Biomedical subjects
Publications and source records attributed to W C Miller-Hance.
Esophageal perforation caused by transesophageal echocardiography in an infant is believed to be extremely rare. If unrecognized, serious morbidity can result. We report a case of pharyngeal perforation in a neonate undergoing an interrupted aortic arch repair.
Remarkable innovations in medical and surgical approaches over the past several decades now allow for correction of major cardiac defects in children, even in early infancy. These advances have provided for survival of many pediatric patients with congenital heart disease into adulthood. Although transthoracic echocardiography remains the primary imaging technique for the characterization of simple and complex congenital cardiovascular malformations in the pediatric and adult age groups, high-resolution transesophageal imaging has markedly expanded the anatomic and hemodynamic assessment in these patients. The benefits of this imaging approach apply particularly to those with challenging or limited transthoracic examinations or poorly characterized congenital cardiovascular malformations. The utility of TEE in defining the anatomy of the usual spectrum of congenital cardiac malformations is well established. The transesophageal approach has been shown to provide additional diagnostic information over conventional transthoracic imaging for specific structural cardiac anomalies and in the perioperative setting, the opportunity for confirmation of preoperative diagnoses, and modification of the surgical plan if new or different pathology is identified. This imaging modality also may reliably provide for immediate detection of suboptimal surgical repairs and significant postoperative residua, potentially improving the efficacy of the surgical intervention. This accounts for the vital role of this technology in perioperative management and integration into the standard of care in many congenital heart centers. The usefulness of TEE also has been documented during diagnostic and therapeutic cardiac catheterizations of patients with structural cardiac anomalies, allowing for safer and more effective application of these technologies. The experience supports the use of TEE as a useful approach in the surveillance of the adult with operated and unoperated congenital heart disease.
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To study the molecular mechanisms that control patterning of the heart tube during early cardiogenesis, we have used the ventricular myosin regulatory light chain (MLC-2v), which is expressed in the ventricular segment of the primitive heart tube, as a genetic marker for ventricular specification in rodents. To assess whether the atrial isoform, MLC-2a, could also serve as a chamber-specific marker, we cloned an atrial MLC-2 cDNA (554 base pairs) which displayed homology to the human MLC-2a cDNA at both the nucleotide (87%) and amino acid (95%) levels. Northern blot, reverse transcriptase-linked polymerase chain reaction, RNase protection, and Western blot analysis revealed atrial restricted expression in the adult mouse heart, very low levels in aorta, and no detectable expression in ventricle, skeletal muscle, uterus, or liver. In situ hybridization studies during mouse embryogenesis revealed cardiac specific expression throughout days 8-16 postcoitum, with atrial restricted expression from day 12 and qualitatively greater atrial expression than ventricular from day 9. Thus, preferential pattern of expression in the atria occurs prior to septation. The MLC-2a gene was differentially regulated when compared with MLC-2v expression during embryonic stem cell cardiogenesis in vitro with MLC-2a transcript levels detectable from day 6 in suspension cultures as compared with day 9 for MLC-2v. The region-specific expression of the MLC-2a and MLC-2v genes in their respective chambers during early cardiogenesis provides genetic markers for chamber specification (atrial and ventricular) in both the in vitro and in vivo context.
The molecular cues that control patterning of the heart tube during early cardiogenesis are largely unknown. The present study has explored the embryonic stem (ES) cell differentiation system to determine if this in vitro model could be useful in studying the process of regional specification of cardiac muscle cells at the earliest possible stages. As assessed by polymerase chain reaction, ribonuclease protection, in situ hybridization, and immunohistochemical analyses, ES cell differentiation into embryoid bodies is characterized by the transcriptional and translational activation of the ventricular regulatory (phosphorylatable) myosin light chain gene, demonstrating that ventricular specification occurs during ES cell cardiogenesis. The finding of a ventricular-specific marker in an in vitro system in the absence of an intact heart tube provides evidence for cardiac regional specification independent of positional cues or physiologic stimuli. The temporal expression of the myogenic regulatory factors, myogenin and MyoD, suggests activation of the skeletal muscle program following cardiac myogenesis in vitro, indicating temporal fidelity to the progression of in vivo myogenesis. These data establish the mouse embryonic stem cell system as a model for cardiac chamber specification and suggest a promising approach in the study of regional specification in genetically engineered cardiac muscle cells.
