MAC. In the third patient, caseous MAC was initially detected on echocardiography, and was further evaluated with CT and cardiac magnetic resonance imaging. In all three patients, the appearances posed a diagnostic dilemma. The appearance of caseous MAC is dissimilar to non-caseous MAC and is usually seen as an ovoid, mass-like structure, with homogeneous hyperattenuation, representing a liquefied form of calcium and proteinaceous fluid. This homogeneous center is surrounded by peripheral, shell-like calcifications. Caseous MAC is likely an under-recognized entity and may present a diagnostic dilemma at CT, magnetic resonance imaging, or echocardiography.

A 35-year-old woman with a history of systemic lupus erythematosus presented with 3 weeks of cough and nasal congestion. She was presumed to have an upper respiratory tract infection. Blood counts showed leukopenia (white blood cell count, 1.8 3 10 9 /L) with absolute neutropenia (0.25 3 10 9 /L). A peripheral blood smear showed granulocytes and lymphocytes with cytoplasmic vacuoles of variable size. Within some vacuoles were dense, basophilic, round to ovoid granules (panel A, lymphocyte; panel B, neutrophil). Review of prior laboratory data reported abnormal granulation within lymphocytes and granulocytes for ;14 months. Evaluation of the patient's medication history revealed that she was started on chloroquine therapy ;16 months prior. Follow-up identified no specific infectious etiology for the patient's symptoms and the neutropenia resolved without intervention. Morphologic changes have been described in leukocytes in patients undergoing chloroquine therapy. Changes seen may include an increase in cytoplasmic vacuoles, some containing irregular inclusions. One theoretical mechanism to explain this phenomenon includes an inhibitory effect of chloroquine on enzymes involved in degradation of lysosomal constituents. Such morphologic changes should be distinguished from intracellular organisms and signs of leukocyte activation (neutrophil toxic granulation, large granular lymphocytes). Careful review of clinical data and medication history may facilitate recognition of this phenomenon.For additional images, visit the ASH IMAGE BANK, a reference and teaching tool that is continually updated with new atlas and case study images. For more information visit http://imagebank.hematology.org.

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