We have investigated in bovine left ventricular coronary arteries the relation between the biochemical regulatory event of myosin light chain phosphorylation and the mechanical events of isometric stress and isotonic shortening, under conditions of stimulation by depolarization (65 mM KCl) or receptor occupancy (2 microM 5-hydroxytryptamine [5-HT]). At rest, levels of light chain phosphorylation were 0.07 +/- 0.01 mol phosphate/mol light chain. Maximal values were significantly different for KCl (0.42 +/- 0.02 mol phosphate/mol light chain at 1 minute) and 5-HT stimulation (0.58 +/- 0.01 mol phosphate/mol light chain at 30 seconds). Increases in light chain phosphorylation preceded isometric stress development, and values remained elevated at approximately 0.35 mol phosphate/mol light chain for up to 2 hours with both KCl and 5-HT. The sites of phosphorylation were identical for KCl and 5-HT at 2 hours. Maximal stresses for each stimulus were also maintained for 2 hours. Values of maximum velocity of shortening (Vo in muscle lengths [ML]/sec), obtained from the force-velocity relation, did not change significantly between 1 minute and 2 hours with KCl (0.070 +/- 0.008 ML/sec at 1 minute and 0.056 +/- 0.007 ML/sec at 2 hours, p greater than 0.2). However, during 5-HT stimulation, Vo declined significantly (0.053 +/- 0.006 ML/sec at 1 minute and 0.032 +/- 0.003 ML/sec at 2 hours, p less than 0.025). The relation between Vo and light chain phosphorylation was different for KCl and 5-HT, indicating that factors in addition to myosin light chain phosphorylation may modulate smooth muscle shortening velocity.
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Biochemical events associated with activation of smooth muscle contraction were studied in neurally stimulated bovine tracheal smooth muscle. A latency period of 500 ms preceded increases in isometric force and myosin light chain phosphorylation. However, stimulation resulted in the rapid hydrolysis of inositol phospholipids as demonstrated by increases in inositol phosphates by 500 ms. Inositol trisphosphate increased 2-fold with no significant change in inositol tetrakisphosphate. The apparent activation state of myosin light chain kinase was assessed indirectly through measurements of the fractional activation of a second calmodulin-dependent enzyme, cyclic nucleotide phosphodiesterase. The fractional activation of cyclic nucleotide phosphodiesterase increased after neural stimulation to a maximal extent by 500 ms and remained at this level for at least 4 s. The monophosphorylation of myosin light chain increased after 500 ms and reached a maximum value by 2 s. Diphosphorylation also occurred but to a much lesser extent. Fractional activation of cyclic nucleotide phosphodiesterase and myosin light chain phosphorylation both decreased after 10 min continuous stimulation, although the force response remained at a maximal level. These observations demonstrate that inositol trisphosphate formation and activation of cyclic nucleotide phosphodiesterase (and hence most likely myosin light chain kinase) by calmodulin precede myosin light chain phosphorylation and that these events are sufficiently rapid to mediate the contractile response of neurally stimulated tracheal smooth muscle.
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In recent years, left ventricular noncompaction (LVNC) has been recognized as a distinct form of cardiomyopathy with its own clinical presentation and natural history. More than 100 cases of LVNC have been described in children. Although LVNC has been described in association with metabolic disorders such as Fabry's disease or genetic disorders such as Roifman's syndrome, this case represents the first report of LVNC in a child with trisomy 13.
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